Improved Skin Delivery of Voriconazole with a Nanostructured Lipid Carrier-Based Hydrogel Formulation

Abstract

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...

Development of nanostructured lipid carrier for dacarbazine delivery

“…In the first phase, Dac could be released from the outer layer of the NLC through a short diffusion path, whilst in the second phase Dac could be released in a sustained manner from the deeper liquid lipid phase and solid lipid cores through diffusion and erosion mechanisms. A similar in vitro profile for drug release from NLC containing Precirol ATO 5 was also reported previously [29,35] (Fig. 4).…”

Novel lecithin-integrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies

“…26,48 The receptor compartment of the Franz diffusion cells was filled with 9 mL of SPB of pH 5.5 5,41 which was suitable for a proper sink condition. The temperature was maintained at 32°C±0.5°C 8,45,49 with shaking at 100 rpm throughout the experiment.…”

“…As expected, Tr release rate was retarded when it was embedded into hydrophobic gel matrix. 49 Whereas, the high drug flux from HPMC gel could be attributed to increase its thermodynamic activity through the hydrophilic gel matrix. According to Higuchi,70 the flux of a drug through a membrane increases as the drug thermodynamic activity increases.…”

Improved Voriconazole Topical Delivery by Nanoparticles (Minireview)

“…The first NLC-gel VRZ formulation for treatment of skin mycotic infections was introduced by Song, et al [22]. VRZ was loaded to NLC dispersions containing Precirol ATO 5 (glycerol distearate; melting point, 56°C), Labrafil 1944 CS (oleoyl macrogol-6 glycerides), and Tween 80 (polysorbate 80) through high-pressure homogenization method, and then inserted into Carbopol 940 hydrogel.…”