JP2006291193A - Reformed substrate and manufacturing method thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a surface reforming method in which during the refomation of the surface of a substrate by introducing a compound unstable against a radiation to the surface of the substrate through the irradiation with a radiation, the degeneration of the compound by a radiation can be largely lowered; and a reformed substrate obtained by the surface reforming method. <P>SOLUTION: This reformed substrate is obtained by irradiating, with a radiation, a substrate with which a compound unstable against a radiation is contacted, in the presence of an organic solvent, wherein, as the substrate, a separation membrane such as a hollow fiber membrane is used and as the above compound, a compound comprising an amino acid as a component thereof, particularly a compound having a blood anticoagulant activity is suitably used. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a substrate surface modification technique suitably used in fields such as medicine, medical care, proteome analysis, and food production.

Surface modification is an effective method for substrates used in various fields when the substrate surface properties are not sufficient or when it is desired to impart functionality to the substrate surface. Generally speaking, surface modification includes various methods such as physical, chemical, and biological methods, and has a wide variety of uses. For example, physical surface modification such as mirror finishing by surface polishing, surface modification to improve optical characteristics such as reflectivity and refractive index by forming thin films of compounds with different refractive indexes by vacuum deposition or sputtering, oxygen plasma It is also possible to modify the surface by introducing hydroxyl groups on the surface to improve hydrophilicity by exposing to the surface, and adsorbing antibodies to the substrate used in enzyme immunoassay (ELISA) to give specific reactivity. A kind of quality.
In recent years, attention has been focused on surface modification technology for introducing a biologically active compound such as a protein onto the surface of a substrate, and a part thereof has been put into practical use. For example, it is used as a medical material application such as blood purification application, blood component separation application, cell separation application, cell culture application and tissue formation application (see Non-Patent Document 1).

  However, since the introduction of these compounds having physiological activity into the base material is due to physical or chemical adsorption, not only does the function decrease due to elution of the compound during use, but also an extracorporeal kidney or other external body. In the case of circulation use, there is a risk that the eluted compound enters the living body.

  To solve the problem of elution of the compound, there is a method of immobilizing the compound on a substrate by a relatively strong bond such as a covalent bond, that is, a method of preventing the elution by graft polymerization of the compound. Such surface modification methods by graft polymerization are roughly classified into two methods, namely, an organic chemical method and a radiation chemical method.

  Organic chemical methods include introduction of active groups onto the substrate surface with cyanogen bromide, introduction of active groups such as succinimide groups and α-chloroacetamidomethyl groups onto the substrate surface, carrier functional groups and physiologically active substances. In this method, a carbodiimide or the like is used to bond the functional groups of the bioactive substance and graft polymerization is performed. However, in this method, when a by-product of the reaction, for example, carbodiimide is used, a urea compound is generated, so that it is necessary to remove them, and there is a problem in terms of cost because the number of steps increases. In addition, when this method is used for medical applications that require sterilization, it must be manufactured in an aseptic condition, and there has been a problem that enormous manufacturing costs are required in terms of equipment including sterilization of raw materials. (See Non-Patent Document 2 and Patent Document 1).

In addition, the radiochemical method is a method in which radicals are generated on the surface of a substrate and a compound by irradiation with radiation, and both radicals react to form a bond (see Patent Document 2). This method has the advantage that the substrate can be sterilized at the same time by selecting the radiation and the irradiation dose, and is advantageous in terms of cost for medical use. However, proteins and the like are unstable with respect to radiation, and there is a problem that structural changes are caused by irradiation and functions such as physiological activity are lost. In order to solve this problem, a method of irradiating radiation in a state of being impregnated with an antioxidant has been proposed (see Patent Document 3). However, this method has a problem of an increase in cost due to the use of an antioxidant and a decomposition product of the antioxidant. For example, sodium pyrosulfite has been a problem because it decomposes into sulfur compounds such as sulfurous acid and sulfur dioxide by irradiation and becomes strongly acidic when used in an aqueous solution, for example.
Japanese Patent No. 2754203 JP-A-10-066846 International Patent Publication No. 97/027878 Pamphlet Yoshito Tsuji et al., “Development of Biomaterials”, CMC, 1989, pp. 56-57 P. T. Sharpe, “Biochemical Experimental Method 13—Cell Separation Method”, Tokyo Chemical Dojin, First Edition, 1991, pp. 151-190

  In view of the above problems, an object of the present invention is to significantly reduce denaturation of a compound due to radiation in surface modification of a substrate in which a radiation labile compound is introduced onto the substrate surface by irradiation. It is in providing the surface modification method which can be performed, and providing the modified base material obtained by this surface modification method.

In order to achieve the above object, the present invention has the following configuration.
(1) A modified base material obtained by irradiating a base material, which is brought into contact with a compound unstable to radiation, in the presence of an organic solvent.
(2) The modified substrate according to (1) above, wherein the organic solvent contains a hydroxyl group.
(3) The modified substrate as described in (2) above, wherein at least one of the hydroxyl groups is a secondary or tertiary hydroxyl group.
(4) The modified base material according to any one of (1) to (3), wherein the moisture content of the organic solvent is 20% or less.
(5) The modified base material according to any one of (1) to (4), wherein the compound unstable to radiation comprises an amino acid as a constituent element.
(6) The modified substrate according to any one of (1) to (5), wherein the compound unstable to radiation has blood anticoagulant activity.
(7) The modified substrate according to any one of (1) to (6), wherein the compound unstable to radiation has antithrombin activity.
(8) The modified base material according to any one of (1) to (7), wherein the organic solvent contains an antioxidant.
(9) The modified substrate according to any one of (1) to (8), wherein the substrate is made of a polymer compound material.
(10) The modified substrate according to any one of (1) to (9), wherein the substrate is a medical substrate.
(11) The modified base material according to (10), wherein the medical base material is incorporated in the biological component separation module.
(12) The modified base material according to (10) or (11), wherein the medical base material is built in the blood purification module.
(13) The modified substrate according to any one of (10) to (12), wherein the medical substrate is incorporated in the artificial kidney module.
(14) The modified substrate according to any one of (10) to (13), wherein the medical substrate is a separation membrane.
(15) The modified substrate according to any one of (1) to (9), wherein the substrate is a separation membrane.
(16) The modified substrate according to (15), wherein the separation membrane is a hollow fiber membrane.
(17) A method for producing a modified base material, which comprises irradiating a base material which has been brought into contact with a solution in which a compound unstable to radiation is dissolved in an organic solvent.

