JPH0994293A - Manufacture of medical material and medical material prepared thereby - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing a medical material which is a substrate onto which heparin is fixed via a quaternary ammonium salt, with ease and uniformity and without any adverse effect on the substrate and such medical material prepared by this method. SOLUTION: An aqueous solution containing an organic solvent and dissolving a quaternary ammonium salt is brought into contact with a substrate surface, and then the substrate surface is washed with water. Next, a heparin solution is brought into contact with the substrate surface, which is again washed with water.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a medical material having excellent antithrombogenicity used for blood treatment, and a medical material obtained by the method.

[0002]

2. Description of the Related Art Conventionally, a circuit tube, a sampling tube, a blood pump, a connector, a three-way stopcock, a temperature sensor, an oxygen saturation sensor, an arterial filter, a venous reservoir, a bubble trap, an intracardiac blood suction reservoir, etc. Attempts have been made to impart antithrombotic properties and biocompatibility to medical materials used in medical devices that come into contact with blood such as extracorporeal circulation circuits and artificial lungs, artificial kidneys, and artificial hearts.

One of them is a method of coating a medical material with heparin, which includes a method of ionic bonding and a method of covalent bonding.

For example, Japanese Patent Publication No. 2-36267 or Japanese Patent Publication No. 5-500314 discloses a method of ionic bonding.

Further, JP-A-58-147404 or JP-A-2-21875 discloses a method of covalent bonding.

[0006] The covalent bonding method has a merit that the manufacturing process is complicated, but the effect is long-lasting. Therefore, in the medical material used for the auxiliary circulation system or the like which is used for a long period of time, the heparin bonding method is used. What is fixed to the substrate is used.

On the other hand, although the ionic bonding method does not have high durability, since the manufacturing process is simple, the ionic bonding is used for medical materials used for artificial heart-lung system for open heart surgery which does not require high durability. Opportunities are increasing in which heparin is immobilized on a substrate by the method.

However, the ionic bonding method has the following disadvantages in manufacturing and quality.

First, regarding the solvent used, the quaternary ammonium salt / heparin complex to be coated is required to be insoluble in water because it suppresses elution into blood during use as much as possible. For this reason, the complex must be dissolved in a solvent having a relatively low polarity to perform the coating operation. Further, in the coating of the quaternary ammonium salt / heparin complex, the complex is dissolved in a solvent having a relatively low polarity to perform the coating operation, so that basically a film is formed on the surface of the substrate, and the following problems occur. There is.

(I) Since the base material (particularly a polyvinyl chloride tube) constituting the artificial heart-lung system contains a plasticizer and a stabilizer, these are eluted into the complex solution during coating, and the base material is Deteriorates faster and the physical properties change. Further, the complex solution after coating cannot be reused because the plasticizer and the stabilizer are eluted. (Ii) Most of the low-polarity solvents in which the complex is to be dissolved have extremely high or low volatility, and it is difficult to control the concentration of a solution using the solvent because of its high volatility. Solvents with a low viscosity have poor workability.

(Iii) Many of the low-polarity solvents in which the complex is to be dissolved deteriorate or deform the plastics constituting the medical device, and it is difficult to select the solvent. (Iv) In the case of coating an artificial lung using a porous hollow fiber, the solvent of low polarity which should dissolve the complex passes through the pores of the hollow fiber, so that when the heparin is brought into contact with the pores, The inner surface is made hydrophilic and plasma leaks during extracorporeal circulation.

(V) The coating of the complex on the surface of the base material causes light and shade during the drying of the solvent.
Unevenness occurs and uniform coating is difficult.

(Vi) Openings 20-300 used in arterial filters, venous reservoirs, bubble traps, intracardiac blood suction reservoirs, etc. which constitute the extracorporeal circulation circuit.
The coating of the complex on the mesh-shaped filter material having a thickness of μm causes a shade during the drying of the solvent, and when it is thickly coated, the yarn diameter becomes thick and the mesh size changes, and the coating is partially formed on the mesh part. The eyes are closed.

(Vii) In the external perfusion type hollow fiber type artificial lung, the complex after drying the solvent serves as a medium, and the adhesion between the hollow fibers occurs, so that the gas exchange performance is significantly reduced.

