Novel compositions, devices and methods

Abstract

The present disclosure relates to injectable pharmaceutical compositions comprising lumateperone or deuterolumateperone or tetradeuterolumateperone, in free, or pharmaceutically acceptable salt form, suspended, dissolved or encapsulated in polymeric microspheres, devices comprising such compositions, and methods of use thereof in the treatment or prophylaxis of disease.

Description

NOVEL COMPOSITIONS, DEVICES AND METHODSCROSS-REFERENCE TO RELATED APPLICATIONSThis application is an International Patent Application which claims priority to, and the benefit of, U.S. Provisional Application Ser. No. 63 / 648,646, filed on May 16, 2024, the contents of which are hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0001] The present disclosure relates to injectable pharmaceutical compositions comprising lumateperone or deuterolumateperone, in free, or pharmaceutically acceptable salt form, suspended, dissolved or encapsulated in polymeric microspheres, devices comprising such compositions, and methods of use thereof in the treatment or prophylaxis of disease.BACKGROUND OF THE INVENTION

[0002] The substituted heterocycle fused gamma-carbolines lumateperone (4-((6bR,10aS)-3- methyl-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4': 4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)-l- (4-fluorophenyl)-l-butanone ) is known to be a serotonin receptor (5-HT2A), dopamine receptor (DI and / or D2), and serotonin transporter (SERT) ligand, which is useful in treating a variety of central nervous system disorders.

[0003] Lumateperone antagonizes the serotonin-2A (5-HT2A) receptor, and / or modulates dopamine receptor signaling at the level of key intra-cellular phosphoproteins. This compound is principally known to be useful for the treatment of positive and negative symptoms of schizophrenia, depression (especially acute depression and bipolar depression), anxiety and traumatic disorders (including acute anxiety and post-traumatic stress disorder), and dementias (including Alzheimer’s disease and the symptoms associated therewith). At dopamine D2 receptors, this compound has dual properties and acts as both a post-synaptic antagonist and a pre-synaptic partial agonist of the D2 receptor. It also stimulates phosphorylation of glutamatergic NMD A NR2B, or GluN2B, receptors in a mesolimbic specific manner. It is believed that this regional selectivity in the brain areas thought to mediate the efficacy of antipsychotic drugs, together with the serotonergic, glutamatergic, and dopaminergicinteractions, may result in antipsychotic efficacy for positive, negative, affective and cognitive symptoms associated with schizophrenia. The compound also exhibits serotonin reuptake inhibition, providing antidepressant activity for the treatment of schizoaffective disorder, co- morbid depression, and / or as a stand-alone treatment for major depressive disorder. Lumateperone is also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disturbances associated with dementia, autism and other CNS diseases. These features may be able to improve the quality of life of patients with schizophrenia and enhance social function to allow them to more fully integrate into their families and their workplace. Lumateperone displays differential dose-dependent effects, selectively targeting the 5-HT2A receptor at low doses, while progressively interacting with the D2 receptor at higher doses. As a result, at lower doses, it is useful in treating sleep, aggression and agitation. At a high dose, it can treat acute exacerbated and residual schizophrenia, bipolar disorders, and mood disorders.

[0004] Lumateperone, having the formula:is a novel therapeutic agent with potent (Ki=0.5nM) 5-HT A receptor antagonism, activity as a mesolimbic / mesocortical-selective dopamine receptor protein phosphorylation modulator consistent with presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki=32nM) in vivo, high DI receptor affinity (Ki-52nM). and inhibition of the serotonin transporter (SERT) (Ki=26-62nM, using different assays for SERT activity). Lumateperone has recently been approved in the United States for the treatment of schizophrenia, and as a treatment for bipolar depression, and it is in clinical development as a treatment for agitation in dementia, including Alzheimer’s Disease.

[0005] Lumateperone and related compounds have been disclosed in U.S. Pat. No.6,548,493, 7,238,690, 6,552,017, 6,713,471, U.S. RE39680, and U.S. RE39679 (each of whichare incorporated herein by reference) as novel compounds useful for the treatment of disorders associated with 5-HT2A receptor modulation such as anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, and social phobias. U.S. Pat. No. 7,081,455, incorporated by reference herein, also disclose methods of making substituted heterocycle fused gamma-carbolines and uses of these gammacarbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders. U.S. 8,598,119, and U.S. 11,124,514, each incorporated herein by reference, disclose the use of specific substituted heterocycle fused gamma-carbolines for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and / or mood disorders in patients with psychosis or Parkinson's disease and for the treatment or prophylaxis of disorders associated with dementia, particularly behavioral or mood disturbances such as agitation, irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts and psychosis and sleep disorders associated with dementia. U.S. 8,648,077, each incorporated herein by reference, disclose methods of preparing toluenesulfonic acid addition salt crystals of particular substituted heterocycle fused gamma-carbolines, e.g., toluenesulfonic acid addition salt of 4-((6bR,10aS)-3- methyl-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4': 4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)-l- (4-fluorophenyl)-l-butanone. US 2020 / 0157100, disclosed herein by reference, similarly discloses various bis-tosylate salts of lumateperone.

[0006] U.S. Patents 10,716,786 and 11,052,083, incorporated herein by reference, discloses subcutaneous, transmucosal and other dosage forms and administration routes for lumateperone and related compounds. US 2021 / 0315891, incorporated herein by reference, discloses transdermal dosage forms and administration routes for lumateperone and related compounds.

[0007] U.S. Patents 10,695,345 and 11,052,084, and US 2021 / 0220280, each of which is incorporated herein by reference, discloses solid oral dosage forms for lumateperone, including tablets and capsules.

[0008] Deuterated lumateperone analogs, including deuterolumateperone, are disclosed in U.S. Patents 10,077,267, 10,597,394, 10,688,097, 10,899,762, and 11,096,944, and patent publication US 2021 / 0008065, and US2023 / 0312573, the contents of each of which are hereby incorporated by reference in their entireties. As used herein, the term “deuterolumateperone” refers to l-(4-fhioro-phenyl)-4-((6bR,10aS)-2,2-< 2-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H-pyrido[3',4':4,5]pyrrolo[l ,2,3-de]quinoxalin-8-yl)-butan-l -one, which has also been referred to as AL-lumatcpcronc” or “dculumatcpcronc,” and which has the following structure:As used herein, the term “tetradeuterolumateperone” refers to l-(4-fluoro-phenyl)-4- ((6bR,10aS)-l,l,2,2-t / 4-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)-butan-l-one, which has also been referred to as “^-lumateperone,” and which has the following structure:

[0009] U.S. Patents 8,993,572 and 9,371,324, each incorporated herein by reference, disclose prodrugs / metabolites of substituted heterocycle fused gamma-carboline for improved formulation, e.g., extended / controlled release formulation. This application discloses that heterocycle fused gamma-carboline N-substituted with a 4-fluorophenyl(4-hydroxy)butyl moiety are shown to have high selectivity for the serotonin transporter (SERT) relative to the heterocycle fused gamma-carboline containing 4-fluorophenylbutanone.

[0010] It has also recently been found that lumateperone may be particularly effective in treating acute depression and acute anxiety owing to its rapid onset of action compared to existing antidepressants, as disclosed in US 2021 / 0060009, incorporated herein by reference. This is believed to be due to it signaling through a neurotransmitter system separate from the traditional monoamine signaling systems. Lumateperone provides a dopamine DI receptordependent enhancement of NMDA and AMPA currents coupled with activation of the mTOR (e.g., mTORCl) signaling pathway.

[0011] U.S. Patents 9,708,322, 10,072,010, 10,472,359, 9,956,227, and 10,322,134, each of which is incorporated herein by reference, disclose and / or claim various long-acting injectable compositions comprising lumateperone and related compounds, as well as various polymeric matrix-based compositions (including PLGA-based compositions) comprising lumateperone.

[0012] However, it is particularly difficult to formulate a long-acting injectable (e.g., depot injection) composition, because of the need to provide a long-lasting, therapeutically effective, and non-toxic drug plasma level with minimal side effects. For example, for any long-acting injectable drug, there will be an optimal plasma concentration range which maximizes the balance between therapeutical efficacy and side effects, while there will also be a minimum therapeutically effective plasma concentration, and for some drugs, a maximum safe and tolerable plasma concentration. The goal of a long-acting injectable therapy is to maintain drug plasma levels within the optimal range for as long as possible, while avoiding plasma levels in above the maximum safe and tolerable value, and avoid plasma levels below the minimum efficacy value. In addition, many experimental long-acting injectable formulations suffer from the problem of “dose-dumping” in which a large an undesirable peak in plasma drug concentration occurs rapidly after injection, such as within the first 1-3 weeks. This can result in insufficient drug remaining in the depot for continued optimal drug release, while also potentially causing undesirable side effects or toxicities caused by the plasma concentration peak.

[0013] The plasma concentration profile of a long-acting injectable formulation can be difficult to predict, as it depends on numerous factors, including: the drug loading in the depot (i.e., concentration), the viscosity of the polymer matrix in which the drug is embedded, the degradation rate of the polymer matrix, the porosity of the polymer matrix, and for solid particles embedded in a polymer matrix, the particle size of the particles. For a microsphere formulation, wherein the drug is embedded in polymer microspheres, the particle size of the microspheres can also be important.

[0014] There remains a need for improved long-acting injectable formulations of lumateperone.BRIEF SUMMARY OF THE INVENTION

[0015] The present disclosure provides injectable pharmaceutical compositions comprising lumateperone or deuterolumateperone or tetradeuterolumateperone in pharmaceutically acceptable salt form. In some embodiments, the compositions are packaged in devices for injection, such as syringes, including pre-filled and / or automatic syringes. In particular embodiments, the syringes are designed for at-home use by patients and the syringes include automatically retracting needles. In some embodiments, the compositions are dual-component compositions (e.g., an aqueous solvent component and a dry solid component) and the injection devices (e.g., syringes) are dual-chambered devices of various designs which permit reconstitution of the dual components during injection. In some embodiments the compositions or composition component(s) may further comprise one or more additional therapeutic agents. The compositions and devices disclosed herein are useful for the treatment or prophylaxis of a variety of central nervous system disorders, such as schizophrenia and bipolar depression.DETAILED DESCRIPTION

[0016] Lumateperone is a novel therapeutic agent with potent (Ki=0.5nM) 5-HT2A receptor antagonism, activity as a mesolimbic / mesocortical- selective dopamine receptor protein phosphorylation modulator consistent with presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki=32nM) in vivo, high DI receptor affinity (Ki=52nM), and inhibition of the serotonin transporter (SERT) (Ki=26-62nM, using different assays for SERT activity). Lumateperone has recently been approved in the United States for the treatment of schizophrenia, and it is in clinical development as a treatment for bipolar depression, and agitation in dementia, including Alzheimer’s Disease.

