EP0941126A1 - Procede d'imagerie - Google Patents

Procede d'imagerie

Info

Publication number
EP0941126A1
EP0941126A1 EP97913321A EP97913321A EP0941126A1 EP 0941126 A1 EP0941126 A1 EP 0941126A1 EP 97913321 A EP97913321 A EP 97913321A EP 97913321 A EP97913321 A EP 97913321A EP 0941126 A1 EP0941126 A1 EP 0941126A1
Authority
EP
European Patent Office
Prior art keywords
contrast agent
contrast
imaging
molecular weight
polymeric material
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97913321A
Other languages
German (de)
English (en)
Inventor
Gregory Lynn Mcintire
David Lee Ladd
Edward Richard Bacon
John Luke Toner
George Chao Na
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
COCKBAIN Julian Roderick Michaelson
GE Healthcare AS
Original Assignee
COCKBAIN Julian Roderick Michaelson
Nycomed Imaging AS
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.)
Filing date
Publication date
Application filed by COCKBAIN Julian Roderick Michaelson, Nycomed Imaging AS filed Critical COCKBAIN Julian Roderick Michaelson
Publication of EP0941126A1 publication Critical patent/EP0941126A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
    • 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
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
    • 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
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
    • A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone

Definitions

  • the invention relates to a method of contrast enhanced imaging, in particular MR and X-ray imaging of the lymphatic system, and to contrast agent compositions useful therefor.
  • the status of the lymphatic system of the human body is often critical to the management of therapy in cancer patients. Accordingly it is highly desirable to be able to carry out diagnostic imaging of the lymphatic system in order to detect the existence or development of abnormalities therein.
  • Water-soluble contrast agents of the type routinely used in diagnostic imaging modalities eg. iohexol and GdDTPA-BMA, do not accumulate adequately in the lymphatic system to provide contrast enhancement thereof either by intravenous or submucosal injection.
  • Ethiodol an iodinated oily ethyl fatty acid ester present in poppyseed oil
  • X-ray lymphography ie. lymphangiography
  • This agent however has severe drawbacks in that it requires cannulation and direct injection into the lymph vessels, an invasive and painful procedure, and in that it requires a very long period before it is cleared from the lymphatic system. Furthermore, lodging of the oil agent in the lung can result in pulmonary embolism and decreased pulmonary function. More recently it has been found that subcutaneously administered nanocrystalline suspensions of substantially insoluble radiopaque materials can be used to provide contrast in X-ray imaging of the lymphatic system. Such nanocrystalline materials however also have potential drawbacks.
  • the particulate agent clears only slowly from the imaging site, is difficult to manufacture with uniform particle size and has to be formulated with a surfactant in order to stabilize the suspension.
  • a surfactant in order to stabilize the suspension.
  • further materials, such as surfactants, in a contrast medium raises the risk of toxicity problems and ensures that additional hurdles have to be overcome before official approval for a product can be obtained.
  • the invention provides a method for contrast enhanced imaging of at least part of the lymphatic system of a human or animal (preferably mammalian) body which comprises administering a diagnostically effective contrast agent to said body and generating a contrast enhanced image of at least part of the lymphatic system of said body, characterised in that said agent is a water-soluble polymeric material having a molecular weight of at least 1 kD (preferably at least 10 kD, especially preferably at least 20 kD, eg. up to 2 mD, preferably up to 100 kD) and is indirectly administered parenterally, preferably in solution.
  • a diagnostically effective contrast agent to said body and generating a contrast enhanced image of at least part of the lymphatic system of said body, characterised in that said agent is a water-soluble polymeric material having a molecular weight of at least 1 kD (preferably at least 10 kD, especially preferably at least 20 kD, eg. up to 2 mD, preferably up to 100 kD) and is indirectly administered
  • the invention provides the use of a diagnostically effective contrast agent which is a physiologically tolerable, water-soluble polymer having a molecular weight of at least 1 kD (preferably at least 10 kD, etc., as above), for the manufacture of an indirectly but parenterally administerable diagnostic imaging contrast medium for use in a method of diagnosis which involves indirect parenteral administration of said contrast medium and subsequent generation of a contrast enhanced image of at least part of the lymphatic system.
  • a diagnostically effective contrast agent which is a physiologically tolerable, water-soluble polymer having a molecular weight of at least 1 kD (preferably at least 10 kD, etc., as above)
