Methods

Abstract

The present disclosure relates to solid oral dosage forms comprising lumateperone, in free, or pharmaceutically acceptable salt form, optionally in combination with one or more additional therapeutic agents, processes for manufacture thereof and methods of use in the treatment or prophylaxis of disease.

Description

TECHNICAL FIELD

The present disclosure relates to solid oral dosage forms comprising lumateperone, in free, or pharmaceutically acceptable salt form, optionally in combination with one or more additional therapeutic agents, processes for manufacture thereof and methods of use in the treatment or prophylaxis of disease.

BACKGROUND OF THE INVENTION

The substituted heterocycle fused gamma-carbolines lumateperone (4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone) is known to be a serotonin receptor (5-HT2A), dopamine receptor (D1 and/or D2), and serotonin transporter (SERT) ligand, which is useful in treating a variety of central nervous system disorders.

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 NMDA 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 dopaminergic interactions, 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.

Lumateperone, having the formula:

is a novel therapeutic agent with potent (Ki=0.5 nM) 5-HT_2A 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=32 nM) in vivo, high D1 receptor affinity (Ki=52 nM), and inhibition of the serotonin transporter (SERT) (Ki=26-62 nM, using different assays for SERT activity). Lumateperone is in Phase III clinical development as a treatment for schizophrenia, bipolar depression and agitation in dementia, including Alzheimer's Disease.

Lumateperone and related compounds have been disclosed in U.S. Pat. Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, U.S. RE39680, and U.S. RE39679 (each of which are 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. PCT/US08/03340 and 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 gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders. WO 2009/145900 and U.S. Pat. No. 8,598,119, and WO 2013/155506 and US 2015/0080404, 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. WO 2009/114181 and U.S. Pat. No. 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-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

WO 2011/133224 and U.S. Pat. No. 8,993,572, 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.

WO 2009/145900 (and U.S. Pat. No. 8,598,119, incorporated herein by reference) teaches that selected substituted heterocycle fused gamma-carboline compounds have nanomolar affinity for the serotonin reuptake transporter (SERT) and so are selective serotonin reuptake inhibitors.

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 PCT/US2019/035845 (incorporated herein by reference in its entirety). This is believed to be due to its signaling through a neurotransmitter system separate from the traditional monoamine signaling systems. Lumateperone provides a dopamine D1 receptor-dependent enhancement of NMDA and AMPA currents coupled with activation of the mTOR (e.g., mTORC1) signaling pathway.

BRIEF SUMMARY OF THE INVENTION

The present disclosure provides solid oral dosage forms comprising lumateperone in free or pharmaceutically acceptable salt form. In some embodiments, the dosage form is a tablet. In some embodiments the dosage form further comprises one or more additional therapeutic agents. These dosage forms are useful for the treatment or prophylaxis of a variety of central nervous system disorders.

DETAILED DESCRIPTION

Lumateperone is a novel therapeutic agent with potent (Ki=0.5 nM) 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=32 nM) in vivo, high D1 receptor affinity (Ki=52 nM), and inhibition of the serotonin transporter (SERT) (Ki=26-62 nM, using different assays for SERT activity). Lumateperone is in Phase III clinical development as a treatment for schizophrenia, bipolar depression and agitation in dementia, including Alzheimer's Disease.

The present disclosure provides a solid oral dosage form (Dosage Form 1), comprising lumateperone:

in free or pharmaceutically acceptable salt form (e.g., in tosylate salt form), optionally wherein the dosage form is an immediate release dosage form. For example, Dosage Form 1 may be as follows:

