JP3431622B1 - High-performance plasma purification membrane - Google Patents

Abstract

An object of the present invention is to provide a plasma purification membrane which is less clogged, has high strength, and has excellent water permeability and fractionation performance, for plasma purification by internal pressure filtration. SOLUTION: The membrane has a sponge structure in which the pore size continuously decreases from the outer surface to the inner surface, the membrane has a breaking strength of 50 kgf / cm ² or more, and the total protein when bovine plasma is subjected to internal pressure filtration. A plasma purification membrane having a transmittance of 50% or more and an immunoglobulin transmittance of 90% or less.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an excellent plasma purification membrane for plasma purification by internal pressure filtration, which has low clogging and high strength.

[0002]

Hollow fiber membranes are widely used for industrial applications from microfiltration to ultrafiltration. Polyethylene, cellulose acetate, polysulfone, polyvinylidene fluoride, polycarbonate, polyacrylonitrile, etc. are used as membrane materials. Has been. Conventional hollow fiber membranes made of these materials were developed with a focus on improving filtration performance, so the hollow fiber membranes have a small breaking strength and elongation at break, and do not undergo rapid temperature changes or backwashing. It has been pointed out that the hollow fiber membrane is often ruptured due to the pressure change.

Various attempts have been made to solve this point, but generally, as suggested by the invention described in Patent Document 1, the polymer concentration in the membrane-forming stock solution is increased to A method of increasing the polymer density of the entire hollow fiber membrane can be considered. However, in this method, the strength of the membrane is improved, but the pore diameter of the membrane is reduced and the water permeation rate of the membrane is significantly reduced. Therefore, a hollow fiber membrane having an excellent balance between strength and water permeation performance has not been obtained.

On the other hand, in order to improve the water permeability of the membrane, a method of enlarging the pore size of the membrane is generally carried out, but an increase in the pore size generally leads to a reduction in the membrane fractionation performance and the membrane strength. As described above, according to the prior art, a high performance hollow fiber membrane having a good balance of strength, water permeability and fractionation performance has not been obtained. For example, Patent Document 2 proposes a method for producing a membrane having high strength and excellent water permeability. However, the membrane produced by this method has a large pore size, and water permeability and fractionation performance are well balanced. Not not.

In Patent Document 3, a hollow fiber type microfiltration membrane in which the pore diameter continuously decreases from the outer surface of the membrane toward the inside thereof, and the pore diameter continuously increases again through the minimum pore diameter of the inner portion to open on the inner surface. Is disclosed. However, when liquid or the like is filtered from the hollow side (inner surface side) of the membrane using the membrane of this structure, rapid clogging occurs and stable filtration cannot be performed for a long time.

As described above, in the conventional hollow fiber membrane,
There is provided a product that has desired strength, water permeability and fractionation performance in a well-balanced manner, and that does not cause clogging even when liquid is filtered from the hollow side (inner surface side). Didn't.

[0007]

[Patent Document 1] JP-A-59-228016

[Patent Document 2] Japanese Patent Laid-Open No. 4-260424

[Patent Document 3] Japanese Patent Laid-Open No. 2-102722

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems, and in plasma purification in internal pressure filtration, there is little clogging, high strength, and water permeability and fractionation performance. It is also to provide an excellent plasma purification membrane.

[0009]

[Means for Solving the Problems] As described above, when a liquid or the like is filtered from the hollow side of the membrane (hereinafter also referred to as "internal pressure filtration"), the plasma purification membrane has less clogging and excellent protein separation properties. Was never here. Because, while maintaining high film strength on the inner surface of the film of the inclined structure, the pore diameter of which gradually decreases from the outer surface to the inner surface of the film,
This is because it has hitherto been impossible to open a large pore size (pore size of the microfiltration membrane region) that allows plasma proteins to pass through without problems.

Therefore, the present inventor basically 1) uses a gradient structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane in order to prevent clogging, and 2).
In particular, as a result of conducting intensive research to solve the above problems while preventing the hydrophobic adsorption of proteins and the like in a membrane with an increased hydrophilicity on the inner surface of the membrane that is in contact with the liquid to be filtered, as a result of a specific manufacturing method, The inventors of the present invention have found that the desired film described above can be obtained and have reached the present invention.

