DE3443251A1 - Iron oxide complexes for NMR diagnosis - Google Patents

Iron oxide complexes for NMR diagnosis

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Publication number
DE3443251A1
DE3443251A1 DE19843443251 DE3443251A DE3443251A1 DE 3443251 A1 DE3443251 A1 DE 3443251A1 DE 19843443251 DE19843443251 DE 19843443251 DE 3443251 A DE3443251 A DE 3443251A DE 3443251 A1 DE3443251 A1 DE 3443251A1
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DE
Germany
Prior art keywords
means according
diagnostic means
complexing agent
magnetite
complex
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.)
Granted
Application number
DE19843443251
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German (de)
Other versions
DE3443251C2 (en
Inventor
Heinz Dr. Gries
Wolfgang Dr. Mützel
Hanns-Joachim Dr. 1000 Berlin Weinmann
Christian Dr. Zurth
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Bayer Pharma AG
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Schering AG
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Application filed by Schering AG filed Critical Schering AG
Priority to DE3443251A priority Critical patent/DE3443251C2/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 ES549144A priority patent/ES8703153A1/en
Priority to GR852815A priority patent/GR852815B/el
Priority to EP85730153A priority patent/EP0186616B2/en
Priority to DE8585730153T priority patent/DE3579899D1/en
Priority to DK198505417A priority patent/DK174946B1/en
Priority to NO854679A priority patent/NO167077C/en
Priority to CA000496054A priority patent/CA1252950A/en
Priority to IE293585A priority patent/IE58324B1/en
Priority to ZA858973A priority patent/ZA858973B/en
Priority to JP60262727A priority patent/JP2740782B2/en
Publication of DE3443251A1 publication Critical patent/DE3443251A1/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
Application granted granted Critical
Publication of DE3443251C2 publication Critical patent/DE3443251C2/en
Priority to US10/105,462 priority patent/US20020136693A1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear 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
    • A61K49/1821—Nuclear 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
    • A61K49/1824—Nuclear 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
    • A61K49/1827—Nuclear 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
    • A61K49/1833—Nuclear 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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    • A61K49/1821—Nuclear 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
    • A61K49/1824—Nuclear 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
    • A61K49/1827—Nuclear 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
    • A61K49/1851—Nuclear 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
    • A61K49/1863—Nuclear 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
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear 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
    • A61K49/1821—Nuclear 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
    • A61K49/1824—Nuclear 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
    • A61K49/1827—Nuclear 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
    • A61K49/1866—Nuclear 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
    • A61K49/1869—Nuclear 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B30/00—Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
    • C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
    • C08B30/18—Dextrin, e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, 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
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
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    • G01N2400/14—Homoglycans, 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N2400/14—Homoglycans, 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
    • G01N2400/22—Dextran
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    • G01N2446/00—Magnetic particle immunoreagent carriers
    • G01N2446/20—Magnetic particle immunoreagent carriers the magnetic material being present in the particle core
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    • G01—MEASURING; TESTING
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    • G01N2446/00—Magnetic particle immunoreagent carriers
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2446/00—Magnetic particle immunoreagent carriers
    • G01N2446/80—Magnetic particle immunoreagent carriers characterised by the agent used to coat the magnetic particles, e.g. lipids
    • G01N2446/86—Magnetic 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 agents which contain a physiologically tolerable ferromagnetic complex which consists of a double metal oxide/hydroxide and a complexing agent are suitable for use in NMR diagnosis.

Description

Eisenoxid-Komplexe für dieIron oxide complexes for that

NMR-Diagnostik Die Erfindung betrifft diagnostische Mittel zur Anwendung in der NMR-Diagnostik, die einen physiologisch verträglichen ferromagnetischen Komplex enthalten, der aus einem Doppelmetall-oxid /-hydroxid und einem Komplexbildner besteht.NMR diagnostics The invention relates to diagnostic Means for use in NMR diagnostics which have a physiologically compatible contain a ferromagnetic complex consisting of a double metal oxide / hydroxide and a complexing agent.

