JPH1057472A - Antimicrobial and antithrombotic medical treatment material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical treatment material which has an excellent antimicrobial and antithrombotic properties over a long period of time even after indwelling in the blood vessels and is highly safe. SOLUTION: This material is a compsn. formed of a physiologically active material having the antithrombotic property, a quaternary phosphonium compd., a surfactant and a polyaddition reactant. The physiologically active material having the antithrombotic property of the antimicrobial and antithrombotic medical treatment material is selected from a group consisting of heparin, chondroitin sulfate, hyaluronic acid, delmatan sulfate, keratin sulfate, phosphorylcholine, antithrombin III, thrombomodulin, prostaglandin, aspirin, sulfinpyrazone and subtilisin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antibacterial agent, which is a composition formed by a physiologically active substance having antithrombotic properties, a quaternary phosphonium compound, a surfactant, and a polyaddition reactant. The present invention relates to an antithrombotic medical material.

[Conventional technology and its problems]

In recent years, artificial materials excellent in processability have been widely used as medical materials. In the future, artificial organs such as artificial kidneys, artificial lungs, assisted circulation devices, artificial blood vessels, and syringes and catheters will be used. The use as disposable products is expected to expand. These artificial materials are required to have properties such as mechanical strength, durability, safety, antithrombotic properties, and antibacterial properties.

Conventionally, as a method for imparting antithrombotic properties to an artificial material, (A) a method of binding mucopolysaccharide or a fibrinolytic factor to the surface of the artificial material. (B) A method of bonding a negative charge or a hydrophilic group to the surface of the artificial material. (C) A method of inactivating the surface of the artificial material. Can be roughly divided into The method (A) further comprises (a) blending the polymer and heparin. (B) A method of coating fat-solubilized heparin on an artificial material.
(C) A method in which heparin is ion-bonded to an artificial material.
(D) A method of covalently binding heparin to an artificial material. Is subdivided into

[0004] Among the above methods (A) to (C), the methods (B) and (C) are based on the fact that a bio-like film is formed on the surface of an artificial material by adsorbing blood components. ,
Although antithrombotic properties can be obtained, it is extremely difficult to realize antithrombotic properties in the initial stage of introducing an artificial material into a living body because coagulation factors in the living body are activated.

In the above method (a), antithrombotic properties and thrombolytic properties are realized by heparin, urokinase and the like in the initial stage when an artificial material is introduced into a living body. It is extremely difficult to achieve thrombolytic properties over a long period of time. That is, in the above methods (a) to (c), the antithrombotic and thrombolytic properties are reduced due to detachment of the antithrombotic material and the thrombolytic material after long-term use. The method of (d) covalently binding heparin to the artificial material can achieve antithrombotic properties over a long period of time. However, as a result of a change in conformation upon covalent bonding of heparin, the antithrombotic properties are reduced. May decrease.

The above methods (c) and (d) are:
There must be a functional group available for the covalent attachment of heparin.
For this reason, there are drawbacks such as limitations on the selection of the material and complicating the processing steps of the artificial material.

[0007] In view of the easiness of antithrombogenicity of the material and the selectivity of the artificial material, (1) a method of blending a polymer and fat-solubilized heparin or (2) a method of coating an artificial material with fat-solubilized heparin is superior. It is believed that there is. However, the methods (1) and (2) have a drawback that the antithrombotic property is reduced due to the detachment of the antithrombotic material from the artificial material due to long-term use.

[0008] In the case of artificial materials that need to be kept in a living body for a long period of time, such as a high-nutrition catheter, in the past, germs propagate in thrombus formed after being placed in the living body and cause infection. Was frequent. Therefore, antithrombotic properties and antibacterial properties are simultaneously required for these artificial materials that need to be left in the living body for a long period of time. However, few artificial materials that simultaneously maintain these properties are known.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide an artificial material having the above-mentioned antithrombotic and antibacterial properties simultaneously.

