JP5332230B2 - Blood processing column - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood treatment column, filling a plasma separation material and a selective adsorption material in the same column, and improving the adsorption efficiency by separating albumin, which decreases the adsorption efficiency of elimination target substance, from blood to be treated. <P>SOLUTION: In this blood treatment column, albumin lowering the adsorption efficiency is eliminated by plasma separation materials 4, 6, 8 made of dextran with a molecular weight of 67,000 and having a hollow fiber form whose sieve coefficient is under 0.3, and further the same column is filled with the above materials and the selective adsorption materials 5, 7, 9. It is considered that an elimination target substance is efficiently eliminated to obtain an improving effect for a morbid state. The same column is filled with the plasma separation material and the selective adsorption material, whereby blood purification can be performed for a patient having unstable circulation kinetics as well as a premature baby and an infant having a small quantity of blood circulated. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a blood processing column used in the medical field, and more particularly to a blood processing column in which a plasma separation material and a selective adsorption material are packed in the same column.

Conventionally, the pathological condition, sepsis, septic shock, acute respiratory distress syndrome (Acute respiratory distress syndrome) acute lung disorder (Abbreviated as SIRS) concept, systemic inflammatory response syndrome (Acute respiratory disorder syndrome) injury), severe acute pancreatitis, cholangitis, psoriasis, systemic lupus erythematosus, Lyme disease, Kawasaki disease, rheumatoid arthritis, collagen disease, ulcerative colitis, Crohn's disease, MPO-ANCA associated nephritis, rapidly progressive glomerulonephritis, In endometriosis, intrauterine infection, and periventricular leukomalacia, therapeutic effects by reducing inflammatory cytokines and anti-inflammatory cytokines in blood have been shown. In addition, there is a treatment method for reducing blood bilirubin in jaundice that develops due to the presence of excess bilirubin in the blood, especially in newborn jaundice. One of the treatment methods for removing these pathogenic substances from the blood is blood purification therapy. As a conventional blood purification therapy, blood adsorption is performed by removing blood by directly passing the blood through a selective adsorption column. (Direct Hemofusion) or a plasma separation column, plasma is separated from whole blood, and the resulting plasma is further subjected to secondary filtration, a double filtration plasma separation exchange method using a plasma fractionation column (Double filtration plasmasphere), There is a technique for purifying blood using so-called two columns using a plasma exchange column and using a selective plasma component adsorbent after separating plasma from whole blood. However, by using two columns, it is circulated outside the body when used in premature infants, newborn infants and infants with low circulating blood volume, and patients with unstable circulatory dynamics such as septic shock and lung disorders. There is a risk that blood volume will increase and circulatory dynamics such as lowering of blood pressure may become irregular. Further, when the number of columns used increases, the operation during blood purification becomes complicated, and the chances of being infected with bacteria and viruses increase. In addition, a circuit for connecting the column and a circulation device for purifying blood are required, which increases the medical cost. Therefore, a blood processing column in which a plasma separation material and a selective adsorption material are packed in one column has been developed (Patent Documents 1, 2, and 3). However, the material used as the plasma separation material is merely defined as hollow fiber-like. The average pore diameter of hollow fibers usually used for plasma separation is 0.2 to 0.3 μm, and plasma-separated materials contain substances having a large molecular weight, proteins, etc., and such substances are contained in plasma. When present, the adsorption efficiency of the removal target substance such as interleukins or bilirubin when in contact with the adsorbent material tends to be low.
JP-A 63-0405563 JP-A-8-164202 Japanese Unexamined Patent Publication No. 2000-167044

  In the present invention, a blood treatment column in which a plasma separation material and a selective adsorption material are packed in the same column, and further, a substance that causes a reduction in the adsorption efficiency of the removal target substance is identified and treated. An object of the present invention is to provide a blood treatment column that can improve the adsorption efficiency by separating from blood.

