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):	Andreas Sommer, Chengzhi Zhang, John Carter, John Arthur, Margaret Bradbury, Thomas Gant, Manouchehr Shahbaz
Assignee:	Auspex Pharmaceuticals Inc
Application Number:	US15/044,655
Patent Claims:	1. An extended-release pharmaceutical formulation comprising 6 to 24 mg of d6-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 d6-α-dihydrotetrabenazine and d6-β-dihydrotetrabenazine relative to α-dihydrotetrabenazine and β-dihydrotetrabenazine of the formulation comprising non-deuterated tetrabenazine. 2. The extended-release pharmaceutical formulation of claim 1, wherein said d6-tetrabenazine is (+/−)-trans-d6-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 Cmax of the total combined d6-α-dihydrotetrabenazine and d6-β-dihydrotetrabenazine of at least 50% relative to the Cmax of α-dihydrotetrabenazine and β-dihydrotetrabenazine following administration of a formulation comprising non-deuterated tetrabenazine to a subject. 6. The extended-release pharmaceutical formulation of claim 1, wherein the Cmax of the total combined d6-α-dihydrotetrabenazine and d6-β-dihydrotetrabenazine is reduced by at least 50% relative to the Cmax of α-dihydrotetrabenazine and β-dihydrotetrabenazine achieved upon administration of an immediate-release formulation of tetrabenazine that yields at least the same AUC of the total combined α-dihydrotetrabenazine and β-dihydrotetrabenazine. 7. The extended-release pharmaceutical formulation of claim 6, wherein the Cmax is reduced by at least 60%. 8. The extended-release pharmaceutical formulation of claim 6, wherein the Cmax is reduced by at least 70%. 9. The extended-release pharmaceutical formulation of claim 6, wherein the Cmax is reduced by at least 75%. 10. The extended-release pharmaceutical formulation of claim 1, comprising 7.5 mg of d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCinf of the total combined amount of d6-dihydrotetrabenazine is about 176.2±69.3 hr·ng/mL mL upon administration of the formulation to the subject. 12. The extended-release pharmaceutical formulation of claim 10, wherein the AUC(0-12) of the total combined amount of d6-dihydrotetrabenazine is about 110.2±32.1 hr·ng/mL upon administration of the formulation to the subject. 13. The extended-release pharmaceutical formulation of claim 10, wherein the Tmax of the total combined amount of d6-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 Thalf of the total combined amount of d6-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 d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCinf of the total combined amount of d6-dihydrotetrabenazine is about 408.3±147.2 hr·ng/mL upon administration of the formulation to the subject. 17. The extended-release pharmaceutical formulation of claim 15, wherein the AUC(0-12) of the total combined amount of d6-dihydrotetrabenazine is about 250.4±64.0 hr·ng/mL upon administration of the formulation to the subject. 18. The extended-release pharmaceutical formulation of claim 15, wherein the Tmax of the total combined amount of d6-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 d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCinf of the total combined amount of d6-dihydrotetrabenazine is about 610±291 hr·ng/mL upon administration of the formulation to the subject. 21. The extended-release pharmaceutical formulation of claim 19, wherein the AUC(0-12) of the total combined amount of d6-dihydrotetrabenazine is about 370±123.7 hr·ng/mL upon administration of the formulation to the subject. 22. The extended-release pharmaceutical formulation of claim 19, wherein the Tmax of the total combined amount of d6-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 d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCinf of the total combined amount of d6-dihydrotetrabenazine is about 132±47 hr·ng/mL upon administration of the formulation to the subject. 25. The extended-release pharmaceutical formulation of claim 23, wherein the AUCt of the total combined amount of d6-dihydrotetrabenazine is about 122±46 hr·ng/mL upon administration of the formulation to the subject. 26. The extended-release pharmaceutical formulation of claim 23, wherein the Tmax of the total combined amount of d6-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 d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCia of the total combined amount of d6-dihydrotetrabenazine is about 289±115 hr·ng/mL upon administration of the formulation to the subject. 29. The extended-release pharmaceutical formulation of claim 27, wherein the AUCt of the total combined amount of d6-dihydrotetrabenazine is about 279±114 hr·ng/mL upon administration of the formulation to the subject. 30. The extended-release pharmaceutical formulation of claim 27, wherein the Tmax of the total combined amount of d6-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 d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCinf of the total combined amount of d6-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 AUCt of the total combined amount of d6-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 Tmax of the total combined amount of d6-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 d6-tetrabenazine, wherein the Cmax of the total combined amount of d6-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 AUCinf of the total combined amount of d6-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 AUCt of the total combined amount of d6-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 Tmax of the total combined amount of d6-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.