JP4288601B2 - Polysulfone permselective hollow fiber membrane - Google Patents

Description

  The present invention relates to a polysulfone-based permselective hollow fiber membrane having high safety and stability of stability, excellent module assemblability, durability against radiation sterilization, and particularly suitable for blood purifiers, and its blood purification The present invention relates to a usage as a container and a manufacturing method thereof.

  In blood purification therapy for the treatment of renal failure, for the purpose of removing urine toxins and waste products in the blood, cellulose is a natural material, and its derivatives are cellulose diacetate and cellulose triacetate. Modules such as hemodialyzers, hemofilters or hemodialyzers using dialysis membranes using polymers such as methyl methacrylate and polyacrylonitrile and ultrafiltration membranes as separation materials are widely used. In particular, modules using hollow fiber membranes as separation materials are important in the dialyzer field due to advantages such as reduction of the amount of blood circulating outside the body, high efficiency of removing substances in the blood, and productivity during module production. high.

  Among the above-mentioned membrane materials, polysulfone-based resins having high water permeability are attracting attention as the best match with the progress of dialysis technology. However, when a semi-permeable membrane is made of polysulfone alone, the polysulfone resin is hydrophobic, so it has poor affinity with blood and causes an airlock phenomenon. Can not.

As a method for solving the above-described problems, a method has been proposed in which a hydrophilic polymer is blended with a polysulfone-based resin to form a film, thereby imparting hydrophilicity to the film. For example, a method of blending a polyhydric alcohol such as polyethylene glycol is disclosed (for example, see Patent Documents 1 and 2).
JP-A-61-232860 JP 58-114702 A

Moreover, the method of mix | blending polyvinylpyrrolidone is disclosed (for example, refer patent document 3, 4).
Japanese Patent Publication No. 5-54373 Japanese Examined Patent Publication No. 6-75667

  The above-described problem is solved by the above-described method. However, in the hydrophilization technology by blending a hydrophilic polymer, the membrane performance of the hollow fiber membrane is large due to the concentration of the hydrophilic polymer existing on the inner surface of the membrane in contact with blood and the outer surface of the opposite membrane. Influence and its optimization is important. For example, blood compatibility can be ensured by increasing the hydrophilic polymer concentration on the inner surface of the membrane. However, if the surface concentration becomes too high, the amount of the hydrophilic polymer eluted into the blood increases, and the hydrophilicity to be eluted is increased. Since accumulation of macromolecules causes side effects and complications during long-term dialysis, it is not preferable.

  On the other hand, if the concentration of the hydrophilic polymer present on the outer surface of the opposite surface is too high, the possibility of high hydrophilic endotoxin (endotoxin) contained in the dialysate to enter the blood increases, causing side effects such as fever. New problems such as deterioration of module assemblability, etc. caused by the presence of hydrophilic polymers existing on the outer surface of the membrane when the membrane is dried and the hollow fiber membranes stick together (adhere). It is. Conversely, lowering the hydrophilic high molecular weight present on the outer surface of the membrane is preferable in terms of suppressing the invasion of endotoxin into the blood side, but since the hydrophilicity of the outer surface decreases, When returning a wet bundle of hollow fiber membranes for assembly to a wet state, the priming property, which is the ability to expel air when the wet operation is performed, is reduced because the familiarity with the physiological saline used for wetting is reduced. This is not preferable because it leads to the generation of a problem.

As a measure for solving the above problems, the concentration of the hydrophilic polymer present in the dense layer on the inner surface of the hollow fiber membrane is within a specific range, and the mass ratio of the hydrophilic polymer present in the dense layer on the inner surface is outside. A method of at least 1.1 times the mass ratio of the hydrophilic polymer present in the surface layer is disclosed (see Patent Document 5). That is, the above technique increases the mass ratio of the hydrophilic polymer present on the dense surface of the inner surface to improve blood compatibility, and conversely lowers the mass ratio of the hydrophilic polymer present on the outer surface to reduce the membrane. This is a technique based on the idea of suppressing the occurrence of sticking between hollow fiber membranes that occurs when dried. In addition to this problem, this technique also improves the problem of endotoxin (endotoxin) contained in dialysate, which is one of the above-mentioned problems, entering the blood side. Since the mass ratio is too low, there remains a problem that leads to generation of the problem that the priming property, which is another problem described above, is lowered, and improvement thereof is necessary.
JP-A-6-165926

In addition, the hollow fiber membrane has a uniform membrane structure, but the hydrophilic polymer content in the inner surface, outer surface, and middle portion of the hydrophilic polymer hollow fiber membrane in the vicinity of the surface determined by the infrared absorption method is By specifying, a method for improving the problem of endotoxin (endotoxin) contained in the dialysate, which is one of the problems described above, entering the blood side has been disclosed (for example, see Patent Document 6). Although one of the above problems is improved by this technique, for example, as in the above technique, the problem that the priming property is lowered is not solved, and since the hole diameter of the outer surface of the hollow fiber membrane is large, the pressure resistance In particular, there is a concern that the hollow fiber membrane may be damaged when used for a treatment that increases fluid pressure more than conventional methods such as hemodiafiltration.
JP 2001-38170 A

Furthermore, by specifying the surface content of the hydrophilic polymer on the inner surface of the hollow fiber membrane, a method for improving blood compatibility and the amount of hydrophilic polymer eluted into the blood is disclosed (for example, (See Patent Documents 7 to 9).
JP-A-6-296686 JP 11-309355 A JP 2000-157852 A

  None of the above-mentioned techniques has been mentioned at all regarding the abundance ratio of the hydrophilic polymer on the outer surface of the opposite surface of the hollow fiber membrane, and all of the above-mentioned problems due to the abundance ratio of the hydrophilic polymer on the outer surface are described. It has not improved.

Among the above-mentioned problems, with regard to the problem that endotoxin (endotoxin) enters the blood side, a method using the characteristic that endotoxin has a hydrophobic portion in its molecule and is easily adsorbed to hydrophobic materials. Is disclosed (for example, see Patent Document 10). That is, it can be achieved by setting the ratio of the hydrophilic polymer to the hydrophobic polymer on the outer surface of the hollow fiber membrane to 5 to 25%. Certainly, this method is a preferable method for suppressing the invasion of endotoxin into the blood side, but to impart this property, it is necessary to remove the hydrophilic polymer present on the outer surface of the membrane by washing. In addition, this cleaning requires a great deal of processing time and is economically disadvantageous. For example, in the embodiment of the above-mentioned patent, shower cleaning with hot water at 60 ° C. and cleaning with hot water at 110 ° C. are performed for 1 hour each.
JP 2000-254222 A

In addition, it is preferable to reduce the hydrophilic high molecular weight present on the outer surface of the membrane from the viewpoint of suppressing the invasion of endotoxin into the blood side. Therefore, when the dried hollow fiber membrane bundle is returned to a wet state, the familiarity with the physiological saline used for wetting becomes low. This is not preferable because it leads to the problem. As a method for improving this point, for example, a method of blending a hydrophilic compound such as glycerin has been disclosed (see, for example, Patent Documents 11 and 12). However, in this method, since the hydrophilic compound acts as a foreign substance during dialysis and the hydrophilic compound is susceptible to deterioration such as oxidative deterioration, it leads to problems such as adversely affecting the storage stability of the module. In addition, there is also a problem of causing adhesive inhibition of the adhesive when the hollow fiber membrane bundle is fixed to the module in module assembly.
JP 2001-190934 A Japanese Patent No. 3193262

As a method for avoiding the sticking of the hollow fiber membranes, which is another problem described above, a method is disclosed in which the porosity of the outer surface of the membrane is 25% or more (for example, Patent Document 6 and Patents listed above). Reference 13). Certainly, this method is a preferable method for avoiding the sticking, but has a problem that the membrane strength is lowered due to the high porosity, leading to problems such as blood leakage.
JP-A-7-289863

On the other hand, a method has been disclosed in which the porosity and area of the outer surface of the membrane are specified (see, for example, Patent Document 14).
JP 2000-140589 A

  The blood purifier needs to be subjected to sterilization because of its requirements as a medical instrument. The hollow fiber membrane for blood purification of the present invention is a blood purifier subjected to radiation sterilization using a hollow fiber membrane made of a polysulfone resin as a member, and the subject of the invention.

  The polysulfone resin has a basic structure in which the main structure of p-phenylene forms a polymer via a sulfone group, an ether group, or the like. From these structures, it is known to have high durability, such as high strength, heat resistance, chemical resistance, and hydrolysis resistance as an engineering plastic. In addition, it has very excellent characteristics regarding film formation from solution, such as ease of dissolution in water-soluble polar solvent, excellent pore formation by liquid-liquid phase separation method from solution, etc. This is a background widely used in the membrane field. These points are all advantages of the polysulfone resin for medical use. In addition, as described above, the polysulfone resin has durability against sterilization by medicine (ethylene oxide gas, formalin, etc.) and heat sterilization (high pressure steam sterilization, etc.).

However, the resistance of polysulfone resin is not satisfactory for radiation sterilization (mainly γ-ray sterilization) which is extremely effective as a non-contact type and non-erosive type sterilization method. It is known that the diphenylsulfone structure in the polysulfone resin has a weak point against radiation. (See Non-Patent Document 1). Here, it is reported that decomposition with SO ₂ gas is caused by intense irradiation in a reaction in a non-oxidizing system. Therefore, it is not appropriate to use a polyphonic resin as a member in a radiation exposure environment. It is said that.
"High-performance aromatic polymer materials", Chapter 2.3, Molecular design of radiation-resistant polymers, edited by the Society of Polymer Science, Maruzen

  From these backgrounds, in order to sterilize a blood purifier using a polysphonic hollow fiber membrane by radiation, a certain degree of deterioration of the polysulfone resin was accepted based on a balance between securing a dose as a sterilization guarantee and deterioration of the members. The radiation sterilization treatment is applied. In other words, in terms of product safety, the actual situation is that production forms include negative factors.

Radiation sterilization is not limited to polysulfone-based resins, and has the effect of property changes on members to be sterilized. In particular, oxidation reactions that involve generation of radicals are feared, and as a measure to suppress this, a method of reducing the presence of oxygen during an sterilization process or making an oxygen-free atmosphere is disclosed. It is known to prevent excessive member deterioration due to radiation depending on the case where the periphery of the hollow fiber membrane is in a gaseous state (for example, Patent Documents 15 and 16) or in the case of a liquid (for example, Patent Document 17). Yes. However, these prior arts present a general countermeasure for suppressing oxidative degradation on the surface of a polymer member at the time of γ sterilization irradiation, and γ-ray energy is sufficient to penetrate the inside of a polymer solid having permeability. It will not prevent the deterioration. In addition, since the focus is on oxidative degradation, no direct reaction suppression effect with gamma ray energy can be expected.
JP-A-6-285162 Japanese Patent Laid-Open No. 3-10343 JP-A-4-338223

  An object of the present invention is to provide a polysulfone-based permselective hollow fiber membrane that has high safety and stability in performance, is excellent in module assembly, and is particularly suitable for a blood purifier.

As a result of intensive studies to solve the above technical problem, the present invention provides a polysulfone-based hollow fiber membrane mainly composed of a polysulfone-based resin and a hydrophilic polymer.
(A) The content of the hydrophilic polymer in the innermost surface layer of the polysulfone-based hollow fiber membrane is 1.1 times or more with respect to the content of the hydrophilic polymer in the inner surface vicinity layer.
(B) The content of the hydrophilic polymer in the outermost surface layer of the polysulfone-based hollow fiber membrane is 1.1 times or more than the content of the hydrophilic polymer in the outermost surface layer of the inner surface.
(C) The breaking strength of the hollow fiber membrane after irradiating the hollow fiber membrane with γ rays of 40 kGy dose is 80% or more with respect to the breaking strength of the hollow fiber membrane before γ ray irradiation.
By using a polysulfone-based permselective hollow fiber membrane characterized by this, the above-mentioned problems have been solved.

