CN118632835A - Tryptamine compositions and methods - Google Patents

Abstract

Disclosed are pharmaceutically acceptable salts of tryptamine compounds, the use of such salt forms in treating diseases associated with serotonin 5- _HT2 receptors, pharmaceutical compositions containing the salt forms (such as those suitable for inhaled administration), methods of delivering the pharmaceutically acceptable salt forms (e.g., via inhalation), and methods of using the salt forms to treat diseases or disorders associated with serotonin 5- _HT2 receptors (such as central nervous system (CNS) disorders or psychological disorders).

Description

Tryptamine compositions and methods

Cross-references

This application claims priority to U.S. Provisional Application No. 63/299,599, filed on January 14, 2022, and U.S. Provisional Application No. 63/384,704, filed on November 22, 2022, each of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates generally to pharmaceutically acceptable salts of tryptamine compounds and, in some embodiments, to serotonin 5- _HT2 receptor agonists and their use in treating diseases associated with the 5- _HT2 receptor.

Background Art

There are three closely related subtypes of serotonin 5-HT ₂ receptors (5-HT ₂ R), 5-HT _2A , 5-HT _2B and 5-HT _2C , and they are the primary targets of classic serotonergic hallucinogens, such as lysergic acid diethylamide (LSD), psilocybin and 2,5-dimethoxy-4-bromoamphetamine (DOB). They share approximately 60% transmembrane amino acid homology, which poses a challenge to designing molecules with selectivity for one subtype over the others. Each subtype is expressed in a unique pattern in mammals (in both peripheral tissues and the central nervous system) and, when stimulated, produces unique biochemical, physiological and behavioral effects. For example, activation of 5-HT _2A R primarily mediates hallucinogenic effects and elicits anti-inflammatory effects, while activation of 5-HT _{2C R reduces feeding behavior. However, chronic activation of 5-HT 2B R} is associated with valvular heart disease (VHD), a life-threatening adverse event (AE). Furthermore, there is concern that patients who might benefit from 5-HT _2A R pharmacotherapy may become resistant to experiencing hallucinogenic effects.

Tryptamines are a class of serotonergic hallucinogens and have very high potency (in some cases with subnanomolar affinity) at the serotonin 5- _HT2R . Certain tryptamines are distinguished from classical hallucinogens and other serotonergic hallucinogens by having selectivity for 5- _HT2A R over 5- _HT2B R and 5- _HT2C R - in some cases 100-fold selectivity.

AEs caused by tryptamines and other serotonergic hallucinogens are associated with the ingestion of relatively high doses. Probably because of the very high potency of 5- _HT2A R and 5- _HT2CR , effective oral doses of tryptamines and other hallucinogens are very low. For example, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethan-1-amine (2C-C-NBOMe) is orally active at doses as low as 25 μg, and very potent hallucinogenic doses are in the range of 500-700 μg. Therefore, misuse or abuse at or above these doses can result in negative experiences for patients, manifested as acute hallucinogenic crises, colloquially known as "bad trips," in which patients experience visual and auditory hallucinations, anxiety, aggression, psychosis, remorse, and distress. Intoxication has also been associated with toxicity (e.g., rhabdomyolysis) and death. Tryptamines, such as N,N-dimethyltryptamine (DMT) (IUPAC: 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine)) may also undergo extensive first-pass metabolism, rendering them orally inactive.

As a result, many tryptamine hallucinogens have a relatively narrow therapeutic index. Therefore, maximizing the therapeutic effect of potential drug candidate molecules requires fine-tuning of the dose and route of administration as well as dose titration to reduce side effects and improve safety.

In addition, like many free base forms of drugs, tryptamines in free base form are generally not well suited for pharmaceutical processing and application. For example, DMT free base is a low melting point solid (about 46°C) and is known to be sensitive to oxygen, heat and light under long-term storage.

Therefore, there is a need for tryptamines that overcome the 5- _HT2BR problem and the problem of adverse events, and there is a need to improve their bioavailability and enhance their activity and exposure. There is a further need for efficient, more convenient and controllable tryptamine formulations that do not provide plasma concentrations that are toxic to the nervous system (e.g., psychotomimetic toxicity). There is also a need for stable physiologically acceptable forms of tryptamines suitable for drug preparation and administration.

Summary of the invention

The present disclosure is based, at least in part, on the identification of salt forms of compounds that modulate the serotonin 5-HT ₂ receptor and methods of using the same to treat diseases associated with the serotonin 5-HT ₂ receptor. More specifically, the present disclosure provides novel salt forms of N,N-dimethyltryptamine (DMT) and its derivatives that have advantageous physical and pharmaceutical characteristics and allow for the preparation of, for example, effective, more convenient and controllable pharmaceutical formulations for the treatment of diseases/conditions such as neuropsychiatric diseases or disorders, inflammatory diseases or disorders, central nervous system (CNS) disorders, autonomic nervous system (ANS) disorders, pulmonary diseases and/or cardiovascular disorders.

These and other objects will become apparent from the detailed description below, and have been achieved by the inventors' discovery of novel salt forms of compounds of formula (I) having desirable physical and pharmaceutical characteristics, such as one or more of: ease and propensity for salt formation and crystallization (e.g., high yield); stable and well-defined physical properties (e.g., crystallinity, lack of polymorphism, high melting point and high enthalpy of fusion); moisture stability, including at high humidity (hygroscopicity); desirable appearance (e.g., free flowing, lack of cohesion/adhesion, regular morphology); acceptable aqueous solubility; and physiological acceptability, particularly for pulmonary administration (e.g., non-irritating).

Thus, such suitable salt forms of the compounds described herein (e.g., compounds of Formula (I)) can be administered, for example, via inhalation in a controlled manner, with rapid absorption and rapid onset of action provided by the vast surface area, rich vasculature, and thin air-blood barrier of the alveolar region, while avoiding first-pass metabolism, thereby enabling the use of relatively low doses, lower incidence of systemic side effects, and more favorable pharmacokinetic characteristics. Specifically, pulmonary administration of suitable salt forms of the compounds described herein (e.g., compounds of Formula (I)) in combination with N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., nitrous oxide, a dissociative anesthetic that provides a sense of sedation and euphoria and controls and/or reduces the activation of 5-HT ₂ ) can reduce the risk of overstimulation and, therefore, reduce the occurrence of psychiatric side effects (e.g., acute hallucinogenic crises).

Accordingly, the present disclosure provides:

(1) a pharmaceutically acceptable salt of a compound of formula (I) or a solvate thereof,

in:

_X1 and _X2 are deuterium,

_Y1 and _Y2 are deuterium,

R ₂ , R ₄ , R ₅ , R ₆ and R ₇ are independently hydrogen or deuterium, and

R ₈ and R ₉ are independently selected from the group consisting of -CH ₃ , -CDH ₂ , -CD ₂ H and -CD ₃ .

(2) The pharmaceutically acceptable salt according to (1), wherein at least one of R ₈ and R ₉ contains deuterium.

(3) The pharmaceutically acceptable salt according to (1) or (2), wherein R ₂ , R ₄ , R ₅ , R ₆ and R ₇ are hydrogen.

(4) The pharmaceutically acceptable salt according to (1) or (2), wherein at least one of R ₂ , R ₄ , R ₅ , R ₆ and R ₇ is deuterium.

(5) The pharmaceutically acceptable salt according to any one of (1) to (4), wherein R ₈ and R ₉ are -CH ₃ .

(6) The pharmaceutically acceptable salt of any one of (1) to (4), wherein R ₈ and R ₉ are independently selected from the group consisting of -CDH ₂ , -CD ₂ H and -CD ₃ .

(7) The pharmaceutically acceptable salt according to any one of (1) to (4), wherein R ₈ and R ₉ are -CD ₃ .

(8) The pharmaceutically acceptable salt according to any one of (1) to (7), wherein the compound of formula (I) is selected from the group consisting of:

(9) The pharmaceutically acceptable salt according to (1), wherein the compound of formula (I) is

(10) The pharmaceutically acceptable salt of any one of (1) to (9), which is crystalline as determined by X-ray powder diffraction (XRPD).

(11) The pharmaceutically acceptable salt of any one of (1) to (10), which has a water solubility of about 10 mg/mL to about 400 mg/mL.

(12) The pharmaceutically acceptable salt of any one of (1) to (11), which has a melting onset temperature of about 100° C. to about 210° C. as determined by differential scanning calorimetry (DSC).

(13) The pharmaceutically acceptable salt of any one of (1) to (12), which has a fusion enthalpy of about 110 J·g ^-1 to about 180 J·g ^-1 , as determined by differential scanning calorimetry (DSC).

(14) The pharmaceutically acceptable salt of any one of (1) to (13), which has a weight gain of less than 1% w/w when exposed to a relative humidity (RH) of >95% RH as determined by dynamic vapor sorption (DVS).

(15) The pharmaceutically acceptable salt according to any one of (1) to (14), which is an addition salt of the compound of formula (I) and an organic acid.

(16) The pharmaceutically acceptable salt according to any one of (1) to (15), which is a fumarate, benzoate, salicylate or succinate of the compound of formula (I).

(17) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a fumarate salt of the compound of formula (I).

(18) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a benzoate salt of the compound of formula (I).

(19) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a salicylate of the compound of formula (I).

(20) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a succinate salt of the compound of formula (I).

(21) The pharmaceutically acceptable salt according to any one of (1) to (16), which is 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-8a).

(22) A pharmaceutically acceptable salt as described in (21), which is in the form of a crystalline solid, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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.

(23) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a benzoate of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8b).

(24) A pharmaceutically acceptable salt as described in (23), which is in the form of a crystalline solid, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the following: 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.

(25) The pharmaceutically acceptable salt according to any one of (1) to (16), which is a salicylate of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8c).

(26) A pharmaceutically acceptable salt as described in (25), which is in the form of a crystalline solid, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the following: 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.

(27) The pharmaceutically acceptable salt according to any one of (1) to (16), which is 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-8d).

(28) A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of (1) to (27) and a pharmaceutically acceptable vehicle.

(29) The pharmaceutical composition of (28), wherein any position in the compound of formula (I) having deuterium has a minimum deuterium incorporation of at least 50 atomic % at the deuterium site.

(30) The pharmaceutical composition as described in (28) or (29), which is suitable for administration via inhalation.

(31) The pharmaceutical composition according to (28) or (29), which is suitable for oral administration.

(32) The pharmaceutical composition according to (28) or (29), which is suitable for intravenous administration.

(33) The pharmaceutical composition according to (28) or (29), which is suitable for subcutaneous administration.

(34) The pharmaceutical composition according to (28) or (29), which is suitable for intramuscular administration.

(35) The pharmaceutical composition according to (28) or (29), which is suitable for nasal administration.

(36) A liquid dosage form prepared by reconstituting the pharmaceutical composition as described in (28) or (29) into a solid dosage form in a pharmaceutically acceptable liquid medium.

(37) A method of delivering the pharmaceutically acceptable salt of any one of (1) to (27) to a patient in need thereof, comprising:

An aerosol is administered to the patient by inhalation, wherein the aerosol comprises the pharmaceutically acceptable salt of the compound of formula (I) in a carrier.

(38) The method of (37), wherein the pharmaceutically acceptable salt is delivered to the patient's central nervous system via pulmonary absorption.

(39) The method according to (37) or (38), wherein the carrier is air, oxygen, or a mixture of helium and oxygen.

(40) The method as described in (39), wherein the carrier is a mixture of helium and oxygen.

(41) The method of (40), wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C.

(42) A method as described in (40) or (41), wherein the helium is present in the mixture of the helium and the oxygen at approximately 50 volume % to 90 volume %, and the oxygen is present in the mixture of the helium and the oxygen at approximately 50 volume % to 10 volume %.

(43) The method as described in any one of (37) to (42), further comprising administering a pretreatment inhalation therapy before administering the aerosol comprising the pharmaceutically acceptable salt of the compound of Formula (I) and the carrier.

(44) The method of (43), wherein the pretreatment inhalation therapy comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C.

(45) The method of (44), comprising (i) administering to the patient via inhalation a mixture of the helium and the oxygen heated to about 90°C to about 120°C, and (ii) administering to the patient via inhalation an aerosol of the pharmaceutically acceptable salt of the compound of formula (I) in a mixture of helium and oxygen heated to about 50°C to about 60°C.

(46) The method as described in (45), which also includes repeating steps (i) and (ii) 1 to 5 times.

(47) The method of any one of (37) to (46), wherein the pharmaceutically acceptable salt of the compound of Formula (I) is delivered to the central nervous system of the patient, thereby providing at least a 25% improvement in drug bioavailability compared to oral delivery, at least a 25% increase in _Cmax compared to oral delivery, at least a 50% decrease in _Tmax compared to oral delivery, or a combination thereof.

(48) The method as described in any one of (37) to (47), wherein the aerosol is mist.

(49) The method according to any one of (37) to (48), wherein the aerosol is prepared by nebulizing the pharmaceutically acceptable salt of the compound of formula (I).

(50) The method as described in (49), wherein the nebulization is performed using a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer and a vibrating mesh nebulizer.

(51) The method of (49) or (50), wherein the nebulization is performed using a driving gas comprising nitrous oxide to entrain the pharmaceutically acceptable salt of the compound of formula (I) in a nebulized form.

(52) The method of (51), wherein the nitrous oxide is present in the driving gas at a concentration of 15% by volume to 25% by volume relative to the total volume of the driving gas.

(53) The method as described in any one of (37) to (52), wherein the aerosol is administered for 20 minutes to 60 minutes.

(54) A method of treating a patient suffering from a central nervous system (CNS) disorder and/or a psychological disorder, comprising:

A therapeutically effective amount of a pharmaceutically acceptable salt according to any one of (1) to (27) is administered to a patient.

(55) A method as described in (54), wherein the CNS disorder and/or psychological disorder is at least one selected from the group consisting of: post-traumatic stress disorder (PTSD), major depressive disorder (MDD), refractory depression (TRD), suicidal ideation, suicidal behavior, depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinogenic crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain, aphasia, childhood-onset speech fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease (Lyme disease), gambling disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, pedophilia disorder, exhibitionism disorder, voyeurism disorder, fetish disorder, sexual sadism and masochism disorder, transvestite disorder, sexual dysfunction, and obesity.

(56) The method of (54), wherein the CNS disorder and/or psychological disorder is alcohol use disorder.

(57) The method of (54), wherein the CNS disorder and/or psychological disorder is generalized anxiety disorder (GAD).

(58) The method of (54), wherein the CNS disorder and/or psychological disorder is social anxiety disorder.

(59) The method of (54), wherein the CNS disorder and/or psychological disorder is treatment-resistant depression (TRD).

(60) A pharmaceutical composition comprising:

An active salt mixture comprising (i) 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 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

A pharmaceutically acceptable vehicle.

(61) The pharmaceutical composition as described in (60), wherein the active salt mixture contains (i) 60 weight % to 98 weight % of the 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), based on the total weight of the active salt mixture, and (ii) 2 weight % to 40 weight % 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-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11), based on the total weight of the active salt mixture.

(62) A pharmaceutical composition as described in (60) or (61), wherein the active salt mixture contains (i) 90 weight % to 98 weight % of the 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), based on the total weight of the active salt mixture, and (ii) 2 weight % to 10 weight % 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-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11), based on the total weight of the active salt mixture.

(63) A pharmaceutical composition as described in any one of (60) to (62), wherein the active salt mixture comprises (i) 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-8a), and (ii) a fumarate 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-10a) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11a).

(64) A pharmaceutical composition as described in any one of (60) to (62), wherein the active salt mixture comprises (i) benzoate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _{d 3} )ethan-1-amine-1,1,2,2-d ₄ (I-8b), and (ii) benzoate 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-10b) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11b).

(65) A pharmaceutical composition as described in any one of (60) to (62), wherein the active salt mixture comprises (i) salicylate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _{d 3} )ethan-1-amine-1,1,2,2-d ₄ (I-8c), and (ii) salicylate 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-10c) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11c).

(66) A pharmaceutical composition as described in any one of (60) to (62), wherein the active salt mixture comprises (i) succinate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _{d 3} )ethan-1-amine-1,1,2,2-d ₄ (I-8d), and (ii) succinate 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-10d) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11d).

(67) A method of treating a patient suffering from a central nervous system (CNS) disorder and/or a psychological disorder, comprising:

A therapeutically effective amount of an aerosol comprising a pharmaceutically acceptable salt of any one of (1) to (27) in a carrier is administered to the patient via inhalation.

(68) The method as described in (67), wherein the aerosol is mist.

(69) The method as described in (67) or (68), wherein the carrier is air, oxygen, or a mixture of helium and oxygen.

(70) The method of (69), wherein the carrier is a mixture of the helium and the oxygen, and the mixture of the helium and the oxygen is heated to about 50°C to about 60°C before the aerosol is administered to the patient.

(71) A method as described in any one of (67) to (70), wherein the CNS disorder and/or psychological disorder is at least one selected from the group consisting of: post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholia, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinogenic crisis, social anxiety disorder, alcohol use disorder , opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain, aphasia, childhood-onset verbal fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, pedophilia disorder, exhibitionism disorder, voyeurism disorder, fetish disorder, sexual sadism and masochism disorder, transvestite disorder, paraphilia, and obesity.

(72) The method of any one of (67) to (71), wherein the CNS disorder and/or psychological disorder is alcohol use disorder.

(73) The method of any one of (67) to (71), wherein the CNS disorder and/or psychological disorder is generalized anxiety disorder (GAD).

(74) The method of any one of (67) to (71), wherein the CNS disorder and/or psychological disorder is social anxiety disorder.

(75) The method of any one of (67) to (71), wherein the CNS disorder and/or psychological disorder is treatment-resistant depression (TRD).

(76) The method as described in any one of (67) to (75), wherein the aerosol is prepared by nebulizing the pharmaceutically acceptable salt of the compound of formula (I).

(77) The method of (76), wherein the nebulization is performed using a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer, and a vibrating mesh nebulizer.

(78) The method of (76) or (77), wherein the nebulization is performed using a driving gas comprising nitrous oxide to entrain the pharmaceutically acceptable salt of the compound of formula (I) in a nebulized form.

(79) The method of (78), wherein the nitrous oxide is present in the driving gas at a concentration of 15% by volume to 25% by volume relative to the total volume of the driving gas.

(80) The method as described in any one of (67) to (79), wherein the aerosol is administered for 20 minutes to 60 minutes.

(81) A method of delivering a pharmaceutically acceptable salt as described in any one of (1) to (27) to a patient in need thereof, comprising:

A dry powder comprising the pharmaceutically acceptable salt of the compound of formula (I) is administered to the patient by inhalation via a dry powder inhaler.

(82) The method as described in (81), wherein the dry powder comprises a particle carrier having the pharmaceutically acceptable salt of the compound of formula (I) on its surface.

(83) A method as described in (82), wherein the pharmaceutically acceptable salt of the compound of formula (I) is releasably absorbed onto the surface of the particle carrier, so that after inhalation by the patient, the compound of formula (I) is released from the particle carrier in the patient's body.

(84) The method as described in (81), wherein the dry powder is formed by the pharmaceutically acceptable salt of the compound of formula (I) in the form of solid particles.

(85) The method of any one of (81) to (84), wherein the pharmaceutically acceptable salt of the compound of formula (I) is delivered to the central nervous system of the patient via pulmonary absorption.

(86) The method of any one of (81) to (85), further comprising administering a pretreatment inhalation therapy prior to administering the dry powder to the patient.

(87) The method of (86), wherein the pretreatment inhalation therapy comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C.

(88) The method of (86) or (87), wherein the pretreatment inhalation therapy and the administration of the dry powder to the patient are repeated 1 to 5 times.

(89) The method of any one of (81) to (88), wherein the pharmaceutically acceptable salt of the compound of Formula (I) is delivered to the central nervous system of the patient, thereby providing at least a 25% improvement in drug bioavailability compared to oral delivery, at least a 25% increase in _Cmax compared to oral delivery, at least a 50% decrease in _Tmax compared to oral delivery, or a combination thereof.

(90) A combination drug therapy comprising:

A pharmaceutically acceptable salt as described in any one of (1) to (27); and

N-methyl-D-aspartate (NMDA) receptor antagonist.

(91) The combination drug therapy as described in (90), wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, nitrous oxide, memantine and dextromethorphan.

(92) The combination drug therapy as described in (90) or (91), wherein the NMDA receptor antagonist is nitrous oxide.

(93) The combination drug therapy of (92), wherein the pharmaceutically acceptable salt and the nitrous oxide are provided for administration as a single aerosol.

(94) The combination drug therapy of (92), wherein the pharmaceutically acceptable salt and the nitrous oxide are provided for administration as separate dosage forms.

(95) The combination drug therapy of (94), wherein the pharmaceutically acceptable salt is provided for administration as an aerosol and the nitrous oxide is provided for administration as a therapeutic gas mixture.

(96) A method of treating a patient suffering from a central nervous system (CNS) disorder and/or a psychological disorder, comprising:

A therapeutically effective amount of a pharmaceutically acceptable salt of any one of (1) to (27) and an N-methyl-D-aspartate (NMDA) receptor antagonist is administered to the patient via inhalation.

(97) A method as described in (96), wherein the CNS disorder and/or psychological disorder is at least one selected from the group consisting of: post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholy, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinogenic crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain, aphasia, childhood-onset speech fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease (Lyme disease), gambling disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, pedophilia disorder, exhibitionism disorder, voyeurism disorder, fetish disorder, sexual sadism and masochism disorder, transvestite disorder, sexual dysfunction, and obesity.

(98) The method of (96) or (97), wherein the CNS disorder and/or psychological disorder is alcohol use disorder.

(99) The method of (96) or (97), wherein the CNS disorder and/or psychological disorder is generalized anxiety disorder (GAD).

(100) The method of (96) or (97), wherein the CNS disorder and/or psychological disorder is social anxiety disorder.

(101) The method of (96) or (97), wherein the CNS disorder and/or psychological disorder is treatment-resistant depression (TRD).

(102) The method as described in any one of (96) to (101), wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, nitrous oxide, memantine and dextromethorphan.

(103) The method as described in any one of (96) to (102), wherein the NMDA receptor antagonist is nitrous oxide.

(104) The method of (103), wherein the pharmaceutically acceptable salt and the nitrous oxide are administered to the patient as a single aerosol.

(105) The method of (103), wherein the pharmaceutically acceptable salt and the nitrous oxide are administered as separate dosage forms.

(106) The method of (105), wherein the pharmaceutically acceptable salt is administered as an aerosol and the nitrous oxide is administered as a therapeutic gas mixture.

(107) The method of (105) or (106), wherein the pharmaceutically acceptable salt and the nitrous oxide are administered sequentially.

(108) The method of (105) or (106), wherein the pharmaceutically acceptable salt and the nitrous oxide are administered substantially simultaneously.

(109) An inhalation delivery device for delivering a combination of nitrous oxide and a pharmaceutically acceptable salt of any one of (1) to (27) to a patient in need thereof by inhalation, comprising:

an inhalation outlet for administering a combination of nitrous oxide and the pharmaceutically acceptable salt to the patient;

a container configured to deliver nitrous oxide gas to the inhalation outlet; and

A device configured to generate an aerosol comprising the pharmaceutically acceptable salt and deliver it to the inhalation outlet.

(110) An inhalation delivery device as described in (109), wherein the inhalation outlet is an interface or mask that covers and locks the patient's nose and mouth.

(111) An inhalation delivery device as described in (109) or (110), wherein the device configured to generate the aerosol and deliver it to the inhalation outlet is a nebulizer.

(112) An inhalation delivery device as described in (111), wherein the nebulizer is a jet nebulizer and the nitrous oxide gas serves as a driving gas for the jet nebulizer.

(113) An inhalation delivery device as described in any one of (109) to (112), further comprising an electronic device configured to provide remote activation and operational control of the inhalation delivery device.

(114) Use of a pharmaceutically acceptable salt according to any one of (1) to (27) for treating a patient suffering from a central nervous system (CNS) disorder and/or a psychological disorder.

(115) A pharmaceutically acceptable salt as described in any one of (1) to (27) for use in therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing 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:

FIG1 illustrates a general synthetic route for preparing compounds of formula (I) (eg, compounds I-1, I-2, I-4, and I-6);

FIG2 illustrates a general synthetic route for preparing compounds of formula (I) (eg, compounds I-1, I-4, I-5, and I-8);

FIG3 shows the X-ray powder diffraction patterns of Example 6 (I-1f; glycolate), Example 9 (I-1i; hemifumarate), and Example 1 (I-1a; fumarate);

FIG4 shows the X-ray powder diffraction patterns of Example 2 (I-1b; benzoate), Example 3 (I-1c; salicylate), and Example 7 (I-1g; hemioxalate);

FIG5 shows the X-ray powder diffraction patterns of Example 5 (I-1e; oxalate), Example 4 (I-1d; succinate), and Example 8 (I-1h; hemifumarate);

FIG6 shows the X-ray powder diffraction pattern of Example 26 (I-8a; fumarate salt) compared to Example 1 (I-1a; fumarate salt);

FIG7 shows the X-ray powder diffraction pattern of Example 27 (I-8b; benzoate salt) compared to Example 2 (I-1b; benzoate salt);

FIG8 shows the X-ray powder diffraction pattern of Example 28 (I-8c; salicylate salt) compared to Example 3 (I-1c; salicylate salt);

FIG9 shows the DSC curve of Example 1 (I-1a; fumarate salt);

FIG10 shows the DSC curve of Example 2 (I-1b; benzoate salt);

Figure 11 shows the DSC curve of Example 4 (I-1d; succinate salt);

FIG12 shows the DSC curve of Example 5 (I-1e; oxalate salt);

FIG13 shows the DSC curve of Example 3 (I-1c; salicylate);

FIG14 shows the DSC curve of Example 6 (I-1f; glycolate salt);

FIG15 shows the DSC curve of Example 9 (I-1i; hemifumarate salt);

Figure 16 shows the DSC curve of Example 8 (I-1h; hemifumarate salt);

Figure 17 shows the DVS isotherm of Example 1 (I-1a; fumarate salt);

Figure 18 shows the DVS isotherm of Example 2 (I-1b; benzoate salt);

Figure 19 shows the DVS isotherm of Example 4 (I-1d; succinate salt);

Figure 20 shows the DVS isotherm of Example 3 (I-1c; salicylate);

Figure 21 shows the DVS isotherm of Example 5 (I-1e; oxalate);

Figure 22 shows the DVS isotherm of Example 6 (I-1f; glycolate salt);

Figure 23 shows the DVS isotherm of Example 8 (I-1h; hemifumarate salt);

Figure 24 shows the DVS isotherm of Example 7 (I-1g; hemioxalate salt);

FIG25 shows the ¹ H NMR spectrum of Example 1 (I-1a; fumarate salt);

FIG26 shows the ¹ H NMR spectrum of Example 2 (I-1b; benzoate salt);

FIG27 shows the ¹ H NMR spectrum of Example 3 (I-1c; salicylate);

FIG28 shows the ¹ H NMR spectrum of Example 5 (I-1e; oxalate salt);

FIG29 shows the ¹ H NMR spectrum of Example 8 (I-1h; hemifumarate salt);

FIG30 shows the ¹ H NMR spectrum of Example 6 (I-1f; glycolate salt);

FIG31 shows the ¹ H NMR spectrum of Example 4 (I-1d; succinate salt);

FIG32 shows the ¹ H NMR spectrum of Example 7 (I-1g; hemioxalate salt); and

33A-33B show single crystals of I-8b (benzoate salt) according to the molecular structure ( FIG. 33A ) and the asymmetric unit cell ( FIG. 33B ).

DETAILED DESCRIPTION

In the following detailed description of the embodiments of the present disclosure, many specific details are set forth to provide a thorough understanding of the disclosed embodiments. However, it will be apparent to those skilled in the art that the embodiments of the present disclosure may be practiced without these specific details. In other cases, well-known methods, procedures, components, and circuits are not described in detail to avoid unnecessarily obscuring various aspects of the embodiments of the present disclosure.

definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

When it is stated that a substituent or group "includes deuterium" or "comprises deuterium", it is understood that the substituent or group itself can be deuterium, or the substituent or group can contain at least one deuterium substitution in its chemical structure. For example, when the substituent "-R" is defined as including deuterium, it is understood that -R can be -D (-deuterium), or a group consistent with the other requirements indicated for -R, such as _-CD3 .

As used herein, the term "fat" describes a compound having a long chain (linear) hydrophobic moiety consisting of hydrogen and anywhere from 4 to 26 carbon atoms, which may be fully saturated or partially unsaturated.

The phrases "pharmaceutically acceptable", "physiologically acceptable", etc. are used herein to refer to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salts", "physiologically acceptable salts", etc. mean salts that are acceptable for administration to patients (e.g., mammals) (salts with counterions that have acceptable mammalian safety for a given dosage regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases, such as sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium salts, and the like, and, when the molecule contains a basic functional group, addition salts with inorganic acids, such as hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, nitrates, perchlorates, and the like, and addition salts with organic acids, such as formates, tartrates, benzenesulfonates, methanesulfonates, acetates, maleates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemioxalates, hemifumarates, propionates, stearates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, toluenesulfonates, edisylate, isethionates, and the like.

"Solvate" refers to the physical combination of a compound or salt of the present disclosure with one or more solvent molecules, which are organic, inorganic or a mixture of the two. This physical association includes hydrogen bonds. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The solvent molecules in the solvate can exist in a conventional arrangement and/or a non-ordered arrangement. The solvate can include stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" covers both solution phase and separable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Therefore, exemplary solvates include, but are not limited to, hydrates, methanol esters, ethanol esters, isopropanol esters, etc. The method of solvation is well known in the art.

"Stereoisomers" and "stereoisomers" refer to compounds with the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms are contemplated herein, such as racemates and optically pure stereoisomers of compounds. Chemical formulas and compounds with at least one stereocenter but without reference to stereochemistry are intended to cover racemic compounds as well as individual stereoisomers, such as both R-stereoisomers and/or S-stereoisomers, each permutation of diastereomers (as long as those diastereomers are geometrically feasible), etc.

A "crystalline" solid is a solid whose basic three-dimensional structure contains a highly regular atomic or molecular diagram-with long-range order-to form a lattice, and therefore shows sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) diagram. In some cases, a crystalline solid can exist in different crystalline forms called "polymorphs", which have the same chemical composition but differ in terms of packing, geometric arrangement and other descriptive properties in the crystalline solid state. Therefore, polymorphs can have different solid-state physical properties to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, fluidity and compressibility of the compound, as well as the safety and efficacy of the drug product based on the compound. In the process of preparing polymorphs, further purification can also be performed in terms of total physical purity or optical purity. As used herein, the term "amorphous" refers to a solid material that is essentially free of long-range order in the position of its molecules-molecules are arranged in a random manner, so that there is actually no well-defined arrangement, such as molecular packing, and there is no long-range order. Amorphous solids are usually isotropic, that is, they exhibit similar properties in all directions and do not have a definite melting point. For example, an amorphous material is a solid material that does not substantially have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., not crystalline as determined by XRPD). In contrast, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Therefore, the "amorphous" subject compound/material is characterized by 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., 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, in some embodiments, the crystallinity % can be determined by determining the intensity of one or more peaks in the XRPD diffraction pattern compared to a reference peak, which can be a reference peak of a known standard or internal standard. Other characterization techniques, such as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods may also be used to determine the percentage of the subject compound/material that is amorphous or crystalline, including quantitative methods that provide such percentages in terms of weight percent.

When referring to the X-ray powder diffraction (XRPD) pattern of the materials of the present disclosure, the phrase "characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from ... " is understood to include those materials characterized by having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (including all) of the listed characteristic XRPD diffraction peaks. In addition, this phrase is intended to include other XRPD diffraction peaks that are not listed.

It should be understood that the compounds herein may exist in different salts, solvates, stereoisomers, crystalline/amorphous (including polymorphic) forms and the present disclosure is intended to include all permutations thereof, such as solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds.

"Vapor" is a solid substance in the gaseous phase at a temperature below its critical temperature, which means that vapor can be condensed into a liquid by increasing the pressure without lowering the temperature.

As used herein, "aerosol" is a suspension of fine solid particles or droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide and other gases, and mixtures thereof). As used herein, "mist" is a subset of aerosol, different from steam, and is a dispersion of droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium and mixtures thereof). The droplets of an aerosol or mist may include a drug portion dissolved in an aqueous liquid, an organic solvent or a mixture thereof. The gas phase of an aerosol or mist may include air, oxygen, helium or other gases, including mixtures thereof. Mist does not include solid particles. Aerosols and mist of the present disclosure may be produced by any suitable method and apparatus, examples of which are described herein, such as by using an inhaler or a nebulizer.

As used herein, the term "slow release" describes the release time period of certain formulations of the present disclosure, which are formulated to increase the release time period, for example, to a maximum value, and in the case of oral formulations, the release time period is ultimately limited to the time when the gastrointestinal tract naturally excretes all drugs with food. As used herein, the term "release time period" describes the time window in which any compound described herein is released from a vehicle (e.g., a matrix) to provide a plasma concentration of a compound described herein. The start time of the release time period is defined from the point of administration to the subject, and when orally ingested, it is considered to be almost equivalent to entering the stomach and starting to dissolve by gastric enzymes and gastric acid. The end time of the release time period is defined as the point at which the entire loaded drug is released. In some embodiments, the release time period may be greater than about 4 hours, 8 hours, 12 hours, 16 hours, or 20 hours, greater than or equal to about 24 hours, 28 hours, 32 hours, 36 hours, or 48 hours, or less than about 48 hours, 36 hours, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

The term "tamper-resistant" is art-recognized and is used to describe those aspects of a drug formulation that make it more difficult to use the formulation to abuse the drug portion of the formulation, such as extraction for intravenous use or crushing for free base use; and thus reduce the risk of drug abuse.

As used herein, the terms "stable", "stability" and the like include chemical stability and solid state (physical) stability. The term "chemical stability" means that the compound can be stored under normal storage conditions in an isolated form or in the form of a formulation, wherein the compound is mixed with, for example, a pharmaceutically acceptable carrier, diluent or adjuvant as described herein, and there is little or no chemical degradation or decomposition. "Solid state stability" means that the compound can be stored under normal storage conditions in an isolated solid form or in the form of a solid formulation, wherein the compound is mixed with, for example, a pharmaceutically acceptable carrier, diluent or adjuvant as described herein, and there is little or no solid state transformation (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization or solid state phase transition).

As used herein, the term "composition" is equivalent to the term "formulation".

As used herein, the term "inhalation phase" describes a dosing event in which a patient inhales a given dose of a drug, regardless of the number of breaths required to inhale the given dose. For example, a subject prescribed 10 mg of a drug twice a day will undergo two inhalation phases, each providing 10 mg of the drug. The length of time and number of breaths during each inhalation phase depend on a variety of factors, such as the inhalation device used, the amount of drug inhaled per breath, the concentration of the drug in the dosage form, the patient's breathing pattern, etc.

As used herein, the term "treating" or "treatment" means to treat or cure a disease or medical condition in a patient, such as a mammal (particularly a human), including: ameliorating the disease or medical condition, such as eliminating or causing regression of the disease or medical condition in the patient; inhibiting the disease or medical condition, such as by slowing or arresting the development of the disease or medical condition in the patient; or alleviating one or more symptoms of the disease or medical condition in the patient. Treatment can provide a therapeutic benefit, such as eradicating or ameliorating one or more physiological or psychological symptoms associated with the underlying condition, disease, or disorder, such that an improvement is observed in the patient, despite the fact that the patient may still be affected by the condition. In some embodiments, treatment can refer to prevention, i.e., preventing the occurrence of a disease or medical condition or delaying the onset of a disease or medical condition in a patient.

A "patient" or "subject," as used interchangeably herein, may be any mammal, including, for example, a human. A patient or subject may have a condition to be treated or may be susceptible to a condition to be treated.

As used herein, and unless otherwise indicated, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Typically, the beneficial effects a subject receives from a prophylactic and/or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term "management" encompasses treating a subject with a specific disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition, or one or more symptoms thereof.

"Therapeutically effective amount" refers to an amount of a compound or its salt form sufficient to treat a particular condition or disease or one or more of its symptoms and/or prevent the occurrence of a disease or condition (prophylactic effective amount). As used herein, and unless otherwise indicated, a "prophylactic effective amount" of an active agent is an amount sufficient to prevent a disease, condition or symptom or to prevent its recurrence. The term "prophylactic effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

The term "administration schedule" is a plan of type, amount, cycle, procedure, etc. The drugs in the drug therapy are shown in a time series, and the dosage, administration method, administration order, administration date, etc. of each drug are indicated. The specified administration date is determined before the administration of the drug begins. Through the repetitive process, a set of administration schedules are continuously administered as a "process". A "continuous" administration schedule means that it is administered every day without interruption during the treatment process. If the administration schedule follows an "intermittent" administration schedule, the administration day may be followed by a "rest day" or a day when the drug is not administered within the process. A "drug holiday" indicates that the drug is not administered in a predetermined administration schedule. For example, after undergoing several courses of treatment, for example, before resuming active treatment, a subject may be prescribed a constrained drug holiday as part of the administration schedule.

The term "toxic peak" is used herein to describe the peak concentration of any compound described herein that will produce sedative or psychotomi c side effects, such as hallucinations, dizziness, and nausea; this will not only have a direct impact, but also affect treatment compliance. Specifically, side effects may become more significant at blood concentration levels above about 300 ng/L (e.g., above about 300 ng/L, 400 ng/L, 500 ng/L, 600 ng/L, or more ng/L).

As used herein and unless otherwise specified, a "neuropsychiatric disease or disorder" is a behavioral or psychiatric problem associated with a known neurological condition and generally defined as a coexisting cluster of symptoms. Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive deficits in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar and manic disorders, depression, or any combination thereof.