[0015]

DISCLOSURE OF THE INVENTION The present invention is a medical treatment with a high antithrombotic property in which heparin is immobilized through a quaternary ammonium salt introduced onto a substrate simply and uniformly without affecting the substrate. An object of the present invention is to provide a method for producing a medical material and a medical material obtained by the method.

[0016]

[Means for Solving the Problems] The method for producing a medical material of the present invention for achieving the above object comprises the following constitutions.

(1) A method for producing a medical material in which an organic solvent-containing aqueous solution of a quaternary ammonium salt is brought into contact with the surface of a base material, and then an aqueous heparin solution is brought into contact with the surface of the base material.

(2) The surface of the base material is brought into contact with an aqueous solution containing a quaternary ammonium salt in an organic solvent, followed by washing the surface of the base material with water, and then contacting the surface of the base material with an aqueous solution of heparin. Then, a method for producing a medical material, in which the surface of the substrate is washed with water.

(3) In the organic solvent-containing aqueous solution of the quaternary ammonium salt, the ratio of the organic solvent to water is 1: 1 to.
The method for producing a medical material according to (1) or (2), which is 1:20.

(4) The organic solvent in the organic solvent-containing aqueous solution of the quaternary ammonium salt is alcohol (1)
~ The method for producing a medical material according to any one of (3).

(5) The method for producing a medical material according to (4), wherein the alcohol is methanol, ethanol, propanol or butanol.

(6) The treatment temperature when the organic solvent-containing aqueous solution of the quaternary ammonium salt and the heparin aqueous solution are brought into contact with the surface of the substrate is 20 ° C. to 50 ° C. (1) to
The method for producing a medical material according to any one of (5).

(7) The method for producing a medical material according to any one of (1) to (6), wherein the aqueous solution containing the quaternary ammonium salt in the organic solvent is an aqueous solution containing alkyldimethylbenzylammonium chloride in the organic solvent.

(8) The organic solvent-containing aqueous solution of alkyldimethylbenzylammonium chloride is selected from the group consisting of stearyldimethylbenzylammonium chloride, myristyldimethylbenzylammonium chloride, eicosanedimethylbenzylammonium chloride and docosanedimethylbenzylammonium chloride.
The method for producing a medical material according to (7), which is an aqueous solution containing an organic solvent containing at least one selected.

(9) The method for producing a medical material according to any one of (1) to (8), wherein the substrate is polyvinyl chloride, polyester elastomer, polyethylene terephthalate, polyurethane, polypropylene, polycarbonate or silicone rubber.

(10) The method for producing a medical material according to any one of (1) to (8), wherein the base material is stainless steel.

(11) A medical material obtained by the method according to any one of (1) to (10).

According to the present invention, by adopting the configuration of (1),
It becomes possible to fix heparin while suppressing the elution of the plasticizer and the stabilizer in the base material.

Further, according to the present invention, by adopting the constitution (2), it is possible to effectively use the quaternary ammonium salt on the surface of the substrate by utilizing the difference in solubility between the aqueous solution containing the quaternary ammonium salt in the organic solvent and water. Since it can be adsorbed on and the excess quaternary ammonium salt and heparin are washed, uniform heparin fixation becomes possible.

Further, according to the present invention, by adopting the constitution (1) or (2), the quaternary ammonium salt can be fixed to the substrate by adsorption or affinity, so that the coating has less unevenness.

Further, by adopting the constitution (3) of the present invention, stable solubility in an aqueous solution can be maintained, so that precipitation of quaternary ammonium salt can be prevented.

Further, it is possible to suppress the elution of the plasticizer and the stabilizer in the base material, and to suppress the penetration into the pores when the base material is a polypropylene porous hollow fiber membrane.

That is, the ratio of water to organic solvent in the organic solvent-containing aqueous solution of quaternary ammonium salt is from 1: 1.
The range is preferably 1:20, more preferably 1: 4 to 1:10. Here, if the ratio of the organic solvent is less than 1:20, the solubility of the quaternary ammonium salt is lowered, and if the ratio of the organic solvent is more than 1: 1, the quaternary ammonium salt aqueous solution is plasticized in the substrate. If the agent or stabilizer is eluted or the substrate is a polypropylene porous hollow fiber membrane, the wettability with respect to the substrate becomes high and there is a risk of invasion into the pores, which is not preferable.

