WO1993010440A1 - Substances de contraste a particules de gel destinees a un procede d'imagerie diagnostique ameliore - Google Patents

Substances de contraste a particules de gel destinees a un procede d'imagerie diagnostique ameliore Download PDF

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Publication number
WO1993010440A1
WO1993010440A1 PCT/US1992/008948 US9208948W WO9310440A1 WO 1993010440 A1 WO1993010440 A1 WO 1993010440A1 US 9208948 W US9208948 W US 9208948W WO 9310440 A1 WO9310440 A1 WO 9310440A1
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Prior art keywords
contrast medium
polymer
contrast
metal
acid
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PCT/US1992/008948
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English (en)
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Evan C. Unger
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Unger Evan C
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Priority to EP92922870A priority Critical patent/EP0614527A4/fr
Priority to JP5509251A priority patent/JPH07501331A/ja
Priority to AU28940/92A priority patent/AU667491B2/en
Publication of WO1993010440A1 publication Critical patent/WO1993010440A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • 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
    • 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
    • A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
    • A61K49/1845—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a carbohydrate (monosaccharides, discacharides)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1863—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels

Definitions

  • Imaging techniques There are a .variety of imaging techniques that have been used to diagnose disease in humans.
  • One of the first imaging techniques employed was X-rays.
  • X-rays the images produced of the patients' body reflect the different densities of body structure.
  • contrast agents are employed to increase the density between various structures, such as between the gastrointestinal tract and its surrounding tissue. Barium and iodinated contrast media, for example, are used extensively for X-ray gastro- intestinal studies to visualize the esophagus, stomach, intestines and rectum.
  • Ultrasound is another imaging technique.
  • sound is transmitted into a patient via a transducer.
  • the sound waves When the sound waves propagate through the body, they encounter interfaces from tissues and fluids in the body, and the ultrasound sound waves are either reflected or absorbed.
  • sound waves When sound waves are reflected by an interface they are detected by the receiver in the transducer and processed to form an image.
  • the acoustic properties of the tissues and fluids within the body determine the contrast which appears in the resultant image. Contrast agents have been sought which will increase the acoustic difference between the target area and the surrounding area. For example, heavy metals have been tested as contrast agents for ultrasound.
  • Magnetic resonance imaging is a relatively new imaging technique which, unlike X-rays, does not utilize ionizing radiation.
  • MRI can make cross-sectional images of the body, however, MRI has the additional advantage of being able to make images in any scan plane (i.e., axial, coronal, sagittal or orthogonal) .
  • any scan plane i.e., axial, coronal, sagittal or orthogonal
  • Contrast agents have been developed for MRI to improve detection of disease, but most of these efforts have been directed to using chelates of paramagnetic ions as contrast agents.
  • Traditionally employed chelates have the disadvantage of decreasing the relaxivity of the chelate ion as well as potentially causing toxicity, should the metal ion escape from the chelate.
  • Such chelates have the further disadvantage that they are rapidly cleared by the kidneys and do not work as effective contrast agents for imaging of the liver, for example. If better contrast agents were available, the overall usefulness of MRI as an imaging modality would improve.
  • the present invention pertains to contrast media useful for diagnostic imaging. Specifically, in one aspect, the present invention is directed to contrast media comprising gel particles, preferably of less than about 90 ⁇ in mean diameter, said gel particles comprising at least one polymer entrapping at least one contrast enhancing metal. Preferably the polymers employed are not cross- linked.
  • the present invention also pertains to contrast media prepared by combining at least one polymer and at least one contrast enhancing metal, optionally in the presence of a gelling agent, to form a gel, and particularizing the mixture to form particles, as well as processes for preparing the same.
  • the subject invention also pertains to methods for providing an image of an internal region of a patient, said methods comprising (i) administering to the patient one or more of the aforementioned contrast agents, and (ii) scanning the patient using magnetic resonance, ultrasound or X-ray imaging to obtain visible images of the region.
  • the present invention encompasses a method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient one or more of the foregoing contrast agents, and (ii) scanning the patient using magnetic resonance, ultrasound, or X-ray imaging to obtain visible images of any diseased tissue in the patient.
  • kits comprising compounds of the present invention and conventional diagnostic kit components are provided.
  • Fig. 1 is a schematic representation of a possible structural configuration for the gel particles of the invention.
  • Fig. la is a schematic representation showing the association of polymer chains by entrapment of metal ions according an "egg box" model.
  • Fig. lb is a detail of the boxed region of Fig. la in which oxygen atoms are shown to coordinate with the divalent cation, Ca +2 .
  • Fig. lc is a schematic representation of a more complex structural configuration involving stacking of a number of polymer chains.
  • Contrast media comprising gel particles having one or more polymers entrapping one or more contrast enhancing metals are provided in the present invention.
  • contrast media have been shown to be heat stable and stable in long term storage, both of obvious advantage in commercial use. They have also been shown to require a lower overall concentration of contrast enhancing metals, often to achieve the same or better imaging than some other metal-containing contrast media known heretofore. By minimizing the amount of metal, toxicity as well as cost may be reduced, since less of the often more expensive and potentially toxic metals are used. Contrast media of the invention have been found to be highly effective contrast agents, useful in many different applications.
  • biocompatible polymers Any of a wide variety of biocompatible polymers known in the art may be employed in preparing the media of the present invention.
  • biocompatible used herein in connection with the term polymer, is employed in its conventional sense, that is, to denote polymers that do not substantially interact with the tissues, fluids and other components of the body in an adverse fashion in the particular application of interest.
  • the polymers useful in the present invention can be of natural, synthetic or semisynthetic origin.
  • semisynthetic polymer denotes a natural polymer that has been chemically modified in some fashion.
  • the polymer is natural or semisynthetic, most preferably natural.
  • polymer denotes a compound comprised of two or more repeating monomeric units, preferably three or more repeating monomeric units, more preferably five or more repeating units, and most preferably ten or more repeating units.
