JP2511410B2 - β2-microglobulin adsorbent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Use) The present invention selectively adsorbs a malignant substance associated with a disease from whole blood or body fluids such as plasma, serum, ascites, and pleural effusion.
An adsorbent for purifying body fluids to be removed. In particular, it relates to an adsorbent for purifying body fluids in which blood cells such as whole blood coexist.

More specifically, β ₂ increases in the body fluids of patients with renal failure and malignant tumors and causes carpal tunnel syndrome, amyloidosis, elastic finger / shoulder / knee joint disease, pruritus dermatitis, bone disorder, etc. The present invention relates to an adsorbent for microglobulin.

(Prior Art) Hemodialysis was performed on a renal failure patient, and about 20 years have passed, and abnormalities such as carpal tunnel syndrome have become apparent. In recent years, it has been clarified that this causative substance is β ₂ microglobulin, which is relatively difficult to remove by dialysis, and various symptoms are caused by its accumulation in the body.

Conventionally, hemofiltration and diafiltration have been used for the purpose of removing such a medium-molecular weight substance, but the removal rate is low, and there is a problem that a large amount of replacement fluid is required for effective removal.
In order to increase the removal rate, it is sufficient to make the pores of the membrane larger, but when the pores become a little larger, albumin, which is a useful protein, is leaked, and controlling the pore size cannot achieve effective selective removal of medium-molecular weight substances. is the current situation.

(Problems to be Solved by the Present Invention) The object of the present invention is generally applicable in view of the problems based on the above-mentioned therapeutic polymer membrane technology, and is a medium molecular weight substance, particularly β ₂ microglobulin. Adsorbs selectively with high efficiency, non-specific adsorption, especially adsorption of albumin is small, further no replacement liquid is required, and there is no safety problem such as generation of fine particles and sterilization operation can be performed easily. The present invention aims to provide an adsorbent which has been used for purification or regeneration of body fluid such as blood or plasma, and particularly to provide an adsorbent for purification of body fluid in which blood cells such as whole blood coexist.

(Means for Solving Problems) As a result of earnest research along the above-mentioned objects, the present inventors have found that
An adsorbent consisting of at least a two-layer structure of a specific water-insoluble material and a blood-compatible polymer suppresses adhesion and activation of thrombotic substances such as platelets, and selectively β ₂ microglobulin, and surprisingly It was found that the water-insoluble material having a contact angle of at least 20 degrees or more adsorbs β ₂ microglobulin selectively and with high efficiency, and has completed the present invention. Was reached.

That is, in the present invention, a water-insoluble material having a contact angle of at least 20 degrees or more is coated with a blood-compatible polymer to form a layer structure of at least two layers, and the water-insoluble material has a β ₂ micro layer. globulin is adsorbent body fluid purifying beta ₂ microglobulin, characterized in that a possible layer structure reaches, body fluid purifying beta ₂ is a polymer hemocompatible polymer having a nitrogen-containing basic functional groups It is an adsorbent for microglobulin.

The beta ₂ microglobulin in the present invention, is a beta ₂ microglobulin, which is measured by enzyme immunoassay or the like in a normal clinical test, more particularly having the following physical properties.

Sedimentation constant 1.6S Partial specific volume 0.72 to 0.73 ml / g Molecular weight 11000 to 12000 Nitrogen content 16 to 17% β ₂ microglobulin itself which is the object of the present invention,
And a complex with another protein, and a partially mutated amino acid sequence of β ₂ microglobulin is also included.

The contact angle referred to in the present invention is the contact angle of air bubbles on a solid surface in water, and WC Hamilton J. Colloid Inter
face Sci., 40,219-222 (1972) [Double Sea Hamilton Journal of Colloid Interface Science, 40,219-222 (1972)], JDAndrade, J.
Polym.Sci.Polym.Symp., 66, 313-336 (1979)
Day Andrade, Journal of Polymer Science Polymer Symposium, 66,313-336 (197
9)] Refers to the measured contact angle according to the principle and method indicated in []. In the conventionally well-known method for measuring the contact angle of a droplet on a solid surface in air, a hydrophilic material has a contact angle value that changes with the passage of time, and is difficult to use as a physical property value of the material. As the sample, a molded product such as a sheet or a film was prepared, the contact angle was measured at a temperature of 25 ° C., and the measurement was performed 10 times or more.

