Abstract
Breaching of the skin barrier is essential for delivering active pharmaceutical ingredients (APIs) for pharmaceutical, dermatological and aesthetic applications. Chemical permeation enhancers (CPEs) are molecules that interact with the constituents of skin’s outermost and rate limiting layer stratum corneum (SC), and increase its permeability. Designing and testing of new CPEs is a resource intensive task, thus limiting the rate of discovery of new CPEs. In-silico screening of CPEs in a rigorous skin model could speed up the design of CPEs. In this study, we performed coarse grained (CG) molecule dynamics (MD) simulations of a multilayer skin lipid matrix in the presence of CPEs. The CPEs are chosen from different chemical functionalities including fatty acids, esters, and alcohols. A multi-layer in-silico skin model was developed. The CG parameters of permeation enhancers were also developed. Interactions of CPEs with SC lipids was studied in silico at three different CPE concentrations namely, 1% w/v, 3% w/v and 5% w/v. The partitioning and diffusion coefficients of CPEs in the SC lipids were found to be highly size- and structure-dependent and these dependencies are explained in terms of structural properties such as radial distribution function, area per lipid and order parameter. Finally, experimentally reported effects of CPEs on skin from the literature are compared with the simulation results. The trends obtained using simulations are in good agreement with the experimental measurements. The studies presented here validate the utility of in-silico models for designing, screening and testing of novel and effective CPEs.
Highlights
Human skin provides an excellent barrier against the external harsh conditions, pathogens and other environmental threats
We present the development of a multilayer in-silico multilayer skin lipid matrix model[34] for testing the effect of Chemical permeation enhancers (CPEs) on stratum corneum (SC) lipids
The molecule dynamics (MD) simulations of each permeation enhancer with skin lipid layer were carried out at three different concentrations (1% w/v, 3% w/v and 5% w/v)
Summary
Human skin provides an excellent barrier against the external harsh conditions, pathogens and other environmental threats. Realizing the full potential of transdermal delivery, is limited by the protective barrier provided by the outermost layer of the skin known as stratum corneum (SC). Effective breaching of the SC’s protective barrier is a major challenge in transdermal drug delivery. Various ways have been proposed to breach the SC barrier and these methods are broadly classified as active and passive methods. The former class uses external energy sources such as iontophoresis[8], sonophoresis[9], microneedles[10], electroporation[11] to www.nature.com/scientificreports/. Temporarily breach the skin barrier whereas the latter class uses chemical permeation enhancers and ionic liquids, among others[12,13]. Attempts have been made to study the mechanisms of action of CPEs and classify them based on their action rather than chemical identity[18,19,22]
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