Permeation of Hydrophilic Molecules across Glycated Skin Is Differentially Regulated by the Stratum Corneum and Epidermis–Dermis

Abstract

The effects of glycation on skin permeation and accumulation of compounds were evaluated using an in vitro glycated skin model. Glycation of the skin of hairless mice was induced using vertical diffusion cells and incubation with phosphate-buffered saline containing 50 mM glyoxal for 24 h. Flux and accumulation in the skin were determined by applying hydrophilic and lipophilic molecules (Sodium fluorescein; FL-Na and Nile red, respectively) to this in vitro glycated skin model. Furthermore, to investigate the effect of glycation on epidermal-dermal barrier properties, we conducted diffusion experiments with FL-Na and fluorescein isothiocyanate-dextran using stratum corneum (SC)-stripped glycated skin. The in vitro glycated skin model demonstrated characteristic glycation alterations like a yellowish change in skin color and surface roughness. For low-molecular weight (MW) hydrophilic molecules, flux across glycated full-thickness skin was higher than that across normal skin, although there was no difference with lipophilic molecules. However, glycated epidermis-dermis showed lower flux, and the difference increased with the MW of the compound. Furthermore, the amount of high-MW hydrophilic molecules accumulated in glycated epidermis-dermis was decreased. These results suggest that glycated SC and epidermis-dermis differentially regulate the permeability of hydrophilic molecules and highlight the importance of controlling drug delivery by modifying the formulation or method of application depending on skin condition. Key words skin permeation; advanced glycation end product; stratum corneum As a route of drug administration, the skin attracts much attention due to non-invasive application, ease of dose control and absorption without hepatic first-pass metabolism. However, human skin changes over time due to chronological aging, exposure to UV radiation, and diseases such as atopic dermatitis and psoriasis. With the increase in the aging population in recent decades, there is a growing need to care for a variety of skin types. Therapeutic applications involving the skin have also increased in diversity in recent years. A variety of chemical and physiological methods are being studied to lower the barrier posed by the skin's outermost layer, the stratum corneum (SC).1) Consisting of corneocytes and intercellular lipids, the SC plays an important role as a rate limiting layer for the penetration of compounds. Serving as the major protection from foreign chemicals and water loss, and also associated with body temperature regulation, the SC is permeable to only lipophilic and <500 Da compounds.2) Therefore, various biochemical approaches to increase permeability across the SC have been attempted over the years.3) Physical methods such as microneedles, thermal ablation and microdermabrasion are also used to enhance the efficiency of penetration by piercing or removing the SC. Additionally, iontophoresis and sonophoresis increase skin permeability by electrical driving force and ultrasound, respectively. 4)Despite many ...

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