DE3443251A1 - Iron oxide complexes for NMR diagnosis - Google Patents
Iron oxide complexes for NMR diagnosisInfo
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- 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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- 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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- 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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- 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
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- 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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- 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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- 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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Abstract
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)
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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 |
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. |
ES549144A ES8703153A1 (en) | 1984-11-23 | 1985-11-21 | 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. |
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 |
DK198505417A DK174946B1 (en) | 1984-11-23 | 1985-11-22 | Use of magnetic particles for 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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DE3508000A1 (en) * | 1985-03-04 | 1986-09-04 | Schering AG, Berlin und Bergkamen, 1000 Berlin | Ferromagnetic particles for NMR diagnosis |
US4735796A (en) * | 1983-12-08 | 1988-04-05 | Gordon Robert T | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
US4770183A (en) * | 1986-07-03 | 1988-09-13 | Advanced Magnetics Incorporated | Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents |
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 |
DE3724188A1 (en) * | 1987-07-17 | 1989-02-02 | Schering Ag | METAL-HOLDING OLIGOSACCHARIDE POLYSULFATE, PROCESS FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEREOF |
US5043101A (en) * | 1983-02-08 | 1991-08-27 | Gordon Robert T | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
US5055288A (en) * | 1987-06-26 | 1991-10-08 | Advanced Magnetics, Inc. | Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides |
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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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US5043101A (en) * | 1983-02-08 | 1991-08-27 | Gordon Robert T | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
US4735796A (en) * | 1983-12-08 | 1988-04-05 | Gordon Robert T | 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 |
US5342607A (en) * | 1986-07-03 | 1994-08-30 | Advanced Magnetics, Inc. | 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 |
US5679323A (en) * | 1986-07-03 | 1997-10-21 | Advanced Magnetics, Inc. | Hepatocyte-specific receptor-mediated endocytosis-type compositions |
US5219554A (en) | 1986-07-03 | 1993-06-15 | Advanced Magnetics, Inc. | Hydrated biodegradable 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 |
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 |
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 |
US5055288A (en) * | 1987-06-26 | 1991-10-08 | Advanced Magnetics, Inc. | Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides |
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 |
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 |
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AU2003278111B2 (en) * | 2002-10-23 | 2009-05-28 | Vifor (International) Ag | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
AU2003278111B8 (en) * | 2002-10-23 | 2009-06-04 | Vifor (International) Ag | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
WO2004037865A1 (en) * | 2002-10-23 | 2004-05-06 | Vifor (International) Ag | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
EP2287204A1 (en) * | 2002-10-23 | 2011-02-23 | Vifor (International) Ag | Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes |
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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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