As used herein, "inflammatory conditions" or "inflammatory diseases" broadly refer to chronic or acute inflammatory diseases. Inflammatory conditions and inflammatory diseases include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis); spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome); crystalline arthropathy (e.g., gout, pseudogout, calcium pyrophosphate deposition disease); multiple sclerosis; Lyme disease; polymyalgia rheumatica; connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome); vasculitis (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome); syndrome); inflammatory conditions, including consequences of trauma or ischemia; sarcoidosis; vascular diseases, including atherosclerotic vascular disease, atherosclerotic and vascular occlusive disease (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; eye diseases, including uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

All diseases and conditions listed herein may be defined as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

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 specification herein and throughout the claims below, the meaning of "a", "an", and "the" includes plural referents as well as singular referents unless the context clearly indicates otherwise. The term "about" in relation to a numerical value means that the value may vary up or down by 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

Compounds and salt forms

Disclosed herein is a pharmaceutically acceptable salt of a compound of formula (I) or a stereoisomer, solvate or prodrug thereof,

in:

_X1 and _X2 are independently hydrogen or deuterium,

_Y1 and _Y2 are independently hydrogen or deuterium,

R ₂ , R ₄ , R ₅ , R ₆ and R ₇ are independently hydrogen or deuterium, and

R ₈ and R ₉ are independently selected from the group consisting of -CH ₃ , -CDH ₂ , -CD ₂ H and -CD ₃ .

X ₁ and X ₂ can be the same or different. In some embodiments, X ₁ and X ₂ are the same. In some embodiments, X ₁ and X ₂ are hydrogen. In some embodiments, X ₁ and X ₂ are deuterium. In some embodiments, X ₁ is deuterium and X ₂ is hydrogen.

Y ₁ and Y ₂ may be the same or different. In some embodiments, Y ₁ and Y ₂ are the same. In some embodiments, Y ₁ and Y ₂ are hydrogen. In some embodiments, Y ₁ and Y ₂ are deuterium. In some embodiments, Y ₁ is deuterium and Y ₂ is hydrogen.

In some embodiments, Xi, _X2 , _Y1 and _{Y2 are hydrogen. In some embodiments, Xi, X2 , Y1 and Y2} are deuterium.

In some embodiments, R ₂ is deuterium. In some embodiments, R ₂ is hydrogen.

In some embodiments, R ₄ is deuterium. In some embodiments, R ₄ is hydrogen.

In some embodiments, R ₅ is deuterium. In some embodiments, R ₅ is hydrogen.

In some embodiments, R ₆ is deuterium. In some embodiments, R ₆ is hydrogen.

In some embodiments, R ₇ is deuterium. In some embodiments, R ₇ is hydrogen.

_R2 , _R4 , _R5 , _R6 and _R7 can be the same, for example, _R2 , _R4 , _R5 , _R6 and _R7 can each be hydrogen, or alternatively, _R2 , R4, _R5 , _R6 and _R7 can 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.

R ₈ and R ₉ may be the same or different. In some embodiments, R ₈ and R ₉ are the same. In some embodiments, R ₈ and R ₉ are methyl (-CH ₃ ). In some embodiments, R ₈ and R ₉ are partially deuterated methyl, i.e., -CDH ₂ or -CD ₂ H. In some embodiments, R ₈ and R ₉ are fully deuterated methyl (-CD ₃ ).

In some embodiments, at least one of X ₁ , X ₂ , Y ₁ , Y ₂ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ comprises deuterium. In some embodiments, at least X ₁ , X ₂ , R ₈ , and R ₉ comprises deuterium. In some embodiments, at least X _{1 , X 2 , Y 1 , Y 2 , R 8 , and R 9 comprises deuterium. In some embodiments, X 1 ,} X ₂ , Y ₁ , Y ₂ , R 8 , and R ₉ comprise deuterium. In some embodiments, X ₁ , X ₂ , Y ₁ , and Y ₂ are deuterium, and R ₈ and R ₉ are fully deuterated methyl (-CD ₃ ).

Without being bound by any particular theory, it is believed that the compounds described herein with site-specific deuteration (e.g., in the exocyclic moiety) retain preferential agonism of the serotonin 5-HT ₂ receptor, have improved exposure (e.g., preventing high drug concentrations (peaks) observed acutely after administration), and have favorable enzymatic degradation characteristics to improve bioavailability and brain penetration. For example, compounds of Formula (I) containing deuterium substitutions can advantageously slow enzymatic degradation compared to compounds that may be susceptible to MAO-mediated deamination/oxidation processes of, for example, indoleacetic acid (IAA) metabolites, thereby improving bioavailability and increasing brain levels of active compounds, with the goal of effectively reducing therapeutic doses and preventing high drug concentrations ("peaks") observed acutely after administration. Thus, such compounds can result in reduced side effects and toxicity, including toxicity caused by activation of 5-HT _2B receptors associated with valvular heart disease.

Formula (I) compounds may contain stereocenters. In such cases, although formula (I) is extracted without reference to stereochemistry, compounds may exist in different stereoisomeric forms. Therefore, the disclosure includes all possible stereoisomers, and not only includes racemic compounds, but also includes each enantiomer (enantiomerically pure compound), each diastereomer (diastereomerically pure compound) and its non-racemic mixture. When a compound in the form of a single enantiomer is required, this can be obtained by stereospecific synthesis, splitting the final product or any convenient intermediate or by chiral chromatography methods known in the art. The splitting of the final product, intermediate or raw material can be carried out by any suitable method known in the art.

In some embodiments, compounds as described herein, such as compounds of formula (I) are non-stereoscopic. In some embodiments, compounds as described herein, such as compounds of formula (I) are racemic. In some embodiments, compounds as described herein, such as compounds of formula (I) are enantiomerically enriched (one enantiomer is present in a higher percentage), comprising enantiomerically pure. In some embodiments, compounds as described herein, such as compounds of formula (I) are provided as single diastereomers. In some embodiments, compounds as described herein, such as compounds of formula (I) are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture may comprise an equal mixture, or a mixture enriched with a specific diastereomer (one diastereomer is present in a higher percentage than another).

In some embodiments, the compound of Formula (I) is an agonist of the serotonin 5- _HT2 receptor.

In some embodiments, the compound of Formula (I) is an agonist of the serotonin 5-HT _2A receptor.

In some embodiments, the compound of formula (I) is selected from the group consisting of:

Table 1 provides the compound numbers, IUPAC names and substituent lists of the above compounds.

Table 1. Exemplary compounds of formula (I)

Acids useful for preparing the pharmaceutically acceptable (acid addition) salts disclosed herein 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, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, naphthalene-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, cyclohexylaminosulfonic acid, cyclohexaneaminosulfonic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactonic acid, glucoheptonic acid, D-glucose acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric 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, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, palmitic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, sugar acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (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, such as adipic/hexandioic acid) acid), lauric acid (dodecanoic acid), linoleic acid, myristic acid (tetradecanoic acid), capric acid (decanoic acid), stearic acid (octadecanoic acid), oleic acid, caprylic acid (octanoic acid), palmitic acid (hexadecenoic acid), sebacic acid, undecenoic acid, caproic acid, etc.).

Certain salts are preferred in the above list because they have physical and pharmaceutical characteristics/properties that make them suitable for pharmaceutical preparation and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of formula (I)) are those having one or more of the following characteristics: being easy to prepare in high yield and being prone to salt formation; being stable and having well-defined physical properties, such as crystallinity, lack of polymorphism, and high melting/fusion enthalpy; being slightly hygroscopic or non-hygroscopic; being free-flowing, non-sticky/adherent to surfaces, and having a regular morphology; having acceptable water solubility for the intended route of administration; and/or being physiologically acceptable, especially for pulmonary administration, e.g., not causing irritation when administered to the lungs.

Crystallinity

The pharmaceutically acceptable salt of the compound of formula (I) may be crystalline or amorphous, preferably crystalline, as determined by, for example, X-ray powder diffraction (XRPD). In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is amorphous. Compared with their crystalline counterparts, amorphous forms generally have higher water solubility and dissolution rate, and therefore may be very suitable for fast-acting dosage forms suitable for rapid release of active ingredients, such as oral dispersible dosage forms, immediate release (IR) dosage forms, etc. The pharmaceutically acceptable salt of the compound of formula (I) may be in a stable amorphous form. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is provided in an amorphous form, for example, as determined by XRPD and/or DSC. Therefore, the pharmaceutical composition can be prepared from a pharmaceutically acceptable salt form of the compound of formula (I) in one or more amorphous forms, and can be used for treatment as described herein. In some embodiments, a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of formula (I) is provided. For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of a compound of formula (I), 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 formula (I) present in the pharmaceutical composition is in amorphous form, for example, as determined by X-ray powder diffraction and/or DSC.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is crystalline. Crystalline forms are advantageous in terms of, for example, stability and providing clear physical properties, which is ideal for drug preparation and administration. The pharmaceutically acceptable salt of the compound of formula (I) can be in a stable crystalline form. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) has a crystallinity percentage 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 the pharmaceutically acceptable salt of the compound of formula (I) is provided. For example, a pharmaceutical composition may include a pharmaceutically acceptable salt of a compound of formula (I), wherein at least 90% by weight, at least 95% by weight, at least 99% by weight or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of formula (I) present in the pharmaceutical composition is in a crystalline form, for example, as determined by X-ray powder diffraction and/or DSC. Salt forms with a high degree of crystallinity are preferred, as determined, for example, by discrete and sharp Bragg diffraction in an X-ray diffraction pattern.

XRPD analysis can be performed using CuKα radiation The diffractometer is a Bruker D5000 X-ray powder diffractometer. The instrument can 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 to 2 mm, and the detector slit width can be set to 0.2 mm. The diffracted radiation can be detected by a NaI scintillation detector. A θ-2θ continuous scan from 2.0 to 40° can be used (4 seconds per step; 0.01 step length).

With regard to pharmaceutical production processes, advantageous salt forms of compounds of formula (I) are those which readily afford crystalline solids in acceptable yields upon crystallization without proceeding via oil, and which have a favourable bulk factor making them suitable for large-scale production.

The salt forms of the compound of formula (I) may exist in different polymorphs (i.e., forms with different crystal structures), however, the preferred salt forms of the present disclosure are salt forms that can crystallize into a single crystalline form or a single polymorph, as determined by XRPD and/or differential scanning calorimetry (DSC). It is also generally desirable that the salts are free-flowing, non-sticky/adherent to surfaces, and have a regular morphology.

Chemical/solid state stability

In some embodiments, the pharmaceutically acceptable salts of the compound of Formula (I) have a melting onset temperature of about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160°C, about 170°C, about 180°C, 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, pharmaceutically acceptable salts of compounds of Formula (I) have enthalpy of fusion of about 90 J·g ^-1 , about 100 J·g ^-1 , about 110 J·g ^-1 , about 120 J·g- ¹ , about 130 J·g ^-1 , about 140 J·g ^-1 , about 150 J·g- ¹ , 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.

The characteristics of the pharmaceutically acceptable salts of the compounds of formula (I) suitable for drug manufacture can also be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic. Hygroscopicity can be measured herein by performing a moisture sorption-desorption isotherm using a dynamic vapor sorption (DVS) analyzer with an initial exposure of 30% relative humidity (RH), increasing the humidity to 95% RH, reducing the 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: enough water is absorbed to form a liquid; All values measured are weight gain (w/w, due to water acquisition) at >95% RH and 25°C.

In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) has a weight gain 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, 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 at >95% RH as determined by DVS.

The dry powder samples of the pharmaceutically acceptable salts disclosed herein can be preserved/stored in an open or closed environment, such as in an open or closed flask/vial, under ambient or pressure conditions, such as 25°C/60%RH, 25°C/90+%RH, 40°C/75%RH, etc., without significant degradation (e.g., no significant reduction in chemical purity) or physical changes (e.g., morphological changes, deliquescence, etc.). For example, when stored under ambient or pressure conditions (e.g., elevated temperature, such as 40°C and/or humidity), the purity or form change of the dry powder samples of the salt forms disclosed herein may be less than 10%, less than 5%, less than 1%.

The solution phase composition (e.g., liquid dosage form) of the pharmaceutically acceptable salt of the present disclosure can be preserved/stored in an open or closed environment, such as an open or closed flask/vial, under ambient or pressure conditions, such as 25°C/90+%RH, 40°C/75%RH, etc., without significant degradation. Therefore, in some embodiments, the present disclosure provides a stable solution phase composition (e.g., liquid dosage form) of a pharmaceutically acceptable salt form of a compound of formula (I) (e.g., a stable solvate of a salt form of a compound of formula (I) in a solvated form, preferably a fully solvated form), which can be stored as a solution, such as in the form of an aqueous solution, an organic solvent solution, or a mixed aqueous-organic solvent solution for a long time without significant degradation or physical changes, such as seeping out of the solution. The solvent that can be used to form the solution phase composition can be any one or more solvents described herein, such as water, ethanol, fruit juice, etc. In some embodiments, the solution phase composition is an aqueous solution phase composition comprising a pharmaceutically acceptable salt of a compound of formula (I) solvated with water (and optionally comprising other components, such as those found in fruit juice). Identifying stable solution phase compositions is advantageous at least because such compositions need not be used immediately after preparation, such as within 5 minutes, within 4 minutes, within 3 minutes, within 2 minutes, within 1 minute, within 45 seconds, within 30 seconds, within 15 seconds, within 10 seconds after preparation. In contrast, stable solution phase compositions (e.g., liquid dosage forms) of pharmaceutically acceptable salts of compounds of Formula (I) described herein can be prepared in advance, optionally stored as needed, and can be administered hours, days, or even weeks after preparation without substantial effects on efficacy, such as without significant degradation of dimethyltryptamine type active substances.

In some embodiments, the aqueous solution formed by the pharmaceutically acceptable salt of the compound of formula (I) is characterized by increased stability compared to the aqueous solution prepared by the compound of formula (I) (free alkali), but is substantially the same in other respects. For example, compared with the aqueous solution prepared by the compound of formula (I) (free alkali), the pharmaceutically acceptable salt of the compound of formula (I) is more stable in the aqueous solution for 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks or longer at 40 ° C. by 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%, but is substantially the same in other respects. Such improved stability behavior can also be found in the pharmaceutical composition of the present disclosure.

Physiological acceptability

Suitable salt forms of the compounds of formula (I) are physiologically acceptable. Specifically, when formulated for pulmonary administration, suitable salt forms are salt forms that do not cause excessive stimulation, because pulmonary irritation may cause coughing after inhalation, which may have an adverse effect on the patient's compliance and therapeutic effect, because it is known that coughing can reduce the delivered dose. For this reason, the addition salt of the preferred compound of formula (I) is a salt formed with an organic acid, preferably an organic acid with weak acidity, such as an organic acid with pKa _of not less than 1.0, not less than 1.5, not less than 2.0, not less than 2.5, not less than 3.0, not less than 3.5, not less than 4.0, not less than 4.5, such as 3.0 to 6.5 in water. Further, it is also desirable to use acid addition salts that impart pleasant taste characteristics (e.g., sweetness, citrus flavor, etc.), but salt forms with poor taste (e.g., bitterness, roughness, etc.) are still acceptable, depending on, for example, the route of administration and taste masking agents, such as the optional use of sweeteners, flavoring agents, etc.

Solubility

The water solubility of the compound of formula (I) and its salt can be determined by balancing the 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 HPLC, and the solubility can be expressed as its free base equivalent (mg FB/mL). For example, a pharmaceutically acceptable salt of the compound of formula (I) can be prepared, and the solubility and solution pH can be measured.

In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has an aqueous solubility of about 5 mg/mL to about 400 mg/mL at 22°C. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) has an aqueous solubility of about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 5 mg/mL, about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, 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. In some embodiments, the salt of the compound of formula (I) has a water solubility of about 200 mg/mL to about 400 mg/mL. In some embodiments, the salt of the compound of formula (I) has a water solubility of about 150 mg/mL to about 250 mg/mL. In some embodiments, the salt of the compound of formula (I) has a water solubility 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 formula (I) is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate or hemifumarate of the compound of formula (I). In terms of providing the desired physical and pharmaceutical properties (such as those described above), preferred pharmaceutically acceptable salts are fumarates, benzoates, salicylates and succinates of the compounds disclosed herein (e.g., compounds of formula (I)), with fumarates, benzoates and salicylates being particularly preferred.

Exemplary pharmaceutically acceptable salt forms (ie, addition salt forms) of the above compounds are provided in Table 2.

Table 2: Exemplary pharmaceutically acceptable salts of compounds of formula (I)

In some embodiments, the pharmaceutically acceptable salt is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a) (ie, a fumarate salt of Compound I-1 depicted below). In some embodiments, Salt I-1a is in the form of a crystalline solid, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIGS. 3 and 6 .

In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b) (ie, the benzoate salt of compound I-1 depicted above). In some embodiments, Salt I-1b is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIGS. 4 and 7 .

In some embodiments, the pharmaceutically acceptable salt is the salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c) (ie, the salicylate salt of Compound I-1 depicted above). In some embodiments, Salt I-1c is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIGS. 4 and 8 .

In some embodiments, the pharmaceutically acceptable salt is the succinate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d) (ie, the succinate salt of compound I-1 depicted above). In some embodiments, Salt I-1d is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 5 .

In some embodiments, the pharmaceutically acceptable salt is the oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1e) (ie, the oxalate salt of compound I-1 depicted above). In some embodiments, Salt I-1e is in the form of a crystalline solid, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 5 .

In some embodiments, the pharmaceutically acceptable salt is the glycolate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1f) (ie, the glycolate salt of compound I-1 depicted above). In some embodiments, Salt I-1f is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 3 .

In some embodiments, the pharmaceutically acceptable salt is a hemioxalate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1g) (i.e., a hemioxalate of compound I-1 described above). In some embodiments, salt I-1g is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the following: 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°, 2 4°, 2.1°, 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 CuKa radiation source, for example, as shown in FIG.

In some embodiments, the pharmaceutically acceptable salt is a hemifumarate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1h) (i.e., a hemifumarate of compound I-1 depicted above). In some embodiments, salt I-1h is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at a diffraction angle (2θ±0.2°) selected from the following: 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°, 2 5 .

In some embodiments, the pharmaceutically acceptable salt is 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-8a) (ie, a fumarate salt of compound I-8 depicted below). In some embodiments, the salt I-8a is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from the group consisting of 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°, 24.7°, 25.9°, 26.1°, 27.3°, 28.4°, 29.8°, 30.9°, 31.1°, 32.4°, 33.5°, 34.7°, 35.8°, 36.9°, 37.9°, 38. 6°, 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 CuKa radiation source, for example, as shown in FIG. In some embodiments, salt I-8a is in the form of a crystalline solid, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 6 . In some embodiments, Salt I-8a is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of: 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, e.g., as shown in FIG. 6 .

In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8b) (ie, the benzoate salt of compound I-8 depicted above). In some embodiments, salt I-8b is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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 CuKa radiation source, e.g., as shown in FIG. 7. In some embodiments, salt I-8b is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 7 . In some embodiments, Salt I-8b is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 7 .

In some embodiments, the pharmaceutically acceptable salt 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). In some embodiments, the salt I-8c is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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°, 23.4°, 24.8°, 25.7°, 26.9°, 27.0°, 28.1°, 29.2°, 30.3°, 31.4°, 32.5°, 33.7°, 34.8°, 35.9°, 36.9°, 37.1°, 38.1°, 39. 8 as determined by XRPD using a CuKa radiation source, for example, as shown in FIG8 . In some embodiments, salt I-8c is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 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, e.g., as shown in FIG. 8 . In some embodiments, salt I-8c is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of: 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, e.g., as shown in FIG. 8 .

In some embodiments, the pharmaceutically acceptable salts of the present disclosure are in the form of solvates. Examples of solvate forms include but are not limited to hydrates, methanolates, ethanolates, isopropanolates, etc., preferably hydrates and ethanolates. Solvates can be formed by stoichiometric or non-stoichiometric amounts of solvent molecules. In a non-limiting example, as a hydrate, the pharmaceutically acceptable salts herein can be monohydrates, dihydrates, etc.

Also disclosed herein is a method for stabilizing a compound of formula (I). The method comprises preparing a pharmaceutically acceptable salt of a compound of formula (I).

Also disclosed herein is a method for preparing a pharmaceutically acceptable salt of a compound of formula (I). Various methods and steps for forming addition salts are known to those of ordinary skill in the art, any of which may be used in the present disclosure. In some embodiments, the method comprises:

(a) suspending the free base of the compound of formula (I) in a solvent or a solvent mixture;

(b) contacting an acid with the compound of formula (I) to provide a mixture;

(c) optionally heating the mixture;

(d) optionally cooling the mixture; and

(e) isolating the salt.

Various solvents can be used in the disclosed method, including one or more protic solvents, one or more aprotic solvents or mixtures thereof. In some embodiments, the solvent used in the method for preparing the salt is a protic solvent. In some embodiments, the solvent used in the method for preparing the salt is selected from the group consisting of: methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., tert-butyl methyl ether (TBME)), hexane, heptane and octane and combinations thereof. In some embodiments, the solvent is ethanol.

Suitable acids for preparing pharmaceutically acceptable acid addition salts may include those acids described hereinbefore. Acid may be an inorganic acid or an organic acid, preferably an organic acid. In some embodiments, 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, acid is an organic acid selected from the group consisting of: fumaric acid, benzoic acid, salicylic acid, and succinic acid, preferably fumaric acid, benzoic acid, and salicylic acid.

In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with a compound of formula (I). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with a compound of formula (I). 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 use of a substoichiometric amount of acid may be desirable.

In some embodiments, the mixture is heated, such as to reflux, prior to cooling.

In some embodiments, the mixture is cooled and the salt is precipitated out of 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.

The separation of the salts can be performed by various well-known separation techniques, such as filtration, decantation, etc. In some embodiments, the separation step comprises filtering the mixture.

After isolation, additional crystallization and/or recrystallization steps may optionally be performed, if desired, for example to increase purity, crystallinity, etc.

Therapeutic applications and methods

Also disclosed herein is a method of treating a subject suffering from a disease or condition comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I).

The dosage and frequency (single dose or multiple doses) of the salt of the compound administered may vary according to a variety of factors, including but not limited to the salt form/compound to be administered; the disease/condition to be treated; the route of administration; the size, age, sex, health, weight, body mass index and diet of the recipient; the nature of the disease to be treated and the extent of the symptoms; the presence of other diseases or other health-related problems; the type of concurrent treatment; and complications from any disease or treatment regimen. Other treatment regimens or agents may be used in conjunction with the methods and compounds disclosed herein.

The therapeutically effective amount for humans can be determined from animal models. For example, the dosage for humans can be adjusted to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring the response to treatment and adjusting the dosage upward or downward.

The dosage can vary according to the needs of the subject and the form of the compound or its salt used. In the context of the pharmaceutical compositions presented herein, the dosage administered to the subject should be sufficient to affect the beneficial therapeutic response of the subject over time. The size of the dosage will also be determined by the presence, nature and extent of any adverse side effects. In general, treatment is started with a smaller dosage that is less than the optimal dosage of the compound. Thereafter, the dosage is increased in small increments until the optimal effect in a variety of situations is achieved.

Dosage amount and interval can be adjusted individually to provide levels of the administered compound that are effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

Administration routes may include oral routes (e.g., enteral/gastric delivery, intraoral administration, such as buccal, lingual, and sublingual routes), parenteral routes (e.g., intravenous, intradermal, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration), topical routes (e.g., conjunctival, intracorneal, intraocular, intraocular, intraaural, transdermal, nasal (e.g., intranasal), vaginal, urethral, respiratory, and rectal administration), inhalation, or other methods sufficient to produce a beneficial therapeutic response.

Administration can follow a continuous administration schedule or an intermittent administration schedule. The administration schedule can vary according to the salt form and compound used, the disease treated, the route of administration, etc. For example, administration can be once a day (QD), or with divided doses all day, such as 2 times a day (BID), 3 times a day (TID), 4 times a day (QID) or more. In some embodiments, administration can be performed at night (QHS). In some embodiments, the compound/pharmaceutical composition can be administered as needed (PRN). Administration can also be performed weekly, for example, once a week, twice a week, three times a week, four times a week, every other week, every two weeks, etc. or less. The administration schedule can also specify the prescribed number of treatments for each course of treatment, for example, each course of treatment can be administered 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times or 8 times. Using reasonable medical judgment, other administration schedules may also be considered appropriate.

Administration can be continuous (administered 7 days a week) or intermittent, for example, depending on the pharmacokinetics of the drug and the clearance/accumulation of a particular subject. If intermittent, the schedule can be, for example, 4 days of administration and 3 days of rest (rest day) in a week or any other intermittent dosing regimen deemed appropriate using reasonable medical judgment. For example, intermittent administration can involve the administration of a single dose within a course of treatment. Whether it is continuous or intermittent administration, a specific course of treatment is continued, usually at least a 28-day cycle (1 month), which can be repeated with or without a drug holiday. Longer or shorter courses of treatment 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 of treatment can be repeated without a drug holiday or with a drug holiday, depending on the subject. Other schedules are possible, depending on the presence or absence of adverse events, the response to treatment, patient convenience, etc.

Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause significant toxicity or adverse side effects (e.g., caused by sedative or hallucinogenic toxicity spikes in plasma concentrations of any compound of Formula (I)), and yet is overall effective in treating the clinical symptoms exhibited by a particular patient. This planning should involve careful selection of active compounds and salt forms by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

The therapeutically effective dosage of the compounds in salt form disclosed herein may vary depending on the various factors mentioned above, but generally provides an amount of the compound of formula (I) of about 0.00001 mg to about 10 mg per kilogram of recipient body weight per day, or any range therebetween, for example, 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 0.01 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 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg, about 10.0 mg/kg of a compound of formula (I) (active substance).

Pharmaceutically acceptable salts of the compounds of the present disclosure may be administered in hallucinogenic doses. In some embodiments, the hallucinogenic dose of the compound of formula (I) (in terms of activity) administered orally or otherwise may be in the range of about 0.083 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.35 mg/kg, about 0.4 mg/kg, about 0.45 mg/kg, about 0.5 mg/kg, and up to about 5 mg/kg, about 4 mg/kg, about 3 mg/kg, about 2 mg/kg, about 1 mg/kg, about 0.95 mg/kg, about 0.9 mg/kg, about 0.85 mg/kg, about 0.8 mg/kg, about 0.75 mg/kg, about 0.7 mg/kg, about 0.65 mg/kg, about 0.6 mg/kg, about 0.55 mg/kg. In some embodiments, as described above, higher doses may also be used. In some embodiments, the hallucinogenic dose is administered once, with the possibility of repeated administration at intervals of at least one week. In some cases, no more than 5 doses are given in any one course of treatment. The course of treatment can be repeated as needed with or without a drug holiday. Such acute treatment regimens can be accompanied by psychotherapy before, during and/or after the hallucinogenic dose. These treatments are applicable to various mental health disorders disclosed herein, examples of which include but are not limited to major depressive disorder (MDD), refractory depression (TRD), anxiety disorders, and substance use disorders (e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking and cocaine use disorder).

In some embodiments, administration of subpsychoactive (but still potentially serotonergic) concentrations may be performed to achieve sustained therapeutic benefit while reducing toxicity, and thus may be amenable to microdosing. In some embodiments, the sub-hallucinogenic dose of the compound of formula (I) (in terms of activity) administered orally or otherwise may be in the following range: 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, and up to about 0.083 mg/kg, about 0.08 mg/kg, about 0.075 mg/kg, about 0.07 mg/kg, about 0.06 mg/kg, about 0.05 mg/kg, about 0.04 mg/kg, about 0.03 mg/kg, about 0.02 mg/kg. Typically, a sub-hallucinogenic dose is administered daily in a course of treatment (e.g., 1 month). However, the number of doses at sub-psychedelic levels is not limited - dosing may be less frequent or more frequent as appropriate. Sessions may be repeated as needed with or without drug holidays.

Administration of the subhallucinogenic agent may be carried out, for example, by transdermal delivery, subcutaneous administration, oral administration, etc., via a modified, controlled, slow or extended release dosage form, including but not limited to reservoir dosage forms, implants, patches and pumps, which may optionally be remotely controlled. Here, the dose will achieve blood levels similar to those of oral administration at low doses, but will still be subhallucinogenic.

Sub-psychedelic doses may be used, for example, for the chronic treatment or maintenance of various diseases or conditions disclosed herein, examples of which include, but are not limited to, depression (eg, MDD disease), inflammation, pain, and neuropathic inflammation.

The pharmaceutically acceptable salt of the compound of the present disclosure can be used for the maintenance regimen. As used herein, "maintenance regimen" generally refers to the administration of a pharmaceutically acceptable salt of the compound of the present disclosure after reaching the target dose, for example, after completing the escalating dose regimen, and/or after a positive clinical response is produced to the same drug or a different drug, for example, after improving the patient's condition. In some embodiments, the first drug for the treatment regimen and the second drug for the maintenance regimen are administered to the patient, wherein the first drug and the second drug are different. For example, a treatment regimen of a first drug that is not a dimethyltryptamine type compound (for example, the first drug is a serotonergic hallucinogen, such as LSD, psilocybin, MDMA, etc. or a non-hallucinogenic drug) can be administered to the patient, followed by a salt form of the compound of the present disclosure in the maintenance regimen (as the second drug). In another embodiment, the salt form of the present disclosure used for the treatment regimen (first drug) is different from the salt form used for the maintenance regimen (second drug). In some embodiments, for both the treatment regimen and the maintenance regimen, the same salt form of the present disclosure is administered to the patient. In any case, the maintenance dose can be used to "maintain" the treatment response and/or prevent relapse. When the same salt form of the present disclosure is used for the initial treatment regimen and the maintenance regimen, the maintenance dose may be equal to or lower than the therapeutic dose. In some embodiments, the maintenance dose is a hallucinogenic dose. In some embodiments, the maintenance dose is a sub-hallucinogenic dose. Typically, administration is performed daily or intermittently for the maintenance regimen, however, the maintenance regimen may also be performed continuously, for example, over several days, weeks, months, or years. In addition, the maintenance dose may be given to the patient over a long period of time or even over a long period of time.

In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) is administered intravenously to a subject in the form of a single bolus within the above-mentioned dosage range (e.g., about 0.1 mg/kg to about 0.8 mg/kg, or about 0.2 mg/kg to about 0.5 mg/kg, or about 0.3 mg/kg). In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) is administered to a subject in the form of an infusion within the above-mentioned dosage range (e.g., about 0.1 mg/kg to about 0.8 mg/kg, or about 0.2 mg/kg to about 0.5 mg/kg, or about 0.45 mg/kg). The infusion may be administered over a duration of, for example, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours. A pharmaceutically acceptable salt of a compound of formula (I) can be administered via infusion at a rate of about 0.1 mg/min, 0.2 mg/min, 0.3 mg/min, 0.4 mg/min, 0.5 mg/min, 0.6 mg/min, 0.7 mg/min, 0.8 mg/min, 0.9 mg/min, 1 mg/min, 1.5 mg/min, 2 mg/min, 2.5 mg/min, 3 mg/min, 3.5 mg/min, 4 mg/min, 4.5 mg/min, 5 mg/min, or in any other manner deemed appropriate by a medical professional. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is administered intravenously to a subject as a bolus within the above-mentioned dose range (e.g., about 0.1 mg/kg to about 0.8 mg/kg, or about 0.2 mg/kg to about 0.5 mg/kg, or about 0.3 mg/kg), followed by an infusion within the above-mentioned dose range (e.g., about 0.1 mg/kg to about 0.8 mg/kg, or about 0.2 mg/kg to about 0.5 mg/kg, or about 0.45 mg/kg).

The subject treated herein may have a disease or disorder associated with the serotonin 5- _HT2 receptor.

In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder or an inflammatory disease or disorder.

In some embodiments, the disease or disorder is a central nervous system (CNS) disorder and/or a psychological disorder, including but not limited to post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, melancholia, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders (including but not limited to bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinogenic crisis, social anxiety disorder, substance use disorders (including but not limited to alcohol use disorder), The following are some of the most common disorders: substance use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking and cocaine use disorder), Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphasia, childhood-onset speech fluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, eating disorders (including but not limited to anorexia nervosa, bulimia nervosa, binge eating disorder, etc.) and paraphilias (including but not limited to pedophilia, exhibitionism, voyeurism, fetishism, sadomasochism and masochism, and transvestite disorder, etc.), sexual dysfunction (e.g., low libido), and obesity.

In some embodiments, the methods provided herein are used to treat subjects suffering from depression. As used herein, the term "depressive disorder" or "depression" refers to a group of symptoms characterized by a low mood that may affect a person's thoughts, behaviors, feelings, and a sense of well-being that lasts for a period of time. In some embodiments, depression destroys people's physical and psychological functions. In some embodiments, depression causes physical symptoms, such as weight loss, pain or pain (ache/pain), headache, cramps, or digestive problems. In some embodiments, depression causes psychological symptoms, such as persistent sadness, anxiety, despair and irritability, guilt, worthlessness or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, memory, or making decisions. In some embodiments, depression is major depressive disorder (MDD), atypical depression, bipolar disorder, tension depression, depression caused by medical conditions, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or refractory depression (TRD).

In some embodiments, the disease or illness is major depressive disorder (MDD). As used herein, the term "major depressive disorder" refers to a condition characterized by a depressed mood period that exists across most situations. Major depressive disorder is usually accompanied by low self-esteem, loss of interest in normal pleasant activities, lack of energy and pain, without a clear cause. In some cases, major depressive disorder is characterized by depressive symptoms that last for at least two weeks. In some cases, the depression period experienced by individuals is separated by several years. In some cases, the depression symptoms experienced by individuals are almost always present. Major depressive disorder may have a negative impact on personal private life, work life or school life, as well as sleep, eating habits and general health. About 2-7% of adults with major depressive disorder commit suicide, and up to 60% of suicides suffer from major depressive disorder or other related mood disorders. Mental depression is a subtype of major depressive disorder composed of the same cognitive and physical problems as major depressive disorder, with less severe but longer lasting symptoms. Exemplary symptoms of major depressive disorder include, but are not limited to, sadness, tearfulness, feelings of emptiness or hopelessness, angry outbursts, irritability, or frustration (even over small things), loss of interest or pleasure in most or all normal activities, sleep disturbances (including insomnia or excessive sleeping), fatigue and lack of energy, decreased appetite, weight loss or gain, anxiety, restlessness or agitation, slowed thinking, speech, or body movements, feelings of worthlessness or guilt, preoccupation with past failures or self-blame, problems with thinking, concentrating, making decisions, and remembering, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems such as back pain or headaches.

As used herein, the term "atypical depression" refers to a condition in which an individual shows mood reactivity (i.e., an upturn in mood in response to actual or potential positive events), significant weight gain, increased appetite, excessive sleeping, heaviness in the arms or legs, a feeling of laziness, and/or a long-standing pattern of sensitivity to interpersonal rejection that leads to significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depressed mood, loss of interest in things that were once pleasurable, significant changes in weight (gain or loss) or appetite, insomnia or excessive sleeping nearly every day, restlessness or a debilitated state that is noticed by others, daily fatigue or loss of energy, feelings of hopelessness, worthlessness, or excessive guilt nearly every day, difficulty concentrating or making decisions nearly every day, recurring thoughts of death or suicide, suicide plans, or suicide attempts.

As used herein, the term "bipolar disorder" refers to a condition that causes an individual to experience abnormal changes in mood energy, activity level, and the ability to perform daily tasks. People with bipolar disorder experience periods of abnormally strong emotions, changes in sleep patterns and activity levels, and abnormal behavior. These different time periods are called "mood episodes." Mood episodes are very different from people's typical emotions and behaviors. Exemplary symptoms of mania, excessive behavior, include but are not limited to abnormal joy, jumping or excited behavior; increased activity, energy or restlessness, excessive feelings of happiness and self-confidence, reduced sleep needs, unusual talkativeness, competing ideas, distraction, and poor decision-making-for example, shopping sprees, taking sexual risks, or making foolish investments. Exemplary symptoms of depressive episodes or low mood include, but are not limited to, depressed mood, such as feelings of sadness, emptiness, despair or tears; obvious loss of interest or no pleasure in all or nearly all activities, significant weight loss, weight gain or decreased or increased appetite, insomnia or excessive sleep (excessive sleep or excessive sleepiness), restlessness or slow behavior, fatigue or loss of energy, worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate, or indecisiveness, and consideration, planning or attempted suicide. Bipolar disorder includes bipolar I disorder, bipolar II disorder and cyclothymia. Bipolar I disorder is defined by manic episodes that last for at least 7 days or by severe manic symptoms that require hospitalization. Subjects with bipolar I disorder may also experience depressive episodes, usually for at least 2 weeks. The onset of depression with mixed features, i.e., simultaneous depression and manic symptoms are also possible. Bipolar II disorder is characterized by a pattern of depression and hypomanic episodes, but not by a typical severe manic episode of bipolar I disorder. Cyclothymic disorder (also called cyclothymia) is characterized by symptoms of hypomania (elevated mood and euphoria) and depression that persist over a period of at least 2 years. The number, severity, or duration of mood swings are not sufficient to meet the full criteria for a hypomanic or depressive episode.

As used herein, the term "catatonic depression" refers to a condition that causes an individual to remain speechless and immobile for an extended period of time. Exemplary symptoms of catatonic depression include, but are not limited to, feelings of sadness that occur daily, loss of interest in most activities, sudden weight gain or loss, changes in appetite, difficulty falling asleep, difficulty waking up, feelings of restlessness, irritability, feelings of worthlessness, feelings of guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and/or suicide attempts.

As used herein, the term "depression caused by a medical condition" refers to a condition in which an individual experiences depression caused by another disease. Examples of medical diseases known to cause depression include, but are not limited to: HIV/AIDS, diabetes, arthritis, stroke, brain diseases (such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease), metabolic conditions (such as vitamin B12 deficiency), autoimmune conditions (such as lupus and rheumatoid arthritis), viral or other infections (hepatitis, mononucleosis, herpes), back pain, and cancer (such as pancreatic cancer).

As used herein, the term "postpartum depression" refers to a condition caused by childbirth and hormonal changes, the psychological adjustment of being a parent, and/or fatigue. Postpartum depression is usually associated with women, but men can also suffer from postpartum depression. Exemplary symptoms of postpartum depression include, but are not limited to, feelings of sadness, despair, emptiness, or being overwhelmed; crying more often than usual or for no apparent reason; worrying or feeling extremely anxious; feeling moody, irritable, or restless; sleeping too much, or being unable to sleep even when the baby is asleep; having trouble concentrating, remembering details, and making decisions; experiencing anger or rage; losing interest in activities that are usually pleasurable; having physical pain, including frequent headaches, stomach problems, and muscle pain; eating too little or too much; withdrawing from or avoiding friends and family; having difficulty bonding or forming an emotional attachment to the baby; persistent doubts about one's ability to care for the baby; and thinking about hurting oneself or the baby.

As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which an individual expresses symptoms of mood lability, irritability, restlessness, and anxiety that recur during the premenstrual phase of the cycle and ease at the onset of menstruation or shortly thereafter. Exemplary symptoms of premenstrual dysphoric disorder include, but are not limited to, mood lability (e.g., mood swings), irritability or anger, gloomy mood, anxiety and tension, decreased interest in daily activities, difficulty concentrating, sleepiness and lack of energy, changes in appetite (e.g., overeating or cravings for specific foods), excessive or insomnia sleeping, feeling overwhelmed or out of control, physical symptoms (e.g., breast pain or swelling, joint or muscle pain, feelings of 'bloating' and weight gain), self-deprecating thoughts, feelings of nervous excitement or jitters, decreased interest in daily activities (e.g., work, school, friends, hobbies), subjective difficulty concentrating, and easy fatigue.

As used herein, the term "seasonal affective disorder" refers to a condition in which an individual experiences mood changes based on the time of year. In some cases, an individual experiences low mood, low energy, or other depressive symptoms during the fall and/or winter. In some cases, an individual experiences low mood, low energy, or other depressive symptoms during the spring and/or summer. Exemplary symptoms of seasonal affective disorder include, but are not limited to, feeling depressed most of the day or almost every day, losing interest in activities that were once pleasurable, low energy, problems sleeping, changes in appetite or weight, feeling sluggish or agitated, difficulty concentrating, feeling hopeless, worthless, or guilty, and frequent thoughts of death or suicide.

In some embodiments, depression comprises a medical diagnosis based on criteria and classification from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. In some embodiments, depression comprises a medical diagnosis based on an independent medical evaluation.

In some embodiments, the methods described herein are provided to subjects with depression that is resistant to treatment. In some embodiments, the subject has been diagnosed with refractory depression (TRD). The term "refractory depression" refers to depression that is unresponsive or resistant to at least one or more treatment attempts of sufficient dosage and duration. In some embodiments, a subject with refractory depression is unresponsive to 1 treatment attempt, 2 treatment attempts, 3 treatment attempts, 4 treatment attempts, 5 treatment attempts or more treatment attempts. In some embodiments, a subject with refractory depression has been diagnosed with major depressive disorder and is unresponsive to 3 or more treatment attempts. In some embodiments, a subject with refractory depression has been diagnosed with bipolar disorder and is unresponsive to 1 treatment attempt.

In some embodiments, the methods provided herein reduce at least one sign or symptom of depression. In some embodiments, compared to before treatment, the methods provided herein reduce at least one sign or symptom of depression by between about 5% to 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.

In some embodiments, the disease or condition is an anxiety disorder. As used herein, the term "anxiety disorder" refers to a state of worry, hesitation and/or fear caused by the anticipation of an event and/or situation. Anxiety disorders cause physiological and psychological signs or symptoms. Non-limiting examples of physiological symptoms include muscle tension, palpitations, sweating, dizziness, shortness of breath, tachycardia, tremors, fatigue, worry, irritability and restless sleep. Non-limiting examples of psychological symptoms include fear of death, fear of embarrassment or humiliation, fear of the occurrence of events, etc. Anxiety disorders also impair the subject's cognition, information processing, stress level and immune response. In some embodiments, the methods disclosed herein treat chronic anxiety disorders. As used herein, "chronic" anxiety disorders are recurrent. Examples of anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, panic attacks, phobia-related disorders (e.g., phobias related to flying, heights, specific animals such as spiders/dogs/snakes, receiving injections, blood, etc., agoraphobia), separation anxiety disorder, selective mutism, anxiety due to medical conditions, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), substance-induced anxiety disorders, etc.

In some embodiments, the subject in need develops an anxiety disorder after experiencing the effects of a disease. The effects of a disease include an individual diagnosed with the disease, a loved one of an individual diagnosed with the disease, social isolation due to the disease, quarantine for the disease, or social distancing due to the disease. In some embodiments, the individual is quarantined to prevent the spread of the disease. In some embodiments, the disease is COVID-19, SARS, or MERS. In some embodiments, the subject develops an anxiety disorder after losing a job, losing a home, or fearing not finding a job.

In some embodiments, disease or illness is generalized anxiety disorder (GAD). Generalized anxiety disorder is characterized by excessive anxiety and worry, fatigue, restlessness, increased muscle pain or soreness, impaired attention, irritability and/or difficulty sleeping. In some embodiments, the subject suffering from generalized anxiety disorder does not suffer from relevant panic attacks. In some embodiments, the method herein is provided to suffer from generalized anxiety disorder and have the subject of the symptom of depression simultaneously. In some embodiments, compared with before treatment, after treatment, symptoms are alleviated 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, disease or illness is social anxiety disorder. As used herein, "social anxiety disorder" is a significant fear or anxiety in which an individual is exposed to one or more social situations that others may review. Non-limiting examples of situations causing social anxiety include social interaction (e.g., having a conversation, meeting with a stranger), observation (e.g., eating or drinking) and performing in front of others (e.g., giving a speech). In some embodiments, social anxiety disorder is limited to speaking or performing in public. In some embodiments, treatment according to the disclosed method reduces or improves the symptoms of social anxiety disorder. In some embodiments, compared with before treatment, symptoms after treatment are alleviated 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 condition is a compulsive disorder, such as obsessive-compulsive disorder (OCD), body-focused repetitive behaviors, hoarding disorder, gambling disorder, compulsive buying, compulsive Internet use, compulsive video gaming, compulsive sexual behavior, compulsive eating, compulsive exercise, body image disorder, hoarding disorder, skin irritation, trichotillomania, excoriation, substance-induced obsessive-compulsive disorder and related disorders, or obsessive-compulsive disorder caused by another medical condition, the like or a combination thereof. In some embodiments, the disease or condition is obsessive-compulsive disorder (OCD).

In some embodiments, at least one sign or symptom of an anxiety disorder is improved following treatment as disclosed herein. In some embodiments, the signs or symptoms of an anxiety disorder are measured according to a diary assessment, a clinician or caregiver assessment, or a clinical scale. In some embodiments, treatment results in an improvement in one or more of the following: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HADS), Generalized Anxiety Disorder Questionnaire-IV (GADQ-IV), Hamilton Anxiety Rating Scale (HARS), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-4 (PHQ-4), Social Phobia Inventory (SPIN), Brief Trauma Questionnaire (BTQ), Combat Exposure Scale (CES), Mississippi Scale for Combat-Related PTSD (M-PTSD), Posttraumatic Maladaptive Beliefs Scale (PMBS), Perceived Threat Scale (DRRI-2 Section: G), PTSD Symptom Scale-DSM-5 Interview (PSS-I-5), Structured Interview for PTSD (SI-PTSD), Davidson Trauma Scale (DSM-5), =Trauma Scale (DTS), Impact of Events Scale-Revised (IES-R), Posttraumatic Diagnostic Scale (PDS-5), Potentially Stressful Events Interview (PSEI), Stressful Life Events Screening Questionnaire (SLESQ), Spielberger's Trait and Anxiety, Generalized Anxiety Disorder 7-Item Scale, Psychiatric Institute Trichotillomania Scale (PITS), MGH Hair Pulling Scale (MGH-HPS), NIMH Trichotillomania Severity Scale (NIMH-TSS), NIMH Trichotillomania Impairment Scale (NIMH TIS), The Clinical Global Impression (CGI), Brief Social Phobia Scale (BSPS), Panic Attack Questionnaire (PAQ), Panic Disorder Severity Scale, Florida Obsessive-Compulsive Inventory (FOCI), Leiden Obsessive-Compulsive Inventory, Vancouver Obsessive-Compulsive Scale (VOCI), The Schedule of Compulsions, Obsessions, and Pathological Impulses (The Schedule of Compulsions, Obsessions, and Pathological Impulses) The Dimensional Obsessive-Compulsive Scale (DY-BOCS) was used as the questionnaire for the assessment of the severity of the obsessive-compulsive disorder (OCD) and the obsessive-compulsive disorder (OCD) of the disorder. The Dimensional Obsessive-Compulsive Scale (DY-BOCS) was used as the questionnaire for the assessment of the severity of the obsessive-compulsive disorder (OCD) of the disorder. The Dimensional Obsessive-Compulsive Scale (DY-BOCS) was used as the questionnaire for the assessment of the severity of the disorder. In some embodiments, treatment according to the methods of the present disclosure results in an improvement in anxiety 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% compared to before treatment according to any of the diary assessments, clinical or caregiver assessments, or clinical scales described herein or known in the art.

In some embodiments, the disease or disorder is attention deficit disorder (ADD). Children under 16 years of age are most often diagnosed with ADD, and these children have 6 or more symptoms of inattention for at least 6 consecutive months (5 or more for older adolescents), but no signs of hyperactivity/impulsivity. Symptoms of inattention include, but are not limited to, difficulty concentrating, avoiding long mental tasks (such as homework), difficulty focusing on tasks, being disorganized or forgetful, not listening when listening to others, and not paying attention to details. Often lose things, make careless mistakes, and try to act according to instructions. In some embodiments, the disease or disorder is attention deficit hyperactivity disorder (ADHD). ADHD is characterized by persistent inattention and/or hyperactivity-impulsivity. Hyperactivity-impulsivity symptoms usually include, but are not limited to, fidgeting or squirming when sitting, leaving the seat when you should be sitting, running, running or climbing at inappropriate times, being unable to quietly engage in hobbies, constantly moving, talking too much, answering questions before asking them completely, having difficulties when waiting for your turn, and interrupting or disturbing others in conversations or activities.

In some embodiments, the disease or disorder is a headache disorder. As used herein, the term "headache disorder" refers to a disorder characterized by recurrent headaches. Headache disorders include migraine, tension-type headache, cluster headache, and chronic daily headache syndrome.

In some embodiments, disclosed herein is a method of treating cluster headache in a subject in need thereof. In some embodiments, at least one sign or symptom of cluster headache is improved after treatment. In some embodiments, the signs or symptoms of cluster headache are measured according to a diary assessment, a physical or psychological assessment by a clinician, an imaging test, or a neurological examination. Cluster headache is a primary headache disorder and belongs to the trigeminal autonomic headache. The definition of a cluster headache is a unilateral headache with at least one autonomic symptom on the same side as the headache. Attacks are characterized by severe unilateral pain primarily in the first branch of the trigeminal nerve-fifth cranial nerve, whose primary function is to provide sensory and motor innervation of the face. Attacks are also associated with significant unilateral cranial autonomic symptoms, and subjects often experience agitation and restlessness during attacks. In some embodiments, subjects with cluster headache also experience nausea and/or vomiting. In some embodiments, a subject with cluster headache experiences unilateral pain, excessive tearing, facial flushing, drooping eyelids, constricted pupils, redness of the eyes, swelling under or around one or both eyes, sensitivity to light, nausea, restlessness, and fidgeting.

In some embodiments, disclosed herein is a method for treating a migraine in a subject in need thereof. Migraine is a moderate to severe headache that affects half or both sides of the head, is pulsating in nature, and lasts for 2 to 72 hours. The symptoms of migraine include headache, nausea, sensitivity to light, sensitivity to sound, sensitivity to smell, dizziness, difficulty speaking, vertigo, vomiting, epilepsy, strabismus, fatigue, or loss of appetite. Some subjects also experience a prodromal phase (appearing a few hours or days before the headache) and/or a post-dromal phase after the headache subsides. Prodromal and post-dromal symptoms include hyperactivity, hypoactivity, depression, craving for specific foods, repeated yawning, fatigue, and neck stiffness and/or pain. In some embodiments, migraine is a migraine without aura, a migraine with aura, a chronic migraine, an abdominal migraine, a basal migraine, a menstrual migraine, an ophthalmoplegic migraine, an ocular migraine, an ocular migraine, or a hemiplegic migraine. In some embodiments, migraine is a migraine without aura. Migraine without aura refers to a migraine that is not accompanied by a headache. In some embodiments, the migraine is a migraine with aura. The main feature of a migraine with aura is a transient focal neurological symptom that usually precedes or sometimes accompanies a headache. Less commonly, an aura can occur without a headache or without a migraine. In some embodiments, the migraine is a hemiplegic migraine. A hemiplegic migraine is a migraine with an aura and associated motor weakness. In some embodiments, a hemiplegic migraine is a familial hemiplegic migraine or a sporadic hemiplegic migraine. In some embodiments, the migraine is a basilar migraine. Subjects with basilar migraine suffer from migraines and have difficulty speaking, a spinning world, tinnitus, or many other brainstem-related symptoms, without the aura of motor weakness. In some embodiments, the migraine is a menstrual migraine. Menstrual migraines occur before and during menstruation. In some embodiments, the subject suffers from abdominal migraine. Children often experience abdominal migraines. Abdominal migraines are not headaches, but stomach pains. In some embodiments, the subject with abdominal migraine develops migraine. In some embodiments, the subject suffers from ocular migraine, also known as "ocular migraine". Subjects with ocular migraine experience monocular vision or blindness during or shortly after the migraine. In some embodiments, the subject suffers from ophthalmoplegic migraine. Ophthalmoplegic migraine is a recurrent attack of migraine associated with paralysis of one or more ocular cranial nerves. In some embodiments, the subject in need of treatment experiences chronic migraine. As defined herein, the subject with chronic migraine has more than fifteen headache days per month. In some embodiments, the subject in need of treatment experiences episodic migraine. As defined herein, the subject with episodic migraine has less than fifteen headache days per month.

In some embodiments, disclosed herein is a method of treating chronic daily headache syndrome (CDHS) in a subject in need thereof. Subjects with CDHS have headaches lasting more than four hours on more than 15 days per month. Some subjects experience these headaches for six months or longer. CHDS affects 4% of the general population. Chronic migraine, chronic tension-type headaches, new daily persistent headaches, and medication overuse headaches account for the vast majority of chronic daily headaches.

In some embodiments, the frequency of headaches and/or related symptoms following treatment according to the methods of the present disclosure is reduced by 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% compared to before treatment.

In some embodiments, the length of a headache episode following treatment according to the methods of the present disclosure is reduced by 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% compared to before treatment.

In some embodiments, at least one sign or symptom of a headache disorder is improved following administration of a compound disclosed herein. In some embodiments, the signs or symptoms of a headache disorder are measured according to a diary assessment, a clinician or caregiver assessment, or a clinical scale. In some embodiments, treatment of the present disclosure results in demonstrated improvement in one or more of the following: a visual analog scale, a numeric rating scale, a short form health survey, a profile of mood states, the Pittsburgh Sleep Quality Index, the Major Depression Inventory, the Perceived Stress Scale, the 5-Level EuroQoL-5D, the Headache Impact Test; ID-Migraine; a 3-item screener; the Minnesota Multiphasic Personality Inventory; the Hospital Anxiety and Depression Scale (HADS), the 50 Beck Depression Inventory (BDI; both the original BD151 and the second version BDI-1152), the 9-item Patient Health Questionnaire (PHQ-9), the Migraine Disability Assessment Questionnaire (MI-DAS), the Migraine Specific Quality of Life Questionnaire version 2.1 (MSQv2.1), the European 5-Dimension Quality of Life Scale (EQ-5D), the Short Form 36 (SF-36), or a combination thereof. In some embodiments, treatment according to the methods of the present disclosure results in an improvement in headache disorder 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% compared to before treatment according to any of a diary assessment, a clinical or caregiver assessment, or a clinical scale described herein or known in the art. In some embodiments, the signs or symptoms of headache disorder are measured according to a diary assessment, a physical or psychological assessment by a clinician, an imaging test, an electroencephalogram, a blood test, a neurological exam, or a combination thereof. In some embodiments, blood tests assess blood chemistry and/or vitamins.

In some embodiments, the disease or illness is a substance use disorder. The substance addiction that can be treated using the methods herein includes addiction to addictive substances/medicaments, such as recreational drugs and addictive drugs. Examples of addictive substances/medicaments include but are not limited to alcohol, such as ethanol, gamma-hydroxybutyrate (GHB), caffeine, nicotine, cannabis (cannabis) (marijuana) and cannabis derivatives, opioids and other morphine opioid agonists such as heroin, phencyclidine and phencyclidine-like compounds, sedative hypnotics such as benzodiazepines, methaqualone, mecloqualone, etaqualone and barbiturates and psychostimulants such as cocaine, amphetamine and amphetamine-related drugs such as dextroamphetamine and methamphetamine. Examples of addictive drugs include, for example, benzodiazepines, barbiturates, and analgesics including alfentanil, allylprodine, alphaprodine, anileridinebenzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, and phenoxyethylamine. butyrate), dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine (metazocine), methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene sufentanil, tramadol, and tilidine. In some embodiments, the disease or condition is alcohol use disorder (AUD). In some embodiments, the disease or condition is nicotine use (e.g., smoking) disorder, and the therapy is used, for example, to quit smoking.

In some embodiments, the present disclosure provides for the management of sexual dysfunction, which management may include but is not limited to sexual desire disorders, such as decreased sexual desire; sexual arousal disorders, such as those resulting in lack of desire, lack of arousal, pain during intercourse, and orgasmic disorders, such as anorgasmia; and erectile dysfunction; particularly sexual dysfunction disorders caused by psychological factors.

In some embodiments, the disease or illness is an eating disorder. As used herein, the term "eating disorder" refers to any of a series of psychological disorders characterized by abnormal or disturbed eating habits. The non-limiting examples of eating disorders include pica, anorexia nervosa, anorexia nervosa, rumination disorder, avoidance/restrictive food intake disorder, binge eating disorder, other specified feeding or dietary disorders, unspecified feeding or dietary disorders or combinations thereof. In some embodiments, eating disorders are pica, anorexia nervosa, anorexia nervosa, rumination disorder, avoidance/restrictive food intake disorder, binge eating disorder or combinations thereof. In some embodiments, methods disclosed herein treat chronic eating disorders. As used herein, "chronic" eating disorders are recurring. In some embodiments, after applying compounds disclosed herein, at least one sign or symptom of eating disorders is improved. In some embodiments, signs or symptoms of eating disorders are measured according to diary assessment, assessment of clinicians or caregivers or clinical scales. Non-limiting examples of clinical scales, diary assessments, and clinician or caregiver assessments include: Mini-International Neuropsychiatric Interview (MINI), McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), Eating Disorders Examination (EDE), Eating Disorders Questionnaire (EDE-Q), Eating Disorders Examination Questionnaire-Short Form (EDE-QS), Appearance State and Trait Anxiety Inventory-State and Trait Version (PASTAS), Spielberg State-Trait Anxiety Inventory (STAI), Eating Disorders Readiness Rule (ED-RR), Visual Analog Rating Scale (VAS), Montgomery-Asberg Depression Rating Scale (MADRS), Yale-Brown Cornell Eating Disorder Inventory (YBDI-QS), and the Eating Disorders Rating Scale (ED-RR). Scale, YBC-EDS), Yale-Brown Cornell Eating Disorder Scale Self-Report (YBC-EDS-SRQ), Body Image Status Scale (BISS), Clinical Impairment Assessment (CIA) Questionnaire, Eating Disorder Inventory (EDI) (e.g., 3rd edition: EDI-3), Five Dimension Altered States of Consciousness Questionnaire (5D-ASC), Columbia-Suicidality Severity Rating Scale (C-SSRS), Life Change Inventory (LCI), and combinations thereof. In some embodiments, treatment according to the methods of the present disclosure results in an improvement in eating disorders by 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% compared to before treatment according to any of the diary assessments, clinical or caregiver assessments, or clinical scales described herein or known in the art.

In some embodiments, the disease or condition is multiple sclerosis (MS). MS is a chronic inflammatory disease of unknown etiology, involving immune-mediated attacks on the central nervous system. Myelin and oligodendrocytes that form myelin appear to be the main targets of inflammatory attacks, although the axons themselves are also damaged. MS disease activity can be monitored by cranial scans, including brain magnetic resonance imaging (MRI), accumulation of disability, and the rate and severity of relapses. The diagnosis of clinically confirmed MS determined by the Poser criteria requires at least two neurological events that are separated in time and location that indicate CNS demyelination. Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Among them, relapsing-remitting multiple sclerosis (RRMS) is the most common form at the time of initial diagnosis. Many subjects with RRMS have an initial relapsing-remitting course of 5-15 years, which then progresses to a secondary progressive MS (SPMS) disease course. Relapse is caused by inflammation and demyelination, and the recovery and relief of nerve conduction are accompanied by the disappearance of inflammation, the redistribution of sodium channels on demyelinated axons and the re-myelination. In some embodiments, multiple sclerosis is relapsing multiple sclerosis. In some embodiments, relapsing multiple sclerosis is relapsing-remitting multiple sclerosis. In some embodiments, the method herein alleviates the symptoms of multiple sclerosis of the subject. In some embodiments, the symptoms are multiple sclerosis disease activity monitored by MRI, relapse rate, accumulation of physical disability, frequency of relapse, time reduction of confirmed disease progression, time reduction of confirmed relapse, frequency of clinical deterioration, brain atrophy, neuronal dysfunction, neuronal damage, neuronal degeneration, neuronal apoptosis, risk of confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in the whole brain MTR histogram, deterioration of overall health, functional status, quality of life and/or severity of work symptoms. In some embodiments, the method herein reduces or inhibits the reduction of brain volume. In some embodiments, brain volume is measured by percentage change of brain volume (PBVC). In some embodiments, the method herein increases the time of confirmed disease progression. In some embodiments, the time of confirmed disease progression increases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, for example, at least 20%-60%. In some embodiments, the method herein reduces the abnormality observed in the whole brain MTR histogram. In some embodiments, the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) scoring. In some embodiments, the accumulation of physical disability is assessed by the time of confirmed disease progression measured by Kurtzke Expanded Disability Status Scale (EDSS) scoring.

In some embodiments, the disease or condition is characterized by or otherwise associated with neuroinflammation. The treatment herein can provide cognitive benefits to subjects with nervous system and neurodegenerative diseases, such as Alzheimer's disease and other dementia subtypes, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and other diseases with neuroinflammation as a disease pathophysiology and progression hallmark. For example, emerging psychedelic research/clinical evidence suggests that hallucinogens can be used as disease-modifying treatments in subjects with neurodegenerative diseases, such as Alzheimer's disease and other forms of dementia. See Vann Jones, S.A. and O’Kelly, A. “Psychedelics as a Treatment for Alzheimer’s Disease Dementia” Front. Synaptic Neurosci., August 21, 2020; Kozlowska, U., Nichols, C., Wiatr, K. and Figiel, M. (2021), “From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders” Journal ofNeurochemistry, 00, 1–20; Garcia-Romeu, A., Darcy, S., Jackson, H., White, T., Rosenberg, P. (2021), “Psychedelics as NovelTherapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms” In: Current Topics in Behavioral Neurosciences. Springer, Berlin, Heidelberg. For example, hallucinogens are believed to stimulate neurogenesis, induce neuroplastic changes, and reduce neuroinflammation. Therefore, in some embodiments, the method of the present disclosure is used to treat nerve and neurodegenerative disorders, such as Alzheimer's disease, dementia subtypes, Parkinson's disease and amyotrophic lateral sclerosis (ALS), wherein neuroinflammation is associated with disease pathogenesis. In some embodiments, the method of the present disclosure is used to treat Alzheimer's disease. In some embodiments, the method of the present disclosure is used to treat dementia. In some embodiments, the method of the present disclosure is used to treat Parkinson's disease. In some embodiments, the method of the present disclosure is used to treat amyotrophic lateral sclerosis (ALS). As described above, such treatments can stimulate neurogenesis, induce neuroplastic changes and/or provide neuroinflammatory benefits (e.g., neuroinflammation reduced compared to before treatment begins), and therefore, disease progression can be slowed down or prevented, brain atrophy can be slowed down or reversed, and symptoms associated therewith can be reduced (e.g., memory loss in the case of Alzheimer's disease and related dementia disorders). Although not limited thereto, pharmaceutical compositions suitable for oral and/or sustained release administration (e.g., subcutaneous administration) are suitable for such treatment methods, preferably sub-psychedelic administration. In some embodiments, treatment according to the methods of the present disclosure results in an improvement in cognition in a subject with a neurological or neurodegenerative disease of 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% compared to before treatment, according to any of the diary assessments, clinical or caregiver assessments, or clinical scales described herein or known in the art.

In addition, many behavioral problems associated with chronic and/or life-threatening diseases, including neurodegenerative diseases such as Alzheimer's disease, can benefit from treatment with the compounds/salt forms disclosed herein. In fact, depression, anxiety or stress can be common in patients with chronic and/or life-threatening diseases such as Alzheimer's disease, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis and psoriasis), cancer, coronary heart disease, diabetes, epilepsy, HIV/AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease and stroke. For example, depression as a consequence of the disease is common in Alzheimer's disease and is a risk factor for the disease itself. Symptoms of depression, anxiety or stress may occur after the disease/illness is diagnosed. Patients with depression, anxiety or stress concurrent with another medical disease/illness may have more severe symptoms of both diseases, and symptoms of depression, anxiety or stress may even continue when the patient's physical health improves. The compounds/salt forms described herein are useful for treating depression, anxiety and/or stress associated with a chronic or life-threatening disease/illness.

Therefore, in some embodiments, the method herein is used to treat symptoms associated with chronic and/or life-threatening diseases or conditions, such as depression, anxiety and/or stress, and the disease or condition comprises nerves and neurodegenerative diseases. In some embodiments, the method provided herein reduces at least one sign or symptom of nerves and/or neurodegenerative diseases. In some embodiments, according to any one of the diary assessments described herein or known in the art, clinical or caregiver's assessments or clinical scales, compared to before treatment, the method provided herein reduces at least one sign or symptom of nerves and/or neurodegenerative diseases (e.g., depression, anxiety and/or stress) by about 5% to 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.

In some embodiments, the disease or condition is Alzheimer's disease. In some embodiments, the methods herein are used to treat depression, anxiety and/or stress associated with Alzheimer's disease. In some embodiments, the disease or condition is Parkinson's disease. In some embodiments, the methods herein are used to treat depression, anxiety and/or stress associated with Parkinson's disease. In some embodiments, the disease or condition is amyotrophic lateral sclerosis (ALS). In some embodiments, the methods herein are used to treat depression, anxiety and/or stress associated with amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition is cancer-related depression and anxiety. As discussed above, oral and/or extended release dosages are suitable for such applications, particularly when the blood concentration of the active ingredient (e.g., a compound of formula (I)) is maintained below the hallucinogenic threshold.

In some embodiments, the methods disclosed herein are used to treat brain injuries, including traumatic brain injury (TBI). TBI is a brain injury caused by external forces and can be classified according to severity, ranging from mild traumatic brain injury (mTBI/concussion) to severe traumatic brain injury. TBI can also be classified by mechanism, divided into closed or penetrating brain injuries, or other characteristics, such as whether it occurs in a specific location or a wide area. TBI can cause physical, cognitive, social, emotional and behavioral symptoms, which can be treated in this article. Some imaging techniques used for diagnosis and recovery markers include computed tomography (CT) and magnetic resonance imaging (MRI).

In some embodiments, the disease or disorder is a neurological and developmental disorder, such as autism spectrum disorder, including Asperger's syndrome. For example, Asperger's syndrome is a subtype of autism spectrum disorder that can be treated with anxiety medications. Subjects with autism spectrum disorder may present with various signs and symptoms, including but not limited to a preference for non-social stimuli, abnormal non-verbal social behavior, reduced attention to social stimuli, irritability, anxiety (e.g., particularly generalized anxiety and social anxiety), and depression. In some embodiments, autism spectrum disorder includes a medical diagnosis based on the criteria and classifications from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Current evidence supports the use of psychedelics to improve behavioral atypicality in autism spectrum disorders, including reducing social behavior, anxiety, and depression (see Markopoulos A, Inserra A, De Gregorio D, Gobbi G. Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder. Front Pharmacol. 2022; 12: 749068). The methods herein can be used to treat the signs and symptoms of autism spectrum disorders.

In some embodiments, the disease or illness is a genetic condition that causes learning disabilities and cognitive impairment. An example of such genetic condition is fragile X syndrome, which is caused by changes in the gene fragile X messenger ribonucleoprotein 1 (FMR1), which may cause mild to moderate intellectual disabilities in most males and about one-third of affected females. Fragile X syndrome is closely related to autism spectrum disorder, because the FMR1 gene is the main genetic cause of autism spectrum disorder (see Markopoulos A, Inserra A, De Gregorio D, Gobbi G. Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder. Front Pharmacol. 2022; 12: 749068). Subjects with fragile X syndrome may show anxiety, overactive behavior (e.g., restlessness and impulsive actions), attention deficit disorder, abnormal emotions and aggression, poor recognition memory and/or autism spectrum disorder, and these signs and symptoms can be treated with the methods herein. Clinical trials of psychedelics for the treatment of fragile X syndrome and autism spectrum disorder are currently underway (ClinicalTrials.gov, number NCT04869930).

In some embodiments, the disease or condition is mental distress, such as mental distress in frontline healthcare workers.

In some embodiments, the compounds and compositions disclosed herein are used to treat tic disorders, including Tourette's Syndrome, which is also variously referred to as Tourette Syndrome, Tourette's Disorder, Gilles de laTourette syndrome (GTS), or simply Tourette's or TS. Tic disorders may also be childhood autoimmune disorders associated with streptococcal infection (PANDAS), transient tic disorders, chronic tic disorders, or unspecified tic disorders (NOS). Tic disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) according to the type (motor or vocal) and duration (sudden, rapid, arrhythmic movements) of tics, or similarly defined by the World Health Organization (ICD-10 codes). Tics are involuntary or semi-voluntary, sudden, brief, intermittent, repetitive movements (movements) or sounds (articulations), classified as simple or complex. Simple tics (such as blinking or grimacing) are relatively easy to disguise and are likely to go unnoticed. Complex tics (such as body contortions, self-injurious behaviors, obscene gestures, or yelling socially inappropriate words or phrases) may appear to be purposeful behaviors and can be particularly distressing. Transient tic disorders are typically characterized by multiple motor and/or vocal tics that last for at least four weeks but less than 12 months. Chronic tic disorders are typically characterized by single or multiple motor or vocal tics, but not both, that persist for more than a year. When motor and vocal tics are present (although not necessarily at the same time) for more than a year, Tourette syndrome is diagnosed. Thus, Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and vocal tics. The typical age of onset is between five and seven years of age. Affected children may become the target of teasing by their peers, which in turn may lead to low self-esteem, social isolation, poor academic performance, depression, and anxiety. In addition to causing social embarrassment, sudden and powerful tics can be painful, and violent head and neck tics have been reported to cause secondary neurological deficits, such as compressive cervical myelopathy. Patients with Tourette syndrome are also at increased risk for obsessive-compulsive disorder (OCD), depression, and attention deficit hyperactivity disorder (ADHD). When tics occur but do not meet the criteria for any specific tic disorder, a tic disorder NOS is diagnosed. The methods disclosed herein can also be used to treat tics induced as a side effect of a drug; tics associated with autism; and Tourettism (the presence of Tourette-like symptoms in the absence of Tourette syndrome (e.g., due to another disease or condition, such as sporadic, hereditary, or neurodegenerative disorders)).

In some embodiments, the disease or disorder may comprise a pathology of the autonomic nervous system (ANS).

In some embodiments, the disease or disorder may include a pulmonary disorder (eg, asthma and chronic obstructive pulmonary disease (COPD)).

In some embodiments, the disease or disorder may include a cardiovascular disorder (eg, atherosclerosis).

In some embodiments, the present disclosure provides for the management of different types of pain, including but not limited to cancer pain, e.g., refractory cancer pain; neuropathic pain; postoperative pain; opioid-induced hyperalgesia and opioid-related tolerance; neuralgia; postoperative/post-surgical pain; complex regional pain syndrome (CRPS); shock; limb amputation; severe chemical or thermal burns; sprains, ligament tears, fractures, wounds and other tissue injuries; dental surgery, procedures and diseases; labor or delivery; during physical therapy; radiation poisoning; acquired immune deficiency syndrome (AIDS); epidural (or extradural) fibrosis; orthopedic pain; back pain; Failed back surgery and failed laminectomy; sciatica; painful sickle cell crisis; arthritis; autoimmune disease; intractable bladder pain; pain associated with certain viruses, e.g., shingles pain or herpes pain; acute vomiting, e.g., pain that may cause vomiting or abdominal pain that is often accompanied by severe vomiting; migraine, e.g., migraine with aura; and other conditions, including depression (e.g., acute depression or chronic depression), depression with pain, alcohol dependence, acute anxiety, refractory asthma, acute asthma (e.g., unrelated painful conditions may induce asthma), epilepsy, acute brain injury and stroke, Alzheimer's disease, and other conditions. Pain can be persistent or chronic pain that persists for weeks to years, in some cases even after the injury or disease causing the pain has healed or disappeared, and in some cases despite taking previous medications and/or treatments. In addition, the present disclosure encompasses treating/managing any combination of these types of pain or conditions.

In some embodiments, the pain treated/managed is acute breakthrough pain or pain associated with wind-up that may occur in chronic pain conditions. In some embodiments of the present disclosure, the pain treated/managed is cancer pain, for example, refractory cancer pain. In some embodiments of the present disclosure, the pain treated/managed is post-surgical pain. In some embodiments of the present disclosure, the pain treated/managed is orthopedic pain. In some embodiments of the present disclosure, the pain treated/managed is back pain. In some embodiments of the present disclosure, the pain treated/managed is neuropathic pain. In some embodiments of the present disclosure, the pain treated/managed is dental pain. In some embodiments of the present disclosure, the condition treated/managed is depression. In some embodiments of the present disclosure, the pain treated/managed is chronic pain in opioid-tolerant patients.

In some embodiments, the disease or condition is arthritis. Types of arthritis include osteoarthritis, rheumatoid arthritis, childhood arthritis, fibromyalgia, gout and lupus. In some embodiments, the disease or condition is osteoarthritis. In some embodiments, the disease or condition is rheumatoid arthritis. In some embodiments, the disease or condition is childhood arthritis. In some embodiments, the disease or condition is gout. In some embodiments, the disease or condition is lupus. In some embodiments, the disease or condition is fibromyalgia. Fibromyalgia is a disease characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and emotional problems. Fibromyalgia is believed to amplify pain by affecting the brain and spinal cord processes involved in pain and non-pain signaling. Symptoms usually occur after an event, such as physical trauma, surgery, infection or major psychological stress. In other cases, symptoms accumulate gradually over time without a single triggering event. Women are more likely to suffer from fibromyalgia than men. Many people with fibromyalgia also suffer from tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, anxiety and depression.

In some embodiments, the disease or disorder is inflammatory bowel disease (IBD). IBD is a term for two conditions, i.e., Crohn's disease and ulcerative colitis, characterized by chronic inflammation of the gastrointestinal (GI) tract, which causes GI tract damage. Subjects with IBD may experience persistent diarrhea, abdominal pain, rectal bleeding/bloody stools, weight loss, and fatigue. Using one or more of endoscopy, colonoscopy, angiography, MRI, computed tomography (CT), stool samples, and blood tests known to those of ordinary skill in the art, IBD can be diagnosed and treatment can be monitored.

In some embodiments, the disease or condition is a sleep disorder, such as narcolepsy, insomnia, nightmare disorder, sleep apnea, central sleep apnea, obstructive sleep apnea, hypopnea, sleep-related hypoventilation, restless legs syndrome, and jet lag. In some embodiments, the disease or condition is narcolepsy.

In some embodiments, the present disclosure relates to a method for treating a disease or condition by modulating N-methyl-D-aspartate (NMDA) activity, wherein the method comprises administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of formula (I)). In some embodiments, the disease or condition is selected from: levodopa-induced dyskinesia; dementia (e.g., Alzheimer's dementia), tinnitus, refractory depression (TRD), major depressive disorder, melancholia, atypical depression, dysthymia, neuropathic pain, agitation caused or associated with Alzheimer's disease, pseudobulbar effect, autism, bulbar function, generalized anxiety disorder, Alzheimer's disease, schizophrenia, diabetic neuropathy, acute pain, depression, bipolar depression, suicidal tendencies, neuropathic pain, or post-traumatic stress disorder (PTSD). In some embodiments, the disease or condition is a psychiatric or mental disorder (e.g., schizophrenia, mood disorders, substance-induced psychosis, major depressive disorder (MDD), bipolar disorder, bipolar depression (BDep), post-traumatic stress disorder (PTSD), suicidal ideation, anxiety, obsessive compulsive disorder (OCD), and treatment-resistant depression (TRD)). In other embodiments, the disease or condition is a neurological disorder (e.g., Huntington's disease (HD), Alzheimer's disease (AD), or systemic lupus erythematosus (SLE)).