[0010]

The antithrombotic antibacterial material of the present invention comprises a composition formed by a physiologically active substance having antithrombotic properties, a quaternary phosphonium compound, a surfactant, and a polyaddition reactant. It is characterized by being. The antithrombotic antibacterial material of the present invention is characterized in that the physiologically active substance having antithrombotic properties is heparin, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate, phosphorylcholine, antithrombin III, thrombomodulin, prostadarandin, aspirin, sulfinpyra. And a subtilisin. In the antithrombotic antibacterial material of the present invention, the antibacterial agent is represented by Chemical Formula 1 above,
It is a quaternary phosphonium compound. The antithrombotic antibacterial material of the present invention is characterized in that the polyaddition reactant is selected from the group consisting of polyurethane, polyurethaneurea, vinyl chloride, polyester and polyethylene.

The antithrombotic antibacterial material of the present invention comprises (1) a physiologically active substance having antithrombotic properties, (2) a phosphonium compound having an antibacterial action, (3) a surfactant, and (4) an addition polymerization reactant. However, by mixing the bioactive substance having the antithrombotic property, the anticoagulant property is retained on the material surface, and the antithrombotic antibacterial material is released from the addition polymerization reactant. Thus, it is considered that antithrombotic properties and antibacterial properties are realized. The antithrombotic antibacterial material of the present invention is characterized in that the release of the antithrombotic antibacterial material is controlled by the affinity between the polyaddition reactant and the physiologically active substance having antithrombotic properties and the phosphonium compound. It is considered that the antithrombotic and antibacterial properties persist even after long-term indwelling.

The antithrombotic antibacterial material of the present invention is characterized by containing a physiologically active substance having antithrombotic properties.
Among the bioactive substances having antithrombotic properties, phosphorylcholine, antithrombin III and heparin are preferred, and heparin is particularly preferred.

The amount of the bioactive substance having antithrombotic properties added to the polyaddition reactant is 0.1 to 0.1% of the bioactive substance having antithrombotic properties based on the total weight of the antibacterial antithrombotic medical material.
Preferably, it is added in an amount of up to 30% by weight, more preferably 1 to 20% by weight.

The antithrombotic antibacterial material of the present invention contains
The quaternary phosphonium compound having an antibacterial action is characterized by having a structure represented by Chemical Formula 1. One of the four carbon chains held by the quaternary phosphonium compound
The species is an alkyl group having 6 to 20 carbon atoms, and the other three are an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 12 carbon atoms.

Specific examples of the quaternary phosphonium compounds having an antibacterial action include tributyl lauryl phosphonium, tributyl myristyl phosphonium, tributyl cetyl phosphonium, tributyl stearyl phosphonium, triphenyl stearyl phosphonium, triphenyl cetyl phosphonium, triphenyl myristyl phosphonium, benzyl Methyl lauryl phosphonium, benzyl dimethyl myristyl phosphonium, benzyl methyl cetyl phosphonium, benzyl methyl stearyl phosphonium and the like.

The total amount of the quaternary phosphonium compound of the present invention is 0.01% based on the total weight of the antibacterial antithrombotic medical material.
Preferably it is in the range from 20% by weight to 20% by weight. The antithrombotic antibacterial material containing the quaternary phosphonium compound in the above range has been confirmed by antibacterial tests to exhibit sufficient antibacterial properties against bacteria and pathogenic yeast (Candida).

The surfactant used in the antithrombotic antibacterial material of the present invention includes an anionic surfactant having a carboxylate, a sulfate, a sulfonate or a phosphate as a hydrophilic group, and a primary amine. Salt, secondary amine salt, tertiary amine salt, or quaternary ammonium salt as a hydrophilic surfactant, cationic surfactant, amino acid type or betaine type amphoteric surfactant, polyethylene glycol type or polyhydric alcohol type nonionic interface One or more surfactants selected from the group consisting of surfactants.

The polyaddition reactants used in the antithrombotic antibacterial material of the present invention include polyurethane, polyurea, polyurethane urea, polyester urea, polyester urethane, polyester urethane urea, polyether urethane, polyether urethane urea, segmented Polyether urethane, segmented polyether urethane urea, vinyl chloride, polyester, and polyethylene are preferred.

