Use of “Bricks and Mortar” Model To Predict Transdermal Permeation: Model Development and Initial Validation

Abstract

Presented in this paper is a general purpose computer model for predicting transdermal permeation of solutes in vivo. The “bricks and mortar” model is employed to represent the stratum corneum (SC), the main barrier to transdermal permeation. Transdermal permeation and absorption is modeled as a dynamic process of mass transfer in the heterogeneous stratum corneum including both the tortuous lipid pathway and the transcellular corneocytes pathway. The partition and diffusion properties of solutes in SC lipid matrix and corneocytes are calculated from the fundamental physical chemical properties of octanol−water partition coefficient, molecular size, and diffusion coefficients in water and lipid, using equations established elsewhere. To test the model, the in vivo tape striping data of 4-cyanophenol is simulated. Using the calculated partition and diffusion properties of 4-cyanophenol in SC lipids and corneocytes, the predicted dynamic profiles of 4-cyanophenol in the SC agreed very well with the experimental data. Results show that for a moderately hydrophobic solute like 4-cyanophenol, the transcellular pathway is also an important route of percutaneous absorption with about 2/3 of the absorbed 4-cyanophenol partitioned into the corneocytes.

In Silico Modelling of Transdermal and Systemic Kinetics of Topically Applied Solutes: Model Development and Initial Validation for Transdermal Nicotine

“…Wang et al (11,12) reported a more predictive two-dimensional model, in which the diffusion and partition coefficients were obtained from fundamental principles, and only the trans-bilayer mass transfer coefficient was fitted to deduce a correlation with the molecular weight. A similar two-dimensional approach was taken by Lian and coworkers (13,14), where data-fitting was only used to derive a correlation for calculating the diffusion coefficient in corneocytes, and the prediction accuracy was significantly improved when compared with the Wang's model in (11,12). With consideration of the two-dimensional microscopic skin structure, both models (11,12,13,14) demonstrated the importance of the trans-cellular diffusion pathway through the stratum corneum.…”

“…A similar two-dimensional approach was taken by Lian and coworkers (13,14), where data-fitting was only used to derive a correlation for calculating the diffusion coefficient in corneocytes, and the prediction accuracy was significantly improved when compared with the Wang's model in (11,12). With consideration of the two-dimensional microscopic skin structure, both models (11,12,13,14) demonstrated the importance of the trans-cellular diffusion pathway through the stratum corneum. In a later study, Lian and co-workers extended their model to include viable epidermis and dermis whilst maintaining the predictive capability (15).…”

“…The majority of the transdermal permeation models developed, especially those incorporating more realistic heterogeneous skin physiology (11,12,13,15), were intended to predict the absorption kinetics in the skin only. When the chemical reaches the dermis, it is cleared from the skin through both diffusion into deeper tissues and convention by the capillary blood vessels.…”

“…Following the previous studies (13,15), the brick-and-mortar model is used to represent the heterogeneous structure of the stratum corneum, while the viable epidermis and dermis are modelled as homogenised material with properties related to the main compositions of cellular lipid, protein and water. The transport of chemicals within skin is governed by diffusion equations, and that into capillary blood is modelled by using the assumption of equilibrium between dermis and blood, following the method in (5).…”

“…The model has been implemented in C++, which allowed fast computation using a much finer grid scheme in stratum corneum than reported previously (13,15). It should be noted that the coarse grids previously used (13,15) were deemed numerically sufficient for predicting one-dimensional pharmacokinetics, as further refinement of the grids did not improve the resolution. However, for the purpose of simulating detailed two-dimensional local disposition, higher resolution is needed and this is the motivation of using finer grids in the present study.…”