Dry microparticles for use as a contrast agent

Details Dry microparticles for use as a contrast agent Dry microparticles for use as a contrast agent

1999-10-14

2001-08-14

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C424S009320, C424S009520, C424S009500, C424S489000

Reexamination Certificate

active

06274120

ABSTRACT:

This invention relates to novel contrast agents, more particularly to new gas-containing and gas-generating contrast agents of use in diagnostic imaging, and to methods for their preparation and use.
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.
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, or by entraining or encapsulating the gas or a precursor therefore in a variety of systems, e.g. as porous gas-containing microparticles or as encapsulated gas microbubbles.
Previous proposals relating to microbubble-containing ultrasound contrast agents have invariably required the use of a polymeric encapsulating coating for the microbubbles. Thus, for example, WO-A-8002365, which in principle suggests use of microbubbles having a coalescence resistant encapsulating membrane comprising non-toxic and non-antigenic organic molecules, in practice discloses only the use of gelatin as the encapsulating material. It has been found that microbubbles so encapsulated do not exhibit adequate stability at the dimensions preferred for use in echocardiography (1-10 &mgr;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 &mgr;m but still do not permit efficient visualisation of the left heart and myocardium. The use of such protein-derived agents may also create problems with regard to potential allergenic reactions.
EP-A-0327490 and WO-A-8906978 disclose, inter alia, ultrasonic contrast agents comprising microparticulate amylose or a synthetic biodegradable polymer containing a gas or volatile fluid (i.e. having a boiling point below 60° C.) in free or bonded form. Representative synthetic biodegradable polymers include polyesters of hydroxy carbonic acids, polyalkyl cyanoacrylates, polyamino acids, polyamides, polyacrylated saccharides and polyorthoesters.
Similar biodegradable microparticulate polymers, based on polymerised aldehydes, are described in EP-A-0441468, while systems based on microparticulate poly (amino acid)—poly (cyclic imide) derivatives are described in EP-A-0458079, U.S. Pat. No. 5,137,928, U.S. Pat. No. 5,190,982, U.S. Pat. No. 5,205,287 and U.S. Pat. No. 5,229,469.
EP-A-0458745 discloses air or gas-filled microballoons in which the encapsulating material is a deformable and resilient interfacially deposited polymer which is preferably biodegradable, examples including polysaccharides, polyamino acids, polylactides, polyglycolides, lactide/lactone copolymers, polypeptides, proteins, polyorthoesters, polydioxanone, poly-&bgr;-aminoketones, polyphosphazenes, polyanhydrides and poly (alkyl cyanoacrylates). The microballoons are normally prepared by emulsion techniques leading to deposition of the polymer around droplets of a volatile liquid which is subsequently evaporated. Such techniques generally involve the use of surfactants, for example lecithins, fatty acids or esters thereof with polyoxyalkylene compounds such as polyoxyethylene glycol or polyoxypropylene glycol, in order to stabilise the emulsion.
It is generally acknowledged that polymer-based contrast agents should desirably be biodegradable in order to facilitate their ultimate elimination from or absorption by the test subject. In many instances it has therefore been proposed to use polymers such as polyesters, polyanhydrides, polycarbonates, polyamides and polyurethanes which are biodegradable as a result of the susceptibility of ester, amide or urethane groups therein to enzymic hydrolysis in vivo.
In WO-A-9317718 there are described polymer-based contrast agents which are designed to exhibit high and controllable levels of biodegradability in vivo by virtue of the presence in the polymer of methylene diester units of formula (I)
&Brketopenst;(O)
m
—CO—O—C(R
1
R
2
)—O—CO—(O)
n
&Brketclosest;  (I)
(where R
1
and R
2
each represent a hydrogen atom or a carbon-attached monovalent organic group or R
1
and R
2
together form a carbon-attached divalent organic group and m and n, which may be the same or different, are each zero or 1). Such units are particularly rapidly degraded by common esterase enzymes but are relatively stable in the absence of enzymes.
In all the above-described encapsulated microbubble contrast agents the material encapsulating the microbubbles consists essentially of polymer, although minor quantities of other materials may be present. Thus, for example, EP-A-0458745 suggests that additives such as fats, waxes, high molecular weight hydrocarbons, phospholipids and plasticisers may be incorporated into the polymer wall, e.g. in amounts of up to 20% by weight. Clearly, however, it has hitherto been thought necessary to employ polymeric encapsulating material, e.g. in order to achieve sufficient structural integrity so as to impart adequate stability to the contrast agent. An isolated exception is WO-A-9401140, which discloses micro-gas bubble-containing echographic contrast agents prepared by lyophilising aqueous emulsions containing a lipid-soluble or water-insoluble builder such as cholesterol; these contrast agents are, however, also required to contain a substantial proportion of an apolar liquid such as petroleum ether.
We have now most surprisingly found that effective contrast agents comprising encapsulated microbubbles may be prepared using a wide range of non-polymeric wall-forming materials to encapsulate the gas or a precursor therefor. It will be appreciated that such contrast agents may exhibit significant advantages over polymer-based contrast agents, in particular that they may be easier and more economical to prepare and easier to characterise; they may also be more readily eliminable from the bodies of subjects to whom they are administered, for example by virtue of the smaller size and/or enhanced biodegradability of the non-polymeric molecules. The selection of materials which are endogeneous or are biodegradable to endogenous substances may also be advantageous.
Thus according to one aspect of the present invention there is provided a microparticulate contrast agent comprising gas or a gas precursor encapsulated by a non-polymeric and non-polymerisable wall-forming material.
The term “non-polymeric” as used herein denotes that the wall-forming materials do not contain multiple repeating units joined head-to-tail, as in polymers, and are not obtained by polymerisation techniques. The wall-forming materials will thus most co

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