Solid pharmaceutical dosage form

• US 8,025,899 B2
• Filed: 08/25/2004
• Issued: 09/27/2011
• Est. Priority Date: 08/28/2003
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Ghosh, Soumojeet, Berndl, Gunther, Reinhold, Ulrich, Liepold, Bernd, Alani, Laman, Breitenbach, Joerg, Rosenberg, Joerg
• Primary Examiner(s): Hui; San-Ming
• Assistant Examiner(s): CRUZ, KATHRIEN ANN
• Application Number:
  US10/925,442
• Publication Number:
  US 20050084529A1
• Time in Patent Office: 2,589 Days
• Field of Search: 514/365, 424/455
• US Class Current: 424/455
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 31/18 for HIV

Abstract

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.

Claims

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 μ

g 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.

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 μ

g h/ml/100 mg, and a dose-adjusted AUC, in dogs under non-fasting conditions, of lopinavir plasma concentration of at least 20 μ

g 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.

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.

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.