• • 1.1. Dosage Form 1, wherein the dosage form comprises lumateperone in free base form (e.g., in free base solid amorphous dispersion form);
  • 1.2. Dosage Form 1, wherein the dosage form comprises lumateperone in pharmaceutically acceptable salt or co-crystal form;
  • 1.3. Dosage Form 1, wherein the dosage form comprises lumateperone in tosylate salt form, e.g., in one or more of mono-tosylate salt form, di-tosylate salt form, and tri-tosylate salt form;
  • 1.4. Dosage Form 1.3, wherein the dosage form comprises a combination of lumateperone in mono-tosylate salt form and lumateperone in di-tosylate salt form;
  • 1.5. Any of Dosage Forms 1 or 1.1-1.3, wherein the Dosage Form comprises lumateperone in mono-tosylate salt form;
  • 1.6. Dosage Form 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. Pat. No. 8,648,077, such as one or more of the XRPD spectrum, IR spectrum, and/or DSC/TGA spectrum as disclosed therein;
  • 1.7. Dosage Form 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;
  • 1.8. Dosage Form 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;
  • 1.9. Dosage Form 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;
  • 1.10. Any of Dosage Forms 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.
  • 1.11. Dosage Form 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.
  • 1.12. Dosage Form 1.11, wherein the dosage form comprises one or more excipients which stabilize the amorphous from of ITI-007 tosylate to prevent conversion of the amorphous form to the crystal form.
  • 1.13. Dosage Form 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, polyvinyl pyrrolidone/vinyl acetate copolymer, and polyethylene glycol/polyvinyl acetate/polyvinylcaprolactam copolymer.
  • 1.14. Any of Dosage Forms 1.11-1.13, wherein the dosage form 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.
  • 1.15. Any of Dosage Forms 1.11-1.14, wherein the dosage form further comprises a surfactant, e.g., an anionic, cationic, zwitterionic or neutral surfactant.
  • 1.16. Any of Dosage Forms 1.5-1.15, wherein the Dosage Form further comprises toluenesulfonic acid, e.g., in a molar ratio of about 1:1 to 1:2 with respect to the lumateperone mono-tosylate, e.g., 1:1 to 1:1.5 molar ratio, or 1:1 to 1:2 molar ratio, or about a 1:1 molar ratio;
  • 1.17. Dosage Form 1 or any of 1.1-1.16, wherein the Dosage Form comprises the lumateperone, in free and/or pharmaceutically acceptable salt form in a total unit amount equivalent to 0.01 to 120 mg of lumateperone free base, e.g., 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to 30 mg, 20 to 30 mg, 20 to 50 mg, 30 mg to 50 mg, 50 to 100 mg, 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, 1 to 10 mg, 25 to 35 mg, or 35 to 45 mg, or about 6 mg, about 14 mg, or about 28 mg, or about 42 mg;
  • 1.18. Dosage Form 1 or any of 1.1-1.17, further comprising one or more pharmaceutically acceptable diluents or carriers (i.e., excipients);
  • 1.19. Dosage Form 1.18, wherein the one or more pharmaceutically acceptable diluents or carriers comprises one or more of (a) diluent/filler (e.g., cellulose or microcrystalline cellulose (e.g., silicified microcrystalline cellulose), mannitol, lactose monohydrate, dicalcium phosphate, or isomalt), (b) binder (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copovidone), (c) disintegrant (e.g., sodium starch glycolate, crospovidone or croscarmellose sodium), (d) lubricant (e.g., magnesium stearate or glyceryl monostearate), (e) glidant (e.g., silicon dioxide or talc), (f) effervescent, (g) polymer, (h) plasticizer, (i) drying agent or desiccant, (j) humectant (e.g., polyol), (k) wetting agent, (1) anti-oxidant (e.g., BHT, citric acid, propyl gallate, ascorbic acid or sodium metabisulfite), (m) thickening agent (e.g., gelling agent), (n) surfactant, (o) buffer, (p) sweetener or flavor, and (q) dye or colorant;
  • 1.20. Dosage Form 1.18, wherein the one or more pharmaceutically acceptable diluents or carriers comprises one or more hydrophilic water-soluble or water swellable polymers;
  • 1.21. Dosage Form 1.20, wherein the polymer is selected from the group consisting of natural or modified cellulosic polymers, polymers of ethylene oxide and/or propylene oxide, polymers comprising acrylic acid monomers, natural or modified gums (e.g. xanthan gum), natural or modified starches (e.g., pre-gelatinized starches), or any mixture thereof;
  • 1.22. Dosage Form 1.20, wherein the one or more pharmaceutically acceptable diluents or carriers comprises one or more hydrophobic polymers or poorly water-soluble polymers, for example, a silicone polymer, or polyalkylene polymer (e.g., polyethylene);
  • 1.23. Dosage Form 1.20, wherein the one or more pharmaceutically acceptable diluents or carriers comprises are selected from any of the following: alcohols (ethanol, glycerol, propylene glycol), gums (e.g., acacia, guar, agar, xanthan, tragacanth, karaya, gellan), polysaccharides and polysaccharide derivatives (e.g., starches, dextrans, pectins, alginates, carrageenans, cellulose, cellulose derivatives (e.g., carboxymethyl cellulose, methylcellulose, hydroxyalkyl celluloses (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose)), gelatins including non-gelling and gelling types (e.g., mammalian gelatins such as bovine gelatin, porcine gelatins, avian gelatins, fish gelatins (e.g., mixed high molecular weight and low molecular weight gelatins), synthetic polymers (e.g., polyvinylpyrrolidones, polyethylene oxide and/or polypropylene oxide polymers and copolymers (e.g., poloxamers, such as poloxamer 188), polyacrylate polymers (e.g., carbopols), polyamide polymers, sugars and sugar alcohols (e.g., dextrose, lactose, galactose, glucose, ribose, sucrose, trehalose, mannitol, maltitol, lactitol, sorbitol, xylitol, erythritol, galactitol, inositol), polypeptides/proteins, amino acids, inorganic or organic acids (e.g., citric acid, lactic acid, malic acid, gluconic acid, benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, formic acid) and their salts (e.g., sodium, potassium, calcium, magnesium, lithium, ammonium salts of aforementioned acids), inorganic or organic bases (e.g., alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxide, oxides), anionic surfactants (e.g., sodium lauryl sulfate, sodium laureth sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl sarcosinate, sodium stearate), cationic surfactants (e.g., benzalkonium halides, cetylpyridinium halides, cetrimonium halides, benzethonium halides), zwitterionic surfactants (e.g., cocamidoalkyl betaines, such as cocamidopropyl betaine), nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g., polyethylene glycol polydodecyl ethers)), sorbitan esters (e.g., sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate), polyethoxylated sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), and antioxidants (e.g., ascorbic acid, citric acid, ascorbyl palmitate, sodium metabisulfite, sodium sulfite, BHT, BHA, TBHQ, propyl gallate, beta-carotene, tocopherols, tocotrienols, citric acid, EDTA);
  • 1.24. Dosage Form 1 or any of 1.1-1.23, wherein the dosage form comprises or consists of (a) lumateperone tosylate (e.g., mono-tosylate), lactose monohydrate, starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose, optionally silicified), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), copovidone (cross-linked polyvinyl pyrrolidone), sodium starch glycolate, flavors and/or colors and/or antioxidants, or (b) lumateperone tosylate (e.g., mono-tosylate), cellulose (e.g., microcrystalline cellulose, optionally silicified), hydroxypropyl cellulose (HPC), croscarmellose sodium (cross-linked carboxymethyl cellulose sodium); silicon dioxide (e.g., colloidal silicon dioxide), magnesium stearate, flavor and/or colors and/or antioxidants;