[0017] In a first aspect, the present disclosure provides an injectable pharmaceutical composition (Composition 1), comprising lumateperone:in pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the lumateperone is suspended, dissolved or encapsulated in polymeric microsphcrcs, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer having a lactic to glycolic ratio from 75:25 to 50:50, and wherein the injectable composition comprises a sterile, aqueous injection vehicle. For example, Composition 1 may be as follows:1.1. Composition 1, wherein the composition comprises the lumateperone in pharmaceutically acceptable salt form selected from a tosylate, hydrochloride, besylate, mesylate, nosylate, naphthalenesulfonate, naphthalenedisulfonate, hydrobromide, hydroiodide, tartrate, malate, maleate, fumarate, nitrate, phosphate, benzoate, 4-aminosalicylate, oxalate, or cyclamate acid addition salt; or wherein the salt form is a Ci-Cnalkylbenzenesulfonate, Ca-Cnalkylsulfonate, or 2-naphthalenesulfonate, such as described in W02024 / 030835, the contents of which are hereby incorporated by reference in its entirety;1.2. Composition 1, wherein the composition comprises the lumateperone in tosylate salt form;1.3. Composition 1, wherein the composition comprises the lumateperone in one or more of mono-tosylate salt form, di-tosylate salt form, and tri-tosylate salt form;1.4. Composition 1.3, wherein the composition comprises the lumateperone in mono-tosylate salt form and di-tosylate salt form, or in free base form;1.5. Any of Compositions 1 or 1.1-1.4, wherein the composition comprises the lumateperone in mono-tosylate salt form;1.6. Composition 1.5, wherein the lumateperone mono-tosylate is in solid crystal form, e.g., having the physical and chemical properties as disclosed in U.S. 8,648,077, such as one or more of the XRPD spectrum, IR spectrum, and / or DSC / TGA spectrum as disclosed therein;1.7. Composition 1.5, wherein the lumateperone mono-tosylate is in solid crystal form, wherein the crystal exhibits an X-ray powder diffraction pattern comprising at least two peaks having 2-theta values selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, each of said peaks ± 0.2°, e.g., wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter;Composition 1 .5, wherein the lumateperone mono-tosylate is in solid crystal form, wherein the crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2-theta values selected from the group consisting of: 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, each of said peaks ± 0.2°, e.g., wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter; Composition 1.5, wherein the lumateperone mono-tosylate is in solid crystal form, wherein the crystal exhibits an X-ray powder diffraction pattern comprising the following peaks having 2-theta values: 5.6811°, 8.5140°, 11.3750°, 12.1088°, 13.3354°, 15.7948°, 16.0419°, 16.4461°, 17.0309°, 17.2606°, 17.5531°, 18.1581°, 18.9968°, 19.8889°, 20.7510°, 21.6724°, 22.25463°, 23.4815°, 23.7411°, 24.3006°, 25.9394°, 27.2321°, 28.3782°, 28.9055°, 29.6695°, 31.6106°, 32.2950°, 34.8530°, 37.5435°, 39.4972°, 40.2502° and 40.8303°, each of said peaks ± 0.2°, e.g., wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter; Any of Compositions 1.3- 1.5, wherein the lumateperone tosylate, e.g., the lumateperone mono-tosylate, is in solid amorphous form or is in the form of a solid amorphous dispersion; Composition 1.10, wherein the lumateperone tosylate, e.g., the lumateperone mono- tosylate, is in the form of a solid amorphous dispersion comprising amorphous lumateperone tosylate in admixture with one or more excipients, e.g., stabilizing excipients; Composition 1.11, wherein the composition form comprises one or more excipients which stabilize the amorphous from of lumateperone tosylate to prevent conversion of the amorphous form to the crystal form; Composition 1.11 or 1.12, wherein the one or more excipients are selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate / methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC-P), polyvinyl acetate, polyvinyl pyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, and polyethylene glycol / polyvinyl acctatc / polyvinylcaprolactam copolymer; Composition 1, or any of 1.1-1.13, wherein the polymeric microspheres of the composition comprises the lumateperone (e.g., lumateperone tosylate) in an average amount of 10 to 50% by weight of the composition, e.g., 10 to 40%, or 10 to 30%, or 10 to 25%, or 10 to 20%, or 10 to 15%, or 15 to 45%, or 15 to 40%, 15 to 35%, or 15 to 30%, or 15 to 25%, or 15 to 20%, or 20 to 45%, or 20 to 40%, or 20 to 35%, or 20 to 30%, or 20 to 25%, or 25 to 50%, or 25 to 45%, or 25 to 40%, or 25 to 35%, or 25 to 30%, or 30 to 40%, or about 15%, or about 20%, or about 25%, or about 30%, about 35%, by weight of the polymeric microsphere, measured as the equivalent amount of free base lumateperone; Composition 1, or any of 1.1-1.13, wherein the composition (e.g., including polymeric microspheres and injection vehicle) comprises the lumateperone (e.g., lumateperone tosylate) in an amount of 5 to 10% by weight of the composition, e.g., 1 to 9%, or 1 to 8%, or 2 to 10%, or 2 to 9%, or 2 to 8%, or 3 to 10%, or 3 to 9%, or 3 to 8%, or 4 to 10%, or 4 to 9%, or 4 to 8%, or 5 to 10%, or 5 to 9%, or 5 to 8%, or 6 to 10%, or 6 to 9%, or 6 to 8%, or 7 to 10%., or 7 to 9%, or 7 to 8%, or about 7%, or about 8%, or about 9%, by weight of the composition, measured as the equivalent amount of free base lumateperone; Composition 1, or any of 1.1-1.15, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 73:27 to 52:48; Composition 1.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 70:30 to 55:45; Composition 1.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 58:42; Composition 1.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 62:38; Composition 1.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 65:35; Composition 1, or any of 1.1-1.20, wherein the poly(lactic-co-glycolic acid) copolymer has an inherent viscosity of 0.1 to 0.9, e.g., 0.1 to 0.75, or 0.1 to 0.7, or 0.6 to 0.6, or 0.1 to 0.5, or 0.1 to 0.4, or 0.1 to 0.3, or 0.1 to 0.2, or 0.15 to 0.45, or 0.15 to 0.3, or 0.15 to0.25, or 0.2 to 0.8, or 0.2 to 0.6, or 0.2 to 0.4, or 0.25 to 0.5, or 0.25 to 0.4, or 0.25 to 0.35, or 0.3 to 0.6, or 0.3 to 0.5, or 0.3 to 0.45, or 0.5 to 0.8, or 0.5 to 0.75, or 0.5 to 0.7, or about 0.19; Composition 1, or any of 1.1-1.21, wherein the poly(lactic-co-glycolic acid) copolymer has average molecular weight of 5,000 to 150,000 Daltons, e.g., 5,000 to 100,000 Da, or 5,000 to 75,000 Da, or 5,000 to 50,000 Da, or 5,000 to 25,000 Da, or 5,000 to 20,000 Da, or 7,000 to 20,000 Da, or 10,000 to 40,000 Da, or 10,000 to 35,000 Da, or 10,000 to 30,000 Da, or 10,000 to 25,000 Da, or 15,000 to 30,000 Da, or 15,000 to 25,000 Da, or20,000 to 50,000 Da, or 20,000 to 45,000 Da, or 20,000 to 40,000 Da, or 25,000 to75,000 Da, or 25,000 to 60,000 Da, or 25,000 to 50,000 Da, or 25,000 to 45,000 Da; Composition 1, or any of 1.1-1.22, wherein the poly(lactic-co-glycolic acid) copolymer has molecular weight range of 5,000 to 150,000 Daltons (e.g., at least 90% of polymer molecules have a molecular weight within the range), e.g., 5,000 to 100,000 Da, or 5,000 to 75,000 Da, or 5,000 to 50,000 Da, or 5,000 to 25,000 Da, or 5,000 to 20,000 Da, or 7,000 to 20,000 Da, or 10,000 to 40,000 Da, or 10,000 to 35,000 Da, or 10,000 to 30,000 Da, or 10,000 to 25,000 Da, or 15,000 to 30,000 Da, or 15,000 to 25,000 Da, or 20,000 to 50,000 Da, or 20,000 to 45,000 Da, or 20,000 to 40,000 Da, or 25,000 to 75,000 Da, or 25,000 to 60,000 Da, or 25,000 to 50,000 Da, or 25,000 to 45,000 Da; Composition 1, or any of 1.1-1.23, wherein the poly(lactic-co-glycolic acid) copolymer has carboxylic acid end groups; Composition 1, or any of 1.1-1.23, wherein the poly(lactic-co-glycolic acid) copolymer has carboxylic ester end groups ((e.g., such as a Cl-6 linear ester end group, e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl ester end groups); Composition 1, or any of 1.1-1.25, wherein the polymeric microspheres of the composition comprises the poly(lactic-co-glycolic acid) copolymer in an average amount of 50 to 90% by weight of the composition, e.g., 55 to 90%, or 60 to 90%, or 65 to 90%, or 70 to 90%, or 75 to 90%, or 85 to 90%, or 50 to 85%, or 55 to 85%, or 60 to 85%, 60 to 85%, or 65 to 85%, or 70 to 85%, or 75 to 85%, or 80 to 85%, or 50 to 80%, or 55 to80%, or 60 to 80%, or 65 to 80%, or 70 to 80%, or 75 to 80%, or 50 to 75%, or 55 to75%, or 60 to 75%, or 65 to 75%, or 70 to 75%, or 50 to 65%, or 55 to 65%, or 60 to65%, or 50 to 60%, or 55 to 60%, or 50 to 55%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, by weight of the polymeric microsphcrc; Composition 1, or any of 1.1-1.26, wherein the composition (e.g., including the polymeric microspheres and the injection vehicle) comprises the poly(lactic-co-glycolic acid) copolymer in an amount of 10 to 40% by weight of the composition, e.g., 15 to40%, or 20 to 40%, or 25 to 40%, or 30 to 40%, or 35 to 40%, or 10 to 35%, or 15 to35%, or 20 to 35%, or 25 to 35%, or 30 to 35%, or 10 to 30%, or 15 to 30%, or 20 to30%, or 25 to 30%, or 10 to 25%, or 15 to 25%, or 20 to 25%, or 10 to 20%, or 15 to20%, or 10 to 15%, about 15%, or about 20%, or about 25%, or about 30%, by weight of the composition; Composition 1, or any of 1.1-1.27, wherein the polymeric microspheres consist essentially of the lumateperone (e.g., lumateperone tosylate) and the poly(lactic-co- glycolic acid) copolymer, optionally, having not more than trace amounts of any organic solvents or polymers from microsphere preparation (e.g., water, methylene chloride or polyvinyl alcohol); Composition 1, or any of 1.1-1.28, wherein the sterile aqueous injection vehicle comprises water (e.g., sterile water for injection) and one or more excipients selected from a surfactant (e.g., polysorbate 20), a buffering agent (e.g., sodium phosphate), an ionic agent (e.g., sodium chloride), a thickener (e.g., carboxymethyl cellulose), a preservative (e.g., citric acid), and / or a co-solvent; Composition 1.29, wherein the aqueous injection vehicle comprises one or more excipients selected from polysorbate 20, polysorbate 30, polysorbate 40, polysorbate 60, polysorbate 80, citric acid, maleic acid, lactic acid, citrate salts (e.g., sodium citrate), bicarbonate salts (e.g., sodium bicarbonate), carbonate salts (e.g., sodium carbonate), hydrochloric acid, sodium hydroxide, sodium chloride, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, ethanol, propylene glycol, and glycerin; Composition 1.30, wherein each of said one or more excipients are present in the injection vehicle in an amount of 0.001 to 2% by weight, e.g., 0.001 to 0.1%, or 0.005 to 0.1%, or 0.05 to 0.1%, or 0.1 to 0.3%, 0.3 to 0.5%, 0.5 to 0.7%, 0.7 to 0.9%, 0.9 to 1.1%, 1.1 to 1.3%, 1.3 to 1.5%, 1.5 to 1.7%, or 1.7 to 1.9%;Composition 1 , or any of 1.1-1.31 , wherein the sterile aqueous injection vehicle comprises water (c.g., sterile water for injection), carboxymethyl cellulose (c.