[go: up one dir, main page]

EP4618946A1 - Formulations de 5-meo-dmt - Google Patents

Formulations de 5-meo-dmt

Info

Publication number
EP4618946A1
EP4618946A1 EP23813030.6A EP23813030A EP4618946A1 EP 4618946 A1 EP4618946 A1 EP 4618946A1 EP 23813030 A EP23813030 A EP 23813030A EP 4618946 A1 EP4618946 A1 EP 4618946A1
Authority
EP
European Patent Office
Prior art keywords
composition
meo
dmt
treatment
benzoate
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
EP23813030.6A
Other languages
German (de)
English (en)
Inventor
Cosmo FEILDING-MELLEN
Timothy Mason
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.)
Beckley Psytech Ltd
Original Assignee
Beckley Psytech 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
Priority claimed from GBGB2216961.9A external-priority patent/GB202216961D0/en
Application filed by Beckley Psytech Ltd filed Critical Beckley Psytech Ltd
Publication of EP4618946A1 publication Critical patent/EP4618946A1/fr
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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse

Definitions

  • This invention relates to formulations of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and uses thereof.
  • 5-MeO-DMT benzoate is the benzoate salt of the pharmacologically active compound of the tryptamine class, 5-MeO-DMT, and has the following structure:
  • 5-MeO-DMT is a psychoactive/psychedelic substance found in nature and is believed to act mainly through serotonin receptors. It is also believed to have a high affinity for the 5-HT2 and 5-HT1A subtypes, and/or inhibits monoamine reuptake. There remains a need in the art for improved formulations of 5-MeO-DMT benzoate.
  • the benzoate salt of 5-MeO-DMT displays dose-proportional pharmacokinetics. This is surprising as it has previously been found that the hydrochloride salt of 5- MeO-DMT displays non-dose proportional pharmacokinetics. It is desirable that a compound for use in treatment has dose-proportional pharmacokinetics, for example, to facilitate dose and dose regimen adjustment in patients.
  • dose proportional should be understood to mean that increases in the administered dose are accompanied by proportional increases in the PK profile, such as the AUC or Cmax.
  • a dose-proportional pharmaceutically acceptable dry powder intranasal composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate dry powder particles, and one or more pharmaceutically acceptable carriers or excipients, for use in a method of treatment, wherein the composition has dose-proportional pharmacokinetics.
  • a pharmaceutically acceptable composition comprising 5-MeO-DMT, wherein administration of said composition to a subject produces in said subject a blood plasma Cmax (ng/mL) of about 4-39, of about 5-35 or of about 6-29.
  • the composition comprises 5-MeO-DMT benzoate. In an embodiment, the 5-MeO-DMT is present as the benzoate salt. In an embodiment, the 5-MeO-DMT composition is a composition for intranasal administration. In an embodiment, the 5-MeO-DMT composition is an intranasal composition. In an embodiment, the composition comprises l-12mg of 5-MeO-DMT benzoate.
  • the composition comprises 4mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 3-13, of about 7-11 or of about 9; a Tmax (h) of about 0.03-0.2, of about 0.09-0.16 or of about 0.12; a tl/2 (h) of about 0.27-0.53, of about 0.30-0.45 or of about 0.37; a AUCIast (h*ng/mL) of about 1.9-7.2, of about 3.5-5.5 or of about 4.5; or a AUCinf (h*ng/mL) of about 2.4-7.4, of about 3.5-6.5 or of about 5.
  • the composition comprises 8mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 16.4-30.9, of about 19-25 or of about 22; a Tmax (h) of about 0.1-0.27, of about 0.1-0.22 or of about 0.17; a tl/2 (h) of about 0.21-0.37, of about 0.25- 0.35 or of about 0.30; a AUCIast (h*ng/mL) of about 9.25-17.23, of about 11-15 or of about 13.1; or a AUCinf (h*ng/mL) of about 9.42-18.7, of about 11-16 or of about 13.9.
  • the composition comprises lOmg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 10.4- 46.4, of about 25-39 or of about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or of about 0.14; a tl/2 (h) of about 0.24-0.59, of about 0.29-0.47 or of about 0.38; a AUCIast (h*ng/mL) of about 9.37-20.41, of about 13-18 or of about 15.4; or a AUCinf (h*ng/mL) of about 9.42-18.7, of about 11-16 or of about 13.9.
  • the composition comprises 12mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 20.9-39, of about 25-35 or of about 29; a Tmax (h) of about 0.17-0.5, of about 0.2-0.3 or of about 0.25; a tl/2 (h ) of about 0.28-0.55, of about 0.40-0.50 or of about 0.44; a AUCIast (h*ng/mL) of about 14.45-22, of about 16-20 or of about 18.5; or a AUCinf (h*ng/mL) of about 19.10-27, of about 22-25 or of about 23.9.
