Pharmaceutical composition

Abstract

A liquid pharmaceutical composition providing improved oral bioavailability is disclosed for compounds which are inhibitors of HIV protease. In particular, the composition comprises a solution in a pharmaceutically acceptable organic solvent of (a) the HIV protease inhibitor and, optionally, (b) a surfactant. The composition can optionally be encapsulated in either hard gelatin capsules or soft elastic capsules (SEC).

What is claimed is:  
     
         1 . A pharmaceutical composition which is a solution comprising 
 (a) an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds,    (b) a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol,    and, optionally,    (c) a pharmaceutically acceptable surfactant.    
     
     
         2 . The composition of  claim 1  comprising 
 (a) an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution and 
 (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% by weight of the total solution.  
 
 
     
     
         3 . The composition of  claim 1  wherein the solution is encapsulated in a hard gelatin capsule or a soft elastic gelatin capsule.  
     
     
         4 . The composition of  claim 1  wherein the solvent comprises (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 70% by weight of the total solution and (2) ethanol or propylene glycol in the amount of from about 1% to about 15% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 1% to about 15% by weight of the total solution.  
     
     
         5 . The composition of  claim 1  wherein the solvent comprises (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 70% by weight of the total solution and (2) ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 5% to about 15% by weight of the total solution.  
     
     
         6 . The composition of  claim 1  wherein the solvent comprises (1) oleic acid in the amount of from about 40% to about 70% by weight of the total solution and (2) ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 10% to about 15% by weight of the total solution.  
     
     
         7 . The composition of  claim 1  wherein the HIV protease inhibiting compound is selected from the group consisting of: 
 (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6 diphenyl-3-hydroxyhexane (ritonavir);  
 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane;  
 N-(2(R)-hydroxy-1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide (indinavir);  
 N-tert-butyl-decahydro-2-(2(R)-hydroxy-4-phenyl-3(S)-)) N-(2-quinolylcarbonyl)-L-asparaginyl)amino)butyl)-(4aS,8aS)-isoquinoline-3(S)-carboxamide (saquinavir);  
 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide;  
 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide;  
 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1 ,3-thiazolidine-4-t-butylamide;  
 (1S-(1R*(R*),2S*)}-N 1 (3-((((1,1-dimethylethyl)amino]carbonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide;  
                     
 or a pharmaceutically acceptable salt of any of the above.  
 
     
     
         8 . The composition of  claim 1  wherein the HIV protease inhibiting compound is ritonavir, (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, indinavir, saquinavir, nelfinavir or VX-478.  
     
     
         9 . The composition of  claim 1  wherein the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and another HIV protease inhibiting compound.  
     
     
         10 . The composition of  claim 1  wherein the combination of HIV protease inhibiting compounds is: 
 ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane;  
 ritonavir and indinavir;  
 ritonavir and saquinavir;  
 ritonavir and nelfinavir;  
 ritonavir and VX-478;  
 saquinavir and nelfinavir;  
 indinavir and nelfinavir;  
 nelfinavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane; or  
 nelfinavir and VX-478.  
 
     
     
         11 . The composition of  claim 1  wherein the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane.  
     
     
         12 . The composition of  claim 1  comprising 
 (a) ritonavir in the amount of from about 1% to about 30% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% by weight of the total solution.  
 
     
     
         13 . The composition of  claim 12  wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC).  
     
     
         14 . The composition of  claim 12  comprising 
 (a) ritonavir in the amount of from about 5% to about 25% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 6% to about 12% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 5% to about 10% by weight of the total solution.  
 
     
     
         15 . The composition of  claim 14  wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC).  
     
     
         16 . The composition of  claim 1  comprising 
 (a) ritonavir in the amount of from about 1% to about 30% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 15% to about 99% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 15% to about 99% by weight of the total solution and 
 (2) ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution.  
 
 
     
     
         17 . The composition of  claim 16  comprising 
 (a) ritonavir in the amount of from about 5% to about 25% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 30% to about 70% by weight of the total solution and  
 (2) ethanol in the amount of from about 10%to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 10% to about 15% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution.  
 
     
     
         18 . The composition of  claim 16  wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC).  
     
     
         19 . The composition of  claim 16  comprising 
 (a) ritonavir in the amount of about 20% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 62% to about 64% by weight of the total solution and (2) ethanol in the amount of from about 10% to about 12% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 6% by weight of the total solution.  
 
     
     
         20 . The composition of  claim 16  comprising 
 (a) ritonavir in the amount of about 20% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises 
 a mixture of (1) oleic acid in the amount of about 65% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 5% by weight of the total solution.  
 
 
     
     
         21 . The composition of  claim 16  comprising 
 (a) ritonavir in the amount of about 20% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 60% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         22 . The composition of  claim 1  comprising 
 (a) (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% by weight of the total solution.  
 
     
     
         23 . The composition of  claim 22  comprising 
 (a) (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 5% to about 35% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 6% to about 12% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 2% to about 20% by weight of the total solution.  
 
     
     
         24 . The composition of  claim 22  comprising 
 (a) (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 20% to about 99% by weight of the total solution and (2) ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution  
 
     
     
         25 . The composition of  claim 24  comprising 
 (a) (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 5% to about 35% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 30% to about 70% by weight of the total solution and (2) ethanol in the amount of from about 10%to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution.  
 
     
     
         26 . The composition of  claim 22  comprising 
 (a) (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises 
 a mixture of (1) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         27 . The composition of  claim 1  comprising 
 (a) a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic. solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 98% by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% by weight of the total solution.  
 
     
     
         28 . The composition of  claim 27  comprising 
 (a) a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and another HIV protease inhibitor in the amount of from about 5% to about 40% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 6% to about 120% by weight of the total solution and  
 (c) a pharmaceutically acceptable surfactant in the amount of from about 5% to about 10% by weight of the total solution.  
 
     
     
         29 . The composition of  claim 27  comprising 
 (a) a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 10% to about 98% by weight of the total solution and (2) ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution.  
 
     
     
         30 . The composition of  claim 29  comprising 
 (a) a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and another HIV protease inhibitor in the amount of from about 5% to about 40% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 30% to about 70% by weight of the total solution and 
 (2) ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 10% to about 15% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution.  
 
 
     
     
         31 . The composition of  claim 29  comprising 
 (a) a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 10% to about 88% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         32 . The composition of  claim 31  comprising 
 (a) a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 40% to about 65% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in.  
 
     
     
         33 . The composition of  claim 27  comprising 
 (a) a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 45% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         34 . The composition of  claim 27  comprising 
 (a) a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         35 . The composition of  claim 27  comprising 
 (a) a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 5% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 60% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and  
 (c) polypxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         36 . The composition of  claim 27  comprising a mixture of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, the ratio (w/w) of ritonavir to (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane being from about 1:16 to about 5:1.  
     
     
         37 . The composition of  claim 36  comprising a mixture of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, the ratio (w/w) of ritonavir to (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane being from about 1:8 to about 3:1.  
     
     
         38 . The composition of  claim 1  comprising 
 (a) a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibiting compound in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 10% to about 88% by weight of the total solution and (2) propylene glycol in the amount of from about 5% to about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         39 . The composition of  claim 38  comprising 
 (a) a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 40% to about 65% by weight of the total solution and (2) propylene glycol in the amount of from about 6% to about 8% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         40 . The composition of  claim 38  comprising 
 (a) a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 10% to about 88% by weight of the total solution and (2) propylene glycol in the amount of from about 5% to about 10% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         41 . The composition of  claim 40  comprising 
 (a) a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 40% to about 65% by weight of the total solution and (2) propylene glycol in the amount of from about 6% to about 8% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         42 . The composition of  claim 41  comprising 
 (a) a mixture of ritonavir in the amount of about 6.0% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         43 . The composition of  claim 41  comprising a solution of (a) a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 25% by weight of the total solution and 
 (b) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution.  
 
     
     
         44 . The composition of  claim 41  comprising 
 (a) a mixture of ritonavir in the amount of about 8% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         45 . The composition of  claim 41  comprising 
 (a) a mixture of ritonavir in the amount of about 8.25% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 22% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.25% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         46 . The composition of  claim 41  comprising 
 (a) a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 47.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         47 . The composition of  claim 41  comprising 
 (a) a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         48 . The composition of  claim 41  comprising 
 (a) a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane in the amount of about 17% by weight of the total solution,  
 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and  
 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution.  
 
     
     
         49 . The composition of  claim 41  comprising a mixture of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, the ratio (w/w) of ritonavir to (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane being from about 1:16 to about 5:1.  
     
     
         50 . The composition of  claim 47  comprising a mixture of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, the ratio (w/w) of ritonavir to (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane being from about 1:8 to about 3:1.