Claims for Patent: 10,933,020

Summary for Patent: 10,933,020

Title:	Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
Abstract:	Provided herein is an oral pharmaceutical composition, comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof, and a plurality of trospium beads having a core comprising a salt of trospium.
Inventor(s):	Aimesther BETANCOURT, Bruce Rehlaender, Roch Thibert
Assignee:	Karuna Therapeutics Inc
Application Number:	US16/585,532
Patent Claims:	1. An oral pharmaceutical composition, comprising: a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof, and a plurality of trospium beads having a core comprising a salt of trospium. 2. The oral pharmaceutical composition of claim 1, wherein the size of the xanomeline beads is between 0.425 mm and 1.18 mm. 3. The oral pharmaceutical composition of claim 2, wherein the size of the xanomeline beads is between 0.6 mm and 0.85 mm. 4. The oral pharmaceutical composition of claim 1, wherein the size of the trospium beads is between 0.425 mm and 1.18 mm. 5. The oral pharmaceutical composition of claim 4, wherein the size of the trospium beads is between 0.6 mm and 0.85 mm. 6. The oral pharmaceutical composition of claim 1, wherein the xanomeline beads contain about 2.5 times as much xanomeline as the trospium beads contain trospium salt. 7. The oral pharmaceutical composition of claim 1, the plurality of xanomeline and the plurality of trospium beads having a dissolution rate of more than about 95% within about the first 45 minutes following entry of the dosage form into an aqueous 8 solution. 8. The oral pharmaceutical composition of claim 7, having a dissolution rate of more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution. 9. The oral pharmaceutical composition of claim 1, when administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean Cmax of trospium at 7850±3360 pg/mL. 10. The oral pharmaceutical composition of claim 1, when administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean AUC0-12 of 41900±15500 hr·pg/mL. 11. The oral pharmaceutical composition of claim 1, wherein the xanomeline is xanomeline tartrate. 12. The oral pharmaceutical composition of claim 11, wherein the xanomeline beads comprise between 30 wt. % and 80 wt. % xanomeline tartrate. 13. The oral pharmaceutical composition of claim 12, wherein the xanomeline beads comprise 66 wt. % xanomeline tartrate. 14. The oral pharmaceutical composition of claim 1, wherein the xanomeline beads comprise between 15 wt. % and 65 wt. % microcrystalline cellulose. 15. The oral pharmaceutical composition of claim 12, wherein the xanomeline beads 16 comprise 33.5 wt. % microcrystalline cellulose. 16. The oral pharmaceutical composition of claim 1, wherein the xanomeline beads comprise between 0 wt. % and 2 wt. % talc. 17. The oral pharmaceutical composition of claim 16, wherein the xanomeline beads comprise 0.5 wt. % talc. 18. The oral pharmaceutical composition of claim 1, wherein the xanomeline beads comprise between 30 wt. % and 80 wt. % xanomeline tartrate, between 15 wt. % and 65 wt. % microcrystalline cellulose, and between 0 wt. % and 2 wt. % talc. 19. The oral pharmaceutical composition of claim 18, wherein the xanomeline beads comprise 66 wt. % xanomeline tartrate, 33.5 wt. % microcrystalline cellulose, and 0.5 wt. % talc. 20. The oral pharmaceutical composition of claim 1, wherein the trospium salt is trospium chloride. 21. The oral pharmaceutical composition of claim 20, wherein the trospium beads comprise between 8 wt. % and 35 wt. % trospium chloride. 22. The oral pharmaceutical composition of claim 21, wherein the trospium beads comprise 17.7 wt. % trospium chloride. 23. The oral pharmaceutical composition of claim 1, wherein the trospium beads comprise between 25 wt. % and 80 wt. % microcrystalline cellulose. 24. The oral pharmaceutical composition of claim 23, wherein the trospium beads comprise 46.8 wt. % microcrystalline cellulose. 25. The oral pharmaceutical composition of claim 1, wherein the trospium beads comprise between 15 wt. % and 70 wt. % lactose monohydrate. 26. The oral pharmaceutical composition of claim 25, wherein the trospium beads comprise 35 wt. % lactose monohydrate. 27. The oral pharmaceutical composition of claim 1, wherein the trospium beads comprise between 0 wt. % and 2 wt. % talc. 28. The oral pharmaceutical composition of claim 27, wherein the trospium beads comprise 0.5 wt. % talc. 29. The oral pharmaceutical composition of claim 1, wherein the trospium beads comprise between 8 wt. % and 35 wt. % trospium chloride, between 25 wt. % and 80 wt. % microcrystalline cellulose, between 15 wt. % and 70 wt. % lactose monohydrate, and between 0 wt. % and 2 wt. % talc. 30. The oral pharmaceutical composition of claim 29, wherein the trospium beads comprise 17.7 wt. % trospium chloride, 46.8 wt. % microcrystalline cellulose, 35 wt. % lactose monohydrate, and 0.5 wt. % talc. 31. The oral pharmaceutical composition of claim 1, further comprising a capsule containing the plurality of xanomeline beads and the plurality of trospium beads. 32. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 25 mg xanomeline free base and 10 mg trospium chloride. 33. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 50 mg xanomeline free base and 20 mg trospium chloride. 34. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 50 mg xanomeline free base and 10 mg trospium chloride. 35. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 75 mg xanomeline free base and 10 mg trospium chloride. 36. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 75 mg xanomeline free base and 20 mg trospium chloride. 37. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 125 mg xanomeline free base and 20 mg trospium chloride. 38. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 125 mg xanomeline free base and 30 mg trospium chloride. 39. The oral pharmaceutical composition of claim 31, wherein the capsule has a dosage strength of 125 mg xanomeline free base and 40 mg trospium chloride. 40. An oral pharmaceutical composition, comprising xanomeline and/or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, wherein when administered to the patient in need thereof, is sufficient to provide an in-vivo plasma profile comprising a median Tmax for xanomeline of 2 hours and a median Tmax for trospium of 1 hour. 41. The oral pharmaceutical composition of claim 40, wherein the in-vivo plasma profile further comprises a mean dose-normalized Cmax of between 48.5 and 121.3 pg/mL/mg and a mean dose-normalized Cmax of trospium of between 156 and 375 pg/mL/mg. 42. The oral pharmaceutical composition of claim 40, wherein the in-vivo plasma profile further comprises a mean dose-normalized AUC0-12 of xanomeline of between 263 and 577 hr·pg/mL/mg and a mean dose-normalized AUC0-12 of trospium of between 881 and 2024 hr·pg/mL/mg. 43. A method for treating a disorder ameliorated by activating muscarinic receptors in a subject in need thereof, comprising administering to a patient in need thereof an oral pharmaceutical composition of claim 1. 44. The method of claim 43, wherein the disorder is chosen from schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy. 45. An oral pharmaceutical composition, comprising xanomeline and/or a salt thereof and less than 0.5 wt. % 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium. 46. A method for preparing an oral pharmaceutical composition of claim 1, comprising admixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium.