CN111107930A - 样品净化装置和方法 - Google Patents
样品净化装置和方法 Download PDFInfo
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- CN111107930A CN111107930A CN201880060945.9A CN201880060945A CN111107930A CN 111107930 A CN111107930 A CN 111107930A CN 201880060945 A CN201880060945 A CN 201880060945A CN 111107930 A CN111107930 A CN 111107930A
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Abstract
本发明涉及一种流通式装置,其包含至少一根分离柱,其中提供包含氧化铝和/或二氧化硅颗粒的第一填充组分和包含一种或多种吸湿性盐的粉末的第二填充组分。两种填充组分可以在装置中共混或分层,该装置可以包含单个管或板式排列的多个管,例如多壁板的孔或支架中的管。另外,本发明涉及一种通过使生物样品穿过包含氧化铝和/或二氧化硅颗粒的第一填料组分和包含一种或多种吸湿性盐的粉末的第二填料组分,而从生物样品中去除一种或多种基质组分例如色素的方法。
Description
技术领域
本发明涉及样品制备领域,更具体地涉及提供用于从生物样品中快速且简单地除去基质组分的装置。本发明还包括从生物样品例如尿液中除去基质组分的方法。
背景技术
处理复杂的生物样品以除去或至少减少在所述样品中存在的可能影响分析物的后续测量的物质,通常称为样品制备(sample preparation),或简称为“样品制备(sampleprep)”。该术语用于各种方法和设备,包括固相萃取(SPE)、支撑液液萃取(SLE)和蛋白质沉淀。在分析有机小分子(例如药物、前药、其代谢产物等)时,样品制备的主要目的是提供质谱(MS)足以分析的纯度。
固相萃取(SPE)是一种色谱技术,广泛用于分析样品的预浓缩、各种化学品的纯化以及从水溶液中移出有毒或有价值的物质。但是,尽管它非常广泛地用于某些应用中,但是事实证明当需要对样品进行不太精确地净化时,例如常规测试大量尿液样品以检测非法物质,例如在各种体育赛事中时,这种方法既昂贵又费时。
支撑液液萃取(SLE)使用与水不混溶的溶剂进行分析物萃取。更具体地,水相通常固定于惰性相(例如硅藻土)上,所述惰性相上负载有水不混溶相。短暂等待后,将洗出液推入或吹过色谱柱,产生与其他简单的样品制备技术(例如蛋白质沉淀或“稀释并进样(dilute and shoot)”(D&S))相比,本质上更清洁的萃取物。
“稀释并进样”(D&S)是一种相对快速的方法,广泛应用在临床以及司法鉴定应用中。D&S的原理是简单地稀释样品然后直接将其注入例如到液相色谱-质谱(LC-MS)系统中。
根据定义,D&S方法本质上仍会包含干扰组分,尽管由于稀释的缘故,干扰组分的浓度低于在原始样品中的浓度。因此,不洁净的D&S萃取物可能会增加色谱柱维护的要求和/或缩短随后使用的液相色谱系统的寿命,并且样品纯度低也会增加LC-MS系统的处理时间。此外,对于某些已知是“困难的”分析物(例如某些鸦片剂类,如丁丙诺啡和去甲丁丙诺啡(norbuprenorphine)),D&S甚至是不可能的。
