期刊
BIOMATERIALS
卷 34, 期 11, 页码 2834-2842出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2013.01.013
关键词
Antidiabetic drug; Thermogel; Peptide delivery; Exenatide; Oral glucose tolerance test; Type II diabetes
资金
- NSF of China [50903021, 21034002, 91127028, 51273217]
- Chinese Ministry of Science and Technology (973 Program) [2009CB930000]
This study is aimed to develop a long-acting injectable formulation in treatment of type II diabetes. A glucoregulatozy polypeptide, exenatide (EXT), was chosen as the model drug, and an aqueous block copolymer system with a sol-gel transition upon the increase of temperature was selected as the delivery matrix of EXT. The thermoreversible hydrogel composed of poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was found to slower the degradation of the polypeptide to a large extent. However, the initial formulation in this study exhibited a significant drug burst effect, which is a common problem to load a hydrophilic small or medium-size polypeptide into a hydrogel. Zinc acetate was then introduced to slow down the EXT release by formation of insoluble Zn-EXT complexes in the thermogel matrix. Yet an incomplete release became another crucial problem, which is also common for peptide and protein delivery. The synergistic effect of three excipients (zinc acetate, PEG, and sucrose) under an appropriate condition overcame these two problems simultaneously, and the sustained release of drug lasted for 1 week. In vivo experiments via mice oral glucose tolerance tests demonstrated an improved glucose tolerance for 1 week after a single subcutaneous injection of the optimal EXT formulation. As a result, a formulation of antidiabetic drugs was set up, and meanwhile a strategy using synergistic excipients to adjust release profiles of peptides from hydrogels was put forward. (c) 2013 Elsevier Ltd. All rights reserved.
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