Quality by design of ultra deformable nanovesicles loaded with flunarizine for brain targeting utilizing risk assessment and multivariate analytical methods

The swiftly changing technological and regulatory environments in the development of pharmaceutical drugs require risk based approach that integrates multivariate analysis utilizing Quality by Design (QbD). Flunarizine, a poorly water-soluble calcium channel blocker utilized for migraine treatment, exhibits low bioavailability. Spanlastics, contemporary nonionic based surfactant nanovesicles, enhance medication penetration due to their fluidic nature. Consequently, we optimized flunarizine spanlastic nanovesicles (FNZ-SNVs) utilizing formulation by design principles and investigated the viability of nose-to-brain delivery for migraine management. Ishikawa diagram was utilized to identify the risk factors that may affect the critical quality attributes of FNZ-SNVs. The use of Plackett–Burman experimental design was employed to test eight distinct formula and process factors affecting vesicle size, zeta potential, vesicle deformability, and encapsulation efficiency. Utilizing Pareto charts, three critical parameters were identified: type of vesicle builder (Span 60), type of EA (Tween 60), and sonication duration. Three levels of these essential factors were tuned by formulation by design to minimize vesicle size and enhance encapsulation efficiency, and vesicle deformability of FNZ-SNVs. The optimized FNZ-SNVs exhibited a vesicle size of 95.5 nm, an encapsulation efficiency of 86%, a relative deformability of 4.8 minutes, and a dissolving efficiency of 90.2%. Consequently, the optimized formula was integrated into an insitu-gel (IG) and investigated for additional in vivo assessment, which demonstrated that the degree of FNZ-SIG intranasal delivered to the brain was significantly greater than that of the intravenous FNZ solution, exhibiting an exceptionally elevated drug targeting index (DTI) of 1.12 and (DTE%) 112.1. This study illustrates the successful implementation of risk management and Quality by Design (QbD) methodologies in the formulation of brain-targeting release of FNZ-SIGs.