EP0741581A1 - Formulation orale comprenant des particules magnetiques - Google Patents

Formulation orale comprenant des particules magnetiques

Info

Publication number
EP0741581A1
EP0741581A1 EP95906454A EP95906454A EP0741581A1 EP 0741581 A1 EP0741581 A1 EP 0741581A1 EP 95906454 A EP95906454 A EP 95906454A EP 95906454 A EP95906454 A EP 95906454A EP 0741581 A1 EP0741581 A1 EP 0741581A1
Authority
EP
European Patent Office
Prior art keywords
composition
magnetically responsive
particles
responsive particles
viscosity
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Withdrawn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
EP95906454A
Other languages
German (de)
English (en)
Inventor
William George Gorman
Fred Andrew Carroll
Kevin Darryl Ostrander
William Hunke
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.)
GE Healthcare AS
Original Assignee
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 Nycomed Imaging AS filed Critical Nycomed Imaging AS
Publication of EP0741581A1 publication Critical patent/EP0741581A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K49/1818—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

Definitions

  • the present invention relates to magnetic resonance imaging (MRI) in general and in particular to compositions useful as or in the preparation of MRI contrast media for imaging the gastrointestinal system or " other body cavities from which contrast media may be discharged without passing through body tissue.
  • MRI magnetic resonance imaging
  • contrast agents for effective MRI of the gastrointestinal tract. Both positive and negative contrast agents have been described, the latter agents generally containing ferromagnetic, ferrimagnetic or superparamagnetic particles. These particles are usually dispersed in a liquid carrier to form a suspension which is administered to the site of interest for imaging.
  • MSIO magnetically susceptible iron oxide
  • Moderate magnetic field distortion causes signal blackening, but excessive magnetic distortion can result in poor imaging by causing magnetic susceptibility artifacts (pixel mismapping and image distortion) .
  • Excessive magnetic distortion is usually caused by high particle concentration, but even at a suitable concentration, excessive magnetic distortion can also be caused by particle aggregation and flocculation, frequently seen vJ.th suspensions (such as MSIO suspensions) that are susceptible to gravitational settling. Since magnetic susceptibility artifacts cause distracting bright signals, interfere with visualization of normal adjacent structures and induce significant image blurring, they have limited the widespread acceptance of MSIO contrast agents. Accordingly, although several MSIO contrast agents have recently been developed, they have not been widely used.
  • Nycomed (PCT/EP90/01196) discloses a negative contrast medium which contains viscosity enhancing agents that reach full viscosity enhancing effect only after administration .
  • the vi scosity enhancing agent is " incompletely hydrated" , meaning that it reaches full viscosity only after exposure to aqueous media, such as water or body fluids like gastric juices .
  • OMP oral magnetic particle
  • the paradigm for an efficient OMP is a good-imaging, low-viscosity, fully hydrated, ready-to-use formulation that is capable of uniformly dispersing the magnetic particles without being so viscous that it is unpalatable .
  • This formulation would contain an appropriate dispersing agent in a sufficient amount . If it is to be stored for long periods prior to administration, a useful feature, it must be preserved against microbial activity and must resist caking that often occurs when active ingredients and excipients settle and adhere to the walls of containers . For better patient compliance, it should preferably be as palatable as possible which means, at the least, that the formulation should mask the taste and color of the act ive metal lic ingredient . This would involve selecting appropriate sweeteners and coloring agents which do not react with the metal particles . - 4 -
  • Viscosity is important only to the extent that it prevents agglomeration or gravitational settling of particles and affords the formation and stability of a homogeneous suspension.
  • the present invention provides formulations for contrast media with viscosities as low as 25 to 465 cP which produce high quality images. These formulations suspend magnetic particles very well for extensive periods of time without caking, lumping or separation. Further, the product is substantially hydrated at the time of consumption.
