Advanced Intranasal Lipid-Based Nanocarrier System for Targeted Nose-to-Brain Delivery of Vortioxetine Hydrobromide: From Formulation to In vivo Pharmacokinetics

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Objective: Vortioxetine HBr is a multimodal antidepressant with a very poor aqueous solubility (50 µg base/ml at pH 7.4) and an oral bioavailability of approximately 75% due to hepatic first-pass metabolism. Nose-to-brain drug delivery can bypass hepatic first-pass metabolism and achieve targeted drug therapy by circumventing the blood-brain barrier via the olfactory and trigeminal nerve pathways using different modalities. A novel dosage form, nasal insert, containing Vortioxetine HBr lipid-based nanocarriers (VRT-NLCs) was used to improve Vortioxetine bioavailability and optimization of different additives such as D-(+)-Trehalose and D-Mannitol to enhance Vortioxetine efficacy. Methods: (VRT-NLCs) were prepared via a 24 full factorial design with four variables; surfactant (Tween 80) concentration (X1), steric stabilizer (PVA) concentration (X2), solid/liquid (Stearic/Oleic acid) ratio (X3), and co-surfactants (Span 60/Poloxamer 188) ratio (X4). Entrapment efficiency (EE%), %released after six hours (Q6h%), particle size (PS), zeta potential (ZP) and polydispersity index (PDI) were evaluated. Design Expert® software was used to select the optimum two formulae with the highest desirability values. Using D-mannitol or D-(+)-trehalose, the two optimized (VRT-NLCs) formulae were incorporated into lyophilized nasal inserts. They were characterized for physical appearance, release profile, muco-adhesion strength, residual water content by Karl Fischer, uniformity of dosage units by content uniformity, mass uniformity and friability. In addition to (DSC), (FTIR), (PXRD) and in vivo pharmacokinetics, the two optimized inserts were evaluated for (Norepinephrine (NE), Dopamine (DA), Serotonin (5-HT), Aspartate (Asp) and γ-amino butyric acid (GABA)) neurotransmitters’ level in the brain and (5-Hydroxy Indoleacetic acid (5HIAA)) metabolite using rats and compared with Vortoxicalm® 5 mg oral tablet. Results: (VRT-NLCs) exhibited (EE%) range of (67.58±1.59% to 99.42±1.91%), sustained release profile with (Q6h%) of (21.49±4.89% to 90.94±4.02%), (ZP)of (-10.4775±0.81to-27.925±2.67mV), (PS) of (81.92±0.68 to 255±5.82 nm), and (PDI)of (0.267±0.02 to 0.545±0.01). Moreover, nasal inserts had promising residual water content values of (0.0072 ±0.03% to 3.971±1.334 %), friability of (zero% to 0.9%), (Q)45 min% of (54.88 ±1.62% to 100 ±3.31%) and muco-adhesion strength of (8297.33±184.79 to 9996±122.23). Solid-state characterization (DSC and PXRD) confirmed D-(+)-trehalose superior cryoprotective effects. N4 (trehalose-based insert) demonstrated the highest brain exposure, with two-fold higher area under the curve from zero to infinity (AUC₀–∞ = 461.28±17.85ng*h/g) when compared to oral tablet (AUC₀–∞ = 230.4±11.5ng*h/g). Nasal inserts increased mood-regulating neurotransmitters’ (5-HT, DA, NE) levels and reduced (5-HIAA) metabolite compared with Vortoxicalm® 5 mg FCT. Conclusion: We recommend conducting further clinical studies to explore potential therapeutic applications of vortioxetine HBr lipid-based nanocarriers, consolidating our research findings.

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