The Effect of Water on a New Binary Transdermal Flux Enhancer (Peg_3- Me/IPP): An In Vitro Evaluation Using Estradiol

Abstract

Isopropyl palmitate (IPP), a skin penetration enhancer, combined with triethylene glycol monomethyl ether (Peg₃-Me) results in an excellent transdermal flux enhancer. A solution of 11% Peg₃-Me/IPP saturated with estradiol delivers the drug at a 60-fold greater rate than from estradiol (E₂)-saturated donors of IPP or Peg₃-Me alone. Unfortunately, a steady-state flu is not maintained. Studies using vertical permeation cells indicated that the back flux of water causes the donor solution to phase separate, with an IPP-rich phase floating away from the skin. The ternary phase diagram for IPP, Peg₃-Me, and H₂O shows that a solution of IPP/Peg₃-Me will only accept 1 % water before phase separating. Additional experiments, involving donor solution replacement and reorientation of the skin relative to the donor solution, demonstrated that phase separation was responsible for the non-steady-state E₂ flux. Finally, a prototype bilayer laminate, which included a hydrophobic polyisobutylene luyer (PIB), minimized the water flux from the receiver chamber into the donor and produced a sustained and high transdennal flux. While the mechanism of enhancement is complex, the Peg₃-Me/IPP flux enhancers may provide significant improvements for transdermal drug delivery