Solid ganaxolone compositions and methods for the making and use thereof

Abstract

In certain embodiments, the invention is directed to composition comprising stable particles comprising ganaxolone, wherein the volume weighted median diameter (D50) of the particles is from about 50 nm to about 500 nm.

1 - 52 . (canceled) 
     
     
         53 . An aqueous injectable ganaxolone formulation comprising
 a) ganaxolone and a water soluble beta cyclodextrin; and   b) water.   
     
     
         54 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the water soluble beta cyclodextrin is selected from the group consisting of beta-sulfobutyl-cyclodextrin, 2-hydroxypropylbetacyclodextrin, and a combination thereof. 
     
     
         55 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the water soluble beta cyclodextrin is beta-sulfobutyl-cyclodextrin. 
     
     
         56 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the water soluble beta cyclodextrin is 2-hydroxypropylbetacyclodextrin. 
     
     
         57 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the ganaxolone is dissolved in the formulation at a concentration greater than 1 mg/ml. 
     
     
         58 . The aqueous injectable ganaxolone formulation of  claim 53 , further comprising a surfactant. 
     
     
         59 . The aqueous injectable ganaxolone formulation of  claim 58 , wherein the surfactant is included in an amount effective to provide proper fluidity to the formulation. 
     
     
         60 . The aqueous injectable ganaxolone formulation of  claim 58 , further comprising an agent selected from the group considering of parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, and sorbic acid. 
     
     
         61 . The aqueous injectable ganaxolone formulation of  claim 53 , further comprising a carrier selected from the group consisting of water, ethanol, polylols, and mixtures thereof. 
     
     
         62 . The aqueous injectable ganaxolone formulation of  claim 53 , which maintains a therapeutically effective amount of ganaxolone of at least 20 ng/ml in plasma at steady state. 
     
     
         63 . The aqueous injectable ganaxolone formulation of  claim 53 , which maintains a therapeutically effective amount of ganaxolone of at least about 50 ng/ml in plasma at steady state while reducing the side effects associated with an elevated Cmax blood plasma level of ganaxolone. 
     
     
         64 . The aqueous injectable ganaxolone formulation of  claim 53 , which provides Cmin ganaxolone blood plasma levels at steady state from about 10 ng/ml to about 100 ng/ml. 
     
     
         65 . The aqueous injectable ganaxolone formulation of  claim 53 , which provides Cmin ganaxolone blood plasma levels at steady state from about 40 ng/ml to about 75 ng/ml. 
     
     
         66 . The aqueous injectable ganaxolone formulation of  claim 53 , further comprising an isotonic agent. 
     
     
         67 . The aqueous injectable ganaxolone formulation of  claim 66 , wherein the isotonic agent is a sugar. 
     
     
         68 . The aqueous injectable ganaxolone formulation of  claim 66 , wherein the isotonic agent is a sodium chloride. 
     
     
         69 . The aqueous injectable ganaxolone formulation of  claim 53 , further comprising an additive selected from the group consisting of a preserving agent and a wetting agent. 
     
     
         70 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the formulation is an intravenous formulation. 
     
     
         71 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the formulation is an intramuscular formulation. 
     
     
         72 . The aqueous injectable ganaxolone formulation of  claim 53 , wherein the formulation is a subcutaneous formulation. 
     
     
         73 . A method of treating a human patient having a central-nervous system disease or disorder, comprising administering to the human patient the aqueous injectable ganaxolone formulation of  claim 53 . 
     
     
         74 . A method of treating a human patient having epileptic seizures, comprising administering to the human patient the aqueous injectable ganaxolone formulation of  claim 53 . 
     
     
         75 . The method of  claim 74 , wherein the epileptic seizures are selected from the group consisting of tonic-clonic (Grand Mal), partial (Focal) seizures, catamenial seizures, acute repetitive seizure, psychomotor (complex partial) seizures, absence (Petit Mal) seizure, and myoclonic seizures. 
     
     
         76 . A method of treating a human patient suffering from a convulsive state selected from the group consisting of status epilepticus, epileptic seizures and spasms, comprising administering to the human patient therapeutically effective amounts of the aqueous injectable ganaxolone formulation of  claim 53 . 
     
     
         77 . The method of  claim 76 , wherein the spasms are Infantile Spasms. 
     
     
         78 . The method of  claim 73 , further comprising administering a second therapeutic agent selected from the group consisting at least one other anti-epileptic agent, at least one anti-anxiety agent, and at least one other anti-depression agent. 
     
     
         79 . A method of treating a human patient suffering from a convulsive state selected from the group consisting of status epilepticus, epileptic seizures and spasms, comprising maintaining a therapeutically effective amount of ganaxolone of at least 20 ng/ml in plasma at steady state while reducing the side effects associated with an elevated Cmax blood plasma level of ganaxolone by administering to the human patient therapeutically effective amounts of an aqueous injectable ganaxolone formulation comprising ganaxolone, a water soluble beta cyclodextrin, and water. 
     
     
         80 . The method of  claim 79 , wherein the administration of the aqueous injectable ganaxolone formulation provides a ganaxolone level of about 50 mg/ml in the plasma of the human patient at steady state. 
     
     
         81 . The method of  claim 79 , wherein the water soluble beta cyclodextrin is selected from the group consisting of beta-sulfobutyl-cyclodextrin, 2-hydroxypropylbetacyclodextrin, and a combination thereof. 
     
     
         82 . The aqueous injectable ganaxolone formulation of  claim 79 , further comprising a surfactant. 
     
     
         83 . The method of  claim 79 , wherein the human patient is suffering from epileptic seizures selected from the group consisting of tonic-clonic (Grand Mal), partial (Focal) seizures, catamenial seizures, acute repetitive seizure, psychomotor (complex partial) seizures, absence (Petit Mal) seizure, and myoclonic seizures. 
     
     
         84 . A method of treating a human patient having a central-nervous system disease or disorder, comprising maintaining a therapeutically effective amount of ganaxolone of at least 20 ng/ml in plasma at steady state while reducing the side effects associated with an elevated Cmax blood plasma level of ganaxolone by administering to the human patient therapeutically effective amounts of an aqueous injectable ganaxolone formulation comprising ganaxolone, a water soluble beta cyclodextrin, and water.