Brain-targeted intranasal aripiprazole via modified chitosan nanoparticles: controlled release, pharmacokinetics, and pharmacodynamics.
Abstract
Schizophrenia remains one of the most disabling mental disorders, and effective therapy is still limited by the difficulty of delivering drugs across the blood-brain barrier. Aripiprazole (Ari), a first-line atypical antipsychotic, exhibits restricted clinical performance due to poor solubility, extensive hepatic metabolism, and limited brain exposure. Herein, a novel intranasal nanocarrier system was developed to enable direct and sustained delivery of Ari to the brain. Chitosan nanoparticles (Cs-NPs) surface-modified with sodium dodecyl sulfate (SDS) were prepared by the ionic gelation method and optimized using a Box-Behnken design to evaluate the effects of SDS concentration, pH, and chitosan-to-tripolyphosphate ratio on particle size, zeta potential, and drug entrapment. The optimized formulation showed a mean particle size of ~ 200 nm, a positive surface charge, and an entrapment efficiency of 76.98 ± 7.6%. Transmission electron microscopy confirmed spherical morphology, while the in vitro release profile exhibited an initial burst followed by a sustained phase, indicating controlled-release behavior. Pharmacokinetic evaluation using LC-MS/MS revealed significantly enhanced Ari bioavailability and brain uptake following intranasal administration of the optimized Cs-NPs compared with oral, intravenous, and intranasal solutions. Pharmacodynamic testing in a ketamine-induced psychosis rat model (open-field and forced-swim tests) demonstrated improved antipsychotic efficacy. Neurochemical analysis showed restoration of dopamine and γ-aminobutyric acid levels, while histopathological findings confirmed structural improvement in hippocampal and cortical regions. Collectively, these results highlight the potential of modified Cs-NPs as a controlled-release, nose-to-brain delivery platform that enhances the therapeutic performance of Ari for the management of schizophrenia.