CN113768871A - 一种羟基红花黄色素a的中药制剂 - Google Patents
一种羟基红花黄色素a的中药制剂 Download PDFInfo
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- CN113768871A CN113768871A CN202111113834.XA CN202111113834A CN113768871A CN 113768871 A CN113768871 A CN 113768871A CN 202111113834 A CN202111113834 A CN 202111113834A CN 113768871 A CN113768871 A CN 113768871A
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Abstract
本发明公开了一种羟基红花黄色素A的中药制剂,本发明通过大量实验来筛选可提高羟基红花黄色素A的最佳天然深共熔溶剂,结果表明,采用90%葡萄糖‑氯化胆碱(90%GCH)在水中溶解,可显著增加羟基红花黄色素A口服生物利用度。与水组相比,90%GCH组的羟基红花黄色素A相对口服生物利用度为326.93%。单向肠灌流实验表明,90%GCH组空肠内羟基红花黄色素A吸收率比H2O组增加2.95倍。药效学评价表明,90%GCH羟基红花黄色素A在高脂饮食诱导的肥胖大鼠中更有效地减轻体重和纠正脂肪性肝炎和血脂异常。90%GCH不仅能改善羟基红花黄色素A的口服吸收,还能增加其抗肥胖作用,取得了显著的技术效果。
Description
技术领域
本发明涉及一种中药制剂,具体涉及羟基红花黄色素A的中药制剂。
背景技术
红花(CarthamustinctoriusL.)属于菊科,几千年来一直被用作食品添加剂和天然色素。红花(干燥的小花)广泛应用于治疗心脏代谢性疾病。羟基红花黄色素A(HSYA)是红花中具有代表性的水溶性醌式查尔酮C-糖苷色素,具有多种诱导的抗心代谢性疾病的药理活性。红花黄色素注射液是从红花中提取的黄色色素,含量不低于70%的HSYA,是销量前列的中药产品之一。除此之外,我国临床上仅使用HSYA氯化钠注射液,但仍有许多不良反应,如过敏反应和轻度肾毒性。因此,HSYA口服制剂急需开发。
尽管HSYA具有显著的治疗潜力,但其化学性质不稳定和口服生物利用度较低严重阻碍了其临床应用。根据生物医学分类系统,HSYA属于高溶解度、低渗透性的III类药物。据报道,HSYA在大鼠体内的口服生物利用度仅为1.2%(H.Zhang,J.Guo,L.Huang,et al.,Pharmacokinetics ofhydroxysafflower yellowA in rats,J.BeijingUniv.Tradit.Chin.Med.5(2006)456-460.)。同时,HSYA在胃肠道和肝脏中快速生物降解,导致消除速度加快,半衰期缩短。鉴于上述问题,有必要通过剂型设计或其它手段来改善HSYA的体内动力学行为,以使其更有效。然而,对HSYA给药系统的研究主要集中在通过增加HSYA的脂溶性来提高生物利用度的脂质载体上,但是许多研究缺乏对生物利用度改善前后总体疗效和安全性的评价。在过去的十年中,由糖、有机酸和氨基酸等天然初级代谢产物组成的天然深共熔溶剂(NADES)在绿色化学领域引起了广泛的关注。NADES在药物传递应用中显示出良好的前景。
发明内容
发明目的:本发明的目的是解决现有技术的不足,通过大量实验塑像出最佳的深共熔溶剂,与红花黄色素A制备成中药制剂,从而可大大提高红花黄色素A的口服生物利用度,并且可增加其减轻体重和纠正脂肪性肝炎和血脂异常功效。
技术方案:为了实现以上目的,本发明采取的技术方案为:
一种羟基红花黄色素A的中药制剂,它包括羟基红花黄色素A和深共熔溶剂。
作为优选方案,以上所述的羟基红花黄色素A的中药制剂,深共熔溶剂为葡萄糖和氯化胆碱加水溶解制得。
作为优选方案,以上所述的羟基红花黄色素A的中药制剂,深共熔溶剂具体制备方法为:
取摩尔比2:5的葡萄糖粉末和氯化胆碱粉末于烧杯中,在50℃下搅拌加热,形成澄清透明液体,继而加入为10%体积比的去离子水,继续搅拌加热,得澄清透明液体即为深共熔溶剂。
