DK174946B1 - Anvendelse af magnetiske partikler til diagnostik - Google Patents

Anvendelse af magnetiske partikler til diagnostik Download PDF

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Publication number
DK174946B1
DK174946B1 DK198505417A DK541785A DK174946B1 DK 174946 B1 DK174946 B1 DK 174946B1 DK 198505417 A DK198505417 A DK 198505417A DK 541785 A DK541785 A DK 541785A DK 174946 B1 DK174946 B1 DK 174946B1
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DK
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Prior art keywords
solution
use according
magnetite
dextran
particles
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DK198505417A
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English (en)
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DK541785A (da
DK541785D0 (da
Inventor
Heinz Gries
Hanns-Joachim Weinmann
Wolfgang Muetzel
Christian Zurth
Original Assignee
Schering Ag
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27192543&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=DK174946(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from DE19843443252 external-priority patent/DE3443252A1/de
Priority claimed from DE3443251A external-priority patent/DE3443251C2/de
Priority claimed from DE19853508000 external-priority patent/DE3508000A1/de
Application filed by Schering Ag filed Critical Schering Ag
Publication of DK541785D0 publication Critical patent/DK541785D0/da
Publication of DK541785A publication Critical patent/DK541785A/da
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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
    • A61K49/1887—Agglomerates, clusters, i.e. more than one (super)(para)magnetic microparticle or nanoparticle are aggregated or entrapped in the same maxtrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • 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
    • 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

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Description

DK 174946 B1
Opfindelsen angår anvendelsen i diagnostikken af magnetiske partikler indeholdende et dobbeltmetaloxid/-hydroxid og en kompleksdanner til fremstilling af kontrastmidler for NMR-diagnostik.
5
Som magnetisk bestanddel kan der være tale om metalpartikler, såsom jern-, kobolt- nikkelpartikler, magnetiske jernoxider såsom y-Fe202 og dobbeltoxider/dobbelthydroxider, der indeholder divalent og/eller trivalent jern, som f.eks. ferritter med den almene formel mMO.nFe^^, hvor M er en divalent metal-10 ion eller en blanding af to divalente metalioner, eller f.eks. ferritter med den almene formel nFeO.mi^C^, hvor M er en trivalent metalion og m og n er tallene 0 og 1 til 6. Foretrukne er dobbeltoxider/dobbelthydroxider, som indeholder de i ringe mængder fysiologisk acceptable grundstoffer magnium, zink, jern og kobolt og eventuelt også i meget ringe mængder 15 indeholder mangan, nikkel, kobber, barium og strontium eller, hvor det drejer sig om de trivalente ioner, krom, lanthan, gadolinium, europium, dysprosium, holmium, ytterbium og samarium.
20
Som fysiologisk tålelige kompleksdannere kan f.eks. anvendes mono-, di-, oligo- og polysaccharider, proteiner, mono- eller polycarbonsyrer, også i form af deres estere eller salte, i og syntetiske beskyttelseskolloider såsom polyvinylalkohol, 25 polysilaner, polyethyleniminer eller polyglutaraldehyd. Foretrukket er sukker, dextraner, dextriner, oliesyrer, ravsyre, gelantiner, globuliner og albuminer, som f.eks. humanserum-albumin, hvortil der eventuelt er knyttet biomolekyler, sådanne biomolekyler kan f.eks. være hormoner som insulin, pro-staglandiner, steroider samt aminosukkere, peptider, proteiner 30 eller lipider. Særligt skal fremhæves konjugater med albuminer, såsom humanserumalbumin, stafylokok-protein A, antistoffer som f.eks. monoklonale antistoffer og konjugater 2 DK 174946 B1 eller inklusionsforbindelser med liposomer, der f.eks. kan anvendes som unilamellare eller multilamellare phosphatidyl-colin-cholesterol-vesikler.
Som komple'ksannere kan også anvendes uorganiske beskyttelses-5 kolloider som f.eks·. zeolitter. r
De anvendte kompleksdannere eller stabilisatorer skal hindre en adskillelse af magnetpartikler og væske. Til dette formål må magnetpartiklerne være dækket med et lag af langkædede molekyler, som er orienteret mere eller mindre vinkelret på I® overfladen i rummet. I adsorptionsstabiliserede magnetiske væsker er den polære del af stabilisatormolekylet forbundet med overfladen af den magnetiske partikel via den elektrostatiske vekselvirkning, og i kemisk stabiliserede magnetiske væsker er stabilisatormolekylerne bundet kemisk til partikeloverfladen. Denne kemiske binding kan f.eks. ske som beskre-1^ vet i DDR patentskrift 160.532.
