Molecular Dynamics Simulations to Elucidate Translocation and Permeation of Active from Lipid Nanoparticle to Skin: Complemented with Experiments

One of the most realistic approaches that could deliver actives (pharmaceuticals/cosmetics) deep into skin layer is encapsulation into nanoparticles (NP). Nonetheless, molecular-level understanding into the mechanism of active delivery from NP to skin has scarcely been studied, compared to their synthesis and characterization. We herein report the underlying mechanism of active translocation and permeation through the outermost layer of skin, stratum corneum (SC), by molecular dynamics (MD) simulations, complemented with experimental results.

A SC molecular model is constructed using current state-of-the-art methodology by incorporating three most abundant skin lipids: ceramide, free fatty acid and cholesterol. As a persuasive antioxidant, ferulic acid (FA) is used as the model active which is loaded into Gelucire 50/13 NP. MD simulations elucidate that first, FA load NP approaches the skin surface quickly followed by slight penetration and adsorption onto the upper skin surface; FA then translocates from the NP surface to the skin surface due to stronger NP-skin interaction compared to that of FA-NP; once the FA is released onto the skin surface, it slowly permeates deep into the skin bilayer. Both free energy and resistance to permeation not only indicates spontaneous transfer of FA from bulk to skin surface, but also reveal that the main barrier for permeation exists in the middle of lipids hydrophobic tails. Significant lower diffusion of FA is obtained in the main barrier region compared to bulk.

The estimated permeability coefficient (log P) found to be higher than experiments. Importantly, permeation process evaluated by MD simulations perfectly match with experiments. The study suggests a molecular simulation platform that enable various crucial insights for active delivery from loaded NP to skin and would facilitate the design and development of novel NP-based formulations for transdermal delivery and topical application of drugs/cosmetics.

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Article information: Krishna M. Gupta, Surajit Das and Pui Shan Chow. Nanoscale, 2021, Accepted Manuscript.