  • 1.25. Any of Dosage Forms 1.12-1.24, wherein any one or more of each said pharmaceutically acceptable carriers or diluents are present in an amount of 0.01 to 80% by weight of the Dosage Form, e.g., 0.1 to 60%, or 0.1 to 40%, or 0.1 to 30%, 0.01 to 15%, or 0.01 to 10%, or 0.1 to 20%, or 0.1 to 15% or 0.1 to 10%, or 0.5 to 10%, or 0.5 to 5%, or 1 to 5%, or 2.5 to 5%, or 1 to 3%, or 0.1 to 1%; optionally wherein the Dosage Form comprises from 60 to 90% by weight of diluent/filler, e.g., 70 to 80% diluent/filler;
  • 1.26. Any of Dosage Forms 1.12-1.25, wherein the Dosage Form comprises from 1% to 90% lumateperone, in free and/or in pharmaceutically acceptable salt form (e.g. tosylate), by weight of the composition and measured as the total content of lumateperone in all forms thereof, e.g., 1% to 80%, or 1% to 70%, or 1% to 60%, or 1% to 50%, or 1% to 40%, or 1% to 30%, or 1% to 20% or 1% to 15%, or 1% to 10%, or 1% to 5%, or 5% to 10%, or 10% to 20%, or 20 to 30%, lumateperone, in free and/or pharmaceutically acceptable salt form;
  • 1.27. Any preceding Dosage Form, wherein the Dosage Form comprises about 60 to 90% by weight of diluents/fillers (e.g., cellulose or microcrystalline cellulose (e.g., silicified microcrystalline cellulose), mannitol, lactose monohydrate, dicalcium phosphate, or isomalt), and about 1 to 10% by weight of binders (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, copovidone), and about 1 to 10% by weight of disintegrants (e.g., sodium starch glycolate, crospovidone or croscarmellose sodium), and about 0.1 to 5% by weight of lubricants (e.g., magnesium stearate or glyceryl monostearate), and about 0.1 to 5% by weight of glidants (e.g., silicon dioxide or talc), and about 0.1 to 5% by weight of anti-oxidants (e.g., BHT, citric acid, propyl gallate, ascorbic acid or sodium metabisulfite);
  • 1.28. Any preceding Dosage Form, wherein the dosage form comprises one or more surface coatings, e.g., polymer surface coatings (e.g., comprising polyvinyl alcohol), optionally wherein the Dosage Form comprises 1-10% by weight of the polymer surface coating(s);
  • 1.29. Any preceding Dosage Form wherein the Dosage Form is a tablet, e.g., a spherical (e.g., round) or approximately spherical (e.g., oval or oblong) tablet;
  • 1.30. Any preceding Dosage Form wherein the Dosage Form is a caplet, e.g., a capsule-shaped tablet;
  • 1.31. Any preceding Dosage Form wherein the lumateperone is present in (a) a mean particle size of 1 to 200 μm, e.g., 1 to 150 μm, 1 to 100 μm, 1 to 50 μm, 1 to 25 μm, 1 to 15 μm, 1 to 10 μm, 5 to 10 μm, or 1 to 5 μm; and/or (b) a D90 of 100 μm or less, 50 μm or less, 25 μm or less, 15 μm or less, or 10 μm or less; and/or (c) a D10 of 50 μm or less, 25 μm or less, 15 μm or less, or 10 μm or less, or 5 μm or less;
  • 1.32. Dosage Form 1 or any of 1.1-1.31, wherein the Dosage Form is formulated for oral (gastrointestinal) administration;
  • 1.33. Dosage Form 1 or any of 1.1-1.31, wherein the Dosage Form is formulated for oral transmucosal administration, e.g., for sublingual or buccal oral disintegration;
  • 1.34. Any foregoing Dosage Form wherein the lumateperone is in combination (e.g. a fixed combination) with an effective amount of an additional therapeutic agent;
  • 1.35. Dosage Form 1.34, wherein the additional therapeutic agent is an anxiolytic or antidepressant agent;
  • 1.36. Dosage Form 1.35, wherein the anxiolytic or antidepressant agent is selected from one or more compounds in free or pharmaceutically acceptable salt form, selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and atypical antipsychotics, e.g. one or more compounds in free or pharmaceutically acceptable salt form, selected from:
    • (a) Selective serotonin reuptake inhibitors (SSRIs), e.g., Citalopram (Celexa), Escitalopram (Lexapro, Cipralex), Paroxetine (Paxil, Seroxat), Fluoxetine (Prozac), Fluvoxamine (Luvox) Sertraline (Zoloft, Lustral);
    • (b) Serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g., Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Tofenacin (Elamol, Tofacine), Venlafaxine (Effexor);
    • (c) Tricyclic antidepressants (TCAs), e.g., Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen/Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil);
    • (d) Benzodiazepines, e.g., selected from 2-keto compounds (e.g., clorazepate, diazepam, flurazepam, halazepam, prazepam); 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adinazolam, alprazolam, estazolam, triazolam); and imidazo compounds (climazolam, loprazolam, midazolam);
  • 1.37. Dosage Form 1.35, wherein the additional antidepressant agent is selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI/NRI, an SRI/DRI, an NRI/DRI, an SRI/NRI/DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof);
  • 1.38. Dosage Form 1.36, wherein the additional therapeutic agent is a NMDA receptor antagonist, for example, selected from ketamine (e.g., S-ketamine and/or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or any combination thereof;
  • 1.39. Any preceding Dosage Form, wherein the Dosage Form is manufactured by a dry-blending or dry-granulating process;
  • 1.40. Any preceding Dosage Form, wherein the Dosage Form is intended to be administered once daily, or twice daily, or three times daily, or every other day, or every third day;
  • 1.41. Any preceding Dosage Form, wherein the Dosage Form is packaged in a blister pack (e.g., push-through pack), e.g., a blister pack made of any suitable material (e.g., aluminum foil, polyvinyl chloride, polyvinylidene chloride, polychlorotrifluoroethylene, cyclic olefin copolymers, polyethylene, polypropylene, polyethylene terephthalate, or a combination thereof);
  • 1.42. Any preceding dosage form, wherein the Dosage Form is packaged in a bottle (e.g., plastic or glass, optionally with a screw cap lid or a child-proof lid), optionally wherein the bottle has a compartment to hold a desiccant (e.g., silica or calcium chloride);
  • 1.43. Any preceding dosage form, wherein the Dosage Form is formulated for immediate-release;
  • 1.44. Any preceding dosage form, wherein the Dosage Form is formulated for delayed or sustained release.
  • 1.45. Any preceding dosage form, wherein the dosage form does not comprise an antioxidant;
  • 1.46. Any preceding dosage form, wherein the dosage form comprises an antioxidant selected from ascorbic acid and citric acid;
  • 1.47. Any preceding dosage form, wherein the an assay (e.g., by RP HPLC) of the dosage form at or shortly after the time of manufacture demonstrates that the dosage form comprises from 90-110% of the label amount of lumateperone (in free or pharmaceutically acceptable salt form), and/or that the dosage form comprises not more than 0.5% (e.g., as measured by RP-HPLC) of any single related substance impurity and not more than 3.0% (e.g., as measured by RP-HPLC) of all related substance impurities combined;
  • 1.48. Any preceding dosage form, wherein the an assay (e.g., by RP HPLC) of the dosage form at up to three months after manufacture (e.g., 1, 2 or 3 months) after the time of manufacture demonstrates that the dosage form comprises from 90-110% of the label amount of lumateperone (in free or pharmaceutically acceptable salt form), and/or that the dosage form comprises not more than 0.5% (e.g., as measured by RP-HPLC) of any single related substance impurity and not more than 3.0% (e.g., as measured by RP-HPLC) of all related substance impurities combined, for example, when the dosage form is stored for the up the three months period at ambient temperature and humidity or at elevated temperature (e.g., 40-50° C.) and/or at elevated humidity (e.g., 60-75% relative humidity);
  • 1.49. Any preceding dosage form, wherein the dosage form dissolves in 500 mL of 0.1N aqueous hydrochloric acid to the extent of at least 75% after 15 minutes (e.g., 80-90%), and/or to the extent of at least 90% after 30 minutes (e.g., 92-98%), and/or at least 92% after 45 minutes (e.g., 95-99%).