Ferner betrifft die Erfindung neue Komplexe aus Doppelmetall -oxidÄhydroxid und einem Komplexbildnes Als ferromagnetischer Bestandteil kommen Doppeloxide / Doppelhydroxide in Betracht, die zwei- und/oder dreiwertige 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 FeObM203, 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.The invention also relates to new complexes of double metal oxide-hydroxide and a complexing agent Double oxides / Double hydroxides that contain divalent and / or trivalent iron are considered, such as for example ferrites of the general formula MO-Fe203, in which M is a divalent Is a metal ion or a mixture of two divalent metal ions, or for example Double oxides of the general formula FeObM203, where M is a trivalent metal ion is. In the first case, preference is given to those which are physiologically acceptable in small amounts Elements magnesium, zinc, iron and cobalt, possibly also in very small amounts Quantities of manganese, cadmium, nickel, copper, barium and strontium, in the 2nd case chromium, Lanthanum, gadolinium, europium, dysprosium, holmium, ytterbium and samarium.

Als Kompiexiianer können wasserlösliche Mono-, Di-, Oligo- und Polysaccharide, Proteine und synthetische Schutzkolloide, wie Polyvinylalkohol oder Polyvinylpyrrolidon verwendet werden. Bevorzugt sind Zucker, Dextrane, Dextrine, Gelatine, Globuline und Albumine, wie zum Beispiel Humanserumalbumin.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.

Komplexe von Magnetit (je304) mit Dextran bzw. mit Humanserumalbumin sind zum Beispiel beschrieben in den US-Patenten 4,101,435 und 4,452,773 bzw. 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.Complexes of magnetite (304 each) with dextran or with human serum albumin are described, for example, in U.S. Patents 4,101,435 and 4,452,773, and US Pat J.Pharm.Sci.68, 79 (1979). They form stable brines in water, the due to their magnetic properties can be used in a variety of ways. 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 has been proposed (Biochem.

and Bio-phys. -Res. Comm. 97, 114 (1980)).and bio-phys. -Res. Comm. 97, 114 (1980)).

Es wurde nun gefunden, daß die erfindungsgemäßen Mittel überraschenderweise die vielfältigen Voraussetzungen für die Eignung als Kontrastmittel für die NMR-Diagnostik erfü-llen. (Eine ausführliche Diskussion dieser Voraussetzungen findet sich in der Europäischen Patentanmeldung 71 564 und der Deutschen Patentanmeldung P 34 01 052.1).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 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 erh-altene -Bild in seiner Aussagekraft zu verbessern.So they are ideally suited for enteral or parenteral Application by changing the signal intensity with the help of the magnetic resonance tomograph erh-altene image to improve its expressiveness.

Ferner zeigen sie die hohe Wirksamkeit, die notwendig ist, um den Körper mit möglichst geringen Mengen an Kontrastmittel zu belasten, und die gute Verträglichkeit, die notwendig ist, um den nicht-invasiven Charakter der Untersuchung aufrechtzuerhalten.They also show the high level of effectiveness that is necessary to achieve the To burden the body with the smallest possible amounts of contrast agent, and the good Tolerance that is necessary to ensure the non-invasive nature of the examination maintain.

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 erfindungsgemäßen Mittel 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 Organsysterr.e 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.A particular advantage of the agents according to the invention is that with them due to specific pharmacokinetic properties tissues, organs and Organsysterr.e are greatly changed in their signal intensity in the magnetic resonance imaging can. For the first time, well-tolerated contrast media represent, among other things, visual Representation of tumors of the liver and spleen are available.

Die Herstellung der Komplexe erfolgt in an sich bekannter Weise dadurch, daß man wäßrige Lösungen der entsprechenden zwei- und dreiwertigen Metallsalze, beispielsweise die Halogenide, zusammengibt. Dann wird mit Alkali, vorzugsweise Ammonium- 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 1 oder Dialyse kann eine Abtrennung und Reinigung der gewünschten Komplexe erfolgen.The complexes are produced in a manner known per se by that one aqueous solutions of the corresponding bivalent and trivalent metal salts, for example the halides. Then with alkali, preferably Ammonium or sodium hydroxide, added to raise the pH and reduce the metal oxide or to generate metal hydroxide particles to which the complexing agent binds. By for example centrifugation as well as for example gel filtration chromatography and 1 or dialysis, the desired complexes can be separated off and purified.

In einer anderen Herstellungsweise wird das fein gemahlene Doppeloxid in wäßriger Lösung mit dem Schutzkclloid komplexiert ( siehe z.B. J.Pharm.Sci 68, 79 (1979)).In another production method, the finely ground double oxide is made complexed with the protective cloid in aqueous solution (see e.g. J.Pharm.Sci 68, 79 (1979)).