In order to achieve the above object, the blood processing column of the present invention has the following constitution.
1. A blood treatment column, wherein a plasma separation material having a hollow fiber form in which dextran having a molecular weight of 67000 has a sieve coefficient of less than 0.3 and a selective adsorption material are packed in the same column.
2. 2. The blood processing column according to 1, wherein the plasma separation material has a sieving coefficient of albumin of less than 0.3.
3. 3. The blood processing column according to 1 or 2, wherein the selective adsorption material has two or more functional groups capable of forming hydrogen bonds, and at least one of the functional groups is a nitrogen-containing functional group.
4). 4. The blood according to any one of 1 to 3, wherein the nitrogen-containing functional group is selected from at least one of urea bond, thiourea bond, amide bond, amino group, pyridyl group, pyrimidyl group and imidazole group. Processing column.
5. The selective adsorption material is used for the purpose of adsorbing at least one of interleukin-1, interleukin-6, interleukin-8, transforming growth factor beta 1 and bilirubin. 5. The blood processing column according to 3 or 4 above.
6). 6. The blood treatment column according to any one of 1 to 5, wherein the selective adsorption material is formed by fixing a compound having a LogP value of 2.5 or more.
7). 7. The blood processing column according to any one of 1 to 6, wherein the selective adsorption material has at least one shape of fiber, bead, felt, sponge, and net.

  According to the present invention, in a blood treatment column in which a plasma separation material and a selective adsorption material are packed in the same column, albumin that reduces the adsorption efficiency of the target substance to be removed is separated from the blood to be treated. An improved blood processing column can be obtained. In particular, plasma obtained by filtering blood with a plasma separation material has a reduced concentration of albumin or globulin present in the blood at a high concentration. Therefore, selective adsorption is performed around the target substance to be removed from the plasma. Depending on the material, it can be removed efficiently.

  In the present invention, the plasma separation material and the selective adsorption material are packed in the same column, and a configuration in which the blood to be treated is brought into contact with the plasma separation material before contacting the selective adsorption material is preferable. The significance of such a configuration is to increase the adsorption efficiency of the removal target material. That is, in the present invention, focusing on albumin as a substance that reduces the adsorption efficiency of the removal target substance, it has been found that the albumin-containing concentration of plasma to be filtered can be adjusted by defining the sieving coefficient of the plasma separation material. It has been found that when the concentration of albumin in plasma is low, the removal efficiency of removal target substances such as interleukins or bilirubin when in contact with the adsorbent material is increased. That is, when blood is first flowed through the plasma separation material arranged in the column, the plasma is separated outside by filtration by filtration and comes into contact with the selectively adsorbing material packed around. At this time, it is possible to increase the removal efficiency of the removal target substance such as interleukins or bilirubin by lowering the albumin concentration in the separated plasma. Furthermore, the plasma from which the removal target substance has been removed can be obtained as purified plasma, or it can be recombined with blood cells discharged through the inside of the plasma separation material. In the present invention, the sieve coefficient of dextran having a molecular weight of 67,000 is used as an index of albumin permeability of the plasma separation material. The dextran sieving coefficient of the plasma separation material should be less than 0.3. Furthermore, by defining the sieving coefficient of albumin (Stokes radius: 3.5 nm) having a particle size smaller than that of dextran to be less than 0.3, the adsorption efficiency of the removal target substance is increased, and useful substances having a large molecular weight such as coagulation factors Leakage can also be suppressed. When the dextran sieving coefficient is 0.3 or more, the pore size of the material is large and the permeation of albumin is increased, thereby reducing the adsorption efficiency by the selective adsorption material. Therefore, the dextran sieving coefficient is preferably less than 0.3, and the albumin sieving coefficient is preferably less than 0.3. On the other hand, as the lower limit of the pore size of the plasma separation material, if the sieving coefficient of albumin is less than 0.1, the target substance to be removed does not pass between the hollow fibers and is difficult to remove outside the body.

  The measuring method of the dextran sieving coefficient of molecular weight 67,000 or the sieving coefficient of albumin is as follows.

