Claims for Patent: 12,070,459

Summary for Patent: 12,070,459

Title:	Pharmaceutical capsule compositions comprising lumateperone mono-tosylate
Abstract:	The present disclosure relates to pharmaceutical capsules 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.
Inventor(s):	Peng Li, Robert Davis
Assignee:	Intra Cellular Therapies Inc
Application Number:	US18/504,345
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 12,070,459
Patent Claims:	1. A pharmaceutical capsule for oral administration, comprising lumateperone: in mono-tosylate salt form, wherein the lumateperone mono-tosylate is in solid crystal form; wherein the capsule comprises the lumateperone mono-tosylate in an amount of about 60 mg lumateperone mono-tosylate in solid crystal form, and wherein the capsule comprises a blend of 10 to 30% by weight of lumateperone mono-tosylate in solid crystal form, and one or more pharmaceutically acceptable diluents or carriers comprising one or more of (a) diluent/filler, (b) binder, (c) disintegrant, (d) lubricant, or (e) a glidant, and wherein administration of an oral dose of a single capsule under fasting conditions provides a maximal plasma concentration of lumateperone of 15-55 ng/mL, and/or a time to maximal plasma concentration of lumateperone of 0.7 to 1.5 hours, and/or an area under the plasma concentration curve (AUC) extrapolated to infinity (AUC(0-inf)) of 51 to 135 hours-ng/mL. 2. The capsule of claim 1, wherein the capsule further comprises one or more colorants selected from FD&C Yellow #6, FD&C Blue #1, FD&C Red #3, black iron oxide, red iron oxide, titanium dioxide, or any combination thereof. 3. The capsule of claim 1, wherein the capsule comprises a blend of the 10 to 30% by weight of lumateperone mono-tosylate in solid crystal form, 60 to 90% by weight of mannitol, 0.5 to 10% by weight of croscarmellose sodium, 0.1 to 1% by weight of talc, and 0.1 to 3% by weight of magnesium stearate, filled into a gelatin capsule. 4. The capsule of claim 1, wherein the lumateperone mono-tosylate is in solid crystal form, and 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°, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter. 5. The capsule of claim 3, wherein the capsule comprises a blend of the 10 to 30% by weight of lumateperone mono-tosylate in solid crystal form, 70 to 80% by weight of mannitol, 0.5 to 5% by weight of croscarmellose sodium, 0.1 to 1% by weight of talc, and 0.1 to 1% by weight of magnesium stearate, filled into the gelatin capsule. 6. The capsule of claim 1, wherein the capsule consists of a blend of the 10 to 30% by weight of lumateperone mono-tosylate in solid crystal form, about 74% by weight of mannitol, about 5% by weight of croscarmellose sodium, about 0.3% by weight of talc, and about 1% by weight magnesium stearate, filled into a gelatin capsule, wherein the gelatin capsule further comprises one or more colorants selected from FD&C Yellow #6, FD&C Blue #1, FD&C Red #3, black iron oxide, red iron oxide, titanium dioxide, or any combination thereof. 7. The capsule of claim 1, wherein the capsule consists of a blend of the 10 to 30% by weight of lumateperone mono-tosylate in solid crystal form, about 87% by weight of mannitol, about 5% by weight of croscarmellose sodium, about 0.3% by weight of talc, and about 1.25% by weight of magnesium stearate, filled into a gelatin capsule, wherein the gelatin capsule further comprises one or more colorants selected from FD&C Yellow #6, FD&C Blue #1, FD&C Red #3, black iron oxide, red iron oxide, titanium dioxide, or any combination thereof. 8. The capsule of claim 1, wherein the capsule comprises or consists of a blend of the 10 to 30% by weight of lumateperone mono-tosylate in solid crystal form and (a) mannitol, croscarmellose sodium, talc, and glyceryl monostearate, and gelatin, or (b) mannitol, croscarmellose sodium, talc, magnesium stearate, and gelatin. 9. The capsule of claim 1, wherein the capsule comprises one or more surface coatings. 10. The capsule of claim 1, wherein the capsule is a hard-shelled capsule. 11. The capsule of claim 1, wherein the lumateperone mono-tosylate in solid crystal form is present in (a) a mean particle size of 1 to 200 μm; and/or (b) a D90 of 100 μm or less; and/or (c) a D10 of 50 μm or less. 12. A method for treatment of a disease or disorder involving or mediated by a 5-HT2A receptor, serotonin transporter (SERT), and/or dopamine D1/D2 receptor signaling pathways, comprising administering to a patient in need thereof the capsule according to claim 1. 