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    VASCULAR MAGNETIC IMAGING METHOD AND AGENT
    1.
    发明申请
    VASCULAR MAGNETIC IMAGING METHOD AND AGENT 审中-公开
    血管成像方法及代理

    公开(公告)号：WO1990001899A1

    公开(公告)日：1990-03-08

    申请号：PCT/US1989003517

    申请日：1989-08-16

    Applicant: ADVANCED MAGNETICS, INCORPORATED

    Inventor： ADVANCED MAGNETICS, INCORPORATED ,  LEWIS, Jerome, M. ,  MENZ, Edward, T. ,  KENNY, Francis, E. ,  GROMAN, Ernest, V. ,  JOSEPHSON, Lee

    IPC: A61B05/05

    CPC classification number: G01R33/5601 ,  A61K49/18 ,  A61K49/1863 ,  A61K49/1887 ,  B82Y5/00 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08G2101/00 ,  C08J9/144 ,  C08J2375/04 ,  Y10T436/24

    Abstract: The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall means diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.

    Abstract translation: 描述了用于血管隔室的可生物降解的超顺磁性MR成像造影剂的制备和分离。 这些聚集体由单个可生物降解的超顺磁金属氧化物晶体组成，其聚集体具有小于约4000埃的整体平均直径。 优选的血管成像造影剂由总平均直径小于约500埃的氧化铁晶体的聚集体组成。 这些造影剂可以与大分子物质相关联，其特别有助于制备这些极小物质，并且可以分散或溶解在生理上可接受的介质中。 优选的介质甚至在恶劣的灭菌条件下也稳定材料以防止进一步聚集。 本发明的高压灭菌的可生物降解的超顺磁性氧化铁理想地适用于药物制剂，并且比先前的血管内成像对比包括几个优点，包括低渗透压，低有效剂量要求，高松弛度，长血液寿命，快速生物降解性和相对于 广泛的适用MR数据采集参数。

    BIODEGRADABLE SUPERPARAMAGNETIC MATERIALS USED IN CLINICAL APPLICATIONS
    2.
    发明申请
    BIODEGRADABLE SUPERPARAMAGNETIC MATERIALS USED IN CLINICAL APPLICATIONS 审中-公开
    在临床应用中使用的生物可降解超临界材料

    公开(公告)号：WO1988000060A1

    公开(公告)日：1988-01-14

    申请号：PCT/US1987001588

    申请日：1987-07-01

    Applicant: ADVANCED MAGNETICS INCORPORATED

    Inventor： ADVANCED MAGNETICS INCORPORATED ,  GROMAN, Ernest, V. ,  JOSEPHSON, Lee ,  LEWIS, Jerome, M.

    IPC: A61K49/00

    CPC classification number: B82Y5/00 ,  A61K49/18 ,  A61K49/1806 ,  A61K49/1863 ,  A61K49/1869 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08G2101/00 ,  C08J9/144 ,  C08J2375/04 ,  G01R33/5601

    Abstract: The in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. In the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image.

    Abstract translation: 生物可降解和代谢的超顺磁性金属氧化物作为MR造影剂的体内应用。 取决于它们的制备，这些金属氧化物是超顺磁性颗粒分散体或超顺磁性流体的形式，其中悬浮介质是生理上可接受的载体，并且可以是未涂覆的或被生物分子可附着的聚合物涂层包围。 在涂覆颗粒的情况下，可以选择生物分子来靶向特定的器官或组织。 金属氧化物在靶器官或组织中的生物分布导致这种器官或组织的更详细的图像，因为金属氧化物由于其超顺磁性质对负责MR图像的氢原子发挥深远的作用。

    RECEPTOR MEDIATED ENDOCYTOSIS TYPE MRI CONTRAST AGENTS
    3.
    发明申请
    RECEPTOR MEDIATED ENDOCYTOSIS TYPE MRI CONTRAST AGENTS 审中-公开
    受体介导的内分泌型MRI对比剂

    公开(公告)号：WO1990001295A1

    公开(公告)日：1990-02-22

    申请号：PCT/US1989003352

    申请日：1989-08-03

    Applicant: ADVANCED MAGNETICS, INCORPORATED

    Inventor： ADVANCED MAGNETICS, INCORPORATED ,  MENZ, Edward, T. ,  ROTHENBERG, Jeffrey, M. ,  GROMAN, Ernest, V. ,  JOSEPHSON, Lee

    IPC: A61B06/00

    CPC classification number: G01R33/5601 ,  A61K49/085 ,  A61K49/12 ,  A61K49/18 ,  A61K49/1845 ,  A61K49/1848 ,  A61K49/1863 ,  A61K49/1866 ,  A61K49/1869 ,  A61K51/06 ,  A61K2123/00 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08G2101/00 ,  C08J9/144 ,  C08J2375/04

