Intranasal delivery of chitosan-coated bilosomes for repurposing Olmesartan in Alzheimer's disease therapy: Formulation, optimization, pharmacokinetic and pharmacodynamic evaluation.

内容摘要

Alzheimer's disease (AD) is a neurological illness that progresses over time and has limited therapeutic options. This is mostly because the blood-brain barrier prevents drugs from reaching the brain efficiently. This study sought to repurpose olmesartan (OLM), an angiotensin II receptor blocker exhibiting promising neuroprotective properties, by improving its brain-targeted delivery via intranasally administered bilosomes with chitosan shell. Chitosan coated bilosomes containing olmesartan (OLM-CTS-BLS) were formulated using a Box-Behnken design to optimize key variables (lecithin, sodium deoxycholate, and chitosan concentration) for achieving minimum diameter together with maximum entrapment efficiency and zeta potential. The optimized formulation demonstrated nanosized vesicles (184.89±6.11 nm), positive surface charge (+34.07±1.72 mV), and high encapsulation (87.36%±1.07). In vitro release showed sustained OLM delivery over 12 hours. Nasal diffusion studies conducted on sheep nasal mucosa demonstrated a significant increase in flux and permeability for OLM-CTS-BLS compared to OLM suspension. Pharmacokinetic studies in rats confirmed significantly improved brain bioavailability and a 1.4 fold increase in brain/plasma AUC ratio for OLM-CTS-BLS versus conventional routes. Behavioral assessments (Y-maze, Morris Water Maze) in lipopolysaccharide-induced AD rats revealed superior cognitive improvement in OLM-CTS-BLS-treated animals. Biochemical assays showed reduced acetylcholinesterase activity and lipid peroxidation. Histopathological and immunohistochemical evaluations demonstrated reduced amyloid-β deposition and preserved neuronal architecture without nasal toxicity. Collectively, these findings underscore the potential of intranasal OLM-CTS-BLS as a safe and effective drug delivery system for repurposing OLM in AD therapy by enhancing its brain delivery and therapeutic efficacy.