JPS6353827B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a device for removing substances dissolved in blood and purifying blood. More specifically, the present invention relates to a blood purification treatment device incorporating an adsorbent that can efficiently adsorb and remove autoantibodies and/or immune complexes dissolved in blood. In recent years, with the remarkable development of so-called artificial organs,
Treatment methods that perform operations such as dialysis, fractionation, and adsorption treatment on blood taken out of the body through extracorporeal circulation have been put into practical use, and the importance of such treatment methods is increasingly being recognized. It is strongly required that the device not cause any damage, and there are many factors that must be included in the equipment for this purpose. One of these is to avoid loss of protein components in the patient's blood, and in artificial kidney devices and the like, it has been avoided to contain plasma proteins in the waste fluid. However, in recent years, certain types of autoantibodies and/or immune complexes have been shown to affect the body's immune system, including cancer, immunoproliferative syndromes, rheumatoid arthritis, autoimmune diseases such as systemic lupus erythematosus, allergies, and organ transplant rejection. It is becoming clear that autoantibodies and/or immune complexes are closely related to the causes and progression of related diseases and phenomena, and plasmapheresis therapy has come to be used to remove these autoantibodies and/or immune complexes. . However, in plasma exchange therapy, there is a problem in securing plasma from healthy people to be transfused to the patient.
In addition, transfusion of healthy human plasma can cause side effects such as infection with new pathogens and serum sickness.
It is considered desirable to further purify one's own plasma before transfusion, and the development of a device for this purpose has been desired. Conventionally, adsorbents that can be used for this purpose include adsorbents in which protein A is immobilized on an insoluble carrier, and porous acrylic ester resins (e.g.
Cation exchangers such as XAD-7 (manufactured by Rohm and Haas) or carboxymethyl cellulose have been proposed. However, although protein A is immobilized on an insoluble carrier and has the ability to specifically adsorb autoantibodies and/or immune complexes, it is difficult to secure raw materials because it is a physiologically active protein derived from Staphylococcus aureus. It has the disadvantage of high product cost, and because its activity is unstable, it has the disadvantage of being easily deactivated due to handling during immobilization, storage after immobilization, etc., and it is also difficult to use it as a blood purification treatment device. In this case, there was a risk that the elution of protein A would cause harmful effects, and in addition, there was a problem in that it was difficult to sterilize while suppressing deactivation. In addition, acrylic acid ester-based porous resins and carboxymethyl cellulose have the disadvantages of low adsorption capacity and low adsorption specificity.Furthermore, they also adsorb albumin in the blood, causing abnormal osmotic pressure. It was impossible to use it as a safe treatment device. In view of the current situation, the present inventors have solved these shortcomings and developed a material that can be generally used, particularly adsorbs autoantibodies and/or immune complexes with high activity, has high adsorption specificity, is stable, The present invention was achieved as a result of intensive research aimed at providing an adsorbent for blood purification treatment that is safe and can be easily sterilized. The present inventors bonded various compounds to insoluble carriers and evaluated their binding activity toward autoantibodies and immune complexes, and found that, surprisingly, they contained hydrophobic organic compounds and/or hydrophobic compounds. An adsorption device consisting of an adsorbent made of an insoluble carrier bound to a polymer with a molecular weight of 1000 or less is packed into a container with a fluid inlet/outlet, which hardly adsorbs albumin and has extremely high activity and specificity. The invention is based on the discovery that autoantibodies and/or immune complexes are adsorbed to
A patent application has already been filed. However, in order to efficiently remove autoantibodies and/or immune complexes from blood, an adsorption device is filled with particulate carriers having a fine particle size in order to increase the surface area of insoluble carriers in the device. When blood flows into an adsorption device that is densely packed with fibrous carriers, the pressure loss becomes extremely large due to the adhesion of blood cells and other causes, and the blood stops flowing in a very short time. .