Sie erfahren in Wasser eine kolloid-disperse Verteilung.They experience a colloid-disperse distribution in water.

Die Konzentration wird dabei so gewählt, daß eine stabile kolloidale Lösung entsteht.The concentration is chosen so that a stable colloidal Solution emerges.

Die Herstellung der erfindungsgemäßen diagnostischen Mittel erfolgt ebenfalls in an sich bekannter Weise, indem man die Komplexe gegebenenfalls unter Zugabe der in der Galenik üblichen Zusätze in wäßrigem Medium suspendiert und anschließend die Suspension sterilisiert. Geeignete Zusätze sind beispielsweise physiologisch unbedenkliche Puffer (wie zum Beispiel Tromethamin) oder, falls erfoderlich, Elektrolyte (wie zum Beispiel Natriumchlorid).The diagnostic agents according to the invention are produced likewise in a manner known per se by optionally submitting the complexes Addition of the additives customary in galenicals, suspended in an aqueous medium and then suspended the suspension is sterilized. Suitable additives are, for example, physiological Safe buffers (such as tromethamine) or, if necessary, electrolytes (such as sodium chloride).

Sind für die enterale Verabreichung oder andere Zwecke Suspensionen der Komplexe in Wasser oder physiologischer Salzlösung erwünscht, wird ein Komplex mit einem oder mehreren der in der Galenik üblichen Hilfsstoffen (z.B. Methylcellulose, Lactose, Mannit) und/oder Tensiden (R) (z. B. Lecithine, Tweens ), Myrj ) und/oder Aromastoffen zur Geschmackskorrektur (z.B. ätherischen Ölen) gemischt.Are for enteral or other purposes suspensions the complexes desired in water or physiological saline solution becomes a complex with one or more of the auxiliary substances commonly used in galenicals (e.g. methyl cellulose, Lactose, mannitol) and / or surfactants (R) (e.g. lecithins, tweens), Myrj) and / or Mixed flavorings to correct the taste (e.g. essential oils).

Die erfindungsgemäßen diagnostischen Mittel enthalten 1 uMol bis 1 Mol, vorzugsweise 0,1 bis 100 mMol Eisen pro Liter und werden in der Regel in Mengen von 0,001 bis 100 uMol, vorzugsweise 0,1 bis 10 uMol Eisen pro kg Körpergewicht dosiert. Sie sind zur enteralen und parenteralen Applikation bestimmt.The diagnostic agents according to the invention contain 1 µmol to 1 Moles, preferably 0.1 to 100 mmoles of iron per liter and are usually in amounts from 0.001 to 100 µmoles, preferably 0.1 to 10 µmoles of iron per kg of body weight dosed. They are intended for enteral and parenteral administration.

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 Fremdionen 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 foreign ions 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 Pulve-r.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 black powder.

Beispiel 3 Eine Lösung von 2,5 g Humanserumalbumin in 10 ml Wasser wird mit 720 mg Eisenchromit, FeOCr203, 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, FeOCr203, 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 1200-heiAes Baumwollsaatöl eingegossen.Then the emulsion is poured dropwise with vigorous stirring in 2 liters Poured in 1200-hot cottonseed oil.

Nach weiterem 10 minütigem 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 40 unter Lichtausschluß erhält man den gewünschten Humanserumalbumin-Eisenchromit-Komplex als tiefschwarzes Pulver.After drying at 40 for 24 hours 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 1100C pasteurisierte Sol dient zur parenteralen Applikation.The sol pasteurized for 15 minutes at 1100C 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.

Claims (20)