That is, the present invention (1) has a sponge structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane, the rupture strength of the membrane is 50 kgf / cm ² or more, and the bovine plasma has an internal pressure. A hollow fiber plasma purification membrane having a total protein permeability of 50% or more and an immunoglobulin permeability of 90% or less when filtered, (2)
The hollow fiber plasma purification membrane according to (1), which has circular or elliptical pores having an average pore diameter of 1 μm or more on the outer surface of the membrane, and (3) the porosity of the outer surface of the membrane is 10 %
The hollow fiber plasma purification membrane according to (1) or (2) above, characterized in that the ratio of the membrane thickness to the inner diameter of the membrane is 0.15 to 0.4. (1) ~
(3) The hollow fiber plasma purification membrane according to (3), wherein the membrane has an outer diameter of 400 μm or less (1) to (4)
(6) The hollow fiber plasma purification membrane according to (6), which comprises aromatic polysulfone and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane is 20 to 45% by weight. (1) to (5) The present invention relates to the hollow fiber plasma purification membrane described above and (7) the hollow fiber plasma purification membrane according to any one of (1) to (6), which contains water-insoluble polyvinylpyrrolidone.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The structure of the hollow fiber plasma purification membrane of the present invention (hereinafter also simply referred to as "membrane" or "hollow fiber membrane") will be described below. In the present invention, plasma purification refers to separation of plasma components. For example, it means that albumin and γ-globulin, which are useful proteins in plasma, are permeated and unnecessary proteins and lipids are removed. However, the components to be removed, the molecular weight cut-off, etc. differ depending on the disease. The blood purification of (1) widely includes the separation of components in plasma.

The hollow fiber membrane of the present invention has an integrally continuous structure from one surface of the membrane to the other surface, for example, from the inner surface to the outer surface. Between one surface of the membrane and the other surface, that is, the inside of the membrane, has a mesh structure having a mesh size (pores) of 10 μm or less, and a polymer deficient site (large size) exceeding 10 μm. Does not include pores or voids. This structure is called a sponge structure in the present invention. The pores of the network structure inside the membrane have a graded structure in which the pore diameter continuously decreases from the outer surface of the membrane toward the inner surface (or inner surface portion) in a cross section perpendicular to the length direction of the membrane. . That is, when considering several cylindrical surfaces having concentric central axes extending in the length direction of the hollow fiber membrane, the average pore diameter of the pores on each surface is:
It becomes smaller continuously from the outer surface of the membrane toward the inner surface (or inner surface portion). When plasma is subjected to internal pressure filtration, this structure is indispensable in order to express sharp fractionation performance (excellent protein separation).

Representative examples of the film of the present invention will be described in more detail with reference to the drawings. FIG. 1 is an electron micrograph of a cross section (a part) perpendicular to the length direction of the hollow fiber membrane. Further, FIG. 2 is an electron micrograph showing the state of the inner surface of the film, and FIG. 3 is an electron micrograph showing the state of the outer surface of the film.

As shown in FIG. 1, this membrane has a graded structure in which the average pore size gradually decreases continuously as it approaches the inner surface of the membrane, that is, a mesh structure having anisotropy in pore size. There is. Although the inner surface of the film has a dense structure, the film of the present invention does not have a clear skin layer as conventionally known. FIG. 2 shows the appearance of the dense inner surface. On the other hand, as can be seen from FIG. 3, circular or elliptical holes are observed on the outer surface.

The pores opening on the inner surface of the membrane are preferably circular, elliptical, mesh-like or slit-like, and the pores on the outer surface are preferably circular or elliptical.

The average pore size of the pores opening on the outer surface of the membrane is 1 μm.
m or more, preferably 2 μm or more and 30 μm or less. 1
It is not preferable that the pores are smaller than μm, because molding defects due to the adhesion of the films to each other occur.

Further, the opening ratio of the holes on the outer surface is also important in order to prevent the films from sticking to each other. The aperture ratio in the present invention is
It is determined by image analysis of the electron micrograph of the outer surface of the dry film and digitization. The aperture ratio in the present invention means
It is defined as the percentage of the sum of the area of the open hole with respect to the area of the captured image, and is given by the following equation (1). In addition,
Below 10 pixels were considered noise and excluded from counting. Open area ratio (%) = (sum of open area of open area / area of captured image) × 100 (1)

The porosity greatly contributes to the adhesion between the membranes, and when the porosity is small, the contact area between adjacent membranes increases and the adhesion occurs. In the worst case, the entire bundle adheres in a rod shape. There are even things. Therefore, it is necessary to secure a porosity of 10% or more. However, if the porosity is unnecessarily increased, this time the film bends in the long axis direction, that is, the strength of the waist is impaired, and as a result, defective molding frequently occurs due to film flow at the bonded portion during molding. Therefore, it is preferable that the upper limit of the porosity is 60% so as not to impair the stiffness of the waist.

