Optimized ethylcellulose films incorporating a novel clotrimazole deep eutectic system for enhanced permeation and antifungal activity

Abstract

Advanced drug delivery systems are engineered by tailoring material interfaces and microstructure to overcome the limitations of conventional formulations, thereby optimizing drug pharmacokinetics and biodistribution. Beyond this, enhancing the efficacy of the loaded drug will be an ideal synergistic outcome. The current work describes developing novel therapeutic deep eutectic solvents (THEDES) of the antifungal drug clotrimazole (CLOT) with capric acid formed at a 1:3 M ratio (C3). The novel THEDES was characterized using FTIR, DSC, and NMR to explore the underlying intermolecular interactions. The antifungal activity of C3 exhibited a 16-fold reduction in the minimum inhibitory concentration (MIC) against C. albicans compared to CLOT. This novel THEDES was subsequently incorporated as a functional excipient into an ethylcellulose (EC) film using a solvent-casting method, serving as both the active ingredient reservoir and a plasticizer. Including C3 in the film maintained the transparency and flexibility of the film, suggesting a plasticizing role. Skin permeation of the optimum film (F4) using Franz diffusion cells fitted with Strat-M® membrane was studied, and the permeation was compared with a commercial CLOT cream. The eutectic film of CLOT demonstrated significantly higher permeation after 24 h compared to the commercial cream. This work presents a green and efficient strategy to enhance the topical delivery of CLOT. By forming a THEDES, we significantly improved drug loading in a hydrophobic EC matrix and achieved a 2.7-fold increase in permeation flux across a skin-mimicking membrane compared to a commercial cream, alongside a 16-fold reduction in the MIC against C. albicans. This approach highlights a promising pathway for developing more effective topical antifungal therapies.