Patentansprüche 1. Diagnostische Mittel zur Anwendung in der NMR-Diagnostik, dadurch gekennzeichnet, daß sie einen physiologisch vertrglichen ferromagnetischen Komplex enthalten, der aus einem Doppelmetall-oxid/ -hydroxid und einem Komplexbildner besteht. Claims 1. Diagnostic means for use in NMR diagnostics, characterized in that it is a physiologically compatible ferromagnetic Contain a complex consisting of a double metal oxide / hydroxide and a complexing agent consists. 2. Diagnostische Mittel gemäß Patentanspruch 1, dadurch gekennzeichnet, daß das Doppelmetall-oxid/-hydroxid ein Ferrit der allgemeinen Formel MO Fe203, worin M ein zwetwertiges Metallion darstellt, ist. 2. Diagnostic means according to claim 1, 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. 3. Diagnostische Mittel gemäß Patentanspruch 1, dadurch gekennzeichnet, daß das Doppelmetall-oxid/ -hydroxid die allgemeine Formel FeO-M2 0 worin M 3, ein dreiwertiges Metallion darstellt, hat. 3. Diagnostic means according to claim 1, characterized in that that the double metal oxide / hydroxide has the general formula FeO-M2 0 wherein M 3, a represents trivalent metal ion has. 4. Diagnostische Mittel gemäß Patentanspruch 1, dadurch gekennzeichnet, daß der Komplexbildner ein wasserlösliches Protein ist. 4. Diagnostic means according to claim 1, characterized in that that the complexing agent is a water soluble protein. 5. Diagnostische Mittel gemäß Patentanspruch 1 und 4, dadurch gekennzeichnet, daß der Komplexbildner Humanserumalbumin ist.5. Diagnostic means according to claim 1 and 4, characterized in that that the complexing agent is human serum albumin. 6. Diagnostische Mittel gemäß Patentanspruch 1, dadurch gekennzeichnet, daß der Komplexbildner ein wasserlösliches Mono-, Di-, Oligo- oder Polysaccharid ist. 6. Diagnostic means according to claim 1, characterized in that that the complexing agent is a water-soluble mono-, di-, oligo- or polysaccharide is. 7. Diagnostische Mittel gemäß Patentanspruch 1 und 6, dadurch gekennzeichnet, daß der Komplexbildner Dextran ist, mit Ausnahme von Dextran-Magnetit. 7. Diagnostic means according to claim 1 and 6, characterized in that that the complexing agent is dextran, with the exception of dextran magnetite. 8. Diagnostische Mittel gemäß Patentanspruch 1 und 6, dadurch gekennzeichnet, daß der Komplexbildner Dextrin ist. 8. Diagnostic means according to claim 1 and 6, characterized in that that the complexing agent is dextrin. 9. Diagnostische Mittel gemäß Patentanspruch 1, 2 und 5, gekennzeichnet durch einen Gehalt an Humanserumalbumin-Magnetit. 9. Diagnostic means according to claim 1, 2 and 5, characterized by a content of human serum albumin magnetite. 10. Diagnostische Mittel gemäß Patentanspruch 1, 2 und 6, gekennzeichnet durch einen Gehalt an Galactose-Magnetit.10. Diagnostic means according to claim 1, 2 and 6, characterized by a content of galactose magnetite. 11. Diagnostische Mittel gemäß Patentanspruch 1, 2 und 6, gekennzeichnet durch einen Gehalt an Dextrin-Magnetit. 11. Diagnostic means according to claim 1, 2 and 6, characterized due to a content of dextrin magnetite. 12. Diagnostische Mittel gemäß Patentanspruch 1, 3 und 7, gekennzeichnet durch einen Gehalt an Dextran-Eisenchromit. 12. Diagnostic means according to claim 1, 3 and 7, characterized due to a content of dextran iron chromite. 13. Diagnostische Mittel gemäß Patentanspruch 1 bis 12, dadurch gekennzeichnet, daß sie pro Liter 1 uMol bis 1 Mol Eisen enthalten. 13. Diagnostic means according to claim 1 to 12, characterized in that that they contain 1 µmol to 1 mol of iron per liter. 14. Verfahren zur Herstellung der diagnostischen Mittel gemäß Patentanspruch 1 bis 13, dadurch gekennzeichnet, daß man den in Wasser oder physiologischer Salzlösung suspendierten Komplex mit den in der Galenik üblichen Zusätzen bzw. Stabilisatoren in eine für die enterale oder parenterale Applikation geeignete Form bringt.14. A method for producing the diagnostic agent according to claim 1 to 13, characterized in that the in water or physiological saline solution suspended Complex with the additives or stabilizers customary in galenicals in one for enteral or parenteral administration brings the appropriate form. 15. Physiologisch verträgliche ferromagnetische Komplexe aus einem Doppelmetall-oxid/-hydroxid der allgemeinen Formel MO.Fe2 037 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.15. Physiologically compatible ferromagnetic complexes from one Double metal oxide / hydroxide of the general formula MO.Fe2 037 in which M is a divalent Represents a metal ion or a mixture of two divalent metal ions, or the general formula FeO-M203, wherein 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. 16. Galactose-Magnetit-Komplex 16. Galactose-magnetite complex 17. Dextrin-Magnetit-Komplex 17. Dextrin-magnetite complex 18. Dextran-Eisenchromit-Komplex 18. Dextran iron chromite complex 19. Verfahren zur Herstellung der Komplexe gemäß Patentanspruch 15, dadurch gekennzeichnet, daß man wäßrige Lösungen des Komplexbildners und der entsprechenden zwei- und dreiwertigen Metallsalze zusammengibt, Alkali hinzufügt und die gewünschten Komplexe in an sich bekannter Weise abtrennt und reinigt.19. A method for producing the complexes according to claim 15, characterized in that that one aqueous solutions of the complexing agent and the corresponding bivalent and trivalent Metal salts put together, alkali adds and the desired complexes in itself separates and cleans in a known manner. 20. Verwendung von diagnostischen Mitteln gemäß Patentanspruch 1 für die NMR-Diagnostik.20. Use of diagnostic agents according to claim 1 for NMR diagnostics.
DE3443251A 1984-11-23 1984-11-23 Iron oxide complexes for NMR diagnosis, diagnostic compounds containing these compounds, their use and process for their preparation Expired - Lifetime DE3443251C2 (en)

