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 any preceding claim, wherein the at least one drug comprises sodium oxybate. 
     
     
         5 . The controlled release dosage form of any preceding claim, 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 any preceding claim, 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 any of  claims 5  through  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 any of  claims 5  through  8 , wherein the immediate release formulation comprises sodium oxybate. 
     
     
         10 . The controlled release dosage form of any of  claims 5  through  9 , wherein the immediate release formulation is applied as a coating over the controlled release formulation. 
     
     
         11 . The controlled release dosage form of any preceding claim, 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 either of  claims 11  and  12 , wherein the at least one coating composition comprises at least one pore-former. 
     
     
         14 . The controlled release dosage form of any of  claims 11  through  13 , 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 any of  claims 11  through  14 , wherein the at least one coating composition comprises ethylcellulose. 
     
     
         16 . The controlled release dosage form of either of  claim 13  and  claim 15 , 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 any of  claims 11  through  16 , wherein the at least one coating composition comprises at least one plasticizer. 
     
     
         18 . The controlled release dosage form of any of  claims 11  through  17 , wherein the at least one coating composition comprises at least one anti-tack agent. 
     
     
         19 . The controlled release dosage form of any of  claims 5  through  18 , 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 sodium oxybate in the controlled release dosage form. 
     
     
         20 . The controlled release dosage form of any of  claims 5  through  19 , 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 sodium oxybate in the controlled release dosage form. 
     
     
         21 . The controlled release dosage form of any of  claims 5  through  20 , wherein the immediate release formulation further comprises at least one pharmaceutically acceptable excipient. 
     
     
         22 . The controlled release dosage form of any of  claims 5  through  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, polyoxyethyelene alkyl ethers, polyoxyethylene stearates, poloxamers, polysorbate, sorbitan esters, and glyceryl monooleate. 
     
     
         28 . The controlled release dosage form of any of  claims 23  through  27 , wherein the at least one coating composition comprises at least one polymer. 
     
     
         29 . The controlled release dosage form of any of  claims 23  through  28 , wherein the at least one coating composition comprises at least one pore-former. 
     
     
         30 . The controlled release dosage form of any of  claims 23  through  29 , 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 any of  claims 23  through  30 , wherein the at least one coating composition comprises ethylcellulose. 
     
     
         32 . The controlled release dosage form of any of  claims 29  through  31 , 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 any of  claims 23  through  32 , wherein the at least one coating composition comprises at least one plasticizer. 
     
     
         34 . The controlled release dosage form of any of  claims 23  through  33 , wherein the at least one coating composition comprises at least one anti-tack agent. 
     
     
         35 . The controlled release dosage form of any of  claims 23  through  34 , 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 any preceding claim, 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 any preceding claim, 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 any preceding claim, 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 any preceding claim, 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 any preceding claim, 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 any preceding claim, 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 any of the preceding claims.   
     
     
         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 . A controlled release dosage form for oral administration, the controlled release dosage form comprising:
 a controlled release core;   a functional coating composition; and   a moisture barrier layer;   wherein the functional coating composition is disposed over the controlled release core, and wherein the moisture barrier layer is disposed over the functional coating composition.   
     
     
         53 . The controlled release dosage form of  claim 52 , wherein the controlled release dosage form comprises:
 (a) a controlled release core comprising:
 a drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB; 
 at least one binder; and 
 at least one lubricant; 
   (b) a functional coating composition comprising:
 at least one base polymer; and 
 at least one pore-former; and 
   (c) a moisture barrier layer.   
     
     
         54 . The controlled release dosage form of  claim 53 , wherein the at least one binder is selected from one of or any combination 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, and the lubricant is selected from one of or any combination 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. 
     
     
         55 . The controlled release dosage form of  claim 52  or  53 , wherein the controlled release core optionally comprises at least one surfactant at least one filler. 
     
     
         56 . The controlled release dosage form of  claim 55 , wherein the at least one surfactant is selected from one of or any combination of docusate sodium, sodium lauryl sulfate, benzalkonium chloride, benzethonium chloride, cetrimide, alkyltrimethylammonium bromide, polyoxyethyelene alkyl ethers, polyoxyethylene stearates, poloxamers, polysorbate, sorbitan esters, and glyceryl monooleate, and the at least one filler is selected from one of or a combination of lactose, calcium carbonate, calcium sulfate, compressible sugars, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, and sucrose 
     
     
         57 . The controlled release dosage form according to any of  claims 53  through  56 , wherein the at least one pore former is selected from one of or any combination of 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. 
     
