COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY

• US 20150111856A1
• Filed: 10/24/2014
• Published: 04/23/2015
• Est. Priority Date: 01/14/2003
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Dahl, Terrence C., Menning, Mark M., Oliyai, Reza
• Granted Patent: US 9,744,181 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• 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 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/683 Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to therapeutic combinations of [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester (tenofovir disoproxil fumarate, Viread®) and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine, Emtriva™, (−)-cis FTC) and their physiologically functional derivatives. The combinations may be useful in the treatment of HIV infections, including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors. The present invention is also concerned with pharmaceutical compositions and formulations of said combinations of tenofovir disoproxil fumarate and emtricitabine, and their physiologically functional derivatives, as well as therapeutic methods of use of those compositions and formulations.

Claims

1. (canceled)

2. (canceled)

3. A chemically stable fixed-dose combination comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine wherein the combination exhibits less than 10% degradation of the tenofovir disoproxil fumarate and emtricitabine after six months at 40°

C./75% relative humidity when packaged and stored with silica gel desiccant at 40°

C./70% relative humidity, and wherein the fixed-dose combination is a tablet.

4. The pharmaceutical dosage form of claim 3 where the tenofovir disoproxil fumarate is not substantially degraded.

5. The pharmaceutical dosage form of claim 4 where there is less than 10% degradation of tenofovir disoproxil fumarate over a 24-hour period.

6. The pharmaceutical dosage form of claim 4 where there is less than 1% degradation of tenofovir disoproxil fumarate over a 24-hour period.

7. The pharmaceutical dosage form of claim 4 where there is less than 0.1% degradation of the tenofovir disoproxil fumarate over a 24-hour.

8. The pharmaceutical dosage form of claim 4 where there is less than 0.01% degradation of the tenofovir disoproxil fumarate over a 24-hour.

9. The pharmaceutical dosage form of claim 3, wherein there is less than 5% degradation of tenofovir disoproxil fumarate and emtricitabine occurs after six months.

10. A chemically stable fixed-dose combination comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine wherein the combination exhibits less than 10% degradation of tenofovir disoproxil fumarate over a 24-hour period.

11. The pharmaceutical dosage form of claim 10, wherein there is less than 1% degradation of tenofovir disoproxil fumarate.

12. The pharmaceutical dosage form of claim 10, wherein there is less than 0.1% degradation of tenofovir disoproxil fumarate.

13. The pharmaceutical dosage form of claim 10, wherein there is less than 0.01% degradation of tenofovir disoproxil fumarate.

14. The pharmaceutical dosage form of claim 10, wherein the combination exhibits less than 10% degradation of the tenofovir disoproxil fumarate and emtricitabine after six months at 40°

C./75% relative humidity when packaged and stored with silica gel desiccant at 40°

C./70% relative humidity.

15. The pharmaceutical dosage form of claim 10 wherein the combination exhibits less than 5% degradation of the tenofovir disoproxil fumarate and emtricitabine after six months at 40°

C./75% relative humidity when packaged and stored with silica gel desiccant at 40°

C./70% relative humidity.

16. The pharmaceutical dosage form of claim 3 or 10 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

17. The pharmaceutical dosage form of claim 16 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, 50 mg pregelatinized starch, 60 mg croscarmellose sodium, 80 mg lactose monohydrate, 300 mg microcrystalline cellulose, and 10 mg magnesium stearate.

18. The pharmaceutical dosage form of claim 16 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, 50 mg pregelatinized starch, 60 mg croscarmellose sodium, 180 mg lactose monohydrate, 200 mg microcrystalline cellulose, and 10 mg magnesium stearate.

19. The pharmaceutical dosage form of claim 3 or 10 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.

20. The pharmaceutical dosage form of claim 19 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, 50 mg pregelatinized starch, 60 mg croscarmellose sodium, 175 mg lactose monohydrate, 200 mg microcrystalline cellulose, 10 mg magnesium stearate, and 5 mg colloidal silicon dioxide.

21. The pharmaceutical dosage form of claim 19 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, hydroxypropyl methylcellulose, lactose B.P., pregelatinized starch B.P, and magnesium stearate.

22. The pharmaceutical dosage form of claim 19 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, 112 g hydroxypropyl methylcellulose, 53 mg lactose B.P., 28 mg pregelatinized starch B.P, and 7 mg magnesium stearate.

23. The pharmaceutical dosage form of claim 3 or 10 comprising less than 1% of impurities related to tenofovir disoproxil fumarate and emtricitabine.

24. The pharmaceutical dosage form of claim 3 or 10, further comprising a third anti-viral agent.

25. The pharmaceutical dosage form of claim 24, wherein the third antiviral agent is selected from the group consisting of protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and integrase inhibitors.

26. The pharmaceutical dosage form of claim 25, wherein the third antiviral agent is a protease inhibitor.

27. The pharmaceutical dosage form of claim 25, wherein the third antiviral agent is a nucleoside reverse transcriptase inhibitor.

28. The pharmaceutical dosage form of claim 25, wherein the third antiviral agent is a non-nucleoside reverse transcriptase inhibitor.

29. The pharmaceutical dosage form of claim 25, wherein the third antiviral agent is an integrase inhibitor.

30. The pharmaceutical dosage form of claim 28, wherein the third antiviral agent is efavirenz.

31. A method for the treatment of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal the pharmaceutical dosage form of claim 3 or 10.

32. A method for the treatment of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal the pharmaceutical dosage form of claim 9 or 11.

33. A method for the treatment of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal the pharmaceutical dosage form of claim 19.

34. A method for the treatment of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal the pharmaceutical dosage form of claim 24.

35. A method for the treatment of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal the pharmaceutical dosage form of claim 25.

36. A method for the treatment of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal the pharmaceutical dosage form of claim 30.