JP4587025B2 - Polysulfone-based selectively permeable hollow fiber membrane with excellent blood compatibility - Google Patents

Description

  The present invention relates to a polysulfone-based permselective hollow fiber membrane that is highly safe and stable in performance and excellent in module assemblability, and particularly suitable for blood purifiers, its use as a blood purifier, and a method for producing the same. .

  In blood purification therapy for the treatment of renal failure, natural materials such as cellulose, cellulose diacetate, cellulose triacetate, synthetic polymers such as polysulfone, 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. Cause new problems such as deterioration of module assemblability, etc. due to 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 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, the technique improves the problem of endotoxin (endotoxin) contained in dialysate, which is one of the above-mentioned problems, entering the blood side, but the mass of the hydrophilic polymer present on the outer surface Since the ratio is too low, there remains a problem that the above-mentioned problem that the priming property, which is another problem described above, is reduced, and the improvement thereof is necessary.
JP-A-6-165926

The hollow fiber membrane has a uniform membrane structure, but the hydrophilic polymer is present in the inner surface, outer surface, and intermediate portion of the hydrophilic polymer hollow fiber membrane in the vicinity of the surface as determined by the infrared absorption method. 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, a method for improving blood compatibility and the amount of hydrophilic polymer eluted into blood by specifying the surface presence ratio of the hydrophilic polymer on the inner surface of the hollow fiber membrane 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 degradation such as light degradation, 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 of setting the porosity of the outer surface of the membrane to 25% or more is disclosed (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

  Also, in recent years, there have been an increasing number of examples of continuous hemofiltration, continuous hemofiltration dialysis, continuous hemodialysis, etc. as acute blood purification therapy for patients with serious pathological conditions such as acute renal failure and sepsis. . Blood purification membrane materials used in these therapies include naturally occurring materials such as cellulose and cellulose derivatives, and synthetic polymer materials such as polysulfone resins, polymethyl methacrylate, polyacrylonitrile, and ethylene vinyl alcohol copolymers. Is being used. Among these, a membrane made of a polysulfone resin has attracted particular attention in recent years because it has advantages such as good mechanical properties, heat resistance, and biocompatibility.

  Since polysulfone-based resins are relatively hydrophobic, they tend to adsorb plasma proteins when they come into contact with blood. For this reason, when a blood purification membrane is produced from a polysulfone resin, it is common to add a hydrophilic polymer in order to impart hydrophilicity and improve blood compatibility.

  However, such materials are essentially foreign to the living body, and even when a method such as adding a hydrophilic polymer is used, when it comes into contact with blood, it causes platelet adhesion and leukocyte activation, resulting in biocompatibility. It may be bad.

Patent Documents 15 and 16 disclose techniques for improving blood compatibility by controlling the unevenness of the blood contact surface. In these techniques, the unevenness of the surface is defined from values measured by a white interference microscope. In Patent Document 15, it is said that the adhesion of platelets is preferably 10 ⁻⁶ cells / cm ² or less. This characteristic means that platelets do not adhere extremely. However, in membranes with extremely high platelet retention, platelets activated by contact with the membrane are released into the blood, which triggers activation of the entire circulating blood in the body, resulting in biocompatibility. It may cause deterioration, which is not preferable.

As can be said in common with Patent Documents 15 and 16, a smooth blood contact surface may have a large contact area with blood cells, which may cause activation of blood cells. Control of the physical properties of the surface is considered to be effective as a technique for improving blood compatibility, but this approach alone has its own limitations as long as it uses materials that are essentially foreign to the living body. I must say that there is.
JP 2000-126286 A JP-A-11-309353

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

As a result of intensive studies to solve the above technical problems, the present invention provides a polysulfone-based hollow fiber membrane mainly composed of a polysulfone-based resin and polyvinylpyrrolidone .
(A) The abundance of polyvinylpyrrolidone in the polysulfone-based hollow fiber membrane is 20 to 40% by mass in the outermost layer portion with a depth of 10 nm from the blood contact side surface, and 25 to 50 in the outermost layer portion on the surface opposite to the blood contact side. The amount of polyvinyl pyrrolidone relative to the polysulfone resin is 5 to 20% by mass in the vicinity of the surface layer having a depth of 1000 to 1500 nm from the blood contact side surface.
(B) The abundance of polyvinylpyrrolidone in the outermost surface layer opposite to the blood contact side in the polysulfone-based hollow fiber membrane is 1.1 times or more than the abundance of polyvinylpyrrolidone in the outermost surface layer on the blood contact side.
(C) Clotted cow blood is encapsulated in the lumen of a polysulfone-based hollow fiber membrane, and the hollow blood membrane resulting from coagulation and coagulation in the encapsulated blood after being immersed in an isotonic solution containing calcium for 10 minutes By using a polysulfone-based permselective hollow fiber membrane that simultaneously satisfies the property of not producing the above-mentioned problems, the above-mentioned problems have been solved. As a detailed embodiment, the amount of polyvinylpyrrolidone present on the blood contact side surface 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 presence ratio of polyvinyl pyrrolidone in the surface vicinity layer adjacent to it is usually about 2 to 37% by mass, and optimally about 5 to 20% by mass. Further, since the amount of polyvinyl pyrrolidone on the outermost surface layer opposite to the blood contact side is 1.1 times or more than the amount of polyvinyl pyrrolidone on the outermost surface layer on the blood contact side, the hollow fiber membrane of polyvinyl pyrrolidone A ratio of about 25 to 50% by mass on the outer surface is sufficient. Appropriate distribution of these layers can be determined in consideration of the elution of polyvinyl pyrrolidone 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. Furthermore, since the polysulfone-based hollow fiber membrane of the present invention has a gentle blood coagulation reaction at the time of blood encapsulation, it has high blood compatibility and is suitable for use in the field of blood purification such as hemodialysis, blood filtration, and hemodiafiltration. It is.

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. 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. Polyvinyl pyrrolidone is the preferred 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 Co., Ltd., and similarly, 45,000 (K30), 450,000 (K60), 900,000 (K80), 1,200, 000 (K90) is preferable, and in order to obtain the intended use, characteristics, and structure, each may be used alone, and the same two types of resins having different molecular weights or different types of resins may be used appropriately. You may use combining a seed | species or more.

  In the present invention, the abundance of the hydrophilic polymer in the outermost layer on the blood contact side surface in the polysulfone-based hollow fiber membrane (i) is defined as 1. More than 1 time means that the abundance of the hydrophilic polymer on the outermost surface is larger than the layer near the surface and that the abundance of the hydrophilic polymer on the outermost layer is 20 to 40% by mass optimal. The range of the ratio of the hydrophilic polymer in the layer near the surface adjacent to it must be in the range of about 2 to 37% by mass. Actually, the appropriate ratio of the hydrophilic polymer in the surface vicinity layer is set to about 5 to 20% by mass based on this reason. 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 abundance of hydrophilic polymer in the outermost layer on the blood contact side surface and in the surface vicinity layer is a numerical value based on 5 to 20% by mass, which is an appropriate abundance of hydrophilic polymer in the surface vicinity layer. By calculating by a simple multiplier of 1.1 to 10 times (5 to 20% by mass), the optimal amount of hydrophilic polymer in the outermost layer on the blood contact side surface is 20 to 40 mass. % Means that it can be The ratio is usually about 1.1 to 5 times, and in some cases, the hydrophilic polymer is preferably present with a difference of about 1.2 to 3 times. Actually, the magnification can be arbitrarily determined in consideration of the performance of the hollow fiber membrane. For example, when the ratio (content) of the hydrophilic polymer in the surface vicinity layer is 5% by mass, which is the lowest value, the ratio (content) of the hydrophilic polymer in the outermost layer corresponds to 4 to 8 times. It can also be taken within an appropriate amount of 20 to 40% by mass.