US 6,541,273(Aventis)涉及用于固相萃取的药筒领域。更具体地,公开了可用于检测存在于土壤、水、血液、组织、尿液和其他类型的农业、医学或药物样品中的农药(例如吡唑类,包括氟虫腈(fipronil))的方法和设备。该设备包括具有用于接收样品的第一开口和用于排出洗出液的第二开口的柱,该柱包括含有氨基官能二氧化硅的第一分离区、含有活性炭的第二分离区、含有镁-硅胶或硅胶的第三分离区以及包含未在第三分离区中使用的镁-硅胶或硅胶的第四分离区。
WO 2007/030847涉及一种用于微吸附柱的填充材料,所述微吸附柱用于干燥和/或纯化溶解的有机或生物分析物,例如毒素、抗生素、维生素、激素、农药等,所述填充材料包含至少一种干燥剂;涉及填充有该填充材料的微吸附柱及其用途。更具体地说,填充材料包含硫酸镁和至少一种选自以下的其他干燥剂:氧化铝、氯化钙、氢化钙、氧化钙、硫酸钙、氢化钾、硅胶、硫酸铜、氧化镁、高氯酸镁、分子筛、氢氧化钠、五氧化二磷、负载在硅酸盐上的硫酸、负载在硅酸盐上的五氧化二磷以及0.5至90重量%的天然产生或合成的具有大的内表面积的载体,例如沸石、硅藻土、膨润土、二氧化硅等。
WO 2008/103828(William Brewer)描述了用于萃取、样品收集和样品净化(例如,胃内容物的净化和从尿液中萃取碱性药物)的移液管吸头。更具体地,移液器吸头在其窄的下端包含筛网或过滤器,以在其宽的上端包含固相吸附剂和屏障。根据WO 2008/103828,溶液与吸附剂的混合产生凝胶,即均质的溶液,从而提供了据称为无与伦比的萃取效率和快速平衡。吸附剂的粒度可为50-200μm,其足够小以提供有效的萃取,但是需要高压。除了高压吸附剂外,还提及其他吸附剂用于除去不需要的样品基质,例如免疫亲和性吸附剂、离子交换剂和用于分子量分离的多孔材料。吸附剂的具体实例为官能化或非官能化的苯乙烯二乙烯基苯;氧化铝(碱性、酸性或中性);硅酸镁;小粒径硅胶;C8、Q18和官能化的C8或C18材料;Na2SO4、MgSO4或CaSO4(用于干燥);硅藻土、交联葡聚糖(Sephadex)和聚乙烯。
由于对化学品(例如使用合法或非法药物)的快速控制的需求不断增长,因此在样品净化方法的领域中存在不变的需求,在速度、简便性和/或成本方面改善这些方法。
发明内容
本发明的一个目的是通过与现有技术中的至少一些相比,在给定的时间段内更有效地除去至少一些其基质组分来降低生物样品的复杂性。
更具体地,本发明涉及一种流通式装置,其包括至少一个分离柱,其中提供包含氧化铝和/或二氧化硅颗粒的第一填充组分、包含一种或多种吸湿性盐的粉末的第二填充组分。
此外,本发明的另一个目的是通过一种方法来降低生物样品的复杂性,所述方法由于其处理简单而适合于例如大量样品的常规测试。
更具体地,本发明涉及一种从生物样品中除去一种或多种基质组分的方法,其中所述基质组分是选自尿素、尿酸、磷脂、氨基酸、肌酸、血红素降解产物(例如尿胆素(urobillin))以及内源性盐中的一种或多种,该方法包括使所述样品穿过包含氧化铝和/或二氧化硅颗粒的第一填充组分、包含一种或多种吸湿性盐的粉末的第二填充组分。
最后,本发明的另一个目的是提供对药物和其他化学品的快速且简单的分析,而不论它们在现有技术中是否被认为是“困难的”。
更具体地,本发明涉及将包含氧化铝和/或二氧化硅的颗粒的第一填充组分与包含一种或多种吸湿性盐的粉末的第二填充组分的组合用于从生物样品中除去其中一种或多种基质组分的用途。
根据本发明的详细说明书、权利要求书和其他部分,本发明的更多细节、实施方案和优点是显而易见的。
定义
术语“流通式装置”在本文中用于能够在上端接收液体例如样品但不适于在其下端提取的装置。
术语“氧化铝(alumina)”在本文中用于Al2O3,也称为氧化铝(aluminium oxide)或氧化铝(aluminum oxide)。
术语“吸湿性盐”在本文中用于由从所述样品中吸收/吸附水的能力定义的盐。
术语“填充物”在本文中用于为分离而使用的任何材料,即包含在柱中的材料,以通过吸附和/或保留使样品分离成若干个级分。填充材料在本领域中以各种术语已知,例如介质,特别是色谱介质;吸着剂;吸附剂或仅称为填充物。术语“填充物”在本文中用于柱的内容物,而与其在柱中如何提供无关,即,不管其是被加压地还是简单地放置在柱中。
在本文中使用术语“填充组分”以便更容易地区分本发明的装置中包括的不同填充物。因此,每种填充组分可以是任何常规的色谱吸附剂,例如在本说明书中示例的,例如二氧化硅;硫酸镁和硫酸钠的混合物等。
术语“基质组分”在本文中以在样品制备领域中通常使用的意义使用。因此,样品的基质包括除目的分析物以外的成分或组分。例如,尿液样品将包括基质组分,例如尿素、磷脂、氨基酸和许多其他组分,如图3所示,所有这些组分都可能给分析物的确定造成困难,因此应在样品制备过程中将其除去。
附图说明
图1a和b示出本发明的装置,其包含分别是共混和分层形式的以板式排列的多个管。
图2a和b示出本发明的装置,其包含单床,即分别为共混和分层形式的单管形式。
图3为说明组成的图,即正常尿液的基质组分的图。
图4a和b在左侧(a)示出未经进一步处理的未加工的水解尿液,并且在右侧(b)示出用所述流通式装置处理后得到的洗出液。
图5a和b示出在色素和盐除去方面的水解尿液提取净化度,左侧培养管详示沉淀的尿液,然后进行离心并将洗出液除去且蒸发。右侧培养管详示相同的样品经本发明处理。
图6a和b示出对于给定的非水解尿液样品,在改变组分1条件下,尿素(a-上图)和肌酐(b-下图)含量的条形图比较。
图7示出对于给定的非水解尿液样品,在改变组分2以及组分1条件下,尿素(水平线图)和肌酐(斜线图)含量的条形图比较。
图8示出对于给定的水解尿液样品,在96孔板和单根柱的方式中,将不同比例的氧化铝(酸性和中性)与吸湿性盐共混后,除去的尿素(水平线图)和肌酐(斜线图)的条形图比较。
图9a和b示出使用分层与共混的氧化铝/吸湿性盐组合,对于给定的非水解尿液样品(上图)和水解尿液样品(下图),除去的尿素(水平线图)和肌酐(斜线图)的条形图比较。
图10a和b示出对于给定的水解尿液样品,除去的尿素(上部痕迹)和肌酐(下部痕迹)的LC-MS/MS TIC。左侧的痕迹示出使用ACN的简单沉淀,右侧的痕迹使用所述流通式装置。
图11a和b示出对于一系列滥用药物,用所述流通式装置使用不同方案获得的来自未水解尿液的回收物的条形图。
具体实施方式
本发明的第一方面是一种流通式装置,其包含至少一个分离柱,其中提供包含氧化铝和/或二氧化硅的颗粒的第一填充组分和包含一种或多种吸湿性盐的粉末的第二填充组分。
氧化铝是一种众所周知的分离介质,其以酸性、中性或碱性形式存在,并被广泛用于从气流中除去水,而且还用作色谱柱和其他实验室设备的吸附剂。技术人员可以从商业来源获得氧化铝,或者购买氧化铝并通过在水浆中添加碱来控制其pH。
类似地,二氧化硅材料被广泛用作各种分离和提取目的的吸附剂。例如,在固相萃取(SPE)中,广泛使用例如用碳官能化的二氧化硅材料,并且可以将具有在两个碳原子至十八个碳原子之间的任何长度的碳链的这类材料提供于本装置中。此类材料通常称为“SPE相”。
另外,可以提供包含较低比例的二氧化硅的其他材料作为本装置中的第一填充组分,例如包含硅藻土的材料。这些材料通常用于支撑液液萃取(SLE)中,因此有时被称为“SLE相”,在本文中其包含在术语“含二氧化硅”范围内。
此外,如果在第一填充组分中提供二氧化硅材料,则它们可具有与上述范围相同的粒径。
第一填充组分的颗粒可例如为球形或任何不规则形状。
此外,第一填充组分可包含酸性或中性氧化铝。对于特定应用,技术人员可以例如根据预期的容量考虑使用哪种形式。对于不同的基质和可能不同的分析物组,中性氧化铝可能更具选择性。
