Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Patent
1998-02-23
2000-08-22
Clardy, S. Mark
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
424497, 424501, 252302, A61B 800, A61K 950
Patent
active
061068071
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the object that is characterized in the claims, i.e., the use of asymmetrical or symmetrical methylenemalondiester derivatives for the production of gas-containing microparticles, as well as the contrast media that contain these particles, for ultrasound diagnosis.
In medicine, ultrasound diagnosis has been very widely used because of its straightforward, simple handling. Ultrasonic waves are reflected at the interfaces of different types of tissue. The echo signals that are produced in this process are electronically enhanced and made visible. The visualization of blood vessels and internal organs using ultrasound generally does not allow the visualization of the blood flow that is present in it. Liquids, especially blood, provide ultrasonic contrast only when differences in density and compressibility exist compared to the surrounding area. As contrast media, e.g., substances that contain gases or that produce gases are used in medical ultrasound diagnosis since the impedance difference between the gas and the surrounding blood is considerably greater than that between liquids or solids and blood (Levine, R. A., J. Am. Coll. Cardiol. 3: 28, 1989; Machi I. J. CU 11:3, 1983).
It is known that peripheral injections of solutions that contain fine gas bubbles can ensure cardiac echo contrasts (Roelandt, J., Ultrasound Med. Biol. 8: 471-492, 1982). These gas bubbles are obtained in physiologically compatible solutions by, e.g., shaking, other agitation, or the addition of carbon dioxide. These gas bubbles are not standardized with respect to number or size, however, and can be produced only in an inadequate manner. They also are not generally stabilized, so that their service life is short. Their average diameters in most cases exceed that of an erythrocyte, so that passage through the lung capillaries, with subsequent contrasting of organs such as the left side of the heart, liver, kidney or spleen, is not possible.
Moreover, such bubbles are not suitable for quantification since the ultrasonic echoes that they produce consist of several processes that cannot be separated from one another, such as bubble production, coalescence, and dissolution. Thus, for example, it is not possible to obtain information on transit times with the aid of these ultrasonic contrast media by measuring the plot of the contrast in the myocardium. For this purpose, contrast media are needed whose scatter elements exhibit sufficient stability.
EP 0 131 540 describes the stabilization of gas bubbles using sugar. Thus, the reproducibility and homogeneity of the contrast effect are improved, but these bubbles do not survive passing through the lungs.
EP 0 122 624 and 0 123 235 describe that the gas bubble-stabilizing effect of sugars, sugar alcohols and salts is improved by the addition of surface-active substances. The ability to pass through the lung capillaries and the possibility of visualizing the arterial femoral blood vessels as well as various organs such as the liver or spleen are provided with these ultrasonic contrast media. In this connection, however, the contrast effect is limited to the vascular lumen since the bubbles are not taken up by the tissue cells.
None of the ultrasonic contrast media described remains unaltered in the body for a prolonged time. Organ visualization with sufficient signal intensity by selective concentration after i.v. administration or quantification is not possible with these media.
Encapsulation of gases such as, for example, air as an ultrasonic contrast medium is described in EP 0 224 934. The wall material that is used in this connection consists of protein, especially human serum albumin with the known allergenic properties; denaturing may also add cytotoxic effects.
Gas-containing microparticles for ultrasound diagnosis based on biodegradable, synthetic materials are described in EP 0 327 490 and EP 0 458 745. These media have a sufficient in-vivo service life and accumulate intravenous administration intracellularly in the reticuloendothelial system and thus also
REFERENCES:
patent: 5425366 (1995-06-01), Reinhardt et al.
Keyser et al., "Poly (dialkyl methylidenemalonate) Nanoparticles as a Potential Drug Carrier" Journal of Pharmaceutical Sciences, vol. 80, No. 1, pp. 67-70, Jan. 1991.
Breton, P. et al., "New Poly(methylidene Malonate Nanoparticles" NATO ASI Ser., Ser. A, pp. 161-172, 1994.
Albayrak Celal
Rossling Georg
Clardy S. Mark
Hartley Michael G.
Schering Aktiengesellschaft
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