Effect of electric field and ultrasound for transdermal drug delivery

Abstract

Transdermal transport of molecules during sonophoresis (delivery or extraction) can be further enhanced by application of an electric field, for example, electroporation or iontophoresis. In a preferred embodiment the ultrasound is low frequency ultrasound which induces cavitation of the lipid layers of the stratum corneum (SC). This method provides higher drug transdermal fluxes, allows rapid control of transdermal fluxes, and allows drug delivery or analyte extraction at lower ultrasound intensities than when ultrasound is applied in the absence of an electric field.

1 . A method for enhancing transdermal transport of compounds comprising administering to the skin an effective amount of low frequency ultrasound to induce cavitation of the skin to enhance transport without increasing skin temperature more than about two degrees Centrigrade in combination with an effective amount of an electric field selected from the group consisting of iontophoresis and electroproration to enhance transport.  
     
     
         2 . (Canceled).  
     
     
         3 . The method of  claim 1  wherein the ultrasound is administered at a frequency of 1 MHz or less.  
     
     
         4 . The method of  claim 1  wherein the intensity of the ultrasound is less than 2.5 W/cm 2 .  
     
     
         5 . The method of  claim 1  wherein the intensity of the ultrasound is less than 1.5 W/cm 2 .  
     
     
         6 . The method of  claim 1  wherein the ultrasound is administered in combination with agents enhancing solubility of the compounds to be transported in combination with agents enhancing the fluidity of lipid bilayers.  
     
     
         7 . (Canceled).  
     
     
         8 . The method of  claim 1  wherein the compound to be transported is a drug the patient is in need of.  
     
     
         9 . The method of  claim 1  wherein the compound to be transported is an analyte to be measured.  
     
     
         10 . The method of  claim 1  wherein the electric field is pulsed.  
     
     
         11 . The method of  claim 1  wherein the ultrasound is pulsed.  
     
     
         12 . An apparatus, comprising a means for applying low frequency ultrasound to induce cavitation of the skin to enhance transport without increasing skin temperature more than about two degrees Centrigrade and a means for applying ant electric field in a form selected from the group consisting of iontophoresis and electroporation to skin in an amount effective to enhance transport of molecules trough the skin without damaging the skin.  
     
     
         13 . The apparatus of  claim 12  further comprising a reservoir for a compound to be transported.  
     
     
         14 . The apparatus of  claim 12  further comprising a reservoir for collection of an analyte to be measured.  
     
     
         15 . The method of  claim 1 , wherein the electric field is iontophoresis.  
     
     
         16 . The method of  claim 1 , wherein the electric field is electroporation.  
     
     
         17 . The method of  claim 1 , wherein the ultrasound is applied simultaneously with the electric field.  
     
     
         18 . The method of  claim 1 , wherein the ultrasound is applied before the electric field.  
     
     
         19 . The method of  claim 1 , wherein the ultrasound is administered at a frequency equivalent to between 20 and 40 kHz.  
     
     
         20 . The method of  claim 1  wherein the frequency is less than 1 MHz, the intensity is in the range of between zero and 1 W/cm 2 .  
     
     
         21 . The apparatus of  claim 12 , which can administer ultrasound at a frequency equivalent to between 20 kHz and 40 kHz.  
     
     
         22 . The apparatus of  claim 12  wherein the apparatus can administer ultrasound at a frequency less than 1 MHz, with an intensity in the range of between zero and 1 W/cm 2 .  
     
     
         23 . The apparatus of  claim 12 , wherein the electric field is iontophoresis.  
     
     
         24 . The apparatus of  claim 12 , wherein the electric field is electroporation.