Hydroxide-releasing agents as skin permeation enhancers

Abstract

A method is provided for increasing the permeability of skin or mucosal tissue to topically or transdermally administered pharmacologically or cosmeceutically active agents. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the active agent through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Topically applied formulations and drug delivery devices employing hydroxide-releasing agents as permeation enhancers are provided as well.

We claim:  
     
         1 . A composition of matter useful for the delivery of a drug through a body surface, comprising: 
 (a) a therapeutically effective amount of a 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 13.0 at the body surface, during drug administration, wherein the amount of hydroxide-releasing agent in the composition applied to the body surface 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 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 , 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 selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof.  
     
     
         9 . The composition of  claim 8 , wherein the inorganic hydroxide is sodium hydroxide.  
     
     
         10 . The composition of  claim 8 , wherein the inorganic hydroxide is potassium hydroxide.  
     
     
         11 . 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.  
     
     
         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 0.5 wt. % to 3.0 wt. % of the composition.  
     
     
         13 . The composition of  claim 12 , 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 formulation.  
     
     
         14 . The composition of  claim 5 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         15 . The composition of  claim 14 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         16 . The composition of  claim 14 , which contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         17 . The composition of  claim 5 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         18 . The composition of  claim 17 , wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium carbonate, tribasic sodium phosphate, dibasic sodium phosphate, sodium borate, potassium carbonate, potassium acetate, dibasic potassium phosphate tribasic potassium phosphate, sodium metaborate, and mixtures thereof.  
     
     
         19 . The composition of  claim 17 , which contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         20 . The composition of  claim 1 , which is an aqueous formulation.  
     
     
         21 . The composition of  claim 20 , wherein the formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.  
     
     
         22 . The composition of  claim 21 , wherein the formulation is a cream.  
     
     
         23 . The composition of  claim 21 , wherein the formulation is a gel.  
     
     
         24 . The composition of  claim 1 , which is a nonaqueous formulation.  
     
     
         25 . The composition of  claim 24 , wherein the formulation is an ointment.  
     
     
         26 . The composition of  claim 1 , wherein the drug is an acid addition salt of a basic compound, and the amount in (a) is the amount required to neutralize the acid addition salt and any other acidic species in the composition.  
     
     
         27 . The composition of  claim 1 , wherein the drug is an acidic drug in the form of a free acid, and the amount in (a) is the amount required to neutralize the acidic drug and any other acidic species in the composition.  
     
     
         28 . The composition of  claim 1 , wherein the drug is a basic drug in the form of a free base.  
     
     
         29 . The composition of  claim 1 , wherein the drug is a basic additional salt of an acidic compound.  
     
     
         30 . The composition of  claim 1 , wherein the drug is nonionizable.  
     
     
         31 . A system for the topical or transdermal administration of a 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 13.0 at the body surface, during drug administration, 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.    
     
     
         32 . The system of  claim 31 , wherein the pH is within the range of approximately 8.0 to 11.5.  
     
     
         33 . The system of  claim 32 , wherein the pH is within the range of approximately 8.5 to 11.5.  
     
     
         34 . The system of  claim 31 , wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.  
     
     
         35 . The system of  claim 34 , wherein the hydroxide-releasing agent is an inorganic hydroxide.  
     
     
         36 . The system of  claim 35 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.  
     
     
         37 . The system of  claim 36 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, 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 35 , 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 0.5 wt. % to 3.0 wt. % of the reservoir.  
     
     
         42 . The system of  claim 41 , 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.  
     
     
         43 . The system of  claim 34 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         44 . The system of  claim 43 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         45 . The system of  claim 43 , wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         46 . The system of  claim 34 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         47 . The system of  claim 46 , wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium carbonate, tribasic sodium phosphate, dibasic sodium phosphate, sodium borate, potassium carbonate, potassium acetate, dibasic potassium phosphate tribasic potassium phosphate, sodium metaborate, and mixtures thereof.  
     
     
         48 . The system of  claim 46 , wherein the reservoir contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         49 . The system of  claim 31 , wherein the backing layer is occlusive.  
     
     
         50 . The system of  claim 31 , wherein the reservoir is comprised of a polymeric adhesive.  
     
     
         51 . The system of  claim 50 , wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface.  
     
     
         52 . The system of  claim 31 , wherein the reservoir is comprised of a hydrogel.  
     
     
         53 . The system of  claim 31 , wherein the reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.  
     
     
         54 . The system of  claim 31 , wherein the drug is an acid addition salt of a basic compound, and the amount in (a) is the amount required to neutralize the acid addition salt and any other acidic species in the reservoir.  
     
     
         55 . The system of  claim 31 , wherein the drug is an acidic drug in the form of a free acid, and the amount in (a) is the amount required to neutralize the acidic drug and any other acidic species in the reservoir.  
     
     
         56 . The system of  claim 31 , wherein the drug is a basic drug in the form of a free base.  
     
     
         57 . The system of  claim 31 , wherein the drug is a basic additional salt of an acidic compound.  
     
     
         58 . The system of  claim 31 , wherein the drug is nonionizable.