Further, by adopting the constitution (4) or (5) in the present invention, the elution of the plasticizer and the stabilizer from the base material is further reduced while maintaining the solubility of the quaternary ammonium salt.

In particular, by adopting the constitution of (5), affinity with water is increased and mixing is facilitated. Here, as the organic solvent that can be mixed with water, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the like are used as necessary in addition to alcohol because of the high solubility of the quaternary ammonium salt.

Further, according to the present invention, by adopting the constitution (6), the solubility of the quaternary ammonium salt can be maintained, so that the precipitation of the quaternary ammonium salt can be prevented.

Further, it becomes possible to keep the concentration of the organic solvent-containing aqueous solution of the quaternary ammonium salt constant.

That is, the temperature at which the organic solvent-containing aqueous solution of the quaternary ammonium salt is brought into contact with the surface of the substrate is 20 to 20.
The temperature is preferably 50 ° C, more preferably 35 to 45 ° C. Here, if the temperature is lower than 20 ° C., precipitation of the quaternary ammonium salt may occur and the amount of the quaternary ammonium salt fixed on the surface of the base material may decrease, which is not preferable. Also,
If the temperature exceeds 50 ° C, the solvent may evaporate and the concentration may change, which is not preferable.

Further, in the present invention, by adopting the constitution (7), the quaternary ammonium salt has a high adsorption force or affinity with the base material.

Further, according to the present invention, by adopting the constitution (8), the main chain of the quaternary ammonium salt is lengthened to have a higher adsorption force or affinity with the base material.

Further, in the present invention, by adopting the constitution (9), the base material has a high adsorption force or affinity with the quaternary ammonium salt.

By adopting the constitution (10), the present invention can provide a medical material in which the elution of the plasticizer and the stabilizer from the substrate is suppressed.

Further, when the substrate is a blood treatment porous membrane (polypropylene porous hollow fiber membrane), the inside of the pores is not treated, so that a medical material in which plasma does not leak during extracorporeal circulation can be provided.

Further, in the case of the mesh-shaped filter material, it is possible to provide a medical material which is free from changes in the openings and crushing.

Further, it is possible to provide a medical material free from unevenness in fixing heparin.

Here, as the medical material of the present invention, a polyvinyl chloride tube for blood circuit or a material constituting a medical device for blood treatment (mesh filter made of polyethylene terephthalate, outer cylinder made of polycarbonate) ,
Examples of the heat exchanger include a stainless steel pipe, a polypropylene porous hollow fiber membrane, and a silicone rubber ring).

[0047]

【Example】

(Examples 1, 2, 3) Preparation of aqueous solution containing 1-1.4 primary ammonium salt in organic solvent Prepare a 60 (w / v)% ethanol solution of stearyldimethylbenzylammonium chloride and gradually add water. Finally, a 10 (w / v)% solution (ethanol: water = 1: 5) was prepared to prepare an organic solvent-containing aqueous solution of a quaternary ammonium salt.

1-2. Heparin Immobilization Operation After heating the organic solvent-containing aqueous solution of the quaternary ammonium salt prepared in 1-1 to 40 ° C., the length was 20 m and the inner diameter was 9.5 m.
m into a roll tube made of soft polyvinyl chloride and left at 45 ° C. for 2 hours.

Next, the above tube was washed with water and immersed in a 0.5 (w / w)% heparin aqueous solution at 45 ° C. for 2 hours.

Next, the above tube is washed with water, dried,
Heparin fixing operation was performed (Example 1).

Thereafter, as in the case of the polyvinyl chloride tube, an externally perfused hollow fiber type artificial lung manufactured by Terumo Corp. (product name: Capiox SX, membrane area 1.8 m)
² ) and an arterial filter manufactured by Terumo Corp. (product name: Capiox arterial filter) were fixed with heparin (Examples 2 and 3).

