Methods of treating depressive disorders with nummuline analogs

Abstract

The present disclosure relates generally to methods of treating various diseases, conditions, and conditions, such as depressive disorder (e.g., major depressive disorder (MDD)), substance use disorder, anxiety disorder, eating disorder, pain, and headache disorder, by administering deuterated gymnosin and pharmaceutically acceptable salts, polymorphs, or solvates thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 487,078, filed on February 27, 2023, U.S. Provisional Application No. 63 / 512,466, filed on July 7, 2023, U.S. Provisional Application No. 63 / 519,992, filed on August 16, 2023, U.S. Provisional Application No. 63 / 602,888, filed on November 27, 2023, U.S. Provisional Application No. 63 / 603,262, filed on November 28, 2023, U.S. Provisional Application No. 63 / 603,886, filed on November 29, 2023, and U.S. Provisional Application No. 63 / 553,321, filed on February 14, 2024, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure generally relates to methods of using deuterated psilocybin and pharmaceutically acceptable salts, polymorphs, or solvates thereof to treat various diseases, disorders, and conditions, such as depressive disorders (e.g., major depressive disorder (MDD)), substance use disorders, anxiety disorders, eating disorders, pain, and headache disorders. Background Art

[0004] Major depressive disorder (MDD) is a leading cause of disability worldwide (Cosgrove 2020) and results in significant economic and social costs (Vigo D, Thornicroft G, Atun R (2016). Estimating the true global burden of mental illness. The Lancet Psychiatry, 3(2), 171-178). In the United States, MDD is a major public health problem, with an estimated 21 million adults experiencing at least one major depressive episode in 2020, representing 8.4% of all US adults (National Institute of Mental Health, 2020 Statistics: Major Depression. Updated January 2022. https: / / www.nimh.nih.gov / health / statistics / major-depression; accessed April 22, 2022). The prevalence of major depressive episodes was higher among adult females (10.5%) compared with males (6.2%), and was highest among individuals aged 18-25 years (17.0%).

[0005] While a variety of medications and psychological interventions are available to treat MDD, up to 30% of patients do not respond to first-line therapy, and up to 30% of patients do not benefit despite multiple treatments (treatment-resistant) (Rizvi SJ, Grima E, Tan M, et al. (2014). Treatment-resistant depression in primary care across Canada. Can J Psychiatry, 59, 349-357; Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: STAR*D Report. Am J Psychiatry, 163, 1905-1917). Further, available antidepressant medications require daily dosing, have a slow onset of action, require several weeks to show any beneficial effect (Cipriani A, Furukawa TA, Salanti G, et al. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet, 391, 1357-1366), require long-term treatment, and are associated with dose-limiting side effects such as gastrointestinal (Gl) disturbances, sedation, and sexual dysfunction (FDA 2019). Thus, there is a significant unmet need for a treatment that rapidly gets to work, is well-tolerated, and does not require long-term adoption.

[0006] Treatment of MDD has traditionally focused on monoamine neurotransmitters, preventing the reuptake of serotonin and / or norepinephrine, and thus increasing their availability at the synaptic cleft. While this has had some success, these treatments are symptomatic and do not address the underlying biopsy social causes. The revival of research into serotonergic psychedelic drugs offers the opportunity to explore alternative approaches in which the use of the psychedelic opens a therapeutic window to facilitate insight and, with the support of psychotherapy, the necessary emotional work to improve depressive symptoms (Nutt D, Erritzoe D, Carhart-Harris R (2020). Psychedelic Psychiatry's Brave New World. Cell, 181, 24-28).

[0007] Psilocybin (PY) and psilocin (PI) are tryptamine alkaloids and structural analogs of the neurotransmitter serotonin. Psilocybin is a prodrug of psilocin. That is, when consumed, psilocybin is rapidly metabolized to the active form psilocin (4-hydroxy-N,N-dimethyltryptamine). Specifically, a chemical process known as dephosphorylation removes the phosphate groups on psilocybin, resulting in psilocin.

[0008]

[0009] Psilocin has been reported to be a short-lived and unstable molecule in vitro. As a result, psilocin has been rarely studied and is generally not considered a viable treatment option. Vaupel et al. studied the effect of ascorbic acid psilocin on food intake in dogs (D.B. Vaupel, M. Nozaki, W.R. Martin, L.D. Bright, E.C. Morton, The inhibition of food intake in the dog by LSD, mescaline, psilocin, d-amphetamine and phenylisopropylamine derivatives, Life Sciences, Vol. 24, No. 26, 1979, 2427-2431).

[0010] Migliaccio et al. studied solutions of psilocin monooxalate in water to confirm (Gerald P. Migliaccio, Tiee-Leou N. Shieh, Stephen R. Byrn, Bruce A. Hathaway, and David E. Nichols, Comparison of solution conformational preferences for the hallucinogens bufotenin and psilocin using 360-MHz proton NMR spectroscopy, Journal of Medicinal Chemistry, 1981 24, 2, 206-209) that psilocin monooxalate is the active ingredient in psilocybin.

[0011] Aghajanian et al. studied the effects of psilocin tartrate on rat serotonergic neurons using microiontophoresis (Aghajanian GK, Hailgler HJ. Hallucinogenic indoleamines: Preferential action upon presynaptic serotonin receptors. Psychopharmacol Commun. 1975, 1, 6, 619-29).

[0012] Kuhnert-Brandstatter et al. describe the preparation of three polymorphic forms of psilocin (Kuhnert, M. et al., Polymorphe Modifikationen und Solvate von Psilocin und Psilocybin [Polymorphic Modifications and Solvates of Psilocin and Psilocybin], 1976, Archiv der Pharmazie, 309:625-631).

[0013] U.S. Patent No. 11,312,684 B1 describes psilocin salts having improved physical properties and handling characteristics.

[0014] Accordingly, therapeutic applications involving the use of psilocybin are typically accomplished by administering the precursor, psilocine or other prodrug. However, psilocine has a slow onset and a long duration of drug action, typically requiring 7-8 hours of supervised clinical observation of the patient prior to discharge. Psilocine also is associated with high variability in delivery due to the need for metabolism to release the active substance. Thus, there is a need for new therapeutic regimens that overcome the limitations of psilocine and related prodrugs. SUMMARY

[0015] The present disclosure is based, at least in part, on methods of treating various diseases, conditions, and disorders with stable forms of psilocybin, including psilocybin-d 10 and novel crystalline forms / polymorphs thereof, novel salt forms of psilocybin-d 10 and novel crystalline forms / polymorphs thereof, and compositions thereof. More specifically, the present disclosure provides methods of treating depressive disorders (e.g., major depressive disorder (MDD)), substance use disorders, anxiety disorders, eating disorders, and headache disorders with stable forms of psilocybin-d 10 by various dosing regimens, including one or two dose regimens (e.g., two doses spaced three weeks apart during a course of treatment, etc.).

[0016] The disclosed stable forms of psilocybin, such as psilocybin-d 10 do not rely on prodrug metabolism to release the active agent, as with psilocine administration or related prodrug approaches, and thus can provide a faster / shorter onset of treatment, a shorter duration of drug action (i.e., short duration of effect), and less inter-subject variability. Accordingly, based on these properties and potential advantages compared to psilocine or related prodrug approaches, human clinical trials were initiated (ClinicalTrials.gov Identifier: NCT05385783). During these clinical trials, it was discovered that treatment involving psilocybin-d 10 or a pharmaceutically acceptable salt, polymorph, or solvate thereof, provided unexpected levels of efficacy, e.g., in terms of effect size, in treating a population of MDD patients. Additionally, unexpected efficacy was achieved at surprisingly low dose levels that were far lower than the inventors would have predicted based on preclinical and clinical modeling studies. These findings led to the therapy being granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of MDD.

[0017] Accordingly, the present disclosure provides:

[0018] (1) a method of treating a depressive disorder in a subject in need thereof, the method comprising orally administering to the subject about 8 mg to about 16 mg (free base equivalent) of a compound of Formula (I-3)

[0019]

[0020] or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0021] (2) The method of (1), the treatment comprising administering to the subject about 12 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0022] (3) The method of (1), the treatment comprising administering to the subject about 12 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0023] (4) The method of (1), the treatment comprising administering to the subject about 14 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0024] (5) The method of (1), the treatment comprising administering to the subject about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0025] (6) The method of any one of (1) to (5), wherein a pharmaceutically acceptable salt of the compound of Formula (I-3) is administered.

[0026] (7) The method of (6), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is selected from the group consisting of a besylate salt, a tartrate salt, a hemifumarate salt, an acetate salt, a citrate salt, a malonate salt, a fumarate salt, a succinate salt, an oxalate salt, a benzoate salt, a salicylate salt, an ascorbate salt, a hydrochloride salt, a maleate salt, a malate salt, a mesylate salt, a tosylate salt, a glucuronate salt, and a glutarate salt of the compound of Formula (I-3).

[0027] (8) The method of (6) or (7), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a besylate salt of the compound of Formula (I-3).

[0028] (9) The pharmaceutical composition according to (8), wherein the besylate salt of the compound of Formula (I-3) is a crystalline besylate salt (I-3a) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from the group consisting of 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988° 2q (± 0.2° 2q).

[0029] (10) The method according to (6) or (7), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a tartrate salt of the compound of Formula (I-3).

[0030] (11) The method according to (10), wherein the tartrate salt of the compound of Formula (I-3) is a crystalline tartrate salt (I-3b) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from the group consisting of 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.597°, 29.035°, 29.257°, 29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049° 2q (± 0.2° 2q).

[0031] (12) The method according to (6) or (7), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a hemifumarate salt of the compound of Formula (I-3).

[0032] (13) The method of (12), wherein the hemifumarate salt of the compound of Formula (I-3) is crystalline hemifumarate salt (I-3c) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999° 2Θ (±0.2° 2Θ).

[0033] (14) The method of (6) or (7), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a citrate salt of the compound of Formula (I-3).

[0034] (15) The method of (14), wherein the citrate salt (I-3e) is amorphous as determined by X-ray powder diffraction.

[0035] (16) The method of (6) or (7), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a benzoate salt of the compound of Formula (I-3).

[0036] (17) The pharmaceutical composition of (16), wherein the benzoate salt of the compound of Formula (I-3) is crystalline benzoate salt (I-3j) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597° 2Θ (±0.2° 2Θ).

[0037] (18) The method according to any one of (1) to (17), wherein the depressive disorder is major depressive disorder (MDD).

[0038] (19) The method of (18), wherein prior to treatment, the subject has been diagnosed with moderate to severe major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

[0039] (20) The method according to any one of (1) to (19), wherein before treatment, the subject's Montgomery-Asberg Depression Rating Scale (MTRS) Depression Scale (MADRS) score greater than or equal to 21.

[0040] (21) The method according to any one of (1) to (20), wherein the first dose and the second dose are administered to the subject one to four weeks (±3 days) apart, and the first dose and the second dose are each about 8 mg to about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

[0041] (22) A method according to any one of (1) to (Error! Reference source not found.), wherein a first dose and a second dose are administered to the subject three weeks (±3 days) apart, and the first dose and the second dose are each about 8 mg to about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

[0042] (23) The method according to any one of (1) to (22), wherein the subject is taking antidepressant medication as part of ongoing treatment and the method is used as an adjunctive therapy.

[0043] (24) A pharmaceutical composition comprising:

[0044] About 8 mg to about 16 mg (free base equivalent) of the compound of formula (I-3)

[0045]

[0046] or a pharmaceutically acceptable salt, polymorph or solvate thereof; and

[0047] A pharmaceutically acceptable vehicle.

[0048] (25) The pharmaceutical composition of (24), wherein the pharmaceutical composition comprises about 12 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0049] (26) The pharmaceutical composition of (24), wherein the pharmaceutical composition comprises about 12 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0050] (27) The pharmaceutical composition of (24), wherein the pharmaceutical composition comprises about 14 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0051] (28) The pharmaceutical composition of (24), wherein the pharmaceutical composition comprises about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0052] (29) The pharmaceutical composition of any one of (24) to (28), wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of Formula (I-3).

[0053] (30) The pharmaceutical composition of (29), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is selected from the group consisting of a besylate salt, a tartrate salt, a hemifumarate salt, an acetate salt, a citrate salt, a malonate salt, a fumarate salt, a succinate salt, an oxalate salt, a benzoate salt, a salicylate salt, an ascorbate salt, a hydrochloride salt, a maleate salt, a malate salt, a mesylate salt, a tosylate salt, a glucuronate salt, and a glutarate salt of the compound of Formula (I-3).

[0054] (31) The pharmaceutical composition of (29) or (30), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a besylate salt of the compound of Formula (I-3).

[0055] (32) The pharmaceutical composition according to (31), wherein the besylate salt of the compound of Formula (I-3) is a crystalline besylate salt (I-3a) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988° 2Θ (+0.2° 2Θ).

[0056] (33) The pharmaceutical composition according to (29) or (30), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a tartrate salt of the compound of Formula (I-3).

[0057] (34) The pharmaceutical composition according to (33), wherein the tartrate salt of the compound of Formula (I-3) is a crystalline tartrate salt (I-3b) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.597°, 29.035°, 29.257°, 29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049° 2Θ (+0.2° 2Θ).

[0058] (35) The pharmaceutical composition according to (29) or (30), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a hemifumarate salt of the compound of Formula (I-3).

[0059] (36) The pharmaceutical composition according to (35), wherein the hemifumarate salt of the compound of Formula (I-3) is a crystalline hemifumarate salt (I-3c) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999° 2Θ (±0.2° 2Θ).

[0060] (37) The pharmaceutical composition according to (29) or (30), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a citrate salt of the compound of Formula (I-3).

[0061] (38) The pharmaceutical composition according to (37), wherein the citrate salt (I-3e) is amorphous as measured by X-ray powder diffraction.

[0062] (39) The pharmaceutical composition according to (29) or (30), wherein the pharmaceutically acceptable salt of the compound of Formula (I-3) is a benzoate salt of the compound of Formula (I-3).

[0063] (40) The pharmaceutical composition according to (39), wherein the benzoate salt of the compound of Formula (I-3) is a crystalline benzoate salt (I-3j) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597° 2Θ (±0.2° 2Θ).

[0064] (41) The pharmaceutical composition of any one of (24) to (40), wherein the pharmaceutically acceptable vehicle comprises an organic acid agent.

[0065] (42) The pharmaceutical composition of (41), wherein the organic acid agent is citric acid.

[0066] (43) The pharmaceutical composition of (41) or (42), wherein the organic acid agent is present in the pharmaceutical composition in an amount of at least 2% by weight and at most 10% by weight, based on the total weight of the pharmaceutical composition (on a dry basis).

[0067] (44) The pharmaceutical composition of any one of (24) to (43), wherein the pharmaceutical composition is in a solid dosage form.

[0068] (45) The pharmaceutical composition of (44), wherein the solid dosage form is a solid dosage form suitable for oral administration.

[0069] (46) The pharmaceutical composition of (44) or (45), wherein the solid dosage form is a powder in a capsule dosage form.

[0070] (47) The pharmaceutical composition of any one of (24) to (43), wherein the pharmaceutical composition is in an oral liquid dosage form.

[0071] (48) A method of treating a depressive disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of any one of (24) to (47).

[0072] (49) The method of (48), wherein the pharmaceutical composition is administered orally to the subject.

[0073] (50) The method of (48) or (49), wherein the pharmaceutical composition is administered by reconstituting the pharmaceutical composition in a solid dosage form in a pharmaceutically acceptable aqueous medium to form an oral liquid dosage form, followed by orally administering the oral liquid dosage form to the subject.

[0074] (51) The method of any one of (48) to (50), wherein the depressive disorder is major depressive disorder (MDD).

[0075] (52) The method of (51), wherein prior to treatment, the subject has been diagnosed with moderate to severe major depressive disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5thEdition (DSM-5).

[0076] (53) The method of any one of (48) to (52), wherein the subject has a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than or equal to 21 prior to treatment.

[0077] (54) The method of any one of (48) to (53), wherein the first and second doses of the pharmaceutical composition are administered to the subject one week to four weeks (± 3 days) apart, each comprising about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0078] (55) The method of any one of (48) to (54), wherein the first and second doses of the pharmaceutical composition are administered to the subject three weeks (± 3 days) apart, each comprising about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0079] (56) The method of any one of (48) to (55), wherein the subject is taking an antidepressant medication as part of an ongoing treatment, and the method is used as adjunctive therapy.

[0080] (57) An adjunctive therapy method for treating a depressive disorder in a subject taking an antidepressant medication as part of an ongoing treatment, the adjunctive therapy method comprising administering to the subject about 8 mg to about 16 mg (free base equivalent) of a compound of Formula (I-3)

[0081]

[0082] or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0083] (58) The adjunctive therapy method of (57), wherein the depressive disorder is major depressive disorder (MDD).

[0084] (59) The adjunctive therapy method of 58, wherein the subject has been diagnosed with moderate to severe major depressive disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), prior to adjunctive therapy.

[0085] ​(60) The adjunct therapy method of any one of (57) to (59), wherein prior to adjunct therapy, the subject has a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than or equal to 21.

[0086] (61) The adjunct therapy method of any one of (57) to (60), wherein a first dose and a second dose are administered to the subject one week to four weeks (± 3 days) apart, each of the first dose and the second dose being about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0087] (62) The adjunct therapy method of any one of (57) to (61), wherein a first dose and a second dose are administered to the subject three weeks (± 3 days) apart, each of the first dose and the second dose being about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0088] (63) The adjunct therapy method of any one of (57) to (62), wherein the antidepressant drug is a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0089] (64) The adjunct therapy method of any one of (57) to (63), wherein the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is administered orally to the subject.

[0090] (65) A method of treating major depressive disorder (MDD) in a subject in need thereof, the method comprising orally administering to the subject a capsule comprising about 8 mg to about 16 mg (free base equivalent) of a besylate salt of a compound of Formula (I-3)

[0091]

[0092] (66) A method of treating major depressive disorder (MDD) in a subject in need thereof, the method comprising orally administering to the subject an oral liquid dosage form comprising:

[0093] (i) about 8 mg to about 16 mg (free base equivalent) of a compound of Formula (I-3)

[0094]

[0095] or a pharmaceutically acceptable salt, polymorph, or solvate thereof; and

[0096] (ii) a pharmaceutically acceptable aqueous medium.

[0097] (67) A medicament comprising about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3)

[0098]

[0099] or a pharmaceutically acceptable salt, polymorph or solvate thereof, for use in therapy, such as for treating a subject suffering from a depressive disorder, preferably major depressive disorder (MDD).

[0100] (68) Use of a medicament comprising about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3)

[0101]

[0102] or a pharmaceutically acceptable salt, polymorph or solvate thereof, for use in therapy, such as for treating a subject suffering from a depressive disorder, preferably major depressive disorder (MDD).

[0103] (69) The pharmaceutical composition according to any one of (24) to (47), for use in therapy, such as for treating a subject suffering from a depressive disorder, preferably major depressive disorder (MDD).

[0104] (70) Use of the pharmaceutical composition according to any one of (24) to (47) for treating a subject suffering from a depressive disorder, preferably major depressive disorder (MDD). BRIEF DESCRIPTION OF THE DRAWINGS

[0105] 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.

[0106] Figures 1A-1C Brown et al. 2017 (N=12) showed that the 25 mg ( Figure 1A )、37.5mg( Figure 1B ) and 50mg( Figure 1C ) Simulation of concentration (ng / mL) of oral psilocybin versus time (hours) after administration; solid line = mean simulation, dashed line = standard deviation, black dots = extracted mean (Usona institute - Figure 5 .3-1); N=1000 per treatment.

[0107] Figure 2Simulations of Hasler et al. 1997 (N=6) for 10-20 mg oral psilocybin vs. time post-dose (hours) for concentration (ng / mL); solid line = mean simulation, dashed line = standard deviation, black dots = extracted mean (Hasler Figure 5 ), error bars = extracted SD (Hasler Figure 5 ); N=200 per individual dose, N=1200 total.

[0108] Figures 3A-3B Simulations of Holze et al. 2022 (N=28) for 13.83 mg Figure 3A ) and 27.66 mg Figure 3B ) oral psilocybin vs. time post-dose (hours) for concentration (ng / mL); solid line = mean simulation, dashed line = standard deviation, black dots = extracted mean (Holze Fig. S6), error bars = extracted SD (Holze Fig. S6), N=1000 per treatment.

[0109] Figure 4 Modelled linear effect relationship between VAS-Any Drug Effect score and mean psilocin concentration (ng / mL) following administration of psilocybin (15 mg and 30 mg psilocybin) based on extracted mean PK and PD data from Holze et al. 2022.

[0110] Figure 5 Reproduced from Madsen et al. 2019 (Fig. 3 in Madsen et al. 2019), showing the relationship between intrascan plasma psilocin levels following psilocybin and neocortical 5-HT 2A R occupancy.

[0111] Figures 6A-6B Reproduced from Madsen et al. 2019 (Fig. 4 in Madsen et al. 2019 Figure 4 ), showing the subjective intensity of the psychedelic experience at PET scan, neocortical 5-HT 2A R occupancy, and plasma psilocin concentration following psilocybin, where Figure 6A shows the relationship between intensity rating and neocortical 5-HT 2A R occupancy, the fitted line obtained using a quadratic function, and Figure 6B shows the relationship between intensity and psilocin concentration fitted to a one-site receptor binding model.

[0112] Figures 7A-7D shows use scenarios 1 Figure 7A ), scenario 2 Figure 7B ), scenario 3 Figure 7C ), and scenario 4 according to Table 5.Figure 7D ) of psilocybin-d 10 Simulated concentration (ng / mL) vs. time (hours) post-dose curves for , benchmarked at various PD thresholds from available data; simulated curves present median values ​​for the simulated population (N=1000 per treatment).

[0113] Figure 8 Shown are the mean (±SD) plasma psilocybin-d values ​​for subjects in Cohorts 1, 2, and 3 by dose (linear scale). 10 Concentration-time curve; excluding 2 psilocin-d 10 8 mg subjects (1 Cohort 3, Day 1 subject with post-dose vomiting and 1 Cohort 3, Day 1 subject with only a 0-2 hour PK sample).

[0114] Figure 9 Shown are mean (±SD) plasma psilocybin-d values ​​for subjects in Cohorts 1, 2, and 3 by dose (semi-log scale). 10 Concentration-time curve; excluding 2 psilocin-d 10 8 mg subjects (1 Cohort 3, Day 1 subject with post-dose vomiting and 1 Cohort 3, Day 1 subject with only a 0-2 hour PK sample).

[0115] Figure 10 A schematic diagram of the study of MDD participants disclosed in the clinical trial protocol (Example III. Clinical Trial Protocol) is shown.

[0116] Figure 11 A schematic diagram of the study of normal healthy volunteer (NHV) participants (cohorts 2-6) disclosed in the clinical trial protocol (Example III. Clinical trial protocol) is shown.

[0117] Figure 12 A study schematic of the NHV participants (vs. BA cohort) disclosed in the clinical trial protocol (Example III. Clinical trial protocol) is shown.

[0118] Figure 13 A single 12 mg dose of psilocybin-d 10 Plot of the mean (±SD) MADRS score change from baseline after placebo up to Day 21 (D21), and the least squares (LS) mean differences between groups.

[0119] Figure 14 A single 16 mg dose of psilocybin-d 10Plot of mean (± SD) MADRS change from baseline over time relative to placebo until Day 21 (D21) and least squares (LS) mean difference between groups.

[0120] Figure 15 Bar plot showing mean (± SD) MADRS change from baseline at Day 21 (after a single dose of bexagliflozin-d 10 ) and further improvement at Day 42 (after the second dose of bexagliflozin-d 10 ) for both 12 mg and 16 mg dose levels.

[0121] Figure 16 Bar plot showing response rate (%) defined as MADRS reduction > 50% from baseline at Day 21 (D21) after a single dose of bexagliflozin-d 10 ), further improvement at Day 42 (D42) after the second dose of bexagliflozin-d 10 ) and persistence of these effects at Day 126 (D126) after both doses; Day 126, 12 mg (N = 15); Day 126, 16 mg (N = 8).

