Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
1. A compound that is crystalline d 6 -tetrabenazine Form II, or a pharmaceutically acceptable salt or hydrate thereof, having deuterium enrichment in each deuterium position of no less than about 1%, and having an X-ray diffractogram comprising three or more peaks, in terms of 2θ±0.2, at 8.3, 11.6, 13.9, 20.0 or 23.7.
2. The compound of claim 1 , having an X-ray diffractogram comprising five or more peaks, in terms of 2θ±0.2, at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5 or 42.3.
3. The compound of claim 1 , having an X-ray diffractogram further comprising five or more peaks, in terms of 2θ±0.2, at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9 or 23.7.
4. The compound of claim 1 , having an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 8.3, 11.6, 13.9, 20.0 and 23.7.
5. The compound of claim 1 , having an X-ray diffractogram in accordance with FIG. 9 .
6. The compound of claim 1 , having a differential calorimetry trace comprising an endotherm between about 120 and about 140° C.
7. The compound of claim 1 , having a differential calorimetry trace in accordance with FIG. 8 .
8. The compound of claim 1 , having a thermogravimetric analysis profile showing about 1.5% weight loss below about 160° C.
9. The compound of claim 1 , having a thermogravimetric analysis profile in accordance with FIG. 7 .
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystalline d 6 -tetrabenazine Form II, or a pharmaceutically acceptable salt or hydrate thereof, having deuterium enrichment in each deuterium position of no less than about 90%, and having an X-ray diffractogram comprising three or more peaks, in terms of 2θ±0.2, at 8.3, 11.6, 13.9, 20.0 or 23.7.
11. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has deuterium enrichment in each deuterium position of no less than 98%.
12. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram comprising five or more peaks, in terms of 2θ±0.2, at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5 or 42.3.
13. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram comprising five or more peaks, in terms of 2θ±0.2, at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9 or 23.7.
14. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 8.3, 11.6, 13.9, 20.0 and 23.7.
15. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram in accordance with FIG. 9 .
16. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has a differential calorimetry trace comprising an endotherm between about 120 and about 140° C.
17. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has a differential calorimetry trace in accordance with FIG. 8 .
18. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has a thermogravimetric analysis profile showing about 1.5% weight loss below about 160° C.
19. The pharmaceutical composition of claim 10 , wherein the crystalline d 6 -tetrabenazine Form II has a thermogravimetric analysis profile in accordance with FIG. 7 .
20. The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable carrier comprises polyoxide.
21. The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable carrier consists of polyoxide.
22. A method of treating a VMAT2-mediated disorder comprising: administering to a patient in need thereof a compound of claim 1 .
23. The method of claim 22 , wherein the VMAT2-mediated disorder is a hyperkinetic movement disorder.
24. The method of claim 23 , wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder.
25. The method of claim 24 , wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's chorea, tardive dyskinesia, Tourette's syndrome, and a tic.
26. The method of claim 22 , wherein the crystalline d 6 -tetrabenazine Form II, pharmaceutically acceptable salt, or hydrate thereof has deuterium enrichment in each deuterium position of no less than about 90%.
27. The method of claim 22 , wherein the crystalline d 6 -tetrabenazine Form II, pharmaceutically acceptable salt, or hydrate thereof has deuterium enrichment in each deuterium position of no less than about 98%.
28. A method of treating a VMAT2-mediated disorder comprising: administering to a patient in need thereof a pharmaceutical composition of claim 10 .
29. The method of claim 28 , wherein the VMAT2-mediated disorder is a hyperkinetic movement disorder.
30. The method of claim 29 , wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder.
31. The method of claim 30 , wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's chorea, tardive dyskinesia, Tourette's syndrome, and a tic.
32. A method of preparing a crystalline d 6 -tetrabenazine Form II, having deuterium enrichment in each deuterium position of no less than about 1%, and having an X-ray diffractogram comprising three or more peaks, in terms of 2θ±0.2, at 8.3, 11.6, 13.9, 20.0 or 23.7, comprising dissolving d 6 -tetrabenazine in methanol and precipitating the crystalline d 6 -tetrabenazine Form II by evaporation at ambient temperature and humidity.
33. The method of claim 32 , wherein the methanol is saturated with the d 6 -tetrabenazine.
34. The method of claim 32 , wherein the crystalline d 6 -tetrabenazine Form II has deuterium enrichment in each deuterium position of no less than about 90%.
35. The method of claim 32 , wherein the crystalline d 6 -tetrabenazine Form II has deuterium enrichment in each deuterium position of no less than about 98%.
36. The method of claim 32 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram comprising five or more peaks, in terms of 2θ±0.2, at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5 or 42.3.
37. The method of claim 32 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram comprising five or more peaks, in terms of 2θ±0.2, at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9 or 23.7.
38. The method of claim 32 , wherein the crystalline d 6 -tetrabenazine Form II has an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 8.3, 11.6, 13.9, 20.0 and 23.7.