药物中磺酸酯类基因毒性杂质研究进展

引用本文: 刘雪薇, 厉程, 韩海云, 张文鹏, 陈东英. 药物中磺酸酯类基因毒性杂质研究进展[J]. 色谱, 2018, 36(10): 952-961. doi: 10.3724/SP.J.1123.2018.05004 shu

Citation: LIU Xuewei, LI Cheng, HAN Haiyun, ZHANG Wenpeng, CHEN Dongying. Advances on genotoxic impurities of sulfonate esters in pharmaceuticals[J]. Chinese Journal of Chromatography, 2018, 36(10): 952-961. doi: 10.3724/SP.J.1123.2018.05004 shu

药物中磺酸酯类基因毒性杂质研究进展

1.
中国科学院上海药物研究所, 上海 201203;
2.
中国科学院大学, 北京 100049;
3.
上海药品审评核查中心, 上海 201203
基金项目:
中国科学院药物创新研究院自主部署科研项目（CASIMM0120163011）.

摘要: 该文概述了近10年来有关药物中基因毒性杂质监管指南的完善历程与相关检测方法的研究进展。介绍了基因毒性杂质从早期的完全避免到目前的阶段化毒理学关注阈值（TTC）的风险控制理念以及各主流监管机构的具体要求。作为一类重要的基因毒性杂质，磺酸酯主要来源于磺酸及衍生物与低级醇（如甲醇、乙醇、异丙醇等）之间发生的副反应，具有化学结构类型多样化的特点。该文较为详尽地介绍了磺酸酯的形成机理和文献所采用的液相色谱法和气相色谱法，并对色谱方法的选择、预处理方式、衍生化方法及相应痕量水平的灵敏度和回收率等进行了评述。由此期望为合理控制药物中磺酸酯类基因毒性杂质，为保证药物的质量安全性提供有益的指导意见。

关键词:

English

Advances on genotoxic impurities of sulfonate esters in pharmaceuticals

1.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
2.
University of Chinese Academy of Sciences, Beijing 100049, China;
3.
Shanghai Center for Drug Evaluation and Inspection, Shanghai 201203, China
Received Date: 03 May 2018
Fund Project:
Chinese Academy of Sciences for Innovative Pharmaceutical Project (No. CASIMM0120163011).

Abstract: This article reviews the refinement of regulatory guidelines and progress of research on the control of genotoxic impurities in pharmaceuticals in the last decade. It outlines advances in the regulatory requirements for genotoxic impurities from strict avoidance to the currently accepted concept of threshold of toxicological concern (TTC), which is based on risk control considerations. Specific control limits, which are required by predominant administrative regulatory agencies, such as U. S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH), etc. Sulfonate esters, an important class of potential genotoxic impurities, are usually generated by side-reactions between sulfonic acids or their derivatives and relative low molecular mass alcohols, such as methanol, ethanol, and isopropanol. The resulting sulfonate esters are characterized with diverse chemical structures. Reaction mechanisms of the formation of sulfonate esters and various strategies to control them have been schematically described. A detailed summary has been given for the analytical methodology developed using high performance liquid chromatography (HPLC) and gas chromatography (GC) to determine trace amounts of sulfonate esters in pharmaceuticals. Furthermore, we have comprehensively discussed the options for the chromatographic methods, sample pretreatments, and derivatization methods, as well as each method's sensitivity and recovery at trace level. This review intended to provide constructive suggestions for the rational control of sulfonate esters in pharmaceuticals to ensure their clinical safety.

Key words:

1. [1] Mcgovern T, Jacobson-kram D. TrAC-Trends Anal Chem, 2006, 25(8):790
2. [2] Greene N, Dobo K L, Kenyon M O, et al. Regul Toxicol Pharmacol, 2015, 72(2):335
3. [3] Reddy A V B, Jaafar J, Umar K, et al. J Pharm Biomed Anal, 2015, 38(5):764
4. [4] Teasdale A, Elder D P. TrAC-Trends Anal Chem, 2018, 101:66
5. [5] European Medicines Agency. Annual Report of the European Agency for the Evaluation of Medicinal Products. (2002-12-18)[2018-05-01].http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500016741&mid=WC0b01ac058009a3dc
6. [6] European Medicines Agency. Guideline on the Limits of Genotoxic Impurities. (2006-06-28)[2018-05-01]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500002903&mid=WC0b01ac058009a3dc
7. [7] Müller L, Mauthe R J, Riley C M, et al. Regul Toxicol Pharmacol, 2006, 44(3):198
8. [8] Ma L, Ma Y N, Chen Z, et al. Chinese Journal of New Drugs, 2014, 23(18):2106 马磊, 马玉楠, 陈震, 等. 中国新药杂志, 2014, 23(18):2106
9. [9] Galloway S M, Reddy M V, McGettigan K, et al. Regul Toxicol Pharmacol, 2013, 66(3):326
10. [10] European Medicines Agency. Question & Answers on the CHMP Guideline on the Limits of Genotoxic Impurities. (2010-01-14)[2018-05-01]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500002907&mid=WC0b01ac058009a3dc
11. [11] U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Genotoxic and Carcinogenic Impurities in Drug Substances and Products:Recommended Approaches.[2018-05-01]. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm528107.html
12. [12] The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). M7 (R1):Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic.[2018-05-01]. http://www.ich.org/products/guidelines/multidisciplinary/article/multidisciplinary-guidelines.html
13. [13] Elder D P, Delaney E D, Teasdale A, et al. J Sep Sci, 2010, 99(7):2948
14. [14] Thomson Reuters Integrity.[2018-02-07]. https://integrity.thomson-pharma.com/integrity/xmlxsl
15. [15] European Directorate for the Quality of Medicines and Healthcare. Pharmeuropa.[2018-05-01]. http://pharmeuropa. edqm.eu/PharmeuropaArchives
16. [16] Müller L, Gocke E, Lavé T, et al. Toxicol Lett, 2009, 190(3):317
17. [17] Szekely G, Amores de Sousa M C, Gil M, et al. Chem Rev, 2015, 115(16):8182
18. [18] Glowienke S, Frieauff W, Allmendinger T, et al. Mutat Res Genet Toxicol Environ Mutagen, 2005, 581(1):23
19. [19] U. S. National Library of Medicine, National Institutes of Health, Chemical Carcinogenesis Research Information System (CCRIS).[2018-02-22]. https://toxnet.nlm.nih.gov/newtoxnet/ccris.htm
20. [20] Teasdale A, Eyley S C, Delaney E, et al. Org Process Res Dev, 2009, 13(3):429
21. [21] Teasdale A, Delaney E J, Eyley S C, et al. Org Process Res Dev, 2010, 14(4):999
22. [22] Snodin D, Teasdale A. Org Process Res Dev, 2015, 19(11):1465
23. [23] Zheng F, Hua G D. Chinese Journal of Modern Applied Pharmacy, 2017, 34(3):396 郑飞, 华国栋. 中国现代应用药学, 2017, 34(3):396
24. [24] Taylor G E, Gosling M, Pearce A. J Chromatogr A, 2006, 1119:231
25. [25] Zhang W, Chen Y H, Zheng F. Chinese Journal of Pharmaceuticals, 2015, 46(12):1334 张薇, 陈夷花, 郑枫. 中国医药工业杂志, 2015, 46(12):1334
26. [26] Qian J Q, Zhang Y F, Wang J, et al. Chinese Journal of Pharmaceutical Analysis, 2017, 37(11):1994 钱建钦, 张云峰, 王建, 等. 药物分析杂志, 2017, 37(11):1994
27. [27] Kakadiya P R, Reddy B P, Singh V, et al. J Pharm Biomed Anal, 2011, 55(2):379
28. [28] Chen C, Yin L, Wang Y, et al. Journal of Shenyang Pharmaceutical University, 2015, 32(9):695 陈成, 尹璐, 王媛, 等. 沈阳药科大学学报, 2015, 32(9):695
29. [29] Guo T, Shi Y Y, Zheng L, et al. J Chromatogr A, 2014, 1355:73
30. [30] Cappiello A, Famiglini G, Palma P, et al. J Chromatogr A, 2012, 1255:286
31. [31] An J G, Sun M J, Bai L, et al. J Pharm Biomed Anal, 2008, 48(3):1006
32. [32] Zhou J, Xu J, Zheng X Y, et al. J Sep Sci, 2017, 40:3414
33. [33] Li W Y. J Chromatogr A, 2004, 1046:297
34. [34] Zheng F, Hua G D. Journal of International Pharmaceutical Research, 2016, 43(3):575 郑飞, 华国栋. 国际药学研究杂志, 2016, 43(3):575
35. [35] Ramakrishna K, Raman N, Rao K M V N, et al. J Pharm Biomed Anal, 2008, 46(4):780
36. [36] Zhang C, Huang L, Wu Z, et al. J Sep Sci, 2016, 39(18):3558
37. [37] Colón I, Richoll S M. J Pharm Biomed Anal, 2005, 39(3/4):477
38. [38] Wollein U, Schramek N. Eur J Pharm Sci, 2012, 45(1/2):201
39. [39] Lee C R, Guivarch F, Van Dau C N, et al. Analyst, 2003, 128(7):857
40. [40] Alzaga R, Ryan R W, Taylor-Worth K, et al. J Pharm Biomed Anal, 2007, 45(3):472
41. [41] European Pharmacopoeia Commission. European Pharmacopoeia, 9th ed. Council of Europe, Strasbourg:2017
42. [42] Fan D, Tu J S. Progress in Pharmaceutical Sciences, 2014, 38(3):220 范达, 涂家生. 药学进展, 2014, 38(3):220
43. [43] Liu X W, Zhang W P, Chen D Y, J Pharm Biomed Anal, 2018, 155:104

扫一扫看文章

计量

PDF下载量: 31
文章访问数: 1219
HTML全文浏览量: 353

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

药物中磺酸酯类基因毒性杂质研究进展

English

Advances on genotoxic impurities of sulfonate esters in pharmaceuticals

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

计量

通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

药物中磺酸酯类基因毒性杂质研究进展

English

Advances on genotoxic impurities of sulfonate esters in pharmaceuticals

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

计量

文章相关

通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs