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Article(id=1208491465488053015, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208491433888166474, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2021-0569, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1618761600000, receivedDateStr=2021-04-19, revisedDate=1624550400000, revisedDateStr=2021-06-25, acceptedDate=null, acceptedDateStr=null, onlineDate=1766056418057, onlineDateStr=2025-12-18, pubDate=1631376000000, pubDateStr=2021-09-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766056418057, onlineIssueDateStr=2025-12-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766056418057, creator=13701087609, updateTime=1766056418057, updator=13701087609, issue=Issue{id=1208491433888166474, tenantId=1146029695717560320, journalId=1189982191388893191, year='2021', volume='56', issue='9', pageStart='2325', pageEnd='2596', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766056410524, creator=13701087609, updateTime=1766137069648, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208829742833332989, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208491433888166474, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208829742833332990, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1208491433888166474, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2346, endPage=2351, ext={EN=ArticleExt(id=1208491465941037901, articleId=1208491465488053015, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Analysis of monosaccharide composition and monosaccharide ratio in propylene glycol alginate sodium sulphate drugs by high performance anion exchange chromatograghy -pulsed amperometric detection, columnId=1208491461608321532, journalTitle=Acta Pharmaceutica Sinica, columnName=Special Reports: Bioanalysis for Drug, runingTitle=null, highlight=null, articleAbstract=

The paper aims to establish the method to determine the monosaccharide composition and monosaccharide ratio in propylene glycol alginate sodium sulphate (PSS). Samples were hydrolyzed with trifluoroacetic acid, neutralized with sodium hydroxide solution after the reaction conditions for sample pretreatment were optimized via orthogonal analysis. A high performance anion exchange chromatograghy (HPAEC) coupled with pulsed amperometric detector (PAD) was performed on a CarboPac®PA20, using 200 mmol·L-1 sodium hydroxide solution and 1 mol·L-1 sodium acetate solution as mobile phase. The established HPAEC-PAD method was validated by testing the linear relationship, precision and accuracy, and showed exclusive, sensitive, rapid and wide use. The monosaccharide composition of PSS from different manufacture can be accurately determined with great significance for the structural identification of PSS.

, correspAuthors=Hui-hong FAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2021 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Yue WANG, Xin-tong CHEN, Zhen-hua LI, Yu-juan SONG, Hui-hong FAN), CN=ArticleExt(id=1208491466830230461, articleId=1208491465488053015, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=高效阴离子交换-脉冲安培法分析藻酸双酯钠的单糖组成和比例, columnId=1208491461948060192, journalTitle=药学学报, columnName=专题报道：药物生物分析, runingTitle=null, highlight=null, articleAbstract=

藻酸双酯钠为类肝素药物，临床上主要用于治疗缺血性心、脑血管疾病，本研究建立藻酸双酯钠的单糖组成和单糖比例测定方法。通过正交分析的方法确定了样品前处理最佳反应条件，样品经过三氟乙酸水解，氢氧化钠溶液中和，采用高效阴离子交换-脉冲安培检测法，使用CarboPac®PA20阴离子交换柱分离，流动相采用200 mmol·L-1氢氧化钠溶液和1 mol·L-1醋酸钠溶液梯度洗脱，采用脉冲安培检测器，金工作电极，Ag/AgCl参比电极进行检测。对方法的线性、准确度和精密度进行了考察，结果表明该方法具有简单、专属、灵敏、应用范围广等特点。对不同企业藻酸双酯钠原料药进行了测定，能够准确测定藻酸双酯钠单糖组成，为藻酸双酯钠的结构鉴定提供单糖信息。

