CN85109750A - 用于体外循环治疗中的脂蛋白吸附剂及其制备方法 - Google Patents
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Abstract
一种用于体外循环治疗的脂蛋白吸附剂是由不溶于水的多孔硬质凝胶构成。该凝胶经用球蛋白测定,其排斥极限值为106~109。构成该凝胶的聚合物至少部分分子含有羟基。该凝胶表面的羟基至少有部分被转化成硫酸酯。使用本发明的吸附剂,能有选择地和有效地除去病人体液中的LDL和VLDL。本发明的吸附剂比根据亲合色谱原理制备的吸附剂生产成本低,因为制备后一种吸附剂要使用相当昂贵的配位体。
Description
本发明涉及用于体外循环治疗中以除去血液中有害脂蛋白的吸附剂及其制备方法。该吸附剂尤其能有选择地吸附血液、血浆或血清中的低密度脂蛋白(下称“LDL”)和极低密度脂蛋白(下称“VLDL”)。
现已知道,在血液脂蛋白中,LDL和VLDL含有大量胆固醇,并能引起动脉硬化。血胆固醇过多症(如家族性高脂血)表明LDL值比在正常情况下观察到的高几倍,并能导致冠状动脉硬化。
虽然已经用DH-581(Probucol)或DOWex(cholestyramine)来治疗血胆固醇过多症(如家族性高脂血)但效果是有限的,并担心会引起不良的副作用。至今,尤其是家族性高脂血仅用所谓血浆交换疗法就能得到有效的治疗。即,将病人体内的血浆分离,并与正常的血浆或含有白蛋白的置换液交换。但如大家所熟知的那样,血浆交换疗法有着许多缺点,即:
(1)它需要使用昂贵的新鲜血浆或血浆成分。
(2)它不仅除去了有害的成份,也除去了有效的成份。
(3)它有感染上肝炎病毒的危险,等等。
为了克服上述缺点,用一种膜除去血液中有害成分的方法已被采用。但是此法仍有缺点。例如,它没有足够的选择性,并需要在血浆中补充与有害成分同时除去的那部分蛋白质。
为了同样的目的,也采用免疫吸附剂的方法。此法可将抗体固定在吸附剂中。尽管此方法的选择性是大体满意的,但还存在许多问题,如难得到抗体;抗体价钱贵;吸附剂难以消毒和在保存过程中稳定性差。
此外,现已采用一种基于亲合色谱原理的吸附剂。即是,将对有害成分具有亲合力的化合物(下称“配位体”)固定于其中。此种吸附剂选择性好,所用的配位体也不太贵。但,为了大量用于体外循环治疗,价格还得降低。由于这种吸附剂有一个由软质凝胶(如琼脂糖)制得的载体,所以使体液流速降低,并常常发生堵塞。
Maaskant N等人已推出了一种廉价的脂蛋白吸附剂。它是在水溶液中,在r-射线照射下由聚硫酸乙烯脂(聚乙烯醇和硫酸生成的酯)发生交联而制得,产物不溶于水。但是,在该制备方法中,由于通过交联作用得到的水不溶性多孔凝胶是由水溶性聚合物予先转变成硫酸酯而得,随着交联反应的进行,硫酸基的量大大降低。同时由于在聚合物转变成硫酸酯中硫酸基的亲水性,在交联反应中使用的溶剂实质上限于水,因此,导致可应用的交联方法受到很大程度的限制,此外,还存在如很难成珠的问题。
用于体外循环的血液灌注或血浆灌住疗法(所谓去血浆法)中的吸附剂需要有足够的机械强度(耐压性),这样才能流速快。而按上述方法制备的凝胶是由具有高度亲水性的聚合物构成。即使是用交联等法制成的水不溶性凝胶,也不是硬质凝胶。由于会发生结块,这种凝胶不适用于体外循环。
本发明的内容是提供一种用于体外循环治疗的安全、廉价的吸附剂。它能有选择性地除去LDL和VLDL。它是通过先制得不溶于水的多孔硬质凝胶,然后再直接硫酸酯化。
本发明提供了一种用于体外循环治疗的脂蛋白吸附剂。该吸附剂由一种不溶于水的经球蛋白测定,排斥极限为106~109的多孔硬质凝胶构成。构成该凝胶的聚合物至少有部分分子含有羟基,至少部分表面羟基转化成硫酸酯。本发明还提供了一种用于体外循环治疗的脂蛋白吸附剂的制备方法。该吸附剂是硬质的,具有很大的吸附能力和极好的选择性。先制得一种不溶于水的多孔硬质凝胶,经球蛋白测定,其排斥极限值为106~109。构成该凝胶的聚合物至少有部分分子含有羟基,并将其表面上的羟基直接转化成硫酸酯。
图1是参照例子中流速与压差的关系图。
在本发明中,使用的是一种不溶于水的多孔硬质凝胶。该凝胶是由至少有部分分子含有羟基的聚合物构成。
上面所说的硬质凝胶,可以是晶状聚合物。或者本来就不溶于水或通过交联后变成不溶于水。
结构单元的聚合物,如聚甲基丙烯酸羟乙酯或含有甲基丙烯酸羟乙酯的共聚物等等;多糖。如纤维素、含羟基的纤维素衍生物,包括羟乙基纤维素、琼脂糖和葡聚糖。其中以至少部分分子中含有
结构单元的聚合物或多糖尤其可取。
聚合物中的羟基可以来自能形成聚合物的单体,如聚乙烯醇或聚甲基丙烯酸羟乙酯;也可以通过对聚合物进行化学改造的方法来导入;或者来自于为形成不溶性凝胶而使用的交联剂。
上面提及的含有羟基或在反应中生成羟基的交联剂的非限制性例子,例如含羟基的多价不饱和化合物,如戊四醇的二甲基丙烯酸酯,二亚丙稀-〔2〕-基戊四醇和丙三醇的二甲基丙烯酸酯;含有环氧乙烷环的化合物,如3-氯-1.2-环氧丙烷,丁二醇二缩水甘油醚和缩水甘油的甲基丙烯酸酯。
如前所述,为了得到不溶于水的聚合物,交联作用可在聚合中、聚合后或者既在聚合中也在聚合后进行。本发明中所用的不溶于水的凝胶可通过任一交联方法制备。如象上面所说的那样,在聚合中交联,聚合后交联或既在聚合中也在聚合后交联。另外本发明中所用的不溶于水的凝胶应是硬质凝胶。
文中“硬质凝胶”这一术语指的是这种凝胶与软质凝胶(如葡聚糖、琼脂糖或聚丙烯酰胺)相比遇溶剂不易溶胀,遇压力不易变形。用下面方法可以将硬质凝胶与软质凝胶相互区别:如下面的参照例子所示,将水溶液通过一均匀填有凝胶的园柱,测定流速与压差的关系。硬质凝胶几乎呈线性关系,软质凝胶却呈非线性关系,而且当压力超过某一点时,还会变形和结块,致使流速不能增大。在本发明中,至少压力在0.3kg/cm2时具有上述线性关系的凝胶就称作“硬质凝胶”。
制备硬质凝胶的方法很多,任何一种方法都能在本发明中使用。
有时,虽然不溶于水的凝胶完全是由含有羟基的聚合物制成,但也仅仅得到软凝胶。通常,这是由于这种聚合物具有高度亲水性的缘故。然而,在这种情况下,如果在含羟基的聚合物中加上另一种不一定含有羟基但能生成硬质凝胶的聚合物,也能形成硬质凝胶。
在此情形下,硬质凝胶的形成可通过某些方法来进行,例如将两种以上聚合物混合;在前先制备好的硬质凝胶表面涂上含有羟基的聚合物。然而,本发明不限于这些方法。
本发明中“多孔”这一术语的含义是指这种凝胶的孔率不少于20%,比表面不小于3m2/g。
本发明中使用的由至少部分分子含有羟基的聚合物制成不溶于水的多孔硬质凝胶。首先,要有直径大的连续孔,以便分子量至少不小于1×106的大分子LDL和VLDL容易进入孔内而被吸附。
测量孔大小的方法很多。最常用的是汞测孔法。对于亲水凝胶,也常常用排斥极限来衡量孔的大小。
如文献(例如“实验高速液相色谱”)中所述,本发明中术语“排斥极限”的含义是指在凝胶渗透色谱中不能渗透入孔中也即被排斥的分子的最小分子量。
大家都知道,排斥极限值随所使用的物质种类不同而变化。通过象球蛋白、葡聚糖和聚乙二醇这样的分子测定排斥极限值已进行过很多研究,而以脂蛋白测排斥极限值则困难很多。因此,在本发明中是用认为最类似于脂蛋白的物质-球蛋白来测排斥极限值。
本发明者对具有不同排斥极限值的各种不溶于水的多孔凝胶进行了研究,其结果意外地表明,排斥极限值约为1×106(较LDL和VLDL的分子量小)的凝胶能够在某种程度上吸附LDL和VLDL。而孔径较大的凝胶并非总是呈现增大的吸附能力,反而可以观察到,这种凝胶的吸附能力降低,或者吸附除LDL和VLDL以外的其它蛋白质。这意味着存在一个最适宜的孔径范围问题。也就是说,发现,排斥极限小于1×106的不溶于水的多孔硬质凝胶几乎不吸附LDL和VLDL,所以不适宜在实际中使用。而排斥极限为一百万至几百万(接近LDL和VLDL的分子量)的不溶于水的多孔硬质凝胶能吸附LDL和VLDL到一定程度,并观察到,吸附LDL和VLDL的量随排斥极限的增大而增加,逐渐达到它的顶点。当排斥极限超过1×108时,则吸附量急剧下降。这是由于在这一排斥极限范围内,单位体积凝胶中构成不溶于水的多孔硬质凝胶的至少部分分子含有羟基的聚合物含量降低,其结果单位体积凝胶中羟基的量也降低,致使聚合物中不能引进足够量的硫酸基。因此,本发明中所用的不溶于水的多孔硬质凝胶的排斥极限是106~108,最好是3×106~7×107。
关于本发明中使用的不溶于水的多孔硬质凝胶结构,为了吸附较大量的LDL和VLDL,凝胶的各个部分都均匀分布有孔的结构,比仅在凝胶表面有孔的结构好。
本发明中使用的不溶于水的多孔硬质凝胶的形状可以任意选择,如粒状、纤维状、片状和空心纤维。当使用粒状不溶于水的多孔硬质凝胶时,颗粒的大小以1~500μm为好。
用多种方法都可以至少将不溶于水的多孔硬质凝胶的部分羟基硫酸酯代。例如,在吡啶或N,N-二甲基甲酰胺存在下,含羟基的不溶于水的多孔硬质凝胶与氯磺酸或三氧化硫反应;在溶剂(如N,N-二甲基甲酰胺)中,羟基与硫酸直接反应。虽然任一方法都可用来将羟基硫酸酯化,但硫酸酯化最好在无水或近于无水的条件下进行,因为这样的条件可提高硫酸酯化效率。
由于本发明中的不溶于水的多孔硬质凝胶是用上述方法转化成硫酸酯,所以在不溶于水的多孔硬质凝胶表面的羟基大体上直接转化成硫酸脂。
硫酸基的引入量以每|m|水不溶的多孔硬质凝胶含0.1μmol至10mmol为宜,含10μmol至1mmol更为合适。当引入量小于0.1μmol时,不能获得足够的吸附能力。当引入量超过10mmol时,会发生非特性吸附,尤其是对纤维蛋白原吸附增加,会引起体液pH改变。这样一来就会使得这种凝胶实际上不能使用。
本发明的吸附剂可以通过各种方法对病人进行治疗。
最简单的方法如下:即将病人的血液引出体外并放入一血袋中,用本发明中的吸附剂与血混合以吸附LDL和VLDL,然后通过过滤器除去吸附剂,经过处理的血液再输回病人体内。虽然这种方法不需要复杂的装置,但存在这样的缺点,即,一次处理的血量很少,花费在处理和操作上的时间较多,所以有点麻烦。
另一方法是将填有本发明吸附剂的柱子装入体外循环系统中,让血液循环。或者将全血直接循环,或者仅让从血液中分得的血浆通过柱子。本发明的吸附剂可用于上述两种方法,但使用后一种方法更好。
加入多价金属离子到要处理的血液或血浆中,可提高本发明吸附剂的选择性和除去LDL及VLDL的效率。如加入碱土金属离子:钙离子、镁离子、钡离子、锶离子;周期表中第Ⅲ族离子:铝离子;第Ⅶ族离子:锰离子;第Ⅷ族离子:钴离子。
使用本发明吸附剂,可以从病人体液中有选择地和有效地将LDL和VLDL除去,而且本发明吸附剂比根据亲合色谱原理制备的吸附剂生产成本低,后一制备方法要使用相当昂贵的配位体。
下面的参照例子、实例和对照例子将本发明作更详细的叙述和说明。当然,本发明不限于这些例子,在不违背本发明的范筹和精神下可以进行种种的变化和改进。
参照例子
用压缩泵分别将水通过三个装有不同凝胶的园玻璃柱。其中,一柱填充琼脂糖凝胶(Biogel A5m Bio-rad公司生产,颗粒大小:50~100目)。另两柱分别填充由聚合物制得的硬质凝胶(Toyopearl HW 65,东洋曹达有限公司制造,颗粒大小:50~100μm;Cellulofine GC-700 chisso公司制造,颗粒大小:45~105μm)。柱长150mm,内径9mm,两头装有孔径为15μm的过滤器。测定流速与压力的关系。结果见图1。
如图1所示,对由聚合物制得的硬质凝胶来说,流速的增大几乎与压力的增加成正比,而琼脂糖凝胶则发生结块,即使增加压力,流速也不增大。
实例1
用在乙醇中临界点干燥法将10ml交联的聚丙烯酸酯凝胶(Toyopearl HW75,一种各部分都有孔的硬质凝胶,蛋白质排斥极限:5×106,颗粒大小:50~100μm)干燥,将得到的干燥凝胶悬浮于10ml已充分脱水的N,N-二甲基甲酰胺中,用冰冷却此悬浮液,在搅拌下滴入1ml氯磺酸。加完后继续搅拌10分钟。反应完毕后,用10%氢氧化钠水溶液中和此反应混合物。过滤此凝胶,用大量过量水洗涤,得到一种不溶于水的多孔硬质凝胶,在其表面引入了0.4mmol/ml硫酸基。
实例2
使用在日本未审查专利公开号12656/1983的例子中所述的方法,即将100克乙酸乙烯酯、24.1克异氰尿酸三烯丙酯、124克乙酸乙酯、124克庚烷、3.1克聚酸乙烯酯(聚合度:500)、3.1克2,2′-偶氮双异丁腈,400ml水(按重量算,水中溶有1%聚乙烯醇,0.05%NaH2PO4·12H2O、1.5%Na2HPO4·12H2O)在烧瓶中混合均匀,于56.5℃搅拌18小时,再在75℃搅拌5小时。经过充分搅拌后,该悬浮液发生聚合,得到一种粒状共聚物。过滤,用水洗涤,丙酮提取,在由46.5克氢氧化钠和2升甲醇组成的溶剂中于40℃进行18小时酯交换反应。所得不溶于水的多孔硬质凝胶是以乙烯醇为主要结构单元(排斥极限:约1.8×106,平均颗粒大小:150μm)。用在丙酮中临界点干燥法将10ml该硬质凝胶干燥,得到的干燥凝胶悬浮于10ml经充分脱水的N,N-二甲基甲酰胺中,用冰冷却此悬浮液,在搅拌下滴入1ml氯磺酸,加完后,继续搅拌10分钟。反应完全后,此反应混合物用10%。氢氧化钠水溶液中和。过滤此凝胶,用水充分洗涤,得到一种不溶于水的多孔硬质凝胶,引入其表面的的硫酸其量为0.8mmol/ml。
实例3、4和对照例1
将实例1和实例2中制得的每种凝胶1ml分别放入试管中,加入患家族性高脂血病人的血浆6ml,将得到的混合物在搅拌下于37℃培养2小时(实例3、4),测定每管上清液中LDL、VLDL、HDL胆固醇和纤维蛋白原的量。结果列于表1。
在不加吸附剂的情况下也测定LDL、VLDL、HDL胆固醇和纤维蛋白原的量,其结果列于表1(对照例子1)。
如表1所示,应用根据本发明的方法制备的吸附剂,能吸附LDL和VLDL,而几乎不吸附HDL胆固醇和纤维蛋白原。
实例5
用在乙醇中临界点干燥法将10ml多孔纤维素凝胶(CKgel A-3 Chisso公司制造,对球蛋白的排斥极限:5×107,颗粒大小:45~105μm)干燥,得到的干燥凝胶被悬浮于10ml经充分脱水的吡啶中,用冰冷却此悬浮液,在搅拌下滴入2ml氯磺酸,加完后继续搅拌10分钟。反应完全后,将此凝胶过滤,相继用吡啶和水洗涤,得到一种纤维素凝胶,引入其表面的硫酸基量见表2。
实例6
用在乙醇中临界点干燥法将10ml多孔纤维素凝胶(cellulofin GCL-2000,Chisso公司制造,球蛋白排斥极限:3×107颗粒大小45-105μm,是一种交联凝胶)干燥。得到的干燥凝胶被悬浮在10ml经充分脱水的吡啶中,用冰冷却此悬浮液,在搅拌下滴入2ml氯磺酸。加完后,继续搅拌10分钟。反应完全后,将此凝胶过滤,相继用吡啶和水洗涤,得到一种纤维素凝胶,引入其表面的硫酸基量见表2。
实例7
用在乙醇中临界点干燥法将10ml CKgel A-3干燥,得到的干燥凝胶被悬浮在10ml经充分脱水的二甲基甲酰胺中。在冰冷却下加入12ml4MN,N-二环己基碳化二亚胺/二甲基甲酰胺溶液,在搅拌下滴入6ml2M硫酸/二甲基甲氯胺溶液,于0℃继续搅拌2小时。反应完成后,将此凝胶过滤,相继用二甲基甲酰胺和水洗涤,得到一种纤维素凝胶,引入其表面的硫酸基量见表2。
实例8
用在乙醇中临界点干燥法将10ml Cellulofine GCL-2000干燥,得到的干燥凝胶被悬浮于10ml经充分脱水的二甲基甲酰胺中,加入12ml 4MN,N-二环己基碳化二亚胺/二甲基甲酰胺溶液,用冰冷却,在搅拌下滴入6ml2M硫酸/二甲基甲酰胺溶液,于0℃继续拌2小时。反应完成后,将此凝胶过滤,相继用二甲基甲酰胺和水洗涤,得到一种纤维素凝胶,引入其表面的硫酸基量见表2。
实例9、10
重复例5的步骤,但实例9和实例10分别使用6ml和8ml氯磺酸,得到一种纤维素凝胶,引入其表面的硫酸基量见表2。
对照例2
重复实例5的步骤,但Cellulofine GC 700(Chisso公司制造,球蛋白排斥极限:4×105,颗粒大小:45-105μm)用作纤维素凝胶,在得到的纤维素凝胶表面引入的硫酸基量见表2。
实例11-16对照例3、4
分别将实例5-10和对照例2制得的凝胶各1ml放入试管中,加入6ml从患家族性高脂血病的病人身上得到的血浆。在搅拌下于37℃培养2小时(分别为实例11-16和对照例3)。
测定LDL、VLDL、HDL胆固醇和纤维蛋白原的量。结果见表2。
在不加入凝胶的情况下,测定LDL、VLDL、HDL胆固醇和纤维蛋白原的量(对照例4)。结果见表2。
Claims (4)
1、一种用于体外循环治疗的脂蛋白吸附剂的制备方法,其特征是,首先制备不溶于水的多孔硬质凝胶,该硬质凝胶由至少部分分子含有羟基的聚合物组成,经用球蛋白测定其排斥极限值为106-109,然后将该凝胶表面上的羟基直接转变成硫酸酯。
2、按照权利要求1规定的方法制备脂蛋白吸附剂,其中所说的至少部分分子含有羟基的聚合物是一种含有
结构单元的聚合物。
3、按照权利要求1规定的方法制备脂蛋白吸附剂,其中所说的至少部分分子含有羟基的聚合物是多糖。
4、按照权利要求3规定的方法制备脂蛋白吸附剂,所说的多糖是纤维素。
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JP231012/84 | 1984-10-31 | ||
JP59231012A JPS61107942A (ja) | 1984-10-31 | 1984-10-31 | リポ蛋白用吸着体 |
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JP110775/1985 | 1985-05-23 | ||
JP60110775A JPS61268355A (ja) | 1985-05-23 | 1985-05-23 | 体外循環治療用リポ蛋白吸着体およびその製法 |
JP110775/85 | 1985-05-23 |
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EP (1) | EP0180168B1 (zh) |
CN (1) | CN1006550B (zh) |
AU (2) | AU582972B2 (zh) |
DE (1) | DE3585076D1 (zh) |
FI (1) | FI854219L (zh) |
NZ (1) | NZ213819A (zh) |
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CN100455349C (zh) * | 2006-03-28 | 2009-01-28 | 南京赛邦医疗用品有限公司 | 用于血液体外循环去除低密度脂蛋白的吸附剂及其制法 |
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CA1239357A (en) * | 1984-12-07 | 1988-07-19 | That T. Ngo | Method of activating polymeric carrier |
FR2586359B1 (fr) * | 1985-08-23 | 1989-09-08 | Commissariat Energie Atomique | Support solide a base d'alcool polyvinylique capable d'adsorber les lipoproteines et son utilisation pour la separation des lipoproteines de basse densite presentes dans un liquide tel que du plasma sanguin |
EP0247592B1 (en) * | 1986-05-30 | 1992-03-04 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Adsorbent for beta2-microglobulin and immunoglobulin l-chain |
IL79945A (en) * | 1986-09-04 | 1991-06-10 | I D L International Diagnostic | Method for the quantitative determination of total cholesterol in blood |
US5258503A (en) * | 1987-09-08 | 1993-11-02 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Autoantibody adsorbent and apparatus for removing autoantibodies using the same |
US5108596A (en) * | 1988-04-05 | 1992-04-28 | Kanebo Ltd. | Borous ion-exchanged fine cellulose particles, method for production thereof, and affinity carrier |
GB8820547D0 (en) * | 1988-08-31 | 1988-09-28 | Vickers Plc | Improvements in/relating to polymeric compounds |
DE3926539A1 (de) * | 1989-08-11 | 1991-02-14 | Braun Melsungen Ag | Verwendung von tentakel-kationenaustauschern zur selektiven eliminierung von low-density-lipoproteinen (ldl), fibrinogen und/oder harnstoff aus fluessigkeiten |
US5236644A (en) * | 1990-11-27 | 1993-08-17 | W. R. Grace & Co.-Conn. | Process of making membrane for removal of low density lipoprotein-cholesterol from whole blood |
US5258149A (en) * | 1990-11-27 | 1993-11-02 | W. R. Grace & Co.-Conn. | Process of making a membrane for high efficiency removal of low density lipoprotein-cholesterol from whole blood |
US5187010A (en) * | 1990-11-27 | 1993-02-16 | W. R. Grace & Co.-Conn. | Membrane having high affinity for low density lipoprotein-cholesterol from whole blood |
DE4300412A1 (de) * | 1993-01-09 | 1994-07-14 | Behringwerke Ag | Hydrophobe Adsorbentien und ihre Verwendung zur Absorption von Lipoproteinen |
CN1988926B (zh) * | 2004-07-23 | 2010-05-05 | 株式会社钟化 | 填充有除去了水不溶性微粒的吸附材料的直接血液灌注用吸附器、与除去了水不溶性微粒的直接血液灌注用吸附材料的取得方法 |
GB2429708B (en) * | 2005-09-01 | 2010-06-02 | Chisso Corp | Spherical sulfated cellulose |
EP2164513A4 (en) * | 2007-05-24 | 2010-09-22 | Hadasit Ltd | PEPTIDES FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS AND METHOD FOR TREATING SYSTEMIC LUPUS ERYTHEMATOSUS |
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NL126243C (zh) * | 1959-06-12 | |||
NZ180199A (en) * | 1976-03-04 | 1978-11-13 | New Zealand Dev Finance | Method of testing for the presence of elevated plasma liprotein concentration |
IT1088861B (it) * | 1976-10-28 | 1985-06-10 | Asahi Chemical Ind | Materiale assorbente per proteine |
US4265959A (en) * | 1977-01-12 | 1981-05-05 | Sumitomo Chemical Company, Limited | Process for producing semipermeable membranes |
DE2834539A1 (de) * | 1978-08-07 | 1980-02-21 | Basf Ag | Makroporoese polymere als traegermaterial zur kovalenten bindung von proteinen |
CA1221307A (en) * | 1982-12-02 | 1987-05-05 | Nobutaka Tani | Adsorbent and process for preparing the same |
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- 1985-10-16 AU AU48773/85A patent/AU582972B2/en not_active Ceased
- 1985-10-21 US US06/789,537 patent/US4656261A/en not_active Expired - Lifetime
- 1985-10-26 DE DE8585113651T patent/DE3585076D1/de not_active Expired - Fee Related
- 1985-10-26 EP EP85113651A patent/EP0180168B1/en not_active Expired - Lifetime
- 1985-10-28 FI FI854219A patent/FI854219L/fi not_active Application Discontinuation
- 1985-10-30 CN CN85109750A patent/CN1006550B/zh not_active Expired
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1986
- 1986-06-23 US US06/877,089 patent/US4654420A/en not_active Expired - Lifetime
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CN100455349C (zh) * | 2006-03-28 | 2009-01-28 | 南京赛邦医疗用品有限公司 | 用于血液体外循环去除低密度脂蛋白的吸附剂及其制法 |
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AU582972B2 (en) | 1986-05-08 |
EP0180168B1 (en) | 1992-01-02 |
US4654420A (en) | 1987-03-31 |
FI854219L (fi) | 1986-05-01 |
CN1006550B (zh) | 1990-01-24 |
US4656261A (en) | 1987-04-07 |
FI854219A0 (fi) | 1985-10-28 |
EP0180168A3 (en) | 1987-02-04 |
AU4877385A (en) | 1986-05-08 |
NZ213819A (en) | 1988-05-30 |
EP0180168A2 (en) | 1986-05-07 |
AU2232188A (en) | 1989-01-05 |
DE3585076D1 (de) | 1992-02-13 |
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