Design and Optimization of Dual-Drug Nanocarriers for Targeted Management of Diabetic Neuropathy (Pregabalin + Alpha-Lipoic Acid): A Quality by Design Approach

Abstract

Background: Diabetic neuropathy is a chronic microvascular complication of diabetes associated with oxidative stress and neuronal damage. Conventional monotherapy with pregabalin provides only symptomatic relief and causes dose-dependent side effects, while alpha-lipoic acid’s therapeutic benefits are limited by poor bioavailability. This study aimed to design a dual-drug lipid–polymer hybrid nanocarrier co-encapsulating pregabalin and alpha-lipoic acid for targeted management of diabetic neuropathy using a Quality by Design (QbD) approach. Methods: A Box–Behnken Design was employed to optimize lipid:polymer ratio, sonication time, and surfactant concentration. The optimized nanocarrier was characterized for particle size, PDI, zeta potential, and entrapment efficiency, followed by in vitro release, stability, and in vivo evaluation in streptozotocin-induced diabetic rats. Results: The optimized nanoparticles exhibited a mean size of 135 ± 12 nm, PDI of 0.18 ± 0.02, and entrapment efficiencies of 82.3% and 76.5% for pregabalin and alpha-lipoic acid, respectively. Sustained release extended up to 72 hours, and in vivo studies revealed significant improvements in nerve conduction, oxidative stress, and pain thresholds compared with free drugs. Conclusion: The QbD-optimized dual-drug nanocarrier demonstrated synergistic neuroprotective efficacy, offering a promising platform for targeted and sustained therapy of diabetic neuropathy.