CN1322914C - 分离/纯化或提取用粒状载体及其生产方法 - Google Patents
分离/纯化或提取用粒状载体及其生产方法 Download PDFInfo
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- CN1322914C CN1322914C CNB018175368A CN01817536A CN1322914C CN 1322914 C CN1322914 C CN 1322914C CN B018175368 A CNB018175368 A CN B018175368A CN 01817536 A CN01817536 A CN 01817536A CN 1322914 C CN1322914 C CN 1322914C
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- carbide
- bead
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- carbonaceous material
- diamond
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Abstract
一种粒状载体,其上能以高密度高度特异性地吸附靶物质,并且能以显著提高的效率回收它;以及一种分离/纯化或提取的方法。所述粒状载体包括碳质材料和/或碳化物,它可用于分离/纯化或提取与生物体相关的物质。所述方法包括,利用上述粒状载体分离/纯化或提取与生物体相关的物质。
Description
技术领域
本发明涉及优选用于分离/纯化或提取与生物相关的物质(例如,核酸,包括DNA和RNA,蛋白质,糖类,以及具有疏水性的低分子有机化合物)的粒状载体,及其生产方法。
按本发明,术语“与生物相关的物质”表示生物的组成成分,例如,核酸,包括DNA和RNA,蛋白质,糖类,以及具有疏水性的低分子有机化合物。
发明背景
人们早已知道用于在其上固定吸附剂和吸收剂的粒状固相载体,包括人们熟知的二氧化硅颗粒。由于使用时固定在这些载体表面的与生物相关的物质的密度低,所以,回收与生物相关的物质的效率低到需要长时间回收的程度。因此,应用这些载体的方法不简便。
例如,如JP-A-11-313670中所述,利用了一种在载体上吸附和分离核酸的方法,所述载体是通过使含磁性物质的二氧化硅颗粒表面载有聚丙烯酰胺而制备的,以及一种分离具有特异性核苷酸序列的核酸的方法,该方法包括如下步骤,即,使核酸与通过利用酰胺键将寡核苷酸固定在无孔的有机聚合物颗粒表面而制备的载体形成杂交体。
然而,这些方法引起这些载体的表面非特异性吸附或更低吸附水平。因此,一直需要改善回收与生物相关的物质的效率。
本发明的一个目的是克服上述问题。具体地说,本发明的一个目的是提供一种粒状载体,它对于靶物质具有高吸附特异性和高吸附密度,并且具有大为提高的回收效率,以及提供一种生产它们的方法。
发明公开
本发明人进行了研究以实现所述目的。本发明人发现了,碳质材料和/或碳化物的粒状物表面或者通过用碳质材料和/或碳化物涂布陶瓷颗粒或磁性颗粒表面而制备的粒状物的表面能在其上以高密度特异性地固定与生物相关的物质,从而能显著提高回收效率。
此外,为了生产这样的粒状载体,本发明人发现了,通过对所述粒状物表面的化学改性,可进一步增大被固定的量。
本发明基于这些发现。
一方面,本发明提供了一种用于分离/纯化或提取与生物相关的物质的碳质材料和/或碳化物的粒状载体。
在本发明第二方面,所述碳质材料可以是选自金刚石、无定形碳、类金刚石碳和石墨的一种材料或多种材料的组合。
此外,在本发明第三方面,所述碳化物可以是选自碳化硅、碳化钨和/或碳化钛的一种碳化物或多种碳化物的组合。
