Injectable and Thermosensitive Hydrogel Containing Liraglutide as a Long-Acting Antidiabetic System.

Diabetes, a global epidemic, has become a serious threat to public health. The present study is aimed at constructing an injectable thermosensitive PEG-polyester hydrogel formulation of liraglutide (Lira), a "smart" antidiabetic polypeptide, in the long-acting treatment of type 2 diabetes mellitus. A total of three thermosensitive poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) triblock copolymers with similar molecular weights but different ε-caprolactone-to-glycolide (CL-to-GA) ratios were synthesized. The polymer aqueous solutions exhibited free-flowing sols at room temperature and formed in situ hydrogels at body temperature. While the different bulk morphologies, stabilities of aqueous solutions, and the varying in vivo persistence time of hydrogels in ICR mice were found among the three copolymers, all of the Lira-loaded gel formulations exhibited a sustained drug release manner in vitro regardless of CL-to-GA ratios. The specimen with a powder form in the bulk state, a stable aqueous solution before heating, and an appropriate degradation rate in vivo was selected as the optimal carrier to evaluate the in vivo efficacy. A single injection of the optimal gel formulation showed a remarkable hypoglycemic efficacy up to 1 week in diabetic db/db mice. Furthermore, three successive administrations of this gel formulation within one month significantly lowered glycosylated hemoglobin and protected islets of db/db mice. As a result, a promising once-weekly delivery system of Lira was developed, which not only afforded long-term glycemic control but also significantly improved patient compliance.