  • a Cmax ng/mL
  • Tmax of about 0.17-0.5, of about 0.2-0.3 or of about 0.25
  • a tl/2 (h ) of about 0.28-0.55, of about 0.40-0.50 or of about 0.44
  • the composition is a dry powder composition.
  • the composition comprises one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM/MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC).
  • the composition comprises one or more of chitosan, chitosan derivatives (such as N,N,N -trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), p-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl cho
  • the 5-MeO-DMT is present as crystalline 5-MeO-DMT benzoate as characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20.
  • a pharmaceutically acceptable dry powder intranasal composition comprising l-12mg of 5-MeO-DMT benzoate and HPMC.
  • intranasal administration of the composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 4-39, of about 5-35 or of about 6-29; a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or of about 0.1-0.25; a tl/2 (h) of about 0.1-0.55, of about 0.2-0.5 or of about 0.25-0.44; a AUCIast (h*ng/mL) of about 1.0-22, of about 1.2-20 or of about 1.5-18.5; or a AUCinf (h*ng/mL) of about 1.5-27, of about 1.7-25 or of about 1.9-23.9.
  • the disease or condition is depression or treatmentresistant depression.
  • a formulation of 5-MeO-DMT benzoate there is provided a pharmaceutically acceptable composition comprising 5-MeO- DMT (hereafter '5-MeO-DMT composition') comprising lmg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 4-8, of about 5-7 or about 6; a Tmax (h) of about 0.05-0.2, of about 0.06-0.15 or about 0.1; a tl/2 (h) of about 0.1-0.4, of about 0.2-0.3 or about 0.25; a AUCIast (h*ng/mL) of about 1.0-1.8, of about 1.2-1.6 or about 1.5; or a AUCin
  • a 5-MeO-DMT composition comprising 2.5mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 4-12, of about 6-10 or about 8; a Tmax (h) of about 0.1-0.3, of about 0.15- 0.25 or about 0.18; tl/2 (h) of about 0.1-0.4, of about 0.20-0.35 or about 0.32; a AUCIast (h*ng/mL) of about 2.3-6.5, of about 3.0-4.4 or about 3.8; or a AUCinf (h*ng/mL) of about 2.9-6.8, of about 3.5- 5.5 or about 4.4.
  • a 5-MeO-DMT composition comprising 4mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 3-13, of about 7-11 or about 9; a Tmax (h) of about 0.03- 0.2, of about 0.09-0.16 or about 0.12; a tl/2 (h) of about 0.27-0.53, of about 0.30-0.45 or about 0.37; a AUCIast (h*ng/mL) of about 1.9-7.2, of about 3.5-5.5 or about 4.5; or a AUCinf (h*ng/mL) of about 2.4-7.4, of about 3.5-6.5 or about 5.
  • a 5-MeO-DMT composition comprising 6mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 7.7-19.3, of about 12.5-17 or about 15; a Tmax (h) of about 0.07-0.27, of about 0.1-0.2 or about 0.15; a tl/2 (h) of about 0.32-0.42, of about 0.35-0.4 or about 0.37; a AUCIast (h*ng/mL) of about 4.6-12, of about 6-10 or about 8; or a AUCinf (h*ng/mL) of about 8.6-11, of about 9-10.5 or about 9.8.
  • a 5-MeO-DMT composition comprising 8mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 16.4-30.9, of about 19-25 or about 22; a Tmax (h) of about 0.1-0.27, of about 0.1-0.22 or about 0.17; a tl/2 (h) of about 0.21-0.37, of about 0.25-0.35 or about 0.30; a AUCIast (h*ng/mL) of about 9.25-17.23, of about 11-15 or about 13.1; or a AUCinf (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
  • the composition comprises l-20mg of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.
  • a 5-MeO-DMT composition comprising lOmg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or about 0.14; a tl/2 (h) of about 0.24-0.59, of about 0.29-0.47 or about 0.38; a AUCIast (h*ng/mL) of about 9.37-20.41, of about 13-18 or about 15.4; or a AUCinf (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
  • a 5-MeO-DMT composition comprising 12mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 20.9-38.6, of about 25-35 or about 29; a Tmax (h) of about 0.17-0.5, of about 0.2-0.3 or about 0.25; a tl/2 (h) of about 0.28-0.55, of about 0.40-0.50 or about 0.44; a AUCIast (h*ng/mL) of about 14.45-22.23, of about 16-20 or about 18.5; or a AUCinf (h*ng/mL) of about 19.10-27.15, of about 22-25 or about 23.9.
  • a 5-MeO-DMT composition comprising l-12mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a subject produces in said subject one or more of: a Cmax (ng/mL) of about 4-38.6, of about 5-35 or about 6-29; a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or about 0.1-0.25; a tl/2 (h) of about 0.1-0.55, of about 0.2-0.5 or about 0.25-0.44; a AUCIast (h*ng/mL) of about 1.0-22.23, of about 1.2-20 or about 1.5-18.5; or a AUCinf (h*ng/mL) of about 1.5-27.15, of about 1.7-25 or about 1.9-23.9.
