WO1989011874A1 - Imagerie par resonance magnetique - Google Patents

Imagerie par resonance magnetique Download PDF

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Publication number
WO1989011874A1
WO1989011874A1 PCT/GB1989/000617 GB8900617W WO8911874A1 WO 1989011874 A1 WO1989011874 A1 WO 1989011874A1 GB 8900617 W GB8900617 W GB 8900617W WO 8911874 A1 WO8911874 A1 WO 8911874A1
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WIPO (PCT)
Prior art keywords
preparation according
iii
particulate substance
acid
preparation
Prior art date
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PCT/GB1989/000617
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English (en)
Inventor
Laurence David Hall
Julian Hugh Braybrook
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Laurence David Hall
Julian Hugh Braybrook
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Laurence David Hall, Julian Hugh Braybrook filed Critical Laurence David Hall
Publication of WO1989011874A1 publication Critical patent/WO1989011874A1/fr

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Classifications

    • 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
    • A61K49/189—Host-guest complexes, e.g. cyclodextrins
    • A61K49/1893—Molecular sieves
    • 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
    • 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
    • A61K49/1878—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 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating

Definitions

  • This invention relates to magnetic resonance imaging (MRI), and concerns magnetic resonance contrast agents suitable for clinical administration.
  • MRI is a well known technique, based on the variation of the magnetic properties of protons and other species in different local environmental conditions, which is used for various analytical purposes including clinical diagnosis. It is known to use contrast agents, such as certain metal ions, which act to enhance spin-lattice relaxation rates (R. values), and spin-spin relaxation rates (R 2 values), increasing sensitivity and enabling improved differentiation of structures. Paramagnetic materials such as ions of copper, manganese, iron and gadolinium are good contrast agents, but their potential toxicity presents difficulties for use in clinical applications.
  • the present invention aims to provide novel magnetic resonance contrast agents, suitable for clinical administra ion.
  • a preparation suitable for clinical administration for use as a contrast agent in magnetic resonance imaging comprising a porous particulate substance with paramagnetic material bound with respect to the surface thereof, the preparation being such that no significant release of the paramagnetic material occurs in undesired locations in clinical use.
  • the preparation is such that no significant release of the paramagnetic material occurs in undesired locations in clinical use, the preparation can be safely used for clinical diagnostic purposes with humans and animals ' .
  • the present invention provides a method of diagnosis using MRI, wherein a preparation in accordance with the invention is administered to a human or animal body.
  • the preparation may be administered orally or as an enema for imaging of regions of the gastro-intestinal (GI) tract.
  • the preparation may be introduced to the circulatory system, eg by injection, for imaging of regions such as the reticulo-endithelical system (RES), lung, liver, spleen, pancreas, kidney, bone-marrow, lymphatic system or vascular system.
  • RES reticulo-endithelical system
  • the porous particulate substance may be selected from a wide range of polymers and other materials. Many suitable materials are commercially available, or can be made by known techniques.
  • Suitable non-polymeric porous particulate substances include eg microporous glasses, zeolites such as zeolite A and zeolite Z, pillared clays, crown ethers such as 18 crown 6 ether, and porphyrins, and derivatives thereof.
  • Suitable polymeric porous particulate substances include eg, serum albumin (eg human or bovine), polystyrene, polyacrylamides, polycyanoacrylates, polymethacrylates, starch, cellulose, dextran, alginates and other polysaccharides, polyacrolein, polypeptides, polyorthoesters and typical hydrogels, Sepharose (agarose) (Sepharose is a Trade Mark) and derivatives thereof.
  • serum albumin eg human or bovine
  • polystyrene polyacrylamides
  • polycyanoacrylates polymethacrylates
  • starch cellulose, dextran, alginates and other polysaccharides
  • polyacrolein polypeptides
  • polyorthoesters polyorthoesters and typical hydrogels
