Factorial Optimization and Ex Vivo Evaluation of Cetirizine Microemulsions: Enhancing Transdermal Delivery via Combined Diffusion and Partitioning Mechanisms

Abstract

Background: Cetirizine is a zwitterionic, second-generation H1-antihistamine widely used to treat allergic rhinitis and chronic urticaria. Although it has high oral bioavailability (> 70%), its use is limited by dose-related sedation and interindividual variability, supporting investigation of alternative topical and transdermal delivery approaches. Objectives: This study aimed to formulate, optimize, and evaluate cetirizine microemulsions containing oleic acid and Transcutol P as natural-origin penetration enhancers, using a two-level full-factorial design, and to elucidate the mechanisms underlying enhanced ex vivo skin permeation. Methods: Eight microemulsions were prepared using oleic acid and Transcutol P as the oil phase, Tween 80 and Span 20 as surfactants, and propylene glycol as a cosurfactant; each contained 1% (w/w) cetirizine. Oil content (5% and 50%), water content (5% and 10%), and the surfactant/cosurfactant ratio (1:1 and 3:1) were varied. The formulations were characterized for droplet size, polydispersity index, viscosity, pH, physical stability, in vitro release, and ex vivo rat-skin permeation. Factorial analysis was used to evaluate effects on steady-state flux (Jss). Results: Droplet sizes ranged from 14.94 to 46.15 nm, with a polydispersity index < 0.5. The optimal formulation, ME-CET-6 (5% oil, 10% water, S/C 1:1), yielded the highest flux (Jss = 0.0431 ± 0.003 mg·cm-2·h-1; ERflux = 5.42), representing an approximately 4.6-fold increase compared with the aqueous control. Factorial analysis identified oil content as the primary negative determinant of flux (P = 0.001), followed by the S/C ratio (P = 0.015), whereas water content was not significant (P = 0.119). Corrected diffusion enhancement ratios exceeded 1 for all microemulsions, indicating that improved diffusivity and partitioning jointly contributed to permeation enhancement. Conclusions: Cetirizine microemulsions containing oleic acid and Transcutol P markedly enhance transdermal flux through combined increases in drug diffusivity and partitioning. These systems are promising candidates for further in vivo pharmacokinetic and skin irritation evaluation.