In some embodiments, binders may include one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, polyvinyl pyrrolidone, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like. Each solid dosage form may comprise from 0.5-10% by weight, e.g., 1-5%, or 1-3% by weight each binder.

Carmellose calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose, powdered agar and the like are used as the disintegrant. The disintegrants such as sodium starch glycolate, croscarmellose sodium and low substituted hydroxypropyl cellulose are preferable. Each tablet can contain 0.1-15% by weight, preferably 1-5% by weight of the disintegrant.

In some embodiments, the solid dosage form of the present disclosure further comprises an appropriate amount of a flavor, a lubricant, a coloring agent and the like, or various additives which are commonly used for preparing a galenic formulation. Lubricants may include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate and the like. Coloring agents may include the food colors such as food yellow no. 5, food red no. 2, food blue no. 2, food lake colors, iron sesquioxide and the like.

In some embodiments, a coating mixture may be applied to the solid dosage form by using a well-known method with the purpose of, for example, further masking of a taste and an odor, and preparation of an enteric formulation or a sustained-release formulation after coating a particle core with the active ingredient, one or more additives and the like. Coating mixtures may comprise any suitable water-soluble or water-swellable polymers, such as polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, and polyacrylic acid, for example.

The solid dosage forms of the present disclosure include, for example, tablets, caplets, and pills. They do not include capsules or the granules used in capsules. A tablet may have a variety of shapes, including but not limited to, round, oval, square, rectangular, and oblong. Tablets and caplets may optionally be scored for easier cutting. Tablets and caplets may be coated with one, two, three or more layers designed for different purposes (e.g., taste-masking, enteric protection, delayed or sustained release, improve swallowing).

The solid dosage forms of the present disclosure may further include any one or more of pharmaceutically acceptable solvents, surface tension modifiers (e.g., surfactants), preservatives, antioxidants, colorants, taste masking agents, flavors and sweeteners. Examples of solvents include water and other solvents, which are miscible with water or solubilizing agents and suitable for oral purposes. Examples of suitable solvents are ethanol, propylene glycol, glycerol, polyethylene glycols, poloxamers, sorbitol and benzyl alcohol. In some embodiments, the aqueous solubility of the lumateperone may further be enhanced by the addition to the solution of a pharmaceutically acceptable co-solvent, a cyclodextrin or a derivative thereof (e.g., dextrans).

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.

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.

In some embodiments, coloring agents may be used to introduce a uniformity of appearance to the product and/or to protect any light-sensitive ingredients. Suitable coloring agents include all dyes and lakes approved by the U.S. Food and Drug Administration (e.g., FD&C colorants).

In some embodiments, sweetening agents may be used to mask unpleasant taste or to achieve a desired taste. Examples of sweetening agents are glucose, sorbitol, glycerol, acesulfame potassium and neohesperidin dihydrochalcon. The taste may be optimized further by the addition of one or more flavoring substances. Suitable flavoring substances are fruit flavors such as cherry, raspberry, black currant, lemon or strawberry flavor or other flavors such as liquorice, anise, peppermint, and caramel.

The solid dosage forms of the present disclosure may be prepared by, for example, wet granulating lumateperone, in free or pharmaceutically acceptable salt form, and one or more pharmaceutically acceptable carriers or diluents (i.e., excipients), for example, a binder and/or a disintegrant with water or a binder solution, using a machine such as a high speed mixer granulator, a fluidized-bed granulator dryer, a centrifugal tumbling fluidized-bed granulator coating machine or a kneading machine; blending or spraying a lubricant to the granules; and then subjecting to compression molding. Alternatively, the solid dosage forms of the present disclosure can be prepared by dry granulating lumateperone, in free or pharmaceutically acceptable salt form, and one or more pharmaceutically acceptable carriers or diluents (i.e., excipients), for example, a binder (a disintegrant may be further contained), using a machine such as a roller compactor; blending or spraying a disintegrant (a lubricant may be further contained) to the granules; and then subjecting to compression molding.

Suitable forms of lumateperone include the free base form, including amorphous solid dispersions thereof, pharmaceutically acceptable salt forms, including amorphous solid dispersions and crystal forms thereof, and pharmaceutically acceptable co-crystal forms. Amorphous solid dispersion forms of lumateperone free base are disclosed in patent publication WO 2018/71233, and related applications thereto, the contents of which are hereby incorporated by reference in their entireties.

Unless otherwise indicated, the term “pharmaceutically acceptable salt” includes acid addition salts between lumateperone 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 includes the mono-hydrochloride, the di-hydrochloride, the tri-hydrochloride, the mono-tosylate, the di-tosylate and the tri-tosylate, or any mixtures thereof. In some embodiments, the lumateperone salt is a crystalline solid (e.g., a salt crystal). In some embodiments, the lumateperone may exist as a co-crystal, i.e., lumateperone free base co-crystallized with a second species. Pharmaceutically acceptable salt and co-crystal forms of lumateperone include all those forms disclosed in U.S. Pat. Nos. 8,648,077, 9,199,995, and 9,586,960, and patent publications WO 2017/1172811 and WO 2017/172784, and U.S. provisional applications 62/563,341 and 62/681,534, the contents of each of which are hereby incorporated by reference in their entireties.