The composition of the polyaddition reactant and the method of synthesis are not particularly limited, but when the polyaddition reactant is a segmented polyether urethane, it can be produced as follows. That is, by reacting a polyoxyalkylene diol having a molecular weight of about 100 to 5000 with a diisocyanate to obtain a terminal isocyanate polymer, and further extending the molecular chain with a compound having a plurality of active hydrogens capable of reacting with an isocyanate group, Obtain a segmented polyether urethane.

Examples of the polyoxyalkylene diol used include polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyhexamethylene glycol, polyhexamethylene glycol and the like. Diisocyanates include 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate,
Xylene diisocyanate, 4,4'-diphenylmethane diisocyanate, 4,4'-diphenylpropane diisocyanate, phenylene diisocyanate, naphthalene diisocyanate hexamethylene diisocyanate, and the like. As the chain extender, diols (ethylene glycol, propylene glycol, tetramethylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,4-dihydroxycyclohexane,
1,4-dihydroxymethylcyclohexane, diethylene glycol, triethylene glycol, etc.), diamine (ethylene diamine, propylene diamine, butylene diamine, hexamethylene diamine, phenylenediamine, hydrazine, dicarboxylic dihydrazide, etc.), amino alcohol (methanol amine, 2-amino Ethanol, 3-aminopropanol, etc.).

The antithrombotic antibacterial material of the present invention can be further introduced into another structure serving as a substrate. There is no particular limitation on the material of the structure, and polyether urethane, polyurethane, polyurethane urea, polyvinyl chloride, polyvinylidene chloride, polyester, polypropylene, polyethylene, polycarbonate and the like can be used.

The method of introducing the antithrombotic antibacterial material of the present invention into a substrate is not particularly limited, and a mixing method, a coating method (a coating method, a spraying method, a dipping method, etc.) can be applied.

[0023]

As described above, the antithrombotic antibacterial material of the present invention is obtained. The antithrombotic antibacterial material of the present invention can maintain its antithrombotic properties even after a long period of contact from the beginning of contact with a living body. Further, by blending a quaternary phosphonium compound having an antibacterial action, it is possible to realize an antibacterial effect for a long time. The antithrombotic antibacterial material of the present invention can be applied to various medical materials.
Specific examples include application of a hemodialysis membrane, a plasma separation membrane, a coating agent thereof, and a blood waste adsorbent to a coating agent. Further, application to a membrane material for an artificial lung, a sheet material for an artificial heart and lung, a blood bag, a catheter, a cannula, a shunt, and the like is also possible.

[0024]

The present invention will be described in more detail with reference to examples.
The present invention is not limited at all by the examples. << Embodiment 1. Preparation of Antithrombotic Antibacterial Film--A commercially available polyether urethane was dissolved in a tetrahydrofuran solution to prepare a 5% solution. For 895 g of the solution,
Fat-solubilized heparin (complex of heparin and natural lipid) 50
g, 5 g of monoglyceride oleate stearic acid and 50 g of tri (n-butyl) cetylphosphonium chloride (manufactured by Nippon Chemical Industry) were added to obtain a uniform solution. The solution 20
g was placed on a horizontal glass plate having a size of 15 cm × 15 cm and solidified and dried to prepare a film (hereinafter, referred to as film No. 1). The film is 5cm
It was cut into a size of × 5 cm and evaluated for antibacterial properties.
In addition, without using fat-solubilized heparin, the film no. 1
The same operation was performed to prepare a film (hereinafter referred to as control film No. 1). Further, without using tri (n-butyl) cetylphosphonium chloride, the film N
o. The same operation as in Example 1 was performed to prepare a film (hereinafter, referred to as Control Film No. 2). Furthermore, without using stearic acid monoglyceride oleate, the film No. The same operation as in Example 1 was performed to prepare a film (hereinafter referred to as Control Film No. 3).

