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

Abstract

Owing to the systematic alignment and ordering of fatty acid and ceramide chains, lipid layers in biological membranes have strongly anisotropic diffusion properties. The diffusivity D lip k for solute transport in the direction parallel to the lipid layer is typically 10 3-10 5 times the diffusivity D lip ⊥ for the perpendicular direction. This article explores the consequences of this strong degree of anisotropy on solute diffusion through the stratum corneum (barrier) layer of the skin based on a realistic representation of a unit cell of the microstructure. Complementary numerical methods (smoothed particle hydrodynamics, finite differences) are used to solve the steady-state unit-cell diffusion problem leading to the average (homogenized, coarse-grained) diffusion tensor characterizing the tissue as an effective continuum. A parametric study is presented characterizing solute concentration profiles in detail for testosterone-and caffeine-like permeants, and it is shown that the results cannot be mimicked by calculations based on an isotropic lipid-phase diffusivity. The ratio of lateral to transdermal effective diffusivities calculated by the present model is of the order of 40 and 300 for fully hydrated (in vitro) and partially hydrated (in vivo) states, respectively. These values compare favorably with the results of recent experiments.

Hydrogel increases diclofenac skin permeation and absorption

“…The overall rate of transdermal transport is a function of the diffusion coefficient of the drug in each compartment or layer as well as physical factors, including the viscosity and the length of the diffusion path (Vitorino et al, 2015). 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).…”

NMRlipids Databank makes data-driven analysis of biomembrane properties accessible for all

“…The resulting perpendicular diffusion coefficients are approximately five orders of magnitude smaller than lateral diffusion coefficients of water (Figs. 5 G and H), which is at the upper limit of the anisotropy estimated from the experimental data 39 . Significant increase in the diffusion anisotropy with membrane packing is observed, as D ⊥ /D || drifts away from one with decreasing area per lipid and increasing thickness in In summary, our results suggest that the bilayer packing has a substantial effect on anisotropic water diffusion in multimembrane lipid systems.…”

“…The anisotropy in water diffusion in parallel and perpendicular directions with respect to membranes can be related to the translocation of drugs through biological material, particularly in skin [37][38][39][40] , and to the formation of signals in diffusion tensor MRI imaging 41 . MD simulations are rarely used to analyze the anisotropic diffusion of water since only few membrane permeation events for water are typically observed in a single MD simulation trajectory 42,43 , thereby making the collection of sufficient amount of data challenging.…”

“…Significant increase in the diffusion anisotropy with membrane packing is observed, as D ⊥ /D || drifts away from one with decreasing area per lipid and increasing thickness in In summary, our results suggest that the bilayer packing has a substantial effect on anisotropic water diffusion in multimembrane lipid systems. Several folds larger anisotropy in membranes with higher lateral density is expected to play a role in pharmacokinetic models not only for water but also for other hydrophilic molecules 39 . Furthermore, the enhanced understanding of this anisotropy may help in developing new diffusion tensor based MRI imaging methods where signals originate from anisotropic diffusion of water in biological material 41 .…”

Analysis of droplet displacement during transport of polydisperse emulsion as drug carriers in microchannels

“…The analysis of the transport of various substances, including multi-phase ones, through the structures of the human body, including the skin, is considered in the literature on the subject in terms of the diffusion process and is often described using the Fick's law or its modification (Couto et al 2014;Nitsche et al 2019;Siepmann and Siepmann 2012;Ibrahim 2018). However, such an approach refers only to changes in the concentration of the substance under consideration.…”