JP2014207989A - Protein adsorbing material, production method thereof, and blood purifier - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an adsorbing material having high blood group compatibility while suppressing deterioration of protein adsorbability.SOLUTION: The protein adsorbing material satisfies the following items (a)-(c). The item (a) is that a ratio of a nitrogen atom to all atoms on the surface of the protein adsorbing material is 0.1-8 (atomic number%) when measured by an X-ray electron spectroscopy (ESCA) method. The item (b) is that the amount of the β-microglobulin to be adsorbed thereon is 0.05 μg/cmor larger. The item (c) is that the number of the blood platelets to be stuck to the surface thereof is 10 (pieces/4.3×10μm) or smaller.

Description

  The present invention relates to an adsorbing material having a high protein adsorbing ability and excellent blood compatibility, and a blood purifier incorporating the adsorbing material.

  As a method for removing substances from body fluids, a blood purifier is used that removes body fluids outside the body, such as extracorporeal circulation typified by an artificial kidney, and returns the body fluids to the body after removing the target substance by the principle of dialysis, adsorption or filtration There is a way. A protein having a medium molecular weight or higher, which has a molecular weight close to that of albumin, which is a protein useful for the human body, has a problem that albumin is also removed by removal only by the principle of dialysis or filtration. On the other hand, in the removal based on the principle of adsorption, the protein to be removed can be efficiently removed while suppressing the loss of albumin.

  Patent Document 1 discloses a method for adsorbing and removing proteins using a hollow fiber. Here, it is described that the substrate is irradiated with radiation in contact with an aqueous solution containing a hydrophilic polymer. The substrate is used as a separation membrane, and “flat membrane, hollow fiber membrane” is mentioned as the shape. Here, a hollow fiber membrane is preferred, and in the examples and the like, a hollow fiber membrane is exclusively used, and only an embodiment in which blood is brought into contact only inside the hollow fiber membrane is described. From the standpoint of efficient protein adsorption and removal, adsorption is performed using only the area inside the hollow fiber membrane, the adsorption area is relatively small, and in addition, polyalkylene glycol as a hydrophilic polymer. And polyvinyl pyrrolidone were used, and a sufficient protein removal rate could not be obtained with this combination.

  On the other hand, blood compatibility is important for materials that come into contact with blood. If blood coagulation substances such as platelets adhere to the surface of the material, the surface of the material is covered and the protein to be removed cannot be sufficiently removed. Therefore, a material to which these components do not adhere is necessary. In the case of an adsorbing material having a hollow fiber shape, there is a concern that blood is likely to stay inside the hollow fiber and a blood coagulation substance is likely to adhere unless the design is made well.

  In particular, in the field of artificial kidneys, it is widely known that hydrophilic treatment of the substrate surface is effective for improving blood compatibility, and it is made of, for example, a polysulfone polymer used as a material for a separation membrane for blood purification. In order to impart blood compatibility to the separation membrane, a method for coating the separation membrane with a hydrophilic polymer is disclosed in Patent Document 2, and examples of the hydrophilic polymer include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, Polypropylene glycol is mentioned. However, when this method is applied to a material capable of adsorbing proteins and the main purpose is to adsorb proteins, it has been impossible to achieve both suppression of adhesion of blood coagulation substances and adsorption of proteins to be removed.

  On the other hand, Patent Document 3 describes an invention in which an ester group-containing polymer is localized on the surface of a separation membrane together with the hydrophilic polymer to improve blood compatibility and maintain membrane performance. Specific examples include polymers containing vinyl acetate groups. However, no protein-adsorbing material is used as a base material, and there is no description of a technical idea that achieves both adsorption and blood compatibility using the material.

JP 2011-183384 A JP-A-6-238139 International Publication No. 2009/123088

An object of the present invention is to provide a protein adsorbing material to which blood compatibility is imparted while maintaining protein adsorbing ability such as β ₂ -microglobulin.

In order to achieve the above object, the present invention comprises the following constitution.
1. A protein adsorbing material characterized by satisfying the following items.
(A) The ratio of nitrogen atoms to all atoms on the surface detected by X-ray electron spectroscopy (ESCA) is 0.1 (number of atoms%) or more and 8 (number of atoms%) or less (b) β ₂ − Microglobulin adsorption amount is 0.05 μg / cm ² or more (c) The number of platelet adhesion on the surface is 10 (pieces / 4.3 × 10 ³ μm ² ) or less 2.1, and the protein adsorption material is incorporated. Blood purifier.
3. Copolymer solution containing a repeating unit provided by a monomer of vinyl pyrrolidone on a substrate containing at least one selected from polymethyl methacrylate, polystyrene, polypropylene, cellulosic polymer, silicon dioxide, aluminosilicate, and amorphous carbon A method for producing a blood purifier, comprising a protein adsorbing material obtained by contacting with water and irradiating with radiation.

  As described above, the present invention relates to an adsorbent material having pores of an optimal size for protein adsorption and a uniform size, and dramatically improves blood compatibility while maintaining excellent protein adsorption characteristics. This is what we found. Here, the base material refers to a material having protein adsorption ability.

  If the polymer (vinylpyrrolidone-containing polymer) containing a repeating unit provided by the vinylpyrrolidone monomer on the surface of the adsorbing material is too small, sufficient blood compatibility cannot be obtained, and if it is too much, the protein adsorbing ability decreases. The present invention has found an optimal amount of a vinylpyrrolidone-containing polymer in order to achieve both properties that are considered to be contradictory.

  Here, since it is difficult to specify and describe blood compatibility or hydrophilic polymer that gives it as a substance, first, as described in the above requirement (a), the amount of nitrogen atoms is conditioned as a substance. It defines the characteristics. However, since it does not mean that any nitrogen atom or nitrogen atom-containing compound may be used, the invention is specified by specifying both characteristics that were considered to be in conflict with each other according to requirements (b) and (c). ing.

  Regarding nitrogen atoms, it is preferable that the concentration of the nitrogen atoms with respect to all atoms constituting the protein adsorbing material detected by elemental analysis is 0.0001 wt% or more and 1 wt% or less.

  Further, when the compound is specified more specifically, at least of the ratio of nitrogen atoms to all atoms on the surface detected by the ESCA, and the concentration of nitrogen atoms with respect to all atoms constituting the protein adsorbing material detected by the elemental analysis, One is preferably derived from a copolymer containing a repeating unit provided by a monomer of vinyl pyrrolidone.

  More specifically, the copolymer containing the repeating unit provided by the vinyl pyrrolidone monomer is further provided by at least one monomer selected from carboxylic acid vinyl ester, acrylic acid ester and methacrylic acid ester. Preferably it contains units.

  According to the present invention, it is possible to provide a protein adsorbing material to which blood compatibility is imparted while maintaining adsorption removal of a protein to be removed.

  The blood compatibility of the protein-adsorbing material depends on the surface state of the portion in contact with blood, and generally increases as the surface hydrophilicity increases. However, when a hydrophilic treatment is performed on the surface of the base material, there is a concern that adhesion of blood coagulation substances such as platelets to the base material is suppressed, and at the same time, the adsorption of the protein to be removed is also suppressed. .

