AU1969900A - Magnetic resonance tomography contrast agent - Google Patents
Magnetic resonance tomography contrast agent Download PDFInfo
- Publication number
- AU1969900A AU1969900A AU19699/00A AU1969900A AU1969900A AU 1969900 A AU1969900 A AU 1969900A AU 19699/00 A AU19699/00 A AU 19699/00A AU 1969900 A AU1969900 A AU 1969900A AU 1969900 A AU1969900 A AU 1969900A
- Authority
- AU
- Australia
- Prior art keywords
- kaolin
- stirring
- contrast agent
- mri contrast
- bentonite
- 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.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- 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
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Chemical & Material Sciences (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an MRT (magnetic resonance tomography) contrast agent with a viscosity of 500 to 2,500 cP, comprising a suspension of kaolin, optionally combined with bentonite in a citrate buffer, and to a method for producing MRT contrast agents of this type.
Description
PCT/EP99/09459 MRI contrast agent The invention relates to an MRI contrast agent which has a viscosity of from 500 to 2 500 cP and which 5 comprises a suspension of kaolin, where appropriate in conjunction with bentonite, in citrate buffer, and to a process for producing such MRI contrast agents. Magnetic resonance imaging (MRI) , also called nuclear spin tomography, is a medical imaging technique 10 in particular for tissues, especially soft tissues, in which, in contrast to conventional X-ray diagnosis or computed tomography, no ionizing radiation is employed. On the contrary, in magnetic resonance imaging there is measurement of the energy emitted from the body in the 15 form of electromagnetic waves on relaxation of the nuclear spin excited by a short high-frequency impulse under the influence of an externally applied strong magnetic field. Typical areas of use of magnetic resonance 20 imaging are especially disorders of nerve tissue such as the white matter of the brain, and the spinal cord, especially associated with multiple sclerosis, and damage to intervertebral disks, joints and muscles. In addition, magnetic resonance imaging is also 25 employed for abdominal diagnosis. In this latter connection, however, the fact that the quality and, in particular, the contrast of the resulting images is in some cases considerably influenced by the contents of the stomach and intestines, which may vary widely 30 between patients, represents a problem. In awareness of this problem, it was realized at an early date that it was possible to improve greatly the accuracy of visuali zation by using contrast agents for distinguishing the stomach and intestine from surrounding tissue. 35 Various types of contrast agents have been proposed for use in magnetic resonance imaging for abdominal diagnosis. These include, inter alia, paramagnetic and superparamagnetic contrast agents such -2 as, for example, iron(III) compounds such as iron(III) chloride or iron(III) ammonium citrate, gadolinium compounds such as gadolinium-DTPA, and manganese salts, which are employed where appropriate in solid particu 5 late form as suspensions to reduce their toxicity, and mineral oils and perfluorocarbon compounds. As a low-cost and non-toxic alternative to said MRI contrast agents, US patent 4,927,624 proposed the use of suspensions of clay minerals in water as MRI 10 contrast agents which can be administered orally or rectally for imaging of the gastrointestinal tract. Examples of clay minerals mentioned in this patent are kaolin, the montmorillonites, e.g. bentonite, hectorite, beidellite, sauconite and nontronite. 15 Especially on oral administration, the viscosity of the administered contrast agent suspension is of central importance for acceptance by the patient. Since the amounts of suspension to be taken in by the patient are considerable, it should have a sufficiently low 20 viscosity for oral intake by the patient to be tolerable. On the other hand, the viscosity must not be too low, because, otherwise, the coating, i.e. the wetting of the walls of the stomach and intestines, is insufficient, which would also impair the contrast of 25 the scan. During investigations in connection with the invention described herein, it has been found that a viscosity of such an MRI contrast agent suspension in the range from 500 to 2 500 cP is accepted well by the patient and also ensures an adequate coating. 