The external perfusion type hollow fiber type oxygenator used here has a bundle of porous polypropylene hollow fiber membranes in an outer cylinder made of polycarbonate, and a stainless steel installed in a casing above it. There is a heat exchanger of a pipe made of blood, blood exchanges heat through this pipe, the heat-exchanged blood flows between the outside of the hollow fiber membrane and the outer cylinder, and gas exchange is performed. It is a thing.

The arterial filter used here is a blood inlet and a blood outlet provided in an outer cylinder made of polycarbonate, and a mesh made of polyethylene terephthalate in the outer cylinder between the blood inlet and the outlet. It is the one that contains the filtration material.

1-3. Evaluation of Heparin Fixation A vinyl chloride tube fixed with heparin in 1-2 was filled with 0.04 (w / w)% toluidine blue solution, left for 15 minutes, washed with water, and dried.

When the dyeing state of the surface was observed, it was found that all areas were dyed in a uniform pale reddish purple.

Next, the heparin-fixed hollow fiber type oxygenator in 1-2 was treated in the same manner to remove the polycarbonate outer cylinder and polypropylene hollow fiber portion constituting the hollow fiber type oxygenator. When the dyeing state of the surface was observed, there was a difference in shade depending on the material, but within the same material, it was dyed in a uniform pale reddish purple.

Also, no adhesion of the hollow fibers was observed.

Next, the arterial filter fixed with heparin in 1-2 was processed in the same manner, and the polycarbonate outer cylinder and the polyethylene terephthalate mesh-like filter material (mesh opening 32 μm) constituting the arterial filter were processed.
Observation of the dyeability of the surface of m) revealed that there was a difference in shade depending on the material, but within the same material, it was dyed in a uniform pale reddish purple.

When the heparin-fixed eyes of the mesh-shaped filter material were observed under a stereoscopic microscope of 30 times, no collapse of the eyes or changes in the openings were observed.

1-4. Performance evaluation The gas exchange performance of the artificial lung fixed with heparin in 1-2 was evaluated by the Association for Medical Instruments.
Advancement of Medical I
nStumentation) and compared with untreated artificial lung, it was confirmed that the performance was equivalent (Table 1).

1-5. Blood Circulation Experiment 1-2 When a heparin-fixed artificial lung was used to conduct a 24-hour bovine blood circulation experiment under the conditions of 37 ° C., a flow rate of 4 l / min and a pressure of 300 mmHg, plasma leakage was not observed.

ACD-heparinized bovine blood was used for the circulation experiment.

1-6. Quantification of eluate The amount of the plasticizer eluted from the solution obtained by filling the polyvinyl chloride tube with the organic solvent-containing aqueous solution of the quaternary ammonium salt in 1-1 was measured by liquid chromatography and found to be 0.04 mg. / Ml.

(Comparative Examples 1, 2, 3) Preparation of 2-1.4 quaternary ammonium salt / heparin complex solution In the same manner as 1-1, a 10 (w / v)% solution of stearyldimethylbenzylammonium chloride (ethanol:
100 ml of a quaternary ammonium salt solution was prepared so that water = 1: 5).

Add 10 (w / w)% heparin aqueous solution 5
0 ml was gradually added, and the precipitated complex was suction filtered, washed with water, and dried in vacuum.

The obtained complex was dissolved in butanol to prepare a 1 (w / v)% quaternary ammonium salt / heparin complex solution.

In selecting the coating solvent, butanol was selected from the viewpoint that the deterioration of the base material such as polycarbonate or urethane is relatively slight.

2-2. Heparin fixing operation Using a silicone pump tube, the quaternary ammonium salt / heparin complex solution 1 prepared in 2-1.
2,000 ml at 25 ° C, length 20 m, inner diameter 9.5 m
2 l / in a roll tube made of soft polyvinyl chloride
It was passed in a single pass at a flow rate of min.

After discharging the above-mentioned excess complex solution, heparin was fixed by drying with air having a flow rate of 10 l / min for 5 hours (Comparative Example 1).

Next, an external perfusion type hollow fiber oxygenator manufactured by Terumo Corp. (Product name: Capiox SX, membrane area 1.8 m)
The blood contact surface of ² ) was filled with the quaternary ammonium salt / heparin complex solution prepared in 2-1 and left at 25 ° C. for 15 minutes. At this time, the gas port was closed.