In the adsorbent of the present invention, the contact angle of the water-insoluble material is β
₂ Adhesion affinity with microglobulin must be at least 20 degrees, and in order to prevent the generation of fine particles and be used as an adsorbent for purifying whole blood, a water-insoluble material with a contact angle of at least 20 degrees must be used for blood It is necessary to form a β ₂ microglobulin adsorbent for body fluid purification, which is composed of at least a two-layer structure of a water-insoluble material having a contact angle of at least 20 degrees and a blood-compatible polymer, by coating a compatible polymer. There is.

The contact angle of the water-insoluble material of the present invention is
It is necessary that the adsorption affinity such as the hydrophobic interaction force acting between the hydrophobic portion of ₂ microglobulin and the like is 20 degrees or more, more preferably the contact angle range is 30 degrees to 95 degrees, and further preferably , 40 degrees to 85 degrees. The 20 degrees or less, the degree of hydrophobicity is low, beta ₂ adsorption affinity, such as hydrophobic interaction force acting between the microglobulin is weakened, beta ₂ microglobulin adsorption efficiency decreases. On the other hand, if the temperature exceeds 95 ° C., the compatibility with the blood compatible material is reduced, and water leakage during use is reduced.

The water-insoluble material having a contact angle of 20 degrees or more referred to in the present invention,
If it is a solid in an aqueous liquid and the contact angle measured by the method shown above is 20 degrees or more, all inorganic materials and organic polymer materials are included, but eluates as blood purification materials, etc. From the viewpoint of safety and moldability, an organic polymer compound is preferable. Examples of such, polyethylene, polypropylene, polymers and copolymers of olefin compounds such as polytetrafluoroethylene, polystyrene, polymers and copolymers of vinyl compounds such as polymethacrylate ester, polyacrylate ester, Nylon
Examples thereof include polyamide-based polymers such as 6,66 and polyester-based polymers such as polyethylene terephthalate.

Of these, polymers and copolymers of vinyl compounds are more preferable. Such examples include styrene, p-
Polymers of styrene-based compounds such as methylstyrene and p-ethylstyrene, polymers of (meth) acrylic acid ester-based compounds such as methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate and the above compounds Divinylbenzene, (meth) acrylic acid diester, methacrylonitrile, vinylpyrrolidone,
Examples thereof include copolymers with vinyl compounds such as methacrylic acid esters.

Among them, a polymer of a (meth) acrylate compound such as methyl (meth) acrylate, ethyl (meth) acrylate, and propyl (meth) acrylate, and a copolymer with the above vinyl compound are more preferably used.

Further, a polymer of a (meth) acrylic acid ester compound and a copolymer with the vinyl compound, which contains 70% by weight or more of a (meth) acrylic acid ester,
In particular, those containing 70% by weight or more of methyl methacrylate give more preferable results as the water-insoluble material of the present invention.

In addition, these organic polymer materials have first, second, third,
An anion exchanger into which a quaternary nitrogen atom is introduced has an increased affinity for β ₂ microglobulin and is preferably used.

The shape of the water-insoluble material may be spherical, granular, film-shaped, hollow fiber-shaped, thread-shaped, etc., but the particle shape such as spherical or granular may be the same volume column rather than a film-shaped, hollow-shaped or thread-shaped form. When a water-insoluble material is filled in, the area of contact with blood is increased, and the efficiency of removing β ₂ microglobulin is increased, and therefore, it is preferably used.

