JPH04371221A - Production of cuprammonium regenerated cellulose porous hollow fiber membrane - Google Patents

Abstract

PURPOSE:To obtain a cuprammonium regenerated cellulose porous hollow fiber membrane high in LRV with respect to a relatively small virus by using a U-shaped thin tube as the coagulation bath when the membrane is produced. CONSTITUTION:Two small funnel tubes are liquid-tightly connected at their lower parts with a U-tube or a connector having an internal U-shaped passage to form a thin tube 4. A spinning soln. A is firstly discharged from the outer outlet of an annular double spinneret 1, and an internal soln. B for separating the microphase of the soln. A and coagulating the soln. A is simultaneously discharged from the central outlet of the spinneret 1. Both solns. are introduced into a spinning cylinder 2 and the one tube 4a of the small funnel tube, and an external soln. C for separating the microphase of the soln. A and coagulating the soln. A is supplied at this time from the inlet of the spinning chamber 2. The coagulation of the soln. A proceeds in the thin tube 4 by the action of the solns. B and C with the microphase being separated. Since the fiber is spun without being sustantially drawn in this way, a membrane capable of permeating proteins and high in LRV is obtained.

Description

Detailed Description of the Invention [0001] [Industrial Application Field] The present invention is directed to the use of pores with an average pore size of 10 to 50
The present invention relates to a method for producing a cuprammonium regenerated cellulose porous hollow fiber membrane having a diameter of 0 nm. More specifically, it relates to a method for producing a porous hollow fiber membrane regenerated by the cuprammonium method, which is suitable for removing microbial particles such as viruses and bacteria from plasma, plasma fraction preparations, and protein-coexisting solutions such as culture media. be. [0002] Blood-borne viruses such as AIDS virus (HIV), hepatitis B virus (HBV), nAn
Infection with hepatitis B virus (NANBHV or HCV) has become a major social problem. Heat treatment and treatment with chemicals are used as methods to inactivate viruses that may be contaminated with blood products, but these treatments alone are not sufficient to inactivate viruses, and these methods In this case, useful proteins in blood products may also be denatured. Against this background, there is an increasing demand for membrane-based virus separation and removal technology as a physical virus removal method that does not involve chemical denaturation. [0003] The average pore diameter of the porous hollow fiber membrane used for this purpose is 10% due to the relationship with the size of the virus to be removed.
~500 nm range is required. In addition, in order to remove viruses from protein-coexisting solutions such as blood products and recover enough useful proteins for practical purposes, it is necessary to have a sharp pore size distribution, and the proteins will adsorb to the membrane material, reducing filtration performance. It is important not to let this happen. As a hollow fiber membrane that satisfies these requirements, a porous hollow fiber membrane made of regenerated cellulose using a cuprammonium method is currently known (Japanese Patent Application Laid-Open No.
9-204912, JP-A-59-204911). Conventionally, as a manufacturing method for this type of hollow fiber membrane, a cellulose cupric ammonia solution (hereinafter referred to as a spinning stock solution) is passed through an outer spinning port of an annular double spinneret to form a microphase separation and coagulation solution for the above-mentioned spinning stock solution. After simultaneously discharging the internal coagulating liquid (hereinafter referred to as the internal liquid) from the central spinneret of the annular double spinneret, the external coagulating liquid that is a microphase separation and coagulating liquid (hereinafter referred to as the external liquid) is discharged simultaneously. Solidification progresses as it flows down and falls through a spinning funnel filled with Next, a method was adopted in which the material was passed through a changing device, where it was further coagulated while traveling horizontally in a coagulation bath also filled with an external liquid, and then wound onto a frame (see FIG. 2). [0005] The cuprammonium regenerated cellulose porous hollow fiber membrane produced by this method can remove the AIDS virus (about 100 nm in size) with a high removal rate, and can also remove useful proteins in plasma with a high permeability. It has been confirmed that it has excellent recovery ability. However, according to the studies of the present inventors, the porous hollow fiber membrane is effective against relatively small viruses such as hepatitis B virus (approximately 42 nm in size) and nAn hepatitis B virus (approximately 30 to 60 nm in size). could not necessarily be said to have sufficient removal performance. For example, in a membrane with an average pore diameter of 30 nm obtained by the conventional manufacturing method described above, Japanese encephalitis virus (
