JPH025098B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION [Technical Field] The present invention relates to a novel rheumatoid factor adsorbent and a rheumatoid factor adsorption device using the adsorbent. Although plate plasma exchange is known to be effective in treating rheumatic diseases, it is difficult to obtain a large amount of fresh frozen plasma necessary for plasma exchange, and there is also a risk of hepatitis. Therefore, treatment methods are being developed that selectively remove rheumatoid factors from autologous plasma and reuse the purified autologous plasma. The rheumatoid factor adsorbent of the present invention is used for such treatment methods. [Prior Art and Problems] All conventional rheumatoid factor adsorbents have used materials in which a substance (ligand) that specifically binds to rheumatoid factor is immobilized on a water-insoluble carrier. Such an adsorbent requires a step of immobilizing the ligand on the carrier, and also has the disadvantage that the ligand is not necessarily uniformly distributed on the carrier. Furthermore, during use of the adsorbent, there is a risk that a portion of the ligand may be separated and mixed into the patient's body fluid, which can cause a serious situation if the ligand is a harmful substance. For example, as a rheumatoid factor adsorbent, human immunoglobulin G (human-IgG) is aggregated with heat or an organic solvent (e.g. dimethyl sulfoxide),
One in which aggregates are immobilized on a carrier is known [Artificial Organs Vol. 11, No. 1, pp. 66-69 (1982)]. This adsorbent has the advantages of selectively and highly adsorbing rheumatoid factors, fast adsorption rate, high stability of adsorption activity, and ease of handling. However, on the other hand, the aggregates are human-
Because IgG is simply aggregated physically by heat or organic solvent treatment, the binding force between molecules is not very strong, and there is a risk that some of the aggregates may detach from the carrier and elute into the plasma. If the aggregate were to elute into the patient's plasma, it would be extremely dangerous due to its antigenicity. Therefore, it has been desired to develop an adsorbent for rheumatoid arthritis in which there is no fear that the ligand will peel off from the carrier. OBJECTS OF THE INVENTION An object of the present invention is to provide a rheumatoid factor adsorbent that selectively and highly adsorbs rheumatoid factor in the plasma of rheumatoid patients and is free from the risk of the ligand desorbing from the carrier. A further object of the present invention is to provide a rheumatoid factor adsorbent that does not require a step of immobilizing a ligand on a carrier. A further object of the present invention is to provide a rheumatoid factor adsorption device using the above rheumatoid factor adsorbent. According to the present invention, there are provided adsorbents and adsorption devices for rheumatoid factors as described in the following items. (1) A rheumatoid factor adsorbent made of a copolymer of vinyl acetate, a vinyl compound with an aromatic ring, and a crosslinking agent. (2) The rheumatoid factor adsorbent according to item 1, wherein the vinyl compound having an aromatic ring is any one of styrene, vinyl carbazole, or allyl phenyl ether, and the crosslinking agent is an ethylene crosslinking agent having a triazine ring. . (3) The rheumatoid factor adsorbent according to item 2, wherein the vinyl compound having an aromatic ring is 9-vinylcarbazole, and the crosslinking agent is triallyl isocyanurate. (4) a rheumatoid factor adsorbent comprising a container having a fluid inlet and outlet, and a copolymer of a hydrophilic vinyl compound, an aromatic ring-containing vinyl compound, and a crosslinking agent filled in the container; A rheumatoid factor adsorption device comprising: means for preventing outflow of the adsorbent provided in the container. (5) The rheumatoid factor adsorption device according to item 4, wherein the device is filled with purified water and sterilized by autoclaving. (6) The rheumatoid factor adsorption device according to item 4, wherein the outflow prevention means is a filter provided in the container. DETAILED DESCRIPTION OF THE INVENTION In order to achieve the above object, the present invention comprises a rheumatoid factor adsorbent comprising a copolymer of vinyl acetate, a vinyl compound having an aromatic ring, and a crosslinking agent. Furthermore, the vinyl compound referred to herein may be one having a group of |C|=|C| and causing copolymerization. Furthermore, the present invention comprises a rheumatoid factor adsorption device in which the above-mentioned adsorbent is housed in a container having a fluid inlet/outlet. The adsorbent of the present invention is a copolymer of vinyl acetate, a vinyl compound having an aromatic ring, and a crosslinking agent. Examples of vinyl compounds having an aromatic ring include styrene, vinyl carbazole, allyl phenyl ether, 1-vinylphthalene, 2-vinylnaphthalene and the like are preferred. The crosslinking agent is preferably a styrene crosslinking agent having a triazine ring, such as triallyl isocyanurate or triallyl cyanurate. These vinyl compound monomers are subjected to a polymerization reaction. For example, vinyl acetate and a crosslinking agent,
An organic solvent solution in which a vinyl compound having an aromatic ring is dissolved in an appropriate organic solvent (for example, ethyl acetate) and an aqueous solution containing polyvinyl alcohol as a dispersant are mixed and suspended, and the suspension is heated to 60°C. ~80
Incubate for 12-18 hours at °C. Since the polymer thus obtained is in the form of particles, it can be used as an adsorbent as it is without further molding. In that case, for the purpose of the present invention, the particle diameter should be between 50 and 3000μ.
m, particularly preferably 100 to 500 μm. Rheumatoid factor is IgG with a molecular weight of 150,000 to IgM with a molecular weight of 1 million.
