Based on experimental concentration depth profiles of the antiinflammatory drug dexamethasone in human skin, we model the time-dependent drug penetration by the 1D general diffusion equation that accounts for spatial variations in the diffusivity and free energy. For this, we numerically invert the diffusion equation and thereby obtain the diffusivity and the free-energy profiles of the drug as a function of skin depth without further model assumptions. As the only input, drug concentration profiles derived from X-ray microscopy at three consecutive times are used. For dexamethasone, skin barrier function is shown to rely on the combination of a substantially reduced drug diffusivity in the stratum corneum (the outermost epidermal layer), dominant at short times, and a pronounced free-energy barrier at the transition from the epidermis to the dermis underneath, which determines the drug distribution in the long-time limit. Our modeling approach, which is generally applicable to all kinds of barriers and diffusors, allows us to disentangle diffusivity from free-energetic effects. Thereby we can predict short-time drug penetration, where experimental measurements are not feasible, as well as long-time permeation, where ex vivo samples deteriorate, and thus span the entire timescales of biological barrier functioning.M ulticellular organisms exhibit numerous structurally distinct protective barriers, such as the blood-brain barrier; intestinal, mouth, and respiratory mucosa; and the skin, the largest human organ. These barriers are generally designed to keep foreign material out and in some cases to allow the highly regulated transfer of certain desired molecules; consequently, they present a severe challenge for drug delivery (1-3). The indepth understanding of barrier function is not only required for controlled drug delivery, but also of central interest in medicine, drug development, and biology.Human skin can be broadly divided into two layers (Fig. 1A): the epidermis with a thickness of about 100 µm, which prevents water loss and the entrance of harmful microorganisms or irritants, and the dermis, which is typically 2 mm thick, contains blood vessels, and protects the body from mechanical stress (4). The epidermis is further divided into the stratum corneum (SC), the 10-to 20-µm thick outermost layer consisting of dried-out dead skin cells, the corneocytes, and the viable epidermis (VE). In the stratum granulosum (SG), which is part of the VE, skin cells (keratinocytes) are gradually flattened and transformed into corneocytes when migrating toward the SC.The SC is structurally similar to a brick wall (5): The bricks are the corneocytes, whereas the mortar is the intercellular matrix, which is composed of stacked lipid bilayers. Several models for the permeation of drugs through skin exist, which incorporate the skin structure on different levels of complexity. In the simplest models the stratified skin structure is reflected by 1D layers with different diffusivities and partition coefficients (6-10), and in ...

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Selective probing of dexamethasone in excised human skin using soft X-ray spectromicroscopy provides quantitative concentration profiles as well as two-dimensional drug distribution maps. Element- and site-selective excitation of dexamethasone at the oxygen K-edge with the lateral step width adjusted to 1 μm provides detailed information on the location of the drug in the different skin layers. The key of this work is to probe dexamethasone selectively at the carbonyl site (C3) by the O 1s → π* transition, providing also a most efficient way to quantify the drug concentration as a function of penetration depth in correlation with structural properties of the skin containing carboxyl and amide oxygen sites occurring at higher transition energy than dexamethasone. Following drug exposure for 4 h, the glucocorticoide is located in about equal amounts in the stratum corneum, the outermost horny layer of skin, and in the viable epidermis, whereas in the dermis no dexamethasone is detected. In the stratum corneum, most of the lipophilic drug is found in regions between corneocytes, where epidermal lipids are dominating.