In addition, the β ₂ -microglobulin (molecular weight 11,800) and albumin (molecular weight 66,000), which is a protein useful for the human body, are close in radius when assuming that the substance is a sphere (Stokes radius). In addition, removal by a separation membrane based on the principle of filtration has a problem that not only β ₂ -microglobulin but also albumin is removed.

The present invention in beta ₂ - The microglobulin adsorption, the column having a built-in protein adsorption material beta ₂ - micro globulin-containing bovine plasma 5 min, beta ₂ when the closed circulation - is calculated from microglobulin concentration decreases The A specific measurement procedure is shown below. After washing the column and adsorbing material, 1 L of bovine plasma solution adjusted so that the concentration of anticoagulated protein is 6.5 ± 0.5 g / dL and the β ₂ -microglobulin concentration is 1 mg / L is added to the column inlet. From the outlet to the outlet and circulate closed for 5 minutes. The β ₂ -microglobulin concentration in the bovine plasma before and after circulation is measured using a latex agglutination immunoassay, and the β ₂ -microglobulin adsorption amount is calculated from the following formula.

β ₂ -microglobulin adsorption amount [μg / cm ² ]
= (Circulation before the bovine blood plasma beta ₂ - microglobulin concentration [μg / mL] - bovine plasma after circulation beta ₂ - microglobulin concentration [μg / mL]) × 1000 [mL] / (1.6 × 10 ⁴ [cm ² ])
In order to perform sufficient protein adsorption, the β ₂ -microglobulin adsorption amount is preferably 0.05 μg / cm ² or more, and more preferably 0.10 μg / cm ² or more.

Alternatively, the degree of adsorption of β ₂ -microglobulin can be measured by clearance. Details of the measurement method will be described later in Examples. The preferred clearance range in the present invention can vary depending on the shape, size, etc. of the column, but is preferably 30 mL / min or more, more preferably 40 mL / min or more, further preferably 50 mL / min or more, while 90 mL / min or less. Is preferred.

As described above, in addition to measuring the adsorption performance of β ₂ -microglobulin in a column containing a protein adsorbing material, a batch test can be performed on the adsorbing material to measure the adsorption rate of β ₂ -microglobulin. The batch test is a test for measuring the adsorption rate of β ₂ -microglobulin when the adsorbing material is immersed in a solution containing β ₂ -microglobulin in a closed system. It is calculated from the decrease in the concentration of β ₂ -microglobulin when the protein adsorbing material is added to the bovine plasma containing β ₂ -microglobulin and shaken for 2 hours. Specific measurement procedures will be described later in Examples. In the present invention, the β ₂ -microglobulin adsorption rate is preferably 30% or more, more preferably 40% or more, and still more preferably 50% or more. Incidentally, the correlation of the beta ₂ over microglobulin adsorbed amount and the adsorption rate is very high, as the adsorption amount is high, high adsorption rate.

The surface platelet adhesion number in the present invention is the number of platelets adhering to the surface of the adsorbing material when blood is brought into contact with the surface of the adsorbing material for 4 hours. In the present invention, since the purpose is to ensure blood compatibility as well as the ability to remove and adsorb proteins, it is mentioned as a condition that the number of platelet adhesion is small. A specific measurement procedure is shown below. First, the surface of the adsorbent material that comes into contact with blood is exposed. Immediately after collecting human venous blood, heparin is added to 50 U / ml, brought into contact with the adsorbent material within 10 minutes after blood collection, and shaken at 37 ° C. for 4 hours. Thereafter, the adsorbing material is washed with physiological saline, blood components are fixed with glutaraldehyde physiological saline, and washed with distilled water. The adsorbing material is dried under reduced pressure at room temperature of 0.5 Torr for 10 hours, and a thin film of Pt—Pd is formed on the adsorbing material surface by sputtering to prepare a sample. The surface of the adsorbent material is observed at a magnification of 1500 times with a scanning electron microscope, and the number of adhering platelets per 4.3 × 10 ³ μm ² is counted. The average value of the number of adhering platelets in 10 different visual fields is defined as the number of adhering platelets (pieces / 4.3 × 10 ³ μm ² ). In order to obtain sufficient blood compatibility, the human platelet adhesion amount is 10 / 4.3 × 10 ³ μm ² or less, and preferably ^{3 /} 4.3 × 10 ³ μm ² or less.

  Since the adsorbing material of the present invention has high blood compatibility, it can be suitably used as a medical substrate. The medical base material used in the present invention is suitable for an application used in contact with a biological component, for example, a blood purifier. Here, the blood purifier refers to a module or column that circulates blood outside the body and adsorbs and removes waste and harmful substances in the blood, such as an exotoxin adsorption column.

  In the present invention, the base material refers to a material having protein adsorption ability. The base material contains polymethyl methacrylate, polystyrene, polyethylene, polypropylene, cellulose polymers such as cellulose acetate, cellulose diacetate, and cellulose triacetate, fluororesins such as polycarbonate, polyurethane, polyvinyl chloride, polyvinylidene fluoride, poly Examples thereof include polyester such as acrylonitrile and polyethylene terephthalate, polyamide, silicon dioxide used for quartz and silica gel, aluminosilicate used for zeolite, amorphous fiber used for carbon fiber, activated carbon and the like. Alternatively, these copolymers and composite materials may be used. Among them, a substrate containing at least one selected from polymethyl methacrylate, polystyrene, polypropylene, silicon dioxide, aluminosilicate, and amorphous carbon is preferable because it has excellent adsorption performance. A substrate containing at least one selected from polymethyl methacrylate, polystyrene, and polypropylene is more preferable because it efficiently adsorbs proteins. In particular, polymethyl methacrylate is preferable because a base material having a uniform pore size can be obtained by mixing an isotactic body and a syndiotactic body to form a stereo complex which is a three-dimensional complex. In particular, for polystyrene and polypropylene, a core-sheath composite fiber in which the core component is polystyrene and the sheath component is polystyrene and polypropylene may be used.

In the present invention, the specific surface area of the adsorbing material represents the area of the surface where the adsorbing material can come into contact with blood with respect to the volume of the adsorbing material. In order to efficiently remove proteins, it is desirable that the specific surface area of the adsorbent material is large, but if it is too large, the strength decreases. In view of the above, 0.0001 μm ² / μm ³ or more is preferable, 0.001 μm ² / μm ³ or more is more preferable, 0.01 μm ² / μm ³ or more is more preferable, and 10 μm ² / μm ³ or less is preferable. , more preferably 1μm ² / μm ³ or less, more preferably 0.1μm ² / μm ³ or less.

  Examples of the shape of the substrate include fibers, nonwoven fabrics, woven fabrics, knitted fabrics, particles, films, and molded articles. Here, the fiber in the present invention refers to a fiber that does not have a continuous cavity in the longitudinal direction. For example, solid yarn, sea-island fiber, core-sheath fiber and the like can be mentioned. The fiber is preferable because the specific surface area can be increased by reducing the fiber diameter. On the other hand, the hollow fiber in the present invention refers to a thread having a continuous cavity in the longitudinal direction. In the hollow fiber, when blood is brought into contact only with the inside, the specific surface area is small and the protein cannot be adsorbed efficiently, which is not suitable. Even if the specific surface area is increased by bringing blood into contact with both the inside and outside of the hollow fiber, the blood flow rate inside the hollow fiber is slower than the outside of the hollow fiber, so the inside of the hollow fiber can contact the blood efficiently. Therefore, sufficient protein removal may not be performed. Moreover, since blood stays inside the hollow fiber, the blood coagulates and high blood compatibility may not be obtained. Therefore, in order to achieve both blood compatibility and protein adsorption / removal performance, fibers that do not have a continuous cavity in the longitudinal direction are preferable.

