JPH10114660A - Antithrombogenic composition having antimicrobial property - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition having convenience and general purpose properties and capable of exhibiting long-term antithrombogenic property as well as antimicrobial property by using a mucopolysaccharide- alkoxysilane-containing compound conjugate. SOLUTION: This antithrombogenic composition comprises an ionic conjugate of (A) at least one kind of mucopolysaccharide, preferably heparin and (B) a quaternary ammonium compound having a trialkoxysilyl group in the molecule or a quaternary phosphonium compound having a trialkoxysilyl group in the molecule. Furthermore, the component B preferably has a structure represented by the formula (A is P or N; R<1> to R<3> , R<5> and R<6> are each a 1-12C alkyl, a 6-12C aryl or a 7-20C aralkyl; R<4> is a 1-12C alkylene, a 6-12C arylene or 7-20C aralkylene; R<7> is a 1-25C alkyl) and e.g. 3-(triethoxysilyl)propyl-dimethyloctadesyl ammonium chloride, etc., is preferably used as the component B.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an ionic complex of a mucopolysaccharide and a quaternary ammonium compound having a trialkoxysilyl group in the molecule or a quaternary phosphonium compound having a trialkoxysilyl group in the molecule. The present invention relates to an antithrombotic composition provided with an antibacterial property.

[0002]

2. Description of the Related Art Artificial materials having excellent workability, elasticity and flexibility have been widely used in recent years as medical materials. However, artificial materials such as artificial kidneys, artificial lungs, assisted circulation devices, and artificial blood vessels have been developed. 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. As these medical materials, in addition to sufficient mechanical strength and durability, safety to the living body,
In particular, it is required that blood does not coagulate when it comes into contact with blood, that is, antithrombotic properties.

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

[0004] Among the above methods (2) and (3), in the case of prolonged contact with body fluid, a protein is 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 a living body (blood contact site), various coagulation factors and the like are in an activated state 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, the method (1) exhibits antithrombotic properties or lytic properties of formed thrombus due to heparin or urokinase on the surface in the initial stage of introduction, but is generally used for a long time. Performance 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. . Further, the material obtained in (D) has an advantage that heparin is hardly detached because it is covalently bonded. However, the conventional bonding method often uses D-glucosamine or D-glucuronic acid which is a component of heparin. However, there is a disadvantage that the conformation is changed and the anticoagulant effect is reduced.

In the methods (C) and (D), it is necessary to select or newly introduce a material containing a functional group which can be used for immobilizing heparin. 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 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 antithrombotic properties of materials and the wide range of materials to be applied, (A) a blend method of a polymer and a fat-solubilized heparin or (B) a fat-solubilized heparin Can be said to be the most excellent method. However, a fatal disadvantage of this method is that heparins are liable to be eliminated by long-term use under physiological conditions as described above. Conversely, by overcoming this drawback, it becomes possible to provide an excellent antithrombotic property which is simple and versatile.

As means for solving this problem, for example, there is a method disclosed in Japanese Patent Laid-Open No. 2-270823. 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, it can be said that this method is useful only in that the cationic substance (lipid solubilizing agent) that 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 the antithrombotic property due to the elution of heparin during long-term use.

A method of using a complex of a silicon-containing compound and heparin as an antithrombotic material is disclosed in Japanese Patent Publication No. 53-9 / 1973.
800 and Japanese Patent Publication No. 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. Sho 62-1362.
No. 41 discloses a technique for immobilizing a physiologically active substance via a silane coupling agent. In these methods, an amino group-containing silane coupling agent is immobilized on the surface of a molded product, and the introduced amino group is immobilized. The bioactive substance is immobilized by utilizing it. In such a method, since the immobilization of the physiologically active substance is performed in a heterogeneous solid-liquid system, there is a high possibility that the introduction efficiency is reduced, and a problem remains in practical use.

Conventionally, a high nutrient infusion catheter (hereinafter referred to as IVH)
In the case of a medical device that needs 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 such antibacterial and antithrombotic materials, at present, few materials applicable to this field have been reported.

[0011]

SUMMARY OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art and provides an antibacterial agent which can exhibit not only simplicity and versatility but also antibacterial properties at the same time as exhibiting long-term antithrombotic properties. It is intended to provide a sex-imparting antithrombotic composition.

