Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Molecular bilayer structure
Patent
1994-03-21
1994-12-06
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Molecular bilayer structure
424 9, 12866202, 549 65, 549229, 558270, 558275, 558276, A61K 4900, A61K 4904
Patent
active
053708610
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to contrast agents for medical X-ray and ultrasound imaging, and to their preparation and use.
It has been proposed to improve the detection of lesions in the liver 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 unduly toxic.
Another possibility is to use liposomes containing water soluble iodinated contrast agents. (Havron A. et al, Radiology, 140 (1981)5071. 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 storing (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. Indeed, 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.
Acyloxyalkyl esters of carboxylic acids containing a tri-iodophenyl group are known as contrast agents from GB-A-1363847, U.S. Pat. No. 4,018,783 and GB-A-2157283. In U.S. Pat. No. 4,018,783 the compounds are primarily suggested for X-ray imaging of the bronchial system, while in GB-A-2157283 the most preferred use is in a liposome carrier in lymphography
We have now found that particularly advantageous contrast agents for the visualisation of the liver and spleen comprise particulate lipophilic iodine-containing carbonate esters which are metabolically labile to form water-soluble substances which are substantially non-toxic and are not retained in the target organs.
According to the present invention we provide metabolically labile water-insoluble iodinated esters of the formula (I): ##STR1## in which R.sup.1 is a substituted or unsubstituted C.sub.1-20 aliphatic, C.sub.7-20 -araliphatic or C.sub.6-20 aryl group or a C.sub.1-20 heterocyclic group having one or more hetero atoms selected from O, S and N; group, C.sub.6-10 aryl group or C.sub.7-20 araliphatic group; or different from R.sup.1, C.sub.1-4 alkylene group,
the molecule containing at least one iodine atom and being metabolisable to products which are soluble in body fluids and are physiologically acceptable.
Where the group R.sup.3 is not joined to R.sup.2 the metabolic products will be R.sup.1 COOH, R.sup.2 CHO, R.sup.3 OH and carbon dioxide. Where R.sup.3 and R.sup.2 together form an alkylene group, the products will be R.sup.1 COOH and HO(R.sup.3.R2)CHO and carbon dioxide.
Aliphatic groups may be str
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Chemical Abstracts Registry Handbook (1965-1971) Registry Numbers 12700-00-4 through 17799-99-4, p. 5556R.
Wiegert, Chemical Abstracts, vol. 84 (1976) No. 84: 89851 h.
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Klaveness Jo
Strande Per
Nycomed Imaging AS
Ramsuer Robert W.
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