, correspAuthors=范慧红, authorNote=null, correspAuthorsNote=
*范慧红, Tel/Fax: 86-10-53851585, E-mail:
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Experiment No. Column
A B AB C AC BC D AD BD CD Combination
1 1 1 1 1 1 1 1 1 1 1 A1B1C1D1
2 1 1 1 1 1 1 2 2 2 2 A1B1C1D2
3 1 1 1 2 2 2 1 1 1 2 A1B1C2D1
4 1 1 1 2 2 2 2 2 2 1 A1B1C2D2
5 1 2 2 1 1 2 1 1 2 1 A1B2C1D1
6 1 2 2 1 1 2 2 2 1 2 A1B2C1D2
7 1 2 2 2 2 1 1 1 2 2 A1B2C2D1
8 1 2 2 2 2 1 2 2 1 1 A1B2C2D2
9 2 1 2 1 2 1 1 2 1 1 A2B1C1D1
10 2 1 2 1 2 1 2 1 2 2 A2B1C1D2
11 2 1 2 2 1 2 1 2 1 2 A2B1C2D1
12 2 1 2 2 1 2 2 1 2 1 A2B1C2D2
13 2 2 1 1 2 2 1 2 2 1 A2B2C1D1
14 2 2 1 1 2 2 2 1 1 2 A2B2C1D2
15 2 2 1 2 1 1 1 2 2 2 A2B2C2D1
16 2 2 1 2 1 1 2 1 1 1 A2B2C2D2
), ArticleFig(id=1208491474451280441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491465488053015, language=CN, label=Table 1, caption=

L16 (215) orthogonal experimental design of hydrolysis conditions of propylene glycol alginate sodium sulphate (PSS). A: Temperature; B: Acid solution concentration; C: Time; D: Volume ratio of sample solution and acid solution

, figureFileSmall=null, figureFileBig=null, tableContent=
Experiment No. Column
A B AB C AC BC D AD BD CD Combination
1 1 1 1 1 1 1 1 1 1 1 A1B1C1D1
2 1 1 1 1 1 1 2 2 2 2 A1B1C1D2
3 1 1 1 2 2 2 1 1 1 2 A1B1C2D1
4 1 1 1 2 2 2 2 2 2 1 A1B1C2D2
5 1 2 2 1 1 2 1 1 2 1 A1B2C1D1
6 1 2 2 1 1 2 2 2 1 2 A1B2C1D2
7 1 2 2 2 2 1 1 1 2 2 A1B2C2D1
8 1 2 2 2 2 1 2 2 1 1 A1B2C2D2
9 2 1 2 1 2 1 1 2 1 1 A2B1C1D1
10 2 1 2 1 2 1 2 1 2 2 A2B1C1D2
11 2 1 2 2 1 2 1 2 1 2 A2B1C2D1
12 2 1 2 2 1 2 2 1 2 1 A2B1C2D2
13 2 2 1 1 2 2 1 2 2 1 A2B2C1D1
14 2 2 1 1 2 2 2 1 1 2 A2B2C1D2
15 2 2 1 2 1 1 1 2 2 2 A2B2C2D1
16 2 2 1 2 1 1 2 1 1 1 A2B2C2D2
), ArticleFig(id=1208491474577109579, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491465488053015, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Experiment number Combination Peak area
G M
1 A1B1C1D1 5.113 9.248
2 A1B1C1D2 5.023 9.754
3 A1B1C2D1 14.449 24.586
4 A1B1C2D2 14.329 24.623
5 A1B2C1D1 7.998 14.366
6 A1B2C1D2 8.957 15.376
7 A1B2C2D1 13.372 22.735
8 A1B2C2D2 12.757 25.164
9 A2B1C1D1 12.602 21.731
10 A2B1C1D2 12.882 22.988
11 A2B1C2D1 10.885 25.633
12 A2B1C2D2 6.107 20.045
13 A2B2C1D1 13.302 29.965
14 A2B2C1D2 9.761 21.765
15 A2B2C2D1 5.539 18.822
16 A2B2C2D2 2.735 16.272
), ArticleFig(id=1208491474707133017, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491465488053015, language=CN, label=Table 2, caption=

