Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1998-08-19
2001-04-24
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C600S458000, C428S402000
Reexamination Certificate
active
06221337
ABSTRACT:
This invention relates to novel gas-containing contrast agents of use in diagnostic imaging, more particularly to such contrast agents comprising phospholipid-stabilised gas microbubbles and to a novel method for the preparation of gas-containing contrast agents.
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 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.
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 echography; 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 therefor in a variety of systems, e.g. as porous gas-containing microparticles or as encapsulated gas microbubbles.
There is a body of prior art regarding use of phospholipids as components of gas-containing ultrasound contrast agents. Thus, for example, the use as ultrasound contrast media of phospholipid liposomes in which a lipid bilayer surrounds a confined composition including a gas or gas precursor is disclosed in U.S. Pat. No. 4,900,540. The encapsulated material is typically a gas precursor such as aqueous sodium bicarbonate, which is said to generate carbon dioxide following administration through exposure to body pH. The cores of the resulting liposomes will therefore tend to comprise liquid containing extremely small microbubbles of gas which will exhibit only limited echogenicity by virtue of their small size.
WO-A-9115244 discloses ultrasound contrast media comprising microbubbles of air or other gas formed in a suspension of liquid-filled liposomes, the liposomes apparently stabilising the microbubbles. Such systems are differentiated from those of the above-mentioned U.S. Pat. No. 4,900,540 in which the air or other gas is inside the liposomes.
WO-A-9211873 describes aqueous preparations designed to absorb and stabilise microbubbles and thereby serve as ultrasound contrast agents, the compositions comprising polyoxyethylene/polyoxypropylene polymers and negatively charged phospholipids. The weight ratio of polymer to phospholipid is typically about 3:1.
Ultrasound contrast agents comprising gas-filled liposomes, i.e. liposomes which are substantially devoid of liquid in the interior thereof, and their preparation by a vacuum drying gas instillation method are described in WO-A-9222247. The preparation of such gas-filled liposomes by a gel state shaking gas instillation method is described in WO-A-9428780. A report on gas-filled lipid bilayers composed of dipalmitoylphosphatidyl-choline as ultrasound contrast agents is presented by Unger et al. in Investigative Radiology 29, Supplement 2, S134-S136 (1994).
WO-A-9409829 discloses injectable suspensions of gas microbubbles in an aqueous carrier liquid comprising at least one phospholipid stabiliser, the concentration of phospholipids in the carrier being less than 0.01% w/w but equal to or above the amount at which phospholipid molecules are present solely at the gas microbubble-liquid interface. The amount of phospholipid may therefore be as low as that necessary for formation of a single monolayer of surfactant around the gas microbubbles, the resulting film-like structure stabilising the bubbles against collapse or coalescence. Microbubbles with a liposome-like surfactant bilayer are to said not to be obtained when such low phospholipid concentrations are used.
A further body of prior art concerns selection of gases for gas microbubble-containing ultrasound contrast media in order to enhance properties such as their stability and duration of echogenic effect. Thus, for example, WO-A-9305819 proposes use of free microbubbles of gases having a coefficient Q greater than 5 where
Q=4.0×10
−7
×&rgr;/C
s
D
(where &rgr; is the density of the gas in kg·m
−3
, C
s
is the water solubility of the gas in moles·
1
−1
and D,is the diffusivity of the gas in solution in cm
3
·sec
−1
). An extensive list of gases said to fulfill this requirement is presented.
EP-A-0554213 suggests that one may impart resistance against collapse under pressure to gas-filled microvesicles by introduction thereto of at least one gas whose solubility in water, expressed in litres of gas/litres of water under standard conditions, divided by the square root of its molecular weight does not exceed 0.003. Preferred gases are said to include sulphur hexafluoride, selenium hexafluoride and various Freonse. Such gases may, inter alia, be used in phospholipid-containing compositions of the type described in the above-mentioned WO-A-9215244.
Schneider et al. in Investigative Radiology 30(8), pp. 451-457 (1995) describe a new ultrasonographic contrast agent based on sulphur hexafluoride-filled microbubbles apparently stabilised by a combination of polyethyleneglycol 4000 and a mixture of the phospholipids distearoylphosphatidylcholine and dipalmitoylphosphatidylglycerol. The use of sulphur hexafluoride rather than air is said to provide improved resistance to pressure increases such as occur in the left heart during systole.
WO-A-9503835 proposes use of microbubbles containing a gas mixture the composition of which is based on considerations of gas partial pressures both inside and outside the microbubbles, so as to take account of osmotic effects on microbubble size. Representative mixtures comprise a gas having a low apour pressure and limited solubility in blood or serum (e.g. a fluorocarbon) in combination with another gas hich is more rapidly exchanged with gases present in normal blood or serum (e.g. nitrogen, oxygen, carbon dioxide or mixtures thereof).
WO-A-9516467 suggests use of ultrasound contrast media containing a mixture of gases A and B, where gas B is present in an amount of 0.5-41% v/v, has a molecular weight greater than 80 daltons and has aqueous solubility below 0.0283 ml/ml water under standard conditions, the balance of the mixture being gas A. Representative gases A include air, oxygen, nitrogen, carbon dioxide and mixtures thereof. Representative gases B include fluorine-containing gases such as sulphur hexafluoride and various perfluorinated hydrocarbons. Preferred stabilisers in such contrast media include phospholipids.
Phospholipids said to be useful in prior art contrast agents include lecithins (i.e. phosphatidylcholines), for example natural lecithins such as egg yolk lecithin or soya bean lecithin and synthetic or semisynthetic lecithins such as dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine; phosphatidic acids; phosphatidylethan
Brænden Jorunn
Dugstad Harald
Klaveness Jo
Rongved Pal
Skurtveit Roald
Bacon & Thomas
Hartley Michael G.
Nycomed Imaging AS
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