CN103782151A - 流体生物样品的稳定化方法 - Google Patents
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Abstract
本发明涉及流体生物样品例如血液样品的快速稳定化方法。更具体地,该方法基于基体中所吸收的流体生物样品的热稳定化。
Description
技术领域
本发明涉及流体生物样品例如血液样品的快速稳定化方法。更具体地,该方法基于基体中所吸收的流体生物样品的热稳定化。
背景技术
药物通过酶或非酶过程而从身体中代谢或者清除。在药物动力学(PK)的研究中测量从身体中代谢/清除的速率。
药物在身体中的代谢主要发生在肝脏中(肝代谢),但也发生在循环系统(血液)及其它部位中。这种代谢分为两个阶段且主要取决于所涉及的酶。
阶段1:氧化、还原、水解、环化、以及氧的解环加成或者氢的去除。
阶段2:甲基化、硫酸化、乙酰化、葡萄糖醛酸化(glucuronidation)、以及谷胱甘肽接合(conjugation)。
许多药物被作为前药生产和给药,所述前药需要在身体中的化学或者酶处理以变得具有活性。全世界批准的药物中的约5-7%可归类为前药。2001和2002年中所批准的全部新药的大约15%是前药。
前药是在体内经历酶和或化学转化以释放出活性母体药物的药物分子的生物可逆衍生物。类型I是细胞内活化的那些,且类型II是细胞外(尤其是在消化液或体循环中)活化的那些。
类型I的前药可在血细胞中细胞内活化,且类型II的前药可通过胞外酶在血液中进行处理。活化可在身体外部在血液样品中继续进行。
在临床前开发及临床开发期间,药物(包括前药)的代谢的PK分析涉及许多血液样品的抽取和分析。需要避免这些血液样品的取样后代谢和降解的精确操作。
在制药工业中,干血斑(DBS)分析一直在快速地获取推进力。围绕实验动物损耗的经济和伦理问题以及与运输和储存生物样品有关的成本已经使DBS分析成为吸引人的选项。
DBS涉及血液样品在滤纸上的施用以及样品的后续干燥。样品的干燥通常需要2小时。
在滤纸上施用之后,对样品进行延长时间的干燥的需求是对DBS可应用方式的严重限制。具有所施用样品的滤纸必须水平干燥以减小重力的影响,当对大量样品进行操作时,这需要扩大的空间。在充分干燥之前,样品是湿的且需要小心操作以避免交叉样品污染、以及来自周围环境的污染(FTADMPK Cards,使用说明书,Whatman,Rev AB4/2011)。干燥时间很大程度上取决于环境温度和湿度,显著降低了再现性(Denniff&Spooner,Bioanalysis(2010)2(11),1817-1822)。暴露于高相对湿度和温度的条件可导致DBS样品的完整性受到损害(Denniff&Spooner,如前所述)。
在干燥期间,发生样品的取样后代谢和降解。为了限制取样后代谢和降解,使用涂布有各种抑制剂和稳定剂的滤纸。但是,该经涂布的滤纸的使用产生了其它类型的不期望的效果,例如,抑制剂和/或稳定剂对于样品后续分析的干扰以及样品的不均匀分布,产生诸如光环效应(haloeffect)(Ren等,Bioanalysis(2010)2(8),1469-1475)。
在干燥期间,还发生血液样品在滤纸上的过滤,引起血细胞与血浆的分离。在干燥期间的这些不期望的过程可导致不准确的DBS样品后续分析结果。
WO2007/024185中描述了生物样品通过快速加热而稳定化。但是,该方法的使用未被认为有可能应用于DBS样品。相反地,在DBS样品的操作中,推荐避免样品的加热,据说样品的加热降低了分析物的稳定性(DBSTechnical Tips,Whatman,2011年2月15日)或者有使样品变质的风险(CDC,Module14,Blood Collection and Handling-Dried Blood Spots)。
发明内容
本发明提供了流体生物样品的稳定化方法。该方法包括以下步骤:
(a)将所述流体的样品施用到基体中;和
(b)快速加热所述基体中的样品。
该方法可进一步包括如下步骤:将基体中的样品干燥足以使样品变得完全干燥的时间,例如,至少30分钟、40分钟、50分钟、1小时、2小时、或者3小时。
干燥可在储存和/或运输期间进行。优选与干燥剂例如二氧化硅一起置于封闭容器中。
所述流体生物样品可选自血液、血浆、血清、唾液、尿、滑液和脑脊髓液、以及组织匀浆。
优选地,所述流体生物样品是血液样品。
样品的加热可通过一种或多种公知的传热形式进行:传导、对流或辐射,例如通过微波辐射。
所述加热优选通过传导进行。
样品的加热优选进行到至少80℃例如至少85℃、至少90℃、或者至少95℃的温度,例如进行到100℃的温度。
样品的加热优选不进行到超过100℃的温度。
