Solid Pharmaceutical Dosage Formulation

Abstract

The present invention provides a pharmaceutical dosage formulation, and more particularly, a pharmaceutical dosage formulation comprising an HIV protease inhibitor.

1 . A solid pharmaceutical dosage form comprising an undissolved form of lopinavir in a therapeutically effective amount wherein when said dosage form is dissolved in vitro using a USP apparatus 2 (paddle) at 75 rpm with a 0.06M POEIOLE (Polyoxyethylene 10 Lauryl Ether) medium at 37° C., 20% to 30% of lopinavir in said dosage form is released from 0 to 15 minutes, or 43% to 63% of lopinavir in said dosage form is released from 15 to 30 minutes, or 61.3% to 81.7% of lopinavir in said dosage form is released from 30 to 45 minutes, or 75.4% to 93.2% of lopinavir in said dosage form is released from 45 to 60 minutes. 
   
   
       2 . The dosage form of  claim 1 , wherein said undissolved form is an amorphous form. 
   
   
       3 . The dosage form of  claim 1 , wherein upon administration of said dosage form to each member of a study population, the mean of lopinavir AUC∞ (fed) over lopinavir AUC∞ (fasted) ratios for all members of the study population is from 0.7 to 1.43. 
   
   
       4 . The dosage form of  claim 1 , wherein upon administration of said dosage form to each member of a study population, the mean of lopinavir Cmax (fed) over lopinavir Cmax (fasted) ratios for all members of the study population is from 0.7 to 1.43. 
   
   
       5 . The dosage form of  claim 1 , wherein upon administration of said dosage form to each member of a study population under fasting conditions, the 5 th  percentile of lopinavir AUC∞ in the study population is greater than 30 μg·h/mL; or the mean of lopinavir AUC∞ in the study population is between 60 μg·h/mL and 95 μg·h/mL. 
   
   
       6 . The dosage form of  claim 1 , wherein upon administration of said dosage form to each member of a study population under fed conditions, the 5 th  percentile of lopinavir AUC∞ in the study population is greater than 50 μg·h/mL. 
   
   
       7 . The dosage form of  claim 1 , wherein upon administration of said dosage form to each member of a study population under fasting conditions, the 5 th  percentile of lopinavir Cmax in the study population is greater than 2.5 μg/mL. 
   
   
       8 . A solid pharmaceutical dosage form comprising a solid dispersion or solid solution of lopinavir in a matrix, said matrix comprising at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein when said dosage form is dissolved in vitro using a USP apparatus 2 (paddle) at 75 rpm with a 0.06M POEIOLE (Polyoxyethylene 10 Lauryl Ether) medium at 37° C., 20% to 30% of lopinavir in said dosage form is released from 0 to 15 minutes, or 43% to 63% of lopinavir in said dosage form is released from 15 to 30 minutes, or 61.3% to 81.7% of lopinavir in said dosage form is released from 30 to 45 minutes, or 75.4% to 93.2% of lopinavir in said dosage form is released from 45 to 60 minutes. 
   
   
       9 . The dosage form of  claim 8 , wherein said surfactant having an HLB value of from 4 to 10. 
   
   
       10 . The dosage form of  claim 8 , wherein each of said at least one pharmaceutically acceptable water-soluble polymer has a Tg of at least 50° C., and each of said at least one pharmaceutically acceptable surfactant has an HLB value of from 4 to 10. 
   
   
       11 . The dosage form of  claim 10 , wherein said at least one pharmaceutically acceptable surfactant accounts for at least 50% by weight of the total amount of all surfactants comprised in said dosage form. 
   
   
       12 . The dosage form of  claim 10 , wherein said at least one pharmaceutically acceptable water-soluble polymer comprises a copolymer of N-vinyl pyrrolidone and vinyl acetate, and said at least one pharmaceutically acceptable surfactant comprises a sorbitan mono fatty acid ester. 
   
   
       13 . The dosage form of  claim 10 , wherein said dosage form comprises from 50 to 85% by weight of the dosage form of said at least one pharmaceutically acceptable water-soluble polymer, and from 2 to 20% by weight of the dosage form of said at least one pharmaceutically acceptable surfactant. 
   
   
       14 . The dosage form of  claim 13 , wherein said at least one pharmaceutically acceptable water-soluble polymer is copovidone, and said at least one pharmaceutically acceptable surfactant is sorbitan monolaurate. 
   
   
       15 . The dosage form of  claim 14 , wherein said dosage form further comprises ritonavir, and said solid dispersion or solid solution is a solid solution. 
   
   
       16 . The dosage form of  claim 8 , wherein upon administration of said dosage form to each member of a study population under fasting conditions, the 5 th  percentile of lopinavir AUC∞ in the study population is greater than 30 μg·h/mL; or the mean of lopinavir AUC∞ in the study population is between 60 μg·h/mL and 95 μg·h/mL. 
   
   
       17 . The dosage form of  claim 8 , wherein upon administration of said dosage form to each member of a study population under fed conditions, the 5 th  percentile of lopinavir AUC∞ in the study population is greater than 50 μg·h/mL. 
   
   
       18 . A solid pharmaceutical dosage form comprising an undissolved form of lopinavir or a solid dispersion or solid solution of lopinavir in a matrix, said matrix comprising at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein upon administration of said dosage form to each member of a study population under fasting conditions, the 5 th  percentile of lopinavir AUC∞ in the study population is greater than 30 μg·h/mL; or the mean of lopinavir AUC∞ in the study population is between 60 μg·h/mL and 95 μg·h/mL. 
   
   
       19 . A solid pharmaceutical dosage form comprising an undissolved form of ritonavir or a solid dispersion or solid solution of ritonavir in a matrix, said matrix comprising at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein when said dosage form is dissolved in vitro using a USP apparatus 2 (paddle) at 75 rpm with a 0.06M POE10LE (Polyoxyethylene 10 Lauryl Ether) medium at 37° C., from 19.8% to 34.4% of ritonavir in said dosage form is released from 0 to 15 minutes, or from 41.6% to 76.5% of ritonavir in said dosage form is released from 15 to 30 minutes, or from 59.4% to 91.1% of ritonavir in said dosage form is released from 30 to 45 minutes, or from 73.4% to 95% of ritonavir in said dosage form is released from 45 to 60 minutes; or wherein upon administration of said dosage form to each member of a study population under fasting conditions, the 5 th  percentile of ritonavir AUC∞ in the study population is greater than 30 μg·h/mL; or the mean of ritonavir AUC∞ in the study population is between 60 μg·h/mL and 95 μg·h/mL. 
   
   
       20 . The dosage form of  claim 19 , wherein said dosage form comprises said solid dispersion or solution, and said dosage form comprises from 50 to 85% by weight of the dosage form of said at least one pharmaceutically acceptable water-soluble polymer, and each of at least one pharmaceutically acceptable water-soluble polymer has a Tg of at least 50° C.