此外,如果第一填充组分包含二氧化硅,则其可以有利地被官能化。合适的官能化可例如为SPE相中常用的那些中的任何一种或多种。例如,官能化的二氧化硅可包含选自以下的官能团中的一种或多种:碳链,如线性C4-C18链;羧基;金属螯合基团;和离子交换基团,例如阳离子交换基团或阴离子交换基团。
另外,第一填充组分可以包含封端的二氧化硅,其通常作为SPE相提供。简而言之,其中的封端是指游离硅烷醇基的封端。
在不希望对所附权利要求书所定义的本发明施加任何限制的情况下,当第一填充组分与溶剂如乙腈(ACN)结合使用时,第一填充组分提供了除去某些基质组分的沉淀物,例如尿盐,这是由于其在溶剂中的溶解度更低。样品与第一填充组分的接触似乎也除去了一些色素,这是使用现有技术方法难以除去的。
因此,在本发明的装置中,第二填充组分在实践中被用于“干燥”样品,而在现有技术中,本文所述种类的吸湿性盐通常用于将分析物从一个相中“盐析”到另一个相中。因此,通过将一种或多种吸湿性盐的粉末与氧化铝和/或二氧化硅颗粒结合,出乎意料地,本发明的装置能够有效且快速地从生物样品中除去基质组分。具体地,如下文的实验部分所示,已经表明本发明有效地从尿液和其他样品中除去甚至更难以去除的基质组分。
更具体地,一种或多种吸湿性盐的粉末例如可包含选自以下的一种或多种:硫酸镁、硫酸钠、乙酸钠、柠檬酸钠、柠檬酸钠倍半水合物(sodium citrate sesquihydrate)、氯化钠和氧化镁。也可以使用其他盐,只要它们达到第二填充组分的上述效果即可。在第二填充组分中有用的盐可被称为干燥剂,或简称为无水盐。
无机盐例如硫酸镁(MgSO4)和乙酸钠(NaOAc,即CH3COONa)可以商品名QuEChERS(http://www.restek.com/)市售获得。因此,技术人员可以从商业来源获得第二填充组分,或由单独的化学品制备第二填充组分。在本发明的装置中,第二填充组分是硫酸镁和乙酸钠的混合物,其可以是粉末形式,并且其比率可以在例如从1:4到约4:1范围内变化。
在有利的形式中,本发明的装置包含不超过两个的填充组分,其中第一填充组分包含二氧化硅;第二填充组分包含硫酸镁和乙酸钠。如本说明书中其他地方将讨论的,两个填充组分可以作为分别的层或作为混合物提供。
在本发明的装置中,柱可以在第一填充组分和第二填充组分的相对侧包含底部玻璃料和顶部玻璃料。换言之,考虑到流通模式的装置,上部玻璃料布置在两个填充组分的上游,而下部玻璃料布置在两个填充组分的下游。在这种情况下,术语“玻璃料”用于任何合适的分离器,例如过滤器、筛网等,其能够在允许液体通过的同时将两个填充组分保持在柱中。这样的玻璃料能够吸附液体,或制备成根本不能或仅以非常小的程度吸附液体的筛网,以减少特别是小型装置的死体积。如本领域技术人员将理解的,在本发明的装置中考虑的所有玻璃料均能够在样品处理期间允许液体通过。
在本装置的一个实施方案中,将第一填充组分和第二填充组分各自作为单独的层提供于柱中。然后,将第一填充组分提供在更靠近顶部玻璃料处,即第二填充组分和底部玻璃料的上游,如图1b和2b所示。
为了使各层之间更清楚地分开,第一填充物组分和第二填充物组分可以由中间玻璃料隔开,也如图1b和2b所示。上述关于第一和第二填充组分的所有特征都适用于该实施方案。
在一个替代实施方案中,第一填充组分和第二填充组分作为共混物在柱中提供,如图1a和2a所示。合适的共混比例例如是氧化铝和/或二氧化硅颗粒:吸湿性盐以1:4至4:1共混。上述关于第一和第二填充组分的所有特征都适用于该实施方案。
本发明的装置可为单床形式,在这种情况下,该柱是管、色谱柱或任何其他合适的桶状容器。上述关于两个填充组分以及它们如何共混或分层的所有特征都适用于该实施方案。