  As a detailed embodiment, the content of the hydrophilic polymer in the innermost outermost layer is usually 5 to 60% by mass, suitably 10 to 50% by mass, more preferably 20 to 40% by mass. The range of the content of the hydrophilic polymer in the surface vicinity layer adjacent thereto is usually about 2 to 37% by mass, and optimally about 5 to 20% by mass. Furthermore, since the content of the hydrophilic polymer on the outermost surface layer is 1.1 times or more than the content of the hydrophilic polymer on the innermost surface layer, the hydrophilic fiber hollow fiber membrane A content of about 25 to 50% by mass on the outer surface is sufficient. Appropriate content distribution of each layer can be determined in consideration of the elution of the hydrophilic polymer from the hollow fiber membrane to 10 ppm or less.

  The polysulfone-based hollow fiber membrane of the present invention has a high safety and performance stability, is excellent in module assembly, and has a high water permeability used for the treatment of chronic renal failure. There is an advantage that it is suitable.

Hereinafter, the present invention will be described in detail.
The hollow fiber membrane used in the present invention is characterized in that it is composed of a polysulfone resin containing a hydrophilic polymer. The polysulfone resin in the present invention is a general term for resins having a sulfone bond and is not particularly limited. However, for example, a polysulfone resin or a polyethersulfone resin having a repeating unit represented by Chemical Formula 1 or Chemical Formula 2 is a polysulfone resin. It is preferred because it is widely available on the market and is easily available.

  The hydrophilic polymer in the present invention is a material such as polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, polypropylene glycol, glycerin, starch and derivatives thereof, but it is preferable to use polyvinyl pyrrolidone from the viewpoint of safety and economy. This is an embodiment. As the molecular weight of polyvinylpyrrolidone, those having a weight average molecular weight of 10,000 to 1,500,000 can be used. Specifically, those having a molecular weight of 9,000 (K17) commercially available from BASF, 45,000 (K30), 450,000 (K60), 900,000 (K80), 1,200,000 (K90) are preferably used in the same manner. In order to obtain the intended use, characteristics, and structure, they may be used alone, or the same two types of resins having different molecular weights, or two or more types of different types of resins may be used in combination.

  In the present invention, the content of the hydrophilic polymer in the outermost surface layer on the inner surface in the (i) polysulfone-based hollow fiber membrane is 1.1 times or more the content of the hydrophilic polymer in the surface vicinity layer on the inner surface. That is, the content of the hydrophilic polymer on the outermost surface is made larger than the layer near the surface and the content of the hydrophilic polymer on the outermost layer is made 20 to 40% by mass is adjacent to it. The range of the hydrophilic polymer content in the near-surface layer needs to be in the range of about 2 to 37% by mass. It is based on this reason that the appropriate content of the hydrophilic polymer in the surface vicinity layer is actually about 5 to 20% by mass. This means that it is acceptable up to about 10 times, but if the magnification of the difference becomes too large, the diffusion movement of the hydrophilic polymer may reversely move from the outermost layer to the vicinity of the surface. There is also a situation that it is difficult to manufacture a hollow fiber membrane having such a structure. Appropriate content of the hydrophilic polymer in the outermost surface layer of the inner surface and the surface vicinity layer is based on 5 to 20% by mass, which is the appropriate content of the hydrophilic polymer in the surface vicinity layer. The content of the hydrophilic polymer on the outermost surface layer on the inner surface is set to an optimum 20 to 40% by mass by calculating with a simple multiplier of about 1.1 to 10 times (up to 20% by mass). Means that it is possible. The ratio is usually about 1.1 to 5 times, and in some cases, it is preferable that the hydrophilic polymer exists in a range of about 1.2 to 3 times optimally. Actually, the magnification can be arbitrarily determined in consideration of the performance of the hollow fiber membrane. For example, if the content of the hydrophilic polymer in the surface vicinity layer is 5% by mass of the lowest value, the content of the hydrophilic polymer in the outermost layer is 20 to 40% by mass of an appropriate amount corresponding to 4 to 8 times. It can also be taken within the range.

  In the present invention, the content of the hydrophilic polymer in the outermost layer on the outer surface in the (b) polysulfone-based hollow fiber membrane is 1.1 times or more than the content of the hydrophilic polymer in the outermost layer on the inner surface. It is sufficient that the content of the above-described hydrophilic polymer on the outer surface of the hollow fiber membrane is about 25 to 50% by mass, and 1.1 of the content of the hydrophilic polymer on the outermost layer on the inner surface. It is preferable that it is more than twice. If the content of the hydrophilic polymer on the outer surface is too small, the amount of protein in the blood adsorbed on the support layer portion of the hollow fiber membrane will increase, and blood compatibility and permeation performance may decrease. Conversely, if the content of the hydrophilic polymer on the outer surface is too high, the endotoxin (endotoxin) contained in the dialysate is likely to enter the blood side, leading to side effects such as fever, When the membrane is dried, a hydrophilic polymer present on the outer surface of the membrane is interposed, and the hollow fiber membranes are fixed to each other, which may cause problems such as deterioration in module assembly.

  In the present invention, the breaking strength of the hollow fiber membrane after irradiating the polysulfone-based hollow fiber membrane (c) with a dose of 40 kGy is 80% or more with respect to the breaking strength of the hollow fiber membrane before γ-ray irradiation. This indicates that in the polysulfone-based hollow fiber membrane mainly composed of a polysulfone-based resin and a hydrophilic polymer, deterioration of the hollow fiber membrane due to γ-rays is slightly suppressed. The hollow fiber membrane of the present invention is formed from a polysulfone resin and an alloy component of a hydrophilic polymer. The main component of strength retention as a yarn is the polysulfone resin, and 99 to 80% by weight is a polysulfone resin. A hollow fiber membrane made of resin. In particular, in the formation of a porous material such as a hollow fiber membrane, it is not possible to perform spinning that expresses the high strength of the fiber such as molecular orientation by performing membrane-forming spinning from a polymer solution by high draft. The porous hollow fiber membrane is fixed in an almost amorphous state as a molecular assembly structure. The breaking strength of the yarn can be considered as a value indicating the total amount per portion of the portion bearing the tensile stress based on the interaction at the molecular level of the polymer chain with respect to the elongation of the yarn. In the hollow fiber membrane, the total amount of interaction itself is small, and changes such as partial deterioration and decomposition of the constituent polymer tend to appear in the strength of the membrane, and can be a serious drawback particularly when used for blood purification therapy. Further, due to the low orientation property of the hollow fiber membrane as described above, it is considered that the deterioration state in the length direction of the yarn also reflects the deterioration state in the film thickness direction (pressure resistance such as burst pressure). Furthermore, in recent years, hemodialysis membranes using polysulfone-based resins have increased porosity and porosity, while being unable to increase film thickness, in order to obtain advanced substance removal performance. The strength of has become very weak, which also leads to a decrease in durability.

  The composition ratio in the membrane of the hydrophilic polymer with respect to the polysulfone resin in the present invention is not particularly limited as long as the hydrophilic polymer has a sufficient hydrophilicity and a high water content, and can be arbitrarily set. However, 1-20 mass% is preferable with the mass ratio of the hydrophilic polymer with respect to 80-99 mass% of polysulfone resin, and 3-15 mass% is more preferable. If it is less than 1% by mass, the hydrophilicity-imparting effect of the film may be insufficient. On the other hand, if it exceeds 20% by mass, the effect of imparting hydrophilicity is saturated and the amount of elution from the membrane of the hydrophilic polymer increases, and the amount of elution from the membrane of the hydrophilic polymer described later may exceed 10 ppm. There is.

The preferred embodiment of the present invention will be described in detail based on technical requirements. In the polysulfone-based hollow fiber membrane containing a hydrophilic polymer, the polysulfone-based selectively permeable hollow characterized by satisfying the following characteristics at the same time: It becomes a thread membrane.
(1) Elution of the hydrophilic polymer from the hollow fiber membrane is 10 ppm or less.
(2) The content of the hydrophilic polymer in the outermost layer on the inner surface in the polysulfone-based hollow fiber membrane is 20 to 40% by mass.
(3) The content of the hydrophilic polymer in the surface vicinity layer on the inner surface in the polysulfone-based hollow fiber membrane is 5 to 20% by mass.
(4) The content of the hydrophilic polymer on the outermost layer on the outer surface in the polysulfone-based hollow fiber membrane is 25 to 50% by mass, and 1.1 of the content of the hydrophilic polymer on the outermost layer on the inner surface. It is more than double.
(5) When the polysulfone-based hollow fiber membrane is subjected to radiation treatment with γ rays, the value of the breaking strength of the hollow fiber membrane at a dose of 40 kGy is 80% of the breaking strength of the hollow fiber membrane before the γ ray treatment. % Or more.

  In the present invention, as described above, it is preferable that (1) the elution amount of the hydrophilic polymer from the hollow fiber membrane is 10 ppm or less (Requirement 1). When the elution amount exceeds 10 ppm, side effects and complications due to long-term dialysis due to the eluted hydrophilic polymer may occur. A method of satisfying the characteristics can be achieved, for example, by setting the ratio of the hydrophilic polymer to the hydrophobic polymer within the above range or optimizing the film forming conditions of the hollow fiber membrane.

  In the present invention, as described above, it is preferable that the content of the hydrophilic polymer in the outermost layer on the inner surface in (2) the polysulfone-based hollow fiber membrane is 20 to 40% by mass (Requirement 2). First, the content of the hydrophilic polymer on the outermost surface of the inner surface of the polysulfone-based hollow fiber membrane can be arbitrarily set in a wide range such as 5 to 60% by mass, for example, 10 to 50% by mass. The optimum content for achieving the above effect appropriately is preferably composed mainly of polysulfone-based resin 60 to 80% by mass and hydrophilic polymer 20 to 40% by mass. If it is less than 20% by mass, the hydrophilicity of the surface of the hollow fiber membrane that comes into contact with blood is low, blood compatibility is deteriorated, blood coagulation tends to occur on the surface of the hollow fiber membrane, and the hollow fiber membrane is blocked by the coagulated thrombus. It may occur and the separation performance of the hollow fiber membrane may decrease, or the residual blood after use for hemodialysis may increase. The content of the hydrophilic polymer in the outermost layer on the inner surface of the hollow fiber membrane is more preferably 21% by weight or more, further preferably 22% by weight or more, and further preferably 23% by weight or more. On the other hand, when the amount exceeds 40% by mass, the hydrophilic polymer eluted in blood increases, and side effects and complications due to long-term dialysis due to the eluted hydrophilic polymer may occur. The content of the hydrophilic polymer in the outermost layer on the inner surface of the hollow fiber membrane is more preferably 39% by mass or less, further preferably 38% by mass or less, and further more preferably 37% by mass or less.

  In the present invention, as described above, it is preferable that the content of the hydrophilic polymer in the layer near the inner surface of the polysulfone-based hollow fiber membrane (3) is 5 to 20% by mass (Requirement 3). In the polysulfone-based hollow fiber membrane of the present invention, the content of the hydrophilic polymer in the surface vicinity layer on the inner surface is mainly composed of a polysulfone-based resin of 60 to 99% by mass and a hydrophilic polymer of 1 to 40% by mass. Although a thing can be set arbitrarily, it is preferable that content of an appropriate hydrophilic polymer is 5-20 mass%. Usually, 7 to 18% by mass is more preferable. As described above, the content of the hydrophilic polymer on the outermost layer on the inner surface of the polysulfone-based hollow fiber membrane is preferably higher than the blood compatibility point, but when the content increases, the hydrophilic polymer to the blood increases. Since this is a contradictory phenomenon in which the amount of elution increases, it is determined to be about 20 to 40% by mass in consideration of the appropriate range.