Further, when the water-insoluble material is in the form of particles, those having a particle diameter of 25 to 2500 μm give more preferable results as the water-insoluble material of the present invention. If the particle size is smaller than 25μ, the distance between the particles becomes small, and when used for whole blood purification, platelets and the like tend to adhere and become clogged easily,
If it is more than 2500 μm, platelets and the like are less likely to adhere, but the area in contact with blood is small, and the efficiency of β ₂ microglobulin removal is reduced, which is not preferable.

Further, those having a particle size of 50 to 2000μ give more preferable results as the water-insoluble material of the present invention, and particles having a particle size of 250 to 1500μ give particularly preferable results.

The surface and internal structure of the water-insoluble material are not particularly limited, but a porous structure is preferable because the substantial surface area in contact with β ₂ microglobulin can be increased. The surface area of a water-insoluble material having a porous structure is measured by BET using nitrogen gas (for example, Catalyst Engineering Course-4, Catalyst Basic Measurement Method, Catalysis Society of Japan, Chijin Shokan, pages 50 to 58). The value is preferably 10 m ² / g or more, and the average pore size of the pores is preferably in the range of 20Å to 2000Å. The average pore size is the mercury porosimetry method (from page 69
Calculated from the mercury intrusion curve obtained on page 73). The larger the surface area, the better the adsorption efficiency of β ₂ microglobulin, but the range must have a mechanical strength that can maintain the pore size and structurally maintain a porous structure.

Further, if it is 10 m ² / g or less, the capacity as an adsorbent is insufficient.
If the average pore size is smaller than 20Å, the adsorption of β ₂ microglobulin becomes extremely poor. That is, as the pore size becomes smaller, the surface area of the porous substance tends to increase, but since β ₂ microglobulin cannot enter inside the pores of the porous material, the substantial surface area for β ₂ microglobulin becomes extremely large. It becomes smaller and the adsorption of β ₂ microglobulin becomes worse. On the other hand, when the pore size is larger than 2000 Å, β ₂ microglobulin can enter the inside of the pores, but the surface area of the porous material becomes small, and the adsorption efficiency of β ₂ microglobulin also deteriorates.

On the other hand, in the range of average pore size 20Å to 2000Å,
Since β ₂ microglobulin can freely enter inside the pores and the substantial surface area capable of adsorbing β ₂ microglobulin is sufficiently large, specific and efficient adsorption of β ₂ microglobulin becomes possible.

Here, the range of surface area and average pore size is that the surface area is 10 m ² / g
Above, and the average pore size is 20 Å to 2000 Å,
More preferably, the surface area is 55 m ² / g or more, and the average pore size is in the range of 45Å to 1000Å. More preferably,
A surface area of 100 m ² / g or more and an average pore size of 100Å
It is in the range of 500Å.

The blood-compatible polymer referred to in the present invention includes all generally known blood-compatible materials, but prevents the generation of fine particles, that is, the ease and safety of coating a water-insoluble material,
From sterilization properties, (meth) acrylic acid ester-based polymers, acrylamide-based polymers, polyvinylpyrrolidone-based polymers,
Examples thereof include polyvinyl alcohol-based polymers, ethylene-vinyl alcohol-based polymers, ethylene-vinyl acetate-based polymers, cellulose nitrate and gelatin.

A polymer having a nitrogen-containing basic functional group is preferably used as the blood-compatible polymer for the purpose of preventing the generation of fine particles, further improving the blood compatibility, and further improving the affinity with β ₂ microglobulin. To be

