JP5114660B2 - Antithrombotic antibacterial composition and medical device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antithrombotic antibacterial material that is more excellent in antithrombotic properties and, in its turn, in biocompatibility than conventional medical materials, can act as a highly hydrophilic surface-treating agent and is made antibacterial by the incorporation of an antibacterial substance. <P>SOLUTION: The antithrombotic antibacterial composition comprises a water-insoluble (meth)acrylate copolymer comprised of an alkyl (meth)acrylate and methoxypolyethylene glycol (meth)acrylate and at least one antibacterial substance. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to an antithrombotic antibacterial composition for treating the surface of a medical device, which comprises an antithrombotic copolymer containing an antibacterial substance.

  In recent years, medical materials using various polymer materials have been studied, such as blood filters, artificial kidney membranes, plasma separation membranes, catheters, artificial lung membranes, artificial blood vessels, adhesion prevention membranes, artificial skin, etc. The use to is expected. In this case, since a synthetic material that is a foreign substance for a living body is used in contact with in vivo tissue or blood, the medical material is required to have biocompatibility.

  When a medical material is used as a material in contact with blood, there are three elements: (a) suppression of blood coagulation system, (b) suppression of platelet adhesion / activation, and (c) suppression of complement system activation. This is an important item for biocompatibility. In particular, when used as a material having a relatively short time of contact with blood, such as a medical material for extracorporeal circulation (eg, artificial kidney, plasma separation membrane), generally, an anticoagulant such as heparin or sodium citrate is used. Since they are used at the same time, it is particularly important to suppress the activation of the platelets and the complement system of (b) and (c).

(B) Regarding suppression of platelet adhesion / activation, microphase-separated surfaces and hydrophilic surfaces, particularly gelled surfaces with water-soluble polymers bonded to the surface are excellent, and hydrophobic properties such as polypropylene The surface is said to be inferior. (See Non-Patent Documents 1 and 2). However, a surface having a microphase separation structure can express good blood compatibility by controlling to an appropriate phase separation state, but the conditions under which such phase separation can be produced are limited. There was a limit to the use. In addition, on the gelled surface with water-soluble polymer bound to the surface, platelet adhesion is suppressed, but platelets and microthrombi activated on the surface of the material are returned to the body, often resulting in abnormal blood cell components (platelet ) Was observed, which could be a problem.
Transactions of American Society of Artificial International Organs (Trans. Am. Soc. Artif. International. Organs), vol. XXXIII, p. 75-84 (1987) Polymer and Medical, Mita Publishing Co., p. 73 (1989)

On the other hand, regarding the activation of the complement system (c), it is known that the surface having a hydroxy group such as cellulose and ethylene-vinyl alcohol copolymer shows high activity and the activity is slight on a hydrophobic surface such as polypropylene. It has been. (Refer nonpatent literature 3). Therefore, when cellulose-based or vinyl alcohol-based materials are used for, for example, membranes for artificial organs, there is a problem of activation of the complement system. Conversely, when hydrophobic surfaces such as polyethylene are used, platelet adhesion / activity Will cause problems.
Artificial organ 16 (2), p. 1045-1050 (1987)

In addition, for example, when used as a material having a relatively long contact time with blood, such as an artificial blood vessel, in addition to the above three items, neonatal intima form and in vivo tissue regeneration and regeneration are performed well. Therefore, it is necessary to be a material having an affinity with in vivo tissues (cells). Examples of the material for the artificial blood vessel include an artificial blood vessel made of extra fine polyester fibers. (Refer nonpatent literature 4). This ultra-fine polyester fiber is one of medical materials utilizing foreign body recognition, wound healing by biological defense, and self-tissue regeneration, and is mainly used as an artificial blood vessel today. However, when this artificial blood vessel is applied to a micro blood vessel for a long period of time, there arises a problem that the artificial blood vessel is blocked.
Artificial organ 19 (3), p. 1287-1291

  Furthermore, in addition to blood, medical materials that come into contact with tissues or body fluids in the living body, such as anti-adhesion films, implant materials, or wounds that are used by being embedded in the living body for a long period of time (the skin is peeled off and damaged, In a wound dressing used in contact with a tissue-exposed part), a surface (non-adhesive surface) that is less likely to be recognized by a foreign body and easily separated from the living body is required. However, silicone, polyurethane, and polytetrafluoroethylene, which have been used as the above-mentioned materials, have not been able to obtain satisfactory performance due to excessive recognition of foreign matter in the living body because tissue in the body adheres to the material surface.

  Another medical material is polyethylene glycol (PEG). PEG has very good blood compatibility, and many applied studies in the medical field have been conducted. However, since PEG is water-soluble, when used as a medical material, it has been necessary to immobilize it on the surface of the material as a block copolymer or graft copolymer with another polymer.

In addition, a technique for expressing antithrombogenicity by coating a blood contact surface with poly (2-methoxyethyl acrylate), which is a biocompatible material, is known. (See Patent Document 1). This material is soluble in methanol as a solvent for the coating, but considering the toxicity of the residual solvent, it can be said that a material soluble in ethanol is more desirable.
JP 2002-105136 A

Furthermore, a water-soluble copolymer of polyethylene glycol acrylate and acrylic acrylate is known. (See Patent Document 2). This technique can protect the surface of the solid phase during immunoassays. However, since this copolymer is water-soluble, it has been difficult to maintain biocompatibility for a long time.
JP 11-287802 A

Separately, a phosphorylcholine-like group-containing polymer is known. (See Patent Document 3). This technology allows water insolubles while maintaining good biocompatibility by copolymerizing hydrophilic (meth) acrylate monomers containing highly biocompatible phosphorylcholine groups with highly hydrophobic alkyl (meth) acrylate monomers. To do. However, biocompatibility from the viewpoint of immunity has not been specialized. It is considered that the ammonium ion (N +) possessed by the phosphorylcholine group activates the living immune system. (See FIG. 1).
Japanese Patent Laid-Open No. 11-35605

As a water-insoluble blood compatible polymer, a copolymer of an alkoxyalkyl acrylate and an alkyl (meth) acrylate is known, and this uses a special copolymer. (See Patent Documents 4 and 5).
JP 2004-161954 A JP 2003-1111836 A

On the other hand, various techniques have been reported for antibacterial materials. As an antibacterial substance, an antibacterial material containing an ammonium salt is disclosed in, for example, Patent Document 6 and Patent Document 7, and an antibacterial material containing a biguanide is disclosed in, for example, Patent Document 8 and Patent Document 9. Yes. Further, Patent Document 10 discloses an antibacterial material containing protein silver as an antibacterial active ingredient.
Japanese Patent Publication No. 4-25301 Japanese Patent Publication No. 3-64143 Japanese Patent Publication No. 5-80225 Japanese Examined Patent Publication No. 2-61261 Japanese Examined Patent Publication No. 6-55892

  However, although these technologies have been studied to exhibit excellent antibacterial properties, no consideration has been given to antithrombogenicity, so long-term indwelling that needs to be placed in the long-term body such as a high nutritional infusion catheter. When used in medical devices or the like, bacteria propagate in thrombus generated by contact between blood and material, and enter bacteria to cause infection. Thus, it is necessary for long-term indwelling devices and the like to develop antithrombotic and antibacterial properties for a long time and simultaneously.

Therefore, antithrombotic and antibacterial catheters (see Patent Document 11) and antithrombotics that have antithrombotic and antibacterial properties developed on the catheter surface in which antibacterial substances are kneaded are coated on the surface of the catheter. An antithrombotic antibacterial catheter (see Patent Document 12) in which a drug is immobilized. However, since it is necessary to mix an antibacterial substance with the resin of the catheter, the antibacterial substance is contained not only on the surface of the medical device where the antibacterial is required but also the entire material, and the antibacterial substance is used excessively. It will be. Further, if the resin containing the antibacterial substance is present only in the vicinity of the surface of the medical device, it is necessary to operate the extruder step by step, which complicates the manufacturing process. Therefore, an antithrombotic antibacterial material that can simultaneously exhibit antibacterial properties and antithrombogenic properties and can be used as a surface treatment agent regardless of the molding of a medical device has been strongly desired.
JP 2005-334216 A Japanese Patent Laid-Open No. 10-211272

  The present invention is a surface treatment agent that is superior in antithrombogenicity and by extension to biocompatibility as compared with conventional medical materials, and has a high hydrophilicity. It is an antithrombotic antibacterial composition imparted with properties.

