DE3443251C2 - Iron oxide complexes for NMR diagnosis, diagnostic compounds containing these compounds, their use and process for their preparation - Google Patents
Iron oxide complexes for NMR diagnosis, diagnostic compounds containing these compounds, their use and process for their preparationInfo
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- DE3443251C2 DE3443251C2 DE3443251A DE3443251A DE3443251C2 DE 3443251 C2 DE3443251 C2 DE 3443251C2 DE 3443251 A DE3443251 A DE 3443251A DE 3443251 A DE3443251 A DE 3443251A DE 3443251 C2 DE3443251 C2 DE 3443251C2
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- agent according
- diagnostic
- diagnostic agent
- complexing agent
- magnetite
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- 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
- A61K49/1833—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
- A61K49/1845—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 the small organic molecule being a carbohydrate (monosaccharides, discacharides)
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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
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- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
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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
- A61K49/1851—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- 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
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- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
- G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- G01N2400/12—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
- G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- G01N2400/12—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
- 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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2446/00—Magnetic particle immunoreagent carriers
- G01N2446/30—Magnetic particle immunoreagent carriers the magnetic material being dispersed in the polymer composition before their conversion into particulate form
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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
Description
Die Erfindung betrifft diagnostische Mittel zur Anwendung in der NMR-Diag nostik, die einen physiologisch verträglichen ferromagnetischen Komplex enthalten, der aus einem Doppelmetall-oxid/-hydroxid und einem Komplexbildner besteht, wobei der Komplexbildner ein wasserlösliches Protein, Mono-, Di-, Oligo- oder Polysaccharid ist.The invention relates to diagnostic agents for use in NMR diagnostics nostik, which is a physiologically compatible ferromagnetic Contain complex consisting of a double metal oxide / hydroxide and a complexing agent, the complexing agent being a is water soluble protein, mono-, di-, oligo- or polysaccharide.
Als ferromagnetischer Bestandteil kommen Doppeloxide/Doppelhydroxide in Betracht, die zwei- und/oder dreiwertiges Eisen enthalten, wie beispielsweise Ferrite der allgemeinen Formel MO·Fe₂O₃, worin M ein zweiwertiges Metallion oder ein Gemisch aus zwei zweiwertigen Metallionen ist, oder beispielsweise Doppeloxide der allgemeinen Formel FeO·M₂O₃, 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.Double oxides / double hydroxides come as a ferromagnetic component into consideration, which contain divalent and / or trivalent iron, such as for example ferrites of the general formula MO · Fe₂O₃, in which 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 · M₂O₃, wherein M is a trivalent metal ion. Prefers are physiologically acceptable in small amounts in the 1st case Elements magnesium, zinc, iron and cobalt, possibly also in very small amounts of manganese, cadmium, nickel, copper, barium and Strontium, in the second case chrome, lanthanum, gadolinium, europium, Dysprosium, holmium, ytterbium and samarium.
Als Komplexbildner können wasserlösliche Mono-, Di-, Oligo- und Polysaccharide und Proteine verwendet werden. Bevorzugt sind Zucker, Dextrane, Dextrine, Gelatine, Globuline und Albumine, wie zum Beispiel Humanserumalbumin.Water-soluble mono-, di-, oligo- and Polysaccharides and proteins are used. Preferred are sugars, Dextrans, dextrins, gelatins, globulins and albumins, such as Example human serum albumin.
Komplexe von Magnetit (Fe₃O₄) 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 Flüssig keit) geeignet. Ferner ist Dextran-Magnetit als Relaxationsagens zur Messung des Wasseraustausches an Erythrozytenmembranen vorgeschlagen worden (Biochem. and Biophys. Res. Comm. 97, 114 (1980)).Complexes of magnetite (Fe₃O₄) with dextran or with Human serum albumin is described, for example, in US Pat U.S. Patents 4,101,435 and 4,452,773 and J. Pharm. Sci. 68, 79 (1979). They form stable brine in water, which due to their magnetic properties are widely used can find. So they are among other things as a drug carrier (especially for cytotoxics in tumor treatment), as Agent for measuring blood flow, as a marker in the scanning / transmission electron microscopy, for labeling and separation of cells and biomolecules (for example an antigen from an antigen mixture by Particles used that are covalently attached to the corresponding Antibodies are bound), as well as for use in the mechanical field (e.g. as a magnetic liquid suitable). Furthermore, dextran magnetite is considered Relaxation agent for measuring water exchange Erythrocyte membranes have been proposed (Biochem. and Biophys. 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 erfüllen. (Eine ausführliche Diskussion dieser Voraus setzungen findet sich in der Europäischen Patentan meldung 71 564 und der Deutschen Patentanmeldung P 34 01 052.1).It has now been found that the agents according to the invention surprisingly, the diverse requirements for suitability as a contrast agent for NMR diagnostics fulfill. (A detailed discussion of this advance Settlement can be found in the European Patent Application message 71 564 and the 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 Kontrastmittel zu belasten, und die gute Verträglichkeit, die notwendig ist, um den nicht-invasiven Charakter der Untersuchung aufrechtzuerhalten. So they are great for after enteral or parenteral administration by changing the Signal intensity with the help of an MRI scanner to improve the meaning of the image obtained. They also show the high effectiveness that is necessary is to the body with the smallest possible amount of Contrast agent, and the good tolerance, which is necessary to maintain the non-invasive nature of the Maintain 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 compared extraordinary for all known contrast media low, and so low that there is no danger with which in vivo necessary dosage to get into the toxic range.
