JPH10168231A - Antibacterial antithrombotic material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a material which possesses long persistent antithrombotic properties and antistatic properties in addition to convenience and general-purpose properties by adding a fat-soluble mucopolysaccharide comprising an ionic complex material made of a mucopolysaccharide and a trialkoxysilyl-containing quat. phosphonium compound to an organic polymer material. SOLUTION: The mucopolysaccharide contains at least heparin or a heparin metal salt. In detail, the trialkoxysilyl-containing quat. phosphonium compound has a structure represented by the formula (wherein R<1> to R<3> , R<5> and R<6> are each a 1-12C alkyl, a 6-12C aryl, a 7-20C aralkyl; R<4> is a 1-12C alkylene, a 6-12C arylene, a 7-20C aralkylene; and R<7> is a 1-12C alkyl). The amount of addition is desirably such that 0.1-100 pts.wt. fat-soluble mucopolysaccharide is used per 100 pts.wt. organic polymeric material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antibacterial material having an antibacterial property and containing an ionic complex of a mucopolysaccharide and a quaternary phosphonium having a trialkoxysilyl group in the molecule and an organic polymer material. It is.

[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. In addition to sufficient mechanical strength and durability as these medical materials, safety to the living body, especially that blood does not coagulate when in contact with blood,
That is, antithrombotic properties are required.

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.

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 have a stable antithrombotic property. It is possible to get. 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 easily detached due to long-term use under normal physiological conditions, and it is difficult to obtain sufficient performance as a medical material to be fixed and used in a living body. . On the other hand, 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 condensate of heparin constituent components D-glucosamine and D-glucuronic acid is often used. There is a disadvantage that the formation is changed and the anticoagulant effect is reduced.

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

[0007] Considering the ease of antithrombosis of the material and the wide range of choice of applicable materials, the blending method of (A) a polymer and a fat-solubilized heparin or (B)
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 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 a material surface with a complex of heparin and an in vivo phospholipid is mentioned as a preferable example. I have.

However, this method is useful only in that the cationic substance (lipidizing agent) eluted simultaneously with the elution of heparin is a natural lipid or a synthetic lipid, so that it does not easily adversely affect the living body. . That is, it cannot be said that this method has solved the decrease in anticoagulability due to the elution of heparin during long-term use. Further, a method of using a complex of a silicon-containing compound and heparin as an antithrombotic material is disclosed in JP-B-53-9800 and JP-B-55-25852. However, in each of these methods, the silane coupling agent and heparin are covalently bonded to each other, and the obtained silicon-containing modified heparin is further immobilized on a molding material. In this method, the activity of heparin may be reduced due to a conformational change due to a covalent bond. Japanese Patent Publication No. 3-66904 and Japanese Patent Application Laid-Open No. 62-136241 disclose techniques for immobilizing a physiologically active substance via a silane coupling agent. After fixing the ring agent,
Immobilization is performed by contact with a physiologically active substance solution. In such a method, the immobilization of the physiologically active substance is performed in a solid-liquid heterogeneous system, so that there is a high possibility that the introduction efficiency is lowered, and a problem remains in practical use.

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 a 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. However, despite the strong demand for antithrombotic materials imparted with antibacterial properties, few materials applicable to this field have been reported at present.

[0011]

SUMMARY OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art, and can exhibit not only simplicity and versatility but also anti-thrombotic properties for a long period of time, and also exhibit antibacterial properties. It is an object of the present invention to provide an antithrombotic material provided with an antibacterial property that can be used.

[0012]

The antithrombotic material provided with antibacterial properties according to the present invention comprises an ionic complex of at least one mucopolysaccharide and a quaternary phosphonium compound having a trialkoxysilyl group in the molecule and an organic compound. It is characterized by containing a polymer material. The antithrombotic material provided with the antibacterial property of the present invention is characterized by containing at least heparin or heparin metal salt as a mucopolysaccharide. The antithrombotic material provided with antibacterial properties according to the present invention is characterized in that the quaternary phosphonium compound having a trialkoxysilyl group in the molecule has the structure of the above formula (1). The antithrombotic material provided with the antibacterial property of the present invention is characterized in that the organic polymer material is polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester or polyamide.

An essential component of the antithrombotic material provided with the antibacterial property of the present invention.
Having a trialkoxysilyl group in the molecule
The class phosphonium compound has the structure of the above formula 1.
However, trialkoxysilicon is contained in this molecule.
Only one quaternary phosphonium compound having
Or several types may be used simultaneously. In Chemical 1
And R¹, R^Two, R^Three, R^Five, R⁶Has 1 to 12 carbon atoms
An alkyl group or an aryl group having 6 to 12 carbon atoms
Or an aralkyl group having 7 to 20 carbon atoms,
5 alkyl groups are preferred. R^FourIs a group having 1 to 12 carbon atoms.
Alkylene group, arylene group having 6 to 12 carbon atoms or carbon
An aralkylene group having 7 to 20 carbon atoms, and an aralkylene group having 1 to 5 carbon atoms.
A alkylene group is preferred. R⁷Is an alk having 1 to 25 carbon atoms
And represents an alkyl group having 12 to 22 carbon atoms.
No. Note that R¹, R^Two, R ^Three, R^Five, R⁶, R⁷Is it
They may be the same or different.

[0014] Has a trialkoxysilyl group in the molecule
As the quaternary phosphonium compound, specifically, for example, 3
-(Trimethoxysilyl) propyldimethyloctadecy
Ruphosphonium chloride, 3- (triethoxysilyl)
Le) Propyl dimethyl octadecyl phosphonium chloride
Id, 3- (trimethoxysilyl) propyldimethyl
Xadecyl phosphonium chloride and the like are exemplified.
Among them, 3- (trimethoxysilyl) propyldimethyl
Octadecylphosphonium chloride is preferred.

The antibacterial and antithrombotic material of the present invention requires the use of mucopolysaccharides. Examples of the mucopolysaccharides include heparin, chondroitin sulfate, hyaluronic acid, dermatan sulfate, and keratan sulfate. Among them, heparin or heparin or heparin metal salt is particularly preferable.

The method for obtaining an ionic complex of mucopolysaccharide with a quaternary phosphonium compound having a trialkoxysilyl group in the molecule (hereinafter abbreviated as fat-solubilized mucopolysaccharide) is not particularly limited. And an aqueous dispersion of the quaternary phosphonium salt having a trialkoxysilyl group in the molecule, and the resulting precipitate is collected and freeze-dried. It is also possible to use a weakly acidic buffer instead of the water used at this time. Examples of the solute used in the buffer include 2- (N-morpholino) ethanesulfonic acid, piperazine-1,4-bis (2-ethanesulfonic acid), and N- (2-acetamido) -2-aminoethanesulfonic acid. 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] ethanesulfone Acids are preferred, and 2- (N-morpholino) ethanesulfonic acid (hereinafter abbreviated as MES), particularly preferably piperazine-
1,4-bis (2-ethanesulfonic acid) (hereinafter PIPE
S) and 3- (N-morpholino) propanesulfonic acid (hereinafter abbreviated as MOPS). As described above, the antibacterial material provided with the antibacterial property of the present invention is obtained. Since the fat-solubilized mucopolysaccharide of the present invention forms a complex with the compound represented by Chemical Formula 1 having a trialkoxysilyl group in the molecule, it reacts with the active hydrogen group of the base polymer to form a covalent bond. Probability is high. For this reason, there is an advantage that the complex is hardly eluted even when it is in contact with blood for a long time, and the durability is high.

The present invention is characterized in that it contains a fat-solubilized mucopolysaccharide and an organic polymer material. The introduction of the fat-solubilized mucopolysaccharide into the organic polymer material inactivates the surface of the polymer material, and at the same time, the antithrombotic and antibacterial properties are partially exhibited by the sustained release from the polymer material. Conceivable. In the medical material having antithrombotic and antibacterial properties of the present invention, due to the affinity of the polymer and the fat-solubilized mucopolysaccharide, the sustained release of the fat-solubilized mucopolysaccharide is controlled even by contact with biological components, and even after long-term dissolution. Very good antithrombotic and antibacterial properties can be maintained.