  When the base material is a fiber, the fiber diameter is desirably thin in order to increase the specific surface area. However, if the fiber diameter is too small, pressure loss increases when blood flows through the column containing the adsorption material. 1 μm or more is preferable, 1 μm or more is more preferable, 10 μm or more is further preferable, while 10 mm or less is preferable, 1 mm or less is more preferable, and 0.5 mm or less is still more preferable.

  A differential scanning calorimeter (DSC) is used as a method for measuring the pore diameter of the adsorbing material. In DSC, the pore diameter of the entire adsorbent material can be measured. Measure the adsorbent material by quenching to -55 ° C, raising the temperature to 5 ° C at 0.3 ° C / min, and using the peak top temperature of the obtained curve as the melting point, calculate the primary average radius of the pores from the following formula To do.

Primary average radius of pores [nm] = (33.30-0.3181 × melting point drop [° C.]) / Melting point drop [° C.]
The above measurement method is based on the description of Kazuhiko Ishikiriyama et al .; JOURNAL OF COLLOID AND INTERFACE SCIENCE, 171, 103-111, (1995).

If the pore size is too small, the protein to be removed cannot enter the inside, which is not suitable. On the other hand, if the pore diameter is too large, the pore surface area per unit volume becomes small, so that the protein cannot be adsorbed efficiently. In order to perform the adsorption removal of β ₂ -microglobulin, the primary average radius of the pores is preferably 1 nm or more, more preferably 3 nm or more, further preferably 5 nm or more, while 200 nm or less is preferable, and 100 nm or less. Is more preferable, and 30 nm or less is still more preferable.

As a method for measuring the surface area ratio of the adsorbing material, there is a method of observing with a scanning electron microscope (SEM) and performing image analysis. Observed with a SEM at a magnification of 50,000 times, an image of 640 × 442 pixels was binarized with image processing software (Matrox Inspector 2.2, manufactured by CRI JOLANTA), the pores were black, and the structural polymer portion became white Images are obtained. The surface area ratio is calculated from the following formula.
Surface area ratio [%] = total area of holes / total area × 100
The same measurement is performed at any five locations on each surface, and the average value is obtained.

  If the surface porosity is too small, blood components cannot enter the adsorbing material, and thus efficient adsorption cannot be performed. On the other hand, if the surface area ratio is too large, the strength is lowered and damage is likely to occur. Therefore, the surface porosity is preferably 0.1% or more, more preferably 1% or more, still more preferably 5% or more, while 95% or less is preferable, 50% or less is more preferable, and 30% or less is still more preferable.

  When comparing the hole diameter in the vicinity of the surface with the hole diameter in the central part, the DSC is not used, and after obtaining the cross section of the material, it can be performed by the SEM method as in the measurement of the surface open area ratio. Here, the cross section refers to a surface obtained by cutting perpendicularly to a surface of the adsorbing material that contacts blood. For example, in the case of a fiber, the surface cut | disconnected perpendicularly to the longitudinal direction is said. Observe the central part of the adsorbent material cross section and the vicinity of the surface, and perform image analysis. The pore diameter in the vicinity of the surface is a pore diameter on the surface of the base material, that is, the outer circumference in the cross section, and more specifically, a visual field perpendicular to the surface with respect to the average pore diameter in the visual field 1 of 256 × 256 pixels in contact with the surface. When the ratio of the average pore diameter in the field 2 of 256 × 256 pixels adjacent to 1 is less than twice, the field of view of 640 × 442 pixels that completely covers the field of view 1 is referred to as the vicinity of the surface. However, in the case of polymethylmethacrylate fibers and the like, there are cases where a layer having a very small pore diameter, such as a dense layer, is present on the surface. From the viewpoint that the pore diameter is optimized without variation for protein adsorption and removal, it is appropriate not to include such a layer portion in the “near surface”. Accordingly, when the ratio of the average pore diameter of the visual field 2 to the average pore diameter in the visual field 1 is twice or more, the visual field of 640 × 442 pixels that completely includes the visual field 2 and does not include the visual field 1 at all is referred to as the vicinity of the surface.

Of the straight lines obtained by connecting two points on the surface, the center of the straight line having the longest length is referred to as a central portion. The average pore diameter is also determined at the central portion.
In any of the above cases, even when the shape of the hole is not a perfect circle, it is assumed that the hole is a perfect circle, and the hole diameter is calculated from the area of the hole by the following equation. Moreover, when calculating the said average hole diameter, it measures about all the holes observed and takes the average.
Pore diameter [nm] = (pore area [nm ² ] / π) ^1/2
The adsorbent material is measured at each of the central portion and the surface vicinity of the cross section obtained by cutting the adsorbing material at arbitrary five locations, and the average value is obtained.

  In order to perform protein adsorption removal, it is necessary to have many pores of optimum size. When pores that are too large or too small exist, protein adsorption cannot be performed efficiently. In order to efficiently perform protein adsorption, the ratio of the pore diameter in the central portion to the pore diameter in the vicinity of the surface of the adsorption material cross section is preferably 0.5 or more, more preferably 0.8 or more, while 1.3 or less. Preferably, 1.1 or less is more preferable.

  In the present invention, in order to impart blood compatibility, it is preferable to treat the substrate surface with a hydrophilic polymer. Among them, treating the substrate surface with a hydrophilic copolymer is preferable. preferable. While one monomer constituting the copolymer expresses hydrophilicity, it can also impart hydrophobicity to other constituent monomers, making it possible to impart a hydrophilic-hydrophobic balance to the substrate, It has been found that the protein adsorption property, which is the original property of the base material, is not impaired while imparting high blood compatibility to the base material. The hydrophilic copolymer treatment in the present invention refers to introducing a hydrophilic copolymer onto the surface of a substrate by coating, chemical reaction, grafting by radiation irradiation, or the like.

In the present invention, as the hydrophilic copolymer, a vinyl pyrrolidone-containing polymer, that is, a polymer containing a repeating unit provided by a monomer of vinyl pyrrolidone is preferably used. , Methyl acrylate, methoxyethyl acrylate, methyl methacrylate, ethyl methacrylate, hydroxyethyl methacrylate, ethylene glycol, propylene glycol, vinyl alcohol, ethyleneimine, allylamine, vinylamine, acrylic acid, repeating acrylamide gives repeat Examples thereof include a copolymer including a unit and a polymer such as a graft polymer. Among them, a copolymer containing a repeating unit provided by monomers of vinyl pyrrolidone and vinyl acetate is particularly suitable because it is excellent in biocompatibility. If the proportion of the repeating units given by the vinylpyrrolidone monomer in the copolymer is too high, the decrease in the adsorption capacity of the substance to be removed is suppressed, but the effect of suppressing the adhesion of blood coagulation substances such as platelets is obtained. Absent. On the other hand, if the proportion of the repeating units provided by the vinylpyrrolidone monomer in the copolymer is too low, the solubility in water becomes low and the substrate surface cannot be uniformly coated. In order to achieve both suppression of adhesion of the blood coagulation substance and maintenance of the adsorption ability of the substance to be removed, it is preferable to use a copolymer having an optimal composition ratio. That is, the proportion of the repeating unit provided by the vinylpyrrolidone monomer in the copolymer is preferably 0.3 or more, more preferably 0.35 or more, while 0.7 or less is preferable, and 0.65 or less. Is more preferable. When the proportion of the repeating unit provided by the monomer of vinylpyrrolidone in the copolymer is 1, it is not suitable because it is impossible to achieve both adhesion inhibitory properties of blood coagulation substances and adsorption removal performance of β ₂ -microglobulin. Absent.

