JP4483230B2 - Membrane for plasma separation and blood purification system using the same - Google Patents

Description

  The present invention relates to a blood separation plasma separation membrane for separating a specific component in blood using an adsorption group supported on the membrane, a module using the same, and a blood purification system.

  Conventionally, beads, cotton made of ultrafine fibers, and knitted fabrics made of ultrafine fibers have been used for applications such as adsorption to purify blood components rather than using membranes. Porous beads have been particularly widely used because the surface area when blood comes into contact can be increased and the adsorbent can be fixed relatively easily. Cotton and knitted fabrics are also widely used for removing cells by adsorbing cells by utilizing the properties of ultrafine fibers.

  In the method using a membrane, in particular, a hollow fiber membrane or the like has been disclosed in which an adsorbing group is attached only to the inner surface in contact with blood, but it cannot earn a large surface area and is not widely used at present ( For example, see Patent Document 1.) For the purpose of increasing the surface area, an invention is disclosed in which a film is constituted by a blend of a modified polymer and an unmodified polymer in order to increase compatibility (see, for example, Patent Document 2). Giving electric charge by modification is also disclosed (for example, refer to Patent Document 3). However, in this method, since the modifying group is large, it is difficult to predict the degree of aggregation of the modifying group during film formation, and it is difficult to optimize the film forming conditions. There is little improvement effect compared with the means.

As examples of the case where a charge is applied to the membrane surface, a membrane made of a polymer having a sulfonic acid group as a charged membrane, a membrane into which an amino group is introduced by an amide methylation reaction after film formation, and the like are known. In addition, patents such as an anion selective adsorptive porous membrane and a production method thereof are disclosed (for example, refer to Patent Document 4). These membranes are not considered to have both an acidic functional group and a basic functional group, and have been used for the purpose of controlling protein adsorption behavior in blood by having a positive or negative charge. . In addition, for those having amphoteric charge, a method of coating an MPC polymer imitating a phospholipid is also known (for example, see Patent Document 5), and an example of forming a film from one stock solution (for example, see Patent Document 6) is also disclosed. However, it is difficult to control the membrane structure, and it is difficult to express desired fractionation characteristics. Basically, MPC polymers are used only to improve biosynthesis and blood compatibility. (For example, see Patent Document 7)
JP-A-10-151196 Japanese Patent Laid-Open No. 10-137565 Japanese Unexamined Patent Publication No. 1-9230 Japanese Patent No. 2796995 Japanese Patent Laid-Open No. 5-220218 JP-A-10-296063 JP-A-5-177119

  In general, when whole blood is perfused, blood coagulates in the blood purifier and the flow is obstructed and red blood cells may be hemolyzed, so the effect of blood coagulation is reduced and red blood cells are not hemolyzed However, a technique capable of perfusion with whole blood is required, but the above-described conventional technique is insufficient. In other words, beads, cotton made of ultrafine fibers, and knitted fabrics made of ultrafine fibers continue to have the following problems.

  As for the problem of blood flow, there are disclosed means for lowering the packing density of adsorbed beads and knitted fabric into the blood purifier and securing the blood flow path, but there is still a risk of circuit blockage due to blood coagulation. It was difficult to efficiently bring blood into contact with the adsorbing group.

  In order to fundamentally avoid the above problems, a method of passing plasma through an adsorbing group after the plasma separation operation has been generally used. However, there are two devices, a device for separating plasma and a blood purifier. , Because it is used at the same time, there is an adverse effect of increasing medical costs.

  In the present invention, blood flow can be stabilized, whole blood can be perfused, the fixed density and purification efficiency of adsorbing groups can be increased to the same level as a system using porous beads, and the surface structure suitable for attaching functional groups to the membrane surface can be reduced. The challenge was to achieve this through cost and labor saving processes. At the same time, the improvement of biocompatibility during blood contact was also an issue.

