DE3508000A1 - Ferromagnetic particles for NMR diagnosis - Google Patents

Ferromagnetic particles for NMR diagnosis

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Publication number
DE3508000A1
DE3508000A1 DE19853508000 DE3508000A DE3508000A1 DE 3508000 A1 DE3508000 A1 DE 3508000A1 DE 19853508000 DE19853508000 DE 19853508000 DE 3508000 A DE3508000 A DE 3508000A DE 3508000 A1 DE3508000 A1 DE 3508000A1
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DE
Germany
Prior art keywords
means according
diagnostic means
magnetite
content
complexing agent
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.)
Withdrawn
Application number
DE19853508000
Other languages
German (de)
Inventor
Heinz Dr. Gries
Wolfgang Dr. Mützel
Hanns-Joachim Dr. 1000 Berlin Weinmann
Christian Dr. Zurth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DE19853508000 priority Critical patent/DE3508000A1/en
Priority to PT81498A priority patent/PT81498B/en
Priority to NZ214228A priority patent/NZ214228A/en
Priority to AU50225/85A priority patent/AU583070B2/en
Priority to AT85730153T priority patent/ATE56880T1/en
Priority to DE8585730153T priority patent/DE3579899D1/en
Priority to EP85730153A priority patent/EP0186616B2/en
Priority to GR852815A priority patent/GR852815B/el
Priority to ES549144A priority patent/ES8703153A1/en
Priority to CA000496054A priority patent/CA1252950A/en
Priority to DK198505417A priority patent/DK174946B1/en
Priority to NO854679A priority patent/NO167077C/en
Priority to IE293585A priority patent/IE58324B1/en
Priority to JP60262727A priority patent/JP2740782B2/en
Publication of DE3508000A1 publication Critical patent/DE3508000A1/en
Priority to ES557099A priority patent/ES8704352A1/en
Priority to US08/484,309 priority patent/US5746999A/en
Priority to US08/997,748 priority patent/US20020064502A1/en
Priority to US10/105,462 priority patent/US20020136693A1/en
Withdrawn legal-status Critical Current

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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/189Host-guest complexes, e.g. cyclodextrins
    • A61K49/1893Molecular sieves
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    • A61K49/1818Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1833Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
    • A61K49/1845Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a carbohydrate (monosaccharides, discacharides)
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    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
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    • A61K49/1827Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1863Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
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    • A61K49/1818Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • A61K49/1869Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1875Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle coated or functionalised with an antibody
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B30/00Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
    • C08B30/12Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
    • C08B30/18Dextrin, e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/12Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
    • G01N2400/14Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar alpha-D-Glucans, i.e. having alpha 1,n (n=3,4,6) linkages between saccharide units, e.g. pullulan
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
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    • G01N2400/12Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
    • G01N2400/14Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar alpha-D-Glucans, i.e. having alpha 1,n (n=3,4,6) linkages between saccharide units, e.g. pullulan
    • G01N2400/22Dextran
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00Magnetic particle immunoreagent carriers
    • G01N2446/20Magnetic particle immunoreagent carriers the magnetic material being present in the particle core
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00Magnetic particle immunoreagent carriers
    • G01N2446/30Magnetic particle immunoreagent carriers the magnetic material being dispersed in the polymer composition before their conversion into particulate form
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00Magnetic particle immunoreagent carriers
    • G01N2446/80Magnetic particle immunoreagent carriers characterised by the agent used to coat the magnetic particles, e.g. lipids
    • G01N2446/86Magnetic particle immunoreagent carriers characterised by the agent used to coat the magnetic particles, e.g. lipids the coating being pre-functionalised for attaching immunoreagents, e.g. aminodextran

Abstract

Diagnostic compositions which contain ferromagnetic particles are suitable for use in NMR diagnosis.

Description

Die Erfindung betrifft diagnostische Mittel zur Anwendung in der NMR-Diagno-The invention relates to diagnostic agents for use in NMR diagnosis

stik, die ferromagnetische Partikel enthalten, bestehend aus einem ferromagnetischen Doppelmetall-oxid/-hydroxid oder einem ferromagnetischen Metall und gegebenenfalls einem Komplexbildner.stik containing ferromagnetic particles, consisting of a ferromagnetic double metal oxide / hydroxide or a ferromagnetic metal and optionally a complexing agent.

Ferner betrifft die Erfindung neue Komplexe aus Doppelmetall-oxid/-hydroxid und einem Komplexbildner.The invention also relates to new complexes of double metal oxide / hydroxide and a complexing agent.

Als ferromagnetischer Bestandteil kommen Metallpartikel, wie Eisen-,Kobalt-, Nickelpartikel und Doppeloxide / Doppelhydroxide in Betracht, die zwei-und/oder dreiwertiges Eisen enthalten, wie beispielsweise Ferrite der allgemeinen Formel MO.Fe203, worin M ein zweiwertiges Metallion oder ein Gemisch aus zwei zweiwertigen Metallionen ist, oder beispielsweise Doppeloxide der allgemeinen Formel FeO.M203, worin M ein dreiwertiges Metallion ist. Bevorzugt sind im 1. Fall die physiologisch in geringen Mengen akzeptablen Elemente Magnesium, Zink, Eisen und Kobalt, gegebenenfalls auch noch in sehr geringen Mengen Mangan, Cadmium, Nickel, Kupfer, Barium und Strontium, im 2. Fall Chrom, Lanthan, Gadolinium, Europium, Dysprosium, Holmium, Ytterbium und Samarium.Metal particles such as iron, cobalt, Nickel particles and double oxides / double hydroxides into consideration, the two and / or contain trivalent iron, such as ferrites of the general formula MO.Fe203, wherein M is a divalent metal ion or a mixture of two divalent Is metal ions, or, for example, double oxides of the general formula FeO.M203, where M is a trivalent metal ion. In the first case, the physiological ones are preferred in small amounts acceptable elements magnesium, zinc, iron and cobalt, if necessary also in very small amounts of manganese, cadmium, nickel, copper, barium and strontium, in the 2nd case chromium, lanthanum, gadolinium, europium, dysprosium, holmium, ytterbium and samarium.

