Formulation and optimization of venlafaxine loaded nanostructure lipid carrier based intranasal drug delivery system for brain targeting through in vivo study.

Abstract

Objective: This study aimed to develop and optimize nanostructured lipid carriers (NLCs) to deliver venlafaxine (VLF) intranasally to optimize its brain bioavailability.

Significance: The present study explores the development of an intranasal nanostructured lipid carrier-based drug delivery system for brain targeting of venlafaxine. Intranasal administration provides a noninvasive pathway for direct drug transport to the brain through the olfactory and trigeminal pathways, potentially bypassing the blood-brain barrier. Designing venlafaxine-loaded NLCs will help to increase the stability of drugs, increase the nasal residence time and provide an efficient method of delivering drugs to the brain, which is one of the promising measures toward the better treatment of depressive disorders.

Methods: VLF-loaded NLCs were prepared via high-pressure homogenization and optimized using the Box-Behnken design. Glycerol monostearate and olive oil were used as lipid matrices, and Tween 80 was used as a surfactant. The physicochemical properties (particle size 112.99 nm, zeta potential -20.85 ± 2.27 mV, entrapment efficiency 94.89 ± 0.27%, drug loading 5.76 ± 0.12%) of the nanoparticles, including particle size, zeta potential, and entrapment efficiency were evaluated. In vitro release studies were conducted, followed by in vivo assessments of brain-targeting efficiency using drug-concentration analysis in brain tissues.

Results: The optimized VLF-loaded NLCs showed a particle size of 112.99 nm, zeta potential of 15.21 + 3.11 mV as well as drug entrapment efficiency of 94.89%. In vitro release showed a biphasic release profile (an initial burst release (39.7 + 0.01% in 2 h)) and a sustained release (94.56 + 1.2% in 24 h). The results of the in vivo experiments showed a significant increase in VLF concentrations in the brain tissues following administration through the intranasal route compared to administration through the oral route, and a 2.15-fold increase in Cmax, 22.5-fold larger Area Under Curve (AUC 0-), and a 9.2-h delay in Tmax (p < 0.05), indicating improved brain-targeting.

Conclusion: The intranasal NLC system developed was able to increase the bioavailability and brain delivery of VLF with the drawback of the oral route avoided. The biphasic release profile favors the lasting therapeutic activity. This method opens a good platform of CNS drug delivery that should be pursued by additional pharmacokinetic and clinical research.