Therefore, it has not been possible to efficiently remove autoantibodies and/or immune complexes. Therefore, in order to improve this point, the present inventors
As a result of further investigation, it was discovered that autoantibodies and/or immune complexes could be efficiently adsorbed and removed without damaging the blood by purifying plasma with an adsorption device, and the present invention was completed and the desired results were achieved. I have reached my goal. The present invention provides a blood distribution system path including a plasma separation device and a blood-plasma mixing device between a blood introduction section and a purified blood output section, and separation by the plasma separation device connected to the system path. and a plasma reflux system through which the purified plasma flows into the mixing device via a plasma purification device, and the purification device includes a hydrophobic carrier having a solubility in physiological saline of 100 mmol/dl or less at 25° C. as an insoluble carrier. A device comprising an adsorbent in which 0.1 to 30 mg of an oligomer containing a hydrophobic compound and/or a hydrophobic compound with a molecular weight of 1000 or less is bound per 1 ml of an insoluble carrier is filled and housed in a container having an inlet and outlet for plasma. By doing so, the blood that entered from the blood introduction part was separated into concentrated blood and plasma using a plasma separator, and autoantibodies and/or immune complexes were removed from the separated plasma by adsorption using a plasma purification device. This is a blood purification treatment device in which the blood is mixed with blood later in a blood-plasma mixing device. The substances targeted for adsorption and removal in the present invention are autoantibodies and/or immune complexes.
Immunization with autoantibodies such as DNA antibodies, anti-lymphocyte antibodies, anti-erythrocyte antibodies, anti-platelet antibodies, acetylcholine receptor antibodies, serum demyelinating antibodies, anti-thyroglobulin antibodies, anti-microsomal antibodies, anti-colon antibodies, and antigens and antigen-like substances It is a complex. In the present invention, the blood introduction section refers to a section for introducing blood into a processing device using a blood sampling device such as a shunt, a syringe needle, other conduits, and a pump if necessary, and a purified blood outlet section. refers to the part where the blood purified by the blood processing device is led out from the blood processing device using a conduit, a tube, a blood pressure control valve, a shunt, an intravenous drip, etc. as necessary. The blood processing device of the present invention is characterized in that blood-
A blood circulation system mainly consisting of a plasma mixing device and a plasma separating device, and a plasma reflux system mainly consisting of a plasma purification device that adsorbs and purifies plasma separated by the plasma separation device of this blood circulation system. The first feature is that the two elements are connected, but valves, valves,
They are connected via a pump and a filter, and configured to allow blood and/or plasma to flow in a circulatory manner. Hereinafter, the present invention will be explained in more detail with reference to the accompanying drawings. FIG. 1 is an explanatory diagram showing one example of the basic configuration of the blood purification treatment device of the present invention. Now, to explain the device of the present invention according to the flow of blood, blood A is introduced from the blood inlet 1 of the blood introduction section, and is transported to the plasma separation device 3 by a pump 2 such as a roller pump as necessary. Ru. For direct introduction of blood, a shunt (not shown) is typically used. The plasma B separated by the plasma separator 3 is transferred to a pump 7 such as a roller pump as necessary.
The plasma is sent to the plasma purification device 4, where autoantibodies and/or immune complexes present in the plasma are removed. The purified plasma is sent to the plasma-plasma mixing device 5, where it is mixed with concentrated blood drawn from the plasma separation device, and drawn out from the blood drawing section 6. FIG. 2 is an explanatory diagram showing another example of the basic configuration of the blood purification treatment device of the present invention. Now, the device of the present invention will be explained according to the flow of blood.
Blood A is introduced from blood inlet 1 of the blood introduction part,
If necessary, it is transported to a blood-plasma mixing device 5 by a pump 2, such as a roller pump.
