Transdermal administration of steroid 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 steroid drugs. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the 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 a steroid drug are provided as well. Optimally, the steroid drugs are a combination of an estrogen and progestin that may be administered in female hormone replacement therapy, to provide female contraception, and the like

We claim:  
     
         1 . A composition of matter useful for the delivery of a steroid drug through a body surface, comprising: 
 (a) a therapeutically effective amount of a steroid 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 0.25 wt % to 25.0 wt % of the composition; and    (c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration.    
     
     
         2 . The composition of  claim 1 , wherein the pH is within the range of approximately 8.0 to 11.5.  
     
     
         3 . The composition of  claim 2 , wherein the pH is within the range of approximately 8.5 to 11.5.  
     
     
         4 . The composition of  claim 1 , which 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 0.75 wt % to 2.0 wt % of the composition.  
     
     
         12 . The composition of  claim 5 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         13 . The composition of  claim 12 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         14 . The composition of claim,  12 , which contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         15 . The composition of  claim 5 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         16 . The composition of  claim 15 , 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.  
     
     
         17 . The composition of  claim 15 , which contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         18 . The composition of  claim 1 , which is an aqueous formulation.  
     
     
         19 . The composition of  claim 18 , wherein the formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.  
     
     
         20 . The composition of  claim 19 , wherein the formulation is a cream.  
     
     
         21 . The composition of  claim 19 , wherein the formulation is a gel.  
     
     
         22 . The composition of  claim 1 , which is a nonaqueous formulation.  
     
     
         23 . The composition of  claim 22 , wherein the formulation is an ointment.  
     
     
         24 . The composition of  claim 1 , wherein the steroid is a progestin selected from the group consisting of acetoxypregneno lone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethyl-progesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, d,1-norgestrel, 1-norgestrel, norgestrienone, normethisterone, progesterone, and combinations thereof.  
     
     
         25 . The composition of  claim 24 , wherein the progestin is selected from the group consisting of progesterone, medroxyprogesterone acetate, norethindrone, norethynodrel, d,1-norgestrel and 1-norgestrel.  
     
     
         26 . The composition of  claim 25 , wherein the progestin is progesterone.  
     
     
         27 . The composition of  claim 1 , wherein the steroid is an estrogen selected from the group consisting of 17α-estradiol, 17β-estradiol, ethinyl estradiol, pharmaceutically acceptable esters and ethers of 17α-estradiol, 17β-estradiol and ethinyl estradiol, estriol, estriol succinate, polyestrol phosphate, estrone, estrone acetate, estrone sulfate, piperazine estrone sulfate, quinestrol, mestranol and conjugated equine estrogens.  
     
     
         28 . The composition of  claim 27 , wherein the estrogen is 17β-estradiol, ethinyl estradiol, or mestranol.  
     
     
         29 . The composition of  claim 27 , which further comprises an androgenic agent.  
     
     
         30 . The composition of  claim 29 , wherein the androgenic agent is testosterone or an ester thereof.  
     
     
         31 . The composition of  claim 27 , which further comprises a progestin.  
     
     
         32 . A system for the topical or transdermal administration of a steroidal drug through a body surface, 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 0.25 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.    
     
     
         33 . The system of  claim 32 , wherein the pH is within the range of approximately 8.0 to 11.5.  
     
     
         34 . The system of  claim 33 , wherein the pH is within the range of approximately 8.5 to 11.5.  
     
     
         35 . The system of  claim 32 , wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.  
     
     
         36 . The system of  claim 35 , wherein the hydroxide-releasing agent is an inorganic hydroxide.  
     
     
         37 . The system of  claim 36 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.  
     
     
         38 . The system of  claim 37 , wherein the inorganic hydroxide is sodium hydroxide.  
     
     
         39 . The system of  claim 37 , wherein the inorganic hydroxide is potassium hydroxide.  
     
     
         40 . The system of  claim 36 , 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.  
     
     
         41 . The system of  claim 40 , 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.  
     
     
         42 . The system of  claim 35 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         43 . The system of  claim 42 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         44 . The system of  claim 42 , wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         45 . The system of  claim 35 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         46 . The system of  claim 45 , 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.  
     
     
         47 . The system of  claim 45 , wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         48 . The system of  claim 32 , wherein the backing layer is occlusive.  
     
     
         49 . The system of  claim 32 , wherein the reservoir is comprised of a polymeric adhesive.  
     
     
         50 . The system of  claim 49 , wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface.  
     
     
         51 . The system of  claim 32 , wherein the reservoir is comprised of a hydrogel.  
     
     
         52 . The system of  claim 32 , wherein the reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.  
     
     
         53 . The system of  claim 32 , wherein the steroid is a progestin selected from the group consisting of acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethyl-progesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, d,1-norgestrel, 1-norgestrel, norgestrienone, normethisterone, progesterone, and combinations thereof.  
     
     
         54 . The system of  claim 53 , wherein the progestin is selected from the group consisting of progesterone, medroxyprogesterone acetate, norethindrone, norethynodrel, d,1-norgestrel and 1-norgestrel.  
     
     
         55 . The system of  claim 54 , wherein the progestin is progesterone.  
     
     
         56 . The system of  claim 32 , wherein the steroid is an estrogen selected from the group consisting of 17α-estradiol, 17β-estradiol, ethinyl estradiol, pharmaceutically acceptable esters and ethers of 17α-estradiol, 17β-estradiol and ethinyl estradiol, estriol, estriol succinate, polyestrol phosphate, estrone, estrone acetate, estrone sulfate, piperazine estrone sulfate, quinestrol, mestranol and conjugated equine estrogens.  
     
     
         57 . The system of  claim 56 , wherein the estrogen is 17β-estradiol, ethinyl estradiol, or mestranol.  
     
     
         58 . The system of  claim 56 , which further comprises an androgenic agent.  
     
     
         59 . The system of  claim 58 , wherein the androgenic agent is testosterone or an ester thereof.  
     
     
         60 . The system of  claim 56 , which further comprises a progestin.