The purpose of this research was to use the ionic gelation method to optimise and develop ondansetron (OND) loaded chitosan nanoparticles (ONDNP) using the Box–Behnken design (BBD). 3 self-directed variants like drug to polymer ratio (X₁), concentration of sodium tripolyphosphate (X₂), and RPM (X₃) were considered to investigate their effect on the dependent variables viz., particle size (Y₁) (PS), Polydispersibility index (Y₂) (PDI), and Zeta potential (Y₃) (ZP). The optimized formula was determined by regression analysis of the output data which was further evaluated morphological, in vitro release, In vitro cell cytotoxicity, Ex vivo histopathology studies and in vivo distribution for brain targeting followed by nasal administration. The designed nanoparticles have average particle size, PDI, ZP   from190.5 ± 6.45, 0.426 ± 0.024, 52.40 ±7.20 respectively. No significant toxicity and structural damage was found in nasal mucosa on histopathology examination. The AUCs of ONDNP in plasma and brain was found to be 562.34 ± 14.81 ng h/mL in plasma and 324.36±15.28 ng h/mL in brain.It has a much In the brain, a higher brain blood ratio and nasal bio-availability than the OND pharmaceutical solution.The current investigation is expected to yield promising results that will push us to design a non-invasive way to address the disadvantages of oral brain delivery.

Keywords: Chitosan nanoparticles, Box-Behnken experimental Design, Ondansetron, particle size, zeta potential, Polydispersibility index, cytotoxicity.