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WO1997030736A2 - Milieu de contraste - Google Patents

Milieu de contraste Download PDF

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Publication number
WO1997030736A2
WO1997030736A2 PCT/GB1997/000473 GB9700473W WO9730736A2 WO 1997030736 A2 WO1997030736 A2 WO 1997030736A2 GB 9700473 W GB9700473 W GB 9700473W WO 9730736 A2 WO9730736 A2 WO 9730736A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
modifier
osmotic
viscosity
viscosity modifier
Prior art date
Application number
PCT/GB1997/000473
Other languages
English (en)
Other versions
WO1997030736A3 (fr
Inventor
Natarajan Rajagopalan
Kevin Darryl Ostrander
Evan Gustow
Brian Doty
Phillip Harnish
Original Assignee
Nycomed Imaging A/S
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 A/S filed Critical Nycomed Imaging A/S
Priority to EP97905227A priority Critical patent/EP0881916A2/fr
Priority to BR9710946-0A priority patent/BR9710946A/pt
Priority to JP9529894A priority patent/JP2000504742A/ja
Priority to AU18852/97A priority patent/AU1885297A/en
Publication of WO1997030736A2 publication Critical patent/WO1997030736A2/fr
Publication of WO1997030736A3 publication Critical patent/WO1997030736A3/fr
Priority to NO983828A priority patent/NO983828L/no

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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
    • A61K49/04—X-ray contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0404—X-ray contrast preparations containing barium sulfate
    • 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
    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • 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

