WO1993010821A1 - Procede et formulations utilises pour ameliorer l'examen des cavites du corps humain - Google Patents

Procede et formulations utilises pour ameliorer l'examen des cavites du corps humain Download PDF

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Publication number
WO1993010821A1
WO1993010821A1 PCT/EP1992/002712 EP9202712W WO9310821A1 WO 1993010821 A1 WO1993010821 A1 WO 1993010821A1 EP 9202712 W EP9202712 W EP 9202712W WO 9310821 A1 WO9310821 A1 WO 9310821A1
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WIPO (PCT)
Prior art keywords
paramagnetic
formulations
formulations according
concentration
weighted sequences
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PCT/EP1992/002712
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English (en)
Inventor
Andrea Giovagnoni
Paola Ercolani
Christoph De Haen
Friedrick Cavagna
Original Assignee
Bracco S.P.A.
Dibra S.P.A.
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 Bracco S.P.A., Dibra S.P.A. filed Critical Bracco S.P.A.
Priority to EP92923789A priority Critical patent/EP0614376A1/fr
Publication of WO1993010821A1 publication Critical patent/WO1993010821A1/fr

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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

Definitions

  • This invention relates to a method and formula ⁇ tions useful for obtaining the in-vivo visualization of body cavities using Nuclear Magnetic Resonance (NMR) .
  • NMR Nuclear Magnetic Resonance
  • it relates to the use of solutions of positive paramagnetic contrast agents for NMR examina ⁇ tions of said cavities via proton-density and T_- weighted sequences, with the proviso that said parama ⁇ gnetic agents are kept in a well-defined concentration range.
  • GI gastro-intestinal
  • NMR magnetic resonance
  • T.-relaxing media if used with T.-weighted sequences, increase the lumen signal intensity of body cavities when compared to the nearby tissues. This causes a loss of differentiation capacity among the normal and the pathological (tumours or other) wall components, affecting and/or reducing the diagnostic efficacy of the method.
  • contrast media formula ⁇ tions containing paramagnetic substances which are usually used as T,-relaxing agents, increase the intra- lu en signal, without affecting the differentiation of normal and pathological wall constituents, when proton- density and/or T_-weighted sequences are used and on the condition that the concentration of said paramagne- tic agent is kept within a precise interval, specific to said agent and lower than that recommended for imaging, with T,-weighted sequences.
  • contrast media containing .- at least one paramagnetic species selected from a series of conventional T,-relaxing contrast media, at a suitable concentration and using NMR proton-density and/or T--weighted sequences. It has been found that images of tumours have an intermediate intensity between that of the organ wall under examina ⁇ tion and the liquid contained in the lumen.
  • neoplastic lesions can be clearly identified and the extent of wall penetration may be determined.
  • images obtained by proton- ensity sequences a good differential contrast among the lesion, the wall and the adjacent adipose tissue can be easily visualized.
  • the amount of paramagnetic species used in the formulation of the contrast medium should be enough to create and keep inside the lumen liquid, after the administration, a concentration of contrast agent suf ⁇ ficient to obtain a contrast/noise ratio of at least 2 between the lumen content and the GI tract or the bladder walls for T_-weighted sequences.
  • the contrast agent concentration in the lumen liquid should be kept preferably in a range in which the signal intensity .of the lumen content, in this case measured under proton-density-sequence conditions, does not exceed the signal intensity of fat by more than 20%.
  • This second type of image that is usually acquired with double echo sequences, can be obtained during the same diagnostic examination after a single administration of the contrast medium used for T_- weighted imaging.
  • Laniado did not recognize at all the general effect exerted by any paramagnetic species on the signal intensity of T ⁇ -weighted sequences.
  • concentration he considered indispensable is far higher than the one useful for obtaining the contrast effects subject of this invention.
  • This technique is essential for obtaining valuable images of the bladder and is preferred for the terminal intestine tract in order to assure the volume and the ideal con ⁇ centration of the contrast medium for the method of this invention.
