Immediate release pharmaceutical granule compositions and a continuous process for making them

Abstract

An immediate or fast release pharmaceutical granule composition comprising at least one drug (i) classifiable as Class II or Class IV of the Biopharmaceutical Classification System, wherein the said drug constitutes at least about 0.5% by weight and no more than 50% by weight of the composition, the said composition further comprising (ii) a first excipient being a dextrin-containing compound and a second excipient (iii) being selected from the group consisting of polyethylene glycols and polypropylene glycols having weight number molecular weights between about 300 and 10,000, glycerol, propylene glycol and glycerides.

1 . An immediate or fast release pharmaceutical solid composition comprising at least one drug (i) classifiable as Class II or Class IV of the Biopharmaceutical Classification System, wherein said drug (i) constitutes no more than about 50% by weight of said pharmaceutical solid composition, and one or more pharmaceutically acceptable excipients, wherein said solid composition is in the form of granules and wherein said one or more pharmaceutically acceptable excipients comprise: 
 (ii) a first excipient being a dextrin-containing compound in an amount from about 40 to about 85% by weight of said composition, and    (iii) a second excipient comprising a solid fraction and optionally a liquid fraction, said second excipient (iii) being in an amount from about 10 to about 40% by weight of the composition and being selected from the group consisting of polyethylene glycols and polypropylene glycols having weight number molecular weights between about 300 and 10,000, glycerol, propylene glycol and glycerides.    
     
     
         2 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said drug (i) is selected from the group consisting of chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazide, ethacrinic acid, nitrendipine, itraconazole, troglitazone, atovaquone, danazol, glibenclamide, griseofulvin, ketoconazole, carbamazepine, florfenicol, sulfadiazine, acetohexamide, ajamaline, benzbromarone, benzyl benzoate, betamethasone, chloramphe-nicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicumarol, digitoxin, ethotoin, glutethimide, hydrocortisone, hydroflumethiazide, hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen, khellin, nitrazepam, nitrofurantoin, novalgin, oxazepam, papaverine, phenylbutazone, phenyloin, prednisolone, prednisone, reserpine, spironolactone, sulfabenzamide, sulfadimethoxine, sulfamerazine, sulfamethazine, sulfamethoxypyridazine, succinylsulfathiazole, sulfamethizole, sulfamethoxazole, sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride, testosterone and diaminopyrimidines.  
     
     
         3 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said dextrin-containing compound (ii) is selected from the group consisting of starch cyclic degradation products containing 6 to 8 glucose residues, and cyclic oligosaccharides composed of L-glucose molecules linked by α or β osidic bonds having a toric form.  
     
     
         4 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said dextrin-containing compound (ii) is selected from the group consisting of maltodextrins, cyclodextrins and derivatives thereof, including hydroxypropyl-β-cyclodextrin.  
     
     
         5 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said first excipient (ii) is a maltodextrin, said second excipient (iii) is a polyethylene glycol and the weight ratio of said first excipient (ii) to said second excipient (iii) is in a range from about 1:1 to 5:1.  
     
     
         6 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , being free from microcrystalline cellulose.  
     
     
         7 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said drug (i) has a water-solubility below about 2.5 mg/ml.  
     
     
         8 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said drug (i) has a water-solubility below about 5 μg/ml.  
     
     
         9 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , wherein said granules have a diameter ranging from about 100 and 2,500 μm.  
     
     
         10 . A continuous process for manufacturing a pharmaceutical granule composition comprising at least one drug (i) classifiable as Class II or Class IV of the Biopharmaceutical Classification System in an amount of no more than about 50% by weight of said pharmaceutical composition, a first excipient (ii) being a dextrin-containing compound in an amount from about 40 to about 85% by weight of said composition, and a second excipient (iii) comprising a solid fraction and optionally a liquid fraction, said second excipient (iii) being in an amount from about 10 to about 40% by weight of the composition and being selected from the group consisting of polyethylene glycols and polypropylene glycols having weight number molecular weights between about 300 and 10,000, glycerol, propylene glycol and glycerides, said process comprising the steps of: 
 (a) homogenising a mixture comprising said drug (i), said first excipient (ii) and the solid fraction of said second excipient (iii),    (b) feeding the mixture obtained in step (a) and optionally the liquid fraction of said second excipient (iii) into an extruding means having one or more mixing zones and one or more transport zones, and    (c) extruding the materials fed in step (b) while operating said extruding means at a temperature not above the melting temperature of the solid fraction of the second excipient until a pharmaceutical granule composition is obtained.    
     
     
         11 . A process according to  claim 10 , wherein said extruding means is a twin screw extruder.  
     
     
         12 . A process according to  claim 10 , wherein said extruding means is operated at a temperature not above about 60° C.  
     
     
         13 . A process according to  claim 10 , wherein said extruding means is operated at a rotating speed between about 5 and 450 rpm.  
     
     
         14 . A process according to  claim 10 , wherein said drug (i) is selected from the group consisting of chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazide, ethacrinic acid, nitrendipine, itraconazole, troglitazone, atovaquone, danazol, glibenclamide, griseofulvin, ketoconazole, carbamazepine, florfenicol, sulfadiazine, acetohexamide, ajamaline, benzbromarone, benzyl benzoate, betamethasone, chloramphe-nicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicumarol, digitoxin, ethotoin, glutethimide, hydrocortisone, hydroflumethiazide, hydro-quinine, indomethacin, ibuprofen, ketoprofen, naproxen, khellin, nitrazepam, nitrofurantoin, novalgin, oxazepam, papaverine, phenylbutazone, phenyloin, prednisolone, prednisone, reserpine, spironolactone, sulfabenzamide, sulfadimethoxine, sulfamerazine, sulfamethazine, sulfamethoxypyridazine, succinylsulfathiazole, sulfamethizole, sulfamethoxazole, sulfaphenazole, sulfathiazole, sulfisoxazole, sulpiride, testosterone and diaminopyrimidines.  
     
     
         15 . A process according to  claim 10 , wherein said drug (i) has a water-solubility below about 2.5 mg/ml.  
     
     
         16 . A process according to  claim 10 , wherein said drug (i) has a water-solubility below about 5 μg/ml.  
     
     
         17 . A process according to  claim 10 , wherein said granules have a diameter ranging from about 100 and 2,500 μm.  
     
     
         18 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , being water-soluble.  
     
     
         19 . An immediate or fast release pharmaceutical granule composition according to  claim 1 , in combination with animal feed or drinking water for oral administration to an animal.  
     
     
         20 . A method of treatment of a warm-blooded animal comprising administration to said animal of an effective amount of a pharmaceutical granule composition comprising at least one drug (i) classifiable as Class II or Class IV of the Biopharmaceutical Classification System in an amount of no more than about 50% by weight of said pharmaceutical composition, a first excipient (ii) being a dextrin-containing compound in an amount from about 40 to about 85% by weight of said composition, and a second excipient (iii) comprising a solid fraction and optionally a liquid fraction, said second excipient (iii) being in an amount from about 10 to about 40% by weight of the composition and being selected from the group consisting of polyethylene glycols and polypropylene glycols having weight number molecular weights between about 300 and 10,000, glycerol, propylene glycol and glycerides.  
     
     
         21 . A method of treatment according to  claim 20 , wherein said drug is florfenicol.