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DE3443251A DE3443251C2 (en) 1984-11-23 1984-11-23 Iron oxide complexes for NMR diagnosis, diagnostic compounds containing these compounds, their use and process for their preparation
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
ES549144A ES8703153A1 (en) 1984-11-23 1985-11-21 Magnetic particles for diagnostic purposes.
GR852815A GR852815B (en) 1984-11-23 1985-11-21
EP85730153A EP0186616B2 (en) 1984-11-23 1985-11-21 Magnetic particles for diagnostic purposes
DE8585730153T DE3579899D1 (en) 1984-11-23 1985-11-21 MAGNETIC PARTICLES FOR DIAGNOSTICS.
AT85730153T ATE56880T1 (en) 1984-11-23 1985-11-21 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.
DK198505417A DK174946B1 (en) 1984-11-23 1985-11-22 Use of magnetic particles for diagnostics
CA000496054A CA1252950A (en) 1984-11-23 1985-11-22 Magnetic particles for diagnostic purposes
IE293585A IE58324B1 (en) 1984-11-23 1985-11-22 Magnetic Particles for Diagnostic Purposes
ZA858973A ZA858973B (en) 1984-11-23 1985-11-22 Magnetic particles for diagnostics 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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US4735796A (en) * 1983-12-08 1988-04-05 Gordon Robert T Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
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US4770183A (en) * 1986-07-03 1988-09-13 Advanced Magnetics Incorporated Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents
US5679323A (en) * 1986-07-03 1997-10-21 Advanced Magnetics, Inc. Hepatocyte-specific receptor-mediated endocytosis-type compositions
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US5352432A (en) * 1986-07-03 1994-10-04 Advanced Magnetics, Inc. Hepatocyte specific composition and their use as diagnostic imaging agents
US5314679A (en) * 1986-07-03 1994-05-24 Advanced Magnetics Inc. Vascular magnetic resonance imaging agent comprising nanoparticles
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DE3710730A1 (en) * 1987-03-31 1988-10-20 Schering Ag SUBSTITUTED COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM
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DE3724188A1 (en) * 1987-07-17 1989-02-02 Schering Ag METAL-HOLDING OLIGOSACCHARIDE POLYSULFATE, PROCESS FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEREOF
EP0670167A1 (en) 1988-08-04 1995-09-06 Advanced Magnetics Incorporated Receptor mediated endocytosis type diagnostic agents
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DE4309333A1 (en) * 1993-03-17 1994-09-22 Silica Gel Gmbh Superparamagnetic particles, process for their production and use thereof
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US10519252B2 (en) 2002-10-23 2019-12-31 Vifor (International) Ag. Aqueous iron carbohydrate complexes, their production and medicaments containing them
US11123321B2 (en) 2002-10-23 2021-09-21 Vifor (International) Ag Aqueous iron carbohydrate complexes, their production and medicaments containing them
US11291645B2 (en) 2002-10-23 2022-04-05 Vifor (International) Ag Aqueous iron carbohydrate complexes, their production and medicaments containing them
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