Thermoresponsive carbohydrate polymer mucoadhesive gel for synergistic delivery of acarbose and fluconazole against Candida biofilms.

The emerging threat of drug-resistant Candida albicans, especially in recurrent vulvovaginal candidiasis (VVC) biofilms, has revealed weaknesses in existing monotherapeutic antifungal treatments. In this study, we investigated the antifungal activity of a new dual-drug in situ mucoadhesive gel system containing acarbose (AC), a pseudo-oligosaccharide sugar and FDA-approved α-glucosidase inhibitor, together with fluconazole (FLC). Although AC showed mild antifungal activity by itself, when combined with FLC, it dramatically potentiated fungicidal activity, disrupted biofilms, blocked morphogenetic switching, and arrested post-treatment hyphal regrowth. In checkerboard assays and time-kill kinetics, AC-FLC combination was highly synergistic against Candida spp., including clinical isolates, with > 2-log₁₀ decrease in CFU/mL. The thermosensitive gel (PCH16), formulated using poloxamer 407 along with the carbohydrate-based polymers chitosan and HPMC, exhibited sustained drug release, favorable rheological properties, and strong mucoadhesion suitable for vaginal delivery. Notably, the formulation retained Lactobacillus species viability, suggesting microbiome compatibility. These results affirm the promise of repurposing acarbose as a novel, non-traditional antifungal adjuvant that, in co-administration with FLC in vaginal gel, represents an encouraging, localized, and microbiota-conserving therapy for treating recurrent and resistant VVC.