Claims for Patent: 6,458,818

Summary for Patent: 6,458,818

Title:	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).
Inventor(s):	Lipari; John (Racine, WI), Al-Razzak; Laman A. (Lake Forest, IL), Ghosh; Soumojeet (Lindenhurst, IL), Gao; Rong (Park City, IL), Kaul; Dilip (Gurnee, IL)
Assignee:	Abbott Laboratories (Abbott Park, IL)
Application Number:	09/347,077
Patent Claims:	1. A pharmaceutical composition for oral administration which is a solution comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl4-thiazolyl)methyl)amino)carb onyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl- 3-hydroxyhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane, (b) a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid selected from the group consisting of saturated, mono-unsaturated and di-unsaturated C.sub.12 to C.sub.18 carboxylic acids which are liquids at room temperature or a mixture of the 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) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl4-thiazolyl)methyl)amino)carb onyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl- 3-hydroxyhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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 selected from the group consisting of saturated, mono-unsaturated and di-unsaturated C.sub.12 to C.sub.18 carboxylic acids which are liquids at room temperature in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of (1) the 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 selected from the group consisting of saturated, mono-unsaturated and di-unsaturated C.sub.12 to C.sub.18 carboxylic acids which are liquids at room temperature 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 selected from the group consisting of saturated, mono-unsaturated and di-unsaturated C.sub.12 to C.sub.18 carboxylic acids which are liquids at room temperature 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 Veto 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 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazoly6)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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 selected from the group consisting of saturated, mono-unsaturated and di-unsaturated C.sub.12 to C.sub.18 carboxylic acids which are liquids at room temperature in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of (1) the 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. 8. The composition of claim 7 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl4-thiazolyl)methyl)amino)carb onyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl- 3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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 (i) a pharmaceutically acceptable long chain fatty acid selected from the group consisting of saturated, mono-unsaturated and di-unsaturated C.sub.12 to C.sub.18 carboxylic acids which are liquids at room temperature in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of (1) the 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. 9. The composition of claim 7 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl4-thiazoyl)methyl)amino)carbo nyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3 -hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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 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. 10. The composition of claim 9 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bony)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl- 3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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 (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. 11. The composition of claim 9 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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% and (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 12. The composition of claim 11 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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% and (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 13. The composition of claim 7 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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% and (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 14. The composition of claim 7 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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% and (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 15. The composition of claim 7 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl4-thiazolyl)methyl)amino)carb onyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl- 3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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% and (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 16. The composition of claim 7 comprising a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in a ratio (w/w) of from about 1:16 to about 5:1. 17. The composition of claim 16 comprising a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in a ratio (w/w) of from about 1:8 to about 3:1. 18. The composition of claim 1 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 19. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 20. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-methylbutanoyl)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. 21. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 25% 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. 22. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 23. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 24. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 25. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 26. The composition of claim 18 comprising (a) a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane 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-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)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. 27. The composition of claim 18 comprising a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in a ratio (w/w) of from about 1:16 to about 5:1. 28. The composition of claim 27 comprising a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in a ratio (w/w) of from about 1:8 to about 3:1. 29. The composition of claim 18 comprising a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in a ratio (w/w) of about 1:4. 30. The composition of claim 7 comprising a mixture of (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)car bonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl -3-hydroxyhexane diphenylhexane and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in a ratio (w/w) of about 1:4.