Transdermal administration of oxybutynin using hydroxide-releasing agents as permeation enhancers

Abstract

A method is provided for increasing the permeability of skin or mucosal tissue to transdermally administered oxybutynin. 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, drug delivery systems and methods of treatment are provided as well.

We claim:  
     
         1 . A composition of matter useful for the delivery of oxybutynin through a body surface, comprising: 
 (a) a therapeutically acceptable amount of oxybutynin;    (b) a hydroxide-releasing agent in an amount effective to enhance the flux of oxybutynin 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 oxybutynin 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 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 composition.  
     
     
         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 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.  
     
     
         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 oxybutynin is in the form of an acid addition salt, and the amount in (a) is the amount required to neutralize the acid addition salt and other acidic species in the composition.  
     
     
         27 . The composition of  claim 1 , wherein the oxybutynin is in the form of the free base.  
     
     
         28 . The composition of  claim 1 , wherein the oxybutynin is in the form of an acid addition salt.  
     
     
         29 . The composition of  claim 28 , wherein the acid addition salt is oxybutynin hydrochloride.  
     
     
         30 . The composition of  claim 1 , wherein the oxybutynin is present as a racemate.  
     
     
         31 . The composition of  claim 1 , wherein the oxybutynin is present as substantially pure (R)-oxybutynin.  
     
     
         32 . The composition of  claim 1 , wherein the oxybutynin is present as substantially pure (S)-oxybutynin.  
     
     
         33 . A system for the transdermal administration of oxybutynin, comprising: 
 (a) at least one reservoir containing oxybutynin and a hydroxide-releasing agent in an amount effective to enhance the flux of oxybutynin through the body surface of a human patient without causing damage thereto and effective to provide a pH in the range of approximately 8.0 to 13 at the body surface during oxybutynin administration; and wherein the amount of hydroxide-releasing agent 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 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.    
     
     
         34 . The system of  claim 33 , wherein the pH is within the range of approximately 8.0 to 11.5.  
     
     
         35 . The system of  claim 34 , wherein the pH is within the range of approximately 8.5 to 11.5.  
     
     
         36 . The system of  claim 33 , wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.  
     
     
         37 . The system of  claim 36 , wherein the hydroxide-releasing agent is an inorganic hydroxide.  
     
     
         38 . The system of  claim 37 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.  
     
     
         39 . The system of  claim 38 , wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof.  
     
     
         40 . The system of  claim 39 , wherein the inorganic hydroxide is sodium hydroxide.  
     
     
         41 . The system of  claim 39 , wherein the inorganic hydroxide is potassium hydroxide.  
     
     
         42 . The system of  claim 37 , 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.  
     
     
         43 . The system of  claim 42 , 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.  
     
     
         44 . The system of  claim 43 , 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.  
     
     
         45 . The system of  claim 36 , wherein the hydroxide-releasing agent is an inorganic oxide.  
     
     
         46 . The system of  claim 45 , wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.  
     
     
         47 . The system of  claim 45 , which contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         48 . The system of  claim 36 , wherein the hydroxide-releasing agent is a metal salt of a weak acid.  
     
     
         49 . The system of  claim 48 , 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.  
     
     
         50 . The system of  claim 48 , which contains up to approximately 20 wt % of the hydroxide-releasing agent.  
     
     
         51 . The system of  claim 33 , wherein the backing layer is occlusive.  
     
     
         52 . The system of  claim 33 , wherein the reservoir is comprised of a polymeric adhesive.  
     
     
         53 . The system of  claim 52 , wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface.  
     
     
         54 . The system of  claim 33 , wherein the reservoir is comprised of a hydrogel.  
     
     
         55 . The system of  claim 33 , wherein the reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.  
     
     
         56 . The system of  claim 33 , wherein the oxybutynin is in the form of an acid addition salt, and the amount in (a) is the amount required to neutralize the acid addition salt and other acidic species in the reservoir.  
     
     
         57 . The system of  claim 33 , wherein the oxybutynin is in the form of the free base.  
     
     
         58 . The system of  claim 33 , wherein the oxybutynin is in the form of an acid addition salt.  
     
     
         59 . The system of  claim 58 , wherein the acid addition salt is oxybutynin hydrochloride.  
     
     
         60 . The system of  claim 33 , wherein the oxybutynin is present as a racemate.  
     
     
         61 . The system of  claim 33 , wherein the oxybutynin is present as substantially pure (R)-oxybutynin.  
     
     
         62 . The system of  claim 33 , wherein the oxybutynin is present as substantially pure (S)-oxybutynin.