In some embodiments, the present disclosure relates to a method of treating ocular diseases (such as uveitis, corneal diseases, iritis, iridocyclitis, glaucoma and cataracts) by administering a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) to a subject in need thereof. For example, the compound/salt forms herein can be administered in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, solution powders, gels, ophthalmic inserts and implants. In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) is administered in the form of an eye drop formulation.

The administering physician may provide a method of prophylactic or therapeutic treatment by adjusting the amount and administration time of any salt form of the compounds described herein, depending on the observation of one or more symptoms of the disease or condition being treated.

In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

Administration can be systemic or local. In some embodiments, administration to a mammal will result in systemic release (e.g., into the bloodstream) of the disclosed compounds. Methods of administration may include, but are not limited to, inhalation, such as via a nebulizer or inhaler; oral; gastric and rectal enteral routes; local, such as transdermal and intradermal; and parenteral administration.

The compounds disclosed herein have favorable metabolic degradation characteristics, which prevent the high drug concentrations observed acutely after administration, while also increasing the brain levels of active compounds, so that in some embodiments, the therapeutic dose can be reduced. Therefore, the compound of formula (I) (salt form) can be administered at a serotonergic but subpsychoactive concentration to achieve a lasting therapeutic benefit while reducing toxicity, such as toxicity associated with activation of 5-HT _2B receptors associated with valvular heart disease (Rothman, RB and Baumann, MH, 2009, Serotonergic drugs and valvular heart disease, Expert Opin Drug Saf8, 317-329). Therefore, the compound of formula (I) in salt form may be suitable for microdosing.

In some embodiments, the pharmaceutically acceptable salt form of the present disclosure can be used as an independent therapy. In some embodiments, the pharmaceutically acceptable salt form of the present disclosure can be used as an auxiliary/combination therapy. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure and at least one additional therapy and/or therapeutic agent are applied to the subject suffering from the disease. In some embodiments, additional therapy and/or therapeutic agent are applied before the pharmaceutically acceptable salt form of the present disclosure is applied. In some embodiments, additional therapy and/or therapeutic agent are applied after the pharmaceutically acceptable salt form of the present disclosure is applied. In some embodiments, additional therapy and/or therapeutic agent are applied simultaneously with the pharmaceutically acceptable salt form of the present disclosure. In some embodiments, additional therapy is an antidepressant, an anticonvulsant, lisdexamfetamine dimesylate, an antipsychotic, an anxiolytic, an anti-inflammatory, a benzodiazepine, an analgesic, a cardiovascular drug, an opioid antagonist or a combination thereof.

In some embodiments, the additional therapy is a benzodiazepine. In some embodiments, the benzodiazepine is diazepam or alprazolam.

In some embodiments, the additional therapy is an N-methyl-D-aspartate (NMDA) receptor antagonist. In some embodiments, the NMDA receptor antagonist is ketamine. In some embodiments, the NMDA receptor antagonist is nitrous oxide.

In some embodiments, additional therapy is an antidepressant. In some embodiments, antidepressants, for example, indirectly affect neurotransmitter receptors by affecting the interaction of the reactivity of other molecules at neurotransmitter receptors. In some embodiments, antidepressants are agonists. In some embodiments, antidepressants are antagonists. In some embodiments, antidepressants (directly or indirectly) act on more than one type of neurotransmitter receptors. In some embodiments, antidepressants are selected from buproprion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline and venlafaxine.

In some embodiments, the antidepressant is a tricyclic antidepressant ("TCA"), a selective serotonin reuptake inhibitor ("SSRI"), a serotonin and norepinephrine reuptake inhibitor ("SNRI"), a dopamine reuptake inhibitor ("DRI"), a norepinephrine reuptake monoamine oxidase inhibitor ("MAOI"), including inhibitors ("NRU"), dopamine, serotonin and norepinephrine reuptake inhibitors ("DSNRI"), a reversible inhibitor of monoamine oxidase type A (RIMA), or a combination thereof. In some embodiments, the antidepressant is a TCA. In some embodiments, the TCA is imipramine or clomipramine. In some embodiments, the antidepressant is an SRI. In some embodiments, the SSRI is escitalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, or a combination thereof. In some embodiments, the SNRI is venlafaxine. In some embodiments, the additional therapy is pregabalin. In some embodiments, the pharmaceutically acceptable salt forms of the present disclosure are administered in combination with a reversible inhibitor of monoamine oxidase type A (RIMA). This combination can be administered in the same dosage form, or co-administered in a separate dosage form. This combination can improve the bioavailability (e.g., oral bioavailability) of the compound of formula (I) by minimizing enzymatic degradation mediated by MAO enzymes (e.g., deamination/oxidation processes). Examples of reversible inhibitors of monoamine oxidase type A (RIMA) include, but are not limited to, moclobemide, tolaxatone, brofaromine, caroxazone, eprobemide, methylene blue, metralindole, minaprine, harmaline, harmine, rosiridin, amiflamine, cimoxatone, sercloremine, CX157, befloxatone, esuprone, tetraindole 5-(2-aminopropyl)indole (5-IT), alpha-methyltryptamine (AMT), natural sources (e.g., syrian rue, tumeric, curcumin).

In some embodiments, the additional therapeutic agent is an anticonvulsant. In some embodiments, the anticonvulsant is gabapentin, carbamazepine, ethosuximide, lamotrigin, felbamate, topiramate, zonisamide, tiagabine, oxcarbazepine, levetiracetam, divalproex sodium, phenytoin, fosphenytoin. In some embodiments, the anticonvulsant is topiramate.

In some embodiments, the additional therapeutic agent is an antipsychotic. In some embodiments, the antipsychotic is a phenothiazine, butryophenone, thioxanthene, clozapine, risperidone, olanzapine or sertindole, quetiapine, aripiprazole, zotepine, perospirone, a neurokinin-3 antagonist such as osanetant and talnetant, rimonabant, or a combination thereof.

In some embodiments, the additional therapeutic agent is an anti-inflammatory drug. In some embodiments, the anti-inflammatory drug is a nonsteroidal anti-inflammatory drug (NSAIDS), a steroid, acetaminophen (COX-3 inhibitor), a 5-lipoxygenase inhibitor, a leukotriene receptor antagonist, a leukotriene A4 hydrolase inhibitor, an angiotensin converting enzyme antagonist, a beta blocker, an antihistamine, a histamine 2 receptor antagonist, a phosphodiesterase-4 antagonist, a cytokine antagonist, a CD44 antagonist, an anti-tumor agent, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor (statin), an estrogen, an androgen, an antiplatelet agent, an antidepressant, a Helicobacter pylori inhibitor, a proton pump inhibitor, a thiazolidinedione, a dual-acting compound, or a combination thereof.

In some embodiments, the additional therapeutic agent is an anxiolytic. In some embodiments, the anxiolytic is selected from alprazolam, alpha blockers, antihistamines, barbiturates, beta blockers, bromazepam, carbamates, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, opioids, oxazepam, temazepam, or triazolam.

In some embodiments, the additional therapy is an opioid antagonist. Non-limiting examples of opioid antagonists include naloxone, naltrexone, nalmefene, nalorphine, nalrphine dinicotinate, levallrphan, samidorphan, nalodeine, alvimopan, methylnaltrexone, naloxegol, 6-naltrexol, axelopran, bevenopran, methylsamidorphan, naldemedine, buprenorphine, decozine, butorphanol, levorphanol, nalbuphine, pentazocine, and finazocine.

In some embodiments, the additional therapy is a cardiovascular drug. Non-limiting examples of cardiovascular drugs include digoxin or (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribose-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribose-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribose-hexopyranosyl)oxy]-12,14-dihydroxy-carbo-20(22)-enolide, lisinopril, captopril, ramipril, trandolapril, benazepril, cilazapril ), enalapril, moexipril, perindopril, quinapril, fludrocortisone, enalaprilate, quinapril, perindopril, apixaban, dabigatran, edoxaban, heparin, rivaroxaban, warfarin, aspirin n), clopidogrel, dipyridamole, prasugrel, ticagrelor, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartanscaubitril, acebutolol, atenolol l), betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisolidipine, verapamil, statins, niacin, diuretics, vasodilators, and combinations thereof.

In some embodiments, at least one therapy is administered to the subject. Non-limiting examples of therapy include transcranial magnetic stimulation, cognitive behavioral therapy, interpersonal psychotherapy, dialectical behavioral therapy, mindfulness techniques, or acceptance and commitment therapy, or a combination thereof.

Pharmaceutical composition

Also disclosed herein are pharmaceutical compositions comprising a pharmaceutically acceptable salt of a compound of formula (I) and a pharmaceutically acceptable vehicle. The pharmaceutical composition may contain one or more pharmaceutically acceptable salts of a compound of formula (I).

"Pharmaceutically acceptable vehicle" can be a vehicle used in mammals such as humans, which is approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopeia or other recognized pharmacopeia. The term "vehicle" refers to a diluent, adjuvant, excipient, carrier or any other auxiliary or supporting component in this article, and the salt form of the compound disclosed is prepared with them for administration to mammals. Such pharmaceutical vehicles can be solid or liquid, such as water and oil, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical vehicles can be water, saline, fruit juice (such as fruit juice), gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea, etc. Pharmaceutical vehicles can include one or more gases, such as a carrier for administration via inhalation. In addition, the disclosed composition can include adjuvants, stabilizers, thickeners, lubricants, taste masking agents, colorants and other pharmaceutical additives, such as those described below.

The pharmaceutical composition may comprise a single compound of formula (I) in salt form, or a mixture of compounds of formula (I) in free base or salt form, i.e., the pharmaceutical composition may be formed from an isotopic mixture of the disclosed compounds. In some embodiments, the subject compound of formula (I) may be present in the pharmaceutical composition in a purity of 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% by weight, based on the total weight of the isotopologues of the compound of formula (I) present in the pharmaceutical composition. For example, a pharmaceutical composition formulated with DMT d-10 salt (a 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 may additionally contain isotopologues (e.g., DMT d-9, DMT d-8, etc.), stereoisomers, solvates, or mixtures thereof, of the subject compound in free base or salt form. In some embodiments, the composition is substantially free of other isotopologues of the compound in free base or salt form, for example, the composition 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 compound.

In some embodiments, any position in the compound with deuterium has a minimum deuterium incorporation greater than the deuterium incorporation naturally occurring in hydrogen (about 0.016 atomic %). In some embodiments, any position in the compound with deuterium has a minimum deuterium incorporation of at least 10 atomic %, at least 20 atomic %, at least 25 atomic %, at least 30 atomic %, at least 40 atomic %, at least 45 atomic %, at least 50 atomic %, at least 60 atomic %, at least 70 atomic %, at least 80 atomic %, at least 90 atomic %, at least 95 atomic %, at least 99 atomic % at the deuterium site.

In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle and at least two pharmaceutically acceptable salts of compounds of Formula (I) (the pharmaceutically acceptable salts of at least two compounds of Formula (I) are referred to as an "active salt mixture"). In some embodiments, the pharmaceutical composition comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of DMTd-10, 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 DMTd-9, 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), and optionally (iii) DMT A pharmaceutically acceptable salt of d-8, 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-1,1-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).

In some embodiments, the active salt mixture is a fumarate mixture, wherein the salt form is a fumarate. In some embodiments, the active salt mixture is a benzoate mixture, wherein the salt form is a benzoate. In some embodiments, the active salt mixture is a salicylate mixture, wherein the salt form is a salicylate. In some embodiments, the active salt mixture is a succinate mixture, wherein the salt form is a succinate.

In some embodiments, the pharmaceutical composition comprises an active salt mixture comprising: (i) based on the total weight of the active salt mixture, 60 wt % to 98 wt %, 65 wt % to 97 wt %, 70 wt % to 96 wt %, 75 wt % to 95 wt %, 80 wt % to 94 wt %, 85 wt % to 93 wt %, 90 wt % to 92 wt % of a pharmaceutically acceptable salt of DMT d-10, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8), or any range therebetween, (ii) a pharmaceutically acceptable salt of DMT d-9, i.e., 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-1,2,2-d 3 , in a total amount of 2 wt % to 40 wt _% , 3 wt % to 35 wt %, 4 wt % to 30 wt %, 5 wt % to 25 wt %, 6 wt % to 20 wt %, 7 wt % to 15 wt %, 8 wt % to ₁₀ wt _% , based on the total weight of the active salt mixture, (I-11) or any range therebetween, and (iii) less than 10 wt%, less than 5 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, less than 0.5 wt%, less than 0.25 wt% or 0 wt% of a pharmaceutically acceptable salt of DMT d-8, i.e., 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-2,2-d ₂ (I-8) based on the total weight of the active salt mixture. The total weight of the pharmaceutically acceptable salts of one or more of (I-12), or any range therebetween.

For example, in some embodiments, a pharmaceutical composition comprises an active salt mixture comprising: (i) 90% to 98% by weight, based on the total weight of the active salt mixture, of 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), or any range therebetween, and (ii) 2% to 10% by weight, based on the total weight of the active salt mixture, of 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), or any range therebetween. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) contains no detectable amount or is substantially free of a pharmaceutically acceptable salt of DMT d-8 (a pharmaceutically acceptable 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)), a pharmaceutically acceptable salt of DMT d-7, a pharmaceutically acceptable salt of DMT d-6 (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 d-5, a pharmaceutically acceptable salt of DMT d-4 (a salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d ₄ (I-5)), a pharmaceutically acceptable salt of DMTd-3, a pharmaceutically acceptable salt of DMT d-2 (a salt of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d ₂ (I-2) and/or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d ₂ (I-3)), DMT Pharmaceutically acceptable salts of d-1 and pharmaceutically acceptable salts of DMT (salts of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1)). For example, in some embodiments, the combined weight of pharmaceutically acceptable salts of isotopologues of the compound of Formula (I) not listed in (i) or (ii), such as a pharmaceutically acceptable salt of DMT d-8, a pharmaceutically acceptable salt of DMT d-7, a pharmaceutically acceptable salt of DMT d-6, a pharmaceutically acceptable salt of DMT d-5, a pharmaceutically acceptable salt of DMT d-4, a pharmaceutically acceptable salt of DMT d-3, a pharmaceutically acceptable salt of DMT d-2, a pharmaceutically acceptable salt of DMT d-1, and a pharmaceutically acceptable salt of DMT is less than 1 weight %, less than 0.75 weight %, less than 0.5 weight %, less than 0.4 weight %, less than 0.3 weight %, less than 0.25 weight %, less than 0.2 weight %, less than 0.1 weight % or 0 weight %, based on the total weight of the active salt mixture.

In one example, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90 to 98 wt% of 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-8a), based on the total weight of the active salt mixture, or any range therebetween, and (ii) 2 to 10 wt% of a fumarate 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-10a) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11a), based on the total weight of the active salt mixture, or any range therebetween. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) contains no detectable amounts or is substantially free of the fumarate salt of DMT d-8 (the 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-6a), 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-2,2-d ₂ (I-7a), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,2-d ₂ (I-12a)), the fumarate salt of DMT d-7, the fumarate salt of DMT d-6 (2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine (I-4a) fumarate), DMT d-5 fumarate, DMT d-4 fumarate (2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d ₄ (I-5a) fumarate), DMT d-3 fumarate, DMT d-2 fumarate (2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d ₂ (I-2a) and/or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d ₂ (I-3a)), fumarate of DMTd-1, and fumarate of DMT (fumarate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a)). For example, in some embodiments, the combined weight of the fumarate salts of isotopologues of the compound of formula (I) not listed in (i) or (ii), such as the fumarate salt of DMT d-8, the fumarate salt of DMT d-7, the fumarate salt of DMT d-6, the fumarate salt of DMT d-5, the fumarate salt of DMT d-4, the fumarate salt of DMT d-3, the fumarate salt of DMT d-2, the fumarate salt of DMT d-1, and the fumarate salt of DMT, is less than 1 wt%, less than 0.75 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, less than 0.25 wt%, less than 0.2 wt%, less than 0.1 wt%, or 0 wt%, based on the total weight of the active salt mixture.

In another example, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90 wt% to 98 wt% of 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-8b), based on the total weight of the active salt mixture, or any range therebetween, and (ii) 2 wt% to 10 wt% in total of 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-10b) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11b), based on the total weight of the active salt mixture, or any range therebetween. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) contains no detectable amounts of or is substantially free of the benzoate salt of one or more of DMT d-8 (benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1-d ₂ (I-6b), 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-2,2-d ₂ (I-7b), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12b)), DMT d-7, DMT d-6 (benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-2,2-d ₂ (I-7b), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,2-d 2 (I-12b)). ) benzoate of ethane-1-amine (I-4b)), benzoate of DMT d-5, benzoate of DMT d-4 (benzoate of 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1,2,2-d ₄ (I-5b)), benzoate of DMT d-3, benzoate of DMT d-2 (2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1-d ₂ (I-2b) and/or 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-2,2-d ₂ (benzoate of one or more of (I-3b)), benzoate of DMTd-1 and benzoate of DMT (benzoate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b)). For example, in some embodiments, the combined weight of benzoate salts of isotopologues of compounds of formula (I) not listed in (i) or (ii), such as DMT d-8 benzoate, DMT d-7 benzoate, DMT d-6 benzoate, DMT d-5 benzoate, DMT d-4 benzoate, DMT d-3 benzoate, DMT d-2 benzoate, DMT d-1 benzoate, and DMT benzoate, is less than 1 wt%, less than 0.75 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, less than 0.25 wt%, less than 0.2 wt%, less than 0.1 wt%, or 0 wt%, based on the total weight of the active salt mixture.

In another example, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90 wt% to 98 wt% of a salicylate of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8c), based on the total weight of the active salt mixture, or any range therebetween, and (ii) 2 wt% to 10 wt% of a salicylate 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-10c) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11c), based on the total weight of the active salt mixture, or any range therebetween. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) contains no detectable amount or is substantially free of salicylate of DMT d-8 (salicylate of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1-d ₂ (I-6c), 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-2,2-d ₂ (I-7c), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,2-d ₂ (I-12c)), salicylate of DMT d-7, salicylate of DMT d-6 (salicylate of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine (I-4c)), DMT salicylate of DMT d-5, salicylate of DMT d-4 (salicylate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d ₄ (I-5c)), salicylate of DMT d-3, salicylate of DMT d-2 (salicylate of one or more of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d ₂ (I-2c) and/or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d ₂ (I-3c)), salicylate of DMT d-1, and salicylate of DMT (salicylate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c)). For example, in some embodiments, the combined weight of salicylates of isotopologues of compounds of formula (I) not listed in (i) or (ii), such as salicylate of DMT d-8, salicylate of DMT d-7, salicylate of DMT d-6, salicylate of DMT d-5, salicylate of DMT d-4, salicylate of DMT d-3, salicylate of DMT d-2, salicylate of DMT d-1, and salicylate of DMT, is less than 1 wt%, less than 0.75 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, less than 0.25 wt%, less than 0.2 wt%, less than 0.1 wt%, or 0 wt%, based on the total weight of the active salt mixture.

In yet another example, the pharmaceutical composition comprises an active salt mixture comprising: (i) 90 to 98 wt% of 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-8d), based on the total weight of the active salt mixture, or any range therebetween, and (ii) 2 to 10 wt% in total of a succinate 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-10d) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11d), based on the total weight of the active salt mixture, or any range therebetween. In some embodiments, the active salt mixture (and therefore the pharmaceutical composition) contains no detectable amounts or is substantially free of succinate salts of DMT d-8 (succinate salts of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1-d ₂ (I-6d), 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-2,2-d ₂ (I-7d), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,2-d ₂ (I-12d)), succinate salts of DMT d-7, succinate salts of DMT d-6 (succinate salts of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ ) succinate of ethane-1-amine (I-4d)), succinate of DMT d-5, succinate of DMT d-4 (succinate of 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1,2,2-d ₄ (I-5d)), succinate of DMT d-3, succinate of DMT d-2 (2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1-d ₂ (I-2d) and/or 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-2,2-d ₂ (I-3d)), the succinate of DMTd-1, and the succinate of DMT (the succinate of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d)). For example, in some embodiments, the combined weight of the succinate salts of isotopologues of the compound of formula (I) not listed in (i) or (ii), such as the succinate salt of DMT d-8, the succinate salt of DMT d-7, the succinate salt of DMT d-6, the succinate salt of DMT d-5, the succinate salt of DMT d-4, the succinate salt of DMT d-3, the succinate salt of DMT d-2, the succinate salt of DMT d-1, and the succinate salt of DMT is less than 1 wt%, less than 0.75 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, less than 0.25 wt%, less than 0.2 wt%, less than 0.1 wt%, or 0 wt%, based on the total weight of the active salt mixture.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is chemically pure, for example, by UPLC or HPLC, having a chemical purity of greater than 90%, 92%, 94%, 96%, 97%, 98% or 99%. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) does not have a single impurity greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3% or greater than 0.2% as measured by UPLC or HPLC. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) 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 pharmaceutically acceptable salt of the compound of formula (I) does not have a 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.

Pharmaceutical compositions can be formulated with enantiomerically pure compounds of the present disclosure, such as compounds of formula (I) or racemic mixtures of these compounds. As described herein, the racemic compound of formula (I) can contain about 50% of the R- and S-stereoisomers based on a molar ratio of one of the isomers (about 48 to about 52 mol%, or about 1: 1 ratio). In some embodiments, compositions, medicaments, or methods of treatment may involve combining compounds of R- and S-stereoisomers produced separately in approximately equal molar ratios (e.g., about 48 to 52%). In some embodiments, medicaments or pharmaceutical compositions may contain mixtures of separate compounds of R- and S-stereoisomers in different ratios. In some embodiments, pharmaceutical compositions contain an excess (greater than 50%) of the R-enantiomer. Suitable molar ratios of R/S may be about 1.5: 1, 2: 1, 3: 1, 4: 1, 5: 1, 10: 1 or higher. In some embodiments, pharmaceutical composition can contain excessive S-enantiomer, wherein ratio is provided for R/S reverse.Other suitable amount of R/S can be selected.For example, R-enantiomer can be enriched, for example, can exist in the amount 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, S-enantiomer can be enriched, for example, with 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 ratio between all these exemplary embodiments and the ratio greater than and less than it when still in the disclosure are all included.Composition can contain racemate and the mixture of independent formula (I) compound in salt form.

The pharmaceutical composition can be formulated with one or more crystalline forms of a pharmaceutically acceptable salt of a compound of formula (I), including one or more crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a single crystalline polymorph. The pharmaceutical composition can be formulated with one or more amorphous forms of a pharmaceutically acceptable salt of a compound of formula (I), including one or more amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a single amorphous polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a highly pure crystalline form of a pharmaceutically acceptable salt of a compound of formula (I). For example, the pharmaceutical composition may comprise a pharmaceutically acceptable salt of a compound of formula (I), 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 formula (I) present in the pharmaceutical composition is in crystalline form, e.g., as determined by X-ray powder diffraction and/or DSC.

The pharmaceutical composition can be in the form of capsules, tablets, pills, spheres, lozenges, powders, microparticles, syrups, elixirs, solutions, suspensions, emulsions, suppositories or their sustained release formulations or any other form suitable for administration to mammals. The administration of the subject compound can be systemic or local. In some cases, the pharmaceutical composition is formulated into a pharmaceutical composition suitable for oral, intravenous, subcutaneous, intramuscular, intradermal, transdermal or inhalation administration or other administration routes described herein according to conventional procedures. Examples of suitable pharmaceutical vehicles and methods for their formulations are described below: Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th edition, 1995, Chapters 86, 87, 88, 91 and 92, the document is incorporated herein by reference. The choice of vehicle will be determined in part by a specific compound, salt form and by a specific method for administering the composition. Therefore, there are various suitable formulations of the subject pharmaceutical composition. Liquid form preparations include solutions and emulsions, for example, water, water/propylene glycol solutions, viscous aqueous solutions/suspensions, or organic solvents.

When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable vehicles can be sterile. In some cases, aqueous media are used as vehicles, such as water, saline solutions, viscous aqueous solutions/suspensions, and aqueous glucose and glycerol solutions, for example, when the subject compounds are administered intravenously, subcutaneously, intramuscularly, intradermally, or via inhalation.

The amount of a pharmaceutically acceptable salt of a compound of formula (I) in a unit dose formulation may be varied or adjusted to provide (based on activity) for example 0.001 mg to 1000 mg, 0.001 mg to 500 mg, 0.001 mg to 100 mg, or 0.001 mg to 75 mg, or 0.001 mg to 50 mg, or 0.001 mg to 25 mg, or 0.001 mg to 10 mg, or 0.01 mg to 8 mg, or 0.1 mg to 5 mg, or 1 mg to 3 mg, or 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, about 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg or any range therebetween of a compound of formula (I), or other substances deemed appropriate using sound medical judgment depending on the specific application, route of administration, potency of the active ingredient, etc. The composition may also contain other compatible therapeutic agents if desired.

In some embodiments, based on the total weight of the drug, the pharmaceutical composition comprises at least 0.1% by weight, at least 0.5% by weight, at least 1% by weight, at least 5% by weight, at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 25% by weight, at least 30% by weight, at least 35% by weight, at least 40% by weight, at least 45% by weight, at least 50% by weight, and up to 99.9% by weight, up to 99.5% by weight, up to 99% by weight, up to 98% by weight, up to 97% by weight, up to 95% by weight, up to 90% by weight, up to 85% by weight, up to 80% by weight, up to 75% by weight, up to 70% by weight, up to 65% by weight, up to 60% by weight, up to 55% by weight of a pharmaceutically acceptable salt of a compound of formula (I).

Pharmaceutical compositions disclosed herein can be administered at intervals one or more times. It should be understood that the precise dosage and duration of treatment can vary with the age, weight and condition of the patient to be treated, and can be determined empirically using known test protocols or by extrapolation of in vivo or in vitro tests or diagnostic data. It should also be understood that for any particular individual, a specific dosage regimen can and in some cases should be adjusted over time according to individual needs and the professional judgment of the personnel administering or supervising the administration of the formulation.

In cases where the patient's condition does not improve, at the physician's discretion, the compounds may be administered chronically, i.e., over an extended period of time, including throughout the patient's life span, in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

In cases where the patient's condition does improve, the compound may be discontinued continuously or temporarily for a certain length of time (ie, a "drug holiday"), at the physician's discretion.

Once the patient's condition improves, a maintenance dose may be administered as necessary. Subsequently, the dose or the frequency of administration, or both, may be reduced to a level that maintains the improved condition as the symptoms develop. However, once any recurrence of symptoms occurs, the patient may require long-term intermittent treatment.

In some embodiments, the pharmaceutical composition has an onset of therapeutic action of 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes or less. In some embodiments, the pharmaceutical composition has an acute effect duration of 480 minutes, 420 minutes, 360 minutes, 300 minutes, 240 minutes, 180 minutes, 120 minutes, 110 minutes, 100 minutes, 90 minutes, 80 minutes, 70 minutes, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes or less. In some embodiments, the pharmaceutical composition has a drug dissolution time of 120 seconds, 90 seconds, 60 seconds, 50 seconds, 40 seconds, 30 seconds, 20 seconds, 10 seconds, 5 seconds or less.

As described below, the pharmaceutical compositions of the present disclosure may be specifically formulated for administration in solid, semisolid or liquid forms, including those suitable for:

A. Oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, films or capsules (e.g., capsules intended for buccal, sublingual and systemic absorption), boluses, powders, granules, syrups, pastes applied to the tongue;

B. Parenteral administration, for example by subcutaneous, intradermal, intramuscular, intravenous or epidural injection, such as a sterile solution or suspension or a sustained release formulation, including viscous aqueous solutions/suspensions or other formulations producing a depot effect;

C. topical application/transdermal administration, for example, to the skin as a cream, ointment or controlled release patch or spray, or to orifices and/or mucosal surfaces, such as intranasal administration, for example, as an aqueous or non-aqueous solution, suspension, liposomal dispersion, emulsion, microemulsion or sol-gel, intravaginal or intrarectal administration, for example, as a vaginal suppository, cream or foam;

D. modified release dosage forms, including delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated, rapid, targeted, programmed release, and gastric retention dosage forms, which can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126); and

E. Administration by inhalation, for example as an aerosol, preferably a mist.

Any of the pharmaceutical compositions described herein may comprise (as an active ingredient) at least one pharmaceutically acceptable salt of a compound of formula (I) described herein.Tamper-resistant dosage forms/packaging of any of the disclosed pharmaceutical compositions are contemplated.

A. Oral administration

Pharmaceutical compositions disclosed herein can be provided in solid, semisolid or liquid dosage forms for oral administration, including intestinal/gastric delivery routes and intraoral routes, such as buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, buccal tablets, lozenges, lozenges, cachets, spheres, medicated chewing gums, microparticles, bulk powders, effervescent or non-effervescent powders or microparticles, solutions, emulsions, suspensions, solutions, wafers, sprays, elixirs and syrups. Oral dosage forms disclosed herein can be optionally formulated with monoamine oxidase (MAO) inhibitors (including reversible inhibitors of monoamine oxidase type A (RIMA)) to improve the oral bioavailability of the compound of formula (I) by minimizing the enzymatic degradation mediated by the MAO enzyme (such as deamination/oxidation process). In addition to the active ingredient and any optional MAO inhibitor, the pharmaceutical composition may contain one or more pharmaceutically acceptable vehicles including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, and flavoring agents.

Binders or granulating agents impart cohesiveness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extracts of Irish moss, Panwar gum, ghattigum, isabgol gum, and tartrate. husk), carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), magnesium aluminum silicate (Veegum), larch arabinogalactan, powdered tragacanth and guar gum; cellulose, such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler can be present in the pharmaceutical compositions disclosed herein at, for example, about 10 wt %, about 20 wt %, about 30 wt %, about 40 wt %, about 50 wt %, about 60 wt %, about 70 wt %, about 80 wt %, about 90 wt %, about 99 wt %, or any range therebetween.

Suitable diluents include but are not limited to dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can impart properties to some compressed tablets, which allow disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to: agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and magnesium aluminum silicate HV; citrus pulp; cross-linked celluloses such as cross-linked carboxymethylcellulose; cross-linked polymers such as cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; arrays; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions disclosed herein may contain, for example, about 0.5% to about 15% by weight or about 1% to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to: calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silicon dioxide or silica gel, such as 200 (WR Grace Co., Baltimore, Md.) and (Cabot Co. of Boston, Mass.); and mixtures thereof. The pharmaceutical compositions disclosed herein may contain, for example, from about 0.1 wt % to about 5 wt % of a lubricant.

Suitable glidants include colloidal silicon dioxide, (Cabot Co. of Boston, Mass.) and asbestos-free talc.

Colorants include any approved, certified water soluble FD&C dyes and water insoluble FD&C dyes suspended on hydrated alumina, as well as color bands and mixtures thereof. Color bands are made by adsorbing water soluble dyes to a combination of oxidized water of heavy metals, thereby producing an insoluble form of the dye.

Flavoring agents include natural flavors extracted from plants, such as fruits, as well as synthetic blends of compounds that produce a pleasant mouthfeel sensation, such as peppermint and methyl salicylate.

Sweeteners include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame.

Suitable emulsifiers include gelatin, gum arabic, gum tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate.

Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, gum tragacanth, magnesium aluminum silicate, acacia, hydroxypropyl methylcellulose and polyvinyl pyrrolidone.

Preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol.

Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

Solvents include glycerol, sorbitol, ethanol and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many excipients may serve multiple functions, even within the same formulation.

Pharmaceutical compositions disclosed herein can be formulated into compressed tablets, capsules, caplets, capsule-shaped tablets and tablet compositions, tablet grinds, chewable tablets, fast dissolving tablets, multiple compressed tablets or enteric coated tablets, caplets and tablets, sugar coated tablets, caplets and tablets, or film coated tablets, caplets and tablets. Enteric coated tablets are compressed tablets coated with substances that resist gastric acid but dissolve or disintegrate in the intestines, thereby protecting the active ingredients from the influence of the gastric acid environment. Enteric coating agents include but are not limited to fatty acids, fats, phenyl salicylate, wax, shellac, ammoniacal shellac and cellulose acetate phthalate. Sugar coated tablets are compressed tablets surrounded by sugar coatings, which can be beneficial for covering unpleasant tastes or smells and preventing tablet oxidation. Film coated tablets are compressed tablets covered by thin layers or films or water-soluble materials. Film coatings include but are not limited to hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coating imparts the same general properties as sugar coating.Multiple compressed tablets are compressed tablets prepared by more than one compression cycle, including layered tablets and compression coatings or dry coated tablets.The oral pharmaceutical composition of the present disclosure can be in a solid dosage form for oral administration, for example, obtained by dry granulation by single or multiple compression of powders or microparticles.In some embodiments, the oral pharmaceutical composition can be obtained by using wet granulation techniques.In some embodiments, the oral pharmaceutical composition can be obtained by molding, heating/annealing or extrusion techniques.

Tablet dosage forms can be prepared from active ingredients in powdered, crystalline or granular form alone or in combination with one or more of the vehicles described herein (including binders, disintegrants, controlled release polymers, lubricants, diluents and/or coloring agents). Flavoring agents and sweeteners are particularly useful for forming chewable tablets and lozenges.

In some embodiments, a pharmaceutical composition (eg, a tablet composition formulated for oral administration, such as a monolayer tablet composition) comprises any pharmaceutically acceptable salt of a compound of Formula (I) described herein and a polymer.

In some embodiments, the tablet composition is a modified release tablet suitable for sustained release and preferably maximum sustained release. In some embodiments, the release time period of any compound described herein (e.g., a compound of formula (I)) in the formulation of the present disclosure is greater than 4 hours, greater than 6 hours, greater than 8 hours, greater than 10 hours, greater than 12 hours, greater than 16 hours, greater than 20 hours, greater than 24 hours, greater than 28 hours, greater than 32 hours, greater than 36 hours, greater than 48 hours.

In some embodiments, tablet compositions are suitable for tamper resistance. In some embodiments, tablet compositions include, for example, a combination of polyoxyethylene (PEO) with a MW of about 2,000 to about 7,000 KDa and HPMC. In some embodiments, the tablet compositions may further include polyethylene glycol (PEG), for example, PEG 8K. In some embodiments, tablet compositions may further include a polymer carrying one or more negatively charged groups, for example, polyacrylic acid. In some embodiments, the tablet compositions including PEO are further subjected to heating/annealing, for example, extrusion conditions.

In some embodiments, the pharmaceutical composition comprises a combination of: (i) a water-insoluble neutrally charged nonionic matrix; (ii) a polymer carrying one or more negatively charged groups; and (iii) any pharmaceutically acceptable salt of a compound of formula (I) described herein.

In some embodiments, the polymer carrying one or more negatively charged groups is selected from the group consisting of: polyacrylic acid, polylactic acid, polyglycolic acid, polyacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic gum, its salt and mixture thereof. In some embodiments, anionic gum is selected from the group consisting of naturally occurring materials and semi-synthetic materials. In some embodiments, naturally occurring materials are selected from the group consisting of: alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, karaya gum, guar gum and tragacanth. In some embodiments, semi-synthetic materials are selected from the group consisting of carboxymethyl-chitin, cellulose gum.

Furthermore, without wishing to be bound by theory, in some embodiments, the action of a polymer carrying one or more negatively charged groups (e.g., an acidic moiety in an acidic polymer as described herein) surprisingly provides significant retention of any compound described herein (e.g., a compound of formula (I)) in a matrix. In some embodiments, this negative charge can be generated in situ, for example, based on proton release due to pKa and under certain pH conditions or by electrostatic interaction/generation of negative charges. It is further noted that the acid polymer can be a salt of a corresponding weak acid, which would be a relevant protonated acid in the stomach; without wishing to be bound by theory, it would neutralize the charge and could reduce the interaction of any compound described herein with the matrix. Additionally, the release matrix can be further envisioned by other inactive pharmaceutical ingredients such as fillers, disintegrants, flow improvers, lubricants, colorants, taste masking agents used to aid in the preparation of appropriate solid dosage forms.

In some embodiments, the water-insoluble neutrally charged nonionic matrix is selected from a cellulose-based polymer, such as HPMC, alone or by mixing with a component selected from the group consisting of: starch; wax; neutral gum; polymethacrylate; PVA; PVA/PVP blend; and mixtures thereof. In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).

In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the tablet composition comprises about 10% to 70%, 20% to 60%, or 30% to 50% by weight of hydroxypropyl methylcellulose, about 10% to 30% or about 15% to 20% by weight of starch, or any combination thereof.

The dosage form can be an immediate release (IR) dosage form, examples of which include, but are not limited to, immediate release (IR) tablets or immediate release (IR) capsules. The dosage form suitable for immediate release can include one or more pharmaceutically acceptable vehicles that are easily dispersed, dissolved or decomposed in the gastric environment so as not to delay or prolong the dissolution/absorption of the active ingredient. Examples of pharmaceutically acceptable vehicles for immediate release dosage forms include, but are not limited to, one or more binders/granulators, matrix materials, fillers, diluents, disintegrants, dispersants, solubilizers, lubricants and/or performance modifiers. In some embodiments, the immediate release (IR) dosage form is an immediate release (IR) tablet comprising one or more of microcrystalline cellulose, sodium carboxymethyl cellulose, magnesium stearate, mannitol, cross-linked polyvinylpyrrolidone and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form includes microcrystalline cellulose, sodium carboxymethyl cellulose and magnesium stearate. In some embodiments, the immediate release (IR) dosage form includes mannitol, cross-linked polyvinylpyrrolidone and sodium stearyl fumarate.