When a filtration test was conducted using a virus with a particle diameter of approximately 45 nm, which is considered to be the same type as the nAn hepatitis B virus, the logarithmic inhibition coefficient LRV of the virus was approximately 2.4, which is satisfactory for practical use. It wasn't something. Here, LRV is a value defined as follows. [0007] LRV=log10(No/Nf)No; Virus concentration in the original solution before filtration Nf; Virus concentration in the filtrate after filtration Heat treatment method and Solvent/Detergent method applied when manufacturing plasma fraction preparations The virus removal level of virus inactivation techniques such as LRV
It is said to be 3 to 4 when expressed as 3 to 4, and with the films obtained by the conventional methods described above, it has not been possible to obtain anything superior to these techniques. [0008] Even with conventional membranes, if the membrane has a smaller average pore diameter, the virus inhibition performance will be improved, but on the other hand, there is a problem that the protein permeation performance will be lowered and the recovery rate of useful proteins will be lowered. Ta. Practically speaking, a membrane having high protein permeability and high virus-blocking performance is desirable. SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing a porous hollow fiber membrane made of regenerated cellulose using the cuprammonium method and having a high LRV for relatively small viruses. [Means for Solving the Problems] As a result of our earnest efforts to solve such practical problems, the present inventors have found that while having practically sufficient protein permeability, hepatitis B virus, nA
We have now invented a method for producing a porous hollow fiber membrane regenerated from cupric ammonia cellulose, in which the LRV is 5 or more even for relatively small viruses such as nB hepatitis virus. That is, the present invention provides a U-shaped coagulation bath when producing a hollow fiber membrane using a spinning dope consisting of a cellulose copper ammonia solution and a solution that causes microphase separation in the spinning dope as a coagulation liquid. This is a method for producing a regenerated cellulose porous hollow fiber membrane using a cuprammonium method, characterized by using molded capillaries. The method for producing a regenerated cellulose porous hollow fiber membrane using the cuprammonium method of the present invention uses at least one organic solvent that does not have hydroxyl groups, has a solubility in a 28% by weight ammonia aqueous solution of 10% by weight or more, and does not swell cellulose. It is characterized in that a mixed solution containing seeds and having a composition that causes microphase separation in the cellulose cuprammonium solution is used as the coagulation liquid (both the external liquid and the internal liquid). [0012] By employing the above-mentioned coagulation liquid, it becomes possible for the first time to produce a regenerated cellulose porous hollow fiber membrane using the cuprammonium method, but this coagulation is carried out using an alkaline aqueous solution such as sodium hydroxide or an aqueous solution such as sulfuric acid. One of its characteristics is that the coagulation rate is much slower than coagulation using an acid aqueous solution. For this purpose, in the conventional spinning method, as shown in Fig. 2, first, the spinning stock solution is first discharged from the outer spinning opening of the annular double spinneret, and the inner solution is simultaneously discharged from the central spinning opening of the annular double spinneret. . After the discharged spinning dope is coagulated while being flow-drawn in a spinning funnel with a length of 1 m or more filled with an external liquid, it is possible to change the direction in the lateral direction via a direction change device. When a certain solidification state was reached, the direction was changed, and the material was further run horizontally in a coagulation bath also filled with external liquid for additional coagulation, and then wound up. [0013] In this spinning method, no matter what spinning conditions are used or how the dimensions of the hollow fiber membrane are changed, it is possible to achieve the object of the present invention, which is to have good protein permeability and to prevent hepatitis B virus and nAnB. It was not possible to obtain relatively small viruses such as hepatitis virus with an LRV of 5 or more. The membrane structure formation process of the cuprammonium regenerated cellulose porous hollow fiber membrane according to the present invention is considered to be as follows. That is, when the spinning stock solution is discharged into a coagulation solution that causes microphase separation, a so-called microphase separation state is formed in which the concentrated cellulose phase is dispersed as particles with a diameter of 0.01 to several μm. be done. The occurrence of a microphase separation state can be observed directly with the naked eye by the devitrification phenomenon of the hollow fiber membrane during spinning, or by the presence of particles with a diameter of 0.02 μm or more and 1 μm or less by electron microscopic observation of the hollow fiber membrane after spinning. You can check it. [0015] These particles formed by microphase separation collide and coalesce, growing into larger particles, and at the same time, due to the coagulation action of the coagulation liquid, these particles gradually begin to solidify from a liquid state, and finally become particles. The membrane structure in which the membranes are connected three-dimensionally is fixed to complete the porous membrane structure. The micropores in the membrane formed in this way capture and remove microscopic particles such as viruses.
