Transdermal administration of androgenic drugs using hydroxide-releasing agents as permeation enhancers

Abstract

A method is provided for increasing the permeability of skin or mucosal tissue to transdermally administered androgenic drugs. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the androgenic drug through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery systems for co-administering a hydroxide-releasing agent with an androgenic drug are provided as well.

We claim:  
     
         1 . A composition of matter useful for the delivery of an androgenic drug through a body surface, comprising: 
 (a) a therapeutically effective amount of an androgenic drug;    (b) a hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto and effective to provide a pH in the range of approximately 8.0 to 13 at the body surface during drug administration, and wherein the amount of hydroxide-releasing agent in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt % to 25.0 wt % of the reservoir; and    (c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration.    
     
     
         2 . The composition of  claim 1 , having a pH in the range of approximately 8.0 to 11.5.  
     
     
         3 . The composition of  claim 2 , having a pH in the range of approximately 8.5 to 11.5.  
     
     
         4 . The composition of  claim 1 , wherein the composition is substantially free of organic solvents.  
     
     
         5 . The composition of  claim 1 , wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof  
     
     
         6 . The composition of  claim 5 , wherein the hydroxide-releasing agent is an inorganic hydroxide.  
     
     
         7 . The composition of  claim 6 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.  
     
     
         8 . The composition of  claim 7 , wherein the inorganic hydroxide is sodium hydroxide.  
     
     
         9 . The composition of  claim 7 , wherein the inorganic hydroxide is potassium hydroxide.  
     
     
         10 . The composition of  claim 6 , wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the composition.  
     
     
         11 . The composition of  claim 10 , wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt % to 3.0 wt % of the composition.  
     
     
         12 . The composition of  claim 11 , wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.75 wt % to 2.0 wt % of the composition.  
     
     
         13 . The composition of  claim 5 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         14 . The composition of  claim 13 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         15 . The composition of  claim 13 , wherein the composition contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         16 . The composition of  claim 5 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         17 . The composition of  claim 16 , wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof.  
     
     
         18 . The composition of  claim 17 , wherein the composition contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         19 . The composition of  claim 1 , which is an aqueous formulation.  
     
     
         20 . The composition of  claim 19 , wherein the formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.  
     
     
         21 . The composition of  claim 20 , wherein the formulation is a cream.  
     
     
         22 . The composition of  claim 20 , wherein the formulation is a gel.  
     
     
         23 . The composition of  claim 1 , which is a nonaqueous formulation.  
     
     
         24 . The composition of  claim 23 , wherein the formulation is an ointment.  
     
     
         25 . The composition of  claim 1 , wherein the androgenic drug is selected from the group consisting of androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate, androstenedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, methyl testosterone, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 4-dihydrotestosterone, 5α-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.  
     
     
         26 . The composition of  claim 25 , wherein the androgenic drug is testosterone or a pharmaceutically acceptable ester thereof.  
     
     
         27 . The composition of  claim 26 , wherein the androgenic agent is testosterone.  
     
     
         28 . The composition of  claim 26 , wherein the androgenic agent is a testosterone ester.  
     
     
         29 . The composition of  claim 28 , wherein the testosterone ester is selected from the group consisting of testosterone enanthate, propionate, cypionate, phenylacetate, acetate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate.  
     
     
         30 . A system for the topical or transdermal administration of an androgenic drug, comprising: 
 (a) at least one reservoir containing the drug and a hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto and effective to provide a pH in,the range of approximately 8.0 to 13 at the body surface during drug administration, and wherein the amount of hydroxide-releasing agent in the reservoir applied to the body surface is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.5 wt % to 25.0 wt % of the reservoir;    (b) a means for maintaining the system in drug and enhancer transmitting relationship to the body surface; and    (c) a backing layer that serves as the outer surface of the system during use.    
     
     
         31 . The system of  claim 30 , wherein the pH is within the range of approximately 8.0 to 11.5.  
     
     
         32 . The system of  claim 30 , wherein the pH is within the range of approximately 8.5 to 11.5.  
     
     
         33 . The system of  claim 30 , wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.  
     
     
         34 . The system of  claim 33 , wherein the hydroxide-releasing agent is an inorganic hydroxide.  
     
     
         35 . The system of  claim 34 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.  
     
     
         36 . The system of  claim 35 , wherein the inorganic hydroxide is sodium hydroxide.  
     
     
         37 . The system of  claim 35 , wherein the inorganic hydroxide is potassium hydroxide.  
     
     
         38 . The system of  claim 34 , wherein the amount of inorganic hydroxide in the reservoir is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.5 wt % to 4.0 wt % of the reservoir.  
     
     
         39 . The system of  claim 38 , wherein the amount of inorganic hydroxide in the reservoir is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.5 wt % to 3.0 wt % of the reservoir.  
     
     
         40 . The system of  claim 39 , wherein the amount of inorganic hydroxide in the reservoir is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.75 wt % to 2.0 wt % of the reservoir.  
     
     
         41 . The system of  claim 33 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         42 . The system of  claim 41 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         43 . The system of  claim 41 , wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         44 . The system of  claim 33 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         45 . The system of  claim 44 , wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof.  
     
     
         46 . The system of  claim 44 , wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         47 . The system of  claim 30 , wherein the backing layer is occlusive.  
     
     
         48 . The system of  claim 30 , wherein the reservoir is comprised of a polymeric adhesive.  
     
     
         49 . The system of  claim 48 , wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface.  
     
     
         50 . The system of  claim 30 , wherein the reservoir is comprised of a hydrogel.  
     
     
         51 . The system of  claim 30 , wherein the reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.  
     
     
         52 . The system of  claim 30 , wherein the androgenic drug is selected from the group consisting of androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate, androstenedione, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, methyl testosterone, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol, testosterone, 4-dihydrotestosterone, 5α-dihydrotestosterone, testolactone, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.  
     
     
         53 . The system of  claim 52 , wherein the androgenic drug is testosterone or a pharmaceutically acceptable ester thereof.  
     
     
         54 . The system of  claim 53 , wherein the androgenic agent is testosterone.  
     
     
         55 . The system of  claim 53 , wherein the androgenic agent is a testosterone ester.  
     
     
         56 . The system of  claim 51 , wherein the testosterone ester is selected from the group consisting of testosterone enanthate, propionate, cypionate, phenylacetate, acetate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate.