Long-term oral administration of Exendin-4 to control type 2 diabetes in a rat model.

Exendin-4 is a glucagon-like peptide-1 (GLP-1) receptor agonist and potent insulinotropic agent for type 2 diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. Long-acting agonists reduce the number of injections, but they can compromise potency. In this study, chondroitin sulfate-g-glycocholic acid-coated and Exendin-4 (Ex-4)-loaded liposomes (EL-CSG) were prepared for oral administration of Ex-4. The Ex-4 loading efficiency was 77% and the loading content in the nanoparticles was 1 wt-%. In rat models, a single oral dose (200 μg/kg) of EL-CSG showed a relative oral bioavailability of 19.5%, compared with subcutaneous administration (20 μg/kg), and sustained pharmacokinetics for up to 72 h. The overall long-term pharmacodynamic effects, assessed by hemoglobin A1c (HbA1c), body weight, and blood lipid concentrations, of daily oral EL-CSG (300 μg/kg) for four weeks were equivalent to or better than daily subcutaneous injections of free Ex-4 solution (20 μg/kg).