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%); Composition 1.32, wherein the sterile aqueous injection vehicle consists essentially of water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 1-1.5%. e.g., 1.25%), sodium chloride (e.g., 0.6-0.8%), sodium phosphate dibasic (e.g., 0.05 to 0.15%), citric acid (e.g., 0.005 to 0.05%), and polysorbate 20 (e.g., 0.005 to 0.05%); Composition 1.32, wherein the sterile aqueous injection vehicle consists essentially of water, carboxymethyl cellulose (e.g., about 1.25%), sodium chloride (e.g., about 0.7%, sodium phosphate dibasic (e.g., about 0.1%), citric acid (about 0.01%), and polysorbate 20 (about 0.01%); Composition 1, or any of 1.1-1.34, wherein the sterile aqueous injection vehicle has a pH of 6 to 8, e.g., 6.5 to 7.5, or about pH 7; Composition 1, or any of 1.1-1.35, wherein the viscosity of the sterile injection vehicle is from 1 to 30 centipoise (cP), e.g., 5 to 25 cP, or 5 to 20 cP, or 5 to 15 cP, or 5 to 10 cP, or about 10 cP; Composition 1, or any of 1.1-1.36, wherein the polymeric microspheres are particulated to form particles having a particle size distribution characterized by a dlO of least 10 microns and a d90 of not more than 120 microns, e.g., a dlO of 10-50 microns (e.g., 20- 40 microns, 25 to 35 microns, or about 30 microns) and / or a d50 of 30-70 microns (e.g., 40-60 microns, 45-55 microns, or about 50 microns), and / or a d90 of 40-80 microns (e.g., 50-70 microns, 55-65 microns, or about 60 microns); Composition 1, or any of Compositions 1.1-1.37, wherein the composition comprises 25 to 500 mg / mL lumateperone, measured as the free base equivalent, e.g., 25 to 450 mg / mL, or 25 to 400 mg / mL, or 25 to 350 mg / mL, or 25 to 300 mg / mL, or 25 to 250 mg / mL, or 25 to 200 mg / mL, or 25 to 150 mg / mL, or 25 to 100 mg / mL, or 25 to 50 mg / mL, or 50 to 300 mg / mL, or 50 to 250 mg / mL, or 50 to 200 mg / mL, or 50 to 150 mg / mL, or 50 to 100 mg / mL, 75 to 300 mg / mL, or 75 to 250 mg / mL, or 75 to 200 mg / mL, or 75 to 150 mg / mL, or 75 to 100 mg / mL, or 100 to 300 mg / mL, or 100 to 250mg / mL, or 100 to 200 mg / mL, or 100 to 150 mg / mL, or 150 to 300 mg / mL, or 150 to 250 mg / mL, or 150 to 200 mg / mL, or 200 to 300 mg / mL, or about 85 mg / mL; Composition 1, or any of Compositions 1.1-1.38, wherein the composition further comprises an anti-oxidant, e.g., selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), carotenoids, glutathione, sodium metabisulfite, sodium ethylenediaminetetraacetate, cysteine, methionine, sesamol, and citric acid. Composition 1, or any of Compositions 1.1-1.39, wherein the polymeric microspheres are suspended in the sterile aqueous injection vehicle; Composition 1, or any of Compositions 1.1-1.40, wherein the composition consists of the polymeric microspheres and the sterile aqueous injection vehicle; Composition 1, or any of Compositions 1.1-1.41, wherein the composition consists essentially of the lumateperone (e.g., lumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water, and one or more excipients selected from a surfactant (e.g., polysorbate 20), a buffering agent (e.g., sodium phosphate), an ionic agent (e.g., sodium chloride), a thickener (e.g., carboxymethyl cellulose), and a preservative (e.g., citric acid); Composition 1, or any of Compositions 1.1-1.42, wherein the composition consists essentially of the lumateperone (e.g., lumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%); Composition 1, or any of 1.1-1.43, wherein the composition is formulated for intramuscular injection; Composition 1, or any of 1.1-1.43, wherein the composition is formulated for subcutaneous injection; Composition 1, or any of 1.1-1.45, wherein the composition is intended to be administered once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, e.g., once per month;Composition 1 , or any of 1.1-1.46, wherein the composition, after intramuscular or subcutaneous injection, releases the lumatcpcronc over a period of at least 1 week, 2 weeks, 3 weeks, or 4 weeks, maintaining a plasma concentration of lumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 1, or any of 1.1-1.46, wherein the composition, after intramuscular or subcutaneous injection, releases the lumateperone over a period of at least 6 weeks maintaining a plasma concentration of lumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 1, or any of 1.1-1.46, wherein the composition, after intramuscular or subcutaneous injection, releases the lumateperone over a period of at least 8 weeks maintaining a plasma concentration of lumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 1, or any of 1.1-1.46, wherein the composition, after intramuscular or subcutaneous injection, releases the lumateperone over a period of at least 10 weeks maintaining a plasma concentration of lumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 1 , or any of 1.1 - 1.46, wherein the composition, after intramuscular or subcutaneous injection, releases the lumateperone over a period of at least 12 weeks maintaining a plasma concentration of lumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 1, or any of 1.1-1.51, wherein the composition, after intramuscular or subcutaneous injection, releases the lumateperone at a rate to provide not more than 100 ng / mL plasma concentration of lumateperone at any time after 9 days after injection, e.g., not more than 85 ng / mL, or not more than 75 ng / mL, or not more than 70 ng / mL, or not more than 65 ng / mL, or not more than 60 ng / mL;Composition 1 , or any of 1.1-1.52, wherein the composition, after intramuscular or subcutaneous injection, releases the lumatcpcronc at a rate to provide not more than 300 ng / mL plasma concentration of lumateperone at any time within 72 hours after injection, e.g., not more than 250 ng / mL, or not more than 200 ng / mL, or not more than 150 ng / mL, or not more than 125 ng / mL, or not more than 100 ng / mL; Composition 1, or any of 1.1-1.53, wherein the composition, after intramuscular or subcutaneous injection, releases not more than 10% of the total amount of lumateperone within the first 8 hours after injection, e.g., not more than 8%, or not more than 6% or not more than 5%; Composition 1, or any of 1.1-1.54, wherein the composition is a bi-component composition consisting of a first component being the polymeric microspheres comprising the poly(lactic-co-glycolic) copolymer and lumateperone, and a second component being the sterile aqueous injection vehicle, such as, where the two components are maintained separately and are admixed immediately prior to injection; Composition 1.55, wherein the first component is a solid (e.g., a dry powder), and the second component is a homogenous liquid; Composition 1, or any of 1.1-1.56, wherein the composition is free of water-miscible organic solvents; Composition 1, or any of 1.1-1.56, wherein the composition is free of N-methyl-2- pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethyl formamide (DMF), dimethylacetamide (DMA), 2-pyrrolidone, propylene carbonate, caprolactam, N- methylcaprolactam, and triacetin; Composition 1, or any of 1.1-1.58, wherein the composition is free of triglyceride oils, e.g., peanut oil, soybean oil, sesame oil, castor oil, and the like; A kit (e.g., single-use or multiple-use) comprising, in separate compartments, two compositions, a first composition comprising lumateperone in pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the lumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer having a lactic to glycolic ratio from 75:25 to 50:50, and a second composition which is a sterile, aqueous injectionvehicle, wherein upon combination of the first composition and the second composition, an injectable composition according to Composition 1 or any of 1.1-1.59 is formed; Kit 1.60, wherein the first composition and the second composition are combined in a ratio of 250-750 mg of the first composition (e.g., about 500 mg) to 0.75 to 1.25 mL of the second composition (e.g., 1.0 mL) to form said injectable composition. Kit 1.60 or 1.61, wherein the first composition is a solid powder and the second composition is a homogenous liquid; Kit 1.60, 1.61, or 1.62, wherein the kit comprises the first composition in a sealed vial, the second composition in a sealed vial, and the kit further comprises a syringe and a needle; Kit 1.63, wherein the needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; A pre-filled dual-compartment syringe (e.g., an automatic syringe) comprising, in separate compartments, two compositions, a first composition comprising lumateperone in pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the lumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer having a lactic to glycolic ratio from 75:25 to 50:50, and a second composition which is a sterile, aqueous injection vehicle, wherein upon actuation of the syringe the first composition and the second composition are combined to form an injectable composition according to Composition 1 or any of 1.1-1.59 is formed; Syringe 1.65, wherein the first composition and the second composition are combined in a ratio of 250-750 mg of the first composition (e.g., about 500 mg) to 0.75 to 1.25 mL of the second composition (e.g., 1.0 mL) to form said injectable composition; Syringe 1.65 or 1.66, wherein the first composition is a solid powder and the second composition is a homogenous liquid; A single-use kit comprising a vial containing the Composition 1, or any of 1.1-1.59, and a single-compartment syringe with a needle (e.g., permanently attached or detachable), with instructions for use;1 .69. A multiple-use kit comprising one or more vials containing the Composition 1 , or any of 1.1-1.59, and one or more single-compartment syringes with needles (e.g., permanently attached or detachable), with instructions for use;1.70. Kit 1.68 or 1.69, wherein the needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge;1.71. A single compartment pre-filled syringe (e.g., an automatic syringe) comprising Composition 1, or any of 1.1-1.59, optionally wherein the syringe needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge;1.72. A kit comprising a single-compartment pre-filled syringe (e.g., an automatic syringe) comprising Composition 1, or any of 1.1-1.59;1.73. Kit 1.72, wherein the syringe needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge;1.74. Any preceding Composition, Kit or Syringe comprising any preceding composition, wherein the administration dose of the composition, kit or syringe is 50 to 200 mg of lumateperone, measured as the free base equivalent, delivered in a single injection, e.g., 50 to 100 mg, or 100 to 150 mg, or 150 to 200 mg, 50 to 75 mg, or 75 to 125 mg, or 125 to 175 mg, or 75 to 150 mg, or 80 to 140 mg, or 90 to 130 mg, or 100 to 120 mg, or 100 to 110 mg;1.75. Any preceding Composition, Kit or Syringe wherein the composition is stable for at least 6 months, e.g., at least 12 months, at least 18 months, or at least 24 months, e.g., as measured by one or more of: stability of color and appearance (e.g., color and appearance are unchanged), stability of lumateperone assay (e.g., by HPLC), stability of particle size distribution, stability of viscosity, stability of water content, and stability of concentration of degradation products or impurities (e.g., wherein “stable” refers to a change from initial condition of not more than 5% of the property).

