Compositions and methods for combination antiviral therapy

Patent metadata

Field	Value
Publication number	US-9457036-B2
Application number	US-201414523758-A
Country	US
Kind code	B2
Filing date	Oct 24, 2014
Priority date	Jan 14, 2003
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

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.

First claim

We claim:

1. A fixed dose combination pharmaceutical dosage form comprising 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine; a binder selected from the group consisting of povidone, gelatin, hydroxypropyl methylcellulose, cellulose, microcrystalline cellulose, starch, and acacia; a disintegrant selected from sodium starch glycolate, crosslinked-povidone, cross-linked sodium carboxymethylcellulose, and alginic acid; and a lubricant selected from the group consisting of magnesium stearate, stearic acid, and talc; wherein said pharmaceutical dosage form exhibits equal to or less than 5% degradation of the tenofovir disoproxil fumarate or emtricitabine after 6 months when packaged and stored with silica gel dessicant at 40° C./75% relative humidity; and wherein said pharmaceutical dosage form is a tablet.

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

3. The pharmaceutical dosage form of claim 1 where there is less than 0.1% degradation of tenofovir disoproxil fumarate over a 24-hour period.

4. The pharmaceutical dosage form of claim 1 where there is less than 0.01% degradation of tenofovir disoproxil fumarate over a 24-hour period.

5. The pharmaceutical dosage form of claim 1 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

6. The pharmaceutical dosage form of claim 5 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.

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

8. The pharmaceutical dosage form of claim 1 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.

9. The pharmaceutical dosage form of claim 8 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.

10. The pharmaceutical dosage form of claim 8 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, hydroxypropyl methylcellulose, lactose, pregelatinized starch, and magnesium stearate.

11. The pharmaceutical dosage form of claim 8 comprising 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, 112 mg hydroxypropyl methylcellulose, lactose, pregelatinized starch, and 7 mg magnesium stearate.

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

13. 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 1 .

14. 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 8 .

15. The pharmaceutical dosage form of claim 1 , wherein the starch is pregelatinized starch.

16. A fixed dose combination pharmaceutical dosage form comprising 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine; a binder selected from the group consisting of povidone, gelatin, hydroxypropyl methylcellulose, cellulose, microcrystalline cellulose, pregelatinized starch, and acacia; a disintegrant selected from sodium starch glycolate, crosslinked-povidone, cross-linked sodium carboxymethylcellulose, maize starch, and alginic acid; and a lubricant selected from the group consisting of magnesium stearate, stearic acid, and talc; wherein said pharmaceutical dosage form exhibits equal to or less than 5% degradation of the tenofovir disoproxil fumarate or emtricitabine after 6 months when packaged and stored with silica gel dessicant at 40° C./75% relative humidity and wherein said pharmaceutical dosage form is a tablet.

Assignees

• Gilead Sciences Inc

Inventors

• Dahl Terrence C
• Menning Mark M
• Oliyai Reza

Classifications

• A61K31/675 Primary

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K9/2009

  Inorganic compounds · CPC title

• A61P31/18

  for HIV · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title