Next, the excess complex solution was discharged and dried with air having a flow rate of 10 l / min for 5 hours to fix heparin (Comparative Example 2).

While being dried with air, the quaternary ammonium salt solution oozes out to the gas blowing side of the artificial lung.

Next, on the blood contact surface of an arterial filter manufactured by Terumo Corp. (product name: Capiox arterial filter),
The quaternary ammonium salt / heparin complex solution prepared in 2-1 was filled and left at 25 ° C. for 15 minutes.

Next, the excess complex solution was discharged, and then dried with air having a flow rate of 10 l / min for 5 hours to fix heparin (Comparative Example 3).

The external perfusion type hollow fiber type artificial lung and the arterial filter were the same as those used in the examples.

2-3. Evaluation of Heparin Fixation A polyvinyl chloride tube fixed with heparin in 2-2 was filled with 0.04 (w / w)% toluidine blue solution, left for 15 minutes, washed with water and dried.

Observation of the surface dyeability revealed that it was dyed in reddish purple, but the dyeability was much higher on the discharge side than on the solution inflow side, and the dark portion was streaked intermittently along the tube length direction. Was seen in the shape.

Then, the hollow fiber type artificial lung fixed with heparin in 2-2 was treated in the same manner as in the case of the polyvinyl chloride tube, and the outside of the polycarbonate forming the hollow fiber type artificial lung was treated. When the dyeing state of the surface of the cylinder and the hollow fiber part made of polypropylene was observed, the outer cylinder was dyed in reddish purple, but it had a mottled pattern. In addition, the hollow fiber portion had a thin upper portion and a dark lower portion in the vertical direction.

A large number of hollow fibers adhered to each other.

Then, the arterial filter fixed with heparin in 2-2 was treated in the same manner as in the case of the polyvinyl chloride tube, and the polycarbonate outer cylinder and the polyethylene terephthalate mesh-shaped filter constituting the arterial filter were treated. When the dyeing state of the surface of the filter material (opening 32 μm) was observed, both the outer cylinder and the mesh-shaped filter material had a thin upper part and a dark lower part in the vertical direction.

When the heparin-fixed eyes of the mesh-shaped filter material of the arterial filter were observed with a 30-fold stereomicroscope, crushed parts were found in the folds, but other parts were observed. Then, no particular change was seen.

2-4. Performance Evaluation In 1-2, the gas exchange performance of the artificial lung fixed with heparin was measured according to the standards of the Japan Medical Instruments Association, and when compared with the untreated artificial lung, a decrease of 40% or more was observed (Table 1).

2-5. Blood circulation experiment When a heparin-fixed artificial lung in 2-2 was used to conduct a bovine blood circulation experiment under the same conditions as in 1-5, plasma leakage was observed in 4 hours.

Comparative Examples 4, 5 and 6 Preparation of 3-1.4 Quaternary Ammonium Salt Solution Stearyl dimethylbenzyl ammonium chloride was dissolved in ethanol to prepare quaternary ammonium salt solution 1
A (w / v)% ethanol solution was prepared.

3-2. Heparin fixing operation Using a silicone rubber pump tube, 1000 ml of the quaternary ammonium salt solution prepared in 3-1 was added at 25 ° C.
In a single pass, a roll-shaped tube made of soft polyvinyl chloride having a length of 20 m and an inner diameter of 9.5 mm was passed at a flow rate of 2 l / min.

Next, the excess quaternary ammonium salt solution was discharged and dried with air at a flow rate of 10 l / min for 5 hours.

Next, a blood contact surface was filled with a 1 (w / w)% heparin aqueous solution and left at 45 ° C. for 2 hours.

Next, the surplus heparin aqueous solution was discharged, washed with 2000 ml of water, and dried with air having a flow rate of 10 l / min for 5 hours to fix heparin (Comparative Example 4).

Next, an external perfusion type hollow fiber oxygenator manufactured by Terumo Corp. (Product name: Capiox SX, membrane area 1.8 m)
The blood contact surface of ² ) was filled with the quaternary ammonium salt solution prepared in 3-1 and left at 25 ° C. for 15 minutes. At this time, the gas port was sealed.