[0122] Figure 17 Bar plot showing remission rate (%) defined as MADRS score < 10 at Day 21 (D21) after a single dose of bexagliflozin-d 10 ), further improvement at Day 42 (D42) after the second dose of bexagliflozin-d 10 ) and persistence of these effects at Day 126 (D126) after both doses; Day 126, 12 mg (N = 15); Day 126, 16 mg (N = 8).

[0123] Figure 18 Plot of mean (± SD) MADRS change from baseline over time until Day 126 (D126) after two doses of bexagliflozin-d 10 (administered on Day 1 and Day 22); 12 mg (N = 15); 16 mg (N = 8).

[0124] Figure 19 Plot showing placebo-subtracted MADRS change from baseline after 12 mg bexagliflozin-d 10 treatment compared to key studies with approved antidepressants at Day 21. DETAILED DESCRIPTION

[0125] In the following detailed description of embodiments of the disclosure, numerous specific details are set forth in order to provide a thorough understanding of the disclosed embodiments. However, it will be apparent to one skilled in the art that the embodiments of the disclosure can be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the disclosure.

[0126] Definitions

[0127] Unless otherwise defined, 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.

[0128] As used herein, the term “major depressive disorder” refers to a condition characterized by periods of low mood that occur across most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in normal pleasurable activities, lack of energy, and pain, without a clear cause. In some cases, major depressive disorder is characterized by depressive symptoms that last at least two weeks. In some cases, individuals experience depressive symptoms for years at a time. In some cases, individuals experience depressive symptoms almost all of the time. Major depressive disorder can have a negative impact on an individual’s 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 suicide victims have major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists 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, crying, emptiness or hopelessness, outbursts of anger, feelings of irritability or frustration, even if minor, loss of interest or pleasure in most or all normal activities, sleep disturbances (including insomnia or hypersomnia), fatigue and lack of energy, decreased appetite, weight loss or gain, anxiety, agitation or restlessness, slowness in thinking, speaking, or physical movement, feelings of worthlessness or guilt, rumination on past failures or self- blaming thoughts, problems with thinking, concentrating, making decisions, and remembering, frequent thoughts of death, suicidal ideation, suicide attempts or suicide, and unexplained physical problems, such as back pain or headaches.

[0129] As used herein, the term “fat” describes a compound having a long chain (linear) hydrophobic portion consisting of hydrogen and from 4 to 26 carbon atoms, which can be fully saturated or partially unsaturated.

[0130] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like, as used herein, refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without an excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like, mean a salt that is acceptable for administration to a patient (a salt with a counterion that is acceptable for a given dosage regimen to have a reasonable mammalian safety profile). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases such as, for example, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and the like, as well as acidic salts such as hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, nitrates, perchlorates, and the like when the molecule contains a basic function; and salts with organic acids such as formates, tartrates, besylates, mesylates, acetates, maleates, malonates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemi-oxalates, hemi-fumarates, propionates, stearates, tartrates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, and the like, as well as the term "salts thereof" means compounds formed when the proton of an acid is replaced by a cation such as a metal cation or an organic cation. In cases where applicable, the salt is a pharmaceutically acceptable salt, but this is not required for salts of intermediate compounds not intended for administration to a patient. For example, salts of the compounds of the present application include those in which the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid comprising the anionic component of the salt.

[0131] "Solvate" refers to a physical association between a compound or salt of this disclosure and one or more solvent molecules, which are organic, inorganic, or a mixture of both. This physical association can include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvent molecules in solvates can be present in a stoichiometric or non-stoichiometric amount. "Solvate" encompasses both solution-phase and isolatable 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.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolate, ethanolates, isopropanolates, and the like. Methods of solvation are well known in the art.

[0132] “stereoisomer” and “stereoisomers” refer to compounds that have the same atomic connectivity but different spatial arrangement of atoms. 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 a compound. Chemical formulas and compounds having at least one stereocenter but not referenced to stereochemistry are intended to encompass racemic compounds as well as individual stereoisomers, such as both R- and / or S-stereoisomers, each permutation of diastereomers (as long as those diastereomers are geometrically feasible), and the like.

[0133] “tautomer” refers to alternative forms of a molecule that differ only in the bonding of atoms and / or the location of protons, such as enol-keto, imine-enamine and neutral / zwitterionic tautomers, or tautomeric forms of heteroaryl containing -N=C(H)-NH- ring atom arrangements, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. Other tautomeric ring atom arrangements are possible.

[0134] A "crystalline" solid is a solid whose basic three-dimensional structure contains highly regular atomic or molecular patterns - with long-range order - that form a lattice, and thus show sharp, characteristic peaks in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid can exist in different crystalline forms, known as "polymorphs," which have the same chemical composition but differ in the packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs can have different solid state physical properties to affect, for example, solubility, dissolution rate, bioavailability, chemical and physical stability, flow and compressibility of the compound, and safety and efficacy of a pharmaceutical product based on the compound. Further purification in terms of total physical or optical purity can also be carried out during the preparation of polymorphs. The crystalline forms, including polymorphic forms, of a material can be designated in the present disclosure by a "pattern" number based on its characterized X-ray powder diffraction (XRPD) pattern (e.g., Pattern 1, Pattern 2, etc.). As used herein, the term "amorphous" refers to a solid material that is substantially free of long-range order in the positions of its molecules - the molecules are arranged in a random manner such that there is virtually no defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are typically isotropic, i.e., exhibit similar properties in all directions, and do not have a definite melting point. For example, an amorphous material is a solid material that is substantially free of sharp, characteristic peaks in its X-ray powder diffraction (XRPD) pattern (i.e., not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., humps) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, an "amorphous" subject compound / material is characterized by being substantially free of 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, % crystallinity can be determined by determining the intensity of one or more peaks in an 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 modulated differential scanning calorimetry (mDSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods can also be employed to determine the percentage of a subject compound / material that is amorphous or crystalline, including quantitative methods that provide the above percentages in weight percent.

[0135] References to X-ray powder diffraction (XRPD) patterns of materials, compounds, salts, etc. of the disclosure featuring X-ray powder diffraction patterns containing “at least three characteristic peaks” should be understood to include those materials / compounds / salts featuring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more (inclusive of all recited) characteristic XRPD diffraction peaks. Further, materials / compounds / salts containing “at least three characteristic peaks at diffraction angles (2Θ ± 0.2°) selected from” are open to include other XRPD diffraction peaks not recited.

[0136] It should be understood that the compounds herein can exist in different salt, solvate, crystalline / amorphous (or polymorphic) forms, and the disclosure is intended to include all such permutations, such as solvates of pharmaceutically acceptable salts. Thus, reference to a compound or a pharmaceutically acceptable salt, polymorph, or salt thereof is intended to include all such permutations, e.g., a pharmaceutically acceptable salt of a compound in crystalline form, a pharmaceutically acceptable salt of a compound in solvate form, a crystalline free base compound, a crystalline free base compound as a solvate, etc.

[0137] As used herein, the term “stable” describes a stable level or homeostatic level of a concentration of a molecule, e.g., a concentration of any of the compounds described herein.

[0138] As used herein, the terms “stable,” “stability,” and the like include chemical stability and solid state (physical) stability. The term “chemical stability” means that a compound can be stored under normal storage conditions, either in isolated form or in the form of a formulation in which the compound is mixed with, e.g., a pharmaceutically acceptable carrier, diluent, or adjuvant as described herein, with little or no chemical degradation or decomposition. “Solid state stability” means that a compound can be stored under normal storage conditions, either in isolated solid form or in the form of a solid formulation in which the compound is mixed with, e.g., a pharmaceutically acceptable carrier, diluent, or adjuvant as described herein, with little or no solid state transformation (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid state phase transition).

[0139] “Psilocybin-based drugs” are any prodrugs of psilocybin-type compounds that release psilocin or a deuterated analog thereof (e.g., a compound of Formula (I-3)) as the active component upon administration, such as alkyl / aryl esters and a-amino esters (e.g., amino acid esters), hemiesters, diesters, phosphate esters, sulfate esters, and the like. Psilocybin-based drugs include psilocybin itself (the dihydrogen phosphate ester of psilocin, in neutral or zwitterionic form).

[0140] As used herein, the term “composition” is equivalent to the term “formulation.”

[0141] As used herein, the term "active ingredient" is equivalent to the term "active pharmaceutical ingredient" (API).

[0142] The language "tamper resistance" is recognized in the art to describe aspects of a pharmaceutical formulation that make it more difficult to use the formulation to abuse the pharmaceutical portion of the formulation by extraction for intravenous use, intradermal use, or the like, or crushing for freebase use; and thus reduce the risk of abuse of the pharmaceutical.

[0143] As used herein, the term "treating" or "treatment" means to treat or treat a disease or medical condition in a patient, such as a mammal (particularly a human), which includes: ameliorating the disease or medical condition, such as eliminating or causing regression of the disease or medical condition in a patient; inhibiting the disease or medical condition, such as slowing or arresting the development of the disease or medical condition in a patient; or relieving one or more symptoms of the disease or medical condition in a patient. In embodiments, prophylactic treatment can result in prevention of the occurrence of a disease or medical condition in a subject.

[0144] "Patient" or "subject" as used interchangeably herein can be any mammal, including, for example, human and non-human subjects. The patient or subject can have a condition to be treated or can be susceptible to a condition to be treated.

[0145] As used herein, and unless otherwise indicated, the terms "prevent," "preventing," and "prevention" refer to preventing the onset, recurrence, or spread of a disease, disorder, or condition, or one or more symptoms thereof. These terms encompass inhibiting or reducing symptoms of a particular disease, disorder, or condition. In particular, a subject with a family history of a disease, disorder, or condition is a candidate for a prophylactic regimen in certain embodiments. Additionally, a subject with a history of recurrent symptoms is also a potential candidate for prevention. In this regard, the term "prevent" can be used interchangeably with "prophylactic treatment."

[0146] 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, a subject derives a benefit from a prophylactic and / or therapeutic agent that does not result in a cure of the disease, disorder, or condition. In this regard, the term "manage" encompasses treating a subject with a particular disease, disorder, or condition in an attempt to prevent or minimize recurrence of the disease, disorder, or condition, or one or more symptoms thereof.

[0147] A "therapeutically effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt, polymorph, or solvate thereof, that is sufficient to treat a particular disorder or disease or one or more symptoms thereof and / or prevent the occurrence of the disease or disorder (prophylactically effective amount).

[0148] As used herein, and unless otherwise specified, a "prophylactically effective amount" of an active ingredient is an amount sufficient to prevent a disease, disorder or condition, or prevent a recurrence thereof. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0149] The term "administration schedule" is a plan of the type, amount, cycle, procedure, etc. The drugs in a drug treatment are shown in a time sequence and the dose of each drug, method of administration, order of administration, date of administration, etc. are indicated. The specified administration dates are determined prior to the start of administration of the drugs. By repeating the process, a set of administration schedules continues as a "course." A "continuous" administration schedule means that the administration is uninterrupted every day during the course of treatment. If the administration schedule follows an "intermittent" administration schedule (where the dosing is less than once daily), the administration days can be followed by "rest days" or days in which no drug is administered within the course. A "drug holiday" indicates that a drug is not administered in the scheduled administration schedule. For example, after undergoing one or several courses, e.g., before reinitiating active treatment, a subject can be prescribed a restricted drug holiday as part of the administration schedule.

[0150] The language "toxicity spike" is used herein to describe a neurologic spike in the concentration of any of the compounds described herein that will produce side effects of sedation or psychotomimetic effects (e.g., hallucinations, dizziness, and nausea), or any undesired and / or unintended secondary effects caused by administration of the drug to an individual, resulting in subjective experiences qualitatively different from ordinary consciousness. These experiences can include loss of reality sense, depersonalization, hallucinations, and / or distortions of sensory perception and / or any other perceptual changes and / or any other substantial subjective changes in cognition, memory, affect, and consciousness in the range of visual, auditory, olfactory, tactile, proprioceptive, and / or interoceptive. When undesired and / or unintended, such side effects not only have immediate impact, but also impact treatment adherence. Specifically, side effects can become more pronounced at blood concentration levels of about 250, 300, 400, 500 ng / L or more.

[0151] All diseases and disorders listed herein can be defined as described in the Diagnostic and Statistical Manual of Mental Disorders, 5thEdition (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0152] As used herein, “adjunct therapy,” “adjuvant therapy,” and the like refer to a therapy administered in addition to a primary or initial therapy to improve or maximize effectiveness. For example, a subject diagnosed with a depressive disorder is taking one or more anti-depressant medications (e.g., an SSRI) as a primary or initial therapy, but is not responding adequately to the anti-depressant medication or otherwise failing to achieve a desired outcome, a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be administered as an “adjunct therapy” to improve or maximize treatment effectiveness by reducing depressive symptoms. In this example of a depressive disorder, the adjunct therapy can improve or maximize treatment effectiveness by reducing depressive symptoms compared to the primary or initial therapy alone. The primary or initial therapy and the adjunct therapy involving a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be, but need not be, prescribed and / or administered by the same person (e.g., clinician). For example, the primary or initial therapy (e.g., SSRI therapy) can be prescribed by a first clinician and self-administered by the patient, while the adjunct therapy involving a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be prescribed and / or administered by a second clinician. Alternatively, the primary or initial therapy (e.g., SSRI therapy) can be prescribed by a first clinician and self-administered by the patient, while the adjunct therapy involving a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be prescribed and / or administered by the same (first) clinician.

[0153] As used herein, the term “inadequate response” means a lack of improvement in symptoms that is clinically meaningful, e.g., as measured by one or more of the rating scales described herein. An inadequate response to a full course of treatment with an anti-depressant medication can be determined retrospectively or prospectively. Prospective determination of an inadequate response is a determination made by the prescribing clinician or therapist after administration of a portion of the full course of treatment. Retrospective determination is a determination made by the prescribing clinician or therapist after administration of the full course of treatment.

[0154] Unless otherwise indicated, references to a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof (bacosine-d10 ) are with respect to free base equivalents. Thus, the amount recited before the phrase "...mg of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof" etc. refers to psilocybin-d 10 That is, if psilocin-d 10 When administered as a pharmaceutically acceptable salt, the stated dosage refers to psilocybin-d in the absence of the weight contribution of the salt counterion. 10 For example, if a subject is administered psilocin-d 10 Benzoate, then after administration of 12.6 mg of psilocybin-d 10 The administration of "8 mg of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof" will be completed when the benzoate salt of formula (I-3) is 0. 10 benzyl sulfonate, then 13.9 mg of psilocin-d 10 The administration of "8 mg of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof" will be completed when the benzenesulfonate salt of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof is taken. In another example, if a subject is administered psilocin-d 10 benzyl sulfonate, then after administration of 27.8 mg of psilocin-d 10 The administration of "16 mg of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof" will be completed when the besylate salt is taken.

[0155] When referring to the compound of formula (I-3) (IUPAC name is 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol; or psilocin-d 10) the term "compound" refers to a collection or population of molecules having the same chemical structure, except for possible isotopic variations between the constituent atoms of the molecules. This is because, in practice, it is not possible to achieve deuterium enrichment with 100% isotopic purity. Thus, it will be clear to one skilled in the art that a compound represented by a particular chemical structure containing a specified deuterium atom (the subject compound) will also contain smaller amounts of isotopologues having hydrogen atoms at one or more of the specified deuterium positions in that structure. The relative amounts of such isotopologues in a compound of Formula (I-3) will depend on a number of factors, including the isotopic purity of the deuterated reagents used to prepare the compound of Formula (I-3) and the efficiency of incorporation of deuterium in the various synthetic steps used to prepare the compound of (I-3). However, as set forth herein, the total relative amount of such isotopologues will preferably be less than 50% of the compound. With respect to the dosages recited herein (e.g., 10 mg, 12 mg, 14 mg, 16 mg, etc.), it will be understood that the recited dosage of the compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof) refers to the amount of the subject compound plus the total amount of any isotopologues administered. For example, administration of 10 mg of a compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof) having an isotopic purity of 90% is considered herein to be a dosage of 10 mg (i.e., 9 mg nudiximab-d 10 As the subject compound + 1 mg total isotopologues of the subject compound.

[0156] The phrase "effect size" refers to a statistical calculation that can be used to compare the efficacy of different agents by quantifying the size of the difference between treatments ("between-group"). It is a dimensionless measure of the difference in outcomes under two different treatment interventions. Thus, the effect size informs the clinician of the magnitude of the treatment effect. Unless otherwise specified, as used herein, the effect size is calculated according to the difference between the mean within-group efficacy endpoint change induced by the treatment group (e.g., administration of a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and the mean within-group efficacy endpoint change induced by placebo using Cohen's d method using the following formula:

[0157]

[0158] Cohen's d is also known as the standardized mean difference. An effect size (Cohen's d score) of zero means that there is no difference in effect between the treatment and placebo. An effect size (Cohen's d score) greater than zero indicates the degree to which the treatment is more effective than the placebo. Conventionally, an effect size (Cohen's d score) of 0.2 is considered small, 0.5 is medium, and 0.8 or higher is large.

[0159] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. As used in the description and the following claims, the meanings of “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The term “about” associated with a numerical value means a value that varies by more than or less than 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0160] Therapeutic applications and methods

[0161] The present applicant has recently discovered a series of stable forms of psilocin and deuterated psilocin, including novel polymorphs of psilocin / deuterated psilocin, novel salt forms of psilocin / deuterated psilocin and polymorphs thereof, and compositions thereof (see WO2022195011 and WO2023078604, which are incorporated by reference herein in their entirety).

[0162] Previously identified compounds include compounds of Formula (I-3)

[0163]

[0164] and pharmaceutically acceptable salts, polymorphs, and solvates thereof. Compounds of Formula (I-3) have the IUPAC name 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol and are also referred to as psilocin-d 10 It will be appreciated that reference to any of the above identifiers is intended to convey a compound of Formula (I-3). Compounds of Formula (I-3) can be suitably considered as a psychedelic in the present disclosure.

[0165] The present disclosure relates to the unexpected discovery that compounds of Formula (I-3)

[0166]

[0167] or a pharmaceutically acceptable salt, polymorph, or solvate thereof are more efficacious and have a better therapeutic window than animal models based on the compound of Formula (I-3), the description of the non-deuterated counterpart psilocin, and psilocin-d 10 The literature reference of data from clinical simulations predicts a more efficacious and better therapeutic window. This discovery allows for methods of treatment comprising administration of lower doses of the compounds of the present disclosure, which is beneficial to the subject undergoing treatment while achieving far greater than expected therapeutic benefit (e.g., effect size). Since side effects and adverse drug reactions can be substantially related to dose, it is predicted that lower doses of the compounds are beneficial to reduce the risk to the subject being treated.

[0168] Disclosed herein are methods of treating various diseases, disorders, and conditions in a subject in need thereof, such as depressive disorders (e.g., major depressive disorder (MDD)), substance use disorders, anxiety disorders, eating disorders, and headache disorders, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I-3)

[0169]

[0170] or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, administered to a subject in need thereof is about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, or any range therebetween, such as about 8 mg to about 16 mg, about 8 mg to about 14 mg, about 8 mg to about 12 mg, about 10 mg to about 16 mg, about 11 mg to about 15 mg, about 12 mg to about 14 mg, about 11 mg to about 13 mg, about 14 mg to about 16 mg, or about 12 mg to about 16 mg (free base equivalent). In some embodiments, the method comprises administering 8 mg to 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 8 mg to 14 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 8 mg to 12 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 8 mg to 10 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 10 mg to 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 12 mg to 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 10 mg to 14 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 12 mg to 14 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 11 mg to 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 11 mg to 15 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 11 mg to 13 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 8 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 8 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.In some embodiments, the method comprises administering about 9 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 9 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 10 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 10 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 11 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 11 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 12 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 12 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 13 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 13 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 14 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 14 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 15 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 15 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering about 16 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 16 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is administered orally, and the dosages recited above are oral dosages.

[0171] Compounds of Formula (I-3) for use in the pharmaceutical compositions and methods of the present application

[0172] In some embodiments, the compound of Formula (I-3) is a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof, as described in WO2022195011 and / or WO2023078604.

[0173] In some embodiments, the compound of Formula (I-3) according to the methods described herein is a free base in crystalline form, e.g., as determined by XRPD and / or mDSC. Thus, a compound of Formula (I-3) as a free base in one or more crystalline (e.g., polymorphic) forms can be used in therapy as set forth herein. In some embodiments, a crystalline form of a compound of Formula (I-3) as a free base is provided. For example, a compound can comprise a free base of a compound of Formula (I-3) wherein 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% by weight of the free base of a compound of Formula (I-3) present is in crystalline form, e.g., as determined by X-ray powder diffraction and / or mDSC. In some embodiments, a highly pure crystalline form of a compound of Formula (I-3) as a free base is provided. For example, a compound can comprise a free base of a compound of Formula (I-3) wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the free base of a compound of Formula (I-3) is in crystalline form, e.g., as determined by X-ray powder diffraction and / or mDSC.

[0174] In some embodiments, the compound of Formula (I-3) according to the methods described herein is a crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3) as determined by X-ray powder diffraction. In some embodiments, I-3 is a crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 7.582°, 8.395°, 9.647°, 10.444°, 11.319°, 12.614°, 13.372°, 14.222°, 15.157°, 16.524°, 16.787°, 17.693°, 19.468°, 19.699°, 20.901°, 21.132°, 21.859°, 22.547°, 23.699°, 24.630°, 25.034°, 25.264°, 26.867°, 27.399°, 27.929°, 28.219°, 28.871°, 29.430°, 30.120°, 30.675°, 31.373°, 32.365°, 33.880°, 34.418°, 34.792°, 35.884°, 36.254°, 37.156°, 38.200°, and 38.417° as determined by XRPD using a CuKa radiation source, e.g., as shown in WO2022195011 and / or WO2023078604. In some embodiments, I-3 is a crystalline solid form (Pattern 2) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 8.124°, 8.357°, 10.059°, 12.630°, 13.420°, 13.743°, 14.053°, 15.220°, 16.272°, 16.763°, 16.954°, 17.328°, 17.662°, 18.062°, 18.742°, 19.413°, 19.658°, 20.172°, 20.836°, 21.267°, 21.833°, 22.213°, 22.504°, 23.334°, 23.701°, 24.385°, 25.431°, 25.721°, 26.049°, 27.291°, 28.368°, 30.349°, 30.656°, 31.337°, 31.538°, 32.091°, 35.870°, 38.514°, and 41.361° as determined by XRPD using a CuKa radiation source, e.g., as shown in WO2022195011 and / or WO2023078604.

[0175] In some embodiments, the compound according to the methods described herein is provided as an amorphous form as a free base, e.g., as determined by XRPD and / or mDSC. Thus, the compound of Formula (I-3) as a free base in one or more amorphous forms, and can be used for treatment as set forth herein. In some embodiments, a highly pure amorphous form of the compound of Formula (I-3) as a free base is provided. For example, the free base of the compound of Formula (I-3) can be at least 92% by weight, at least 94% by weight, at least 96% by weight, at least 98% by weight, at least 99% by weight, or at least 99.5% by weight of the amorphous form of the free base of the compound of Formula (I-3), e.g., as determined by X-ray powder diffraction and / or mDSC.

[0176] In some embodiments, the compound according to the methods described herein is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3), as determined by X-ray powder diffraction.

[0177] Such amorphous forms of the compound of Formula (I-3) (free base) can be advantageous in terms of solubility rate in water compared to crystalline forms, thereby enabling fast systemic absorption for fast treatment initiation and short drug action duration. Further, in some embodiments, pharmaceutical compositions comprising the amorphous form of the compound of Formula (I-3) as a free base can be prepared (see below). The pharmaceutical compositions of the present disclosure, such as those set forth herein, can be used to stabilize amorphous forms of the compound of Formula (I-3) that tend to be unstable and have a tendency to crystallize. Thus, the pharmaceutical compositions can be used to stabilize these amorphous forms and deliver them to a subject in need of treatment, i.e., for the treatment of a condition or disease associated with major depressive disorder.