  • Exemplary natural polymers suitable for use in the present invention may include naturally occurring polysaccharides such as, for example, arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylan ⁇ (such as, for example, inulin) , levan, fucoidan, carrageenan, galactocarolose, pectins, pectic acids, amylose, pullulan, glycogen, amylopectin, cellulose, dextran, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, alginic acid, xanthin gum, starch, and various other natural homopolymers or heteropolymers such as those containing one or more of the following aldoses, ketoses, acids or amines: erythrose, threose, ribose, arabinose, xylose, lyxose, allose
  • Exemplary natural polymers may also include, for example, polypeptides and polyalcohols, as will be readily apparent to those skilled in the art.
  • Exemplary semisynthetic polymers include such modified natural polymers as carboxymethylcellulose, hydroxymethylcellulose, hydroxypropyl ethylcellulose, methylcellulose and methoxycellulose.
  • Exemplary synthetic polymers suitable for use in the present invention include polyethylenes (such as, for example, polyethylene glycol, polyoxyethylene, polyoxyethylene glycol, and polyethylene terephthlate) , polypropylenes (such as, for example, polypropylene glycol) , polyurethanes (such as, for example, polyurethane ureas) , pluronic acids and alcohols, polyvinyls (such as, for example, polyvinyl alcohol, polyvinylchloride and polyvinylpyrrolidone) , nylon, polystyrene, polylactic acids, fluorinated hydrocarbons, fluorinated carbons (such as, for example, polytetrafluoroethylene) , polyacrylates (such as polymethylmethacrylate) , polyacrylic acids (such as polymethacrylic acid) and polyacryla ides, as well as derivatives thereof.
  • polyethylenes such as, for example, polyethylene glycol, polyoxyethylene, polyoxyethylene glycol
  • Such polymers may range in size, for example, from a molecular weight of about 500 to about 500,000. In some instances, the preferable molecular weight of the polymers is from about 100,000 to about 500,000. To suit other parameters, preferable molecular is from about 500 to about 100,000.
  • the polymer employed is one which has a relatively high water binding capacity, that is, a polymer which is capable of binding at least about 50% of its weight in water.
  • the polymer chosen is one which is not substantially absorbed from or degraded within the gastrointestinal region.
  • Preferred polymers include polygalacturonic acid and pectins. As those skilled in the art are aware, pectins are generally methyl esters of polygalacturonic acid.
  • low methoxy pectins are particularly preferred.
  • low methoxy it is meant a pectin having less than about 40% methoxylation (that is, less than about 40% of the carboxylic acid groups are converted to methylesters) .
  • the degree of methoxylation of pectin may be measured by titrating the pectin with base.
  • Numerous contrast enhancing metals which are suitable for use in the present invention are known to those skilled in the art and include, for example, paramagnetic ions and/or heavy metal ions.
  • Exemplary metals useful, for example, in magnetic resonance imaging include paramagnetic metal ions such as gadolinium, manganese (Mn + and Mn + ) , copper, chromium, iron (Fe * and Fe *3 ) , cobalt, erbium, nickel, europium, technetium, indium, samarium, dysprosium, ruthenium, ytterbium, yttrium, and holmium, most preferably manganese (Mn * ) .
  • Exemplary metals useful, for example, in ultrasound or X-ray imaging are heavy metals such as hafnium, lanthanum, ytterbium, dysprosium and gadolinium. These and other contrast enhancer metals useful in magnetic resonance, ultrasound, and X-ray imaging will be readily apparent to those skilled in the art.
  • an admixture is first formed between the polymers and the contrast enhancing metals.
  • the contrast enhancing metals are added to the polymer containing medium, and are not chemically bound to the polymer molecules by a covalent linkage. Partial or complete gelation of the polymers to entrap the contrast enhancing metals may occur spontaneously, simply upon adding these two components together. For example, agarose and high methoxy (greater than about 40%) pectin polymers will generally gel spontaneously and entrap the contrast enhancing metals merely upon addition of such metals to the polymers.
  • partial or complete gelation of an admixture may occur as a result of, or be facilitated by, the addition of a gelling agent, thereby causing entrapment of the contrast enhancing metals by the polymers.
  • entrap or variations thereof, as used herein in connection with polymers entrapping contrast enhancing metals, it is meant that the polymers physically surround or enclose the metals. Such entrapment may occur through electrostatic interactions, hydrogen bonding, van der Waals forces, or the like.
  • gelling agents such as polyvalent metal cations, sugars and polyalcohols may be employed.
  • Exemplary polyvalent metal cations useful as gelling agents include calcium, zinc, manganese, iron and magnesium.
  • Useful sugars include monosaccharides such as glucose, galactose, fructose, arabinose, allose and altrose, disaccharides such as maltose, sucrose, cellobiose and lactose, and polysaccharides such as starch.
  • the sugar is a single sugar, that is, monosaccharide or a disaccharide.
  • Polyalcohol gelling agents useful in the present invention include, for example, glycidol, inositol, mannitol, sorbitol, pentaerythritol, galacitol and polyvinylalcohol.
  • the gelling agent employed in the present invention is sucrose and/or calcium.
  • sucrose is particularly useful for gelling admixtures of polygalacturonic acid and manganese.
  • low methoxy pectins gel especially quickly upon addition of calcium ions.
  • sucrose is a useful polymer molecule, however, it may also be added to an admixture of, for example, polygalacturonic acid and manganese to effect gelation of the admixture.
  • iron may be effective as both a contrast enhancing metal and a gelling agent to cause gelation of an admixture which does not spontaneously gel.
  • the polymer molecules and contrast enhancing metals of the present invention arrange during the gelation process in an "egg box" type configuration such as that described in Figure 1 and in Grant, et al. FEBS Letters , Vol. 32, No. 1, pp. 195- 198 (1973), or in a tight coil-like aggregation such as that described in Vollmert, Polymer Chemistry, pp. 1-8, 541-561, Springer-Verlag, N.Y., New York (1973), the disclosures of each of which are hereby incorporated herein by reference in their entirety.
