The objective of this study was to develop novel invaethosomes (I-ETS) and invaflexosomes (I-FXS) to enhance the dermal delivery of clotrimazole (CZ). Twenty model CZ-loaded I-ETS and I-FXS formulations were created according to a face-centered central composite experimental design. CZ-loaded vesicle formulations containing a constant concentration of 0.025% w/v CZ and various amounts of ethanol, d-limonene, and polysorbate 20 as penetration enhancers were prepared using the thin film hydration method. The physicochemical characteristics, skin permeability, and antifungal activity were characterized. The skin permeability of the experimental CZ-loaded I-ETS/I-FXS was significantly higher than that of conventional ethosomes, flexosomes, and the commercial product (1% w/w CZ cream). The mechanism of action was confirmed to be skin penetration of low ethanol base vesicles through the disruption of the skin microstructure. The optimal I-ETS in vitro antifungal activity against C. albicans differed significantly from that of ETS and the commercial cream (control). The response surface methodology predicted by Design Expert® was helpful in understanding the complicated relationship between the causal factors and the response variables of the 0.025% w/v CZ-loaded I-ETS/I-FXS formulation. Based on the available information, double vesicles seem to be promising versatile carriers for dermal drug delivery of CZ.
Keywords: cineole; d-limonene; ethanol; menthol; polysorbate 20.