Design principles of chemical penetration enhancers for transdermal drug delivery

TLDR

Chemical penetration enhancers are widely used in transdermal, dermatological, and cosmetic products, yet only a few molecules—primarily three to four chemical functionalities—have been employed over the past five decades. The study aims to elucidate the fundamental mechanisms governing CPE barrier disruption and skin safety, and to apply this knowledge to design over 300 novel CPEs. Using more than 100 diverse CPEs, the authors investigated barrier effects and safety, then reengineered the insights into new structures, which were screened computationally and tested in vitro for delivery efficacy. Fourier‑transform infrared spectroscopy revealed that CPEs perturb the skin barrier through lipid extraction or fluidization, while irritation correlates with protein denaturation; these mechanistic insights expose constraints on CPE performance and the newly designed molecules expand the usable repertoire for optimized formulations.

Abstract

Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro . Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future.