[0178] Salt forms

[0179] In some embodiments, the compound according to the methods described herein is a pharmaceutically acceptable salt of a compound of Formula (I-3) or a pharmaceutically acceptable polymorph or solvate thereof. The acid used to form a pharmaceutically acceptable salt of a compound of Formula (I-3) can be a mono-acid, di-acid, tri-acid, tetra-acid, or can contain a greater number of acid groups. The acid group can be, for example, a carboxylic acid, a sulfonic acid, a phosphonic acid, or other acidic moiety containing at least one replaceable hydrogen atom. Examples of acids (which can be organic or inorganic acids) used to prepare 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., benzene sulfonic acid, camphor sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, and the like), benzoic acid (e.g., benzoic acid, 4-acetylaminobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, and the like), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfic acid, formic acid, fumaric acid, galacturonic acid, gluconic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-keto-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty acid mono- and di-acids, e.g., adipic acid (hexanedioic 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 (hexadecanoic acid), sebacic acid, undecanoic acid, hexanoic acid, and the like).

[0180] Certain salts are preferred in the above list because they possess the physical and pharmaceutical characteristics / properties that make them more suitable for pharmaceutical manufacture and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of Formula (I-3)) are those salt forms that possess one or more of the following properties: are readily prepared in high yield, and tend to salt formation; are stable, and possess well-defined physical properties such as crystallinity, well-defined and reproducible polymorphism where polymorphism exists, and high melting / fusing enthalpy; have slight hygroscopicity or no hygroscopicity; are free-flowing, non-sticky / adhesive to surfaces, and have regular morphology; have acceptable aqueous solubility and dissolution rates for the intended dosage form; and / or are physiologically acceptable, e.g., do not cause undue irritation.

[0181] crystallinity

[0182] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I-3) according to the methods described herein can be crystalline or amorphous, as determined, for example, by X-ray powder diffraction (XRPD) and / or mDSC. In some embodiments, the salt of a compound of Formula (I-3) is amorphous. Amorphous forms generally have higher aqueous solubility and dissolution rates compared to their crystalline counterparts, and thus can be well suited for fast-acting dosage forms that rapidly release the active ingredient, such as oral dispersible dosage forms (ODx), immediate release (IR) dosage forms, and the like. The salt of a compound of Formula (I-3) can be in a stable amorphous form. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I-3) is provided in an amorphous form, for example, as determined by XRPD and / or mDSC. Thus, the pharmaceutically acceptable salt form of a compound of Formula (I-3) in one or more amorphous forms, and can be used in therapy as set forth herein. In some embodiments, a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of Formula (I-3) is provided. For example, the pharmaceutically acceptable salt of a compound of Formula (I-3) can be at least 92% by weight, at least 94% by weight, at least 96% by weight, at least 98% by weight, at least 99% by weight, or at least 99.5% by weight of the amorphous form of the pharmaceutically acceptable salt of a compound of Formula (I-3), for example, as determined by X-ray powder diffraction and / or mDSC.

[0183] In some embodiments, the pharmaceutically acceptable salts of the compound of Formula (I-3) according to the methods described herein are crystalline. Crystalline forms are advantageous in terms of stability and provide well-defined physical properties, which are desirable for pharmaceutical manufacturing and administration. The salts of the compound of Formula (I-3) can be in a stable crystalline form. In some embodiments, the percent crystallinity of the pharmaceutically acceptable salts of the compound of Formula (I-3) is 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 mDSC analysis. For example, the crystalline form of the pharmaceutically acceptable salts of the compound of Formula (I-3) can constitute 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% by weight of the pharmaceutically acceptable salts of the compound of Formula (I-3), for example, as determined by X-ray powder diffraction and / or mDSC. In some embodiments, a highly pure crystalline form of the pharmaceutically acceptable salts of the compound of Formula (I-3) is provided. For example, the crystalline form of the pharmaceutically acceptable salts of the compound of Formula (I-3) can constitute at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salts of the compound of Formula (I-3) present, for example, as determined by X-ray powder diffraction and / or mDSC. Salt forms with high crystallinity are preferred, as determined, for example, by discrete and sharp Bragg diffraction in the X-ray diffraction pattern.

[0184] XRPD analysis can be performed, for example, on a Bruker AXS D2 diffractometer using Cu Kα radiation The instrument can be equipped with a fine focus X-ray tube. The tube voltage and amperage can be set to 30 kV and 10 mA, respectively, and a theta-theta geometry can be used, using a LynxEye detector from 5-42° 2theta, with a step size of 0.024° 2theta and a collection time of 0.1 seconds per step.

[0185] In terms of pharmaceutical production processes, advantageous salt forms of the compound of Formula (I-3) according to the methods described herein are those that are easy to provide as solid material, i.e. crystalline solid or amorphous solid, in acceptable yield, and do not require further processing by oiling, and have an advantageous volume factor, making them suitable for large scale production.

[0186] For example, salt forms of the compound of Formula (I-3) according to the methods described herein can in some cases exist in different polymorphs (i.e., forms having different crystal structures), however, the preferred salt forms of the present disclosure are those that can be produced as single crystalline forms or single polymorphs or single amorphous forms, as determined by XRPD and / or mDSC and / or differential scanning calorimetry (DSC). It is also generally desirable that the salts be free-flowing, not sticky / adhesive to surfaces, and have a regular morphology.

[0187] Chemical / Solid State Stability

[0188] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) according to the methods described herein has a melting onset from about 90 °C, from about 100 °C, from about 110 °C, from about 120 °C, from about 130 °C, from about 140 °C, from about 150 °C, from about 160 °C, from about 170 °C, from about 180 °C, from about 190 °C, to at most about 250 °C, at most about 240 °C, at most about 230 °C, at most about 225 °C, at most about 210 °C, at most about 200 °C, as determined by DSC.

[0189] The pharmaceutically acceptable salt of the compound of Formula (I-3) according to the methods described herein 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 40% relative humidity (RH), increasing humidity to 90% RH, decreasing humidity to 0% RH, increasing humidity to 90% RH, decreasing humidity to 0% RH, and finally increasing humidity back to the initial 40% RH, and according to the following classification:

[0190] Non-hygroscopic; <0.2%; Slightly hygroscopic; >0.2% and <2%; Hygroscopic: >2% and <15%; Very hygroscopic: >15%; Deliquescent: sufficient water is absorbed to form a liquid; all values measured as weight gain (w / w due to water acquisition) at >90% RH and 25 °C.

[0191] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) according to the methods described herein 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 >90% RH, as determined by DVS.

[0192] Dry powder samples of the free base and salts can be maintained / stored in an open or closed environment, such as in an open or closed flask / vial, under ambient or stressed conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc. without significant degradation or physical change (e.g., altered form, deliquescence, etc.). For example, dry powder samples of the free base and salt forms disclosed herein can have less than 10%, less than 5%, less than 1% purity or form change when stored under ambient conditions or stressed conditions (e.g., elevated temperature, e.g., 40°C and / or humidity).

[0193] Solution phase compositions of the free base and salts can be maintained / stored in an open or closed environment, such as in an open or closed flask / vial, under ambient or stressed conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc. without significant degradation. Thus, in some embodiments, the present disclosure provides stable solution phase compositions of the free base or salt forms of the compound of Formula (I-3) (e.g., stable solvates of the free base or salt forms of the compound of Formula (I-3) in solvated form, preferably 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 extended periods of time without significant degradation or physical change, such as oiling out in solution. Solvents that can be used to form the solution phase compositions can be any one or more of the solvents set forth herein, e.g., water, ethanol, juice, etc. In some embodiments, the solution phase composition is an aqueous solution phase composition comprising the free base or pharmaceutically acceptable salt of the compound of Formula (I-3) solvated with an aqueous solvent (and optionally comprising other components found in juice). It is advantageous to identify stable solution phase compositions of the compound of Formula (I-3) and salts thereof at least because such compositions do not need to 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. Rather, the stable solution phase compositions of the compound of Formula (I-3) and salts thereof described herein can be prepared in advance, optionally stored, and can be administered hours, days, or even weeks after preparation without substantially affecting efficacy, e.g., without significant degradation of psilocybin or psilocybin-like activity.

[0194] In some embodiments, an aqueous solution formed from a pharmaceutically acceptable salt of a compound of Formula (I-3) is characterized by increased stability compared to an aqueous solution prepared from a compound of Formula (I-3) (free base), but is otherwise substantially identical. For example, an aqueous solution of a pharmaceutically acceptable salt of a compound of Formula (I-3) can be at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% more stable in terms of % remaining (active) compared to an aqueous solution prepared with a compound of Formula (I-3) (free base) in the presence or absence of metal ions at 40 °C for 24 hours, but is otherwise substantially identical. Such improved stability behavior can also be found in the pharmaceutical compositions of the present disclosure.

[0195] Samples can be drawn at predetermined time points and analyzed for stability, form change, etc. For example, by 1 HNMR, XRPD, HPLC with UV-visible multi-wavelength detector, UPLC, etc.

[0196] Physiological acceptability

[0197] Suitable salt forms of a compound of Formula (I-3) are physiologically acceptable. Thus, preferred addition salts of a compound of Formula (I-3) are formed with organic acids, preferably organic acids having a medium or low acidity, such as pK a those formed with organic acids having an acidity of not less than -3.0, not less than -2.0, not less than -1.0, not less than 0, 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 from 3.0 to 6.5. Further, it is also desirable to use acid addition salts that impart pleasant organoleptic properties (e.g., sweet, citrus, etc.), although salt forms that are organoleptically poor (e.g., bitter, harsh, etc.) are still acceptable, depending, for example, on the route of administration and the optional use of taste masking agents, such as sweeteners, flavorants, etc.

[0198] Solubility

[0199] The aqueous solubility of a salt form of a compound of Formula (I-3) can be determined by equilibrating an excess of solid with 1 mL of water at 22 °C for 24 hours. A 200 μL 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 a compound of Formula (I-3) can be prepared, and the solubility and solution pH can be measured.

[0200] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a water solubility at 22 °C of about 1 mg / mL to about 400 mg / mL. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a water solubility of from about 1 mg / mL, from about 2 mg / mL, from about 3 mg / mL, from about 5 mg / mL, from about 10 mg / mL, from about 20 mg / mL, from about 30 mg / mL, from about 40 mg / mL, from about 50 mg / mL, from about 60 mg / mL, from about 70 mg / mL, from about 80 mg / mL, from about 90 mg / mL, from about 100 mg / mL, from about 110 mg / mL, from about 120 mg / mL, from about 130 mg / mL, from about 140 mg / mL, from about 150 mg / mL to at most about 400 mg / mL, at most about 380 mg / mL, at most about 360 mg / mL, at most about 340 mg / mL, at most about 320 mg / mL, at most about 300 mg / mL, at most about 280 mg / mL, at most about 260 mg / mL, at most about 250 mg / mL. Several salt forms of the compounds described herein can exhibit the solubility described above, resulting in a final aqueous pH of approximately between pH 3 to 6 without gelling.

[0201] In some embodiments, the salt of the compound of Formula (I-3) 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-3) 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-3) 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.

[0202] In some embodiments, the salt form of the compound of Formula (I-3) has a dissolution rate that enables rapid systemic absorption for rapid treatment onset and short duration of drug action. In some embodiments, the salt of the compound of Formula (I-3) is capable of dissolving in aqueous media at less than about pH 7.5, such as pH 1-7, pH 3-7, or pH 4-7.

[0203] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a besylate, tartrate, hemifumarate, acetate, citrate, hemimalonate, malonate, fumarate, succinate, hemisuccinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, mesylate, tosylate, glucuronate, or glutarate salt of the compound of Formula (I-3). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a salt formed from a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, and the like). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a salt formed from a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, and the like). When the acid used to form the salt contains more than one acidic group (e.g., more than one carboxylic acid moiety), the pharmaceutically acceptable salt of the compound of Formula (I-3) can be a hemi salt of any of the salts listed above.

[0204] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a benzenesulfonate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a tartrate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a hemifumarate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is an acetate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a citrate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a hemimalonate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a fumarate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a hemisuccinate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is an oxalate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a benzoate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a salicylate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is an ascorbate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a maleate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a malate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a mesylate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a tosylate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a glucuronate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a glutarate salt.

[0205] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, fumarate, hemisuccinate, oxalate, benzoate, or salicylate salt of the compound of Formula (I-3), and the benzenesulfonate, hemisuccinate, or benzoate salt of the compound of Formula (I-3) is preferred, and the benzenesulfonate or benzoate salt of the compound of Formula (I-3) is particularly preferred.

[0206] Exemplary pharmaceutically acceptable salt forms (i.e., addition salt forms) of the above compounds are provided in Table 1.

[0207] Table 1. Exemplary pharmaceutically acceptable salts of the compound of Formula (I-3)

[0208] I-3a Benzenesulfonate salt of I-3 I-3b Tartrate salt of I-3 I-3c Hemifumarate salt of I-3 I-3d Acetate salt of I-3 I-3e Citrate salt of I-3 I-3f Hemipropionate salt of I-3 I-3g Fumarate salt of I-3 I-3h Hemisuccinate salt of I-3 I-3i Oxalate salt of I-3 I-3j Benzoate salt of I-3 I-3k Salicylate salt of I-3

[0209] In some embodiments, the pharmaceutically acceptable salt is 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol hydrochloride (I-3b). In some embodiments, salt I-3b is in crystalline solid form (Pattern 1), characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988°, as determined by XRPD using a Cu Ka radiation source, e.g., as shown in WO 2022195011 and / or WO 2023078604.

[0210] In some embodiments, the pharmaceutically acceptable salt is 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol tartrate salt (I-3b). In some embodiments, salt I-3b is in a crystalline solid form of Pattern 1, characterized by an X-ray powder diffraction pattern, for example, as shown in WO2022195011 and / or WO2023078604. In some embodiments, salt I-3b is in a crystalline solid form (Pattern 2) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.597°, 29.035°, 29.257°, 29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049°, as determined by XRPD using a CuKa radiation source, for example, as shown in WO2022195011 and / or WO2023078604.

[0211] In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c). In some embodiments, salt I-3c is in a crystalline solid form of Pattern 1, characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604. In some embodiments, salt I-3c is in a crystalline solid form (Pattern 2), characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999°, as determined by XRPD using a CuKa radiation source, for example, as shown in WO2022195011 and / or WO2023078604.

[0212] In some embodiments, the pharmaceutically acceptable salt is the hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c). In some embodiments, salt I-3c is in a crystalline solid form of Pattern 1, characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604. In some embodiments, salt I-3c is in a crystalline solid form (Pattern 2), characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999°, as determined by XRPD using a CuKa radiation source, for example, as shown in WO2022195011 and / or WO2023078604.

[0213] In some embodiments, the pharmaceutically acceptable salt is 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol hydrochloride (I-3a). In some embodiments, salt I-3a is in crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597°, as determined by XRPD using a Cu Ka radiation source, e.g., as shown in WO2022195011 and / or WO2023078604.

[0214] The preferred pharmaceutically acceptable salts of the compound of Formula (I-3) enhance stability, aqueous solubility, and dissolution rate compared to the free base compound, while also having favorable pharmaceutical properties (e.g., well-defined physical properties such as crystallinity, reproducible polymorphism where polymorphism exists, high melting onset such as greater than 160 °C, slight or no hygroscopicity, free-flowing, etc.), which allow for direct oral administration to patients without the need for prodrug approaches. As a result, the pharmaceutically acceptable salts of the compound of Formula (I-3) can have faster / shorter therapeutic onset, shorter duration of drug action (e.g., short duration of effect), and less exposure variability compared to the naked harmane-based drugs (e.g., naked harmane). Most importantly, the pharmaceutically acceptable salts of the compound of Formula (I-3) have demonstrated surprising efficacy in the treatment of MDD.

[0215] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a fatty acid salt. The fatty acid used to prepare the fatty acid salt of the compound of Formula (I-3) can be a mono- or di-fatty acid, and can contain a fatty hydrocarbon moiety consisting of from 4, from 6, from 8, from 10, from 12, from 14, from 16, to at most 26, to at most 24, to at most 22, to at most 20, to at most 18 carbon atoms, which can be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is adipate, laurate, linoleate, myristate, caprate, stearate, oleate, octanoate, palmitate, sebacate, undecylenate, or hexanoate salt of the compound of Formula (I-3). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is adipate, laurate, linoleate, myristate, caprate, stearate, oleate, or octanoate salt of the compound of Formula (I-3), wherein laurate, linoleate, caprate, or octanoate salt of the compound of Formula (I-3) is preferred.

[0216] Exemplary pharmaceutically acceptable fatty acid salt forms (i.e., addition salt forms) of the above compounds are provided in Table 2.

[0217] Table 2. Exemplary pharmaceutically acceptable fatty acid salts of the compound of Formula (I-3)

[0218] Salt form identifier Salt type of the compound I-3l Adipate salt of I-3 I-3m Laurylate salt of I-3 I-3n Linoleate salt of I-3 I-3o Myristate salt of I-3 I-3p Decanoate salt of I-3 I-3q Stearate salt of I-3 I-3r Oleate salt of I-3 I-3s Octanoate salt of I-3

[0219] In some embodiments, the pharmaceutically acceptable salt is laurate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3m). In some embodiments, salt I-3m is in a crystalline solid form of Pattern 1, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0220] In some embodiments, the pharmaceutically acceptable salt is linoleate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3n). In some embodiments, salt I-3n is in a crystalline solid form of Pattern 1, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0221] In some embodiments, the pharmaceutically acceptable salt is the myristate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3o). In some embodiments, the salt I-3o is in a crystalline solid form of Pattern 1, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0222] In some embodiments, the pharmaceutically acceptable salt is the decanoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3p). In some embodiments, the salt I-3p is in a crystalline solid form of Pattern 1, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0223] In some embodiments, the pharmaceutically acceptable salt is the stearate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3q). In some embodiments, the salt I-3q is in a crystalline solid form of Pattern 1 or 2, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0224] In some embodiments, the pharmaceutically acceptable salt is the oleate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3r). In some embodiments, the salt I-3r is in a crystalline solid form of Pattern 1 or 2, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0225] In some embodiments, the pharmaceutically acceptable salt is the octanoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3s). In some embodiments, the salt I-3s is in a crystalline solid form of Pattern 1, which is characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.

[0226] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in corn oil at 22 °C of from about 0.4 mg / mL, from about 0.5 mg / mL, from about 0.6 mg / mL, from about 0.7 mg / mL, from about 0.8 mg / mL, from about 0.9 mg / mL, from about 1 mg / mL, up to about 2 mg / mL, up to about 1.9 mg / mL, up to about 1.8 mg / mL, up to about 1.7 mg / mL, up to about 1.6 mg / mL, up to about 1.5 mg / mL, up to about 1.4 mg / mL, up to about 1.3 mg / mL, up to about 1.2 mg / mL.

[0227] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in GTCC (medium chain glycerides from Croda) at 22 °C of from about 0.4 mg / mL, from about 0.6 mg / mL, from about 0.8 mg / mL, from about 1 mg / mL, from about 1.2 mg / mL, from about 1.4 mg / mL, from about 1.6 mg / mL, up to about 4 mg / mL, up to about 3.8 mg / mL, up to about 3.6 mg / mL, up to about 3.4 mg / mL, up to about 3.2 mg / mL, up to about 3 mg / mL, up to about 2.8 mg / mL, up to about 2.6 mg / mL, up to about 2.4 mg / mL, up to about 2.2 mg / mL. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in GTCC (medium chain glycerides from Croda) at 22 °C of from about 0.4 mg / mL, from about 0.6 mg / mL, from about 0.8 mg / mL, from about 1 mg / mL, from about 1.2 mg / mL, from about 1.4 mg / mL, from about 1.6 mg / mL, up to about 4 mg / mL, up to about 3.8 mg / mL, up to about 3.6 mg / mL, up to about 3.4 mg / mL, up to about 3.2 mg / mL, up to about 3 mg / mL, up to about 2.8 mg / mL, up to about 2.6 mg / mL, up to about 2.4 mg / mL, up to about 2.2 mg / mL.

[0228] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in GTCC (medium chain glycerides from Croda) at 22 °C of from about 0.4 mg / mL, from about 0.6 mg / mL, from about 0.8 mg / mL, from about 1 mg / mL, from about 1.2 mg / mL, from about 1.4 mg / mL, from about 1.6 mg / mL, up to about 4 mg / mL, up to about 3.8 mg / mL, up to about 3.6 mg / mL, up to about 3.4 mg / mL, up to about 3.2 mg / mL, up to about 3 mg / mL, up to about 2.8 mg / mL, up to about 2.6 mg / mL, up to about 2.4 mg / mL, up to about 2.2 mg / mL. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in GTCC (medium chain glycerides from Croda) at 22 °C of from about 0.4 mg / mL, from about 0.6 mg / mL, from about 0.8 mg / mL, from about 1 mg / mL, from about 1.2 mg / mL, from about 1.4 mg / mL, from about 1.6 mg / mL, up to about 4 mg / mL, up to about 3.8 mg / mL, up to about 3.6 mg / mL, up to about 3.4 mg / mL, up to about 3.2 mg / mL, up to about 3 mg / mL, up to about 2.8 mg / mL, up to about 2.6 mg / mL, up to about 2.4 mg / mL, up to about 2.2 mg / mL.

[0229] Due to the relative hydrophobicity of the fatty acid salts of the compounds of Formula (I-3), the fatty acid salts can be advantageous when used in a medicament suitable for a modified, controlled, slow, or extended release profile. Thus, the fatty acid salts of the compounds of Formula (I-3) can be well suited for the route of administration and / or for a dosage form suitable for providing a low dose of the active pharmaceutical ingredient (API) over an extended period of time, as can be achieved with sub-psychedelic dosing regimens. Non-limiting examples of such dosage forms include, but are not limited to, liposomes, micelles, microspheres, nanosystems, or other controlled release devices, such as those set forth herein.

[0230] Also disclosed herein is a method for stabilizing a compound of Formula (I-3). The method comprises preparing a pharmaceutically acceptable salt of the compound of Formula (I-3).

[0231] Also disclosed herein is a method for preparing a pharmaceutically acceptable salt of a compound of Formula (I-3). In some embodiments, the method comprises:

[0232] (a) suspending the free base of the compound of Formula (I-3) in a solvent or mixture of solvents;

[0233] (b) contacting an acid with the compound of Formula (I-3) to provide a mixture;

[0234] (c) optionally heating the mixture;

[0235] (d) optionally cooling the mixture; and

[0236] (e) isolating the salt.

[0237] Various solvents can be used in the disclosed methods, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent in the method for preparing the salt is a protic solvent. In some embodiments, the solvent 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), an ether solvent (e.g., t-butyl methyl ether (TBME)), hexane, heptane, and octane, and combinations thereof. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is tetrahydrofuran.

[0238] Suitable acids for preparing pharmaceutically acceptable acid addition salts can include those previously described. The acid can be an inorganic acid such as hydrochloric acid or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, maleic acid, malonic acid, (-)-L-malic acid, (+)-L-tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, D-glucuronic acid, glutaric acid, and acetic acid. In some embodiments, the acid is an organic acid selected from the group consisting of benzenesulfonic acid, (+)-L-tartaric acid, fumaric acid, acetic acid, citric acid, malonic acid, succinic acid, oxalic acid, benzoic acid, and salicylic acid, with benzenesulfonic acid, succinic acid, and benzoic acid being preferred. In some embodiments, the acid is a fatty acid such as adipic acid (hexanedioic 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 (hexadecanoic acid), sebacic acid, undecanoic acid, hexanoic acid, and the like, and adipic acid (hexanedioic acid), lauric acid (dodecanoic acid), linoleic acid, myristic acid (tetradecanoic acid), capric acid (decanoic acid), stearic acid (octadecanoic acid), oleic acid, and caprylic acid (octanoic acid) are specifically mentioned.

[0239] In some embodiments, a stoichiometric (or super-stoichiometric) amount of acid is contacted with the compound of Formula (I-3). In some embodiments, a sub-stoichiometric (e.g., 0.5 molar equivalents) amount of acid is contacted with the compound of Formula (I-3). The use of a sub-stoichiometric amount of acid can be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the salt of interest is a hemi- salt.