  On the other hand, the content of the hydrophilic polymer in the inner layer near the surface of the hollow fiber membrane can be in a relatively wide range of 1 to 40% by mass, but more than the outermost layer, for example, 30% by mass of the outermost layer and 35% of the layer near the surface. %, The diffusion and movement of the hydrophilic polymer to the outermost layer becomes active, and the content of the hydrophilic polymer in the outermost layer accumulates more than a predetermined design value, which is not preferable. In short, considering the mechanism of supplying the amount of hydrophilic polymer consumed in the outermost layer by diffusion movement, the hydrophilic polymer content in the surface vicinity layer is relatively lower than that of the outermost layer. It is more preferably no greater than mass%, and even more preferably no greater than 18 mass%. In addition, if the content of the hydrophilic polymer in the vicinity of the inner surface of the hollow fiber membrane is too small, the hydrophilic polymer is not supplied to the outermost layer, so that the solute removal performance and the blood compatibility stability with time decrease. there is a possibility. Therefore, the content of the hydrophilic polymer in the vicinity of the inner surface of the hollow fiber membrane is more preferably 6% by mass or more, and further preferably 7% by mass or more as the optimum amount. The content of the hydrophilic polymer in the surface vicinity layer is slightly higher than the average content of 80 to 99% by mass of the polysulfone polymer constituting the hollow fiber membrane of the present invention and 1 to 20% by mass of the hydrophilic polymer. It is common that it is high.

  This requirement 3 is a factor for overcoming the above-mentioned contradictory phenomenon and achieving the optimization of the above phenomenon at a high level that could not be achieved by the prior art, and is one of the novel features of the present invention. That is, the content of the hydrophilic polymer in the outermost layer of the hollow fiber membrane that governs blood compatibility was set to the lowest level at which blood compatibility could be expressed. However, with the content of the outermost layer, the initial blood compatibility is satisfactory, but the hydrophilic polymer present in the outermost layer gradually elutes into the blood after long-term dialysis. The problem that blood compatibility gradually decreases occurs. This blood compatibility persistence is improved by specifying the content of the hydrophilic polymer in the layer near the inner surface of the polysulfone-based hollow fiber membrane. By specifying the hydrophilic polymer content in the near-surface layer, blood compatibility by decreasing the content of the hydrophilic polymer in the outermost layer due to elution of the outermost hydrophilic polymer into the blood due to the progress of dialysis It has been completed by the technical idea of ensuring a sustained decrease in blood compatibility in which the property deteriorates with time by transferring the hydrophilic polymer present in the surface vicinity layer to the outermost layer. Therefore, if the content of the hydrophilic polymer in the surface vicinity layer on the inner surface is less than 5% by mass, it may be insufficient to suppress the decrease in blood compatibility. On the other hand, when the amount exceeds 20% by mass, the amount of the hydrophilic polymer eluted in the blood increases, which may cause side effects and complications due to long-term dialysis. There has been no example of elucidating the material content based on the appropriate content and structure of the hydrophilic polymer in the near-surface layer and near-surface layer of this hollow fiber membrane, and based on the very novel knowledge of the inventors etc. It is.

  In the present invention, as described above, (4) the content of the hydrophilic polymer on the outermost layer on the outer surface in the polysulfone-based hollow fiber membrane is 25 to 50% by mass, and the hydrophilic polymer on the outermost layer on the inner surface. It is preferable that it is 1.1 times or more of content (requirement 4). If the content of the hydrophilic polymer on the outer surface is too small, the amount of protein in the blood adsorbed on the support layer portion of the hollow fiber membrane will increase, and blood compatibility and permeation performance may decrease. Although it may be composed mainly of 90 to 40% by mass of a polysulfone resin and 10 to 60% by mass of a hydrophilic polymer, the content of the hydrophilic polymer on the outer surface is actually 27% by mass. The above is more preferable, and 29% by mass or more is more preferable. In the case of a dry film, the priming property may be deteriorated. Conversely, if the content of the hydrophilic polymer on the outer surface is too high, the endotoxin (endotoxin) contained in the dialysate is likely to enter the blood side, leading to side effects such as fever, When the membrane is dried, a hydrophilic polymer present on the outer surface of the membrane is interposed, and the hollow fiber membranes are fixed to each other, which may cause problems such as deterioration in module assembly. The content of the hydrophilic polymer on the outer surface of the hollow fiber membrane is more preferably 43% by mass or less, and further preferably 40% by mass or less.

In addition, as one of the requirements 4, the content of the hydrophilic polymer in the outermost surface outer layer is preferably 1.1 times or more the content of the hydrophilic polymer in the outermost surface layer. The content of the hydrophilic polymer affects the shrinkage rate of the hollow fiber membrane after film formation. That is, the shrinkage rate of the hollow fiber membrane increases as the content of the hydrophilic polymer increases. For example, when the content of the hydrophilic polymer on the innermost outermost layer is higher than the content of the hydrophilic polymer on the outermost outermost layer, the inner surface side may be affected by the difference in shrinkage between the inner surface side and the outer surface side. Micro wrinkles may occur or the hollow fiber membrane may break. If wrinkles enter the inner surface, for example, when used for hemodialysis, blood proteins and the like are likely to be deposited on the membrane surface when blood is flowed, so the permeation performance deteriorates over time. There is a possibility of connection. For these reasons, it is preferable to increase the content of the hydrophilic polymer on the outer surface side. Furthermore, the hollow fiber membrane of the present invention has a dense layer on the inner surface and a structure in which the pore diameter gradually increases toward the outer surface. That is, since the porosity on the outer surface side is higher than that on the inner surface side, the shrinkage rate on the outer surface side is larger. In consideration of the influence, the content of the hydrophilic polymer in the outermost outermost layer is preferably 1.1 times or more the content of the hydrophilic polymer in the outermost outermost layer. More preferably, it is 1.2 times or more, and further preferably 1.3 times or more.
For the above reasons, the content of the hydrophilic polymer on the outermost surface layer is preferably high, but if it exceeds 2.0 times, the content of the hydrophilic polymer with respect to the polysulfone polymer polymer becomes too high and the strength is insufficient. May cause problems such as sticking between hollow fiber membranes, reverse influx of endotoxin when using hemodialysis, and elution of hydrophilic polymer. More preferably, it is 1.9 times or less, More preferably, it is 1.8 times or less, More preferably, it is 1.7 times or less.

  In the present invention, as described above, when the polysulfone-based hollow fiber membrane is subjected to radiation treatment with γ rays, the value of the breaking strength of the hollow fiber membrane at a dose of 40 kGy is the hollow fiber membrane before the γ ray treatment. It is preferable that it is 80% or more with respect to the breaking strength of. (Requirement 5). Requirement 5 indicates that the polysulfone-based hollow fiber membrane after γ sterilization has high safety when used as a blood purifier. According to requirement 5, 80% or more is maintained against the change from the non-irradiation of the breaking strength accompanying the 40 kGy γ-ray irradiation. This shows the durability at the value of the sterilization amount by the cobalt 60 radiation source normally used as a medical device. The current sterilization dose of medical devices has been implemented at a dose level of 20 to 25 kGy as a dose level with a sufficient sterilization guarantee from validation using standard adherent bacteria, and the dose setting at 40 kGy shown in this application is almost this It is a safety factor of double dose. The absorbed dose to the irradiation target of γ rays is controlled by multiplying the irradiation time by this depending on the intensity of the radiation source. A gamma irradiation device used for sterilization of a normal medical device is a device that is placed while moving around a radiation source for a certain period of time while being irradiated on a conveyor or the like. Therefore, the sterilization dose is difficult to control precisely due to the operating conditions of the irradiation device, the intensity change of the radiation source, the form of the material, the composite material, the packing state, interference due to mixed loading with other irradiated objects, and the like. The above dose level is usually set as the minimum dose based on these factors. Therefore, it is necessary to give consideration to safety assuming a certain amount of absorbed dose.

  Confirmation of the quality of sterilized products after sterilization can be confirmed only by destructive inspection at the stage of use after sterilization is broken. However, if it can be assumed that the stability is 80% or more, sterilization of the sterilized product is also possible. It can be seen that the hollow fiber membrane has the same durability as the handling properties (impact resistance, pressure resistance, etc.) in the previous manufacturing process. Therefore, it means that the stability of the product from γ sterilization until it is distributed and stored in a hospital or the like and used for treatment can be guaranteed. Deterioration, such as a decrease in breaking strength, may cause serious treatment problems such as blood leakage from the yarn during use, and this can be prevented, and the product's safety can be trusted. The degree improves. The hemodialyzer may be subjected to daily impacts such as vibration and dropping due to the nature of the product, and such resistance under a certain standardized condition can be implemented as a product inspection by sampling. However, as described above, a high-performance blood purification separation membrane made of a polysulfone resin is not necessarily a separation membrane having high strength. In addition to this, a decrease caused by γ-ray sterilization increases safety risks. Due to these problems, it is necessary to maintain 80% or more of the change in the breaking strength caused by 40 kGy γ-ray irradiation from the non-irradiation in the hollow fiber membrane made of the polysphonic resin shown in Requirement 5. Further, for further ensuring safety, it is more preferably 85% or more, and further preferably 90% or more.

  Furthermore, it is a preferred embodiment that the hydrophilic polymer is insolubilized by crosslinking. There is no limitation on the crosslinking method, the degree of crosslinking, etc. For example, the crosslinking method includes γ-rays, electron beams, heat, chemical crosslinking, etc. Among them, residues such as initiators do not remain, and in terms of high material permeability, γ-rays and electron beams are used. Crosslinking is preferred. A hydrophilic polymer that forms a hollow fiber membrane together with a polysulfone-based resin may cause a crosslinking reaction by the energy of γ rays. This behavior is particularly noticeable when the membrane is in water. This is because some of the molecular chains of the hydrophilic polymer exist in the free state in water, have relatively free molecular mobility, and the cross-linking points due to radicals formed by γ-rays react with other molecules. It is estimated that this is because it is possible to approach the distance of the potential that can cause Further, it is presumed that the water molecule itself generates a hydroxy radical by γ-ray, and this radical induces the initiation of the crosslinking reaction to the polymer. Although the crosslinking reaction itself, mainly composed of hydrophilic polymer, is not clearly related to the retention of the breaking strength of the hollow fiber membrane after γ-ray irradiation of requirement 5 above, elution of the hydrophilic polymer of requirement 1 Is an effective implementation.

  Furthermore, it is a preferred embodiment that the hydrophilic polymer is insolubilized by crosslinking. There is no limitation on the crosslinking method, the degree of crosslinking, etc. For example, the crosslinking method includes γ-rays, electron beams, heat, chemical crosslinking, etc. Among them, residues such as initiators do not remain, and in terms of high material permeability, γ-rays and electron beams are used. Crosslinking is preferred.

  Insolubilization in the present invention refers to solubility in dimethylformamide in a crosslinked film. That is, 1.0 g of the crosslinked film is taken, dissolved in 100 ml of dimethylformamide, and the presence or absence of insoluble matter is visually observed and determined. In the case of a module in which a liquid is filled in the module, the filling liquid is first withdrawn, and then pure water is allowed to flow at 500 mL / min for 5 minutes in the dialysate side flow path, and then pure water is similarly applied to the blood side flow path. Flow for 5 minutes at 200 mL / min. Finally, 200 mL / min of pure water is passed through the membrane from the blood side to the dialysate side to finish the washing process. The hollow fiber membrane is taken out from the obtained module and freeze-dried to make a sample for measuring unnecessary components. In the case of a dry hollow fiber membrane module, the same washing treatment is performed to obtain a measurement sample.

