Transvaginal phosphodiesterase inhibitors for infertility treatment

Abstract

The present invention relates to a new application of phosphodiesterase inhibitors for couple infertility treatment which forms an effective alternative to the invasive assisted reproductive techniques such as conjugal artificial insemination and which consists of the transvaginal administration of a phosphodiesterase inhibitor immediately before and/or after coitus. It also relates to dosage forms suitable for the intravaginal administration of phosphodiesterase inhibitors.

What is claimed is: 
     
         1 . A pharmaceutical composition for treating infertility in a subject in need thereof comprising an effective amount of a phosphodiesterase inhibitor, a polyhydroxy alcohol, water, a carbomer and an alkaline agent, wherein the pharmaceutical composition is in the form of hydrophilic gel for transvaginal administration. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the phosphodiesterase inhibitor is selected from the group consisting of a phosphodiesterase 1 (PDE1) inhibitor, a phosphodiesterase 3 (PDE3) inhibitor, a phosphodiesterase 4 (PDE4) inhibitor and a non-selective phosphodiesterase inhibitor, and a combination thereof. 
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, rolipram, milrinone and ibudilast. 
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein the phosphodiesterase inhibitor is pentoxifylline. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the polyhydroxy alcohol is selected from the group consisting of propylene glycol, dipropyleneglycol, glycerin, 1,2,6-hexanetriol, sorbitol, polyethylene glycol 100 (PEG100), polyethylene glycol 200 (PEG200), polyethylene glycol 300 (PEG300) and polyethylene glycol 400 (PEG400). 
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein the polyhydroxy alcohol is propylene glycol. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the carbomer has a viscosity between 25,000 and 700,000 mPa·s determined in an aqueous carbomer solution at 0.5% by weight/volume and at a pH value comprised between 6 and 11. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein the carbomer has a viscosity between 40,000 and 60,000 mPa·s determined in an aqueous carbomer solution at 0.5% by weight/volume and at pH comprised between 6 and 11. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the alkaline agent is selected from the group consisting of L-lysine, L-arginine, borax, potassium hydroxide, sodium hydroxide, ammonia, sodium bicarbonate, aminomethylpropanol, tetrahydroxypropylethylenediamine, tromethamine, ethoxylated cocoamine (cocamine PEG15), diisopropanolamine, triisopropanolamine, and triethanolamine. 
     
     
         10 . The pharmaceutical composition according to  claim 9 , wherein the alkaline agent is triethanolamine. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the proportion of the phosphodiesterase inhibitor by weight is between 2% and 10%. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the composition has a pH comprised between 5.5 and 7.5. 
     
     
         13 . The pharmaceutical composition according to  claim 3 , wherein the polyhydroxy alcohol is selected from the group consisting of propylene glycol, dipropyleneglycol, glycerin, 1,2,6-hexanetriol, sorbitol, polyethylene glycol 100 (PEG100), polyethylene glycol 200 (PEG200), polyethylene glycol 300 (PEG300) and polyethylene glycol 400 (PEG400);
 the carbomer has a viscosity between 25,000 and 700,000 mPa·s determined in an aqueous carbomer solution at 0.5% by weight/volume and at a pH value comprised between 6 and 11; and   the alkaline agent is selected from the group consisting of L-lysine, L-arginine, borax, potassium hydroxide, sodium hydroxide, ammonia, sodium bicarbonate, aminomethylpropanol, tetrahydroxypropylethylenediamine, tromethamine, ethoxylated cocoamine (cocamine PEG15), diisopropanolamine, triisopropanolamine, and triethanolamine.   
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein
 the polyhydroxy alcohol is propylene glycol;   the carbomer has a viscosity between 40,000 and 60,000 mPa·s determined in an aqueous carbomer solution at 0.5% by weight/volume and at pH comprised between 6 and 11; and   the alkaline agent is triethanolamine.   
     
     
         15 . The composition according to  claim 14 , wherein the composition comprises a phosphodiesterase inhibitor in a proportion by weight between 2% and 10%, propylene glycol in a proportion by weight comprised between 2% and 15%, carbomer in a proportion by weight comprised between 0.5% and 2%, triethanolamine in a proportion by weight comprised between 0.1% and 1% and water in a proportion by weight comprised between 75% and 95%. 
     
     
         16 . A kit comprising the composition according to  claim 1  and instructions for administrating the pharmaceutical composition. 
     
     
         17 . The kit according to  claim 13 , wherein the kit comprises three single-doses of phosphodiesterase inhibitor between 200 mg and 800 mg in each of dose. 
     
     
         18 . A kit comprising the composition according to  claim 15  and instructions for administrating the pharmaceutical composition. 
     
     
         19 . The kit according to  claim 18 , wherein the kit comprises three single-doses of phosphodiesterase inhibitor between 200 mg and 800 mg in each of dose.