In a second aspect, the present disclosure provides a process (Process 1) for the manufacture of Dosage Form 1, or any of 1.1-1.49, wherein the process comprises the steps of:

• • (a) combining lumateperone, in free or pharmaceutically acceptable salt form (e.g., tosylate salt form), with at least one diluent or carrier (e.g., with a filler, such as mannitol);
  • (b) blending and/or milling and/or granulating (e.g., dry granulating) the resulting the mixture;
  • (c) optionally filtering (e.g., screening) the resulting mixture, e.g., to achieve a uniform particle size;
  • (d) adding at least one other diluent or carrier (e.g., a disintegrant (e.g., croscarmellose sodium), or a glidant (e.g., talc), or a lubricant (e.g., magnesium stearate), or a combination thereof);
  • (e) blending and/or milling and/or granulating (e.g., dry granulating) the resulting mixture;
  • (f) optionally filtering (e.g. screening) the resulting mixture, e.g., to achieve a uniform particle size;
  • (g) pressing the mixture to form the Dosage Form;
  • (h) optionally applying one or more coatings to the Dosage Form.

It is understood that in embodiments of the present disclosure wherein lumateperone is provided in the form of an amorphous solid dispersion (either of lumateperone free base or lumateperone tosylate), that in step (a) of Process 1 it is the dispersion that is combined with at least one further diluent or carrier. As such, the amorphous solid dispersion would be prepared in a step antecedent to step (a) by combining the lumateperone and any excipients necessary to form the solid dispersion thereof.

In some embodiments, steps (d), (e), and/or (f) may be repeated for additional diluents or carriers. For example, the process steps may comprise steps (a), (b), (c), (d1), (e1), (f1), (d2), (e2), (f2), (g), and (h). The steps (d), (e), and (f) may be repeated any number of times to provide for the additional addition, blending/milling and/or filtering of any individual ingredients or portions of ingredients in order to optimize process flow. Thus, for example, in some embodiments, the binder components may be added in two or three portions, such as in steps (a), (d1) and (d2), or the lubricant may be added in a final addition step (e.g., step (d2)). In some embodiments, the process optionally further includes one or more dry granulation steps (e.g., roller compaction or slugging) which serve to increase the size of solid particles from powder-scale to granule-scale. In some embodiments, one or more blending steps may further include running the blend through a roller compactor, and optionally then milling the roller compacter ribbons. In some embodiments, any dry granulation step may be followed by a blending step to blend the resulting granules with one or more other excipients (e.g., lubricant).

In some embodiments, the final step of coating the Dosage Form is performed by suspending the un-coated Dosage Form in an aqueous suspension of coating polymer followed by drying to remove the water and any co-solvents. Optionally, the coating is applied at high temperature and/or the coated tablets are dried at high temperature (e.g., 40 to 60° C.). In some embodiments, the coating is applied by spraying an aqueous suspension of the coating polymer onto uncoated Dosage Form, followed by drying.

In a third 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-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, comprising administering to a patient in need thereof the solid dosage form according to Dosage Form 1 or any of 1.1-1.49. In some embodiments, said 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).

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.

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

Methods of synthesizing lumateperone and related compounds are known in art, and include the methods disclosed in WO PCT/US08/03340 (WO 2008/112280); U.S. application Ser. No. 10/786,935; U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 8,309,722; 8,779,139; 9,315,504; U.S. RE39680, and U.S. RE39679, and WO 2015/154025, the contents of each of which are incorporated by reference in their entirety. Salts of the Compounds of the Invention may also be prepared as similarly described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282, 8,648,077; 9,199,995; 9,588,960; U.S. RE39680; U.S. RE39679; and WO 2009/114181, the contents of each of which are incorporated by reference in their entirety.

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.

The pharmaceutically acceptable salts of lumateperone 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.

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 is based 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).

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: Excipient Compatibility Study

The chemical compatibility of lumateperone monotosylate with selected excipients is studied. Excipients evaluated are (1) Fillers (silicified microcrystalline cellulose, and lactose monohydrate); (2) Disintegrants (sodium starch glycolate); (3) Binders (pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and copovidone); and (4) Coating Polymers (polyvinyl alcohol-based film coating comprising PVA, titanium dioxide and talc). Lumateperone tosylate is mixed in a 1:1 weight ratio with each excipient and the mixture is evaluated (1) immediately after mixing, (2) after 4, 8 and 12 weeks of aging at 25° C. and 60% relative humidity, and (3) after 4, 8 and 12 weeks of accelerated aging at 40° C. and 75% relative humidity. Comparisons are made to lumateperone tosylate under the same conditions without excipient. Potency, appearance, moisture content and related substances levels are evaluated. It is found that there are no chemical incompatibilities with the selected excipients. All potency measurements of the binary mixtures show lumateperone tosylate levels comparable to the control. Under the accelerated aging conditions, slight decreases in potency are observed for both the control (90.9-93.5% potency over 4-12 weeks) and the binary mixtures, and this is believed due to air oxidation of the lumateperone tosylate. Slight increase in moisture content are observed for samples in the accelerated aging arm, with larger increases for the more hydroscopic excipients (e.g., pregelatinized starch). Related substance levels are acceptable for all binary mixtures analyzed.

Example 2: Tablet Development Process

14 mg, 28 mg, and 42 mg immediate-release film-coated tablets of lumateperone monotosylate are prepared according to the formulae shown in the tables below. Batches are prepared on a multi-kilogram scale, and each batch is prepared in three different runs:

Ingredient                       14 mg Batch
Lumateperone tosylate            7.6 wt %
Silicified microcrystalline cellulose (SMCC) 60 wt %
Mannitol                         19 wt %
Hydroxypropyl cellulose          3 wt %
Croscarmellose sodium            3 wt %
BHT                              0.8 wt %
Colloidal silicon dioxide        0.4 wt %
Magnesium stearate               1 wt %
PVA Coating                      4.8 wt %
Common Blend                     95 wt %
PVA Coating                      5 wt %

	Ingredient	28/42 mg Batch Common Blend
	Lumateperone tosylate	16 wt %
	SMCC	55 wt %
	Mannitol	20 wt %
	Hydroxypropyl cellulose	3.2 wt %
	Croscarmellose sodium	3.2 wt %
	BHT	0.8 wt %
	Colloidal silicon dioxide	0.4 wt %
	Magnesium stearate	1 wt %
		28 mg	42 mg
		Batch	Batch
	Common Blend	95 wt %	95 wt %
	PVA Coating	5 wt %	5 wt %

