Methods of treating disorders with psilocybin analogs

Abstract

The present disclosure generally relates to methods of treating 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, via administration of deuterated psilocin and its pharmaceutically acceptable salts, polymorphs, or solvates.

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 487,078, filed February 27, 2023, U.S. Provisional Patent Application No. 63 / 512,466, filed July 7, 2023, U.S. Provisional Patent Application No. 63 / 519,992, filed August 16, 2023, U.S. Provisional Patent Application No. 63 / 602,888, filed November 27, 2023, U.S. Provisional Patent Application No. 63 / 603,262, filed November 28, 2023, U.S. Provisional Patent Application No. 63 / 603,886, filed November 29, 2023, and U.S. Provisional Patent Application No. 63 / 553,321, filed February 14, 2024, each of which is incorporated by reference in its entirety herein.

[0002] The present disclosure relates generally to methods of using deuterated psilocin and its pharmaceutically acceptable salts, polymorphs, or solvates in the treatment of 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 technology]

[0003] Major depressive disorder (MDD) is a leading cause of disability worldwide (Cosgrove 2020) and carries significant economic and societal 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 significant public health problem, with an estimated 21 million adults experiencing at least one major depressive episode in 2020, representing 8.4% of all U.S. 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 is higher in adult women (10.5%) compared with men (6.2%) and is highest among individuals aged 18–25 (17.0%).

[0004] Although multiple medications and psychological interventions are available to treat MDD, up to 30% of patients do not respond to primary treatment, and up to 30% do not benefit despite multiple treatments (treatment resistance) (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: A STAR*D Report. Am J Psychiatry, 163, 1905-1917). Furthermore, available antidepressant treatments require daily dosing, have a slow onset of action, and take several weeks to show any beneficial effects (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 (GI) disorders, sedation, and sexual dysfunction (FDA 2019). Therefore, there is a significant unmet need for treatments that are rapidly acting, well-tolerated, and do not require long-term administration.

[0005] Treatments for MDD have traditionally focused on monoamine transmitters, preventing the reuptake of serotonin and / or norepinephrine, thereby increasing their availability in the synaptic cleft. While this has provided some success, these are symptomatic treatments and do not address the underlying biopsychosocial causes. The resurgence of research into serotonergic hallucinogens offers an opportunity to explore alternative approaches, opening a therapeutic window for the use of hallucinogens to promote insight and, with psychotherapeutic support, undertake the emotional work necessary to improve depressive symptoms (Nutt D, Erritzoe D, Carhart-Harris R (2020). Psychedelic Psychiatry's Brave New World. Cell, 181, 24-28).

[0006] 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 its active form, psilocin (4-hydroxy-N,N-dimethyltryptamine). Specifically, a chemical process called dephosphorylation removes the phosphate group on psilocybin, producing psilocin. [ka]

[0007] In vitro, psilocin has been reported to be a short-lived and unstable molecule. For this reason, psilocin has been little studied and is not generally recognized as a viable therapeutic option. Vaupel et al. studied the effects of psilocin ascorbate 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, Volume 24, Issue 26, 1979, pp. 2427-2431).

[0008] Migliaccio et al. studied the solution confirmation of psilocin monooxalate in water (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).

[0009] Aghajanian et al. used iontophoresis techniques to study the effects of psilocin tartrate on serotonergic neurons in rats (Aghajanian GK, Hailgler HJ. Hallucinogenic indoleamines: Preferential action upon presynaptic serotonin receptors. Psychopharmacol Commun. 1975, 1, 6, 619-29).

[0010] Kuhnert-Brandstatter et al. described the preparation of three polymorphs of psilocin (Kuhnert, M. et al., Polymorphic Modifications and Solvates of Psilocin and Psilocybin, 1976, Archive der Pharmazie, 309:625-631).

[0011] US Patent No. 11,312,684 B1 describes syrosin salts with improved physical properties and handling.

[0012] Therefore, therapeutic applications involving the use of psilocin have generally been achieved through the administration of precursors, psilocybin, or other prodrug approaches. However, psilocybin has a slow onset of action and a prolonged duration of drug action, often requiring 7-8 hours of monitored clinical observation before the patient is discharged. Because psilocybin must be metabolized to release the active ingredient, there is also a high level of variability during delivery. Therefore, there is a need for new therapeutic options that overcome the limitations of psilocybin and related prodrugs. Summary of the Invention

[0013] The present disclosure provides psilocin-d 10 and its novel crystalline form / polymorph, psilocin-d10 The present disclosure is based, at least in part, on methods of treating various diseases, disorders, and conditions with stabilized forms of psilocin, including novel salt forms and novel crystalline forms / polymorphs thereof, as well as compositions thereof. More specifically, the present disclosure provides a method of treating various diseases, disorders, and conditions with psilocin-d via various administration regimens, including one-dose or two-dose regimens (e.g., two doses spaced three weeks apart within a course of treatment). 10 The present invention provides a method for treating depressive disorders (e.g., major depressive disorder (MDD)), substance use disorders, anxiety disorders, eating disorders, and headache disorders with a stabilized form of

[0014] Psilocin-d 10 The disclosed stabilized forms of psilocin, such as psilocybin-d, do not rely on prodrug metabolism for release of the active agent, as is the case with psilocybin-d or related prodrug approaches, and therefore may have a faster / rapid therapeutic onset of action, a shorter duration of drug action (i.e., shorter duration of effect), and less subject-to-subject variability. Therefore, based on these characteristics and their potential advantages over psilocybin or related prodrug approaches, human clinical trials (ClinicalTrials.gov Identifier: NCT05385783) have been initiated. During these clinical trials, psilocin-d 10 It has been discovered that treatments comprising benzodiazepine, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, provide unexpected levels of efficacy, e.g., in terms of effective dose, in treating MDD patient populations. Moreover, the unexpected efficacy is achieved at surprisingly low dosage levels, i.e., at dosages much lower than the inventors predicted based on preclinical and clinical simulation studies. These discoveries have led to the granting of breakthrough therapy designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of MDD.

[0015] That is, the present disclosure provides: (1) A method for treating a depressive disorder in a subject in need thereof, comprising administering to the subject about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3), [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof. (2) The method according to (1), comprising administering to the subject about 12 mg to about 16 mg (free base equivalent) of a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. (3) The method according to (1), comprising administering to the subject about 12 mg (free base equivalent) of a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. (4) The method according to (1), comprising administering to the subject about 14 mg (free base equivalent) of a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. (5) The method according to (1), comprising administering to the subject about 16 mg (free base equivalent) of a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. (6) The method according to any one of (1) to (5), wherein a pharmaceutically acceptable salt of the compound of formula (I-3) is administered. (7) The method according to (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 method according to (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 benzenesulfonate of the compound of formula (I-3) is a crystalline benzenesulfonate (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), the method according to (8). (10) The pharmaceutically acceptable salt of the compound of formula (I-3) is the tartrate of the compound of formula (I-3), the method according to (6) or (7). (11) The tartrate of the compound of formula (I-3) is a crystalline tartrate (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), the method according to (10). (12) The pharmaceutically acceptable salt of the compound of formula (I-3) is the hemifumarate of the compound of formula (I-3), the method according to (6) or (7). (13) The hemifumarate salt of the compound of formula (I-3) is crystalline hemifumarate salt (I-3c), and the values ​​are: 9.713, 11.209, 11.605, 12.338, 12.852, 13.718, 15.117, 16.066, 16.627, 19.026, 19.427, 20.108, 21.06 8, 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 degrees 2θ (±0.2 degrees 2θ). (14) The method according to (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 method according to (14), wherein the citrate salt (I-3e) is amorphous by X-ray powder diffraction. (16) The method according to (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 benzoate salt of the compound of formula (I-3) is a crystalline benzoate salt (I-3j), and the values ​​are: 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, 22.8 60, 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 degrees 2θ (±0.2 degrees 2θ). (18) The method according to any one of (1) to (17), wherein the depressive disorder is major depressive disorder (MDD). (19) The method according to (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) The method according to any one of (1) to (19), wherein the subject has a score of 21 or more on the Montgomery Asberg Depression Rating Scale (MADRS) before treatment. (21) The method of any one of (1) to (20), wherein the first and second doses, each of which is 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, are administered to a subject at an interval of one to four weeks (±3 days). (22) The method of any one of (1) to (Error! Reference source not found), wherein a first dose and a second dose, each of which is 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, are administered to a subject at an interval of three weeks (±3 days). (23) The method according to any one of (1) to (22), wherein the subject is receiving antidepressant treatment as part of ongoing treatment and the method is used as adjunctive treatment. (twenty four) about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3); [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof, and a pharmaceutically acceptable vehicle. (25) The pharmaceutical composition according to (24), comprising 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 is the pharmaceutical composition according to (24), comprising 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 is the pharmaceutical composition according to (24), comprising 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 is the pharmaceutical composition according to (24), comprising 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 is the pharmaceutical composition according to any one of (24) to (28), comprising a pharmaceutically acceptable salt of the compound of formula (I-3). (30) 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, or glutarate of the compound of formula (I-3), for the pharmaceutical composition according to (29). (31) The pharmaceutically acceptable salt of the compound of formula (I-3) is the benzenesulfonate of the compound of formula (I-3), for the pharmaceutical composition according to (29) or (30). (32) The benzenesulfonate of the compound of formula (I-3) is crystalline benzenesulfonate (I-3a), and is 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), for the pharmaceutical composition according to (31). (33) The pharmaceutical composition according to (29) or (30), wherein the pharmaceutically acceptable salt of the compound of formula (I-3) is a tartrate of the compound of formula (I-3). (34) The tartrate salt of compound of formula (I-3) is the crystalline tartrate salt (I-3b), which has the following peaks: 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, 26.069, 27.069, 28.069, 29.069, 30.069, 31.069, 32.069, 33.069, 34.069, 35.069, 36.069, 37.069, 38.069, 39.069, 40.069, 41.069, 42.069, 43.069, 44.069, 45.069, 46.069, 47.069, 48.069, 49.069, 50.069, 51.069, 52.069, 53.069, 54.069, 55.069, 56.069, 57.069, 58.069, 59.069, 60.069, 61.069, 62.069, 63.069, 64.069, 65.069, 66.069 33. The pharmaceutical composition of claim 32, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 6.685, 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). (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). (36) The hemifumarate salt of the compound of formula (I-3) is crystalline hemifumarate (I-3c), and the values ​​are: 9.713, 11.209, 11.605, 12.338, 12.852, 13.718, 15.117, 16.066, 16.627, 19.026, 19.427, 20.108, 21.06 8, 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 degrees 2θ (±0.2 degrees 2θ). (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). (38) The pharmaceutical composition according to (37), wherein the citrate salt (I-3e) is amorphous by X-ray powder diffraction. (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). (40) The benzoate salt of the compound of formula (I-3) is a crystalline benzoate salt (I-3j), and the values ​​are: 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, 22.8 60, 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 degrees 2θ (±0.2 degrees 2θ). (41) The pharmaceutical composition according to any one of (24) to (40), wherein the pharmaceutically acceptable vehicle comprises an organic acid reagent. (42) The pharmaceutical composition according to (41), wherein the organic acid reagent is citric acid. (43) The pharmaceutical composition according to (41) or (42), wherein the organic acid reagent is present in the pharmaceutical composition in an amount of at least 2% by weight to at most 10% by weight, based on the total weight of the pharmaceutical composition (on a dry weight basis). (44) The pharmaceutical composition according to any one of (24) to (43), wherein the pharmaceutical composition is in a solid dosage form. (45) The pharmaceutical composition according to (44), wherein the solid dosage form is a solid dosage form adapted for oral administration. (46) The pharmaceutical composition of (44) or (45), wherein the solid dosage form is a powder dosage form in a capsule. (47) The pharmaceutical composition according to any one of (24) to (43), wherein the pharmaceutical composition is an oral liquid dosage form. (48) A method for treating a depressive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of (24) to (47). (49) The method according to (48), wherein the pharmaceutical composition is orally administered to the subject. (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, and then orally administering the oral liquid dosage form to a subject. (51) The method according to any one of (48) to (50), wherein the depressive disorder is major depressive disorder (MDD). (52) The method according to (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 method according to any one of (48) to (52), wherein the subject has a score of 21 or more on the Montgomery Asberg Depression Rating Scale (MADRS) before treatment. (54) The method of any one of (48) to (53), wherein the first and second doses of a pharmaceutical composition, each comprising 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, are administered to a subject at an interval of one to four weeks (±3 days). (55) The method of any one of (48) to (54), wherein the first and second doses of a pharmaceutical composition, each comprising 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, are administered to a subject at an interval of three weeks (±3 days). (56) The method according to any one of (48) to (55), wherein the subject is receiving antidepressant treatment as part of ongoing treatment and the method is used as adjunctive treatment. (57) An adjunctive treatment method for treating a depressive disorder in a subject receiving antidepressant therapy as part of ongoing treatment, comprising administering to the subject about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3), [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof. (58) The adjunctive treatment method according to (57), wherein the depressive disorder is major depressive disorder (MDD). (59) The adjunctive treatment method according to (58), wherein, prior to the adjunctive 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). (60) The adjunctive treatment method according to any one of (57) to (59), wherein the subject has a score of 21 or more on the Montgomery Asberg Depression Rating Scale (MADRS) before the adjunctive treatment. (61) The method of any one of (57) to (60), wherein the first and second doses, each of which is 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, are administered to a subject at an interval of one to four weeks (±3 days). (62) The method of any one of (57) to (61), wherein the first and second doses, each of which is 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, are administered to a subject at an interval of three weeks (±3 days). (63) The adjunctive treatment method according to any one of (57) to (62), wherein the antidepressant treatment is a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenaline reuptake inhibitor (SNRI), or a combination thereof. (64) The method for adjunctive treatment according to any one of (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 method for treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to the subject about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3). [ka] orally administering a capsule containing the benzenesulfonate salt of (66) A method for treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to the subject: (i) about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3); [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof, and (ii) orally administering an oral liquid dosage form comprising a pharmaceutically acceptable aqueous medium. (67) A medicament comprising about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3) for use in therapy, such as treating a subject with a depressive disorder, preferably major depressive disorder (MDD). [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof. (68) Pharmaceutical use, for example, for treating a subject having a depressive disorder, preferably major depressive disorder (MDD), comprising about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3). [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof. (69) The pharmaceutical composition according to any one of (24) to (47) for use in therapy, such as for treating a subject with a depressive disorder, preferably major depressive disorder (MDD). (70) Use of the pharmaceutical composition according to any one of (24) to (47) for treating a subject with a depressive disorder, preferably major depressive disorder (MDD). [Brief explanation of the drawings]

[0016] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. 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, in which:

[0017] [Figure 1A] Figures 1A-1C are simulations of oral psilocybin concentration (ng / mL) versus time post-dose (h) for 25 mg (Figure 1A), 37.5 mg (Figure 1B), and 50 mg (Figure 1C) doses from Brown et al., 2017 (N=12). Solid lines = simulated means, dashed lines = standard deviations, black dots = extracted means (Usona Institute - Figure 5.3-1), N=1000 per treatment. [Figure 1B] Figures 1A-1C are simulations of oral psilocybin concentration (ng / mL) versus time post-dose (h) for 25 mg (Figure 1A), 37.5 mg (Figure 1B), and 50 mg (Figure 1C) doses from Brown et al., 2017 (N=12). Solid lines = simulated means, dashed lines = standard deviations, black dots = extracted means (Usona Institute - Figure 5.3-1), N=1000 per treatment. [Figure 1C]Figures 1A-1C are simulations of oral psilocybin concentration (ng / mL) versus time post-dose (h) for 25 mg (Figure 1A), 37.5 mg (Figure 1B), and 50 mg (Figure 1C) doses from Brown et al., 2017 (N=12). Solid lines = simulated means, dashed lines = standard deviations, black dots = extracted means (Usona Institute - Figure 5.3-1), N=1000 per treatment. [Figure 2] Figure 2 shows a simulation of concentration (ng / mL) versus time after administration (h) of 10–20 mg oral psilocybin from Hasler et al. (N=6) in 1997. Solid line = simulated mean, 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 in total. [Figure 3A] Figures 3A-3B show simulations of oral psilocybin concentration (ng / mL) versus time after administration (h) of 13.83 mg (Figure 3A) and 27.66 mg (Figure 3B) of psilocybin from Holze et al., 2022 (N=28). Solid lines = simulated means, dashed lines = standard deviations, black dots = extracted means (Holze Figure S6), error bars = extracted SD (Holze Figure S6). N=1000 per treatment. [Figure 3B] Figures 3A-3B show simulations of oral psilocybin concentration (ng / mL) versus time after administration (h) of 13.83 mg (Figure 3A) and 27.66 mg (Figure 3B) of psilocybin from Holze et al., 2022 (N=28). Solid lines = simulated means, dashed lines = standard deviations, black dots = extracted means (Holze Figure S6), error bars = extracted SD (Holze Figure S6). N=1000 per treatment. [Figure 4] Figure 4 shows the modeled linear effect relationship between the Any drug effect score on the VAS and the mean psilocybin concentration (ng / mL) after psilocybin administration (15 mg and 30 mg psilocybin) based on the mean PK and PD data extracted from Holze et al., 2022. [Figure 5]Figure 5, reproduced from Madsen et al., 2019 (Figure 3 in Madsen et al., 2019), shows the relationship between intra-scan post-psilocybin plasma psilocin levels and neocortical 5-HT2AR occupancy. [Figure 6A] Figures 6A-6B are reproduced from Madsen et al., 2019 (Figure 4 in Madsen et al., 2019) and show the intensity of subjective hallucinatory experiences during PET scans, neocortical 5-HT2AR occupancy, and plasma psilocybin concentrations after psilocybin. Figure 6A shows the relationship between intensity ratings and neocortical 5-HT2AR occupancy, with the fitted line obtained using a quadratic function. Figure 6B shows the relationship between intensity and psilocin concentration, fitted to a single-site receptor binding model. [Figure 6B] Figures 6A-6B are reproduced from Madsen et al., 2019 (Figure 4 in Madsen et al., 2019) and show the intensity of subjective hallucinatory experiences during PET scans, neocortical 5-HT2AR occupancy, and plasma psilocybin concentrations after psilocybin. Figure 6A shows the relationship between intensity ratings and neocortical 5-HT2AR occupancy, with the fitted line obtained using a quadratic function. Figure 6B shows the relationship between intensity and psilocin concentration, fitted to a single-site receptor binding model. [Figure 7A] Figures 7A-7D show simulated concentration (ng / mL) and time post-administration (h) profiles of psilocin-d10 using Scenario 1 (Figure 7A), Scenario 2 (Figure 7B), Scenario 3 (Figure 7C), and Scenario 4 (Figure 7D) from Table 5, benchmarked based on various PD thresholds from available data. Simulation profiles represent the median values ​​of the simulated population (N=1000 per treatment). [Figure 7B] Figures 7A-7D show simulated concentration (ng / mL) and time post-administration (h) profiles of psilocin-d10 using Scenario 1 (Figure 7A), Scenario 2 (Figure 7B), Scenario 3 (Figure 7C), and Scenario 4 (Figure 7D) from Table 5, benchmarked based on various PD thresholds from available data. Simulation profiles represent the median values ​​of the simulated population (N=1000 per treatment). [Figure 7C]Figures 7A-7D show simulated concentration (ng / mL) and time post-administration (h) profiles of psilocin-d10 using Scenario 1 (Figure 7A), Scenario 2 (Figure 7B), Scenario 3 (Figure 7C), and Scenario 4 (Figure 7D) from Table 5, benchmarked based on various PD thresholds from available data. Simulation profiles represent the median values ​​of the simulated population (N=1000 per treatment). [Figure 7D] Figures 7A-7D show simulated concentration (ng / mL) and time post-administration (h) profiles of psilocin-d10 using Scenario 1 (Figure 7A), Scenario 2 (Figure 7B), Scenario 3 (Figure 7C), and Scenario 4 (Figure 7D) from Table 5, benchmarked based on various PD thresholds from available data. Simulation profiles represent the median values ​​of the simulated population (N=1000 per treatment). [Figure 8] Figure 8 shows the mean (±SD) plasma psilocin-d10 concentration-time profiles (linear scale) for subjects in Cohorts 1, 2, and 3 by dose, excluding two psilocin-d10 8 mg subjects (one Cohort 3 Day 1 subject who vomited after dosing and one Cohort 3 Day 1 subject who only had a 0-2 hour PK sample). [Figure 9] Figure 9 shows the mean (±SD) plasma psilocin-d10 concentration-time profiles (semi-log scale) for subjects in Cohorts 1, 2, and 3 by dose, excluding two psilocin-d10 8 mg subjects (one Cohort 3 Day 1 subject who vomited after dosing and one Cohort 3 Day 1 subject who only had a 0-2 hour PK sample). [Figure 10] FIG. 10 shows a study schematic of MDD participants as disclosed in the clinical trial protocol (Example III. Clinical Trial Protocol). [Figure 11] FIG. 11 shows the study schematic of normal healthy volunteer (NHV) participants (Cohorts 2-6) as disclosed in the clinical trial protocol (Example III. Clinical Trial Protocol). [Figure 12]FIG. 12 shows the study schematic of NHV participants (relative BA cohort) as disclosed in the clinical trial protocol (Example III. Clinical Trial Protocol). [Figure 13] FIG. 13 shows a plot of the mean (±SD) change in MADRS from baseline score to day 21 (D21) following a single 12 mg dose of psilocin-d10 versus placebo and the least squares (LS) mean difference between groups. [Figure 14] FIG. 14 shows a plot of the mean (±SD) change in MADRS from baseline score to day 21 (D21) following a single 16 mg dose of psilocin-d10 versus placebo and the least squares (LS) mean difference between groups. [Figure 15] FIG. 15 shows bar graphs of the mean (±SD) change from baseline score on the MADRS at Day 21 (after a single dose of psilocin-d10) and further improvement at Day 42 (after a second dose of psilocin-d10) for both the 12 mg and 16 mg dosage levels. [Figure 16] FIG. 16 shows bar graphs of response rate (%, defined as a ≧50% reduction from baseline MADRS) at Day 21 (D21) after a single dose of psilocin-d10, further improvement at Day 42 (D42) after a second dose of psilocin-d10, and persistence of these effects at Day 126 (D126) after these two doses, for both the 12 mg and 16 mg dose levels: Day 126, 12 mg (N=15), Day 126, 16 mg (N=8). [Figure 17] FIG. 17 shows bar graphs of remission rates (%, defined as MADRS score ≦10) at Day 21 (D21) after a single dose of psilocin-d10, further improvement at Day 42 (D42) after a second dose of psilocin-d10, and persistence of these effects at Day 126 (D126) after these two doses, for both the 12 mg and 16 mg dose levels: Day 126, 12 mg (N=15), Day 126, 16 mg (N=8). [Figure 18]FIG. 18 shows a plot of the mean (±SD) change in MADRS from baseline score to day 126 (D126) following two 12 mg doses or two 16 mg doses, 12 mg (N=15), 16 mg (N=8) of psilocin-d10 (administration on days 1 and 22). [Figure 19] FIG. 19 shows the difference versus placebo in the change from baseline in MADRS after 12 mg psilocin-d10 treatment on day 21 compared to a pivotal trial of approved antidepressant treatments. DETAILED DESCRIPTION OF THE INVENTION

