CN109991334A - 一种测定血浆中洛索洛芬及其反式羟基体浓度的方法 - Google Patents
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Abstract
本发明公开了一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,包括以下步骤:储备液的配制、工作液的配制、标准曲线和质控样本的配制、样品预处理方法以及LC‑MS/MS分析;本法建立了一种简单、快速、耐用、灵敏度高和选择性好的用于同时测定EDTA‑K2抗凝人血浆中洛索洛芬及其活性代谢物反式‑OH血药浓度的LC‑MS/MS方法,该方法可用于EDTA‑K2抗凝人血浆中洛索洛芬和反式‑OH体洛索洛芬的同时定量分析,与荧光法和紫外检测法相比,本法更为灵敏,洛索洛芬的定量下限从0.31mg/mL和0.20mg/mL降低到了0.050mg/mL,反式‑OH体洛索洛芬的定量下限从0.31mg/mL和0.20mg/mL降低到了0.010mg/mL,同时分析时间大为缩短,从25min和30min缩短到了3.5min。
Description
技术领域
本发明涉及生物医药技术领域,具体为一种测定血浆中洛索洛芬及其反式羟基体浓度的方法。
背景技术
洛索洛芬钠为非甾体类消炎镇痛药,具显著的镇痛、抗炎、解热的作用,尤其具有较强的镇痛作用,作为新型的非甾体类消炎药,洛索洛芬钠与其他药物不同的是该药是一个前体药物,本身没有活性,经肝脏迅速转化成反式-OH体以后才有活性,因此可减少对胃肠道的损害。
目前,药物药代动力学以及生物等效性的研究均通过测定药物的药动学参数来评价,因此,血浆中洛索洛芬及其活性代谢物反式-OH的浓度测定对于洛索洛芬钠新药开发显得极为重要,洛索洛芬的代谢物除了反式-OH体外,还有顺式-OH体,两代谢物互为对映体,结构上的极为相似性决定了很难从色谱和质谱上将其分离;另外,洛索洛芬和反式-OH体在人血浆中浓度差异大,同时定量人血浆中洛索洛芬和反式-OH体浓度的生物分析方法鲜有报道,目前,能同时测定洛索洛芬及其活性代谢物反式-OH体血药浓度的定量分析方法主要以HPLC法为主,LC-MS/MS 法未有报道。
至今,有两种HPLC法能同时测定血浆中洛索洛芬及其活性代谢物反式-OH体的浓度,分别是荧光法和紫外检测法,这两种方法虽然达到了分离顺式-OH体和反式-OH体的目的,但前处理过程均很复杂,并且灵敏度低,线性范围窄,分析时间长,无法满足快速分析大批量样本的需要。
发明内容
本发明的目的在于提供一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,以解决背景技术提出的问题。
为实现上述目的,本发明提供如下技术方案:一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,包括以下步骤:
S1:储备液的配制:用甲醇:水(1:1,v:v)作为稀释液溶解洛索洛芬和反式-OH体洛索洛芬对照品,得浓度为400μg/mL的洛索洛芬标准曲线储备液(STD Stock-LSLF)和洛索洛芬质控储备液(QC Stock-LSLF),浓度为200μg/mL的反式-OH体洛索洛芬标准曲线储备液(STDStock-Trans-OH)和反式-OH体洛索洛芬质控储备液(QC Stock-Trans-OH);
S2:工作液的配制:标准曲线工作液以STD Stock-LSLF和STD Stock-Trans-OH为起始溶液,以甲醇:水(1:1,v:v)溶液为稀释溶剂逐级稀释得到同时含有洛索洛芬和反式-OH体洛索洛芬的各级标准曲线工作液;质控工作液以QC Stock-LSLF和QC Stock-Trans-OH为起始溶液,以甲醇:水(1:1,v:v)溶液为稀释溶剂逐级稀释得到同时含有洛索洛芬和反式-OH体洛索洛芬的各级质控工作液;
S3:标准曲线和质控样本的配制:吸取95%体积的EDTA-K2抗凝人空白血浆,加入5%体积上述各浓度的工作液,得到曲线样本和质控样本;
S4:样品预处理方法:取50μL血浆样品于96孔板中,加入内标溶液30μL(氘代洛索洛芬2μg/mL),加入沉淀剂甲醇 450μL,震荡5min,高速离心(4000rpm)15分钟,取上清200μL 于另一96 深孔板中,高速离心(4000 rpm)3分钟后进LC-MS/MS 分析,进样体积1μL;
