Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1994-12-09
1996-09-24
Robinson, Allen J.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 952, 424 951, A61K 4900
Patent
active
055588565
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/00027 filed Jan. 08, 1993.
This invention relates to novel contrast agents, more particularly to new microparticulate contrast agents of use in diagnostic imaging.
It is well known that ultrasonic imaging comprises a potentially valuable diagnostic tool, for example in studies of the vascular system, particularly in cardiography, and of tissue microvasculature. A variety of contrast agents has been proposed to enhance the acoustic images so obtained, including suspensions of solid particles, emulsified liquid droplets, gas microbubbles and encapsulated gases or liquids. It is generally accepted that low density contrast agents which are easily compressible are particularly efficient in terms of the acoustic backscatter they generate, and considerable interest has therefore been shown in the preparation of gas-containing and gas-generating systems.
Initial studies involving free gas microbubbles generated in vivo by intracardiac injection of physiologically acceptable substances have demonstrated the potential efficiency of such bubbles as contrast agents in echocardiography; such techniques are severely limited in practice, however, by the short lifetime of the free bubbles. Interest has accordingly been shown in methods of generating and/or stabilising gas microbubbles for echocardiography and other ultrasonic studies, for example using emulsifiers, oils, thickeners or sugars.
Techniques involving the use of sugars in ultrasound contrast agents are described in, for example, U.S. Pat. Nos. 4,681,119, 4,442,843 and 4,657,756, which disclose the use of particulate solids having a plurality of gas-filled voids and preferably also a plurality of nuclei for microbubble formation. EP-A-0123235 and EP-A-0122624 suggest ultrasound contrast agents consisting of surfactant-coated or surfactant-containing gas-containing microparticles which may include a variety of sugars. Where surfactant-containing microparticles are described, these are prepared simply by commingling the surfactant with the microparticulate materials, e.g. by trituration.
DE-A-3834705 proposes the use of suspensions containing microparticles of mixtures of at least one C.sub.10-20 fatty acid with at least one non-surface active substance, including sugars such as cyclodextrins, monosaccharides, disaccharides or trisaccharides, as well as other polyols and inorganic and organic salts; in practice only the use of galactose as the non-surface active material and only the use of saturated fatty acids are exemplified. The microparticulate materials are typically prepared by coprecipitating the fatty acid and non-surface active substance and comminuting the resulting product, e.g. using an air-jet mill.
One material of the type described in DE-A-3834705, SHU 508 (Levovist.RTM.), is described in the following publications: Schlief, R. et al., Circulation Supplement III (1990) 82, p. 28; Schartl, M. et al., Circulation Supplement III (1990) 82, p. 261; Fritzsch, T. et al., Invest. Radiol. (1990) 25 (Suppl), pp. 160-161; Schlief, R. et al., Echocardiography (1990) 7, pp. 61-64; Loughery, E. J. et al., Echocardioqraph (1990) 7, pp. 279-292; and Smith, M. D. et al., JACC (1989) 13, pp. 1622-1628.
Gas-containing contrast media are also known to be effective in magnetic resonance (MR) imaging, e.g. as susceptibility contrast agents which will act to reduce MR signal intensity. Oxygen-containing contrast media also represent potentially useful paramagnetic MR contrast agents.
Furthermore, in the field of X-ray imaging it has been observed that gases such as carbon dioxide may be used as negative oral contrast agents.
A general disadvantage of most of the existing gas-containing/gas-generating particulate contrast agents such as the sugar-based agents discussed above is their relative lack of stability in vivo. This is a particular problem in applications such as echocardiography, where there is a need for improved contrast agents combining sufficient stability and small microbubble size (typically less than about 10 .mu.m,
REFERENCES:
patent: 5141738 (1992-08-01), Rasor
Schlief et al., Invest. Radiol., 26, suppl. 1, pp. S-188-189 and discussions 198-200, 1991.
Klaveness Jo
Rongved Pal
Stubberud Lars
Cebulak Mary C.
Nycomed Imaging AS
Robinson Allen J.
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