作为优选方案,以上所述的羟基红花黄色素A的中药制剂,羟基红花黄色素A浓度为1~100mg/mL。
有益效果:本发明提供的羟基红花黄色素A的中药制剂和现有技术相比具有以下优点:
本发明通过大量实验来筛选可提高羟基红花黄色素A的最佳天然深共熔溶剂,结果表明,采用90%葡萄糖-氯化胆碱(v/v)在水中溶解(90%GCH),可显著增加HSYA口服生物利用度。与水组相比,90%GCH组的羟基红花黄色素A相对口服生物利用度为326.93%。单程肠灌注实验表明,90%GCH组空肠内HSYA吸收率比H2O组增加2.95倍。药效学评价表明,90%GCH HSYA在高脂饮食诱导的肥胖大鼠中更有效地减轻体重和纠正脂肪性肝炎和血脂异常。因此90%GCH不仅能改善HSYA的口服吸收,还能增加其抗肥胖作用,取得了显著的技术效果。
附图说明
图1为空白血浆(A)、含有HSYA(B)和IS(C)的血浆质谱图;
图2HSYA在SD大鼠血浆中的浓度-时间曲线(n=5);
图3为剪切速率为50±1/s时粘液的平均粘度值。*P<0.05,与未进行NADES处理组相比(n=3);
图4为90%GCH对HSYA抗HFD肥胖的影响。(A)体重。(B)食物摄入。(C)肝脏指数。(D)口服葡萄糖耐量试验(OGTT)曲线。(E)OGTT曲线下面积。(F)血清丙氨酸氨基转移酶。(G)血清天冬氨酸转氨酶。(H)血清尿素氮(BUN)。(I)肌酐。(J)空腹血糖(GLU)。(K)血清总胆固醇。(L)血清总甘油三酯。(M)高密度脂蛋白。(N)低密度脂蛋白。*P<0.05,**P<0.01(n=6)。
具体实施方式
下面结合具体实施例进一步阐明本发明,应理解这些实施例仅用于说明本发明而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
实施例1不同深共熔溶剂对羟基红花黄色素A提高生物利用度的筛选实验
本发明进行了不同深共熔溶剂对羟基红花黄色素A提高生物利用度的筛选实验,筛选了氯化胆碱-氯化锌、氯化胆碱-草酸、氯化胆碱-乙二醇、氯化胆碱-丙三醇、葡萄糖和氯化胆碱等不同深共熔溶剂,发现羟基红花黄色素A在葡萄糖和氯化胆碱中不但溶解度好,且促进其生物利用率最高。然后本发明筛选了不同浓度10~100%的葡萄糖和氯化胆碱深共熔溶剂,发现90%浓度的葡萄糖和氯化胆碱对羟基红花黄色素A提高生物利用度最优。
实施例2
1、化学品和药材
羟基红花黄色素A、芦丁(IS,纯度>98.0%)购自上海源叶生物技术有限公司(中国上海)。D-葡萄糖、氯化胆碱、胰酶、来自猪胃粘膜的胃蛋白酶和粘蛋白II型购自Sigma(St.Louis,MO,USA)。高脂肪饮食(D12492,60%热量来自脂肪)购自研究饮食公司(NewBrunswick,NJ,USA)。液相色谱-质谱级甲醇和乙腈购自Honeywell Burdick和Jackson公司(Muskegon,MI,USA),高效液相色谱级甲酸购自Merck公司(Darmstadt,Germany)。所有其他试剂和溶剂均为分析等级。去离子水使用Millipore Milli-Q system(Bedford,MA,USA)进行净化。90%GCH深共熔溶剂的制备
取葡萄糖粉末和氯化胆碱粉末(摩尔比2:5)于烧杯中,在50℃下搅拌加热,形成澄清透明液体,继而加入为10%(体积比)的去离子水,继续搅拌加热,得澄清透明液体即为深共熔溶剂。
2、溶解度测试
溶解度测试是通过在50℃的EP管中用过量的HSYA饱和溶剂(90%GCH和H2O)放2h,并静置3h,以12,000r/min的速度离心20min来进行的。样品用去离子水稀释。用高效液相色谱法进行定量分析。高效液相色谱法作为验证方法。
3、大鼠体内药代动力学研究
3.1仪器和色谱条件