The shape and size of the holes opened on the surface of the film can be observed and measured using an electron microscope.
Further, the average pore diameter D of the holes opened on the inner surface and the outer surface is a value represented by the following formula (2). D = [{(D _i ² ) ² + ... + (D _n ² ) ² } / {D _i ² + ... + D _n ² }] ^1/2 (2) where D is the average pore diameter and D _i is The measured diameter of the i-th hole, D _n
Is the measured diameter of the n-th hole. However, the measured diameters of D _i and D _n are represented by the diameter of the hole when the hole is close to a circle, and by the diameter of a circle having the same area as the hole when the hole is not circular.

The membrane of the present invention has a total protein permeability of 50% or more, preferably 80%, when bovine plasma is subjected to internal pressure filtration.
It is the above film. When the total protein permeability is less than 50%, albumin (Alb), which is extremely effective for the human body, γ
-Globulin (IgG) is greatly lost, and it is difficult to use for the treatment of patients with weak physical strength.

Further, the membrane of the present invention has a performance of immunoglobulin (IgM) permeability of 90% or less when bovine plasma is subjected to internal pressure filtration. Albumin and γ-globulin are extremely effective proteins for the human body, whereas high molecular weight proteins such as immunoglobulins or lipids need to be removed depending on the disease. 90 transmittance
If it exceeds%, it tends to be ineffective against diseases such as hyperlipidemia.

The membrane of the present invention has an inclined structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane, and has a large pore diameter that allows plasma proteins to pass through the inner surface of the membrane without any problem. Nevertheless, the breaking strength of the film is 50k
It is gf / cm ² or more, and further 60 kgf / cm ² or more. If the rupture strength of the film is less than 50 kgf / cm ² , leaks frequently occur, which is not practical. The breaking strength referred to in the present invention is obtained by dividing the load (kgf) at the time of breaking per hollow fiber membrane by the cross-sectional area (cm ² ) of the membrane before being pulled.

Examples of the material constituting the hollow fiber membrane of the present invention include polysulfone-based polymers, polyvinylidene fluoride-based polymers, polyacrylonitrile-based polymers,
Polymethacrylic acid type polymer, polyamide type polymer,
Examples include polyimide-based polymers, polyetherimide-based polymers, and cellulose acetate-based polymers. Among them, aromatic polysulfone is preferably used because it has improved blood compatibility by adding a hydrophilic polymer to a stock solution for forming a film in addition to its thermal stability, acid resistance and alkali resistance. Bisphenol A type polysulfone is particularly preferably used as the aromatic polysulfone. When the material forming the hollow fiber membrane is aromatic polysulfone, polyvinylpyrrolidone is most preferable as the hydrophilic polymer.

From the above, the membrane of the present invention is most preferably composed of aromatic polysulfone and polyvinylpyrrolidone. Further, since the plasma purification membrane of the present invention is used by internal pressure filtration, it is preferable that the concentration of polyvinylpyrrolidone on the inner surface of the membrane which is in contact with plasma is 20 to 45% by weight. Plasma proteins are prone to hydrophobic adsorption. Therefore, an important factor in suppressing clogging in internal pressure filtration is the hydrophilicity of the inner surface of the membrane with which plasma is in contact,
Polyvinylpyrrolidone (hereinafter also simply referred to as "PVP")
In the polysulfone-based membrane containing, the PVP concentration on the inner surface of the membrane is important. If the PVP concentration on the inner surface of the membrane is too low, the inner surface of the membrane becomes hydrophobic and plasma proteins are easily adsorbed. On the other hand, if the PVP concentration on the inner surface of the membrane is too high, the amount of PVP eluted into plasma increases, giving unfavorable results. Therefore, the concentration of PVP in plasma pressure filtration is 20
The range is from 45 to 45% by weight, preferably 25 to 40% by weight.

Examples of the aromatic polysulfone used in the present invention include those having a repeating unit represented by the following formula (3) or formula (4). In addition, A in the formula
r represents a 2-substituted phenyl group at the para position, and the degree of polymerization and the molecular weight are not particularly limited. _{-O-Ar-C (CH 3} ) 2 -Ar-O-Ar-SO 2 -Ar- (3) -O-Ar-SO 2 -Ar- (4)

Since the higher the molecular weight of polyvinylpyrrolidone is, the higher the hydrophilic effect on the membrane is, the smaller the molecular weight of polyvinylpyrrolidone is, the smaller the amount of polyvinylpyrrolidone is. Is used. A large amount of polyvinylpyrrolidone must be left in the membrane in order to impart a hydrophilic effect to the membrane by using polyvinylpyrrolidone having a weight average molecular weight of less than 900,000. Will increase. On the contrary, if the residual amount of polyvinylpyrrolidone having a weight average molecular weight of less than 900,000 in the film is reduced in order to reduce the eluate, the hydrophilic effect becomes insufficient. In addition, since the hydrophilicity in the film thickness portion is insufficient unless polyvinylpyrrolidone having a weight average molecular weight of 900,000 or more is used, the plasma protein that has passed through the inner membrane surface dense layer (inner membrane surface site) has a membrane thickness. It is adsorbed on the part, and as a result, good separation characteristics cannot be exhibited.

