Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
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.
1. A method comprising administering to a patient in need thereof a dosage form comprising between 50 mg and 125 mg xanomeline and/or a salt thereof and between 20 mg and 30 mg trospium salt, wherein the dosage form releases the xanomeline and/or salt thereof and the trospium salt at comparable rates such that the method achieves 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.
2. The method of claim 1 , wherein the in-vivo plasma profile comprises the mean dose-normalized C max of between 48.5 and 121.3 pg/mL/mg and the mean dose-normalized C max of trospium of between 156 and 375 pg/mL/mg.
3. The method of claim 1 , wherein the in-vivo plasma profile 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.
4. The method of claim 1 , wherein the administration is oral.
5. The method of claim 1 , wherein the dosage form is administered to the patient for at least 7 days.
6. The method of claim 1 , wherein the dosage form is administered to the patient twice daily.
7. The method of claim 1 , wherein the xanomeline and/or a salt thereof is xanomeline tartrate.
8. The method of claim 1 , wherein the trospium salt is trospium chloride.
9. The method of claim 1 , wherein the xanomeline and/or a salt thereof is xanomeline tartrate and the trospium salt is trospium chloride.
10. The method of claim 9 , wherein the dosage form is administered to the patient twice daily for at least 7 days.
11. A method comprising administering to a patient in need thereof a dosage form comprising between 50 mg and 125 mg xanomeline and/or a salt thereof and between 20 mg and 30 mg trospium salt, wherein the dosage form releases the xanomeline and/or salt thereof and the trospium salt at comparable rates such that the dosage form has a dissolution rate such that at least 80% of the xanomeline or a salt thereof and the trospium salt is released within 20 minutes in pH 6.8 buffer solution.
12. The method of claim 11 , wherein the in-vivo plasma profile comprises the mean dose-normalized C max of between 48.5 and 121.3 pg/mL/mg and the mean dose-normalized C max of trospium of between 156 and 375 pg/mL/mg.
13. The method of claim 11 , wherein the in-vivo plasma profile 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.
14. The method of claim 11 , wherein the in-vivo plasma profile comprises the median T max for xanomeline of 2 hours and the median T max for trospium of 1 hour.
15. The method of claim 11 , wherein the administration is oral.
16. The method of claim 11 , wherein the dosage form is administered to the patient for at least 7 days.
17. The method of claim 11 , wherein the dosage form is administered to the patient twice daily.
18. The method of claim 11 , wherein the xanomeline and/or a salt thereof is xanomeline tartrate.
19. The method of claim 11 , wherein the trospium salt is trospium chloride.
20. The method of claim 11 , wherein the xanomeline and/or a salt thereof is xanomeline tartrate and the trospium salt is trospium chloride.
21. The method of claim 17 , wherein the dosage form is administered to the patient twice daily for at least 7 days.