Intranasal delivery of sertraline hydrochloride enhanced brain concentration and antidepressant activity: A comparative pharmacokinetic and pharmacodynamic study.

Sertraline hydrochloride is the first-line drug for the treatment of major depressive disorder; however, its oral administration is significantly affected by poor aqueous solubility, high first-pass metabolism and low oral systemic availability. The present work focused on the development and head-to-head comparison of PEGylated lipidic and polymeric nanoparticles for the intranasal delivery of sertraline hydrochloride to address shortcomings of oral delivery. The optimised solid-lipid nanoparticles showed a particle size of 153.43 nm and an encapsulation efficiency of 88.64%, while polylactic-co-glycolic acid nanoparticles demonstrated a particle size of 174.60 nm and an encapsulation efficiency of 86.64%. In-vitro drug release study showed controlled and sustained release for solid-lipid nanoparticles, while polymeric nanoparticles exhibited comparably faster release with distinct release kinetics. In an ex vivo permeation study, both the nanoparticles exhibited greater permeability than the pure drug across the goat nasal mucosa. Furthermore, a pharmacokinetic study revealed that intranasal delivery markedly increased brain exposure compared with oral delivery. Brain maximum concentration increased from 21.67 ng/g (oral) to 322 ng/g (lipid nanoparticles) and 1096 ng/g (polymeric nanoparticles), while brain exposure increased from 515.62 ng·g⁻¹·h to 5489 ng·g⁻¹·h and 14,362 ng·g⁻¹·h, respectively. Compared with oral administration, both polymeric and lipidic nanoparticles alleviate chronic unpredictable stress-induced depressive behaviour in mice, with solid lipid nanoparticles showing a slight edge over polymeric nanoparticles. Overall, intranasal nanoparticle systems improved brain availability and antidepressant response, with distinct performance differences between lipidic and polymeric carriers.