Abstract
To initiate our research into the development of biocompatiîle gelled-microemulsions based on essential oils (EOs) and sucrose esters (SEs) for the topical delivery of fluconazole, this formulation study investigated the usefulness of two relatively harmless natural non-ionic surfactants from the group of SEs (sucrose laurate and stearate) to form, in the presence of antifungal EOs, stable, isotropic microemulsions effective on fluconazole solubilization. Fluconazole’s solubility in EO significantly depended on their chemical composition, showing higher values for cinnamon, oregano and clove essential oils, further selected as oil phase components for microemulsion formulations. The phase behavior of several EO–isopropyl miristate/SE–isopropanol/water systems was assessed through pseudo-ternary phase diagrams constructed by microplate dilution technique. The hydrocarbon chain length of the SE and EO type strongly influenced the size of the microemulsion region in the pseudo-ternary phase diagrams. Ten microemulsion formulations containing 2% fluconazole, 6% or 10% oil mixture of EO–isopropyl myristate in 1:1 ratio, 45% SE-isopropanol mixture and water, were selected and evaluated for physicochemical properties (droplet size, polydispersity, viscosity, refractive index, zeta potential and pH). All formulations were physicochemically acceptable, but viscosity enhancement and further in vitro and in vivo tests are required for the development of biocompatible, clinically safe and effective fluconazole topical preparations.
Highlights
For the treatment of mild or localized forms of superficial and cutaneous fungal infections, topical preparations containing antifungal drugs, including azoles, are of first choice, allowing to restrict the therapeutic effect on the affected skin area and minimalize the systemic adverse effects [1]
The solubility data reported in the literature, including those of a previous own study [13], showed that fluconazole is very slightly soluble in water (5.551 mg/mL), slightly soluble or soluble in fatty oils, soluble or freely soluble in isopropyl alcohol, propyleneglycol and ethanol (60.614, 103.436, and 126.991 mg/mL, respectively)
The results of a preliminary evaluation for the maximum fluconazole dissolution capacity of the selected essential oils are presented in Table 3 as apparent solubility
Summary
For the treatment of mild or localized forms of superficial and cutaneous fungal infections, topical preparations containing antifungal drugs, including azoles, are of first choice, allowing to restrict the therapeutic effect on the affected skin area and minimalize the systemic adverse effects [1]. The intrinsic antifungal effect of sucrose esters, scientifically demonstrated [21,22], was considered when they were selected for developing FZ-loaded ME formulations, based on the hypothesis that they could potentiate through synergism the antifungal effect of FZ Extending this hypothesis for other natural products that are described in the literature as skin-compatible penetration enhancers, in order to accomplish the abovementioned formulation aims of dermal antifungal MEs, essential oils were of interest for the present study. As complex mixtures of lipophilic volatile and non-volatile compounds, essential oils have demonstrated antifungal activity and even synergistic effects with synthetic antifungal drugs like fluconazole [23,24]; they are effective penetration enhancers, GRAS (generally recognized as safe) certified by FDA [25,26] Considering these properties, several essential oils were combined as components of the oil phase with sucrose esters as surfactants (stabilizers), isopropyl alcohol as cosurfactant and water in order to form stable ME systems for topical FZ delivery.
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