A one-pot, zinc gluconate crosslinked gellan gum formulation co-loaded with CAPE and punicalagin: in vitro and ex vivo activity against Candida albicans

Background Salivary washout, limited mucosal retention, and Candida albicans biofilms hinder topical treatment of oral candidiasis (OC). Incorporating caffeic acid phenethyl ester (CAPE) and punicalagin into gellan gum (GG) may improve antifungal efficacy.Objective To develop a one-pot, zinc gluconate-cross-linked GG formulation co-loaded with CAPE and punicalagin and evaluate its antifungal activity.Methods Physicochemical properties, release in artificial saliva, antifungal activity, cytotoxicity, haemolysis, simulated chewing, and ex vivo efficacy on porcine buccal tissue were assessed.Results The cumulative release was 284.9 μg (CAPE-GG) and 756.3 μg (punicalagin-GG) versus 247.2 μg CAPE and 370.1 μg punicalagin from CAPE+punicalagin-GG in 24 h. CAPE+punicalagin-GG reduced the C. albicans burden to 103 CFU/mL under shaking and maintained activity for 72 h under static conditions (P < 0.0001). It reduced biofilm viability to 20% (P < 0.0001), compared with fluconazole-GG (49–66%) and untreated control (100%) in 24 and 48 h biofilms. It also inhibited hyphal formation (P < 0.0001), maintained 56% HGF-1 viability, and exhibited low haemolysis (P < 0.0001). GG formulations retained antifungal activity under simulated chewing. CAPE+punicalagin-GG reduced early fungal porcine buccal tissue colonisation by 1.7 log10 CFU (P = 0.0057) relative to the untreated control.Conclusions CAPE+punicalagin-GG demonstrated antibiofilm, antihyphal activity and reduced ex vivo fungal colonization. These study support the GG formulation's translational potential against C. albicans.