    Abstract: Magnetic resonance (MR) contrast agents are described whose in vivo biodistribution is based upon the ability of certain cells to recognize and internalize the MR contrast agents of the present invention, via receptor mediated endocytosis. The RME-type MR contrast agents are comprised of biodegradable superparamagnetic metal oxides associated with macromolecular species including serum proteins, hormones, asialoglycoproteins, galactose-terminal species, polysaccharides, arabinogalactan, or conjugates of these molecules with other polymeric substances such as a poly(organosilane) and dextran. An MR contrast agent prepared from biodegradable superparamagnetic iron oxide and asialofetuin, for example, arabinogalactan, is selectively localized in the hepatocytes of the liver with no significant accumulation in the spleen. The contrast agents provide an enhanced MR image and valuable information regarding the functional or metabolic state of the organ or tissue under examination.

    Abstract translation: 描述了磁共振（MR）造影剂，其体内生物分布基于某些细胞通过受体介导的胞吞作用来识别和内化本发明的MR造影剂的能力。 RME型MR造影剂由与大分子物质相关的可生物降解的超顺磁性金属氧化物组成，包括血清蛋白，激素，去唾液酸糖蛋白，半乳糖末端物质，多糖，阿拉伯半乳聚糖或这些分子与其他聚合物质的共轭物，如聚（有机硅烷 ）和葡聚糖。 由可生物降解的超顺磁性氧化铁和脱唾液酸蛋白（例如阿拉伯半乳聚糖）制备的MR造影剂选择性地定位在肝脏的肝细胞中，在脾脏中没有显着的积累。 造影剂提供增强的MR图像和关于被检查的器官或组织的功能或代谢状态的有价值的信息。

    VASCULAR MAGNETIC IMAGING METHOD AND AGENT
    5.
    发明公开
    VASCULAR MAGNETIC IMAGING METHOD AND AGENT 失效
    血管磁成像方法和手段。

    公开(公告)号：EP0441797A1

    公开(公告)日：1991-08-21

    申请号：EP89910555.0

    申请日：1989-08-16

    Applicant: ADVANCED MAGNETICS INCORPORATED

    Inventor： LEWIS, Jerome, M. ,  MENZ, Edward, T. ,  KENNY, Francis, E. ,  GROMAN, Ernest, V. ,  JOSEPHSON, Lee

    IPC: A61K49 ,  C08G18 ,  C08J9 ,  G01R33

    CPC classification number: G01R33/5601 ,  A61K49/18 ,  A61K49/1863 ,  A61K49/1887 ,  B82Y5/00 ,  C08G18/1808 ,  C08G18/1816 ,  C08G18/1825 ,  C08G18/2036 ,  C08G18/246 ,  C08G18/26 ,  C08G2101/00 ,  C08J9/144 ,  C08J2375/04 ,  Y10T436/24

    Abstract: La préparation et l'isolement d'agents de contraste d'imagerie par résonance magnétique, supraparamagnétiques, biodégradables pour le compartiment vasculaire sont décrits. Ces agrégats se composent de cristaux d'oxydes métalliques supraparamagnétiques biodégradables, et ont un diamètre moyen global inférieur à environ 4000 ansgtroms. L'agent de contraste d'imagerie vasculaire préféré se compose d'agrégats de cristaux d'oxyde de fer ayant un diamètre moyen global inférieur à environ 500 angstroms. Ces agents de contraste peuvent être associés à une espèce macromoléculaire aidant, entre autres choses, à la préparation de ces matières extrêmement petites, et peuvent être dispersés ou dissous dans un milieu physiologiquement acceptable. Les milieux préférés stabilisent également les matières contre une agrégation accrue même dans des conditions de stérilisation rudes. Les oxydes de fer supraparamagnétiques biodégradables de l'invention stérilisés à l'autoclave, sont particulièrement bien adaptés pour une préparation pharmaceutique et jouissent de plusieurs avantages par rapport aux milieux de contraste d'imagerie intravasculaire tels qu'une faible osmolarité, des doses faibles, des relaxivités élevées, des longues durées de vie dans le sang, une biodégradabilité rapide, et une polyvalence en ce qui concerne une large gamme de paramètres d'acquisistion de données de résonance magnétique applicables.