[0012]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, the use of the mucopolysaccharide-alkoxysilane-containing compound complex shows excellent antibacterial and antithrombotic properties. Moreover, they have found that the properties are maintained for a long period of time, and arrived at the present invention. That is, the antibacterial antithrombotic composition of the present invention comprises a quaternary ammonium compound having at least one mucopolysaccharide and a trialkoxysilyl group in the molecule or a quaternary ammonium compound having a trialkoxysilyl group in the molecule. It is a composition comprising an ionic complex with a phosphonium compound. More preferably, the mucopolysaccharide is heparin, and a fourth amino acid having a trialkoxysilyl group in the molecule.
A quaternary ammonium compound or a quaternary phosphonium compound having a trialkoxysilyl group in the molecule,
Having the following structure.

The antithrombotic properties of the material can be easily obtained by introducing the antibacterial composition of the present invention into a general polymer material as a base material. Further, by using the antithrombotic composition provided with the antibacterial property of the present invention, it is possible to maintain extremely excellent antithrombotic properties even after long-term dissolution. Further, by the effect of quaternary ammonium or quaternary phosphonium in the molecule, it is possible to impart anti-thrombotic property and antibacterial property to the material.

The base polymer into which the antibacterial composition having antibacterial properties of the present invention is introduced as an anticoagulant is not particularly limited. If there is a functional group having active hydrogen in the molecule, alkoxysilyl may be used. A quaternary ammonium compound or a quaternary phosphonium compound is introduced via a covalent bond by a reaction with the group, and it becomes possible to immobilize heparin more stably. Specifically, for example, cellulose,
Examples thereof include those conventionally used such as polyether urethane, polyurethane, polyurethane urea, polyvinyl chloride, polyester, polypropylene, polyethylene, ethylene-vinyl alcohol copolymer (EVAL), and vinyl acetate-vinyl alcohol copolymer. Further, materials that will be used in the future can be widely applied. Among them, cellulose, polyvinyl chloride, polyurethane, polyether urethane, EVAL, and vinyl acetate-vinyl alcohol copolymer are particularly preferable. Also, it can be introduced for the purpose of imparting antithrombotic properties to blood treatment agents such as hemodialysis membranes, plasma separation membranes and adsorbents made of existing and new materials.

The method of introduction into the substrate is not particularly limited, either.
Besides the usual blending method and coating method, there may be mentioned a method of blending the antibacterial antithrombotic composition of the present invention with a polymer and coating the blended material. As for the coating method, application method, spray method,
It can be applied without any particular limitation such as a dip method. In general, a method of coating a mixture with a composition by using it as a binder can also be applied. At this time, a heat treatment may be performed to further strengthen the coating layer.

The amount of the antithrombotic composition provided with the antibacterial property-imparting antibacterial composition of the present invention is not particularly limited. Preferably, the composition is added in an amount of 0.1 to 60 parts by weight, more preferably about 1 to 30 parts by weight (hereinafter, when 1 part by weight of the additive is added to 100 parts by weight of the base material, Is indicated as 1 phr).

The mucopolysaccharide in the antithrombotic composition having antibacterial properties of the present invention includes, for example, heparin, chondroitin sulfate, hyaluronic acid, dermatan sulfate, and keratan sulfate. Of these, heparin is particularly preferred.

The fourth component having a trialkoxysilyl group in the molecule, which is an essential component of the antithrombotic composition provided with the antibacterial property of the present invention.
The quaternary ammonium compound or the quaternary phosphonium compound having a trialkoxysilyl group in the molecule is represented by
Those having the following structure are preferred. The quaternary ammonium compound having a trialkoxysilyl group in the molecule or the quaternary phosphonium compound having the trialkoxysilyl group in the molecule may be used alone or in combination. In the chemical formula 1, A represents P (phosphorus atom) or N (nitrogen atom). R ¹ , R ² , R ³ , R ⁵ , R
⁶ represents 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, preferably an alkyl group having 1 to 5 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, preferably an alkyl group having 1 to 5 carbon atoms. R ⁷ represents an alkyl group having 1 to 25 carbon atoms, preferably an alkyl group having 12 to 22 carbon atoms. In addition,
R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ⁷ may be the same or different.