30 At present, many different clay minerals such as kaolin and bentonite are commercially available in a large number of different qualities and, in some cases, also in different crystal forms. Simple suspension in water of commercially available clay minerals such as 35 bentonite in a concentration which is necessary inter alia for a sufficient coating, as described in US patent 4,927,624, usually leads to paste- or cement like preparations of very high viscosity, which are unacceptable for administration to patients. In 7 -3 addition, with high-viscosity preparations with a viscosity exceeding 2 500 cP, the time taken for passage through the gastrointestinal tract to the target site in the stomach and/or intestine is 5 distinctly lengthened. Depending on the viscosity, the time taken for the passage may increase from a normal duration of 30-45 min to 1.5 h or more, which is equally undesirable for the patient and the physician. It is known in the prior art to use lauryl 10 sulfate to reduce the viscosity of kaolin suspensions. However, such suspensions produce much foam, which may significantly impair the contrast of the MRI scan. The object on which the invention is based was accordingly to provide alternative MRI contrast agents 15 based on clay minerals and, in particular, on kaolin, which have a clay mineral concentration sufficient for a good coating and good contrast, also have sufficiently low viscosity for oral intake by a patient without excessive disinclination, additionally do not foam, 20 which always ensures good T 1 and T 2 contrast, and have good long-term stability. This object is achieved by the MRI contrast agents defined in the claims. Essential for achieving the object of the 25 invention is to adjust the desired viscosity with a suitable kaolin in the chosen concentration range. It has proved very particularly advantageous to use so-called kaolin light, which is explained in more detail hereinafter. It has also emerged that the use of 30 a citric acid/citrate buffer system, and thus adjust ment of the pH in the range 6-8, is particularly advantageous. The MRI contrast agent of the invention, which has a viscosity in the acceptable viscosity range from 35 500 to 2 500 cP, is characterized in that it comprises a suspension of 25-50% by weight of kaolin in 6-10 mmol/l citrate buffer, pH 6-8. A viscosity range which is usually preferred by ST patients is between 500 and 1 800 cP, and MRI contrast -4 agent suspensions of the invention which are felt to be particularly acceptable have a viscosity not exceeding 1 500 cP. The viscosities stated in the present documents were measured using a Brookfield DV II+ 5 viscometer with spindle 3, 3 x 3 rpm and 3 x 6 rpm (= 3 min at 3 rpm and 3 min at 6 rpm) at 20 0 C. The choice of the citrate buffer system with a molarity in the range 6-10 mmol/1 and a pH between 6 and 8 is essential to the invention. Comparative tests 10 with phosphate buffers of approximately the same molarity and with a pH between 6 and 8 afforded suspensions whose viscosity was too low (viscosity < 500 cP) and which did not provide an adequate coating or sufficient contrast either. In preferred embodiments, 15 the pH of the citrate buffer is between 6.5 and 7.5 and the citrate buffer concentration is between 7.5 and 8.2 mmol/l. The MRI contrast agent of the invention comprises 25-50 (28-50) % by weight of kaolin and, in 20 preferred embodiments, 25-40% by weight of kaolin. The coating and the contrast are both inadequate below 25% by weight of kaolin. The kaolin which can be employed for the MRI contrast agents of the invention must be carefully 25 selected. Kaolin light with a low swelling capacity is used in particular within the framework of the invention. However, the kaolin light must pass the test of swelling power of the European and German Pharmacopoieia, in which the mixture resulting from 30 trituration of 2 g of kaolin light with 2 ml of water must not flow. The kaolin light entirely complies with the definition of "light kaolin" in the British Pharmacopoieia, HMSO Publications Center, London, 1993, and thus has pharmaceutical quality for internal use. 35 A kaolin which is particularly suitable for the MRI contrast agents of the invention is marketed under the name "kaolin light" by Richard Baker Harrison Ltd., Ilford, United Kingdom. This kaolin has an original particle size between 7 and 9 gm and can be employed -5 without any pretreatment for producing the MRI contrast agents of the invention. In a very particularly preferred embodiment, the MRI contrast agent of the invention additionally 5 comprises bentonite, and in particular in a concentra tion of 4-5% by weight. When bentonite is added in the aforementioned concentration, the MRI contrast agent of the invention preferably contains kaolin light in a concentration of 25-42% by weight. Above 42-43% by 10 weight of kaolin light in such an MRI contrast agent there may often be a distinct increase in viscosity, depending on the clay mineral qualities used. It is necessary, quite analogously to the kaolin constituent, for the bentonite to be carefully 15 chosen for use in the MRI contrast agent of the inven tion. Besides pharmaceutical quality for internal use, the bentonite