  A hollow fiber membrane, which is a selectively permeable separation membrane, is inserted into a column case made of plastic or the like, and both ends are fixed with an epoxy resin or the like to create a minimodule. The molecular weight is in the range of 1000 to 300,000, and at least 35 And dextran having molecular weight distributions including 67,000 and 67,000 are dissolved in ultrafiltrated water to a predetermined concentration. This solution is heated to a temperature of 37 ° C. and kept warm, and a pump is used on the blood side (inside the hollow fiber) to flow at a predetermined flow rate (for example, 10 ml / min). After flowing at a predetermined filtration flow rate (for example, 2 ml / min) and acclimatizing the membrane for a certain period of time, the solution flows from the blood side inlet, blood side outlet (both hollow and inner), and filtration side outlet (hollow fiber outside). The dextran concentration of the sampling solution is measured using gel permeation chromatography, and the dextran sieving coefficient having a molecular weight of 67,000 is calculated from the following equation from the calibration curve obtained from the molecular weight and the dextran concentration. Further, the sieve coefficient of albumin (Stokes radius 3.5 nm) is also calculated from the following formula.

Sieve coefficient = 2C _F / (CBi + CBo)
Here, CBi: Module blood side inlet concentration, CBo: Module blood side outlet concentration, C _F : Module filtration side outlet concentration (mg / mL) are shown.

  The material of the plasma separation material is not particularly limited, and synthetic polymer materials such as nylon, polymethyl methacrylate, polysulfone, polystyrene, polyethylene, polyvinyl alcohol, polytetrafluoroethylene, cellulose, collagen, chitosan and derivatives thereof. Natural polymer materials containing, can be used alone or in combination. The plasma separation material is used in the form of a hollow fiber membrane having a large surface area.

  The selective adsorbing material is capable of selectively adsorbing a physiologically active substance existing in blood compared to a useful substance such as albumin from substances in plasma, and is not particularly limited. A known technique is also used. It is possible. Among these, materials that selectively adsorb at least one removal target substance among interleukin-1, interleukin-6, interleukin-8, transforming growth factor beta 1, and bilirubin are preferably used. .

  Although the shape of the selective adsorption material in the present invention is not particularly limited, it can be used as beads, fibers (composite fibers, hollow fibers, yarn bundles, yarns, etc.), sponges, nets, knitted fabrics, woven fabrics, and the like. Considering that the surface area is large and the channel resistance is small, fibers (particularly hollow fibers and composite fibers), knitted fabrics, and woven fabrics are preferably used. If the substrate or carrier is a polymer, many of them have fiber-forming ability and can easily be made fibrous. However, if the strength is insufficient for use as a column packing material, Improvements can be made by using a composite fiber, blending with other fibers, blending, weaving, or the like. For example, polystyrene / polypropylene sea-island fiber is a more preferable embodiment because it has easy modification of polystyrene and is easy to handle due to strength reinforcement by polypropylene. In the case of a coating material, a shape such as a knitted fabric or a film is preferable.

  In the present invention, the significance of filling the plasma separation material and the selective adsorption material in the same column is that it is possible to reduce the amount of blood circulated outside the body, which is used for premature babies, newborns and infants with a small amount of circulating blood. Even if it does, there is no adverse effect on the circulatory dynamics and it can be safely implemented. In particular, blood purification therapy in premature babies and newborns has become widespread in recent years, and there is a movement to actively carry out treatment even in patients whose body weight is 1,000 g or less. However, for example, a 1,000 g patient has a very small amount of circulating blood of about 80 mL, and circulatory dynamics are also unstable. However, by filling the plasma separation material and the selective adsorption material in the same column, the amount of blood circulated outside the body can be reduced. Further, by removing albumin in plasma with a plasma separation material, it is possible to efficiently adsorb and remove the target substance to be removed, and an early disease state improving effect can be expected. Furthermore, the treatment for premature babies and newborns can shorten the time required for blood purification therapy, thereby reducing the burden on the patient. In addition, when each column is filled with plasma separation material and selective adsorption material, the number of columns used increases, blood purification becomes complicated, and there is an opportunity to be infected with bacteria and viruses. Increased, there are also problems with hygiene. In particular, when blood purification therapy is performed, if an infection such as bacteria or virus occurs in a column or circuit, sepsis is induced and the risk of such infection is increased. It is important to mitigate.

