PEGylated flexosomes as a novel intranasal carrier for quetiapine: formulation, characterization, and <i>in vivo</i> studies

The present study aimed to fabricate PEGylated flexosomes (PFs) for intranasal delivery of quetiapine (QTP), addressing its poor oral bioavailability. QTP-loaded PFs were formulated via thin-film hydration and optimized using a 2³ factorial design to evaluate Brij type and concentration, with or without 0.1% cholesterol, providing ultradeformable nanovesicles capable of efficient brain targeting. Brij surfactants served dual roles as elasticity-enhancing edge activators and PEGylating agents, thereby improving steric stabilization and mucosal interactions. The formulae were assessed by determining particle size, entrapment efficiency, polydispersity, zeta potential, and drug release. The optimized formulation (QTP-OPF) was assessed for deformability, stability, morphology, and <i>ex vivo</i> nasal permeation. Finally, <i>in vivo</i> pharmacokinetic and histopathological assessments were accomplished to estimate the <i>in vivo</i> performance of QTP-OPF. The QTP-OPF exhibited reduced particle size and polydispersity, a high zeta potential, and enhanced drug release. Additionally, it demonstrated superior deformability and maintained stability for 90 days. Transmission electron microscopy confirmed spherical, PEG-coated vesicles. <i>The ex vivo</i> nasal permeation study revealed a 1.6-fold increase over QTP suspension, while <i>in vivo</i> pharmacokinetics revealed a 3.8-fold enhancement in brain C_max and a 7.5-fold higher brain AUC_0-∞. Histopathological evaluation confirmed the formulation's safety. PFs present a promising platform for enhanced intranasal QTP delivery.