  When the molecular weight of the hydrophilic copolymer is too small, the movable region of the molecular chain in the molecular motion is small and sufficient hydrophilicity cannot be obtained. In addition, since the low molecular weight polymer has a small Stokes radius, it penetrates into the pores of the base material and modifies the target protein adsorption site, so that the protein cannot be adsorbed efficiently. The molecular weight of the hydrophilic copolymer is preferably 1000 or more, more preferably 5000 or more, and still more preferably 10,000 or more. Conversely, if the molecular weight is too large, entanglement of the molecular chains and cross-linking reaction between the molecules during radiation irradiation will proceed, and the movable region of the molecular chain will be reduced. Therefore, the molecular weight of the hydrophilic copolymer should be 2 million or less. Preferably, 500,000 or less is more preferable, and 100,000 or less is more preferable.

If the amount of the hydrophilic copolymer on the substrate surface is too large, the protein to be removed cannot be sufficiently adsorbed and removed, and if it is too small, blood coagulation substances such as platelets adhere. The amount of the hydrophilic copolymer the surface, preferably 0.01 mg / ^{m 2} or more, 0.1 mg / ^{m 2} or more, and further preferably 1 mg / ^{m 2} or more, while the 10000 mg / ^{m 2} or less preferably , more preferably from 1000 mg / ^{m 2} or less, 100 mg / ^{m 2} or less is more preferable.

X-ray electron spectroscopy (ESCA) is used as a method for measuring the amount of the hydrophilic copolymer present on the surface of the adsorbing material. After rinsing the measurement sample with ultrapure water, the sample is dried at room temperature and 0.5 Torr for 10 hours and used for measurement. Specific conditions and preferred measuring devices are as follows.
Measuring device: Quantera SXM
Excitation X-ray: monochromatic Al Kα1,2 line (1486.6 eV)
X-ray diameter: 20 μm
Photoelectron escape angle: 45 ° (inclination of detector with respect to sample surface)
As the amount of nitrogen atoms, the ratio of the peak area to the total elements (all elements other than hydrogen atoms cannot be detected since hydrogen atoms cannot be detected) is calculated from the area of the peak appearing near 400 eV of N1s, and the amount of nitrogen atoms (number of atoms) Ask for.

  If the amount of the hydrophilic copolymer on the substrate surface is too large, the adsorption ability of the protein to be removed cannot be maintained, and if it is too small, the effect of inhibiting the adhesion of the blood coagulation substance cannot be obtained sufficiently. When using the hydrophilic copolymer containing a nitrogen atom, it is preferable that the ratio of the nitrogen atom with respect to all the atoms of the surface detected by ESCA is 0.1 (number of atoms%) or more. On the other hand, it is preferably 8 (number of atoms%) or less, more preferably 5 (number of atoms%) or less, still more preferably 3 (number of atoms%) or less, and 2 (number of atoms%). More preferably, it is more preferably 1 or less (number of atoms%) or less.

  While the hydrophilic copolymer is present on the surface of the adsorbing material, it suppresses the adhesion of blood coagulation substances, while if the amount present in the adsorbing material is too large, the adsorption site is blocked and adsorption of the substance to be removed is prevented. Since it is suppressed, it is not preferable. Since the surface area formed by the network structure is larger in the interior than the surface of the adsorbent material, the surface can be ignored by measuring the amount of the hydrophilic copolymer in the entire adsorbent material, and the amount present inside is measured. can do. Therefore, if the amount of the hydrophilic copolymer present in the entire adsorbing material is too large, a large amount of the hydrophilic copolymer is also present inside, and the amount of adsorption of the substance to be removed decreases. If the amount of the hydrophilic copolymer present in the entire adsorbing material is too small, the amount of the hydrophilic copolymer on the surface of the adsorbing material decreases, and adhesion of blood coagulation substances cannot be suppressed. The amount of hydrophilic copolymer present in the entire adsorbent material can be determined by elemental analysis. For example, the abundance of the nitrogen atom-containing polymer is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, and more preferably 1% by weight or less with respect to all elements detected by elemental analysis. It is preferably 0.1% by weight or less, more preferably 0.05% by weight or less.

  In the present invention, α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams and the like are used as radiation. In addition, medical devices such as blood purifiers need to be sterilized, and in recent years, radiation sterilization methods using γ rays and electron beams are frequently used from the viewpoint of low residual toxicity and simplicity. Furthermore, when the method of the present invention is used for a medical substrate, it can be expected that sterilization of the substrate and modification for improving blood compatibility can be achieved at the same time, which is preferable. In addition, when coating the surface of a substrate with a hydrophilic group-containing copolymer, etc., there is a concern about the dissolution of these polymers from the substrate surface, but the effect of reducing dissolution by crosslinking and insolubilization by irradiation with radiation. Are conceivable and preferred. In particular, blood purifiers are mainly of a so-called wet type in which the adsorbing material is in a state of immersing water. Therefore, by simply changing this water to an aqueous solution containing a hydrophilic copolymer solution, The method is preferred because it can be used conveniently.

  When performing sterilization and modification of the substrate at the same time, it is preferable to perform radiation irradiation with an absorbed dose of 15 kGy or more. This is because an absorbed dose of 15 kGy or more is effective for sterilizing blood purification modules and the like with γ rays. However, when the irradiation dose exceeds 100 kGy, blood compatibility is deteriorated because three-dimensional crosslinking or collapse of the hydrophilic copolymer occurs.

  In the present invention, the adsorbent material can be produced by contacting the substrate with an aqueous solution containing a hydrophilic copolymer such as a vinylpyrrolidone-containing polymer and then irradiating with radiation. As a method of contacting, a method of immersing the substrate in an aqueous solution containing a hydrophilic copolymer is preferable.

  Further, for a system composed of a plurality of components including not only the adsorbing material but also a blood circuit, etc., by simultaneously irradiating the plurality of members of the system in a state of contact through an aqueous solution containing a hydrophilic copolymer, It can also be modified at once. In particular, the effect is great when the plurality of members are made of different materials. This can be said to be a feature that it is difficult to modify a plurality of substrates made of different materials at the same time because the conventional modification methods are highly dependent on the substrate.

  Here, examples of the system constituted by a plurality of constituent members include a blood purification system including a port portion, an adsorbing material, and a circuit. For example, a blood purifier such as an exotoxin adsorption column is composed of a plurality of members made of different materials such as catheters, blood circuits, chambers, module inlet and outlet ports, and adsorbent materials. In the present invention, it is possible to modify all or a part of these simultaneously. For example, in the case of a blood purification system, the module inlet and outlet ports and the blood circuit are connected to the module, and a hydrophilic polymer aqueous solution is passed through the blood circuit to fill the entire system with radiation. Irradiation may be performed.