  • an aqueous carrier for dispersing magnetically responsive particles comprising one or more substantially hydrated dispersion-enhancing agent.
  • the invention also provides a contrast medium comprising a suspension of magnetically responsive particles dispersed in a substantially hydrated carrier.
  • Yet another aspect of the invention provides a ready-to- use contrast medium which remains'unchanged after storage.
  • a method of generating a magnetic resonance image of a human or nonhuman body is also provided.
  • Figure 1 represents four plots showing the relationship between viscosity and signal intensity ratios.
  • Figure 1A represents the-T ⁇ -weighted pulse sequence.
  • Figure IB represents the T 2 ⁇ weighted pulse sequence.
  • Figure 1C represents the proton density-weighted pulse sequence.
  • Figure ID represents all three pulse sequences combined.
  • Figure 2 is a plot showing the viscosity values for various formulations of the invention measured during the course of study.
  • Substantially hydrated means that one or more dispersion enhancement agents in the formulation are in contact with water, such that a desirable viscosity is achieved prior to patient dosing.
  • a desirable viscosity is one that is palatable, yet is capable of uniformly dispersing the magnetic particles. While it is possible that viscosity might increase during passage to the site of interest, such increase is not critical for high performance.
  • Magnetically responsive particles relates to particles having paramagnetic, diamagnetic, and especially ferromagnetic, ferrimagnetic or superparamagnetic properties. Such particles produce blackening by creating local distortion of the magnetic field, resulting in T2 relaxation time shortening.
  • agnetically susceptible iron oxide MSIO is exemplary.
  • Ready-to-use means that the product is capable of being administered to the patient directly from the package with no preparation other than mild shaking. No diluting or reconstitution is required. - 6 -
  • OMP means .oral magnetic particles , indicating that magnetically responsive particles have been added to a liquid carrier to provide a suspension for oral consumption.
  • Carrier means a chemical vehicle used to assist or transport the active component to the desired anatomical site.
  • Pultom refers to a twin coaxial tube apparatus of which the outer tube contains water and the inner tube contains MRI contrast medium. It is used for in-vitro MR evaluation.
  • Negative contrast agent describes an agent which contains materials whose effect of reducing the spin-spin relaxation time (T2) of the imaging nuclei outweighs any Tl reducing effect and results in a reduction in MR signal intensity from the body regions into which they distribute .
  • Negative contrast media generally contain ferromagnetic, ferrimagnetic or superparamagnetic particles .
  • “Positive contrast agent” describes a paramagnetic compound which shorten the spin-lattice relaxation time (Tl) of the imaging nuclei and so result in an increase in image intensity in the body regions into which they distribute .
  • One such positive contrast agent is Gd DTPA.
  • LVL denotes lowest yiscosity limit. Formulations with viscosities lower than the LVL are prone to gravitational settling.
  • the present invention provides a fully hydrated, low viscosity carrier which contains one or more dispersing agents in sufficient amounts to uniformly disperse magnetically responsive particles .
  • the composition is a contrast medium which affords high quality magnetic resonance images .
  • Suitable dispersing agents are capable of dispersing magnetically responsive particles under the physiological conditions of the body cavity to be imaged and thus are preferably of a non-biodegradable material, especially where the composition is intended for oral ingestion.
  • Dispersing agents may conveniently be soluble in aqueous media to produce a viscous solution .
  • examples of such materials include natural , semisynthetic and synthetic high molecular weight substances such as natural or semi synthetic gums and polysaccharides, e . g. guar gum, tragacanth , methylcellulose , hydroxypropylcel lulose, carboxymethylcellulose, xanthan gum, a lginates and, where applicable, their physiologically acceptable salts .
  • Many examples of such materials are known as thickening agents in the food industry .
  • Alternative dispersion enhancing agents include insoluble materials which swell in aqueous media to produce viscous dispersions .
