JPH10158432A - Antimicrobial antithrombotic material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antithrombotic material which is easily and simply handled, is widely used, exhibits antithrombotic properties for a long term, has a wide antimicrobial spectrum, and is excellent in antimicrobial properties by incorporating an ionic complex of mucopolysaccharide and a quat. phosphonium, an inorg. antimicrobial agent, and an org. polymer material into the same. SOLUTION: Examples of the mucopolysaccharide used are heparin and its metal salts. The quat. phosphonium used is represented by the formula (wherein R<1> to R<3> are each-12C alkyl, 6-12C aryl, or 7-20C aralkyl; and R<4> is a 1-25C alkyl), e.g. tributyllaurylphosphonium. As the antimicrobial agent is used a silver-base one (e.g. silver zeolite) or an antimicrobial glass. A polyvinyl halide is an example of the polymer material used. The ionic complex of a mucopolysaccharide and a quat. phosphonium is obtd. by mixing an aq. soln. of the mucopolysaccharide with an aq. soln. of the quat. phosphonium and recovering and freeze drying the resultant precipitate.

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 an ionic complex of a class phosphonium, an inorganic antibacterial agent and an organic polymer material 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. 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.

Conventional techniques for imparting antithrombotic properties to medical materials include (1) a method in which a mucopolysaccharide such as heparin or a fibrinolytic activator such as urokinase is immobilized on the surface of the 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 material surface to form a biomembrane-like surface, and a stable antithrombotic property is obtained. 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 introduction, antithrombotic properties or dissolution of formed thrombus are exhibited by heparin or urokinase on the surface, but the performance generally deteriorates with long-term use. Tend to. In other words, in (A), (B) and (C), heparins are easily detached by long-term use under normal physiological conditions, and it is difficult to obtain sufficient performance as a medical material 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 conformation of D-glucosamine or D-glucuronic acid, which is a component of heparin, is often obtained. It has the disadvantage of giving a change and reducing the anticoagulant effect.

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 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.

[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 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 (lipidizing 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 anticoagulability due to elution of heparin during long-term use.

[0010] In addition, in the case of a medical device such as a high nutritional 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. Despite the strong demand for antithrombotic materials 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. 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 and the antibacterial material containing biguanide include, for example, Japanese Patent Publication No. 5-80225, Japanese Patent Publication No. 2-61261, Japanese Patent Publication No. 3-10341, and the antibacterial material containing an acridine compound. It is disclosed by Japanese Patent Publication No. 3-76343. Also, JP-A-7-82511, JP-A-7-53316, and JP-A-4-
266912 and JP-A-5-310820 disclose antibacterial materials containing phosphonium salts. Furthermore, Japanese Patent Publication No. 6-55892 discloses an antibacterial material containing silver protein as an antibacterial active ingredient.

In these techniques, the antibacterial property is exhibited by one kind of antibacterial substance, and it is difficult to exhibit sufficient antibacterial property 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 comprises at least one ionic complex of mucopolysaccharide and quaternary phosphonium, an inorganic antibacterial agent and an organic polymer material. It is characterized by containing. 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 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 quaternary phosphonium, which is an essential component of the antithrombotic material having antibacterial properties of the present invention, is characterized by having the structure of the above-mentioned formula (1).
Only the types may be used, or some types may be used simultaneously. One of the four hydrocarbon chains bonded to the phosphorus atom of the quaternary phosphonium 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 are an alkyl group having 1 to 12, preferably 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms, or 7 to 20 carbon atoms.
Preferred are 7 to 12 aralkyl groups.

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

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 metal salt is particularly excellent in antithrombotic activity, and many examples have been reported and are preferred.

A method for obtaining an ionic complex of mucopolysaccharide and quaternary phosphonium (hereinafter abbreviated as fat-solubilized mucopolysaccharide) is not particularly limited. For example, an aqueous solution or aqueous dispersion of mucopolysaccharide, And a method of mixing an aqueous solution or aqueous dispersion of a quaternary phosphonium salt, collecting the resulting precipitate, and freeze-drying the precipitate. 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 provided with antibacterial properties according to the present invention contains, in addition to the fat-solubilized mucopolysaccharide, an inorganic antibacterial agent as an essential component. 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-based antibacterial agent or antibacterial glass is preferably used, and among them, silver zeolite is more preferably used.

