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)-( 1 H)-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 comprising administering a therapeutically effective amount of a composition comprising [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) to a patient in need of antiviral therapy consisting of anti-HIV therapy.  
   
   
       60 . The method of  claim 59  wherein the anti-HIV active ingredients in the composition consist of tenofovir disoproxil fumarate and emtricitabine.  
   
   
       61 . The method of  claim 60  wherein the composition comprises about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.  
   
   
       62 . The method of  claim 59  wherein the amount of the total tenofovir disoproxil fumarate and emtricitabine in the composition in relation to carrier material is about 5% to about 95% of the total composition (weight:weight, exclusive of coating).  
   
   
       63 . The method of  claim 59  wherein tenofovir disoproxil fumarate and emtricitabine are present in a tablet.  
   
   
       64 . The method of  claim 63  wherein tenofovir disoproxil fumarate and emtricitabine are present in an amount of 300 mg and 200 mg respectively.  
   
   
       65 . The method of  claim 59  wherein the manufacture is by wet granulation.  
   
   
       66 . The method of  claim 62  wherein the weight ratio of the total of tenofovir disoproxil fumarate and emtricitabine in the composition in relation to ingredients other than tenofovir disoproxil fumarate and emtricitabine is 50:50 (excluding coating).  
   
   
       67 . The method of  claim 66  wherein the composition comprises in weight percent (excluding coating) tenofovir disoproxil fumarate 30, emtricitabine 20, pregelatinized starch 5, croscarmellose sodium 6, lactose monohydrate 8, microcrystalline cellulose 30, magnesium stearate 1.  
   
   
       68 . The method according to  claim 59  wherein the composition further comprises a third active ingredient selected from an HIV protease inhibitor (PI), an HIV nucleoside reverse transcriptase inhibitor (NRTI), an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), and an HIV integrase inhibitor.  
   
   
       69 . The method according to  claim 68  wherein the third active ingredient is selected from the Reyataz, Kaletra, or Sustiva anti-HIV agents.  
   
   
       70 . The method according to  claim 59  wherein the composition further comprises a pharmaceutically acceptable glidant.  
   
   
       71 . The method according to  claim 70  wherein the glidant is selected from silicon dioxide, powdered cellulose, microcrystalline cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and formulations thereof.  
   
   
       72 . The method according to  claim 71  wherein the metallic stearates are selected from calcium stearate, magnesium stearate, zinc stearate, and formulations thereof.  
   
   
       73 . A pharmaceutical formulation comprising [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine).  
   
   
       74 . The pharmaceutical formulation according to  claim 73  further comprising one or more pharmaceutically acceptable carriers or excipients.  
   
   
       75 . The pharmaceutical formulation according to  claim 74  wherein the pharmaceutically acceptable carriers or excipients are selected from pregelatinized starch, croscarmellose sodium, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate, and formulations thereof.  
   
   
       76 . The pharmaceutical formulation according to  claim 74  wherein the amount of the total tenofovir disoproxil fumarate and emtricitabine in the formulation in relation to carrier and excipient material (weight:weight, excluding coating) is about 5% to about 95% (weight ratio 0.08).  
   
   
       77 . The pharmaceutical formulation according to  claim 76  wherein the weight ratio of tenofovir disoproxil fumarate and entricitabine together: total carrier and excipient in the formulation (excluding coating) is 500:1000, 400:900, 325:825, 225:725, 200:700, 500:700, 500:670, 500:763, 500:2840 or 500:2270.  
   
   
       78 . The pharmaceutical formulation according to  claim 77  wherein the weight ratio (excluding coating) is 0.50, 0.44, 0.39, 0.31, 0.29, 0.71, 0.75, 0.65, 0.18 or 0.22.  
   
   
       79 . The pharmaceutical formulation according to  claim 76  wherein the weight ratio (excluding coating) is from 0.18 to 0.75.  
   
   
       80 . The pharmaceutical formulation according to  claim 73  in pharmaceutical dosage form.  
   
   
       81 . The pharmaceutical formulation according to  claim 80  wherein the pharmaceutical dosage form is a tablet.  
   
   
       82 . The pharmaceutical formulation according to  claim 73  wherein tenofovir disoproxil fumarate and emtricitabine are present in a ratio of about 300:200 by weight.  
   
   
       83 . The pharmaceutical formulation according to  claim 82  comprising about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.  
   
   
       84 . The pharmaceutical formulation according to  claim 73  suitable for oral administration.  
   
   
       85 . The pharmaceutical formulation according to  claim 84  wherein the pharmaceutical dosage form is a capsule.  
   
   
       86 . The pharmaceutical formulation according to  claim 73  suitable for administration once per day to an infected human.  
   
   
       87 . A patient pack comprising (a) at least one coformulated pharmaceutical formulation comprising [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine), and (b) an information insert containing directions for the use of tenofovir disoproxil fumarate and emtricitabine in formulation for the treatment of a patient in need of antiviral treatment consisting of anti-HIV therapy.  
   
   
       88 . The patient pack according to  claim 87  wherein the pharmaceutical dosage form is a tablet, caplet, or capsule comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine.  
   
   
       89 . The pharmaceutical formulation of any of claims  73  or  87  which further comprises a third antiviral agent.  
   
   
       90 . The formulation of  claim 89  wherein the third agent is selected from an HIV protease inhibitor (PI), an HIV nucleoside reverse transcriptase inhibitor (NRTI), an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), and an HIV integrase inhibitor.  
   
   
       91 . The formulation of  claim 90  wherein the third antiviral agent is a PI.  
   
   
       92 . The formulation of  claim 90  wherein the third antiviral agent is an NNRTI.  
   
   
       93 . The formulation of  claim 90  wherein the third antiviral agent is selected from the Reyataz, Kaletra, or Sustiva anti-HIV agents.  
   
   
       94 . An oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Reyataz.  
   
   
       95 . An oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Kaletra.  
   
   
       96 . An oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Sustiva.  
   
   
       97 . The pharmaceutical formulation of  claim 73  comprising in weight percent (excluding coating) tenofovir disoproxil fumarate 30, emtricitabine 20, pregelatinized starch 5, croscarmellose sodium 6, lactose monohydrate 8, microcrystalline cellulose 30, and magnesium stearate 1.  
   
   
       98 . A tablet comprising 300 mg of tenofovir disoproxil fumarate, 200 mg of emtricitabine and carriers and/or excipients sufficient to produce less than 5% acid degradation of tenofovir disoproxil fumarate or emtricitabine after six months storage with desiccant at 40° C./25% relative humidity.  
   
   
       99 . An oral dosage form comprising Sustiva, 300 mg tenofovir disoproxil fumarate, 200 mg of emtriva and pharmaceutically acceptable carriers or excipients.