     
         58 . The controlled release dosage form of any of  claims 53  through  57 , wherein the functional coating composition optionally comprises at least one plasticizer selected from triethyl citrate and dibutyl sebacate and at least one anti-tack agent selected from talc, glyceryl monostearate, and magnesium stearate. 
     
     
         59 . The controlled release dosage form according to any of  claims 53  through  58 , wherein the moisture barrier layer is selected from a polyvinyl alcohol-based coating, a hydroxypropyl methylcellulose/wax-based coating, a hydroxypropyl methylcellulose/stearic acid-based coating, and reverse enteric material. 
     
     
         60 . The controlled release dosage according to any of  claims 53  through  59 , wherein the relative amount drug present in the controlled release core is at least 90% or greater by weight of the controlled release core. 
     
     
         61 . The controlled release dosage form according to any of  claims 53  through  60 , wherein the relative amount of drug present in the controlled release core is selected from a range of about 90% to about 98%, about 91% to about 98%, about 92% to about 98%, about 93% to about 98%, about 94% to about 98%, about 95% to about 98%, about 96% to about 98%, and between about 97% to about 98% by weight of the controlled release core. 
     
     
         62 . The controlled release dosage form according to any of  claims 53  through  60 , wherein the relative amount of drug present in the controlled release core is selected from about 94 to about 98%, about 94 to about 97%, about 94 to about 96%, about 95 to about 98%, about 95 to about 97%, and about 95 to about 96.5% by weight of the controlled release core. 
     
     
         63 . The controlled release dosage form according to any of  claims 53  through  60 , wherein the relative amount of drug present in the controlled release core is selected from about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, and 98% by weight of the controlled release core. 
     
     
         64 . The controlled release dosage form according to any of  claims 53  through  64 , wherein the amount of binder present in the controlled release core is about 1% to about 10% by weight of the controlled release core. 
     
     
         65 . The controlled release dosage form according to any of  claims 53  through  64 , wherein the amount of binder present in the controlled release core is selected from about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 9% and about 1% to about 10% by weight of the controlled release core. 
     
     
         66 . The controlled release dosage form according to any of  claims 53  through  64 , wherein the amount of binder present in the controlled release core is selected from about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, and 10% by weight of the controlled release core. 
     
     
         67 . The controlled release dosage form according to any of  claims 53  through  66 , wherein the amount of lubricant present in the controlled release core is about 0.5% to about 5% by weight of the controlled release core. 
     
     
         68 . The controlled release dosage form according to any of  claims 53  through  67 , wherein the amount of lubricant present in the controlled release core is selected from about 0.5% to about 2%, about 1% to about 2%, about 1% to about 3%, about 2% to about 3%, and about 2% to about 4% by weight of the controlled release core. 
     
     
         69 . The controlled release dosage form according to any of  claims 53  through  68 , wherein the amount of lubricant present in the controlled release core is selected from about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5% by weight of the controlled release core. 
     
     
         70 . The controlled release dosage form according to any of  claims 55  through  69 , wherein the amount of surfactant present in the controlled release core is 3.0% or less by weight of the controlled release core. 
     
     
         71 . The controlled release dosage form according to any of  claims 55  through  70 , wherein the amount of surfactant present in the controlled release core is selected from about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.5% to about 3%, about 0.5% to about 2%, and about 0.5% to about 1% by weight of the controlled release core. 
     
     
         72 . The controlled release dosage form according to any of  claims 53  through  71 , wherein the amount of base polymer present in the functional coating composition is about 50% to about 80% by weight of the functional coating composition. 
     
     
         73 . The controlled release dosage form according to any of  claims 53  through  72 , wherein the amount of base polymer present in the functional coating composition is selected from about 50% to about 75%, about 55% to about 75%, about 60% to about 75%, and about 65% to about 75% by weight of the functional coating composition. 
     