  According to the present invention, irradiation with a compound having a blood anticoagulant activity unstable to radiation in contact with a substrate in the presence of an organic solvent, for example, is unstable against radiation. It is possible to carry out radiation graft polymerization on the surface of the base material while maintaining the activity of a compound having excellent blood anticoagulant activity, and the amount of anticoagulant used can be reduced. Can be expected to reduce. As described above, according to the present invention, it is possible to perform radiation graft polymerization on a substrate surface while suppressing denaturation of various physiologically active substances that are unstable to radiation.

  The modified substrate of the present invention is irradiated with radiation in a state where the substrate is in contact with a compound unstable to radiation in the presence of an organic solvent.

  The radiation used in the present invention refers to high-energy particle beams and electromagnetic waves, and examples include α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams, and neutron rays. Among these, γ rays and electron beams are more preferably used because they have particularly high energy and can be modified efficiently. Further, γ-rays, X-rays, and electron beams can be sterilized simultaneously by controlling the dose, and thus are suitable for medical materials and the like.

  In addition, the compound unstable to radiation used in the present invention means that when irradiated with radiation, at least a part of the compound causes a change in the molecular structure due to chemical bond breaking, generation or oxidation reaction. Mechanical properties such as strength, electrical properties such as conductivity, optical properties such as refractive index, physical functions such as surface tension and / or chemical functions such as catalytic activity and adsorption properties and / or biocompatibility It refers to a compound that changes biological functions such as sex, enzyme activity and antibody activity. Details of the compound unstable to radiation used in the present invention will be described later.

In addition, when irradiating the substrate, the dose of radiation is 1 kGy or more because it is difficult to control the dose because the absorbed dose in the substrate varies when the dose of radiation is small. And more preferably 5 kGy or more. Further, when sterilization is performed simultaneously with medical materials, the radiation dose is preferably 15 kGy or more, more preferably 25 kGy or more. However, since irradiation with excessive radiation degrades the substrate itself, the radiation dose is preferably 5000 kGy or less, more preferably 1000 kGy or less, and even more preferably 100 kGy or less.
Examples of the organic solvent suitably used in the present invention include a solvent containing a carbon atom and / or a silicon atom in the molecule. Hydroxyl groups have a high effect of stabilizing radicals generated by radiation irradiation, are nonionic functional groups, have little interaction with compounds with strong surface charges, have little redox power, and have little modification of compounds. An organic solvent having a hydroxyl group in the molecule is preferably used. Examples of the organic solvent having a hydroxyl group include alcohols such as methanol and ethanol, polyethylene glycol, and ethylene glycol. In particular, since secondary and tertiary hydroxyl groups are more effective in stabilizing radicals, organic solvents in which at least one of the hydroxyl groups has a secondary or tertiary hydroxyl group, such as glycerin, propylene glycol, and isopropanol are more preferred. Preferably used. These organic solvents may be used alone or in combination of two or more. Further, when the modified base material of the present invention is used for a medical device, it is necessary to consider its safety, and therefore, an organic solvent having low toxicity is preferable.

As a method for bringing a compound unstable to radiation into contact with a substrate in the presence of an organic solvent, the compound is dissolved and / or dispersed in an organic solvent, and the substrate is immersed in the obtained liquid. The method of apply | coating to a material is mentioned. If the compound is difficult to dissolve in the target organic solvent, the compound may be dissolved in a solvent having high solubility in the compound and contacted with the substrate, and then replaced with the target organic solvent. An inorganic solvent such as Further, a base material on which a compound is previously applied or adsorbed on the base material may be immersed in an organic solvent. The dissolution of a compound means that the compound is dissolved in a solvent to form a uniform mixture, that is, a solution. Further, the dispersion of the compound means that the compound is scattered in the solvent.
If the organic solvent has a high water content, irradiation with radiation may generate a highly active hydroxy radical and denature surrounding compounds. Therefore, the water content is preferably 20% or less, more preferably 15% or less. More preferably, it is 10% or less. Further, a desiccant such as silica gel may be used in order to suppress an increase in moisture content during storage until irradiation.

Here, the moisture content in the present invention is defined as follows, and the moisture content is measured by the Karl Fischer method of the Japanese Pharmacopoeia.
Moisture content = (weight of water contained in radiation labile compound and organic solvent) / (weight of radiation labile compound and organic solvent) × 100
In the present invention, when a compound unstable to radiation is brought into contact with the substrate, an antioxidant can be used in combination. This is because the antioxidant can be expected to supplement the hydroxy radical generated by irradiation and suppress the denaturation of the compound unstable to radiation. The term “antioxidant” as used herein refers to a compound having a molecule that easily gives electrons to other molecules, but the base material, functional substance, and nonionic hydrophilic polymer are modified by radiation. It has the property of suppressing Examples of the antioxidant include water-soluble vitamins such as vitamin C, polyphenols, sugars such as glucose, galactose, mannose and trehalose, inorganic salts such as sodium hydrosulfite, sodium pyrosulfite and sodium dithionate, Examples thereof include, but are not limited to, polyvinyl alcohol, uric acid, cysteine, and glutathione. These antioxidants may be used alone or in combination of two or more.
When using the modified base material of the present invention for a medical device, it is necessary to consider its safety, and therefore, an antioxidant having low toxicity is preferably used. Since the concentration of the aqueous solution containing the antioxidant varies depending on the type of the antioxidant contained, the irradiation dose of radiation, and the like, it may be used at an appropriate concentration as appropriate.

