Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances

Abstract

Controlled release dosage forms are described herein. The controlled release formulations described herein provide prolonged delivery of high dose drugs that are highly water soluble and highly hygroscopic. In specific embodiments, controlled release dosage forms for delivery of a drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB. The controlled release dosage forms described herein may incorporate both controlled release and immediate release formulations in a single unit dosage form.

1 . A controlled release dosage form for oral administration, the controlled release dosage form comprising:
 a controlled release formulation comprising at least one drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB; and   wherein less than 30% of the at least one drug included in the controlled release formulation is released from the controlled release formulation during the first hour after administration.   
     
     
         2 . The controlled release dosage form of  claim 1 , wherein less than 60% of the at least one drug included in the controlled release formulation is released within two hours after administration, and wherein less than 80% of the at least one drug included in the controlled release formulation is released within four hours after administration, and wherein greater than 90% of the at least one drug included in the controlled release formulation is released within 12 hours after administration. 
     
     
         3 . The controlled release dosage form of either of  claim 1  and  claim 2 , wherein the at least one drug is selected from calcium, lithium, potassium, sodium and magnesium salts of GHB. 
     
     
         4 . The controlled release dosage form of  claim 3 , wherein the at least one drug comprises sodium oxybate. 
     
     
         5 . The controlled release dosage form of  claim 1 , wherein the dosage form further comprises an immediate release component comprising the at least one drug, and further wherein greater than 90% of the at least one drug included in the immediate release component is released from the immediate release component within the first hour after administration. 
     
     
         6 . The controlled release dosage form of  claim 5 , wherein the controlled release dosage formulation begins to release the at least one drug within 1 hour after administration. 
     
     
         7 . The controlled release dosage form of either of  claim 5  and  claim 6 , wherein the immediate release formulation comprises at least one drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB. 
     
     
         8 . The controlled release dosage form of  claim 7 , wherein the at least on drug included within the immediate release formulation comprises at least one drug selected from calcium, lithium, potassium, sodium and magnesium salts of GHB. 
     
     
         9 . The controlled release dosage form of  claim 8 , wherein the immediate release formulation comprises sodium oxybate. 
     
     
         10 . The controlled release dosage form of  claim 5 , wherein the immediate release formulation is applied as a coating over the controlled release formulation. 
     
     
         11 . The controlled release dosage form of either of  claim 1  and  claim 5 , wherein the controlled release formulation comprises a controlled release core comprising the at least one drug, wherein the controlled release core is coated with at least one coating composition that is formulated to control the release rate of the at least one drug after administration. 
     
     
         12 . The controlled release dosage form of  claim 11 , wherein the at least one coating composition comprises at least one polymer. 
     
     
         13 . The controlled release dosage form of  claim 11 , wherein the at least one coating composition comprises at least one pore-former. 
     
     
         14 . The controlled release dosage form of  claim 11 , wherein the at least one coating composition comprises at least one polymer and at least one pore-former. 
     
     
         15 . The controlled release dosage form of  claim 11 , wherein the at least one coating composition comprises ethylcellulose. 
     
     
         16 . The controlled release dosage form of either of  claim 13  and  claim 14 , wherein the pore-former is at least one of a polyethylene glycol, poloxamer, polyvinyl alcohol, copovidone, povidone, a water soluble sugar, a water soluble organic acid, such as carboxylic acids and their salts, and a hydroxyalkyl cellulose selected from hydroxyethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. 
     
     
         17 . The controlled release dosage form of  claim 14 , wherein the at least one coating composition comprises at least one plasticizer. 
     
     
         18 . The controlled release dosage form of  claim 17 , wherein the at least one coating composition comprises at least one anti-tack agent. 
     
     
         19 . The controlled release dosage form of  claim 11 , wherein the controlled release dosage form comprises an immediate release formulation and the immediate release formulation comprises between 10% and 50% by weight of the total drug included in the controlled release dosage form. 
     
     
         20 . The controlled release dosage form of  claim 11 , wherein the controlled release dosage form comprises an immediate release formulation and the immediate release formulation comprises between 50% and 90% by weight of the total drug included in the controlled release dosage form. 
     