  • Typical examples of such swellable dispersion enhancing agents include clays, eg kaolin, and related minerals such as, for example, magnesium aluminum silicate, bentonite, etc . Mixtures of soluble and insoluble dispersion enhancing agents can also be used.
  • bulking agents such as those used in the treatment of constipation such as bran, psyllium and methylcellulose may also be used as dispersion enhancing agents alone or in combination with other dispersion enhancing agents .
  • Preferred dispersing agents include carboxymethylcellu ⁇ lose sodium, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, carbomers, gum tragacanth, sodium alginate, gelatin, pectin, polyvinylpyrrolidone, guar gum, xanthan gum, pregelatinized starch, locust bean gum, montmorillonite, bentonite, hectorite, carrageenan, starch, xylitol, sorbitol, mannitol, and lactose.
  • the complete contrast agent of the invention comprises magnetically responsive particles, the components actually responsible for the negative MRI contrast , dispersed in the carrier composition of the invention.
  • the particles may be free or may be coated by or embedded in or on particles of a non-magnetic carrier material , e . g . a natural or synthet ic polymer, for example cellulose or a sulphonated styrene-divinyl benzene copolymer (see for example WO83/03920 of Ugelstad) .
  • the magnetically responsive particles may be ferromagnetic or ferrimagnetic or may be sufficiently small as to be superparamagnetic and indeed superparamagnetic particles are generally preferred.
  • the magnetically responsive particles used according to the present invention may be of any material which (although preferably non-radioactive unless the particles are also intended to be detected by their radioactive decay emissions) exhibits ferromagnetism, ferrimagnetism or superpara- magnetism.
  • the particles may conveniently be particles of a magnetic metal or alloy, eg of pure iron, but particularly preferably will be of a magnetic compound such as a ferrite, for example magnetite, gamma ferric oxide and cobalt, nickel or manganese ferrites.
  • the mean particle size of the magnetically responsive particles be less than about 5 micrometers, preferably less than 1 micrometer and that the overall size of the non-magnetic carrier particles be less than 50 micrometers, preferably less than 20 micrometers, especially preferably 0.1 to 5 micrometers.
  • the magnetically responsive particles will generally have mean particle sizes in the range 0.002 to 1 micrometers, preferably 0.005 to 0.2 micrometers.
  • the magnetically responsive particles are carried by carrier particles, these are preferably of a material which is physiologically tolerable and which is not biodegradable, at least in the environments it will experience on the way to and at the body cavity being imaged.
  • compositions of the invention may, include components other than the dispersion enhancing agent and the magnetic particles.
  • conventional pharmaceutical formulation aids such as wetting agents, disintegrants, binders, fillers, dyes, osmoactive agents, flavoring agents and liquid carrier media.
  • the compositions may also contain mucoadhesives, such as for example a polyacrylic acid or a derivative thereof, xanthan gum, etc.
  • compositions of the invention are particularly suited for use as MRI contrast media for imaging of the gastrointestinal tract and in particular for imaging the duodenum and the intestines.
  • the contrast medium may be administered orally or rectally or by orally or rectally inserted tubes.
  • the contrast media are also suitable for use in imaging other externally voided body cavities such as the bladder, uterus and vagina.
  • the present invention provides the use of a physiologically tolerable dispersion enhancing carrier for dispersing magnetic particles in a composition.
  • the composition is suitable for use in magnetic resonance imaging.
  • the present invention provides a method of generating a magnetic resonance image of a human or non-human, e.g. mammalian, subject in which method a contrast medium comprising magnetically responsive particles in a dispersion enhancing carrier is administered into an externally voided body cavity of the subject (e.g. the gastrointestinal tract) , wherein said dispersion enhancing carrier acts to increase the dispersion of the magnetically responsive particles following administration of said medium into the subject.
  • the present invention provides a packaged, substantially hydrated, ready-to-use diagnostic contrast agent comprising a plurality of magnetically responsive particles dispersed in a physiologically tolerable dispersion enhancing agent.
