Nonracemic mixtures and uses thereof
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.
1. A liquid pharmaceutical composition comprising:
one or more pharmaceutically acceptable excipients; and
an aqueous solution comprising an unequal mixture of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, with a combined amount that is about 5 mg/mL to about 200 mg/mL, wherein the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 65:35 to about 88:12 by weight of free base.
2. The liquid pharmaceutical composition of claim 1 , wherein the liquid pharmaceutical composition is provided in a liquid oral dosage form.
3. The liquid pharmaceutical composition of claim 1 , wherein the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 75:25 to about 88:12 by weight of free base.
4. The liquid pharmaceutical composition of claim 1 , wherein the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 80:20 to about 88:12 by weight of free base.
5. The liquid pharmaceutical composition of claim 1 , wherein the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 85:15 by weight of free base.
6. The liquid pharmaceutical composition of claim 1 , wherein the combined amount is about 10 mg/mL, 15 mg/mL, 20 mg/mL, 30 mg/mL, 33 mg/mL, 35 mg/mL, or 100 mg/mL.
7. The liquid pharmaceutical composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprise:
a buffer; and
a sweetener comprising about 2% to about 60% of the total weight of the aqueous solution.
8. The liquid pharmaceutical composition of claim 7 , wherein the buffer comprises citric acid.
9. The liquid pharmaceutical composition of claim 8 , wherein the buffer comprises citric acid in an amount sufficient to maintain the pH of the aqueous solution between 3 to 5.
10. The liquid pharmaceutical composition of claim 7 , wherein the sweetener comprises one or more of glycerin and sucralose.
11. The liquid pharmaceutical composition of claim 7 , further comprising a preservative.
12. The liquid pharmaceutical composition of claim 11 , wherein the preservative comprises sodium benzoate.
13. A method of alleviating bipolar disorder comprising administering to a subject in need thereof a liquid pharmaceutical composition comprising:
one or more pharmaceutically acceptable excipients; and
an aqueous solution comprising an unequal mixture of (R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, with a combined amount that is about 5 mg/mL to about 200 mg/mL, wherein the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 65:35 to about 88:12 by weight of free base.
14. The method of claim 13 , wherein the bipolar disorder is bipolar depression.
15. The method of claim 13 , wherein the liquid pharmaceutical composition comprising a combined amount of (R)-(+)-amisulpride, or pharmaceutically acceptable salts thereof, 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 13 , wherein the liquid pharmaceutical composition comprising a combined amount of (R)-(+)-amisulpride, or pharmaceutically acceptable salts thereof, 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 13 , wherein the liquid pharmaceutical composition comprising a combined amount of (R)-(+)-amisulpride, or pharmaceutically acceptable salts thereof, 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 13 , wherein the liquid pharmaceutical composition comprising a combined amount of (R)-(+)-amisulpride, or pharmaceutically acceptable salts thereof, 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 that is about 15 to about 45 minutes.
19. The method of claim 13 , wherein the combined amount is about 10 mg/mL, 15 mg/mL, 20 mg/mL, 30 mg/mL, or 35 mg/mL.
20. The method of claim 13 , wherein the liquid pharmaceutical composition is administered to the subject as a dosage unit form comprising about 100 mg, about 200 mg, about 300 mg, or about 400 mg of a combined amount of (R)-(+)-amisulpride, or pharmaceutically acceptable salts thereof, and (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, by weight of free base.