Abstract
Neurological disorders (ND) pose a major global health challenge, in large part due to the restrictive nature of the blood–brain barrier (BBB), which prevents most therapeutic agents from reaching the central nervous system (CNS). Intranasal delivery (IN) offers a non-invasive and patient-friendly route to bypass the BBB via the olfactory and trigeminal pathways, but its success requires advanced nanocarrier systems capable of enhancing drug retention, stability, and controlled release. In this study, a Quality by Design (QbD) framework was applied to systematically develop and optimize 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG 2000 )-functionalized nanostructured lipid carriers (NLCs) using Donepezil (DPZ) as a model drug. Through sequential risk assessment, Plackett–Burman screening design (PBD), and Central Composite Design (CCD) optimization, the Critical Formulation Variables (CFVs) and Critical Process Parameters (CPPs) influencing particle size (PS) and entrapment efficiency (%EE) were identified. The optimized DSPE-PEG 2000 —NLCs exhibited nanoscale size (133.4 ± 2.91 nm), high %EE (89.5 ± 1.51%), strong mucin binding (84.6 ± 2.68%), and a distinct core–shell morphology. In vitro and ex vivo studies confirmed a biphasic and sustained drug release up to 60 h & 67 h, outperforming uncoated NLCs and conventional formulations. Stability studies demonstrated improved preservation under refrigerated conditions. Beyond DPZ, the QbD-guided strategy presented here provides a generalizable and regulatory-aligned platform for designing IN nanocarriers, paving the way for reproducible, scalable, and translational drug delivery systems targeting a wide range of ND. Graphical Abstract