  • the invention relates to contrast media, in particular contrast media containing contrast agents, preferably orally administrable particulate contrast agents, for administration into the gastrointestinal tract, and to the use of such contrast media in methods of diagnostic imaging, especially X-ray, CT, magnetic resonance (MR) or ultrasound investigations of the colon.
  • diagnostic imaging especially X-ray, CT, magnetic resonance (MR) or ultrasound investigations of the colon.
  • contrast media for enhancing contrast in imaging of the gastrointestinal (GI) tract is well established in several imaging modalities, such as X- ray, CT, ultrasound and MR imaging for example.
  • the contrast medium may be administered either orally or rectally, the administration route generally depending on the section of the GI tract of interest to the physician.
  • Contrast enhanced imaging of the lower portion of the GI tract is generally effected with either volume rendering (in which the contrast medium fills the lumen of the tract) or surface rendering (in which the contrast medium simply coats the mucosa and the tract may be insufflated with air or another non-toxic gas) .
  • contrast medium is administered by the oral route however, surface rendering of the colon is frequently unsatisfactory with coating being patchy and non-uniform.
  • the procedure of administering the current barium formulations is also tied to the fluoroscopic portion of the examination.
  • fluoroscopic examinations involve higher radiation exposures for both patients and for the technical staff.
  • a formulation with improved colonic mucosal coating characteristics could serve to reduce fluoroscopic exposure during examinations.
  • the invention provides an aqueous diagnostic composition suitable for oral administration for colonic imaging, said composition comprising a diagnostically effective amount of a contrast agent, eg. an X-ray, CT, MR, ultrasound or radionuclide-containing agent preferably a heavy metal or iodine containing X-ray contrast agent, and especially preferably a particulate agent, together with an amount of an osmotic modifier (eg. a polyol or polyalkyleneglycol) sufficient to prevent caking of the composition in the GI tract and an amount of an organic mucoadhesive viscosity modifier sufficient to cause substantially uniform coating of colonic mucosa by the composition.
  • an osmotic modifier eg. a polyol or polyalkyleneglycol
  • an organic mucoadhesive viscosity modifier sufficient to cause substantially uniform coating of colonic mucosa by the composition.
  • the invention also provides a diagnostic composition
  • a diagnostic composition comprising a diagnostically effective amount of a contrast agent together with a viscosity modifier and an osmotic modifier, said modifiers together being present at a weight ratio relative to said agent of at least 1:20, said viscosity modifier being selected from the group consisting of polyvinylpyrrolidone, natural gums, polysaccharides and polysaccharide derivatives, and said osmotic modifier being selected from the group consisting of C 3 -polyhydric alkanols, polyalkyleneoxides and polyalkyleneoxide derivatives.
  • compositions in accordance with the invention are those having a viscosity in the range of from 2 to 2000 cPs and an osmolality in the range of from 50 to 500 mOsm .
  • the invention also provides an improved method of imaging a human or non-human, preferably mammalian, animal subject, which involves administering a contrast medium into the gastrointestinal tract of the subject and generating an image of at least part of said tract, the improvement comprising administering as said contrast medium a composition according to the invention.
  • the invention provides a process for the preparation of a diagnostic composition, said process comprising admixing a contrast agent together with a viscosity modifier and an osmotic modifier as defined above, in a weight ratio of modifiers to contrast agent of at least 1:20.
  • the invention provides the use of a viscosity modifier and an osmotic modifier for the manufacture of a diagnostic composition according to the invention for use in a method of diagnosis involving imaging of the gastrointestinal tract .
  • compositions of the invention may preferably be in a low-viscosity liquid form and especially a ready-to-use form, eg. a storage stable form possibly requiring some shaking but not requiring dilution before use.
  • Such compositions advantageously have viscosities below 500 cP, preferably below 200 cP at ambient temperature (21°C) and contain the contrast agent at concentrations of 5 to 25%, preferably 10 to 20% by weight, for x-ray imaging at concentrations of 0.05 to 10% for CT imaging and at concentrations of 0.001 to 0.5% for MR imaging.
  • the invention also provides an aqueous pharmaceutical composition suitable for oral administration for drug delivery to the lower GI tract of a patient, said composition comprising a therapeutic agent (eg.
  • Figures 1 and 2 show X-ray images of the GI tract in the dog pre and post oral administration of the formulation of Example 1;
  • Figures 3, 4, 5 and 6 show X-ray images of the GI tract in the dog after oral administration of the formulation of Example 1 and, by way of comparison, of the commercial barium preparation (50% Liquid Polibar (EZM) ) and the commercial iodinated contrast media Gastrografin and Omnipaque (90 mgl/mL) ;
  • Figures 2 and 7 show X-ray images of the GI tract in the dog after oral and rectal administration respectively of the formulation of Example 1;
  • Figures 2 and 8 show X-ray images of the GI tract in the dog after oral administration of the formulation of Example 1 and of an equivalent coloured and flavoured formulation.
  • Figures 9 and 10 show CT images of the dog after oral administration of the formulation of Example 11.
  • Figure 11 shows MR images of the dog after oral administration of the formulation of Example 12.
  • the contrast agent in the diagnostic composition of the invention may be any material capable of enhancing image contrast in a diagnostic imaging modality, eg. X-ray, CT, ultrasound, MR, electrical impedance tomography, magnetotomography, SPECT, scintigraphy, etc.
  • the invention is however particularly suited to compositions containing particulate contrast agents or emulsions, eg. inorganic, organic or organometallic particles or, less preferably, molecular aggregates or liposomes. These particulate agents will conveniently be substantially insoluble, or at most poorly soluble, in the composition and in gastric fluid.
  • the contrast agent is an inorganic heavy metal compound, such as barium sulphate or a poorly soluble or essentially water insoluble iodinated organic compound, for example an iodinated compound as discussed in US-A- 5330739, US-A-5318768, US-A-5310537, US-A-5308607, US-A- 5312616, US-A-5316755, US-A-5260049, US-A-5326553 , US-A- 5310538, US-A-5260478, US-A-5318767 and US-A-5264610.
  • inorganic heavy metal compound such as barium sulphate or a poorly soluble or essentially water insoluble iodinated organic compound, for example an iodinated compound as discussed in US-A- 5330739, US-A-5318768, US-A-5310537, US-A-5308607, US-A- 5312616, US-A-5316755, US-A-5260049, US
  • the contrast agent is preferably an inorganic ferromagnetic, ferrimagnetic, superparamagnetic or paramagnetic material optionally provided with a coating or matrix material, eg. a gastric juice resistant polymeric coating such as a silane or polystyrene.
  • a coating or matrix material eg. a gastric juice resistant polymeric coating such as a silane or polystyrene.
  • Particles of the type present in Nycomed' s ABDOSCAN product or Advanced Magnetics' Biomag M4200 product may thus be used.
  • particles of gadolinium oxalate or another relatively insoluble paramagnetic compound may be used.