  • the polymers are believed to be in random motion.
  • the polymer chains are believed to be brought together by the interaction of the polymers with the contrast enhancing metals and/or gelling agents to "entrap" the contrast enhancing metals, thereby forming “egg boxes” or tight aggregation around the metals.
  • egg boxes or tight aggregation around the metals.
  • the contrast enhancing metals and/or the polyvalent metal cation gelling agents form bridges between two or more adjacent polymers, thereby effecting gelation.
  • the sugars or polyalchohol polymers and/or gelling agents provide a lower energy state, thereby allowing the polymers and contrast enhancing metals to gel more effectively.
  • gels will form gels of different consistencies, depending upon the particular formulation employed.
  • calcium ions form relatively firm gels with various polymers
  • manganese and ferrous ions form relatively weaker, somewhat watery, gels.
  • the term gel refers to a semisolid material, and includes both watery and firm gels.
  • the gel is firm.
  • Firm gels are gels that have lost fluidity, as indicated by the inability of gas bubbles to rise in the gel. This phenomenon is described, for example, in Odian, Principles of Polymerization, pp.
  • a watery gel will generally be formed by a combination of manganese and polygalacturonic acid
  • a firm gel will generally be formed by a combination of manganese, polygalacturonic acid and calcium.
  • the degree of gel firmness is related to the degree in which the polymer is capable of stabily retaining the contrast enhancing metal.
  • firm gels are capable of retaining at least about 50% of the contrast enhancing metal in prolonged (greater than 24 hours) dialysis against physiological saline, preferably at least about 60% of the contrast enchancing metal, more preferably at least about 70% of the contrast enhancing metal, even more preferably at least about 80% of the contrast enchancing metal, and most preferably at least about 90% of the contrast enhancing metal.
  • the resultant gel may then be treated to form gel particles.
  • treatment may include any one of a variety of techniques, as will be readily apparent to those skilled in the art, such as blenderizing, microemulsification, microfluidization, extrusion, sonication, lyophilization, ball mixing, colloid mixing, etc. , as well as any and all combinations thereof.
  • Blenderizing for example, may be accomplished by using any of a number of commercial blenders, and may be followed, if desired, by extrusion with a commercial extruder device having a filter of a defined size.
  • gel particles of micrometer or nanometer size may be prepared.
  • the particles Preferably the particles have diameters of less than about 90 ⁇ , more preferably, diameters ranging from about 5 nm to about 90 ⁇ .
  • the larger gel particles such as those ranging from about 1 ⁇ to about 90 ⁇ , are particularly useful for parenteral applications, and in gastrointestinal studies.
  • the smaller gel particles such as those ranging in mean diameter from about 5 nm to about 400 nm, more preferably from about 10 nm to about 200 nm, are particularly useful contrast media for intravenous injections, for imaging the liver, and for controlling biodistribution.
  • nanogels and microgels denote gel particles ranging from about 1 nm to less than 1000 nm (less than 1 ⁇ ) (nanogels) and from 1 ⁇ (1000 nm) to about 1000 ⁇ (microgels) .
  • Gel particles prepared in accordance with the present invention are stable to heat and long term storage, characteristics which make these contrast media especially attractive as a diagnostic agent.
  • the gel particles of the invention may be stored dried, or alternatively may be stored in an aqueous media.
  • the polymer is present in a concentration of at least about 1%, by weight, more preferably, between about 5% and about 50%, by weight, and generally, most preferably at about 40% by weight.
  • concentration of at least about 1%, by weight, more preferably, between about 5% and about 50%, by weight, and generally, most preferably at about 40% by weight.
  • the optimum polymer concentration will be influenced by various factors such as the particular polymer employed, the particular metal employed, the particular diagnostic use intended, etc.
  • the contrast enhancing metals may be present in a concentration of at least about 0.01% by weight, more preferably between about 0.1% and about 5% by weight, and most preferably between about 0.5% and 0.7% by weight.
  • a preferable concentration of heavy metals for ultrasound or X-ray imaging is at least about 0.1% by weight, more preferably between about 0.5% and about 30% by weight, most preferably between about 5% and about 25% by weight.
  • a preferable concentration of gelling agent, where employed, is at least about 0.5% by weight, more preferably between about 0.5% and about 25% by weight, most preferably between about 5% and about 15% by weight.
  • the polymers employed in the present invention may, if desired, be phosphorylated such that when these phosphorylated polymers are mixed with contrast enhancing metals or gelling agents such as polyvalent metal cations (e.g., calcium), gels may form more rapidly. In general, higher degrees of polymer phosphorylation result in firmer gels that entrap the contrast enhancing metals more tightly.
  • contrast enhancing metals or gelling agents such as polyvalent metal cations (e.g., calcium)
  • Phosphorylation of the polymers may be carried out using conventional techniques which will be readily apparent to those skilled in the art. Specifically, starting with an aliphatic or alicyclic compound containing one or more hydr ⁇ xyl groups, for example, phosphorylation can be easily carried out by suspending the starting material in chloroform, then adding a phosphoric ester monochloride compound to the suspension, preferably dropwise.
  • Suitable phosphoric ester monochloride compounds include C1P(0) (0R) 2 , wherein R is selected from C(0)CH 3 , C(0)H, CH 3 , C 2 I_ 5 , C 3 H 7 , and C ⁇ .
  • the resulting phosphorylated compound can then be treated with water to hydrolyze it to the corresponding phosphoric acid derivatives.
  • Such hydrolyzed derivatives are included within the scope of the phrase phosphorylated compounds herein.
  • Unbound phosphorus may be removed by passing the solution through a column filled anion exchanger.