Til anvendelse i NMR-diagnostikken skal den gennemsnitlige partikelstørrelse for metalpartiklerne i almindelighed være mindre en 500 Ångstrøm og for ferritterne mindre end 150 Ångstrøm i diameter.
20
Komplekser af magnetit (Fe^O^) med dextran henholdsvis med humanserumalbumin er f.eks. beskrevet i de amerikanske patenter nr. 4.101.435 og 4.452.773 eller i J. Pharm. Sci. 68, 79 (1979). De danner i vand stabile soler, som på grund af deres magnetiske egenskaber finder mange forskellige anven- f 25 delser. Således er de blandtandet egnede som lægemiddelbærere (frem for alt til cytotoksika ved tumorbehandling) som middel til måling af blodstrømmen, som markører ved scanning/transmis-sionselektronmikroskopi, til karakterisering og fraskil,lelse af celler og biomolekyler (f.eks. et antigen fra en antigenblanding, idet man benytter partikler, der er bunde co-valent til de pågældende antistoffer), og også til anvendelse på det mekaniske område (f.eks. til lyd- og videobånd). Endvi- 3 DK 174946 B1 dere er dextran-magnetit blevet foreslået som relaxationsagens til måling af vandudvekslingen ved erythrocytmembraner (Biochem. og Biophys. Res. Comm. 97, 114 (1980)). Ferromagnetiske zeolitpartikler er f.eks. blevet anvendt til opdeling af kulbrin-Λ 5 teblandinger (europæisk patentansøgning publikations nr.
0130043).
Mange af de hidtil beskrevne magnetiske væsker er uegnede til en diagnostisk anvendelse, da de indeholder komponenter, 10 som ikke tåles fysiologisk.
Det har nu vist sig, at de ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede midler overraskende opfylder de mange forskellige forudsætninger for egnethed som kontrastmiddel til NMR-diagnostikken. (En udførlig diskussion af disse 15 forudsætninger findes i europæisk patentansøgning publikations nr. 71 564 og tysk patentansøgning P 34 01 052.1).
Anvendelsen ifølge opfindelsen er karakteriseret ved det i krav 1 angivne. Anvendelsen ifølge opfindelsen er yderligere karakteriseret ved det i de kendetegnende dele af kra-20 vene 2 til 10 angivne.
Således er de ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede midler fremragende egnede til efter enteral eller parental applikation i kraft af forandring af signalintensiteten at forbedre udsagnskraften af de ved hjælp af kemespinto-25 mografer fremkomne billede. Endvidere udviser de den høje virkning, som er nødvendig for at belaste legemet med de mindst mulige mængder kontrastmidler, og den gode tålelighed som er nødvendig for at opretholde den ikke invaderende karakter af undersøgelsen.
30 Herved må det anses for særligt gunstigt, når jern fungerer som bærer af de magnetiske egenskaber, idet jern er et fysio- DK 174946 B1 4 logisk uskadeligt grundstof, . der endog er væsentligt for den menneskelige organisme. Da den virksomme dosis overraskende er overordentlig lav sammenlignet med alle tidligere kendte kontrastmidler fås en meget høj sikkerhedsafstand til anven-5 delsen af komplekserne in vivo. r
Den gode vandopløselighed af de ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede midler gør det muligt at fremstille høj koncentrerede opløsninger for at holde volumenbelastningen af kredsløbet inden for forsvarlige grænser og udligne 10 fortyndingen med legemsvæsken. Endvidere har de ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede midler ikke kun en høj stabilitet in vitro, men også en overraskende høj stabilitet in vivo.
Et særligt fortrin ved de ifølge opfindelsen ved anvendelse af magnetiske partikler 15 fremstillede midler er, at på grund af specifikke farmakokinetiske egenskaber kan væv, organer og organsystemer forandres stærkt i deres signalintensitet i kernespintomogrammet ved hjælp af den. For første gang haves der til rådighed godt tålelige konstrastmidler blandt andet til afbildning af tumorer i leveren og milten.