  Next, in detail regarding the innermost surface layer and the inner layer near the inner surface of the hollow fiber membrane, the difference between the two layers shows a two-layer structure due to the difference in the concentration of the hydrophilic polymer. Since the pore diameter tends to increase from the dense layer on the surface toward the outer surface, a two-layer structure with a density difference between the outermost layer portion and the portion in the vicinity of the surface may be formed. The thickness of each layer and its boundary line are arbitrarily changed depending on the manufacturing conditions of the hollow fiber membrane, and the structure of the layer also has some influence on the performance. Then, even if we infer from the manufacturing process by coagulation of the hollow fiber membrane, if the outermost layer and the near-surface layer are manufactured almost simultaneously and both layers are manufactured adjacent to each other, two layers are formed. Can be recognized, but the boundary is not something that can be drawn clearly.If you look at the distribution curve of the content of hydrophilic polymer across two layers, it is often connected by a continuous line, hydrophilic polymer There may be a difference in concentration between the two layers due to the difference in the content of. In general, it is technically impossible to assume that two discontinuous layers with different material behaviors are formed because the distribution curve of the hydrophilic polymer content can be broken at the boundary between the two layers. The hydrophilic polymer content of the outermost layer is 20-40% by mass and that of the surface vicinity layer is 5-20% by mass as the optimum range. From the mechanism of diffusion and movement to the outermost layer, for example, a design in which the outermost layer is 40% by mass and the near-surface layer is 5% by mass may not function sufficiently. In short, it is important to design by paying attention to the difference in the content of simple hydrophilic polymers present in the two layers. As an appropriate difference value, for example, 1.1 times or more between the two layers consisting of the outermost surface and the surface vicinity layer, based on the numerical value expressed by mass% expressed in the content of both hydrophilic polymers. That is, if calculated by converting the difference in the mass% of the hydrophilic polymer content between the two layers, the simple difference in the content of the hydrophilic polymer in the two layers is reduced to about 1 to 35% by mass. Optimally, if there is a difference of about 5 to 25% by mass, it can be said that the hydrophilic polymer can smoothly diffuse and move from the surface vicinity layer to the outermost layer. For example, when the outermost layer is 32% by mass, the surface vicinity layer is in the range of about 7 to 27% by mass, which satisfies the requirement of about 1.1 to 10 times.

  The content of the outermost layer of the above-mentioned hydrophilic polymer hollow fiber membrane was measured and calculated by the ESCA method as described later, and the outermost layer of the hollow fiber membrane (depth from several to several layers) The absolute value of the content of 10) was obtained. Usually, the ESCA method (outermost layer) can measure the hydrophilic polymer (PVP) content up to about 10 nm (100 mm) deep from the blood contact surface. In addition, the hydrophilic polymer content in the surface vicinity layer is an absolute value of the ratio existing in a range up to a depth corresponding to several hundreds of nanometers. In the ATR method (surface vicinity layer), the blood contact surface The hydrophilic polymer content up to a depth of about 1000 to 1500 nm (1 to 1.5 μm) can be measured.

  The content of the hydrophilic polymer on the inner surface and the outer surface may be related to the molecular weight of the hydrophilic polymer. For example, when polyvinyl pyrrolidone with a molecular weight of about 450,000 is used lower than when using a high molecular weight polyvinyl pyrrolidone with a molecular weight of about 1,200,000, the solubility and elution amount of polyvinyl pyrrolidone during coagulation is large, and diffusion transfer Compared to the content of 1 to 20% by mass of the average mass ratio of the hydrophilic polymer to the polysulfone-based polymer, the outermost layer part 20 to 40% by mass and the surface vicinity layer part 5 to 20% by mass % Having a relatively high hydrophilic polymer concentration tends to be produced. For example, a hollow fiber membrane produced by using 80% by mass of a polysulfone resin and 15% by mass of a polyvinyl pyrrolidone having a molecular weight of 900,000 and 5% by mass of a polyvinyl pyrrolidone having a molecular weight of about 45,000 is also used. The content and performance of the polyvinyl pyrrolidone in the layer may be affected, and the design of the hollow fiber membrane from this viewpoint also belongs to the category of the present invention.

  Examples of the method for achieving the above requirements 2 and 3 and 4 in the present invention include setting the ratio of the hydrophilic polymer to the hydrophobic polymer in the above-described range, optimizing the film forming conditions of the hollow fiber membrane, etc. Can be achieved. Specifically, it is preferable that the dense layer formed on the inner surface side of the hollow fiber membrane has a two-layer structure in which there is a density difference between the outermost layer portion and the surface vicinity portion. That is, although the detailed reason is not known, by adjusting the mass ratio of the polysulfone polymer and the hydrophilic polymer in the spinning dope and the concentration and temperature of the internal coagulation liquid within the ranges described later, There is a difference in the solidification rate and / or phase separation rate between the surface layer and the vicinity of the surface, and the difference in solubility between the polysulfone polymer and the hydrophilic polymer in the solvent / water has the characteristics as in requirements 2 and 3. I think that it may be expressed. For requirement 4, it is important to optimize the drying conditions. That is, when the wet hollow fiber membrane is dried, the hydrophilic polymer dissolved in water moves from the inside of the hollow membrane to the surface side as the water moves. Here, by using drying conditions as described later, it is possible to give a certain speed to the movement of water and to make the movement speed uniform throughout the hollow fiber membrane, and the hydrophilic polymer inside the hollow fiber membrane. Move quickly to both surfaces without spots. Since the evaporation of water from the membrane surface is greater from the outer surface side than from the inner surface side of the hollow fiber membrane, the amount of the hydrophilic polymer that moves to the outer surface side is increased, and thus the hollow fiber membrane of the present invention is increased. It is presumed that requirement 4 which is a characteristic of the above can be achieved.

  Further, as a means for achieving the requirement 5, the present inventors have intensively studied from the viewpoint that it is effective to contribute to the stabilization of the high energy of γ rays of the diphenylsulfone structure. The knowledge that contributes to the resistance to γ sterilization was obtained. Although this mechanism is unknown in detail, divalent ions may have an effect of reducing the decomposability with radiation derived from the terminal group of the polysulfone resin. Most of the polysulfone-based resins are polycondensated with dichlorodiphenylsulfone as a polymerization monomer and a unit having a phenolic group at both ends (dihydroxydiphenylsulfone, bisphenol A, etc.) as constituent components. In this method, there always exists a chlorophenyl structure or a phenolic end having chlorine as a terminal group. There is a possibility that divalent ions have an effect of reducing the decomposability with radiation derived from these end groups. In addition, ionic protective action between divalent ions and sulfone groups, or ionic cross-linking structure formation between sulfone groups and other groups via divalent ionic substances, or in the molecule acts on protection. It is also possible that this is happening. Such properties may be similar to other chemical substances, for example, behavior in which a polymer having a sulfate ester group is improved in heat resistance in the presence of a divalent ionic substance. However, since the residual amount of divalent ions is effective with a trace amount, the effect on the former end group is considered to be dominant.

  As for the addition of divalent ions to the polysulfone resin of the present invention, any one of (1) a state of spinning stock solution and (2) a state after forming into a hollow fiber can be considered. The former method is advantageous for direct action on the polysulfone resin, and the latter is advantageous for obtaining a sufficient residual effect on the hollow fiber membrane. The purpose is to obtain a distribution state of the conductive polymer. From this, it is difficult to control the treatment of sufficient divalent ions to the polysulfone resin in the post-treatment, and the former treatment is considered to be a reliable method. Even if the divalent ion component is not added in the hollow fiber production process, the same effect can be expected even if the raw material used contains it in advance.

  Alkaline earth metal ions such as calcium and magnesium are suitable for the type of divalent ions that act on the resin. When heavy metal ions are used, there is a concern that a decomposition catalytic action due to heavy metals may appear. Examples of the addition of the ion include a method of adding the salt as a salt having solubility in a spinning solution, water in contact with the hollow fiber, and the like.

The concentration of addition can be determined by how much ions can contact as a total amount per weight of the polysulfone resin. Addition to the spinning dope is the easiest way to estimate. In the present invention, an effect is obtained by the action of several mg to several tens mg with respect to 1 kg of the polyphonic resin.
The addition to the spinning dope is preferably 1 mg or more as ion atoms with respect to 1 kg of the polysulfone resin. If the addition is small, a sufficient effect cannot be obtained. More preferably, it is 5 mg or more. Moreover, about an upper limit, there exists a problem of solubility, and excessive addition is unpreferable.
Therefore, it is more preferably 100 mg or less. More preferably, it is 50 mg or less.

  The mass ratio of the hydrophilic polymer to the polysulfone polymer in the dope is preferably 0.1 to 0.6. If the PVP content in the dope is too low, it may be difficult to control the PVP abundance ratio in the film within the range of requirements 2, 3, and 4. Therefore, the hydrophilic polymer / polysulfone polymer in the dope is more preferably 0.15 or more, further preferably 0.2 or more, still more preferably 0.25 or more, and particularly preferably 0.3 or more. Further, if the PVP content in the dope is too large, the amount of PVP in the film also increases, so it is necessary to strengthen the cleaning after film formation, which may lead to an increase in cost. Therefore, the PVP ratio in the dope is more preferably 0.57 or less, and further preferably 0.55 or less.

  As the internal coagulation liquid, a 15 to 70 mass% dimethylacetamide (DMAc) aqueous solution is preferable. If the concentration of the internal coagulation liquid is too low, the solidification rate of the inner surface is increased, which may make it difficult to control the content of the hydrophilic polymer in the vicinity of the inner surface. Therefore, the internal coagulation liquid concentration is more preferably 20% by mass or more, further preferably 25% by mass or more, and further preferably 30% by mass or more. On the other hand, if the concentration of the internal coagulating liquid is too high, the coagulation rate on the inner surface becomes slow, and it may be difficult to control the content of the hydrophilic polymer on the outermost surface. Therefore, the internal coagulation liquid concentration is more preferably 60% by mass or less, further preferably 55% by mass or less, and further preferably 50% by mass or less. Furthermore, it is preferable to control the internal coagulation liquid temperature to -20 to 30 ° C. If the internal coagulating liquid temperature is too low, the outermost surface is solidified immediately after nozzle discharge, and it may be difficult to control the content of the hydrophilic polymer in the vicinity of the inner surface. The internal coagulation liquid temperature is more preferably −10 ° C. or higher, further preferably 0 ° C. or higher, and further preferably 10 ° C. or higher. In addition, if the internal coagulation liquid temperature is too high, the difference in the film structure (dense / dense) between the innermost surface layer and the surface becomes too large, making it difficult to control the content of the hydrophilic polymer near the outermost surface and the surface. Sometimes. The internal coagulation liquid temperature is more preferably 25 ° C. or lower, and further preferably 20 ° C. or lower. In addition, by setting the internal coagulating liquid temperature within the above range, it is possible to suppress the dissolved gas that has dissolved into bubbles when the internal coagulating liquid is discharged from the nozzle. In other words, by suppressing the bubbling of the dissolved gas in the internal coagulation liquid, there is also a secondary effect of suppressing yarn breakage directly below the nozzle and the occurrence of knobs. As a means for controlling the internal coagulating liquid temperature within the above range, it is preferable to provide a heat exchanger in the pipe from the internal coagulating liquid tank to the nozzle.