S5:LC-MS/MS分析:LC-MS/MS系统由Q-Trap 5500 型三重四极杆串联质谱仪(ABSciex)、高压泵(LC-30AD)、在线脱气机(DGU-20A-5R)、自动进样器(SIL-30AC)、柱温箱(CTO-20A)及控制器CBM-20Alite组成;柱温箱和进样器的温度分别设定为40℃和4℃,使用型号为Welch,Ultimate XP-C18, 5.0 μm, 2.1*100 mm的色谱柱作为分离柱,乙腈:水:乙酸(40:60:1,v:v:v)作为流动相,等度条件,流速为0.60mL/min分离分析物,分析时间为3.5分钟;离子源的极性为正模式,离子监测方式为多反应监测(MRM),经过电参数优化后,去簇电压(DP)分别为-80、50、55V,碰撞电压(CE)分别为-18、-11和-19V,数据采集系统为Analyst1.6.3。
优选的,所述S5中高压泵的型号为LC-30AD、在线脱气机的型号为DGU-20A-5R、自动进样器的型号为SIL-30AC、柱温箱的型号为CTO-20A、控制器的型号为CBM-20Alite。
优选的,所述S5中洛索洛芬、反式-OH体洛索洛芬以及内标(氘代洛索洛芬)的离子对分别为245.1-83.1、247.1-203.1和249.1-87.1。
与现有技术相比,本发明的有益效果是:本法建立了一种简单、快速、耐用、灵敏度高和选择性好的用于同时测定EDTA-K2抗凝人血浆中洛索洛芬及其活性代谢物反式-OH血药浓度的LC-MS/MS方法,该方法可用于EDTA-K2抗凝人血浆中洛索洛芬和反式-OH体洛索洛芬的同时定量分析,与荧光法和紫外检测法相比,本法更为灵敏,洛索洛芬的定量下限从0.31mg/mL和0.20mg/mL降低到了0.050mg/mL,反式-OH体洛索洛芬的定量下限从0.31mg/mL和0.20mg/mL降低到了0.010mg/mL,同时分析时间大为缩短,从25min和30min缩短到了3.5min。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明提供一种技术方案:一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,包括以下步骤:
S1:储备液的配制:用甲醇:水(1:1,v:v)作为稀释液溶解洛索洛芬和反式-OH体洛索洛芬对照品,得浓度为400μg/mL的洛索洛芬标准曲线储备液(STD Stock-LSLF)和洛索洛芬质控储备液(QC Stock-LSLF),浓度为200μg/mL的反式-OH体洛索洛芬标准曲线储备液(STDStock-Trans-OH)和反式-OH体洛索洛芬质控储备液(QC Stock-Trans-OH);
S2:工作液的配制:标准曲线工作液以STD Stock-LSLF和STD Stock-Trans-OH为起始溶液,以甲醇:水(1:1,v:v)溶液为稀释溶剂逐级稀释得到同时含有洛索洛芬和反式-OH体洛索洛芬的各级标准曲线工作液;质控工作液以QC Stock-LSLF和QC Stock-Trans-OH为起始溶液,以甲醇:水(1:1,v:v)溶液为稀释溶剂逐级稀释得到同时含有洛索洛芬和反式-OH体洛索洛芬的各级质控工作液;
S3:标准曲线和质控样本的配制:吸取95%体积的EDTA-K2抗凝人空白血浆,加入5%体积上述各浓度的工作液,得到曲线样本和质控样本;
S4:样品预处理方法:取50μL血浆样品于96孔板中,加入内标溶液30μL(氘代洛索洛芬2μg/mL),加入沉淀剂甲醇 450μL,震荡5min,高速离心(4000rpm)15分钟,取上清200μL 于另一96 深孔板中,高速离心(4000 rpm)3分钟后进LC-MS/MS 分析,进样体积1μL;
S5:LC-MS/MS分析:LC-MS/MS系统由Q-Trap 5500 型三重四极杆串联质谱仪(ABSciex)、高压泵(LC-30AD)、在线脱气机(DGU-20A-5R)、自动进样器(SIL-30AC)、柱温箱(CTO-20A)及控制器CBM-20Alite组成;柱温箱和进样器的温度分别设定为40℃和4℃,使用型号为Welch,Ultimate XP-C18, 5.0 μm, 2.1*100 mm的色谱柱作为分离柱,乙腈:水:乙酸(40:60:1,v:v:v)作为流动相,等度条件,流速为0.60mL/min分离分析物,分析时间为3.5分钟;离子源的极性为正模式,离子监测方式为多反应监测(MRM),经过电参数优化后,去簇电压(DP)分别为-80、50、55V,碰撞电压(CE)分别为-18、-11和-19V,数据采集系统为Analyst1.6.3。
进一步地,S5中高压泵的型号为LC-30AD、在线脱气机的型号为DGU-20A-5R、自动进样器的型号为SIL-30AC、柱温箱的型号为CTO-20A、控制器的型号为CBM-20Alite。
进一步地,S5中洛索洛芬、反式-OH体洛索洛芬以及内标(氘代洛索洛芬)的离子对分别为245.1-83.1、247.1-203.1和249.1-87.1。
本实施例中工作液的浓度设置如下:
本实施例中曲线样本和质控样本的浓度设置如下:
本实施例的方法验证如下:
按照中国药典 2015 版《生物样品定量分析方法验证指导原则》的要求,对本方法进行了验证,验证内容包括选择性、标准曲线、定量下限、精密度和准确度、提取回收率、基质效应、稀释效应、残留效应、稳定性;经过验证,本法达到了中国药典 2015 版《生物样品定量分析方法验证指导原则》的技术要求,可用于EDTA-K2抗凝人血浆中洛索洛芬和反式-OH体洛索洛芬的同时定量分析,与荧光法和紫外检测法相比,本法更为灵敏,洛索洛芬的定量下限从0.31mg/mL和0.20mg/mL降低到了0.050mg/mL,反式-OH体洛索洛芬的定量下限从0.31mg/mL和0.20mg/mL降低到了0.010mg/mL;同时,分析时间大为缩短,从25min和30min缩短到了3.5min。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (3)
1.一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,其特征在于,包括以下步骤:
S1:储备液的配制:用甲醇:水(1:1,v:v)作为稀释液溶解洛索洛芬和反式-OH体洛索洛芬对照品,得浓度为400μg/mL的洛索洛芬标准曲线储备液(STD Stock-LSLF)和洛索洛芬质控储备液(QC Stock-LSLF),浓度为200μg/mL的反式-OH体洛索洛芬标准曲线储备液(STDStock-Trans-OH)和反式-OH体洛索洛芬质控储备液(QC Stock-Trans-OH);
S2:工作液的配制:标准曲线工作液以STD Stock-LSLF和STD Stock-Trans-OH为起始溶液,以甲醇:水(1:1,v:v)溶液为稀释溶剂逐级稀释得到同时含有洛索洛芬和反式-OH体洛索洛芬的各级标准曲线工作液;质控工作液以QC Stock-LSLF和QC Stock-Trans-OH为起始溶液,以甲醇:水(1:1,v:v)溶液为稀释溶剂逐级稀释得到同时含有洛索洛芬和反式-OH体洛索洛芬的各级质控工作液;
S3:标准曲线和质控样本的配制:吸取95%体积的EDTA-K2抗凝人空白血浆,加入5%体积上述各浓度的工作液,得到曲线样本和质控样本;
S4:样品预处理方法:取50μL血浆样品于96孔板中,加入内标溶液30μL(氘代洛索洛芬2μg/mL),加入沉淀剂甲醇 450μL,震荡5min,高速离心(4000rpm)15分钟,取上清200μL 于另一96 深孔板中,高速离心(4000 rpm)3分钟后进LC-MS/MS 分析,进样体积1μL;
S5:LC-MS/MS分析:LC-MS/MS系统由Q-Trap 5500 型三重四极杆串联质谱仪(ABSciex)、高压泵(LC-30AD)、在线脱气机(DGU-20A-5R)、自动进样器(SIL-30AC)、柱温箱(CTO-20A)及控制器CBM-20Alite组成;柱温箱和进样器的温度分别设定为40℃和4℃,使用型号为Welch,Ultimate XP-C18, 5.0 μm, 2.1*100 mm的色谱柱作为分离柱,乙腈:水:乙酸(40:60:1,v:v:v)作为流动相,等度条件,流速为0.60mL/min分离分析物,分析时间为3.5分钟;离子源的极性为正模式,离子监测方式为多反应监测(MRM),经过电参数优化后,去簇电压(DP)分别为-80、50、55V,碰撞电压(CE)分别为-18、-11和-19V,数据采集系统为Analyst1.6.3。
2.根据权利要求1所述的一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,其特征在于:所述S5中高压泵的型号为LC-30AD、在线脱气机的型号为DGU-20A-5R、自动进样器的型号为SIL-30AC、柱温箱的型号为CTO-20A、控制器的型号为CBM-20Alite。
3.根据权利要求1所述的一种测定血浆中洛索洛芬及其反式羟基体浓度的方法,其特征在于:所述S5中洛索洛芬、反式-OH体洛索洛芬以及内标(氘代洛索洛芬)的离子对分别为245.1-83.1、247.1-203.1和249.1-87.1。
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CN110261531A (zh) * | 2019-07-27 | 2019-09-20 | 湖南九典制药股份有限公司 | 一种洛索洛芬或其钠盐中有关物质的检测方法 |
CN110261531B (zh) * | 2019-07-27 | 2021-02-19 | 湖南九典制药股份有限公司 | 一种洛索洛芬或其钠盐中有关物质的检测方法 |
CN111879875A (zh) * | 2020-08-06 | 2020-11-03 | 武汉伯瑞恒医药科技有限公司 | 一种测定血浆中阿糖胞苷和阿糖尿苷的方法 |
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