Pharmaceutical compositions disclosed herein can be formulated into soft capsules or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules (also referred to as dry filled capsules (DFC)) consist of two parts, one part is enclosed on the other part, so as to completely encapsulate the active ingredient. Soft elastic capsules (SEC) are soft spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. Soft gelatin shells can contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methylparaben and propylparaben and sorbic acid. Liquid, semisolid and solid dosage forms disclosed herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oil or triglycerides. Capsules can also be coated as known to those skilled in the art to modify or maintain the dissolution of active ingredients.

Pharmaceutical compositions disclosed herein can be in the form of an oral dispersible dosage form (ODF). Such dosage forms allow for the pregastric absorption of the compounds herein, such as when administered intraorally by the oral mucosal layer, such as buccal, tongue and sublingual administration, compared with oral administration by the gastrointestinal tract, bioavailability is improved and the onset is faster. Oral dispersible dosage forms can be prepared by different techniques, such as freeze drying (lyophilization), molding, spray drying, mass extrusion or compression. Preferably, oral dispersible dosage forms are prepared by lyophilization. In some embodiments, the oral dispersible dosage form is received in the oral cavity in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20, less than about 10 seconds, less than about 5 seconds or less than about 2 seconds. In some embodiments, the oral dispersible dosage form is received in the oral cavity in less than about 90 seconds, less than about 60 seconds or less than about 30 seconds. Dissolve. In some embodiments, the orally dispersible dosage form is dispersed in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the pharmaceutical composition is in the form of an orally dispersible dosage form, such as an orally disintegrating tablet (ODT), with a disintegration time of no more than about 30 seconds, no more than about 20 seconds, no more than about 10 seconds, no more than about 5 seconds, no more than about 2 seconds according to the United States Pharmacopeia (USP) disintegration test <701>. Orally dispersible dosage forms with longer disintegration times according to the United States Pharmacopeia (USP) disintegration test <701> are also contemplated, such as when suitable for delayed release, for example, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, or any range or longer therebetween.

In some embodiments, the orally dispersible dosage form is a sublingual dosage form that disintegrates/dissolves under the tongue, whereby the contents (e.g., compounds of the present disclosure) are absorbed by the mucosa under the tongue that enters the venous circulation. In some embodiments, the sublingual dosage form disintegrates/dissolves under the tongue, whereby the contents are converted into a liquid or semisolid dosage form, such as a solution, syrup, or paste, when mixed with saliva, and then swallowed. In some embodiments, the orally dispersible dosage form is a buccal dosage form to be disintegrated/dissolved in the buccal cavity, whereby the contents (e.g., compounds of the present disclosure) are absorbed by the oral mucosal lining, which enters the venous circulation in the mouth. In some embodiments, the buccal dosage form disintegrates/dissolves in the buccal cavity, whereby the contents are converted into a liquid or semisolid dosage form, such as a solution, syrup, or paste, after mixing with saliva, and then swallowed.

In some embodiments, pharmaceutical composition is in the form of oral dispersible dosage form, such as quick dissolving tablet, also referred to as oral dispersible tablet or oral disintegrating tablet (ODT) or fast dispersible tablet (FDT). Quick dissolving tablet can be prepared by different techniques, such as freeze drying (lyophilization), molding, spray drying, mass extrusion or compression. Preferably, quick dissolving tablet is prepared by freeze drying. In some embodiments, quick dissolving tablet is received in the oral cavity in the oral cavity in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20, less than about 10 seconds, less than about 5 seconds or less than about 2 seconds. In some embodiments, when placed in an aqueous environment (such as in the oral cavity), quick dissolving tablet is less than about 90 seconds, less than about 60 seconds or less than about 30 seconds.

In some embodiments, the pharmaceutical composition is in the form of freeze-dried FDT. In some embodiments, freeze-dried FDT is produced by subliming water from a drug pre-frozen aqueous formulation containing a matrix forming agent and other media (such as those described herein, such as one or more freeze-dried protective agents, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc.) to produce a porous matrix. In some embodiments, FDT comprises two component frameworks of a freeze-dried matrix system, which work together to ensure the development of a successful formulation. In some embodiments, the first component is a water-soluble polymer, such as gelatin, dextrose, alginic acid, and maltodextrin. This component maintains shape and provides mechanical strength (adhesive) for tablets. In some embodiments, the second component is a matrix support/disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium phosphate, and/or starch, which acts and accelerates the disintegration of FDT by gluing the porous skeleton provided by a water-soluble polymer. In some embodiments, freeze-dried FDT includes gelatin and mannitol. In some embodiments, the lyophilized oral dispersible dosage form (e.g., lyophilized FDT) includes gelatin, mannitol, and one or more lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc., with particular mention of citric acid. A non-limiting example is Orally dispersible tablets (available from Catalent). In some embodiments, the formulation (e.g. Oral dispersible tablets) include one or more water-soluble polymers (such as gelatin), one or more matrix materials, fillers or diluents (such as mannitol), a pharmaceutically acceptable salt of a compound of formula (I), and optional lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers and/or flavoring agents. In some embodiments, formulations (such as Zydis oral dispersible tablets) include gelatin, mannitol, a pharmaceutically acceptable salt of a compound of formula (I) and an organic acid, non-limiting examples of organic acids being citric acid and/or tartaric acid.

In some embodiments, the pharmaceutical composition is in the form of an oral dispersible dosage form, such as a freeze-dried disc. In some embodiments, the pharmaceutical composition is in the form of a freeze-dried disc, and long-term storage protection is carried out by special packaging that is moisture-proof, oxygen-proof and light-proof. In some embodiments, a porous matrix is produced by sublimating water from a pharmaceutical pre-freezing aqueous formulation containing a matrix forming agent and other excipients (such as a freeze-dried protective agent, a preservative and a flavoring agent), thereby producing a freeze-dried disc. In some embodiments, the freeze-dried disc includes a water-soluble film matrix. In some embodiments, the disc includes two component frameworks of a freeze-dried matrix system, which work together to ensure the development of a successful formulation. In some embodiments, the first component is a water-soluble polymer, such as gelatin, dextrose, alginic acid and maltodextrin. This component maintains shape and provides mechanical strength (adhesive) for the disc. In some embodiments, the second component is a matrix support/disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium phosphate and/or starch, which acts by cementing the porous framework provided by the water-soluble polymer and accelerates the disintegration of the disc. In some embodiments, the lyophilized disc includes gelatin and mannitol. In some embodiments, the lyophilized disc includes gelatin, mannitol and one or more lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc., particularly citric acid.

In some embodiments, the disc may include a single layer, a double layer or a triple layer. In some embodiments, the single layer disc contains an active agent and one or more mediators, such as those described herein. In some embodiments, the double layer disc contains one or more mediators, such as a solubilizing agent, in the first layer, and contains an active agent in the second layer. Compared with the case where the mediator and the active agent are contained in a single layer, this structure allows the active agent to be stored separately from the mediator, and the stability of the active agent can be increased, and the shelf life of the composition can be optionally increased. For a three-layer disc, each layer can be different, or two layers (such as an upper layer and a lower layer) can have substantially the same composition. In some embodiments, the lower layer and the upper layer surround the core layer containing the active agent. In some embodiments, the lower layer and the upper layer can contain one or more mediators, such as a solubilizing agent. In some embodiments, the lower layer and the upper layer have the same composition. Alternatively, the lower layer and the upper layer can contain different mediators or different amounts of the same mediator. The core layer generally contains an active agent, optionally containing one or more mediators.

Pharmaceutically acceptable vehicles (e.g., carriers or excipients) that can be used in an orally dispersible dosage form (ODF) include, but are not limited to, lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, cyclodextrins, bioadhesives, permeation agents/absorption enhancers, or other pharmaceutically acceptable vehicles listed herein.

Examples of pharmaceutically acceptable lyoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose; anionic polymers such as sulfobutyl ether-β-cyclodextrin (SBECD) and hyaluronic acid and hydroxylated cyclodextrin.

Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol.

Examples of pharmaceutically acceptable antioxidants, which can act to further enhance the stability of the composition, include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine or its salts (cysteine hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

Examples of pharmaceutically acceptable stabilizers 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 pyrrolidone, polyvinyl ethers, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerol, methionine, monothioglycerol, ascorbic acid, citric acid, polysorbates, arginine, cyclodextrins, microcrystalline cellulose, modified cellulose (e.g., carboxymethyl cellulose, sodium salt), sorbitol, and cellulose gel.

Examples of pharmaceutically acceptable solubilizers (or dissolution aids) include, but are not limited to, citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyethylene glycol 40 stearate, purified shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-asparagine, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginic acid, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, powdered agar, guar gum, succinic acid, povidone, cellulose phthalate, tartaric acid, dioctyl sodium sulfosuccinate, zein, powdered skim milk, sorbitan trihydrate. , lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol 35 castor oil, poly (sodium 4-styrene sulfonate), polyvinyl acetal diethylamino acetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauroyl alcohol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzene sulfonate, vinyl pyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyl tryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate. Among them, in some embodiments, such as in ODT formulations, citric acid is preferred.

Flavoring agents include natural flavors extracted from plants such as fruits, as well as synthetic blends of compounds that produce a pleasant mouthfeel sensation or a taste-masking effect. Examples of flavoring agents include, but are not limited to, aspartame, saccharin (such as sodium, potassium or calcium saccharin), cyclic esters (such as sodium, potassium or calcium salts), sucrose, acesulfame-K, thaumatin, neohesperidin, dihydrochalcone, ammoniated glycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime and lemon lime.

Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin or other solvated derivatives may also be advantageously used to enhance the delivery of the compositions described herein.

Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, modified cellulose gum, and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as moderately cross-linked starch, modified starch, and sodium carboxymethyl starch; acrylic acid polymers such as carbomer and its derivatives (polycarbophil, etc.); polyvinyl pyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; poly-co-(methyl vinyl ether/maleic anhydride); and cross-linked carboxymethyl cellulose (e.g., cross-linked sodium carboxymethyl cellulose). Such polymers can be cross-linked. Combinations of two or more bioadhesives can also be used.

Examples of permeation agents/absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide, and the like; menthol; surfactant-lecithin organogels (PLOs), such as those formed from an aqueous phase having one or more of poloxamers, CARBOPOL, and PEMULEN, a lipid phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate and lecithin; fatty acids, esters, and alcohols such as oleyl oleate and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers such as diethylene glycol monoethyl ether; including mixtures thereof.

Disclosed herein are pharmaceutical compositions in modified release dosage forms, comprising a compound as disclosed herein and one or more controlled release excipients or carriers as described herein. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multi-particulate devices, and combinations thereof. The pharmaceutical composition may also include non-controlled release excipients or carriers.

Further disclosed herein are pharmaceutical compositions in enteric-coated dosage forms, comprising a compound as disclosed herein and one or more controlled-release excipients or carriers for use in enteric-coated dosage forms. The pharmaceutical composition may also include non-controlled-release excipients or carriers.

Further disclosed herein are pharmaceutical compositions in effervescent dosage form, comprising a compound as disclosed herein and one or more excipients or carriers for controlled release in effervescent dosage form. The pharmaceutical composition may also include non-release-controlling excipients or carriers.

In addition, a pharmaceutical composition in a dosage form having an immediate release component and at least one delayed release component and capable of discontinuously releasing a compound in the form of at least two consecutive pulses is disclosed, wherein the pulses are separated in time by about 0.1 hour to about 24 hours (e.g., about 0.1 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 10 hours, 22 hours or 24 hours). The pharmaceutical composition comprises a compound as disclosed herein and one or more controlled and non-controlled release excipients or carriers, such as those excipients or carriers suitable for a destructible semipermeable membrane and as a swellable substance.

Also disclosed herein is a pharmaceutical composition in a dosage form for oral administration to a subject, comprising a salt form of a compound disclosed herein and one or more pharmaceutically acceptable vehicles, encapsulated in an intermediate reaction layer comprising a gastro-resistant polymer layered material partially neutralized with a base and having cation exchange capacity and a gastro-resistant outer layer.

In some embodiments, the pharmaceutical composition is in the form of an immediate release capsule for oral administration, and may further include cellulose, iron oxide, lactose, magnesium stearate, and sodium carboxymethyl starch.

In some embodiments, the pharmaceutical composition is in the form of a delayed-release capsule for oral administration, and may further include cellulose, ethyl cellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

In some embodiments, the pharmaceutical composition is in the form of an enteric-coated delayed-release tablet for oral administration, and may further include carnauba wax, crospovidone, diacetyl monoglyceride, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow iron oxide.

In some embodiments, the pharmaceutical composition is in the form of an enteric-coated delayed-release tablet for oral administration and may further include calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

Further disclosed herein is a pharmaceutical composition of an effervescent dosage form, comprising a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutically acceptable vehicles, which may be a controlled release vehicle and/or a non-controlled release vehicle. Effervescent means that the dosage form forms gas when mixed with liquids such as water, juice, saliva, etc. In some embodiments, the effervescent dosage form of the present disclosure comprises an organic acid and a carbon dioxide source, referred to herein as "effervescent pair". This effervescent dosage form effervescents (releases gas) by a chemical reaction between an organic acid and a carbon dioxide source, which occurs when exposed to an aqueous environment, such as when placed in water, juice or other drinkable fluids, or from an aqueous environment in the oral cavity (such as saliva in the oral cavity). Specifically, the reaction between an organic acid and a carbon dioxide source produces carbon dioxide gas when in contact with an aqueous medium such as water, juice or saliva. Although the use of a disintegrant is optional, an effervescent dosage form does not require a disintegrant because the generation of in-situ gas promotes the disintegration process.

For clarity, an "effervescent pair" refers to at least one organic acid and at least one carbon dioxide source contained in a dosage form, regardless of assembly, e.g., the organic acid and carbon dioxide source can be mixed (as powders), layered on top of each other, agglomerated or "glued" together in granular form, or kept separate from each other, such as in separate layers within a dosage form. In addition, the term "pair" herein is not meant to be limited to an organic acid and a carbon dioxide source, and other materials may be included unless otherwise specified; for example, an effervescent agglomerate/microparticle made by combining (or "gluing") an organic acid and a carbon dioxide source may include other media, including a binder ("glue"), and the effervescent agglomerate/microparticle may still be referred to as an effervescent pair.

The organic acid can be a monoacid, a diacid, a triacid, a tetraacid, or can contain a greater number of acid groups. One organic acid or a mixture of organic acids can be used. In addition to the acid group (e.g., one or more carboxylic acid moieties), the organic acid can also contain one or more hydroxyl functional groups as part of its structure (i.e., the organic acid can be a hydroxy acid). In some embodiments, the organic acid is an α-hydroxy acid. In some embodiments, the organic acid is a β-hydroxy acid. In some embodiments, the organic acid is a γ-hydroxy acid. Examples of hydroxy acids include but are not limited to glycolic acid, lactic acid, citric acid, tartaric acid, and malic acid. In some embodiments, the organic acid is citric acid and/or tartaric acid. In some embodiments, the organic acid is citric acid. In some embodiments, the organic acid is tartaric acid. In some embodiments, the organic acid is a diacid, examples of which may include but are not limited to fumaric acid and maleic acid. In some embodiments, the organic acid is fumaric acid. In some embodiments, the organic acid is maleic acid. Disclosed mixtures and/or hydrates of organic acids can also be used in disclosed pharmaceutical compositions. In some embodiments, the organic acid is not a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the organic acid is not a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, gentisic acid, etc.).

Carbon dioxide source can include but is not limited to sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate and sesquicarbonate. Carbon dioxide source can be used alone or in combination. In some embodiments, carbon dioxide source is sodium bicarbonate. In some embodiments, carbon dioxide source is sodium carbonate. In some embodiments, carbon dioxide source is potassium carbonate. In some embodiments, carbon dioxide source is potassium bicarbonate. However, in addition to carbon dioxide source or instead of carbon dioxide source, it is also envisioned that in the disclosed effervescent dosage form, oxygen or other gases that form in addition to carbon dioxide and reactants that are safe for human consumption are used. Although it is not desired to be bound by theory, it is believed that effervescence can help to quickly decompose dosage forms, and in some routes of administration such as oral routes, it can help to reduce the sense of grit by providing a dispersed sensory experience of effervescence.

In some embodiments, the effervescent dosage form will be restored in a drinkable fluid such as water or juice, thereby forming an oral liquid dosage form (e.g., solution) before consumption. In some embodiments, the effervescent dosage form will be placed in the oral cavity, contacting with an aqueous environment (saliva) in the oral cavity causes disintegration/dissolution and effervescence of the dosage form. Here, the contents of the effervescent dosage form can be converted into a liquid or semisolid dosage form when mixed with saliva, such as a solution, syrup or paste, and swallowed subsequently. Alternatively, the effervescent dosage form can be an intraoral dosage form, such as a cheek, tongue or sublingual dosage form, thereby being placed in the aqueous environment (saliva) of the oral cavity causing disintegration/dissolution and effervescence of the dosage form, and the contents are absorbed before the stomach by the oral mucosa. Compared with oral administration by the gastrointestinal tract, such pregastric absorption can provide increased bioavailability and faster initiation. In some embodiments, the effervescent dosage form is a sublingual dosage form that disintegrates/dissolves under the tongue, whereby the contents (e.g., a compound of the present disclosure) are absorbed by the mucosa under the tongue that enters the venous circulation. In some embodiments, the effervescent dosage form is a buccal dosage form to be disintegrated/dissolved in the buccal cavity, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the oral mucosal lining, which enters the venous circulation in the mouth. Effervescent dosage forms may be advantageous for treating pediatric/adolescent patients or patients who generally have difficulty swallowing traditional dosage forms such as conventional tablets or capsules, because the effervescent dosage form can be reconstituted into an easy-to-swallow liquid or semisolid dosage form or taken orally.

When suitable for oral administration, in addition to the effervescent pair, it may be beneficial to formulate an effervescent dosage form with a bioadhesive. A "bioadhesive" is a substance that promotes adhesion or adhesion to a biological surface such as a mucous membrane. For example, when placed in contact with the surface (e.g., mucous membrane), the bioadhesive itself can adhere to the biological surface so that the composition of the present disclosure can adhere to the surface, which promotes the content to be more effectively transferred from the dosage form to the biological surface. Various polymers known in the art can be used as bioadhesives, such as polymeric substances, preferably with an average (weight average) molecular weight higher than 5,000 g/mol. Preferably, such polymeric materials can swell rapidly when placed in contact with an aqueous medium such as water or saliva, and/or are substantially insoluble in water at room temperature and atmospheric pressure. Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, modified cellulose gum, and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as moderately cross-linked starch, modified starch, and sodium carboxymethyl starch; acrylic acid polymers such as carbomer and its derivatives (polycarbophil, etc.); polyvinyl pyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; poly-co-(methyl vinyl ether/maleic anhydride); and cross-linked carboxymethyl cellulose (e.g., cross-linked sodium carboxymethyl cellulose). Such polymers can be cross-linked. Combinations of two or more bioadhesives can also be used.

The effervescent pair can be coated with a pharmaceutically acceptable vehicle, for example, with a binder, a protective coating (such as a solvent protective coating), an enteric coating, an anti-caking agent and/or a pH adjusting agent, to prevent, for example, premature reaction with other components included in air, moisture and/or a pharmaceutical composition. Each component of the effervescent pair (such as an organic acid and/or a carbon dioxide source) can also be coated with a pharmaceutically acceptable vehicle alone, for example, with a binder, a protective coating (such as a solvent protective coating), an enteric coating, an anti-caking agent and/or a pH adjusting agent, to prevent, for example, premature reaction with other components included in air, moisture and/or a pharmaceutical composition. The effervescent pair can also be mixed with previously lyophilized particles, such as one or more pharmaceutically active ingredients coated with a solvent protective or enteric coating.

Effervescent dosage forms can be prepared by methods known to those skilled in the art, including but not limited to slugging, direct compression, roller compaction, dry or wet granulation, fusion granulation, melt granulation, vacuum granulation and fluidized bed spray granulation, any of which can optionally be followed by compression/tabletting.

Pharmaceutical composition disclosed herein can be formulated as non-effervescent or effervescent microparticles and powders.Non-effervescent or effervescent microparticles and powders can be restored to liquid dosage forms, or alternatively compressed to form tablet dosage forms, which are non-effervescent or effervescent, respectively. Pharmaceutically acceptable vehicles for non-effervescent or effervescent microparticles or powders can include but are not limited to adhesives, granulators, fillers, diluents, sweeteners, wetting agents, stabilizers, solubilizers, anti-caking agents, pH adjusting agents or any other pharmaceutical vehicles described herein. In some embodiments, pharmaceutically acceptable vehicles include organic acids, such as glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid and/or maleic acid.

Pharmaceutically acceptable vehicles for effervescent microparticles or powders include effervescent pairs, i.e., organic acids and carbon dioxide sources. Effervescent powders can be produced by blending or mixing organic acids and carbon dioxide sources (effervescent pairs) and any other pharmaceutically acceptable vehicles required optionally. Effervescent microparticles can be produced by physically adhering or "gluing" effervescent pairs (organic acids and carbon dioxide sources) together using edible or pharmaceutically acceptable adhesives, such as polyvinyl pyrrolidone, polyvinyl alcohol, L-leucine, polyethylene glycol, gum arabic, etc., including their combinations. These types of microparticles are made by the process commonly referred to as "wet granulation". Granulation solvents such as ethanol and/or isopropanol are generally used to help the granulation process of this type. Because the effervescent pair is physically combined in microparticles, the gas generation reaction is usually quite violent, thereby resulting in rapid dissolution time. Another type of "wet granulation" product having specificity to effervescent products is referred to as "fusion" type microparticles. These microparticles are formed by reacting an organic acid and a source of carbon dioxide with a small amount of water (or sometimes an aqueous alcohol granulation solvent, such as various commercial grades of ethanol or isopropanol) in a highly controlled manner. Since the effervescent reaction produces carbon dioxide, the fused microparticles are often quite porous, which reduces the density of the fused microparticles and the dissolution time of the fused microparticles. Therefore, the effervescent microparticles prepared by wet granulation or fusion type methods may be required for preparing oral dispersible dosage forms or other dosage forms seeking fast dissolution/disintegration characteristics. The effervescent tablet dosage form prepared by the tableting of effervescent microparticles or powders, for example, compression is also included in the present disclosure.

The pharmaceutical compositions disclosed herein can be formulated into liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.

In some embodiments, the oral liquid dosage form is prepared by reconstituting a solid dosage form (e.g., an effervescent dosage form) disclosed herein into a pharmaceutically acceptable liquid medium (e.g., an aqueous medium) (e.g., water, juice, or other potable fluid) prior to use. In some embodiments, the oral liquid dosage form is prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of a compound of Formula (I) in crystalline form into a pharmaceutically acceptable aqueous medium. In some embodiments, the oral liquid dosage form is prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of a compound of Formula (I) in amorphous form into a pharmaceutically acceptable aqueous medium.

Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid, which may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may include a pharmaceutically acceptable suspending agent and an optional preservative. Aqueous alcoholic solutions may contain pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes (the term "lower" means an alkyl group having between 1 and 6 carbon atoms), such as acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to facilitate measurement for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients disclosed herein, and dialkylated monoalkylene glycols or polyalkylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, sodium metabisulfite, sulfadipropionic acid and its esters, and dithiocarbamates. In some embodiments, examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin or other solvated derivatives may also be advantageously used to enhance the delivery of the compositions described herein.

The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres or nanosystems.

Pharmaceutical compositions disclosed herein can be disclosed as non-effervescent or effervescent microparticles and powders to be reconstituted into liquid dosage forms. Pharmaceutically acceptable vehicles used in non-effervescent microparticles or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable vehicles used in effervescent microparticles or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions disclosed herein can be formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that supplement the desired effect. An example is an oral dosage form formulated with a monoamine oxidase (MAO) inhibitor (including a reversible inhibitor of monoamine oxidase type A (RIMA)) to improve the oral bioavailability of the compound of formula (I) by minimizing MAO enzyme-mediated enzymatic degradation (such as deamination/oxidation processes).

B. Parenteral Administration

Pharmaceutical compositions disclosed herein can be administered parenterally by injection, infusion, perfusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intradermal, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solutions or suspensions in liquids before injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

In some embodiments, the pharmaceutical composition is in the form of an injectable (liquid) dosage form (e.g., for intravenous, intramuscular, subcutaneous, etc. administration). In some embodiments, the injectable (liquid) dosage form (e.g., for intravenous, intramuscular, subcutaneous, etc. administration) is prepared by reconstituting a solid dosage form disclosed herein into a pharmaceutically acceptable liquid medium before use, such as water, saline solution, viscous aqueous solution/suspension, water-miscible vehicle (e.g., organic solvent, such as N-methyl-2-pyrrolidone), etc. In some embodiments, the injectable (liquid) dosage form is prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of a compound of formula (I) in crystalline form into a pharmaceutically acceptable liquid medium. In some embodiments, the injectable (liquid) dosage form is prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of a compound of formula (I) in amorphous form into a pharmaceutically acceptable liquid medium.

Pharmaceutical compositions for parenteral administration may include one or more pharmaceutically acceptable vehicles including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickeners or viscosity-increasing agents, pH adjusters, and inert gases.

Suitable aqueous vehicles include but are not limited to water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include but are not limited to fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower seed oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil medium chain triglycerides and palm seed oil. Water miscible vehicles include but are not limited to ethanol, 1,3-butylene glycol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide.

Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphate, acetate, and citrate buffers. Suitable antioxidants are those described herein, including bisulfites and sodium pyrosulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable isolating agents or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ca-cyclodextrin, β-cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-7-O-cyclodextrin ( CyDex, Lenexa, Kans.). Suitable thickeners or viscosity enhancers include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose (e.g., sodium carboxymethylcellulose), hydroxypropyl cellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, including cross-linked versions of any of the foregoing and combinations of the foregoing.

In some embodiments, the pharmaceutical composition is in an injectable (liquid) dosage form. In some embodiments, the injectable (liquid) dosage form comprises a pharmaceutically acceptable salt of a compound of formula (I), an aqueous vehicle (e.g., isotonic saline), a buffer (e.g., a citric acid buffer), an optional pH adjusting agent (e.g., sodium hydroxide) and an optional isotonic agent. In some embodiments, the injectable (liquid) dosage form comprises a pharmaceutically acceptable salt of a compound of formula (I), an aqueous vehicle (e.g., isotonic saline) and a pH adjusting agent (e.g., sodium hydroxide), wherein the injectable (liquid) dosage form is prepared without a buffer (e.g., a citric acid buffer). In some embodiments, the injectable (liquid) dosage form is prepared by reconverting a solid dosage form of a pharmaceutically acceptable salt of a compound of formula (I) in crystalline form into an aqueous vehicle (e.g., isotonic saline). The recovery of the pharmaceutically acceptable salt of a compound of formula (I) in crystalline form can be performed immediately before use.

The pharmaceutical compositions disclosed herein can be formulated for single or multiple dose administration. Single dose formulations are packaged in ampoules, vials or syringes. Multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

In some embodiments, the pharmaceutical composition is disclosed as a ready-to-use sterile solution. In some embodiments, the pharmaceutical composition is disclosed as a sterile soluble dry product, including lyophilized powders and subcutaneous tablets, to be reconstituted with a vehicle before use. In some embodiments, the pharmaceutical composition is disclosed as a ready-to-use sterile suspension. In some embodiments, the pharmaceutical composition is disclosed as a sterile insoluble dry product to be reconstituted with a vehicle before use. In some embodiments, the pharmaceutical composition is disclosed as a ready-to-use sterile emulsion.

The pharmaceutical composition may be formulated as a suspension, solid, semisolid or thixotropic liquid for administration as an implanted depot or to produce a depot-like effect.

In some embodiments, the pharmaceutical composition disclosed herein is dispersed in a solid inner matrix, and the pharmaceutical composition is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through. Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicic acid ester copolymers, hydrophilic polymers (such as hydrogels of acrylic acid and methacrylate), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. Suitable outer polymer films include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/vinyloxyethanol copolymers.

In some embodiments, the pharmaceutical composition is in the form of a viscous aqueous solution/suspension for injection, to provide slow/continuous absorption or a reservoir-like effect. Here, a pharmaceutical vehicle for increasing viscosity, such as a thickener or a tackifier, can be used, including but not limited to polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose), hydroxypropyl cellulose, chondroitin sulfate and its salt, hyaluronic acid and its salt and a combination of the foregoing substances. In some embodiments, a pharmaceutically acceptable vehicle includes sodium carboxymethyl cellulose, hyaluronic acid and its salt or a combination thereof. In some embodiments, a pharmaceutically acceptable vehicle includes hyaluronic acid or its salt. Such viscous aqueous solution/suspension dosage forms may be particularly suitable for subcutaneous or intramuscular administration, wherein the active ingredient can be slowly released from the injection site and absorbed within the duration, producing a reservoir-like release effect. In addition, a cross-linked form of any of the foregoing substances can be used. The release rate of the active ingredient can be controlled by the degree of cross-linking of any thickener or tackifier described herein, or by controlling the cross-linking rate of any of the foregoing substances by using a cross-linking agent, the amount or type of the cross-linking agent. For example, by using or forming cross-linked hyaluronic acid at the injection site, slow/sustained absorption or a reservoir effect can be achieved. In some embodiments, the administration of a viscous aqueous solution/suspension dosage form (e.g., by subcutaneous or intramuscular injection) provides a release period of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or any range therebetween or longer.

In some embodiments, the pharmaceutical composition is formulated with a poorly water-soluble pharmaceutically acceptable salt of a compound of formula (I) (e.g., a fatty acid salt of a compound of formula (I)) (e.g., a water solubility of less than 5 mg/mL, less than 4 mg/mL, less than 3 mg/mL, less than 2 mg/mL, less than 1 mg/mL, less than 0.5 mg/mL, less than 0.1 mg/mL at 22°C). Examples of fatty acid salt forms include, but are not limited to, those formed by contacting a compound of formula (I) with adipic/hexandioic, lauric (dodecanoic), linoleic, myristic (tetradecanoic), capric (decanoic), stearic (octadecanoic), oleic, caprylic (octanoic), palmitic (hexadecenoic), sebacic, undecenoic, or caproic acid. Such pharmaceutical compositions are particularly suitable for subcutaneous or intramuscular administration, where the active ingredient can be slowly dissolved and slowly released from the injection site and continuously absorbed, resulting in a depot-like release effect. These "slow release" salts can be optionally formulated with thickeners or viscosity enhancers, for example in viscous aqueous/suspension formulations. In some embodiments, pharmaceutical compositions formulated with a poorly water-soluble pharmaceutically acceptable salt of a compound of formula (I) administered, for example, by subcutaneous or intramuscular injection provide a release period of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or any range therebetween or longer.

C. Topical application

The pharmaceutical compositions disclosed herein can be topically applied to the skin, orifices or mucosa.Topical administration described herein includes conjunctival, intracorneal, intraocular, intraocular, intraauricular, transdermal, nasal (e.g., intranasal), vaginal, urethral, respiratory and rectal administration.

The pharmaceutical compositions disclosed herein can be suitable for topical application for any dosage form formulation for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, infusions, sprays, suppositories, bandages, skin patches. The topical formulations of the pharmaceutical compositions disclosed herein can contain active ingredients, which can be mixed with pharmaceutically acceptable vehicles and any preservatives, buffers, absorption enhancers, and propellants that may be needed under aseptic conditions. Liposomes, micelles, microspheres, nanosystems, and mixtures thereof can also be used. The dosage form for topical application (e.g., intranasal application) can be optionally formulated with a monoamine oxidase (MAO) inhibitor (including a reversible inhibitor of monoamine oxidase type A (RIMA)) to improve the bioavailability of the compound of formula (I) by minimizing the enzymatic degradation mediated by the MAO enzyme (e.g., deamination/oxidation process).

Pharmaceutically acceptable vehicles suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubilizers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickeners or viscosity-increasing agents, and inert gases.

Ointments, pastes, creams and gels may contain, in addition to the active ingredient, vehicles such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the active ingredient, powders and sprays may contain vehicles, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays, such as those for (intranasal) administration, may additionally contain customary propellants, such as fluorocarbons, chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal delivery devices (e.g., patches) can be used. Such dosage forms have the additional advantage of providing controlled delivery of active ingredients to the body. That is, pharmaceutically acceptable salts of compounds of formula (I) can be administered via transdermal patches at steady-state concentrations, whereby active ingredients are gradually administered over time, thereby avoiding drug peaks and adverse events/toxicity associated therewith.

Depending on the disease/condition being treated, transdermal patch dosage forms can be formulated with different amounts of active agent (compound of formula (I) provided in salt form). Depending on the specific application, the amount of active agent in the unit dose formulation can be varied or adjusted, for example 5 mg, 10 mg, 20 mg, about 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 5 mg to 25 mg, or 10 mg to 20 mg, or 12 mg to 18 mg, or 13 mg to 16 mg, or 14 mg to 15 mg, or an amount deemed appropriate based on reasonable medical judgment. Transdermal patches formulated with the disclosed compounds can be suitable for microdosing to obtain a lasting therapeutic effect while reducing toxicity. In some embodiments, the compounds of the present disclosure may be administered via a transdermal patch at subpsychoactive (but still potentially serotonergic) concentrations, e.g., over an extended period of time, such as over a period of 8 hours, 24 hours, 48 hours, 72 hours, 84 hours, 96 hours, or 168 hours.

In addition to the active ingredient and any optional pharmaceutically acceptable vehicle, a transdermal patch may comprise one or more of a pressure-sensitive adhesive layer, a backing, and a release liner, as known to those of ordinary skill in the art.

Transdermal patch dosage form can be prepared by dissolving or dispersing active ingredient in suitable medium. In some embodiments, the pharmaceutically acceptable salt of formula (I) compound can be directly dissolved/dispersed into the polymer matrix forming pressure-sensitive adhesive layer. Such transdermal patch is called drug adhesive (drug-in-adhesive, DIA) patch. Preferred DIA patch form is those forms in which active ingredient is evenly distributed in the whole pressure-sensitive adhesive polymer matrix. In some embodiments, active ingredient can be arranged in the layer containing active ingredient plus the polymer matrix separated from the pressure-sensitive adhesive layer. In any case, the pharmaceutically acceptable salt of formula (I) compound can be optionally prepared together with suitable vehicle (such as carrier, permeation agent/absorption enhancer, wetting agent/crystallization inhibitor, etc.), to increase the flux across the skin.

Examples of carriers may include, but are not limited to, _C8 - _C22 fatty acids, such as oleic acid, undecanoic acid, valeric acid, heptanoic acid, nonanoic acid, capric acid, lauric acid, and eicosapentaenoic acid; _C8 - _C22 fatty alcohols, such as octanol, nonanol, oleyl alcohol, capric alcohol, and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids, such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower) alkyl esters of C6-C22 diacids, such as diisopropyl adipate; _C8 - _C22 fatty alcohols, such as octanol, nonanol, oleyl alcohol, capric alcohol, and lauryl alcohol; lower alkyl esters of C8- _C22 fatty acids, such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower) alkyl esters of _C6 - _C22 diacids, such as diisopropyl adipate; ₂₂ Monoglycerides of fatty acids, such as monolaurin; polyethylene glycol ether of tetrahydrofurfuryl alcohol; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkyl aryl ethers of polyethylene oxide; polyethylene oxide monomethyl ether; polyethylene oxide dimethyl ether; glycerol; ethyl acetate; acetoacetate; N-alkyl pyrrolidone; cyclodextrin, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or derivatives, such as 2-hydroxypropyl-β-cyclodextrin; and terpenes/terpenoids, such as limonene, linalool, myrcene, pinene such as α-pinene, caryophyllene, citral, eucalyptol, etc.; including mixtures thereof.

Examples of permeation agents/absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide, and the like; menthol; surfactant-lecithin organogels (PLOs), such as those formed from an aqueous phase having one or more of poloxamers, CARBOPOL, and PEMULEN, a lipid phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate and lecithin; fatty acids, esters, and alcohols such as oleyl oleate and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers such as diethylene glycol monoethyl ether; including mixtures thereof.

Examples of humectants/crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone-co-vinyl acetate, HPMC, polymethacrylates, and mixtures thereof.

The pressure-sensitive adhesive layer can be formed by a polymer, and the polymer includes but is not limited to acrylic acid (polyacrylates comprising alkyl acrylic acid), polyvinyl acetate, natural and synthetic rubbers (e.g., polyisobutylene), ethylene vinyl acetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene-butadiene rubber block copolymers, and mixtures thereof. The pressure-sensitive adhesive layer used in the transdermal patch of the present disclosure can be formed by an acrylic polymer pressure-sensitive adhesive, preferably an acrylic copolymer pressure-sensitive adhesive. Acrylic copolymer pressure-sensitive adhesives can be obtained by copolymerization of one or more of the following: alkyl (meth)acrylates (e.g., 2-ethylhexyl acrylate); aryl (meth)acrylates; aryl alkyl (meth)acrylates; and (meth)acrylates having functional groups, such as hydroxyalkyl (meth)acrylates (e.g., hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate and 4-hydroxybutyl methacrylate), carboxylic acids containing (meth)acrylates (e.g., acrylic acid) and alkoxy (meth)acrylates (e.g., methoxyethyl acrylate); optionally copolymerized with one or more copolymerizable monomers (e.g., vinyl pyrrolidone, vinyl acetate, etc.). Specific examples of acrylic pressure-sensitive adhesives may include, but are not limited to, DURO-TAK products (Henkel), such as DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK87-2510, DURO-TAK 87-2287, DURO-TAK87-4287, DURO-TAK87-2516, DURO-TAK387-2052, and DURO-TAK87-2677.

