Development and Optimization of Memantine-PEGylated PLGA Liposomal Formulation for Nose-to-Brain Delivery in Alzheimer's Disease: A Quality-by-Design (QbD) Approach

Aim: This study aimed to develop and evaluate Memantine-PEGylated-PLGA Liposomal Formulation for Nose-to-Brain Delivery in Alzheimers Disease: A Quality-by-Design (QbD) Approach. Background: Alzheimer’s disease is a progressive neurodegenerative disorder characterized by neuronal degeneration and the accumulation of β-amyloid plaques and hyperphosphorylated tau proteins. Conventional drug delivery systems face significant challenges in achieving effective brain targeting due to the presence of the Blood-Brain Barrier (BBB). Therefore, the development of alternative delivery strategies such as nose- to-brain targeting has gained considerable attention for enhancing therapeutic efficacy. Materials and Methods: Liposomal formulations, PEGylated PLGA-based memantine liposomes (PEG-MEM-PLGA-LIPO), were developed using the thin-film hydration method. A Quality by Design (QbD) approach with Box- Behnken design was employed for systematic optimization of formulation variables. The prepared multilamellar vesicles were characterized for particle size, entrapment efficiency, morphology, compatibility, and in vitro drug release. Analytical techniques such as Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR) were utilized. Results: The optimized liposomal formulations exhibited nanoscale particle sizes, with PEG-MEM- PLGA-LIPO 262.5 nm. High entrapment efficiencies were achieved 82%. SEM analysis confirmed spherical morphology with smooth surfaces. DSC and FTIR studies indicated compatibility between drug and excipients and successful incorporation within the lipid matrix. In vitro drug release studies demonstrated sustained release of memantine over 72 hr, indicating controlled drug delivery behavior. Conclusion: The developed liposomal formulations demonstrated significant potential as non-invasive drug delivery systems for nose-to-brain targeting. The integration of PEG and PLGA enhanced stability and performance, while the QbD approach ensured optimized formulation characteristics. These findings suggest that the proposed liposomal systems could effectively overcome BBB limitations and improve therapeutic outcomes in Alzheimer’s disease management.