Gamma-hydroxybutyrate compositions and their use 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 . A pharmaceutical composition of gamma-hydroxybutyrate comprising a mixture of two or more salts of gamma-hydroxybutyrate (GHB), wherein the mixture comprises between about 50% to about 80% of a sodium salt of gamma-hydroxybutyrate (Na.GHB) and further comprises one or more of a potassium salt of gamma-hydroxybutyrate (K.GHB) and a calcium salt of gamma-hydroxybutyrate (Ca.(GHB) 2 ). 
     
     
         2 . (canceled) 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the mixture comprises about 50% to about 70% Na.GHB. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the mixture comprises about 50% to about 60% Na.GHB. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the mixture comprises about 50% to about 55% Na.GHB. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the composition does not have a substantial amount of a magnesium salt of gamma-hydroxybutyrate (Mg.(GHB) 2 ) or a calcium salt of gamma-hydroxybutyrate (Ca.(GHB) 2 ). 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the composition is an aqueous solution having a volume of about 25 mL to about 100 mL. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the composition is an aqueous solution having a volume of about 40 mL to about 75 mL. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the composition is an aqueous solution having a volume of about 55 mL to about 65 mL. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the composition comprises a mixture of three or more salts of GHB, wherein the mixture comprises of between 50% to 80% Na.GHB, between 10% to 40% K.GHB, and between 10% and 20% Ca.(GHB) 2 . 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the composition is bioequivalent to a pharmaceutical composition comprising about 100% Na.GHB when administered to a patient. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the average maximum GHB plasma concentration (Cmax) is within 10% of the Cmax of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the average maximum GHB plasma area under the curve (AUC) is within 10% of the AUC of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the composition comprises a mixture of three salts of GHB, wherein the mixture comprises at least 50% Na.GHB, and further comprises K.GHB and Ca.(GHB) 2 . 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the composition comprises between 50% and 60% of Na.GHB, between 20% and 40% K.GHB, and between 10% and 20% Ca.(GHB) 2 . 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the mixture comprises about 50% Na.GHB, about 34% K.GHB, and about 16% Ca.(GHB) 2 . 
     
     
         17 . A pharmaceutical composition of GHB comprising less than 100 mL of an aqueous solution, wherein the aqueous solution comprises a mixture of two or more salts of GHB, the mixture comprising about 40% to about 50% Na.GHB, and further comprising one or more salts selected from K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 . 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the Cmax is within 10% of the Cmax of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the aqueous solution has a volume of about 25 mL to about 75 mL. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the aqueous solution has a volume of about 55 mL to about 65 mL. 
     
     
         21 . The pharmaceutical composition of  claim 17 , wherein the aqueous solution has a volume of about 60 mL. 
     
     
         22 . The pharmaceutical composition of  claim 17 , wherein the composition comprises Na.GHB and K.GHB. 
     
     
         23 . The pharmaceutical composition of  claim 17 , wherein the composition is formulated as a liquid formulation. 
     
     
         24 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is bioequivalent to a pharmaceutical composition comprising about 100% Na.GHB when administered to a patient. 
     
     
         25 . The pharmaceutical composition of  claim 17 , wherein the AUC is within 10% of the AUC of a pharmaceutical composition comprising about the same amount of 100% Na.GHB when administered to a patient. 
     
     
         26 . The pharmaceutical composition of  claim 17 , wherein the composition does not comprise a substantial amount of Mg.(GHB) 2  or Ca.(GHB) 2 . 
     
     
         27 . A method for treating a disease or condition in a patient that is suitable to treatment by GHB, comprising administering the pharmaceutical composition of  claim 1  to the patient. 
     
     
         28 . The method according to  claim 27 , wherein the disease is cataplexy or narcolepsy. 
     
     
         29 . A method of treating a patient who is in need of GHB comprising administering to the patient two nightly doses of GHB or a salt thereof, wherein the first dose comprises a pharmaceutical composition comprising less than 40% Na.GHB and at least two other GHB salts selected from the group of K.GHB, Ca.(GHB) 2 , and Mg.(GHB) 2 , and the second dose comprises the pharmaceutical composition of  claim 1 . 
     
     
         30 . The method of  claim 29 , wherein the first dose is administered within 4 hours of eating.