The backing used in the transdermal patch of the present disclosure can include a flexible backing, such as a film, a nonwoven fabric, Japanese paper, a cotton fabric, a knitted fabric, a woven fabric, and a laminated composite of a nonwoven fabric and a film. Such backing is preferably composed of a soft material that can be in close contact with the skin and can follow the movement of the skin and can suppress rashes and other uncomfortable materials after long-term use of the patch. The example of backing material includes but is not limited to polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, acetate rayon, rayon, rayon/polyethylene terephthalate complex, polyacrylonitrile, polyvinyl alcohol, acrylic polyurethane, ester polyurethane, ether polyurethane, styrene-isoprene-styrene copolymer, styrene-butadiene-styrene copolymer, styrene-ethylene-propylene-styrene copolymer, styrene-butadiene rubber, ethylene-vinyl acetate copolymer or cellophane. Preferred backing does not adsorb or release active ingredients. In order to inhibit the adsorption and release of active ingredients, improve the percutaneous absorbability of active ingredients, and inhibit rashes and other discomforts, the backing preferably comprises one or more layers composed of the above materials and has water vapor permeability. Specific examples of the backing may include, but are not limited to, 3M COTRAN products, such as 3M COTRAN ethylene vinyl acetate film film 9702, 3M COTRAN ethylene vinyl acetate film film 9716, 3M COTRAN polyethylene film film 9720, 3M COTRAN ethylene vinyl acetate film film 9728, and the like.

The release liner used in the transdermal patch of the present disclosure can include but is not limited to polyester film with one or both sides processed with release coating, polyethylene laminated high-quality paper processed with release coating and cellophane processed with release coating.The release coating can be any other release coating known to fluoropolymer, silicone, fluorosilicone or those of ordinary skill in the art.The release liner can have an uneven surface, so that the transdermal patch is easily taken out from packaging.The example of release liner can include but is not limited to the SCOTCHPAK product from 3M, such as 3M SCOTCHPAK9744, 3M SCOTCHPAK9755, 3MSCOTCHPAK 9709 and 3M SCOTCHPAK 1022.

Other layers, such as abuse deterrent layers, formulated with one or more irritants (eg, sodium lauryl sulfate, poloxamers, sorbitan monoesters, glycerol monooleate, fragrances, etc.) may also be employed.

The methods disclosed herein using transdermal patch dosage forms provide systemic delivery of small doses of active ingredients, preferably over an extended period of time, such as a period of up to 168 hours, for example 2 to 96 hours, or 4 to 72 hours, or 8 to 24 hours, or 10 to 18 hours, or 12 to 14 hours. In particular, the compounds of formula (I) can be delivered in small, stable and consistent doses so that harmful or undesirable side effects can be avoided. In some embodiments, the compounds of formula (I) are administered transdermally in sub-psychedelic (but still potentially serotonergic) concentrations.

An exemplary drug adhesive (DIA) patch formulation may include 5 wt % to 30 wt % of a pharmaceutically acceptable salt of a compound of formula (I), 30 wt % to 70 wt % of a pressure-sensitive adhesive (e.g., DURO-TAK 387-2052, DURO-TAK 87-2677, and DURO-TAK 87-4098), 1 wt % to 10 wt % of a permeabilizer/absorption enhancer (e.g., oleyl oleate, oleyl alcohol, levulinic acid, diethylene glycol monoethyl ether, etc.), and 5 wt % to 35 wt % of a crystallization inhibitor (e.g., polyvinyl pyrrolidone-co-vinyl acetate, HPMC, polymethacrylate, etc.), each based on the total weight of the DIA patch formulation, although it should be understood that many variations are possible in light of the teachings herein.

Automatic injection devices provide a method for delivering the compositions disclosed herein to a patient. The compositions disclosed herein can be administered to a patient using an automatic injection device by a number of known devices, a non-limiting list of which includes transdermal, subcutaneous, and intramuscular delivery.

In some percutaneous, subcutaneous or intramuscular applications, compositions disclosed herein are absorbed by the skin. Passive transdermal patch devices generally include an absorption layer or film placed on the outer layer of the skin. Films generally contain a certain amount of permission to absorb through the skin to deliver the composition to the patient's material. Generally, only materials that are easily absorbed by the outer layer of the skin can be delivered with this type of transdermal patch device.

Other automatic injection devices disclosed herein are configured to provide increased skin permeability to improve delivery of the disclosed compositions. Non-limiting examples of structures for increasing permeability to improve transfer of the composition into the skin, across the skin, or intramuscularly into the skin include the use of one or more microneedles, which in some embodiments may be coated with the compositions disclosed herein. Alternatively, hollow microneedles may be used to provide fluid channels for delivering the disclosed compositions beneath the outer layer of the skin. Other devices disclosed herein include transdermal delivery by iontophoresis, ultrasound, reverse iontophoresis, or a combination thereof, as well as other techniques known in the art for increasing skin permeability to facilitate drug delivery.

The pharmaceutical compositions may also be administered topically by electroporation, iontophoresis, phonophoresis, ultrasound, and microneedle or needle-free injection, such as POWDERJECT ^™ (Chiron Corp., Emeryville, Calif.) and BIOJECT ^™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

The pharmaceutical compositions disclosed herein can be disclosed in the form of ointments, creams and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, lard containing benzoic acid esters, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorbent vehicles, such as hydrophilic petrolatum, hydroxy stearyl sulfate and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols with different molecular weights; emulsion vehicles, water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see, Remington: The Science and Practice of Pharmacy, see above). These vehicles are emollient, but antioxidants and preservatives are usually required to be added.

Suitable cream bases can be oil-in-water or water-in-oil. The cream vehicle can be water-washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "internal" phase, which generally comprises petrolatum and fatty alcohols such as hexadecyl or stearyl alcohol. The aqueous phase generally contains a humectant, although not necessarily exceeding the oil phase volume. The emulsifier in the cream formulation can be a nonionic, anionic, cationic or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules substantially uniformly distributed throughout a liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes, Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and/or stirring.

The pharmaceutical compositions disclosed herein can be administered rectally, urethrally, vaginally or perivabally in the form of suppositories, vaginal suppositories, bougies, poultices or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or enemas. These dosage forms can be manufactured using conventional processes such as those described in Remington: The Science and Practice of Pharmacy, supra.

Rectal, urethral and vaginal suppositories are solids for insertion into body orifices, which are solid at room temperature but melt or soften at body temperature to release the active ingredient in the orifice. Pharmaceutically acceptable vehicles used in rectal and vaginal suppositories include bases (such as hardeners) that produce a melting point close to body temperature when formulated with the pharmaceutical compositions disclosed herein; and antioxidants as described herein, including bisulfites and sodium pyrosulfite, which produce a melting point close to body temperature when formulated together. Suitable vehicles include but are not limited to cocoa butter (cocoa butter), glycerol-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white wax and yellow wax, and appropriate mixtures of monoglycerides, diglycerides and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylic acid, polyacrylic acid; glycerol gelatin. Various combinations of vehicles can be used. Rectal and vaginal suppositories can be prepared by compression methods or molding. The typical weight of rectal and vaginal suppositories is about 2 to about 3 g.

The pharmaceutical compositions disclosed herein may be ophthalmically administered in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

Pharmaceutical compositions disclosed herein can be administered intranasally. The terms "nasal", "intranasal", etc. refer to a dosage form suitable for a route of administration or a route of administration, wherein the pharmaceutical dosage form is delivered to or through the nose (e.g., nasal cavity). Similarly, "nasal delivery device" or "intranasal delivery device" refers to a device for applying active ingredients to the nasal cavity. In some embodiments, the intranasal dosage form can be in the form of an aqueous or non-aqueous solution, suspension, liposomal dispersion, emulsion, microemulsion, or sol-gel. Non-limiting examples of intranasal administration include the introduction of a solution or suspension in the form of a nasal spray or drops (direct instillation), or the intranasal application of a gel, emulsion, or ointment. Relative to oral dosage forms (such as tablets or capsules), intranasal delivery provides rapid absorption, faster onset of therapeutic action, and avoidance of first-pass metabolism. The amount of active ingredient absorbed depends on many factors. These factors include, but are not limited to, drug concentration, drug delivery vehicle, mucosal contact time, venous drainage of mucosal tissue, the degree of ionization of the drug at the pH of the absorption site, the size of the drug molecule, and its relative fat solubility.

The pharmaceutical composition of the present disclosure for nasal administration comprises a compound of the present disclosure, such as a pharmaceutically acceptable salt of a compound of formula (I), and an optional pharmaceutically acceptable vehicle, including but not limited to a permeabilizer/absorption enhancer that promotes nasal absorption of the active ingredient after nasal administration and an agent that improves brain penetration of the drug after nasal administration, a diluent, a binder, a lubricant, a glidant, a disintegrant, a desensitizer, an emulsifier, a bioadhesive, a solubilizer, a suspending agent and a dispersant, a thickener or a viscosity enhancer, an isotonic agent, a pH adjuster, a buffer, a carrier, a flavoring agent, a sweetener, and a mixture thereof. In some embodiments, the active ingredient is present in the pharmaceutical composition in the form of particles. In some embodiments, the particle size of the active ingredient is less than or equal to about 60 microns, which helps to ensure the uniformity of any blend of particles with other ingredients, or to provide sufficient dispersion in a liquid vehicle.

The delivery of active ingredients across normal mucosal surfaces (such as nasal mucosa) can be enhanced by optionally combining them with permeants/absorption enhancers. Examples of these permeants/absorption enhancers include, but are not limited to, cationic polymers, surfactants, chelating agents, mucolytic agents, cyclodextrins, polymer hydrogels, and combinations thereof, and any other similar absorption enhancers known to those skilled in the art. Representative examples of permeants/absorption enhancers include, but are not limited to, phospholipids, such as phosphatidylglycerol or phosphatidylcholine; lysophosphatidyl derivatives, such as lysophosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylglycerol, lysophosphatidylserine, or lysophosphatidic acid; polyols, such as glycerol or propylene glycol; fatty acid esters thereof, such as glycerides, amino acids, and esters thereof; cyclodextrins; or other substances described herein. Gelling excipients or viscosity-enhancing excipients may also be used.

The transport of active ingredients through normal mucosal surfaces can also be enhanced by increasing the time that the formulation adheres to the mucosal surface. Bioadhesives (such as those forming hydrogels) show mucoadhesion and drug controlled release properties, and can be included in the intranasal composition described herein. Representative bioadhesives that can be combined with nasal mucosa include but are not limited to polycarbophil (polycarbophil), polylysine, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, pectin, Carbopol 934P, polyethylene oxide 600K, one or more poloxamers (such as Pluronic F127 and/or Pluronic F-68), polyisobutylene (PIB), polyisoprene (PIP), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), xanthan gum, guar gum and locust bean gum. Other nasal delivery compositions are chitosan-based and are suitable for increasing the residence time of active ingredients on mucosal surfaces, thereby improving its bioavailability. Thiolated polymer vehicles that form covalent bonds with the mucosal cysteine-rich subdomains can also provide mucoadhesion, which prolongs the contact time between the active ingredient and the membrane.

The intranasal composition may also contain one or more preservatives. Representative preservatives include quaternary ammonium salts, such as lauryl ammonium chloride, benzalkonium chloride, benzododecinium chloride, cetylpyridinium chloride, cetrimide, domiphen bromide; alcohols, such as benzyl alcohol, chlorobutanol, o-cresol, phenylethyl alcohol; organic acids or their salts, such as benzoic acid, sodium benzoate, potassium sorbate, parabens; or complexing agents, such as EDTA.

Intranasal dosage forms can also include ion exchange resins, such as microspheres, which carry suitable anionic groups, such as carboxylic acid residues, carboxymethyl, sulfopropyl and methylsulfonate groups. Ion exchange resins, such as cation exchangers, can also be used. For example, the pharmaceutical composition can be formulated with chitosan (which is partially deacetylated chitin) or poly-N-acetyl-D-glucosamine or its pharmaceutically acceptable salts (such as hydrochloride, lactate, glutamate, maleate, acetate, formate, propionate, malate, malonate, adipate or succinate). Examples of non-ion exchange resins (e.g., microspheres) that can be used include, but are not limited to, starch, gelatin, collagen and albumin.

The pharmaceutical composition may further comprise a suitable pH adjusting agent, including but not limited to sodium hydroxide, hydrochloric acid, citric acid, lactic acid, glutamic acid, maleic acid, acetic acid, formic acid, propionic acid, malic acid, malonic acid, adipic acid and succinic acid.

Other ingredients (such as diluents) are cellulose, microcrystalline cellulose, hydroxypropyl cellulose, starch, hydroxypropyl methylcellulose, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, kaolin, mannitol, sodium chloride and powdered sugar, etc.

Isotonic agents may be added to adjust the tonicity of the composition, including, but not limited to, sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose, and the like.

Acidic, neutral or alkaline buffers may also be added to the intranasal composition to control pH, including but not limited to phosphate buffers, acetate buffers and citrate buffers.

In addition to using permeabilizing agents/absorption enhancers that increase the active ingredient's transport through the mucosa and bioadhesives that extend the active ingredient's contact time along the mucosa, the application of the active ingredient can be controlled by using a controlled release formulation. There are many granular drug delivery vehicles known to those skilled in the art, which can contain active ingredients and deliver in a controlled manner. Examples include granular polymer drug delivery vehicles, such as biodegradable polymers, and particles formed by non-polymer components. These granular drug delivery vehicles can be in the form of powders, microparticles, nanoparticles, microcapsules, liposomes, etc. Generally, if the active ingredient is in the form of particles without added components, its release rate depends on the release of the active ingredient itself. Typically, the absorption rate is improved by providing the drug in a micronized form, wherein the particle diameter is less than 20 microns. On the contrary, if the active ingredient is in the form of particles as a blend of an active agent and a polymer, the release of the active agent is at least partially controlled by the removal of the polymer, typically by dissolving, biodegrading or diffusing from a polymer matrix. In some embodiments, the pharmaceutical composition is in the form of a viscous aqueous solution/suspension for intranasal administration, to provide slow/sustained release and absorption. Here, the pharmaceutical vehicle for increasing viscosity can be used, such as thickener or tackifier, including but not limited to polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose (for example, sodium carboxymethyl cellulose), hydroxypropyl cellulose, chondroitin sulfate and its salt, hyaluronic acid and its salt, including the cross-linked variant of any of the foregoing substances, and the combination of the foregoing substances. In some embodiments, pharmaceutically acceptable vehicles include sodium carboxymethyl cellulose, hyaluronic acid and its salt or their combination. Such viscous aqueous solution/suspension dosage forms may be particularly suitable for relatively short intranasal dosage forms of active ingredient and/or dosage forms that require longer action formulations, because active ingredient can be slowly released from the site of application and absorbed over the duration.

In some embodiments, the pharmaceutical composition is formulated with a poorly water-soluble pharmaceutically acceptable salt of a compound of formula (I) (e.g., a fatty acid salt of a compound of formula (I)) (e.g., a water solubility of less than 5 mg/mL, less than 4 mg/mL, less than 3 mg/mL, less than 2 mg/mL, less than 1 mg/mL, less than 0.5 mg/mL, less than 0.1 mg/mL at 22°C). Examples of fatty acid salt forms include, but are not limited to, those formed by contacting a compound of formula (I) with adipic/hexandioic, lauric (dodecanoic), linoleic, myristic (tetradecanoic), capric (decanoic), stearic (octadecanoic), oleic, caprylic (octanoic), palmitic (hexadecenoic), sebacic, undecenoic, or caproic acid. Such pharmaceutical compositions may be particularly suitable for relatively short-acting intranasal dosage forms of the active ingredient and/or dosage forms requiring longer-acting formulations because the active ingredient can be slowly released from the site of administration and absorbed over a sustained period of time.

Other intranasal dosage forms and methods contemplated herein are disclosed in van Woensel M et al. Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM? Cancers (Basel). 2013 Aug 14;5(3):1020-48, which is incorporated herein by reference in its entirety.

Intranasal delivery devices are known in the art. Therefore, any device suitable for drug delivery to the nasal mucosa can be used. Non-limiting examples of devices used for liquid dosage forms include steam devices (e.g., steam inhalers), dropper devices (e.g., catheters, single-dose droppers, multi-dose droppers, and unit dose pipettes), mechanical jet pump devices (e.g., squeeze bottles, multi-dose metered jet pumps, and single-dose/double-dose jet pumps), bidirectional jet pumps (e.g., breath-actuated nasal delivery devices), gas-driven spray systems/atomizers (e.g., single-dose or multi-dose HFA or nitrogen propellant-driven metered-dose inhalers, including traditional and peripheral speed inhalers) and electric sprayers/atomizers (e.g., pulsating membrane sprayers, vibrating mechanical sprayers, and handheld mechanical sprayers). Non-limiting examples of devices for administering powder compositions (e.g., lyophilized or otherwise dried mixed compositions) include, but are not limited to, mechanical powder sprayers (e.g., manual capsule-type powder spray devices and manual powder spray devices, manual gel delivery devices), breath-actuated inhalers (e.g., single-dose or multi-dose nasal inhalers and capsule-type single-dose or multi-dose nasal inhalers), and insufflators (e.g., breath-actuated nasal delivery devices).

The use of a metered spray for intranasal delivery may also be accomplished by including the active ingredient in a solution or dispersion in a suitable vehicle that can be administered as a spray. Representative devices of this type are disclosed in the following patents, patent applications and publications: WO2003026559, WO2002011800, WO200051672, WO2002068029, WO2002068030, WO2002068031, WO2002068032, WO2003000310, WO2003020350, WO2003082393, WO2003084591, WO2003090812, WO200041755 and in the pharmaceutical literature (see, e.g., Bell, A. Intranasal Delivery Devices, Drug Delivery Devices Fundamentals and Applications, Tyle P. (ed.), Dekker, New York, 1988), Remington's Pharmaceutical Sciences, Mack Publishing Co., Ltd. Co., 1975, which is incorporated herein by reference in its entirety.

In some embodiments, the pharmaceutical composition can be in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, nebulizer (e.g., a nebulizer that uses electrohydrodynamics to produce a fine mist), or a nebulizer, alone or in combination with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes (such as 1,1,1,2-tetrafluoroethane (HFA 134A) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227)), carbon dioxide, perfluorinated hydrocarbons (such as perfluorocarbons), and other suitable gases. The pharmaceutical composition can also be disclosed as a dry powder, which is used for insufflation alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can include a bioadhesive, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable substitute for a propellant to disperse, dissolve or prolong the release of the active ingredient disclosed herein as a solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

Pharmaceutical compositions disclosed herein can be micronized to a size suitable for delivery, e.g., about 50 microns or less, or about 10 microns or less. Such sized particles can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules, bubbles and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the pharmaceutical composition disclosed herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include dextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical composition for inhalation/intranasal administration disclosed herein may also include suitable flavoring agents, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

In addition to the foregoing, the compounds of the present disclosure may also be administered intranasally in the form of irrigation and lavage, as is known in the art. Nasal irrigation involves regular irrigation of the nasal cavity with a solution containing the drug. Typically, a nasal lavage device is used by filling the nasal lavage device with a solution containing the drug, inserting the nozzle from the lavage device into one nostril, opening the mouth to breathe, and allowing the solution to flow into one nostril, rinsing around the septum, and draining from the other nostril.

The pharmaceutical compositions disclosed herein for topical administration may be formulated for immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

D. Modified Release Dosage Forms

The pharmaceutical compositions disclosed herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the release rate or release position of the active ingredient is different from the release rate or release position of the direct dosage form when administered by the same route. Various modified release devices and methods known to those skilled in the art can be used to prepare pharmaceutical compositions of modified release dosage forms, including but not limited to matrix controlled release devices, osmotic controlled release devices, multi-particle controlled release devices, ion exchange resins, enteric coatings, multi-layer coatings, microspheres, liposomes and combinations thereof. The release rate of the active ingredient can also be changed by changing the particle size and polymorphic form of the active ingredient.

1. Matrix controlled release device

The pharmaceutical compositions disclosed herein can be prepared in modified release dosage forms using matrix controlled release devices known to those skilled in the art (see Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz, ed., Wiley, 1999).

In some embodiments, the pharmaceutical compositions disclosed herein in modified release dosage forms are formulated using an erodible matrix device that is a water-swellable, erodible, or soluble polymer, including synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

Materials that can be used to form the erodible matrix include, but are not limited to, chitin, chitosan, dextrose, and pullulan; agar, gum arabic, gum karaya, gum locust bean, gum tragacanth, carrageenan, gum karai, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and celluloses, such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose, and cellulose derivatives. cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose ethyl trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylic acid or methacrylic acid ( Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactic acid; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl)methyl acrylate, and (trimethylaminoethyl)chloromethyl acrylate.

In other embodiments, pharmaceutical compositions are formulated with non-erodible matrix devices. The active ingredient is dissolved or dispersed in an inert matrix, and is mainly released by diffusion through the inert matrix after administration. Materials suitable for use as non-erodible matrix devices include but are not limited to: insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol trimer and ethylene/ethyleneoxyethanol copolymer. , polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicic acid ester copolymers, and; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone and cross-linked partially hydrolyzed polyvinyl acetate, and fatty compounds such as carnauba wax, microcrystalline wax and triglycerides.

In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer used, polymer viscosity, particle size of the polymer and/or active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

The pharmaceutical compositions disclosed herein in modified release dosage forms can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.

2. Osmotic controlled release device

The pharmaceutical compositions disclosed herein in modified release dosage forms can be manufactured using osmotic controlled release devices, including single-chamber systems, dual-chamber systems, asymmetric membrane technology (AMT) and extruded core systems (ECS). Typically, such devices have at least two components: (a) a core containing an active ingredient; and (b) a semipermeable membrane having at least one delivery port, the semipermeable membrane encapsulating the core. The semipermeable membrane controls water flow from the aqueous environment into the core so as to cause drug release by extrusion through the delivery port.

In addition to the active ingredient, the core of the osmotic device optionally comprises an osmotic agent that creates a driving force for transporting water from the environment of use into the core of the device. One class of osmoagents are water-swellable hydrophilic polymers (which are also referred to as "osmopolymers" and "hydrogels") including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinyl pyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, copolymers of PVA/PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

Another class of osmotic agents is osmogens, which are capable of absorbing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

Osmotic agents with different dissolution rates can be used to affect the speed at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPIPharma, Lewes, Del.) can be used to provide faster delivery during the first few hours to produce the desired therapeutic effect immediately, and gradually and continuously release the remaining amount to maintain the desired level of treatment or preventive effect over an extended period of time. In this case, the active ingredient is released at such a rate to replace the amount of the active ingredient that is metabolized and discharged.

The core may also contain various other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

Materials that can be used to form the semipermeable membrane include various grades of acrylic acid, vinyl, ether, polyamide, polyester and cellulose derivatives that are water permeable and water insoluble at physiologically relevant pH, or are susceptible to becoming water insoluble by chemical changes such as cross-linking. Examples of suitable polymers that can be used to form the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan Sugar acetates, beta glucan triacetate, dimethyl acetate, triacetate of carob bean gum, hydroxyethylene-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextrose, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrenes, polyethylene halides, polyethylene esters and ethers, natural waxes and synthetic waxes.

The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by aqueous media, but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798, 119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyethylene halides, polyvinylidene fluoride, polyethylene esters and ethers, natural waxes and synthetic waxes.

The delivery port on the semipermeable membrane can be formed after coating by mechanical or laser drilling. The delivery port can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, the delivery port can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents Nos. 5,612,059 and 5,698,220.

The total amount of active ingredient released and the rate of release can be generally controlled by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

Pharmaceutical compositions in osmotic controlled-release dosage forms may also contain additional conventional excipients as described herein to facilitate performance or processing of the formulation.

Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT controlled release dosage forms, which include an asymmetric osmotic membrane coating a core including an active ingredient and other pharmaceutically acceptable excipients or carriers. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating methods.

In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled-release dosage forms, which include a permeable membrane coating a core including the active ingredient, hydroxyethylcellulose and other pharmaceutically acceptable excipients or carriers.

3. Multi-particle controlled release device

The pharmaceutical compositions disclosed herein in modified release dosage forms can be made into multiparticulate controlled release devices, which include a variety of granules, microparticles or spheres with diameters ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Such multiparticulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, roller compaction, melt-condensation, and by spraying seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other vehicles described herein can be blended with the pharmaceutical composition to aid in processing and forming multi-particulates. The resulting particles themselves can constitute a multi-particulate device, or can be coated with various film-forming materials, such as enteric polymers, water-swellable and water-soluble polymers. The multi-particulates can be further processed into capsules or tablets.

4. Targeted delivery

The pharmaceutical compositions disclosed herein may also be formulated to target specific tissues, receptors or other areas of the body of the subject to be treated, including liposomes, resealed erythrocytes and antibody-based delivery systems.

E. Inhalation administration

Pharmaceutical compositions disclosed herein can be formulated for inhalation administration, for example, for pulmonary absorption. Suitable formulations can include liquid form formulations, such as those described above, such as solutions and emulsions, wherein the solvent or carrier is, for example, water, a water/water miscible medium, such as a water/propylene glycol solution, or an organic solvent, with an optional buffer, which can be delivered as an aerosol, preferably a mist, with a carrier gas, such as a mixture of air, oxygen, helium and oxygen, or other gases and gas mixtures. Pharmaceutical compositions can also be formulated as dry powders, which are used for insufflation alone or in combination with inert carriers such as lactose or phospholipids.

The pharmaceutical composition can be in the form of an aerosol or solution for delivery using a pressurized container, a pump, a spray, an atomizer (e.g., an atomizer that uses electrohydrodynamics to produce a fine mist), or a nebulizer, alone or in combination with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes (such as 1,1,1,2-tetrafluoroethane (HFA134A) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227)), carbon dioxide, perfluorinated hydrocarbons (such as perfluorocarbons), and other suitable gases.

Aqueous solutions suitable for inhalation can be prepared by dissolving a pharmaceutically acceptable salt of a compound of formula (I) in water. Suitable stabilizers and thickeners may also be added. Emulsions suitable for inhalation may be prepared by dissolving a pharmaceutically acceptable salt of a compound of formula (I) in an aqueous medium and dispersing the dissolved form in a hydrophobic medium, optionally using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspending agents.

Solutions or suspensions for pressurized containers, pumps, sprays, atomizers or nebulizers can be formulated to contain surfactants or other suitable cosolvents, or suitable alternative agents for dispersing, solubilizing or prolonging the release of the active ingredients disclosed herein, and optionally propellants. Such surfactants or cosolvents may include, but are not limited to, polysorbates 20, 60 and 80; Pluronic F-68, F-84, and P-103; cyclodextrins; polyoxyethylene 35 castor oil; sorbitan trioleate, oleic acid or oligolactic acid. Surfactants and cosolvents are typically used at a level of about 0.01% to about 2% by weight of the pharmaceutical composition. In some cases, a viscosity greater than that of a simple aqueous solution may be desirable to reduce the variability of formulation distribution, reduce physical separation of formulation emulsion components, and/or otherwise improve formulations. Such viscosity increasing agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. When desired, such agents are generally used at a level of about 0.01% to about 2%, about 0.1% to about 1%, about 0.5% to about 0.8% by weight of the pharmaceutical composition.

The compound of formula (I) in salt form can also be dissolved in an organic solvent or an aqueous mixture of an organic solvent. The organic solvent can be, for example, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloromethane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, ethanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methyl-2-pyrrolidone, nitromethane, pyridine, cyclopentane, tetralin, toluene, 1,1,2-trichloroethylene or dimethylbenzene, including combinations thereof. The organic solvent can belong to a functional group category, such as an ester solvent, a ketone solvent, an alcohol solvent, an amide solvent, an ether solvent, a hydrocarbon solvent, etc., each of which can be used.

Further description of pharmaceutical compositions and methods for administration by inhalation is provided below.

Inhalation Method and Administration

Disclosed herein is a method of delivering a pharmaceutically acceptable salt of a compound of formula (I) to a patient in need thereof, comprising administering via inhalation a pharmaceutically acceptable salt of a compound of formula (I) dissolved in an aerosol, preferably a mist. Delivery of a pharmaceutically acceptable salt of a compound of formula (I) can be used to treat a disease or condition, such as a disease or condition associated with a serotonin 5- _HT2 receptor, such as, in particular, a central nervous system (CNS) condition and/or a psychological condition, as described herein. Preferably, an aerosol is produced without external heating (this does not exclude a slight temperature rise caused by the formation of the aerosol itself, such as using a vibrating net or other nebulizer. However, this slight temperature rise is usually offset by the evaporation of the drug, resulting in cooling of the composition). A pharmaceutically acceptable salt of a compound of formula (I) can be any salt described herein. In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) can be delivered as an aerosol (preferably a mist), the aerosol having a carrier, such as air, oxygen, or a mixture of helium and oxygen, or other gas mixtures including a therapeutic gas mixture. In some cases, the carrier can be a mixture of helium and oxygen heated to about 50°C to about 60°C.

In addition, by using via inhalation, the pharmaceutically acceptable salt of formula (I) compound can be systemically delivered to the central nervous system of the patient. Carrier gas (for example, mixture of air, oxygen, helium and oxygen or other gases and gas mixture) can be heated to about 50 DEG C to about 60 DEG C or about 55 DEG C to about 56 DEG C. When the mixture of helium and oxygen is used as carrier, helium can be present in the mixture of oxygen and helium with about 50 volume %, 60 volume %, 70 volume %, 80 volume % or 90 volume %, and oxygen can be present in the mixture with about 50 volume %, 40 volume %, 30 volume % or 10 volume %, or any scope therebetween.

The method may also include administering a pre-treatment inhalation therapy prior to administering an aerosol comprising a pharmaceutically acceptable salt of a compound of Formula (I). Pre-treatment may include administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C, about 92°C, about 94°C, about 96°C, about 98°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, or any range therebetween.

The method may include (i) administering to the patient via inhalation a mixture of helium and oxygen heated to about 90° C. to about 120° C., followed by (ii) administering to the patient via inhalation a mixture of helium and oxygen heated to about 50° C. to about 60° C. and an aerosol containing a pharmaceutically acceptable salt of a compound of formula (I), and then repeating steps (i) and (ii). Steps (i) and (ii) may be repeated 1, 2, 3, 4, 5 or more times.

In some embodiments, the present disclosure provides a method for treating central nervous system (CNS) disorders and/or psychological disorders, comprising administering a pharmaceutically acceptable salt of a compound of formula (I) in the form of an aerosol (preferably a mist) via inhalation. The pharmaceutically acceptable salt of a compound of formula (I) can be delivered as an aerosol with a carrier gas, such as air, oxygen, a mixture of helium and oxygen, or other gases and gas mixtures. Before administering an aerosol comprising a pharmaceutically acceptable salt of a compound of formula (I) to a patient, the mixture of helium and oxygen can be heated to about 50°C to about 60°C.

The central nervous system and/or psychological disorder may be, for example, any of those disclosed herein, with particular mention being made of substance use disorders (e.g., alcohol use disorder), generalized anxiety disorder (GAD), GAD with depression, social anxiety disorder, and treatment-resistant depression (TRD).

In some embodiments, delivery of a pharmaceutically acceptable salt of a compound of Formula (I) to the central nervous system of a patient by inhalation results in at least a 25% improvement in drug bioavailability compared to oral delivery, an increase in _Cmax by at least 25% compared to oral delivery, a decrease in _Tmax by at least 50% compared to oral delivery, or a combination thereof.

In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) can be administered in an amount of about 1 μg to about 200 mg or more (or any range between about 1 μg to about 200 mg) per inhalation session, for example, about 1 μg, 2 μg, 5 μg, 6 μg, 10 μg, 13 μg, 15 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, In some embodiments, the subject may be administered with 1, 2, 3, 4, 5 or more inhalation sessions per day. In some embodiments, the subject may perform 1, 2, 3, 4, 5 or more inhalation sessions every other day, once a week, twice a week, or three times a week. In some embodiments, the subject may perform 1, 2, 3, 4, 5 or more inhalation sessions every other month, twice a month, three times a month, or four times a month. In some embodiments, the subject may perform 1, 2, 3, 4, 5, 6, 7, 8 or more inhalation sessions in each course of treatment, such as over a 28-day period.

aerosol

In some embodiments, a method of delivering the disclosed salt form by aerosol inhalation is provided. Air, oxygen, a mixture of helium and oxygen, or other gases and gas mixtures can be used as a carrier gas to deliver an aerosol, preferably a mist. The carrier gas can be delivered at room temperature or heated. In some embodiments, an aerosol, preferably a mist, of a pharmaceutically acceptable salt of a compound of formula (I) is delivered via inhalation using a heated helium-oxygen (HELIOX) mixture. Due to the very low viscosity of helium, a helium-oxygen mixture produces an airflow characterized by laminar flow, which is a very desirable feature for penetrating deep into the lung region and reducing the deposition of the drug in the respiratory tract, which is one of the main obstacles to dose delivery via inhalation. The patient can inhale the dissolved salt form disclosed herein as a mist into the alveolar region of the patient's lungs. Then, the compound of formula (I) can be delivered to the fluid lining of the alveolar region of the lungs, and can be systemically absorbed into the patient's blood circulation. Advantageously, these formulations can be effectively delivered to the bloodstream when inhaled into the alveolar region of the lungs.

Devices suitable for delivering heated or unheated carrier gases (e.g., air, oxygen, or helium-oxygen mixtures) include, for example, continuous mode nebulizers Flo-Mist (Phillips) and Hope (B&B Medical Technologies) and accessories such as regulators, such as Medipure ^™ Heliox-LCQ systems (PraxAir) and control boxes, such as Precision Control Flow (PraxAir). In some embodiments, the complete delivery setup can be, for example, a device described in Russian Patent RU199823U1.

As used herein, the term "heliox" refers to a breathing gas mixture of helium (he) and oxygen (O ₂ ). In some embodiments, the helium-oxygen mixture may contain about 50%, 60%, 70%, 80%, or 90% helium by volume in the mixture of helium and oxygen, and about 50%, 40%, 30%, or 10% oxygen by volume in the mixture of helium and oxygen, or any range therebetween. Thus, the helium-oxygen mixture may contain helium and oxygen in a volume ratio of 50:50, 60:40, 70:30, 80:20, 90:10, or any range therebetween. In some embodiments, helium-oxygen may create less airway resistance by increasing laminar flow tendency and reducing turbulent drag.

The use of heat in helium-oxygen mixtures can further enhance drug delivery by increasing the permeability of key physical barriers to drug absorption. Heating mucosal surfaces can increase permeability by enhancing peripheral blood circulation and relaxing interstitial junctions, among other mechanisms. Helium has a thermal conductivity that is almost 10 times higher than oxygen and nitrogen and can facilitate heat transfer more effectively. When heated to up to 110°C, dry helium-oxygen mixtures can be safely used as a pretreatment step, which can make dry helium-oxygen mixtures more effective in heating mucosal surfaces in the lungs and respiratory tract.

Various types of personal vaporizers are known in the prior art. Generally speaking, personal vaporizers are characterized by heating a solid drug or compound. A vaporizer can work by directly heating the solid drug or compound to a smoldering point. Vaporizing a solid or solid concentrate can be accomplished by convection or conduction. Convection heating of a solid concentrate involves contacting a heating element with water or another liquid, which then evaporates. The hot vapor in turn directly heats the solid or solid concentrate to a smoldering point, releasing vapor for inhalation by the user. Conduction heating involves direct contact between the solid or solid concentrate and a heating element, which causes the solid to reach a smoldering point, releasing vapor for inhalation by the user. Although vaporizers have advantages over smoking in terms of lung damage, the vaporized drug/active agent can be significantly deteriorated by the heat of vaporization.

In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) is delivered via a nebulizer that produces an aqueous droplet aerosol containing the salt form, preferably a mist, which is optionally combined with a heated helium-oxygen mixture. In some embodiments, the salt form of the disclosed compound is delivered via a nebulizer that produces an aqueous droplet aerosol containing the salt form, preferably a mist, which is combined with a driving gas comprising nitrous oxide. The driving gas comprising nitrous oxide can be nitrous oxide gas itself or a therapeutic gas mixture, such as a N ₂ OO ₂ mixture or a N ₂ O-air mixture. The therapeutic gas mixture may also include other gases, such as one or more of N ₂ , Ar, CO ₂ , Ne, CH ₄ , He, Kr, H ₂ , Xe, H ₂ O (e.g., steam), etc. In some embodiments, the driving gas is a therapeutic gas mixture comprising _N2O , which is present in a concentration ranging from 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, or any range therebetween, relative to the total volume of the therapeutic gas mixture. The presence of nitrous oxide (which is an NMDA receptor antagonist) in (or as) the driving gas can enhance the effects of the disclosed compounds and provide the ability to obtain similar levels of effect using lower doses thereof.

For example, the preparation of the pharmaceutically acceptable salt of the compound of formula (I) can be placed in a liquid medium and placed in an aerosol by a device (such as a nebulizer). In some embodiments, the nebulizer can be, for example, a pneumatic compressor nebulizer, an ultrasonic nebulizer, a vibrating mesh or a horn nebulizer, or a microprocessor-controlled breath-actuated nebulizer. In some embodiments, the nebulizer device can be, for example, the device described in Russian Patent RU199823U1.

A nebulizer is a device that converts a drug in a solution or suspension (such as a pharmaceutically acceptable salt of a compound of formula (I)) into a fine aerosol (such as fog) for delivery to the lungs. A nebulizer may also be referred to as a nebulizer. Nebulization is the process of making a dissolved drug into an aerosol, such as in the form of fog. In order to deliver the drug by atomization, the drug may be dispersed in a liquid medium, such as water, ethanol or propylene glycol. In addition, the salt form of the disclosed compound may be carried in a vehicle, such as, for example, liposomes, polymers, emulsions, micelles, nanoparticles or polyethyleneimine (PEI). The liquid drug formulation for a nebulizer may be, for example, an aqueous solution or a viscous solution. After applying a dispersing force (such as, a gas jet, ultrasound or vibration of a net), the dissolved drug is contained in a droplet and then inhaled. The mist may contain droplets containing a drug in air or another gas mixture (such as, a mixture of helium and oxygen).

