Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Patent
1993-10-29
1996-06-25
Robinson, Allen J.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
A61K 4900
Patent
active
055297668
DESCRIPTION:
BRIEF SUMMARY
This application has been filed under 35 U.S.C. 371 from application PCT/EP92/00716.
This invention relates to novel contrast agents, more particularly to new gas-containing or gas-generating 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 stabilising gas bubbles for echocardiography and other ultrasonic studies, for example using emulsifiers, oils, thickeners or sugars.
WO 80/02365 discloses the use of gelatin encapsulated gas microbubbles for enhancing ultrasonic images. Such microbubbles do not, however, exhibit adequate stability at the dimensions preferred for use in echocardiography (1-10 .mu.m) in view of the extreme thinness of the encapsulating coating.
EP-A-0327490 discloses, inter alia, ultrasonic contrast agents comprising a microparticulate synthetic biodegradable polymer (e.g. a polyester of a hydroxy carbonic acid, a polyalkyl cyanoacrylate, a polyamino acid, a polyamide, a polyacrylated saccharide or a polyorthoester) containing a gas or volatile fluid (i.e. having a boiling point below 60.degree. C.) in free or bonded form. Emulsifiers may be employed as stabilisers in the preparation of such agents, but such emulsifiers do not chemically interact with the polymer.
U.S. Pat. No. 4,774,958 discloses the use of microbubble dispersions stabilised by encapsulation in denatured protein, e.g. human serum albumin (HSA). Such systems permit the production of microbubble systems having a size of e.g. 2-5 .mu.m but still do not permit efficient visualisation of the left heart and myocardium.
Other ultrasound contrast agents using proteins as encapsulating agents have been described in the literature, for example in EP 0359 246 (Molecular Biosystems), U.S. Pat. No. 4,832,941 (Max-Planck Gessellschaft), U.S. Pat. No. 4,844,882 (Molecular Biosystems), WO 84/02838 (Feinstein), U.S. Pat. No. 4,572,203 (Feinstein), EP 0077 752 (Schering), U.S. Pat. No. 4,747,610 (The Regents of the University of California), WO 80/02365 (Rasor), U.S. Pat. No. 4,774,958 (Feinstein), U.S. Pat. No. 4,718,433 (Feinstein), EP 0224 934 (Feinstein).
The only protein-based ultrasound contrast agent under commercial development consists of a suspension of gas-filled albumin, microbubbles Albunex.RTM., prepared by sonication of a solution of albumin.
Albumin based ultrasound contrast agents are described in the following publications:
Feinstein et al. in Circulation 78S, 565 (1988), Reisner et al. in Circulation 78S, 565 (1988), Dick et al. in Circulation 78S, 565 (1988), Armstrong et al. in Circulation 78S, 565 (1988), Desir et al. in Circulation 78S, 566 (1988), Heidenreich et al. in Circulation 78S, 566 (1988), Keller et al. in Circulation 78S, 567 (1988), Barnhart et al. in Contrast Media Research (1989), Silverman et al. in Circulation 80S, 369 (1989), Silverman et al. in Circulation 80S, 349 (1989), Segar et al. in Clin. Res. 37, 294 (1989), Heidenreich et al. in Circulation 80S, 370 (1989), Reiser et al. in Circulation 80S, 370 (1989), Heidenreich et al. in Circulat
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Klaveness Jo
Rongved Pal
Strande Per
Cebulak Mary C.
Nycomed Imaging AS
Robinson Allen J.
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