In-Silico Skin Model: A Multiscale Simulation Study of Drug Transport

Accurate in-silico models are required to predict the release of drug molecules through skin in order to supplement the in-vivo experiments for faster development/testing of drugs. The upper most layer of the skin, stratum corneum (SC), offers the main resistance for permeation of actives. Most of the SC's molecular level models comprise cholesterol and phospholipids only, which is far from reality. In this study we have implemented a multiscale modeling framework to obtain the release profile of three drugs, namely, caffeine, fentanyl, and naphthol, through skin SC. We report for the first time diffusion of drugs through a realistic skin molecular model comprised of ceramides, cholesterol, and free fatty acid. The diffusion coefficients of drugs in the SC lipid matrix were determined from multiple constrained molecular dynamics simulations. The calculated diffusion coefficients were then used in the macroscopic models to predict the release profiles of drugs through the SC. The obtained release profiles were in good agreement with available experimental data. The partition coefficient exhibits a greater effect on the release profiles. The reported multiscale modeling framework would provide insight into the delivery mechanisms of the drugs through the skin and shall act as a guiding tool in performing targeted experiments to come up with a suitable delivery system.

[1]  T. Hankemeier,et al.  Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients[S] , 2012, Journal of Lipid Research.

[2]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[3]  J. Bouwstra,et al.  Free fatty acids chain length distribution affects the permeability of skin lipid model membranes. , 2016, Biochimica et biophysica acta.

[4]  J. Hadgraft,et al.  Topical delivery of caffeine from some commercial formulations. , 1999, International journal of pharmaceutics.

[5]  Russell O. Potts,et al.  Predicting Skin Permeability , 1992, Pharmaceutical Research.

[6]  Beena Rai,et al.  Effect of Size and Surface Charge of Gold Nanoparticles on their Skin Permeability: A Molecular Dynamics Study , 2017, Scientific Reports.

[7]  Gerrit Groenhof,et al.  GROMACS: Fast, flexible, and free , 2005, J. Comput. Chem..

[8]  Herman J. C. Berendsen,et al.  Permeation Process of Small Molecules across Lipid Membranes Studied by Molecular Dynamics Simulations , 1996 .

[9]  B. S. Dwadasi,et al.  Molecular Dynamics Simulation of Skin Lipids: Effect of Ceramide Chain Lengths on Bilayer Properties. , 2016, The journal of physical chemistry. B.

[10]  Berk Hess,et al.  LINCS: A linear constraint solver for molecular simulations , 1997, J. Comput. Chem..

[11]  Herman J. C. Berendsen,et al.  Simulation of Water Transport through a Lipid Membrane , 1994 .

[12]  E. Lindahl,et al.  Molecular dynamics simulations of phospholipid bilayers with cholesterol. , 2003, Biophysical journal.

[13]  Peter M. Pinsky,et al.  Multiscale Modeling Framework of Transdermal Drug Delivery , 2009, Annals of Biomedical Engineering.

[14]  Massimo G. Noro,et al.  Water permeation through stratum corneum lipid bilayers from atomistic simulations , 2009, 0907.1664.

[15]  J. Bouwstra,et al.  The role of ceramide chain length distribution on the barrier properties of the skin lipid membranes. , 2014, Biochimica et biophysica acta.

[16]  B. Rai,et al.  Molecular Dynamics Simulation Study of Skin Lipids: Effects of the Molar Ratio of Individual Components over a Wide Temperature Range. , 2015, The journal of physical chemistry. B.

[17]  Y. Kalia,et al.  Characterization of the permeability barrier of human skin in vivo. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Langer,et al.  Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism. , 1997, Journal of pharmaceutical sciences.

[19]  H. Frasch,et al.  Steady-state flux and lag time in the stratum corneum lipid pathway: results from finite element models. , 2003, Journal of pharmaceutical sciences.

[20]  S. Ollmar,et al.  Inter- and intra-individual differences in human stratum corneum lipid content related to physical parameters of skin barrier function in vivo. , 1999, The Journal of investigative dermatology.

[21]  R. Burnette.  A Monte-Carlo model for the passive diffusion of drugs through the stratum corneum , 1984 .

[22]  Peter M. Pinsky,et al.  Finite Element Modeling of Coupled Diffusion with Partitioning in Transdermal Drug Delivery , 2005, Annals of Biomedical Engineering.

[23]  H. Berendsen,et al.  Interaction Models for Water in Relation to Protein Hydration , 1981 .

[24]  T. Engels,et al.  Molecular dynamics simulations of stratum corneum lipid models: fatty acids and cholesterol. , 2001, Biochimica et biophysica acta.

[25]  Beena Rai,et al.  Molecular Dynamics Simulation Study of Permeation of Molecules through Skin Lipid Bilayer. , 2016, The journal of physical chemistry. B.

[26]  D. van der Spoel,et al.  GROMACS: A message-passing parallel molecular dynamics implementation , 1995 .

[27]  S. Masich,et al.  The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. , 2012, The Journal of investigative dermatology.

[28]  Peter M. Kasson,et al.  Gromacs User Manual Version 4.6 , 2013 .

[29]  J Bajgar,et al.  Transdermal drug delivery in vitro using diffusion cells. , 2012, Current medicinal chemistry.

[30]  B. Rai,et al.  Molecular dynamics simulation study of translocation of fullerene C60 through skin bilayer: effect of concentration on barrier properties. , 2017, Nanoscale.

[31]  Kakuji Tojo,et al.  Mathematical modeling of transdermal drug delivery. , 1987 .

[32]  Robert Langer,et al.  First-principles, structure-based transdermal transport model to evaluate lipid partition and diffusion coefficients of hydrophobic permeants solely from stratum corneum permeation experiments. , 2007, Journal of pharmaceutical sciences.

[33]  Gabriel Wittum,et al.  In-silico model of skin penetration based on experimentally determined input parameters. Part I: experimental determination of partition and diffusion coefficients. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[34]  J. Ayres,et al.  Diffusion model for drug release from suspensions II: release to a perfect sink. , 1977, Journal of pharmaceutical sciences.

[35]  Peter M. Kasson,et al.  GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit , 2013, Bioinform..

[36]  Beena Rai,et al.  Transdermal cellular membrane penetration of proteins with gold nanoparticles: a molecular dynamics study. , 2017, Physical chemistry chemical physics : PCCP.

[37]  Peter M. Pinsky,et al.  Using the method of homogenization to calculate the effective diffusivity of the stratum corneum with permeable corneocytes , 2008 .

[38]  B. Rai,et al.  Penetration of Gold Nanoparticles through Human Skin: Unraveling Its Mechanisms at the Molecular Scale. , 2016, The journal of physical chemistry. B.

[39]  P. Olmsted,et al.  Lamellar and inverse micellar structures of skin lipids: effect of templating. , 2013, Physical review letters.

[40]  O. Berger,et al.  Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. , 1997, Biophysical journal.

[41]  A. Weerheim,et al.  Determination of stratum corneum lipid profile by tape stripping in combination with high-performance thin-layer chromatography , 2001, Archives of Dermatological Research.

[42]  P. Elias,et al.  Epidermal lipids, barrier function, and desquamation. , 1983, The Journal of investigative dermatology.