CN115389658A - 一种ma105佐剂中脂质含量的测定方法 - Google Patents
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Abstract
本发明涉及一种MA105佐剂中脂质成分含量的测定方法,脂质成分包括1,2‑二油酰基‑3‑三甲基氯化铵丙烷(DOTAP),二油酰基磷脂酰胆碱(DOPC)和胆固醇。所述的测定方法包括如下步骤:(1)样品预处理,包括:样品用乙醇溶液处理,溶解脂质体组分;离心取上清,去杂质;(2)色谱检测,包括:洗脱液为甲醇‑水‑TFA(93:7:0.15),洗脱液流速为0.15ml/min;使用外标法计算出DOTAP、DOPC及胆固醇含量。
Description
技术领域
本发明属于医药生物技术领域,具体的,涉及一种MA105佐剂中脂质含量的测定方法。
背景技术
本公司重组带状疱疹疫苗(CHO细胞)采用自制MA105佐剂系统,脂质成分包括1,2-二油酰基-3-三甲基氯化铵丙烷(DOTAP),二油酰基磷脂酰胆碱(DOPC)和胆固醇,脂质各组分含量为佐剂系统的核心质控指标。以此佐剂系统制备的重组亚单位疫苗中包含的组分较多,需要与其配套的标准含量测定方法,以监控佐剂质量,基于此,提出本发明。
本发明同时开发了一种同时测定重组带状疱疹疫苗(CHO细胞)中三种脂质体成分含量的高效液相色谱检测方法。
发明内容
本发明涉及一种MA105佐剂中脂质含量的测定方法,所述MA105佐剂为CN2021116270833所述方法制备得到的免疫佐剂;所述的脂质成分为1,2-二油酰基-3-三甲基氯化铵丙烷(DOTAP),二油酰基磷脂酰胆碱(DOPC)和胆固醇;所述的方法包括如下步骤:
(1)供试品预处理,所述预处理步骤包括:用无水乙醇溶解所述佐剂样品中的脂质体组分,将溶解后的脂质体组分置于离心机内,离心去除杂质,取上清液;
(2)使用高效液相色谱法检测各个脂质成分的含量;所述的高效液相色谱法的参数为:
色谱柱:十八烷基硅烷键合硅胶为填充剂,尺寸4.6×250mm,粒径5μm;
流动相:甲醇-水-TFA(93:7:0.15);
流动相流速:1.5ml/min;检测波长:205nm;柱温:50℃;进样量:20μl;采样时间:35min;
本色谱条件下,DOTAP、胆固醇及DOPC的出峰时间依次约为9~11min、19~21min、28~30min;
使用外标法以峰面积计算供试品溶液中DOTAP、DOPC及胆固醇的含量。
进一步的,
步骤(1)所述的样品预处理步骤中,样品取样量为1.5ml,无水乙醇用量为3.5ml;离心参数为:10000g离心10min;
步骤(2)所述的高效液相色谱法中,使用外标法计算出DOTAP、DOPC及胆固醇含量的方法为:
分别以对照品溶液中DOTAP、DOPC及胆固醇各自的峰面积,
按外标法以峰面积计算供试品溶液中DOTAP、胆固醇和DOPC的含量。
本发明的有益效果是:
(1)采用高效液相色谱法测定重组带状疱疹疫苗中MA105佐剂的脂质成分,具体包括DOTAP、DOPC及胆固醇的含量,通过无水乙醇处理并离心取上清的方式排除疫苗中其它组分对于检测产生的干扰;
(2)所述方法可以一次检测三种脂质体组分,可进行大批量检测,具有操作简单、灵敏度高、重复性强、准确度高等优势。
附图说明
图1、供试品的色谱图(图1中,DOTAP、胆固醇及DOPC的出峰时间依次为9.344min、19.974min、28.371min)。
图2、对照品的色谱图(图2中,DOTAP、胆固醇及DOPC的出峰时间依次为10.415min、20.370min、28.766min)。
具体实施方式
仪器设备
Agilent 1260高效液相色谱仪;
SPOLAR,4.6×250mm 5μm C18色谱柱分析柱,艾本德(上海)国际贸易有限公司:
