我们的网站为什么显示成这样?

可能因为您的浏览器不支持样式,您可以更新您的浏览器到最新版本,以获取对此功能的支持,访问下面的网站,获取关于浏览器的信息:

|本期目录/Table of Contents|

去大分子注射用聚山梨酯80的安全性提高(PDF)

《云南中医学院学报》[ISSN:1000-2723/CN:53-1048/R]

期数:
2021年01期
页码:
1-16
栏目:
实验研究
出版日期:
2021-06-28

文章信息/Info

Title:
The Safety of Polysorbate 80 for Injection was Improved by Removing Macromolecular Substances
文章编号:
1000-2723(2021)01-0001-16
作者:
夏恒段金连李月邱玲韩依伦陈欢黎勇坤段为钢
(云南中医药大学云南省中医药学分子生物学重点实验室,云南 昆明 650500)
Author(s):
XIA Heng DUAN Jinlian LI Yue QIU Ling HAN Yilun CHEN Huan LI Yongkun DUAN Weigang
(Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan Universityof Chinese Medicine, Kunming 650500, China)
关键词:
注射用聚山梨酯80大分子杂质类过敏反应器官毒性临界胶束浓度增溶
Keywords:
polysorbate 80 for injection macromolecular impurities anaphylactoid reactions organic toxicity critical micelle concentration solubilization
分类号:
R285.5
DOI:
10.19288/j.cnki.issn.1000-2723.2021.01.001
文献标识码:
-
摘要:
目的发现并证明大分子杂质是影响注射用聚山梨酯80安全性的因素,测定去大分子聚山梨酯80的主要物理常数。方法 理论分子量为1 310 Da的注射用聚山梨酯80原液用超滤膜得到组分A(>100 kDa)、组分B(10~100 kDa)和组分C(<10 kDa)。各组分冷冻干燥后获得各组分在原液中的比例。各组分用生理盐水配置成10%浓度,按照《中国药典》2015年版进行豚鼠过敏和类过敏反应检查,同时用昆明种小鼠进行静脉注射的5 d毒性检查,并观察5 d恢复期。按照《中国药典》方法检测各组分的物理常数。结果 分子量大于10 kDa的组分占85%以上,聚山梨酯80原液、组分A和组分B能诱发过敏和类过敏反应,而组分C反应阴性。组分A和B能在5 d恢复期减慢体重恢复;根据器官指数变化,聚山梨酯80原液能导致小鼠肝脏、肾脏、脾脏和肺轻度损伤,5 d后仍不能完全恢复;其中肝肾损伤得到了显微病理支持。其中组分C对各器官的影响最小,且容易恢复。去大分子后(组分C),其增溶能力、粘度、密度、吸收光谱、pH和颗粒大小得到了不同程度的改善。结论 注射用聚山梨酯80中含有大量的大分子杂质,这些杂质是导致器官毒性、过敏和类过敏反应的重要因素,去除大分子杂质能提高其安全性。
Abstract:
Objective The major aim of the present study were to prove that macromolecular impurities in polysorbate 80 for injection are a risk factor, and determine the main physical indexes of polysorbate 80 free of macromolecular substances. Methods The original polysorbate 80 for injection, with a theoretical molecular weight of 1 310 Da, was treated with ultra-filters to obtain component A (>100 kDa), B (10~100 kDa), and C (<10 kDa). The components were lyophilized to obtain their contents.Each component was prepared with normal saline at a concentration of 10%,anaphylactic and anaphylactoid reactions on guinea pigs that may be caused by the original polysorbate 80 and its components were recorded according to Chinese Pharmacopoeia of 2015th edition. Kunming mice were intravenously injected with them for 5 days administration and 5 days’ recovery to observe their organic toxicity. Results The proportion of substances with a molecular weight above 10 kDa in the original polysorbate 80 was above 85%. The original polysorbate 80 and its component A and B resulted in positive reactions in both anaphylactic and anaphylactoid guinea pigs, while component C didnt. In Kunming mice, component A and B caused an obvious retard of body weight increase in the 5 days’ recovery. The original polysorbate 80 and its components caused mild but significant toxicity in the liver, kidney, spleen, and lung at organ indexes both in 5 days administration and recovery. Their mild toxicity on the liver and kidney was verified by histological assay. However, toxicity caused by component C was much milder and more recoverable. The physicochemical constants of component C, including solubilization capacity, viscosity, density, absorption spectrum, pH, and particle size were improved. Conclusion All the results suggested that the main substances in polysorbate 80 for injection are macromolecular impurities that are an important risk factor to cause anaphylactoid reactions and organic toxicity, and macromolecular impurity removal improved its safety and physicochemical constants.