  • any echogenic material may be used as a contrast agent and for the composition according to the invention these may, for example, be particles of greater or lesser density than gastric fluid, eg.
  • inorganic particulates eg. barium sulphate
  • gas filled synthetic polymer capsules eg. inorganic particulates (eg. barium sulphate) or gas filled synthetic polymer capsules.
  • the contrast agent must obviously contain an appropriate radionuclide, eg in a radionuclide metal ion chelate complex, or a radionuclide containing organic or inorganic material.
  • the contrast agent is an inorganic particulate, and especially preferably a barium compound, in particular barium sulphate.
  • a barium compound in particular barium sulphate.
  • Oral administration of barium sulphate compositions according to the invention has resulted in generation of excellent X-ray images of the lower GI tract and of the colon in particular.
  • the particle or droplet size is not critical but preferably lies in the range 1 nm to 100 ⁇ m, especially 5 nm to 10 ⁇ m, particularly 10 nm to 5 ⁇ m.
  • Such particles or droplets can be prepared by milling or precipitation or emulsification for example.
  • the particle or droplet size distribution be narrow and preferably substantially monodisperse.
  • the contrast agent concentration in the compositions of the invention [where these are not concentrates for dilution with water (or another appropriate, preferably aqueous, vehicle) prior to administration] will be selected to be appropriate for the particular contrast agent and imaging modality but will preferably be in the range 0.001 to 95% w/v, preferably 3 to 9C - w/v, particularly preferably 5 to 30% w/v and especially preferably 10 to 20% w/v. Too high a concentration of an X-ray contrast agent may make the GI tract too radio- opaque and not allow sufficient delineation of the tract. For X-ray imaging, contrast agent concentration will preferably be 10 to 20% w/v.
  • the viscosity modifier used according to the invention is preferably a natural gum (eg. guar gum or xanthan gum) , polyvinylpyrrolidone or a polysaccharide or polysaccharide derivative. Polysaccharides which are branched, or which carry mono or oligosaccharide side chains or ether derivatives of polysaccharides are preferred.
  • suitable materials include alginates, pectin, amylopectin, methylceUulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and microcrystalline cellulose/carboxymethyl cellulose; cellulosic ethers however are preferred.
  • the viscosity modifier will preferably be a natural gum or a polysaccharide having a molecular weight in the range 25 kD to 2MD.
  • Such cellulosic ether viscosity modifiers may be any soluble cellulose ether, for example C ⁇ _ 6 alkyl or substituted C h alky!, eg. hydroxyalkyl, alkoxyalkyl or carboxyalkyl, ether for example ethyl cellulose, methyl cellulose, propyl cellulose, hydroxyethyl cellulose, methylcarboxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose (and its salts with physiologically tolerable counterions such as alkali metals, eg. sodium) , etc.
  • suitable, commercially available cellulosic ethers include Methocel K4M, K50, K100LVP and E5, Phar acoat 615 and Avicel CL-611.
  • viscosity modifiers capable of producing a range of viscosities, eg. 2-2000 cP at 1.5% w/v in water at ambient temperature
  • the lower viscosity modifiers are particularly preferred, eg. ones capable of yielding viscosities as above in the range 2-100 cP, preferably 2 to 60 cP and especially 2-50 cP.
  • the viscosity and the viscosity modifier content should be kept as low as feasible within the ranges mentioned in order to maximize patient acceptance.
  • the viscosity modifier will generally be used at 0.1 to 50% w/v of the compositions in aqueous ready-to-use form, preferably 0.1 to 10% w/v more especially 1 to 2.5% w/v.
  • the osmotic modifier used according to the invention is preferably a C 3 -polyhydric alcohol (eg. propylene glycol or more preferably glycerine) or a polyalkylene oxide or polyalkylene oxide derivative, for example a polyalkylene glycol .
  • a C 3 -polyhydric alcohol eg. propylene glycol or more preferably glycerine
  • a polyalkylene oxide or polyalkylene oxide derivative for example a polyalkylene glycol .
  • Such polyalkyleneglycol osmotic modifiers may be homopolymers or co-polymers, eg a block copolymer.
  • the alkylene units contain 2 to 6, preferably 2, 3 or 4 carbons and may be the same or different.
  • this modifier may be a polyethyleneglycol (PEG) , polypropyleneglycol, a poloxamer or a poloxamine.
  • PEG polyethyleneglycol
  • polypropyleneglycol polypropyleneglycol
  • a poloxamer a poloxamine.
  • Such polyalkyleneglycols are available commercially in a wide range of molecular weights and preferably those used according to the invention have molecular weights of 150 to 200000 D, especially 200 to 10000 D, and particularly 200 to 4000 D.
  • polyalkyleneglycols examples include PEG types 200, 400, 600, 1450, 3350, 4000, 6000 200K, and 2M.
  • block copolymers examples include the pluronics and tetronics, eg pluronic F127 and F108 and tetronic 1508. The polyethylene glycols however are preferred.
  • the amount of osmotic modifier used is conveniently 0.1 to 50% w/v in the aqueous ready-to-use formulations, preferably 0.1 to 25% w/v (eg. 1 to 25% w/v) , more preferably 1 to 10% w/v, especially 2 to 8% w/v.
  • the quantity of osmotic modifier will generally be kept as low as feasible.
  • the osmotic modifier preferably contributes 5 to 500 mOsm, especially 10 to 300 mOsm, and particularly 15 to 150 mOsm, to the overall osmolarity of aqueous formulations according to the invention.
  • the overall weight ratio of the two modifiers to the contrast agent is, as stated above, at least 1:20. More preferably, particularly with oral barium sulphate compositions, the ratio will be at least 1:10, especially at least 1:5, particularly at least 1:3, and preferably less than 1:1.
  • the weight ratio of the osmotic modifer to the viscosity modifier is preferably in the range 1:2 to 10:1, especially 1:3 to 8:1, particularly 1:1 to 4:1.
  • the compositions according to the invention achieve good coating of the small bowel and effectively coat the colon, whether administered orally or rectally, and exhibit appropriate colonic residence times. Unlike existing barium sulphate products, they do not exhibit pooling or settling in the small or large intestines, they demonstrate transradiation properties (ie. the ability to allow visualization of multiple overlapping bowel loops) over wide regions, and they demonstrate good edge appearance. By consistently providing high quality mucosal coating the compositions reduce operator work load and interdependencies (ie.
  • compositions of the invention may conveniently be administered into the GI tract orally or rectally, in doses of 0.1 to 15 mL/kg bodyweight .
  • the compositions are especially suited for oral administration and for this route dosages of 1.5 to 15 mL/kg, especially 4 mL to 10 mL/kg, are preferred.
  • the volume of composition administered will depend on whether surface rendering or volume rendering is intended. In the former case a volume of 0.1 to 10 mL/kg may be sufficient whereas in the latter case a larger volume of 10 to 15 mL/kg may be required.
  • gas sufflation of the lower portion of the GI tract will generally be desirable.
  • image generation may be effected immediately or within a period of up to 60 minutes. If the composition is administered orally however enough time must be allowed post administration to permit the composition to pass to the desired portion of the gut. Generally, for colonic imaging of an adult human, this will be in the range of 1 to 12 hours.
  • the imaging technique used may be any of the known imaging modalities.
  • the compositions of the invention are particularly suitable for use in ultrasound and MR imaging, and especially in a wide range of X-ray imaging modalities (eg CT, flat-film, digital, fluoroscopy, spiral CT, virtual colonoscopy, etc) .