或者,本发明的装置可为多床形式,在这种情况下,将两根或更多根(例如多根)柱排列在板上,例如作为板(例如多壁板)的固定孔,或支架中的管或小瓶。上述关于两个填充组分以及它们如何共混或分层的所有特征都适用于该实施方案。
从本申请的其他部分可以看出,本发明的装置有利地用于从生物样品中除去基质组分。
因此,在一个实施方案中,本发明的装置可包含布置在第一填充组分和第二填充组分上游的疏水性顶部玻璃料。在本发明的范围内,以上讨论的所有装置特征,例如两个填充组分的性质、其在柱中的共混/分层和形式,可以与这种顶部玻璃料组合。
本发明的第二方面是从生物样品中除去一种或多种基质组分的方法,其中所述基质组分为选自以下的一种或多种:尿素、尿酸、磷脂、氨基酸、肌酸、血红素降解产物(例如尿胆素)和内源性盐。本发明的方法包含使所述样品穿过包含氧化铝和/或二氧化硅颗粒的第一填充组分和包含一种或多种吸湿性盐的粉末的第二填充组分。
可以在本发明的方法的范围内应用上述两个填充组分的性质、其在柱中的共混/分层和示例性形式。
生物样品可以是任何需要降低其复杂性以便随后成功分析分析物的样品。在本文中,术语“生物(biological)”应理解为源自哺乳动物,例如人类或动物,或任何其他生物来源。生物样品可以是生物液体,例如尿液或唾液。
从样品中除去的基质组分可例如为选自以下的一种或多种:尿素、尿酸、磷脂、氨基酸、肌酸、血红素降解产物(例如尿胆素)和内源性盐;这些都是已知干扰分析方法(例如MS)的尿液组分。
或者,生物样品可包含液化的或机械细分的组织,例如活检或源自人类或动物的其他组织。
更具体地,并且如将在下文的实验部分中更详细地说明的,本发明的方法可以包含简单的工作流程,其中例如用合适的溶剂(例如乙腈)稀释可能已水解或未水解的未加工尿液。将得到的液体加入到柱中,例如本发明的装置中,根据任何公知技术施加正压,并收集提取物。然后可以将得到的提取物蒸发并在适合LC-MS的溶剂中复溶,甚至直接注入LC-MS中。
在本发明的有利方法中,生物样品在穿过两个填充组分之前被水解。这可以例如通过使其穿过疏水性玻璃料来实现。
本发明的第三方面是包含氧化铝和/或二氧化硅的颗粒的第一填充组分和包含一种或多种吸湿性盐的粉末的第二填充组分的组合,用于从生物样品中除去一种或多种更多基质组分的用途。
本申请中提供的关于两个填充组分的性质、其在柱中的共混/分层、示例性形式和方法的所有细节可在本发明的范围内,以任何组合使用或应用于任何实施方案中。
使用本发明有利于从任何生物样品(例如从个体中采集的样品)中除去基质组分以便鉴定或追踪药物的使用、生物标志物、代谢物等。例如,本发明可以用于例如常规控制中,用于鉴别个人使用非法药物,例如在体育赛事中改善身体机能的药物(掺杂剂)。它也可以用于追踪滥用药物和/或由于合法或非法摄入化学物质而形成的代谢产物。因此,在本发明随后的例如MS中作为目标的分析物可以例如选自苯丙胺类;鸦片剂(opiates)类;可卡因类;苯二氮卓类;巴比妥类;非苯二氮卓类药物,称为z药物;四氢大麻酚(THC);类固醇;和相关代谢产物。
在本发明的有利的用途中,除去的至少一种基质组分为色素,并且样品为尿液。
附图的详细说明
图1示出本发明的装置的原理,该装置包含以板式排列的多个管:图1a示出如何将两个填充组分共混以在每个管中提供单床形式;而图1b则示出两个填充组分分开并且是分层的形式,其中第二填充组分即吸湿性盐为底层,第一填充组分即氧化铝和/或二氧化硅为顶层,并且各层用玻璃料隔开。
图2示出本发明的装置的原理,该装置包含清除排列方式的单床:图2a示出如何将两种填充组分共混以提供单床形式;而图2b示出具有第二填充组分即吸湿性盐为底层以及第一填充组分即氧化铝和/或二氧化硅为顶层的层状形式,其中各层用玻璃料隔开。