  • the dose of the contrast medium will generally be at least 500 mL for an adult human subject and more usually 600 to 1100 mL, especially 750 to 1000 -10-
  • the content of the magnetically responsive particles will depend on the particular particles used. However, the particles will generally be contained at a concentration of 0.01 to 10 g/litre, preferably 0.1 to 3 g/litre.
  • the dose may be taken in portions, e.g. for oral administration about 2/3 being ingested 20 minutes before imaging and the remainder being ingested immediately before the subject is placed within the magnet (or scanner) .
  • Avicel CL-611 contains microcrystalline cellulose and carboxymethylcellulose sodium.
  • the invention is further illustrated by the following non-limiting examples.
  • microcrystalline cellulose and carboxymethylcellulose sodium were added and dispersed with vigorous mixing and side scraper agitation. With continuous mixing xanthan gum was slowly added until it was wetted and completely dispersed. Temperature was maintained at not less than 70°C. The dispersion was then cooled to 25°C - 35°C with continued side scraper agitation.
  • FD&C Red No. 40 To approximately 25 g of purified water in a stainless steel or glass-lined manufacturing vessel, the FD&C Red No. 40, FD&C Yellow No. 6, and FD&C Blue No. 1 were added and dispersed.
  • the pH of the dispersion thus obtained was adjusted within the pH range of 4.2 - 4.3, using IN Hydrochloric Acid and/or IN Sodium Hydroxide and again mixed for not less than 10 minutes to ensure uniformity.
  • the dispersion viscosity was measured to ensure a viscosity of 395 cP or higher.
  • an additional 10% of the formula amount of Xanthan Gum was slowly added with continuous mixing for not less than 15 minutes.
  • the dispersion was then screened throught a 100 mesh stainless steel sieve, into a tared stainless steel or glass- lined mixing vessel.
  • a homogenous suspension of magnetically responsive particles was prepared by inversion mixing of the active ingredient (MSIO from Nycomed) for not less than 1 hour until it was confirmed that all solids were suspended.
  • a calculated amount of MSIO to achieve a total iron concentration of 150 mcgFe/mL was slowly added with stirring to the OMP carrier described in Example 1 hereinabove. Stirring continued for not less than 15 minutes.
  • the weight (volume) of the final suspension was determined and if necessary adjusted to the final weight (volume) (1 liter) with purified water. Slow mixing continued for not less than 10 minutes to ensure uniformity.
  • the final product was adjusted with IN Hydrochloric Acid and/or IN Sodium Hydroxide to a pH range of 4.2 - 4.3.
  • the active ingredient in the contrast media used in the examples is MSIO (supplied by Nycomed AS, Oslo, Norway) consisting of monodisperse 3-4 ⁇ m polymer particles coated with approxi ately 50 nm particles of iron ferrite. (Described in Norwegian Patents 142022; 143403; and 155316) .
  • the L-type formulations (LI, L2, L3) shown in Table 2 are the ready-to-use preparations of the invention described hereinabove.
  • the G-type formulations (Gl and G2) shown in Table 3 differ from the L-type in composition and, further, are prepared from a granular concentrate reconstituted with water just prior to administration.
  • the G-type preparation represents the prior art.
  • the animals -for in vivo studies were mongrel dogs anaesthetized with 2% SuritalTM I.V. (Thiamylal Sodium by Parke Davis) titrated to maintain light anaesthesia.
  • SuritalTM I.V. Thiamylal Sodium by Parke Davis
  • a nasogastric tube was inserted into the stomach of the animals and they were positioned in the MR scanner in the supine position.
  • In vitro MR imaging which was obtained using a Signa (GE Medical Systems , Milwaukee) superconducting magnet system operating at 1.5T, was performed on phantoms containing 20 mL of WIN 39996 samples immediately after manual shaking. A head coil and conventional 2DFT spin-warp technique were used . Multi-section axial acquisitions were obtained with a 24 cm field of view, 256x256 imaging matrix, 7 mm section thickness, and 3 mm intersecton gap . Pulse sequences used were Tl-weighted (TR/TE 300/15 msec, 1 excitation) , T2- weighted (2000/70, 1) , and proton density-weighted (2000/20, 1 ) .
  • Ratios less than 2.0 were considered to be "sufficiently black”, greater than 2.0 "insufficiently black”, and close to 2 "marginal”. This criterion was chosen based on preliminary results indicating that ratios above 2 tended to produce insufficient blackening along with image distortions. This criterion was supported by the results of the present studies Table 4.