For 14 mg tablets, mannitol, silicon dioxide, BHT, and lumateperone tosylate are combined in a 3-cubic foot V-blender and mixed for 5 minutes at 25 rpm. A first portion of the microcrystalline cellulose is then added, and the mixture is blended for 5 additional minutes. The blended mixture is passed through a Comil brand conical mill with a round impeller using a 1.6 mm aperture screen and milled/screened. A second portion of cellulose is milled and then combined with the milled blend and a third portion of cellulose, and the mixture is blended for 10 minutes at 25 rpm. The HPMC and croscarmellose sodium portions are pre-screened through a 20-mesh screen, then added to the blended mixture and the further blended for 5 minutes at 25 rpm. Finally, the magnesium stearate portion is pre-screened through a 30-mesh screen, added to the blended mixture, and the mixture is further blended for 3 minutes at 25 rpm.

The common blend for 28 mg and 42 mg tablets is prepared analogously using a 10 cubic foot V-blender, operated at a reduced speed of 20.5 rpm, with similar blending times.

For both the 14 mg and 28/42 mg blends, blend uniformity and physical properties are evaluated by taking samples from throughout the blender at the time final blending is stopped (10 locations are each sampled for each V-blender). Mean blend uniformity is found to be about 97% for the 14 mg batch and about 96% for the common blend batch over all three runs of each batch. Physical properties, including particle size distribution, bulk density, tapped density, and flow, are found to be highly consistent between the three runs of each batch.

From each batch, tablets are prepared using a commercial tablet press using 0.2000 inch by 0.4758-inch modified capsule embossed B tooling and tapered dies. Target weight for the 14 mg and 28 mg tablets is 250 mg, and for the 42 mg tablets 375 mg. All batches are compressed using force feed frame. Compression parameters and compression yields are evaluated for each batch run, including average tablet weight, hardness, thickness, friability, and disintegration time. All parameters are found to be compliant and consistent between the batch runs.

Tablets are then coated using a commercial multi-pan laboratory coating system using a 30-inch pan. Each batch is coated with a target weight of 5 wt % coating, using a commercial, aqueous polyvinyl alcohol coating suspension comprising 20 wt % solids, using two anti-bearding guns equipped with 1.2 mm nozzles. The coating suspension is mixed for 45 minutes in a stainless-steel tank and then allowed to de-aerate for at least 60 minutes prior to use. Target coating parameters are based on the manufacturer's guidelines. The coating process is found to be acceptable.

The coated tablets from each batch run are then tested in standard dissolution and other analytical assays. Each batch is tested in a standard dissolution study using 500 mL of 0.1N aqueous hydrochloric acid as the dissolution media. The results (batch means) are shown in the table below for 14 mg and 42 mg tablets. Results for 28 mg tablets are comparable.

	Batch
	14 mg tablets	42 mg tablets
	1	2	3	1	2	3
Dissolution (%) at 15 min	86	90	93	86	81	83
Dissolution (%) at 30 min	95	96	99	96	92	93
Dissolution (%) at 45 min	98	97	100	100	98	98
Dissolution (%) at 60 min	98	98	100	101	100	99
Uniformity (%) [USP 905]	99.8	100.4	99.7	100.7	100.2	98.9
Assay (%)	98	99	98	100	99	99

Example 3: Alternative Tablet Formulation and Process

Alternative, anti-oxidant free, tablet formulations are prepared according to the formulas shown below for 14-mg, 28-mg and 42-mg tablets:

	14 mg* Tablets	28 mg* Tablets	42 mg* Tablets
	Weight	Weight	Weight	Weight	Weight	Weight
Ingredient	%	(mg)	%	(mg)	%	(mg)
Lumateperone tosylate	8.0	20.0	16.0	40.0	16.0	60.0
SMCC (e.g., Prosolv HD 90)	64.2	160.5	56.2	140.5	56.2	210.75
Mannitol	20.0	50.0	20.0	50.0	20.0	75.0
Hydroxypropyl cellulose	3.2	8.0	3.2	8.0	3.2	12.0
Croscarmellose sodium	3.2	8.0	3.2	8.0	3.2	12.0
Colloidal Silicon Dioxide	0.4	1.0	0.4	1.0	0.4	1.5
Magnesium Stearate	1.0	2.5	1.0	2.5	1.0	3.75
TOTAL	100%	250	100%	250	100%	375
*equivalent weight of lumateperone free base in each tablet

14 mg and 28 mg tablets are each coated with 12.5 mg of PVA coating (5 wt % of core weight), while 42 mg tablets are coated with 18.75 mg of PVA coating (5 wt % of core weight).

Tablets are prepared, as shown in the above table, in 14 mg, 28 mg and 42 mg sizes (free base equivalent; corresponding to 20 mg, 40 mg, or 60 mg, respectively, of lumateperone tosylate). The procedure for preparing the tablets is as follows (amounts in parentheses are with reference to the total amount of indicated ingredient in the composition):

• • a. Mannitol (e.g., 50%) is added to a V-blender and is blended;
  • b. Lumateperone tosylate (100%) and additional mannitol (e.g., 50%) are added to the V-blender and blended;
  • c. SMCC (e.g., 40%) is added to the V-blender, and blended;
  • d. The preblend from step (c) is milled in a Comil conical mill; additional SMCC (e.g., 40%) is also milled in the Comil;
  • e. The milled materials from step (d) are returned to the V-blender and blended;
  • f. Croscarmellose sodium (e.g., 50%), HPC (e.g., 50%), and silicon dioxide (e.g., 50%) are added to the V-blender and blended;
  • g. Magnesium stearate (e.g., 50%) is added to the v-blender and blended;
  • h. The blend from step (g) is run through a roller compactor and milled to create granules;
  • i. The granules from step (h) are returned to the V-blender, additional croscarmellose sodium (e.g., 50%) and HPC (e.g., 50%) are added, and the mixture is blended;
  • j. Additional SMCC (e.g., 20%) is added to the v-blender and blended;
  • k. Additional magnesium stearate (e.g., 50%) is added to the v-blender and blended;
  • l. The blend is compressed to form tablets on a rotary tablet press;
  • m. The tablets are coated in a perforated coating pan.

