Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1999-10-21
2001-01-23
Hollinden, Gary E. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009520, C600S431000
Reexamination Certificate
active
06177061
ABSTRACT:
This invention relates to diagnostic imaging, more particularly to novel contrast agent preparations and their use in ultrasound imaging.
It is well known that ultrasound imaging constitutes a potentially valuable diagnostic tool, for example in studies of the vascular system and tissue microvasculature, particularly in cardiography. A variety of contrast agents has been proposed to enhance 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 gas-containing and gas-generating systems.
Over about the last five years particular attention has been focussed on the selection of gases and gas mixtures which exhibit enhanced stability and therefore longer-lasting contrast effects in vivo compared to the hitherto most commonly used gases such as air and components thereof, for example nitrogen, oxygen and carbon dioxide. Thus, for example, in WO-A-9305819 there is proposed the use of dispersions of free microbubbles of gases having a coefficient Q greater than 5 where
Q=
4.0×10
−7
×&rgr;/C
s
D
(in which &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 fulfil this requirement is presented, including fluorine-containing gases such as sulphur hexafluoride and various fluorocarbons. It is noted that significant echogenicity is observed only for dispersions of gaseous materials; thus, for example, in vitro experiments at 37° C. showed an aqueous dispersion of perfluoropentane (b.p. 29.5° C.) to be highly echogenic, whereas a similar dispersion of perfluorohexane (b.p. 59-60° C.), which has an approximately 8-fold greater Q-coefficient, was undetectable by ultrasound scanning under the same conditions.
In EP-A-0554213 it is suggested 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 liters of gas/liter 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 Freons®.
In WO-A-9503835 there is proposed the use of membrane-encapsulated microbubbles containing a gas mixture having a composition 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 vapour pressure and limited solubility in blood or serum (e.g. a fluorocarbon) in combination with another gas which is more rapidly exchanged with gases present in normal blood or serum (e.g. nitrogen, oxygen, carbon dioxide or mixtures thereof); the fluorocarbon or like gas preferably has a molecular weight at least four times that of the more rapidly exchanged gas.
In WO-A-9516467 there is suggested the use of ultrasound contrast media containing a surfactant-stabilised 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 an aqueous solubility of less than 0.0283 ml/ml water under standard conditions, the balance of the mixture being gas A, which may comprise one or more gases with molecular weights below 80 daltons. 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. It is postulated that the high molecular weight gas B has the effect of “plugging holes” in the encapsulating membranes at the microbubble boundaries, thereby preventing escape by transmembrane diffusion of the low molecular weight gas A.
Gas-generating ultrasound contrast agents comprising colloidal liquid-in-liquid dispersions in which the dispersed phase comprises a volatile liquid having a boiling point below the body temperature of the subject to be imaged (typically 37-40° C.) are described in WO-A-9416739; such phase shift colloids are said to exhibit excellent storage stability while generating highly echogenic microbubbles following administration. Preferred dispersed phase liquids include fluorine-containing chemicals such as perfluoropentane. It is stated that the dispersed phase may also be selected from azeotropic mixtures having a boiling point at or below the body temperature of the subject; acetone-pentane, ethyl ether-isoprene, ethyl ether-methyl formate, ethyl ether-water, isoprene-(2-methylbutane), isopropyl chloride-water, methyl vinyl chloride-water, pentane-water, vinyl ethyl ether-water, acetone-isoprene-water, carbon disulphide-methanol-methyl acetate and carbon disulphide-methanol-methylal azeotropic mixtures are described by way of example.
Such azeotropic mixtures would not in practice be expected to give long-lasting contrast effects in vivo in view of the relatively high water solubilities and relatively low molecular weights (in all cases less than 80) of the components. Moreover, phase shift colloids in general have been found to exhibit a number of potentially disadvantageous properties. Thus some workers have suggested that their administration may lead to generation of microbubbles which grow uncontrollably and unevenly, possibly to the extent where at least a proportion of the microbubbles may cause potentially dangerous embolisation, for example of the myocardial vasculature and brain (see e.g. Schwarz,
Advances in Echo
-
Contrast [
1994(3)], pp. 48-49). Others have found that administration of phase shift colloids may not lead to reliable or consistent volatilisation of the dispersed phase in vivo. Thus Grayburn et al. in
J. Am. Coll. Cardiol.
26(5) [1995], pp. 1340-1347 suggest that preactivation of perfluoropentane emulsions may be required to achieve myocardial opacification in dogs if doses low enough to avoid haemodynamic side effects are to be effective. An activation technique for such colloidal dispersions, involving application of hypobaric forces thereto, is described in WO-A-9640282; this typically involves partially filling a syringe with the emulsion and subsequently forcibly withdrawing and then releasing the plunger of the syringe to generate a transient pressure change which causes formation of gas microbubbles within the emulsion: clearly this is an inherently somewhat cumbersome technique which may fail to give consistent levels of activation.
The present invention is based on the finding that contrast agents comprising halocarbon-containing azeotropic mixtures in which the halocarbon has a molecular weight of at least 100 exhibit a number of useful and advantageous properties. Thus, for example, azeotrope formation may be used effectively to enhance the volatility of relatively high molecular weight halocarbons which under standard conditions are liquid at the normal human body temperature of 37° C., such that they may be administered in gaseous form at this temperature. This has substantial benefits as regards the effective echogenic lifetime in vivo of contrast agents containing such azeotropic mixtures since, as is apparent from the prior art discussed above, parameters such as the water solubility and diffusibility of halocarbons decrease with increasing molecular weight and size, as does their fat solubility.
Azeotrope formation may similarly be used where appropriate to generate mixtures which are gaseous at normal room and storage temperatures (e.g. 15-20° C.) despite containing halocarbons which in isolation have boiling points above such temperatures. Contrast agents containing such mixtures may be administered directly to a subject without a
Hoff Lars
Klaveness Jo
Rongved Pal
Skurtveit Roald
Bacon & Thomas
Hollinden Gary E.
Nycomed Imaging AS
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