Effect of stratum corneum heterogeneity, anisotropy, asymmetry and follicular pathway on transdermal penetration

Abstract

The impact of the complex structure of the stratum corneum on transdermal penetration is not yet fully described by existing models. A quantitative and thorough study of skin permeation is essential for chemical exposure assessment and transdermal delivery of drugs. The objective of this study is to analyze the effects of heterogeneity, anisotropy, asymmetry, follicular diffusion, and location of the main barrier of diffusion on percutaneous permeation. In the current study, the solution of the transient diffusion through a two-dimensional-anisotropic brick-and-mortar geometry of the stratum corneum is obtained using the commercial finite element program COMSOL Multiphysics. First, analytical solutions of an equivalent multilayer geometry are used to determine whether the lipids or corneocytes constitute the main permeation barrier. Also these analytical solutions are applied for validations of the finite element solutions. Three illustrative compounds are analyzed in these sections: diethyl phthalate, caffeine and nicotine. Then, asymmetry with depth and follicular diffusion are studied using caffeine as an illustrative compound. The following findings are drawn from this study: the main permeation barrier is located in the lipid layers; the flux and lag time of diffusion through a brick-and-mortar geometry are almost identical to the values corresponding to a multilayer geometry; the flux and lag time are affected when the lipid transbilayer diffusivity or the partition coefficients vary with depth, but are not affected by depth-dependent corneocyte diffusivity; and the follicular contribution has significance for low transbilayer lipid diffusivity, especially when flux between the follicle and the surrounding stratum corneum is involved. This study demonstrates that the diffusion is primarily transcellular and the main barrier is located in the lipid layers.

Keywords: Corneocyte; Diffusion; Lag time; Lipid bilayers; Partition coefficient; Skin appendages.

Fig. 1.

B & M geometry, unit cell not to scale. Actual dimensions listed in Table 2.

Fig. 2.

ML geometry not to scale with one pair of layers, n = 1.

Fig. 3.

Finite element mesh and parameters used in finite element solutions of brick-and-mortar (B & M) models.

Fig. 4.

B & M geometry with follicle.

Fig. 5.

Permeability and lag time calculated using Eqs. (11) and (14) for n = 14 pairs of lipid-corneocytes layers with l_lip and l_cor from Table 2. A and B main barrier located in the lipid. C and D main barrier located in the corneocyte.

Fig. 6.

Diffusivities in the lipid layers versus corneocyte for n = 14, log K_ow = −4, 0 and 4 and MW = 200 computed using Eq. (22).

Fig. 7.

Transcellular diffusion through a B & M geometry and ML geometry when the main barrier of diffusion is located in the lipids compared to experimental values for CAF, NIC and DEP.

Fig. 8.

Transcellular diffusion through a 2D B & M geometry and ML geometry when the main barrier of diffusion is located in the corneocytes compared to experimental values for CAF, NIC and DEP.

Fig. 9.

Caffeine transient flux at the bottom of the SC, y = 0, as function of time for constant and depth dependent lipid diffusivity compared to experimental caffeine flux.

Fig. 10.

Transcellular diffusion of CAF thru a B & M geometry for two ranges of depth-dependent lipid diffusivities (grey symbols) versus lag time. Also shown is the CAF experimental flux and lag time (white circle) with error bars indicating standard deviation. The solid line connects points computed with constant diffusivity.

Fig. 11.

Effect of depth-dependent corneocyte-lipid partition coefficient K_cor-lip (grey symbols) on steady state flux and lag time of CAF diffusion through a B & M geometry compared to the corresponding constant K_cor-lip values through the depth (black symbols). The solid line connects points computed with constant partition coefficient. Also shown is the CAF experimental value (white circle) with error bars indicating standard deviation.

Fig. 12.

Concentration distribution profile through the SC thickness of a B & M geometry with constant and variable diffusivity and variable partition parameters for CAF.

Fig. 13.

Effect of follicular permeation on flux and lag time for caffeine as a function of the transbilayer lipid diffusivity.

Fig. 14.

Results of caffeine transcellular diffusion through a ML and B & M geometry without follicle, and through a B & M geometry with follicle and flux or not to SC surroundings.