must have only a very low swelling capacity, i.e. a swelling capacity in the range from approximately 16 to a maximum of 20 ml per 2 g. 20 A particularly suitable special bentonite quality is marketed by Stid-Chemie AG, Moosburg, Germany under the name EX75. This bentonite has a swelling power of 16 to 20 ml per 2 g, which is distinctly less than the value of 22 ml per 2 g described by the 25 pharmacopeias. Its original particle size is 12-17 gm. This bentonite can be employed without any pretreatment for producing the MRI contrast agents of the invention. In another preferred embodiment of the MRI contrast agent of the invention, the kaolin light or 30 the kaolin light and the bentonite or the bentonite alone are employed with an average particle size of 2.5-5 gm. For this purpose it is possible to micronize suitable kaolin and bentonite qualities where appro priate to an average particle size in the stated 35 particle size range before the production of the contrast agent. If kaolin light and bentonite with an average particle size of less than about 2 gm are employed, a large increase in the viscosity is to be found, so that such kaolin and bentonite starting -6 minerals are unsuitable for the MRI contrast agents of the invention. The micronization to a particle size in the stated particle size range of 2.5-5 gm leads to a 5 slight but nevertheless usually desired reduction in viscosity, to an improvement in the contrast because of the increase in the particle surface area and, in addition, to an improvement in the taste, because the sandy taste of the MRI contrast agents is alleviated. 10 In addition, the MRI contrast agents of the invention may comprise conventional additives and excipients such as flavorings, e.g. cyclamate, saccharin, sorbitol, fruit flavors, or preservatives such as parabens, in the amounts normally employed. 15 These additives and excipients have no effect at all on the flow characteristics and the viscosity of the MRI contrast agents of the invention. The MRI contrast agents of the invention all have various advantages, namely good drinkability 20 because the viscosity is sufficiently low, good T 1 and
T
2 contrast, good coating properties and avoidance of foam formation, and an excellent long-term stability of the suspension of at least 2 to 3 years. They are suitable both for oral and rectal administration. 25 In addition, the invention relates to processes for producing the MRI contrast agents of the invention. One process for producing an MRI contrast agent of the invention based on kaolin alone comprises the following steps: 30 - dissolving citric acid and a citrate salt and, where appropriate, other excipients in 75-85% of the required water with stirring to form a citrate buffered solution with a pH between 6 and 8, - adding the kaolin light in portions with stirring, 35 in each case followed by stirring for several minutes to suspend the kaolin light, - adding the remaining water, - finally stirring for several hours. A process for producing an MRI contrast agent -7 -7 which additionally comprises bentonite is characterized by the following steps: - dissolving citric acid and a citrate salt and, where appropriate, other excipients in 75-85% of the 5 required water with stirring to form a citrate buffered solution with a pH between 6 and 8, - adding 70-85% of the kaolin light in portions with stirring, in each case followed by stirring for several minutes to suspend the kaolin light, 10 - mixing the remaining 30-15% of the kaolin light with the bentonite in the dry state to give a homogeneous mixture, - adding the homogeneous mixture in portions to the previously prepared kaolin suspension with stirring, 15 in each case followed by stirring for several minutes to suspend the homogeneous mixture, - adding the remaining water, - finally stirring for several hours. The sequence of the addition of the components 20 set forth in the production process described above for a kaolin- and bentonite-containing MRI contrast agent may be important, depending on the kaolin light and bentonite used, for achieving the desired viscosity of the MRI contrast agent. 25 The suspension steps may, where appropriate, be carried out at elevated temperature, e.g. between 50 and 60 0 C. The stirring after each individual addition of kaolin light or homogeneous mixture preferably takes 30 place for at least 10 min, and in particular for 10 to 15 min. The final stirring step preferably takes place for at least 2 h. The stirring speed must in this connection be controlled individually where appropriate in order to 35 avoid an irreversible increase in viscosity because the stirring speed is too high. In the present connection, a stirring speed of 350 ± 50 rpm has proved suitable for suspending the kaolin light and/or the homogeneous mixture, and for the final stirring step.
