Controlled release of liraglutide using thermogelling polymers in treatment of diabetes

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.

Narrow molecular weight margins for the thermogelling property of polyester–polyether block copolymers in aqueous solutions

“…Previous reports have indicated that GPC often yields higher values than those determined by 1 H‐NMR, and this effect has been observed by other researchers for PEG‐PLGA polymers. For example, it was reported that M n by GPC was 31% higher than that obtained by 1 H‐NMR for PLGA‐PEG‐PLGA . The GPC‐ES results relative to the NMR data in this study varied across the polymers.…”

Structures and Applications of Thermoresponsive Hydrogels and Nanocomposite-Hydrogels Based on Copolymers with Poly (Ethylene Glycol) and Poly (Lactide-Co-Glycolide) Blocks

“…As examples of using peptide/protein drugs, a delivery system for liraglutide (Lira), a fatty acid- As for the drugs for drug delivery systems, peptide/protein drugs and genes should be considered because their use as therapeutic agents has increased considerably in recent years. As examples of using peptide/protein drugs, a delivery system for liraglutide (Lira), a fatty acid-modified antidiabetic polypeptide, for the treatment of diabetes was investigated by Chen et al [44], and controlled release of growth hormone-releasing peptide 6 (GHRP-6) for the growth of rex rabbits was investigated by Guan et al [45]. In order to prolong the bioactivity of peptide/protein drugs, an incorporation into microparticles and a complex formation were performed.…”

Biodegradable Thermogelling Polymers

“…Chen et al developed a sustainable Liraglutide (drug for Type 2 diabetes) release system consisting of poly(ε‐caprolactone‐co‐glycolic acid)‐poly(ethylene glycol)‐poly(ε‐caprolactone‐co‐glycolic acid) (PCGA–PEG–PCGA) thermogels. They reported a sustained release for 1 week in mice, attributed to the amphiphilicity of Liraglutide and the high chain mobility of the PCGA part at body temperature . The delayed diffusion of drug was due to hydrophobic interactions between C16 fatty side chain of Lira and the hydrophobic cores of copolymer micelles.…”