  There are various methods for manufacturing a blood purifier depending on its application, but the rough process can be divided into a process for manufacturing an adsorbent for blood purification and a process for incorporating the adsorbent into a module. it can.

  An example of a method for producing a fiber built-in column is shown below.

  A spinning dope prepared by dissolving the polymer in a solvent is prepared. In the present invention, the concentration of the stock solution is preferably 30% by weight or less, more preferably 22% by weight or less. The fibers are obtained by discharging these liquids and the like from a cylindrical die, passing through a dry air part of a certain distance, and then passing through a coagulation bath. In the case of an undiluted solution system in which gelation is caused by temperature change, gelation can be promoted by blowing cold air in the dry part. The fiber diameter can be controlled by the discharge amount of the spinning dope.

  The spinning dope discharged from the die is solidified into a yarn shape in a coagulation bath. The coagulation bath usually consists of a mixture with a coagulant such as water or alcohol, or a solvent constituting the spinning dope. Usually, water can be used. In the present invention, the liquid retention rate can be changed by controlling the temperature of the coagulation bath. Since the liquid retention rate can be affected by the type of spinning dope, etc., the temperature of the coagulation bath is also appropriately selected. In general, the liquid retention rate can be increased by increasing the coagulation bath temperature. . Although this mechanism is not exactly clear, it is thought that the solvent reaction in the high temperature bath is fast and the solvent is solidified and fixed before shrinkage due to the competitive reaction between the solvent removal from the stock solution and the solidification shrinkage. However, if the coagulation bath temperature becomes too high, the pore size becomes too large and it is not suitable for adsorption of the target protein. Therefore, the coagulation bath temperature is preferably 20 ° C or higher, more preferably 30 ° C or higher, and further preferably 40 ° C or higher. . On the other hand, 80 degrees C or less is preferable, 60 degrees C or less is more preferable, and 50 degrees C or less is still more preferable.

  Next, a step of washing the solvent adhering to the solidified fiber is passed. The means for washing the fibers is not particularly limited, but a method of allowing the fibers to pass through a multi-staged water bath (referred to as a washing bath) is preferably used. What is necessary is just to determine the temperature of the water in a washing bath according to the property of the polymer which comprises a fiber. In the case of a fiber containing polymethyl methacrylate, 30 to 50 ° C. is used.

  Moreover, in order to hold | maintain a hole diameter for a fiber after a water-washing bath, you may put the process which provides a moisturizing component. The term “moisturizing component” as used herein refers to a component capable of maintaining the humidity of the fiber or a component capable of preventing a decrease in the humidity of the fiber in the air. Typical examples of moisturizing ingredients include glycerin and its aqueous solutions.

  After completion of washing with water and applying a moisturizing component, it is possible to pass through a bath (referred to as a heat treatment bath) filled with a heated aqueous solution of the moisturizing component in order to increase the dimensional stability of highly shrinkable fibers. The heat treatment bath is filled with an aqueous solution of a heated moisturizing component, and when the fiber passes through the heat treatment bath, the fiber is subjected to a thermal action and shrinks. It can be stabilized. The heat treatment temperature at this time varies depending on the material of the fiber, but in the case of a fiber containing polymethyl methacrylate, it is preferably 60 ° C. or higher, more preferably 70 ° C. or higher, and further preferably 80 ° C. or higher. On the other hand, 100 degrees C or less is preferable, 95 degrees C or less is more preferable, and 90 degrees C or less is still more preferable.

  The means for using the obtained fiber as a blood purifier is not particularly limited, but an example is as follows.

  First, after bundling the required number of fibers, the fibers are put in a plastic case that becomes a cylindrical portion of a blood purifier column. Thereafter, the thread bundle protruding to both ends is cut, both ends are fixed with a mesh, and blood inlet and outlet ports called header caps are attached to obtain a column for a blood purifier.

  EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

-Column creation method (Production Example 1)
31.7 parts by weight of syn (syndiotactic) -polymethyl methacrylate having a weight average molecular weight of 400,000, 31.7 parts by weight of syn-polymethyl methacrylate having a weight average molecular weight of 1.4 million, and a weight average molecular weight of 500,000 16.7 parts by weight of iso (isotactic) -polymethyl methacrylate and 20 parts by weight of a polymethyl methacrylate copolymer having a molecular weight of 300,000 containing 1.5 mol% of parastyrene sulfonic acid soda are mixed with 376 parts by weight of dimethyl sulfoxide. The mixture was stirred at 110 ° C. for 8 hours to prepare a spinning dope.

This film-forming stock solution was discharged from a cylindrical die, passed through 380 mm in the air, and then introduced into a coagulation bath with 100% water and a temperature of 42 ° C. to obtain a fiber. The fiber diameter of the obtained fiber was 0.12 mm. The obtained fiber was assembled in a plastic case, and both ends were fixed with a mesh to prepare a fiber column having an effective area of 1.6 m ² .
(Production Example 2)
A sea island composite fiber of 36 islands, in which the island is further composed of a core-sheath composite, was obtained using the following components under spinning conditions of a spinning speed of 800 m / min and a draw ratio of 3 times.
Island core component; Polypropylene island sheath component: Polystyrene 90% by weight, polypropylene 10% by weight
Sea component; Polyethylene terephthalate composite ratio (weight ratio) obtained by copolymerization of 3% by weight of 5-sodiumsulfoisophthalic acid; core: sheath: sea = 40: 40: 20
After preparing a sheet-like material composed of 70% by weight of this fiber and 30% by weight of polypropylene fiber having a diameter of 25 μm, a polyester net having a 3 mm square aperture (thickness 0.4 mm, single yarn diameter 0.3 mm, basis weight 30 g) / M ² ) is sandwiched between them and needle punched to obtain a three-layered adsorption carrier. Next, this non-woven fabric was treated with an aqueous solution of sodium hydroxide (3 wt%) at 90 ° C. to dissolve the sea component, whereby the core-sheath fiber had a diameter of 4 μm and a bulk density of 0.05 g / cm ³ (total A nonwoven fabric having a basis weight of 210 g / m ² ) was produced.
(Production Example 3)
Sea-island composite fiber (thickness: 2.6 denier, number of islands) consisting of 50 parts by weight of sea component (mixture of 46 parts by weight of PSt and 4 parts by weight of PP) and 50 parts by weight of island component (PP) : 16; U.S. Pat. No. 4,661,260) was made into a tubular mesh.
(Production Example 4)
16 parts by weight of polysulfone (Amoco Udel-P3500), 2 parts by weight of polyvinylpyrrolidone (International Special Products; hereinafter referred to as ISP) K30, 2 parts by weight of polyvinylpyrrolidone (ISP K90), 79 parts of dimethylacetamide,
One part of water was dissolved by heating to prepare a spinning dope.