-8 The kaolin light and/or the bentonite may, where appropriate, be subjected beforehand to a micronization treatment to give a smaller particle size. As explained above, a micronization leads inter 5 alia to an increase in the particle surface area of the clay minerals and, because of this, to a better contrast of the MRI image. In a preferred embodiment of the process of the invention, the MRI contrast agent is additionally 10 stored after the final stirring, whereby its viscosity can be reduced significantly in some cases, e.g. from values above 2 500 cP to values distinctly below 2 500 cP. This storage, which can take place at room temperature or slightly elevated temperature and with 15 normal humidity, usually takes place for at least 24 h. The reduction in viscosity is normally complete within two to five days. The invention is illustrated in detail below by means of an example which describes the production of 20 two MRI contrast agents of the invention. Example The production process described hereinafter was used to produce two MRI contrast agents with the 25 following composition: MRI contrast agent MRI contrast agent with 40% kaolin with 30% kaolin Kaolin light 432.0 g 323.5 g Bentonite EX75 49.5 g 49.5 g Methylparaben 0.54 g 0.54 g Propylparaben 0.243 g 0.243 g Sodium citrate dihydrate 0.189 g 0.189 g Citric acid 1.08 g 1.08 g Sodium saccharin 0.54 g 0.54 g Banana flavor 3.24 g 3.24 g Water 592.668 g 701.168 g Density 1.369 g/cm 3 1.234 g/cm 3 The pH of the MRI contrast agents was between 6.5 and 7.5. Before starting the production process, the 5 kaolin, "kaolin light" from Richard Baker Harrison Ltd., Ilford, United Kingdom, was micronized to an average particle size of about 3.6 ym, and the bentonite, bentonite EX75 from Sd-Chemie AG, Moosburg, Germany, was micronized to an average particle size of 10 about 4.2 gm. Approximately 80% of the required amount of sterilized, preferably deionized, sterilized and depyrogenated water are introduced into a container and heated to 550C. The methyl 4 -hydroxybenzoate (methyl 15 paraben), the propyl 4 -hydroxybenzoate (propylparaben), the sodium citrate dihydrate, the sodium saccharin as dihydrate and the citric acid, anhydrous, are then added. The mixture is stirred at 350 ± 50 rpm until all the substances have completely dissolved. 20 80% of the total amount of kaolin are added in portions and with stirring (350 ± 50 rpm) to the solution. Each individual addition is followed by stirring (350 ± 50 rpm) for about 10 min. The remaining amount of kaolin and the total 25 amount of bentonite are homogeneously mixed in the dry state in a separate container and then added, likewise in portions, with stirring (350 50 rpm) to the mixture. Each individual addition is followed by stirring (350 ± 50 rpm) for about 10 min. 30 After addition of the banana flavor, the remaining amount of water is added to make up to the specified weight of the mixture. This mixture is finally stirred further (350 50 rpm) for at least 2 h until a homogeneous and lump 35 free suspension is present. The mixture is then stored for up to three days, whereby the viscosity of the MRI contrast agents falls to distinctly below 2 500 cP.
Claims (4)
1. MRI contrast agent with a viscosity of from 500 to 2 500 cP, comprising a suspension of 25-50% by 5 weight of kaolin in 6-10 mmol/l citrate buffer, pH 6-8.