另外,在本发明第四方面,所述碳质材料可以是金刚石和/或非金刚石碳。
在第五方面描述的、本发明这样的粒状载体可通过用所述碳质材料和/或碳化物涂布陶瓷颗粒或磁性颗粒表面而制备。
在该情况下,在本发明第六方面,所述陶瓷颗粒可以是选自二氧化硅、氧化铝和/或碳化硅的一种陶瓷或多种陶瓷的组合。
在本发明第七方面,所述碳质材料和/或碳化物的涂层厚度优选是1nm或更大。
那么,在本发明第八方面,优选对所述碳质材料和/或碳化物的表面进行化学改性,以致可在末端排列一种极性基。
此外,在本发明第九方面,优选将核酸和/或蛋白质固定在所述碳质材料和/或碳化物的表面。
在第十方面,上述本发明的粒状载体可通过一种生产粒状载体的方法以简单的方式生产,该方法包括这一步骤,即,对所述碳质材料和/或碳化物的表面进行化学改性,以致可在末端排列一种极性基。
在第十一方面,在生产粒状载体的方法中,进行化学改性以致可在末端排列一种极性基的步骤优选包括,对所述碳质材料和/或碳化物的表面进行氢化处理、氯化处理、氨基化处理和羧基化处理。
换句话说,在第十二方面,进行化学改性以致可在末端排列一种极性基的步骤优选包括,所述碳质材料和/或碳化物的表面的氢化处理,在氯气中借助于紫外线辐照对其表面的氯化处理,在氨气中借助于紫外线辐照的氨基化处理和通过在非水溶剂中与羧酸酰氯反应的羧基化处理,以及中和处理。
在第十三方面,生产本发明的粒状载体的方法可通过在流体槽型光反应器中进行化学改性以致可在末端排列一种极性基的步骤来实施,所述反应器包括:一个真空容器,一个在该真空容器上以可移动的方式安装的玻璃滤器,一块处于真空容器外侧的石英玻璃板,一个在石英玻璃板外部的高压水银弧光灯,一条通氯、氩气和氨的管,一条抽真空的管,以及用于控制进入管内的流量的阀。
附图简述
图1是一个流体槽型光反应器的剖面图。图2是一个用于测定金刚石颗粒表面固定的物质量的装置示意图。
实施本发明的最佳方式
现在将在下文更详细地描述本发明。
在本发明第一方面,本发明的粒状载体的构成成分包括碳质材料和/或碳化物。
碳质材料表示通过共价键连接在金属等物质上的碳原子,该材料包括例如,选自金刚石、无定形碳、类金刚石碳和石墨的一种材料或多种材料的组合,如在第二方面中所述。
具体地说,具有高得多的固定化密度的金刚石是优选的。
在第四方面,所述碳质材料是金刚石和/或非金刚石碳。
就金刚石来说,可应用任何合成的金刚石,在高压下制备的金刚石或天然金刚石。另外,它的结构可以是单晶的或多晶的。就生产率来说,优选应用通过气相合成法(例如,微波等离子体CVD)生产的金刚石。
至于非金刚石碳,可应用石墨、无定形碳或类金刚石碳的任一种。
术语“碳化物”表示碳与比碳更正性的元素的化合物,它包括例如,选自碳化硅、碳化钨和/或碳化钛的一种碳化物或多种碳化物的组合,如本发明第三方面中所述。
至于在第五方面,本发明粒状载体可通过用碳质材料和/或碳化物涂布陶瓷颗粒或磁性颗粒表面而制备。
术语“陶瓷颗粒”表示由陶瓷材料制备的颗粒,它包括例如,二氧化硅、氧化铝和碳化硅的颗粒,如本发明第六方面中所述。
术语“磁性颗粒”表示具有磁性的材料颗粒。优选的是,优选利用具有一种性能的磁性颗粒,以致该磁性颗粒在磁场中能产生强的磁性,但是当离开磁场时就失去磁性(即,具有顺磁性)。
磁性颗粒包括例如,尖晶石型或铅酸盐(bran bite)型铁氧体,以及主要成分是铁、镍和钴的合金。
在该情况下,如在第七方面中所述,涂层的厚度是1nm或更大,优选是1nm~1,000nm。
在1nm以下,基本上不能发挥涂层的效果。另一方面,在1,000nm以上,应用了实体涂层的顶表面。所以,从劳动力和成本方面考虑是效率低的。
用碳质材料和/或碳化物的涂布可通过已知方法进行。例如,可通过下列方法进行涂布:例如,微波等离子体CVD、ECRCVD、IPC、直流溅射、ECR溅射、离子镀敷、电弧离子镀敷、EB沉积、电阻加热沉积和淤浆涂布。
