Pharmaceutical composition

Abstract

A pharmaceutical composition comprising: (A) an androgen; (B) a cyclic enhancer of the type used in the compositions and methods claimed by U.S. Pat. No. 5,023,252 to Hsieh; and (C) a thickening agent; including, for example, a composition in which the cyclic enhancer is a macrocyclic ester or a macrocyclic ketone; the use of the composition to treat a condition, for example, male hypogonadism, in a patient by applying the composition to the membrane of the patient; and a method for making the composition.

What is claimed is: 
     
         1 . A method for maintaining a therapeutically effective concentration of testosterone in the blood serum of a male for treating hypogonadism which comprises transdermally delivering to the male by applying to the skin a composition which is in the form of a topical gel, which has a viscosity of about 500 to about 20,000 cps and a pH of about 3 to about 9, and comprises: (A) about 0.1 to about 5 wt. % of testosterone; (B) about 0.01 to about 25 wt. % of at least one enhancer having a partition coefficient ranging from about 4.2 to about 6.9; (C) about 0.1 to about 10 wt. % of a thickening agent; and, (D) a mixture of solvents which include about 40 wt. % to about 80 wt. % of a lower alkanol
 the enhancer being a Hsieh enhancer having the following structure:   
       
         
           
           
               
               
           
         
         wherein X and Y are oxygen, sulfur or an imino group of the structure 
       
       
         
           
           
               
               
           
         
         or —N—R with the proviso that when Y is the imino group, X is an imino group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure 
       
       
         
           
           
               
               
           
         
         wherein X and Y me defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R 1 , R 2 , R 3 , R 4 , R 5  and R 6  is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1  to R 6  can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, than m+n is at least 11. 
       
     
     
         2 . The method of  claim 1  further comprising a crystallization inhibitor that is capable of inhibiting crystallization of testosterone. 
     
     
         3 . The method of  claim 1  wherein the lower alkanol ranges from about 50 wt. % to about 75 wt. %. 
     
     
         4 . The method of  claim 3  wherein the lower alkanol ranges from about 60 wt. % to about 75 wt. %. 
     
     
         5 . The method of  claim 4  wherein the lower alkanol comprises ethanol. 
     
     
         6 . The method of  claim 4  wherein the lower alkanol comprises isopropanol. 
     
     
         7 . The method of  claim 5  further comprising propylene glycol. 
     
     
         8 . The method of  claim 7  further comprising glycerin. 
     
     
         9 . The method of  claim 1  wherein the enhancer is selected from the group of consisting of 3-methylcyclopentadecanone, 9-cycloheptadecen-1-one, cyclohexadecanone, cyclopentadecanone, oxacyclohexadecan-2-one and mixtures thereof. 
     
     
         10 . The method of  claim 9  wherein the macrocyclic enhancer is 3-methylcyclopentadecanone. 
     
     
         11 . The method of  claim 9  wherein the macrocyclic enhancer is 9-cycloheptadecen-1-one. 
     
     
         12 . The method of  claim 9  wherein the macrocyclic enhancer is cyclohexadecanone. 
     
     
         13 . The method of  claim 9  wherein the macrocyclic enhancer is cyclopentadecanone. 
     
     
         14 . The method of  claim 9  wherein the macrocyclic enhancer is oxacyclohexadecan-2-one. 
     
     
         15 . The method of  claim 1  wherein said composition is maintained on said skin for a period of time sufficient for delivery of the testosterone to the body of the male and is applied to the skin in the form of a unit dose which contains about 1 to about 300 mg of testosterone and such that, following a single application of the unit dose to the skin, the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the male achieved in the 24-hour period following the application is about 100 to about 35,000 ng·h/dL greater than the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the male than would have been achieved in the same 24-hour period had the dose not been administered. 
     
     
         16 . A method for maintaining a therapeutically effective concentration of testosterone in the blood serum of a male for treating hypogonadism which comprises transdermally delivering to the male by applying to the skin a composition which is in the form of a topical gel, which has a viscosity of about 500 to about 20,000 cps and a pH of about 3 to about 9, and comprises: (A) about 0.1 to about 5 wt. % of testosterone; (B) about 0.01 to about 25 wt. % of at least one enhancer having a partition coefficient ranging from about 2.0 to about 9.0; (C) about 0.1 to about 10 wt. % of a thickening agent; and, (D) a mixture of solvents which include about 40 wt. % to about 80 wt. % of a lower alkanol.