Ved binding af det ferromagnetiske materiale til biomoleky-2® ler som f.eks. monoklonale for tumorassocierede antigener, specifikke antistoffer eller anti-myosin opnås en forbedring af tumordiagnostikken og infarktdiagnostikken. Som monoklonale antistoffer til konjugationen kan der især være tale om sådanne, som er rettet mod overvejende cellemembranstillede antigener. Som sådanne egner sig f.eks. til tumoraf-25 bildning monoklonale antistoffer eller deres fragmenter (Flab^), der f.eks. er rettet mod det carcinoembryonale antigen (CEA), humant choriogonadotropin (3-hCG) eller andre tumorstillede antigener såsom glycoproteiner. Egnede er blandt andet også anti-myosin-, anti-insulin- og anti-fibrin-anti- stoffer.
30 5 DK 174946 B1
Konjugater eller inklusionsforbindelser med liposomer egner sig til leverundersøgelser. NMR-diagnostikken i mave-tarm-området forbedres ved enteral applikation af midlerne ifølge opfindelsen, hvorved der f.eks. opnås en bedre afgrænsning 5 af tarmafsnit ved pankreasundersøgelser. Specielt mikrosus-pensioner af kun lidet dissocierende bariumferritter er også udmærket egnede som røntgenkontrastmidler især til enteral applikation til diagnostik af mave-tarm-området.
10 Da den akustiske impedans af de ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede midler er højere end den af legemsvæsker og væv, er de også egnede som kontrastmidler til ultralyddiagnostik.
Fremstillingen af mikrosuspensionerne af dobbeltmetaloxid/-hy-15 droxid-komplekserne sker på i og for sig kendt måde, ved at man sammenfører vandige opløsninger af de pågældende divalente og trivalente metalsalte f.eks. halogeniderne. Derefter tilsætte alkalihydroxider som f.eks. ammoniumhydroxid eller natriumhydroxid og/eller alkalicarbonater som f.eks. natrium-carbonat for at forhøje pH-værdien og frembringe metaloxiderne 20 eller metalhydroxiderne i form af de fineste partikler, hvortil kompleksdanneren binder sig. Ved f.eks. centrifugering samt f.eks. gelfiltrerings-kromatografi og/eller dialyse kan der ske en fraskillelse og rensning af de ønskede komplekser.
Λ 25
Ved en anden fremstillingsmåde bliver det fintformalede dobbeltoxid eller metal behandlet med beskyttelseskolloidet (se f.eks. J. Pharm. Sci. 68, 79 (1979)).
6 DK 174946 B1
Bindingen af biomolekylerne sker på i og for sig kendt måde efter metoder, der f.eks. er beskrevet i Rev. roum. Morphol. Embryol. Physiol., Physiologie 1981, 18, 241 og J. Pharm.
Sci. 68, 79 (1979).
5
Fremstillingen af magnetiske zeolitpartikler kan f.eks. ske efter den forskrift, der findes i europæisk patentansøgning (publikations nr. 130043).
10
Magnetiske silaniserede partikler kan f.eks. fremstilles efter den forskrift, der findes i europæisk patentansøgning (publikations nr. 125995).
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Fremstillingen af de diagnostiske midler ved ifølge opfindelsen at anvende magnetiske partikler sker ligeledes på i og for sig kendt måde, idet man suspenderer partiklerne under eventuel tilsætning af de i galenikken sædvanlige tilsætninger i vandigt medium, og eventuelt derefter steriliserer suspensionen. Egnede tilsætninger er f.eks. fysiologisk 20 uskadelige stødpuder (som f.eks. tromethamin) eller, hvis det er nødvendigt, elektrolytter, som f.eks. natriumchlorid eller, om nødvendigt, antioxidanter som f.eks. ascorbin-syre.
25 Hvis der til enteral indgift eller andre formål ønskes suspensioner af de ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede midler i vand eller fysiologisk saltopløsning, blandes de med et eller flere i galenikken sædvanlige hjælpestoffer (f.eks. methylcellulose, lactose, manit) og/eller tensider (lecitiner, Tween , Myij ) og/eller aromastoffer til smagskorrigens (f.eks. æteriske olier).
7 DK 174946 B1
Midler, der indeholder ikke kompleksbundne magnetiske partikler, er fortrinsvis egnet til enteral applikation.
5 De ifølge opfindelsen ved anvendelse af magnetiske partikler fremstillede diagnostiske midler indeholder 1 μτηοΐ til 1 mol, fortrinsvis 0,1 til 100 mmol magnetisk metal pr. liter og doseres i reglen i mængder på 0,001 til 100 /miol, fortrinsvis 0,1 til 10 μπιοί magnetisk metal pr. kg. legemsvægt. De er bestemt til enteral og parenteral applikation.
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De følgende udførelseseksempler tjener til nærmere at belyse opfindelsen.