  The base material used in the present invention refers to a material to which a compound unstable to radiation is to be imparted, and a polymer compound material is preferably used. Examples of the polymer compound constituting the polymer compound material include, for example, polymethyl methacrylate, polypropylene, polyethylene, polyvinyl chloride, polyvinylidene chloride, polyvinylidene fluoride, polyvinyl acetate, polycarbonate, cellulose, cellulose acetate, and cellulose triacetate. , Polyacrylonitrile, polysulfone, polyethersulfone, polystyrene, polyurethane and the like, but are not limited thereto.

  In the present invention, a medical base material can be used as the base material. Examples of medical base materials include artificial blood vessels, catheters, blood bags, contact lenses, intraocular lenses, and surgical aids, and separation membranes built in and used in biological component separation modules and blood purification modules. Is also included. A separation membrane for separating biological components refers to a membrane that separates a biological substance by filtration or dialysis and collects a part thereof.

In the present invention, the blood purification module refers to a module having a function of removing waste and harmful substances in blood by adsorption, filtration, and diffusion when circulating blood outside the body. There are kidney and exotoxin adsorption column.
The form of the separation membrane incorporated in the blood purification module is not particularly limited, and is used in the form of a flat membrane or a hollow fiber membrane. However, considering the processing efficiency, that is, securing the surface area in contact with blood, the hollow fiber membrane type is preferable.

  In the present invention, a compound having an amino acid as a constituent can be preferably used as the compound unstable to radiation. A compound having an amino acid as a constituent element is a compound containing a naturally occurring amino acid, such as a compound composed only of an amino acid such as a protein or a peptide, a glycoprotein, an amino acid complex, an aminoacyl adenylic acid, or the like. Although what is comprised from a thing other than these amino acids and amino acids is mentioned, It is not limited to these.

  When blood comes into contact with a foreign substance, the coagulation system is activated, and eventually a thrombus is formed. If a thrombus is generated in a circuit or dialyzer in an extracorporeal blood circulation such as an artificial kidney, the circulation pressure rises and it becomes impossible to circulate eventually, and if a part of the generated thrombus enters the body, there is a risk of clogging the blood vessel . Therefore, in extracorporeal blood circulation, it is necessary to add a compound having blood anticoagulant activity to the blood. However, when a compound having a blood anticoagulant action is added to blood such as a patient immediately after surgery or a patient with gastrointestinal bleeding, there is a risk of bleeding. Thus, by forming a compound having blood anticoagulant activity on the surface of a substrate used for extracorporeal circulation, thrombus formation can be suppressed without adding a compound having anticoagulant activity to blood.

The compound having blood anticoagulant activity refers to a compound whose prothrombin time is extended by 30% or more when blood is added with a compound at a concentration of 10 μg / ml. The prothrombin time can be measured by the method described in the following document.
Masamitsu Kanai et al., “Proposal for Clinical Examination Revised 30th Edition”, Kanehara Publishing, 1993, pp. 416-418
That is, mix 1 volume of 3.2% sodium citrate and 9 volumes of blood, and take 0.1 ml of citrated plasma collected in a small test tube (inner diameter: 8 mm, length: 7.5 cm), at a temperature of 37 ° C. Place in a constant temperature water bath and heat for about 3 minutes. At the same time as adding 0.2 ml of tissue thromboplastin / calcium reagent kept at the same temperature, start the second clock, shake gently, and measure the time until fibrin precipitates while tilting.

In the present invention, examples of the compound unstable to radiation include compounds having blood anticoagulant activity. The compound having a blood anticoagulant activity, for example, heparin, nafamostat mesylate, sodium citrate, sodium oxalate, alpha ₁ antitrypsin, alpha ₂ macroglobulin, C1 inhibitor, but thrombomodulin and protein C and the like, It is not limited to these. Among compounds having blood anticoagulant activity, there are compounds that exhibit a strong blood anticoagulant effect by inhibiting the activity of thrombin, that is, compounds having antithrombin activity.

The compound having antithrombin activity used in the present invention is a compound that suppresses the activity of thrombin, which is a coagulation-related substance in blood, and the plasma HEAMOSYS “ECA” added with a compound at a concentration of 10 μg / ml. -Tkit "refers to a compound whose measured value increases by 50% or more compared to that of plasma without compound addition. Among these compounds, a compound having antithrombin activity that is unstable to radiation refers to a compound having such a measured value of 90% or less when an aqueous solution of the compound is irradiated with γ rays having an absorbed dose of 25 kGy.
A compound having antithrombin activity in ultrapure water is represented by the following chemical formula.
4-methoxy-benzensulfonyl-Asn (PEG2000-Ome) -Pro-4amidinobenzamide (hereinafter abbreviated as Compound A), antithrombin III, hirudin and the like.

(In the formula, PEG represents a polyethylene glycol residue, and Me represents a methyl group.)
The modified base material of the present invention can be produced by irradiating a base material in contact with a solution in which a compound unstable to radiation is dissolved in an organic solvent.

If the dissolution rate of a compound unstable to radiation is low in an organic solvent, prepare a solution previously dissolved in a solvent with a high dissolution rate, mix with the desired organic solvent, and extract or dry. It is also possible to prepare a solution of the target organic solvent by solvent separation by operation such as distillation or distillation.
When the base material is a separation membrane, it is possible to efficiently bring the solute molecules into contact with the inside of the membrane by filtering the solution. However, if the Stokes radius of the solute molecule is equal to or larger than the pore radius of the membrane, the membrane may be clogged and the originally planned membrane performance may not be obtained, so care must be taken.

  Hereinafter, the modified base material and the production method thereof of the present invention will be described with reference to examples, but the present invention is not limited to these examples.