  • contrast media of the invention having a viscosity of at least of ⁇ 25 cP produces excellent signal blackening without significant image artifacts.
  • in vivo LVL was found to be -25 cP
  • the in vitro LVL was found to be between -25 and -50 cP (Table 4) .
  • the exact reasons for the discrepancy between the in vivo and in vitro LVL values are unknown. It may be the result of in vivo peristaltic activity continuously mixing intraluminal contrast agent and preventing gravitational settling. It may also be the result of enhancement of signal blackening by intraluminal contrast/medium that was above and below the plane of image. It appears that the imaging quality of the contrast agent is dependent on the degree of dispersion of the magnetically susceptible iron ferrite in the formulation, and that a minimum viscosity is needed to insure such dispersion.
  • Formulations with viscosity lower than the LVL value are prone to gravitational settling, resulting in particle aggregation which in turn leads to uneven distribution of particle concentrations. Inhomogeneity in particle concentrations in turn causes insufficient signal blackening and magnetic susceptibility artifacts.
  • This example compares the imaging qualities of five different OMP formulations (See Tables 2 and 3) after these formulations had been exposed to various temperatures for various periods (Table 5) .
  • Formulation L2 was inferior to formulations LI and L3 because after one-week exposure to 70°C, poor signal blackening
  • Image artifacts image blurring
  • formulations LI and L3 were found to provide excellent signal blackening (See the comparative experiments above) they were further evaluated in vitro for performance after storage.
  • the results (Table 6) show that after exposure to room temperature for eight weeks both formulations provided excellent signal blackening (reflected by SI ratios smaller than 2) on all three pulse sequences with no image artifacts. After exposure to 70°C for one week followed by room temperature for seven weeks, both formulations also provided excellent signal blackening (SI ratios below or close to 2) on all three pulse sequences with no image artifacts.
  • the pre-ingestion gradient echo MR images showed intermediate signal intensity within the stomach .
  • the signal intensity within the stomach had decreased due to the presence of -28-
  • Pre-ingestion gradient echo MR images demonstrated moderate to high signal intensity in the lumen of the small bowel which was darkened by the presence of formulation within the lumen of the small bowel on the 60 minute post-ingestion image.
  • Multiple axial MR images were obtained from the mid-stomach to pelvic region both prior to and following ingestion of the formulation. Images at multiple time periods were acquired following ingestion.
  • the T ⁇ -weighted pre-ingestion MR images demonstrated intermediate signal within the stomach, small bowel, and regions of the large bowel.
  • the immediate post-ingestion T__-weighted images demonstrated distension and darkening of the stomach due to the presence of the formulation.
  • the formulation was seen distributed throughout segments of the small bowel with resultant darkening of the small bowel lumen.
  • the 60 minute post-ingestion T ⁇ -weighted MR images showed continued darkening of the stomach however, less distension of the stomach was noted. Further distribution and darkening of small bowel segments were noted in the 60 minute post-ingestion images.
  • the 60 minute post-ingestion images demonstrated occasional segments of large bowel with intermediate to dark signal intensity.
  • the pre-ingestion T ⁇ -weighted MR images of the lower abdomen and pelvis demonstrated intermediate signal within the lumen of the large bowel and sigmoid colon.
  • the three hour post- ingestion Ti-weighted images demonstrated darkening of the luminal contents of the large bowel, sigmoid colon and rectum.
  • the T 2 ⁇ weighted pre-ingestion MR images demonstrated intermediate signal within the stomach, small bowel and large bowel. This intermediate signal was mixed with areas of dark signal within the bowel lumen.
  • the immediate post-ingestion T 2 - weighted MR images showed darkening and distension of the stomach. In addition, segments of the small bowel demonstrated areas of darkening compared to the pre-ingestion images representing the presence of the contrast agent formulation.