  • an indirectly but parenterally administerable diagnostic imaging contrast medium for use in a method of diagnosis which involves indirect parenteral administration of said contrast medium and subsequent generation of a contrast enhanced image of at least part of the lymphatic system.
  • the contrast agent in order to be capable of functioning as such, will contain at least one diagnostically effective moiety.
  • the invention provides an indirectly but parenterally administrable diagnostic contrast agent composition, preferably an aqueous solution, for use in lymphography comprising a physiologically tolerable, diagnostically effective water-soluble polymer having a molecular weight of at least 1 kD (preferbly at least 10 kD, etc., as above), together with at least one pharmaceutically acceptable carrier or excipien .
  • Indirect parenteral administration involves administration into tissue beneath the skin or mucosal membranes, eg. by injection, infusion or depot placement. Administration may thus be subcutaneous, intramuscular, peritumoral, intraperitoneal, and submucosal (ie. intratracheal, intracervical, etc.), or by pulmonary deposition. Subcutaneous administration is preferred.
  • administration according to the invention is differentiated from direct lymphographic techniques which involve administration of the contrast medium directly into the lymph vessels or nodes and from intravenous or intraarterial administration which involves locating a major blood vessel and administering the contrast medium into that.
  • direct injection into the lymphatic system may also be effective using the water-soluble contrast agents of the invention .
  • the polymeric contrast agent incorporates at least one component (a label) which is effective at generating contrast in the selected imaging modality.
  • Suitable imaging modalities include X-ray (eg. CT) , MRI, light imaging, scintigraphy, magnetotomography, SPECT, PET, electrical impedance tomography etc., preferably X-ray, MRI or scintigraphy.
  • the contrast agents may if desired be diagnostically effective in more than one imaging modality; thus for example a soluble polymer may carry paramagnetic or heavy metal ions detectable in MRI or X- ray imaging as well as a dye detectable in light imaging .
  • suitable labels include non-proton atoms which have non-zero nuclear spin or, more preferably, metal ions or metal cluster ions which are paramagnetic, eg. transition metals such as Mn, Fe or Cr or lanthanides such as Gd and Dy.
  • metal ions or metal cluster ions which are paramagnetic, eg. transition metals such as Mn, Fe or Cr or lanthanides such as Gd and Dy.
  • suitable paramagnetic metal ions are well known from the patent literature relating to MR contrast media including the patent publications referred to herein.
  • MR imaging will preferably be T x - weighted imaging, however in the case of T 2 or T 2 * agents (eg. dysprosium labelled materials) T 2 -weighted imaging will also be useful.
  • the label will conveniently be a heavy atom (eg. having atomic number 37 or higher), conveniently iodine or a metal from period 5 or higher, eg. Bi, Pb, Ba or W. Again suitable heavy atoms are well known from the patent literature, including publications concerned with heavy metal cluster ions. Metals useful as MR imaging agents may also be useful for X-ray, albeit at lower efficiency than the heavy metals mentioned above.
  • the label will be a chromophore or fluorophore, eg. a triphenylmethane or cyanine or a fluorescent metal ion (eg. europium) .
  • the label may be any of the currently used analytical labels (eg. fluorescein and analogs thereof, or a dansyl group) as well as the visibly coloured dye groups.
  • the label will be a radiolabel conveniently a metal radionuclide such as a Sc, Fe, Pb, Ga, Y, Bi, Mn, Cu, Cr, Zn, Ge, Mo, Tc, Ru, In, Sm, Sn, Sb, W, Re, Po, Ta or Tl radionuclide, eg. 44 Sc, 64 Cu, 67 Cu, lu In, 212 Pb, 68 Ga, 90 Y, 212 Bi, 52 Fe, 3 Sc or 5 Co.
  • a metal radionuclide such as a Sc, Fe, Pb, Ga, Y, Bi, Mn, Cu, Cr, Zn, Ge, Mo, Tc, Ru, In, Sm, Sn, Sb, W, Re, Po, Ta or Tl radionuclide, eg. 44 Sc, 64 Cu, 67 Cu, lu In, 212 Pb, 68 Ga, 90 Y, 212 Bi, 52 Fe, 3 Sc or 5 Co.
  • the label is a metal
  • metal chelating groups eg. groups such as EDTA, DTPA, DOTA, D03A, TMT, etc.
  • chelant groups may form part of the polymer backbone or additionally or alternatively may be present in pendant side chains.
  • non-metal labels may be covalently attached to the end groups of linear, branched or dendrimeric polymers.
  • non-metal labels may again be included in the backbone polymer repeat units (eg. as iodophenyl chain components) or again may additionally or alternatively be present in pendant side chains.
  • non-metal labels may be covalently attached onto or into the polymer backbone, eg. by covalent attachment to the end groups of a linear, branched or dendrimeric polymer.