  • compositions of the invention may contain a liquid carrier medium (eg. water, juice or a water/alcohol mixture) or one or more of the other additives conventional in contrast media formulated for administration into the GI tract, eg. further viscosity or osmotic modifiers, and conventional pharmaceutical or veterinary formulation agents such as preservatives, wetting agents, disintegrants, binders, fillers, stabilizers, flavouring agents, colouring agents, buffers and pH adjusting agents.
  • a liquid carrier medium eg. water, juice or a water/alcohol mixture
  • conventional pharmaceutical or veterinary formulation agents such as preservatives, wetting agents, disintegrants, binders, fillers, stabilizers, flavouring agents, colouring agents, buffers and pH adjusting agents.
  • the contrast media compositions of the invention may be formulated in a physiologically tolerable aqueous carrier medium (eg. as a suspension, emulsion, solution or dispersion) ready for use or in concentrate form for dilution before use. Concentrates may be diluted, eg. with water, juice, etc. prior to administration. Alternatively, the contrast medium may be formulated in a dry form, eg. in powder, granule, pellet or tablet form for dispersion before use. Ready-to-use aqueous formulations may however be preferred.
  • a physiologically tolerable aqueous carrier medium eg. as a suspension, emulsion, solution or dispersion
  • Concentrates may be diluted, eg. with water, juice, etc. prior to administration.
  • the contrast medium may be formulated in a dry form, eg. in powder, granule, pellet or tablet form for dispersion before use. Ready-to-use aqueous formulations may however be preferred.
  • compositions of the invention may contain further (alternative) osmotic and viscosity modifiers.
  • Alternative viscosity modifiers include bentonite, dextrin, veegum, polyvinyl alcohol, carboxymethyl ⁇ cellulose sodium, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylceUulose and polyacrylic acids.
  • Alternative osmotic modifiers include polyethylene glycol, glycerin, propylene glycol, sorbitol, mannitol, alpha amino acids and ionic species, e.g. NaCl, citric acid etc.
  • Example 1 X-ray imaging with the above formulation administered orally to dogs demonstrated transport to the colon, complete and efficient coating of ascending, transverse and descending colon, transradiation with good edge appearance, (all of which enhance the diagnostic quality of the radiograph) without retention in the stomach or small bowel. No manipulation was required to obtain high quality images. Pre and post-contrast images appear as Figures 1 and 2 hereto.
  • the composition of Example 1 is preferably formulated containing color and flavoring agents, eg. FD&C yellow No. 6 Powder 0.015% w/v and Natural and Artificial Citrus Flavour No. 325070 0.5% w/v.
  • Example 1 A side-by-side comparison of the formulation of Example 1 with a 50% (the clinically optimal concentration) commercial barium sulfate suspension and two iodine containing formulations was performed in the canine model following oral administration. Representative of the images generated are Figures 3 (Example 1) , 4 (50% Liquid Polibar) , 5 (Gastrografin) and 6 (Omnipaque 90 mgl/mL) of the accompanying drawings. The X-ray images were compared for percent colon coating, uniformity, transradiation, edge appearance and mucosal coating of the ascending, transverse and descending colon. The results demonstrated that the performance of the formulation of Example 1 was far superior to that of the prior art, and that the formulation of Example 1 delivered high image quality more consistently and was the only product to meet the needs for diagnostic imaging of the colon via the oral route.
  • Example 1 The reproducibility of image quality and consistent colonic imaging of the formulation of Example 1 per oral and rectal routes were determined using a 20 dog reproducibility study in beagles. The study utilized an oral and rectal crossover design. The results of this study show that the formulation of Example 1 demonstrates highly reproducible, high quality colonic imaging per oral and rectal routes. The X-ray images were compared by three independent evaluators using the same grading criteria as described in Example 5. The results demonstrated excellent imaging and reproducibility for the formulation.
  • the colon was defined into six areas: proximal ascending, distal ascending, proximal transverse, distal transverse, proximal descending and distal descending.
  • Table 1 shows the duration of coating when all areas in the colon were coated, i.e. when all areas were scored as 100% by all three evaluators.
  • Example 8 The utility of oral and rectal administration in obtaining similar high quality colonic imaging was demonstrated in the study mentioned in Example 6 in which image quality, as evaluated by percent colon coating, uniformity, transradiation, edge appearance and mucosal coating of the ascending, transverse and descending colon, exhibited similar qualities. These qualities were consistent throughout the reproducibility study. An interesting observation was made with retrograde administration of the formulation, in which it performed well in coating the colon and displayed excellent image quality after 5-10 minutes post dosing. This image quality persisted over 60 minutes post rectal dosing.
  • Example 8
  • Example 1 A distinct advantage that was observed with the formulation of Example 1 over competitor products was the imaging window seen with oral and rectal administration. Diagnostic imaging persistence of 1-4 hours was observed. Coating of the colon occurred from 4 hours post dosing to at least 8 hours post dosing, in most cases, when the formulation of Example 1 was administered orally to canine dog models. Rectal administration demonstrated high quality imaging, similar to oral administration, over at least a 60 minute window (duration of study) . These are demonstrated in the images which appear as Figures 2 (5 hours post dose - oral administration) and 7 (30 minutes post dose - rectal administration) of the accompanying drawings.
  • Prototype suspensions were formulated containing flavour and colouring agents to enhance patient acceptance and palatability of the dosage form and compared with the formulation of Example 1 for image quality per oral administration. These imaging studies demonstrated that the addition of flavouring and colouring agents did not change the image quality of the formulation which appears to be independent of the flavour and colour used.
  • An exemplary formulation is set out below. Representatives of the images obtained are presented in Figures 2 (formulation of Example 1) and 8 (flavoured and coloured formulations) of the accompanying drawings.
  • Prototype formulation with flavour and colour are presented in Figures 2 (formulation of Example 1) and 8 (flavoured and coloured formulations) of the accompanying drawings.
  • This may be used as either an X-ray contrast agent or an ultrasound contrast agent.
  • Other ethogenic materials eg. gas-filled particulates or microballoons may be substituted for the barium sulphate.
  • CT imaging with the formulation of Example 11, administered orally to dogs demonstrated transport to the colon with complete and efficient coating with good edge delineation. Additionally, multiple loops of the small intestine demonstrated uniform and complete coating with good edge delineation (see Figures 9 and 10) .
  • the compositions are thus clearly useful for both CT and non-CT applications, eg. virtual colonoscopy.
  • Example 13 Magnetic resonance imaging using the formulation of Example 12 administered orally to dogs demonstrated efficient coating of the GI tract with good edge delineation (see Figure 11) .
  • Example 13
  • MethylceUulose NF (25 cP and 1500 cP) 2.0 mg/mL

