Mahmoud M. Abd El Gawad

Purpose: Fungal infections remain a major concern due to rising incidence related to immunosuppression and chemotherapy, alongside growing antifungal resistance. Though Voriconazole (VCZ) displays robust potential against infections like aspergillosis and candidemia , its limited formulation availability highlights the need for alternative delivery approaches. Nanovesicle-based systems like novasomes (NV) have emerged as promising systems capable of enhancing delivery and overcoming current therapeutic limitations. Methods: 2 ³ factorial design was adopted to develop VCZ-loaded NV, with optimization based on entrapment efficiency (EE), vesicle size (VS), polydispersity index (PDI), and zeta potential (ZP), alongside evaluation of in-vitro release behavior, antifungal activity, Fourier transform infrared spectroscopy (FTIR), morphological characteristics, and stability of the optimized formula. The optimized formulation was incorporated into a Carbopol gel (DN1G) for ex vivo permeation studies. Results: The formulation was optimized through a 2³ factorial design with EE%, VS, PDI, and ZP as critical responses, yielding the optimized VCZ-loaded NVs (DN1) with EE% (97.27±0.12 %), VS (256.93±4.40 nm), PDI (0.27±0.00), and ZP (-47.63±0.92 mV). In-vitro release studies confirmed controlled and sustained release. FTIR showed compatibility with the excipient, TEM analysis revealed spherical, non-aggregated vesicles, and stability evaluation revealed no significant alterations in selected parameters. DN1 demonstrated potent antifungal activity (MIC of 0.25 µg/mL) against C. albicans, and its incorporation into gel (DN1G) enhanced VCZ permeation by 1.89-fold. Conclusion: This study highlights the potential of NV as a promising approach for VCZ, offering an effective alternative to conventional VCZ formulations, and encourages further exploration of vesicular systems for antifungal therapy. Graphical

Voriconazole, a potent antifungal agent, has emerged as a promising candidate for managing vulvovaginal candidiasis. The market availability of voriconazole as tablets or injections, along with potential side effects, highlights the need for a successful alternative delivery system. Through comprehensive experimental design, voriconazole-loaded spanlastics were developed using a 3²-factorial design. The optimized system based on factorial outcomes exhibited desirable characteristics in terms of entrapment efficiency (74.31 ± 0.39%), vesicle size (246.4 ± 2.2 nm), polydispersibility index (0.369 ± 0.01), & zeta potential (-37.5 ± 0.17 mV). Further characterization for the optimized system was performed in terms of transmission electron microscopy, Fourier transform infrared spectroscopy, and in-vitro antifungal assessment, where the latter showcased the potent effectiveness of voriconazole against various Candida species. Moreover, the integration of the optimized voriconazole-loaded spanlastic system into a gel was implemented for the assessment of ex-vivo permeation through the vaginal mucosa of rats, where the optimized system gel revealed a remarkable 1.3-fold enhancement in permeation relevant to the control VCZ gel. Notably, the clinical performance of optimized system gel was involved in a randomized controlled study for assessment of safety and efficacy in comparison to a market product (Canesten^® 2% clotrimazole). Clinical evaluation revealed that the optimized VCZ-loaded SP gel and the market product, Canesten. (2% clotrimazole) exhibited comparable efficacy in terms of clinical satisfaction, side effects, and time to clinical cure from VVC. These findings highlight the potential of the optimized system as a promising approach for improved treatment outcomes in women with vaginal candidiasis with no adverse effects. Graphical Abstract