[0018] In the following detailed description of embodiments of the present disclosure, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present disclosure. However, it will be apparent to those skilled in the art that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail as not to unnecessarily obscure aspects of the embodiments of the present disclosure.

[0019] definition 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.

[0020] As used herein, the term "major depressive disorder" refers to a condition characterized by a period of depressed mood present under most circumstances. Major depressive disorder is often accompanied by low self-esteem, loss of interest in usually enjoyable activities, low energy, and pain without a clear cause. In some cases, major depressive disorder is characterized by depressive symptoms lasting at least two weeks. In some cases, individuals experience periods of depression separated by several years. In some cases, individuals experience depressive symptoms nearly constantly. Major depressive disorder can adversely affect a person's personal, work, or school life, as well as sleep, eating habits, and overall health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of those who commit suicide also had 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, but with less severe but longer-lasting symptoms. Examples of symptoms of major depressive disorder include, but are not limited to, sadness, tearfulness, feelings of emptiness or hopelessness, outbursts of anger over trivial matters, irritability or frustration, loss of interest or pleasure in most or all usual activities, sleep disturbances including insomnia or hypersomnia, fatigue and lack of energy, loss of appetite, weight loss or gain, anxiety, agitation or restlessness, diminished ability to think, speak or move, feelings of worthlessness or guilt, preoccupation with past failures or self-blame, difficulty thinking, concentrating, making decisions and remembering things, frequent thoughts of death, suicidal thoughts, suicide attempts or suicide, and unexplained physical problems such as back pain or headaches.

[0021] As used herein, the term "fat" describes a compound that has a long-chain (straight-chain) hydrophobic moiety composed of hydrogen and ranging from 4 to 26 carbon atoms, and can be fully saturated or partially unsaturated.

[0022] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without 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 salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given dosage regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, where the molecule contains a basic functional group, from addition salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, perchlorate, and the like, as well as from addition salts with organic acids such as formate, tartrate, besylate, mesylate, acetate, maleate, malonate, oxalate, fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, hemifumarate, propionate, stearate, tartrate, lactate, citrate, ascorbate, pamoate, hydroxymaleate, phenylacetate, glutamate, 2-acetoxybenzoate, tosylate, ethanedisulfonate, isethionate, and the like. The term "salt thereof" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to patients. As an example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0023] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate can exist in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "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, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0024] "Stereoisomer" refers to a compound that has the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of compounds, including racemates and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one asymmetric center but are drawn without reference to stereochemistry are intended to include both racemates and individual stereoisomers, e.g., R- and / or S-stereoisomers, including each diastereomeric substitution, so long as the diastereomers are geometrically feasible.

[0025] "Tautomers" refers to alternative forms of molecules that differ only in the electronic bonding of atoms and / or the location of protons, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomeric ring atom configurations are also possible.

[0026] A "crystalline" solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules forming a crystal lattice with long-range order and therefore exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid may exist in different crystalline forms known as "polymorphs" that have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have different solid-state physical properties that affect, for example, the compound's solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility, as well as the safety and efficacy of pharmaceuticals based on the compound. In the process of preparing polymorphs, further refinement, in terms of overall physical or optical purity, may also be achieved. Crystalline forms of materials, including polymorphs, may be designated throughout this disclosure by "pattern" numbers (e.g., pattern 1, pattern 2, etc.) based on their characterized X-ray power diffraction (XRPD) patterns. As used herein, the term "amorphous" refers to a solid material that does not have substantial long-range order in the position of its molecules, i.e., the molecules are arranged randomly, so that there is effectively no clearly defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions, and do not have a clear melting point. For example, an amorphous material is a solid material that does not have a substantially sharp characteristic crystalline peak in its X-ray power diffraction (XRPD) pattern (i.e., it is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids.Thus, an "amorphous" subject compound / material is a compound / material characterized as having substantially no crystallinity, e.g., 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, percent crystallinity can be determined by measuring the intensity of one or more peaks in an XRPD diffractogram compared to a reference peak, which can be 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, including quantitative methods that provide the above percentages in terms of weight percent, can also be used to determine the percent amorphous or crystalline nature of a subject compound / material.

[0027] Reference to an X-ray powder diffraction (XRPD) pattern of a substance, compound, salt, etc. of the present disclosure characterized by an X-ray powder diffraction pattern comprising "at least three characteristic peaks" should be understood to include those substances / compounds / salts characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more (inclusive) of the listed characteristic XRPD diffraction peaks. Furthermore, a substance / compound / salt comprising "at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from" is open to the inclusion of other XRPD diffraction peaks not listed.

[0028] It will be understood that the compounds herein may exist in different salt, solvate, crystalline / amorphous (or polymorphic) forms, and the present disclosure is intended to include all permutations thereof, such as pharmaceutically acceptable salt solvates, etc. Thus, a reference to a compound, or a pharmaceutically acceptable salt, polymorph, or salt thereof, is intended to include all permutations thereof, e.g., a pharmaceutically acceptable salt of the compound in crystalline form, a pharmaceutically acceptable salt of the compound in solvate form, the crystalline free base compound, the crystalline free base compound as a solvate, etc.

[0029] As used herein, the term "steady state" describes a stable or steady state level of a molecule concentration, such as the concentration of any compound described herein.

[0030] As used herein, the terms "stable," "stability," and the like include chemical stability and solid-state (physical) stability. The term "chemical stability" means that the compound can be stored under normal storage conditions with little or no chemical degradation or decomposition, either in an isolated form or in the form of a formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein. "Solid-state stability" means that the compound can be stored under normal storage conditions with little or no solid-state changes (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid-state phase transition) in an isolated solid form or in the form of a solid formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein.

[0031] A "psilocybin-based" drug is any prodrug of a psilocybin-type compound, such as an alkyl / aryl ester, α-amino ester (e.g., amino acid ester), hemiester, bisester, phosphate ester, sulfate ester, etc., that upon administration releases psilocin or a deuterated analog thereof (e.g., a compound of Formula (I-3)) as the active ingredient. Psilocybin-based drugs include psilocybin itself (the dihydrogen phosphate ester of psilocin, as well as other neutral or zwitterionic forms).

[0032] As used herein, the term "composition" is equivalent to the term "formulation."

[0033] As used herein, the term "active ingredient" is equivalent to the term "active pharmaceutical ingredient" (API).

[0034] The phrase "tamper resistant" is art-recognized to describe aspects of a pharmaceutical formulation in which the formulation is used to make it more difficult to abuse the drug portion of the formulation, such as through extraction for intravenous use, intradermal use, or through crushing for purified cocaine use, thereby reducing the risk of drug abuse.

[0035] As used herein, the term "treating" or "treatment" means treating or treating a disease or medical condition in a patient, e.g., a mammal (particularly a human), including ameliorating a disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a patient, inhibiting a disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in a patient, or alleviating one or more symptoms of a disease or medical condition in a patient. In one embodiment, prophylactic treatment may prevent the occurrence of a disease or medical condition in a subject.

[0036] A "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 the condition being treated or can be susceptible to the condition being treated.

[0037] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more symptoms thereof. These terms encompass the suppression or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are particularly, in certain embodiments, candidates for a preventative regimen. Additionally, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0038] As used herein and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or delaying the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease, disorder, or condition in an effort to prevent or minimize the recurrence of the disease, disorder, or condition, or one or more symptoms thereof.

[0039] A "therapeutically effective amount" refers to an amount of a compound, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or prevent the occurrence of the disease or disorder.

[0040] 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 to prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0041] The term "administration schedule" refers to a plan that chronologically indicates the type, amount, duration, and procedure of drugs in drug treatment, as well as the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration is continued by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means daily administration without interruption during the treatment course. If the administration schedule follows an "intermittent" administration schedule (administration occurs less frequently than once a day), within the course, an administration day may be followed by a "rest day" or non-administration day of the drug. A "drug holiday" indicates that the drug is not administered according to a specified administration schedule. For example, after receiving one or several courses of treatment, a subject may be instructed to take a prescribed drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0042] The term "toxic spike" is used herein to describe a neural spike at concentrations of any compound described herein that produces sedative or psychotomimetic side effects (e.g., hallucinations, dizziness, and nausea), or any undesirable and / or unintended secondary effects resulting from administration of the pharmaceutical to an individual, resulting in a subjective experience that is qualitatively different from normal conscious experience. These experiences may include derealization, depersonalization, hallucinations, and / or sensory distortions in the visual, auditory, olfactory, tactile, proprioceptive, and / or interoceptive ranges, and / or other perceptual alterations, and / or other significant subjective changes in cognition, memory, emotion, and consciousness. If unwanted and / or unintended, such side effects may affect not only the immediate effects but also compliance with treatment. In particular, side effects may be more pronounced at blood concentration levels of about 250, 300, 400, 500 ng / L or greater.

[0043] All diseases and disorders listed herein may be defined as set forth in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0044] As used herein, "adjunctive therapy," "adjunctive therapy," etc. refer to a therapy given in addition to a primary or initial therapy to improve or maximize its effectiveness. For example, a subject diagnosed with a depressive disorder who is receiving one or more antidepressant treatments (e.g., SSRIs) as a primary or initial therapy but who has an inadequate response to the antidepressant treatment or who has otherwise failed to achieve the desired outcome from the antidepressant treatment may be administered a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, as an "adjunctive therapy" to improve or maximize the therapeutic efficacy. In this example involving a depressive disorder, the adjunctive therapy may improve or maximize the therapeutic efficacy by reducing depressive symptoms compared to the primary or initial therapy alone. The primary or initial therapy and adjunctive therapy comprising a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, may be prescribed and / or administered by the same person (e.g., a clinician), but need not be. 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 adjunctive therapy comprising the 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 adjunctive therapy comprising the 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.

[0045] As used herein, the term "inadequate response" refers to the lack of clinically meaningful improvement in symptoms, for example, as measured by one or more of the rating scales described herein. An inadequate response to an adequate course of treatment with antidepressant therapy can be determined retrospectively or prospectively. A prospective determination of an inadequate response refers to a determination made by a prescribing clinician or therapist after administering a partial course of treatment. A retrospective determination refers to a determination made by a prescribing clinician or therapist after administering a full course of treatment.

[0046] Unless otherwise specified, the compound of formula (I-3) or a pharmaceutically acceptable salt, polymorph or solvate thereof (psilocin-d 10 References to the administration of psilocin-d 2 mg are to the free base equivalent. Thus, the recited amount preceding the phrase "mg of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof" refers to the administration of psilocin-d 2 mg. 10 The amount of psilocysin-d (free base equivalent) 10 When administered as a pharmaceutically acceptable salt, the listed doses are based on the weight of psilocin-d present without any weight contribution from salt counterions. 10 For example, the amount of psilocin-d 10 of benzoate, administration of "8 mg of the compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof" corresponds to administration of 12.6 mg of psilocin-d 10 Similarly, when subjects were given psilocin-d 10 When administering 8 mg of the benzenesulfonate salt of the compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, the administration of 13.9 mg of psilocin-d 10 In another embodiment, the subject is administered psilocin-d 10 When administering 16 mg of the benzenesulfonate salt of the compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, administration of 27.8 mg of psilocin-d 10This is achieved when the benzenesulfonate salt is administered.

[0047] The compound of formula (I-3) (IUPAC name 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol, or psilocin-d 10 When referring to a compound of formula (I-3), the term "compound" refers to a collection or population of molecules having identical chemical structure, except for possible isotopic variations among the molecule's component atoms. This is because, in practice, it is generally impossible to achieve deuterium enrichment with 100% isotopic purity. Thus, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure (the subject compound) containing a deuterium atom as shown will also contain minor amounts of isotopologues bearing hydrogen atoms at one or more of the designated deuterium positions within that structure. The relative amounts of such isotopologues within a compound of formula (I-3) will depend on many factors, including the isotopic purity of the deuteration reagent used to make the compound of formula (I-3) and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound of formula (I-3). However, as described herein, it is preferred that the total relative amount of such isotopologues be less than 50% of the compound. With respect to the dosage amounts recited herein (e.g., 10 mg, 12 mg, 14 mg, 16 mg, etc.), it should be understood that the recited dosage amount 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 the compound of formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof) having 90% isotopic purity corresponds to a 10 mg dose (i.e., 9 mg of psilocin-d as the subject compound). 10 + 1 mg of total isotopologues of the subject compound).

[0048] The phrase "effect size" refers to a statistical calculation that can be used to compare the effectiveness of different drugs by quantifying the magnitude of the difference between treatments ("between groups"). It is a dimensionless measure of the difference in outcomes under two different therapeutic interventions. Thus, effect size informs clinicians about the magnitude of the therapeutic effect. Unless otherwise specified, as used herein, effect size is calculated from the difference between the mean change in the efficacy endpoint within 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 change in the efficacy endpoint within the treatment group from the placebo, using Cohen's d method with the following formula:

number

[0049] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used throughout this description and the claims that follow, the meaning of "a," "an," and "the" includes plural references in addition to the singular, unless the context clearly indicates otherwise. The term "about" in connection with a numerical value means that the value varies above or below 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0050] Therapeutic Uses and Methods Applicant has recently discovered a series of stabilized 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 WO 2022195011 and WO 2023078604, which are incorporated by reference in their entireties).

[0051] The previously identified compounds include compounds of formula (I-3) [ka] The compound of formula (I-3) has the IUPAC name 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol and is known as psilocin-d 10 It will be understood that reference to any of the above identifiers refers to delivering a compound of formula (I-3), which may properly be considered a hallucinogen in this disclosure.

[0052] The present disclosure provides a compound of formula (I-3) [ka] or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in animal models, the non-deuterated counterparts of the compound of formula (I-3), psilocin and psilocin-d 10 Based on the literature references describing clinical simulation data, the unexpected discovery relates to a more effective and better therapeutic window than expected.This discovery allows for a treatment method that includes administering a low dose of the compound of the present disclosure, which is beneficial to the subject undergoing treatment, while achieving a much greater therapeutic benefit (e.g., effective dose) than expected.Because side effects and adverse drug reactions can be substantially dose-related, it is predicted that a lower dose of the compound will be beneficial to reduce the risk to the subject being treated.

[0053] Provided herein are methods 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 administering to the subject a therapeutically effective amount of a compound of formula (I-3): [ka] or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, a therapeutically effective amount of a compound of Formula (I-3) or a pharmaceutically acceptable salt, polymorph, or solvate thereof administered to a subject in need of treatment 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, e.g., about 8 to about 16 mg, about 8 to about 14 mg, about 8 to about 12 mg, about 10 to about 16 mg, about 11 to about 15 mg, about 12 to about 14 mg, about 11 to about 13 mg, about 14 to about 16 mg, or about 12 to about 16 mg (free base equivalent). In some embodiments, the method comprises administering 8 mg to 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 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 the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 9 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 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 of the 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 the 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 the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof. In some embodiments, the method comprises administering 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 about 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 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 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 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 about 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 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 about 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 16 mg of the 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 doses recited above are oral doses.

[0054] Compounds of Formula (I-3) for Use in Pharmaceutical Compositions and Methods of the Invention 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, described in WO2022195011 and / or WO2023078604.

[0055] In some embodiments, the compound of Formula (I-3) according to the methods described herein is a crystalline form of the free base, as determined, for example, by XRPD and / or mDSC. Thus, one or more crystalline (e.g., polymorphic) forms of the compound of Formula (I-3) as the free base can be used in the treatments described herein. In some embodiments, a crystalline form of the compound of Formula (I-3) as the free base is provided. For example, the compound can include the free base of Formula (I-3), in which 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 the compound of Formula (I-3) present is in crystalline form, as determined, for example, by X-ray powder diffraction and / or mDSC. In some embodiments, a highly pure crystalline form of the compound of Formula (I-3) as the free base is provided. For example, the compound can include the free base of the 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 the compound of formula (I-3) is in crystalline form, as determined, for example, by X-ray powder diffraction and / or mDSC.