  • a retrograde administra ⁇ tion requires an advantageously short preparation time.
  • any physiologically tolerable water-soluble substance containing at least one paramagnetic metal species is useful for the aim of the present invention, providing that it is used in a precise interval of concentra ⁇ tions, that is specific to it.
  • Particularly preferred species are, for instance, chelates of linear or cyclic aminopolycarboxylic acids or their derivatives, such as, for instance, amides, hydroxyamides and esters, with paramagnetic metal ions.
  • Preferred compounds are, for instance, the Gd complex of N,N-bis-(2-(bis (carboxymethyl)amino)ethyl)- glycine (Gd-DTPA), its corresponding amido or bisamido derivatives like Gd-DTPA-bismethylamide and Gd-DTPA- bismorpholide or its ethoxy-benzyl (EOB) derivatives like Gd-EOBDTPA, the Gd complex of 4-carboxy-5, 8 , 11- tris(carboxymethyl)-l-phenyl-2-oxa-5, 8, 11-triaazatride- can-13-oic acid (Gd-30PTA) and its salts and derivati ⁇ ves, the Gd complex of 1,4 , 7 , 10-tetraazacyclododecan- 1, 4 ,7 , 10-tetraacetic acid (Gd-DOTA) and its derivati- ves, the Gd complex of 1,4 , 7 , 10-tetraazacyclo
  • Equally preferred metal chelates are also those with phosphonates, phosphinates, sulphonates or analo ⁇ gous compounds: non-limiting examples are the Gd complex of diethyl-triamino-pentakis(methylenephospho- nate) (Gd-PMP) and the Mn complexes of ethylene- diamino-tetrakis(methylenephosphonate) (Mn-TP) or of ,N'-1,2-ethanediyl-bis-(N-( (3-hydroxy-2-methyl-5-
  • iron salts such as 5 Fe ⁇ -citrate or Fe -gluconate, or Fe l + ' chelates with aminopolycarboxylic acids containing at least one aryl ring, preferably two, such as the Fe 1 complex of N,N'-1,2-ethanediyl-bis-(2-(2-hydroxy-4-methylphe- nyl))-glycine [FE II:[ -EHPG].
  • ferrioxamine paramagnetic compounds like for .example ferrioxamine mesylate or manganese desferrioxamine mesylate.
  • Paramagnetic metal ions may be conveniently selec ⁇ ted from those of the metal elements having atomic 15 numbers of from 21 to 29, 42, and 44 and from 57 to 83, preferably from among iron, manganese, copper, chromium, nickel, gadolinium, holmium, europium, dy ⁇ sprosium, lanthanum, ytterbium, terbium, erbium and sa ⁇ marium. 20.
  • Preferred concentration ranges for paramagnetic contrast media in the formulations of this invention have been individually determined and they have shown to be far lower than the ranges preferred when these agents are used to obtain T,-weighted images (see 25 Laniado, and experimental examples from 1 to 6).
  • concentration ranges of the above-mentioned agents in the formulations object of the invention are between 0.01 and 0.8 - preferably between 0.02 and 0.4 - times the concentration which gives the highest water 0 signal with T.-weighted sequences with , the same compounds.
  • Examples 1 to 6 do not limit the invention and only •report concentration intervals obtained for some preferred contrast agents which were used to produce the formulations of the present invention. Applying the procedure disclosed in the given examples to any para ⁇ magnetic agent with the intention of determining the potentially useful ranges of concentration, should not present any major difficulty for skilled technicians.
  • concentration intervals useful for obtaining images using T 2 -weighted sequences for some of the preferred paramagnetic agents of this invention are herein reported:
  • Preferred formulations of this invention may also contain suitable additives, for instance, excipients which are useful for controlling the transit speed of the administered bolus, or for keeping the dilution of the formulation in the lumen fluid within the desired operation limits. Particularly desired are also additives useful for maintaining the homogeneity and the initial concentra ⁇ tion of the formulations after patient administration.
  • Xanthan gum may be, for instance, a useful agent influencing viscosity.
  • Other possible excipients useful for meeting the above mentioned criteria may be selected from among those usually used in pharmaceutical techniques. Non-limiting examples include: carrageenines, alginates, pectins, carboxy - methylcellulose, hydroxyethylcellul ⁇ se, polyvi ⁇ nylpyrrolidone, polyethylene glycol, barium sulphate, kaolin and bentonite,
  • the preferred concentration varies according to the type of excipient used and according to the administration route. In any case, the viscosity of formulations should be kept between 0 and 700 mPa " s.