13. The capsule of claim 11, wherein the lumateperone mono-tosylate in solid crystal form is present in (a) a mean particle size of 1 to 5 μm; and/or (b) a D90 of 10 μm or less; and/or (c) a D10 of 5 μm or less. 14. The capsule of claim 13, wherein the lumateperone mono-tosylate in solid crystal form is present as particles having a D90 of not more than 10 μm, a D10 of not more than 5 μm, and/or a particle size distribution (PSD) D50 of 2 to 5 μm. 15. The capsule of claim 1, wherein the capsule dissolves in 500 ml of 0.1N aqueous hydrochloric acid to the extent of at least 85% after 15 minutes, and/or to the extent of at least 92% after 30 minutes, and/or at least 94% after 45 minutes. 16. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides a mean maximal plasma concentration (Cmax) of lumateperone of 30-40 ng/mL, and/or a mean time to maximal plasma concentration (Tmax) of lumateperone of 1-1.2 hours, and/or an area under the plasma concentration curve (AUC) extrapolated to infinity (AUC(0-inf)) of 70 to 115 hr-ng/mL. 17. The capsule of claim 16, wherein administration of an oral dose of a single capsule under fasting conditions provides a mean maximal plasma concentration (Cmax) of lumateperone of 30-40 ng/mL, and/or a mean time to maximal plasma concentration (Tmax) of lumateperone of about 1 hour, and/or an area under the plasma concentration curve (AUC) extrapolated to infinity (AUC(0-inf)) of 85 to 100 hr-ng/mL. 18. The method of claim 12, wherein the disease or disorder is selected from the group consisting of obesity, anorexia, bulimia, depression, major depressive disorder (MDD), acute depression, post-traumatic depression, anxiety, acute anxiety, panic disorders, phobias, social anxiety disorder, social withdrawal, psychosis, acute psychosis, schizophrenia, positive and/or negative symptoms of schizophrenia, obsessive-compulsive disorder, migraine, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorders, anger disorders, agitation, dementia, Alzheimer's disease, Parkinson's dementia, bipolar disorder, bipolar depression, and behavioral disturbances associated with autism. 19. The method of claim 18, wherein the disease or disorder is selected from the group consisting of depression, major depressive disorder (MDD), schizophrenia, negative symptoms of schizophrenia, bipolar disorder, and bipolar depression. 20. The capsule of claim 1, wherein the capsule comprises about 60 mg of lumateperone mono-tosylate in solid crystal form and administration of an oral dose of a single capsule under fasting conditions provides one or more of the following plasma metabolite values: (a) a mean Cmax for Metabolite A of 25-38 ng/ml; (b) a mean Cmax for Metabolite B of 16-25 ng/ml; (c) a mean Cmax for Metabolite C of 16-25 ng/ml; (d) a mean Cmax for Metabolite E of 8-13 ng/ml; (e) a mean Cmax for Metabolite F of 16-25 ng/ml; (f) a mean AUC(0-inf) for Metabolite A of 270-410 hr-ng/ml; (g) a mean AUC(0-inf) for Metabolite B of 43-65 hr-ng/mL; (h) a mean AUC(0-inf) for Metabolite C of 220-335 hr-ng/ml; (i) a mean AUC(0-inf) for Metabolite E of 45-68 hr-ng/ml; (j) a mean AUC(0-inf) for Metabolite F of 330-500 hr-ng/ml; (k) a ratio of Cmax (metabolite A)/Cmax (lumateperone) of 0.8-1.3; (l) a ratio of Cmax (metabolite B)/Cmax (lumateperone) of 0.5-0.8; (m) a ratio of Cmax (metabolite C)/Cmax (lumateperone) of 0.5-0.8; (n) a ratio of Cmax (metabolite E)/Cmax (lumateperone) of 0.3-0.4; (o) a ratio of Cmax (metabolite F)/Cmax (lumateperone) of 0.5-0.8; (p) a ratio of AUC(0-inf)(metabolite A)/AUC(0-inf)(lumateperone) of 3.2-4.8; (q) a ratio of AUC(0-inf)(metabolite B)/AUC(0-inf)(lumateperone) of 0.5-0.8; (r) a ratio of AUC(0-inf)(metabolite C)/AUC(0-inf)(lumateperone) of 2.6-4.0; (s) a ratio of AUC(0-inf)(metabolite E)/AUC(0-inf)(lumateperone) of 0.5-0.8; and/or (t) a ratio of AUC(0-inf)(metabolite F)/AUC(0-inf)(lumateperone) of 3.9-6.0; wherein metabolites A, B, C, E, and F, are defined as follows: 21. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides a maximal plasma concentration of lumateperone of 15-55 ng/mL. 22. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides a time to maximal plasma concentration of lumateperone of 0.7 to 1.5 hours. 23. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions an area under the plasma concentration curve (AUC) extrapolated to infinity (AUC(0-inf)) of 51 to 135 hours-ng/mL. 24. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides a mean maximal plasma concentration (Cmax) of lumateperone of 30-40 ng/mL. 25. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides a mean time to maximal plasma concentration (Tmax) of lumateperone of 1-1.2 hours. 26. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides an area under the plasma concentration curve (AUC) extrapolated to infinity (AUC(0-inf)) of 70 to 115 hr-ng/mL. 27. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides a mean time to maximal plasma concentration (Tmax) of lumateperone of about 1 hour. 28. The capsule of claim 1, wherein administration of an oral dose of a single capsule under fasting conditions provides an area under the plasma concentration curve (AUC) extrapolated to infinity (AUC(0-inf)) of 85 to 100 hr-ng/mL.