As a specific example of the method for drying the wet hollow fiber membrane, the wet hollow fiber membrane bundle is put in a microwave dryer and dried by irradiating with a microwave with an output of 0.1 to 20 kW under a reduced pressure of 20 kPa or less. Is a preferred embodiment. In consideration of shortening the drying time, a higher microwave output is preferable.For example, in hollow fiber membranes containing hydrophilic polymers, degradation or decomposition of the hydrophilic polymers may occur due to overdrying or overheating. It is preferable that the output is not increased too much due to problems such as a decrease in wettability. Therefore, the microwave output is more preferably 18 kW or less, further preferably 16 kW or less, and further preferably 14 kW or less. Further, the hollow fiber membrane bundle can be dried even with an output of less than 0.1 kW, but there is a possibility that a problem of reduction in throughput due to an increase in drying time may occur. The output of the microwave is more preferably 0.15 kW or more, and further preferably 0.2 kW or more. The degree of reduced pressure combined with the output is preferably 15 kPa or less, more preferably 10 kPa or less, although it depends on the moisture content of the hollow fiber membrane bundle before drying. A lower degree of vacuum is preferable because the drying speed increases, but it is preferable to set the lower limit to 0.1 kPa in view of cost increase for increasing the degree of sealing of the system. More preferably, it is 0.2 kPa or more, and further preferably 0.3 kPa or more. The optimum value of the combination of the microwave output and the degree of reduced pressure varies depending on the moisture content of the hollow fiber membrane bundle and the number of treatments of the hollow fiber membrane bundle.
For example, as a temporary guideline for carrying out the drying conditions of the present invention, when 20 hollow fiber membrane bundles having a moisture content of 50 g per hollow fiber membrane are dried, the total moisture content is 50 g × 20 = 1,000 g. At this time, the output of the microwave is suitably 1.5 kW and the degree of decompression is suitably 5 kPa.

  The microwave irradiation frequency is preferably 1,000 to 5,000 MHz in consideration of suppression of irradiation spots on the hollow fiber membrane bundle and the effect of extruding water in the pores from the pores. More preferably, it is 1,500-4,500 MHz, More preferably, it is 2,000-4,000 MHz.

  In drying by microwave irradiation, it is important to uniformly heat and dry the hollow fiber membrane bundle. In the above-described microwave drying, nonuniform heating due to the reflected wave that occurs accompanying the generation of the microwave occurs, so it is important to take measures to reduce the nonuniform heating due to the reflected wave. The method is not limited and is arbitrary. For example, a method of providing a reflector in an oven disclosed in Japanese Patent Application Laid-Open No. 2000-340356 to reflect reflected waves and uniformize heating is a preferred embodiment. One.

  With the above combination, the hollow fiber membrane is preferably dried within 5 hours. If the drying time is too long, the movement speed of the water in the hollow fiber membrane is slow, which may affect the movement of the hydrophilic polymer dissolved in the water. As a result, it becomes impossible to move the hydrophilic polymer to the target layer in the hollow fiber membrane, or it becomes easy to cause movement spots, thereby controlling the content of the hydrophilic polymer in each part. It may not be possible. Therefore, the drying time of the hollow fiber membrane is more preferably within 4 hours, and further preferably within 3 hours. A shorter drying time is preferable because the movement of the hydrophilic polymer is less, but a combination of microwave frequency, output, and degree of vacuum is preferred from the viewpoint of suppressing degradation and decomposition of the hydrophilic polymer due to heat generation and reducing dry spots. When selected, it is preferable to take a drying time of 5 minutes or more, more preferably 10 minutes or more, and even more preferably 15 minutes or more.

  Further, the maximum temperature reached by the hollow fiber membrane bundle during drying is preferably 80 ° C. or lower. If the temperature is too high, the hydrophilic polymer may be deteriorated or decomposed. Therefore, the temperature of the hollow fiber membrane during drying is more preferably 75 ° C. or less, and further preferably 70 ° C. or less. However, if the temperature is too low, the drying time becomes long, so that there is a possibility that the hydrophilic high molecular weight of each part of the hollow fiber membrane cannot be controlled as described above. Therefore, the temperature during drying is preferably 20 ° C. or higher, more preferably 30 ° C. or higher, and further preferably 40 ° C. or higher.

  Furthermore, it is preferable that the hollow fiber membrane does not dry out. If it is completely dried, there is a possibility that the wettability decreases during re-wetting at the time of use, and the hydrophilic polymer is less likely to absorb water, so that it can be easily eluted from the hollow fiber membrane. The moisture content of the hollow fiber membrane after drying is preferably 1% by weight or more, and more preferably 1.5% by weight or more. If the water content of the hollow fiber membrane is too high, bacteria may be easily proliferated during storage, and the hollow fiber membrane may be crushed by its own weight. Therefore, the water content of the hollow fiber membrane is 5% by weight. The following is preferable, more preferably 4% by weight or less, and still more preferably 3% by weight or less. The moisture content (%) of the present invention means the mass of the hollow fiber membrane bundle before drying (a) the mass (b) of the hollow fiber membrane bundle after drying, and the moisture content (%) = (a− b) can be easily calculated by / b × 100.

In the present invention, the hole area ratio of the outer surface of the hollow fiber membrane is 8 to 25%, and the average hole area of the hole portion on the outer surface of the hollow fiber membrane is 0.3 to 1.0 μm ² . This is effective for imparting the above-mentioned characteristics and is a preferred embodiment. If the open area ratio is less than 8% or the average pore area is less than 0.3 μm ² , the water permeability may decrease. In addition, when the membrane is dried, hydrophilic polymers present on the outer surface of the membrane are interposed so that the hollow fiber membranes are fixed to each other, which may cause problems such as deterioration in module assemblability. Therefore, the open area ratio is more preferably 9% or more, and further preferably 10% or more. The average pore area is more preferably 0.4 μm ² or more, further preferably 0.5 μm ² or more, and further preferably 0.6 μm ² or more. On the contrary, when the open area ratio exceeds 25% or the average pore area exceeds 1.0 μm ² , the burst pressure may decrease. Therefore, the porosity is more preferably 23% or less, further preferably 20% or less, still more preferably 17% or less, and particularly preferably 15% or less. The average pore area is more preferably 0.95 .mu.m ² or less, more preferably 0.90 .mu.m ² or less.

  As a method for setting the content of the hydrophilic polymer on the outer surface of the hollow fiber membrane in the above range and a method for setting the opening ratio of the outer surface of the hollow fiber membrane in the above range, hydrophilicity to the polysulfone polymer in the spinning dope described above is used. In addition to adjusting the mass ratio of the conductive polymer and optimizing the drying conditions of the hollow fiber membrane, it is also effective to optimize the cleaning conditions in cleaning the formed hollow fiber membrane. Film forming conditions include temperature and humidity adjustment of the air gap at the nozzle exit, stretching conditions, optimization of the temperature and composition of the external coagulation bath, and cleaning methods include hot water cleaning, alcohol cleaning, and centrifugal cleaning. It is valid. Among these methods, as the film forming conditions, optimization of the humidity of the air gap and the composition ratio of the solvent and the non-solvent in the external coagulating liquid is particularly effective as the cleaning method.

  The air gap portion is preferably surrounded by a member for blocking outside air, and the humidity inside the air gap is preferably adjusted by the spinning solution composition, the nozzle temperature, the air gap length, and the temperature and composition of the external coagulation bath. For example, a spinning stock solution consisting of polyethersulfone / polyvinylpyrrolidone / dimethylacetamide / water = 10-25 / 0.5-12.5 / 52.5-89.5 / 0-10.0 is used at a nozzle of 30-60 ° C. When the air gap is discharged through the air gap of 100 to 1000 mm and led to an external coagulation bath having a concentration of 0 to 70 mass% and a temperature of 50 to 80 ° C., the absolute humidity of the air gap portion is 0.01 to 0.3 kg / kg. It becomes dry air. By adjusting the humidity of the air gap part to such a range, it becomes possible to control the outer surface open area ratio, the outer surface average pore area, and the outer surface hydrophilic polymer content to an appropriate range.

  As the external coagulation liquid, it is preferable to use a DMAc aqueous solution of 0 to 50% by mass. If the concentration of the external coagulation solution is too high, the outer surface opening ratio and the outer surface average pore area become too large, which may increase the backflow of endotoxin to the blood side when using dialysis. Therefore, the external coagulation liquid concentration is more preferably 40% by mass or less, further preferably 30% by mass or less, and still more preferably 25% by mass or less. If the concentration of the external coagulation liquid is too low, it is necessary to use a large amount of water to dilute the solvent brought in from the spinning stock solution, and the cost for waste liquid treatment increases. Therefore, the lower limit of the external coagulation liquid concentration is more preferably 5% by mass or more.

  In the production of the hollow fiber membrane of the present invention, it is preferable that stretching is not substantially applied before the hollow fiber membrane structure is completely fixed. “Substantially no stretching” means that the roller speed during the spinning process is controlled so that the spinning dope discharged from the nozzle is not loosened or excessively tensioned. The discharge linear speed / coagulation bath first roller speed ratio (draft ratio) is preferably in the range of 0.7 to 1.8. If the ratio is less than 0.7, the traveling hollow fiber membrane may be loosened, leading to a decrease in productivity, and if it exceeds 1.8, the membrane structure is destroyed such as the dense layer of the hollow fiber membrane is torn. Sometimes. More preferably, it is 0.85-1.7, More preferably, it is 0.9-1.6, Most preferably, it is 1.0-1.5. By adjusting the draft ratio to this range, deformation and destruction of the pores can be prevented, clogging of blood protein into the membrane pores can be prevented, and performance stability over time and sharp fractionation characteristics can be expressed. Is possible.

The hollow fiber membrane that has passed through the water-washing bath is wound into a basket in a wet state to form a bundle of 3,000 to 20,000. Next, the obtained hollow fiber membrane bundle is washed to remove excess solvent and hydrophilic polymer. As a method for cleaning the hollow fiber membrane bundle, in the present invention, it is preferable to treat the hollow fiber membrane bundle by immersing it in hot water at 70 to 130 ° C., or from room temperature to 50 ° C. and 10 to 40 vol% ethanol or isopropanol aqueous solution. .
(1) In the case of hot water washing, the hollow fiber membrane bundle is immersed in excess water and treated at 70 to 90 ° C. for 15 to 60 minutes, and then the hollow fiber membrane bundle is taken out and subjected to centrifugal dehydration. This operation is repeated three or four times while renewing the water to perform the cleaning process.
(2) A method of treating a hollow fiber membrane bundle immersed in excess water in a pressurized container at 121 ° C. for about 2 hours can also be employed.
(3) When using an ethanol or isopropanol aqueous solution, it is preferable to repeat the same operation as in (1).
(4) It is also a preferable washing method that the hollow fiber membrane bundle is radially arranged in the centrifugal washer and centrifugal washing is performed for 30 minutes to 5 hours while spraying washing water at 40 ° C. to 90 ° C. from the rotation center in a shower shape. .
Two or more cleaning methods may be combined. In any of the methods, if the processing temperature is too low, it is necessary to increase the number of times of cleaning, which may lead to an increase in cost. On the other hand, when the treatment temperature is too high, the decomposition of the hydrophilic polymer is accelerated, and conversely, the cleaning efficiency may be lowered. By performing the above-described cleaning, it is possible to optimize the abundance of the hydrophilic polymer on the outer surface, thereby suppressing sticking and reducing the amount of eluate.

  In the present invention, it is important to satisfy the above requirements 1 to 5 at the same time. By simultaneously achieving the requirements, all the above-mentioned characteristics can be satisfied.

  Since the hollow fiber membrane bundle of the present invention has characteristics as described above, it is a preferred embodiment to be used for a blood purifier.

When used for the above-mentioned blood purifier, the blood purifier is a hollow fiber membrane having a burst pressure of 0.5 MPa or more, and the water permeability of the blood purifier is 150 ml / m ² / hr / mmHg or more. preferable.