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 Körper flüssigkeit auszugleichen. Weiterhin weisen die erfindungs gemäßen 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 to produce highly concentrated solutions around the volume load of the circuit in reasonable Keep limits and thinning through the body to balance liquid. Furthermore, the invention appropriate means not only 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 Kernspinto mogramm stark verändert werden können. Zum ersten Mal stehen gut ver trägliche 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 that with them due to specific pharmacokinetic properties Tissue; Organs and organ systems in their signal intensity in magnetic resonance imaging mogram can be changed greatly. For the first time, ver inert contrast media u. a. for imaging tumors of the liver and spleen.
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, vorzugs weise Ammonium- oder Natriumhydroxid, versetzt, um den pH-Wert zu erhöhen und die Metalloxid- bzw. Metall hydroxid-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.The complexes are prepared in a manner known per se Way, by having aqueous solutions of the corresponding divalent and trivalent metal salts, for example the Halides. Then with alkali, preferred as ammonium or sodium hydroxide, added to increase the pH and the metal oxide or metal generate hydroxide particles to which the complexing agent binds. By, for example, centrifuging and Example gel filtration chromatography and / or Dialysis can separate and cleanse the desired Complexes take place.
In einer anderen Herstellungsweise wird das fein ge mahlene Doppeloxid in wäßriger Lösung mit dem Schutz kolloid komplexiert ( siehe z. B. J. Pharm. Sci 68, 79 (1979)). In another production method, this is fine milled double oxide in aqueous solution with protection colloidally complexed (see e.g. J. Pharm. Sci 68, 79 (1979)).
Sie erfahren in Wasser eine kolloid-disperse Verteilung. Die Konzentration wird dabei so gewählt, daß eine stabile kolloidale Lösung entsteht.They experience a colloidally disperse distribution in water. The concentration is chosen so that a stable colloidal solution is created.
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 sterili siert. Geeignete Zusätze sind beispielsweise physio logisch unbedenkliche Puffer (wie zum Beispiel Tromethamin) oder, falls erforderlich, Elektrolyte (wie zum Beispiel Natriumchlorid).The preparation of the diagnostic according to the invention Means are also carried out in a manner known per se, by adding the complexes if necessary the additives common in galenics in an aqueous medium suspended and then the suspension sterile siert. Suitable additives are, for example, physio logically harmless 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 (z. B. Lecithine, Tweens®, Myrj® und/oder Aroma stoffen zur Geschmackskorrektur (z. B. ätherischen Ölen) gemischt.Are for enteral administration or other purposes Suspensions of the complexes in water or physiological If a saline solution is desired, a complex with one or several of the auxiliaries common in galenics (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. Lecithine, Tweens®, Myrj® and / or Aroma substances for flavor correction (e.g. essential oils) mixed.
Die erfindungsgemäßen diagnostischen Mittel enthalten 1 µMol bis 1 Mol, vorzugsweise 0,1 bis 100 µMol Eisen pro Liter und werden in der Regel in Mengen von 0,001 bis 100 µMol, vorzugsweise 0,1 bis 10 µMol 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 mol, preferably 0.1 to 100 µmol iron per liter and are usually in amounts of 0.001 up to 100 µmol, preferably 0.1 to 10 µmol iron per kg body weight dosed. They are for enteral and parenteral application.
Die folgenden Ausführungsbeispiele dienen zur weiteren Erläuterung der Erfindung. The following examples serve for further Explanation of the invention.
Eine Lösung von 100 g Galactose in 824 ml Wasser wird mit 140 ml einer 1-molaren Eisen-III-chlorid lösung und mit 70 ml einer 1-molaren Eisen-II-chlorid lösung 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.A solution of 100 g galactose in 824 ml water with 140 ml of a 1 molar iron (III) chloride solution and with 70 ml of a 1 molar iron (II) chloride solution added so that an iron content of 11.71 g results. The mixture is passed through at room temperature dropwise addition of a 20 wt .-% aqueous Sodium carbonate solution brought to pH 2.4. After Stop the evolution of gas, put 45 ml of one Add 10 normal sodium hydroxide solution and heat the mixture 30 minutes to reflux. After cooling to room temperature apply by adding 6 normal hydrochloric acid pH 6.2 and then drops the complex by adding of 2 liters of ethanol with stirring. You centrifuge, dissolves the residue in water and removes foreign ions through dialysis. The cleaned solution is in a vacuum concentrated, filtered and lyophilized. You get the desired galactose-magnetite complex as a brown Powder.