Als Komplexbildner können wasserlösliche Mono-, Di-, Oligo- und Polysaccharide, Proteine und synthetische Schutzkolloide, wie Polyvinylalkohol oder Polyvinylpyrrolidon verwendet werden. Bevorzugt sind Zucker, Dextrane, Dextrine, Gelantine, Globuline und Albumine, wie zum Beispiel Humanserumalbumin, an die gewünschtenfalls Biomoleküle geknüpft sind. Solche Biomoleküle können beispielsweise Hormone, wie Insulin, Prostaglandine, Steroide, sowie Aminozucker, Peptide, Proteine oder Lipide sein. Besonders hervorzuheben sind Konjugate mit Albuminen, wie Humanserumalbumin, Staphylokokken-Protein A, Antikörpern, wie zum Beispiel monoklonale Antikörper und Konjugate oder Einschlußverbindungen mit Liposomen, die beispielsweise als unilamellare oder multilamellare Phosphatidylcholin-Cholesterol-Vesikel eingesetzt werden.Water-soluble mono-, di-, oligo- and polysaccharides, Proteins and synthetic protective colloids, such as polyvinyl alcohol or polyvinyl pyrrolidone be used. Sugar, dextrans, dextrins, gelatin, globulins are preferred and albumins, such as human serum albumin, to biomolecules, if desired are linked. Such biomolecules can, for example, hormones such as insulin, prostaglandins, Be steroids, as well as amino sugars, peptides, proteins or lipids. Of particular note are conjugates with albumins, such as human serum albumin, staphylococcal protein A, antibodies, such as monoclonal antibodies and conjugates or inclusion compounds with liposomes, for example as unilamellar or multilamellar phosphatidylcholine-cholesterol vesicles can be used.

Als Komplexbildner können auch anorganische Schutzkolloide, wie zum Beispiel Zeolithe verwendet werden.Inorganic protective colloids, such as Example zeolites can be used.

Komplexe von Magnetit (Fe304) mit Dextran bzw. mit Humanserumalbumin sind zum Beispiel beschrieben in den US-Patenten 4.101.435 und 4.452.773 bzw.Complexes of magnetite (Fe304) with dextran or with human serum albumin are described, for example, in U.S. Patents 4,101,435 and 4,452,773, respectively.

in J. Pharm.Sci.68, 79 (1979). Sie bilden in Wasser stabile Sole, die aufgrund ihrer magnetischen Eigenschaften vielfältige Verwendung finden können. So sind sie unter anderem als Drug-Carrier (vor allem für Cytotoxika bei der Tumorbehandlung), als Agens zur Messung des Blutstroms, als Marker in der Scanning/transmission-Elektronenmikroskopie, zur Kennzeichnung und Abtrennung von Zellen und Biomolekülen (zum Beispiel eines Antigens aus einer Antigenmischung, indem man Partikel benutzt, die kovalent an den entsprechenden Antikörper gebunden sind), sowie auch zur Anwendung auf mechanischem Gebiet (z.B. als magnetische Flüssigkeit) geeignet. Ferner ist Dextran-Magnetit als Relaxationsagens zur Messung des Wasseraustausches an Erythrozytenmembranen vorgeschlagen worden (Biochem. and Biophys. Res. Comm. 97, 114 (1980).in J. Pharm. Sci. 68, 79 (1979). They form stable brines in water, which can be used in a variety of ways due to their magnetic properties. Among other things, they are used as drug carriers (especially for cytotoxics in tumor treatment), as an agent for measuring blood flow, as a marker in scanning / transmission electron microscopy, to identify and separate cells and biomolecules (for example a Antigens from a mixture of antigens by using particles that are covalently attached the corresponding antibodies are bound), as well as for use on mechanical Area (e.g. as a magnetic fluid). Furthermore, dextran is magnetite as a relaxation agent for measuring the water exchange on erythrocyte membranes (Biochem. and Biophys. Res. Comm. 97, 114 (1980).

Ferromagnetische Zeolith-Partikel sind zum Beispiel zur Auftrennung von Kohlenwasserstoffgemischen verwendet worden (Europäische Patentanmeldung Publikations Nr. 0130043) Es wurde nun gefunden, daß die erfindungsgemäßen Mittel überraschenderweise die vielfältigen Voraussetzungen für die Eignung als Kontrastmittel für die NMR-Diagnostik erfüllen. (Eine ausführliche Diskussion dieser Voraussetzungen findet sich in der Europäischen Patentanmeldung Publikations Nr.Ferromagnetic zeolite particles are for example used for separation of hydrocarbon mixtures has been used (European patent application publications No. 0130043) It has now been found that, surprisingly, the agents according to the invention the diverse requirements for suitability as a contrast agent for NMR diagnostics fulfill. (A detailed discussion of these requirements can be found in the European patent application publication no.

71 564 und der Deutschen Patentanmeldung P 34 01 052.1).71 564 and German patent application P 34 01 052.1).

So sind sie hervorragend dazu geeignet, nach enteraler oder parenteraler Applikation durch Veränderung der Signalintensität das mit Hilfe des Kernspintomographen erhaltene Bild in seiner Aussagekraft zu verbessern. Ferner zeigen sie die hohe Wirksamkeit, die notwendig ist, um den Körper mit möglichst geringen Mengen an Kontrastmitteln zu belasten, und die gute Verträglichkeit, die notwendig ist, um den nicht-invasiven Charakter der Untersuchung aufrechtzuerhalten.So they are ideally suited for enteral or parenteral Application by changing the signal intensity with the help of the magnetic resonance tomograph to improve the expressiveness of the image received. They also show the high Effectiveness that is necessary to the body with the smallest possible amounts of contrast media to strain, and the good tolerance that is necessary to the non-invasive Maintain the character of the investigation.

Überraschenderweise ist die wirksame Dosis im Vergleich zu allen vorbekannten Kontrastmitteln außerordentlich gering, und zwar so gering, daß keinerlei Gefahr besteht, mit der in vivo notwendigen Dosierung in den toxischen Bereich zu gelangen.Surprisingly, the effective dose is in comparison to all previously known Contrast media extremely small, and so small that there is no danger whatsoever exists to get into the toxic range with the dosage necessary in vivo.

Die gute Wasserlöslichkeit der erfindungsgemäßenMittel erlaubt es, hochkonzentrierte Lösungen herzustellen, um die Volumenbelastung des Kreislaufs in vertretbaren Grenzen zu halten und die Verdünnung durch die Körperflüssigkeit auszugleichen. Weiterhin weisen die erfindungsgemäßen Mittel nicht nur eine hohe Stabilität in vitro, sondern auch eine überraschend hohe Stabilität in vivo auf.The good water solubility of the agents according to the invention allows Prepare highly concentrated solutions to reduce the volume load on the circulatory system to keep within reasonable limits and the dilution by the body fluid balance. Furthermore, the agents according to the invention not only have a high Stability in vitro, but also a surprisingly high stability in vivo.

Ein besonderer Vorzug der erfindungsgemäßen Mittel ist es, daß mit ihnen aufgrund spezifischer pharmakokinetischer Eigenschaften Gewebe, Organe und Organsysteme in ihrer Signalintensität im Kernspintomogramm stark verändert werden können. Zum ersten Mal stehen gut verträgliche Kontrastmittel u.a. für die bildliche Darstellung von Tumoren der Leber und Milz zur Verfügung. Durch Bindung des ferromagnetischen Materials an Biomoleküle wie zum Beispiel monoklonale für tumorassoziierte Antigene spezifische Antikörper oder Anti-.N1yosin, gelingt eine Verbesserung der Tumor- und Infarkt-Diagnostik.A particular advantage of the agents according to the invention is that with them due to specific pharmacokinetic properties tissues, organs and Organ systems are greatly changed in their signal intensity in the magnetic resonance tomogram can. For the first time, well-tolerated contrast media represent, among other things, visual Representation of tumors of the liver and spleen are available. By binding the ferromagnetic Materials to biomolecules such as monoclonals for tumor-associated antigens specific antibodies or anti-.N1yosin, an improvement in the tumor and heart attack diagnostics.

Als monoklonale Antikörper für die Konjugation kommen insbesondere solche infrage , die gegen überwiegend zellmembranständige Antigene gerichtet sind.The monoclonal antibodies used for conjugation are in particular those in question that are directed against predominantly cell membrane-based antigens.

Als solche sind zum Beispiel für die Tumordarstellung monoklonale Antikörper bzw. deren Fragmente (F(ab)2) geeignet, die zum Beispiel gegen das Carcinoembryonale Antigen (CEA), humanes Choriogonadotropin (n-hCG) oder andere tumorständige Antigene, wie Glycoproteine, gerichtet sind. Geeignet sind u.a.As such, monoclonals are used, for example, for tumor imaging Antibodies or their fragments (F (ab) 2) suitable, for example against the carcinoembryonic Antigen (CEA), human choriogonadotropin (n-hCG) or other tumor-related antigens, such as glycoproteins. Suitable are i.a.

auch Anti-lyosin-, Anti-Insulin- und Anti-Fibrin-Antikörper.also anti-lyosin, anti-insulin and anti-fibrin antibodies.

Für Leberurtersuchungen eignen sich vorzugsweise Konjugate oder Einschlußverbindungen mit Liposomen. Die Diagnostik im Magen-Darm-Bereich wird durch enterale Applikation der erfindungsgemäßen Mittel verbessert, wodurch beispielsweise eine bessere Abgrenzung von Darmabschnitten bei Pankreas-Untersuchungen erreicht wlrd.Conjugates or inclusion compounds are preferably suitable for liver ure investigations with liposomes. The diagnosis in the gastrointestinal area is carried out by enteral application of the agents according to the invention improved, which means, for example, a better delimitation of intestinal sections in pancreas examinations wlrd.

Die Herstellung der Doppelmetall-oxid/-hydroxid-Komplexe erfolgt in an sich bekannter :eise dadurch, daß man wäßrige Lösungen der entsprechenden zwei-und dreiwertigen Metallsalze, beispielsweise die Halogenide, zusammengibt.The double metal oxide / hydroxide complexes are produced in better known per se: alternatively by using aqueous solutions of the corresponding two and trivalent Metal salts, for example the halides, together.

Dann wird mit Alkalicarbonaten und mit Alkalihydroxiden, vorzugsweise AmmDnium- oder Natriumhydroxid, versetzt, um den pH-Wert zu erhöhen und die Metalloxid- bzw. Metallhydroxid-Partikel zu erzeugen, an die der Komplexbildner bindet. Durch zum Beispiel Zentrifugieren sowie zum Beispiel Gelfiltrations-Chromatographie und/oder Dialyse kann eine Abtrennung und Reinigung der gewünschten Komplexe erfolgen. Then with alkali carbonates and with alkali hydroxides, preferably AmmDnium or sodium hydroxide, added to increase the pH and reduce the metal oxide or to generate metal hydroxide particles to which the complexing agent binds. By for example centrifugation and for example gel filtration chromatography and / or Dialysis can be used to separate and purify the desired complexes.

In einer anderen Herstellungsweise wird das fein gemahlene Doppeloxid bzw.In another production method, the finely ground double oxide is made respectively.

Metall mit dem Schutzkolloid komplexiert (siehe z.B. J. Pharm. Sci. 68, 79, (1979).Metal complexed with the protective colloid (see e.g. J. Pharm. Sci. 68, 79, (1979).

Die Bindung der Biomoleküle an die organischen Schutzkolloide erfolgt in an sich bekannter Weise nach Methoden, wie Beispiel in Rev.roum.Morphol.The biomolecules are bound to the organic protective colloids in a manner known per se according to methods such as the example in Rev.roum.Morphol.

Embryol. Physiol., Physiologie 1981, 18, 241 und J.Pharm. Sci.68,79 (1979) beschrieben sind.Embryol. Physiol., Physiologie 1981, 18, 241 and J. Pharm. Sci. 68.79 (1979).

Die Herstellung ferromagnetischer Zeolith-Partikel kann zum Beispiel nach der in der Europäischen Patentanmeldung -Publikations Nr. 130043 angegebenen Vorschrift erfolgen.The production of ferromagnetic zeolite particles can for example according to that given in European Patent Application Publication No. 130043 Regulation.

Die Herstellung der erfindungsgemäßen diagnostischen Mittel erfolgt ebenfalls in an sich bekannter Weise, indem man die erfindungsgemäßen Partikel gegebenenfalls unter Zugabe der in der Galenik üblichen Zusätze in wäßrigem Medium suspendiert und anschließend die Suspension gegebenenfalls sterilisiert.The diagnostic agents according to the invention are produced likewise in a manner known per se, by optionally adding the particles according to the invention suspended in an aqueous medium with the addition of the additives customary in galenicals and then optionally sterilizing the suspension.

Geeignete Zusätze sind beispielsweise physiologisch unbedenkliche Puffer (wie z.B. Tromethamin) oder, falls erforderlich, Elektrolyte wie zum Beispiel Natriumchlorid.Suitable additives are, for example, physiologically harmless ones Buffers (such as tromethamine) or, if necessary, electrolytes such as Sodium chloride.

Sind für die enterale Verabreichung oder andere Zwecke Suspensionen der erfindungsgemäßen Mittel in Wasser oder physiologischer Salzlösung erwünscht, werden sie mit einem oder mehreren in der Galenik üblichen Hilfsstoffen (z.B. Methylcellulose, Lactose, Mannit) und/oder Tensiden (z.B. Lecithine, Tweens (R), Myrj (R) )und/oder Aromastoffen zur Geschmackskorrektur (z.B.Are for enteral or other purposes suspensions the agents according to the invention in water or physiological saline solution are desirable, they are mixed with one or more of the usual galenical auxiliaries (e.g. methyl cellulose, Lactose, mannitol) and / or surfactants (e.g. lecithins, Tweens (R), Myrj (R)) and / or Flavorings to correct taste (e.g.

ätherischen Ölen) gemischt.essential oils).

Die Mittel, die unkomplexierte ferromagnetische Partikel enthalten, sind vorzugsweise für die enterale Applikation geeignet.The means that contain uncomplexed ferromagnetic particles, are preferably suitable for enteral application.

Die erfindungsgemBen diagnostischen Mittel enthalten 1 llMol bis 1 Mol, vorzugsweise 0,1 bis 100 mMol ferromagnetisches Metall pro Liter und werden in der Regel in Mengen von 0,001 bis 100 uMol, vorzugsweise 0,1 bis 10 uMol ferromagnetisches Metall pro Kilogramm Körpergewicht dosiert. Sie sind zur enteralen und parenteralen Applikation bestimmt.The diagnostic agents according to the invention contain 1 ll mol to 1 Moles, preferably 0.1 to 100 mmoles of ferromagnetic metal per liter and will usually in amounts of 0.001 to 100 µmoles, preferably 0.1 to 10 µmoles of ferromagnetic Metal dosed per kilogram of body weight. They are used both enterally and parenterally Application determined.

Die folgenden Ausführungsbeispiele dienen zur weiteren Erläuterung der Erfindung.The following exemplary embodiments serve for further explanation the invention.

Beispiel 1 Eine Lösung von 100 g Galactose in 824 ml Wasser wird mit 140 ml einer 1-molaren Eisen-III-chloridlösung und mit 70 ml einer 1-molaren Eisen-II-chloridlösung versetzt, so daß ein Eisengehalt von 11,71 g resultiert. Die Mischung wird bei Raumtemperatur durch tropfenweise Zugabe einer 20 gew.-%igen wäßrigen Natriumcarbonatlösung auf pH 2,4 gebracht. Nach Beendigung der Gasentwicklung setzt man 45 ml einer 10-normalen Natronlauge zu und erhitzt die Mischung 30 Minuten zum Rückfluß. Nach Abkühlen auf Raumtemperatur bringt man durch Zugabe von 6-normaler Salzsäure auf pH 6,2 und fällt anschließend den Komplex durch Zugabe von 2 Liter Ethanol unter Rühren. Man zentrifugiert ab, löst den Rückstand in Wasser und entfernt Frendionen durch Dialyse. Die gereinigte Lösung wird im Vakuum eingeengt, filtriert und lyophilisiert. Man erhält den gewünschten Galactose-Magnetit-Komplex als braunes Pulver.Example 1 A solution of 100 g of galactose in 824 ml of water is mixed with 140 ml of a 1 molar iron (III) chloride solution and 70 ml of a 1 molar iron (II) chloride solution added so that an iron content of 11.71 g results. The mixture is at room temperature by adding dropwise a 20% strength by weight aqueous sodium carbonate solution pH 2.4 brought. After the evolution of gas has ended, 45 ml of a 10 normal are added Sodium hydroxide solution and the mixture is refluxed for 30 minutes. After cooling down Room temperature is brought to pH 6.2 by adding 6 normal hydrochloric acid and the mixture is precipitated then the complex by adding 2 liters of ethanol with stirring. Centrifuge from, dissolves the residue in water and removes frendions by dialysis. The cleaned Solution is concentrated in vacuo, filtered and lyophilized. The desired one is obtained Galactose magnetite complex as a brown powder.

Beispiel 2 80 g Dextrin (Polymaltose, basale Viskosität 0,05/250C) werden in 180 ml Wasser bei 700C in Lösung gebracht.Example 2 80 g dextrin (polymaltose, basal viscosity 0.05 / 250C) are brought into solution in 180 ml of water at 70.degree.

Nach Abkühlen auf Raumtemperatur wird in eine Mischung aus 70 ml 1-molarer Eisen-III-chloridlösung und 35 ml einer 1-molaren Eisen-II-chloridlösung eingerührt. Dann bringt man die Mischung durch tropfenweise Zugabe einer 20 gewichts-%igen wäßrigen Natriumcarbonatlösung auf pH 1,7. Nach Beendigung der Gasentwicklung stellt man durch tropfenweise Zugabe von 10 n-Natronlauge einen pH-Wert von 11,0 ein und erhitzt 30 Minuten zum Rückfluß. Nach Abkühlen auf Raumtemperatur bringt man durch Zugabe von 6-normaler Salzsäure auf pH 6,2, fällt den Komplex durch Zugabe von 500 ml Ethanol, zentrifugiert, löst den Rückstand in Wasser und entfernt Fremdionen durch Dialyse. Die kolloide Lösung wird nach Filtration lyphilisiert. Man erhält den gewünschten Dextrin-Magnetit-Komplex als schwarzes Pulver.After cooling to room temperature, a mixture of 70 ml of 1 molar Iron (III) chloride solution and 35 ml of a 1 molar iron (II) chloride solution are stirred in. The mixture is then brought up by the dropwise addition of a 20% strength by weight aqueous solution Sodium carbonate solution to pH 1.7. After the evolution of gas has ended, one sets by adding 10 N sodium hydroxide solution dropwise to a pH value of 11.0 and heating 30 minutes to reflux. After cooling to room temperature, bring through Encore of 6 normal hydrochloric acid to pH 6.2, the complex is precipitated by adding 500 ml of ethanol, centrifuged, dissolves the residue in water and removes foreign ions by dialysis. The colloidal solution is lyophilized after filtration. The desired one is obtained Dextrin-magnetite complex as a black powder.

Beispiel 3 Eine Lösung von 2,5 g Humanserumalbumin in 10 ml Wasser wird mit 720 mg Eisenchromit, FeO*Cr203, 3, in Form von Partikeln mit einem Durchmesser von 10-20 nm versetzt. Die Suspension wird in 600 ml Baumwollsaatöl eingetragen und die Emulsion durch Ultrabeschallung (100w, 1 min bei 4°C) homogenisiert.Example 3 A solution of 2.5 g of human serum albumin in 10 ml of water is made with 720 mg of iron chromite, FeO * Cr203, 3, in the form of particles with a diameter offset by 10-20 nm. The suspension is introduced into 600 ml of cottonseed oil and the emulsion is homogenized by ultrasound (100w, 1 min at 4 ° C).

Dann wird die Emulsion tropfenweise unter intensivem Rühren in 2 Liter 120°-heißes Baumwollsaatöl eingegossen.Then the emulsion is poured dropwise with vigorous stirring in 2 liters 120 ° hot cottonseed oil poured in.

Nach weiterem 10 minütigen Erhitzen auf 1200 kühlt man auf Raumtemperatur ab und wäscht die erhaltenen Micropartikel mit Hilfe von Methyl-t-Butylether ölfrei.After heating to 1200 for a further 10 minutes, the mixture is cooled to room temperature and the microparticles obtained are washed free of oil with the aid of methyl t-butyl ether.

Nach 24 stündigem Trocknen bei 4° unter Lichtausschluß erhält man den gewünschten Humanserumalbumin-Eisenchromit-Komplex als tiefschwarzes Pulver.After drying for 24 hours at 4 ° with exclusion of light, one obtains the desired human serum albumin iron chromite complex as a deep black powder.

Beispiel 4 112 mg Dextrin-Magnetit-Komplex (Beispiel 2) werden in 20 ml einer 0,9%igen Kochsalzlösung eingetragen.Example 4 112 mg of dextrin-magnetite complex (example 2) are used in Entered 20 ml of a 0.9% saline solution.

Das 15 Minuten bei 11000 pasteurisierte Sol dient zur parenteralen Applikation.The sol pasteurized at 11,000 for 15 minutes is used for parenteral use Application.

Beispiel 5 Ein Granulat, hergestellt aus 12 mg Dextrin-Magnetit-Komplex (Beispiel 2), 2,42 g Tromethamin, 45 g Mannit und 10 g Tylose, wird in 1000 ml Aqua dest. eingerührt für die enterale Applikation verwendet.Example 5 A granulate produced from 12 mg of dextrin-magnetite complex (Example 2), 2.42 g of tromethamine, 45 g of mannitol and 10 g of Tylose, in 1000 ml of Aqua least. used for enteral application.

Beispiel 6 150 mg Galactose-Magnetit-Komplex (Beispiel 1) werden in 25 ml einer 0,9%igen Kochsalzlösung eingerührt. Man füllt in Ampullen ab, die hitzesterilisiert werden.Example 6 150 mg of galactose-magnetite complex (Example 1) are in Stir in 25 ml of a 0.9% saline solution. It is filled into ampoules which are heat-sterilized will.

Beispiel 7 Ein Granulat, hergestellt aus 50 mg Galactose-Magnetit-Komplex (Beispiel 1), 3,00 g Tromethamin, 50 g Mannit und 10 g Tylose wird in 1000 ml Aqua dest. eingerührt und in Flaschen zur enteralen Applikation abgefüllt.Example 7 A granulate produced from 50 mg of galactose-magnetite complex (Example 1), 3.00 g of tromethamine, 50 g of mannitol and 10 g of Tylose is in 1000 ml of Aqua least. stirred in and filled into bottles for enteral application.

Beispiel 8 Ein Granulat, hergestellt aus 20 mg Albumin-Eisenchromit-Komplex (Beispiel 3), 1,8 g Tromethamin, 50 g Mannit und 8 g Tylose, wird in 750 ml Aqua dest. eingerührt und für die enterale Applikation verwendet.Example 8 A granulate made from 20 mg of albumin-iron chromite complex (Example 3), 1.8 g of tromethamine, 50 g of mannitol and 8 g of Tylose, is in 750 ml of Aqua least. stirred in and used for enteral application.

BEISPIEL 9: Eine Lösung von 25C mg Humanserumalbumin in 0,75 ml Wasser wird mit 65 mg Zinkferrit, ZnFe204, in Form von Partikeln mit einer Teilchengrösse von 10 - 2C nm im Durchmesser, versetzt. Die Suspension wird in 20 ml Baumwollsaatöl eingegossen und die gebildete Emulsion durch Ultrabeschallung (100 w, 1 min bei 40 C) homogenisiert. Dann wird das gekühlte Homogenat unter intensivem Rühren in 10 ml ca. 1200 C - heißes Baumwollsaatöl eingegossen. Man läßt noch 10 min bei 1200 C rühren, kühlt auf Raumtemperatur ab und wäscht die Mikropartikel mit Hilfe von Methyltert.butylether ölfrei. Nach 24 stündigem Trocknen im Vakuum unter Lichtausschluß bei 40 C erhält man den gewünschten Humanserumalbumin -Zinkferrit-Komplex in Form von Mikropartikeln mit einem Durchmesser von 500 + 100 ntn. EXAMPLE 9: A solution of 25C mg human serum albumin in 0.75 ml water is with 65 mg zinc ferrite, ZnFe204, in the form of particles with a particle size of 10-2C nm in diameter, offset. The suspension is in 20 ml of cottonseed oil poured in and the emulsion formed by ultrasound (100 w, 1 min at 40 C) homogenized. Then the cooled homogenate is in 10 ml approx. 1200 C - hot cottonseed oil poured in. It is left at 1200 for a further 10 minutes Stir at C, cool to room temperature and wash the microparticles with the help of Methyl tert-butyl ether, oil-free. After drying for 24 hours in vacuo with exclusion of light at 40 C the desired human serum albumin-zinc ferrite complex is obtained in the form of microparticles with a diameter of 500 + 100 ntn.

BEISPIEL 10: Eine Suspension von 31 mg Humanserumalbumin, 10 mg Magnetit, Fe304, und 6 mg Protein A (Pharmacia, Freiburg) in 0,12 ml Wasser wird mit 20 ml Baumwollsaatöl im Ultraschallbad homogenisiert (100 w, 1 Min bei 40 C). Dann wird das Homogenat unter intensivem Rühren in 15 ml ca. 1200 - heißes Baumwollsaatöl eingegossen. Man läßt noch 10 min bei 1200 rühren, kühlt auf Raumtemperatur ab und wäscht die Mikropartikel mit Hilfe von Methyl-tert.butylether ölfrei (jeweils 15 min Zentrifugieren bei 2000 xg). Nach 24 stündigem Trocknen im Vakuum unter Lichtausschluß bei 40 C erhält man das gewünschte Humanserumalbumin - Magnetit-Protein A - Konjugat in Form von Mikropartikeln mit einem Durchmesser von 200 + 80 nm. 0,5 mg Konjugat werden in 1 ml 0,01 m Phosphatpuffer bei ph 8 und 370 C 30 min mit 500 lag Anti-CEA inkubiert.EXAMPLE 10: A suspension of 31 mg human serum albumin, 10 mg magnetite, Fe304, and 6 mg protein A (Pharmacia, Freiburg) in 0.12 ml water is mixed with 20 ml Cottonseed oil homogenized in an ultrasonic bath (100 w, 1 min at 40 C). Then it will be the homogenate with intensive stirring in 15 ml approx. 1200 - hot cottonseed oil poured. The mixture is stirred for a further 10 min at 1200, cooled to room temperature and washes the microparticles oil-free with the help of methyl tert-butyl ether (15 min centrifugation at 2000 xg). After drying for 24 hours in vacuo with exclusion of light at 40 C the desired human serum albumin - magnetite-protein A conjugate is obtained in the form of microparticles with a diameter of 200 + 80 nm. 0.5 mg conjugate are in 1 ml of 0.01 M phosphate buffer at pH 8 and 370 C for 30 min with 500 anti-CEA incubated.

Dann werden die Mikropartikel dreimal mit Pufferlösung gewaschen und nach Zentrifugieren gefriergetrocknet. Die Bindungskapazität beträgt 80 i 3 ug / mg Antikörper / Mikropartikel. Das Konjugat wird in physiologischer Kochsalzlösung zur parenteralenApplikation verwendet.Then the microparticles are washed three times with buffer solution and freeze-dried after centrifugation. The binding capacity is 80 i 3 ug / mg antibody / microparticle. The conjugate is in physiological saline solution used for parenteral application.

Durch Inkubieren des Humanserumalbumin-Magnetit-Protein A-Konjugates mit Anti-Myosin erhält mnn in analoger Weise das entsprechende Anti-Körperkonjugat zurparenteralen Applikation.By incubating the human serum albumin-magnetite-protein A conjugate with anti-myosin, mnn receives the corresponding anti-body conjugate in an analogous manner for parenteral application.

BEISPIEL 11: Zu einer Lösung von 2 g Dextran Magnetit (Meito Sangyo Co.Ltd.) in 30 ml Wasser gibt man eine Lösung von 3,3 g Kaliumhydroxid in 12 ml Wasser. Man läßt 10 Min rühren, kühlt auf 50 C ab und versetzt mit einer Lösung von 1,5 g 2-Bromethylamin in 1,8 ml Wasser. Man läßt zwei Stunden unter Kühlung nachrühren und dann über Nacht auf Raumtemperatur kommen. Dann gibt man bei pH 6,8 2,5 g Glutaraldehyd zu und hält den Ansatz 18 Stunden bei Raumtemperatur. Nach Filtration über Aktivkohle wird eingeengt und das polymere Produkt durch Fällen mit Aceton isoliert. Man wäscht das abgesaugte Produkt mit Aceton und trocknet es im Vakuum. Zu 20 ul einer Lösung von 0,3 mg Anti-CEA in 0,05 molarem Natriumnicarbonatpuffer (pH 7 - 8) werden 2 mg des derivatisierten Dextran-Magnetits gegeben. Nach mehrstündiger Inkubationszeit wird die erhaltene Lösung gegen 0,3 molaren Natriumphosphatpuffer dialysiert und anschließend über eine Sephadex G 25 -Säule gereinigt. Durch Gefriertrocknung wird das gewünschte Antikörper-Konjugat isoliert, das zur parenteralen Applikation verwendet wird.EXAMPLE 11: To a solution of 2 g of dextran magnetite (Meito Sangyo Co.Ltd.) In 30 ml of water is added a solution of 3.3 g of potassium hydroxide in 12 ml Water. The mixture is stirred for 10 minutes, cooled to 50 ° C. and a solution is added of 1.5 g of 2-bromoethylamine in 1.8 ml of water. It is left with cooling for two hours stir and then come to room temperature overnight. Then it is added at pH 6.8 2.5 g of glutaraldehyde are added and the batch is kept at room temperature for 18 hours. After filtration It is concentrated over activated charcoal and the polymeric product is precipitated with acetone isolated. The suctioned product is washed with acetone and dried in vacuo. To 20 µl of a solution of 0.3 mg anti-CEA in 0.05 molar sodium bicarbonate buffer (pH 7-8) 2 mg of the derivatized dextran magnetite are added. After several hours The solution obtained is incubated against 0.3 molar sodium phosphate buffer dialyzed and then purified on a Sephadex G 25 column. By freeze drying the desired antibody conjugate is isolated, which is intended for parenteral administration is used.

In analoger Weise erhält man das entsprechende Dextran-Magnetit-Anti-Myosin-Konjugat.The corresponding dextran-magnetite-anti-myosin conjugate is obtained in an analogous manner.

BEISPIEL 12: Ein Granulat, hergestellt aus 50 mg Zeolith Y- Magnetit - Komplex (hergestellt nach Europ. Pat. Anm. 0130 043), 3 g Tromethamin, 30 g Mannit und 15 g Tylose wird in 1000 ml Wasser prd injectione eingerührt und in Flaschen zur enteralen Applikation abgefüllt.EXAMPLE 12: A granulate made from 50 mg of zeolite Y magnetite - Complex (manufactured according to European Pat. Note 0130 043), 3 g tromethamine, 30 g mannitol and 15 g of Tylose is stirred into 1000 ml of water prd injectione and bottled bottled for enteral application.

BEISPIEL 13: 150 mg Humanserumalbumin - Zinkferrit-Komplex (Beispiel 9) werden in 25 ml 0,9 % iger Kochsalzlösung suspendiert und in Ampullen abgefüllt, die pasteurisiert werden.EXAMPLE 13: 150 mg human serum albumin - zinc ferrite complex (Example 9) are suspended in 25 ml of 0.9% saline solution and filled into ampoules, which are pasteurized.

BEISPIEL 14: Ein Granulat, hergestellt aus 1000 mg Eisen-Zeolith-Y - Komplex (hergestellt nach Europ. Ann. 0130043), 5 g Tromethamin, 300 g Mannit und 100 g Tylose werden in 20 1 Wasser pro injectione suspendiert und in Flaschen zur oralen Applikation abgefüllt. EXAMPLE 14: A granulate made from 1000 mg of iron-zeolite-Y - Complex (manufactured according to Europ. Ann. 0130043), 5 g tromethamine, 300 g mannitol and 100 g of Tylose are suspended in 20 l of water per injection and bottled bottled for oral application.

BEISPIEL 15: Nach den in Proc.Natl. Acad. Sci.USA 75, 4194 beschriebenen Vorgehensweise wird ein r,ipidgemisch aus 75 Mol % Ei-Phosphatidylcholin und 25 mol % Cholesterol als Trockensubstanz hergestellt. Hiervon werden 500 mg in 30 ml Diethylether gelöst und im Ultraschallbad tropfenweise mit 3 ml eines mit 0,9 oSeiger Kochsalzlsöung im Verhältnis 1:2 verdünnten Dextran-Maznetit-Sols versetzt. Dann setzt man ale Ultrabeschallung noch 10 Min fort und engt im Rotavapor schonend ein. Der gelartige Rückstand wird in einer 0,125 molaren Kochsalzlösung suspendiert und bei 40 C wiederholt durch Zentrifugieren (20000 g / 20 Min) von nicht verkapselten Anteilen befreit. Die so behandelten Liposomen werden im Multivial gefriergetrocknet. Die intravasale Applikation erfolgt als kolloidale Dispersion in physiologischer Kochsalzlösung. EXAMPLE 15: According to the in Proc.Natl. Acad. Sci. USA 75, 4194 The procedure is an ipid mixture of 75 mol% egg phosphatidylcholine and 25 mol% cholesterol produced as dry matter. 500 mg of this are in 30 ml Dissolve diethyl ether and add 3 ml of a 0.9 oSeiger solution dropwise in an ultrasonic bath Saline solution in a ratio of 1: 2 diluted dextran-maznetite sol was added. then all ultrasound is continued for another 10 minutes and gently concentrated in the Rotavapor. The gel-like residue is suspended in a 0.125 molar saline solution and repeated at 40 C by centrifuging (20,000 g / 20 min) of non-encapsulated Shares exempt. The liposomes treated in this way are freeze-dried in the multivial. The intravascular application takes place as a colloidal dispersion in physiological Saline solution.

Claims (32)

PATENT ANSPRUCH E 1. Diagnostische Mittel zur Anwendung in der NMR-Diagnostik, dadurch gekennzeichnet, daß sie ferromagnetische Partikel enthalten. PATENT CLAIM E 1. Diagnostic means for use in NMR diagnostics, characterized in that they contain ferromagnetic particles. 2. Diagnostische Mittel gemäß Patentanspruch 1, dadurch gekennzeichnet, daß die ferromagnetischen Partikel Eisen-, Kobalt- oder Nickel-Partikel sind.2. Diagnostic means according to claim 1, characterized in that that the ferromagnetic particles are iron, cobalt or nickel particles. 3. Diagnostische Mittel gemäß Anspruch 1, dadurch gekennzeichnet, daß die ferromagnetischen Partikel aus einem Doppelmetall-oxid/-hydroxid bestehen.3. Diagnostic agent according to claim 1, characterized in that that the ferromagnetic particles consist of a double metal oxide / hydroxide. 4. Diagnostische Mittel gemäß Patentansprüchen 1 bis 3, dadurch gekennzeichnet, daß sie einen Komplexbildner enthalten.4. Diagnostic agents according to claims 1 to 3, characterized in that that they contain a complexing agent. 5. Diagnostische Mittel gemäß Patentanspruch 3, dadurch gekennzeichnet, daß das Doppelmetall-oxid-/-hydroxid ein Ferrit der allgemeinen Formel MO . Fe203, worin M ein zweiwertiges Metallion darstellt, ist.5. Diagnostic means according to claim 3, characterized in that that the double metal oxide - / - hydroxide is a ferrite of the general formula MO. Fe203, wherein M represents a divalent metal ion. 6. Diagnostische Mittel gemäß Patentanspruch 3, dadurch gekennzeichnet, daß das Doppelmetall-oxid/-hydroxid die allgemeine Formel FeO.M203, worin M ein dreiwertiges Metallion darstellt, hat.6. Diagnostic means according to claim 3, characterized in that that the double metal oxide / hydroxide has the general formula FeO.M203, where M is a represents trivalent metal ion has. 7. Diagnostische Mittel gemäß Patentanspruch 4, dadurch gekennzeichnet, daß der Komplexbildner ein wasserlösliches Protein ist.7. Diagnostic means according to claim 4, characterized in that that the complexing agent is a water soluble protein. 8. Diagnostische Mittel gemäß Patentansprüchen 4 und 7, dadurch gekennzeichnet, daß der Komplexbildner Humanserumalbumin ist.8. Diagnostic means according to claims 4 and 7, characterized in that that the complexing agent is human serum albumin. 9. Diagnostische Mittel gemäß Patentanspruch 4, dadurch gekennzeichnet, daß der Komplexbildner ein wasserlösliches Mono-, Di-, Oligo- oder Polysaccharid ist.9. Diagnostic means according to claim 4, characterized in that that the complexing agent is a water-soluble mono-, di-, oligo- or polysaccharide is. 10. Diagnostische Mittel gemäß Patentansprüchen 4 und 9, dadurch gekennzeichnet, daß der Komplexbildner Dextran ist, mit Ausnahme von Dextran-Magnetit.10. Diagnostic means according to claims 4 and 9, characterized in that that the complexing agent is dextran, with the exception of dextran magnetite. 11. Diagnostische Mittel gemäß Patentansprüchen 4 und 9, dadurch gekennzeichnet, daß der Komplexbildner Dextrin ist.11. Diagnostic means according to claims 4 and 9, characterized in that that the complexing agent is dextrin. 12. Diagnostische Mittel gemäß Patentanspruch 4, dadurch gekennzeichnet, daß der Komplexbildner ein Zeolith ist.12. Diagnostic means according to claim 4, characterized in that that the complexing agent is a zeolite. 13. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 12, gekennzeichnet durch einen Gehalt an Magnetit-Zeolith.13. Diagnostic means according to claims 4, 5 and 12, characterized due to a content of magnetite zeolite. 14. Diagnostische Mittel gemäß Patentansprüchen 4,5 und 8, gekennzeichnet durch einen Gehalt an Humanserumalbumin-Magnetit.14. Diagnostic means according to claims 4, 5 and 8, characterized by a content of human serum albumin magnetite. 15. Diagnostische Mittel gemäß Patentansprüchen 4, 5, und 9, gekennzeichnet durch einen Gehalt an Galactose-Magnetit.15. Diagnostic means according to claims 4, 5 and 9, characterized by a content of galactose magnetite. 16. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 9, gekennzeichnet durch einen Gehalt an Dextrin-Magnetit.16. Diagnostic means according to claims 4, 5 and 9, characterized due to a content of dextrin magnetite. 17. Diagnostische Mittel gemäß Patentansprüchen 4, 6 und 10, gekennzeichnet durch einen Gehalt an Dextran-Eisen-Chromit.17. Diagnostic means according to claims 4, 6 and 10, characterized due to a content of dextran-iron-chromite. 18. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 10, gekennzeichnet durch einen Gehalt an Dextran-Zinkferrit.18. Diagnostic means according to claims 4, 5 and 10, characterized due to a content of dextran zinc ferrite. 19. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 10, gekennzeichnet durch einen Gehalt an Dextran-Magnetit-Anti-Myosin-Konjugat.19. Diagnostic means according to claims 4, 5 and 10, characterized due to a content of dextran-magnetite-anti-myosin conjugate. 20. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 10, gekennzeichnet durch einen Gehalt an Dextran-Magnetit-Anti-CEA-Konjugat.20. Diagnostic means according to claims 4, 5 and 10, characterized by containing dextran magnetite anti-CEA conjugate. 21. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 8, gekennzeichnet durch einen Gehalt an Humanserumalbumin-Magnetit-Protein A-Anti-CEA-Konjugat.21. Diagnostic means according to claims 4, 5 and 8, characterized by a content of human serum albumin-magnetite-protein A-anti-CEA conjugate. 22. Diagnostische Mittel gemäß Patentansprüchen 4, 5 und 8, gekennzeichnet durch einen Gehalt an Humanserumalbumin-Magnetit-Protein A-Anti-Myosin-Konjugat.22. Diagnostic means according to claims 4, 5 and 8, characterized by a content of human serum albumin-magnetite-protein A-anti-myosin conjugate. 23. Diagnostische Mittel gemäß Patentanspruch 1, gekennzeichnet durch einen Gehalt an ferromagnetischen Liposomen.23. Diagnostic means according to claim 1, characterized by a content of ferromagnetic liposomes. 2 4. Diagnostische Mittel gemäß Patentansprüchen 1 bis 2 3, dadurch gekennzeichnet, daß sie pro Liter 1 Mol bis 1 Mol ferromagnetisches Metall enthalten.2 4. Diagnostic means according to claims 1 to 2 3, thereby characterized in that they contain 1 mole to 1 mole of ferromagnetic metal per liter. 2 5.Verfahren zur Herstellung der diagnostischen Mittel gemäß Patentansprüchen 1 bis z 4,dadurch gekennzeichnet, daß man die in Wasser oder physiologischer Salzlösung suspendierten Partikel mit den in der Galenik üblichen Zusätzen bzw. Stabilisatoren in eine für die enterale oder parenterale Applikation geeignete Form bringt.2 5. The method for producing the diagnostic agent according to the claims 1 to z 4, characterized in that the in water or physiological salt solution suspended particles with the additives or stabilizers customary in galenicals brings into a form suitable for enteral or parenteral administration. 2 6.Physiologisch verträgliche ferromagnetische Komplexe aus einem Doppelmetall-oxid/-hydroxid der allgemeinen Formel MO.Fe203, worin M ein zweiwertiges Metallion oder ein Gemisch aus zwei zweiwertigen Metallionen darstellt, oder der allgemeinen Formel FeO.M203, worin M ein dreiwertiges Metallion darstellt, und einem wasserlöslichen Mono-, Di-, Oligo- oder Polysaccharid oder Protein als Komplexbildner mit der Maßgabe, daß, wenn der Komplexbildner Humanserumalbumin oder Dextran ist, das Doppelmetall-oxid/-hydroxid nicht Magnetit ist.2 6. Physiologically compatible ferromagnetic complexes from one Double metal oxide / hydroxide of the general formula MO.Fe203, in which M is a divalent Represents a metal ion or a mixture of two divalent metal ions, or the general formula FeO.M203, in which M represents a trivalent metal ion, and one water-soluble mono-, di-, oligo- or polysaccharide or protein as complexing agent with the proviso that if the complexing agent is human serum albumin or dextran, the double metal oxide / hydroxide is not magnetite. 2 7.. Galactose-Magnetit-Komplex 2 8.. 2 7 .. galactose magnetite complex 2 8 .. Dextrin-Magnetit-Komplex Dextrin-magnetite complex 2 9. Dextrane isenchromit-Komplex 2 9. Dextrans isenchromite complex 30. Dextran-Zinkferrit-Komplex 30. Dextran-zinc ferrite complex 31. Verfahren zur Herstellung der Komplexe gemäß Patentanspruch 26, dadurch gekennzeichnet, daß man wäßrige Lösungen des Komplexbildners und der entsprechenden zwei- und dreiwertigen Metallsalze zusammengibt, Alkalicarbonate und -hydroxide hinzufügt und die gewünschten Komplexe in an -sich bekannter Weise abtrennt und reinigt.31. Process for the preparation of the complexes according to claim 26, characterized in that that one aqueous solutions of the complexing agent and the corresponding bivalent and trivalent Metal salts put together, alkali carbonates and hydroxides added and the desired Separates and cleans complexes in a manner known per se. 32. Verwendung von diagnostischen Mitteln gemäß Patentanspruch 1 für die NMR-Diagnostik.32. Use of diagnostic agents according to claim 1 for NMR diagnostics.
DE19853508000 1984-11-23 1985-03-04 Ferromagnetic particles for NMR diagnosis Withdrawn DE3508000A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
DE19853508000 DE3508000A1 (en) 1985-03-04 1985-03-04 Ferromagnetic particles for NMR diagnosis
PT81498A PT81498B (en) 1984-11-23 1985-11-15 METHOD FOR PREPARING COMPOSITIONS FOR DIAGNOSTICS CONTAINING MAGNETIC PARTICLES
NZ214228A NZ214228A (en) 1984-11-23 1985-11-18 Agents for in vivo diagnostic use containing magnetic particles
AU50225/85A AU583070B2 (en) 1984-11-23 1985-11-19 Magnetic particles for diagnostic purposes
AT85730153T ATE56880T1 (en) 1984-11-23 1985-11-21 MAGNETIC PARTICLES FOR DIAGNOSTICS.
DE8585730153T DE3579899D1 (en) 1984-11-23 1985-11-21 MAGNETIC PARTICLES FOR DIAGNOSTICS.
EP85730153A EP0186616B2 (en) 1984-11-23 1985-11-21 Magnetic particles for diagnostic purposes
GR852815A GR852815B (en) 1984-11-23 1985-11-21
ES549144A ES8703153A1 (en) 1984-11-23 1985-11-21 Magnetic particles for diagnostic purposes.
CA000496054A CA1252950A (en) 1984-11-23 1985-11-22 Magnetic particles for diagnostic purposes
DK198505417A DK174946B1 (en) 1984-11-23 1985-11-22 Use of magnetic particles for diagnostics
NO854679A NO167077C (en) 1984-11-23 1985-11-22 Diagnostic agents for use in in vivo NMR diagnostics, X-ray diagnostics or ultrasound diagnostics.
IE293585A IE58324B1 (en) 1984-11-23 1985-11-22 Magnetic Particles for Diagnostic Purposes
JP60262727A JP2740782B2 (en) 1984-11-23 1985-11-25 In vivo contrast NMR diagnostic medicine
ES557099A ES8704352A1 (en) 1984-11-23 1986-09-30 Magnetic particles for diagnostic purposes.
US08/484,309 US5746999A (en) 1984-11-23 1995-06-07 Magnetic particles for diagnostic purposes
US08/997,748 US20020064502A1 (en) 1984-11-23 1997-12-24 Magnetic particles for diagnostic purposes
US10/105,462 US20020136693A1 (en) 1984-11-23 2002-03-27 Magnetic particles for diagnostic purposes