For direct introduction of blood, a shunt (not shown) is usually used. The blood mixed with plasma B in the mixing device 5 is sent to the plasma separation device 3, where it is separated into plasma B and purified blood. The separated purified blood is drawn out from the blood outlet 6, and the separated plasma B is sent to the plasma purification device 4 by a pump 7 such as a roller pump as required, where autoantibodies and /or immune complexes are removed. The purified plasma is sent to the blood-plasma mixing device 5, where it is mixed with blood A introduced from the blood inlet. Examples in which the basic configurations shown in FIGS. 1 and 2 are combined are also included in the present invention. As shown in FIG. 3, a part of the plasma C that has been adsorbed is sent to a plasma mixer 9 by a pump 8 such as a roller pump, mixed with fresh plasma B, and then transferred to a plasma purifier 4 where autoantibodies are detected. The present invention also includes a circulating reflux method for adsorbing and/or removing immune complexes. The plasma purification device used in the present invention includes a plasma inlet and an outlet, and between the inlet and the outlet,
It has an adsorbent layer filled with an adsorbent formed by bonding a hydrophobic organic compound and/or a polymer containing the compound to an insoluble carrier. FIG. 4 is a sectional view showing an example of the plasma purification device of the present invention.
10 is a plasma inlet, 11 is a plasma outlet, 12 is an adsorbent layer, 13, 13' is a filter, 14, 1
4' is a packing that also serves as a filter retaining ring, 1
5, 15' and 15'' indicate purification device cylinders. The adsorbent layer 12 can also be used fixed with a mesh made of polyester or the like. The adsorbent layer 12 can be filled with the adsorbent alone. It may also be mixed or laminated with other adsorbents.The appropriate volume of the adsorbent layer 12 is about 50 to 400 ml.The insoluble carrier used in the present invention may be either a hydrophilic carrier or a hydrophobic carrier. However, when a hydrophobic carrier is used, non-specific adsorption of albumin to the carrier sometimes occurs, so a hydrophilic carrier gives preferable results.The shape of the insoluble carrier may be particulate, fibrous, Any known shape such as hollow fiber shape or membrane shape can be used, but the retained amount of the hydrophobic organic compound and/or the polymer containing the compound,
From the viewpoint of ease of handling as an adsorbent, particles and fibers are preferred. As a particulate carrier, the average particle size is 25μ or more.
2500μ, more preferably 40μ to 1000μ, still more preferably 50μ to 500μ can be used. The average particle size is determined by classifying in running water using a sieve specified in JIS-Z-8801.
The intermediate value between the upper limit particle size and the lower limit particle size of each class is defined as the particle size of each class, and the average particle size is calculated as the weight average.
Further, the particle shape is preferably spherical, but is not particularly limited. If the average particle size is 2500μ or more, the adsorption amount and adsorption rate of autoantibodies and/or immune complexes will decrease, and if it is less than 25μ, the pressure loss will become too large, which is not preferable. Particulate carriers that can be used include agarose-based, dextran-based, cellulose-based, polyacrylamide-based, glass-based, and activated carbon-based carriers, but particularly hydrophilic porous polymer particles with a gel structure give good results. . Since porous polymer particles can immobilize a large amount of hydrophobic organic compounds and/or polymers containing the compounds on their surfaces, they have an average particle diameter of 300 mm.
Å to 9000Å, more preferably 1000Å to
A thickness in the range of 6000 Å is desirable. For the polymer composition, known polymers that can have a porous structure, such as polyamides, polyesters, polyurethanes, and vinyl compound polymers, can be used, but in particular, porous vinyl compounds made hydrophilic with hydrophilic monomers can be used. Polymeric particles give favorable results. Preferably, the porous structure has an average pore diameter in the range of 300 Å to 9000 Å; however, if the average pore diameter is too small, the amount of autoantibodies and/or immune complexes adsorbed is small; if it is too large,
This is not practical because the strength of the polymer particles decreases and the surface area decreases. The average pore diameter was measured using a mercury intrusion porosimeter. In this method, mercury is injected into a porous material, and the pore volume is determined from the amount of mercury infiltrated, and the pore diameter is determined from the pressure required for intrusion, and pores of 40 Å or more can be measured. A pore in the present invention is defined as a pore communicating from the surface with a pore diameter of 40 Å or more. The average pore diameter is dV/d log, where r is the pore diameter and v is the cumulative pore volume measured with a porosimeter.
