Óvulos vaginais a base de polímeros híbridos ureasil-poliéter para coadministração de curcumina e miconazol para o tratamento da candidíase vulvovaginal

Abstract

Vulvovaginal candidiasis (VVC) is an infection caused by fungi of the genus Candida. The low efficacy of monotherapies and poor compliance with commercial semisolid formulations limits standard treatment. The clinical efficacy can be increased with combining curcumin (CUR) and miconazole (MCZ). These actives can be loaded into solid formulations, such as vaginal ovules based on ureasil-polyether hybrid polymers. Thus, this work aimed to develop ureasilpoly(ethylene oxide) (U-PEO500) and ureasil-poly(propylene oxide) (U-PPO400) loaded with CUR and MCZ for the treatment of VCC. The hybrid materials were obtained by the sol-gel method and cold-molded into ovules. The physicochemical and morphological characterization was carried out through nuclear magnetic resonance (NMR), thermogravimetry (TGA), differential thermal analysis (DTA), Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), scanning electron microscopy (SEM), and in vitro release. The antifungal activity was verified by microdilution and agar diffusion assays. The biocompatibility of the drugs and the ovules was evaluated with Lactobacillus jensenii and the VK2/E6E7 cell line. DTA showed an interaction between CUR, MCZ, and the precursors. FTIR showed no chemical interactions between the drugs and the ureasil-polyethers. The crystalline nature of the drugs and the amorphous character of the hybrids were observed in XRD, and crystals of CUR and MCZ were also detected in the ovules, which SEM confirmed. In vitro release showed that 80-90% of CUR and MCZ were released from U-PEO500 in 144 hours, while only 12.06% of CUR and 60.95% of MCZ were released in the same period. The minimum inhibitory concentrations of CUR were equal to 256, > 1024, 512, and 512 µg.mL−1 for C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata, respectively. For MCZ, the values were 2.5, 2.5, 1.25, and 12.5 µg.mL−1 , in the same order. Synergism was observed for the first three mentioned strains, which presented fractional inhibitory concentration indices equal to 0.375, 0.265, and 0.265 (< 0.5). In agar diffusion, the ovules containing CUR and MCZ showed zones of inhibition ≥ 16.5 mm, characteristic of sensitivity. The biocompatibility studies showed that MCZ concentrations higher than 95 µg/mL and 5.94 µg/mL impact the growth of L. jensenii and VK2/E6E7, respectively. The hybrid ovules proved biocompatible and safe in the preclinical in vitro studies. Therefore, U-PEO500 and U-PPO400 ovules with CUR and MCZ are promising candidates for overcoming the limitations of conventional VVC treatments.