[go: up one dir, main page]

WO2024251807A1 - Companion animal treatments - Google Patents

Companion animal treatments Download PDF

Info

Publication number
WO2024251807A1
WO2024251807A1 PCT/EP2024/065453 EP2024065453W WO2024251807A1 WO 2024251807 A1 WO2024251807 A1 WO 2024251807A1 EP 2024065453 W EP2024065453 W EP 2024065453W WO 2024251807 A1 WO2024251807 A1 WO 2024251807A1
Authority
WO
WIPO (PCT)
Prior art keywords
unsubstituted
substituted
salt
deuterium
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/065453
Other languages
French (fr)
Inventor
Doug Drysdale
Alex Nivorozhkin
Mohammed I. SHUKOOR
Ju FENG
Kenneth L. Avery
Pradip M. Pathare
Geoffrey B. VARTY
Michael E. Morgan
Michael Palfreyman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cybin IRL Ltd
Original Assignee
Cybin IRL Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cybin IRL Ltd filed Critical Cybin IRL Ltd
Publication of WO2024251807A1 publication Critical patent/WO2024251807A1/en
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present disclosure relates generally to injectable pharmaceutical formulations comprising a drug/psychopharmaceutical agent and uses in the treatment of mental disorders in subjects such as companion animals, including those associated with a 5-HT2 receptor, such as anxiety disorders and depressive disorders.
  • anxiety symptoms may include trembling, hiding, attempts to leave or escape, compulsive licking or grooming, self-injuring, diarrhea or vomiting, reduced activity, and destructive behavior.
  • Symptoms of depression may include loss of appetite, drastic weight loss, reduced activity, lethargy or more sleeping, less social interaction or avoidance and hiding, refusal of water or treats, excessive shedding, and sudden and drastic behavior changes.
  • Symptoms of obsessive-compulsive disorder (OCD) may include repetitive or intensified behavior, self-mutilation, excessive tail chasing, and decrease in playfulness.
  • Serotonin and norepinephrine reuptake inhibitors like fluoxetine (Prozac®), are some of the most commonly prescribed drugs in veterinary behavioral medicine. Others include benzodiazepines (e.g., alprazolam; Xanax®), tricyclic antidepressants, beta- blockers, and even lithium. Indeed, the psychopharmacopeia for dogs is nearly the same as for humans (Berns G. Decoding the Canine Mind. Cerebrum : the Dana Forum on Brain Science. 2020 Mar-Apr;2020:cer-04-20. PMID: 32395197).
  • Lysergic acid diethylamide has shown clinical promise in alcohol use disorder [Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J Neurol Sci. 2020, 411 : 116715; Fuentes JJ, et al. Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials. Front Psychiatry.
  • N,N-dimethyltryptamine (also referred to as 2-(U/-indol-3-yl)-N,N-dimethylethan-l -amine) (usually as an active ingredient in ayahuasca)
  • DMT N,N-dimethyltryptamine
  • N,N-dimethyltryptamine (DMT) an endogenous hallucinogen: Past, present, and future research to determine its role and function.
  • Nolli LM et al. Effects of the hallucinogenic beverage ayahuasca on voluntary ethanol intake by rats and on cFos expression in brain areas relevant to drug addiction.
  • Alcohol. 2019; Fabregas JM et al. Assessment of addiction severity among ritual users of ayahuasca. Drug Alcohol Depend. 2010;! 11 : 257-261;
  • Argento E et al. Exploring ayahuasca-assisted therapy for addiction: A qualitative analysis of preliminary findings among an Native community in Canada. Drug Alcohol Rev. 2019;38: 781-789; and Noorani T, et al. Psychedelic therapy for smoking cessation: Qualitative analysis of participant accounts. J Psychopharmacol. 2018;32: 756-769],
  • DMT binding profile is well characterized. DMT acts on numerous ionotropic and metabotropic receptors. It binds with affinity to 5-hydroxytryptamine-(5-HT)iA, 5-HT2A, 5-HT2C, and serotonin transporter (SERT) receptors from the 5-HT/serotonin family [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). ACS Chem Neurosci.
  • DMT is a potent agonist at the 5-HT2A receptor, through which (not unlike other serotonergic psychedelics), it exerts many subjective, visual, and potentially therapeutic effects [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N, N- Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9: 2344-2357; Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016;126: 74-88], 5-HT2A activation has also been linked with increased synaptic plasticity [Ly C, et al.
  • DMT binds to other receptors, including trace amine-associated receptors (TAARs) and the sigma- 1 receptor, potentially contributing to its neuroprotective plasticity enhancing effects [Carbonaro TM, Gatch MB.
  • TAARs trace amine-associated receptors
  • N,N-dimethyltryptamine Brain Res Bull. 2016; 126: 74-88; Barker SA.
  • DMT N-dimethyltryptamine
  • an endogenous hallucinogen Past, present, and future research to determine its role and function.
  • MAO-mediated metabolism is also believed to contribute to high variability in the pharmacokinetic (PK) profiles of various tryptamines in humans, including significant patient-to-patient pharmacokinetic variability after oral psilocybin administration and intravenous (IV) administration of DMT.
  • PK pharmacokinetic
  • IV intravenous
  • the duration of action time course of short-acting tryptamine psychedelics such as DMT and 5-MeO-DMT administered as a bolus to humans via inhalation or intravenous or intramuscular injection is brief — so short as to limit their use in effective therapies.
  • DMT the onset of subjective effects on perception and consciousness (sometimes referred to as the “psychedelic state”) are rapid and overwhelming, with profound and intense visual peak experiences noted within 2 minutes of administration.
  • the psychedelic state dissipates rapidly, with subjective effects returning to baseline (or close to) following roughly 20 to 30 minutes post administration [Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R. Dose-response study of N,N- Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994;51 : 98-108], On one hand, the short time course spent in the psychedelic state is seen as therapeutically limiting and makes sophisticated granular assessment of pharmacodynamic (PD) effects and safety profiles inherently difficult.
  • PD pharmacodynamic
  • short- acting tryptamine psychedelics are potentially more controllable and clinically scalable compared to longer-acting psychedelic compounds such as LSD and psilocybin, which often require 7 to 8 hours or more of supervised clinical observation of a patient before discharge.
  • infusion protocols e.g., where the subject is administered the drug over prolonged periods such as over an hour or longer
  • infusion protocols are not generally clinically practical, particularly for veterinary medicine, as they require significant clinical resources and personnel that represent major challenges in scaling up the treatment for larger populations of subjects.
  • the present disclosure is based at least in part on the identification of novel injectable pharmaceutical formulations, kits, and treatment methods which allow for a time- restricted temporal controlled-release of a psychopharmaceutical agent.
  • a psychopharmaceutical agent such as DMT, 5-MeO-DMT, and their analogs (e.g., deuterated analogs)
  • this controlled-release may be tuned to provide a duration of action of about 30 to 120 minutes to maximize therapeutic benefits and reduce side effects.
  • the injectable pharmaceutical formulations extend the time the subject spends in an efficacious window compared to bolus IV injection of the same tryptamine psychedelic, preferably without overextending the release and the resulting duration of action beyond about 120 minutes.
  • An injectable pharmaceutical formulation comprising: a drug/psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof, wherein:
  • Xi and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
  • Yi and Y2 are independently selected from the group consisting of hydrogen and deuterium;
  • R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
  • R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy;
  • Re and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and
  • Rs and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively Rs and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
  • Xi and X2 are independently hydrogen or deuterium
  • Y1 and Y2 are independently hydrogen or deuterium
  • each Z 1 is independently hydrogen or deuterium
  • each Z 2 is independently hydrogen or deuterium
  • R2, R4, R5, R6, and R7 are independently hydrogen or deuterium.
  • the psychopharmaceutical agent is an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); and (ii
  • the injectable pharmaceutical formulation of (7), wherein the active salt mixture comprises (i) from 60% to 99% by weight of the pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8), based on a total weight of the active salt mixture; and (ii) from 1% to 40% by weight, in sum, of the pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), based on a total weight of the active salt mixture.
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, or a succinate salt.
  • a method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of the injectable pharmaceutical formulation of any one of (1) to (31).
  • An injectable pharmaceutical formulation comprising: a drug/psychopharmaceutical agent; a carboxymethyl cellulose salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof, wherein: X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstit
  • An injectable pharmaceutical formulation comprising: a drug/psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of ketamine, or a stereoisomer, solvate, or prodrug thereof.
  • Fig. 1 illustrates a general synthetic route for making Compounds of Formula (I), e.g., compounds 1-2 and 1-6;
  • Fig. 2 illustrates a general synthetic route for making Compounds of Formula (I), e.g., compounds 1-1, 1-4, 1-5, and 1-8;
  • Fig. 3 shows the percent drug release versus time profile of Formulations 1-6 compared to control when subjected to the Dialysis — Drug Release Test
  • Fig. 4 shows the percent drug release versus time profile of Formulation 7 compared to control when subjected to the Dialysis — Drug Release Test
  • Fig. 5 shows the percent drug release versus time profile of Formulation 8 compared to control when subjected to the Dialysis — Drug Release Test
  • Fig. 6 shows the percent drug release versus time profile of Formulation 9 compared to control when subjected to the Dialysis — Drug Release Test
  • Figs. 7A and 7B show the percent drug release versus time profile of Formulations 10-12 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 7A) and the corresponding first order release kinetic plot (Fig. 7B);
  • Figs. 8A and 8B show the percent drug release versus time profile of Formulations 13-15 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 8A) and the corresponding first order release kinetic plot (Fig. 8B);
  • Figs. 9A and 9B show the percent drug release versus time profile of Formulations 16-18 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 9A) and the corresponding first order release kinetic plot (Fig. 9B);
  • Figs. 10A and 1OB show the percent drug release versus time profile of Formulations 19- 21 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 10A) and the corresponding first order release kinetic plot (Fig. 10B);
  • Fig. 11 shows the percent drug release versus time profile of Formulations 22-27 compared to control when subjected to the Dialysis — Drug Release Test;
  • Figs. 12A and 12B show individual DMT-t/io plasma concentration-time curves in male Beagle dogs (animal IDs: 068M, 069M, 070M) after subcutaneous administration of DMT-t/io at 0.1 mg/kg from control (Fig. 12A) and Formulation 28 (Fig. l2B);
  • Figs. 13 A and 13B show mean DMT-t/io plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-t/io at 0.1, 0.5, and 1 mg/kg from Formulations 28-30, respectively, in linear scale (Fig. 13A) and log scale (Fig. 13B);
  • Fig. 14 shows the dose proportionality of Cmax and AUCinf from the mean DMT-t/io plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-t/io at 0.1, 0.5, and 1 mg/kg from Formulations 28-30, respectively;
  • Fig. 15 shows the effect of sodium hyaluronate concentration on mean concentration-time profiles of DMT-t/io after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
  • Fig. 16 shows the effect of sodium hyaluronate concentration on mean residence time (MRTinf) of DMT-t/io after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
  • Fig. 17 shows the effect of sodium hyaluronate concentration on plasma half-life (ti/2) of DMT-t/10 after SC administration of DMT-t/10 at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
  • Fig. 18 shows the effect of sodium hyaluronate concentration on maximum plasma concentration (Cmax) of DMT-t/io after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
  • Fig. 19 shows the effect of sodium hyaluronate concentration on total exposure (AUCinf) of DMT-t/w after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
  • Figs. 20A and 20B show mean DMT-t/10 plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-t/10 at 1 mg/kg free base from Formulation 34 (dose solution concentration of 20 mg/mL nominal delivered at dosing volume of 0.05 mL/kg) compared to control (dose solution concentration of 4 mg/mL nominal delivered at dosing volume of 0.25 mL/kg) in linear scale (Fig. 20A) and log scale (Fig. 20B);
  • Figs. 21A and 21B show mean DMT and DMT -dw plasma concentration-time curves in male Beagle dogs after subcutaneous co-dose administration of DMT and DMT-t/io at 0.5 mg/kg/analyte free base from Formulation 35 in linear scale (Fig. 21 A) and log scale (Fig. 2 IB); and
  • Fig. 22 shows the percent drug release (ketamine) versus time profile of Formulations 36- 38 compared to control when subjected to the Dialysis — Drug Release Test.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHj ⁇ CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH2-), sec-butyl ((CH 3 )(CH 3 CH2)CH-), t-butyl (t- BU)((CH 3 ) 3 C-), n-pentyl (CH3CH2CH2CH2-), and neopentyl ((CH 3 ) 3 CCH2-).
  • substituted alkyl refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -O-, -N- , -S-, -S(O) n - (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 10 substituents selected from the group consisting of deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
  • Alkylene refers to divalent aliphatic hydrocarbyl groups having from 1 to 6, including, for example, 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, -NR 10 -, -NR 10 C(O), -C(O)NR 10 - and the like. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n- propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-),
  • Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.
  • alkane refers to alkyl group and alkylene group, as defined herein.
  • alkylaminoalkyl refers to the groups R NHR - where R is alkyl group as defined herein and R is alkylene, alkenylene or alkynylene group as defined herein.
  • alkaryl or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.
  • Alkoxy refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n- pentoxy, and the like.
  • alkoxy also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • substituted alkoxy refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • alkoxyamino refers to the group -NH-alkoxy, wherein alkoxy is defined herein.
  • haloalkoxy refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • haloalkyl refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group.
  • groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • alkylthioalkoxy refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Alkenyl refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms, for example 2 to 4 carbon atoms and having at least 1, for example from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
  • substituted alkenyl refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxy
  • substituted alkynyl refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, al
  • Alkynyloxy refers to the group -O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substitute
  • “Acylamino” refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, N R 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl,
  • Aminocarbonyl or the term “aminoacyl” refers to the group -C(O)NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloal
  • Aminocarbonylamino refers to the group -NR 21 C(O)NR 22 R 23 where R 21 , R 22 , and R 23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.
  • alkoxycarbonylamino refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • Aminosulfonyl refers to the group -SO2NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl
  • “Sulfonylamino” refers to the group -NR 21 SO2R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thi
  • Aryloxy refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.
  • Amino refers to the group -NH2.
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
  • Carboxyl refers to -CO2H or salts thereof.
  • Carboxyl ester or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-
  • (Carboxyl ester)oxy” or “carbonate” refers to the groups -O-C(O)O- alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O- alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O- cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,
  • Cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and for example, from 1 to 2 double bonds.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamin
  • Cycloalkynyl refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.
  • Cycloalkoxy refers to -O-cycloalkyl
  • Cycloalkenyloxy refers to -O-cycloalkenyl.
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • “Hydroxy” or “hydroxyl” refers to the group -OH.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring.
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N— >0), sulfinyl, or sulfonyl moieties.
  • This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
  • heteroarylkyl refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
  • Heteroaryl oxy refers to -O-heteroaryl.
  • Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or - SO2- moieties.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2,3,4- tetrahydroisoquinoline, 4,5,
  • heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
  • Heterocyclyloxy refers to the group -O-heterocyclyl.
  • heterocyclylthio refers to the group heterocyclic-S-.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein.
  • hydroxyamino refers to the group -NHOH.
  • Niro refers to the group -NO2.
  • “Sulfonyl” refers to the group S02-alkyl, S02-substituted alkyl, S02-alkenyl, SO2- substituted alkenyl, SO2-cycloalkyl, S02-substituted cylcoalkyl, SO2-cycloalkenyl, SO2- substituted cylcoalkenyl, S02-aryl, S02-substituted aryl, SO2-heteroaryl, S02-substituted heteroaryl, SO2-heterocyclic, and S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitute
  • “Sulfonyloxy” refers to the group -0S02-alkyl, 0S02-substituted alkyl, 0S02-alkenyl, 0S02-substituted alkenyl, OSO2-cycloalkyl, 0S02-substituted cylcoalkyl, OSO2-cycloalkenyl, 0S02-substituted cylcoalkenyl, 0S02-aryl, 0S02-substituted aryl, OSO2-heteroaryl, OSO2- substituted heteroaryl, OSO2-heterocyclic, and OSO2 substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, ary
  • aminocarbonyloxy refers to the group -0C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Alkylthio or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein.
  • sulfur may be oxidized to -S(0)-.
  • the sulfoxide may exist as one or more stereoisomers.
  • substituted thioalkoxy refers to the group -S-substituted alkyl.
  • thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.
  • thioheteroaryl oxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.
  • thioheterocyclooxy refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.
  • substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
  • each R 80 is independently R 70 or alternatively, two R 80 ’s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from
  • Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 )4; or an alkaline earth ion, such as [Ca 2+ ]o.s, [Mg 2+ ]o.s, or [Ba 2+ ]o.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the disclosure can serve as the counter ion for such divalent alkali earth ions).
  • an alkali ion such as K + , Na + , Li +
  • an ammonium ion such as + N(R 60 )4
  • -NR 80 R 80 is meant to include -NH2, -NH-alkyl, 7V-pyrrolidinyl, 7V-piperazinyl, 47V-methyl-piperazin-l-yl and N- morpholinyl.
  • substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, deuterium, -R 60 , halo, -O-M + , -OR 70 , -SR 70 , -S – M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 – M + , -SO 3 R 70 , -OSO 2 R 70 , -OSO 3 – M + , -OSO 3 R 70 , -PO 3 -2 (M + ) 2 , -P(O)(OR 70 )O – M + , -P(O)(OR 70 ) , -C(O)R 70 , -C 70 70 70
  • substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O-M + , -OR 70 , -SR 70 , -S-M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R 70 , -S(O) 2 O-M + , -S(O) 2 OR 70 , -OS(O) 2 R 70 , -OS(O) 2 O-M + , -OS(O)2OR 70 , -P(O)(O-)2(M + )2, -P(O)(OR 70 )O-M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein, unless specified otherwise. In such cases, the maximum number of such substitutions is three.
  • serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.
  • substituent groups defined as e.g., polyethers may contain serial substitution greater than three, e.g., -O-(CH2CH2O)n-H, where n can be 1, 2, 3, or greater.
  • the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • the substituent “arylalkyloxy carbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.
  • any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • substituent “-R” is defined to comprise deuterium, it is to be understood that -R may be -D (-deuterium), or a group such as -CD3 that is consistent with the other requirements set forth of -R.
  • fatty describes a compound with a long-chain (linear) hydrophobic portion made up of hydrogen and anywhere from 4 to 26 carbon atoms, which may be fully saturated or partially unsaturated.
  • phrases “pharmaceutically acceptable,” “physiologically acceptable,” and the like, are employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals such as human beings and non-human mammals (e.g., companion animals) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime).
  • such salts can be derived from pharmaceutically acceptable inorganic or organic bases, by way of example, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and the like, and when the molecule contains a basic functionality, addition salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, perchlorate salts, and the like, and addition salts with organic acids, such as formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemi -oxalate, hemi-fumarate, propionate, stearate, lactate, citrate, ascorbate, pamoate, hydroxymaleate, phenyl acetate, glutamate, 2-acetoxybenz
  • salts designated as “hemi-” salts indicate that the stoichiometry of subject compound to counterion is about 2:1, whereas solid salt forms without the “hemi-” descriptor possess a subject compound to counterion stoichiometry of about 1 : 1.
  • DMT hemi -fumarate indicates that the ratio of DMT to fumarate is 2:1
  • DMT fumarate indicates that the ratio of DMT to fumarate is 1 : 1.
  • Solvate refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates.
  • solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • the solvent is water
  • the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.).
  • Exemplary solvates thus include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.
  • Stereoisomer and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms such as racemates and optically pure stereoisomers of the compounds are contemplated herein. Chemical formulas and compounds which possess at least one stereogenic center, but are drawn without reference to stereochemistry, are intended to encompass both the racemic compound, as well as the separate stereoisomers, e.g., R- and/or S-stereoisomers, each permutation of diastereomers so long as those diastereomers are geometrically feasible, etc.
  • a “crystalline” solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules — with long range order — forming a crystal lattice, and thus displays sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern.
  • crystalline solids can exist in different crystalline forms known as “polymorphs,” which have the same chemical composition, but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. As such, polymorphs may have different solid-state physical properties to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility, etc.
  • amorphous refers to a solid material having substantially no long range order in the position of its molecules — the molecules are arranged in a random manner so that there is effectively no well-defined arrangement, e.g., molecular packing, and no long range order.
  • Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having substantially no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
  • an “amorphous” subject compound/material is one characterized as having substantially no crystallinity — less than 10% crystallinity, less than 8% crystallinity, less than 6% crystallinity, less than 4% crystallinity, less than 2% crystallinity, less than 1% crystallinity, or 0% crystallinity — i.e., is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined for example by XRPD.
  • the % crystallinity can in some embodiments be determined by measuring the intensity of one or more peaks in the XRPD diffractogram compared to a reference peak, which may be that of a known standard or an internal standard.
  • Other characterization techniques such as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, may also be employed to determine the percent a subject compound/material is amorphous or crystalline, including quantitative methods which provide the above percentages in terms of weight percent.
  • the phrase “characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (29 ⁇ 0.2°) selected from. . .” should be understood to include those materials characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (including all) of the recited characteristic XRPD diffraction peaks. Further, this phrase is intended to be open to the inclusion of other XRPD diffraction peaks not recited.
  • the compounds herein can exist in different salt, solvate, stereoisomer, crystalline/amorphous (including polymorphic) forms, and the present disclosure is intended to include all permutations thereof, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of the subject compound.
  • stamper resistant is art-recognized to describe aspects of a drug formulation that make it more difficult to use the formulation to abuse the drug moiety of the formulation through e.g., extraction for intravenous use, or crushing for freebase use; and therefore, reduce the risk for abuse of the drug.
  • stable includes chemical stability and solid state (physical) stability.
  • chemical stability means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no chemical degradation or decomposition.
  • Solid-state stability means the compound can be stored in an isolated solid form, or the form of a solid formulation in which it is provided in admixture with, for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no solid-state transformation (e.g., hydration, dehydration, solvatization, desolvatization, crystallization, recrystallization or solid-state phase transition).
  • solid-state transformation e.g., hydration, dehydration, solvatization, desolvatization, crystallization, recrystallization or solid-state phase transition.
  • composition is equivalent to the term “formulation.”
  • treating means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a companion animal) that includes: ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or alleviating one or more symptoms of the disease or medical condition in a patient.
  • a treatment can provide a therapeutic benefit such as the eradication or amelioration of one or more of the physiological or psychological symptoms associated with the underlying condition, disease, or disorder such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be affected by the condition.
  • treatment may refer to prophylaxis, i.e., preventing the disease or medical condition from occurring or otherwise delaying the onset of the disease or medical condition in a patient.
  • a “patient” or “subject,” used interchangeably herein, can be any animal, most commonly a mammal, including, for example, a human, a non-human mammal, a companion animal, livestock, etc.
  • a patient or subject can have a condition to be treated or can be susceptible to a condition to be treated.
  • the patient or subject is a companion animal.
  • a “companion animal” refers to a domesticated or domestic-bred animal whose physical, emotional, behavioral, and social needs can be readily met as companions in the home, or in close daily relationship with humans.
  • companion animals include, but are not limited to, dogs, cats, horses, rabbits, ferrets, birds, and guinea pigs.
  • a “psychopharmaceutical agent” is a chemical substance with the ability to cross the blood-brain barrier and act on the nervous system, resulting in alterations in perception, mood, consciousness, cognition, and/or behavior.
  • Categories of psychopharmaceutical agents include anxiolytics (e.g., benzodiazepines, barbiturates, etc.), empathogen-entactogens (e.g., MDMA, MDA, AMT, etc.), stimulants (e.g., amphetamines, modafinil, etc.), depressants (e.g., sedatives, hypnotics, and opioids), and hallucinogens such as psychedelics, dissociatives, and deliriants (e.g., psilocybin, LSD, DMT, mescaline, salvia divinorum, scopolamine, etc.).
  • anxiolytics e.g., benzodiazepines, barbiturates,
  • the terms “manage,” “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease, disorder, or condition, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term “managing” encompasses treating a subject who had suffered from the particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition, or of one or more symptoms thereof.
  • “Therapeutically effective amount” refers to an amount of a compound(s) or its salt form sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder (prophylactically effective amount).
  • a “prophylactically effective amount” of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or prevent its recurrence.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • administration schedule is a plan in which the type, amount, period, procedure, etc. of the drug in the drug treatment are shown in time series, and the dosage, administration method, administration order, administration date, and the like of each drug are indicated.
  • the date specified to be administered is determined before the start of the drug administration.
  • the administration is continued by repeating the course with the set of administration schedules as “courses”.
  • a “continuous” administration schedule means administration every day without interruption during the treatment course. If the administration schedule follows an “intermittent” administration schedule, then days of administration may be followed by “rest days” or days of non-administration of drug within the course.
  • a “drug holiday” indicates that the drug is not administered in a predetermined administration schedule. For example, after undergoing several courses of treatment, a subject may be prescribed a regulated drug holiday as part of the administration schedule, e.g., prior to re-recommencing active treatment.
  • a “bolus” is where a discrete amount of active pharmaceutical ingredient (API) (e.g., a psychopharmaceutical agent) is administered (e.g., by injection) within 30 minutes or less such that the concentration of the API in the body quickly increases.
  • API active pharmaceutical ingredient
  • Bolus injections are typically administered intravenously (directly into the vein), intramuscularly (within the muscle), intradermally (beneath the skin), or subcutaneously (within the fat or skin).
  • a bolus injection thus differs from an “infusion,” whereby a discrete amount of API (e.g., a psychopharmaceutical agent) is administered by single injection or multiple injections over a prolonged period of greater than 30 minutes, such that the concentration of the API in the body follows a more stable kinetic profile, in some cases reaching a steady-state, with a prolonged exposure period.
  • API e.g., a psychopharmaceutical agent
  • toxic spikes is used herein to describe spikes in concentration of any compound described herein that would produce side-effects of sedation or psychotomimetic effects, e.g., hallucination, dizziness, and nausea; which can not only have immediate repercussions, but also influence treatment compliance.
  • side effects may become more pronounced at blood concentration levels above about 300 ng/mL (e.g. above about 300, 400, 500, 600 or more ng/mL), and toxic levels in non-human mammals such as companion animals may be determined through allometric scaling from the aforementioned human blood concentrations.
  • osmolality is the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water.
  • osmolality is an expression of the number of osmotically active particles (the number of solute particles) in 1 kg of a solution, represented herein as the number of milliosmoles (mOsm) per 1 kg of solution.
  • mOsm milliosmoles
  • one mole of a nondissociating substance e.g., glucose
  • a substance that dissociates into two separate species in solution e.g., sodium chloride
  • solutions are defined herein to be “isotonic” with one another, the solutions have the same osmolality.
  • a formulation is defined to be isotonic with blood serum
  • the formulation has the same osmolality as blood serum.
  • Blood serum typically has an osmolality of about 290 to about 310 mOsm/kg in dogs, about 308 to about 335 mOsm/kg in cats, and about 280 to about 310 mOsm/kg in horses.
  • “Syringeable” or “syringeability” refers to the force required to inject a given solution at a given rate via a chosen needle length and gauge, and relates to whether the formulation is administrable through a syringe.
  • concentrations expressed in terms of weight per volume are calculated from grams (g) per milliliter (mL). These concentrations may be expressed as a percentage (% w/v), for example, the concentration of 1 g of solute in 100 mL of a solution is 1% w/v.
  • the term “and/or” includes any and all combinations of one or more of the associated listed items.
  • the meaning of “a”, “an”, and “the” includes plural reference as well as the singular reference unless the context clearly dictates otherwise.
  • the term “about” in association with a numerical value means that the value may vary up or down by 5%. For example, for a value of about 100, means 95 to 105 (or any value between 95 and 105).
  • an injectable pharmaceutical formulation comprising a drug/psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the pharmaceutical formulation is suitable for injection, thus its administration in therapy typically comprises parenteral injection of the formulation through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active pharmaceutical ingredient(s) contained therein is administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion.
  • injectable or “injectability,” it is meant that the formulation is in accordance with Pharmacopeial requirements of injections, for example as set forth in The United States Pharmacopeial (USP) Convention, General Requirements/ ⁇ 1> Injections, 33.
  • the injectable pharmaceutical formulations are prepared by methods designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and where appropriate, contain inhibitors of the growth of organisms (e.g., antimicrobial preservatives) and/or anti-oxidants.
  • Pharmacopeial requirements include, but are not limited to, USP Pyrogen Test ⁇ 151>, USP Bacterial Endotoxins Test ⁇ 85>, USP Antimicrobial Effectiveness Testing ⁇ 51>, USP Antimicrobial Agents — Content ⁇ 341 >, USP Sterilization and Sterility Assurance of Compendial Articles ⁇ 1211>, USP Particulate Matter in Injections ⁇ 788>, and USP Sterility Tests ⁇ 71>.
  • Escherichia coli should be absent in 1 g of formulation; the total aerobic microbial count (TAMC) should be under 1,000 colony forming units (CFU)/g; and the total yeast and mold count (TYMC) should not exceed 100 CFU/g.
  • TAMC total aerobic microbial count
  • CFU colony forming units
  • TYMC total yeast and mold count
  • injectable or “injectability,” it is further meant that the pharmaceutical formulation is characterized as having physiochemical properties, such as pH, osmolality, and viscosity, which enables administration through the skin or other external boundary tissue via needle, syringe, canula, catheter, or other suitable injection device without causing excessive tissue necrosis, pain, or inflammation (e.g., phlebitis) at the injection site.
  • Injectable drug products generally have a pH of about 2 to 11 for IV and intramuscular injection, and a pH of about 3 to 9 for subcutaneous injection (Usach I, et al.
  • Injectable drug products generally have an osmolality of 150 to 600 mOsm/kg, with osmolalities closest to that of subject blood serum (e.g., 275 to about 335 mOsm/kg) being preferred.
  • Hypertonic injection solutions with an osmolality above 600 mOsm/kg have been reported to possibly cause crenation of red blood cells and significant pain, while hypotonic solutions with an osmolality below 150 mOsm/kg may cause hemolysis and pain at the injection site (Roethlisberger D. et al. If Euhydric and Isotonic Do Not Work, What Are Acceptable pH and Osmolality for Parenteral Drug Dosage Forms?, Journal of Pharmaceutical Sciences, 106(2), 2017, 446-456).
  • Injectable drug products administered with common syringes and needle gauge generally have a viscosity of less than about 50 centipoise (cP), with higher viscosities sometimes requiring injection forces too high for common syringes and gauge needles to withstand.
  • the drug may not even be administrable through a syringe (may not be “syringeable”).
  • some injectable drug products with much higher viscosities can be administered by injection, for example, when administering non-Newtonian fluids or when using injection devices designed for high viscosity fluids such as auto-injectors for high viscosity fluids.
  • the pH, osmolality, and viscosity of the pharmaceutical formulation of the present disclosure fall within the ranges reported to be suitable for injection, and suitable for subcutaneous injection in particular.
  • the pharmaceutical formulation is typically in the form of a solution, although other dosage forms are also contemplated such as suspensions, emulsions, micelles, liposomes, microspheres, and nanosystems which are suitable for injection. Solid forms which are suitable for solutions or suspensions in liquid prior to injection are also disclosed.
  • the pharmaceutical formulations are disclosed as ready -to-use sterile solutions.
  • the pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dry soluble products, including lyophilized powders and hypodermic tablets, reconstituted with an aqueous vehicle prior to use.
  • the pharmaceutical formulations are disclosed as ready-to-use sterile suspensions.
  • the pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dry insoluble products reconstituted with an aqueous vehicle prior to use. In some embodiments, the pharmaceutical formulations are disclosed as ready-to-use sterile emulsions.
  • the injectable pharmaceutical formulation is suitable for intravenous administration (directly into the vein), i.e., is an intravenous pharmaceutical formulation.
  • the injectable pharmaceutical formulation is suitable for intramuscular administration (within the muscle), i.e., is an intramuscular pharmaceutical formulation.
  • the injectable pharmaceutical formulation is suitable for intradermal administration intradermally (beneath the skin), i.e., is an intradermal pharmaceutical formulation.
  • the injectable pharmaceutical formulation is suitable for subcutaneous administration (within the fat or the layer of skin directly below the dermis and epidermis), i.e., is a subcutaneous pharmaceutical formulation.
  • Subcutaneous administration is a minimally invasive mode of administration.
  • Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of depot effect. Compared with other routes of administration, it is slower than intravenous and intramuscular injections but still faster than intradermal injections. The convenience and speed of subcutaneous delivery allows for increased treatment compliance and quicker access to medication when needed.
  • Subcutaneous administration can be performed by injection or by implantation of a sustained or timed-release device beneath the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed. Subcutaneous formulations are usually much easier to handle for the practitioner/veterinarian.
  • a particular advantage of the subcutaneous delivery route in the therapeutic methods of the present disclosure is that it allows the medical practitioner/veterinarian to perform the administration in a rather short intervention, compared to intravenous infusion protocols associated with DMT -based therapy.
  • Injection volumes of up to about 50 mL are tolerated via the subcutaneous route in dogs, up to about 100 mL in cats, and up to about 10 mL in horses. Large subcutaneous injection volumes greater than these volumes are often associated with pain.
  • multiple doses severe unit dose formulations
  • Particular pharmacopeial requirements for subcutaneous injections include, but are not limited to, passing specifications of USP Particulate Matter in Injections ⁇ 788>.
  • the pharmaceutical formulation may be suitable for bolus injection, in which a discrete amount of the psychopharmaceutical agent is administered by injection within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less.
  • the bolus injection may involve a single injection or multiple injections performed within the above-described time range. Thus, administering multiple bolus injections within the above-mentioned time range of 30 minutes or less (e.g., two injections lasting 30 seconds each, administered within 5 minutes of one another) would be considered a bolus administration herein.
  • the bolus injection involves a single injection within the above time range.
  • the pharmaceutical formulation may be suitable for bolus subcutaneous injection, such as a single bolus subcutaneous injection, i.e., the pharmaceutical formulation is a bolus subcutaneous pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for bolus intramuscular injection, such as a single bolus intramuscular injection, i.e., the pharmaceutical formulation is a bolus intramuscular pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for bolus intradermal injection, such as a single bolus intradermal injection, i.e., the pharmaceutical formulation is a bolus intradermal pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for bolus intravenous injection, such as a single bolus intravenous injection, i.e., the pharmaceutical formulation is a bolus intravenous pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for infusion injection, in which a discrete amount of the psychopharmaceutical agent is administered by injection over a prolonged period of greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, greater than 110 minutes, greater than 120 minutes.
  • the infusion injection may involve a single prolonged injection, or multiple injections (short or prolonged) within the above- described time range. Thus, administering multiple bolus injections over a prolonged period of greater than 30 minutes would be considered an infusion administration herein.
  • the infusion injection involves a single injection within the above time range.
  • the pharmaceutical formulation may be suitable for infusion subcutaneous injection.
  • the pharmaceutical formulation may be suitable for infusion intramuscular injection.
  • the pharmaceutical formulation may be suitable for infusion intravenous injection.
  • the injectable pharmaceutical formulation comprises a psychopharmaceutical agent (or more simply, a drug).
  • the psychopharmaceutical agent may be an anxiolytic (e.g., benzodiazepines, barbiturates, etc.), an empathogen-entactogen (e.g., MDMA, MDA, AMT, etc.), a stimulant (e.g., amphetamines, modafinil, etc.), a depressant (e.g., sedatives, hypnotics, and opioids), and/or a hallucinogen such as a psychedelic (e.g., a tryptamine psychedelic), a dissociative, or a deliriant (e.g., psilocybin, LSD, DMT, mescaline, salvia divinorum, scopolamine, etc.).
  • anxiolytic e.g., benzodiazepines, barbiturates, etc.
  • the psychopharmaceutical agent may be a free base compound, or a pharmaceutically acceptable salt of the free base compound. Combinations of psychopharmaceutical agents may also be used.
  • the psychopharmaceutical agent is a dissociative, a dissociative hallucinogen, an anesthetic, an arylcyclo-hexylamine, a 1,2-diarylethylamine, a P-keto- arylcyclohexylamine, and/or a compound that modulates the NMDA receptor.
  • Examples of such psychopharmaceutical agents include, but are not limited to, ketamine, methoxetamine, deschloroketamine, N-ethyl deschloroketamine (eticyclidone), 3 -methoxyphencyclidine, methoxieticyclidine, ephenidine, lanicemine, dextromethorphan, dextrorphan, methoxyketamine, norketamine (e.g., (R)-norketamine, (S)-norketamine, or mixtures thereof), hydroxynorketamine (e.g., 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, or mixtures thereof), or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
  • ketamine methoxetamine, deschloroketamine, N-ethyl deschloroketamine (eticyclidone), 3 -methoxyphen
  • the psychopharmaceutical agent is an opioid.
  • opioids include, but are not limited to, racemorphan, levorphanol, racemethorphan, buprenorphine, morphine, loperamide, morphine, codeine, hydrocodone, oxymorphone, buprenorphine, fentanyl, methadone, tramadol, alpha-methyl acetyl fentanyl, alfentanil, butyrfentanyl, carfentanil, 3- methylcarfentanil, 4-fluorofentanyl, beta-hydroxyfentanyl, alpha-methylfentanyl, cis-3- methylfentanyl, beta-hydroxy-3 -methylfentanyl, remifentanil, sufentanil, 3 -methylthiofentanyl, naloxone, and naltrexone, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof
  • the psychopharmaceutical agent is a cathinone, a 3,4- methylenedioxyamphetamine compound, an aminoalkyl-substituted benzofuran, a substituted amphetamine, an aminoindane, a stimulant, diphenhydramine, hydroxazine, phenylephrine, dopamine, adrenaline, lidocaine, oxymetazoline, clemastine, chlorpheniramine, or 6-chloro-2- aminotetralin.
  • the pharmaceutical compound is a cathinone, an aminoalkyl- substituted benzofuran, and an aminoindane, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof.
  • the psychopharmaceutical agent is a lysergamide.
  • lysergamides include, but are not limited to, methylisopropyllysergamide, ethylisopropyllysergamide, 6-allyl-6-nor-LSD, 6-ethyl-6-nor-lysergic acid diethylamide, 1-acetyl- LSD, l-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 1 -propionyl -lysergic acid diethylamide, 1-cyclopropionyl-d-lysergic acid diethylamide, N1 -butyryl -lysergic acid diethylamide, and 6-propyl-6-nor-lysergic acid diethylamide, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
  • the psychopharmaceutical agent is a phenethylamine.
  • phenethylamines include, but are not limited to, mescaline, 2, 5 -dimethoxy -4- bromophenethyl amine (2C-B), 2-(4-iodo-2,5-dimethoxyphenyl)ethan-l -amine (2C-I), 2-(4- chloro-2,5-dimethoxyphenyl)ethan-l-amine (2C-C), 2,5-dimethoxy-4-iodoamphetamine, 2-[2,5- dimethoxy-4-(propylsulfanyl)phenyl]ethan-l -amine, and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
  • the psychopharmaceutical agent is a tryptamine psychedelic.
  • tryptamine psychedelics include, but are not limited to, N,N-dimethyltryptamine, N,N-diethyltryptamine, N,N-dipropyltryptamine, N-Methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, N,N-diisopropyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5- methoxy-N,N-diisopropyltryptamine, 5-methoxy-N,N-dimethyltryptamine, O-acetylpsilocin, psilocin, as well as those tryptamine
  • Examples of psychopharmaceutical agents which can be categorized as hallucinogens such as a psychedelic (e.g., a tryptamine psychedelic), a dissociative, or a deliriant include, but are not limited to, 9,10-didehydro-6-allyl-N,N-diethylergoline-8P-carboxamide, 9,10-didehydro-6,N,N- triethylergoline-8P-carboxamide, N,N-dimethyltryptamine, N,N-diethyltryptamine, 5-methoxy- N,N-dimethyltryptamine, N,N-dibutyltryptamine, N,N-diethyltryptamine, N,N- diisopropyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N-isopropyltryptamine, N,N-dial
  • the psychopharmaceutical agent is a tryptamine psychedelic.
  • Tryptamine psychedelics generally share a basic core structure of an indole (a fused a fused benzene and pyrrole ring), and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen), as represented below.
  • Many tryptamine psychedelics are 5-HT2A receptor agonists, i.e., they increase the activity of a 5-HT2A receptor, which is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family, and includes both partial and full agonists.
  • the tryptamine psychedelic is optionally substituted on the tryptamine ring.
  • the tryptamine psychedelic is an N,N-dialkyltryptamine.
  • the tryptamine psychedelic is N,N-dimethyltryptamine, N,N- diethyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, N,N-diisopropyltryptamine, wherein the tryptamine is optionally substituted, or a combination thereof.
  • the tryptamine psychedelic is substituted with one or more deuterium atoms. In some embodiments, the tryptamine psychedelic is optionally substituted at the 4- or 5-position of the tryptamine ring with a substituent selected from hydroxy, acetoxy, or methoxy.
  • the tryptamine is 4-hydroxy-N-methyl-N- ethyltryptamine, psilocin, 5-methoxy-N,N-diisopropyltryptamine, 5 -methoxy -N,N- dimethyltryptamine, or O-acetylpsilocin (4-acetoxy-N,N-dimethyltryptamine), or a combination thereof.
  • the tryptamine psychedelic may be a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), defined hereinafter.
  • the tryptamine psychedelic may be a pharmaceutically acceptable salt of a single compound of the present disclosure or a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure.
  • the injectable pharmaceutical formulation comprises (as the tryptamine psychedelic) a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), when it comprise ions (protonated forms) of the compounds of the present disclosure and ions that counter the charge of the compounds of the present disclosure (counterions) in solution.
  • the pharmaceutically acceptable salt of a compound of the present disclosure may be pre-formed, for example as a fumarate salt of a compound of the present disclosure, and subsequently combined with the release modifier and the aqueous vehicle, to form the injectable pharmaceutical formulation.
  • the injectable pharmaceutical formulation may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)).
  • the pharmaceutically acceptable salt of a compound of the present disclosure within the pharmaceutical formulation may be formed in-silu.
  • the compound of the present disclosure e.g., a compound of Formula (I) through (III)
  • an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the compounds of the present disclosure.
  • an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the compounds of the present disclosure.
  • the pharmaceutical formulation generally contains a molar proportion of protonated compound (salt form) of least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%.
  • the pharmaceutical formulation contains a molar proportion of protonated compound (salt form) of least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, at least 99.9% for most favorable aqueous solubility.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I), or a stereoisomer, solvate, or prodrug thereof,
  • Xi and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
  • Yi and Y2 are independently selected from the group consisting of hydrogen and deuterium;
  • R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
  • R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy;
  • Re and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and
  • Rs and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively Rs and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
  • Xi and X2 may be the same, or different. In some embodiments, Xi and X2 are the same. In some embodiments, Xi and X2 are hydrogen. In some embodiments, Xi and X2 are deuterium. In some embodiments, Xi and X2 are different. In some embodiments, Xi is hydrogen or deuterium, and X2 is a substituted or unsubstituted Ci-Ce alkyl. In some embodiments, X2 is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, and n- propyl, preferably methyl.
  • X2 is a substituted Ci-Ce alkyl.
  • the alkyl group may contain one, or more than one, substituent.
  • the alkyl group is a Ci alkyl group (i.e., methyl group)
  • the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • one of Xi and X2 is deuterium while the other is hydrogen.
  • one or more of Xi and X2 is a substituted or unsubstituted C3-C10 cycloalkyl.
  • one or more of Xi and X2 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • one or more of Xi and X2 is a substituted C3-C10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • Xi and/or X2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl.
  • Yi and Y2 may be the same, or different. In some embodiments, Yi and Y2 are the same. In some embodiments, Yi and Y2 are hydrogen. In some embodiments, Yi and Y2 are deuterium. In some embodiments, Yi and Y2 are different. In some embodiments, one of Yi and Y2 is deuterium while the other is hydrogen.
  • R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R2 is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is a substituted Ci-Ce alkyl.
  • R2 is a substituted Ci-Ce alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • R2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R2 is an unsubstituted or substituted alkynyl. In some embodiments, R2 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R2 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R2 is a substituted C3-C10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R2 is an unsubstituted or substituted heterocycloalkyl.
  • R2 is an unsubstituted or substituted aryl.
  • R2 is an unsubstituted or substituted heteroaryl.
  • R4 and R5 may be the same, or different.
  • R4 is deuterium.
  • R4 is hydrogen.
  • R4 is hydroxyl.
  • R4 is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl.
  • R4 is a substituted Ci-Ce alkyl.
  • R4 is a substituted Ci-Ce alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy.
  • R4 is a substituted alkoxy.
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkoxy group may contain one, or more than one, substituent.
  • the substituted Ci alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc.
  • R4 is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio.
  • R4 is a substituted alkylthio.
  • the alkylthio group may contain one, or more than one, substituent.
  • R4 is an alkylthio group substituted with one or more deuterium.
  • the alkylthio group may contain one, or more than one, deuterium substituent.
  • the alkylthio group is a Ci alkylthio group (i.e., a methylthio group)
  • the deuterium substituted Ci alktlthio group may be -SCDH2, -SCD2H, and -SCD3.
  • R4 is a haloalkylthio (an alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH 2 F, -SCHF 2 , -SCF 3 , -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH2CH2CH2CF3, with particular mention being made to -SCH2F, -SCHF2, -SCF3.
  • a haloalkylthio an alkylthio substituted with one or more halogen atoms
  • R4 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy (- OCOCH2CH2CH3).
  • R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, Rs is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R5 is a substituted Ci-Ce alkyl.
  • R5 is a substituted Ci-Ce alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • R5 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy.
  • Rs is a substituted alkoxy.
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkoxy group may contain one, or more than one, substituent.
  • the substituted Ci alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, - OCF2H, -OCF3, etc.
  • Rs is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio.
  • Rs is a substituted alkylthio.
  • the alkylthio group may contain one, or more than one, substituent.
  • Rs is an alkylthio group substituted with one or more deuterium.
  • the alkylthio group may contain one, or more than one, deuterium substituent.
  • the alkylthio group is a C1 alkylthio group (i.e., a methylthio group)
  • the deuterium substituted C 1 alktlthio group may be -SCDH 2 , -SCD 2 H, and -SCD 3 .
  • R 5 is a haloalkylthio (an alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH 2 CH 2 CH 2 CF 3 , with particular mention being made to -SCH 2 F, -SCHF 2 , -SCF 3 .
  • R5 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy ( -OCOCH 2 CH 2 CH 3 ).
  • R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. In some embodiments, R6 is hydrogen. In some embodiments, R 6 is deuterium. In some embodiments, R 6 is a halogen, e.g., fluoro, chloro, bromo, and iodo.
  • R 6 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted a C1-C6 alkyl).
  • R6 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, neopentyl, and hexyl.
  • R 6 is a substituted C 1 -C 6 alkyl.
  • R6 is a substituted C1-C6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • R6 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R 6 is an unsubstituted or substituted alkynyl. In some embodiments, R 6 is an unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, R6 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R 6 is a substituted C 3 -C 10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R 6 is an unsubstituted or substituted heterocycloalkyl.
  • R 6 is an unsubstituted or substituted aryl.
  • R6 is an unsubstituted or substituted heteroaryl.
  • R7 is hydrogen. In some embodiments, R7 is deuterium.
  • R7 is a halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R7 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted a C 1 -C 6 alkyl).
  • R 7 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl.
  • R7 is a substituted C1-C6 alkyl.
  • R7 is a substituted C1-C6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, -CD 3 , -CFH 2 , -CF 2 H, -CF 3 , etc.
  • R7 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R7 is an unsubstituted or substituted alkynyl. In some embodiments, R 7 is an unsubstituted or substituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is an unsubstituted C 3 -C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R7 is a substituted C3-C10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R7 is an unsubstituted or substituted heterocycloalkyl.
  • R 7 is an unsubstituted or substituted aryl.
  • R 7 is an unsubstituted or substituted heteroaryl.
  • R8 and R9 may be the same, or different.
  • R8 and R9 are the same. In some embodiments, R 8 and R 9 are hydrogen. In some embodiments, R 8 and R 9 are deuterium. In some embodiments, R 8 and R 9 are unsubstituted or substituted alkyl, such as an unsubstituted or substituted C1-C6 alkyl. In some embodiments, R8 and R9 are different. In some embodiments, R8 is hydrogen, and R9 is an unsubstituted or substituted C1-C6 alkyl.
  • R 8 and/or R 9 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl, preferably methyl.
  • R8 and/or R9 is a substituted C1-C6 alkyl.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, -CD 3 , -CFH 2 , -CF 2 H, -CF 3 , etc.
  • R8 and/or R9 is an alkyl substituted with one or more deuterium, e.g., a C1-C6 alkyl group substituted with one or more deuterium.
  • the alkyl group may contain one, or more than one, deuterium substituent.
  • the deuterium substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, and -CD 3 , with particular mention being made to -CD 3 .
  • R 8 and/or R 9 is a haloalkyl, examples of which include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, - CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular mention being made to -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , and -CH 2 CH 2 CF 3 .
  • R8 and/or R9 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R8 and/or R9 is an unsubstituted or substituted alkynyl. In some embodiments, R 8 and/or R 9 is a substituted or unsubstituted C 3 -C 10 cycloalkyl.
  • R8 and/or R9 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R 8 and/or R 9 is a substituted C 3 -C 10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R8 and/or R9 is an unsubstituted or substituted heterocycloalkyl.
  • R 8 and/or R 9 is an unsubstituted or substituted aryl.
  • R8 and/or R9 is an unsubstituted or substituted heteroaryl.
  • R8 and R9 together with the nitrogen atom attached thereto are joined to form an unsubstituted or substituted heterocycloalkyl.
  • R 8 and R 9 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl.
  • the unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4- membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s).
  • the unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R8 and R9), and may optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom).
  • Examples of unsubstituted heterocycloalkyl groups formed from joining R8 and R9 together with the nitrogen atom attached thereto include, but are not limited to,
  • R9 together with the nitrogen atom attached thereto are joined to form a substituted heterocycloalkyl.
  • the substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s).
  • the substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening Rs and R9), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom).
  • additional hetero-ring atoms e.g., nitrogen, sulfur, or oxygen
  • substituted heterocycloalkyl group examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1, 2,3,4- tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at least one substituent.
  • the substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl.
  • halogen e.g., fluorine
  • polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substitute
  • the substituted heterocycloalkyl formed from joining Rs and R9 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents.
  • the substituent may be located on a carbon ring atom or on a hetero-ring atom.
  • substituted heterocycloalkyl groups formed from joining R8 and R9 together with the nitrogen atom attached thereto include, but are not limited to,
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I), or a stereoisomer, solvate, or prodrug thereof, wherein any one or more of X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 optionally comprises deuterium.
  • at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 comprises deuterium.
  • At least one of X 1 , X 2 , Y 1 , Y 2 , R 5 , R 8 , and R 9 comprises deuterium. In some embodiments, at least one of X 1 , X 2 , Y 1 , Y 2 , R 8 , and R 9 comprises deuterium. In some embodiments, X1, X2, R8, and R9 comprise deuterium. In some embodiments, X1, X2, Y1, Y2, R8, and R9 comprise deuterium. In some embodiments, X1, X2, and R5 comprise deuterium.
  • X 1 , X 2 , Y 1 , Y 2 , R 5 , R 8 , and R 9 comprise deuterium.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (II), or a stereoisomer, solvate, or prodrug thereof
  • X1 and X2 are independently hydrogen or deuterium
  • Y 1 and Y 2 are independently hydrogen or deuterium
  • each Z1 is independently hydrogen or deuterium
  • each Z2 is independently hydrogen or deuterium
  • R 2 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen or deuterium.
  • X 1 and X 2 may be the same, or different. In some embodiments, X 1 and X 2 are the same.
  • X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen.
  • Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y 1 and Y 2 are different. In some embodiments, Y 1 is deuterium and Y 2 is hydrogen. In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y 2 are deuterium. In some embodiments, each Z1 is hydrogen. In some embodiments, each Z1 is deuterium. In some embodiments, one Z1 is hydrogen, while the other two Z1’s are deuterium.
  • one Z 1 is deuterium, while the other two Z 1 ’s are hydrogen.
  • each Z 2 is hydrogen.
  • each Z 2 is deuterium.
  • one Z 2 is hydrogen, while the other two Z2’s are deuterium.
  • one Z2 is deuterium, while the other two Z2’s are hydrogen.
  • each Z1 and Z2 is hydrogen.
  • each Z 1 and Z 2 is deuterium.
  • R 2 is deuterium.
  • R 2 is hydrogen.
  • R4 is deuterium.
  • R4 is hydrogen.
  • R5 is deuterium.
  • R5 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R 6 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R7 is hydrogen. R2, R4, R5, R6, and R7 may be the same, for example, R2, R4, R5, R6, and R7 may each be hydrogen, or alternatively, R2, R4, R5, R6, and R7 may each be deuterium.
  • At least one of R 2 , R 4 , R 5 , R 6 , and R 7 is deuterium, or at least two of R 2 , R 4 , R 5 , R6, and R7 are deuterium, or at least three of R2, R4, R5, R6, and R7 are deuterium, or at least four of R2, R4, R5, R6, and R7 are deuterium.
  • at least one of X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , R 2 , R 4 , R 5 , R 6 , and R 7 is deuterium.
  • X 1 , X 2 , Z 1 and Z 2 are deuterium.
  • X 1 , X 2 , Y1, and Y2 are deuterium. In some embodiments, X1, X2, Y1, Y2, Z1, and Z2 are deuterium.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (III), or a stereoisomer, solvate, or prodrug thereof wherein: X1 and X2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, each Z 1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, each Z3 is independently hydrogen or deuterium, and R 2 , R 4 , R 6 , and R 7 are independently hydrogen or deuterium.
  • X 1 and X 2 may be the same, or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen. Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y 1 and Y 2 are different.
  • Y 1 is deuterium and Y 2 is hydrogen.
  • X1, X2, Y1, and Y2 are hydrogen.
  • X1, X2, Y1, and Y 2 are deuterium.
  • each Z 1 is hydrogen.
  • each Z 1 is deuterium.
  • one Z1 is hydrogen, while the other two Z1’s are deuterium.
  • one Z1 is deuterium, while the other two Z1’s are hydrogen.
  • each Z 2 is hydrogen.
  • each Z 2 is deuterium.
  • one Z 2 is hydrogen, while the other two Z2’s are deuterium.
  • one Z2 is deuterium, while the other two Z2’s are hydrogen.
  • each Z1 and Z2 is hydrogen.
  • each Z 1 and Z 2 is deuterium.
  • each Z 3 is hydrogen.
  • each Z 3 is deuterium.
  • one Z3 is hydrogen, while the other two Z3’s are deuterium.
  • one Z 3 is deuterium, while the other two Z 3 ’s are hydrogen.
  • each Z 1 , Z 2 , and Z 3 is hydrogen.
  • each Z 1 and Z 2 is hydrogen and each Z 3 is deuterium.
  • each Z1, Z2, and Z3 is deuterium.
  • each Z1 and Z2 is deuterium, and each Z3 is hydrogen.
  • R 2 is deuterium.
  • R 2 is hydrogen.
  • R4 is deuterium.
  • R4 is hydrogen.
  • R6 is deuterium.
  • R6 is hydrogen.
  • R7 is deuterium.
  • R 7 is hydrogen.
  • R 2 , R 4 , R 6 , and R 7 may be the same, for example, R 2 , R 4 , R 6 , and R 7 may each be hydrogen, or alternatively, R 2 , R 4 , R 6 , and R 7 may each be deuterium.
  • At least one of R2, R4, R6, and R7 is deuterium, or at least two of R2, R4, R6, and R7 are deuterium, or at least three of R2, R4, R6, and R7 are deuterium.
  • at least one of X1, X2, Y1, Y2, Z1, Z2, Z3, R2, R4, R6, and R7 is deuterium.
  • X 1 , X 2 , Z 1 and Z 2 are deuterium and each Z 3 is hydrogen.
  • X 1 , X 2 , Y 1 , and Y 2 are deuterium and each Z 3 is hydrogen.
  • X1, X2, Y1, Y2, Z1, and Z2 are deuterium and each Z3 is hydrogen.
  • X1, X2, and Z3 are deuterium.
  • X1, X2, Z1, Z2, and Z3 are deuterium.
  • X 1 , X 2 , Y 1 , Y 2 , and Z 3 are deuterium.
  • X1, X2, Y1, Y2, Z1, Z2, and Z3 are deuterium.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I) through (III), which include, but are not limited to, the following exemplary compounds
  • the compound e.g., a compound of Formula (I) or (II), is a deuterated analog of DMT, examples of which include, but are not limited to,
  • the deuterated analog of DMT is one or more of 2-(1H-indol-3-yl)- N,N-dimethylethan-1-amine-1,1-d 2 (I-2); 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine- 1,1,2,2-d4 (I-8); 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10); 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); 2-(1H-indol-3-yl)-N,N-bis(methyl- d 3 )e
  • the compound e.g., a compound of Formula (I) or (III), is a deuterated analog of 5-MeO-DMT, examples of which include, but are not limited to,
  • the deuterated analog of 5-MeO-DMT is one or more of 2-(5- methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-20); 2-(5-methoxy-1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-22); 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23); 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1
  • any position in the compounds defined herein as having deuterium have a minimum deuterium incorporation that is greater than that found naturally occurring in hydrogen (about 0.016 atom %).
  • any position in the compound defined as having deuterium has a minimum deuterium incorporation of at least 10 atom %, at least 20 atom %, at least 25 atom %, at least 30 atom %, at least 40 atom %, at least 45 atom %, at least 50 atom %, at least 60 atom %, at least 70 atom %, at least 80 atom %, at least 90 atom %, at least 95 atom %, at least 99 atom % at the site of deuteration.
  • the compounds described herein may contain a stereogenic center.
  • the compounds may exist as different stereoisomeric forms, even though Formula (I) through (III) are drawn without reference to stereochemistry.
  • the present disclosure includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and their non-racemic mixtures as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art.
  • the compounds described herein, e.g., compounds of Formula (I) through (III), are non-stereogenic.
  • the compounds described herein, e.g., compounds of Formula (I) through (III) are racemic.
  • the compounds described herein, e.g., compounds of Formula (I) through (III) are enantiomerically enriched (one enantiomer is present in a higher percentage), including enantiomerically pure.
  • the compounds described herein, e.g., compounds of Formula (I) through (III) are provided as a single diastereomer.
  • the compounds described herein are provided as a mixture of diastereomers.
  • the mixtures may include equal mixtures, or mixtures which are enriched with a particular diastereomer (one diastereomer is present in a higher percentage than another).
  • a racemic compound e.g., a compound of Formula (I) through (III) may contain about 50% of the R- and S-stereoisomers based on a molar ratio (about 48 to about 52 mol %, or about a 1 : 1 ratio)) of one of the isomers.
  • a pharmaceutical formulation, medicament, or method of treatment may involve combining separately produced compounds of the R- and S-stereoisomers in an approximately equal molar ratio (e.g., about 48 to 52%).
  • a medicament or pharmaceutical formulation may contain a mixture of separate compounds of the R- and S-stereoisomers in different ratios.
  • the pharmaceutical formulation contains an excess (greater than 50%) of the R-enantiomer. Suitable molar ratios of R/S may be from about 1.5: 1, 2: 1, 3: 1, 4: 1, 5: 1, 10:1, or higher. In some embodiments, a pharmaceutical formulation may contain an excess of the S-enantiomer, with the ratios provided for R/S reversed. Other suitable amounts ofR/S may be selected.
  • the R-enantiomer may be enriched, e.g., may be present in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%.
  • the S-enantiomer may be enriched, e.g., in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between all these exemplary embodiments as well as greater than and less than them while still within the disclosure, all are included.
  • Pharmaceutical formulations may contain a mixture of the racemate and a separate compound of Formula (I) through (III), in salt form.
  • the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2 receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2A receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HTIA receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2C receptor.
  • the tryptamine psychedelic used in the preparation of the pharmaceutical formulation is chemically pure, for example has a purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by UPLC or HPLC.
  • the tryptamine psychedelic has no single impurity of greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2%, measured by UPLC or HPLC.
  • the tryptamine psychedelic has a chemical purity of greater than 97 area %, greater than 98 area %, or greater than 99 area % by UPLC or HPLC.
  • the tryptamine psychedelic has no single impurity greater than 1 area %, greater than 0.5 area %, greater than 0.4 area %, greater than 0.3 area %, or greater than 0.2 area % as measured by UPLC or HPLC.
  • Acids which may be used to form the pharmaceutically acceptable (acid addition) salts of the compounds disclosed herein, e.g., compounds of Formula (I) through (III), include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2- hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthal ene-2-sulfonic acid, naphthalene- 1,5- disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids
  • Combinations of acids may also be used to form a mixture of acid addition salts.
  • the injectable pharmaceutical formulation is prepared from a pre-formed pharmaceutically acceptable salt of a compound disclosed herein, certain salt forms are preferred among the list above because they possess physical and pharmaceutical characteristics/properties which make them well-suited for pharmaceutical preparation and administration.
  • preferred salt forms of the compounds disclosed herein are those that possess one or more of the following characteristics: are easy to prepare in high yield with a propensity towards salt formation; are stable and have well-defined physical properties such as crystallinity, lack of polymorphism, and high melting/enthalpy of fusion; have slight or no hygroscopicity; are free flowing, do not cohere/adhere to surfaces, and possess a regular morphology; have acceptable aqueous solubility for the intended route of administration; and/or are physiologically acceptable, e.g., do not cause irritation when administered to mammals.
  • the pharmaceutically acceptable salt of the compound of the present disclosure may be crystalline or amorphous, preferably crystalline, as determined e.g., by X-ray powder diffraction (XRPD).
  • the pharmaceutically acceptable salt of the compound of the present disclosure is amorphous, e.g., as determined by XRPD and/or DSC.
  • the pharmaceutically acceptable salt of the compound of the present disclosure can be in a stable amorphous form.
  • a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of the present disclosure is provided, wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of the present disclosure is in amorphous form, e.g., as determined by X-ray powder diffraction and/or DSC.
  • the pharmaceutically acceptable salt of the compound of the present disclosure is crystalline. Crystalline forms are advantageous in terms of e.g., stability and providing well-defined physical properties, which is desirable for pharmaceutical preparation and administration.
  • the pharmaceutically acceptable salt of the compound of the present disclosure can be in a stable crystalline form.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a percent crystallinity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5%, and up to 100%, as determined by XRPD and/or DSC analysis.
  • a highly pure crystalline form of a pharmaceutically acceptable salt of a compound of the present disclosure is provided, wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of present disclosure is in crystalline form, e.g., as determined by X-ray powder diffraction and/or DSC.
  • the instrument may be equipped with a fine focus X-ray tube.
  • the tube voltage and amperage can be set to 40 kV and 30 mA, respectively.
  • the divergence and scattering slit widths can be set at 2 mm and the detector slit width can be set at 0.2 mm.
  • Diffracted radiation can be detected by a NaI scintillation detector.
  • a theta-two theta continuous scan from 2.0 to 40° (4 seconds per step; 0.01° step size) can be used.
  • advantageous salt forms of the compounds of the present disclosure are those that readily afford a crystalline solid on crystallization in acceptable yield without proceeding via an oil, and with favorable volume factors, making them suitable for mass production.
  • Salts forms of the compound of the present disclosure e.g., a compound of Formula (I) through (III)
  • preferred salt forms of the present disclosure are those which can be crystallized into a single crystalline form or single polymorph, as determined by XRPD and/or differential scanning calorimetry (DSC).
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a melt onset of from about 100°C, from about 110°C, from about 120°C, from about 130°C, from about 140°C, from about 150°C, from about 160°C, from about 170°C, from about 180°C, from about 190°C, and up to about 250°C, up to about 225°C, up to about 210°C, up to about 200°C, as determined by DSC.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has an enthalpy of fusion of from about 90 J ⁇ g -1 , from about 100 J ⁇ g -1 , from about 110 J ⁇ g -1 , from about 120 J ⁇ g -1 , from about 130 J ⁇ g -1 , from about 140 J ⁇ g -1 , from about 150 J ⁇ g -1 , from about 160 J ⁇ g -1 , and up to about 190 J ⁇ g -1 , up to about 180 J ⁇ g -1 , up to about 170 J ⁇ g -1 , as determined by DSC.
  • Pre-formed pharmaceutically acceptable salts of the compound of the present disclosure suitable for pharmaceutical manufacture may also be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic.
  • the hygroscopicity may be measured herein by performing a moisture adsorption-desorption isotherm using a dynamic vapor sorption (DVS) analyzer with a starting exposure of 30% relative humidity (RH), increasing humidity up to 95% RH, decreasing humidity to 0%, and finally increasing the humidity back to the starting 30% RH, and classified according to the following: non-hygroscopic: ⁇ 0.2%; slightly hygroscopic: ⁇ 0.2% and ⁇ 2%; hygroscopic: ⁇ 2% and ⁇ 15%; very hygroscopic: ⁇ 15%; deliquescent: sufficient water is absorbed to form a liquid; all values measured as weight increase (w/w due to acquisition of water) at >95% RH and 25°C.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a weight increase at >95% RH of less than 1% w/w, less than 0.8% w/w, less than 0.6% w/w, less than 0.5% w/w, less than 0.4% w/w, less than 0.3% w/w, less than 0.2% w/w, less than 0.1% w/w, less than 0.08% w/w, less than 0.06% w/w, less than 0.05% w/w, less than 0.02% w/w, as determined by DVS.
  • Pre-formed pharmaceutically acceptable salts of the compounds of the present disclosure can be maintained/stored in open or closed environments, such as in open or closed flasks/vials, under ambient or stress conditions e.g., 25°C/60% RH, 25°C/90+% RH, 40°C/75% RH, etc. without appreciable degradation (e.g., without appreciably diminished chemical purity) or physical changes (e.g., changed forms, deliquesced, etc.).
  • dry powder samples of salt forms disclosed herein may have a purity change or form change of less than 10%, less than 5%, less than 1%, when stored under ambient conditions or stress conditions (e.g., increased temperature, e.g., 40°C, and/or humidity).
  • Suitable salt forms of the compounds of the present disclosure are physiologically acceptable and do not cause excessive irritation or tissue damage at the injection site.