  • Sepharose agarose
  • Sepharose Sepharose is a Trade Mark
  • hydrophilic materials such as polymers with hydrophilic backbones, as it is found that the enhancement of the spin-lattice relaxation rate increases with hydrophilicity. This accords with the intuitive expectation that the effect depends on the exchange rates of water through the sphere of influence of the bound paramagnetic material.
  • biodegradable materials such as the hydrogels, polylactic acid (polylactide ) , polyglycolic acid (polyglycolide) , polydactic acid-co- glycolic acid), poly(lac ide-co-glycolide ) or poly ortho- esters, poly acetals, synthetic polypeptides, cross-linked proteins, polycyanoacrylates, etc.
  • the porous particulate substance is conveniently of spherical configuration, but the form is not critical.
  • the size of the porous particulate substance may be selected to suit the intended use and typically may range from less than micron size (eg prepared using known emulsion polymerisation techniques) to millimetre size and over (eg prepared using known drop teqhniques).
  • a common particle diameter size range is 5 to 500 urn.
  • particles are conveniently in the range of about 50 um to a few millimetres in diameter.
  • particles for use in the circulatory system particles are conveniently in the range 0.1 to 100 um, generally 1 to 5 um, with particles for imaging the RES typically being about 0.1 um, and those for the lung 7 to 12 um.
  • the size of the particles may affect the ultimate location of the material in use.
  • the surface area of the porous particulate substance can also be selected as appropriate depending on the intended use. For diagnostic purposes, the availability for interaction of the preparation with its surrounding media is important, with a large surface area giving a better availability for interaction and a stronger effect. However, for certain applications a large surface area is not a pre-requisite.
  • the porosity of the particulate substance and the nature of channels therein can also be appropriately selected, depending on the indended use. For example, the extent of porosity and tortuosity as well as the rate of diffusion through channels is important-
  • the pores are preferably relatively large, being sufficiently large for access of molecules without being so large that leakage of attached material occurs, and are typically in the range of 30A to a few hundred A in diameter.
  • Porous particulate substance of desired chemical composition and with desired physical properties can either be obtained commercially or made using known techniques.
  • the desired material may be made directly, or may be produced by surface modification of an existing material.
  • the paramagnetic material can be selected from a range of known materials having paramagnetic properties. These include ions of elements having an atomic number from 21 to 29, 42, 44, and from 58 to 70 such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), copper (II), nickel (II), praseodymium (III), neodymium (III), samarium (III) and ytterbium (III). Of particular interest are ions having a strong magnetic moment, such as gadolinium (III), terbium (III), dysprosium (JII), holmium (III) and erbium (III).
  • elements having an atomic number from 21 to 29, 42, 44, and from 58 to 70 such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), copper (II), nickel (II), praseodymium (III), n
  • a further class of paramagnetic materials is nitroxide stable free radicals, which can be divided into two groups: pyrrolidone-N-oxyl and piperidine-N-oxyl. These radicals have good chemical versatility and may be made tissue-specific, enabling targeting of materials.
  • the paramagnetic material may be bound directly to the particulate substance in appropriate cases, where the pore size of the particulate substance is such that the paramagnetic material can be held directly.
  • porphyrins have a suitable pore size for holdinq certain metal ions .
  • the paramagnetic material is bound (covalently or otherwise) to a ligand or linking group, attached to the porous particulate substance.
  • Suitable ligands include acids containing methylenephosphonic acid groups (-CH 2 SO,Y) , methylenecarbohydroxamic acid groups (- CH-CONHOY) , carboxyethylidene groups (-CH 2 CH 2 COOY) , or carboxymethylene groups (-CH_COOY) of which at least 1,2 or 3 are bound to a nitrogen atom supporting the complex formation, eg EDTA, DTPA, etc.
  • Such chelating acids form complex salts with paramagnetic metal ions.
  • chelating ligands/sites may be -S0 3 Y, -COOY, -PO-FY, -CONHOY, where Y is a H atom, a metal equivalent and/or cation of an inorganic or organic base or amino acid as long as two of the substituents Y- are paramagnetic metal equivalents as aforementioned, or a nitroxide stable free radical.
  • Complex-forming acids required for the preparations may ' be manufactured in a manner known per se. Also known are techniques for conjugation to biomolecules, ie, nucleophilic groups of biomolecules, eg, amino, hydroxy, etc, with an activated derivative of complex-forming acid, eg, acid chlorides, acid anhydrides, activated esters, etc. Also known per se is the manufacture of some of the complex salts (excess acid groups should be converted to neutral complex salts using cation-forming inorgainc and/or organic bases or amino acids).
  • the ligand may be attached directly to the porous particulate substance in known manner, or may be linked thereto via a spacer arm.
  • Suitable spacers include, eg, hydrophilic groups such as the bis oxirane, 1 ,4-bis-(2, 3- epoxypropoxy)-butane (an ether linkage), 6-amino-hexanoic acid and hexa-methylenedia ine, and hydrophobic groups such as a pentyl grouping (consisting of 5 methylene groups) .
  • the porous particulate substance with bound paramagnetic material may be provided with an outer coating of controlled and variable prorsity, primarily to prevent unwanted release of the paramagnetic material in use, but possibly also for controlling timing of release of the paramagnetic material and/or for targeting the preparation to particular sites such as certain tissues.
  • a coating is generally essential: with biodegradable substances coatings are optional.
  • Suitable coating materials include, eg, known enteric coatings, which may be applied in known manner, eg by a spray coating technique. The nature of the coating will depend on the intended use. For instance preparations for use in the GI tract must generally be coated to enable them to withstand the highly acid (about pH 1.3) environment of the stomach.
  • Suitable coatings for this purpose include cellulose acetate coatings eg phthallate, butyrate (resistant to acid pH; dissolves thereafter), ethyl cellulose (only swells), coatings derived from copolymers of methacrylic acid, amino-ethyl methacrylates and- neutral esters of acrylic and methacrylic acid, the Eudragit resins (these materials are both resistant to acid and swell).
  • coatings typically have a thickness in the range 5 to 15 um.
  • Preparations for use in the circulatory system require biodegradable particulate material, so coating is optional: a typical coating suitable for this use is polylysine.
  • coatings may be desirable in some cases not only for tissue recognition (possibly by addition of suitable groups to the coating), but possibly also for protection from the reticuloendothelial system.
  • coated material will function effectively as a contrast agent, as it might be expected that the coating would inhibit the interaction of the paramagnetic material with protons or other species. Although it is found that the presence of a coating reduces relaxivity as compared with uncoated material, the preparations can nevertheless still function as effective contrast agents.
  • the present invention provides a preparation suitable for clinical administration for use as a contrast agent in magnetic resonance imaging, comprising a porous particulate substance with paramagnetic material bound with respect to the surface thereof, and an outer coating which acts to prevent significant release of the paramagnetic material in undesired locations in clinical use.
  • the invention also provides a preparation suitable for clinical administration for use as a contrast agent in magnetic resonance imaging, comprising a biodegradable porous particulate substance with paramagnetic material bound with respect to the surface thereof, the preparation being such that no significant release of the paramagnetic material occurs in undesired locations in clinical use.
  • the characteristics and behaviour of the preparation can be precisely controlled and tailored to the intended clinical use, so that the invention provides useful preparations for clinical diagnostic purposes.
  • the preparation can be formulated to control distribution and rate of transport of the particulate matter as well as control, if appropriate, the release of material at a specific locus.
  • the preparation can be formulated to prevent any osmotic shock upon administration of such matter and to aid the hydrophilic/hydrophobic environment.
  • Preparations in accordance with the invention can be used in generally conventional manner for diagnostic purposes, particularly in the GI tract and circulatory system, with improved results as compared with existing materials used for these purposes. Typical uses of these materials include study of a wide variety of pathology in tioth the GI tract and the circulatory system and associated organs, such as identification/localisation of ulcers, tumours, obstructions, organ disease and abnormality.
  • the properties of preparations in accordance with the invention additionally mean they can be used in various novel ways, eg for studying processes occuring in the circulatory system such as phagocytosis, adhesion and filtration, and for measurement of transit times through, and spatial distribution of pH within, specific regions of the GI tract to provide information useful for estimating nutritional uptake and pharmaceutical delivery.
  • Figure 1 is a graph showing the variation of the proton relaxation. rates of water induced by: (A) lO M solutions of the free metal ions, (B) lOmM solutions of the free metal ions in 2% carboxy ethylcellulose, (C) 24% w/v suspensions, in 2% carboxymethlcellul ⁇ se, of resin that had been fully saturated with metal ions;
  • Figure 2 is a graph showing the variation of the proton spin-lattice relaxation rates of water induced by a variation of the concentration of a fully saturated, manganese-bound resin, suspended in 2% carboxymethylcellulose;
  • Figure 3 is a graph showing the variation of the proton relaxation rates of water induced by 24 % w/v suspensions, in 2% carboxymethylcellulose, of: (A) Resonium A resinr (B) AGMP-50 resin, (C) Chelex 100 resin, each of which had been fully saturated with metal ions;
  • Figure 4 is a graph showing variation of the proton relaxation rates of water induced by: (A) lOmM solutions of the free metal ions, (B) 24% w/v suspentions, in 2% carboxy ethylellulose, of Chelating Sepharose 6B resin that had been fully saturated with metal ions; and
  • Figure 5 is a graph showing the variation of the proton spin-lattice relaxation rates of water induced by metal- bound sulphonated polystyrene resins pre-and post-acid treatment.
  • Samples of sulphonated polystyrene resin ( inthrop Laboratories; mesh size 85-170um; pore size 30 A; C 36.6%: H 4.92%; S 10.86%) were immersed in solutions of the appropriate metal salts for 2.5 days, washed with distilled water, and then vacuum dried. The amount of sequestered metal ions was determined by atomic absorption and ultra-violet spectroscopy.
  • Nuclear magnetic resononce (NMR) relaxation measurements were made at 26°C with a Varian VXR-300 spectrometer using the inversion recovery sequence (see references 1 and 2) with phase-cycling and a composite 180° pulse (see references 3 to 5), and the R.. values were calculated from an exponential fit of the data using the Varian software. Standard 5mm NMR tubes were fitted with polytetraflouroethylene plugs to keep the sample within the region of the reciever coil (see reference 2).
  • the commercial samples used were: (A) Resonium A, a sulphonated polystyrene resin (Winthrop Laboratories; mesh size 85-170um pore size 30 A), (B) AGMP-50, a macroporous sulphonated polystyrene resin (Bio-Rad Laboratories Ltd.; mesh size 200-400um; effective pore size, large), (C) Chelex 100 resin based on a polystyrene lattice with imino-diacetic acid ligands (Bio-Rad Laboratories Ltd.; mesh size 200-400um; effective pore size, large), and (D) Chelating Sepharose (Sepharose is a Trade Mark) resin composed of imino-diacetic acid functional groups coupled by hydrophilic spacer arms to epoxy-activated Sepharose 6!
  • the metal-bound Chelating Sepharose resin in the same form of suspension shows a very much larger increase in the relaxation rate of water from its normal value (R. ⁇ l!60), even though the amount of F ( 111) complexed (2.53% Fe ) was less than half that of the least effective of the polystyrene resins. Further, the relaxivity is much larger than even that of free Fe(III) ions in solution ( Figure 4). Very similar results were obtained at 84.851 MHz. Furthermore, similar findings were obtained for other metal ions such as Gd(III), although some of the formulations no longer had the consistency of the thick gel.
  • each of the coated, metallated resins had significantly decreased relaxivity as compared with the uncoated material, the reduction depending on the type of coating. Furthermore, each coating prevented the acidic solution from leaching out any significant proportion of the metal ions.
  • the cellulose acetate and Eudragit resin coatings are soluble in the pH of the human intestine (pH 6-8) and treatment at that pH for 1 hour almost totally restored the relaxivity of the beads to their original value.

Abstract

Une préparation adaptée pour une administration clinique utilisée comme agent de contraste en imagerie par résonance magnétique comprend une substance particulaire poreuse comportant une matière paramagnétique liée à sa surface, ladite préparation étant telle qu'aucune libération significative de matière paramagnétique ne se produit aux endroits où cela n'est pas souhaitable en utilisation clinique. On peut utiliser sans danger de telles matières à des fins de diagnostic clinique sur l'homme et l'animal.
PCT/GB1989/000617 1988-06-07 1989-06-02 Imagerie par resonance magnetique WO1989011874A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8813425.9 1988-06-07
GB888813425A GB8813425D0 (en) 1988-06-07 1988-06-07 Magnetic resonance imaging

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WO1989011874A1 true WO1989011874A1 (fr) 1989-12-14

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992010213A1 (fr) * 1990-12-07 1992-06-25 Board Of Regents, The University Of Texas System Ion paramagnetique de diagnostic inclus dans un tamis moleculaire
WO1992019272A1 (fr) * 1991-04-30 1992-11-12 The Du Pont Merck Pharmaceutical Company Agents de contraste inorganiques poreux pour exploration ultrasonique
EP0526503A1 (fr) * 1990-04-10 1993-02-10 Evan C Unger Polymeres utilises comme milieux de contraste en imagerie par resonance magnetique.
WO1993008846A1 (fr) * 1991-10-30 1993-05-13 Cockbain, Julian, Roderick, Michaelson Milieux de contraste
WO1993025895A1 (fr) * 1992-06-15 1993-12-23 Board Of Regents, The University Of Texas System Ions de metaux de transition et de terre rare enfermes dans une argile et utilises comme agents de contraste pour les voies gastro-intestinales
US5368840A (en) * 1990-04-10 1994-11-29 Imarx Pharmaceutical Corp. Natural polymers as contrast media for magnetic resonance imaging
US5514379A (en) * 1992-08-07 1996-05-07 The General Hospital Corporation Hydrogel compositions and methods of use
US5863519A (en) * 1994-08-18 1999-01-26 Nycomed Imaging As Composition and method of MRI using both a positive and a negative contrast agent
WO1999012577A1 (fr) * 1997-09-05 1999-03-18 Nycomed Imaging As Particules polymeres en alcool polyvinylique comprenant un agent de contraste destine a la chimio-embolisation
WO2000069474A1 (fr) * 1999-05-13 2000-11-23 Micro Therapeutics, Inc. Procedes pour traiter des malformations arterio-veineuses au moyen de compositions radioactives
EP1106186A2 (fr) * 1999-12-08 2001-06-13 Mallinckrodt Inc. Bioconjugués non-covalents pour application dans la IRM
US7056466B2 (en) 2002-03-28 2006-06-06 Scimed Life Systems, Inc. Method of manufacture medical devices employing microwave energy
US7163655B2 (en) 2002-03-28 2007-01-16 Scimed Life Systems, Inc. Method and apparatus for extruding polymers employing microwave energy
US7531122B2 (en) 2002-03-28 2009-05-12 Boston Scientific Scimed, Inc. Polymer welding using ferromagnetic particles
US8673266B2 (en) 1998-10-16 2014-03-18 Biosphere Medical, S.A. Polyvinyl alcohol microspheres, injectable solutions and therapeutic uses of the same
US8753641B2 (en) 1999-02-24 2014-06-17 University Of Zurich Combination of intercalating organometallic complexes and tumor seeking biomolecules for DNA cleavage and radiotherapy
US8862203B2 (en) 2003-03-27 2014-10-14 Boston Scientific Scimed Inc. Medical device with temperature modulator for use in magnetic resonance imaging
US20160000942A1 (en) * 2013-01-04 2016-01-07 Industry-Academic Cooperation Foundation, Yonsei University Mri contrast agent including t1 contrast material coated on surface of nanoparticle support

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US5658550A (en) * 1990-04-10 1997-08-19 Imarx Pharmaceutical Corp. Non cross-linked synthetic polymers as contrast media for magnetic resonance imaging
US5624661A (en) * 1990-04-10 1997-04-29 Unger; Evan C. Hypoosmotic compositions comprising a polymer and a complexed contrast agent for MRI
EP0526503A1 (fr) * 1990-04-10 1993-02-10 Evan C Unger Polymeres utilises comme milieux de contraste en imagerie par resonance magnetique.
EP0526503A4 (en) * 1990-04-10 1993-02-24 Evan C Unger Polymers as contrast media for magnetic resonance imaging
US5985244A (en) * 1990-04-10 1999-11-16 Imarx Pharmaceutical Corp. Polymers with a gas magnetic resonance imaging
US5681542A (en) * 1990-04-10 1997-10-28 Imarx Pharmaceutical Corp. Compositions comprising a biocompatible gas and a polymer for magnetic resonance imaging
US5368840A (en) * 1990-04-10 1994-11-29 Imarx Pharmaceutical Corp. Natural polymers as contrast media for magnetic resonance imaging
US5645816A (en) * 1990-04-10 1997-07-08 Imarx Pharmaceutical Corp. Synthetic polyuronic and hypoosmotic polymer compositions in admixture with proteinaceously bound contrast agents for MRI
EP0693288A1 (fr) * 1990-04-10 1996-01-24 UNGER, Evan C Polymères commes substances de contraste pour résonance magnétique
WO1992010213A1 (fr) * 1990-12-07 1992-06-25 Board Of Regents, The University Of Texas System Ion paramagnetique de diagnostic inclus dans un tamis moleculaire
US5277896A (en) * 1990-12-07 1994-01-11 Board Of Reagents, The University Of Texas System Clay enclosed transition and rare earth metal ions as contrast agents for the gastrointestinal tract
AU652213B2 (en) * 1990-12-07 1994-08-18 Board Of Regents, The University Of Texas System Molecular sieve-enclosed paramagnetic ion for diagnosis
US5429814A (en) * 1990-12-07 1995-07-04 Board Of Regents, The University Of Texas System Molecular sieve-enclosed transition and rare earth metal ions as contrast agents for the gastrointestinal tract
WO1992019272A1 (fr) * 1991-04-30 1992-11-12 The Du Pont Merck Pharmaceutical Company Agents de contraste inorganiques poreux pour exploration ultrasonique
EP0630652A2 (fr) * 1991-10-30 1994-12-28 Nycomed Salutar, Inc. Milieux de contraste
EP0630652A3 (fr) * 1991-10-30 1995-03-01 Nycomed Salutar Inc Milieux de contraste.
WO1993008846A1 (fr) * 1991-10-30 1993-05-13 Cockbain, Julian, Roderick, Michaelson Milieux de contraste
WO1993025895A1 (fr) * 1992-06-15 1993-12-23 Board Of Regents, The University Of Texas System Ions de metaux de transition et de terre rare enfermes dans une argile et utilises comme agents de contraste pour les voies gastro-intestinales
US5514379A (en) * 1992-08-07 1996-05-07 The General Hospital Corporation Hydrogel compositions and methods of use
US5863519A (en) * 1994-08-18 1999-01-26 Nycomed Imaging As Composition and method of MRI using both a positive and a negative contrast agent
WO1999012577A1 (fr) * 1997-09-05 1999-03-18 Nycomed Imaging As Particules polymeres en alcool polyvinylique comprenant un agent de contraste destine a la chimio-embolisation
US8673266B2 (en) 1998-10-16 2014-03-18 Biosphere Medical, S.A. Polyvinyl alcohol microspheres, injectable solutions and therapeutic uses of the same
US8753641B2 (en) 1999-02-24 2014-06-17 University Of Zurich Combination of intercalating organometallic complexes and tumor seeking biomolecules for DNA cleavage and radiotherapy
WO2000069474A1 (fr) * 1999-05-13 2000-11-23 Micro Therapeutics, Inc. Procedes pour traiter des malformations arterio-veineuses au moyen de compositions radioactives
US6333020B1 (en) 1999-05-13 2001-12-25 Micro Therapeutics, Inc. Methods for treating AVM's using radio active compositions
US6759028B2 (en) 1999-05-13 2004-07-06 Micro Therapeutics, Inc. Methods for treating AVM's using radioactive compositions
EP1106186A2 (fr) * 1999-12-08 2001-06-13 Mallinckrodt Inc. Bioconjugués non-covalents pour application dans la IRM
EP1106186A3 (fr) * 1999-12-08 2003-08-13 Mallinckrodt Inc. Bioconjugués non-covalents pour application dans la IRM
US7056466B2 (en) 2002-03-28 2006-06-06 Scimed Life Systems, Inc. Method of manufacture medical devices employing microwave energy
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