Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1998-08-06
2001-10-23
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
Reexamination Certificate
active
06306366
ABSTRACT:
The invention relates to the object characterized in the claims, i.e., new microparticles that contain gas, diagnostic media that contain the latter, their use in ultrasonic diagnosis as well as process for the production of the particles and media.
Since the discovery by Gramiak at the end of the 1960's that ultrasonic contrasts are caused by small gas bubbles in fluids (blood), the most varied types of gaseous ultrasonic contrast media have been developed and described in the literature.
The simplest type of ultrasonic contrast medium can be produced, e.g., by vigorous shaking, by quick drawing-up in and again squirting out of a hypodermic syringe (so-called “pumping”) or irradiation with ultrasound of solutions, such as salt solutions, dye solutions or from blood removed in advance. The small gas bubbles necessary for the echo opacification are introduced in the suspension medium by the previously described methods. Depending on the selection of the medium, a more or less stabilizing effect of the medium on the microgas bubbles can be achieved.
Such contrast media are described, e.g., in EP-0 077 752. Here, mixtures of viscosity-increasing substance and surfactant are used as suspension medium. Air and CO
2
are disclosed as gases in EP 0 077 752. The mentioned contrast media as well as similar contrast media that can be produced according to the mentioned methods are affected by the serious disadvantage that the size of the small gas bubbles varies greatly and can be reproduced only poorly, by which a high risk of embolism exists. Further, the small bubbles that are only slightly stabilized by the suspension medium quickly dissolve, so that a contrast effect can be observed only over a short period. A left ventricular contrast after intravenous administration generally cannot be observed with such contrast media.
In WO 93/05819, contrast media based on small bubble emulsions are described, but in which instead of the conventional gases (air, nitrogen, CO
2
and noble gases), gases with a specific Q-factor are used. These gases are generally halogenated hydrocarbons. By the use of the latter, it was possible to prolong the contrast effect and especially the duration of the signal. Since the gases also in this case—as already in the case of the previously described contrast media—are introduced, e.g., by recycling several starting substances between two syringes via a three-way cock, into the suspension medium, these media also show a very inhomogeneous distribution of small bubble sizes with the associated risk of embolism.
The use of certain fluorinated substances as gases for various types of ultrasonic contrast media is also claimed in EP 0 554 213. This patent specification also does not relate to the microparticle preparations according to the invention. The closest example (3) of EP 0 554 213 contains microparticles based on galactose [as they are described in EP 0 052 575/Example 1], which contain SF
6
instead of air. The effects observed for these particles, however, are weak and only slightly exceed the scattering between the double values of the samples (see Table 3 of EP 0 554 213).
Contrast media with standardized small bubble size are described in EP 0 122 624 and 0 123 235. These contrast media consist of gas-containing microparticles. As particle material, mixtures of surface-active substances, such as, e.g., fatty acids and non-surface-active substances, such as, e.g., saccharides, are used; air is disclosed as gas. These media specifically show the desired standardization relative to the small bubble size, but the small gas bubbles dissolve relatively quickly in the blood plasma, so that the diagnostic time window is small.
Similar contrast media are disclosed in EP 0 365 467. The latter, after i.v. administration of the medium, survive the passage of the pulmonary capillary bed and are thus suitable for the contrasting of the left ventricle and the arterial blood. For a sufficiently long and intensive contrast effect, however, the latter must be administered, as also the contrast media described in EP 0 122 624 and 0 123 235, at a concentration that is not blood-isotonic, which can result in known irritations in patients.
Other ultrasonic contrast media with standardized small bubble size are disclosed in DE 38 03 972 and EP 0 441 468 as well as in DE 38 03 972 and EP 0 357 163. The two first-mentioned patent specifications describe microparticles for ultrasonic diagnosis in which the imaging substances (gases or low-boiling organic liquids) are present in encapsulated form. As shell material, polycyanacrylates (DE 38 03 972) or polymerized aldehydes (EP 0 441 468) are used. The last-mentioned patent specifications describe microparticles in which the gases (or low-boiling organic liquids) are present in complex form (i.e., in the form of a host/guest complex). Although in these patent specifications halogenated hydrocarbons (such as, e.g., bromomethane or dibromodifluoromethane) or in the case of EP 0 357 163 and EP 0 441 468, sulfur hexafluoride, are also disclosed as gases or low-boiling liquids in addition to the usual substances, such as air, nitrogen, no or only a slight effect of the enclosed imaging components on the contrast intensity or period is observed or described for ultrasonic contrast medium preparations that are prepared from these microparticles.
The object of this invention was therefore to provide a contrast medium with defined small bubble size for ultrasonic diagnosis, which, after intravenous administration, is able to achieve long-term contrast effects in the blood and to make its flow conditions on the right and left ventricular sides visible for ultrasound. In particular, the contrast medium should already be able to achieve contrasting that can be evaluated diagnostically in a dose range in which the medium is largely blood-isotonic.
Moreover, the other requirements to be set for an in-vivo contrast medium should also be met. In addition to good compatibility, especially a wide spectrum of use is desired for a modern contrast medium, thus it should also be suitable for the visualization of the blood flow of other organs or tissues, such as, e.g., the myocardium, liver, spleen, kidneys and brain, or after peroral or rectal administration also for the visualization of the gastrointestinal tract. After administration in the bladder, a visualization of the urinary flow should also be possible, such as a contrasting of the tubes after intrauterine administration. The contrast medium should also be universally usable in the various sonographic modes (e.g,, B-mode, Doppler, “Harmonic Imaging”).
This object is achieved by this invention.
It has been found that microparticles that consist of the mixture of at least one surface-active substance with at least one non-surface-active substance and a component that is gaseous at body temperature, characterized in that a substance or a substance mixture is contained as a gaseous component, which is (are) more poorly water-soluble than air, meet the set requirement profile and are therefore extremely well suited as contrast media in ultrasonic diagnosis.
The ultrasonic contrast media obtained by suspending the microparticles according to the invention in a liquid vehicle result especially in—in comparison to the known prior art—surprisingly intensive and long-term contrasting. As a result, the dose necessary for imaging can be reduced by 90% and more relative to the contrast media that are disclosed in BP 0 365 467 (see also Example 18). in this way, contrast media can be obtained that are blood-isotonic or almost blood-isotonic, by which the compatibility is clearly increased. Based on the long-term contrast effects, the media according to the invention are especially suitable also as “blood pool agents.”
As surface-active substances, there are phospholipids, sterols, glycolipids, saccharose esters, such as, e.g., soybean oil saccharose glycerides, saturated or unsaturated fatty acids or their salts, fatty alcohols, mono-, di- and triglycerides, fatty acid esters, such as, e.g
Fritzsch Thomas
Heldmann Dieter
Speck Ulrich
Weitschies Werner
Hartley Michael G.
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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