Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1997-10-28
2001-07-24
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C600S458000
Reexamination Certificate
active
06264917
ABSTRACT:
This invention relates to diagnostic and/or therapeutically active agents, more particularly to diagnostic and/or therapeutically active agents incorporating moieties which interact with or have affinity for sites and/or structures within the body so that diagnostic imaging and/or therapy of particular locations within the body may be enhanced. Of particular interest are diagnostic agents for use in ultrasound imaging, which are hereinafter referred to as targeted ultrasound contrast agents.
It is well known that ultrasound 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 or intravascular contrast agents.
The use of radioactive gases, e.g. radioactive isotopes of inert gases such as xenon, has also been proposed in scintigraphy, for example for blood pool imaging.
Targeted ultrasound contrast agents may be regarded as comprising (i) a reporter moiety capable of interacting with ultrasound irradiation to generate a detectable signal; (ii) one or more vectors having affinity for particular target sites and/or structures within the body, e.g. for specific cells or areas of pathology; and (iii) one or more linkers connecting said reporter and vector(s), in the event that these are not directly joined.
The molecules and/or structure to which the agent is intended to bind will hereinafter be referred to as the target. In order to obtain specific imaging of or a therapeutic effect at a selected region/structure in the body the target must be present and available in this region/structure. Ideally it will be expressed only in the region of interest, but usually will also be present at other locations in the body, creating possible background problems. The target may either be a defined molecular species (i.e. a target molecule) or an unknown molecule or more complex structure (i.e. a target structure) which is present in the area to be imaged and/or treated, and is able to bind specifically or selectively to a given vector molecule.
The vector is attached or linked to the reporter moiety in order to bind these moieties to the region/structure to be imaged and/or treated. The vector may bind specifically to a chosen target, or it may bind only selectively, having affinty also for a limited number of other molecules/structures, again creating possible background problems.
There is a limited body of prior art relating to targeted ultrasound contrast agents. Thus, for example, U.S. Pat. No. 5,531,980 is directed to systems in which the reporter comprises an aqueous suspension of air or gas microbubbles stabilised by one or more film-forming surfactants present at least partially in lamellar or laminar form, said surfactant(s) being bound to one or more vectors comprising “bioactive species designed for specific targeting purposes”. It is stated that the microbubbles are not directly encapsulated by surfactant material but rather that this is incorporated in liquid-filled liposomes which stabilise the microbubbles. It will be appreciated that lamellar or laminar surfactant material such as phospholipids present in such liposomes will inevitably be present in the form of one or more lipid bilayers with the lipophilic tails “back-to-back” and the hydrophilic heads both inside and outside (see e.g. Schneider, M. on “Liposomes as drug carriers: 10 years of research” in
Drug targeting
, Nyon, Switzerland, Oct. 3-5, 1984, Buri, P. and Gumma, A. (Ed), Elsevier, Amsterdam 1984).
EP-A-0727225 describes targeted ultrasound contrast agents in which the reporter comprises a chemical having a sufficient vapour pressure such that a proportion of it is a gas at the body temperature of the subject. This chemical is associated with a surfactant or albumin carrier which includes a protein-, peptide- or carbohydrate-based cell adhesion molecule ligand as vector. The reporter moieties in such contrast agents correspond to the phase shift colloid systems described in WO-A-9416739; it is now recognised that administration of such phase shift colloids may lead to generation of microbubbles which grow uncontrollably, possibly to the extent where they cause potentially dangerous embolisation of, for example, the myocardial vasculature and brain (see e.g. Schwarz,
Advances in Echo
-
Contrast [
1994(3)], pp 48-49).
WO-A-9320802 proposes that tissue-specific ultrasonic image enhancement may be achieved using acoustically reflective oligolamellar liposomes conjugated to tissue-specific ligands such as antibodies, peptides, lectins etc. The liposomes are deliberately chosen to be devoid of gas and so will not have the advantageous echogenic properties of gas-based ultrasound contrast agents. Further references to this technology, e.g. in targeting to fibrin, thrombi and atherosclerotic areas are found in publications by Alkanonyuksel, H. et al. in
J. Pharm. Sci
. (1996) 85(5), 486-490
; J. Am. Coll. Cardiol
. (1996) 27(2) Suppl A, 298A; and
Circulation
, 68 Sci. Sessions, Anaheim Nov. 13-16, 1995.
There is also a number of publications concerning ultrasound contrast agents which refer in passing to possible use of monoclonal antibodies as vectors without giving significant practical detail and/or to reporters comprising materials which may be taken up by the reticuloendothelial system and thereby permit image enhancement of organs such as the liver—see, for example WO-A-9300933, WO-A-9401140, WO-A-9408627, WO-A-9428874, U.S. Pat. No. 5,088,499, U.S. Pat. No. 5,348,016 and U.S. Pat. No. 5,469,854.
The present invention is based on the finding that gas-filled microbubbles stabilised by monolayers of film-forming surfactant material are particularly useful reporters in targeted diagnostic and/or therapeutic agents. Thus, for example, the flexibility and deformability of such thin monolayer membranes substantially enhances the echogenicity of such reporters relative to liposome systems containing lipid bilayers or multiples of such bilayers. This may permit the use of very low doses of the reporter material to achieve high ultrasound contrast efficacy, with consequent safety benefits.
Thus according to one aspect of the present invention there is provided a targetable diagnostic and/or therapeutically active agent, e.g. an ultrasound contrast agent, comprising a suspension in an aqueous carrier liquid, e.g. an injectable carrier liquid, of a reporter comprising gas-filled microbubbles stabilised by monolayers of film-forming surfactant material, said agent further comprising at least one vector.
The term “monolayer” is used herein to denote that the amphiphilic surfactant moieties form monolayer films or membranes similar to so-called Langmuir-Blodgett films at the gas-liquid interfaces, with the lipophilic parts of the amphiphiles aligning towards the gas phase and the hydrophilic parts interacting with the water phase.
As indicated in WO-A-9729783, it is believed that electrostatic repulsion between charged phospholipid membranes encourages the formation of stable and stabilising monolayers at microbubble-carrier liquid interfaces. The flexibility and deformability of such thin membranes are
Klaveness Jo
Løvhaug Dagfinn
Rongved Pal
Bacon & Thomas
Hartley Michael G.
Nycomed Imaging AS
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