[0018] In a second aspect, the present disclosure provides an injectable pharmaceutical composition (Composition 2), comprising deuterolumateperone:in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the deuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer and wherein the injectable composition comprises a sterile, aqueous injection vehicle. For example, Composition 2 may be as follows:2.1. Composition 2, wherein the composition comprises the deuterolumateperone in pharmaceutically acceptable salt form selected from a tosylate, hydrochloride, besylate, mesylate, nosylate, hydrobromide, hydroiodide, tartrate, malate, maleate, fumarate, nitrate, phosphate, benzoate, 4-aminosalicylate, oxalate, or cyclamate acid addition salt;2.2. Composition 2, wherein the composition comprises the deuterolumateperone in tosylate salt form;2.3. Composition 2, wherein the composition comprises the deuterolumateperone in one or more of mono-tosylate salt form, di-tosylate salt form, and tri-tosylate salt form;2.4. Composition 2.3, wherein the composition comprises the deuterolumateperone in mono- tosylate salt form and di-tosylate salt form, or in free base form;2.5. Any of Compositions 2 or 2.1-2.4, wherein the composition comprises the deuterolumateperone in mono-tosylate salt form;2.6. Composition 2.5, wherein the deuterolumateperone mono-tosylate is in solid form;2.7. Composition 2.6, wherein the deuterolumateperone mono-tosylate is in solid crystal form;2.8. Composition 2.7, wherein the deuterolumateperone mono-tosylate is in solid crystal form, e.g., having the physical and chemical properties as disclosed in US 2023 / 0312573, such as one or more of the XRPD spectrum and / or DSC / TGA spectrum as disclosed therein;Composition 2.5, wherein the deuteroium ateperone mono-tosylate is in solid amorphous form; Any of Compositions 2.3-2.5, wherein the deuterolumateperone (e.g., free base or tosylate, e.g., deuterolumateperone mono-tosylate), is in solid amorphous form or is in the form of a solid amorphous dispersion; Composition 2.10, wherein the deuterolumateperone (e.g., free base or tosylate, e.g., deuterolumateperone mono-tosylate), is in the form of a solid amorphous dispersion comprising amorphous deuterolumateperone in admixture with one or more excipients, e.g., stabilizing excipients; Composition 2.11, wherein the composition form comprises one or more excipients which stabilize the amorphous from of the deuterolumateperone to prevent conversion of the amorphous form to the crystal form; Composition 2.11 or 2.12, wherein the one or more excipients are selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate / methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC-P), polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl pyrrolidone / vinyl acetate copolymer, and polyethylene glycol / polyvinyl acetate / polyvinylcaprolactam copolymer; Composition 2, or any of 2.1-2.13, wherein the polymeric microspheres of the composition comprises the deuterolumateperone (e.g., deuterolumateperone tosylate) in an average amount of 10 to 50% by weight of the composition, e.g., 10 to 40%, or 10 to 30%, or 10 to 25%, or 10 to 20%, or 10 to 15%, or 15 to 45%, or 15 to 40%, 15 to 35%, or 15 to 30%, or 15 to 25%, or 15 to 20%, or 20 to 45%, or 20 to 40%, or 20 to 35%, or 20 to 30%, or 20 to 25%, or 25 to 50%, or 25 to 45%, or 25 to 40%, or 25 to 35%, or 25 to 30%, or 30 to 40%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, by weight of the polymeric microsphere, measured as the equivalent amount of free base deuterolumateperone; Composition 2, or any of 2.1-2.13, wherein the composition (e.g., including polymeric microspheres and injection vehicle) comprises the deuterolumateperone (e.g., deuterolumateperone tosylate) in an amount of 5 to 10% by weight of the composition,e.g., 1 to 9%, or 1 to 8%, or 2 to 10%, or 2 to 9%, or 2 to 8%, or 3 to 10%, or 3 to 9%, or 3 to 8%, or 4 to 10%, or 4 to 9%, or 4 to 8%, or 5 to 10%, or 5 to 9%, or 5 to 8%, or 6 to 10%, or 6 to 9%, or 6 to 8%, or 7 to 10%., or 7 to 9%, or 7 to 8%, or about 7%, or about 8%, or about 9%, by weight of the composition, measured as the equivalent amount of free base deuterolumateperone; Composition 2, or any of 2.1-2.15, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 75:25 to 50:50, e.g., 73:27 to 52:48; Composition 2.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 70:30 to 55:45; Composition 2.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 58:42; Composition 2.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 62:38; Composition 2.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 65:35; Composition 2, or any of 2.1-2.20, wherein the poly(lactic-co-glycolic acid) copolymer has an inherent viscosity of 0.1 to 0.9, e.g., 0.1 to 0.75, or 0.1 to 0.7, or 0.6 to 0.6, or 0.1 to 0.5, or 0.1 to 0.4, or 0.1 to 0.3, or 0.1 to 0.2, or 0.15 to 0.45, or 0.15 to 0.3, or 0.15 to 0.25, or 0.2 to 0.8, or 0.2 to 0.6, or 0.2 to 0.4, or 0.25 to 0.5, or 0.25 to 0.4, or 0.25 to 0.35, or 0.3 to 0.6, or 0.3 to 0.5, or 0.3 to 0.45, or 0.5 to 0.8, or 0.5 to 0.75, or 0.5 to 0.7, or about 0.19; Composition 2, or any of 2.1-2.21, wherein the poly(lactic-co-glycolic acid) copolymer has average molecular weight of 5,000 to 150,000 Daltons, e.g., 5,000 to 100,000 Da, or 5,000 to 75,000 Da, or 5,000 to 50,000 Da, or 5,000 to 25,000 Da, or 5,000 to 20,000 Da, or 7,000 to 20,000 Da, or 10,000 to 40,000 Da, or 10,000 to 35,000 Da, or 10,000 to 30,000 Da, or 10,000 to 25,000 Da, or 15,000 to 30,000 Da, or 15,000 to 25,000 Da, or 20,000 to 50,000 Da, or 20,000 to 45,000 Da, or 20,000 to 40,000 Da, or 25,000 to 75,000 Da, or 25,000 to 60,000 Da, or 25,000 to 50,000 Da, or 25,000 to 45,000 Da; Composition 2, or any of 2.1-2.22, wherein the poly(lactic-co-glycolic acid) copolymer has molecular weight range of 5,000 to 150,000 Daltons (e.g., at least 90% of polymer molecules have a molecular weight within the range), e.g., 5,000 to 100,000 Da, or 5,000to 75,000 Da, or 5,000 to 50,000 Da, or 5,000 to 25,000 Da, or 5,000 to 20,000 Da, or 7,000 to 20,000 Da, or 10,000 to 40,000 Da, or 10,000 to 35,000 Da, or 10,000 to 30,000 Da, or 10,000 to 25,000 Da, or 15,000 to 30,000 Da, or 15,000 to 25,000 Da, or 20,000 to 50,000 Da, or 20,000 to 45,000 Da, or 20,000 to 40,000 Da, or 25,000 to 75,000 Da, or 25,000 to 60,000 Da, or 25,000 to 50,000 Da, or 25,000 to 45,000 Da; Composition 2, or any of 2.1-2.23, wherein the poly(lactic-co-glycolic acid) copolymer has carboxylic acid end groups; Composition 2, or any of 2.1-2.23, wherein the poly(lactic-co-glycolic acid) copolymer has carboxylic ester end groups (e.g., such as a Cl-6 linear ester end group, e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl ester end groups); Composition 2, or any of 2.1-2.25, wherein the polymeric microspheres of the composition comprises the poly(lactic-co-glycolic acid) copolymer in an average amount of 50 to 90% by weight of the composition, e.g., 55 to 90%, or 60 to 90%, or 65 to 90%, or 70 to 90%, or 75 to 90%, or 85 to 90%, or 50 to 85%, or 55 to 85%, or 60 to 85%, 60 to 85%, or 65 to 85%, or 70 to 85%, or 75 to 85%, or 80 to 85%, or 50 to 80%, or 55 to 80%, or 60 to 80%, or 65 to 80%, or 70 to 80%, or 75 to 80%, or 50 to 75%, or 55 to 75%, or 60 to 75%, or 65 to 75%, or 70 to 75%, or 50 to 65%, or 55 to 65%, or 60 to 65%, or 50 to 60%, or 55 to 60%, or 50 to 55%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, by weight of the polymeric microsphere; Composition 2, or any of 2.1-2.26, wherein the composition (e.g., including the polymeric microspheres and the injection vehicle) comprises the poly(lactic-co-glycolic acid) copolymer in an amount of 10 to 40% by weight of the composition, e.g., 15 to40%, or 20 to 40%, or 25 to 40%, or 30 to 40%, or 35 to 40%, or 10 to 35%, or 15 to35%, or 20 to 35%, or 25 to 35%, or 30 to 35%, or 10 to 30%, or 15 to 30%, or 20 to30%, or 25 to 30%, or 10 to 25%, or 15 to 25%, or 20 to 25%, or 10 to 20%, or 15 to20%, or 10 to 15%, about 15%, or about 20%, or about 25%, or about 30%, by weight of the composition; Composition 2, or any of 2.1-2.27, wherein the polymeric microspheres consist essentially of the deuterolumateperone (e.g., deuterolumateperone tosylate) and the poly(lactic-co-glycolic acid) copolymer, optionally, having not more than trace amountsof any organic solvents or polymers from microsphere preparation (e.g., water, methylene chloride or polyvinyl alcohol); Composition 2, or any of 2.1-2.28, wherein the sterile aqueous injection vehicle comprises water (e.g., sterile water for injection) and one or more excipients selected from a surfactant (e.g., polysorbate 20), a buffering agent (e.g., sodium phosphate), an ionic agent (e.g., sodium chloride), a thickener (e.g., carboxymethyl cellulose), a preservative (e.g., citric acid), and / or a co-solvent; Composition 2.29, wherein the aqueous injection vehicle comprises one or more excipients selected from polysorbate 20, polysorbate 30, polysorbate 40, polysorbate 60, polysorbate 80, citric acid, maleic acid, lactic acid, citrate salts (e.g., sodium citrate), bicarbonate salts (e.g., sodium bicarbonate), carbonate salts (e.g., sodium carbonate), hydrochloric acid, sodium hydroxide, sodium chloride, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, ethanol, propylene glycol, and glycerin; Composition 2.30, wherein each of said one or more excipients are present in the injection vehicle in an amount of 0.001 to 2% by weight, e.g., 0.001 to 0.1%, or 0.005 to 0.1%, or 0.05 to 0.1%, or 0.1 to 0.3%, 0.3 to 0.5%, 0.5 to 0.7%, 0.7 to 0.9%, 0.9 to 1.1%, 1.1 to 1.3%, 1.3 to 1.5%, 1.5 to 1.7%, or 1.7 to 1.9%; Composition 2, or any of 2.1-2.31, wherein the sterile aqueous injection vehicle comprises water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%); Composition 2.32, wherein the sterile aqueous injection vehicle consists essentially of water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 1-1.5%. e.g., 1.25%), sodium chloride (e.g., 0.6-0.8%), sodium phosphate dibasic (e.g., 0.05 to 0.15%), citric acid (e.g., 0.005 to 0.05%), and polysorbate 20 (e.g., 0.005 to 0.05%); Composition 2.32, wherein the sterile aqueous injection vehicle consists essentially of water, carboxymethyl cellulose (e.g., about 1.25%), sodium chloride (e.g., about 0.7%, sodium phosphate dibasic (e.g., about 0.1%), citric acid (about 0.01%), and polysorbate 20 (about 0.01%); Composition 2, or any of 2.1-2.34, wherein the sterile aqueous injection vehicle has a pH of 6 to 8, e.g., 6.5 to 7.5, or about pH 7;Composition 2, or any of 2.1 -2.35, wherein the viscosity of the sterile injection vehicle is from 1 to 30 centipoise (cP), e.g., 5 to 25 cP, or 5 to 20 cP, or 5 to 15 cP, or 5 to 10 cP, or about 10 cP; Composition 2, or any of 2.1-2.36, wherein the polymeric microspheres are particulated to form particles having a particle size distribution characterized by a dlO of least 10 microns and a d90 of not more than 120 microns, e.g., a dlO of 10-50 microns (e.g., 20- 40 microns, 25 to 35 microns, or about 30 microns) and / or a d50 of 30-70 microns (e.g., 40-60 microns, 45-55 microns, or about 50 microns), and / or a d90 of 40-80 microns (e.g., 50-70 microns, 55-65 microns, or about 60 microns); Composition 2, or any of Compositions 2.1-2.37, wherein the composition comprises 25 to 500 mg / mL lumateperone, measured as the free base equivalent, e.g., 25 to 450 mg / mL, or 25 to 400 mg / mL, or 25 to 350 mg / mL, or 25 to 300 mg / mL, or 25 to 250 mg / mL, or 25 to 200 mg / mL, or 25 to 150 mg / mL, or 25 to 100 mg / mL, or 25 to 50 mg / mL, or 50 to 300 mg / mL, or 50 to 250 mg / mL, or 50 to 200 mg / mL, or 50 to 150 mg / mL, or 50 to 100 mg / mL, 75 to 300 mg / mL, or 75 to 250 mg / mL, or 75 to 200 mg / mL, or 75 to 150 mg / mL, or 75 to 100 mg / mL, or 100 to 300 mg / mL, or 100 to 250 mg / mL, or 100 to 200 mg / mL, or 100 to 150 mg / mL, or 150 to 300 mg / mL, or 150 to 250 mg / mL, or 150 to 200 mg / mL, or 200 to 300 mg / mL, or about 85 mg / mL; Composition 2, or any of Compositions 2.1-2.38, wherein the composition further comprises an anti-oxidant, e.g., selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), carotenoids, glutathione, sodium metabisulfite, sodium ethylenediaminetetraacetate, cysteine, methionine, sesamol, and citric acid. Composition 2, or any of Compositions 2.1-2.39, wherein the polymeric microspheres are suspended in the sterile aqueous injection vehicle; Composition 2, or any of Compositions 2.1-2.40, wherein the composition consists of the polymeric microspheres and the sterile aqueous injection vehicle; Composition 2, or any of Compositions 2.1-2.41, wherein the composition consists essentially of the deuterolumateperone (e.g., deuterolumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water, and one or more excipients selected from a surfactant (e.g., polysorbate 20), abuffering agent (e.g., sodium phosphate), an ionic agent (e.g., sodium chloride), a thickener (e.g., carboxymethyl cellulose), and a preservative (e.g., citric acid); Composition 2, or any of Compositions 2.1-2.42, wherein the composition consists essentially of the deuterolumateperone (e.g., deuterolumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%); Composition 2, or any of 2.1-2.43, wherein the composition is formulated for intramuscular injection; Composition 2, or any of 2.1-2.43, wherein the composition is formulated for subcutaneous injection; Composition 2, or any of 2.1-2.45, wherein the composition is intended to be administered once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, e.g., once per month; Composition 2, or any of 2.1-2.46, wherein the composition, after intramuscular or subcutaneous injection, releases the deuterolumateperone over a period of at least 1 week, 2 weeks, 3 weeks, or 4 weeks, maintaining a plasma concentration of deuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 2, or any of 2.1-2.46, wherein the composition, after intramuscular or subcutaneous injection, releases the deuterolumateperone over a period of at least 6 weeks maintaining a plasma concentration of deuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 2, or any of 2.1-2.46, wherein the composition, after intramuscular or subcutaneous injection, releases the deuterolumateperone over a period of at least 8 weeks maintaining a plasma concentration of deuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL;Composition 2, or any of 2.1 -2.46, wherein the composition, after intramuscular or subcutaneous injection, releases the dcutcrolumatcpcronc over a period of at least 10 weeks maintaining a plasma concentration of deuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 2, or any of 2.1-2.46, wherein the composition, after intramuscular or subcutaneous injection, releases the deuterolumateperone over a period of at least 12 weeks maintaining a plasma concentration of deuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 2, or any of 2.1-2.51, wherein the composition, after intramuscular or subcutaneous injection, releases the deuterolumateperone over at a rate to provide not more than 100 ng / mL plasma concentration of deuterolumateperone at any time after 9 days after injection, e.g., not more than 85 ng / mL, or not more than 75 ng / mL, or not more than 70 ng / mL, or not more than 65 ng / mL, or not more than 60 ng / mL; Composition 2, or any of 2.1-2.52, wherein the composition, after intramuscular or subcutaneous injection, releases the deuterolumateperone at a rate to provide not more than 300 ng / mL plasma concentration of deuterolumateperone at any time within 72 hours after injection, e.g., not more than 250 ng / mL, or not more than 200 ng / mL, or not more than 150 ng / mL, or not more than 125 ng / mL, or not more than 100 ng / mL; Composition 2, or any of 2.1-2.53, wherein the composition, after intramuscular or subcutaneous injection, releases not more than 10% of the total amount of deuterolumateperone within the first 8 hours after injection, e.g., not more than 8%, or not more than 6% or not more than 5%; Composition 2, or any of 2.1-2.54, wherein the composition is a bi-component composition consisting of a first component being the polymeric microspheres comprising the poly(lactic-co-glycolic) copolymer and deuterolumateperone, and a second component being the sterile aqueous injection vehicle, such as, where the two components are maintained separately and are admixed immediately prior to injection; Composition 2.55, wherein the first component is a solid (e.g., a dry powder), and the second component is a homogenous liquid;Composition 2, or any of 2.1 -2.56, wherein the composition is free of water-miscible organic solvents; Composition 2, or any of 2.1-2.56, wherein the composition is free of N-methyl-2- pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethyl formamide (DMF), dimethylacetamide (DMA), 2-pyrrolidone, propylene carbonate, caprolactam, N- methylcaprolactam, and triacetin; Composition 2, or any of 2.1-2.58, wherein the composition is free of triglyceride oils, e.g., peanut oil, soybean oil, sesame oil, castor oil, and the like; A kit (e.g., single-use or multiple-use) comprising, in separate compartments, two compositions, a first composition comprising deuterolumateperone in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the deuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer, and a second composition which is a sterile, aqueous injection vehicle, wherein upon combination of the first composition and the second composition, an injectable composition according to Composition 2 or any of 2.1-2.59 is formed; Kit 2.60, wherein the first composition and the second composition are combined in a ratio of 250-750 mg of the first composition (e.g., about 500 mg) to 0.75 to 1.25 mL of the second composition (e.g., 1.0 mL) to form said injectable composition. Kit 2.60 or 2.61, wherein the first composition is a solid powder and the second composition is a homogenous liquid; Kit 2.60, 2.61, or 2.62, wherein the kit comprises the first composition in a sealed vial, the second composition in a sealed vial, and the kit further comprises a syringe and a needle; Kit 2.63, wherein the needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; A pre-filled dual-compartment syringe (e.g., an automatic syringe) comprising, in separate compartments, two compositions, a first composition comprising deuterolumateperone in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the deuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer, and a second composition which is a sterile, aqueous injection vehicle, wherein upon actuation of the syringe the first composition and the second composition are combined to form an injectable composition according to Composition 2 or any of 2.1-2.59 is formed; Syringe 2.65, wherein the first composition and the second composition are combined in a ratio of 250-750 mg of the first composition (e.g., about 500 mg) to 0.75 to 1.25 mL of the second composition (e.g., 1.0 mL) to form said injectable composition; Syringe 2.65 or 2.66, wherein the first composition is a solid powder and the second composition is a homogenous liquid; A single-use kit comprising a vial containing the Composition 2, or any of 2.1-2.59, and a single-compartment syringe with a needle (e.g., permanently attached or detachable), with instructions for use; A multiple-use kit comprising one or more vials containing the Composition 2, or any of 2.1-2.59, and one or more single-compartment syringes with needles (e.g., permanently attached or detachable), with instructions for use; Kit 2.68 or 2.69, wherein the needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; A single compartment pre-filled syringe (e.g., an automatic syringe) comprising Composition 2, or any of 2.1-2.59, optionally wherein the syringe needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; A kit comprising a single-compartment pre-filled syringe (e.g., an automatic syringe) comprising Composition 2, or any of 2.1-2.59; Kit 2.72, wherein the syringe needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; Any preceding Composition, Kit or Syringe comprising any preceding composition, wherein the administration dose of the composition, kit or syringe is 50 to 200 mg of deuterolumateperone, measured as the free base equivalent, delivered in a single injection, e.g., 50 to 100 mg, or 100 to 150 mg, or 150 to 200 mg, 50 to 75 mg, or 75 to 125 mg, or 125 to 175 mg, or 75 to 150 mg, or 80 to 140 mg, or 90 to 130 mg, or 100 to 120 mg, or 100 to 110 mg;2.75. Any preceding Composition, Kit or Syringe wherein the composition is stable for at least 6 months, e.g., at least 12 months, at least 18 months, or at least 24 months, e.g., as measured by one or more of: stability of color and appearance (e.g., color and appearance are unchanged), stability of deuterolumateperone assay (e.g., by HPLC), stability of particle size distribution, stability of viscosity, stability of water content, and stability of concentration of degradation products or impurities (e.g., wherein “stable” refers to a change from initial condition of not more than 5% of the property).