Let this be the value of r when the value of r is maximum. When using a fibrous carrier, the fiber diameter is
0.02 denier to 10 denier, more preferably
It is preferable to use one in the range of 0.1 denier to 5 denier. If the fiber diameter is too large, the adsorption amount and adsorption rate of the autoantibody-containing substance will decrease, and if it is too small, the pressure loss will become too high, which is not preferable. As the fibrous carrier, known fibers such as regenerated cellulose fibers, nylon, acrylic, and polyester can be used without exception. Any known method can be used to immobilize the hydrophobic compound on the surface of the insoluble carrier, such as covalent bonding, ionic bonding, physical adsorption, embedding, or precipitation insolubilization on the polymer surface. Therefore, it is preferable to use it after being fixed and insolubilized by covalent bonding. Therefore, it is possible to use an immobilized enzyme, a known method for activating an insoluble carrier used in affinity chromatography, and a method for bonding the carrier with a hydrophobic organic compound. In addition, if necessary, a molecule (spacer) of any length may be placed between the insoluble carrier and the hydrophobic organic compound.
It is also possible to introduce and use it. For example, the hydroxyl group of agarose and the isocyanate group on one side of hexamethylene diisocyanate are reacted and bonded, and the remaining isocyanate group is reacted with the amino group, hydroxyl group, sulfhydryl group, carboxylyl group, etc. of a hydrophobic organic compound. It can be implemented as if it were combined. As for the spacer length, a range from no spacer to 20 atoms in the spacer gives particularly preferable results. The amount of hydrophobic organic compound bound to the insoluble carrier in the present invention ranges from 0.1 mg to 30 mg, more preferably from 0.5 mg to 15 mg per ml of insoluble carrier. If the retained amount is less than 0.1 mg/ml, the adsorbed amount of autoantibodies and/or immune complexes will be extremely reduced, and if it exceeds 30 mg/ml, the adsorption specificity will be decreased, which is not preferable. The hydrophobic compound used in the present invention refers to a compound having a solubility in physiological saline of 100 mmol/dl or less (at 25°C), more preferably 30 mmol/dl or less.
A compound having a solubility in physiological saline of more than 100 mmol/dl becomes too hydrophilic and has a reduced affinity for autoantibodies and/or immune complexes, resulting in an extremely reduced adsorption capacity. Furthermore, an affinity for albumin, which is more hydrophilic, is generated, and albumin is also non-specifically adsorbed, which is undesirable. Among hydrophobic compounds, compounds having at least one aromatic ring give particularly favorable results. Aromatic ring refers to a cyclic compound having aromatic properties, and any of them can be usefully used, including benzene-based aromatic rings such as benzene, naphthalene, and phenanthrene, pyridine, quinoline, acridine, isoquinoline, and phenanthridine. nitrogen-containing 6-membered rings such as indole, carbazole, isoindole, indolizine, porphyrin, 2,3,2′,
Nitrogen-containing 5-membered rings such as 3'-pyrrolopyrrole, polyvalent nitrogen-containing 6-membered rings such as pyridazine, pyrimidine, sym-triazine, sym-tetrazine, quinazoline, 1,5-naphthyridine, buteridine, phenazine, pyrazole, iminazole, Polyvalent nitrogen-containing five-membered rings such as 1,2,4-triazole, 1,2,3-triazole, tetrazole, benziminazole, imidazole, purine, norharman ring, perimidine ring, benzofuran, isobenzofuran, dibenzofuran, etc. Oxygen aromatic ring, sulfur-containing aromatic ring such as benzothiophene, thienothiophene, thievine, oxazole, isoxazole, 1,
Aromatic rings such as oxygen-containing heteroaromatic rings such as 2,5-oxadiazole and benzoxazole, sulfur-containing heteroaromatic rings such as thiazole, isothiazole, 1,3,4-thiadiazole and benzothiazole, and derivatives thereof. A hydrophobic low-molecular-weight organic compound having at least one of these gives preferable results. Among these, compounds containing an indole ring such as tryptamine give particularly favorable results. This can be interpreted as a result of the hydrophobicity and molecular rigidity of the compound effectively interacting with the autoantibody and/or immune complex. Furthermore, as a result of intensive research in search of inexpensive hydrophobic compounds that can be used more safely and practically, the present inventors have discovered that hydrophobic amino acids and their derivatives can be used to effectively and specifically immunize autoantibodies and/or antibodies. It was discovered that the complex can be removed by adsorption. What are hydrophobic amino acids and their derivatives?