  The burst pressure in the present invention is an index of the pressure resistance of the hollow fiber membrane after the hollow fiber is made into a module, and the hollow fiber is inside when the inside of the hollow fiber is pressurized with air and the pressure is gradually increased. It is a pressure that bursts without bursting. The higher the burst pressure, the fewer latent defects that lead to the cutting of the hollow fiber membrane and the generation of pinholes during use, so 0.5 MPa or more is preferable, 0.7 MPa or more is more preferable, and 1.0 MPa or more is particularly preferable. If the burst pressure is less than 0.5 MPa, there is a possibility that it is impossible to detect a potential defect that leads to a blood leak as described later. The higher the burst pressure, the better. However, if the focus is on increasing the burst pressure and the film thickness is increased or the porosity is decreased too much, the desired film performance may not be obtained. Therefore, when finished as a hemodialysis membrane, the burst pressure is preferably less than 2.0 MPa. More preferably, it is less than 1.7 MPa, more preferably less than 1.5 MPa, and particularly preferably less than 1.3 MPa.

Further, when the water permeability is less than 150 ml / m ² / hr / mmHg, the solute permeability may be lowered. In order to increase the solute permeability, the pore diameter is increased or the number of pores is increased. However, this tends to cause problems such as a decrease in membrane strength and formation of defects. However, in the hollow fiber membrane of the present invention, the porosity of the support layer portion is optimized by optimizing the pore diameter of the outer surface, and the reduction in solute permeation resistance and the improvement in membrane strength are balanced. A more preferable range of water permeability is 200 ml / m ² / hr / mmHg or more, more preferably 300 ml / m ² / hr / mmHg or more, still more preferably 400 ml / m ² / hr / mmHg or more, particularly preferably 500 ml / m. ² / hr / mmHg or more. In addition, when the water permeability is too high, it becomes difficult to control water removal during hemodialysis, and therefore, 2000 ml / m ² / hr / mmHg or less is preferable. More preferably 1800 ml / m ² / hr / mmHg or less, further preferably 1500 ml / m ² / hr / mmHg or less, even more preferably 1300 ml / m ² / hr / mmHg or less, particularly preferably 1000 ml / m ² / hr / h / g. It is below mmHg.

  Usually, a module used for blood purification is subjected to a leak test in which the inside or outside of the hollow fiber is pressurized with air in order to confirm defects of the hollow fiber or the module at the final stage of production. When a leak is detected by the pressurized air, the module is discarded as a defective product or an operation for repairing the defect is performed. The air pressure in this leak test is often several times the guaranteed pressure resistance (usually 500 mmHg) of the hemodialyzer. However, in the case of a hollow fiber type blood purification membrane having a particularly high water permeability, microscopic scratches, crushing, and tearing of the hollow fiber that cannot be detected by a normal pressure leak test are caused by manufacturing processes (mainly sterilization and (Packing), transportation process, or handling in clinical settings (unpacking, priming, etc.) will lead to the occurrence of hollow fiber cutting and pinholes. It is. The trouble can be avoided by setting the burst pressure to the above characteristic.

  Further, the uneven thickness of the hollow fiber membrane is effective for suppressing the occurrence of the above-described potential defects. It is a preferred embodiment in which the thickness deviation when observing the cross section of 100 hollow fiber membranes in the hollow fiber membrane module is high, and the thickness deviation ratio shown by the ratio between the maximum value and the minimum value is high. The uneven thickness of 100 hollow fiber membranes is preferably 0.6 or more. If at least one hollow fiber membrane includes 100 hollow fiber membranes with an uneven thickness of less than 0.6, the hollow fiber membrane may easily cause a potential defect that causes a leak during clinical use. The thickness deviation of the present invention is not an average value but represents a minimum value of 100. A higher unevenness degree increases the uniformity of the film, suppresses the occurrence of latent defects, and improves the burst pressure. Therefore, it is more preferably 0.65 or more, more preferably 0.7 or more, and still more preferably 0. .75 or more. If it is less than 0.6, latent defects are likely to occur, and the burst pressure becomes low, which may lead to blood leakage.

  In order to make the thickness deviation 0.6 or more, for example, it is preferable to make the slit width of the nozzle that is the discharge port of the film forming solution strictly uniform. The spinning nozzle of the hollow fiber membrane is generally a tube-in-orifice type nozzle having an annular portion for discharging the spinning stock solution and a core liquid discharge hole serving as a hollow forming agent inside thereof. This refers to the width of the annular portion that discharges the spinning dope. By reducing the variation in the slit width, uneven thickness of the spun hollow fiber membrane can be reduced. Specifically, the ratio between the maximum value and the minimum value of the slit width is 1.00 to 1.11, and the difference between the maximum value and the minimum value is preferably 10 μm or less, and more preferably 5 μm or less. In addition, methods such as optimizing the nozzle temperature, reducing discharge spots of the internal liquid during film formation, and optimizing the draw ratio are also effective.

  Further, as a measure for increasing the burst pressure, it is also an effective method to reduce the potential defects by reducing the flaws on the surface of the hollow fiber membrane, the mixing of foreign matter and bubbles. As a method of reducing the occurrence of scratches, the material and surface roughness of rollers and guides in the manufacturing process of the hollow fiber membrane are optimized, the container and the hollow fiber membrane are inserted when the hollow fiber membrane bundle is inserted into the module container at the time of module assembly. It is effective to devise such that contact with the fiber or rubbing between the hollow fiber membranes is reduced. In the present invention, it is preferable to use a roller having a mirror-finished surface in order to prevent the hollow fiber membrane from slipping and scratching the surface of the hollow fiber membrane. Further, it is preferable to use a guide whose surface is textured or knurled in order to avoid contact resistance with the hollow fiber membrane as much as possible. When the hollow fiber membrane bundle is inserted into the module container, the hollow fiber membrane bundle is not directly inserted into the module container. It is preferable to use a method in which a film is inserted into a module container, and after insertion, only the film is extracted from the module container.

  As a method for suppressing the mixing of foreign matter into the hollow fiber membrane, a method using a raw material with less foreign matter, filtering the spinning dope for forming a membrane, and reducing foreign matter is effective. In the present invention, it is preferable to filter the spinning dope using a filter having a pore size smaller than the film thickness of the hollow fiber membrane. Specifically, the pore size provided while the uniformly dissolved spinning dope is led from the dissolution tank to the nozzle. Pass through a 10-50 μm sintered filter. The filtration treatment may be performed at least once. However, when the filtration treatment is performed in several stages, it is preferable to reduce the pore size of the filter as it is in the latter stage in order to extend the filtration efficiency and the filter life. The pore diameter of the filter is more preferably 10 to 45 μm, further preferably 10 to 40 μm. If the filter pore size is too small, the back pressure may increase and the quantitativeness may decrease.

  Further, as a method for suppressing the mixing of bubbles, it is effective to defoam a polymer solution for film formation. Depending on the viscosity of the spinning dope, static defoaming or vacuum defoaming can be used. Specifically, after the pressure in the dissolution tank is reduced to -100 to -760 mmHg, the tank is sealed and allowed to stand for 5 to 30 minutes. This operation is repeated several times to perform defoaming treatment. If the degree of vacuum is too low, the treatment may take a long time because it is necessary to increase the number of defoaming times. On the other hand, when the degree of vacuum is too high, the cost for increasing the degree of sealing of the system may increase. The total treatment time is preferably 5 minutes to 5 hours. If the treatment time is too long, the hydrophilic polymer may deteriorate or decompose due to the effect of reduced pressure. If the treatment time is too short, the defoaming effect may be insufficient.

  Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto. In addition, the evaluation method of the physical property in the following examples is as follows.

1. Measurement of water permeability The flow is stopped by forceps at the blood outlet circuit of the dialyzer (on the outlet side from the pressure measurement point) and total filtration is performed. Purified water kept at 37 ° C is placed in a pressurized tank and the pressure is controlled by a regulator. Pure water is sent to the dialyzer kept at 37 ° C constant temperature bath, and the amount of filtrate flowing out from the dialysate side is measured with a graduated cylinder. taking measurement. The transmembrane pressure difference (TMP) is
TMP = (Pi + Po) / 2
And Here, Pi is the dialyzer inlet side pressure, and Po is the dialyzer outlet side pressure. Change the TMP at four points, measure the filtration flow rate, and calculate the water permeability (mL / hr / mmHg) from the slope of the relationship. At this time, the correlation coefficient between TMP and filtration flow rate should be 0.999 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100mmHg or less. The water permeability of the hollow fiber membrane is calculated from the membrane area and the water permeability of the dialyzer.
UFR (H) = UFR (D) / A
Where UFR (H) is the water permeability of the hollow fiber membrane (mL / m ² / hr / mmHg), UFR (D) is the water permeability of the dialyzer (mL / hr / mmHg), and A is the membrane area of the dialyzer ( m ² ).

2. Calculation of membrane area The membrane area of the dialyzer is determined as a reference for the inner diameter of the hollow fiber.
A = n × π × d × L
Here, n is the number of hollow fibers in the dialyzer, π is the circumference, d is the inner diameter (m) of the hollow fiber, and L is the effective length (m) of the hollow fiber in the dialyzer.

3. Burst pressure Fill the dialysate side of the module consisting of about 10,000 hollow fiber membranes with water and plug it. Dry air or nitrogen is fed from the blood side at room temperature and pressurized at a rate of 0.5 MPa per minute. The pressure is increased, and the air pressure when the hollow fiber membrane bursts (bursts) with pressurized air and bubbles are generated in the liquid filled on the dialysate side is defined as the burst pressure.

4. Unevenness of thickness The cross section of 100 hollow fibers is observed with a 200 times projector. In one field of view, the thickness of the thickest part and the thinnest part is measured with respect to one yarn cross section having the largest film thickness difference.
Thickness unevenness = thinnest part / thickest part thickening degree = 1, and the film thickness is perfectly uniform.

5. Elution amount of hydrophilic polymer An example of the measurement method when polyvinylpyrrolidone is used as the hydrophilic polymer is shown below.
<Dry hollow fiber membrane module>
Saline was passed through the dialysate side channel of the module at 500 mL / min for 5 minutes, and then passed through the blood side channel at 200 mL / min. Thereafter, the solution was passed for 3 minutes from the blood side to the dialysate side while filtering at 200 mL / min.
<Wet hollow fiber membrane module>
After extracting the module filling liquid, the same processing operation as that of the dry hollow fiber membrane module was performed.
Using the hollow fiber membrane module subjected to the priming treatment, extraction was performed by a method defined in the dialysis artificial kidney device production approval standard, and polyvinylpyrrolidone in the extract was quantified by a colorimetric method.
That is, 100 ml of pure is added to 1 g of the hollow fiber membrane and extracted at 70 ° C. for 1 hour. The obtained extract (2.5 ml), 0.2 molar aqueous citric acid solution (1.25 ml) and 0.006 normal iodine aqueous solution (0.5 ml) were mixed well and allowed to stand at room temperature for 10 minutes, and the absorbance at 470 nm was measured. The quantification was performed with a calibration curve obtained by measuring according to the above method using a standard polyvinylpyrrolidone.