所述粒状载体的平均粒径范围优选是1~5,000μm。在该范围以外,反应效率(例如,分离/纯化或提取期间的分离密度(separationdensity)和分离速率)太差而从强度的保持方面考虑不是优选的。
优选的是,特意使本发明的粒状载体表面变得粗糙。这样的粗糙表面优选可具有增大的基材表面积,于是,可以固定大量DNA等。
在本发明的粒状载体中,优选地对所述碳质材料和/或碳化物的表面进行化学改性以致可在末端排列一种极性基,以便容易在基材表面固定与生物相关的物质。
所述极性基包括,例如,羟基、羧基、硫酸基、氰基、硝基、巯基、氨基、环氧基和活性酯基。可通过0~12个碳原子(优选0~6个碳原子)的烃基将极性基固定在所述碳质材料和/或碳化物的表面。
例如,当极性基是羧基时,在碳质材料和/或碳化物的表面连接一元羧酸(例如,甲酸、乙酸和丙酸),二元羧酸(例如,草酸、丙二酸、琥珀酸、马来酸和富马酸),多元羧酸(例如,偏苯三酸)。优选地,在其上连接草酸和琥珀酸。这样的化学改性可通过肽键或酯键等固定在碳质材料和/或碳化物的表面。
如第九方面中所述,本发明的粒状载体可在碳质材料和/或碳化物的表面固定核酸和/或蛋白质。
通过本方法对碳质材料和/或碳化物的表面进行化学改性以后,可在其上固定结合到与生物相关的靶物质上的核酸(例如,DNA和RNA)和/或蛋白质。
待固定的核酸可选自DNA、RNA、多核苷酸等,适当地,取决于需要有意分离/纯化的与生物相关的物质。对来源没有特别限制。还可应用来自高等动物、高等植物、真菌、细菌和病毒的天然核酸以及人工修饰的核酸和合成多核苷酸。对于链长度没有特别限制,但从简单操作的角度来考虑,链长度优选是4~50kb。
不但可固定单链核酸,还可固定双链核酸。
就双链核酸来说,至少一端优选是粘性末端,以便以简单的方式稳固地固定所述双链。
如果对碳质材料和/或类似物的表面进行化学改性,至少一端具有两个或更多个含伯胺的核苷酸,用于通过酰胺键与活性酯基强烈固定化来进行化学改性。
含伯胺的核苷酸的典型实例包括腺嘌呤(A)、胞嘧啶(C)和鸟嘌呤(G)。特别地,腺嘌呤(A)或鸟嘌呤(G)是优选的。
现在举例说明固定具有两个或更多个在其末端含伯胺的核苷酸的双链DNA的方法。
第一种方法是,利用具有两个或更多个在5′端含伯胺的引物,通过从mRNA逆转录获得互补DNA。
就引物来说,可应用在5′端含伯胺的核苷酸,优选具有两个或更多个腺嘌呤(A)分子和/或鸟嘌呤(G)分子。
第二种方法是,利用具有两个或更多个在5′端含伯胺的引物,通过PCR扩增(特异性模板DNA)。
就引物来说,制备了在5′端含伯胺的核苷酸,优选一组具有两个或更多个腺嘌呤(A)分子和/或鸟嘌呤(G)分子的引物。
第三种生产方法包括,使需要有意固定的DNA与限制酶反应,该限制酶例如是,具有对一个位点(其中,序列中存在两个或更多个含伯胺的核苷酸)的特异性切割活性的EcoRI。
第四种方法是,直接将末端具有伯胺的核苷酸添加到平端多核苷酸。
此外,可以根据需要分离或纯化的与生物相关的物质来适当地选择需要固定的蛋白质。当与生物相关的物质例如是酶时,可选定底物。就抗体来说,可选定抗原或半抗原。
如在第十方面中所述,一种包括如下步骤的方法可生产本发明的粒状载体,即,对碳质材料和/或碳化物的表面进行化学改性,以致可在末端排列一种极性基。
对碳质材料和/或碳化物的表面进行化学改性以致可在末端排列一种极性基的方法包括下述方法:一种方法,它包括用氧等离子体氧化碳质材料和/或类似物的表面的步骤以及后续蒸汽处理的步骤;一种方法,它包括氢化处理碳质材料和/或类似物的表面的步骤,在氯气中用紫外线辐照而氯化碳质材料和/或类似物的表面的步骤,以及后续在碱性溶液中水解而羟基化的步骤;一种方法,它包括用氧等离子体氧化碳质材料和/或类似物的表面的步骤,随后氯化和在碱溶液中水解而羟基化的步骤;一种方法,它包括氢化处理碳质材料和/或类似物的表面的步骤,随后在氯气中用紫外线辐照而氯化碳质材料和/或类似物的表面的步骤,以及在非水溶剂中与苏打羧酸盐反应的步骤;等等。