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un milieu de contraste, capable de bien se déposer sur la partie inférieure du tube digestif, après une administration par voie orale. Le milieu comprend une quantité suffisante d'agent de contraste pour pouvoir effectuer les diagnostics requis, en combinaison avec un modificateur de viscosité et un modificateur osmotique, ces deux modificateurs étant présents tous deux en une proportion pondérale par rapport audit agent d'au moins 1:20.
PCT/GB1997/000473 1996-02-20 1997-02-20 Milieu de contraste WO1997030736A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP97905227A EP0881916A2 (fr) 1996-02-20 1997-02-20 Milieu de contraste
BR9710946-0A BR9710946A (pt) 1996-02-20 1997-02-20 Meio de contraste
JP9529894A JP2000504742A (ja) 1996-02-20 1997-02-20 コントラスト媒体
AU18852/97A AU1885297A (en) 1996-02-20 1997-03-20 Contrast medium
NO983828A NO983828L (no) 1996-02-20 1998-08-20 Kontrastmiddel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9603547.2 1996-02-20
GBGB9603547.2A GB9603547D0 (en) 1996-02-20 1996-02-20 Contrast media

Publications (2)

Publication Number Publication Date
WO1997030736A2 true WO1997030736A2 (fr) 1997-08-28
WO1997030736A3 WO1997030736A3 (fr) 1997-12-18