  • the composition produces in a subject, per each lOmg of 5-MeO-DMT present in the composition, one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or about 0.14; a tl/2 (h) of about 0.24-0.59, of about 0.29-0.47 or about 0.38; a AUCIast (h*ng/mL) of about 9.37-20.41, of about 13-18 or about 15.4; or a AUCinf (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
  • the 5-MeO-DMT composition comprises a mucoadhesive.
  • the 5-MeO-DMT composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM/MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC).
  • PVM/MA methyl vinyl ether and maleic anhydride
  • HPC hydroxypropyl cellulose
  • Na-CMC sodium carboxymethylcellulose
  • the 5-MeO-DMT composition comprises HPMC.
  • the 5-MeO-DMT composition comprises crystalline 5-MeO- DMT benzoate, as described subsequently or previously.
  • the composition disclosed herein is for use as a medicament.
  • the disease or condition is depression.
  • the disease or condition is treatment-resistant depression.
  • the disease or condition is: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, treatment resistant depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT
  • the method of use is a method of treatment.
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
  • the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent.
  • the further active agent is a psychedelic compound, optionally a tryptamine.
  • the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.
  • the further active agent is an antidepressant compound.
  • the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
  • the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Ami
  • the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).
  • Figure 1 is a schematic of a one-step synthesis of 5-MeO-DMT from the reaction of 4- methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanal dimethyl acetal.
  • Figure 2 is a schematic of a three step synthesis of 5-MeO-DMT. The first step involves the reaction of 5-methoxyindole with oxalyl chloride. The resultant product is aminated with dimethylamine and then is reduced with lithium aluminium hydride.
  • Figure 3 is a schematic route for the formation of a powder form of 5-MeO-DMT using a spray drying process.
  • FIG. 4 is an overview of the slug mucosal irritation (SMI) test.
  • A First 15 minute contact period between slug and test item.
  • B Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour.
  • C Second 15 minute contact period between slug and test item.
  • D Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour.
  • E Third 15 minute contact period between slug and test item.
  • Figure 5 is a graph showing that the benzoate salt of 5-MeO-DMT has higher permeation compared with the hydrochloride salt, as per the experiment detailed in Example 7.
  • Figure 7 is an XRPD diffractogram of 5-MeO-DMT benzoate following particle size reduction.
  • Figure 9 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL003) plasma linear concentrationtime plot.
  • Figure 10 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL003) plasma log concentration-time plot.
  • Figure 11 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL002) plasma linear concentrationtime plot.
  • Figure 12 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL002) plasma log concentration-time plot.
  • Figure 13 shows Forced Swim Test results, Time Immobile, for 5-MeO-DMT benzoate, vehicle and imipramine.
  • Figure 14 shows Forced Swim Test results, Latency to Immobility, for 5-MeO-DMT benzoate, vehicle and imipramine.
  • Figure 15 shows a Dynamic Vapour Sorption (DVS) isotherm for 5-MeO-DMT benzoate.
  • Figure 16 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/20/126-FP).
  • Figure 17 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/45/006-FP).
  • Double-blind, randomized, Phase 1, single ascending dose studies to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT hydrochloride and intranasal 5-MeO-DMT benzoate in healthy subjects have been performed.
  • the results of these studies have surprisingly shown that only the benzoate salt of 5-MeO-DMT exhibits dose-proportional pharmacokinetics. It is desirable that a compound for use in treatment has dose-proportional pharmacokinetics, for example, to facilitate dose and dose regimen adjustment in patients.
  • a method of treating a condition or disease in a subject comprising the administration of 5-MeO-DMT benzoate to a subject in need thereof, wherein the 5-MeO-DMT benzoate has dose-proportional pharmacokinetics.
