Quantitative Structure–Enhancement Relationship and the Microenvironment of the Enhancer Site of Action

Abstract

In the last several decades, a large number of studies on chemical permeation enhancers were performed to assist the development of topical and transdermal products. The mechanisms of chemical permeation enhancers on skin transport have been investigated and quantitative structure–enhancement relationships for permeation enhancers have been examined. The understanding of the enhancer mechanisms of action would allow effective prediction of the effects of skin permeation enhancers, minimize chemical permeation enhancer screening, and improve topical and transdermal formulation development. Based on the systematic approaches in our previous studies, it was determined that enhancer-induced permeation enhancement across the skin lipoidal pathway was directly related to the concentration of the enhancers in the stratum corneum lipid domain. Relationships between skin permeation enhancer potency (based on either enhancer aqueous concentration in the diffusion cell chamber or enhancer concentration in the stratum corneum lipids) and enhancer lipophilicity (enhancer n-octanol–water partition coefficient) were established. The nature of the microenvironment of the enhancer site of action in the stratum corneum was found to be mimicked by n-octanol. The present chapter summarizes these findings and reviews the quantitative structure–enhancement relationship deduced in these systematic studies.