JPH10295799A - Antibacterial antithrombogenic material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve convenience, flexibility, retainability of long time antithrombogenic performance and antibacterial performance of an antibacterial antithrombogenic material, by making the material contain liposoluble mucopolysaccharide consisting of at least one kind of mucopolysaccharide and an ionic complex of quaternary ammonium and aliphatic polyurethane as indispensable components. SOLUTION: An ionic complex of liposoluble mucopolysaccharide consisting of at least one kind of mucopolysaccharide, for instance heparin, etc., and quaternary ammonium is made one indispensable component. Further aliphatic polyurethane is made contained as the second indispensable component, An antibacterial antithrombogenic material is constituted by that way. Controlled releasing of the liposoluble mucopolysaccharide is controlled by a contact with an organism component by affinity between aliphatic polyurethane and liposoluble mucopolysaccharide to keep excellent antithrombogenic performance even after long time dissolution. Further, antibacterial performance can be simultaneously induced by the effect of quaternary ammonium.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a mucopolysaccharide and a fourth type.
The present invention relates to an antithrombotic material having antibacterial properties, which comprises at least a fat-solubilized mucopolysaccharide comprising an ionic complex of quaternary ammonium and an aliphatic polyurethane as essential components.

[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 technique for imparting antithrombotic properties to medical materials, there are immobilized mucopolysaccharides such as heparin and fibrinolytic activators such as urokinase on the surface of the material, and modification of the material surface to form a negative charge. And those with hydrophilicity, etc.
The material surface can be roughly classified into three types in which the surface is inactivated. These methods (hereinafter abbreviated as surface heparin method) are further divided into (1) a method of blending a polymer and fat-solubilized heparin, (2) a method of coating a material surface with fat-solubilized heparin, and (3)
The method is subdivided into a method in which heparin is ion-bonded to a cationic group in the material, and a method (4) in which heparin is covalently bonded to the material.

[0004] Among the above-mentioned methods, in the method described above, when the body fluid comes into contact with the body fluid for a long period of time, the protein is adsorbed on the material surface to form a biomembrane-like surface, and a stable antithrombotic property can be obtained. It is. 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 the anticoagulant therapy such as heparin administration is sufficient. It is difficult to obtain good antithrombotic properties.

[0005] On the other hand, in the initial stage of the introduction, heparin or urokinase on the surface exerts antithrombotic properties or dissolution of the formed thrombus, but the performance generally decreases with long-term use. There is a tendency. That is, in (1), (2) and (3), heparins are usually easily detached by long-term use under physiological conditions, and sufficient performance is obtained as a medical material to be fixed and used in a living body. Hateful. The material obtained in (4) has an advantage that heparin is hardly detached because it is covalently bonded. However, in the conventional bonding method, the heparin component 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 (3) and (4), 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 antithrombogenicity of materials and the wide range of applicable materials, (1) a method of blending a polymer and a fat-solubilized heparin, or (2)
It can be said that the method of coating the material surface with heparin solubilized is the most excellent 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 that 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 a material surface with a complex of heparin and an in vivo phospholipid is mentioned as a preferable example. I have.

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

[0010] In addition, a high nutrient infusion catheter (hereinafter referred to as IVH).
In the case of medical devices that need to be kept in the body for a long period of time, infection from the bio-material interface has been a problem. Bacteria multiply in blood clots created by the contact of blood and materials, which enter the body and cause infection. Therefore, materials used for such medical devices are required to have both antithrombotic properties and antibacterial properties at the same time. However, despite the strong demand for antithrombotic materials imparted with antibacterial properties, at present, few materials applicable to this field have been reported.

On the other hand, various techniques have been reported for antibacterial materials. As an antibacterial material containing an ammonium salt as an antibacterial agent, 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. 3-10341, antimicrobial 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, although studies have been made to exhibit excellent antibacterial properties, no consideration has been given to antithrombotic properties, so that antibacterial properties applicable to long-term indwelling medical devices and the like are provided. It is difficult to use as an antithrombotic material.

[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. It is an object of the present invention to provide an antibacterial-imparting antithrombotic material that also exhibits antibacterial properties.

[0014]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above problems, and as a result, have found that an ionic complex of mucopolysaccharide and quaternary ammonium is useful, and have reached the present invention. . That is, the present invention is an antithrombotic material provided with an antibacterial property, comprising at least an ionic complex of at least one mucopolysaccharide and a quaternary ammonium and an aliphatic polyurethane as essential components. . The mucopolysaccharide of the present invention preferably contains at least heparin or heparin metal salt.
The quaternary ammonium of the present invention preferably has a structure of the formula [1]. The ionic complex of the mucopolysaccharide and the quaternary ammonium preferably has a fat-solubilized mucopolysaccharide content of 1 to 100 parts by weight based on 100 parts by weight of the aliphatic polyurethane.

[0015]

Embedded image

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The quaternary ammonium, which is an essential component of the antibacterial material having antibacterial properties according to the present invention, is characterized by having the structure of the formula [1]. Only the types may be used alone or a plurality of types may be used simultaneously. One of the four hydrocarbon chains bonded to the nitrogen atom of the quaternary ammonium has one or two carbon atoms.
5, preferably 3 to 20, more preferably 6 to 20 alkyl groups. The other three hydrocarbon chains have 1 carbon
-12, preferably 1-8 alkyl groups, or 6-12, preferably 6-10 aryl groups, 7 carbon atoms
To 20 or 7 to 12 aralkyl groups.

Specific examples of the quaternary ammonium in the present invention include tributyl lauryl ammonium,
Tributyl myristyl ammonium, tributyl cetyl ammonium, tributyl stearyl ammonium, triphenyl lauryl ammonium, triphenyl myristyl ammonium, triphenyl cetyl ammonium,
Triphenylstearyl ammonium, benzyl dimethyl lauryl ammonium, benzyl dimethyl myristyl ammonium, benzyl dimethyl cetyl ammonium,
Examples thereof include benzyldimethylstearylammonium, but are not limited thereto as long as they are compounds having a structure represented by the formula [1].

The mucopolysaccharide in the present invention includes, for example, heparin, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate, and metal salts thereof. Among them, heparin or heparin metal salt has particularly excellent antithrombotic properties. It is also preferable because there are many reports.

The 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 may be used. A method of mixing an aqueous solution or an aqueous dispersion of a quaternary ammonium salt, collecting the resulting precipitate, and freeze-drying the resulting precipitate is exemplified. It is also possible to use a weakly acidic buffer instead of the water used at this time.

The 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 preferred, and 2- (N-morpholino) ethanesulfonic acid (hereinafter abbreviated as MES), piperazine-1,4-bis (2-ethanesulfonic acid) (hereinafter, referred to as MES) is particularly preferred. PIPES) and 3- (N-morpholino) propanesulfonic acid (hereinafter abbreviated as MOPS).

The present invention is characterized by comprising at least a fat-solubilized mucopolysaccharide and an aliphatic polyurethane as essential components. When the fat-solubilized mucopolysaccharide is introduced into a polymer material (substrate) containing an aliphatic polyurethane as at least one of the components, the surface of the substrate is inactivated, and at the same time, a part of the material is gradually released from the substrate. It is considered that antithrombotic and antibacterial properties are exhibited.

In the antithrombotic material imparting antibacterial property of the present invention, the affinity between the aliphatic polyurethane and the fat-solubilized mucopolysaccharide causes
The sustained release of fat-solubilized mucopolysaccharide is also controlled by contact with a biological component, and it is possible to maintain excellent antithrombotic properties even after long-term dissolution. Furthermore, the effect of the quaternary ammonium functioning as a fat solubilizer makes it possible to introduce antibacterial as well as antithrombotic properties into the material.

The antithrombotic material provided with antibacterial properties according to the present invention is characterized in that an aliphatic polyurethane is at least one of components as a base to which fat-solubilized heparin is added. The polymer material that can be a base material is, for example, polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester, polyamide, polypropylene,
Although polyethylene and the like are conceivable, as a result of intensive research, although the detailed mechanism is unknown, long-term stable antithrombotic and antibacterial properties are exhibited by including aliphatic polyurethane as at least one of the components. I found that.

The base material used may be a blend with another polymer material as long as it contains an aliphatic polyurethane as one of the components. Examples of the base component other than the aliphatic polyurethane include polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester, polyamide, polypropylene, and polyethylene. When using a blend base material, the content of the aliphatic polyurethane is preferably 20%.
To 100%, and more preferably 40 to 100%.

The amount of the fat-solubilized mucopolysaccharide to be mixed with the polymer material as the base material is preferably 0.1 to 200 parts by weight of the fat-solubilized mucopolysaccharide with respect to 100 parts by weight of the polymer material. Is more preferably added in an amount of 1 to 100 parts by weight (hereinafter, when 1 part by weight of the additive is added to 100 parts by weight of the polymer, the amount of the additive is expressed as 1 phr).

The antithrombotic material imparting antibacterial property of the present invention may contain an inorganic antibacterial agent in addition to the fat-solubilized mucopolysaccharide.
Examples of the inorganic antibacterial agent include an antibacterial agent containing a metal such as silver, copper, and zinc as an active ingredient, and an antibacterial glass.
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. Further, a metal organic compound complex such as silver protein silver or silver sulfadiazine can also 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, when an inorganic antibacterial agent is added, a more excellent antibacterial property and a broader antibacterial spectrum can be introduced into the material by a surplus effect with a quaternary ammonium functioning as a fat solubilizing agent. Can be expected.

In the present invention, when the inorganic antibacterial agent is introduced into the polymer material serving as the base material, the amount added is preferably 0.1 to 50 phr with respect to 100 parts by weight of the base polymer material. Preferably, it is recommended to add in an amount of about 1 to 30 phr. In addition, the addition ratio of the fat-solubilized mucopolysaccharide to the inorganic antibacterial agent is preferably 50: 1 to 1: 4, and 25: 1 to
1: 1 is more preferred.

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

The method of introduction into the above-mentioned structure is not particularly limited, but a usual blending method, coating method and the like can be applied. The coating method can be applied without any particular limitation, such as a coating method, a spray method, and a dipping method. Among the above-mentioned methods, it is preferable to carry out under conditions that do not give heat history to mucopolysaccharide.

The antithrombotic material provided with the antibacterial property of the present invention can maintain a good anti-defeat property not only in the initial stage of contact with a biological component, but also after a prolonged contact. In addition, due to the effect of the quaternary ammonium, an excellent antibacterial property as well as an antithrombotic property can be introduced.

The antithrombotic material provided with the antibacterial property of the present invention can be widely applied to the antithrombotic treatment of materials used for various medical devices or devices. Specifically, the present invention can be applied to a hemodialysis membrane, a plasma separation membrane, a coating agent thereof, and a coating agent for a blood waste adsorbent. In addition, membrane materials for artificial lungs (partition walls of blood and oxygen), sheet materials for sheet lungs in cardiopulmonary bypass, aortic balloons, blood bags, catheters,
It can be used in a wide range of fields, such as cannulas, shunts, and blood circuits. 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.

Hereinafter, the present invention will be described in detail with reference to examples. The present invention is not limited by the embodiments.

Example 1 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 to recover the precipitate, and the operation of suspending the suspension by adding distilled water and then washing the precipitate by centrifugation was repeated three times. Thereafter, the precipitate was dried to obtain BDMLA · Cl and heparin. (Hereinafter, abbreviated as BDMLA-Hep) was obtained. This BDMLA-Hep was soluble in organic solvents such as benzene, DMF, THF, and chloroform.

A commercially available aliphatic polyurethane (Tecoflex (trade name) EG80A; hereinafter abbreviated as Teco) was converted to TH
F to give a 5% solution. This Teco solution 100
0 g, BDMLA-Hep 15.00 obtained above.
g was added to make a uniform solution. This BDMLA-He
12 cm holding 20 g of p / Teco blend solution horizontally
× 12 cm uniformly placed on a glass plate, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried under reduced pressure at 40 ° C. for 15 hours.
A film having a thickness of about 60 μm was obtained (hereinafter, this BDML)
The A-Hep / Teco blend material is abbreviated as material A, and the film obtained from material A is abbreviated as film A). Film A
In this case, 30 phr of BDMLA-Hep was added.