     
         74 . The controlled release dosage form according to any of  claims 53  through  73 , wherein the amount of base polymer present in the functional coating composition is selected from about 50%, 55%, 60%, 65%, 70%, 75%, and 80% by weight of the functional coating composition. 
     
     
         75 . The controlled release dosage form according to any of  claims 53  through  74 , wherein the amount of pore-former present in the functional coating composition is about 20% to about 50% by weight of the functional coating composition. 
     
     
         76 . The controlled release dosage form according to any of  claims 53  through  75 , wherein the amount of pore-former present in the functional coating composition is selected from about 20% to about 45%, about 25% to about 45%, about 30% to about 45%, and about 35% to about 45% by weight of the functional coating composition. 
     
     
         77 . The controlled release dosage form according to any of  claims 53  through  76 , wherein the amount of pore-former present in the functional coating composition is selected from about 20%, 25%, 30%, 35%, 40%, 45%, and 50% by weight of the functional coating composition. 
     
     
         78 . The controlled release dosage form according to any of  claims 58  through  77 , wherein the amount of plasticizer present in the functional coating composition is about 5% to about 15% by weight relative to the base polymer. 
     
     
         79 . The controlled release dosage form according to any of  claims 58  through  78 , wherein the amount of plasticizer present in the functional coating composition is selected from about 5%, 8%, 10%, 12%, and 15% by weight relative to the base polymer. 
     
     
         80 . A controlled release dosage form according to any of  claims 52  through  79  further comprising an immediate release component comprising a drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB, wherein the immediate release component is disposed over the functional coating composition, wherein the moisture barrier layer is disposed over the functional coating composition, and wherein the immediate release component provides immediate release of the at least one drug upon administration to the gastro-intestinal tract. 
     
     
         81 . The controlled release dosage form of  claim 80 , wherein the immediate release component further comprises at least one pharmaceutically acceptable excipient. 
     
     
         82 . The controlled release dosage form of any of  claim 81 , wherein the at least one pharmaceutically acceptable excipient included in the immediate release comprises one or more of at least one anti-tack agent, at least one plasticizer, at least one surfactant. 
     
     
         83 . The controlled release dosage form according to any of  claims 80  through  82 , wherein the amount of drug present in the immediate release component is about 10% to about 50% by weight of the total drug included in the unit dosage form. 
     
     
         84 . The controlled release dosage form according to any of  claims 80  through  83 , wherein the amount of drug present in the immediate release component is selected from about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of the total drug included in the unit dosage form. 
     
     
         85 . The controlled release dosage form according to any of  claims 80  through  84 , wherein the amount of drug present in the immediate release component is between about 75% and about 98% by weight of the immediate release component. 
     
     
         86 . The controlled release dosage form according to any of  claims 80  through  85 , wherein the amount of drug present in the immediate release component is selected from a range of about 75% to about 98%, about 80% to about 98%, about 85% to about 98%, about 90% to about 98%, and about 95% to about 98% by weight of the immediate release component. 
     
     
         87 . The controlled release dosage form according to any of  claims 52  through  86 , wherein the dosage form delivers the drug in a manner that provides a C max  to C min  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. 
     
     
         88 . The controlled release dosage form according to any of  claims 52  through  86 , wherein the dosage form delivers the drug in a manner that provides a C max  to C min  ratio of the at least one drug selected from less than 3 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. 
     
     
         89 . The controlled release dosage form according to any of  claims 52  through  86 , wherein the dosage form delivers the drug in a manner that provides a C max to C min  ratio of the at least one drug selected from 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. 
     
     
         90 . The controlled release dosage form according to any of  claims 52  through  89 , wherein, after administration, the dosage form provides plasma concentrations of the drug of at least 10 μg/mL 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. 
     
     
         91 . The controlled release dosage form according to any of  claims 52  through  90 , wherein not more than about 10% to about 60% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first two hours post-administration, and not more than about 40% to about 90% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first four hours post-administration. 
     
     
         92 . The controlled release dosage form according to any of  claims 52  through  90 , wherein not more than about 30% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first hour post-administration, not more than about 60% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first two hours post-administration, and not more than about 90% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first four hours post-administration. 
     
