Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

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 C max 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 AUC 0-12 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 T max for xanomeline of 2 hours and a median T max 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 C max of between 48.5 and 121.3 pg/mL/mg and a mean dose-normalized C max 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 AUC 0-12 of xanomeline of between 263 and 577 hr·pg/mL/mg and a mean dose-normalized AUC 0-12 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.