此外,如果碳质材料表面存在羟基,就用硅烷偶联剂、钛偶联剂和铝偶联剂在其上进行处理,于是化学改性更强烈。
如果极性基是羧基,进行化学改性的最优选的步骤是,如在第十一方面中所述,优选进行碳质材料和/或碳化物的表面的氢化处理,它的氯化处理,它的氨基化处理和它的羧基化处理。
至于第十二方面,更具体地说,下述方法是优选的,它包括:碳质材料和/或类似物的表面的氢化处理,在氯气中用紫外线辐照而氯化碳质材料和/或类似物的表面,在氨气中用紫外线辐照而氨基化,在非水溶剂中与羧酸酰氯反应和在弱碱性溶液中中和。
至于第十三方面,可通过在流体槽型光反应器中进行化学改性以致可在末端排列一种极性基来进行这样的化学改性,所述反应器包括:一个真空容器,一个在该真空容器上以可移动的方式安装的玻璃滤器,一块处于真空容器外侧的石英玻璃板,一个在石英玻璃板外部的高压水银弧光灯,一条通氯、氩气和氨的管,一条抽真空的管,以及用于控制进入管内的流量的阀。
流体槽型光反应器的一个实例如图1中所示。
图1的装置装有真空容器2,其中包含玻璃滤器1。玻璃滤器的作用是作为容纳需要在其中有意进行化学改性的碳质材料和/或碳化物的部件,而且以相对于真空容器2可移动的方式安装。
通过真空容器2外侧的石英玻璃板3安装了高压水银弧光灯4,于是,可在结构上对真空容器内部进行紫外线辐照、
真空容器2装有管5,氯、氩气(Ar)和氨可流过它,以及将真空容器内部抽真空的管6。这些管受三通阀V1、阀V2、阀V3和三通阀V4的控制。
当应用图1的光反应器时,可进行氢化、氯化和氨基化,而碳质材料和/或碳化物可留在玻璃滤器1中,无需将碳质材料和/或碳化物从真空容器2中取出。另外,可将碳质材料和/或碳化物与玻璃滤器1一起取出,并且可按简单方式羧基化。
本发明的粒状载体可用于分离/纯化或提取与生物相关的物质。
换句话说,在反应液中,与生物相关的物质(例如,DNA、RNA、蛋白质、糖类和具有疏水性的低分子有机化合物)被吸附在粒状载体上,然后从溶液中被分离或纯化。此外,可通过从所述粒状载体(其上已经预先吸附了DNA等)中溶解DNA等而获得靶物质。
除了分离/纯化或提取以外,所述粒状载体也可用于各种检验方法而分析与生物相关的物质等,还可用作分离工具的载体而通过亲和层析法分离与生物相关的物质。
利用本发明的粒状载体来分离/纯化或提取与生物相关的物质的方法的一个实例如下所述:利用本发明的粒状载体,将该粒状载体与含有与生物相关的物质的样品混合,使样品中的核酸吸附到粒状载体上,可用NaOH水溶液或热水从粒状载体提取核酸。
实施例
实施例1(金刚石粒状载体)
应用图1中所示的光反应器,通过下述方法生产了粒状载体。
(1)金刚石颗粒表面的氢化
在900℃的氢气氛中处理金刚石颗粒(粒径为30μm;由OsakaDiamond Co.,Ltd.生产的)3小时而氢化。
(2)金刚石颗粒表面的氯化和氨基化
打开图1装置中的真空容器并取出玻璃滤器,在其中放置上文(2)中氢化的金刚石颗粒。将玻璃滤器固定在真空容器内,盖好盖子。
调节三通阀V1而流通通道B,开启阀V2。开启阀V3,另外,调节三通阀V4而流通通道C,对真空容器的内部抽真空。
关闭阀V3,调节三通阀V1而流通通道A,Ar流入真空容器而调节容器内部至1.1atm。随后,停止Ar的流动。开启阀V3,对真空容器的内部抽真空。
重复让Ar流入真空容器的操作三次。
关闭阀V3,调节三通阀V4而流通通道D,流入氯气而调节容器内部至1.1atm。随后,停止氯的流动。开启阀V3,再次开始氯的流动,用高压水银弧光灯辐照金刚石颗粒达5分钟,同时使金刚石颗粒在氯气中流动。停止氯的流动,调节三通阀V4而流通通道C,抽真空。
重复让Ar流入真空容器的操作三次。
关闭阀V3,调节三通阀V4而流通通道D。流入氨而调节容器内部至1.1atm。停止氨的流动。开启阀V3。再次开始氨的流动,用高压水银弧光灯辐照金刚石颗粒达30分钟,同时使金刚石颗粒流动。停止氨的流动,调节三通阀V4而流通通道C,抽真空。关闭阀V3,并且开启Ar的流动,打开真空容器的盖子,将样品与玻璃滤器一起取出。
(3)金刚石颗粒表面的羧基化
将图1装置的玻璃滤器安装在具有一个旋塞的吸气瓶内(瓶内装有10vol.%琥珀酰氯和1,4-二烷溶液),浸溃15min。随后,开启旋塞,吸出琥珀酰氯。然后,依次用1,4-二烷(三次)和10 wt%碳酸钾水溶液(三次)漂洗所述金刚石颗粒,另外用水漂洗三次。将所得金刚石颗粒干燥。
(4)评估对于与生物相关的物质的分离特性
用一种如图2中所示评估固定量的装置来评估形成的粒状载体对于与生物相关的物质的分离/纯化或提取特性。图2的固定化装置包括:用来放置需要评估的粒状载体的池11,用来循环溶液的泵12,管13和盛溶液的容器14。
1)活化
将1mL羧基化金刚石颗粒置于用来评估固定量的装置的池11内。在压力下用泵12将下列组成的溶液填充入池11。使金刚石颗粒在室温下在其中静置30分钟而活化。
溶液
N-羟基琥珀酰亚胺 20mM
1-[(二甲氨基)丙基]3-乙基碳二亚胺 0.1M
磷酸盐缓冲液,pH6 0.1M
2)寡核苷酸的固定
在压力下用泵将寡核苷酸(见序列表中的序列号No.1)的无菌10nm/mL水溶液填充入池中。使金刚石颗粒在室温下在其中静置2小时而固定寡核苷酸。
3)互补寡核苷酸的杂交
用泵将C端被Cy3(由Amersham-Pharmacia Biotech Co.,Ltd.生产的)修饰了的寡核苷酸(见序列表中的序列号No.2)的无菌10nm/mL水溶液在池中循环60分钟。随后,用无菌水将池漂洗三次。
4)互补寡核苷酸的脱杂交和检测
在60℃下在池内循环0.3M NaOH水溶液,使互补寡核苷酸脱杂交。
检测Cy3的荧光强度(570nm)并基于浓度计算,从而测定每1mL金刚石颗粒的固定量。
结果,上述粒状载体上的固定量是5×104pmol/mL。
实施例2(DLC粒状载体的生产)
按与实施例1中相同的方式,不同的是,用类金刚石碳(DLC)颗粒代替金刚石颗粒,生产了一种粒状载体。同样评估了粒状载体上的固定量。
结果,上述粒状载体上的固定量是5×103pmol/mL
实施例3(石墨粒状载体的生产)
按与实施例1中相同的方式,不同的是,用石墨颗粒代替金刚石颗粒,生产了一种粒状载体。同样评估了粒状载体上的固定量。
结果,上述粒状载体上的固定量是1×103pmol/mL。
实施例4(碳化物粒状载体的生产)
按与实施例1中相同的方式,不同的是,用碳化物颗粒代替金刚石颗粒,生产了一种粒状载体。同样评估了粒状载体上的固定量。
结果,上述粒状载体上的固定量是1×103pmol/mL。对比例(可商购的产品)
利用通过将抗生物素蛋白结合在纤维素载体上而生产的可商购的粒状载体(由Amersham-Pharmacia Biotech Co.,Ltd.生产的“Av idin-sepharose”),按与实施例1中相同的方式评估了粒状载体上的固定量。
结果,上述粒状载体上的固定量是5×102pmol/mL。
上述结果表明,与可商购的产品相比,本发明的粒状载体以高固定密度固定与生物相关的物质。
工业适用性
本发明的粒状载体以高固定密度固定与生物相关的物质,具有更少的非特异性吸附。所以,本发明的粒状载体适用于分离/纯化或提取与生物相关的物质。
此外,本发明的粒状载体可通过本发明的生产方法以简单方式生产。
当使用时,本发明的粒状载体可在短时间实现高效率回收与生物相关的物质。所以,本发明的粒状载体适用于在医疗领域中诊断疾病,还适用于生物化学和分子生物学各个领域中的研究工作。
序列表
<110>TOYO KOHAN CO.,LTD.
<120>分离/纯化或提取用粒状载体及其生产方法
<130>4071PCT
<150>JP 2000-318337
<151>2000-10-18
<160>2
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<212>DNA
<213>人工序列
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Claims (10)
1.一种用于分离/纯化或提取与生物相关的物质的碳质材料和/或碳化物的粒状载体,其中,所述碳质材料是选自金刚石、无定形碳、类金刚石碳和石墨的一种材料或多种材料的组合,或者所述碳化物是选自碳化硅、碳化钨和碳化钛的一种碳化物或多种碳化物的组合,所述碳质材料和/或碳化物的粒状载体的表面在末端含有羟基、羧基、硫酸基、氰基、硝基、巯基、氨基、环氧基或活性酯基。
2.权利要求1的粒状载体,其中,所述碳质材料是金刚石和/或非金刚石碳。
3.权利要求1或2的粒状载体,其中,在陶瓷颗粒或磁性颗粒表面涂布所述碳质材料和/或碳化物。
4.权利要求3的粒状载体,其中,所述陶瓷颗粒是选自二氧化硅、氧化铝和碳化硅的一种陶瓷或多种陶瓷的组合。
5.权利要求3的粒状载体,其中,所述碳质材料和/或碳化物的涂层厚度是1nm或更大。
6.权利要求1或2的粒状载体,其中,将核酸和/或蛋白质固定在所述碳质材料和/或碳化物的表面。
7.一种生产权利要求1~6任一项所述的粒状载体的方法,其中,所述碳质材料是选自金刚石、无定形碳、类金刚石碳和石墨的一种材料或多种材料的组合,或者所述碳化物是选自碳化硅、碳化钨和碳化钛的一种碳化物或多种碳化物的组合,该方法包括这一步骤,即,对所述碳质材料和/或碳化物的表面进行化学改性,以致可在末端排列一种极性基,所述极性基由羟基、羧基、硫酸基、氰基、硝基、巯基、氨基、环氧基或活性酯基组成。
8.权利要求7的生产粒状载体的方法,其中,进行化学改性以致可在末端排列一种极性基的步骤包括,对所述碳质材料和/或碳化物的表面进行氢化处理、氯化处理、氨基化处理和羧基化处理。
9.权利要求7的生产粒状载体的方法,其中,进行化学改性以致可在末端排列一种极性基的步骤包括,所述碳质材料和/或碳化物的表面的氢化处理,在氯气中借助于紫外线辐照对其表面的氯化处理,在氨气中借助于紫外线辐照的氨基化处理和通过在非水溶剂中与羧酸酰氯的反应的羧基化处理,以及中和处理。
10.权利要求7~9任一项的生产粒状载体的方法,其中,进行化学改性以致可在末端排列一种极性基的步骤是在一个流体槽型光反应器中进行的,该反应器包括:一个真空容器,一个在该真空容器上以可移动的方式安装的玻璃滤器,一块处于真空容器外侧的石英玻璃板,一个在石英玻璃板外部的高压水银弧光灯,一条通氯、氩气和氨的管,一条抽真空的管,以及用于控制进入管内的流量的阀。
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US5182016A (en) * | 1990-03-22 | 1993-01-26 | Regents Of The University Of Minnesota | Polymer-coated carbon-clad inorganic oxide particles |
US5431821A (en) * | 1992-02-07 | 1995-07-11 | The Ohio State University | Glassy carbon in separation processes |
JPH06298508A (ja) * | 1993-04-08 | 1994-10-25 | Nippon Steel Corp | 黒鉛状炭素吸着体 |
