Chemical Permeation Enhancers Enhance Nerve Blockade by Toxins

Abstract

Chemical permeation enhancers (CPEs) improve access of local anesthetics to the nerve, thereby improving their performance. Surfactants, representing three CPE sub-groups: anionic, cationic, and nonionic surfactants, were co-injected with tetrodotoxin (TTX) or bupivacaine at the sciatic nerve of Sprague-Dawley rats. All enhancers produced marked concentration-dependent improvements in the frequency and duration of block with TTX but not bupivacaine. An in vitro toxicity assay showed a wide range of CPE myotoxicity, but in vivo histological assessment showed no signs of muscle or nerve damage at concentrations of CPEs that produced a half-maximal increase in the duration of block of TTX. There was no systematic relationship between the enhancers' charge or hydrophobicity and their enhancement of block duration or potency. Thus, CPEs can provide marked prolongation of nerve blockade from TTX, without apparent local tissue toxicity, and therefore enhance the clinical applicability of TTX for prolonged-duration local anesthesia.

We claim: 
     
         1 . A method for enhancing nerve blockade without significant cytotoxicity comprising administering a site I sodium channel local anesthetic in combination with an effective amount of chemical permeation enhancer selected from the group consisting of surfactants, terpenes, amino amides, amino esters, azide-like compounds and alcohols, to increase blockade more than the additive effect of the local anesthetic or chemical, permeation enhancer alone. 
     
     
         2 . The method of  claim 1  wherein the local anesthetic is selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, neosaxitoxin, and the gonyanloxins. 
     
     
         3 . The method of  claim 1  wherein the chemical penetration enhancer is selected from the group consisting of anionic, cationic, and nonionic surfactants. 
     
     
         4 . The method of  claim 1  further comprising, administering a vasoconstrictor. 
     
     
         5 . The method of  claim 1  further comprising a charged local anesthetic selected from the group consisting of amino-amide or amino-ester local anesthetics or derivatives thereof, at least partly amphophilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics. 
     
     
         6 . The method of  claim 1  comprising providing a kit comprising a vial having the local anesthetic therein and a second vial containing a diluent therein. 
     
     
         7 . The method of  claim 1  comprising administering the anesthetic as a bolus dosage unit. 
     
     
         8 . The method of  claim 1  comprising administering the anesthetic in a continuous or sustained release formulation. 
     
     
         9 . The method of  claim 1  comprising administering the anesthetic in a topical or aerosol formulation. 
     
     
         10 . An anesthetic composition for enhancing nerve blockade without significant cytotoxicity comprising a site I sodium channel local anesthetic in combination with an effective amount of chemical permeation enhancer selected from the group consisting of surfactants, terpenes, amino amides, amino esters, azide-like compounds and alcohols, to increase blockade more than the additive effect of the local anesthetic or chemical permeation enhancer alone. 
     
     
         11 . The composition of  claim 10  wherein the local anesthetic is selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, neosaxitoxin, and the gonyautoxins. 
     
     
         12 . The composition of  claim 10  wherein the chemical penetration enhancer is selected from the group consisting of anionic, cationic, and nonionic surfactants. 
     
     
         13 . The composition of  claim 10  further comprising a vasoconstrictor. 
     
     
         14 . The composition of  claim 10  further comprising a charged local anesthetic selected from the group consisting of amino-amlde or amino-ester local anesthetics or derivatives thereof, at least partly amphiphilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics. 
     
     
         15 . The composition of  claim 10  in a kit comprising a vial comprising the local anesthetic therein and a second vial comprising a diluent therein. 
     
     
         16 . The composition of  claim 10  comprising the anesthetic as a bolus dosage unit. 
     
     
         17 . The composition of  claim 10  comprising the anesthetic in a continuous or sustained release formulation. 
     
     
         18 . The composition of  claim 10  comprising the anesthetic in a topical or aerosol formulation. 
     
     
         19 . A method for providing local anesthesia comprising providing an effective amount of a site I sodium channel, blocker in combination with a local anesthetic selected from the group consisting of a charged local anesthetic selected from the group consisting of amino-amide or amino-ester local anesthetics or derivatives thereof, at least partly amphiphilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics. 
     
     
         20 . The method of  claim 19  wherein the local anesthetic is a lidocaine or lidocaine derivative. 
     
     
         21 . A composition for providing local anesthesia comprising an effective amount of a sited sodium channel blocker in combination with a local anesthetic selected from the group consisting of a charged local anesthetic selected from the group consisting of amino-amide or amino-ester local anesthetics or derivatives thereof, at least partly amphophilic local anesthetics, local anesthetics that act not on the surface of the cell and at least partly charged local anesthetics. 
     
     
         22 . The composition of  claim 21  wherein the local anesthetic is a lidocaine or lidocaine derivative.