Controlled release of liraglutide using thermogelling polymers in treatment of diabetes.

Yipei Chen,Jiandong Ding,Yuzhuo Li,Qinghua Chen,Kun Li,Wenjia Shen,Lin Yu

doi:10.1038/srep31593

Abstract

In treatment of diabetes, it is much desired in clinics and challenging in pharmaceutics and material science to set up a long-acting drug delivery system. This study was aimed at constructing a new delivery system using thermogelling PEG/polyester copolymers. Liraglutide, a fatty acid-modified antidiabetic polypeptide, was selected as the model drug. The thermogelling polymers were presented by poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) and poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA). Both the copolymers were soluble in water, and their concentrated solutions underwent temperature-induced sol-gel transitions. The drug-loaded polymer solutions were injectable at room temperature and gelled in situ at body temperature. Particularly, the liraglutide-loaded PCGA-PEG-PCGA thermogel formulation exhibited a sustained drug release manner over one week in both in vitro and in vivo tests. This feature was attributed to the combined effects of an appropriate drug/polymer interaction and a high chain mobility of the carrier polymer, which facilitated the sustained diffusion of drug out of the thermogel. Finally, a single subcutaneous injection of this formulation showed a remarkably improved glucose tolerance of mice for one week. Hence, the present study not only developed a promising long-acting antidiabetic formulation, but also put forward a combined strategy for controlled delivery of polypeptide.

Highlights

Different from hydrophilic polypeptides such as exenatide and insulin, Lira is of relatively higher global hydrophobicity due to the introduction of 16-carbon fatty acid into the peptide backbone, resulting in the increased capacity of chain aggregation and non-covalent binding to other amphiphilic molecules[1,6]
PEG-poly(lactic acid-co-glycolic acid) (PLGA) were synthesized by us, and characterized via proton nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). 1H NMR spectra of both the polymers are presented in the Supplementary Fig. S1
The glass transition temperatures (Tg) of the two specimens were determined by differential scanning calorimetry (DSC)

Summary

Introduction

Among the polymers undergoing a thermo-reversible sol-gel transition in water, block copolymers composed of hydrophobic polyesters, such as poly(lactic acid-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly (ε-caprolactone-co-glycolic acid) (PCGA), and hydrophilic PEG are interesting and important because of the good safety profile and facile synthesis[33,34,35]. Their thermogelling properties and degradation behavior can be well-modulated by many molecular parameters including molecular weight (MW), MW distribution, polyester composition, block ratio, sequence of polyester block, as well as end group[25,26,28,35,36,37,38]. We evaluated the in vivo drug release and efficacy of an optimal Lira-loaded thermogel formulation

Objectives

Results

Discussion

Conclusion