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公开(公告)号：US07041800B1
公开(公告)日：2006-05-09
申请号：US10018599
申请日：2000-07-07
IPC分类号： C07K14/805 , A61B19/02
CPC分类号： A61J1/05 , A01N1/02 , A01N1/0263 , A61K38/00 , A61K38/42 , A61M1/0272 , B32B15/08 , B32B27/08 , B32B27/32 , C07K14/805
摘要： The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The method for preserving a deoxygenated hemoglobin blood substitute comprises maintaining the deoxygenated hemoglobin blood substitute in an oxygen barrier film overwrap package. In one embodiment, the package comprises a transparent laminate material comprising an oxygen barrier layer and a polyolefin layer, wherein the laminant has a thickness of between about 0.001 and about 0.01 inches (or about 0.0254 to about 0.254 millimeters) and an oxygen permeability of less than about 0.01 cubic centimeters per 100 square inches (or about 0.01 cc per 645 square centimeters) over 24 hours at 1 atmosphere and at about 23° C. The oxygen barrier layer comprises ethylene vinyl alcohol. Aso provided herein is a preserved deoxygenated hemoglobin blood substitute comprises a deoxygenated hemoglobin blood substitute and an oxygen barrier film overwrap package. The package comprises a transparent laminant material comprising an oxygen barrier layer and a polyolefin layer. Said oxygen barrier layer has an oxygen permeability of less than about 0.01 cubic centimeters per 100 square inches (or about 0.01 cc per 645 square centimeters) over 24 hours at 1 atmosphere and at about 27° C. room temperature, wherein the deoxygenated hemoglobin blood substitute is sealed within the overwrap package. In one embodiment, the oxygen barrier layer comprises ethylene vinyl alcohol.
摘要翻译： 本发明涉及一种保持血红蛋白血液替代品的稳定性的方法，包括将血红蛋白血液替代物维持在基本上不含氧的气氛中。 保存脱氧血红蛋白血液替代物的方法包括将脱氧血红蛋白血液替代物保持在氧阻隔膜外包装中。 在一个实施方案中，包装包括包含氧阻隔层和聚烯烃层的透明层压材料，其中层压剂具有约0.001至约0.01英寸（或约0.0254至约0.254毫米）的厚度，并且氧渗透性较小 超过约0.01立方厘米每100平方英寸（或约0.01cc / 645平方厘米），在1个大气压和约23℃下经24小时。氧气阻隔层包括乙烯乙烯醇。 本文提供的是保存的脱氧血红蛋白血液替代物，其包含脱氧血红蛋白血液替代物和氧阻隔膜外包装。 该包装包括透明层压材料，其包含氧阻隔层和聚烯烃层。 所述氧阻隔层在1个大气压和约27℃的室温下经24小时内具有小于约0.01立方厘米/ 100平方英寸（或约0.01cc / 645平方厘米）的透氧性，其中脱氧血红蛋白血液 替代品密封在外包装包装内。 在一个实施方案中，氧阻隔层包含乙烯乙烯醇。
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公开(公告)号：US5952470A
公开(公告)日：1999-09-14
申请号：US477916
申请日：1995-06-07
IPC分类号： C07K1/14 , C07K14/805 , C07K1/30
CPC分类号： C07K14/805
摘要： A method for separating unmodified hemoglobin from cross-linked hemoglobin in a hemoglobin solution. The method involves contacting the hemoglobin solution with a least one dissociating agent to form a dissociation solution wherein unmodified tetrameric hemoglobin is dissociated to form hemoglobin dimers. The hemoglobin dimers are then separated from the dissociation solution, while retaining the cross-linked hemoglobin in the dissociation solution.
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公开(公告)号：US4675292A
公开(公告)日：1987-06-23
申请号：US707774
申请日：1985-03-04
摘要： Extracellular enzymes are stabilized with a carboxyalkylated or phosphonoalkylated polymer having a molecular weight of at least 500 Daltons. Exemplified is the stabilization of the enzyme glucose isomerase used in a process to convert D-glucose to D-fructose. In a preferred embodiment of the invention the feedstream containing the substrate is contacted initially with the stabilizer and then with the enzyme. In this system the stabilizer and enzyme are maintained in separate reactors. This separation, advantageously, results in a higher half-life for the enzyme.
摘要翻译： 用分子量至少为500道尔顿的羧基烷基化或膦酰基烷基化聚合物稳定细胞外酶。 示例是用于将D-葡萄糖转化为D-果糖的方法中使用的酶葡萄糖异构酶的稳定化。 在本发明的优选实施方案中，含有底物的进料流最初与稳定剂接触，然后与酶接触。 在该系统中，稳定剂和酶保持在单独的反应器中。 这种分离有利地导致酶的较长的半衰期。
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公开(公告)号：US07041799B1
公开(公告)日：2006-05-09
申请号：US10018529
申请日：2000-07-07
IPC分类号： C07K14/805 , A61B19/02
CPC分类号： A61J1/05 , A01N1/02 , A01N1/0263 , A61K35/00 , A61K38/42 , B32B7/02 , B32B15/08 , B32B27/08 , B32B27/18 , B32B27/304 , B32B27/32 , B32B27/36 , B32B2250/24 , B32B2264/102 , B32B2307/412 , B32B2307/7244 , B32B2439/80 , B32B2535/00 , C07K14/805
摘要： The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The method for preserving the deoxygenated hemoglobin blood substitute comprises maintaining the deoxygenated blood substitute in an oxygen barrier film overwrap package, wherein at least one face of the overwrap package comprises a transparent laminate material and wherein at least one other face of the overwrap package comprises a foil laminate material. The preserved deoxygenated hemoglobin blood substitute comprises a deoxygenated hemoglobin blood substitute and an oxygen barrier film overwrap package wherein at least one face of the overwrap package comprises a transparent laminate material and wherein at least one other face of the overwrap package comprises a foil laminate material.
摘要翻译： 本发明涉及一种保持血红蛋白血液替代品的稳定性的方法，包括将血红蛋白血液替代物维持在基本上不含氧的气氛中。 用于保存脱氧血红蛋白血液替代物的方法包括将脱氧血液替代物保持在氧阻隔膜外包装中，其中外包裹包装的至少一个面包括透明层压材料，并且其中外包裹包装的至少另一个面包括 箔层压材料。 保存的脱氧血红蛋白血液替代物包括脱氧血红蛋白血液替代物和氧阻隔膜外包装，其中外包装包装的至少一个面包括透明层压材料，并且其中外包裹包装的至少另一个面包括箔层压材料。
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公开(公告)号：US07001715B2
公开(公告)日：2006-02-21
申请号：US10090428
申请日：2002-02-28
CPC分类号： A61K35/18
摘要： Red blood cells are purified by separating whole blood, such as by centrifugation, to form a red blood cell fraction and a liquid fraction. The whole blood can be defibrinated or treated to prevent coagulation prior to separation. Preferably, the whole blood is bovine blood. The red blood cell fraction is then diafiltered to purify the red blood cells. The purified red blood cells can then be lysed to form a lysate of purified red blood cells. The purified red blood cells and the lysate of purified red blood cells are suitable for use in producing hemoglobin blood substitute.
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公开(公告)号：US5753616A
公开(公告)日：1998-05-19
申请号：US478004
申请日：1995-06-07
申请人： Carl W. Rausch , Maria S. Gawryl , Robert A. Houtchens , Anthony J. Laccetti , William R. Light
发明人： Carl W. Rausch , Maria S. Gawryl , Robert A. Houtchens , Anthony J. Laccetti , William R. Light
IPC分类号： A01N1/02 , A61J1/00 , A61J1/05 , A61K38/00 , A61M1/36 , B32B15/08 , B32B27/08 , C07K14/805 , A61K38/42
CPC分类号： C07K14/805 , A01N1/02 , A01N1/0221 , B32B15/08 , B32B27/08 , A61J1/05 , A61K38/00 , A61M1/3693 , A61M2202/0433
摘要： A method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulant to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized. The polymerized hemoglobin solution is then diafiltered with a physiologic solution and with a sulfhydryl compound, whereby the polymerized hemoglobin solution is made physiologically acceptable, and whereby the sulfhydryl compound scavenges oxygen, to form a stable polymerized hemoglobin blood-substitute.
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7.发明授权Use of defibrinated blood for manufacture of hemoglobin-based oxygen carrier 有权使用去纤颤的血液制造基于血红蛋白的氧载体公开(公告)号：US07553613B2
公开(公告)日：2009-06-30
申请号：US11289048
申请日：2005-11-29
CPC分类号： A61K38/42 , C12N5/0641 , C12N2509/00 , Y10S530/812 , Y10S530/829
摘要： Red blood cells are purified by defibrinating whole blood and then filtering the defibrinated whole blood, whereby at least a portion of a plasma component is separated from the red blood cells to form a suspension of red blood cells, thereby purifying the red blood cells. Whole blood is defibrinated by, for example, using a chemical coagulating agent or mechanical agitation. Separation of the plasma component from red blood cells can be completed by, for example, diafiltration. The suspension of red blood cells can then be employed to produce a hemoglobin-based oxygen carrier.
摘要翻译： 通过除血全血，然后过滤去纤维化的全血来纯化红细胞，由此将血浆成分的至少一部分与红细胞分离，形成红细胞的悬浮液，从而纯化红细胞。 全血通过例如使用化学凝结剂或机械搅动来脱纤维蛋白。 可以通过例如渗滤来完成血浆成分与红细胞的分离。 然后可以使用红细胞的悬浮液来产生基于血红蛋白的氧载体。
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公开(公告)号：US06288027B1
公开(公告)日：2001-09-11
申请号：US09348881
申请日：1999-07-07
IPC分类号： C07K14805
CPC分类号： B32B1/02 , A01N1/02 , A01N1/0263 , A61J1/05 , A61J1/10 , A61K38/42 , A61M1/0272 , B32B15/08 , B32B15/082 , B32B27/08 , B32B27/306 , B32B27/32 , B32B37/153 , B32B2307/412 , B32B2307/7244 , B32B2439/80 , C07K14/805
摘要： The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The invention also involves a method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulent to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized. The polymerized hemoglobin solution is then diafiltered with a physiologic solution and with a sulfhydryl compound, whereby the polymerized hemoglobin solution is made physiologically acceptable, and whereby the sulfhydryl compound scavenges oxygen, to form a stable polymerized hemoglobin blood-substitute, which is then packaged and stored in an atmosphere substantially free of oxygen.