As a result of intensive research, the present inventors have discovered that in a method for manufacturing porous hollow fiber membranes using microphase separation, the microphase is We have discovered that maintaining the membrane structure formed by the growth and fusion of separated particles as undamaged as possible is an essential condition for obtaining a membrane with high performance in removing microparticles such as viruses. In particular, in the conventional hollow fiber spinning method, various resistances inevitably occur as the hollow fiber runs (bath resistance of the coagulation bath, frictional resistance due to contact between the yarn support and the yarn, etc.). Therefore, the stretching force that tries to stretch the hollow fiber is
The present invention was conceived based on the realization that the membrane constantly acts on the hollow fibers, destroying the membrane structure that is being formed or has already been formed, and causing a non-uniform void structure. Conventionally, in the production of conventional wet-spun fibers, drawing during the spinning process (including the coagulation process) has been generally considered preferable as it improves the yarn strength. However, in the production of porous hollow fiber membranes by microphase separation, such stretching should be avoided as much as possible for the reasons mentioned above. The present inventors have found that the use of a U-shaped capillary in the coagulation bath is the most effective and efficient means of achieving this. Next, the present invention will be specifically explained based on the drawings. FIG. 1 is a schematic diagram showing an example of the manufacturing method of the present invention. The U-shaped thin tube 4 used in the present invention is a tube in which the lower part of two funnel tubes erected substantially vertically is U-shaped, or the internal flow path is shaped like a U-shaped tube, as shown in FIG. means a device that is fluid-tightly connected by a connecting device with First, the spinning dope A is simultaneously fed from the outer spinning spout of the annular double spinneret 1, and the inner solution B, which is a microphase separation and coagulating liquid for the spinning dope, is simultaneously fed from the central spinning spout of the annular double spinneret. Discharge, spinning tube 2, and one tube of the funnel tube (
(hereinafter referred to as the descending tube) 4a. At this time, an external liquid C, which serves as a microphase separation and coagulation liquid for the spinning dope, is supplied from an inlet provided in the spinning tube. Most or all of the spinning tube, or the U-shaped tube, is filled with external liquid, which is constantly fed, and flows down in the descending tube together with the spinning dope. When the spinning dope is introduced into the spinning tube, it may be introduced into the external liquid by providing an air gap length (travel length in air), or it may be introduced directly into the external liquid. The air gap length is preferably such that the spinning dope enters straight into the air gap. In the case of the present invention, the distance is preferably within 10 cm. At the stage of flowing down the descending tube, the spinning stock solution takes on the shape of a hollow fiber membrane, and this hollow fiber membrane is diverted at the U-shaped portion at the lower end of the U-shaped capillary, and the spinning dope is passed through the spinning funnel. It rises together with the external liquid in the other tube (hereinafter referred to as the ascending tube) 4b of the thin tubes, is pulled out from the opening of the ascending tube, and is wound up on the winding frame 10. [0021] In this manner, the spinning dope continues to solidify in the U-shaped tube while microphase separation occurs due to the action of the inner and outer liquids. If spinning is performed using such a U-shaped thin tube, the hollow fiber membrane can run through the coagulation bath without contacting the tube walls in either the descending tube or the ascending tube. Furthermore, at this time, a rotating body (
(Hereinafter, referred to as drive direction change roll) 5, the lower end U
The stretching force that inevitably acts on the hollow fiber membrane due to the contact resistance between the hollow fiber membrane and the U-shaped tube wall at the shaped portion can also be reduced to substantially zero. [0022] At this time, if the speed of the drive direction change roll is extremely slower than the winding speed, stretching will naturally occur in the ascending tube, which is not preferable. In the present invention, it is desirable that the relationship between the driving direction change roll speed and the winding speed is such that the speed difference is 20% or less. Furthermore, the present invention has the great advantage of suppressing bath resistance in the coagulation bath. This bath resistance can be minimized by making the flow rate of the coagulation liquid (external liquid) in the U-shaped tube as high as possible. However, at this time, if the flow rate of the external liquid becomes too high, the hollow fiber membrane in the descending tube will violently shake, making spinning difficult, so it is necessary to set it to an appropriate value. Most preferably, the maximum flow rate is selected