The relative coagulation 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.

Material A solution was diluted with THF to 2%,
The glass beads of 40 to 60 mesh are immersed in the solution for 30 minutes and then filtered with a glass filter.
The material A was coated on the glass bead surface by performing drying at 40 ° C. for 8 hours and drying at 40 ° C. under reduced pressure for 15 hours. PB of normal 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 fixati
on ”Experimental Immunochemistry 2nd Ed., p133-24
0, CCThomas Publisher, 1961) to determine the hemolytic complement value (CH50). 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 concentration C of 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 solution) 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 x 5 cm and then EOG sterilized 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 placed on a normal agar medium, and 24 hours later, the number of P. aeruginosa colonies formed on the normal agar plate was 3
Measurements were taken on 0 to 300 plates. When the number of colonies obtained by measuring the N _n pieces, the number of bacteria N _a after contact with the film A of 25 cm ² is given by the following equation. N _a = 40 × 10 ⁿ × N _n /0.1

The concentration of the bacteria stock solution prior to contact with the film A are as defined above C, stock amount used was from a 100 [mu] l, cell count N _b before contacting the film A is expressed by the following equation. N _b = 10 ⁴ × N

[0040] The number variation of N _b → N _a by contact between the size of the film 25 cm ² in a dipping stock 40ml 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 solution of the material A was prepared, and an existing polypropylene hollow fiber for artificial lung was immersed in the solution, pulled up, and dried at 40 ° C. for 12 hours to coat the hollow fiber.
Using this hollow fiber, antithrombotic properties were evaluated in vivo. The experimental method is as follows.

Under pentobarbital anesthesia, the femoral vein of a rabbit (Japanese white species, ♂, 2.5-3.0 kg) was peeled off, the peripheral side was ligated with a thread, and 2-3 cm from the thread was subjected to vascular forceps. Clamped. 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. Cut. 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.

Dip film A 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.

[0045]

[Table 1]

The five-step evaluation of in vivo antithrombotic properties in Table 1 is 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. 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. This suspension was centrifuged at 3,300 rpm to collect the precipitate, and the operation of suspending the suspension by adding distilled water and then washing the precipitate by centrifugation was repeated three times. Thereafter, the precipitate was dried to obtain BDMCA · Cl and heparin. (Hereinafter, abbreviated as BDMCA-Hep) was obtained. This BDMCA-Hep was soluble in organic solvents such as benzene, DMF, THF, and chloroform.

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

Comparative Example 1 The aliphatic polyurethane Teco used in Example 1 was replaced with a commercially available aromatic polyurethane (Pe
llethane (trade name) 2363-80AE;
BDMLA-Hep / Pell blend material C and film C made of material C were obtained in the same manner as in Example 1 except that the above-described method was changed to "1". Using the material C and the film C, the plasma relative coagulation time, complement value, antibacterial property, and in vivo antithrombotic property were measured in the same manner as in Example 1. Further, the dissolution test of the film C 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 C ′ were also measured. The results are shown in Table 1.

Comparative Example 2 A method similar to that of Example 1 except that the aliphatic polyurethane Teco used in Example 1 was changed to commercially available polyvinyl chloride (containing 50 phr of dioctyl phthalate, hereinafter abbreviated as PVC). And BDML
A film D comprising A-Hep / PVC blend material C and material D was obtained. Using the material D and the film D, the plasma relative coagulation time, complement value, antibacterial property, and in vivo antithrombotic property were measured in the same manner as in Example 1. Further, a dissolution test of the film D was performed in the same manner as in Example 1,
The relative clotting time of plasma and antibacterial property of the obtained dissolution film D ′ were also measured. The results are shown in Table 1.