图3示出正常的尿液组成。基质的大部分(56.1%)由尿素组成,还有各种盐、少量有机酸、所占比例较小的肌酐。图从左至右示出以下比例:尿酸1.3%、磷脂0.5%、氨基酸6%、肌酐2%、其他0.2%、钾3%、钠8%、氨1%、钙0.3%、硫酸盐4%、氯化物14%和磷酸盐3.6%。
图4左侧示出没有进一步处理的未加工的水解尿液,并且右侧示出使用所述流通式装置处理后得到的洗出液。可以看出,当使用所述流通式装置时,实现了基质色素的完全除去,从而得到澄清的液体。
图5示出在除去色素和盐方面,水解尿液提取物净化度。示出的目测提取物来自蒸发后的样品。左侧培养管详示沉淀的尿液,然后进行离心,并将洗出液除去并蒸发。右侧培养管详示使用上述流通设备处理的相同样品,然后洗出液蒸发。左侧培养管示出大量残余物和色素,而右侧示出透明的管。
图6a和b示出对于给定的非水解尿液样品,在改变填充组分1条件下,尿素(a-上图)和肌酐(b-下图)含量的条形图比较。将使用改性吸湿性盐组合物的提取物与稀释并进样方法比较。从左到右的项目:AOAC QuEChERs盐;EN QuEChERs盐;仅MgSO4;仅Na2SO4;1:9稀释并进样。详示尿液与ACN碰撞比(crash ratio)为1:4(斜线图)和1:9(水平线图)。与单一盐的形式相比,使用不同的QuEChERs盐组合物更可靠。
图7示出对于给定的非水解尿液样品,在改变的填充组分2以及填充组分1条件下,尿素(水平线图)和肌酐(斜线图)含量的条形图比较。从左到右的项目:仅AOAC盐;在AOAC盐上的层状C8-末端封端;在AOAC盐上的层状C4;在AOAC盐上的层状Si;仅氧化铝-N;1:9稀释并进样。当使用各种改性的二氧化硅吸附剂时,与仅使用填充组分1相比,仅观察到轻微的改善。在单独使用氧化铝时,提供>40%的除去率,同时还消除样品中的色素。
图8示出对于给定的水解尿液样品,在96孔板和单根柱的方式中,将不同比例的氧化铝(酸性和中性)与吸湿性盐共混时,除去的尿素(水平线图)和肌酐(斜线图)的条形图比较。从左到右的项目:Al-N/盐1:1板;Al-N/盐1:1柱;Al-N/盐3:4板;Al-N/盐2:3板;Al-N/盐2:3柱;Al-A/盐1:1板;Al-A/盐1:1柱;Al-A/盐3:4板;Al-A/盐3:4柱;Al-A/盐2:3板;Al-A/盐2:3柱。观察到在不同比例下的良好的肌酐和尿素除去率。
图9a和b示出使用分层与共混的氧化铝/吸湿性盐组合,对给定的非水解尿液样品(上图)和水解尿液样品(下图),除去的尿素(水平线图)和肌酐(斜线图)的条形图比较。两张图从左到右示出不同的项目:分层板200/200盐/Al-N;200/200盐/Al-A;300/200盐/Al-N;300/200盐/Al-A;共混板400mg盐/Al-N;450mg盐/Al-N;400mg盐/Al-A;450mg盐/Al-A。分层形式与共混形式的比较表明,使用分层形式,肌酐和尿素除去率更好,同时酸性氧化铝也略优于中性等同物。
图10a和b示出对于给定的水解尿液样品,除去的尿素(上部痕迹)和肌酐(下部痕迹)的LC-MS/MS TIC。左侧的痕迹示出使用ACN的简单沉淀,右侧的痕迹使用所述流通式装置。与传统工艺相比,当使用所述流通式装置时,观察到高水平的尿素和肌酐除去率,通常大于90%。
