Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same

Abstract

A pharmaceutical formulation of testosterone undecanoate is provided. Methods of treating a testosterone deficiency or its symptoms with the inventive formulations are also provided.

1 . An oral pharmaceutical composition comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipophilic surfactant to total hydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to 3.5:1, which composition, upon once- or twice-daily oral administration, provides an average serum testosterone concentration at steady state falling in the range of about 300 to about 1100 ng/dL. 
     
     
         2 . The pharmaceutical composition of  claim 1 , which provides a C max  that does not exceed 2500 ng/dL when administered with a meal. 
     
     
         3 . The pharmaceutical composition of  claim 1 , which provides a C max  that does not exceed 1800 ng/dL when administered with a meal. 
     
     
         4 . The pharmaceutical composition of  claim 1 , which provides a C max  that does not exceed 1500 ng/dL when administered with a meal. 
     
     
         5 . The oral pharmaceutical composition of  claim 1  in which the at least one hydrophilic surfactant comprises Cremophor RH 40 (polyoxyethyleneglycerol trihydroxystearate). 
     
     
         6 . The oral pharmaceutical composition of  claim 1  in which the at least one lipophilic surfactant comprises oleic acid. 
     
     
         7 . The oral pharmaceutical composition of  claim 1  comprising 18 to 22 percent by weight of a solubilized testosterone undecanoate. 
     
     
         8 . The oral pharmaceutical composition of  claim 7  in which the testosterone undecanoate is solubilized in a carrier substantially free of ethanol. 
     
     
         9 - 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipophilic surfactant to total hydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to 3.5:1, which composition, upon once- or twice-daily oral administration to a subject suffering from testosterone deficiency or its symptoms, provides a mean serum testosterone concentration at day 30 of a daily treatment regimen, which is substantially the same as that observed on day 7. 
     
     
         17 . The pharmaceutical composition of  claim 16  in which the mean serum testosterone concentration obtained at day 30 of a daily treatment regimen is substantially the same as that observed on day 60. 
     
     
         18 . A method of treating testosterone deficiency or its symptoms comprising orally administering to a subject suffering from testosterone deficiency or its symptoms an effective amount of a pharmaceutical composition comprising testosterone undecanoate solubilized in a carrier comprising at least one lipophilic surfactant and at least one hydrophilic surfactant in a total lipophilic surfactant to total hydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to 3.5:1 to provide an average serum testosterone concentration at steady state falling in the range of about 300 to about 1100 ng/dL. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18  in which the composition is administered twice daily. 
     
     
         21 . The method of  claim 18  which gives rise to a C max  value falling in the range of about 900 to 1100 ng/dL 
     
     
         22 . The method of  claim 18  in which the composition is administered with a meal comprising at least 20 wt % fat. 
     
     
         23 . The method of  claim 18  which gives rise to substantially no diurnal testosterone pharmacokinetic variation. 
     
     
         24 . The method of  claim 18  which gives rise to an average serum T max  value falling in the range of about 3 to 7 hours after oral administration. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 18  in which substantially no significant decline in steady state serum testosterone response is observed upon repeat dosing.