  In the present invention, the abundance of the hydrophilic polymer in the outermost layer on the surface opposite to the blood contact side in the (b) polysulfone-based hollow fiber membrane is compared with the abundance of the hydrophilic polymer in the outermost layer on the blood contact side surface. , 1.1 times or more is sufficient if the ratio of the hydrophilic polymer described above on the outer surface of the hollow fiber membrane is about 25 to 50% by mass, and the hydrophilic polymer on the outermost surface of the inner surface It is preferable that it is 1.1 times or more of the existence ratio. If the proportion of the hydrophilic polymer on the outer surface is too small, the amount of protein adsorbed in the blood to the support layer portion of the hollow fiber membrane will increase, and blood compatibility and permeation performance may decrease. Conversely, if there is too much proportion of hydrophilic polymer on the outer surface, the endotoxin (endotoxin) contained in the dialysate increases the possibility of entering the blood, 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.

  Conventionally, as an index indicating blood compatibility, there is a method for evaluating adhesion of platelets when in contact with blood. In order to improve blood compatibility, studies have been made with the goal of reducing the amount of platelet adhesion, but the activation of blood components by contact with materials that are foreign to the living body varies to some extent. It is considered inevitable in a sense. In the case of a membrane with a very small amount of platelet adhesion, the apparent blood compatibility is judged to be good, but in fact, even platelets activated by contact with a foreign material are released into the blood. It may be closed. For this reason, it is considered that the evaluation of platelet adhesion alone is not sufficient to evaluate blood compatibility, and as a result of intensive studies on blood compatibility evaluation, blood was actually sealed and contacted with the material. It has been found that a method of observing the whole blood, that is, a method of observing the coagulation state of blood is appropriate, and the present invention has been achieved. In a test in which blood is enclosed in a hollow fiber membrane, 10 minutes after the blood encapsulation, the enclosed blood does not clog the hollow fiber membrane, and the blood extruded from the hollow fiber membrane is uniformly in physiological saline. It is preferably in a state of being dispersed and free from lumps. In this evaluation method, it is possible to examine the state of blood that has not been adsorbed to the material, which has been overlooked in the conventional method for evaluating platelet adhesion.

In the present invention, (c) citrated bovine blood is enclosed in the lumen of the polysulfone-based hollow fiber membrane, and the resultant blood is immersed in an isotonic solution containing calcium for 10 minutes. The compatibility with the blood of the hollow fiber type membrane which evaluates that the yarn membrane is not clogged is performed by the following method.
(1) A bundle of 10 hollow fiber membranes cut to 20 cm, both ends are inserted into a silicon tube, and a micromodule fixed with an adhesive is prepared.
(2) The hollow fiber membrane part of the micromodule is immersed in a kinderly solution.
(3) Fill the micromodule lumen with (ACD) bovine blood to which citric acid has been added using a syringe.
(4) After filling, close both ends of the micromodule with forceps.
(5) After 10 minutes of blood filling, the forceps are removed, and the blood sealed with a syringe is pushed out from one end of the micromodule into a petri dish filled with physiological saline.
(6) The case where the encapsulated blood does not come out at the time of extruding the blood in (5) is defined as “that is”.
(7) The blood extruded into the petri dish is not uniform in physiological saline but is agglomerated, and is referred to as “coagulation”.
(8) If the blood pushed out in the petri dish becomes uniform in physiological saline, “no coagulation reaction” is set.

  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 ratio of the hydrophilic polymer in the outermost layer on the blood contact side surface in the polysulfone-based hollow fiber membrane is 20 to 40% by mass.
(3) The ratio of the hydrophilic polymer in the surface vicinity layer on the blood contact side surface in the polysulfone-based hollow fiber membrane is 5 to 20% by mass.
(4) The proportion of the hydrophilic polymer in the outermost layer on the surface opposite to the blood contact side in the polysulfone-based hollow fiber membrane is 25 to 50% by mass, and the proportion of the hydrophilic polymer in the outermost layer on the inner surface 1.1 times or more.
(5) Excellent blood compatibility.

  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 ratio of the hydrophilic polymer in the outermost layer on the blood contact surface in the (2) polysulfone-based hollow fiber membrane is 20 to 40% by mass (Requirement 2). First, the proportion of hydrophilic polymer in the outermost surface layer on the blood contact side surface in 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 ratio for achieving the effects of the present invention 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 ratio 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 proportion 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 ratio of the hydrophilic polymer in the surface vicinity layer on the blood contact side surface in (3) the polysulfone-based hollow fiber membrane is 5 to 20% by mass (Requirement 3). In the polysulfone-based hollow fiber membrane of the present invention, the abundance of the hydrophilic polymer in the surface vicinity layer on the blood contact side 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. However, it is preferable that the appropriate amount of the hydrophilic polymer is 5 to 20% by mass. Usually, 7 to 18% by mass is more preferable. As described above, the ratio of the hydrophilic polymer in the outermost layer on the blood contact side surface in the polysulfone-based hollow fiber membrane is preferably higher than the blood compatibility point, but when the ratio increases, the hydrophilicity to blood increases. Since this is a contradictory phenomenon in which the amount of molecular elution increases, it is determined to be about 20 to 40% by mass in consideration of the appropriate range.

  On the other hand, the abundance of the hydrophilic polymer in the layer near the inner surface of the hollow fiber membrane can be in a relatively wide range of 1 to 40% by mass, which is the abundance of the hydrophilic polymer in the outermost layer, but more than the outermost layer. For example, if the outermost layer is 30% by mass and the surface vicinity layer is 35% by mass, the diffusion movement of the hydrophilic polymer to the outermost layer becomes active, and the abundance of the hydrophilic polymer in the outermost layer is more than the predetermined design value. A large amount is accumulated, 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 amount of hydrophilic polymer present 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 ratio 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 ratio 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 ratio of the hydrophilic polymer in the vicinity of the surface is slightly higher than the average ratio 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. This is common.

  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 ratio 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, in the proportion of the outermost layer, the initial blood compatibility is satisfactory, but when the long-term dialysis is carried out, the hydrophilic polymer present in the outermost layer gradually elutes in the blood, and with the progress of dialysis The problem that blood compatibility gradually decreases occurs. This persistence of blood compatibility is improved by specifying the proportion of hydrophilic polymer in the surface vicinity layer on the blood contact side surface in the polysulfone-based hollow fiber membrane. By specifying the ratio of the hydrophilic polymer in the near-surface layer, blood compatibility by decreasing the ratio of the hydrophilic polymer in the outermost layer by elution of the outermost hydrophilic polymer in 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 ratio of the hydrophilic polymer in the surface vicinity layer on the blood contact side 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 behavior based on the appropriate ratio of hydrophilic polymer and the 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. It is.

