CN1184472C - 葡萄糖传感器 - Google Patents
葡萄糖传感器 Download PDFInfo
- Publication number
- CN1184472C CN1184472C CN00802139.2A CN00802139A CN1184472C CN 1184472 C CN1184472 C CN 1184472C CN 00802139 A CN00802139 A CN 00802139A CN 1184472 C CN1184472 C CN 1184472C
- Authority
- CN
- China
- Prior art keywords
- sensor
- glucose sensor
- glucose
- acid
- layer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- 239000008103 glucose Substances 0.000 title claims abstract description 69
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims abstract description 18
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Abstract
本发明提供了保存稳定性良好、应答特性有所提高的高性能葡萄糖传感器。该传感器具备电绝缘性基板，设置在前述基板上的至少由工作电极和配极形成的电极系统，以及接触前述电极系统或形成于其附近的至少以吡咯并喹啉醌为辅酶且包含葡萄糖脱氢酶的反应层，前述反应层中包含了选自葡糖酸及其盐的至少1种添加剂。
Description
技术领域
本发明涉及能够以高精度迅速、简便地对试样中的特定组分进行定量的葡萄糖传感器。更具体涉及以吡咯并喹啉醌为辅酶的使用了葡萄糖脱氢酶的葡萄糖传感器。
背景技术
以往，提出了各种生物传感器用于不用对试样溶液进行稀释和搅拌就能够简易地对试样溶液中的特定组分进行定量的方法。这种生物传感器的例子如下所述(日本专利公开公报平2-062952号)。
利用丝网印刷等方法在绝缘性基板上形成由工作电极、配极和参考电极组成的电极系统，然后，接触该电极系统形成包含亲水性高分子、氧化还原酶和电子接受体的酶反应层，就构成了上述生物传感器。
在该生物传感器的酶反应层上滴下包含基质的试样溶液，使酶反应层溶解，并使酶和基质反应，与此同时电子接受体被还原。然后，通过电化学方法使被还原的电子接受体氧化，由此时获得氧化电流值求得试样溶液中的基质浓度。
从原理上讲，通过以测定对象物质为基质，对酶进行适当的选择，能够用上述生物传感器进行各种物质的测定。
例如，如果选择葡萄糖氧化酶，则能够制得可对试样溶液中的葡萄糖浓度进行测定的葡萄糖传感器。
一般，酶在上述构成的生物传感器中保持干燥状态。由于酶的主要组分为蛋白质，所以，如果和空气中的水分长时间接触，就有出现变性的危险。此外，在极端情况下，也可能出现酶失活。
因此，传感器如果长时间保存，有时会出现酶活性下降，和基质反应的酶量不足，所得应答电流值和基质浓度不成比例等现象。
所以，为了获得具备良好保存稳定性的生物传感器，关键是调整酶附近的环境使酶活性能够长时间保持。另外，为了使酶反应时电子和基质的移动顺利进行，还有必要提高传感器的应答性。
另一方面，为了制得高性能的葡萄糖传感器，可采用以吡咯并喹啉醌为辅酶的葡萄糖脱氢酶(以下称为“PQQ-GDH”)。由于使用了PQQ-GDH的葡萄糖传感器中PQQ-GDH的催化反应和氧无关，所以具备血液等中的溶氧对酶反应完全无影响的特性。因此，由该葡萄糖传感器测得的值不会因为试样溶液中的氧分压而出现误差，即，能够获得高性能的传感器。
但是，使用了PQQ-GDH的葡萄糖传感器还是明显存在因长期保存而使应答值下降的缺陷。这就说明葡萄糖传感器的保存时间如果较长，就会导致应答值下降。传感器的制作完成后，一般在一定时间以后传感器就不能够再使用了。因此，因长期保存而导致应答值下降的传感器不能够正确地对葡萄糖浓度进行定量测定。
本发明鉴于上述问题提供了保存稳定性良好、且初期应答性有所提高的高性能葡萄糖传感器。
发明的揭示
本发明的葡萄糖传感器具备电绝缘性基板，设置在前述基板上的至少由工作电极和配极形成的电极系统，以及接触前述电极系统或形成于其附近的至少以吡咯并喹啉醌为辅酶且包含葡萄糖脱氢酶的反应层，该传感器的特征是，前述反应层中包含了选自葡糖酸及葡糖酸盐的至少1种添加剂。
前述反应层中还可包含选自邻苯二甲酸、邻苯二甲酸盐、马来酸、马来酸盐、琥珀酸及琥珀酸盐的至少1种添加剂。
前述反应层中还可包含钙离子。
前述葡糖酸盐为葡糖酸钾、葡糖酸钠、葡糖酸钙、葡糖酸钴或葡糖酸铜。
前述反应层中还可包含电子传递体。
对附图的简单说明
图1为除去了反应层的本发明实施例之一的葡萄糖传感器的斜视图。
图2为图1所示葡萄糖传感器的主要部位的纵截面图。
图3为比较例1的葡萄糖传感器的应答特性图。
图4为本发明实施例1的葡萄糖传感器的应答特性图。
图5为实施例1的葡萄糖传感器及比较例1的葡萄糖传感器在保存前的应答特性图。
图6为本发明实施例2的葡萄糖传感器的应答特性图。
图7为实施例2的葡萄糖传感器及比较例1的葡萄糖传感器在保存前的应答特性图。
图8为本发明实施例3的葡萄糖传感器的应答特性图。
图9为实施例3的葡萄糖传感器及比较例1的葡萄糖传感器在保存前的应答特性图。
图10为本发明实施例4的葡萄糖传感器的应答特性图。
图11为实施例4的葡萄糖传感器及比较例1的葡萄糖传感器在保存前的应答特性图。
图12为本发明实施例5的葡萄糖传感器的应答特性图。
实施发明的最佳状态
如上所述，本发明的葡萄糖传感器的包含PQQ-GDH的反应层中添加了葡糖酸及/或其盐。
本发明者们在包含PQQ-GDH的反应层中添加葡糖酸及/或其盐后发现，传感器的保存稳定性有了大幅度的提高。葡糖酸及/或盐在温度、湿度、电荷状态等不断变化的环境中保护了PQQ-GDH，通过这种方式使保存稳定性有所提高。为了使这种效果更好地发挥出来，最好在反应层形成部位滴下葡糖酸及/或其盐和PQQ-GDH的混合溶液，然后通过干燥形成反应层。由这种方法形成反应层后，由于酶被葡糖酸分子包围，所以能够在温度、湿度、电荷状态等不断变化的环境中有效地保护PQQ-GDH。其结果是，能够长期稳定地保持酶活性。
此外，本发明者们在包含了PQQ-GDH的反应层中添加葡糖酸及/或其盐后发现，传感器保存前的应答性，即初期特性也有所提高。由于葡糖酸或其盐都易溶于水，当它们包含在反应层中时，如果在反应层中添加试样溶液，则反应层马上溶于试样溶液中，能够使酶反应和电极反应顺利进行。
能够显现上述效果的添加剂除了葡糖酸之外，还包括葡糖酸钾、葡糖酸钠、葡糖酸钙、葡糖酸钴和葡糖酸铜等。特别是使用葡糖酸钾时，能够获得保存稳定性和应答特性俱佳，空白值非常小的葡萄糖传感器。这里的空白值是指使用完全不包含作为基质的葡萄糖的试样溶液，例如水时的传感器应答值。
单独使用邻苯二甲酸、马来酸、琥珀酸及它们的盐虽然也能够保护PQQ-GDH，但其效果不如葡糖酸及其盐，所以，将其与葡糖酸或其盐一起添加，能够起到协同的效果，使传感器的保存稳定性更高。此外，由于邻苯二甲酸、马来酸、琥珀酸及它们的盐易溶于水，所以，当它们包含在反应层中时，如果在反应层中添加试样溶液，则反应层马上溶于试样溶液中，能够使酶反应和电极反应顺利进行，并能够提高初期特性。
邻苯二甲酸、马来酸、琥珀酸及它们的盐都是能够起到缓冲剂作用的化合物，根据需要，可用盐酸、乙酸等酸或NaOH、KOH等碱调整到规定pH，再添加到反应层形成试剂中。较好的pH范围是5.0～8.5。当然，也可采用在其他缓冲剂中加入了上述添加剂的溶液。
由于葡糖酸、邻苯二甲酸、马来酸、琥珀酸及它们的盐都是易吸湿的化合物，为使其在葡萄糖传感器制作开始时才和酶接触，所以，应该在制作葡萄糖传感器时添加，而不是预先加入酶中。包含了上述添加剂的葡萄糖传感器最好以密封状态保存。保存葡萄糖传感器时，最好将其保存在加入了硅胶等吸湿剂的密封容器中。
以0.5～5μl作为试样溶液的血液为测定对象的一次性传感器中，对应于0.2～20U/传感器的酶量，上述葡糖酸或其盐的添加量应该在1.5～150μg/传感器的范围内。从保存稳定性和减小空白值考虑，最好在15～50μg/传感器的范围内。另一方面，对应于前述传感器，邻苯二甲酸、马来酸、琥珀酸及它们的盐的添加量较好是在O.025～25μg/传感器的范围内，更好是在0.1～3μg/传感器的范围内。这里的U表示单位(unit)。
其他较好的添加剂还有赋予钙离子的氯化钙等。一般，在形成PQQ-GDH的二聚物时，钙离子是必需的。因此，在反应层形成试剂中由氯化钙等导入钙离子，在传感器的制作过程中或制作完成后，起到防止PQQ-GDH解离成二聚体、对保持其活性有用。氯化钙的添加量是，对应于上述传感器，最好在5～70ng(纳克)/传感器。
本发明的生物传感器的反应层中还可包含随着酶反应的进行而被还原的电子传递体。该电子传递体可用铁氰化钾、对苯醌及其衍生物、N-甲基吩嗪甲基硫酸盐(phenazine methosulfate)、亚甲蓝和二茂铁及其衍生物等。
本发明的生物传感器的反应层中还可包含亲水性高分子。通过在反应层中添加亲水性高分子，能够防止反应层从电极系统表面或基板表面剥离。此外，亲水性高分子还具备防止反应层表面破裂的效果，能够有效提高生物传感器的可靠性。
所用亲水性高分子包括羧甲基纤维素、羟乙基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、乙基羟乙基纤维素、羧乙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚赖氨酸等聚氨基酸、聚苯乙烯磺酸、明胶及其衍生物、丙烯酸及其盐的聚合物、甲基丙烯酸及其盐的聚合物、淀粉及其衍生物、马来酸酐及其盐的聚合物、琼脂糖凝胶及其衍生物。
生物传感器内的反应层除了形成于电绝缘性基板上的电极系统上之外，在不影响本发明效果的前提下，可配置在其他各种位置上。例如，能够配置在前述基板的电极系统上以外的位置。此外，生物传感器最好还具备盖板。这种盖板和前述基板组合，在和基板形成的空隙间形成向前述电极系统供给试样溶液的试样溶液供给通道。前述反应层也可配置在盖板在试样溶液供给通道中露出的表面上。
随着酶反应的进行而被还原的电子传递体的氧化电流测定方法包括仅由工作电极和配极形成的二电极方式，以及工作电极、配极和参考电极形成的三电极方式，其中，三电极方式更能够进行正确的测定。
本发明的生物传感器的反应层中添加了前述添加剂，在不影响本发明效果的前提下，也可添加其他稳定剂。该稳定剂包括金属盐、蛋白质、氨基酸、糖、有机酸和表面活性剂等。
可使用的金属盐包括锶和锰等的卤化物、硫酸盐和硝酸盐等。可使用的蛋白质只要不影响酶活性即可，包括牛血清白蛋白(BSA)、卵白蛋白和明胶等。
可使用的氨基酸除了赖氨酸、组氨酸和谷氨酸等普通氨基酸之外，还包括甘氨酰甘氨酸和聚赖氨酸等。其中，较好的是具备较高水溶性的氨基酸。
可使用的糖包括单糖、二糖、低聚糖和多糖等各种类型的糖，此外，还可使用它们的衍生物。具体包括葡萄糖、果糖、半乳糖、甘露糖、木糖、蔗糖、乳糖、麦芽糖、海藻糖、麦芽三糖、麦芽环糊精、α-环糊精、β-环糊精、γ-环糊精、糊精、直链淀粉、动物淀粉、淀粉、旋覆花素、葡萄糖胺、肌醇、甘露糖醇、山梨糖醇、核糖醇和脱氧葡萄糖等。
可使用的有机酸包括α-氧代戊二酸、苹果酸、富马酸、胆酸及脱氧胆酸等。
表面活性剂最好为非离子性表面活性剂。
其他还可添加硼酸、硼砂、氯化钾、氯化钠、硫酸铵、甘油、フィコ-ル、EDTA、EGTA、DTT、DTE、GSH、2-巯基乙醇等。
这些稳定剂的添加量是，对应于100重量份PQQ-GDH，较好为0.01～100重量份。
为防止作为辅酶的吡咯并喹啉醌(PQQ)从PQQ-GDH脱离，还可在反应层中添加PQQ。PQQ的添加量最好在0.04～20ng/传感器的范围内。
本发明所用的酶PQQ-GDH可用各种来源的材料。
包含上述添加剂，还根据需要包含前述稳定剂的本发明的使用了PQQ-GDH的葡萄糖传感器不仅价格低廉，而且，对酶的基本性能不会产生不良影响，能够保持酶的性能。
以下，通过实施例对本发明进行说明，但本发明并不仅限于此。
图1为除去了反应层的本发明实施例之一的生物传感器的分解斜视图。通过丝网印刷在聚对苯二甲酸乙二醇酯形成的电绝缘性基板1上涂上银糊状物，形成引线2和3。然后，在基板1上印刷包含树脂粘合剂的导电性碳糊状物，形成工作电极4，该工作电极4和引线2接触。接着，在基板1上印刷绝缘性糊状物，形成绝缘层。绝缘层6覆盖工作电极4的外周部，使工作电极4的露出部分面积保持一定。然后，在基板1上印刷包含树脂粘合剂的导电性碳糊状物使糊状物和引线3接触，形成环状配极5。
在上述绝缘性基板1上形成后述的反应层后，在图1的点划线所示位置粘接带有切口10的隔层8及备有空气孔11的盖板9，制得生物传感器。在隔层8的切口10的部分形成了试样溶液供给通道。传感器端部的切口10的开放端口为试样溶液供给通道的试样溶液供给口。
图2是本发明的生物传感器的纵截面图。在形成了电极系统的基板1上形成了包含酶和电子传递体的反应层7。反应层7最好形成于电极系统上，也可在电极系统附近，例如配置在盖板侧，露出在试样溶液供给通道中。反应层7如图所示，由亲水性高分子层7a及形成于其上的包含PQQ-GDH和添加剂的层7b构成。
比较例1
在图1的基板1的电极系统上滴下5μl作为亲水性高分子的羧甲基纤维素的钠盐(以下略称为“CMC”)的0.5wt％水溶液，于50℃的温热风干燥器中进行10分钟干燥后，形成CMC层7a。然后，在CMC层7a上滴下5μl包含1000U/ml的PQQ-GDH和50mM的铁氰化钾的混合水溶液，干燥后形成层7b。制得葡萄糖传感器。
接着，准备作为试样溶液的葡萄糖浓度为30～620mg/dl的血液。在反应层7上滴下该试样溶液，向反应层供给这种包含葡萄糖的试样溶液后，试样溶液中的葡萄糖通过PQQ-GDH氧化，与此同时，反应层中的铁氰化钾被还原成亚铁氰化钾。在试样溶液滴下30秒后，以配极5为基准，对工作电极4施加+0.5V的电压，进行亚铁氰化钾的氧化。5秒钟后，测定配极和工作电极间的电流值。
测定各种不同葡萄糖浓度的血液的电流值，以葡萄糖浓度为横轴、电流值为纵轴，绘制传感器的应答特性图，其结果如图3的实线所示。
将同样制得的生物传感器置于添加了作为吸湿剂的硅胶的密封容器中，于40℃保存1周后，绘制该生物传感器的应答特性图。其结果如图3中的虚线所示。
从图3可看出，葡萄糖浓度和应答电流值间存在一定的相关性。但是，和刚制作完毕的传感器，即保存前的传感器相比，在40℃保存1周后的传感器的应答性有所下降。
实施例1
与比较例1同样形成CMC层7a后，在CMC层7a上滴下5μl包含1000U/ml的PQQ-GDH、50mM的铁氰化钾和40mM的葡糖酸钾的混合水溶液，干燥后形成层7b。制得葡萄糖传感器。
与比较例1同样，绘制刚制作完毕时的传感器和于40℃在装入了硅胶的密封容器内保存1周后的传感器的应答特性图，其结果如图4所示。从图4可看出，葡萄糖浓度和应答电流值间存在一定的相关性。本实施例的传感器和比较例1相比，在40℃保存1周后的应答中，特别在浓度400mg/dl以上的范围内，应答电流值下降幅度较小。这是因为添加葡糖酸钾后大幅度提高了葡萄糖传感器的保存特性。
不包含葡糖酸钾的比较例1的传感器和包含葡糖酸钾的本实施例的传感器在保存前的应答特性的比较如图5所示。从图5可看出，包含葡糖酸钾的葡萄糖传感器和不包含葡糖酸钾的葡萄糖传感器相比，在600mg/dl附近的应答值较高。这是因为添加葡糖酸钾后改善了在高浓度区域的葡萄糖传感器的应答性。
实施例2
与比较例1同样形成CMC层7a后，在CMC层7a上滴下5μl包含1000U/ml的PQQ-GDH、50mM的铁氰化钾、40mM的葡糖酸钾及0.5mM的邻苯二甲酸氢钾的混合水溶液，干燥后形成层7b。制得葡萄糖传感器。
与比较例1同样，绘制刚制作完毕时的传感器和于40℃在装入了硅胶的密封容器内保存1周后的传感器的应答特性图，其结果如图6所示。从图6可看出，刚制作完毕时的传感器和在40℃保存了1周的传感器的应答特性几乎无差别，这说明和比较例1相比，本实施例的传感器的保存特性有了大幅度提高。
不包含葡糖酸钾的比较例1的传感器和包含葡糖酸钾及邻苯二甲酸氢钾的本实施例的传感器在保存前的应答特性的比较如图7所示。从图7可看出，包含葡糖酸钾及邻苯二甲酸氢钾的葡萄糖传感器和比较例1的传感器相比，在600mg/dl附近的应答值较高。这是因为添加葡糖酸钾及邻苯二甲酸氢钾后改善了在高浓度区域的葡萄糖传感器的应答性。
实施例3
与比较例1同样形成CMC层7a后，在CMC层7a上滴下5μl包含1000U/ml的PQQ-GDH、50mM的铁氰化钾、40mM的葡糖酸钾及0.5mM的马来酸的混合水溶液，干燥后形成层7b。制得葡萄糖传感器。
与比较例1同样，绘制刚制作完毕时的传感器和于40℃在装入了硅胶的密封容器内保存1周后的传感器的应答特性图，其结果如图8所示。从图8可看出，刚制作完毕时的传感器和在40℃保存了1周的传感器的应答特性几乎无差别，这说明和比较例1相比，本实施例的传感器的保存特性有了提高。
不包含葡糖酸钾的比较例1的传感器和包含葡糖酸钾及马来酸的本实施例的传感器在保存前的应答特性的比较如图9所示。从图9可看出，包含葡糖酸钾及马来酸的葡萄糖传感器，在600mg/dl附近的应答值较高。这是因为添加葡糖酸钾及马来酸后改善了在高浓度区域的葡萄糖传感器的应答性。
实施例4
与比较例1同样形成CMC层7a后，在CMC层7a上滴下5μl包含1000U/ml的PQQ-GDH、50mM的铁氰化钾、40mM的葡糖酸钾及0.5mM的琥珀酸的混合水溶液，干燥后形成层7b。制得葡萄糖传感器。
与比较例1同样，绘制刚制作完毕时的传感器和于40℃在装入了硅胶的密封容器内保存1周后的传感器的应答特性图，其结果如图10所示。从图10可看出，刚制作完毕时的传感器和在40℃保存了1周的传感器的应答特性几乎无差别，这说明和比较例1相比，本实施例的传感器的保存特性有了提高。
比较例1的传感器和包含葡糖酸钾及琥珀酸的本实施例的传感器在保存前的应答特性的比较如图11所示。从图11可看出，包含葡糖酸钾及琥珀酸的葡萄糖传感器，在600mg/dl附近的应答值较高。这是因为添加葡糖酸钾及琥珀酸后改善了在高浓度区域的葡萄糖传感器的应答性。
实施例5
与比较例1同样形成CMC层7a后，在CMC层7a上滴下5μl包含1000U/ml的PQQ-GDH、50mM的铁氰化钾、40mM的葡糖酸钾及0.5mM的邻苯二甲酸氢钾及75μM的氯化钙的混合水溶液，干燥后形成层7b。制得葡萄糖传感器。
与比较例1同样，绘制刚制作完毕时的传感器和于40℃在装入了硅胶的密封容器内保存1周后的传感器的应答特性图，其结果如图12所示。从图12可看出，刚制作完毕时的传感器和在40℃保存了1周的传感器的应答特性几乎无差别，这说明在40℃的高温条件下保存1周时，本实施例的传感器显现出良好的保存特性。
产业上利用的可能性
如上所述，本发明获得了保存稳定性良好、且应答性有所提高、具备高性能的葡萄糖传感器。
Claims (5)
1.葡萄糖传感器，所述传感器具备电绝缘性基板，设置在前述基板上的至少由工作电极和配极形成的电极系统，以及接触前述电极系统或形成于其附近的至少以吡咯并喹啉醌为辅酶且包含葡萄糖脱氢酶的反应层，其特征在于，前述反应层中包含了选自葡糖酸及其盐的至少1种添加剂。
2.如权利要求1所述的葡萄糖传感器，其中，前述反应层中还可包含选自邻苯二甲酸、邻苯二甲酸盐、马来酸、马来酸盐、琥珀酸及琥珀酸盐的至少1种添加剂。
3.如权利要求1或2所述的葡萄糖传感器，其中，前述反应层中还可包含钙离子。
4.如权利要求1所述的葡萄糖传感器，其中，前述葡糖酸盐为葡糖酸钾、葡糖酸钠、葡糖酸钙、葡糖酸钴或葡糖酸铜。
5.如权利要求1所述的葡萄糖传感器，其中，前述反应层中还可包含电子传递体。
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| JP284871/1999 | 1999-10-05 | ||
| JP28487199 | 1999-10-05 |
Publications (2)
| Publication Number | Publication Date |
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| CN1327536A CN1327536A (zh) | 2001-12-19 |
| CN1184472C true CN1184472C (zh) | 2005-01-12 |
Family
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| CN00802139.2A Expired - Lifetime CN1184472C (zh) | 1999-10-05 | 2000-10-02 | 葡萄糖传感器 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US7005048B1 (zh) |
| EP (1) | EP1146332B8 (zh) |
| JP (1) | JP3867959B2 (zh) |
| CN (1) | CN1184472C (zh) |
| AT (1) | ATE313790T1 (zh) |
| CA (1) | CA2347594C (zh) |
| DE (1) | DE60024965T2 (zh) |
| WO (1) | WO2001025776A1 (zh) |
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- 2000-10-02 AT AT00963053T patent/ATE313790T1/de not_active IP Right Cessation
- 2000-10-02 US US09/807,692 patent/US7005048B1/en not_active Expired - Lifetime
- 2000-10-02 EP EP00963053A patent/EP1146332B8/en not_active Expired - Lifetime
- 2000-10-02 JP JP2001528689A patent/JP3867959B2/ja not_active Expired - Lifetime
- 2000-10-02 WO PCT/JP2000/006853 patent/WO2001025776A1/ja active IP Right Grant
- 2000-10-02 DE DE60024965T patent/DE60024965T2/de not_active Expired - Lifetime
- 2000-10-02 CN CN00802139.2A patent/CN1184472C/zh not_active Expired - Lifetime
- 2000-10-02 CA CA002347594A patent/CA2347594C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ATE313790T1 (de) | 2006-01-15 |
| EP1146332A4 (en) | 2004-05-12 |
| EP1146332A1 (en) | 2001-10-17 |
| JP3867959B2 (ja) | 2007-01-17 |
| EP1146332B1 (en) | 2005-12-21 |
| DE60024965T2 (de) | 2006-07-13 |
| EP1146332B8 (en) | 2006-06-07 |
| WO2001025776A1 (fr) | 2001-04-12 |
| CA2347594C (en) | 2006-11-28 |
| CN1327536A (zh) | 2001-12-19 |
| CA2347594A1 (en) | 2001-04-12 |
| US7005048B1 (en) | 2006-02-28 |
| DE60024965D1 (de) | 2006-01-26 |
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