  • Polymers such as pectin, polygalacturonic acid or polyvinylalcohol may be phosphorylated in such a manner to yield the corresponding phosphorylated derivatives.
  • urea catalyzed phosphoric acid (or phosphorous acid) phosphorylation procedures may be conveniently utilized.
  • aliphatic or alicyclic compounds are soaked with mixtures of urea and phosphoric acid (or phosphorous acid) , then heated to at least 120°C.
  • phosphorylation of compounds such as polyvinyl alcohol can be carried out by dissolving polyvinyl alcohol in an organic solvent such as pyridine, dimethylformamide, or dimethylsulfoxide with triethylamine, and then adding dialkyloxyphosphoric monochloride
  • the polymers employed in gel particles may be crosslinked using crosslinking agents known to those skilled in the art, either before or after particularization.
  • Crosslinking may be accomplished by methods known to those skilled in the art.
  • polymers may be crosslinked by a linker moiety.
  • the structure of such linkers may, for example, be of the following formula:
  • each R is, independently, H or X; L is a substituted or unsubstituted C,-C 20 alkyl, cycloalkyl, or aryl group; each X is, independently, OH, NH 2 , NHR, COOH, COOR, SH, epoxide or Z; Y is O, S, CO, N or SiRR; Z is Cl, Br or I; each n is, independently, 0-10; m is 0-10,000; and o is 0-1,000.
  • Linkers may be linked with COOH, OH or NH 2 bearing groups on polymers by using condensation agents, for example, dicylohexylcarboimide (DCC) .
  • condensation agents for example, dicylohexylcarboimide (DCC) .
  • DCC dicylohexylcarboimide
  • formaldehyde, glyoxal, epichlorhydrin, dimethyldichlorosilane, diepoxybutane and ⁇ , ⁇ - dichloroethylsulfide may be used to crosslink gel particles of the present invention.
  • Treatment with formaldehyde for example, leads to crosslinkages between secondary hydroxyl groups to form mainly intermolecular methylene bridges.
  • Crosslinking between carboxyl groups may be formed by agents such as diepoxybutane and j3,
  • Sulfur containing cross-linkers may be used if desired, so as to be readily degradable within the body.
  • Such cross- linkers include but are not limited to dithiobis(succinimidylpropionate) (DSP) and 3,3'- dithiobis(sulfosuccinimidylpropionate) (DTSSP) .
  • DSP dithiobis(succinimidylpropionate)
  • DTSSP 3,3'- dithiobis(sulfosuccinimidylpropionate)
  • Other procedures for cross-linking the polymers of the invention will be readily apparent to those skilled in the art, and include, for example, Staros, Biochemistry, Vol. 21, pp. 3950-3955 (1982), Lomant et al.
  • cross-linking may prolong the circulation or staying time of the gels within the patient in, for example, intravascular imaging or imaging of the gastrointestinal 5 tract.
  • Such cross-linking is not preferred, however, since it has been found that the degree of tissue inflammation and patient discomfort tends to increase with the use of cross-linked polymers.
  • the polymers are
  • Polymers may also, if desired, be modified prior or subsequent to gelation or particularization, such as by
  • targeting agents on their surface and in other ways that will be readily apparent to those skilled in the art.
  • agents such as antibodies, proteins, carbohydrates, and lectins may be incorporated on the polymeric surface of gel particles.
  • targeting agents may be useful for example, for localizing gel particles to target regions or organs.
  • Fab ' 2 fragments of antibodies may be covalently bound to the surface of the gels, such as through amide linkages from amino groups of the antibodies to the
  • carboxylic acids groups on the polymers e.g., polygalacturonic acid
  • other synthetic or natural peptides may be so attached.
  • carboxylic acid groups of proteins e.g. , antibodies or peptides
  • the resulting labelled gel particles may then be used for imaging specific tissues.
  • fragments of antileukocyte antigen antibody covalently bound to gel contrast media may be used to detect metastases from colonic carcinoma.
  • diagnostic kits comprising gel particles in combination with conventional diagnostic kit components such as buffering agents, antibacterial agents, stabilizing agents or excipients.
  • conventional diagnostic kit components such as buffering agents, antibacterial agents, stabilizing agents or excipients.
  • buffering agents such as buffering agents, antibacterial agents, stabilizing agents or excipients.
  • Such components are well known in the art, and are discussed, for example, in The United States Pharmacopeia — The National Formulary. 22nd Revision, January 1, 1990, Mack Publishing Company, Easton, PA, Remington r s Pharmaceutical Sciences, Gennaro, A.R. , ed. , Mack Publishing Company, Easton, PA (1985) , the disclosures of each of which are hereby incorporated herein by reference in their entirety.
  • the present invention is useful in imaging a patient generally, and/or in specifically diagnosing the presence of diseased tissue in a patient.
  • the imaging process of the present invention may be carried out by administering a contrast medium of the present invention to a patient, and then scanning the patient using ultrasound, X-ray or magnetic resonance imaging to obtain visible images of an internal region of a patient and/or of any diseased tissue in that region.
  • region of a patient it is meant the whole patient or a particular area or portion of the patient.
  • the contrast media of the invention are particularly useful in providing images of the liver.
  • the subject contrast media are also particularly suited to imaging the gastrointestinal region and the vasculature.
  • gastrointestinal tract includes the region of a patient defined by the esophagus, stomach, small and large intestines and rectum.
  • vasculature denotes the blood vessels in the body or in an organ or part of the body.
  • the patient can be any type of mammal, but most preferably is a human.
  • administration may be carried out in various fashions, such as intravascularly, orally, rectally, etc., using a variety of dosage forms.
  • the region to be scanned is the gastrointestinal region
  • administration of the contrast medium of the invention is preferably carried out orally or rectally.
  • the vasculature such as the vasculature of the liver
  • the preferred mode of administration is intravascular administration.
  • the useful dosage to be administered and the particular mode of administration will vary depending upon the age, weight and the particular mammal and region thereof to be scanned, the type of scanning and the particular medium of the invention to be employed. Typically, dosage is initiated at lower levels and increased until the desired contrast enhancement is achieved.
  • the contrast medium can be used alone, or in combination with other diagnostic, therapeutic or additional agents.
  • additional agents include excipients such as flavoring, coloring, stabilizing agents, thickening materials, osmotic agents and antibacterial agents.
  • Such agents may enhance the contrast media's use in vitro, the stability of the composition during storage, or other properties important to achieving optimal effectiveness.
  • the contrast media of the present invention may also be sterilized prior to use by, for example, autoclaving, if desired.
  • Contemplated magnetic resonance imaging techniques include, but are not limited to, nuclear magnetic resonance (NMR) and electronic spin resonance (ESR) .
  • NMR nuclear magnetic resonance
  • ESR electronic spin resonance
  • ultrasound techniques are carried out by conventional procedures known to those skilled in the art, such as those disclosed in Brown, R. E. , Ultrasonography, Basic Principles and Clinical Applications (Warren H. Green, Inc., St. Louis, MO 1975) the disclosures of which are hereby incorporated herein by reference in their entirety.
  • Such imaging may be performed with an Acuson 128 Scanner (Milpitas, CA) using a 7.5 megahertz linear array transducer.
  • the post processing function may be linear with pre-processing set at 0 and persistence at 2. Multifocal zones with a decreased frame rate can be used for most images.
  • X-ray imaging is also conventional, and includes such X-ray imaging techniques as computed tomography (CT) , such as those described in Computed Body Tomography, Lee, J.K.T., Sagel, S.S., and
  • the gel particles may operate as Tl, T2 or proton density contrast medium, depending upon the type of polymer used, the molecular weight of the polymer, the concentration of the polymer, the type of metal ions mixed with the polymer, the type of MRI modality used, and the details of the pulse sequence employed for MRI imaging, and all such mechanisms of operation are considered to be within the ambit of " the present invention.
  • the gel particles of the present invention have been shown to be extremely useful as contrast enhancement media.
  • lower overall concentration of the contrast enhancing metals may be used to achieve the same, or in many cases a better degree of, contrast enhancement results.
  • This has benefits not only in terms of toxicity, by avoiding the use of large amounts of the potentially toxic metal ions, but also in terms of cost, since less of the often more expensive conventional metal ions are used.
  • the potentially toxic metal ions have less of an opportunity to be released and exhibit any toxic side effects.
  • polygalacturonic acid For preparation of the polygalacturonic acid, manganese and calcium gel contrast medium, 4.4 grams of polygalacturonic acid (poly-G) (Fluka, Ronkonkoma, N.Y.) was added to about 200 ml of deionized water, and the pH raised to a pH of 6.5 with sodium bicarbonate (30 ml 1 M sodium bicarbonate) at room temperature. The poly-G was then placed into a blender (commercial household blender) , after which 680 mg of Mn *2 was added as 24.5 ml of a 0.5 M MnCl 2 stock solution. A clear inho ogeneous gel formed.
  • poly-G polygalacturonic acid
  • the gel was blended on a liquify setting for 3 minutes after which time 250 mg Ca +2 was added by the addition of 9.2 ml of a CaCl 2 solution.
  • the resulting white gel was blended for 4 minutes on a liquify setting until homogenous and rather thin.
  • the solution was then removed from the blender and the volume was brought up to 250 ml volumetrically with deionized water.
  • the solution was returned to the blender and mixed on a liquify setting for 2 minutes to homogenize the solution.
  • the solution was then extruded via an Extruder Device (Lipex Biomembranes,
  • 1% Red Pectin and 0.6% Mn *2 One gram of pure red pectin was dissolved in 100 ml deionized water. Sixty mg of Mn * was added as 2.16 ml of a 500 mM MnCl 2 stock solution. The solution was then blended on a liquify setting for thirty seconds and extruded through filters having pore sizes of 200, 100, 50, and 30 nm (sequentially downsizing the filters) to produce nanogel contrast media of present invention.
  • 1% Red Pectin, 0.6% Mn *2 and 0.1% Ca *2 One gram of pure red pectin was dissolved in 100 ml deionized water. Sixty mg of Mn * was added as 2.16 ml of 500 mM MnCl 2 stock solution. An inhomogeneous suspension resulted. To this suspension 10 mg of Ca * was added as 0.036 g of CaCl 2 . The gel was still inhomogeneous. The solution was then blended on a liquify setting for 1 minute. A thick, homogeneous gel resulted. The sample was extruded through filters having pore sizes of 200, 100, 50 and 15 nm (sequentially downsizing the filters) to produce nanogel contrast media of the present invention. 1% Purple Pectin, 0.6% Mn *2 :
  • the gel was extruded through filters having pore sizes 200,
  • nanogel contrast media of the present invention 20 100, 50 and 15 n (sequentially downsizing the filters) to produce nanogel contrast media of the present invention.
  • the contrast medium was prepared by adding 3.3 g of polygalacturonic acid (poly-G) to 150 ml of deionized water and raised to a pH of 6.0 with sodium bicarbonate (30 ml of 1 M sodium bicarbonate) at room temperature. The poly-G was then put into a blender, after which 2.49 g of polygalacturonic acid (poly-G)
  • the gel was prepared by adding 1.5 grams of polygalacturonic acid to 150 ml of deionized water. Sodium bicarbonate was added to raise the pH to 6.0. Fifty grams of sucrose was then added and the solution was blended on a liquify setting for 20 seconds. Manganese ion (Mn * ) 680 mg was then added as 24.5 ml 0.5 M MnCl 2 stock. The solution was blended on a liquify setting and brought up to 250 ml volumetrically by the addition of deionized water. The solution was returned to the blender and blended on a liquify setting for 20 seconds to homogenize the solution.
  • Mn * Manganese ion
  • Samples prepared substantially in accordance with Examples 1 through 4 were dialyzed for 24 hours in SPECTRA/POR Ce (cellulose ester) Membrane, molecular weight cutoff 100 (Spectrum Medical Industries Inc. , Los Angeles California) against 5% propylene glycol in normal saline. The samples were then spectrophotometrically analyzed for cation concentration (i.e., Mn * ) following dialysis, using a Milton Roy Spectronic 20D variable wavelength spectrophotometer (Rochester, N.Y.). Cation concentrations were as shown in Table 1. In Table 1, PG denotes polygalacturonic acid (Poly-G) . TABLE 1
  • Example 2 The solution was taken and subjected to a decolorization step by adding two grams of activated charcoal to the solution and heating the solution to 80°C for 30 minutes. The solution was then filtered, resulting in a clear colorless liquid. Next, the solution was evaporated to dryness, yielding a yellow-brown powder (Sample 2), which was low molecular weight polygalacturonic acid (Poly-G) , as shown in Table 2 (last entry) .
  • the Poly-G is suitable for use in preparing a gel particle contrast medium of the invention.
  • G (Fluka, Ronkonknoma, N.Y.) which is known to be comprised of a mixture of polymers of Poly-G with molecular weights ranging from 25,000 to 50,000 has a retention time on the column of 5.33 minutes.
  • Commercially available mono- galacturonic acid (molecular weight 194) , has the longest retention time, a retention time of 9.04 minutes.
  • Deca galacturonic acid (prepared by the method described in Lakatos et al. , U.S. Patent No.
  • Lakatos 4,225,592 issued September 30, 1980, hereinafter referred to as Lakatos, the disclosures of which are hereby incorporated herein by reference in their entirety
  • Lakatos the disclosures of which are hereby incorporated herein by reference in their entirety
  • Poly-G Specifically, the Poly-G from Sample 2 has a retention time of 7.9 minutes, indicating a MW range near that of deca galacturonic acid ( «2,200 dalton) . Evaluation of the dark brown precipitate (Sample 1) showed a retention time of 5.53 minutes (data not shown) — almost identical to that of high molecular weight Poly-G.
  • Contrast media of the invention prepared substantially in accordance with the procedures in Examples 1, 2, 3, 4 and 5, were analyzed for relaxivity and compared with the relaxivity of other samples.
  • Samples A through D are provided for comparative purposes only. All samples were analyzed for relaxivity using a Toshiba 0.5 T clinical MR magnet.
  • Samples E through J are gel particle contrast media within the scope of the invention. Samples A through D are provided for comparative purposes only. Table 3 below shows the relaxivity of the various samples.
  • manganese ion (Mn +2) as the free ion manganese chloride has an R, and R 2 of about 8 and 39 per millimole/sec ' respectively (Sample C) .
  • the chelates (Samples A and B) showed reduce relaxivity.
  • the polymeric chelate Mh-Poly-EDTA-EOEA-DP has an R, and R 2 , respectively, of about 6 and 13 (Sample B)
  • the simple chelate Mn- EDTA-MEA has an R 1 and R 2 , respectively, of about 3 and 8 (Sample A) .
  • the monomer of galacturonate has no appreciable effect on the relaxivity of manganese (Sample D) .
  • the contrast media of the invention have a large effect on the relaxivity of manganese.
  • algin (Sample F) appreciably increase the relaxivity of manganese.
  • different preparations of Poly-G within the scope of the invention show still greater relaxivity. Most effective are low molecular weight polygalacturonates.
  • hydrolyzed pectin prepared according to Example 5 had an R., and R 2 relaxivity of 46 and 68, respectively (Sample J) .
  • a mixture of 40% deca Poly-G prepared according to Example 5 and 60% normal Poly-G obtained from Fluka (MW 22,000 to 50,000) (Sample I) has relaxivity greater than pure deca Poly-G (Sample H) .
  • the gel particles of the invention show retention of manganese upon prolonged dialysis, evidence of the good stability of compounds of the invention. Specifically, as Table 4 shows, between 22% and 52% of the manganese is retained after 24 hours, for gel particles prepared in accordance with Example 4. After the first 24 hours of dialysis where some unbound manganese is removed, the particles were found to retain the remaining manganese even after prolonged dialysis (e.g. greater than 72 hours of dialysis) (data not shown) .
  • Contrast media of the invention prepared substantially in accordance with the procedures of Examples 1, 3 and 4, were analyzed for relaxivity and for stability on dialysis.
  • Table 5 shows the percent retention and relaxivity of manganese by gel particles prepared in accordance with the invention.
  • the gel comprising polygalacturonic acid (Poly-G; PG) , manganese, and sucrose exhibits the highest relaxivity and retention of manganese.
  • Tables 6 through 9 Shown in the Tables 6 through 9 are NMR imaging data from four rats injected intravenously with doses of 2.33 to 2.5 micromples/kg of manganese and polygalacturonic acid (Poly-G; PG) or pectin gel particles and scanned via NMR.
  • Tables 6 and 7 are data from intravenous injections of contrast medium comprising gel particles prepared substantially in accordance with Example l.
  • Table 8 is data from intravenous injections of contrast media comprising gel particles prepared substantially in accordance with Example 2.
  • Table 9 is data from intravenous injections of contrast media comprising gel particles prepared substantially in accordance with Example 4.
  • enhancement by gel particles prepared by gelation of Poly-G and manganese with calcium showed some enhancement. Better enhancement was observed with red pectin and manganese gels. The greatest enhancement is observed with the gel particles prepared by gelation of Poly-G and manganese with sucrose.
  • Percent enhancement [(signal intensity post-contrast agent - signal intensity pre-contrast agent)/(signal intensity pre-contrast agent) ] x 100.
  • Percent enhancement [ (signal intensity post-contrast agent - signal intensity pre-contrast agent) / (signal intensity pre-contrast agent)] x 100.