  • the polymer agents of the invention will preferably incorporate hydrophilic groups (such as polyhydroxyalkyl or polyalkyleneoxy groups) , within the polymer backbone or additionally or alternatively in pendant side chains.
  • hydrophilic groups such as polyhydroxyalkyl or polyalkyleneoxy groups
  • the polymer structure of the agents used according to the invention may be linear, branched or highly branched (eg. dendritic) . Linear polymers and dendrimeric polymers will however be preferred.
  • polymeric agent may contain repeat units of formula
  • PB the polymer backbone repeat unit
  • a label eg. iodine atoms or a metallated chelate group
  • a hydrophilic backbone segment eg. a polyalkyleneoxy linker group
  • SC the side chain
  • SC may incorporate a label (eg. iodine atoms or a metallated chelate group) and/or a hydrophilic segment (eg. a hydroxy poly (alkyleneoxy) group) .
  • Polyiodinated polymeric agents for use according to the invention may for example include compounds having repeat units of formula
  • a and b are integers having values of from 1 to 4 ; c is zero or an integer having a value of 1 to 4; X is a first linker group providing a zero, 1, 2, 3 or 4 atom chain between iodophenyl groups; and L is a second hydrophilic linker group providing a chain of molecular weight up to 5000 between iodophenyl groups, preferably having pendant hydroxyl groups and incorporating ether oxygens within the chain, eg. as in polyalkyleneoxy residues.
  • the phenyl :X or phenyl :L linkages may particularly conveniently be carbonyl groups or oxygen atoms, eg. in amide or ether functionalities.
  • a is 1, 2, 3 or 4 , preferably 2 or 3 ;
  • b is 1, 2, 3 or 4, preferably 2 or 3 ;
  • c is 0, 1, 2, 3 or 4, preferably 0 or 1 ;
  • R is H, alkyl, aryl, acyl, aroyl or aralkyl (eg. containing up to 20 carbons, preferably up to 6 carbons) optionally substituted with hydroxy groups;
  • R' is an optionally substituted (eg. with hydroxy or hydroxyalkyl) alkylene, preferably C 2 _ 20 alkylene, optionally interrupted by one or more oxygen or sulphur atoms ;
  • X is a linker providing a chain of 0 , 1, 2 or 3 atoms, eg. a bond, oxygen, carbonyl, SO, S0 2 , CH 2; C(CH 3 ) 2 or a 2 or 3 atom chain made up or such components; and
  • R" is hydroxy, H, NHAc, or another hydrophilic group .
  • Such compounds may be prepared by iodination of mono or oligo phenyl alcohols (eg. bisphenol-A,
  • 1,3,5 trihydroxybenzene followed by treatment with an ' epoxide introducing agent (eg. BrCH 2 CHCH 2 ) and polymer formation with a diamine (eg. H 2 N (CH 2 ) 2 0 (CH 2 ) 2 NH 2 ) .
  • an ' epoxide introducing agent eg. BrCH 2 CHCH 2
  • a diamine eg. H 2 N (CH 2 ) 2 0 (CH 2 ) 2 NH 2
  • Treatment of the polymer with acetic anhydride will convert any amine hydrogens to CH 3 CO and base treatment will hydrolyse any unwanted esters that are formed.
  • the polymeric agent used according to the invention will preferably have a molecular weight in the range 1 to 2000 kD, eg. 3 to 70 kD, especially 10 to 50 kD.
  • the contrast agent is conveniently injected or infused, preferably in aqueous solution or less preferably as an aqueous suspension, eg. at one or more injection sites in the hand, arm, foot, leg, crotch, chest or neck, preferably relatively close to and upstream of the lymph nodes or vessels of particular interest.
  • administration may be by peri-lesional injection.
  • injection sites analogous to those used for 99m ⁇ c sulphur colloids may be used, eg. peri-rectal, peri-lesional, peri-tumoral and classic injection sites such as the interdigital webbed spaces between the fingers or toes.
  • Dosages will preferably be relatively small volume, eg. 0.05 to 50 mL, preferably 2.0 to 10 mL for humans, the larger volumes conveniently being administered as a series of smaller injections, eg. 5 x 2 mL or 10 x 1 mL.
  • Imaging can be effected immediately or after a delay of from minutes up to several days . Preferably however imaging is effected at from 30 minutes to 2 days, especially from 1 hour to 18 hours post injection.
  • massage and/or application of heat to the injection site may promote transport of the contrast agent into the lymphatic system, so permitting imaging to be effected more rapidly.
  • dosages of from 0.0001 to 5.0 mmoles of chelated diagnostically effective metal is effective to achieve adequate contrast enhancement .
  • preferred dosages of imaging metal ion will be in the range from 0.02 to 1.2 mmoles/kg bodyweight (eg. at concentrations of 5 to 200 mM paramagnetic metal, eg. 20 to 100 mM) while for X-ray applications dosages of from 0.5 to 2.0 mmoles/kg are generally effective to achieve X-ray attenuation.
  • Preferred dosages for most X-ray applications are from 0.8 to 1.5 mmoles of the metal/kg bodyweight .
  • the agent is iodinated dosages of from 10 to 400 mgl/kg will generally be used.
  • dosages of from 0.0001 to 4 mmoles radionuclide/kg bodyweight will generally be used.
  • the polymeric contrast agents of the present invention may be formulated with conventional pharmaceutical or veterinary aids, for example emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc., and may be in a form suitable for subcutaneous administration, or for pre-use formulation for injection or infusion.
