Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2

Patent metadata

Field	Value
Publication number	US-9814708-B2
Application number	US-201615044655-A
Country	US
Kind code	B2
Filing date	Feb 16, 2016
Priority date	Sep 18, 2012
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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.

First claim

What is claimed is:

1. An extended-release pharmaceutical formulation comprising 6 to 24 mg of d 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 6 -α-dihydrotetrabenazine and d 6 -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 d 6 -tetrabenazine is (+/−)-trans-d 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 max of the total combined d 6 -α-dihydrotetrabenazine and d 6 -β-dihydrotetrabenazine of at least 50% relative to the C max 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 C max of the total combined d 6 -α-dihydrotetrabenazine and d 6 -β-dihydrotetrabenazine is reduced by at least 50% relative to the C max 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 C max is reduced by at least 60%.

8. The extended-release pharmaceutical formulation of claim 6 , wherein the C max is reduced by at least 70%.

9. The extended-release pharmaceutical formulation of claim 6 , wherein the C max is reduced by at least 75%.

10. The extended-release pharmaceutical formulation of claim 1 , comprising 7.5 mg of d 6 -tetrabenazine, wherein the C max of the total combined amount of d 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 inf of the total combined amount of d 6 -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 d 6 -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 T max of the total combined amount of d 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 half of the total combined amount of d 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 6 -tetrabenazine, wherein the C max of the total combined amount of d 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 inf of the total combined amount of d 6 -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 d 6 -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 T max of the total combined amount of d 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 6 -tetrabenazine, wherein the C max of the total combined amount of d 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 inf of the total combined amount of d 6 -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 d 6 -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 T max of the total combined amount of d 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 6 -tetrabenazine, wherein the C max of the total combined amount of d 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 inf of the total combined amount of d 6 -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 AUC t of the total combined amount of d 6 -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 T max of the total combined amount of d 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 6 -tetrabenazine, wherein the C max of the total combined amount of d 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 ia of the total combined amount of d 6 -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 AUC t of the total combined amount of d 6 -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 T max of the total combined amount of d 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 6 -tetrabenazine, wherein the C max of the total combined amount of d 6 -dihydrotetrabenazine is about 47.8±12 ng/mL upon administration of the formula

Assignees

• Auspex Pharmaceuticals Inc

Inventors

• Sommer Andreas
• Zhang Chengzhi
• Carter John
• Arthur John
• Bradbury Margaret
• Gant Thomas
• Shahbaz Manouchehr

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61K9/288

  Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/282) · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title