Tablets prepared according to the above formulas are packaged in blister packs comprising PVC/PE/PCTFE film and 20-micron aluminum foil (peel-push). The packaged tablets are tested for stability using standard procedures. Tested conditions are (1) initial, (2) 50° C./ambient humidity for 1-3 months, (3) 40° C./75% relative humidity for 1-3 months, and (4) 25° C./60% relative humidity for 1 month. Tablets are assayed using reverse-phase HPLC for lumateperone tosylate content, as well as for known impurities. Tablets are also subject to a standard dissolution test (dissolution in 500 mL 0.1N aqueous hydrochloric acid). The results (batch means) are shown in the table below:

		3 mo.	3 mo.	1 mo.
		50° C./	40° C./	25° C./
	Initial	amb RH	75% RH	60% RH
28 mg Tablets
Assay (% of label claimed	100.0%	98.8%	97.9%	99.8%
amount)
Net Related Substance	0.28%	0.97%	1.1%	0.34%
Impurities (max single)	(0.15%)	(0.22%)	(0.24%)	(0.17%)
R.S. Impurities Detectable	4 (2)	9 (6)	14 (6)	4 (2)
(Quantifiable)
Dissolution (%) at 15 min	76%	83%	78%	79%
Dissolution (%) at 30 min	90%	94%	90%	91%
Dissolution (%) at 45 min	99%	99%	97%	97%
Dissolution (%) at 60 min	104%	100%	99%	101%
Moisture (%) [USP 921]	2.6%	1.2%	3.0%	2.5%
14 mg Tablets
Assay (% of label claimed	100.0%	97.9%	95.6%	100.0%
amount)
Net Related Substance	0.44%	1.5%	2.3%	0.49%
Impurities (max single)	(0.17%)	(0.29%)	(0.31%)	(0.21%)
R.S. Impurities Detectable	3 (3)	12 (7)	24 (12)	5 (3)
(Quantifiable)
Dissolution (%) at 15 min	81%	95%	82%	90%
Dissolution (%) at 30 min	90%	101%	95%	99%
Dissolution (%) at 45 min	92%	103%	99%	101%
Dissolution (%) at 60 min	92%	103%	100%	102%
Moisture (%) [USP 921]	2.8%	1.3%	3.4%	2.8%
42 mg Tablets
Assay (% of label claimed	100.8%	98.9%	97.5%	100.4%
amount)
Net Related Substance	0.25%	1.1%	1.3%	0.40%
Impurities (max single)	(0.15%)	(0.27%)	(0.28%)	(0.16%)
R.S. Impurities Detectable	4 (2)	12 (6)	19 (7)	6 (3)
(Quantifiable)
Dissolution (%) at 15 min	82%	85%	73%	79%
Dissolution (%) at 30 min	92%	94%	86%	95%
Dissolution (%) at 45 min	96%	98%	93%	100%
Dissolution (%) at 60 min	97%	99%	96%	101%
Moisture (%) [USP 921]	2.6%	1.3%	3.1%	2.7%

The lumateperone assay FIGURE is a reflection of the accuracy of the label claim, as it is presented as a percentage of the label amount (e.g., 14-mg, 28-mg or 42-mg) rather than as a percentage of the tablet composition. Acceptance of a batch requires that the batch of tablets is measured to have a mean of 90.0-110.0% of the claimed label amount of active drug.

The FIGURE for Net Related Substance Impurities indicates the percentage of all related substance impurities in the composition (as judged by HPLC peak area). Parenthetically provided is the highest percentage of any single impurity detected. Acceptance of a batch requires that total related substance impurities amount to not more than 3.0%, with no single related substance impurity amounting to more than 0.5%.

The Quantifiable R.S. (Related Substances) Impurities FIGURE is the number of distinct detectable HPLC peaks associated with related substance impurities, while the parenthetical FIGURE is for the number of such peaks above the lower limit of quantifiability. For all conditions reported in the table above, no single impurity exceeded the 0.5% acceptance limit.

The presence of increasing amounts of impurities during the test conditions reflects instability of the active ingredient, as does a drop in the Assay FIGURE. The data demonstrates that the tablets formulated according to the invention have acceptable physical and chemical stability based on all measured tested.

Example 4: Alternative Anti-Oxidants

A study is conducted to evaluate the effectiveness of the anti-oxidants propyl gallate, ascorbic acid, citric acid (anhydrous) and sodium metabisulfite. Each antioxidant is combined with either lumateperone tosylate (pure API) or with the lumateperone tosylate tablet formulation final blend of Example 3 (not pressed into tablets) in various weight ratios in amber scintillation vials. In addition, as controls, one vial holds lumateperone tosylate API and another holds the lumateperone tosylate tablet formulation final blend (42 mg strength). All vials are then stored at 60° C. for 2 weeks, 4 weeks, or 8 weeks, after which the vial contents are tested for physical appearance, HPLC potency and HPLC impurities (related substances/degradation products). The samples can be summarized as follows:

Sample	Active	Anti-oxidant
1	Lumateperone blend	2250 mg	—	0
2	Lumateperone API	362 mg	—	0
3	—	0	Propyl Gallate	8.16 mg
4	—	0	Ascorbic Acid	170.6 mg
5	—	0	Citric Acid (anhyd.)	122.4 mg
6	—	0	Sodium metabisulfite	48 mg
7	Lumateperone API	362	Propyl Gallate	8.16 mg
8	Lumateperone API	362	Ascorbic Acid	170.6 mg
9	Lumateperone API	362	Citric Acid (anhyd.)	122.4 mg
10	Lumateperone API	362	Sodium metabisulfite	48 mg
11	Lumateperone blend	2250 mg	Propyl Gallate	8.16 mg
12	Lumateperone blend	2250 mg	Ascorbic Acid	170.6 mg
13	Lumateperone blend	2250 mg	Citric Acid (anhyd.)	122.4 mg
14	Lumateperone blend	2250 mg	Ascorbic Acid	85.3 mg
15	Lumateperone blend	2250 mg	Citric Acid (anhyd.)	61.2 mg
16	Lumateperone blend	2250 mg	Sodium metabisulfite	24 mg