使用Waters ACQUITY I-Class UPLC系统(Milford,MA,USA)进行色谱分析,该系统配有二元泵溶剂输送系统、自动取样器和在线脱气器。使用UPLC BEH C18柱(100mm×2.1mm,1.7μL)进行分离。流动相由A(乙腈)和B(含0.1%甲酸的水溶液)组成。梯度洗脱程序如下:0.0-1.0min,5%A;1.0-2.5min,5-25%A;2.5-5.0min,25-55%A;5.0-5.5min,55-95%A;5.5-6.0min,95-5%A;6.00-7.50min,5-5%A。流速为0.30mL/min。色谱柱温度和自动进样器温度分别设定为30℃和10℃。质谱检测使用高灵敏的Xevo TQ-XS质谱系统(Waters,Milford,MA,USA)进行,该系统在负离子模式下配备有电喷雾源。电离源的条件设置如下:毛细管电压2.6kv,去溶剂化温度400℃,锥孔气流量150L/min,去溶剂气流量1,000L/h。氩气(99.99%)用作碰撞气体。分析物的检测和定量使用多反应监测模式。针对HSYA和IS优化了锥孔电压和碰撞能量。保留时间由MasslynxTM v 4.2软件(WatersCorporation)自动设置。
3.2方法验证
从六只不同的大鼠获得空白血浆样品,并在没有HSYA和IS的情况下进行处理。空白血浆、添加HSYA或IS的空白血浆的色谱图比较用于确定分析的特异性。HSYA的校准曲线基于HSYA与IS的峰面积比和标准浓度,这符合线性回归y=ax+b。分析物的浓度可以通过使用校准曲线来计算。线性和定量下限(LLOQ)被认为是校准曲线上的最低浓度,精度变化<20%。对低、中和高浓度的质量控制(QC)样品进行了连续三个验证日的分析,以评估日内和日间的精确度。精密度和准确度分别用相对标准偏差(RSD)和相对误差(RE)表示,均在15%以内。在室温下放置6h、反复冻融3次和-20℃低温保存6天的条件下,研究了含有低、中、高浓度HSYA的血浆样品的稳定性。
3.3药代动力学研究
10只雄性大鼠(230-250g)由成都达硕实验动物有限公司提供。实验前一周,将动物关在塑料笼子中,在适宜温度40%-60%湿度的环境下,在12h的光照和黑暗循环下,自由获取水和食物。将大鼠随机分为两组(H2O组和90%GCH组),在实验前禁食12h,自由饮水。剂量制剂通过将适量的HSYA溶解在H2O和90%GCH(40±157mg/mL)中制成,然后通过灌胃法以单次口服剂量(100mg/kg)给药。在两组大鼠的眼眶静脉给药后0.083、0.25、0.5、0.75、1、1.5、2、3、4、6、8、10和12h,立即在肝素化聚乙烯管中收集约500μL的血样。在以5,000r/min离心10min后,最终获得血浆,并储存在-80℃直至分析。动物和实验程序严格按照《实验动物的护理和使用指南》(美国国家研究委员会,1996)和陕西中医药大学伦理委员会相关伦理规定执行。
3.4样品制备
在1.5毫升EP管中,向100μL血浆样品中加入10μL IS和190μL甲醇。混合物涡旋30s,然后以14,000r/min离心10min。将上清液转移到新的1.5mL EP管中,并以14,000r/min的速度再离心10min。最后,注入1.5μL上清液用于UPLC-MS/MS分析。
3.5粘液流变学研究
生物相似性粘液根据文献(M.Boegh,S.G.Baldursdóttir,A.Müllertz,et al.,Property profiling of biosimilar mucus in a novel mucus-containing in vitromodel for assessment of intestinal drug absorption,Eur.J.Pharm.Biopharm.87(2014)227-235.)中报告的方法进行了修改,并用5%(w/v)粘蛋白、0.75%聚山梨酯80(Tween 80)和0.5%羧甲基纤维素钠(CMC-Na)制备。在搅拌条件下,将0.75%(w/v)吐温80加入到0.5%的CMC-Na中,并加入5%的粘液制成模拟粘液。将10μL的0、3.13、6.25、12.5、25和50%v/v的90%GCH添加到200μL的模拟粘液中,用流变仪在37℃(1-200L/s)的剪切速率范围内测量粘度。
3.6.单向原位肠灌流
3.6.1.单向肠灌流