     
         21 . The controlled release dosage form of  claim 5 , wherein the immediate release formulation further comprises at least one pharmaceutically acceptable excipient. 
     
     
         22 . The controlled release dosage form of  claim 21 , wherein the pharmaceutically acceptable excipient comprises at least one of copovidone, plasacryl, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxymethyl cellulose. 
     
     
         23 . A controlled release dosage form for oral administration, the controlled release dosage form comprising:
 a controlled release formulation comprising at least one pharmaceutically active ingredient selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB;   at least one coating composition applied over the controlled release formulation; and   an immediate release formulation comprising at least one pharmaceutically active ingredient selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB, wherein the immediate release formulation is applied over the coating composition.   
     
     
         24 . The controlled release dosage form of  claim 23 , wherein the controlled release formulation further comprises at least one pharmaceutically acceptable excipient. 
     
     
         25 . The controlled release dosage form of  claim 24 , wherein the at least one pharmaceutically acceptable excipient comprises at least one of hydroxypropyl cellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, povidone, copovidone, pregelatinized starch, dextrin, gelatin, maltodextrin, starch, zein, acacia, alginic acid, carbomers, cross-linked polyacrylates, polymethacrylates, carboxymethylcellulose sodium, guar gum, hydrogenated vegetable oil, methylcellulose, magnesium aluminum silicate, and sodium alginate. 
     
     
         26 . The controlled release dosage form of  claim 24 , wherein the at least one pharmaceutically acceptable excipient comprises at least one of magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, and zinc stearate. 
     
     
         27 . The controlled release dosage form of  claim 24  wherein the at least one pharmaceutically acceptable excipient comprises at least one of docusate sodium, sodium lauryl sulfate, benzalkonium chloride, benzethonium chloride, cetrimide, alkyltrimethylammonium bromide, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamers, polysorbate, sorbitan esters, and glyceryl monooleate. 
     
     
         28 . The controlled release dosage form of  claim 23 , wherein the at least one coating composition comprises at least one polymer. 
     
     
         29 . The controlled release dosage form of  claim 23 , wherein the at least one coating composition comprises at least one pore-former. 
     
     
         30 . The controlled release dosage form of  claim 23 , wherein the at least one coating composition comprises at least one polymer and at least one pore-former 
     
     
         31 . The controlled release dosage form of  claim 23 , wherein the at least one coating composition comprises ethylcellulose. 
     
     
         32 . The controlled release dosage form of either of  claim 29  and  claim 30 , wherein the at least one pore-former is at least one of a polyethylene glycol, poloxamer, polyvinyl alcohol, copovidone, povidone, a water soluble sugar, a water soluble organic acid, such as carboxylic acids and their salts, and a hydroxyalkyl cellulose selected from hydroxyethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. 
     
     
         33 . The controlled release dosage form of  claims 28 - 30 , wherein the at least one coating composition comprises at least one plasticizer. 
     
     
         34 . The controlled release dosage form of  claims 28 - 30 , wherein the at least one coating composition comprises at least one anti-tack agent. 
     
     
         35 . The controlled release dosage form of  claim 23 , wherein the immediate release formulation further comprises at least one pharmaceutically acceptable excipient. 
     
     
         36 . The controlled release dosage form of  claim 35 , wherein the pharmaceutically acceptable excipient comprises at least one of copovidone, glyceryl monostearate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxymethyl cellulose. 
     
     
         37 . The controlled release dosage form of  claim 23 , wherein the immediate release formulation further comprises an overcoat layer. 
     
     
         38 . The controlled release dosage form of  claim 23 , wherein both the immediate release formulation and the controlled release core formulation comprise a pharmaceutically active ingredient comprising sodium oxybate. 
     
     
         39 . The controlled release dosage form according to  claim 23 , wherein the dosage form delivers the at least one drug in a manner that provides a Cmax to Cmin ratio of the at least one drug selected from less than 3 and less than 2 over a period of time selected from up to about 5 hours, up to about 6 hours, up to about 7 hours, up to about 8 hours, up to about 9 hours, and up to about 10 hours. 
     