  In the present invention, as described above, the proportion of the hydrophilic polymer in the outermost layer on the surface opposite to the blood contact side in the polysulfone-based hollow fiber membrane is 25 to 50% by mass, and the outermost layer on the inner surface is It is preferable that the ratio is 1.1 times or more of the existence ratio of the hydrophilic polymer (Requirement 4). If the proportion of the hydrophilic polymer on the outer surface is too small, the amount of protein adsorbed in the blood to the support layer portion of the hollow fiber membrane will increase, and blood compatibility and permeation performance may decrease. Although it may consist of 90 to 40% by mass of a polysulfone-based resin and 10 to 60% by mass of a hydrophilic polymer as a main component, the actual proportion of the hydrophilic polymer on the outer surface is 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 there is too much proportion of hydrophilic polymer on the outer surface, the endotoxin (endotoxin) contained in the dialysate increases the possibility of entering the blood, 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 proportion of the hydrophilic polymer present 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, it is preferable that the ratio of the hydrophilic polymer in the outermost outermost layer is 1.1 times or more the ratio of the hydrophilic polymer in the outermost outermost layer. The proportion of the hydrophilic polymer present 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 proportion of the hydrophilic polymer increases. For example, when the ratio of the hydrophilic polymer on the outermost surface layer is higher than the ratio of the hydrophilic polymer on the outermost surface 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 and the hollow fiber membrane may break. If wrinkles occur on the inner surface side, for example, when used for hemodialysis, blood proteins and the like are likely to deposit on the membrane surface when blood is flowed, leading to problems such as deterioration in permeation performance over time. there is a possibility. For these reasons, it is preferable to increase the ratio of the hydrophilic polymer on the outer surface side. Furthermore, the hollow fiber membrane of the present invention has a structure in which the inner surface has a dense layer and 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, it is preferable that the hydrophilic polymer existing ratio on the outermost surface outermost layer is 1.1 times or more of the hydrophilic polymer existing ratio on the innermost outermost layer. More preferably, it is 1.2 times or more, and further preferably 1.3 times or more.
For the above reasons, it is preferable that the ratio of the hydrophilic polymer on the outermost surface layer is 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, (5) blood compatibility is excellent (requirement 5). As means for satisfying this requirement, the balance between the hydrophilic polymer and the hydrophobic polymer on the surface on the blood contact side and appropriate charge control during the production process are important. Simply increasing the concentration of the hydrophilic polymer on the blood contact surface is one way to improve blood compatibility, but if the surface concentration becomes too high, the amount of elution into the blood will increase and activate the blood. There is a risk of promoting platelet aggregation and clotting. Therefore, in order to achieve better blood compatibility, it is necessary that the coagulation and clogging of the citrated blood encapsulated in the hollow fiber membrane be suppressed for at least 10 minutes after the blood encapsulation. Depending on the characteristics, blood compatibility, performance retention when using blood contact, and safety are realized at a high level.

  As described above, limiting the existence distribution of the hydrophilic polymer in the hollow fiber membrane is effective in increasing the stability of safety and performance and improving the module assembly property. On the other hand, in order to improve the blood compatibility of the hollow fiber membrane, it is important to balance the hydrophilic polymer and the hydrophobic polymer and to appropriately control the charge during the production process. In either case, the control of the hydrophilic polymer remains important, but even if one performance is satisfied, the other performance is not necessarily satisfied. The present invention features a polysulfone-based permselective hollow fiber membrane that can satisfy both.

  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 amount of hydrophilic polymer that spans two layers, it is often connected by a continuous line. There may be a difference in concentration between the two layers due to the difference in the amount of the benzene. In general, it is technically impossible to assume that there are two discontinuous layers with different material behavior, because the distribution curve of the abundance of hydrophilic polymer can be broken at the boundary between the two layers. The optimal range of the hydrophilic polymer is 20-40% by mass for the outermost layer and 5-20% by mass for the surface vicinity layer, but the hydrophilic polymer is the surface vicinity layer. 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 also important to design by paying attention to the difference in the amount of simple hydrophilic polymer present in the two layers. As an appropriate difference value, for example, 1.1 times or more between two layers consisting of the outermost surface and the surface vicinity layer, based on the numerical value shown by mass% expressed in the abundance of the hydrophilic polymer of both. That is, if calculated by converting the difference in mass% of the hydrophilic polymer existing between the two layers, a simple difference in the existing ratio (content) of the hydrophilic polymer in the two layers is 1 to 35. If there is a difference of about 5% to 25% by mass, optimally about 5% 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.

  In addition, the abundance ratio of the outermost layer of the hollow fiber membrane of the hydrophilic polymer described above was measured and calculated by the ESCA method as described later, and the outermost layer portion of the hollow fiber membrane (the depth from the surface layer was several to The absolute value of the existence ratio of several tens of liters) is 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. The ratio of the hydrophilic polymer in the surface vicinity layer was measured by surface infrared spectroscopy (surface IR), and the absolute value of the ratio existing up to a depth corresponding to several hundred nm was evaluated. In the ATR method (surface vicinity layer), it is possible to measure the hydrophilic polymer content from the blood contact surface to a depth of about 1000 to 1500 nm (1 to 1.5 μm).