[0056] 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 has the following wavelengths as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604: 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°, 24.722°, 25.722°, 26.722°, 27.722°, 28.722°, 29.722°, 30.722°, 31.722°, 32.722°, 33.722°, 34.722°, 35.722°, 36.722°, 37.722°, 38.722°, 39.722°, 40.722°, 41.722°, 42.722°, 43.722°, 44.722°, 45.722°, 46.722°, 47.722°, 48.722°, 49.722°, 50.722°, 51.722°, 52.722°, 53.722°, 54.722°, 5 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 4.630°, 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°.In some embodiments, I-3 is at any of the following wavelengths as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604: 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°, 20.83°, 21.053°, 22.053°, 23.053°, 24.053°, 25.220°, 26.272°, 26.763°, 27.328°, 27.662°, 28.062°, 28.742°, 29.413°, 30.658°, 31.053°, 32.053°, 33.053°, 34.053°, 35.220°, 36.272°, 36.763°, 37.328°, 37.662°, 38.062°, 38.742°, 39.413°, 40.658°, 41.053°, 42.053°, 43.053°, 44.053°, 45.220° and 41.361°, 35.6°, 38.514°, 38.514°, and 41.361°.

[0057] In some embodiments, the compounds according to the methods described herein are provided as free bases in amorphous form, as determined, for example, by XRPD and / or mDSC. Thus, the compound of Formula (I-3) as a free base can be used in the treatments described herein in one or more amorphous forms. In some embodiments, highly pure amorphous forms of the compound of Formula (I-3) as a free base are 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 free base of the compound of Formula (I-3) in amorphous form, as determined, for example, by X-ray powder diffraction and / or mDSC.

[0058] 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.

[0059] Such amorphous forms of the compound of formula (I-3) (free base) may have an advantageous dissolution rate in water compared to crystalline forms, thereby enabling rapid systemic absorption for rapid onset of therapeutic action and a short duration of drug action. Furthermore, in some embodiments, pharmaceutical compositions comprising the amorphous form of the free base of the compound of formula (I-3) can be prepared (see below). Pharmaceutical compositions of the present disclosure, such as those described herein, can act to stabilize amorphous forms of the compound of formula (I-3), which are unstable and prone to crystallization. Thus, 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 conditions or diseases related to major depressive disorder.

[0060] Salt Form In some embodiments, the compound 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 the pharmaceutically acceptable salt of a compound of Formula (I-3) may be a mono-, di-, tri-, tetra-, or more acid groups. The acid group may be, for example, a carboxylic acid, sulfonic acid, phosphonic acid, or other acidic moiety containing at least one replaceable hydrogen atom.Examples of acids, which may be organic or inorganic, for use in preparing the pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene -2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo- Glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 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, alcohol These include, but are not limited to, tartaric acids (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including mono- and di-fatty acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0061] Certain salts are preferred among the above list because they have physical and pharmaceutical characteristics / properties that make them more suitable for pharmaceutical preparation and administration. For example, preferred salt forms of the compounds disclosed herein (e.g., compounds of Formula (I-3)) have one or more of the following characteristics: they tend to form salts, are easy to prepare in high yields, are stable, and have well-defined physical properties such as, for example, crystallinity, defined and reproducible polymorphism, if polymorphism exists, and high melting / fusion enthalpy; they are little or not hygroscopic; they are free-flowing, do not aggregate / adhere to surfaces, and have a regular morphology; they have an acceptable aqueous solubility and dissolution rate for the intended dosage form; and / or are physiologically acceptable, for example, do not cause undue irritation.

[0062] Crystallinity In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) according to the methods described herein can be crystalline or amorphous, for example, as determined by X-ray powder diffraction (XRPD) and / or mDSC. In some embodiments, the salt of the compound of Formula (I-3) is amorphous. Amorphous forms typically have higher aqueous solubility and dissolution rates than their crystalline counterparts and may therefore be well suited for fast-acting dosage forms adapted to rapidly release the active ingredient, such as orodispersible dosage forms (ODx) and immediate-release (IR) dosage forms. The salt of the compound of Formula (I-3) can be in a stable amorphous form. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is provided in amorphous form, for example, as determined by XRPD and / or mDSC. Thus, the pharmaceutically acceptable salt form of the compound of Formula (I-3) can be used in the treatments described herein in one or more amorphous forms. In some embodiments, a highly pure amorphous form of the pharmaceutically acceptable salt of the compound of formula (I-3) is provided.For example, the pharmaceutically acceptable salt 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 pharmaceutically acceptable salt of the compound of formula (I-3) is amorphous, as determined by, for example, X-ray powder diffraction and / or mDSC.

[0063] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) according to the methods described herein is crystalline. Crystalline forms are advantageous in that they provide stability and well-defined physical properties, which are desirable for pharmaceutical preparation and administration. The salt of the compound of Formula (I-3) can be in a stable crystalline form. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a percent crystallinity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5%, and up to 100%, as determined by XRPD and / or mDSC analysis. For example, the pharmaceutically acceptable salt of the compound of Formula (I-3) can be, for example, as determined by X-ray powder diffraction and / or mDSC, 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, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I-3) can be in crystalline form. In some embodiments, a highly pure crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I-3) is provided. For example, the pharmaceutically acceptable salt of the compound of Formula (I-3) can be, for example, as determined by X-ray powder diffraction and / or mDSC, at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of Formula (I-3) present can be in crystalline form. For example, as determined by discrete and sharp Bragg diffraction in an X-ray diffractogram, a salt form with high crystallinity is preferred.

[0064] XRPD analysis can be performed, for example, on a Bruker AXS D2 diffractometer using CuKα radiation (wavelength = 1.54060 Å). 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 θ-θ geometry can be used with a step size of 0.024° 2θ and a collection time of 0.1 seconds per step using a LynxEye detector from 5 to 42° 2θ.

[0065] For pharmaceutical manufacturing processes, advantageous salt forms of the compound of formula (I-3) according to the methods described herein are those that readily yield solid materials, either crystalline or amorphous, in acceptable yields that proceed without oil and with favorable volume factors that make them suitable for large-scale production.

[0066] While salt forms of the compound of Formula (I-3) according to the methods described herein can, in some cases, exist in different polymorphic forms (i.e., forms having different crystal structures), preferred salt forms of the present disclosure are those that can be produced as a single crystalline form, a single polymorphic form, or a single amorphous form, as determined, for example, by XRPD and / or mDSC and / or differential scanning calorimetry (DSC). It is also generally desirable that the salt be free-flowing, not aggregate / adhere to surfaces, and have an ordered morphology.

[0067] Chemical / Solid State Stability In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) according to the methods described herein has an onset of melting 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, and up to about 250°C, up to about 240°C, up to about 230°C, up to about 225°C, up to about 210°C, or up to about 200°C, as determined by DSC.

[0068] The pharmaceutically acceptable salts of the compound of formula (I-3) according to the methods described herein may also be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic. Hygroscopicity can be measured herein using a dynamic vapor sorption (DVS) analyzer by performing a water vapor sorption / desorption isotherm starting at 40% relative humidity (RH), increasing the humidity up to 90% RH, decreasing the humidity to 0% RH, increasing the humidity to 90% RH, decreasing the humidity to 0% RH, and finally increasing the humidity back to the starting 40% RH, and is classified according to: Non-hygroscopic: <0.2%, Slightly hygroscopic: ≥0.2% and <2%, Hygroscopic: ≥2% and <15%, Very hygroscopic: ≥15%, Deliquescent: Enough water is absorbed to form a liquid, all values ​​measured as weight gain (w / w, due to water gain) at >90% RH, 25°C.

[0069] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I-3) according to the methods described herein has a weight gain at >90% RH of less than 1% w / w, less than 0.8% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, less than 0.1% w / w, less than 0.08% w / w, less than 0.06% w / w, less than 0.05% w / w, or less than 0.02% w / w as determined by DVS.

[0070] Dry powder samples of the free base and salts can be maintained / stored in open or closed environments, such as in open or closed flasks / vials, without significant degradation or physical change (e.g., change in morphology, decomposition, etc.) under ambient or stress conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc. For example, dry powder samples of the free base and salt forms disclosed herein can have less than 10%, less than 5%, and less than 1% change in purity or morphology when stored under ambient or stress conditions (e.g., elevated temperature, e.g., 40°C, and / or elevated humidity).

[0071] The 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 stress conditions, e.g., 25°C / 90+% RH, 40°C / 75% RH, etc., without significant decomposition. Thus, in some embodiments, the present disclosure provides stable solution-phase compositions of the free base and salt forms of the compound of Formula (I-3) (e.g., stable solvates of the free base or salt form of the compound of Formula (I-3) in a solvated form, preferably a fully solvated form), that can be stored for extended periods of time as a solution, e.g., in the form of an aqueous solution, an organic solvent solution, or an aqueous-organic solvent mixture, without significant decomposition or physical changes, such as oiling of the solution. The solvent that can be used to form the solution-phase composition can be any one or more of the solvents described herein, e.g., water, ethanol, fruit juice, etc. In some embodiments, the solution-phase composition is an aqueous phase composition comprising the free base or pharmaceutically acceptable salt of the compound of Formula (I-3) solvated with water (and optionally containing other components, such as those found in fruit juice). The identification of stable solution phase compositions of compounds of Formula (I-3) and their salts is advantageous at least because the compositions do not need to be used immediately after preparation, e.g., within 5, 4, 3, 2, 1, 45, 30, 15, or 10 seconds of preparation. Instead, the stable solution phase compositions of compounds of Formula (I-3) and their salts described herein can be prepared in advance, if desired, and optionally stored, and can be administered hours, days, or even weeks after preparation without substantially affecting efficacy, e.g., without significant degradation of the psilocin or psilocin-type active ingredient.

[0072] In some embodiments, aqueous solutions formed from pharmaceutically acceptable salts of the compound of Formula (I-3) are characterized by increased stability compared to aqueous solutions prepared from the compound of Formula (I-3) (free base) but otherwise substantially the same. For example, the pharmaceutically acceptable salts of the compound of Formula (I-3) may be at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more stable in terms of percent (active ingredient) remaining in aqueous solutions prepared using the compound of Formula (I-3) (free base) but otherwise substantially the same, regardless of the presence or absence of metal ions, at 40°C for 24 hours. Such improved stability behavior may also be observed in pharmaceutical compositions of the present disclosure.

[0073] Samples are removed at predetermined time points and analyzed for stability, morphology changes, etc., e.g. 1 Analysis can be performed using H NMR, XRPD, HPLC with UV-visible multi-wavelength detector, UPLC, etc.

[0074] Physiological acceptability Suitable salt forms of the compounds of formula (I-3) are physiologically acceptable. Thus, preferred addition salts of the compounds of formula (I-3) are formed from organic acids, preferably organic acids having a moderate or mild acidity, such as an aqueous pK of -3.0 or more, -2.0 or more, -1.0 or more, 0 or more, 1.0 or more, 1.5 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, 4.0 or more, 4.5 or more, for example, 3.0 to 6.5. a Furthermore, depending, for example, on the route of administration and the optional use of taste-masking agents such as sweeteners, flavorings, etc., it may be desirable to use acid addition salts that impart pleasant taste characteristics (e.g., sweetness, citrus flavor, etc.), while unpleasant tasting salt forms (e.g., bitter, acrid, etc.) may still be acceptable.

[0075] solubility The aqueous solubility of the salt form of the compound of formula (I-3) can be determined by equilibrating an excess of the 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 the compound of formula (I-3) can be prepared, and the solubility and pH of the solution can be measured.

[0076] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has an aqueous solubility of about 1 mg / mL to about 400 mg / mL at 22° C. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has an aqueous 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. The aqueous solubilities range from about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, and up to about 400 mg / mL, up to about 380 mg / mL, up to about 360 mg / mL, up to about 340 mg / mL, up to about 320 mg / mL, up to about 300 mg / mL, up to about 280 mg / mL, up to about 260 mg / mL, and up to about 250 mg / mL. Some salt forms of the compounds described herein exhibit the above solubilities and can achieve a final aqueous pH of approximately 3 to 6 without gelling.

[0077] In some embodiments, the salt of the compound of Formula (I-3) has an aqueous solubility of about 200 mg / mL to about 400 mg / mL. In some embodiments, the salt of the compound of Formula (I-3) has an aqueous solubility of about 150 mg / mL to about 250 mg / mL. In some embodiments, the salt of the compound of Formula (I-3) has an aqueous solubility of 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 greater than 150 mg / mL.

[0078] In some embodiments, the salt form of the compound of Formula (I-3) has a dissolution rate that allows for rapid systemic absorption for rapid therapeutic onset and a short duration of drug action. In some embodiments, the salt of the compound of Formula (I-3) can be dissolved in aqueous media below about pH 7.5, e.g., pH 1-7, pH 3-7, or pH 4-7.

[0079] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is a benzenesulfonate, tartrate, hemifumarate, acetate, citrate, hemimalonate, malonate, fumarate, succinate, hemisuccinate, oxalate, benzoate, salicylate, ascorbate, hydrochloride, maleate, malate, methanesulfonate, toluenesulfonate, 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 with 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 pharmaceutically acceptable salt of the compound of Formula (I-3) is a salt formed with a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, etc.). A pharmaceutically acceptable salt of a compound of formula (I-3) may be the hemi-acid salt of any of the salts listed above when the acid used to form the salt contains multiple acidic groups (e.g., multiple carboxylic acid moieties).

[0080] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a benzenesulfonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a tartrate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a hemifumarate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is an acetate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a citrate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a hemimalonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a fumarate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a hemisuccinate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is an oxalate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a benzoate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a salicylate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is an ascorbate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a hydrochloride salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a maleate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a malate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a methanesulfonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a toluenesulfonate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a glucuronate salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I-3) is a glutarate salt.

[0081] 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), with the benzenesulfonate, hemisuccinate, or benzoate salt of the compound of Formula (I-3) being preferred, and the benzenesulfonate or benzoate salt of the compound of Formula (I-3) being particularly preferred.

[0082] Exemplary pharmaceutically acceptable salt forms (ie, addition salt forms) of the above-identified compounds are provided in Table 1. [Table 1]

[0083] In some embodiments, the pharmaceutically acceptable salt is the benzenesulfonic acid salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a). In some embodiments, salt I-3a has a peak intensity 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°, 23.007°, 24.007°, 25.007°, 26.007°, 27.007°, 28.007°, 29.007°, 30.007°, 31.007°, 32.007°, 33.007°, 34.007°, 35.007°, 36.007°, 37.007°, 38.007°, 39.007°, 40.007°, 41.007°, 42.007°, 43.007°, 44.007°, 45.007°, 46.007°, 47.007°, 48.007°, 49.007°, 50.007°, 51.007°, 52.007°, 53.007°, 54.007°, 55.007°, 56.007°, 57.007°, 58.007°, 59 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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°.

[0084] In some embodiments, the pharmaceutically acceptable salt is the 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 a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604. In some embodiments, salt I-3b has a molecular weight 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° as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604. , 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° (Pattern 2).

[0085] 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 a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604. In some embodiments, salt I-3c has a molecular weight of 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° as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604. , 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° (Pattern 2).

[0086] In some embodiments, the pharmaceutically acceptable salt is the citrate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3e). In some embodiments, salt I-3e is in an amorphous solid form as characterized by X-ray powder diffraction (XRPD).

[0087] In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j). In some embodiments, salt I-3j has a peak intensity of 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°, 23.060°, 24.060°, 25.060°, 26.060°, 27.060°, 28.060°, 29.060°, 30.060°, 31.060°, 32.060°, 33.060°, 34.060°, 35.060°, 36.060°, 37.060°, 38.060°, 39.060°, 40.060°, 41.060°, 42.060°, 43.060°, 44.060°, 45.060°, 46.060°, 47.060°, 48.060°, 49.060°, 50.060°, 51.060°, 52.060°, 53.060°, 54.060°, 55.060°, 56.060°, 57.0 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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°.

[0088] Preferred pharmaceutically acceptable salts of the compound of Formula (I-3) have increased stability, aqueous solubility, and dissolution rate compared to the free base compound, while possessing advantageous pharmaceutical properties (e.g., crystallinity, reproducible polymorphism, if present, well-defined physical properties, such as high melting onset (e.g., above 160°C), little or no hygroscopicity, and free flowing properties), allowing for direct oral administration to patients without the need for a prodrug approach. As a result, pharmaceutically acceptable salts of the compound of Formula (I-3) can provide a faster / rapid therapeutic onset, a shorter duration of drug action (e.g., shorter duration of effect), and less variability in exposure than psilocybin-based drugs (e.g., psilocybin). Notably, pharmaceutically acceptable salts of the compound of Formula (I-3) have demonstrated surprising efficacy in treating MDD.

[0089] 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) may be a mono- or di-fatty acid, and may contain a fatty hydrocarbon moiety composed of hydrogen and 4, 6, 8, 10, 12, 14, 16, and up to 26, up to 24, up to 22, up to 20, or up to 18 carbon atoms, which may be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, caprylate, palmitate, sebacate, undecylenate, or caproate salt of the compound of Formula (I-3). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) is an adipate, laurate, linoleate, myristate, caprate, stearate, oleate, or caprylate salt of the compound of Formula (I-3), with the laurate, linoleate, caprate, or caprylate salt of the compound of Formula (I-3) being preferred.

[0090] Exemplary pharmaceutically acceptable fatty acid salt forms (ie, addition salt forms) of the above-identified compounds are provided in Table 2. [Table 2]

[0091] In some embodiments, the pharmaceutically acceptable salt is the 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 a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604.

[0092] In some embodiments, the pharmaceutically acceptable salt is the linoleic acid 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 a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604.

[0093] 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, salt I-3o is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604.

[0094] In some embodiments, the pharmaceutically acceptable salt is the caprate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3p). In some embodiments, salt I-3p is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604.

[0095] 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, salt I-3q is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1 or 2, e.g., as shown in WO2022195011 and / or WO2023078604.

[0096] 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, salt I-3r is a crystalline solid form characterized by an X-ray powder diffraction pattern of pattern 1 or 2, e.g., as shown in WO2022195011 and / or WO2023078604.

[0097] In some embodiments, the pharmaceutically acceptable salt is the caprylic acid salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3s). In some embodiments, salt I-3s is a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604.

[0098] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in corn oil at 22°C 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, and 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.

[0099] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a solubility in Crodamol® GTCC (medium chain fatty acids, from Croda) at 22°C 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, and 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.

[0100] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I-3) has a concentration of 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, from about 1.8 mg / mL, from about 2 mg / mL, and up to about 5 mg / mL, up to about 4.8 mg / mL, up to about 4.6 mg / mL, up to about 4.4 mg / mL, up to about 4.2 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 4 mg / mL, up to about 5 mg / mL, up to about 6 mg / mL, up to about 7 mg / mL, up to about 8 mg / mL, up to about 9 mg / mL, up to about 10 mg / mL, up to about 11 mg / mL, up to about 12 mg / mL, up to about 13 mg / mL, up to about 14 mg / mL, up to about 15 mg / mL, up to about 16 mg / mL, up to about 17 mg / mL, up to about 18 mg / mL, up to about 19 mg / mL, up to about 20 mg / mL, up to about 21 mg / mL, up to about 22 mg / mL, up to about 23 mg / mL, up to about 25 mg / mL, up to about 26 mg / mL, up to about 27 mg / mL, up to about 28 mg / mL, up to about 29 mg / mL, up to about 30 mg / mL, up to about 31 mg / mL, up to about 32 mg / mL, up to about 33 mg / mL, up to about 34 mg / mL, up to about 35 mg / mL, up to It has a solubility of about 2.8 mg / mL, a maximum of about 2.6 mg / mL, a maximum of about 2.4 mg / mL, and a maximum of about 2.2 mg / mL.

[0101] Due to their relatively hydrophobic nature, fatty acid salts of compounds of formula (I-3) may be advantageous for use in pharmaceuticals that are adapted for modified, controlled, slow-release, or sustained-release profiles.As a result, fatty acid salts of compounds of formula (I-3) may be well suited to administration routes and / or dosage forms that are adapted to provide low doses of active pharmaceutical ingredients (APIs) over long periods of time, as may be the case with slightly hallucinogenic administration regimens.Non-limiting examples of such dosage forms include, but are not limited to, liposomes, micelles, microspheres, nanosystems, or other controlled-release devices as described herein.

[0102] Also disclosed herein is a method for stabilizing a compound of formula (I-3), comprising preparing a pharmaceutically acceptable salt of the compound of formula (I-3).