<< Embodiment 2. -----Antithrombotic test using antithrombotic antibacterial film (measurement of relative coagulation time)----- 1 was attached to a watch glass having a diameter of 10 cm. Next, 200 ul of ACD plasma of Japanese white rabbit was taken on the film, and 025 mol
/ L of calcium chloride solution and add the watch glass to 37.
The mixture was gently shaken in a constant temperature bath at ℃, and the time from the time when the calcium chloride solution was added to the time when the plasma solidified was measured. The same operation was performed on a glass plate, and the time from the time when the calcium chloride solution was added to the time when the plasma coagulated was measured. The value obtained by dividing the time required for the plasma used for the test of the test sample to coagulate by the time required for the plasma to coagulate on the glass plate was defined as the relative coagulation time. If the plasma did not coagulate over 10 times the time required for the plasma to coagulate on the glass plate, the test was stopped at that point and the relative coagulation time was set to 10 or more. As a result, the film No. prepared in Example 1 1
Had a relative coagulation time of 10 or more. In addition, the control film No. 1, control film no. The relative coagulation times of No. 2 and Control Film No. 3 were 10 or more, 2, 8, and 10 or more, respectively.

Embodiment 3 ----Antibacterial test of antithrombotic antibacterial film---39.5 ml of sterile physiological saline and 0.5 ml of ordinary broth were dispensed into a 50 ml sterile centrifuge tube. Next, one film No. 1 prepared in Example 1 which had been sterilized in advance was inserted by aseptic operation. Next, a Staphylococcus aureus bacterium solution (added bacterial amount 6.0 × 10 ⁶⁾ cultured in normal broth for 24 hours was used.
cfu) 0.1 ml and shaken in a thermostat at 37 ° C. for 24 hours. After culture for 24 hours, the culture solution is 0.1 ml.
Was seeded on a normal agar medium and cultured in an incubator at 37 ° C. for 24 hours. Control film no. 1, control film no. 2 and control film no. The same operation was performed using No. 3. As a result, the film No. 1 and control film N
o. No Staphylococcus aureus was detected in the culture solution of No. 1. On the other hand, the control film No. 6.0 × 10 ⁹ cfu of Staphylococcus aureus was detected in the culture solution of No. 2. In addition, the control film No. In the culture solution of No. 3, 72
× 10 ⁹ cfu of S. aureus was detected. A similar test was performed using Pseudomonas aeruginosa and pathogenic yeast (in the test using pathogenic yeast, each was cultured for 48 hours using a peptone medium and a potato dextrose agar medium). As a result, the film No. 1 and control film no. No Pseudomonas aeruginosa and pathogenic yeast were detected in the culture solution of No. 1. On the other hand, the control film No. In the culture solution of No. 2, 7.0 × 10 ⁹ cfu of Pseudomonas aeruginosa and 3.0 × 10 ⁸ cfu of pathogenic yeast were detected. In addition, the control film No. 64 × 10 in the culture solution of No. 3
⁹ cfu of Pseudomonas aeruginosa and 3.8 × 10 ⁸ cfu of pathogenic yeast were detected.

<< Embodiment 4. 》 −−−− Plasma extraction of antithrombotic antibacterial film −−−
-The pre-sterilized film No. prepared in Example 1 1,
Control film No. 1 2 and control film no. 5 were placed separately in sterile centrifuge tubes having a capacity of 50 ml. Next, 50 human plasma is placed in the sterilized centrifuge tube.
ml was aseptically added and shaken in a thermostat at 37 ° C. for 30 days. Human plasma was aseptically replaced with fresh plasma every day. After 30 days, each of the five films was aseptically removed, aseptically dried and stored. After a lapse of 30 days, the film was slightly pale yellow in comparison with the unused film prepared in Example 1.

Embodiment 5 FIG. -----Antithrombotic test using plasma-extracted antithrombotic antibacterial film (measurement of relative coagulation time)---The plasma-extracted antithrombotic antibacterial film prepared in Example 4 was used. An antithrombotic test was performed by the method shown in Example 2. As a result, even after 30 days from the plasma extraction, the film no. One had a relative coagulation time of 10 or more. In addition, the control film No.
1, control film no. 2 and control film no. 3
Had a relative coagulation time of 10 or more, 3.2 or 10 or more, respectively.