within a range that does not cause the hollow fiber membrane to sway in the descending tube. The present invention provides a porous hollow fiber regenerated by the cuprammonium method, which is characterized in that the hollow fiber membrane is spun so as not to be substantially stretched in the longitudinal direction of the fiber during the coagulation step, as described above. A method for manufacturing a membrane is provided. The larger the diameter of the U-shaped tube, the easier the spinning operation, but since a large amount of coagulation liquid is required, a smaller diameter is desirable, and a diameter between 3 mm and 20 mm is preferable. More preferably, it is between 5 mm and 10 mm. [0024] The length of the U-shaped capillary must be such that it can provide an appropriate coagulation time in accordance with the formation of the hollow fiber membrane structure. It is preferable to set it to . The material of the U-shaped tube is
Any material can be used as long as it is durable against the coagulating liquid, but a transparent material that allows the spinning state to be observed is preferable, such as glass, polyethylene, polypropylene, polyester, etc. Tetrafluoroethylene etc. can be used. The most suitable material for the spinning funnel tube and the lower U-shaped tube of the U-shaped tube is polytetrafluoroethylene, which is characterized in that the spinning stock solution does not easily adhere to it, making the spinning operation easy. By the method of the present invention, the LRV for relatively small viruses such as hepatitis B virus and nAn hepatitis B virus that has practically sufficient protein permeability is 5.
A cuprammonium regenerated cellulose porous hollow fiber membrane having the above performance is obtained. In addition, the cuprammonium solution in the present invention is a solution whose main components are copper and ammonia, that is, a dark blue solution called Schweitzer's reagent, and means a solvent system that can substantially dissolve cellulose. , including those containing some cations other than copper or solvents other than ammonia. Moreover, the cellulose concentration means the weight concentration of cellulose in a cupric ammonia solution. [0026] In the present invention, the average molecular weight is
It was measured by the same method as described in JP-204912. The porosity Pr is calculated by the following method. From the inner diameter, membrane thickness, length, and absolute dry weight of the hollow fiber membrane, the apparent density ρa
was calculated, and the porosity was calculated from equation (1). ρa = Wd /Vw =4Wd /π・l(Do 2
-Di 2 ) Pr = (1-ρa /ρ
p ) × 100 ……………… (1)
Pr; porosity
(%) Wd; Absolute dry weight of hollow fiber membrane (g) Vw; Volume of hollow fiber membrane (cm3) l; Length of hollow fiber membrane (cm) Do; Outer diameter of hollow fiber membrane (cm) Di;
Inner diameter of hollow fiber membrane (cm)ρp
; Density of cellulose (g/cm3
) The average pore diameter is calculated by the following method. A module is created by bundling 10 hollow fiber membranes so that the effective length of each fiber is 16 cm. One end of this module was closed, a pressure of 200 mmHg was applied from the opposite end, and the temperature was 37°C.
Let the water pass through. At this time, the amount of water coming out through this hollow fiber membrane module is measured as the amount of water permeation. Then,
The average pore diameter 2γ is calculated from equation (2). [Equation 1] 2r; Average pore diameter (
nm) Kw ; constant (2.0) V ; water permeability
(ml/min) d ; Thickness of hollow fiber membrane
(μm) μ ; Viscosity of water
(cp)p; pressure difference
(mmHg)A; Membrane area
(cm2)Pr
; Porosity (
%) Japanese encephalitis virus was prepared from Perkin strain, and its titer before and after filtration was measured by TCID50 using BHK-21 cells. The titer of the original solution is 10
It was 10.5TCID50 (ml-1). here,
The TCID50 (50% end point of infection) method is a method for measuring the infectious amount of a virus. First, the virus solution to be measured is serially diluted 10 times, each dilution is inoculated into a certain number of cells or more, cultured for a certain period of time, and cells in which cytopathic effect (CPE) caused by the virus is observed are determined to be positive. Those that are not recognized are considered negative. The appearance rate of positive cells in each dilution is plotted logarithmically, and the dilution rate showing 50% positivity is defined as TCID50. The Reed-Muench method was used for this calculation. LRV was calculated using the following formula. The reason why the double encephalitis virus was used as an index of virus removal performance is that the nAnB virus is considered to be the same type as the Japanese encephalitis virus, and the particle sizes of both are similar. LRV=1og10(No/Nf)No; Virus titer in the original solution before filtration Nf; Virus titer in the filtrate after filtration The protein permeability was determined as follows. First, prepare 400 ml of fresh baboon blood, and add 400 ml of fresh baboon blood.