     
         93 . The controlled release dosage form according to any of  claims 52  through  90 , wherein not more than about 50% of the drug initially contained within the controlled release core of the controlled release dosage form 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 core of the controlled release dosage form is released during the first two hours post-administration, and not less than about 80% of the drug initially contained within the controlled release core of the controlled release dosage form is released after the first four hours post-administration. 
     
     
         94 . The controlled release dosage form according to any of  claims 52  through  90 , wherein not more than about 20% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first hour post-administration, between about 5% to about 30% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first two hours post-administration, between about 30% to about 50% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first four hours post-administration, between about 50% to about 70% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first six hours post-administration, and not less than about 80% of the drug initially contained within the controlled release core of the controlled release dosage form is released after the first 10 hours post administration. 
     
     
         95 . The controlled release dosage form according to any of  claims 52  through  90 , wherein not more than about 20% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first hour post-administration, between about 20% and about 50% of the drug initially contained within the controlled release core of the controlled release dosage form is released during the first two hours post-administration, between about 50% and about 80% of drug initially contained within the controlled release core of the controlled release dosage form is released during the first four hours post-administration, and not less than about 85% of the drug initially contained within the controlled release core of the controlled release dosage form is released after the first eight hours post-administration. 
     
     
         96 . The controlled release dosage form according to any of  claims 52  through  90 , wherein about 90% or more of the drug initially contained within the controlled release core of the controlled release dosage form is released within about 4 to 10 hours of administration. 
     
     
         97 . The controlled release dosage form according to any of  claims 52  through  90 , wherein about 90% or more of the drug initially contained within the controlled release core of the controlled release dosage form is released within a period of time selected from about 4, about 5, about 6, about 7, about 8, about 9, about 10, and about 12 hours post-administration. 
     
     
         98 . The controlled release dosage form according to any of  claims 52  through  97 , wherein more than about 95% of the drug initially contained within the immediate release component of the dosage form is released within a period of time selected from less than 45 minutes post-administration, less than 30 minutes post-administration, and less than 15 minutes post-administration. 
     
     
         99 . The controlled release dosage form according to any one of  claims 52  through  97 , wherein more than about 80% of the drug initially contained within the immediate release component is released within a period of time selected from less than 45 minutes post-administration, less than 30 minutes post-administration, and less than 15 minutes post-administration. 
     
     
         100 . The controlled release dosage form according to any one of  claims 52  through  97 , wherein more than about 90% of the drug initially contained within the immediate release component is released over a period of time selected from less than one hour post-administration, less than 45 minutes post-administration, less than 30 minutes post-administration, and less than 15 minutes post-administration, wherein as the immediate release component is released, the controlled release core begins release of the drug contained within the control release core. 
     
     
         101 . The controlled release dosage form according to any one of  claims 52  through  97 , wherein more than about 90% of the drug initially contained within the immediate release component is released over a period of time selected from less than one hour post-administration, less than 45 minutes post-administration, less than 30 minutes post-administration, and less than 15 minutes post-administration, wherein after the immediate release component is released, the controlled release core begins release of the drug contained within the control release core. 
     
     
         102 . 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 any of  claims 52  through  101 .   
     
     
         103 . A method according to  claim 102 , 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 
     
     
         104 . A method according to either of  claims 102  and  103 , wherein not more than about 10% to 60% of the drug initially contained within the controlled release core 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 core of the one or more controlled release dosage forms is released during the first four hours post-administration. 
     
     
         105 . A method according to either of  claims 102  and  103 , wherein not more than about 30% of the drug initially contained within the controlled release core 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 core 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 controlled release core of the one or more controlled release dosage forms is released during the first four hours post-administration. 
     
     
         106 . A method according to either of  claims 102  and  103 , wherein not more than about 50% of the drug initially contained within the controlled release core 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 core 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 core of the one or more controlled release dosage forms is released after the first four hours post-administration. 
     
     
         107 . A method according to either of  claims 102  and  103 , wherein not more than about 20% of the drug initially contained within the controlled release core 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 core 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 core 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 core 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 the controlled release core of the one or more controlled release dosage forms is released after the first 10 hours post administration. 
     
     
         108 . A method according to either of  claims 102  and  103 , wherein not more than about 20% of the drug initially contained within the controlled release core 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 core 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 core 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 core of the one or more controlled release dosage forms is released after the first eight hours post-administration.