  • preferred pharmaceutical salts of the compounds of the present disclosure are those formed with an organic acid, preferably an organic acid with a mild acidity, for example an organic acid with a pK a in water of no less than 1.0, no less than 1.5, no less than 2.0, no less than 2.5, no less than 3.0, no less than 3.5, no less than 4.0, no less than 4.5, for example, from 3.0 to 6.5. Solubility
  • the aqueous solubility of the pharmaceutical salts of the compounds of the present disclosure can be determined by equilibrating excess solid with 1 mL of water for 24 hours at 22° C. A 200 uL aliquot can be centrifuged at 15,000 rpm for 15 minutes. The supernatant can be analyzed by UPLC or HPLC and the solubility can be expressed as its free base equivalent (mg FB/mL). For example, pharmaceutically acceptable salt forms of the compounds of the present disclosure can be prepared and the solubility and solution pH can be measured.
  • the pharmaceutically acceptable salt of the compound of the present disclosure e.g., a compound of Formula (I) through (III), has a water solubility at 22°C of from about 5 mg/mL to about 400 mg/mL.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility of from about 1 mg/mL, from about 2 mg/mL, from about 3 mg/mL, from about 5 mg/mL, from about 10 mg/mL, from about 20 mg/mL, from about 30 mg/mL, from about 40 mg/mL, from about 50 mg/mL, from about 60 mg/mL, from about 70 mg/mL, from about 80 mg/mL, from about 90 mg/mL, from about 100 mg/mL, from about 110 mg/mL, from about 120 mg/mL, from about 130 mg/mL, from about 140 mg/mL, from about 150 mg/mL, and up to about 400 mg/mL, up to about 380
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility from about 200 mg/mL to about 400 mg/mL. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility from about 150 mg/mL to about 250 mg/mL.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility of greater than about 1 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, or 150 mg/mL.
  • the pharmaceutically acceptable salt of the compound of the present disclosure is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt.
  • preferred pharmaceutically acceptable salts are fumarate salts, hemi-fumarate salts, benzoate salts, salicylates, and succinate salts of the compounds disclosed herein, e.g., the compounds of Formula (I) through (III), with fumarate, benzoate, and salicylate salts being particularly preferred.
  • the pharmaceutically acceptable salt of the compound of the present disclosure e.g., the compound of Formula (I) through (III)
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of N,N- dimethyltryptamine (DMT).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (DMT-d 10 ).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d 2 (a DMT-d 8 ).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d 2 (a DMT-d 2 ).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5- MeO-DMT-d 10 ).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(5-(methoxy-d 3 )- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d13).
  • the pharmaceutically acceptable salt of DMT or a deuterated analog of DMT is a crystalline solid as disclosed in PCT/EP2023/050702, which is incorporated herein by reference in its entirety.
  • Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) and (II) are provided in Table 1. Table 1.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a) (i.e., a fumarate salt of compound I-1, depicted below).
  • salt I-1a when salt I-1a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b) (i.e., a benzoate salt of compound I-1 depicted above).
  • salt I-1b when salt I-1b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c) (i.e., a salicylate salt of compound I-1 depicted above).
  • salt I-1c when salt I-1c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a succinate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d) (i.e., a succinate salt of compound I-1 depicted above).
  • salt I-1d when salt I-1d is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.8°, 11.7°, 14.3°, 14.7°, 17.0°, 17.4°, 19.6°, 20.6°, 22.3°, 22.6°, 22.9°, 23.1°, 23.4°, 24.9°, 25.2°, 26.3°, 26.8°, 27.3°, 27.7°, 28.8°, 29.1°, 30.9°, 31.5°, 33.8°, 34.5°, 36.5°, and 39.2°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is an oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1e) (i.e., an oxalate salt of compound I-1 depicted above).
  • salt I-1e when salt I-1e is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 11.3°, 12.3°, 15.6°, 17.7°, 19.5°, 20.0°, 20.8°, 21.4°, 22.3°, 22.7°, 24.8°, 25.7°, 26.7°, 27.9°, 28.7°, 29.5°, 31.4°, 33.0°, 35.4°, 36.5°, and 38.6°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a glycolate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1f) (i.e., a glycolate salt of compound I-1 depicted above).
  • salt I-1f when salt I-1f is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 8.2°, 12.2°, 12.9°, 15.8°, 16.3°, 17.8°, 19.2°, 20.1°, 21.7°, 23.6°, 24.4°, 24.6°, 24.9°, 26.0°, 26.6°, 27.8°, 29.6°, 30.2°, 32.0°, 32.3°, 33.0°, 33.9°, and 34.6°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a hemi-oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1g) (i.e., a hemi-oxalate salt of compound I-1 depicted above).
  • salt I-1g when salt I-1g is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 8.7°, 11.5°, 13.6°, 14.2°, 15.2°, 17.4°, 17.6°, 18.0°, 19.3°, 19.6°, 20.1°, 20.6°, 21.9°, 22.1°, 22.9°, 23.2°, 23.5°, 24.5°, 25.0°, 25.5°, 26.1°, 26.4°, 27.1°, 28.4°, 28.7°, 29.8°, 30.4°, 30.7°, 31.4°, 31.8°, 33.4°, and 33.9°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a hemi-fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1h) (i.e., a hemi-fumarate salt of compound I-1 depicted above).
  • salt I-1h when salt I-1h is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 8.1°, 11.3°, 12.2°, 13.3°, 14.2°, 16.2°, 17.6°, 18.3°, 18.6°, 19.5°, 19.8°, 20.0°, 20.2°, 20.9°, 21.4°, 21.9°, 22.3°, 22.7°, 22.9°, 23.8°, 24.5°, 25.0°, 25.2°, 26.1°, 26.4°, 26.9°, 28.4°, 28.8°, 29.5°, 29.8°, 30.9°, and 32.7°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 8a) (i.e., a fumarate salt of compound I-8 depicted below).
  • salt I-8a when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 12.5°, 13.6°, 14.6°, 15.2°, 15.5°, 15.8°, 16.1°, 16.6°, 17.0°, 18.4°, 19.0°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.3°, 23.8°, 24.1°, 25.1°, 26.2°, 26.8°, 27.3°, 27.9°, 28.3°, 28.9°, 29.3°, 29.6°, 29.9°, 30.6°, 31.0°, 31.3°, 32.4°, 32.9°, 33.3°, 33.6°, 34.3°, 34.9°, 35.7°, 36.1°, 37.4°, 38.0°, and 38.5°,
  • salt I-8a when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.8°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8a when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 23.8°, 24.1°, and 25.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 8b) (i.e., a benzoate salt of compound I-8 depicted above).
  • salt I-8b when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.3°, 24.6°, 25.1°, 25.3°, 25.5°, 26.9°, 28.3°, 28.9°, 29.3°, 31.4°, 31.6°, 32.0°, 32.3°, 32.8°, 35.1°, and 36.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8b when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.6°, 26.9°, 29.3°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8b when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 23.8°, 24.6°, 26.9°, 29.3°, and 35.1° as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I- 8c) (i.e., a salicylate salt of compound I-8 depicted above).
  • salt I-8c when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 10.5°, 11.4°, 12.3°, 13.4°, 14.2°, 14.9°, 15.6°, 16.1°, 17.1°, 18.1°, 18.7°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 22.2°, 22.6°, 23.7°, 24.6°, 25.2°, 25.6°, 26.1°, 26.4°, 27.4°, 27.5°, 27.8°, 28.5°, 28.8°, 29.4°, 29.7°, 30.3°, 31.0°, 31.3°, 32.1°, 32.7°, 33.1°, 33.5°, 34.4°, and 35.0°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8c when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8c when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.3°, 24.6°, 25.6°, 28.5°, and 32.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) and (III) are provided in Table 2. Table 2. Exemplary pharmaceutically acceptable salts of compounds of Formula (I)/(III) Table 2. (continued)
  • the pharmaceutically acceptable salt is hydrochloride salt of N,N- dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 5-hydroxy-V,V-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 5-methoxy-V,V-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(U/-indol-3-yl)-7V,7V-bis(methyl-t/5)ethan-l-amine-l,l,2,2-t4 (DMT-t/io).
  • DMT N,N- dimethyltryptamine
  • the pharmaceutically acceptable salt is a hydrochloride salt of 5-hydroxy-V,V-dimethyltryptamine (5-OH-DMT).
  • the pharmaceutically acceptable salt is a hydrochloride salt of 5-methoxy-V,
  • the pharmaceutically acceptable salt is a hydrochloride salt of 2-(lH-indol-3-yl)- N,N-bis(methyl-t/3)ethan-l-amine-l,l-t/2 (a DMT-tZs). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(U/-indol-3-yl)-N,N-dimethylethan- 1 -amine- l,l-6?2 (a DMT-tfe).
  • the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5-methoxy-lH-indol-3-yl)-N,N-bis(methyl-t/3)ethan-l-amine-l,l,2,2-t/4 (5-MeO-DMT -t/io). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5-(methoxy-t/3)-lH-indol-3-yl)-N,N-dimethylethan-l-amine-l,l-t/2 (5-MeO-DMT-tZs).
  • the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5- (m ethoxy -di)- IH-indol -3 -yl)-N,N-bis(methyl-t/3)ethan- 1 -amine- 1 , 1 ,2,2-d$ (5-MeO-DMT -dvi).
  • the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure is prepared by:
  • solvents may be used, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof.
  • the solvent(s) is a protic solvent(s).
  • the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxanes (1,4-di oxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., t-butylmethyl ether (TBME)), hexane, heptane, and octane, and combinations thereof.
  • the solvent is ethanol.
  • Suitable acids for use during the contacting step may include those described heretofore.
  • the acid may be an inorganic acid (e.g., hydrochloric acid) or an organic acid, with organic acids being preferred.
  • the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, and glycolic acid.
  • the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, and succinic acid, with fumaric acid, benzoic acid, and salicylic acid being preferred.
  • a stoichiometric (or superstoichiometric) quantity of the acid is contacted with the compound of the present disclosure.
  • a sub-stoichiometric (e.g., 0.5 molar equivalents) quantity of the acid is contacted with the compound of the present disclosure.
  • the use of sub-stoichiometric quantities of the acid may be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt.
  • the mixture is heated, e.g., refluxed, prior to cooling.
  • the mixture is cooled and the salt is precipitated out of the solution.
  • the salt is precipitated out of solution in crystalline form.
  • the salt is precipitated out of solution in amorphous form.
  • Isolation of the salt may be performed by various well-known isolation techniques, such as filtration, decantation, and the like.
  • the isolating step includes filtering the mixture.
  • the pharmaceutical formulation may comprise, as the psychopharmaceutical agent, a pharmaceutically acceptable salt of a single compound of the present disclosure (e.g., a single of compound of Formula (I) through (III)) or a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure (e.g., a mixture of compounds of Formula (I) through (III)).
  • the pharmaceutical formulation may contain an isotopologue mixture of compounds of the present disclosure in salt form as the psychopharmaceutical agent.
  • a subject compound of Formula (I) through (III) in salt form may be present in the pharmaceutical formulation at a purity of at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, based on a total weight of the isotopologue mixture of compounds of Formula (I) through (III) in salt form present in the pharmaceutical formulation.
  • a pharmaceutical formulation formulated with a DMT-d 10 salt (salt form of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 ), as the subject compound in salt form, may additionally contain isotopologues of the subject compound in salt form, e.g., DMT-d9 salt, a DMT-d8 salt, etc.
  • the pharmaceutical formulation is substantially free of other isotopologues of the subject compound in salt form, e.g., the pharmaceutical formulation has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 or 0.5 mole percent of other isotopologues of the subject compound in salt form.
  • the injectable pharmaceutical formulation comprises, as the psychopharmaceutical agent, a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure (e.g., a mixture of compounds of Formula (I) through (III)), that mixture may be referred to herein an “active salt mixture”.
  • the active salt mixture is a fumarate salt mixture, wherein the salt forms recited are fumarate salts.
  • the active salt mixture is a benzoate salt mixture, wherein the salt forms recited are benzoate salts.
  • the active salt mixture is a salicylate salt mixture, wherein the salt forms recited are salicylate salts.
  • the active salt mixture is a succinate salt mixture, wherein the salt forms recited are succinate salts.
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol- 3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11); and optionally (iii) a pharmaceutically acceptable salt of DMT
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8).
  • a pharmaceutically acceptable salt of DMT-d10 i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • a pharmaceutically acceptable salt of DMT-d9 i.e., a pharmaceutically acceptable salt of one or more of
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I- 6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)- N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d 4 (I-8); and (ii) a pharmaceutically acceptable salt of DMT-d 9 , i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a pharmaceutically acceptable salt of DMT-d10 i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) from 90% to 99% by weight of a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 1,1,2,2-d 4 (I-8), or any range therebetween, based on a total weight of the active salt mixture; and (ii) from 1% to 10% by weight, in sum, of a pharmaceutically acceptable salt of DMT-d 9 , i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), or any range therebetween, based on a pharmaceutically acceptable
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of: (1) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12); (2) a pharmaceutically acceptable salt of DMT-d7; (3) a pharmaceutically acceptable salt of DMT-d6 (a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-4)); (4)
  • a weight, in sum, of pharmaceutically acceptable salts of isotopologues of DMT not listed in (i) or (ii), such as those listed in (1) through (9), is less than 1% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.25% by weight, less than 0.2% by weight, less than 0.1% by weight, or 0% by weight, based on a total weight of the active salt mixture.
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a fumarate salt of DMT-d 10 , i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a fumarate salt of DMT-d 9 , i.e., a fumarate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a fumarate salt of DMT-d 8 , i.e., a fumarate salt of one or more of 2-(1H-indol-3-yl)
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a fumarate salt of DMT-d10, i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d 4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a fumarate salt of DMT-d 9 , i.e., a fumarate salt of one or more of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a fumarate salt of DMT-d 9 i.e., a fumarate salt of one or more of 2-(1
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a fumarate salt of DMT-d 8 , i.e., a fumarate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a fumarate salt of DMT-d 10 , i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a fumarate salt of DMT-d9, i.e., a fumarate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • DMT-d 10 i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a benzoate salt of DMT-d 9 , i.e., a benzoate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a benzoate salt of DMT-d8, i.e., a benzoate salt of one or more of 2-(1H-indol-3-
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a benzoate salt of DMT-d9, i.e., a benzoate salt of one or more of 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a benzoate salt of DMT-d9 i.e., a benzoate salt of one or more of 2-(
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a benzoate salt of DMT-d8, i.e., a benzoate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- amine-2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d 4 (I-8); and (ii) a benzoate salt of DMT-d 9 , i.e., a benzoate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a benzoate salt of DMT-d10 i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a salicylate salt of DMT-d 10 , i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11); and optionally (iii) a salicylate salt of DMT-d8, i.e., a salicylate salt of one or more of 2-(1H-indol-3-
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8).
  • a salicylate salt of DMT-d10 i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • a salicylate salt of DMT-d9 i.e., a salicylate salt of one or more of 2- (1H
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a salicylate salt of DMT-d8, i.e., a salicylate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a salicylate salt of DMT-d10 i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a succinate salt of DMT-d 10 , i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a succinate salt of DMT-d 9 , i.e., a succinate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11); and optionally (iii) a succinate salt of DMT-d 8 , i.e., a succinate salt of one or more of 2-(1H-indol-3-yl)
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a succinate salt of DMT-d 10 , i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8).
  • a succinate salt of DMT-d 10 i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a succinate salt of DMT-d 9 , i.e., a succinate salt of one or more of 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a succinate salt of DMT-d 9 i.e., a succinate salt of one or more of 2- (1H-indol
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a succinate salt of DMT-d 8 , i.e., a succinate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12).
  • a succinate salt of DMT-d 8
  • the active salt mixture consists of or consists essentially of (i) a succinate salt of DMT-d 10 , i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a succinate salt of DMT-d9, i.e., a succinate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • a succinate salt of DMT-d 10 i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d 2 (I-6); (ii) a pharmaceutically acceptable salt of DMT-d 7 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1-d; and optionally (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine (I-4).
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6).
  • the active salt mixture comprises from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1-d.
  • the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine (I-4).
  • a pharmaceutically acceptable salt of DMT-d6 i.e., a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine (I-4).
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6); and (ii) a pharmaceutically acceptable salt of DMT-d 7 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- amine-1-d.
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d 2 (I-2); (ii) a pharmaceutically acceptable salt of DMT-d 1 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d; and optionally (iii) a pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-dimethylethan-1-amine.
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2).
  • the active salt mixture comprises from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d 1 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine-1-d.
  • the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine.
  • a pharmaceutically acceptable salt of DMT i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine.
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d 2 (I-2); and (ii) a pharmaceutically acceptable salt of DMT-d 1 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d.
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I- 20); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I- 22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-23); and optionally (iii) a pharmaceutically acceptable salt of 5-MeO-d10,
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-20).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d10 i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I- 22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-23).
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO- DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-18), 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-2,2-d2 (I-19), and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-18), 2- (5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-2,2-d 2 (I-19), and 2-(5-methoxy- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-24).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d8 i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5-MeO- DMT-d 10 , i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20); and (ii) a pharmaceutically acceptable salt of 5- MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol- 3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-23).
  • a pharmaceutically acceptable salt of 5-MeO- DMT-d 10 i.e
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-34); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2,2-d 3 (I-36) and/or 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- amine-1,1,2-d 3 (I-37); and optional
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan- 1-amine-1,1,2,2-d 4 (I-34).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d13 i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT- d 12 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-36) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-37).
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 11 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1-d2 (I-32), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d 3 )-1H-indol-3-yl
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d11, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)- 1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-32), 2-(5-(methoxy-d 3 )-1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,2-d2 (I-38).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d11 i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(me
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d 13 , i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan- 1-amine-1,1,2,2-d4 (I-34); and (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-36) and/or 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d 5 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine- 1,1-d2 (I-28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-29); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 4 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d3)-1H-in
  • the active salt mixture comprises, in sum, from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d 5 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I- 28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-29).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 4 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d (I-27).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d 4 i
  • the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 , i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-dimethylethan- 1-amine (I-25).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-dimethylethan- 1-amine (I-25).
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 , i.e., a pharmaceutically acceptable salt of 2- (5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-25).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 i.e., a pharmaceutically acceptable salt of 2- (5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-25).
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5- MeO-DMT-d 5 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H- indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)- N,N-dimethylethan-1-amine-2,2-d2 (I-29); and (ii) a pharmaceutically acceptable salt of 5-MeO- DMT-d 4 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3- yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d
  • the pharmaceutical formulation comprises a therapeutically effective amount of the psychopharmaceutical agent.
  • the pharmaceutical formulation comprising the psychopharmaceutical agent typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or any range therebetween.
  • a free base dose free base equivalence when a salt form is used
  • a pharmaceutical formulation prepared with 40.4 mg of DMT fumarate would have a free base equivalence of DMT (molar mass of 188.27 g/mol) of about 25 mg as the unit dose.
  • the pharmaceutical formulation typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or any range therebetween as the unit dose.
  • the pharmaceutical formulation typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, or any range therebetween as the unit dose.
  • a free base dose free base equivalence when a salt form is used
  • the pharmaceutical formulation typically contains a free base dose (free base equivalence when a salt form is used) of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 250 mg, about 300 mg, or any range therebetween as the unit dose.
  • the pharmaceutical formulation can, if desired, also contain other compatible therapeutic agents.
  • the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about
  • a pharmaceutical formulation prepared from 40.4 mg of DMT fumarate (molar mass of 304.34 g/mol) in 1 mL of total volume of pharmaceutical formulation would have a free base concentration of psychopharmaceutical agent (in this example DMT free base; molar mass of 188.27 g/mol), of about 25 mg/mL.
  • Free base concentrations of psychopharmaceutical agent below about 70 mg/mL provide advantageous controlled-release profiles across the broadest range of release modifier molecular weight and release modifier concentrations.
  • difficulties with the pharmaceutical formulation may be encountered at free base concentrations of about 70 mg/mL or higher. Firstly, to achieve the targeted controlled- release effects at these higher free base concentrations, it may be necessary to correspondingly increase the concentration of release modifier.
  • Pushing the limits of the release modifier concentration may be problematic as the higher viscosities thus obtained may complicate or preclude the use of sterile filtration (which in the case of pharmaceutical formulations containing hyaluronate salts is effectively the only suitable sterilization technique available) and may cause increased pain at the injection site.
  • sterile filtration which in the case of pharmaceutical formulations containing hyaluronate salts is effectively the only suitable sterilization technique available
  • a deterioration of pharmaceutical formulation stability may be experienced at the higher free base concentrations of about 70 mg/mL or more, with precipitation being a main concern owing to the pharmacopeial requirements for particulate matter in injectables such as subcutaneous dosage forms (USP Particulate Matter in Injections ⁇ 788>).
  • the free base concentration of psychopharmaceutical agent e.g., tryptamine psychedelic such as a compound of Formula (I) through (III)
  • the free base concentration of psychopharmaceutical agent is typically kept below about 70 mg/mL, below about 60 mg/mL, below about 50 mg/mL, below about 40 mg/mL, below about 30 mg/mL.
  • the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, or any range therebetween.
  • a free base concentration of psychopharmaceutical agent e.g., a free base
  • the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, or any range therebetween.
  • a free base concentration of psychopharmaceutical agent e.g., a free base concentration of a compound of Formula (I) through (III) (free base equi
  • the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, or any range therebetween.
  • a free base concentration of psychopharmaceutical agent e.g.
  • tryptamine psychedelics with longer half-lives such as deuterated tryptamine psychedelics may provide significant advantages over their non-deuterated counterparts, especially in subcutaneous dosage forms.
  • deuterated tryptamine psychedelics possess advantageous metabolic degradation profiles which can lead to higher plasma concentrations and enhanced brain penetration, so that in some embodiments the therapeutic doses may be reduced.
  • a therapeutically relevant psychedelic dose of DMT may be in the range of about 70 mg or higher (free base), whereas for deuterated analogs of DMT such as 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1,2,2-d 4 (DMT-d 10 ) less drug (e.g., 10 to 50 mg, 15 to 50 mg, 20 to 40 mg, 30 to 50 mg, free base) may be needed to maintain desired blood concentrations owing to its longer half-life in vivo.
  • DMT-d 10 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1,2,2-d 4
  • the lower dosing requirements of deuterated analogs of DMT such as DMT-d10 allow for lower concentrations of release modifier to be used to achieve desirable controlled-release profiles, and for lower injection volumes.
  • Release modifier The pharmaceutical formulation comprises a release modifier.
  • the release modifier is the component primarily responsible for providing a controlled, tunable, and linear release of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) upon injection of the pharmaceutical formulation, such as upon subcutaneous injection.
  • a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier acts by thickening and building viscosity of the pharmaceutical formulation, while potentially also providing electrostatic attraction with the psychopharmaceutical agent, such that upon injection the psychopharmaceutical agent can be slowly released from the injection site (e.g., in the case of subcutaneous injection, within the fat or the layer of skin directly below the dermis and epidermis) and absorbed more slowly, generating a depot-like release effect.
  • the release modifier may be a polymeric material, such as a hyaluronate salt or a carboxymethyl cellulose salt, which may, or may not, be crosslinked.
  • the rate of release of the psychopharmaceutical agent can be controlled through cross-linking or the lack thereof, or the extent of cross-linking of the release modifier.
  • Release modifiers which are not cross-linked will typically provide a shorter release profile than those which are crosslinked, with crosslinking capable of extending the release significantly, such as over the course of a day or multiple days.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier is generally not crosslinked so as not to overextend the release period.
  • the release modifier is considered a separate component from the psychopharmaceutical agent.
  • the release modifier is also considered a separate component from the pharmaceutically acceptable additive(s) described hereinafter (such as a buffering agent, a tonicity agent, a pH adjusting agent, etc.) when such pharmaceutically acceptable additives are included in the pharmaceutical formulation of the present disclosure, even though the release modifier may perform a similar function to a particular additive(s).
  • the release modifier is considered different from a tonicity agent even though the release modifier contributes to the overall osmolality of the pharmaceutical formulation.
  • the release modifier is considered different from a buffering agent or a pH adjusting agent, even though the release modifier may influence the pH of the pharmaceutical formulation.
  • Hyaluronate salt in some embodiments, is a hyaluronate salt (anionic salt form of hyaluronic acid), which is non-sulfated glycosaminoglycan and long- chain polymer of disaccharide units of glucuronate-N-acetylglucosamine.
  • Hyaluronate salts are biocompatible and are distributed widely throughout animal connective, epithelial, and neural tissues.
  • the hyaluronate salt may include, but is not limited to, a sodium salt of hyaluronate (sodium hyaluronate), a potassium salt of hyaluronate (potassium hyaluronate), a calcium salt of hyaluronate (calcium hyaluronate), a zinc salt of hyaluronate (zinc hyaluronate), and a magnesium salt of hyaluronate (magnesium hyaluronate), or a combination thereof.
  • the release modifier is sodium hyaluronate.
  • the hyaluronate salt may be produced by a microbial fermentation and purification process and is preferably pharmacopoeia compliant.
  • hyaluronate salts are known to be heat sensitive, and so cannot be typically sterilized by thermal sterilization methods such as steam sterilization, dry-heat sterilization/depyrogenation, etc., which can cause polymer degradation.
  • thermal sterilization methods such as steam sterilization, dry-heat sterilization/depyrogenation, etc., which can cause polymer degradation.
  • hyaluronate salts are sterilized by sterile filtration such as sterile filtration through a 0.25 ⁇ m filter size or less.
  • hyaluronate salts may be optionally sterilized with a secondary sterilization process such as ethylene oxide (ETO) gas sterilization or gamma sterilization under less harsh conditions.
  • ETO ethylene oxide
  • the hyaluronate salt is a native hyaluronate salt, meaning it is not substituted, modified with pendant groups, conjugated, crosslinked, or otherwise covalently modified. Rather, the native hyaluronate salt possesses unmodified disaccharide units of glucuronate-N-acetylglucosamine. Examples may include, but are not limited to, sodium hyaluronate products available from Lifecore Biomedical, Inc. or Bloomage Freda Biopharm Co. Ltd.
  • the hyaluronate salt is a non-native hyaluronate salt, i.e., those that are substituted, modified with pendant groups, conjugated, crosslinked, deacetylated, or otherwise covalently modified.
  • the non-native hyaluronate salts may be, inter alia, acetylated, deacetylated, alkylated, esterified, amidated, hydrazidated, epoxy grafted, silylated, sulfated, and/or crosslinked hyaluronate salts. These modifications such as crosslinking may enable the formation of hydrogels of hyaluronate salts.
  • the degree of modification or substitution in non-native hyaluronate salts is typically about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any range therebetween.
  • non-native hyaluronate salts include, but are not limited to, sodium hyaluronate salts modified with pendant tyramine groups (an amidated hyaluronate salt) whereby tyramine is introduced onto glucuronate units using amide bond chemistry (EDC chemistry); and Corgel® BioHydrogel products available from Lifecore Biomedical, Inc., whereby the tyramine substituted sodium hyaluronate (TS-NaHy) from above is subsequently cross-linked by forming stable dihydroxyphenyl covalent bonds through an enzyme driven reaction involving e.g., horseradish peroxidase.
  • EDC chemistry amide bond chemistry
  • hyaluronate salts may be employed in some cases where extended duration of action is desired, for the delivery of tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) in which a controlled-release is sought that provides a duration of action of about 30 to 120 minutes, the hyaluronate salt is generally not crosslinked or in hydrogel form so as not to overextend the release period and the resulting duration of action beyond about 120 minutes.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the hyaluronate salt is generally not crosslinked or in hydrogel form so as not to overextend the release period and the resulting duration of action beyond about 120 minutes.
  • the weight average molecular weight (Mw) of the hyaluronate salt may be about 500 kDa, about 550 kDa, about 600 kDa, about 650 kDa, about 700 kDa, about 750 kDa, about 800 kDa, about 850 kDa, about 900 kDa, about 950 kDa, about 1,000 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 kDa, about 1,800 kDa, about 1,900 kDa, about 2,000 kDa, or any range therebetween such as from about 500 kDa to about 2,000 kDa, from about 600 kDa to about 1,500 kDa, from about 750 kDa to about 1,000 kDa, from about 1,000 kDa to about 2,000 kDa, from about 1,000 k
  • a weight average molecular weight of the hyaluronate salt which is above the aforementioned upper limit may result in pharmaceutical formulations which are too viscous, thereby complicating the sterile filtration process and resulting in painful injections, especially in the case of subcutaneous injections.
  • hyaluronate salts with a weight average molecular weight above the aforementioned upper limit may provide a release profile which is too slow for achieving the desired duration of action time course of about 30 to 120 minutes in the case of some tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)).
  • hyaluronate salts with a weight average molecular weight below the aforementioned lower limit may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier.
  • the hyaluronate salt has a molecular weight range in between about 500 kDa, about 600 kDa, about 700 kDa, about 800 kDa, about 900 kDa, about 1,000 kDa, about 1,100 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 kDa, about 1,800 kDa, about 1,900 kDa, and about 2,000 kDa, or any intermediate range between any of these values.
  • the hyaluronate salt has a molecular weight range of about 500 kDa to about 2,000 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 500 kDa to about 750 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 750 kDa to about 1,000 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 750 kDa to about 1,500 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 1,000 kDa to about 1,800 kDa.
  • the hyaluronate salt has a molecular weight range of about 900 kDa to about 1,400 kDa. The weight average molecular weight of the hyaluronate salt would then fall somewhere within the molecular weight range.
  • hyaluronate salts include, but are not limited to, sodium hyaluronate products HA700K (molecular weight range of 500 – ⁇ 750 kDa), HA1M (molecular weight range of 750 – 1,000 kDa), and HA15M (molecular weight range of >1,000 – 1,800 kDa), available from Lifecore Biomedical, Inc., and Hyatrue® HA-EP1.8 (molecular weight range of 900-1,400 kDa) available from Bloomage Freda Biopharm Co. Ltd.
  • a concentration of hyaluronate salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) may be about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to
  • the concentration of hyaluronate salt preferably does not exceed about 1%, about 0.95%, about 0.9%, about 0.85%, about 0.8%, about 0.75%, about 0.7%, about 0.65%, about 0.6%, about 0.55%, about 0.5% w/v.
  • the concentration of hyaluronate salt is from about 0.1% to about 0.5% w/v. Attempts to lower the concentration of hyaluronate salt by dilution (increasing injection volume) may not be possible in subcutaneous dosage forms, for example, since higher injection volumes are associated with higher levels of pain at the injection site.
  • a ratio of free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), to the concentration of hyaluronate salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) is about 0.1:1, about 0.5:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 105:1,
  • the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of hyaluronate salt of about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.8:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, or any range therebetween.
  • the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of hyaluronate salt of about 0.1:1, about 0.15:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, or any range therebetween.
  • the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of hyaluronate salt of about 5:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 105:1, about 110:1, about 115:1, about 120:1, about 125:1, about 130:1, or any range therebetween.
  • ratios below the aforementioned lower limit may result in pharmaceutical formulations with a release profile which is overextended (too slow) in terms of clinical practicality.
  • extended release profiles providing a duration of action beyond 120 minutes may be preferred in some cases, which may be achieved by lowering the ratio. Ratios above the aforementioned upper limit tend to provide a release that is not meaningfully different from formulations lacking release modifier (too fast).
  • a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), is about 17:1, about 18:1, about 19:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 500:1, about 1,000:1, about 1,500:1, about 2,000:1, about 3,000:1, about 4,000:1, about 4,500:1, about 5,000:1, about 6,000:1, about 7,000:1, about 8,000:1, about 9,000:1, about 10,000:1, about 11,000:1, about 12,000:1, or any range therebetween, such as from
  • the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 100:1, about 500:1, about 1,000:1, about 1,200:1, about 1,400:1, about 1,600:1, about 1,800:1, about 2,000:1, about 2,200:1, about 2,400:1, about 2,600:1, about 2,800:1, about 3,000:1, about 3,200:1, about 3,400:1, about 3,600:1, about 3,800:1, about 4,000:1, about 4,200:1, about 4,400:1, about 4,600:1, about 4,800:1, about 5,000:1, about 6,000:1, about 7,000:1, about 8,000:1, about 9,000:1, about 10,000:1, or any range therebetween.
  • Mw weight average molecular weight
  • the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 1,000:1, about 1,500:1, about 2,000:1, about 2,500:1, about 3,000:1, about 3,500:1, about 4,000:1, about 4,500:1, about 5,000:1, about 5,500:1, about 6,000:1, about 6,500:1, about 7,000:1, about 7,500:1, about 8,000:1, about 8,500:1, about 9,000:1, about 9,500:1, about 10,000:1, about 10,500:1, about 11,000:1, about 11,500:1, about 12,000:1, or any range therebetween.
  • Mw weight average molecular weight
  • the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 17:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 120:1, about 140:1, about 160:1, about 180:1, about 200:1, about 220:1, about 240:1, about 260:1, about 280:1, about 300:1, about 320:1, about 340:1, about 360:1, about 380:1, about 400:1, about 420:1, about 460:1, about 480:1, about 500:1, or any range therebetween.
  • Mw weight average molecular weight
  • a free base concentration of psychopharmaceutical agent of about 17:1, about 20:1, about 25:1, about
  • Ratios below the aforementioned lower limit may result in pharmaceutical formulations with a release profile similar to those which are formulated without any release modifier (too fast), whereas ratios above the aforementioned upper limit may overextend the release (too slow) and the resulting duration of action, which is not generally favorable in the case of certain tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) where a duration of action of about 30 minutes to about 120 minutes is targeted. Even so, there are instances where lower ratios can be used when a faster release profile is desirable, or where higher ratios can be used to provide a duration of action beyond 120 minutes.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier is a carboxymethyl cellulose salt, which is a cellulose derivative with carboxymethyl groups (-CH2COO-) bound to some of the hydroxyl groups of the glucopyranose monomers that make up the cellulose backbone.
  • the carboxymethyl cellulose salt may include, but is not limited to, a sodium salt of carboxymethyl cellulose (sodium carboxymethyl cellulose).
  • the carboxymethyl cellulose salt may be produced by reacting alkali cellulose with sodium monochloroacetate, and this reaction may be performed under rigidly controlled conditions to control the degree of substitution (DS), which is the average number of hydroxyl groups of the glucopyranose monomers that are carboxymethylated, with the theoretical limit being a DS of 3.0.
  • the resultant polymer is purified and dried for pharmacopoeia compliance.
  • the carboxymethyl cellulose salt is not substituted, modified with pendant groups, conjugated, crosslinked, or otherwise covalently modified. Rather, the carboxymethyl cellulose salt possesses a cellulose backbone formed from glucopyranose monomers which are substituted only with carboxymethyl groups.
  • the carboxymethyl cellulose salt is not crosslinked with glycolic acid to form a croscarmellose salt such as sodium croscarmellose.
  • the carboxymethyl cellulose salt may have a degree of substitution (DS) of 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, or any range therebetween, such as from 0.45 to less than 0.9, from 0.7 to less than 0.9, from 0.9 to less than 1.2, or from 1.2 to 1.5.
  • the carboxymethyl cellulose salt has a DS of 0.7 to 0.8, 0.85 to 1.15 or 0.9 to 1.0.
  • the weight average molecular weight (Mw) of the carboxymethyl cellulose salt is typically below about 500 kDa, for example, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa, about 210 kDa, about 220 kDa, about 230 kDa, about 240 kDa, about 250 kDa, about 300 kDa, about 350 kDa, about 400 kDa, about 450 kDa, or any range therebetween, such as from about 90 kDa to about 300 kDa, from about 100 kDa to about 300 kDa, from about
  • a weight average molecular weight of the carboxymethyl cellulose salt which is above the aforementioned upper limit generally results in pharmaceutical formulations that exceed viscosity specifications for being injectable and syringeable, and are not generally approved by the Food & Drug Administration (FDA) for use in injectables.
  • FDA Food & Drug Administration
  • suitable carboxymethyl cellulose salts are typically those with a Brookfield viscosity, measured as 2% aqueous solutions using spindle number 3 at 30 rpm, of from about 400 cP, about 600 cP, about 800 cP, about 1,000 cP, about 1,200 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, about 2,500 cP, about 2,750 cP, about 3,000 cP, about 3,100 cP, or any range therebetween, such as from about 400 cP to about 3,100 cP, or about 1,500 cP to about 3,100 cP, or about 470 to about 700 cP.
  • a Brookfield viscosity measured as 2% aqueous solutions using spindle number 3 at 30 rpm
  • carboxymethyl cellulose salt may include, but are not limited to, AqualonTM and BlanoseTM sodium carboxymethyl cellulose products available from Ashland, such as AqualonTM/BlanoseTM grades 9M8F PH, 9M8XF, 9M31F PH, 9M31XF PH, and 7MF PH.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%.
  • Concentrations of carboxymethyl cellulose salt which exceed the aforementioned upper limit provide pharmaceutical formulations which are too viscous for sterile filtration, injectability, and/or syringeability, for example may cause increased pain at the injection site.
  • a ratio of free base concentration of psychopharmaceutical agent (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), to the concentration of carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) is about 0.1:1, about 0.5:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, or any range therebetween.
  • the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of carboxymethyl cellulose salt of about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.5:1, about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, about 4.5:1, about 5:1, or any range therebetween.
  • the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of carboxymethyl cellulose salt of about 0.1:1, about 0.15:1, about 0.2:1, about 0.25:1, about 0.3:1, about 0.35:1, about 0.4:1, about 0.45:1, about 0.5:1, about 0.55:1, about 0.6:1, about 0.65:1, about 0.7:1, about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, or any range therebetween.
  • the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of carboxymethyl cellulose salt of about 5:1, about 6:1, about 8:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 22:1, about 25:1, about 28:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, or any range therebetween.
  • a ratio of the weight average molecular weight of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 8:1, about 10:1, about 12:1, about 14:1, about 16:1, about 18:1, about 20:1, about 22:1, about 24:1, about 26:1, about 28:1, about 30:1, about 32:1, about 34:1, about 36:1, about 38:1, about 40:1, about 42:1, about 44:1, about 46:1, about 48:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 200:1, about 300:1, about 400:1, about 500:1, about 600:
  • the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 120:1, about 140:1, about 160:1, about 180:1, about 200:1, about 220:1, about 240:1, about 260:1, about 280:1, about 300:1, about 320:1, about 340:1, about 360:1, about 380:1, about 400:1, about 420:1, about 460:1, about 480:1, about 500:1, about 550:1, about 600:1, about 650:1, about 700:1, about 750:1, about 800:1, about 850:1, about 900:1, about 950:1, about 1,000:1, about 1,100:1, about 1,200:1, about 1,300:1, about 1,400:
  • the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 100:1, about 120:1, about 140:1, about 160:1, about 180:1, about 200:1, about 220:1, about 240:1, about 260:1, about 280:1, about 300:1, about 320:1, about 340:1, about 360:1, about 380:1, about 400:1, about 420:1, about 460:1, about 480:1, about 500:1, about 550:1, about 600:1, about 650:1, about 700:1, about 750:1, about 800:1, about 850:1, about 900:1, about 950:1, about 1,000:1, about 1,500:1, about 2,000:1, about 2,500:1, about 3,000:1, about 3,500:1, about 4,000:1, about 4,500:1, about 5,000:1, or any range therebetween.
  • Mw weight average molecular weight
  • the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 8:1, about 10:1, about 12:1, about 14:1, about 16:1, about 18:1, about 20:1, about 22:1, about 24:1, about 26:1, about 28:1, about 30:1, about 32:1, about 34:1, about 36:1, about 38:1, about 40:1, about 42:1, about 44:1, about 46:1, about 48:1, about 50:1, or any range therebetween.
  • Aqueous vehicle The pharmaceutical formulation comprises an aqueous vehicle.
  • aqueous vehicle refers to a diluent, adjuvant, excipient, carrier, and/or any other auxiliary or supporting ingredient with which a psychopharmaceutical agent and release agent of present disclosure is formulated for administration to a mammal.
  • the aqueous vehicle comprises water, such as water for injection (WFI).
  • WFI water for injection
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • the aqueous vehicle may optionally contain one or more pharmaceutically acceptable additives, as desired/needed.
  • “Pharmaceutically acceptable additives” may be diluents, adjuvants, excipients, carriers, or any other auxiliary or supporting ingredient approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, such as companion animals.
  • Examples of pharmaceutically acceptable additives include, but are not limited to, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof. It should be understood that many pharmaceutically acceptable additives may serve several functions, even within the same pharmaceutical formulation, for example, a buffering agent may also act as a tonicity agent and vice versa.
  • Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide, or a combination thereof.
  • Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil, or a combination thereof.
  • Antimicrobial agents or preservatives include, but are not limited to, phenols (e.g., phenol), cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl-, ethyl-, and propyl-parabens, benzoic acid, sodium benzoate, and sorbic acid, or a combination thereof.
  • phenols e.g., phenol
  • cresols cresols
  • mercurials e.g., benzyl alcohol
  • chlorobutanol methyl and propyl p-hydroxybenzates
  • thimerosal benzalkonium chloride
  • benzethonium chloride methyl-, ethyl-, and propyl-parabens
  • benzoic acid sodium benzoate
  • sorbic acid or a combination thereof.
  • Stabilizing agents include, but are not limited to, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl alcohols, glycerol, methionine, monothioglycerol, ascorbic acid, citric acid, polysorbate, arginine, and sorbitol, or a combination thereof.
  • fatty acids may act as lipid carriers.
  • the fatty acid may have from 4 to 30 carbon atoms, 6 to 28 carbon atoms, 8 to 24 carbon atoms, 10 to 20 carbon atoms, or 12 to 18 carbon atoms.
  • the fatty acid may be a fatty monoacid or a fatty diacid.
  • Exemplary fatty acids may include, but are not limited to, adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, arachidic acid, behenic acid, lignoceric acid, palmitolic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof.
  • the pharmaceutical formulation is formulated without a fatty acid to prevent hydrogel formation and an overextended release (for an example of a hydrogel that generates a release over days, see Kang NW, et al. Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin. Pharmaceutics.2021 Jun 11;13(6):864).
  • a tonicity agent is a chemical that, on inclusion within a pharmaceutical formulation, modulates the osmolality of the pharmaceutical formulation.
  • the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation provides a desired osmolality, and so no tonicity agent is needed/included.
  • the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation does not provide the osmolality specifications for injection, and so one or more tonicity agents may be included to reach a desired osmolality.
  • the pharmaceutical formulation comprises a tonicity agent
  • the concentration of the tonicity agent will be adjusted considering the osmolality contributions from the concentrations of psychopharmaceutical agent and the release modifier to provide a pharmaceutical formulation with a desirable osmolality range (e.g., 150 to 600 mOsm/kg).
  • Tonicity agents include, but are not limited to, sodium chloride; potassium chloride; calcium chloride; magnesium chloride; dextrose; glucose; mannitol; lactose; sorbitol; sucrose; alanine; ethanol; benzyl alcohol; creatinine; glycine; glycerol; histidine; polyethylene glycol; propylene glycol; sodium bicarbonate; sodium hydroxide; hydrochloric acid; phosphoric acid; a phosphate salt such as sodium phosphate or potassium phosphate; acetic acid; an acetate salt such as sodium acetate, potassium acetate, or ammonium acetate; citric acid; a citrate salt such as sodium citrate or potassium citrate; arginine; ascorbic acid; an ascorbate salt such as potassium ascorbate or sodium ascorbate; edetic acid; an edetate salt such as sodium edetate or calcium edetate; lactic acid; a lactate salt such as
  • the tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, magnesium chloride, dextrose, glucose, mannitol, lactose, sorbitol, sucrose, and sodium lactate.
  • the tonicity agent is sodium chloride.
  • the pharmaceutical formulation comprises sodium chloride at a concentration, in terms of weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or any range therebetween such as from about 0.1% to about 0.6%, about 0.2% to about 0.55%, about 0.3% to about 0.5% w/v.
  • a buffering agent is a chemical that on inclusion into the pharmaceutical formulation comprises a weak acid and its conjugate base in equilibrium, which resist changes in pH on addition of acid or base to the pharmaceutical formulation.
  • the buffering agent is considered a separate component from the psychopharmaceutical agent (e.g., a pharmaceutically acceptable salt of a compound of the present disclosure such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)). In this sense, the buffering agent is not merely a counterion to the protonated form of the compound of the present disclosure.
  • the buffering agent when included, provides a buffering effect to resist changes in pH above that which may be provided by the psychopharmaceutical agent.
  • the buffering agent is also considered a separate component from the release modifier, and again, provides a buffering effect to resist changes in pH above that which may be provided by the release modifier.
  • a phosphate buffer a phosphate salt and phosphoric acid
  • a suitable buffer is optionally selected that comprises an acid with a pKa value (or an acid having at least one pKa value in the case of polyprotic acids) that lies within ⁇ 1 of the desired pH of the pharmaceutical formulation.
  • the pharmaceutical formulation is not formulated with a buffering agent.
  • Antioxidants include, but are not limited to, bisulfite and sodium metabisulfite, ascorbic acid, citric acid, tartaric acid, thiol derivatives, or combinations thereof.
  • the pharmaceutical formulation has an oxygen content of less than 2 ppm, such as between 0.1 ppm and 2 ppm.
  • Local anesthetics include, but are not limited to, procaine hydrochloride.
  • Complexing agents include, but are not limited to, cyclodextrins, including ca- cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.), or combinations thereof.
  • Sequestering or chelating agents include, but are not limited to EDTA.
  • pH adjusting agents include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid, or combinations thereof. pH adjusting agents may be optionally employed to adjust the pH of the pharmaceutical formulation into a desirable range. Sometimes, the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation provides a desirable pH, and so no pH adjusting agent is needed/included. Alternatively, the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation does not provide the pH specifications for injection, and so one or more pH adjusting agents may be included to reach a desired pH.
  • Absorption enhancers include, but are not limited to, a hyaluronidase enzyme.
  • the hyaluronidase enzyme may have the added effect of breaking down the hyaluronate salt to speed drug release in cases where increased release rates are desired.
  • This additive may be added to the pharmaceutical formulation immediately prior to injection or may be injected separately as part of a multi-component injection, such as using a dual chamber syringe or a multi-syringe (e.g., two syringe) set up.
  • the pharmaceutical formulation does not contain a hyaluronidase enzyme, nor is a hyaluronidase enzyme employed during or post injection of the pharmaceutical formulation.
  • the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of water for injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent.
  • a pharmaceuticalpharmaceutical agent e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • an aqueous vehicle made up of water for injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent.
  • the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the pharmaceutical formulation is formulated without a buffering agent.
  • a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • an aqueous vehicle made up of saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the pharmaceutical formulation is formulated without a buffering agent.
  • the pharmaceutical formulation consists of, or consists essentially of, the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and water and optional tonicity agent (e.g., sodium chloride) and optional pH adjusting agent (e.g., sodium hydroxide) as the aqueous vehicle.
  • the psychopharmaceutical agent e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier e.g., water and optional tonicity agent (e.g., sodium chloride) and optional pH adjusting agent (e.g., sodium hydroxide)
  • water and optional tonicity agent e.g., sodium chloride
  • optional pH adjusting agent e.g., sodium hydroxide
  • this time-restricted controlled-release would provide a duration of action of about 30 to 120 minutes.
  • the pharmaceutical formulation may have a pH of about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, about 10, about 10.25, about 10.5, about 10.75, about 11, or any range therebetween.
  • pH values which are too high are associated with tissue necrosis
  • pH values which are too low are associated with pain and inflammation at the injection site.
  • the pharmaceutical formulation is suitable for intravenous injection (is an intravenous pharmaceutical formulation) or intramuscular injection (is an intramuscular pharmaceutical formulation), and has a pH ranging from about 2 to about 11, about 3 to about 9, about 4 to about 7, about 4.5 to about 6.
  • the pharmaceutical formulation is suitable for subcutaneous injection (is a subcutaneous pharmaceutical formulation), and has a pH ranging from about 3 to about 9, about 3 to about 7, about 4 to about 9, about 4 to about 7.5, about 4 to about 7, about 4.5 to about 7.5, about 4.5 to about 7, about 4.5 to about 6.5, about 4.5 to about 6.
  • the pharmaceutical formulation may have an osmolality of about 150 mOsm/kg, about 155 mOsm/kg, about 160 mOsm/kg, about 165 mOsm/kg, about 170 mOsm/kg, about 175 mOsm/kg, about 180 mOsm/kg, about 185 mOsm/kg, about 190 mOsm/kg, about 195 mOsm/kg, about 200 mOsm/kg, about 225 mOsm/kg, about 250 mOsm/kg, about 275 mOsm/kg, about 300 mOsm/kg, about 325 mOsm/kg, about 350 mOsm/kg, about 375 mOsm/kg, about 400 mOsm/kg, about 425 mOsm/kg, about 450 mOsm/kg, about 475 mOsm/kg, about 500 mOsm/
  • the pharmaceutical formulation is isotonic with subject blood serum, e.g., has an osmolality of about 275 to about 335 mOsm/kg.
  • the pharmaceutical formulation may have viscosity of less than about 10,000 cP, less than about 9,000 cP, less than about 8,000 cP, less than about 7,000 cP, less than about 6,000 cP, less than about 5,000 cP, less than about 4,000 cP, less than about 3,000 cP, less than about 2,000 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less than about 50 cP, less than about 45 cP, less than about 40 cP, less than about 35 cP, less than about 30 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, about 25 cP, about 28
  • viscosity values allow the pharmaceutical formulation to be syringeable and injectable, for example without causing excessive pain at the injection site.
  • suitable viscosity values also enable the use of sterile filtration as the sterilization technique.
  • the pharmaceutical formulation is suitable for subcutaneous injection (is a subcutaneous pharmaceutical formulation), and preferably has a viscosity of less than about 3,000 cP, less than about 2,500 cP, less than about 2,000 cP, less than about 1,500 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less than about 50 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, or any range therebetween.
  • the pharmaceutical formulation has a shelf-life as an aqueous solution of at least 1 day, 2 days, 3 days, 4 days 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or longer, without significant product degradation or physical changes such as precipitation.
  • the pharmaceutical formulation can be maintained/stored as an aqueous solution in open or closed environments, such as in open or closed flasks/vials under sub-ambient, ambient, or stress conditions (elevated temperatures) without appreciable degradation or physical changes such as precipitation.
  • compositions with a prolonged shelf-life of at least several days or at least several weeks are advantageous because they may be prepared well in advance of administration if desired, and optionally stored, without materially affecting efficacy or injectability.
  • pharmaceutical formulations formed from a pharmaceutically acceptable salt of a compound of the present disclosure e.g., a compound of Formula (I) through (III), as the psychopharmaceutical agent, are characterized by increased stability compared to formulations prepared using the same compound as free base but are otherwise substantially the same.
  • the pharmaceutical formulation of the present disclosure formed from a pharmaceutically acceptable salt of a compound of the present disclosure may be at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% more stable upon storage for 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, or longer, in terms of degradation or physical changes such as precipitation, compared to formulations prepared from a free base counterpart but are otherwise substantially the same.
  • the pharmaceutical formulation enables time-restricted temporal controlled-release of the psychopharmaceutical agent via bolus injection to subjects such as companion animals, and via bolus subcutaneous injection in particular.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the pharmaceutical formulations enable controlled-release of the tryptamine psychedelic via bolus injection to subjects, and via bolus subcutaneous injection in particular, that mimics the clinically advantageous duration of action of about 30 to 120 minutes achievable by IV infusion of such psychopharmaceutical agents over about 90 minutes.
  • the duration of action following bolus injection of the pharmaceutical formulation is about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween, such as from about 30 to about 120 minutes, from about 30 to about 45 minutes, from about 40 to about 100 minutes, from about 45 to about 90 minutes, from about 50 to about 75 minutes, from about 60 to about 70 minutes.
  • the controlled-release of a tryptamine psychedelic places the subject into a psychedelic state (a correlate of positive clinical outcomes) for about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, or any range therebetween, such as a psychedelic state time course of from about 10 minutes to about 100 minutes, from about 20 minutes to about 80 minutes, from about 30 to about 45 minutes, from about 30 minutes to about 60 minutes, from about 40 minutes to about 50 minutes.
  • a psychedelic state time course of from about 10 minutes to about 100 minutes, from about 20 minutes to about 80 minutes, from about 30 to about 45 minutes, from about 30 minutes to about 60 minutes, from about 40 minutes to about 50 minutes.
  • Observation of pharmacological effects and/or symptom monitoring by a clinician/veterinarian or caregiver can be used to assess the duration of action and/or psychedelic state of the subject following injection.
  • Pharmacological effects which can be monitored to assess the duration of action and/or psychedelic state include, but are not limited to, licking, salivation, panting, vocalization, and wide eyes (dilated pupils).
  • Assessment may also be conducted by, for example, functional magnetic resonance imaging (fMRI), pharmaco electroencephalogram (EEG), etc.
  • the duration of action and/or time course that the subject spends in the psychedelic state may also be assessed by the time the subject has a therapeutically relevant concentration of the drug in the blood, e.g., the time that the subject has a drug concentration between about 50 ng/mL and about 300 ng/mL, between about 60 ng/mL and about 280 ng/mL, between about 80 ng/mL to about 260 ng/mL, between about 100 ng/mL to about 240 ng/mL, between about 120 ng/mL to about 220 ng/mL, between about 140 ng/mL to about 200 ng/mL, between about 160 ng/mL to about 180 ng/mL, etc., or any range between these values.
  • the pharmaceutical formulation may be adjusted to provide a duration of action beyond about 120 minutes, such as up to about 1,200 minutes, up to about 1,080 minutes, up to about 960 minutes, up to about 840 minutes, up to about 720 minutes, up to about 600 minutes, up to about 480 minutes, up to about 360 minutes, up to about 240 minutes, up to 180 minutes, for example, by increasing the loadings, molecular weight, and/or crosslinking of the release modifier.
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves an onset of effects within about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes post administration, such as from about 1 minute to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 15 minute to about 30 minutes.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves an offset of effects of greater than about 30 minutes and up to about 150 minutes post administration, such as about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, about 125 minutes, about 130 minutes, about 135 minutes, about 140 minutes, about 145 minutes, about 150 minutes post administration, or any range therebetween.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • bolus subcutaneous injection which achieves an offset of effects
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a therapeutically relevant concentration of the drug in the blood of about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115
  • these drug concentrations are preferably provided for a duration of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween. In some cases, higher plasma concentrations may be targeted.
  • desirable pharmaceutical formulations provide a controlled-release of the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, to achieve the aforementioned duration of action and/or psychedelic state time course, but do so without a burst release of the tryptamine psychedelic exceeding plasma levels of about 500 ng/mL, about 480 ng/mL, about 460 ng/mL, about 440 ng/mL, about 420 ng/mL, about 400 ng/mL, about 380 ng/mL, about 360 ng/mL, about 340 ng/mL, or about 320 ng/mL.
  • the tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • pharmaceutical formulations of the present disclosure provide a smoother, more controlled delivery of the psychopharmaceutical agent contained therein compared to bolus IV or intramuscular injections of the same agent formulated without release modifier, which are known to cause high levels of drug spiking immediately following IV or intramuscular injection.
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a therapeutically relevant maximum concentration of the drug in the blood of about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a plasma half-life (t 1/2 ) of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 30 minutes to about 60 minutes, or from about 35 minutes to about 50 minutes, or from about 40 minutes to about 45 minutes.
  • tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • bolus subcutaneous injection which achieves a plasma half-life (t 1/2 ) of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 30 minutes to about 60 minutes, or from about 35
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a time to maximum drug concentration (T max ) of about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 20 minutes to about 60 minutes, or from about 25 minutes to about 50 minutes, or from about 30 minutes to about 45 minutes, or from about 10 minutes to about 30 minutes.
  • tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • T max time to maximum drug concentration
  • the pharmaceutical formulation may extend the release of the psychopharmaceutical agent compared to the release of the same psychopharmaceutical agent from a formulation without release modifier but is otherwise substantially the same.
  • the time required for release of 25% of a total psychopharmaceutical agent content (free base equivalence) in the pharmaceutical formulation (t 25% ) is at least about 35% longer, at least about 40% longer, at least about 45% longer, at least about 50% longer, at least about 55% longer, at least about 60% longer, at least about 65% longer, at least about 70% longer, at least about 75% longer, at least about 80% longer, at least about 85% longer, at least about 90% longer, at least about 95% longer, at least about 100% longer than the t25% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test (see Example section for experimental protocol).
  • the time required for release of 50% of a total psychopharmaceutical agent content (free base equivalence) in the pharmaceutical formulation (t50%) is at least about 35% longer, at least about 40% longer, at least about 45% longer, at least about 50% longer, at least about 55% longer, at least about 60% longer, at least about 65% longer, at least about 70% longer, at least about 75% longer, at least about 80% longer, at least about 85% longer, at least about 90% longer, at least about 95% longer, at least about 100% longer than the t50% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test.
  • the pharmaceutical formulation provides a time-restricted controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) so as not to overextend the release and the resulting duration of action beyond about 120 minutes.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the t25% is no more than about 250% longer, no more than about 225% longer, no more than about 200% longer, no more than about 190% longer, no more than about 180% longer, no more than about 170% longer, no more than about 160% longer, no more than about 150% longer no more than about 140% longer no more than about 130% longer than the t25% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test.
  • the t 50% is no more than about 250% longer, no more than about 225% longer, no more than about 200% longer, no more than about 190% longer, no more than about 180% longer, no more than about 170% longer, no more than about 160% longer, no more than about 150% longer, no more than about 140% longer, no more than about 130% longer than the t 50% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test.
  • the time required for release of 50% of a total psychopharmaceutical agent content in the pharmaceutical formulation is no more than about 120 minutes, no more than about 110 minutes, no more than about 100 minutes, no more than about 90 minutes, no more than about 80 minutes, no more than about 70 minutes, no more than about 60 minutes, no more than about 50 minutes, no more than about 40 minutes, no more than about 30 minutes, as determined by the Dialysis—Drug Release Test.
  • Kits Also disclosed herein is a kit suitable for preparing the injectable pharmaceutical formulation of the present disclosure.
  • the kit comprises a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the kit comprises (a1) a first solution comprising a psychopharmaceutical agent and an aqueous vehicle, and (b1) a second solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt and an aqueous vehicle.
  • the kit components (a1) and (b1) are intended to be combined, contacted, or otherwise brought together to generate the injectable pharmaceutical formulation of the present disclosure.
  • the first solution comprises (as psychopharmaceutical agent) a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III).
  • the (a1) first solution may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)) by contacting the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure with aqueous vehicle.
  • the first solution may be prepared by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the free base to form the pharmaceutically acceptable salt of a compound of the present disclosure within (a1) the first solution in-situ.
  • the first solution comprises a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of first solution of about 0.1 mg/mL, about 0.4 mg/mL, about 0.6 mg/mL, about 0.8 mg/mL, about 1 mg/mL, about 1.2 mg/mL, about 1.4 mg/mL, about 1.6 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 32 mg/m
  • the second solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.
  • the second solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.6% to about 2%, about 0.7% to about 1.8%, about 0.8% to about 1.7%, about 0.9% to about 1.6%, about 1% to about 1.5%.
  • Kits may be provided with different concentrations of psychopharmaceutical agent in component (a1), different concentrations of release modifier in component (b1), and/or different volume ratios of kit components (a1) and (b1) may be combined, contacted, or otherwise brought together to generate different pharmaceutical formulations with differentiated release characteristics, unit doses, and/or psychopharmaceutical agent concentrations.
  • kits may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, unit dose, psychopharmaceutical agent concentration, release modifier, and release characteristics, by using different volume ratios of kit components (a1) : (b1).
  • a suitable volume ratio of (a1) : (b1) used to generate the pharmaceutical formulation may be from about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range therebetween, such as from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1:1.
  • kit components (a1) and (b1) to generate the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the kit may include instructions for what volume ratios of (a1) : (b1) can be used to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc.
  • the kit comprises (a2) a psychopharmaceutical agent in solid form and (b2) a solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • kit components (a2) and (b2) are intended to be combined, contacted, or otherwise brought together to generate the injectable pharmaceutical formulation of the present disclosure.
  • the psychopharmaceutical agent is a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form.
  • any pre-formed, solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) of the present disclosure can be used in kit component (a2).
  • the solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to about 0.75%, or about 0.25% to about 0.5%.
  • the solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%.
  • Kits may be combined, contacted, or otherwise brought together with kit component (a2) to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable psychopharmaceutical agent concentrations.
  • Kits may be provided with different concentrations of release modifier in component (b2) and/or different volumes of kit component (b2) may be combined, contacted, or otherwise brought together with kit component (a2) to generate different pharmaceutical formulations with differentiated release characteristics and psychopharmaceutical agent concentrations.
  • Kits may be provided with different amounts of psychopharmaceutical agent in solid form in component (a2) to generate different pharmaceutical formulations with differentiated unit doses and psychopharmaceutical agent concentrations.
  • kit component (b2) with the solid dosage form of the psychopharmaceutical agent in kit component (a2) can be accurately described as an act of reconstituting the solid dosage form of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form and in some case in crystalline solid form). Reconstitution may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • a tryptamine psychedelic such as a a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the kit may include instructions for what volume of kit component (b2) can be combined, contacted, or otherwise brought together with kit component (a2) to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc.
  • kits component (a1), kit component (b1), kit component (b2) may optionally contain one or more pharmaceutically acceptable additives, as desired/needed, such as water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • pharmaceutically acceptable additives such as water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • the aqueous vehicle is made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • the aqueous vehicle is made up of water for injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent.
  • the aqueous vehicle is made up of water or saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle is formulated without a buffering agent.
  • the aqueous vehicle used in one or more of kit components (a1), (a2), and/or (b2), independent of one another, is water, such as water for injection (WFI).
  • WFI water for injection
  • the aqueous vehicle used in one or more of kit components (a1), (a2), and/or (b2), independent of one another comprises sodium chloride at a concentration, in terms of weight per volume expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 1.5%, about 0.2% to about 1%, about 0.3% to about 0.5% w/v.
  • a pH adjustment may be performed with a pH adjusting agent on one or more of kit component (a1), kit component (b1), and/or kit component (b2).
  • a pH adjustment may be performed with a pH adjusting agent on one or more of kit component (a1), kit component (b1), and/or kit component (b2) prior to combining, contacting, or otherwise bringing together the respective kit components (kit components (a1) with (b1) or kit components (a2) with (b2)).
