Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Patent
1995-05-04
1998-02-17
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
A61K 4904
Patent
active
057188840
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel contrast agents, more particularly to new gas-containing or gas-generating 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 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 as ultrasound contrast agents.
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.
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 stabilising gas bubbles for echocardiography and other ultrasonic studies, for example using emulsifiers, oils, thickeners or sugars.
It will be appreciated that for applications in echocardiography such bubble systems should preferably not exceed 8-10 microns in diameter in order to permit free passage through the capillary beds of the pulmonary system to the left atrium and ventricular cavity, with a view to facilitating ultrasonic visualisation of the left side of the heart and myocardium following intravenous injection of the contrast agent. To provide effective visualisation of the left side of the heart such bubble systems (which will hereinafter be referred to as "microbubbles") will clearly be required to exhibit adequate stability in vivo, preferably for more than one passage of circulation.
It will likewise be apparent that preformed microbubble contrast agent systems desirably exhibit good storage stability, for example in order to permit manufacture at a central location and distribution to and storage at hospitals etc. prior to use.
One area which has attracted a substantial volume of research is the manufacture of protein-encapsulated gas microbubbles for use as ultrasound contrast agents. As described in U.S. Pat. No. 4,718,433 and U.S. Pat. No. 4,774,958 such agents may, for example, be prepared by sonicating a viscous protein solution to generate a microbubble system and thermally or chemically denaturing at least a part of the encapsulating protein to stabilise the microbubbles. Thermal denaturation may be effected by application of heat or simply by heat generated during sonication. Chemical denaturation is effected by reaction of the protein with formaldehyde or glutaraldehyde, e.g. in an aqueous medium at pH 4.5. A preferred proteinaceous starting material is 5% human serum albumin (HSA); its use is said to encourage the formation of small microbubbles primarily having a diameter in the range 2-4 microns. Microspheres produced by this technique are said to be stable on storage for 48 hours or longer.
EP-A-0324938 describes a process for preparing an improved protein-encapsulated microbubble system of the above type. This process involves a two stage sonication procedure in which the sonicator horn is first immersed in the protein solution to generate a microbubble system and is then withdrawn to a position above but proximate to the surfac
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patent: 4452773 (1984-06-01), Molday
patent: 5284646 (1994-02-01), Menz et al.
patent: 5501863 (1996-03-01), Rossling et al.
Oestensen et al., Chemical Abstracts, vol. 116, No. 23, 8 Jun. 1992, abstract No. 231235m.
Foss Per Antonius
H.o slashed.gset Anders
Hvoslef Anne Marie
Johansen John Henrik
Klaveness Jo
Hartley Michael G.
Hollinden Gary E.
Nycomed Imaging AS
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