Solid pharmaceutical dosage form

Abstract

A solid pharmaceutical dosage form providing improved oral bioavailability is disclosed for inhibitors of HIV protease. In particular, the dosage form comprises a solid dispersion of at least one HIV protease inhibitor and at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, said pharmaceutically acceptable water-soluble polymer having a Tg of at least about 5° C. Preferably, the pharmaceutically acceptable surfactant has an HLB value of from about 4 to about 10.

What is claimed is: 
     
         1 . A solid pharmaceutical dosage form comprising a solid dispersion, wherein said solid dispersion comprises
 at least one HIV protease inhibitor, wherein said at least one HIV protease inhibitor comprises ritonavir;   at least one pharmaceutically acceptable surfactant having an HLB value of from about 4 to about 10 or a combination of pharmaceutically acceptable surfactants having an HLB value of from about 4 to about 10; and   at least one pharmaceutically acceptable water-soluble polymer having a Tg of at least about 50° C. or a combination of pharmaceutically acceptable water-soluble polymers having a Tg of at least about 50° C.   
     
     
         2 . The dosage form of  claim 1 , wherein said solid dispersion is a solid solution or a glassy solution. 
     
     
         3 . The dosage form of  claim 2 , wherein said solid dispersion is a solid solution. 
     
     
         4 . The dosage form of  claim 1 , wherein said surfactant is from about 2 to about 20% by weight of the total dosage form. 
     
     
         5 . The dosage form of  claim 1 , wherein said solid dispersion comprises a combination of pharmaceutically acceptable surfactants having an HLB value of from about 4 to about 10. 
     
     
         6 . The dosage form of  claim 1 , wherein said surfactant is a sorbitan fatty acid ester. 
     
     
         7 . The dosage form of  claim 6 , wherein said surfactant is sorbitan monolaurate. 
     
     
         8 . The dosage form of  claim 1 , wherein said water-soluble polymer is from about 50 to about 85% by weight of the total dosage form. 
     
     
         9 . The dosage form of  claim 1 , wherein said water-soluble polymer has a Tg of from about 80 to about 180° C. 
     
     
         10 . The dosage form of  claim 1 , wherein said solid dispersion comprises a combination of pharmaceutically acceptable water-soluble polymers having a Tg of at least about 50° C. 
     
     
         11 . The dosage form of  claim 1 , wherein said pharmaceutically acceptable water-soluble polymer is selected from the group consisting of homopolymer of N-vinyl lactam, copolymer of N-vinyl lactam, cellulose ester, cellulose ether, polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligosaccharide, and polysaccharide. 
     
     
         12 . The dosage form of  claim 11 , wherein said pharmaceutically acceptable water-soluble polymer is selected from the group consisting of homopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinyl pyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydloxyalkylcelluloses, hydloxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly(hydloxyalkyl acrylate), poly(hydloxyalkyl methacrylate), copolymer of vinyl acetate and crotonic acid, partially hydlolyzed polyvinyl acetate, carrageenan, galactomannan, and xanthan gum. 
     
     
         13 . The dosage form of  claim 12 , wherein said water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate. 
     
     
         14 . The dosage form of  claim 13 , wherein said at least one pharmaceutically acceptable water-soluble polymer comprises copovidone. 
     
     
         15 . The dosage form of  claim 1 , wherein said surfactant is from about 2 to about 20% by weight of the total dosage form, and said water-soluble polymer is from about 50 to about 85% by weight of the total dosage form. 
     
     
         16 . The dosage form of  claim 1 , wherein said water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate, and said surfactant is a sorbitan fatty acid ester. 
     
     
         17 . The dosage form of  claim 1 , wherein said water-soluble polymer is copovidone, and said surfactant is sorbitan monolaurate. 
     
     
         18 . The dosage form of  claim 1 , wherein said dosage form is prepared by a process comprising solidifying a melt comprising ritonavir, said at least one pharmaceutically acceptable surfactant, and said at least one pharmaceutically acceptable water-soluble polymer. 
     
     
         19 . The dosage form of  claim 1 , wherein said solid dispersion is prepared by melt-extrusion, spray-drying or solution evaporation. 
     
     
         20 . The dosage form of  claim 1  which contains, upon storage for 6 weeks at 40° C. and 75% humidity, at least 98% of the initial content of ritonavir. 
     
     
         21 . The dosage form of  claim 1 , wherein said dosage form improves ritonavir bioavailability in dogs as compared to the same dosage form without surfactant having an HLB value of from 4 to 10. 
     
     
         22 . The dosage form of  claim 1 , wherein said dosage form has a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least 9 μg h/ml/100 mg. 
     
     
         23 . The dosage form of  claim 1 , wherein the at least one HIV protease inhibitor further comprises lopinavir. 
     
     
         24 . The dosage form of  claim 23 , wherein said dosage form improves ritonavir and lopinavir bioavailability in dogs as compared to the same dosage form without surfactant having an HLB value of from 4 to 10. 
     
     
         25 . The dosage form of  claim 23 , wherein said dosage form has a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least 9 μg h/ml/100 mg, and a dose-adjusted AUC, in dogs under non-fasting conditions, of lopinavir plasma concentration of at least 20 μg h/ml/100 mg.