Synergistic Effect of Chemical Penetration Enhancers on Lidocaine Permeability Revealed by Coarse-Grained Molecular Dynamics Simulations

Abstract

The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs—linoleic acid (LA) and ethanol—through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid. In our simulations, we probed the effects of individual CPEs as well as their combination on various properties of the SC membrane and the lidocaine penetration across it. We demonstrated that the addition of both CPEs decreases the membrane thickness and the order parameters of the DPCE hydrocarbon chains. Moreover, LA also enhances diffusion of the SC membrane components, especially cholesterol. The estimated potential of mean force (PMF) profiles for the lidocaine translocation across SC in the presence/absence of two individual CPEs and their combination demonstrated that while ethanol lowers the free energy barrier for lidocaine to enter SC, LA decreases the depth of the free energy minima for lidocaine inside SC. These two effects supposedly result in synergistic penetration enhancement of drugs. Altogether, the present simulations provide a detailed molecular picture of CPEs’ action and their synergistic effect on the penetration of small molecular weight therapeutics that can be beneficial for the design of novel drug and cosmetics formulations.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…The cyclic peptide (Trp-D-Leu)4-Gln-D-Leu has the ability to assemble into tube-like structures in lipid bilayers; this has been demonstrated to possibly be capable of acting as an enhancer for the antitumor drug 5-fluorouracil [206]-the drug is believed to pass the bilayer through the tube created by the peptide as free energy calculations indicate the presence of only a small 5 kJ/mol barrier against such a translocation. In coarse-grained simulations of lidocaine translocation through a lipid bilayer, two enhancers, ethanol and linoleic acid, were shown to have a synergistic effect on lidocaine permeability [603]. Finally, Gupta et al [604] performed extensive screening of possible enhancers through a massively parallel array of umbrella sampling calculations using the coarse-grained MARTINI model [605,606] to obtain approximate results for the free energy barriers to translocation for each case (Figure 12) [604].…”

Beneath the Skin: A Review of Current Trends and Future Prospects of Transdermal Drug Delivery Systems

“…Karande et al [46] demonstrated the feasibility of systemic delivery of macromolecules from a transdermal patch employing a combination of penetration enhancers (sodium lauryl sulfate and phenyl piperazine). Additionally, Bozdaganyan et al [47] reported that using two CPEs (linoleic acid and ethanol) on an SC model enhanced the delivery of lidocaine in a synergistic way [47]. Moreover, the effect of a penetration enhancer on the permeation of atenolol through excised rat skin was investigated by Cho et al [48].…”