Nanoliposomal in situ gel of fluoxetine and embelin as a potent intervention for depression via the intranasal route in CUMS animal model

Due to the intricate mechanism of depression, slow therapeutic effect, and intolerable side effects, fluoxetine does not treat its many symptoms. To address monotherapy's limitations, novel and synergistic therapies are needed. This study delves into the potential of thermosensitive nanoliposomal gel loaded with fluoxetine and embelin (FXT-EMB NLs in situ gel) to manage depression via the intranasal route in a chronic unpredictable mild stress (CUMS) animal model. FXT-EMB NLs were prepared using thin-film hydration, optimized by a central composite design, and loaded into an in situ gel containing Poloxamer-407 and HPMC polymers. The optimized NLs had satisfactory vesicle size (92.6 ± 1.3 nm), TEM, SEM, PDI (0.22 ± 0.01), zeta potential (35.1 ± 0.2 mV), and entrapment efficiency (87.09 and 73.26 % for FXT and EMB) results. DSC, FTIR, and XRD confirmed the purity of APIs, compatibility, and loading efficiency of the in situ gel. The in vitro release showed sustained release, whereas the ex vivo permeation and CLSM studies demonstrated enhanced permeation across goat nasal mucosa (19.351 and 19.6 μg/cm2/h). DPPH assay confirmed the antioxidant potential of the NLs and was non-irritant according to the nasal toxicity and HET-CAM studies. The N2a neuroblastoma cell line revealed cell viability and the synergistic effect of the drug combination (CI