p-Coumaric acid loaded into liquid crystalline systems as a novel strategy to the treatment of vulvovaginal candidiasis

Abstract

Vulvovaginal candidiasis (VVC) is an extremely common type of vaginal infection, which is mainly caused by Candida albicans. However, non-albicans Candida species are frequently more resistant to conventional antifungal agents and can represent up to 30% of cases. Due to side effects and increasing antifungal resistance presented by standard therapies, phenolic compounds, such as p-coumaric acid (p-CA), have been studied as molecules from natural sources with potential antifungal activity. p-CA is a poorly water-soluble compound, thus loading it into liquid crystals (LCs) may increase its solubility and effectiveness on the vaginal mucosa. Thereby, here we propose the development of mucoadhesive liquid crystalline systems with controlled release of p-CA, for the local treatment of VVC. Developed LCs consisted of fixed oily and aqueous phases (oleic acid and cholesterol (5:1) and poloxamer dispersion 16%, respectively), changing only the surfactant phase components (triethanolamine oleate (TEA-Oleate) or triethanolamine (TEA), the latter producing TEA-Oleate molecules when mixed with oleic acid). Systems were also diluted in artificial vaginal mucus (1:1 ratio) to mimic the vaginal environment and verify possible structural changes on formulations upon exposure to the mucosa. From the characterization assays, p-CA loaded TEA-Oleate systems presented mucoadhesive profile, liquid crystalline mesophases, well-organized structures and pseudoplastic behaviour, which are desirable parameters for topical formulations. Moreover, they were able to control the release of p-CA throughout the 12 h assay, as well as decrease its permeation into the vaginal mucosa. p-CA showed antifungal activity in vitro against reference strains of C. albicans (SC5314), C. glabrata (ATCC 2001) and C. krusei (ATCC 6258), and exhibited higher eradication of mature biofilms than amphotericin B and fluconazole. In vivo experiments demonstrated that the formulations reduced the presence of filamentous forms in the vaginal lavages and provided an improvement in swelling and redness present in the mice vaginal regions. Altogether, here we demonstrated the potential and feasibility of using p-CA loaded liquid crystalline systems as a mucoadhesive drug delivery system for topical treatment of VVC.

Keywords: And biofilm; Candida albicans; Candida glabrata; Liquid crystalline systems; P-coumaric acid; Vulvovaginal candidiasis.