Antifungal Activity, Cytocompatibility, and Wound Healing Potential of Novel Mucoadhesive Formulations for Oral Drug Delivery

ABSTRACT Conventional treatments for oral candidiasis often fail due to the complexities of the oral environment and the increasing antifungal drug resistance. Therefore, there is a growing demand for new therapies that optimize drug bioavailability, allowing for lower therapeutic doses while enhancing cytocompatibility, maintaining antifungal, anti‐inflammatory, and wound healing efficacy. This study investigated the antifungal activity, cytocompatibility, wound healing potential, and mucosal adhesion of novel mucoadhesive formulations containing nystatin (NYS) or chlorhexidine (CHX) complexed with β‐cyclodextrin (βCD), compared with the drug‐free formulation (GEL) and the standard treatment with 2% miconazole gel (DK—Daktarin). Efficacy against Candida albicans was evaluated by measuring the metabolic activity, whereas cytocompatibility with human gingival fibroblasts (HGFs) was analyzed for viability, morphology, lactate dehydrogenase (LDH) release, and apoptosis. Additionally, wound healing potential was investigated by assessing cell migration efficacy, anti‐inflammatory activity, and reactive oxygen species (ROS) scavenging activity. Mucoadhesion was evaluated using mucin discs and a texture analyzer. Mucoadhesive gels containing βCD‐complexed NYS or CHX exhibited significantly higher antifungal activity when compared to the GEL and DK groups ( p < 0.05). Compared to fibroblast control cultures, those exposed to drug‐complexed gels exhibited similar viability ( p > 0.05) and morphological parameters, lower LDH release ( p < 0.05), and similar apoptosis rates ( p > 0.05). Additionally, exposure to the βCD‐modified gels was associated with complete wound closure ( p > 0.05), significant anti‐inflammatory effect, with downregulation of pro‐inflammatory gene expression ( p < 0.05), and higher ROS scavenging activity ( p < 0.05). The developed formulations showed no difference in mucoadhesiveness ( p > 0.05), which was superior to that of DK ( p < 0.05). Therefore, the proposed drug‐complexed mucoadhesives are promising therapeutic options for oral candidiasis.