图11a和b示出对于一系列滥用药物,用所述流通式装置使用各种方案获得的来自未水解尿液的回收物的条形图。其中条形图从左开始代表:吗啡、苯丙胺、可待因、MDMA、甲氧麻黄酮、氯胺酮、可卡因、7-氨基氟硝西泮、PCP、奥沙西泮(oxazepam)、扎来普隆(zaleplon)和α-苯基哌啶基-2-乙酸(ritalinic acid)。上部的图(11a)详示如实验部分所述的标准方法,在前方以水平线图表示;通过加入另外的小等份的ACN而进行的改性,在中部以斜线图表示;通过加入另外的小等份的MeOH而进行的改性,在后部以实心图表示。下部的图(11b)使用提取前用甲酸改性的尿液,如实验部分所述,重复了上述趋势。
实验
提供本发明的实施例仅用于说明目的,并且不应解释为限制由所附权利要求书限定的本发明。本申请下文或其他地方提供的所有参考文献均通过引用的方式并入本文中。
材料和方法
药品标准物和相关的内标物均购自LGC Standards(Teddington,UK)。乙酸铵、氢氧化铵、HCl、甲酸和乙酸以及β-葡萄糖醛酸酶(勃艮第蜗牛)购自Sigma-Aldrich Companyltd(Gillingham,UK)。尿液是由健康的人类志愿者捐赠的。所有溶剂均为购自HoneywellResearch Chemicals(Bucharest,Romania)的LC/MS级。每天从Direct-Q 5净水器(MerckMillipore,Watford,UK)中抽取新鲜水(18.2MΩ.cm)。
水解尿液方法
将1mL尿液(空白或加标)用950μL的100mM乙酸铵pH 5和50μL β-葡萄糖醛酸酶(相当于约4500U/mL尿液)稀释。尿液在60℃下水解至多2小时,然后冷却,再进一步处理。替代性的水解方法是使用不同的重组和非重组酶,也是有效的。当使用经专门处理的疏水性玻璃料时,水解方法可以在板上进行。
尿液提取方法
·将通常为100μL的未水解或酶水解的尿液(如上述实施例)与600μL ACN充分混合。混合可通过涡旋作用(20秒)或通过重复抽吸/分配移液(3-4个循环)在Eppendorf管或其他合适的容器或板上离线进行。
o更大的尿量也是可能的。
·如果在管中离线处理,则可以将它们在13300rpm下离心10分钟以除去颗粒物。对于在板上处理,由于玻璃料组分具有足够的过滤能力,因此不需要离心步骤。
·如果使用离线处理,则将上清液施用至上述流通式装置。
·施加正压或真空以引发流动。当使用标准类型的顶部玻璃料时,与使用经专门处理的疏水性顶部玻璃料相比,对所述流通式装置的流动建议将有所不同。典型的处理应使用精细的条件,可能会在处理将近结束时使压力或真空度逐渐变化。示例性处理可为:1PSI进行10秒钟,3PSI进行10秒钟,5PSI进行10秒钟,然后10PSI进行10秒钟。
·然后可以将洗出液蒸发,并将其复溶于适当的流动相中用于LC/MS分析。如果色谱条件和方法灵敏度允许,则洗出液可以用水稀释或不用水稀释直接注入LC/MS系统。
方法优化策略
对于困难的分析物,包括某些两性分析物(如加巴喷丁(gabapentin)和普瑞巴林(pregabalin)),以及为了提高某些其他药物的回收率,可以包含以下额外的步骤:
·在即将与ACN混合之前向尿液样品中添加10μL甲酸。
·在样品/ACN混合物流过后,另外等份的有机溶剂(例如ACN或MeOH)可以提高回收率。本文中100-200μL是有效的。应使用先前所述的真空或正压方法进行处理。
Claims (20)
1.流通式装置,包含至少一根分离柱,其中提供包含氧化铝和/或二氧化硅颗粒的第一填充组分和包含一种或多种吸湿性盐的粉末的第二填充组分。
2.根据权利要求1所述的装置,其中,所述第一填充组分包含氧化铝和/或官能化的二氧化硅。
3.根据权利要求2所述的装置,其中,所述二氧化硅包含一种或多种选自以下的官能团:具有4-18个碳原子的线性碳链、羧基、金属螯合基团和离子交换基团。