The present inventors have obtained a PEG biocompatible copolymer obtained by copolymerizing a (meth) acrylate having a hydrophilic polyethylene glycol (PEG) skeleton and a hydrophobic long-chain alkyl (meth) acrylate, As a result, it was found that it became insoluble in water while maintaining blood compatibility, and it was found that blood compatibility could be imparted to medical devices by applying it. Furthermore, since the copolymer obtained does not have a highly polar functional group such as an ionic group, it has been found that the activation of the immune system upon contact with blood can be suppressed. Moreover, it discovered that long-term antibacterial property could be provided by making this acrylate polymer contain an antibacterial substance. That is, the present invention has the following configuration.
(1) A water-insoluble and viscous (meth) acrylate copolymer containing an alkyl (meth) acrylate represented by the following general formula 1 and a methoxypolyethylene glycol (meth) acrylate represented by the following general formula 2 and an antibiotic, chlorhexidine An antithrombotic antibacterial composition comprising at least one antibacterial substance selected from the group consisting of a biguanide compound such as benzalkonium, a salt compound thereof, and a metal compound such as silver sulfadiazine.
(In the formula, R1 represents an alkyl group or aralkyl group having 2 to 30 carbon atoms, and R2 represents a hydrogen atom or a methyl group.)
(In the formula, R3 represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 5.)
(2) The antithrombotic antibacterial composition according to (1), wherein the antibacterial substance is at least one selected from the group consisting of benzalkonium chloride, penicillin G potassium, streptomycin sulfate, sulfadiazine silver, and chlorhexidine.
(3) The anti-resistor according to (1) or (2), comprising a (meth) acrylate copolymer comprising an alkyl (meth) acrylate and a methoxypolyethylene glycol (meth) acrylate in a molar ratio of 30 to 90/70 to 10. Thrombotic antibacterial composition.
(4) The antithrombotic antibacterial composition according to any one of (1) to (3), wherein the (meth) acrylate copolymer is soluble in any of alcohols having 1 to 6 carbon atoms.
(5) The antithrombotic antibacterial composition according to any one of (1) to (4), comprising a (meth) acrylate copolymer having a glass transition temperature of −100 to 20 ° C. of the (meth) acrylate copolymer.
(6) The antithrombotic antibacterial composition according to any one of (1) to (5), wherein the (meth) acrylate copolymer has a number average molecular weight of 2,000 to 200,000.
(7) The antithrombotic antibacterial according to any one of (1) to (6), wherein the antibacterial substance is contained in an amount of 0.1% to 50.0% by weight with respect to the antithrombotic antibacterial composition. Sex composition.
(8) The antithrombotic antibacterial composition according to any one of (1) to (7), wherein the antibacterial activity value evaluated based on the film adhesion method of JIS Z 2801 is 1.3 or more.
(9) A medical device, wherein the antithrombotic antibacterial composition according to any one of (1) to (8) is supported on at least a part of a blood contact portion.

  The copolymer of the present invention can be used as a material having excellent biocompatibility and high hydrophilicity. In addition, since the material is a viscous substance that is insoluble in water, it can be coated on the entire blood circuit without impairing the physical properties of medical equipment. In addition, a long-term antibacterial material is provided by including an antibacterial substance. To do.

  In the present invention, it is preferable that the (meth) acrylate copolymer containing alkyl (meth) acrylate and methoxypolyethylene glycol (meth) acrylate is substantially water-insoluble. Here, substantially water-insoluble means that the (meth) acrylate copolymer is allowed to stand for 30 days in 37% physiological saline at 99% by weight with respect to 1% by weight of the copolymer. The weight reduction rate of the polymer is 1% by weight or less. By being substantially insoluble in water, it is preferable from the viewpoint of preventing elution of the copolymer into blood or the like even when it comes into contact with living tissue or blood.

In the present invention, the alkyl (meth) acrylate represented by the following general formula 1 constituting the (meth) acrylate copolymer is preferably one having 2 to 30 carbon atoms in R ₁ , more preferably. Is 4 to 24, more preferably 6 to 18. Specific examples of such alkyl (meth) acrylates include normal hexyl (meth) acrylate, cyclohexyl (meth) acrylate, phenyl (meth) acrylate, benzyl (meth) acrylate, heptyl (meth) acrylate, and n-octyl (meth). Acrylate, 2-ethylhexyl (meth) acrylate, n-nonyl (meth) acrylate, decyl (meth) acrylate, lauryl (meth) acrylate, myristyl (meth) acrylate, palmityl (meth) acrylate, stearyl (meth) acrylate, etc. However, those having 8 to 12 carbon atoms are more preferable from the viewpoint of cost and performance, such as 2-ethylhexyl (meth) acrylate and lauryl (meth) acrylate, but those having 8 to 12 carbon atoms from the viewpoint of cost and performance. But Ri Preferably, 2-ethylhexyl (meth) acrylate, lauryl (meth) acrylate.
(In the formula, R ₁ represents an alkyl group or aralkyl group having 2 to 30 carbon atoms, and R ₂ represents a hydrogen atom or a methyl group.)

In the present invention, the methoxypolyethylene glycol (meth) acrylate represented by the following general formula 2 constituting the (meth) acrylate copolymer is preferably one having an ethylene oxide unit of 1 to 1,000. . More preferably, it is 1-500, More preferably, it is 1-100, More preferably, it is 2-10, Most preferably, it is 2-5. Specifically, methoxydiethylene glycol (meth) acrylate, methoxytriethylene glycol (meth) acrylate, methoxytetraethylene glycol (meth) acrylate, methoxypentaethylene glycol (meth) acrylate, methoxyhexaethylene glycol (meth) acrylate, methoxyhepta Examples include ethylene glycol (meth) acrylate, methoxyoctaethylene glycol (meth) acrylate, methoxy nonaethylene glycol (meth) acrylate, and methoxydecaethylene glycol (meth) acrylate. If the repeating unit is large and the hydrophilicity increases too much, the solubility of the co-polymer in the blood is high, and thus there is a possibility that it will be easily eluted from the medical material. That is, there is a possibility that long-term antithrombogenicity cannot be brought to the medical device. Accordingly, methoxytetraethylene glycol (meth) acrylate having 4 ethylene oxide units and 3 methoxytriethylene glycol (meth) acrylate are preferred. Methoxytriethylene glycol (meth) acrylate having 3 ethylene oxide units, which is excellent in the hydrophilic-hydrophobic balance of the copolymer, is more preferred.
(In the formula, R ₃ represents a hydrogen atom or a methyl group, and n represents an integer of 1 to 1,000.)

In the present invention, specific examples of water-insoluble (meth) acrylate copolymers include normal hexyl (meth) acrylate-methoxydiethylene glycol (meth) acrylate copolymer, normal hexyl (meth) acrylate. -Methoxytriethylene glycol (meth) acrylate copolymer, normal hexyl (meth) acrylate -methoxytetraethylene glycol (meth) acrylate copolymer, normal hexyl (meth) acrylate -methoxyhexaethylene glycol (meth) acrylate copolymer , Normal hexyl (meth) acrylate-methoxytetraethylene glycol (meth) acrylate copolymer, cyclohexyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate Rate copolymer, phenyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, phenyl (meth) acrylate-methoxytetraethylene glycol (meth) acrylate copolymer, phenyl (meth) acrylate-methoxypentaethylene Glycol (meth) acrylate copolymer, n-octyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, n-octyl (meth) acrylate-methoxytetraethylene glycol (meth) acrylate copolymer, 2 -Ethylhexyl (meth) acrylate-methoxydiethylene glycol (meth) acrylate copolymer, 2-ethylhexyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate Copolymer, 2-ethylhexyl (meth) acrylate-methoxytetraethylene glycol (meth) acrylate copolymer, lauryl (meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, n-nonyl (meth) acrylate Methoxydiethylene glycol (meth) acrylate copolymer, n-nonyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, n-nonyl (meth) acrylate-methoxytetraethylene glycol (meth) acrylate copolymer, n-nonyl (meth) acrylate-methoxyhexaethylene glycol (meth) acrylate copolymer, n-decyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, steer (Meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, stearyl (meth) acrylate-methoxyhexaethylene glycol (meth) acrylate copolymer, lauryl (meth) acrylate-methoxytriethylene glycol (meth) acrylate Such as, but not limited to, a myristyl (meth) acrylate-methoxytriethylene glycol (meth) acrylate copolymer, and an alkyl (meth) acrylate of general formula 1 and A methoxy polyethylene glycol (meth) acrylate monomer is arbitrarily combined at a molar ratio of 30 to 90/70 to 10 and copolymerized according to a conventional polymerization method. Considering the polymerization conditions of the copolymer and the properties as a medical material, the copolymer was preferably copolymerized so that the number average molecular weight was 2,000 to 200,000 at a molar ratio of 50 to 80/50 to 20. Things are optimal.
In consideration of the use as a medical material, a product obtained by purifying unreacted monomer so as to be 5 mol% or less by a reprecipitation method is suitable.