  • Step 1 Add methyl tert-butyl ether (MTBE) (15vol) into the reaction vessel and cool to -20 to -30°C, before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. Add a solution of 5-methoxyindole (1.0 eq) in THF (Ivol) to the reaction vessel, maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.
  • MTBE methyl tert-butyl ether
  • Step 2 Add the compound obtained in step 1 (1.0 eq) to a reaction vessel together with dimethylamine hydrochloride (3.0 eq) and methanol (2vol). Add 25% NaOMe in methanol (3.5 eq), to the reaction maintaining the temperature at no more than 30°C. Warm to and stir for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remains. Adjust the temperature to 0-5°C over no less than 2 hours, then add water (5vol) over no less than 1 hour with stirring at 0-5°C for no less than 1 hour.
  • Step 3 Add the compound obtained in step 2 (1.0 eq) to a reaction vessel. Add IM LiAl H4 in THF (1.5 eq) in THF (8vol) to the reaction maintaining no more than 40°C. Heat at reflux for no less than 4 hours ensuring that no more than 2% of the starting material from step 2 remains.
  • the benzoate salt of 5-MeO-DMT has improved characteristics over the common hydrochloride salt, including reduced mucosal irritation, increased epithelial permeability and increased stability.
  • 5- MeO-DMT benzoate is a white to off white solid powder, soluble in water at >50mg/ml with a pH of 7-8 at 50mg/ml and a pKa of 9.71.
  • Spray drying a solution containing the substance(s) of interest (e.g. 5-MeO-DMT, or the salt, thereof inclusive of any excipients).
  • This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
  • a ProCepT spray dryer is used. In an embodiment, a ProCepT spray dryer with an ultrasonic nozzle is used.
  • the Slug Mucosal Irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potency of pharmaceutical formulations and ingredients.
  • the test utilizes the terrestrial slug Arion lusitanicus.
  • the body wall of the slugs is a mucosal surface composed of different layers.
  • the outer single-layered columnar epithelium that contains cells with cilia, cells with micro-villi and mucus secreting cells covers the subepithelial connective tissue. Slugs that are placed on an irritating substance will produce mucus. Additionally tissue damage can be induced which results in the release of proteins and enzymes from the mucosal surface.
  • the purpose of this assay was to assess the stinging, itching or burning potential of the test item(s) defined below.
  • Using the objective values obtained for the mucus production the stinging, itching or burning potential of the test item(s) can be estimated by means of the prediction model that is composed of four categories (no, mild, moderate and severe).
  • Test System Slugs (Arion lusitanicus); 3 slugs per treatment group.
  • the parental slugs of Arion lusitanicus collected in local gardens along Gent and Aalter (Belgium) are bred in the laboratory in an acclimatized room (18-20°C).
  • the slugs are housed in plastic containers and fed with lettuce, cucumber, carrots and commercial dog food.
  • Test Design A single study was performed. Treatment time was 15 minutes three times on the same day.
  • the amount of mucus produced during each contact period was measured by weighing the Petri dishes with the test item before and after each 15-min contact period.
  • the mucus production was expressed as % of the body weight.
  • the slugs were weighed before and after each 15-min contact.
  • test results were based upon the total amount of mucus production during 3 repeated contact periods with the test item.
  • the mucus production was expressed in % of the body weight by dividing the weight of the mucus produced during each contact period by the body weight of the slug before the start of that contact period.
  • the total mucus was calculated for each slug and then the mean per treatment group was calculated.
  • the classification prediction model shown in the Table below was used to classify the compounds.
  • the negative control should be classified as causing no stinging, itching and burning (Total mucus production ⁇ 5.5%)
  • the positive control item should be classified as causing severe stinging, itching and burning (Total mucus production > 17.5%)
  • NC negative control
  • PC positive control
  • the average amount of mucus produced during each 15-min contact period and total mucus production (total MP) is presented in the Table above. According to the classification prediction model of the SMI test, the negative control (untreated slugs) did not induce reactions in the slugs (mean total MP ⁇ 5.5%).
