Solid pharmaceutical dosage form
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 method of treating HIV, comprising administering a solid pharmaceutical dosage form to a patient in need thereof, wherein the dosage form comprises ritonavir formulated in solid dispersion, and said solid dispersion comprises (1) a pharmaceutically acceptable surfactant having an HLB value of from 4 to 10, or a combination of pharmaceutically acceptable surfactants having an HLB value of from 4 to 10, and (2) a pharmaceutically acceptable water-soluble polymer having a Tg of at least 50° C., or a combination of pharmaceutically acceptable water-soluble polymers having a Tg of at least 50° C., and wherein the dosage form comprises from 50% to 85% by weight of the total dosage form of said water-soluble polymer or said combination of water-soluble polymers.
2. The method of claim 1 , wherein said solid dispersion is glassy solution or solid solution.
3. The method of claim 2 , wherein said solid dispersion comprises a copolymer of N-vinyl pyrrolidone and vinyl acetate.
4. The method of claim 3 , wherein said solid dispersion comprises a sorbitan mono fatty acid ester.
5. The method of claim 2 , wherein said solid dispersion comprises copovidone and sorbitan monolaurate.
6. The method of claim 2 , wherein said surfactant or said combination of surfactants is present in an amount of from 2% to 20% by weight of the total dosage form.
7. The method of claim 2 , wherein the dosage form comprises at least one additive selected from flow regulators, disintegrants, bulking agents or lubricants.
8. The method of claim 2 , wherein the dosage from contains, upon storage for 6 weeks at 40° C. and 75% humidity, at least 98% of the initial content of ritonavir.
9. The method of claim 2 , wherein the 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.
10. The method of claim 1 , wherein the dosage form further comprises lopinavir formulated in solid dispersion.
11. The method of claim 2 , wherein the dosage form further comprises lopinavir formulated in solid solution or glassy solution.
12. The method of claim 2 , wherein the dosage form further comprises lopinavir formulated in solid solution or glassy solution which comprises (i) a pharmaceutically acceptable surfactant having an HLB value of from 4 to 10, or a combination of pharmaceutically acceptable surfactants having an HLB value of from 4 to 10, and (ii) a pharmaceutically acceptable water-soluble polymer having a Tg of at least 50° C. or a combination of pharmaceutically acceptable water-soluble polymers having a Tg of at least 50° C.
13. The method of claim 1 , wherein said solid dispersion comprises said pharmaceutically acceptable surfactant and said pharmaceutically acceptable water-soluble polymer, and said pharmaceutically acceptable water-soluble polymer is present in an amount of from 50% to 85% by weight of the total dosage form.
14. The method of claim 2 , wherein said solid dispersion comprises said pharmaceutically acceptable surfactant and said pharmaceutically acceptable water-soluble polymer, and said pharmaceutically acceptable water-soluble polymer is present in an amount of from 50% to 85% by weight of the total dosage form.
15. The method of claim 2 , wherein the dosage form comprises a copolymer of N-vinyl pyrrolidone and vinyl acetate in an amount of from 50% to 85% by weight of the total dosage form.
16. The method of claim 15 , wherein the dosage form comprises a sorbitan mono fatty acid ester in an amount of from 2% to 20% by weight of the total dosage form.
17. The method of claim 2 , wherein the dosage form comprises copovidone in an amount of from 50% to 85% by weight of the total dosage form, and sorbitan monolaurate in an amount of from 2% to 20% by weight of the total dosage form.
18. The method of claim 17 , wherein the dosage form further comprises lopinavir formulated in solid dispersion.
19. The method of claim 17 , wherein the dosage form further comprises lopinavir formulated in solid solution or glassy solution.
20. The method of claim 17 , wherein the dosage form further comprises lopinavir formulated in solid solution or glassy solution which comprises copovidone and sorbitan monolaurate.