L16 (215) orthogonal experimental results of hydrolysis conditions of PSS

, figureFileSmall=null, figureFileBig=null, tableContent=
Experiment number Combination Peak area
G M
1 A1B1C1D1 5.113 9.248
2 A1B1C1D2 5.023 9.754
3 A1B1C2D1 14.449 24.586
4 A1B1C2D2 14.329 24.623
5 A1B2C1D1 7.998 14.366
6 A1B2C1D2 8.957 15.376
7 A1B2C2D1 13.372 22.735
8 A1B2C2D2 12.757 25.164
9 A2B1C1D1 12.602 21.731
10 A2B1C1D2 12.882 22.988
11 A2B1C2D1 10.885 25.633
12 A2B1C2D2 6.107 20.045
13 A2B2C1D1 13.302 29.965
14 A2B2C1D2 9.761 21.765
15 A2B2C2D1 5.539 18.822
16 A2B2C2D2 2.735 16.272
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Source of variation G M
Sum of squares df Mean square F value P value Sum of squares df Mean square F value P value
A 4.188 1 4.188 3.522 0.119 0.5575 1 61.502 11.142 0.021*
B 3.035 1 3.035 2.553 0.171 4.5734 1 2.144 0.388 0.560
C 1.286 1 1.286 1.081 0.346 1.7289 1 66.781 12.098 0.018*
D 7.168 1 7.168 6.028 0.058 0.9477 1 7.698 1.395 0.291
AB 14.648 1 14.648 12.319 0.017* 0.7662 1 10.567 1.914 0.225
AC 163.199 1 163.199 137.249 < 0.001*** 127.0766 1 256.338 46.440 0.001**
BC 15.532 1 15.532 13.063 0.015* 5.9486 1 54.929 9.951 0.025*
AD 7.530 1 7.530 6.333 0.053 2.4590 1 22.709 4.114 0.098
BD 0.105 1 0.105 0.088 0.779 5.7834 1 0.775 0.140 0.723
CD 2.194 1 2.194 1.845 0.232 0.0002 1 0.004 0.001 0.980
Error 5.945 5 1.189
Total variation 224.831 15
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The orthogonal experiment variance analysis of the influence of four hydrolysis conditions on the area of M and G peaks (*P < 0.05; **P < 0.01; ***P < 0.001)

, figureFileSmall=null, figureFileBig=null, tableContent=
Source of variation G M
Sum of squares df Mean square F value P value Sum of squares df Mean square F value P value
A 4.188 1 4.188 3.522 0.119 0.5575 1 61.502 11.142 0.021*
B 3.035 1 3.035 2.553 0.171 4.5734 1 2.144 0.388 0.560
C 1.286 1 1.286 1.081 0.346 1.7289 1 66.781 12.098 0.018*
D 7.168 1 7.168 6.028 0.058 0.9477 1 7.698 1.395 0.291
AB 14.648 1 14.648 12.319 0.017* 0.7662 1 10.567 1.914 0.225
AC 163.199 1 163.199 137.249 < 0.001*** 127.0766 1 256.338 46.440 0.001**
BC 15.532 1 15.532 13.063 0.015* 5.9486 1 54.929 9.951 0.025*
AD 7.530 1 7.530 6.333 0.053 2.4590 1 22.709 4.114 0.098
BD 0.105 1 0.105 0.088 0.779 5.7834 1 0.775 0.140 0.723
CD 2.194 1 2.194 1.845 0.232 0.0002 1 0.004 0.001 0.980
Error 5.945 5 1.189
Total variation 224.831 15
), ArticleFig(id=1208491475038483078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491465488053015, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. Sample Factory code Sample code M/G ratio
1 PSS API T T-1 1.67
2 PSS API W Q4-1 1.95
3 PSS API W W2-1z 2.23
4 PSS API W W2-2 2.38
5 PSS API W M3-2 1.57
6 PSS API D H-5 1.55
7 PSS API D J6-1 1.64
8 PSS API D HN-Y3 1.57
9 PSS API D WZT-7 1.73
10 PSS API Q Y20-4 2.54
11 PSS API Q HN-Y5 2.24
12 PSS API Q Q7-1P 2.26
13 PSS API Q BD2-3 2.13
), ArticleFig(id=1208491475181089429, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1208491465488053015, language=CN, label=Table 4, caption=