The “nitrogen-containing basic functional group” referred to in the present invention is a functional group which has a positive charge on the nitrogen atom and can become a cation in an acidic aqueous solution. Examples of such functional groups include primary amino groups, secondary amino groups, tertiary amino groups, quaternary ammonium groups, and nitrogen-containing aromatic ring groups such as pyridyl groups and imidazolinyl groups. Therefore, as the polymer having a nitrogen-containing basic functional group used in the present invention, for example, vinylamine; 2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine, 4-vinylimidazole, N-vinyl-2-ethylimidazole, N
-Vinyl derivatives of nitrogen-containing aromatic compounds such as vinyl-2-methylimidazole; dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, dimethylaminopropyl (meth) acrylate, 3
Acrylic acid and methacrylic acid derivatives such as dimethylamino-2-hydroxypropyl (meth) acrylate; acrylic acid amides such as N-dimethylaminoethyl (meth) acrylic acid amide and N-diethylaminoethyl (meth) acrylic acid amide; Examples of the polymer include a methacrylic acid amide derivative; a styrene derivative such as p-dimethylaminomethylstyrene and p-diethylaminoethylstyrene; and a derivative obtained by converting the above vinyl compound into a quaternary ammonium salt by using an alkyl halide or the like. To be

Of these, particularly preferred are dimethylaminoethyl (meth) acrylate and diethylaminoethyl (meth).
Acrylate, p-dimethylaminomethylstyrene, p
-Examples include polymers containing diethylaminoethylstyrene and the like.

Furthermore, the polymer having a nitrogen-containing basic functional group referred to in the present invention is preferably a copolymer of a vinyl compound and a monomer having a nitrogen-containing basic functional group, and the nitrogen content is 0.05 to
It is preferably 3.5% by weight. In addition, the nitrogen content
More preferable results are obtained when the amount is 0.1 to 2.5% by weight.
The nitrogen content referred to here is the weight% of the nitrogen atoms in the above functional groups in the total polymer.

As the vinyl compound referred to here, 5-hydroxyethyl methacrylate, methyl (meth) acrylate,
Alkyl (meth) acrylates such as ethyl (meth) acrylate and n-butyl (meth) acrylate, amides such as (meth) acrylamide and N-methyl (meth) acrylamide, N-vinylpyrrolidone, vinyl acetate,
Styrene and the like can be mentioned.

Further, as the copolymer of the vinyl compound and the monomer having a nitrogen-containing basic functional group, there are a block copolymer, a graft copolymer, a random copolymer, and the like. It is preferable that the polymer has a microdomain structure having an average length of 100 A to 100 μ, because of its blood compatibility.

Further, the copolymer of the vinyl compound and the monomer having a nitrogen-containing basic functional group is a random copolymer, which makes it difficult to produce the copolymer, the stability of the two-layer structure, and the blood compatibility. Is most preferable.

The two-layer structure referred to in the present invention means that the water-insoluble material of the present invention is coated with a blood-compatible polymer by a generally known method, and the first layer is a water-insoluble material and the second layer is a blood-compatible polymer. Says a structure. The second or higher layer can be made into a multi-layer structure by further coating the same or different blood compatible polymer. With such a structure, generation of fine particles of the water-insoluble material can be prevented, and safety problems such as eluates are eliminated. By selecting a blood-compatible polymer, generation of fine particles can be prevented, blood compatibility can be improved, and affinity with β ₂ microglobulin can be further improved. Furthermore, by having a multi-layered structure, it is possible to further prevent the generation of fine particles, further improve blood compatibility, and further improve the affinity with β ₂ microglobulin without adsorbing useful proteins such as albumin. However, it is necessary to make the layered structure accessible to β ₂ microglobulin.

Hereinafter, (1) a method for producing a water-insoluble material, (2) a method for producing a blood-compatible polymer, (3) production of an adsorbent having at least a two-layer structure of the above water-insoluble material and a blood-compatible polymer Although the method, conditions, etc. are illustrated, it goes without saying that the present invention is not limited to this example.

(1) Method for producing water-insoluble material The method for producing the water-insoluble material of the present invention is a generally known method such as bulk polymerization, solution polymerization, suspension polymerization, emulsion polymerization, etc., and a commercially available monomer is purchased. Then, it is carried out by a method for producing each polymer together with a solvent for dissolving, suspending or emulsifying the additive, the polymerization initiator and the monomer. For example, in the case of styrene-divinylbenzene copolymer, stirring under the coexistence of styrene, ethylbenzene, divinylbenzene, toluene, octanol and AIBN (azobisisobutyronitrile) results in a pore size of about 50-1000μ. Can make fine particles. Further, radical polymerization in a suspension polymerization system can also produce particles having various particle diameters and pore sizes.

