In vitro and in vivo evaluation of a once-weekly formulation of an antidiabetic peptide drug exenatide in an injectable thermogel.
In vitro and in vivo evaluation of a once-weekly formulation of an antidiabetic peptide drug exenatide in an injectable thermogel.
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DOI：
10.1002/jps.23735
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发表时间：
2013-11
影响因子：
3.8
通讯作者：
Lin Yu;Kun Li;Xiaojun Liu;Chang-qing Chen;Yongchu Bao;Tianyuan Ci;Qinghua Chen;Jiandong Ding-Jiandong-Din
中科院分区：
文献类型：
--
作者：
Lin Yu;Kun Li;Xiaojun Liu;Chang-qing Chen;Yongchu Bao;Tianyuan Ci;Qinghua Chen;Jiandong Ding-Jiandong-Din
以聚乳酸-羟基乙酸-聚乙二醇-聚乳酸-羟基乙酸（PLGA-PEG-PLGA）三嵌段共聚物为骨架材料，制备了一种可注射的热凝胶，用于制备抗糖尿病多肽艾塞那肽（EXT）的长效释药系统。皮下注射含2 mg/mL EXT和3种药用辅料（1.25 wt %醋酸锌、5 wt %PEG 200和5 wt %蔗糖）的最佳凝胶制剂，并研究其药代动力学。体外和体内释放曲线均显示EXT持续释放超过1周。将EXT制剂皮下注射到db/db小鼠中后，血糖水平维持在正常范围内长达7天，同时体重的生长受到抑制。体内结果与体外EXT释放曲线一致。此外，与每天两次注射EXT溶液18天相比，两次注射凝胶制剂导致更高的血液胰岛素水平和更低的糖化血红蛋白血浆浓度。组织学观察表明，由于施用凝胶制剂，胰岛得到保护。因此，PLGA-PEG-PLGA热凝胶为EXT每周一次的递送系统提供了极好的候选物，并且最佳的EXT制剂不仅提供了治疗功效，而且还改善了患者依从性。
An injectable thermogel composed of poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was evaluated as the matrix of a long-acting drug delivery system of exenatide (EXT), an antidiabetic peptide. The optimal gel formulation containing 2 mg/mL EXT and three pharmaceutical excipients (1.25 wt % zinc acetate, 5 wt % PEG200, and 5 wt % sucrose) was injected subcutaneously, and its pharmacokinetics was investigated. Both in vitro and in vivo release profiles exhibited a sustained release of EXT over 1 week. After a subcutaneous injection of the EXT formulation into db/db mice, the blood glucose level was maintained in a normal range up to 7 days and meanwhile the growth of body weight was suppressed. The in vivo results were consistent with the in vitro EXT-release profile. Moreover, twice injections of the gel formulation resulted in the higher blood insulin level and lower plasma concentration of glycosylated hemoglobin compared with twice-daily injections of an EXT solution for 18 days. Histological observations manifested the protection of islet due to administration of the gel formulation. Therefore, the PLGA-PEG-PLGA thermogel provided an excellent candidate for a once-weekly delivery system of EXT, and the optimal EXT formulation not only afforded therapeutic efficacy but also improved patient compliance.