[0019] In a third aspect, the present disclosure provides an injectable pharmaceutical composition (Composition 3), comprising tetradeuterolumateperone:in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the deuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer and wherein the injectable composition comprises a sterile, aqueous injection vehicle. For example, Composition 3 may be as follows:3.1. Composition 3, wherein the composition comprises the tetradeuterolumateperone in pharmaceutically acceptable salt form selected from a tosylate, hydrochloride, besylate, mesylate, nosylate, hydrobromide, hydroiodide, tartrate, malate, maleate, fumarate, nitrate, phosphate, benzoate, 4-aminosalicylate, oxalate, or cyclamate acid addition salt;3.2. Composition 3, wherein the composition comprises the tetradeuterolumateperone in tosylate salt form;3.3. Composition 3, wherein the composition comprises the tetradeuterolumateperone in one or more of mono-tosylate salt form, di-tosylate salt form, and tri-tosylate salt form;3.4. Composition 3.3, wherein the composition comprises the tetradeuterolumateperone in mono-tosylate salt form and di-tosylate salt form;Any of Compositions 3 or 3.1-3.4, wherein the composition comprises the tctradcutcrolumatcpcronc in mono-tosylatc salt form; Composition 3.5, wherein the tetradeuterolumateperone mono-tosylate is in solid form; Composition 3.6, wherein the tetradeuterolumateperone mono-tosylate is in solid crystal form; Composition 3.6, wherein the tetradeuterolumateperone mono-tosylate is in solid amorphous form; Any of Compositions 3 or 3.1-3.4, wherein the composition comprises the tetradeuterolumateperone in free base form; Any of Compositions 3.3-3.5, wherein the tetradeuterolumateperone (e.g., free base or tosylate, e.g., tetradeuterolumateperone mono-tosylate), is in solid amorphous form or is in the form of a solid amorphous dispersion; Composition 3.10, wherein the tetradeuterolumateperone (e.g., free base or tosylate, e.g., tetradeuterolumateperone mono-tosylate), is in the form of a solid amorphous dispersion comprising amorphous tetradeuterolumateperone in admixture with one or more excipients, e.g., stabilizing excipients; Composition 3.11, wherein the composition form comprises one or more excipients which stabilize the amorphous from of the tetradeuterolumateperone to prevent conversion of the amorphous form to the crystal form; Composition 3.11 or 3.12, wherein the one or more excipients are selected from the group consisting of cellulose acetate, cellulose acetate phthalate, methacrylate / methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), hydroxypropyl methyl cellulose phthalate (HPMC-P), polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl pyrrolidone / vinyl acetate copolymer, and polyethylene glycol / polyvinyl acetate / polyvinylcaprolactam copolymer; Composition 3, or any of 3.1-3.13, wherein the polymeric microspheres of the composition comprises the tetradeuterolumateperone (e.g., tetradeuterolumateperone tosylate) in an average amount of 10 to 50% by weight of the composition, e.g., 10 to 40%, or 10 to 30%, or 10 to 25%, or 10 to 20%, or 10 to 15%, or 15 to 45%, or 15 to 40%, 15 to 35%, or 15 to 30%, or 15 to 25%, or 15 to 20%, or 20 to 45%, or 20 to 40%,or 20 to 35%, or 20 to 30%, or 20 to 25%, or 25 to 50%, or 25 to 45%, or 25 to 40%, or 25 to 35%, or 25 to 30%, or 30 to 40%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, by weight of the polymeric microsphere, measured as the equivalent amount of free base tetradeuterolumateperone; Composition 3, or any of 3.1-3.13, wherein the composition (e.g., including polymeric microspheres and injection vehicle) comprises the tetradeuterolumateperone (e.g., tetradeuterolumateperone tosylate) in an amount of 5 to 10% by weight of the composition, e.g., 1 to 9%, or 1 to 8%, or 2 to 10%, or 2 to 9%, or 2 to 8%, or 3 to 10%, or 3 to 9%, or 3 to 8%, or 4 to 10%, or 4 to 9%, or 4 to 8%, or 5 to 10%, or 5 to 9%, or 5 to 8%, or 6 to 10%, or 6 to 9%, or 6 to 8%, or 7 to 10%., or 7 to 9%, or 7 to 8%, or about 7%, or about 8%, or about 9%, by weight of the composition, measured as the equivalent amount of free base tetradeuterolumateperone; Composition 3, or any of 3.1-3.15, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 75:25 to 50:50, e.g., 73:27 to 52:48; Composition 3.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 70:30 to 55:45; Composition 3.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 58:42; Composition 3.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 62:38; Composition 3.16, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 65:35; Composition 3, or any of 3.1-3.20, wherein the poly(lactic-co-glycolic acid) copolymer has an inherent viscosity of 0.1 to 0.9, e.g., 0.1 to 0.75, or 0.1 to 0.7, or 0.6 to 0.6, or 0.1 to 0.5, or 0.1 to 0.4, or 0.1 to 0.3, or 0.1 to 0.2, or 0.15 to 0.45, or 0.15 to 0.3, or 0.15 to 0.25, or 0.2 to 0.8, or 0.2 to 0.6, or 0.2 to 0.4, or 0.25 to 0.5, or 0.25 to 0.4, or 0.25 to 0.35, or 0.3 to 0.6, or 0.3 to 0.5, or 0.3 to 0.45, or 0.5 to 0.8, or 0.5 to 0.75, or 0.5 to 0.7, or about 0.19; Composition 3, or any of 3.1-3.21, wherein the poly(lactic-co-glycolic acid) copolymer has average molecular weight of 5,000 to 150,000 Daltons, e.g., 5,000 to 100,000 Da, or 5,000 to 75,000 Da, or 5,000 to 50,000 Da, or 5,000 to 25,000 Da, or 5,000 to 20,000 Da,or 7,000 to 20,000 Da, or 10,000 to 40,000 Da, or 10,000 to 35,000 Da, or 10,000 to 30,000 Da, or 10,000 to 25,000 Da, or 15,000 to 30,000 Da, or 15,000 to 25,000 Da, or20,000 to 50,000 Da, or 20,000 to 45,000 Da, or 20,000 to 40,000 Da, or 25,000 to75,000 Da, or 25,000 to 60,000 Da, or 25,000 to 50,000 Da, or 25,000 to 45,000 Da; Composition 3, or any of 3.1-3.22, wherein the poly(lactic-co-glycolic acid) copolymer has molecular weight range of 5,000 to 150,000 Daltons (e.g., at least 90% of polymer molecules have a molecular weight within the range), e.g., 5,000 to 100,000 Da, or 5,000 to 75,000 Da, or 5,000 to 50,000 Da, or 5,000 to 25,000 Da, or 5,000 to 20,000 Da, or 7,000 to 20,000 Da, or 10,000 to 40,000 Da, or 10,000 to 35,000 Da, or 10,000 to 30,000 Da, or 10,000 to 25,000 Da, or 15,000 to 30,000 Da, or 15,000 to 25,000 Da, or 20,000 to 50,000 Da, or 20,000 to 45,000 Da, or 20,000 to 40,000 Da, or 25,000 to 75,000 Da, or 25,000 to 60,000 Da, or 25,000 to 50,000 Da, or 25,000 to 45,000 Da; Composition 3, or any of 3.1-3.23, wherein the poly(lactic-co-glycolic acid) copolymer has carboxylic acid end groups; Composition 3, or any of 3.1-3.23, wherein the poly(lactic-co-glycolic acid) copolymer has carboxylic ester end groups (e.g., such as a Cl-6 linear ester end group, e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl ester end groups); Composition 3, or any of 3.1-3.25, wherein the polymeric microspheres of the composition comprises the poly(lactic-co-glycolic acid) copolymer in an average amount of 50 to 90% by weight of the composition, e.g., 55 to 90%, or 60 to 90%, or 65 to 90%, or 70 to 90%, or 75 to 90%, or 85 to 90%, or 50 to 85%, or 55 to 85%, or 60 to 85%, 60 to 85%, or 65 to 85%, or 70 to 85%, or 75 to 85%, or 80 to 85%, or 50 to 80%, or 55 to 80%, or 60 to 80%, or 65 to 80%, or 70 to 80%, or 75 to 80%, or 50 to 75%, or 55 to 75%, or 60 to 75%, or 65 to 75%, or 70 to 75%, or 50 to 65%, or 55 to 65%, or 60 to 65%, or 50 to 60%, or 55 to 60%, or 50 to 55%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, by weight of the polymeric microsphere; Composition 3, or any of 3.1-3.26, wherein the composition (e.g., including the polymeric microspheres and the injection vehicle) comprises the poly(lactic-co-glycolic acid) copolymer in an amount of 10 to 40% by weight of the composition, e.g., 15 to 40%, or 20 to 40%, or 25 to 40%, or 30 to 40%, or 35 to 40%, or 10 to 35%, or 15 to 35%, or 20 to 35%, or 25 to 35%, or 30 to 35%, or 10 to 30%, or 15 to 30%, or 20 to30%, or 25 to 30%, or 10 to 25%, or 15 to 25%, or 20 to 25%, or 10 to 20%, or 15 to 20%, or 10 to 15%, about 15%, or about 20%, or about 25%, or about 30%, by weight of the composition; Composition 3, or any of 3.1-3.27, wherein the polymeric microspheres consist essentially of the tetradeuterolumateperone (e.g., tetradeuterolumateperone tosylate) and the poly(lactic-co-glycolic acid) copolymer, optionally, having not more than trace amounts of any organic solvents or polymers from microsphere preparation (e.g., water, methylene chloride or polyvinyl alcohol); Composition 3, or any of 3.1-3.28, wherein the sterile aqueous injection vehicle comprises water (e.g., sterile water for injection) and one or more excipients selected from a surfactant (e.g., polysorbate 20), a buffering agent (e.g., sodium phosphate), an ionic agent (e.g., sodium chloride), a thickener (e.g., carboxymethyl cellulose), a preservative (e.g., citric acid), and / or a co-solvent; Composition 3.29, wherein the aqueous injection vehicle comprises one or more excipients selected from polysorbate 20, polysorbate 30, polysorbate 40, polysorbate 60, polysorbate 80, citric acid, maleic acid, lactic acid, citrate salts (e.g., sodium citrate), bicarbonate salts (e.g., sodium bicarbonate), carbonate salts (e.g., sodium carbonate), hydrochloric acid, sodium hydroxide, sodium chloride, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, ethanol, propylene glycol, and glycerin; Composition 3.30, wherein each of said one or more excipients are present in the injection vehicle in an amount of 0.001 to 2% by weight, e.g., 0.001 to 0.1%, or 0.005 to 0.1%, or 0.05 to 0.1%, or 0.1 to 0.3%, 0.3 to 0.5%, 0.5 to 0.7%, 0.7 to 0.9%, 0.9 to 1.1%, 1.1 to 1.3%, 1.3 to 1.5%, 1.5 to 1.7%, or 1.7 to 1.9%; Composition 3, or any of 3.1-3.31, wherein the sterile aqueous injection vehicle comprises water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%); Composition 3.32, wherein the sterile aqueous injection vehicle consists essentially of water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 1-1.5%. e.g., 1.25%), sodium chloride (e.g., 0.6-0.8%), sodium phosphate dibasic (e.g., 0.05 to 0.15%), citric acid (e.g., 0.005 to 0.05%), and polysorbate 20 (e.g., 0.005 to 0.05%);Composition 3.32, wherein the sterile aqueous injection vehicle consists essentially of water, carboxymethyl cellulose (c.g., about 1.25%), sodium chloride (c.g., about 0.7%, sodium phosphate dibasic (e.g., about 0.1%), citric acid (about 0.01%), and polysorbate 20 (about 0.01%); Composition 3, or any of 3.1-3.34, wherein the sterile aqueous injection vehicle has a pH of 6 to 8, e.g., 6.5 to 7.5, or about pH 7; Composition 3, or any of 3.1-3.35, wherein the viscosity of the sterile injection vehicle is from 1 to 30 centipoise (cP), e.g., 5 to 25 cP, or 5 to 20 cP, or 5 to 15 cP, or 5 to 10 cP, or about 10 cP; Composition 3, or any of 3.1-3.36, wherein the polymeric microspheres are particulated to form particles having a particle size distribution characterized by a dlO of least 10 microns and a d90 of not more than 120 microns, e.g., a dlO of 10-50 microns (e.g., 20- 40 microns, 25 to 35 microns, or about 30 microns) and / or a d50 of 30-70 microns (e.g., 40-60 microns, 45-55 microns, or about 50 microns), and / or a d90 of 40-80 microns (e.g., 50-70 microns, 55-65 microns, or about 60 microns); Composition 3, or any of Compositions 3.1-3.37, wherein the composition comprises 25 to 500 mg / mL lumateperone, measured as the free base equivalent, e.g., 25 to 450 mg / mL, or 25 to 400 mg / mL, or 25 to 350 mg / mL, or 25 to 300 mg / mL, or 25 to 250 mg / mL, or 25 to 200 mg / mL, or 25 to 150 mg / mL, or 25 to 100 mg / mL, or 25 to 50 mg / mL, or 50 to 300 mg / mL, or 50 to 250 mg / mL, or 50 to 200 mg / mL, or 50 to 150 mg / mL, or 50 to 100 mg / mL, 75 to 300 mg / mL, or 75 to 250 mg / mL, or 75 to 200 mg / mL, or 75 to 150 mg / mL, or 75 to 100 mg / mL, or 100 to 300 mg / mL, or 100 to 250 mg / mL, or 100 to 200 mg / mL, or 100 to 150 mg / mL, or 150 to 300 mg / mL, or 150 to 250 mg / mL, or 150 to 200 mg / mL, or 200 to 300 mg / mL, or about 85 mg / mL; Composition 3, or any of Compositions 3.1-3.38, wherein the composition further comprises an anti-oxidant, e.g., selected from one or more of tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), carotenoids, glutathione, sodium metabisulfite, sodium ethylenediaminetetraacetate, cysteine, methionine, sesamol, and citric acid. Composition 3, or any of Compositions 3.1-3.39, wherein the polymeric microspheres are suspended in the sterile aqueous injection vehicle;Composition 3, or any of Compositions 3.1 -3.40, wherein the composition consists of the polymeric microsphcrcs and the sterile aqueous injection vehicle; Composition 3, or any of Compositions 3.1-3.41, wherein the composition consists essentially of the tetradeuterolumateperone (e.g., tetradeuterolumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water, and one or more excipients selected from a surfactant (e.g., polysorbate 20), a buffering agent (e.g., sodium phosphate), an ionic agent (e.g., sodium chloride), a thickener (e.g., carboxymethyl cellulose), and a preservative (e.g., citric acid); Composition 3, or any of Compositions 3.1-3.42, wherein the composition consists essentially of the tetradeuterolumateperone (e.g., tetradeuterolumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%); Composition 3, or any of 3.1-3.43, wherein the composition is formulated for intramuscular injection; Composition 3, or any of 3.1-3.43, wherein the composition is formulated for subcutaneous injection; Composition 3, or any of 3.1-3.45, wherein the composition is intended to be administered once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, e.g., once per month; Composition 3, or any of 3.1-3.46, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone over a period of at least 1 week, 2 weeks, 3 weeks, or 4 weeks, maintaining a plasma concentration of tetradeuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL; Composition 3, or any of 3.1-3.46, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone over a period of at least 6 weeks maintaining a plasma concentration of tetradeuterolumateperone of at least 5ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5- 20 ng / mL, or 10-20 ng / mL; Composition 3, or any of 3.1-3.46, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone over a period of at least 8 weeks maintaining a plasma concentration of tetradeuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5- 20 ng / mL, or 10-20 ng / mL; Composition 3, or any of 3.1-3.46, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone over a period of at least 10 weeks maintaining a plasma concentration of tetradeuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5- 20 ng / mL, or 10-20 ng / mL; Composition 3, or any of 3.1-3.46, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone over a period of at least 12 weeks maintaining a plasma concentration of tetradeuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5- 20 ng / mL, or 10-20 ng / mL; Composition 3, or any of 3.1-3.51, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone over at a rate to provide not more than 100 ng / mL plasma concentration of tetradeuterolumateperone at any time after 9 days after injection, e.g., not more than 85 ng / mL, or not more than 75 ng / mL, or not more than 70 ng / mL, or not more than 65 ng / mL, or not more than 60 ng / mL; Composition 3, or any of 3.1-3.52, wherein the composition, after intramuscular or subcutaneous injection, releases the tetradeuterolumateperone at a rate to provide not more than 300 ng / mL plasma concentration of tetradeuterolumateperone at any time within 72 hours after injection, e.g., not more than 250 ng / mL, or not more than 200 ng / mL, or not more than 150 ng / mL, or not more than 125 ng / mL, or not more than 100 ng / mL; Composition 3, or any of 3.1-3.53, wherein the composition, after intramuscular or subcutaneous injection, releases not more than 10% of the total amount oftetradeuterolumateperone within the first 8 hours after injection, e.g., not more than 8%, or not more than 6% or not more than 5%; Composition 3, or any of 3.1-3.54, wherein the composition is a bi-component composition consisting of a first component being the polymeric microspheres comprising the poly(lactic-co-glycolic) copolymer and tetradeuterolumateperone, and a second component being the sterile aqueous injection vehicle, such as, where the two components are maintained separately and are admixed immediately prior to injection; Composition 3.55, wherein the first component is a solid (e.g., a dry powder), and the second component is a homogenous liquid; Composition 3, or any of 3.1-3.56, wherein the composition is free of water-miscible organic solvents; Composition 3, or any of 3.1-3.56, wherein the composition is free of N-methyl-2- pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethyl formamide (DMF), dimethylacetamide (DMA), 2-pyrrolidone, propylene carbonate, caprolactam, N- methylcaprolactam, and triacetin; Composition 3, or any of 3.1-3.58, wherein the composition is free of triglyceride oils, e.g., peanut oil, soybean oil, sesame oil, castor oil, and the like; A kit (e.g., single-use or multiple-use) comprising, in separate compartments, two compositions, a first composition comprising tetradeuterolumateperone in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the tetradeuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer, and a second composition which is a sterile, aqueous injection vehicle, wherein upon combination of the first composition and the second composition, an injectable composition according to Composition 3 or any of 3.1-3.59 is formed; Kit 3.60, wherein the first composition and the second composition are combined in a ratio of 250-750 mg of the first composition (e.g., about 500 mg) to 0.75 to 1.25 mL of the second composition (e.g., 1.0 mL) to form said injectable composition. Kit 3.60 or 3.61, wherein the first composition is a solid powder and the second composition is a homogenous liquid;Kit 3.60, 3.61 , or 3.62, wherein the kit comprises the first composition in a sealed vial, the second composition in a scaled vial, and the kit further comprises a syringe and a needle; Kit 3.63, wherein the needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; A pre-filled dual-compartment syringe (e.g., an automatic syringe) comprising, in separate compartments, two compositions, a first composition comprising tetradeuterolumateperone in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), wherein the tetradeuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer, and a second composition which is a sterile, aqueous injection vehicle, wherein upon actuation of the syringe the first composition and the second composition are combined to form an injectable composition according to Composition 3 or any of 3.1-3.59 is formed; Syringe 3.65, wherein the first composition and the second composition are combined in a ratio of 250-750 mg of the first composition (e.g., about 500 mg) to 0.75 to 1.25 mL of the second composition (e.g., 1.0 mL) to form said injectable composition; Syringe 3.65 or 3.66, wherein the first composition is a solid powder and the second composition is a homogenous liquid; A single-use kit comprising a vial containing the Composition 3, or any of 3.1-3.59, and a single-compartment syringe with a needle (e.g., permanently attached or detachable), with instructions for use; A multiple-use kit comprising one or more vials containing the Composition 3, or any of 3.1-3.59, and one or more single-compartment syringes with needles (e.g., permanently attached or detachable), with instructions for use; Kit 3.68 or 3.69, wherein the needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge; A single compartment pre-filled syringe (e.g., an automatic syringe) comprising Composition 3, or any of 3.1-3.59, optionally wherein the syringe needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge;3.72. A kit comprising a single-compartment pre-filled syringe (e.g., an automatic syringe) comprising Composition 3, or any of 3.1-3.59;3.73. Kit 3.72, wherein the syringe needle is an 18 to 25 Gauge needle, e.g., 19 to 25 Gauge, or 20 to 25 Gauge, or 21 to 25 Gauge, or 23 to 25 Gauge;3.74. Any preceding Composition, Kit or Syringe comprising any preceding composition, wherein the administration dose of the composition, kit or syringe is 50 to 200 mg of tetradeuterolumateperone, measured as the free base equivalent, delivered in a single injection, e.g., 50 to 100 mg, or 100 to 150 mg, or 150 to 200 mg, 50 to 75 mg, or 75 to 125 mg, or 125 to 175 mg, or 75 to 150 mg, or 80 to 140 mg, or 90 to 130 mg, or 100 to 120 mg, or 100 to 110 mg;3.75. Any preceding Composition, Kit or Syringe wherein the composition is stable for at least 6 months, e.g., at least 12 months, at least 18 months, or at least 24 months, e.g., as measured by one or more of: stability of color and appearance (e.g., color and appearance are unchanged), stability of tetradeuterolumateperone assay (e.g., by HPLC), stability of particle size distribution, stability of viscosity, stability of water content, and stability of concentration of degradation products or impurities (e.g., wherein “stable” refers to a change from initial condition of not more than 5% of the property).

