In order to develop topical preparations of voriconazole (VRC) for the treatment of mycotic infections of the skin, a nanostructured lipid carrier-based hydrogel (NLC-gel) formulation was developed and its physical characteristics, in vitro skin permeation, and retention profiles were examined. A VRC-loaded NLC dispersion, consisting of Precirol ATO 5, Labrafil 1944 CS, and Tween 80, was prepared by high-pressure homogenization and embedded into Carbopol 940 hydrogel. The lipid nanoparticles in the hydrogel were approximately 210 nm in size, with a spherical shape and zeta potential of 30 mV. In a skin permeation study using a Franz diffusion cell mounted with depilated mouse skin, the NLC-gel was superior to conventional cream and microemulsion-based gel formulations, showing 2.8-and 1.7-fold greater flux values, respectively. In addition, the NLC-gel led to markedly greater accumulation of VRC in deeper skin layers as compared with the reference formulations. In conclusion, the novel topical formulation reported here represents an alternative treatment for skin infections such as candidiasis, with less potential for systemic adverse effects than oral therapy.Key words voriconazole; nanostructured lipid carrier; hydrogel; topical delivery Voriconazole (VRC), a second-generation triazole derived from fluconazole, is a broad-spectrum anti-fungal agent that inhibits cytochrome P450-dependent 14α-lanosterol demethylation, which is a vital step in cell membrane ergosterol synthesis.1) VRC is active against all Candida species that have acquired resistance to fluconazole and is currently used for the treatment of aspergillosis and candidiasis infections in the abdomen, kidney, bladder wall, wounds, and skin.1,2) Despite its advantageous pharmacological activity, systemic exposure to VRC as a result of oral and/or intravenous administration can cause several side effects, not fatal but considerable, including photopsia, abdominal pain, and visual hallucinations.3,4) In addition, VRC triggers elevations in hepatic enzyme levels in patients at a high risk of pharmacokinetic drug-drug interactions. 4)A need exists for a topical delivery system for VRC to overcome limitations in oral and intravenous treatment, and which will be particularly useful against candidiasis in wounds and skin tissue. Topical drug application provides higher local tissue levels, more rapid drug delivery, and lower systemic exposure than oral administration. 5) However, because of the poor aqueous solubility of VRC, 6) solubilization of the drug is necessary for delivery in a topical formulation. Furthermore, a penetration-enhancing system is required to achieve therapeutic concentrations in stratum corneum and deeper skin layers, including epidermis and/or dermis.In recent years, nanostructured lipid carriers (NLC) have emerged as a promising topical delivery system for pharmaceutical and cosmetic molecules, especially for the delivery of lipophilic compounds. 7-9) NLC dispersions composed of a solid lipid matrix with a liquid-lipid are colloidal...