QbD-based Optimization of Stimuli-sensitive Nanoemulgel of Miconazole Nitrate for Safe and Effective Treatment of Oral Candidiasis

Abstract

Oral candidiasis is an opportunistic infection that affects 30–50% of individuals. Available antifungal therapeutics pose challenges of poor solubility, low bioavailability, and inadequate retention at the application site. The present research aimed to develop an in-situ nanoemulgel (NEG) combining nanoemulsion (NE) with stimuli-responsive hydrogel-forming polymers for miconazole nitrate for enhanced efficacy. In due course, characterization of the formulation including in-vitro and ex-vivo release patterns along with cytotoxicity study and antifungal efficacy were evaluated to establish the safety and efficacy of the optimized formulation. Optimization of the NE formulation was performed using Box-Behnken statistical design with Phosal^®50PG, Cremophor-EL and isopropyl alcohol. The optimized NE had droplets of 118.7 ± 0.64 nm, a PDI of 0.165 ± 0.05, and a surface charge of − 15.54 ± 0.35mV, while the NEG had 152.2 ± 0.21 nm droplets, a PDI of 0.193 ± 0.07, and a surface charge of − 18.3 ± 0.49mV. The formulation’s viscosity, mucoadhesive properties, spreadability, and pH were 3028 ± 192.39cP, 37.61 g.sec, 14.02 ± 0.46 cm²/g and 6.46 ± 0.130, respectively. In-vitro drug release studies showed first-order kinetics indicating concentration-dependent release. Ex-vivo permeation studies across goat oral mucosa revealed 2.05-fold higher for NEG compared to marketed gel. The NEG’s steady-state flux was 2.04-fold higher than the marketed gel due to enhanced mucosal penetration. Furthermore, the results of the cytotoxicity studies on HaCaT cell lines are comparable to ex-vivo toxicity, confirming its safety on mucosal tissues. Finally, the NEG demonstrated superior antifungal efficacy compared to the marketed formulation, highlighting its potential for advancing oral candidiasis therapy. Therefore, the NEG approach demonstrates superior efficacy and safety compared to existing treatment, conferring a promising antifungal therapy.

Graphical Abstract