The glucose-lowering potential of exendin-4 orally delivered via a pH-sensitive nanoparticle vehicle and effects on subsequent insulin secretion in vivo

Exendin-4 is a potent insulinotropic agent in diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. In this study, an orally available exendin-4 formulation, using an enteric-coated capsule containing pH-responsive NPs, was developed. Following oral administration of I-123-labeled-exendin-4 loaded NPs in rats, the biodistribution of the administered drug was investigated using a dual isotope dynamic SPECT/CT scanner. The results showed that the radioactivity of I-123-exendin-4 propagated from the esophagus, stomach, and small intestine and then was absorbed into the systemic circulation; with time progressing, 123I-exendin-4 was metabolized and excreted into the urinary bladder. In the in vivo dissolution study, it was found that the enteric-coated capsule remained intact while in the stomach; the capsule was completely dissolved in the proximal segment of the small intestine and the loaded contents were then released. Oral administration of the capsule containing exendin-4 loaded NPs showed a maximum plasma concentration at 5 h after treatment; the bioavailability, relative to its subcutaneous counterpart, was found to be 14.0 +/- 1.8%. The absorbed exendin-4 could then stimulate the insulin secretion and provide a prolonged glucose-lowering effect. The aforementioned results suggest that the orally available exendin-4 formulation developed warrants further exploration as a potential therapy for diabetic patients. (C) 2011 Elsevier Ltd. All rights reserved.