Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Patent
1994-02-09
1997-03-04
Dees, Jos e G.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
424 95, A61K 4900
Patent
active
056076614
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/01477 filed Jul. 3, 1992.
This invention relate to contrast agents of use in diagnostic ultrasonic 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 bubbles 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 bubbles 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 longer lived gas microbubble systems for use in echocardiography and other ultrasonic studies.
One technique which has been proposed, for example in U.S. Pat. No. 4,681,119, U.S. Pat. No. 4,442,843 and U.S. Pat. No. 4,657,756, comprises the injection of a suspension of a particulate solid (typically a saccharide such as galactose) having a plurality of gas-filled voids and preferably also a plurality of nuclei for microbubble formation.
The present invention is based on our finding that microparticulate X-ray contrast agents may be administered in similar manner to provide substantial enhancement of contrast in ultrasound studies such as echocardiography. While we do not wish to be bound by theoretical considerations, it would appear that the particularly high density which is characteristic of conventional X-ray contrast agents serves to enhance the density differential between the generated microbubbles and their surroundings, thereby improving the echogenicity of the system.
This use of X-ray contrast agents in suspension to generate microbubble systems effective as ultrasound contrast agents may be contrasted with the previously proposed use of sonicated solutions of X-ray contrast agents such as meglumine diatrizoate as preformed microbubble systems and with previous proposals (e.g. as described in WO 90/07491) to use simple suspensions of particles of insoluble X-ray contrast agents to enhance ultrasound images by virtue of reflection of ultrasound by the particles themselves.
Thus according to one aspect of the present invention we provide X-ray contrast agents in microparticulate form adapted for administration as a microbubble-generating suspension in an appropriate liquid carrier medium (e.g. sterile, pyrogen-free water for injection, or physiologically saline), thereby acting as an ultrasound contrast agent.
X-ray contrast agents may thus, for example, be presented in accordance with the invention in the form of a pack comprising an appropriate amount of microparticulate X-ray contrast agent, and advantageously also a separate volume of liquid carrier, together with instructions for preparing an intravenously administrable suspension of the microparticulate X-ray contrast agent in the carrier liquid.
According to a further embodiment of the invention there is provided a method of diagnosis in a human or animal subject by ultrasonic imaging wherein the contrast of the ultrasound image is enhanced by intravenous administration of a microbubble-generating suspension of a microparticulate X-ray contrast agent in an appropriate liquid carrier medium. A preferred method of diagnosis according to this embodiment of the invention is echocardiography.
The microparticulate X-ray contrast agents are advantageously presented in the form of aggregates, for example having an aggregate size of 20-125 microm
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patent: 2680133 (1954-06-01), Wallingford
patent: 5205290 (1993-04-01), Unger
patent: 5233995 (1993-08-01), Yudelson et al.
patent: 5354549 (1994-10-01), Klaveness et al.
Becher et al.; STN File Server, File Medline, AN=89333475, & Am. J. Cardiol., (1 Aug. 1989); 64(5), 374-7.
Berg Arne
Klaveness Jo
Strande Per
Stubberud Lars
Cebulak Mary C.
Dees Jos e G.
Nycomed Imaging AS
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