Surface-engineered Niosomes of Esculin Hydrate for the management of depression via intranasal route: Optimization, In vitro, Ex vivo and pharmacokinetic assessment

Abstract

Present research explored the potential of surface-engineered niosomes of Esculin hydrate (ESCH), coated with chitosan, as a novel approach for managing depression through intranasal administration. Formulation optimization was done by Design Expert® software, employing Central Composite Rotatable Design (CCRD) to investigate the impact of independent factors on dependent variables. Characterization of the chitosan-coated ESCH-loaded niosomes (Ch-ESCH-Ns) included the assessment of vesicle-size (190.3 nm), polydispersity-index (PDI; 0.243), zeta potential (ZP, +27.5 mV), and surface morphology by TEM. In vitro release and ex vivo permeation studies were performed to evaluate the formulation's performance compared to the pure drug suspension (ESCH-SUSPN), revealing sustained drug release (89.2 %) with increased drug permeation (353.1 μg/cm2) at 24 h from Opt-Ch-ESCH-Ns. Antioxidant properties were assessed by ABTS assay, demonstrating the formulation's ability to mitigate oxidative stress, with Opt-Ch-ESCH-Ns exhibiting 79.8 % scavenging activity as compared to 52.6 % for ESCH-SUSPN. Confocal laser scanning microscopy revealed an efficient penetration of Opt-Ch-ESCH-Ns that reaches to 45 μm deep into nasal mucosa layer, indicating a promising carrier for intranasal delivery of ESCH to cross blood-brain barrier and manage neurological disorders. Un-noticeable changes in physical appearance, phase separation, size, PDI and ZP, confirmed 6-months storage stability of Opt-Ch-ESCH-Ns at 4 °C and 25 °C. The intranasal Opt-Ch-ESCH-Ns has shown substantially increased pharmacokinetics in plasma (Cmax 18.98 μg/mL; AUC0-t 152.05 μg/mL; MRT0-∞ 9.5 h; t1/2 of 6.1 h) and brain (Cmax 27.89 μg/mL; AUC0-t 334.67 μg/mL; MRT0-∞ 15.9 h and t1/2 of 10.5 h) of rats, which significantly improved the neuroprotection against the induced neurotoxicity as compared to oral ESCH-SUSPN. Thus, this study highlighted the potential of Opt-Ch-ESCH-Ns as a promising strategy for enhancing the therapeutic efficacy of ESCH in depression management via intranasal delivery, which requisite the further clinical investigations.