Then, the excess quaternary ammonium salt solution was discharged and dried with air at a flow rate of 10 l / min for 5 hours.

While being dried with air, the quaternary ammonium salt solution exudes to the gas blowing side of the artificial lung.

Next, after filling the blood contact surface with a 1 (w / w)% heparin aqueous solution and leaving it for 2 hours, the excess heparin aqueous solution was discharged, washed with 2000 ml of water and washed with 10
Heparin was fixed by drying with air at a flow rate of 1 / min for 5 hours (Comparative Example 5).

Next, the arterial filter manufactured by Terumo Corp. (product name: Capiox artery filter) was fixed with heparin in the same manner as in the case of the artificial lung (Comparative Example 6).

The external perfusion type hollow fiber type artificial lung and the arterial filter were the same as those used in the examples.

3-3. Evaluation of Heparin Fixation A polyvinyl chloride tube fixed with heparin in 3-2 was filled with 0.04 (w / w)% toluidine blue solution, left for 15 minutes, washed with water, and dried.

Observation of the surface dyeability revealed that it was dyed in reddish purple, but the dyeability was much higher on the discharge side than on the solution inflow side, and the dark portion was intermittently streaked along the tube length direction. Was seen in the shape.

Next, the hollow fiber type artificial lung fixed with heparin in 3-2 was treated in the same manner as in the case of the polyvinyl chloride tube, and the polycarbonate outer cylinder constituting the hollow fiber type artificial lung was treated. When the dyeing state of the surface of the polypropylene and the hollow fiber portion was observed, the outer cylinder was dyed in reddish purple, but it had a mottled pattern as a whole. Further, the hollow fiber portion had a thin upper portion and a dark lower portion in the vertical direction.

A large number of hollow fibers adhered to each other.

Next, the arterial filter fixed with heparin in 3-2 was treated in the same manner as in the case of the polyvinyl chloride tube, and the polycarbonate outer cylinder and the polyethylene terephthalate mesh-shaped filter constituting the arterial filter were treated. When observing the dyeing state of the surface of the material,
Both the outer cylinder and the mesh filter material had a thin upper part and a thicker lower part in the vertical direction.

When the heparin-fixed eyes of the mesh-shaped filter material (opening 32 μm) of the arterial filter were observed under a stereoscopic microscope of 30 times, crushed parts were found in the folds. However, there was no particular change in other areas.

3-4. Performance evaluation In 3-2, the gas exchange performance of the artificial lung fixed with heparin was measured according to the standards of the Medical Instruments Association and compared with the untreated artificial lung, and a decrease of 20% or more was observed (Table 1).

[0102]

[Table 1]

3-5. Blood circulation experiment When a heparin-fixed artificial lung in 3-2 was used to conduct a bovine blood circulation experiment under the same conditions as in 1-5, plasma leakage was observed at 12 hours.

3-6. Quantification of Eluate The amount of the plasticizer eluted was measured by liquid chromatography for the solution after the quaternary ammonium solution was brought into contact with the polyvinyl chloride tube in 3-1.
It was 0.5 mg / ml.

[0105]

The method for producing a medical material of the present invention and the medical material obtained by the method have the following effects.

(1) Since heparin can be fixed while the elution of the plasticizer and the stabilizer in the base material is suppressed, deterioration of the base material and changes in the physical properties thereof are small.

(2) By washing with water, the quaternary ammonium salt is effectively adsorbed on the surface, and at the same time, excess quaternary ammonium salt and heparin are removed, so that uniform heparin fixation is possible, so that the surface of the base material is fixed. No unevenness occurs on the top.

Further, in the mesh-shaped filter material, the opening of the mesh does not change and the mesh portion is not crushed.

Moreover, the adhesion between the hollow fibers does not occur.

(3) By adjusting the ratio of water and the organic solvent, it becomes possible to prevent the precipitation of quaternary ammonium salt,
The stable quaternary ammonium salt can be fixed to the substrate.

When the base material is a blood treatment porous membrane (polypropylene porous hollow fiber membrane), the wettability to the base material is low and the inside of the pores is not treated, so plasma does not leak during extracorporeal circulation. 4) The use of alcohol reduces the elution of the plasticizer and the stabilizer in the base material while maintaining the solubility of the quaternary ammonium salt, thereby reducing the deterioration or change in the physical properties of the base material. .