5425R冷冻离心机
试剂:
无水乙醇(HPLC级),甲醇(HPLC级),TFA(HPLC级),实验用水为超纯水
样品:
重组带状疱疹疫苗,由我司(成都迈科康康生物科技有限公司)自行制备(参见CN2021116270833)。
实验流程:
1、样品预处理
溶解脂质体组分:准确吸取1.5ml供试品至5ml容量瓶,用无水乙醇定容至刻度,混匀。
去杂质:将溶解后的脂质体组分置于离心机内,10000g离心10min去除杂质,取上清液样品。
2、对照品贮备液及对照品溶液制备
对照品贮备液制备:分别称取相应质量的DOTAP、DOPC及胆固醇至对应的100mL容量瓶中,用无水乙醇溶解并定容,混匀,1.5ml/瓶分装,-20℃保存。
对照品溶液制备:取-20℃保存的DOTAP对照品贮备液、胆固醇对照品贮备液、DOPC对照品贮备液各1瓶,平衡至室温。准确量取DOTAP对照品贮备液、胆固醇对照品贮备液、DOPC对照品贮备液各1.0mL至同一10mL容量瓶中,加入3.0mL纯化水后,用无水乙醇定容至刻度,混匀。
3、高效液相色谱检测
高效液相色谱检测过程包括以下步骤:
打开高效液相色谱,连接色谱分析柱,设置检测参数如下:流动相流速:1.5ml/min;检测波长:205nm;柱温:50℃;进样量:20μl;分析时间:35min。
配制洗脱流动相甲醇-水-TFA(93:7:0.15),打开泵开关,令洗脱流动相在1.5ml/min流速下冲洗色谱柱及UV检测器。
当色谱工作站中显示压力数值无明显变化时,将预处理的对照品溶液组及样品组进样至高效液相色谱进行分析
4、结果计算
分别以对照品溶液中的DOTAP、胆固醇和DOPC峰面积平均值,按外标法以计算供试品溶液中DOTAP、胆固醇和DOPC的含量。
式中,
C1为对照品溶液的浓度:
V1为对照品溶液进样体积;
Ai为供试品溶液峰面积;
Vi为供试品溶液进样体积;
N为供试品溶液稀释倍数,N=10/3。
供试品报告结果为两次进样检测结果的平均值。
实施例1、检测方法的精密度-重复性
取同批供试品,依照上述实验流程步骤1至4平行制备六份样品并进行检测及结果计算,每份样品测试1次,收集DOTAP、DOPC和胆固醇的峰面积。
检测结果表明重复性中DOTAP、DOPC和胆固醇峰面积的RSD分别为2.2%、2.4%及2.1%。
实施例2、检测方法的精密度-中间精密度
另取实验例1中同批供试品,依照上述实验流程步骤1至4平行制备六份样品并进行检测,每份样品测试1次,收集DOTAP、DOPC和胆固醇的峰面积。
综合实验例1中收集的六份样品的DOTAP、DOPC和胆固醇的峰面积,总计十二份样品的DOTAP、DOPC和胆固醇的峰面积检测结果计算,DOTAP、DOPC和胆固醇峰面积的RSD分别为5.4%、5.6%及6.2%。
实施例3、检测方法的线性
取平衡至室温的DOTAP单一组分储备液,制备成浓度值分别为疫苗中DOTAP理论浓度值的50%、70%、80%、100%、120%及130%的6个DOTAP对照品溶液。
取平衡至室温的DOPC单一组分储备液,制备成浓度值分别为疫苗中DOPC理论浓度值的50%、70%、80%、100%、120%及130%的6个DOPC对照品溶液。
取平衡至室温的胆固醇单一组分储备液,制备成浓度值分别为疫苗中胆固醇理论浓度值的50%、70%、80%、100%、120%及130%的6个胆固醇对照品溶液。
将各组分的对照品溶液依照上述实验流程步骤1至4进行检测,每个浓度水平配制3份各进样一次。以各组分浓度为横坐标,各组分的峰值响应为纵坐标,绘制线性曲线,并计算相关系数和百分截距。
检测结果表明DOTAP、DOPC及胆固醇的线性曲线分别为
DOTAP:Y=1439.7X+2.9764,相关系数为0.999,百分截距为3.0%;