15 Eksempel 1
Til en opløsning af 100 g glucose i 824 ml vand sættes 140 ml af en 1 molær jern-III-chloridopløsning og 70 ml af en 1 molær jern-II-chloridopløsning, således at der fremkommer et jernindhold på 11,71 g. Blandingen bliver ved stuetempe-20 ratur bibragt en pH-værdi på 2,4 ved dråbevis tilsætning af en 20 vægt%-dig vandig natriumcarbonatopløsning. Efter endt gasudvikling tilsætter man 45 ml af en 10 normal natronlud og opvarmer blandingen i 30 minutter under tilbagesvaling.
Efter afkøling til stuetemperatur bibringer man en pH-værdi på 6,2 ved tilsætning af 6 normal saltsyre og fælder derefter 25 komplekset ved tilsætning af 2 liter ethanol under omrøring.
8 DK 174946 B1
Man fracentrifugerer, opløser remanensen i vand og fjerner fremmede ioner ved dialyse. Den rensede opløsning inddampes i vakuum, filtreres og lyofiliseres. Man får det ønskede glucose-magnetitkompleks som et brunt pulver.
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Eksempel 2 80 g dextrin (polymaltose basal viskositet 0,05/25°C) bringes i opløsning i 180 ml vand ved 70°C. Efter afkøling til stue-10 temperatur indrøres i en blanding af 70 ml 1 molær jern-m-chloridopløsning og 35 ml af en 1 molær jern-II-chloridopløs-ning. Derefter bibringer man blandingen en pH-værdi på 1,7 ved dråbevis tilsætning af en 20 vægt%- i'g vandig natrium-carbonatopløsning. Efter endt gasudvikling indstiller man 15 en pH-værdi på 11,0 ved dråbevis tilsætning af 10 n natronlud og opvarmer i 30 minutter under tilbagesvaling. Efter afkøling til stuetemperatur bibringer man en pH-værdi på 6,2 ved tilsætning af 6 normal saltsyre, fælder komplekset ved tilsætning af 500 ml ethanol, centrifugerer, opløser remanen-20 sen i vand og fjerner fremmede ioner ved dialyse. Efter filtrering lyofiliseres den kolloide opløsning. Man får det ønskede dextrin-magnetitkompleks som et sort pulver.
Eksempel 3 25
Til en opløsning af 2,5 g humanserumalbumin i 10 ml vand sættes 720 mg jernkromit FeO.C^O^ i form af partikler med en diameter på 10 til 20 nm. Suspensionen indføres i 600 ml /' bomouldsfrøolie og emulsionen homogeniseres ved ultralydbe-30 handling (100 w, 1 minut ved 4°C). Derpå indhældes emulsionen dråbevis under kraftig omrøring i 2 liter 120°C varm bomuldsfrøolie. Efter yderligere 10 minutters opvarming til 120°C afkøler man til stuetemperatur og vasker de fremkomne mikropartikler oliefri ved hjælp af methyl-t-butylether.
35 Efter 24 timers tørring ved 4°C under udelukkelse af lys, får man det ønskede humanserumalbumin-jernkromitkompleks som et dybt sort pulver.
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Eksempel 4 DK 174946 B1 112 mg dextrin-magnetitkompleks (eksempel 2) indføres i 20 ml af en 0,9% kogsaltopløsning- Solen, der er pasteuriseret 5 i 15 minutter ved 110°C, tjener til parenteral applikation.
Eksempel 5
Et granulat fremstillet af 12 mg dextrin-magnetitkompleks 10 (eksempel 2), 2,42 g tromethamin, 45 g mannit og 10 g tylose indrøres i 1000 ml destilleret vand og anvendes til enteral applikation.
Eksempel 6 15 150 mg glucose-magnetitkompleks (eksempel 1) indrøres i 25 ml af en 0,9% kogsaltopløsning. Man fylder i ampuller, der varmesteri1i seres.
20 Eksempel 7
Et granulat fremstillet af 50 mg glucose-magnetitkompleks (eksempel 1), 3,00 g tromethamin, 50 g mannit og 10 g tylose indrøres i 1000 ml destilleret vand og fyldes i flasker til enteral applikation.
Eksempel 8 Λ
Et granulat fremstillet af 20 mg albumin-jernkromitkompleks 30 (eksempel 3), 1,8 g tromethamin, 50 g mannit og 8 g tylose indrøres i 750 ml destilleret vand og anvendes til enteral applikation.