This film-forming stock solution was discharged from a cylindrical die. The discharged film-forming solution passes through a dry zone atmosphere having a dry length of 380 mm, a temperature of 30 ° C., and a relative humidity of 78% RH, and is then introduced into a coagulation bath of 100% water and a temperature of 40 ° C. The fiber was obtained by passing through a second water washing step, a drying step at 130 ° C. for 2 minutes, and a fiber obtained through a 160 ° C. crimping step. The fiber diameter of the obtained fiber was 0.12 mm. Using the obtained fiber, both ends were fixed with a mesh to prepare a fiber column having an effective membrane area of 1.6 m ² .
(Production Example 5)
A spinning dope was prepared in the same manner as in Production Examples 1 and 2 and Comparative Production Example 1-4.

This membrane-forming stock solution was discharged from a double tube hollow fiber membrane die. Dry nitrogen was discharged from the inner tube as an internal injection gas. After passing through 380 mm in the air, the hollow fiber was obtained by being led into a 100% water coagulation bath. The hollow fiber thus obtained had an inner diameter of 0.2 mm and a film thickness of 0.03 mm. The obtained hollow fiber was assembled in a plastic case, and both ends were fixed with a mesh to produce a hollow fiber column having an effective membrane area of 1.6 m ² .
2. Measurement Method Used (1) X-ray Electron Spectroscopy (ESCA) Measurement Columns prepared in Examples 1 and 2 and Comparative Example 4-8 below were measured. The fiber surface was measured at three points. In the case of the hollow fiber membrane, it was cut into a semicylindrical shape with a single blade, and the inner surface of the hollow fiber membrane was measured at three points. The measurement sample was rinsed with ultrapure water, dried at room temperature and 0.5 Torr for 10 hours, and then subjected to measurement. Measurement equipment and conditions are as follows.
Measuring device: Quantera SXM
Excitation X-ray: monochromatic Al Kα1,2 line (1486.6 eV)
X-ray diameter: 20 μm
Photoelectron escape angle: 45 ° (inclination of detector with respect to sample surface)
As the amount of nitrogen atoms, the ratio of the peak area to the total atoms (all atoms other than hydrogen atoms cannot be detected since hydrogen atoms cannot be detected) is calculated from the area of the peak appearing near 400 eV of N1s, and the amount of nitrogen atoms (number of atoms) Asked.
(2) Elemental analysis The columns prepared in the following Examples 1 and 2 and Comparative Example 4-8 were measured. 3 g of the adsorbent material was freeze-dried and measured with a fully automatic elemental analyzer varioEL (Elemental) at a sample decomposition path of 950 ° C., a reduction furnace of 500 ° C., a helium flow rate of 200 ml / min, and an oxygen flow rate of 20-25 ml / min. It was. The ratio of nitrogen atoms to all detected atoms was determined.
(3) Measurement of surface area ratio The surface of the adsorbent material was observed with a scanning electron microscope (SEM), and image analysis was performed. Observed with a SEM at a magnification of 50,000 times, an image of 640 × 442 pixels was binarized with image processing software (Matrox Inspector 2.2, manufactured by CRI JOLANTA), the pores were black, and the structural polymer portion became white I got an image. The surface area ratio was calculated from the following formula.
Surface open area ratio [%] = total area of holes / total area The same measurement was carried out at five locations on each surface, and the average value was obtained.
(4) Measurement of cross-sectional pore diameter Similar to the measurement of the surface open area ratio, it is a method of observing at the magnification of 50,000 times using SEM. Analysis was performed. As described above, assuming that the hole is a perfect circle, the hole diameter was calculated from the following equation using the area of the hole.
Pore diameter [nm] = (pore area [nm ² ] / π) ^1/2
Measurements were made at five locations at the center and in the vicinity of the surface of the adsorbent material, and the average value was determined.
(5) Measurement of pore diameter The DSC Q100 manufactured by TA Instruments was used to rapidly cool the adsorbent material to −55 ° C. and raise the temperature to 5 ° C. at a rate of 0.3 ° C./min. The primary average radius of the holes was calculated from the following formula.

Pore size [nm] = (33.30-0.3181 × melting point drop [° C.]) / Melting point drop [° C.] Kazuhiko Ishikiriyama et al.; JOURNAL OF COLLOID AND INTERFACE SCIENCE, 171, 103-111, (1995 )
(6) Human platelet adhesion test Double-sided tape was affixed to an 18 mmφ polystyrene circular plate, and fibers and hollow fiber membranes were fixed on the double-sided tape. In the case of the hollow fiber membrane test, the pasted hollow fiber membrane was cut into a semi-cylindrical shape with a single blade to expose the inner surface of the hollow fiber membrane. The circular plate was attached to a Falcon (registered trademark) tube (18 mmφ, No. 2051) cut into a cylindrical shape so that the surface on which the hollow fiber membrane was attached was inside the cylinder, and the gap was filled with parafilm. The cylindrical tube was washed with physiological saline and then filled with physiological saline. Immediately after collecting venous blood from a healthy human, heparin was added to 50 U / ml. After discarding the physiological saline in the cylindrical tube, within 10 minutes after blood collection, 1.0 ml of the blood was placed in the cylindrical tube and shaken at 37 ° C. for 4 hours. Thereafter, the inside of the cylindrical tube was washed with 10 ml of physiological saline, blood components were fixed with 2.5% glutaraldehyde physiological saline, and washed with 20 ml of distilled water. The circular plate on which the adsorbing material was fixed was dried under reduced pressure at room temperature of 0.5 Torr for 10 hours, and then attached to the sample stage of the scanning electron microscope with double-sided tape. Thereafter, a thin film of Pt—Pd was formed on the surface of the adsorbing material by sputtering to prepare a sample. The surface of the adsorbent material is observed with a field emission scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times, and the number of adhering platelets in one field of view (4.3 × 10 ³ μm ² ) is determined. I counted. The average value of the number of platelet adhesion in 10 different visual fields was defined as the number of platelet adhesion (pieces / 4.3 × 10 ³ μm ² ). Since the blood pool is easily formed at the end portion in the longitudinal direction of the hollow fiber, the vicinity of the center was observed.
(7) Measurement of β ₂ -microglobulin adsorption amount by column The column inlet and outlet were connected by a silicone tube, and physiological saline was flowed from the inlet at a flow rate of 200 mL / min for 5 minutes to wash the fiber or hollow fiber and the inside of the column. The bovine plasma solution anticoagulated with the biological preparation reference blood preservation solution A was adjusted so that the protein concentration was 6.5 ± 0.5 g / dL and the β ₂ -microglobulin concentration was 1 mg / L. . 1 L of the bovine plasma flowed from the inlet to the outlet of the column and was circulated closed for 5 minutes. Circulation before the bovine blood plasma beta ₂ - microglobulin concentration and 5 minutes bovine plasma after circulation beta ₂ - micro globulin concentration was determined using a latex agglutination immunoassay, the following equation beta ₂ - microglobulin adsorption The amount was calculated.