[0240] In some embodiments, the mixture is heated, e.g., refluxed, prior to cooling.

[0241] 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.

[0242] The salt can be isolated by various well-known separation techniques, such as filtration, decantation, and the like. In some embodiments, the isolation step comprises filtering the mixture.

[0243] Following isolation, additional crystallization and / or recrystallization steps can optionally be performed, if desired, e.g., to increase purity, crystallinity, and the like.

[0244] In some embodiments, the compounds of the disclosure, e.g., the compounds of Formula (I-3), or pharmaceutically acceptable salts or polymorphs thereof, are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanols, ethanolols, isopropanols, and the like, preferably hydrates and ethanolols. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. Solvates of the compounds herein can be in the form of isolatable solvates. In one non-limiting example, as a hydrate, a compound can be a monohydrate, a dihydrate, and the like. Solvates of the compounds herein also include solution phase forms. Thus, in some embodiments, the disclosure provides solution phase compositions of the compounds of the disclosure, or any pharmaceutically acceptable salts thereof, in solvated form, preferably fully solvated form.

[0245] In some embodiments, the minimum deuterium incorporation at any position indicated as having deuterium in the compounds of Formula (I-3) is greater than the naturally occurring deuterium incorporation in hydrogen (about 0.016 atom %). In some embodiments, the minimum deuterium incorporation at the deuterium site at any position indicated as having deuterium in the compounds of Formula (I-3) is at least 10 atom %, at least 20 atom %, at least 25 atom %, at least 30 atom %, at least 40 atom %, at least 45 atom %, at least 50 atom %, at least 60 atom %, at least 70 atom %, at least 80 atom %, at least 90 atom %, at least 95 atom %, at least 99 atom %. Typically, the minimum deuterium incorporation at the deuterium site at any position indicated as having deuterium in the compounds of Formula (I-3) is at least 40 atom %, at least 45 atom %, at least 50 atom %, at least 60 atom %, at least 70 atom %, at least 80 atom %, at least 90 atom %, at least 95 atom %, at least 99 atom %.

[0246] Compounds of Formula (I-3), or pharmaceutically acceptable salts, polymorphs, or solvates thereof, having less than 100% isotopic purity can be used. In some embodiments, the isotopic purity of a compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof) is at least 50 wt %, at least 60 wt %, at least 70 wt %, at least 80 wt %, at least 90 wt %, at least 95 wt %, at least 99 wt %, based on the total weight of isotopologues of the compound of Formula (I-3) present. For example, a compound of Formula (I-3) can be used as a mixture containing as the subject compound, in free base or salt form, naked pellitorin-d 10(Compound I-3; 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol), solvates or mixtures thereof, are present, and which can additionally contain minor amounts of isotopologues of the subject compound, e.g., nudixanthin-d9 (one or more of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol and 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H-indol-4-ol), nudixanthin-d8 (one or more of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol, 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol, and 3-(2-(bis(methyl-d3)amino)ethyl-1,2-d2)-1H-indol-4-ol), etc., polymorphs, stereoisomers, solvates or mixtures thereof, in free base or salt form. In some embodiments, the compound of Formula (I-3) is substantially free of other isotopologues of the compound, e.g., less than 20 mole percent, 15 mole percent, 10 mole percent, 9 mole percent, 8 mole percent, 7 mole percent, 6 mole percent, 5 mole percent, 4 mole percent, 3 mole percent, 2 mole percent, or 1 mole percent or 0.5 mole percent of other isotopologues of the compound in free base or salt form. In some embodiments, the isotopic purity of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof is at least 60 weight percent, at least 65 weight percent, at least 70 weight percent, at least 75 weight percent, at least 77 weight percent, at least 79 weight percent, at least 80 weight percent, at least 82 weight percent, at least 84 weight percent, at least 85 weight percent, at least 87 weight percent, at least 89 weight percent, at least 90 percent, wherein the isotopic purity is at most 99 weight percent, at most 98 weight percent, at most 97 weight percent, at most 96 weight percent, at most 95 weight percent, at most 94 weight percent, at most 93 weight percent, at most 92 weight percent, at most 91 weight percent, at most 90 weight percent, at most 89 weight percent, at most 88 weight percent, at most 87 weight percent, at most 86 weight percent, at most 85 weight percent, at most 84 weight percent, at most 83 weight percent, at most 82 weight percent, at most 81 weight percent, at most 80 weight percent.In some embodiments, the compound of Formula (I-3) or pharmaceutically acceptable salt, polymorph, or solvate thereof is an isotopologue mixture (or active mixture) comprising: (i) 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 75% to 90% by weight, 76% to 89% by weight, 77% to 88% by weight, 78% to 87% by weight, 79% to 86% by weight of Gymnosterol-d based on the total weight of the isotopologue mixture; (ii) 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 10% to 25% by weight, 11% to 24% by weight, 12% to 23% by weight, 13% to 22% by weight, 14% to 21% by weight, 13% to 17% by weight of one or more of Gymnosterol-d9 (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol and 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H-indol-4-ol) or a pharmaceutically acceptable salt, polymorph, or solvate thereof based on the total weight of the isotopologue mixture; and (iii) less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or 0% by weight, or 1% to 3% by weight of one or more of Gymnosterol-d8 (3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol, 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol, and 3-(2-(bis(methyl-d3)amino)ethyl-1,2-d2)-1H-indol-4-ol) or a pharmaceutically acceptable salt, polymorph, or solvate thereof based on the total weight of the isotopologue mixture. 10 or a pharmaceutically acceptable salt, polymorph, or solvate thereof; (ii) 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 10% to 25% by weight, 11% to 24% by weight, 12% to 23% by weight, 13% to 22% by weight, 14% to 21% by weight, 13% to 17% by weight of one or more of Gymnosterol-d9 (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol and 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H-indol-4-ol) or a pharmaceutically acceptable salt, polymorph, or solvate thereof based on the total weight of the isotopologue mixture; and (iii) less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or 0% by weight, or 1% to 3% by weight of one or more of Gymnosterol-d8 (3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol, 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol, and 3-(2-(bis(methyl-d3)amino)ethyl-1,2-d2)-1H-indol-4-ol) or a pharmaceutically acceptable salt, polymorph, or solvate thereof based on the total weight of the isotopologue mixture.

[0247] In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is chemically pure, e.g., greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% chemically pure by HPLC. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, has no 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 HPLC. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is greater than 97 area%, greater than 98 area%, or greater than 99 area% chemically pure by HPLC. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4 area%, greater than 0.3 area%, or greater than 0.2 area% as measured by HPLC.

[0248] Pharmaceutical compositions useful in the methods of the invention

[0249] In any embodiment of the application, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be administered as a pharmaceutical composition comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, according to any embodiment described herein. Accordingly, the present application describes a pharmaceutical composition and method for treating various diseases, disorders, and conditions such as depressive disorders (e.g., major depressive disorder (MDD)), substance use disorders, anxiety disorders, eating disorders, and headache disorders, in a subject in need thereof, comprising about 8-16 mg, or about 8-14 mg, or about 8-12 mg, or about 12-16 mg, or about 12 mg, or about 16 mg of a compound of Formula (I-3)

[0250]

[0251] or a pharmaceutically acceptable salt, polymorph, or solvate thereof; and

[0252] a pharmaceutically acceptable vehicle. In some embodiments, the compound of Formula (I-3) is a compound of Formula (I-3) or a salt or polymorph thereof as described in any embodiment described herein.

[0253] A pharmaceutical composition according to any embodiment described herein can contain one or more than one compound, salt form, polymorph, and / or solvate of the present disclosure.

[0254] A pharmaceutical composition of the present disclosure can be formulated with a therapeutically effective amount of a compound of Formula (I-3)

[0255]

[0256] or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof is about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, or any range therebetween, such as about 8 mg to about 16 mg, about 8 mg to about 14 mg, about 8 mg to about 12 mg, about 10 mg to about 16 mg, about 11 mg to about 15 mg, about 12 mg to about 14 mg, about 11 mg to about 13 mg, about 14 mg to about 16 mg, or about 12 mg to about 16 mg (free base equivalent). In some embodiments, the pharmaceutical composition comprises 8 mg to 16 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 8 mg to 14 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 8 mg to 12 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 8 mg to 10 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 10 mg to 16 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 12 mg to 16 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 10 mg to 14 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 12 mg to 14 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 11 mg to 16 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 11 mg to 15 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 11 mg to 13 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 8 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 8 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof.In some embodiments, the pharmaceutical composition comprises 9 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 10 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 11 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 11 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 12 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 12 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 13 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 13 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 14 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 14 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 15 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 15 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition comprises 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the pharmaceutical composition is administered orally, and the dosage of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in the pharmaceutical composition recited above is an oral dosage.

[0257] The pharmaceutical composition can comprise a single compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, or a mixture of compounds of Formula (I-3) in free base or salt form, including one or more polymorphs of such materials.

[0258] The pharmaceutical composition can be formed from a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, having less than 100% isotopic purity, i.e., having a mixture of isotopologues. In some embodiments, the isotopic purity of a compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof) is at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, based on the total weight of the isotopologues of the compound of Formula (I-3) present in, for example, the pharmaceutical composition. For example, the subject compound in free base or salt form can be a mixture of isotopologues of Formula (I-3) having the following isotopic purity: 10Pharmaceutical compositions, solvates, or mixtures thereof, of Compound I-3; 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol) can additionally contain minor amounts of isotopologues of the subject compound, e.g., nudixindine-d9 (one or more of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol and 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H-indol-4-ol), nudixindine-d8 (one or more of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol, 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol, and 3-(2-(bis(methyl-d3)amino)ethyl-1,2-d2)-1H-indol-4-ol), etc., polymorphs, stereoisomers, solvates, or mixtures thereof, 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, e.g., less than 20 mole percent, 15 mole percent, 10 mole percent, 9 mole percent, 8 mole percent, 7 mole percent, 6 mole percent, 5 mole percent, 4 mole percent, 3 mole percent, 2 mole percent, or 1 mole percent or 0.5 mole percent of other isotopologues of the compound of the composition. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in at least 60 weight percent, at least 65 weight percent, at least 70 weight percent, at least 75 weight percent, at least 77 weight percent, at least 79 weight percent, at least 80 weight percent, at least 82 weight percent, at least 84 weight percent, at least 85 weight percent, at least 87 weight percent, at least 89 weight percent, at least 90 percent isotopic purity, with at most 99 weight percent, at most 98 weight percent, at most 97 weight percent, at most 96 weight percent, at most 95 weight percent, at most 94 weight percent, at most 93 weight percent, at most 92 weight percent, at most 91 weight percent, at most 90 weight percent, at most 89 weight percent, at most 88 weight percent, at most 87 weight percent, at most 86 weight percent, at most 85 weight percent, at most 84 weight percent, at most 83 weight percent, at most 82 weight percent, at most 81 weight percent, at most 80 weight percent.In some embodiments, the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof is an isotopologue mixture (or active mixture) comprising: (i) 60% to 99% by weight, 60% to 98% by weight, 65% to 97% by weight, 70% to 96% by weight, 75% to 95% by weight, 80% to 94% by weight, 85% to 93% by weight, 90% to 92% by weight, 75% to 90% by weight, 76% to 89% by weight, 77% to 88% by weight, 78% to 87% by weight, 79% to 86% by weight of psilocybin-d, based on the total weight of the isotopologue mixture. 10 or a pharmaceutically acceptable salt, polymorph or solvate thereof; and (ii) 1% to 40% by weight, 2% to 40% by weight, 3% to 35% by weight, 4% to 30% by weight, 5% to 25% by weight, 6% to 20% by weight, 7% to 15% by weight, 8% to 10% by weight, 10% to 25% by weight, 11% to 24% by weight, 12% to 23% by weight, 13% to 22% by weight, 14% to 21% by weight, 13% to 17% by weight of psilocin-d9(3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol and 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H -indol-4-ol) or a pharmaceutically acceptable salt, polymorph or solvate thereof; and (iii) less than 10 weight %, less than 5 weight %, less than 3 weight %, less than 2 weight %, less than 1 weight %, less than 0.5 weight %, less than 0.25 weight %, or 0 weight %, or 1 weight % to 3 weight % of psilocin-d8 (one or more of 3-(2-(bis(methyl-d3)amino)ethyl-2,2-d2)-1H-indol-4-ol, 3-(2-(bis(methyl-d3)amino)ethyl-1,1-d2)-1H-indol-4-ol and 3-(2-(bis(methyl-d3)amino)ethyl-1,2-d2)-1H-indol-4-ol) or a pharmaceutically acceptable salt, polymorph or solvate thereof, based on the total weight of the isotopologue mixture.

[0259] The pharmaceutical compositions can be formulated with one or more polymorphs of the compound of Formula (I-3) and / or salt forms thereof, including crystalline and / or amorphous polymorphs of the compound or its salts. In some embodiments, the pharmaceutical composition includes a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition includes a single crystalline polymorph. In some embodiments, the pharmaceutical composition includes a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition includes a single amorphous polymorph. In some embodiments, the pharmaceutical composition includes a mixture of crystalline and amorphous polymorphs.

[0260] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I-3) or a pharmaceutically acceptable salt or solvate thereof in a crystalline form. In some embodiments, the pharmaceutical composition comprises a highly pure crystalline form of the compound of Formula (I-3) as a free base. For example, the pharmaceutical composition can comprise the free base of the compound of Formula (I-3), wherein at least 90 wt%, at least 95 wt%, at least 99 wt%, or at least 99.5 wt% of the free base of the compound of Formula (I-3) present in the pharmaceutical composition is in a crystalline form, e.g., as determined by X-ray powder diffraction and / or mDSC. In some embodiments, the pharmaceutical composition comprises a highly pure crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I-3). For example, the pharmaceutical composition can comprise a pharmaceutically acceptable salt of the compound of Formula (I-3), wherein at least 90 wt%, at least 95 wt%, at least 99 wt%, or at least 99.5 wt% of the pharmaceutically acceptable salt of the compound of Formula (I-3) present in the pharmaceutical composition is in a crystalline form, e.g., as determined by X-ray powder diffraction and / or mDSC.

[0261] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I-3), or a pharmaceutically acceptable salt or solvate thereof, in amorphous form. In some embodiments, only the amorphous form of the compound of Formula (I-3), or a pharmaceutically acceptable salt or solvate thereof, is present in the pharmaceutical composition, e.g., no crystalline form of the compound of Formula (I-3) is detectable, e.g., by XRPD. In some embodiments, the pharmaceutical composition comprises a highly pure amorphous form of the compound of Formula (I-3) as the free base. For example, the pharmaceutical composition can comprise the free base of the compound of Formula (I-3), 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 free base of the compound of Formula (I-3) present in the pharmaceutical composition is in amorphous form, e.g., as determined by X-ray powder diffraction and / or mDSC. In some embodiments, the pharmaceutical composition comprises a highly pure amorphous form of a pharmaceutically acceptable salt of the compound of Formula (I-3). For example, the pharmaceutical composition can comprise a pharmaceutically acceptable salt of the compound of Formula (I-3), 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-3) present in the pharmaceutical composition is in amorphous form, e.g., as determined by X-ray powder diffraction and / or mDSC.

[0262] In addition to the compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph or solvate, the pharmaceutical composition of the present disclosure can also include a pharmaceutically acceptable vehicle. "Pharmaceutically acceptable vehicle" can be a vehicle approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopeia (US Pharmacopeia) or other generally recognized pharmacopoeias in mammals such as humans. The term "vehicle" refers to a diluent, adjuvant, excipient or carrier for administering to mammals that is formulated with the compound of the present disclosure. Such pharmaceutically acceptable vehicles can be solid or liquid. Pharmaceutically acceptable vehicles can include water, saline, juice, particularly juice (e.g., orange juice, such as Tang, grape juice, apple juice, cranberry juice, pineapple juice, etc.) of juice containing citric acid, oil, including oil from petroleum, animals, plants or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, etc. Pharmaceutically acceptable vehicles can include but are not limited to adjuvants, stabilizers, solubilizers, thickeners, lubricants, bonding agents, granulating agents, fillers, diluents, disintegrants, wetting agents, glidants, anti-caking agents, coloring agents, sweeteners, dye migration inhibitors, preservatives, antioxidants, lyophilization protectants, compounding agents, flavoring agents, matrix forming agents, dispersants, performance modifiers, controlled release polymers, solvents, pH regulators, carbon dioxide sources or other pharmaceutical additives described herein. In certain embodiments, the fruit orange beverage is used as a pharmaceutically acceptable vehicle. Except water, the fruit orange beverage can also contain sugar, fructose, citric acid, maltodextrin, calcium phosphate, sodium acid pyrophosphate, ascorbic acid (vitamin C), natural flavors, artificial colors, guar gum, yellow 5, yellow 6 and xanthan gum.

[0263] Among these pharmaceutically acceptable vehicles, some organic acids have been identified as agents for the psilocin-d 10 Compound (for example, compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph or solvate) provides both stabilizing function and solubilizing function, thus improves the delivery and therapeutic characteristics of disclosed dosage form.These organic acid vehicles that provide unique stabilization and solubilizing effect (acting as stabilizer / solubilizer) can be referred to as " organic acid agent " in this article. In a preferred embodiment, pharmaceutical composition comprises compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph or solvate and organic acid agent. Pharmaceutical composition can optionally be deployed together with other pharmaceutically acceptable vehicles as needed or expected.

[0264] In some embodiments, the solid dosage form is formulated with an organic acid agent, wherein the organic acid agent is considered separate and distinct from the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, i.e., the organic acid agent is not considered to form a salt with the compound of Formula (I-3) when formulated in a solid dosage form. For example, in these embodiments where the pharmaceutical composition is a solid dosage form formulated with the free base of the compound of Formula (I-3), the organic acid agent is not considered to form an addition salt with the compound of Formula (I-3), but rather the compound of Formula (I-3) remains as the free base at least until the point of dissolution / disintegration in an appropriate medium (e.g., water, juice, saline, saliva, etc.). In another example, where the pharmaceutical composition is formulated with a salt form of the compound of Formula (I-3), the organic acid agent remains separate from the salt form and provides a stabilizing / solubilizing effect greater than that provided by the salt form of the compound of Formula (I-3) alone.

[0265] The organic acid agent can be any organic acid described herein and can be a mono-acid, di-acid, tri-acid, tetra-acid, or can contain a greater number of acid groups. A mixture of organic acid agents or organic acid agents can be used. In addition to an acid group (e.g., one or more carboxylic acid moieties), the organic acid agent can contain one or more hydroxyl functional groups as part of its structure (i.e., the organic acid agent can be a hydroxy acid). In some embodiments, the organic acid agent is an a-hydroxy acid. In some embodiments, the organic acid agent is a β-hydroxy acid. In some embodiments, the organic acid agent 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 agent is citric acid and / or tartaric acid. In some embodiments, the organic acid agent is citric acid. In some embodiments, the organic acid agent is tartaric acid. In some embodiments, the organic acid agent is an en-dioic acid, examples of which can include, but are not limited to, fumaric acid and maleic acid. In some embodiments, the organic acid agent is fumaric acid. In some embodiments, the organic acid agent is maleic acid. Mixtures and / or hydrates of the disclosed organic acid agents can also be used in the disclosed pharmaceutical compositions. In some embodiments, the organic acid agent is not a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the organic acid agent is not benzoic acid (e.g., benzoic acid, 4-acetylamino benzoic acid, 2-acetyloxy benzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.).

[0266] In some embodiments, the pharmaceutical composition comprises at least 0.5 wt.%, at least 1 wt.%, at least 2 wt.%, at least 3 wt.%, at least 4 wt.%, at least 5 wt.%, at least 6 wt.%, at least 7 wt.%, at least 8 wt.%, at least 9 wt.%, at least 10 wt.%, at least 11 wt.%, at least 12 wt.%, at least 13 wt.%, at least 14 wt.%, at least 15 wt.%, and up to 60 wt.%, up to 55 wt.%, up to 50 wt.%, up to 45 wt.%, up to 40 wt.%, up to 35 wt.%, up to 30 wt.%, up to 27 wt.%, up to 25 wt.%, up to 23 wt.%, up to 20 wt.%, up to 18 wt.%, up to 16 wt.%, or any range therebetween, of the organic acid agent, based on the total weight of the pharmaceutical composition (on a dry basis). For example, the pharmaceutical composition can contain 1 wt.% to 20 wt.% of the organic agent, or 2 wt.% to 10 wt.% of the organic agent, or 5 wt.% to 40 wt.% of the organic acid agent, or 10 wt.% to 30 wt.% of the organic agent, or 15 wt.% to 20 wt.% of the organic acid agent, or 2 wt.% to 3 wt.% of the organic acid agent, or about 2.5 wt.% to 3 wt.% of the organic acid agent, based on the total weight of the pharmaceutical composition (on a dry basis). Dry basis can refer to the pharmaceutical composition in a solid dosage form or a liquid dosage form after subtracting the weight contribution from water or other pharmaceutically acceptable aqueous medium (e.g., fruit juice).

[0267] In some embodiments, the weight ratio of the organic acid agent to the compound of Formula (I-3) (on an active basis) is from 1 : 1, from 1.5: 1, from 2: 1, from 2.5: 1, from 3: 1, from 3.5: 1, from 4: 1, from 4.5: 1, from 5: 1, to up to 20: 1, up to 15: 1, up to 10: 1, up to 9: 1, up to 8: 1, up to 7: 1, up to 6: 1, or any range therebetween.

[0268] When the pharmaceutical composition is formulated with a pharmaceutically acceptable salt of the compound of Formula (I-3), the acid used to form the pharmaceutically acceptable salt of the compound of Formula (I-3) and the organic acid agent (vehicle) can be the same. For example, the pharmaceutical composition can comprise a tartrate salt of the compound of Formula (I-3) (e.g., I-3b), and tartaric acid as the organic acid agent (vehicle). In another example, the pharmaceutical composition can comprise a citrate salt of the compound of Formula (I-3) (e.g., I-3e), and citric acid as the organic acid agent (vehicle).

[0269] When a pharmaceutical composition is formulated with a pharmaceutically acceptable salt of a compound of Formula (I-3), the acid and organic acid agent (vehicle) used to form the pharmaceutically acceptable salt of the compound of Formula (I-3) can be different. For example, a pharmaceutical composition can comprise a besylate salt of a compound of Formula (I-3) (I-3a), and citric acid and / or tartaric acid, etc. as the organic acid agent (vehicle). In another example, a pharmaceutical composition can comprise a benzoate salt of a compound of Formula (I-3) (e.g., I-3j), and citric acid and / or tartaric acid as the organic acid agent (vehicle).

[0270] Any of the pharmaceutical compositions disclosed herein that are formulated with an organic acid agent can contain an uncoated organic acid agent, or alternatively, can contain an organic acid agent that is coated with a pharmaceutically acceptable vehicle (“coated organic acid agent”). Examples of coated organic acid agents are set forth below.

[0271] The pharmaceutical compositions disclosed herein can be administered once or more than once at time intervals. It will be appreciated that the precise dose and duration of treatment can vary with the age, weight, and condition of the patient to be treated, and can be determined by using known test protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It will be further appreciated that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual’s need and the professional judgment of the person administering or supervising the administration of the formulations.

[0272] In the event that the patient’s condition does not improve, the compound can be administered chronically, i.e., over an extended period of time, including for the duration of the patient’s lifetime, according to the judgment of the physician, in order to ameliorate or otherwise control or limit the patient’s disease or condition symptoms.

[0273] In the event that the patient’s condition does improve, the compound can be continued or temporarily discontinued for a certain length of time (i.e., a “drug holiday”), according to the judgment of the physician.

[0274] Once the patient’s condition has been improved, a maintenance dose can be administered, if necessary. Subsequently, the dose or the frequency of administration, or both, can be reduced, to a level at which symptoms are reduced to that of maintaining the improved condition. However, once any recurrence of symptoms occurs, the patient can require resumption of longer-term intermittent treatment.