快速加热是指在比不进行加热的情况下样品干燥所需的时间短的时间以内,优选地例如,在60分钟以内、在30分钟以内、在15分钟以内、在10分钟以内、在5分钟以内、在2分钟以内、或者在1分钟以内,进行流体生物样品的加热。
所述加热进行足够长以允许样品中的蛋白质和酶发生变性的时间,例如,至少1秒,例如2秒、5秒、10秒、15秒、20秒、30秒、1分钟、2分钟、3分钟、4分钟、或者至少5分钟的时间。
样品的快速加热具有多个目的,
i)使样品快速稳定,最小化污染的风险,
ii)使样品快速稳定,允许简化操作、即时储存和/或运输,
iii)使能够导致样品中所存在的物质和代谢物的取样后酶降解和代谢的酶变性,
iv)消除对使用涂布有抑制剂和/或稳定剂的基体的需求,所述抑制剂和/或稳定剂已知在样品后续分析期间导致不均匀的样品和/或干扰,
v)降低或者防止细胞在基体中的过滤,提供均匀样品,和/或
vi)防止物质和代谢物在基体内的扩散,提供均匀样品。
在不加热的情况下,仅在完全干燥后获得样品的稳定化。由于干燥时间取决于环境温度和湿度,因此,样品的干燥时间将根据主要条件而显著变化,导致低的再现性和可重复性。
通过快速对样品进行加热限定的时间,在取样后的短且限定的时间后获得样品的稳定化,提供高的再现性和可重复性,在不同的时间和在不同的环境条件下取出的样品之间也是如此。
通过样品的快速加热,获得样品的稳定化,使得后续干燥条件不太关键。可允许在储存和/或运输期间进行后续干燥,优选在具有干燥剂例如二氧化硅的封闭容器内。
通过样品的快速加热,获得样品的稳定化,允许简化操作、即时储存和/或运输。
快速加热将产生基本上均匀的样品,允许以高精确度对样品的一部分进行后续冲孔和分析。
如由以下实施例中所示的结果表明的,即使样品的快速加热仅对总的干燥时间具有适中的影响,但是,快速加热确实导致了样品的稳定化,通过允许即时储存和/或运输而允许样品的简化操作,以及减少样品中所存在的物质的取样后酶降解和代谢。
因此,基体中的流体样品的快速加热消除了大量与操作流体样品的已知技术有关的问题,例如与用于操作DBS样品的当前技术有关的问题。
定义
基体是指多孔材料。
所述基体可由选自如下材料的材料制成:
·基于纤维素的材料,例如但不限于
-硝化纤维
-硝酸纤维素
-醋酸纤维素
-纤维素,例如
·Whatman FTA-DMPK-A、B和C Cards
·Whatman ET31Chr
·Whatman FTA Elute
·Ahlstrom226样品采集纸(Specimen Collection Paper)
-混合纤维素酯
·玻璃纤维介质,例如但不限于
-Agilent Dried Matrix Spotting Cards
·塑料聚合物,例如但不限于
-聚酯
-聚丙烯(LDPE、HDPE)
-聚醚砜
-丙烯酸类聚合物
-聚四氟乙烯(PTFE)
·混合聚合物
·聚酰胺
-天然的
·羊毛
·丝
-合成的
·芳族聚酰胺
·尼龙
·金属
-金属膜和箔
-金属网
所述基体可由两种或更多种前述材料的混合物制成。
所述基体可为不同种类的形状的前述材料,且具有或不具有结构体。所述结构体可为多孔的或纤维状的,纤维可为有序的,例如横向地、径向地、轴向地或者竖直地。
优选的基体为:
·Whatman DMPK-C Cards
·Whatman ET31Chr
·Agilent Dried Matrix Spotting Cards
·Ahlstrom226样品采集纸
本发明方法可用于流体生物样品的稳定化,以避免以下类型化合物的酶降解或代谢:
·制药化合物
·药物
·前药
·药物代谢物
·代谢物
·蛋白质
·肽
·脂质
·RNA
·DNA
可以预见的是,本文所述的任意方法或组合物可针对本文所述的任意其它方法或组合物实施。类似地,针对本发明的一个实施方式所讨论的任意特征可用于本发明的任意其它实施方式的范围内。
附图说明
图1是示出了25μl经稳定化的血液样品(◆)和25μl未经稳定化的血液样品(■)在室温下的纸上的干燥时间的图。
图2是示出了在按照不同处理的样品中的经代谢的奥司他韦(Oseltamivir)的量的图。样品A根据制造商的说明书按照标准程序处理,即,露天干燥2小时。样品B在具有二氧化硅的密封袋中干燥。样品C进行热稳定化并随后露天干燥。样品D进行热稳定化并随后在具有二氧化硅的密封袋中干燥。图2中的显示经代谢的奥司他韦%的数值是三个试样的平均值。
实施例
实施例1.血液样品的干燥时间
通过每5分钟对纸进行称重来监测25μl经稳定化的血液样品(-◆-)和25μl未经稳定化的血液样品(-■-)在室温下的纸上的干燥时间。通过使用StabilizorTM系统(Denator AB,Sweden)加热30秒来进行稳定化。在大约50分钟后,所述纸不失去更多的重量。发现,对于这两个样品,终点血液干物质为初始重量的约21%。结果示于图1中。