Eksempel 9 35
Til en opløsning af 250 mg humanserumalbumin i 0,75 ml vand sættes 65 mg zinkferrit ZnFe^O^ i form af partikler med en 10 DK 174946 B1 partikelstørrelse på 10 - 20 ran i diameter. Suspensionen indhældes i 20 ml bomuldsfrøolie og den dannede emulsion homogeniseres ved ultralydbehandling (100 w, 1 minut ved 4°C). Derefter indhældes det afkølede homogenat under intensiv om-5 røring i 10 ml ca. 120°C varm bomuldsfrøolie. Man omrører i endnu 10 minutter ved 120°C, afkøler til stuetemperatur og vasker mikropartiklerne oliefri ved hjælp af methyl-ter-tiær-butylether. Efter 24 timers tørring i vakuum under udelukkelse af lys ved 4°C får man det ønskede humanserumalbu-10 min-zinkferritkompleks i form af mikropartikler med en diameter på 500 + 100 nm.
Eksempel 10 15 En suspension af 31 mg humanserumalbumin, 10 mg magnetit
Fe^O^ og 6 mg protein A (Pharmacia, Freiburg) i 0,12 ml vand bliver sammen med 20 ml bomuldsfrøolie homogeniseret i ultralydbad (100 w, 1 minut ved 4°C). Derpå indhældes homogenatet under intensiv omrøring i 15 ml ca. 120°C varm bomuldsfrø-20 olie. Man omrører i endnu 10 minutter ved 120°C, afkøler til stuetemperatur og vasker mikropartiklerne oliefri ved hjælp af methyl-tert-butylether (hver gange 15 minutters centrifugering ved 2000 x g). Efter 24 timers tørring i vakuum under udelukkelse af lys ved 4°C, får man det ønskede human-25 serumalbumin-magnetit-protem A konjugat i form af mikropartikler med en diameter på 200 + 80 nm. 0,5 mg konjugat inkuberes i 1 ml 0,01 m phosphatstødpude ved pH 8 og 37°C i 30 minutter med 500 μg anti-CEA. Derpå vaskes mikropartiklerne tre gange med stødpudeopløsning og frysetørres efter centri-30 fugering. Bindingskapaciteten er 80 + 3pg/mg antistof/mikro-partikel. Konjugatet anvendes i fysiologisk kogsaltopløsning til parenteral applikation. Ved inkubering af human-serumalbumin-magnetit-protein A konjugatet med anti-myosin får man på analog måde det tilsvarende antistofkonjugat til 35 parenteral applikation.
Eksempel 11 11 DK 174946 B1
Til en opløsning af 2 g dextran-magnetit (Meito Sangyo Co.
Ltd.) i 30 ml vand sætter man en opløsning af 3,3 g kalium-5 hydroxid i. 12 ml vand. Man omrører i 10 minutter, afkøler til 5°C og tilsætter en opløsning af 1,5 g 2-bromethylamin i 1,8 ml vand. Man lader efterrøre i 2 timer under afkøling og lader materialet nå stuetemperatur natten over. Derefter tilsætter man ved pH 6,8 2,5 g glutaraldehyd og holder mate-10 rialet i 18 timer ved stuetemperatur. Efter filtrering over aktivt kul inddampes og det polymere produkt isoleres ved fældning med acetone. Man vasker det frasugede produkt med acetone og tørrer det i vakuum. Til 20 μΐ af en opløsning af 0,3 mg anti-CEA i 0,05 molær natriumbicarbonatstødpude 15 (pH 7 - 8) sættes 2 mg af det derivatiserede dextran-magnetit. Efter flere timers inkubationstid dialyseres den fremkomne opløsning over for 0,3 molær natriumphosphatstødpude og renses derefter over en Sephadex G 25 søjle. Ved frysetørring isoleres det ønskede antistofkonjugat, som anvendes 20 til parenteral applikation.
På analog måde får man det tilsvarende dextran-magnetit-an-ti-myosin-konjugat.
25 Eksempel 12
Et granulat fremstillet af 50 mg zeolit Y-magnetitkompleks ' (fremstillet ifølge europæisk patentansøgning 0130043), 3 g tromethamin, 30 g mannit og 15 g tylose indrøres i 1000 30 ml vand pro injectione og fyldes i flasker til enteral applikation.
Eksempel 13 35 150 mg humanserumalbumin-zinkferritkompleks (eksempel 9) suspenderes i 25 ml 0,9% kogsaltopløsning og fyldes i ampuller, som pasteuriseres.
