Rivastigmine, used in the treatment of Alzheimer's disease (AD), faces challenges of poor stability and low permeability when delivered through conventional methods. To address these issues, rivastigmine-loaded nanofibers were systematically prepared via an electrospinning process utilizing the Design of Experiments (DoE) methodology and subsequently transformed into an in-situ hydrogel using the cold process method. Preliminary experiments determined optimal polymer concentration, ratio, and electrospinning parameters. A 32 factorial design optimized nanofibers, with polyvinyl alcohol (PVA) concentration (X1) and PVA: chitosan ratio (X2) as independent variables, and % cumulative drug release (Y1) and % entrapment efficiency (Y2) as dependent variables. Using the desirability model, the final batch achieved % cumulative drug release and % entrapment efficiency of 90.17 ± 2.64 and 91.46 ± 4.83 respectively. Fourier Transform Infrared Spectroscopy (FTIR) and X-ray diffraction (XRD) studies showed no significant excipient interactions. Field emission scanning electron microscopy (FE-SEM) analysis revealed nanofiber diameters of 160–230 nm. Findings demonstrated that the nanofiber-reinforced in-situ hydrogel exhibited significantly improved gelling capacity at 34.2 °C and increased spreadability (19.51 ± 1.75 cm2) compared to the hydrogel formulations without nanofibers. In-vitro and ex-vivo studies showed controlled rivastigmine release over 8 h. Additionally, enhanced mucoadhesion (236.7 ± 8.83 gm/cm2), pH compatibility (5.9 ± 0.12) with nasal fluid, and moisture resistance uptake highlight suitability for nasal drug delivery. Therefore, this approach offers an efficient delivery platform for rivastigmine with enhanced delivery characteristics and promising therapeutic potential.
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