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.

We claim:  
     
         1 . A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal 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) or a physiologically functional derivative thereof, and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.  
     
     
         2 . The method according to  claim 1  wherein the composition comprises tenofovir disoproxil fumarate and emtricitabine.  
     
     
         3 . The method according to  claim 2  wherein the composition comprises about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.  
     
     
         4 . The method according to  claim 1  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of about 1:50 to about 50:1 by weight.  
     
     
         5 . The method according to  claim 1  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of about 1:10 to about 10:1 by weight.  
     
     
         6 . The method according to  claim 1  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are each present in an amount from about 1 mg to about 1000 mg per unit dosage form.  
     
     
         7 . The method according to  claim 1  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are each present in an amount from about 100 mg to about 300 mg per unit dosage form.  
     
     
         8 . A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal 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) or a physiologically functional derivative thereof, and a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein B is selected from adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, 06-methylguanine, N 6 -methyladenine, 04-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and  
         R is selected from H, C 1 -C 18  alkyl, C 1 -C 18  substituted alkyl, C 2 -C 18  alkenyl, C 2 -C 18  substituted alkenyl, C 2 -C 18  alkynyl, C 2 -C 18  substituted alkynyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 2 -C 20  heterocycle, C 2 -C 20  substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy, and a prodrug moiety.  
       
     
     
         9 . The method according to  claim 1  wherein one component of composition is (2R, 5S, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC).  
     
     
         10 . The method according to  claim 1  wherein the composition comprises a physiologically functional derivative of emtricitabine which is a racemic mixture of the enantiomers (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one and (2S, 5R, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.  
     
     
         11 . The method according to  claim 1  wherein the composition comprises a physiologically functional derivative of tenofovir disoproxil fumarate which has the structure:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from H, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 6 -C 20  arylalkyl, C 6 -C 20  substituted arylalkyl, acyloxymethyl esters —CH 2 OC(═O)R and acyloxymethyl carbonates —CH 2 OC(═O)OR 9  where R 9  is C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 6 -C 20  aryl and C 6 -C 20  substituted aryl;  
         R 3  is selected from H, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, or CH 2 OR 8  where R 8  is C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl and C 1 -C 6  haloalkyl;  
         R 4  and R 5  are independently selected from H, NH 2 , NHR and NR 2  where R is C 1 -C 6  alkyl; and  
         R 6  and R 7  are independently selected from H and C 1 -C 6  alkyl;  
         or a pharmaceutically acceptable salt or solvate thereof.  
       
     
     
         12 . The method according to  claim 11  wherein at least one of R 1  and R 2  is —CH 2 OC(═O)C(CH 3 ) 3 .  
     
     
         13 . The method according to  claim 11  wherein at least one of R 1  and R 2  is —CH 2 OC(═O)OC(CH 3 ) 3 .  
     
     
         14 . The method according to  claim 11  wherein at least one of R 1  and R 2  is —CH 2 OC(═O)OCH(CH 3 ) 2 .  
     
     
         15 . A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal comprising administering in combination or alternation a therapeutically effective amount of [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) or a physiologically functional derivative thereof, and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.  
     
     
         16 . The method according to  claim 15  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof, and emtricitabine or a physiologically functional derivative thereof, are administered in alternation.  
     
     
         17 . The method according to  claim 15  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof, and emtricitabine or a physiologically functional derivative thereof, are administered in combination as a single combined formulation.  
     
     
         18 . The method according to  claim 17  wherein the single combined formulation is administered once per day to an infected human.  
     
     
         19 . The method according to  claim 1  in which said animal is a human.  
     
     
         20 . The method according to  claim 1  wherein the composition further comprises a third active ingredient selected from a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and an integrase inhibitor.  
     
     
         21 . The method according to  claim 20  wherein the third active ingredient is 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340).  
     
     
         22 . The method according to  claim 1  wherein the composition further comprises a pharmaceutically acceptable glidant.  
     
     
         23 . The method according to  claim 22  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 combinations thereof.  
     
     
         24 . The method according to  claim 23  wherein the metallic stearates are selected from calcium stearate, magnesium stearate, zinc stearate, and combinations thereof.  
     
     
         25 . A pharmaceutical formulation comprising [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) or a physiologically functional derivative thereof and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.  
     
     
         26 . The pharmaceutical formulation according to  claim 25  further comprising one or more pharmaceutically acceptable carriers or excipients.  
     
     
         27 . The pharmaceutical formulation according to  claim 26  wherein the pharmaceutically acceptable carriers or excipients are selected from pregelatinized starch, croscarmellose sodium, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate; and combinations thereof.  
     