实施例2.奥司他韦在小鼠血液中的稳定化
奥司他韦的药物动力学
奥司他韦是羧酸奥司他韦(甲型流感中的病毒性神经氨酸苷酶糖蛋白的选择性抑制剂)的口服前药。奥司他韦主要通过羧酸酯酶1(CES1)经历向羧酸奥司他韦的快速生物转化。
虚线描绘了所述化合物在MRM测量期间的断裂(fragmentation)。
向小鼠血液中掺入(spike)500ng/mL奥司他韦。将25μL血液在WhatmanFTA DMPK-C Card上成斑。将所述斑点在室温下放置干燥,或者使用StabilizorTM系统(Denator AB,Sweden)进行热处理然后放置干燥。
表1.奥司他韦在小鼠血液中的稳定化
结果
与仅仅被动干燥所述样品相比,纸上样品的热处理大大地减少了前药奥司他韦的代谢。
实施例3.不同干燥条件的影响
向小鼠血液中掺入2000ng/mL奥司他韦。将25μL血液在Whatman FTADMPK-C Card上成斑。使所述斑点在进行或不进行预先热稳定化的情况下在不同条件下干燥。样品A根据制造商的说明书按照标准程序处理,即,露天干燥2小时。样品B在具有二氧化硅的密封袋中干燥。样品C进行热稳定化并随后露天干燥。样品D进行热稳定化并随后在具有二氧化硅的密封袋中干燥。图2中的显示经代谢的奥司他韦%的数值是三个试样的平均值。
结果
在已经经过热稳定化的样品中,存在显著较低量的经代谢的奥司他韦。在具有二氧化硅的密封袋中对未经热稳定化的样品进行干燥导致甚至更高量的经代谢的奥司他韦。与露天干燥相比,在具有二氧化硅的密封袋中对经热稳定化的样品进行干燥不影响经代谢的奥司他韦的量。这表明,经热稳定化的样品的干燥时间不影响经代谢的奥司他韦的量,使得可在收集和热稳定化后直接在具有二氧化硅的袋中储存和/或运输样品。
Claims (5)
1.流体生物样品的稳定化方法,所述方法包括以下步骤:
(a)将所述流体的样品施用到基体中;和
(b)快速加热所述基体中的所述样品。
2.权利要求1的方法,进一步包括以下步骤:
(c)干燥所述基体中的所述样品。
3.权利要求1-2中任一项的方法,其中所述流体生物样品选自血液、血浆、血清、唾液、尿、滑液和脑脊髓液、以及组织匀浆。
4.权利要求3的方法,其中所述流体生物样品是血液样品。
5.权利要求1-4中任一项的方法,其中所述基体由选自纤维素、基于纤维素的材料、玻璃纤维介质、塑料聚合物、混合聚合物、聚酰胺及金属的材料组成。
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- 2012-07-09 CN CN201280034584.3A patent/CN103782151A/zh active Pending
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- 2012-07-09 US US14/131,721 patent/US20140154730A1/en not_active Abandoned
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US6103192A (en) * | 1997-04-14 | 2000-08-15 | Genetec Corporation | Immobilizing and processing specimens on matrix materials for the identification of nucleic acid sequences |
WO2004023144A1 (en) * | 2002-09-05 | 2004-03-18 | Mirari Biosciences, Inc. | Directed microwave chemistry |
US20040191831A1 (en) * | 2003-03-25 | 2004-09-30 | Council Of Scientific And Industrial Research | Rapid heat - mediated method for enzyme - linked immunosorbent assay procedure |
WO2007024185A1 (en) * | 2005-08-26 | 2007-03-01 | Denator Ab | Preparing biological samples for analysis |
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WO2013009254A1 (en) | 2013-01-17 |
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