Comparative Example 3 BDMLA- obtained in Example 1
Benzene was added to 100 mg of Hep to make the total amount 100 g, and a BDMLA-Hep / benzene solution was obtained. 12cm
3.00 g of this solution was evenly placed on a × 12 cm Teco film, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried.
C. for 15 hours to obtain a film having a thickness of about 60 .mu.m (hereinafter Teco by BDMLA-Hep).
The coating film is abbreviated as film E).

The BDMLA-Hep / benzene solution was coated to determine the complement value and in vivo antithrombotic properties, and the film E was used to determine the plasma relative coagulation time and antibacterial properties.
The measurement was performed in the same manner as described above. Further, the dissolution test of the film E was performed in the same manner as in Example 1, and the relative coagulation time of plasma and the antibacterial property of the obtained dissolution film E ′ were also measured. The results are shown in Table 1.

<Comparative Example 4> BDMCA- obtained in Example 2
Benzene was added to 100 mg of Hep to make the total amount 100 g, and a BDMCA-Hep / benzene solution was obtained. 12cm
3.00 g of this solution was evenly placed on a × 12 cm Teco film, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried.
C. for 15 hours to obtain a film having a thickness of about 60 .mu.m (hereinafter Teco by BDMCA-Hep).
The coating film is abbreviated as film D).

The BDMCA-Hep / benzene solution was coated to determine the complement value and the in vivo antithrombotic property, and the film F was used to determine the plasma relative coagulation time and the antibacterial property.
The measurement was performed in the same manner as described above. 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 coagulation time of plasma and antibacterial property were measured using a Teco film (film G) into which fat-solubilized heparin was not 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 antibacterial 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 aromatic polyurethane or polyvinyl chloride was used as the polymer material serving as the base material, the performance was slightly inferior. It turns out that the interaction between the aliphatic polyurethane and the fat-solubilized mucopolysaccharide is particularly preferable for maintaining the performance.

Comparative Examples 3 and 4 in which the film surface was coated with a fat-solubilized mucopolysaccharide without containing a polymer material
Indicates that although the performance before elution is relatively good, the performance is significantly reduced due to plasma elution. It is considered that when no polymer material is contained, the fat-solubilized mucopolysaccharide is easily exfoliated by elution with plasma, resulting in a decrease in performance.

[0058]

The antithrombotic material provided with the antibacterial property of the present invention has excellent antithrombotic properties and antibacterial properties, and its performance is maintained not only immediately after the material preparation but also after a long-term dissolution operation. . In addition, the antibacterial property-imparting antithrombotic material of the present invention can easily impart antithrombotic property and antibacterial property to an existing structure by being introduced by a method such as coating. It has excellent suitability as an antibacterial material.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Masakazu Tanaka, Inventor 2-1-1 Katata, Otsu-shi, Shiga Inside Toyobo Co., Ltd. (72) Inventor Sou Arimori 2-1-1 Katata, Otsu-shi, Shiga No. Toyobo Co., Ltd.

Claims (4)

[Claims] 1. An antithrombotic material provided with antibacterial properties, comprising at least the following (a) and (b) as essential components: (A) a fat-solubilized mucopolysaccharide comprising an ionic complex of at least one mucopolysaccharide and a quaternary ammonium (b) an aliphatic polyurethane 2. The antithrombotic material imparted with antibacterial properties according to claim 1, wherein the mucopolysaccharide contains at least heparin or heparin metal salt. 3. The antithrombotic material having antibacterial properties according to claim 1, wherein the quaternary ammonium has a structure represented by the following formula [1]. Embedded image In the formula [1], R ¹ , R ² and R ^{3 each} have 1 to 12 carbon atoms.
Alkyl group or an aryl group having 6 to 12 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, a, R ⁴ is 1 to carbon atoms
Each of the 25 alkyl groups may be the same or different. 4. The antithrombotic material provided with an antibacterial property according to claim 1, wherein the fat-solubilized mucopolysaccharide is contained in an amount of 1 to 100 parts by weight based on 100 parts by weight of the aliphatic polyurethane.