  The plasma separation material and the selective adsorption material can be filled by the same thread bundle insertion operation as in the conventional method of housing the hollow fiber bundle in a hollow fiber module such as an artificial kidney. Further, there is no particular limitation on the filling method of these materials, and it is only necessary to have a structure or arrangement in which blood is treated with a selective adsorption material after blood is separated with a plasma separation material. For example, a method of filling a plasma exchange material in the center and a selective adsorption material such as fiber, knitted fabric, woven fabric, felt, sponge, beads or net to surround the plasma separation material, or filling the plasma separation material There is also a method of filling a selective adsorption material on the side on which plasma is filtered. There is also a method of filling a selective adsorption material between individual plasma separation materials and plasma separation materials.

  Furthermore, the kind of selective adsorption material can be filled with one or a plurality of selective adsorption materials, and there is a method of filling a net or the like outside the adsorption material.

  The selective adsorption material in the present invention preferably has a functional group capable of forming a hydrogen bond in the material. The functional group capable of forming a hydrogen bond is not particularly limited as long as it is a functional group capable of forming a hydrogen bond. For example, urea bond, thiourea bond, amide group, amino group, pyridyl group, pyrimidyl group, imidazole group, hydroxyl group , Carboxyl group, aldehyde group, mercapto group and the like, nitrogen-containing functional group is preferable, and is at least one of urea bond, thiourea bond or amide bond, amino group, pyridyl group, pyrimidyl group, imidazole group It is preferable. The functional group capable of forming a hydrogen bond may have a subsequent structure. The structure following the functional group capable of forming a hydrogen bond is not particularly limited, and aliphatic compounds such as propane, hexane, octane and dodecane, and alicyclic compounds such as cyclohexane and cyclopentane can be used. In view of the height, aromatic compounds such as benzene, naphthalene and anthracene are more preferably used. Derivatives such as bromoheptane, chlorocyclohexane, methylbenzene, chlorobenzene, nitrobenzene, diphenylmethane, chloronaphthalene and the like are also preferably used.

  Moreover, in this invention, it is more preferable to have 2 or more types of functional groups which can form a hydrogen bond, and it is preferable that at least 1 type is the above-mentioned nitrogen-containing functional group. In particular, at least one of the nitrogen-containing functional groups is preferably selected from functional groups having a plurality of urea bonds, thiourea bonds, or amide bonds. In this case, different functional groups capable of forming hydrogen bonds may be bonded to the substrate, or another type of functional group capable of forming hydrogen bonds may be bonded to a certain functional group capable of forming hydrogen bonds as a subsequent structure. It is also possible to use such a mode. In particular, as a structure following a urea bond, a thiourea bond or an amide bond, for example, a structure further having a functional group capable of forming a hydrogen bond such as an amino group, a hydroxyl group and a carboxyl group is preferably used. For example, as a structure having an amino group, aminohexane, monomethylaminohexane, dimethylaminohexane, aminooctane, aminododecane, aminodiphenylmethane, 1- (3-aminopropyl) imidazole, 3-amino-1-propene, aminopyridine, Aminobenzenesulfonic acid, tris (2-aminoethyl) amine and the like, and more preferably diaminoethane, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, dipropylenetriamine, polyethyleneimine, N-methyl-2,2′- A compound (polyamine) having a plurality of amino groups such as diaminodiethylamine, N-acetylethylenediamine, 1,2-bis (2-aminoethoxyethane) and the like is used. In addition, examples of the structure having a hydroxyl group include hydroxypropane, 2-ethanolamine, 1,3-diamino-2-hydroxypropane, hydroxybutanone, hydroxybutyric acid, hydroxypyridine and the like, glucose, glucosamine, galactosamine, maltose, cellobiose, sucrose. Monosaccharides such as agarose, cellulose, chitin and chitosan, carbohydrates such as oligosaccharides and polysaccharides, or derivatives thereof can be used. Furthermore, as the structure having a carboxyl group, for example, β-alanine, n-caproic acid, isobutyric acid, γ-amino-β-hydroxybutyric acid and the like can be used. The most preferred embodiment of the present invention is one having both an aromatic compound and a compound capable of forming a hydrogen bond as a structure following a urea, thiourea or amide group. The selective adsorption material having such a functional group can be used for applications that adsorb at least one of interleukin-1, interleukin-6, interleukin-8, transforming growth factor beta 1 and bilirubin. is there.

  Furthermore, polyurea, polythiourea and polyamide having a plurality of urea bonds, thiourea bonds or amide bonds in the molecular structure can also be used as the base material or carrier of the material of the present invention. In these cases, any of the above structures can be used as a structure following a urea bond, a thiourea bond, or an amide bond, but most preferably a compound having a hydroxyl group, an amino group, or a carboxyl group (a carbohydrate or a derivative thereof) Or an aromatic compound is used.

  Further, the substrate or carrier in the present invention may be any of a monomer, an oligomer, and a polymer, such as polyamide, polymethyl methacrylate, polysulfone, polystyrene, polyethylene, polyvinyl alcohol, and polytetrafluoroethylene, cellulose, Natural polymers including collagen, chitin, chitosan and derivatives thereof are preferably used. That is, it is preferable to introduce a functional group capable of forming a hydrogen bond into these synthetic polymer or natural polymer homopolymerized, copolymerized or blended. Furthermore, a material in which an inorganic material such as metal, ceramic, or glass is coated with an appropriate polymer as a base material or the surface is directly modified is preferably used. In particular, polystyrene, polysulfone, polymethyl methacrylate, and the like are preferably used because surface modification can be easily performed.

  In the case of having the functional group, the material of the selective adsorption material is not particularly limited, and synthetic polymers such as polyethylene, polypropylene, polymethyl methacrylate, polystyrene, polyvinyl alcohol, polyamide, and composites thereof or cellulose, Any of natural polymers such as agarose, dextran, chitosan, polyamino acids or complexes thereof or derivatives thereof, and inorganic materials such as metals, glass, ceramics, etc. can be used.

  The selective adsorption material in the present invention preferably has a compound having a LogP value of 2.5 or more, preferably a LogP value of 2.8 or more, more preferably 3.0 or more. Here, LogP refers to a distribution coefficient in an octanol aqueous system. When these compounds are included, interleukin-1, interleukin-2, interleukin-6 and interleukin-8 are adsorbed at a high rate. The compound having a LogP value of 2.5 or more is not particularly limited. Among the compounds having a LogP value of 2.5 or more, unsaturated hydrocarbons, alcohols, amines, thiols, carboxylic acids and derivatives thereof, halides, Compounds having a functional group that can be used for bonding to a carrier, such as oxirane ring-containing compounds such as aldehydes, hydrazides, isocyanates, glycidyl ethers, and halogenated silanes are preferred.

  In the case of having the functional group, the material of the selective adsorption material is selected according to the kind of the target substance, and is not particularly limited, but may be any of a monomer, an oligomer, and a polymer, such as polyamide, Synthetic polymers such as polymethyl methacrylate, polysulfone, polystyrene, polyethylene, polyvinyl alcohol, and polytetrafluoroethylene, and natural polymers including cellulose, collagen, chitin, chitosan, and derivatives thereof are preferably used. In other words, it is suitable to introduce a functional group capable of forming a hydrogen bond into a homopolymerized, copolymerized, crosslinked or blended synthetic polymer or natural polymer, or to fix a compound having a log P value of 2.5 or more. To be done.

The calculation method of the removal rate was as follows.
Removal rate (%) = (CBi− (CBo + CFo) / 2) / CBi × 100
CBi: cytokine or total bilirubin concentration at the column inlet CBo: cytokine or total bilirubin concentration at the column outlet CFo: cytokine or total bilirubin concentration at the filtrate side outlet