In the present invention, the number average molecular weight of the (meth) acrylate copolymer is preferably 2,000 or more from the viewpoint of ease of purification by reprecipitation of the polymer. If the number average molecular weight is too small, not only may there be a risk of elution into the blood, but the strength and stability of the coating film may be lost. Moreover, since the viscosity at the time of preparing a coating solution increases as the molecular weight increases, there is also a secondary effect that the adhesion to the coating substrate is improved. That is, it leads to bringing a long-term antithrombogenicity to a medical device. Therefore, the number average molecular weight of the (meth) acrylate copolymer is more preferably 5,000 or more, and further preferably 8,000 or more. The number average molecular weight of the (meth) acrylate copolymer is preferably 200,000 or less in order to reduce the viscosity of the coating solution when the (meth) acrylate copolymer is coated on a medical device or the like. More preferably, it is 150,000 or less, More preferably, it is 100,000 or less, Even more preferably, it is 50,000 or less, Most preferably, it is 25,000 or less. Here, the number average molecular weight is obtained by dividing the sum of the molecular weights of all molecules by the number of molecules, and is one of the characteristics of the polymer.
Methods for measuring number average molecular weight include end group quantification method, osmotic pressure method, vapor pressure osmometry, vapor pressure drop method, freezing point drop method, boiling point rise method, gel permeation chromatography (GPC) method, etc. In the present invention, the gel permeation chromatography (GPC) method is preferably employed from the viewpoint of ease of operation.
Setting the number average molecular weight of the (meth) acrylate copolymer to 2,000 to 200,000 means that the copolymer is purified, treated with a treatment solution, adaptable to medical materials, and the stability of the coating film. It is also a very important technical requirement to achieve specific technical issues related to

  In this invention, it is preferable that the alkyl (meth) acrylate and methoxypolyethyleneglycol (meth) acrylate which comprise a (meth) acrylate copolymer are copolymerized by the molar ratio of 30-90 / 10-70. If the amount of alkyl (meth) acrylate is too small, the copolymer tends to dissolve in water such as blood, and if it is too large, the blood compatibility of methoxypolyethylene glycol (meth) acrylate may not be sufficiently exhibited. Therefore, the molar ratio is more preferably 40 to 90/10 to 60, further preferably 45 to 85/15 to 55, and still more preferably 50 to 80/20 to 50.

  The (meth) acrylate copolymer may be a copolymer in which the monomer of the general formula [1] and the monomer of the general formula [2] are alternately arranged, but if analyzed from the total amount, the hydrophobic monomer It is also possible that the copolymer is composed of a segment or block consisting of the above and a segment or block consisting of a hydrophilic monomer. A segment or block made of a hydrophobic monomer may take a complicated structure such as a so-called microphase-separated structure or a mosaic pattern that functions to fix a segment or block made of a hydrophilic monomer. Can be assumed once. In any case, the size of the molecular weight of the copolymer and the type and characteristics of the hydrophilic monomer will have some influence, but if the amount of the hydrophobic monomer is slightly increased, the segment consisting of the hydrophilic monomer of the copolymer Or elution of a block can be suppressed. In addition, increasing the number of the hydrophobic segments slightly seems to fulfill the function of increasing the affinity with the hydrophobic medical material, and it can be assumed that the film plays an advantageous role for fixing to the medical material. Although the current state of the presence or absence of the segment and the behavior related to the affinity state cannot be accurately verified based on the technical basis, the copolymer is a polymer material having affinity friendly to the living body.

  According to “Acrylic Resin Synthesis / Design and New Application Development, Chubu Business Development Center, Issued in 1985”, “Acrylic Esters and Their Polymers [II] Shoshodo Co., Ltd., Showa 50” As the number increases, the glass transition point of the polymer tends to decrease and increase after reaching a certain minimum. The minimum value is 8 carbon atoms for n-alkyl acrylate and 12 carbon atoms for n-alkyl methacrylate. That is, it is shown that the glass transition temperature of the copolymer can be lowered by incorporating an alkyl acrylate having 8 carbon atoms by copolymerization.

In addition, methoxypolyethylene glycol (meth) acrylate homopolymer has high hydrophilicity and is excellent in blood compatibility. However, since it is water-soluble, there is a problem of gradual elution when contacted with blood for a long time. It was. As a result of intensive studies on materials that can withstand long-term use as well as being excellent in blood compatibility, the present inventors have found that they have moderate hydrophobicity to prevent elution into blood and the like, and physical removal of the coating film (desorption). It has been found that this problem can be solved by imparting flexibility to the antithrombotic substance to prevent separation. That is, the inventors have found that the above-mentioned problems can be solved by copolymerizing a specific methoxypolyethylene glycol (meth) acrylate as described above and an alkyl (meth) acrylate having a specific carbon number, and completed the present invention.
Thus, the copolymer is composed of hydrophilic monomers, segments, or blocks having functions such as antithrombotic and anti-elution functions that deal with blood, and those that deal with medical materials, such as affinity, It consists essentially of two types of monomer components that perform so-called two-sided interfacial functions, that is, composed of hydrophobic monomers, segments or blocks having functions such as stickiness. It also appears that the monomers, segments, or blocks that make up the copolymer complement each other in the molecular structure, forming a bond or structure that is stable to elution, dispersion, and the like.

  In the present invention, the (meth) acrylate copolymer is preferably soluble in any alcohol having 1 to 6 carbon atoms. It is more preferable that it is soluble in an alcohol having 1 to 3 carbon atoms because drying after coating becomes easy. Here, the term “soluble” means that when 1 g of a (meth) acrylate copolymer is immersed in 10 ml of the alcohol at 25 ° C., at least 90% by weight of the (meth) acrylate copolymer is dissolved within 16 hours at room temperature. Say that.

  According to “Polymer Basic Science, Shosodo Co., Ltd., published in 1991”, if a polymer is cooled from a molten state, it will not crystallize but will eventually go into a glassy state and solidify. is there. This transition from the molten state to the glass state is called the glass transition, and this temperature is called the glass transition temperature. Below the glass transition temperature, the polymer loses fluidity and is glassy, while above the glass transition temperature, it has fluidity, that is, in a liquid state. That is, in order to give flexibility to the copolymer of the present invention, it is necessary to have a glass transition temperature lower than room temperature (25 ° C.).

  The glass transition temperature of the (meth) acrylate copolymer of the present invention is preferably -100 to 20 ° C. −80 to 5 ° C. is more preferable, −60 to −10 ° C. is more preferable, and −60 to −25 ° C. is even more preferable. If the glass transition temperature is too high, the antithrombotic substance (copolymer) carried on the medical device may be physically peeled off. If the glass transition temperature is too low, the fluidity of the copolymer increases and the workability of the coating may be reduced.

