Claims for Patent: 10,695,345

Summary for Patent: 10,695,345

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):	Li; Peng (New Milford, NJ), Davis; Robert (San Diego, CA)
Assignee:	INTRA-CELLULAR THERAPIES, INC. (New York, NY)
Application Number:	16/557,083
Patent Claims:	1. A pharmaceutical capsule for oral administration, comprising lumateperone: ##STR00004## in mono-tosylate salt form, wherein the lumateperone mono-tosylate is 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, 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. 2. The capsule of claim 1, wherein the gelatin capsule is a size 0 gelatin capsule. 3. The capsule of claim 2, wherein the size 0 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. 4. The capsule of claim 1, wherein the capsule comprises the lumateperone mono-tosylate in an amount equivalent to 35 to 45 mg of lumateperone free base. 5. The capsule of claim 4, wherein the capsule comprises the lumateperone mono-tosylate in an amount equivalent to about 42 mg of lumateperone free base. 6. The capsule of claim 4, wherein the capsule comprises about 60 mg of lumateperone mono-tosylate. 7. The capsule of claim 1, wherein the capsule comprises a blend of about 60 mg 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 a size 0 gelatin capsule. 8. The capsule of claim 1, wherein the lumateperone mono-tosylate in 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.degree. , 12.11.degree. , 16.04.degree. , 17.03.degree. , 18.16.degree. , 19.00.degree. , 21.67.degree. , 22.55.degree. , 23.48.degree. and 24.30.degree. , each of said peaks .+-.0.2.degree. . 9. The capsule of claim 1, wherein the capsule comprises about 60 mg 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 a size 0 gelatin capsule, wherein the size 0 gelatin capsule optionally 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. 10. The capsule of claim 1, wherein the capsule comprises of a blend of about 60 mg lumateperone mono-tosylate in solid crystal form, about 221 mg mannitol, about 15 mg croscarmellose sodium, about 0.9 mg talc, and about 3 mg magnesium stearate, filled into a size 0 gelatin capsule, wherein the size 0 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. 11. The capsule of claim 1, wherein the capsule is a hard-shelled capsule. 12. The capsule of claim 1, wherein the lumateperone is present in (a) a mean particle size of 1 to 200 .mu.m; and/or (b) a D90 of 100 .mu.m or less; and/or (c) a D10 of 50 .mu.m or less; optionally wherein the lumateperone particles have a D90 of not more than 10 .mu.m, a D10 of not more than 5 .mu.m, and/or a particle size distribution (PSD) D50 of 2 to 5 .mu.m. 13. A process for the manufacture of the capsule according to claim 1, wherein the process comprises the steps of: (a) combining the lumateperone, in solid crystal mono-tosylate salt form, with a portion of mannitol; (b) blending the resulting mixture; (c) optionally filtering the resulting mixture; (d) adding additional mannitol, croscarmellose sodium, talc, and magnesium stearate; (e) blending the resulting mixture; (f) optionally filtering the resulting mixture; (g) encapsulating the resulting mixture into a gelatin capsule; and (h) optionally applying one or more coatings to the gelatin capsule. 14. A method for the treatment or prophylaxis of a disease or disorder involving or mediated by the 5-HT.sub.2A 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, wherein the disease or disorder is schizophrenia. 15. The capsule of claim 12, wherein the lumateperone is present in (a) a mean particle size of 1 to 5 .mu.m; and/or (b) a D90 of 10 .mu.m or less; and/or (c) a D10 of 5 .mu.m or less. 16. The capsule of claim 15, wherein the lumateperone particles have a D90 of not more than 10 .mu.m, a D10 of not more than 5 .mu.m, and/or a particle size distribution (PSD) D50 of 2 to 5 .mu.m. 17. The capsule of claim 1, wherein a single 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. 18. The capsule of claim 1, wherein administration of an oral dose of a single capsule comprising 60 mg of lumateperone tosylate under fasting conditions provides a maximal plasma concentration of lumateperone of 15-55 ng/mL or a mean Cmax of 30-40 ng/mL; and/or a time to maximal plasma concentration of lumateperone of 0.7 to 1.5 hours or a mean Tmax of 1-1.2 hours, or a median Tmax of about 1 hour; and/or an area under the plasma concentration curve (AUC) extrapolated to infinity of 51 to 135 hours-ng/mL or a mean AUC extrapolated to infinity of 70 to 115 hr-ng/mL, or 85 to 100 hr-ng/mL.