Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1999-03-30
2001-03-27
Hollinden, Gary E. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009500
Reexamination Certificate
active
06207135
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the object that is characterized in the claims, i.e., gaseous microparticles for ultrasonic diagnosis, whose wall material is built up from block copolymers of polyesters of &agr;-, &bgr;- or &ggr;-hydroxycarboxylic acids with linear or star-shaped polyethylene glycols and optionally liquid crystals or from polyesters of &agr;-, &bgr;- or &ggr;-hydroxycarboxylic acids and liquid crystals, media that contain these particles for ultrasonic diagnosis, as well as a process for the production of the media and particles.
BACKGROUND OF THE INVENTION
Ultrasonic diagnosis has been used very extensively in medicine because of the trouble-free, simple handling. Ultrasonic waves are reflected at interfaces of different types of tissues. The echo signals that are produced in this case 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, yield ultrasonic contrast only if density and compressibility differences exist compared to the surrounding area. In medical ultrasonic diagnosis, e.g., substances that contain gases or that produce gas are used as contrast media since the impedance difference between gas and surrounding blood is considerably greater than that of liquids or solids and blood [Levine, R. A., J. Am. Coll. Cardiol. 3 (1989) 28; Machi, I. J. CU 11 (1983) 3].
Roelandt et al. [Ultrasound Med. Biol. 8 (1982) 471-492] describe that cardial echo contrasts can be achieved by peripheral injections of solutions that contain fine gas bubbles. These gas bubbles are created in physiologically compatible solutions by, e.g., shaking, other stirring or by addition of carbon dioxide. They are not standardized with respect to number or size, however, and can be reproduced only inadequately. Also, they are generally not stabilized, so that their service life is short. Their average diameters in most cases exceed that of an erythrocyte, so that it is not possible for them to pass through the pulmonary capillaries with subsequent contrasting of organs such as left heart, liver, kidney or spleen. Moreover, they are not suitable for quantification since the ultrasonic echo that they produced consists of several processes that cannot be separated from one another, such as bubble production, coalescence and dissolution. Thus, it is not possible, e.g., with the aid of these ultrasonic contrast media to obtain information on transit times by measuring the history of the contrast in the myocardium. To this end, contrast media are needed whose scatter elements have sufficient stability.
EP 0 131 540 describes the stabilization of gas bubbles by sugar. This improves the reproducibility and homogeneity of the contrast effect, 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 passage through pulmonary capillaries and the possibility of visualizing the arterial femoral blood vessel and various organs such as the liver or spleen are provided for with these ultrasonic contrast media. In this case, however, the contrast effect is limited to the vascular lumen, since the bubbles are not absorbed by the tissue cells.
None of the ultrasonic contrast media described remains unaltered in the body for a prolonged period of 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 ultrasonic contrast media is described in EP 0 224 934. The wall material that is used in this case consists of protein, especially human serum albumin with the known allergenic properties, which may also be accompanied by cytotoxic effects caused by denaturation.
Patent EP 0 327 490 describes gaseous microparticles for ultrasonic diagnosis based on biodegradable, synthetic materials. As biodegradable polymers, i.a., &agr;-, &bgr;- or &ggr;-hydroxycarboxylic acids are also disclosed. The diagnostic action of contrast medium preparations that are prepared therefrom is therefore not satisfactory in all cases.
A functional analysis is not possible with any of the ultrasonic contrast media described.
SUMMARY OF THE INVENTION
The object of this invention was therefore to find compounds and media prepared therefrom that overcome the drawbacks of the prior art.
This object is achieved by this invention.
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patent: 5863520 (1999-01-01), Bichon et al.
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patent: 0 327 490 (1989-08-01), None
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patent: 93/25 242 (1993-12-01), None
Albayrak Celal
Rossling Georg
Rothe Matthias
Cagan Felissa H.
Evans Susan T.
Hollinden Gary E.
Inhale Therapeutic Systems Inc.
Rafa Michael J.
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