  In the present invention, the antibacterial substance is not particularly limited, and any antibacterial substance may be used. For example, ampicillin, nafcillin, amoxicillin, oxacillin, azurocillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, pheneticillin, floxacillin, piperacillin, mesilinum, sulbenicillin, methicillin, ticarcirin, mezucirceline , Cefradine, cephatridin, cefsulodin, cephazoline, ceftazidime, ceforanide, ceftriaxone, cefoxitin, cefuroxime, cefacetril, latamoxef, cephalexin, amikacin, neomycin, dibekacin, kanamycin, gentamicin, netilomycin, kanamycin, tobramycin, Antibiotics such as nystatin, clindamycin, polymyxin, colistin, lovamicin, erythromycin, streptomycin, spectinomycin, lincomycin, vancomycin, chlortetracycline, oxytetracycline, demeclocycline, loritetracycline, doxycycline, tetracycline, minocycline, Antifungal agents such as amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatin, griseofulvin, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate Such as paraoxybenzoic acid esters, chlorhexidine, etc. Compounds, benzethonium, benzalkonium, lauryl sulfate, alkylpolyaminoethylglycine, fatty acids, surface active compounds such as domifene bromide, phenol derivatives such as thymol, phenol, hexachlorophene, resorcin, boric acid such as boric acid and borax Compounds, iodine compounds such as iodine, iodoform, povidone iodine, metals such as gold, silver, copper, mercury, metal compounds such as thimerosal, methylobromine, sulfadiazine silver, antibacterial pigment compounds such as acrinol, methylrosalinine, mafenide acetate, sulfadiazine, And sulfa drugs such as sulfisomidine and sulfamethoxazole. These antibacterial substances may be salt compounds such as sodium salt, potassium salt, magnesium salt, calcium salt, hydrochloride, sulfate, gluconate, etc., and two or more kinds of antibacterial substances are used in combination. May be.

  The antibacterial substances can be broadly classified into water-soluble and poorly water-soluble, and typical examples of water-soluble antibacterial substances include benzalkonium chloride, povidone iodine, penicillin G potassium, streptomycin sulfate and the like. Representative examples of poorly water-soluble antibacterial substances include silver sulfadiazine and chlorhexidine.

  In the present invention, when an antithrombotic substance (copolymer) and a sparingly water-soluble antibacterial substance are coated on a medical device or the like, the copolymer is water-insoluble or the copolymer is water-insoluble and antibacterial. It is unclear whether the poorly water-soluble substances function in a complementary manner, but the elution of the antibacterial substances becomes extremely small and lasting, and long-term antibacterial properties can be maintained. On the other hand, when the copolymer is coated with a water-soluble antibacterial substance, the copolymer is insoluble in water, but since the antibacterial substance is water-soluble, its elution amount is slightly water-soluble antibacterial. Compared to the case where a substance is used, the antibacterial property can be instantly expressed and strong, but long-term antibacterial property cannot be maintained. For example, an indwelling catheter, an infusion tube, an artificial lung, and the like are medical devices that are used continuously for 1 to several days. For such applications, long-term antimicrobial activity is required. In addition, by using a water-soluble and poorly water-soluble antibacterial substance in combination with the copolymer, it exerts a strong bactericidal power by the water-soluble antibacterial substance in the initial stage, and thereafter, the long-term use of the water-insoluble antibacterial substance It is also possible to impart multistage antibacterial properties such as exhibiting excellent antibacterial properties. If this multi-stage antibacterial property is applied to an indwelling catheter, water-soluble antibacterial substances elute early and express strong antibacterial properties. Sterilize and reduce the risk of infection during insertion. During catheter placement, the long-term antibacterial properties of poorly water-soluble antibacterial substances can prevent bacterial colonization and bacterial growth that has penetrated from the insertion site. Risk can be reduced.

  In the present invention, the antibacterial substance is preferably 0.01 to 70% by weight, more preferably 0.05 to 60% by weight, still more preferably 0.1 to 50% by weight based on the weight of the antithrombotic antibacterial composition. %. If the content of the antibacterial substance is too low, the antibacterial property of the antibacterial substance may not be sufficiently exhibited. In addition, if the content of antibacterial substances is too high, the appearance of medical devices after surface treatment such as coatings may increase, or the dissolution of antibacterial substances into the body may increase. May cause irritation. Accordingly, the antibacterial substance may be present on the entire surface of the medical device, but it is preferable that the antibacterial substance is present only in the vicinity of the insertion portion through which the skin is inserted, from the viewpoint of suppressing local inflammation.

  The copolymer of the present invention may be any of a random copolymer, a block copolymer, and a graft copolymer. Further, the copolymerization reaction itself for producing the copolymer of the present invention is not particularly limited, and known methods such as radical polymerization, ionic polymerization, photopolymerization, and polymerization using a macromer can be used.

As an example for producing the (meth) acrylate copolymer of the present invention, a production method by radical polymerization is shown below.
That is, a monomer, a polymerization solvent, and an initiator are added to a stirrable reaction apparatus equipped with a reflux tower, and the polymerization is started by heating after nitrogen substitution, and the polymerization proceeds by maintaining the temperature for a certain time. More preferably, nitrogen is bubbled during the polymerization. In this polymerization, a chain transfer agent can be used in combination to control the molecular weight. The solvent is removed from the solution after completion of the polymerization to obtain a crude (meth) acrylate copolymer. Subsequently, the obtained crude (meth) acrylate copolymer is dissolved in a good solvent and dropped into a poor solvent under stirring to perform a purification treatment (hereinafter sometimes referred to as reprecipitation treatment). The purification treatment is repeated 1 to several times to increase the purity of the (meth) acrylate copolymer. The copolymer thus obtained is dried.

  As a polymerization solvent used in the copolymerization, alcohols such as methanol, ethanol and isopropyl alcohol, organic solvents such as ethyl acetate, toluene, benzene and methyl ethyl ketone, or water can be used. From the viewpoint of the solubility and easy availability of the resulting copolymer, it is preferable to use ethyl acetate, methanol, ethanol or the like. In addition, a plurality of kinds of the solvents can be mixed and used. The charging weight ratio of these polymerization solvent and monomer is preferably 20 to 90/80 to 10, more preferably 30 to 90/70 to 10, and still more preferably 35 to 85/65 to 15. When the charging ratio is within the above range, the polymerization reaction rate can be maximized.

  As the polymerization initiator, a peroxide type or azo type radical initiator generally used in radical polymerization is used. Examples of peroxide radical initiators include inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide, and organic peroxides such as benzoyl peroxide, t-butyl hydroperoxide, cumene peroxide, and the like. As the azo radical initiator, for example, 2,2′-azobisisobutyronitrile, 2,2′-azobis (2-amidinopropane) dihydrochloride, dimethyl 2,2′-azobisbutyrate, dimethyl 2 , 2′-azobis (2-methylpropionate) and the like are used. Moreover, the redox initiator which combined the reducing agent with the peroxide type initiator can also be used. These polymerization initiators and the like are preferably added in an amount of 0.01 to 1% by weight based on the monomers in the polymerization solution. More preferable addition amount is 0.05 to 0.5% by weight, more preferably 0.05 to 0.3% by weight. By making the addition amount of a polymerization initiator etc. into the said range, the copolymer which has a suitable number average molecular weight with a favorable monomer reaction rate can be obtained.

  Although the temperature at the time of polymerization varies depending on the type of solvent and the type of initiator, it is preferable to use the vicinity of the 10-hour half-life temperature of the initiator. Specifically, when using the said initiator, 20-90 degreeC is preferable. 30-90 degreeC is more preferable, and 40-90 degreeC is further more preferable. As the chain transfer agent used for controlling the molecular weight during polymerization, a high-boiling thiol compound such as dodecyl mercaptan, thiomalic acid, thioglycolic acid, isopropyl alcohol, phosphorous acid, hypophosphorous acid, etc. may be used. it can.

