Solubility of Foreign Molecules in Stratum Corneum Brick and Mortar Structure.

The barrier function of the skin is mainly assured by its outermost layer, stratum corneum (SC). One key aspect in predicting dermal drug delivery and in safety assessment of skin exposure to chemicals is the need to determine the amount of chemical that is taken up into the SC. We here present a strategy that allows for direct measures of the amount of various solid chemicals that can be dissolved in the SC in any environmental relative humidity (RH). A main advantage of the presented method is that it distinguishes between molecules that are dissolved within the SC and molecules that are not dissolved but might be present at, for example, the skin surface. In addition, the method allows for studies of uptake of hydrophobic chemicals without the need to use organic solvents. The strategy relies on the differences in the molecular properties of the added molecules in the dissolved and the excess states, employing detection methods that act as a dynamic filter to spot only one of the fractions, either the dissolved molecules or the excess solid molecules. By measuring the solubility in SC and delipidized SC at the same RHs, the same method can be used to estimate the distribution of the added chemical between the extracellular lipids and corneocytes at different hydration conditions. The solubility in porcine SC is shown to vary with hydration, which has implications for the molecular uptake and transport across the skin. The findings highlight the importance of assessing the chemical uptake at hydration conditions relevant to the specific applications. The methodology presented in this study can also be generalized to study the solubility and partitioning of chemicals in other heterogeneous materials with complex composition and structure.

Membrane permeability based on mesh analysis.

The main function of a membrane is to control the exchange of matter between the surrounding regions. As such, accurate modeling of membranes is important to properly describe their properties. In many cases in both biological systems and technical applications, the membranes are composite structures where transport properties may vary between the different sub-regions of the membrane. In this work we develop a method based on Mesh analysis that is asymptotically exact and can describe diffusion in composite membrane structures. We do this by first reformulating a generalized Fick's law to include the effects from activity coefficient, diffusion coefficient, and solubility using a single condensed parameter. We then use the derived theory and Mesh analysis to, in essence, retrieve a finite element method approach. The calculated examples are based on a membrane structure that reassembles that of the brick and mortar structure of stratum corneum, the upper layer of our skin. Resulting concentration profiles from this procedure are then compared to experimental results for the distribution of different probes within intact stratum corneum, showing good agreement. Based on the derived approach we further investigate the impact from a gradient in the fluidity of the stratum corneum mortar lipids across the membrane, and find that it is substantial. We also show that anisotropic organisation of the lipid mortar can have large impact on the effective permeability compared to isotropic mortar lipids. Finally, we examine the effects of corneocyte swelling, and their lateral arrangement in the membrane on the overall membrane permeability.

Skin hydration as a tool to control the distribution and molecular effects of intermediate polarity compounds in intact stratum corneum.

The barrier function of the skin is mainly assured by its outermost layer, stratum corneum (SC), which consists of dead keratin-filled cells embedded in a lipid matrix. The skin is daily exposed to an environment with changing conditions in terms of hydration and different chemicals. Here we investigate how a molecule that has reasonable solubility in both hydrophobic and hydrophilic environments can be directed to certain regions in SC by changing the skin hydration. We use 1,2,3-trimethoxy propane (TMP) as a model substance and solid-state NMR on natural abundance 13C to obtain atomically resolved information on the molecular dynamics of TMP as well as SC lipid and protein components at varying hydration conditions. Upon dehydration, TMP redistributes from the hydrophilic corneocytes to the hydrophobic SC lipid regions. In this way, TMP can act to prevent the fluid-solid lipid transition in drying conditions and be present in the corneocytes in more humid conditions. Hydration can thereby be used as a switch to control the location and action of TMP or similar compounds in complex materials like SC. The general principles described here can also have impact on other applications including lipid-based formulations in food, drug delivery and cosmetics.

Drug delivery to the skin from sub-micron polymeric particle formulations: influence of particle size and polymer hydrophobicity.

PURPOSE: To investigate the influence of particle size and polymer properties on the topical delivery of a lipophilic "active" species (Nile Red (NR)) from sub-micron polymeric particles. METHODS: Three poly-(epsilon-caprolactone) (CAPA) formulations were examined to assess the impact of particle size. Three other formulations, based on cellulose acetate butyrate (CAB), CAPA and polystyrene were studied to address the role of polymer hydrophobicity. In vitro skin permeation, and confocal microscopy and stratum corneum (SC) tape-stripping were used to evaluate the cutaneous disposition of NR. RESULTS: NR delivery into the SC was greater from the larger particles, the overall smaller surface area of which enhanced the "leaving tendency" of the lipophilic "active". Skin uptake of NR (measured as "%payload released") from polystyrene, CAPA and CAB particles increased with decreasing polymer hydrophobicity (polystyrene > CAPA > CAB) as expected. Confocal microscopy revealed that NR released from the particles accumulated in, and penetrated via, lipid domains between the SC corneocytes. The particles showed affinity for hairs, and concentrated on the skin surface at the follicular openings. CONCLUSIONS: Delivery of a model drug to the skin from sub-micron polymeric particle formulations is sensitive to the particle size and the relative hydrophobicity of the carrier.