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JP2000143225A (ja) * | 1998-11-06 | 2000-05-23 | Showa Denko Kk | 活性炭素材およびその製造法 |
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2000
- 2000-10-18 JP JP2000318337A patent/JP4001710B2/ja not_active Expired - Fee Related
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2001
- 2001-10-15 AU AU2001294249A patent/AU2001294249A1/en not_active Abandoned
- 2001-10-15 US US10/399,564 patent/US20040035787A1/en not_active Abandoned
- 2001-10-15 WO PCT/JP2001/009024 patent/WO2002032568A1/ja not_active Application Discontinuation
- 2001-10-15 KR KR10-2003-7005471A patent/KR20040010545A/ko not_active Application Discontinuation
- 2001-10-15 EP EP01974847A patent/EP1342502A1/en not_active Withdrawn
- 2001-10-15 CN CNB018175368A patent/CN1322914C/zh not_active Expired - Fee Related
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JPS529696A (en) * | 1975-07-14 | 1977-01-25 | Cosmo Co Ltd | Manufacturing method of magnetic-sensitive active carbon |
JPS63243022A (ja) * | 1987-03-31 | 1988-10-07 | Tokyo Organ Chem Ind Ltd | 超純水中のエンドトキシン除去法 |
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Also Published As
Publication number | Publication date |
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EP1342502A1 (en) | 2003-09-10 |
CN1469775A (zh) | 2004-01-21 |
JP2002126510A (ja) | 2002-05-08 |
WO2002032568A1 (fr) | 2002-04-25 |
JP4001710B2 (ja) | 2007-10-31 |
US20040035787A1 (en) | 2004-02-26 |
AU2001294249A1 (en) | 2002-04-29 |
KR20040010545A (ko) | 2004-01-31 |
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