6. Content of hydrophilic polymer in outermost surface of inner and outer surfaces The content of hydrophilic polymer was determined by X-ray photoelectron spectroscopy (ESCA method). The measurement method when polyvinylpyrrolidone (PVP) is used as the hydrophilic polymer will be exemplified.
One hollow fiber membrane was cut obliquely with a razor so that a part of the inner surface was exposed, and was attached to a sample stage so that the inner and outer surfaces could be measured, and measurement was performed by ESCA. The measurement conditions are as follows.
Measuring device: ULVAC-Phi ESCA5800
Excitation X-ray: MgKα ray X-ray output: 14 kV, 25 mA
Photoelectron escape angle: 45 °
Analysis diameter: 400μmφ
Pass energy: 29.35 eV
Resolution: 0.125 eV / step
Degree of vacuum: about 10 ⁻⁷ Pa or less From the measured value (N) of nitrogen and the measured value (S) of sulfur, the PVP content ratio on the surface was calculated by the following formula.
<In case of PVP-added PES (polyethersulfone) membrane>
PVP content ratio (Hpvp) [%]
= 100 × (N × 111) / (N × 111 + S × 232)
<In the case of PVP-added PSf (polysulfone) membrane>
PVP content ratio (Hpvp) [%]
= 100 × (N × 111) / (N × 111 + S × 442)

7. Measuring method of hydrophilic polymer content rate in the whole hollow fiber membrane The measuring method at the time of using PVP as a hydrophilic polymer is illustrated. The sample was dried at 80 ° C. for 48 hours using a vacuum dryer, 10 mg of which was analyzed with a CHN coder (manufactured by Yanaco Analytical Co., Ltd., MT-6 type), and the mass ratio of PVP from the nitrogen content was expressed by the following formula: Calculated with
Mass ratio (mass%) of PVP = nitrogen content (mass%) × 111/14

8. Content of hydrophilic polymer in surface vicinity layer of blood contact surface of hollow fiber membrane An example of a measurement method using PVP as the hydrophilic polymer is illustrated. Measurement was performed by infrared absorption analysis. A measurement sample prepared by the same method as in 6 above was used, the measurement in the vicinity of the surface was performed by the ATR method, and the entire film was measured by the transmission method. In the ATR method, an infrared absorption spectrum was measured by a method using diamond 45 ° as an internal reflection element. For the measurement, IRμs / SIRM manufactured by SPECTRA TECH was used. In the infrared absorption spectrum, the ratio Ap / As of the peak absorption intensity Ap derived from C═O of PVP near 1675 cm ⁻¹ and the peak absorption intensity As derived from polysulfone-based polymer near 1580 cm ⁻¹ was determined. In the ATR method, since the absorption intensity depends on the measured wave number, a ratio υp / υs between the peak position υs of the polysulfone polymer and the peak position υp (wave number) of the PVP was applied to the measured value as a correction value. The content of PVP in the blood contact surface vicinity layer was calculated by the following formula.
Content (mass%) of hydrophilic polymer in the surface vicinity layer = Cav × Ap / As × υp / υs
However, Cav is a PVP mass ratio determined by a method for measuring the hydrophilic polymer content in the entire hollow fiber membrane.

9. Opening ratio of outer surface of hollow fiber membrane The outer surface of the hollow fiber membrane is observed with an electron microscope of 10,000 times and a photograph (SEM photograph) is taken. The image was processed with image analysis processing software to obtain the porosity of the outer surface of the hollow fiber membrane. The image analysis processing software is measured using, for example, Image PRO Plus (Media Cybernetics, Inc.). The emphasis / filtering operation is performed on the captured image so that the hole and the blockage are identified. Thereafter, the holes are counted, and when the lower polymer chain can be seen inside the holes, the holes are combined and counted as one hole. The area (A) of the measurement range and the cumulative area (B) of the pores within the measurement range were determined, and the area ratio (%) = B / A × 100. This was carried out 10 views and the average was obtained. Scale setting is performed as an initial operation, and holes on the measurement range boundary are not excluded during counting.

10. Average pore area of the apertures on the outer surface of the hollow fiber membrane Counted in the same manner as in the previous section, and the area of each pore was determined. In addition, holes on the measurement range boundary were excluded during counting. This was carried out for 10 fields of view and the average of all pore areas was determined.

11. Thickness of hollow fiber membrane The cross section of 100 hollow fibers is observed with a 200 × projector. In one field of view, the thickness of the thickest part and the thinnest part was measured for one yarn cross section having the largest film thickness difference.
Thickness unevenness = thinnest part / thickest part thickening degree = 1, and the film thickness is perfectly uniform.

12. Blood Leakage Test Add 37 ml of cattle blood to which citrate has been added to suppress coagulation to a blood purifier at 200 mL / min, and filter the blood at a rate of 10 mL / min · m ² . At this time, the filtrate is returned to blood to be a circulatory system. After 60 minutes, the filtrate from the blood purifier is collected, and the red color resulting from red blood cell leakage is visually observed. In this blood leak test, 30 blood purifiers were used in each of the examples and comparative examples, and the number of blood leaked modules was examined.

13. Fixing property of hollow fiber membrane About 10,000 hollow fibers were bundled, loaded into a module case of 30 mmφ to 35 mmφ, and sealed with a two-component polyurethane resin to prepare a module. A leak test was conducted for each level of five, and the number of modules that had leaked due to poor urethane resin sealing was counted.

14. Residual blood of hollow fiber membrane Fill the dialysate side of the module with a membrane area of 1.5m ² with physiological saline, fill the blood bag with 200ml of heparinized blood collected from a healthy person, and connect the blood bag and the module with a tube And circulate at 37 ° C. for 1 hour at a blood flow rate of 100 ml / min. Blood samples before the start of circulation and 60 minutes of circulation are sampled, and the white blood cell count and platelet count are measured. The measured value is corrected with the value of hematocrit.
Correction value = measured value (60 minutes) x hematocrit (0 minutes) / hematocrit (60 minutes)
The rate of change of white blood cells and platelets is calculated from the correction value.
Rate of change = correction value (60 minutes) / pre-circulation value x 100
After the circulation for 60 minutes, the blood was returned with physiological saline, and the number of remaining blood was counted. The evaluation was carried out with the number of remaining blood threads being 10 or less, ◯, 11 to 30 threads as Δ, and 31 or more threads as ×.

15. With the lid on the dialysate side port of the priming property module, distilled water for injection is flowed from the blood side inlet port at 200 mL / min until 10 seconds elapses after the distilled water for injection reaches the outlet port. The module case was detaped by tapping the module case 5 times with forceps, and the number of bubbles passed for 1 minute was visually confirmed. The determination was made according to the following criteria.
10 / min or less: ○
11 / min or more and less than 30 / min: △
30 pieces / minute or more: ×

16. Measurement of breaking strength of yarn Using a hollow fiber test piece having an effective sample length of 10 cm, a tensile test was conducted using Tensilon (UTM11 manufactured by Toyo Baldwin) under a crosshead speed of 10 cm, and the breaking point was measured. Measure 30 samples and use the average value as the result. The measurement was performed in a temperature and humidity environment of 20 ± 5 ° C. and 60 ± 10% RH. When the hollow fiber was in a wet state, it was allowed to stand for 24 hours in a measurement environment and was substantially dried.

Example 1
Polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (R) 4800P) 17.6% by mass, polyvinyl pyrrolidone (BASF Koridone (R) K-90) 4.8% by mass, dimethylacetamide (DMAc) 74. Magnesium chloride is added in an amount equivalent to 20 ppm of polyethersulfone to a spinning stock solution having a composition of 6% by mass and RO water of 3.0% by mass, and uniformly dissolved at 50 ° C. Then, using a vacuum pump After reducing the pressure in the system to -500 mmHg, the system was immediately sealed and allowed to stand for 15 minutes so that the solvent and the like were evaporated and the film-forming solution composition was not changed. This operation was repeated three times to degas the film forming solution. The membrane-forming solution is passed through a 30 μm and 15 μm two-stage sintered filter in order, and then discharged from the outer slit of a tube-in orifice nozzle heated to 60 ° C., and at the same time, degassed as an internal coagulating liquid at −700 mmHg for 60 minutes. The processed 46 mass% DMAc aqueous solution at 20 ° C. was discharged from the inner liquid discharge hole, passed through a 450 mm dry part cut off from the outside air by a spinning tube, and then solidified in a 20 mass% DMAc aqueous solution at 60 ° C. I whispered to the wall. The winding speed at this time was 75 m / min. The nozzle slit width of the tube-in-orifice nozzle used was an average of 60 μm, the maximum was 61 μm, the minimum was 59 μm, the ratio of the maximum and minimum slit width was 1.03, and the draft ratio of the film forming solution was 1.04. .

  A polyethylene film whose surface on the hollow fiber bundle side was textured was wound around about 10,000 bundles of the hollow fiber membranes, and then cut into a length of 27 cm to obtain a bundle. This bundle was washed in hot water at 80 ° C. for 30 minutes × 4 times. The obtained wet bundle is centrifuged and drained for 600 rpm × 5 min, and the hollow fiber membrane bundle is set in 12 × 2 stages on the rotary table in the drying apparatus, and the reflector is installed in the oven so that it can be heated uniformly. The microwave generator having the structure was irradiated with an initial 1.5 kW microwave, and the inside of the drying apparatus was reduced to 7 kPa by a vacuum pump, and the drying treatment was performed for 28 minutes. Subsequently, a drying process was performed for 12 minutes at a microwave output of 0.5 kW and a reduced pressure of 7 kPa. Further, the microwave output was reduced to 0.2 kW, and the drying process was similarly completed for 8 minutes. At the same time, far infrared irradiation was used in combination. The maximum temperature reached on the surface of the hollow fiber membrane bundle at this time was 65 ° C., and the moisture content of the hollow fiber membrane after drying was an average of 2.2% by mass. The resulting hollow fiber membrane had an inner diameter of 199.9 μm and a film thickness of 29.5 μm. During the spinning process, the roller contacted with the hollow fiber membrane was a mirror-finished surface, and the guides were all finished with a satin finish.

  As a result of assembling a blood purifier using the hollow fiber membrane thus obtained and conducting a leak test, no adhesion failure due to the sticking of the hollow fibers was found.

  The blood purifier was filled with RO water and subjected to γ-ray sterilization at a dose of 25 kGy. When the hollow fiber membrane was cut out from the blood purifier after γ-irradiation and subjected to the eluate test, the PVP elution amount was 4 ppm, which was a satisfactory level. Further, when the outer surface of the hollow fiber membrane taken out from the blood purifier was observed with a microscope, defects such as scratches were not observed.

In addition, citrated fresh bovine blood was passed through the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 10 mL / min · m ² , but no blood cell leak was observed. Endotoxin filtered from the outer side of the hollow fiber to the inner side of the hollow fiber was below the detection limit and was at a level with no problem. The other analysis results are shown in Table 1.

  Using the blood purification module produced in the same manner, the blood purification device was filled with RO water and γ-ray sterilized at a dose of 40 kGy. The hollow fiber membrane was cut out from the blood purifier before and after γ-ray irradiation, and the breaking strength was measured. The intensity before γ-ray irradiation was 14.3 g, and the intensity after 40 kGy γ-ray irradiation was 13.4 g, which was sufficient.

(Comparative Example 1)
Wet hollow fiber in the same manner as in Example 1, except that the spinning dope was changed to 2.4% by mass of polyvinylpyrrolidone (Collidon (R) K-90 manufactured by BASF) and 77% by mass of DMAc, and the dry part length was changed to 650 mm. A membrane was obtained. The obtained hollow fiber membrane was washed in the same manner as in Example 1 and dried in a 60 ° C. hot air dryer. The resulting hollow fiber membrane had a water content of 3.3% by mass, an inner diameter of 199.8 μm, and a film thickness of 29.7 μm. Table 1 shows the characteristics of the hollow fiber membrane bundle and the blood purifier obtained from the same evaluation sample as in Example 1. The hollow fiber membrane of Comparative Example 1 had poor residual blood properties, which is presumed to be due to the low PVP content in the vicinity of the inner surface.

