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 anti-diabetes treatment. Protamine-conjugated polymer (ProCP) was developed to form ionic-nano-complexes with Ex-4, as 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 nano-particles 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-complex and hydrolysis of ProCP. Given that the Ex-4 release occurs after the complex release 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 anti-diabetes treatment.