    FILTER STERILIZATION FOR PRODUCTION OF COLLOIDAL, SUPERPARAMAGNETIC MR CONTRAST AGENTS
    7.
    发明公开
    FILTER STERILIZATION FOR PRODUCTION OF COLLOIDAL, SUPERPARAMAGNETIC MR CONTRAST AGENTS 失效
    过滤灭菌制备胶体超顺磁性MR造影剂。

    公开(公告)号：EP0514493A1

    公开(公告)日：1992-11-25

    申请号：EP91906230.0

    申请日：1991-02-06

    Applicant: ADVANCED MAGNETICS INCORPORATED

    Inventor： JOSEPHSON, Lee ,  GROMAN, Ernest, V. ,  PALMACCI, Stephen

    IPC: A61K49 ,  A61L2

    CPC classification number: A61K49/1809 ,  A61K49/1863 ,  A61L2/0017 ,  A61L2/025

    Abstract: On a amélioré un procédé d'obtention d'une image de résonance magnétique in vivo d'un organe ou d'un tissu d'un sujet animal ou humain, du type consistant à administrer au sujet à titre d'agent de contraste permettant d'améliorer ladite image de résonance magnétique, une dose efficace d'un colloïde comprenant des particules d'oxyde de métal superparamagnétiques dispersées dans un support physiologiquement acceptable. Selon l'amélioration, le procédé consiste à préparer le colloïde d'une manière permettant de réduire la toxicité comparée à celle associée à l'administration du colloïde après stérilisation terminale. L'amélioration peut comprendre la stérilisation du colloïde par filtration. Dans un mode de réalisation supplémentaire, on peut stériliser le colloïde par filtration et le conserver par lyophilisation. On peut lyophiliser le colloïde en présence d'un excipient compatible. L'excipient utilisé peut comprendre un dextran ou un anion de citrate. D'autres modes de réalisation comprennent des compositions et des procédés apparentés.

    SYNTHESIS OF POLYSACCHARIDE COVERED SUPERPARAMAGNETIC OXIDE COLLOIDS
    9.
    发明公开
    SYNTHESIS OF POLYSACCHARIDE COVERED SUPERPARAMAGNETIC OXIDE COLLOIDS 失效
    多糖的用涂超PARA磁性氧化物胶体合成

    公开(公告)号：EP0713602A1

    公开(公告)日：1996-05-29

    申请号：EP93920085.0

    申请日：1993-08-12

    Applicant: ADVANCED MAGNETICS INCORPORATED

    Inventor： PALMACCI, Stephen ,  JOSEPHSON, Lee ,  GROMAN, Ernest, V.

    IPC: G01R33 ,  A61B5 ,  A61K49 ,  H01F1

    CPC classification number: H01F1/445 ,  A61K49/1809 ,  A61K49/1863

    Abstract: In a method for the synthesis of a colloid including a superparamagnetic metal oxide coated with a polymer, an acidic solution of a metal salt and a polymer may be cooled, and then neutralized by the controlled addition of a cool solution of a base, and may then be converted, by the application of heat, to a homogenous superparamagnetic metal oxide colloid. According to a preferred embodiment, the polymer may be a polysaccharide. In a further embodiment of the invention, the polysaccharide may be dextran and the metal salt may be ferrous and ferric salts, which produces, according to the methods of the invention, a superparamagnetic iron oxide colloid with an extended plasma half-line.

    FILTER STERILIZATION FOR PRODUCTION OF COLLOIDAL, SUPERPARAMAGNETIC MR CONTRAST AGENTS and the use thereof
    10.
    发明授权
    FILTER STERILIZATION FOR PRODUCTION OF COLLOIDAL, SUPERPARAMAGNETIC MR CONTRAST AGENTS and the use thereof 失效
    过滤灭菌制备胶体超顺磁共振造影剂及其使用

    公开(公告)号：EP0514493B1

    公开(公告)日：1996-03-27

    申请号：EP91906230.7

    申请日：1991-02-06

    Applicant: ADVANCED MAGNETICS INCORPORATED

    Inventor： JOSEPHSON, Lee ,  GROMAN, Ernest, V. ,  PALMACCI, Stephen

    IPC: A61K49/00 ,  A61L2/00 ,  A61L2/02

    CPC classification number: A61K49/1809 ,  A61K49/1863 ,  A61L2/0017 ,  A61L2/025

    Abstract: An improvement is provided to a method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject, of the type including administering to the subject as a contrast agent to enhance such MR image an effective amount of a colloid including superparamagnetic metal oxide particles dispersed in a physiologically acceptable carrier. In accordance with the improvement, the method includes preparing the colloid in a manner that provides a reduction in toxicity in comparison with that associated with administration of the colloid after terminal sterilization. The improvement may include sterilizing the colloid by filtration. In an additional embodiment, the colloid may be sterilized by filtration and preserved by lyophilization. The colloid may be lyophilized in the presence of a compatible excipient. The excipient utilized may include a dextran or a citrate anion. Other embodiments include related compositions and methods.

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