Effect of Chemical Permeation Enhancers on Skin Permeability: In silico screening using Molecular Dynamics simulations

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.

Design Principles of Ionic Liquids for Transdermal Drug Delivery

“…It was shown that the enhancers can be classified as lipid fluidizers or extractors, and the mechanism of their action in each class can be correlated to their molecular properties including octanol–water partition coefficient and solubility parameters . Computational studies have also confirmed molecular mechanisms of enhancers . Such studies with chemical enhancers have led to unique insights into their mechanism of action as well as the design of novel penetration enhancers.…”

The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application

“…The stratum corneum is the outermost layer of the epidermis with insoluble transglutaminase-cross-linked proteins and lipids, and is considered to function as a barrier [85,86]. It is highly selective and allows only small lipophilic molecules to pass through [87]. This brings up a new hypothesis: differences may exist in the accessibility to the receptors, depending on the permeability of the chemicals.…”

Integrated “Generate, Make, and Test” for Formulated Products using Knowledge Graphs

“…The platform leverages micro-and macro-scale [41] and is capable of in-silico testing [42]. It can emulate the physicochemical properties of human skin, thereby facilitating the study of how constituents of new formulations are transported through its layers [43].…”