80 g Dextrin (Polymaltose, basale Viskosität 0,05/25°C) werden in 180 ml Wasser bei 70°C in Lösung gebracht. 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 Rück fluß. 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, zentri fugiert, 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.80 g dextrin (polymaltose, basal viscosity 0.05 / 25 ° C) are dissolved in 180 ml of water at 70 ° C. After cooling to room temperature it is mixed from 70 ml of 1 molar iron (III) chloride solution and 35 ml a 1 molar iron (II) chloride solution. Then bring the mixture by adding a drop by drop 20% by weight aqueous sodium carbonate solution pH 1.7. After the gas evolution has ended, one poses by the dropwise addition of 10 n sodium hydroxide solution pH of 11.0 and heated for 30 minutes to return flow. After cooling to room temperature, bring it through Adding 6 normal hydrochloric acid to pH 6.2 drops the complex by adding 500 ml of ethanol, centri fugiert, dissolves the residue in water and removed Foreign ions through dialysis. The colloidal solution is lyphilized after filtration. You get the one you want Dextrin-magnetite complex as a black powder.
Eine Lösung von 2,5 g Humanserumalbumin in 10 ml Wasser wird mit 720 mg Eisenchromit, FeO·Cr₂O₃, 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 (100 w, 1 min bei 4°C) homogenisiert. Dann wird die Emulsion tropfenweise unter intensivem Rühren in 2 Liter 120°-heißes Baumwollsaatöl eingegossen. Nach weiterem 10 minütigem Erhitzen auf 120° kühlt man auf Raumtemperatur ab und wäscht die erhaltenen Micro partikel mit Hilfe von Methyl-t-Butylether ölfrei. Nach 24-stündigem Trocknen bei 4° unter Lichtausschluß erhält man den gewünschten Humanserumalbumin-Eisenchromit-Kom plex als tiefschwarzes Pulver.A solution of 2.5 g human serum albumin in 10 ml Water is mixed with 720 mg iron chromite, FeO · Cr₂O₃, in the form of particles with a diameter of 10-20 nm offset. The suspension is in 600 ml Cottonseed oil entered and the emulsion through Ultrasound (100 w, 1 min at 4 ° C) homogenized. Then the emulsion is added dropwise under intense Pour stirring into 2 liters of 120 ° hot cottonseed oil. After heating for a further 10 minutes at 120 °, the mixture is cooled to room temperature and washes the micro particles free of oil with the help of methyl t-butyl ether. After drying for 24 hours at 4 ° with exclusion of light the desired human serum albumin-iron chromite com plex as a deep black powder.
112 mg Dextrin-Magnetit-Komplex (Beispiel 2) werden in 20 ml einer 0,9%igen Kochsalzlösung eingetragen. Das 15 Minuten bei 110°C pasteurisierte Sol dient zur parenteralen Applikation. 112 mg of dextrin-magnetite complex (Example 2) entered in 20 ml of a 0.9% saline solution. The sol pasteurized for 15 minutes at 110 ° C is used for parenteral application.
Ein Granulat, hergestellt aus 12 mg Dextrin-Magnetit-Kom plex (Beispiel 2), 2,42 g Tromethamin, 45 g Mannit und 10 g Tylose, wird in 1000 ml Aqua dest. einge rührt für die enterale Applikation verwendet.A granulate made from 12 mg of dextrin-magnetite com plex (Example 2), 2.42 g tromethamine, 45 g mannitol and 10 g tylose, is distilled in 1000 ml distilled water. turned on stirrer used for enteral application.
150 mg Galactose-Magnetit-Komplex (Beispiel 1) werden in 25 ml einer 0,9%igen Kochsalzlösung einge rührt. Man füllt in Ampullen ab, die hitzesterilisiert werden.150 mg galactose-magnetite complex (example 1) are placed in 25 ml of 0.9% saline stirs. It is filled into ampoules which are heat sterilized will.
Ein Granulat, hergestellt aus 50 mg Galactose-Magnetit-Kom plex (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.A granulate made from 50 mg galactose magnetite com plex (Example 1), 3.00 g tromethamine, 50 g mannitol and 10 g of tylose is distilled in 1000 ml of aqua. stirred in and filled into bottles for enteral application.
Ein Granulat, hergestellt aus 20 mg Albumin-Eisenchromit-Kom plex (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.A granulate made from 20 mg of albumin-iron chromite com plex (Example 3), 1.8 g tromethamine, 50 g mannitol and 8 g of tylose, is distilled in 750 ml of distilled water. stirred in and used for enteral application.