β ₂ -microglobulin adsorption amount [μg / cm ² ]
= (Circulation before the bovine blood plasma beta ₂ - microglobulin concentration [μg / mL] - bovine plasma after circulation beta ₂ - microglobulin concentration [μg / mL]) × 1000 [mL] / (1.6 × 10 ⁴ [cm ² ])
(8) β ₂ -microglobulin clearance measurement β ₂ -microglobulin clearance is measured according to the method defined by the Japanese Society for Dialysis Medicine (Performance Evaluation Method for Blood Purifier, Dialysis Society Journal 29 (8) 1231-1245, 1996). It carried out at 200 mL / min. In Comparative Example 6, the test was conducted by flowing only inside the hollow fiber.
(9) Measurement of β ₂ -microglobulin adsorption rate by batch test A protein concentration of 6.5 ± 0.5 g / dL, β _{2 of} an anticoagulated bovine plasma solution using a biological preparation standard blood preservation solution A solution -The microglobulin concentration was adjusted to 10 mg / L. 1.2 mL of the bovine plasma and the adsorbent material were added to a glass container having a volume of 5 mL, and the mixture was shaken at 37 ° C. for 2 hours. When the shape of the adsorbing material was fiber, 49 fibers cut into 5 cm were used. The amount of the adsorbing material having other shapes will be described later. Shaking before bovine plasma of beta ₂ - microglobulin concentration and 2 hours with shaking beta ₂ bovine plasma after - micro globulin concentration was determined using a latex agglutination immunoassay, the following equation beta ₂ - Micro The globulin adsorption rate was calculated.

β ₂ -microglobulin adsorption rate [%]
= (In prior shaking bovine plasma beta ₂ - microglobulin concentration [μg / mL] - β ₂ bovine plasma after shaking - microglobulin concentration [μg / mL]) / shake before bovine plasma Β ₂ -microglobulin concentration [μg / mL] × 100
Example 1
From the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, 0.001 weight by weight of vinylpyrrolidone / vinyl acetate (6/4) copolymer (“Collidon VA64” manufactured by BASF) 900 mL of a% aqueous solution was passed, and the column was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About this column, ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, batch test (Beta) _2- microglobulin adsorption rate measurement was performed. As a result, it was as shown in Table 1. That is, the platelet adhesion inhibitory property and the β ₂ -microglobulin adsorption / removal performance were high. Although the surface is grafted using the above-mentioned hydrophilic polymer solution with a low concentration, on the other hand, as seen in the measurement result of the amount of nitrogen atoms, the amount of the hydrophilic polymer on the surface of the adsorbent material is not too much, so the above Compared to Comparative Example 4 in which the polymer grafting was not performed, the adsorption ability of β ₂ -microglobulin could be maintained without decreasing.
(Example 2)
0.1 weight of vinyl pyrrolidone / vinyl acetate (6/4) copolymer (“Collidon VA64” manufactured by BASF) from the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1 900 mL of a% aqueous solution was passed, and the column was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About this column, ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, batch test (Beta) _2- microglobulin adsorption rate measurement was performed. As a result, it was as shown in Table 1. That is, the platelet adhesion inhibitory property and the β ₂ -microglobulin adsorption / removal performance were high. Compared to Example 1, since a hydrophilic polymer solution with a high concentration was used, the amount of hydrophilic polymer on the surface of the adsorbing material was large, but not so much that the adsorption ability of β ₂ -microglobulin was greatly reduced.
Example 3
A non-woven fabric containing polystyrene (PSt) and polypropylene (PP) produced in Production Example 2 was cut into a circle having a diameter of 6 mm, and a vinylpyrrolidone / vinyl acetate (6/4) copolymer (“Collidon VA64” manufactured by BASF) was obtained. It was immersed in 2 mL of a 1% by weight aqueous solution and irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. The nonwoven fabric was subjected to ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, and β ₂ -microglobulin adsorption rate measurement by batch test. As a result, it was as shown in Table 1. That is, the platelet adhesion inhibitory property and the β ₂ -microglobulin adsorption / removal performance were high. Since the amount of the hydrophilic polymer on the surface of the adsorbing material is in the optimum range, compared to the following Comparative Example 9 in which the polymer grafting is not performed, sufficient platelet adhesion inhibitory property is obtained and the β ₂ -microglobulin adsorbing ability is reduced. It was possible to maintain without letting.
Example 4
Three pieces of a knitted fabric containing polystyrene (PSt) and polypropylene (PP) produced in Production Example 3 were cut into a circle having a diameter of 6 mm, and a vinylpyrrolidone / vinyl acetate (6/4) copolymer (BASF Co., Ltd. VA64 ″) was immersed in 2 mL of a 0.1 wt% aqueous solution and irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. The knitted fabric was subjected to ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, and β ₂ -microglobulin adsorption rate measurement by batch test. As a result, it was as shown in Table 1. That is, the platelet adhesion inhibitory property and the β ₂ -microglobulin adsorption / removal performance were high. Since the amount of the hydrophilic polymer on the surface of the adsorbing material is in the optimum range, compared to the following Comparative Example 10 in which the polymer grafting is not performed, sufficient platelet adhesion inhibitory activity is obtained, and the β ₂ -microglobulin adsorbing ability is reduced. It was possible to maintain without letting.
(Example 5)
From the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, 0.5 weight of vinylpyrrolidone / vinyl acetate (7/3) copolymer (“Collidon VA73” manufactured by BASF) 900 mL of a% aqueous solution was passed, and the column was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About this column, ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, batch test (Beta) _2- microglobulin adsorption rate measurement was performed. As a result, it was as shown in Table 1. That is, compared with Example 1, the platelet adhesion number was large and the adsorption removal performance of β ₂ -microglobulin was high. Compared to Example 1, since the proportion of repeating units provided by vinylpyrrolidone monomer in the hydrophilic polymer is high, the platelet adhesion inhibitory effect was low, while the decrease in the adsorption ability of β ₂ -microglobulin was suppressed. It is thought that it was done.
(Comparative Example 1)
From the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, 0.001 wt% aqueous solution of polyvinylpyrrolidone (“K90” manufactured by ISP) was passed through the column, Filled with aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About the column, surface area ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, β ₂ -microglobulin by batch test The adsorption rate was measured. As a result, it was as shown in Table 1. That is, compared to Comparative Example 4 in which the polymer grafting was not performed, the adsorption ability of β ₂ -microglobulin could be maintained without greatly decreasing, but platelet adhesion inhibitory property was not obtained.
(Comparative Example 2)
From the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, 900 mL of 0.001 wt% aqueous solution of polyethylene glycol (“Macrogol 6000” manufactured by NOF Corporation) was passed through the column. The inside was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About the column, surface area ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, β ₂ -microglobulin by batch test The adsorption rate was measured. As a result, it was as shown in Table 1. That is, compared to Comparative Example 4 in which the polymer grafting was not performed, the adsorption ability of β ₂ -microglobulin could be maintained without greatly decreasing, but platelet adhesion inhibitory property was not obtained.
(Comparative Example 3)
From the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, 900 mL of a 0.075 wt% aqueous solution of polyethylene glycol (“Macrogol 6000” manufactured by NOF Corporation) was passed through the column. The inside was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About the column, surface area ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, β ₂ -microglobulin by batch test The adsorption rate was measured. As a result, it was as shown in Table 1. That is, since a hydrophilic polymer solution having a higher concentration than that of Comparative Example 2 was used and the amount of hydrophilic polymer on the surface of the adsorbing material was large, the platelet adhesion inhibitory activity was high, but even the adsorption of β ₂ -microglobulin was suppressed. It was.
(Comparative Example 4)
900 mL of water was passed from the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, and the column was filled with water. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About this column, ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, batch test (Beta) _2- microglobulin adsorption rate measurement was performed. As a result, it was as shown in Table 1. That is, nitrogen atoms on the surface of the adsorbing material and the entire adsorbing material were not detected. Moreover, although the adsorption removal performance of (beta) _2- microglobulin is high, platelet adhesion inhibitory property was not acquired.
(Comparative Example 5)
From the inlet side to the outlet side of the fiber column containing polysulfone (PSf) produced in Production Example 4, a vinylpyrrolidone / vinyl acetate (6/4) copolymer (“Collidon VA64” manufactured by BASF) 0.001 wt% aqueous solution Was passed through 900 mL, and the column was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. For the column, ESCA measurement, elemental analysis, surface porosity measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, β ₂ -microglobulin adsorption rate measurement by batch test went. As a result, it was as shown in Table 1. That is, the platelet adhesion inhibitory property was high, but the adsorption removal performance of β ₂ -microglobulin was low. High protein adsorption capacity due to the large amount of nitrogen atoms contained in the adsorbent material, the base material is polysulfone, and the ratio of the pore diameter in the central part to the pore diameter near the surface of the adsorbent material is large and the pore size is not uniform. It is thought that was not obtained.
(Comparative Example 6)
From the inlet side to the outlet side of the hollow fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 5, a vinylpyrrolidone / vinyl acetate (6/4) copolymer ("Collidon VA64" manufactured by BASF) 0.001 900 mL of a weight% aqueous solution was passed, and the column was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About this column, ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, batch test (Beta) _2- microglobulin adsorption rate measurement was performed. As a result, it was as shown in Table 1. That is, although the platelet adhesion inhibitory activity was high, the adsorption removal performance of β ₂ -microglobulin was low. The shape is used an adsorbent material is a hollow fiber, due to the slow flow rate of the blood on the inside than the outside of the hollow fiber, the hollow fiber inner does not contact the blood efficiently beta ₂ - microglobulin efficient adsorption It is thought that removal could not be performed.
(Comparative Example 7)
From the inlet side to the outlet side of the fiber column containing polymethyl methacrylate (PMMA) produced in Production Example 1, 0.5 weight of vinylpyrrolidone / vinyl acetate (6/4) copolymer (“Collidon VA64” manufactured by BASF) 900 mL of a% aqueous solution was passed, and the column was filled with the aqueous solution. Thereafter, the column was irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. Further, this aqueous copolymer solution and γ-ray irradiation were repeated 3 times in total. About this column, ESCA measurement, elemental analysis, surface pore ratio measurement, pore diameter measurement, cross-sectional pore diameter measurement, platelet adhesion test, β ₂ -microglobulin adsorption test by column, β ₂ -microglobulin clearance measurement, batch test (Beta) _2- microglobulin adsorption rate measurement was performed. As a result, it was as shown in Table 1. That is, although the platelet adhesion inhibitory activity was high, the adsorption removal performance of β ₂ -microglobulin was low. Compared to Example 1, using a high concentration of the hydrophilic polymer solution, also liquid passage of the polymer solution, since it was repeated three times γ-irradiation, since the hydrophilic polymer content of the adsorbent material surface is too large, beta ₂ - It is thought that the ability to adsorb microglobulin decreased.
(Comparative Example 8)
The nonwoven fabric containing polystyrene (PSt) and polypropylene (PP) produced in Production Example 2 was cut into a circle with a diameter of 6 mm, immersed in 2 mL of water, and irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. About this nonwoven fabric, the surface opening rate measurement, the pore diameter measurement, the measurement of the hole diameter of a cross section, the platelet adhesion test, and the β ₂ -microglobulin adsorption rate measurement by a batch test were performed. As a result, it was as shown in Table 1. That is, although the adsorption removal performance of β ₂ -microglobulin is high, the platelet adhesion inhibitory property was not obtained.
(Comparative Example 9)
Three pieces of a knitted fabric containing polystyrene (PSt) and polypropylene (PP) produced in Production Example 3 were cut into a circle having a diameter of 6 mm, immersed in 2 mL of water, and irradiated with γ rays. The absorbed gamma ray dose was 25 kGy. The knitted fabric was subjected to measurement of surface area porosity, pore size, cross-sectional pore size, platelet adhesion test, and β ₂ -microglobulin adsorption rate by batch test. As a result, it was as shown in Table 1. That is, although the adsorption removal performance of β ₂ -microglobulin is high, the platelet adhesion inhibitory property was not obtained.

