Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-06-02
2001-03-13
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C427S002100, C427S002240, C427S002300, C514S056000, C514S642000, C514S822000
Reexamination Certificate
active
06200588
ABSTRACT:
TECHICAL FIELD OF THE INVENTION
The present invention relates to a blood-compatible composition useful as a coating material for medical devices used in contact with blood. The present invention also relates to a medical device coated with said composition, and having an improved compatibility with blood.
BACKGROUND OF THE INVENTION
Along with the progress of medicine, more medical devices made from a polymer material have been widely used, and highly advanced medical devices such as assistant circulation devices (e.g., artificial heart, artificial kidney, pump-oxygenator, intra-aortic balloon pumping and the like), catheters for various diagnoses and therapies, synthetic vascular prosthesis and the like have been put to practical use. However, most of these medical devices are made from polymer materials developed for industrial use without modification, and they require a combined use of an anticoagulant when in use, that prevents coagulation of blood on contact with the medical devices.
However, anticoagulants not only prevent coagulation on the surface of a medical device but also deprive systemic hemostatic function. The use, therefore, is associated with the risk of causing complications such as hemorrhage at the site of insertion or use of medical device, at an operative wound and, in a serious case, from a cerebral vessel. Thus, in an attempt to prevent the above-mentioned complications, methods have been studied that involve imparting antithrombogenicity to a medical device, thereby to reduce administration of anticoaglant.
As a method for imparting antithrombogenicity to a medical device, there have been practiced (A) a method comprising mixing highly fine particles of a polymer material and an anticoagulant substance (e.g., heparin), dispersing the mixture in a solvent and applying the resulting dispersion onto a medical device, (B) a method comprising introducing cation groups such as quaternary ammonium salts into a polymer, dissolving the cation group-containing polymer in a solvent, applying the solution onto a medical device and bringing an aqueous solution of heparin into contact therewith to form ionic bonds between anion groups in heparin and cation groups in the polymer, (C) a method comprising introducing amino groups or aldehyde groups into heparin, directly immobilizing substances or functional groups capable of crosslinking with the above-mentioned functional groups onto a medical device to be a substrate and covalently binding them to immobilize heparin, and (D) a method comprising binding organic cations to anion groups in heparin to make the heparin water-insoluble but soluble to a specific organic solvent and applying the heparin solution onto the medical device.
According to the method (A), however, heparin is directly eluted into blood, so that quick elution occurs in the early stage and antithrombogenic effect is soon disappears. In addition, small holes remain on the surface of the medical device after elution of heparin, thereby possibly causing formation of thrombus on the holes.
The method (B) can provide an antithrombogenic material capable of maintaining higher anticoagulant activity for a long time due to ionic bond. However, this method requires two separate steps of coating a medical device with a quaternary ammonium salt-containing polymer to be a substrate and of binding heparin to the surface of the coated medical device. This in turn increases production cost of a medical device to be in contact with blood, which should be disposable.
The method (C) aims at antithrombogenicity retained for an extended period of time by semi-permanently immobilizing heparin on the surface of a medical device. However, the heparin immobilized on the surface by a covalent bond has limited mobility and cannot bind sufficiently with antithrombin III required for an expression of antithrombogenicity, to the point that the surface cannot exert sufficient antithrombogenicity.
The method (D) comprises dissolving water-insoluble toridecylmethylammonium chloride in isopropyl alcohol, applying the solution onto the surface of a medical device, and then bringing the surface into contact with an aqueous solution of heparin to form an ionic complex of toridecylmethylammonium and heparin on the surface, whereby to provide antithrombogenicity. Like the method of (B), this method again requires two separate steps of coating a medical device with toridecylmethylammonium chloride and of binding heparin, which is undesirable from the aspects of cost and work efficiency.
For this shortcoming to be obliterated, a method has been proposed, which comprises dissolving an ionic complex of a benzalkonium salt and heparin in isopropyl alcohol and applying the solution onto the surface of a medical device. According to this method, the ionic complex is formed first, so that a single step of coating is sufficient. In addition, this solution is sold on the market and easily available. However, benzalkonium salts are produced from an aromatic halide as a staring material, which leaves an issue with the safety of residual starting material. Furthermore, the high cytotoxicity of the resultant benzalkonium salt, as evidenced by the use thereof as a bacteriocide during operation, poses the risk of hemolysis once it elutes out into the blood. Another problem of this method is in connection with the retention of antithiombogenicity during a long-term use of the medical device, because this ionic complex has poor durability in blood.
As can be appreciated from the foregoing, known methods have, without exception, problems in at least one aspect from long-term durability of antithrombogenic effect, production efficiency, production cost and safety.
It is therefore an object of the present invention to provide a means for producing a medical device capable of retaining stable antithrombogenicity for an extended period of time, easily and economically.
SUMMARY OF THE INVENTION
The present invention is based on the finding that an ionic complex comprising an organic cationic compound having a specific number of total carbon atoms, and heparin or a heparin derivative is a useful coating material capable of imparting a sustained antithiombogenicity to a medical device.
Accordingly, the present invention provides a novel blood-compatible composition comprising an ionic complex comprising an organic cationic compound, and heparin or a derivative thereof, the organic cationic compound being an ammonium or a phosophonium bound with 4 aliphatic alkyl groups, and the 4 aliphatic alkyl groups having a total number of carbon atoms of 24 to 32 and at least 2 of the alkyl groups having not less than 10 carbon atoms; preferably, the blood-compatible composition, wherein at least two alkyl groups are methyl; and more preferably, the blood-compatible composition, wherein the alkyl groups having 10 or more carbon atoms have the same number of carbon atoms. The present invention also provides a blood-compatible composition comprising two or more kinds of the above-mentioned ionic complexes.
The present invention further provides a medical device whose surface is coated with any of the above-mentioned ionic complexes.
The composition of the present invention, which comprises the above-noted particular organic cationic compound, and heparin or a derivative thereof, shows superior antithrombogenic effect as compared to known coating materials for medical devices. The inventive composition shows stable retention of the effect for a long time. Therefore, it is particularly useful as a coating material for a medical device potent in contact with blood when in use. Furthermore, the inventive composition allows for the production of an antithrombogenic medical device by a single application of the coating, which is extremely useful in terms of cost and work efficiency.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is characterized by the relationship present in an ionic complex of heparin and an organic cation group in the method of (D) above between the total number of carbon atoms in 4 alkyl groups bi
Kashiwabara Susumu
Satoh Masayoshi
Tanaka Hidenori
Dees Jose′ G.
Lamm Marina
Leydig Voit & Mayer Ltd
Toyo Boseki Kabushiki Kaisha
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