In order to solve the above problems, the present invention has the following configuration.
(1) Water permeability is 7500 ml / hr · kPa · m ² or more, albumin permeability is 10% or more, and at least one acidic functional group selected from carboxyl group and sulfonic acid group, first grade, second grade It comprises a hollow fiber membrane carrying one or more basic functional groups selected from tertiary, quaternary amine and imine, and both the density of the acidic groups and the density of the basic groups are both 10 μmol / g or more. der Ru plasma separation membrane.
(2) wherein the acidic functional group or the basic functional group through, characterized in that combines materials and different molecules of the membrane (1) film for plasma separation according to.
(3), characterized in that it comprises a polysulfone-based resin and polyvinylpyrrolidone (1) or (2) film for plasma separation according to.
(4) membranes for plasma separation according to any one of the materials different from the polymer of the membrane is characterized in that linked by radiation crosslinking (1) to (3).
( 5 ) The polymer is one or more selected from the group consisting of polyethyleneimine, polyethylene glycol, alginic acid, chitosan, polyphosphoric acid and hyaluronic acid, according to any one of (1) to ( 4 ) film for plasma separation.
( 6 ) The substance for plasma separation according to any one of (1) to ( 5 ), wherein a substance that binds to unwanted substances in blood and / or a substance that can induce an immunostimulatory effect is supported on the membrane . film.
( 7 ) A module incorporating the film according to any one of (1) to ( 6 ).
( 8 ) A blood purification system using the module incorporating the membrane for plasma separation according to ( 7 ).
( 9 ) The blood purification system according to ( 8 ), which has a mechanism for recirculating the plasma after plasma separation, rejoining it with blood, and introducing it into the module.
( 10 ) When the plasma is recirculated and merged with the blood again, it has a mechanism for changing the blood volume to be introduced into the module to a total amount of the initial blood volume and the circulating plasma volume (8) or ( The blood purification system according to 9) .

  According to the present invention, blood flow can be stabilized and whole blood can be perfused, the fixed density and purification efficiency of adsorbing groups can be increased to the same level as a system using porous beads, and the surface structure suitable for attaching functional groups to the membrane surface can be reduced. The cost and labor saving process could be realized.

  The present invention will be described in further detail below.

  The present invention relates to a blood purification plasma separation membrane used in a blood purification method that adsorbs and removes unnecessary substances from blood and a blood purification system thereof, which stabilizes blood flow, enables whole blood perfusion, and immobilizes adsorption groups. Provides increased density and purification efficiency comparable to systems using porous beads.

Water permeability 7500ml / hr · kPa · m ² or more is desirable for the film, in order to stabilize the plasma separation rate is more preferably 75000ml / hr · kPa · m ² or more. If it exceeds 1000 ml / hr · Pa · m ² , the risk of hemolysis of erythrocytes arises. In the case of a membrane having high water permeability, the measured value may vary greatly depending on the membrane form, and the water permeability referred to here is based on a value measured by modularizing 20 hollow fiber membranes having an effective length of 12 cm.

  Similarly, the albumin permeability is preferably 10% or more, and more preferably 40% or more in order to stabilize the plasma separation rate. The albumin permeability referred to here was measured using the same module as the water permeability measurement. Furthermore, the membrane contains one or more acidic functional groups selected from carboxyl groups and sulfonic acid groups, and one or more basic functional groups selected from primary, secondary, tertiary, quaternary amines, and imines. It is necessary to have the entire membrane surface including the porous part used for separation. These functional groups are abundant on biological materials and are considered to be less harmful to the living body.

  The porous part used in the plasma separation here is a hole opened in the inner and outer surfaces of the hollow fiber membrane, and includes a hole in the membrane. In addition, the amount of each functional group can be quantified by volumetric titration. In this application, it measured by the back titration method described below. That is, it is a method of volumetric titration of the amount of acid or base consumed on the membrane surface.

  The acidic basic functional group density is preferably 10 μmol / g or more. In order to further fix physiologically active substances, polymers and monomers using this functional group, 30 μmol / g or more is preferable.

  Moreover, biocompatibility at the time of blood contact improves because these two functional groups are distributed on the membrane surface. The detailed mechanism is unknown, but it seems to mimic the micro electrification distribution on the surface of the biological membrane.