[0275] Pharmaceutical compositions can take the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, or sustained-release formulations thereof, or any other form suitable for administration to a mammal. Administration of the subject compounds can be systemic or local. In some cases, the pharmaceutical compositions are formulated in accordance with conventional procedures for administration as pharmaceutical compositions suitable for oral administration or other routes of administration as set forth herein. Examples of suitable pharmaceutically acceptable vehicles and methods for their formulation are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, editor, Mack Publishing Co. Easton, Pa., 19th edition, 1995, Chapters 86, 87, 88, 91 and 92, which is incorporated herein by reference. The choice of vehicle will be determined, in part, by the particular compound, salt form, and by the particular method used to administer the composition. Thus, there are a variety of suitable formulations of the subject pharmaceutical compositions. Liquid form preparations include solutions and emulsions, for example, aqueous or non-aqueous solutions or suspensions. When used in mammals, the compounds and compositions of the present disclosure, and the pharmaceutically acceptable vehicles can be sterile. In some cases, for example, when the subject compounds are administered orally, an aqueous medium is employed as a vehicle, such as water or fruit juice.

[0276] Any of the pharmaceutical compositions described herein can comprise, as an active ingredient, at least one compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. As described below, pharmaceutical compositions comprising the compounds disclosed herein can be formulated in various dosage forms, and are specifically formulated for administration in solid, semisolid, or liquid form, including administration adapted for:

[0277] A. oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, thin films or capsules (e.g., capsules intended for buccal, sublingual, and systemic absorption), boluses, powders, granules, syrups, pastes applied to the tongue;

[0278] B. modified release dosage forms, including delayed release, extended release, prolonged release, sustained release, pulsatile release, controlled release, accelerated release, fast release, targeted release, programmed release, and gastric retention dosage forms, such modified release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, e.g., 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).

[0279] Tamper-resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated.

[0280] A. oral administration

[0281] The pharmaceutical compositions disclosed herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration includes gastric (intestinal) delivery, for example, by which the drug is taken orally and swallowed, as well as intraoral administration, such as through the mucosal lining of the oral cavity, for example, buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, candy lozenges, caplets, pellets, medicinal chewing gum, microparticles, bulk powders, effervescent or non-effervescent dosage forms (e.g., effervescent or non-effervescent tablets, films, powders, or microparticles), solutions, emulsions, suspensions, solutions, wafers, films, sprinkles, elixirs, and syrups. In addition to the active ingredients, the pharmaceutical compositions can contain one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients), including, but not limited to, adjuvants, stabilizers, solubilizers, thickening agents, lubricants, binding agents, granulating agents, fillers, diluents, disintegrants, wetting agents, glidants, anti-caking agents, colorants, sweeteners, dye migration inhibitors, preservatives, antioxidants, lyophilization protectants, complexing agents, flavoring agents, matrix forming agents, dispersing agents, performance modifiers, controlled release polymers, solvents, pH adjusting agents, and sources of carbon dioxide. In some embodiments, the pharmaceutically acceptable vehicles comprise organic acid agents, as discussed herein, which have been found to provide unique benefits as both stabilizers and solubilizers to aid in release from the disclosed dosage forms and provide stability of the compounds herein.

[0282] In some embodiments, the pharmaceutical compositions of the present disclosure can be in an orally dispersible dosage form (ODx), including a sublingual dosage form, a buccal dosage form, such as an orally disintegrating tablet (ODT) (sometimes also referred to as a fast-disintegrating tablet, an orally dispersible tablet, or a fast dispersible tablet), or an orally dispersible film (ODF) (or wafer). Such dosage forms can be particularly advantageous in the present disclosure as they allow for pre-gastric absorption of the compounds / salts herein, for example, when administered intraorally through the mucosal lining of the oral cavity, e.g., buccal, lingual, and sublingual administration, to increase bioavailability and faster onset as compared to oral administration through the gastrointestinal tract. Additionally, orally dispersible dosage forms can be advantageous for treating pediatric / adolescent patients or patients who generally have difficulty swallowing traditional dosage forms such as conventional tablets or capsules.

[0283] In some embodiments, an orally dispersible dosage form (ODx) is a sublingual dosage form that disintegrates / dissolves under the tongue, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the sublingual mucosa that enters the venous circulation. In some embodiments, a sublingual dosage form disintegrates / dissolves under the tongue, whereby the contents are converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, upon mixing with saliva, and are subsequently swallowed. In some embodiments, an orally dispersible dosage form (ODx) is a buccal dosage form that is to disintegrate / dissolve in the buccal cavity, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the inner lining of the oral mucosa that enters the venous circulation in the mouth. In some embodiments, a buccal dosage form disintegrates / dissolves in the buccal cavity, whereby the contents are converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, upon mixing with saliva, and are subsequently swallowed. In addition to the active ingredient, a pharmaceutical composition in an orally dispersible dosage form (ODx) can contain one or more pharmaceutically acceptable vehicles (e.g., a binding agent, a filler, a diluent, a disintegrant, a lyophilization protectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, a source of carbon dioxide, a bioadhesive agent, etc., and / or any other pharmaceutically acceptable vehicle set forth herein, with particular mention of one or more of the organic acid agents).

[0284] Orally dispersible dosage forms can be prepared by different techniques, such as freeze-drying (lyophilization), molding, spray-drying, mass-extrusion, or compression. In some embodiments, the orally dispersible dosage form is prepared by lyophilization. In some embodiments, the orally dispersible dosage form disintegrates within 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 orally dispersible dosage form dissolves within less than about 90 seconds, less than about 60 seconds, or less than about 30 seconds after being received in the oral cavity. In some embodiments, the orally dispersible dosage form disperses within 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), which has a disintegration time of no more than about 30 seconds, no more than about 20, 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 having longer disintegration times according to the United States Pharmacopeia (USP) Disintegration Test <701> are also contemplated, such as when a time delay release is appropriate, 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 therebetween or longer.

[0285] In some embodiments, the pharmaceutical composition is in the form of a sublingual tablet prepared by direct compression, compression molding, or lyophilization. In some embodiments, the sublingual tablet is produced by direct compression, whereby a directly compressible pharmaceutical vehicle such as an organic acid agent (optionally coated), a binding agent, a filler, a lubricant, and the like is mixed with the compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and compressed into a tablet by direct compression. In some embodiments, the sublingual tablet contains one or more binding agents / fillers / diluents such as lactose, mannitol, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), polyvinylpyrrolidone (PVP). In some embodiments, the sublingual tablet contains a lubricant, for example, magnesium stearate. Other pharmaceutically acceptable vehicles such as soluble excipients, dry binding agents, pH adjusters / buffers, surfactants, sweeteners, flavorings, and the like can also be used. A non-limiting example of a sublingual tablet formulation is a sublingual tablet formulation comprising the compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof), an organic acid agent such as citric acid (which can be optionally coated), lactose, mannitol, PVP, and magnesium stearate, and optionally one or more additional pharmaceutically acceptable vehicles set forth herein.

[0286] In some embodiments, the sublingual tablet can comprise a single layer, a double layer, or a triple layer. In some embodiments, a single layer sublingual tablet contains the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid). In some embodiments, the single layer sublingual tablet is effervescent, and is formulated with an “effervescent couple,” i.e., a combination of an organic acid agent and a source of carbon dioxide. In some embodiments, a double layer sublingual tablet contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid) in a first layer, and the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) in a second layer. The second layer can optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented, which in some cases can increase the stability of the active ingredient and optionally the shelf life of the composition, as compared to a situation in which the vehicles and active ingredient are contained in a single layer. In some embodiments, the double layer sublingual tablet is an effervescent sublingual tablet, whereby the first layer is effervescent, the first layer comprising the effervescent couple and optionally other pharmaceutically acceptable vehicles, and the second layer comprises the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, the second layer being non-effervescent or effervescent. For triple layer sublingual tablets, each of the layers can be different, or two of the layers, such as the upper and lower layers, can have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof). In some embodiments, the lower and upper layers can contain one or more vehicle components, such as a solubilizing agent, a stabilizing agent, etc. (e.g., an organic acid agent, such as citric acid). In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers can contain different vehicles or different amounts of the same vehicle. The core layer typically contains the active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As described above, such triple layer sublingual tablet configurations allow the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented. In some embodiments, the triple layer sublingual tablet is an effervescent sublingual tablet, whereby at least one, at least two, or all three of the layers are effervescent (formulated with an effervescent couple).In some embodiments, the lower layer and the upper layer are effervescent, comprising an organic acid agent (e.g., citric acid), a source of carbon dioxide, and, optionally, other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and, optionally, one or more pharmaceutically acceptable vehicles, which core layer is non-effervescent or effervescent.

[0287] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orally dispersible dosage form, such as a lyophilized ODT. In some embodiments, the lyophilized orally dispersible dosage form (e.g., lyophilized ODT) is produced from water produced by sublimation from a pre-freeze aqueous formulation of a drug containing a matrix-forming agent, as well as other vehicles, such as those set forth herein, e.g., one or more lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the orally dispersible dosage form comprises a two-component framework of a lyophilized matrix system that works together to ensure successful development of the 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 to the dosage form (binder). In some embodiments, the second component is a matrix support / disintegration enhancer, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), calcium diphosphate, and / or starch, which acts by binding the porous framework provided by the water-soluble polymer and accelerates disintegration of the orally dispersible dosage form. In some embodiments, the lyophilized orally dispersible dosage form (e.g., lyophilized ODT) comprises gelatin and mannitol. In some embodiments, the lyophilized orally dispersible dosage form (e.g., lyophilized ODT) comprises gelatin, mannitol, and one or more of a lyoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, and / or another pharmaceutically acceptable vehicle set forth herein, with particular mention of an organic acid agent (e.g., citric acid). Non-limiting examples of ODT formulations are OraSolv® orally dispersible tablets (available from Catalent). In some embodiments, the ODT formulation (e.g., Orally dispersible tablet) comprises one or more water-soluble polymers, such as gelatin, one or more matrix materials, a filler or diluent, such as mannitol, a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and, optionally, a lyoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, and / or another pharmaceutically acceptable vehicle set forth herein. In some embodiments, the ODT formulation (e.g., Orally dispersible tablet) comprises gelatin, mannitol, a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and citric acid and / or tartaric acid.

[0288] In some embodiments, the ODT can comprise a single layer, a double layer, or a triple layer. In some embodiments, a single layer ODT contains the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid). In some embodiments, the single layer ODT is effervescent, and is formulated with an “effervescent pair,” i.e., a combination of an organic acid agent and a source of carbon dioxide. In some embodiments, a double layer ODT contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid) in a first layer, and the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) in a second layer. The second layer can optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented, which in some cases can increase the stability of the active ingredient and optionally the shelf life of the composition, as compared to a situation in which the vehicles and active ingredient are contained in a single layer. In some embodiments, the double layer ODT is an effervescent ODT, whereby the first layer is effervescent, the first layer comprising the effervescent pair and optionally other pharmaceutically acceptable vehicles, and the second layer comprises the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, the second layer being non-effervescent or effervescent. For triple layer ODTs, each of the layers can be different, or two of the layers, such as the upper and lower layers, can have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof). In some embodiments, the lower and upper layers can contain one or more vehicle components, such as solubilizers, stabilizers, etc. (e.g., an organic acid agent, such as citric acid). In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers can contain different vehicles or different amounts of the same vehicle. The core layer typically contains the active ingredient, optionally with one or more pharmaceutically acceptable vehicles. Such triple layer ODT configurations, as described above, allow the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented. In some embodiments, the triple layer ODT is an effervescent ODT, whereby at least one, at least two, or all three of the layers are effervescent (formulated with an effervescent pair).In some embodiments, the lower layer and the upper layer are effervescent, comprising an organic acid agent (e.g., citric acid), a source of carbon dioxide, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, which is non-effervescent or effervescent.

[0289] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orally dispersible film (ODF) (or wafer). In some embodiments, the pharmaceutical composition is in the form of a lyophilized ODF protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the lyophilized ODF is produced from a pre-frozen aqueous formulation of a drug containing a matrix-forming agent, and other vehicles as set forth herein, e.g., one or more of a lyoprotectant, a preservative, an antioxidant, a stabilizing agent, a solubilizing agent, a flavoring agent, and / or another pharmaceutically acceptable vehicle as set forth herein. In some embodiments, the lyophilized ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of a lyophilized matrix system that works together to ensure successful development of a 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 to the film wafer (binder). In some embodiments, the second component is a matrix support / disintegration enhancer, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), dicalcium phosphate, and / or starch, which acts by binding the porous framework provided by the water-soluble polymer and accelerates disintegration of the wafer. In some embodiments, the lyophilized ODF comprises gelatin and mannitol. In some embodiments, the lyophilized ODF comprises gelatin, mannitol, and one or more of a lyoprotectant, a preservative, an antioxidant, a stabilizing agent, a solubilizing agent, a flavoring agent, and / or another pharmaceutically acceptable vehicle as set forth herein, with particular mention of an organic acid agent (e.g., citric acid).

[0290] In some embodiments, the ODF (or wafer) can comprise a single layer, a double layer, or a triple layer. In some embodiments, a single layer ODF (or wafer) contains an active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid). In some embodiments, a single layer ODF (or wafer) is effervescent and is formulated with an effervescent couple. In some embodiments, a double layer ODF (or wafer) contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid) in a first layer, and an active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) in a second layer. The second layer can optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented, which in some cases can increase the stability of the active ingredient and optionally increase the shelf life of the composition, as compared to a situation in which the vehicles and active ingredient are contained in a single layer. In some embodiments, a double layer ODF (or wafer) is an effervescent ODF (or wafer), whereby the first layer is effervescent, the first layer comprising an effervescent couple and optionally other pharmaceutically acceptable vehicles, and the second layer comprises an active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, the second layer being non-effervescent or effervescent. For a triple layer ODF (or wafer), each of the layers can be different, or two of the layers, such as the upper and lower layers, can have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing an active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof). In some embodiments, the lower and upper layers can contain one or more vehicle components, such as a solubilizing agent, a stabilizing agent, etc. (e.g., an organic acid agent, such as citric acid). In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers can contain different vehicles or different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. Such triple layer ODF (or wafer) configurations allow the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented, as described above. In some embodiments, a triple layer ODF (or wafer) is an effervescent ODF (or wafer), whereby at least one, at least two, or all three of the layers are effervescent (formulated with an effervescent couple).In some embodiments, the lower layer and the upper layer are effervescent, comprising an organic acid agent (e.g., citric acid), a source of carbon dioxide, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, which is non-effervescent or effervescent.

[0291] Examples of pharmaceutically acceptable lyoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose; anionic polymers such as sulfobutyl ether-beta-cyclodextrin (SBECD) and hyaluronic acid and hydroxylated cyclodextrins.

[0292] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohols.

[0293] Examples of pharmaceutically acceptable antioxidants, which can act to further enhance the stability of the compositions, include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteine or salts thereof (cysteine hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0294] Examples of pharmaceutically acceptable stabilizers include, but are not limited to: organic acid agents (e.g., citric acid), fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ether, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerol, ascorbic acid, polysorbate, arginine, cyclodextrins, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), modified celluloses (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0295] Examples of pharmaceutically acceptable solubilizing agents (or dissolution aids) include, but are not limited to: organic acid agents (e.g., citric acid, fumaric acid, DL-malic acid, tartaric acid, lactic acid, maleic acid, etc.), hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyethylene glycol 40 stearate, purified shellac, sodium dehydroacetate, L-ascorbyl stearate, L-asparagine acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethylcellulose, powdered agar, guar gum, succinic acid, povidone, cellulose phthalate, sodium dioctyl sulfosuccinate, zein, powdered skim milk, sorbitol trioleate, 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(4-sodium styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, lauroyl polyoxyl glycerides, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, methyl sodium sulfate, ethyl sodium sulfate, butyl sodium sulfate, octyl sodium sulfate, decyl sodium sulfate, myristyl sodium sulfate, cetyl sodium sulfate, and stearyl sodium sulfate. Of these, citric acid is preferred in some embodiments.

[0296] Flavoring agents include natural flavors extracted from plants such as fruits, as well as synthetic co-mixtures of compounds that produce a pleasing mouth feel perception or taste masking effect. Examples of flavoring agents include, but are not limited to: aspartame, saccharin (e.g., sodium, potassium, or calcium saccharin), cyclamate (e.g., sodium, potassium, or calcium salt), sucrose, acesulfame-K, thaumatin, neohesperidin dihydrochalcone, ammoniated glycyrrhizin, dextrose, maltodextrin, fructose, levulose, sucrose, dextrose, cornstarch, citrus aurantium, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, orange flavor, lemon, lime, and lemon-lime.

[0297] Cyclodextrins, such as a-cyclodextrin, b-cyclodextrin, g-cyclodextrin, methyl- b-cyclodextrin, hydroxyethyl b-cyclodextrin, hydroxypropyl-b-cyclodextrin, hydroxypropyl g-cyclodextrin, sulfated b-cyclodextrin, sulfated a-cyclodextrin, sulfobutyl ether b-cyclodextrin, or other solvated derivatives can also be advantageously used to enhance delivery of the compositions described herein.

[0298] Pharmaceutical compositions adapted for oral administration, e.g., capsules and tablets, including compressed tablets, can be formulated using various vehicles, such as those set forth herein. Examples of suitable vehicles can include, but are not limited to, binding agents, fillers, diluents, disintegrating agents, wetting agents, lubricating agents, glidants, anti-caking agents, coloring agents, dye migration inhibitors, sweetening agents, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, adjuvants, thickening agents, lubricants, granulating agents, lyophilization protectants, complexing agents, matrix forming agents, dispersing agents, performance modifiers, controlled release polymers, solvents, pH adjusting agents, and sources of carbon dioxide.

[0299] Binding agents or granulating agents impart cohesiveness to capsules or tablets to ensure that the dosage form remains intact and uniform even after compression. Suitable binding agents 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, dextrin, molasses, and lactose; natural and synthetic gums such as acacia (gum arabic), alginic acid, alginates, extracts of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose including silicified microcrystalline cellulose (SMCC) 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 including silicified microcrystalline cellulose (SMCC), powdered cellulose, dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, partially hydrolyzed starch (e.g., maltodextrin), and mixtures thereof. In some embodiments, the binding agent, granulating agent, or filler is present at about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, to about 99%, about 90%, about 80%, about 70%, about 60% by weight, or any range in between, based on the total weight of the pharmaceutical composition disclosed herein.

[0300] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, myo-inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and myo-inositol, when present in a sufficient amount, can impart a property to some compressed tablets that allows for disintegration in the mouth by mastication. Such compressed tablets can be used as chewable tablets.

[0301] Suitable disintegrants include, but are not limited to, agar-agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums such as guar gum and Veegum® magnesium aluminum silicate HV; citrus pulp; crosscarmcloses such as crosscarmclose sodium; polacrilin potassium; starches such as com starch, potato starch, tapioca starch, pregelatinized starch, and partially hydrolyzed 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. In some embodiments, the pharmaceutical compositions disclosed herein contain, for example, about 0.5%, about 1%, about 3%, about 5%, about 10%, about 15%, to about 50%, about 40%, about 30%, about 20%, by weight of the total weight of the pharmaceutical composition, of a disintegrant, for example, about 1% to about 5%, by weight, of a disintegrant.

[0302] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; ethylene glycol, such as glyceryl behenate and polyethylene glycol (PEG) (e.g., PEG 4,000, PEG 6,000, PEG 8,000, etc., where the number refers to the approximate average molecular weight of the PEG); stearic acid; sodium lauryl sulfate; sodium stearyl fumarate; talc; hydrogenated vegetable oil, 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 Syloid® 244-F (available from W. R. Grace Co., Baltimore, Md.); and 200 (W. R. Grace Co., Baltimore, Md.) and (Cabot Co. of Boston, Mass.); and mixtures thereof. In some embodiments, the pharmaceutical compositions disclosed herein contain, for example, about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 20 wt%, about 15 wt%, about 10 wt%, about 7 wt% of a lubricant, for example, about 0.1 wt% to about 5 wt% of a lubricant, based on the total weight of the pharmaceutical composition.

[0303] Suitable glidants include, but are not limited to, colloidal silicon dioxide, (Cabot Corporation, Boston, Massachusetts) and asbestos-free talc.

[0304] Suitable anti-caking agents include, but are not limited to, silicon dioxide.

[0305] Colorants include any approved, certified water-soluble FD&C dye and water-insoluble FD&C dye suspended on hydrated alumina, as well as color ribbons and mixtures thereof. Color ribbons are made by adsorbing water-soluble dyes onto a combination of heavy metal-oxidized water, thereby producing an insoluble form of the dye.

[0306] Sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweeteners such as saccharin and aspartame.

[0307] Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, gum tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate ( 20), polyoxyethylene sorbitan monooleate 80 ( 80) and triethanolamine oleate.

[0308] Suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, gum tragacanth, magnesium aluminum silicate, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0309] Preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol.

[0310] Wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0311] Solvents include, but are not limited to, glycerol, sorbitol, ethanol, and syrup. Examples of non-aqueous liquids used in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0312] Examples of pH adjusting agents include acids (including organic acid agents) such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases of salts of organic acid agents, for example, sodium acetate, potassium acetate, sodium citrate (e.g., monosodium citrate, disodium citrate, and / or trisodium citrate), potassium citrate (e.g., monopotassium citrate, dipotassium citrate, and / or tripotassium citrate), sodium tartrate (e.g., monosodium tartrate and / or disodium tartrate), potassium tartrate (e.g., monopotassium tartrate and / or dipotassium tartrate), potassium sodium tartrate, ammonium citrate (e.g., monobasic ammonium citrate, dibasic ammonium citrate, and / or tribasic ammonium citrate), ammonium tartrate (e.g., monobasic ammonium tartrate and / or dibasic ammonium tartrate), sodium fumarate (e.g., monosodium fumarate and / or disodium fumarate), potassium fumarate (e.g., monopotassium fumarate and / or dipotassium fumarate), sodium maleate (e.g., monosodium maleate and / or disodium maleate), potassium maleate (e.g., monopotassium maleate and / or dipotassium maleate), sodium lactate, potassium lactate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, as well as buffers that generally comprise a mixture of an acid and a salt of the acid.

[0313] The source of carbon dioxide can include, but is not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, and sesqui-carbonate salts. The source of carbon dioxide can be used individually or in combination.

[0314] As described above, a preferred dosage form is one that is formulated with an organic acid agent that can act as a stabilizing agent and / or a solubilizing agent in the disclosed pharmaceutical compositions. The organic acid agent can be any of the organic acid agents set forth herein, with particular mention of citric acid and / or tartaric acid.

[0315] In some embodiments, the dosage form is a tablet. In some embodiments, the tablet (e.g., a tablet including a compressed tablet generally) can comprise a single layer, a bilayer, or a trilayer. In some embodiments, a single layer tablet contains the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid). In some embodiments, a single layer tablet is effervescent and is formulated with an effervescent couple. In some embodiments, a bilayer tablet contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid agent, such as citric acid) in a first layer, and the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) in a second layer. The second layer can optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented, which in some cases can increase the stability of the active ingredient and optionally the shelf life of the composition, as compared to a situation in which the vehicles and active ingredient are contained in a single layer. In some embodiments, a bilayer tablet is an effervescent tablet, whereby the first layer is effervescent, the first layer comprising an effervescent couple and optionally other pharmaceutically acceptable vehicles, and the second layer comprising the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, the second layer being non-effervescent or effervescent. For sublingual tablets, each of the layers can be different, or two of the layers, such as the upper and lower layers, can have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active ingredient (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof). In some embodiments, the lower and upper layers can contain one or more vehicle components, such as a solubilizer, a stabilizer, etc. (e.g., an organic acid agent, such as citric acid). In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers can contain different vehicles or different amounts of the same vehicle. The core layer typically contains the active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As described above, such a trilayer tablet configuration allows the active ingredient to be stored separately from all or some of the pharmaceutically acceptable vehicles, such that contact between the active ingredient and those vehicles is minimized or completely prevented. In some embodiments, a trilayer tablet is an effervescent tablet, whereby at least one, at least two, or all three of the layers are effervescent (formulated with an effervescent couple).In some embodiments, the lower layer and the upper layer are effervescent, comprising an organic acid agent (e.g., citric acid), a source of carbon dioxide, and optionally other pharmaceutically acceptable vehicles, and the core layer comprises an active ingredient (e.g., a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and optionally one or more pharmaceutically acceptable vehicles, which is non-effervescent or effervescent.