(Mini-module blood circulation experiment)
FIG. 2 is a schematic system diagram illustrating a blood circuit used in a blood circulation experiment of each example of the present invention. In FIG. 2, a silicon tube 7 having an inner diameter of 0.8 mm and a length of 52 cm was connected to a blood port on one side of the mini module 6, and a peristaltic pump 8 and a pressure gauge 11 (AP-32A manufactured by Keyence Corporation) were installed in the middle. A silicon tube having an inner diameter of 0.8 mm and a length of 16 cm was connected to the other blood port. The side not connected to the blood port of both silicon tubes was inserted into a 5 ml polystyrene round tube 9 (352054) manufactured by BECTON DICKINSON to produce the circulation circuit shown in FIG.

Immediately after collecting human venous blood, “Heparin Sodium Injection” manufactured by Shimizu Pharmaceutical Co., Ltd. was added to 0.5 U / ml. 5 ml of the blood 10 was added to the polystyrene round tube 9 and circulated with a peristaltic pump 8 at a flow rate of 0.5 ml / min, and the change in circulation pressure was measured.
(Measurement of moisture content)
The organic solvent contained in the hollow fiber membrane of the mini module immediately before irradiation is extracted, and the moisture content of the organic solvent is measured using Hiranuma Sangyo Co., Ltd. AQ-7 Hiranuma trace moisture measuring device. Measurement was performed using Hydranal Aqualite RS and Aqualite CN according to the instruction manual attached to the apparatus.
Example 1
5 parts by weight of iso-polymethyl methacrylate and 20 parts by weight of syn-polymethyl methacrylate were added to 75 parts by weight of dimethyl sulfoxide and dissolved by heating to obtain a film forming stock solution. This membrane-forming stock solution was discharged from an orifice-type double-cylinder die and allowed to pass through 300 mm in the air, and then led into a 100% water coagulation bath to obtain a hollow fiber separation membrane. At this time, dry nitrogen was used as the internal injection gas. The resulting hollow fiber separation membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.
FIG. 3 is a schematic side view illustrating a mini-module. A module case in which 50 polymethyl methacrylate hollow fiber separation membranes 4 prepared as described above are bundled and both ends are made of glass tube with an epoxy potting agent 5 so as not to block the hollow portion of the hollow fiber separation membrane 4. The mini-module having the structure shown in FIG. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, there are two ports (blood port 1) inside the hollow fiber separation membrane, Port (dialysate port 2). The hollow fiber separation membrane of the mini module and the inside of the module were washed with distilled water. Thereafter, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity was dissolved in ultrapure water to prepare an aqueous solution of compound A having a concentration of 11.7 ppm by weight. 30 ml at a flow rate of 10 ml / min by the peristaltic pump 8 is introduced from one blood port 1 inside the mini-module hollow fiber separation membrane 4 and taken out from the other blood port 1 through the hollow fiber separation membrane 4 and polystyrene. It was put into the dialysate port 2 on the blood port 1 side through the round tube 9 and exited from the other dialysate port 2. Thereafter, glycerin (Sigma Aldrich release code: 12-1120-5) is dissolved in ultrapure water to prepare a 65 vol / vol% glycerin aqueous solution, and 30 ml of the minimodule hollow fiber is supplied at a flow rate of 10 ml / min with a peristaltic pump. Inserted from one blood port 1 inside the separation membrane 4, exited from the other blood port 1 through the hollow fiber separation membrane 4, and inserted into the dialysate port 2 on the blood port 1 side through the polystyrene round tube 9 Out from the other dialysate port 2. Thereafter, 20 kPa of compressed air is passed from the blood port 1 inside the minimodule hollow fiber separation membrane 4 to the other blood port 1 for 30 seconds, and then 20 kPa is passed from the dialysate port 2 to the other dialysate port 2. Compressed air was passed for 60 seconds. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ rays with the four ports sealed, at this time, the absorbed dose of γ rays was 26 kGy. Using the peristaltic pump 8, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane 4 of the mini-module and the inside of the module were washed with a peristaltic pump at a flow rate of 10 ml / min. A membrane minimodule (minimodule (1)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. The circulation pressure 4 hours after the start of the circulation was 18 kPa. The moisture content was 1.6%. The results are shown in Table 1.
(Example 2)
Mixing of 18 parts by weight of polysulfone ("Udel" (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) with 72 parts by weight of N, N'-dimethylacetamide and 1 part by weight of water In addition to the solvent, the film was dissolved by heating at a temperature of 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as a core liquid. The discharged membrane forming stock solution passed through a distance of 350 mm from the die to the coagulation bath liquid level, and was then led to a coagulation bath with 100% water to obtain a hollow fiber separation membrane. When the structure of the obtained hollow fiber separation membrane was confirmed with an electron microscope (S800 manufactured by Hitachi, Ltd.), it had an asymmetric structure.