  A third molecule different from the membrane material can be bonded to the membrane material, and the third molecule is directly bonded to the membrane material or bonded through the acidic functional group and / or the basic functional group. can do. By binding the third molecule to the membrane material, an effect of further changing the blood compatibility can be obtained. In order to obtain such an effect, a charged molecule (third molecule material), such as polyethyleneimine, alginic acid, chitosan, polyphosphoric acid, hyaluronic acid, should be used as the third molecule. Although preferable, it is not limited to these substances.

  As the membrane material, a material based on a polysulfone material is preferably used, but other polymers can also be applied. A material having a glass transition point exceeding 140 ° C. is preferably used, but a material having a glass transition point lower than that can be used if it has radiation resistance. Specifically, any material that can maintain a tensile strength of 50% or more by irradiation with 50 KGy can be preferably used. Examples of membrane materials include fluorine resins such as cellulose, cellulose acetate, cellulose triacetate, polyolefin, polyimide, polycarbonate, polyarylate, polyester, polyacrylonitrile, polymethyl methacrylate, polyamide, polysulfone resin, and polyvinylidene fluoride. . As a membrane material, a polysulfone resin is superior for reasons such as biocompatibility, heat resistance, sterilization resistance, and workability.

  As the film-forming stock solution, a liquid mixture of the above-mentioned film material having main physical strength and polyvinylpyrrolidone is preferably used. Polyvinyl pyrrolidone is preferable because it is extremely excellent in compatibility with the above polymer.

  Application of acidic and basic functional groups to the membrane can be realized by the following methods, but other methods may be used.

First of all, a method of mixing with an ionic polymer when preparing a yarn stock solution, for example, mixing with polyphosphoric acid or mixing with polyamine is considered, but in this case, it may be difficult to uniformly dissolve the stock solution, More preferably, mixing with polyvinylpyrrolidone is performed. Polyvinyl pyrrolidone is compatible with various engineering plastics such as fluorine resins such as polysulfone, polyethersulfone, PMMA, polyvinylidene fluoride, etc., and this combination is good as a spinning stock solution because the stock solution viscosity can be increased. Used. Various molecular weights can be used, but it is convenient to use commercially available ones such as K90, K60, K30, K15. A mixture thereof or a polymer having a molecular weight other than those described above may be polymerized and used, but the higher the molecular weight, the easier it is to use as a stock solution. For this reason, it is more preferable to use K90. The solvent is preferably a high-boiling polar solvent such as dimethylacetamide (hereinafter abbreviated as DMAc) or N-methylpyrrolidone, but other combinations can be used as long as they can be dissolved uniformly. A hollow fiber membrane is produced using this stock solution. A membrane having a water permeability of 7500 ml / hr · kPa · m ² or more is produced by increasing the number of pores by utilizing the phase separation phenomenon. be able to. The water permeability can be changed by changing the ratio of resin and solvent and the amount of mixed polyvinylpyrrolidone. For example, if this ratio is increased to about 95/5, the water permeability is about 75000 ml / hr · kPa · m ² It is possible to make a film. As for the albumin permeability, a membrane having a water permeability of 7500 ml / hr · kPa · m ² and an albumin permeability of 10% or more can be obtained by increasing the pore size. Can be manufactured. The film thus formed can be imparted with both acidic groups and basic groups to the film surface by, for example, post-treatment described below. Basically, the pyrrolidone ring opening reaction of polyvinylpyrrolidone can be used to form the entire film surface. For this reason, it is possible to form both acidic and basic functional groups in every corner of the porous part, and the membrane structure does not change during this treatment and does not affect the material filtration performance. Manufacture is easy because there is no need to conduct research to improve membrane technology. Specifically, it is achieved by performing heat treatment at a temperature at which the film material of 70 ° C. or higher does not melt in the presence of oxygen, or by performing radiation treatment in the absence of a radical scavenger. It is an example. Plasma treatment or the like is possible, but attention should be paid to the loss of productivity. As a basic idea, the hollow fiber membrane is first washed with water, more preferably with boiling water, and the amount of adhered polyvinylpyrrolidone is adjusted. When washed for 5 hours or more, the residual amount of polyvinyl pyrrolidone is too small, and acidic groups and basic groups cannot be imparted to the film surface at a desired density. 4 hours or less is more preferable, and if it is about 2 hours, the amount of surface functional groups is sufficient, and it is possible to carry a physiologically active substance or the like. Thereafter, the membrane is permeated and washed, and then dried, and heat treatment is performed at a temperature at which the film material of 70 ° C. or higher does not melt in the presence of oxygen and / or radiation treatment is performed in the absence of a radical scavenger. This is achieved. It is not necessary to keep it basic. The treatment time can be from about 2 hours, but the longer the treatment time, the higher the surface functional group density. The treatment temperature is preferably equal to or lower than the glass transition temperature of the film structure constituting polymer used. The higher the temperature, the higher the surface functional group density. The surface functional group density can be adjusted by a combination of temperature and time. In order to increase the functional group concentration on the film surface, a desired surface functional group density can be obtained by repeating these treatments for a long time and / or repeatedly. Similarly, when using radiation treatment, it depends on the radiation absorbed dose. Further, these two or more processes may be combined. The sulfonic acid group is simply added by a known technique by using concentrated sulfuric acid and / or fuming sulfuric acid.

