Transdermal and topical administration of local anesthetic agents using basic enhancers

Abstract

Compositions and transdermal systems are provided for enhancing the permeability of skin or mucosal tissue to topical or transdermal application of local anesthetic agents. The compositions and systems include a base in order to increase the flux of the agent through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. The permeation enhancer can be an inorganic or organic base. Methods of use are also described.

We claim:  
     
         1 . A composition for the enhanced delivery of a local anesthetic agent through a body surface, comprising a formulation of: (a) a therapeutically effective amount of the local anesthetic agent; (b) a pharmaceutically acceptable inorganic base in an amount effective to provide a pH within the range of about 8.0-13.0 at the body surface during administration of the local anesthetic agent and to enhance the flux of the local anesthetic agent through the body surface without causing damage thereto; and (c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration.  
     
     
         2 . The composition of  claim 1  wherein the basic permeation enhancer is contained within an aqueous formulation.  
     
     
         3 . The composition of  claim 2  wherein the aqueous formulation has a pH within the range of about 8.0-13.0.  
     
     
         4 . The composition of  claim 3  wherein the pH is within the range of about 8.0-11.5.  
     
     
         5 . The composition of  claim 4  wherein the pH is within the range of about 8.5-10.5.  
     
     
         6 . The composition of  claim 2  wherein the aqueous formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.  
     
     
         7 . The composition of  claim 1  wherein the composition provides for at least about 1.5-fold enhanced delivery.  
     
     
         8 . The composition of  claim 7  wherein the composition provides for at least about 3-fold enhanced delivery.  
     
     
         9 . The composition of  claim 1  wherein the local anesthetic agent is an acidic species.  
     
     
         10 . The composition of  claim 9  wherein the base is present in an amount that is the total of (a) the amount required to neutralize the acidic species plus (b) an amount equal to about 0.5-4.0 wt % of the composition.  
     
     
         11 . The composition of  claim 1  wherein the local anesthetic agent is a non-acidic species.  
     
     
         12 . The composition of  claim 11  wherein the base is present in an amount equal to about 0.5-4.0 wt % of the composition.  
     
     
         13 . The composition of  claim 1  wherein the base is selected from the group consisting of inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, and combinations thereof.  
     
     
         14 . The composition of  claim 13  wherein the base is an inorganic hydroxide selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.  
     
     
         15 . The composition of  claim 13  wherein the base is an inorganic oxide selected from the group consisting of magnesium oxide and calcium oxide.  
     
     
         16 . The composition of  claim 13  wherein the base is an inorganic salt of a weak acid selected from the group consisting of ammonium phosphate, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, and potassium phosphate.  
     
     
         17 . The composition of  claim 1  wherein the base is effective to provide a pH within the range of about 8.0-11.5 at the localized region of the body surface during administration of the local anesthetic agent.  
     
     
         18 . The composition of  claim 17  wherein the base is effective to provide a pH within the range of about 8.5-10.5 at the localized region of the body surface during administration of the local anesthetic agent.  
     
     
         19 . The composition of  claim 1  wherein the local anesthetic agent is selected from the group consisting of benzocaine, benzyl benzoate, bupivacaine, calamine, chloroprocaine, chloroxylenol, cinchocaine, cocaine, dexivacaine, diamocaine, dibucaine, dyclonine, etidocaine, hexylcaine, ketamine, levobupivacaine, lidocaine, menthol, mepivacaine, oxethazaine, phenol, pramoxine, prilocaine, procaine, proparacaine, propoxycaine, pyrrocaine, resorcinol, risocaine, rodocaine, ropivacaine, tetracaine, troclosan, and pharmaceutically acceptable derivatives thereof, and combinations thereof.  
     
     
         20 . The composition of  claim 19  wherein the local anesthetic agent is selected from the group consisting bupivacaine, chloroprocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, tetracaine, and pharmaceutically acceptable derivatives thereof.  
     
