Molecular Docking‐Guided Engineering of TPGS/Tween 80 Mixed Micelles for the Intranasal Delivery of Paliperidone Palmitate

Poor aqueous solubility severely limits the brain delivery of paliperidone palmitate (PP), necessitating formulation strategies. Here, a docking‐guided approach is employed to engineer intranasal mixed micelles for improved intranasal delivery and potential brain targeting. Molecular docking identifies D‐α‐tocopheryl polyethylene glycol succinate (TPGS) as the primary interacting excipient (ΔG = −4.0 kcal mol −1 ), while Tween 80 provides complementary interactions enabling cooperative micellization. The optimized PP‐loaded mixed micelles (PP‐MM), developed via a 3 2 factorial design, exhibit nanoscale size (14.97 ± 0.82 nm), narrow dispersity (PDI 0.270 ± 0.021), and efficient drug loading (4.1 ± 0.27%). The formulation demonstrates markedly enhanced in vitro release (89.3 ± 8.2% vs. 33.8 ± 2.8% at 360 min) and substantially improved ex vivo nasal permeation (66.30 ± 5.32% vs. 21.40 ± 2.21%), achieving a 2.64‐fold increase in steady‐state flux (compared to drug suspension). In vivo pharmacodynamic evaluation shows superior suppression of ketamine‐induced hyperlocomotion (279.16 ± 18 vs. 448.33 ± 21.60 counts) without detectable neurotoxicity, supported by preserved neuronal architecture. Collectively, these findings establish docking‐guided mixed micelle engineering as a robust and translational strategy to enhance solubilization, mucosal transport, and therapeutic efficacy, supporting further investigation of this scalable, non‐invasive platform for intranasal delivery of poorly soluble antipsychotic agents.