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EP (1) EP0881916A2 (fr)
JP (1) JP2000504742A (fr)
KR (1) KR19990087196A (fr)
CN (1) CN1215342A (fr)
AU (1) AU1885297A (fr)
BR (1) BR9710946A (fr)
CA (1) CA2247041A1 (fr)
GB (1) GB9603547D0 (fr)
HU (1) HUP9901323A2 (fr)
NO (1) NO983828L (fr)
WO (1) WO1997030736A2 (fr)

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WO2001069539A3 (fr) * 2000-03-10 2002-01-24 Mayo Foundation Colographie de colon non prepare
EP1138331A3 (fr) * 2000-03-07 2003-02-05 K.B.A.S. Pty Limited Marqueur de selles
US6928314B1 (en) 1998-01-23 2005-08-09 Mayo Foundation For Medical Education And Research System for two-dimensional and three-dimensional imaging of tubular structures in the human body
US7591998B2 (en) 2000-03-07 2009-09-22 Kevin Tait Stool marker
US8031921B2 (en) 2005-02-14 2011-10-04 Mayo Foundation For Medical Education And Research Electronic stool subtraction in CT colonography
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WO2015024025A1 (fr) 2013-08-16 2015-02-19 The Regents Of The University Of California Produit de contraste à base de silicium pour administration par voie entérale pour examen par scanner
US10111970B2 (en) 2015-09-30 2018-10-30 Duke University Contrast agents for magnetic resonance imaging
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US11033640B2 (en) 2013-03-15 2021-06-15 The Regents Of The University Of California Enteric CT contrast material based on low-z atoms
CN117503959A (zh) * 2023-08-30 2024-02-06 中国医科大学附属盛京医院 一种基于硅酸镁铝和微晶纤维素的即用液态型口服胃超声显影剂配方及制作方法
US12303572B2 (en) 2021-07-28 2025-05-20 Duke University Ascorbate formulations and methods of use as contrast agents

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JP3461750B2 (ja) 1999-03-04 2003-10-27 パナソニック コミュニケーションズ株式会社 通信装置、通信方法、および発信者情報の登録方法
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CA2247041A1 (fr) 1997-08-28
NO983828D0 (no) 1998-08-20
GB9603547D0 (en) 1996-04-17
AU1885297A (en) 1997-09-10
NO983828L (no) 1998-10-15
EP0881916A2 (fr) 1998-12-09
KR19990087196A (ko) 1999-12-15
HUP9901323A2 (hu) 1999-08-30
WO1997030736A3 (fr) 1997-12-18

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