  • a pH adjustment may be performed with a pH adjusting agent to generate the final pharmaceutical formulation.
  • the kit may optionally comprise (c) a pH adjusting agent.
  • the pH adjusting agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • the pH adjustment involves increasing the pH, and so kit component (c) comprises a suitable base as pH adjusting agent, for example one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide.
  • the pH is adjusted with sodium hydroxide or potassium hydroxide, for example to generate the final pharmaceutical formulation.
  • the pharmaceutical formulation does not contain a buffering agent.
  • Preparative methods Also disclosed herein is a method for preparing the pharmaceutical formulation of the present disclosure, the pharmaceutical formulation being suitable for injection.
  • the method comprises contacting a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the contacting of the method may be conducted in a variety of ways, including through the use of conventional techniques known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy).
  • the method for preparing the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the psychopharmaceutical agent is a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III).
  • the method involves reconstituting a pre-formed, typically solid form and in some cases crystalline solid form of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) in an aqueous vehicle.
  • the method involves contacting a solution comprising a pharmaceutically acceptable salt of a compound of Formula (I) through (III) in an aqueous vehicle with a release modifier in solid form or as a solution in an aqueous vehicle.
  • the method may involve contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the compounds of the present disclosure, thereby forming the pharmaceutically acceptable salt of a compound of Formula (I) through (III) in-situ.
  • the method may comprise contacting a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle from components of a kit intended to be combined, contacted, or otherwise brought together.
  • the method comprises contacting (a1) a first solution comprising a psychopharmaceutical agent and an aqueous vehicle, with (b1) a second solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt and an aqueous vehicle.
  • a1) the first solution comprises (as psychopharmaceutical agent) a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III).
  • the (a1) first solution may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)) by contacting the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure with aqueous vehicle.
  • the first solution may be prepared by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the free base to form the pharmaceutically acceptable salt of a compound of the present disclosure within (a1) the first solution in-situ.
  • the first solution comprises a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of first solution of about 0.1 mg/mL, about 0.4 mg/mL, about 0.6 mg/mL, about 0.8 mg/mL, about 1 mg/mL, about 1.2 mg/mL, about 1.4 mg/mL, about 1.6 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 32 mg/m
  • the second solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.
  • the second solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.6% to about 2%, about 0.7% to about 1.8%, about 0.8% to about 1.7%, about 0.9% to about 1.6%, about 1% to about 1.5%.
  • a suitable volume of each of the first solution (a1) and the second solution (b1) may be contacted to generate the pharmaceutical formulation with suitable physiochemical and controlled- release characteristics, as well as suitable unit doses and psychopharmaceutical agent concentrations.
  • suitable physiochemical and controlled- release characteristics as well as suitable unit doses and psychopharmaceutical agent concentrations.
  • Different concentrations of psychopharmaceutical agent in (a1) the first solution, different concentrations of release modifier in (b1) the second solution, and/or different volume ratios of (a1) the first solution to (b1) the second solution may be contacted to generate different pharmaceutical formulations with differentiated release characteristics, unit doses, and/or psychopharmaceutical agent concentrations.
  • the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, unit dose, psychopharmaceutical agent concentration, release modifier, and release characteristics, by combining different volume ratios of (a1) the first solution to (b1) the second solution.
  • a suitable volume ratio of (a1) the first solution to (b1) the second solution used to generate the pharmaceutical formulation may be from about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range therebetween, such as from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1:1.
  • the contacting of (a1) the first solution to (b1) the second solution to generate the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the method may involve following instructions for what volume ratios of (a1) : (b1) can be used to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc.
  • the method involves contacting (a2) a psychopharmaceutical agent in solid form with (b2) a solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the psychopharmaceutical agent is a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form.
  • any pre-formed, solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) of the present disclosure can be used as (a2).
  • the solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to about 0.75%, or about 0.25% to about 0.5%.
  • the solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%.
  • a suitable volume of (b2) the solution may be contacted with (a2) the psychopharmaceutical agent in solid form to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable psychopharmaceutical agent concentrations.
  • Different concentrations of release modifier in (b2) the solution and/or different volumes of (b2) the solution may be contacted with (a2) the psychopharmaceutical agent in solid form to generate different pharmaceutical formulations with differentiated release characteristics and psychopharmaceutical agent concentrations.
  • the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, psychopharmaceutical agent concentration, etc., by contacting different volumes of (b2) the solution with (a2) the psychopharmaceutical agent in solid form. Further, different amounts of (a2) the psychopharmaceutical agent in solid form may be used to generate different pharmaceutical formulations with differentiated unit doses and psychopharmaceutical agent concentrations.
  • the contacting of (b2) the solution with (a2) the solid dosage form of the psychopharmaceutical agent can be accurately described as an act of reconstituting the solid dosage form of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form and in some case in crystalline solid form). Reconstitution may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the method may involve following instructions for what volume of (b2) the solution can be contacted with (a2) the psychopharmaceutical agent in solid form to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc.
  • the aqueous vehicle used in any of (a1) the first solution, (b1) the second solution, and/or (b2) the solution may optionally contain one or more pharmaceutically acceptable additives, as desired/needed, such as water-miscible vehicles, non- aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • one or more pharmaceutically acceptable additives such as water-miscible vehicles, non- aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • the aqueous vehicle is made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • the aqueous vehicle is made up of water, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent.
  • the aqueous vehicle is made up of water or saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle is formulated without a buffering agent.
  • the aqueous vehicle used in one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution, independent of one another, is water, such as water for injection (WFI).
  • WFI water for injection
  • the aqueous vehicle used in one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution, independent of one another comprises sodium chloride at a concentration, in terms of weight per volume expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 1.5%, about 0.2% to about 1%, about 0.3% to about 0.5% w/v.
  • a pH adjustment may be performed with a pH adjusting agent on one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution.
  • a pH adjustment may be performed with a pH adjusting agent on one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution prior to contacting (a1) the first solution with (b1) the second solution or (a2) the psychopharmaceutical agent in solid form with (b2) the solution.
  • the method may comprise adjusting the pH with a pH adjusting agent to generate the final pharmaceutical formulation.
  • the kit may optionally comprise (c) a pH adjusting agent.
  • the pH adjusting agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • the adjusting of the pH involves increasing the pH, and so (c) comprises a suitable base as pH adjusting agent, for example one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide.
  • the pH is adjusted with sodium hydroxide or potassium hydroxide, for example to generate the final pharmaceutical formulation.
  • the pharmaceutical formulation does not contain a buffering agent.
  • the pharmaceutical formulations of the present disclosure must be sterile, as known and practiced in the art.
  • the method of the present disclosure may optionally comprise sterilizing the pharmaceutical formulation, for example as a final preparative step.
  • the method may optionally comprise sterilizing any one or more (including all) components used to prepare the pharmaceutical formulation, such as (a1) the first solution, (b1) the second solution, (a2) the psychopharmaceutical agent in solid form, and/or (b2) the solution.
  • the method may optionally comprise sterilizing any one or more (including all) components used to prepare the pharmaceutical formulation, such as (a1) the first solution, (b1) the second solution, (a2) the psychopharmaceutical agent in solid form, and/or (b2) the solution, and optionally sterilizing the pharmaceutical formulation, for example as a final preparative step.
  • sterilization may be carried out by steam sterilization, dry-heat sterilization/depyrogenation, gas sterilization, sterilization by ionizing radiation, sterilization by filtration, or unidirectional aseptic processing, for example according to the requirements set forth in USP Sterilization and Sterility Assurance of Compendial Articles ⁇ 1211> and/or USP Sterility Tests ⁇ 71>.
  • the release modifier employed is a hyaluronate salt
  • sterile filtration is used.
  • sterile filtration is usually carried out with assemblies having membranes of nominal pore size rating of 0.2 ⁇ m or less or 0.1 ⁇ m or less, according to the requirements set forth in USP Sterilization and Sterility Assurance of Compendial Articles ⁇ 1211>.
  • Sterile filtration may be carried out by passing the pharmaceutical formulation (or various components making up the pharmaceutical formulation, separately) through a membrane, a syringe filter, a vacuum device, a capsule assembly, a high pressure cartridge or filter assembly, and the like, each equipped with a suitable membrane, typically a membrane which is capable of passing a bacterial challenge to retain a minimum of 10 7 CFU/cm 2 of B.dimunita.
  • membranes include, but are not limited to, those made from polyethersulfone (PES), polyvinylidene fluoride (PVDF), cellulose, cellulose acetate, mixed cellulose esters (MCE), nylon, and hydrophilic polytetrafluoroethylene (PTFE).
  • PES polyethersulfone
  • PVDF polyvinylidene fluoride
  • MCE mixed cellulose esters
  • PTFE hydrophilic polytetrafluoroethylene
  • the preparative method for producing the pharmaceutical formulation may not involve any sterilization processing, and instead the method involves assembly of already sterilized components.
  • the various kit components to be assembled e.g., (a1) the first solution with (b1) the second solution, or (a2) the psychopharmaceutical agent in solid form with (b2) the solution
  • the various kit components to be assembled may be provided in sterilized form, where appropriate.
  • the pharmaceutical formulations disclosed herein may be formulated for single or multiple dosage administration.
  • the pharmaceutical formulation may be optionally stored and/or packaged in any suitable container, examples of which include, but are not limited to, an ampule, a vial, a syringe such as a pre-filled syringe, a cartridge, a reservoir or cartridge for an injection device such as an on-body drug delivery device or an auto-injector, etc.
  • the pharmaceutical formulation is stored and/or packaged in a container adapted to prevent penetration of ultraviolet light, such as amber glass vial.
  • the container within which the pharmaceutical formulation is stored and/or packaged is not so adapted (and may be, for example, made of clear glass) with protection against ultraviolet light, if desired, provided by secondary packaging (for example packaging within which the receptacle containing the pharmaceutical formulation may be placed).
  • secondary packaging for example packaging within which the receptacle containing the pharmaceutical formulation may be placed.
  • the container is airtight and the pharmaceutical formulation is stored under an inert atmosphere, such as under nitrogen or argon, typically nitrogen.
  • the formulation may be stored at room temperature, e.g., at about 20 to about 30°C, or at cooler temperatures, for example at about 2 to about 8°C.
  • the pharmaceutical formulation may be stored in a freezer. Further, tamper resistant dosage forms/packaging of any of the disclosed pharmaceutical formulations are contemplated.
  • Therapeutic applications and methods Also disclosed herein is a method of treating a disease or disorder such as a mental disorder in a subject (e.g., a companion animal) in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of the present disclosure.
  • the mental disorder may be associated with a 5-HT2 receptor, namely an anxiety disorder and/or a depressive disorder.
  • the pharmaceutical formulation is suitable for injection, thus its administration in therapy typically comprises parenteral administration via injection to affect a beneficial therapeutic response.
  • Injection may involve administration through a needle (hypodermic needle), microneedles including hollow microneedles, or using a needle-free injection system whereby a fine, high velocity jet is generated by driving liquid through an orifice at high pressure to pierce the skin and underlying tissue.
  • the method comprises administering the pharmaceutical formulation intravenously to the subject (directly into the vein).
  • the method comprises administering the pharmaceutical formulation intramuscularly to the subject (within the muscle).
  • the method comprises administering the pharmaceutical formulation intradermally to the subject (beneath the skin).
  • the method comprises administering the pharmaceutical formulation subcutaneously to the subject (within the fat or the layer of skin directly below the dermis and epidermis).
  • Subcutaneous administration is a minimally invasive mode of administration.
  • Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of depot effect. Compared with other routes of administration, it is slower than intravenous and intramuscular injections but still faster than intradermal injections. The convenience and speed of subcutaneous delivery allows increased compliance and quicker access to medication when needed.
  • Subcutaneous administration can be performed by injection or by implantation of a sustained or timed-release device beneath the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed. When a subject requires multiple doses, the method may involve subcutaneously injecting several unit dose pharmaceutical formulations at multiple sites of the body surface.
  • a particular advantage of the subcutaneous delivery route in the therapeutic methods of the present disclosure is that it allows the medical practitioner/veterinarian to perform the administration in a rather short intervention with the patient, compared to intravenous infusion protocols associated with DMT-based therapy. Moreover, in the case of companion animal treatment, the owner of the companion animal can be trained to perform administration, e.g., at home.
  • the injection volume of the pharmaceutical formulation administered is usually about 50 mL or less, such as about 0.1 mL, about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, or any range therebetween.
  • the injection volume of the pharmaceutical formulation administered is usually about 100 mL or less, such as about 0.1 mL, about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, about 100 mL, or any range therebetween.
  • the injection volume of the pharmaceutical formulation administered is usually about 10 mL or less, such as about 0.1 mL, about 0.2 mL, about 0.4 mL, about 0.6 mL, about 0.8 mL, about 1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 4.5 mL, about 5 mL, about 5.5 mL, about 6 mL, about 6.5 mL, about 7 mL, about 7.5 mL, about 8 mL, about 8.5 mL, about 9 mL, about 9.5 mL, about 10 mL, or any range therebetween.
  • the method comprises administering the pharmaceutical formulation as a bolus injection, in which a discrete amount of psychopharmaceutical agent (e.g., tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) is administered by injection within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less, or any range therebetween.
  • a discrete amount of psychopharmaceutical agent e.g., tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the bolus injection may involve a single injection or multiple injections performed within the above-described time range. Thus, administering multiple bolus injections within the above-mentioned time range of 30 minutes or less (e.g., two injections lasting 30 seconds each, administered within 5 minutes of one another) would be considered a bolus administration herein.
  • the bolus injection involves a single injection within the above time range.
  • the method comprises administering the pharmaceutical formulation as a bolus subcutaneous injection, such as a single bolus subcutaneous injection.
  • the method comprises administering the pharmaceutical formulation as a bolus intramuscular injection, such as a single bolus intramuscular injection.
  • the method comprises administering the pharmaceutical formulation as a bolus intradermal injection, such as a single bolus intradermal injection. In some embodiments, the method comprises administering the pharmaceutical formulation as a bolus intravenous injection, such as a single bolus intravenous injection.
  • the method comprises administering the pharmaceutical formulation as an infusion injection, in which a discrete amount of psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) is administered by injection over a prolonged period of greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, greater than 110 minutes, greater than 120 minutes, etc.
  • the infusion injection may involve a single prolonged injection, or multiple injections (short or prolonged) within the above-described time range.
  • the infusion injection involves a single injection within the above time range.
  • the method comprises administering the pharmaceutical formulation as an infusion subcutaneous injection.
  • the method comprises administering the pharmaceutical formulation as infusion intramuscular injection.
  • the method comprises administering the pharmaceutical formulation as infusion intravenous injection.
  • injection devices that enables administration of the pharmaceutical formulation through the skin or other external boundary tissue of the subject may be used in the disclosed methods.
  • injection devices include, but are not limited to, needle and syringe, pre- filled syringe, canula, catheter, pen, auto-injector (e.g., ACTpen®, ArQ® - Bios from Oval Medical Technologies), semi-auto injector (such as those from UnionMedico®) on-body drug delivery devices (e.g., patches, pumps, those with automatic needle insertion/retraction, belt worn devices, such as those available from Gerresheimer AG, etc.), implants, embedded needle tip devices, a needle-free injection system (e.g., a jet injector), automatic injection devices, or other suitable injection device.
  • auto-injector e.g., ACTpen®, ArQ® - Bios from Oval Medical Technologies
  • semi-auto injector such as those from UnionMedico®
  • on-body drug delivery devices e.g., patches, pumps,
  • the injection device may be resuable or disposable (e.g., disposable hypodermic needle and syringe, disposable pen, disposable pump, disposable on-body drug delivery device, etc.), or may contain a reusable or disposable needle guide.
  • the injection device may be actuated manually or automatically.
  • Some automatic injection devices may be configured with automatic needle insertion/retraction, auto-pumps, or one or more microneedles, which in some embodiments may be coated with a pharmaceutical formulation disclosed herein.
  • hollow microneedles may be used to provide a fluid channel for delivery of the disclosed pharmaceutical formulations below the outer layer of the skin to improve delivery.
  • needle-free injection systems e.g., a jet injector
  • a fine, high velocity jet is generated by driving liquid through an orifice at high pressure to pierce the skin and underlying tissue.
  • These needle-free injection systems may include those adapted with spring systems, lasers, or energy propelled systems such as Lorentz force, gas propelled/air forced, or shove wave driven devices.
  • Examples of needle-free injection devices include, but are not limited to, Bioject® jet injectors such as Biojector® 2000, Viajet 3, DoseProTM, ZetaJetTM, Stratis® IM/SC, and Jupiter JetTM.
  • Multi- component injections such as using a dual chamber syringe or a multi-syringe (e.g., two syringe) set up, may also be performed.
  • the injection device can be optionally manufactured with smart technology enabling remote activation and/or control of delivery.
  • the remote activation can be performed via computer or mobile app.
  • the remote activation device can be password encoded. This technology enables a provider to perform telehealth sessions, during which the provider can remotely activate and administer the pharmaceutical formulation via the desired delivery device while supervising the subject on the televisit.
  • Subcutaneous injections may be performed by cleaning the area to be injected followed by an injection, usually at about a 45-degree angle to the skin when using a syringe and needle, or at about a 90-degree angle (perpendicular) if using an injector pen or other suitable injector device.
  • the appropriate injection angle is based on the length of needle or injection device used, and the depth of the subcutaneous fat in the skin of the subject receiving the treatment. If administered at an angle, the skin and underlying tissue may be pinched upwards prior to injection (the “pinch-up” technique).
  • Subcutaneous injection may be administered, inter alia, in the subject’s back of the neck region, the upper area of the buttock, just behind the hip bone, and the like.
  • injection site is based on the pharmaceutical formulation being administered, for example taking into account the volume of injection needed, as well as preference. Injections administered frequently or repeatedly should be administered in a different location each time, either within the same general site or a different site, but at least one inch away from recent injections as known and practiced in the art. In most cases, subcutaneous injections can be easily performed by people with minor skill and training required.
  • Administration may follow a continuous administration schedule, or an intermittent administration schedule.
  • the administration schedule may be varied depending on the psychopharmaceutical agent employed, the condition being treated, etc.
  • administration may be performed once a day (QD), or in divided dosages throughout the day, such as 2-times a day (BID), 3 -times a day (TID), 4-times a day (QID), or more.
  • administration may be performed nightly (QHS).
  • the pharmaceutical formulation may be administered as needed (PRN).
  • Administration may also be performed on a weekly basis, e.g., once a week, twice a week, three times a week, four times a week, every other week, every two weeks, etc., or less.
  • the pharmaceutical formulation may be administered monthly, for example, once monthly dosing or dosing every two months.
  • the administration schedule may also designate a defined number of treatments per treatment course, for example, administration may be performed 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, or 8 times per treatment course. Other administration schedules may also be deemed appropriate using sound medical judgement.
  • the dosing can be continuous (7 days of administration in a week) or intermittent, for example, depending on the pharmacokinetics and a particular subject’s clearance/accumulation of the psychopharmaceutical agent. If intermittently, the schedule may be, for example, 4 days of administration and 3 days off (rest days) in a week or any other intermittent dosing schedule deemed appropriate using sound medical judgement. For example, intermittent dosing may involve administration of a single dose within a treatment course. The dosing whether continuous or intermittent is continued for a particular treatment course, typically at least a 28-day cycle (1 month), which can be repeated with or without a drug holiday.
  • Longer or shorter courses can also be used such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 days, or longer, or any range therebetween.
  • the course may be repeated without a drug holiday or with a drug holiday depending upon the subject.
  • Other schedules are possible depending upon the presence or absence of adverse events, response to the treatment, convenience, and the like.
  • the dosage and frequency (single or multiple doses) of administration can vary depending upon a variety of factors, including, but not limited to, the psychopharmaceutical agent to be administered; the disease/condition being treated; route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.
  • the pharmaceutical formulation comprises a therapeutically effective amount of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), i.e., an amount that is sufficient to reduce or halt the rate of progression of the disease or disorder, to ameliorate or cure the disease or disorder and thus produce the desired therapeutic or inhibitory effect, or to alleviate one or more symptoms of the disease or disorder.
  • the dosage can be adjusted by monitoring response to the treatment and adjusting the dosage upwards or downwards.
  • Dosages may be varied depending upon the requirements of the subject and the psychopharmaceutical agent being employed.
  • the dose administered to a subject should be sufficient to effect a beneficial therapeutic response in the subject over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.
  • treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the subject’s disease state.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity or adverse side effects (e.g., caused by sedative or psychotomimetic toxic spikes in plasma concentration of any of the psychopharmaceutical agents), and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of psychopharmaceutical agent by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.
  • a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) provided by the pharmaceutical formulation is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about
  • a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) in dogs is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween.
  • a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) in cats is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween.
  • a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) in horses is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, or any range therebetween.
  • the pharmaceutical formulation comprises a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent, and a therapeutically effective amount may be a psychedelic dose.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • a therapeutically effective amount may be a psychedelic dose.
  • a psychedelic dose (therapeutically effective amount) in dogs in terms of weight-based dosing (free base equivalence) may in some embodiments be about 0.5 mg/kg, about 0.55 mg/kg, about 0.6 mg/kg, about 0.65 mg/kg, about 0.7 mg/kg, about 0.75 mg/kg, about 0.8 mg/kg, about 0.85 mg/kg, about 0.9 mg/kg, about 0.95 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3.0 mg/kg,
  • a psychedelic dose (therapeutically effective amount) in cats in terms of weight-based dosing (free base equivalence) may in some embodiments be about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween.
  • a psychedelic dose (therapeutically effective amount) in horses in terms of weight- based dosing (free base equivalence) may in some embodiments be about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, or any range therebetween.
  • a psychedelic dose (therapeutically effective amount) of a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) (free base equivalence) may in some embodiments be about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 300 mg, or any range therebetween, such as from about 15 mg to about 150 mg,
  • a fixed psychedelic dose (free base equivalence) in dogs may in some embodiments be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, or any range therebetween.
  • a fixed psychedelic dose (free base equivalence) in cats may in some embodiments be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg., or any range therebetween.
  • a fixed psychedelic dose (free base equivalence) in horses may in some embodiments be about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 300 mg, or any range therebetween.
  • compositions comprising a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent in sub-psychedelic (yet still potentially serotonergic concentrations) doses may be performed in some embodiments to achieve durable therapeutic benefits, with decreased toxicity, and may thus be suitable for microdosing.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • sub-psychedelic et still potentially serotonergic concentrations
  • Sub-psychedelic dosing in dogs may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), in terms of free base equivalence, in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, or about less than 0.5 mg/kg, or any range therebetween.
  • Sub-psychedelic dosing in cats may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), in terms of free base equivalence, in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, or about less than 0.4 mg/kg, or any range therebetween.
  • Sub-psychedelic dosing in horses may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), in terms of free base equivalence, in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about less than 0.1 mg/kg.
  • the tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III
  • sub- psychedelic doses are administered up to every day, for a treatment course (e.g., 1 month).
  • a treatment course e.g. 1 month
  • doses at sub-psychedelic doses dosing can be less frequent or more frequent as deemed appropriate.
  • Courses can be repeated as necessary, with or without a drug holiday.
  • Sub-psychedelic doses can be used, e.g., for the chronic treatment or maintenance of a variety of diseases or disorders disclosed herein.
  • a “maintenance regimen” generally refers to the administration of a psychopharmaceutical agent following achievement of a target dose, e.g., following completion of an up-titration regimen, and/or following a positive clinical response, e.g., improvement of the patient's condition, either to the same agent or to a different agent.
  • the maintenance dose may be used to ‘maintain’ the therapeutic response and/or to prevent occurrences of relapse.
  • the maintenance dose may be at or below the therapeutic dose.
  • the maintenance dose is a psychedelic dose.
  • the maintenance dose is a sub-psychedelic dose.
  • dosing is carried out daily or intermittently for the maintenance regimen, however, maintenance regimens can also be carried out continuously, for example, over several days, weeks, months, or years.
  • the maintenance dose may be given to a patient over a long period of time, even chronically.
  • a maintenance regimen is dosed monthly, e.g., once a month, once every two months, etc.
  • the methods provided herein may be used to treat a disease or disorder, such as a mental disorder, in a subject (e.g., companion animal) in need thereof.
  • a disease or disorder such as a mental disorder
  • the disease or disorder may be associated with a serotonin 5-HT2 receptor.
  • the mental disorder is central nervous system (CNS) disorder and/or psychological disorder.
  • the mental disorder is an anxiety disorder, a depressive disorder, or both.
  • the disease or disorder is an anxiety disorder.
  • anxiety disorder refers to a state of apprehension, uncertainty, and/or fear resulting from the anticipation of an event and/or situation.
  • Anxiety disorders cause physiological and psychological signs or symptoms. Non-limiting examples of signs or symptoms include trembling, hiding, attempts to leave or escape, compulsive licking or grooming, self-injuring, diarrhea or vomiting, depression, drooling, panting, reduced activity, destructive behavior, frantic vocalization (e.g., barking, whimpering, whining, crying, yowling, howling, meowing, etc.), housebreaking accidents, not eating or exercising, pacing, restlessness, aggression, etc.
  • Anxiety disorders may increase a subject’s stress levels, and impair their immune response and overall health.
  • the methods disclosed herein treat chronic anxiety disorders.
  • a “chronic” anxiety disorder is recurring.
  • the methods disclosed herein treat transient anxiety episodes. Examples of anxiety disorders include, but are not limited to, separation anxiety, social anxiety, a phobia-related disorder (e.g., a noise phobia), a compulsive disorder such as obsessive-compulsive disorder (OCD), age-related anxiety, etc.
  • OCD obsessive-compulsive disorder
  • the anxiety disorder can develop at any age, and in any animal breed.
  • the subject in need thereof has always harbored an anxiety disorder, i.e., the anxiety was not driven by a particular event.
  • an anxiety disorder comprises a medical diagnosis based on an independent medical or veterinary evaluation.
  • an anxiety disorder comprises a medical or veterinary diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., published by the American Psychiatric Association, or in International Classification of Diseases (ICD), published by the World Health Organization.
  • the disease or disorder is separation anxiety.
  • separation anxiety is a disorder that causes the subject (e.g., a companion animal) to panic when they suspect they will be left alone or when they are in fact left alone. Generally, separation anxiety results in extreme stress from the time an owner or caregiver leaves until they return.
  • Subjects with separation anxiety often demonstrate signs such as destructive behavior (e.g., chewing household items like shoes, furniture, etc., getting into the trash, destroying or damaging their shelter, housing, doors or other household items etc.), frantic vocalization (e.g., barking, whimpering, whining, crying, yowling, howling, meowing, etc.), housebreaking accidents (e.g., urinating and/or defecating), excessive salivation, drooling, or panting, desperate and prolonged attempts to escape confinement, potentially ending in serious injury, etc.
  • at least one sign or symptom of separation anxiety is improved following treatment disclosed herein.
  • treating according to the methods of disclosure reduces or ameliorates a sign or symptom of separation anxiety. In some embodiments, after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the disease or disorder is social anxiety.
  • social anxiety is a marked fear or anxiety about one or more social situations. Subjects often develop social anxiety when they have previously experienced neglect; for instance, dogs who have been rescued from puppy mills, were strays, or have experienced situations of abuse or neglect. This social condition can cause subjects to experience crippling anxiety when being around other animals or humans and can even lead to aggression.
  • an animal that has experienced abuse from a male human may suffer from social anxiety around male humans.
  • an animal that has been attacked by another animal e.g., a dog
  • Non-limiting examples of signs or symptoms include trembling, hiding, attempts to leave or escape, diarrhea or vomiting, reduced activity, frantic vocalization (e.g., barking, whimpering, whining, crying, yowling, howling, meowing, etc.), housebreaking accidents, not eating or exercising, etc.
  • at least one sign or symptom of social anxiety is improved following treatment disclosed herein.
  • treating according to the methods of disclosure reduces or ameliorates a sign or symptom of social anxiety.
  • the sign or symptom after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the disease or disorder is a phobia-related disorder.
  • phobia-related disorder is an excessive fear or anxiety brought about by a specific stimulus.
  • a non-limiting example of a phobia-related disorder is a noise phobia (noise anxiety), wherein the subject has an irrational, intense, and/or persistent fear of a noise or sound that may cause the subject to avoid or escape from the noise or sound.
  • noise or sound stimuli that may provoke the fear response include thunderstorms (e.g., thunder), fireworks, loud voices or shouting, sirens or alert systems (e.g., fire engines, storm sirens, etc.), or other loud noises.
  • a phobia-related disorder include phobias to strange people or animals, visual stimuli like hats or umbrellas, new or strange environments in specific situations like the veterinarian office or car rides, or surfaces like grass or wood floors. Although some animals may only have brief reactions to these kinds of stimuli, they may affect anxious animals more consequentially.
  • the phobia can develop at any age, and in any animal breed. Animals (e.g., companion animals) suffering from a phobia-related disorder may show similar signs to those with social or separation anxiety, non-limiting examples of signs or symptoms include trembling, hiding, attempts to leave or escape, diarrhea or vomiting, reduced activity, frantic vocalization (e.g., barking), housebreaking accidents, not eating or exercising, etc.
  • At least one sign or symptom of a phobia-related disorder is improved following treatment disclosed herein.
  • treating according to the methods of disclosure reduces or ameliorates a sign or symptom of phobia-related disorder.
  • after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the disease or disorder is a compulsive disorder, such as obsessive- compulsive disorder (OCD).
  • OCD obsessive- compulsive disorder
  • CCD canine compulsive disorder
  • Subjects experiencing OCD may excessively repeat certain obsessive behaviors, non-limiting examples of which include sucking on their flanks or a toy, acral lick dermatitis (incessant licking or grooming), pacing, spinning, and tail chasing, freezing and staring, digging, biting objects such as biting a food dish or bowl, snapping at flies or invisible items, unabated and patterned vocalization, excessive drinking of water or eating dirt, etc. When performed in an extreme, repetitive way, these behaviors may interfere with the subject’s ability to function.
  • at least one sign or symptom of a compulsive disorder is improved following treatment disclosed herein.
  • treating according to the methods of disclosure reduces or ameliorates a sign or symptom of a compulsive disorder.
  • after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the disease or disorder is age-related anxiety.
  • age-related anxiety is an anxiety brought about by a decline in memory, learning, perception, and/or awareness in older animals.
  • Age-related anxiety affects older animals and can be associated with cognitive dysfunction syndrome (CDS).
  • CDS cognitive dysfunction syndrome
  • Non-limiting examples of signs or symptoms include trembling, hiding, urinating or defecating in the house, reduced activity, depression, not eating or exercising, etc.
  • at least one sign or symptom of age-related anxiety is improved following treatment disclosed herein.
  • treating according to the methods of disclosure reduces or ameliorates a sign or symptom of age- related anxiety.
  • the sign or symptom after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • a sign or symptom of an anxiety disorder is measured according to an assessment by a clinician/veterinarian or caregiver, or a clinical scale.
  • treating according to the methods of the disclosure results in an improvement in an anxiety disorder compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the assessments by a clinician/veterinarian or caregiver, or clinical scales, described herein or known in the art.
  • the methods provided herein are used to treat a subject with a depressive disorder.
  • depressive disorder or “depression” refer to a mood disorder characterized by low mood or loss of interest that can affect behavior, feelings, and well-being lasting for a period of time.
  • Non-limiting examples of signs or symptoms of depression include a marked change in appetite, which may involve eating less and losing weight in some instances, or eating more and gaining weight in other instances; lethargy or changes in sleep habits such as a change from routine napping to excessive napping; general loss of interest, such as loss of interest in toys, treats, food, car rides, physical affection such as petting, or other previously enjoyed activities or objects; excessive grooming or licking, which in the case of dogs for example can indicate distress or unhappiness and an attempt to self-soothe; avoidance and hiding such as under beds, sofas, tables, etc.; increased demand in attend on/affecti on from caregivers; a change in vocalization (e.g., increased meowing, barking, howling, etc.); unusually aggressive behavior; housebreaking accidents, etc.
  • a marked change in appetite which may involve eating less and losing weight in some instances, or eating more and gaining weight in other instances
  • lethargy or changes in sleep habits such as a change from routine napping to excessive nap
  • the depressive disorder disrupts the physical and psychological functions of a subject.
  • the depressive disorder causes a physical symptom such as weight loss, aches or pains, or digestive problems.
  • the depressive disorder causes a psychological symptom such as persistent sadness, anxiety, feelings of hopelessness and irritability, loss of interest or pleasure in activities, etc.
  • the depressive disorder is acute.
  • the depressive disorder is chronic.
  • a depressive disorder comprises a medical diagnosis based on an independent medical or veterinary evaluation.
  • a depressive disorder comprises a medical or veterinary diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., published by the American Psychiatric Association, or in International Classification of Diseases (ICD), published by the World Health Organization.
  • the depressive disorder is caused by environmental changes.
  • the subject may become sad or depressed after a stay in a kennel or boarding facility, adoption or arrival of a new animal or pet in the household, a change in caregiver routine such as a new job or altered work schedule.
  • a highly distressing event some subjects experience depression and grief. For instance, a subject may experience distress when a household member moves away permanently or when new household members arrive.
  • a subject such as a dog living with children may experience depression once summer ends and the children return to school. Such events could trigger separation anxiety and loneliness as well.
  • a household incorporates new members, such as babies or other pets, subjects may feel excluded if the new member receives more attention.
  • the depressive disorder is caused by changes to the subject’s social group. Dogs are most likely to become depressed due to a significant change in their social group, but this can affect other animals as well. Subjects such as companion animals often have an emotional bond with the other animals/pets they live with, especially if they all get along. When such connections are lost, the subject may experience grief, ultimately resulting in depression.
  • the depressive disorder is caused by boredom or lack of stimulation. Boredom may cause sadness and depression in a subject, which may result in destructive behavior. In some embodiments, the depressive disorder is the result of a fear of phobia. Common fears or phobias include loud noises and separation from their caregiver or family members. The subject may show fear by lip licking, yawning, flattened ears, pacing, destructive behavior, panting, etc. The subject may experience constant anxiety from the fear and phobia, waiting for the following fear-inducing incident, and as a result the subject may become withdrawn and depressed.
  • the depressive disorder is seasonal affective disorder.
  • seasonal affective disorder refers to a condition wherein subject experiences mood changes or a depressive episode during a particular season or time of the year, that does not persist throughout the year.
  • the subject experiences low mood, low energy, or other depressive symptoms during the fall and/or winter season.
  • the subject experiences low mood, low energy, or other depressive symptoms during the spring and/or summer season. Dogs in particular may be most prone to seasonal affective disorder in the wintertime when some of their favorite activities become more difficult.
  • the depressive disorder is caused by poor training methods.
  • dogs that are subjected to punishment-based training methods e.g., positive punishment which administers an unpleasant stimulus for misbehavior, or negative punishment which removes a pleasant incentive for misbehavior
  • punishment-based training methods e.g., positive punishment which administers an unpleasant stimulus for misbehavior, or negative punishment which removes a pleasant incentive for misbehavior
  • the depressive disorder is cause by physical illness or pain. Painful physical conditions in subjects, such as injury or fatigue, may lead to psychological distress. Shaking, aggression, loss of appetite, limping, and whining are all signs that a subject is in pain, which may cause depressive episodes.
  • the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • a sign or symptom of a depressive disorder is measured according to an assessment by a clinician/veterinarian or caregiver, or a clinical scale.
  • treating according to the methods of the disclosure results in an improvement in a depressive disorder compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the assessments by a clinician/veterinarian or caregiver, or clinical scales, described herein or known in the art.
  • the disease or disorder is attention deficit hyperactivity disorder (ADHD).
  • ADHD is marked by an ongoing pattern of inattention and/or hyperactivity -impulsivity.
  • Hyperactivity-impulsivity symptoms may often include, but are not limited to, fidgeting or squirming, leaving situations where staying seated is expected, running, dashing, or climbing around at inappropriate times, being unable to engage in activities quietly, being constantly in motion, and vocalizing (e.g., barking) excessively.
  • About 12 to 15% of dogs exhibit hyperactivity and impulsivity, and about 20% exhibit inattention. These qualities have been found to be highly heritable but also influenced by environmental factors, similar to humans. In canines, young male dogs may be the most likely to display hyperactivity, impulsivity, and inattention. Further, certain breeds of working dog, which have been bred to be highly active such as German Shepherds and Border Collies, may be the most liable to hyperactivity and impulsivity.
  • the methods provided herein are used to manage pain in a subject in need thereof.
  • pain associated with an illness such as cancer pain, e.g., refractory cancer pain; neuropathic pain; postoperative pain; severe chemical or thermal burn injury; sprains, ligament tears, fractures, wounds and other tissue injuries; dental surgery, procedures and maladies; arthritis; autoimmune disease and pain associated therewith; acute nausea, e.g., pain that may be causing the nausea or the abdominal pain that frequently accompanies sever nausea; pain associated with depression, refractory asthma, acute asthma, epilepsy, and acute brain injury and stroke.
  • the pain may be persistent or chronic pain that lasts for weeks to years, in some cases even though the injury or illness that caused the pain has healed or gone away, and in some cases despite previous medication and/or treatment.
  • the disclosure includes the treatment/management of any combination of these types of pain or conditions.
  • the disease or disorder is arthritis. Types of arthritis include osteoarthritis, rheumatoid arthritis, gout, and lupus. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is gout. In some embodiments, the disease or disorder is lupus.
  • the administering physician or caregiver can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of administration on the basis of observations of one or more symptoms of the disorder or condition being treated.
  • the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a companion animal, including but not limited to, a dog, a cat, a horse, a rabbit, a ferret, a bird, a guinea pig, livestock (e.g., cattle, sheep, pigs, goats, donkeys, mules, etc.). In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a cat. In some embodiments, the companion animal is a horse.
  • the pharmaceutical formulations of the present disclosure may be used as a standalone therapy. In some embodiments, the pharmaceutical formulations of the present disclosure may be used as an adjuvant/combination therapy. In some embodiments, the subject with a disorder is administered a pharmaceutical formulation of the present disclosure and at least one additional therapy and/or therapeutic. In some embodiments, administration of an additional therapy and/or therapeutic is prior to administration of the pharmaceutical formulation of the present disclosure. In some embodiments, administration of an additional therapy and/or therapeutic is after administration of the pharmaceutical formulation of the present disclosure. In some embodiments, administration of an additional therapy and/or therapeutic is concurrent with administration of the pharmaceutical formulation of the present disclosure.
  • the pharmaceutical formulation comprises a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent
  • the additional therapy is an antidepressant, an anticonvulsant, an antipsychotic, an anxiolytic, an anti-inflammatory drug, a benzodiazepine, an analgesic drug, a cardiovascular drug, an opioid antagonist, or combinations thereof.
  • compositions and methods are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the compositions and methods are also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
  • salt forms are prepared by crystallization of 1-2 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol.
  • the salt form identifier and salt type are provided in Table 3.
  • salt forms are prepared by crystallization of 1-6 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol.
  • the salt form identifier and salt type are provided in Table 4.
  • salt forms of were prepared by crystallization of 1-1 (free base) with stoichiometric (1.0 molar equivalent) quantities, or with sub-stoichiometric (0.5 molar equivalents) quantities in the case of hemi-salts, of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, or glycolic acid), from ethanol.
  • the salt form identifier and salt type are provided in Table 5.
  • salt forms are prepared by crystallization of 1-4 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol.
  • the salt form identifier and salt type are provided in Table 6. Table 6.
  • salt forms are prepared by crystallization of 1-5 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol.
  • the salt form identifier and salt type are provided in Table 7.
  • Lithium aluminum deuteride (LiAlD4)(4.04g, 96.23 mmol, 3.0 eq) was charged in portions over 45 minutes, maintaining the temperature of the reaction mixture ⁇ 40°C. After complete addition, the reaction mixture was heated to 65°C for 16 hours. The batch was cooled to room temperature and completion confirmed by HPLC analysis. A water/THF mixture (35 ml, 5 vol, 1 :9) was added dropwise over 90 minutes, maintaining the temperature ⁇ 30°C. 15% NaOH (aq) (3.5 ml, 0.5 vol) was then added dropwise, followed by further water (10.5 ml, 1.5 vol).
  • I-8a A flask was charged with 15 ml of 1-8 (free base) ethanol solution which was heated to reflux, and a single charge of fumaric acid (1.07g, 1.05 eq) added. After complete dissolution, this was allowed to cool to room temperature, then cooled further to 0°C and filtered, with additional ethanol (3 x 5ml, 3 x 2 vol) used to rinse out the flask and wash the cake.
  • I-8a was isolated as a crystalline solid with a yield of 1.480g (4.71 mmol, 44.6%, 97.0% by LC, J H NMR confirmed identity as 1 : 1 fumarate salt).
  • I-8b A flask was charged with 18 ml of 1-8 (free base) ethanol solution which was heated to reflux, and then benzoic acid (4.04g, 3.15 eq) was added in one charge. After ensuring all solid had dissolved, the solution was cooled in an ice bath and stirred for an additional 60 minutes at this temperature then filtered and further ice cold ethanol (2 x 2 vol) used to rinse out the flask and wash the cake. 2.272g (7.09 mmol) of I-8b was obtained. Due to residual impurities observed in the HPLC analysis of this compound, it was slurried in ethanol (5 ml, 2 vol) for 16 hours.
  • I-8c A flask was charged with 18 ml of 1-8 (free base) ethanol solution which was heated to reflux, and further ethanol (11.7 ml, total 12 vol) and salicylic acid (1.52g, 1.05 eq) was added as a single charge. Once fully dissolved, the solution was cooled to 0°C. The resulting solids were filtered and washed with ice cold ethanol (2 x 2 vol), providing I-8c with a yield of 2.860g (8.50 mmol). Due to residual impurities observed in the HPLC analysis of this compound, it was slurried in ethanol (5ml, 2 vol) for 16 hours.
  • I-8d is prepared analogously by crystallization of I-8 (free base) with a stoichiometric (1.0 molar equivalent) quantity of succinic acid from ethanol.
  • pH was measured by AccumetTM Research Model AR10 pH meter, available from Fisher Scientific.
  • Osmolality Osmolality was measured using Advanced® Micro-Osmometer, Model 3320, from Advanced Instruments.
  • Dialysis — Drug Release Test A 200 mL Erlenmeyer flask containing 100 mL of release medium (0.9% w/v NaCl) was equipped with a magnetic stir bar and placed into a water bath to maintain a release medium temperature of 37°C. The stirring rate was set to 400 rpm. A 1-2 mL volume of test item (formulation or control) was introduced into a Pur-A-LyzerTM Maxi dialysis tube (pore size: 6-8 kDa molecular weight cutoff (MWCO), available from Sigma Aldrich). The dialysis tube was then immersed into the 100 mL of release medium inside the Erlenmeyer flask and a timer was started.
  • MWCO molecular weight cutoff
  • Dissolution medium (0.5 mL) was withdrawn from the Erlenmeyer flask at 10, 20, 30, 45, 60, 90, and 120 minutes for assays, and an equal volume of fresh release medium was used to replace the withdrawn dissolution medium.
  • the time-sampled dissolution medium was assayed by ultra performance liquid chromatography (UPLC) to analyze the drug release of the test item.
  • the percent drug release was then plotted versus time (minutes), and also modelled as a first order kinetic plot. From these plots, the time in minutes required for 25% of drug release (t25%) and 50% of drug release (tso%) were calculated.
  • Ultra Performance Liquid Chromatography Analysis was performed on an Agilent 1100/1200 Quaternary Pump 1 system equipped with a diode array detector UV Diode array 220-269 nm.
  • the UPLC method parameters used for the analysis are presented in Table 10.
  • Formulations and release profiles Formulations and their preparative methods are presented below.
  • the physiochemical properties of the formulations such as pH and osmolality were determined where indicated.
  • Formulations may be presented in terms of the parameters A, B, and C shown in Table 11.
  • the ratio of A:B and the ratio of C:A may also be indicated, rounded to the closest whole number.
  • the ratio of A:B was calculated by dividing parameter A in mg/mL (nominal) by parameter B in % w/v (nominal).
  • the ratio of C: A was calculated by dividing the Mw value in kDa by the parameter A in mg/mL (nominal).
  • Both the ratio of A:B and C:A are written below without the consequent “1” and the ratio symbol (:), for example a ratio of 50: 1 is simply represented as 50.
  • the release profiles of the formulations are also evaluated by the Dialysis — Drug Release Test, including the time in minutes required for 25% of drug release (t25%) and 50% of drug release (t5o%), and the respective percent changes in these values compared to the control (made without release modifier).
  • sodium hyaluronate solutions were made by dissolving a corresponding amount of sodium hyaluronate (750 - 1,000 kDa) (1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, and 7.5 mg, respectively), in water (0.7 mL), followed by incubation at 37°C and stirring. The sodium hyaluronate solutions were then filtered through a 0.22 pm PVDF filter.
  • Solutions of DMT-t/io fumarate were prepared by dissolving 15.85 mg of DMT-t/io fumarate (10 mg free base equivalence of DMT-t/io) in water (0.3 mL), followed by incubation at 37°C and stirring. Each sodium hyaluronate solution was then mixed with the solution of DMT-t/io fumarate, and the resulting formulations were vigorously stirred to ensure complete mixing.
  • a control formulation (10 mg/mL free base equivalence of DMT-t/io, nominal) without release modifier was prepared by diluting the solution of DMT-t/io fumarate with water (0.7 mL). Formulations are shown in Table 12. Table 12.
  • Fig. 3 shows the drug release is highly controlled by the concentration of sodium hyaluronate in the formulation, with the control formulation providing the fastest release, and increasing sodium hyaluronate concentrations providing increasingly slower drug release, with the slowest release provided by the highest sodium hyaluronate content (Formulation 6).
  • formulation 6 To increase osmolality for improved clinical tolerance, these formulations will be remade with an appropriate saline vehicle instead of water without effecting the release profile. Nonetheless, these formulations support the notion that sodium hyaluronate serves as a robust polymer matrix for tunable and controlled-release of drug.
  • formulations were prepared using a fixed sodium hyaluronate concentration (1% w/v, nominal) at 10 mg/mL, 25 mg/mL, and 50 mg/mL free base equivalence of DMT-t/io (nominal).
  • Solutions of DMT-t/io fumarate were prepared by dissolving 15.85 mg of DMT-t/io fumarate (10 mg free base equivalence of DMT-t/w), 39.62 mg of DMT-t/io fumarate (25 mg free base equivalence of DMT-t/w), or 79.25 mg of DMT-t/io fumarate (50 mg free base equivalence of DMT-t/io) in water (0.3 mL), followed by incubation at 37°C and stirring.
  • Sodium hyaluronate solutions were prepared using 10 mg of sodium hyaluronate (750 - 1,000 kDa) and water (0.7 mL), followed by incubation at 37°C and stirring.
  • Figs. 4-6 show the drug release of Formulations 7, 8, and 9, respectively, and that each formulation provided a desirable controlled-release profile at the tested drug loading.
  • Formulations 13-15 made from higher molecular weight sodium hyaluronate, 500 - ⁇ 750 kDa, 750 - 1,000 kDa, and >1,000 - 1,800 kDa, respectively, provided a desirable controlled-release profile, with the highest molecular weight (Formulation 15) providing a nearly 130% increase at each of T25% and Tso% (Figs. 8A and 8B, and Table 16).
  • Solutions of DMT-t/io fumarate were prepared by dissolving 15.85 mg of DMT-t/io fumarate (10 mg free base equivalence of DMT-t/io)in water (0.3 mL), followed by incubation at 37°C and stirring. Each sodium carboxymethyl cellulose solution was then mixed with the solution of DMT-t/io fumarate, and the resulting formulations were vigorously stirred to ensure complete mixing.
  • a control formulation (10 mg/mL free base equivalence of DMT-t/io, nominal) without release modifier was prepared by diluting the solution of DMT-t/io fumarate with water (0.7 mL). Formulations are shown in Table 21.
  • Fig. 11 shows that the release properties from sodium carboxymethyl cellulose formulations was markedly different from sodium hyaluronate-based formulations.
  • the fastest release profile was observed for control and no prominent delayed release effects were achieved with 0.1, 0.2, 0.3, 0.4, or 0.5% w/v (nominal) sodium carboxymethyl cellulose (Formulations 22-26).
  • a delayed effect was only seen with sodium carboxymethyl cellulose loadings higher than 0.5% w/v (nominal), such as 0.75% w/v (nominal) (Formulation 27), which was modest compared to the effects at the same concentration of sodium hyaluronate.
  • 0000040525 was supplied by Biosynth. Table 22 shows the material characteristics. Table 22. Sodium hyaluronate was Hyatrue® HA-EP1.8 (molecular weight range of 900-1,400 kDa), available from Bloomage Freda Biopharm Co. Ltd. Test Items. DMT-d 10 fumarate was formulated as a solution in 0.9% (w/v) saline, pH 5.5- 6 (control) or in 1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) (Formulation 28) at a free base concentration of 0.4 mg/mL (nominal) for SC injection.
  • WFI water for injection
  • test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • Control (0.9% w/v saline):
  • DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature.
  • 9.7 mg of DMT-d 10 fumarate was weighed into a 20 mL headspace vial which was pre-calibrated to a final volume of 15 mL with a magnetic stir bar inside. The weighed API was returned to storage.
  • the weighed API was removed from storage and allowed to equilibrate to room temperature.13.55 mL of vehicle (0.9% w/v saline) was added to the vial (equivalent to 90% of final volume) and set to magnetically stir for ca 35 minutes. Using a calibrated pH meter, the solution pH was measured. The initial reading showed the pH as 3.90, this was then adjusted using 0.1M NaOH to a final pH of 5.97. The solution was made to final volume of 15 mL, using the pre- calibrated line, with 0.9% w/v saline. The final pH was recorded as 5.53.
  • the solution was then filtered using a 0.22 ⁇ M PVDF syringe filter in the laminar air flow cabinet (LAFC). The visual appearance of the solution was recorded as a clear, colorless, homogenous solution.
  • the final control solution had a free base concentration of 0.41 mg/mL DMT-d10. The control solution was protected from light at all times.
  • Formulation 28 On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature.
  • DMT-d 10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.3.5 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 2 mg/mL (nominal) DMT-d 10 . Once homogenous, 2 mL of the stock solution was dispensed into a vial containing 8 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous.
  • the formulation thus had a free base concentration of 0.4 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 1% w/v (nominal).
  • the target dose was 0.1 mg/kg, free base at a dose concentration of 0.4 mg/mL.
  • Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. Three male Beagle dogs received a SC administration of control. After a 7-day washout period, the same animals were administered Formulation 28 as shown in Table 23.
  • the resultant plasma was decanted into appropriately labelled polypropylene tubes in 96-well plate format and stored in a freezer set to maintain a temperature of ⁇ -65°C until analysis. The samples were protected from light. Bioanalysis. Plasma samples were analyzed for DMT-d10 using an established LC-MS/MS assay. Pharmacokinetic parameters were determined from the DMT-d 10 plasma concentration-time profiles using commercially available software (Phoenix® WinNonlin®). Results. All dose administrations of DMT-d 10 were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical signs were recorded post-dose.
  • DMT-d 10 formulated in either 0.9% w/v saline (control) or 1% w/v (nominal) sodium hyaluronate (Formulation 28) are presented.
  • DMT-d 10 was administered SC at a free base equivalent dose of 0.1 mg/kg.
  • Plasma DMT-d10 concentrations were quantifiable up to 2 hours in all animals following SC administration of control (Fig.12A), and up to 4 hours following SC administration of Formulation 28 (Fig.12B).
  • Fig.12A controls
  • Fig.12B up to 4 hours following SC administration of Formulation 28
  • B Dose Proportionality – Pharmacokinetics (PK) of DMT-d10 in Male Beagle Dogs Following Subcutaneous Administration Formulated in 1% w/v Sodium Hyaluronate at Increasing Dose Levels of DMT-d10
  • the objective of this study was to determine if a SC administration of DMT-d10 formulated in 1% w/v (nominal) sodium hyaluronate yields a dose proportional increase in plasma DMT-d 10 concentrations.
  • Test Items DMT-d 10 fumarate was formulated in 1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 2 mg/mL (Formulation 29) or 4 mg/mL (Formulation 30) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • WFI water for injection
  • Formulation 29 On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 110.7 mg of DMT-d 10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.6.914 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 10.1 mg/mL (nominal) DMT-d 10 . The stock solution had a density of 1.002 g/cm 3 .
  • the formulation thus had a free base concentration of 4.15 mg/mL (nominal) DMT-d 10 and a sodium hyaluronate concentration of 1% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution.
  • Subcutaneous injections The target dose was 0.5 mg/kg free base at a dose concentration of 2 mg/mL, or 1.0 mg/kg free base at a dose concentration of 4 mg/mL.
  • Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo.
  • the pharmacokinetic parameters for DMT-d10 formulated in Formulations 28-30 SC at 0.1, 0.5 and 1 mg/kg are presented.
  • the 0.1 mg/kg data (Formulation 28) were calculated in part A (see Table 24) and are repeated here to determine dose proportionality.
  • Plasma DMT-d10 concentrations were quantifiable up to 4 hours in all animals following SC administration.
  • Median T max ranged from 0.5 to 0.75 hr suggesting similar absorption profiles after SC administration for the lower dose levels (Figs.13A-13B).
  • the interpretation of the absorption kinetics may be impacted by the sparse samples collected during the phase and the interindividual variability at the high dose (1 mg/kg; Table 26).
  • DMT-d10 fumarate was formulated in 0.1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 2 mg/mL (Formulation 31), 0.25% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 4 mg/mL (Formulation 32), or 0.5% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 4 mg/mL (Formulation 33) for SC injection.
  • Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • Formulation 31 On the morning of dosing, DMT-d 10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 58.32 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.16.9 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 2.18 mg/mL (nominal) DMT-d 10 . The stock solution had a density of 0.999 g/cm 3 .
  • the formulation thus had a free base concentration of 4.08 mg/mL (nominal) DMT-d 10 and a sodium hyaluronate concentration of 0.25% w/v (nominal).
  • the visual appearance of the formulation was recorded as a clear, colorless, homogenous solution and the pH was 3.59.
  • Formulation 33 On the morning of dosing, DMT-d 10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature.
  • the formulation thus had a free base concentration of 4.01 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.50% w/v (nominal).
  • the visual appearance of the formulation was recorded as a clear, colorless, homogenous solution and the pH was 3.76.
  • Subcutaneous injections The target dose was 0.5 mg/kg free base at a dose concentration of 2 mg/mL, or 1.0 mg/kg free base at a dose concentration of 4 mg/mL.
  • Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo.
  • DMT-d 10 plasma concentration-time profiles formulated in 0.1% (Formulation 31), 0.25% (Formulation 32), 0.5% (Formulation 33), and 1% (Formulation 30) w/v (nominal) sodium hyaluronate at a SC dose of 1 mg/kg are presented in Fig.15 (Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg).
  • Corresponding pharmacokinetic parameters for DMT- d 10 are presented in Table 28.
  • the PK parameters for Formulation 30 and control were calculated in part B and A, respectively, and are shown here for ease of comparison. Plasma DMT-d10 concentrations were quantifiable up to 4 hours in all animals following SC administration.
  • MRTinf a parameter describing the duration of DMT- d 10 systemic exposure
  • MRTinf incrementally increased with higher sodium hyaluronate concentrations, i.e., 0.921 hr at 0.1% w/v (nominal) sodium hyaluronate (Formulation 31) to 1.50 hr at 1% w/v (nominal) sodium hyaluronate (Formulation 30).
  • the incremental increase in MRTinf can be seen graphically in Fig.16. However, over the same formulations, t 1/2 , C max and AUC inf values were not changed (Figs. 17-19, respectively).
  • DMT-d 10 fumarate was formulated as a solution in 0.9% (w/v) saline, pH 5.5- 6, at a free base concentration of 4 mg/mL (nominal) (control) or in 0.4% (w/v, nominal) sodium hyaluronate in 0.3% (w/v) saline at a free base concentration of 20 mg/mL (nominal) (Formulation 34) for SC injection.
  • Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • the pH was adjusted using 1M NaOH and 2M HCl to achieve a final pH of 5.51.
  • the control solution was then made to final volume using a pre-calibrated line on the glass vial with 0.9% (w/v) saline. Sterile filtration using a 0.22 ⁇ M filter was then carried out.
  • the control solution had a free base concentration of 4 mg/mL (nominal) DMT-d 10 .
  • Formulation 34 A 0.3% (w/v) saline solution was prepared by adding 3.35 mL of 0.9% (w/v) to a sterile glass vial with 6.65 mL of WFI, followed by magnetically mixing. Once homogeneous, the density was measured to be 1.000 g/cm 3 .
  • DMT-d 10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature.
  • 311.1 mg of DMT-d 10 fumarate was weighed into a suitably sized sterile glass container.2.839 mL of the previously prepared 0.3% (w/v) solution (equivalent to 60% of the final stock volume) was added to the container and set to stir at a temperature of 37°C at 300 rpm.
  • the visual appearance was recorded as a clear/yellowish homogenous solution at this stage.
  • the pH was measured using a calibrated pH meter and recorded to be 3.24.
  • the pH was then adjusted to 5.98 by adding 1M NaOH until a final volume of 5 mL using a volumetric flask, and was set to stir magnetically. The density was measured to be 1.012 g/cm 3 . Sterile filtration using a 0.22 ⁇ M PVDF filter was then carried out.
  • the stock solution had a free base concentration of 40 mg/mL (nominal) DMT-d10.
  • a 0.8% (w/v, nominal) sodium hyaluronate solution was prepared by precisely mixing 3.193 mL of 1.25% (w/v, nominal) sodium hyaluronate and 1.799 mL of 0.8% (w/v) saline in a glass container until homogeneous.
  • the density of the resultant 0.8% (w/v, nominal) sodium hyaluronate solution was recorded to be 1.002 g/cm 3 .
  • 2.032 mL of the DMT-d10 fumarate stock solution and 1.988 mL of the 0.8% (w/v, nominal) sodium hyaluronate solution were added to a new sterile vial and magnetically stirred until homogeneous.
  • the formulation thus had a free base concentration of 20 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.40% w/v (nominal).
  • the final visual appearance of the formulation was recorded as a clear, colorless, homogenous solution. Subcutaneous injections.
  • the target dose was 1 mg/kg free base at a dose concentration of 20 mg/mL (nominal), or 1.0 mg/kg free base at a dose concentration of 4 mg/mL (nominal).
  • Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.05 mL/kg or 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. The same animals were used with a 7-day washout period in between administrations as shown in Table 29.
  • Blood samples (ca 1 mL) were collected from the jugular vein by venipuncture into tubes containing K2EDTA anticoagulant at the following time-points: Predose, 0.033 (2 min), 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45min), 1, 2, and 4 hr post dose.
  • DMT-t/io was formulated in 0.4% w/v (nominal) sodium hyaluronate containing 0.3% w/v NaCl at a SC dose solution concentration of 20 mg/mL (nominal) (Formulation 34) and delivered as a dose volume of 0.05 mL/kg or in 0.9% w/v NaCl at a SC dose solution concentration of 4 mg/mL (nominal) (control) and delivered as a dose volume of 0.25 mL/kg, both at a free base dose of 1 mg/kg.
  • the DMT-t/w plasma concentration-time concentrations are presented in Figs. 20A and 20B.
  • Corresponding pharmacokinetic parameters for DMT-t/w are presented in Table 30. Plasma DMT-t/w concentrations were quantifiable up to 4 hours in all animals following SC administration. Median T ma x values were 0.25 hr for both Formulation 34 and control.
  • Test Items DMT fumarate and DMT-d10 fumarate were formulated together as a solution in 0.5% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a free base concentration of 10 mg/mL/analyte (nominal); total free base concentration of 20 mg/mL (nominal) (Formulation 35) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • Formulation 35 On the morning of dosing, DMT-d 10 fumarate and DMT fumarate were removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 80.1 mg of DMT- d 10 fumarate and 82.3 mg of DMT fumarate were weighed into a suitably sized sterile glass container. 2.853 mL of WFI was added to the container and magnetically stirred. Once homogeneous, the stock solution was sterile filtered using a 0.22 ⁇ M PVDF filter.
  • the stock solution had a free base concentration of 17.7 mg/mL (nominal) DMT-d 10 and a free base concentration 17.8 mg/mL DMT (combined free base concentration of DMT-d10 + DMT of 35.5 mg/mL).
  • 1.832 mL of the stock solution was added to a new sterile glass vial.1.203 mL of 1.25% (w/v, nominal) sodium hyaluronate solution was added to the vial and vortex mixed to homogenize.
  • the formulation thus had a free base concentration of 10.7 mg/mL (nominal) DMT- d10 and a free base concentration of 10.8 mg/mL (nominal) DMT (combined free base concentration of DMT-d 10 + DMT of 21.5 mg/mL) and a sodium hyaluronate concentration of 0.5% w/v (nominal). Subcutaneous injections.
  • DMT + DMT-d10 were co-dosed (via Formulation 35) at 0.5 mg/kg/analyte, total dose of 1.0 mg/kg (free base), each at a dose concentration of 10 mg/mL (nominal), total dose concentration of 20 mg/mL (nominal) and a dose volume of 0.05 mL/kg calculated per each animal based on real animal bodyweights.
  • the volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose.
  • the experimental design is shown in Table 31. Table 31.
  • DMT and DMT-d10 were co-dosed via Formulation 35 in 0.5% w/v (nominal) sodium hyaluronate in water for injection (WFI) at a SC dose solution concentration of 10 mg/mL/analyte (total: 20 mg/mL) (nominal) and dose volume of 0.05 mL/kg (0.5 mL for a 10 kg dog).
  • WFI water for injection
  • DMT and DMT-d10 plasma concentration-time concentrations are presented in Figs 21A and 21B.
  • Corresponding pharmacokinetic parameters for DMT and DMT-d 10 are presented in Table 32. Plasma concentrations were quantifiable to 2 hr for DMT and 4 hr for DMT-d10 following SC administration.
  • Formulations were prepared using water for injection (WFI). Filtration was performed using a Syringe filter unit, 0.22 ⁇ m, PVDF, 33 mm filter, available from Sigma-Aldrich. The Dialysis—Drug Release Test and UPLC were performed as previously described in section II.
  • Formulations and release profiles Formulations and their preparative methods are presented below. Formulations are presented in terms of the parameters A, B, and C as shown previously in Table 11.
  • Formulations 36-38 To investigate the role of different concentrations of sodium hyaluronate (0.5, 0.75, and 1% w/v, nominal) at fixed molecular weight on the release of ketamine (12.5 mg/mL free base equivalence, nominal), three different stock sodium hyaluronate solutions were made at 1, 1.5, and 2% w/v (nominal) concentrations by dissolving 10 mg, 15 mg, and 20 mg of sodium hyaluronate (>1,000 – 1,800 kDa), respectively, in a volume of WFI to reach 1 mL, followed by incubation at 37°C and stirring. The stock sodium hyaluronate solutions were then filtered through a 0.22 ⁇ m PVDF filter.
  • a stock solution of ketamine HCl (25 mg/mL free base equivalence of ketamine, nominal) was prepared by dissolving 115 mg of ketamine HCl in 4 mL of WFI, followed by incubation at 37°C and stirring. The solutions were used as is and no pH adjustments were made. Each stock sodium hyaluronate solution was then mixed in a 1:1 volume ratio with the stock solution of ketamine HCl, and the resulting formulations were vigorously stirred to ensure complete mixing.
  • a control formulation (12.5 mg/mL free base equivalence of ketamine, nominal) without release modifier was prepared by mixing stock solution of ketamine HCl with WFI in a 1:1 volume ratio. Formulations are shown in Table 34. Table 34.
  • Fig. 22 shows the drug release is highly controlled by the concentration of sodium hyaluronate in the formulation, with the control formulation providing the fastest release, and increasing sodium hyaluronate concentrations providing increasingly slower drug release, with the slowest release provided by the highest sodium hyaluronate content (Formulation 38).
  • These formulations support the notion that sodium hyaluronate serves as a robust polymer matrix for tunable and controlled-release of drug.
  • the preceding merely illustrates the principles of the methods and compositions. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the disclosure and are included within its spirit and scope.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Provided herein are injectable pharmaceutical formulations, methods for their production, kits, and uses thereof in the treatment of disorders such as mental disorders in subjects such as companion animals. The injectable pharmaceutical formulations include a psychopharmaceutical agent, a release modifier, and an aqueous vehicle. The pharmaceutical formulations allow for a time-restricted temporal controlled-release of the psychopharmaceutical agent upon administration by injection such as subcutaneous injection. The mental disorders treatable with the pharmaceutical formulations include those associated with a 5-HT2 receptor, such as anxiety disorders (e.g., separation anxiety, social anxiety, noise phobia, obsessive-compulsive disorder (OCD)) and depressive disorders.