Claims (14)

A protein adsorbing material characterized by satisfying the following items.
(A) The ratio of nitrogen atoms to all atoms on the surface detected by X-ray electron spectroscopy (ESCA) is 0.1 (number of atoms%) or more and 8 (number of atoms%) or less (b) β ₂ − Microglobulin adsorption amount 0.05 μg / cm ² or more (c) The number of platelet adhesion on the surface is 10 (pieces / 4.3 × 10 ³ μm ² ) or less   2. The protein adsorbing material according to claim 1, wherein the ratio of the pore diameter in the central portion to the pore diameter in the vicinity of the surface is 0.5 or more and 1.3 or less.   The protein adsorption according to claim 1 or 2, wherein the concentration of nitrogen atoms with respect to all atoms constituting the protein adsorbing material detected by elemental analysis is 0.0001 wt% or more and 1 wt% or less. material.   Nitrogen derived from a copolymer in which the nitrogen atom on the surface detected by the ESCA and / or the nitrogen atom constituting the protein adsorbing material detected by the elemental analysis contains a repeating unit given by the monomer of vinylpyrrolidone The protein adsorbing material according to claim 1, comprising an atom.   The protein-adsorbing material according to claim 4, wherein the copolymer further comprises a repeating unit provided by at least one monomer selected from a carboxylic acid vinyl ester, an acrylic acid ester, and a methacrylic acid ester. 6. The protein adsorbing material according to claim 1, wherein the specific surface area is 0.0001 μm ² / μm ³ or more and 10 μm ² / μm ³ or less.   The protein-adsorbing material according to any one of claims 1 to 6, wherein the surface porosity is 0.1% or more and 95% or less.   The protein-adsorbing material according to any one of claims 1 to 7, wherein a primary average radius of the pores is 1 nm or more and 200 nm or less. The protein according to any one of claims 1 to 8, wherein the substrate comprises one or more selected from polymethyl methacrylate, polystyrene, polypropylene, cellulosic polymer, silicon dioxide, aluminosilicate, and amorphous carbon. Adsorption material.   The protein-adsorbing material according to claim 9, wherein the base material contains polymethyl methacrylate.   The protein adsorbing material according to claim 1, wherein the shape is at least one selected from fibers, nonwoven fabrics, woven fabrics, knitted fabrics, particles, films, and molded articles.   The protein adsorption material according to claim 10 or 11, wherein the polymethyl methacrylate forms a stereocomplex structure.   A blood purifier comprising the protein adsorbing material according to claim 1 incorporated therein. Copolymer solution containing a repeating unit provided by a monomer of vinyl pyrrolidone on a substrate containing at least one selected from polymethyl methacrylate, polystyrene, polypropylene, cellulosic polymer, silicon dioxide, aluminosilicate, and amorphous carbon A method for producing a protein-adsorbing material obtained by contacting with a substance and irradiating with radiation.