[0316] It is understood that many vehicles (carriers, excipients, etc.) can serve several functions, even within the same formulation. It is specifically mentioned that pharmaceutical compositions herein containing an organic acid agent, such as citric acid, can serve multiple roles, such as a stabilizer, e.g., to stabilize a bryaclinopside compound of the disclosure in free base or salt form; as a solubilizer, to provide rapid dissolution of the active for rapid onset, etc., particularly dosage forms adapted for rapid onset and shorter duration of drug action, such as orally dispersible dosage forms (e.g., ODTs and ODFs), as a flavoring agent, a pH adjusting agent, and / or an antioxidant.

[0317] Tablet dosage forms can be prepared from active ingredients in powdered, crystalline, or granular form, alone or in combination with one or more vehicles (e.g., carriers or excipients) described herein, including binding agents, disintegrants, controlled release polymers, pH adjusting agents, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

[0318] The pharmaceutical compositions herein can be in the form of compressed tablets, tablet triturates, chewable lozenges, fast dissolve tablets, multiple compressed tablets, or any of the above in a coated form such as an enteric coated tablet, a sugar coated or an film coated tablet. Coated tablets are tablets covered by one or more layers of a pharmaceutically acceptable vehicle or a mixture of vehicles such as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers, polyols, waxes, organic bases, coloring substances and flavoring substances authorized by the appropriate national or regional regulatory agency, and the like. Such coating materials typically do not contain any active ingredient, e.g., any of the compounds described herein (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof). Tablets can be coated for a variety of reasons, such as to protect the active ingredient from burst release from the matrix, air, moisture, or light, to mask unpleasant tastes and odors, or to improve appearance. The substances used for coating can be applied in the form of a solution or suspension. Enteric coated tablets are compressed tablets that are coated with a substance that is resistant to gastric acids but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the gastric acid environment. Enteric coating agents include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial to cover unpleasant tastes or odors and to prevent oxidation of the tablet. Film coated tablets are compressed tablets that are covered by a thin layer or film or water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets that are prepared by more than one compression cycle, including layered tablets and compressed coated or dry coated tablets.

[0319] In some embodiments, the pharmaceutical composition (e.g., a tablet composition formulated for oral administration, such as a monolayer tablet composition) comprises any of the compounds described herein (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and a polymer.

[0320] In some embodiments, the tablet composition is a modified release tablet suitable for sustained release and preferably maximum sustained release. In some embodiments, any of the compounds described herein (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) has a release period in the formulation of the present disclosure of 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.

[0321] In some embodiments, the tablet composition is suitable for tamper resistance. In some embodiments, the tablet composition comprises, for example, polyethylene oxide (PEO) in combination with HPMC, having a MW of about 2,000 to about 7,000 KDa. In some embodiments, the tablet composition can further comprise polyethylene glycol (PEG), for example, PEG 8,000. In some embodiments, the tablet composition can further comprise a polymer carrying one or more negatively charged groups, for example, polyacrylic acid. In some embodiments, the tablet composition comprising PEO is further subjected to heating / annealing, for example, extrusion conditions.

[0322] In some embodiments, the pharmaceutical composition comprises a combination of: (i) a water insoluble, neutral charge, non-ionic matrix; (ii) a polymer carrying one or more negatively charged groups; and (iii) any of the compounds disclosed herein (e.g., a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof). Other pharmaceutical vehicles, such as organic acid agents, lubricants, and the like, can also optionally be included therein.

[0323] In some embodiments, the water insoluble, neutral charge, non-ionic matrix is selected from a cellulose-based polymer, such as a microcrystalline cellulose polymer or HPMC, alone or enhanced by mixing with a component selected from the group consisting of: starch; wax; neutral gum; polymethacrylate; PVA; PVA / PVP blend; silicon dioxide and mixtures thereof. In some embodiments, the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the cellulose-based polymer is a microcrystalline cellulose polymer, such as siliconized microcrystalline cellulose (SMCC). In some embodiments, the pharmaceutical composition (e.g., a tablet or capsule) comprises about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, or any range therebetween, of the water insoluble, neutral charge, non-ionic matrix, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a microcrystalline cellulose polymer, such as siliconized microcrystalline cellulose (SMCC), for example, in an amount of about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, or any range therebetween, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical comprises a combination of HPMC and starch.

[0324] 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, salts thereof, and mixtures thereof. In some embodiments, the anionic gum is selected from the group consisting of naturally occurring materials and semi-synthetic materials. In some embodiments, the naturally occurring material is selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan gum, locust bean gum, gum arabic, gum karaya, guar gum, and tragacanth gum. In some embodiments, the semi-synthetic material is selected from the group consisting of carboxymethyl-chitin and cellulose gum (sodium carboxymethylcellulose). In some embodiments, the pharmaceutical composition comprises about 0.5 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 5.5 wt%, 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, or any range therebetween, of the polymer carrying one or more negatively charged groups, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises cellulose gum (sodium carboxymethylcellulose), for example, about 0.5 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 5.5 wt%, or any range therebetween, based on the total weight of the pharmaceutical composition. In some embodiments, the drug comprises a combination of HPMC and starch.

[0325] Further, without wishing to be bound by theory, in some embodiments, the presence of one or more negatively charged groups, e.g., acidic moieties, as those in the acidic polymers described herein, surprisingly provides for the significant retention of any of the compounds described herein, e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in the matrix. In some embodiments, this negative charge can be generated in situ, e.g., based on the pKa and proton release under certain pH conditions or through electrostatic interactions / production of negative charges. It is further noted that the acidic polymer can be a salt of the corresponding weak acid, which would be the relevant protonated acid in the stomach; which would neutralize the charge and can reduce the interaction of any of the compounds described herein, e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, with the matrix, without wishing to be bound by theory. Additionally, the release matrix can further be envisioned by other inactive pharmaceutical ingredients used to help prepare the appropriate solid dosage form, such as fillers, disintegrants, flow improvers, lubricants, colorants, and taste-masking agents.

[0326] Disclosed herein are pharmaceutical compositions in a modified release dosage form comprising a compound as disclosed herein, e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and one or more controlled release mediators as described herein. Suitable modified release control mediators 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 compositions can further comprise non-controlled release mediators.

[0327] In some embodiments, oral pharmaceutical compositions for low-dose maintenance therapy can be constructed using the compounds described herein, taking advantage of their ability to bind to anionic polymers.

[0328] Further disclosed herein are pharmaceutical compositions in an enteric coated dosage form comprising a compound as disclosed herein, e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and one or more controlled release mediators for use in an enteric coated dosage form. The pharmaceutical compositions can further comprise non-controlled release mediators.

[0329] Further disclosed herein are pharmaceutical compositions in effervescent dosage forms comprising a compound as disclosed herein (e.g., a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and one or more pharmaceutically acceptable vehicles, which can be controlled release vehicles and / or non-controlled release vehicles. Effervescent means that the dosage form forms gas upon mixing with a liquid, including water, juice, saliva, and the like. Generally, the effervescent dosage forms of the present disclosure comprise an organic acid agent and a carbon dioxide source, referred to herein as an "effervescent pair." Such effervescent dosage forms effervesce (form gas) through a chemical reaction between the organic acid agent and the carbon dioxide source, which occurs upon exposure to an aqueous environment, such as when placed in water, juice, or other potable fluid, or from an aqueous environment in the mouth, such as saliva in the mouth. Specifically, the reaction between the organic acid agent and the carbon dioxide source produces carbon dioxide gas upon contact with an aqueous medium, such as water, juice, or saliva. While the use of disintegrants is optional, effervescent dosage forms do not require disintegrants, as the generation of gas in situ facilitates the disintegration process.

[0330] For clarity, an "effervescent pair" refers to at least one organic acid agent and at least one carbon dioxide source included in a dosage form, regardless of assembly, e.g., the organic acid agent and the carbon dioxide source can be mixed (as a powder), layered on top of each other, agglomerated or otherwise "bound" together in granular form, or separated from each other, such as in separate layers within the dosage form. Further, unless otherwise indicated, the term "pair" in this context is not intended to be limited to only an organic acid agent and a carbon dioxide source, and is open to other materials; for example, an effervescent agglomerate / particle made from putting an organic acid agent and a carbon dioxide source together (or "bound") can include other vehicles, including binding agents ("binders"), and the effervescent agglomerate / particle can still be referred to as an effervescent pair.

[0331] In some embodiments, the carbon dioxide source is sodium bicarbonate. In some embodiments, the carbon dioxide source is sodium carbonate. In some embodiments, the carbon dioxide source is potassium carbonate. In some embodiments, the carbon dioxide source is potassium bicarbonate. However, in addition to or instead of carbon dioxide sources, it is also contemplated to use reactants in the disclosed effervescent dosage forms that form oxygen or other gases other than carbon dioxide and that are safe for human consumption. While not wishing to be bound by theory, it is believed that effervescence can help rapidly break down the dosage form, and in some administration routes, such as intraoral routes, can help reduce grittiness by providing an effervescent, dispersed sensory experience.

[0332] In some embodiments, the effervescent dosage form will be reconstituted in a drinkable fluid such as water or juice, thereby forming an oral liquid dosage form (e.g., a solution) prior to consumption. In some embodiments, the effervescent dosage form will be placed in the oral cavity, where contact with the aqueous environment (saliva) causes disintegration / dissolution of the dosage form and effervescence. Here, the contents of the effervescent dosage form can be converted to a liquid or semi-solid dosage form, such as a solution, syrup, or paste upon mixing with saliva, and subsequently swallowed. Alternatively, the effervescent dosage form can be an intraoral dosage form, such as a buccal, lingual, or sublingual dosage form, whereby placement in the aqueous environment (saliva) of the oral cavity causes disintegration / dissolution of the dosage form and effervescence, and pre-gastric absorption of the contents through the oral mucosa. Such pre-gastric absorption can provide increased bioavailability and faster onset compared to oral administration through the gastrointestinal tract. 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 disclosure) are absorbed through the sublingual mucosa that enters the venous circulation. In some embodiments, the effervescent dosage form is a buccal dosage form that disintegrates / dissolves in the buccal cavity, whereby the contents (e.g., a compound of the disclosure) are absorbed through the inner layer of the oral mucosa that enters the venous circulation in the mouth. Effervescent dosage forms can be advantageous for treating pediatric / adolescent patients or patients who generally have difficulty swallowing traditional dosage forms such as conventional tablets or capsules, as the effervescent dosage form can be reconstituted into a liquid or semi-solid dosage form that is easily swallowed or taken intraorally.

[0333] When adapted for intraoral administration, it can be beneficial to formulate the effervescent dosage form with a bioadhesive agent in addition to the effervescent pair. A "bioadhesive agent" is a substance that promotes adhesion or sticking to a biological surface such as a mucosa. For example, a bioadhesive agent is capable of adhering to a biological surface by itself when placed in contact with the surface (e.g., a mucosa), so as to enable the compositions of the disclosure to adhere to the surface, which promotes more efficient transfer of the contents from the dosage form to the biological surface. Various polymers known in the art can be used as bioadhesive agents, such as polymeric substances, preferably having an average (weight average) molecular weight higher than 5,000 g / mol. It is preferred that such polymeric materials are capable of swelling 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 bioadhesive agents include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methylcellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose, modified cellulose gum, and sodium carboxymethylcellulose (NaCMC); starch derivatives, such as medium cross-linked starch, modified starch, and sodium carboxymethyl starch; acrylic acid polymers, such as carbomer and its derivatives (polycarbophil, polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); and cross-linked carboxymethylcellulose (e.g., sodium croscarmellose). Such polymers can be cross-linked. Combinations of two or more bioadhesives can also be used.

[0334] The effervescent pair can be coated with a pharmaceutically acceptable vehicle, e.g., with a binding agent, a protective coating, such as a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjusting agent, to prevent premature reaction, e.g., with air, moisture, and / or other ingredients included in the pharmaceutical composition. Each component of the effervescent pair, e.g., the organic acid agent and / or the carbon dioxide source, can also be individually coated with a pharmaceutically acceptable vehicle, e.g., with a binding agent, a protective coating, such as a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjusting agent, to prevent premature reaction, e.g., with air, moisture, and / or other ingredients included in the 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.

[0335] The effervescent dosage form 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, melt granulation, melt granulation, vacuum granulation, and fluid bed spray granulation, any of which can be optionally followed by compression / tabletting.

[0336] The pharmaceutical compositions disclosed herein can be formulated as non-effervescent or effervescent microparticles and powders. The non-effervescent or effervescent microparticles and powders can be reconstituted into liquid dosage forms, or alternatively, compressed to form tablet dosage forms, which are non-effervescent or effervescent, respectively. Pharmaceutically acceptable vehicles for use in non-effervescent or effervescent microparticles or powders can include, but are not limited to, binding agents, granulating agents, fillers, diluents, sweeteners, wetting agents, stabilizers, solubilizers, anti-caking agents, pH adjusting agents, or any other pharmaceutical vehicle described herein. In some embodiments, the pharmaceutically acceptable vehicle comprises an organic acid agent, such as glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and / or maleic acid.

[0337] Pharmaceutically acceptable vehicles for use in effervescent microparticles or powders include effervescent pairs, i.e., an organic acid agent and a source of carbon dioxide. Effervescent powders can be produced by blending or mixing an organic acid agent and a source of carbon dioxide (effervescent pair), and optionally any other desired pharmaceutically acceptable vehicle. Effervescent microparticles can be produced by physically adhering or “binding” the effervescent pair (organic acid agent and source of carbon dioxide) together using an edible or pharmaceutically acceptable binding agent such as polyvinylpyrrolidone, polyvinyl alcohol, L-leucine, polyethylene glycol, gum arabic, and the like, including combinations thereof. These types of microparticles are made by a process commonly referred to as “wet granulation.” A granulation solvent, such as ethanol and / or isopropyl alcohol, is often used to aid this type of granulation process. Because the effervescent pair is physically bound together in the microparticle, the gas generation reaction is typically quite vigorous, resulting in a fast dissolution time. Another type of “wet granulation” product specific to effervescent products is referred to as “fusion” type microparticles. These microparticles are formed by reacting the organic acid agent and the source of carbon dioxide with a small amount of water (or sometimes a hydroalcoholic granulation solvent, such as various commercial grades of ethanol or isopropyl alcohol) in a highly controlled manner. Because the effervescent reaction produces carbon dioxide, fusion microparticles tend to be quite porous, which decreases the density of the fusion particles as well as the dissolution time of the fusion particles. Thus, for the preparation of an orally dispersible dosage form (ODx) or other dosage form seeking fast dissolution / disintegration properties, it can be desirable to produce effervescent microparticles by a wet granulation or fusion type method. Effervescent tablet dosage forms prepared by tableting of effervescent microparticles or powders are also included in the present disclosure.

[0338] Also disclosed are pharmaceutical compositions in dosage form having an immediate release component and at least one delayed release component and capable of intermittent release of a compound in the form of at least two consecutive pulses spaced apart over a period of from about 0.1 up to about 24 hours (e.g., about 0.1, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 10, 22, or 24 hours). The pharmaceutical compositions comprise a compound as disclosed herein (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) and one or more controlled and / or non-controlled release vehicles, such as those excipients or carriers suitable for a disruptable semipermeable membrane and as swellable substances.

[0339] Also disclosed herein are pharmaceutical compositions in dosage form for oral administration to a subject, comprising a compound as disclosed herein (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), and one or more pharmaceutically acceptable vehicles (e.g., excipients or carriers) enclosed in an intermediate reactive layer comprising a gastric fluid resistant polymeric layer material neutralized with a base moiety and having a cation exchange capacity and a gastric fluid resistant outer layer.

[0340] The dosage form can be an immediate release (IR) dosage form, examples of which include, but are not limited to, an immediate release (IR) tablet or an immediate release (IR) capsule. In addition to the API, dosage forms suitable for immediate release can include one or more pharmaceutically acceptable vehicles that readily disperse, dissolve, or otherwise break down in the stomach environment so as to not delay or prolong dissolution / absorption of the API. Examples of pharmaceutically acceptable vehicles for immediate release dosage forms include, but are not limited to, one or more of an adjuvant, a stabilizer, a solubilizer, a thickening agent, a lubricant, a binding agent, a granulating agent, a filler, a diluent, a disintegrant, a wetting agent, a glidant, an anti-caking agent, a coloring agent, a sweetener, a dye migration inhibitor, a preservative, an antioxidant, a lyophilization protective agent, a complexing agent, a flavoring agent, a matrix forming agent, a dispersing agent, and a performance modifier. In some embodiments, the immediate release (IR) dosage form is an immediate release (IR) tablet or capsule comprising one or more of microcrystalline cellulose including siliconized microcrystalline cellulose (SMCC), sodium carboxymethylcellulose, magnesium stearate, mannitol, crospovidone, citric acid, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form comprises microcrystalline cellulose including siliconized microcrystalline cellulose (SMCC), sodium carboxymethylcellulose, and magnesium stearate. In some embodiments, the immediate release (IR) dosage form comprises siliconized microcrystalline cellulose (SMCC), sodium carboxymethylcellulose, anhydrous citric acid, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form such as a powder-filled capsule comprises a naked head capsule, a push-through capsule, or a push-fit capsule. In some embodiments, the immediate release (IR) dosage form comprises mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form comprises an organic acid agent, such as citric acid. 10 In some embodiments, the immediate release (IR) dosage form comprises mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the immediate release (IR) dosage form comprises an organic acid agent, such as citric acid.

[0341] The pharmaceutical compositions disclosed herein can be disclosed as soft or hard capsules, which can be prepared from gelatin, methylcellulose, hydroxypropyl methylcellulose (HPMC), starch, or calcium alginate. Hard (e.g., gelatin, HPMC, etc.) capsules, also known as dry-filled capsules (DFC) or powder-in-capsule (PIC), consist of two parts, one part slides over the other, thus completely enclosing the active ingredient and any pharmaceutically acceptable vehicles. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin or HPMC shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells can contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those preservatives as described herein, including methyl paraben and propyl paraben and sorbic acid. The liquid, semi-solid, and solid dosage forms disclosed herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules can also be coated as known to those skilled in the art in order to modify or maintain the dissolution of the active ingredient.

[0342] In some embodiments, the pharmaceutical composition is in the form of an immediate release capsule for oral administration and can further comprise cellulose, ferric oxide, lactose, magnesium stearate, and sodium starch glycolate.

[0343] In some embodiments, the pharmaceutical composition is in the form of a delayed release capsule for oral administration and can further comprise cellulose, ethyl cellulose, gelatin, hypromellose, ferric oxide, and titanium dioxide.

[0344] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed release tablet for oral administration and can further comprise carnauba wax, crospovidone, diacetyl glycerol monolaurate, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow iron oxide.

[0345] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed release tablet for oral administration and can further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, ferric oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0346] Any of the pharmaceutical compositions disclosed herein formulated with an organic acid agent can contain an uncoated organic acid agent, or alternatively, can contain an organic acid agent coated with a pharmaceutically acceptable vehicle ("coated organic acid agent"). Various pharmaceutically acceptable vehicles can be used as coating materials to alter the properties of the organic acid agent and / or prevent undesirable or premature reactions, e.g., with air, moisture, and / or other ingredients contained in the pharmaceutical composition, without losing the desired function of the organic acid agent. The coated organic acid agent can comprise an organic acid agent core and a film coating, such as a film powder coating or a film polymer coating. The coated organic acid agent can be in the form of a core-shell material comprising an organic acid agent core and a protective coating, i.e., shell, surrounding the core. Any of the organic acid agents disclosed herein can be coated, including but not limited to glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and maleic acid.

[0347] In some embodiments, the coated organic acid agent contains at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 1.5 wt%, at least 2 wt%, at least 2.5 wt%, at least 3 wt%, at least 3.5 wt%, and at most 15 wt%, at most 10 wt%, at most 9 wt%, at most 8 wt%, at most 7 wt%, at most 6 wt%, at most 5 wt%, at most 4 wt% by weight, or any range therebetween, based on the total weight of the coated organic acid agent; when the coated organic acid agent is formulated with essentially only the organic acid agent and the coating, the balance is the organic acid agent.

[0348] In some embodiments, the organic acid agent is coated with a water-soluble polymer, a binder, a granulating agent, a filler, etc. A non-limiting example of this type of coated organic acid agent is Citric Acid DC (available from Jungbunzlauer), which is a directly compressible microparticle powder of citric acid coated with a thin layer of maltodextrin.

[0349] In certain embodiments, the organic acid is coated with an anti-caking agent. The organic acid of this type of coating shows a high ability to absorb moisture stimulation. The non-limiting example of an organic acid of this type of coating is Citric Acid S40 (available from Jungbenzlauer), which is a very fine (powdery) particulate powder of citric acid coated with silicon dioxide.

[0350] In some embodiments, the organic acid agent is coated with a pH adjusting agent. In some embodiments, the organic acid agent is coated with a salt of the organic acid agent (i.e., a conjugate base salt of the organic acid agent). The salt of the organic acid agent can be an alkali metal salt of the organic acid agent, an alkaline earth salt of the organic acid agent, an ammonium salt of the organic acid agent, or a mixture thereof, including mixed salts of the organic acid agent (e.g., a sodium and potassium mixed salt). The salt of the organic acid agent can be mono-, di-, tri-, etc. The salt of the organic acid agent can be formed from one type of cation (e.g., sodium cations) or two or more different cations (e.g., a mixed salt with both sodium and potassium cations) in the case of a polybasic (di-, tri-, etc.) salt. Examples of salts of the organic acid agent that can be used as coating materials include, but are not limited to, sodium citrate (e.g., monosodium citrate, disodium citrate, and / or trisodium citrate), potassium citrate (e.g., monopotassium citrate, dipotassium citrate, and / or tripotassium citrate), sodium tartrate (e.g., monosodium tartrate and / or disodium tartrate), potassium tartrate (e.g., monopotassium tartrate and / or dipotassium tartrate), potassium sodium tartrate, ammonium citrate (e.g., monomethyl citrate, dimethyl citrate, and / or trimethyl citrate), ammonium tartrate (e.g., monomethyl tartrate and / or dimethyl tartrate), sodium fumarate (e.g., monosodium fumarate and / or disodium fumarate), potassium fumarate (e.g., monopotassium fumarate and / or dipotassium fumarate), sodium maleate (e.g., monosodium maleate and / or disodium maleate), potassium maleate (e.g., monopotassium maleate and / or dipotassium maleate), sodium lactate, and potassium lactate, including mixtures and / or hydrates thereof. The organic acid agent coated with a salt of the organic acid agent can be in the form of a core-shell material. The organic acid agent (core) and the salt of the organic acid agent (shell) can belong to the same conjugate acid-base pair. For example, the organic acid agent (core) can be citric acid, and the salt of the organic acid agent (shell) can be an alkali metal salt, an alkaline earth salt, and / or an ammonium salt of citric acid. In another example, the organic acid agent (core) can be tartaric acid, and the salt of the organic acid agent (shell) can be an alkali metal salt, an alkaline earth salt, and / or an ammonium salt of tartaric acid. In yet another example, the organic acid agent (core) can be fumaric acid, and the salt of the organic acid agent (shell) can be an alkali metal salt, an alkaline earth salt, and / or an ammonium salt of fumaric acid. Alternatively, the organic acid agent (core) and the salt of the organic acid agent (shell) can belong to different conjugate acid-base pairs. For example, the organic acid agent (core) can be citric acid, and the salt of the organic acid agent (shell) can be an alkali metal salt, an alkaline earth salt, and / or an ammonium salt of tartaric acid. In another example, the organic acid agent (core) can be citric acid, and the salt of the organic acid agent (shell) can be an alkali metal salt, an alkaline earth salt, and / or an ammonium salt of fumaric acid. In yet another example, the organic acid agent (core) can be tartaric acid, and the salt of the organic acid agent (shell) can be an alkali metal salt, an alkaline earth salt, and / or an ammonium salt of citric acid. Non-limiting examples of organic acid agents coated with a salt of the organic acid agent are N (available from Nippon Shokubai Co., Ltd.), the N is a microparticulate powder made from citric acid as the core material and a layer of citric acid monosodium (1.5-3.5%) as the shell.

[0351] Coated organic acid agents can also be used in the disclosed effervescent dosage forms. Here, the effervescent pair can be formed from any of the coated organic acid agents disclosed herein and a source of carbon dioxide. In contrast to uncoated organic acid agents, the use of coated organic acid agents in the effervescent pair can advantageously provide improved storage stability to the effervescent dosage form without significantly sacrificing reactivity when placed in an aqueous environment, such as in water, juice, or other potable fluids, or from an aqueous environment in the mouth, such as saliva in the mouth. Non-limiting examples of effervescent pairs formulated with coated organic acid agents are EP (available from Noveon Zeon Corp.), the EP is an agglomerated microparticle created by bringing together N (a citric acid core coated with a layer of citric acid monosodium, 1.5-3.5%, as the shell) and sodium bicarbonate.

[0352] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I-3) as a free base in crystalline form and a coated organic acid agent, such as coated citric acid, coated tartaric acid, coated fumaric acid, and the like. For effervescent dosage forms, a source of carbon dioxide (e.g., sodium bicarbonate) is also included in the coated organic acid agent. In some embodiments, the compound is a crystalline form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3), as determined by X-ray powder diffraction. In some embodiments, I-3 is a crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 7.582°, 8.395°, 9.647°, 10.444°, 11.319°, 12.614°, 13.372°, 14.222°, 15.157°, 16.524°, 16.787°, 17.693°, 19.468°, 19.699°, 20.901°, 21.132°, 21.859°, 22.547°, 23.699°, 24.630°, 25.034°, 25.264°, 26.867°, 27.399°, 27.929°, 28.219°, 28.871°, 29.430°, 30.120°, 30.675°, 31.373°, 32.365°, 33.880°, 34.418°, 34.792°, 35.884°, 36.254°, 37.156°, 38.200°, and 38.417°, as determined by XRPD using a Cu Ka radiation source, e.g., as shown in WO 2022195011 and / or WO 2023078604.In some embodiments, I-3 is a crystalline solid form (Pattern 2) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2Q ± 0.2°) selected from 8.124°, 8.357°, 10.059°, 12.630°, 13.420°, 13.743°, 14.053°, 15.220°, 16.272°, 16.763°, 16.954°, 17.328°, 17.662°, 18.062°, 18.742°, 19.413°, 19.658°, 20.172°, 20.836°, 21.267°, 21.833°, 22.213°, 22.504°, 23.334°, 23.701°, 24.385°, 25.431°, 25.721°, 26.049°, 27.291°, 28.368°, 30.349°, 30.656°, 31.337°, 31.538°, 32.091°, 35.870°, 38.514°, and 41.361°, as determined by XRPD using a Cu Ka radiation source, WO2022195011 and / or WO2023078604.

[0353] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I-3) as a free base in an amorphous form and a coated organic acid agent, such as a coated citric acid, a coated tartaric acid, a coated fumaric acid, and the like. For effervescent dosage forms, a source of carbon dioxide (e.g., sodium bicarbonate) is also included in the coated organic acid agent. In some embodiments, is an amorphous form of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3), as determined by X-ray powder diffraction.

[0354] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of Formula (I-3) in crystalline form and a coated organic acid agent, such as coated citric acid, coated tartaric acid, coated fumaric acid, and the like. For effervescent dosage forms, a source of carbon dioxide (e.g., sodium bicarbonate) is also included in the coated organic acid agent. In some embodiments, the pharmaceutically acceptable salt is the besylate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a). In some embodiments, the salt I-3a is in a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 19.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988°, as determined by XRPD using a CuKa radiation source, e.g., as shown in WO2022195011 and / or WO2023078604 (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the benzoic acid salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j). In some embodiments, the salt I-3j is in a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.831°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597°, as determined by XRPD using a CuKa radiation source, as shown in WO2022195011 and / or WO2023078604 (Pattern 1).In some embodiments, the pharmaceutically acceptable salt is a tartrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3b). In some embodiments, salt I-3b is in a crystalline solid form of Pattern 1, characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604. In some embodiments, salt I-3b is in a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2q ± 0.2°) selected from 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.597°, 29.035°, 29.257°, 29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049°, as determined by XRPD using a CuKa radiation source, for example, as shown in WO2022195011 and / or WO2023078604 (Pattern 2). In some embodiments, the pharmaceutically acceptable salt is a hemifumarate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3c). In some embodiments, salt I-3c is in a crystalline solid form of Pattern 1, characterized by, for example, an X-ray powder diffraction pattern as shown in WO2022195011 and / or WO2023078604.In some embodiments, the salt I-3c 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 (2q ± 0.2°) selected from 9.713°, 11.209°, 11.605°, 12.338°, 12.852°, 13.718°, 15.117°, 16.066°, 16.627°, 19.026°, 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999°, as determined by XRPD using a CuKa radiation source, as shown in WO2022195011 and / or WO2023078604 (Pattern 2).

[0355] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of Formula (I-3) in an amorphous form and a coated organic acid agent, such as a coated citric acid, a coated tartaric acid, a coated fumaric acid, and the like. For effervescent dosage forms, a source of carbon dioxide (e.g., sodium bicarbonate) is also included in the coated organic acid agent. In some embodiments, the pharmaceutically acceptable salt is a citrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3e). In some embodiments, the salt I-3e is in the form of an amorphous solid, as characterized by X-ray powder diffraction (XRPD).

[0356] When the pharmaceutical composition is formulated with a pharmaceutically acceptable salt of the compound of Formula (I-3), the acid used to form the pharmaceutically acceptable salt of the compound of Formula (I-3) and the organic acid agent (vehicle) can be the same. For example, the pharmaceutical composition can comprise a tartrate salt of the compound of Formula (I-3) (e.g., I-3b), and tartaric acid as the organic acid agent (vehicle). In another example, the pharmaceutical composition can comprise a citrate salt of the compound of Formula (I-3) (e.g., I-3e), and citric acid as the organic acid agent (vehicle).

[0357] When a pharmaceutical composition is formulated with a pharmaceutically acceptable salt of a compound of Formula (I-3), the acid and organic acid agent (vehicle) used to form the pharmaceutically acceptable salt of the compound of Formula (I-3) can be different. For example, a pharmaceutical composition can include a besylate salt of a compound of Formula (I-3) (e.g., I-3a), and citric acid and / or tartaric acid, etc., as the organic acid agent (vehicle). In another example, a pharmaceutical composition can include a benzoate salt of a compound of Formula (I-3) (e.g., I-3j), and citric acid and / or tartaric acid as the organic acid agent (vehicle).

[0358] The pharmaceutical compositions disclosed herein can be disclosed in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.

[0359] In some embodiments, an oral liquid dosage form is prepared by reconstituting a solid dosage form disclosed herein (e.g., an effervescent dosage form) into a pharmaceutically acceptable aqueous medium, such as water, juice, or other potable fluid, prior to use.

[0360] In some embodiments, an oral liquid dosage form is prepared by reconstituting a solid dosage form comprising a compound of Formula (I-3) (e.g., I-3) as a free base in a crystalline form into a pharmaceutically acceptable aqueous medium. The solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent. An effervescent solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent and a source of carbon dioxide.

[0361] In some embodiments, an oral liquid dosage form is prepared by reconstituting a solid dosage form comprising a compound of Formula (I-3) (e.g., I-3) as a free base in a crystalline form into a pharmaceutically acceptable aqueous medium. The solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent. An effervescent solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent and a source of carbon dioxide.

[0362] In some embodiments, an oral liquid dosage form is prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of a compound of Formula (I-3) in a crystalline form into a pharmaceutically acceptable aqueous medium. The solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent. An effervescent solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent and a source of carbon dioxide.

[0363] In some embodiments, an oral liquid dosage form is prepared by reconstituting a solid dosage form comprising a pharmaceutically acceptable salt of a compound of Formula (I-3) in amorphous form into a pharmaceutically acceptable aqueous medium. The solid dosage form can additionally be formulated with an organic acid agent, including a coated organic acid agent. Effervescent solid dosage forms can additionally be formulated with an organic acid agent, including a coated organic acid agent and a source of carbon dioxide.

[0364] In some embodiments, an oral liquid dosage form is prepared by first dissolving a solid dosage form according to any of the embodiments described herein in a pharmaceutically acceptable vehicle, such as an organic acid agent, to make a stock solution, and then mixing the stock solution with a pharmaceutically acceptable aqueous medium, such as water, juice, or other potable fluid, prior to use. In some embodiments, the solid dosage form is dissolved in a solution of an organic acid agent. In some embodiments, the organic acid agent is citric acid. In some embodiments, the organic acid agent is tartaric acid. In some embodiments, the stock solution is a 0.01 M, 0.05 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, or 1.0 M, or any range therebetween, solution.

[0365] In some embodiments, an oral liquid dosage form is prepared by first dissolving a solid dosage form comprising a compound of Formula (I-3) as a free base in citric acid to make a stock solution, and then mixing the stock solution with a pharmaceutically acceptable aqueous medium, such as water, juice, or other potable fluid, prior to use.

[0366] In some embodiments, an oral liquid dosage form is prepared by first dissolving a solid dosage form comprising a compound of Formula (I-3) as a free base in citric acid to make a 0.1 M stock solution, and then mixing the stock solution with a pharmaceutically acceptable aqueous medium, such as water, juice, or other potable fluid, prior to use.

[0367] Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions can include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions can include a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions can include 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 can also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to facilitate measurement for administration.

[0368] 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 contain 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.

[0369] 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 can also be advantageously used to enhance the delivery of the compositions described herein.

[0370] The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0371] Colorants and flavoring agents can be used in all of the above dosage forms.

[0372] The pharmaceutical compositions disclosed herein can be co-administered with other active ingredients which do not impair the desired therapeutic action, or with substances which supplement the desired action.

[0373] B. Modified Release

[0374] 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 rate or location of release of the active ingredient is different from that of a direct dosage form when administered by the same route. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including but not limited to matrix controlled release devices, osmotic controlled release devices, multiple unit controlled release devices, ion exchange resins, enteric coatings, multiple layer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by varying the particle size and polymorphism of the active ingredient.

[0375] 1. Matrix Controlled Release Devices

[0376] The pharmaceutical compositions disclosed herein in modified release dosage forms can be manufactured using matrix controlled release devices known to those skilled in the art (see Takada et al. in "Encyclopedia of Controlled Drug Delivery", Vol. 2, Mathiowitz, Ed., Wiley, 1999).

[0377] In one embodiment, the pharmaceutical compositions disclosed herein in modified release dosage forms are formulated using erodible matrix devices, which are water swellable, erodible or soluble polymers, including synthetic polymers, as well as naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0378] Materials that can be used to form erodible matrices include, but are not limited to, chitin, chitosan, dextrose, and pullulan; agar gum, gum arabic, gum karaya, gum tragacanth, gum xanthan, carrageenan gum, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, if colloids; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and celluloses, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose ethyl trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylate or methacrylic acid Rohm America, Inc., Piscataway, N.J.); 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 homo- and co-polymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, methyl (2-dimethylaminoethyl) acrylate, and chloromethyl (trimethylaminoethyl) acrylate.

[0379] In further embodiments, the pharmaceutical composition is formulated with an erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix, and is released primarily by diffusion through the inert matrix after administration. Materials suitable for use as 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, partial vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / ethylene vinyl alcohol copolymer, ethylene / vinyl acetate / ethylene vinyl alcohol terpolymer, and ethylene / ethyleneoxy ethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, and hydrophilic polymers such as ethyl cellulose, cellulose acetate, cross-linked povidone, and cross-linked partially hydrolyzed polyvinyl acetate, and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0380] In matrix controlled release systems, the desired release kinetics can be controlled, for example, by the type of polymer employed, the viscosity of the polymer, the particle size of the polymer and / or the active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0381] 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.

[0382] 2. Osmotic controlled release devices

[0383] The pharmaceutical compositions disclosed herein in modified release dosage forms can be manufactured using osmotic controlled release devices, including single compartment systems, double compartment systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one delivery port, which encloses the core. The semipermeable membrane controls the influx of water from the aqueous environment into the core in order to cause drug release by extrusion through the delivery port.

[0384] In addition to the active ingredient, the core of the osmotic device optionally includes an osmagent that creates a driving force for the transport of water from the environment of use into the core of the device. One class of osmagent is a water-swellable hydrophilic polymer, also known as "osmopolymer" and "hydrogel", including but not limited to: hydrophilic ethylene 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, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, cross-linked sodium carboxymethylcellulose, 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 carboxymethyl starch.

[0385] Another class of osmagent is an osmogen, which is 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.

[0386] Osmagents with different dissolution rates can be employed to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be used to provide faster delivery during the first few hours to immediately produce the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at such a rate to replace the amount of active ingredient that is metabolized and excreted.

[0387] The core can also include a variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0388] Materials useful for forming the semipermeable membrane include various grades of acrylic, ethylene, ether, polyamide, polyester, and cellulose derivatives that are water permeable and water insoluble at physiologically relevant pHs, or susceptible to becoming water insoluble by chemical alteration such as cross-linking. Examples of suitable polymers useful for forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA carbamate, CAP, CA carbamate methyl, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetoxy acetaldehyde dimethyl ester, triacetate of locust 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, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0389] The semipermeable membrane can also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and not wetted by aqueous media, but permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically constructed of hydrophobic polymers such as polyolefins, polyethylenes, polypropylenes, polytetrafluoroethylenes, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluorides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0390] Delivery ports on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery ports 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 a dimple in the core. Additionally, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0391] The total amount and rate of release of the active ingredient can be generally adjusted by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0392] The pharmaceutical composition in the osmotic controlled release dosage form can further comprise additional conventional excipients or carriers as described herein to facilitate the performance or processing of the composition.

[0393] 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).

[0394] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT controlled release dosage forms comprising an asymmetric osmotic membrane that coats a core comprising an active ingredient and other pharmaceutically acceptable vehicles, such as 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.

[0395] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled release dosage forms comprising an osmotic membrane that coats a core comprising an active ingredient, hydroxyethylcellulose, and other pharmaceutically acceptable excipients or carriers.

[0396] 3. Multi-particulate controlled release devices

[0397] The pharmaceutical compositions disclosed herein in modified release dosage forms can be made into multi-particulate controlled release devices comprising a plurality of particles, microparticles, or pellets having diameters ranging from about 10 pm to about 3 mm, about 50 m to about 2.5 mm, or about 100 m to about 1 mm. Such multi-particulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt-congealing, and by spray seeding of crystalline cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0398] Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and formation of the multi-particulates. The resulting particles can themselves constitute the multi-particulate devices, or can be coated by 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.

[0399] Pharmacokinetics

[0400] In some embodiments, the onset of therapeutic effect of the pharmaceutical composition is 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, or 5 minutes or less. In some embodiments, the duration of acute effect of the pharmaceutical composition is 240 minutes or less, 180 minutes or less, 120 minutes or less, 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, or 5 minutes or less. In some embodiments, the drug dissolution time of the pharmaceutical composition is 120 seconds or less, 90 seconds or less, 60 seconds or less, 50 seconds or less, 40 seconds or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less.

[0401] Stable compositions

[0402] In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in a stable form, and a pharmaceutically acceptable vehicle. For example, an amorphous form of a compound of Formula (I-3) can be stable in the disclosed pharmaceutical compositions. In some embodiments, a formulation of a compound of Formula (I-3) in which the compound of Formula (I-3) is stably present in an amorphous form can be achieved, for example, by immobilizing the compound within a matrix formed by a polymer, for example, as a solid dispersion or solid molecular complex of the compound of Formula (I-3) and a polymer.

[0403] Provided herein are solid dispersions and solid molecular complexes comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. For example, a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be dispersed within a matrix formed by a polymer in a solid state, such that it is immobilized in its amorphous form. In some embodiments, the polymer can prevent intramolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of the compound of Formula (I-3). In some embodiments, the solid dispersion provides a large surface area, thus further allowing for improved solubility and bioavailability of the compound of Formula (I-3). In some embodiments, the solid dispersion or solid molecular complex comprises about 8-16 mg, or about 8-14 mg, or about 8-12 mg, or about 12-16 mg, or about 12 mg, or about 16 mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0404] In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is present in the solid dispersion in an amount of about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, or any range therebetween, e.g., about 1% to about 50%; or about 10% to about 40%; or about 20% to about 35%; or about 25% to about 30%, by weight based on the total weight of the solid dispersion. In some embodiments, the polymer is present in the solid dispersion in an amount of about 0%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, or any range therebetween, e.g., 0% to about 50%; or about 5% to about 60%; or 10% to about 70%, by weight based on the total weight of the solid dispersion. In some embodiments, the polymer is present in the solid dispersion in an amount of greater than about 10%; or greater than about 20%; or greater than about 30%; or greater than about 40%; or greater than about 50%, by weight based on the total weight of the solid dispersion. In some embodiments, the solid dispersion has about 30% of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and about 70% of the polymer, by weight.

[0405] The solid dispersion can comprise the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed in a non-ionic polymer. This can be achieved, for example, by melting the polymer and dissolving the compound in the polymer and then cooling the mixture. The resulting solid dispersion can comprise the compound dispersed in the polymer in an amorphous form.

[0406] Solid dispersions can be formed by dispersing a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in an ionic polymer. Such solid dispersions can increase the stability of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. This can be achieved by various means, including the methods described above for forming dispersions in non-ionic polymers. Because ionic polymers have pH-dependent solubility in aqueous systems, the resulting solid dispersion of a compound of Formula (I-3) and a polymer can be stable in the stomach at low pH, and release the compound of Formula (I-3) in the intestine at higher pH. In some embodiments, a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in such a solid dispersion with an ionic polymer can be less able to separate from the polymer, and can be immobilized by the polymer in an amorphous form. Examples of such ionic polymers include, but are not limited to, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMCP), and methacrylic acid copolymer. In some embodiments, a polymer is used that is able to immobilize a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, such that it exists primarily in one particular polymorphic form, e.g., an amorphous form, for an extended period of time.

[0407] In some embodiments, the polymer can be linear, branched, or cross-linked. In some embodiments, the polymer can be a homopolymer or a copolymer. In some embodiments, the polymer can be a synthetic polymer derived from vinyl, acrylate, methacrylate, urethane, ester, and oxide monomers. In some embodiments, the polymer can be a derivative of a naturally occurring polymer, such as polysaccharides (e.g., chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, gum tragacanth, gum xanthan, carrageenan gum, ghatti gum, guar gum, xanthan gum, and scleroglucan); starches (e.g., dextrin and maltodextrin); hydrophilic colloids (e.g., pectin); phospholipids (e.g., lecithin); alginates (e.g., ammonium alginate, sodium alginate, potassium alginate, or calcium alginate, propylene glycol alginate); gelatin; collagen; and cellulose polymers. In some embodiments, the cellulose polymer is selected from the group consisting of ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose ethyl trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC). In some embodiments, the polymer can be selected from the group consisting of gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, and cellulose polymers that have been disclosed. In some embodiments, the cellulose polymer comprises a low viscosity of various grades, e.g., a MW less than or equal to 50,000 daltons.

[0408] In some embodiments, the composition can include a solid dispersion and a solid molecular complex including the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed within a matrix formed from gelatin. In some embodiments, the composition can include a solid dispersion and a solid molecular complex including the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed within a matrix formed from gelatin and a non-reducing sugar, such as mannitol. In some embodiments, the composition can include a solid dispersion and a solid molecular complex including the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed within a matrix formed from a cellulose polymer described herein. In some embodiments, the composition can include a solid dispersion and a solid molecular complex including the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed within a matrix formed from a cellulose polymer described herein and polyvinylpyrrolidone.

[0409] In some embodiments, the ratio of the amount by weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to the amount by weight of the polymer in the solid complex is about 1:9 to about 1:1. In some embodiments, the ratio of the amount by weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to the amount by weight of the polymer in the solid complex is about 2:8 to about 4:6. In some embodiments, the ratio of the amount by weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to the amount by weight of the polymer in the solid complex is about 3:7.

[0410] In some embodiments, the composition can further include one or more pharmaceutically acceptable vehicles, such as solubilizers, for the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. Solubilizers include those set forth herein, such as organic acid agents (e.g., citric acid), sodium phosphate, and natural amino acids. Other solubilizers include, but are not limited to: acacia, cholesterol, diethanolamine (additive), glycerol monostearate, lanolin alcohols, glycerol mono- and diesters, monoethanolamine (additive), lecithin, oleic acid (additive), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, diacetate, monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, triethanolamine, and emulsifying wax.

[0411] Various additives can be mixed, ground, or granulated with the solid dispersion as described herein to form a material suitable for the dosage forms described above. Potentially beneficial additives generally fall into the following categories: other matrix materials or diluents, surfactants, pharmaceutical complexing agents or solubilizers, fillers, disintegrants, binders, lubricants, and pH adjusting agents (e.g., agents, acids, bases, or buffers). Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), dicalcium phosphate, and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of pharmaceutical complexing agents or solubilizers include polyethylene glycol, caffeine, xanthan, quinolinic acid, and cyclodextrins. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and crosscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), starch, and gums such as guar gum and tragacanth gum. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH adjusting agents include acids (including organic acid agents) such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprise a mixture of an acid and a salt of the acid.

[0412] In addition to the solid dispersion or solid molecular complex, the composition can also include a therapeutically inert, inorganic or organic vehicle, such as those set forth herein.

[0413] Dose, frequency, and route of administration

[0414] The dose and frequency (single or multiple doses) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, administered can vary according to a variety of factors, including, but not limited to, the salt form / compound / polymorph to be administered; the route of administration; the size, age, sex, health, body weight, body mass index, and diet of the recipient; the nature and extent of the disease treated and the stage of the symptoms; the existence of other diseases or other health-related problems; the kind of concurrent treatment; and the presence of complications from any disease or treatment regimen. Other treatment regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0415] Therapeutically effective amounts for humans can be determined from animal models. For example, a dose for humans can be formulated according to concentration ranges found to be effective in animals. The dosage in humans can be adjusted by monitoring to ensure that the dosage is effective and that any adverse side effects are within acceptable limits.

[0416] The dosage can vary according to the needs of the subject and the active ingredient employed. In the context of the pharmaceutical compositions presented herein, the dosage administered to a subject should be sufficient to affect a beneficial therapeutic response in the subject over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages that are less than the optimum dose.

[0417] The dosage and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0418] Routes of administration can include oral routes (e.g., enteral / ingestional 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), and topical routes (e.g., dermal, conjunctival, intracorneal, intraocular, ocular, aural, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration), or other aspects sufficient to affect a beneficial therapeutic response.

[0419] Administration can follow a continuous administration schedule (administered 7 days a week) or an intermittent administration schedule. The administration schedule can vary according to the active ingredient adopted, the condition of illness treated, route of administration, the pharmacokinetics of the drug, and the clearance / accumulation of a specific subject. For example, the administration of a compound of formula (I-3) or a pharmaceutically acceptable salt thereof, a polymorph, or a solvate thereof can be once a day (QD) or all day long, such as twice a day (BID), three times a day (TID), four times a day (QID), or more. In certain embodiments, administration can be performed at night (QHS). In certain embodiments, administration is performed as needed (PRN). 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 schedule considered suitable using reasonable medical judgment. Intermittent administration can also be carried out weekly or monthly, for example, once a week, twice a week, three times a week, four times a week, every other week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, every twelve weeks etc. or any scope of lower frequency or therebetween.Such administration schedule can provide administration day flexibility, for example ± 1 day, 2 days, 3 days etc.The administration schedule can also specify the limited treatment number of times of each treatment course, for example, the compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph or solvate can be applied 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times or 8 times per treatment course.Use reasonable medical judgment, other administration schedules also may be considered as appropriate.