  • Table 10 represents enhancement of the liver using polygalacturonic acid manganese sucrose gel particles prepared substantially in accordance with Example 4 in three studies. As the data indicates, enhancement is increased from 40 to 50% by the use of the gel particles.
  • Percent enhancement [(signal intensity post-contrast agent - signal intensity pre-contrast agent)/(signal intensity pre-contrast agent)] x 100.
  • Table 11 provides data of three tests of contrast to noise. Contrast to noise was approximately double in tests using poly-G manganese sucrose gels prepared substantially in accordance with Example 4. Contrast to noise was calculated by measuring the signal intensity of the liver, subtracting the signal intensity of the tumor, and dividing this by the standard deviation of the background noise.
  • Tables 12 and 13 provide data from tests of signal intensity in the heart, kidney/medulla and kidney/cortex. All tests show an increase in signal intensity in tests using gel particles prepared substantially in accordance with Example 4. Signal intensity increased only slightly in the heart, but increased more significantly in the kidney/medulla, and most substantially in the kidney/cortex.

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Abstract

Une substance de contraste adaptée aux procédés d'imagerie diagnostique est décrite. La substance de contraste comprend des particules de gel, de préférence d'un diamètre moyen inférieur à 90 ν environ, les particules de gel comprenant au moins un polymère encapsulant au moins un métal améliorant le constraste.
PCT/US1992/008948 1991-11-19 1992-10-20 Substances de contraste a particules de gel destinees a un procede d'imagerie diagnostique ameliore WO1993010440A1 (fr)

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JP5509251A JPH07501331A (ja) 1991-11-19 1992-10-20 改良された診断用の造影のためのゲル粒子造影剤
AU28940/92A AU667491B2 (en) 1991-11-19 1992-10-20 Gel particle contrast media for improved diagnostic imaging

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0613690A2 (fr) * 1993-03-01 1994-09-07 Nycomed Imaging As Compositions à base de dérivés de l'iodoanaline pour visualiser les voies gastrointestinales
EP0613689A2 (fr) * 1993-03-01 1994-09-07 Nycomed Imaging As Compositions, contenant des dérivés de l'iodoaniline dans des matériaux de formation de couches, pour visualiser les voies gastro-intestinales
EP0639270A1 (fr) * 1991-02-01 1995-02-22 UNGER, Evan C Agents de contraste phosphoryles utiles dans la resonance magnetique nucleaire (rmn) du tractus gastro-intestinal
US5558854A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals Ultrasound contrast media comprising perfluoropentane and perfluorohexane gas
US5558094A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals, Inc. Methods for using persistent gases as ultrasound contrast media
US5573751A (en) * 1991-09-17 1996-11-12 Sonus Pharmaceuticals, Inc. Persistent gaseous bubbles as ultrasound contrast media
US5885549A (en) * 1991-02-01 1999-03-23 Imarx Pharmaceutical Corp. Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region
US6569404B1 (en) 1993-01-25 2003-05-27 Amersham Health A/S Phase shift colloids as ultrasound contrast agents
WO2003086474A2 (fr) * 2002-04-11 2003-10-23 Carbomer, Inc Nouvelles sondes d'imagerie
WO2004004786A1 (fr) * 2002-07-02 2004-01-15 Universitair Medisch Centrum Utrecht Suspension de balayage comprenant une particule dont le diametre s'eleve a au moins 1 micrometre
WO2005065725A1 (fr) * 2003-12-29 2005-07-21 Advanced Cardiovascular Systems, Inc. Marqueur polymere a radio-opacite elevee a utiliser dans des dispositifs medicaux
WO2005120589A2 (fr) * 2004-06-14 2005-12-22 Ntnu Technology Transfer Nouvel agent de contraste
US7303798B2 (en) 2003-09-22 2007-12-04 Advanced Cardiovascular Systems, Inc. Polymeric marker with high radiopacity for use in medical devices
US8163326B2 (en) 2001-11-27 2012-04-24 Boston Scientific Scimed, Inc. Implantable or insertable medical devices visible under magnetic resonance imaging

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10224352A1 (de) * 2002-06-01 2003-12-11 Mueller Schulte Detlef Thermosensitive Polymerträger mit veränderbarer physikalischer Struktur für die biochemische Analytik, Diagnostik und Therapie

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452773A (en) * 1982-04-05 1984-06-05 Canadian Patents And Development Limited Magnetic iron-dextran microspheres
US4692325A (en) * 1983-06-09 1987-09-08 Field Group Chemicals Pty. Ltd. Radiopaque medium
US4735796A (en) * 1983-12-08 1988-04-05 Gordon Robert T Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
US4749560A (en) * 1984-08-13 1988-06-07 Research Corporation Metal organo phosphorous compounds for NMR analysis
US4863715A (en) * 1984-03-29 1989-09-05 Nycomed As Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material
US4985233A (en) * 1984-11-01 1991-01-15 Nycomed /As A diagnostic agent containing a non-radioactive paramagnetic metal species in a macromolecular carrier
US5128121A (en) * 1988-04-08 1992-07-07 Nycomed As Mixture of a positive and negative contrast agent for magnetic resonance imaging
US5160725A (en) * 1987-03-24 1992-11-03 Silica Gel Gesellschaft Mbh Adsorptions-Technik, Apparatebau Magnetic liquid compositions

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1985233A (en) * 1928-10-06 1934-12-25 Petroleum Conversion Corp Process and apparatus for converting hydrocarbon oils