  FIG. 3 is a schematic side view illustrating a mini-module. 50 polysulfone hollow fiber separation membranes 4 prepared as described above are bundled, and both ends are attached to a module case 3 of a glass tube with an epoxy potting agent 5 so as not to block the hollow portion of the hollow fiber separation membrane 4. The mini module having the structure shown in FIG. 3 was fixed. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, two inner ports (blood port 1) of the hollow fiber separation membrane 4 and two outer ports are provided. Port (dialysate port 2). The hollow fiber separation membrane 4 of the mini module and the inside of the module were washed with distilled water. Then, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity in ultrapure water was dissolved to prepare a compound A aqueous solution having a concentration of 11.7 ppm by weight. A polystyrene round tube 10 is inserted with 30 ml of a peristaltic pump at a flow rate of 10 ml / min from one blood port 1 inside the mini-module hollow fiber separation membrane, through the hollow fiber separation membrane 4 and from the other blood port 1. Was put into the dialysate port 2 on the blood port side and exited from the other dialysate port 2. Thereafter, glycerin (Sigma Aldrich release code: 12-1120-5) is dissolved in ultrapure water to prepare a 65 vol / vol% glycerin aqueous solution, and 30 ml of the minimodule hollow fiber is supplied at a flow rate of 10 ml / min with a peristaltic pump. Inserted from one blood port 1 inside the separation membrane 4, passed through the hollow fiber separation membrane 4, exited from the other blood port 1, and inserted into the dialysate port 2 on the blood port 1 side through the tube. Exited from liquid port 2. Thereafter, 20 kPa of compressed air is passed from the blood port 1 inside the minimodule hollow fiber separation membrane 4 to the other blood port 1 for 30 seconds, and then 20 kPa is passed from the dialysate port 2 to the other dialysate port 2. Compressed air was passed for 60 seconds. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ rays with the four ports sealed, at this time, the absorbed dose of γ rays was 26 kGy. Using the peristaltic pump 8, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane 4 of the mini-module and the inside of the module were washed with a peristaltic pump 8 at a flow rate of 25 ml. A membrane minimodule (minimodule (2)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. The circulation pressure 4 hours after the start of the circulation was 23 kPa. The moisture content was 2.1%. The results are shown in Table 1.
(Comparative Example 1)
5 parts by weight of iso-polymethyl methacrylate and 20 parts by weight of syn-polymethyl methacrylate were added to 75 parts by weight of dimethyl sulfoxide and dissolved by heating. This membrane-forming stock solution was discharged from an orifice-type double cylindrical die and passed through 300 mm in the air, and then led into a 100% water coagulation bath to obtain a hollow fiber separation membrane. At this time, dry nitrogen was used as the internal injection gas. The hollow fiber separation membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.

  A bundle of 50 polymethyl methacrylate hollow fiber separation membranes prepared in this way is bundled, and both ends are fixed to a glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber separation membrane. A mini module having the structure shown in FIG. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, the inner port (blood port) of the hollow fiber separation membrane has two ports and an outer port ( 2 dialysate ports). The hollow fiber separation membrane of the mini module and the inside of the module were washed with distilled water. Then, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity in ultrapure water was dissolved to prepare a compound A aqueous solution having a concentration of 11.7 ppm by weight. With a peristaltic pump, 30 ml at a flow rate of 10 ml / min is introduced from one blood port inside the mini-module hollow fiber separation membrane, and is taken out from the other blood port through the hollow fiber separation membrane, and the blood port is passed through the polystyrene round tube. Put in the dialysate port on the side and exit from the other dialysate port. The mixture was filled with an aqueous solution of Compound A and irradiated with γ rays while the four ports were sealed. At this time, the absorbed dose of γ rays was 26 kGy. Using a peristaltic pump, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane of the mini-module and the inside of the module were washed with a peristaltic pump at a flow rate of 10 ml / min. A module (minimodule (3)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. A pressure increase was observed immediately after the start of circulation, and circulation was impossible after about 2 hours because the circulation pressure exceeded 80 kPa. The moisture content was 100%. The results are shown in Table 1.
(Comparative Example 2)
5 parts by weight of iso-polymethyl methacrylate and 20 parts by weight of syn-polymethyl methacrylate were added to 75 parts by weight of dimethyl sulfoxide and dissolved by heating. This membrane-forming stock solution was discharged from an orifice-type double cylindrical die and passed through 300 mm in the air, and then led into a 100% water coagulation bath to obtain a hollow fiber separation membrane. At this time, dry nitrogen was used as the internal injection gas. The hollow fiber separation membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.

  A bundle of 50 polymethyl methacrylate hollow fiber separation membranes prepared in this way is bundled, and both ends are fixed to a glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber separation membrane. A mini module having the structure shown in FIG. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber membrane type dialyzer, two inner ports (blood ports) and an outer port (dialysis port) of a hollow fiber separation membrane are used. 2 liquid ports). The hollow fiber separation membrane of the mini module and the inside of the module were washed with distilled water. Thereafter, glycerin (Sigma Aldrich release code: 12-1120-5) is dissolved in ultrapure water to prepare a 65 vol / vol% glycerin aqueous solution, and 30 ml of the minimodule hollow fiber is supplied at a flow rate of 10 ml / min with a peristaltic pump. The blood was inserted from one blood port on the inner side of the membrane, passed through the hollow fiber, taken out from the other blood port, put into a dialysate port on the blood port side through a tube, and exited from the other dialysate port. Thereafter, 20 kPa of compressed air is passed from the blood port inside the mini-module hollow fiber membrane to the other blood port for 30 seconds, and then 20 kPa of compressed air is passed from the dialysate port to the other dialysate port for 60 seconds. did. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ rays with the four ports sealed, at this time, the absorbed dose of γ rays was 26 kGy. Using a peristaltic pump, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane of the mini-module and the inside of the module were washed with a peristaltic pump at a flow rate of 10 ml / min. A module (minimodule (4)) was obtained.

As a result of the blood circulation experiment using the module, the change in the circulation pressure with respect to the circulation time is shown in FIG. A pressure increase was observed immediately after the start of circulation, and circulation was impossible after about 2 hours because the circulation pressure exceeded 80 kPa. The moisture content was 1.8%. The results are shown in Table 1.
(Comparative Example 3)
Mixing of 18 parts by weight of polysulfone ("Udel" (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) with 72 parts by weight of N, N'-dimethylacetamide and 1 part by weight of water In addition to the solvent, the film was dissolved by heating at a temperature of 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as a core liquid. The discharged membrane forming stock solution passed through a distance of 350 mm from the die to the coagulation bath liquid level, and was then led to a coagulation bath with 100% water to obtain a hollow fiber separation membrane. When the structure of the obtained hollow fiber separation membrane was confirmed with an electron microscope (Hitachi S800), it had an asymmetric structure.