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US5284646A (en) * 1986-07-03 1994-02-08 Advanced Magnetics Inc. Hepatocyte specific receptor mediated endocytosis type magnetic resonance imaging contrast agents
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DE19514515A1 (en) * 1995-04-12 1996-11-21 Dirk Dipl Chem Guenther Magnetisable iron oxide nano-particle dispersion with high saturation polarisation
EP2612683A3 (en) * 2003-04-15 2014-04-16 Koninklijke Philips N.V. Electro-physiologic contrast composition and method for manufacture.
US7919333B2 (en) 2003-11-25 2011-04-05 Magnamedics Gmbh Spherical and magnetical silicagel carriers having an increase surface for purifying nucleic acids
DE102007059939A1 (en) 2007-12-12 2009-06-18 Müller-Schulte, Detlef, Dr. Noncovalently crosslinked spherical polymer particles for separating biological substances and cells can be dissolved by heating or adding a metal-complexing agent
DE102011112898A1 (en) * 2011-09-08 2013-03-14 Charité - Universitätsmedizin Berlin Nanoparticulate phosphate adsorbent based on maghemite or maghemite / magnetite, its preparation and uses
US10548874B2 (en) 2011-09-08 2020-02-04 Charite-Universitatsmedizin Berlin Nanoparticulate phosphate adsorbent on the basis of maghemite or maghemite/magnetite, production and uses thereof

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