Intranasal Chitosan Nanoparticles for Direct Nose-to-Brain Delivery of Cariprazine: A Noninvasive Strategy for...

Cariprazine is a hydrophobic antipsychotic with poor oral bioavailability and limited blood-brain barrier penetration, restricting its therapeutic potential for CNS disorders. Chitosan-based nanoparticles (CZNPs) were designed for intranasal nose to brain delivery. Key formulation variables were screened using a two level fractional factorial design (FFD) and optimized via a Box Behnken design (BBD). Nanoparticles were prepared by ionic gelation and characterized for particle size, zeta potential, and encapsulation efficiency. In vitro release, ex vivo nasal permeation (sheep mucosa), in vivo pharmacokinetics (rats), and nasal histopathology were evaluated. Optimized CZNPs exhibited a particle size of 164.8 nm, zeta potential of +45.3 mV, and 67.6 ± 0.08% encapsulation efficiency. They showed biphasic sustained release over 24 h and significantly enhanced nasal permeation versus a drug suspension. In vivo, intranasal CZNPs achieved 6.2-fold higher brain targeting efficiency, 91% direct transport percentage, and a brain to plasma AUC ratio of 0.67. Early brain C_max (106 /mL at 2 h) indicated olfactory/trigeminal transport. Relative plasma bioavailability was 91%, with no nasal epithelial or ciliary damage observed. CZNPs exhibited effective brain targeting, controlled release, and mucosal safety, highlighting their potential as a noninvasive intranasal system for CNS delivery of cariprazine in neuropsychiatric disorders.