Description

COMPANION ANIMAL TREATMENTS
CROSS-REFERENCE
This application claims priority to U.S. Provisional Application No. 63/507,059, filed on June 8, 2023, and U.S. Provisional Application No. 63/600,179, filed on November 17, 2023, each incorporated herein by reference in their entireties.
FIELD
The present disclosure relates generally to injectable pharmaceutical formulations comprising a drug/psychopharmaceutical agent and uses in the treatment of mental disorders in subjects such as companion animals, including those associated with a 5-HT2 receptor, such as anxiety disorders and depressive disorders.
BACKGROUND
In 2016 the American Veterinary Medical Association estimated that 59% of households in the United States had a companion animal such as a dog or cat. Worldwide, the dog population is approaching one billion and there are 9.2 million horses in the United States alone. Mental disorders such as anxiety and depression are not limited to humans, and many companion animals are prone to suffer from conditions of anxiety or depression or other behavioral problems. For example, it has been estimated that over 17% of all pets suffer from anxiety due to loud noises (e.g., thunder) and 14% of dogs suffer from separation anxiety. Like humans, companion animals who suffer from conditions of anxiety or depression or other behavioral problems can display various symptoms. For example, anxiety symptoms may include trembling, hiding, attempts to leave or escape, compulsive licking or grooming, self-injuring, diarrhea or vomiting, reduced activity, and destructive behavior. Symptoms of depression may include loss of appetite, drastic weight loss, reduced activity, lethargy or more sleeping, less social interaction or avoidance and hiding, refusal of water or treats, excessive shedding, and sudden and drastic behavior changes. Symptoms of obsessive-compulsive disorder (OCD) may include repetitive or intensified behavior, self-mutilation, excessive tail chasing, and decrease in playfulness.
Existing treatments for animal mental disorders involve the use of human medications for depression and anxiety. Serotonin and norepinephrine reuptake inhibitors, like fluoxetine (Prozac®), are some of the most commonly prescribed drugs in veterinary behavioral medicine. Others include benzodiazepines (e.g., alprazolam; Xanax®), tricyclic antidepressants, beta- blockers, and even lithium. Indeed, the psychopharmacopeia for dogs is nearly the same as for humans (Berns G. Decoding the Canine Mind. Cerebrum : the Dana Forum on Brain Science. 2020 Mar-Apr;2020:cer-04-20. PMID: 32395197). The use of human medications on companion animals such as dogs is perhaps not surprising, given the striking similarities to human brain function, especially when it comes to emotions (Berns GS, Brooks AM, Spivak M. Functional MRI in awake unrestrained dogs. PLoS One 2012;7:e38027; Berns GS, Brooks AM, Spivak M. Scent of the familiar: an fMRI study of canine brain responses to familiar and unfamiliar human and dog odors. Behav Processes 2015;110:37-46; Berns GS, Brooks A, Spivak M. Replicability and heterogeneity of awake unrestrained canine FMRI responses. PLoS One 2013;8:e81698). However, like in humans, the use of such currently available drugs is characterized by (partial) ineffectiveness, and are often associated with burdensome adverse effects.
In the last three decades, there has been a resurgence of interest in psychedelic, dissociative, and entactogenic drug research. In humans, such drugs when combined with psychotherapy, have shown early, but robust effectiveness following a limited number of administrations (typically 1-3 drug assisted psychotherapy sessions). For instance, the entactogen methylenedioxymethamphetamine (MDMA) has recently passed the first phase-III trial in patients with PTSD [Mitchell JM, et al. MDMA-assisted therapy for severe PTSD: a randomized, double- blind, placebo-controlled phase 3 study. Nat Med. 2021;27: 1025-1033], Lysergic acid diethylamide (LSD) has shown clinical promise in alcohol use disorder [Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J Neurol Sci. 2020, 411 : 116715; Fuentes JJ, et al. Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials. Front Psychiatry. 2020;10: 1-14], In the tryptamine class of serotonergic psychedelics, psilocybin (the active ingredient in ‘magic mushrooms’) has shown promise in a phase II trial for MDD, end of life anxiety [Griffiths RR, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: Arandomized double-blind trial. JPsychopharmacol. 2016;30: 1181— 1197], and smoking cessation [Garcia-Romeu A, Griffiths RR, Johnson MW. Psilocybin- occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev. 2014;7: 157-164; de Veen BTH, et al. Psilocybin for treating substance use disorders? ExpertRev Neurother. 2017;17: 203-212; Johnson MW, et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014;28: 983-992; and Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse. 2017;43: 55-60]; and N,N-dimethyltryptamine (DMT; also referred to as 2-(U/-indol-3-yl)-N,N-dimethylethan-l -amine) (usually as an active ingredient in ayahuasca) has shown promising effects on mood [Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci. 2020;21 : 611-624; Barker SA. N,N-dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function. Front Neurosci. 2018;12: 1- 17; and Strassman RJ, et al. Dose-response study of N,N-Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994;51 : 98-108] and potentially, addictions [Thomas G, et al. Ayahuasca-assisted therapy for addiction: Results from a preliminary observational study in Canada. Curr Drug Abuse Rev. 2013; Oliveira- Lima AJ, et al. Effects of ayahuasca on the development of ethanol -induced behavioral sensitization and on a post-sensitization treatment in mice. Physiol Behav. 2015;142: 28-36; Nolli LM, et al. Effects of the hallucinogenic beverage ayahuasca on voluntary ethanol intake by rats and on cFos expression in brain areas relevant to drug addiction. Alcohol. 2019; Fabregas JM, et al. Assessment of addiction severity among ritual users of ayahuasca. Drug Alcohol Depend. 2010;! 11 : 257-261; Argento E, et al. Exploring ayahuasca-assisted therapy for addiction: A qualitative analysis of preliminary findings among an Indigenous community in Canada. Drug Alcohol Rev. 2019;38: 781-789; and Noorani T, et al. Psychedelic therapy for smoking cessation: Qualitative analysis of participant accounts. J Psychopharmacol. 2018;32: 756-769],
DMT’s binding profile is well characterized. DMT acts on numerous ionotropic and metabotropic receptors. It binds with affinity to 5-hydroxytryptamine-(5-HT)iA, 5-HT2A, 5-HT2C, and serotonin transporter (SERT) receptors from the 5-HT/serotonin family [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9: 2344-2357], DMT is a potent agonist at the 5-HT2A receptor, through which (not unlike other serotonergic psychedelics), it exerts many subjective, visual, and potentially therapeutic effects [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N, N- Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9: 2344-2357; Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016;126: 74-88], 5-HT2A activation has also been linked with increased synaptic plasticity [Ly C, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23: 3170-3182; Ly C, et al. Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth. ACS Pharmacol Transl Sci. 2020; and Inserra A, De Gregorio D, Gobbi G. Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms. Pharmacol Rev. 2021;73: 202-277], Additionally, DMT binds to other receptors, including trace amine-associated receptors (TAARs) and the sigma- 1 receptor, potentially contributing to its neuroprotective plasticity enhancing effects [Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016; 126: 74-88; Barker SA. N, N-dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function. Front Neurosci. 2018;12: 1-17],
Despite high potencies at serotonin 5-HT2RS, the therapeutic value of certain tryptamine psychedelics has been hampered by their accelerated metabolism in the liver and gastrointestinal tract most notably by monoamine oxidase (MAO) enzymes. For example, DMT is not orally active — it is converted to inactive metabolites before sufficient brain penetration can occur. For this reason, DMT is typically dosed with a monoamine oxidase inhibitor (as is the case in ayahuasca) to prolong its duration of action. Likewise, 5-methoxy-A,A-dimethyltryptamine (5- MeO-DMT) lacks oral bioavailability and is instead ordinarily vaporized and inhaled to produce psychedelic effects. Such MAO-mediated metabolism is also believed to contribute to high variability in the pharmacokinetic (PK) profiles of various tryptamines in humans, including significant patient-to-patient pharmacokinetic variability after oral psilocybin administration and intravenous (IV) administration of DMT.
Additionally, in marked contrast to the hours-long subjective effects of other serotonergic psychedelics such as LSD (8 to 20 hour duration of action) and psilocybin (6 to 8 hour duration of action), the duration of action time course of short-acting tryptamine psychedelics such as DMT and 5-MeO-DMT administered as a bolus to humans via inhalation or intravenous or intramuscular injection is brief — so short as to limit their use in effective therapies. For DMT, the onset of subjective effects on perception and consciousness (sometimes referred to as the “psychedelic state”) are rapid and overwhelming, with profound and intense visual peak experiences noted within 2 minutes of administration. The psychedelic state dissipates rapidly, with subjective effects returning to baseline (or close to) following roughly 20 to 30 minutes post administration [Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R. Dose-response study of N,N- Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994;51 : 98-108], On one hand, the short time course spent in the psychedelic state is seen as therapeutically limiting and makes sophisticated granular assessment of pharmacodynamic (PD) effects and safety profiles inherently difficult. On the other hand, short- acting tryptamine psychedelics are potentially more controllable and clinically scalable compared to longer-acting psychedelic compounds such as LSD and psilocybin, which often require 7 to 8 hours or more of supervised clinical observation of a patient before discharge.
To improve treatment profiles of DMT by avoiding excessive drug levels associated with bolus IV injections or inhalation administration, and to provide more scalable duration of effects (e.g., peak effects of about 30 to 120 minutes), continuous-controlled IV infusions have been studied in humans [Gallimore AR, Strassman RJ. A model for the application of target-controlled intravenous infusion for a prolonged immersive DMT psychedelic experience. Front Pharmacol. 2016;7: 1-11], DMT infusions administered over about 90 minutes allowed for expanding, in a time-controlled manner, the exposure while maximizing the effects of the drug. However, infusion protocols (e.g., where the subject is administered the drug over prolonged periods such as over an hour or longer) are not generally clinically practical, particularly for veterinary medicine, as they require significant clinical resources and personnel that represent major challenges in scaling up the treatment for larger populations of subjects.
Consequently, there is a need for new formulations, delivery approaches, and treatment options for mental disorders, which retain the pharmacokinetic and pharmacologic benefits of intravenous infusion administration (i.e., provide a target-controlled duration of action of about 30 to 120 minutes), yet offer an alternative that is clinically practical, convenient, and economical for providers.
SUMMARY
Accordingly, the present disclosure is based at least in part on the identification of novel injectable pharmaceutical formulations, kits, and treatment methods which allow for a time- restricted temporal controlled-release of a psychopharmaceutical agent. In the case of short-acting tryptamine psychedelics such as DMT, 5-MeO-DMT, and their analogs (e.g., deuterated analogs), this controlled-release may be tuned to provide a duration of action of about 30 to 120 minutes to maximize therapeutic benefits and reduce side effects. By doing so, the injectable pharmaceutical formulations extend the time the subject spends in an efficacious window compared to bolus IV injection of the same tryptamine psychedelic, preferably without overextending the release and the resulting duration of action beyond about 120 minutes.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors’ discovery of novel injectable pharmaceutical formulations containing a psychopharmaceutical agent in combination with specific release modifiers which can be administered as a bolus injection, including as a subcutaneous bolus injection, that display a tunable and linear release of the psychopharmaceutical agent. In the case of tryptamine psychedelics such as DMT, 5-MeO-DMT, and their analogs (e.g., deuterated analogs), a desirable controlled-release can be achieved to mimic the clinically advantageous 30 to 120 minute duration of action profile that has only been achieved in humans by IV infusion of such psychopharmaceutical agents.
Thus, the present disclosure provides:
(1) An injectable pharmaceutical formulation, comprising: a drug/psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000007_0001
wherein:
Xi and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
Yi and Y2 are independently selected from the group consisting of hydrogen and deuterium;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy;
Re and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and
Rs and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively Rs and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
(2) The injectable pharmaceutical formulation of (1), wherein the compound has a structure of Formula (II), or a stereoisomer, solvate, or prodrug thereof
Figure imgf000008_0001
wherein:
Xi and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, and R2, R4, R5, R6, and R7 are independently hydrogen or deuterium. (3) The injectable pharmaceutical formulation of (1) or (2), wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of
Figure imgf000009_0001
Figure imgf000010_0001
solvate, or prodrug thereof. (4) The injectable pharmaceutical formulation of any one of (1) to (3), wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8). (5) The injectable pharmaceutical formulation of any one of (1) to (3), wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6). (6) The injectable pharmaceutical formulation of any one of (1) to (3), wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine-1,1-d2 (I-2). (7) The injectable pharmaceutical formulation of any one of (1) to (3), wherein the psychopharmaceutical agent is an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); and (ii) a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). (8) The injectable pharmaceutical formulation of (7), wherein the active salt mixture comprises (i) from 60% to 99% by weight of the pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8), based on a total weight of the active salt mixture; and (ii) from 1% to 40% by weight, in sum, of the pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), based on a total weight of the active salt mixture. (9) The injectable pharmaceutical formulation of (1), wherein the compound has a structure of Formula (III), or a stereoisomer, solvate, or prodrug thereof
Figure imgf000011_0001
wherein: X1 and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, each Z3 is independently hydrogen or deuterium, and R2, R4, R6, and R7 are independently hydrogen or deuterium. (10) The injectable pharmaceutical formulation of (1) or (9), wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
stereoisomer, solvate, or prodrug thereof. (11) The injectable pharmaceutical formulation of any one of (1), (9), or (10) wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20). (12) The injectable pharmaceutical formulation of any one of (1) or (9) to (11), wherein the psychopharmaceutical agent is an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 20); and (ii) a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23). (13) The injectable pharmaceutical formulation of any one of (1) to (12), wherein the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt. (14) The injectable pharmaceutical formulation of any one of (1) to (13), wherein the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, or a succinate salt.
(15) The injectable pharmaceutical formulation of any one of (1) to (14), wherein a concentration of the psychopharmaceutical agent by weight (in terms of free base equivalence) per total volume of the pharmaceutical formulation is about 0.1 mg/mL to about 70 mg/mL.
(16) The injectable pharmaceutical formulation of any one of (1) to (15), wherein a concentration of the psychopharmaceutical agent by weight (in terms of free base equivalence) per total volume of the pharmaceutical formulation is about 0.1 mg/mL to about 20 mg/mL.
(17) The injectable pharmaceutical formulation of any one of (1) to (16), wherein the hyaluronate salt is sodium hyaluronate.
(18) The injectable pharmaceutical formulation of any one of (1) to (17), wherein the hyaluronate salt has a weight average molecular weight of about 500 kDa to about 2,000 kDa.
(19) The injectable pharmaceutical formulation of any one of (1) to (18), wherein the hyaluronate salt has a weight average molecular weight of about 1,000 kDa to about 1,800 kDa.
(20) The injectable pharmaceutical formulation of any one of (1) to (19), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 2% (w/v).
(21) The injectable pharmaceutical formulation of any one of (1) to (20), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 1% (w/v).
(22) The injectable pharmaceutical formulation of any one of (1) to (21), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 0.75% (w/v).
(23) The injectable pharmaceutical formulation of any one of (1) to (22), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 0.5% (w/v).
(24) The injectable pharmaceutical formulation of any one of (1) to (23), wherein the aqueous vehicle comprises water and sodium chloride.
(25) The injectable pharmaceutical formulation of (24), wherein the pharmaceutical formulation comprises sodium chloride at a concentration, in terms of weight per total volume of the pharmaceutical formulation, of about 0.1% to about 0.8% (w/v).
(26) The injectable pharmaceutical formulation of any one of (1) to (25), which has a pH of about 3 to about 7.
(27) The injectable pharmaceutical formulation of any one of (1) to (26), which has an osmolality of about 150 mOsm/kg to about 600 mOsm/kg.
(28) The injectable pharmaceutical formulation of any one of (1) to (27), which has a viscosity of less than about 3,000 cP.
(29) The injectable pharmaceutical formulation of any one of (1) to (28), which is suitable for subcutaneous injection.
(30) The injectable pharmaceutical formulation of any one of (1) to (29), which is suitable for bolus subcutaneous injection.
(31) The injectable pharmaceutical formulation of any one of (1) to (30), wherein the injectable pharmaceutical formulation provides a duration of action of about 30 minutes to about 120 minutes after being administered to a companion animal via bolus subcutaneous injection.
(32) A kit suitable for preparing the injectable pharmaceutical formulation of any one of (1) to (31), the kit comprising:
(al) a first solution comprising the psychopharmaceutical agent and the aqueous vehicle; and
(bl) a second solution comprising the hyaluronate salt and the aqueous vehicle.
(33) A method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of the injectable pharmaceutical formulation of any one of (1) to (31).
(34) The method of (33), wherein the mental disorder is an anxiety disorder.
(35) The method of (34), wherein the anxiety disorder is separation anxiety.
(36) The method of (34), wherein the anxiety disorder is social anxiety.
(37) The method of (34), wherein the anxiety disorder is noise phobia.
(38) The method of (34), wherein the anxiety disorder is obsessive-compulsive disorder (OCD).
(39) The method of (33), wherein the mental disorder is a depressive disorder.
(40) The method of any one of (33) to (39), wherein the companion animal is a dog.
(41) The method of any one of (33) to (39), wherein the companion animal is a cat.
(42) The method of any one of (33) to (39), wherein the companion animal is a horse.
(43) The method of any one of (33) to (42), wherein the injectable pharmaceutical formulation is administered via injection.
(44) The method of any one of (33) to (43), wherein the injectable pharmaceutical formulation is administered via subcutaneous injection. (45) The method of any one of (33) to (44), wherein the injectable pharmaceutical formulation is administered via bolus subcutaneous injection. (46) The method of (45), wherein the bolus subcutaneous injection provides a duration of action of about 30 minutes to about 120 minutes after being administered. (47) An injectable pharmaceutical formulation, comprising: a drug/psychopharmaceutical agent; a carboxymethyl cellulose salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000019_0001
wherein: X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively R8 and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl. (48) The injectable pharmaceutical formulation of (47), wherein the carboxymethyl cellulose salt is sodium carboxymethyl cellulose. (49) The injectable pharmaceutical formulation of (47) or (48), wherein the carboxymethyl cellulose salt has a weight average molecular weight of about 50 kDa to about 450 kDa. (50) The injectable pharmaceutical formulation of any one of (47) to (49), wherein a concentration of the carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation is from about 0.55% to about 1% (w/v). (51) A kit suitable for preparing the injectable pharmaceutical formulation of any one of (47) to (50), the kit comprising: (a1) a first solution comprising the psychopharmaceutical agent and the aqueous vehicle; and (b1) a second solution comprising the carboxymethyl cellulose salt and the aqueous vehicle. (52) A method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of the injectable pharmaceutical formulation of any one of (47) to (50).
(53) The method of (52), wherein the mental disorder is an anxiety disorder.
(54) The method of (53), wherein the anxiety disorder is separation anxiety.
(55) The method of (53), wherein the anxiety disorder is social anxiety.
(56) The method of (53), wherein the anxiety disorder is noise phobia.
(57) The method of (53), wherein the anxiety disorder is obsessive-compulsive disorder (OCD).
(58) The method of (52), wherein the mental disorder is a depressive disorder.
(59) The method of any one of (52) to (58), wherein the companion animal is a dog.
(60) The method of any one of (52) to (58), wherein the companion animal is a cat.
(61) The method of any one of (52) to (58), wherein the companion animal is a horse.
(62) The method of any one of (52) to (61), wherein the injectable pharmaceutical formulation is administered via injection.
(63) The method of any one of (52) to (62), wherein the injectable pharmaceutical formulation is administered via subcutaneous injection.
(64) The method of any one of (52) to (63), wherein the injectable pharmaceutical formulation is administered via bolus subcutaneous injection.
(65) The method of any one of (52) to (64), wherein the bolus subcutaneous injection provides a duration of action of about 30 minutes to about 120 minutes after being administered.
(66) An injectable pharmaceutical formulation, comprising: a drug/psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of ketamine, or a stereoisomer, solvate, or prodrug thereof.
(67) The injectable pharmaceutical formulation of (66), wherein the pharmaceutically acceptable salt is an inorganic salt.
(68) The injectable pharmaceutical formulation of (66) or (67), wherein the pharmaceutically acceptable salt is a hydrochloride salt.
(69) The injectable pharmaceutical formulation of any one of (66) to (68), wherein a concentration of the psychopharmaceutical agent by weight (in terms of free base equivalence) per total volume of the pharmaceutical formulation is about 0.1 mg/mL to about 70 mg/mL.
(70) The injectable pharmaceutical formulation of any one of (66) to (69), wherein a concentration of the psychopharmaceutical agent by weight (in terms of free base equivalence) per total volume of the pharmaceutical formulation is about 0.1 mg/mL to about 20 mg/mL.
(71) The injectable pharmaceutical formulation of any one of (66) to (70), wherein the hyaluronate salt is sodium hyaluronate.
(72) The injectable pharmaceutical formulation of any one of (66) to (71), wherein the hyaluronate salt has a weight average molecular weight of about 500 kDa to about 2,000 kDa.
(73) The injectable pharmaceutical formulation of any one of (66) to (72), wherein the hyaluronate salt has a weight average molecular weight of about 1,000 kDa to about 1,800 kDa. (74) The injectable pharmaceutical formulation of any one of (66) to (73), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 2% (w/v).
(75) The injectable pharmaceutical formulation of any one of (66) to (74), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 1% (w/v).
(76) The injectable pharmaceutical formulation of any one of (66) to (75), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 0.75% (w/v).
(77) The injectable pharmaceutical formulation of any one of (66) to (76), wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 0.5% (w/v).
(78) The injectable pharmaceutical formulation of any one of (66) to (77), wherein the aqueous vehicle comprises water and sodium chloride.
(79) The injectable pharmaceutical formulation of (78), wherein the pharmaceutical formulation comprises sodium chloride at a concentration, in terms of weight per total volume of the pharmaceutical formulation, of about 0.1% to about 0.8% (w/v).
(80) The injectable pharmaceutical formulation of any one of (66) to (79), which has a pH of about 3 to about 7.
(81) The injectable pharmaceutical formulation of any one of (66) to (80), which has an osmolality of about 150 mOsm/kg to about 600 mOsm/kg.
(82) The injectable pharmaceutical formulation of any one of (66) to (81), which has a viscosity of less than about 3,000 cP. (83) The injectable pharmaceutical formulation of any one of (66) to (82), which is suitable for subcutaneous injection.
(84) The injectable pharmaceutical formulation of any one of (66) to (83), which is suitable for bolus subcutaneous injection.
(85) The injectable pharmaceutical formulation of any one of (66) to (84), wherein the injectable pharmaceutical formulation provides a duration of action of about 30 minutes to about 120 minutes after being administered to a companion animal via bolus subcutaneous injection.
(86) A kit suitable for preparing the injectable pharmaceutical formulation of any one of (66) to (85), the kit comprising:
(al) a first solution comprising the psychopharmaceutical agent and the aqueous vehicle; and
(bl) a second solution comprising the hyaluronate salt and the aqueous vehicle.
(87) A method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of the injectable pharmaceutical formulation of any one of (66) to (85).
(88) Use of the injectable pharmaceutical formulation of any one of (1) to (31) for treating a companion animal with a central nervous system (CNS) disorder and/or psychological disorder such as a mental disorder.
(89) The injectable pharmaceutical formulation of any one of (1) to (31) for use in therapy.
(90) Use of the injectable pharmaceutical formulation of any one of (47) to (50) for treating a companion animal with a central nervous system (CNS) disorder and/or psychological disorder such as a mental disorder.
(91) The injectable pharmaceutical formulation of any one of (47) to (50) for use in therapy. (92) Use of the injectable pharmaceutical formulation of any one of (66) to (85) for treating a companion animal with a central nervous system (CNS) disorder and/or psychological disorder such as a mental disorder.
(93) The inj ectable pharmaceutical formulation of any one of (66) to (85) for use in therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
The forgoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the following claims. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, wherein:
Fig. 1 illustrates a general synthetic route for making Compounds of Formula (I), e.g., compounds 1-2 and 1-6;
Fig. 2 illustrates a general synthetic route for making Compounds of Formula (I), e.g., compounds 1-1, 1-4, 1-5, and 1-8;
Fig. 3 shows the percent drug release versus time profile of Formulations 1-6 compared to control when subjected to the Dialysis — Drug Release Test;
Fig. 4 shows the percent drug release versus time profile of Formulation 7 compared to control when subjected to the Dialysis — Drug Release Test;
Fig. 5 shows the percent drug release versus time profile of Formulation 8 compared to control when subjected to the Dialysis — Drug Release Test;
Fig. 6 shows the percent drug release versus time profile of Formulation 9 compared to control when subjected to the Dialysis — Drug Release Test;
Figs. 7A and 7B show the percent drug release versus time profile of Formulations 10-12 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 7A) and the corresponding first order release kinetic plot (Fig. 7B);
Figs. 8A and 8B show the percent drug release versus time profile of Formulations 13-15 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 8A) and the corresponding first order release kinetic plot (Fig. 8B);
Figs. 9A and 9B show the percent drug release versus time profile of Formulations 16-18 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 9A) and the corresponding first order release kinetic plot (Fig. 9B); Figs. 10A and 1OB show the percent drug release versus time profile of Formulations 19- 21 compared to control when subjected to the Dialysis — Drug Release Test (Fig. 10A) and the corresponding first order release kinetic plot (Fig. 10B);
Fig. 11 shows the percent drug release versus time profile of Formulations 22-27 compared to control when subjected to the Dialysis — Drug Release Test;
Figs. 12A and 12B show individual DMT-t/io plasma concentration-time curves in male Beagle dogs (animal IDs: 068M, 069M, 070M) after subcutaneous administration of DMT-t/io at 0.1 mg/kg from control (Fig. 12A) and Formulation 28 (Fig. l2B);
Figs. 13 A and 13B show mean DMT-t/io plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-t/io at 0.1, 0.5, and 1 mg/kg from Formulations 28-30, respectively, in linear scale (Fig. 13A) and log scale (Fig. 13B);
Fig. 14 shows the dose proportionality of Cmax and AUCinf from the mean DMT-t/io plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-t/io at 0.1, 0.5, and 1 mg/kg from Formulations 28-30, respectively;
Fig. 15 shows the effect of sodium hyaluronate concentration on mean concentration-time profiles of DMT-t/io after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
Fig. 16 shows the effect of sodium hyaluronate concentration on mean residence time (MRTinf) of DMT-t/io after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
Fig. 17 shows the effect of sodium hyaluronate concentration on plasma half-life (ti/2) of DMT-t/10 after SC administration of DMT-t/10 at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
Fig. 18 shows the effect of sodium hyaluronate concentration on maximum plasma concentration (Cmax) of DMT-t/io after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
Fig. 19 shows the effect of sodium hyaluronate concentration on total exposure (AUCinf) of DMT-t/w after SC administration of DMT-t/io at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg;
Figs. 20A and 20B show mean DMT-t/10 plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-t/10 at 1 mg/kg free base from Formulation 34 (dose solution concentration of 20 mg/mL nominal delivered at dosing volume of 0.05 mL/kg) compared to control (dose solution concentration of 4 mg/mL nominal delivered at dosing volume of 0.25 mL/kg) in linear scale (Fig. 20A) and log scale (Fig. 20B);
Figs. 21A and 21B show mean DMT and DMT -dw plasma concentration-time curves in male Beagle dogs after subcutaneous co-dose administration of DMT and DMT-t/io at 0.5 mg/kg/analyte free base from Formulation 35 in linear scale (Fig. 21 A) and log scale (Fig. 2 IB); and
Fig. 22 shows the percent drug release (ketamine) versus time profile of Formulations 36- 38 compared to control when subjected to the Dialysis — Drug Release Test.
DETAILED DESCRIPTION
In the following detailed description of the embodiments of the instant disclosure, numerous specific details are set forth in order to provide a thorough understanding of the disclosed embodiments. However, it will be obvious to one skilled in the art that the embodiments of this disclosure may be practiced without these specific details. In other instances, well known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the instant disclosure.
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.
“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHj^CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl (t- BU)((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
The term “substituted alkyl” refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -O-, -N- , -S-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 10 substituents selected from the group consisting of deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2- alkyl, -SCh-aryl, -SCh-heteroaryl, and -NRR ”, wherein R and R may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
“Alkylene” refers to divalent aliphatic hydrocarbyl groups having from 1 to 6, including, for example, 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, -NR10-, -NR10C(O), -C(O)NR10- and the like. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n- propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-),
(-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like.
“Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.
The term “alkane” refers to alkyl group and alkylene group, as defined herein.
The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl” refers to the groups R NHR - where R is alkyl group as defined herein and R is alkylene, alkenylene or alkynylene group as defined herein.
The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.
“Alkoxy” refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n- pentoxy, and the like. The term “alkoxy” also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
The term “substituted alkoxy” refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
The term “alkoxyamino” refers to the group -NH-alkoxy, wherein alkoxy is defined herein. The term “haloalkoxy” refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
The term “haloalkyl” refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
“Alkenyl” refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms, for example 2 to 4 carbon atoms and having at least 1, for example from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
The term “substituted alkenyl” refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and - SCh-heteroaryl.
“Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, for example, 2 to 3 carbon atoms and having at least 1 and for example, from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C=CH), and propargyl (-CH2OCH).
The term “substituted alkynyl” refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl, and - SCh-heteroaryl.
“Alkynyloxy” refers to the group -O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.
“Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the “acetyl” group CHsC(O)
“Acylamino” refers to the groups -NR20C(O)alkyl, -NR20C(O)substituted alkyl, N R20C(O)cycloalkyl, -NR20C(O)substituted cycloalkyl,
NR20C(O)cycloalkenyl, -NR20C(O)substituted cycloalkenyl, -NR20C(O)alkenyl, NR20C(O) substituted alkenyl, -NR20C(O)alkynyl, -NR20C(O) substituted alkynyl, -NR20C(O)aryl, -NR20C(O)substituted aryl, -NR20C(O)heteroaryl, -NR20C(O)substituted heteroaryl, -NR20C(O)heterocyclic, and -NR20C(O)substituted heterocyclic, wherein R20 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
“Aminocarbonyl” or the term “aminoacyl” refers to the group -C(O)NR21R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
“Aminocarbonylamino” refers to the group -NR21C(O)NR22R23 where R21, R22, and R23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.
The term “alkoxycarbonylamino” refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
The term “acyloxy” refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
“Aminosulfonyl” refers to the group -SO2NR21R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
“Sulfonylamino” refers to the group -NR21SO2R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21 and R22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SO2- substituted alkyl, -SCh-aryl, -SCh-heteroaryl and trihalom ethyl.
“Aryloxy” refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.
“Amino” refers to the group -NH2.
The term “substituted amino” refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
The term “azido” refers to the group -N3.
“Carboxyl,” “carboxy” or “carboxylate” refers to -CO2H or salts thereof.
“Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. “(Carboxyl ester)oxy” or “carbonate” refers to the groups -O-C(O)O- alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O- alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O- cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
“Cyano” or “nitrile” refers to the group -CN.
“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and - SCh-heteroaryl.
“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and for example, from 1 to 2 double bonds.
The term “substituted cycloalkenyl” refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and - SCh-heteroaryl.
“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.
“Cycloalkoxy” refers to -O-cycloalkyl.
“Cycloalkenyloxy” refers to -O-cycloalkenyl.
“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.
“Hydroxy” or “hydroxyl” refers to the group -OH.
“Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring. In certain embodiments, the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N— >0), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, - SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -S02-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl.
The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
“Heteroaryl oxy” refers to -O-heteroaryl.
“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or - SO2- moieties.
Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2,3,4- tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo [b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1- dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, benzo[d][l,3]oxathiole, benzo[d][l,3]dioxole, and the like.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SO2- substituted alkyl, -SCh-aryl, -SCh-heteroaryl, and fused heterocycle.
“Heterocyclyloxy” refers to the group -O-heterocyclyl.
The term “heterocyclylthio” refers to the group heterocyclic-S-.
The term “heterocyclene” refers to the diradical group formed from a heterocycle, as defined herein.
The term “hydroxyamino” refers to the group -NHOH.
“Nitro” refers to the group -NO2.
“Oxo” refers to the atom (=0).
“Sulfonyl” refers to the group S02-alkyl, S02-substituted alkyl, S02-alkenyl, SO2- substituted alkenyl, SO2-cycloalkyl, S02-substituted cylcoalkyl, SO2-cycloalkenyl, SO2- substituted cylcoalkenyl, S02-aryl, S02-substituted aryl, SO2-heteroaryl, S02-substituted heteroaryl, SO2-heterocyclic, and S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-S02-, phenyl-S02-, and 4-methylphenyl-SO2-.
“Sulfonyloxy” refers to the group -0S02-alkyl, 0S02-substituted alkyl, 0S02-alkenyl, 0S02-substituted alkenyl, OSO2-cycloalkyl, 0S02-substituted cylcoalkyl, OSO2-cycloalkenyl, 0S02-substituted cylcoalkenyl, 0S02-aryl, 0S02-substituted aryl, OSO2-heteroaryl, OSO2- substituted heteroaryl, OSO2-heterocyclic, and OSO2 substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
The term “aminocarbonyloxy” refers to the group -0C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
“Thiol” refers to the group -SH.
“Thioxo” or the term “thioketo” refers to the atom (=S).
“Alkylthio” or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(0)-. The sulfoxide may exist as one or more stereoisomers.
The term “substituted thioalkoxy” refers to the group -S-substituted alkyl.
The term “thioaryloxy” refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.
The term “thioheteroaryl oxy” refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein. The term “thioheterocyclooxy” refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.
In addition to the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with =0, =NR70, =N-OR70, =N2 or =S) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, deuterium, -R60, halo, =0, -OR70, -SR70, -NR80R80, trihalomethyl, -CN, -OCN, -SCN, -NO, -N02, =N2, -N3, -SO2R70, -S020 M+, -SO2OR70, -OSO2R70, -OSO2O M+ -OSO2OR70, -P(0)(0 )2(M+)2, -P(O)(OR70)O M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -C(0)0
M+, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -0C(0)0 M+, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2
M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R70 is independently hydrogen or R60; each R80 is independently R70 or alternatively, two R80’s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H or C1-C3 alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each M+ may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R60)4; or an alkaline earth ion, such as [Ca2+]o.s, [Mg2+]o.s, or [Ba2+]o.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the disclosure can serve as the counter ion for such divalent alkali earth ions). As specific examples, -NR80R80 is meant to include -NH2, -NH-alkyl, 7V-pyrrolidinyl, 7V-piperazinyl, 47V-methyl-piperazin-l-yl and N- morpholinyl. In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, deuterium, -R60, halo, -O-M+, -OR70, -SR70, -S–M+, -NR80R80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3– M+, -SO3R70, -OSO2R70, -OSO3 –M+, -OSO3R70, -PO3 -2(M+)2, -P(O)(OR70)O– M+, -P(O)(OR70) , -C(O)R70, -C 70 70 70 – 2 (S)R , -C(NR )R , -CO2 M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO – 2 M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2– M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not -O-M+, -OR70, -SR70, or -S–M+. In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R60, -O-M+, -OR70, -SR70, -S-M+, -NR80R80, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R70, -S(O)2O-M+, -S(O)2OR70, -OS(O)2R70, -OS(O)2 O-M+, -OS(O)2OR70, -P(O)(O-)2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)(OR70), -C(O)R70, - C(S)R70, -C(NR70)R70, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -O C(S)R70, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70C(O)OR70, -NR70C(S) OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined. In addition to the disclosure herein, in some embodiments, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein, unless specified otherwise. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl. However, substituent groups defined as e.g., polyethers may contain serial substitution greater than three, e.g., -O-(CH2CH2O)n-H, where n can be 1, 2, 3, or greater. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxy carbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.
As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
When it is stated that a substituent or group “comprise(s) deuterium” or is “comprising deuterium,” it is to be understood that the substituent or group may itself be deuterium, or the substituent or group may contain at least one deuterium substitution in its chemical structure. For example, when substituent “-R” is defined to comprise deuterium, it is to be understood that -R may be -D (-deuterium), or a group such as -CD3 that is consistent with the other requirements set forth of -R.
As used herein, the term “fatty” describes a compound with a long-chain (linear) hydrophobic portion made up of hydrogen and anywhere from 4 to 26 carbon atoms, which may be fully saturated or partially unsaturated.
The phrases “pharmaceutically acceptable,” “physiologically acceptable,” and the like, are employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals such as human beings and non-human mammals (e.g., companion animals) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. When referencing salts, the phrase “pharmaceutically acceptable salt” and the like, means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases, by way of example, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and the like, and when the molecule contains a basic functionality, addition salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, perchlorate salts, and the like, and addition salts with organic acids, such as formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemi -oxalate, hemi-fumarate, propionate, stearate, lactate, citrate, ascorbate, pamoate, hydroxymaleate, phenyl acetate, glutamate, 2-acetoxybenzoate, tosylate, ethanedi sulfonate, isethionate salts, and the like. When in the form of a solid, salts designated as “hemi-” salts indicate that the stoichiometry of subject compound to counterion is about 2:1, whereas solid salt forms without the “hemi-” descriptor possess a subject compound to counterion stoichiometry of about 1 : 1. For example, DMT hemi -fumarate indicates that the ratio of DMT to fumarate is 2:1, whereas DMT fumarate indicates that the ratio of DMT to fumarate is 1 : 1.
“Solvate” refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Exemplary solvates thus include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.
“Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms such as racemates and optically pure stereoisomers of the compounds are contemplated herein. Chemical formulas and compounds which possess at least one stereogenic center, but are drawn without reference to stereochemistry, are intended to encompass both the racemic compound, as well as the separate stereoisomers, e.g., R- and/or S-stereoisomers, each permutation of diastereomers so long as those diastereomers are geometrically feasible, etc.
A “crystalline” solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules — with long range order — forming a crystal lattice, and thus displays sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern. In some instances, crystalline solids can exist in different crystalline forms known as “polymorphs,” which have the same chemical composition, but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. As such, polymorphs may have different solid-state physical properties to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility, etc. of the compound as well as the safety and efficacy of drug products based on the compound. In the process of preparing a polymorph, further purification, in terms of gross physical purity or optical purity, may be accomplished as well. As used herein, the term “amorphous” refers to a solid material having substantially no long range order in the position of its molecules — the molecules are arranged in a random manner so that there is effectively no well-defined arrangement, e.g., molecular packing, and no long range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having substantially no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. Thus, an “amorphous” subject compound/material is one characterized as having substantially no crystallinity — less than 10% crystallinity, less than 8% crystallinity, less than 6% crystallinity, less than 4% crystallinity, less than 2% crystallinity, less than 1% crystallinity, or 0% crystallinity — i.e., is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined for example by XRPD. For example, the % crystallinity can in some embodiments be determined by measuring the intensity of one or more peaks in the XRPD diffractogram compared to a reference peak, which may be that of a known standard or an internal standard. Other characterization techniques, such as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, may also be employed to determine the percent a subject compound/material is amorphous or crystalline, including quantitative methods which provide the above percentages in terms of weight percent.
When referencing X-ray powder diffraction (XRPD) patterns of materials of the present disclosure, the phrase “characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (29 ± 0.2°) selected from. . .” should be understood to include those materials characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (including all) of the recited characteristic XRPD diffraction peaks. Further, this phrase is intended to be open to the inclusion of other XRPD diffraction peaks not recited. It will be appreciated that the compounds herein can exist in different salt, solvate, stereoisomer, crystalline/amorphous (including polymorphic) forms, and the present disclosure is intended to include all permutations thereof, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of the subject compound.
The language “tamper resistant” is art-recognized to describe aspects of a drug formulation that make it more difficult to use the formulation to abuse the drug moiety of the formulation through e.g., extraction for intravenous use, or crushing for freebase use; and therefore, reduce the risk for abuse of the drug.
The term “stable,” “stability,” and the like, as used herein includes chemical stability and solid state (physical) stability. The term “chemical stability” means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no chemical degradation or decomposition. “Solid-state stability” means the compound can be stored in an isolated solid form, or the form of a solid formulation in which it is provided in admixture with, for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no solid-state transformation (e.g., hydration, dehydration, solvatization, desolvatization, crystallization, recrystallization or solid-state phase transition).
As used herein, the term “composition” is equivalent to the term “formulation.”
The term “treating” or “treatment” as used herein means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a companion animal) that includes: ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or alleviating one or more symptoms of the disease or medical condition in a patient. A treatment can provide a therapeutic benefit such as the eradication or amelioration of one or more of the physiological or psychological symptoms associated with the underlying condition, disease, or disorder such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be affected by the condition. In some embodiments, treatment may refer to prophylaxis, i.e., preventing the disease or medical condition from occurring or otherwise delaying the onset of the disease or medical condition in a patient. A “patient” or “subject,” used interchangeably herein, can be any animal, most commonly a mammal, including, for example, a human, a non-human mammal, a companion animal, livestock, etc. A patient or subject can have a condition to be treated or can be susceptible to a condition to be treated. In some embodiments, the patient or subject is a companion animal.
A “companion animal” refers to a domesticated or domestic-bred animal whose physical, emotional, behavioral, and social needs can be readily met as companions in the home, or in close daily relationship with humans. Examples of companion animals include, but are not limited to, dogs, cats, horses, rabbits, ferrets, birds, and guinea pigs.
A “psychopharmaceutical agent” is a chemical substance with the ability to cross the blood-brain barrier and act on the nervous system, resulting in alterations in perception, mood, consciousness, cognition, and/or behavior. Categories of psychopharmaceutical agents include anxiolytics (e.g., benzodiazepines, barbiturates, etc.), empathogen-entactogens (e.g., MDMA, MDA, AMT, etc.), stimulants (e.g., amphetamines, modafinil, etc.), depressants (e.g., sedatives, hypnotics, and opioids), and hallucinogens such as psychedelics, dissociatives, and deliriants (e.g., psilocybin, LSD, DMT, mescaline, salvia divinorum, scopolamine, etc.).
As used herein, and unless otherwise specified, the terms “manage,” “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease, disorder, or condition, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term “managing” encompasses treating a subject who had suffered from the particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition, or of one or more symptoms thereof.
“Therapeutically effective amount” refers to an amount of a compound(s) or its salt form sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder (prophylactically effective amount). As used herein, and unless otherwise specified, a “prophylactically effective amount” of an active agent, is an amount sufficient to prevent a disease, disorder, or condition, or prevent its recurrence. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
The term “administration schedule” is a plan in which the type, amount, period, procedure, etc. of the drug in the drug treatment are shown in time series, and the dosage, administration method, administration order, administration date, and the like of each drug are indicated. The date specified to be administered is determined before the start of the drug administration. The administration is continued by repeating the course with the set of administration schedules as “courses”. A “continuous” administration schedule means administration every day without interruption during the treatment course. If the administration schedule follows an “intermittent” administration schedule, then days of administration may be followed by “rest days” or days of non-administration of drug within the course. A “drug holiday” indicates that the drug is not administered in a predetermined administration schedule. For example, after undergoing several courses of treatment, a subject may be prescribed a regulated drug holiday as part of the administration schedule, e.g., prior to re-recommencing active treatment.
As used herein, a “bolus” is where a discrete amount of active pharmaceutical ingredient (API) (e.g., a psychopharmaceutical agent) is administered (e.g., by injection) within 30 minutes or less such that the concentration of the API in the body quickly increases. Bolus injections are typically administered intravenously (directly into the vein), intramuscularly (within the muscle), intradermally (beneath the skin), or subcutaneously (within the fat or skin). A bolus injection thus differs from an “infusion,” whereby a discrete amount of API (e.g., a psychopharmaceutical agent) is administered by single injection or multiple injections over a prolonged period of greater than 30 minutes, such that the concentration of the API in the body follows a more stable kinetic profile, in some cases reaching a steady-state, with a prolonged exposure period.
The language “toxic spikes” is used herein to describe spikes in concentration of any compound described herein that would produce side-effects of sedation or psychotomimetic effects, e.g., hallucination, dizziness, and nausea; which can not only have immediate repercussions, but also influence treatment compliance. In humans, side effects may become more pronounced at blood concentration levels above about 300 ng/mL (e.g. above about 300, 400, 500, 600 or more ng/mL), and toxic levels in non-human mammals such as companion animals may be determined through allometric scaling from the aforementioned human blood concentrations.
According to IUPAC, “osmolality” is the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water. In simpler terms, osmolality is an expression of the number of osmotically active particles (the number of solute particles) in 1 kg of a solution, represented herein as the number of milliosmoles (mOsm) per 1 kg of solution. Thus, osmolality is a function only of the number of particles, and is not related to particle molecular weight, size, shape, or charge (see D. K. Faria et al., M. E. Mendes and N. M. Sumita, J. Bras. Patol e. Med. Lab., 53, 1, 38-45 (2017) for a review of the measurement of serum osmolality). For example, one mole of a nondissociating substance (e.g., glucose) dissolved in 1 kg of water has an osmolality of 1 Osm/kg (1000 mOsm/kg), whilst one mole of a substance that dissociates into two separate species in solution (e.g., sodium chloride) dissolved in 1 kg of water has an osmolality of 2 Osm/kg (2000 mOsm/kg).
Where solutions are defined herein to be “isotonic” with one another, the solutions have the same osmolality. For example, where a formulation is defined to be isotonic with blood serum, the formulation has the same osmolality as blood serum. Blood serum typically has an osmolality of about 290 to about 310 mOsm/kg in dogs, about 308 to about 335 mOsm/kg in cats, and about 280 to about 310 mOsm/kg in horses.
“Syringeable” or “syringeability” refers to the force required to inject a given solution at a given rate via a chosen needle length and gauge, and relates to whether the formulation is administrable through a syringe. Flow through a hollow needle is characterized by the Hagen- Poiseuille equation (1):
Figure imgf000045_0001
where F = syringe stopper (plunger) force, Q = volumetric flow rate, p = dynamic viscosity, L = needle length, D = needle bore diameter, and A = syringe area.
Unless stated otherwise, concentrations expressed in terms of weight per volume (w/v) are calculated from grams (g) per milliliter (mL). These concentrations may be expressed as a percentage (% w/v), for example, the concentration of 1 g of solute in 100 mL of a solution is 1% w/v.
As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. As used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference as well as the singular reference unless the context clearly dictates otherwise. The term “about” in association with a numerical value means that the value may vary up or down by 5%. For example, for a value of about 100, means 95 to 105 (or any value between 95 and 105).
Pharmaceutical Formulation
Disclosed herein is an injectable pharmaceutical formulation comprising a drug/psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle. The pharmaceutical formulation is suitable for injection, thus its administration in therapy typically comprises parenteral injection of the formulation through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active pharmaceutical ingredient(s) contained therein is administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion. To be suitable for injection, i.e., “injectable” or “injectability,” it is meant that the formulation is in accordance with Pharmacopeial requirements of injections, for example as set forth in The United States Pharmacopeial (USP) Convention, General Requirements/<1> Injections, 33. For example, the injectable pharmaceutical formulations are prepared by methods designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and where appropriate, contain inhibitors of the growth of organisms (e.g., antimicrobial preservatives) and/or anti-oxidants. Examples of Pharmacopeial requirements include, but are not limited to, USP Pyrogen Test <151>, USP Bacterial Endotoxins Test <85>, USP Antimicrobial Effectiveness Testing <51>, USP Antimicrobial Agents — Content <341 >, USP Sterilization and Sterility Assurance of Compendial Articles <1211>, USP Particulate Matter in Injections <788>, and USP Sterility Tests <71>. For instance, to be suitable for injection, inter alia, Escherichia coli should be absent in 1 g of formulation; the total aerobic microbial count (TAMC) should be under 1,000 colony forming units (CFU)/g; and the total yeast and mold count (TYMC) should not exceed 100 CFU/g.
To be suitable for injection, i.e., “injectable” or “injectability,” it is further meant that the pharmaceutical formulation is characterized as having physiochemical properties, such as pH, osmolality, and viscosity, which enables administration through the skin or other external boundary tissue via needle, syringe, canula, catheter, or other suitable injection device without causing excessive tissue necrosis, pain, or inflammation (e.g., phlebitis) at the injection site. Injectable drug products generally have a pH of about 2 to 11 for IV and intramuscular injection, and a pH of about 3 to 9 for subcutaneous injection (Usach I, et al. Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Adv Ther. 2019 Nov;36(l l):2986-2996). pH values which are too high are associated with tissue necrosis, whereas pH values which are too low are associated with pain and inflammation at the injection site. Injectable drug products generally have an osmolality of 150 to 600 mOsm/kg, with osmolalities closest to that of subject blood serum (e.g., 275 to about 335 mOsm/kg) being preferred. Hypertonic injection solutions with an osmolality above 600 mOsm/kg have been reported to possibly cause crenation of red blood cells and significant pain, while hypotonic solutions with an osmolality below 150 mOsm/kg may cause hemolysis and pain at the injection site (Roethlisberger D. et al. If Euhydric and Isotonic Do Not Work, What Are Acceptable pH and Osmolality for Parenteral Drug Dosage Forms?, Journal of Pharmaceutical Sciences, 106(2), 2017, 446-456). Injectable drug products administered with common syringes and needle gauge generally have a viscosity of less than about 50 centipoise (cP), with higher viscosities sometimes requiring injection forces too high for common syringes and gauge needles to withstand. The drug may not even be administrable through a syringe (may not be “syringeable”). However, some injectable drug products with much higher viscosities (>100 to 10,000+ cP) can be administered by injection, for example, when administering non-Newtonian fluids or when using injection devices designed for high viscosity fluids such as auto-injectors for high viscosity fluids. The pH, osmolality, and viscosity of the pharmaceutical formulation of the present disclosure fall within the ranges reported to be suitable for injection, and suitable for subcutaneous injection in particular.
The pharmaceutical formulation is typically in the form of a solution, although other dosage forms are also contemplated such as suspensions, emulsions, micelles, liposomes, microspheres, and nanosystems which are suitable for injection. Solid forms which are suitable for solutions or suspensions in liquid prior to injection are also disclosed. In some embodiments, the pharmaceutical formulations are disclosed as ready -to-use sterile solutions. In some embodiments, the pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dry soluble products, including lyophilized powders and hypodermic tablets, reconstituted with an aqueous vehicle prior to use. In some embodiments, the pharmaceutical formulations are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dry insoluble products reconstituted with an aqueous vehicle prior to use. In some embodiments, the pharmaceutical formulations are disclosed as ready-to-use sterile emulsions.
In some embodiments, the injectable pharmaceutical formulation is suitable for intravenous administration (directly into the vein), i.e., is an intravenous pharmaceutical formulation. In some embodiments, the injectable pharmaceutical formulation is suitable for intramuscular administration (within the muscle), i.e., is an intramuscular pharmaceutical formulation. In some embodiment, the injectable pharmaceutical formulation is suitable for intradermal administration intradermally (beneath the skin), i.e., is an intradermal pharmaceutical formulation. In some embodiments, the injectable pharmaceutical formulation is suitable for subcutaneous administration (within the fat or the layer of skin directly below the dermis and epidermis), i.e., is a subcutaneous pharmaceutical formulation.
Subcutaneous administration is a minimally invasive mode of administration. Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of depot effect. Compared with other routes of administration, it is slower than intravenous and intramuscular injections but still faster than intradermal injections. The convenience and speed of subcutaneous delivery allows for increased treatment compliance and quicker access to medication when needed. Subcutaneous administration can be performed by injection or by implantation of a sustained or timed-release device beneath the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed. Subcutaneous formulations are usually much easier to handle for the practitioner/veterinarian. A particular advantage of the subcutaneous delivery route in the therapeutic methods of the present disclosure is that it allows the medical practitioner/veterinarian to perform the administration in a rather short intervention, compared to intravenous infusion protocols associated with DMT -based therapy. Injection volumes of up to about 50 mL are tolerated via the subcutaneous route in dogs, up to about 100 mL in cats, and up to about 10 mL in horses. Large subcutaneous injection volumes greater than these volumes are often associated with pain. When necessary or desirable, multiple doses (several unit dose formulations) can be injected at multiple sites of the body surface. Particular pharmacopeial requirements for subcutaneous injections include, but are not limited to, passing specifications of USP Particulate Matter in Injections <788>.
The pharmaceutical formulation may be suitable for bolus injection, in which a discrete amount of the psychopharmaceutical agent is administered by injection within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less. The bolus injection may involve a single injection or multiple injections performed within the above-described time range. Thus, administering multiple bolus injections within the above-mentioned time range of 30 minutes or less (e.g., two injections lasting 30 seconds each, administered within 5 minutes of one another) would be considered a bolus administration herein. In some embodiments, the bolus injection involves a single injection within the above time range. The pharmaceutical formulation may be suitable for bolus subcutaneous injection, such as a single bolus subcutaneous injection, i.e., the pharmaceutical formulation is a bolus subcutaneous pharmaceutical formulation. The pharmaceutical formulation may be suitable for bolus intramuscular injection, such as a single bolus intramuscular injection, i.e., the pharmaceutical formulation is a bolus intramuscular pharmaceutical formulation. The pharmaceutical formulation may be suitable for bolus intradermal injection, such as a single bolus intradermal injection, i.e., the pharmaceutical formulation is a bolus intradermal pharmaceutical formulation. The pharmaceutical formulation may be suitable for bolus intravenous injection, such as a single bolus intravenous injection, i.e., the pharmaceutical formulation is a bolus intravenous pharmaceutical formulation.
The pharmaceutical formulation may be suitable for infusion injection, in which a discrete amount of the psychopharmaceutical agent is administered by injection over a prolonged period of greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, greater than 110 minutes, greater than 120 minutes. The infusion injection may involve a single prolonged injection, or multiple injections (short or prolonged) within the above- described time range. Thus, administering multiple bolus injections over a prolonged period of greater than 30 minutes would be considered an infusion administration herein. In some embodiments, the infusion injection involves a single injection within the above time range. The pharmaceutical formulation may be suitable for infusion subcutaneous injection. The pharmaceutical formulation may be suitable for infusion intramuscular injection. The pharmaceutical formulation may be suitable for infusion intravenous injection.
Psychopharmaceutical agent
The injectable pharmaceutical formulation comprises a psychopharmaceutical agent (or more simply, a drug). The psychopharmaceutical agent may be an anxiolytic (e.g., benzodiazepines, barbiturates, etc.), an empathogen-entactogen (e.g., MDMA, MDA, AMT, etc.), a stimulant (e.g., amphetamines, modafinil, etc.), a depressant (e.g., sedatives, hypnotics, and opioids), and/or a hallucinogen such as a psychedelic (e.g., a tryptamine psychedelic), a dissociative, or a deliriant (e.g., psilocybin, LSD, DMT, mescaline, salvia divinorum, scopolamine, etc.). The psychopharmaceutical agent may be a free base compound, or a pharmaceutically acceptable salt of the free base compound. Combinations of psychopharmaceutical agents may also be used. In some embodiments, the psychopharmaceutical agent is a dissociative, a dissociative hallucinogen, an anesthetic, an arylcyclo-hexylamine, a 1,2-diarylethylamine, a P-keto- arylcyclohexylamine, and/or a compound that modulates the NMDA receptor. Examples of such psychopharmaceutical agents include, but are not limited to, ketamine, methoxetamine, deschloroketamine, N-ethyl deschloroketamine (eticyclidone), 3 -methoxyphencyclidine, methoxieticyclidine, ephenidine, lanicemine, dextromethorphan, dextrorphan, methoxyketamine, norketamine (e.g., (R)-norketamine, (S)-norketamine, or mixtures thereof), hydroxynorketamine (e.g., 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, or mixtures thereof), or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
In some embodiments, the psychopharmaceutical agent is an opioid. Examples of opioids include, but are not limited to, racemorphan, levorphanol, racemethorphan, buprenorphine, morphine, loperamide, morphine, codeine, hydrocodone, oxymorphone, buprenorphine, fentanyl, methadone, tramadol, alpha-methyl acetyl fentanyl, alfentanil, butyrfentanyl, carfentanil, 3- methylcarfentanil, 4-fluorofentanyl, beta-hydroxyfentanyl, alpha-methylfentanyl, cis-3- methylfentanyl, beta-hydroxy-3 -methylfentanyl, remifentanil, sufentanil, 3 -methylthiofentanyl, naloxone, and naltrexone, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
In some embodiments, the psychopharmaceutical agent is a cathinone, a 3,4- methylenedioxyamphetamine compound, an aminoalkyl-substituted benzofuran, a substituted amphetamine, an aminoindane, a stimulant, diphenhydramine, hydroxazine, phenylephrine, dopamine, adrenaline, lidocaine, oxymetazoline, clemastine, chlorpheniramine, or 6-chloro-2- aminotetralin. In some embodiments, the pharmaceutical compound is a cathinone, an aminoalkyl- substituted benzofuran, and an aminoindane, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof.
In some embodiments, the psychopharmaceutical agent is a lysergamide. Examples of lysergamides include, but are not limited to, methylisopropyllysergamide, ethylisopropyllysergamide, 6-allyl-6-nor-LSD, 6-ethyl-6-nor-lysergic acid diethylamide, 1-acetyl- LSD, l-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 1 -propionyl -lysergic acid diethylamide, 1-cyclopropionyl-d-lysergic acid diethylamide, N1 -butyryl -lysergic acid diethylamide, and 6-propyl-6-nor-lysergic acid diethylamide, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof. In some embodiments, the psychopharmaceutical agent is a phenethylamine. Examples of phenethylamines include, but are not limited to, mescaline, 2, 5 -dimethoxy -4- bromophenethyl amine (2C-B), 2-(4-iodo-2,5-dimethoxyphenyl)ethan-l -amine (2C-I), 2-(4- chloro-2,5-dimethoxyphenyl)ethan-l-amine (2C-C), 2,5-dimethoxy-4-iodoamphetamine, 2-[2,5- dimethoxy-4-(propylsulfanyl)phenyl]ethan-l -amine, and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
In some embodiments, the psychopharmaceutical agent is a tryptamine psychedelic. Examples of tryptamine psychedelics include, but are not limited to, N,N-dimethyltryptamine, N,N-diethyltryptamine, N,N-dipropyltryptamine, N-Methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, N,N-diisopropyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5- methoxy-N,N-diisopropyltryptamine, 5-methoxy-N,N-dimethyltryptamine, O-acetylpsilocin, psilocin, as well as those tryptamine psychedelics described hereinafter, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
Examples of psychopharmaceutical agents which can be categorized as hallucinogens such as a psychedelic (e.g., a tryptamine psychedelic), a dissociative, or a deliriant include, but are not limited to, 9,10-didehydro-6-allyl-N,N-diethylergoline-8P-carboxamide, 9,10-didehydro-6,N,N- triethylergoline-8P-carboxamide, N,N-dimethyltryptamine, N,N-diethyltryptamine, 5-methoxy- N,N-dimethyltryptamine, N,N-dibutyltryptamine, N,N-diethyltryptamine, N,N- diisopropyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5-methoxy-N,N- diisopropyltryptamine, 5 -Methoxy-a-m ethyltryptamine, 2,a-dimethyltryptamine, a,N- dimethyltryptamine, N,N-dipropyltryptamine, N-ethyl-N-isopropyltryptamine, a-ethyltryptamine, O-acetylpsilocin, psilocin, harmaline (7-methoxy-l-methyl-p-carboline), harmine (7-Methoxy-p- carboline), 4-hydroxy-diethyltryptamine and phosphate ester, 4-hydroxy-diisopropyltryptamine, 4-hydroxy-methyl-tryptamine, 4-hydroxy-tryptamine, 5 -hydroxy -tryptamine, 4-hydroxy- dipropyltryptamine, 4-hydroxy-N-methyl-N-ethyl-tryptamine, 4-hydroxy-N-methyl-N-isopropyl- tryptamine, 4-hydroxy-N-N-tetramethylene-tryptamine, d-iso-LSD, I-LSD, I-iso-LSD, N,N- diisopropyl-4,5-methylenedioxy tryptamine, N,N-diisopropyl-5,6-methylenedioxy tryptamine, N,N-dimethyl-4,5-methylenedioxy tryptamine, N,N-dimethyl-5,6-methylenedioxy tryptamine, 2- methyl-DMT, 5-MeO-diethyltryptamine, 5-MeO-diisopropyltryptamine, 4-MeO-N-isopropyl-N- methyl-tryptamine, 5-MeO-N-isopropyl-N-methyl-tryptamine, 5-MeO-NMT, 5-MeO-2,N,N- trimetyltryptamine, N-isopropyl-N-methyl-tryptamine, alpha-methyltryptamine, alpha-methyl-4- OH-tryptamine, N-methyl-tryptamine, 5-MeO-a,N-dimethyl-tryptamine, 4-allyloxy-3,5- dimethoxyphenethylamine, 2,5-dimethoxy-4-methylthioamphetamine, 2, 5 -dimethoxy -4- ethylthioamphetamine, 2, 5-dimethoxy-4-i -propylthioamphetamine, 2,5-dimethoxy-4- phenylthioamphetamine, 2,5-dimethoxy-4-n-propylthioamphetamine, 2,5-dimethoxy-a-ethyl-4- methylphenethylamine, 3, 4-diethoxy-5-methoxy -phenethylamine, 4-n-butoxy-3, 5 -dimethoxy- phenethylamine, 2.5-dimethoxy-4,N-dimethylamphetamine, 4-bromo-2,5-P- trimethoxyphenethyl amine, 4-methyl-2,5,P-trimethoxyphenethylamine, P-m ethoxy-3, 4- methylenedi oxyphenethylamine, , 3,4,5,3-tetramethoxyphenethylamine, 3, 5 -dimethoxy -4- bromoamphetamine, 2-bromo-4,5-methylenedi oxy amphetamine, 4-bromo-
2, 5, dimethoxyphenethylamine, 4-benzyloxy-3,5-dimethoxy amphetamine, 2, 5 -dimethoxy -4- chlorophenethylamine, 2,5-dimethoxy-4-methylphenethylamine, 2, 5 -dimethoxy -4- ethylphenethylamine, 3 , 5 -dimethoxy-4-ethoxy amphetamine, 2,5-dimethoxy-4- fluorophenethylamine, 2.5-dimethoxy-3,4-dimethylphenethylamine, 2,5-dimethoxy-3,4-
(trimethylene)phenethylamine, 2,5-dimethoxy-3,4-(tetramethylene)phenethylamine, 3,6- dimethoxy-4-(2-aminoethyl)benzonorborane, l,4-dimethoxynapthyl-2-ethylamine, 2,5- dimethoxyphenethylamine, 2,5-dimethoxy-4-iodoophenethylamine, 2,5-dimethoxy-4- nitrophenethylamine, 2,5-dimethoxy-4-i-propoxyphenethylamine, 2, 5 -dimethoxy -4-n- propoxyphenethyl amine, 4-cyclopropyl-3,5-dimethoxyphenethylamine, 2,5-dimethoxy-4- methylseleneophenethylamine, 2,5-dimethoxy-4-methylthiophenethylamine, 2, 5 -dimethoxy -4- ethylthiophenethylamine, 2,5-dimethoxy-4-i-propylthiophenethylamine, 2,6-dimethoxy-4-i- propylthiophenethylamine, 2,5-dimethoxy-4-n-propylthiophenethylamine, 2,5-dimethoxy-4- cyclopropylmethylthiothiophenethylamine, 2,5-dimethoxy-4-t-butylthiophenethylamine, 2,5- dimethoxy-4-(2-methoxyrthylthio)phenethylamine, 2, 5 -dimethoxy -4- cyclopropylthiophenethylamine, 2,5-dimethoxy-4-s-butylthiophenethylamine, 2,5-dimethoxy-4- (2-fluorothio)phenethylamine, 2,5-dimethoxy-4-trideuteromethoxyphenethylamine, 2,4,5- trimethoxy-P,P-dideuterophenethylamine, 2,5-dimethoxy-4-methylphenethylamine, 2,4- dimethoxy amphetamine, 2, 5 -dimethoxy amphetamine, 2, 4-dimethoxy amphetamine, 2,5- dimethoxy-3,4-methylenedi oxyamphetamine, 2,5-dimethoxy-4-bromoamphetamine, 2,5- dimethoxy-4-chloroamphetamine, 2,5-dimethoxy-4-(2-fluoroethyl)-amphetamine, 2,5- dimethoxy-4-iodoamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,6-dimethoxy-4- methylamphetamine, 2,5-dimethoxy-4-n-propylamphetamine, 3, 5 -dimethoxy -4- ethoxyphenethylamine, 2,4,5-triethoxyamphetamine, 2,4-diethoxy-5-methoxyamphetamine, 2,5- diethoxy-4-methoxyamphetamine, 4,5-dimethoxy-2-ethoxyamphetamine, N-hydroxy-N-methyl- 3, 4-m ethylenedi oxyamphetamine, 2,5-dimethoxy-3,4-(trimethylene)amphetamine, 3,6- dimethoxy-4-(2-aminopropyl)benzonorborane, 2,5-dimethoxy-3,4-dimethylamphetamine, 2,5- dimethoxy-4-ethylthio-N-hydroxyphenethylamine, 2,5-dimethoxy-N-hydroxy-4-n- propylthiophenethylamine, 2,5-dimethoxy-4-s-butylthio-N-hydroxyphenethylamine, 3,5- dimethoxy-4-i-propoxyphenethylamine, 5-ethoxy-2-methoxy-4-methylamphetamine, 2-amino- (3 ,4-methylenedioxyphenyl)butane, 3 -methoxy -4, 5 -methylenedi oxyphenethylamine, 3,4,5- trimethoxyphenethyl amine, 3,5-dimethoxy-4-methalloxyphenethylamine, 3,4- m ethylenedi oxyamphetamine, 3,4-methylenedioxy-N-ethylamphetamine, 3,4-methylenedioxy-N- methylamphetamine, 3,4-methylenedioxy-N-hydroxyamphtamine, 3,4-methylenedioxy-5- ethoxyphenethylamine, 2, 5 -dimethoxy -4-ethoxyapmphetamine, 3-methoxy-4- ethoxyphenethylamine, 2-methylamino-l-(3,4-methylenedioxyphenyl)butane, 3 -m ethoxy-4, 5- methylenedi oxyamphetamine, 2-methoxy-4,5-methylenedi oxyamphetamine, 2-m ethoxy-3, 4- methylenedi oxyamphetamine, 4-m ethoxy-2, 3 -methylenedi oxyamphetamine, 3,5-dimethoxy-4-n- propoxyphenethyl amine, 4-ethoxy-5-methoxy-3-methylthiophenethylamine, 3,5-dimethoxy-4- ethylthiophenethylamine, 3,4-dimethoxy-5-methylthiophenethylamine, 3,5-dimethoxy-5- methylthiophenethylamine, 3,4,5-trimethoxyamphetamine, 2,4, 5 -trimethoxy amphetamine, 2,3,5- trimethoxyamphetamine, 2,3,6-trimethoxyamphetamine, 2,4,6-trimethoxyamphetamine, 4,5- dimethoxy-3-ethylthiophenethylamine, 4-ethyl-2-methoxy-5-methylthioamphetamine, 5- methoxy-4-methyl-2-methylthioamphetamine, 2-methoxy-4-methyl-5-methylthioamphetamine, 2-methoxy-4-methyl-5-methylsulfinylamphetamine, 3,5-dimethoxy-4-n- propylthiophenethylamine, salvinorin A, ibotenic acid, muscimol, dextromethorphan, ketamine, esketamine (the S(+)-enantiomer of ketamine), norketamine (e.g., (R)-norketamine, (S)- norketamine, or mixtures thereof), hydroxynorketamine (e.g., 2R,6R-hydroxynorketamine, 2S,6S- hydroxynorketamine, or mixtures thereof), phencyclidine, dizocilpine (MK-801), scopolamine, hyoscyamine, aporphine, lysergic acid amide, cathine, cathinone, and voacangine, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
Tryptamine psychedelic In some embodiments, the psychopharmaceutical agent is a tryptamine psychedelic. Tryptamine psychedelics generally share a basic core structure of an indole (a fused a fused benzene and pyrrole ring), and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen), as represented below. Many tryptamine psychedelics are 5-HT2A receptor agonists, i.e., they increase the activity of a 5-HT2A receptor, which is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family, and includes both partial and full agonists.