[0103] Also disclosed herein are methods for preparing pharmaceutically acceptable salts of compounds of formula (I-3). In some embodiments, the methods include: (a) suspending the free base of the compound of formula (I-3) in a solvent or mixture of solvents; (b) contacting an acid with a compound of formula (I-3) to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; and (e) isolating the salt.

[0104] The disclosed methods can use a variety of solvents, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method of preparing the salt is a protic solvent. In some embodiments, the solvent used in the method of preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., 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.

[0105] Acids suitable for use in preparing pharmaceutically acceptable acid addition salts may include those previously described. The acid may 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, glutarate, 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 (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, caprylic (octano) acid, palmitic (hexadeceno) acid, sebacic acid, undecylenic acid, caproic acid, and the like, with particular mention being made of adipic (hexanedio) acid, lauric (dodecano) acid, linoleic acid, myristic (tetradecano) acid, capric (decano) acid, stearic (octadecano) acid, oleic acid, and caprylic (octano) acid.

[0106] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with the compound of Formula (I-3). In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with the compound of Formula (I-3). For example, when the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, using a substoichiometric amount of acid may be desirable.

[0107] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0108] In some embodiments, the mixture is cooled, causing the salt to precipitate from solution. In some embodiments, the salt precipitates from solution in crystalline form. In some embodiments, the salt precipitates from solution in amorphous form.

[0109] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0110] After isolation, additional crystallization and / or recrystallization steps may also optionally be performed, if desired, to, for example, increase purity, crystallinity, etc.

[0111] In some embodiments, the compounds of the present disclosure, such as 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, methanolates, ethanolates, isopropanolates, etc., with hydrates and ethanolates being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. The solvates of the compounds of the present disclosure may be in the form of an isolable solvate. In one non-limiting example, as a hydrate, the compound may be a monohydrate, a dihydrate, etc. The solvates of the compounds of the present disclosure also include solution-phase forms. Thus, in some embodiments, the present disclosure provides solution-phase compositions of the compounds of the present disclosure, or any pharmaceutically acceptable salt thereof, in a solvated form, preferably a fully solvated form.

[0112] In some embodiments, any position in a compound of Formula (I-3) designated as having deuterium has a minimum deuterium incorporation greater than naturally occurring deuterium in hydrogen (about 0.016 atomic %). In some embodiments, any position in a compound of Formula (I-3) designated as having deuterium has a minimum deuterium incorporation of at least 10 atomic %, at least 20 atomic %, at least 25 atomic %, at least 30 atomic %, at least 40 atomic %, at least 45 atomic %, at least 50 atomic %, at least 60 atomic %, at least 70 atomic %, at least 80 atomic %, at least 90 atomic %, at least 95 atomic %, or at least 99 atomic % at the deuteration sites. In some embodiments, any position in a compound of Formula (I-3) designated as having deuterium has a minimum deuterium incorporation of at least 40 atomic %, at least 45 atomic %, at least 50 atomic %, at least 60 atomic %, at least 70 atomic %, at least 80 atomic %, at least 90 atomic %, at least 95 atomic %, or at least 99 atomic % at the deuteration sites.

[0113] The compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph, or solvate having less than 100% isotopic purity can be used. In some embodiments, the compound of formula (I-3) (or its pharmaceutically acceptable salt, polymorph, or solvate) has an isotopic purity of 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, or at least 99% by weight, based on the total weight of the isotopologues of the compound of formula (I-3) present. For example, the compound of formula (I-3) can be used as the subject compound in the form of its free base or salt, solvate, or mixture, as psilocin-d 10(Compound I-3, 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol) and may further contain lesser amounts of isotopologues of the subject compounds, such as psilocin-d9 (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol) and psilocin-d9 (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol) as their free base or salt forms, polymorphs, stereoisomers, solvates, or mixtures. and 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H-indol-4-ol), psirosin-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). In some embodiments, the compound of Formula (I-3) is substantially free of other isotopologues of the compound in either free base or salt form, e.g., having less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologues of the compound. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, has an isotopic purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 77%, at least 79%, at least 80%, at least 82%, at least 84%, at least 85%, at least 87%, at least 89%, at least 90% by weight, with an isotopic purity of up to 99%, up to 98%, up to 97%, up to 96%, up to 95%, up to 94%, up to 93%, up to 92%, up to 91%, up to 90%, up to 89%, up to 88%, up to 87%, up to 86%, up to 85%, up to 84%, up to 83%, up to 82%, up to 81%, up to 80% by weight.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) that is (i) between 60% and 99%, 60% and 98%, 65% and 97%, 70% and 96%, 75% and 95%, 80% and 94%, 85% and 93%, 90% and 92%, 75% and 90%, 76% and 89%, 77% and 88%, 78% and 87%, or 79% and 86% by weight of psilocin-d, based on the total weight of the isotopologue mixture. 10 or a pharmaceutically acceptable salt, polymorph, or solvate thereof, (ii) 1 wt.% to 40 wt.%, 2 wt.% to 40 wt.%, 3 wt.% to 35 wt.%, 4 wt.% to 30 wt.%, 5 wt.% to 25 wt.%, 6 wt.% to 20 wt.%, 7 wt.% to 15 wt.%, 8 wt.% to 10 wt.%, 10 wt.% to 25 wt.%, 11 wt.% to 24 wt.%, based on the total weight of the isotopologue mixture. , 12% to 23%, 13% to 22%, 14% to 21%, or 13% to 17% by weight of one or more 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%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25%, or 0%, or between 1% and 3% by weight of psirosin-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.

[0114] In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is chemically pure, e.g., has a chemical purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by HPLC. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, has no single impurity of greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, has no single impurity of more than 1 area%, more than 0.5 area%, more than 0.4 area%, more than 0.3 area%, or more than 0.2 area%, as measured by HPLC.

[0115] Pharmaceutical compositions useful in the methods of the invention In any embodiment of the present invention, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, may be administered as a pharmaceutical composition comprising the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, according to any embodiment described herein. Accordingly, the present invention provides pharmaceutical compositions and methods useful 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, wherein the pharmaceutical composition 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 the compound of Formula (I-3). [ka] or a pharmaceutically acceptable salt, polymorph or solvate thereof, and and a pharmaceutically acceptable vehicle. In some embodiments, the compound of formula (I-3) is a compound of formula (I-3) described in any embodiment herein, or a salt or polymorph thereof.

[0116] Pharmaceutical compositions according to any embodiment described herein may contain one or more compounds, salt forms, polymorphs and / or solvates of the present disclosure.

[0117] The pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of a compound of formula (I-3) [ka] 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, e.g., about 8 to about 16 mg, about 8 to about 14 mg, about 8 to about 12 mg, about 10 to about 16 mg, about 11 to about 15 mg, about 12 to about 14 mg, about 11 to about 13 mg, about 14 to about 16 mg, or about 12 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 compositions listed above is an oral dosage.

[0118] The pharmaceutical compositions may 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 either free base or salt form, including one or more polymorphs of such a substance.

[0119] Pharmaceutical compositions may be formed from a compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, having an isotopic purity of less than 100%, i.e., an isotope mixture. In some embodiments, the compound of formula (I-3) (or its pharmaceutically acceptable salt, polymorph, or solvate) has an isotopic purity of 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, or at least 99% by weight, based on the total weight of the isotopes of the compound of formula (I-3) present in, for example, a pharmaceutical composition. For example, the subject compound may be psilocin-d, either in free base or salt form, solvate, or a mixture thereof. 10Pharmaceutical compositions formulated using (Compound I-3, 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol) may further contain lesser amounts of isotopologues of the subject compound, as free base or salt forms, polymorphs, stereoisomers, solvates, or mixtures thereof, such as psilocin-d9 (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2-d3)-1H-indol-4-ol and 3-(2- (one or more of 3-(2-(bis(methyl-d3)amino)ethyl-1,2,2-d3)-1H-indol-4-ol), psirosin-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). In some embodiments, the composition is substantially free of other isotopologues of either the free base or salt form of the compound, e.g., the composition has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologues of the compound. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, with an isotopic purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 77%, at least 79%, at least 80%, at least 82%, at least 84%, at least 85%, at least 87%, at least 89%, at least 90% by weight, and with an isotopic purity of up to 99%, up to 98%, up to 97%, up to 96%, up to 95%, up to 94%, up to 93%, up to 92%, up to 91%, up to 90%, up to 89%, up to 88%, up to 87%, up to 86%, up to 85%, up to 84%, up to 83%, up to 82%, up to 81%, or up to 80% by weight.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) that is (i) between 60% and 99%, 60% and 98%, 65% and 97%, 70% and 96%, 75% and 95%, 80% and 94%, 85% and 93%, 90% and 92%, 75% and 90%, 76% and 89%, 77% and 88%, 78% and 87%, or 79% and 86% by weight of psilocin-d, based on the total weight of the isotopologue mixture. 10 or a pharmaceutically acceptable salt, polymorph, or solvate thereof, (ii) 1 wt.% to 40 wt.%, 2 wt.% to 40 wt.%, 3 wt.% to 35 wt.%, 4 wt.% to 30 wt.%, 5 wt.% to 25 wt.%, 6 wt.% to 20 wt.%, 7 wt.% to 15 wt.%, 8 wt.% to 10 wt.%, 10 wt.% to 25 wt.%, 11 wt.% to 24 wt.%, based on the total weight of the isotopologue mixture. , 12% to 23%, 13% to 22%, 14% to 21%, or 13% to 17% by weight of one or more 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%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25%, or 0%, or between 1% and 3% by weight of psirosin-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.

[0120] Pharmaceutical compositions may be formulated using one or more polymorphs of the compound of Formula (I-3) or a salt thereof, including crystalline and / or amorphous polymorphs of the compound of Formula (I-3) or a salt thereof. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a single crystalline polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a single amorphous polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous polymorphs.

[0121] In some embodiments, the pharmaceutical composition comprises a crystalline form of the compound of formula (I-3), or a pharmaceutically acceptable salt or solvate thereof. 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 may comprise the free base of the compound of formula (I-3), wherein at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.5% by weight of the free base of the compound of formula (I-3) present in the pharmaceutical composition is in crystalline form, as determined, for example, 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 may comprise a pharmaceutically acceptable salt of the compound of formula (I-3), wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of formula (I-3) present in the pharmaceutical composition is in crystalline form, as determined, for example, by X-ray powder diffraction and / or mDSC.

[0122] In some embodiments, the pharmaceutical composition comprises an amorphous form of the compound of Formula (I-3), or a pharmaceutically acceptable salt or solvate thereof. 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; for example, no crystalline form of the compound of Formula (I-3) is detected, for example, by XRPD. In some embodiments, the pharmaceutical composition comprises a highly pure amorphous form of the compound of Formula (I-3) as a free base. For example, the pharmaceutical composition may 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, as determined, for example, 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 may 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, as determined, for example, by X-ray powder diffraction and / or mDSC.

[0123] In addition to the compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph, or solvate, the pharmaceutical composition of the present disclosure may also include a pharmaceutically acceptable vehicle. A "pharmaceutically acceptable vehicle" may be a vehicle approved by a federal or state government regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, such as humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier in which the compound of the present disclosure is formulated for administration to a mammal. Such a pharmaceutically acceptable vehicle may be solid or liquid. Pharmaceutically acceptable vehicles may include water, saline, juices, including fruit juices, especially those containing citric acid (e.g., orange juice such as Tang, grape juice, apple juice, cranberry juice, pineapple juice, etc.), oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Pharmaceutically acceptable vehicles include, but are not limited to, adjuvants, stabilizers, solubilizers, thickeners, lubricants, binders, granulating agents, bulking agents, diluents, disintegrants, wetting agents, glidants, anti-caking agents, colorants, sweeteners, dye transfer inhibitors, preservatives, antioxidants, lyoprotectants, complexing agents, flavoring agents, matrix-forming agents, dispersants, performance modifiers, controlled-release polymers, solvents, pH adjusters, carbon dioxide sources, or other pharmaceutical additives described herein. In some embodiments, Tang orange beverage is used as a pharmaceutically acceptable vehicle. In addition to water, Tang orange beverage may 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.

[0124] Among these pharmaceutically acceptable vehicles, some organic acids are suitable for the psilocin-d 10It has been identified that organic acid vehicles provide both stabilizing and solubilizing functions to a compound (e.g., a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof), thereby improving the delivery and therapeutic properties of the dosage forms of the present disclosure. These organic acid vehicles, which provide inherent stabilizing and solubilizing effects (acting as stabilizers / solubilizers), may be referred to herein as "organic acid reagents." In a preferred embodiment, a pharmaceutical composition comprises a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and an organic acid reagent. The pharmaceutical composition may optionally be formulated with other pharmaceutically acceptable vehicles, as needed or desired.

[0125] In some embodiments, a solid dosage form is formulated using an organic acid reagent, in which case the organic acid reagent is considered to be separate and distinct from the compound of Formula (I-3) or its pharmaceutically acceptable salt, polymorph, or solvate. That is, when formulated into a solid dosage form, the organic acid reagent is not considered to form a salt with the compound of Formula (I-3). For example, in those embodiments in which the pharmaceutical composition is a solid dosage form formulated with the free base of the compound of Formula (I-3), the organic acid reagent is not considered to form an addition salt with the compound of Formula (I-3); instead, the compound of Formula (I-3) remains as a free base, at least until it dissolves / disintegrates in an appropriate medium (e.g., water, juice, saline, saliva, etc.). In another example, when a pharmaceutical composition is formulated using a salt form of the compound of Formula (I-3), the organic acid reagent remains separate from the salt form and provides a stabilizing / solubilizing effect that exceeds the effect provided by the salt form of the compound of Formula (I-3) alone.

[0126] The organic acid reagent may be any organic acid described herein and may be a mono-, di-, tri-, tetra-, or more acid group. One organic acid reagent or a mixture of organic acid reagents may be used. In addition to an acid group (e.g., one or more carboxylic acid moieties), the organic acid reagent may also contain one or more hydroxyl functional groups as part of its structure (i.e., the organic acid reagent may be a hydroxy acid). In some embodiments, the organic acid reagent is an α-hydroxy acid. In some embodiments, the organic acid reagent is a β-hydroxy acid. In some embodiments, the organic acid reagent 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 reagent is citric acid and / or tartaric acid. In some embodiments, the organic acid reagent is citric acid. In some embodiments, the organic acid reagent is tartaric acid. In some embodiments, the organic acid reagent is an enedioic acid, examples of which include, but are not limited to, fumaric acid and maleic acid. In some embodiments, the organic acid reagent is fumaric acid. In some embodiments, the organic acid reagent is maleic acid. Mixtures and / or hydrates of the disclosed organic acid reagents may also be used in the pharmaceutical compositions of the present disclosure. In some embodiments, the organic acid reagent 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 reagent is not a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.).

[0127] In some embodiments, the pharmaceutical composition comprises at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, and up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 27%, up to 25%, up to 23%, up to 20%, up to 18%, up to 16%, or any range therebetween, by weight of the organic acid reagent, based on the total weight of the pharmaceutical composition (or on a dry weight basis). For example, the pharmaceutical composition may contain, based on the total weight of the pharmaceutical composition (on a dry weight basis), 1% to 20% by weight of the organic reagent, or 2% to 10% by weight of the organic reagent, or 5% to 40% by weight of the organic acid reagent, or 10% to 30% by weight of the organic reagent, or 15% to 20% by weight of the organic acid reagent, or 2% to 3% by weight of the organic acid reagent, or about 2.5% to 3% by weight of the organic acid reagent. A dry weight basis may refer to a pharmaceutical composition in solid or liquid dosage form after subtracting the weight contribution from water or other pharmaceutically acceptable aqueous medium (e.g., fruit juice).

[0128] In some embodiments, the weight ratio of organic acid reagent to compound of Formula (I-3) (active substance 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, and 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.

[0129] When a pharmaceutical composition is formulated using a pharmaceutically acceptable salt of the compound of formula (I-3), the acid used in forming the pharmaceutically acceptable salt of the compound of formula (I-3) and the organic acid reagent (vehicle) may be the same. For example, the pharmaceutical composition may contain a tartrate salt of the compound of formula (I-3) (e.g., I-3b) and tartaric acid as the organic acid reagent (vehicle). In another example, the pharmaceutical composition may contain a citrate salt of the compound of formula (I-3) (e.g., I-3e) and citric acid as the organic acid reagent (vehicle).

[0130] When a pharmaceutical composition is formulated using 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 reagent (vehicle) may be different. For example, the pharmaceutical composition may contain a benzenesulfonic acid salt of the compound of Formula (I-3) (I-3a) and citric acid and / or tartaric acid as the organic acid reagent (vehicle). In another example, the pharmaceutical composition may contain a benzoic acid salt of the compound of Formula (I-3) (e.g., I-3j) and citric acid and / or tartaric acid as the organic acid reagent (vehicle).

[0131] Any of the pharmaceutical compositions disclosed herein formulated with an organic acid reagent may contain an uncoated organic acid reagent or may contain an organic acid reagent coated with a pharmaceutically acceptable vehicle (a "coated organic acid reagent"). Examples of coated organic acid reagents are described below.

[0132] The pharmaceutical compositions disclosed herein can be administered at once or at intervals of several times.It is understood that the exact dosage and duration of treatment can vary according to the age, weight and condition of the patient being treated, and can be empirically determined by using the protocol of known test or by extrapolating from in vivo or in vitro test or diagnostic data.It is further understood that for any specific individual, specific dosage regimen should be adjusted over time according to individual need and the professional judgment of the person who manages or supervises the administration of the preparation.

[0133] If the patient's condition does not improve, at the physician's discretion, the compound may be administered chronically, i.e., for an extended period of time, such as throughout the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0134] If the patient's condition improves, the compound may be continued or temporarily discontinued for a period of time (i.e., a "drug holiday"), at the physician's discretion.

[0135] Once the patient's condition has improved, a maintenance dose is administered as needed.Then, the dosage or frequency of administration, or both, can be reduced depending on the symptoms, to a level at which the improved condition is maintained.However, the patient may need to be treated intermittently for a long period of time if symptoms recur.

[0136] The pharmaceutical composition may be in the form of a capsule, tablet, pill, pellet, lozenge, powder, granule, syrup, elixir, solution, suspension, emulsion, or sustained-release formulation thereof, or any other form suitable for administration to a mammal. Administration of the subject compound may be systemic or local. In some cases, the pharmaceutical composition is formulated for administration to humans according to routine procedures as a pharmaceutical composition adapted for oral administration or other administration routes described herein. Examples of suitable pharmaceutically acceptable vehicles and their formulation methods are described in Chapters 86, 87, 88, 91, and 92 of Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co., Easton, Pa., 19th ed., 1995, which are incorporated herein by reference. The choice of vehicle will be determined in part by the particular compound, salt form, and the particular method used to administer the composition. Accordingly, there are a wide variety of suitable formulations for the subject pharmaceutical compositions. Liquid form preparations include solutions and emulsions, for example, water, water / propylene glycol solution or organic solvent.When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable vehicles can be sterilized.In some cases, for example, when the subject compound is orally administered, aqueous medium such as water or fruit juice is used as vehicle.

[0137] Any of the pharmaceutical compositions described herein may contain (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 containing the compounds disclosed herein may be formulated in a variety of dosage forms and may be specifically formulated for administration in solid, semi-solid, or liquid form, including those compatible with the following: A. Oral administration, e.g., liquids (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boli, powders, granules, syrups, pastes for application to the tongue; B. Modified-release dosage forms, such as delayed-release, sustained-release, extended-release, sustained-release, pulsed-release, controlled-release, accelerated-release, rapid-release, targeted-release, programmed-release, and gastric retention dosage forms, which can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).

[0138] Tamper-resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated.