US4069306A (en) * 1974-03-14 1978-01-17 Pharmacia Aktiebolag X-ray contrast preparation containing a hydrophilic polymer containing amino groups
GB8310038D0 (en) * 1983-04-13 1983-05-18 Amersham Int Plc Technetium-99 labelled tin colloid
DE3619746A1 (de) * 1986-06-12 1987-12-17 Basf Ag Superparamagnetische feststoffteilchen
JPH04501265A (ja) * 1988-10-14 1992-03-05 マリンクロッド・インコーポレイテッド ラジオ標識粒状組成物
EP0526503B1 (fr) * 1990-04-10 1997-06-04 Imarx Pharmaceutical Corp. Polymeres utilises comme milieux de contraste en imagerie par resonance magnetique
US5358702A (en) * 1990-04-10 1994-10-25 Unger Evan C Methoxylated gel particle contrast media for improved diagnostic imaging

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452773A (en) * 1982-04-05 1984-06-05 Canadian Patents And Development Limited Magnetic iron-dextran microspheres
US4692325A (en) * 1983-06-09 1987-09-08 Field Group Chemicals Pty. Ltd. Radiopaque medium
US4735796A (en) * 1983-12-08 1988-04-05 Gordon Robert T Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease
US4863715A (en) * 1984-03-29 1989-09-05 Nycomed As Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material
US4749560A (en) * 1984-08-13 1988-06-07 Research Corporation Metal organo phosphorous compounds for NMR analysis
US4985233A (en) * 1984-11-01 1991-01-15 Nycomed /As A diagnostic agent containing a non-radioactive paramagnetic metal species in a macromolecular carrier
US5160725A (en) * 1987-03-24 1992-11-03 Silica Gel Gesellschaft Mbh Adsorptions-Technik, Apparatebau Magnetic liquid compositions
US5128121A (en) * 1988-04-08 1992-07-07 Nycomed As Mixture of a positive and negative contrast agent for magnetic resonance imaging

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0614527A4 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0639270A1 (fr) * 1991-02-01 1995-02-22 UNGER, Evan C Agents de contraste phosphoryles utiles dans la resonance magnetique nucleaire (rmn) du tractus gastro-intestinal
EP0639270A4 (fr) * 1991-02-01 1996-07-10 Evan C Unger Agents de contraste phosphoryles utiles dans la resonance magnetique nucleaire (rmn) du tractus gastro-intestinal.
US5885549A (en) * 1991-02-01 1999-03-23 Imarx Pharmaceutical Corp. Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region
US5558854A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals Ultrasound contrast media comprising perfluoropentane and perfluorohexane gas
US5558094A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals, Inc. Methods for using persistent gases as ultrasound contrast media
US5573751A (en) * 1991-09-17 1996-11-12 Sonus Pharmaceuticals, Inc. Persistent gaseous bubbles as ultrasound contrast media
US6569404B1 (en) 1993-01-25 2003-05-27 Amersham Health A/S Phase shift colloids as ultrasound contrast agents
EP0613690A2 (fr) * 1993-03-01 1994-09-07 Nycomed Imaging As Compositions à base de dérivés de l'iodoanaline pour visualiser les voies gastrointestinales
EP0613689A2 (fr) * 1993-03-01 1994-09-07 Nycomed Imaging As Compositions, contenant des dérivés de l'iodoaniline dans des matériaux de formation de couches, pour visualiser les voies gastro-intestinales
EP0613690A3 (fr) * 1993-03-01 1994-10-19 Sterling Winthrop Inc Compositions à base de dérivés de l'iodoanaline pour visualiser les voies gastrointestinales.
EP0613689A3 (fr) * 1993-03-01 1994-10-19 Sterling Winthrop Inc Compositions, contenant des dérivés de l'iodoaniline dans des matériaux de formation de couches, pour visualiser les voies gastro-intestinales.
US8163326B2 (en) 2001-11-27 2012-04-24 Boston Scientific Scimed, Inc. Implantable or insertable medical devices visible under magnetic resonance imaging
US7090829B2 (en) 2002-04-11 2006-08-15 Carbomer, Inc. Imaging probes
WO2003086474A3 (fr) * 2002-04-11 2004-04-01 Carbomer Inc Nouvelles sondes d'imagerie
WO2003086474A2 (fr) * 2002-04-11 2003-10-23 Carbomer, Inc Nouvelles sondes d'imagerie
US9731037B2 (en) 2002-07-02 2017-08-15 Universitair Medisch Centrum Utrecht Scanning suspension comprising a particle with a diameter of at least 1 micrometer
JP2005531643A (ja) * 2002-07-02 2005-10-20 ユニベルシテア、メディッシュ、セントラム、ユトレヒト 直径が少なくとも１マイクロメートルの粒子を含んでなる走査懸濁液
US8632751B2 (en) 2002-07-02 2014-01-21 Universitair Medisch Centrum Utrecht Scanning suspension comprising a particle with a diameter of at least 1 micrometer
WO2004004786A1 (fr) * 2002-07-02 2004-01-15 Universitair Medisch Centrum Utrecht Suspension de balayage comprenant une particule dont le diametre s'eleve a au moins 1 micrometre
US7303798B2 (en) 2003-09-22 2007-12-04 Advanced Cardiovascular Systems, Inc. Polymeric marker with high radiopacity for use in medical devices
US7833597B2 (en) 2003-09-22 2010-11-16 Advanced Cardiovascular Systems, Inc. Polymeric marker with high radiopacity for use in medical devices
US8637132B2 (en) 2003-09-22 2014-01-28 Advanced Cardiovascular Systems, Inc. Polymeric marker with high radiopacity for use in medical devices
CN102000364A (zh) * 2003-12-29 2011-04-06 阿博特心血管系统公司 用于医疗装置的具有高度射线不透性的聚合物标记
WO2005065725A1 (fr) * 2003-12-29 2005-07-21 Advanced Cardiovascular Systems, Inc. Marqueur polymere a radio-opacite elevee a utiliser dans des dispositifs medicaux
WO2005120589A3 (fr) * 2004-06-14 2006-06-15 Ntnu Technology Transfer Nouvel agent de contraste
WO2005120589A2 (fr) * 2004-06-14 2005-12-22 Ntnu Technology Transfer Nouvel agent de contraste

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