(2) Method for producing blood-compatible polymer No particular limitation is imposed on the production of the polymer of the present invention. Radical polymerization by monomers, addition polymerization including anionic polymerization, ring-opening polymerization, dehalogenation. Polymerization with hydrogen, a condensation reaction or the like can be used. Furthermore, a method by polymer reaction can also be adopted. For example, a given raw material polymer can be aminated by a known method, or a hydroxyl group can be introduced if necessary. In the case of producing a graft polymer, it can be obtained by copolymerizing a macromer with another monomer, or a graft reaction can be performed on a polymer raw material.

(3) Method and conditions for producing adsorbent having at least two-layer structure of the above water-insoluble material and blood-compatible polymer All known coating methods such as spraying method and dipping method are used. Here, the details of the immersion method will be described.

A solution in which a blood compatible polymer is dissolved in a polymer solvent is prepared in advance. The solvent of the polymer is a solvent that dissolves the polymer uniformly and facilitates impregnation or coating of the polymer on the surface of the water-insoluble material.In the present invention, basically, the polymer is dissolved. Any solvent can be used. Appropriate solvent must be selected in consideration of ease of removal and safety when a trace amount remains.
In the present invention, as such a solvent, lower alcohols such as methanol and ethanol, acetone and dimethylformamide, and mixtures of these with water are preferable.

After immersing water-insoluble materials with various spherical diameters in this solution under a nitrogen atmosphere at room temperature for about 5 minutes (sometimes stirring), remove excess solution by suction on a glass filter, and then feed nitrogen gas amount. And balance the amount of suction nitrogen gas
Dry with nitrogen on a glass filter for a minute. Then, it is dried in a vacuum dryer at room temperature under the conditions of 755 mmHg or more for 24 hours.

When producing an adsorbent having two or more layers, the adsorbent having a two-layer structure of the water-insoluble material and the blood-compatible polymer produced by the above operation is used as the water-insoluble material, and the operation shown above is performed. It is achieved by repeating. The blood-compatible polymer used here can be the same or different from the blood-compatible polymer used in the second layer.

The method of using the β ₂ microglobulin adsorbent for purifying whole blood of the present invention will be illustrated below, but the present invention is not limited to this example.

The adsorbent of the present invention may be used alone, or may be mixed with other adsorbents or laminated and used. Examples of other adsorbents include activated carbon and the like used in adsorptive artificial kidneys. As a result, a broader clinical effect due to the synergistic effect of the adsorbent can be expected. When used for extracorporeal circulation, the adsorbent volume is preferably about 50 to 600 ml.

When the adsorbent of the present invention is used for extracorporeal circulation, there are roughly the following two methods. One is a method of purifying blood taken from the body directly through the device, and the other is a method of purifying blood taken from the body using a centrifuge or a membrane plasma separator. After separating into blood cell component and blood cell component, after passing the plasma component through the device and purifying,
It is a method of returning to the body together with blood cell components. The adsorbent of the present invention is particularly preferably used in the direct blood purification method.

Regarding the passage rate of blood or plasma, since the adsorption efficiency of the adsorbent is very high, the particle size of the adsorbent can be made coarse and the packing degree can be lowered, so that the shape of the adsorbent layer can be determined. A high passing speed can be given without any change. Therefore, a large amount of body fluid can be treated.

As a method for passing body fluids such as blood and plasma, the liquid may be continuously passed or may be used intermittently depending on the clinical need or the equipment condition of the facility. Good.

As described above, the adsorbent of the present invention is simple and safe because it adsorbs and removes β ₂ microglobulin in a body fluid with high efficiency and specificity.

The present invention, autologous blood, can be used for general usage of purifying body fluids such as plasma, regeneration, adsorption of β ₂ microglobulin that accumulates in body fluids in renal failure, malignant tumors, etc.,
It is effective, safe and reliable for removal.

