Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1996-10-04
1998-03-10
Kight, John
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 94, 424 942, 424 945, 424 9455, 534 15, 534 16, 540 3, 540120, 558270, 558275, A61K 4900, C07F 500, C07C 6996
Patent
active
057258406
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB95/00065, filed Jan. 13, 1995 published as WO95/19186 Jul. 20, 1995.
The present invention relates to contrast agents for medical X-ray and/or magnetic resonance imaging, and to their preparation and use.
It has been proposed to improve the detection of lesions in the liver, suprarenal glands and spleen by the use of contrast agents which accumulate in these organs. A number of substances have been suggested but there is no such product on the market at the present time and each of the contrast agents so far proposed has some disadvantages.
Since the reticuloendothelial system of the liver and spleen is well known to trap particles by phagocytosis, contrast agents in particulate form are particularly well adapted for visualisation of these organs.
Emulsions of iodinated oils have been proposed in this context, particularly iodinated ethyl esters of poppy seed oil. (Vermess, M. et al., Radiology, 137 (1980) 217). However, these substances have proved to be unduly toxic.
Another possibility for X-ray diagnosis is to use liposomes containing water soluble iodinated contrast agents. (Havron, A., et al., Radiology, 140 (1981) 507). However, since only a limited amount of iodine can be incorporated in each liposome, it is necessary to administer relatively large amounts of lipids in order to attain adequate contrast enhancement. This tends to cause emboli in the lung capillaries. Furthermore, liposomes have been found to be relatively unstable on storage. (Shulkin, P. M., et al., J. Microencapsul., 1 (1984) 73).
Submicron thorium dioxide particles have been used for liver visualisation and have shown effective enhancement of contrast in clinical testing but their use has been discontinued because of the extremely lengthy retention of the particles in the liver. This, in combination with the inherent radioactivity of thorium, has led to serious adverse side effects, including neoplasm and fibrosis. (Thomas, S. F., Radiology, 78 (1962) 435).
It has also been proposed to use particles comprising the ethyl ester of the water soluble X-ray contrast agent iodipamide (Violante, M. R., et al., Invest. Radiol., 2 (1984) 133). However, ethyl esters are not sufficiently metabolically labile and thus would be expected to be retained in the liver for a considerable period. Both this ester and an iodinated ethyl ester of poppy seed oil gave an increase in lipid vacuoles in the hepatocytes after intravenous administration. (Vermess et al., Radiology, 137 (1980) 217 and Violante, M. R., Invest. Radiol., 2 (1984) 133). Such morphological changes indicate an adverse effect on the hepatocytes.
For magnetic resonance imaging a number of paramagnetic and ferromagnetic/superparamagentic particles are proposed for visualisation of the liver and spleen (Watson, A. D. et al., chapter 14 in Stark, D. D. et al., Magnetic Resonance Imaging, 2nd edition Mosby Year Book 1992 and Fahlvik, A. K., J. Magnetic Resonance Imaging, 3, (1993), 187). However, these particulate products have proved to be unduly toxic.
Another possibility for magnetic resonance imaging of the liver in particular is to use water soluble paramagnetic chelates such as the manganese (2+) chelate of N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid (MnDPDP), the gadolinium (3+) chelate GdBOPTA where the chelator BOPTA has a diethylene triamine pentaacetic acid (DTPA) structure in which one of the N-carboxymethyl groups is replaced by a 2-benzyloxy-1-carboxyethyl group, or the gadolinium (3+) chelate GdEOB-DTPA where the chelator EOB-DTPA means ethoxybenzyl-DTPA (de Haen, C. et al., J. Magnetic Resonance Imaging, 3 (1993) 179).
Liposomes containing water soluble paramagnetic chelates have been proposed as contrast media for magnetic resonance imaging of the liver (Unger, E. C., J. Magnetic Resonance Imaging 3 (1993) 195). However, liposomes have, as earlier pointed out, proven to be relatively unstable on storage (Shulkin, P. M. et al., J. Microencapsul 1 (1984) 73).
The proposed liver contrast agents for magnetic resonance
REFERENCES:
patent: 3793350 (1974-02-01), Crabbe 260397.45
Iida et al., Journal of Organic Chemistry, 47, 1982, 2978-2981.
Longino et al., Investigative Radiology, vol. 18, pp. 275-278 (1983).
Aasen Arne J.o slashed.rgen
Klaveness Jo
Rise Frode
Varadarajan John
Kelley Lara C.
Kight John
Nycomed Imaging AS
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