Tanford Nozaki〔J.Am.Chem.Soc. 184 , 4240
(1962), J.Biol.Chem., 246 , 2211 (1971)] [Tanford, Nozaki (Journal of American Chemical Society, 184 , 4240 (1962),
Journal of Biological Chemistry, 246 , 2211 (1971)] Amino acids and their derivatives with a concentration of 1500 cal/mol or more and compounds with a solubility in physiological saline of 100 mmol/dl or less means. Examples include lysine, valine, leucine, tyrosine, phenylalanine, isoleucine, tryptophan and derivatives thereof. Among these hydrophobic amino acids and their derivatives, tryptophan and its derivatives give particularly good results. Moreover, the amino acid can be used without any particular limitation on the 1 and d conformations. Among hydrophobic compounds, non-dissociable, zwitterionic, and cationic compounds adsorb autoantibodies and/or immune complexes more selectively when bound to insoluble carriers than anionic compounds. preferable. Anionic compounds have an affinity for albumin, contrary to what might be expected given that albumin molecules are more electronegative than autoantibodies and/or immune complexes, and the adsorption amount of globulin compounds is reduced. did. For example, phenylalanine methyl ester, phenylalanine, and tyrosine do not differ greatly in their hydrophobicity, but when their amino groups were covalently bonded to an insoluble carrier and their autoantibody adsorption ability was evaluated, phenylalanine methyl ester > Phenylalanine and tyrosine, and an example of this can be seen in the fact that the adsorption ability of phenylalanine and tyrosine deteriorates. Furthermore, non-aromatic ring compounds also showed similar results. In particular, a more hydrophilic compound having a sulfonic acid group as an anionic group had more affinity for albumin than autoantibodies and/or immune complexes, and acted as an albumin adsorbent. This is presumed to be due to the interaction between the charge of the compound, albumin, and the charge of the microenvironment within the molecule. In view of the above experimental results, it is believed that the mechanism of action of the present invention is based on the hydrophobic interaction force (Van der Waals force) between the hydrophobic compound bound to the insoluble carrier and the autoantibody and/or immune complex. It is also presumed that the interaction force between charges (Coulomb force) acts secondarily as a long-distance force. The polymer containing the hydrophobic compound of the present invention has a molecular weight of
It is a polymer of 1000 or less. This makes handling such as immobilization and presence after immobilization easier than with natural polymers such as protein A (molecular weight 42,000). Furthermore, even when the substance is eluted from the insoluble carrier, a polymer with a molecular weight of 1000 or less has negligible antigenicity to living organisms, is safe, and can be easily sterilized. The polymer can be obtained by copolymerizing the hydrophobic compound monomer alone or with other compounds. As the hydrophobic compound monomer, for example, a vinyl derivative of a compound containing an indole ring such as tryptamine, or a hydrophobic amino acid such as tryptophan can be used. As the plasma separation device used in the present invention, a device using a porous filtration membrane or a device using centrifugation can be used. As a plasma separation device using a porous filtration membrane,
For example, as shown in FIG. 5, a structure in which a porous filtration membrane is installed parallel to a flow path connecting an inlet and an outlet is preferable. In order to perform filtration efficiently and stably over time, it is preferable to have a structure in which the flow path is as narrow as possible, and the shape of the porous filtration membrane used can be any shape, such as a flat membrane or a hollow fiber membrane. , can be used. however,
A preferred method is to use a membrane shaped like a hollow fiber and use the hollow portion as a flow path. FIG. 5 is a sectional view showing an example of a plasma separation device, in which a blood inlet 16, a blood outlet 17, and a plasma outlet 1 are shown.
