(585ai) Multiscale Modeling of Drug Transport through Human Skin Stratum Corneum | AIChE

(585ai) Multiscale Modeling of Drug Transport through Human Skin Stratum Corneum


Gajula, K. - Presenter, TCS Research
Gupta, R., TCS Research
Balarama Sridhar, D., TCS Research
Rai, B., TCS Research
Skin is the largest organ of the human body. Owing to the high surface area, it provides a convenient route for administration of drugs. Thus, transdermal delivery provides a potential alternative to other regular modes of administration of drugs. Understanding the mechanism of drug permeation through the skin, and, dermal uptake, is beneficial for the development of effective trans-dermal delivery formulations. The current standard in both pharma and cosmetic industries is to conduct extensive in-vivo/in-vitro experiments to arrive at the optimized formulations. This is expensive and also highly time consuming In view of this, a realistic in-silico molecular model of human skin coupled with accurate transport models, which could supplement/replace some of the elaborate in-vivo/in-vitro tests with in-silico tests, are required.

Most of the SC’s molecular level models reported in the literature comprise of cholesterol and phospholipids only, which is far from the reality. Also, in the previous studies, permeation data from the experiments was fitted to the model to predict the diffusion coefficient and partition coefficient. The fitted diffusion coefficient is an approximate one because it doesn’t account for the heterogeneity of the SC lipids. In this study, we have implemented a multiscale modelling 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 the available experimental data. Our simulations show that the partition coefficient exhibits more effect on the release profiles. The reported multiscale modelling 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. Elias, P. M. Epidermal Lipids, Barrier Dunction, and Desquamation. J. Invest. Dermatol. 1983,80.

  2. Pirot, F.; Kalia, Y.; Stinchcomb, A.; Keating, G.; Bunge, A.; Guy, R. Characterization Of The Permeability Barrier Of Human Skin In Vivo. Proceedings of the National Academy of Sciences 1997, 94, 1562-1567.

  3. Kushner, J., Deen, W., Blankschtein, D., & Langer, R. (2007). First‐principles, structure‐based transdermal transport model to evaluate lipid partition and diffusion coefficients of hydrophobic permeants solely from stratum corneum permeation experiments. Journal of pharmaceutical sciences, 96(12), 3236-3251.

  4. Rim, Jee E., Peter M. Pinsky, and William W. van Osdol. "Multiscale modeling framework of transdermal drug delivery." Annals of biomedical engineering 37.6 (2009): 1217-1229.

  5. Dias, M., et al. "Topical delivery of caffeine from some commercial formulations." International journal of pharmaceutics 182.1 (1999): 41-47.

  6. Hansen, Steffi, et al. "In-silico model of skin penetration based on experimentally determined input parameters. Part I: Experimental determination of partition and diffusion coefficients." European Journal of Pharmaceutics and Biopharmaceutics 68.2 (2008): 352-367.

  7. Gupta, Rakesh, D. B. Sridhar, and Beena Rai. "Molecular Dynamics Simulation Study of Permeation of Molecules through Skin Lipid Bilayer." The Journal of Physical Chemistry B 120.34 (2016): 8987-8996.

  8. Gupta, Rakesh, Balarama Sridhar Dwadasi, and Beena Rai. "Molecular Dynamics Simulation of Skin Lipids: Effect of Ceramide Chain Lengths on Bilayer Properties." The Journal of Physical Chemistry B 120.49 (2016): 12536-12546