  • conventional pharmaceutical or veterinary aids for example emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc.
  • the polymeric compounds may be in conventional pharmaceutical administration forms such as powders, solutions, suspensions, dispersions, etc.; however, solutions in physiologically acceptable carrier media, for example water for injections, will generally be preferred.
  • the polymeric compounds may be formulated for administration using physiologically acceptable carriers or excipients in a manner fully within the skill of the art.
  • the compounds optionally with the addition of pharmaceutically acceptable excipients, may be suspended or dissolved in an aqueous medium, with the resulting solution or suspension then being sterilized.
  • suitable additives include, for example, physiologically biocompatible buffers (as for example, tromethamine hydrochloride) , additions (eg.
  • chelants such as, for example, DTPA, DTPA-bisamide or non-complexed polychelant
  • calcium chelate complexes as for example calcium DTPA, CaNaDTPA- bisamide, calcium polychelant or CaNa salts of polychelants
  • additions eg. 1 to 50 mole percent
  • calcium or sodium salts for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate
  • Parenterally administrable forms eg. suspensions and solutions
  • Suitable vehicles include aqueous vehicles customarily used for administering parenteral solutions such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection and other solutions such as are described in Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., pp. 1405-1412 and 1461-1487 (1975) and The National Formulary XIV, 14th ed. Washington: American Pharmaceutical Association (1975) .
  • the solutions can contain preservatives, antimicrobial agents, buffers and antioxidants conventionally used for parenteral solutions, excipients and other additives which are compatible with the chelates and which will not interfere with the manufacture, storage or use of products.
  • the various polymeric agents herein described as diagnostic imaging agents for the lymphatic system can be modified for delivery of. therapeutically active moieties to the lymph system.
  • therapeutic moieties can be attached to or otherwise incorporated within the structure of the water soluble polymer, in the same fasion as iodinated agents .
  • Any therapeutic agent can be used, including peptides, proteins, and nucleic acids, as well as more conventional pharmaceutical molecules. Oncologies for metastatic disease, anti-inflammatories, antiviral agents as used against HIV and other viruses, antibiotics and radiotherapeutic agents are preferred.
  • a 10% NaCl (USP grade) solution (filtered through a 0.22 micron filter) was used for the first four turnovers and water was used for the remaining 6 turnovers.
  • the solution was neutralized to pH ⁇ 5 with NaOH and filtered through a 0.45 micron filter.
  • the filtered solution was diafiltered using a Pellicon diafiltration unit with a 10K cutoff filter for 10 turnovers.
  • a 10% NaCl (USP grade) solution (filtered through a 0.22 micron filter) was used for the first five turnovers and water was used for the remaining 5 turnovers .
  • NC 66368 (Example 1) was aseptically dissolved in physiological saline with the addition of enough TRIS buffer to make the solution 20 mM in buffer. The resulting solution was passed through a sterile 0.2 ⁇ m filter and packaged in 10 ml glass vials with teflon faced stoppers and conventional metal crimp tops . The vials were sealed and heat sterilized at 121°C for 15 minutes. The final composition of the solution was: NC 66368 80 mM Gd
  • NC 22181 600 mg was aseptically dissolved in physiological saline (10 ML) with the addition of enough TRIS buffer to make the solution 10 mM in buffer.
  • the resulting solution was passed through a sterile 0.2 ⁇ m filter and packaged in 10 ml glass vials with teflon faced stoppers and conventional metal crimp tops .
  • the vials were sealed and heat sterilized at 121°C for 15 minutes.
  • the final composition of the solution was:
  • FIG. 1 of the accompanying drawings shows one MR image generated showing substantial contrast enhancement in the right axillary node (magnified in the box) as compared, by way of control, with the left axillary node (arrowed) .
  • NC 66368 was administered subcutaneously in the paw to New Zealand white rabbits at dosages of 0.064 and 0.128 mmole Gd/kg bodyweight (1 and 2 mL injections) .
  • T 2 - weighted MR imaging was carried out at 0, 0.16, 0.33, 0.5, 2 and 24 hours post injection and the detected enhancement of the popliteal was as set out in Table 1 below:
  • NC 22181 Example 4
  • saline a solution of NC 22181 (Example 4) in saline was injected subcutaneously in the paws of New Zealand white rabbits at dosages of 0.1 ml, and 2.0 ml (approximately 0.006, 0.015, 0.064, and 0.128 mM Gd/kg body weight).
  • TL weighted MR imaging was carried out at 24 hours post injection with the following % enhancements noted. Dose % enhancement

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention porte sur un procédé d'accroissement des contrastes d'une image d'une partie au moins du système lymphatique d'un corps humain ou animal consistant à lui administrer une dose suffisante pour un diagnostic d'un agent de contraste permettant d'obtenir une image plus contrastée d'une partie au moins du système lymphatique dudit corps, et caractérisé en ce que ledit agent est un matériau polymère d'un poids moléculaire d'au moins 1 kD s'administrant indirectement par voie parentérale.
EP97913321A 1996-11-28 1997-11-21 Procede d'imagerie Withdrawn EP0941126A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9624822 1996-11-28
GBGB9624822.4A GB9624822D0 (en) 1996-11-28 1996-11-28 Method
PCT/GB1997/003204 WO1998023295A1 (fr) 1996-11-28 1997-11-21 Procede d'imagerie

Publications (1)

Publication Number Publication Date
EP0941126A1 true EP0941126A1 (fr) 1999-09-15

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP97913321A Withdrawn EP0941126A1 (fr) 1996-11-28 1997-11-21 Procede d'imagerie

Country Status (5)

Country Link
EP (1) EP0941126A1 (fr)
JP (1) JPH10158197A (fr)
AU (1) AU5062198A (fr)
GB (1) GB9624822D0 (fr)
WO (1) WO1998023295A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19525924A1 (de) 1995-07-04 1997-01-09 Schering Ag Kaskaden-Polymer-Komplexe, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel
US6166200A (en) * 1995-07-04 2000-12-26 Schering Aktiengesellschaft Cascade polymer complexes, process for their production and pharmaceutical agents containing said complexes
GB2337523A (en) * 1998-04-29 1999-11-24 Nycomed Imaging As Light imaging contrast agents
DK1051116T3 (da) * 1998-12-01 2009-02-02 Univ Washington Emboliseringsanordning
EP2606912A1 (fr) * 2011-12-23 2013-06-26 Central Medical Service Co., Ltd. Composition de substance de contraste avec effet d'amélioration de contraste comprenant un agent hautement concentré

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Publication number Priority date Publication date Assignee Title
US3733397A (en) * 1966-12-02 1973-05-15 Pharmacia Ab Method for the x-ray visualization of body cavities and a preparation for carrying out the method
CA2125188A1 (fr) * 1991-12-04 1993-06-10 Dominique Meyer Nouveau compose macromoleculaire polyamine iode, son procede de preparation et son utilisation comme agent de contraste
US5324503A (en) * 1992-02-06 1994-06-28 Mallinckrodt Medical, Inc. Iodo-phenylated chelates for x-ray contrast
JPH07509467A (ja) * 1992-07-21 1995-10-19 ザ　ゼネラル　ホスピタル　コーポレーション リンパ組織への薬物輸送システム
US5756688A (en) * 1992-10-14 1998-05-26 Sterling Winthrop Inc. MR imaging compositions and methods
US5534241A (en) * 1993-07-23 1996-07-09 Torchilin; Vladimir P. Amphipathic polychelating compounds and methods of use
US5567410A (en) * 1994-06-24 1996-10-22 The General Hospital Corporation Composotions and methods for radiographic imaging
DE19521940A1 (de) * 1995-06-07 1996-12-12 Schering Ag Iodhaltige lineare Polyamine und Polyamide

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Title
See references of WO9823295A1 *

Also Published As

Publication number Publication date
GB9624822D0 (en) 1997-01-15
AU5062198A (en) 1998-06-22
JPH10158197A (ja) 1998-06-16
WO1998023295A1 (fr) 1998-06-04

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