The M/G ratio results of PSS samples

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Sample Factory code Sample code M/G ratio
1 PSS API T T-1 1.67
2 PSS API W Q4-1 1.95
3 PSS API W W2-1z 2.23
4 PSS API W W2-2 2.38
5 PSS API W M3-2 1.57
6 PSS API D H-5 1.55
7 PSS API D J6-1 1.64
8 PSS API D HN-Y3 1.57
9 PSS API D WZT-7 1.73
10 PSS API Q Y20-4 2.54
11 PSS API Q HN-Y5 2.24
12 PSS API Q Q7-1P 2.26
13 PSS API Q BD2-3 2.13
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高效阴离子交换-脉冲安培法分析藻酸双酯钠的单糖组成和比例
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王悦 1, 2 , 陈欣桐 1, 2 , 李振华 1 , 宋玉娟 1, 2 , 范慧红 1, 2, *
药学学报 | 专题报道：药物生物分析 2021,56(9): 2346-2351
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药学学报 | 专题报道：药物生物分析 2021, 56(9): 2346-2351
高效阴离子交换-脉冲安培法分析藻酸双酯钠的单糖组成和比例
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王悦1, 2, 陈欣桐1, 2, 李振华1, 宋玉娟1, 2, 范慧红1, 2, *
作者信息
  • 1.中国食品药品检定研究院, 北京 102629
  • 2.化学药品质量研究与评价重点实验室, 北京 102629

通讯作者:

*范慧红, Tel/Fax: 86-10-53851585, E-mail:
Analysis of monosaccharide composition and monosaccharide ratio in propylene glycol alginate sodium sulphate drugs by high performance anion exchange chromatograghy -pulsed amperometric detection
Yue WANG1, 2, Xin-tong CHEN1, 2, Zhen-hua LI1, Yu-juan SONG1, 2, Hui-hong FAN1, 2, *
Affiliations
  • 1. National Institute for Food and Drug Control, Beijing 102629, China
  • 2. NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drugs, Beijing 102629, China
出版时间: 2021-09-12 doi: 10.16438/j.0513-4870.2021-0569
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摘要
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藻酸双酯钠为类肝素药物，临床上主要用于治疗缺血性心、脑血管疾病，本研究建立藻酸双酯钠的单糖组成和单糖比例测定方法。通过正交分析的方法确定了样品前处理最佳反应条件，样品经过三氟乙酸水解，氢氧化钠溶液中和，采用高效阴离子交换-脉冲安培检测法，使用CarboPac®PA20阴离子交换柱分离，流动相采用200 mmol·L-1氢氧化钠溶液和1 mol·L-1醋酸钠溶液梯度洗脱，采用脉冲安培检测器，金工作电极，Ag/AgCl参比电极进行检测。对方法的线性、准确度和精密度进行了考察，结果表明该方法具有简单、专属、灵敏、应用范围广等特点。对不同企业藻酸双酯钠原料药进行了测定，能够准确测定藻酸双酯钠单糖组成，为藻酸双酯钠的结构鉴定提供单糖信息。

阴离子交换  /  脉冲安培法  /  糖组成  /  藻酸双酯钠  /  甘露糖醛酸  /  古罗糖醛酸

The paper aims to establish the method to determine the monosaccharide composition and monosaccharide ratio in propylene glycol alginate sodium sulphate (PSS). Samples were hydrolyzed with trifluoroacetic acid, neutralized with sodium hydroxide solution after the reaction conditions for sample pretreatment were optimized via orthogonal analysis. A high performance anion exchange chromatograghy (HPAEC) coupled with pulsed amperometric detector (PAD) was performed on a CarboPac®PA20, using 200 mmol·L-1 sodium hydroxide solution and 1 mol·L-1 sodium acetate solution as mobile phase. The established HPAEC-PAD method was validated by testing the linear relationship, precision and accuracy, and showed exclusive, sensitive, rapid and wide use. The monosaccharide composition of PSS from different manufacture can be accurately determined with great significance for the structural identification of PSS.