摘要翻译： 本发明涉及一种保持血红蛋白血液替代品的稳定性的方法，包括将血红蛋白血液替代物维持在基本上不含氧的气氛中。 本发明还涉及从血液制备稳定的聚合血红蛋白血液代用品的方法。 本发明的方法包括将血液与抗凝血剂混合以形成血液溶液，洗涤血液中的红细胞，然后从白细胞中分离洗涤的红细胞。 该方法还包括破坏红细胞以释放血红蛋白并形成血红蛋白溶液，然后通过高效液相色谱法处理以形成血红蛋白洗脱液。 然后将血红蛋白洗脱液脱氧，与第一巯基化合物接触以形成氧化稳定的脱氧血红蛋白溶液，并与交联剂混合以形成聚合反应混合物，然后将其聚合。 然后将聚合的血红蛋白溶液与生理溶液和巯基化合物进行渗滤，由此将聚合的血红蛋白溶液制成生理学上可接受的，由此巯基化合物清除氧气，形成稳定的聚合血红蛋白血液替代物，然后将其包装， 储存在基本上不含氧的气氛中。
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公开(公告)号：US6150507A
公开(公告)日：2000-11-21
申请号：US113953
申请日：1998-07-10
CPC分类号： A01N1/02 , A01N1/0205 , A01N1/0221 , B32B15/08 , B32B27/08 , C07K14/805 , A61J1/05
摘要： A method for producing a purified hemoglobin product includes loading a hemoglobin solution onto an anion exchange chromatography column. At least one tris(hydroxymethyl) aminomethane acetate buffer solution is injected into the column. The buffer solution has a pH lower than that of the column, whereby a purified hemoglobin product elutes from the column. In one embodiment, the hemoglobin solution initially can be equilibrated at a pH of greater than about 8.7. In another embodiment, contaminants can be removed by equilibrating the column with at least about eleven column void volumes of buffer solution at an intermediate pH of between about 8.2 and about 8.6, to thereby form a stepped pH gradient. In still another embodiment, all buffer solutions employed are tris(hydroxymethyl) aminomethane acetate.
摘要翻译： 制备纯化血红蛋白产品的方法包括将血红蛋白溶液加载到阴离子交换色谱柱上。 将至少一种三（羟甲基）氨基甲酸乙酯缓冲溶液注入柱中。 缓冲溶液的pH值低于色谱柱，纯化的血红蛋白产物从柱中洗脱出来。 在一个实施方案中，血红蛋白溶液最初可以在大于约8.7的pH下平衡。 在另一个实施方案中，可以通过在约8.2至约8.6之间的中间pH下用至少约十一个柱空隙体积的缓冲溶液平衡柱来除去污染物，从而形成阶梯式pH梯度。 在另一个实施方案中，所用的所有缓冲溶液是三（羟甲基）氨基甲烷乙酸酯。
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公开(公告)号：US4950596A
公开(公告)日：1990-08-21
申请号：US20407
申请日：1987-03-02
摘要： The subject invention concerns a process for stabilizing intact or ruptured microbial cells having glucose isomerase associated therewith. Specifically exemplified is a process for stabilizing glucose isomerase producing cells of a microorganism belonging to the genus Ampullariella. In the invention process the whole or ruptured microbial cells are contacted with a partially carboxyalkylated- or partially phosphonoalkylated-cationic polyelectrolyte, for example, a partially carboxymethylated polyethyleneimine to flocculate and stabilize the cells. The flocculated cells are further stabilized by encapsulation with a partially carboxyalkylated- or partially phosphonoalkylated-cationic polyelectrolyte. The encapsulation can be done prior to or after the flocculated cells are crosslinked. The net effect is manifested by a dramatic increase in the half-life of the glucose isomerase.
摘要翻译： 本发明涉及用于稳定具有与其相关的葡萄糖异构酶的完整或破裂的微生物细胞的方法。 具体举例说明了稳定葡萄糖异构酶产生细胞的方法，该细胞属于安瓿属（Ampullariella）属。 在本发明方法中，将全部或破裂的微生物细胞与部分羧烷基化或部分膦酰烷基化阳离子聚电解质（例如部分羧甲基化的聚乙烯亚胺）接触以使细胞絮凝和稳定。 通过用部分羧烷基化或部分膦酰烷基化阳离子聚电解质包封进一步稳定絮凝的细胞。 可以在絮凝的细胞交联之前或之后进行封装。 净效应表现在葡萄糖异构酶的半衰期急剧增加。
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