8. It has a large number of hollow fibers 19 filled inside. The ends of the hollow fibers 19 are coated with adhesives 20, 20'.
A nozzle 2 having a blood inlet 16 and a blood outlet 17 is formed near the solidified part.
1 and 21 are tightened by caps 23 and 23' that screw into the threaded portion of the container body 22. The space surrounded by the outer wall of the hollow fibers and the main body 22 is a space where separated plasma is temporarily stored. This is a structure in which blood flows through the hollow part of the hollow fiber, and plasma moves outward from the hollow part of the hollow fiber. Conversely, a plasma separator having a structure in which blood flows outside the hollow fiber and plasma moves into the hollow part can also be used in the present invention. The porous membrane for plasma separation used in this device is a membrane that allows substantially all of the autoantibodies and/or immune complexes in the plasma to pass through, without allowing blood cell components to pass through. , more preferably has an average pore diameter of 0.08 to 0.8 μ, has a structure in which pores penetrating the front and back surfaces of the membrane are distributed almost uniformly on the surface of the membrane, and has a structure in which pores penetrating the front and back surfaces of the membrane are distributed almost uniformly on the surface of the membrane, and 3/m ² · hr · mmHg.
Those having the above hydrophobicity are preferably used. In order to stably obtain plasma without damaging blood cells using the plasma separator using the membrane described above, the fifth step must be taken.
In the separator shown in the figure, it is necessary to control the pressure difference between the blood inlet 16 and the plasma outlet 18 to between 10 and 60 mmHg. Materials for the selectively permeable membrane that can be used in the present invention include ethylene, propylene, polycarbonate,
Polyvinyl alcohol, polysulfone, cellulose acetate, polymethyl methacrylate, etc.
It can be used regardless of its material. A plasma separation device using centrifugation can be used regardless of its structure as long as it can continuously introduce blood from one side and separate concentrated blood cells and plasma from the other side. Although it can be used, a continuous centrifuge without sliding parts is particularly preferably used. The mixing device used in the present invention is for mixing purified plasma and concentrated blood or freshly separated plasma, or purified plasma and freshly purified plasma. Although it is desirable that the mixing be completed by stirring or the like, a device such as a Y-shaped connector for merging two fluids can also sufficiently achieve the purpose. In carrying out the present invention, FIGS.
A buffer tank may be further provided in the circuit shown in the figure, or a plasma separation device or a plasma filtration device may be separately inserted to form a multistage system. Next, the present invention will be described in more detail with reference to Examples. Example 1 The blood purification device shown in FIG. 1 was assembled using a plasma separator having the structure shown in FIG. 5 and a plasma purification device having the structure shown in FIG. 4. Cellulose acetate hollow fiber (outer diameter
450μ, inner diameter 300μ, effective length 115mm, average pore diameter 0.3μ)
A plasma separation device was created using 100 bottles. As a plasma purification device, CNBr activated Ceph Arrows
4B (manufactured by Pharmacia, Sweden, average particle size
An adsorbent made by bonding tryptophan methyl ester to (260μ) using a conventional method and blocking excess active groups with ethanolamine.