Examples of the quaternary ammonium compound having a trialkoxysilyl group in the molecule or the quaternary phosphonium compound having the trialkoxysilyl group in the molecule include, for example, 3- (trimethoxysilyl) propyldimethyloctadecyl ammonium Chloride, 3
-(Triethoxysilyl) propyldimethyloctadecyl ammonium chloride, 3- (trimethoxysilyl) propyldimethylhexadecyl ammonium chloride, 3- (trimethoxysilyl) propyldimethyloctadecylphosphonium chloride, 3- (triethoxysilyl) propyldimethyloctadecylphosphonium Chloride and 3- (trimethoxysilyl) propyldimethylhexadecylphosphonium chloride. Among them, 3- (triethoxysilyl) propyldimethyloctadecyl ammonium chloride and 3- (triethoxysilyl) propyldimethyloctadecylphosphonium chloride are particularly preferable, but are not particularly limited thereto.

The method for obtaining an ionic complex of the mucopolysaccharide with a quaternary ammonium salt having a trialkoxysilyl group in the molecule or a quaternary phosphonium salt having a trialkoxysilyl group in the molecule is not particularly limited. For example, an aqueous solution or dispersion of mucopolysaccharide is mixed with a methanol solution or dispersion of a quaternary ammonium salt having a trialkoxysilyl group in the molecule or a quaternary phosphonium salt having a trialkoxysilyl group in the molecule. And a method of collecting and drying the precipitate obtained.

The antithrombotic composition provided with the antibacterial property of the present invention is obtained as described above. Since the antibacterial property-imparting antithrombotic composition of the present invention has a trialkoxysilyl group in the molecule, it is rich in crosslinking reactivity between molecules. As a result, heparin is less likely to be eluted due to the increased stability of the bond with the base polymer, and good anticoagulant properties can be maintained in the initial stage of contact with the biological component and even after prolonged contact. The action of quaternary ammonium or quaternary phosphonium can also introduce antibacterial properties as well as antithrombotic properties.

Taking advantage of the above advantages, the antibacterial antithrombotic composition of the present invention can be widely applied as a material 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. In addition, taking advantage of its antibacterial properties, infection from the bio-material interface has been a problem in the past.
It is particularly suitable for application to VH and the like.

[0023]

The present invention will be described below with reference to examples. The present invention is not particularly limited to these.

<Example 1> Heparin sodium salt
00 g was dissolved in distilled water to make a total volume of 100 ml.
3- (trimethoxysilyl) propyldimethylalkylammonium chloride (hereinafter abbreviated as TSPN) 2
0.4 g of methanol: distilled water = 1: 1 mixed solution 20
It was dissolved in 0 ml to make a total volume of 300 ml. Both solutions were mixed under ice cooling, and allowed to stand at 4 ° C. for 15 hours to obtain a suspension. The suspension is centrifuged at 3,300 rpm, collected by centrifugation, suspended in distilled water, and then washed three times by centrifugation. The precipitate is dried and dried to obtain a TSPN · Cl-heparin complex (hereinafter referred to as “TSPN · Cl-heparin complex”). TSPN-
Hep).

A commercially available polyurethane (Pellethane (trade name), hereinafter abbreviated as PU) was dissolved in THF to form a 5% solution. To 1000 g of this PU solution, 1.00 g of TSPN-Hep obtained above was added. This TSPN-
12cm holding 20g of Hep / PU blend solution horizontally
The film was uniformly placed on a × 12 cm glass plate, dried at 40 ° C. for 8 hours under a nitrogen stream, and dried under reduced pressure at 40 ° C. for 15 hours to obtain a film having a thickness of about 60 μm (hereinafter, this TSP).
The N-Hep / PU blend material is abbreviated as material A, and the film obtained from material A is abbreviated as film A). In this case,
This means that 2 phr of TSPN-Hep was added to film A.

The plasma relative coagulation time on the film A was evaluated by the following method. The film A was cut out 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, and add 0.025 mol / l
200 μl of an aqueous solution of calcium chloride
The mixture was gently shaken so that the liquid was mixed while floating in a 7 ° C. thermostat. 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, and expressed as a relative coagulation time. did. However, when the plasma did not clot even when the coagulation time exceeded 12 times on the glass plate, the evaluation was interrupted, and the relative coagulation time was> 1.
It was designated as 2. The results are shown in Table 1.