DOPC:Y=1325.03X-20.7440,相关系数为1.000,百分截距为-2.9%;
胆固醇:Y=6391.1X-16.861,、1.000及1.000,百分截距为3.0%、-2.9%及-1.6%。
实施例4、检测方法的准确度
精密配制疫苗中DOTAP理论浓度值70%、100%、130%浓度水平DOTAP、DOPC和胆固醇加样对照品各2份,分别精密加入等体积的样品,混匀,制备成低、中、高三个浓度的供试品溶液,依照上述实验流程步骤1至4进行检测,每份样品测定1次,代入同一序列中的标准曲线,计算样品终浓度,将测得量与理论浓度比较,计算回收率及RSD。
DOTAP组分的回收率为84%~105%(RSD%=6.6%);
DOPC组分的回收率为100%~107%(RSD%=2.7%);
胆固醇组分的回收率为98%~105%(RSD%=2.6%)。
最后需要说明的是,以上实施例仅用于帮助本领域技术人员理解本发明的实质,不用于限定本发明的保护范围。
Claims (5)
1.一种MA105佐剂中脂质含量的测定方法,所述MA105佐剂为CN2021116270833所述方法制备得到的免疫佐剂;所述的脂质成分为1,2-二油酰基-3-三甲基氯化铵丙烷(DOTAP),二油酰基磷脂酰胆碱(DOPC)和胆固醇;所述的方法包括如下步骤:
(1)供试品预处理,所述预处理步骤包括:用无水乙醇溶解所述佐剂样品中的脂质体组分,将溶解后的脂质体组分置于离心机内,离心去除杂质,取上清液;
(2)使用高效液相色谱法检测各个脂质成分的含量。
2.根据权利要求1所述的方法,其特征在于,所述的高效液相色谱法的参数为:
色谱柱:十八烷基硅烷键合硅胶为填充剂,尺寸4.6×250mm,粒径5μm;
流动相:甲醇-水-TFA的比例为93:7:0.15;
流动相流速:1.5ml/min;检测波长:205nm;柱温:50℃;进样量:20μl;采样时间:35min;
使用外标法以峰面积计算供试品溶液中DOTAP、DOPC及胆固醇的含量。
3.根据权利要求1或2所述的方法,其特征在于,所述的高效液相色谱法的条件下,DOTAP、胆固醇及DOPC的出峰时间依次约为9~11min、19~21min、28~30min。
4.根据权利要求1或2所述的方法,其特征在于,
步骤(1)所述的样品预处理步骤中,样品取样量为1.5ml,无水乙醇用量为3.5ml;离心参数为:10000g离心10min。
5.根据权利要求1或2所述的方法,其特征在于,步骤(2)所述的高效液相色谱法中,使用外标法计算出DOTAP、DOPC及胆固醇含量的方法为:分别以对照品溶液中DOTAP、DOPC及胆固醇各自的峰面积,按外标法以峰面积计算供试品溶液中DOTAP、胆固醇和DOPC的含量。
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CN112630365A (zh) * | 2020-11-27 | 2021-04-09 | 江苏东南纳米材料有限公司 | 一种高效液相色谱测定二肉豆蔻酰磷脂酰胆碱含量的方法 |
CN114324622A (zh) * | 2020-10-11 | 2022-04-12 | 北京泰德制药股份有限公司 | 一种改进的药物制剂中溶血磷脂酰胆碱的检测方法 |
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CN114324622A (zh) * | 2020-10-11 | 2022-04-12 | 北京泰德制药股份有限公司 | 一种改进的药物制剂中溶血磷脂酰胆碱的检测方法 |
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