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

Abstract

L'invention se rapporte à un véhicule de faible viscosité, sensiblement hydraté, utilisé pour disperser des particules magnétiquement sensibles. L'invention se rapporte également à des milieux de contraste utilisés pour visualiser, par résonance magnétique nucléaire, le système gastrointestinal en vue d'une administration orale ou rectale. Un procédé générant une image par résonance magnétique à l'aide de la composition de l'invention est également décrit.
EP95906454A 1994-01-28 1995-01-30 Formulation orale comprenant des particules magnetiques Withdrawn EP0741581A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US18851294A 1994-01-28 1994-01-28
US188512 1994-01-28
PCT/GB1995/000175 WO1995020405A1 (fr) 1994-01-28 1995-01-30 Formulation orale comprenant des particules magnetiques

Publications (1)

Publication Number Publication Date
EP0741581A1 true EP0741581A1 (fr) 1996-11-13

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Application Number Title Priority Date Filing Date
EP95906454A Withdrawn EP0741581A1 (fr) 1994-01-28 1995-01-30 Formulation orale comprenant des particules magnetiques

Country Status (7)

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EP (1) EP0741581A1 (fr)
JP (1) JPH09510698A (fr)
CN (1) CN1142191A (fr)
AU (1) AU1464595A (fr)
CA (1) CA2182213A1 (fr)
MX (1) MX9603001A (fr)
WO (1) WO1995020405A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2001074406A2 (fr) * 2000-03-31 2001-10-11 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The National Institutes Of Health Composition dendrimere sensible au magnetisme et son utilisation pour l'analyse a resonance magnetique
US7427391B2 (en) * 2001-11-21 2008-09-23 E-Z-Em, Inc. Formulations for use in medical and diagnostic procedures
BRPI0414438A (pt) * 2003-09-18 2006-11-14 Fmc Corp método para preparar uma dispersão estável de óxido de metal em água, e, composição
WO2008099331A1 (fr) * 2007-02-15 2008-08-21 Philips Intellectual Property & Standards Gmbh Dispositif pour une imagerie à particules magnétiques, procédé pour influencer et/ou détecter des particules magnétiques et particule magnétique
EP3833402A4 (fr) * 2018-08-09 2022-05-04 The Regents of the University of California Procédé et matériau pour acquérir des données d'imagerie par résonance magnétique
CN113069129B (zh) * 2021-02-26 2023-04-11 四川省肿瘤医院 一种18f-fdg pet/ct检查去除胃内伪影的方法

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US4615879A (en) * 1983-11-14 1986-10-07 Vanderbilt University Particulate NMR contrast agents for gastrointestinal application
PT81498B (pt) * 1984-11-23 1987-12-30 Schering Ag Processo para a preparacao de composicoes para diagnostico contendo particulas magneticas
GB8916780D0 (en) * 1989-07-21 1989-09-06 Nycomed As Compositions
GB8916782D0 (en) * 1989-07-21 1989-09-06 Nycomed As Compositions
DK0525199T4 (da) * 1991-01-19 2004-06-01 Meito Sangyo Kk Sammensætning indeholdende ultrafine partikler af magnetisk metaloxid
US5370901A (en) * 1991-02-15 1994-12-06 Bracco International B.V. Compositions for increasing the image contrast in diagnostic investigations of the digestive tract of patients

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Title
See references of WO9520405A1 *

Also Published As

Publication number Publication date
WO1995020405A1 (fr) 1995-08-03
CN1142191A (zh) 1997-02-05
JPH09510698A (ja) 1997-10-28
CA2182213A1 (fr) 1995-08-03
MX9603001A (es) 1997-06-28
AU1464595A (en) 1995-08-15

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