Either a flat membrane or a hollow fiber membrane can be produced as the membrane, but for the purpose of blood purification, a hollow fiber membrane having a shape that makes it difficult to form a blood retention portion is preferably used.
It is also possible to combine by using radiation irradiation. Preferably used are polyethyleneimine, polyalkylene glycol, alginic acid, chitosan, polyphosphoric acid, hyaluronic acid, fucoidan, etc., using these molecular properties to carry different types of adsorbing functional groups, It is possible to change the balance between acidic groups and basic groups present on the membrane surface. Of course, it is also possible to fix these molecules by acidic groups or basic groups. The third molecule listed above can be directly bonded to the membrane material by radiation treatment. If a basic group is used, the third molecule can be bonded to an acidic functional group. If an acidic group is used, Can be bonded to a basic functional group.

  As the type of the adsorbing functional group, it is possible to use various known antibodies that bind unnecessary substances in blood (including excessively produced cytokines) and physiologically active substances, There are no limitations on the types of products, including those that will be developed in the future. In addition, antibiotics and lectin-like substances related to immunostimulation can be used in the same manner. It is possible to bind to the membrane by a condensation reaction between an acidic group and / or a basic group on the membrane surface and a carboxyl group and / or an amino group such as a protein or other physiologically active substance.

  The blood purifier (that is, the module) incorporating the membrane thus designed and produced according to the present invention is a novel blood purification system that replaces the two functions of the plasma separation membrane and the adsorber that have been conventionally performed. provide. FIG. 1 shows the basic system. Although an example of blood flow rate of 100 ml / min and plasma filtration rate of 20 ml / min was given, it is not limited to this. A high-performance plasma separation membrane can be manufactured that can stably filter to a plasma filtration rate of about 60 ml / min at a blood flow rate of 100 ml / min.

  While blood is introduced from 1 human or animal to 2 plasma separation membrane modules using 2 blood pumps and plasma separation is performed, the separated plasma is supported on the surface of the 1 membrane while being filtered. Unnecessary components are adsorbed and removed by the adsorbing groups. Thereafter, the plasma is pumped from the plasma outlets 1 to 3 to the blood through the 6 branch valves by the plasma pump of 3 and led again to 1 plasma separation membrane. The pump flow rate at the moment 2 is changed. FIG. 1 shows an example of the setting of each pump when the blood flow rate is 100 ml / min. This circulation mechanism can increase the removal efficiency of unnecessary components in the plasma, and the blood can be diluted by merging the separated plasma, so the hematocrit value before the plasma separation is lowered and the plasma separation operation is prolonged. It also brings the effect of stabilizing. Even if the filtration pressure increases due to protein adhesion on the membrane surface, the pump 3 can be stopped and reversed, and the plasma can be returned to 5 using the pump 4. Since the inner diameter of the plasma separation membrane 1 is 300 μm, blood is not clogged. For this reason, there is very little risk of a medical accident and blood purification can be performed safely. In the adsorbed blood purifier prepared by the bead method, if the circulatory pressure once increases due to blood coagulation, a large amount of blood may not be changed. In addition, since the plasma separation membrane and the purification membrane are integrated, the priming volume can be reduced, and the implementation is easy even for subjects with a small amount of body fluid such as newborns and children.