anion exchange chromatograghy  /  pulsed amperometric detection  /  monosaccharide composition  /  propylene glycol alginate sodium sulphate  /  mannuronic acid  /  guluronic acid
王悦, 陈欣桐, 李振华, 宋玉娟, 范慧红. 高效阴离子交换-脉冲安培法分析藻酸双酯钠的单糖组成和比例. 药学学报, 2021 , 56 (9) : 2346 -2351 . DOI: 10.16438/j.0513-4870.2021-0569
Yue WANG, Xin-tong CHEN, Zhen-hua LI, Yu-juan SONG, Hui-hong FAN. Analysis of monosaccharide composition and monosaccharide ratio in propylene glycol alginate sodium sulphate drugs by high performance anion exchange chromatograghy -pulsed amperometric detection[J]. Acta Pharmaceutica Sinica, 2021 , 56 (9) : 2346 -2351 . DOI: 10.16438/j.0513-4870.2021-0569
正文
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藻酸双酯钠(propylene glycol alginate sodium sulfate, PSS, 图 1) 是以海带提取物褐藻酸钠为原料, 经丙酯化和磺化等结构修饰步骤得到的一种海洋低分子硫酸多糖化合物, 其糖链具有较强聚阴离子性质, 为类肝素药物, 临床上主要用于缺血性心、脑血管疾病的治疗[1, 2]。
藻酸双酯钠的化学名称是褐藻酸丙二醇酯硫酸酯钠盐, 分子骨架由β-D-甘露糖醛酸(D-mannuronic acid, M) 和α-L-古罗糖醛酸(L-guluronic acid, G) 通过1→4糖苷键连接而成[3], 在一个褐藻酸钠分子中, 两种糖醛酸单体无序排列, 某一个糖链片段可能是只含有M或G的连续嵌段, 也可能是由MG交替连接构成嵌段共聚物, 不同来源的海藻酸或褐藻酸钠(如巨藻、海带等), 其G和M的比例有所不同。M和G的结构只有C5位置上的羟基位置不同, 但聚合后的糖链空间构象差异很大, 因此M、G比例不同的样品, 理化和药效性质有很大差异, 高G的样品糖链刚性较强, 且具有较高的出血风险, 因此需对产品的单糖比例加以控制[3, 4]。此外, 测定单糖组成以及M和G的比例有助于对藻酸双酯钠样品的结构确证及鉴别, 还可以在一定程度上间接显示不同厂家产品起始物料的种属差别, 该方法的建立对类似品种结构分析也有借鉴意义。
高效阴离子交换-脉冲安培法可直接对几乎所有单糖和大部分寡糖、低聚糖等进行分析, 与液相色谱、毛细管电泳、气相色谱法相比, 该方法解决了梯度洗脱条件在示差折光或低波长紫外检测器中应用的困难, 而且具有无需衍生化处理、灵敏度高、不使用有毒、有机溶剂的优点, 对糖的检出限可达到pmol级。方法采用适当的水解方式将糖链进行降解, 在强碱性流动相(pH > 12) 中, 水解后的糖醛酸形成氧负离子进行阴离子交换, 根据羟基在金电极表面发生氧化还原反应产生的电流大小实现糖的检测[5]。
本研究建立了三氟乙酸(trifluoroacetic acid, TFA) 水解糖链, HPAEC-PAD法测定藻酸双酯钠单糖组成和比例的方法, 该方法可对藻酸双酯钠进行特异性鉴别, 还可以通过M、G的比值评估藻酸双酯钠起始物料质量的稳定性, 在一定程度上保证产品的质量和药效稳定。
材料与方法
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材料  本实验所用样品包括不同生产企业的藻酸双酯钠原料药13批(其中厂家T生产样品1批, 样品编号T1; 厂家W生产样品4批, 样品编号Q4-1、W2-1z、W2-2、M3-2; 厂家D生产样品4批, 编号H-5、J6-1、HN-Y3、WZT-7; 厂家Q生产样品4批, 编号Y20-4、HN-Y5、Q7-1P、BD2-3)。