(Example) Next, the present invention will be described in more detail with reference to Examples.

Example 1 As a water-insoluble material, a sheet of nylon 6/6, polymethylmethacrylate, polystyrene, and polyethylene (thickness 200 μm) was prepared, and the contact angle of air bubbles in water was measured. Next, a 2% wt / V methanol solution of a polymer of 2-hydroxyethyl methacrylate (manufactured by Aldrich) was prepared, and 100 ml of this solution was cut into the above-mentioned sheet (20 cm × 10 cm into 3 mm × 3 mm). After soaking for 5 minutes (stirring occasionally), remove excess solution by suction on a glass filter, and then nitrogen is dried on the glass filter for 20 minutes while balancing the amount of nitrogen gas introduced and the amount of nitrogen gas suctioned. To do. Then, in a vacuum dryer at room temperature, 75
It was dried for 24 hours under the condition of 5 Hmmg or more. By this operation,
An adsorbent is produced.

Next, after mixing the adsorbent prepared above with 3 ml of plasma of a healthy person and shaking at 37 ° C for 1 hour, β _{2 in} plasma before and after was mixed.
Microglobulin and albumin were quantified. The RIA method was used for β ₂ microglobulin, and the BCG method was used for albumin.

Table 1 shows the quantitative results of β ₂ microglobulin and albumin in plasma before and after shaking at 37 ° C. for 1 hour, and Table 2 shows the outline of the materials used.

Example 2 Polystyrene and polymethylmethacrylate (the same as in Example 1) were used as the water-insoluble material, and a random copolymer of 2-hydroxyethyl methacrylate and diethylaminoethyl methacrylate (2-hydroxyethyl) was used as the blood compatible material. Content of methacrylate 90mo
l%), 2-hydroxyethyl methacrylate and N, N '
An adsorbent was obtained in the same manner as in Example 1 except that a graft copolymer with -diethyl-N- (4-vinylphenethyl) ethylenediamine (content of 2-hydroxyethyl methacrylate was 95 mol%) was used. Table 3 shows the evaluation results.
Table 4 shows the outline of the materials used.

Example 3 As a water-insoluble material, each sheet of methyl methacrylate-divinylbenzene copolymer (80: 20% by weight), styrene-divinylbenzene copolymer (80: 20% by weight) and particles of 420-800μ were prepared. Then, the contact angle of air bubbles in water was measured. Next, a 2% wt / V methanol solution of 2-hydroxyethyl methacrylate was prepared, and 35 ml of the above-mentioned particles was immersed in 100 ml of this solution for 5 minutes (sometimes agitated), and then an excess solution was placed on a glass filter. After removing by suction, balance the amount of introduced nitrogen gas with the amount of sucked nitrogen gas and dry for 20 minutes on a glass filter with nitrogen. Then, it was dried in a vacuum dryer for 24 hours under the conditions of room temperature and 755 mmHg or more. By this operation, the adsorbent is produced.

Next, the plasma of renal failure patient and the adsorbent were mixed at a volume ratio of 6: 1 and shaken at 37 ° C. for 1 hour, and β ₂ microglobulin and albumin were quantified in the plasma before and after. The RIA method was used for β ₂ microglobulin, and the BCG method was used for albumin.

The evaluation results are shown in Table-5, and the outline of the materials used is shown in Table-6.

Next, as blood compatibility evaluation, platelet permeability was evaluated. The evaluation method is described below, and the results are shown in Table-7.
Shown in

Evaluation of Platelet Passability A) Preparation of Evaluation Column First, the prepared adsorbent is packed into a cylindrical column having a diameter of 5 mmφ and a length of 10 mm while flowing a physiological saline solution under suction at a vacuum degree of 200 to 300 mmHg ( An 80 mesh polyester mesh is installed at the inlet and outlet of the column). Then, let stand for 16 hours.