  50 polysulfone hollow fiber separation membranes prepared in this way were bundled, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber separation membrane. A mini module with the structure shown was created. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, two inner ports (blood ports) and an outer port of the hollow fiber separation membrane are used. It has 2 (dialysate ports). The hollow fiber membrane of the mini module and the inside of the module were washed with distilled water. Then, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity in ultrapure water was dissolved to prepare a compound A aqueous solution having a concentration of 11.7 ppm by weight. With a peristaltic pump, 30 ml at a flow rate of 10 ml / min is introduced from one blood port inside the mini-module hollow fiber separation membrane, is discharged from the other blood port through the hollow fiber separation membrane, and is connected to the blood port side through the tube. Entered dialysate port and exited from the other dialysate port. The solution was filled with an aqueous solution of Compound A, and γ-rays were irradiated in the state where the four ports were sealed. At this time, the absorbed dose of γ-rays was 26 kGy. Using a peristaltic pump, 300 ml of ultrapure water at 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane of the mini-module and the inside of the module were washed with a peristaltic pump at 25 ° C. at a temperature of 10 ml / min. Module (5)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. A pressure increase was observed immediately after the start of circulation, and circulation was impossible after about 2 hours because the circulation pressure exceeded 80 kPa. The moisture content was 100%. The results are shown in Table 1.
(Comparative Example 4)
Mixing of 18 parts by weight of polysulfone ("Udel" (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) with 72 parts by weight of N, N'-dimethylacetamide and 1 part by weight of water In addition to the solvent, the film was dissolved by heating at a temperature of 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as a core liquid. The discharged membrane forming stock solution passed through a distance of 350 mm from the die to the coagulation bath liquid level, and was then led to a coagulation bath with 100% water to obtain a hollow fiber separation membrane. When the structure of the obtained hollow fiber separation membrane was confirmed with an electron microscope (Hitachi S800), it had an asymmetric structure.

  50 polysulfone hollow fiber separation membranes prepared in this way were bundled, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber separation membrane. A mini module with the structure shown was created. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber membrane type dialyzer, two inner ports (blood ports) and an outer port (dialysis port) of a hollow fiber separation membrane are used. 2 liquid ports). The hollow fiber separation membrane of the mini module and the inside of the module were washed with distilled water. Thereafter, glycerin (Sigma Aldrich release code: 12-1120-5) is dissolved in ultrapure water to prepare a 65 vol / vol% glycerin aqueous solution, and 30 ml of the minimodule hollow fiber is supplied at a flow rate of 10 ml / min with a peristaltic pump. The blood was inserted from one blood port inside the separation membrane, passed through the hollow fiber, taken out from the other blood port, put into a dialysate port on the blood port side through a tube, and taken out from the other dialysate port. Thereafter, 20 kPa of compressed air is passed from the blood port inside the mini-module hollow fiber separation membrane to the other blood port for 30 seconds, and then 20 kPa of compressed air is passed from the dialysate port to the other dialysate port for 60 seconds. I passed. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ rays with the four ports sealed, at this time, the absorbed dose of γ rays was 26 kGy. Using a peristaltic pump, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane of the mini-module and the inside of the module were washed with a peristaltic pump at a flow rate of 10 ml / min. A module (minimodule (6)) was obtained.

As a result of the blood circulation experiment using the module, the change in the circulation pressure with respect to the circulation time is shown in FIG. A pressure increase was observed immediately after the start of circulation, and circulation was impossible after about 2 hours because the circulation pressure exceeded 80 kPa. The moisture content was 1.9%. The results are shown in Table 1.
(Example 3)
5 parts by weight of iso-polymethyl methacrylate and 20 parts by weight of syn-polymethyl methacrylate were added to 75 parts by weight of dimethyl sulfoxide and dissolved by heating to obtain a film forming stock solution. This membrane-forming stock solution was discharged from an orifice-type double-cylinder die and allowed to pass through 300 mm in the air, and then led into a 100% water coagulation bath to obtain a hollow fiber separation membrane. At this time, dry nitrogen was used as the internal injection gas. The resulting hollow fiber separation membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.
FIG. 3 is a schematic side view illustrating a mini-module. A module case in which 50 polymethyl methacrylate hollow fiber separation membranes 4 prepared as described above are bundled and both ends are made of glass tube with an epoxy potting agent 5 so as not to block the hollow portion of the hollow fiber separation membrane 4. The mini-module having the structure shown in FIG. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, there are two ports (blood port 1) inside the hollow fiber separation membrane, Port (dialysate port 2). The hollow fiber separation membrane of the mini module and the inside of the module were washed with distilled water. Thereafter, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity was dissolved in ultrapure water to prepare an aqueous solution of compound A having a concentration of 11.7 ppm by weight. 30 ml at a flow rate of 10 ml / min by the peristaltic pump 8 is introduced from one blood port 1 inside the mini-module hollow fiber separation membrane 4 and taken out from the other blood port 1 through the hollow fiber separation membrane 4 and polystyrene. It was put into the dialysate port 2 on the blood port 1 side through the round tube 9 and exited from the other dialysate port 2. Thereafter, propylene glycol (Code: 164-04996 manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in ultrapure water to prepare a 65 vol / vol% propylene glycol aqueous solution, and 30 ml of the propylene glycol is supplied at a flow rate of 10 ml / min. Dial-in from one blood port 1 inside the hollow fiber separation membrane 4 of the mini-module, exits from the other blood port 1 through the hollow fiber separation membrane 4, and is dialyzed on the blood port 1 side through a polystyrene round tube 9 Entered into fluid port 2 and exited from the other dialysate port 2. Thereafter, 20 kPa of compressed air is passed from the blood port 1 inside the minimodule hollow fiber separation membrane 4 to the other blood port 1 for 30 seconds, and then 20 kPa is passed from the dialysate port 2 to the other dialysate port 2. Compressed air was passed for 60 seconds. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ-rays with the four ports sealed up. At this time, the absorbed dose of γ-rays was 27 kGy. Using the peristaltic pump 8, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane 4 of the mini-module and the inside of the module were washed with a peristaltic pump at a flow rate of 10 ml / min. A membrane minimodule (minimodule (7)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. The circulation pressure 4 hours after the start of the circulation was 8 kPa. The moisture content was 1.8%. The results are shown in Table 1.
Example 4
Mixing of 18 parts by weight of polysulfone ("Udel" (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) with 72 parts by weight of N, N'-dimethylacetamide and 1 part by weight of water In addition to the solvent, the film was dissolved by heating at a temperature of 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as a core liquid. The discharged membrane forming stock solution passed through a distance of 350 mm from the die to the coagulation bath liquid level, and was then led to a coagulation bath with 100% water to obtain a hollow fiber separation membrane. When the structure of the obtained hollow fiber separation membrane was confirmed with an electron microscope (S800 manufactured by Hitachi, Ltd.), it had an asymmetric structure.

