The effect of penetration enhancers on drug delivery through skin: a QSAR study

Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise

insufficiently skin-permeable. A full understanding of the mode of action could be beneficial for the design of potent enhancers

and for the choice of the enhancer to be used in the topical formulation of a special drug. In this study, the structural

requirements of penetration enhancers have been investigated using the Quantitative Structure–Activity Relationship (QSAR)

technique. Activities of naturally occurring terpenes, pyrrolidinone and N-acetylprolinate derivatives on the skin penetration of

5-fluorouracil, diclofenac sodium (DFS), hydrocortisone (HC), estradiol and benazepril have been considered. The resulting

QSARs indicated that for 5-fluorouracil and diclofenac sodium, less hydrophobic enhancers were the most active. More

precisely, molecular descriptors in the corresponding QSARs indicated the possible involvement of intermolecular electron

donor–acceptor interactions. This was in contrast to the skin permeation promotion of hydrocortisone, estradiol and benazepril

by enhancers, where a linear relationship between enhancement activity and n-octanol/water partition coefficients of enhancers

was evident. The possible mechanisms of penetration enhancement as suggested by the QSARs will be discussed.