Effect of different enhancers on the transdermal permeation of insulin analog.

Using chemical penetration enhancers (CPEs), transdermal drug delivery (TDD) offers an alternative route for insulin administration, wherein the CPEs reversibly reduce the barrier resistance of the skin. However, there is a lack of sufficient information concerning the effect of CPE chemical structure on insulin permeation. To address this limitation, we examined the effect of CPE functional groups on the permeation of insulin. A virtual design algorithm that incorporates quantitative structure-property relationship (QSPR) models for predicting the CPE properties was used to identify 43 potential CPEs. This set of CPEs was pre-screened using a resistance technique, and the 22 best CPEs were selected. Next, standard permeation experiments in Franz cells were performed to quantify insulin permeation. Our results indicate that specific functional groups are not directly responsible for enhanced insulin permeation. Rather, permeation enhancement is produced by molecules that exhibit positive logK(ow) values and possess at least one hydrogen donor or acceptor. Toluene was the only exception among the 22 potential CPEs considered. In addition, toxicity analyses of the 22 CPEs were performed. A total of eight CPEs were both highly enhancing (permeability coefficient at least four times the control value) and non-toxic, five of which are new discoveries. Copyright 2010 Elsevier B.V. All rights reserved.