仪器与试剂  ICS3000型离子色谱仪(美国戴安公司), 配有溶液组织器EO, 单四元梯度泵SP (带脱气装置), 色谱箱组合DC, 电化学检测器ED, 自动加样器AS, 色谱工作站chromeleon 6.80 SP1, 11250-RT型氮吹仪(美国OA公司)。
M对照品(河北百灵威科技有限公司, 98.0%, 批号L5C0T05), G对照品(河北百灵威科技有限公司, 98.0%, 批号LMC0R64)。50%氢氧化钠溶液(美国Akfa Aesar公司), 醋酸钠(美国Dionex公司), TFA (美国Sigma公司), 氢氧化钠(国药集团, 分析纯)。
色谱条件  色谱柱: Carbopac PA20 (3 mm×150 mm, 6 μm); 保护住: Carbopac PA20G(3 mm×50 mm, 6 μm); 淋洗液: A为去离子水、B为200 mmol·L-1氢氧化钠溶液、C为1 mol·L-1醋酸钠溶液, 梯度洗脱: 0~10 min (70% A, 10% B, 20% C), 10.1~25 min (60% B, 40% C), 25.1~30 min (70% A, 10% B, 20% C); 流速为0.45 mL·min-1; 脉冲安培检测器, 金工作电极, Ag/AgCl参比电极, 四电位波形[6]; 柱温: 30 ℃; 进样量: 5 μL。
糖醛酸对照品溶液的制备  分别取M、G对照品, 配制成糖醛酸混标溶液(1 mg·mL-1), 取0.5、1、2、5和8 mL分别置100 mL量瓶中, 加水稀释至刻度, 制得浓度为0.005, 0.01、0.02、0.05和0.08 mg·mL-1糖醛酸混标溶液线性系列溶液。
供试品溶液的制备  取藻酸双酯钠原料药, 精密称定, 加水制得约含藻酸双酯钠1 mg·mL-1溶液; 加入适量的酸溶液加热彻底水解糖链, 取出后氮吹10 min; 用20%氢氧化钠溶液中和至弱碱性后全部转移至25 mL量瓶中, 加水定容, 经0.45 μm滤膜过滤, 取续滤液作为供试品溶液, 4 h内完成进样。
糖链水解条件考察[7-9]  以M、G糖醛酸峰面积、未水解完全糖峰面积为考察指标, 对糖链的水解方式进行考察。取供试品溶液适量, 按单因素实验分别考察硫酸溶液(0.3和0.5 mol·L-1) 和TFA溶液、反应温度(100、120和140 ℃)、TFA溶液浓度(2、4和6 mol·L-1)、水解时间(30、60和90 min) 对糖链水解效果的影响。
在单因素实验基础上, 选取反应温度(A)、酸溶液浓度(B)、水解时间(C) 以及V样品溶液∶V酸溶液体积比(D) 4个因素, 每个因素取两个水平。A: 120和140 ℃; B: 4和6 mol·L-1; C: 30和60 min; D: V样品溶液∶V酸溶液= 3∶1.5和3∶3, 按正交表L16 (215) (表 1) 进行实验组合, 并考察4个因素的全一级交互作用。
准确度考察  取已知M、G比例供试品溶液3 mL, 平行9份。按照最佳水解条件将供试品溶液水解、氮吹、中和至弱碱性后, 分别按照待测样品M、G含量的80%、100%和120%加入3个浓度水平的糖醛酸对照品溶液, 每个浓度平行制备3份, 同时计算原料药中两种糖醛酸的回收率。
精密度考察  取对照品溶液(0.02 mg·mL-1) 5 μL, 注入离子色谱仪, 记录色谱图, 连续进样6针。计算G和M峰面积(peak area, A) 的相对标准偏差(relative standard deviation, RSD)。
线性范围考察  取糖醛酸混标溶液线性系列溶液0.005、0.01、0.02、0.05和0.08 mg·mL-1分别进样, 考察方法对M、G两种糖醛酸的测定线性范围。
结果
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1 糖链水解条件单因素考察
1.1 水解方式
分别考察了TFA、硫酸溶液对糖链的水解情况, 对比不同水解用酸的色谱图后发现, 和硫酸水解效果相比, TFA作为水解用酸时样品色谱图中未水解完全的寡糖峰较少, 得到的G和M峰面积更大, 在一定程度上说明水解更为完全(图 2); 此外, 硫酸水解后的样品色谱图中会出现多个杂质峰, 峰面积随着水解时间的延长显著增大, 推测与硫酸具有的强氧化性有关。高浓度硫酸根对于离子色谱的分离系统会造成一定的干扰, 进样前应尽量去除, 和TFA相比, 前处理的步骤比较复杂, 因此选用TFA作为水解用酸更加简便。