[0420] In some embodiments, a dose of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof is administered to the subject during treatment. In some embodiments, the treatment herein may involve administering a dose of about 8-16 mg, about 8-14 mg, about 8-12 mg, or about 12-16 mg, or about 12 mg or about 16 mg of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof to the subject during treatment. In some embodiments, the treatment herein may involve administering a single dose of about 12 mg or a single dose of about 16 mg of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof to the subject during treatment.

[0421] In some embodiments, the subject is administered multiple doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, over the course of treatment. Multiple doses can involve a first dose, a second dose, a third dose, a fourth dose, and so on. In some embodiments, the subject is administered multiple doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, over the course of treatment, spaced one week apart, spaced two weeks apart, spaced three weeks apart, or spaced four weeks apart (± 3 days). For example, a treatment herein can involve administering multiple doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, spaced three weeks apart (e.g., days 1 and 22) (± 3 days). In some embodiments, a treatment herein can involve administering multiple doses to the subject over the course of treatment, spaced three weeks apart (± 3 days), each dose being about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, or about 12 mg or about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, a treatment herein can involve administering multiple doses to the subject spaced three weeks apart (± 3 days), each dose being about 12 mg or each dose being about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0422] In some embodiments, the subject is administered a first dose and a second dose of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, over the course of treatment, spaced one week apart, spaced two weeks apart, spaced three weeks apart, or spaced four weeks apart (± 3 days). In some embodiments, the subject is administered two doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, over the course of treatment, spaced one week apart, spaced two weeks apart, spaced three weeks apart, or spaced four weeks apart (± 3 days). For example, a treatment herein can involve administering two doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, spaced three weeks apart (e.g., days 1 and 22 ± 3 days). In some embodiments, a treatment herein can involve administering two doses to the subject over the course of treatment, spaced three weeks apart (± 3 days), each dose being about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, or about 12 mg or about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, a treatment herein can involve administering two doses to the subject spaced three weeks apart (± 3 days), each dose being about 12 mg or each dose being about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0423] In some embodiments, the first, second, third, and fourth doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject at intervals of one week, at intervals of two weeks, at intervals of three weeks, or at intervals of four weeks (± 3 days) over the course of treatment. In some embodiments, the four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject at intervals of one week, at intervals of two weeks, at intervals of three weeks, or at intervals of four weeks (± 3 days) over the course of treatment. For example, a treatment herein can involve administering four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, at intervals of three weeks (e.g., day 1, day 22, day 43, and day 64 ± 3 days). In some embodiments, a treatment herein can involve administering four doses to the subject at intervals of three weeks (± 3 days) over the course of treatment, each dose being about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, or about 12 mg or about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, a treatment herein can involve administering four doses to the subject at intervals of three weeks (± 3 days), each dose being about 12 mg or each dose being about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0424] In some embodiments, the first, second, third, and fourth doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject at intervals of one week, at intervals of two weeks, at intervals of three weeks, or at intervals of four weeks (± 3 days) over the course of treatment. In some embodiments, the four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject at intervals of one week, at intervals of two weeks, at intervals of three weeks, or at intervals of four weeks (± 3 days) over the course of treatment. For example, a treatment herein can involve administering four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, at intervals of three weeks (e.g., day 1, day 22, day 43, and day 64 ± 3 days). In some embodiments, a treatment herein can involve administering four doses to the subject at intervals of three weeks (± 3 days) over the course of treatment, each dose being about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, or about 12 mg or about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, a treatment herein can involve administering four doses to the subject at intervals of three weeks (± 3 days), each dose being about 12 mg or each dose being about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0425] In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 2-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 3-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 4-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 5-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 6-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 7-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 8-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 9-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 10-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 11-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 12-month period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 2-year period. In some embodiments, only one, two, three, or four doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to the subject in any 3-year period.In any embodiment where multiple (e.g., two, three, or four) doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered over a specified period of time, it is preferred that each dose is administered with a one-week, two-week, three-week, or four-week (±3 days) interval. For example, a preferred administration schedule can involve only two doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, over any 2-month, 3-month, 4-month, 5-month, 6-month, 7-month, or 8-month period, wherein the two doses are administered with a three-week (±3 days) interval, each dose being about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, or about 12 mg or about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0426] Each dose (e.g., a single dose in a single-dose regimen, each dose in a multiple-dose regimen, etc.) can be accompanied by psychotherapy before, during, and / or after each dose, whereby the subject participates in one or more pre-administration psycho-support sessions; the subject participates in one or more psycho-support sessions during each medical session; and / or the subject participates in one or more post-administration psycho-support sessions.

[0427] Regardless of whether the dosing is continuous or intermittent, it continues for a specified treatment course, typically a cycle of at least 28 days (1 month), which can be repeated with or without a drug holiday. Longer or shorter treatment courses can also be used, such as 14 days, 18 days, 21 days, 24 days, 28 days, 35 days, 42 days, 48 days, 52 days, 56 days, 64 days, or more, or any range therebetween. The treatment course can be repeated without a drug holiday or with a drug holiday, depending on the subject. In some embodiments, the methods herein involve one treatment course for the lifetime of the subject, where the administration follows an administration schedule (e.g., a single dose, two doses administered with a three-week interval, etc.), with no repeat dosing during the remaining lifetime of the subject. In some embodiments, the methods herein involve more than one treatment course, e.g., if the subject does not respond to the initial treatment or if a relapse occurs. Other schedules are possible, depending on the presence or absence of adverse events, response to treatment, potential relapse, patient convenience, etc.

[0428] In some embodiments, the use of the compositions of the present disclosure can be used as a standalone therapy. In some embodiments, the use of the compositions of the present disclosure can be used as an adjuvant / combination therapy.

[0429] Utilizing the teachings provided herein, one can plan an effective prophylactic or therapeutic treatment regimen that does not cause significant toxicity or adverse side effects (e.g., caused by a sedative or hallucinogenic spike in the plasma concentration of any compound of Formula (I-3)) and yet is overall effective in treating the clinical symptoms exhibited by a particular subject. This planning should involve careful selection of the active compound and salt form 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.

[0430] In some embodiments, the dose is administered once orally, with the possibility of repeated doses spaced at least one week apart. In some cases, no more than five doses are administered in any one course of treatment. Courses of treatment can be repeated as needed with or without drug holidays. Such acute treatment regimens can be accompanied by psychotherapy before, during, and / or after the hallucinogenic dose.

[0431] The compounds of the present disclosure (e.g., compounds of formula (I-3) or pharmaceutically acceptable salts thereof, polymorphs or solvates thereof) can be used in a maintenance regimen. As used herein, a "maintenance regimen" generally refers to administering a compound of the present disclosure (e.g., a compound of formula (I-3) or pharmaceutically acceptable salts thereof, polymorphs or solvates thereof) after reaching a target dose, e.g., after completing an upward titration regimen, and / or after a positive clinical response is produced to the same drug or a different drug, e.g., after the patient's condition improves. In some embodiments, a first drug for a treatment regimen and a second drug for a maintenance regimen are administered to a patient, wherein the first drug and the second drug are different. For example, a treatment regimen in which a first drug that is not a compound of the present disclosure is administered to a patient (e.g., a first drug that is a serotonin-inducing drug, such as LSD, psilocybin, MDMA, dimethyltryptamine, etc., or a non-hallucinogenic drug) is followed by a compound of the present disclosure (as a second drug) in a maintenance regimen. In another example, different compounds of the present disclosure are used in a treatment regimen (the first drug) rather than a maintenance regimen (the second drug). In certain embodiments, the same compound of the present invention is administered to the patient for both the treatment regimen and the maintenance regimen. In any case, the maintenance dose of the compound of the present invention can be used to 'maintain' the treatment response and / or prevent the occurrence of relapse. When the same compound of the present invention is used for both the original treatment regimen and the maintenance regimen, the maintenance dose of the compound can be a therapeutic dose or less than a therapeutic dose. Typically, administration is performed daily or intermittently for the maintenance regimen, however, the maintenance regimen can also be performed continuously, for example, over several days, several weeks, several months or several years. In addition, the maintenance dose can be given to the patient over a long period of time or even for a long time.

[0432] The administering physician can provide a preventive or therapeutic treatment method based on the observation of one or more symptoms of the disorder or condition being treated by adjusting the amount and timing of any compound / salt form described herein. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0433] Diseases, disorders and conditions

[0434] The subject treated herein may have serotonin 5-HT2 receptors, particularly 5-HT 2A 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, including but not limited to major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar and related disorders (including but not limited to bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders (including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking and cocaine use disorder), eating disorders (including but not limited to anorexia nervosa, bulimia nervosa, binge eating disorder, disorder), Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, heart blindness, speech fluency disorders such as childhood-onset speech fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorders (including but not limited to pedophilic disorder, exhibitionist disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and transvestic disorder), sexual dysfunction (such as low libido and hypoactive sexual desire disorder (HSDD)), peripheral neuropathy, and obesity.

[0435] In some embodiments, the methods provided herein are used to treat a subject having a depressive disorder. As used herein, the term “depressive disorder” or “depression” refers to a group of mood disorders characterized by emotional lowing that can affect a person’s thoughts, behavior, feelings, and sense of well-being for a period of time. In some embodiments, depressive disorders impair a person’s physical and mental functioning. In some embodiments, depressive disorders cause physical symptoms such as weight loss, aches or pains, headaches, cramps, or digestive problems. In some embodiments, depressive disorders cause mental symptoms such as feelings of persistent sadness, anxiety, hopelessness, and irritability, feelings of guilt, worthlessness, or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, remembering, or making decisions. In some embodiments, the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, catatonic depression, depression caused by a medical condition, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or treatment-resistant depression (TRD). In some embodiments, the methods provided herein are used to treat a subject at least 18 years old (e.g., 18 to 65 years old) having a depressive disorder. In some embodiments, the methods provided herein are used to treat a subject at least 21 years old having a depressive disorder.

[0436] In some embodiments, the disease or disorder is major depressive disorder (MDD). As used herein, the term “major depressive disorder” refers to a condition characterized by periods of low mood that occur across most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in normal happy activities, lack of energy, and pain, without an explicit cause. In some cases, major depressive disorder is characterized by symptoms of depression that last at least two weeks. In some cases, an individual experiences depression for years at a time. In some cases, an individual experiences symptoms of depression almost all of the time. Major depressive disorder can have a negative impact on an individual’s 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 suicide victims have major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists 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, crying, emptiness or hopelessness, angry outbursts, feelings of irritability or frustration, even if minor, loss of interest or pleasure in most or all normal activities, sleep disturbances (including insomnia or hypersomnia), fatigue and lack of energy, decreased appetite, weight loss or gain, anxiety, restlessness or agitation, slowness in thinking, speaking, or physical movement, feelings of worthlessness or guilt, preoccupation with past failures or self-reproach, problems with thinking, concentrating, paying attention, remembering, frequent thoughts of death, suicidal ideation, suicide attempts, or suicide, and unexplained physical problems, such as back pain or headaches.

[0437] As used herein, the term “atypical depression” refers to a condition in which an individual shows a pattern of emotional reactivity (i.e., mood brightening in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, heaviness in the arms or legs, a feeling of laziness, and / or long-range interpersonal rejection sensitivity that results in significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, sadness or emotional frustration every day, loss of interest in once-pleasurable activities, significant change in weight (gain or loss) or appetite, insomnia or hypersomnia almost every day, restlessness or weakness noticed by others, fatigue or loss of energy every day, feelings of hopelessness, worthlessness, or excessive guilt almost every day, difficulty concentrating or making decisions almost every day, recurrent thoughts of death or suicide, suicide plans, or suicide attempts.

[0438] As used herein, the term "bipolar disorder" refers to a condition that causes an individual to experience ...

Claims

1. A compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof for use in treating a depressive disorder in a subject in need thereof, The treatment comprises orally administering to the subject about 8 mg to about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

2. The compound for use according to claim 1, wherein the treatment comprises administering to the subject about 12 mg to about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

3. The compound for use according to claim 1, wherein the treatment comprises administering to the subject about 12 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

4. The compound for use according to claim 1, wherein the treatment comprises administering to the subject about 14 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

5. The compound for use according to claim 1, wherein the treatment comprises administering to the subject about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

6. The compound for use according to any one of claims 1 to 5, wherein a pharmaceutically acceptable salt of the compound of formula (I-3) is administered.

7. The compound for use according to claim 6, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is selected from the group consisting of benzenesulfonate, tartrate, hemifumarate, acetate, citrate, malonate, fumarate, succinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate and glutarate salts of the compound of formula (I-3).

8. The compound for use according to claim 6 or 7, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a benzenesulfonate salt of the compound of formula (I-3).

9. The compound for use according to claim 8, wherein the benzenesulfonate salt of the compound of formula (I-3) is a crystalline benzenesulfonate salt (I-3a), wherein the crystalline benzenesulfonate salt is characterized by an X-ray powder diffraction pattern containing a chromatogram selected from the group consisting of 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 1 9.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988° 2θ ( + At least three characteristic peaks at 0.2°2θ).

10. The compound for use according to claim 6 or 7, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a tartaric acid salt of the compound of formula (I-3).

11. The compound for use according to claim 10, wherein the tartrate salt of the compound of formula (I-3) is a crystalline tartrate salt (I-3b), characterized by an X-ray powder diffraction pattern containing 20.54°, 21.709°, 22.762°, 23.470°, 24.774°, 25.921°, 26.268°, 27.295°, 28.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 24. 2θ(24.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.597°, 29.035°, 29.257°, ​​29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049° + At least three characteristic peaks at 0.2°2θ).

12. The compound for use according to claim 6 or 7, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a hemifumarate salt of the compound of formula (I-3).

13. The compound for use according to claim 12, wherein the hemifumarate salt of the compound of formula (I-3) is a crystalline hemifumarate salt (I-3c), wherein the crystalline hemifumarate salt is characterized by an X-ray powder diffraction pattern containing 1.577°, 1.540°, 1.591°, 1.613°, 1.627°, 1.637°, 1.640°, 1.661 ... 2θ(°), 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999°2θ( + At least three characteristic peaks at 0.2°2θ).

14. The compound for use according to claim 6 or 7, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a citrate salt of the compound of formula (I-3).

15. The compound for use according to claim 14, wherein the citrate salt (I-3e) is amorphous as determined by X-ray powder diffraction.

16. The compound for use according to claim 6 or 7, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a benzoate salt of the compound of formula (I-3).

17. The compound for use according to claim 16, wherein the benzoate salt of the compound of formula (I-3) is a crystalline benzoate salt (I-3j), characterized by an X-ray powder diffraction pattern containing a chromatogram selected from the group consisting of 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.8 31°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597° 2θ ( + At least three characteristic peaks at 0.2°2θ).

18. The compound for use according to any one of claims 1 to 17, wherein the depressive disorder is major depressive disorder (MDD).

19. The compound for use according to claim 18, wherein prior to treatment, the subject has been diagnosed with moderate to severe major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

20. A compound for use according to any one of claims 1 to 19, wherein prior to treatment, the subject's Montgomery-Asberg Depression Rating Scale ( Depression Scale (MADRS) score greater than or equal to 21.

21. The compound for use according to any one of claims 1 to 20, wherein a first dose and a second dose are administered to the subject one to four weeks (±3 days) apart, and the first dose and the second dose are each about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

22. The compound for use according to any one of claims 1 to 21, wherein a first dose and a second dose are administered to the subject three weeks (±3 days) apart, and each of the first dose and the second dose is about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

23. The compound for use according to any one of claims 1 to 22, wherein the subject is taking an antidepressant medication as part of an ongoing treatment and the treatment with the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof is used as an adjunct therapy.

24. A pharmaceutical composition comprising: About 8 mg to about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof; and A pharmaceutically acceptable vehicle.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition comprises about 12 mg to about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

26. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition comprises about 12 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

27. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition comprises about 14 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

28. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition comprises about 16 mg (free base equivalent) of the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

29. The pharmaceutical composition according to any one of claims 24 to 28, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of formula (I-3).

30. The pharmaceutical composition of claim 29, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is selected from the group consisting of benzenesulfonate, tartrate, hemifumarate, acetate, citrate, malonate, fumarate, succinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, glucuronate, and glutarate salts of the compound of formula (I-3).

31. The pharmaceutical composition according to claim 29 or 30, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a besylate salt of the compound of formula (I-3).

32. The pharmaceutical composition of claim 31, wherein the benzenesulfonate salt of the compound of formula (I-3) is a crystalline benzenesulfonate salt (I-3a), wherein the crystalline benzenesulfonate salt is characterized by an X-ray powder diffraction pattern containing a chromatogram selected from the group consisting of 7.023°, 7.767°, 11.822°, 12.550°, 12.860°, 13.994°, 15.521°, 18.436°, 1 9.503°, 20.760°, 21.070°, 22.007°, 22.745°, 23.340°, 24.187°, 25.532°, 26.880°, 27.856°, 28.163°, 31.267°, 33.024°, 35.030°, 36.835°, 39.312°, 40.545°, and 40.988° 2θ ( + At least three characteristic peaks at 0.2°2θ).

33. The pharmaceutical composition according to claim 29 or 30, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a tartrate salt of the compound of formula (I-3).

34. The pharmaceutical composition of claim 33, wherein the tartrate salt of the compound of formula (I-3) is a crystalline tartrate salt (I-3b), characterized by an X-ray powder diffraction pattern comprising a crystalline tartrate salt selected from the group consisting of 6.732°, 12.708°, 13.470°, 14.774°, 15.921°, 16.268°, 17.295°, 18.869°, 20.079°, 20.208°, 20.877°, 21.894°, 22.657°, 23.491°, 23.702°, 2 4.636°, 24.882°, 25.569°, 26.685°, 27.060°, 27.502°, 28.179°, 28.597°, 29.035°, 29.257°, ​​29.527°, 31.017°, 31.527°, 32.059°, 32.307°, 33.012°, 34.024°, 34.388°, 34.905°, 35.361°, 36.183°, 37.372°, 37.764°, 38.657°, and 41.049° 2θ ( + At least three characteristic peaks at 0.2°2θ).

35. The pharmaceutical composition according to claim 29 or 30, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a hemifumarate salt of the compound of formula (I-3).

36. The pharmaceutical composition of claim 35, wherein the hemifumarate salt of the compound of formula (I-3) is a crystalline hemifumarate salt (I-3c), wherein the crystalline hemifumarate salt is characterized by an X-ray powder diffraction pattern containing 1.577°, 1.540°, 1.591°, 1.613°, 1.627°, 1.637°, 1.640°, 1.661°, 1.666°, 1.671°, 1.691°, 1.704°, 1.713°, 1.713°, 1.661°, 1.666°, 1.666°, 1.671°, 1.691°, 1.6 ... , 19.427°, 20.108°, 21.068°, 21.335°, 21.837°, 22.429°, 23.262°, 23.478°, 23.900°, 24.720°, 25.318°, 27.912°, 28.532°, 29.565°, 30.457°, 32.698°, 34.155°, 37.910°, 39.566°, and 40.999° 2θ ( + At least three characteristic peaks at 0.2°2θ).

37. The pharmaceutical composition according to claim 29 or 30, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a citrate salt of the compound of formula (I-3).

38. The pharmaceutical composition of claim 37, wherein the citrate salt (I-3e) is amorphous as determined by X-ray powder diffraction.

39. The pharmaceutical composition according to claim 29 or 30, wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a benzoate salt of the compound of formula (I-3).

40. The pharmaceutical composition of claim 39, wherein the benzoate salt of the compound of formula (I-3) is a crystalline benzoate salt (I-3j), wherein the crystalline benzoate salt is characterized by an X-ray powder diffraction pattern containing a chromatogram selected from the group consisting of 9.486°, 11.006°, 12.379°, 13.428°, 14.608°, 15.446°, 16.389°, 18.247°, 18.977°, 19.346°, 19.83 1°, 20.868°, 21.447°, 22.860°, 23.878°, 24.944°, 25.737°, 26.144°, 26.341°, 26.990°, 27.708°, 28.595°, 30.048°, 30.763°, 31.127°, 31.839°, 32.800°, 34.460°, 35.444°, 37.725°, and 38.597° 2θ ( + At least three characteristic peaks at 0.2°2θ).

41. The pharmaceutical composition of any one of claims 24 to 40, wherein the pharmaceutically acceptable vehicle comprises an organic acid agent.

42. The pharmaceutical composition of claim 41, wherein the organic acid agent is citric acid.

43. The pharmaceutical composition of claim 41 or 42, wherein the organic acid agent is present in the pharmaceutical composition in an amount of at least 2 wt% and at most 10 wt% based on the total weight of the pharmaceutical composition (on a dry basis).

44. The pharmaceutical composition of any one of claims 24 to 43, wherein the pharmaceutical composition is in solid dosage form.

45. The pharmaceutical composition of claim 44, wherein the solid dosage form is a solid dosage form suitable for oral administration.

46. ​​The pharmaceutical composition of claim 44 or 45, wherein the solid dosage form is a powder in capsule form.

47. The pharmaceutical composition of any one of claims 24 to 43, wherein the pharmaceutical composition is in an oral liquid dosage form.

48. A pharmaceutical composition according to any one of claims 24 to 47 for use in treating a depressive disorder in a subject in need thereof.

49. The pharmaceutical composition for use of claim 48, wherein the pharmaceutical composition is administered orally to the subject.

50. The pharmaceutical composition for use of claim 48 or 49, wherein the pharmaceutical composition is administered by reconstituting the pharmaceutical composition in a solid dosage form in a pharmaceutically acceptable aqueous medium to form an oral liquid dosage form, followed by orally administering the oral liquid dosage form to the subject.

51. The pharmaceutical composition for use of any one of claims 48 to 50, wherein the depressive disorder is major depressive disorder (MDD).

52. The pharmaceutical composition for use of claim 51, wherein prior to treatment, the subject has been diagnosed with moderate to severe major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

53. The pharmaceutical composition for use of any one of claims 48 to 52, wherein prior to treatment, the subject has a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than or equal to 21.

54. A pharmaceutical composition for use according to any one of claims 48 to 53, wherein a first dose and a second dose of the pharmaceutical composition are administered to the subject one to four weeks (±3 days) apart, and each of the first dose and the second dose of the pharmaceutical composition comprises about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

55. A pharmaceutical composition for use according to any one of claims 48 to 54, wherein a first dose and a second dose of the pharmaceutical composition are administered to the subject three weeks (±3 days) apart, and each of the first dose and the second dose of the pharmaceutical composition comprises about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

56. A pharmaceutical composition for use according to any one of claims 48 to 55, wherein the subject is taking antidepressant medication as part of an ongoing treatment and the treatment with the pharmaceutical composition is used as an adjunctive therapy.

57. A compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof for use as an adjunctive therapy for treating a depressive disorder in a subject taking an antidepressant drug, The adjunctive therapy comprises administering to the subject about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

58. The compound for use of claim 57, wherein the depressive disorder is major depressive disorder (MDD).

59. The compound for use of claim 58, wherein prior to the adjunctive therapy, the subject has been diagnosed with moderate to severe major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).

60. The compound for use according to any one of claims 57 to 59, wherein prior to the adjunctive therapy, the subject has a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than or equal to 21.

61. The compound for use according to any one of claims 57 to 60, wherein a first dose and a second dose are administered to the subject one to four weeks (±3 days) apart, and the first dose and the second dose are each about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

62. The compound for use according to any one of claims 57 to 61, wherein a first dose and a second dose are administered to the subject three weeks (±3 days) apart, and each of the first dose and the second dose is about 8 mg to about 16 mg (free base equivalent) of the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof.

63. A compound for use according to any one of claims 57 to 62, wherein the antidepressant drug is a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

64. The compound for use according to any one of claims 57 to 63, wherein the compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof is orally administered to the subject.

65. A capsule comprising from about 8 mg to about 16 mg (free base equivalent) of a besylate salt of a compound of formula (I-3) for use in treating major depressive disorder (MDD) in a subject in need thereof.

66. An oral liquid dosage form for treating major depressive disorder (MDD) in a subject in need thereof, wherein the oral liquid dosage form comprises: (i) about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof; and (ii) a pharmaceutically acceptable aqueous medium.

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