     
         21 . The composition of  claim 1  which further comprises at least one irritation-mitigating additive.  
     
     
         22 . A system for the enhanced topical or transdermal administration of a local anesthetic agent, comprising: (a) at least one drug reservoir containing the local anesthetic agent and a pharmaceutically acceptable inorganic base, in an amount effective to enhance the flux of the local anesthetic agent through the body surface without causing damage thereto; (b) a means for maintaining the system in agent and base transmitting relationship to the body surface and forming a body surface-system interface; and (c) a backing layer that serves as the outer surface of the system during use, wherein the base is effective to provide a pH within the range of about 8.0-13.0 at the body surface-system interface during administration of the local anesthetic agent.  
     
     
         23 . The system of  claim 22  wherein the backing layer is occlusive.  
     
     
         24 . The system of  claim 22  wherein the drug reservoir is comprised of a polymeric adhesive.  
     
     
         25 . The system of  claim 24  wherein the polymeric adhesive serves as the means for maintaining the system in agent and base transmitting relationship to the body service.  
     
     
         26 . The system of  claim 22  wherein the drug reservoir is comprised of a hydrogel.  
     
     
         27 . The system of  claim 22  wherein the drug reservoir is comprised of a sealed pouch containing the local anesthetic agent and inorganic base in a liquid or semi-solid formulation.  
     
     
         28 . The system of  claim 22  wherein the system provides for at least about 1.5-fold enhanced delivery.  
     
     
         29 . The system of  claim 28  wherein the composition provides for at least about 3-fold enhanced delivery.  
     
     
         30 . The system of  claim 1  wherein the base is effective to provide a pH within the range of about 8.0-11.5 at the body surface-system interface during administration of the local anesthetic agent.  
     
     
         31 . The system of  claim 30  wherein the base is effective to provide a pH within the range of about 8.5-10.5 at the body surface-system interface during administration of the local anesthetic agent.  
     
     
         32 . The system of  claim 22  wherein the local anesthetic agent is an acidic species.  
     
     
         33 . The system of  claim 32  wherein the base is present in an amount that is the total of (a) the amount required to neutralize the acidic species plus (b) an amount equal to about 0.5-4.0 wt % of the drug reservoir.  
     
     
         34 . The system of  claim 22  wherein the local anesthetic agent is a non-acidic species.  
     
     
         35 . The system of  claim 34  wherein the base is present in an amount equal to about 0.5-4.0 wt % of the drug reservoir.  
     
     
         36 . The system of  claim 22  wherein the base is selected from the group consisting of inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, and combinations thereof.  
     
     
         37 . The system of  claim 36  wherein the base is an inorganic hydroxide selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.  
     
     
         38 . The system of  claim 36  wherein the base is an inorganic oxide selected from the group consisting of magnesium oxide and calcium oxide.  
     
     
         39 . The system of  claim 36  wherein the base is an inorganic salt of a weak acid selected from the group consisting of ammonium phosphate, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, and potassium phosphate.  
     
     
         40 . The system of  claim 22  wherein the local anesthetic agent is selected from the group consisting of benzocaine, benzyl benzoate, bupivacaine, calamine, chloroprocaine, chloroxylenol, cinchocaine, cocaine, dexivacaine, diamocaine, dibucaine, dyclonine, etidocaine, hexylcaine, ketamine, levobupivacaine, lidocaine, menthol, mepivacaine, oxethazaine, phenol, pramoxine, prilocaine, procaine, proparacaine, propoxycaine, pyrrocaine, resorcinol, risocaine, rodocaine, ropivacaine, tetracaine, troclosan, and pharmaceutically acceptable derivatives thereof, and combinations thereof.  
     
     
         41 . The system of  claim 40  wherein the local anesthetic agent is selected from the group consisting of bupivacaine, chloroprocaine, dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, tetracaine, and pharmaceutically acceptable derivatives thereof.  
     
     
         42 . The system of  claim 22  which further comprises at least one irritation-mitigating additive.