Enhanced antifungal efficacy of clotrimazole and itraconazole delivered via solid lipid nanoparticles for potential otomycosis therapy

Abstract

This study aimed to develop solid lipid nanoparticles (SLNs) loaded with clotrimazole (CLT), itraconazole (ITR), and their combination as potential delivery systems for otomycosis treatment. SLNs were prepared using the emulsification/ultrasonication method with 2.0 % (w/v) cetyl palmitate incorporating 0.1 % (w/w) CLT and/or 0.1 % (w/w) ITR in the lipid matrix and 3.0 % (w/v) Poloxamer 188 as surfactant. The formulations exhibited mean hydrodynamic sizes of 115–130 nm, high encapsulation efficiencies (>80 %), and relevant drug-loading capacities.Structural characterization by X-ray diffraction, small-angle X-ray scattering, differential scanning calorimetry, thermogravimetric analysis, and Fourier-transform infrared spectroscopy confirmed the formation of stable SLNs and successful drug incorporation into the lipid matrix. The three formulations significantly increased drug apparent solubility compared to the pure drugs, with 2224–2387-fold and 760,000–980,000-fold increases for CLT and ITR, respectively. In vitro release studies revealed a sustained release profile best fitting the Korsmeyer-Peppas model. CLT/ITR SLNs demonstrated long-term storage stability over six months at 4 °C.Cytotoxicity assays in Vero cells at confirmed good biocompatibility. In vitro antifungal studies against otomycosis-related fungal species demonstrated that CLT-SLN and CLT/ITR-SLN formulations exhibited potent antifungal activity. In this regard, CLT/ITR-SLN formulations exhibited significantly higher activity -up to 16.7-fold compared to CLT and ITR in DMSO and up to 33.3-fold compared to the drug suspensions attributed to the synergistic antifungal effect of both drugs. These findings support CLT/ITR SLNs as a safe and promising strategy for otomycosis treatment. To the best of our knowledge, this is the first report of CLT and ITR co-encapsulation in nanoparticles.