  In the present invention, since the (meth) acrylate copolymer is obtained by copolymerizing hydrophilic and hydrophobic monomers, it has both hydrophilic and hydrophobic properties. Therefore, the solution after copolymerization comprises a hydrophilic monomer (methoxypolyethylene glycol (meth) acrylate), a hydrophobic monomer (alkyl (meth) acrylate), and a (meth) acrylate copolymer which are unreacted monomers. Ingredients are mixed. In order to isolate a water-insoluble (meth) acrylate copolymer from these mixtures, for example, the copolymer solution is dropped into a reprecipitation solution that dissolves a hydrophilic monomer, followed by purification. The copolymer can be purified using a reprecipitation solution that dissolves the hydrophobic monomer. However, such a combination of purification methods has problems such as not only complicated purification work, but also increased purification costs and increased copolymer loss. As a result of intensive studies on a purification method for obtaining a (meth) acrylate copolymer at a low cost and a high recovery rate, the present inventors have conducted reprecipitation poor by mixing alcohol and water at a specific ratio. It has been found that a (meth) acrylate copolymer can be efficiently recovered by using a solvent.

  In the present invention, it is preferable to use a solvent that does not dissolve the copolymer but dissolves both hydrophilic and hydrophobic monomers as a solvent used for purifying the copolymer by reprecipitation. In the case of using only alcohol, in order to precipitate the (meth) acrylate copolymer, it is necessary to improve or lower the hydrophilicity than alcohol. As a method for controlling the hydrophilicity of such an alcohol, a method in which a highly hydrophilic solvent is mixed with the alcohol is used. Specific examples of such solvents include water, 1,4-dioxane, tetrahydrofuran, N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, and the like. It is preferable to use water from the viewpoint of volatilization and cost. By mixing alcohol and water at a constant mixing ratio and using as a poor solvent, a (meth) acrylate copolymer can be obtained simply, at low cost, and at a high recovery rate.

  In the present invention, the alcohol used for the reprecipitation treatment is preferably an alcohol having 1 to 10 carbon atoms, more preferably an alcohol having 1 to 7 carbon atoms, and still more preferably an alcohol having 1 to 4 carbon atoms. is there. Specific examples of such alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxy-1-propanol, and tertiary butanol. Methanol, ethanol, 1-propanol and 2-propanol are particularly preferable.

  As the reprecipitation solvent in the present invention, it is preferable to use a mixture of alcohol having 1 to 10 carbon atoms and water in a weight ratio of 40 to 99/60 to 1, more preferably 50 to 99/50 to 1. More preferably, it is 60-95 / 40-5. If the alcohol ratio is too large, the (meth) acrylate copolymer is difficult to precipitate, and if the water ratio is too large, the precipitated (meth) acrylate copolymer may contain unreacted monomers as impurities. 70-95 / 30-5 are particularly preferred.

  In this invention, the aspect which uses the liquid mixture of C1-C10 alcohol and water as a poor solvent for reprecipitation is demonstrated in detail. Any good solvent may be used as long as the (meth) acrylate copolymer is dissolved and can be mixed with the poor solvent. Specifically, for example, tetrahydrofuran, chloroform, acetone, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc., tetrahydrofuran having a low boiling point in terms of easy drying, Acetone is particularly preferred. It is preferable to purify by repeating the reprecipitation treatment using these as a good solvent and adding to the poor solvent a plurality of times.

  By performing the reprecipitation operation as described above 2 to 8 times as necessary, the water-insoluble (meth) acrylate copolymer having an unreacted monomer content of less than 5 mol% can be recovered at a high recovery rate of 50% by weight or more. It becomes possible to collect. When the content of unreacted monomers, oligomers and polymerization residues contained in the copolymer is large, it is considered that it is eluted into blood and becomes a causative substance such as a patient's shock symptoms. Most of those causative substances can be removed by the reprecipitation purification method. However, if the causative substances are converted into reaction monomers and the patient's safety is taken into consideration, the content must be 5 mol% or less. However, considering the purification process, it is preferably 3 mol% or less, preferably 1 mol% or less. In the present invention, as a result of careful attention in consideration of the special use of medical materials, as a result of employing a purification step involving a slight loss or abandonment of the copolymer in reprecipitation purification, unreacted monomer residue It was possible to provide a copolymer having an amount of about 0.06 mol%, far exceeding the ideal of 0.1 mol% or less. If this is expressed by purity, which is another conventional index, the weight of the copolymer alone (W2) contained in the previous weight (W1) of the purified copolymer is W2 / W1 × 100 in the ratio of the two. When calculated by the above, it can be said that it is 90% by weight or more, preferably 95% by weight or more, particularly 99% by weight or more in terms of the purity of the copolymer. Can be provided.

  In the present invention, if the recovery rate of the (meth) acrylate copolymer after reprecipitation exceeds 90% by weight, there is a fear of containing unreacted monomers in the recovered product, and if it is less than 50% by weight, the production efficiency decreases. The recovery rate is preferably 50 to 90% by weight. Keeping the recovery rate to 50 to 90% by weight means that the recovery of the copolymer is slightly lost or abandoned, but it is inevitable from the viewpoint of preventing mixing of unreacted monomers as much as possible. is there. This is because, given the unique situation of being a copolymer having both hydrophilic and hydrophobic properties applied to medical materials, such consideration must be taken into account.

  The purified copolymer requires removal of the solvent by drying. As a drying method, for example, it may be carried out continuously at 60 ° C. under a reduced pressure of 1 Torr or less for 2 to 10 days, and when sufficient drying is not obtained, the reduced pressure drying may be continued. The (meth) acrylate copolymer thus obtained preferably has a purity of 95 mol% or more. When the copolymer purity is 95 mol% or more, for example, when used as a coating material for a medical device as described later, a highly safe material for medical use is provided such that monomers, oligomers, etc. do not elute into blood. Can do.

  In addition, the above-described copolymer of the present invention is water-insoluble and can be preferably used as a surface treatment agent that imparts antithrombogenic properties to medical devices and the like. As a specific embodiment, a solution obtained by dissolving the obtained copolymer in an organic solvent is applied to the surface of a substrate such as a medical device or the medical device is once immersed in the solution, and then the solvent is removed. Can be obtained. As a method for supporting the copolymer of the present invention on the surface of a substrate, known methods such as a coating method, a method using graft polymerization by radiation, electron beam or ultraviolet light, a method using a chemical reaction with a functional group of a substrate, etc. The method is mentioned. Among these, the coating method is preferable in practice because the manufacturing process is easy. Of course, a medical device material and a copolymer previously mixed may be molded into various medical devices. The coating method is not particularly limited, and an application method, a spray method, a dip method, or the like can be used. For example, the coating method includes, for example, immersing the base material in a coating solution in which the (meth) acrylate copolymer of the present invention is dissolved in a suitable organic solvent such as alcohol, chloroform, acetone, tetrahydrofuran, dimethylformamide, and the like. It can be carried out by a simple operation such as air drying. Moreover, it is also preferable to heat and dry the substrate after coating. Thereby, the adhesiveness of a base material and the copolymer of this invention can be improved more, and it can fix more firmly. The coating of the antithrombotic antibacterial composition of the present invention on the medical device may be performed once, but it is also within the scope of the present invention to repeat the treatment several times depending on the purpose and application.

  In the present invention, the method of coating the antibacterial substance on the medical device is not particularly limited. After the antithrombotic substance (copolymer) is coated on the medical device, the antibacterial substance is separately applied to the medical device. The medical device may be coated with an antithrombotic substance and an antibacterial substance mixed and dissolved or dispersed in advance in an organic solvent or the like. The antithrombotic antibacterial composition in the coating solution is preferably 0.005 to 2.5% by weight, more preferably 0.01 to 2.0% by weight. If the content of the antithrombotic antibacterial composition is too low, sufficient antibacterial properties may not be exhibited, and long-term antibacterial properties may not be exhibited. When the content of the antithrombotic antibacterial composition is too high, the viscosity of the coating liquid becomes high, and the workability of the coating may be reduced. In addition, the coating layer becomes thick, and the frictional resistance at the time of catheter insertion may increase. If the frictional resistance is high, it becomes difficult to insert the catheter, and if it is inserted forcibly, the skin of the insertion part may become inflamed.

  In the present invention, it is preferable that the antibacterial activity after 7 days is 1.3 or more when evaluated by an antibacterial test described later. If the antibacterial activity after 7 days is 1.3 or more, it can be determined that sufficient antibacterial activity is maintained even in a long-term use medical device. Since it shows that it is excellent in antibacterial property, so that an antibacterial activity value is large, 1.6 or more are more preferable, and 2.0 or more are further more preferable.

