Optimization and Evaluation of Functionally Engineered Paliperidone Nanoemulsions for Improved Brain Delivery via...

Paliperidone, a second-generation antipsychotic approved by USFDA for schizophrenia, exhibits low aqueous solubility and high permeability, classifying it under BCS II. The present study focused on brain delivery of paliperidone through the nasal route in the form of nanoemulsions functionally engineered with chitosan. Mucoadhesive and permeation enhancing properties of cationic chitosan are favored by the presence of hydrophilic groups. These groups allow interactions with anionic nasal mucosa, resulting in bioadhesion via noncovalent bonds. Paliperidone nanoemulsions were optimized using StatEase Design-Expert Software and prepared via spontaneous emulsification and ultrasonication using oleic acid, stearic acid, Tween 80, propylene glycol, Labrasol and chitosan. The resulting nanoemulsions showed a droplet size of 155 ± 5.5 nm, polydispersity index of 0.259 ± 0.1 and zeta potential of +40.5 ± 3.5 mV. Functional engineering of chitosan on the surface of paliperidone nanoemulsion droplets was confirmed qualitatively as well as quantitatively by FTIR, Ninhydrin assay and TEM studies. In vitro release of paliperidone from nanoemulsions and functionally engineered nanoemulsions was found to be 69.55 ± 1.5% and 59.29 ± 0.47%, respectively, at the end of 8 h. Ex vivo studies across goat nasal mucosa demonstrated a higher paliperidone flux of 23.31 ± 0.296 μg/cm²/h from nanoemulsions as compared to 17.87 ± 0.163 μg/cm²/h from functionally engineered nanoemulsions. Studies in RPMI 2650 nasal and Neuro2A brain cell lines indicated that functionally engineered paliperidone nanoemulsions were biocompatible, which was also confirmed from histopathological evaluation. Studies in Wistar rats showed enhanced cataleptic effects with improved memory and anxiolytic effects, demonstrating the effectiveness of this advanced strategy in brain delivery of paliperidone via the nasal route.