Vilazodone Hydrochloride-Loaded Nanostructured Lipid Carrier In Situ Gel for Intranasal Nose-to-Brain Antidepressant Delivery.

The Oral delivery of vilazodone hydrochloride (VLZ), a serotonin partial agonist-reuptake inhibitor for major depressive disorder, suffers from extensive hepatic first-pass metabolism, food-dependent absorption, and poor blood-brain barrier (BBB) penetration, limiting its central therapeutic impact. Here, VLZ-loaded nanostructured lipid carriers (NLCs) were engineered and embedded within a Poloxamer 407/188-chitosan thermosensitive in situ gel to enable direct nose-to-brain delivery. The NLCs were fabricated by combined high-shear and high-pressure homogenisation and optimised through central composite design, yielding a batch with particle size 24.74 ± 2.23 nm, polydispersity index 0.248 ± 0.012, and entrapment efficiency 91.37 ± 4.56%. The lyophilised NLCs were incorporated into an in situ gel with a physiologically appropriate gelation temperature of 34°C and gelation time of 42 s. Fourier Transform Infrared FTIR spectroscopy confirmed complete drug encapsulation, evidenced by disappearance of the diagnostic nitrile (C≡N) absorption band, while DSC and XRPD verified conversion of VLZ to an amorphous state within the lipid matrix. Drug release followed Korsmeyer-Peppas kinetics, sustained over 24 h, and the formulation remained stable under refrigerated storage. In Swiss albino mice, the intranasal NLC-in situ gel (1 mg/kg) produced a profound antidepressant-like effect relative to oral pure drug (10 mg/kg) across open field, tail suspension, and sucrose preference tests, consistent with enhanced nose-to-brain delivery via the olfactory and trigeminal pathways. Hence this nanocarrier-hydrogel strategy offers a promising, non-invasive route to enhanced CNS delivery of antidepressants.