Figure imgf000054_0001
In some embodiments, the tryptamine psychedelic is optionally substituted on the tryptamine ring. In some embodiments, the tryptamine psychedelic is an N,N-dialkyltryptamine. In some embodiments, the tryptamine psychedelic is N,N-dimethyltryptamine, N,N- diethyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, N,N-diisopropyltryptamine, wherein the tryptamine is optionally substituted, or a combination thereof. In some embodiments, the tryptamine psychedelic is substituted with one or more deuterium atoms. In some embodiments, the tryptamine psychedelic is optionally substituted at the 4- or 5-position of the tryptamine ring with a substituent selected from hydroxy, acetoxy, or methoxy. In some embodiments, the tryptamine is 4-hydroxy-N-methyl-N- ethyltryptamine, psilocin, 5-methoxy-N,N-diisopropyltryptamine, 5 -methoxy -N,N- dimethyltryptamine, or O-acetylpsilocin (4-acetoxy-N,N-dimethyltryptamine), or a combination thereof.
The tryptamine psychedelic may be a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), defined hereinafter. The tryptamine psychedelic may be a pharmaceutically acceptable salt of a single compound of the present disclosure or a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure. The injectable pharmaceutical formulation comprises (as the tryptamine psychedelic) a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), when it comprise ions (protonated forms) of the compounds of the present disclosure and ions that counter the charge of the compounds of the present disclosure (counterions) in solution. Accordingly, the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., e.g., a compound of Formula (I) through (III)) may be pre-formed, for example as a fumarate salt of a compound of the present disclosure, and subsequently combined with the release modifier and the aqueous vehicle, to form the injectable pharmaceutical formulation. In other words, the injectable pharmaceutical formulation may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)). Alternatively, the pharmaceutically acceptable salt of a compound of the present disclosure within the pharmaceutical formulation may be formed in-silu. for example, by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H+ (aq) ions capable of ionizing/protonating the compounds of the present disclosure. While a distribution of free base and protonated species (salt form) of the compound may exist in solution depending on the pH of the pharmaceutical formulation, the pharmaceutical formulation generally contains a molar proportion of protonated compound (salt form) of least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%. In most cases, the pharmaceutical formulation contains a molar proportion of protonated compound (salt form) of least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, at least 99.9% for most favorable aqueous solubility.
In some embodiments, the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I), or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000056_0001
wherein:
Xi and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
Yi and Y2 are independently selected from the group consisting of hydrogen and deuterium;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy;
Re and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and
Rs and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively Rs and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
Xi and X2 may be the same, or different. In some embodiments, Xi and X2 are the same. In some embodiments, Xi and X2 are hydrogen. In some embodiments, Xi and X2 are deuterium. In some embodiments, Xi and X2 are different. In some embodiments, Xi is hydrogen or deuterium, and X2 is a substituted or unsubstituted Ci-Ce alkyl. In some embodiments, X2 is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, and n- propyl, preferably methyl. In some embodiments, X2 is a substituted Ci-Ce alkyl. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a Ci alkyl group (i.e., methyl group), the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of Xi and X2 is deuterium while the other is hydrogen. In some embodiments, one or more of Xi and X2 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, one or more of Xi and X2 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, one or more of Xi and X2 is a substituted C3-C10 cycloalkyl. Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, Xi and/or X2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl.
Yi and Y2 may be the same, or different. In some embodiments, Yi and Y2 are the same. In some embodiments, Yi and Y2 are hydrogen. In some embodiments, Yi and Y2 are deuterium. In some embodiments, Yi and Y2 are different. In some embodiments, one of Yi and Y2 is deuterium while the other is hydrogen.
In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R2 is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is a substituted Ci-Ce alkyl. When R2 is a substituted Ci-Ce alkyl, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a Ci alkyl group (i.e., methyl group), the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R2 is an unsubstituted or substituted alkynyl. In some embodiments, R2 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R2 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R2is a substituted C3-C10 cycloalkyl. Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R2 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R2 is an unsubstituted or substituted aryl. In some embodiments, R2 is an unsubstituted or substituted heteroaryl.
R4 and R5 may be the same, or different. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxyl. In some embodiments, R4is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R4 is a substituted Ci-Ce alkyl. When R4 is a substituted Ci-Ce alkyl, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a Ci alkyl group (i.e., methyl group), the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4is a substituted alkoxy. When R4is a substituted alkoxy, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkoxy group may contain one, or more than one, substituent. For example, when the alkoxy group is a Ci alkoxy group (i.e., methoxy group), the substituted Ci alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R4 is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio. In some embodiments, R4 is a substituted alkylthio. The alkylthio group may contain one, or more than one, substituent. In some embodiments, R4is an alkylthio group substituted with one or more deuterium. The alkylthio group may contain one, or more than one, deuterium substituent. For example, when the alkylthio group is a Ci alkylthio group (i.e., a methylthio group), the deuterium substituted Ci alktlthio group may be -SCDH2, -SCD2H, and -SCD3. In some embodiments, R4 is a haloalkylthio (an alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH2CH2CH2CF3, with particular mention being made to -SCH2F, -SCHF2, -SCF3. In some embodiments, R4 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy (- OCOCH2CH2CH3).
In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, Rs is an unsubstituted Ci-Ce alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R5 is a substituted Ci-Ce alkyl. When R5 is a substituted Ci-Ce alkyl, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a Ci alkyl group (i.e., methyl group), the substituted Ci alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R5 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, Rs is a substituted alkoxy. When Rs is a substituted alkoxy, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkoxy group may contain one, or more than one, substituent. For example, when the alkoxy group is a Ci alkoxy group (i.e., methoxy group), the substituted Ci alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, - OCF2H, -OCF3, etc. In some embodiments, Rs is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio. In some embodiments, Rs is a substituted alkylthio. The alkylthio group may contain one, or more than one, substituent. In some embodiments, Rs is an alkylthio group substituted with one or more deuterium. The alkylthio group may contain one, or more than one, deuterium substituent. For example, when the alkylthio group is a C1 alkylthio group (i.e., a methylthio group), the deuterium substituted C1 alktlthio group may be -SCDH2, -SCD2H, and -SCD3. In some embodiments, R5 is a haloalkylthio (an alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH2CH2CH2CF3, with particular mention being made to -SCH2F, -SCHF2, -SCF3. In some embodiments, R5 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy ( -OCOCH2CH2CH3). R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. In some embodiments, R6 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is a halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R6 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted a C1-C6 alkyl). In some embodiments, R6 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R6 is a substituted C1-C6 alkyl. When R6 is a substituted C1-C6 alkyl, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a C1 alkyl group (i.e., methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R6 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R6 is an unsubstituted or substituted alkynyl. In some embodiments, R6 is an unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, R6 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R6 is a substituted C3-C10 cycloalkyl. Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R6 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R6 is an unsubstituted or substituted aryl. In some embodiments, R6 is an unsubstituted or substituted heteroaryl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is a halogen, e.g., fluoro, chloro, bromo, and iodo. In some embodiments, R7 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted a C1-C6 alkyl). In some embodiments, R7 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R7 is a substituted C1-C6 alkyl. When R7 is a substituted C1-C6 alkyl, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a C1 alkyl group (i.e., methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R7 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R7 is an unsubstituted or substituted alkynyl. In some embodiments, R7 is an unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, R7 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R7 is a substituted C3-C10 cycloalkyl. Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R7 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R7 is an unsubstituted or substituted aryl. In some embodiments, R7 is an unsubstituted or substituted heteroaryl. R8 and R9 may be the same, or different. In some embodiments, R8 and R9 are the same. In some embodiments, R8 and R9 are hydrogen. In some embodiments, R8 and R9 are deuterium. In some embodiments, R8 and R9 are unsubstituted or substituted alkyl, such as an unsubstituted or substituted C1-C6 alkyl. In some embodiments, R8 and R9 are different. In some embodiments, R8 is hydrogen, and R9 is an unsubstituted or substituted C1-C6 alkyl. In some embodiments, R8 and/or R9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl, preferably methyl. In some embodiments, R8 and/or R9 is a substituted C1-C6 alkyl. The alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a C1 alkyl group (i.e., methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R8 and/or R9 is an alkyl substituted with one or more deuterium, e.g., a C1-C6 alkyl group substituted with one or more deuterium. The alkyl group may contain one, or more than one, deuterium substituent. For example, when the alkyl group is a C1 alkyl group (i.e., methyl group), the deuterium substituted C1 alkyl group may be -CDH2, -CD2H, and -CD3, with particular mention being made to -CD3. In some embodiments, R8 and/or R9 is a haloalkyl, examples of which include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, - CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular mention being made to -CH2CH2CH2F, -CH2CH2CHF2, and -CH2CH2CF3. In some embodiments, R8 and/or R9 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R8 and/or R9 is an unsubstituted or substituted alkynyl. In some embodiments, R8 and/or R9 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R8 and/or R9 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R8 and/or R9 is a substituted C3-C10 cycloalkyl. Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R8 and/or R9 is an unsubstituted or substituted heterocycloalkyl. In some embodiments, R8 and/or R9 is an unsubstituted or substituted aryl. In some embodiments, R8 and/or R9 is an unsubstituted or substituted heteroaryl. In some embodiments, R8 and R9 together with the nitrogen atom attached thereto are joined to form an unsubstituted or substituted heterocycloalkyl. In some embodiments, R8 and R9 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl. The unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4- membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R8 and R9), and may optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of unsubstituted heterocycloalkyl groups formed from joining R8 and R9 together with the nitrogen atom attached thereto include, but are not limited to,
Figure imgf000062_0001
Figure imgf000063_0001
In some embodiments, Rs and R9 together with the nitrogen atom attached thereto are joined to form a substituted heterocycloalkyl. The substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening Rs and R9), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of the substituted heterocycloalkyl group include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1, 2,3,4- tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at least one substituent. The substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The substituted heterocycloalkyl formed from joining Rs and R9 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents. The substituent may be located on a carbon ring atom or on a hetero-ring atom. Examples of substituted heterocycloalkyl groups formed from joining R8 and R9 together with the nitrogen atom attached thereto include, but are not limited to,
Figure imgf000064_0001
In some embodiments, the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I), or a stereoisomer, solvate, or prodrug thereof, wherein any one or more of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 optionally comprises deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 comprises deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, R5, R8, and R9 comprises deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, R8, and R9 comprises deuterium. In some embodiments, X1, X2, R8, and R9 comprise deuterium. In some embodiments, X1, X2, Y1, Y2, R8, and R9 comprise deuterium. In some embodiments, X1, X2, and R5 comprise deuterium. In some embodiments, X1, X2, Y1, Y2, R5, R8, and R9 comprise deuterium. In some embodiments, the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (II), or a stereoisomer, solvate, or prodrug thereof
Figure imgf000065_0001
wherein: X1 and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, and R2, R4, R5, R6, and R7 are independently hydrogen or deuterium. X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen. Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, Y1 is deuterium and Y2 is hydrogen. In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium. In some embodiments, each Z1 is hydrogen. In some embodiments, each Z1 is deuterium. In some embodiments, one Z1 is hydrogen, while the other two Z1’s are deuterium. In some embodiments, one Z1 is deuterium, while the other two Z1’s are hydrogen. In some embodiments, each Z2 is hydrogen. In some embodiments, each Z2 is deuterium. In some embodiments, one Z2 is hydrogen, while the other two Z2’s are deuterium. In some embodiments, one Z2 is deuterium, while the other two Z2’s are hydrogen. In some embodiments, each Z1 and Z2 is hydrogen. In some embodiments, each Z1 and Z2 is deuterium. In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is hydrogen. R2, R4, R5, R6, and R7 may be the same, for example, R2, R4, R5, R6, and R7 may each be hydrogen, or alternatively, R2, R4, R5, R6, and R7 may each be deuterium. In some embodiments, at least one of R2, R4, R5, R6, and R7 is deuterium, or at least two of R2, R4, R5, R6, and R7 are deuterium, or at least three of R2, R4, R5, R6, and R7 are deuterium, or at least four of R2, R4, R5, R6, and R7 are deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, Z1, Z2, R2, R4, R5, R6, and R7 is deuterium. In some embodiments, X1, X2, Z1 and Z2 are deuterium. In some embodiments, X1, X2, Y1, and Y2 are deuterium. In some embodiments, X1, X2, Y1, Y2, Z1, and Z2 are deuterium. In some embodiments, the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (III), or a stereoisomer, solvate, or prodrug thereof
Figure imgf000066_0001
wherein: X1 and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, each Z3 is independently hydrogen or deuterium, and R2, R4, R6, and R7 are independently hydrogen or deuterium. X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen. Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, Y1 is deuterium and Y2 is hydrogen. In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium. In some embodiments, each Z1 is hydrogen. In some embodiments, each Z1 is deuterium. In some embodiments, one Z1 is hydrogen, while the other two Z1’s are deuterium. In some embodiments, one Z1 is deuterium, while the other two Z1’s are hydrogen. In some embodiments, each Z2 is hydrogen. In some embodiments, each Z2 is deuterium. In some embodiments, one Z2 is hydrogen, while the other two Z2’s are deuterium. In some embodiments, one Z2 is deuterium, while the other two Z2’s are hydrogen. In some embodiments, each Z1 and Z2 is hydrogen. In some embodiments, each Z1 and Z2 is deuterium. In some embodiments, each Z3 is hydrogen. In some embodiments, each Z3 is deuterium. In some embodiments, one Z3 is hydrogen, while the other two Z3’s are deuterium. In some embodiments, one Z3 is deuterium, while the other two Z3’s are hydrogen. In some embodiments, each Z1, Z2, and Z3 is hydrogen. In some embodiments, each Z1 and Z2 is hydrogen and each Z3 is deuterium. In some embodiments, each Z1, Z2, and Z3 is deuterium. In some embodiments, each Z1 and Z2 is deuterium, and each Z3 is hydrogen. In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is hydrogen. R2, R4, R6, and R7 may be the same, for example, R2, R4, R6, and R7 may each be hydrogen, or alternatively, R2, R4, R6, and R7 may each be deuterium. In some embodiments, at least one of R2, R4, R6, and R7 is deuterium, or at least two of R2, R4, R6, and R7 are deuterium, or at least three of R2, R4, R6, and R7 are deuterium. In some embodiments, at least one of X1, X2, Y1, Y2, Z1, Z2, Z3, R2, R4, R6, and R7 is deuterium. In some embodiments, X1, X2, Z1 and Z2 are deuterium and each Z3 is hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium and each Z3 is hydrogen. In some embodiments, X1, X2, Y1, Y2, Z1, and Z2 are deuterium and each Z3 is hydrogen. In some embodiments, X1, X2, and Z3 are deuterium. In some embodiments, X1, X2, Z1, Z2, and Z3 are deuterium. In some embodiments, X1, X2, Y1, Y2, and Z3 are deuterium. In some embodiments, X1, X2, Y1, Y2, Z1, Z2, and Z3 are deuterium. In some embodiments, the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I) through (III), which include, but are not limited to, the following exemplary compounds
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
or a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
In some embodiments, the compound, e.g., a compound of Formula (I) or (II), is a deuterated analog of DMT, examples of which include, but are not limited to,
Figure imgf000098_0002
Figure imgf000099_0001
In some embodiment, the deuterated analog of DMT is one or more of 2-(1H-indol-3-yl)- N,N-dimethylethan-1-amine-1,1-d2 (I-2); 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 1,1,2,2-d4 (I-8); 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10); 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1-d2 (I-6); 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7); and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the compound, e.g., a compound of Formula (I) or (III), is a deuterated analog of 5-MeO-DMT, examples of which include, but are not limited to,
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
In some embodiment, the deuterated analog of 5-MeO-DMT is one or more of 2-(5- methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20); 2-(5-methoxy-1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-22); 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23); 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1-d2 (I-18); 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 2,2-d2 (I-19); 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-24); 2-(5- (methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-34); 2-(5-(methoxy- d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-36); 2-(5-(methoxy-d3)-1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-37); 2-(5-(methoxy-d3)-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-32); 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33); 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,2-d2 (I-38); 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine- 1,1-d2 (I-28); 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-29); 2-(5- (methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26); 2-(5-(methoxy-d3)-1H- indol-3-yl)-N,N-dimethylethan-1-amine-2-d (I-27); and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- dimethylethan-1-amine (I-25). Any position in the compounds defined herein as having deuterium have a minimum deuterium incorporation that is greater than that found naturally occurring in hydrogen (about 0.016 atom %). In some embodiments, any position in the compound defined as having deuterium has a minimum deuterium incorporation of at least 10 atom %, at least 20 atom %, at least 25 atom %, at least 30 atom %, at least 40 atom %, at least 45 atom %, at least 50 atom %, at least 60 atom %, at least 70 atom %, at least 80 atom %, at least 90 atom %, at least 95 atom %, at least 99 atom % at the site of deuteration. The compounds described herein, e.g., compounds of Formula (I) through (III), may contain a stereogenic center. In such cases, the compounds may exist as different stereoisomeric forms, even though Formula (I) through (III) are drawn without reference to stereochemistry. Accordingly, the present disclosure includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known in the art. In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (III), are non-stereogenic. In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (III), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (III), are enantiomerically enriched (one enantiomer is present in a higher percentage), including enantiomerically pure. In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (III), are provided as a single diastereomer. In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (III), are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixtures may include equal mixtures, or mixtures which are enriched with a particular diastereomer (one diastereomer is present in a higher percentage than another).
As described herein, a racemic compound, e.g., a compound of Formula (I) through (III), may contain about 50% of the R- and S-stereoisomers based on a molar ratio (about 48 to about 52 mol %, or about a 1 : 1 ratio)) of one of the isomers. In some embodiments, a pharmaceutical formulation, medicament, or method of treatment may involve combining separately produced compounds of the R- and S-stereoisomers in an approximately equal molar ratio (e.g., about 48 to 52%). In some embodiments, a medicament or pharmaceutical formulation may contain a mixture of separate compounds of the R- and S-stereoisomers in different ratios. In some embodiments, the pharmaceutical formulation contains an excess (greater than 50%) of the R-enantiomer. Suitable molar ratios of R/S may be from about 1.5: 1, 2: 1, 3: 1, 4: 1, 5: 1, 10:1, or higher. In some embodiments, a pharmaceutical formulation may contain an excess of the S-enantiomer, with the ratios provided for R/S reversed. Other suitable amounts ofR/S may be selected. For example, the R-enantiomer may be enriched, e.g., may be present in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In other embodiments, the S-enantiomer may be enriched, e.g., in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between all these exemplary embodiments as well as greater than and less than them while still within the disclosure, all are included. Pharmaceutical formulations may contain a mixture of the racemate and a separate compound of Formula (I) through (III), in salt form.
In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2 receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2A receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HTIA receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2C receptor. In some embodiments, the tryptamine psychedelic used in the preparation of the pharmaceutical formulation is chemically pure, for example has a purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by UPLC or HPLC. In some embodiments, the tryptamine psychedelic has no single impurity of greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2%, measured by UPLC or HPLC. In some embodiments, the tryptamine psychedelic has a chemical purity of greater than 97 area %, greater than 98 area %, or greater than 99 area % by UPLC or HPLC. In some embodiments, the tryptamine psychedelic has no single impurity greater than 1 area %, greater than 0.5 area %, greater than 0.4 area %, greater than 0.3 area %, or greater than 0.2 area % as measured by UPLC or HPLC.
Acids which may be used to form the pharmaceutically acceptable (acid addition) salts of the compounds disclosed herein, e.g., compounds of Formula (I) through (III), include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2- hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthal ene-2-sulfonic acid, naphthalene- 1,5- disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acids (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di- acids, e.g., adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.). Combinations of acids may also be used to form a mixture of acid addition salts. When the injectable pharmaceutical formulation is prepared from a pre-formed pharmaceutically acceptable salt of a compound disclosed herein, certain salt forms are preferred among the list above because they possess physical and pharmaceutical characteristics/properties which make them well-suited for pharmaceutical preparation and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of Formula (I) through (III)) are those that possess one or more of the following characteristics: are easy to prepare in high yield with a propensity towards salt formation; are stable and have well-defined physical properties such as crystallinity, lack of polymorphism, and high melting/enthalpy of fusion; have slight or no hygroscopicity; are free flowing, do not cohere/adhere to surfaces, and possess a regular morphology; have acceptable aqueous solubility for the intended route of administration; and/or are physiologically acceptable, e.g., do not cause irritation when administered to mammals.
Crystallinity
When pre-formed as a solid, the pharmaceutically acceptable salt of the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) may be crystalline or amorphous, preferably crystalline, as determined e.g., by X-ray powder diffraction (XRPD). In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure is amorphous, e.g., as determined by XRPD and/or DSC. The pharmaceutically acceptable salt of the compound of the present disclosure can be in a stable amorphous form. In some embodiments, a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of the present disclosure is provided, wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of the present disclosure is in amorphous form, e.g., as determined by X-ray powder diffraction and/or DSC. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure is crystalline. Crystalline forms are advantageous in terms of e.g., stability and providing well-defined physical properties, which is desirable for pharmaceutical preparation and administration. The pharmaceutically acceptable salt of the compound of the present disclosure can be in a stable crystalline form. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a percent crystallinity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5%, and up to 100%, as determined by XRPD and/or DSC analysis. In some embodiments, a highly pure crystalline form of a pharmaceutically acceptable salt of a compound of the present disclosure is provided, wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of present disclosure is in crystalline form, e.g., as determined by X-ray powder diffraction and/or DSC. Preference is given to those pre-formed salt forms with high crystallinity, as determined e.g., by discrete and sharp Bragg diffractions in the X-ray diffractograms. XRPD analyses can be carried out, e.g., on a Bruker D5000 X-ray powder diffractometer using CuKα radiation (wavelength = 1.54060 Å). The instrument may be equipped with a fine focus X-ray tube. The tube voltage and amperage can be set to 40 kV and 30 mA, respectively. The divergence and scattering slit widths can be set at 2 mm and the detector slit width can be set at 0.2 mm. Diffracted radiation can be detected by a NaI scintillation detector. A theta-two theta continuous scan from 2.0 to 40° (4 seconds per step; 0.01° step size) can be used. In terms of pharmaceutical production processes, advantageous salt forms of the compounds of the present disclosure are those that readily afford a crystalline solid on crystallization in acceptable yield without proceeding via an oil, and with favorable volume factors, making them suitable for mass production. Salts forms of the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) can in some cases exist in different polymorphs (i.e., forms having a different crystal structure), however, preferred salt forms of the present disclosure are those which can be crystallized into a single crystalline form or single polymorph, as determined by XRPD and/or differential scanning calorimetry (DSC). It is also generally desirable for the salt forms to be free flowing, not cohere/adhere to surfaces, and possess a regular morphology. Chemical/Solid-state Stability In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a melt onset of from about 100°C, from about 110°C, from about 120°C, from about 130°C, from about 140°C, from about 150°C, from about 160°C, from about 170°C, from about 180°C, from about 190°C, and up to about 250°C, up to about 225°C, up to about 210°C, up to about 200°C, as determined by DSC. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has an enthalpy of fusion of from about 90 J·g-1, from about 100 J·g-1, from about 110 J·g-1, from about 120 J·g-1, from about 130 J·g-1, from about 140 J·g-1, from about 150 J·g-1, from about 160 J·g-1, and up to about 190 J·g-1, up to about 180 J·g-1, up to about 170 J·g-1, as determined by DSC. Pre-formed pharmaceutically acceptable salts of the compound of the present disclosure suitable for pharmaceutical manufacture may also be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic. The hygroscopicity may be measured herein by performing a moisture adsorption-desorption isotherm using a dynamic vapor sorption (DVS) analyzer with a starting exposure of 30% relative humidity (RH), increasing humidity up to 95% RH, decreasing humidity to 0%, and finally increasing the humidity back to the starting 30% RH, and classified according to the following: non-hygroscopic: < 0.2%; slightly hygroscopic: ≥ 0.2% and < 2%; hygroscopic: ≥ 2% and < 15%; very hygroscopic: ≥ 15%; deliquescent: sufficient water is absorbed to form a liquid; all values measured as weight increase (w/w due to acquisition of water) at >95% RH and 25°C. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a weight increase at >95% RH of less than 1% w/w, less than 0.8% w/w, less than 0.6% w/w, less than 0.5% w/w, less than 0.4% w/w, less than 0.3% w/w, less than 0.2% w/w, less than 0.1% w/w, less than 0.08% w/w, less than 0.06% w/w, less than 0.05% w/w, less than 0.02% w/w, as determined by DVS. Pre-formed pharmaceutically acceptable salts of the compounds of the present disclosure can be maintained/stored in open or closed environments, such as in open or closed flasks/vials, under ambient or stress conditions e.g., 25°C/60% RH, 25°C/90+% RH, 40°C/75% RH, etc. without appreciable degradation (e.g., without appreciably diminished chemical purity) or physical changes (e.g., changed forms, deliquesced, etc.). For example, dry powder samples of salt forms disclosed herein may have a purity change or form change of less than 10%, less than 5%, less than 1%, when stored under ambient conditions or stress conditions (e.g., increased temperature, e.g., 40°C, and/or humidity). Physiologically Acceptability Suitable salt forms of the compounds of the present disclosure are physiologically acceptable and do not cause excessive irritation or tissue damage at the injection site. Accordingly, preferred pharmaceutical salts of the compounds of the present disclosure, e.g., compounds of Formula (I) through (III), are those formed with an organic acid, preferably an organic acid with a mild acidity, for example an organic acid with a pKa in water of no less than 1.0, no less than 1.5, no less than 2.0, no less than 2.5, no less than 3.0, no less than 3.5, no less than 4.0, no less than 4.5, for example, from 3.0 to 6.5. Solubility
The aqueous solubility of the pharmaceutical salts of the compounds of the present disclosure can be determined by equilibrating excess solid with 1 mL of water for 24 hours at 22° C. A 200 uL aliquot can be centrifuged at 15,000 rpm for 15 minutes. The supernatant can be analyzed by UPLC or HPLC and the solubility can be expressed as its free base equivalent (mg FB/mL). For example, pharmaceutically acceptable salt forms of the compounds of the present disclosure can be prepared and the solubility and solution pH can be measured.
In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure, e.g., a compound of Formula (I) through (III), has a water solubility at 22°C of from about 5 mg/mL to about 400 mg/mL. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility of from about 1 mg/mL, from about 2 mg/mL, from about 3 mg/mL, from about 5 mg/mL, from about 10 mg/mL, from about 20 mg/mL, from about 30 mg/mL, from about 40 mg/mL, from about 50 mg/mL, from about 60 mg/mL, from about 70 mg/mL, from about 80 mg/mL, from about 90 mg/mL, from about 100 mg/mL, from about 110 mg/mL, from about 120 mg/mL, from about 130 mg/mL, from about 140 mg/mL, from about 150 mg/mL, and up to about 400 mg/mL, up to about 380 mg/mL, up to about 360 mg/mL, up to about 340 mg/mL, up to about 320 mg/mL, up to about 300 mg/mL, up to about 280 mg/mL, up to about 260 mg/mL, up to about 250 mg/mL, or any range therebetween. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility from about 200 mg/mL to about 400 mg/mL. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility from about 150 mg/mL to about 250 mg/mL. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility of greater than about 1 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, or 150 mg/mL.
In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure, e.g., the compound of Formula (I) through (III), is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt. In terms of providing desirable physical and pharmaceutical characteristics, such as those described above, preferred pharmaceutically acceptable salts are fumarate salts, hemi-fumarate salts, benzoate salts, salicylates, and succinate salts of the compounds disclosed herein, e.g., the compounds of Formula (I) through (III), with fumarate, benzoate, and salicylate salts being particularly preferred. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure, e.g., the compound of Formula (I) through (III), is a benzenesulfonate salt. In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of N,N- dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d10). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d2 (a DMT-d8). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d2 (a DMT-d2). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5- MeO-DMT-d10). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5). In some embodiments, the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(5-(methoxy-d3)- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d13). In some embodiments, the pharmaceutically acceptable salt of DMT or a deuterated analog of DMT (e.g., DMT-d10) is a crystalline solid as disclosed in PCT/EP2023/050702, which is incorporated herein by reference in its entirety. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) and (II) are provided in Table 1. Table 1. Exemplary pharmaceutically acceptable salts of compounds of Formula (I)/(II)
Figure imgf000111_0001
In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a) (i.e., a fumarate salt of compound I-1, depicted below). In some embodiments, when salt I-1a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source.
Figure imgf000112_0001
In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b) (i.e., a benzoate salt of compound I-1 depicted above). In some embodiments, when salt I-1b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c) (i.e., a salicylate salt of compound I-1 depicted above). In some embodiments, when salt I-1c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a succinate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d) (i.e., a succinate salt of compound I-1 depicted above). In some embodiments, when salt I-1d is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.8°, 11.7°, 14.3°, 14.7°, 17.0°, 17.4°, 19.6°, 20.6°, 22.3°, 22.6°, 22.9°, 23.1°, 23.4°, 24.9°, 25.2°, 26.3°, 26.8°, 27.3°, 27.7°, 28.8°, 29.1°, 30.9°, 31.5°, 33.8°, 34.5°, 36.5°, and 39.2°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is an oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1e) (i.e., an oxalate salt of compound I-1 depicted above). In some embodiments, when salt I-1e is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 11.3°, 12.3°, 15.6°, 17.7°, 19.5°, 20.0°, 20.8°, 21.4°, 22.3°, 22.7°, 24.8°, 25.7°, 26.7°, 27.9°, 28.7°, 29.5°, 31.4°, 33.0°, 35.4°, 36.5°, and 38.6°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a glycolate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1f) (i.e., a glycolate salt of compound I-1 depicted above). In some embodiments, when salt I-1f is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 8.2°, 12.2°, 12.9°, 15.8°, 16.3°, 17.8°, 19.2°, 20.1°, 21.7°, 23.6°, 24.4°, 24.6°, 24.9°, 26.0°, 26.6°, 27.8°, 29.6°, 30.2°, 32.0°, 32.3°, 33.0°, 33.9°, and 34.6°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a hemi-oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1g) (i.e., a hemi-oxalate salt of compound I-1 depicted above). In some embodiments, when salt I-1g is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 8.7°, 11.5°, 13.6°, 14.2°, 15.2°, 17.4°, 17.6°, 18.0°, 19.3°, 19.6°, 20.1°, 20.6°, 21.9°, 22.1°, 22.9°, 23.2°, 23.5°, 24.5°, 25.0°, 25.5°, 26.1°, 26.4°, 27.1°, 28.4°, 28.7°, 29.8°, 30.4°, 30.7°, 31.4°, 31.8°, 33.4°, and 33.9°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a hemi-fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1h) (i.e., a hemi-fumarate salt of compound I-1 depicted above). In some embodiments, when salt I-1h is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 8.1°, 11.3°, 12.2°, 13.3°, 14.2°, 16.2°, 17.6°, 18.3°, 18.6°, 19.5°, 19.8°, 20.0°, 20.2°, 20.9°, 21.4°, 21.9°, 22.3°, 22.7°, 22.9°, 23.8°, 24.5°, 25.0°, 25.2°, 26.1°, 26.4°, 26.9°, 28.4°, 28.8°, 29.5°, 29.8°, 30.9°, and 32.7°, as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 8a) (i.e., a fumarate salt of compound I-8 depicted below). In some embodiments, when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 7.8°, 10.3°, 10.9°, 12.5°, 13.6°, 14.6°, 15.2°, 15.5°, 15.8°, 16.1°, 16.6°, 17.0°, 18.4°, 19.0°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.3°, 23.8°, 24.1°, 25.1°, 26.2°, 26.8°, 27.3°, 27.9°, 28.3°, 28.9°, 29.3°, 29.6°, 29.9°, 30.6°, 31.0°, 31.3°, 32.4°, 32.9°, 33.3°, 33.6°, 34.3°, 34.9°, 35.7°, 36.1°, 37.4°, 38.0°, and 38.5°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.8°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 23.8°, 24.1°, and 25.1°, as determined by XRPD using a CuKα radiation source.
Figure imgf000114_0001
In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 8b) (i.e., a benzoate salt of compound I-8 depicted above). In some embodiments, when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.3°, 24.6°, 25.1°, 25.3°, 25.5°, 26.9°, 28.3°, 28.9°, 29.3°, 31.4°, 31.6°, 32.0°, 32.3°, 32.8°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.6°, 26.9°, 29.3°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 23.8°, 24.6°, 26.9°, 29.3°, and 35.1° as determined by XRPD using a CuKα radiation source. In some embodiments, the pharmaceutically acceptable salt of a compound of the present disclosure is a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 8c) (i.e., a salicylate salt of compound I-8 depicted above). In some embodiments, when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 10.5°, 11.4°, 12.3°, 13.4°, 14.2°, 14.9°, 15.6°, 16.1°, 17.1°, 18.1°, 18.7°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 22.2°, 22.6°, 23.7°, 24.6°, 25.2°, 25.6°, 26.1°, 26.4°, 27.4°, 27.5°, 27.8°, 28.5°, 28.8°, 29.4°, 29.7°, 30.3°, 31.0°, 31.3°, 32.1°, 32.7°, 33.1°, 33.5°, 34.4°, and 35.0°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source. In some embodiments, when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 9.6°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.3°, 24.6°, 25.6°, 28.5°, and 32.1°, as determined by XRPD using a CuKα radiation source. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) and (III) are provided in Table 2. Table 2. Exemplary pharmaceutically acceptable salts of compounds of Formula (I)/(III)
Figure imgf000116_0001
Table 2. (continued)
Figure imgf000117_0001
In some embodiments, the pharmaceutically acceptable salt is hydrochloride salt of N,N- dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 5-hydroxy-V,V-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 5-methoxy-V,V-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(U/-indol-3-yl)-7V,7V-bis(methyl-t/5)ethan-l-amine-l,l,2,2-t4 (DMT-t/io). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(lH-indol-3-yl)- N,N-bis(methyl-t/3)ethan-l-amine-l,l-t/2 (a DMT-tZs). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(U/-indol-3-yl)-N,N-dimethylethan- 1 -amine- l,l-6?2 (a DMT-tfe). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5-methoxy-lH-indol-3-yl)-N,N-bis(methyl-t/3)ethan-l-amine-l,l,2,2-t/4 (5-MeO-DMT -t/io). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5-(methoxy-t/3)-lH-indol-3-yl)-N,N-dimethylethan-l-amine-l,l-t/2 (5-MeO-DMT-tZs). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5- (m ethoxy -di)- IH-indol -3 -yl)-N,N-bis(methyl-t/3)ethan- 1 -amine- 1 , 1 ,2,2-d$ (5-MeO-DMT -dvi).
Various methods and procedures may be used to prepare pre-formed pharmaceutically acceptable salts of the compounds of the present disclosure, such methods and procedures being generally known to those of ordinary skill in the art. In some embodiments, the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure is prepared by:
(a) suspending or dissolving a free base of the compound of the present disclosure (e.g., a compound of Formula (I) through (III) in a solvent or mixture of solvents;
(b) contacting an acid with the compound of the present disclosure to provide a mixture;
(c) optionally heating the mixture;
(d) optionally cooling the mixture; and
(e) isolating the salt. Various solvents may be used, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent(s) is a protic solvent(s). In some embodiments, the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxanes (1,4-di oxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., t-butylmethyl ether (TBME)), hexane, heptane, and octane, and combinations thereof. In some embodiments, the solvent is ethanol.
Suitable acids for use during the contacting step may include those described heretofore. The acid may be an inorganic acid (e.g., hydrochloric acid) or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, and glycolic acid. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, and succinic acid, with fumaric acid, benzoic acid, and salicylic acid being preferred. In some embodiments, a stoichiometric (or superstoichiometric) quantity of the acid is contacted with the compound of the present disclosure. In some embodiments, a sub-stoichiometric (e.g., 0.5 molar equivalents) quantity of the acid is contacted with the compound of the present disclosure. The use of sub-stoichiometric quantities of the acid may be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt.
In some embodiments, the mixture is heated, e.g., refluxed, prior to cooling.
In some embodiments, the mixture is cooled and the salt is precipitated out of the solution. In some embodiments, the salt is precipitated out of solution in crystalline form. In some embodiments, the salt is precipitated out of solution in amorphous form.
Isolation of the salt may be performed by various well-known isolation techniques, such as filtration, decantation, and the like. In some embodiments, the isolating step includes filtering the mixture.
After isolation, additional crystallization and/or recrystallization steps may also optionally be performed, if desired, for example to increase purity, crystallinity, etc.
Active salt mixture
The pharmaceutical formulation may comprise, as the psychopharmaceutical agent, a pharmaceutically acceptable salt of a single compound of the present disclosure (e.g., a single of compound of Formula (I) through (III)) or a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure (e.g., a mixture of compounds of Formula (I) through (III)). In one example, the pharmaceutical formulation may contain an isotopologue mixture of compounds of the present disclosure in salt form as the psychopharmaceutical agent. In some embodiments, a subject compound of Formula (I) through (III) in salt form may be present in the pharmaceutical formulation at a purity of at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, based on a total weight of the isotopologue mixture of compounds of Formula (I) through (III) in salt form present in the pharmaceutical formulation. For example, a pharmaceutical formulation formulated with a DMT-d10 salt (salt form of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), as the subject compound in salt form, may additionally contain isotopologues of the subject compound in salt form, e.g., DMT-d9 salt, a DMT-d8 salt, etc. In some embodiments, the pharmaceutical formulation is substantially free of other isotopologues of the subject compound in salt form, e.g., the pharmaceutical formulation has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 or 0.5 mole percent of other isotopologues of the subject compound in salt form. When the injectable pharmaceutical formulation comprises, as the psychopharmaceutical agent, a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure (e.g., a mixture of compounds of Formula (I) through (III)), that mixture may be referred to herein an “active salt mixture”. In some embodiments, the active salt mixture is a fumarate salt mixture, wherein the salt forms recited are fumarate salts. In some embodiments, the active salt mixture is a benzoate salt mixture, wherein the salt forms recited are benzoate salts. In some embodiments, the active salt mixture is a salicylate salt mixture, wherein the salt forms recited are salicylate salts. In some embodiments, the active salt mixture is a succinate salt mixture, wherein the salt forms recited are succinate salts. In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I- 6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) from 90% to 99% by weight of a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 1,1,2,2-d4 (I-8), or any range therebetween, based on a total weight of the active salt mixture; and (ii) from 1% to 10% by weight, in sum, of a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11), or any range therebetween, based on a total weight of the active salt mixture. In some embodiments, the active salt mixture (and thus the pharmaceutical formulation) contains no detectable amount of, or is otherwise substantially free of: (1) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12); (2) a pharmaceutically acceptable salt of DMT-d7; (3) a pharmaceutically acceptable salt of DMT-d6 (a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-4)); (4) a pharmaceutically acceptable salt of DMT-d5; (5) a pharmaceutically acceptable salt of DMT- d4 (a salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d4 (I-5)); (6) a pharmaceutically acceptable salt of DMT-d3; (7) a pharmaceutically acceptable salt of DMT-d2 (a salt of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2) and/or 2-(1H- indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-3)); (8) a pharmaceutically acceptable salt of DMT-d1; and (9) a pharmaceutically acceptable salt of DMT (a salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine (I-1)). For example, in some embodiments, a weight, in sum, of pharmaceutically acceptable salts of isotopologues of DMT not listed in (i) or (ii), such as those listed in (1) through (9), is less than 1% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.25% by weight, less than 0.2% by weight, less than 0.1% by weight, or 0% by weight, based on a total weight of the active salt mixture. In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a fumarate salt of DMT-d10, i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a fumarate salt of DMT-d9, i.e., a fumarate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a fumarate salt of DMT-d8, i.e., a fumarate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a fumarate salt of DMT-d10, i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a fumarate salt of DMT-d9, i.e., a fumarate salt of one or more of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a fumarate salt of DMT-d8, i.e., a fumarate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture consists of or consists essentially of (i) a fumarate salt of DMT-d10, i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a fumarate salt of DMT-d9, i.e., a fumarate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a benzoate salt of DMT-d9, i.e., a benzoate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a benzoate salt of DMT-d8, i.e., a benzoate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a benzoate salt of DMT-d9, i.e., a benzoate salt of one or more of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a benzoate salt of DMT-d8, i.e., a benzoate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture consists of or consists essentially of (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a benzoate salt of DMT-d9, i.e., a benzoate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a salicylate salt of DMT-d8, i.e., a salicylate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a salicylate salt of DMT-d8, i.e., a salicylate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture consists of or consists essentially of (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a succinate salt of DMT-d10, i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a succinate salt of DMT-d9, i.e., a succinate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a succinate salt of DMT-d8, i.e., a succinate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-7), and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a succinate salt of DMT-d10, i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a succinate salt of DMT-d9, i.e., a succinate salt of one or more of 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a succinate salt of DMT-d8, i.e., a succinate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12). In some embodiments, the active salt mixture consists of or consists essentially of (i) a succinate salt of DMT-d10, i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a succinate salt of DMT-d9, i.e., a succinate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d2 (I-6); (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1-d; and optionally (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-4). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6). In some embodiments, the active salt mixture comprises from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1-d. In some embodiments, the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine (I-4). In some embodiments, the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6); and (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1-d. In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d2 (I-2); (ii) a pharmaceutically acceptable salt of DMT-d1, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d; and optionally (iii) a pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-dimethylethan-1-amine. In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2). In some embodiments, the active salt mixture comprises from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d1, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine-1-d. In some embodiments, the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine. In some embodiments, the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d2 (I-2); and (ii) a pharmaceutically acceptable salt of DMT-d1, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d. In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 20); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I- 22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23); and optionally (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 1,1-d2 (I-18), 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-19), and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-24). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I- 22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO- DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-18), 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-2,2-d2 (I-19), and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2-d2 (I-24). In some embodiments, the active salt mixture (and thus the pharmaceutical formulation) contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-18), 2- (5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-19), and 2-(5-methoxy- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-24). In some embodiments, the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5-MeO- DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20); and (ii) a pharmaceutically acceptable salt of 5- MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-34); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2,2-d3 (I-36) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1,2-d3 (I-37); and optionally (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d11, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1-d2 (I-32), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,2-d2 (I-38). In some embodiments, the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1,2,2-d4 (I-34). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT- d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-36) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-37). In some embodiments, the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d11, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1-d2 (I-32), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-38). In some embodiments, the active salt mixture (and thus the pharmaceutical formulation) contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d11, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-32), 2-(5-(methoxy-d3)-1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,2-d2 (I-38). In some embodiments, the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1,2,2-d4 (I-34); and (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-36) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-37). In some embodiments, the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d5, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine- 1,1-d2 (I-28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-29); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d4, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d (I-27); and optionally (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d3, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-25). In some embodiments, the active salt mixture comprises, in sum, from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d5, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I- 28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-29). In some embodiments, the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d4, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d (I-27). In some embodiments, the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d3, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan- 1-amine (I-25). In some embodiments, the active salt mixture (and thus the pharmaceutical formulation) contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d3, i.e., a pharmaceutically acceptable salt of 2- (5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-25). In some embodiments, the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5- MeO-DMT-d5, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H- indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)- N,N-dimethylethan-1-amine-2,2-d2 (I-29); and (ii) a pharmaceutically acceptable salt of 5-MeO- DMT-d4, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3- yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- dimethylethan-1-amine-2-d (I-27). Psychopharmaceutical agent content For use in the treatment of a mental disorder disclosed herein, including those associated with a 5-HT2 receptor, namely an anxiety disorder and/or a depressive disorder, the pharmaceutical formulation comprises a therapeutically effective amount of the psychopharmaceutical agent. In terms of unit dose, the pharmaceutical formulation comprising the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of the compound of Formula (I) through (III)) typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or any range therebetween. For example, a pharmaceutical formulation prepared with 40.4 mg of DMT fumarate (molar mass of 304.34 g/mol) would have a free base equivalence of DMT (molar mass of 188.27 g/mol) of about 25 mg as the unit dose. For use in dogs, the pharmaceutical formulation typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or any range therebetween as the unit dose. For use in cats, the pharmaceutical formulation typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, or any range therebetween as the unit dose. For use in horses, the pharmaceutical formulation typically contains a free base dose (free base equivalence when a salt form is used) of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 250 mg, about 300 mg, or any range therebetween as the unit dose. The pharmaceutical formulation can, if desired, also contain other compatible therapeutic agents. The pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, or any range therebetween, such as from about 5 mg/mL to about 70 mg/mL, from about 10 mg/mL to about 50 mg/mL, from about 15 mg/mL to about 40 mg/mL, from about 20 mg/mL to about 35 mg/mL, from about 0.1 mg/mL to about 70 mg/mL, from about 0.1 mg/mL to about 20 mg/mL. For example, a pharmaceutical formulation prepared from 40.4 mg of DMT fumarate (molar mass of 304.34 g/mol) in 1 mL of total volume of pharmaceutical formulation would have a free base concentration of psychopharmaceutical agent (in this example DMT free base; molar mass of 188.27 g/mol), of about 25 mg/mL. Free base concentrations of psychopharmaceutical agent below about 70 mg/mL provide advantageous controlled-release profiles across the broadest range of release modifier molecular weight and release modifier concentrations. However, difficulties with the pharmaceutical formulation may be encountered at free base concentrations of about 70 mg/mL or higher. Firstly, to achieve the targeted controlled- release effects at these higher free base concentrations, it may be necessary to correspondingly increase the concentration of release modifier. Pushing the limits of the release modifier concentration may be problematic as the higher viscosities thus obtained may complicate or preclude the use of sterile filtration (which in the case of pharmaceutical formulations containing hyaluronate salts is effectively the only suitable sterilization technique available) and may cause increased pain at the injection site. Secondly, a deterioration of pharmaceutical formulation stability may be experienced at the higher free base concentrations of about 70 mg/mL or more, with precipitation being a main concern owing to the pharmacopeial requirements for particulate matter in injectables such as subcutaneous dosage forms (USP Particulate Matter in Injections <788>). Attempts to lower the free base concentration by dilution (increasing injection volume) may not always be possible in subcutaneous dosage forms, for example, since higher injection volumes are associated with pain at the injection site. Consequently, for subcutaneous pharmaceutical formulations, the free base concentration of psychopharmaceutical agent (e.g., tryptamine psychedelic such as a compound of Formula (I) through (III)) is typically kept below about 70 mg/mL, below about 60 mg/mL, below about 50 mg/mL, below about 40 mg/mL, below about 30 mg/mL. In some embodiments, for use in dogs, the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, or any range therebetween. In some embodiments, for use in cats, the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, or any range therebetween. In some embodiments, for use in horses, the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, or any range therebetween. In terms of pharmaceutical formulations containing a tryptamine psychedelic, it is for these reasons that tryptamine psychedelics with longer half-lives, such as deuterated tryptamine psychedelics may provide significant advantages over their non-deuterated counterparts, especially in subcutaneous dosage forms. Specifically deuterated tryptamine psychedelics possess advantageous metabolic degradation profiles which can lead to higher plasma concentrations and enhanced brain penetration, so that in some embodiments the therapeutic doses may be reduced. For example, initial human clinical studies indicate that a therapeutically relevant psychedelic dose of DMT (non-deuterium enriched) may be in the range of about 70 mg or higher (free base), whereas for deuterated analogs of DMT such as 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1,2,2-d4 (DMT-d10) less drug (e.g., 10 to 50 mg, 15 to 50 mg, 20 to 40 mg, 30 to 50 mg, free base) may be needed to maintain desired blood concentrations owing to its longer half-life in vivo. The lower dosing requirements of deuterated analogs of DMT such as DMT-d10 allow for lower concentrations of release modifier to be used to achieve desirable controlled-release profiles, and for lower injection volumes. Release modifier The pharmaceutical formulation comprises a release modifier. The release modifier is the component primarily responsible for providing a controlled, tunable, and linear release of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) upon injection of the pharmaceutical formulation, such as upon subcutaneous injection. Without being limited by theory, it is believed that the release modifier acts by thickening and building viscosity of the pharmaceutical formulation, while potentially also providing electrostatic attraction with the psychopharmaceutical agent, such that upon injection the psychopharmaceutical agent can be slowly released from the injection site (e.g., in the case of subcutaneous injection, within the fat or the layer of skin directly below the dermis and epidermis) and absorbed more slowly, generating a depot-like release effect. The release modifier may be a polymeric material, such as a hyaluronate salt or a carboxymethyl cellulose salt, which may, or may not, be crosslinked. The rate of release of the psychopharmaceutical agent can be controlled through cross-linking or the lack thereof, or the extent of cross-linking of the release modifier. Release modifiers which are not cross-linked will typically provide a shorter release profile than those which are crosslinked, with crosslinking capable of extending the release significantly, such as over the course of a day or multiple days. For delivery of tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), whereby a target controlled-release is sought which provides a duration of action of about 30 to 120 minutes, the release modifier is generally not crosslinked so as not to overextend the release period. For clarity, the release modifier is considered a separate component from the psychopharmaceutical agent. The release modifier is also considered a separate component from the pharmaceutically acceptable additive(s) described hereinafter (such as a buffering agent, a tonicity agent, a pH adjusting agent, etc.) when such pharmaceutically acceptable additives are included in the pharmaceutical formulation of the present disclosure, even though the release modifier may perform a similar function to a particular additive(s). For example, the release modifier is considered different from a tonicity agent even though the release modifier contributes to the overall osmolality of the pharmaceutical formulation. In another example, the release modifier is considered different from a buffering agent or a pH adjusting agent, even though the release modifier may influence the pH of the pharmaceutical formulation. Hyaluronate salt In some embodiments, the release modifier is a hyaluronate salt (anionic salt form of hyaluronic acid), which is non-sulfated glycosaminoglycan and long- chain polymer of disaccharide units of glucuronate-N-acetylglucosamine. Hyaluronate salts are biocompatible and are distributed widely throughout animal connective, epithelial, and neural tissues. The hyaluronate salt may include, but is not limited to, a sodium salt of hyaluronate (sodium hyaluronate), a potassium salt of hyaluronate (potassium hyaluronate), a calcium salt of hyaluronate (calcium hyaluronate), a zinc salt of hyaluronate (zinc hyaluronate), and a magnesium salt of hyaluronate (magnesium hyaluronate), or a combination thereof. In some embodiments, the release modifier is sodium hyaluronate. While not limited thereto, the hyaluronate salt may be produced by a microbial fermentation and purification process and is preferably pharmacopoeia compliant. In terms of purification, hyaluronate salts are known to be heat sensitive, and so cannot be typically sterilized by thermal sterilization methods such as steam sterilization, dry-heat sterilization/depyrogenation, etc., which can cause polymer degradation. Instead, hyaluronate salts are sterilized by sterile filtration such as sterile filtration through a 0.25 μm filter size or less. After sterile filtration, hyaluronate salts may be optionally sterilized with a secondary sterilization process such as ethylene oxide (ETO) gas sterilization or gamma sterilization under less harsh conditions. In some embodiments, the hyaluronate salt is a native hyaluronate salt, meaning it is not substituted, modified with pendant groups, conjugated, crosslinked, or otherwise covalently modified. Rather, the native hyaluronate salt possesses unmodified disaccharide units of glucuronate-N-acetylglucosamine. Examples may include, but are not limited to, sodium hyaluronate products available from Lifecore Biomedical, Inc. or Bloomage Freda Biopharm Co. Ltd. In some embodiments, the hyaluronate salt is a non-native hyaluronate salt, i.e., those that are substituted, modified with pendant groups, conjugated, crosslinked, deacetylated, or otherwise covalently modified. The non-native hyaluronate salts may be, inter alia, acetylated, deacetylated, alkylated, esterified, amidated, hydrazidated, epoxy grafted, silylated, sulfated, and/or crosslinked hyaluronate salts. These modifications such as crosslinking may enable the formation of hydrogels of hyaluronate salts. The degree of modification or substitution in non-native hyaluronate salts is typically about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any range therebetween. Examples of non-native hyaluronate salts include, but are not limited to, sodium hyaluronate salts modified with pendant tyramine groups (an amidated hyaluronate salt) whereby tyramine is introduced onto glucuronate units using amide bond chemistry (EDC chemistry); and Corgel® BioHydrogel products available from Lifecore Biomedical, Inc., whereby the tyramine substituted sodium hyaluronate (TS-NaHy) from above is subsequently cross-linked by forming stable dihydroxyphenyl covalent bonds through an enzyme driven reaction involving e.g., horseradish peroxidase. While crosslinked or hydrogels of hyaluronate salts may be employed in some cases where extended duration of action is desired, for the delivery of tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) in which a controlled-release is sought that provides a duration of action of about 30 to 120 minutes, the hyaluronate salt is generally not crosslinked or in hydrogel form so as not to overextend the release period and the resulting duration of action beyond about 120 minutes. The weight average molecular weight (Mw) of the hyaluronate salt may be about 500 kDa, about 550 kDa, about 600 kDa, about 650 kDa, about 700 kDa, about 750 kDa, about 800 kDa, about 850 kDa, about 900 kDa, about 950 kDa, about 1,000 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 kDa, about 1,800 kDa, about 1,900 kDa, about 2,000 kDa, or any range therebetween such as from about 500 kDa to about 2,000 kDa, from about 600 kDa to about 1,500 kDa, from about 750 kDa to about 1,000 kDa, from about 1,000 kDa to about 2,000 kDa, from about 1,000 kDa to about 1,900 kDa, from about 1,000 kDa to about 1,800 kDa, from about 1,200 kDa to about 1,800 kDa, from about 1,500 kDa to about 1,700 kDa, from about 1,600 kDa to about 1,800 kDa. A weight average molecular weight of the hyaluronate salt which is above the aforementioned upper limit may result in pharmaceutical formulations which are too viscous, thereby complicating the sterile filtration process and resulting in painful injections, especially in the case of subcutaneous injections. Further, hyaluronate salts with a weight average molecular weight above the aforementioned upper limit may provide a release profile which is too slow for achieving the desired duration of action time course of about 30 to 120 minutes in the case of some tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)). On the other hand, hyaluronate salts with a weight average molecular weight below the aforementioned lower limit may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier. In some embodiments, the hyaluronate salt has a molecular weight range in between about 500 kDa, about 600 kDa, about 700 kDa, about 800 kDa, about 900 kDa, about 1,000 kDa, about 1,100 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 kDa, about 1,800 kDa, about 1,900 kDa, and about 2,000 kDa, or any intermediate range between any of these values. In some embodiments, the hyaluronate salt has a molecular weight range of about 500 kDa to about 2,000 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 500 kDa to about 750 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 750 kDa to about 1,000 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 750 kDa to about 1,500 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 1,000 kDa to about 1,800 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 900 kDa to about 1,400 kDa. The weight average molecular weight of the hyaluronate salt would then fall somewhere within the molecular weight range. Examples of suitable hyaluronate salts include, but are not limited to, sodium hyaluronate products HA700K (molecular weight range of 500 – <750 kDa), HA1M (molecular weight range of 750 – 1,000 kDa), and HA15M (molecular weight range of >1,000 – 1,800 kDa), available from Lifecore Biomedical, Inc., and Hyatrue® HA-EP1.8 (molecular weight range of 900-1,400 kDa) available from Bloomage Freda Biopharm Co. Ltd. A concentration of hyaluronate salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) may be about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to about 0.75%, or about 0.25% to about 0.5%. As the concentration of hyaluronate salt is increased, so to is the viscosity of the pharmaceutical formulation. Exceeding viscosity specifications is problematic for sterile filtration (and hyaluronate salts are sensitive to thermal sterilization techniques) and may cause increased pain at the injection site. Moreover, in the case of tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) in which a release is sought that provides a duration of action of about 30 to 120 minutes, too high a concentration of hyaluronate salt may overextend the release profile and the resulting duration of action beyond about 120 minutes, which may not be clinically favorable in some instances. For these reasons, in such embodiments, the concentration of hyaluronate salt preferably does not exceed about 1%, about 0.95%, about 0.9%, about 0.85%, about 0.8%, about 0.75%, about 0.7%, about 0.65%, about 0.6%, about 0.55%, about 0.5% w/v. In preferred embodiments, the concentration of hyaluronate salt is from about 0.1% to about 0.5% w/v. Attempts to lower the concentration of hyaluronate salt by dilution (increasing injection volume) may not be possible in subcutaneous dosage forms, for example, since higher injection volumes are associated with higher levels of pain at the injection site. Conversely, hyaluronate salt concentrations which are below the aforementioned lower limit may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier. In some embodiments, a ratio of free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), to the concentration of hyaluronate salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) is about 0.1:1, about 0.5:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 105:1, about 110:1, about 115:1, about 120:1, about 125:1, about 130:1, or any range therebetween, such as from about 10:1 to about 130:1, about 15:1 to about 120:1, about 20:1 to about 110:1, or about 25:1 to about 100:1. In some embodiments, for use in dogs, the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of hyaluronate salt of about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.8:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, or any range therebetween. In some embodiments, for use in cats, the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of hyaluronate salt of about 0.1:1, about 0.15:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, or any range therebetween. In some embodiments, for use in horses, the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of hyaluronate salt of about 5:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 105:1, about 110:1, about 115:1, about 120:1, about 125:1, about 130:1, or any range therebetween. In the case of tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) in which a release profile is sought that provides a duration of action of about 30 to 120 minutes, ratios below the aforementioned lower limit may result in pharmaceutical formulations with a release profile which is overextended (too slow) in terms of clinical practicality. On the other hand, extended release profiles providing a duration of action beyond 120 minutes may be preferred in some cases, which may be achieved by lowering the ratio. Ratios above the aforementioned upper limit tend to provide a release that is not meaningfully different from formulations lacking release modifier (too fast). Even so, there are instances where higher ratios of free base concentration of psychopharmaceutical agent (mg/mL) to the concentration of hyaluronate salt (% w/v) can be used, for example up to about 500:1, about 400:1, about 300:1, about 200:1, or about 140:1, such as when a faster release profile is desirable or where other parameters in the formulation can counteract any fast release effects attributable to the use of such higher ratios. In some embodiments, a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), is about 17:1, about 18:1, about 19:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 500:1, about 1,000:1, about 1,500:1, about 2,000:1, about 3,000:1, about 4,000:1, about 4,500:1, about 5,000:1, about 6,000:1, about 7,000:1, about 8,000:1, about 9,000:1, about 10,000:1, about 11,000:1, about 12,000:1, or any range therebetween, such as from about 17:1 to about 100:1, about 20:1 to about 100:1, about 22:1 to about 80:1, about 24:1 to about 60:1, or about 25:1 to about 55:1, or about 26:1 to about 100:1, or about 28:1 to about 100:1, or about 30:1 to about 75:1. In some embodiments, for use in dogs, the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 100:1, about 500:1, about 1,000:1, about 1,200:1, about 1,400:1, about 1,600:1, about 1,800:1, about 2,000:1, about 2,200:1, about 2,400:1, about 2,600:1, about 2,800:1, about 3,000:1, about 3,200:1, about 3,400:1, about 3,600:1, about 3,800:1, about 4,000:1, about 4,200:1, about 4,400:1, about 4,600:1, about 4,800:1, about 5,000:1, about 6,000:1, about 7,000:1, about 8,000:1, about 9,000:1, about 10,000:1, or any range therebetween. In some embodiments, for use in cats, the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 1,000:1, about 1,500:1, about 2,000:1, about 2,500:1, about 3,000:1, about 3,500:1, about 4,000:1, about 4,500:1, about 5,000:1, about 5,500:1, about 6,000:1, about 6,500:1, about 7,000:1, about 7,500:1, about 8,000:1, about 8,500:1, about 9,000:1, about 9,500:1, about 10,000:1, about 10,500:1, about 11,000:1, about 11,500:1, about 12,000:1, or any range therebetween. In some embodiments, for use in horses, the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 17:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 120:1, about 140:1, about 160:1, about 180:1, about 200:1, about 220:1, about 240:1, about 260:1, about 280:1, about 300:1, about 320:1, about 340:1, about 360:1, about 380:1, about 400:1, about 420:1, about 460:1, about 480:1, about 500:1, or any range therebetween. Ratios below the aforementioned lower limit may result in pharmaceutical formulations with a release profile similar to those which are formulated without any release modifier (too fast), whereas ratios above the aforementioned upper limit may overextend the release (too slow) and the resulting duration of action, which is not generally favorable in the case of certain tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) where a duration of action of about 30 minutes to about 120 minutes is targeted. Even so, there are instances where lower ratios can be used when a faster release profile is desirable, or where higher ratios can be used to provide a duration of action beyond 120 minutes. Carboxymethyl cellulose salt In some embodiments, the release modifier is a carboxymethyl cellulose salt, which is a cellulose derivative with carboxymethyl groups (-CH2COO-) bound to some of the hydroxyl groups of the glucopyranose monomers that make up the cellulose backbone. The carboxymethyl cellulose salt may include, but is not limited to, a sodium salt of carboxymethyl cellulose (sodium carboxymethyl cellulose). While not limited thereto, the carboxymethyl cellulose salt may be produced by reacting alkali cellulose with sodium monochloroacetate, and this reaction may be performed under rigidly controlled conditions to control the degree of substitution (DS), which is the average number of hydroxyl groups of the glucopyranose monomers that are carboxymethylated, with the theoretical limit being a DS of 3.0. The resultant polymer is purified and dried for pharmacopoeia compliance. In some embodiments, the carboxymethyl cellulose salt is not substituted, modified with pendant groups, conjugated, crosslinked, or otherwise covalently modified. Rather, the carboxymethyl cellulose salt possesses a cellulose backbone formed from glucopyranose monomers which are substituted only with carboxymethyl groups. For example, in some embodiments, the carboxymethyl cellulose salt is not crosslinked with glycolic acid to form a croscarmellose salt such as sodium croscarmellose. The carboxymethyl cellulose salt may have a degree of substitution (DS) of 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, or any range therebetween, such as from 0.45 to less than 0.9, from 0.7 to less than 0.9, from 0.9 to less than 1.2, or from 1.2 to 1.5. In some embodiments, the carboxymethyl cellulose salt has a DS of 0.7 to 0.8, 0.85 to 1.15 or 0.9 to 1.0. The weight average molecular weight (Mw) of the carboxymethyl cellulose salt is typically below about 500 kDa, for example, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about 160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa, about 210 kDa, about 220 kDa, about 230 kDa, about 240 kDa, about 250 kDa, about 300 kDa, about 350 kDa, about 400 kDa, about 450 kDa, or any range therebetween, such as from about 90 kDa to about 300 kDa, from about 100 kDa to about 300 kDa, from about 100 kDa to about 275 kDa, from about 150 kDa to about 250 kDa. A weight average molecular weight of the carboxymethyl cellulose salt which is above the aforementioned upper limit generally results in pharmaceutical formulations that exceed viscosity specifications for being injectable and syringeable, and are not generally approved by the Food & Drug Administration (FDA) for use in injectables. Accordingly, suitable carboxymethyl cellulose salts are typically those with a Brookfield viscosity, measured as 2% aqueous solutions using spindle number 3 at 30 rpm, of from about 400 cP, about 600 cP, about 800 cP, about 1,000 cP, about 1,200 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, about 2,500 cP, about 2,750 cP, about 3,000 cP, about 3,100 cP, or any range therebetween, such as from about 400 cP to about 3,100 cP, or about 1,500 cP to about 3,100 cP, or about 470 to about 700 cP. Examples of the carboxymethyl cellulose salt may include, but are not limited to, Aqualon™ and Blanose™ sodium carboxymethyl cellulose products available from Ashland, such as Aqualon™/Blanose™ grades 9M8F PH, 9M8XF, 9M31F PH, 9M31XF PH, and 7MF PH. In some embodiments, the carboxymethyl cellulose salt is 7MF PH from Ashland (sodium carboxymethyl cellulose; Mw = 250 kDa; DS = 0.7; Brookfield viscosity, measured as 2% aqueous solution using spindle number 3 at 30 rpm, of from 400 cP to 800 cP). A concentration of carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%. Concentrations of carboxymethyl cellulose salt which exceed the aforementioned upper limit provide pharmaceutical formulations which are too viscous for sterile filtration, injectability, and/or syringeability, for example may cause increased pain at the injection site. On the contrary, carboxymethyl cellulose salt concentrations which are below the aforementioned lower limit may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier. In some embodiments, a ratio of free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), to the concentration of carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) is about 0.1:1, about 0.5:1, about 1:1, about 2:1, about 4:1, about 6:1, about 8:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, or any range therebetween. In some embodiments, for use in dogs, the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of carboxymethyl cellulose salt of about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.5:1, about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, about 4.5:1, about 5:1, or any range therebetween. In some embodiments, for use in cats, the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of carboxymethyl cellulose salt of about 0.1:1, about 0.15:1, about 0.2:1, about 0.25:1, about 0.3:1, about 0.35:1, about 0.4:1, about 0.45:1, about 0.5:1, about 0.55:1, about 0.6:1, about 0.65:1, about 0.7:1, about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, about 1:1, about 1.2:1, about 1.4:1, about 1.6:1, about 1.8:1, about 2:1, or any range therebetween. In some embodiments, for use in horses, the pharmaceutical formulations may have a ratio of free base concentration of psychopharmaceutical agent to the concentration of carboxymethyl cellulose salt of about 5:1, about 6:1, about 8:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 22:1, about 25:1, about 28:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, or any range therebetween. In some embodiments, a ratio of the weight average molecular weight of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent, (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 8:1, about 10:1, about 12:1, about 14:1, about 16:1, about 18:1, about 20:1, about 22:1, about 24:1, about 26:1, about 28:1, about 30:1, about 32:1, about 34:1, about 36:1, about 38:1, about 40:1, about 42:1, about 44:1, about 46:1, about 48:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 200:1, about 300:1, about 400:1, about 500:1, about 600:1, about 700:1, about 800:1, about 900:1, about 1,000:1, about 1,500:1, about 2,000:1, about 3,000:1, about 4,000:1, about 4,500:1, about 5,000:1, or any range therebetween, such as from about 1:1 to about 50:1, about 5:1 to about 40:1, about 10:1 to about 30:1, about 15:1 to about 20:1, or about 1:1 to about 10:1. In some embodiments, for use in dogs, the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 120:1, about 140:1, about 160:1, about 180:1, about 200:1, about 220:1, about 240:1, about 260:1, about 280:1, about 300:1, about 320:1, about 340:1, about 360:1, about 380:1, about 400:1, about 420:1, about 460:1, about 480:1, about 500:1, about 550:1, about 600:1, about 650:1, about 700:1, about 750:1, about 800:1, about 850:1, about 900:1, about 950:1, about 1,000:1, about 1,100:1, about 1,200:1, about 1,300:1, about 1,400:1, about 1,500:1, or any range therebetween. In some embodiments, for use in cats, the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 100:1, about 120:1, about 140:1, about 160:1, about 180:1, about 200:1, about 220:1, about 240:1, about 260:1, about 280:1, about 300:1, about 320:1, about 340:1, about 360:1, about 380:1, about 400:1, about 420:1, about 460:1, about 480:1, about 500:1, about 550:1, about 600:1, about 650:1, about 700:1, about 750:1, about 800:1, about 850:1, about 900:1, about 950:1, about 1,000:1, about 1,500:1, about 2,000:1, about 2,500:1, about 3,000:1, about 3,500:1, about 4,000:1, about 4,500:1, about 5,000:1, or any range therebetween. In some embodiments, for use in horses, the pharmaceutical formulations may have a ratio of the weight average molecular weight (Mw) of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 8:1, about 10:1, about 12:1, about 14:1, about 16:1, about 18:1, about 20:1, about 22:1, about 24:1, about 26:1, about 28:1, about 30:1, about 32:1, about 34:1, about 36:1, about 38:1, about 40:1, about 42:1, about 44:1, about 46:1, about 48:1, about 50:1, or any range therebetween. Aqueous vehicle The pharmaceutical formulation comprises an aqueous vehicle. The term “vehicle” herein refers to a diluent, adjuvant, excipient, carrier, and/or any other auxiliary or supporting ingredient with which a psychopharmaceutical agent and release agent of present disclosure is formulated for administration to a mammal. The aqueous vehicle, and thus the pharmaceutical formulation, comprises water, such as water for injection (WFI). Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. In addition to water, the aqueous vehicle, and thus the pharmaceutical formulation, may optionally contain one or more pharmaceutically acceptable additives, as desired/needed. “Pharmaceutically acceptable additives” may be diluents, adjuvants, excipients, carriers, or any other auxiliary or supporting ingredient approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, such as companion animals. Examples of pharmaceutically acceptable additives include, but are not limited to, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof. It should be understood that many pharmaceutically acceptable additives may serve several functions, even within the same pharmaceutical formulation, for example, a buffering agent may also act as a tonicity agent and vice versa. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide, or a combination thereof. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil, or a combination thereof. Antimicrobial agents or preservatives include, but are not limited to, phenols (e.g., phenol), cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl-, ethyl-, and propyl-parabens, benzoic acid, sodium benzoate, and sorbic acid, or a combination thereof. Stabilizing agents include, but are not limited to, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl alcohols, glycerol, methionine, monothioglycerol, ascorbic acid, citric acid, polysorbate, arginine, and sorbitol, or a combination thereof. For example, fatty acids may act as lipid carriers. The fatty acid may have from 4 to 30 carbon atoms, 6 to 28 carbon atoms, 8 to 24 carbon atoms, 10 to 20 carbon atoms, or 12 to 18 carbon atoms. The fatty acid may be a fatty monoacid or a fatty diacid. Exemplary fatty acids may include, but are not limited to, adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, arachidic acid, behenic acid, lignoceric acid, palmitolic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof. In some embodiments, the pharmaceutical formulation is formulated without a fatty acid to prevent hydrogel formation and an overextended release (for an example of a hydrogel that generates a release over days, see Kang NW, et al. Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin. Pharmaceutics.2021 Jun 11;13(6):864). A tonicity agent is a chemical that, on inclusion within a pharmaceutical formulation, modulates the osmolality of the pharmaceutical formulation. Sometimes, the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation provides a desired osmolality, and so no tonicity agent is needed/included. Alternatively, the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation does not provide the osmolality specifications for injection, and so one or more tonicity agents may be included to reach a desired osmolality. When the pharmaceutical formulation comprises a tonicity agent, the concentration of the tonicity agent will be adjusted considering the osmolality contributions from the concentrations of psychopharmaceutical agent and the release modifier to provide a pharmaceutical formulation with a desirable osmolality range (e.g., 150 to 600 mOsm/kg). Tonicity agents include, but are not limited to, sodium chloride; potassium chloride; calcium chloride; magnesium chloride; dextrose; glucose; mannitol; lactose; sorbitol; sucrose; alanine; ethanol; benzyl alcohol; creatinine; glycine; glycerol; histidine; polyethylene glycol; propylene glycol; sodium bicarbonate; sodium hydroxide; hydrochloric acid; phosphoric acid; a phosphate salt such as sodium phosphate or potassium phosphate; acetic acid; an acetate salt such as sodium acetate, potassium acetate, or ammonium acetate; citric acid; a citrate salt such as sodium citrate or potassium citrate; arginine; ascorbic acid; an ascorbate salt such as potassium ascorbate or sodium ascorbate; edetic acid; an edetate salt such as sodium edetate or calcium edetate; lactic acid; a lactate salt such as potassium lactate or sodium lactate; tartaric acid; a tartrate salt such as sodium tartrate or potassium tartrate, as well as combinations thereof. In some embodiments, the tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, magnesium chloride, dextrose, glucose, mannitol, lactose, sorbitol, sucrose, and sodium lactate. Typically, the tonicity agent is sodium chloride. In some embodiments, the pharmaceutical formulation comprises sodium chloride at a concentration, in terms of weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or any range therebetween such as from about 0.1% to about 0.6%, about 0.2% to about 0.55%, about 0.3% to about 0.5% w/v. A buffering agent is a chemical that on inclusion into the pharmaceutical formulation comprises a weak acid and its conjugate base in equilibrium, which resist changes in pH on addition of acid or base to the pharmaceutical formulation. In other words, addition of acid or base to the pharmaceutical formulation shifts the position of equilibrium in favor of the weak acid or conjugate base, respectively, and as a consequence, the concentration of free protons in the pharmaceutical formulation (and thus the pH) is relatively unchanged or changed by less than the amount expected for the quantity of acid or base added (until the buffer capacity is reached). For clarity, the buffering agent is considered a separate component from the psychopharmaceutical agent (e.g., a pharmaceutically acceptable salt of a compound of the present disclosure such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)). In this sense, the buffering agent is not merely a counterion to the protonated form of the compound of the present disclosure. Rather the buffering agent, when included, provides a buffering effect to resist changes in pH above that which may be provided by the psychopharmaceutical agent. The buffering agent is also considered a separate component from the release modifier, and again, provides a buffering effect to resist changes in pH above that which may be provided by the release modifier. Buffering agents include, but are not limited to, a phosphate buffer (a phosphate salt and phosphoric acid; pKa = 2.14, 7.20, and 12.37), an acetate buffer (an acetate salt and acetic acid; pKa = 4.76), a citrate buffer (a citrate salt and citric acid; pKa = 3.13, 4.76, and 6.40), an ascorbate buffer (an ascorbate salt and ascorbic acid; pKa = 4.10 and 11.6), a benzoate buffer (a benzoate salt and benzoic acid; pKa = 4.20), an oxalate buffer (an oxalate salt and oxalic acid; pKa = 1.25 and 4.14), a formate buffer (a formate salt and formic acid; pKa = 3.75), or a combination thereof. Generally, a suitable buffer is optionally selected that comprises an acid with a pKa value (or an acid having at least one pKa value in the case of polyprotic acids) that lies within ±1 of the desired pH of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation is not formulated with a buffering agent. Antioxidants include, but are not limited to, bisulfite and sodium metabisulfite, ascorbic acid, citric acid, tartaric acid, thiol derivatives, or combinations thereof. In some embodiments, the pharmaceutical formulation has an oxygen content of less than 2 ppm, such as between 0.1 ppm and 2 ppm. Local anesthetics include, but are not limited to, procaine hydrochloride. Complexing agents include, but are not limited to, cyclodextrins, including ca- cyclodextrin, β-cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.), or combinations thereof. Sequestering or chelating agents include, but are not limited to EDTA. pH adjusting agents include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid, or combinations thereof. pH adjusting agents may be optionally employed to adjust the pH of the pharmaceutical formulation into a desirable range. Sometimes, the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation provides a desirable pH, and so no pH adjusting agent is needed/included. Alternatively, the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation does not provide the pH specifications for injection, and so one or more pH adjusting agents may be included to reach a desired pH. Absorption enhancers include, but are not limited to, a hyaluronidase enzyme. In pharmaceutical formulations containing a hyaluronate salt, the hyaluronidase enzyme may have the added effect of breaking down the hyaluronate salt to speed drug release in cases where increased release rates are desired. This additive may be added to the pharmaceutical formulation immediately prior to injection or may be injected separately as part of a multi-component injection, such as using a dual chamber syringe or a multi-syringe (e.g., two syringe) set up. In some embodiments, the pharmaceutical formulation does not contain a hyaluronidase enzyme, nor is a hyaluronidase enzyme employed during or post injection of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride. In some embodiments, the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of water for injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent. In some embodiments, the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the pharmaceutical formulation is formulated without a buffering agent. In some embodiments, the pharmaceutical formulation consists of, or consists essentially of, the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and water and optional tonicity agent (e.g., sodium chloride) and optional pH adjusting agent (e.g., sodium hydroxide) as the aqueous vehicle. By consists essentially of, it is meant that the presence of additional components within the pharmaceutical formulation is permitted, provided the amounts of such additional components do not materially affect the essential characteristics of the pharmaceutical formulation—namely that the pharmaceutical formulation is suitable for injection and provides time-restricted temporal controlled-release of a psychopharmaceutical agent. In some embodiments of administering tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), this time-restricted controlled-release would provide a duration of action of about 30 to 120 minutes. Physiochemical properties The pharmaceutical formulation may have a pH of about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, about 10, about 10.25, about 10.5, about 10.75, about 11, or any range therebetween. Generally, pH values which are too high are associated with tissue necrosis, whereas pH values which are too low are associated with pain and inflammation at the injection site. In some embodiments, the pharmaceutical formulation is suitable for intravenous injection (is an intravenous pharmaceutical formulation) or intramuscular injection (is an intramuscular pharmaceutical formulation), and has a pH ranging from about 2 to about 11, about 3 to about 9, about 4 to about 7, about 4.5 to about 6. In some embodiments, the pharmaceutical formulation is suitable for subcutaneous injection (is a subcutaneous pharmaceutical formulation), and has a pH ranging from about 3 to about 9, about 3 to about 7, about 4 to about 9, about 4 to about 7.5, about 4 to about 7, about 4.5 to about 7.5, about 4.5 to about 7, about 4.5 to about 6.5, about 4.5 to about 6. The pharmaceutical formulation may have an osmolality of about 150 mOsm/kg, about 155 mOsm/kg, about 160 mOsm/kg, about 165 mOsm/kg, about 170 mOsm/kg, about 175 mOsm/kg, about 180 mOsm/kg, about 185 mOsm/kg, about 190 mOsm/kg, about 195 mOsm/kg, about 200 mOsm/kg, about 225 mOsm/kg, about 250 mOsm/kg, about 275 mOsm/kg, about 300 mOsm/kg, about 325 mOsm/kg, about 350 mOsm/kg, about 375 mOsm/kg, about 400 mOsm/kg, about 425 mOsm/kg, about 450 mOsm/kg, about 475 mOsm/kg, about 500 mOsm/kg, about 525 mOsm/kg, about 550 mOsm/kg, about 575 mOsm/kg, about 600 mOsm/kg, or any range therebetween, such as from about 150 to about 600 mOsm/kg, about 200 to about 500 mOsm/kg, about 250 to about 550 mOsm/kg, about 275 to about 500 mOsm/kg, about 300 to about 450 mOsm/kg, about 150 mOsm/kg to about 200 mOsm/kg, about 150 mOsm/kg to about 175 mOsm/kg. Osmolalities which are outside of these values are reported to cause pain. In some embodiments, the pharmaceutical formulation is isotonic with subject blood serum, e.g., has an osmolality of about 275 to about 335 mOsm/kg. The pharmaceutical formulation may have viscosity of less than about 10,000 cP, less than about 9,000 cP, less than about 8,000 cP, less than about 7,000 cP, less than about 6,000 cP, less than about 5,000 cP, less than about 4,000 cP, less than about 3,000 cP, less than about 2,000 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less than about 50 cP, less than about 45 cP, less than about 40 cP, less than about 35 cP, less than about 30 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, about 25 cP, about 28 cP, about 30 cP, about 32 cP, about 35 cP, about 38 cP, about 40 cP, about 42 cP, about 45 cP, about 50 cP, about 60 cP, about 70 cP, about 80 cP, about 90 cP, about 100 cP, about 150 cP, about 200 cP, about 250 cP, about 300 cP, about 350 cP, about 400 cP, about 500 cP, about 600 cP, about 800 cP, about 1,000 cP, about 1,200 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, about 2,500 cP, about 2,750 cP, about 3,000 cP, about 3,100 cP, about 3,500 cP, about 4,000 cP, about 4,500 cP, about 5,000 cP, about 6,000 cP, about 7,000 cP, about 8,000 cP, about 9,000 cP, about 10,000 cP, or any range therebetween. Such viscosity values allow the pharmaceutical formulation to be syringeable and injectable, for example without causing excessive pain at the injection site. In some embodiments, such as when the release modifier employed is a hyaluronate salt, suitable viscosity values also enable the use of sterile filtration as the sterilization technique. In some embodiments, the pharmaceutical formulation is suitable for subcutaneous injection (is a subcutaneous pharmaceutical formulation), and preferably has a viscosity of less than about 3,000 cP, less than about 2,500 cP, less than about 2,000 cP, less than about 1,500 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less than about 50 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, or any range therebetween. In some embodiments, the pharmaceutical formulation has a shelf-life as an aqueous solution of at least 1 day, 2 days, 3 days, 4 days 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or longer, without significant product degradation or physical changes such as precipitation. In some embodiments, the pharmaceutical formulation can be maintained/stored as an aqueous solution in open or closed environments, such as in open or closed flasks/vials under sub-ambient, ambient, or stress conditions (elevated temperatures) without appreciable degradation or physical changes such as precipitation. Pharmaceutical formulations with a prolonged shelf-life of at least several days or at least several weeks are advantageous because they may be prepared well in advance of administration if desired, and optionally stored, without materially affecting efficacy or injectability. In some embodiments, pharmaceutical formulations formed from a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), as the psychopharmaceutical agent, are characterized by increased stability compared to formulations prepared using the same compound as free base but are otherwise substantially the same. For example, the pharmaceutical formulation of the present disclosure formed from a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), may be at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% more stable upon storage for 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, or longer, in terms of degradation or physical changes such as precipitation, compared to formulations prepared from a free base counterpart but are otherwise substantially the same. Release kinetics The pharmaceutical formulation enables time-restricted temporal controlled-release of the psychopharmaceutical agent via bolus injection to subjects such as companion animals, and via bolus subcutaneous injection in particular. In the case of delivering a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), the pharmaceutical formulations enable controlled-release of the tryptamine psychedelic via bolus injection to subjects, and via bolus subcutaneous injection in particular, that mimics the clinically advantageous duration of action of about 30 to 120 minutes achievable by IV infusion of such psychopharmaceutical agents over about 90 minutes. In some embodiments, the duration of action following bolus injection of the pharmaceutical formulation, preferably bolus subcutaneous injection of the pharmaceutical formulation, is about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween, such as from about 30 to about 120 minutes, from about 30 to about 45 minutes, from about 40 to about 100 minutes, from about 45 to about 90 minutes, from about 50 to about 75 minutes, from about 60 to about 70 minutes. In some embodiments, the controlled-release of a tryptamine psychedelic places the subject into a psychedelic state (a correlate of positive clinical outcomes) for about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, or any range therebetween, such as a psychedelic state time course of from about 10 minutes to about 100 minutes, from about 20 minutes to about 80 minutes, from about 30 to about 45 minutes, from about 30 minutes to about 60 minutes, from about 40 minutes to about 50 minutes. Observation of pharmacological effects and/or symptom monitoring by a clinician/veterinarian or caregiver can be used to assess the duration of action and/or psychedelic state of the subject following injection. Pharmacological effects which can be monitored to assess the duration of action and/or psychedelic state include, but are not limited to, licking, salivation, panting, vocalization, and wide eyes (dilated pupils). Assessment may also be conducted by, for example, functional magnetic resonance imaging (fMRI), pharmaco electroencephalogram (EEG), etc. The duration of action and/or time course that the subject spends in the psychedelic state may also be assessed by the time the subject has a therapeutically relevant concentration of the drug in the blood, e.g., the time that the subject has a drug concentration between about 50 ng/mL and about 300 ng/mL, between about 60 ng/mL and about 280 ng/mL, between about 80 ng/mL to about 260 ng/mL, between about 100 ng/mL to about 240 ng/mL, between about 120 ng/mL to about 220 ng/mL, between about 140 ng/mL to about 200 ng/mL, between about 160 ng/mL to about 180 ng/mL, etc., or any range between these values. In some embodiments when prolonged exposures are desired, the pharmaceutical formulation may be adjusted to provide a duration of action beyond about 120 minutes, such as up to about 1,200 minutes, up to about 1,080 minutes, up to about 960 minutes, up to about 840 minutes, up to about 720 minutes, up to about 600 minutes, up to about 480 minutes, up to about 360 minutes, up to about 240 minutes, up to 180 minutes, for example, by increasing the loadings, molecular weight, and/or crosslinking of the release modifier. In some embodiments, the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves an onset of effects within about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes post administration, such as from about 1 minute to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to about 20 minutes, about 15 minute to about 30 minutes. In some embodiments, the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves an offset of effects of greater than about 30 minutes and up to about 150 minutes post administration, such as about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, about 125 minutes, about 130 minutes, about 135 minutes, about 140 minutes, about 145 minutes, about 150 minutes post administration, or any range therebetween. In some embodiments, the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a therapeutically relevant concentration of the drug in the blood of about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 125 ng/mL, about 130 ng/mL, about 135 ng/mL, about 140 ng/mL, about 145 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, about 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, or any range therebetween, such as from about 20 to about 150 ng/mL, or from about 30 to about 100 ng/mL, or from about 60 to about 100 ng/mL or from about 40 to about 80 ng/mL, or from about 45 to about 60 ng/mL, or from about 60 to about 80 ng/mL, or from about 50 to about 80 ng/mL, or from about 50 to about 300 ng/mL, or from about 100 to about 300 ng/mL, or from about 150 to about 280 ng/mL. For maximum therapeutic benefits and clinical scalability, these drug concentrations are preferably provided for a duration of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween. In some cases, higher plasma concentrations may be targeted. Further, desirable pharmaceutical formulations provide a controlled-release of the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, to achieve the aforementioned duration of action and/or psychedelic state time course, but do so without a burst release of the tryptamine psychedelic exceeding plasma levels of about 500 ng/mL, about 480 ng/mL, about 460 ng/mL, about 440 ng/mL, about 420 ng/mL, about 400 ng/mL, about 380 ng/mL, about 360 ng/mL, about 340 ng/mL, or about 320 ng/mL. Consequently, pharmaceutical formulations of the present disclosure, and in particular subcutaneous pharmaceutical formulations of the present disclosure, provide a smoother, more controlled delivery of the psychopharmaceutical agent contained therein compared to bolus IV or intramuscular injections of the same agent formulated without release modifier, which are known to cause high levels of drug spiking immediately following IV or intramuscular injection. In some embodiments, the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a therapeutically relevant maximum concentration of the drug in the blood of about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 125 ng/mL, about 130 ng/mL, about 135 ng/mL, about 140 ng/mL, about 145 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, about 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, or any range therebetween, such as from about 20 to about 150 ng/mL, or from about 30 to about 100 ng/mL, or from about 60 to about 100 ng/mL or from about 40 to about 80 ng/mL, or from about 45 to about 60 ng/mL, or from about 60 to about 80 ng/mL, or from about 50 to about 80 ng/mL, or from about 50 to about 300 ng/mL, or from about 100 to about 300 ng/mL, or from about 150 to about 280 ng/mL. In some embodiments, the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a plasma half-life (t1/2) of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 30 minutes to about 60 minutes, or from about 35 minutes to about 50 minutes, or from about 40 minutes to about 45 minutes. In some embodiments, the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a time to maximum drug concentration (Tmax) of about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 20 minutes to about 60 minutes, or from about 25 minutes to about 50 minutes, or from about 30 minutes to about 45 minutes, or from about 10 minutes to about 30 minutes. The pharmaceutical formulation may display first order release kinetics of the psychopharmaceutical agent, as determined by the Dialysis—Drug Release Test (see Example section for experimental protocol). Accordingly, the release kinetics may fit best to the first order mathematical equation (2): ^^ (− ^^ ^^) ^^0 = 1 − ^^ (2) where Q is the concentration of the drug, Q0 is the initial concentration of the drug, k is the first order rate constant, and t is the time. The pharmaceutical formulation may extend the release of the psychopharmaceutical agent compared to the release of the same psychopharmaceutical agent from a formulation without release modifier but is otherwise substantially the same. In the case of short-acting tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) for example, a longer release period may result in a more clinically advantageous duration of action time course and clinical efficacy. In some embodiments, the time required for release of 25% of a total psychopharmaceutical agent content (free base equivalence) in the pharmaceutical formulation (t25%) is at least about 35% longer, at least about 40% longer, at least about 45% longer, at least about 50% longer, at least about 55% longer, at least about 60% longer, at least about 65% longer, at least about 70% longer, at least about 75% longer, at least about 80% longer, at least about 85% longer, at least about 90% longer, at least about 95% longer, at least about 100% longer than the t25% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test (see Example section for experimental protocol). In some embodiments, the time required for release of 50% of a total psychopharmaceutical agent content (free base equivalence) in the pharmaceutical formulation (t50%) is at least about 35% longer, at least about 40% longer, at least about 45% longer, at least about 50% longer, at least about 55% longer, at least about 60% longer, at least about 65% longer, at least about 70% longer, at least about 75% longer, at least about 80% longer, at least about 85% longer, at least about 90% longer, at least about 95% longer, at least about 100% longer than the t50% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test. In some embodiments, the pharmaceutical formulation provides a time-restricted controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) so as not to overextend the release and the resulting duration of action beyond about 120 minutes. In some embodiments, the t25% is no more than about 250% longer, no more than about 225% longer, no more than about 200% longer, no more than about 190% longer, no more than about 180% longer, no more than about 170% longer, no more than about 160% longer, no more than about 150% longer no more than about 140% longer no more than about 130% longer than the t25% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test. In some embodiments, the t50% is no more than about 250% longer, no more than about 225% longer, no more than about 200% longer, no more than about 190% longer, no more than about 180% longer, no more than about 170% longer, no more than about 160% longer, no more than about 150% longer, no more than about 140% longer, no more than about 130% longer than the t50% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test. In some embodiments, the time required for release of 50% of a total psychopharmaceutical agent content in the pharmaceutical formulation (t50%) is no more than about 120 minutes, no more than about 110 minutes, no more than about 100 minutes, no more than about 90 minutes, no more than about 80 minutes, no more than about 70 minutes, no more than about 60 minutes, no more than about 50 minutes, no more than about 40 minutes, no more than about 30 minutes, as determined by the Dialysis—Drug Release Test. Kits Also disclosed herein is a kit suitable for preparing the injectable pharmaceutical formulation of the present disclosure. The kit comprises a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle. Any of the embodiments disclosed herein for the pharmaceutical formulation and the ingredients contained therein apply to the kit of the present disclosure. In some embodiments, the kit comprises (a1) a first solution comprising a psychopharmaceutical agent and an aqueous vehicle, and (b1) a second solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt and an aqueous vehicle. The kit components (a1) and (b1) are intended to be combined, contacted, or otherwise brought together to generate the injectable pharmaceutical formulation of the present disclosure. In some embodiments, (a1) the first solution comprises (as psychopharmaceutical agent) a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III). The (a1) first solution may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)) by contacting the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure with aqueous vehicle. Alternatively, (a1) the first solution may be prepared by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H+ (aq) ions capable of ionizing/protonating the free base to form the pharmaceutically acceptable salt of a compound of the present disclosure within (a1) the first solution in-situ. In some embodiments, (a1) the first solution comprises a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of first solution of about 0.1 mg/mL, about 0.4 mg/mL, about 0.6 mg/mL, about 0.8 mg/mL, about 1 mg/mL, about 1.2 mg/mL, about 1.4 mg/mL, about 1.6 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, or any range therebetween, such as from about 10 mg/mL to about 140 mg/mL, from about 20 mg/mL to about 100 mg/mL, from about 30 mg/mL to about 80 mg/mL, from about 40 mg/mL to about 70 mg/mL, from about 0.2 mg/mL to about 40 mg/mL, from about 0.2 mg/mL to about 20 mg/mL. In some embodiments, (b1) the second solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle. A concentration of the hyaluronate salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, or any range therebetween, such as from about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.15% to about 1%, about 0.2% to about 1%, or about 0.25% to about 0.75%. In some embodiments, (b1) the second solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle. A concentration of carboxymethyl cellulose salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.6% to about 2%, about 0.7% to about 1.8%, about 0.8% to about 1.7%, about 0.9% to about 1.6%, about 1% to about 1.5%. A suitable volume of each of kit components (a1) and (b1) may be combined, contacted, or otherwise brought together to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable unit doses and psychopharmaceutical agent concentrations. Kits may be provided with different concentrations of psychopharmaceutical agent in component (a1), different concentrations of release modifier in component (b1), and/or different volume ratios of kit components (a1) and (b1) may be combined, contacted, or otherwise brought together to generate different pharmaceutical formulations with differentiated release characteristics, unit doses, and/or psychopharmaceutical agent concentrations. For example, the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, unit dose, psychopharmaceutical agent concentration, release modifier, and release characteristics, by using different volume ratios of kit components (a1) : (b1). A suitable volume ratio of (a1) : (b1) used to generate the pharmaceutical formulation may be from about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range therebetween, such as from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1:1. The combining, contacting, or otherwise bringing together of kit components (a1) and (b1) to generate the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use. The kit may include instructions for what volume ratios of (a1) : (b1) can be used to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc. In some embodiments, the kit comprises (a2) a psychopharmaceutical agent in solid form and (b2) a solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle. The kit components (a2) and (b2) are intended to be combined, contacted, or otherwise brought together to generate the injectable pharmaceutical formulation of the present disclosure. In some embodiments, (a2) the psychopharmaceutical agent is a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form. Here, any pre-formed, solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) of the present disclosure can be used in kit component (a2). In some embodiments, (b2) the solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle. A concentration of the hyaluronate salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to about 0.75%, or about 0.25% to about 0.5%. In some embodiments, (b2) the solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle. A concentration of carboxymethyl cellulose salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%. A suitable volume of kit component (b2) may be combined, contacted, or otherwise brought together with kit component (a2) to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable psychopharmaceutical agent concentrations. Kits may be provided with different concentrations of release modifier in component (b2) and/or different volumes of kit component (b2) may be combined, contacted, or otherwise brought together with kit component (a2) to generate different pharmaceutical formulations with differentiated release characteristics and psychopharmaceutical agent concentrations. Kits may be provided with different amounts of psychopharmaceutical agent in solid form in component (a2) to generate different pharmaceutical formulations with differentiated unit doses and psychopharmaceutical agent concentrations. The combining, contacting, or otherwise bringing together the kit component (b2) with the solid dosage form of the psychopharmaceutical agent in kit component (a2) can be accurately described as an act of reconstituting the solid dosage form of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form and in some case in crystalline solid form). Reconstitution may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use. The kit may include instructions for what volume of kit component (b2) can be combined, contacted, or otherwise brought together with kit component (a2) to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc. As described previously, in addition to water, the aqueous vehicle used in any of the aforementioned kit components (e.g., kit component (a1), kit component (b1), kit component (b2)) may optionally contain one or more pharmaceutically acceptable additives, as desired/needed, such as water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof. Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. In some embodiments, the aqueous vehicle is made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride. In some embodiments, the aqueous vehicle is made up of water for injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent. In some embodiments, the aqueous vehicle is made up of water or saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle is formulated without a buffering agent. In some embodiments, the aqueous vehicle used in one or more of kit components (a1), (a2), and/or (b2), independent of one another, is water, such as water for injection (WFI). In some embodiments, the aqueous vehicle used in one or more of kit components (a1), (a2), and/or (b2), independent of one another, comprises sodium chloride at a concentration, in terms of weight per volume expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 1.5%, about 0.2% to about 1%, about 0.3% to about 0.5% w/v. In some embodiments, a pH adjustment may be performed with a pH adjusting agent on one or more of kit component (a1), kit component (b1), and/or kit component (b2). In some embodiments, a pH adjustment may be performed with a pH adjusting agent on one or more of kit component (a1), kit component (b1), and/or kit component (b2) prior to combining, contacting, or otherwise bringing together the respective kit components (kit components (a1) with (b1) or kit components (a2) with (b2)). In some embodiments, after combining, contacting, or otherwise bringing together the respective kit components (kit components (a1) with (b1) or kit components (a2) with (b2)), a pH adjustment may be performed with a pH adjusting agent to generate the final pharmaceutical formulation. Therefore, the kit may optionally comprise (c) a pH adjusting agent. In some embodiments, the pH adjusting agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid. In some embodiments, the pH adjustment involves increasing the pH, and so kit component (c) comprises a suitable base as pH adjusting agent, for example one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide. In some embodiments, the pH is adjusted with sodium hydroxide or potassium hydroxide, for example to generate the final pharmaceutical formulation. In some embodiments, the pharmaceutical formulation does not contain a buffering agent. Preparative methods Also disclosed herein is a method for preparing the pharmaceutical formulation of the present disclosure, the pharmaceutical formulation being suitable for injection. The method comprises contacting a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle. The contacting of the method may be conducted in a variety of ways, including through the use of conventional techniques known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy). The method for preparing the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use. In some embodiments, the psychopharmaceutical agent is a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III). In some embodiments, the method involves reconstituting a pre-formed, typically solid form and in some cases crystalline solid form of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) in an aqueous vehicle. In some embodiments, the method involves contacting a solution comprising a pharmaceutically acceptable salt of a compound of Formula (I) through (III) in an aqueous vehicle with a release modifier in solid form or as a solution in an aqueous vehicle. Alternatively, the method may involve contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H+ (aq) ions capable of ionizing/protonating the compounds of the present disclosure, thereby forming the pharmaceutically acceptable salt of a compound of Formula (I) through (III) in-situ. The method may comprise contacting a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle from components of a kit intended to be combined, contacted, or otherwise brought together. Any of the embodiments disclosed herein for the kit may be optionally used in the preparative methods herein. In some embodiments, the method comprises contacting (a1) a first solution comprising a psychopharmaceutical agent and an aqueous vehicle, with (b1) a second solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt and an aqueous vehicle. In some embodiments, (a1) the first solution comprises (as psychopharmaceutical agent) a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III). The (a1) first solution may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)) by contacting the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure with aqueous vehicle. Alternatively, (a1) the first solution may be prepared by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H+ (aq) ions capable of ionizing/protonating the free base to form the pharmaceutically acceptable salt of a compound of the present disclosure within (a1) the first solution in-situ. In some embodiments, (a1) the first solution comprises a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of first solution of about 0.1 mg/mL, about 0.4 mg/mL, about 0.6 mg/mL, about 0.8 mg/mL, about 1 mg/mL, about 1.2 mg/mL, about 1.4 mg/mL, about 1.6 mg/mL, about 1.8 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, or any range therebetween, such as from about 10 mg/mL to about 140 mg/mL, from about 20 mg/mL to about 100 mg/mL, from about 30 mg/mL to about 80 mg/mL, from about 40 mg/mL to about 70 mg/mL, from about 0.2 mg/mL to about 40 mg/mL, from about 0.2 mg/mL to about 20 mg/mL. In some embodiments, (b1) the second solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle. A concentration of the hyaluronate salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, or any range therebetween, such as from about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.15% to about 1%, about 0.2% to about 1%, or about 0.25% to about 0.75%. In some embodiments, (b1) the second solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle. A concentration of carboxymethyl cellulose salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.6% to about 2%, about 0.7% to about 1.8%, about 0.8% to about 1.7%, about 0.9% to about 1.6%, about 1% to about 1.5%. A suitable volume of each of the first solution (a1) and the second solution (b1) may be contacted to generate the pharmaceutical formulation with suitable physiochemical and controlled- release characteristics, as well as suitable unit doses and psychopharmaceutical agent concentrations. Different concentrations of psychopharmaceutical agent in (a1) the first solution, different concentrations of release modifier in (b1) the second solution, and/or different volume ratios of (a1) the first solution to (b1) the second solution may be contacted to generate different pharmaceutical formulations with differentiated release characteristics, unit doses, and/or psychopharmaceutical agent concentrations. For example, when the preparative method involves the use of a kit, the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, unit dose, psychopharmaceutical agent concentration, release modifier, and release characteristics, by combining different volume ratios of (a1) the first solution to (b1) the second solution. A suitable volume ratio of (a1) the first solution to (b1) the second solution used to generate the pharmaceutical formulation may be from about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range therebetween, such as from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1:1. The contacting of (a1) the first solution to (b1) the second solution to generate the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use. The method may involve following instructions for what volume ratios of (a1) : (b1) can be used to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc. In some embodiments, the method involves contacting (a2) a psychopharmaceutical agent in solid form with (b2) a solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle. In some embodiments, (a2) the psychopharmaceutical agent is a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form. Here, any pre-formed, solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) of the present disclosure can be used as (a2). In some embodiments, (b2) the solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle. A concentration of the hyaluronate salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to about 0.75%, or about 0.25% to about 0.5%. In some embodiments, (b2) the solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle. A concentration of carboxymethyl cellulose salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%. A suitable volume of (b2) the solution may be contacted with (a2) the psychopharmaceutical agent in solid form to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable psychopharmaceutical agent concentrations. Different concentrations of release modifier in (b2) the solution and/or different volumes of (b2) the solution may be contacted with (a2) the psychopharmaceutical agent in solid form to generate different pharmaceutical formulations with differentiated release characteristics and psychopharmaceutical agent concentrations. For example, when the preparative method involves the use of a kit, the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, psychopharmaceutical agent concentration, etc., by contacting different volumes of (b2) the solution with (a2) the psychopharmaceutical agent in solid form. Further, different amounts of (a2) the psychopharmaceutical agent in solid form may be used to generate different pharmaceutical formulations with differentiated unit doses and psychopharmaceutical agent concentrations. The contacting of (b2) the solution with (a2) the solid dosage form of the psychopharmaceutical agent can be accurately described as an act of reconstituting the solid dosage form of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form and in some case in crystalline solid form). Reconstitution may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use. The method may involve following instructions for what volume of (b2) the solution can be contacted with (a2) the psychopharmaceutical agent in solid form to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc. As described previously, in addition to water, the aqueous vehicle used in any of (a1) the first solution, (b1) the second solution, and/or (b2) the solution may optionally contain one or more pharmaceutically acceptable additives, as desired/needed, such as water-miscible vehicles, non- aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof. Suitable aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. In some embodiments, the aqueous vehicle is made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride. In some embodiments, the aqueous vehicle is made up of water, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent. In some embodiments, the aqueous vehicle is made up of water or saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle is formulated without a buffering agent. In some embodiments, the aqueous vehicle used in one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution, independent of one another, is water, such as water for injection (WFI). In some embodiments, the aqueous vehicle used in one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution, independent of one another, comprises sodium chloride at a concentration, in terms of weight per volume expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 1.5%, about 0.2% to about 1%, about 0.3% to about 0.5% w/v. In some embodiments, a pH adjustment may be performed with a pH adjusting agent on one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution. In some embodiments, a pH adjustment may be performed with a pH adjusting agent on one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution prior to contacting (a1) the first solution with (b1) the second solution or (a2) the psychopharmaceutical agent in solid form with (b2) the solution. In some embodiments, after contacting (a1) the first solution with (b1) the second solution or (a2) the psychopharmaceutical agent in solid form with (b2) the solution, the method may comprise adjusting the pH with a pH adjusting agent to generate the final pharmaceutical formulation. Here, when the preparative method involves the use of a kit, the kit may optionally comprise (c) a pH adjusting agent. In some embodiments, the pH adjusting agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid. In some embodiments, the adjusting of the pH involves increasing the pH, and so (c) comprises a suitable base as pH adjusting agent, for example one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide. In some embodiments, the pH is adjusted with sodium hydroxide or potassium hydroxide, for example to generate the final pharmaceutical formulation. In some embodiments, the pharmaceutical formulation does not contain a buffering agent. To be injectable, the pharmaceutical formulations of the present disclosure must be sterile, as known and practiced in the art. The method of the present disclosure may optionally comprise sterilizing the pharmaceutical formulation, for example as a final preparative step. The method may optionally comprise sterilizing any one or more (including all) components used to prepare the pharmaceutical formulation, such as (a1) the first solution, (b1) the second solution, (a2) the psychopharmaceutical agent in solid form, and/or (b2) the solution. The method may optionally comprise sterilizing any one or more (including all) components used to prepare the pharmaceutical formulation, such as (a1) the first solution, (b1) the second solution, (a2) the psychopharmaceutical agent in solid form, and/or (b2) the solution, and optionally sterilizing the pharmaceutical formulation, for example as a final preparative step. When sterilization is performed, sterilization may be carried out by steam sterilization, dry-heat sterilization/depyrogenation, gas sterilization, sterilization by ionizing radiation, sterilization by filtration, or unidirectional aseptic processing, for example according to the requirements set forth in USP Sterilization and Sterility Assurance of Compendial Articles <1211> and/or USP Sterility Tests <71>. In some embodiments, such as when the release modifier employed is a hyaluronate salt, sterile filtration is used. While not limited thereto, sterile filtration is usually carried out with assemblies having membranes of nominal pore size rating of 0.2 µm or less or 0.1 µm or less, according to the requirements set forth in USP Sterilization and Sterility Assurance of Compendial Articles <1211>. Sterile filtration may be carried out by passing the pharmaceutical formulation (or various components making up the pharmaceutical formulation, separately) through a membrane, a syringe filter, a vacuum device, a capsule assembly, a high pressure cartridge or filter assembly, and the like, each equipped with a suitable membrane, typically a membrane which is capable of passing a bacterial challenge to retain a minimum of 107 CFU/cm2 of B.dimunita. Examples of membranes include, but are not limited to, those made from polyethersulfone (PES), polyvinylidene fluoride (PVDF), cellulose, cellulose acetate, mixed cellulose esters (MCE), nylon, and hydrophilic polytetrafluoroethylene (PTFE). Alternatively, the preparative method for producing the pharmaceutical formulation may not involve any sterilization processing, and instead the method involves assembly of already sterilized components. For example, when the preparative method involves the use of a kit, the various kit components to be assembled (e.g., (a1) the first solution with (b1) the second solution, or (a2) the psychopharmaceutical agent in solid form with (b2) the solution) may be provided in sterilized form, where appropriate. Here, the end user such as a treating clinician/veterinarian or caregiver, would simply assemble the already sterilized kit components thereby forming the pharmaceutical formulation ready-to-use, with no additional sterilization processing needed. The pharmaceutical formulations disclosed herein may be formulated for single or multiple dosage administration. The pharmaceutical formulation may be optionally stored and/or packaged in any suitable container, examples of which include, but are not limited to, an ampule, a vial, a syringe such as a pre-filled syringe, a cartridge, a reservoir or cartridge for an injection device such as an on-body drug delivery device or an auto-injector, etc. In some embodiments, to help prevent degradation or physical changes to the pharmaceutical formulation, the pharmaceutical formulation is stored and/or packaged in a container adapted to prevent penetration of ultraviolet light, such as amber glass vial. In some embodiments, the container within which the pharmaceutical formulation is stored and/or packaged is not so adapted (and may be, for example, made of clear glass) with protection against ultraviolet light, if desired, provided by secondary packaging (for example packaging within which the receptacle containing the pharmaceutical formulation may be placed). Often, the container is airtight and the pharmaceutical formulation is stored under an inert atmosphere, such as under nitrogen or argon, typically nitrogen. The formulation may be stored at room temperature, e.g., at about 20 to about 30°C, or at cooler temperatures, for example at about 2 to about 8°C. Alternatively, the pharmaceutical formulation may be stored in a freezer. Further, tamper resistant dosage forms/packaging of any of the disclosed pharmaceutical formulations are contemplated. Therapeutic applications and methods Also disclosed herein is a method of treating a disease or disorder such as a mental disorder in a subject (e.g., a companion animal) in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of the present disclosure. The mental disorder may be associated with a 5-HT2 receptor, namely an anxiety disorder and/or a depressive disorder. The pharmaceutical formulation is suitable for injection, thus its administration in therapy typically comprises parenteral administration via injection to affect a beneficial therapeutic response. Injection may involve administration through a needle (hypodermic needle), microneedles including hollow microneedles, or using a needle-free injection system whereby a fine, high velocity jet is generated by driving liquid through an orifice at high pressure to pierce the skin and underlying tissue. In some embodiments, the method comprises administering the pharmaceutical formulation intravenously to the subject (directly into the vein). In some embodiments, the method comprises administering the pharmaceutical formulation intramuscularly to the subject (within the muscle). In some embodiments, the method comprises administering the pharmaceutical formulation intradermally to the subject (beneath the skin). In some embodiments, the method comprises administering the pharmaceutical formulation subcutaneously to the subject (within the fat or the layer of skin directly below the dermis and epidermis). Subcutaneous administration is a minimally invasive mode of administration. Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of depot effect. Compared with other routes of administration, it is slower than intravenous and intramuscular injections but still faster than intradermal injections. The convenience and speed of subcutaneous delivery allows increased compliance and quicker access to medication when needed. Subcutaneous administration can be performed by injection or by implantation of a sustained or timed-release device beneath the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed. When a subject requires multiple doses, the method may involve subcutaneously injecting several unit dose pharmaceutical formulations at multiple sites of the body surface. A particular advantage of the subcutaneous delivery route in the therapeutic methods of the present disclosure is that it allows the medical practitioner/veterinarian to perform the administration in a rather short intervention with the patient, compared to intravenous infusion protocols associated with DMT-based therapy. Moreover, in the case of companion animal treatment, the owner of the companion animal can be trained to perform administration, e.g., at home. In methods comprising administering the pharmaceutical formulation subcutaneously to a dog, the injection volume of the pharmaceutical formulation administered is usually about 50 mL or less, such as about 0.1 mL, about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, or any range therebetween. In methods comprising administering the pharmaceutical formulation subcutaneously to a cat, the injection volume of the pharmaceutical formulation administered is usually about 100 mL or less, such as about 0.1 mL, about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, about 100 mL, or any range therebetween. In methods comprising administering the pharmaceutical formulation subcutaneously to a horse, the injection volume of the pharmaceutical formulation administered is usually about 10 mL or less, such as about 0.1 mL, about 0.2 mL, about 0.4 mL, about 0.6 mL, about 0.8 mL, about 1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 4.5 mL, about 5 mL, about 5.5 mL, about 6 mL, about 6.5 mL, about 7 mL, about 7.5 mL, about 8 mL, about 8.5 mL, about 9 mL, about 9.5 mL, about 10 mL, or any range therebetween. Such injection volumes are generally recognized as tolerated via the subcutaneous route in the respective species without undue pain. In some embodiments, the method comprises administering the pharmaceutical formulation as a bolus injection, in which a discrete amount of psychopharmaceutical agent (e.g., tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) is administered by injection within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less, or any range therebetween. The bolus injection may involve a single injection or multiple injections performed within the above-described time range. Thus, administering multiple bolus injections within the above-mentioned time range of 30 minutes or less (e.g., two injections lasting 30 seconds each, administered within 5 minutes of one another) would be considered a bolus administration herein. In some embodiments, the bolus injection involves a single injection within the above time range. In some embodiments, the method comprises administering the pharmaceutical formulation as a bolus subcutaneous injection, such as a single bolus subcutaneous injection. In some embodiments, the method comprises administering the pharmaceutical formulation as a bolus intramuscular injection, such as a single bolus intramuscular injection. In some embodiments, the method comprises administering the pharmaceutical formulation as a bolus intradermal injection, such as a single bolus intradermal injection. In some embodiments, the method comprises administering the pharmaceutical formulation as a bolus intravenous injection, such as a single bolus intravenous injection.
In some embodiments, the method comprises administering the pharmaceutical formulation as an infusion injection, in which a discrete amount of psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) is administered by injection over a prolonged period of greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, greater than 110 minutes, greater than 120 minutes, etc. The infusion injection may involve a single prolonged injection, or multiple injections (short or prolonged) within the above-described time range. Thus, administering multiple bolus injections over a prolonged period of greater than 30 minutes would be considered an infusion administration herein. In some embodiments, the infusion injection involves a single injection within the above time range. In some embodiments, the method comprises administering the pharmaceutical formulation as an infusion subcutaneous injection. In some embodiments, the method comprises administering the pharmaceutical formulation as infusion intramuscular injection. In some embodiments, the method comprises administering the pharmaceutical formulation as infusion intravenous injection.
Any injection device that enables administration of the pharmaceutical formulation through the skin or other external boundary tissue of the subject may be used in the disclosed methods. Examples of injection devices include, but are not limited to, needle and syringe, pre- filled syringe, canula, catheter, pen, auto-injector (e.g., ACTpen®, ArQ® - Bios from Oval Medical Technologies), semi-auto injector (such as those from UnionMedico®) on-body drug delivery devices (e.g., patches, pumps, those with automatic needle insertion/retraction, belt worn devices, such as those available from Gerresheimer AG, etc.), implants, embedded needle tip devices, a needle-free injection system (e.g., a jet injector), automatic injection devices, or other suitable injection device. The injection device may be resuable or disposable (e.g., disposable hypodermic needle and syringe, disposable pen, disposable pump, disposable on-body drug delivery device, etc.), or may contain a reusable or disposable needle guide. The injection device may be actuated manually or automatically. Some automatic injection devices may be configured with automatic needle insertion/retraction, auto-pumps, or one or more microneedles, which in some embodiments may be coated with a pharmaceutical formulation disclosed herein. Alternatively, hollow microneedles may be used to provide a fluid channel for delivery of the disclosed pharmaceutical formulations below the outer layer of the skin to improve delivery. In needle-free injection systems (e.g., a jet injector) a fine, high velocity jet is generated by driving liquid through an orifice at high pressure to pierce the skin and underlying tissue. These needle- free injection systems may include those adapted with spring systems, lasers, or energy propelled systems such as Lorentz force, gas propelled/air forced, or shove wave driven devices. Examples of needle-free injection devices include, but are not limited to, Bioject® jet injectors such as Biojector® 2000, Viajet 3, DosePro™, ZetaJet™, Stratis® IM/SC, and Jupiter Jet™. Multi- component injections, such as using a dual chamber syringe or a multi-syringe (e.g., two syringe) set up, may also be performed. The injection device can be optionally manufactured with smart technology enabling remote activation and/or control of delivery. The remote activation can be performed via computer or mobile app. To ensure security, the remote activation device can be password encoded. This technology enables a provider to perform telehealth sessions, during which the provider can remotely activate and administer the pharmaceutical formulation via the desired delivery device while supervising the subject on the televisit.
Subcutaneous injections may be performed by cleaning the area to be injected followed by an injection, usually at about a 45-degree angle to the skin when using a syringe and needle, or at about a 90-degree angle (perpendicular) if using an injector pen or other suitable injector device. Of course, as is known in the art, the appropriate injection angle is based on the length of needle or injection device used, and the depth of the subcutaneous fat in the skin of the subject receiving the treatment. If administered at an angle, the skin and underlying tissue may be pinched upwards prior to injection (the “pinch-up” technique). Subcutaneous injection may be administered, inter alia, in the subject’s back of the neck region, the upper area of the buttock, just behind the hip bone, and the like. Any of which may be performed using the “pinch-up” technique. The choice of injection site is based on the pharmaceutical formulation being administered, for example taking into account the volume of injection needed, as well as preference. Injections administered frequently or repeatedly should be administered in a different location each time, either within the same general site or a different site, but at least one inch away from recent injections as known and practiced in the art. In most cases, subcutaneous injections can be easily performed by people with minor skill and training required.
Administration may follow a continuous administration schedule, or an intermittent administration schedule. The administration schedule may be varied depending on the psychopharmaceutical agent employed, the condition being treated, etc. For example, administration may be performed once a day (QD), or in divided dosages throughout the day, such as 2-times a day (BID), 3 -times a day (TID), 4-times a day (QID), or more. In some embodiments administration may be performed nightly (QHS). In some embodiments, the pharmaceutical formulation may be administered as needed (PRN). Administration may also be performed on a weekly basis, e.g., once a week, twice a week, three times a week, four times a week, every other week, every two weeks, etc., or less. In some embodiments, the pharmaceutical formulation may be administered monthly, for example, once monthly dosing or dosing every two months. The administration schedule may also designate a defined number of treatments per treatment course, for example, administration may be performed 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, or 8 times per treatment course. Other administration schedules may also be deemed appropriate using sound medical judgement.
The dosing can be continuous (7 days of administration in a week) or intermittent, for example, depending on the pharmacokinetics and a particular subject’s clearance/accumulation of the psychopharmaceutical agent. If intermittently, the schedule may be, for example, 4 days of administration and 3 days off (rest days) in a week or any other intermittent dosing schedule deemed appropriate using sound medical judgement. For example, intermittent dosing may involve administration of a single dose within a treatment course. The dosing whether continuous or intermittent is continued for a particular treatment course, typically at least a 28-day cycle (1 month), which can be repeated with or without a drug holiday. Longer or shorter courses can also be used such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 days, or longer, or any range therebetween. The course may be repeated without a drug holiday or with a drug holiday depending upon the subject. Other schedules are possible depending upon the presence or absence of adverse events, response to the treatment, convenience, and the like.
The dosage and frequency (single or multiple doses) of administration can vary depending upon a variety of factors, including, but not limited to, the psychopharmaceutical agent to be administered; the disease/condition being treated; route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.
In order to treat the disease or disorder, the pharmaceutical formulation comprises a therapeutically effective amount of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), i.e., an amount that is sufficient to reduce or halt the rate of progression of the disease or disorder, to ameliorate or cure the disease or disorder and thus produce the desired therapeutic or inhibitory effect, or to alleviate one or more symptoms of the disease or disorder. The dosage can be adjusted by monitoring response to the treatment and adjusting the dosage upwards or downwards.
Dosages may be varied depending upon the requirements of the subject and the psychopharmaceutical agent being employed. The dose administered to a subject, in the context of the pharmaceutical formulations presented herein, should be sufficient to effect a beneficial therapeutic response in the subject over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the subject’s disease state.
Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity or adverse side effects (e.g., caused by sedative or psychotomimetic toxic spikes in plasma concentration of any of the psychopharmaceutical agents), and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of psychopharmaceutical agent by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.
In some embodiments, in terms of weight-based dosing (per kilogram body weight of the subject), a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) provided by the pharmaceutical formulation is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, about 5.5 mg/kg, about 6.0 mg/kg, about 6.5 mg/kg, about 7.0 mg/kg, about 7.5 mg/kg, about 8.0 mg/kg, about 8.5 mg/kg, about 9.0 mg/kg, about 9.5 mg/kg, about 10.0 mg/kg, or any range therebetween. In some embodiments, a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) in dogs is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween. In some embodiments, a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) in cats is about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween. In some embodiments, a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) in horses is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, or any range therebetween.
In some embodiments, the pharmaceutical formulation comprises a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent, and a therapeutically effective amount may be a psychedelic dose. Here, a psychedelic dose (therapeutically effective amount) in dogs in terms of weight-based dosing (free base equivalence) may in some embodiments be about 0.5 mg/kg, about 0.55 mg/kg, about 0.6 mg/kg, about 0.65 mg/kg, about 0.7 mg/kg, about 0.75 mg/kg, about 0.8 mg/kg, about 0.85 mg/kg, about 0.9 mg/kg, about 0.95 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween. Higher dosing may also be used in some embodiments, as described above. A psychedelic dose (therapeutically effective amount) in cats in terms of weight-based dosing (free base equivalence) may in some embodiments be about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg, about 4.6 mg/kg, about 4.8 mg/kg, about 5.0 mg/kg, or any range therebetween. A psychedelic dose (therapeutically effective amount) in horses in terms of weight- based dosing (free base equivalence) may in some embodiments be about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, or any range therebetween.
In terms of fixed doses, a psychedelic dose (therapeutically effective amount) of a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) (free base equivalence) may in some embodiments be about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 300 mg, or any range therebetween, such as from about 15 mg to about 150 mg, from about 20 mg to about 100 mg, from about 25 mg to about 75 mg. A fixed psychedelic dose (free base equivalence) in dogs may in some embodiments be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, or any range therebetween. A fixed psychedelic dose (free base equivalence) in cats may in some embodiments be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg., or any range therebetween. A fixed psychedelic dose (free base equivalence) in horses may in some embodiments be about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 300 mg, or any range therebetween.
Furthermore, administration of pharmaceutical formulations comprising a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent in sub-psychedelic (yet still potentially serotonergic concentrations) doses may be performed in some embodiments to achieve durable therapeutic benefits, with decreased toxicity, and may thus be suitable for microdosing. Sub-psychedelic dosing in dogs may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), in terms of free base equivalence, in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, or about less than 0.5 mg/kg, or any range therebetween. Sub-psychedelic dosing in cats may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), in terms of free base equivalence, in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, or about less than 0.4 mg/kg, or any range therebetween. Sub-psychedelic dosing in horses may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), in terms of free base equivalence, in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about less than 0.1 mg/kg. Typically, sub- psychedelic doses are administered up to every day, for a treatment course (e.g., 1 month). However, there is no limitation on the number of doses at sub-psychedelic doses — dosing can be less frequent or more frequent as deemed appropriate. Courses can be repeated as necessary, with or without a drug holiday. Sub-psychedelic doses can be used, e.g., for the chronic treatment or maintenance of a variety of diseases or disorders disclosed herein.
