JPH10155898A - Antimicrobial property-imparting antithrombotic material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve simplicity, versatility, a property to maintain an antithrombotic property for a long period of time and an antimicrobial property by incorporating at least one kind of mucopolysaccharides, a quaternary ammonium ionic composite, an inorg. antimicrobial agent and an org. high-molecular material into the subject material. SOLUTION: The mucopolysaccharides, such as heparin, the quaternary ammonium, ionic composite, the org. high-molecular material, such as vinyl polyhalide, and at least one kind of the inorg. antimicrobial agents, such as silver, are incorporated into the antimicrobial property-imparting antithrombotic material. In such a case, about 0.1 to 50 pts.wt. of a lipophilic polysaccharide and about 0.1 to 50 pts.wt. inorg. antimicrobial agent are incorporated into 100 pts.wt. org. high-molecular material. The quaternary ammonium ionic composites have the structure expressed by the formula and one kind or several kinds may be mixed. In the formula, R<1> to R<3> denote each a 1 to 12C alkyl group or a 6 to 12C aryl group, a 7 to 20C aralkyl group, R<4> groups denote 1 to 25C alkyl groups which may be respectively same or different. The excellent antithrombotic and antimicrobial properties are obtd. by this constitution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antibacterial material provided with antibacterial properties, which comprises at least an ionic complex of mucopolysaccharide and quaternary ammonium, an inorganic antibacterial agent and an organic polymer material as essential components. Things.

[0002]

2. Description of the Related Art Artificial materials having excellent workability, elasticity and flexibility have been widely used as medical materials in recent years. However, artificial kidneys, artificial lungs, assisted circulation devices, artificial blood vessels and the like have been used. It is expected that its use as disposable products such as artificial organs, syringes, blood bags, heart catheters and the like will further increase in the future. These medical materials are required to have sufficient mechanical strength and durability, as well as safety for living bodies, in particular, that blood does not coagulate when it comes into contact with blood, that is, antithrombotic properties.

Conventionally, as a method for imparting antithrombotic properties to medical materials, (1) a method in which a mucopolysaccharide such as heparin or a fibrinolytic activator such as urokinase is immobilized on the surface of a material;
It can be broadly classified into three types: (2) a material surface modified to impart a negative charge or hydrophilicity, and (3) a material surface inactivated. Among them, the method (1) (hereinafter abbreviated as surface heparin method) further comprises (A) a method of blending a polymer and fat-solubilized heparin, (B) a material surface coating method with fat-solubilized heparin, and (C) a material. The method is subdivided into a method in which heparin is ion-bonded to a cationic group therein and a method (D) in which heparin is covalently bonded to a material.

[0004] Among the above methods (2) and (3), when they come into contact with body fluids for a long period of time, proteins are adsorbed on the surface of the material to form a biomembrane-like surface, and a stable antithrombotic property is obtained. It is possible to obtain However, in the initial stage when the material is introduced into the living body (blood contact site), various coagulation factors and the like are activated in the living body, so that sufficient anticoagulant therapy such as heparin administration is not performed. It is difficult to obtain antithrombotic properties.

[0005] On the other hand, in the case of (1), in the initial stage of the introduction, the antithrombotic property or the dissolving performance of the formed thrombus is exhibited by heparin or urokinase on the surface, but the performance generally increases with long-term use. It tends to decrease. That is, in (A), (B), and (C), heparins are usually easily detached by long-term use under physiological conditions, and it is difficult to obtain sufficient performance as a medical material to be fixed and used in a living body. . The material obtained in (D) has an advantage that heparin is hardly detached because it is covalently bonded. However, in the conventional bonding method, the heparin constituent D
-There is a disadvantage that the conformation of glucosamine or D-glucuronic acid is changed, and the anticoagulant effect is reduced.

In the methods (C) and (D), it is necessary to select a material containing a functional group that can be used for immobilizing heparin or to introduce a new material. For this reason, there is a possibility that the selection range of the material may be narrowed, or the mechanical strength of the material may be reduced due to the introduction of the functional group. There is also a problem that the number of steps for obtaining a medical material increases due to complicated operation.

