(T1230-03-18) Lateral Transport in Anisotropic Membrane during Permeation Study with Diffusion Cell

Purpose: In membrane transport studies utilizing a diffusion cell such as in vitro permeation test (IVPT), lateral diffusion within the membrane into the surrounding clamped region can lead to edge effect: an increase in flux due to lateral transport. A previous study has shown the importance of edge effect under conditions when the membrane is relatively thick compared to the diameter of the diffusion cell opening (Nimmansophon et al., 2023). When the relative thickness decreases (or the opening diameter increases), the edge effect decreases. Therefore, in conventional skin permeation studies, edge effect is insignificant under the isotropic diffusion condition. However, biological membranes such as skin can be anisotropic. The objective of the present study was to evaluate the edge effect on mass transport in a membrane model mimicking skin permeation in a diffusion cell when the membrane was anisotropic and by varying the sizes of the membrane and diffusion cell opening.

Methods: Model simulations of time-dependent and steady-state transport were performed using COMSOL Multiphysics finite element analysis software (version 6.2). A series of 3D-diffusion models consisting of a circular pathway (diffusional opening) and square-shape structure (the membrane) sandwiched between two chambers representing the donor and receptor chambers in a diffusion cell were created. The membrane was a composite of two separate layers (a two-layer membrane model to mimic the epidermis and dermis), each with its own properties. Simulations were conducted under conditions of varying membrane sizes and diffusion parameters such as the diffusion coefficients in the x, y, and z-axis directions (Dx, Dy, and Dz, respectively) including the isotropic condition when Dx = Dy = Dz. The membrane was orientated in a way that Dx and Dy represented lateral diffusion and Dz represented transverse diffusion across the membrane.

Results: A flux ratio (the total flux across the membrane with edge effect divided by total flux without edge effect) was defined to analyze the model simulation results. In membrane models mimicking the skin conditions in IVPT, when the ratio of lateral diffusion coefficient to transmembrane diffusion coefficient (Dx/Dz and Dy/Dz) in the membrane increased (anisotropic diffusion), the flux ratio increased. In general, when the membrane area (size) increased, the flux ratio increased and reached a plateau that further increasing the membrane area had no significant impact on the edge effect. The flux ratio also increased when the membrane size was kept constant and the size of the diffusion cell opening decreased. Despite the noticeable influence of edge effect on diffusion cell transport, such effects were relatively small. For example, the flux across the membrane increased only 10% when the lateral diffusion was 30 times larger than the transmembrane diffusion (Dx and Dy = 30 Dz), the membrane area was 1.5 cm x 1.5 cm, and the diffusion cell opening was 1.0 cm in diameter. When the lateral diffusion was 100 times larger than transmembrane diffusion (Dx and Dy = 100 Dz), the increase in flux due to the edge effect was 23% in the membrane models of similar dimensions.

Conclusion: The vertical diffusion cell is commonly used to evaluate skin permeation of drug formulations in topical and transdermal delivery studies such as IVPT (US FDA, 2022). The nature of the diffusion cell in skin permeation setting requires the use of excess skin area clamped between the diffusion cell donor and receptor chambers to ensure complete coverage of the diffusion cell opening, which can lead to edge effect in practice. The results in our previous study indicated insignificant edge effect with a membrane model mimicking skin permeation in IVPT under the isotropic diffusion condition (Nimmansophon et al., 2023). However, previous studies have suggested that the transport properties of the stratum corneum (SC) are highly anisotropic, and lateral diffusion is significantly faster than transmembrane diffusion (Anissimov et al., 2012; Rush et al., 2015; Wang et al., 2006). The present study showed that the edge effect remained small, e.g., flux increase of ~4% to 25% when the lateral diffusion coefficients were 10x to 100x larger than the transmembrane diffusion coefficients in the membrane and membrane area was as large as 5x the area of diffusion cell opening in model simulations mimicking the conditions in IVPT. These results suggested that the excess skin area used to mount the skin sample on the diffusion cell and to ensure coverage of the diffusion cell opening (even with skin sample area significantly exceeding the cell opening area) would not significantly influence the flux results in IVPT.

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Acknowledgements: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.