Claims (14)
Priority Applications (19)
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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 |
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. |
ES549144A ES8703153A1 (en) | 1984-11-23 | 1985-11-21 | Magnetic particles for diagnostic purposes. |
AT85730153T ATE56880T1 (en) | 1984-11-23 | 1985-11-21 | MAGNETIC PARTICLES FOR DIAGNOSTICS. |
GR852815A GR852815B (en) | 1984-11-23 | 1985-11-21 | |
DK198505417A DK174946B1 (en) | 1984-11-23 | 1985-11-22 | Use of magnetic particles for diagnostics |
ZA858973A ZA858973B (en) | 1984-11-23 | 1985-11-22 | Magnetic particles for diagnostics purposes |
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 |
NO854679A NO167077C (en) | 1984-11-23 | 1985-11-22 | Diagnostic agents for use in in vivo NMR diagnostics, X-ray diagnostics or ultrasound diagnostics. |
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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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 |
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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 |
EP0330801A1 (en) * | 1983-02-08 | 1989-09-06 | Schering Aktiengesellschaft | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
DE3508000A1 (en) * | 1985-03-04 | 1986-09-04 | Schering AG, Berlin und Bergkamen, 1000 Berlin | Ferromagnetic particles for NMR diagnosis |
US5679323A (en) * | 1986-07-03 | 1997-10-21 | Advanced Magnetics, Inc. | Hepatocyte-specific receptor-mediated endocytosis-type compositions |
US5055288A (en) * | 1987-06-26 | 1991-10-08 | Advanced Magnetics, Inc. | Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides |
US5284646A (en) * | 1986-07-03 | 1994-02-08 | Advanced Magnetics Inc. | Hepatocyte specific receptor mediated endocytosis type magnetic resonance imaging contrast agents |
US4770183A (en) * | 1986-07-03 | 1988-09-13 | Advanced Magnetics Incorporated | Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents |
US5342607A (en) * | 1986-07-03 | 1994-08-30 | Advanced Magnetics, Inc. | Receptor mediated endocytosis type magnetic resonance imaging contrast agents |
US5314679A (en) * | 1986-07-03 | 1994-05-24 | Advanced Magnetics Inc. | Vascular magnetic resonance imaging agent comprising nanoparticles |
US5352432A (en) * | 1986-07-03 | 1994-10-04 | Advanced Magnetics, Inc. | Hepatocyte specific composition and their use as diagnostic imaging agents |
US5219554A (en) | 1986-07-03 | 1993-06-15 | Advanced Magnetics, Inc. | Hydrated biodegradable superparamagnetic metal oxides |
DE3709851A1 (en) * | 1987-03-24 | 1988-10-06 | Silica Gel Gmbh Adsorptions Te | NMR DIAGNOSTIC LIQUID COMPOSITIONS |
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 |
DE3724188C2 (en) * | 1987-07-17 | 1995-05-18 | Heinz Dr Gries | Metal-containing oligosaccharide polysulfates, process for their preparation and pharmaceutical compositions containing them |
WO1990001295A1 (en) | 1988-08-04 | 1990-02-22 | Advanced Magnetics, Incorporated | Receptor mediated endocytosis type mri contrast agents |
US5314681A (en) * | 1988-12-23 | 1994-05-24 | Nycomed Innovation Ab | Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging |
DE4309333A1 (en) * | 1993-03-17 | 1994-09-22 | Silica Gel Gmbh | Superparamagnetic particles, process for their production and use thereof |
DE19509694A1 (en) * | 1995-03-08 | 1996-09-19 | Schering Ag | Use of magnetites to determine the perfusion of human tissue using MR diagnostics |
DE10249552A1 (en) * | 2002-10-23 | 2004-05-13 | Vifor (International) Ag | Water-soluble iron-carbohydrate complexes, their preparation and medicaments containing them |
EP1615551B1 (en) * | 2003-04-15 | 2016-06-08 | Philips Intellectual Property & Standards GmbH | Device and method for examination and use of an electrical field in an object under examination containing magnetic particles |
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EP0071564A1 (en) * | 1981-07-24 | 1983-02-09 | Schering Aktiengesellschaft | Paramagnetic complex salts, their preparation and their use in NMR diagnostics |
US4452773A (en) * | 1982-04-05 | 1984-06-05 | Canadian Patents And Development Limited | Magnetic iron-dextran microspheres |
DE3401052A1 (en) * | 1983-01-21 | 1984-07-26 | Schering AG, 1000 Berlin und 4709 Bergkamen | Diagnostic agent |
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US4452773A (en) * | 1982-04-05 | 1984-06-05 | Canadian Patents And Development Limited | Magnetic iron-dextran microspheres |
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