Optimization of intranasal trifluoperazine/SPION-leciplex thermosensitive organogel for depression therapy: Pharmacodynamic and pharmacokinetic comparison of magnet placement effects on brain versus nose.

Trifluoperazine (TFP), an antipsychotic used in depression management, suffers from extensive first-pass metabolism and poor oral bioavailability. Intranasal delivery offers a promising non-invasive route for direct nose-to-brain targeting, while magnetic nanoparticles can further enhance drug localization and absorption. This study aimed to optimize and evaluate a superparamagnetic iron oxide nanoparticle (SPION)-loaded leciplex organogel for intranasal delivery of TFP, with emphasis on the effect of external magnet location. The study compared magnet application on the brain to promote olfactory targeting versus on the nose to enhance systemic absorption. TFP/SPION-leciplex nanoparticles were optimized and incorporated into a thermosensitive mucoadhesive organogel. Pharmacodynamic efficacy was assessed via the forced swimming test, and pharmacokinetics were determined in plasma and brain across four groups: no magnet, magnet on nose, magnet on brain, and oral marketed product. The optimized formulation (266.20 nm, +50.9 mV, 5.90 emu/g, IC50 393.92 μg/ml) showed safety and favorable characteristics. Both magnet-assisted groups significantly reduced immobility time versus the non-magnet and oral controls, with no significant difference between the two strategies. However, the "magnet on nose" group achieved the highest plasma levels, favoring systemic absorption, while the "magnet on brain" group achieved the highest brain levels, favoring olfactory targeting. The SPION-loaded leciplex organogel significantly improved intranasal TFP delivery, enabling dose reduction and superior efficacy compared with oral therapy. Magnet placement was profound in directing drug distribution toward systemic circulation or brain, suggesting that the two approaches may be clinically tailored-"magnet on nose" for systemic delivery and "magnet on brain" for CNS targeting.