The material A solution is 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. Human serum PBS
(-) This coated bead 100
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., p133-24
0, CC Thomas 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. A Staphylococcus aureus suspension having a bacterial count of about 1 × 10 ⁷ cells / ml was prepared by diluting with a 1/50 broth solution (hereinafter, this bacterial suspension is referred to as a bacterial stock solution). The number of bacteria in this bacterial stock solution was determined as follows. After diluting the bacterial stock solution 10 ⁴ times, 100
μl was spread on a normal agar medium, and the number of S. aureus colonies formed after 24 hours was counted. Assuming that the number of colonies is N, the number C of bacteria in the bacterial stock solution is calculated as follows: C = 10 ⁴ × N / 0.1 = 10 ⁵ × N [cells / ml] 10 μl of this bacterial stock solution was previously added to 5 cm ×
The pieces were cut into 5 cm pieces, sterilized, dropped on the film A placed on a sterile petri dish, and tightly covered with a sterilized commercial food packaging wrap of the same size and cultured at 37 ° C. for 24 hours.
After the culture, the coated wrap was peeled off, and the bacteria were washed out from the film A and the coated wrap using 10 ml of SCDLP medium.
It was diluted by a factor of 1 and spread on a normal agar medium. Twenty-four hours later, the number of Staphylococcus aureus colonies formed on the ordinary agar medium was counted. Assuming that the number of colonies is N ', 25 cm ²
Cell count N _a after contact with the film A is given by the following equation. N _a = 100 × N 'number of bacteria bacteria stock solution prior to contact with the film A are as defined above C, because bacteria stock solution amount used was 10 [mu] l, cell count N _b before contact film A N _b = 1000 × N. The change in the number of bacteria from N _b to N _a on the film size of 25 cm ² are shown in Table 1. A decrease in the number of bacteria upon contact indicates that the film exhibits antimicrobial properties.

A 4% THF solution of the material A was prepared, and the existing hollow hollow fiber made of polypropylene for artificial lungs was immersed in the solution, pulled up, and dried at 40 ° C. for 12 hours to coat the hollow fiber. . The antithrombotic properties were evaluated in vivo using this hollow fiber. The experimental method is as follows. Under pentobarbital anesthesia, rabbits (Japanese white, ♂, 2.5
The femoral vein (approximately 3.0 kg) was peeled off, the peripheral 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 part is 1/4 to 1 of the blood vessel diameter with an underscissor.
/ 3, cut the hollow fiber sample as 1
It was inserted 0 cm toward the central side. 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,
After bleeding the rabbit from the abdominal aorta using an appropriate tube and sacrificing the rabbit, the blood vessel where the hollow fiber was inserted was cut. The blood vessel was incised, the hollow fiber and the inside of the blood vessel were visually observed, and a five-step evaluation was performed. The results are shown in Table 1.

The film A was immersed in PBS (-),
Elution was performed for 2 weeks in a shaking thermostat at ° C. PB
S (-) was replaced daily. Hereinafter, the film after elution is referred to as film A ′. In the same manner as for the film A, the film A 'was evaluated for plasma relative coagulation time and antibacterial properties. The results are shown in Table 1.

[0031]

[Table 1]

In vivo antithrombotic properties in Table 1
The grading 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 TSPN-H obtained in Example 1
Ep is a 0.1% benzene solution, and 12 cm × 12 cm P
3.00 g of the solution was uniformly placed on the U film so as to be introduced at a rate of 3 mg / 144 cm ² , dried at 40 ° C. for 8 hours under a nitrogen stream, and dried at 40 ° C. under reduced pressure for 15 hours.
A film having a thickness of about 60 μm was obtained (hereinafter, this TSPN-Hep / PU coating film is abbreviated as film B).

In the same manner as in Example 1, the plasma relative coagulation time and antibacterial property of the film B were measured. 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 the obtained dissolution film B ′ were also measured. The results are shown in Table 1.

Example 3 Heparin sodium salt
00 g was dissolved in distilled water to make a total volume of 100 ml. 3
22.0 g of-(trimethoxysilyl) propyldimethylalkylphosphonium chloride (hereinafter abbreviated as TSPP · Cl) was dissolved in 200 ml of a mixed solvent of methanol: distilled water = 1: 1 to make a total volume of 320 ml. Both solutions were mixed under ice cooling, and allowed to stand at 4 ° C. for 15 hours to obtain a suspension. This suspension is collected by centrifugation at 3,300 rpm, and the precipitate is further washed three times by suspending it in distilled water and then centrifuging to dry the precipitate.
-Heparin complex (hereinafter abbreviated as TSPP-Hep)
I got

The antithrombotic composition imparted with antibacterial properties is TSPN-H
A film C comprising a TSPP-Hep / PU blend material C and a material C was obtained in the same manner as in Example 1 except that ep was changed to TSPP-Hep. Using the material C and the film C, the plasma relative coagulation time, complement value, antibacterial property, and in vivo antithrombotic property were evaluated in the same manner as in Example 1. Further, a dissolution test of the film C 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 C ′ were also evaluated. The results are shown in Table 1.