  As the solvent for preparing the coating solution of the antithrombotic antibacterial composition of the present invention, a solvent that does not damage the medical device as a base as much as possible is selected. Specifically, methanol, ethanol, isopropyl alcohol, normal propyl alcohol, acetone, normal hexane, cyclohexane, tetrahydrofuran, 1,4-dioxane, cyclohexanone, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone Among them, methanol, ethanol, and isopropyl alcohol are preferred because they have a low boiling point and can be easily dried after coating. In order to disperse the antibacterial substance more uniformly, it is more preferable to use a mixture of water or ammonia water in these organic solvents as a solvent for the antithrombotic antibacterial composition.

Since the (meth) acrylate copolymer obtained by copolymerizing the alkyl (meth) acrylate of the present invention and methoxypolyethylene glycol (meth) acrylate has an appropriate balance between hydrophilicity and hydrophobicity, it is blood compatible. It can be suitably used as a surface treatment agent for medical devices and artificial organ membranes. In addition, since the (meth) acrylate copolymer of the present invention is a viscous substance insoluble in water, even if it is coated on the surface of a medical device or a membrane for an artificial organ, it is not easily eluted into blood and has a long period of time. Sustains blood compatibility (antithrombotic) effect. And, it is considered that due to the above-mentioned properties of the antithrombotic substance, the sustained release of the antibacterial substance is appropriately controlled, and it is possible to maintain a relatively long-term antithrombogenicity and antibacterial property. A (meth) acrylate copolymer having such characteristics is not found in the prior art, and was first found in the present invention.
In addition, either (meth) acrylate copolymer of this invention can also be used independently, and 2 or more types can also be mixed and used for it.

  When a medical device treated with this (meth) acrylate copolymer comes into contact with blood, highly hydrophilic methoxypolyethylene glycol (meth) acrylate projects over the surface and exhibits antithrombogenic properties. The (meth) acrylate is considered to prevent blood and medical devices from coming into direct contact by staying in the vicinity of the substrate.

  In the present invention, an aging treatment may be mentioned as a method for confirming the water insolubility of the (meth) acrylate copolymer. As the extraction solvent used in the aging treatment, it is preferable to use physiological saline in terms of improving convenience and reliability of blood compatibility evaluation performed thereafter. More preferably, it is carried out at a constant temperature of 37 ° C. If the (meth) acrylate copolymer is insoluble in water, high blood compatibility is maintained even after aging treatment.

In the present invention, a comparison of complement values is given as a method for evaluating the degree of immune activation of the (meth) acrylate copolymer. The Mayer method for measuring CH50 is preferable because it is simple and quick, and the measurement kit is easily available and inexpensive. (Refer nonpatent literature 5). The sensitized red blood cells are hemolyzed by the reaction between the sheep sensitized red blood cells and the complement in serum. Since the degree of hemolysis decreases as the complement system is activated, it can be used significantly as an evaluation method.
Artificial organ 23 (3), 654-659 (1994)

  Another aspect of the present invention is a medical device in which the antibacterial (meth) acrylate copolymer according to the present invention is supported on at least a part of a blood contact portion. In the medical device of the present invention, it is preferable that at least a part of the surface, preferably the entire surface in contact with blood or the like, is treated with the (meth) acrylate copolymer of the present invention. In one preferred embodiment, the medical device of the present invention is required to have excellent antithrombogenicity and antibacterial properties. Examples of such medical devices include blood filters, blood storage containers, blood circuits, indwelling needles, catheters, guide wires, stents, artificial lung devices, dialysis devices, adhesion prevention materials, wound dressings, and biological tissue adhesive materials. And a repair material for living tissue regeneration. In particular, it is effective for medical devices that need to be placed in the long term and are likely to cause infections.

  Here, all the materials normally used are included as a base material of a medical device. That is, polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, poly-4-methylpentene-1, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubber such as polydimethylsiloxane having a crosslinked portion, polymethyl methacrylate , Polyvinylidene fluoride, tetrafluoropolyethylene, polysulfone, polyethersulfone, polyacetal, polystyrene, ABS resin and mixtures of these resins, metals such as stainless steel, titanium, and aluminum.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these.

(Measurement of number average molecular weight)
To 15 mg of the sample, 3 mL of a mobile phase for GPC measurement was added and dissolved, followed by filtration with 0.45 μm hydrophilic PTFE (Millex-LH, Nihon Millipore). GPC measurement uses 510 high pressure pump, 717plus automatic injection device (Nippon Waters), RI-101 (Showa Denko) measuring device, column PLgel 5μMIXED-D (600x7.5 mm) ((Polymer Laboratories), column The temperature was room temperature, and the mobile phase was tetrahydrofuran (THF) to which 0.03% by weight of dibutylhydroxytoluene (BHT) was added, detected by RI, and injected with 50 μL. The molecular weight composition was monodisperse PMMA (Easi Cal: Polymer Laboratories).

(Measurement of copolymer composition ratio)
Use a Pasteur pipette to add 50 mg of sample to an NMR test tube (standard: N-5, Nippon Seimitsu Chemical), then add 0.7 mL of deuterated chloroform (Wako Pure Chemical Industries, Ltd.) and mix well. The cap was closed with a cap (Standard NC-5, Nippon Seimitsu Chemical Co., Ltd.). The copolymer composition ratio was calculated by performing 1H NMR measurement at room temperature using GEMINI-200 manufactured by VARIAN.

(Measurement of unreacted monomer residue)
Add 50 mg of sample to a NMR test tube (standard N-5, Nippon Seimitsu Chemical Co., Ltd.) with a Pasteur pipette, add 0.7 mL of deuterated chloroform (Wako Pure Chemical Industries, Ltd.), mix well, and use the sample cap. Covered with (Standard NC-5, Nippon Seimitsu Chemical Co., Ltd.). The copolymer composition ratio was calculated by performing 1H NMR measurement at room temperature using GEMINI-200 manufactured by VARIAN. The unreacted monomer contained in the (meth) acrylate copolymer was calculated from the integral ratio obtained by measurement.

(Yield calculation)
The weight ratio of the copolymer after reprecipitation and drying to the total weight of charged monomers was calculated as the yield. When the yield was within the range of 50 to 90% by weight, it was evaluated as good.

(Alcohol solubility test)
After adding 500 mg of a sample into a 50 mL vial, 2 mL of an alcohol having 1 to 6 carbon atoms was added and mixed well. Then, dissolution was confirmed visually.

(Measurement of glass transition temperature)
A differential scanning calorimeter (Shimadzu DSC-50) was used. A 10 mg sample was placed in a cell (Al cell, 6 mmφ, Shimadzu Corporation), covered, crimped and sealed with a sealer crimper (Shimadzu Corporation), and then set in a measuring instrument for measurement. The measurement was carried out from −150 ° C. to 60 ° C. under a N ₂ gas stream at a rate of temperature increase of 5 ° C./min after cooling with liquid nitrogen.

(Aging process)
The antithrombotic antibacterial composition was dissolved in ethanol to obtain a surface treatment agent. A 25 × 25 × 1 mm PVC sheet was immersed in the obtained surface treatment agent, and then the sheet was taken out and dried at 60 ° C. for 24 hours. Further, aging was performed in 37 ° C. physiological saline for 30 days to obtain an aging sample for blood compatibility test. Regarding samples after aging for 30 days, samples with a weight reduction rate of 20% by weight or less were marked with ◯, and samples with a weight loss greater than 20% by weight were marked with ×. When the weight loss exceeds 20% by weight, it can be determined that the sample is significantly dissolved in the physiological saline even when the measurement error is taken into consideration.