Therefore, the adsorption limit of the polymer is preferably a molecular weight of 150,000 to 10,000,000, particularly 1,000,000 to 3,000,000. In the copolymer of the present invention, the vinyl acetate component plays the role of a carrier, and the vinyl component having an aromatic ring plays the role of a ligand. Preferably, the vinyl acetate component is greater than the vinyl component having an aromatic ring. The copolymer thus formed has hydrophilic properties and island-like hydrophobic groups, which is a favorable state for the adsorption of rheumatoid factors. The adsorbent of the present invention can be used in any known shape such as particulate, fibrous, hollow fiber, or membrane, but from the viewpoint of blood and plasma permeability, ease of handling during adsorbent preparation, etc. Particulate carriers are particularly preferably used. Furthermore, it is preferably particulate and porous. A method for manufacturing a porous body is to mix a pore-forming substance that will be extracted later and form a porous part during molding of the copolymer, and then wash it with a good medium for the pore-forming substance. You can get a quality body. As the gap-forming substance, polymers such as polyvinyl acetate can be used. The holes formed are preferably through holes with a diameter of 300 to 3000 Å. More preferably, the pore size is
It is 400 to 1000 Å. Next, the apparatus of the present invention will be explained with reference to the accompanying drawings. FIG. 1 is a sectional view showing an example of the device of the present invention. This device consists of a container 1 having an inlet 4 and an outlet 5 at both ends, an adsorbent 2 housed inside the container, and an inlet 4.
Filters 3 and 3' are provided at the outlet 5 to prevent the adsorbent 2 from flowing out. The filters 3, 3' not only prevent the adsorbent from flowing out, but also prevent its fragments from entering the body fluid and flowing into the body. The body fluid is introduced through the body fluid inlet 4, treated with the adsorbent 2, and then led out through the body fluid outlet 5. The adsorbent is retained in the container by filters 3, 3'. For convenience of use, the adsorption device of the present invention is desirably filled with purified water such as distilled water or physiological saline and sterilized in an autoclave to produce a product. FIG. 2 is a schematic diagram showing an example of blood purification treatment using the adsorption device of the present invention. Blood is introduced through the body fluid inlet 6 and supplied to the plasma separator 8 through the pump 7, where it is separated into blood cells and plasma. The separated plasma is supplied to the adsorption container 1 through the pump 7', and after being adsorbed, it is mixed with blood cells in the plasma/blood cell mixing device 9 and then sent to the blood outlet port 10.
It is derived from When the device of the present invention is used for extracorporeal circulation, there are roughly two methods as follows. One method is to separate blood taken from the body into plasma components and blood cell components using a centrifuge or a membrane or hollow fiber plasma separator, and then pass the plasma components through the device for purification. There is a method in which the blood is then returned to the body together with blood cell components, and another method is to directly pass the blood taken out from the body through the device and purify it. The method for passing body fluids may be continuous or intermittent depending on clinical needs or the installation status of the equipment. Next, the present invention will be explained in more detail with reference to Examples. Example 1 Triallyl isocyanurate purified by distillation 6.4
g, an organic phase consisting of 10 g of vinyl acetate and 1.6 g of 9-vinylcarbazole dissolved in 40 g of ethyl acetate, to which 0.75 g of polyvinyl acetate and 0.36 g of α,α′-azobisbutyronitrile were added;
Polyvinyl alcohol (saponification degree 88%, polymerization degree
Suspension polymerization was carried out using 40 ml of an aqueous phase containing 0.4 g of 1700) dissolved therein. Polymerization reaction at 65℃
After reacting for 12 hours, the temperature inside the system was raised to 75°C, and the reaction was continued for an additional 2 hours. After the reaction was completed, the remaining amount of the raw material was examined by TLC and UV specific absorption, and no raw material was detected, indicating that the reaction had progressed to approximately 100%. Wash the generated gel thoroughly with water and acetone,
The above polyvinyl acetate was extracted to obtain a porous gel. The carbazole group introduced into the gel is
It was 500 μmol/g resin. The average particle size of the resulting polymer was 150 μm. The thus obtained polymer was examined for rheumatoid factor adsorption ability, albumin and γ-globulin adsorption ability. Rheumatoid factor adsorption capacity was determined by adding 3 ml of rheumatoid patient plasma salting-out reusable solution to 300 mg of polymer gel, incubating with shaking at 37°C for 2 hours, and then measuring the rheumatoid factor concentration in the solution by latex agglutination reaction (dilution method). It was determined by measuring. The adsorption ability of albumin and γ-globulin is determined by gel
300mg of 10mM phosphate buffer (PH) containing 1mg/ml each of human albumin and human γ-globulin.
7.3) After adding 3 ml and incubating with shaking at 37°C for 2 hours, the decrease in the peaks of albumin and γ-globulin was determined by high performance liquid chromatography, and the adsorption rate was calculated. The results are shown in Table 1. Example 2 Triallyl isocyanurate purified by distillation 7.22
g, vinyl acetate 10g, allyl phenyl ether
1.30g, α,α′-azobisbutyronitrile 0.38g,
0.75 g of polyvinyl acetate and 20 g of ethyl acetate were dissolved in 15 g of heptane. Add 35 ml of water containing 1 W% polyvinyl alcohol to this organic phase, and
Time suspension polymerization was carried out. At this point, the reaction solution was subjected to gas chromatography, but no residual monomer was observed. The average particle size of the gel produced was 80 μm. The generated gel was thoroughly washed with water and acetone to obtain a porous gel. The rheumatoid factor adsorption capacity, albumin and γ-globulin adsorption capacity of the obtained polymer were determined by the same method as in Example 1. The results are shown in Table 1.