本文研究了90%GCH对小肠段(即十二指肠、空肠、回肠)吸收HSYA的影响。手术前,大鼠禁食12h,自由饮水。制备Krebs-Ringer(K-R)缓冲液。体重300±20g的大鼠用10%(v/w)水合氯醛麻醉,并用红外灯保持其体温正常。在确认疼痛反射消失后,小心地拔出十二指肠、空肠和回肠(约10cm),并在开始和结束时进行小切口,插入并结扎硅胶管。入口用装有测试溶液的称重良好的EP管填充,另一个称重良好的EP管放置在出口以收集流出物。手术后,用生理盐水浸泡的棉垫覆盖伤口。用生理盐水冲洗肠内容物,并以0.2mL/min的流速在37℃下平衡30min的预热K-R缓冲液和含药物的灌注液。在平衡30min后,立即使用5mL含有已知重量HSYA的H2O或90%GCH的Ep管进行肠灌注。使用已知重量的5mL EP管在出口接收流出液,每15min更换一次,总共90min。在实验结束时,切断灌注的肠段。在4℃的生理盐水下测量肠段的长度和周长,以确保肠段不被拉伸。
3.6.2.样品测定
取500μL流出物。接下来,加入500μL甲醇,在4℃下以12,000r/min的速度离心10min。最后,将10μL上清液注入高效液相色谱系统。
3.6.3.数据分析
吸收速率常数(Ka)、有效渗透系数(Peff)和在肠中的吸收百分比(Fab)根据以下数学表达式计算:
Cout(corrected)=Cout(Vout/Vin) (1)
Ka=[1-Cout(corrected)/Cin]Q/πr2L (2)
Peff=-Q/πrL·ln[Cout(corrected)/Cin] (3)
Fab=Qt(Cin-Cout(corrected)) (4)
其中Vin和Vout分别是进入和离开肠的灌注液的体积;Q为灌注流速;Cin和Cout分别是灌注入口和出口中药物的浓度;L是肠段的长度(cm),r是肠段的半径(cm)。
3.7. 90%GCH对高脂饮食诱导肥胖的影响
3.7.1.动物与实验设计
将大鼠分成3组(6只/组),用高脂肪饮食(HFD)喂养5周。其中两组给药为5周,每日HSYA的H2O组和90%GCH组(100mg/kg)。另一组老鼠没有得到治疗,但是可以进入同一个HFD。在整个试验过程中,每周记录体重。所有实验在五周结束时终止。
3.7.2.口服葡萄糖耐量试验(OGTT)
OGTT在第四周结束时表演。大鼠给予D-glucose(2.0g/kg,50%溶液;湖北科伦药业有限公司)通过口服管饲法在禁食6h后进行。在服用D-glucose之前和之后30、239、60、90和120min,使用从尾静脉尖端收集的血液,用血糖计(Abbott FreeStyle Optium,Witney,UK)测定血糖。血液葡萄糖反应的累积变化由曲线下的增量面积量化。
3.7.3.血清和组织样本的采集
在10%水合氯醛麻醉(v/w)下,于第五周末进行12h禁食后,从腹主动脉采集血样。血液在4℃下以3000r/min离心10min。然后,收集血清样品并储存在-80℃条件下。立即切除每只大鼠的附睾脂肪、肝脏、胃、十二指肠、空肠、回肠、肺、脾、心脏和肾,并称重。所有样品都储存在4%多聚甲醛中,用于后续分析。肝指数计算为肝湿重与体重的百分比。
3.7.4.生化检测
丙氨酸氨基转移酶(ALT)、天冬氨酸转氨酶(AST)、血尿素氮(BUN)、肌酸酐、总甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C),并且使用大鼠试剂盒测量低密度脂蛋白胆固醇(LDL-C)(Royta life and Analytical Sciences,Shenzhen,China)。根据制造商的说明,使用所有套件。
3.7.5.组织病理学分析
大鼠组织样品在4%多聚甲醛中固定24h,并包埋在石蜡中。将组织切成切片(每片4μL厚),用苏木精和曙红染色。在光学显微镜下分析和拍摄组织切片(Nikon EclipseE100,Nikon,Japan)。
3.8.统计分析
为了确定HSYA在H2O和90%GCH组中的药代动力学参数,使用DAS 2.0软件采用非房室法分析浓度-时间数据。所有实验数据用SPSS 25.0进行分析。组间差异用单向方差分析。对于两组之间的比较,t检验用于参数分布数据,而man-Whitney检验用于非参数分布数据。所有数据均表示为平均标准差(n=3)。当P<0.05时,认为有统计学意义。
4.结果和讨论
4.1.HSYA在H2O和90%GCH的溶解度
