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 50° C. Preferably, the pharmaceutically acceptable surfactant has an HLB value of from about 4 to about 10.

1 . A solid pharmaceutical dosage form which comprises a solid dispersion of at least one HIV protease inhibitor in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein said HIV protease inhibitor is selected from the group consisting of (2S,3S,5S)-5-(N-(N-(N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxyhexane (ritonavir) and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane (lopinavir), and said water-soluble polymer has a Tg of at least about 50° C. and is present in an amount of from about 50 to about 85% by weight of the dosage form.  
   
   
       2 . The dosage form of  claim 1 , wherein said solid dispersion is a glassy solution or solid solution, and consists of one phase.  
   
   
       3 . The dosage form of  claim 2 , wherein said surfactant has an HLB value of from about 4 to about 10.  
   
   
       4 . The dosage form of  claim 2 , wherein said solid dispersion further comprises another pharmaceutically acceptable surfactant.  
   
   
       5 . The dosage form of  claim 2 , wherein said surfactant is a sorbitan fatty acid ester.  
   
   
       6 . The dosage form of  claim 2  which comprises, relative to the weight of the dosage form, from about 5 to about 30% by weight of said HIV protease inhibitor, from about 2 to about 20% by weight of said surfactant, and from about 0 to about 15% by weight of additives.  
   
   
       7 . The dosage form of  claim 2 , wherein said HIV protease inhibitor is ritonavir.  
   
   
       8 . The dosage form of  claim 7  which has a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least about 9 μg h/ml/100 mg.  
   
   
       9 . The dosage form of  claim 2 , wherein said HIV protease inhibitor is lopinavir.  
   
   
       10 . The dosage form of  claim 9  which has a dose-adjusted AUC, in dogs under non-fasting conditions, of lopinavir plasma concentration of at least about 20 μg h/ml/100 mg.  
   
   
       11 . The dosage form of  claim 2 , wherein said at least one HIV protease inhibitor includes ritonavir and lopinavir.  
   
   
       12 . The dosage form of  claim 11  which has a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least about 9 μg h/ml/100 mg and a dose-adjusted AUC of lopinavir plasma concentration of at least about 20 μg h/ml/100 mg.  
   
   
       13 . The dosage form of  claim 2 , wherein said water-soluble polymer has a Tg of from about 80 to about 180° C.  
   
   
       14 . The dosage form of  claim 2 , wherein said water-soluble polymer is a homopolymer or copolymer of N-vinyl pyrrolidone.  
   
   
       15 . The dosage form of  claim 2 , wherein said water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate.  
   
   
       16 . The dosage form of  claim 2  comprising at least one additive selected from flow regulators, disintegrants, bulking agents or lubricants.  
   
   
       17 . The dosage form of  claim 2  which contains, upon storage for about 6 weeks at about 40° C. and about 75% humidity, at least about 98% of the initial content of HIV protease inhibitor.  
   
   
       18 . The dosage form of  claim 1 , wherein said water-soluble polymer has a Tg of from about 80 to about 180° C., and said surfactant has an HLB value of from about 4 to about 10 and is present in an amount of from about 2 to about 20% by weight of the dosage form.  
   
   
       19 . 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 which has an HLB value of from about 4 to about 10 and is present in an amount of from about 2 to about 20% by weight of the dosage form.  
   
   
       20 . A process of preparing a solid dosage form of  claim 1 , comprising: 
 preparing a melt comprising said at last one HIV protease inhibitor, said at least one pharmaceutically acceptable water-soluble polymer and said at least one pharmaceutically acceptable surfactant; and    allowing the melt to solidify to obtain said solid dispersion.    
   
   
       21 . The process of  claim 20 , comprising grinding and compressing said solid dispersion into a tablet.  
   
   
       22 . A solid pharmaceutical dosage form comprising a solid dispersion of ritonavir in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein said water-soluble polymer has a Tg of at least about 50° C. and is present in an amount of from about 50% to about 85% by weight of the dosage form.  
   
   
       23 . The dosage form of  claim 22 , wherein said water-soluble polymer has a Tg of from about 80 to about 180° C.  
   
   
       24 . The dosage form of  claim 22 , wherein said water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate.  
   
   
       25 . The dosage form of  claim 22 , wherein said water-soluble polymer is a homopolymer or copolymer of N-vinyl pyrrolidone.  
   
   
       26 . A solid pharmaceutical dosage form comprising a solid dispersion of ritonavir and lopinavir in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein said water-soluble polymer has a Tg of at least about 50° C. and is present in an amount of from about 50 to about 85% by weight of the dosage form, and said surfactant has an HLB value of from about 4 to about 10 and is present in an amount of from about 2 to about 20% by weight of the dosage form.  
   
   
       27 . The dosage form of  claim 26 , wherein said solid dispersion is a glassy or solid solution, and consists of one phase.  
   
   
       28 . The dosage form of  claim 26 , wherein said water-soluble polymer has a Tg of from about 80 to about 180° C.  
   
   
       29 . The dosage form of  claim 26 , wherein said water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate, and said surfactant is a sorbitan fatty acid ester.  
   
   
       30 . The dosage form of  claim 26 , wherein said water-soluble polymer is a homopolymer or copolymer of N-vinyl pyrrolidone, and said surfactant is a sorbitan fatty acid ester.  
   
   
       31 . The dosage form of  claim 26 , wherein said water-soluble polymer is copovidone, and said surfactant is sorbitan monolaurate.  
   
   
       32 . The dosage form of  claim 26  comprising at least one additive selected from flow regulators, disintegrants, bulking agents or lubricants.  
   
   
       33 . A solid pharmaceutical dosage form comprising a solid or glassy solution of ritonavir and lopinavir in a matrix comprising a sorbitan fatty acid ester and a copolymer of N-vinyl pyrrolidone and vinyl acetate, wherein said ritonavir and lopinavir are present in an amount of from about 5 to about 30% by weight of the dosage form, said co-polymer is present in an amount of from about 50% to about 85% by weight of the dosage form, and said sorbitan fatty acid ester is present in an amount of from about 2% to about 20% by weight of the dosage form.  
   
   
       34 . The dosage form of  claim 33 , wherein said copolymer is copovidone, and said sorbitan fatty acid ester is sorbitan monolaurate.  
   
   
       35 . A solid pharmaceutical dosage form comprising a one-phase solid or glassy solution of at least one HIV protease inhibitor in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein said water-soluble polymer has a Tg of at least about 50° C. and is present in an amount of from about 50 to about 85% by weight of the dosage form.  
   
   
       36 . The dosage form of  claim 35 , wherein said surfactant has an HLB value of from about 4 to about 10.  
   
   
       37 . A method of treating HIV infection, comprising administering the solid dosage form of  claim 1  to a mammal in need of such treatment.  
   
   
       38 . A solid pharmaceutical dosage form which comprises a solid dispersion of at least one HIV protease inhibitor in at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein said water-soluble polymer has a Tg of at least about 50° C. and is present in an amount of from about 50 to about 85% by weight of the dosage form.  
   
   
       39 . A process of preparing a solid dosage form of  claim 38 , comprising: 
 preparing a melt comprising said at last one HIV protease inhibitor, said at least one pharmaceutically acceptable water-soluble polymer and said at least one pharmaceutically acceptable surfactant; and    allowing the melt to solidify to obtain said solid dispersion.    
   
   
       40 . A method of treating HIV infection, comprising administering the solid dosage form of  claim 38  to a mammal in need of such treatment.