参考文献/References

[1] FUJIMURA S, WATANABE A. Generic antibiotics in Japan[J]. J Infect Chemother, 2012, 18(4): 421-427.
[2] LI M Z, DU Y A, WANG Q Y, et al. Risk assessment of supply chain for pharmaceutical excipients with AHP-fuzzy comprehensive evaluation[J]. Drug Dev Ind Pharm, 2016, 42(4): 676-684.
[3] ZHANG M Y. Advance of polysorbate 80 for injection accessories[J]. Zhongguo Zhongyao Zazhi, 2011, 36(14): 1910-1915.
[4] MIYAMOTO K, SHIMADA T, SAWAMOTO K, et al. Disposition kinetics of taxanes in peritoneal dissemination[J]. Gastroenterol Res Pract,2012, 2012: 963403.
[5] CHEN C C, WU C C. Acute hepatotoxicity of intravenous amiodarone: case report and review of the literature[J]. Am J Ther, 2016, 23(1): e260-e263.
[6] TAN Z G, CHAO Z M, SUI Y, et al. Effect of Tween 80 on Yuxingcao injection and volatile oils from Houttuynia cordata[J]. Zhongguo Zhongyao Zazhi, 2011, 36(2): 175-179.
[7] CHAN A L, HSIEH H J, HSIEH Y A, et al. Fatal amiodarone-induced hepatotoxicity: A case report and literature review[J]. Int J Clin Pharmacol Ther, 2008, 46(2): 96-101.
[8] MI Y N, PING N N, XIAO X, et al. The severe adverse reaction to vitamin k1 injection is anaphylactoid reaction but not anaphylaxis[J]. PLoS One, 2014, 9(3): e90199.
[9] XU Y P, LIU C Y, DOU D Q, et al. Evaluation of anaphylactoid constituents in vitro and in vivo[J]. Int Immunopharmacol, 2017, 43: 79-84.
[10] LI Y, DUAN J L, XIA H, et al. Macromolecular substances as a dangerous factor in traditional Chinese medicine injections were determined by size-exclusive chromatography[J]. Toxicol Res, 2020, 9(3): 323-330.
[11] DUAN J L, LI Y, ZHANG L M, et al. Identification and removal of microbial contaminats from herbal drugs for traditional Chinese medicine injection[J]. Yunnan Zhongyi Xueyuan Xuebao, 2019, 42(4): 1-8.
[12] ZHANG R, WANG Y, JI Y, et al. Quantitative analysis of oleic acid and three types of polyethers according to the number of hydroxy end groups in Polysorbate 80 by hydrophilic interaction chromatography at critical conditions[J]. J Chromatogr A, 2013, 1272: 73-80.
[13] CHINESE PHARMACOPOEIA COMMITTEE. Chinese Pharmacopoeia, 2015 edition, Book 4[M]. Beijing: China Medical Science Press, 2015: 159.
[14] LAVKUSH BHAISARE M, PANDEY S, SHAHNAWAZ KHAN M, et al. Fluorophotometric determination of critical micelle concentration(CMC) of ionic and non-ionic surfactants with carbon dots via Stokes shift[J]. Talanta, 2015, 132: 572-578.
[15] SCHOLZ N, BEHNKE T, RESCH-GENGER U. Determination of the critical micelle concentration of neutral and ionic surfactants with fluorometry, conductometry, and surface tension-a method comparison[J]. J Fluoresc, 2018, 28(1): 465-476.
[16] CHINESE PHARMACOPOEIA COMMITTEE. Chinese Pharmacopoeia, 2015 edition, Book 4[M]. Beijing: China Medical Science Press, 2015: 624-625.
[17] HAN Y Y, DU J H, LI J, et al. Quantification of the organic acids in hawthorn wine: A comparison of two HPLC methods[J]. Molecules, 2019, 24(11): 2150.
[18] WIERSINGA W J, LEOPOLD S J, CRANENDONK D R, et al. Host innate immune responses to sepsis[J]. Virulence, 2014, 5(1): 36-44.
[19] COORS E A, SEYBOLD H, MERK H F, et al. Polysorbate 80 in medical products and nonimmunologic anaphylactoid reactions[J]. Ann Allergy Asthma Immunol, 2005, 95(6): 593-599.
[20] PAUDEL R, DOGRA P, SUMAN S, et al. Acute liver and renal failure: A rare adverse effect exclusive to intravenous form of amiodarone[J]. Case Rep Crit Care, 2016, 2016: 5232804.

备注/Memo

备注/Memo:
收稿日期: 2020-12-26 基金项目: 国家自然科学基金(81560645);云南省中医药联合专项重点项目(2018FF001-002) 第一作者简介: 夏恒(1995-),男,在读硕士研究生,研究方向:中药注射剂安全性提高。 △通信作者: 段为钢, E-mail: deardwg@126.com
更新日期/Last Update: 1900-01-01