Contrast agents

Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent

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Details

424 951, A61K 3800, A61K 4900

Patent

active

055364900

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP92/00715 filed Mar. 28, 1992.
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-capsulated 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.
U.S. Pat. No. 4,774,958 discloses the use of microbubble dispersions stabilised by encapsulation in denatured protein, e.g. human serum albumin. 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.
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.
We have now found that particularly effective ultrasonic contrast agents may be obtained by encapsulating gas bubbles or gas generating systems with polymers containing chemically linked surface active, i.e. amphiphilic, moieties. Thus the surface active properties of the amphiphilic groups stabilise the microbubble system by reducing surface tension at the gas-liquid interfaces, e.g. by forming monolayers or one or more bilayers (alternatively known by the terms micelles, vesicles, liposomes and niosomes) at said interfaces, while the linking of the groups through the polymer system generates further stability. Flexibility of the encapsulating materials also enhances the image density afforded by such contrast agents. For simplicity the terms "vesicle" is used herein to denote all such microbubble structures prior to or after cross-linking or polymerisation. It should be noted that under some conditions irregularly shaped structures may be formed, e.g. microtubules which may join with or even entrap spherical structures.
Thus according to one aspect of the present invention there are provided contrast agents for use in diagnostic ultrasound studies comprising microbubbles of gas or a gas precursor encapsulated by non-proteinaceous crosslinked or polymerised amphiphilic moieties.
The term "crosslinked" is used herein to denote that the amphiphilic moieties are linked to each other to form a polymeric structure which may incorporate one or more polymer systems (including copolymers)

REFERENCES:
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patent: 5362478 (1994-11-01), Desai et al.
Juliano et al., "Interactions of polymerized phospholipid vesicles w/cells. Update, processing, and toxicity in macrophages." Biochim. Biophys. ACTA 812(1985) 42-48.
Juliano, et al., STN File Server, File Biosis, & Biological Abstract, vol. 79, 1985.

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