  FIG. 3 is a schematic side view illustrating a mini-module. 50 polysulfone hollow fiber separation membranes 4 prepared as described above are bundled, and both ends are attached to a module case 3 of a glass tube with an epoxy potting agent 5 so as not to block the hollow portion of the hollow fiber separation membrane 4. The mini module having the structure shown in FIG. 3 was fixed. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, two inner ports (blood port 1) of the hollow fiber separation membrane 4 and two outer ports are provided. Port (dialysate port 2). The hollow fiber separation membrane 4 of the mini module and the inside of the module were washed with distilled water. Thereafter, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity in ultrapure water was dissolved to prepare an aqueous solution of compound A having a concentration of 11.7 ppm by weight, A polystyrene round tube 10 is inserted with 30 ml of a peristaltic pump at a flow rate of 10 ml / min from one blood port 1 inside the mini-module hollow fiber separation membrane, through the hollow fiber separation membrane 4 and from the other blood port 1. Was put into the dialysate port 2 on the blood port side and exited from the other dialysate port 2. Thereafter, propylene glycol (Code: 164-04996 manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in ultrapure water to prepare a 65 vol / vol% propylene glycol aqueous solution, and 30 ml of the propylene glycol is supplied at a flow rate of 10 ml / min. It enters from one blood port 1 inside the hollow fiber separation membrane 4 of the mini-module, passes through the hollow fiber separation membrane 4 and exits from the other blood port 1 to the dialysate port 2 on the blood port 1 side through the tube. Put out from the other dialysate port 2. Thereafter, 20 kPa of compressed air is passed from the blood port 1 inside the minimodule hollow fiber separation membrane 4 to the other blood port 1 for 30 seconds, and then 20 kPa is passed from the dialysate port 2 to the other dialysate port 2. Compressed air was passed for 60 seconds. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ-rays with the four ports sealed up. At this time, the absorbed dose of γ-rays was 27 kGy. Using the peristaltic pump 8, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane 4 of the mini-module and the inside of the module were washed with a peristaltic pump 8 at a flow rate of 25 ml. A membrane minimodule (minimodule (8)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. The circulation pressure 4 hours after the start of circulation was 5 kPa. The moisture content was 2.1%. The results are shown in Table 1.
(Example 5)
5 parts by weight of iso-polymethyl methacrylate and 20 parts by weight of syn-polymethyl methacrylate were added to 75 parts by weight of dimethyl sulfoxide and dissolved by heating to obtain a film forming stock solution. This membrane-forming stock solution was discharged from an orifice-type double-cylinder die and allowed to pass through 300 mm in the air, and then led into a 100% water coagulation bath to obtain a hollow fiber separation membrane. At this time, dry nitrogen was used as the internal injection gas. The resulting hollow fiber separation membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.
FIG. 3 is a schematic side view illustrating a mini-module. A module case in which 50 polymethyl methacrylate hollow fiber separation membranes 4 prepared as described above are bundled and both ends are made of glass tube with an epoxy potting agent 5 so as not to block the hollow portion of the hollow fiber separation membrane 4. The mini-module having the structure shown in FIG. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, there are two ports (blood port 1) inside the hollow fiber separation membrane, Port (dialysate port 2). The hollow fiber separation membrane of the mini module and the inside of the module were washed with distilled water. Thereafter, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity was dissolved in ultrapure water to prepare an aqueous solution of compound A having a concentration of 11.7 ppm by weight. 30 ml at a flow rate of 10 ml / min by the peristaltic pump 8 is introduced from one blood port 1 inside the mini-module hollow fiber separation membrane 4 and taken out from the other blood port 1 through the hollow fiber separation membrane 4 and polystyrene. It was put into the dialysate port 2 on the blood port 1 side through the round tube 9 and exited from the other dialysate port 2. Thereafter, isopropanol (Code: 15-2320-5 manufactured by Sigma-Aldrich Japan Co., Ltd.) is dissolved in ultrapure water to prepare a 65 vol / vol% isopropanol aqueous solution, and 30 ml of the mini-water is supplied with a peristaltic pump at a flow rate of 10 ml / min. Dial-in from the blood port 1 inside the hollow fiber separation membrane 4 of the module, through the hollow fiber separation membrane 4 and out of the other blood port 1, and through the polystyrene round tube 9 on the blood port 1 side dialysate Entered into port 2 and exited from the other dialysate port 2. Thereafter, 20 kPa of compressed air is passed from the blood port 1 inside the minimodule hollow fiber separation membrane 4 to the other blood port 1 for 30 seconds, and then 20 kPa is passed from the dialysate port 2 to the other dialysate port 2. Compressed air was passed for 60 seconds. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ-rays with the four ports sealed up. At this time, the absorbed dose of γ-rays was 27 kGy. Using the peristaltic pump 8, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane 4 of the mini-module and the inside of the module were washed with a peristaltic pump at a flow rate of 10 ml / min. A membrane minimodule (minimodule (9)) was obtained.

As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. The circulation pressure 4 hours after the start of the circulation was 11 kPa. The moisture content was 2.0%. The results are shown in Table 1.
(Example 6)
Mixing of 18 parts by weight of polysulfone ("Udel" (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) with 72 parts by weight of N, N'-dimethylacetamide and 1 part by weight of water In addition to the solvent, the film was dissolved by heating at a temperature of 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as a core liquid. The discharged membrane forming stock solution passed through a distance of 350 mm from the die to the coagulation bath liquid level, and was then led to a coagulation bath with 100% water to obtain a hollow fiber separation membrane. When the structure of the obtained hollow fiber separation membrane was confirmed with an electron microscope (S800 manufactured by Hitachi, Ltd.), it had an asymmetric structure.