  • the positive control on the other hand (DDWM/SLS 80/20) induced a high mucus production during each contact period (mean total MP > 17.5%) resulting in a classification as severe stinging, itching, and burning (SIB) reactions. The acceptance criteria were met and the experiment was considered valid. In total, 4 different solutions were tested. The amount of mucus produced during each 15-min contact period was between 10% and 17.5%, indicating moderate SIB reactions.
  • test items can be ranked according to increasing total mucus production: sodium acetate (10% w/v) ⁇ sodium citrate (10% w/v) ⁇ disodium fumarate (10% w/v) ⁇ sodium phosphate (10% w/v).
  • NC negative control
  • PC positive control
  • the total MP for a 60-m in treatment (historical data) was compared with the total MP of the SIB protocol (3x 15-min treatment; current data).
  • a ranking is proposed from least SIB reactions to highest SIB reactions:
  • Sodium oxalate appears to be the most irritating salt since a 1% concentration results in 11.2% total MP after 1 hour of contact.
  • Sodium benzoate is the least irritating salt.
  • less 5-MeO-DMT benzoate salt may be needed by inhalation to provide the same benefit as the HCI salt and the benzoate salt is less irritating, and so provides a synergistic benefit. Smaller amounts of compound also make inhalation easier to accomplish.
  • the XRPD pattern of 5-MeO-DMT benzoate salt was acquired before and following particle size reduction with a mortar and pestle. This reduced the intensity of dominant diffractions and revealed that the XRPD pattern of the benzoate salt was prone to preferred orientation prior to particle size reduction, which is a function of the habit and particle size of the material.
  • XRPD patterns of the benzoate salt prior to and following particle size reduction can be seen in Figures 6 and 7 respectively.
  • the XRPD patterns of the benzoate salt prior to and following particle size reduction overlaid on one another can be seen in Figure 8.
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.0’2010.1’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.0’2010.2’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.3°20.
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.0’2010.1’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.0’20+0.2’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.0’2010.3’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3’2010.1’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3’2010.2’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3’20+0.3’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3’2010.1’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3’20+0.2’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3’2010.3’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3’2010.1’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3’20+0.2’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3’2010.3’20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3’2010.1’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3’2010.2’20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7,
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5,
  • crystalline 5- MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram as substantially illustrated in Figures 6, 7 or 8.
  • a formulation of 5-MeO-DMT benzoate which is a dry powder.
  • this formulation is presented in a single dose nasal applicator.
  • 5-MeO-DMT benzoate and HMPC input solutions are made up using sterile water and left to stir until fully dissolved.
  • the spray drying parameters used to produce a dry powder of 5-MeO-DMT benzoate and HPMC are selected from those set out in the Table below:
  • Example 10 A double-blind, randomized, Phase 1, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT benzoate (BPL-003) in healthy subjects
  • the mean Cmax was 29ng/mL for the 12mg dosage.
  • the mean Tmax was 9.5 minutes whilst the mean half-life (TI/ 2 ) was 21 minutes.
  • Bufotenin the O-demethylated metabolite of 5-MeO-DMT, was only detected at very low levels at the 6mg dose level after the 16 minutes timepoint.
  • Example 11 A double-blind, randomized, Phase 1, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT HCI (BPL-002) in healthy subjects
  • BPL-002 A single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT HCI (BPL-002) was performed.
  • BPL-002 comprises 5-MeO-DMT HCI, HPMC, water for injection (WFI) and a sodium hydroxide solution to adjust pH.
