Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

Abstract

Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.

What is claimed is: 
     
         1 . A formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein the immediate release portion comprises particles comprising one or more salts of gamma-hydroxybutyrate and the modified release portion comprises particles comprising one or more salts of gamma-hydroxybutyrate, wherein the particles of the modified release portion are coated with a coating comprising:
 a polymer carrying free carboxylic groups, and   a hydrophobic compound having a melting point equal or greater than 40° C.,   
       wherein the formulation is suitable for administration to a human only once nightly, and 
       wherein the formulation induces sleep for at least 6 consecutive hours. 
     
     
         2 . The formulation of  claim 1 , wherein the one or more salts of gamma-hydroxybutyrate comprises at least one of a sodium salt of gamma-hydroxybutyric acid, a potassium salt of gamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid, a magnesium salt of gamma-hydroxybutyric acid, a lithium salt of gamma-hydroxybutyric acid, and a tetra-ammonium salt of gamma-hydroxybutyric acid. 
     
     
         3 . The formulation of  claim 1 , wherein the one or more salts of gamma-hydroxybutyrate in the immediate release portion and the one or more salts of gamma-hydroxybutyrate in the modified release portion are the same salt or same mixtures thereof. 
     
     
         4 . The formulation of  claim 1 , wherein the one or more salts of gamma-hydroxybutyrate in the immediate release portion and the one or more salts of gamma-hydroxybutyrate in the modified release portion are different salts or different mixtures thereof. 
     
     
         5 . The formulation of  claim 1 , wherein the hydrophobic compound is selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, wax yellow, wax white, wax microcrystalline, lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogol glycerides, polyglyceryl diisostearate, diesters or triesters of glycerol with a fatty acid, and mixtures thereof. 
     
     
         6 . The formulation of  claim 5 , wherein the hydrophobic compound is hydrogenated vegetable oil. 
     
     
         7 . The formulation of  claim 1 , wherein the polymer carrying free carboxylic groups is selected from the group consisting of (meth)acrylic acid/alkyl (meth)acrylate copolymers, methacrylic acid and methyl methacrylate copolymers, methacrylic acid and ethyl acrylate copolymers or methacrylic acid copolymers type A, B or C, cellulose derivatives carrying free carboxylic groups, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethylethyl cellulose, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginate, and mixtures thereof. 
     
     
         8 . The formulation of  claim 7 , wherein the polymer carrying free carboxylic groups is a methacrylic acid copolymer. 
     
     
         9 . The formulation of  claim 1 , further comprising an acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, and mixtures thereof. 
     
     
         10 . The formulation of  claim 9 , wherein the acidifying agent is malic acid. 
     
     
         11 . The formulation of  claim 1 , further comprising a suspending or viscosifying agent selected from the group consisting of xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, guar gum, hydroxyethyl cellulose, agar, sodium alginate, sodium alginate, calcium alginate, gellan gum, carrageenan gum, hydroxypropylmethyl cellulose, and mixtures thereof. 
     
     
         12 . The formulation of  claim 11 , wherein the suspending or viscosifying agent is a mixture of xanthan gum, hydroxyethyl cellulose, and carrageenan gum. 
     
     
         13 . The formulation of  claim 1 , further comprising a lubricant or glidant selected from the group consisting of salts of stearic acid, in particular magnesium stearate, calcium stearate or zinc stearate, esters of stearic acid, in particular glyceryl monostearate or glyceryl palmitostearate, stearic acid, glycerol behenate, sodium stearyl fumarate, talc, and colloidal silicon dioxide. 
     
     
         14 . The formulation of  claim 13 , wherein the lubricant or glidant is magnesium stearate. 
     
     
         15 . The formulation of  claim 1 , wherein the amount of gamma-hydroxybutyrate in the immediate release portion is equal to the amount of gamma-hyrdoxybutyrate in the modified release portion. 
     
     
         16 . The formulation of  claim 1 , wherein the wherein the polymer carrying free carboxylic groups has a pH trigger from 5.5 to 6.97. 
     
     
         17 . The formulation of  claim 1 , wherein the free carboxylic groups are ionized at pH 7.5. 
     
     
         18 . The formulation of  claim 2 , wherein the one or more salts of gamma-hydroxybutyrate in the immediate release portion is the potassium salt of gamma-hydroxybutyric acid. 
     
     
         19 . The formulation of  claim 2 , wherein the one or more salts of gamma-hydroxybutyrate in the modified release portion is the sodium salt of gamma-hydroxybutyric acid. 
     
     
         20 . The formulation of  claim 2 , wherein the one or more salts of gamma-hydroxybutyrate in the immediate release portion is the sodium salt of gamma-hydroxybutyric acid. 
     
     
         21 . The formulation of  claim 2 , wherein the one or more salts of gamma-hydroxybutyrate in the modified release portion is the calcium salt of gamma-hydroxybutyric acid. 
     
     
         22 . The formulation of  claim 2 , wherein the one or more salts of gamma-hydroxybutyrate in the immediate release portion is a combination of the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, and the calcium salt of gamma-hydroxybutyric acid. 
     
     
         23 . The formulation of  claim 1  in a dosage form selected from the group consisting of tablets, powders, capsules, coated particles, microparticles, granules, pellets, microspheres, liquids, and orally dissolving tablets. 
     
     
         24 . The formulation of  claim 1  in an amount effective to treat narcolepsy Type 1 or Type 2 in a human, wherein said treatment of narcolepsy comprises reducing excessive daytime sleepiness, reducing the frequency of cataplectic attacks, or a combination thereof. 
     
     
         25 . The formulation of  claim 1  in an amount effective to induce sleep for at least eight consecutive hours. 
     
     
         26 . The formulation of  claim 1 , wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35. 
     
     
         27 . The formulation of  claim 26 , wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 40/60 to 60/40. 
     
     
         28 . The formulation of  claim 1 , wherein the particles of gamma-hydroxybutyrate in the immediate release portion have a mean diameter from 10 to 1000 microns, and the particles of gamma-hydroxybutyrate in the modified release portion have a mean diameter from 100 to 1200 microns. 
     
     
         29 . The formulation of  claim 28 , wherein the particles of gamma-hydroxybutyrate in the immediate release portion have a mean diameter from 150 to 400 microns, and the particles of gamma-hydroxybutyrate in the modified release portion have a mean diameter from 200 to 800 microns. 
     
     
         30 . The formulation of  claim 1 , wherein the formulation comprises an amount of gamma-hydroxybutyrate that provides the same amount of gamma-hydroxybutyrate as about 3.0 to 12.0 grams of sodium oxybate.