The pharmaceutical formulations of present disclosure may be administered via injection for a maintenance regimen. As used herein, a “maintenance regimen” generally refers to the administration of a psychopharmaceutical agent following achievement of a target dose, e.g., following completion of an up-titration regimen, and/or following a positive clinical response, e.g., improvement of the patient's condition, either to the same agent or to a different agent. The maintenance dose may be used to ‘maintain’ the therapeutic response and/or to prevent occurrences of relapse. When the same psychopharmaceutical agent is used for both the original therapeutic regimen and for the maintenance regimen, the maintenance dose may be at or below the therapeutic dose. In some embodiments, the maintenance dose is a psychedelic dose. In some embodiments, the maintenance dose is a sub-psychedelic dose. Generally, dosing is carried out daily or intermittently for the maintenance regimen, however, maintenance regimens can also be carried out continuously, for example, over several days, weeks, months, or years. Moreover, the maintenance dose may be given to a patient over a long period of time, even chronically. In some embodiments, a maintenance regimen is dosed monthly, e.g., once a month, once every two months, etc.
The methods provided herein may be used to treat a disease or disorder, such as a mental disorder, in a subject (e.g., companion animal) in need thereof. The disease or disorder may be associated with a serotonin 5-HT2 receptor. In some embodiments, the mental disorder is central nervous system (CNS) disorder and/or psychological disorder. In some embodiments, the mental disorder is an anxiety disorder, a depressive disorder, or both.
In some embodiments, the disease or disorder is an anxiety disorder. As used herein, the term “anxiety disorder” refers to a state of apprehension, uncertainty, and/or fear resulting from the anticipation of an event and/or situation. Anxiety disorders cause physiological and psychological signs or symptoms. Non-limiting examples of signs or symptoms include trembling, hiding, attempts to leave or escape, compulsive licking or grooming, self-injuring, diarrhea or vomiting, depression, drooling, panting, reduced activity, destructive behavior, frantic vocalization (e.g., barking, whimpering, whining, crying, yowling, howling, meowing, etc.), housebreaking accidents, not eating or exercising, pacing, restlessness, aggression, etc. Anxiety disorders may increase a subject’s stress levels, and impair their immune response and overall health. In some embodiments, the methods disclosed herein treat chronic anxiety disorders. As used herein, a “chronic” anxiety disorder is recurring. In some embodiments, the methods disclosed herein treat transient anxiety episodes. Examples of anxiety disorders include, but are not limited to, separation anxiety, social anxiety, a phobia-related disorder (e.g., a noise phobia), a compulsive disorder such as obsessive-compulsive disorder (OCD), age-related anxiety, etc. The anxiety disorder can develop at any age, and in any animal breed. In some embodiments, the subject in need thereof has always harbored an anxiety disorder, i.e., the anxiety was not driven by a particular event. In some embodiments, the subject in need thereof develops an anxiety disorder after experiencing a particular event such as a traumatic event. In some embodiments, an anxiety disorder comprises a medical diagnosis based on an independent medical or veterinary evaluation. In some embodiments, an anxiety disorder comprises a medical or veterinary diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., published by the American Psychiatric Association, or in International Classification of Diseases (ICD), published by the World Health Organization.
In some embodiments, the disease or disorder is separation anxiety. As used herein, “separation anxiety” is a disorder that causes the subject (e.g., a companion animal) to panic when they suspect they will be left alone or when they are in fact left alone. Generally, separation anxiety results in extreme stress from the time an owner or caregiver leaves until they return. Subjects with separation anxiety often demonstrate signs such as destructive behavior (e.g., chewing household items like shoes, furniture, etc., getting into the trash, destroying or damaging their shelter, housing, doors or other household items etc.), frantic vocalization (e.g., barking, whimpering, whining, crying, yowling, howling, meowing, etc.), housebreaking accidents (e.g., urinating and/or defecating), excessive salivation, drooling, or panting, desperate and prolonged attempts to escape confinement, potentially ending in serious injury, etc. In some embodiments, at least one sign or symptom of separation anxiety is improved following treatment disclosed herein. In some embodiments, treating according to the methods of disclosure reduces or ameliorates a sign or symptom of separation anxiety. In some embodiments, after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
In some embodiments, the disease or disorder is social anxiety. As used herein, “social anxiety” is a marked fear or anxiety about one or more social situations. Subjects often develop social anxiety when they have previously experienced neglect; for instance, dogs who have been rescued from puppy mills, were strays, or have experienced situations of abuse or neglect. This social condition can cause subjects to experience crippling anxiety when being around other animals or humans and can even lead to aggression. In one non-limited example, an animal that has experienced abuse from a male human may suffer from social anxiety around male humans. In another non-limited example, an animal that has been attacked by another animal (e.g., a dog) may suffer from social anxiety around other animals (e.g., dogs). Non-limiting examples of signs or symptoms include trembling, hiding, attempts to leave or escape, diarrhea or vomiting, reduced activity, frantic vocalization (e.g., barking, whimpering, whining, crying, yowling, howling, meowing, etc.), housebreaking accidents, not eating or exercising, etc. In some embodiments, at least one sign or symptom of social anxiety is improved following treatment disclosed herein. In some embodiments, treating according to the methods of disclosure reduces or ameliorates a sign or symptom of social anxiety. In some embodiments, after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
In some embodiments, the disease or disorder is a phobia-related disorder. As used herein, “phobia-related disorder” is an excessive fear or anxiety brought about by a specific stimulus. A non-limiting example of a phobia-related disorder is a noise phobia (noise anxiety), wherein the subject has an irrational, intense, and/or persistent fear of a noise or sound that may cause the subject to avoid or escape from the noise or sound. Non-limiting examples of noise or sound stimuli that may provoke the fear response include thunderstorms (e.g., thunder), fireworks, loud voices or shouting, sirens or alert systems (e.g., fire engines, storm sirens, etc.), or other loud noises. Other non-limiting examples of a phobia-related disorder include phobias to strange people or animals, visual stimuli like hats or umbrellas, new or strange environments in specific situations like the veterinarian office or car rides, or surfaces like grass or wood floors. Although some animals may only have brief reactions to these kinds of stimuli, they may affect anxious animals more consequentially. The phobia can develop at any age, and in any animal breed. Animals (e.g., companion animals) suffering from a phobia-related disorder may show similar signs to those with social or separation anxiety, non-limiting examples of signs or symptoms include trembling, hiding, attempts to leave or escape, diarrhea or vomiting, reduced activity, frantic vocalization (e.g., barking), housebreaking accidents, not eating or exercising, etc. In some embodiments, at least one sign or symptom of a phobia-related disorder is improved following treatment disclosed herein. In some embodiments, treating according to the methods of disclosure reduces or ameliorates a sign or symptom of phobia-related disorder. In some embodiments, after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
In some embodiments, the disease or disorder is a compulsive disorder, such as obsessive- compulsive disorder (OCD). As used herein, “obsessive-compulsive disorder” is a marked change in a subject’s behavior which is out of context, strange, and/or directed toward objects. When present in dogs, OCD may be referred to as canine compulsive disorder (CCD). Subjects experiencing OCD may excessively repeat certain obsessive behaviors, non-limiting examples of which include sucking on their flanks or a toy, acral lick dermatitis (incessant licking or grooming), pacing, spinning, and tail chasing, freezing and staring, digging, biting objects such as biting a food dish or bowl, snapping at flies or invisible items, unabated and patterned vocalization, excessive drinking of water or eating dirt, etc. When performed in an extreme, repetitive way, these behaviors may interfere with the subject’s ability to function. In some embodiments, at least one sign or symptom of a compulsive disorder is improved following treatment disclosed herein. In some embodiments, treating according to the methods of disclosure reduces or ameliorates a sign or symptom of a compulsive disorder. In some embodiments, after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
In some embodiments, the disease or disorder is age-related anxiety. As used herein, “age- related anxiety” is an anxiety brought about by a decline in memory, learning, perception, and/or awareness in older animals. Age-related anxiety affects older animals and can be associated with cognitive dysfunction syndrome (CDS). In animals with CDS, the decline in memory, learning, perception, and/or awareness leads to confusion and anxiety. Non-limiting examples of signs or symptoms include trembling, hiding, urinating or defecating in the house, reduced activity, depression, not eating or exercising, etc. In some embodiments, at least one sign or symptom of age-related anxiety is improved following treatment disclosed herein. In some embodiments, treating according to the methods of disclosure reduces or ameliorates a sign or symptom of age- related anxiety. In some embodiments, after treating the sign or symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
In some embodiments, a sign or symptom of an anxiety disorder is measured according to an assessment by a clinician/veterinarian or caregiver, or a clinical scale. In some embodiments, treating according to the methods of the disclosure results in an improvement in an anxiety disorder compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the assessments by a clinician/veterinarian or caregiver, or clinical scales, described herein or known in the art.
In some embodiments, the methods provided herein are used to treat a subject with a depressive disorder. As used herein, the terms “depressive disorder” or “depression” refer to a mood disorder characterized by low mood or loss of interest that can affect behavior, feelings, and well-being lasting for a period of time. Non-limiting examples of signs or symptoms of depression include a marked change in appetite, which may involve eating less and losing weight in some instances, or eating more and gaining weight in other instances; lethargy or changes in sleep habits such as a change from routine napping to excessive napping; general loss of interest, such as loss of interest in toys, treats, food, car rides, physical affection such as petting, or other previously enjoyed activities or objects; excessive grooming or licking, which in the case of dogs for example can indicate distress or unhappiness and an attempt to self-soothe; avoidance and hiding such as under beds, sofas, tables, etc.; increased demand in attend on/affecti on from caregivers; a change in vocalization (e.g., increased meowing, barking, howling, etc.); unusually aggressive behavior; housebreaking accidents, etc. In some embodiments, the depressive disorder disrupts the physical and psychological functions of a subject. In some embodiments, the depressive disorder causes a physical symptom such as weight loss, aches or pains, or digestive problems. In some embodiments, the depressive disorder causes a psychological symptom such as persistent sadness, anxiety, feelings of hopelessness and irritability, loss of interest or pleasure in activities, etc. In some embodiments the depressive disorder is acute. In some embodiments, the depressive disorder is chronic. In some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical or veterinary evaluation. In some embodiments, a depressive disorder comprises a medical or veterinary diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., published by the American Psychiatric Association, or in International Classification of Diseases (ICD), published by the World Health Organization.
In some embodiments, the depressive disorder is caused by environmental changes. For example, the subject may become sad or depressed after a stay in a kennel or boarding facility, adoption or arrival of a new animal or pet in the household, a change in caregiver routine such as a new job or altered work schedule. In a highly distressing event, some subjects experience depression and grief. For instance, a subject may experience distress when a household member moves away permanently or when new household members arrive. Similarly, a subject such as a dog living with children may experience depression once summer ends and the children return to school. Such events could trigger separation anxiety and loneliness as well. In addition, when a household incorporates new members, such as babies or other pets, subjects may feel excluded if the new member receives more attention.
In some embodiments, the depressive disorder is caused by changes to the subject’s social group. Dogs are most likely to become depressed due to a significant change in their social group, but this can affect other animals as well. Subjects such as companion animals often have an emotional bond with the other animals/pets they live with, especially if they all get along. When such connections are lost, the subject may experience grief, ultimately resulting in depression.
In some embodiments, the depressive disorder is caused by boredom or lack of stimulation. Boredom may cause sadness and depression in a subject, which may result in destructive behavior. In some embodiments, the depressive disorder is the result of a fear of phobia. Common fears or phobias include loud noises and separation from their caregiver or family members. The subject may show fear by lip licking, yawning, flattened ears, pacing, destructive behavior, panting, etc. The subject may experience constant anxiety from the fear and phobia, waiting for the following fear-inducing incident, and as a result the subject may become withdrawn and depressed.
In some embodiments, the depressive disorder is seasonal affective disorder. As used herein, the term “seasonal affective disorder” refers to a condition wherein subject experiences mood changes or a depressive episode during a particular season or time of the year, that does not persist throughout the year. In some instances, the subject experiences low mood, low energy, or other depressive symptoms during the fall and/or winter season. In some instances, the subject experiences low mood, low energy, or other depressive symptoms during the spring and/or summer season. Dogs in particular may be most prone to seasonal affective disorder in the wintertime when some of their favorite activities become more difficult.
In some embodiments, the depressive disorder is caused by poor training methods. For example, dogs that are subjected to punishment-based training methods (e.g., positive punishment which administers an unpleasant stimulus for misbehavior, or negative punishment which removes a pleasant incentive for misbehavior) are prone to higher levels of stress, and may develop anxiety and depression.
In some embodiments, the depressive disorder is cause by physical illness or pain. Painful physical conditions in subjects, such as injury or fatigue, may lead to psychological distress. Shaking, aggression, loss of appetite, limping, and whining are all signs that a subject is in pain, which may cause depressive episodes.
In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment. In some embodiments, a sign or symptom of a depressive disorder is measured according to an assessment by a clinician/veterinarian or caregiver, or a clinical scale. In some embodiments, treating according to the methods of the disclosure results in an improvement in a depressive disorder compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the assessments by a clinician/veterinarian or caregiver, or clinical scales, described herein or known in the art.
In some embodiments, the disease or disorder is attention deficit hyperactivity disorder (ADHD). ADHD is marked by an ongoing pattern of inattention and/or hyperactivity -impulsivity. Hyperactivity-impulsivity symptoms may often include, but are not limited to, fidgeting or squirming, leaving situations where staying seated is expected, running, dashing, or climbing around at inappropriate times, being unable to engage in activities quietly, being constantly in motion, and vocalizing (e.g., barking) excessively. About 12 to 15% of dogs exhibit hyperactivity and impulsivity, and about 20% exhibit inattention. These qualities have been found to be highly heritable but also influenced by environmental factors, similar to humans. In canines, young male dogs may be the most likely to display hyperactivity, impulsivity, and inattention. Further, certain breeds of working dog, which have been bred to be highly active such as German Shepherds and Border Collies, may be the most liable to hyperactivity and impulsivity.
In some embodiments, the methods provided herein are used to manage pain in a subject in need thereof. Examples of different kinds of pain include, but are not limited to, pain associated with an illness such as cancer pain, e.g., refractory cancer pain; neuropathic pain; postoperative pain; severe chemical or thermal burn injury; sprains, ligament tears, fractures, wounds and other tissue injuries; dental surgery, procedures and maladies; arthritis; autoimmune disease and pain associated therewith; acute nausea, e.g., pain that may be causing the nausea or the abdominal pain that frequently accompanies sever nausea; pain associated with depression, refractory asthma, acute asthma, epilepsy, and acute brain injury and stroke. The pain may be persistent or chronic pain that lasts for weeks to years, in some cases even though the injury or illness that caused the pain has healed or gone away, and in some cases despite previous medication and/or treatment. In addition, the disclosure includes the treatment/management of any combination of these types of pain or conditions.
In some embodiments, the disease or disorder is arthritis. Types of arthritis include osteoarthritis, rheumatoid arthritis, gout, and lupus. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is gout. In some embodiments, the disease or disorder is lupus.
The administering physician or caregiver can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of administration on the basis of observations of one or more symptoms of the disorder or condition being treated.
In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a companion animal, including but not limited to, a dog, a cat, a horse, a rabbit, a ferret, a bird, a guinea pig, livestock (e.g., cattle, sheep, pigs, goats, donkeys, mules, etc.). In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a cat. In some embodiments, the companion animal is a horse.
In some embodiments, the pharmaceutical formulations of the present disclosure may be used as a standalone therapy. In some embodiments, the pharmaceutical formulations of the present disclosure may be used as an adjuvant/combination therapy. In some embodiments, the subject with a disorder is administered a pharmaceutical formulation of the present disclosure and at least one additional therapy and/or therapeutic. In some embodiments, administration of an additional therapy and/or therapeutic is prior to administration of the pharmaceutical formulation of the present disclosure. In some embodiments, administration of an additional therapy and/or therapeutic is after administration of the pharmaceutical formulation of the present disclosure. In some embodiments, administration of an additional therapy and/or therapeutic is concurrent with administration of the pharmaceutical formulation of the present disclosure. In some embodiments, the pharmaceutical formulation comprises a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent, and the additional therapy is an antidepressant, an anticonvulsant, an antipsychotic, an anxiolytic, an anti-inflammatory drug, a benzodiazepine, an analgesic drug, a cardiovascular drug, an opioid antagonist, or combinations thereof.
All patents, patent applications, and other scientific or technical writings referred to anywhere herein are incorporated by reference herein in their entirety. The embodiments illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations that are specifically or not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising," "consisting essentially of," and "consisting of can be replaced with either of the other two terms, while retaining their ordinary meanings. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims. Thus, although the present methods and compositions have been specifically disclosed by embodiments and optional features, modifications and variations of the concepts herein disclosed can be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of the compositions and methods as defined by the description and the appended claims.
Any single term, single element, single phrase, group of terms, group of phrases, or group of elements described herein can each be specifically excluded from the claims.
Whenever a range is given in the specification, for example, a temperature range, a time range, a composition, or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the aspects herein. It will be understood that any elements or steps that are included in the description herein can be excluded from the claimed compositions or methods.
In addition, where features or aspects of the compositions and methods are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the compositions and methods are also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
The following are provided for exemplification purposes only and are not intended to limit the scope of the embodiments described in broad terms above.
EXAMPLES
I. Synthetic Procedures
Synthetic procedures for accessing DMT, 5-MeO-DMT, deuterated analogs thereof, and salt forms thereof, are presented below and in Figs. 1-2. See also PCT/EP2023/050702, which is incorporated herein by reference in its entirety.
Salt forms of 2-(17/-indol-3-yl)-N,N-dimethylethan-l-amine-l,l-t/2 (1-2)
Synthesis of 2-(U/-indol-3-yl)-N,N-dimethylethan-l-amine-l,l-t/2 (1-2) was carried out according to Fig. 1. Indole (A) (R5 = H) was iminoformylated using formaldehyde/dimethylamine to produce intermediate (B), which was then converted to the 3 -acetic acid intermediate (C) using potassium cyanide in HC1. Subsequent treatment with thionyl chloride and dimethylamine (Rs = R9 = CH3) produced amide (D, Rs = R9 = CH3), that was reduced by IJAID4 to yield compound I- 2 (free base). The structure of the product was confirmed by JH NMR.
Various salt forms are prepared by crystallization of 1-2 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifier and salt type are provided in Table 3.
Table 3.
Figure imgf000189_0001
Salt forms of 2-(lJ/-indol-3-yl)-N,N-bis(methyl-t/3)ethan-l-amine-l,l-t/2 (1-6)
Synthesis of 2-(lJ/-indol-3-yl)-N,N-bis(methyl-t/3)ethan-l-amine-l,l-t/2 (1-6) was carried out according to Fig. 1. Indole (A) (R5 = H) was iminoformylated using formaldehyde/dimethylamine to produce intermediate (B), which was then converted to the 3- acetic acid intermediate (C) using potassium cyanide in HC1. Subsequent treatment with thionyl chloride and dimethyl-t/6-amine (Rs = R9 = CD3) produced amide (D, Rs = R9 = CD3), that was reduced by LiAlD4 to yield compound 1-6 (free base). The structure of the product was confirmed by 'HNMR.
Various salt forms are prepared by crystallization of 1-6 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifier and salt type are provided in Table 4.
Table 4.
Figure imgf000189_0002
Salt forms of 2-( l//-indol-3-yl)-N,N-dimethylethan- l -amine (1-1)
Synthesis of 2-(U/-indol-3-yl)-N,N-dimethylethan-l-amine (1-1) was carried out according to Fig. 2. Indole (A) (Rs = H) was acylated with oxalyl chloride and then reacted with dimethylamine to produce amide (F, Rs = R9 = CH3). Subsequent reduction with LiAIFU yielded compound 1-1 (free base). The structure of the product was confirmed by JH NMR.
Various salt forms of were prepared by crystallization of 1-1 (free base) with stoichiometric (1.0 molar equivalent) quantities, or with sub-stoichiometric (0.5 molar equivalents) quantities in the case of hemi-salts, of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, or glycolic acid), from ethanol. The salt form identifier and salt type are provided in Table 5.
Table 5.
Figure imgf000190_0001
a) Two crystalline polymorphs of the hemi-fumarate salt were isolated
Salt forms of 2-(lJ/-indol-3-yl)-N,N-bis(methyl-6(?)ethan-l-amine (1-4)
Synthesis of 2-(lJ/-indol-3-yl)-N,N-bis(methyl-6(?)ethan-l-amine (1-4) is carried out according to Fig. 2. Indole (A) (R5 = H) is acylated with oxalyl chloride and is then reacted with dimethyl-t/6-amine to produce amide (F, Rs = R9 = CD3). Subsequent reduction with LiAIFU yields compound 1-4 (free base). The structure of the product will be confirmed by JH NMR.
Various salt forms are prepared by crystallization of 1-4 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifier and salt type are provided in Table 6. Table 6.
Figure imgf000191_0001
Salt forms of 2-(17/-indol-3-yl)-N,N-dimethylethan-l-amine-l,l,2,2-t4 (1-5)
Synthesis of 2-(17/-indol-3-yl)-N,N-dimethylethan-l-amine-l,l,2,2-t4 (1-5) was carried out according to Fig. 2. Indole (A) (Rs = H) was acylated with oxalyl chloride and then reacted with dimethylamine to produce amide (F, Rs = R9 = CH3). Subsequent reduction with IJAID4 yielded compound 1-5 (free base). The structure of the product was confirmed by JH NMR.
Various salt forms are prepared by crystallization of 1-5 (free base) with stoichiometric (1.0 molar equivalent) quantities of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifier and salt type are provided in Table 7.
Table 7.
Figure imgf000191_0002
Salt forms of 2-(lJ/-indol-3-yl)-N,N-bis(methyl-t/s)ethan-l-amine-l,l,2,2-t4 (1-8)
Synthesis of 2-(17/-indol-3-yl)-N,N-bis(methyl-tZ?)ethan-l-amine-l,l,2,2-t4 (1-8) was carried out according to Fig. 2. Indole (A) (Rs = H) was acylated with oxalyl chloride and then reacted with dimethyl-t/6-amine to produce amide F (Rs = R9 = CD3). Amide F (Rs = R9 = CD3) (7.04g, 31.67 mmol) was charged to a flask under a nitrogen atmosphere. 2-MeTHF (140 ml, 20 vol) was then charged and stirred at room temperature for 15 minutes, though not all solid dissolved fully in this time. Lithium aluminum deuteride (LiAlD4)(4.04g, 96.23 mmol, 3.0 eq) was charged in portions over 45 minutes, maintaining the temperature of the reaction mixture <40°C. After complete addition, the reaction mixture was heated to 65°C for 16 hours. The batch was cooled to room temperature and completion confirmed by HPLC analysis. A water/THF mixture (35 ml, 5 vol, 1 :9) was added dropwise over 90 minutes, maintaining the temperature <30°C. 15% NaOH (aq) (3.5 ml, 0.5 vol) was then added dropwise, followed by further water (10.5 ml, 1.5 vol). This mixture was stirred at room temperature for 30 minutes then filtered and the solids washed with 2-MeTHF (3 x 70 ml, 3 x 10 vol), slurrying them each time before deliquoring. The liquors were concentrated to dryness, leaving compound 1-8 (free base) as a viscous orange-red oil. The structure of the product was confirmed by JH NMR. Compound 1-8 (free base) was then taken up in ethanol (49 ml, 7 vol), and this 1-8 (free base) ethanol solution was used in the salt formation experiments provided below. The salt form identifier and salt type are provided in Table 8.
Table 8.
Figure imgf000192_0001
I-8a: A flask was charged with 15 ml of 1-8 (free base) ethanol solution which was heated to reflux, and a single charge of fumaric acid (1.07g, 1.05 eq) added. After complete dissolution, this was allowed to cool to room temperature, then cooled further to 0°C and filtered, with additional ethanol (3 x 5ml, 3 x 2 vol) used to rinse out the flask and wash the cake. I-8a was isolated as a crystalline solid with a yield of 1.480g (4.71 mmol, 44.6%, 97.0% by LC, JH NMR confirmed identity as 1 : 1 fumarate salt).
I-8b: A flask was charged with 18 ml of 1-8 (free base) ethanol solution which was heated to reflux, and then benzoic acid (4.04g, 3.15 eq) was added in one charge. After ensuring all solid had dissolved, the solution was cooled in an ice bath and stirred for an additional 60 minutes at this temperature then filtered and further ice cold ethanol (2 x 2 vol) used to rinse out the flask and wash the cake. 2.272g (7.09 mmol) of I-8b was obtained. Due to residual impurities observed in the HPLC analysis of this compound, it was slurried in ethanol (5 ml, 2 vol) for 16 hours. It was then cooled to 0°C and filtered, with further ethanol (5 ml, 2 vol) used to rinse out the flask and wash the solids. However, the solids were amorphous and did not have a crystalline form. They were therefore dissolved in ethanol (15 ml, 7.5 vol) at reflux, cooled to 0°C and filtered, using ethanol (5 ml, 2 vol) to wash them. The isolated I-8b was thus obtained as a white crystalline solid in a yield of 1.534g (4.79 mmol, 45.4%, 91.1% by LC, 'H NMR confirmed identity as 1 : 1 benzoate salt).
I-8c: A flask was charged with 18 ml of 1-8 (free base) ethanol solution which was heated to reflux, and further ethanol (11.7 ml, total 12 vol) and salicylic acid (1.52g, 1.05 eq) was added as a single charge. Once fully dissolved, the solution was cooled to 0°C. The resulting solids were filtered and washed with ice cold ethanol (2 x 2 vol), providing I-8c with a yield of 2.860g (8.50 mmol). Due to residual impurities observed in the HPLC analysis of this compound, it was slurried in ethanol (5ml, 2 vol) for 16 hours. It was then cooled to 0°C and filtered, with further ethanol (5ml, 2 vol) used to rinse out the flask and wash the solids. However, the solids were amorphous and did not have a crystalline form. They were therefore dissolved in ethanol (60ml, 30 vol) at reflux, cooled to 0°C and filtered, using ethanol (5ml, 2 vol) to wash them. The isolated I-8c was thus obtained as a white crystalline solid in a yield of 2.311g (6.87 mmol, 65.1%, 91.5% by LC, 1H NMR confirmed identity as 1:1 salicylate salt). I-8d: I-8d is prepared analogously by crystallization of I-8 (free base) with a stoichiometric (1.0 molar equivalent) quantity of succinic acid from ethanol. II. Formulations and release testing—Tryptamines Materials and Methods Fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT- d10 fumarate; 1:1)(I-8a) was prepared as described above. Hemi-fumarate salt of 2-(5-methoxy- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d10 hemi-fumarate; 2:1) was made analogously to I-8a, except starting from Indole (A) (R5 = OMe) and using 0.5 eq of fumaric acid, by Sterling Pharma Solutions (HPLC purity: 99.85%; LCMS (M+H)+: 229.37). All water used was deionized water. Sodium chloride was ACS reagent grade, >99.0% (available from Sigma Aldrich). The release modifier used is shown in Table 9 in terms of the molecular weight range (and in parentheses the weight average molecular weight, Mw), and the commercial supplier.
Table 9.
Figure imgf000194_0001
pH. pH was measured by Accumet™ Research Model AR10 pH meter, available from Fisher Scientific. Osmolality. Osmolality was measured using Advanced® Micro-Osmometer, Model 3320, from Advanced Instruments.
Filtration was performed using a Syringe filter unit, 0.22 pm, PVDF, 33 mm filter, available from Sigma-Aldrich.
Dialysis — Drug Release Test. A 200 mL Erlenmeyer flask containing 100 mL of release medium (0.9% w/v NaCl) was equipped with a magnetic stir bar and placed into a water bath to maintain a release medium temperature of 37°C. The stirring rate was set to 400 rpm. A 1-2 mL volume of test item (formulation or control) was introduced into a Pur-A-Lyzer™ Maxi dialysis tube (pore size: 6-8 kDa molecular weight cutoff (MWCO), available from Sigma Aldrich). The dialysis tube was then immersed into the 100 mL of release medium inside the Erlenmeyer flask and a timer was started. Dissolution medium (0.5 mL) was withdrawn from the Erlenmeyer flask at 10, 20, 30, 45, 60, 90, and 120 minutes for assays, and an equal volume of fresh release medium was used to replace the withdrawn dissolution medium. The time-sampled dissolution medium was assayed by ultra performance liquid chromatography (UPLC) to analyze the drug release of the test item. The percent drug release was then plotted versus time (minutes), and also modelled as a first order kinetic plot. From these plots, the time in minutes required for 25% of drug release (t25%) and 50% of drug release (tso%) were calculated.
Ultra Performance Liquid Chromatography (UPLC). Analysis was performed on an Agilent 1100/1200 Quaternary Pump 1 system equipped with a diode array detector UV Diode array 220-269 nm. The UPLC method parameters used for the analysis are presented in Table 10.
Table 10.
Figure imgf000195_0001
Formulations and release profiles Formulations and their preparative methods are presented below. The physiochemical properties of the formulations such as pH and osmolality were determined where indicated. Formulations may be presented in terms of the parameters A, B, and C shown in Table 11. The ratio of A:B and the ratio of C:A may also be indicated, rounded to the closest whole number. The ratio of A:B was calculated by dividing parameter A in mg/mL (nominal) by parameter B in % w/v (nominal). The ratio of C: A was calculated by dividing the Mw value in kDa by the parameter A in mg/mL (nominal). Both the ratio of A:B and C:A are written below without the consequent “1” and the ratio symbol (:), for example a ratio of 50: 1 is simply represented as 50.
Table 11.
Figure imgf000196_0001
The release profiles of the formulations are also evaluated by the Dialysis — Drug Release Test, including the time in minutes required for 25% of drug release (t25%) and 50% of drug release (t5o%), and the respective percent changes in these values compared to the control (made without release modifier).
Formulations 1-6
To investigate the role of different concentrations of sodium hyaluronate (0.1, 0.2, 0.3, 0.4, 0.5, and 0.75% w/v, nominal) in the formulations, six different sodium hyaluronate solutions were made by dissolving a corresponding amount of sodium hyaluronate (750 - 1,000 kDa) (1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, and 7.5 mg, respectively), in water (0.7 mL), followed by incubation at 37°C and stirring. The sodium hyaluronate solutions were then filtered through a 0.22 pm PVDF filter. Solutions of DMT-t/io fumarate were prepared by dissolving 15.85 mg of DMT-t/io fumarate (10 mg free base equivalence of DMT-t/io) in water (0.3 mL), followed by incubation at 37°C and stirring. Each sodium hyaluronate solution was then mixed with the solution of DMT-t/io fumarate, and the resulting formulations were vigorously stirred to ensure complete mixing. A control formulation (10 mg/mL free base equivalence of DMT-t/io, nominal) without release modifier was prepared by diluting the solution of DMT-t/io fumarate with water (0.7 mL). Formulations are shown in Table 12. Table 12.
Figure imgf000197_0001
Each formulation was subjected to the Dialysis — Drug Release Test. Fig. 3 shows the drug release is highly controlled by the concentration of sodium hyaluronate in the formulation, with the control formulation providing the fastest release, and increasing sodium hyaluronate concentrations providing increasingly slower drug release, with the slowest release provided by the highest sodium hyaluronate content (Formulation 6). To increase osmolality for improved clinical tolerance, these formulations will be remade with an appropriate saline vehicle instead of water without effecting the release profile. Nonetheless, these formulations support the notion that sodium hyaluronate serves as a robust polymer matrix for tunable and controlled-release of drug.
Formulations 7-9
To investigate the effects of drug concentration, formulations were prepared using a fixed sodium hyaluronate concentration (1% w/v, nominal) at 10 mg/mL, 25 mg/mL, and 50 mg/mL free base equivalence of DMT-t/io (nominal). Solutions of DMT-t/io fumarate were prepared by dissolving 15.85 mg of DMT-t/io fumarate (10 mg free base equivalence of DMT-t/w), 39.62 mg of DMT-t/io fumarate (25 mg free base equivalence of DMT-t/w), or 79.25 mg of DMT-t/io fumarate (50 mg free base equivalence of DMT-t/io) in water (0.3 mL), followed by incubation at 37°C and stirring. Sodium hyaluronate solutions were prepared using 10 mg of sodium hyaluronate (750 - 1,000 kDa) and water (0.7 mL), followed by incubation at 37°C and stirring. The sodium hyaluronate solutions were then filtered through a 0.22 pm PVDF filter. Each solution of DMT - tZio fumarate was then mixed with a sodium hyaluronate solution, and the resulting formulations were vigorously stirred to ensure complete mixing. Corresponding control formulations (10, 25, or 50 mg/mL free base equivalence of DMT-t/io, nominal) without release modifier were prepared by diluting each solution of DMT-t/io fumarate with water (0.7 mL). Formulations are shown in Table 13.
Table 13.
Figure imgf000198_0001
Each formulation was subjected to the Dialysis — Drug Release Test. Figs. 4-6 show the drug release of Formulations 7, 8, and 9, respectively, and that each formulation provided a desirable controlled-release profile at the tested drug loading.
Formulations 10-15
To investigate the role of sodium hyaluronate molecular weight, different formulations were prepared with varying molecular weights of sodium hyaluronate using a fixed sodium hyaluronate concentration (0.5% w/v, nominal) and free base concentration of DMT-t/io (25 mg/mL, nominal). Stock solutions were prepared as follows:
Stock (a). 79.25 mg of DMT-t/io fumarate (50 mg free base equivalence of DMT-t/io) was dissolved in 0.5% (w/v) saline (0.75 mL). The pH was then adjusted to 6.0±0.1 using IM NaOH solution (0.25 mL). The pH and osmolality were measured.
Stock (b). 10 mg of sodium hyaluronate was dissolved in 0.5% (w/v) saline (1.0 mL), followed by incubation at 37°C and intermittent vortexing until the solution became clear. The osmolality was then measured.
The stock solutions (a) and (b) were then mixed in a 1 : 1 volume ratio to form the formulations, after which the osmolality was measured. A control formulation (25 mg/mL free base equivalence of DMT-t/io, nominal) without release modifier was prepared by diluting stock solution (a) with 1.0 mL of 0.5% (w/v) saline. Formulations are shown in Table 14. Table 14.
Figure imgf000199_0001
The osmolality of all formulations remained within an acceptable range for injection, and the pH adjustment of stock (a) (solution of DMT-t/io fumarate) was well tolerated with respect to stability of the final formulations.
Each formulation was subjected to the Dialysis — Drug Release Test. As shown in Figs. 7A and 7B, and Table 15, Formulations 10-12 made from low molecular weight sodium hyaluronate, <5 kDa, 66 - 99 kDa, and 301 - 475 kDa, respectively, failed to provide meaningful controlled- release effects and instead provided a release similar to control (no release modifier). Table 15.
Figure imgf000200_0001
To the contrary, Formulations 13-15 made from higher molecular weight sodium hyaluronate, 500 - <750 kDa, 750 - 1,000 kDa, and >1,000 - 1,800 kDa, respectively, provided a desirable controlled-release profile, with the highest molecular weight (Formulation 15) providing a nearly 130% increase at each of T25% and Tso% (Figs. 8A and 8B, and Table 16).
Table 16.
Figure imgf000200_0002
These data indicate that a sodium hyaluronate molecular weight cutoff of at least 500 kDa seems to exist for establishing controlled-release characteristics.
Formulations 16-18
To investigate the role of sodium hyaluronate molecular weight at high drug loadings, different formulations were prepared with varying molecular weights of sodium hyaluronate using a fixed sodium hyaluronate concentration (0.5% w/v, nominal) and free base concentration of DMT-t/io (70 mg/mL, nominal) in 0.9% (w/v) saline with no pH adjustments. Stock solutions were prepared as follows:
Stock (a). 221.9 mg of DMT-t/io fumarate (140 mg free base equivalence of DMT-t/io) was dissolved in 0.9% (w/v) saline (1.0 mL). The pH and osmolality were measured.
Stock (b). 10 mg of sodium hyaluronate was dissolved in 0.9% (w/v) saline (1.0 mL), followed by incubation at 37°C and intermittent vortexing until the solution became clear. The osmolality was then measured.
The stock solutions (a) and (b) were then mixed in a 1 : 1 volume ratio to form the formulations, after which the osmolality was measured. A control formulation (70 mg free base equivalence of DMT-t/w, nominal) without release modifier was prepared by diluting stock solution (a) with 1.0 mL of 0.9% (w/v) saline. Formulations are shown in Table 17.
Table 17.
Figure imgf000201_0001
Each formulation was subjected to the Dialysis — Drug Release Test. As shown in Figs. 9A and 9B, and Table 18, Formulations 16-18 made from high drug loading in high molecular weight sodium hyaluronate (500 - <750 kDa, 750 - 1,000 kDa, and >1,000 - 1,800 kDa) provided a release that was marginally slower than control (no release modifier), with percent change of Tso% values compared to control of +32%, + 28%, and +24%, respectively. This is indicative of not enough sodium hyaluronate being used to compensate for the high drug content.
Table 18.
Figure imgf000202_0001
However, the physiochemical properties of Formulations 16-18 were not within acceptable ranges; the osmolality of all formulations exceeded the acceptable upper limit of 600 mOsm/kg, and the pH values were very acidic. As a result, a precipitation event was observed in all formulations within hours of storage under refrigerated conditions.
Formulations 19-21
To investigate the release profile with 2-(5-methoxy-lH-indol-3-yl)-N,N-bis(methyl- t/3)ethan-l-amine-l,l,2,2-t/4 (5-MeO-DMT-tZio), different formulations were prepared with varying molecular weights of sodium hyaluronate using a fixed sodium hyaluronate concentration (0.5% w/v, nominal) and free base concentration of 5-MeO-DMT-t/io (25 mg/mL, nominal) in 0.3% (w/v) saline with no pH adjustments. Stock solutions were prepared as follows:
Stock (a). 62.7 mg of 5-MeO-DMT-t/io hemi-fumarate (50 mg free base equivalence of 5-MeO-DMT-t/io) was dissolved in 0.3% (w/v) saline (1.0 mL). The pH and osmolality were measured.
Stock (b). 10 mg of sodium hyaluronate was dissolved in 0.3% (w/v) saline (1.0 mL), followed by incubation at 37°C and intermittent vortexing until the solution became clear. The pH and osmolality was then measured.
The stock solutions (a) and (b) were then mixed in a 1 : 1 volume ratio to form the formulations, after which the pH and osmolality was measured. A control formulation (25 mg free base equivalence of 5-MeO-DMT-t/io, nominal) without release modifier was prepared by diluting stock solution (a) with 1.0 mL of 0.3% (w/v) saline. Formulations are shown in Table 19. Table 19.
Figure imgf000203_0001
All formulations were prepared with 0.3% (w/v) saline and had an osmolality within an acceptable range for injection. The formulations also had an acceptable pH (about 5.7) without any pH adjustments, and there was no observed instability.
Each formulation was subjected to the Dialysis — Drug Release Test. As shown in Figs. 10A and 10B, and Table 20, Formulation 19 made using 5-MeO-DMT-t/io hemi-fumarate in the lowest molecular weight sodium hyaluronate tested (500 - <750 kDa) gave a release profile which was practically no different than control (no release modifier), and Formulation 20 made with sodium hyaluronate 750 - 1,000 kDa fared somewhat better. Formulation 21 made with sodium hyaluronate >1,000 - 1,800 kDa was much more effective in providing a controlled-release, with percent change of T25% and Tso% values compared to control of +93% each.
Table 20.
Figure imgf000203_0002
Formulations 22-27 To investigate the release modifier sodium carboxymethyl cellulose and the role of different concentrations thereof (0.1, 0.2, 0.3, 0.4, 0.5, and 0.75% w/v, nominal) in the formulations, six different sodium carboxymethyl cellulose solutions were made by dissolving a corresponding amount of sodium carboxymethyl cellulose (Aquaion™ 7MF PH; Mw = 250 kDa) (1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, and 7.5 mg, respectively), in water (0.7 mL), followed by incubation at 37°C and stirring. The sodium carboxymethyl cellulose solutions were then filtered through a 0.22 pm PVDF filter. Solutions of DMT-t/io fumarate were prepared by dissolving 15.85 mg of DMT-t/io fumarate (10 mg free base equivalence of DMT-t/io)in water (0.3 mL), followed by incubation at 37°C and stirring. Each sodium carboxymethyl cellulose solution was then mixed with the solution of DMT-t/io fumarate, and the resulting formulations were vigorously stirred to ensure complete mixing. A control formulation (10 mg/mL free base equivalence of DMT-t/io, nominal) without release modifier was prepared by diluting the solution of DMT-t/io fumarate with water (0.7 mL). Formulations are shown in Table 21.
Table 21.
Figure imgf000204_0001
Each formulation was subjected to the Dialysis — Drug Release Test. Fig. 11 shows that the release properties from sodium carboxymethyl cellulose formulations was markedly different from sodium hyaluronate-based formulations. Here, the fastest release profile was observed for control and no prominent delayed release effects were achieved with 0.1, 0.2, 0.3, 0.4, or 0.5% w/v (nominal) sodium carboxymethyl cellulose (Formulations 22-26). A delayed effect was only seen with sodium carboxymethyl cellulose loadings higher than 0.5% w/v (nominal), such as 0.75% w/v (nominal) (Formulation 27), which was modest compared to the effects at the same concentration of sodium hyaluronate. These results indicate that sodium carboxymethyl cellulose can serve as a polymer matrix for controlled-release of drug, but that the workable concentration range is narrow and the release is not highly tunable. III. Animal studies—Tryptamines The pharmacokinetics of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d10) were investigated in dogs following subcutaneous (SC) administration of DMT-d10. Three studies were conducted to establish whether: 1) SC administration produced quantifiable plasma concentrations of DMT-d10; 2) hyaluronate salt modified the release of DMT-d10 after SC administration; 3) hyaluronate salt aqueous concentration altered the absorption profile of DMT- d10; and 4) an increase in dose concentration produced an extemporaneous release (‘dumping’) of DMT-d10 from the formulation. The following studies were conducted at the same Contract Research Organization (CRO). Detailed animal care, test materials, bioanalytical and pharmacokinetic analysis are described in part A and pertain to parts B and C also. A: Proof of Concept - Pharmacokinetics (PK) of DMT-d10 in Male Beagle Dogs Following Subcutaneous Administration in Saline or Sodium Hyaluronate The objective of this study was to determine if a 1% (w/v) sodium hyaluronate formulation could modify the SC release of DMT-d10 compared to 0.9% (w/v) saline formulation. Animals. Three, non-naïve, male Beagle dogs aged ca 2-5 years and weighing 10-15 kg at dosing were supplied by Charles River for use on this study and were bred for use in scientific procedures. The animal work in this study was conducted under the UK Home Office Project License No. PPL PP9376768, Pharmacokinetics of Pharmaceuticals. This was a cross-over design study to reduce the number of dogs in use and as well as decrease interindividual variability. Housing. Animals were uniquely identified by microchip and tattoo in this study. During pre-trial and on-study periods, the animals were group housed in caging appropriate to the species. The animals were housed singly for up to 4 h per day and during this time had access to their daily ration of diet. IPS 5007 diet was provided as a daily ration throughout the study. A 350 g ration of feed per dog was provided once daily, except during designated procedures. On the morning of dosing (pre-dose), the animals were deprived from their daily food allowance until 2 h post dose. Mains quality tap water was available ad libitum. Details of diet and water are maintained at the test facility. Prior to acceptance for use on study, animals were subject to an examination and the results found to be satisfactory. All animals were weighed prior to each dose administration and the bodyweights recorded. Animals were checked regularly throughout the duration of the study. Any clinical signs were closely monitored and recorded. Holding and study areas had automatic control of light cycles and temperature. Light hours were 07:00-19:00 h. Ranges of temperature and humidity measured during the study were 15-24°C and 40-70%, respectively. Materials. DMT-d10 fumarate (I-8a), Batch No. ABN-1177 was supplied by Quotient Sciences and was stored frozen and protected from light and moisture in a freezer set to maintain a temperature of ≤-20ºC at the Test Facility. DMT fumarate (I-1a) Batch No. 0000040525 was supplied by Biosynth. Table 22 shows the material characteristics. Table 22.
Figure imgf000206_0001
Sodium hyaluronate was Hyatrue® HA-EP1.8 (molecular weight range of 900-1,400 kDa), available from Bloomage Freda Biopharm Co. Ltd. Test Items. DMT-d10 fumarate was formulated as a solution in 0.9% (w/v) saline, pH 5.5- 6 (control) or in 1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) (Formulation 28) at a free base concentration of 0.4 mg/mL (nominal) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing. Control (0.9% w/v saline): On the day prior to dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 9.7 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial which was pre-calibrated to a final volume of 15 mL with a magnetic stir bar inside. The weighed API was returned to storage. On the morning of dosing, the weighed API was removed from storage and allowed to equilibrate to room temperature.13.55 mL of vehicle (0.9% w/v saline) was added to the vial (equivalent to 90% of final volume) and set to magnetically stir for ca 35 minutes. Using a calibrated pH meter, the solution pH was measured. The initial reading showed the pH as 3.90, this was then adjusted using 0.1M NaOH to a final pH of 5.97. The solution was made to final volume of 15 mL, using the pre- calibrated line, with 0.9% w/v saline. The final pH was recorded as 5.53. The solution was then filtered using a 0.22µM PVDF syringe filter in the laminar air flow cabinet (LAFC). The visual appearance of the solution was recorded as a clear, colorless, homogenous solution. The final control solution had a free base concentration of 0.41 mg/mL DMT-d10. The control solution was protected from light at all times. Formulation 28: On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 11.02 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.3.5 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 2 mg/mL (nominal) DMT-d10. Once homogenous, 2 mL of the stock solution was dispensed into a vial containing 8 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous. The formulation thus had a free base concentration of 0.4 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 1% w/v (nominal). Subcutaneous injections. The target dose was 0.1 mg/kg, free base at a dose concentration of 0.4 mg/mL. Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. Three male Beagle dogs received a SC administration of control. After a 7-day washout period, the same animals were administered Formulation 28 as shown in Table 23.
Table 23. Experimental Design – Dose Formulation
Figure imgf000208_0001
a calculated as free base b nominal free base concentration Sample collection. Blood samples (ca 1 mL) were collected from the jugular vein by venipuncture into tubes containing K2EDTA anticoagulant at the following time-points: Predose, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45min), 1, 2, 4 and 8 hr post dose. Immediately following blood sample collection, the tubes were inverted to ensure mixing with the anticoagulant and immediately placed on wet ice. As soon as practically possible, but no later than 30 minutes from collection, samples were centrifuged in a refrigerated (ca +4°C) centrifuge at approximately 1500 g for 10 minutes. The resultant plasma was decanted into appropriately labelled polypropylene tubes in 96-well plate format and stored in a freezer set to maintain a temperature of ≤-65°C until analysis. The samples were protected from light. Bioanalysis. Plasma samples were analyzed for DMT-d10 using an established LC-MS/MS assay. Pharmacokinetic parameters were determined from the DMT-d10 plasma concentration-time profiles using commercially available software (Phoenix® WinNonlin®). Results. All dose administrations of DMT-d10 were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical signs were recorded post-dose. The pharmacokinetic parameters for DMT-d10 formulated in either 0.9% w/v saline (control) or 1% w/v (nominal) sodium hyaluronate (Formulation 28) are presented. DMT-d10 was administered SC at a free base equivalent dose of 0.1 mg/kg. Plasma DMT-d10 concentrations were quantifiable up to 2 hours in all animals following SC administration of control (Fig.12A), and up to 4 hours following SC administration of Formulation 28 (Fig.12B). As shown in Table 24 and Figs.12A-12B, after SC administration of DMT-d10 at 0.1 mg/kg the pharmacokinetic profiles were dependent on formulation. The use of 1% w/v (nominal) sodium hyaluronate (n=2) increased the median Tmax from 0.25 to 0.75 hr with subsequent reduction of mean Cmax from 39.5 to 15.0 ng/mL, control (n=3) to Formulation 28 (n=2), respectively. The total exposure of DMT-d10, AUC0-t (31.1 h*ng/mL) from Formulation 28 was similar to that observed with control (30.6 h*ng/mL) indicating that sodium hyaluronate did not affect SC bioavailability. The elimination t1/2 after Formulation 28 was 0.836 hr (n=1); after control t1/2 was 0.479 hr (n=3), though these data are based on limited numbers. Table 24. DMT-d10 PK Profile after SC Administration of Control or Formulation 28.
Figure imgf000209_0001
a DMT-d10 free base b n=3 unless otherwise noted c n=2; therefore, standard deviations were not calculated d median (minimum-maximum) e n=1 B: Dose Proportionality – Pharmacokinetics (PK) of DMT-d10 in Male Beagle Dogs Following Subcutaneous Administration Formulated in 1% w/v Sodium Hyaluronate at Increasing Dose Levels of DMT-d10 The objective of this study was to determine if a SC administration of DMT-d10 formulated in 1% w/v (nominal) sodium hyaluronate yields a dose proportional increase in plasma DMT-d10 concentrations. This study was conducted using the same CRO, male Beagle dogs, housing, and materials as described above in part A. All conditions described in part A pertain to this study with the exceptions noted below. Test Items. DMT-d10 fumarate was formulated in 1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 2 mg/mL (Formulation 29) or 4 mg/mL (Formulation 30) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing. Formulation 29: On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 110.7 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.6.914 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 10.1 mg/mL (nominal) DMT-d10. The stock solution had a density of 1.002 g/cm3. Once homogenous, 2.796 mL of the stock solution was dispensed into a vial containing 11.029 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous. The formulation thus had a free base concentration of 2.04 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 1% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution. Formulation 30: On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 222.2 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.6.816 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 20.6 mg/mL (nominal) DMT-d10. The stock solution had a density of 1.006 g/cm3. Once homogenous, 2.830 mL of the stock solution was dispensed into a vial containing 11.208 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous. The formulation thus had a free base concentration of 4.15 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 1% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution. Subcutaneous injections. The target dose was 0.5 mg/kg free base at a dose concentration of 2 mg/mL, or 1.0 mg/kg free base at a dose concentration of 4 mg/mL. Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. The same animals were used with a 7-day washout period in between administrations as shown in Table 25. Table 25. Experimental Design – Dose proportionality
Figure imgf000211_0001
a calculated as free base b nominal free base concentration c The 0.1 mg/kg dose with Formulation 28 was administered in part A. It is provided here for ease of comparing the PK parameters Results. All dose administrations of DMT-d10 were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical signs were recorded post-dose. The pharmacokinetic parameters for DMT-d10 formulated in Formulations 28-30 SC at 0.1, 0.5 and 1 mg/kg are presented. The 0.1 mg/kg data (Formulation 28) were calculated in part A (see Table 24) and are repeated here to determine dose proportionality. Plasma DMT-d10 concentrations were quantifiable up to 4 hours in all animals following SC administration. Median Tmax ranged from 0.5 to 0.75 hr suggesting similar absorption profiles after SC administration for the lower dose levels (Figs.13A-13B). However, the interpretation of the absorption kinetics may be impacted by the sparse samples collected during the phase and the interindividual variability at the high dose (1 mg/kg; Table 26). Independent of dose, elimination (t1/2) of DMT-d10 from the systemic circulation was consistent, approximately 0.9 hr, as was the length of time (MRTinf) that DMT-d10 presided in the circulation about 1.5 hr. As shown in Fig. 14, Cmax and AUCinf increased in a dose proportional manner. Taken together, these data indicate that a SC injection of DMT-d10 formulated in 1% w/v (nominal) sodium hyaluronate behaves in a first order manner, resulting in dose independent absorption and elimination from the systemic circulation. Table 26. DMT-d10 PK Profile after SC Administration of Formulations 28-30
Figure imgf000212_0001
a DMT-d10 free base b n=2; therefore, standard deviations were not calculated (NC) c median (minimum-maximum) d n=1 C: Formulation Stability – Pharmacokinetics (PK) of DMT-d10 in Male Beagle Dogs Following Subcutaneous Administration at 1 mg/kg Formulated in Increasing Sodium Hyaluronate Concentrations The objective of this study was to determine how increasing concentrations of sodium hyaluronate affect the release of DMT-d10 into systemic circulation after SC administration. This study was conducted using the same CRO, housing, and materials as described above in part A. All conditions described in part A pertain to this study with the exceptions noted below. Test Items. DMT-d10 fumarate was formulated in 0.1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 2 mg/mL (Formulation 31), 0.25% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 4 mg/mL (Formulation 32), or 0.5% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 4 mg/mL (Formulation 33) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing. Formulation 31: On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 58.32 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.16.9 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 2.18 mg/mL (nominal) DMT-d10. The stock solution had a density of 0.999 g/cm3. Once homogenous, 12.9 mL of the stock solution was dispensed into a vial containing 1.14 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous. The formulation thus had a free base concentration of 2.00 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.1% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution and the pH was 3.90. Formulation 32: On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 120.4 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.14.9 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 5.10 mg/mL (nominal) DMT-d10. The stock solution had a density of 1.000 g/cm3. Once homogenous, 11.2 mL of the stock solution was dispensed into a vial containing 2.80 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous. The formulation thus had a free base concentration of 4.08 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.25% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution and the pH was 3.59. Formulation 33: On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 130.92 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.12.4 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 6.66 mg/mL (nominal) DMT-d10. The stock solution had a density of 1.001 g/cm3. Once homogenous, 8.39 mL of the stock solution was dispensed into a vial containing 5.55 mL of 1.25% (w/v, nominal) sodium hyaluronate and vortex mixed until homogenous. The formulation thus had a free base concentration of 4.01 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.50% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution and the pH was 3.76. Subcutaneous injections. The target dose was 0.5 mg/kg free base at a dose concentration of 2 mg/mL, or 1.0 mg/kg free base at a dose concentration of 4 mg/mL. Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. The same animals were used with a 7-day washout period in between administrations as shown in Table 27. Table 27. Experimental Design – Formulation Stability
Figure imgf000214_0001
a calculated as free base b nominal free base concentration c The 1 mg/kg dose formulated in Formulation 30 was administered in part B. It is provided here for ease of comparing the PK parameters Results. All dose administrations of DMT-d10 were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical signs were recorded post-dose. DMT-d10 plasma concentration-time profiles formulated in 0.1% (Formulation 31), 0.25% (Formulation 32), 0.5% (Formulation 33), and 1% (Formulation 30) w/v (nominal) sodium hyaluronate at a SC dose of 1 mg/kg are presented in Fig.15 (Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg). Corresponding pharmacokinetic parameters for DMT- d10 are presented in Table 28. The PK parameters for Formulation 30 and control were calculated in part B and A, respectively, and are shown here for ease of comparison. Plasma DMT-d10 concentrations were quantifiable up to 4 hours in all animals following SC administration. Median Tmax increased as sodium hyaluronate concentration increased 3-fold from 0.25 hr at 0.1% w/v (nominal) sodium hyaluronate (Formulation 31) to 0.75 hr at 1% w/v (nominal) sodium hyaluronate (Formulation 30) (Figs.16-19). MRTinf, a parameter describing the duration of DMT- d10 systemic exposure, incrementally increased with higher sodium hyaluronate concentrations, i.e., 0.921 hr at 0.1% w/v (nominal) sodium hyaluronate (Formulation 31) to 1.50 hr at 1% w/v (nominal) sodium hyaluronate (Formulation 30). The incremental increase in MRTinf can be seen graphically in Fig.16. However, over the same formulations, t1/2, Cmax and AUCinf values were not changed (Figs. 17-19, respectively). The data suggest that an increase in the sodium hyaluronate in the formulation can modulate the release of DMT-d10 from the subcutaneous space (increases Tmax and MRTinf) without affecting the Cmax and AUCinf or the elimination of DMT-d10 from the circulation. Table 28. DMT-d10 PK Profile after SC Administration of Formulations 30-33
Figure imgf000215_0001
a DMT-d10 free base b dose adjusted from 0.5 to 1.0 mg/kg c dose adjusted from 0.1 to 1.0 mg/kg d median (minimum-maximum) e Administered in part A. It is provided here for ease of comparing the PK parameters D: Dose Concentration and Dose Volume - Pharmacokinetics of DMT-d10 in Male Beagle Dogs Following Subcutaneous Administration at 1 mg/kg Formulated in Hyaluronic Acid Concentrations at higher dosing solution concentrations and lower dosing volume The objective of this study was to determine the effect of increasing the dosing solution concentration of DMT-d10 and decreasing the dose volume on the SC release of DMT-d10 into the systemic circulation. This study was conducted using the same CRO, housing, and materials as described above in part A. All conditions described in part A pertain to this study with the exceptions noted below. Test Items. DMT-d10 fumarate was formulated as a solution in 0.9% (w/v) saline, pH 5.5- 6, at a free base concentration of 4 mg/mL (nominal) (control) or in 0.4% (w/v, nominal) sodium hyaluronate in 0.3% (w/v) saline at a free base concentration of 20 mg/mL (nominal) (Formulation 34) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing. Control (0.9% w/v saline): On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 88.8 mg of DMT-d10 fumarate was weighed into a suitably sized sterile glass container, pre-calibrated to the final volume required.90% final volume of vehicle (0.9% w/v saline) was added to the vial and set to magnetically stir. The pH was then measured using a calibrated pH meter and was found to be 3.18 initially. The pH was adjusted using 1M NaOH and 2M HCl to achieve a final pH of 5.51. The control solution was then made to final volume using a pre-calibrated line on the glass vial with 0.9% (w/v) saline. Sterile filtration using a 0.22 μM filter was then carried out. The control solution had a free base concentration of 4 mg/mL (nominal) DMT-d10. Formulation 34: A 0.3% (w/v) saline solution was prepared by adding 3.35 mL of 0.9% (w/v) to a sterile glass vial with 6.65 mL of WFI, followed by magnetically mixing. Once homogeneous, the density was measured to be 1.000 g/cm3. On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 311.1 mg of DMT-d10 fumarate was weighed into a suitably sized sterile glass container.2.839 mL of the previously prepared 0.3% (w/v) solution (equivalent to 60% of the final stock volume) was added to the container and set to stir at a temperature of 37°C at 300 rpm. The visual appearance was recorded as a clear/yellowish homogenous solution at this stage. The pH was measured using a calibrated pH meter and recorded to be 3.24. The pH was then adjusted to 5.98 by adding 1M NaOH until a final volume of 5 mL using a volumetric flask, and was set to stir magnetically. The density was measured to be 1.012 g/cm3. Sterile filtration using a 0.22 µM PVDF filter was then carried out. The stock solution had a free base concentration of 40 mg/mL (nominal) DMT-d10. A 0.8% (w/v, nominal) sodium hyaluronate solution was prepared by precisely mixing 3.193 mL of 1.25% (w/v, nominal) sodium hyaluronate and 1.799 mL of 0.8% (w/v) saline in a glass container until homogeneous. The density of the resultant 0.8% (w/v, nominal) sodium hyaluronate solution was recorded to be 1.002 g/cm3. 2.032 mL of the DMT-d10 fumarate stock solution and 1.988 mL of the 0.8% (w/v, nominal) sodium hyaluronate solution were added to a new sterile vial and magnetically stirred until homogeneous. The formulation thus had a free base concentration of 20 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.40% w/v (nominal). The final visual appearance of the formulation was recorded as a clear, colorless, homogenous solution. Subcutaneous injections. The target dose was 1 mg/kg free base at a dose concentration of 20 mg/mL (nominal), or 1.0 mg/kg free base at a dose concentration of 4 mg/mL (nominal). Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.05 mL/kg or 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. The same animals were used with a 7-day washout period in between administrations as shown in Table 29.
Table 29. Experimental Design - Effect of Dose Solution Concentration and Dose Volume on the PK Profile of DMT-tZio
Figure imgf000218_0001
Sample collection. Blood samples (ca 1 mL) were collected from the jugular vein by venipuncture into tubes containing K2EDTA anticoagulant at the following time-points: Predose, 0.033 (2 min), 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45min), 1, 2, and 4 hr post dose.
Results.
All dose administrations of DMT-t/w were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical signs were recorded post-dose.
DMT-t/io was formulated in 0.4% w/v (nominal) sodium hyaluronate containing 0.3% w/v NaCl at a SC dose solution concentration of 20 mg/mL (nominal) (Formulation 34) and delivered as a dose volume of 0.05 mL/kg or in 0.9% w/v NaCl at a SC dose solution concentration of 4 mg/mL (nominal) (control) and delivered as a dose volume of 0.25 mL/kg, both at a free base dose of 1 mg/kg. The DMT-t/w plasma concentration-time concentrations are presented in Figs. 20A and 20B. Corresponding pharmacokinetic parameters for DMT-t/w are presented in Table 30. Plasma DMT-t/w concentrations were quantifiable up to 4 hours in all animals following SC administration. Median Tmax values were 0.25 hr for both Formulation 34 and control. The ti/2
(0.682 and 0.667 hr) and MRTinf (1.11 and 1.10 hr) of Formulation 34 and control, respectively, were similar for both formulations. Cmax and AUCinf decreased by about 35% for Formulation 34 compared to control. In summary, both formulations have solubility limits ≥ 20 mg/mL. The high dose solution concentration affords a lower SC injection volume (0.5 mL for a 10 kg dog) thereby diminishing possible discomfort and/or local tissue damage associated with the injection site. The resulting plasma concentration-time profiles were similar with the exception that the apparent bioavailability DMT-d10 when administered in Formulation 34 was 65% compared to control. Table 30. DMT-d10 PK Profile after SC Administration of Control or Formulation 34.
Figure imgf000219_0001
a DMT-d10 free base b dose solution concentration at 20 mg/mL (nominal); dose volume administration at 0.05 mL/kg c dose solution concentration at 4 mg/mL (nominal); dose volume administration at 0.25 mL/kg d median (minimum-maximum) E: Deuteration Effect - Pharmacokinetics of DMT-d10 and DMT co-dosed in Male Beagle Dogs Following Subcutaneous Administration at 0.5 mg/kg/analyte (total dose: 1 mg/kg) Formulated in Sodium Hyaluronate The objective of this study was to determine the effect of deuteration on the PK profile of DMT after a SC administration at 0.5 mg/kg/analyte formulated in 0.5% w/v (nominal) sodium hyaluronate in water for injection (WFI). This study was conducted using the same CRO, housing, and materials as described above in part A. All conditions described in part A pertain to this study with the exceptions noted below. Test Items. DMT fumarate and DMT-d10 fumarate were formulated together as a solution in 0.5% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a free base concentration of 10 mg/mL/analyte (nominal); total free base concentration of 20 mg/mL (nominal) (Formulation 35) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing. Formulation 35: On the morning of dosing, DMT-d10 fumarate and DMT fumarate were removed from storage (frozen, in a freezer set to maintain ≤-20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 80.1 mg of DMT- d10 fumarate and 82.3 mg of DMT fumarate were weighed into a suitably sized sterile glass container. 2.853 mL of WFI was added to the container and magnetically stirred. Once homogeneous, the stock solution was sterile filtered using a 0.22 µM PVDF filter. The stock solution had a free base concentration of 17.7 mg/mL (nominal) DMT-d10 and a free base concentration 17.8 mg/mL DMT (combined free base concentration of DMT-d10 + DMT of 35.5 mg/mL).1.832 mL of the stock solution was added to a new sterile glass vial.1.203 mL of 1.25% (w/v, nominal) sodium hyaluronate solution was added to the vial and vortex mixed to homogenize. The formulation thus had a free base concentration of 10.7 mg/mL (nominal) DMT- d10 and a free base concentration of 10.8 mg/mL (nominal) DMT (combined free base concentration of DMT-d10 + DMT of 21.5 mg/mL) and a sodium hyaluronate concentration of 0.5% w/v (nominal). Subcutaneous injections. DMT + DMT-d10 were co-dosed (via Formulation 35) at 0.5 mg/kg/analyte, total dose of 1.0 mg/kg (free base), each at a dose concentration of 10 mg/mL (nominal), total dose concentration of 20 mg/mL (nominal) and a dose volume of 0.05 mL/kg calculated per each animal based on real animal bodyweights. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose. The experimental design is shown in Table 31. Table 31. Experimental Design – Effect of Deuteration on the PK Profile of DMT in Sodium Hyaluronate Formulations
Figure imgf000220_0001
concentration of 20 mg/mL Sample collection. Blood samples (ca 1 mL) were collected from the jugular vein by venipuncture into tubes containing K2EDTA anticoagulant at the following time-points: Predose, 0.033 (2 min), 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45min), 1, 2, and 4 hr post dose. Results. All dose administrations were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical signs were recorded post-dose. DMT and DMT-d10 were co-dosed via Formulation 35 in 0.5% w/v (nominal) sodium hyaluronate in water for injection (WFI) at a SC dose solution concentration of 10 mg/mL/analyte (total: 20 mg/mL) (nominal) and dose volume of 0.05 mL/kg (0.5 mL for a 10 kg dog). DMT and DMT-d10 plasma concentration-time concentrations are presented in Figs 21A and 21B. Corresponding pharmacokinetic parameters for DMT and DMT-d10 are presented in Table 32. Plasma concentrations were quantifiable to 2 hr for DMT and 4 hr for DMT-d10 following SC administration. Median Tmax values were 0.5 hr for DMT and DMT-d10. Deuteration of DMT, however, decreased apparent clearance (Cl/F) by 2.2x (10400 to 4650 mL/hr/kg) and decreased in the apparent volume of distribution (Vz/F) by 1.6x (7590 to 4729 mL/kg) leading to increased Cmax, AUCinf, t1/2 and MRTinf by 1.3x, 2.2x, 1.4x and 1.4x, respectively. These data indicate that deuteration has a significant impact on elimination from the systemic circulation as manifested in the 2.2x decrease in apparent systemic clearance.
Figure imgf000222_0001
F: Clinical Observation Summary in Male Beagle Dogs After SC Administration of DMT or DMT-d10 formulated in Sodium Hyaluronate As detailed in Table 33, clinical observations were dose and formulation dependent. At 1% w/v (nominal) sodium hyaluronate, the pharmacodynamic behaviors began to emerge at 1 mg/kg to include salivation and vocalization. With a decrease in sodium hyaluronate from 1% to 0.25%, 0.4%, and 0.5% w/v (nominal), at 1 mg/kg, a cluster of pharmacological effects included licking, salivation, panting, vocalization, and wide eyes (dilated pupils) occurred. In some cases, animals appeared calm. Categorized as mild to moderate clinical symptoms began to appear 10 min postdose with resolution over 1 hour.
Table 33. Clinical Observation Summary in Male Beagle Dogs After SC Administration of Formulations 28-35 formulated in Sodium Hyaluronate.
Figure imgf000224_0001
a DMT or DMT-d10 free base b DMT and DMT-d10 were co-dosed at 0.5 mg/kg/analyte: total dose of 1.0 mg/kg N/O = Not Observed IV. Formulations and release testing—Dissociatives Materials and Methods Ketamine (±) HCl was purchased from Patheon Pharma Services. Sodium chloride was 10 ACS reagent grade, >99.0% (available from Sigma Aldrich). The release modifier used was sodium hyaluronate HA15M (molecular weight range of >1,000 – 1,800 kDa; Mw = 1,670 kDa; available from Lifecore Biomedical, Inc.). Formulations were prepared using water for injection (WFI). Filtration was performed using a Syringe filter unit, 0.22 µm, PVDF, 33 mm filter, available from Sigma-Aldrich. The Dialysis—Drug Release Test and UPLC were performed as previously described in section II. Formulations and release profiles Formulations and their preparative methods are presented below. Formulations are presented in terms of the parameters A, B, and C as shown previously in Table 11. Formulations 36-38 To investigate the role of different concentrations of sodium hyaluronate (0.5, 0.75, and 1% w/v, nominal) at fixed molecular weight on the release of ketamine (12.5 mg/mL free base equivalence, nominal), three different stock sodium hyaluronate solutions were made at 1, 1.5, and 2% w/v (nominal) concentrations by dissolving 10 mg, 15 mg, and 20 mg of sodium hyaluronate (>1,000 – 1,800 kDa), respectively, in a volume of WFI to reach 1 mL, followed by incubation at 37°C and stirring. The stock sodium hyaluronate solutions were then filtered through a 0.22 µm PVDF filter. A stock solution of ketamine HCl (25 mg/mL free base equivalence of ketamine, nominal) was prepared by dissolving 115 mg of ketamine HCl in 4 mL of WFI, followed by incubation at 37°C and stirring. The solutions were used as is and no pH adjustments were made. Each stock sodium hyaluronate solution was then mixed in a 1:1 volume ratio with the stock solution of ketamine HCl, and the resulting formulations were vigorously stirred to ensure complete mixing. A control formulation (12.5 mg/mL free base equivalence of ketamine, nominal) without release modifier was prepared by mixing stock solution of ketamine HCl with WFI in a 1:1 volume ratio. Formulations are shown in Table 34. Table 34.
Figure imgf000226_0001
Each formulation was subjected to the Dialysis—Drug Release Test. Fig. 22 shows the drug release is highly controlled by the concentration of sodium hyaluronate in the formulation, with the control formulation providing the fastest release, and increasing sodium hyaluronate concentrations providing increasingly slower drug release, with the slowest release provided by the highest sodium hyaluronate content (Formulation 38). These formulations support the notion that sodium hyaluronate serves as a robust polymer matrix for tunable and controlled-release of drug. The preceding merely illustrates the principles of the methods and compositions. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the disclosure and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the disclosure and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the disclosure as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present disclosure, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present disclosure is embodied by the following.