As the organic polymer material used for the antibacterial and 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. Furthermore, our study confirmed that when a plasticizer was added, the antithrombotic and antibacterial properties were more likely to be exerted. 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,
5 to 100 phr, preferably 10 to 80 phr, based on the polymer
phr.

In the present invention, when the fat-solubilized mucopolysaccharide is introduced into the organic polymer material, the amount of fat-solubilized mucopolysaccharide is preferably 0.1 to 10 parts by weight per 100 parts by weight of the base material.
It is recommended to add it in an amount of 0 parts by weight, more preferably about 1 to 60 parts by weight (hereinafter, when 1 part by weight of the additive is added to 100 parts by weight of the base material, the amount of the additive Is expressed as 1 phr).

The antimicrobial-imparting antithrombotic material of the present invention can be further introduced into another structure serving as a substrate. The material of the structure is not particularly limited, and conventionally used materials such as polyether urethane, polyurethane, polyurethane urea, polyvinyl chloride, polyvinylidene chloride, polyester, polypropylene, polyethylene, polycarbonate, etc. The materials that will be used are widely available. Further, 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.
Normal blending and coating methods are applicable,
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 a prolonged contact. In addition, a quaternary phosphonium compound having a trialkoxysilyl group in the molecule can 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 for 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. The anti-thrombotic material provided with the antibacterial property of the present invention has the advantage of having the antibacterial property simultaneously,
It is also particularly preferable to apply to IVH or the like where infection from the material interface has been a problem.

Hereinafter, the present invention will be described with reference to examples.
Note that the present invention is not limited to the embodiments. Example 1 10.0 g of heparin sodium salt was dissolved in ion-exchanged water to make a total volume of 100 ml. 3- (trimethoxysilyl) propyldimethyloctadecylphosphonium chloride (hereinafter abbreviated as TSPP) 22.0
g of methanol: ion-exchanged water = 1: 1 mixed solution 20
Dissolved in 0 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 suspension, and the operation of adding and suspending distilled water to wash the precipitate by centrifugation was repeated three times. Thereafter, the precipitate was dried to obtain a complex of TSPP and heparin ( (Hereinafter abbreviated as TSPP-Hep)
I got

A commercially available polyurethane (Pellethane (trade name), hereinafter abbreviated as PU) was dissolved in THF to form a 5% solution. To 1,000 g of this PU solution, 5.00 g of TSPP-Hep obtained above was added to form a uniform suspension. 20 g of this TSPP-Hep / PU blend solution
Was uniformly 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. under reduced pressure for 15 hours to obtain a film having a thickness of about 60 μm (hereinafter referred to as “film”). The TSPP-Hep / PU blend material is referred to as material A, and the film obtained from material A is referred to as film A). Film A contains 10 phr of TSPP-Hep.
It has been added.

The plasma relative coagulation time 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.

The material A 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 Complementfixatio
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 bacterial count 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) to prepare a total volume of 40 ml (hereinafter, this solution is referred to as immersion stock solution). In the immersion stock solution,
The film A was previously cut into 5 cm × 5 cm and sterilized by EOG, immersed in the film A, and cultured at 37 ° C. for 24 hours. After culture
The immersion stock solution was diluted with sterile physiological saline to 10 ⁴ times in a 10-fold series. 100 μl each of immersion stock solution and 10 ^n- fold diluted solution
1 was spread on a normal agar medium, and 24 hours later, the number of Pseudomonas aeruginosa colonies formed on the normal agar plate was counted for 30 to 300 plates. When the number of colonies from the 10 ⁿ times Mareeki solution to N _n pieces, the number of bacteria N _a after contact with 25 cm ² film A is given by the following equation. The concentration of 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, the number of bacteria before Film A contact N _b showed the number changes in N _b → N _a by contact between the size of the film 25 cm ² in a N _b = 10 ⁵ × N immersed stock 40ml 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% suspension of THF of the material A is prepared, and the existing hollow hollow fiber made of polypropylene for artificial lung is dipped 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, and blood was removed from the abdominal aorta using an appropriate tube, and the rabbit was sacrificed. 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.