  Hereinafter, it demonstrates still in detail according to an Example.

The measurement method used is as follows.
(1) Back titration method The density of an acidic functional group and a basic functional group was measured by a back titration method.

  1 g of the dried membrane is prepared. The measurement was performed at room temperature at 23 ° C. The measurement was repeated three times and the average value was adopted.

  For quantification of acidic groups, immerse in advance with 10 ml of 1/10 mol HCl aqueous solution (for volumetric analysis) for 15 min or longer to remove Na salts. The membrane is thoroughly washed with ultrapure water, and it is confirmed that the water after washing has become neutral (pH is 7 ± 1) and freeze-dried. The obtained membrane was shaken and immersed in 100 ml of 1/100 mol NaOH aqueous solution (for volumetric analysis) for 1 hour, 30 ml of which was taken out, and volumetric analysis was performed using 1/100 mol HCl aqueous solution (for volumetric analysis). Do. 30 ml of the 1/100 mol NaOH aqueous solution (for volumetric analysis) used above was titrated in the same manner (control), and the difference in the amount of 1/100 mol HCl aqueous solution (for volumetric analysis) used for neutralization The concentration of acidic groups attached to the surface is calculated.

  Similarly, those for quantifying basic groups are preliminarily immersed in 10 ml of 1/10 mol NaOH aqueous solution (for volumetric analysis) for 15 min or longer to remove, for example, HCl salts. The membrane is thoroughly washed with ultrapure water, and it is confirmed that the washing solution is neutral (pH is 7 ± 1) and dried. The obtained film was immersed in 100 ml of 1/100 mol HCl aqueous solution (for volumetric analysis) for 1 hr with shaking, 30 ml of which was taken out, and volumetric analysis was performed using 1/100 mol NaOH aqueous solution (for volumetric analysis). Do. 30 ml of the 1/100 mol HCl aqueous solution (for volumetric analysis) used previously was volume titrated in the same manner (control), and the membrane was determined from the difference in the amount of 1/100 mol NaOH aqueous solution (for volumetric analysis) used for neutralization. The concentration of acidic groups attached to the surface is calculated.

  The functional group density of acidic groups and basic groups per gram of membrane was calculated by the following formula.

Functional group density (μmol / g) = 33.3 × (Amount of liquid necessary for neutralization of sample (ml) −Amount of control liquid (ml)) Formula 1
(2) Measurement of water permeability The amount of filtration per unit time flowing out to the outside by applying a water pressure of 100 mmHg to the inside of the hollow fiber of a glass tube mini-module (20 pieces: effective length 12 cm) sealed at both ends of the hollow fiber Was measured.

  The water permeability was calculated by the following formula.

Permeability (ml / hr · kPa · m ² ) = Filtration water volume (ml) ÷ Outflow time (hr) ÷ Pressure difference (kPa) ÷ Hollow fiber membrane surface area (m ² ) Equation 2
(3) Measurement of albumin permeability Using bovine blood (heparin-treated blood) having a hematocrit of 30% and a total protein content of 6.5 g / dl kept at 37 ° C. in a blood tank, the inner side of the hollow fiber is pumped at 200 ml / min. Sent by. At that time, the pressure on the module outlet side was adjusted so that the filtration amount was 20 ml / min per 1 m ^{2 of} module area (that is, 32 ml / min at 1.6 m ² ), and the filtrate and outlet blood were returned to the blood tank. One hour after the start of recirculation, 5 ml of the blood at the inlet and outlet of the hollow fiber and the filtrate were sampled, and the blood was separated into serum by centrifugation, and then BCG (Brom, trade name) of A / GB B-Test Wako (Wako Pure Chemical Industries) Cresol green) method kit was used, and albumin permeability (%) was calculated from the concentration. In calculating the concentration of the filtrate, an albumin calibration curve was prepared by appropriately diluting the serum albumin attached to the kit for the purpose of creating a calibration curve at a low concentration in order to obtain good sensitivity.