The PVP concentration on the inner surface of the film is determined by X-ray photoelectron spectrum (X-ray Photoelectron spectroscopy).
n spectroscopy, hereinafter XPS). That is, the XPS of the inner surface of the film is measured by arranging the samples on the double-sided tape, incising in the fiber axis direction with a cutter, expanding the inside of the film so that it is on the front side, and then measuring by an ordinary method. . That is, C1s, O1s, N1
It means the concentration obtained from the surface intensity of s, S2p spectrum and the surface concentration of nitrogen (nitrogen atom concentration) and the surface concentration of sulfur (sulfur atom concentration) using the relative sensitivity coefficient attached to the device. When is the structure of equation (3), it can be calculated by equation (5). PVP concentration (% by weight) = C ₁ M ₁ × 100 / (C ₁ M ₁ + C ₂ M ₂ ) (5) where C ₁ : nitrogen atom concentration (%) C ₂ : sulfur atom concentration (%) M ₁ : Molecular weight of PVP repeating unit (111) M ₂ : Molecular weight of repeating unit of polysulfone polymer (442)

Further, the membrane of the present invention contains P which is insoluble in water.
Have a VP. When all PVP in the membrane is soluble in water, the amount eluted from the membrane is large, which is not preferable, and when all PVP is insoluble in water, the swelling property of the inner surface (or inner surface portion) of the membrane during plasma filtration may be poor. It does not exhibit excellent protein separation performance because it is bad. Therefore, the membranes of the present invention are P-insoluble in water.
It has excellent film performance because it contains VP in an appropriate amount.

A representative example of the method for producing the hollow fiber membrane of the present invention will be described below. The hollow fiber membrane of the present invention is a method for producing a hollow fiber membrane in which a membrane-forming stock solution and an internal solution are discharged from a double annular nozzle, and then passed through an air gap and then solidified in a coagulation bath. Is a film-forming polymer, a solvent for the polymer,
And a hydrophilic polymer, the ratio of the hydrophilic polymer to the film-forming polymer is 30 to 60% by weight, b) the internal liquid is water and at least one kind of solvent, and the water content is 40 to 55% by weight, c) the temperature of the film forming stock solution in the nozzle portion is 50 ° C. or higher, d) the coagulation bath temperature exceeds 90 ° C. and 100 ° C. or lower , and e) the ratio of the air gap to the spinning speed is 0.01 to 0.
It is possible to produce the membrane obtained by the production method of 1 m / (m / min) by drying without impregnating the membrane pore retaining agent.

The hollow fiber membrane of the present invention is a film-forming polymer,
A solvent for the polymer and a film-forming stock solution essentially consisting of a hydrophilic polymer are discharged from a double annular nozzle together with an internal solution consisting of an aqueous solution of a good solvent for the polymer at a specific concentration, and after passing through an air gap, It is produced by coagulating in a coagulating bath.

The film-forming polymer used in the production method of the present invention may be any polymer capable of forming a film by wet film formation, and examples thereof include polysulfone-based polymers, polyvinylidene fluoride-based polymers, polyacrylonitrile-based polymers, and polyacrylonitrile-based polymers. Examples thereof include methacrylic acid-based polymers, polyamide-based polymers, polyimide-based polymers, polyetherimide-based polymers and cellulose acetate-based polymers. Among them, aromatic polysulfone is preferably used because it is improved in blood compatibility by adding a hydrophilizing agent to a stock solution for film formation in addition to its thermal stability, acid resistance and alkali resistance. Bisphenol A type polysulfone is particularly preferably used as the aromatic polysulfone.

The hydrophilic polymer is compatible with the solvent,
A polymer that does not dissolve the film-forming polymer is used. If the film-forming polymer is a polysulfone-based polymer, polyvinylpyrrolidone is preferably used as the hydrophilic polymer. When the film-forming polymer is aromatic polysulfone, it is difficult to obtain the film of the present invention by using a hydrophilic polymer other than polyvinylpyrrolidone.

