Gamma-hydroxybutyrate compositions and their use for the treatment of disorders
View Patent ↗Provided herein are pharmaceutical compositions and formulations comprising mixed salts of gamma-hydroxybutyrate (GHB). Also provided herein are methods of making the pharmaceutical compositions and formulations, and methods of their use for the treatment of sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.
1. A pharmaceutical composition of gamma-hydroxybutyrate (GHB) comprising a mixture of salts of GHB, wherein the mixture consists of a sodium salt of gamma-hydroxybutyrate (Na.GHB), a potassium salt of gamma-hydroxybutyrate (K.GHB), a magnesium salt of gamma-hydroxybutyrate (Mg.(GHB) 2 ), and a calcium salt of gamma-hydroxybutyrate (Ca.(GHB) 2 ); and optionally, one or more of a buffering agent, sweetening agent, flavoring agent or coloring agent, in a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable carrier comprises more of a solvent, dispersion medium, coating, antibacterial agent, antifungal agent, isotonic agent, or absorption delaying agent.
3. The pharmaceutical composition of claim 2 , wherein the Na.GHB salt is present in a wt/wt % of 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%.
4. The pharmaceutical composition of claim 2 , wherein the K.GHB salt is present in a wt/wt % of 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%.
5. The pharmaceutical composition of claim 2 , wherein the Mg.(GHB) 2 salt is present in a wt/wt % of 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%.
6. The pharmaceutical composition of claim 2 , wherein the Ca.(GHB) 2 salt is present in a wt/wt % of 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to about 75%, or 75% to 80%.
7. The pharmaceutical composition of claim 2 , wherein the Na.GHB salt is present in a wt/wt % of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%.
8. The pharmaceutical composition of claim 2 , wherein the K.GHB salt is present in a wt/wt % of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%.
9. The pharmaceutical composition of claim 2 , wherein the Mg.(GHB) 2 salt is present in a wt/wt % of about 5%, about 10%, about 15%, about 20%, about 25%, or about 30%.
10. The pharmaceutical composition of claim 2 , wherein the Ca.(GHB) 2 salt is present in a wt/wt % of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%.
11. The pharmaceutical composition of claim 2 , wherein the Na.GHB salt is present in a wt/wt % of 5% to 40%, the K.GHB salt is present in a wt/wt % of 10% to 40%, the Mg(GHB) 2 salt is present in a wt/wt % of 5% to 30%, and the Ca.(GHB) 2 salt is present in a wt/wt % of 20% to 80%.
12. The pharmaceutical composition of claim 2 , wherein the Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 salts are present in a wt/wt % ratio of about 8%:32%:20%:40%, respectively.
13. The pharmaceutical composition of claim 2 , wherein the Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 salts are present in a wt/wt % ratio of about 29%:31%:13%:27%, respectively.
14. The pharmaceutical composition of claim 2 , wherein the Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 salts are present in a wt/wt % ratio of about 8%:23%:21%:48%, respectively.
15. The pharmaceutical composition of claim 2 , wherein the solvent comprises one or more of water, ethanol, polyol, or vegetable oil.
16. The pharmaceutical composition of claim 15 , wherein the Na.GHB salt is present in a wt/wt % of 5% to 40%, the K.GHB salt is present in a wt/wt % of 10% to 40%, and the Ca.(GHB) 2 salt is present in a wt/wt % of 20% to 80%.
17. The pharmaceutical composition of claim 15 , wherein the Na.GHB, K.GHB, and Ca.(GHB) 2 salts are present in a wt/wt % ratio of about 11%:39%:50%, respectively.
18. The pharmaceutical composition of claim 15 , wherein the polyol is one or more of glycerol, propylene glycol, or liquid polyethylene glycol.
19. The pharmaceutical composition of claim 1 , wherein the K.GHB salt is present in a wt/wt % of 10% to 50%, the Mg.(GHB) 2 salt is present in a wt/wt % of 20% to 60%, and the Ca.(GHB) 2 salt is present in a wt/wt % of 10% to 40%.
20. The pharmaceutical composition of claim 19 , wherein the K.GHB, Mg.(GHB) 2 and Ca.(GHB) 2 salts are present in a wt/wt % ratio of about 33%:42%:25%, respectively.
21. The pharmaceutical composition of claim 1 , comprising an aqueous solution of about 250 mg/mL to about 750 mg/mL of the mixture of salts of GHB, wherein the composition has a pH of about 7.0 to about 9.0, wherein the composition is chemically stable and resistant to microbial growth, and wherein the composition is free of preservatives.
22. The pharmaceutical composition of claim 21 , wherein the composition has a pH of about 7.3 to about 8.5.
23. The pharmaceutical composition of claim 21 , wherein the composition additionally comprises a pH adjusting or buffering agent.
24. The pharmaceutical composition of claim 23 , wherein the pH adjusting or buffering agent is an acid.
25. The pharmaceutical composition of claim 24 , wherein the acid is an inorganic acid or an organic acid, wherein the acid is selected from the group consisting of malic acid, citric acid, acetic acid, boric acid, lactic acid, hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, and nitric acid.
26. The pharmaceutical composition of claim 25 , wherein the acid is malic acid.
27. The pharmaceutical composition of claim 1 , wherein the composition is formulated as a liquid formulation.
28. The formulation of claim 27 , wherein the formulation is chemically stable and resistant to microbial growth, and wherein the formulation is free of preservatives.
29. The formulation of claim 27 , which is suitable for oral administration.