Chitosan-coated nanoemulsion for the direct nose-to-brain delivery of sildenafil: Development and in vivo evaluation in a brain oxidative stress and inflammation model

The aim of this study was to develop chitosan-coated nanoemulsion (NE) for the direct nose-to-brain delivery of sildenafil and evaluate its potential to address hyperlipidemia and brain oxidative stress. Pseudoternary phase diagrams were employed to formulate NEs with minimal surfactant and co-surfactant concentrations. These NEs were loaded with sildenafil and subjected to various physical stability tests. Parameters such as droplet size, polydispersity index, zeta potential, and drug release kinetics were assessed. The most optimal NE formulation (NE2) was then coated with varying concentrations of chitosan (0.25-1.0% w/v). The chitosan-coated NE was subsequently evaluated through in vivo studies using a rat model of hyperlipidemia induced by poloxamer 407, which was associated with brain oxidative stress. Formulations NE1-3 remained stable during the physical stability testing and had a droplet size and zeta potential varying from 123 nm to 158 nm and from -15.17±1.34 mV to -26.37±0.81 mV, respectively. The chitosan coating increased the droplet size, and converted the surface charge from negative to positive. NE2 demonstrated sustained release, with approximately 70% of sildenafil released over 7 days. In vivo studies illustrated that sildenafil suspension and nanoemulsion effectively reduced elevated levels of triglycerides, cholesterol, and low-density lipoprotein. The effect was more pronounced for chitosan-coated NE. Moreover, chitosan-coated NE showed superior efficacy in alleviating brain oxidative stress, as indicated by restored glutathione levels and decreased malondialdehyde concentrations. These results underscore the potential of chitosan-coated sildenafil nanoemulsion as a promising therapeutic approach for treating hyperlipidemia and its associated brain oxidative stress.