Example 1
As a plasma separation material, a polysulfone hollow fiber was prepared by the following procedure. Polysulfone (Amoco Udel-P3500) 18 parts by weight, polyvinylpyrrolidone (BASF K90) 3 parts by weight, polyvinylpyrrolidone (BASF K30) 6 parts by weight were added to 72 parts by weight of dimethylacetamide and 1 part by weight of water to obtain a film forming stock solution. . This stock solution is sent to a spinneret part at a temperature of 50 ° C., and a solution comprising 55 parts by weight of dimethylacetamide and 45 parts by weight of water is used as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. After forming a hollow fiber membrane by discharging from the inner tube, a temperature consisting of 20% by weight of dimethylacetamide and 80% by weight of water passes through a space of 250 mm length having a dry zone atmosphere adjusted to a temperature of 30 ° C. and a dew point of 28 ° C. A hollow fiber membrane was obtained by passing through a coagulation bath at 40 ° C. Then, the hollow fiber membrane obtained through the water washing process performed with 80 degreeC water for 20 second, and the moisture retention process by glycerol was used as the winding bundle. 100 plasma bundles were bundled, and both ends were fixed to a column case having an inner diameter of 5 mmφ with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber, thereby producing a minicolumn. The effective length of the column (the length of the portion excluding both ends sealed with an epoxy potting agent in the longitudinal direction of the column) is 10 cm, and the dialysate port is provided in the same manner as a general hollow fiber membrane dialyzer. It had two, one on the dialysate side was closed, and the other was connected to a silicone tube and connected to a circulation pump to allow filtration. Next, using a 5% human serum albumin solution (molecular weight 66,458, Bayer Yakuhin Co., Ltd.), this solution is heated and kept at 37 ° C., and a flow rate of 2 ml / min is used using a pump on the blood side (inside the hollow fiber). The flow rate was 1.5 min, the filtration flow rate was 1.5 ml / min, and the membrane was conditioned for 20 minutes. Then, the solution flowing from the blood side inlet, blood side outlet, and filtration side outlet (hollow fiber outer side) was sampled, and the sieving coefficient was calculated. . Next, the following cytokine and bilirubin adsorbing fibers were packed on the outside of the polysulfone membrane hollow fiber and the polymethylmethacrylate membrane hollow fiber to produce a column in which the plasma separation material and the adsorbing material were integrated. That is, a method for producing cytokines and bilirubin-adsorbing fibers is as follows. Sea-island type composite fiber (strength: 1.0 g / d, elongation: 47.7%, thickness: 132 denier, island) consisting of 65 parts by weight sea component (polystyrene) and 35 parts by weight island component (polypropylene) 16) 30 g was reacted with a mixed solution of 60 g of N-methylol-α-chloroacetamide, 400 g of nitrobenzene, 400 g of 98% by mass sulfuric acid and 0.86 g of paraformaldehyde at 20 ° C. for 1 hour. After the reaction, the fiber was washed with nitrobenzene, then stopped with methanol, and further washed with methanol to obtain α-chloroacetamidomethylated crosslinked polystyrene fiber (hereinafter abbreviated as AMPSt fiber).

  Next, the AMPSt fiber was added to 500 ml of dimethyl sulfoxide (hereinafter abbreviated as DMSO) in which 20.0 g of tetraethylenepentamine was dissolved, and the reaction was carried out at 30 ° C. for 3 hours. Further, the fiber was added to a solution of 1000 ml of DMSO in which 1.9 g of 4-chlorophenyl isocyanate was dissolved, and the reaction was carried out at 30 ° C. for 1 hour. Thereafter, the glass filter was washed with 1000 ml of DMSO and further with 1000 ml of distilled water to obtain AMPSt fibers (abbreviated as UAMP fibers) into which urea bonds were introduced.

  Next, 50 mL of blood was collected from healthy adults, and heparin was added to 10 IU / ml. Furthermore, human interleukin 1β, 6, 8, TGFβ1 and bilirubin were added to the blood. The blood thus prepared was allowed to flow through the column for 4 hours, and at the same time, filtration was performed. At that time, the solution flowing from the blood side inlet, the blood side outlet, and the filtration side outlet (hollow fiber outer side) was sampled, and the albumin concentration, cytokine and bilirubin concentration were measured. The removal rate was calculated from the cytokine and bilirubin concentrations. The albumin concentration was measured with a Human Albumin ELISA Quantification Kit (manufactured by BETHYL). Human interleukins 1β, 6 and 8 were measured with Human, ELISA Kit (manufactured by ENDOGEN), and TGFβ1 was measured with Human, ELISA Kit (manufactured by R & D). The bilirubin concentration was determined using Fuji Dry Chem (Fuji Photo Film Co., Ltd.) by a diazotization reaction. The results are shown in Table 1.

