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The Permeability Enhancing Mechanism of DMSO in Ceramide Bilayers Simulated by Molecular Dynamics

Rebecca Notman ^*, Wouter K. den Otter , Massimo G. Noro , W. J. Briels  and Jamshed Anwar 

^* Molecular Biophysics, Division of Pharmaceutical Science, King's College London, London, United Kingdom; Computational Biophysics, University of Twente, Enschede, The Netherlands; Physical and Chemical Insights Group, Unilever Research and Development, Port Sunlight, United Kingdom; and Computational Laboratory, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, United Kingdom

Correspondence: Address reprint requests to Jamshed Anwar, Computational Laboratory, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, UK. E-mail: j.anwar{at}bradford.ac.uk.

The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predominant lipid in the stratum corneum, by means of molecular dynamics simulations. The simulations satisfactorily reproduce the phase behavior and the known structural parameters of ceramide 2 bilayers in water. The effect of DMSO on the gel-phase bilayers was investigated at various concentrations over the range 0.0–0.6 mol fraction DMSO. The DMSO molecules accumulate in the headgroup region and weaken the lateral forces between the ceramides. At high concentrations of DMSO (0.4 mol fraction), the ceramide bilayers undergo a phase transition from the gel phase to the liquid crystalline phase. The liquid-crystalline phase of ceramides is expected to be markedly more permeable to solutes than the gel phase. The results are consistent with the experimental evidence that high concentrations of DMSO fluidize the stratum corneum lipids and enhance permeability.