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

The present invention is characterized in that it contains 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 activities of the present invention, due to the affinity of the polymer with the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent, the sustained release of the fat-solubilized mucopolysaccharide and the inorganic antibacterial agent even upon contact with a biological component It is possible to maintain excellent antithrombotic and antibacterial properties even after long-term dissolution.

The organic polymer material used for the antibacterial property-imparting antithrombotic material of the present invention includes, for example, polyvinyl halide, polyvinylidene halide, polyurethane, and the like.
Conventionally used materials such as polyurethane urea, polyester, polyamide, polypropylene, and polyethylene, and materials that will be used in the future can be widely used. Among them, polyvinyl halide, polyvinylidene halide, polyurethane, polyurethane urea , Polyester and polyamide are preferred, and polyvinyl chloride, polyvinylidene chloride, polyurethane and polyurethaneurea 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 addition amount is not particularly limited, but is 5 to 100 phr with respect to the polymer, preferably 10 to 100 phr.
~ 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). .
The amount of the inorganic antibacterial agent added is preferably 0.1 to the substrate.
It is recommended to add in an amount of about 1 to 50 phr, more preferably about 1 to 30 phr, and the addition ratio of the fat-solubilized mucopolysaccharide to the inorganic antibacterial agent is preferably 40: 1 to 1: 4, and 20: 1 to 1
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, conventionally used materials such as polyether urethane, polyurethane, polyurethane urea, polyvinyl chloride, polyvinylidene chloride, polyester, polypropylene, polyethylene, polycarbonate, and in the future The materials that will be used are widely available. In addition, 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, due to the synergistic effect of the quaternary phosphonium 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 antithrombotic materials used for various medical instruments and 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 adsorbing waste products in blood. In addition, membrane materials for artificial lungs (partition of blood and oxygen), sheet materials for sheet lungs in artificial heart lungs, aortic balloons, blood bags, catheters, cannulas, shunts,
It can be used in a wide range of fields such as blood circuits. Utilizing the antibacterial property of the antithrombotic material imparted with antibacterial property of the present invention at the same time, the infection from the bio-material interface was a problem in the related art.
Application to H or the like is also particularly preferred.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not particularly limited thereto.

<Example 1> Heparin sodium salt
00 g was dissolved in ion-exchanged water to make a total volume of 100 ml. 19.07 g of tri (n-butyl) cetylphosphonium chloride (hereinafter abbreviated as TBCP · Cl) was dissolved in ion-exchanged water to make a total volume of 191 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. The operation of suspending the suspension in distilled water and washing the precipitate by centrifugation was repeated three times. Thereafter, the precipitate was dried to obtain a composite of TBCP · Cl and heparin. Body (hereinafter TB)
CP-Hep). This TBCP-He
p 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 1,000 g of this PU solution, 5.00 g of the TBCP-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 TBCP-Hep, Ag
20 g of the Zeo / PU blend suspension was kept horizontal 12
The film was uniformly placed on a glass plate having a size of 12 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 referred to as TBC).
A P-Hep, AgZeo / PU blend material is used as material A,
The film obtained from material A is abbreviated as film A). Film A contains 10 phr of TBCP-Hep and AgZe
This means that 2 phr of o 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 below.

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 Complimentfixatio
n ”Experiment 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. After diluting the bacterial stock solution 10 ⁴ times, 100 μl was spread on an ordinary agar plate, and the number of P. aeruginosa colonies formed 24 hours later was counted. If the number of colonies is N,
The concentration C of the bacterial stock solution is shown 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 (hereinafter abbreviated as 10 ^n- fold diluted solution). 100 μl of each diluted solution was spread on an ordinary agar medium, and after 24 hours, the number of P. aeruginosa colonies formed on the ordinary agar plate 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. 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 is represented by the following equation. 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 soaked 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 suspension of 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, 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.