  • An initial stock solution of 0.5 %w/w HMPC was prepared using sterile water for injection which was further diluted with sterile water for injection to approximately 90% of the final weight required.
  • the required amount of drug substance (70 mg/ml or 140 mg/ml Freebase) was then dissolved in an aliquot of the 0.5% w/w HPMC stock solution with stirring and the pH of the active stock solution was then adjusted to 6.00 +/- 0.25 by adding sodium hydroxide (0.1M solution). The IPC measurement was taken to ensure the pH is adjusted within the accepted range before making up to the final weight with sterile water for injection The concentration of the HPMC in the final solution was 0.1% w/w.
  • Placebo solutions of 0.1%w/w HPMC were made up by dissolving the required amount of HPMC in sterile water for injection (approximately 90% of final weight) and adjusted for pH 5.75 +/- 0.25 if necessary by the addition of sodium hydroxide solution (0.05M). The in process check measurement was taken to ensure the pH is adjusted within the accepted range before making up so the final weight with sterile water for injection. The concentration of the HPMC in the final solution was 0.1% w/w.
  • the mean (+/- SD) 5-MeO-DMT plasma linear concentration-time plot and plasma log concentration-time plot are shown in Figures 11 and 12, respectively. Summary statistics for the plasma 5-MeO-DMT, bufotenin PK concentrations, can be seen in the Table below:
  • CCAC Canadian Council on Animal Care
  • mice Male CD-I mice from Charles River Laboratories (St. Constant, Quebec, Canada) served as test subjects in this study. Animals generally weighed 25-30 g at the time of testing. Schedule of Events
  • mice received the appropriate dose of vehicle, test article, or positive control (treatments summarized above). Following the appropriate pre-treatment time, animals were gently placed into tall glass cylinders filled with water (20-25°C). After a period of vigorous activity, each mouse adopted a characteristic immobile posture which is readily identifiable. The swim test involves scoring the duration of immobility. Over a 6-minute test session, the latency to first immobility is recorded (in seconds). The duration of immobility (in seconds) during the last 4 minutes of the test is also measured. Activity or inactivity from 0-2 minutes is not recorded. Test Articles
  • Latency to immobility vehicle: 95.5 ⁇ 4.6 seconds - 5-MeO-DMT benzoate 121.8 ⁇ 22.0 seconds (0.5 mg/kg), 120.9 ⁇ 13.3 seconds (1.5 mg/kg), 85.0 ⁇ 9.5 seconds (5 mg/kg), imipramine 268.6 ⁇ 30.3 second, Figure 14).
  • Example 13 Dynamic Vapour Sorption (DVS) comparison of 5-MeO-DMT benzoate and HCI
  • the DVS profile for 5-MeO-DMT benzoate salt revealed reversible water uptake/loss over the humidity range and no hysteresis.
  • the water uptake/loss from 0 to 90% was gradual and amounted to a maximum of ca 0.20% and was a consequence of wetting of the solid.
  • the DVS isotherm can be seen in Figure 15.
  • the DVS isotherm of a 5-MeO-DMT Hydrochloride, lot 20/20/126-FP (Figure 16) was found to undergo significant moisture uptake upon the first sorption cycle from 70%RH. Approximately 23% w / w uptake is observed between 70-80%RH, whereas less than 0.3% w / w moisture uptake from 0- 70%RH was observed. A further 20% w / w moisture uptake is observed up to and when held at 90%RH before commencement of the second desorption cycle. Subsequent sorption and desorption cycles follow a similar profile with some observed hysteresis between operations that do not match the original desorption step. These return to ca.
  • Example 14 Phase 1 study results on the effects of 5-MeO-DMT benzoate (BPL-003) on facial emotion processing in psychedelic-naive healthy subjects
  • the FERT is a digital task in which participants are serially presented faces expressing different emotions (anger, disgust, fear, happiness, sadness, surprise, neutral) at valenced intensities and they respond by selecting the emotion they identify via a touchscreen.
  • the FERT was conducted on Day 1 pre-dose (baseline), on Day 2 at 22-24 hours post-dose, and at follow-up on Day 8.
  • Other assessments of safety, pharmacokinetics, and pharmacodynamics were also conducted.
  • a method of increasing a patient's ability to recognise happiness comprising the administration of 5-MeO-DMT, or a composition thereof, optionally as described herein, to a patient in need thereof.
  • a method of decreasing a patient's ability to recognise sadness comprising the administration of 5-MeO-DMT, or a composition thereof, optionally as described herein, to a patient in need thereof.
  • it is the benzoate salt of 5-MeO-DMT.
  • it is the benzoate salt of 5-MeO- DMT.