(Comparative Example 2)
A spinning dope was obtained in the same manner as in Example 1 except that the amount of PVP (Collidon (R) K-90 manufactured by BASF) was 12.0% by mass and DMAc was 67.4% by mass. It was. Further, the hollow fiber was not subjected to temperature control of the hollow forming agent, was not subjected to the washing treatment, and the hollow fiber membrane bundle was subjected to the same hollow fiber as in Example 1 except that the drying treatment was the same as in Comparative Example 1. A membrane bundle and blood purifier were obtained. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane obtained in this comparative example had a high PVP content in the outermost layer on the inner surface and a high PVP elution amount. Further, since the PVP content on the outer surface of the hollow fiber membrane was high, endotoxin permeation to the blood side was observed.

(Comparative Example 3)
In Comparative Example 2, a hollow fiber membrane bundle and a blood purifier were obtained in the same manner as in Comparative Example 2 except that the number of hot water washings was changed to 8. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane bundle obtained in this comparative example had a low priming property because the outermost surface PVP content was low and the outer surface hydrophilicity was low.

(Example 2)
19.0% by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (R) 4800P), 5.0% by mass of polyvinylpyrrolidone (Collidon (R) K-90, manufactured by BASF), 72.0% by mass of DMAc, water After adding magnesium chloride in an amount equivalent to 10 ppm of polyethersulfone to a spinning stock solution having a composition of 4% by mass and dissolving at 50 ° C., the pressure inside the system was reduced to −700 mmHg using a vacuum pump. The system was immediately sealed and allowed to stand for 10 minutes so that the solvent and the like were volatilized and the film forming solution composition did not change. This operation was repeated three times to degas the film forming solution. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and then discharged from the outer slit of a tube-in orifice nozzle heated to 70 ° C., and at the same time degassed as an internal coagulation liquid at −700 mmHg for 2 hours. The treated 55 mass% DMAc aqueous solution at 15 ° C. was discharged from the inner liquid discharge hole, passed through a 450 mm air gap portion blocked from the outside air by a spinning tube, and then solidified in water at 60 ° C. The nozzle slit width of the tube-in-orifice nozzle used is an average of 45 μm, the maximum is 45.5 μm, the minimum is 44.5 μm, the ratio of the maximum and minimum slit width is 1.02, the draft ratio is 1.06, and the dry type The absolute humidity of the part was 0.12 kg / kg dry air. The hollow fiber membrane pulled up from the coagulation bath was passed through a 90 ° C. water washing tank for 30 seconds to remove the solvent and excess hydrophilic polymer, and then wound up. A polyethylene film similar to that of Example 1 was wrapped around a bundle of about 10,000 hollow fiber membranes, and then immersed in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × twice and replaced with water. did.

  The resulting wet hollow fiber membrane bundle is centrifuged and drained for 600 rpm × 5 min, set on a rotary table in the drying device in 48 × 2 stages, irradiated with an initial 7 kW of microwaves, and inside the drying device. The pressure was reduced to 5 kPa and the drying process was performed for 65 minutes. Subsequently, a drying process was performed for 50 minutes at a microwave output of 3.5 kW and a degree of vacuum of 5 kPa. Further, the microwave output was reduced to 2.5 kW, and similarly a drying treatment was performed for 10 minutes to complete the process. The highest temperature reached on the surface of the hollow fiber membrane bundle during the drying treatment was 65 ° C., and the moisture content was 2.5% by mass on average. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. The obtained hollow fiber membrane had an inner diameter of 200.3 μm and a film thickness of 29.9 μm.

  As a result of assembling a blood purifier using the hollow fiber membrane thus obtained and conducting a leak test, no adhesion failure due to the sticking of the hollow fibers was found.

  The blood purifier was put in a bag made of an aluminum thin / PET laminated film, and nitrogen substitution was repeated several times to change the internal atmosphere to nitrogen, followed by complete sealing. Thereafter, sterilization with γ rays of 25 kGy was performed. A hollow fiber membrane was cut out from the blood purifier, and the same test as in Example 1 was performed.

  No blood cell leak was found in the blood leak test using bovine blood. In addition, as a result of the endotoxin permeation test, endotoxin filtered from the outside of the hollow fiber to the inside of the hollow fiber was below the detection limit and was at a level with no problem. The other analysis results are shown in Table 1.

  Using a blood purification module prepared in the same manner, it was put in a bag made of an aluminum thin / PET laminated film, and nitrogen substitution was repeated several times to change the internal atmosphere to nitrogen, followed by complete sealing. Thereafter, sterilization with γ rays of 40 kGy was performed. The hollow fiber membrane was cut out from the blood purifier before and after γ-ray irradiation, and the breaking strength was measured. The intensity before γ-irradiation was 16.4 g, and the intensity after 40 kGy γ-irradiation was 14.3 g, which was sufficient.

(Example 3)
In Example 2, a hollow fiber membrane bundle and a blood purifier were obtained in the same manner as in Example 2 except that the calcium chloride was changed to an amount equivalent to 30 ppm of polyethersulfone with respect to the spinning dope. The γ-ray sterilization treatment was performed in the same manner as in Example 2. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane bundle obtained in this example had a strength of 16.6 g before γ-ray irradiation and a strength after irradiation of 40 kGy of γ-ray of 14.2 g.

(Comparative Example 4)
A hollow fiber membrane bundle and a blood purifier were obtained in the same manner as in Example 1 except that magnesium was not added to the spinning dope. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane bundle obtained in this comparative example had a strength before γ-ray irradiation of 14.2 g, and a strength after irradiation of 40 kGy of γ-ray was 10.4 g, and the strength retention was not sufficient.

(Comparative Example 5)
A hollow fiber membrane bundle and a blood purifier were obtained in the same manner as in Example 2, except that magnesium was not added to the spinning dope. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane bundle obtained in this Comparative Example had a strength before γ-ray irradiation of 16.5 g, and a strength after 40 kGy of γ-ray irradiation was 11.0 g, and the strength retention was not sufficient.

(Example 4)
Polysulfone (Amoco P-1700) 17% by mass, polyvinylpyrrolidone (BASF K-60) 4.8% by mass, DMAc 73.7% by mass, water 4.5% by mass, magnesium chloride is polysulfone After adding the equivalent amount of 20 ppm, dissolving at 50 ° C., and then reducing the system pressure to −400 mmHg using a vacuum pump, immediately seal the system so that the solvent etc. volatilizes and the film forming solution composition does not change. Left for 30 minutes. This operation was repeated three times to degas the film forming solution. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and then discharged from the outer slit of the tube-in orifice nozzle heated to 40 ° C., and at the same time, the 0 ° C. A 40 mass% DMAc aqueous solution was discharged from the inner discharge hole of the tube-in orifice nozzle, and after passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in 50 ° C. water. The average nozzle slit width of the tube-in-orifice nozzle used is 60 μm, the maximum is 61 μm, the minimum is 59 μm, the ratio between the maximum and minimum slit width is 1.03, the draft ratio is 1.01, the absolute humidity of the dry section Was 0.07 kg / kg dry air. The hollow fiber membrane pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess hydrophilic polymer, and then wound up. A bundle of 10,700 hollow fiber membranes was immersed in pure water and washed in an autoclave at 121 ° C. for 1 hour. A polyethylene film was wound around the washed hollow fiber membrane bundle and then dried in the same manner as in Example 2. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. The hollow fiber membrane thus obtained had an inner diameter of 203.5 μm and a film thickness of 40.8 μm.

  As a result of assembling a blood purifier using the hollow fiber membrane thus obtained and conducting a leak test, no adhesion failure due to the sticking of the hollow fibers was found. The blood purifier was filled with RO water and irradiated with γ rays at an absorbed dose of 25 kGy for crosslinking treatment.

  When the hollow fiber membrane was cut out from the blood purifier after γ-irradiation and subjected to the eluate test, the PVP elution amount was 4 ppm, which was a satisfactory level. Further, when the outer surface was observed with a microscope, no defects such as scratches were observed.

  Citrated fresh bovine blood was passed through the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 10 mL / min, but no blood cell leak was observed. Further, endotoxin filtered from the outside of the hollow fiber to the inside of the hollow fiber was below the detection limit, and was at a level with no problem. The other analysis results are shown in Table 1.

  Using the blood purification module produced in the same manner, the blood purification device was filled with RO water and γ-ray sterilized at a dose of 40 kGy. The hollow fiber membrane was cut out from the blood purifier before and after γ-ray irradiation, and the breaking strength was measured. The intensity before γ-ray irradiation was 16.8 g, and the intensity after 40 kGy γ-ray irradiation was 15.3 g, and the intensity was sufficiently maintained.

(Comparative Example 6)
A hollow fiber membrane bundle and a blood purifier were obtained in the same manner as in Example 4 except that magnesium was not added to the spinning dope. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane bundle obtained in this comparative example had a strength before γ-ray irradiation of 16.6 g, and a strength after 40 kGy of γ-ray irradiation was 12.3 g, and the strength was not sufficiently maintained.

  The polysulfone-based hollow fiber membrane of the present invention has high safety and stability of performance, is excellent in module assembly, has durability against radiation sterilization, and has high water permeability for use in the treatment of chronic renal failure. It is suitable for use as a hollow fiber blood purifier and contributes greatly to the industry.

Claims (9)

A polysulfone-based permselective hollow fiber membrane comprising a polysulfone-based resin and a hydrophilic polymer as main components, wherein the following (i) to (c) are simultaneously satisfied:
(A) The content of the hydrophilic polymer in the outermost surface layer of the inner surface of the hollow fiber membrane is 1.1 times or more than the content of the hydrophilic polymer in the surface vicinity layer of the inner surface.
(B) The content of the hydrophilic polymer in the outermost surface layer of the hollow fiber membrane is 1.1 times or more than the content of the hydrophilic polymer in the outermost surface layer of the inner surface.
(C) The breaking strength of the hollow fiber membrane after irradiating the hollow fiber membrane with γ rays of 40 kGy dose is 80% or more with respect to the breaking strength of the hollow fiber membrane before γ ray irradiation.   In the polysulfone-based permselective hollow fiber membrane, the innermost surface layer is a layer having a depth of up to 10 nm from the inner surface, and the near surface layer is a depth of 1000 to 1500 nm (1 to 1.5 μm from the inner surface). The polysulfone-based permselective hollow fiber membrane according to claim 1, which is intended for layers up to).   The content of the hydrophilic polymer in the polysulfone-based permselective hollow fiber membrane is 20 to 40% by mass in the innermost surface layer, 5 to 20% by mass in the surface vicinity layer, and 25 to 50% by mass in the outermost surface layer. The polysulfone-based permselective hollow fiber membrane according to claim 1 or 2, wherein:   The polysulfone-based selectively permeable hollow fiber membrane according to any one of claims 1 to 3, comprising 99 to 80 mass% of a polysulfone resin and 1 to 20 mass% of a hydrophilic polymer as main components.   The polysulfone-based permselective hollow fiber membrane according to any one of claims 1 to 4, wherein the hydrophilic polymer is polyvinylpyrrolidone.   The polysulfone-based permselective hollow fiber membrane according to any one of claims 1 to 5, wherein an elution amount of the hydrophilic polymer from the hollow fiber membrane is 10 ppm or less.   The polysulfone-based permselective hollow fiber membrane according to any one of claims 1 to 6, wherein the porosity of the outer surface of the hollow fiber membrane is 8% or more and less than 25%.   The polysulfone-based permselective hollow fiber membrane according to any one of claims 1 to 7, wherein the hydrophilic polymer is crosslinked and insoluble in water.   The polysulfone-based selectively permeable hollow fiber membrane according to any one of claims 1 to 8, which is used for a blood purifier.