The 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.

[0031]

[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 was observed. b: Fibrin formation or platelet aggregation is observed but thrombus formation is not observed. c: Fibrin formation or platelet aggregation is observed, and thrombus formation is slightly observed. d: Fibrin formation or platelet aggregation is observed, and thrombus formation is considerably observed. e: Fibrin formation or platelet aggregation is observed, and a large amount of thrombus formation is observed.

Example 2 Heparin sodium salt
0 g was dissolved in ion-exchanged water to make a total volume of 100 ml. 3- (trimethoxysilyl) propyldimethyloctadecylphosphonium chloride (TSPP) 22.0
g was dissolved in 200 ml of a mixed solution of methanol: MES buffer at pH 5.5 = 1: 1. 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 suspension, and the operation of adding and suspending distilled water to wash the precipitate by centrifugation was repeated three times. Thereafter, the precipitate was dried to obtain a complex of TSPP and heparin ( The following TSPP-H
ep).

Commercially available polyvinyl chloride (DOP content 50 ph
r, hereinafter this polyvinyl chloride is abbreviated as PVC)
Dissolved in HF to 5%. 1000 g of this PVC solution
Was added with 5.00 g of the TSPP-Hep obtained above to obtain a uniform solution. 20 g of this TSPP-Hep / PVC blend solution was evenly placed on a 12 cm × 12 cm glass plate kept horizontal, and dried under reduced pressure at 40 ° C. for 15 hours to obtain a film having a thickness of about 60 μm (hereinafter, this TSP).
The P-Hep / PVC blend material is referred to as material B, and the film obtained from material B is referred to as film B). This means that 10 phr of TSPP was added to film 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. Further, the dissolution test of the film B was carried out in the same manner as in Example 1, and the obtained dissolution film B ′ was obtained.
Were also measured for plasma relative coagulation time and antimicrobial activity. The results are shown in Table 1.

<Comparative Example 1> TSPP-H obtained in Example 1
Add benzene to 100mg of ep to make the total amount 100g,
A TSPP-Hep benzene suspension was obtained. 12cm × 12
3.00 g of this suspension was uniformly placed on a PU film having a thickness of 10 cm, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried at 40 ° C. under reduced pressure for 15 hours to obtain a film having a thickness of about 60 μm ( Hereinafter, this TSPP-Hep / PU coating film is abbreviated as film C).

The TSPP-Hep / benzene suspension was coated to determine the complement value and in vivo antithrombotic properties, and to determine the relative coagulation time and antibacterial properties of plasma using Film C.
The measurement was performed in the same manner as described above. 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> TSPP-H obtained in Example 2
Add benzene to 100mg of ep to make the total amount 100g,
A TSPP-Hep / benzene suspension was obtained. 12cm x 1
3.00 g of this suspension was uniformly placed on a 2 cm PVC film, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried at 40 ° C. under reduced pressure for 15 hours to obtain a film having a thickness of about 60 μm (hereinafter referred to as “film”). This TSPP-Hep / PVC coating film is abbreviated as film D).

The TSPP-Hep / benzene suspension was coated to determine the complement value and in vivo antithrombotic properties, and the relative clotting time and antibacterial properties of the plasma were measured using Film D.
Was evaluated in the same manner as described above. Further, the dissolution test of the film D was carried out in the same manner as in Example 1, and the relative dissolution time of plasma and the antibacterial property of the obtained dissolution film D ′ were also evaluated. The results are shown in Table 1.

Comparative Example 3 Heparin sodium salt
00 g was dissolved in pH 5.5 MES buffer to make a total volume of 100 ml. This solution and benzalkonium chloride 1
110 ml of a 0% aqueous solution (hereinafter abbreviated as Ben) was mixed under ice cooling, and allowed to stand at 4 ° C. for 15 hours to obtain a precipitate. The precipitate was collected by centrifugation at 3300 rpm,
A Ben-heparin complex (hereinafter abbreviated as Ben-Hep) was obtained by freeze-drying.

