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.

Hydrogel increases diclofenac skin permeation and absorption

“…Importantly, the physical and chemical composition of the stratum corneum creates a barrier with anisotropic diffusion properties featuring lateral diffusion coefficients 40 to 300 times the transdermal diffusion coefficients (Nitsche, et al, 2019). In addition, diffusion through hair follicles may be an important transdermal pathway, especially for molecules with low lipid solubility (Barbero & Frasch, 2017).…”

Microscopic Models of Drug/Chemical Diffusion Through the Skin Barrier: Effects of Diffusional Anisotropy of the Intercellular Lipid

“…Excepting Barbero and Frasch,19 the previous diffusion models that have incorporated anisotropy 8,9,12 have treated solute transport within the intercellular lipid phase using a hybrid approach combining the continuous process of lateral diffusion along the~6 bilayers between corneocytes with the discrete process of hopping between bilayers. (Use of the term "bilayer" in connection with SC lipid 5,6,8,9,12,32,65,66 may be regarded as shorthand for the more complicated structure of the 13 nm repeat unit, 34,35,39,66 not to be conflated with that of phospholipid bilayers.)…”

“…(Use of the term "bilayer" in connection with SC lipid 5,6,8,9,12,32,65,66 may be regarded as shorthand for the more complicated structure of the 13 nm repeat unit, 34,35,39,66 not to be conflated with that of phospholipid bilayers.) As discussed in the Supplementary Material, using diffusivities for both lateral and transverse directions, as done by Barbero and Frasch,19 is arguably the better way to handle the lipid phase. The associated numerical challenge is significant given the typically 3-5 order-of-magnitude disparity between D lip k and D lip ⊥ .…”

“…This article addresses detailed theories ("brick-and-mortar" models) explicitly representing solute diffusion through the lipid and aqueous (cellular, corneocyte) phases of the underlying microstructure. Two-dimensional treatments of the tissue as seen in cross-section [7][8][9][10][11][12][13][14][15][16][17][18][19] ("ribbon models" 20 ) and analytical approximations for the tortuosity associated with staggered square flakes 21 have given way to sophisticated, fully 3-dimensional numerical analyses representing corneocytes as flattened cuboids 20,22,23 and tetrakaidecahedra. 20,24 A particularly useful application of such analyses is the calculation of effective (average, homogenized, coarse-grained) diffusion coefficients of the tissue by solution of a well-defined steady-state diffusion problem posed in one unit cell of the microstructure.…”

“…The reason is that overall macroscopic outcomes often result from two or more simultaneousdand possibly competing or opposingdmicroscopic mechanisms." 27 With few exceptions, 8,9,12,19 the models cited above have treated transport in the SC lipid phase as an isotropic process characterized by a single scalar diffusion coefficient. This assumption is at odds with the well-known anisotropy of lipids, in terms of both structure and transport properties.…”