ABSTRACT
Introduction ...................................................................................................................................... 35 Methods ............................................................................................................................................ 36 Quantitative Structure-Enhancement Relationships Based on Aqueous
Concentrations of the Enhancer.................................................................................................. 38 Quantitative Structure-Enhancement Relationship Based on Enhancer
Concentrations in the Stratum Corneum Intercellular Lipids .................................................... 42 Microenvironment of the Site of Enhancer Action.......................................................................... 45 Transdermal Drug Delivery.............................................................................................................. 46 Acknowledgment ............................................................................................................................. 47 References......................................................................................................................................... 47
Over the past 30 years, numerous studies on the influence of chemical permeation enhancers upon drug permeation across skin have been performed. The literature is abundantwithhundredsof articles, patents, and reviewson this topic (e.g., reviewed in Leeet al., 1991; Williams and Barry, 1992; Smith and Maibach, 1995; Walters and Hadgraft, 1993; Potts and Guy, 1997). It is generally believed that the mechanisms of action for most transdermal enhancers are through physical enhancer-membrane interactions (e.g., intercalation and
perturbation) and by fluidizing the lipids in the stratum corneum (SC) (e.g., Barry, 1987; Yoneto et al., 1996). Some enhancers can also act by SC lipid solubilization and lipid extraction (e.g., Goates and Knutson, 1994; Ogiso et al., 1995). Despite continuing advances in the knowledge of transdermal absorption and enhancer mechanisms, the effects of enhancers upon drug permeation have been quite unpredictable, and the mechanism of action of permeation enhancers and their site of action in the SC are not fully understood. A clear quantitative structure-enhancement relationship (relationship between the enhancer molecular structures and their enhancing potencies) for predicting the effectiveness of enhancers is not available. Arbitrary screening remains a common approach in industrial practice to identify effective permeation enhancers for improving percutaneous absorption as opposed to a rational design approach. A screening approach is generally ineffective, and therefore obtaining a quantitative structure-enhancement relationship for permeation enhancers based on a clear understanding of the mechanism of action of enhancers and the nature of the microenvironment of the enhancer site of action is important. If one does not understand the structure-enhancement relationship, the rational design of an effective enhancer and the prediction of the enhancer effects will remain a difficult task.
