Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
1997-07-21
2002-05-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S009400
Reexamination Certificate
active
06383470
ABSTRACT:
The invention relates to the object characterized in the claims, i.e., microparticles produced from biopolymers, monomers capable of polymerization, active ingredients and/or diagnostically detectable components, a process for their production as well as their use in diagnosis and treatment, especially as contrast media in ultrasonic diagnosis.
It is known that particles, whose diameter is smaller or in the range of the size of red blood cells, can circulate within the circulatory system after injection in the circulatory pathway. Pharmaceutical preparations of such microparticles are thus suitable as vehicle systems injectable in the circulatory system for active ingredients or diagnostic agents in medicine. As vehicle materials, in principle all biodegradable, compatible and non-water-soluble substances are suitable. So far, above all fats, waxes, lipids (e.g., soybean lecithin), denatured biopolymers (e.g., albumin, gelatin) and synthetically biodegradable polymers (e.g., polylactic acid, polyhydroxybutyric acid, polyalkylcyanoacrylates, poly-L-lysine) are described.
There is a difference in how quickly and in the numbers in which the microparticles circulating in the circulatory pathway are recognized, as a function of their physical and chemical properties, by the cells of the monocytic phagocytizing system (MPS) and taken up (mainly in the liver, lung and spleen). The particle charge, the particle size, the properties (molecular weight, amphiphilia) on the particle surface of adsorbed substances, as well as the affinity of the particle surface for blood components such as fibronectin, albumin, etc. are considered as essential factors, which determine the kinetics of the absorption of the microparticles by the cells of the MPS. By specific variation of the physicochemical surface properties of microparticles, the kinetics of the phagocytosis can be influenced by the cells of the MPS and the extent of the concentration of the particles within the corresponding organs (i.a., liver, lung, spleen, bone marrow) (passive targeting). A specific concentration of microparticles in target tissues or body structures, which are not among the organs of the RES, is in this way not possible. It can rather be achieved only by the combination of the microparticles with substances which have site-specific, structure-specific or tissue-specific binding properties (homing devices). But the particles previously described for use in ultrasonic diagnosis are suitable only insufficiently as preparations suitable for the combination with homing devices.
Thus, it has to be accepted in the case of the contrast media described in EP 0 458 079 and DE 38 03 972 that they can be produced only with the help of expensive processes, which make necessary the use of organic solvents, whose use is harmful for reasons of protection of the environment and work place safety. In addition, before using the preparations, there has to be assurance that the used organic solvents are no longer contained in the product to be used pharmaceutically. Moreover, surface-active adjuvants (e.g., surfactants) are necessary for the production, which are frequently considered as harmful in the case of injection preparations. Further, a control of the concentration behavior in various organs is not controllable in the case of these particles, a linkage of the particles of DE 38 03 972 with selectively accumulating compounds (so-called homing devices, such as, e.g., monoclonal antibodies) is not possible.
The microparticles made of polymerized aldehydes described in DE 40 04 430 are also not suitable as vehicles for substance-specific or structure-specific substances because of the unclear biodegradability. Another drawback is that also in this case surface-active adjuvants are necessary for the production of the particles.
The microparticles made of proteins, especially of albumin, described in EP 0 224 934 exhibit an only very low in vitro and in vivo stability.
It was therefore the object of the invention to provide microparticle preparations especially for use in ultrasonic diagnosis, which get by without the use of physiologically harmful solvents or adjuvants (e.g., surfactants), are easily producible and biodegradable, which either contain substances with site-specific, structure-specific or tissue-specific binding properties in the wall material or can be linked covalently with such and which exhibit a sufficient in vitro and in vivo stability.
According to the invention, this object is achieved by microparticles whose shell is formed from the combination of biopolymers—preferably polypeptides (also glycosylated)—and synthetic material polymerized during the production.
Therefore, microparticles made of a copolymer of at least one synthetic polymer and at least one biopolymer are an object of the invention, and polypeptides, preferably natural ones, or produced synthetically or partially synthetically or obtained by genetic engineering as biopolymers, such as, e.g., albumin, collagen decomposition products, gelatin, fibrinogen, fibronectin, polygeline, oxypolygelatin, their decomposition products as well as poly-L-lysine are suitable. The biopolymers can also be glycosylated. As polymerizable monomers, preferably alkylcyanoacrylates, acrylic acid, acrylamide, acrylic acid chloride and acrylic acid glycide ester are suitable.
The microparticles according to the invention are suitable in the production in gas-saturated solution by the inclusion of the gas, especially as a contrast medium for ultrasonic studies. They act as highly effective scatter elements in the ultrasonic field because of the contained gas. In addition, they can be excited by diagnostic ultrasound to radiate independent signals, which can be evaluated, e.g., with the help of the color Doppler technology.
As gases, air, nitrogen, carbon dioxide, oxygen, helium, neon, argon, krypton or their mixtures are suitable. The charge with the corresponding gas or gas mixture takes place by production of the particles in an aqueous solution saturated with the respective gas or gas mixture.
The microparticles can also (optionally in addition) contain other substances, detectable with the help of medicinally-diagnostic processes, such as magnetic resonance tomography, magnetic resonance spectroscopy, scintigraphy or highly sensitive magnetic field measurements with suitable magnetometers (biomagnetism), both microencapsulated and in the wall material and (optionally with the help of suitable substances, such as, e.g., chelating agents) coupled to the wall material. Thus, it is possible, e.g., in using radioactive isotopes, to use the microparticles according to the invention in scintigraphy. Likewise, its use as contrast medium in magnetic resonance tomography, magnetic resonance spectroscopy or in measurements of the magnetic field is possible by the microencapsulation or incorporation in the wall material of suitable para-, superpara-, ferri- or ferromagnetic substances.
Surprisingly, it has been found that in the production of the particles according to the invention (in maintaining sufficient concentrations of biopolymers), the addition of surface-active substances, such as, e.g., surfactants, is not necessary. This represents a decisive advantage in comparison with the previously known production process for microparticles based on synthetic polymers, since the surfactants usually necessary for reducing the interfacial tension and for preventing the particle aggregation are considered as physiologically harmful and therefore are to be removed again from the preparations before the use in the organism up to compatible residue contents.
As a further advantage of the microparticle preparations according to the invention, the varied particle properties that can be matched to the respective use can be mentioned, which are easily controllable by variation of various production parameters. Thus, the pharmacokinetic parameters of the microparticle preparations, (organ distribution, retention period in the circulatory pathway) can be influenced by the selection of the res
Fritzsch Thomas
Heldmann Dieter
Weitschies Werner
Joynes Robert
Page Thurman K.
LandOfFree
Microparticle preparations made of biodegradable copolymers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Microparticle preparations made of biodegradable copolymers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Microparticle preparations made of biodegradable copolymers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2843527