Crisaborole-Loaded Nanoemulsion for Atopic Dermatitis: Localized Dermal Delivery of a Phosphodiesterase-4 Inhibitor

Background/Objectives: Crisaborole (CRB) is a phosphodiesterase-4 inhibitor used for the topical treatment of mild-to-moderate atopic dermatitis (AD). However, its low aqueous solubility presents challenges for topical formulation and localized drug delivery. This study aimed to develop a CRB-loaded nanoemulsion (CRB-NE) and evaluate its physicochemical and biopharmaceutical characteristics, tolerability, and anti-inflammatory activity. Methods: CRB-NE (0.5% w/w) was developed using pseudo-ternary phase diagrams. Droplet size, morphology, rheological behavior, spreadability, and stability were characterized. Drug release and ex vivo permeation in human skin were evaluated. Biological compatibility was investigated using HaCaT keratinocytes and the hen’s egg test–chorioallantoic membrane (HET-CAM) assay, while skin barrier compatibility was assessed in healthy volunteers. Anti-inflammatory activity was evaluated through IL-8 secretion in stimulated HaCaT cells and a xylene-induced ear inflammation model in mice. Results: CRB-NE showed a droplet size of 105.3 ± 6.7 nm, a polydispersity index of 0.287 ± 0.012, Newtonian flow behavior, and physical stability over 60 days. Approximately 80% of CRB was released following first-order kinetics. After 24 h, ex vivo experiments showed cutaneous retention of 1098.43 μg CRB/g skin/cm2 and cumulative permeation of 23.75 ± 4.44 μg/cm2. Keratinocyte viability exceeded 80% at CRB concentrations of 2.5–10 μg/mL, and HET-CAM results indicated low irritation potential. The vehicle did not adversely affect skin barrier measurements in healthy volunteers. CRB-NE significantly reduced IL-8 secretion in TNF-α-stimulated keratinocytes and attenuated erythema, inflammatory cell infiltration, edema, vascular congestion, and tissue damage in vivo. Conclusions: CRB-NE demonstrated favorable physicochemical properties, substantial cutaneous drug retention, and anti-inflammatory activity, supporting its potential as a localized topical delivery system.