[0020] Preservative agents may be added to prevent the growth of microorganisms such as bacteria, yeasts and fungi in liquid formulations, which are likely to be used repeatedly. Suitable preservatives should be physicochemical stable and effective in the desired pH range. Examples of preservative agents include ethanol, methylparaben, propylparaben and benzyl alcohol.

[0021] In some embodiments, the solid dosage forms of the present disclosure include one or more anti-oxidants to guard against degradation of the active. Examples of antioxidants include propyl gallate, ascorbyl palmitate, ascorbic acid, t-butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherols, tocotrienols, sodium sulfite, sodium metabisulfite, beta-carotene, citric acid and EDTA.

[0022] Suitable forms of lumateperone or deuterolumateperone or tetradeuterolumateperone include pharmaceutically acceptable salt forms, including amorphous solid dispersions and crystal forms thereof, and pharmaceutically acceptable co-crystal forms. Amorphous solid dispersion forms of lumateperone and deuterolumateperone are disclosed in US 2019 / 0192511and US 2019 / 0388418, the contents of each of which are hereby incorporated by reference in their entireties.

[0023] Unless otherwise indicated, the term “pharmaceutically acceptable salt” includes acid addition salts between lumateperone or deuterolumateperone or tetradeuterolumateperone and any pharmaceutically acceptable acid (e.g., Bronsted acid) in any molar ratio permitted by the structure of the acid. For example, “pharmaceutically acceptable salt form” of lumateperone or deuterolumateperone or tetradeuterolumateperone includes the mono-hydrochloride, the dihydrochloride, the tri-hydrochloride, the mono-tosylate, the di-tosylate and the tri-tosylate, or any mixtures thereof. In some embodiments, the lumateperone or deuterolumateperone or tetradeuterolumateperone salt is a crystalline solid (e.g., a salt crystal). In some embodiments, the lumateperone or deuterolumateperone or tetradeuterolumateperone may exist as a co-crystal, i.e., lumateperone free base co-crystallized with a second species.

[0024] Pharmaceutically acceptable salt and co-crystal forms of lumateperone or deuterolumateperone or tetradeuterolumateperone include all those forms disclosed in the following: U.S. Patents: 8,648,077, 9,199,995, 9,586,960, 10,654,854, 10,688,097, 11,014,925, 11,096,944, and RE48,825; and patent publications US 2020 / 247805, US 2020 / 0157100, US 2019 / 0211015 (Assia Pharm.), and W02020 / 112941 (Teva Czech), and PCT / US2021 / 071366, the contents of each of which are hereby incorporated by reference in their entireties.

[0025] In some embodiments, the pharmaceutically acceptable salt may be a low-solubility salt, such as those described in W02024 / 030835, the contents of which are hereby incorporated by reference in its entirety. Such salts are typically unsuitable for oral or intravenous administration, but may be particularly well-suited to the sustained / delayed bioabsorption required by the compositions of the present disclosure. Such salts include C2-Ci2alkylbenzenesulfonate salts, such as 4-octylbenzenesulfonate, 4-butylbenzenesulfonate, 4-propylbenzenesulfonate, and 4- ethylbenzenesulfonate, as well as Ca-Cnalkylsulfonate salts, such as pentane- 1- sulfonate, hexane- 1 -sulfonate, and heptane- 1 -sulfonate, and other arylsulfonate salts, such as benzenesulfonate and 2-naphthalenesulfonate. Such salts preferably have an aqueous solubility of less than 20 mg / mL at pH 7 or pH 7.4, e.g., less than 15 mg / mL, or less than 10 mg / mL, or less than 5 mg / mL, or less than 3 mg / mL, or less than 2 mg / mL, or less than 1 mg / mL, or less than 0.5 mg / mL, or less than 0.1 mg / mL, and / or at least 0.001 mg / mL, or at least 0.01 mg / mL, or at least 0.1 mg / mL, or at least 1 mg / mL. Preferably, such salts are solid, crystalline salts. Suchsalts may have a molar ratio of lumateperone free base to acid counterion of about 1 :1 : or about 1:2. In some embodiments, the salt is a mono-4-octylbcnzcncsulfonatc salt (e.g., in solid, crystalline form). In some embodiments, the salt is a di-4-octylbenzenesulfonate salt (e.g., in solid crystalline form).

[0026] In a fourth aspect, the present disclosure provides a process (Process 1) for the manufacture of Composition 1, or any of 1.1-1.59, wherein the process comprises the steps of:(a) in a first vessel, combining lumateperone, in pharmaceutically acceptable salt form (e.g., tosylate salt form), with poly(lactic-co-glycolic acid) copolymer (e.g., PLGA 65:35) in a suitable solvent (e.g., dichloromethane) (optionally combining the polymer with the solvent first to form a solution, and then adding the lumateperone);(b) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the dispersed phase (DP);(c) optionally filtering the DP to remove undissolved particles;(d) in a second vessel, combining water (e.g., sterile water for injection), and a suitable surfactant or dispersant (e.g., polyvinyl alcohol);(e) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the continuous phase (CP) (e.g., about 2 wt.% PVA solution);(f) optionally adding the same solvent as in step (a) (e.g., dichloromethane) to the continuous phase;(g) emulsifying the dispersed phase into the continuous phase, e.g., by mixing the DP and CP and mixing, agitating, stirring, vortexing, or sonicating the resulting mixture until a uniform emulsion is formed, and / or passing the DP and CP into packed bed column at a suitable flow rate;(h) removing the solvent (e.g., dichloromethane), e.g., by evaporation, and / or washing, and / or extraction, and / or freeze-drying;(i) optionally washing and / or filtering the resulting product;(j) drying (e.g., dewatering, vacuum drying, heated drying, and / or freeze-drying) the resulting product to provide solid polymeric micro spheres);(k) optionally sieving the polymeric microspheres to a desired particle size distribution;(l) optionally sterilizing the resulting polymeric microspheres;(m) optionally packaging the resulting polymeric microspheres into vials or pre-filled syringes (e.g., for inclusion in a Kit or Syringe as hereinbefore described);(n) optionally, either at the time of manufacture or at the time of administration, mixing the resulting polymeric microspheres with the sterile aqueous injection vehicle to provide the composition ready for injection.

[0027] In a fifth aspect, the present disclosure provides a process (Process 2) for the manufacture of Composition 2, or any of 2.1-2.59, wherein the process comprises the steps of:(a) in a first vessel, combining deuterolumateperone, in pharmaceutically acceptable salt form (e.g., tosylate salt form), with poly(lactic-co-glycolic acid) copolymer (e.g., PLGA 65:35) in a suitable solvent (e.g., dichloromethane) (optionally combining the polymer with the solvent first to form a solution, and then adding the deuterolumateperone);(b) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the dispersed phase (DP);(c) optionally filtering the DP to remove undissolved particles;(d) in a second vessel, combining water (e.g., sterile water for injection), and a suitable surfactant or dispersant (e.g., polyvinyl alcohol);(e) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the continuous phase (CP) (e.g., about 2 wt.% PVA solution);(f) optionally adding the same solvent as in step (a) (e.g., dichloromethane) to the continuous phase;(g) emulsifying the dispersed phase into the continuous phase, e.g., by mixing the DP and CP and mixing, agitating, stirring, vortexing, or sonicating the resulting mixture until a uniform emulsion is formed, and / or passing the DP and CP into packed bed column at a suitable flow rate;(h) removing the solvent (e.g., dichloromethane), e.g., by evaporation, and / or washing, and / or extraction, and / or freeze-drying;(i) optionally washing and / or filtering the resulting product;(j) drying (e.g., dewatering, vacuum drying, heated drying, and / or freeze-drying) the resulting product to provide solid polymeric micro spheres);(k) optionally sterilizing the resulting polymeric microspheres;(l) optionally packaging the resulting polymeric microspheres into vials or pre-filled syringes (e.g., for inclusion in a Kit or Syringe as hereinbefore described);(m) optionally, either at the time of manufacture or at the time of administration, mixing the resulting polymeric microspheres with the sterile aqueous injection vehicle to provide the composition ready for injection.

