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.

1 - 58 . (canceled) 
   
   
       59 . 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   (c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration,   
     wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof. 
   
   
       60 . A composition of  claim 59  wherein the drug is present in a formulation having inorganic hydroxide present at a concentration of approximately 2 wt % to 20 wt %. 
   
   
       61 . The composition of  claim 60  wherein the active agent is selected from the group consisting of pharmacologically active amines; nonsteroidal antiinflammatory agents, estrogens and progestins, androgenic drugs, peptidyl drugs, and locally administered active agents. 
   
   
       62 . The composition of  claim 61  wherein the active agent comprises a nonsteroidal anti-inflammatory agent selected from the group consisting of propionic acid derivatives such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen and tiaprofenic acid; acetylsalicylic acid; apazone; diclofenac; difenpiramide; diflunisal; etodolac; flufenamic acid; indomethacin; ketorolac; meclofenamate; mefenamic acid; nabumetone; phenylbutazone; piroxicam; salicylic acid; sulindac; tolmetin; and combinations of any of the foregoing. Preferred NSAIDs are ibuprofen, diclofenac sodium, ketoprofen, ketorolac and piroxicam. 
   
   
       63 . The composition of  claim 62  wherein the composition is provided in the form of a topical or transdermal patch, wherein the active agent is contained within one or more reservoir layers within a laminated structure that is to be affixed to the skin. 
   
   
       64 . The composition of  claim 63  wherein the reservoir comprises a polymeric matrix of a pharmaceutically acceptable adhesive material that serves to affix the system to the skin during drug delivery. 
   
   
       65 . The composition of claim  6  wherein the polymeric matrix comprises a pressure-sensitive adhesive selected from the group consisting of polyethylenes; polysiloxanes; polyisobutylenes; polyacrylates; polyacrylamides; polyurethanes; plasticized ethylene-vinyl acetate copolymers; and tacky rubbers such as polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). 
   
   
       66 . 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;   (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,   
     wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof. 
   
   
       67 . The system of  claim 66  wherein the active agent is selected from the group consisting of pharmacologically active amines; nonsteroidal antiinflammatory agents, estrogens and progestins, androgenic drugs, peptidyl drugs, and locally administered active agents. 
   
   
       68 . The composition of  claim 67  wherein the active agent comprises a nonsteroidal anti-inflammatory agent selected from the group consisting of propionic acid derivatives such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen and tiaprofenic acid; acetylsalicylic acid; apazone; diclofenac; difenpiramide; diflunisal; etodolac; flufenamic acid; indomethacin; ketorolac; meclofenamate; mefenamic acid; nabumetone; phenylbutazone; piroxicam; salicylic acid; sulindac; tolmetin; and combinations of any of the foregoing. Preferred NSAIDs are ibuprofen, diclofenac sodium, ketoprofen, ketorolac and piroxicam. 
   
   
       69 . The composition of  claim 68  wherein the composition is provided in the form of a topical or transdermal patch, wherein the active agent is contained within one or more reservoir layers within a laminated structure that is to be affixed to the skin, and wherein the drug is present in the reservoir at a concentration of approximately 2 wt % to 20 wt %. 
   
   
       70 . The composition of  claim 69  wherein the reservoir comprises a polymeric matrix of a pharmaceutically acceptable adhesive material that serves to affix the system to the skin during drug delivery. 
   
   
       71 . The composition of  claim 70  wherein the polymeric matrix comprises a pressure-sensitive adhesive selected from the group consisting of polyethylenes; polysiloxanes; polyisobutylenes; polyacrylates; polyacrylamides; polyurethanes; plasticized ethylene-vinyl acetate copolymers; and tacky rubbers such as polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene).