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 solid pharmaceutical dosage form which includes a solid dispersion comprising:
ritonavir,
lopinavir,
a pharmaceutically acceptable water-soluble polymer having a Tg of at least 50° C., and
sorbitan monolaurate.
2. The solid dosage form of claim 1 which contains, upon storage for 6 weeks at 40° C. and 75% humidity, at least 98% of the initial content of ritonavir.
3. The solid dosage form of claim 1 which has a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least 9 μg h/ml/100 mg.
4. The solid dosage form of claim 1 , wherein said solid dispersion is a glassy or solid solution.
5. The solid dosage form of claim 4 , wherein said pharmaceutically acceptable water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate.
6. The solid dosage form of claim 4 , wherein said pharmaceutically acceptable water-soluble polymer is copovidone.
7. A solid pharmaceutical dosage form which includes a solid dispersion comprising:
ritonavir,
lopinavir,
from 50 to 85% by weight of the total dosage form of copovidone, and
from 2 to 20% by weight of the total dosage form of sorbitan monolaurate.
8. The solid dosage form of claim 7 , wherein said solid dispersion is a glassy or solid solution.
9. The dosage form of claim 1 , wherein said pharmaceutically acceptable water-soluble polymer is selected from the group consisting of homopolymer of N-vinyl lactam, copolymer of N-vinyl lactam, cellulose ester, cellulose ether, polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligosaccharide, and polysaccharide.
10. The dosage form of claim 1 , wherein said pharmaceutically acceptable water-soluble polymer is selected from the group consisting of homopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinyl pyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyalkylcelluloses, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymer of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, and xanthan gum.
11. The dosage form of claim 1 which has a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least 9 μg h/ml/100 mg, and a dose-adjusted AUC, in dogs under non-fasting conditions, of lopinavir plasma concentration of at least 20 μg h/ml/100 mg.
12. The solid dosage form of claim 1 , wherein said pharmaceutically acceptable water-soluble polymer is present in an amount of from 50% to 85% by weight of the dosage form, and said sorbitan monolaurate is present in an amount of from 2% to 20% by weight of the dosage form.
13. The solid dosage form of claim 1 , wherein said dosage form markedly improves ritonavir and lopinavir bioavailability in beagle dogs as compared to the same dosage form but without any surfactant.
14. The solid dosage form of claim 7 , wherein said dosage form markedly improves ritonavir and lopinavir bioavailability in beagle dogs as compared to the same dosage form but without any surfactant.