[0028] In a sixth aspect, the present disclosure provides a process (Process 3) for the manufacture of Composition 3, or any of 3.1-3.59, wherein the process comprises the steps of:(a) in a first vessel, combining tetradeuterolumateperone, in pharmaceutically acceptable salt form (e.g., tosylate salt form), with poly(lactic-co-glycolic acid) copolymer (e.g., PLGA 65:35) in a suitable solvent (e.g., dichloromethane) (optionally combining the polymer with the solvent first to form a solution, and then adding the tetradeuterolumateperone);(b) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the dispersed phase (DP);(c) optionally filtering the DP to remove undissolved particles;(d) in a second vessel, combining water (e.g., sterile water for injection), and a suitable surfactant or dispersant (e.g., polyvinyl alcohol);(e) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the continuous phase (CP) (e.g., about 2 wt.% PVA solution);(f) optionally adding the same solvent as in step (a) (e.g., dichloromethane) to the continuous phase;(g) emulsifying the dispersed phase into the continuous phase, e.g., by mixing the DP and CP and mixing, agitating, stirring, vortexing, or sonicating the resulting mixture until a uniform emulsion is formed, and / or passing the DP and CP into packed bed column at a suitable flow rate;(h) removing the solvent (e.g., dichloromethane), e.g., by evaporation, and / or washing, and / or extraction, and / or frcczc-drying;(i) optionally washing and / or filtering the resulting product;(j) drying (e.g., dewatering, vacuum drying, heated drying, and / or freeze-drying) the resulting product to provide solid polymeric micro spheres);(k) optionally sterilizing the resulting polymeric microspheres;(l) optionally packaging the resulting polymeric microspheres into vials or pre-filled syringes (e.g., for inclusion in a Kit or Syringe as hereinbefore described);(m) optionally, either at the time of manufacture or at the time of administration, mixing the resulting polymeric microspheres with the sterile aqueous injection vehicle to provide the composition ready for injection.

[0029] In a seventh aspect, the present disclosure provides a method (Method 1) for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HTIA receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways, comprising administering to a patient in need thereof the Composition 1, or any of 1.1-1.75. In further embodiments, the present disclosure provides:1.1 Method 1, wherein the disease or disorder is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD), acute depression, post- traumatic depression), anxiety (including acute anxiety, panic disorders, phobias, social anxiety disorder, or social withdrawal), psychosis (including acute psychosis), schizophrenia (including residual symptoms of schizophrenia, such as positive and / or negative symptoms of schizophrenia), obsessive-compulsive disorder, sexual disorders, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, anger disorders, agitation (including acute agitation), dementia (including Alzheimer’s Disease and Parkinson’s dementia), gastrointestinal disorders such as dysfunction of gastrointestinal tract motility, and bipolar disorder (e.g., bipolar' depression);1.2 Method 1, wherein the disease or disorder is selected from schizophrenia, bipolar depression, anxiety, agitation, and dementia;1.3 Method 1, wherein the disease or disorder is schizophrenia (e.g., negative symptoms of schizophrenia);Method 1 , wherein the disease or disorder is depression (e.g., bipolar depression, bipolar I disorder, or bipolar II disorder); Method 1.4, wherein the depression is characterized by major depressive episodes (e.g., major depressive episodes associated with major depressive disorder, bipolar depression, bipolar I disorder, or bipolar II disorder); Method 1.4 or 1.5, wherein treatment is adjunct to oral administration of valproate (e.g., valproic acid or sodium valproate) or adjunct to oral administration of an antidepressant agent (e.g., a selective serotonin reuptake inhibitor); Method 1, wherein the disease or disorder is anxiety (e.g., general anxiety disorder); Method 1, wherein the disease or disorder is bipolar mania (e.g., manic episodes associated with bipolar disorder, e.g., associated with bipolar I disorder); Method 1, wherein the disease or disorder is autism spectrum disorder; Method 1.9, wherein the disease or disorder is irritability in autism spectrum disorder; Method 1 , or any of 1.1 - 1.10, wherein the composition is administered by intramuscular injection; Method 1 , or any of 1.1 - 1.10, wherein the composition is administered by subcutaneous injection; Method 1, or any of 1.1-1.12, wherein the composition is administered as a single injection once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, e.g., once per month; Method 1, or any of 1.1-1.13, wherein administration of a single injection of the composition provides a plasma concentration of lumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL, for a period of at least 4 weeks, e.g., at least 6 weeks, or at least 8 weeks, or at least 10 weeks, or at least 12 weeks; Method 1, or any of 1.1-1.14, wherein the dose administered in a single injection is 50 to 200 mg of lumateperone, measured as the free base equivalent, e.g., 50 to 100 mg, or 100 to 150 mg, or 150 to 200 mg, 50 to 75 mg, or 75 to 125 mg, or 125 to 175mg, or 75 to 150 mg, or 80 to 140 mg, or 90 to 130 mg, or 100 to 120 mg, or 100 to 110 mg;1.16 Method 1, or any of 1.1-1.15, wherein the patient was previously treated with oral lumateperone (e.g., the patient is switched from oral lumateperone to long-acting injectable lumateperone according to Composition 1 et seq.).

[0030] In a sixth aspect, the present disclosure provides a method (Method 2) for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HT2A receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways, comprising administering to a patient in need thereof the Composition 2, or any of 2.1-2.75. In further embodiments, the present disclosure provides:2.1. Method 2, wherein the disease or disorder is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD), acute depression, post- traumatic depression), anxiety (including acute anxiety, panic disorders, phobias, social anxiety disorder, or social withdrawal), psychosis (including acute psychosis), schizophrenia (including residual symptoms of schizophrenia, such as positive and / or negative symptoms of schizophrenia), obsessive-compulsive disorder, sexual disorders, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, anger disorders, agitation (including acute agitation), dementia (including Alzheimer’s Disease and Parkinson’s dementia), gastrointestinal disorders such as dysfunction of gastrointestinal tract motility, and bipolar disorder (e.g., bipolar depression);2.2.Method 2, wherein the disease or disorder is selected from schizophrenia, bipolar depression, anxiety, agitation, and dementia;2.3.Method 2, wherein the disease or disorder is schizophrenia (e.g., negative symptoms of schizophrenia);2.4.Method 2, wherein the disease or disorder is depression (e.g., bipolar depression, bipolar I disorder, or bipolar II disorder);2.5. Method 2.4, wherein the depression is characterized by major depressive episodes (e.g., major depressive episodes associated with major depressive disorder, bipolar depression, bipolar I disorder, or bipolar II disorder);Method 2.4 or 2.5, wherein treatment is adjunct to oral administration of valproate (e.g., valproic acid or sodium valproate) or adjunct to oral administration of an antidepressant agent (e.g., a selective serotonin reuptake inhibitor); Method 2, wherein the disease or disorder is anxiety (e.g., general anxiety disorder); Method 2, wherein the disease or disorder is bipolar mania (e.g., manic episodes associated with bipolar disorder, e.g., associated with bipolar I disorder); Method 2, wherein the disease or disorder is autism spectrum disorder; . Method 2.9, wherein the disease or disorder is irritability in autism spectrum disorder; . Method 2, or any of 2.1-2.10, wherein the composition is administered by intramuscular injection; . Method 2, or any of 2.1-2.10, wherein the composition is administered by subcutaneous injection; . Method 2, or any of 2.1-2.12, wherein the composition is administered as a single injection once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, e.g., once per month; . Method 2, or any of 2.1-2.13, wherein administration of a single injection of the composition provides a plasma concentration of deuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL, for a period of at least 4 weeks, e.g., at least 6 weeks, or at least 8 weeks, or at least 10 weeks, or at least 12 weeks; . Method 2, or any of 2.1-2.14, wherein the dose administered in a single injection is 50 to 200 mg of deuterolumateperone, measured as the free base equivalent, e.g., 50 to 100 mg, or 100 to 150 mg, or 150 to 200 mg, 50 to 75 mg, or 75 to 125 mg, or 125 to 175 mg, or 75 to 150 mg, or 80 to 140 mg, or 90 to 130 mg, or 100 to 120 mg, or 100 to 110 mg; . Method 2, or any of 2.1-2.15, wherein the patient was previously treated with oral lumateperone or deuterolumateperone (e.g., the patient is switched from oral lumateperone or deuterolumateperone to long-acting injectable deuterolumateperone according to Composition 2 et seq.).

[0031] In a seventh aspect, the present disclosure provides a method (Method 3) for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HTIA receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways, comprising administering to a patient in need thereof the Composition 3, or any of 3.1-3.75. In further embodiments, the present disclosure provides:3.1. Method 3, wherein the disease or disorder is selected from obesity, anorexia, bulimia, depression (including major depressive disorder (MDD), acute depression, post- traumatic depression), anxiety (including acute anxiety, panic disorders, phobias, social anxiety disorder, or social withdrawal), psychosis (including acute psychosis), schizophrenia (including residual symptoms of schizophrenia, such as positive and / or negative symptoms of schizophrenia), obsessive-compulsive disorder, sexual disorders, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, conditions associated with cephalic pain, anger disorders, agitation (including acute agitation), dementia (including Alzheimer’s Disease and Parkinson’s dementia), gastrointestinal disorders such as dysfunction of gastrointestinal tract motility, and bipolar disorder (e.g., bipolar depression);3.2.Method 3, wherein the disease or disorder is selected from schizophrenia, bipolar depression, anxiety, agitation, and dementia;3.3.Method 3, wherein the disease or disorder is schizophrenia (e.g., negative symptoms of schizophrenia);3.4.Method 3, wherein the disease or disorder is depression (e.g., bipolar depression, bipolar I disorder, or bipolar II disorder);3.5.Method 3.4, wherein the depression is characterized by major depressive episodes (e.g., major depressive episodes associated with major depressive disorder, bipolar depression, bipolar’ I disorder, or bipolar II disorder);3.6.Method 3.4 or 3.5, wherein treatment is adjunct to oral administration of valproate (e.g., valproic acid or sodium valproate) or adjunct to oral administration of an antidepressant agent (e.g., a selective serotonin reuptake inhibitor);3.7.Method 3, wherein the disease or disorder is anxiety (e.g., general anxiety disorder);3.8.Method 3, wherein the disease or disorder is bipolar- mania (e.g., manic episodes associated with bipolar disorder, e.g., associated with bipolar I disorder);3.9. Method 3, wherein the disease or disorder is autism spectrum disorder;3.10. Method 3.9, wherein the disease or disorder is irritability in autism spectrum disorder;3.11. Method 3, or any of 3.1-3.10, wherein the composition is administered by intramuscular injection;3.12. Method 3, or any of 3.1-3.10, wherein the composition is administered by subcutaneous injection;3.13. Method 3, or any of 3.1-3.12, wherein the composition is administered as a single injection once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months, e.g., once per month;3.14. Method 3, or any of 3.1-3.13, wherein administration of a single injection of the composition provides a plasma concentration of tetradeuterolumateperone of at least 5 ng / mL, e.g., at least 10 ng / mL or at least 20 ng / mL, or 5-30 ng / ml, or 10-30 ng / mL, or 5-20 ng / mL, or 10-20 ng / mL, for a period of at least 4 weeks, e.g., at least 6 weeks, or at least 8 weeks, or at least 10 weeks, or at least 12 weeks;3.15. Method 3, or any of 3.1-3.14, wherein the dose administered in a single injection is 50 to 200 mg of tetradeuterolumateperone, measured as the free base equivalent, e.g., 50 to 100 mg, or 100 to 150 mg, or 150 to 200 mg, 50 to 75 mg, or 75 to 125 mg, or 125 to 175 mg, or 75 to 150 mg, or 80 to 140 mg, or 90 to 130 mg, or 100 to 120 mg, or 100 to 110 mg;3.16. Method 3, or any of 3.1-3.15, wherein the patient was previously treated with oral lumateperone or deuterolumateperone (e.g., the patient is switched from oral lumateperone or deuterolumateperone to long- acting injectable tetradeuterolumateperone according to Composition 3 et seq.).

[0032] The present disclosure further provides Composition 1, et seq., for use in the treatment of a disease or disorder according to any of Method 1, et seq., and for use in the manufacture of a medicament for the treatment of a disease or disorder according to any of Method 1, et seq.

[0033] The present disclosure further provides Composition 2, et seq., for use in the treatment of a disease or disorder according to any of Method 2, et seq., and for use in the manufacture of a medicament for the treatment of a disease or disorder according to any of Method 2, et seq.

[0034] The present disclosure further provides Composition 3, et seq., for use in the treatment of a disease or disorder according to any of Method 3, ct seq., and for use in the manufacture of a medicament for the treatment of a disease or disorder according to any of Method 3, et seq.

[0035] The words “treatment” and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease and / or treatment of the cause of the disease. In particular embodiments, the words “treatment” and “treating” refer to prophylaxis or amelioration of symptoms of the disease.

[0036] The term “patient” may include a human or non-human patient.

[0037] Methods of synthesizing lumateperone, deuterolumateperone, tetradeuterolumateperone, and related compounds, and salts and co-crystals thereof, are known in art, and include the methods disclosed in U.S. Patents Nos. 6,552,017, 6,548,493, 7,071,186, 7,183,282, 7,238,690, 8,309,722, 8,779,139; 9,315,504, 9,751,883, 10,077,267, 10,221,176, 10,464,938, 10,597,394, 10,597,395, 10,654,854, 10,688,097, 10,899,762, 11,014,925, 11,066,407, 11,096,944, RE39,679, and U.S. RE39,680; and US 2020 / 0102309, US 2020 / 0157100, and US 2020 / 0247805, the contents of each of which are incorporated by reference in their entirety.