(Blood compatibility test)
60 mL of fresh citrated blood removed from the rabbit was aliquoted into two 50 mL centrifuge tubes and centrifuged at 1000 rpm for 10 minutes. The supernatant was equally divided into four 10 mL centrifuge tubes. After further centrifuging at 1500 rpm for 10 minutes, the supernatant was removed, and the pelleted platelet pellet was separated. A platelet solution with a platelet concentration of 3.0 × 10 ⁸ / mL was obtained by adding HBSS (Hank's balanced salt solution) and diluting it. Platelet concentration was confirmed with a blood cell counter (KX-21 Sysmex). This concentration of platelet solution was used as a test solution. 0.2 mL of the obtained test solution was taken and dropped onto the upper surface of an aging sample for blood compatibility test in a 60 × 15 mm petri dish (Corning, polystyrene), and then the lid was covered and incubated at 37 ° C. for 1 hour. Thereafter, 5 mL of a 2.5% by weight aqueous glutaraldehyde solution was added, and the mixture was allowed to stand at room temperature for 24 hours. After replacing the solution in the petri dish with water three times, water was removed. The PVC sheet washed with water was frozen at −5 ° C. for 24 h, and then dried at 0.1 Torr for 24 h. A 10 × 10 mm piece was cut out from the part to which the platelets adhered, and was attached to a scanning electron microscope (SEM) sample stage with double-sided tape to obtain a measurement sample. The state of adherent platelets was photographed with an SEM using a sample subjected to ion deposition. The photographed SEM photograph (x3000 magnification) was compared and observed visually, and the case where the number of adhering platelets was 50 or less was evaluated as good.

(Complement value evaluation-sample preparation)
A solution obtained by dissolving or dispersing the copolymer and the antibacterial substance in ethanol was used as a surface treatment agent. After 1 g of a glass sphere having a diameter of 1 mm was immersed in the obtained surface treatment agent, the glass sphere was taken out and dried at 60 ° C. for 24 hours. Furthermore, the sample was aged in 37 ° C. physiological saline for 30 days to obtain a sample for complement value evaluation.

(Complement value evaluation-measurement)
By allowing 10 mL of fresh human blood collected in a 50 mL polypropylene centrifuge tube (IWAKI) to stand at room temperature for coagulation and centrifuging at 3000 rpm for 30 minutes (using LC06, TOMY SEIKO CO. LTD) 3.5 mL of serum was obtained. After adding 0.1 mL of diluted solution to 1 g of 1 mmφ glass spheres surface-treated as described above, incubate at 37 ° C. for 1 hour, add 0.2 mL of the obtained serum, and similarly incubate at 37 ° C. for 1 hour. Went. After thoroughly mixing 2.6 mL of diluted solution, 12.5 μL of contacted serum and 0.4 mL of sensitized sheep erythrocytes, incubate at 37 ° C. for 1 hour, cool at 0 ° C. for 10 minutes, and then centrifuge at 2000 rpm. The absorbance of 2 mL of the supernatant was measured at 541 nm (U-2000 Spectrometer, HITACHI was used). At the same time, 2.6 mL of diluent and 0.4 mL of sensitized sheep erythrocytes were added and data was subtracted assuming that no hemolysis occurred. Auto CH50-L “Seiken” (unified product number 400437, diluent 52 mL, sensitized sheep erythrocyte 6 mL) was used for the measurement. The relative absorbance was calculated with the absorbance value of the glass sphere not subjected to the surface treatment being 1, and 1.2 or more was judged good and less than 1.2 was judged as poor. If it is less than 1.2, it can be determined that complement is significantly activated even when measurement errors are taken into account.

(Antimicrobial test)
The copolymer and the antibacterial substance were mixed and dissolved or dispersed with ethanol to prepare an ethanol mixed solution to obtain a surface treating agent. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Further, aging was carried out in physiological saline at 37 ° C. for 7 days to obtain an aging sample for antibacterial test. Antibacterial evaluation was performed based on the film adhesion method of JIS Z 2801. In this antibacterial test, the antibacterial activity value can be calculated from the number of viable bacteria. When the antibacterial activity value is 2 or more, the antibacterial effect is obtained. (See FIG. 2).

(Example 1)
Methoxytriethylene glycol acrylate (MTEGA) (Shin Nakamura Chemical Co., Ltd.) 15.1 g and 2-ethylhexyl acrylate (EHA) (Tokyo Kasei Kogyo Co., Ltd.) 29.7 g to azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.) 0.0447 g was added, and a polymerization reaction was performed in 178.9 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) at 80 ° C. for 20 hours. After the completion of the polymerization reaction, the reaction solution was added dropwise to methanol and precipitated to isolate the product. The product was dissolved in tetrahydrofuran (THF) and dropped into methanol twice, and purified. This was dried under reduced pressure at 60 ° C. overnight to obtain a copolymer 1. Various evaluation was performed using the obtained copolymer. The results are summarized in Table 1.

  Prepare 1wt% ethanol mixture as antithrombotic antibacterial composition concentration by dissolving or dispersing 1.998g of antithrombotic substance (Copolymer 1) and 0.002g silver sulfadiazine as antibacterial substance in ethanol Thus, a surface treating agent was obtained. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 1.

(Example 2)
A surface treatment agent was prepared by dissolving or dispersing 1.998 g of the copolymer obtained in Example 1 and 0.002 g of chlorhexidine as an antibacterial substance in ethanol to prepare a 1 wt% ethanol mixed solution as an antithrombotic antibacterial composition concentration. Got. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 1.

(Example 3)
Add 0.0543 g of azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.) to 22.2 g of methoxytriethylene glycol acrylate (MTEGA) (Shin Nakamura Chemical Co., Ltd.) and 44.2 g of EHA (Tokyo Chemical Industry Co., Ltd.), and add ethyl acetate (Tokyo Chemical Industry Co., Ltd.) The polymerization reaction was carried out in 178.9 g under conditions of 80 ° C. and 20 hours. After the completion of the polymerization reaction, the reaction solution was added dropwise to methanol and precipitated to isolate the product. The product was dissolved in tetrahydrofuran (THF) and dropped into methanol twice, and purified. This was dried under reduced pressure at 60 ° C. all day and night to obtain a copolymer 2. Various evaluation was performed using the obtained copolymer. The results are summarized in Table 1.

  1.98 g of the obtained copolymer and 0.02 g of sulfadiazine silver as an antibacterial substance are dissolved or dispersed in ethanol to prepare a 0.1 wt% ethanol mixture as an antithrombotic antibacterial composition concentration to obtain a surface treatment agent It was. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 1.

Example 4
By dissolving or dispersing 1.98 g of the copolymer obtained in Example 3 and 0.01 g of sulfadiazine silver as an antibacterial substance and 0.01 g of benzalkonium chloride in ethanol, 0.1 wt% ethanol as an antithrombotic antibacterial composition concentration is obtained. A mixed solution was prepared to obtain a surface treating agent. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 1.

(Example 5)
Methoxytriethylene glycol acrylate (MTEGA) (Shin Nakamura Chemical Co., Ltd.) 33.4 g and lauryl acrylate (LA) (Tokyo Chemical Industry Co., Ltd.) 38.9 g were charged with Azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.) 0.0747 g In addition, the polymerization reaction was performed in 178.9 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) at 80 ° C. for 20 hours. After the completion of the polymerization reaction, the reaction solution was added dropwise to methanol and precipitated to isolate the product. The product was dissolved in tetrahydrofuran (THF) and dropped into methanol twice, and purified. This was dried under reduced pressure at 60 ° C. all day and night to obtain a copolymer 3. Various evaluation was performed using the obtained copolymer. The results are summarized in Table 1.

  A surface treatment agent was obtained by preparing a 2.0% by weight ethanol mixture as an antithrombotic antibacterial composition concentration by dissolving or dispersing 1.8 g of the obtained copolymer and 0.2 g of sulfadiazine silver as an antibacterial substance in ethanol. It was. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 1.

(Example 6)
A 2.0 wt% ethanol mixed solution was prepared as an antithrombotic antibacterial composition concentration by dissolving or dispersing 1.8 g of the copolymer obtained in Example 5 and 0.2 g of penicillin G potassium as an antibacterial substance in ethanol, A surface treating agent was obtained. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Further, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial properties against Staphylococcus aureus before aging and after aging for 1 week were examined. The results are summarized in Table 1.

(Example 7)
Methoxytriethylene glycol acrylate (MTEGA) (Shin Nakamura Chemical Co., Ltd.) 22.2 g and lauryl acrylate (LA) (Shin Nakamura Chemical Co., Ltd.) 44.2 g and azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.) 0.0655 g And the polymerization reaction was carried out in 178.9 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) at 80 ° C. for 20 hours. After the completion of the polymerization reaction, the reaction solution was added dropwise to methanol and precipitated to isolate the product. The product was dissolved in tetrahydrofuran (THF) and dropped into methanol twice, and purified. This was dried under reduced pressure at 60 ° C. all day and night to obtain a copolymer 4. Various evaluation was performed using the obtained copolymer. The results are summarized in Table 2.

