Claims for Patent: 9,814,708

Summary for Patent: 9,814,708

Title:	Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
Abstract:	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.
Inventor(s):	Sommer; Andreas (Carlsbad, CA), Zhang; Chengzhi (San Diego, CA), Carter; John (Vista, CA), Arthur; John (Vista, CA), Bradbury; Margaret (Vista, CA), Gant; Thomas (Carlsbad, CA), Shahbaz; Manouchehr (San Diego, CA)
Assignee:	Auspex Pharmaceuticals, Inc. (Frazer, PA)
Application Number:	15/044,655
Patent Claims:	1. An extended-release pharmaceutical formulation comprising 6 to 24 mg of d.sub.6-tetrabenazine and between about 5% and about 20% by weight, based on the weight of the formulation, of a poly(ethylene oxide) polymer, wherein upon administration to a subject: the formulation provides a reduction in dose relative to a formulation comprising non-deuterated tetrabenazine; and maintains at least the same AUC of the total combined amount of d.sub.6-.alpha.-dihydrotetrabenazine and d.sub.6-.beta.-dihydrotetrabenazine relative to .alpha.-dihydrotetrabenazine and .beta.-dihydrotetrabenazine of the formulation comprising non-deuterated tetrabenazine. 2. The extended-release pharmaceutical formulation of claim 1, wherein said d.sub.6-tetrabenazine is (+/-)-trans-d.sub.6-tetrabenazine. 3. The extended-release pharmaceutical formulation of claim 1, wherein the said reduction in dose is at least 30%. 4. The extended-release pharmaceutical formulation of claim 1, wherein said reduction in dose is at least 40%. 5. The extended-release pharmaceutical formulation of claim 1, wherein the formulation provides a reduction in C.sub.max of the total combined d.sub.6-.alpha.-dihydrotetrabenazine and d.sub.6-.beta.-dihydrotetrabenazine of at least 50% relative to the C.sub.max of .alpha.-dihydrotetrabenazine and .beta.-dihydrotetrabenazine following administration of a formulation comprising non-deuterated tetrabenazine to a subject. 6. The extended-release pharmaceutical formulation of claim 1, wherein the C.sub.max of the total combined d.sub.6-.alpha.-dihydrotetrabenazine and d.sub.6-.beta.-dihydrotetrabenazine is reduced by at least 50% relative to the C.sub.max of .alpha.-dihydrotetrabenazine and .beta.-dihydrotetrabenazine achieved upon administration of an immediate-release formulation of tetrabenazine that yields at least the same AUC of the total combined .alpha.-dihydrotetrabenazine and .beta.-dihydrotetrabenazine. 7. The extended-release pharmaceutical formulation of claim 6, wherein the C.sub.max is reduced by at least 60%. 8. The extended-release pharmaceutical formulation of claim 6, wherein the C.sub.max is reduced by at least 70%. 9. The extended-release pharmaceutical formulation of claim 6, wherein the C.sub.max is reduced by at least 75%. 10. The extended-release pharmaceutical formulation of claim 1, comprising 7.5 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 21.37.+-.6.78 ng/mL upon administration of the formulation to the subject. 11. The extended-release pharmaceutical formulation of claim 10, wherein the AUC.sub.inf of the total combined amount of d.sub.6-dihydrotetrabenazine is about 176.2.+-.69.3 hrng/mL mL upon administration of the formulation to the subject. 12. The extended-release pharmaceutical formulation of claim 10, wherein the AUC.sub.(0-12) of the total combined amount of d.sub.6-dihydrotetrabenazine is about 110.2.+-.32.1 hrng/mL upon administration of the formulation to the subject. 13. The extended-release pharmaceutical formulation of claim 10, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.17.+-.0.68 hr upon administration of the formulation to the subject. 14. The extended-release pharmaceutical formulation of claim 10, wherein the T.sub.half of the total combined amount of d.sub.6-dihydrotetrabenazine is about 7.18.+-.1.35 hr upon administration of the formulation to the subject. 15. The extended-release pharmaceutical formulation of claim 1, comprising 15 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 45.33.+-.8.31 ng/mL upon administration of the formulation to the subject. 16. The extended-release pharmaceutical formulation of claim 15, wherein the AUC.sub.inf of the total combined amount of d.sub.6-dihydrotetrabenazine is about 408.3.+-.147.2 hrng/mL upon administration of the formulation to the subject. 17. The extended-release pharmaceutical formulation of claim 15, wherein the AUC.sub.(0-12) of the total combined amount of d.sub.6-dihydrotetrabenazine is about 250.4.+-.64.0 hrng/mL upon administration of the formulation to the subject. 18. The extended-release pharmaceutical formulation of claim 15, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.21.