Engineered polymeric nanosponge in-situ gel enables sustained and enhanced nose-to-brain delivery of quetiapine fumarate

Quetiapine fumarate is a second-generation antipsychotic with limited oral bioavailability owing to extensive hepatic first-pass metabolism, making it a suitable candidate for intranasal brain delivery. This study aimed to develop a quetiapine fumarate-loaded nanosponge in-situ gel for sustained and enhanced brain delivery. Nanosponges were prepared by the quasi-emulsion solvent diffusion method and screened using a Plackett-Burman design to identify critical formulation and process variables. Stirring speed, drug amount, and Eudragit L100 amount were further optimized using a Box-Behnken design with particle size, PDI, encapsulation efficiency, and 24 h drug release as responses. The optimized nanosponges showed a particle size of 248.7 nm, PDI of 0.250, and encapsulation efficiency of 97.48%. FTIR, DSC, and XRD analyses confirmed successful drug incorporation and reduced crystallinity of quetiapine fumarate within the nanosponge matrix. The optimized in-situ gel containing quetiapine fumarate-loaded nanosponges (QF-NS) showed physiological pH, appropriate viscosity and gelation, and defined textural characteristics. In vitro release studies showed an apparent sustained-release profile under dialysis conditions, reaching 87.37 ± 3.7% over 24 h, while ex vivo permeation across goat nasal mucosa demonstrated controlled permeation compared with QF solution. Histopathological evaluation showed no overt mucosal damage following short-term ex vivo exposure. In vivo pharmacokinetic studies in rats showed greater brain exposure following intranasal administration than with the intravenous comparator, with a brain Cmax of 9.27 ± 2.34 μg/g compared with 0.57 ± 0.12 μg/g. The observed brain AUC0-6 h was 7.73 μg·h/g after intranasal administration and 2.01 μg·h/g after intravenous administration. The intranasal formulation produced a brain-to-plasma exposure ratio substantially greater than that of the intravenous solution, with DTE and DTP values of 536.51% and 81.36%, respectively. Overall, these findings support the optimized QF-NS-loaded in-situ gel as a promising intranasal platform for sustained drug delivery and enhanced relative brain exposure to quetiapine fumarate.