B) Flow of human blood and calculation of platelet permeability Add 0.1 ml to the above evaluation column (column volume 0.2 ml).
A heparin-supplemented diet (1 unit / ml; heparin concentration) is flown with a syringe-type micropump at a speed of / min for 20 minutes. Next, the human peripheral blood (15 unit / ml; heparin concentration) was stored at room temperature (20 units).
℃) at a rate of 0.1 ml / min. Sampling of blood is performed from the column outlet with a sample bottle containing ethylenediaminetetraacetic acid = sodium, with the time point when the saline in the column is pushed out from the column outlet as 0 hour of sampling. BRECHER- within 2 hours after sampling is completed
Platelet V at the column inlet and column outlet by CRONKITE method
And the morphological change was measured.

Example 4 As a blood compatible material, a random copolymer of 2-hydroxyethyl methacrylate and diethylaminoethyl methacrylate (content of 2-hydroxyethyl was 70 mol.
l%), 2-hydroxyethyl methacrylate and N, N '
An adsorbent was obtained in the same manner as in Example 3 except that a graft copolymer with -diethyl-N- (4-vinylphenethyl) ethylenediamine (content of 2-hydroxyethyl methacrylate was 95 mol%) was used.

 The evaluation results are shown in Table-8 and Table-9.

Further, with respect to all the samples of Examples 3 to 4, the morphological changes in the platelets in the blood at the column inlet and outlet sides were observed by a microscope, but the morphological changes in the platelets at the column inlet and outlet sides were hardly observed. .

Example 5 Except that aluminum foil was used as the water-insoluble material,
In the same manner as in Example 1, an adsorbent having a 2-hydroxyethyl methacrylate polymer layer formed thereon was obtained. The aluminum foil having a size of 20 cm × 10 cm was cut into 3 mm × 3 mm before use. The contact angle of the aluminum foil was measured in the same manner as in Example 1.

Next, the adsorption experiment of β ₂ microglobulin and albumin was performed using healthy human blood. At this time, the same procedure as in Example 1 was performed except that the amount of albumin was determined by the nephelometry method.

The results are shown in Table 9-2. Before and after the treatment, β ₂ microglobulin in plasma decreased and adsorption occurred, but the concentration of albumin changed only slightly and β ₂ microglobulin was selectively adsorbed and removed.

Comparative Example 1 As in Example 3, the methyl methacrylate-divinylbenzene copolymer particles and styrene-divinylbenzene copolymer particles used in Example 3 were used as the adsorbent without coating the blood-compatible material. It evaluated by various methods. The evaluation results are shown in Tables 10 and 11.

(Effect of the invention) As is clear from the above description, the adsorbent having at least a two-layer structure of a water-insoluble material having a contact angle of 20 degrees or more and a blood-compatible polymer is an adhesive material for adhering thrombotic substances such as platelets. ,
It can be seen that β ₂ microglobulin is selectively and surprisingly efficiently adsorbed and removed without inhibiting activation and without removing useful proteins such as albumin in body fluids such as whole blood or plasma. The adsorbent of the present invention is particularly safe and easy for extracorporeal circulation treatment with whole blood because it has less adhesion and activation of thrombotic substances such as platelets and does not have safety problems such as fine particles and eluates. Can be used.

Therefore, it can be used for general usage of purifying and regenerating body fluids such as autologous blood and plasma, and adsorption of β ₂ microglobulin accumulated in body fluids in renal failure, malignant tumor, etc.,
It is effective, safe and reliable for removal.

Claims (2)

(57) [Claims] 1. A water-insoluble material having a contact angle of at least 20 degrees is coated with a blood-compatible polymer to form a layered structure of at least two layers, and β ₂ is added to the layer of the water-insoluble material.
Adsorbent for β ₂ microglobulin for body fluid purification characterized by a layered structure that allows microglobulin to reach _2. The adsorbent for β ₂ microglobulin for body fluid purification according to claim 1, wherein the blood-compatible polymer is a polymer having a nitrogen-containing basic functional group.