Example 4 TSPP-H obtained in Example 3
ep to O. 1% benzene solution, 12cm x 12cm P
3.00 g of the solution was uniformly placed on the U film so as to be introduced at a rate of 3 mg / 144 cm ² , dried at 40 ° C. for 8 hours under a nitrogen stream, and dried at 40 ° C. under reduced pressure for 15 hours.
A film having a thickness of about 60 μm was obtained (hereinafter, this TSPP-
Hep / PU coating film is abbreviated as film D). This was also evaluated in the same manner as in Example 1,
The results are shown in Table 1.

Comparative Example 1 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 10
110 ml of an aqueous solution (hereinafter abbreviated as Ben.Cl) was mixed under ice-cooling, and allowed to stand at 4 ° C for 15 hours to obtain a precipitate. The precipitate was collected by centrifugal sedimentation at 3300 rpm, and lyophilized to obtain a Ben.Cl-heparin complex (hereinafter abbreviated as Ben-Hep). This Ben-Hep was soluble in organic solvents such as benzene, DMF and chloroform.

The antithrombotic composition imparted with antibacterial properties is TBCP-H
A film E comprising a TBLP-Hep / PU blend material E and material E was obtained in the same manner as in Example 1 except that ep was changed to Ben-Hap. Using the material E and the film E, the plasma relative coagulation time, complement value, antibacterial properties, and in vivo antithrombotic properties were evaluated in the same manner as in Example 1. Further, the dissolution test of the film E 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 E ′ were also evaluated. The results are shown in Table 1.

<Comparative Example 2> The material E solution obtained in Comparative Example 1 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).

In the same manner as in Example 1, the relative coagulation time of plasma and the antibacterial property of the film F were evaluated. Further, the dissolution test of the film F 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 F ′ were also evaluated. The results are shown in Table 1.

Comparative Example 3 The relative clotting time of plasma, complement value, and antibacterial property were measured using a PU film (film G) into which the antithrombotic composition having antibacterial properties 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 evaluated. The results are shown in Table 1.

As shown in Table 1, the antithrombotic composition provided with the antibacterial property of the present invention has excellent antithrombotic properties, and its performance is maintained even after elution. On the other hand, in the materials of Comparative Examples 1 and 2 using benzalkonium, performance degradation after elution is remarkably observed. Although it is not clear what mechanism causes this difference in performance, the effectiveness of the present invention is suggested. It also shows that the antibacterial composition of the present invention is effective for antibacterial properties.

[0044]

As described above, the antithrombotic composition provided with the antibacterial property of the present invention has excellent antithrombotic properties and antibacterial properties, and its performance is not only immediately after the material preparation but also for a long time. It is maintained after the operation. Therefore, the antithrombotic composition provided with the antibacterial property of the present invention has excellent suitability as a material having improved antithrombotic property and antibacterial property of a medical material.

 ──────────────────────────────────────────────────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 (3)

[Claims] 1. An ionic complex of at least one mucopolysaccharide and a quaternary ammonium compound having a trialkoxysilyl group in the molecule or a quaternary phosphonium compound having a trialkoxysilyl group in the molecule. An anti-thrombotic composition having antibacterial properties. 2. The antithrombotic composition having antibacterial properties according to claim 1, wherein the mucopolysaccharide is heparin. 3. A quaternary ammonium compound having a trialkoxysilyl group in a molecule or a quaternary phosphonium compound having a trialkoxysilyl group in a molecule has a structure represented by the following chemical formula 1. 3. The antithrombotic composition provided with the antibacterial property according to 1 or 2. Embedded image In Formula 1, A is P (phosphorus atom) or N (nitrogen atom)
Is shown. R ¹ , R ² , R ³ , R ⁵ and R ^{6 each} have 1 to 1 carbon atoms.
2 represents an alkyl group, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. R ⁴ has 1 carbon atom
An alkylene group having 6 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. Note that R ¹ ,
R ² , R ³ , R ⁵ , R ⁶ , and R ⁷ may be the same or different.