1.2 水解温度
采用4 mol·L-1 TFA溶液分别在100、120和140 ℃温度条件下水解60 min, M、G峰面积在120 ℃达到最大值后下降, 可见温度对水解产生了较大的影响, 温度较低时水解不完全, 而温度过高会破坏水解得到的单糖组分, 因此采用120 ℃作为水解温度。
1.3 酸溶液浓度
在120 ℃温度水平下分别以2、4和6 mol·L-1 TFA反应60 min, 结果显示G峰面积基本保持不变, M峰面积在4 mol·L-1 TFA条件下达到最大值后趋于稳定, 可见水解所用酸溶液浓度对水解效果影响较小。但是2 mol·L-1 TFA不能充分将糖链水解完全, 考虑到在水解完全的情况下尽量选用温和的水解条件以保护单糖醛酸, 因此初步确定采用4 mol·L-1 TFA溶液进行水解。
1.4 水解时间
在120 ℃温度水平下采用4 mol·L-1 TFA分别水解30、60和90 min, M、G峰面积在60 min时达到峰值并下降, 初步确定60 min为最佳水解时间。
2 4因素2水平水解条件正交实验考察
按G和M峰面积进行方差分析(表 2、3) 可知, 各因素影响大小排序为温度×时间 > 浓度×时间 > 温度×浓度 > 温度×体积比, 选择峰面积最大的交互作用作为优选条件, 确定G峰面积达到最大时的水解条件为120 ℃、4 mol·L-1、60 min, 体积比为3∶3。
3 方法学考察
3.1 准确度
在80%、100%和120%加标水平下, G的回收率在88%~102%内(n = 9, RSD = 6.1%); M的回收率在98%~105%内(n = 9, RSD = 3.8%)。在剧烈水解条件下, 糖醛酸不稳定, 因此本次回收率实验中, 没有在样品的水解步骤前加入糖醛酸标样, 而且和M相比, G在酸溶液中更加不稳定, 因此G的回收率略低于M。
3.2 精密度
计算连续进样6针的G和M峰面积的RSD分别为1.89%和0.93%。
3.3 专属性
糖混标溶液(0.02 mg·mL-1) 的色谱图中M、G的分离度大于20, 分离度满足要求。
3.4 线性范围
分别以G和M的峰面积A为纵坐标, 对照品溶液的质量浓度c (mg·mL-1) 为横坐标绘制标准曲线, G线性方程为A = 865.17c + 0.473 2, R2为0.999 8, M的线性方程为A = 984.64c - 0.175 8, R2为0.999 7, 表明M和G在0.005~0.08 mg·mL-1浓度内线性关系良好。
3.5 样品溶液稳定性
供试品溶液在分别放置0、1、2、3、4、5和12 h后进样分析, 考察完成前处理后的供试品溶液的放置稳定性, 结果显示样品溶液在4 h内稳定, 12 h后峰面积明显下降, 因此应在制备完成后4 h内完成进样分析。
4 样品测定
4个厂家生产的藻酸双酯钠原料共13批样品的测定结果(表 4) 显示, 受试样品M/G比值均大于1.5, 但Q企业和W企业的部分样品M/G均在2.0以上, T企业和D企业样品的M/G比值均在1.5~1.7之间, 提示不同原料药生产企业的M/G比值有一定差别。
讨论
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藻酸双酯钠是我国首个自主研发的海洋多糖一类新药, 在临床上有着广泛的应用, 对该产品的二次开发以及以褐藻胶为母体结构的其他药物研发也是目前的研究热点之一。对其结构进行准确的测定和表征是更好地研究其药理活性、稳定工艺和产品质量的基础。
多糖的降解方法主要包括物理降解法(超声波和辐射降解)、化学降解法(酸、碱、氧化、自由基降解等) 和生物降解法(酶法) 等, 每种降解方式的原理、降解强度、作用位点和产物结构都不相同, 应根据不同的目的选择适用的降解方式。其中酸降解法操作简便、速度快、对糖链水解效果较为彻底, 而且能够保持糖环本身的结构特点, 比较适用于藻酸双酯钠单糖组成的分析, 但酸性多糖糖链的降解难度要大于中性糖, 因此对降解条件的控制要求更高。之前有研究表明TFA会使G糖醛酸降解[7], 推荐使用稀硫酸溶液对藻酸双酯钠糖链进行降解。本文对比了TFA溶液和稀硫酸溶液的降解效果以及G糖峰面积的变化, 发现在适当的水解条件下, 可以最大程度保护单糖不被破坏, 两种酸溶液的水解效果基本相当。但是采用具有强氧化性的硫酸溶液降解时, 会产生较多杂质峰, 而且使用离子色谱进行分析时, 硫酸根会对测定产生较大的影响, 需要尽量除尽硫酸根的干扰。而TFA可采用氮吹的方式将其除尽, 处理较为简便, 因此推荐使用TFA进行水解。
