Sustained Release of Exendin 4 Using Injectable and Ionic-Nano-Complex Forming Polymer Hydrogel System for Long-Term Treatment of Type 2 Diabetes Mellitus

Daily treatment of diabetes to stabilize blood glucose level poses a challenge for patients with diabetes mellitus. Diabetes is a long-term metabolic disorder, and the treatment lasts for the rest of the patient's life after diagnosis. We presented a new injectable hydrogel depot system using exendin 4 (Ex-4) interactive and complex forming polymeric ionic-nano-particles for long-term antidiabetes treatment. Protamine-conjugated polymer (ProCP) was developed to form ionic-nano-complexes with Ex-4, as the amino-group-rich protamine and the negatively charged Ex-4 ( pI: 4.86) interact with each other due to their opposite electric charges in physiological conditions. Morphologically, the ProCP were nanoparticles in aqueous condition (10 wt % of ProCP in phosphate-buffered solution, <25 °C) and formed condensed ionic- and nano-complexes with Ex-4. The complexes formed a bulk hydrogel when exposed to body temperature. A slow release of the Ex-4/ProCP ionic-nano-complexes occurred from the hydrogel depot, followed by Ex-4 dissociation from the ionic-nano-complexes and hydrolysis of ProCP. Given that the Ex-4 release occurs after the complex releases from the hydrogel, the periods of Ex-4 release and hydrogel maintenance may be similar. The present system showed a considerably prolonged Ex-4 release. Additionally, it showed potential as a long-term effective and reproducible antidiabetes treatment.