Gamma-hydroxybutyrate compositions and their uses for the treatment of disorders

Abstract

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 - 46 . (canceled) 
     
     
         47 . A method of treating a condition responsive to gamma-hydroxybutyrate (GHB) comprising administering a pharmaceutical composition of GHB comprising a mixture of salts of GHB, wherein the mixture comprises three or four salts of GHB selected from the group consisting 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 ). 
     
     
         48 . The method of  claim 47 , wherein the condition is fibromyalgia. 
     
     
         49 . The method of  claim 47 , wherein the condition is a sleep disorder. 
     
     
         50 . The method of  claim 49 , wherein the condition the sleep disorder is selected from the group consisting of a sleep time disturbance, excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus. 
     
     
         51 . The method of  claim 50 , wherein the condition is a sleep time disturbance. 
     
     
         52 . The method of  claim 47 , wherein the pharmaceutical composition further comprises one or more of a buffering agent, sweetening agent, flavoring agent or coloring agent, in a pharmaceutically acceptable carrier. 
     
     
         53 . The method of  claim 47 , wherein the mixture comprises Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2 . 
     
     
         54 . The method of  claim 47 , wherein the Na.GHB salt is present in a wt/wt % of about 5% to about 40%, the K.GHB salt is present in a wt/wt % of about 10% to about 40%, the Mg.(GHB) 2  salt is present in a wt/wt % of about 5% to about 30%, and the Ca.(GHB) 2  salt is present in a wt/wt % of about 20% to about 80%. 
     
     
         55 . The method of  claim 47 , wherein the Na.GHB salt is present in a % molar equivalents of about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%. 
     
     
         56 . The method of  claim 47 , wherein the K.GHB salt is present in a % molar equivalents of about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40%. 
     
     
         57 . The method of  claim 47 , wherein the Mg.(GHB) 2  salt is present in a % molar equivalents of about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30%. 
     
     
         58 . The method of  claim 47 , wherein the Ca.(GHB) 2  salt is present in a % molar equivalents of about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, or about 75% to about 80%. 
     
     
         59 . The method of  claim 47 , wherein the Na.GHB, K.GHB, Mg.(GHB) 2 , and Ca.(GHB) 2  salts are present in a % molar equivalents ratio of about 8:23:21:48, respectively. 
     
     
         60 . The method of  claim 47 , wherein the pharmaceutical composition of GHB comprises 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. 
     
     
         61 . The method of  claim 60 , wherein the composition has a pH of about 7.3 to about 8.5. 
     
     
         62 . The method of  claim 60 , wherein the total concentration of the GHB is between 300 mg/ml to 750 mg/ml. 
     
     
         63 . The method of  claim 60 , wherein the total concentration of the GHB is between 400 mg/ml to 600 mg/ml. 
     
     
         64 . The method of  claim 47 , wherein the total concentration of the mixture of salts of GHB in the solution is about 500 mg/ml. 
     
     
         65 . The method of  claim 47 , wherein the pharmaceutical composition of GHB is formulated as a liquid formulation. 
     
     
         66 . The method of  claim 47 , wherein the pharmaceutical composition of GHB is formulated as a solid formulation. 
     
     
         67 . The method of  claim 47 , wherein the administration is an oral administration. 
     
     
         68 . A method of treating a condition responsive to gamma-hydroxybutyrate (GHB) comprising administering a pharmaceutical composition of GHB and at least three or four cations selected from the group consisting of sodium, potassium, magnesium and calcium. 
     
     
         69 . The method of  claim 68 , wherein the condition is a sleep disorder. 
     
     
         70 . The method of  claim 69 , wherein the condition the sleep disorder is selected from the group consisting of a sleep time disturbance, excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus. 
     
     
         71 . The method of  claim 68 , wherein the pharmaceutical composition further comprises one or more of a buffering agent, sweetening agent, flavoring agent or coloring agent, in a pharmaceutically acceptable carrier. 
     
     
         72 . The method of  claim 68 , wherein the pharmaceutical composition of GHB comprises an aqueous solution of about 400 mg/mL to about 600 mg/mL of GHB. 
     
     
         73 . The method of  claim 68 , comprising administering a pharmaceutical composition of GHB and four cations selected from the group consisting of sodium, potassium, magnesium and calcium. 
     
     
         74 . The method of  claim 68 , wherein the cations are present in a % molar equivalents ratio of about 8:23:21:48, for sodium, potassium, magnesium and calcium, respectively. 
     
     
         75 . The method of  claim 68 , wherein the pharmaceutical composition of GHB is formulated as a liquid formulation. 
     
     
         76 . The method of  claim 68 , wherein the pharmaceutical composition of GHB is formulated as a solid formulation.