Solid pharmaceutical dosage form

• US 20050084529A1
• Filed: 08/25/2004
• Published: 04/21/2005
• Est. Priority Date: 08/28/2003
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Breitenbach, Jorg, Ghosh, Soumojeet, Alani, Laman L., Berndl, Gunther, Reinhold, Ulrich, Liepold, Bernd, Rosenberg, Joerg
• Granted Patent: US 8,025,899 B2
• Time in Patent Office: Days
• US Class Current: 424/464
• 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 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.

2. The dosage form of claim 1 comprising a glassy solution or solid solution of said HIV protease inhibitor.

3. The dosage form of claim 1, wherein said pharmaceutically acceptable surfactant has an HLB value of from about 4 to about 10.

4. The dosage form of claim 1, wherein said pharmaceutically acceptable surfactant is a combination of at least one pharmaceutically acceptable surfactant having an HLB value of from about 4 to about 10 and at least one further pharmaceutically acceptable surfactant.

5. The dosage form of claim 1 wherein said pharmaceutically acceptable surfactant is a sorbitan fatty acid ester.

6. The dosage form of claim 1 which comprises, relative to the weight of the dosage form, from about 5 to about 30% by weight of said HIV protease inhibitor, from about 50 to about 85% by weight of said water-soluble polymer, from about 2 to about 20% by weight of said surfactant, and from about 0 to about 15% by weight of additives.

7. The dosage form of claim 1, wherein said HIV protease inhibitor is selected from the group consisting of:

2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4- thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-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-methylbutanoyl]amino-1,6-diphenylhexane (lopinavir);

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-4t-butylamide;

5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide;

[1S-[R-(R-),2S*])-N′

-[3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylpropyl)amino]-2hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide;

amprenavir (VX-478);

DMP-323;

DMP-450;

AG1343 (nelfinavir);

atazanavir (BMS 232,632)

tipranavir

palinavir

TMC-114

R0033-4649

fosamprenavir (GW433908)

P-1946,

BMS 186,318;

SC-55389a;

BILA 1096 BS;

U-140690, or combinations thereof.

8. The dosage form of claim 1 wherein said HIV protease inhibitor is (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)amino-1,6-diphenyl-3-hydroxyhexane (ritonavir).

9. The dosage form of claim 8 which shows a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least about 9 μ

g.h/ml/100 mg.

10. The dosage form of claim 1 wherein said HIV protease inhibitor is (2S,3S,5S)-2-(2,6- Dimethylphenoxyacetyl)-amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methyl-butanoyl]amino-1,6-diphenylhexane (lopinavir).

11. The dosage form of claim 10 which shows a dose-adjusted AUC, in dogs under non-fasting conditions, of lopinavir plasma concentration of at least about 20 μ

g.h/ml/100 mg.

12. The dosage form of claim 1 wherein said HIV protease inhibitor is a combination of (2S,3S,5S)-5-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxyhexane(ritonavir) and (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane(lopinavir).

13. The dosage form of claim 12 which shows a dose-adjusted AUC, in dogs under non-fasting conditions, of ritonavir plasma concentration of at least 9 about μ

g.h/ml/100 mg and a dose-adjusted AUC of lopinavir plasma concentration of at least about 20 μ

g.h/ml/100 mg.

14. The solid dosage form of claim 1 wherein said water-soluble polymer has a Tg of from about 80 to about 180°

C.

15. The solid dosage form of claim 1 wherein said water-soluble polymer is a homopolymer or copolymer of N-vinyl pyrrolidone.

16. The solid dosage form of claim 1 wherein said water-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate.

17. The solid dosage form of claim 1 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

18. The solid dosage form of claim 1 which contains, upon storage for about 6 weeks at about 40°

C. and about 75% humidity, at least about 98% of the initial content of HIV protease inhibitor.

19. A method of preparing a solid dosage form of claim 1 which comprises:

i. preparing a homogeneous melt of said HIV protease inhibitor(s), said water-soluble polymer(s) and said surfactant(s), and

ii. allowing the melt to solidify to obtain a solid dispersion product.

20. The method of claim 19 additionally comprising grinding said solid dispersion product and compressing said solid dispersion product into a tablet.

21. A method of treating an HIV infection comprising administering the solid dosage form of claim 1 to a mammal in need of such treatment.

22. A solid pharmaceutical dosage form comprising,

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxyhexane(ritonavir);

a homopolymer of N-vinyl pyrrolidone; and

a sorbitan fatty acid ester.

23. The solid dosage form of claim 22 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

37. A method of treating an HIV infection comprising administering the solid dosage form of any one of claims 22-36 to a mammal in need of such treatment.

24. A solid pharmaceutical dosage form comprising,

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane(lopinavir);

a copolymer of N-vinyl pyrrolidone; and

a sorbitan fatty acid ester.

25. The solid dosage form of claim 24 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

26. A solid pharmaceutical dosage form comprising,

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxyhexane(ritonavir) and (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane(lopinavir);

a copolymer of N-vinyl pyrrolidone and vinyl acetate; and

a sorbitan fatty acid ester.

27. The solid dosage form of claim 26 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

28. A solid pharmaceutical dosage form comprising,

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxyhexane(ritonavir) from about 5% to about 30% by weight of the dosage form;

a homopolymer of N-vinyl pyrrolidone from about 50% to about 85% by weight of the dosage form; and

a sorbitan fatty acid ester from about 2% to about 20% by weight of the dosage form.

29. The solid dosage form of claim 28 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

30. The solid dosage form of claim 29 wherein the at least one additive is present in an amount from about 0% to about 15% by weight.

31. A solid pharmaceutical dosage form comprising,

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane (lopinavir) from about 5% to about 30% by weight of the dosage form;

a copolymer of N-vinyl pyrrolidone from about 50% to about 85% by weight of the dosage form; and

a sorbitan fatty acid ester from about 2% to about 20% by weight of the dosage form.

32. The solid dosage form of claim 31 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

33. The solid dosage form of claim 32 wherein the at least one additive is present in an amount from about 0% to about 15% by weight.

34. A solid pharmaceutical dosage form comprising,

(2S,3 S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3-hydroxyhexane(ritonavir) and (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino- 1,6-diphenylhexane(lopinavir) present in an amount from about 5% to about 30% by weight of the dosage form;

a copolymer of N-vinyl pyrrolidone and vinyl acetate from about 50% to about 85% by weight of the dosage form; and

a sorbitan fatty acid ester from about 2% to about 20% by weight of the dosage form.

35. The solid dosage form of claim 34 containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

36. The solid dosage form of claim 35 wherein the at least one additive is present in an amount from about 0% to about 15% by weight of the dosage form.