HSYA在H2O的溶解度为321.877±6.756mg/mL,在90%GCH的溶解度为176.550±7.921mg/mL。与H2O相比,HSYA在90%GCH中的溶解度因粘度增加而降低,但90%GCH仍具有良好的溶解HSYA的能力。
4.2.UPLC质谱/质谱方法验证
为了研究90%GCH能否提高HSYA的口服生物利用度,本发明建立并验证了一种UPLC-质谱/质谱法测定HSYA的血浆浓度。HSYA和IS的保留时间分别为3.03和3.51min。在分析物和IS保留时间内,未观察到血浆的内源性干扰。空白血浆和添加了HSYA和IS的空白血浆的色谱图显示在支持信息的图1中。回归方程是通过绘制不同浓度的分析物与IS的峰面积比绘制的。HSYA的校准曲线为y=0.00150532x-0.0126754,r2=0.9992。HSYA的最低检测限度被认为是25ng/mL。在浓度为25、100、5000ng/mL时,加标样品的日内和日间精密度和准确度得到验证。所有验证数据都在支持信息的表1-3中给出。平均提取回收率为93.1%~104.9%,平均基质效应为93.7%~102.2%。高萃取回收率,无明显基质效应,表明样品的预处理是合适的。
表1大鼠血浆中HSYA的精密度、准确度和提取回收率的实验结果(n=6)
表2大鼠血浆中HSYA和IS的基质效应(n=6)
表3 HSYA在大鼠血浆中的稳定性实验结果(n=6)
4.3.药代动力学研究
该方法灵敏、重现性好,已成功应用于药动学研究。HSYA浓度-时间曲线如图2所示。同时,主要药代动力学参数列于表4。H2O和90%GCH组的HSYA吸收迅速,1h内达到最大值,12h后完全消除。90%GCH组药动学参数大幅度提高。90%GCH组HSYA的最大值是90%H2O组的5.19倍。AUC值也显著增加(P<0.05)。口服HSYA的生物利用度提高了326.93%。这些结果表明,90%GCH增加了口服吸收的HSYA。这些结果表明,90%GCH增加了口服吸收的HSYA。HSYA在90%的GCH中的相对口服生物利用度(相对于L-proline-acetamide提取物)提高了1.78倍,表明90%的GCH在提高HSYA的口服生物利用度方面更有效。HSYA的口服生物利用度可能受肠屏障、吸收部位及其在胃肠道中的稳定性的影响。
表4 HSYA在大鼠体内的药代动力学参数(n=5)
4.4. 90%GCH对粘液粘度的影响
肠粘液的粘度对肠屏障有重要影响。为了研究90%GCH对粘液的影响,评估了用90%GCH处理的粘液的流变性。结果显示在支持信息的图3。与未处理的粘液相比,用90%GCH处理的粘液的粘度在整个测量的剪切范围内显著下降。例如,在501/s的剪切速率下,测量未处理的粘液的平均粘度为10.07mpa*s。添加90%GCH的3.13、6.25、12.5、25和50%v/v后,平均粘液粘度分别降至9.08、8.03、8.93、9.02和8.34mpa*s,最小值对应于90%GCH的6.25%v/v。90%GCH降低粘液粘度的能力可以促进HSYA向肠上皮的递送,以增加HSYA的口服吸收。
4.5.单向原位肠灌流
采用单向原位肠灌流模型,探讨H2O和90%GCH对HSYA肠吸收的影响。空肠Ka值从(0.1744±0.0305)×10-3增加到(0.5136±0.0970)×10-3厘米/秒,比H2O组高2.95倍。同时,空肠和回肠的Peff和Fab值显著增加(P<0.05)。令人惊讶的是,90%GCH组的空肠的Peff值和Fab值明显高于十二指肠和回肠(P<0.05)。根据单向原位肠灌流研究,90%GCH可显著改善肠壁通透性,从而增加HSYA在小肠中的吸收,其中空肠是促进HSYA吸收的重要部位。90%GCH高粘度性可能通过分子相互作用粘附于肠粘膜,HSYA与肠上皮细胞的相互作用时间和强度将延长和加强。
表5 HSYA在大鼠小肠不同部位的吸收参数(n=3)
*P<0.05,与水组相比;#P<0.05,与空肠组相比;△P<0.05,与十二指肠组相比
4.6. 90%GCH对高脂饮食诱导肥胖的影响
