Formulations 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 I having deuterium enrichment of no less than about 1%, and having an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 6.5, 12.2, 14.4, 22.4 and 23.4; or a pharmaceutically acceptable salt or hydrate thereof.
2. The compound of claim 1 , having an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 6.5, 10.8, 12.2, 13.0, 14.4, 17.1, 18.0, 21.4, 22.4 and 23.4.
3. The compound of claim 1 , having an X-ray diffractogram in accordance with FIG. 9 .
4. The compound of claim 1 , having a differential calorimetry trace comprising an endotherm between about 115 and about 135° C.
5. The compound of claim 1 , having a differential calorimetry trace in accordance with FIG. 8 .
6. The compound of claim 1 , having a thermogravimetric analysis profile showing about 1.5% weight loss below about 150° C.
7. The compound of claim 1 , having a thermogravimetric analysis profile in accordance with FIG. 7 .
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystalline d 6 -tetrabenazine Form I having deuterium enrichment of no less than about 90%, and having an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 6.5, 12.2, 14.4, 22.4 and 23.4, or a pharmaceutically acceptable salt or hydrate thereof.
9. The pharmaceutical composition as recited in claim 8 , wherein crystalline d 6 -tetrabenazine Form I has deuterium enrichment of no less than 98%.
10. The pharmaceutical composition as recited in claim 8 , wherein the crystalline d 6 -tetrabenazine Form I has an X-ray diffractogram comprising peaks, in terms of 2θ±0.2, at 6.5, 10.8, 12.2, 13.0, 14.4, 17.1, 18.0, 21.4, 22.4 and 23.4.
11. The pharmaceutical composition as recited in claim 8 , wherein the crystalline d 6 -tetrabenazine Form I has an X-ray diffractogram in accordance with FIG. 9 .
12. The pharmaceutical composition as recited in claim 8 , wherein the crystalline d 6 -tetrabenazine Form I has a differential calorimetry trace comprising an endotherm between about 115 and about 135° C.
13. The pharmaceutical composition as recited in claim 8 , wherein the crystalline d 6 -tetrabenazine Form I has a differential calorimetry trace in accordance with FIG. 8 .
14. The pharmaceutical composition as recited in claim 8 , wherein the crystalline d 6 -tetrabenazine Form I has a thermogravimetric analysis profile showing about 1.5% weight loss below about 150° C.
15. The pharmaceutical composition as recited in claim 8 , wherein the crystalline d 6 -tetrabenazine Form I has a thermogravimetric analysis profile in accordance with FIG. 7 .
16. The pharmaceutical composition as recited in claim 8 , wherein the pharmaceutically acceptable carrier comprises polyoxide.
17. The pharmaceutical composition of claim 8 , wherein the pharmaceutically acceptable carrier consists of polyoxide.
18. A method of treating a VMAT2-mediated disorder comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
19. The method as recited in claim 18 , wherein the VMAT2-mediated disorder is a hyperkinetic movement disorder.
20. The method as recited in claim 19 , wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder.
21. The method as recited in claim 20 , wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's chorea, tardive dyskinesia, Tourette's syndrome, and a tic.
22. The method as recited in claim 18 , wherein the crystalline d 6 -tetrabenazine Form I, pharmaceutically acceptable salt, or hydrate thereof has deuterium enrichment of no less than about 90%.
23. The method as recited in claim 18 , wherein the crystalline d 6 -tetrabenazine Form I, pharmaceutically acceptable salt, or hydrate thereof has deuterium enrichment of no less than about 98%.
24. A method of treating a VMAT2-mediated disorder comprising: administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 8 .
25. The method as recited in claim 24 , wherein the VMAT2-mediated disorder is a hyperkinetic movement disorder.
26. The method as recited in claim 25 , wherein the hyperkinetic movement disorder is a chronic hyperkinetic movement disorder.
27. The method as recited in claim 26 , wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's chorea, tardive dyskinesia, Tourette's syndrome, and a tic.