  • the formulations of this invention may also contain other physiologically tolerable additives, which make them isotonic.
  • physiologically tolerable additives such as sodium chloride (NaCl),. potassium chloride (KC1) , sodium hydrogen carbonate (NaHCO-), sodium sulphate (Na 2 SO.) , alcoholic sugars such as glucose or mannitol and/or ionic or neutral iodinated organic compounds, usually known or used as X-ray contrast media, are useful for this purpose.
  • This invention is also aimed at obtaining a method for producing images of wall organic alterations (whether neoplastic or not) of the GI tract, the bladder and/or the cavities of the female reproductive apparatus.
  • This method foresees the oral or retrograde administration to patients of a suitable dose of a paramagnetic formulation according to the invention. Patients are submitted to NMR tomography following the most appropriate operating conditions, that is to say, for instance, double echo sequences, proton-density (SE
  • the concentration interval which may be used to obtain useful images using T 2 -weighted sequences ranges from about 0.01 mM to about 0.9 mM.
  • T 2 -weighted sequences corresponded to a concentration equal to 0.4 mM, while for T.-weighted sequences the maximum value was reached at a concentration of about 2 mM.
  • the concentration interval which may be used in T 2 -weighted sequences ranges from about 0.05 mM to about 0.8 mM.
  • the maximum enhancement of signal intensity for T 2 -weighted sequences corresponded to a concentration equal to 0.3 mM, while for T, -weighted sequences the maximum value was reached at a concentration of 1.3 mM.
  • the concentration interval which may be used in T 2 -weighted sequences ranges from about 0.04 mM to about 1 mM.
  • EXAMPLE 4 In-vitro experimental determination of the concentra ⁇ tion interval useful for obtaining NMR images, using T 2 -weighted sequences and Gd-HPD03A complex.
  • the maximum enhancement of signal intensity for T 2 -weighted sequences corresponded to a concentration equal to 0.3 mM, while for T..-weighted sequences the maximum value was reached at a concentration of 1.25 mM.
  • the concentration interval which may be used in T 2 -weighted sequences ranges from about 0.04 mM to about 0.9 mM.
  • the maximum enhancement of signal intensity for T_-weighted sequences corresponded to a concentration equal to 11.2 mM, -•while for T.-weighted sequences the maximum value was reached at a concentration of 112 mM.
  • the concentration interval which may be used in T 2 -weighted sequences ranges from about 1 mM to about 70 mM. " - EXAMPLE 6
  • the maximum increase in signal intensity for T 2 - weighted sequences corresponded to a concentration equal to 0.4 mM, while for T.-weighted sequences the maximum value was reached at a concentration of 3.1 mM.
  • the concentration interval which may be used in T 2 -weighted sequences ranges from about 0.05 mM to about 2.5 mM.
  • a 0.25-M Gd-BOPTA/dimeg aqueous solution was diluted with a saline solution in order to obtain a 0.125-mM solution (at which concentration the detected "in-vitro" signal intensity for T 2 ⁇ weighted sequences is at a maximum) .
  • contrast medium two male Sprague-Dawley rats, weighing 200 to 300 g, and fasted for 24 h, were used. Before administering the contrast medium, the animals were anaesthetized with 30 ml/kg of i.p. sodium pentobarbital.
  • Transverse images (T 2 -weighted) were taken before and 5, 15 and 30 min after the administration of contrast medium using a 2000/100/2 (TR/TE/NEX) spin echo sequence, a 2-mm slice, a 15.91-cm FOV, and a 128 x 256 matrix. After administering the contrast medium, a clear remarkable hyperintensity of the intestinal lumen when compared to the wall, was recorded in all cases.
  • T 2 -weighted images were taken before and after administering the contras t medium using 2000 / 90 ( TE/TE ) spin echo sequences , 40-cm FOV, 256 x 256 matrix.
  • Case A patient suffering from rectal adenocarcinoma
  • Case D patient affected by bladder papilloma
  • Fig. 5-a shows the relaxed bladder containing 25 the urine only.
  • the lesion contours are very blurred .
  • Fig. 5-b shows the bladder filled by the contrast medium.
  • the hyperintensity generated by this agent enables an excellent identification of papilloma 30. contours .
  • the arrows define the neoplasia limits and its wall penetration.
  • a small, otherwise hardly detectable polypous-shaped lesion (X) is also identified.