[0038] Isolation or purification of the diastereomers of the Compounds of the Invention may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving beds and the like.

[0039] The pharmaceutically acceptable salts of lumateperone or deuterolumateperone or tetradeuterolumateperone, can be synthesized from the parent compound, which contains basic moieties, by reaction with a suitable acid, by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0040] Dosages employed in practicing the present disclosure will of course vary depending, e.g., on the particular disease or condition to be treated, the particular active compounds used, the mode of administration, and the therapy desired. Unless otherwise indicated, an amount of an active compound for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the compound in free form (i.e., the calculation of the amount isbased on the amount of active moiety in free form, not taking into account the weight of the counter ion in the case of a salt).

[0041] For the avoidance of doubt, any disclosure of a numerical range, e.g., “up to X” amount is intended to include the upper numerical limit X. Therefore, a disclosure of “up to 60 mg” is intended to include 60 mg.Example 1: Long Acting Injectable Composition Development

[0042] It is desired to provide an aqueous microsphere-based (i.e., non-micro sphere) long acting injectable composition which provides for at least 1 -month of in vitro release of drug, preferably maintaining an optimum plasma drug concentration of 10 to 20 ng / mL with less than 5% net drug release in the first 8 hours (i.e., no “dose-dumping”), which has a viscosity enabling it to be administered via 25 gauge needle, and stability for at least 6 months of storage.

[0043] It is further desirable to develop a long-acting injectable composition which, after injection, provides a relatively steady rate of drug release. Several compositions are developed and tested in a rat pharmacokinetic study.

[0044] An optimized polymeric microsphere formulation is developed which comprises lumateperone tosylate and PLGA 65:35 with ester end groups in an injection vehicle comprising 1.25% carboxymethyl cellulose, 0.01% polysorbate 20, sodium chloride, pH adjusting agent, buffer, and about 98% sterile water for injection, by weight.

[0045] The PLGA polymer used has a lactide to glycolide molar ratio of 65:35 (range 60- 70:30:40 is permissible), an average molecular weight of about 10,000 to 20,000 Daltons (e.g., number average of about 10,000 D and / or weight average of about 16,000 D), and an inherent viscosity of about 0.19 dL / g (range 0.15 to 0.25 dL / g is permissible). The optimized formulation has the following properties:Microsphere particle size distribution: Dio ~ 30 microns, D50 ~ 50 microns, D90 ~ 60 microns;Injection vehicle viscosity: 10 cP (range 5 to 30 cP);Injection vehicle pH 7.1 (range 6.5-7.5);Injection vehicle osmolality about 280 mOsm / kg (range 260-310 mOsm / kg).

[0046] The composition is formulated for subcutaneous injection, with mixing of the injection vehicle and the sterilized microsphere formulation immediately prior to injection.

[0047] The microsphere formulation is manufactured according to the following procedure. In a first vessel, 420 g of the PLGA polymer is dissolved in about 730 mL of dichloromcthanc solvent to form a solution. To this solution is added 280 g of lumateperone tosylate, resulting in formation of a dispersion (the dispersed phase, DP). In a second vessel, 100 grams of polyvinyl alcohol 4-88 (PVA) is combined with 4.9 L of sterile water for injection, heating to about 85-90 °C, and cooled to room temperature, to form a solution. 4.0L of this about 2 wt.% aqueous PVA solution is combined with about 50 mL of dichloromethane, and the mixture is stirred for 30 minutes to form the continuous phase (CP). The DP and CP are then each filtered, and then they are emulsified together by passing them through a packed bed column (e.g., having beads with 50-1000 micron pores) at a suitable flow rate (e.g., 32 mL / min for DP and 64 mL / min for CP, extraction How rate 16 mL / min). If necessary, the emulsion can be cycled through the column on additional passes until the desired globule size is reached. The resulting microsphere emulsion is then rinsed with water for injection. After dewatering (using a Sweco SW3100 separator), the resulting slurry is wet- sieved (125 micron sieve), then freeze-dried using an isopropanol / dry ice bath (about - 77 °C, at least 96 hours). The dried microparticles are then dry-sieved (125-micron sieve), and then blended for ten minutes at about 46 rpm, to provide the final dried polymeric microparticles. Final product has no more than trace presence of polyvinyl alcohol and dichloromethane.Example 2: Rat Pharmacokinetic Study

[0048] A 30-day rat pharmacokinetic study is performed on the microparticles prepared according to Example 1. Microparticles are combined with injection vehicle (1.25% CMC) at the ratio of 500 mg of microparticles to 1.2 mL vehicle. A single injection providing a dose of 30 mg / kg is used.

[0049] The results demonstrate a favorable plasma concentration profile. Peak plasma concentration of about 15 ng / mL is achieved at day 10 and maintained through day 14. At day 21, the plasma concentration drops to 5 ng / mL, and then to about 2 ng / mL at day 30. A minimal amount of drug is released during the first 8 hours after injection.Example 3: Long Acting Injectable Composition Stability

[0050] A stability study is conducted on the microparticles and injection vehicle. The injection vehicle and microp articles are assessed for (1) 3 to 24 months at 2-8 °C and 60% relative humidity, (2) 3 to 24 months at 25 °C and 60% relative humidity, and (3) 3 to 6 months at 30 °Cand 65% relative humidity (accelerated aging conditions). For the microparticles, appearance, particle size distribution, HPLC assay, related substances impurities (HPLC), in vitro release, and water content are evaluated at 3, 6, 9, 12, 18, and 24 months (only 3 and 6 months for accelerated aging). For the injection vehicle, appearance, osmolality, pH, viscosity, particulates, endotoxins, and sterility are evaluated at 3, 6, 9, 12, 18, and 24 months (only 3 and 6 months for accelerated aging).

[0051] The results show that both the microparticles and the injection vehicle are stable and meet all acceptance criteria at 3 months for all conditions tested, and through 12 months for condition (1).Example 4: Human Pharmacokinetic Study

[0052] A Phase I human PK trial is conducted using the composition of Example 1 to determine optimal dosing parameters for human treatment. About 24 male and female patients aged 18-50 years with a clinical diagnosis of schizophrenia, receiving stable antipsychotic treatment for at least 3 months, and having a Clinical Global Impression Severity (CGI-S) score of not more than 3 are included in the study.

[0053] All patients receive oral lumateperone tosylate (60 mg / day, equivalent to 42 mg free base) for 5 days, followed by a 5-day washout. Patients then receive a single dose of lumateperone tosylate LAI according to Example 1. The patients are divided into three cohorts, receiving either a 50 mg dose, a 100 mg dose, or a 200 mg dose of lumateperone, measured as the free base equivalent. Plasma samples are taken over a six- week period to evaluate pharmacokinetic parameters. Patients are also evaluated for the occurrence of adverse events, and changes in various clinical analytical parameters (e.g., serum hemoglobin, platelet count, white blood cell count, aspartate aminotransferase, alanine aminotransferase, glucose and creatine kinase; and electrocardiogram QT interval), and changes in the Abnormal Involuntary Movement Scale (AIMS).

Claims

1. CLAIMSWe claim:

1. An injectable pharmaceutical composition, comprising lumateperone:or deuterolumateperone:or tetradcut crolumatcpcronc:each in pharmaceutically acceptable salt form (e.g., tosylate salt form), wherein the lumateperone or deuterolumateperone or tetradeuterolumateperone is suspended, dissolved or encapsulated in polymeric microspheres, wherein the polymeric microspheres comprise poly(lactic-co-glycolic acid) copolymer having a lactic to glycolic ratio from 75:25 to 50:50, and wherein the injectable composition comprises a sterile, aqueous injection vehicle.

2. The composition of claim 1, wherein the composition comprises lumateperone.

3. The composition of claim 1 , wherein the composition comprises deuterolumateperone or tctradcutcrolumatcpcronc .

4. The composition of any one of claims 1-3, wherein the composition comprises the lumateperone or deuterolumateperone or tetradeuterolumateperone in pharmaceutically acceptable salt form selected from a tosylate, hydrochloride, besylate, mesylate, nosylate, hydrobromide, hydroiodide, tartrate, malate, maleate, fumarate, nitrate, phosphate, benzoate, 4-aminosalicylate, oxalate, or cyclamate acid addition salt.

5. The composition of claim 4, wherein the composition comprises the lumateperone or deuterolumateperone or tetradeuterolumateperone in tosylate salt form, e.g., in one or more of mono-tosylate salt form, di-tosylate salt form, and tri-tosylate salt form.

6. The composition of any one of claims 1-5, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 73:27 to 52:48.

7. The composition of claim 6, wherein the poly (lactic-co-gly colic acid) copolymer has a lactic to glycolic molar ratio of about 70:30 to 55:45.

8. The composition of claim 6, wherein the poly (lactic-co-gly colic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 58:42.

9. The composition of claim 6, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 68:32 to 62:38.

10. The composition of claim 6, wherein the poly(lactic-co-glycolic acid) copolymer has a lactic to glycolic molar ratio of about 65:35.

11. The composition of any one of claims 1-10, wherein the polymeric microspheres of the composition comprises the lumateperone or deuterolumateperone or tetradeuterolumateperone (e.g., lumateperone or deuterolumateperone or tetradeuterolumateperone tosylate) in an average amount of 10 to 50% by weight of the composition, e.g., 10 to 40%, or 10 to 30%, or 10 to 25%, or 10 to 20%, or 10 to 15%, or 15 to 45%, or 15 to 40%, 15 to 35%, or 15 to 30%, or 15 to 25%, or 15 to 20%, or 20 to 45%, or 20 to 40%, or 20 to 35%, or 20 to 30%, or 20 to 25%, or 25 to 50%, or 25 to 45%, or 25 to 40%, or 25 to 35%, or 25 to 30%, or 30 to 40%, or about 15%, or about 20%, or about 25%, or about 30%, by weight of the polymeric microsphere, measured as the equivalent amount of free base lumateperone.

12. The composition of any one of claims 1-1 1 , wherein the sterile aqueous injection vehicle comprises water (c.g., sterile water for injection), carboxymethyl cellulose (c.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%).

13. The composition of any one of claims 1-12, wherein the composition consists essentially of the lumateperone or deutero lumateperone or tetradeuterolumateperone (e.g., lumateperone or deuterolumateperone or tetradeuterolumateperone tosylate), the poly(lactic-co-glycolic) copolymer (e.g., PLGA having a 65:35 lactic to glycolic ratio), water (e.g., sterile water for injection), carboxymethyl cellulose (e.g., 0.1-2%), sodium chloride (e.g., 0.5-1.25%), sodium phosphate dibasic (e.g., 0.01 to 0.25%), citric acid (e.g., 0.001 to 0.1%), and polysorbate 20 (e.g., 0.001 to 0.1%).

14. The composition of any one of claims 1-12, wherein the composition is a bi-component composition consisting of a first component being the polymeric microspheres comprising the poly(lactic-co-glycolic) copolymer and the lumateperone or deuterolumateperone or tetradeuterolumateperone, and a second component being the sterile aqueous injection vehicle, such as, where the two components are maintained separately and are admixed immediately prior to injection.

15. The composition of claim 14, wherein the first component is a solid (e.g., a dry powder), and the second component is a homogenous liquid.

16. A single-use kit, multiple-use kit, or pre-filled syringe (e.g., an automatic syringe) comprising the composition of any one of claims 1-15.

17. A process for the manufacture of the composition according to any of claims 1 to 16, wherein the process comprises the steps of:(a) In a first vessel, combining lumateperone or deuterolumateperone or tetradeuterolumateperone, in pharmaceutically acceptable salt form (e.g., tosylate salt form), with poly(lactic-co-glycolic acid) copolymer (e.g., PLGA 65:35) in a suitable solvent (e.g., dichloromethane) (optionally combining the polymer with the solvent first to form a solution, and then adding the lumateperone deuterolumateperone or tetradeuterolumateperone);(b) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the dispersed phase (DP);(c) optionally filtering the DP to remove undissolved particles;(d) in a second vessel, combining water (e.g., sterile water for injection), and a suitable surfactant or dispersant (e.g., polyvinyl alcohol);(e) mixing, agitating, stirring, vortexing, or sonicating the resulting mixture, optionally with concurrent heating, to form the continuous phase (CP) (e.g., about 2 wt.% PVA solution);(f) optionally adding the same solvent as in step (a) (e.g., dichloromethane) to the continuous phase;(g) emulsifying the dispersed phase into the continuous phase, e.g., by mixing the DP and CP and mixing, agitating, stirring, vortexing, or sonicating the resulting mixture until a uniform emulsion is formed, and / or passing the DP and CP into packed bed column at a suitable flow rate;(h) removing the solvent (e.g., dichloromethane), e.g., by evaporation, and / or washing, and / or extraction, and / or freeze-drying;(i) optionally washing and / or filtering the resulting product;(j) drying (e.g., dewatering, vacuum drying, heated drying, and / or freeze-drying) the resulting product to provide solid polymeric micro spheres);(k) optionally sieving the polymeric microspheres to a desired particle size distribution;(l) optionally sterilizing the resulting polymeric microspheres;(m) optionally packaging the resulting polymeric microspheres into vials or pre-filled syringes (e.g., for inclusion in a Kit or Syringe as hereinbefore described);(a) optionally, either at the time of manufacture or at the time of administration, mixing the resulting polymeric microspheres with the sterile aqueous injection vehicle to provide the composition ready for injection.

18. A method for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HTIA receptor, serotonin transporter (SERT), and / or dopamine D1 / D2 receptor signaling pathways, comprising administering to a patient in need thereof the composition according to any of claims 1 to 16.

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