Investigation of Levomilnacipran Nanostructured Lipid Carriers for CNS Drug Delivery Through Intranasal Administration Using Rat Model

Objective: This study aims to enhance the pharmacokinetics and pharmacodynamics of levomilnacipran by developing a nanostructured lipid carrier for nasal delivery, bypassing the blood-brain barrier via olfactory and trigeminal pathways to improve drug availability in treating depression. Methods: The solvent diffusion approach was used to create levomilnacipran nanostructured lipid carriers (LEV-NLC), which was then tuned for different physicochemical properties. The rat model was used to assess the antidepressant effects of optimised levomilnacipran, in conjunction with biochemical assessment of brain monoamines. In addition, this estimated various pharmacokinetic parameters by measuring levomilnacipran levels in brain and blood plasma at different time intervals. Results: The optimized LEV-NLC showed a particle size of 121 nm, zeta potential of-25 mV, and entrapment efficiency of 88%. Transmission electron microscopy (TEM) analysis revealed spherical nanoparticles with uniform morphology. In vitro release studies demonstrated sustained drug release, with cumulative LEV release of 77.21±3.87% at pH 7.4 and 76.32±3.54% at pH 6.0 over 24 h. Pharmacokinetic analysis showed enhanced bioavailability for LEV-NLC (62%) compared to LEV solution (28%), based on plasma AUC values. In behavioural studies, LEV-NLC significantly reduced immobility (by 101 counts), and increased swimming time (by 128 s), climbing time (by 50 s), and locomotor activity (by 193 counts), indicating antidepressant-like effects. Neurochemical analysis revealed significantly increased serotonin (P<0.01) and noradrenaline (P<0.05) levels in the LEV-NLC group, while dopamine levels showed a non-significant increase (P>0.05). Conclusion: The pharmacokinetic profile of levomilnacipran in the brain and the brain/blood ratio at various time points were both enhanced by the nose-to-brain delivery of the NLC. Therefore, the intranasal administration of levomilnacipran NLC may hold promise as a treatment for depression.