Abstract

Formulations utilisées dans l'imagerie diagnostique par résonance magnétique nucléaire (NMR) du tube digestif (GI), de la vessie et des cavités des organes de reproduction de la femme, à l'aide de séquences pondérées au T2, caractérisées en ce qu'elles contiennent des substances paramagnétiques hydrosolubles dont les concentrations sont de 0,01 à 0,8, de préférence de 0,02 à 0,4, fois supérieures à la concentration qui produit le signal de présence d'eau le plus intense lorsqu'on emploie des séquences pondérées au T1 avec les mêmes composés.
PCT/EP1992/002712 1991-11-29 1992-11-25 Procede et formulations utilises pour ameliorer l'examen des cavites du corps humain WO1993010821A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP92923789A EP0614376A1 (fr) 1991-11-29 1992-11-25 Procede et formulations utilises pour ameliorer l'examen des cavites du corps humain

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI913218A IT1252145B (it) 1991-11-29 1991-11-29 Metodo e formulazioni adatte a migliorare lo studio degli organi cavi nell'uomo
ITMI91A003218 1991-11-29

Publications (1)

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WO1993010821A1 true WO1993010821A1 (fr) 1993-06-10

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EP (1) EP0614376A1 (fr)
AU (1) AU2945492A (fr)
IT (1) IT1252145B (fr)
WO (1) WO1993010821A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0639270A1 (fr) * 1991-02-01 1995-02-22 UNGER, Evan C Agents de contraste phosphoryles utiles dans la resonance magnetique nucleaire (rmn) du tractus gastro-intestinal
WO1998011921A2 (fr) * 1996-09-23 1998-03-26 Nycomed Imaging As Procede
US5885549A (en) * 1991-02-01 1999-03-23 Imarx Pharmaceutical Corp. Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region
WO2001049326A1 (fr) * 1999-12-29 2001-07-12 Bracco Imaging S.P.A Utilisation d'agents de contraste dans la fabrication d'agents diagnostiques pour la visualisation de la lumiere intestinale
US9023780B2 (en) 2010-04-14 2015-05-05 Ecolab Usa Inc. Ferric hydroxycarboxylate as a builder

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0463644A2 (fr) * 1986-08-04 1992-01-02 Nycomed Salutar, Inc. Utilisation de complexes chelatés
EP0516198A2 (fr) * 1985-10-04 1992-12-02 Nycomed Imaging As Particules magnétiques-polymères

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0516198A2 (fr) * 1985-10-04 1992-12-02 Nycomed Imaging As Particules magnétiques-polymères
EP0463644A2 (fr) * 1986-08-04 1992-01-02 Nycomed Salutar, Inc. Utilisation de complexes chelatés

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
American journal of roentgenology, Volume 142, March 1984, R C Brasch et al, "Contrast-Enhanced NMR Imaging: Animal Studies Using Gadolinium-DTPA Complex" *
American journal of roentgenology, Volume 150, April 1988, M Laniado et al, "MR Imaging of the Gastrointestinal Tract: Value of Gd-DTPA" *
Radiol. diagn., Volume 30, 1989, S Kaminsky et al, "Gadolinium-DTPA als orales Kontrastmittel in der Magnetischen Resonanz-Tomographie" *
STN International, File CA, Chemical Abstracts, volume 101, no. 17, 22 October 1984, (Columbus, Ohio, US), Wolf, Gerald L et al: "The tissue proton T1 and T2 response to gadolinium DTPA injection in rabbits. A potential renal contrast agent for NMR imaging", abstract 147134j, & Invest.Radiol., 19(4), 324-8 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0639270A1 (fr) * 1991-02-01 1995-02-22 UNGER, Evan C Agents de contraste phosphoryles utiles dans la resonance magnetique nucleaire (rmn) du tractus gastro-intestinal
EP0639270A4 (fr) * 1991-02-01 1996-07-10 Evan C Unger Agents de contraste phosphoryles utiles dans la resonance magnetique nucleaire (rmn) du tractus gastro-intestinal.
US5885549A (en) * 1991-02-01 1999-03-23 Imarx Pharmaceutical Corp. Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region
WO1998011921A2 (fr) * 1996-09-23 1998-03-26 Nycomed Imaging As Procede
WO1998011921A3 (fr) * 1996-09-23 1998-08-13 Nycomed Imaging As Procede
WO2001049326A1 (fr) * 1999-12-29 2001-07-12 Bracco Imaging S.P.A Utilisation d'agents de contraste dans la fabrication d'agents diagnostiques pour la visualisation de la lumiere intestinale
JP2003519200A (ja) * 1999-12-29 2003-06-17 ブラッコ イメージング エッセ ピ ア 腸管腔の視覚化のための診断剤の製造における造影剤の使用
CN1302814C (zh) * 1999-12-29 2007-03-07 布雷克成像有限公司 造影剂在制备用于对肠腔造影的诊断试剂中的用途
JP4798919B2 (ja) * 1999-12-29 2011-10-19 ブラッコ イメージング エッセ ピ ア 腸管腔の視覚化のための診断剤の製造における造影剤の使用
US9023780B2 (en) 2010-04-14 2015-05-05 Ecolab Usa Inc. Ferric hydroxycarboxylate as a builder

Also Published As

Publication number Publication date
ITMI913218A1 (it) 1993-05-29
AU2945492A (en) 1993-06-28
ITMI913218A0 (it) 1991-11-29
IT1252145B (it) 1995-06-05
EP0614376A1 (fr) 1994-09-14

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