As described above, considering the ease of antithrombosis of materials and the wide range of choice of applicable materials, (A) a blend method of a polymer and a fat-solubilized heparin, or (B) a fat-solubilized heparin. The material surface coating method with heparin can be said to be the best method. However, a fatal disadvantage of this method is that, as described above, heparins are liable to be eliminated by long-term use under physiological conditions. Conversely, by overcoming this drawback, it becomes possible to provide an excellent antithrombotic agent which is simple and versatile.

As means for solving this problem, Japanese Patent Laid-Open No.
-270823. This method is characterized in that a complex of a natural mucopolysaccharide and a natural lipid or a synthetic lipid is formed, and a technique of coating the material surface with a complex of heparin and an in vivo phospholipid is mentioned as a preferable example. .

However, this method can be said to be useful only in that it does not adversely affect the living body, since the cationic substance (lipid solubilizing agent) eluted simultaneously with the elution of heparin is a natural lipid or a synthetic lipid. That is, it cannot be said that this method has solved the decrease in anticoagulant property due to the elution of heparin during long-term use.

[0010] In addition, in the case of a medical device such as a high-nutrient infusion catheter (hereinafter abbreviated as IVH), which needs to be kept in the body for a long period of time, infection from the biomaterial interface has been a problem. Bacteria grow on blood clots formed by the contact of blood and materials, which enter the body and cause infection. Therefore, materials used for such medical devices need to have both antithrombotic properties and antibacterial properties at the same time. Despite the strong demand for antithrombotic materials with antibacterial properties, few materials applicable to this field have been reported so far.

On the other hand, various techniques have been reported for antibacterial materials. Antibacterial materials containing an ammonium salt as an antibacterial agent are described in, for example, Japanese Patent Publication No. Hei 4-2530.
1, Japanese Patent Publication No. 3-64143, antibacterial material containing biguanide, for example, Japanese Patent Publication No. 5-80225, Japanese Patent Publication No. 2-61261, Japanese Patent Publication No. 3-103341, and the antibacterial material containing an acridine compound, for example, It is disclosed by Japanese Patent Publication No. 3-76343. Also, JP-A-7-82511, JP-A-7-53316, and
JP-A-266912 and JP-A-5-310820 disclose antibacterial materials containing a phosphonium salt. Furthermore, Japanese Patent Publication No. 6-55892 discloses an antibacterial material containing silver protein as an antibacterial active ingredient.

[0012] In these technologies, the antibacterial property is exhibited by one kind of antibacterial substance, and it is difficult to exhibit sufficient antibacterial activity against many bacterial species. In particular, organic antibacterial agents containing ammonium and phosphonium as active ingredients often have insufficient effects on Gram-negative bacteria. In addition, since these materials are not considered for antithrombotic properties, it is difficult to use them as antibacterial materials having antibacterial properties applicable to medical devices for long-term indwelling.

[0013]

SUMMARY OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art, and is capable of exhibiting long-term antithrombotic properties in addition to simplicity and versatility, and having a broad antibacterial spectrum. It is an object of the present invention to provide an antibacterial property-imparting antithrombotic material exhibiting excellent antibacterial properties.

[0014]

The antithrombotic material provided with antibacterial properties according to the present invention contains an ionic complex of at least one kind of mucopolysaccharide and quaternary ammonium, an inorganic antibacterial agent and an organic polymer material. It is characterized by comprising. The antithrombotic material provided with the antibacterial property of the present invention is characterized by containing at least heparin as a mucopolysaccharide. The antithrombotic material having antibacterial properties according to the present invention is characterized in that the quaternary ammonium has the structure of the above formula (1). The antithrombotic material provided with antibacterial properties according to the present invention is characterized in that the organic polymer material is any one of polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester and polyamide. The antibacterial property-imparting antithrombotic material of the present invention contains 0.1 to 50 parts by weight of a fat-solubilized mucopolysaccharide and 0.1 to 50 parts by weight of an inorganic antibacterial agent based on 100 parts by weight of an organic polymer material. It is characterized by being.

The quaternary ammonium, which is an essential component of the antithrombotic material having antibacterial properties according to the present invention, is characterized by having the structure of the above-mentioned formula (1). May be used at the same time. One of the four hydrocarbon chains bonded to the nitrogen atom of the quaternary ammonium has 1 to 25 carbon atoms, preferably 3 carbon atoms.
To 20 and more preferably 6 to 20 alkyl groups. The other three hydrocarbon chains have 1 to 12 carbon atoms, preferably 1 to 8 alkyl groups, or 6 to 12 carbon atoms, preferably 6 to 10 aryl groups, or 7 to 20, preferably 7 to 7 carbon atoms. And 12 aralkyl groups.

Specific examples of quaternary ammonium include, for example, tributyl lauryl ammonium, tributyl myristyl ammonium, tributyl cetyl ammonium,
Tributyl stearyl ammonium, triphenyl lauryl ammonium, triphenyl myristyl ammonium, triphenyl cetyl ammonium, triphenyl stearyl ammonium, benzyl dimethyl lauryl ammonium, benzyl dimethyl myristyl ammonium,
Examples thereof include benzyldimethylcetylammonium and benzyldimethylstearylammonium, but are not limited thereto as long as they are compounds having the structure represented by Chemical Formula 1.

The antibacterial material having antibacterial properties of the present invention essentially requires the use of mucopolysaccharides. Examples of the mucopolysaccharides include heparin, chondroitin sulfate, hyaluronic acid, dermatan sulfate, and keratan sulfate. But,
Among them, heparin or heparin metal salt has particularly excellent antithrombotic activity, and many examples have been reported and are preferred.

A method for obtaining an ionic complex of mucopolysaccharide and quaternary ammonium (hereinafter abbreviated as fat-solubilized mucopolysaccharide) is not particularly limited. For example, an aqueous solution or aqueous dispersion of mucopolysaccharide and quaternary ammonium may be used. An aqueous solution or aqueous dispersion of a quaternary ammonium salt is mixed, and the obtained precipitate is collected and freeze-dried. It is also possible to use a weakly acidic buffer instead of the water used at this time. Solutes used in the buffer include, for example, 2- (N-morpholino) ethanesulfonic acid, piperazine-1,4-bis (2
-Ethanesulfonic acid), N- (2-acetamido) -2
-Aminoethanesulfonic acid, N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid, 3- (N
-Morpholino) propanesulfonic acid, 3- (N-morpholino) -2-hydroxypropanesulfonic acid, 2- [4
-(2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid is preferable, and 2- (N-morpholino) ethanesulfonic acid (hereinafter abbreviated as MES), piperazine-1,4-bis (2-ethane Sulfonic acid) (hereinafter abbreviated as PIPES), 3- (N-morpholino) propanesulfonic acid (hereinafter abbreviated as MOPS)
It is.

The antithrombotic material having antibacterial properties of the present invention contains, as an essential component, an inorganic antibacterial agent in addition to the fat-solubilized mucopolysaccharide. As the inorganic antibacterial agent, for example, an antibacterial agent containing a metal such as silver, copper, or zinc as an active ingredient, an antibacterial glass, or the like can be used. As an antibacterial agent containing silver as an active ingredient, specifically, for example, silver zeolite, silver-zirconium phosphate composite, silver ceramics, and the like can be used. In addition, metal organic compound complexes such as silver protein and silver sulfadiazine can be used as the inorganic antibacterial agent in the present invention. Among these inorganic antibacterial agents, in the present invention, a silver antibacterial agent or antibacterial glass is preferably used, and among them, silver zeolite is more preferably used.

In the present invention, a superior antibacterial property and a broad antibacterial spectrum can be introduced into the material by the synergistic effect of the added inorganic antibacterial agent and the quaternary ammonium functioning as a fat solubilizing agent. .

The present invention is characterized by comprising at least a fat-solubilized mucopolysaccharide, an inorganic antibacterial agent and an organic polymer material as essential components. The introduction of the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent into the organic polymer material inactivates the surface of the polymer material, and at the same time, the antithrombotic properties and antibacterial properties are partially released from the polymer material by slow release. It is considered to be exhibited. In the medical material having antithrombotic and antibacterial properties of the present invention, the affinity of the polymer with the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent allows the lipid-solubilized mucopolysaccharide and the inorganic antibacterial agent to be gradually released by contact with a biological component. The release is controlled and it is possible to maintain excellent antithrombotic and antibacterial properties even after long-term dissolution.

As the organic polymer material used for the antibacterial property-imparting antithrombotic material of the present invention, specifically, for example, polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester, polyamide,
Conventionally used materials such as polypropylene and polyethylene, and materials that will be used in the future can be widely used, among which polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester and polyamide are preferable, and poly Vinyl chloride, polyvinylidene chloride, polyurethane and polyurethane urea are more preferred.

Usually, an aromatic carboxylic acid ester or an aliphatic carboxylic acid ester is added to polyvinyl chloride or polyvinylidene chloride as a plasticizer. Particularly in polyvinyl chloride, dioctyl phthalate (hereinafter referred to as DO)
The use of such additives is not limited by the present invention. Rather, it is preferable to add a plasticizer in consideration of mechanical properties such as processability, elasticity, and flexibility required for a medical material. Further, according to our study, it was confirmed that the addition of a plasticizer tends to more easily exert antithrombotic and antibacterial activities. Although the detailed mechanism is not clear, it is because the mobility of the fat-solubilized mucopolysaccharide in the polymer is improved by the coexistence of the plasticizer, and the lipophilic mucopolysaccharide oozes out at the interface between the material and the biological component while taking a conformation that is more active. It is thought. The amount of addition is not particularly limited, but is 5 to 100 phr, preferably 10 to 100 phr based on the polymer.
80 phr.

In the present invention, when the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent are introduced into the organic polymer material, the amount of fat-solubilized mucopolysaccharide is preferably 0.1 part by weight per 100 parts by weight of the base material. To 100 parts by weight, more preferably 1
It is recommended to add in an amount of about 50 parts by weight to 50 parts by weight (hereinafter, when 1 part by weight of the additive is added to 100 parts by weight of the base material, the additive amount is expressed as 1 phr) . It is recommended that the amount of the inorganic antibacterial agent be added to the base material in an amount of preferably 0.1 to 50 phr, more preferably about 1 to 30 phr. Is preferably 40: 1 to 1: 4, and 2
0: 1 to 1: 1 is more preferred.

The antibacterial material having antibacterial properties of the present invention can be further introduced into another structure serving as a substrate. The material of the structure is not particularly limited, for example, polyether urethane, polyurethane, polyurethane urea, polyvinyl chloride, polyvinylidene chloride, polyester, polypropylene, polyethylene, polycarbonate and other conventionally used materials, The materials that will be used in the future are widely available. Also, it can be introduced for the purpose of imparting antithrombotic properties to blood treatment agents such as hemodialysis membranes, plasma separation membranes, and adsorbents made of existing and new materials.

The method of introduction into the substrate is not particularly limited, either.
A normal blending method, a coating method, and the like can be applied, and the coating method can be applied without any particular limitation, such as a coating method, a spray method, and a dipping method. Among these methods, it is preferable to select a method that does not impart heat history to mucopolysaccharide, which is a physiologically active substance.

Although the detailed mechanism is not clear, the antithrombotic material provided with the antibacterial property of the present invention can maintain good antithrombotic properties not only in the initial stage of contact with a biological component, but also after long-term contact. Further, due to the synergistic effect of the quaternary ammonium and the inorganic antibacterial agent, it is possible to introduce not only antithrombotic properties but also excellent antibacterial properties. Taking advantage of these advantages, the antibacterial material with antibacterial properties of the present invention can be widely applied to the antithrombotic treatment of materials used for various medical instruments or devices. Specifically, for example, the present invention can be applied to a hemodialysis membrane, a plasma separation membrane, a coating agent thereof, and a coating agent for adsorbing waste products in blood. Further, it can be used in a wide range of fields such as a membrane material for an artificial lung (a partition wall of blood and oxygen), a sheet material for a sheet lung in an artificial heart lung, an aortic balloon, a blood bag, a catheter, a cannula, a shunt, and a blood circuit. It is particularly preferable that the antithrombotic material of the present invention is applied to IVH or the like, which has a problem of infection from the interface between a living body and a material, utilizing the advantage that the antithrombotic material having the antibacterial property has antibacterial properties.

[0028]

Hereinafter, the present invention will be described with reference to Examples.
The present invention is not particularly limited to these.

Example 1 Heparin sodium salt
00 g was dissolved in ion-exchanged water to make a total volume of 100 ml. Benzyldimethylcetylammonium chloride (hereinafter B
16.30 g of DMCA.Cl) was dissolved in ion-exchanged water to make a total volume of 163 ml. Both solutions were mixed under ice cooling, and allowed to stand at 4 ° C. for 15 hours to obtain a suspension. The suspension was centrifuged at 3,300 rpm, collected by centrifugation, suspended in distilled water, suspended, and washed three times by centrifugation. Thereafter, the precipitate was dried to form a complex of BDMCA.Cl and heparin. Body (hereinafter B
DMCA-Hep). This BDMCA
-Hep was soluble in organic solvents such as benzene, DMF, THF and chloroform.

A commercially available polyurethane (Pellethane (trade name), hereinafter abbreviated as PU) was dissolved in THF to form a 5% solution. To 1000 g of this PU solution, 5.00 g of the BDMCA-Hep obtained above and 1.00 g of silver zeolite (Zeomic (trade name) manufactured by Shinagawa Fuel Co., Ltd .; hereinafter abbreviated as AgZeo) as a commercially available antibacterial agent were added. To form a uniform suspension. This BDMCA-Hep, A
20 g of gZeo / PU blend suspension held horizontally
The film was uniformly placed on a glass plate of 2 cm × 12 cm, dried at 40 ° C. for 8 hours under a nitrogen stream, and dried under reduced pressure at 40 ° C. for 15 hours to obtain a film having a thickness of about 60 μm (hereinafter referred to as BDM).
The CA-Hep, AgZeo / PU blend material is abbreviated as material A, and the film obtained from material A is abbreviated as film A). Film A contains 10 phr of BDMCA-Hep
, AgZeo was added at 2 phr.

The relative clotting time of plasma on the film A obtained above was evaluated by the following method. The film A was cut into a circle having a diameter of about 3 cm and attached to the center of a watch glass having a diameter of 10 cm. Take 200 μl of citrated plasma of rabbit (Japanese white species) on this film,
200 μl of a 1 / l calcium chloride aqueous solution was added, and the watch glass was gently shaken so that the liquids were mixed while floating in a thermostat at 37 ° C. The elapsed time from the time when the calcium chloride aqueous solution was added to the time when the plasma coagulated (when the plasma stopped moving) was measured and divided by the time required for plasma coagulation when the same operation was performed on glass, as a relative coagulation time. expressed. However, when the plasma did not clot even when the clotting time exceeded 12 times the clotting time on the glass plate, the evaluation was interrupted, and the relative clotting time was expressed as> 12. The results are shown in Table 1 below.

Material A The suspension was diluted to 2% with THF, and 40-60 mesh glass beads were added to the solution.
After immersion for 0 minutes, the mixture was filtered with a glass filter, and dried under reduced pressure at 40 ° C. for 8 hours and at 40 ° C. for 15 hours to coat the material A on the surface of the glass beads. PB in human serum
100 ml of this coated bead in 1 ml of S (-)
mg was soaked and incubated at 37 ° C. for 30 minutes with gentle shaking. Use this solution as a sample for Mayer
Law (Mayer, MM, “Complement and complement Fixatio
n ”Experimental Immunochemistry 2nd Ed. p133 〜240
, CCThomas Publisher, 1961). The results are shown in Table 1 by percentage, where the complement value in 1 ml of the diluted serum without beads was 100%.

The antibacterial property of the film A was evaluated by the following method. In addition, a series of operations were all performed aseptically. About 1 × 10 with broth solution (diluted 50-fold with sterile physiological saline)
A Pseudomonas aeruginosa solution having a concentration of ⁷ cells / ml (hereinafter referred to as a bacterial stock solution) was prepared. The concentration of this stock solution was measured as follows. 100 µl after diluting the bacterial stock solution 10 ⁴ times
Was spread on an ordinary agar plate, and the number of P. aeruginosa colonies formed 24 hours later was counted. Assuming that the number of colonies is N, the number C of bacteria in the bacterial stock solution is expressed as C = 10 ⁴ × N / 0.1 = 10 ⁵ × N [cells / ml]. 100 μl of this bacterial stock solution was diluted with broth solution (40-fold dilution with sterile physiological saline) to prepare a total volume of 40 ml (hereinafter, this solution is referred to as immersion stock solution). The film A was cut into 5 cm × 5 cm in advance and sterilized by EOG and immersed in the immersion stock solution, and cultured at 37 ° C. for 24 hours. After the culture, the immersion stock solution was diluted to 10 ⁴ times with sterile physiological saline in a 10-fold series (hereinafter abbreviated as 10 ^n- fold dilution). 100 μl of each diluted solution was spread on a normal agar medium, and after 24 hours, the number of P. aeruginosa colonies formed on the normal agar medium was 30
The measurement was performed for ~ 300 plates. When the number of colonies obtained by measuring the N _n pieces, the number of bacteria N _a after contact with 25 cm ² film A is given by the following equation. Number of bacteria bacteria stock solution prior to contact with the ^{_{N a = 40 × 10 n ×}} N n /0.1 film A are as defined above C, since stock quantity used is 100 [mu] l, before contacting the film A bacterium the number changes in N _b → N _a by contact with several ^{_{N b N b = 10 4 ×}} N immersion in 25 cm ² in a stock solution 40ml size of the film are shown in Table 1. The fact that the number of bacteria is reduced by contact indicates that the antibacterial property of the film is exhibited.

A 4% THF suspension of the material A is prepared, and the existing hollow hollow fiber made of polypropylene for artificial lungs is immersed in the suspension, pulled up, and dried at 40 ° C. for 12 hours to coat the hollow fiber. Was. Using this hollow fiber, antithrombotic properties were evaluated in vivo. The experimental method is as follows. Under pentobarbital anesthesia, rabbits (Japanese white species, Δ, 2.5-3.
(0 kg) of the femoral vein was peeled off, the distal side was ligated with a thread, and a portion 2-3 cm from the thread was clamped with vascular forceps. The central side of the ligated portion was cut by 下 to ３ of the diameter of the blood vessel with an incisor under the eye, and a hollow fiber, which was a sample, was inserted toward the central side by 10 cm from there. At about 1 cm from the insertion position, the end of the hollow fiber projecting out of the blood vessel was sewn to prevent the hollow fiber from flowing. The incision was sutured, antibiotics were administered, and the animals were kept for 2 weeks before removing samples. Two weeks later, a median incision was made under anesthesia with pentobarbital with heparin, blood was removed from the abdominal aorta using an appropriate tube, and the rabbit was sacrificed. Then, the blood vessel in which the hollow fiber was inserted was cut off. The blood vessel was incised, the hollow fiber and the inside of the blood vessel were photographed, and visually observed for a five-point evaluation. The results are shown in Table 1.

Film A is immersed in citrated beef plasma,
Elution was performed for 2 weeks in a shaking thermostat at 37 ° C.
Citrated beef plasma was changed every other day. Hereinafter, the film after elution is referred to as film A ′. The plasma relative clotting time and antibacterial properties of the film A ′ were evaluated in the same manner as for the film A. The results are shown in Table 1.

[0036]

[Table 1]

The five grades of in vivo antithrombotic properties in Table 1 are as follows. a: No platelet aggregation, thrombus formation, or fibrin formation is observed. b: Fibrin formation or platelet aggregation is observed, but no thrombus formation is observed. c: Fibrin formation or platelet aggregation is observed, and thrombus formation is slightly observed. d: E: Fibrin formation or platelet aggregation is observed and a large amount of thrombus formation is observed.

Example 2 Heparin sodium salt
00 g was dissolved in ion-exchanged water to make a total volume of 100 ml. 13.99 g of benzyldimethyllauryl ammonium chloride (hereinafter abbreviated as BDMLA.Cl) was dissolved in ion-exchanged water to make a total volume of 140 ml. Both solutions were mixed under ice cooling, and allowed to stand at 4 ° C. for 15 hours to obtain a suspension. The suspension was centrifuged at 3,300 rpm, collected by centrifugation, suspended in distilled water, and then washed three times by centrifugation. The precipitate was dried three times, and dried to form a complex of BDMLA.Cl and heparin. (Hereinafter abbreviated as BDMLA-Hep). This BDML
A-Hep was soluble in organic solvents such as benzene, DMF, THF, and chloroform.

In the same manner as in Example 1, except that the fat-solubilized heparin was changed from BDMCA-Hep to BDMLA-Hep, a BDMLA-Hep, AgZeo / PU blend material B, and a film B comprising the material B were obtained. Using this material B and film B, the plasma relative coagulation time, complement value, antibacterial properties, and in vivo antithrombotic properties were evaluated in the same manner as in Example 1. Further, the dissolution test of the film B was carried out in the same manner as in Example 1, and the relative coagulation time of plasma and the antibacterial property of the obtained dissolution film B ′ were also evaluated. The results are shown in Table 1.

<Comparative Example 1> The BDMCA- obtained in Example 1
Hep100 mg and AgZeo20 mg were added with benzene to make the total amount 100 g, and BDMCA-Hep, AgZ
An eo / benzene suspension was obtained. 3.00 g of this suspension was evenly placed on a 12 cm × 12 cm PU film,
For 8 hours under a nitrogen stream, and then dried at 40 ° C. under reduced pressure for 15 hours.
After that, a film having a thickness of about 60 μm was obtained (hereinafter, this BDMCA-Hep, AgZeo / PU coating film is abbreviated as film C).

Coating with this BDMCA-Hep, AgZeo / benzene suspension was performed to determine complement titer and in vivo
Using anti-thrombotic properties, the relative coagulation time of plasma and antibacterial properties were evaluated using Film C in the same manner as in Example 1. Example 1
The dissolution test of the film C was carried out in the same manner as described above, and the relative coagulation time of plasma and the antibacterial property of the obtained dissolution film C ′ were also evaluated. The results are shown in Table 1.

<Comparative Example 2> BDMLA- obtained in Example 3
Hep 100 mg and AgZeo 20 mg were added with benzene to make the total amount 100 g, and BDMLA-Hep, Ag
A Zeo / benzene suspension was obtained. 12cm x 12cm PU
3.00 g of this suspension was evenly placed on a film, and 40
After drying at 80 ° C for 8 hours under a nitrogen stream, drying under reduced pressure at 40 ° C was performed for 1 hour.
After 5 hours, a film having a thickness of about 60 μm was obtained (hereinafter, this BDMLA-Hep, AgZeo / PU coating film is abbreviated as film D).

Coating with this BDMLA-Hep, AgZeo / benzene suspension was performed to determine complement titer and in vivo
The antithrombotic property was evaluated using the film D in the same manner as in Example 1 for the plasma relative coagulation time and the antibacterial property. Example 1
The dissolution test of the film D was carried out in the same manner as described above, and the plasma relative coagulation time and the antibacterial property of the obtained dissolution film D ′ were also evaluated. The results are shown in Table 1.

<Comparative Example 3> PU was dissolved in THF at 5%
The solution was used. Example 1 against 1000 g of this PU solution
5.00 g of BDMCA-Hep obtained in the above was added to obtain a homogeneous solution. 20 g of this BDMCA-Hep / PU blend solution was evenly placed on a 12 cm × 12 cm glass plate kept horizontal, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried at 40 ° C.
For 15 hours to obtain a film having a thickness of about 60 μm (hereinafter, the BDMCA-Hep / PU blend material is abbreviated as material E, and the film obtained from the material E is abbreviated as film E). BDMCA-Hep is 1 in film E
This means that 0 phr has been added.

Using the material E and the film E, the plasma relative coagulation time, complement value, antibacterial property and in vivo antithrombotic property were evaluated in the same manner as in Example 1. Further, the dissolution test of the film E was carried out in the same manner as in Example 1, and the plasma relative coagulation time and the antibacterial property of the obtained dissolution film E ′ were also evaluated. The results are shown in Table 1.