The following table provides the result of the study at 8-weeks:

		Assay	RS Impurities (%)
Sample	Appearance	(%)	Known	Unknown	Mass Bal.
1	Original (off-white	95.7	0.61	0.93	97.2
	powder)
2	Granules present	99.7	0.36	None	100.0
7	Black residue and	95.5	0.65	1.1	97.3
	granules
8	Original	99.8	0.42	none	100.2
9	Dark lumps present	95.5	0.62	0.59	96.7
10	Granules present	98.6	0.44	0.14	99.2
11	Black particles present	94.6	0.57	1.1	96.3
12	Original	96.4	0.60	0.36	97.4
13	Black granules present	96.8	0.59	0.60	98.0
14	Original	96.8	0.60	1.0	98.4
15	Dark lumps present	95.8	0.56	0.73	97.1
16	Grey powder	86.8	0.64	1.6	80.7

The results of the study are summarized as follows:

• • a. Both controls remain off-white powders through 8 weeks, although pure API formed some granules by 8 weeks. Pure API retains full potency at 8 weeks (99.7%), while the blend (without antioxidant) drops from 100.0% to 95.7% potency at 8 weeks.
  • b. Ascorbic acid is the only anti-oxidant which maintained full physical stability (appearance unchanged) at 8 weeks, and it was effective both for lumateperone tosylate API and for the blend formula. Sodium metabisulfite was substantially unchanged at 8 weeks when mixed with API (some granules formed), but mixed with the blend the powder changed to a grey color.
  • c. Ascorbic acid mixed with API retained full chemical potency, but the other anti-oxidants resulted in a drop in pure API potency (from 99.7% to 95.5-98.6%).
  • d. At both weight ratios, ascorbic acid mixed with the blend retained >95.7% potency, as did citric acid, but the other anti-oxidants mixed with the blend resulted in <95.7% potency at 8 weeks (and thus less than blend without antioxidants). In addition, for both ascorbic acid and citric acid mixed with blend, after 8 weeks, known and known related substances impurities were comparable to or better than the blend alone.

Overall, the study suggests that ascorbic acid is a preferred anti-oxidant for maintaining physical and chemical stability of lumateperone tosylate in a tablet formulation blend.

Claims

1. A solid oral dosage form, comprising lumateperone:

2. The dosage form of claim 1, wherein the dosage form further comprises lumateperone in di-tosylate salt form.

3. The dosage form of claim 1, wherein the lumateperone mono-tosylate solid crystal form 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°, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

4. The dosage form of claim 1, wherein the dosage form further comprises toluenesulfonic acid.

5. The dosage form of claim 1, wherein the dosage form comprises the lumateperone mono-tosylate in a total unit amount equivalent to 0.01 to 120 mg of lumateperone free base.

6. The dosage form of claim 1, wherein the one or more pharmaceutically acceptable diluents or carriers further comprises one or more of (f) effervescent, (g) polymer, (h) plasticizer, (i) drying agent or desiccant, (j) humectant, (k) wetting agent, (l) anti-oxidant, (m) thickening agent, (n) surfactant, (o) buffer, (p) sweetener or flavor, and (q) dye or colorant.

7. The dosage form of claim 1, wherein the dosage form comprises or consists of (a) lumateperone mono-tosylate, lactose monohydrate, starch, cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), copovidone (cross-linked polyvinyl pyrrolidone), sodium starch glycolate, flavors and/or colors and/or antioxidants, or (b) lumateperone mono-tosylate, cellulose, hydroxypropyl cellulose (HPC), croscarmellose sodium (cross-linked carboxymethyl cellulose sodium), silicon dioxide, magnesium stearate, flavor and/or colors and/or antioxidants.

8. The dosage form of claim 1, wherein the dosage form comprises one or more surface coatings.

9. The dosage form of claim 1, wherein the dosage form is a spherical or approximately spherical, oval or oblong tablet, or is a caplet.

10. The dosage form of claim 1, wherein the lumateperone mono-tosylate is in the form of paricles having (a) a mean particle size of 1 to 200 μm, 1 to 150 μm, 1 to 100 μm, 1 to 50 μm, 1 to 25 μm, 1 to 15 μm, 1 to 10 μm, 5 to 10 μm, or 1 to 5 μm; and/or (b) a D90 of 100 μm or less, 50 μm or less, 25 μm or less, 15 μm or less, or 10 μm or less; and/or (c) a D10 of 50 μm or less, 25 μm or less, 15 μm or less, or 10 μm or less, or 5 μm or less.

11. The dosage form of claim 1, wherein the lumateperone is in combination with an effective amount of an additional therapeutic agent.

12. A process for the manufacture of the dosage form according to claim 1, wherein the process comprises the steps of: (a) combining lumateperone mono-tosylate, with at least one diluent or carrier;(b) blending and/or milling and/or granulating the resulting the mixture;(c) optionally filtering the resulting mixture to achieve a uniform particle size;(d) adding at least one other diluent or carrier, or a glidant, or a lubricant, or a combination thereof;(e) blending and/or milling and/or granulating the resulting mixture;(f) optionally filtering the resulting mixture to achieve a uniform particle size;(g) pressing the mixture to form the dosage form; and(h) optionally applying one or more coating to the dosage form.

13. A method 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 solid dosage form according to claim 1.

14. The dosage form of claim 1, wherein the dosage form comprises silicified microcrystalline cellulose, mannitol, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, and silicon dioxide.

15. The dosage form of claim 14, wherein the dosage form comprises 60-90% by weight of microcrystalline cellulose and mannitol, 1-10% by weight of hydroxypropyl cellulose, 1-10% by weight of croscarmellose sodium, 0.1-5% by weight of magnesium stearate, and 0.1-5% by weight of silicon dioxide.

16. The dosage form of claim 15, wherein the dosage form comprises the lumateperone mono-tosylate in a total unit amount equivalent to 1 to 60 mg of lumateperone free base.

17. The dosage form of claim 1, wherein the dosage form comprises the lumateperone mono-tosylate in a total unit amount equivalent to 1 to 60 mg of lumateperone free base.