Nonracemic mixtures and uses thereof

• US 10,369,134 B2
• Filed: 12/04/2018
• Issued: 08/06/2019
• Est. Priority Date: 12/05/2017
• Status: Active Grant

• Current Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Original Assignee: Sunovion Pharmaceuticals Inc. (Sumitomo Chemical Company Limited)
• Inventors: Hopkins, Seth Cabot, Koblan, Kenneth Stephen, Snoonian, John R., Wilkinson, Harold Scott
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US16/209,412
• Publication Number:
  US 20190167635A1
• Time in Patent Office: 245 Days
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61P 25/24 Antidepressants

Abstract

Provided are compositions comprising unequal mixtures of (R)-amisulpride and (S)-amisulpride, or pharmaceutically acceptable salts thereof, where the amount of (R)-amisulpride is greater than the amount of (S)-amisulpride, compositions and medicaments comprising the same used for the treatment of various diseases and disorders, and methods of using same for the treatment of various diseases and disorders, including, but not limited to, dosage regimens. In addition, provided are various formulations thereof, including, but not limited to, formulations employing polymorphs of enantiomeric amisulpride.

Claims

1. A method of alleviating bipolar disorder comprising administering to a subject in need thereof an effective amount of a composition comprising:

an amount about 85 mg to about 600 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base; and

an amount about 15 mg to about 100 mg (S)-(−

)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base;

wherein the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(−

)-amisulpride in the composition is about 65;

35 to about 88;

12 by weight of free base.

2. The method of claim 1 wherein the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(−

)-amisulpride is about 75;

25 to about 88;

12 by weight of free base.

3. The method of claim 1 wherein the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(−

)-amisulpride is about 80;

20 to about 88;

12 by weight of free base.

4. The method of claim 1 wherein the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(−

)-amisulpride is about 85;

15 by weight of free base.

5. The method of claim 1 wherein the composition comprising:

an amount about 170 mg to about 340 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base; and

an amount about 30 mg to about 60 mg (S)-(−

)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base.

6. The method of claim 1 wherein the composition comprising:

an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base; and

an amount about 30 mg of (S)-(−

)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base.

7. The method of claim 1 wherein the composition comprising:

an amount about 340 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base; and

an amount about 60 mg of (S)-(−

)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base.

8. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg or about 700 mg by weight of free base.

9. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is about 200 mg to about 600 mg by weight of free base.

10. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is about 200 mg to about 400 mg by weight of free base.

11. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is about 200 mg by weight of free base.

12. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is about 400 mg by weight of free base.

13. The method of claim 1 wherein the bipolar disorder is bipolar depression.

14. The method of claim 1 wherein the (R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal Form A;

and the (S)-(−

)-amisulpride is crystalline (S)-(−

)-amisulpride of crystal Form A′

;

wherein Form A is characterized by a powder x-ray diffraction pattern comprising peaks, in terms of 2-theta, at 7.0±

0.2°

, 9.7±

0.2°

, and 15.4±

0.2°

; and

Form A′

is characterized by a powder x-ray diffraction pattern comprising peaks, in terms of 2-theta, at 7.0±

0.2°

, 9.7±

0.2°

, and 15.4±

0.2°

.

15. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration an occupancy of dopamine D2 receptors about 20% to about 60%.

16. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration an occupancy of dopamine D2 receptors about 30% to about 50%.

17. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a decrease in REM sleep by an amount greater than 10 minutes.

18. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a decrease in REM sleep by an amount about 15 minutes to about 45 minutes.

19. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a decrease in REM sleep by an amount about 15 minutes to about 30 minutes.

20. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a latency to REM sleep by an amount greater than 20 minutes.

21. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a latency to REM sleep by an amount greater than 30 minutes.

22. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a decrease in total REM sleep time relative to total sleep time by an amount greater than 5%.

23. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration a suppression of the time in rapid eye movement (REM) sleep as characterized by a decrease in total REM sleep time relative to total sleep time by an amount greater than 6.5%.

24. The method of claim 1 wherein the composition comprising a combined amount of (R)-(+)-amisulpride and (S)-(−

)-amisulpride, or pharmaceutically acceptable salts thereof, is effective to provide in the subject after administration;

an occupancy of dopamine D2 receptors about 30% to about 50%; and

a suppression of the time in rapid eye movement (REM) sleep by an amount about 15 minutes to about 45 minutes.

25. The method of claim 1 wherein the composition is administered once daily.

26. A method of alleviating bipolar depression comprising administering once daily to a subject in need thereof an effective amount of a composition comprising:

an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base; and

an amount about 30 mg of (S)-(−

)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base.

27. The method of claim 26 wherein the (R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal Form A;

and the (S)-(−

)-amisulpride is crystalline (S)-(−

)-amisulpride of crystal Form A′

;

wherein Form A is characterized by a powder x-ray diffraction pattern comprising peaks, in terms of 2-theta, at 7.0±

0.2°

, 9.7±

0.2°

, and 15.4±

0.2°

; and

Form A′

is characterized by a powder x-ray diffraction pattern comprising peaks, in terms of 2-theta, at 7.0±

0.2°

, 9.7±

0.2°

, and 15.4±

0.2°

.

28. A method of alleviating bipolar depression comprising administering once daily to a subject in need thereof an effective amount of a composition comprising:

an amount about 340 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base; and

an amount about 60 mg of (S)-(−

)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of free base.

29. The method of claim 28 wherein the (R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal Form A;

and the (S)-(−

)-amisulpride is crystalline (S)-(−

)-amisulpride of crystal Form A′

;

wherein Form A is characterized by a powder x-ray diffraction pattern comprising peaks, in terms of 2-theta, at 7.0±

0.2°

, 9.7±

0.2°

, and 15.4±

0.2°

; and

Form A′

is characterized by a powder x-ray diffraction pattern comprising peaks, in terms of 2-theta, at 7.0±

0.2°

, 9.7±

0.2°

, and 15.4±

0.2°

.