      Albumin permeability (%) = 100 × 2 × albumin concentration in filtrate ÷ (module inlet albumin concentration + module outlet albumin concentration) Equation 3

14 parts of polysulfone, 7 parts of polyvinyl pyrrolidone (K90) and 2 parts of water are dissolved in 77 parts of dimethylacetamide by heating, and dimethylacetamide / water is used as an injection solution from the mouth of the annular orifice having an outer diameter of 1.0 mm and an inner diameter of 0.7 mm. 85/15 was injected while being discharged, passed through a coagulation bath having water kept at 80 ° C. installed 1.0 cm below the base surface, and after washing with water, scraped into a casserole, hollow with an inner diameter of 300 μm and an outer diameter of 460 μm A yarn membrane was obtained. The base was kept at 60 ° C. The obtained hollow fiber membrane was washed with water at 100 ° C. for 2 hours, dried at 100 ° C., and then treated in air at 150 ° C. for 3 hours to obtain the membrane of Example 1. Twenty membranes obtained were bundled, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber, thereby producing a mini module. The minimodule has a diameter of about 7 mm and a length of about 12 cm. The water permeability was 153 ml / hr · Pa · m ² , the density of acidic groups was 21.7 μmol / g, and the basic groups were 11.1 μmol / g. The albumin permeability was 98%. Infrared spectroscopic analysis of the surface of the hollow fiber membrane confirmed the presence of a carboxyl group as an acidic group and an amino group as a basic group.

14 parts of polysulfone (Amoco Udel-P1700), 7 parts of polyvinylpyrrolidone (K90) and 2 parts of water are dissolved by heating in 77 parts of dimethylacetamide, and injected from the mouth of the annular orifice having an outer diameter of 1.0 mm and an inner diameter of 0.7 mm. While injecting dimethyl sulfoxide / water = 95/5 as a liquid, the liquid was discharged, passed through a coagulation bath having water kept at 80 ° C. installed 1.0 cm below the base surface, rinsed with water, and taken up in a cake. A hollow fiber membrane having an outer diameter of 300 μm and an outer diameter of 460 μm was obtained. The base was kept at 60 ° C. The obtained hollow fiber membrane was washed with water at 100 ° C. for 2 hours, dried at 100 ° C., and then treated at 150 ° C. in air for 5 hours to obtain the membrane of Example 2. Twenty membranes obtained were bundled, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber, thereby producing a mini module. The minimodule has a diameter of about 7 mm and a length of about 12 cm. The water permeability was 224 ml / hr · Pa · m ² , the density of acidic groups was 52.3 μmol / g, and the basic groups were 26.3 μmol / g. The albumin permeability was 98%. Infrared spectroscopic analysis of the surface of the hollow fiber membrane confirmed the presence of a carboxyl group as an acidic group and an amino group as a basic group.

Anti-human interleukin-6 antibody is dissolved in 10 ml of aqueous solution at a concentration of 1000 pg / ml, and the membrane of Example 2 is immersed therein and reacted with water-soluble carbodiimide. Were bound to amino and carboxyl groups on the membrane surface. Human interleukin IL-6 is dissolved in 25 ml of rabbit whole blood at a concentration of 500 pg / ml, and a circuit is formed by a peristaltic pump in accordance with the basic system of FIG. 1, and the membrane area (inside surface conversion) is 100 ml / min per 1 m ^2. Perfusion was performed for 20 min toward the hollow fiber lumen side at a flow rate. The concentration of human interleukin-6 in the rabbit blood after perfusion was measured and found to be 5 pg / ml.

In the same system as in Example 3, the blood flow was changed from 100 ml / min to a flow rate of 200 ml / min per 1 m ² of membrane area (inner surface conversion), and was carried out following the basic system of FIG. The filtration rate was 20 ml / min to 50 ml / min per m ² of membrane area (inner surface equivalent). The blood flow was stable, and within this filtration rate range, it could be carried out without fluctuation of the transmembrane pressure difference.

