High dosage valbenazine formulation and compositions, methods, and kits related thereto

1. A unit dosage form comprising:

(S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate;

silicified microcrystalline cellulose;

isomalt;

hydroxypropyl methylcellulose;

partially pregelatinized maize starch; and

magnesium stearate;

wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level ranging from about 20 mg to 160 mg as measured as the free base, and

(S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of at least 30% by weight of the total weight of the unit dosage form.

2. The unit dosage form of claim 1 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 20 mg as measured as the free base.

3. The unit dosage form of claim 1 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 40 mg as measured as the free base.

4. The unit dosage form of claim 1 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 60 mg as measured as the free base.

5. The unit dosage form of claim 1 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 80 mg as measured as the free base.

6. The unit dosage form of claim 1 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 100 mg as measured as the free base.

7. The unit dosage form of claim 1 , wherein the unit dosage form is suitable for oral administration.

8. The unit dosage form of claim 1 , wherein the unit dosage form is formulated for dosing once daily.

9. The unit dosage form of claim 1 , wherein the unit dosage form is in a capsule form.

10. The unit dosage form of claim 9 , wherein the capsule is a size 3 capsule or smaller.

11. The unit dosage form of claim 9 , wherein the capsule is a size 2 capsule or smaller.

12. The unit dosage form of claim 9 , wherein the capsule is a size 1 capsule or smaller.

13. The unit dosage form of claim 9 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 40 mg as measured as the free base and the capsule is a size 2 capsule or smaller.

14. The unit dosage form of claim 9 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 60 mg as measured as the free base and the capsule is a size 2 capsule or smaller.

15. The unit dosage form of claim 9 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate is present at a level of about 80 mg as measured as the free base and the capsule is a size 1 capsule or smaller.

16. The unit dosage form of claim 1 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate has a d(0.9) particle size distribution less than 100 μm.

17. The unit dosage form of claim 1 , wherein said dosage form comprises:

about 40 wt % of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate;

about 25 wt % of silicified microcrystalline cellulose;

about 20 wt % of isomalt;

about 5 wt % of hydroxypropyl methylcellulose;

about 7.5 wt % of partially pregelatinized maize starch;

about 2.5 wt % of magnesium stearate; and

the unit dosage form is in a capsule form that is a size 1 capsule or smaller.

18. The unit dosage form of claim 17 , wherein the capsule is a size 2 capsule or smaller.

19. The unit dosage form of claim 17 , wherein the unit dosage form is suitable for oral administration.

20. The unit dosage form of claim 17 , wherein the unit dosage form is formulated for dosing once daily.

21. The unit dosage form of claim 17 , wherein (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate has a d(0.9) particle size distribution less than 100 μm.

22. A method of treating a hyperkinetic movement disorder in a patient in need thereof, comprising administering to the patient the unit dosage form of claim 1 .

23. The method according to claim 22 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

24. The method according to claim 22 , wherein the hyperkinetic movement disorder is chorea.

25. The method according to claim 24 , wherein chorea is associated with Huntington's disease.

26. A method of treating a hyperkinetic movement disorder in a patient in need thereof, comprising administering to the patient the unit dosage form of claim 17 .

27. The method according to claim 26 , wherein the hyperkinetic movement disorder is tardive dyskinesia.

28. The method according to claim 26 , wherein the hyperkinetic movement disorder is chorea.

29. The method according to claim 28 , wherein chorea is associated with Huntington's disease.