12
Eksempel 14 DK 174946 B1
Et granulat fremstillet af 1000 mg jern-zeolit-Y-kompleks (fremstillet ifølge europæisk ansøgning 0130043), 5 g tro-5 methamin, 300 g mannit og 100 g tylose suspenderes i 20 1 vand pro injectione og fyldes i flasker til oral applikation.
Eksempel 15 10 Efter den i Proc. Natl. Acad. Sci. USA 75, 4194 beskrevne fremgangsmåde fremstilles en lipidblandingen af 75 mol% ægge phosphatidycholin og 25 mol% cholesterol som tørstof. Heraf opløses 500 mg i 30 ml diethylether og i ultralydbad tilsættes dråbevis 3 ml af en 0,9% kogsaltopløsning i forholdet 15 1:2 fortyndet dextran-magnetitsol. Derefter fortsætter man ultralydbehandlingen i 10 minutter mere og inddamper skånsomt på roterende fordamper. Den gelagtige remanens suspenderes i en 0,125 molær kogsaltopløsning og bliver ved 4°C gentagne gange ved centrifugering (20.000 g/20 minutter) be- 20 friet for ikke indkapslede bestanddele. De således behandlede liposomer frysetørres i multiflasker. nen intravasale applikation sker som kolloid dispersion i fysiologisk kogsaltopløsning.
25 Eksempel 16 112 mg dextran-magnetitkompleks (fra firmaet Meito Sangyo,
Japan) indføres under omrøring i 20 ml af en 0,9% kogsaltopløsning. Den fremkomne sol fyldes i ampuller og varmeste-30 riliseres.
Eksempel 17
Et granulat fremstillet af 12 mg dextran-magnetitkompleks 35 (fra firmaet Meito Sangyo, Japan), 2,42 g tromethamin, 45 g mannit og 10 g tylose indrøres i 1000 ml destilleret vand og anvendes til enteral applikation.
13
Eksempel 18 DK 174946 B1
Man blander 40 ml en 1 molær jern-III-chloridopløsning og 20 ml af en 1 molær zinkchloridopløsning og opvarmer til 80°C.
5 Den varme opløsning hældes under intensiv omrøring i en opløsning af 6,8 g natriumhydroxid i 28 ml vand- Man holder 24 timer under tilbagesvaling, centrifugerer suspensionen efter afkøling til stuetemperatur, suspenderer remanensen i 100 ml vand og bibringer suspensionen en pH-værdi på 1,4 med 10 koncentreret saltsyre. Man opløser 18 g dextran T 10 (Pharmacia) i 100 ml vand og opvarmer efter tilsætning af 1,8 ml 40% natronlud til tilbagesvaling i 1 time. Efter afkøling til stuetemperatur sættes til den neutrale opløsning 1000 ml methanol. Efter henstand natten over dekanteres fra vandig 15 methanol og remanensen opløses i 100 ml vand. Til denne opløsning sætter man zinkferritsuspensionen og opvarmer blandingen under intensiv omrøring i 40 minutter til tilbagesvaling. Efter afkøling neutraliseres den kolloide opløsning og gøres, ionfri ved dialyse. Efter lyofilisering får man 20 dextran-ZlnO.FejO^ komplekset som et brunt pulver. På analog måde under anvendelse af en 1 molær bariumchloridopløsning fås et dextran-bariumferritkompleks som brunt pulver.
Eksempel 19 25
Det i eksempel 18 fremstillede dextran-zinkferritkompleks fyldes i multiflasker. Efter tilsætning af fysiologisk kogsaltopløsning opvarmer man i 20 minutter til 120°C. ’ Man får en brugsfærdi steriliseret kolloid injektionsopløsning.
30
Eksempel 20
Man fremstiller en homogen blanding af 1000 g bariumferrit med en gennemsnitlig kornstørrelse på 35 1 μΐη fremstillet ifølge eksempel 18, 20 g sorbit 20 g natriumcitrat 5 g tylose.
14 DK 174946 B1 250 g af blandingen udrøres med 80 ml vand og tjener som rønt-genkontrastmiddel til enteral applikation.
Eksempel 21 5 Γ
Man blander 40 ml af en 1 molær jern-III-chloridopløsning og 20 ml af en 1 molær jern-II-chloridopløsning og opvarmer til 80°C. Den varme opløsning hælder man under intensiv omrøring i en opløsning af 6,8 g natriumhydroxid i 28 ml vand.
