PHARMACEUTICALLY ACCEPTABLE SOLUBILIZING COMPOSITION AND PHARMACEUTICAL DOSAGE FORM CONTAINING SAME

• US 20100247635A1
• Filed: 07/17/2007
• Published: 09/30/2010
• Est. Priority Date: 07/19/2006
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Inventors: Liepold, Bernd, Schmidt, Christoph, Lander, Ute, Breitenbach, Jörg, Rosenberg, Jörg, Marsh, Kennan
• Granted Patent: US 9,078,921 B2
• Time in Patent Office: Days
• US Class Current: 424/455
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 38/55 Protease inhibitors
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 31/18 for HIV

Abstract

A pharmaceutically acceptable solubilizing composition comprising (i) at least one tocopheryl compound having a polyalkylene glycol moiety and (ii) at least one alkylene glycol fatty acid monoester or mixture of alkylene glycol fatty acid mono- and diester is disclosed. The solubilizing composition is useful in the manufacture of a pharmaceutical dosage form which comprises a melt-processed mixture of at least one active ingredient, at least one pharmaceutically acceptable polymer. The active ingredient(s) may be inhibitors of HIV protease. The solubilizing composition enhances the bioavailability of the active ingredient after oral intake.

Claims

1. A pharmaceutically acceptable solubilizing composition comprising (i) at least one tocopheryl compound having a polyalkylene glycol moiety and (ii) at least one alkylene glycol fatty acid monoester or mixture of alkylene glycol fatty acid mono- and diester.

2. The solubilizing composition of claim 1, wherein the tocopheryl compound is alpha tocopheryl polyethylene glycol succinate.

3. The solubilizing composition of claim 1, wherein the alkylene glycol fatty acid monoester is propylene glycol monolaurate.

4. The solubilizing composition of claim 1, wherein the weight ratio of tocopheryl compound and alkylene glycol fatty acid ester is in the range of from 9:

1 to 1;

9.

5. A pharmaceutical dosage form which comprises a melt-processed mixture of at least one active ingredient, at least one pharmaceutically acceptable polymer and a solubilizing composition, the solubilizing composition comprising (i) at least one tocopheryl compound having a polyalkylene glycol moiety and (ii) at least one alkylene glycol fatty acid monoester or mixture of alkylene glycol fatty acid mono- and diester.

6. The dosage form of claim 5, wherein the tocopheryl compound is alpha tocopheryl polyethylene glycol succinate.

7. The dosage form of claim 5, wherein the alkylene glycol fatty acid monoester is propylene glycol monolaurate.

8. The dosage form of claim 5, wherein the weight ratio of tocopheryl compound and alkylene glycol fatty acid ester is in the range of from 9:

1 to 1;

9.

9. The dosage form of claim 5 which comprises, relative to the weight of the melt-processed mixture, from about 0.5 to 40% by weight of said active ingredient, 40 to 99% by weight of said pharmaceutically acceptable polymer, 0.5 to 20% by weight of said solubilizing composition, and 0 to 15% by weight of additives.

10. The dosage form of claim 5 which comprises, relative to the weight of the melt-processed mixture, from about 15 to 40% by weight of said active ingredient, 40 to 70% by weight of said pharmaceutically acceptable polymer, 4 to 20% by weight of said solubilizing composition, and 0 to 15% by weight of additives.

11. The dosage form of claim 5 which comprises, relative to the weight of the melt-processed mixture, from about 0.5 to 15% by weight of said active ingredient, 60 to 99% by weight of said pharmaceutically acceptable polymer, 0.5 to 15% by weight of said solubilizing composition, and 0 to 15% by weight of additives

12. The dosage form of claim 5, wherein the active ingredient is an HIV protease inhibitor or a combination of HIV protease inhibitors.

13. The dosage form of claim 12, 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-(I-(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)phenylmethyl-hexanoyl-(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-[1R-(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;

darunavir (TMC-114);

RO033-4649;

fosamprenavir (GW433908);

P-1946;

tert-butyl [3-hydroxy-4-[2-hydroxy-4-[4-(morpholin-4-ylcarbonylmethoxy)phenyl]-3-tert-butoxycarbonylamino-butyl]amino-1-phenyl-butan-2-yl]aminoformate (BMS 186,318);

SC-55389a;

BILA 1906 BS;

N-[3-[1-(2-hydroxy-4-oxo-6-phenethyl-6-propyl-5H-pyran-3-yl)propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide (tipranavir, U-140690);

or combinations thereof.

14. The dosage form of claim 13, 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).

15. The dosage form of claim 13 wherein said HIV protease inhibitor is (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)-amino-3-hydroxy-5-[2S-(I-tetrahydropyrimid-2-onyl)-3-methyl-butanoyl]amino-1,6-diphenylhexane (lopinavir).

16. The dosage form of claim 13, wherein said HIV protease inhibitor is a combination 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) and (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane (lopinavir).

17. The solid dosage form of claim 5, wherein said pharmaceutically acceptable polymer is a homopolymer or copolymer of N-vinyl pyrrolidone.

18. The solid dosage form of claim 17, wherein said pharmaceutically acceptable polymer is a copolymer of N-vinyl pyrrolidone and vinyl acetate.

19. The solid dosage form of claim 5, containing at least one additive selected from flow regulators, disintegrants, bulking agents and lubricants.

20. The solid dosage form of claim 5, wherein the melt-processed mixture has a Tg of 10°

C. or higher.

21. A method of preparing a solid dosage form of claim 5 which comprises:

a) preparing a homogeneous melt of said active ingredient(s), said pharmaceutically acceptable polymer(s) and said solubilizing composition, and

b) allowing the melt to solidify to obtain a solid dispersion product.

22. The method of claim 21, additionally comprising grinding said solid dispersion product and compressing said solid dispersion product into a tablet.

23. The method of claim 21, additionally comprising grinding said solid dispersion product and filling said solid dispersion product into a capsule shell.

24. The method of claim 21, wherein the melt is shaped into a film or a foam before being allowed to solidify.