As a solvent for the polymer, N-methyl-2
-Pyrrolidone, N, N-dimethylformamide, N, N
Examples of the solvent include dimethylacetamide, and when the film-forming polymer is a polysulfone-based polymer, N-methyl-2-pyrrolidone (hereinafter simply referred to as “NMP”) is preferable. NMP is a solvent having the highest dissolving power for polysulfone-based polymers. For example, it has a dissolving power of about 1.5 times at room temperature as compared with another good solvent, N, N-dimethylacetamide. In order to open a large pore size that allows plasma proteins to pass through the inner surface of the membrane in a gradient structure where the pore size continuously decreases from the outer surface to the inner surface of the membrane, liquid-liquid phase separation is induced by the non-solvent in the inner liquid. It is necessary to lengthen the time from the completion of the separation to the completion of phase separation (solidification), that is, the particle growth time. In polysulfone-based polymers, it is possible to extend the particle growth time by using NMP, which has a very high dissolving power, than by using any solvent. Furthermore, since NMP is the best solvent in the polysulfone-based polymer, the molecular chains of the polysulfone-based polymer in the stock solution for film formation are well entangled with each other, and as a result, a high-strength film can be obtained. For the above reasons, when the film-forming polymer is a polysulfone-based polymer, it is difficult to obtain the film of the present invention by using a solvent other than NMP.

The film-forming stock solution essentially consists of a film-forming polymer, a specific hydrophilic polymer such as polyvinylpyrrolidone, and a specific solvent such as N-methyl-2-pyrrolidone. If other additives such as water and metal salts, which are conventionally known as additives, are added to the film-forming stock solution, it is difficult to obtain the film of the present invention.

The polymer concentration of the stock solution for film formation used in the present invention is not particularly limited as long as it is within a concentration range such that film formation from the stock solution is possible and the obtained film has performance as a film. , 10 to 35% by weight, preferably 10 to 30% by weight. In order to achieve high water permeability or large molecular weight cutoff, it is preferable that the polymer concentration is low,
5% by weight is preferred.

What is more important is the amount of the hydrophilic polymer in the stock solution for film formation, and the mixing ratio of the hydrophilic polymer to the film-forming polymer is 27 to 60% by weight, preferably 30 to 60% by weight.
It is 60% by weight. If the mixing ratio of the hydrophilic polymer to the film-forming polymer is less than 27% by weight, the protein permeability tends to decrease when bovine plasma is subjected to internal pressure filtration.
If it exceeds 0% by weight, the viscosity of the stock solution for film formation becomes high and the spinnability during film formation tends to deteriorate, such being undesirable.

Further, the temperature of the film-forming stock solution is important, and the temperature of the film-forming stock solution at the time of discharge by the nozzle is 50 ° C. or higher, preferably 60 to 100 ° C. If it is less than 50 ° C, the spinnability during film formation tends to be poor.

The internal liquid is used to form the hollow portion of the hollow fiber membrane and is composed of water and a good solvent for at least one kind of the film-forming polymer. The water content is preferably 40 to 55% by weight. If the water content is less than 40% by weight, the spinnability during film formation is poor, and if it exceeds 55% by weight, the protein permeability tends to decrease when bovine plasma is subjected to internal pressure filtration.

Air gap means the gap between the nozzle and the coagulation bath. In order to obtain the membrane of the present invention, the spinning speed (m /
The ratio of air gap (m) to minute) is extremely important. Because the membrane structure of the present invention, the non-solvent in the internal solution is contacted with the film-forming stock solution to induce phase separation over time from the inner surface part of the film-forming stock solution to the outer surface part side,
Further, if the phase separation from the inner surface portion to the outer surface portion of the film is not completed by the time the stock solution for film formation enters the coagulation bath, it cannot be obtained.

The ratio of the air gap to the spinning speed is 0.
It is preferably from 01 to 0.1 m / (m / min), more preferably from 0.01 to 0.05 m / (m / min). The ratio of air gap to spinning speed is 0.010m /
When it is less than (m / min), it is difficult to obtain a film having the structure and performance of the present invention, and when it exceeds 0.1 m / (m / min), the tension to the film is high, so that the film is formed in the air gap portion. It is not preferable because it often breaks and tends to be difficult to manufacture.

Here, the spinning speed means a series of manufacturing steps of a hollow fiber membrane in which a membrane-forming raw solution discharged from a nozzle together with an internal solution passes through an air gap and is wound up in a coagulating bath. It means the winding speed when there is no stretching operation inside. Also, by enclosing the air gap with a cylindrical tube or the like and flowing a gas having a constant temperature and humidity at a constant flow rate into the air gap, the hollow fiber membrane can be manufactured in a more stable state.

As the coagulation bath, for example, water; methanol,
Liquids such as alcohols such as ethanol; ethers; aliphatic hydrocarbons such as n-hexane and n-heptane that do not dissolve the polymer are used, and water is preferable. Also,
It is also possible to control the coagulation rate and the like by adding a small amount of a solvent that dissolves the polymer to the coagulation bath.
The temperature of the coagulation bath is preferably 90 to 100 ° C. If the temperature of the coagulation bath is lower than 90 ° C., the protein permeability tends to decrease when bovine plasma is subjected to internal pressure filtration, and if the temperature is 100 ° C. or higher, thread breakage and the like frequently occur during film formation, which is not preferable.