     
         40 . The controlled release dosage form according to  claim 39 , wherein not more than about 10% to 60% of the at least one drug initially contained within the controlled release formulation is released during the first two hours post-administration, and not more than about 40% to 90% of the drug initially contained within the controlled release formulation is released during the first four hours post-administration. 
     
     
         41 . The controlled release dosage form according to  claim 39 , wherein not more than about 30% of the at least one drug initially contained within the controlled release formulation is released during the first hour post-administration, not more than about 60% of the at least one drug initially contained within the controlled release formulation is released during the first two hours post-administration, and not more than about 90% of the at least one drug initially contained within the controlled release formulation is released during the first four hours post-administration. 
     
     
         42 . The controlled release dosage form according to  claim 39 , wherein not more than about 50% of the at least one drug initially contained within the controlled release formulation is released during the first hour post-administration, not more than about 50% to about 75% of the at least one drug initially contained within the controlled release formulation is released during the first two hours post-administration, and not more than about 80% of the at least one drug initially contained within the controlled release formulation is released during the first four hours post-administration. 
     
     
         43 . The controlled release dosage form according to  claim 23 , wherein not more than about 20% of the at least one drug initially contained within the controlled release formulation is released during the first hour post-administration, between about 5% to about 30% of the at least one drug initially contained within the controlled release formulation is released during the first two hours post-administration, between about 30% to about 50% of the at least one drug initially contained within the controlled release formulation is released during the first four hours post-administration, between about 50% to about 70% of the at least one drug initially contained within the controlled release formulation is released during the first six hours post-administration, and not more than 80% of the at least one drug initially contained within the controlled release formulation is released during the first 10 hours post administration. 
     
     
         44 . The controlled release dosage form according to  claim 23 , wherein not more than about 20% of the at least one drug initially contained within the controlled release formulation is released during the first hour post-administration, between about 20% and about 50% of the at least one drug initially contained within the controlled release formulation is released during the first two hours post-administration, between about 50% and about 80% of the at least one drug initially contained within the controlled release formulation is released during the first four hours post-administration, and not more than about 85% of the at least one drug initially contained within the controlled release formulation is released during the first eight hours post-administration. 
     
     
         45 . A method for delivering a drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB, the method comprising;
 delivering to a patient in need thereof, one or more dosage forms according to  claim 23 .   
     
     
         46 . A method according to  claim 45 , wherein delivery of the one or more dosage forms provides a Cmax to Cmin ratio of the drug selected from less than 3 and less than 2 over a period of time selected from up to about 5 hours, up to about 6 hours, up to about 7 hours, up to about 8 hours, up to about 9 hours, and up to about 10 hours 
     
     
         47 . A method according to either of  claims 45  and  46 , wherein not more than about 10% to 60% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first two hours post-administration, and not more than approximately 40% to 90% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first four hours post-administration. 
     
     
         48 . A method according to either of  claims 45  and  46 , wherein not more than about 30% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first hour post-administration, not more than about 60% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first two hours post-administration, and not more than about 90% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first four hours post-administration. 
     
     
         49 . A method according to either of  claims 45  and  46 , wherein not more than about 50% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first hour post-administration, not more than about 50% to about 75% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first two hours post-administration, and not less than about 80% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released after the first four hours post-administration. 
     
     
         50 . A method according to either of  claims 45  and  46 , wherein not more than about 20% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first hour post-administration, between about 5% to about 30% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first two hours post-administration, between about 30% to about 50% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first four hours post-administration, between about 50% to about 70% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first six hours post-administration, and not less than 80% of the drug initially contained within controlled release formulation of the one or more controlled release dosage forms is released after the first 10 hours post administration. 
     
     
         51 . A method according to either of  claims 45  and  46 , wherein not more than about 20% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first hour post-administration, between about 20% and about 50% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first two hours post-administration, between about 50% and about 80% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released during the first four hours post-administration, and not less than about 85% of the drug initially contained within the controlled release formulation of the one or more controlled release dosage forms is released after the first eight hours post-administration. 
     
     
         52 - 108 . (canceled)