  FIG. 3 is a schematic side view illustrating a mini-module. 50 polysulfone hollow fiber separation membranes 4 prepared as described above are bundled, and both ends are attached to a module case 3 of a glass tube with an epoxy potting agent 5 so as not to block the hollow portion of the hollow fiber separation membrane 4. The mini module having the structure shown in FIG. 3 was fixed. The mini-module has a diameter of about 7 mm and a length of about 12 cm. Similar to a general hollow fiber separation membrane type dialyzer, two inner ports (blood port 1) of the hollow fiber separation membrane 4 and two outer ports are provided. Port (dialysate port 2). The hollow fiber separation membrane 4 of the mini module and the inside of the module were washed with distilled water. Then, compound 4-methoxy-benzenesulfonyl-Asn (PEG2000-Ome) -Pro-4 amidenobenzamide (compound A) having antithrombin activity in ultrapure water was dissolved to prepare a compound A aqueous solution having a concentration of 11.7 ppm by weight. A polystyrene round tube 10 is inserted with 30 ml of a peristaltic pump at a flow rate of 10 ml / min from one blood port 1 inside the mini-module hollow fiber separation membrane, through the hollow fiber separation membrane 4 and from the other blood port 1. Was put into the dialysate port 2 on the blood port side and exited from the other dialysate port 2. Thereafter, isopropanol (Code: 15-2320-5 manufactured by Sigma-Aldrich Japan Co., Ltd.) is dissolved in ultrapure water to prepare a 65 vol / vol% isopropanol aqueous solution, and 30 ml of the mini-water is supplied at a flow rate of 10 ml / min with a perista pump. Inserted from one blood port 1 inside the hollow fiber separation membrane 4 of the module, passed through the hollow fiber separation membrane 4 and out from the other blood port 1 and inserted into the dialysate port 2 on the blood port 1 side through the tube. Out from the other dialysate port 2. Thereafter, 20 kPa of compressed air is passed from the blood port 1 inside the minimodule hollow fiber separation membrane 4 to the other blood port 1 for 30 seconds, and then 20 kPa is passed from the dialysate port 2 to the other dialysate port 2. Compressed air was passed for 60 seconds. The mini-module was dried at a temperature of 50 ° C. for 3 hours and then irradiated with γ-rays with the four ports sealed up. At this time, the absorbed dose of γ-rays was 27 kGy. Using the peristaltic pump 8, 300 ml of ultrapure water at a temperature of 25 ° C. was washed at a flow rate of 10 ml / min. Thereafter, the hollow fiber separation membrane 4 of the mini-module and the inside of the module were washed with a peristaltic pump 8 at a flow rate of 25 ml. A membrane minimodule (minimodule (10)) was obtained.

  As a result of the blood circulation experiment using the mini-module, changes in the circulation pressure with respect to the circulation time are shown in FIG. The circulation pressure 4 hours after the start of the circulation was 18 kPa. The moisture content was 1.9%. The results are shown in Table 1.

The present invention is a modified base material obtained by subjecting a compound having blood anticoagulant activity unstable to radiation to radiation graft polymerization on the surface of the base material while maintaining the activity, thereby reducing the amount of anticoagulant used. Therefore, it can be expected to reduce the risk of side effects to anticoagulants. Thus, according to the present invention, it is possible to carry out radiation graft polymerization of a physiologically active substance unstable to various radiations on the surface of a substrate while suppressing denaturation.

FIG. 1 is a graph showing changes in circulating pressure over time in Examples 1 to 6 and Comparative Examples 1 to 4 of the present invention. FIG. 2 is a schematic system diagram illustrating a blood circuit used in blood circulation experiments of Examples 1 to 6 of the present invention. FIG. 3 is a schematic side view illustrating the mini module used in Examples 1 to 6 and Comparative Examples 1 to 4 of the present invention.

Explanation of symbols

1. 1. Blood port 2. Dialysate port Module case 4. 4. Hollow fiber separation membrane 5. Potting agent Mini module 7. Silicon tube 8. Perista pump9. Polystyrene round tube10. Blood 11. Pressure gauge

Claims (17)

  A modified substrate obtained by irradiating a substrate in contact with a compound unstable to radiation in the presence of an organic solvent.   The modified base material according to claim 1, wherein the organic solvent contains a hydroxyl group.   The modified base material according to claim 2, wherein at least one of the hydroxyl groups is a secondary or tertiary hydroxyl group.   The moisture content of an organic solvent is 20% or less, The modified base material in any one of Claims 1-3 characterized by the above-mentioned.   The modified substrate according to any one of claims 1 to 4, wherein the compound unstable to radiation comprises an amino acid as a constituent element.   6. The modified base material according to claim 1, wherein the compound unstable to radiation has blood anticoagulant activity.   The modified substrate according to any one of claims 1 to 6, wherein the compound unstable to radiation has antithrombin activity.   The modified base material according to claim 1, wherein the organic solvent contains an antioxidant.   The modified substrate according to claim 1, wherein the substrate is made of a polymer compound material.   The modified substrate according to claim 1, wherein the substrate is a medical substrate.   The modified base material according to claim 10, wherein the medical base material is built in the biological component separation module.   The modified base material according to claim 10 or 11, wherein the medical base material is built in the blood purification module.   The modified base material according to claim 10, wherein the medical base material is built in the artificial kidney module.   The modified substrate according to any one of claims 10 to 13, wherein the medical substrate is a separation membrane.   The modified base material according to claim 1, wherein the base material is a separation membrane.   The modified substrate according to claim 15, wherein the separation membrane is a hollow fiber membrane.   A method for producing a modified substrate, which comprises irradiating a substrate in contact with a solution in which a compound unstable to radiation is dissolved in an organic solvent.

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