(5) By using a lower alcohol, affinity with water is increased and mixing is facilitated, so that a uniform solution can be obtained.

(6) By adjusting the processing temperature, 4
Since the solubility of the quaternary ammonium salt can be maintained, it is possible to prevent the precipitation of the quaternary ammonium salt.

Further, it becomes possible to keep the concentration of the quaternary ammonium salt constant.

(7) Since the quaternary ammonium salt has a high adsorptivity or high affinity with the substrate, the quaternary ammonium salt is less likely to flow out during washing with water or during extracorporeal circulation,
The effect lasts.

(8) The longer the side chain of the quaternary ammonium salt, the higher the adsorptive power or the higher affinity with the base material, so that the effect is more sustained.

(9) Since the base material has a high adsorptivity or a high affinity with the quaternary ammonium salt, the quaternary ammonium salt is less likely to flow into the blood and the effect is maintained.

(10) It is possible to provide a medical material in which the elution of the plasticizer and the stabilizer in the base material is suppressed and the deterioration of the base material and the change in the physical properties thereof are small.

When the base material is a blood treatment porous membrane (polypropylene porous hollow fiber membrane), the inside of the pores is not treated, so that a medical material in which plasma does not leak during extracorporeal circulation can be provided.

Further, when the base material is a mesh-shaped filter material, it is possible to provide a medical material having no change in opening and no crushing.

Further, in fixing heparin, an effect such that a medical material free from unevenness can be provided can be obtained.

Here, as the medical material of the present invention, a polyvinyl chloride tube for blood circuit or a material constituting a medical device for blood treatment (polyethylene terephthalate mesh filter material, polycarbonate outer cylinder) ,
Examples of the heat exchanger include stainless steel pipes, polypropylene porous hollow fiber membranes, and silicone rubber rings.

[0123]

Claims (11)

[Claims] 1. A method for producing a medical material, which comprises contacting a surface of a base material with an aqueous solution containing a quaternary ammonium salt in an organic solvent, and then contacting an aqueous solution of heparin on the surface of the base material. 2. A surface of a substrate is contacted with an aqueous solution containing a quaternary ammonium salt in an organic solvent, followed by washing the surface of the substrate with water, and subsequently contacting an aqueous solution of heparin on the surface of the substrate, Subsequently, the method for producing a medical material, characterized in that the surface of the base material is washed with water. 3. The medical treatment according to claim 1, wherein the ratio of the organic solvent to the water in the organic solvent-containing aqueous solution of the quaternary ammonium salt is 1: 1 to 1:20. Method for manufacturing materials. 4. The method for producing a medical material according to any one of claims 1 to 3, wherein the organic solvent of the organic solvent-containing aqueous solution of the quaternary ammonium salt is alcohol. 5. The method for producing a medical material according to claim 4, wherein the alcohol is methanol, ethanol, propanol or butanol. 6. The treatment temperature at which the organic solvent-containing aqueous solution of the quaternary ammonium salt and the heparin aqueous solution are brought into contact with the surface of the base material is from 20 ° C. to 50 ° C. A method for producing a medical material according to claim 1. 7. The method for producing a medical material according to claim 1, wherein the organic solvent-containing aqueous solution of the quaternary ammonium salt is an organic solvent-containing aqueous solution of alkyldimethylbenzylammonium chloride. . 8. The organic solvent-containing aqueous solution of alkyldimethylbenzylammonium chloride is at least one selected from the group consisting of stearyldimethylbenzylammonium chloride, myristyldimethylbenzylammonium chloride, eicosanedimethylbenzylammonium chloride and docosanedimethylbenzylammonium chloride. The method for producing a medical material according to claim 7, which is an aqueous solution containing an organic solvent containing the obtained product. 9. The method for producing a medical material according to claim 1, wherein the substrate is polyvinyl chloride, polyester elastomer, polyethylene terephthalate, polyurethane, polypropylene, polycarbonate or silicone rubber. 10. The substrate is stainless steel.
9. The method for producing the medical material according to any one of 8 to 8. 11. A medical material obtained by the method according to any one of claims 1 to 10.