The module of Example 2 was filled with a 1000 ppm aqueous solution of polyethyleneimine (molecular weight 50,000), and sterilized by irradiation with γ rays at 25 kGy. Polyethyleneimine was partially cut but could be fixed on the membrane surface.
[ Comparative Example 3 ]

14 parts of polysulfone, 7 parts of polyvinyl pyrrolidone (K90) and 2 parts of water are dissolved in 77 parts of dimethylacetamide by heating, and dimethylacetamide / water is used as an injection solution from the mouth of the annular orifice having an outer diameter of 1.0 mm and an inner diameter of 0.7 mm. 85/15 was injected while being discharged, passed through a coagulation bath having water kept at 80 ° C. installed 1.0 cm below the base surface, and after washing with water, scraped into a casserole, hollow with an inner diameter of 300 μm and an outer diameter of 460 μm A yarn membrane was obtained. The base was kept at 60 ° C. The obtained hollow fiber membrane was washed with water at 100 ° C. for 2 hours, dried at 100 ° C., and then treated in air at 150 ° C. for 2 hours to obtain a membrane of Example 6. Twenty membranes obtained were bundled, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber, thereby producing a mini module. The minimodule has a diameter of about 7 mm and a length of about 12 cm. The water permeability was 147 ml / hr · Pa · m ² , the density of acidic groups was 15.7 μmol / g, and the basic group was 7.1 μmol / g. The albumin permeability was 95%. The presence of carboxyl groups and amino groups was confirmed by infrared spectroscopic analysis of the hollow fiber membrane surface.
[Example 6 ]

  Polysulfone (Amoco Corporation Udel-P3500) 8 parts, (Amoco Corporation Udel-P1700) 8 parts, Polyvinylpyrrolidone (International Special Products Inc .; hereinafter abbreviated as ISP) K30 4 parts, Polyvinylpyrrolidone (ISP K90) 2 parts 77 parts of acetamide and 1 part of water were dissolved by heating to obtain a stock solution.

The viscosity of the stock solution was 1.2 Pa · sec at 50 ° C. This stock solution is sent to a spinneret at a temperature of 50 ° C., and a solution consisting of 70 parts of dimethylacetamide and 30 parts of water is discharged 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 the formation, humidity was adjusted at a temperature of 30 ° C. and a dew point of 28 ° C., and after passing through a 250 mm dry zone atmosphere to which a dry mist of 10 microns or less was added, a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water was achieved. It was passed through a coagulation bath and passed through a water washing step at 80 ° C. for 15 minutes to obtain a wound bundle. The hollow fiber has an inner diameter of 300 μm and an outer diameter of 460 μm. This bundle is washed with water at 100 ° C. for 2 hours, dried at 100 ° C., further treated in a heat treatment process at 170 ° C. for 3.5 hours, filled into a case so as to have a membrane area of 1.6 m ² and potted. The blood purification module was obtained by opening both ends of the end portion. Thereafter, in a dry state, γ-ray irradiation (25 KGy) was performed to sterilize to obtain a membrane of Example 7.

  The obtained membrane was cut out, bundled 20 pieces, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber, thereby producing a mini module. The minimodule has a diameter of about 7 mm and a length of about 12 cm.

Further, the water permeability of the hollow fiber after drying was 8200 ml / hr · kPa · m ² , and the surface functional group amount was 56.2 μmol / g acidic group and 28.3 μmol / g basic group. The albumin permeability was 10.5%. The presence of carboxyl groups and amino groups was confirmed by infrared spectroscopic analysis of the hollow fiber membrane surface.

