Sustained release heterodisperse hydrogel systems for insoluble drugs

Abstract

A sustained release pharmaceutical formulation includes a sustained release excipient including a gelling agent, an inert pharmaceutical diluent, an optional cationic cross-linking agent, and a medicament having moderate to poor solubility is disclosed. In certain embodiments, the sustained release excipient is granulated with a solution or suspension of a hydrophobic polymer in an amount effective to slow the hydration of the gelling agent when the formulation is exposed to an environmental fluid. In another embodiment, the tablet is coated with a hydrophobic polymer.

1 - 81 . (canceled)  
     
     
         82 . A method of preparing a sustained release excipient comprising: 
 dry blending a gelling agent, 
 an inert pharmaceutically acceptable diluent selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, and  
 a pharmaceutically acceptable cationic crosslinking agent capable of cross-linking with said gelling agent when exposed to an environmental fluid to increase the gel strength,  
 wherein said gelling agent is from about 10 to about 99 percent by weight of the excipient, said diluent is from about 0 to about 89 percent by weight, said cationic cross-linking agent is from about 1 to about 20 by weight of the excipient; said excipient is used to provide sustained release to a pharmaceutical formulation when said excipient is combined with a medicament.  
   
     
     
         83 . The method of  claim 82 , further comprising: 
 (i) adding water to the dry blend to form a mixture;    (ii) granulating the mixture of step (i);    (iii) drying the mixture of step (ii);    (iv) milling the mixture of step (iii).    
     
     
         84 . The method of  claim 82 , wherein said excipient is pre-manufactured.  
     
     
         85 . The method of  claim 82 , further comprising granulating said excipient with a solution of a hydrophobic material, said hydrophobic material being included in an amount effective to slow the hydration of the gelling agent without disrupting the hydrophilic matrix formed upon exposure to an environmental fluid.  
     
     
         86 . The method of  claim 85 , wherein said hydrophobic material is selected from the group consisting of an alkylcellulose, a hydrophobic cellulosic material, a copolymer of acrylic and methacrylic acid esters, shellac, waxes, zein and mixtures of any of the foregoing.  
     
     
         87 . The method of  claim 86 , wherein said hydrophobic material is ethylcellulose.  
     
     
         88 . The method of  claim 82 , wherein said gelling agent comprises xanthan gum and locust bean gum in a ratio of from about 1:3 to about 3:1.  
     
     
         89 . A method of preparing an oral solid dosage form comprising: 
 (i) dry blending 
 a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum when exposed to an environmental fluid,  
 an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, and  
 a pharmaceutically acceptable cationic cross-linking agent capable of cross-linking with said gelling agent and increasing the gel strength when the dosage form is exposed to an environmental fluid;  
   (ii) adding water to the dry blend of step (i) to form a mixture;    (iii) granulating the mixture of step (ii);    (iv) drying the mixture of step (iii);    (v) milling the mixture of step (iv);    (vi) adding to the milled mixture of step (v) an effective amount of a medicament having a solubility of less than about 10 g/l to render a therapeutic effect;    wherein the ratio of said heteropolysaccharide gum to said homopolysaccharide gum is from about 1:3 to about 3:1; wherein the ratio of said inert diluent to said gelling agent is from about 1:8 to about 8:1; and the ratio of said medicament to said gelling agent is from about 1:3 to about 1:8.    
     
     
         90 . The method of  claim 89 , further comprising granulating the mixture of step (v) with a hydrophobic material.  
     
     
         91 . The method of  claim 89 , wherein said medicament is a therapeutically effective dihydropyridine.  
     
     
         92 . The method of  claim 89 , wherein said medicament is nifedipine.  
     
     
         93 . The method of  claim 89 , wherein said cationic cross-linking agent is calcium sulfate.  
     
     
         94 . The method of  claim 89 , wherein said hydrophobic material is selected from the group consisting of an alkylcellulose, a hydrophobic cellulosic material, a copolymer of acrylic and methacrylic acid esters, shellac, waxes, zein and mixtures of any of the foregoing.  
     
     
         95 . The method of  claim 94 , wherein said hydrophobic material is ethylcellulose.  
     
     
         96 . A method of preparing an oral tablet comprising: 
 (i) dry blending 
 a gelling agent comprising xanthan gum and locust bean gum,  
 a pharmaceutically acceptable cationic cross-linking agent capable of cross-linking with said gelling agent and increasing the gel strength when the dosage form is exposed to environmental fluid, and  
 an inert pharmaceutical diluent;  
   (ii) adding a medicament having a solubility of less than about 10 g/l;    wherein the ratio of said xanthan gum to said locust bean gum in the gelling agent is from about 1:3 to about 3:1; wherein the ratio of said inert diluent to said gelling agent being from about 1:8 to about 8:1.    
     
     
         97 . The method of  claim 96  further comprising adding a pharmaceutically acceptable wetting agent to said medicament to form a mixture.  
     
     
         98 . The method of  claim 96  further comprising coating said tablet with a hydrophobic material selected from the group consisting of an alkylcellulose, a hydrophobic cellulosic material, a copolymer of acrylic and methacrylic acid esters, waxes, shellac, zein, hydrogenated vegetable oils, and mixtures of any of the foregoing; wherein said tablet is coated with said hydrophobic coating to a weight gain from about 1 to about 20 percent of the total weight of said tablet.  
     
     
         99 . The method of  claim 96  further comprising wet granulating the mixture of step (i).  
     
     
         100 . The method of  claim 96 , wherein the ratio of said medicament to said gelling agent being from about 1:3 to about 1:8.  
     
     
         101 . The method of  claim 96 , wherein said hydrophobic material is ethylcellulose.