Embodiment 6 FIG. ------ Antibacterial test using antithrombotic antibacterial film extracted from plasma --- Using the antithrombotic antibacterial film extracted from plasma prepared in Example 4 and shown in Example 3. The antibacterial test was performed by the following method. As a result, even after 30 days from the plasma extraction, the film no. The antimicrobial activity of No. 1 and control film No. 1 was retained. On the other hand, the control film No. 2 and control film no. 3, No antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa and pathogenic yeast was observed as in Example 3.

Embodiment 7 -----Extract test using antithrombotic antibacterial film-
--- 10 cm × 10 cm prepared in the same manner as in Example 1.
No. size film No. 1 is finely cut, and the capacity is 30
The mixture was placed in a 0 ml Erlenmeyer flask, added with 100 ml of a phosphate buffer, and extracted with hot water for 1 hour in a constant temperature bath at 70 ° C. The extract was subjected to an eluate test based on the potassium permanganate reducing substance of the dialysis type artificial kidney apparatus approval standard. As a result, the potassium permanganate consumption (value obtained by subtracting the blank test value) of the extract was 0.10 or less.
Therefore, the film No. Safety of 1 was proved.

[0031]

The antithrombotic antibacterial material according to the present invention comprises:
It has excellent antithrombotic and antibacterial properties, and its antithrombotic and antibacterial properties are maintained for a long time after plasma extraction. Therefore, the antithrombotic antibacterial material of the present invention is suitable as a medical material.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 31/71 A61K 31/71 31/725 ACB 31/725 ACB 38/55 45/00 45/00 37/64

Claims (8)

[Claims] 1. An antibacterial antithrombotic medical material characterized by being a composition formed by a physiologically active substance having an antithrombotic property, a quaternary phosphonium compound, a surfactant, and a polyaddition reactant. . 2. The physiologically active substance having antithrombotic properties is heparin, chondroitin sulfate, hyaluronic acid, dermatan sulfate, keratan sulfate, phosphorylcholine, antithrombin III, thrombomodulin, prostadarandin,
The antibacterial antithrombotic medical material according to claim 1, wherein the medical material is selected from the group consisting of aspirin, sulfinpyrazone, and subtilisin. 3. The content of the physiologically active substance having antithrombotic properties is 0.1 to 2 with respect to the total weight of the antibacterial antithrombotic medical material.
The antibacterial and antithrombotic medical material according to claim 1, wherein the content is 0.0% by weight. 4. The antibacterial and antithrombotic medical material according to claim 1, wherein the quaternary phosphonium compound has the structure shown below. Embedded image (In the chemical formula ¹ , R ¹ , R ² , and R ³ are an alkyl group having 6 to 20 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms, and R ⁴ is ^{.R 1,} R ^2, R 3 is an alkyl group having 6 to 20 carbon atoms, ^{R 4}
May be the same or different. ) 5. The content of the quaternary phosphonium compound is as follows:
0.01 to 2 based on the total weight of the antibacterial and antithrombotic medical material
The antibacterial and antithrombotic medical material according to claim 1, wherein the content is 0.0% by weight. 6. The antibacterial antithrombotic medical material according to claim 1, wherein the polyaddition reactant is selected from the group consisting of polyurethane, polyurethaneurea, vinyl chloride, polyester, and polyethylene. 7. An anionic surfactant having a carboxylic acid salt, a sulfate salt, a sulfonate salt or a phosphate salt as a hydrophilic group, a primary amine salt, a secondary amine salt, and a tertiary amine. A salt or a cationic surfactant having a quaternary ammonium salt as a hydrophilic group, an amino acid type or betaine type amphoteric surfactant, one selected from the group consisting of a polyethylene glycol type or a polyhydric alcohol type nonionic surfactant or The antibacterial antithrombotic medical material according to claim 1, wherein the medical material is two or more surfactants. 8. The antibacterial antithrombotic agent according to claim 1, wherein the content of the surfactant is 0.01 to 10.0% by weight based on the total weight of the antibacterial antithrombotic medical material. Sex medical materials.