[0139] A. Oral Administration 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, for example, enteral delivery, in which the drug is taken orally and swallowed, and oral administration through the mucous membrane 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, lozenges, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent dosage forms (for example, effervescent or non-effervescent tablets, films, powders or granules), liquids, emulsions, suspensions, solutions, wafers, films, sprinkles, elixirs and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable vehicles (e.g., carriers or excipients), including, but not limited to, adjuvants, stabilizers, solubilizers, thickeners, lubricants, binders, granulating agents, bulking agents, diluents, disintegrants, wetting agents, glidants, anti-caking agents, colorants, sweeteners, dye transfer inhibitors, preservatives, antioxidants, lyoprotectants, complexing agents, flavoring agents, matrix-forming agents, performance modifiers, release-controlling polymers, solvents, pH adjusters, and carbon dioxide sources. In some embodiments, the pharmaceutically acceptable vehicle comprises an organic acid reagent, which, as discussed herein, has been found to offer unique advantages as both a stabilizer and a solubilizer, aiding in release from the dosage forms of the present disclosure and providing stabilization of the compounds herein.

[0140] In some embodiments, the pharmaceutical compositions of the present disclosure may be orodispersible dosage forms (ODx), including sublingual dosage forms, buccal dosage forms, such as orally disintegrating tablets (ODTs) (sometimes also referred to as fast-disintegrating tablets, orodispersible tablets, or rapid-dispersing tablets), or orodispersible films (ODFs) (or wafers). Such dosage forms may be particularly advantageous in the present disclosure, for example, when administered intraorally through the mucosal lining of the oral cavity, e.g., buccal, lingual, and sublingual administration, because they provide increased bioavailability and a more rapid onset of action compared to oral administration via the gastrointestinal tract, allowing for pre-gastric absorption of the compounds / salts herein. Furthermore, orodispersible dosage forms may be advantageous for treating pediatric / adolescent patients, or for treating patients who generally have difficulty swallowing conventional dosage forms, such as regular tablets or capsules.

[0141] In some embodiments, the orodispersible 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 mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the 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, when mixed with saliva, and then swallowed. In some embodiments, the orodispersible dosage form (ODx) is a buccal dosage form that disintegrates / dissolves in the oral cavity, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the mucosal lining of the oral cavity into the mouth, whereby they enter the venous circulation there. In some embodiments, the buccal dosage form disintegrates / dissolves in the oral cavity, whereby the contents are converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, when mixed with saliva, and then swallowed. In addition to the active ingredient, the orodispersible dosage form (ODx) pharmaceutical composition may include one or more pharmaceutically acceptable vehicles (e.g., one or more of a binder, a filler, a diluent, a disintegrant, a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, a carbon dioxide source, a bioadhesive agent, etc., and / or any other pharmaceutically acceptable vehicle described herein with specific reference to the organic acid reagent).

[0142] Orodispersible dosage forms can be prepared by various techniques, such as, for example, freeze drying (lyophilization), molding, spray drying, mass extrusion, or compression. In some embodiments, the orodispersible dosage form is prepared by lyophilization. In some embodiments, the orodispersible dosage form disintegrates in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the orodispersible dosage form dissolves in 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 orodispersible dosage form disperses in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being received in the oral cavity. In some embodiments, the pharmaceutical composition has a disintegration test of about 30 seconds or less, about 20 seconds or less, about 10 seconds or less, about 5 seconds or less, or about 2 seconds or less in the United States Pharmacopeia (USP). <701> The form of an orodispersible dosage form, such as an orally disintegrating tablet (ODT), having a disintegration time according to the United States Pharmacopeia (USP) Disintegration Test. <701> Orodispersible dosage forms having longer disintegration times, e.g., 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, are also contemplated, e.g., when adapted for sustained release.

[0143] 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 reagent (optionally coated), a binder, a filler, or a lubricant, 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 binders / fillers / diluents, such as lactose, mannitol, microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), polyvinylpyrrolidone (PVP), etc. In some embodiments, the sublingual tablet contains a lubricant, such as magnesium stearate. Other pharmaceutically acceptable vehicles, such as soluble excipients, dry binders, pH adjusters / buffers, surfactants, sweeteners, and flavoring agents, may also be used. A non-limiting example of a sublingual tablet formulation is one comprising a compound of Formula (I-3) (or a pharmaceutically acceptable salt, polymorph, or solvate thereof), an organic acid agent such as citric acid (which may optionally be coated), lactose, mannitol, PVP, and magnesium stearate, and optionally one or more additional pharmaceutically acceptable vehicles described herein.

[0144] In some embodiments, the sublingual tablet may comprise a single layer, a double layer, or a triple layer. In some embodiments, the single layer sublingual tablet 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 reagent such as citric acid). In some embodiments, the single layer sublingual tablet is effervescent and is formulated using an "effervescent couple," i.e., a combination of an organic acid reagent and a carbon dioxide source. In some embodiments, the double layer sublingual tablet contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid reagent 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 may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicle compared to when the vehicle and the active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and potentially increase the shelf life of the composition. In some embodiments, the bilayer sublingual tablet is an effervescent sublingual tablet, whereby the first layer is effervescent and comprises an effervescent couple and optionally another pharmaceutically acceptable vehicle, 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), and the second layer is either non-effervescent or effervescent. For trilayer sublingual tablets, each layer may be different, and Two of the layers, e.g., the upper and lower layers, may 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 may contain one or more vehicle components, e.g., a solubilizer, a stabilizer, etc. (e.g., an organic acid reagent such as citric acid). In some embodiments, the lower and upper layers have the same composition.Alternatively, the lower and upper layers may contain different vehicles, or may contain different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As noted above, the configuration of such tri-layer sublingual tablets keeps the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the tri-layer sublingual tablet is an effervescent sublingual tablet, whereby at least one, at least two, or all three of the layers are effervescent (formulated using an effervescent couple). In some embodiments, the bottom and top layers are effervescent and comprise an organic acid reagent (e.g., citric acid), a carbon dioxide source, 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), and the core layer is either non-effervescent or effervescent.

[0145] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orodispersible dosage form, such as a lyophilized ODT. In some embodiments, the lyophilized orodispersible dosage form (e.g., a lyophilized ODT) is prepared by forming a porous matrix by sublimation of water from a pre-frozen aqueous formulation of a drug containing a matrix-forming agent and other vehicles as described herein, such as one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the orodispersible dosage form comprises a two-component framework of a lyophilized matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, 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 promoter such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), calcium diphosphate, and / or starch, which acts by anchoring the porous framework provided by the water-soluble polymer and promoting disintegration of the orodispersible dosage form. In some embodiments, the lyophilized orodispersible dosage form (e.g., lyophilized ODT) comprises gelatin and mannitol. In some embodiments, the lyophilized orodispersible dosage form (e.g., lyophilized ODT) comprises gelatin, mannitol, and one or more of the other pharmaceutically acceptable vehicles described herein, with specific reference to cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, and / or organic acid agents (e.g., citric acid). A non-limiting example of an ODT formulation is Zydis® orally dispersible tablets (available from Catalent).In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) comprises one or more water-soluble polymers, such as gelatin, one or more matrix materials, fillers, or diluents, such as mannitol, a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and optionally a cryoprotectant, preservative, antioxidant, stabilizer, solubilizer, flavoring agent, and / or another pharmaceutically acceptable vehicle described herein. In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) 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.

[0146] In some embodiments, the ODT can comprise a single layer, a double layer, or a triple layer. In some embodiments, the single layer ODT 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 reagent such as citric acid). In some embodiments, the single layer ODT is effervescent and is formulated using an "effervescent couple," i.e., a combination of an organic acid reagent and a carbon dioxide source. In some embodiments, the double layer ODT contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid reagent 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 may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles compared to when the vehicles and active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and potentially increase the shelf life of the composition. In some embodiments, the bilayer ODT is an effervescent ODT, whereby the first layer is effervescent and comprises 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, and the second layer is either non-effervescent or effervescent. For a three-layer ODT, each layer can be different, or two of the layers, e.g., the top and bottom layers, can have substantially the same composition. In some embodiments, the bottom and top 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 bottom and top layers can contain one or more vehicle components, such as, for example, a solubilizer, a stabilizer, etc. (e.g., an organic acid reagent such as citric acid). In some embodiments, the bottom and top layers have the same composition.Alternatively, the lower and upper layers may 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. As discussed above, the configuration of such a three-layer ODT keeps the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the three-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 couple). In some embodiments, the bottom and top layers are effervescent and comprise an organic acid reagent (e.g., citric acid), a carbon dioxide source, 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), and the core layer is either non-effervescent or effervescent.

[0147] In some embodiments, the pharmaceutical composition is in the form of a freeze-dried orodispersible film (ODF) (or wafer). In some embodiments, the pharmaceutical composition is in the form of a freeze-dried ODF protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the freeze-dried ODF is made by forming a porous matrix by sublimation of water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and other vehicles as described herein, such as one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, and / or other pharmaceutically acceptable vehicles as described herein. In some embodiments, the freeze-dried ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of a freeze-dried matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, 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 promoter such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose including silicified microcrystalline cellulose (SMCC), calcium diphosphate, and / or starch, which acts by anchoring the porous framework provided by the water-soluble polymer and promoting disintegration of the wafer. In some embodiments, the freeze-dried ODF comprises gelatin and mannitol. In some embodiments, the freeze-dried ODF comprises gelatin, mannitol, and one or more of the other pharmaceutically acceptable vehicles described herein, with specific reference to cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, and / or organic acid reagents (e.g., citric acid).

[0148] In some embodiments, the ODF (or wafer) can comprise a single layer, a double layer, or a triple layer. In some embodiments, the 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 reagent such as citric acid). In some embodiments, the single-layer ODF (or wafer) is effervescent and formulated with an effervescent couple. In some embodiments, the double-layer ODF (or wafer) contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid reagent 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 may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicle compared to when the vehicle and the active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and possibly increase the shelf life of the composition. In some embodiments, the bilayer ODF (or wafer) is an effervescent ODF (or wafer), whereby the first layer is effervescent and comprises 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), and the second layer is either non-effervescent or effervescent. Three-layer ODFs (or wafers) For example, in the case of a granule-shaped tablet (oblate), each layer may be different, or two of the layers, e.g., an upper and lower layer, may 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 may contain one or more vehicle components, such as a solubilizer, stabilizer, etc. (e.g., an organic acid reagent such as citric acid).In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers may 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. As described above, the construction of such a three-layer ODF (or wafer) keeps the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the three-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 bottom and top layers are effervescent and comprise an organic acid reagent (e.g., citric acid), a carbon dioxide source, 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), and the core layer is either non-effervescent or effervescent.

[0149] Examples of pharmaceutically acceptable cryoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, anionic polymers such as sulfobutylether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0150] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0151] Examples of pharmaceutically acceptable antioxidants that may be effective to further enhance the stability of the compositions include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​or its salts (cysteine ​​hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0152] Examples of pharmaceutically acceptable stabilizers include, but are not limited to, organic acid reagents (e.g., citric acid), fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerol, methionine, monothioglycerol, ascorbic acid, polysorbates, arginine, cyclodextrins, microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), modified celluloses (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0153] Examples of pharmaceutically acceptable solubilizers (or solubilizing agents) include, but are not limited to, organic acid reagents (e.g., citric acid, fumaric acid, DL-malic acid, tartaric acid, lactic acid, maleic acid, etc.), hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl 40 stearate, purified shellac, sodium dehydroacetate, L-ascorbic acid stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, powdered agar, guar gum, succinic acid, copolyvidone, cellulose acetate phthalate, sodium dioctyl sulfosuccinate, zein, nonfat powdered milk, sorbitan trioleate, aluminum lactate, palmitoyl cellulose, sorbitan hydroxypropyl ... Examples of suitable surfactants include ascorbyl tincture, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, poly(sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, lauromacrogol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate. Of these, citric acid is preferred in some embodiments.

[0154] Flavoring agents include natural flavors extracted from plants such as fruit, and synthetic blends of compounds that produce pleasant taste and taste-masking effects.Examples of flavoring agents include, but are not limited to, aspartame, saccharin (as saccharin sodium, saccharin potassium, or saccharin calcium), cyclamate (as sodium, potassium, or calcium salt), sucralose, acesulfame K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, glucose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, orange flavor, lemon, lime, and lemon lime.

[0155] 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 solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0156] For example, pharmaceutical compositions adapted for oral administration, such as capsules and tablets, including compressed tablets, can be formulated with a variety of vehicles, such as those described herein. Examples of suitable vehicles can include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, anti-caking agents, colorants, dye transfer inhibitors, sweeteners, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, adjuvants, thickeners, lubricants, granulating agents, cryoprotectants, complexing agents, matrix-forming agents, dispersing agents, performance modifiers, release-controlling polymers, solvents, pH adjusters, and carbon dioxide sources.

[0157] Binders or granulating agents impart cohesiveness to capsules or tablets, ensuring that the dosage form remains intact and unchanged after compression. Suitable binders or granulating agents include starches, such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrin, molasses, and lactose; natural and synthetic gums, such as acacia (gum arabic), alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch abogalactan, etc. Suitable bulking agents include, but are not limited to, cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC); microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable bulking agents include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, partially hydrolyzed starch (e.g., maltodextrin), and mixtures thereof.In some embodiments, the binder, granulating agent, or filler is present in about 1 wt%, about 5 wt%, about 10 wt%, about 20 wt%, about 30 wt%, about 40 wt%, about 50 wt% to about 99 wt%, about 90 wt%, about 80 wt%, about 70 wt%, about 60 wt%, or any range therebetween, based on the total weight of the pharmaceutical compositions disclosed herein.

[0158] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can give some compressed tablets the property of being able to disintegrate in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0159] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resin; alginic acid; gum, such as guar gum and Veegum HV; citrus pulp; cross-linked cellulose, such as croscarmellose; cross-linked polymer, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), such as sodium starch glycolate, polacrilin potassium; starch, such as corn starch, potato starch, tapioca starch, pregelatinized starch and partially hydrolyzed starch; clay; align; and mixtures thereof.The amount of disintegrant in the pharmaceutical compositions disclosed herein varies according to the type of formulation, and is easily recognized by those skilled in the art. In some embodiments, the pharmaceutical compositions disclosed herein contain, for example, about 0.5 wt%, about 1 wt%, about 3 wt%, about 5 wt%, about 10 wt%, about 15 wt%, to about 50 wt%, about 40 wt%, about 30 wt%, about 20 wt% of disintegrant, for example, about 1 to about 5 wt% of disintegrant, based on the total weight of the pharmaceutical composition.

[0160] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycols (PEG) (e.g., PEG 4,000, PEG 6,000, PEG 8,000, etc., the numbers referring to the approximate average molecular weight of the PEG); stearic acid; sodium lauryl sulfate; sodium stearyl fumarate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; club moss; silica or silica gel, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA); 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 %, up to about 20 wt %, about 15 wt %, about 10 wt %, about 7 wt % of a lubricant, e.g., about 0.1 wt % to about 5 wt % of a lubricant, based on the total weight of the pharmaceutical composition.

[0161] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Massachusetts), and asbestos-free talc.

[0162] Suitable anti-caking agents include, but are not limited to, silicon dioxide.

[0163] Coloring agents include any of the approved, certified, water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrate, as well as color lakes, and mixtures thereof. Color lakes are combinations of water-soluble dyes by adsorption onto hydrous heavy metal oxides, resulting in an insoluble form of the dye.

[0164] Sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweetening agents, such as saccharin and aspartame.

[0165] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0166] Suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0167] Preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0168] Wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0169] Solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0170] Examples of pH adjusters include acids (including organic acid reagents) such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, and phosphoric acid; bases including salts of organic acid reagents, such as 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., monoammonium citrate, diammonium citrate, and / or tripotassium citrate), and the like. or triammonium citrate), ammonium tartrate (e.g., monoammonium tartrate and / or diammonium 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, etc., and buffers generally comprising a mixture of an acid and a salt of the acid.

[0171] Carbon dioxide sources may include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, and sesquicarbonate. Carbon dioxide sources may be used alone or in combination.

[0172] As mentioned above, preferred dosage forms are those formulated with an organic acid reagent that can act as a stabilizer and / or solubilizer in the disclosed pharmaceutical compositions. The organic acid reagent may be any of those described herein with specific reference to citric acid and / or tartaric acid.

[0173] In some embodiments, the dosage form is a tablet. In some embodiments, the tablet (e.g., a conventional tablet, including compressed tablets) can comprise a single layer, a double layer, or a triple layer. In some embodiments, the single layer tablet 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 reagent such as citric acid). In some embodiments, the single layer tablet is effervescent and is formulated with an effervescent couple. In some embodiments, the double layer tablet contains one or more pharmaceutically acceptable vehicles (e.g., an organic acid reagent 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 may optionally contain one or more pharmaceutically acceptable vehicles. This configuration allows the active ingredient to be stored separately from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles compared to when the vehicles and active ingredient are contained in a single layer, which in some instances may increase the stability of the active ingredient and potentially increase the shelf life of the composition. In some embodiments, the bilayer tablet is an effervescent sublingual tablet, whereby the first layer is effervescent and comprises 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, and the second layer is either non-effervescent or effervescent. For trilayer tablets, each layer may be different, or two of the layers, e.g., the upper and lower layers, may 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 may contain one or more vehicle components, such as, for example, a solubilizer, a stabilizer, etc. (e.g., an organic acid reagent such as citric acid). In some embodiments, the lower and upper layers have the same composition.Alternatively, the lower and upper layers may contain different vehicles, or may contain different amounts of the same vehicle. The core layer typically contains an active ingredient, optionally with one or more pharmaceutically acceptable vehicles. As noted above, such trilayer tablet configurations keep the active ingredient separate from all or certain pharmaceutically acceptable vehicles, minimizing or completely preventing contact between the active ingredient and the vehicles. In some embodiments, the 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 bottom and top layers are effervescent and comprise an organic acid reagent (e.g., citric acid), a carbon dioxide source, 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), and the core layer is either non-effervescent or effervescent.

[0174] It should be understood that many vehicles (carriers, excipients, etc.) can serve multiple functions, even within the same formulation. For example, particular reference is made herein to pharmaceutical compositions containing organic acid reagents such as citric acid, which can serve multiple roles: as a stabilizer for stabilizing the silosin compounds of the present disclosure in free base or salt form, as a solubilizer for rapidly dissolving the active ingredient to provide rapid onset of action, particularly for dosage forms adapted for rapid onset and short duration of drug action, such as orally dispersible dosage forms (e.g., ODTs and ODFs), as a flavoring agent, as a pH adjuster, and / or as an antioxidant.

[0175] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more vehicles (e.g., carriers or excipients) described herein, including binders, disintegrants, release-controlling polymers, pH adjusters, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0176] The pharmaceutical compositions herein may be in any of the above-mentioned coated forms, such as compressed tablets, powder tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or coated tablets, such as enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Coated tablets are tablets coated with one or more layers of pharmaceutically acceptable vehicles, such as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers, polyols, waxes, organic bases, coloring substances approved by appropriate national or regional authorities, and flavoring substances, or mixtures of vehicles. Such coating materials generally do not contain any active ingredients, such as the compounds described herein (e.g., the compound of Formula (I-3) or its pharmaceutically acceptable salts, polymorphs, or solvates). Tablets may be coated for various 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 material used for coating may be applied as a solution or suspension. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredients from the acidic stomach environment. Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a 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 produced using multiple compression cycles, including layered tablets, compression-coated tablets, and dry-coated tablets.

[0177] In some embodiments, a 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.

[0178] In some embodiments, the tablet composition is a modified release tablet adapted for sustained release, preferably for maximum sustained release.In some embodiments, in the formulations of the present disclosure, the release period of any of the compounds described herein (e.g., the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate) is more than 4 hours, more than 6 hours, more than 8 hours, more than 10 hours, more than 12 hours, more than 16 hours, more than 20 hours, more than 24 hours, more than 28 hours, more than 32 hours, more than 36 hours, or more than 48 hours.

