Plastic and nonmetallic article shaping or treating: processes – Encapsulating normally liquid material – Liquid encapsulation utilizing an emulsion or dispersion to...
Reexamination Certificate
2002-03-27
2003-11-25
Acquah, Samuel A. (Department: 1711)
Plastic and nonmetallic article shaping or treating: processes
Encapsulating normally liquid material
Liquid encapsulation utilizing an emulsion or dispersion to...
C526S064000, C526S065000, C526S071000, C526S072000, C428S402200, C428S402210, C428S402220, C264S004700
Reexamination Certificate
active
06652782
ABSTRACT:
The invention relates to a multi-stage process for the production of gas-filled microcapsules, in which the process steps of polymerization of the encasing substance and build-up of the microcapsule are carried out separately. The microcapsules that-are produced with the process according to the invention have a core-shell structure and are distinguished by a defined size distribution. Based on their properties, they can be used for ultrasound as contrast media that can pass capillaries.
The application is based on the following definitions:
A microcapsule is a particle that measures several &mgr;m and that consists of a gaseous core and a solid shell with variable thickness. The core can also contain a small proportion of liquid, in which the production is carried out.
Stirring is the mixing of a liquid with a liquid, solid or gaseous substance in such a way that the gas-phase proportion in the stirring medium is <1%.
Dispersing is the mixing of a liquid with a liquid, solid or gaseous substance in such a way that the gas-phase proportion in the dispersing medium is >1%, preferably greater than 10%.
Dispersion is a colloidal (particle size<500 nm) or coarsely dispersed (particle size>500 nm) multi-phase system.
Primary dispersion is a colloidal dispersion that consists of polymer particles, produced by polymerization of a monomer.
Self-gassing is the input of gas into a liquid by the movement of the gas or by the production of a dynamic flow underpressure.
External gassing is the active input of gas into a liquid.
Flotation is the movement of microparticles directed against the acceleration force (acceleration due to gravity g, radial acceleration a) based on a difference in density between microparticles and dispersing agents.
Floated material is the creamed layer of gas-filled microparticles after flotation.
Hydraulically filled is the same as completely filled without gas supernatant.
In the case of echocardiography (also: cardiac sonography), conclusions can be drawn on morphology and sequences of movements of cardiac valves as well as the direction, rate and quality of the circulation. In this process of diagnosis, the procedure is done with ultrasound, whose interactions are shown color-coded (Doppler process). Because of their complication-free, simple application, ultrasonic diagnosis has found wide use in medicine.
The quality of the results is considerably improved by the use of contrast media.
As contrast media, substances that contain or release gases are used in medical ultrasonic diagnosis as a rule, since a more efficient density and thus impedance difference than between liquids or solids and blood can be produced with them.
The observation of cardiac echo effects with solutions that contain finely dispersed gas bubbles have been known in the literature for a long time [1]. Since these unstabilized gas bubbles have only a very short service life, solutions that are produced in this way are unsuitable as contrast media for medical ultrasonic diagnosis.
In U.S. Pat. No. 4,276,885, a process for the production of gas bubbles, which are protected by a gelatin membrane before running together [2], is described. These microbubbles are preferably produced by an injection of the desired gas into a substance that can gel (for example gelatin) using a capillary. Storage of these microbubbles is possible only at low temperatures, whereby the latter are to be brought to body temperature again before in-vivo use. Heat-sterilization is excluded in principle, since in this case the microbubbles are destroyed just as in sterile filtration.
In European Patent EP 0 052 575 B1, ultrasonic contrast media that are based on physiologically well-tolerated solid aggregates that release gas bubbles into the blood stream after administration [3] are described. The released gas bubbles are not stabilized and do not survive passage through the lungs, so that after intravenous administration, only a contrasting of the right half of the heart is possible.
In Patents EP 0 122 624 and EP 0 123 235, ultrasonic contrast media that consist of microparticles and gas bubbles are described [4, 5]. In contrast to EP 0 052 575 B1, a stabilization of the gas bubbles is carried out by means of a surface-active substance. Passage through the lungs is possible, so that these contrast media allow a contrasting of the entire vascular volume.
Both production processes are very expensive, however.
According to European Patent EP 0 324 938 B1, encapsulated microbubbles can be produced by microbubbles being produced by ultrasound in a protein solution, which are subsequently stabilized in that because of a local temperature increase, the protein is partially denatured and the gas bubbles included [6].
The proposed use of human serum albumin (HSA) involves a considerable allergenic risk, however.
In European Patent EP 0 398 935 B1, microparticles whose shell substance consists of synthetic, biodegradable polymer material are described as ultrasonic contrast media. As a shell substance, in this case, a whole series of polymers are suitable, which are dissolved in a water-immiscible solvent or solvent mixture and are emulsified in water after possible addition of other solvents. As solvents, according to [7], furan, pentane and acetone can be used in addition to others. In a process variant, the monomer that is dissolved in one of the above-mentioned solvents is polymerized immediately in an aqueous solution that contains gas bubbles.
In all processes that are mentioned in the claims, the obligatory use of an organic solvent is of considerable disadvantage, since the latter has to be removed completely during the course of the production process.
With the techniques that are disclosed in European Patent EP 0 458 745, gas-filled microballoons can be produced in a wide range of sizes [8]. To this end, first a solution of the shaping polymer is emulsified in an organic solvent in water and then diluted, by which the finely dispersed polymer solution drops are solidified. The enclosed solvent must be removed in an additional step, which is an expensive process. It is advantageous in this process that there is a direct possible way of influencing the size of the microcapsules that are produced by the selection of the surfactant or the rpm. In this case, however, different forms of administration, such as the intravenous injection, which requires in particular small particles for passing through the lungs, as well as the oral administration with correspondingly larger particles, are to be covered by the process. A solvent-free synthesis of gas-filled microparticles is also not possible in this way, however.
A spray-drying process for the production of echogenic microparticles, of which concave surface segments are the first and foremost characteristic, is disclosed in European Patent EP 0 535 387 B1 [9]. In addition, the synthesis of various shell polymers with use of organic solvent is described. The echogenic microparticles are obtained by a spray-drying process of an organic solution of the shaping polymer. Disadvantageous in this process is also the use of organic solvents and the spray-drying process that is expensive under sterile conditions.
By process optimization, which is described in European Patent EP 0 644 777 B1, the ultrasonic activity of the microcapsules that are described in EP 0 327 490 could be significantly improved [10]. An increase of the ultrasonic activity (with specific frequency and smaller amplitude) is achieved by the diameter of the air core having been enlarged in the case of constant particle diameter. Despite the smaller wall thickness that results therefrom, the particles nevertheless survive passing through the cardiopulmonary system.
The optimized process is characterized in that the monomer is dispersed and polymerized in an acidic, gas-saturated, aqueous solution, and in this case the build-up of the microcapsule is carried out immediately. In this way, microcapsules can be produ
Briel Andreas
Budde Uwe
Gottfried Michael
Ingwersen Jan-Peter
Lovis Kai
Acquah Samuel A.
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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