Jet nebulizer (also referred to as pneumatic nebulizer or compressor nebulizer) uses compressed gas to make mist. In some embodiments, jet nebulizer is a microprocessor-controlled breath-actuated nebulizer, also referred to as a breath-actuated nebulizer. Breath-actuated nebulizers only produce mist when the patient inhales, rather than continuously producing mist. For example, mist can be produced by passing an airflow through a venturi in a nebulizer bowl or cup. Venturi is a system that accelerates fluid flow by contracting the fluid in a conical tube. In restriction, the fluid must increase its velocity, thereby reducing its pressure and producing a partial vacuum. When the fluid leaves the contraction point, its pressure increases back to ambient pressure or pipeline horizontal pressure. This can form a low-pressure area, which draws droplets from the drug solution in the nebulizer bowl through a feed tube, and this in turn produces a stream of atomized droplets, which flows to the interface. Higher airflow leads to a reduction in particle size and an increase in output. Because the droplets and solvent saturate the outflowing gas, the jet nebulizer can cool the drug solution in the nebulizer and increase the solute concentration in the residual volume. Baffles in the nebulizer bowl or cup may be impacted by larger particles, causing them to be retained and returned to the solution in the nebulizer bowl or cup for re-nebulization. Entrainment of air through the nebulizer bowl as the subject inhales may increase mist output during inspiration. A smaller particle size distribution will produce mist, but using a smaller particle size may result in an increase in nebulization time.

The unit of measurement commonly used for droplet size is the mass median diameter (MMD), which is defined as the average droplet diameter by mass. This unit may also be referred to as the mass mean aerodynamic diameter, or MMAD. The MMD droplet size of a jet nebulizer may be about 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 5.0 μm, 6.0 μm, 7.0 μm, 8.0 μm, 9.0 μm, 10.0 μm or more (or any range between about 1.0 μm and 10.0 μm), which may be smaller than the size of an ultrasonic nebulizer.

Ultrasonic nebulizers generate mist by using the vibration of a piezoelectric crystal, which converts alternating current into high-frequency (about 1 MHz to about 3 MHz) acoustic energy. The solution breaks down into droplets on the surface, and the resulting mist is sucked out of the device by the patient's inhalation, or is pushed out by an airflow through the device generated by a small compressor. Ultrasonic nebulizers can include large-volume ultrasonic nebulizers and small-volume ultrasonic nebulizers. The droplet size of ultrasonic nebulizers is often larger than that of jet nebulizers. The MMD droplet size of an ultrasonic nebulizer can be about 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm, 9.0 μm, 10.0 μm or larger (or any range between about 2.0 μm and 10.0 μm). The ultrasonic nebulizer can produce a dense mist with droplets of about 100 μm/L, 150 μm/L, 200 μm/L, 250 μm/L, 300 μm/L or more.

A mesh nebulizer device uses the vibration of a piezoelectric crystal to indirectly produce mist. Mesh nebulizers include, for example, active mesh nebulizers and passive mesh nebulizers. Active mesh nebulizers use a piezoelectric element that contracts and expands when an electric current is applied, and vibrates a precisely drilled mesh that is in contact with a drug solution to produce mist. The vibration of a piezoelectric crystal can be used to vibrate a thin metal plate with thousands of holes punched in it. One side of the plate is in contact with the liquid to be atomized, and the vibration forces the liquid through the holes, producing a mist of tiny droplets. Passive mesh nebulizers use a transducer horn that induces passive vibrations in a perforated plate with tapered holes to produce mist. Examples of active mesh nebulizers include (Aerogen, Galway, Ireland) and (PARI,Starnberg,Germany), while Microair (Omron, Bannockburn, IL) is a passive mesh nebulizer. The mesh nebulizer is precise and customizable. By changing the pore size of the mesh, the device can be adapted to drug solutions of different viscosities, and the output rate can be varied. Using this atomization method can provide several advantages. The size of the droplets can be very precise because the size of the droplets can be determined by the size of the holes in the mesh (which can be customized depending on the application). The nebulizer mesh can be manufactured using methods such as electrodeposition, electroplating, and laser cutting to produce liquid particles in a gas within the respirable range. The mesh can be made of a metal alloy. The metals used in the manufacture of the mesh can include platinum, palladium, nickel, and stainless steel. The size of the droplets is approximately twice the size of the mesh. Therefore, the mesh can be about 0.1 μm, 0.5 μm, 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm or larger (or any value between about 0.1 μm and 5.0 μm). The mist generation in the mesh sprayer can vary according to the shape of the mesh, the material of the mesh, and the way the mesh is made. In other words, different meshes can produce liquid particles of different sizes suspended in the gas. Typically, the MMD droplet size of the mesh sprayer can be about 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm, 5.5. μm, 6.0 μm, 6.1 μm, 6.2 μm, 6.3 μm, 6.4 μm, 6.5 μm, 6.6 μm, 6.7 μm, 6.8 μm, 6.9 μm, 7.0 μm or larger (or any value between about 1.0 μm and 7.0 μm).

Furthermore, the droplet size can be programmed. In particular, the geometry of the sprayer can be altered to provide a specific desired droplet size. Furthermore, the droplet size can be controlled independently of the droplet velocity. The volume of atomized liquid and the droplet velocity can also be precisely controlled by adjusting the frequency and amplitude of the mesh vibration. Furthermore, the number of holes in the mesh and their layout on the mesh can be customized. The mesh sprayer can be powered by electricity or batteries.

The mist output rate in mL of stationary cloud per minute (for any of the nebulization methods described herein) can range between, for example, 0.1 mL/min, 0.2 mL/min, 0.3 mL/min, 0.4 mL/min, 0.5 mL/min, 0.6 mL/min, 0.7 mL/min, 0.8 mL/min, 0.9 mL/min or more (or any range between about 0.1 mL/min and 0.9 mL/min), and the remaining volume in the reservoir of any type of nebulizer can range between about 0.01 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, 2.0 mL or more (or any range between about 0.01 mL and 2.0 mL). Precise droplet size control may be advantageous because droplet size can be directly related to drug release kinetics (KDR). Precise control of KDR can be achieved by precise control of droplet size. Pharmaceutically acceptable salts of compounds herein can be delivered using any method via a mist having a MMD droplet size of about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 μm or more (or any range between about 0.5 μm and 10.0 μm).

In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) can be delivered via continuous positive airway pressure (CPAP) or other pressure-assisted respiratory devices. The pressure-assisted respiratory device applies continuous compressed air or other gas columns to the face and nose of the patient wearing a mask or nose cap at a fixed specified pressure. When the patient's glottis opens to inhale, the pressure is transmitted to the entire airway, helping to open the airway. When the patient exhales, the pressure from the lungs and chest wall pushes the air out against the continuous pressure until the two pressures are equal. The air pressure in the airway at the end of exhalation is equal to the external air pressure of the machine, and this helps to "splint" the airway to open, allowing better oxygenation and airway supplementation. The pressure-assisted respiratory device can be connected to a device for introducing mist particles into the airflow in the breathing circuit and/or a device for stopping the introduction of mist particles into the breathing circuit when the patient exhales. See, for example, disclosed in U.S. Patent No. 7,267,121.

In some embodiments, a mist can be delivered by a device such as a metered dose inhaler (MDI) (also known as a pressurized metered dose inhaler or pMDI) that produces a mist of organic solvent droplets containing a disclosed salt form of a compound of formula (I), optionally in combination with a heated helium-oxygen mixture. In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) can be delivered via a metered dose inhaler MDI. An MDI device can include a canister containing a pharmaceutically acceptable salt of a compound of formula (I) and a propellant, a metering valve for dispensing the drug from the canister, an actuator body that holds the canister and forms an opening for oral inhalation, and an actuator rod that receives the drug from the canister and directs it from the opening of the actuator body. A non-limiting example of a metering valve and actuator is Recipharm's Bespak's BK357 valve and actuator (nominal diameter d=0.22 mm). Moving the canister relative to the actuator body and the actuator rod causes the metering valve to release a predetermined amount of drug. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) can be dissolved in a liquid propellant mixture (sometimes including a small amount of volatile organic solvent) stored in a pressurized container of an MDI. "Metered dose" refers to a dose prepackaged in a single-dose inhaler, or a dose automatically metered out from a reservoir in a multiple-dose inhaler to prepare for inhalation. The MDI device can be provided with a septum. The MDI septum is a septum between the MDI and the mouth of the MDI user. The MDI septum allows the droplets in the atomized dose to settle slightly and mix with air or other gases, thereby allowing the metered dose to be delivered to the user's lungs more effectively during inhalation. The MDI septum helps prevent the user from inhaling the metered dose directly from the MDI, in which case the dose will move too fast, causing the droplets of the atomized spray from the MDI to hit and adhere to the back of the user's throat, rather than being inhaled into the user's lungs, where the metered dose of the drug is designed to be delivered. The MDI device has the advantage of regular dosing, which can be controlled during drug manufacturing.

The pharmaceutically acceptable salt of the compound of formula (I) can also be delivered by a dry powder inhaler (DPI). In such a DPI device, the drug itself can be formed into a powder, or the powder can be formed by a pharmaceutically acceptable medium, and the drug is releasably bound to the surface of the carrier powder, so that when inhaled, the moisture in the lungs releases the drug from the surface, so that the drug can be used for systemic absorption. In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is delivered by using a dry powder inhaler (DPI). According to the salt form used, the drug itself can form the necessary powder (the pharmaceutically acceptable salt of the present disclosure is in the form of solid particles), or can be releasably bound to the surface of the carrier powder. Such carrier powders are known in the art (see, for example, Hamishehkar et al., "The Role of Carrier in Dry Powder Inhaler", Recent Advances in Novel Drug Carrier Systems, 2012, pages 39-66). When the pharmaceutically acceptable salt of the compound of formula (I) itself forms a dry powder, it becomes more important to select a suitable physiologically acceptable salt form, for example, in order to prevent irritation of the patient's lungs.

DPIs are typically formulated as a powder mixture of coarse carrier particles and micronized drug particles having an aerodynamic particle diameter of 1–5 μm (see, e.g., Iida, Kotaro et al., “Preparation of dry powder inhalation by surface treatment of lactose carrier particles” Chemical and Pharmaceutical Bulletin 51.1 (2003): 1-5). Carrier particles are typically used to improve the flowability of drug particles, thereby improving the accuracy of dosing and minimizing the dose variability observed when drug formulations are used alone, while making them easier to handle in manufacturing operations. Carrier particles should have several characteristics, such as physicochemical stability, biocompatibility and biodegradability, be compatible with the drug substance, and must be inert, available and economical. The choice of carrier particles (content and size) is well within the knowledge of those of ordinary skill in the art. The most common carrier particles are made of lactose or other sugars, with α-lactose monohydrate being the most common lactose grade used for such particle carriers in the inhalation field.

Any delivery device above can be optionally manufactured with intelligent technology to enable remote activation of drug delivery. Remote activation can be performed via a computer or mobile application. In order to ensure safety, the remote activation device can be encoded with a password. This technology enables a medical service provider to conduct a telemedicine session with a patient, during which the medical service provider can remotely activate and administer a pharmaceutically acceptable salt of a compound of formula (I) via the required delivery device, while supervising the patient in a remote visit.

Delivered with a helium-oxygen mixture

In some embodiments, the methods disclosed herein provide systemic delivery of a small dose of a pharmaceutically acceptable salt of a compound of formula (I) or a derivative thereof. In particular, a pharmaceutically acceptable salt of a compound of formula (I) or a derivative thereof may be delivered to the CNS of a patient. The dosage may be optimized for the metabolism and treatment needs of individual patients. Larger doses with harmful or adverse side effects may be avoided by using a small dose. Methods for treating various central nervous system (CNS) diseases and other symptom conditions are described herein. The method may include delivering a pharmaceutically acceptable salt of a compound of formula (I) or a derivative thereof to a patient in need via inhalation of an aerosol comprising a drug and a carrier gas, such as air, oxygen, helium, a mixture of helium and oxygen (i.e., a helium-oxygen mixture), other gases, or other gas mixtures. In some embodiments, the carrier gas may be heated. The method may also include the use of a device comprising a balloon with an oxygen-helium mixture, the balloon being equipped with a pressure reducer and a mask interconnected by a gas or air connection tube, the device comprising an additional heating element capable of heating the gas mixture to 120°C, a nebulizer with a vibrating porous plate or mesh (ensuring that droplets with a size of less than 5 microns pass through it), and a disinfection unit.

In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) or a derivative thereof is delivered to the lower respiratory tract, for example, to a lung chamber, such as an alveolar, an alveolar duct and/or a bronchiole. From there, the drug can enter the blood and enter the central nervous system. In some embodiments of the present disclosure, a pharmaceutically acceptable salt of a compound of formula (I) is delivered to a patient in need via inhalation mist, and the compound of formula (I) can be delivered to the CNS of the patient without passing through the liver. Administration via inhalation can make a gaseous drug or a drug dispersed in a liquid or mist quickly deliver the compound of formula (I) to the bloodstream, bypassing first-pass metabolism. First-pass metabolism (also referred to as "first-pass effect" or "pre-systemic metabolism") describes drugs that enter the liver and undergo extensive biotransformation.

In some embodiments, the present disclosure provides a treatment step, wherein a pharmaceutically acceptable salt of a compound of formula (I) can be administered to a patient in need thereof via inhalation of a mixture of helium and oxygen heated to about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C or higher (or any range between 50°C and 60°C) and a nebulized pharmaceutically acceptable salt of a compound of formula (I). In some embodiments, the mist or vapor of a pharmaceutically acceptable salt of a compound of formula (I) can have a particle size of about 0.1 microns to about 10 microns (e.g., about 10 microns, 5 microns, 4 microns, 3 microns, 2 microns, 1 micron, 0.1 micron or less). In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) can be nebulized via a nebulizer to produce an inhalant as a mist. In some embodiments, a nebulized pharmaceutically acceptable salt of a compound of formula (I) is driven into the patient's delivery line by the patient's inhalation. In some embodiments, the aerosolized pharmaceutically acceptable salt of the compound of formula (I) is driven along the patient delivery line by the patient's inhalation using a carrier gas. The carrier gas can be air, oxygen, a mixture of oxygen and helium, hot air, hot oxygen, a mixture of hot helium and oxygen, etc.

In some embodiments, the treating step may be preceded by a pre-treatment step. In some embodiments, the pre-treatment step may include first administering a pre-treatment inhalation therapy prior to administering a nebulizer of a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, the pretreatment inhalation step may comprise (i) administering via inhalation air, oxygen, or a mixture of helium and oxygen heated to about 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, 101°C, 102°C, 103°C, 104°C, 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C, 116°C, 117°C, 118°C, 119°C, 120°C or more (or any range between about 90°C and 120°C) and without a pharmaceutically acceptable salt of a compound of formula (I) and then (ii) administering a treatment step of inhaling air, oxygen, a mixture of oxygen and helium, heated air, heated oxygen, or a mixture of heated helium and oxygen. Hot air, hot oxygen, or a mixture of hot helium and oxygen in combination with atomized pharmaceutically acceptable salts of a compound of formula (I) or a derivative thereof can be heated to about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C or higher (or any range between about 50°C and 60°C).

In some embodiments of the present disclosure, the pre-treatment step (i) and the treatment step (ii) can be repeated 0 times, 1 time, 2 times, 3 times, 4 times, 5 times or more times. In some embodiments of the present disclosure, steps (i) and (ii) can be repeated 0 times, 1 time, 2 times, 3 times, 4 times, 5 times or more times, followed by the treatment step, which can be repeated 0 times, 1 time, 2 times, 3 times, 4 times, 5 times or more times. In some embodiments of the present disclosure, the treatment step can be repeated 0 times, 1 time, 2 times, 3 times, 4 times, 5 times or more times without the pre-treatment step.

Treatment with optional pretreatment can be administered once a week, twice a week, once a day, twice a day, three times a day or more, as well as other treatment regimens described herein. Each treatment (i.e., inhalation phase) can last for about 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes or longer.

The drug delivery procedure may include inhalation of a non-drug heated helium-oxygen mixture to effectively preheat the mucosal layer, followed by inhalation of a pharmaceutically acceptable salt of a nebulized compound of formula (I), also driven by heated helium-oxygen, but at a lower temperature, which is determined by the lower thermal resistance to wet inspired airflow versus dry inspired airflow. Thus, this process can be performed in multiple repeated cycles, where the target PK and drug exposure are controlled by drug concentration, temperature, flow rate of the helium-oxygen mixture, composition of the mixture, number and duration of cycles, time, and combinations of the above factors.

The delivery methods described herein can be used to treat certain diseases and conditions, such as central nervous system (CNS) disorders or psychological disorders, comprising administering a heated mixture of heated helium and oxygen and aerosolized pharmaceutically acceptable salts of a compound of formula (I) via inhalation. The treatment can alleviate one or more symptoms of the disorder.

In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) may be administered to treat CNS diseases or other conditions. In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) may be administered to treat depression, including but not limited to major depressive disorder, melancholia, atypical depression or dysthymia. In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) may be administered to treat psychological conditions, including anxiety, obsessive-compulsive disorder, addiction (narcotic addiction, tobacco addiction, opioid addiction), alcoholism, depression and anxiety (chronic or associated with a diagnosed life-threatening or terminal illness), compulsive behavior or related symptoms.

In some embodiments, the disease or disorder may include a central nervous system (CNS) disorder and/or a psychological disorder, including, for example, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, melancholia, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders (including but not limited to bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinogenic crisis, social anxiety disorder, substance use disorders (including but not limited to alcohol Use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder and cocaine use disorder), Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphasia, childhood verbal fluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, eating disorders (including but not limited to anorexia nervosa, bulimia nervosa, binge eating disorder, etc.) and paraphilia (including but not limited to pedophilia, exhibitionism, voyeurism, fetishism, sexual sadism and sexual masochism and transvestite, etc.), sexual dysfunction (e.g., low libido) and obesity. In some embodiments, the disease or disorder may include a condition of the autonomic nervous system (ANS). In some embodiments, the disease or disorder may include a pulmonary disorder (e.g., asthma and chronic obstructive pulmonary disease (COPD)). In some embodiments, the disease or disorder may include a cardiovascular disorder (e.g., atherosclerosis). Other diseases and disorders that can be treated are described herein.

Compared to oral delivery, methods of administering a pharmaceutically acceptable salt of a compound of formula (I) via inhalation, thereby delivering the compound of formula (I) to the CNS (systemic drug delivery), such as by a nebulizer or other devices described herein (including, for example, the use of a heated helium-oxygen mixture), can result in favorable improvements in multiple PK parameters. In particular, once administered, the compound of formula (I) can cross the blood-brain barrier and be delivered to the brain. Compared to oral delivery, methods of administering a pharmaceutically acceptable salt of a compound of formula (I) to a patient via inhalation, such as using a nebulizer or other devices described herein, optionally using a heated helium-oxygen mixture, can increase bioavailability by at least 25% compared to oral delivery. In some embodiments, the method of administering a pharmaceutically acceptable salt of a compound of Formula (I) to a patient via inhalation, such as using a nebulizer or other device described herein, can increase bioavailability by about 10%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 99%, 99.9% or more. Compared to oral delivery, the method of administering a pharmaceutically acceptable salt of a compound of Formula (I) to a patient via a nebulizer described herein can reduce _Tmax by at least 50%. In some embodiments, the method of administering a pharmaceutically acceptable salt of a compound of Formula (I) to a patient via a nebulizer described herein can reduce _Tmax by 30%, 40%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 99%, 99.9% or more. In some embodiments, the method of administering a pharmaceutically acceptable salt of a compound of formula (I) to a patient via a nebulizer or other device as described herein can increase _Cmax by at least 25% compared to oral delivery. In some embodiments, the method of administering a pharmaceutically acceptable salt of a compound of formula (I) to a patient via a nebulizer or other device as described herein can increase _Cmax by about 10%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 99%, 99.9% or more. In addition, the method of administering a pharmaceutically acceptable salt of a compound of formula (I) to a patient via inhalation using a nebulizer or other device as described herein can allow clinical protocols to achieve dose titration and more controlled exposure. Controlled exposure can adjust patient experience and provide an overall improved therapeutic effect. Using the device for inhalation delivery supported by the above-mentioned smart technology, medical staff can perform dose titration and controlled delivery remotely, enabling patients to administer medication in the comfort of their own homes, thereby improving patient experience and efficacy.

In some embodiments, a system for administering a pharmaceutically acceptable salt of a compound of formula (I) is provided, the system comprising a container containing a solution of a pharmaceutically acceptable salt of a compound of formula (I) and a nebulizer physically connected to or co-packaged with the container, the nebulizer being suitable for generating an aerosol, preferably a mist, of the solution having a particle size of about 0.1 microns to about 10 microns (e.g., about 10 microns, 5 microns, 4 microns, 3 microns, 2 microns, 1 micron, 0.1 micron or less).

Combination of 5-HT _2A receptor agonist and NMDA receptor antagonist

The present disclosure also relates to combination drug therapies based on the administration of a salt form of a compound of formula (I) as a 5-HT _2A receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. It has been found that when treating diseases or conditions associated with 5-HT _2A and/or NMDA receptors (e.g., neuropsychiatric diseases or conditions, central nervous system (CNS) disorders, and/or psychological disorders), combination drug therapies exhibit enhanced activity and improved patient experience, for example, by providing therapeutic efficacy while reducing or eliminating psychiatric side effects, such as acute hallucinogenic crises (bad trips) and dissociative effects (out-of-body experiences) of hallucinogens.

Non-limiting examples of NMDA receptor antagonists suitable for the combined drug delivery methods disclosed herein may include, but are not limited to, ketamine, nitrous oxide, memantine, amantadine, dextromethorphan (DXM), phencyclidine (PCP), mesothelin (MXE), dizocilpine (MK-801), esmethadone, or a combination thereof. In particular, nitrous oxide ( _N2O ) (commonly known as laughing gas) is a fast and effective analgesic gas that is fast-acting and rarely produces side effects when used under appropriate medical supervision. Nitrous oxide is also a dissociative inhalant that is known to cause euphoria during inhalation. The prominent effects of nitrous oxide are increased euphoria, increased pain threshold, and involuntary laughter. In addition, unlike ketamine, nitrous oxide is not addictive. For these reasons, it is preferred to use nitrous oxide as an NMDA receptor antagonist.

In some embodiments, the combination therapy includes providing a salt form of the compound of formula (I) (as a 5-HT _2A receptor agonist) and an NMDA receptor antagonist (e.g., combining the two to provide a single aerosol for the patient to inhale) in a single dosage form for administration to the patient. For example, when the NMDA receptor antagonist is nitrous oxide, the pharmaceutically acceptable salt of the compound of formula (I) may be present in the liquid phase of the aerosol, and the nitrous oxide may be present in the gas phase of the aerosol. Nitrous oxide (or a therapeutic gas mixture comprising nitrous oxide) may be used to generate an aerosol or as a carrier gas for delivering the generated aerosol to the patient. When the generated aerosol is combined with a carrier gas, the carrier gas becomes a part of the aerosol gas phase, i.e., the liquid phase of the aerosol is entrained/diluted by the carrier gas. In some embodiments, the combination therapy includes providing a pharmaceutically acceptable salt of the compound of formula (I) and an NMDA receptor antagonist in a separate dosage form. For example, the salt form of the compound of formula (I) can be provided as an aerosol, preferably a mist, while the NMDA receptor antagonist is provided separately as a therapeutic gas mixture. Alternatively, the pharmaceutically acceptable salt of the compound of formula (I) can be provided as an injection (e.g., intravenous, intradermal, subcutaneous, intramuscular, etc.), a bolus, an infusion, an infusion, etc., while the NMDA receptor antagonist is provided as a therapeutic gas mixture for inhalation delivery.

The combined action of a salt form of a compound of formula (I) and an NMDA receptor antagonist (e.g., nitrous oxide) can provide a variety of benefits. For example, an NMDA receptor antagonist can control and/or reduce the activation of 5-HT ₂ R, thereby reducing the risk of overstimulation and adverse psychiatric reactions (such as acute hallucinogenic crises). In addition, the administration of an NMDA receptor antagonist can reduce the therapeutic dose of an HT _2A receptor agonist (e.g., a pharmaceutically acceptable salt of a compound of formula (I)), thereby reducing the likelihood of a negative experience for the patient. Similarly, the administration of a pharmaceutically acceptable salt of a compound of formula (I) can reduce the amount of NMDA receptor antagonist necessary for the therapeutic effect, which in the case of nitrous oxide can alleviate certain side effects, such as induced involuntary laughter and the general anxiety associated therewith. Therefore, it is believed that the combined administration will reduce the likelihood of negative experiences of hallucinogen administration, because less hallucinogen is administered or a lower dose of an NMDA receptor antagonist (e.g., nitrous oxide, ketamine, etc.) will allow the hallucinogen to work more effectively. Similarly, such co-administration will reduce the time or amount of NMDA receptor antagonist (eg, nitrous oxide, ketamine, etc.) necessary for a therapeutic effect.

NMDA receptor antagonists (e.g., nitrous oxide) and 5-HT _2A receptor agonists work via different pharmacological pathways. However, these two pathways seem to eventually converge in a cascade manner at mTOR (mammalian target of rapamycin or mechanical target of rapamycin). Therefore, there seems to be a common mechanism of action between NMDA receptor antagonists and tryptamine hallucinogens. Specifically, the signaling pathway of mTOR may be regulated by 5-HT _2A receptor activation and NMDA antagonism. Without being bound by theory, such regulation of the mTOR pathway can support the immediate and lasting treatment and synergistic benefits of the combined administration of the two drugs. Therefore, in some embodiments, the administration of two agents in sub-hallucinogenic doses can achieve a therapeutic effect without a hallucinogenic experience.

In addition, it has been found that neuronal atrophy in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related conditions, neurological and neurodegenerative conditions, and other diseases or conditions related to neuroplasticity changes disclosed herein, such as diseases or conditions related to inhibited neurogenesis or maladaptive neuroplasticity. It is speculated that the ability to promote PFC structural and functional plasticity is the basis for the rapid antidepressant properties of dissociative anesthetic ketamine, and is also the basis for lasting effects after a single administration. Without being bound by theory, it is believed that the combined drug therapy disclosed herein can play a role by synergistically increasing neurite formation and spine formation (including increasing the density of dendritic spines), thereby providing or contributing to long-term and sustained therapeutic benefits.

In fact, the combination drug therapies disclosed herein are designed to act synergistically because both NMDA receptor antagonists (e.g., produced by nitrous oxide administration) and 5-HT _2A receptor agonist administration activate neuroplasticity, thereby achieving a significant therapeutic enhancement effect compared to the administration of either the NMDA receptor antagonist or the 5-HT _2A receptor agonist alone.

It will be understood that the ratio of the compound of formula (I) (provided in salt form) and the NMDA receptor antagonist (e.g., nitrous oxide) administered to any particular patient will depend on a variety of factors, such as the activity of the particular compound employed, the patient's age, sex, general health, time of administration, rate of excretion, and the type and severity of the particular disease or condition being treated. In some embodiments, the weight ratio of the compound of formula (I) and the NMDA receptor antagonist administered to the patient can range from about 1:100 to about 100:1, or any range therebetween, such as about 1:75, about 1:50, about 1:40, about 1:30, about 1:20, about 1:10, about 1:8, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 2:3, about 1:1, and up to about 100:1, up to about 75:1, up to about 50:1, up to about 40:1, up to about 30:1, up to about 20:1, up to about 10:1, up to about 8:1, up to about 6:1, up to about 5:1, up to about 4:1, up to about 3:1, up to about 2: 1. In some cases, ratios outside of this range can also be used.

Combined drug therapy is intended to include the form of salt formula (I) compound and NMDA receptor antagonist (for example, nitrous oxide) administered in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, and these therapeutic agents or at least two therapeutic agents (for example, co-administered) are administered in a substantially simultaneous manner. For example, substantially simultaneous administration can be achieved by administering to a subject a single dosage form having a fixed ratio of each therapeutic agent or a plurality of single dosage forms of each therapeutic agent. The administration of the salt form of formula (I) compound and NMDA receptor antagonist (for example, nitrous oxide) can be performed by any administration route described herein, whether it is a single dosage form or a separate dosage form. In some embodiments, via inhalation, preferably in the form of aerosol (for example, mist) administering the salt form of formula (I) compound and NMDA receptor antagonist. In some embodiments, the salt form of formula (I) compound is administered intravenously (IV), and NMDA receptor antagonist is administered via inhalation. In some embodiments, the salt form of formula (I) compound is administered subcutaneously, and NMDA receptor antagonist is administered via inhalation. In some embodiments, the salt form of the compound of formula (I) is administered intramuscularly, and the NMDA receptor antagonist is administered via inhalation. In some embodiments, the salt form of the compound of formula (I) is administered intranasally, and the NMDA receptor antagonist is administered via inhalation. In some embodiments, the salt form of the compound of formula (I) is administered orally, and the NMDA receptor antagonist is administered via inhalation. In some embodiments, the salt form of the compound of formula (I) and the NMDA receptor antagonist are administered transdermally or subcutaneously. Compositions for inhalation (such as pharmaceutically acceptable vehicles/carriers, etc.) are described herein for single or separate dosage forms.

When a pharmaceutically acceptable salt of a compound of Formula (I) and an NMDA receptor antagonist (e.g., nitrous oxide) are administered sequentially (i.e., separately), the time interval between administrations of the therapeutic agents can range from about 5 seconds to about one week or longer, or any time therebetween, for example, about 5 seconds, about 10 seconds, about 20 seconds, about 30 seconds, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 8 hours, about 10 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week. For sequential administration, the composition containing the pharmaceutically acceptable salt of the compound of formula (I) and the composition containing the NMDA receptor antagonist are preferably administered at intervals of about 5 seconds to less than 1 minute, less than 2 minutes, less than 2 minutes, less than 3 minutes, less than 4 minutes, less than 5 minutes, less than 10 minutes, less than 15 minutes, less than 30 minutes, less than 45 minutes, less than 1 hour, less than 2 hours or less than 4 hours. When administered substantially simultaneously, the pharmaceutically acceptable salt of the compound of formula (I) and the NMDA receptor antagonist (e.g., nitrous oxide) are administered within 5 seconds, 4 seconds, 3 seconds, 2 seconds, 1 second of each other, including simultaneous administration (e.g., when administered in the same dosage form, such as in the same aerosol).

In some embodiments, the NMDA receptor antagonist used in the combination drug therapy is nitrous oxide. Nitrous oxide can be administered alone or as a therapeutic gas mixture, such as _N2O and _O2 ; _N2O and air; _N2O and medical air (medical air is 78% nitrogen, 21% oxygen and 1% other gases); _N2O and _N2 / _O2 mixture; medical air enriched with _N2O and _O2 ; _N2O and He/ _O2 mixture, etc. Therefore, in addition to nitrous oxide and oxygen, the therapeutic gas mixture can also include other gases, such as one or more of _N2 , Ar, _CO2 , Ne, _CH4 , He, Kr, _H2 , Xe, _H2O (e.g., vapor), etc. For example, nitrous oxide can be administered using a mixing system that combines N ₂ O, O ₂ and optionally other gases from separate compressed gas cylinders into a therapeutic gas mixture that is delivered to the patient via inhalation. Alternatively, the therapeutic gas mixture containing nitrous oxide can be packaged in, for example, a pressurized tank or a small pressurized canister that is easy to use and/or portable. The mixing system and/or pressurized tank/canister can be adapted to be fluidically connected to an inhalation device, such as a device capable of producing an aerosol of a pharmaceutically acceptable salt of a compound of formula (I). Nitrous oxide itself or a therapeutic gas mixture comprising nitrous oxide can be used to generate an aerosol (i.e., as a gas phase component of an aerosol) or as a carrier gas to facilitate the transfer of the generated aerosol to the patient's lungs. In some embodiments, _N2 is present in the therapeutic gas mixture at a concentration of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50% by volume relative to the total volume of the therapeutic gas mixture. The therapeutic gas mixture comprising nitrous oxide can be administered for any desired duration, such as 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or any range therebetween.

Previously, mixtures of nitrous oxide and oxygen have been proposed to treat MDD and TRD (see, e.g., Nagele, P. et al. Biol. Psych. 2015 and Nagele, P. et al. Science Transl. Med., 2021), showing efficacy of a 50/50 mixture and a 25/75 mixture of nitrous oxide/oxygen, with a treatment schedule of 1 hour. However, the inventors have found that lower levels of nitrous oxide can provide similar efficacy over the same or shorter time, but with a significantly reduced side effect profile. Thus, in some embodiments, N2O is administered in a therapeutic gas mixture at a concentration ranging from 15%, 16%, 17%, 18%, 19% and up to 25%, up to 24%, up to 23%, up to 22%, up to 21%, up to 20% by volume relative to the total volume of the therapeutic _gas mixture, substantially simultaneously with the salt form of the compound of Formula (I), or in some cases sequentially (administered separately) with the salt form of the compound of Formula (I).

A fast-acting combination drug therapy can also be selected by selecting a 5-HT _2A receptor agonist (e.g., a salt form of a compound of formula (I)) with a short elimination half-life (t _1/2 ) and selecting a fast-acting NMDA receptor antagonist (e.g., nitrous oxide). In some embodiments, a salt form of a compound of formula (I) with an elimination half-life (t _1/2 ) of less than 2 hours, e.g., from about 15 minutes to less than about 120 minutes, less than about 110 minutes, less than about 100 minutes, less than about 90 minutes, less than about 80 minutes, less than about 70 minutes, less than about 60 minutes, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 20 minutes is selected. With respect to fast-acting NMDA receptor antagonists, nitrous oxide is particularly fast-acting, but is quickly cleared from the body, and its action ceases almost immediately after clearance, e.g., when airflow ceases. Therefore, when a fast-acting combined drug therapy is needed, nitrous oxide is very suitable for use with a fast-acting and short-duration 5-HT _2A receptor agonist. The above-mentioned fast-acting therapeutic combination may be advantageous for acute therapeutic applications, such as treating acute psychotic symptoms, for example as a rescue drug when someone has suicidal tendencies. The therapeutic combination may be particularly useful for treating acute conditions that require a fast onset, a short duration of action, and minimal psychiatric side effects. Non-limiting examples of acute psychotic symptoms include, but are not limited to, suicidal ideation and suicide attempts, social anxiety disorder, drug withdrawal, post-traumatic stress disorder (PTSD), and panic attacks.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) and the NMDA receptor antagonist (for example, nitrous oxide) are each administered by aerosol inhalation in a single dosage form or a separate dosage form. Aerosol (preferably mist) can be produced by any capable device (for example, pressurized container, pump, spray, atomizer or sprayer) with or without the use of a propellant, such as those devices disclosed herein. When nitrous oxide is administered simultaneously with the pharmaceutically acceptable salt of the compound of formula (I), nitrous oxide can be used as a carrier gas or a propellant and a therapeutic agent (NMDA receptor antagonist) produced by the aerosol at the same time.

In some embodiments, the delivery device is an inhalation delivery device for delivering a combination of nitrous oxide and a pharmaceutically acceptable salt of a compound of formula (I) to a patient in need by inhalation, comprising an inhalation outlet for applying the combination to the patient; a container configured to deliver nitrous oxide gas to the inhalation outlet; and a device configured to generate and deliver an aerosol comprising a pharmaceutically acceptable salt of a compound of formula (I) to the inhalation outlet. In some embodiments, the inhalation outlet is selected from an interface or a mask covering the patient's nose and mouth. In some embodiments, the device configured to generate an aerosol and deliver it to the inhalation outlet is a nebulizer. In some embodiments, the nebulizer is a jet nebulizer, and nitrous oxide gas is used alone or in combination with other gases (a therapeutic gas mixture comprising nitrous oxide) as a driving gas for the jet nebulizer. Therefore, the nitrous oxide delivered using a nebulizer (e.g., a jet nebulizer) can be used as a therapeutic agent and a driving gas to entrain a pharmaceutically acceptable salt of a compound of formula (I) in atomized form. In some embodiments, the device further comprises smart technology, such as an electronic device, configured to provide remote activation and operational control of the inhalation delivery device as described above.

In some embodiments, the device is a dual delivery device, which is configured to apply a pharmaceutically acceptable salt (preferably in the form of an aerosol) of a compound of formula (I), and simultaneously applies a controlled amount of nitrous oxide. Any of the above-mentioned aerosol delivery devices can be used for this device, adding a nitrous oxide source, which is configured to provide metered, controlled dose/flow rate nitrous oxide by the same application outlet as the aerosol delivery device. In some embodiments, the driving gas for the pharmaceutically acceptable salt of atomized formula (I) compound is nitrous oxide itself.

All patents, patent applications and other scientific or technical writings mentioned anywhere else herein are incorporated herein by reference in their entirety. The embodiments described illustratively herein can be appropriately implemented in the absence of any one or more elements, one or more restrictions specifically or not specifically disclosed herein. Thus, for example, in each case herein, the terms "comprising", "consisting essentially of" and "consisting of" can be replaced with any of the other two terms while retaining their common meaning. The terms and expressions that have been adopted are used as illustrative rather than limiting terms, and are not intended to use such terms and expressions that do not include any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications can be made within the scope of the claims. Therefore, although the methods and compositions of the present invention are specifically disclosed by embodiments and optional features, those skilled in the art can modify and change the concepts disclosed herein, and these modifications and changes are considered to be within the scope of the compositions and methods defined by the specification and the appended claims.

Any individual term, individual element, individual phrase, group of terms, group of phrases or group of elements described herein may each be specifically excluded from the claims.

