The Molecular Mechanism of Propylene Glycol Monocaprylate on Skin Retention: Probing the Dual Roles on the Molecular Mobility and Collagen Connection in Roflumilast Cream.

ABSTRACT

The present work was to construct a roflumilast (ROF) cream for the treatment of psoriasis and clarify the dual roles of propylene glycol monocaprylate (PGM) in both molecular mobility of the cream, and drug-skin miscibility via drug-PGM-ceramide and drug-PGM-collagen intermolecular interaction. The cream formulation was screened through the stability study and in vitro skin administration study, optimized by Plackett-Burman and Box-Behnken design, and finally verified by the in vivo tissue distribution study. PGM demonstrated a significant drug skin retention enhancement effect (Rmax in vivo = 19.5 µg/g). It increased the molecular mobility of the oil phase of the cream by decreasing the molecular interaction of oil molecules proven by the rheology study (Ec = 3.73 × 10-4 mJ·m-3). More importantly, because of the good stratum corneum (SC) compatibility (∆H = - 403.88 J/g), PGM promoted an orderly flow of SC lipids (X-ray scattering, ΔLPP = 1.18 nm) and entered the viable epidermis/dermis (VE/DE) in large quantities (RPGM = 1186 µg/g), acting as a bridge to connect the drug to collagen through two H-bonds (LengthH-bond = 2.846 Å and 3.313 Å), thus increasing the miscibility of drug and VE/DE significantly (∆H = - 310.10 J/g, Emix = 21.66 kcal/mol). In this study, a ROF cream was developed successfully and the effect of PGM on the skin retention was clarified at molecular level.