[0179] In some embodiments, the tablet composition is adapted for tamper resistance. In some embodiments, the tablet composition comprises polyethylene oxide (PEO) of about 2,000 to about 7,000 KDa MW, e.g., in combination with HPMC. In some embodiments, the tablet composition may further comprise polyethylene glycol (PEG), e.g., PEG 8,000. In some embodiments, the tablet composition may further comprise a polymer carrying one or more negatively charged groups, e.g., polyacrylic acid. In some embodiments, the tablet composition comprising PEO is further subjected to heating / annealing, e.g., under extrusion conditions.

[0180] In some embodiments, the pharmaceutical composition comprises a combination of (i) a water-insoluble, neutrally charged nonionic matrix, (ii) a polymer bearing one or more negatively charged groups, and (iii) any of the compounds described 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 reagents, lubricants, etc., may optionally be included.

[0181] In some embodiments, the water-insoluble, neutrally charged nonionic matrix is ​​selected from a cellulose-based polymer such as microcrystalline cellulose polymer or HPMC, either alone or by being mixed 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 hydroxypropylmethylcellulose (HPMC).In some embodiments, the cellulose-based polymer is a microcrystalline cellulose polymer such as silicified microcrystalline cellulose (SMCC). In some embodiments, the pharmaceutical composition (e.g., tablet or capsule) comprises about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, or any range therebetween, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a microcrystalline cellulose polymer, such as silicified microcrystalline cellulose (SMCC), in an amount of about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, or any range therebetween, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a combination of HPMC and starch.

[0182] 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, polymethacrylate carboxylate, cation exchange resins, clays, zeolites, hyaluronic acid, anionic gums, their salts, and mixtures thereof. In some embodiments, the anionic gum is selected from the group consisting of naturally occurring substances and semi-synthetic substances. In some embodiments, the naturally occurring substances are selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, karaya gum, guar gum, and tragacanth gum. In some embodiments, the semi-synthetic substances are selected from the group consisting of carboxymethyl-chitin and cellulose gum (sodium carboxymethylcellulose). In some embodiments, the pharmaceutical composition comprises about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10% by weight of a polymer carrying one or more negatively charged groups, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises, for example, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5% by weight of cellulose gum (sodium carboxymethylcellulose), based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical product comprises a combination of HPMC and starch.

[0183] Furthermore, without intending to be bound by theory, in some embodiments, the role of a polymer bearing one or more negatively charged groups, e.g., a moiety of acidic nature such as the acidic polymers described herein, surprisingly results in significant retention of any of the compounds described herein (e.g., the 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, for example, based on the release of a proton due to the pKa and under certain pH conditions, or through electrostatic interactions / negative charge generation. It is further noted that the acidic polymer can be a salt of a corresponding weak acid that becomes the relevant protonated acid in the stomach; without wishing to be bound by theory, this can result in charge neutralization and reduce the interaction of any of the compounds described herein (e.g., the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) with the matrix. Additionally, the release matrix may be further supplemented with other inert pharmaceutical ingredients that aid in the preparation of a suitable solid dosage form, such as fillers, disintegrants, flow improvers, lubricants, colorants, and taste masking agents.

[0184] Disclosed herein are pharmaceutical compositions in modified release dosage forms comprising a compound 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 vehicles described herein. Suitable controlled-release vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical composition may also comprise a non-controlled-release vehicle.

[0185] In some embodiments, oral pharmaceutical compositions are for low-dose maintenance therapy that can be formulated using compounds described herein that utilize their ability to bind anionic polymers.

[0186] Additionally, disclosed herein are pharmaceutical compositions in enteric-coated dosage forms comprising a compound 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 vehicles for use in enteric-coated dosage forms. The pharmaceutical composition may also include a non-controlled-release vehicle.

[0187] Additionally, disclosed herein are pharmaceutical compositions in effervescent dosage forms comprising a compound 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 may be controlled-release vehicles and / or non-controlled-release vehicles. Effervescent means that the dosage form releases gas when mixed with a liquid, including water, juice, saliva, and the like. Generally, the effervescent dosage forms of the present disclosure comprise an organic acid reagent and a carbon dioxide source, referred to herein as an "effervescent couple." Such effervescent dosage forms effervescent (release gas) through a chemical reaction between the organic acid reagent and the carbon dioxide source. Effervescence occurs upon exposure to an aqueous environment, such as when placed in water, juice, or other drinkable liquid, or from the aqueous environment in the oral cavity, such as saliva in the mouth. Specifically, a reaction between an organic acid reagent and a carbon dioxide source produces carbon dioxide gas upon contact with an aqueous medium, such as, for example, water, juice, or saliva. While the use of a disintegrant is optional, effervescent dosage forms do not require a disintegrant because the disintegration process is facilitated by in situ gas generation.

[0188] For purposes of clarity, "effervescent couple" refers to at least one organic acid reagent and at least one carbon dioxide source contained in a dosage form, regardless of assembly. For example, the organic acid reagent and carbon dioxide source may be mixed (as powders), layered on top of each other, agglomerated or otherwise "glued" together in the form of granules, or kept separate from each other, for example, in separate layers within the dosage form. Furthermore, the term "couple" in this context is not intended to be limited to only the organic acid reagent and the carbon dioxide source, and is open to the inclusion of other materials unless otherwise specified. For example, an effervescent aggregate / granule made by bringing together (or "gluing") an organic acid reagent and a carbon dioxide source may include other vehicles, including a binder ("adhesive"), and the effervescent aggregate / granule may still be referred to as an effervescent couple.

[0189] 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, reactants that liberate oxygen or gases other than carbon dioxide and that are safe for human consumption are also contemplated for use in the disclosed effervescent dosage forms in addition to or in place of a carbon dioxide source. Without wishing to be bound by theory, it is believed that effervescence helps to rapidly disintegrate the dosage form and, for some routes of administration, such as the oral route, may help reduce the perception of grittiness by providing a distracting effervescent sensory experience.

[0190] In some embodiments, the effervescent dosage form is reconstituted in a drinkable fluid, such as water or juice, to form an oral liquid dosage form (e.g., a solution), which is then ingested. In some embodiments, the effervescent dosage form is placed in the oral cavity, where it comes into contact with an aqueous environment (saliva) and effervesces, causing disintegration / dissolution of the dosage form. Here, the contents of the effervescent dosage form are converted into a liquid or semi-solid dosage form, such as a solution, syrup, or paste, upon mixing with saliva, which can then be swallowed. Alternatively, the effervescent dosage form may be an intraoral dosage form, such as a buccal, lingual, or sublingual dosage form, where it is placed in the aqueous environment (saliva) of the oral cavity, where it effervesces, causing disintegration / dissolution of the dosage form, resulting in pre-gastric absorption of the contents through the oral mucosa. Such pre-gastric absorption may increase bioavailability and provide a rapid onset of action compared to oral administration via the digestive tract. In some embodiments, the effervescent dosage form is a sublingual dosage form that disintegrates / dissolves under the tongue, thereby allowing the contents (e.g., a compound of the present disclosure) to be absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the effervescent dosage form is a buccal dosage form that disintegrates / dissolves in the oral cavity, thereby allowing the contents (e.g., a compound of the present disclosure) to be absorbed through the oral mucous membrane lining the mouth and enter the venous circulation there. Because effervescent dosage forms can be reconstituted into an easy-to-swallow liquid or semi-solid dosage form or taken orally, they may be beneficial for treating pediatric / adolescent patients or patients who generally have difficulty swallowing conventional dosage forms, such as regular tablets or capsules.

[0191] When adapted for oral administration, it may be beneficial to formulate the effervescent dosage form with a bioadhesive in addition to the effervescent couple. A "bioadhesive" is a substance that promotes adhesion or attachment to a biological surface, such as a mucous membrane. For example, when placed in contact with a biological surface (e.g., a mucous membrane), the bioadhesive can adhere to the surface, thereby allowing the composition of the present disclosure to adhere to the surface and promoting more efficient transfer of the contents from the dosage form to the biological surface. Various polymers known in the art can be used as bioadhesives, such as polymeric substances, preferably polymeric substances having an average (weight average) molecular weight of more than 5,000 g / mol. Preferably, such polymeric substances are capable of rapidly swelling when placed in contact with an aqueous medium, such as water or saliva, and / or are substantially insoluble in water at room temperature and atmospheric pressure. Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, modified cellulose gum, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starch, modified starch, and sodium starch glycolate; acrylic polymers such as carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; methyl vinyl ether / maleic anhydride copolymer; and croscarmellose (e.g., croscarmellose sodium). Such polymers may be crosslinked. Combinations of two or more bioadhesives may also be used.

[0192] The effervescent couple can be coated with a pharmaceutically acceptable vehicle, such as, for example, a binder, a protective coating, e.g., a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjuster, to prevent premature reaction, e.g., due to air, moisture, and / or other components contained in the pharmaceutical composition. Each component of the effervescent couple, e.g., the organic acid reagent and / or the carbon dioxide source, can also be individually coated with a pharmaceutically acceptable vehicle, e.g., a binder, a protective coating, e.g., a solvent protective coating, an enteric coating, an anti-caking agent, and / or a pH adjuster, to prevent premature reaction, e.g., due to air, moisture, and / or other components contained in the pharmaceutical composition. The effervescent couple can also be mixed with previously lyophilized particles, e.g., one or more pharmaceutically active ingredients coated with a solvent protective coating or an enteric coating.

[0193] Effervescent dosage forms may be prepared by methods known to those skilled in the art, including, but not limited to, slugging, direct compression, roller compaction, dry or wet granulation, fusion granulation, melt granulation, vacuum granulation, and fluidized bed spray granulation, any of which may optionally be followed by compression / tabletting.

[0194] The pharmaceutical compositions disclosed herein may be formulated as non-effervescent or effervescent granules and powders. The non-effervescent or effervescent granules and powders may be reconstituted into a liquid dosage form or alternatively compressed to form a tablet dosage form, either non-effervescent or effervescent, respectively. The pharmaceutically acceptable vehicle used in the non-effervescent or effervescent granules or powders may include, but is not limited to, binders, granulating agents, fillers, diluents, sweeteners, wetting agents, stabilizers, solubilizers, anti-caking agents, pH adjusters, or any other pharmaceutical vehicle described herein. In some embodiments, the pharmaceutically acceptable vehicle includes an organic acid agent, such as glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and / or maleic acid.

[0195] Pharmaceutically acceptable vehicles used in effervescent granules or powders include an effervescent couple, i.e., an organic acid reagent and a carbon dioxide source. Effervescent powders can be produced by blending or mixing the organic acid reagent and carbon dioxide source (effervescent couple) with, optionally, other desired pharmaceutically acceptable vehicles. Effervescent granules can be produced by physically adhering or "gluing" the effervescent couple (organic acid reagent and carbon dioxide source) together using an edible or pharmaceutically acceptable binder, including, for example, polyvinylpyrrolidone, polyvinyl alcohol, L-leucine, polyethylene glycol, gum arabic, or combinations thereof. These types of granules are generally made by a process known as "wet granulation." Granulation solvents, such as ethanol and / or isopropyl alcohol, are often used to aid this type of granulation process. Because the effervescent couple is physically bound together within the granules, the gas-generating reaction is usually very vigorous, leading to rapid dissolution times. Another type of "wet granulation" product specific to effervescent products is known as a "fused" granule. These granules are formed by reacting an organic acid reagent and a carbon dioxide source in a highly controlled manner with a small amount of water (or sometimes a hydroalcoholic granulation solvent, such as various commercial grades of ethanol or isopropyl alcohol). Because the effervescent reaction produces carbon dioxide, fused granules tend to be very porous, which reduces their density and also their dissolution time. Therefore, effervescent granules prepared by wet granulation or fusion processes may be desirable for making orodispersible dosage forms (ODx) or other dosage forms requiring rapid dissolution / disintegration performance. Effervescent tablet dosage forms prepared by tableting, e.g., compression, of effervescent granules or powders are also included in the present disclosure.

[0196] Also disclosed are pharmaceutical compositions in dosage forms capable of discontinuously releasing a compound in at least two successive pulses separated by about 0.1 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) having an immediate-release component and at least one delayed-release component. The pharmaceutical compositions include a compound 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 and / or non-controlled-release vehicles, e.g., excipients or carriers suitable for disruptable semipermeable membranes and swellable materials.

[0197] Also disclosed herein is a pharmaceutical composition in a dosage form for oral administration to a subject, comprising a compound 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), encapsulated in a gastric juice-resistant outer layer and an intermediate reactive layer comprising a gastric juice-resistant polymer layer material that has been partially neutralized with alkali and has cation exchange capacity.

[0198] The dosage form may be an immediate release (IR) dosage form, examples of which include, but are not limited to, immediate release (IR) tablets or immediate release (IR) capsules. In addition to the API, dosage forms adapted for immediate release may contain one or more pharmaceutically acceptable vehicles that readily disperse, dissolve, or otherwise disintegrate in the gastric environment so as not to delay or prolong the dissolution / absorption of the API. Examples of pharmaceutically acceptable vehicles for immediate release dosage forms include, but are not limited to, one or more adjuvants, stabilizers, solubilizers, thickeners, lubricants, binders, granulating agents, fillers, diluents, disintegrants, wetting agents, glidants, anti-caking agents, colorants, sweeteners, dye transfer inhibitors, preservatives, antioxidants, cryoprotectants, complexing agents, flavoring agents, matrix-forming agents, dispersing agents, and performance modifiers. 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 silicified 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 silicified microcrystalline cellulose (SMCC), sodium carboxymethylcellulose, and magnesium stearate. In some embodiments, the immediate release (IR) dosage form comprises silicified 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 psilocin-d 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.

[0199] The pharmaceutical compositions disclosed herein may be disclosed as soft or hard capsules, which may be made from gelatin, methylcellulose, hydroxypropylmethylcellulose (HPMC), starch, or calcium alginate. Hard (e.g., gelatin, HPMC, etc.) capsules, also known as dry-filled capsules (DFCs) or powder-filled capsules (PICs), consist of two sections, one overlying the other, completely enclosing the active ingredient and any pharmaceutically acceptable vehicle. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin or HPMC shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms disclosed herein may be encapsulated within capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules may also be coated as known by those skilled in the art to control or maintain dissolution of the active ingredient.

[0200] In some embodiments, the pharmaceutical composition is in the form of an immediate release capsule for oral administration and may further comprise cellulose, iron oxide, lactose, magnesium stearate, and sodium starch glycolate.

[0201] In some embodiments, the pharmaceutical composition is in the form of a delayed release capsule for oral administration and may further comprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0202] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0203] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0204] Any of the pharmaceutical compositions disclosed herein formulated with an organic acid reagent may contain an uncoated organic acid reagent or may contain an organic acid reagent coated with a pharmaceutically acceptable vehicle ("coated organic acid reagent"). Various pharmaceutically acceptable vehicles can be used as coating materials to adjust the performance of the organic acid reagent and / or to prevent undesired or premature reactions with air, moisture, and / or other components contained in the pharmaceutical composition, for example, without losing the desired functionality of the organic acid reagent. A coated organic acid reagent may include a core of the organic acid reagent and a thin coating, such as, for example, a thin powder coating or a thin polymer coating. A coated organic acid reagent may also be in the form of a core-shell material, including a core of the organic acid reagent and a protective coating surrounding the core, such as, for example, a shell. Any of the organic acid reagents disclosed herein may be coated, including, but not limited to, glycolic acid, lactic acid, citric acid, tartaric acid, malic acid, fumaric acid, and maleic acid.

[0205] In some embodiments, the coated organic acid reagent 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 up to 15 wt.%, up to 10 wt.%, up to 9 wt.%, up to 8 wt.%, up to 7 wt.%, up to 6 wt.%, up to 5 wt.%, up to 4 wt.%, or any range therebetween, based on the total weight of the coated organic acid reagent, with the remainder being organic acid reagent when the coated organic acid reagent is formulated essentially only with the organic acid reagent and the coating.

[0206] In some embodiments, the organic acid reagent is coated with a water-soluble polymer, binder, granulating agent, bulking agent, etc. A non-limiting example of this type of coated organic acid reagent is Citric Acid DC (available from Jungbunzlauer), which is a directly compressible granular powder type of citric acid coated with a thin layer of maltodextrin.

[0207] In some embodiments, the organic acid reagent is coated with an anti-caking agent. Such coated organic acid reagents exhibit a high ability to absorb moisture. A non-limiting example of this type of coated organic acid reagent is citric acid S40 (available from Jungbunzlauer), which is a very fine (milled) granular powder of citric acid coated with silicon dioxide.

[0208] In some embodiments, the organic acid reagent is coated with a pH adjuster. In some embodiments, the organic acid reagent is coated with a salt of the organic acid reagent (i.e., a conjugate base salt of the organic acid reagent). The salt of the organic acid reagent may be an alkali metal salt of the organic acid reagent, an alkaline earth salt of the organic acid reagent, an ammonium salt of the organic acid reagent, or a mixture thereof, including a mixed salt of the organic acid reagent (e.g., a mixed salt of sodium and potassium). The salt of the organic acid reagent may be monobasic, dibasic, tribasic, etc. When the salt of the organic acid reagent is polybasic (dibasic, tribasic, etc.), the salt may be formed from a single cation (e.g., a sodium cation) or two or more different cations (e.g., a mixed salt having both sodium and potassium cations). Examples of salts of organic acid reagents 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., monoammonium citrate, diammonium citrate, and / or tripotassium citrate), or triammonium citrate), ammonium tartrate (e.g., monoammonium tartrate and / or diammonium 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 reagent coated with the organic acid reagent salt may be in the form of a core-shell material. The organic acid reagent (core) and the organic acid reagent salt (shell) may belong to the same conjugate acid-base pair.For example, the organic acid reagent (core) may be citric acid, and the salt (shell) of the organic acid reagent may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of citric acid. In another example, the organic acid reagent (core) may be tartaric acid, and the salt (shell) of the organic acid reagent may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of tartaric acid. In yet another example, the organic acid reagent (core) may be fumaric acid, and the salt (shell) of the organic acid reagent may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of fumaric acid. Alternatively, the organic acid reagent (core) and the salt (shell) of the organic acid reagent may belong to different conjugate acid-base pairs. For example, the organic acid reagent (core) may be citric acid, and the salt (shell) of the organic acid reagent may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of tartaric acid. In another example, the organic acid reagent (core) may be citric acid, and the salt of the organic acid reagent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of fumaric acid. In yet another example, the organic acid reagent (core) may be tartaric acid, and the salt of the organic acid reagent (shell) may be an alkali metal salt, alkaline earth salt, and / or ammonium salt of citric acid. A non-limiting example of an organic acid reagent coated with a salt of an organic acid reagent is Citrocoat® N (available from Jungbunzlauer), which is a granular powder made from citric acid as the core material and has a layer of monosodium citrate (1.5-3.5%) as the shell.

[0209] Coated organic acid reagents may be utilized in the effervescent dosage forms of the present disclosure, where the effervescent couple may be formed from any of the coated organic acid reagents disclosed herein and a carbon dioxide source. In contrast to uncoated organic acid reagents, the use of coated organic acid reagents in effervescent couples may advantageously provide the effervescent dosage form with improved storage stability without significantly sacrificing reactivity when placed in an aqueous environment, such as in water, juice, or other drinkable fluid, or from the aqueous environment in the oral cavity, such as saliva. A non-limiting example of an effervescent couple formulated with a coated organic acid reagent is Citrocoat® EP (available from Jungbunzlauer), which is an agglomerated granule made by combining Citrocoat® N (a citric acid core coated with a layer of 1.5-3.5% monosodium citrate as a shell) with sodium bicarbonate using gum arabic as a binder.