     
         28 . The pharmaceutical formulation according to  claim 25  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of 1:50 to 50:1 by weight.  
     
     
         29 . The pharmaceutical formulation according to  claim 25  wherein tenofovir or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of 1:10 to 10:1 by weight.  
     
     
         30 . The pharmaceutical formulation according to  claim 25  in unit dosage form.  
     
     
         31 . The pharmaceutical formulation according to  claim 30  wherein tenofovir disoproxil fumarate or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are each and individually present in an amount from 100 mg to 1000 mg per unit dosage form.  
     
     
         32 . The pharmaceutical formulation according to  claim 31  comprising tenofovir disoproxil fumarate and emtricitabine.  
     
     
         33 . The pharmaceutical formulation according to  claim 32  comprising about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.  
     
     
         34 . The pharmaceutical formulation according to  claim 25  suitable for oral administration.  
     
     
         35 . The pharmaceutical formulation according to  claim 25  in the form of a tablet or capsule.  
     
     
         36 . The pharmaceutical formulation according to  claim 25  suitable for administration once per day to an infected human.  
     
     
         37 . The pharmaceutical formulation according to  claim 25  comprising a physiologically functional derivative of emtricitabine which is (2R, 5S, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC).  
     
     
         38 . The pharmaceutical formulation according to  claim 25  wherein the combination comprises a physiologically functional derivative of tenofovir disoproxil fumarate which has the structure:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from H, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 6 -C 20  arylalkyl, C 6 -C 20  substituted arylalkyl, acyloxymethyl esters —CH 2 OC(═O)R and acyloxymethyl carbonates —CH 2 OC(═O)OR 9  where R 9  is C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 6 -C 20  aryl or C 6 -C 20  substituted aryl;  
         R 3  is H, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, or CH 2 OR 8  where R 8  is C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl or C 1 -C 6  haloalkyl;  
         R 4  and R 5  are independently selected from H, NH 2 , NHR and NR 2  where R is C 1 -C 6  alkyl; and  
         R 6  and R 7  are independently selected from H and C 1 -C 6  alkyl;  
         or a pharmaceutically acceptable salt or solvate thereof.  
       
     
     
         39 . The pharmaceutical formulation according to  claim 38  wherein at least one of R 1  and R 2  is —CH 2 OC(═O)C(CH 3 ) 3 .  
     
     
         40 . The pharmaceutical formulation according to  claim 38  wherein at least one of R 1  and R 2  is —CH 2 OC(═O)OC(CH 3 ) 3 .  
     
     
         41 . The pharmaceutical formulation according to  claim 38  wherein at least one of R 1  and R 2  is —CH 2 OC(═O)OCH(CH 3 ) 2 .  
     
     
         42 . A patient pack comprising at least one active ingredient selected from [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 an information insert containing directions on the use of tenofovir and emtricitabine together in combination.  
     
     
         43 . The patient pack according to  claim 42  comprising a co-formulated pill, tablet, caplet, or capsule of 100 to 1000 mg of tenofovir disoproxil fumarate and 100 to 1000 mg of emtricitabine.  
     
     
         44 . The patient pack according to  claim 43  comprising a co-formulated pill, tablet, caplet, or capsule of 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine.  
     
     
         45 . The patient pack according to  claim 42  comprising a separate pill, tablet, caplet, or capsule of 100 to 1000 mg of tenofovir disoproxil fumarate and 100 to 1000 mg of emtricitabine.  
     
     
         46 . The patient pack according to  claim 45  comprising a separate pill, tablet, caplet, or capsule of 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine.  
     
     
         47 . A chemically stable combination of tenofovir disoproxil fumarate and emtricitabine.  
     
     
         48 . The chemically stable combination of  claim 47  wherein the combination is a pharmaceutical dosage form.  
     
     
         49 . The chemically stable combination of  claim 48  wherein the dosage form is oral.  
     
     
         50 . The chemically stable combination of any of claims  47 ,  48 , or  49  which further comprises a third antiviral agent.  
     
     
         51 . The chemically stable combination of  claim 50  where in the third antiviral agent is an NNRTI or PI.  
     
     
         52 . The chemically stable combination of  claim 51  wherein the third antiviral agent is a PI.  
     
     
         53 . The chemically stable combination of Clam 51 wherein the third antiviral agent is an NNRTI.  
     
     
         54 . The chemically stable combination of  claim 50  wherein the third antiviral agent is selected from Reyataz, Kaletra or Sustiva.  
     
     
         55 . A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate and emtricitabine.  
     
     
         56 . A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Reyataz.  
     
     
         57 . A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Kaletra.  
     
     
         58 . A chemically stable oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emtricitabine and Sustiva.