Compositions and Methods for Combination Antiviral Therapy

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.

1 - 58 . (canceled) 
     
     
         59 . A method for the prevention of the symptoms or effects of an HIV infection in an animal which comprises administering to said animal a fixed-dose combination comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine. 
     
     
         60 . The method of  claim 59  wherein the fixed-dose combination is a tablet. 
     
     
         61 . A method for the prevention of the symptoms or effects of an HIV infection in an animal which comprises administering to said animal a fixed-dose combination comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine, wherein the combination exhibits equal to or 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, and wherein the fixed-dose combination is a tablet. 
     
     
         62 . The method of  claim 61  where there is less than 10% degradation of tenofovir disoproxil fumarate over a 24-hour period. 
     
     
         63 . The method of  claim 61  where there is less than 1% degradation of tenofovir disoproxil fumarate over a 24-hour period. 
     
     
         64 . The fixed-dose combination of  claim 61  where there is less than 0.1% degradation of the tenofovir disoproxil fumarate over a 24-hour period. 
     
     
         65 . The fixed-dose combination of  claim 61  where there is less than 0.01% degradation of the tenofovir disoproxil fumarate over a 24-hour period. 
     
     
         66 . The method of  claim 61  wherein the fixed-dose combination comprises 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide. 
     
     
         67 . The method of  claim 61  wherein the fixed-dose combination comprises less than 1% of impurities related to tenofovir disoproxil fumarate and emtricitabine. 
     
     
         68 . The method of  claim 61  wherein the fixed-dose combination further comprises a third anti-viral agent. 
     
     
         69 . The method of  claim 68 , 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. 
     
     
         70 . The method of  claim 68 , wherein the third antiviral agent is efavirenz. 
     
     
         71 . A method for the prevention of the symptoms or effects of an HIV infection in an animal which comprises administering to said animal a 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, and wherein the fixed-dose combination is a tablet. 
     
     
         72 . The method of  claim 71 , wherein there is less than 1% degradation of tenofovir disoproxil fumarate. 
     
     
         73 . The method of  claim 71 , wherein there is less than 0.1% degradation of tenofovir disoproxil fumarate. 
     
     
         74 . The method of  claim 71 , wherein there is less than 0.01% degradation of tenofovir disoproxil fumarate. 
     
     
         75 . The method of  claim 71  wherein the fixed-dose combination exhibits equal to or 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. 
     
     
         76 . The method of  claim 71  wherein the fixed-dose combination comprises 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and magnesium stearate. 
     
     
         77 . The method of  claim 76  wherein the fixed-dose combination comprises 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. 
     
     
         78 . The method of  claim 76  wherein the fixed-dose combination comprises 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. 
     
     
         79 . The method of  claim 71 , wherein the fixed-dose combination comprises 300 mg tenofovir disoproxil fumarate, 200 mg emtricitabine, pregelatinized starch, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide. 
     
     
         80 . The method of  claim 71 , wherein the fixed-dose combination comprises less than 1% of impurities related to tenofovir disoproxil fumarate and emtricitabine. 
     
     
         81 . The method of  claim 71 , wherein the fixed-dose combination further comprises a third anti-viral agent. 
     
     
         82 . The method of  claim 81 , 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. 
     
     
         83 . The method of  claim 81 , wherein the third antiviral agent is efavirenz.