[0210] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I-3) as a crystalline free base and a coated organic acid reagent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid reagent. 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 has the following wavelengths as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604: 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°, 24.722°, 25.722°, 26.722°, 27.722°, 28.722°, 29.722°, 30.722°, 31.722°, 32.722°, 33.722°, 34.722°, 35.722°, 36.722°, 37.722°, 38.722°, 39.722°, 40.722°, 41.722°, 42.722°, 43.722°, 44.722°, 45.722°, 46.722°, 47.722°, 48.722°, 49.722°, 50.722°, 51.722°, 52.722°, 53.722°, 54.722°, 5 A crystalline solid form (Pattern 1) characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 4.630°, 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°.In some embodiments, I-3 is at 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°, 23.345°, 24.345°, 25.345°, 26.345°, 27.345°, 28.345°, 29.345°, 30.345°, 31.345°, 32.345°, 33.345°, 35.345°, 36.345°, 37.345°, 38.345°, 39.345°, 40.345°, 41.345°, 42.345°, 43.345°, 44.345°, 45.345°, 46.345°, 47.345°, 48.345°, 49.345°, 50.345°, 51.345°, 52.345°, 53.345°, 54.345°, 55.345°, a crystalline solid form (Pattern 2) characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ ± 0.2°) selected from 0.701°, 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°; and the X-ray powder diffraction pattern (Pattern 2) is described in WO 2022195011 and / or WO 2023078604.

[0211] In some embodiments, the pharmaceutical composition comprises the compound of Formula (I-3) as a free base in amorphous form and a coated organic acid reagent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid reagent. In some embodiments, this 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.

[0212] In some embodiments, the pharmaceutical composition comprises a crystalline form of a pharmaceutically acceptable salt of the compound of Formula (I-3) and a coated organic acid reagent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid reagent. In some embodiments, the pharmaceutically acceptable salt is the benzenesulfonate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3a). In some embodiments, salt I-3a has a molecular weight 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°, 23.007°, 24.007°, 25.007°, 26.007°, 27.007°, 28.007°, 29.007°, 30.007°, 31.007°, 32.007°, 33.007°, 34.007°, 35.007°, 36.007°, 37.007°, 38.007°, 39.007°, 40.007°, 41.007°, 42.007°, 43.007°, 44.007°, 45.007°, 46.007°, 47.007°, 48.007°, 49.007°, 50.007°, 51.007°, 52.007°, 53.007°, 54.007°, 55.007°, 56.007°, 57.007°, 58.007°, 59.007°, 60.007°, 61.007°, 62.007°, 63.007°, 64.007°, 65.007°, 66. It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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° (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-3j).In some embodiments, salt I-3j has a chromatographically determined peak intensity at 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°, 23.060°, as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604. It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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° (Pattern 1). In some embodiments, the pharmaceutically acceptable salt is the 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 a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, for example, as shown in WO2022195011 and / or WO2023078604.In some embodiments, salt I-3b has a molecular weight 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° as determined by XRPD using a CuKα radiation source, e.g., as shown in WO2022195011 and / or WO2023078604. , 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° (Pattern 2). 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 a crystalline solid form characterized by an X-ray powder diffraction pattern of Pattern 1, e.g., as shown in WO2022195011 and / or WO2023078604.In some embodiments, salt I-3c has the following peaks: 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°, 22.026°, 23.026°, 24.026°, 25.026°, 26.026°, 27.026°, 28.026°, 29.026°, 30.026°, 31.026°, 32.026°, 33.026°, 34.026°, 35.026°, 36.026°, 37.026°, 38.026°, 39.026°, 40.026°, 41.026°, 42.026°, 43.026°, 44.026°, 45.026°, 46.026°, 47.026°, 48.026°, 49.026°, 50.026°, 51.026°, 52.026°, 53.026°, 54.026°, 55.026°, 56.026°, 57.026°, 58.026°, 59.026°, 60.026°, 61.026°, 62.026°, 6 It is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 1.837°, 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° (Pattern 2).

[0213] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of Formula (I-3) in amorphous form and a coated organic acid reagent, such as coated citric acid, coated tartaric acid, or coated fumaric acid. For effervescent dosage forms, a carbon dioxide source (e.g., sodium bicarbonate) is also included with the coated organic acid reagent. In some embodiments, the pharmaceutically acceptable salt is the 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 an amorphous solid form when characterized by X-ray powder diffraction (XRPD).

[0214] When a pharmaceutical composition is formulated using a pharmaceutically acceptable salt of the compound of formula (I-3), the acid used in forming the pharmaceutically acceptable salt of the compound of formula (I-3) and the organic acid reagent (vehicle) may be the same. For example, the pharmaceutical composition may contain a tartrate salt of the compound of formula (I-3) (e.g., I-3b) and tartaric acid as the organic acid reagent (vehicle). In another example, the pharmaceutical composition may contain a citrate salt of the compound of formula (I-3) (e.g., I-3e) and citric acid as the organic acid reagent (vehicle).

[0215] When a pharmaceutical composition is formulated using 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 reagent (vehicle) may be different. For example, the pharmaceutical composition may contain a benzenesulfonic acid salt of the compound of Formula (I-3) (I-3a) and citric acid and / or tartaric acid as the organic acid reagent (vehicle). In another example, the pharmaceutical composition may contain a benzoic acid salt of the compound of Formula (I-3) (e.g., I-3j) and citric acid and / or tartaric acid as the organic acid reagent (vehicle).

[0216] The pharmaceutical compositions disclosed herein may be disclosed in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.

[0217] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form (e.g., an effervescent dosage form) disclosed herein in a pharmaceutically acceptable aqueous medium, such as, for example, water, juice, or other drinkable fluid, prior to use.

[0218] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising the compound of Formula (I-3) as a crystalline free base (e.g., I-3) in a pharmaceutically acceptable aqueous medium. The solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent. The effervescent solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent, and a carbon dioxide source.

[0219] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising the compound of formula (I-3) as an amorphous free base in a pharmaceutically acceptable aqueous medium.The solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent.The effervescent solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent, and a carbon dioxide source.

[0220] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I-3) in a pharmaceutically acceptable aqueous medium. The solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent. The effervescent solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent, and a carbon dioxide source.

[0221] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form comprising an amorphous form of a pharmaceutically acceptable salt of the compound of formula (I-3) in a pharmaceutically acceptable aqueous medium.The solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent.The effervescent solid dosage form may further be formulated with an organic acid reagent, including a coated organic acid reagent, and a carbon dioxide source.

[0222] In some embodiments, oral liquid dosage forms are prepared by first dissolving a solid dosage form according to any embodiment described herein in a pharmaceutically acceptable vehicle, such as an organic acid reagent, to create a stock solution, and then mixing the stock solution with a pharmaceutically acceptable aqueous medium, such as water, juice, or other drinkable fluid, prior to use. In some embodiments, the solid dosage form is dissolved in a solution of the organic acid reagent. In some embodiments, the organic acid reagent is citric acid. In some embodiments, the organic acid reagent is tartaric acid. In some embodiments, the stock solution is 0.01M, 0.05M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, or 1.0M, or any range therebetween.

[0223] In some embodiments, oral liquid dosage forms are prepared by first dissolving a solid dosage form comprising the 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 drinkable fluid, prior to use.

[0224] In some embodiments, the oral liquid dosage form is prepared by first dissolving a solid dosage form comprising the 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 drinkable fluid, prior to use.

[0225] Emulsions are two-phase systems, with one liquid dispersed in the form of small globules throughout the other, and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may contain a pharmaceutically acceptable di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxyl groups, e.g., propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain a preservative. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[0226] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients disclosed herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic 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, 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 chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0227] 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 solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0228] The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0229] Coloring and flavoring agents may be used in all of the above dosage forms.

[0230] The pharmaceutical compositions disclosed herein can be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that supplement the desired action.

[0231] B. Modified release The pharmaceutical compositions disclosed herein can be formulated as modified-release dosage forms. As used herein, the term "modified-release" refers to a dosage form in which the release rate or location of the active ingredient is different from that of an immediate-release dosage form when administered by the same route. Modified-release pharmaceutical compositions can be prepared using various release-modifying devices and methods known to those skilled in the art, including, but not limited to, matrix release control devices, osmotic release control devices, multiparticulate release control devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be adjusted by changing the particle size and polymorphism of the active ingredient.

[0232] 1. Matrix controlled release devices Modified-release dosage forms of the pharmaceutical compositions disclosed herein can be made using matrix release control devices known to those skilled in the art (see Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999).

[0233] In one embodiment, the pharmaceutical compositions disclosed herein in modified release dosage form are formulated using erodible matrix devices, which are water-swellable, erodible, or soluble polymers, including synthetic polymers, and natural polymers and derivatives, such as polysaccharides and proteins.

[0234] Materials useful for forming the erodible matrix include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose. Cellulose (EC), methylethyl 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 methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) methyl cellulose acetate trimellitate), and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0235] In a further embodiment, the pharmaceutical composition is formulated using a non-leaching matrix device: the active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Suitable materials for use as non-leaching matrix devices include insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers; and Hydrophilic polymers include, but are not limited to, ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate, and aliphatic compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0236] In matrix controlled-release systems, the desired release kinetics can be controlled, for example, through the type of polymer used, the polymer viscosity, 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.

[0237] The pharmaceutical compositions disclosed herein in modified release dosage forms may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0238] 2. Osmotic release controlled device The pharmaceutical compositions disclosed herein in modified-release dosage forms can be manufactured using osmotic release control devices, including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing an active ingredient, and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous environment into the core during use, causing drug release by extrusion through the delivery port.

[0239] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that generates a driving force for the transport of water from the environment of use into the core of the device. Water-swellable hydrophilic polymers, a type of osmotic agent, also referred to as "osmopolymers" and "hydrogels," include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, such as PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0240] Another type of osmotic agent is an osmogen, which can absorb water and affect an osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as glucose, 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.

[0241] Osmotic agents with different dissolution rates can be used 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, Delaware) can be used to provide more rapid delivery in the first few hours, resulting in an immediate desired therapeutic effect, with the remaining amount gradually and continuously released to maintain a desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0242] The core may also include various other excipients and carriers described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0243] Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH, or that are susceptible to being rendered water-insoluble by chemical modification, such as crosslinking. Examples of suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, and the like. acetate), amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-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, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0244] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially gas-filled and not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0245] Delivery ports in the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can be formed in situ by erosion of a plug of water-soluble material or by rupture of a thin section of the membrane over a core depression. 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. Patents 5,612,059 and 5,698,220.

[0246] The total amount and rate of release of the active ingredient can be substantially controlled via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0247] The osmotic controlled-release dosage form pharmaceutical composition may further comprise additional conventional excipients or carriers as described herein to facilitate performance or processing of the composition.

[0248] 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).

[0249] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT controlled-release dosage forms comprising an asymmetric osmotic membrane coating a core containing the active ingredient and other pharmaceutically acceptable vehicles (e.g., excipients or carriers). The 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.

[0250] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled-release dosage forms comprising an osmotic membrane coating a core comprising the active ingredient(s), hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

[0251] 3. Multiparticulate controlled release device The pharmaceutical compositions disclosed herein in modified-release dosage form can be manufactured as multiparticulate controlled-release devices containing a multiplicity of particles, granules, or pellets ranging in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. Such multiparticulates can be manufactured by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994, and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0252] Other excipients or carriers described herein may be blended with the pharmaceutical composition to aid in the processing and formation of the multiparticulates. The resulting particles themselves constitute the multiparticulate device or may be coated with various film-forming materials, such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticulates can be further processed into capsules or tablets.

[0253] Pharmacokinetics In some embodiments, the pharmaceutical composition has an onset of therapeutic action of 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 pharmaceutical composition has an acute effect duration of 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 pharmaceutical composition has a drug dissolution time of 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.

[0254] Stabilized Composition In some embodiments, a pharmaceutical composition is provided that comprises a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in a stabilized form together with a pharmaceutically acceptable vehicle. For example, the amorphous form of the compound of formula (I-3) can be stabilized in the disclosed pharmaceutical composition. In some embodiments, the compound of formula (I-3) can be formulated so that the compound of formula (I-3) is stably present in an amorphous form, for example, by immobilizing the compound in a matrix formed by a polymer, for example, as a solid dispersion or solid molecular complex of the compound of formula (I-3) with a polymer.

[0255] Solid dispersions and solid molecular complexes comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are provided. For example, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, can be dispersed in a matrix formed by a polymer in its solid state so as to be 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 improving the 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 the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0256] 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 wt%, about 5 wt%, 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%, or any range therebetween, e.g., about 1 wt% to about 50 wt%; or about 10 wt% to about 40 wt%; or about 20 wt% to about 35 wt%; or about 25 wt% to about 30 wt%, 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% by weight, or any range therebetween, e.g., 0% to about 50% by weight; or about 5% to about 60% by weight; 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 greater than about 10% by weight, or greater than about 20% by weight, or greater than about 30% by weight, or greater than about 40% by weight, or greater than about 50% by weight, based on the total weight of the solid dispersion. In some embodiments, the solid dispersion is about 30% by weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and about 70% by weight of the polymer.

[0257] The solid dispersion may comprise a compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph, or solvate dispersed in a non-ionic polymer. This may be achieved, for example, by melting the polymer, dissolving the compound in the polymer, and then cooling the mixture. The resulting solid dispersion may comprise the compound dispersed in the polymer in an amorphous form.

[0258] A solid dispersion can be formed by dispersing the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in an ionic polymer. Such a solid dispersion can result in increased stability of the 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 use in forming dispersions in non-ionic polymers. Because ionic polymers have pH-dependent solubility in aqueous systems, the resulting solid dispersion of the compound of Formula (I-3) and the polymer is stable at low pH in the stomach, while the compound of Formula (I-3) can be released in the intestine at higher pH. Thus, in some embodiments, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in such a solid dispersion containing an ionic polymer may be less able to separate from the polymer and be immobilized by the polymer in its amorphous form. Examples of such ionic polymers include, but are not limited to, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), hydroxypropylmethylcellulose phthalate (HPMCP), and methacrylic acid copolymers. In some embodiments, a polymer is used that can immobilize the compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, so that the compound of formula (I-3) exists primarily in one particular polymorphic form, e.g., amorphous form, for an extended period of time.

[0259] In some embodiments, the polymer may be linear, branched, or crosslinked. In some embodiments, the polymer may be a homopolymer or a copolymer. In some embodiments, the polymer may be a synthetic polymer derived from vinyl, acrylate, methacrylate, urethane, ester, and oxide monomers. In some embodiments, the polymer may be a naturally occurring polymer, such as a polysaccharide (e.g., chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan), starch (e.g., dextrin and maltodextrin), hydrophilic colloid (e.g., pectin), phospholipid (e.g., lecithin), alginate (e.g., ammonium alginate, sodium alginate, potassium or calcium alginate, propylene glycol alginate), gelatin, collagen, and derivatives of 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 acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC). In some embodiments, the polymer may be selected from the group consisting of gelatin, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, and cellulose polymers previously disclosed herein. In some embodiments, the cellulose polymer includes various grades of low viscosity, e.g., MW of 50,000 Daltons or less.

[0260] In some embodiments, compositions can include solid dispersions and solid molecular complexes comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed in a matrix formed by gelatin. In some embodiments, compositions can include solid dispersions and solid molecular complexes comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed in a matrix formed by gelatin and a non-reducing sugar, such as mannitol. In some embodiments, compositions can include solid dispersions and solid molecular complexes comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed in a matrix formed by a cellulose polymer described herein. In some embodiments, compositions can include solid dispersions and solid molecular complexes comprising a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, dispersed in a matrix formed by a cellulose polymer described herein and polyvinylpyrrolidone.

[0261] In some embodiments, the ratio of the weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in the solid composite to the weight of the polymer therein is about 1:9 to about 1:1. In some embodiments, the ratio of the weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in the solid composite to the weight of the polymer therein is about 2:8 to about 4:6. In some embodiments, the ratio of the weight of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in the solid composite to the weight of the polymer therein is about 3:7.

[0262] In some embodiments, the composition may further comprise one or more pharmaceutically acceptable vehicles, such as a solubilizing agent for the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, including those described herein, such as organic acid reagents (e.g., citric acid), sodium phosphate, and natural amino acids. Other solubilizing agents include, but are not limited to, acacia, cholesterol, diethanolamine (adjuvant), glyceryl monostearate, lanolin alcohol, mono- and diglycerides, monoethanolamine (adjuvant), lecithin, oleic acid (adjuvant), oleyl alcohol (solubilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl 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, trolamine, and emulsifying wax.

[0263] Various additives can be mixed, milled, or granulated with the solid dispersions described herein to form materials suitable for the dosage forms described above. Potentially useful additives can be broadly categorized into the following classes: other matrix materials or diluents, surfactants, drug complexing or solubilizing agents, fillers, disintegrants, binders, lubricants, and pH adjusters (e.g., acids, bases, or buffers). Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), calcium diphosphate, and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and croscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose, including silicified microcrystalline cellulose (SMCC), starch, and gums such as guar gum and tragacanth.Examples of lubricants include magnesium stearate and calcium stearate.Examples of pH adjusters include acids (including organic acid reagents), such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc.; 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, etc., and buffers generally comprise the mixture of acids and the salts of these acids.

[0264] In addition to the solid dispersion or solid molecular complex, the composition may also include a therapeutically inert inorganic or organic vehicle as described herein.

[0265] Dosage, frequency, and route of administration The dosage and frequency (single or multiple doses) of the compound of formula (I-3) or its pharmaceutically acceptable salt, polymorph, or solvate can vary depending on various factors, including but not limited to: the salt form / compound / polymorph administered; the route of administration; the subject's body size, age, sex, health condition, weight, body mass index, and diet; the nature and severity of the symptoms of the disease being treated; the presence of other diseases or other health problems; the type of concomitant therapy; and complications due to any disease or treatment regimen.Other treatment regimens or drugs can be used in conjunction with the methods and compounds disclosed herein.

[0266] The therapeutically effective amount for human use can be determined from animal models.For example, the dose for human can be formulated to achieve the concentration that has been found to be effective in animals.The dose for human can be adjusted by monitoring the response to treatment and adjusting the dose upward (gradual increase) or downward (gradual decrease).

[0267] Dosage can be varied according to the requirements of the patient and the active ingredient used.In the context of the pharmaceutical compositions provided herein, the dosage administered to the patient should be sufficient to bring about beneficial therapeutic response in the patient over time.The size of the dosage will also be determined by the existence, nature and degree of adverse side effects.Generally, treatment is started with a smaller dosage that is less than the optimal dosage of compound.Then, dosage is increased by small increments until the optimal effect under the circumstances is reached.

[0268] Dosage amount and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual's disease state.

[0269] Routes of administration can include oral routes (e.g., enteral / gastric delivery, buccal administration, e.g., buccal, lingual, and sublingual routes), parenteral routes (e.g., intravenous, intradermal, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration), and topical routes (e.g., (intra)dermal, conjuctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration), or other routes sufficient to affect a beneficial therapeutic response.

[0270] Administration may follow a continuous administration schedule (administration 7 days a week) or an intermittent administration schedule. The administration schedule may vary depending on the active ingredient employed, the condition being treated, the route of administration, the pharmacokinetics, and the subject's specific clearance / accumulation of the drug, etc. For example, administration of a compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, may be administered once daily (QD) or in divided doses throughout the day, for example, twice daily (BID), three times daily (TID), four times daily (QID), or more. In some embodiments, administration may be performed every night (QHS). In some embodiments, administration is performed as needed (PRN). If intermittent, the schedule may be, for example, four days of administration and three days off (rest days) per week, or any other intermittent administration schedule deemed appropriate based on sound medical judgment. Intermittent administration may also be performed on a weekly or monthly basis, such as once weekly, twice weekly, three times weekly, four times weekly, every other week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, etc., or less, or any range therebetween. Such administration schedules may also provide flexibility in administration dates, e.g., ±1, 2, 3, etc. The (intermittent) administration schedule may specify a set number of treatments per treatment course; for example, the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, may be administered 1, 2, 3, 4, 5, 6, 7, or 8 times per treatment course. Other administration schedules may be deemed appropriate using sound medical judgment.