Further, in order to obtain the film of the present invention, the ratio of the film thickness to the inner diameter of the film after coagulation is 0.15 to 0.4, preferably 0.2 to 0.3. If the ratio of the film thickness to the inner diameter of the film is less than 0.15, the absolute strength of the film tends to be weak. If the ratio exceeds 0.4, it tends to be difficult to obtain a graded structure in which the pore diameter decreases from the outer surface to the inner surface (or the inner surface portion) of the membrane as in the present invention. Because the ratio of the amount of solvent in the film-forming stock solution to the amount of non-solvent in the internal solution is large, only the amount of non-solvent in the internal solution is enough to remove the amount of non-solvent in the internal solution from the inner surface of the film before entering the coagulation bath. This is because the phase separation up to the outer surface part cannot be completed.

The outer diameter of the film is 400 μm or less, preferably 300 μm or less. When the outer diameter of the membrane becomes large, the membrane area (filling amount) in the module is unavoidably reduced, resulting in poor processing capacity per unit time, which is not preferable. On the contrary, in order to increase the outer diameter of the membrane to make the membrane area (filling amount) in the module the same, the module container must be enlarged, resulting in an increase in cost, which is not preferable. Since the membrane of the present invention is used in medical applications, it is necessary to avoid making an expensive large-sized module in order to reduce the burden of medical expenses on the patient. The outer diameter of the film is preferably 400 μm or less in view of the above-mentioned processing capacity and cost.

Further, the membrane of the present invention can be dried, and a humectant such as glycerin may or may not be impregnated at the time of drying.

Furthermore, by irradiating the membrane with radiation such as electron rays and γ rays, a part of PVP in the membrane can be insolubilized in water, so that the amount eluted from the membrane can be reduced. Irradiation may be performed before or after modularization. The water-insoluble PVP referred to in the present invention means PV that is soluble in water from the total amount of PVP in the membrane.
The amount of P is subtracted. The total amount of PVP in the film can be easily calculated by elemental analysis of nitrogen and sulfur.

The amount of PVP soluble in water can be determined by the following method. For example, when the film-forming polymer is a polysulfone-based polymer, the film is N-methyl-
After completely dissolving with 2-pyrrolidone, water is added to the obtained polymer solution to completely precipitate the film-forming polymer. After allowing the polymer solution to stand still, the amount of PVP in the supernatant can be quantified by liquid chromatography to quantify the PVP soluble in water.

[0049]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto. Each measuring method is as follows. The hollow fiber membranes used as measurement samples were all in a dry state.

(Measurement of Water Permeability) A yarn bundle having an effective length of 180 mm with both ends fixed by an adhesive (110 ± 10 in terms of internal surface area)
It was permeated from the inner surface to the outer surface of a mini module (having a uniform number of membranes so as to be cm ² ), and the amount was expressed in mL (milliliter) / (m ² · hr · mmHg). However,
The effective film area was converted to the inner surface.

(Measurement of breaking strength) The film strength was measured by using Autograph AGS-5D manufactured by Shimadzu Corporation at a sample length of 20 mm and a pulling speed of 300 mm / min.

(Evaluation of bovine plasma) Bovine plasma was supplied at 0.5 mL / min into one hollow portion (inner surface side) of a yarn bundle (mini module) having an effective length of 180 mm with both ends fixed with an adhesive.
Further, cross-flow filtration was performed for 180 minutes by one pass under the condition that the liquid was extracted from the other hollow portion at 0.1 mL / min. Regarding the membrane area of the yarn bundle, the number of membranes was adjusted so that the linear velocity was 1 cm / min with respect to the bovine plasma supply amount of 0.5 mL / min. The membrane performance was evaluated by determining the concentration of each protein in the solution obtained by uniformly stirring the entire filtrate filtered for 180 minutes and in the plasma before filtration. Further, the transmittance is a value represented by (6) below. Transmittance (%) = (concentration in filtrate) / (concentration in original solution) × 100 (6)

(Measurement of total protein amount) The total protein amount (concentration) was determined by measuring the total protein coloring reagent (Wako Pure Chemical Industries, Ltd.) for 0.1 mL of liquid (plasma (original liquid) or filtrate from the membrane).
(Manufactured by K.K.) and mixed with each other for 30 minutes and then measured with a spectrophotometer at a wavelength of 540 nm.

(Measurement of Immunoglobulin Concentration) The concentration of immunoglobulin in the plasma (original solution) or the filtrate from the membrane is
Behring Nepherometer-Anal
It measured using yzer BM (made by Dade Behring Co., Ltd.).