Example 2
As a plasma separation material, a minicolumn was prepared in the same manner as in Example 1 except that the composition of the core solution was changed to a solution composed of 60 parts by weight of dimethylacetamide and 40 parts by weight of water. Next, six types of dextrans having different molecular weight distribution (average molecular weight 1,200 (No. 31394), 6,000 (No. 31388), 15,000 to 20,000 (No. 31387), 40, manufactured by FULKA) 000 (No. 31389), 56,000 (No. 31997), 222,000 (No. 31398)) were dissolved in ultrafiltered water so that the concentration was 0.5 mg / ml. This solution was heated to 37 ° C. and kept warm, and the blood side (inside the hollow fiber) was pumped at a flow rate of 2 ml / min. The filtration flow rate was 1.5 ml / min. The solution flowing from the inlet, blood side outlet, and filtration side outlet (outside of the hollow fiber) is sampled, and the dextran concentration of the sampling solution is measured using gel permeation chromatography manufactured by Tosoh Corporation. The dextran sieving coefficient having a molecular weight of 67,000 is measured. Was calculated. Next, the adsorbing material described in Example 1 was filled on the outside of the polysulfone membrane hollow fiber and integrated to prepare a blood processing column.

  Subsequent preparation, operation, and evaluation of the adsorbent material were the same as in Example 1. The results are shown in Table 2.

Comparative Example 1
A 100% hollow fiber made of ethylene vinyl alcohol membrane (Plasma Flow, OP-05W: Asahi Medical Co., Ltd.) is bundled, and both ends are fixed to the column case with an epoxy potting agent so as not to block the hollow part of the hollow fiber. It was created. Subsequent preparation, operation, and evaluation of the adsorbent material were the same as in Example 1. The results are shown in Table 3.

  The present invention can be applied not only to blood purification therapy but also to a method for detecting a trace amount of a pathogenic substance in blood, but the application range is not limited thereto.

It is a schematic sectional drawing of a blood processing column. A method for filling a plasma separation material and a selective adsorption material.

Explanation of symbols

1. 1. Blood treatment column 2. Blood pump 3. filtration pump 4. Plasma separation material Selective adsorption material (fiber)
6). 6. Plasma separation material Selective adsorption material (beads)
8). 8. Plasma separation material Selective adsorption material (felt)
10. Net 11. Filtration side

Claims (7)

A plasma separation material having a hollow fiber form in which the sieving coefficient of dextran having a molecular weight of 67000 is less than 0.3 and a selective adsorption material that selectively adsorbs a physiologically active substance present in blood are packed in the same column. ,
The blood processing column, wherein the selective adsorption material is packed so as to come into contact with blood after plasma separation by the plasma separation material.   The blood processing column according to claim 1, wherein the sieving coefficient of albumin of the plasma separation material is less than 0.3.   The blood processing column according to claim 1 or 2, wherein the selective adsorption material has two or more functional groups capable of forming hydrogen bonds, and at least one of the functional groups is a nitrogen-containing functional group. . The blood processing column according to claim 3, wherein the nitrogen-containing functional group is selected from at least one of urea bond, thiourea bond, amide bond, amino group, pyridyl group, pyrimidyl group and imidazole group.   The selective adsorption material is used for the purpose of adsorbing at least one of interleukin-1, interleukin-6, interleukin-8, transforming growth factor beta 1 and bilirubin. The blood processing column according to claim 3 or 4.   The blood processing column according to any one of claims 1 to 5, wherein the selective adsorption material is formed by fixing a compound having a LogP value of 2.5 or more.   The blood processing column according to any one of claims 1 to 6, wherein the selective adsorption material has at least one shape of fiber, bead, felt, sponge, and net.

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