Formulation, Optimization, and in vivo Evaluation of Repaglinide-Loaded Solid Lipid Nanoparticles with Enhanced Bioavailability and Sustained Hypoglycemic Effect

Abstract

Background: Repaglinide is an oral antidiabetic agent which has inadequate water solubility and is highly first-pass metabolized (poor bioavailability 50-60%), thus necessitating frequent administration. Solid Lipid Nanoparticles (SLNs) present a promising approach to improve the absorption of drugs and extend their release. Materials and Methods: Repaglinide-SLNs were prepared by incorporating hot melt emulsification-ultrasonication using glycerol behenate as lipid core, Poloxamer 188 as the surfactant and phospholipid 90G as stabilizer. The formulation was optimized with the help of a 20-batch factorial design. The size, zeta potential, entrapment efficiency, drug loading, in vitro release, morphology, crystallinity and stability of the particles were characterized. The pharmacokinetics and pharmacodynamics of in vivo animals were determined in alloxan-induced diabetic rats. Results: Optimized formulation (RSLN-12) had a particle size of 238.4±12.4 nm, PDI of 0.319±0.021, zeta potential of -29.43±1.38 mV, and a drug loading of 7.86±0.23%. Sustained profile was demonstrated in vitro (78.6±1.6% at 24 hr). Extended half-life (3.7±0.3 vs. 0.9±0.1 hr), increased relative bioavailability compared to pure drug suspension (68.3±2.5% vs. 56.0±2.1%), and sustained glucose lowering was shown in vivo as compared to pure drug. The formulation was stable in refrigeration and as well as at room temperature (six months). Conclusion: Repaglinide-loaded SLNs were effective in increasing drug bioavailability and sustained release, and should be considered in the future as a means to enhance diabetes control with decreased dosage frequency.