[0271] In some embodiments, a single dose of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, is administered to a subject within a course of treatment. In some embodiments, the treatment herein may involve a single 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 the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, administered to a subject within a course of treatment. In some embodiments, the treatment herein may involve a single dose of about 12 mg, or a single dose of about 16 mg, of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, administered to a subject within a course of treatment.

[0272] In some embodiments, multiple doses of the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to a subject within a course of treatment. Multiple doses can include a first dose, a second dose, a third dose, a fourth dose, etc. In some embodiments, multiple doses of the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to a subject at weekly, biweekly, triweekly, or quaternary intervals (±3 days) within a course of treatment. For example, the treatment herein can include multiple doses of the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, administered at 3-week intervals (e.g., day 1 and day 22) (±3 days). In some embodiments, treatment herein may involve multiple doses administered to a subject at three-week intervals (±3 days) within a 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, treatment herein may involve multiple doses administered to a subject at three-week intervals (±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.

[0273] In some embodiments, the first and second doses of the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to the subject at weekly intervals, biweekly intervals, triweekly intervals, or 4-weekly intervals (±3 days) within a course of treatment. In some embodiments, the two doses of the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to the subject at weekly intervals, biweekly intervals, triweekly intervals, or 4-weekly intervals (±3 days) within a course of treatment. For example, the treatment herein may involve two doses of the compound of formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, administered at three-week intervals (e.g., day 1 and day 22 ±3 days). In some embodiments, a treatment herein may involve two doses administered to a subject three weeks (±3 days) apart within a course of treatment, each of 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 may involve two doses administered to a subject three weeks (±3 days) apart, each of about 12 mg, or two doses each of about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0274] In some embodiments, the first dose, second dose, and third dose of the compound of Formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to a subject at weekly, biweekly, triweekly, or 4-weekly intervals (±3 days) within a course of treatment. In some embodiments, three doses of the compound of Formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to a subject at weekly, biweekly, triweekly, or 4-weekly intervals (±3 days) within a course of treatment. For example, the treatment herein may involve three doses of the compound of Formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, administered at three-week intervals (e.g., on days 1, 22, and 43, ±3 days). In some embodiments, the treatment herein may involve three doses administered to a subject at three-week (±3 day) intervals within a course of treatment, each of about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, 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, the treatment herein may involve three doses administered to a subject at three-week (±3 day) intervals, each of about 12 mg, or three doses each of about 16 mg of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0275] In some embodiments, the first dose, second dose, third dose, and fourth dose of the compound of Formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to a subject at weekly, biweekly, triweekly, or 4-weekly intervals (±3 days) within a course of treatment. In some embodiments, four doses of the compound of Formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, are administered to a subject at weekly, biweekly, triweekly, or 4-weekly intervals (±3 days) within a course of treatment. For example, the treatment herein may involve four doses of the compound of Formula (I-3), or its pharmaceutically acceptable salt, polymorph, or solvate, administered at three-week intervals (e.g., on days 1, 22, 43, and 64, ±3 days). In some embodiments, the treatment herein may involve four doses administered to a subject at three-week (±3 day) intervals within a course of treatment, each of the four doses being about 8-16 mg, about 8-14 mg, about 8-12 mg, about 12-16 mg, 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, the treatment herein may involve four doses administered to a subject at three-week (±3 day) intervals, each of the four doses being about 12 mg, or about 16 mg each, of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0276] In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any two-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any three-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any four-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any five-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any 6-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any 7-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any 8-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any 9-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any 10-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a subject in any 11-month period. In some embodiments, only one, two, three, or four doses of a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered to a 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 a subject in any two-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 a subject in any three-year period. In any embodiment in which multiple doses (e.g., two, three, or four) of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, are administered within a certain period, it is preferred that each dose be administered at weekly, biweekly, three-weekly, or four-weekly intervals (±3 days). For example, a preferred dosing schedule may involve only two doses of the compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, in any 2, 3, 4, 5, 6, 7, or 8 month period, with the two doses each 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, administered three weeks apart (±3 days).

[0277] The administration of each dose (e.g., a single dose in a single dose regimen, each dose in a two dose regimen or a multiple dose regimen, etc.) may be accompanied by psychological therapy before, during, and / or after each dose, whereby the subject participates in one or more pre-dose psychological support sessions, the subject participates in one or more psychological support sessions during each drug session, and / or the subject participates in one or more post-dose psychological support sessions.

[0278] Whether continuous or intermittent, administration continues for a specific treatment course, typically at least a 28-day cycle (one month), which may be repeated with or without a drug holiday. Longer or shorter courses, such as 14, 18, 21, 24, 28, 35, 42, 48, 52, 56, 64, or more days, or any range therebetween, may also be used. The course may be repeated without or with a drug holiday, depending on the subject. In some embodiments, the methods herein involve a single treatment course during the subject's lifetime, and administration follows a dosing schedule (e.g., a single dose, two doses administered three weeks apart, etc.) without repeated administration for the remainder of the subject's life. In some embodiments, the methods herein involve multiple treatment courses, for example, if the subject does not respond to initial treatment or relapses. Other schedules are possible depending on the presence or absence of adverse events, response to treatment, likelihood of relapse, patient convenience, etc.

[0279] In some embodiments, the use of the compositions of the present disclosure can be used as an independent therapy. In some embodiments, the use of the compositions of the present disclosure can be used as an adjunctive / combined therapy.

[0280] Utilizing the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial toxic or adverse side effects (e.g., caused by sedative or psychotomimetic toxic spikes in the plasma concentration of any of the compounds of Formula (I-3)), yet is fully effective in treating the clinical symptoms exhibited by a particular subject. This design should involve careful selection of active compounds and salt forms by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

[0281] In some embodiments, the dose is administered orally once, and may be repeatedly administered at intervals of at least one week.In some cases, five or fewer doses are administered in any one treatment course.The course can be repeated as needed, with or without a drug holiday.Such acute treatment regimen can involve psychotherapy before, during, and / or after the hallucinogenic dose.

[0282] A compound of the present disclosure (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) may be used in a maintenance regimen. As used herein, "maintenance regimen" generally refers to the administration of a compound of the present disclosure (e.g., a compound of Formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof) after achieving a target dose, for example, after completing an escalation regimen, and / or after a positive clinical response, such as an improvement in the patient's condition, for example, to either the same drug or a different drug. In some embodiments, a patient is administered a first drug for the treatment regimen and a second drug for the maintenance regimen, wherein the first and second drugs are different. For example, a patient may be administered a treatment regimen with a first drug that is not a compound of the present disclosure (e.g., the first drug is a serotonergic hallucinogen such as LSD, psilocybin, MDMA, dimethyltryptamine, or a non-hallucinogenic drug), followed by administration of a compound of the present disclosure (as the second drug) in the maintenance regimen. In another example, a compound of the present disclosure is used in the treatment regimen (first drug) that is different from the drug (second drug) used in the maintenance regimen. In some embodiments, the patient is administered the same compound of the present disclosure for both the treatment regimen and the maintenance regimen. In either case, a maintenance dose of the compound of the present disclosure can be used to "maintain" the therapeutic response and / or prevent relapse. When the same compound of the present disclosure is used in both the original treatment regimen and the maintenance regimen, the maintenance dose of the compound can be sub-therapeutic. Generally, during a maintenance regimen, administration is performed daily or intermittently, but the maintenance regimen can also be performed continuously, for example, over days, weeks, months, or years. Furthermore, the maintenance dose can be administered to the patient chronically or for an extended period of time.

[0283] The administering physician can provide a prophylactic or therapeutic treatment method by adjusting the amount and timing of any of the compounds / salt forms described herein based on the observation of one or more symptoms of the disorder or condition being treated. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0284] Diseases, Disorders, and Conditions The subjects treated herein have a receptor for serotonin 5-HT2 receptors, particularly 5-HT 2A The patient may have a disease or disorder associated with the receptor. In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder, or an inflammatory disease or disorder. In some embodiments, the disease or disorder is major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar disorder and related disorders (including but not limited to bipolar I disorder, bipolar II disorder, and 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, etc.), Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), and the like. ), pain and neuropathic pain, aphantasia, fluency disorders such as childhood-onset dysfluency disorder, severe 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, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and cross-dressing disorder), sexual dysfunction (e.g., decreased libido, hypoactive sexual desire disorder (HSDD)), peripheral neuropathy, and central nervous system (CNS) disorders including, but not limited to, obesity.

[0285] In some embodiments, the methods provided herein are used to treat subjects with depressive disorders. As used herein, the term "depressive disorder" or "depression" refers to a group of disorders characterized by a persistent low mood that can affect a person's thoughts, behavior, emotions, and sense of well-being over a period of time. In some embodiments, depressive disorders disrupt a person's physical and psychological functioning. In some embodiments, depressive disorders cause physical symptoms such as weight loss, aches and pains, headaches, cramps, or indigestion. In some embodiments, depressive disorders cause psychological symptoms such as persistent sadness, anxiety, feelings of despair and irritability, guilt, feelings of worthlessness or powerlessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, difficulty remembering, or difficulty making decisions. In some embodiments, the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, catatonic depression, depressive disorder due to 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 with a depressive disorder who is at least 18 years of age (e.g., 18-65 years of age). In some embodiments, the methods provided herein are used to treat a subject with a depressive disorder who is at least 21 years of age.

[0286] 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 a period of depressed mood present in most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in usually enjoyable activities, low energy, and pain without a clear cause. In some cases, major depressive disorder is characterized by depressive symptoms lasting at least two weeks. In some cases, individuals experience periods of depression several years apart. In some cases, individuals experience depressive symptoms nearly constantly. Major depressive disorder can negatively impact a person's personal, work, or school life, as well as sleep, eating habits, and overall health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of those who commit suicide also had 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, but with less severe but longer-lasting symptoms. Examples of symptoms of major depressive disorder include, but are not limited to, sadness, tearfulness, feelings of emptiness or hopelessness, outbursts of anger over trivial matters, irritability or frustration, loss of interest or pleasure in most or all usual activities, sleep disturbances including insomnia or hypersomnia, fatigue and lack of energy, loss of appetite, weight loss or gain, anxiety, agitation or restlessness, diminished ability to think, speak or move, feelings of worthlessness or guilt, preoccupation with past failures or self-blame, difficulty thinking, concentrating, making decisions and remembering things, frequent thoughts of death, suicidal thoughts, suicide attempts or suicide, and unexplained physical problems such as back pain or headaches.

[0287] As used herein, the term " atypical depression " refers to a state in which individuals show a long-term pattern of mood reactivity symptoms (i.e., mood brightens in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, heavy and sluggish feeling in arms or legs, and / or sensitivity to interpersonal rejection, which causes significant social or occupational harm.Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or melancholy, loss of enjoyment in things that were once enjoyable, significant changes (increase or decrease) in weight or appetite, nearly daily insomnia or hypersomnia, physical restlessness or exhaustion that is noticeable to others, daily fatigue or low energy, nearly daily feelings of hopelessness, worthlessness or excessive guilt, nearly daily concentration or decision-making problems, recurring thoughts of death or suicide, suicide attempts, or suicide attempts.

[0288] As used herein, the term "bipolar disorder" refers to a condition in which an individual experiences unusual changes in mood, energy, activity level, and ability to perform daily tasks. Individuals with bipolar disorder experience periods of abnormal agitation, changes in sleep patterns and activity levels, and abnormal behavior. These characteristic periods are called "mood episodes." Mood episodes are significantly different from the person's typical mood and behavior. Examples of excessive manic behavioral symptoms include, but are not limited to, abnormally cheerful, volatile, or irritable behavior; increased activity, energy, or irritability; exaggerated feelings of happiness and self-confidence; decreased need for sleep; abnormal talkativeness, racing thoughts, distractibility, and poor decision-making, such as continuous spending sprees, sexual risk-taking, or foolish investments. Exemplary symptoms of depressive episodes or depressed mood include, but are not limited to, melancholy feelings, such as sadness, emptiness, despair, or tearfulness; a marked loss of interest in or a lack of enjoyment in all or almost all activities; significant weight loss, weight gain, or decreased or increased appetite; insomnia or hypersomnia (excessive sleep or excessive sleepiness); restlessness or slow behavior; fatigue or low energy; feelings of worthlessness or excessive or inappropriate guilt; impaired thinking ability or impaired concentration or indecisiveness; and thoughts of suicide or attempt.Bipolar disorders include bipolar I disorder, bipolar II disorder, and cyclothymic disorder.Bipolar I disorder is defined by a manic episode lasting at least 7 days or by severe manic symptoms requiring hospitalization.Subjects with bipolar I disorder may also experience depressive episodes, which typically last at least 2 weeks.Depressive episodes with mixed characteristics, i.e., depressive and manic symptoms may occur simultaneously, are also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but without the severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also called cyclothymia) is characterized by periods of hypomanic symptoms (elevated and euphoric mood) and depressive symptoms that last for at least two years.The mood swings are not sufficient in frequency, severity, or duration to meet full criteria for a hypomanic or depressive episode.

[0289] As used herein, term " catatonic depression " refers to the state that individual remains silent and immobile for a long time.Examples of catatonic depression symptoms include but are not limited to: the sadness that may occur every day, the loss of interest in most activities, sudden weight gain or loss, appetite change, difficulty falling asleep, difficulty getting up, restlessness, irritability, worthlessness, guilty feeling, fatigue,...

Claims

1. 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: 【Chemistry 1】 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, 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.

3. The compound for use according to claim 1, 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.

4. The compound for use according to claim 1, 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.

5. The compound for use according to claim 1, 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.

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, or glutarate salt 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 benzenesulfonate salt of the compound of formula (I-3) is a crystalline benzenesulfonate salt (I-3a), and has the following peaks: 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° 9. The compound for use according to claim 8, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from the X-ray diffraction patterns of the compounds of formula (I) and (II).

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 tartrate salt of the compound of formula (I-3).

11. The tartrate salt of the compound of formula (I-3) is crystalline tartrate salt (I-3b) and has the following peaks: 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, 26.021, 27.021, 28.021, 29.021, 30.021, 31.021, 32.021, 33.021, 34.021, 35.021, 36.021, 37.021, 38.021, 39.021, 40.021, 41.021, 42.021, 43.021, 44.021, 45.021, 46.021, 47.021, 48.021, 49.021, 50.021, 51.021, 52.021, 53.021, 54.021, 55.021, 56.021, 57.021, 58.021, 59.021, 60.021, 61.021, 62.021, 63.021, 64.021, 65.021, 66.021, 67 11. The compound for use according to claim 10, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 6.685, 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 degrees 2θ (±0.2 degrees 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 hemifumarate salt of the compound of formula (I-3) is crystalline hemifumarate salt (I-3c) and has the following pH values: 9.713, 11.209, 11.605, 12.338, 12.852, 13.718, 15.117, 16.066, 16.627, 19.026, 19.427, 20.108, 21.06 13. The compound for use according to claim 12, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from: 21.8, 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 degrees 2θ (±0.2 degrees 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. 15. The compound for use according to claim 14, wherein the citrate salt (I-3e) is amorphous 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 benzoate salt of the compound of formula (I-3) is crystalline benzoate salt (I-3j) and has the following pH values: 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, 22.8 17. The compound for use according to claim 16, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from: 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 degrees 2θ (±0.2 degrees 2θ).

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

19. 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. 20. The compound for use according to any one of claims 1 to 19, wherein prior to treatment, the subject has a score of 21 or greater on the Montgomery Asberg Depression Rating Scale (MADRS).

21. 21. The compound for use according to any one of claims 1 to 20, wherein a first dose and a second dose, each of which 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, are administered to the subject at an interval of one to four weeks (±3 days).

22. 22. The compound for use according to any one of claims 1 to 21, wherein a first dose and a second dose, each of which 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, are administered to the subject at an interval of three weeks (±3 days).

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

24. about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3); 【Chemistry 2】 or a pharmaceutically acceptable salt, polymorph or solvate thereof, and a pharmaceutically acceptable vehicle.

25. 25. The pharmaceutical composition according to 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. 25. 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. 25. The pharmaceutical composition of 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. 25. The pharmaceutical composition of 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. 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 benzenesulfonate salt of the compound of formula (I-3).

32. The benzenesulfonate salt of the compound of formula (I-3) is a crystalline benzenesulfonate salt (I-3a), and has the following peaks: 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° 32. The pharmaceutical composition of claim 31, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from the X-ray diffraction patterns of the compound of formula (I) and the compound of formula (II).

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 tartrate salt of the compound of formula (I-3) is crystalline tartrate salt (I-3b) and has the following peaks: 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, 26.021, 27.021, 28.021, 29.021, 30.021, 31.021, 32.021, 33.021, 34.021, 35.021, 36.021, 37.021, 38.021, 39.021, 40.021, 41.021, 42.021, 43.021, 44.021, 45.021, 46.021, 47.021, 48.021, 49.021, 50.021, 51.021, 52.021, 53.021, 54.021, 55.021, 56.021, 57.021, 58.021, 59.021, 60.021, 61.021, 62.021, 63.021, 64.021, 65.021, 66.021, 67 34. The pharmaceutical composition of claim 33, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from 6.685, 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 degrees 2θ (±0.2 degrees 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 hemifumarate salt of the compound of formula (I-3) is crystalline hemifumarate salt (I-3c) and has the following pH values: 9.713, 11.209, 11.605, 12.338, 12.852, 13.718, 15.117, 16.066, 16.627, 19.026, 19.427, 20.108, 21.06 36. The pharmaceutical composition of claim 35, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from: 21.8, 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 degrees 2θ (±0.2 degrees 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. 38. The pharmaceutical composition of claim 37, wherein the citrate salt (I-3e) is amorphous 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 benzoate salt of the compound of formula (I-3) is crystalline benzoate salt (I-3j) and has the following pH values: 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, 22.8 40. The pharmaceutical composition of claim 39, characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks selected from: 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 degrees 2θ (±0.2 degrees 2θ).

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

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

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

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

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

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

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

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

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

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

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

54. 54. The pharmaceutical composition for use according to any one of claims 48 to 53, wherein the first and second doses of the pharmaceutical composition, 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, are administered to the subject at an interval of one to four weeks (±3 days).

55. 55. The pharmaceutical composition for use according to any one of claims 48 to 54, wherein the first and second doses of the pharmaceutical composition, 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, are administered to the subject at an interval of three weeks (±3 days).

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

57. 1. A compound of formula (I-3), or a pharmaceutically acceptable salt, polymorph, or solvate thereof, for use in adjunctive therapy in the treatment of depressive disorders in subjects receiving antidepressant therapy, 【Transformation 3】 The adjunctive treatment comprises 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.

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

59. 59. The compound for use of claim 58, wherein prior to said adjunctive treatment, said 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. 60. The compound for use according to any one of claims 57 to 59, wherein prior to said adjunctive treatment, said subject has a score of 21 or greater on the Montgomery Asberg Depression Rating Scale (MADRS).

61. 61. The compound for use according to any one of claims 57 to 60, wherein a first dose and a second dose, each of which 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, are administered to the subject at an interval of one to four weeks (±3 days).

62. 62. The compound for use according to any one of claims 57 to 61, wherein a first dose and a second dose, each of which 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, are administered to the subject at an interval of three weeks (±3 days).

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

64. 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 about 8 mg to about 16 mg (free base equivalent) of the benzenesulfonate salt of the compound of formula (I-3) for use in treating major depressive disorder (MDD) in a subject in need thereof. 【Chemistry 4】

66. 1. An oral liquid dosage form for use in treating major depressive disorder (MDD) in a subject in need thereof, said oral liquid dosage form comprising: (i) about 8 mg to about 16 mg (free base equivalent) of a compound of formula (I-3); 【Transformation 5】 or a pharmaceutically acceptable salt, polymorph or solvate thereof, and (ii) an oral liquid dosage form comprising a pharmaceutically acceptable aqueous medium.

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