+-.0.45 hr upon administration of the formulation to the subject. 19. The extended-release pharmaceutical formulation of claim 1, comprising 22.5 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 67.49.+-.16.72 ng/mL upon administration of the formulation to the subject. 20. The extended-release pharmaceutical formulation of claim 19, wherein the AUC.sub.inf of the total combined amount of d.sub.6-dihydrotetrabenazine is about 610.+-.291 hrng/mL upon administration of the formulation to the subject. 21. The extended-release pharmaceutical formulation of claim 19, wherein the AUC.sub.(0-12) of the total combined amount of d.sub.6-dihydrotetrabenazine is about 370.+-.123.7 hrng/mL upon administration of the formulation to the subject. 22. The extended-release pharmaceutical formulation of claim 19, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.79.+-.0.84 hr upon administration of the formulation to the subject. 23. The extended-release pharmaceutical formulation of claim 1, comprising 6 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 15.5.+-.3.5 ng/mL upon administration of the formulation to the subject with food. 24. The extended-release pharmaceutical formulation of claim 23, wherein the AUC.sub.inf of the total combined amount of d.sub.6-dihydrotetrabenazine is about 132.+-.47 hrng/mL upon administration of the formulation to the subject. 25. The extended-release pharmaceutical formulation of claim 23, wherein the AUC.sub.t of the total combined amount of d.sub.6-dihydrotetrabenazine is about 122.+-.46 hrng/mL upon administration of the formulation to the subject. 26. The extended-release pharmaceutical formulation of claim 23, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.74.+-.0.99 hr upon administration of the formulation to the subject. 27. The extended-release pharmaceutical formulation of claim 1, comprising 12 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 32.1.+-.8.1 ng/mL upon administration of the formulation to the subject with food. 28. The extended-release pharmaceutical formulation of claim 27, wherein the AUC.sub.ia of the total combined amount of d.sub.6-dihydrotetrabenazine is about 289.+-.115 hrng/mL upon administration of the formulation to the subject. 29. The extended-release pharmaceutical formulation of claim 27, wherein the AUC.sub.t of the total combined amount of d.sub.6-dihydrotetrabenazine is about 279.+-.114 hrng/mL upon administration of the formulation to the subject. 30. The extended-release pharmaceutical formulation of claim 27, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.90.+-.1.27 hr upon administration of the formulation to the subject. 31. The extended-release pharmaceutical formulation of claim 1, comprising 18 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 47.8.+-.12 ng/mL upon administration of the formulation to the subject with food. 32. The extended-release pharmaceutical formulation of claim 31, wherein the AUC.sub.inf of the total combined amount of d.sub.6-dihydrotetrabenazine is about 419.+-.165 hr*ng/mL upon administration of the formulation to the subject. 33. The extended-release pharmaceutical formulation of claim 31, wherein the AUC.sub.t of the total combined amount of d.sub.6-dihydrotetrabenazine is about 407.+-.163 hr*ng/mL upon administration of the formulation to the subject. 34. The extended-release pharmaceutical formulation of claim 31, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.63.+-.0.85 hr upon administration of the formulation to the subject. 35. The extended-release pharmaceutical formulation of claim 1, comprising 24 mg of d.sub.6-tetrabenazine, wherein the C.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 60.9.+-.13.8 ng/mL upon administration of the formulation to the subject with food. 36. The extended-release pharmaceutical formulation of claim 35, wherein the AUC.sub.inf of the total combined amount of d.sub.6-dihydrotetrabenazine is about 580.+-.229 hr*ng/mL upon administration of the formulation to the subject. 37. The extended-release pharmaceutical formulation of claim 35, wherein the AUC.sub.t of the total combined amount of d.sub.6-dihydrotetrabenazine is about 569.+-.225 hr*ng/mL upon administration of the formulation to the subject. 38. The extended-release pharmaceutical formulation of claim 35, wherein the T.sub.max of the total combined amount of d.sub.6-dihydrotetrabenazine is about 3.92.+-.1.19 hr upon administration of the formulation to the subject. 39. The extended-release pharmaceutical formulation of claim 1, comprising between about 10% and about 20% by weight, based on the weight of the formulation, of the poly(ethylene oxide) polymer.