本发明研究了90%GCH对高脂饮食诱导的HFD肥胖大鼠模型的影响。与HFD组相比,90%GCH显著降低了体重(图4A)。在90%GCH剂量下服用HSYA的大鼠每天比HFD大鼠吃的食物少,4周后观察。HFD大鼠平均食用约18.5g食物,而H2O组为17.55g,90%GCH组为17.23g(图4B)。90%GCH组的肝指数较HFD组明显下降(P<3520.01)(图4C)。OGTT反映了大鼠的葡萄糖耐量程度(图4D)。与HFD组相比,90%GCH组的OGTT曲线下面积(AUC)显著降低(P<0.01),表明90%GCH改善了HFD大鼠的葡萄糖耐量受损(图4E)。
还测量了下列血清生物化学生物标记物:ALT,AST,BUN,Creatinine,GLU,TC,TG,HDL,LDL(图4F-4N)。其中,90%GCH组AST显著低于HFD组(P<0.05),提示90%GCH可能减轻HFD所致的肝损伤(图4G)。此外,90%GCH组的TG低于HFD组,但无统计学差异(图4L)。90%GCH组的高密度脂蛋白高于HFD组(P<0.01)(图4M),而90%GCH组的低密度脂蛋白低于HFD组(P<0.05)(图4N)。这些结果表明,90%GCH的HSYA具有调节血脂异常的作用。在三组大鼠中,ALT,BUN,Creatinine,GLU和TC水平无明显差异。此外,与HFD组相比,90%GCH组附睾脂肪面积减少。在90%GCH组中,油红O染色显示肝脏中的脂滴尺寸减小,表明HFD诱导的肝脏脂肪蓄积可减少90%GCH。对胃、十二指肠、空肠、回肠、肺、脾、心脏和肾脏进行组织学分析。没有观察到形态异常,并且组织形态在所有组中都是相同的。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种羟基红花黄色素A的中药制剂,其特征在于,它包括羟基红花黄色素A和深共熔溶剂。
2.根据权利要求1所述的羟基红花黄色素A的中药制剂,其特征在于,深共熔溶剂为葡萄糖和氯化胆碱加水溶解制得。
3.根据权利要求2所述的羟基红花黄色素A的中药制剂,其特征在于,深共熔溶剂具体制备方法为:取摩尔比2:5的葡萄糖粉末和氯化胆碱粉末于烧杯中,在50℃下搅拌加热,形成澄清透明液体,继而加入10%体积比的去离子水,继续搅拌加热,得澄清透明液体。
4.根据权利要求1所述的羟基红花黄色素A的中药制剂,其特征在于,羟基红花黄色素A用深共熔溶剂溶解的浓度为1~100mg/mL。
5.权利要求1~4任一项所述的羟基红花黄色素A的中药制剂在制备降血脂的药物中的应用。
6.权利要求1~4任一项所述的羟基红花黄色素A的中药制剂在制备减肥的药物中的应用。
7.权利要求1~4任一项所述的羟基红花黄色素A的中药制剂的药代动力学研究方法,其特征在于,羟基红花黄色素A的中药制剂给药后,取血浆样品,注入超高效液相色谱仪进行分析;
使用Waters ACQUITY I-Class UPLC系统进行色谱分析,该系统配有二元泵溶剂输送系统、自动取样器和在线脱气器,使用UPLC BEH C18柱,规格为100mm×2.1mm,1.7μL进行分离。流动相由A相为乙腈和B相为含0.1%甲酸的水溶液;梯度洗脱程序如下:0.0-1.0min,5%A;1.0-2.5min,5至25%A;2.5-5.0min,25至55%A;5.0-5.5min,55至95%A;5.5-6.0min,95至5%A;6.00-7.50min,5至5%A,流速为0.30mL/min;色谱柱温度和自动进样器温度分别设定为30℃和10℃;质谱检测使用高灵敏的Xevo TQ-XS质谱系统进行,该系统在负离子模式下配备有电喷雾源;电离源的条件设置如下:毛细管电压2.6kv,去溶剂化温度400℃,锥孔气流量150L/min,去溶剂气流量1,000L/h,氩气作碰撞气体;分析物的检测和定量使用多反应监测模式。
8.根据权利要求7所述的羟基红花黄色素A的中药制剂的药代动力学研究方法,其特征在于,血浆样品处理方法为:在1.5毫升EP管中,向100μL血浆样品中加入10μL IS和190μL甲醇,混合物涡旋30s,然后以14,000r/min离心10min,将上清液转移到新的1.5mL EP管中,并以14,000r/min的速度再离心10min;注入1.5μL上清液用于UPLC-质谱/质谱分析。
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