4.根据前述权利要求中任一项所述的装置,其中,所述吸湿性盐的粉末包含选自以下的一种或多种:硫酸镁、硫酸钠、乙酸钠、柠檬酸钠、柠檬酸钠倍半水合物、氯化钠和氧化镁。
5.根据权利要求4所述的装置,其中,所述第二填充组分是硫酸镁和乙酸钠的混合物。
6.根据前述权利要求中的任一项所述的装置,其中,所述填充组分被限制为第一填充组分是二氧化硅以及第二填充组分是硫酸镁和乙酸钠。
7.根据前述权利要求中的任一项所述的装置,其中,所述柱包含布置在所述第一填充组分和所述第二填充组分的相对侧的底部玻璃料和顶部玻璃料。
8.根据前述权利要求中任一项所述的装置,其中,所述第一填充组分和所述第二填充组分在所述柱中作为分别的层布置。
9.根据权利要求8所述的装置,其中,所述第一填充组分和所述第二填充组分已被中间玻璃料隔开。
10.根据权利要求1至7中任一项所述的装置,其中,所述第一填充组分和所述第二填充组分在所述柱中作为共混物提供。
11.根据前述权利要求中任一项所述的装置,其中,所述至少一根柱是管。
12.根据前述权利要求中任一项所述的装置,其包含排列在板上的多根柱。
13.根据前述权利要求中任一项所述的装置,其中,所述柱包含布置在所述第一填充组分和所述第二填充组分的上游的疏水性顶部玻璃料。
14.一种从生物样品中除去一种或多种基质组分的方法,其中所述基质组分是选自尿素、尿酸、磷脂、氨基酸、肌酸、血红素降解产物例如尿胆素以及内源性盐中的一种或多种,该方法包括使所述样品穿过包含氧化铝和/或二氧化硅颗粒的第一填充组分以及包含一种或多种吸湿性盐的粉末的第二填充组分。
15.根据权利要求14所述的方法,其中,所述样品是尿液。
16.根据权利要求14所述的方法,其中,所述样品是口腔液体,例如唾液。
17.根据权利要求14-16中任一项所述的方法,所述方法包含使所述样品穿过疏水性材料,然后穿过所述第一和第二填充组分。
18.包含氧化铝和/或二氧化硅的颗粒的第一填充组分与包含一种或多种吸湿性盐的粉末的第二填充组分的混合物用于从生物样品中除去一种或多种基质组分的用途。
19.根据权利要求18的用途,其中被除去的至少一种基质组分是色素,并且所述样品是尿液。
20.权利要求1至13中任一项所述的装置用于在分析例如质谱分析之前制备尿液样品的用途。
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JP2023100810A (ja) | 2023-07-19 |
US20200254362A1 (en) | 2020-08-13 |
US11617968B2 (en) | 2023-04-04 |
AU2018351586B2 (en) | 2023-03-02 |
AU2018351586A1 (en) | 2020-03-12 |
JP7274474B2 (ja) | 2023-05-16 |
EP3474011A1 (en) | 2019-04-24 |
CN117323698A (zh) | 2024-01-02 |
US20230191281A1 (en) | 2023-06-22 |
CA3078179A1 (en) | 2019-04-25 |
JP2021500555A (ja) | 2021-01-07 |
EP4389277A2 (en) | 2024-06-26 |
WO2019078773A1 (en) | 2019-04-25 |
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CN111107930B (zh) | 2024-03-29 |
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