It was created by filling 10ml. Using this device, blood treatment was performed for 2 hours using 50 ml of blood from a patient suffering from chronic rheumatoid arthritis. Before treatment, albumin concentration 3.4
g/dl, γ-globulin 1.8 g/dl, and rheumatoid factor (negative dilution factor) 1240 times, but after treatment, the blood decreased to 3.2 g/dl, 1.1 g/dl, and 360 times, respectively. At that time, immune complexes were reduced by 69%. Example 2 Blood was processed in the same manner as in Example 1, except that blood from a patient with systemic lupus erythematosus was used. Before treatment, albumin concentration 3.3
g/dl, γ-globulin 1.9 g/dl, antinuclear antibody 640
Blood that was twice as hot was 3.1g/dl after treatment, and 1.2g/dl.
g/dl, respectively, decreased by 320 times. At that time, immune complexes decreased by 67%. As explained in detail above, by using the device of the present invention, it becomes possible for the first time to remove harmful autoantibodies and/or immune complexes from the blood extremely efficiently without causing damage to blood cell components. , is extremely useful in treating collagen diseases such as chronic rheumatism patients. Examples 3 to 7, Comparative Examples 1 to 3 Tyrosine (Example 3) as a hydrophobic organic compound,
Tryptophan (Example 4), phenylalanine (Example 5), histidine (Example 6), and valine (Example 7) were used, and DL-threonine (Comparative Example 1) and hydroxyproline were used as hydrophilic organic compounds. (Comparative Example 2) and Proline (Comparative Example 3), an adsorbent was produced in the same manner as in Example 1.
The same blood treatment as in Example 1 was carried out using the same apparatus as in Example 1 except that the volume of blood from a patient with chronic rheumatoid arthritis was changed to 15 ml. The results are shown in Table 1. These results show that the blood purification treatment device of the present invention, which uses an adsorbent bound to a hydrophobic organic compound with a solubility in physiological saline of 100 mmol/dl or less at 25°C, can efficiently remove rheumatoid factors and immune complexes. It can be seen that it can be removed by adsorption. 【table】

[Brief explanation of the drawing]

FIG. 1 is an explanatory diagram showing one example of the basic configuration of the blood purification treatment device of the present invention, FIGS. 2 and 3 are explanatory diagrams showing another example, and FIG. FIG. 5 is a sectional view showing an example of a plasma separation device. DESCRIPTION OF SYMBOLS 1...Blood introduction part, 2...Pump, 3...Plasma separation device, 4...Plasma purification device, 5...Blood/plasma mixing device, 6...Blood extraction part, 7...Pump,
8... Pump, 9... Plasma mixing device, 10... Plasma inlet, 11... Plasma outlet, 12... Adsorbent layer, 13, 13'... Filter, 14, 14'...
...Filter retaining ring combined packing, 15,
15', 15''...Purifier cylinder, 16...Blood inlet, 17...Blood outlet, 18...Plasma outlet, 19
...Hollow fiber, 20,20'...Adhesive, 21,
21'... Nozzle, 22... Container body, 23,2
3'...cap.

Claims (1)

[Scope of Claims] 1. A blood distribution system path including a plasma separation device and a blood-plasma mixing device between the blood introduction section and the purified blood output section, and the plasma separation system connected to the system path. and a plasma reflux system for causing plasma separated by the device to flow into the mixing device via a plasma purification device, and the purification device has an insoluble carrier having a solubility in physiological saline of 100 mmol/dl or less at 25°C. An adsorbent in which 0.1 to 30 mg of a hydrophobic compound and/or an oligomer containing the hydrophobic compound with a molecular weight of 1000 or less is bound per 1 ml of the insoluble carrier is filled and stored in a container having an inlet and outlet for plasma. A blood purification treatment device that adsorbs and removes autoantibodies and/or immune complexes from plasma. 2. The plasma separator has a blood inlet, a concentrated blood outlet, a porous membrane that allows plasma components to pass through but not blood cell components, and a space that can temporarily store the separated plasma, and the blood inlet. 2. The blood purification treatment device according to claim 1, wherein the blood outlet is a device having a plasma outlet separated by the porous membrane. 3. The blood purification treatment device according to claim 2, which is a plasma separation device using a porous membrane in which pores having an average pore diameter of 0.05 to 2.0 μ are uniformly distributed on the membrane surface. 4. The blood purification treatment according to claim 1, wherein the plasma separator is a centrifugal separator that can continuously introduce blood from one side and separate concentrated blood cells and plasma from the other side. Device.