10 Man opvarmer i 24 timer til tilbagesvaling og neutraliserer ved tilsætning af koncentreret saltsyre. En blanding af 8 g oliesyre, 10 ml 3 n natronlud og 50 ml vand opvarmes til 60°C, indtil natriumoleatet er gået i opløsning. Derefter sætter man opløsningen til magnetit-mikrosuspensionen og hol-15 der under intensiv omrøring i 30 minutter ved 90°C. Efter afkøling til stuetemperatur indstiller man en pH-værdi på 7,2, fraskiller de grovere partikler ved centrifugering og får efter dialyse en kolloid opløsning, der indeholder 520 mg jern pr. ml, og som med henblik på anvendelse fyldes i 20 ampuller og varmesteriliseres eventuelt fortyndet efter behov med fysiologisk kogsaltopløsning. På analog måde fås under anvendelse af en 1 molær opløsning af zinkchlorid i stedet for jern-II-chloridopløsningen en kolloid opløsning af det tilsvarende zinkferritkompleks, og under anvendelse 25 af en 1 molær opløsning af bariumchlorid en kolloid opløsning ‘af det tilsvarende bariumferritkompleks.
Eksempel 22 30
Til en mikrosuspension af 50 mg aminopropylsilaniserede mag-netitpartikler fremstillet på den måde, der er beskrevet i europæisk patentansøgning publikations nr. 125995, i i vand sætter man en opløsning af 0,5 mg immunoglobulin G, hvis kulhydratandel var blevet partielt oxideret på den i J. Biol.
35
Chem. 243 445-48 beskrevne måde,i 0,3 ml vand. Man indstiller alkalisk ved tilsætning af stødpudeopløsning, inkuberer i 3 timer og tilsætter så natriumborhydrid. Opløsningen ren- 15 DK 174946 B1 ses ved gelfiltreringskromatografi, og proteinkonjugatet isoleres ved lyofilisering som brunt pulver. Gensuspendering i fysiologisk kogsaltopløsning giver efter sterilfiltrering det ønskede diagnostiske middel til parenteral applikation.
5 På analog måde fås med monoklonalt antistof som f.eks anti-myosin den tilsvarende magnetit-protein konjugatopløsning..
Eksempel 23 10 120 mg polyethylenimin-magnetitkompleks fremstillet ifølge US patent nr. 4.267.234 indføres under omrøring i 20 ml af en 0,9% kogsaltopløsning. Den fremkomne sol fyldes i ampuller og varmesteriliseres.
15
Eksempel 24 120 mg aminopropylsilaniserede magnetitpartikler fremstillet på den måde, der er beskrevet i europæisk patentansøgning 20 publikations nr. 125.995, indføres under omrøring i 20 ml af en 0,9% kogsaltopløsning. Den fremkomne sol fyldes i ampuller og varmesteriliseres.
Eksempel 25 25 910 mg dextran T 10 (Pharmacia) opløses i 40 ml vand. Ved tilsætning af 1 normal natronlud bibringer man en pH-værdi på 11 og tildrypper, medens pH-værdien holdes konstant, en opløsning af 295 mg bromcyan i 10 ml vand. Man lader materi- • 30 alet efterøre i 30 minutter og tilsætter sa 0,3 ml af en 6 millimolær hydrazinhydratopløsning. Ved tilsætning af 1 normal saltsyre bibringer man en pH-værdi på 8,5 og lader omrøre natten over ved stuetemperatur. Efter udtømmende dialyse frysetørres opløsningen. Det som hvidt pulver udvundne og 35 med hydrazingrupper aktiverede dextran anvendes i form af en vandig opløsning som stabilisator for magnetitpartikler analogt med eksempel 2, og den efterfølgende binding til pro- teiner sker analogt med eksempel 22.
DK 174946 B1 16
Eksempel 26 5 1080 mg dextran M 8 (Pharmacia) opløses i 5 ml af en 10 vægt% » kogsaltopløsning og efter hinanden tilsættes 283 mg hydra-ziniumchlorid og 1257 mg natriumcyanoborhydrid. Man holder-materialet i 35 timer ved 100°C og hælder så den afkølede opløsning i 25 ml methanol. Udfældningen frasuges og tørres.
10 Det fremkomne gullige krystallinske produkt opløses i vand og anvendes analogt med eksempel 2 som stabilisator for mag-netitpartikler. Bindingen af de stabiliserede partikler sker analogt med eksempel 22.
