Brain-targeted mucoadhesive in situ gel incorporating quercetin-PEG conjugate and rivastigmine-loaded chitosan nanoparticles for Alzheimer's therapy.

Alzheimer's dementia (AD) is a progressive neurodegenerative impairment driven by a pronounced cholinergic deficit. Quercetin (QUE) and rivastigmine (RVS) have been used in the treatment of AD, however, clinical translation of QUE and RVS is limited by poor solubility, and short half-life, respectively. To overcome these limitations, QUE was PEG-conjugated (Q-PEG) and co-encapsulated with RVS in chitosan nanoparticles (CNPs) and further incorporated in mucoadhesive in situ gel for nose-to-brain delivery. Q-PEG conjugation was confirmed by Fourier transform infrared spectroscopy (FTIR) and Proton nuclear magnetic resonance (1HNMR). The RVS-Q-PEG-CNPsG was optimized through systematic formulation development. The optimized formulation exhibited a mean particle size (134.7 ± 0.35 nm), narrow size distribution (0.213 ± 0.01), optimal zeta potential (+21.5 ± 0.45 mV) and suitable entrapment efficiency of QUE (92.3 ± 0.50%) and RVS (81.5 ± 0.81%). Structural characterization using Transmission electron microscopy (TEM), FTIR, X-Ray diffraction (XRD), and Differential scanning calorimetry (DSC) confirmed spherical morphology, components compatibility, amorphous nature and thermal stability, respectively. Moreover, the poloxamer based in situ gel demonstrated homogeneity, optimal viscosity and robust mucoadhesive strength, thereby markedly enhancing drug retention of CNPs at the administration site. Moreover, it depicted a sustained drug release profile in vitro, and enhanced nasal permeation, ex vivo. Additionally, histopathological evaluation validated the safety and mucosal compatibility of the formulation. Furthermore, pharmacokinetic studies demonstrated significantly enhanced brain bioavailability of RVS-Q-PEG-CNPsG (5.6 ∼ fold and 12.6 ∼ fold) compared to intranasal free RVS and QUE. These findings suggested that intranasally administered RVS-Q-PEG-CNPsG provides effective brain delivery, which may be a promising approach for the treatment of AD.