Novel solid pharmaceutical dispersions

Abstract

A novel solid pharmaceutical dispersion that improves the bioavailability of poorly water soluble drugs is produced by combining the drug with a polymer carrier such as polyvinylpyrrolidone. The drug is combined with the carrier without the need for using organic solvents or melting temperatures (fusion) through the use of a transition compound such as polyethylene glycol which partially solubilizes the drug and/or plasticizes the polymer.

What we claim is:  
     
         1 . A process for the preparation of a poorly water soluble drug in solid dispersion comprising 
 a) blending the drug with a carrier;    b) dissolving a surfactant and a plasticizer/solubilizer in water;    c) spraying the surfactant-plasticizer/solubilizer solution onto the drug/carrier mixture in a fluid bed granulator;    d) extruding the resulting granulation through a twin screw extruder with at least one heating zone; and,    e) milling the extrudate to a powdery mass of the solid drug dispersion.    
     
     
         2 . The process of  claim 1  wherein said drug is selected from the group consisting of acetohexamide, ajamaline, amylobarbitone, bendrofluozide, benzbromarone, benzonatate, benzylbenzoate, betamethazone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, corticesteroids, diazepam, dicumerol, digitoxin, dihydroxypropyltheophylline, ergot alkaloids, ethotoin, frusemide, glutethimide, griseofulvin, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkyl-xanthines, indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin, meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin, novalgin, nystatin, papaverine, paracetamol, phenylbutazone, phenobarbitone, prednisolone, prednisone, primadone, reserpine, romglizone, salicylic acid, spiranolactone, sulphabenzamide, sulphadiamadine, sulphamethoxydiazine, sulphamerazine, succinylsulphathiazole, sulphamethizole, sulphamethoxazole, sulphathiazole, sulphisoxazole, testosterone, tolazoline, tolbutamide, trifluoperazine, trimethaprim and mixtures thereof.  
     
     
         3 . The process of  claim 2  wherein said carrier is selected from the group consisting of polyvinyl pyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, Eudragit® acrylic polymers, succinic acid, sugars and mixtures thereof.  
     
     
         4 . The process of  claim 3  wherein said plasticizer/solubilizer is selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof.  
     
     
         5 . The process of  claim 4  wherein said surfactant is selected from the group consisting of Tween, Span, Plumonics, polyoxyethylene sorbitol esters, monodiglycerides, polyoxyethylene acid polyoxyethylene alcohol and mixtures thereof.  
     
     
         6 . The process of  claim 5  wherein said granulation is extruded at a temperature less than the decomposition point of said drug.  
     
     
         7 . The process of  claim 6  wherein said drug and carrier are mixed in ratios of from about 1:9 to about 5:1 respectively, on a percent weight basis.  
     
     
         8 . The process of  claim 7  wherein said drug and carrier are mixed in a ratio of from about 3:1 to about 1:3 respectively, on a percent weight basis.  
     
     
         9 . A solid pharmaceutical dispersion with improved solubility characteristics consisting essentially of a poorly water soluble drug and; 
 a) a carrier selected from the group consisting of polyvinyl pyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, Eudragit® acrylic polymers, succinic acid and mixtures thereof and,    b) a solubilizer/plasticizer selected from the group consisting of polyols, phthalate esters, glycerol esters, citrate esters, sugar alcohols and mixtures thereof.    
     
     
         10 . The solid pharmaceutical dispersion of  claim 9  wherein said poorly water soluble drug is selected from the group consisting of acetohexamide, ajamaline, amylobarbitone, bendrofluozide, benzbromarone, benzonatate, benzylbenzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, corticesteroids, diazepam, dicumerol, digitoxin, dihydroxypropyltheophylline, ergot alkaloids, ethotoin, frusemide, glutethimide, griseofulvin, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkyl-xanthines, indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin, meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin, novalgin, nystatin, papaverine, paracetamol, phenylbutazone,. phenobarbitone, prednisolone, prednisone, primadone, reserpine, romglizone, salicylic acid, spiranolactone, sulphabenzamide, sulphadiamadine, sulphamethoxydiazine, sulphamerazine, succinylsulphathiazole, sulphamethizole, sulphamethoxazole, sulphathiazole, sulphisoxazole, testosterone, tolazoline, tolbutamide, trifluoperazine, trimethaprim and mixtures thereof.  
     
     
         11 . The solid pharmaceutical dispersion of  claim 10  wherein said drug and carrier are formulated in ratios of from about 1:9 to about 5:1 respectively, on a percentage weight basis.  
     
     
         12 . The solid pharmaceutical dispersion of  claim 11  wherein said drug and said carrier are formulated in ratios of from about 3:1 to about 1:3, respectively on a percentage weight basis.  
     
     
         13 . A solid pharmaceutical dispersion with improved solubility characteristics comprised of a poorly water soluble drug and a carrier produced by the process consisting of: 
 a) mixing said drug and the carrier in a ratio of approximately 1:9 to about 5:1 respectively, on a percent weight basis;    b) spraying onto said mixture a solution consisting of a plasticizer/solubilizer, and optionally, a surfactant;    c) extruding the resultant granulation in a twin screw extruder with at least one heating zone; and    d) milling the extrudate to a powdery mass.    
     
     
         14 . The solid pharmaceutical dispersion of  claim 13  wherein said drug is selected from the group consisting of acetohexamide, ajamaline, amylobarbitone, bendrofluozide, benzbromarone, benzonatate, benzylbenzoate, betamethazone, chloramphenicol, chlorpropamid, chlorthalidone, clofibrate, corticesteroids, diazepam, dicumerol, digitoxin, dihydroxypropyltheophylline, ergot alkaloids, ethotoin, frusemide, glutethimid, griseofulvin, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, hydroquinone, hydroxyalkyl-xanthines, indomethacin, isoxsuprine hydrochloride, ketoprofen, khellin, meprobamate, nabilone, nicotainamide, nifedipine, nitrofurantoin, novalgin, nystatin, papaverine, paracetamol, phenylbutazone, phenobarbitone, prednisolone, prednisone, primadone, reserpine, romglizone, salicylic acid, spiranolactone, sulphabenzamide, sulphadiamadine, sulphamethoxydiazine, sulphamerazine, succinylsulphathiazole, sulphamethizole, sulphamethoxazole, sulphathiazole, sulphisoxazole, testosterone, tolazoline, tolbutamide, trifluoperazine, trimethaprim and mixtures thereof.  
     
     
         15 . The solid pharmaceutical dispersion of  claim 14  wherein said carrier is selected from the group consisting of polyvinyl pyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, Eudragit® acrylic polymers, succinic acid, sugars and mixtures thereof.  
     
     
         16 . The solid pharmaceutical disperson of  claim 15  wherein said plasticizer/solubilizer is selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof.  
     
     
         17 . The solid pharmaceutical dispersion of  claim 16  wherein said surfactant is selected from the group consisting of Tween, Span, Pluronics, polyoxyethylene sorbitol esters, polyoxyethylene acid, polyoxyethylene alcohols and mixtures thereof.  
     
     
         18 . The solid pharmaceutical dispersion of  claim 17  wherein said extrusion is carried out at a temperature below the decomposition point of said drug.  
     
     
         19 . The solid pharmaceutical dispersion of  claim 18  wherein said extrusion occurs at a rate of approximately 2 gm/sec. to about 7 gm/sec.