[0055]

[Example 1] (Film formation and removal of residual solvent) Polysulfone (Amoco Engineering Polymer)
rs P-1700) 20.0 wt%, polyvinylpyrrolidone (BASF K90, weight average molecular weight 1,
6.0% by weight of 200,000) was dissolved in 74.0% by weight of N-methyl-2-pyrrolidone to obtain a uniform solution.
Here, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 30.0% by weight. This film-forming stock solution was kept at 60 ° C., and the spinneret (double ring) was formed along with an internal solution (water content was 54% by weight) consisting of a mixed solution of 46% by weight of N-methyl-2-pyrrolidone and 54% by weight of water. Nozzle 0.1 mm-0.2 mm-0.3 mm, nozzle temperature 60 ° C., temperature of the stock solution for film formation at the nozzle part 60 ° C.), and the mixture was passed through an air gap of 0.96 m to reach 95
It was immersed in a coagulation bath consisting of water at ± 1 ° C. At this time, the spinneret and the coagulation bath were surrounded by a cylindrical tube and sealed so that outside air did not enter. The spinning speed was fixed at 80 m / min. here,
The ratio of air gap to spinning speed is 0.012m /
(M / min). After cutting the wound yarn bundle, the residual solvent in the film was removed by washing from above the cut surface of the yarn bundle with a hot water shower at 80 ° C. for 2 hours. The film was further dried with hot air at 87 ° C. for 7 hours to obtain a dry film having a water content of less than 1%. Furthermore, 2.5 Mrad γ
A part of PVP in the film was insolubilized by irradiation with a ray.

Observation of the obtained film with an electron microscope revealed that the film had a sponge structure in which the pore size continuously decreased from the outer surface to the inner surface of the film. 1 to 3 show electron micrographs of the film obtained in this example. Table 1 shows other film structures and film performances.
The rupture strength of the membrane was as high as 50 kgf / cm ² or more, and the total protein permeability was 50% or more when bovine plasma was subjected to internal pressure filtration. Further, even in the internal pressure filtration of bovine plasma, a stable amount of filtrate was maintained for a long time without sudden clogging.

[0057]

Example 2 The same operation as in Example 1 except that an internal liquid (water content of 46% by weight) consisting of a mixed solution of 54% by weight of N-methyl-2-pyrrolidone and 46% by weight of water was used. I went. When the obtained film was observed with an electron microscope,
It was revealed that the sponge structure has a pore size that continuously decreases from the outer surface to the inner surface of the membrane. Table 1 shows other film structures and film performances. The breaking strength of the film is 5
The strength was as high as 0 kgf / cm ² or more, and the total protein permeability was 50% or more when bovine plasma was subjected to internal pressure filtration. Further, even in the internal pressure filtration of bovine plasma, a stable amount of filtrate was maintained for a long time without sudden clogging.

[0058]

[Example 3] The same operation as in Example 1 except that an internal solution (content of water was 42% by weight) consisting of a mixed solution of 58% by weight of N-methyl-2-pyrrolidone and 42% by weight of water was used. I went. When the obtained film was observed with an electron microscope,
It was revealed that the sponge structure has a pore size that continuously decreases from the outer surface to the inner surface of the membrane. Table 1 shows other film structures and film performances. The breaking strength of the film is 5
The strength was as high as 0 kgf / cm ² or more, and the total protein permeability was 50% or more when bovine plasma was subjected to internal pressure filtration. Further, even in the internal pressure filtration of bovine plasma, a stable amount of filtrate was maintained for a long time without sudden clogging.

[0059]

[Example 4] 1 polyvinylpyrrolidone in the film-forming stock solution
0.0 wt%, N-methyl-2-pyrrolidone 70.0
The same operation as in Example 1 was performed except that the content was changed to wt%.
At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 50.0% by weight. When the obtained film was observed by an electron microscope, it was revealed that the film had a sponge structure in which the pore size continuously decreased from the outer surface to the inner surface. Table 1 shows other film structures and film performances. The breaking strength of the film is 50kgf / c
It showed a high strength of m ² or more, and the total protein permeability was 50% or more when bovine plasma was subjected to internal pressure filtration. further,
Even in the internal pressure filtration of bovine plasma, a stable amount of filtrate was maintained for a long time without sudden clogging.

