Retrospective Quality-By-Design Optimization of Memantine-Loaded Pegylated Plga Liposomal Formulation for Enhanced Nose-To-Brain Delivery in Alzheimer’s Disease

Background: Alzhimer's Disease is one of the major neurodegenerative disorders where there is limited efficacy of therapeutic drug action, primarily because of the lack of gene transfer across the blood–brain barrier. Nanocarrier-based delivery systems capable of targeting the brain following intranasal administration are under investigation for the improvement of brain targeting of anti-Alzheimer drugs. To find the optimal formulation for carrying memantine in PEGylated PLGA liposomal nanoparticles towards nasal–brain delivery, the present study was designed in a retro view manner employing the Quality by Design (QbD).

Materials and methods: In order to formulate memantine loaded- PEGylated PLGA liposomes, a modified solvent evaporation and thin-film ($ март as per previously mentioned technique. Memantine-loaded-PEGylated PLGA liposomes were prepared by modification of solvent evaporation and thin-film ($ март technique. The particle size, zeta potential, polydispersity index, entrapment efficiency, in vitro drug release, ex vivo nasal permeation and stability were measured. The formulation optimization has been done by applying the principle of retrospective QbD and by using statistical assessment.

Results: The optimized formulation gave the particle size of 156.2 ± 3.9 nm, polydispersity index of 0.184 ± 0.01, zeta potential of −29.4 ± 1.5 mV and entrapment efficiency of 89.8 ± 1.9%. The Higuchi diffusion kinetic model showed sustained release of drug to the greater extent of 91.8 ± 3.2% after 24 hours. Ex vivo permeation studies revealed that the permeation flux and nasal tissue retention were significantly better than pure memantine solution (p < 0.001). The physicochemical stability was acceptable with no significant aggregation or leakage of the drug throughout the study period as observed in the stability analysis.

Conclusion: The optimized formulation gave the particle size of 156.2 ± 3.9 nm, polydispersity index of 0.184 ± 0.01, zeta potential of −29.4 ± 1.5 mV and entrapment efficiency of 89.8 ± 1.9%. The Higuchi diffusion kinetic model showed sustained release of drug to the greater extent of 91.8 ± 3.2% after 24 hours. Ex vivo permeation studies revealed that the permeation flux and nasal tissue retention were significantly better than pure memantine solution (p < 0.001). The physicochemical stability was acceptable with no significant aggregation or leakage of the drug throughout the study period as observed in the stability analysis.

Keywords: Alzheimer’s disease, PEGylated PLGA liposomes, Nose-to-brain delivery, Nanoparticles, Intranasal drug delivery.