The fat-solubilized heparin was converted from TSPP-Hep to B
Except for changing to en-Hep, in the same manner as in Example 1,
A Ben-Hep / PU blend material E and a film E composed of the material E were obtained. This material E and film E
, Using the same method as in Example 1, plasma relative coagulation time,
Complement titers, antibacterial properties, and in vivo antithrombotic properties were measured. Further, the dissolution test of the film E was performed in the same manner as in Example 1,
The relative coagulation time of plasma and antibacterial property of the obtained dissolution film E ′ were also measured. The results are shown in Table 1.

<Comparative Example 4> The solution of Material E obtained in Comparative Example 3 was diluted with THF to form a 0.1% solution, and introduced onto a 12 cm × 12 cm PU film at a rate of 3 mg / 144 cm ^2. After uniformly loading 3.00 g of the solution and drying under a nitrogen stream at 40 ° C. for 8 hours, drying under reduced pressure at 40 ° C. was performed for 15 hours.
A film having a thickness of about 60 μm was obtained (hereinafter referred to as Ben-H).
Ep / PU coated PU film is abbreviated as film F).

Using this film F, the relative coagulation time of plasma, antibacterial properties, and in vivo antithrombotic properties were evaluated in the same manner as in Example 1. Further, in the same manner as in Example 1, the film F
Was performed, and the relative dissolution time of plasma and the antibacterial property of the obtained dissolution film F ′ were also evaluated. The results are shown in Table 1.

Comparative Example 5 A plasma relative coagulation time 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 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 the film surface was coated with the fat-solubilized mucopolysaccharide without containing the organic polymer material, the performance before elution was relatively good, but the decrease in performance due to plasma elution was large. . When no organic polymer material is contained, the fat-solubilized mucopolysaccharide is easily exfoliated by elution with plasma,
It is considered that the performance has been reduced. The material of Comparative Example 3, in which a heparin complex with benzalkonium chloride was added instead of the quaternary phosphonium compound having a trialkoxysilyl group in the molecule, had relatively good antithrombotic properties, but had antibacterial properties. It is inferior, and the antibacterial property after dissolution is particularly large. In Comparative Example 5, which does not contain the fat-solubilized mucopolysaccharide, the antithrombotic properties are remarkably inferior, and the antibacterial properties are not as good as the antibacterial antithrombotic material of the present invention. It shows that antithrombotic properties are exerted by lipophilic heparin and also suggests that strong antibacterial properties are exerted by the effect of quaternary phosphonium compounds having a trialkoxysilyl group in the molecule. .

[0045]

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.

Continued on the front page (72) Inventor Kanade Arimori 2-1-1 Katata, Otsu City, Shiga Prefecture Inside Toyobo Co., Ltd. (72) Inventor Masakazu Tanaka 2-1-1 Katata Katsuta, Otsu City, Shiga Prefecture Toyobo Co., Ltd. Inside Research Institute Co., Ltd.

Claims (5)

[Claims] 1. A composition comprising a fat-solubilized mucopolysaccharide comprising an ionic complex of at least one mucopolysaccharide and a quaternary phosphonium compound having a trialkoxysilyl group in the molecule, and an organic polymer material. An anti-thrombotic material provided with an antibacterial property, which is a substance. 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 having antibacterial properties according to claim 1 or 2, wherein the quaternary phosphonium having a trialkoxysilyl group in the molecule has the structure shown below. Embedded image In Chemical Formula 1, R ¹ , R ² , R ³ , R ⁵ , and R ⁶ represent 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. R ⁴ represents an alkylene group having 1 to 12 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 20 carbon atoms.
R ⁷ represents an alkyl group having 1 to 25 carbon atoms. In addition,
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ⁷ may be the same or different. 4. The antithrombotic material provided with antibacterial properties according to claim 1, wherein the organic polymer material is polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea, polyester or polyamide. 5. The antithrombotic material provided with an antibacterial property according to claim 1, wherein the fat-solubilized mucopolysaccharide is contained in an amount of 0.1 to 100 parts by weight based on 100 parts by weight of the organic polymer material.