Landscapes

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

Abstract

Une composition pharmaceutiquement acceptable peut comprendre la 5-méthoxy-N, N-diméthyltryptamine (5-MeO-DMT). Une méthode de traitement d'un sujet peut comprendre l'administration de la composition au sujet. Le procédé peut traiter ou prévenir la dépression chez le sujet. L'administration de la composition au sujet peut produire chez le sujet un Cmax de plasma sanguin d'environ 4 ng/mL à environ 39 ng/mL.
EP23813030.6A 2022-11-14 2023-11-14 Formulations de 5-meo-dmt Pending EP4618946A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB2216961.9A GB202216961D0 (en) 2022-11-14 2022-11-14 5-meo-mt formulations
US202218065030A 2022-12-13 2022-12-13
PCT/GB2023/052977 WO2024105379A1 (fr) 2022-11-14 2023-11-14 Formulations de 5-meo-dmt

Publications (1)

Publication Number Publication Date
EP4618946A1 true EP4618946A1 (fr) 2025-09-24

Family

ID=88965221

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23813030.6A Pending EP4618946A1 (fr) 2022-11-14 2023-11-14 Formulations de 5-meo-dmt

Country Status (2)

Country Link
EP (1) EP4618946A1 (fr)
WO (1) WO2024105379A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025068714A1 (fr) * 2023-09-28 2025-04-03 Beckley Psytech Limited Compositions pharmaceutiques comprenant de la 5-méthoxy-n,n-diméthyltryptamine (5-meo-dmt)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4595962A3 (fr) * 2020-06-12 2025-10-22 Beckley Psytech Limited Composition pharmaceutique
WO2023111544A2 (fr) * 2021-12-13 2023-06-22 Beckley Psytech Limited Sel de benzoate de 5-méthoxy-n,n-diméthyltryptamine

Also Published As

Publication number Publication date
WO2024105379A1 (fr) 2024-05-23

Similar Documents

Publication Publication Date Title
EP3941583B1 (fr) Composition comprenant un sel de benzoate de 5-méthoxy-n,n-diméthyltryptamine
US8729070B2 (en) CNS pharmaceutical compositions and methods of use
CN1241569C (zh) 用于治疗鼻炎/结膜炎的非镇静抗组胺药物与影响白三烯活性物质的新药物并用
US9579299B2 (en) CNS pharmaceutical compositions and methods of use
US20210046044A1 (en) Use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane to treat addictive and alcohol-related disorders
IE65336B1 (en) Use of the active substance azelastine in the treatment of psoriasis diseases
CN1252722A (zh) 脱羰乙氧氯雷他定在治疗尿失禁、晕动病和眩晕药剂的制备中的应用
EP4618946A1 (fr) Formulations de 5-meo-dmt
WO2016027259A1 (fr) Compositions pharmaceutiques pour le système nerveux central et procédés d'utilisation
EA010868B1 (ru) Применение производных бицикло[2.2.1]гептана для приготовления нейропротекторных фармацевтических композиций
CN106390128B (zh) β-肾上腺素能反向激动剂用于戒烟的用途
JP2011246478A (ja) テルカゲパントカリウムの固形投与製剤
JP2009539990A (ja) Ｃｘｃｒ２またはｃｘｃｒ１とｃｘｃｒ２との両方のいずれかの選択的アンタゴニストの薬学的処方物および組成物ならびに炎症性障害を治療するためにそれらを使用する方法
US6281248B1 (en) Composition for treating asthma
JP2016518406A (ja) 嗜癖障害およびアルコール関連障害を治療するための（＋）−１−（３，４−ジクロロフェニル）−３−アザビシクロ［３．１．０］へキサンの使用
HK1197916A (en) Use of beta-adrenergic inverse agonists for smoking cessation
HK1008185B (en) Use of descarboethoxyloratadine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating allergic rhinitis
HK1008185A1 (en) Use of descarboethoxyloratadine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating allergic rhinitis
BG109702A (bg) Комбинация на дерамциклан и опиоиди като аналгетици
JP2000302761A (ja) モルファン誘導体またはその塩

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250612

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR