Controlled release compositions of gamma-hydroxybutyrate

Abstract

The present invention is directed to oral pulse-release pharmaceutical dosage form containing an immediate release component of gamma-hydroxybutyric acid, and one or more delayed/controlled release components of gamma-hydroxybutyric acid.

1 .- 56 . (canceled) 
     
     
         57 . An oral pharmaceutical dosage form, comprising (a) an immediate release component comprising gamma-hydroxybutyric acid (GHB), and (b) a delayed release component comprising GHB. 
     
     
         58 . The oral dosage form of  claim 57 , wherein said delayed release component comprises particles containing GHB in a core, which core is immediately surrounded by a barrier coat to control the migration of GHB from the core, which in turn is surrounded by an enteric release coat that releases GHB at a predetermined pH after ingestion. 
     
     
         59 . The oral dosage form of  claim 58 , wherein said barrier coat contains a neutralizing agent or agents selected from the group consisting of malic acid, citric acid, tartaric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoic acid, a polyacid, and acidic ionic resins. 
     
     
         60 . The oral dosage form of  claim 59 , wherein the neutralizing agent(s) are used in amounts sufficient to neutralize any migrating gamma-hydroxybutyric acid salts. 
     
     
         61 . The oral dosage form of  claim 60 , wherein said neutralizing agent(s) are used in an amount of about 0.01% to about 10% mol/mol of the GHB. 
     
     
         62 . The oral dosage form of  claim 61 , wherein the amount is from about 1% to about 5% mol/mol of the GHB. 
     
     
         63 . The oral dosage form of  claim 58 , wherein the barrier coat is composed of materials selected from ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, or other water-based or solvent-based coating materials. 
     
     
         64 . The oral dosage form of  claim 58 , wherein the core is surrounded by more than one barrier coat. 
     
     
         65 . The oral dosage form of  claim 64 , wherein a first barrier coat comprises Opadry AMB, a second barrier coat comprises ethylcellulose, and a third barrier coat comprises Opadry. 
     
     
         66 . The oral dosage for of  claim 58 , wherein the enteric release coat is a pH sensitive material, which releases GHB at a predetermined pH in the gastrointestinal tract. 
     
     
         67 . The oral dosage form of  claim 66 , wherein the pH sensitive material comprises methacrylate-based coating materials, cellulose-based coating materials, shellac-based coating materials such as Emcoat 120N and Marcoat 125, polyvinyl acetate phthalate, or combinations thereof. 
     
     
         68 . The oral dosage form of  claim 67 , wherein the methacrylate-based coating materials are polymers of methacrylic acid and methacrylates and are selected from Eudragit E 100, Eudragit E PO, Eudragit 1, 12.5, Eudragit L 100-55, Eudragit L 30-D55, Eudragit L 100, Eudragit S 100, and Eudragit FS 30D. 
     
     
         69 . The oral dosage form of  claim 67 , wherein the cellulose-based coating materials are selected from cellulose acetate phthalate, carboxymethyl ethylcellulose, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate. 
     
     
         70 . The oral dosage form of  claim 58 , wherein the core further comprises one or more excipients selected from binders, lubricants, anti-adherents, glidants and neutralizing agents. 
     
     
         71 . The oral dosage form of  claim 66 , wherein the pH sensitive enteric release coat allows the release of GLIB in the upper gastrointestinal tract. 
     
     
         72 . The oral dosage form of  claim 71 , wherein the enteric release coat comprises Eudragit L 30 D-55, Eudragit L 100-55, Eudragit L 12.5, Eudragit L 100, or combinations thereof. 
     
     
         73 . The oral dosage form of  claim 66 , wherein the enteric release coat further comprises acidic materials that counteract the alkaline effects of GHB. 
     
     
         74 . The oral dosage form of  claim 57 , wherein the immediate release component is a solid, a semi-solid or a liquid. 
     
     
         75 . The oral dosage form of  claim 57 , comprising two delayed release components, each of which releases GHB in different regions of the gastrointestinal tract. 
     
     
         76 . The oral dosage form of  claim 75 , wherein one of the delayed release components releases GHB in the duodenum, and the other delayed release component releases GHB in the jejunum. 
     
     
         77 . The oral dosage form of  claim 76 , wherein the delayed release component that releases GHB in the duodenum comprises a GHB containing core surrounded by a barrier coat, which is turn is surrounded by an enteric coating comprising Eudragit I, 30 D-55 or Eudragit L 100-55, and the delayed release component that releases GLIB in the jejunum comprises a GLIB containing core surrounded by a barrier coat, which in turn is surrounded by a coating comprising Eudragit L 12.5 or Eudragit L100. 
     
     
         78 . An oral pharmaceutical composition, comprising a delayed release component comprising gamma-hydroxybutyric acid (GHB). 
     
     
         79 . A method for the treatment of a subject in need of the effects of GHB, comprising administering an effective amount of the oral dosage form of  claim 57  to the subject. 
     
     
         80 . The method of  claim 79 , wherein the subject is a human. 
     
     
         81 . The method of  claim 79  for the treatment of a condition selected from narcolepsy, cataplexy, sleep paralysis, alcoholism, chronic schizophrenia, catatonic schizophrenia, atypical psychoses, chronic brain syndrome, neurosis, drug addiction and withdrawal, Parkinson's disease, neuropharmacological illnesses, hypertension, ischemia, circulatory collapse, radiation exposure, cancer, and myocardial infarction.