2. MRI contrast agent according to claim 1, characterized in that the kaolin is suspended in a 7.5
8.2 mmol citrate buffer, pH 6-8. 3. MRI contrast agent according to claim 1 or 10 claim 2, characterized in that the pH of the citrate buffer is between 6.5 and 7.5. 4. MRI contrast agent according to any of claims 1 to 3, characterized in that it contains
25-40% by weight of kaolin. 15 5. MRI contrast agent according to any of the preceding claims, characterized in that it additionally contains bentonite. 6. MRI contrast agent according to claim 5, characterized in that it contains 25-40% by weight of 20 kaolin and 4-5% by weight of bentonite. 7. MRI contrast agent according to any of the preceding claims, characterized in that the kaolin, and where appropriate also the bentonite, have a particle size of 2.5-5 pm. 25 8. Process for producing an MRI contrast agent according to any of claims 1 to 4, characterized in that it comprises the following steps: - dissolving citric acid and a citrate salt and, where appropriate, other excipients in 75-85% of the 30 required water with stirring to form a citrate buffered solution with a pH between 6 and 8, - adding the kaolin in portions with stirring, in each case followed by stirring for several minutes to suspend the kaolin, 35 - adding the remaining water, - finally stirring for several hours. 9. Process for producing an MRI contrast agent according to claim 5 or 6, characterized in that it comprises the following steps: - 11 - dissolving citric acid and a citrate salt and, where appropriate, other excipients in 75-85% of the required water with stirring to form a citrate buffered solution with a pH between 6 and 8, 5 - adding 70-85% of the kaolin in portions with stirring, in each case followed by stirring for several minutes to suspend the kaolin, - mixing the remaining 30-15% of the kaolin with the bentonite in the dry state to give a homogeneous 10 mixture, - adding the homogeneous mixture in portions to the previously prepared kaolin suspension with stirring, in each case followed by stirring for several minutes to suspend the homogeneous mixture, 15 - adding the remaining water, - finally stirring for several hours. 10. Process according to either of claims 8 or 9, characterized in that the stirring to suspend the kaolin light and/or the homogeneous mixture takes place 20 at 350 ± 50 rpm. 11. Process according to claim 10, characterized in that the stirring after each individual addition of kaolin or homogeneous mixture takes place for 10 to 15 min. 25 12. Process according to any of claims 8 to 11, characterized in that the final stirring for several hours takes place at 350 ± 50 rpm for at least 2 h. 13. Process according to any of claims 8 to 12, characterized in that the kaolin and, where appropriate, 30 the bentonite are subjected beforehand to a microniza tion treatment to give a smaller particle size. 14. Process according to any of claims 8 to 13, characterized in that the MRI contrast agent is additionally stored after the final stirring. 35 15. Process according to claim 14, characterized in that the storage takes place for at least 24 h. 16. Process according to claim 15, characterized in that the storage takes place for 2 to 5 days.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19857345A DE19857345A1 (en) | 1998-12-11 | 1998-12-11 | MRI contrast media |
DE19857345 | 1998-12-11 | ||
PCT/EP1999/009459 WO2000035489A1 (en) | 1998-12-11 | 1999-12-03 | Magnetic resonance tomography contrast agent |
Publications (2)
Publication Number | Publication Date |
---|---|
AU1969900A true AU1969900A (en) | 2000-07-03 |
AU752874B2 AU752874B2 (en) | 2002-10-03 |
Family
ID=7890842
