Exenatide loaded PLGA microspheres for long-acting antidiabetic therapy: preparation, characterization, pharmacokinetics and pharmacodynamics

摘要

Clinical application of exenatide, a peptide drug widely used for the treatment of type 2 diabetes mellitus, is greatly limited due to its short plasma half-life of 2.4 hours. To prolong the half-life of exenatide, a water in oil in oil (W/O/O) method was employed to prepare exenatide-loaded PLGA microspheres with a satisfactory particle size of 75.22 mu m and a span value of 1.13. Optimized exenatide-loaded microspheres were endowed with high entrapment efficiency (83.8 +/- 1.3%) and low initial burst release (1.31 +/- 0.13%). Degradation pattern of the peptide-loaded microspheres was investigated by monitoring the changes in molecular weight, appearance, and release profile. Histological study proved the safety of the microspheres. In the pharmacokinetics and pharmacodynamics study, the long acting formulation had relative bioavailability of 70.31% and it achieved a hypoglycemic activity for up to 3 weeks in diabetic mice. A single subcutaneous injection of exenatide-loaded microspheres exhibited a comparable effect on controlling blood glucose to exenatide solution, which was injected twice per day at the same dose of exenatide. In conclusion, the exenatide-loaded microspheres might be a promising long acting formulation for glycemic control with low initial burst release and reduced risk of gastrointestinal intolerance and hypoglycemia.