Comparative Example 1

14 parts of polysulfone (Amoco Udel-P1700), 7 parts of polyvinylpyrrolidone (K90) and 2 parts of water are dissolved by heating in 77 parts of dimethylacetamide, and injected from the mouth of the annular orifice having an outer diameter of 1.0 mm and an inner diameter of 0.7 mm. While injecting dimethyl sulfoxide / water = 95/5 as a liquid, the liquid was discharged, passed through a coagulation bath having water kept at 80 ° C. installed 1.0 cm below the base surface, rinsed with water, and taken up in a cake. A hollow fiber membrane having an outer diameter of 300 μm and an outer diameter of 460 μm was obtained. The base was kept at 60 ° C. The obtained hollow fiber membrane was washed with water at 100 ° C. for 2 hours and then dried at 100 ° C. for 1 hour to obtain a membrane of Comparative Example 1. Twenty membranes obtained were bundled, and both ends were fixed to the glass tube module case with an epoxy-based potting agent so as not to block the hollow portion of the hollow fiber, thereby producing a mini module. The minimodule has a diameter of about 7 mm and a length of about 12 cm. The water permeability was 91 ml / hr · Pa · m ² , the density of acidic groups was 4.3 μmol / g, the basic groups were 2.1 μmol / g, and the basic groups could not be detected substantially. The albumin permeability was 64%. Infrared spectroscopic analysis of the surface of the hollow fiber membrane confirmed only the presence of carboxyl groups.

Comparative Example 2

The anti-human IL-6 membrane was immersed in the aqueous solution system at a concentration of 10 ml and 1000 pg / ml using water-soluble carbodiimide on the membrane of Comparative Example 1, and bound to the amino group and carboxyl group on the membrane surface. Human IL-6 is dissolved in 25 ml of rabbit whole blood at a concentration of 500 pg / ml, and a circuit is formed according to the basic system of FIG. 1 by a peristaltic pump, at a flow rate of 100 ml / min per 1 m ^{2 of} membrane area (inner surface equivalent). Perfusion was performed for 20 min toward the hollow fiber lumen. The concentration of human interleukin IL-6 in the rabbit blood after perfusion was measured and found to be 385 pg / ml. Real adsorption was not possible.

FIG. 1 is a schematic view of one embodiment of the blood purification system of the present invention.

Explanation of symbols

1: Plasma separation membrane (addition of adsorption group)
2: Plasma pump (100ml / min-120ml / min fluctuation)
3: Plasma pump (20ml / min)
4: Plasma pump (20ml / min)
5: Subject (human, animal)
6: Branch valve 7: Plasma outlet 1
8: Plasma outlet 2
9: Blood inlet 10: Plasma outlet 11: Branch valve

Claims (10)

Permeability is 7500ml / hr · kPa · m ² or more, albumin permeability is 10% or more, and one or more acidic functional groups selected from carboxyl group and sulfonic acid group, first grade, second grade, third grade , and one or more basic functional group selected from quaternary amines and imines, consists loaded with hollow fiber membranes, Ru der both 10 .mu.mol / g or more density is the density and the basic group of the acidic group plasma membrane for separation. The acidic functional group or the basic film for plasma separation according to claim 1 which the functional group through, characterized in that combines materials with different molecules of the film. Membrane for plasma separation according to claim 1 or 2, characterized in that it comprises a polysulfone-based resin and polyvinylpyrrolidone. Membrane for plasma separation according to any one of claims 1 to 3, characterized in that the material is different from the polymer of the membrane were bound by radiation crosslinking. The polymer is polyethylene imine, polyethylene glycol, alginate, chitosan, membranes for plasma separation according to claim 4, characterized in that from one or more selected group consisting of polyphosphoric acid and hyaluronic acid. Unnecessary substance and binding substance and / or membrane for plasma separation according to claim 1, a substance capable of inducing immunostimulatory effects, characterized in that supported on the membrane in the blood. Module incorporating membrane according to any one of claims 1-6. Using modules incorporating a membrane for plasma separation according to claim 7, blood purification system. 9. The blood purification system according to claim 8 , further comprising a mechanism for recirculating the plasma after plasma separation, rejoining the blood, and introducing the blood into the module. When merged with the recirculated again blood plasma, according to claim 8 or 9, characterized in that it has a mechanism for changing the amount of blood introduced to the module on the total amount of blood volume and the circulating plasma volume of initial setting Blood purification system.

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