About 250 ml of fresh human plasma was obtained by centrifugation at 00G and 4°C for 10 minutes. The protein concentration before and after filtration was measured by the following method. Total protein and albumin concentrations were measured using an automatic analyzer. The concentrations of IgA, IgG, and IgM were measured using turbidimetric immunoassay reagents. Protein permeability was calculated using the following formula. [0031] SC=(Cf/Co)×100 SC; Protein permeability Cr; Protein concentration after filtration Co; Protein concentration before filtration [Example] Hereinafter, the porosity of regenerated cellulose using the cuprammonium method of the present invention will be explained. The method for manufacturing hollow fiber membranes will be specifically explained using examples. [Example 1] Cotton linter (average molecular weight 1.44×
105) was dissolved in a copper ammonia solution prepared by a known method, filtered and defoamed, and the cellulose concentration was reduced to 5.
．． The spinning dope had a spinning stock solution of 7% by weight, an ammonia concentration of 4.0% by weight, and a copper concentration of 2.1% by weight. The spinning stock solution is discharged from the outer spinning opening of the annular double spinneret at a rate of 2.0 cc/min, and at the same time, the inner solution consisting of acetone/ammonia/water under the conditions shown in Table 1 is discharged from the central spinning opening of the spinneret at a rate of 2.0 cc/min. It was discharged at 7cc/min. The discharged spinning stock solution was introduced into a device equipped with a U-shaped tube shown in FIG. 1, which was filled with an external liquid consisting of acetone/ammonia/water under the conditions shown in Table 1, and microphase separation was carried out. is caused and continues to solidify, and the spinning speed is increased to 5.
It was wound up onto a flat frame at m/min. At this time, the diameter of the funnel tube is 7 mm, the external liquid flow rate is 1.0 m/min, the driving direction change roll speed is 4.7 m/min, and the rate-limiting roll speed is 5 m/min.
n, the flat frame speed was 5 m/min. The components of the winding bath are:
After winding it up for 40 minutes using 30°C water, it was further immersed in the same 30°C water as the winding bath for 60 minutes. Thereafter, it was regenerated with a 3% by weight aqueous sulfuric acid solution and further washed with water. Water in the obtained hollow fiber membrane was replaced with methanol, and then heated at 50°C and 2 Tor under tension.
It was vacuum dried under conditions of r. Table 1 shows the manufacturing conditions and physical properties of the hollow fiber membrane thus obtained. [Comparative Example 1] Cotton linter (average molecular weight 1.44×
105) was dissolved in a cupric ammonia solution prepared by a known method, filtered and defoamed, and the cellulose concentration reached 6.
．． A spinning stock solution having an ammonia concentration of 7% by weight, an ammonia concentration of 4.7% by weight, and a copper concentration of 2.4% by weight was prepared. The spinning dope was simultaneously discharged from the outer spinning port of the annular double spinneret, and the internal solution shown in Table 2 was simultaneously discharged from the central spinning port of the spinneret. Using the apparatus shown in FIG. Introduce the liquid into the external liquid shown in Figure 2, using a 1.6 m long funnel (tube diameter 16 mm).
After that, the coagulation bath was changed direction using a direction change rod, and a coagulation bath having a length of 4.4 m was run, and the coagulation bath was wound up at a spinning speed of 10 m/min. At this time, the external liquid of the coagulation bath flows into the funnel. The winding bath component uses a liquid with the same composition as the external liquid, and
After winding for a minute, a liquid with the same composition as the external liquid (immersion liquid) is added.
immersed in for 60 minutes. Thereafter, it was regenerated with a 3% by weight aqueous sulfuric acid solution and further washed with water. The moisture in the obtained hollow fiber membrane was replaced with methanol, and then it was vacuum-dried under tension at 50° C. and 2 Torr. Table 1 shows the manufacturing conditions and physical properties of the hollow fiber membrane thus obtained. [Table 1] [Effects of the Invention] According to the production method of the present invention, the production method has practically sufficient protein permeability, and the hepatitis B virus, nAn
A cuprammonium-method regenerated cellulose porous hollow fiber membrane having an LRV of 5 or more for relatively small viruses such as hepatitis B virus can be obtained.

[Brief explanation of the drawing]

FIG. 1 is a schematic cross-sectional view showing one embodiment of an apparatus for carrying out the method for producing a porous hollow fiber membrane according to the present invention.

FIG. 2 is a schematic cross-sectional view of the device used in Comparative Example 1.

[Explanation of symbols]

1. Annular double spinneret 2 Spinning cylinder 3. Current plate 4 U-shaped tube 4a Descending canal 4b Ascending canal 5 Drive direction change roll 6　Direction change roll cover 7 Rate-limiting roll 8 Discharge pipe 9 Winding bath 10 Winding flat frame 11. Winding water 12　Direction rod 13 Coagulation bath 14 Winding liquid

Claims (1)

[Claims] Claim 1: A U-shaped capillary is used as a coagulation bath when manufacturing a hollow fiber membrane using a spinning dope consisting of a cellulose cupric ammonia solution and a solution that causes microphase separation in the spinning dope as a coagulation liquid. A method for producing a regenerated cellulose porous hollow fiber membrane using a cuprammonium method, characterized by: