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    Method of producing a product with crosslinked crystals of thermolysin
    1.
    发明授权
    Method of producing a product with crosslinked crystals of thermolysin 失效
    用嗜热溶菌蛋白交联晶体生产产品的方法

    公开(公告)号：US5801022A

    公开(公告)日：1998-09-01

    申请号：US474968

    申请日：1995-06-07

    申请人： Manuel A. Navia ,  Nancy L. St. Clair

    发明人： Manuel A. Navia ,  Nancy L. St. Clair

    IPC分类号： A61K38/43 ,  A61K38/46 ,  C07K5/072 ,  C12M1/40 ,  C12N9/14 ,  C12N9/20 ,  C12N9/36 ,  C12N9/54 ,  C12N9/66 ,  C12N9/80 ,  C12N9/82 ,  C12N11/00 ,  C12Q1/00 ,  C12Q1/37 ,  G01N33/531 ,  C12P13/22 ,  C07K17/00 ,  C12P13/20 ,  G01N33/543

    CPC分类号： C12N9/2462 ,  C07K5/0613 ,  C12N11/00 ,  C12N9/14 ,  C12N9/20 ,  C12N9/54 ,  C12N9/6448 ,  C12N9/80 ,  C12N9/82 ,  C12Q1/00 ,  C12Q1/003 ,  C12Q1/37 ,  G01N33/531 ,  Y10S530/81

    摘要： A protein such as an enzyme or antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent such as glutaraldehyde, and if desired lyophilizing the crosslinked crystals for storage. Crosslinking of the protein crystals provides stabilization for use under harsh conditions and for lyophilizing. The crystals crosslinked may be microcrystals having a cross-section of 10.sub.-1 mm or less. Crosslinked thermolysin, esterase, elastase, asparaginase and lysozyme crystals and crosslinked crystals of lipase from Geotrichum candidum and Candida cylindracea and of porcine origin can be used to convert a substrate to a product. Crosslinked thermolysin crystals are prepared that retain at least 96% of their initial activity after incubation for 4 days in the presence of a concentration of Pronase.TM. such as a thermolysin:Pronase.TM. ratio of 1:40 that causes the soluble uncrosslinked form of thermolysin that is crystallized to form the crystals that are crosslinked to lose at least 99% of its initial activity after incubation for 90 minutes under the same conditions. Crosslinked thermolysin crystals can be used to produce aspartame by combining the crystals with N-(benzyloxycarbonyl)-L-aspartic acid and L-phenylalanine methyl ester in a mixed aqueous/organic solvent such as a water-ethyl acetate mixture, and maintaining the combination under conditions to cause a condensation reaction to produce N-(benzyloxycarbonyl)-L-aspartyl-L-phenylalanine methyl ester, and removing the benzyloxycarbonyl group to obtain aspartame. Crosslinked antibody crystals have uses as an immunospecific reagent such as for detection of a substance in a sample, and for therapeutic purposes.

    摘要翻译： 通过用多官能交联剂如戊二醛交联蛋白质的晶体来固定蛋白质如酶或抗体，如果需要，将交联的晶体冻干以进行保存。 蛋白质晶体的交联提供在恶劣条件下使用和冻干的稳定性。 交联的晶体可以是横截面为10-1mm或更小的微晶。 交联的嗜热菌蛋白酶，酯酶，弹性蛋白酶，天冬酰胺酶和溶菌酶晶体，以及来自地热赤霉素和念珠菌和猪来源的脂肪酶的交联晶体可用于将底物转化成产物。 制备交联的嗜热菌解蛋白晶体，其在浓度为Pronase TM的浓度的例如1:40的嗜热菌蛋白酶：Pronase TM比率存在下孵育4天后保持其初始活性的至少96％，其导致可溶性未交联形式的嗜热菌蛋白酶， 结晶以形成交联的晶体，在相同条件下孵育90分钟后，其至少99％的初始活性损失。 通过将结晶与N-（苄氧基羰基）-L-天冬氨酸和L-苯丙氨酸甲酯在混合的水/有机溶剂如水 - 乙酸乙酯混合物中混合，可以使用交联的嗜热溶蛋白晶体制备天冬甜素，并保持组合 在引起缩合反应以产生N-（苄氧基羰基）-L-天冬氨酰基-L-苯丙氨酸甲酯的条件下，并除去苄氧羰基以得到阿斯巴甜。 交联抗体晶体具有作为免疫特异性试剂的用途，例如用于检测样品中的物质以及用于治疗目的。

    Methods of enzyme therapy by orally administering crosslinked enzyme crystals
    2.
    发明授权
    Methods of enzyme therapy by orally administering crosslinked enzyme crystals 失效
    口服交联酶晶体的酶疗法

    公开(公告)号：US5976529A

    公开(公告)日：1999-11-02

    申请号：US477109

    申请日：1995-06-07

    申请人： Manuel A. Navia ,  Nancy L. St. Clair

    发明人： Manuel A. Navia ,  Nancy L. St. Clair

    IPC分类号： A61K38/43 ,  A61K38/46 ,  C07K1/107 ,  C07K5/072 ,  C12M1/40 ,  C12N9/14 ,  C12N9/20 ,  C12N9/36 ,  C12N9/54 ,  C12N9/66 ,  C12N9/80 ,  C12N9/82 ,  C12N11/00 ,  C12Q1/00 ,  C12Q1/37 ,  G01N33/531 ,  C07K17/00 ,  C12P1/00

    CPC分类号： C12N9/2462 ,  C07K1/1077 ,  C07K5/0613 ,  C12N11/00 ,  C12N9/14 ,  C12N9/20 ,  C12N9/54 ,  C12N9/6448 ,  C12N9/80 ,  C12N9/82 ,  C12Q1/00 ,  C12Q1/003 ,  C12Q1/37 ,  G01N33/531 ,  A61K38/00 ,  Y10S435/817 ,  Y10S530/81

    摘要： A protein such as an enzyme or antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. A preferred protein is an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease. Crosslinked enzyme crystals preferably retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred enzyme:Pronase.TM. ratio is 1:40. Enzyme crystals that are crosslinked may be microcrystals having a cross-section of 10.sup.-1 mm or less. Crosslinked enzyme or antibody crystals may be used in an assay, diagnostic kit or biosensor for detecting an analyte, in an extracorporeal device for altering a component of a fluid, in producing a product such as using crosslinked thermolysin crystals to produce aspartame and in separating a substance from a mixture. Enzyme therapy such as lipase therapy can be performed by administering orally crosslinked lipase crystals.

    摘要翻译： 通过用多功能交联剂交联蛋白质的晶体来固定蛋白质如酶或抗体。 交联的蛋白质晶体可以冻干以储存。 优选的蛋白质是酶，例如嗜热菌蛋白酶，弹性蛋白酶，天冬酰胺酶，溶菌酶，脂肪酶或脲酶。 交联的酶晶体优选保持在Termase TM浓度存在下温育3小时后的至少91％的活性，其导致可溶性的未交联形式的酶在相同条件下损失至少94％的初始活性。 优选的酶：Pronase TM比为1:40。 交联的酶晶体可以是横截面为10-1mm或更小的微晶。 交联的酶或抗体晶体可用于用于检测分析物的测定，诊断试剂盒或生物传感器，用于改变流体组分的体外装置中，用于产生例如使用交联的嗜热溶菌素晶体产生天冬酰苯丙氨酸并在分离 物质从混合物。 酶治疗如脂肪酶治疗可以通过口服交联的脂肪酶晶体进行。

    Biosensors, extracorporeal devices and methods for detecting substances using crosslinked protein crystals
    3.
    发明授权
    Biosensors, extracorporeal devices and methods for detecting substances using crosslinked protein crystals 失效
    生物传感器，体外装置和使用交联蛋白质晶体检测物质的方法

    公开(公告)号：US6004768A

    公开(公告)日：1999-12-21

    申请号：US484238

    申请日：1995-06-07

    申请人： Manuel A. Navia ,  Nancy L. St. Clair

    发明人： Manuel A. Navia ,  Nancy L. St. Clair

    IPC分类号： A61K38/43 ,  A61K38/46 ,  C07K1/107 ,  C07K5/072 ,  C12M1/40 ,  C12N9/14 ,  C12N9/20 ,  C12N9/36 ,  C12N9/54 ,  C12N9/66 ,  C12N9/80 ,  C12N9/82 ,  C12N11/00 ,  C12Q1/00 ,  C12Q1/37 ,  G01N33/531 ,  C12Q1/34 ,  C12M1/34

    CPC分类号： C12N9/2462 ,  C07K1/1077 ,  C07K5/0613 ,  C12N11/00 ,  C12N9/14 ,  C12N9/20 ,  C12N9/54 ,  C12N9/6448 ,  C12N9/80 ,  C12N9/82 ,  C12Q1/00 ,  C12Q1/003 ,  C12Q1/37 ,  G01N33/531 ,  A61K38/00 ,  Y10S435/817 ,  Y10S530/81

    摘要： Proteins such as enzymes and antibodies are immobilized by crosslinking crystals of the proteins such as microcrystals having a cross-section of 10.sup.-1 mm or less with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. Crystals of an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease may be crosslinked to provide crosslinked enzyme crystals that retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred Pronase.TM.:enzyme ratio is 1:40. Crosslinked enzyme or antibody crystals may be used in an assay, diagnostic kit or biosensor for detecting an analyte, in an extracorporeal device for altering a component of a fluid, in producing a product such as using crosslinked thermolysin crystals to produce aspartame, in separating a substance from a mixture, and in therapy.

    摘要翻译： 蛋白质如酶和抗体通过用多官能交联剂交联具有10-1mm或更小截面的微晶的蛋白质的晶体来固定。 交联的蛋白质晶体可以冻干以储存。 可以交联酶，例如嗜热菌蛋白酶，弹性蛋白酶，天冬酰胺酶，溶菌酶，脂肪酶或脲酶的晶体以提供交联的酶晶体，其在浓度为Pronase TM的浓度存在下孵育3小时后保持至少91％的活性，其导致可溶性 未交联形式的酶在相同条件下损失至少94％的初始活性。 Pronase TM：酶比为1:40。 交联的酶或抗体晶体可用于用于检测分析物的测定，诊断试剂盒或生物传感器，用于改变流体组分的体外装置中，用于在产生例如使用交联的嗜热溶蛋白晶体产生阿斯巴甜的产物时分离 物质从混合物和治疗。

    Crosslinked enzyme crystals
    4.
    发明授权
    Crosslinked enzyme crystals 失效
    交联酶晶体

    公开(公告)号：US5618710A

    公开(公告)日：1997-04-08

    申请号：US17510

    申请日：1993-02-12

    申请人： Manuel A. Navia ,  Nancy L. St. Clair

    发明人： Manuel A. Navia ,  Nancy L. St. Clair

    IPC分类号： A61K38/43 ,  A61K38/46 ,  C07K1/107 ,  C07K5/072 ,  C12M1/40 ,  C12N9/14 ,  C12N9/20 ,  C12N9/36 ,  C12N9/54 ,  C12N9/66 ,  C12N9/80 ,  C12N9/82 ,  C12N11/00 ,  C12Q1/00 ,  C12Q1/37 ,  G01N33/531 ,  C12N1/00 ,  C07K17/00 ,  C12P1/00 ,  G01N33/543

    CPC分类号： C12N9/2462 ,  C07K1/1077 ,  C07K5/0613 ,  C12N11/00 ,  C12N9/14 ,  C12N9/20 ,  C12N9/54 ,  C12N9/6448 ,  C12N9/80 ,  C12N9/82 ,  C12Q1/00 ,  C12Q1/003 ,  C12Q1/37 ,  G01N33/531 ,  A61K38/00 ,  Y10S435/817 ,  Y10S530/81

    摘要： A protein such as an enzyme of antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. A preferred protein is an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease. Crosslinked enzyme crystals preferably retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred enzyme:Pronase.TM. ratio is 1:40. Enzyme crystals that are crosslinked may be microcrystals having a cross-section of 10.sup.-1 mm or less. Crosslinked enzyme or antibody crystals may be used in an assay, diagnostic kit or biosensor for detecting an analyte, in an extracorporeal device for altering a component of a fluid, in producing a product such as using crosslinked thermolysin crystals to produce aspartame, in separating a substance from a mixture, and in therapy.

    摘要翻译： 通过用多官能交联剂交联蛋白质的晶体来固定蛋白质如抗体的酶。 交联的蛋白质晶体可以冻干以储存。 优选的蛋白质是酶，例如嗜热菌蛋白酶，弹性蛋白酶，天冬酰胺酶，溶菌酶，脂肪酶或脲酶。 交联的酶晶体优选保持在Termase TM浓度存在下温育3小时后的至少91％的活性，其导致可溶性的未交联形式的酶在相同条件下损失至少94％的初始活性。 优选的酶：Pronase TM比为1:40。 交联的酶晶体可以是横截面为10-1mm或更小的微晶。 交联的酶或抗体晶体可用于用于检测分析物的测定，诊断试剂盒或生物传感器，用于改变流体组分的体外装置中，用于在产生例如使用交联的嗜热溶蛋白晶体产生阿斯巴甜的产物时分离 物质从混合物和治疗。

    Method of protein therapy by orally administering crosslinked protein crystals
    5.
    发明授权
    Method of protein therapy by orally administering crosslinked protein crystals 失效
    通过口服给予交联蛋白质晶体的蛋白质治疗方法

    公开(公告)号：US6011001A

    公开(公告)日：2000-01-04

    申请号：US484978

    申请日：1995-06-07

    申请人： Manuel A. Navia ,  Nancy L. St. Clair

    发明人： Manuel A. Navia ,  Nancy L. St. Clair

    IPC分类号： A61K38/43 ,  A61K38/46 ,  C07K1/107 ,  C07K5/072 ,  C12M1/40 ,  C12N9/14 ,  C12N9/20 ,  C12N9/36 ,  C12N9/54 ,  C12N9/66 ,  C12N9/80 ,  C12N9/82 ,  C12N11/00 ,  C12Q1/00 ,  C12Q1/37 ,  G01N33/531 ,  A61K38/00 ,  A61K39/00 ,  C07K1/00

    CPC分类号： C12N9/2462 ,  C07K1/1077 ,  C07K5/0613 ,  C12N11/00 ,  C12N9/14 ,  C12N9/20 ,  C12N9/54 ,  C12N9/6448 ,  C12N9/80 ,  C12N9/82 ,  C12Q1/00 ,  C12Q1/003 ,  C12Q1/37 ,  G01N33/531 ,  A61K38/00 ,  Y10S435/817 ,  Y10S530/81

    摘要： A protein such as an enzyme or antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. A preferred protein is an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease. Crosslinked enzyme crystals preferably retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred enzyme:Pronase.TM. ratio is 40:1. Enzyme crystals that are crosslinked may be microcrystals having a cross-section of 10.sup.-1 mm or less. Crosslinked enzyme or antibody crystals may be used in an assay, diagnostic kit or biosensor for detecting an analyte, in an extracorporeal device for altering a component of a fluid, in producing a product such as using crosslinked thermolysin crystals to produce aspartame and in separating a substance from a mixture. Enzyme or non-enzyme protein therapy can be performed by administering orally crosslinked enzyme crystals or crosslinked non-enzyme protein crystals that have a therapeutic affect. The crosslinked crystals have improved stability to proteases in the gut. Crosslinked lipase crystals may be administered for treatment where there is pancreatic insufficiency and/or fat malabsorption conditions in which lipase secretion is abnormally low.