Whenever a range is given in the specification, such as a temperature range, time range, composition or concentration range, all intermediate ranges and subranges and all individual values contained within the given range are intended to be included in the present disclosure. It should be understood that any subrange or individual value within a range or subrange contained in the specification herein may be excluded from aspects of the present invention. It should be understood that any element or step contained in the specification herein may be excluded from the claimed compositions and methods.

In addition, where features or aspects of compositions and methods are described in terms of Markush groups or other alternative groupings, 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 is provided for illustrative purposes only and is not intended to limit the scope of the embodiments broadly described above.

Example

I. Synthesis Procedure

Examples 1-9

Examples 1-9 were prepared by crystallizing from ethanol a stoichiometric (1.0 molar equivalent) amount or, in the case of a half salt, a substoichiometric (0.5 molar equivalent) amount of the free base of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1) of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, or glycolic acid). The salt form identifier and salt type are provided in Table 3.

Table 3: Examples 1-9

^a) Isolation of two crystalline polymorphs of the hemifumarate salt

Examples 10-13

The synthesis of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1- _d2 (I-2) was performed according to Figure 1. Indole (A) was iminoformylated using formaldehyde/dimethylamine to produce intermediate (B), which was then converted to the 3-acetic acid intermediate (C) using potassium cyanide in HCl. Subsequent treatment with thionyl chloride and dimethylamine ( _R8 = _R9 = _CH3 ) produced the amide (D, _R8 = _R9 = _CH3 ), which was reduced by _LiAlD4 to produce compound I-2. The structure of the product was confirmed ^by1H NMR.

Examples 10-13 were prepared by crystallizing a stoichiometric (1.0 molar equivalent) amount of the free base of 1-2 of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifiers and salt types are provided in Table 4.

Table 4: Examples 10-13

Example No. Salt form identifier Salt type of compound 10 I-2a Fumarate of I-2 11 I-2b I-2 Benzoate 12 I-2c Salicylate of I-2 13 I-2d Succinate of I-2

Examples 14-17

The synthesis of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine (I-4) was carried out according to Figure 2. Indole (A) was acylated with oxalyl chloride and then reacted with dimethyl-d 6 amine to produce an amide (F, R ₈ ＝R ₉ ＝CD ₃ ). Subsequent reduction with LiAlH ₄ gave compound I-4. The structure of the product was confirmed by ¹ H NMR.

Examples 14-17 were prepared by crystallizing a stoichiometric (1.0 molar equivalent) amount of the free base of 1-4 of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifiers and salt types are provided in Table 5.

Table 5: Examples 14-17

Example No. Salt form identifier Salt type of compound 14 I-4a I-4 Fumarate 15 I-4b I-4 Benzoate 16 I-4c Salicylate of I-4 17 I-4d I-4 succinate

Examples 18-21

The synthesis of 2-(1H-indol-3-yl)--N,N-dimethylethan-1-amine-1,1,2,2-d ₄ (I-5) was carried out according to Figure 2. Indole (A) was acylated with oxalyl chloride and then reacted with dimethylamine to produce an amide (F, R ₈ =R ₉ =CH ₃ ). It was subsequently reduced with LiAlD ₄ to give compound I-5. The structure of the product was confirmed by ¹ H NMR.

Examples 18-21 were prepared by crystallizing a stoichiometric (1.0 molar equivalent) amount of the free base of 1-5 of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifiers and salt types are provided in Table 6.

Table 6: Examples 18-21

Example No. Salt form identifier Salt type of compound 18 I-5a I-5 Fumarate 19 I-5b I-5 Benzoate 20 I-5c Salicylate of I-5 twenty one I-5d I-5 succinate

Examples 22-25

The synthesis of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1-d ₂ (I-6) was performed according to Figure 1. Indole (A) was iminoformylated using formaldehyde/dimethylamine to produce intermediate (B), which was then converted to the 3-acetic acid intermediate (C) using potassium cyanide in HCl. Subsequent treatment with thionyl chloride and dimethyl-d 6 -amine (R ₈ ＝R ₉ ＝CD ₃ ) produced the amide (D, R ₈ ＝R ₉ ＝CD ₃ ), which was reduced by LiAlD ₄ to produce compound I-6. The structure of the product was confirmed by ¹ H NMR.

Examples 22-25 were prepared by crystallizing a stoichiometric (1.0 molar equivalent) amount of the free base of 1-6 of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, or succinic acid) from ethanol. The salt form identifiers and salt types are provided in Table 7.

Table 7: Examples 22-25

Example No. Salt form identifier Salt type of compound twenty two I-6a I-6 Fumarate twenty three I-6b I-6 Benzoate twenty four I-6c Salicylate of I-6 25 I-6d I-6 succinate

Examples 26-29

The synthesis of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8) was performed according to Figure 2. Indole (A) was acylated with oxalyl chloride and then reacted with dimethyl-d 6 -amine to produce amide F (R ₈ =R ₉ =CD ₃ ). Amide F (R ₈ =R ₉ =CD ₃ ) (7.04 g, 31.67 mmol) was charged to a flask under nitrogen atmosphere. 2-MeTHF (140 ml, 20 volumes) was then charged and stirred at room temperature for 15 minutes, although not all solids were completely dissolved during this time. Lithium aluminum deuteride (LiAlD ₄ ) (4.04 g, 96.23 mmol, 3.0 equiv) was charged in portions over 45 minutes, maintaining the temperature of the reaction mixture <40°C. After the addition was complete, the reaction mixture was heated to 65°C for 16 hours. The batch was cooled to room temperature and confirmed to be complete by HPLC analysis. Water/THF mixture (35ml, 5 volumes, 1:9) was added dropwise within 90 minutes, keeping the temperature <30°C. Then 15% NaOH (aqueous solution) (3.5ml, 0.5 volume) was added dropwise, followed by the addition of water (10.5ml, 1.5 volumes). This mixture was stirred at room temperature for 30 minutes, then filtered, and the solid was washed with 2-MeTHF (3×/70ml, 3×10 volumes), each time before dehydration, they were slurried. The liquid was concentrated to dryness, leaving compound I-8 in a viscous orange-red oily state. The structure of the product was confirmed by ¹ H NMR. Compound I-8 was then dissolved in ethanol (49ml, 7 volumes), and this I-8 ethanol solution was used in the salt-forming experiment provided below. Salt form identifiers and salt types are provided in Table 8.

Table 8: Examples 26-29

Example No. Salt form identifier Salt type of compound 26 I-8a I-8 Fumarate 27 I-8b I-8 Benzoate 28 I-8c Salicylate of I-8 29 I-8d I-8 succinate

Example 26. A flask was charged with 15 ml of ethanolic solution of I-8, heated to reflux, and fumaric acid (1.07 g, 1.05 eq) was added in one portion. After complete dissolution, it was cooled to room temperature, then further cooled to 0°C and filtered, and the flask was rinsed with additional ethanol (3×5 ml, 3×2 volumes) and the filter cake was washed. I-8a was isolated as a crystalline solid with a yield of 1.480 g (4.71 mmol, 44.6%, 97.0%, confirmed as 1:1 fumarate by LC, ¹ H NMR identity).

Example 27. 18 ml of ethanolic solution of I-8 was charged into a flask, heated to reflux, and then benzoic acid (4.04 g, 3.15 equivalents) was added in one go. After ensuring that all solids were dissolved, the solution was cooled in an ice bath and stirred for another 60 minutes at this temperature, then filtered, and the flask was rinsed with ice-cold ethanol (2×2 volumes) and the filter cake was washed. 2.272 g (7.09 mmol) of I-8b was obtained. Since residual impurities were observed in the HPLC analysis of this compound, it was slurried in ethanol (5 ml, 2 volumes) for 16 hours. It was then cooled to 0°C and filtered, and the flask was rinsed with ethanol (5 ml, 2 volumes) and the solid was washed. However, the solid was amorphous and did not have a crystalline form. Therefore, they were dissolved in ethanol (15 ml, 7.5 volumes) under reflux, cooled to 0°C and filtered, and washed with ethanol (5 ml, 2 volumes). Isolated I-8b was thus obtained as a white crystalline solid in a yield of 1.534 g (4.79 mmol, 45.4%, 91.1%, identity confirmed by LC, ¹ H NMR as 1:1 benzoate salt).

Example 28. A flask was charged with 18 ml of an ethanolic solution of I-8, heated to reflux, and additional ethanol (11.7 ml, 12 volumes in total) and salicylic acid (1.52 g, 1.05 equivalents) were added in one go. Once completely dissolved, the solution was cooled to 0°C. The resulting solid was filtered and washed with ice-cold ethanol (2×2 volumes) to give a yield of 2.860 g (8.50 mmol) of I-8c. Since residual impurities were observed in the HPLC analysis of this compound, it was slurried in ethanol (5 ml, 2 volumes) for 16 hours. It was then cooled to 0°C and filtered, and the flask was rinsed with ethanol (5 ml, 2 volumes) and the solids were washed. However, the solids were amorphous and did not have a crystalline form. Therefore, they were dissolved in ethanol (60 ml, 30 volumes) under reflux, cooled to 0°C and filtered, and washed with ethanol (5 ml, 2 volumes). Isolated I-8c was thus obtained as a white crystalline solid in a yield of 2.311 g (6.87 mmol, 65.1%, 91.5%, identity confirmed as 1:1 salicylate salt by LC, ¹ H NMR).

Example 29 was similarly prepared by crystallizing the free base of 1-8 from ethanol using a stoichiometric (1.0 molar equivalent) amount of succinic acid.

II. Analysis

Using the experimental details listed below, the samples were analyzed in detail using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS), and ¹ H nuclear magnetic resonance (NMR) spectroscopy.

Differential Scanning Calorimetry (DSC)

All DSC curves were collected using a Mettler Toledo 823 calorimeter connected to a TA8000 workstation running Mettler Toledo Stare software version 9.01. Typical analysis conditions were as follows:

Starting temperature: 20℃

Heating rate: 10℃·min ^-1

End temperature: 320℃

Purge gas: 70 mL·min ^-1 nitrogen

Sample Pan; 40 μL aluminum pan with perforated lid

4-7 mg of sample was loaded into an aluminum sample pan. Before any measurements were made, the instrument was calibrated for temperature and heat flow using traceable indium, water, and cyclohexane standards.

X-ray powder diffraction (XRPD)

X-ray powder diffraction patterns were obtained using a Bruker D5000 diffractometer in a Bragg-Brentano configuration. Extended acquisition parameters were used for each batch of drug substance, as detailed below:

Source: CuKα

wavelength;

Step range: 2-40°(2θ)

Step size: 0.01°(2θ)

Time per step: 4.0 seconds

Divergence slit width: 2mm

Anti-scattering slit width: 2mm

Detector slit width: 0.2mm

Sample rotation; joint

Tube accelerating potential: 40kV

Tube accelerating current: 30mA

Temperature: Ambient temperature (nominal temperature is 18-22°C)

Approximately 2-5 mg of each sample was mounted on a silicon substrate and a glass slide was used to create a flat surface for analysis. All data were smoothed using a Fourier algorithm and the background was subtracted from each diffraction pattern.

Prior to the measurements, instrument performance checks were completed using a NIST traceable corundum standard and an Arkansas quartz standard. Arkansas quartz is a recognized standard provided by the instrument manufacturer but without a lot number. Its use has continued since the creation of a database with performance monitoring standards. However, parameters such as diffraction angle accuracy, resolution, and sensitivity were evaluated using a traceable corundum standard.

Dynamic Vapor Sorption (DVS)

Dynamic vapor sorption-desorption experiments were performed using a DVS resolution instrument provided by Surface Measurement Systems. Data were collected using the following acquisition parameters:

Solvent; Water

Initial relative humidity: 30% RH

Relative humidity cycle (%RH); 30, 40, 50, 60, 70, 80, 90, 95, 90, 80, 70, 60, 50, 40, 30, 20, 10, 0, 10, 20, 30

Balance condition (dm/dt): 0.002%/min

Equilibrium condition window: 10 minutes

Minimum stage period: 5 minutes

Maximum phase period: 360 minutes

Temperature: 25℃

Carrier gas: Nitrogen

Carrier gas flow rate: 200mL·min ^-1 (total amount)

Typically, 20-50 mg of the test material is placed in a gauze basket and transferred to the sampling port. During sample handling and sample mounting, excess static electricity is eliminated using a ²¹⁰ Po static eliminator. Instrument performance checks are completed using traceable sodium chloride and lithium chloride samples. For selected samples, the cycle is repeated using the same sample to evaluate any physical form changes caused by exposure to elevated relative humidity.

¹ H Nuclear Magnetic Resonance (NMR) Spectroscopy

Assessment of counterion stoichiometry was performed using 1H nuclear magnetic resonance (NMR) spectroscopy.

Samples were stored at ambient laboratory temperature (18-22°C) until required for analysis. For NMR analysis, the material was dissolved in 0.6 mL of deuterated dimethyl sulfoxide (DMSO-d6) and subsequently transferred to high-precision 5 mm OD NMR tubes. In each case, the drug substance samples were dissolved without heating. After optimization and stabilization of the magnet, analysis was initiated within 60 minutes of dissolving the material in the deuterated solvent.

All NMR experiments were performed using a Bruker Avance III HD spectrometer equipped with an 11.7 Tesla magnet. Spectra were acquired using a 5 mm BBO ¹ H multinuclear z-gradient broadband normal geometry probe. Sample temperature was controlled throughout the analysis, allowing appropriate time for thermal equilibrium to establish.

¹ H NMR spectra were acquired using a direct pulse acquisition sequence and the following parameters were used for each material analyzed:

The chemical shifts of tetramethylsilane (TMS) were indirectly referenced using the residual proton signal of DMSO-d6. No internal reference was used to circumvent the possibility of induced degradation. An exponential multiplicative convolution of 0.3 Hz was applied to the free induction decay before Fourier transformation.

III. Results

The samples were analyzed by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and dynamic vapor sorption (DVS). In addition, the appearance and visual properties of each sample were evaluated in addition to the crystallization tendency. Table 9 lists some of the main target properties obtained from each analytical evaluation.

A summary of the data obtained from the analysis of the individual salt forms of Examples 1-9 is presented in Table 10, with favorable and unfavorable properties summarized using the following nomenclature: "+/+/+" indicates most favorable; "+/+" indicates more favorable; "+" indicates favorable; "-" indicates unfavorable; "-/-" indicates more unfavorable; "-/-/-" indicates least unfavorable.

Table 9: Target properties of salt forms

Table 10: Summary summary of salt properties of Examples 1-9

^a) Combined results of two crystalline polymorphs

X-ray powder diffraction (XRPD)

The X-ray powder diffraction patterns of Example 6 (I-1f; glycolate), Example 9 (I-1i; hemifumarate) and Example 1 (I-1a; fumarate) are presented in Figure 3. The X-ray powder diffraction patterns of Example 2 (I-1b; benzoate), Example 3 (I-1c; salicylate) and Example 7 (I-1g; hemioxalate) are presented in Figure 4. The X-ray powder diffraction patterns of Example 5 (I-1e; oxalate), Example 4 (I-1d; succinate) and Example 8 (I-1h; hemifumarate) are presented in Figure 5. The characteristic X-ray diffraction peaks (2θ±0.2°) of Examples 1-8 are listed in Table 11. In each case, the diffraction pattern included discrete and sharp Bragg diffractions consistent with crystalline material. The diffraction pattern of each salt form is different, reflecting the different lattice parameters. However, it is noted that the two samples of the hemifumarate salt (Example 8 and Example 9) show slightly different diffraction patterns, indicating a polymorphic tendency for this salt form. The latter salt has some common diffractions, confirming that one or both samples contain a physical mixture. Subjectively, the samples provided contain one physical form except for the hemifumarate salt. It is noted that the Bragg diffraction of the hemioxalate salt (Example 7; I-1g) has some slight broadening; this effect is very small, but indicates some disorder or reduced crystallinity.

X-ray powder diffraction studies showed that all salt forms as part of this study were crystalline and suitable for salt form evaluation. It was noted that the hemifumarate (Example 8 and Example 9) showed some polymorphic tendencies, which is undesirable. Although the effect was not significant, it was also noted that the hemioxalate (Example 7; I-1g) showed some slight broadening of the diffraction, indicating a slight disorder in the crystallinity or the presence of a small amount of amorphous material. The two observations associated with the hemifumarate and hemioxalate salts are not completely prohibitive, but they are less suitable for drug development purposes than other salt forms.

Table 11: Characteristic XRD peaks (2θ±0.2°) of Examples 1-8

The X-ray powder diffraction pattern of Example 26 (I-8a; fumarate salt) is presented in Figure 6 compared to Example 1 (I-1a; fumarate salt). The X-ray powder diffraction pattern of Example 27 (I-8b; benzoate salt) is presented in Figure 7 compared to Example 2 (I-1b; benzoate salt). The X-ray powder diffraction pattern of Example 28 (I-8c; salicylate salt) is presented in Figure 8 compared to Example 3 (I-1c; salicylate salt). The characteristic X-ray diffraction peaks (2θ±0.2°) of Examples 26-28 are listed in Table 12. It can be seen that the X-ray powder diffraction patterns of the deuterated (DMT d-10) salts are identical or nearly identical to their respective protonated analogs. Therefore, it can be concluded that the physical form of the deuterated salts is identical or nearly identical to the protonated salts. Therefore, the favorable properties identified in Tables 9 and 10 (such as crystallization tendency, physical properties, hygroscopicity, appearance, physiological acceptability and overall salt compatibility) can be extended to the deuterated salt forms.

Table 12: Characteristic XRD peaks (2θ±0.2°) of Examples 26-28

Differential Scanning Calorimetry (DSC)

The DSC curve of Example 1 (I-1a; fumarate salt) is shown in Figure 9, and it is clear that the salt has a high melting onset temperature (192.7°C) and a high fusion enthalpy (136.3 J·g ^-1 ), which is beneficial for drug development. Also, no events were observed before the melting endotherm, indicating that multiple physical forms are not present in the sample, and there is no conversion of physical forms before melting. Post-melting events are attributed to decomposition.

The DSC curve of Example 2 (I-1b; benzoate salt) is shown in Figure 10 and similar to the fumarate salt, it is apparent that the salt has a high melting onset temperature (166.6°C) and high fusion enthalpy (166.1 J·g ^-1 ). Again, no events were observed prior to the melting endotherm, indicating that multiple physical forms were not present in the sample and that there was no conversion of physical forms prior to melting. Post-melting events were attributed to decomposition.

The DSC curve of Example 4 (I-1d; succinate salt) is shown in Figure 11 and similar to the fumarate and benzoate salts, it is apparent that the salt has a high melting onset temperature (141.9°C) and high fusion enthalpy (159.1 J·g ^-1 ). Again, no events were observed prior to the melting endotherm, indicating that multiple physical forms were not present in the sample and that there was no conversion of physical forms prior to melting. Post-melting events were attributed to decomposition.

The DSC curve of Example 5 (I-1e; oxalate salt) is shown in Figure 12 and similar to the previous salt, it is clear that the salt has a high melting onset temperature (148.4°C) and a high fusion enthalpy (125.8 J·g ^-1 ). Again, no significant events were observed before the melting endotherm, indicating that there are no multiple physical forms in the sample and no conversion of physical forms before melting; the broad low intensity endotherm between 20°C and 80°C is due to the loss of water/solvent. Post-melting events are attributed to decomposition.

The DSC curve for Example 3 (I-1c; salicylate) is shown in Figure 13 and is similar to the previous salts, evidently having a high melting onset temperature (191.9°C) and high fusion enthalpy (155.6 J·g ^-1 ). Again, no events were observed prior to the melting endotherm, indicating that multiple physical forms were not present in the sample and that there was no conversion of physical forms prior to melting. Post-melting events were attributed to decomposition.

The DSC curve of Example 6 (I-1f; glycolate salt) is shown in Figure 14. The melting onset temperature (105.6°C) and fusion enthalpy (117.5 J·g ^-1 ) are slightly lower than the previous salts, but can still be used for drug development purposes. The excellent physical properties of the other salts make the glycolate slightly inferior in this regard. No events were observed before the melting endotherm, indicating that multiple physical forms are not present in the sample, and there is no conversion of physical forms before melting. Post-melting events are attributed to decomposition.

The DSC curves of Example 9 (I-1i; hemifumarate salt) and Example 8 (I-1h; hemifumarate salt) are shown in Figures 15 and 16, respectively. The melting onset temperature is quite high (typically >138°C), but the fusion enthalpy is slightly lower than that of the other salts (about 90 J·g ^-1 ). In Example 9, the endotherm is slightly broadened, which is consistent with the presence of physical or chemical impurities, and for the other batch, a small endothermic event is observed immediately before the main melting. Both DSC curves confirm the trend of multiple physical forms, which is consistent with the X-ray powder diffraction data provided previously. The presence of multiple forms or the tendency to exhibit multiple forms is not completely prohibited, but in the presence of alternatives, these salt forms are less favorable than other salt forms. Post-melting events are attributed to decomposition.

In summary, all tested salt forms exhibited satisfactory melting onset temperatures and fusion enthalpies with no inhibitory polymorphic tendencies, except for the hemifumarate salt. The hemifumarate salt clearly showed the presence of different physical forms. Although none of the salt forms showed features that would make them unusable for drug development purposes, there were clearly preferred candidate salts, i.e., fumarate, benzoate, salicylate, and succinate, considering only the DSC data.

Dynamic Vapor Sorption (DVS)

The DVS isotherm of Example 1 (I-1a; fumarate salt) is shown in Figure 17. There is no apparent hygroscopicity, and even when exposed to elevated relative humidity of >95% RH (<0.2% w/w), water acquisition is very low. Within the typical ambient relative humidity range, there is little mass change, and no evidence of physical form conversion during the entire cycle. This isotherm represents favorable behavior for drug development purposes.

The DVS isotherm of Example 2 (I-1b; benzoate) is shown in Figure 18. As for the fumarate salt, there is no apparent hygroscopicity, and even when exposed to elevated relative humidity of >95%RH (<0.05%w/w), water uptake is very low. Within the typical ambient relative humidity range, there is little mass change, and no evidence of physical form conversion during the entire cycle. This isotherm represents favorable behavior for drug development purposes.

The DVS isotherm of Example 4 (I-1d; succinate) is shown in Figure 19. Similar to the fumarate and benzoate salts, there is no significant hygroscopicity, and even when exposed to elevated relative humidity of >95%RH (<0.5%w/w), water acquisition is very low. Although water uptake increases when exposed to 95%RH, the level is quite acceptable, and the curve between 30%RH and 80%RH is very flat, so that the quality does not change significantly at typical ambient relative humidity. There is no evidence of physical form conversion during the entire cycle. This isotherm represents acceptable behavior for drug development purposes.

The DVS isotherm for Example 3 (I-1c; salicylate) is shown in Figure 20. There is no apparent hygroscopicity, and water uptake is very low even when exposed to elevated relative humidity of >95% RH (<0.06% w/w). There is little mass change over the typical ambient relative humidity range, and no evidence of physical form conversion over the course of the cycle. This isotherm represents favorable behavior for drug development purposes.

The DVS isotherm plot for Example 5 (I-1e; oxalate) is shown in Figure 21. In this case, when exposed to 95% RH, the water uptake is about 3% w/w, and there is no discernible plateau at any point between 0% RH and 95% RH. This curve is not preferred and may present some challenges from an analytical perspective. Typically, this behavior is also accompanied by crystallization challenges.

The DVS isotherms of Example 6 (I-1f; glycolate salt) and Example 8 (I-1h; hemifumarate salt) are shown in Figure 22 and Figure 23, respectively. These salt forms effectively deliquesce at elevated relative humidity, which is not preferred for drug development.

The DVS isotherm plot for Example 7 (I-1g; hemioxalate salt) is shown in Figure 24. The equilibrium water content at typical ambient relative humidity is >3% and varies with changes in relative humidity. In fact, water uptake at relative humidity above 80% is excessive and, based on the reproducibility of two cycles, induces a phase transition when exposed to elevated relative humidity. Without additional work to investigate alternative physical forms, this salt form may not be suitable for drug development.

In summary, the vapour sorption behaviour of the salt forms evaluated in this paper is highly variable and different. The fumarate, benzoate, succinate and salicylate salts are all very well behaved, with no deliquesce and low water uptake at typical ambient relative humidities.

¹ H Nuclear Magnetic Resonance (NMR) Spectroscopy

The 1 H nuclear magnetic resonance (NMR) spectra of Example 1 (I-1a; fumarate), Example 2 (I-1b; benzoate), Example 3 (I-1c; salicylate), Example 5 (I-1e; oxalate), Example 8 (I-1h; hemifumarate), Example 6 (I-1f; glycolate), Example 4 (I-1d; succinate), and Example 7 (I-1g; hemioxalate) are shown in Figures ²⁵ to 32, respectively. In each case, the spectrum is consistent with the proposed molecular structure in terms of chemical shift, multiplicity, and integration. The signal integral values of the counterion resonances were compared with the integral values of the DMT signal to confirm the described stoichiometry (i.e., 2:1 DMT: counterion for half salts and, 1:1 DMT: counterion for all other salts).

Single crystal X-ray diffraction

The benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8b) was slowly crystallized from an ethanol/water mixture by controlled evaporation over a period of approximately 1 week. A single crystal of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ (I-8b) (C ₁₉ H ₁₂ D ₁₀ N ₂ O ₂ ) was selected and mounted on a Mitegen head coated with Fomblin oil. It was placed on a dual source Rigaku Oxford Diffraction Synergy-S diffractometer equipped with a hybrid pixel array detector. The crystal was held at 100(2)K during data collection. The structure was solved with the SHELXT (Sheldrick, GM (2015). Acta Cryst. A71, 3-8) structure solution program using intrinsic phasing using Olex2 (Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK & Puschmann, H. (2009), J. Appl. Cryst. 42, 339-341), and least squares minimization was improved with the SHELXL (Sheldrick, GM (2015). Acta Cryst. C71, 3-8) improvement package.

The solid state structure of I-8b was generated; the molecular structure is shown in Figure 33A. The asymmetric unit contains DMT d-10 and benzoate counterions; as shown in Figure 33B, two compounds are present in the unit cell connected by the inversion center. NH moieties are detected in the difference map of N2 and N12. N2 is modified in a calculated position. These NH moieties form short contacts with the benzoate counterions listed in Table 13 below.

Table 13: Hydrogen bond parameters in the asymmetric unit

D-H H…A D…A <(DHA) Key Descriptor 0.88 1.91 2.7859(13) 175.2 N2-H2...O16_$1 0.987(17) 1.681(17) 2.6652(12) 174.1(15) N12-H12...O15

The symmetry operator used to generate symmetry equivalent atoms in the above contacts is $11-X,2-Y,1-Z

A summary of the crystal structure data for I-8b is listed in Table 14. The proposed crystal structure is of very high certainty and is consistent with expectations based on the determined counterion stoichiometry.

Table 14: Crystallographic data and structural refinement of I-8b

Storage stability evaluation

The storage stability of Example 26 (I-8a; fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2,2-d ₄ ) was evaluated based on appearance, HPLC chemical purity and quantitative NMR (qNMR) at three different storage conditions: 20°C, 25°C 60% RH and 40°C 75% RH. The samples were placed in the following primary and secondary containers: Primary container: 10 mL clear glass bottle, black cap, ribbed cap with reflective insert; Secondary container: amber 100 mL glass bottle, black cap, with white insert.

Table 15

Table 15 shows the stability data generated. There were no significant changes in any of the parameters tested at the 2-week or 4-week time points under the test conditions. According to the Arrhenius equation, the rate of a chemical reaction approximately doubles for every 10°C increase in temperature. Therefore, the stability of I-8a for at least 1 month at 40°C indicates that the material has a suitable shelf life of at least 1 year when stored at -20°C.

The above only illustrates the principle of method and composition.It should be understood that those skilled in the art will be able to design various arrangements, although not explicitly described or shown in this article, but the various arrangements embody the principle of the present disclosure and are closed within the spirit and scope of the present invention.In addition, all embodiments and conditional language described herein are mainly intended to help readers understand the principles of the present disclosure and the concepts contributed by the inventors to promote the development of the art, and will be interpreted as without being limited to the embodiments and conditions of this particular description.In addition, all statements describing the principles, aspects and embodiments of the present disclosure and its specific embodiments herein are intended to cover both its structural equivalents and functional equivalents.In addition, this equivalent is intended to include both currently known equivalents and equivalents developed in the future, that is, any element developed to perform the same function, regardless of the structure.Therefore, the scope of the present disclosure is not intended to be limited to the exemplary embodiments shown and described herein.On the contrary, the scope and spirit of the present disclosure are embodied by the appended claims.

Claims (66)

1. A pharmaceutically acceptable salt or solvate thereof of a compound of formula (I), in: _X1 and _X2 are deuterium, _Y1 and _Y2 are deuterium, R ₂ , R ₄ , R ₅ , R ₆ and R ₇ are independently hydrogen or deuterium, and R ₈ and R ₉ are independently selected from the group consisting of -CH ₃ , -CDH ₂ , -CD ₂ H and -CD ₃ . 2. The pharmaceutically acceptable salt of claim 1, wherein at least one of R ₈ and R ₉ comprises deuterium. 3. The pharmaceutically acceptable salt of claim 1, wherein _R2 , _R4 , _R5 , _R6 and _R7 are hydrogen. The pharmaceutically acceptable salt of claim 1 , wherein at least one of R ₂ , R ₄ , R ₅ , R ₆ and R ₇ is deuterium. The pharmaceutically acceptable salt of claim 1 , wherein R ₈ and R ₉ are —CH ₃ . 6. The pharmaceutically acceptable salt of claim 1, wherein _R8 and _R9 are independently selected from the group consisting of _-CDH2 , _-CD2H and _-CD3 . 7. The pharmaceutically acceptable salt of claim 1, wherein _R8 and _R9 are _-CD3 . 8. The pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is selected from the group consisting of: 9. The pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is 10. The pharmaceutically acceptable salt of claim 1, which is crystalline as determined by X-ray powder diffraction (XRPD). 11. The pharmaceutically acceptable salt of claim 1, having a water solubility of about 10 mg/mL to about 400 mg/mL. 12. The pharmaceutically acceptable salt of claim 1, having a melting onset temperature of about 100°C to about 210°C as determined by differential scanning calorimetry (DSC). 13. The pharmaceutically acceptable salt of claim 1, having a fusion enthalpy of about 110 J·g ^-1 to about 180 J·g ^-1 as determined by differential scanning calorimetry (DSC). 14. The pharmaceutically acceptable salt of claim 1, having a weight gain of less than 1% w/w when exposed to a relative humidity (RH) of >95% RH as determined by dynamic vapor sorption (DVS). 15. The pharmaceutically acceptable salt according to claim 1, which is an addition salt of the compound of formula (I) and an organic acid. 16. The pharmaceutically acceptable salt of claim 1, which is a fumarate, benzoate, salicylate or succinate of the compound of formula (I). 17. The pharmaceutically acceptable salt according to claim 1, which is a fumarate salt of the compound of formula (I). 18. The pharmaceutically acceptable salt according to claim 1, which is a benzoate salt of the compound of formula (I). 19. The pharmaceutically acceptable salt of claim 1, which is a salicylate salt of the compound of formula (I). 20. The pharmaceutically acceptable salt according to claim 1, which is a succinate salt of the compound of formula (I). The pharmaceutically acceptable salt of claim 1 , which is 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-8a). 22. The pharmaceutically acceptable salt of claim 21 in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from the group consisting of 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. 23. The pharmaceutically acceptable salt of claim 1, which is a benzoate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2,2- _d4 (I-8b). 24. The pharmaceutically acceptable salt of claim 23 in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from the group consisting of 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. 25. The pharmaceutically acceptable salt of claim 1, which is a salicylate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2,2- _d4 (I-8c). 26. The pharmaceutically acceptable salt of claim 25 in the form of a crystalline solid characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from the group consisting of 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. 27 . The pharmaceutically acceptable salt of claim 1 , which is 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-8d). 28. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable vehicle. 29. The pharmaceutical composition of claim 28, wherein any position in the compound of formula (I) having deuterium has a minimum deuterium incorporation of at least 50 atomic % at the deuterium site. 30. The pharmaceutical composition of claim 28, which is suitable for administration via inhalation. 31. The pharmaceutical composition of claim 28, which is suitable for oral administration. 32. The pharmaceutical composition of claim 28, which is suitable for intravenous administration. 33. The pharmaceutical composition of claim 28, which is suitable for subcutaneous administration. 34. The pharmaceutical composition of claim 28, which is suitable for intramuscular administration. 35. The pharmaceutical composition of claim 28, which is suitable for nasal administration. 36. A liquid dosage form prepared by reconstituting the pharmaceutical composition of claim 28 into a solid dosage form in a pharmaceutically acceptable liquid medium. 37. A method of delivering a pharmaceutically acceptable salt of claim 1 to a patient in need thereof, comprising: An aerosol is administered to the patient by inhalation, wherein the aerosol comprises the pharmaceutically acceptable salt of the compound of formula (I) in a carrier. 38. The method of claim 37, wherein the pharmaceutically acceptable salt is delivered to the patient's central nervous system via pulmonary absorption. 39. The method of claim 37, wherein the carrier is air, oxygen, or a mixture of helium and oxygen. 40. The method of claim 39, wherein the carrier is a mixture of helium and oxygen. 41. The method of claim 40, wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C. 42. The method of claim 40, wherein the helium is present in the mixture of the helium and the oxygen at about 50% to 90% by volume, and the oxygen is present in the mixture of the helium and the oxygen at about 50% to 10% by volume. 43. The method of claim 37, further comprising administering a pretreatment inhalation therapy prior to administering the aerosol comprising the pharmaceutically acceptable salt of the compound of Formula (I) and the carrier. 44. The method of claim 43, wherein the pre-treatment inhalation therapy comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C. 45. The method of claim 44, comprising (i) administering to the patient via inhalation a mixture of the helium and the oxygen heated to about 90°C to about 120°C, and (ii) administering to the patient via inhalation an aerosol comprising the pharmaceutically acceptable salt of the compound of formula (I) in a mixture of helium and oxygen heated to about 50°C to about 60°C. 46. The method of claim 45, further comprising repeating steps (i) and (ii) 1 to 5 times. 47. The method of claim 37, wherein the pharmaceutically acceptable salt of the compound of Formula (I) is delivered to the patient's central nervous system, thereby providing at least a 25% improvement in drug bioavailability compared to oral delivery, at least a 25% increase in _Cmax compared to oral delivery, at least a 50% decrease in _Tmax compared to oral delivery, or a combination thereof. 48. The method of claim 37, wherein the aerosol is a mist. 49. The method of claim 37, wherein the aerosol is prepared by nebulizing the pharmaceutically acceptable salt of the compound of formula (I). 50. The method of claim 49, wherein the atomizing is performed with a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer, and a vibrating mesh nebulizer. 51. The method of claim 49, wherein said nebulization is performed using a driving gas comprising nitrous oxide to entrain said pharmaceutically acceptable salt of said compound of formula (I) in aerosolized form. 52. The method of claim 51 , wherein the nitrous oxide is present in the drive gas at a concentration of 15% to 25% by volume relative to the total volume of the drive gas. 53. The method of claim 37, wherein the aerosol is administered for 20 minutes to 60 minutes. 54. A method of treating a patient suffering from a central nervous system (CNS) disorder and/or a psychological disorder, comprising: A therapeutically effective amount of a pharmaceutically acceptable salt according to claim 1 is administered to the patient. 55. The method of claim 54, wherein the CNS disorder and/or psychological disorder is at least one selected from the group consisting of: post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholia, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinogenic crisis, social anxiety disorder, alcohol use disorder, opioids Substance use disorders, amphetamine use disorder, nicotine use disorder, cocaine use disorder, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain, aphasia, childhood-onset speech fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, pedophilia disorder, exhibitionism disorder, voyeurism disorder, fetish disorder, sexual sadism and masochism disorder, transvestite disorder, paraphilia, and obesity. 56. The method of claim 54, wherein the CNS disorder and/or psychological disorder is alcohol use disorder. 57. The method of claim 54, wherein the CNS disorder and/or psychological disorder is generalized anxiety disorder (GAD). 58. The method of claim 54, wherein the CNS disorder and/or psychological disorder is social anxiety disorder. 59. The method of claim 54, wherein the CNS disorder and/or psychological disorder is treatment resistant depression (TRD). 60. A pharmaceutical composition comprising: An active salt mixture comprising (i) 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 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 A pharmaceutically acceptable vehicle. 61. The pharmaceutical composition of claim 60, wherein the active salt mixture comprises (i) 60 to 98 wt% of the 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), based on the total weight of the active salt mixture, and (ii) 2 to 40 wt% in total 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), based on the total weight of the active salt mixture. 62. The pharmaceutical composition of claim 60, wherein the active salt mixture comprises (i) 90 to 98 wt% of the 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), based on the total weight of the active salt mixture, and (ii) 2 to 10 wt% in total 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), based on the total weight of the active salt mixture. 63. A pharmaceutical composition as described in claim 60, wherein the active salt mixture comprises (i) 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-8a), and (ii) a fumarate 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-10a) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-1-amine-1,1,2-d ₃ (I-11a). 64. The pharmaceutical composition of claim 60, wherein the active salt mixture comprises (i) a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2,2- _d4 (I-8b), and (ii) 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-10b) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2- _d3 (I-11b). 65. The pharmaceutical composition of claim 60, wherein the active salt mixture comprises (i) a salicylate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2,2- _d4 (I-8c), and (ii) a salicylate of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,2,2- _d3 (I-10c) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2- _d3 (I-11c). 66. A pharmaceutical composition as described in claim 60, wherein the active salt mixture comprises (i) succinate of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2,2- _d4 (I-8d), and (ii) succinate of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,2,2- _d3 (I-10d) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- _d3 )ethan-1-amine-1,1,2- _d3 (I-11d).