Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Patent
1995-05-25
1997-12-09
Kight, John
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
424 945, 424 94, 424 91, A61K 4900, G01N 3100, G01N 3348
Patent
active
056957424
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention refers to injectable aqueous formulations containing radiopaque contrast agents useful for X-ray imaging of human or animal body.
One of the preferred aspects of this invention specially deals with injectable aqueous solutions of mixtures of non-ionic and water-soluble iodinated aromatic compounds preferably constituted by: triiodo-substituted--from now on referred to as monomers or monomeric, together, each one at least triiodo substituted--from now on referred to as dimers or dimeric.
Beyond the compounds of type a) and b), this invention also includes other possible mixtures comprising opacifying derivatives with molecular structures of three or more polyiodinated aromatic nuclei.
BACKGROUND OF THE INVENTION
Formulations containing X-ray contrast agents (CM) have long been used to enhance the image contrast of human and animal cavities in X-ray examinations. Among the past radiopaque products which have been investigated, it is worth mentioning derivatives of elements such as Ba, Bi, Ta. But afterwards it was found that certain classes of water-soluble brominated and/or iodinated organic compounds are far greatly useful as contrast agents for the vascular system.
2,4,6-triiodo-benzene derivatives are commonly used as iodinated aromatic X-ray-opaque compounds since their remaining positions 1,3,5 are substituted by suitable organic substituents to reach a sufficient watersolubility, a iodine concentration of 300-450 g/L or more, and a good tolerability.
A good solubility, for example, can be obtained through the introduction on the aromatic nucleus of carboxylic functions which can be salified. These compounds are the so-called ionic iodinated contrast agents. A typical example is the diatrizoic acid (3,5-diacetamido-2,4,6-triiodobenzoic acid) and its meglumine salt, particularly used in angiography. It is highly water-soluble and has a relatively low molecular weight. These features allow injectable solutions with a high iodine content and a low viscosity, essential for a good vascular X-ray imaging.
Unfortunately, ionic contrast media solutions show a high toxicity. Furthermore they are hyperosmotic to plasma (the presence of ions considerably increases osmolality and therefore the osmotic pressure when compared to other physiological fluids), causing possible painful effects in patients after injection. Other drawbacks related to ionic contrast agents rely on the presence of massive counter-cation concentrations (Na.sup.+, Ca2.sup.+ and others): the consequence is an increase in the osmotic load, that's to say the amount of administered osmoles, pro dose. It is known that a high osmotic load causes a toxicity increase. Moreover cardiovascular effects may occur as a result of the increase in plasma volume.
To overcome this problem, non-ionic iodinated agents have been developed, where the substituents on the aromatic nucleus have no ionizable functions. In this case a sufficient water-solubility is granted by highly hydrophilic neutral groups in positions 1,3,5 of the aromatic nucleus. Non-limiting examples of compounds belonging to this last mentioned class of opacifying agents are given by "iopamidol" (BRACCO), or hthalamide, and "iomeprol" (BRACCO) or N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-5-(N-methyl-hydroxyacetyl amino)-isophthalamide.
Disregarding the improvements obtained on non-ionic aromatic triiodo-derivatives, there was still the need of decreasing the osmolality in the corresponding opacifying injectable formulations in order to obtain an osmotic pressure more similar to blood. Osmolality is the common term used to relate molality to osmotic pressure. In fact, highly concentrated solutions of different iododerivatives, can show osmolality values that are too high to be tolerable by the human body. By way of an example, a 1 osmol/kg. H.sub.2 O (=1000 mosmol/kg) solution can generate a 25.5-atm or 2.58-MPa osmotic pressure, hence a physiologically unacceptable value. A way to decrease osmolality, by keeping the total iodine content of aqueous so
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De Haen Christoph
Felder Ernst
Dibra S.p.A.
Jones Dameron
Kight John
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