[Table] It is clear from Table 1 that the adsorbent of the present invention hardly adsorbs albumin or γ-globulin, but specifically adsorbs rheumatoid factor. Effects of the Invention The rheumatoid factor adsorbent of the present invention is made of a copolymer of vinyl acetate, a vinyl compound having an aromatic ring, and a crosslinking agent, and contains the vinyl compound having an aromatic ring, which is a ligand, as a component of the polymer. are doing. Therefore, in the copolymer described above, the carrier and the ligand are integrated, and unlike conventional adsorbents, there is no need for a step of fixing the ligand to the carrier. Furthermore, since the ligand of the present invention is a constituent component of a polymer, there is no risk of it peeling off during use. Furthermore, since the adsorbent of the present invention selectively adsorbs rheumatoid factors, it can be safely used for the treatment of rheumatism. Furthermore, according to the device of the present invention, rheumatoid factors can be easily removed.

[Brief explanation of drawings]

FIG. 1 is a sectional view showing an example of the adsorption device of the present invention. FIG. 2 is a schematic diagram showing an example of blood purification treatment using the adsorption device of the present invention. 1... Container, 2... Adsorbent, 3, 3'... Filter, 4... Inlet, 5... Outlet, 6... Blood inlet, 7, 7... Pump, 8... Plasma separation device,
9...Blood cell mixing device, 10...Blood outlet.

Claims (1)

[Scope of Claims] 1. A rheumatoid factor adsorbent comprising a copolymer of vinyl acetate, a vinyl compound having an aromatic ring, and a crosslinking agent. 2. The rheumatoid factor according to claim 1, wherein the vinyl compound having an aromatic ring is any one of styrene, vinyl carbazole, or allyl phenyl ether, and the crosslinking agent is an ethylene crosslinking agent having a triazine ring. adsorbent. 3. The rheumatoid factor adsorbent according to claim 2, wherein the vinyl compound having an aromatic ring is 9-vinylcarbazole, and the crosslinking agent is triallyl isocyanurate. 4. A container having a fluid inlet/outlet, a rheumatoid factor adsorbent made of a copolymer of vinyl acetate, a vinyl compound having an aromatic ring, and a crosslinking agent filled in the container, and a rheumatoid factor adsorbent filled in the container. A rheumatoid factor adsorption device comprising means for preventing outflow of the adsorbent. 5. The rheumatoid factor adsorption device according to claim 4, wherein the device is filled with purified water and sterilized in an autoclave. 6. The rheumatoid factor adsorption device according to claim 4, wherein the outflow prevention means is a filter provided in the container.