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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 3<jats:sup>2<\/jats:sup>-factorial design. The optimized system based on factorial outcomes exhibited desirable characteristics in terms of entrapment efficiency (74.31\u2009\u00b1\u20090.39%), vesicle size (246.4\u2009\u00b1\u20092.2 nm), polydispersibility index (0.369\u2009\u00b1\u20090.01), &amp; zeta potential (-37.5\u2009\u00b1\u20090.17 mV). Further characterization for the optimized system was performed in terms of transmission electron microscopy, Fourier transform infrared spectroscopy, and <jats:italic>in-vitro<\/jats:italic> 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 <jats:italic>ex-vivo<\/jats:italic> 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<jats:sup>\u00ae<\/jats:sup> 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.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1208\/s12249-025-03205-5","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T16:04:25Z","timestamp":1756137865000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Voriconazole Loaded Spanlastics: Design, Formulation, Optimization, and Randomized Controlled Clinical Insights for Vulvovaginal Candidiasis Therapy"],"prefix":"10.1208","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0375-4946","authenticated-orcid":false,"given":"Nermin M.","family":"Sheta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-6842","authenticated-orcid":false,"given":"Rehab Nabil","family":"Shamma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-685X","authenticated-orcid":false,"given":"Raghda R. 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