<Comparative Example 4> PU was dissolved in THF at 5%
The solution was used. For 1000 g of this PU solution, AgZe
o1.00 g was added to make a uniform suspension. This Ag
20 g of the Zeo / PU blend suspension was kept horizontal 12
The film was uniformly placed on a glass plate of cm × 12 cm, dried at 40 ° C. for 8 hours under a nitrogen stream, and dried at 40 ° C. under reduced pressure for 15 hours to obtain a film having a thickness of about 60 μm (hereinafter AgZ).
The eo / PU blend material is abbreviated as material F, and the film obtained from material F is abbreviated as film F). Film F contains Ag
This means that 2 phr of Zeo has been added.

Using this material F and film F, in the same manner as in Example 1, plasma relative coagulation time, antibacterial property, in v
The ivo antithrombotic properties were measured. Further, the dissolution test of the film F was carried out in the same manner as in Example 1, and the relative coagulation time of plasma and the antibacterial property of the obtained dissolution film F ′ were also measured. The results are shown in Table 1.

Comparative Example 5 The relative clotting time of plasma and antibacterial property were measured using a PU film (film G) into which no fat-solubilized heparin was introduced. Further, a dissolution test of the film G was carried out in the same manner as in Example 1, and the relative coagulation time of plasma and the antibacterial property of the obtained dissolution film G ′ were also measured. The results are shown in Table 1.

As can be seen from the results shown in Table 1, the antithrombotic material provided with the antibacterial property of the present invention shows excellent antithrombotic property and antibacterial property, and the performance is maintained even after elution. In Comparative Examples 1 and 2 in which the film surface was coated with a fat-solubilized mucopolysaccharide and an inorganic antibacterial agent without containing an organic polymer material,
It can be seen that the performance before elution is relatively good, but the performance is significantly reduced by plasma elution. When the organic polymer material is not contained, the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent are liable to be peeled off by elution with plasma, which is considered to cause a decrease in performance. Comparative Example 3 in which no inorganic antibacterial agent was added
This material has relatively good antithrombotic properties, but is inferior in antibacterial properties, and particularly has a large decrease in antibacterial properties after elution. In Comparative Example 4, which does not contain the fat-solubilized mucopolysaccharide, the antithrombotic properties are remarkably inferior, and the antibacterial properties are also inferior to those of the antibacterial antithrombotic material of the present invention. It shows that antithrombotic properties are exerted by heparin solubilized, and also suggests that antibacterial properties are improved by the synergistic effect of quaternary ammonium and inorganic antibacterial agents.

[0050]

The antithrombotic material having antibacterial properties of the present invention can easily impart antithrombotic properties and antibacterial properties to a polymer as a base material. It is maintained after the elution operation. Therefore, the antibacterial property-imparting antithrombotic material of the present invention has excellent suitability as an antithrombotic and antibacterial material for medical materials.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kanade Arimori 2-1-1 Katata, Otsu City, Shiga Prefecture Inside Toyobo Co., Ltd. Research Institute (72) Masakazu Tanaka 2-1-1 Katata, Otsu City, Shiga Prefecture No. Toyobo Co., Ltd.

Claims (5)

[Claims] 1. An antithrombotic material provided with an antibacterial property, comprising at least the following (a), (b) and (c): (A) a fat-solubilized mucopolysaccharide comprising an ionic complex of at least one mucopolysaccharide and a quaternary ammonium (b) an inorganic antibacterial agent (c) an organic polymer material 2. The antithrombotic material provided with antibacterial properties according to claim 1, wherein the mucopolysaccharide contains at least heparin or heparin metal salt. 3. The antithrombotic material provided with antibacterial properties according to claim 1, wherein the quaternary ammonium has the following structure. Embedded image In Chemical Formula 1, R ¹ , R ² , and R ³ are an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms, and R ⁴ has 1 to 25 carbon atoms.
And each may be the same or different. 4. The antimicrobial agent according to claim 1, wherein the organic polymer material is selected from the group consisting of polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester and polyamide. Thrombotic material. 5. The method according to claim 1, wherein the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent are contained in an amount of 0.1 to 50 parts by weight and 0.1 to 50 parts by weight, respectively, based on 100 parts by weight of the organic polymer material. The antibacterial property imparting antithrombotic material according to any one of the above.