[0060]

[Example 5] The polyvinylpyrrolidone in the stock solution for film formation was changed to 8.
The same operation as in Example 1 was performed except that 0% by weight and 70.0% by weight of N-methyl-2-pyrrolidone were used. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 40.0% by weight. When the obtained film was observed by an electron microscope, it was revealed that the film had a sponge structure in which the pore size continuously decreased from the outer surface to the inner surface. Table 1 shows other film structures and film performances. The breaking strength of the film is 50 kgf / cm ²
The strength was high as described above, and the total protein permeability was 50% or more when bovine plasma was subjected to internal pressure filtration. Further, even in the internal pressure filtration of bovine plasma, a stable amount of filtrate was maintained for a long time without sudden clogging.

[0061]

[Comparative Example 1] The same operation as in Example 1 except that an internal solution (water content of 57% by weight) consisting of a mixed solution of 43% by weight of N-methyl-2-pyrrolidone and 57% by weight of water was used. I went. When the obtained film was observed with an electron microscope,
It was revealed that the sponge structure has a pore size that continuously decreases from the outer surface to the inner surface of the membrane. Table 2 shows other film structures and film performances. The permeation rate of total protein was less than 50% when bovine plasma was subjected to internal pressure filtration.

[0062]

[Comparative Example 2] The same operation as in Example 1 except that an internal solution (containing 38% by weight of water) consisting of a mixed solution of 62% by weight of N-methyl-2-pyrrolidone and 38% by weight of water was used. However, the yarn was frequently broken and the spinning could not be performed.

[0063]

[Comparative Example 3] The polyvinylpyrrolidone in the stock solution for film formation was compared with 5.
The same operation as in Example 1 was performed except that 0% by weight and 75.0% by weight of N-methyl-2-pyrrolidone were used. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 25.0% by weight. When the obtained film was observed by an electron microscope, it was revealed that the film had a sponge structure in which the pore size continuously decreased from the outer surface to the inner surface. Table 2 shows other film structures and film performances. The permeation rate of total protein was less than 50% when bovine plasma was subjected to internal pressure filtration.

[0064]

COMPARATIVE EXAMPLE 4 20% by weight of the polysulfone used in Example 1, 13% by weight of polyvinylpyrrolidone, and 67% by weight of N-methyl-2-pyrrolidone were not dissolved to form a uniform solution. .

[0065]

[Comparative Example 5] The temperature of the film forming solution was 45 ° C and the nozzle temperature was 4
The same operation as in Example 2 was carried out except that the temperature was 5 ° C. (the temperature of the stock solution for film formation at the nozzle portion was 45 ° C.), but yarn breakage occurred frequently and spinning was not possible.

[0066]

Comparative Example 6 The same operation as in Example 1 was carried out except that the solvent was changed from N-methyl-2-pyrrolidone to N, N-dimethylacetamide. When the obtained film was observed by an electron microscope, it was revealed that the film had a sponge structure in which the pore size continuously decreased from the outer surface to the inner surface. Table 2 shows other film structures and film performances. The permeation rate of total protein was less than 50% when bovine plasma was subjected to internal pressure filtration.

[0067]

[Table 1]

[0068]

[Table 2]

[0069]

INDUSTRIAL APPLICABILITY The membrane of the present invention is a membrane having less clogging in plasma purification in internal pressure filtration, has high strength, and is also excellent in water permeability and fractionation performance, and therefore is used in medicine. It can be used for medical applications and general industrial applications.

[Brief description of drawings]

FIG. 1 is an electron micrograph of a cross section perpendicular to the length direction of the hollow fiber membrane of the present invention (magnification: 1,500 times).

FIG. 2 is an electron micrograph of the inner surface of the film of the present invention (magnification: 10,000 times).

FIG. 3 is an electron micrograph of the outer surface of the film of the present invention (magnification: 10,000 times).

Claims (7)

(57) [Claims] 1. A sponge structure having a pore size that continuously decreases from the outer surface to the inner surface of the membrane, the breaking strength of the membrane is 50 kgf / cm ² or more, and the total protein when the bovine plasma is subjected to internal pressure filtration. Of 50% or more and 90% or less of immunoglobulin permeation rate. 2. The hollow fiber plasma purification membrane according to claim 1, which is a membrane having circular or elliptical pores having an average pore diameter of 1 μm or more on the outer surface of the membrane. 3. The hollow fiber plasma purification membrane according to claim 1, wherein the porosity of the outer surface of the membrane is 10% or more. 4. The ratio of the film thickness to the inner diameter of the film is 0.15.
It is -0.4, The hollow fiber plasma purification membrane in any one of Claims 1-3 characterized by the above-mentioned. 5. The hollow fiber-like plasma purification membrane according to claim 1, wherein the outer diameter of the membrane is 400 μm or less. 6. The hollow fiber plasma purification according to claim 1, which comprises aromatic polysulfone and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane is 20 to 45% by weight. film. 7. The hollow fiber plasma purification membrane according to claim 1, which contains polyvinylpyrrolidone which is insoluble in water.