15 Eksempel 27 20 ml dextran-magnetit sol (Meito Sangyo) fortyndes til 200 ml med 1 vægt% kogsaltopløsning. 60 ml af denne opløsning bliver ved tilsætning af 1 normal natronlud bibragt en pH- 20 værdi på 11, og gradvis tilsættes 292 mg bromcyan, idet pH- vaerdien holdes konstant. Efter tilsætning af 0,2 ml hydra- zinhydratopløsning indstiller man med 1 normal saltsyre en pH-værdi på 8,5 og lader omrøre natten over. Opløsningen dialyseres og det deri indeholdte med hydrazingrupper akti-25 verede dextran-magnetit bindes analogt med eksempel 22 til aldehydgruppeholdige glycoproteiner.
30 35

Claims (10)

1. Anvendelse af magnetiske partikler, der indeholder et dobbeltmetal- < 5 oxid/hydroxid og kompleksdanner, idet kompleksdanneren er alkalibehandlet, oligo- eller polysaccharid, til fremstilling af kontrastmidler for NMR-diagnostik.
2. Anvendelse ifølge krav 1, kendetegnet ved, at dobbeltmetal-oxid/hydroxidet er et ferrit med den almene formel mM0.nFe203, hvor M betegner en divalent metal- 10 ion, og m og n er tallene 0 eller 1 til 6.
3. Anvendelse ifølge krav 1, kendetegnet ved, at dobbeltmetal-oxid/hydroxidet har den almene formel nFe0.mM2C>3, hvor M betegner en trivalent metalion, og m og n er tallene 0 eller 1 til 6. 15
4. Anvendelse ifølge krav 1, kendetegnet ved, at kompleksdanneren er dextran eller dextrin.
5. Anvendelse ifølge krav 1, kendetegnet ved, at partiklerne indeholder magne-20 tit, bariumferrit eller zinkferrit.
6. Anvendelse ifølge krav 1, kendetegnet ved, at partiklerne indeholder dextran-magnetit.
7. Anvendelse ifølge krav 1, kendetegnet ved, at partiklerne indeholder dextrin- magnetit. $
8. Anvendelse ifølge krav 1, kendetegnet ved, at partiklerne indeholder dextran-zinkferrit. 30
9. Anvendelse ifølge krav 1, kendetegnet ved, at partiklerne indeholder dextran-bariumferrit. DK 174946 B1
10. Anvendelse ifølge et hvilket som helst af kravene 1-9, kendetegnet ved, at kontrastmidleme indeholder ffa 1 μίτίοΐ til 1 mol magnetisk metal per liter. 5 \
DK198505417A 1984-11-23 1985-11-22 Anvendelse af magnetiske partikler til diagnostik DK174946B1 (da)

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DE3443252 1984-11-23
DE19843443252 DE3443252A1 (de) 1984-11-23 1984-11-23 Dextran-magnetit-komplexe fuer die nmr-diagnostik
DE3443251A DE3443251C2 (de) 1984-11-23 1984-11-23 Eisenoxid-Komplexe für die NMR-Diagnostik, diese Verbindungen enthaltende diagnostische Mittel, ihre Verwendung und Verfahren zu deren Herstellung
DE3443251 1984-11-23
DE3508000 1985-03-04
DE19853508000 DE3508000A1 (de) 1985-03-04 1985-03-04 Ferromagnetische partikel fuer die nmr-diagnostik

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US20020064502A1 (en) 2002-05-30
US20020136693A1 (en) 2002-09-26
ES8704352A1 (es) 1987-04-16
DK541785A (da) 1986-05-24
AU583070B2 (en) 1989-04-20
GR852815B (da) 1986-03-21
CA1252950A (en) 1989-04-18
EP0186616B2 (de) 1995-01-04
IE852935L (en) 1986-05-23
EP0186616A1 (de) 1986-07-02
PT81498B (pt) 1987-12-30
NO854679L (no) 1986-05-26
ES557099A0 (es) 1987-04-16
ES8703153A1 (es) 1987-02-16
EP0186616B1 (de) 1990-09-26
DK541785D0 (da) 1985-11-22
AU5022585A (en) 1986-05-29
IE58324B1 (en) 1993-09-08
ES549144A0 (es) 1987-02-16
JP2740782B2 (ja) 1998-04-15
NZ214228A (en) 1990-04-26
JPS61171434A (ja) 1986-08-02
PT81498A (de) 1985-12-01
NO167077B (no) 1991-06-24
NO167077C (no) 1994-06-22
DE3579899D1 (de) 1990-10-31

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