  A surface treatment agent is prepared by dissolving or dispersing 1.0 g of the obtained copolymer and 1.0 g of benzalkonium chloride as an antibacterial substance in ethanol to prepare a 0.01 wt% ethanol mixed solution as the antithrombotic antibacterial composition concentration. Got. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial properties against Escherichia coli before aging and after aging for 1 week were examined. The results are summarized in Table 2.

(Example 8)
A 0.01 wt% ethanol mixture was prepared as an antithrombotic antibacterial composition concentration by dissolving or dispersing 1.0 g of the copolymer obtained in Example 7 and streptomycin sulfate as an antibacterial substance in ethanol. A treating agent was obtained. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial properties against Escherichia coli before aging and after aging for 1 week were examined. The results are summarized in Table 2.

(Comparative Example 1)
Add 0.125 g of azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.) to 95.2 g of methoxypolyethylene glycol acrylate (MPEGA) (Shin Nakamura Chemical Co., Ltd.) and 5.1 g of ethyl acrylate (EA) (Tokyo Chemical Industry Co., Ltd.) The polymerization reaction was performed in 250 g of isopropyl alcohol (Tokyo Chemical Industry Co., Ltd.) at 80 ° C. for 20 hours. In addition, polyethylene glycol having a polymerization degree of ethylene oxide of 9 in methoxypolyethylene glycol acrylate was used. After completion of the polymerization reaction, the reaction solution was dropped into n-hexane to precipitate, and the product was isolated. An operation of dissolving the product in isopropyl alcohol and adding it dropwise to n-hexane was carried out twice for purification. This was dried under reduced pressure at 60 ° C. all day and night to obtain a copolymer 5. Various evaluation was performed using the obtained copolymer. The results are summarized in Table 2.

  By dissolving or dispersing 0.2 g of the obtained copolymer and 0.8 g of chlorhexidine as an antibacterial substance in ethanol, a 0.001 wt% ethanol mixed solution was prepared as an antithrombotic antibacterial composition concentration to obtain a surface treatment agent. . After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 2.

(Comparative Example 2)
A 1.0 wt% ethanol mixed solution was prepared by dissolving or dispersing 1.0 g of silver sulfadiazine in ethanol so as to be 1.0 wt% to obtain a surface treating agent. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Furthermore, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial activity against Pseudomonas aeruginosa before aging and after aging for 1 week was examined. The results are summarized in Table 2.

(Comparative Example 3)
Add 0.0467 g of azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.) to 22.3 g of 2-ethylhexyl acrylate (EHA) (Tokyo Chemical Industry Co., Ltd.), and add 80 ℃ in 100 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) The polymerization reaction was carried out for 20 hours. After the completion of the polymerization reaction, the reaction solution was added dropwise to methanol and precipitated to isolate the product. An operation of dissolving the product in n-hexane and adding it dropwise to methanol was carried out twice for purification. This was dried under reduced pressure at 60 ° C. all day and night to obtain a copolymer 6. Various evaluation was performed using the obtained copolymer. The results are summarized in Table 2.

  By dissolving or dispersing 100 g of the obtained copolymer and 0.001 g of chlorhexidine as an antibacterial substance in ethanol, a 3.0 wt% ethanol mixed solution was prepared as an antithrombotic antibacterial composition concentration to obtain a surface treatment agent. After immersing a 50 × 50 × 0.3 mm polyethylene film in the obtained surface treatment agent for 5 seconds, the film was taken out and dried at 60 ° C. for 24 hours. Further, aging was performed in 37 ° C. physiological saline for 7 days, and antibacterial properties against Staphylococcus aureus before aging and after aging for 1 week were examined. The results are summarized in Table 2.

  As a result of the blood compatibility test, as shown in Tables 1 and 2, in Comparative Examples 1 and 3, the platelets adhered to each other so that a large number of platelets were stacked. It was found to show blood compatibility. Moreover, as a result of immune system evaluation, it was found that there is a good complement activity inhibitory action.

  In the present invention, it was found that good blood compatibility was exhibited even after aging for 30 days. Thereby, long-term performance maintenance is predicted.

  From the results of the antibacterial test, it was found that in Examples 1 to 8, a good antibacterial activity value was exhibited even after aging for 7 days. Thereby, it is considered that the medical device coated with the antithrombotic antibacterial composition of the present invention can maintain long-term antibacterial properties.

  In Comparative Example 2, the antibacterial property is lost after aging for 7 days, but this is considered to be because the retention of the antibacterial material is reduced due to the absence of the antithrombotic material. Therefore, it is presumed that long-term antibacterial property can be maintained only when the copolymer of the present invention and the antibacterial substance coexist.

  The antithrombotic antibacterial composition (copolymer containing an antibacterial substance) of the present invention can be used as a material having excellent blood compatibility and antibacterial properties and high hydrophilicity. Moreover, since the physical property of the material is a viscous substance that is insoluble in water, a material that can be coated on the entire blood circuit without impairing the physical properties of medical equipment can be provided. Therefore, it is important to contribute to industrial development.

The conceptual diagram which shows the difference between this invention and prior art. A photograph showing an example of antibacterial test results based on the JIS2801 film adhesion method. 2 is an SEM image showing the results of blood compatibility evaluation in Example 1. 3 is an SEM image showing the result of blood compatibility evaluation in Example 3. 6 is an SEM image showing the results of blood compatibility evaluation in Example 5. 10 is an SEM image showing the result of blood compatibility evaluation in Example 7. 3 is an SEM image showing the result of blood compatibility evaluation of Comparative Example 1. 10 is an SEM image showing the result of blood compatibility evaluation of Comparative Example 3.

Claims (9)

A water-insoluble and viscous (meth) acrylate copolymer containing an alkyl (meth) acrylate represented by the following general formula 1 and a methoxypolyethylene glycol (meth) acrylate represented by the following general formula 2 and a biguanide such as an antibiotic or chlorhexidine An antithrombotic antibacterial composition comprising at least one antibacterial substance selected from the group consisting of compounds, benzalkonium, and their salt compounds, and metal compounds such as silver sulfadiazine .
(In the formula, R1 represents an alkyl group or aralkyl group having 2 to 30 carbon atoms, and R2 represents a hydrogen atom or a methyl group.)
(In the formula, R3 represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 5.) The antithrombotic antibacterial composition according to claim 1, wherein the antibacterial substance is at least one selected from the group consisting of benzalkonium chloride, penicillin G potassium, streptomycin sulfate, silver sulfadiazine, and chlorhexidine. The antithrombotic antibacterial composition according to claim 1 or 2, comprising a (meth) acrylate copolymer comprising an alkyl (meth) acrylate and a methoxypolyethylene glycol (meth) acrylate in a molar ratio of 30 to 90/70 to 10. object. The anti-thrombotic antibacterial composition according to any one of claims 1 to 3, wherein the (meth) acrylate copolymer is soluble in any one of alcohols having 1 to 6 carbon atoms. The antithrombotic antibacterial composition according to any one of claims 1 to 4 , comprising a (meth) acrylate copolymer having a glass transition temperature of -100 to 20 ° C of the (meth) acrylate copolymer. The antithrombotic antibacterial composition according to any one of claims 1 to 5 , wherein the (meth) acrylate copolymer has a number average molecular weight of 2,000 to 200,000. The antithrombotic antibacterial composition according to any one of claims 1 to 6, wherein the antibacterial substance is contained in an amount of 0.1 wt% to 50.0 wt% with respect to the antithrombotic antibacterial composition. The antithrombotic antibacterial composition according to any one of claims 1 to 7, wherein the antibacterial activity value evaluated based on the film adhesion method of JIS Z 2801 is 1.3 or more. A medical device, wherein the antithrombotic antibacterial composition according to any one of claims 1 to 8 is carried on at least a part of a blood contact portion.