    摘要翻译： 通过用多功能交联剂交联蛋白质的晶体来固定蛋白质如酶或抗体。 交联的蛋白质晶体可以冻干以储存。 优选的蛋白质是酶，例如嗜热菌蛋白酶，弹性蛋白酶，天冬酰胺酶，溶菌酶，脂肪酶或脲酶。 交联的酶晶体优选保持在Termase TM浓度存在下温育3小时后的至少91％的活性，其导致可溶性的未交联形式的酶在相同条件下损失至少94％的初始活性。 优选的酶：Pronase TM比为40:1。 交联的酶晶体可以是横截面为10-1mm或更小的微晶。 交联的酶或抗体晶体可用于用于检测分析物的测定，诊断试剂盒或生物传感器，用于改变流体组分的体外装置中，用于产生例如使用交联的嗜热溶菌素晶体产生天冬酰苯丙氨酸并在分离 物质从混合物。 可以通过施用具有治疗作用的口服交联的酶晶体或交联的非酶蛋白质晶体来进行酶或非酶蛋白质治疗。 交联的晶体具有改善肠道中蛋白酶的稳定性。 交联的脂肪酶晶体可以在存在胰腺功能不全和/或脂肪分解异常低的脂肪吸收障碍的情况下进行治疗。

    Crosslinked protein crystals
    6.
    发明授权
    Crosslinked protein crystals 失效
    交联蛋白晶体

    公开(公告)号：US5849296A

    公开(公告)日：1998-12-15

    申请号：US476267

    申请日：1995-06-07

    申请人： Manuel A. Navia ,  Nancy L. St. Clair

    发明人： Manuel A. Navia ,  Nancy L. St. Clair

    IPC分类号： A61K38/43 ,  A61K38/46 ,  C07K1/107 ,  C07K5/072 ,  C12M1/40 ,  C12N9/14 ,  C12N9/20 ,  C12N9/36 ,  C12N9/54 ,  C12N9/66 ,  C12N9/80 ,  C12N9/82 ,  C12N11/00 ,  C12Q1/00 ,  C12Q1/37 ,  G01N33/531 ,  A61K39/395 ,  C07K17/00 ,  C12N1/00 ,  C12P1/00

    CPC分类号： C12N9/2462 ,  C07K1/1077 ,  C07K5/0613 ,  C12N11/00 ,  C12N9/14 ,  C12N9/20 ,  C12N9/54 ,  C12N9/6448 ,  C12N9/80 ,  C12N9/82 ,  C12Q1/00 ,  C12Q1/003 ,  C12Q1/37 ,  G01N33/531 ,  A61K38/00 ,  Y10S435/817 ,  Y10S530/81

    摘要： A protein such as an enzyme or antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. A preferred protein is an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease. Crosslinked enzyme crystals preferably retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred enzyme:Pronase.TM. ratio is 1:40. Enzyme crystals that are crosslinked may be microcrystals having a cross-section of 10.sup.-1 mm or less. Crosslinked enzyme or antibody crystals may be used in an assay, diagnostic kit or biosensor for detecting an analyte, in an extracorporeal device for altering a component of a fluid, in producing a product such as using crosslinked thermolysin crystals to produce aspartame, in separating a substance from a mixture, and in therapy.

    摘要翻译： 通过用多功能交联剂交联蛋白质的晶体来固定蛋白质如酶或抗体。 交联的蛋白质晶体可以冻干以储存。 优选的蛋白质是酶，例如嗜热菌蛋白酶，弹性蛋白酶，天冬酰胺酶，溶菌酶，脂肪酶或脲酶。 交联的酶晶体优选保持在Termase TM浓度存在下温育3小时后的至少91％的活性，其导致可溶性的未交联形式的酶在相同条件下损失至少94％的初始活性。 优选的酶：Pronase TM比为1:40。 交联的酶晶体可以是横截面为10-1mm或更小的微晶。 交联的酶或抗体晶体可以用于用于检测分析物的测定，诊断试剂盒或生物传感器，用于改变流体组分的体外装置中，以产生例如使用交联的嗜热菌解蛋白晶体产生阿斯巴甜的产物，以分离 物质从混合物和治疗。