单糖化合物在阴离子交换柱上的洗脱顺序依次为氨基糖、中性糖、酸性糖, 因此对于糖醛酸的分析, 需要在保证分离效果的前提下加大洗脱强度。寡糖和多聚糖在阴离子交换柱上的保留行为主要与分子大小(聚合度) 和形状(连接位置和构型) 有关, 藻酸双酯钠水解不完全的寡糖色谱峰在M、G后面被洗脱, 随着水解强度的增加, 寡糖峰面积逐渐下降, 因此除了考察M、G峰面积外, 水解不完全的糖峰个数、面积(图 2) 也是作为水解程度的辅助判断因素。
液相色谱、气相色谱是分离单糖、低聚糖等常用的分离技术[10, 11], 通常需将样品进行柱前衍生化处理, 产生疏水性、紫外吸收或挥发性化合物后进行检测。对于基体复杂, 前处理步骤较多的样品来说, 会有多种因素影响衍生化效果, 衍生物的稳定性也会影响测定结果, 并且检测器的非选择性容易造成测定误差。高效阴离子交换-脉冲安培法可用于糖类的直接分离测定, 该方法具有不用衍生、灵敏度高、准确度高、不使用有机溶剂的优点[12-15]。
褐藻中所含褐藻胶在生物合成过程中其M单糖随着成熟而逐渐部分地在分子水平上转变成G, 其在分子中转变的量和位置等依海藻的种类、生态环境、季节有明显的变化, 而且海藻不同组织部位的M/G比值也不同[16]。此外, 褐藻胶糖链聚M、聚G嵌段的理化性质、对酸碱的敏感度, 溶解性等也不相同。受试各原料药生产企业的M/G比值有所差异, 提示各生产企业所用原材料或生产工艺有所区别, 但同一生产企业的产品结果比较稳定, 说明当原材料和生产工艺确定, M/G比值是可以控制在一个稳定的范围内的。藻酸双酯钠单糖组成与药理活性直接相关, 有报道称高G含量与临床出血倾向直接相关, 因此应该在原料药质量标准中对M/G比例进行相应的控制。本文方法可实现对藻酸双酯钠原料药以及起始物料褐藻酸盐的单糖组成检测, 使企业可以更加注意原材料的选择和生产工艺。保证药品的临床效果, 减少不良反应发生。
作者贡献: 王悦负责实验设计和实施、结果分析、文章构思和撰写工作; 陈欣桐负责实验的实施和数据的整理工作; 李振华负责部分实验实施工作; 宋玉娟负责材料的收集和整理; 范慧红负责文章的审核。
利益冲突: 本文研究内容无任何利益冲突。
基金
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  • 国家重大新药创制课题资助项目(2015ZX09303001)
  • 海洋药物国家重点实验室开放性课题资助项目(LMDBKF201806)
文献
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2021年第56卷第9期
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doi: 10.16438/j.0513-4870.2021-0569
  • 接收时间：2021-04-19
  • 首发时间：2025-12-18
  • 出版时间：2021-09-12
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  • 收稿日期：2021-04-19
  • 修回日期：2021-06-25
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国家重大新药创制课题资助项目(2015ZX09303001)
海洋药物国家重点实验室开放性课题资助项目(LMDBKF201806)
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    1.中国食品药品检定研究院, 北京 102629
    2.化学药品质量研究与评价重点实验室, 北京 102629

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*范慧红, Tel/Fax: 86-10-53851585, E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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