'Development and evaluation of naringin-loaded phytosomes for the management of diabetic neuropathy: in vitro and in vivo studies'.

OBJECTIVES: Diabetic neuropathy (DN), a common complication of type 2 diabetes, is associated with oxidative stress, inflammation, and persistent hyperglycemia. Naringin, a flavonoid with antioxidant and anti-inflammatory properties, is limited by poor bioavailability. This study aimed to develop and optimize a naringin-loaded phytosomal formulation to enhance bioavailability and evaluate its efficacy in DN. METHODS: Naringin-loaded phytosomes were prepared and optimized using a Box-Behnken design to achieve high entrapment efficiency, favorable particle size, polydispersity index (PDI), and zeta potential. In silico docking assessed binding with PPAR-γ, α-glycosidase, AMPK, NF-κB, and Nrf2. Ex vivo intestinal permeability studies evaluated absorption. In vivo efficacy was tested in streptozotocin-induced diabetic rats by assessing pain thresholds, biochemical parameters, antioxidant enzyme activities, TNF-α levels, and gastric emptying time. RESULTS: The optimized formulation showed 93% entrapment efficiency, desirable particle size, low PDI, stable zeta potential, and enhanced permeability. Docking confirmed strong binding to molecular targets regulating glucose metabolism and oxidative stress. In vivo, naringin phytosomes significantly improved pain thresholds, reduced glucose and lipid levels, increased antioxidant enzyme activities, decreased TNF-α, and improved delayed gastric emptying compared to plain naringin. DISCUSSION: Phytosomal delivery markedly enhanced naringin's bioavailability and therapeutic potential in DN, likely due to improved uptake and multi-targeted action. These findings support naringin phytosomes as a promising candidate for DN management, meriting further clinical evaluation.