Sustained release matrix systems for highly soluble drugs

Abstract

Disclosed are sustained release oral solid dosage forms comprising a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l; a pH modifying agent; and a sustained release matrix comprising a gelling agent, said gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid, said dosage form providing a sustained release of said medicament after oral administration to human patients.

1 - 64 . (canceled) 
     
     
         65 . A sustained release oral tablet comprising a sustained release matrix comprising:
 a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l;   a pH modifying agent which is an organic acid;   a sustained release excipient comprising a gelling agent and an inert pharmaceutical diluent selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof; an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the sustained release excipient further comprising an optional surfactant selected from the group consisting of monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, alkyl sulfates, ethoxylated alkyl sulfates, ester linked sulfonates, alpha olefin sulfonates, phosphated ethoxylated alcohols, monoalkyl quaternary ammonium salts, dialkyl quaternary ammonium compounds, amidoamines, aminimides, N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and N-alkyl β-aminoproprionates, an ester of polyethyleneglycol, an ether of polyethyleneglycol, and mixtures of any of the foregoing, and an optional ionizable gel strength enhancing agent selected from the group consisting of an alkali metal sulfate, an alkali metal chloride, an alkali metal chloride, an alkali metal borate, an alkali metal bromide, an alkali metal citrate, an alkali metal acetate, an alkali metal lactate, an alkaline earth metal sulfate, an alkaline earth metal chloride, an alkaline earth metal chloride, an alkaline earth metal borate, an alkaline earth metal bromide, an alkaline earth metal citrate, an alkaline earth metal acetate, an alkaline earth metal lactate, and mixtures of any of the foregoing; the ingredients of the sustained release excipient being granulated together prior to incorporation of the medicament; the medicament being incorporated into the sustained release matrix together with the sustained release excipient and the pH modifying agent such that said tablet provides a sustained release of said medicament after oral administration to human patients for at least about 12 hours or at least about 24 hours, and the tablet having a total weight from about 300 mg to about 1000 mg, wherein the medicament is not oxybutynin.   
     
     
         66 . The sustained release oral tablet of  claim 65  which provides a sustained release of said medicament for at least about 12 hours after oral administration. 
     
     
         67 . The sustained release oral tablet of  claim 65  which provides a sustained release of said medicament for at least about 24 hours after oral administration. 
     
     
         68 . The sustained release oral tablet of  claim 65 , wherein said medicament has a solubility of more than about 100 g/l. 
     
     
         69 . The sustained release oral tablet of  claim 65 , wherein said medicament has a solubility of more than about 1000 g/l. 
     
     
         70 . The sustained release oral tablet of  claim 65 , wherein the ratio of said medicament to said gelling agent is from about 1:5 to about 5:1. 
     
     
         71 . The sustained release oral tablet of  claim 65 , wherein the ratio of said inert diluent to said gelling agent is from about 1:3 to about 3:1 
     
     
         72 . The sustained release oral tablet of  claim 65 , further comprising an ionizable gel strength enhancing agent capable of crosslinking with said gelling agent and increasing the gel strength when the dosage form is exposed to an environmental fluid, the ionizable gel strength enhancing agent comprising an alkali metal or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate, or lactate. 
     
     
         73 . The sustained release oral tablet of  claim 72 , wherein said ionizable gel strength enhancing comprises calcium sulfate. 
     
     
         74 . The sustained release oral tablet of  claim 65 , wherein the gel comprises xanthan gum and locust bean gum. 
     
     
         75 . The sustained release oral solid tablet of  claim 65 , wherein said organic acid is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and combinations thereof. 
     
     
         76 . The sustained release oral tablet of  claim 65 , wherein said organic acid is fumaric acid or succinic acid. 
     
     
         77 . The sustained release oral tablet of  claim 65 , wherein said pH modifying agent is present in an amount from about 1% to about 10%. 
     
     
         78 . The sustained release oral tablet of  claim 65 , further comprising a surfactant. 
     
     
         79 . The sustained release oral tablet of  claim 78 , wherein said surfactant is selected from the group consisting of sodium lauryl sulfate and a pharmaceutically effective salt of docusate. 
     
     
         80 . The sustained release oral tablet of  claim 65 , further comprising a hydrophobic or enteric coating on the tablet. 
     
     
         81 . A sustained release oral tablet comprising a sustained release matrix comprising:
 a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l;
 a pH modifying agent which is an organic acid; 
   a sustained release excipient comprising a gelling agent and an inert pharmaceutical diluent selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the sustained release excipient further comprising an optional surfactant selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphophilic) surfactants, and non-ionic surfactants and an optional ionizable gel strength enhancing agent which comprises an alkali metal or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate, or lactate; the ingredients of the sustained release excipient being granulated together prior to incorporation of the medicament; the medicament being incorporated into the sustained release matrix together with the sustained release excipient and the pH modifying agent such that said tablet provides a sustained release of said medicament after oral administration to human patients for at least about 12 hours or at least about 24 hours, and the tablet having a total weight from about 300 mg to about 1000 mg, wherein the medicament is not oxybutynin.   
     
     
         82 . The sustained release oral tablet of  claim 81 , wherein the ratio of said inert diluent to said gelling agent is from about 1:3 to about 3:1, and the pH modifying agent is present in an amount from about 1% to about 10%. 
     
     
         83 . The sustained release oral solid tablet of  claim 82 , wherein said organic acid is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and combinations thereof. 
     
     
         84 . The sustained release oral tablet of  claim 83 , wherein said organic acid is fumaric acid. 
     
     
         85 . A sustained release oral tablet comprising a sustained release matrix comprising:
 a therapeutically effective amount of a medicament having a solubility of more than about 10 g/l;
 a pH modifying agent which is an organic acid; 
   a sustained release excipient comprising a gelling agent and an inert pharmaceutical diluent selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the sustained release excipient further comprising an optional surfactant and an optional ionizable gel strength enhancing agent which are not an organic acid; the ingredients of the sustained release excipient being granulated together prior to incorporation of the medicament; the medicament being incorporated into the sustained release matrix together with the sustained release excipient and the pH modifying agent such that said tablet provides a sustained release of said medicament after oral administration to human patients for at least about 12 hours or at least about 24 hours, and the tablet having a total weight from about 300 mg to about 1000 mg, wherein the medicament is not oxybutynin.   
     
     
         86 . The sustained release oral tablet of  claim 85 , wherein the ratio of said inert diluent to said gelling agent is from about 1:3 to about 3:1, and the pH modifying agent is present in an amount from about 1% to about 10%. 
     
     
         87 . The sustained release oral solid tablet of  claim 86 , wherein said organic acid is selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and combinations thereof.