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU19699/00A Ceased AU752874B2 (en) | 1998-12-11 | 1999-12-03 | Magnetic resonance tomography contrast agent |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1137443B1 (en) |
JP (1) | JP2002532439A (en) |
KR (1) | KR20010081078A (en) |
AT (1) | ATE234119T1 (en) |
AU (1) | AU752874B2 (en) |
BG (1) | BG105545A (en) |
CA (1) | CA2353871A1 (en) |
CZ (1) | CZ20011522A3 (en) |
DE (2) | DE19857345A1 (en) |
EE (1) | EE200100291A (en) |
HR (1) | HRP20010307A2 (en) |
HU (1) | HUP0104429A2 (en) |
IL (1) | IL142916A0 (en) |
NO (1) | NO20012860L (en) |
PL (1) | PL348197A1 (en) |
SK (1) | SK6542001A3 (en) |
TR (1) | TR200101641T2 (en) |
WO (1) | WO2000035489A1 (en) |
ZA (1) | ZA200104691B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2621952C1 (en) * | 2016-04-01 | 2017-06-08 | Федеральное государственное бюджетное учреждение "Научно-исследовательский институт онкологии имени Н.Н. Петрова" Министерства здравоохранения Российской Федерации | Method for computer-tomographic study of stomach |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4615879A (en) * | 1983-11-14 | 1986-10-07 | Vanderbilt University | Particulate NMR contrast agents for gastrointestinal application |
US4927624A (en) * | 1987-11-19 | 1990-05-22 | The University Of Rochester | Clay magnetic resonance contrast agents for gastrointestinal comsumption or introduction |
IL101492A0 (en) * | 1992-04-03 | 1992-12-30 | Shalom Levy | Anti-skin rash preparation |
US5424142A (en) * | 1993-05-20 | 1995-06-13 | E-Z-Em, Inc. | Negative contrast agents for magnetic resonance imaging comprising barium sulfate and a clay |
-
1998
- 1998-12-11 DE DE19857345A patent/DE19857345A1/en not_active Withdrawn
-
1999
- 1999-12-03 PL PL99348197A patent/PL348197A1/en unknown
- 1999-12-03 AT AT99963379T patent/ATE234119T1/en not_active IP Right Cessation
- 1999-12-03 IL IL14291699A patent/IL142916A0/en unknown
- 1999-12-03 HU HU0104429A patent/HUP0104429A2/en unknown
- 1999-12-03 AU AU19699/00A patent/AU752874B2/en not_active Ceased
- 1999-12-03 JP JP2000587808A patent/JP2002532439A/en active Pending
- 1999-12-03 DE DE59904570T patent/DE59904570D1/en not_active Expired - Fee Related
- 1999-12-03 CA CA002353871A patent/CA2353871A1/en not_active Abandoned
- 1999-12-03 TR TR2001/01641T patent/TR200101641T2/en unknown
- 1999-12-03 EP EP99963379A patent/EP1137443B1/en not_active Expired - Lifetime
- 1999-12-03 WO PCT/EP1999/009459 patent/WO2000035489A1/en not_active Application Discontinuation
- 1999-12-03 SK SK654-2001A patent/SK6542001A3/en unknown
- 1999-12-03 CZ CZ20011522A patent/CZ20011522A3/en unknown
- 1999-12-03 EE EEP200100291A patent/EE200100291A/en unknown
- 1999-12-03 KR KR1020017007192A patent/KR20010081078A/en not_active Application Discontinuation
-
2001
- 2001-05-02 HR HR20010307A patent/HRP20010307A2/en not_active Application Discontinuation
- 2001-05-29 BG BG105545A patent/BG105545A/en unknown
- 2001-06-08 ZA ZA200104691A patent/ZA200104691B/en unknown
- 2001-06-08 NO NO20012860A patent/NO20012860L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
NO20012860L (en) | 2001-08-01 |
HRP20010307A2 (en) | 2002-06-30 |
KR20010081078A (en) | 2001-08-25 |
ATE234119T1 (en) | 2003-03-15 |
AU752874B2 (en) | 2002-10-03 |
CA2353871A1 (en) | 2000-06-22 |
JP2002532439A (en) | 2002-10-02 |
WO2000035489A1 (en) | 2000-06-22 |
EP1137443B1 (en) | 2003-03-12 |
DE59904570D1 (en) | 2003-04-17 |
EP1137443A1 (en) | 2001-10-04 |
EE200100291A (en) | 2002-08-15 |
PL348197A1 (en) | 2002-05-06 |
IL142916A0 (en) | 2002-04-21 |
SK6542001A3 (en) | 2001-11-06 |
BG105545A (en) | 2001-12-29 |
DE19857345A1 (en) | 2000-06-15 |
ZA200104691B (en) | 2002-07-31 |
CZ20011522A3 (en) | 2001-09-12 |
NO20012860D0 (en) | 2001-06-08 |
TR200101641T2 (en) | 2001-10-22 |
HUP0104429A2 (en) | 2002-03-28 |
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