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.

[0037]

[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. 16.76 g of tri (n-butyl) laurylphosphonium chloride (hereinafter abbreviated as TBLP.Cl) was dissolved in ion-exchanged water to make a total volume of 168 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 suspending the suspension in distilled water and washing the precipitate by centrifugation was repeated three times. Thereafter, the precipitate was dried to form a complex of TBLP · Cl and heparin. Body (hereinafter T
BLP-Hep). This TBLP-H
Ep was soluble in organic solvents such as benzene, DMF, THF, and chloroform.

The fat-solubilized heparin was converted from TBCP-Hep to T
A film B composed of TBLP-Hep, AgZeo / PU blend material B, and material B was obtained in the same manner as in Example 1 except that BLP-Hep was used. 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 film B was prepared in the same manner as in Example 1.
Was performed, and the relative dissolution time of blood plasma and the antibacterial property of the obtained dissolution film B ′ were also evaluated. Table 1 shows the results
It was shown to.

<Comparative Example 1> TBCP-H obtained in Example 1
benzene was added to 100 mg of ep 100 mg and 20 mg of AgZeo to make the total amount 100 g, and TBCP-Hep, AgZe
o / benzene suspension was obtained. 3.00 g of this suspension was uniformly placed on a 12 cm × 12 cm PU 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. (This T
BCP-Hep, AgZeo / PU coating film is abbreviated as Film C).

Coating with this TBCP-Hep, AgZeo / benzene suspension was used to determine complement titer and in vivo antithrombotic properties, and using film C for plasma relative coagulation time and antibacterial properties. Was evaluated. 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> TBLP-H obtained in Example 2
benzene was added to 100 mg of ep and 20 mg of AgZeo to make the total amount 100 g, and TBLP-Hep, AgZe
o / benzene suspension was obtained. 3.00 g of this suspension was uniformly placed on a 12 cm × 12 cm PU 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. (This T
BLP-Hep, AgZeo / PU coating film is abbreviated as film D).

Coating with this TBLP-Hep, AgZeo / benzene suspension to determine complement titer and in vivo antithrombotic properties, and film D to determine plasma relative coagulation time and antibacterial properties in the same manner as in Example 1. Was evaluated. 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 and 5%
The solution was used. Example 1 against 1000 g of this PU solution
5.00 g of TBCP-Hep obtained in the above was added to obtain a homogeneous solution. This TBCP-Hep / PU blend solution 20
g was placed horizontally on a 12 cm × 12 cm glass plate kept horizontal, dried at 40 ° C. for 8 hours under a nitrogen stream, and then dried under reduced pressure at 40 ° C. for 15 hours to obtain a film having a thickness of about 60 μm ( Hereinafter, this TBCP-Hep / PU blend material is abbreviated as a material E, and a film obtained from the material E is abbreviated as a film E). This means that the film E was added with 10 phr of TBCP-Hep.

Using the material E and the film E, the plasma relative coagulation time, complement titer, 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 in the same manner as in Example 1, and the obtained dissolution film E ′ was also evaluated for the relative coagulation time of plasma and the antibacterial property. The results are shown in Table 1.

Comparative Example 4 PU was dissolved in THF and 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
ivo Antithrombotic properties were evaluated. Further, the 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 F ′ were also evaluated. The results are shown in Table 1.

Comparative Example 5 The relative clotting time of plasma and antibacterial property were evaluated using a PU film (film G) into which no fat-solubilized heparin was introduced. Further, the dissolution test of the film G 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 G ′ were also evaluated. 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 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 phosphonium and inorganic antibacterial agents.

[0051]

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 phosphonium (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 having antibacterial properties according to claim 1 or 2, wherein the quaternary phosphonium has the structure shown below. 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 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 are contained based on 100 parts by weight of the organic polymer material. Anti-thrombotic material provided with antibacterial properties in any of the above.