Biopolymeric Zein Protein Nanoparticles for Oral Vildagliptin Delivery: Fabrication, Statistical Optimization, and In Vivo Pharmacokinetics and Pharmacodynamics Insights

Vildagliptin (VLD) is a powerful oral hypoglycemic agent used in the management of type II diabetes. The goal of the current research was to develop VLD-loaded zein protein-based nanoparticles (VLD-ZP NPs) for enhancing their oral hypoglycemic effect, achieving a sustained release profile, and addressing the issues associated with rapid metabolism and side effects. A 2³ full factorial design was utilized to assess the influence of independent formulation variables on the observed responses. The independent variables considered were VLD-to-zein weight ratio (X₁), ethanol-to-water volume ratio (X₂), and stirring time (X₃). The dependent responses evaluated were particle size (Ps), zeta potential (Zp), entrapment efficiency (EE), and percent of drug release after 2H (Q_2H) and 8H (Q_8H). The optimized VLD-ZP NPs formula (F04), with a desirability value of 0.94, exhibited a small Ps (149.64 ± 1.4nm), low Q_2H (23.97 ± 2.1%), high Zp (- 37.67 ± 1.8mV), high EE (68.67 ± 2.3%), and sustained Q_8H release (62.57 ± 2.4%). Further investigations of F04 confirmed sustained drug release, spherical vesicle morphology through TEM, and effective entrapment via DSC and X-ray diffraction. In vivo pharmacokinetic studies revealed that C_max and AUC_0-12H of F04 were enhanced by 1.25-fold and 1.8-fold compared to the marketed VLD product. Also, t_1/2 and MRT were extended by 1.84-fold and 1.56-fold, respectively. These findings indicated improved oral bioavailability and prolonged residence time of VLD. Additionally, the in vivo pharmacodynamic study revealed that F04 provided markedly superior and sustained hypoglycemic effects over the marketed VLD product, with higher R_max, longer TR_½, and a 2.8-fold increase in AUC_(0-24H).