Claims

CLAIMS 1. A method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of an injectable pharmaceutical formulation comprising: a psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000227_0001
wherein: X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively R8 and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
2. The method of claim 1, wherein the compound has a structure of Formula (II), or a stereoisomer, solvate, or prodrug thereof
Figure imgf000228_0001
wherein: X1 and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, and R2, R4, R5, R6, and R7 are independently hydrogen or deuterium.
3. The method of claim 1, wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of
Figure imgf000229_0001
Figure imgf000230_0001
4. The method of claim 1, wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8).
5. The method of claim 1, wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6).
6. The method of claim 1, wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2).
7. The method of claim 1, wherein the psychopharmaceutical agent is an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1,2,2-d4 (I-8); and (ii) a pharmaceutically acceptable salt of one or more of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11).
8. The method of claim 7, wherein the active salt mixture comprises (i) from 60% to 99% by weight of the pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1,2,2-d4 (I-8), based on a total weight of the active salt mixture; and (ii) from 1% to 40% by weight, in sum, of the pharmaceutically acceptable salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11), based on a total weight of the active salt mixture.
9. The method of claim 1, wherein the compound has a structure of Formula (III), or a stereoisomer, solvate, or prodrug thereof
Figure imgf000231_0001
wherein: X1 and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, each Z3 is independently hydrogen or deuterium, and R2, R4, R6, and R7 are independently hydrogen or deuterium.
10. The method of claim 1, wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of at least one compound selected from the group consisting of
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
stereoisomer, solvate, or prodrug thereof.
11. The method of claim 1, wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 20).
12. The method of claim 1, wherein the psychopharmaceutical agent is an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20); and (ii) a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23).
13. The method of claim 1, wherein the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt.
14. The method of claim 1, wherein the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, or a succinate salt.
15. The method of claim 1, wherein a concentration of the psychopharmaceutical agent by weight (in terms of free base equivalence) per total volume of the pharmaceutical formulation is about 0.1 mg/mL to about 70 mg/mL.
16. The method of claim 1, wherein a concentration of the psychopharmaceutical agent by weight (in terms of free base equivalence) per total volume of the pharmaceutical formulation is about 0.1 mg/mL to about 20 mg/mL.
17. The method of claim 1, wherein the hyaluronate salt is sodium hyaluronate.
18. The method of claim 1, wherein the hyaluronate salt has a weight average molecular weight of about 500 kDa to about 2,000 kDa.
19. The method of claim 1, wherein the hyaluronate salt has a weight average molecular weight of about 1,000 kDa to about 1,800 kDa.
20. The method of claim 1, wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 2% (w/v).
21. The method of claim 1, wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 1% (w/v).
22. The method of claim 1, wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 0.75% (w/v).
23. The method of claim 1, wherein a concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 0.5% (w/v).
24. The method of claim 1, wherein the aqueous vehicle comprises water and sodium chloride.
25. The method of claim 24, wherein the pharmaceutical formulation comprises sodium chloride at a concentration, in terms of weight per total volume of the pharmaceutical formulation, of about 0.1% to about 0.8% (w/v).
26. The method of claim 1, wherein the pharmaceutical formulation has a pH of about 3 to about 7.
27. The method of claim 1, wherein the pharmaceutical formulation has an osmolality of about 150 mOsm/kg to about 600 mOsm/kg.
28. The method of claim 1, wherein the pharmaceutical formulation has a viscosity of less than about 3,000 cP.
29. The method of claim 1, wherein the mental disorder is an anxiety disorder.
30. The method of claim 29, wherein the anxiety disorder is separation anxiety.
31. The method of claim 29, wherein the anxiety disorder is social anxiety.
32. The method of claim 29, wherein the anxiety disorder is noise phobia.
33. The method of claim 29, wherein the anxiety disorder is obsessive-compulsive disorder (OCD).
34. The method of claim 1, wherein the mental disorder is a depressive disorder.
35. The method of claim 1, wherein the companion animal is a dog.
36. The method of claim 1, wherein the companion animal is a cat.
37. The method of claim 1, wherein the companion animal is a horse.
38. The method of claim 1, wherein the injectable pharmaceutical formulation is administered via injection.
39. The method of claim 1, wherein the injectable pharmaceutical formulation is administered via subcutaneous injection.
40. The method of claim 1, wherein the injectable pharmaceutical formulation is administered via bolus subcutaneous injection.
41. The method of claim 40, wherein the bolus subcutaneous injection provides a duration of action of about 30 minutes to about 120 minutes after being administered.
42. A method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of an injectable pharmaceutical formulation comprising: a psychopharmaceutical agent; a carboxymethyl cellulose salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000238_0001
wherein: X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively R8 and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
43. A method of treating a mental disorder in a companion animal in need thereof, comprising administering to the companion animal a therapeutically effective amount of an injectable pharmaceutical formulation comprising: a psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of ketamine, or a stereoisomer, solvate, or prodrug thereof.
44. An injectable pharmaceutical formulation, comprising: a psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000240_0001
wherein: X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively R8 and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
45. A kit suitable for preparing the injectable pharmaceutical formulation of claim 44, the kit comprising:
(al) a first solution comprising the psychopharmaceutical agent and the aqueous vehicle; and
(bl) a second solution comprising the hyaluronate salt and the aqueous vehicle.
46. An injectable pharmaceutical formulation, comprising: a psychopharmaceutical agent; a carboxymethyl cellulose salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof,
Figure imgf000241_0001
wherein:
Xi and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
Yi and Y2 are independently selected from the group consisting of hydrogen and deuterium;
R2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkylthio, and unsubstituted or substituted acyloxy;
Re and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; and
Rs and R9 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, or alternatively Rs and R9 together with the nitrogen atom attached thereto are optionally joined to form an unsubstituted or substituted heterocycloalkyl.
47. A kit suitable for preparing the injectable pharmaceutical formulation of claim 46, the kit comprising:
(al) a first solution comprising the psychopharmaceutical agent and the aqueous vehicle; and
(bl) a second solution comprising the carboxymethyl cellulose salt and the aqueous vehicle.
48. An injectable pharmaceutical formulation, comprising: a psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of ketamine, or a stereoisomer, solvate, or prodrug thereof.
49. A kit suitable for preparing the injectable pharmaceutical formulation of claim 48, the kit comprising: (al) a first solution comprising the psychopharmaceutical agent and the aqueous vehicle; and
(bl) a second solution comprising the hyaluronate salt and the aqueous vehicle.
PCT/EP2024/065453 2023-06-08 2024-06-05 Companion animal treatments Pending WO2024251807A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363507059P 2023-06-08 2023-06-08
US63/507,059 2023-06-08
US202363600179P 2023-11-17 2023-11-17
US63/600,179 2023-11-17

Publications (1)

Publication Number Publication Date
WO2024251807A1 true WO2024251807A1 (en) 2024-12-12

Family

ID=91465275

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/065453 Pending WO2024251807A1 (en) 2023-06-08 2024-06-05 Companion animal treatments

Country Status (1)

Country Link
WO (1) WO2024251807A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046882A1 (en) * 2010-10-07 2012-04-12 Takeda Pharmaceutical Company Limited 1,4-oxazepane derivatives
WO2020169850A1 (en) * 2019-02-22 2020-08-27 Gh Research Limited 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) for treating depression
WO2021234608A1 (en) * 2020-05-19 2021-11-25 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046882A1 (en) * 2010-10-07 2012-04-12 Takeda Pharmaceutical Company Limited 1,4-oxazepane derivatives
WO2020169850A1 (en) * 2019-02-22 2020-08-27 Gh Research Limited 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) for treating depression
WO2021234608A1 (en) * 2020-05-19 2021-11-25 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
"Diagnostic and Statistical Manual of Mental Disorders", AMERICAN PSYCHIATRIC ASSOCIATION
ARGENTO E ET AL.: "Exploring ayahuasca-assisted therapy for addiction: A qualitative analysis of preliminary findings among an Indigenous community in Canada", DRUG ALCOHOL REV, vol. 38, 2019, pages 781 - 789
BARKER SA: "N, N-dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function", FRONT NEUROSCI, vol. 12, 2018, pages 1 - 17
BARKER SA: "N,N-dimethyltryptamine (DMT), an endogenous hallucinogen: Past, present, and future research to determine its role and function", FRONT NEUROSCI, vol. 12, 2018, pages 1 - 17
BERNS G, DECODING THE CANINE MIND. CEREBRUM : THE DANA FORUM ON BRAIN SCIENCE, March 2020 (2020-03-01)
BERNS GSBROOKS AMSPIVAK M: "Functional MRI in awake unrestrained dogs", PLOS ONE, vol. 7, 2012, pages e38027
BERNS GSBROOKS AMSPIVAK M: "Scent of the familiar: an fMRI study of canine brain responses to familiar and unfamiliar human and dog odors", BEHAV PROCESSES, vol. 110, 2015, pages 37 - 46
BERNS GSBROOKS ASPIVAK M: "Replicability and heterogeneity of awake unrestrained canine FMRI responses", PLOS ONE, vol. 8, 2013, pages e81698
CAMERON LPOLSON DE: "Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT", ACS CHEM NEUROSCI, vol. 9, 2018, pages 2344 - 2357, XP055871220, DOI: 10.1021/acschemneuro.8b00101
CARBONARO TMGATCH MB: "Neuropharmacology of N,N-dimethyltryptamine", BRAIN RES BULL, vol. 126, 2016, pages 74 - 88, XP029753113, DOI: 10.1016/j.brainresbull.2016.04.016
CHI TGOLD JA: "A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses", J NEUROL SCI, vol. 411, 2020, pages 116715, XP086096021, DOI: 10.1016/j.jns.2020.116715
D. K. FARIAM. E. MENDESN. M. SUMITA ET AL., J. BRAS. PATOL E. MED. LAB., vol. 53, no. 1, 2017, pages 38 - 45
FÁBREGAS JM ET AL.: "Assessment of addiction severity among ritual users of ayahuasca", DRUG ALCOHOL DEPEND, vol. 111, 2010, pages 257 - 261, XP027379698
FUENTES JJ ET AL.: "Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials", FRONT PSYCHIATRY, vol. 10, 2020, pages 1 - 14
GALLIMORE ARSTRASSMAN RJ: "A model for the application of target-controlled intravenous infusion for a prolonged immersive DMT psychedelic experience", FRONT PHARMACOL, vol. 7, 2016, pages 1 - 11
GARCIA-ROMEU AGRIFFITHS RRJOHNSON MW: "Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction", CURR DRUG ABUSE REV, vol. 7, 2014, pages 157 - 164
GRIFFITHS RR ET AL.: "Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial", J PSYCHOPHARMACOL, vol. 30, 2016, pages 1181 - 1197, XP055611143, DOI: 10.1177/0269881116675513
INSERRA ADE GREGORIO DGOBBI G: "Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms", PHARMACOL REV, vol. 73, 2021, pages 202 - 277
JOHNSON MW ET AL.: "Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction", J PSYCHOPHARMACOL, vol. 28, 2014, pages 983 - 992, XP055935138, DOI: 10.1177/0269881114548296
JOHNSON MWGARCIA-ROMEU AGRIFFITHS RR: "Long-term follow-up of psilocybin-facilitated smoking cessation", AM J DRUG ALCOHOL ABUSE, vol. 43, 2017, pages 55 - 60
KANG NW ET AL.: "Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin", PHARMACEUTICS, vol. 13, no. 6, 11 June 2021 (2021-06-11), pages 864
LARSEN N E ET AL: "Drug delivery systems using hyaluronan and its derivatives", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, AMSTERDAM , NL, vol. 7, no. 2, 1 September 1991 (1991-09-01), pages 279 - 293, XP023844354, ISSN: 0169-409X, [retrieved on 19910901], DOI: 10.1016/0169-409X(91)90007-Y *
LY C ET AL.: "Psychedelics Promote Structural and Functional Neural Plasticity", CELL REP, vol. 23, 2018, pages 3170 - 3182, XP093063512, DOI: 10.1016/j.celrep.2018.05.022
LY C: "Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth", PHARMACOL TRANSL SCI, 2020
MITCHELL JM ET AL.: "MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study", NAT MED, vol. 27, 2021, pages 1025 - 1033, XP037589827, DOI: 10.1038/s41591-021-01336-3
NOLLI LM ET AL.: "Effects of the hallucinogenic beverage ayahuasca on voluntary ethanol intake by rats and on cFos expression in brain areas relevant to drug addiction", ALCOHOL, 2019
NOORANI T ET AL.: "Psychedelic therapy for smoking cessation: Qualitative analysis of participant accounts", J PSYCHOPHARMACOL, vol. 32, 2018, pages 756 - 769
OLIVEIRA-LIMA AJ ET AL.: "Effects of ayahuasca on the development of ethanol-induced behavioral sensitization and on a post-sensitization treatment in mice", PHYSIOL BEHAV, vol. 142, 2015, pages 28 - 36
ROETHLISBERGER D. ET AL.: "If Euhydric and Isotonic Do Not Work, What Are Acceptable pH and Osmolality for Parenteral Drug Dosage Forms?", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 106, no. 2, 2017, pages 446 - 456
STRASSMAN RJQUALLS CRUHLENHUTH EHKELLNER R: "Dose-response study of N,N-Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale", ARCH GEN PSYCHIATRY, vol. 51, 1994, pages 98 - 108, XP055871027
THOMAS G ET AL.: "Ayahuasca-assisted therapy for addiction: Results from a preliminary observational study in Canada", CURR DRUG ABUSE REV, 2013
USACH I ET AL.: "Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site", ADV THER, vol. 36, no. 11, November 2019 (2019-11-01), pages 2986 - 2996, XP036922023, DOI: 10.1007/s12325-019-01101-6
VEEN BTH ET AL.: "Psilocybin for treating substance use disorders?", EXPERT REV NEUROTHER, vol. 17, 2017, pages 203 - 212, XP055707549, DOI: 10.1080/14737175.2016.1220834
VOLLENWEIDER FXPRELLER KH: "Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders", NAT REV NEUROSCI, vol. 21, 2020, pages 611 - 624, XP037271177, DOI: 10.1038/s41583-020-0367-2

Similar Documents

Publication Publication Date Title
RU2527327C2 (en) Medications, containing fluoroquinolones
CA2781436C (en) Arachidonic acid analogs and methods for analgesic treatment using same
JP4863867B2 (en) Controlled release system
KR20200033307A (en) Organic compounds
AU2017212651A1 (en) Biologically active cannabidiol analogs
EP2910242B1 (en) Durable analgetic sebacoyl dinalbuphine ester-plga controlled release formulation
WO2006032202A1 (en) Long acting sustained-release formulation containing dopamine receptor agonist and the preparation method thereof
EP3615084A1 (en) Membrane active molecules
US20250109127A1 (en) Methods of use of phenoxypropylamine compounds to treat depression
CN103893184B (en) Comprise the local medicine composition of activating agent
US20090264535A1 (en) Liquid drug formulation
WO2024251807A1 (en) Companion animal treatments
US6593331B2 (en) Method for treatment of pain
JP2020536089A (en) Acetaminophen-pregabalin combination and how to treat pain
AU2011295694B2 (en) High dose buprenorphine compositions and use as analgesic
Koppisetti et al. Unveiling the Future: Opportunities in Long-Acting Injectable Drug Development for Veterinary Care
US20140112957A1 (en) Analegisic (Sebacoyl dinalbuphine ester) PLGA controlled release formulation form
WO2024089226A1 (en) Phenethylamine compounds, compositions, and methods of use
WO2024231331A1 (en) Injectable pharmaceutical formulations
US20250325567A1 (en) Coadministration of polycannabinoid with amine/amide anesthetics to enhance efficacy against pain
JP5376481B1 (en) Pharmaceutical composition for transdermal absorption
CN118141792A (en) Compositions comprising epinephrine and prodrugs thereof
US20160287711A1 (en) Formulation Solution Adapted to Prolong Plasma Times of Drugs in Mammals Including Humans
EA032511B1 (en) Therapeutic agent for frontal lobe dysfunction
HK1131890A (en) Liquid pharmaceutical formulation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24731902

Country of ref document: EP

Kind code of ref document: A1