  The ratio of the hydrophilic polymer present on the inner surface and the gear surface may be related to the molecular weight of the hydrophilic polymer. For example, using polyvinyl pyrrolidone with a molecular weight of about 450,000 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 The reason is that the outermost layer portion is 20 to 40 mass% and the surface vicinity layer portion is 5 to 20 mass compared to the existence ratio of 1 to 20 mass% of the average mass ratio of the hydrophilic polymer to the polysulfone-based polymer. % 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. It may affect the abundance and performance of the polyvinylpyrrolidone in the layer, and designing a hollow fiber membrane from this point of view also belongs to the category of the present invention.

  As a method for achieving the above requirements 2, 3, 4, and 5 in the present invention, for example, the composition ratio of the hydrophilic polymer to the hydrophobic polymer is set to the above range, or the film forming conditions of the hollow fiber membrane are optimized. This 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 having a density difference between the outermost layer portion and the portion in the vicinity of the surface. That is, although the detailed reason is not known, by setting the mass ratio of the polysulfone polymer and the hydrophilic polymer in the spinning dope and the concentration and temperature of the internal coagulating solution to the ranges described later, the innermost surface of the hollow fiber membrane can be obtained. Differences in the solidification rate and / or phase separation rate between the surface layer and the vicinity of the surface occur, 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.

  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 small, it may be difficult to control the abundance ratio of PVP 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. Moreover, when there is too much PVP content in dope, since the amount of PVP in a film | membrane will also increase, it is necessary to strengthen the washing | cleaning after film forming, and may lead to a cost increase. Therefore, the PVP ratio in dope is more preferably 0.57 or less, and further preferably 0.55 or less.

  As the internal coagulation liquid, a 15 to 70% by 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 increases, and it may be difficult to control the amount of hydrophilic polymer present 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 coagulation liquid is too high, the solidification rate of the inner surface becomes slow, and it may be difficult to control the abundance 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 coagulation liquid temperature is too low, the outermost surface is solidified immediately after nozzle discharge, and it may be difficult to control the abundance 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. Also, if the internal coagulation liquid temperature is too high, the difference in film structure (denseness) between the innermost surface layer and the surface becomes too large, making it difficult to control the abundance of hydrophilic polymers 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.

When spinning the hollow fiber membrane, the inner surface of the hollow fiber when the internal coagulation liquid discharge linear velocity immediately after being discharged from the nozzle and the dope discharge linear velocity are in the relationship of internal coagulation liquid discharge linear velocity> dope discharge linear velocity Shear stress acts at the interface between the solidified liquid and the internal solidified liquid, friction is generated, and moderate charge is imparted. The internal coagulation liquid discharge linear velocity is more preferably 3 to 10 times the dope discharge linear velocity. If it is less than 3 times, the stress at the interface between the inner surface of the hollow fiber and the internal coagulation liquid is small, and there is a possibility that the charge cannot be controlled appropriately. If it exceeds 10 times, the pressure loss of the spinneret becomes large and uneven discharge may occur, resulting in non-uniform film shape. The dope discharge speed is preferably 15000 cm / min or less. When the dope discharge speed is higher than this, there is a possibility that the pressure loss of the spinneret becomes large and discharge unevenness occurs, spinning becomes unstable, and the film structure becomes non-uniform.
The discharge linear velocity and the linear velocity ratio can be calculated by the following equation.
(Discharge linear velocity immediately after discharge) (cm / min) = Discharge amount (ml / min) / (Discharge hole area) (cm ² )

As a specific example of the method for drying the wet hollow fiber membrane, a wet hollow fiber membrane bundle is put in a microwave dryer and dried by irradiating with a microwave 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, higher microwave output is preferable.For example, in hollow fiber membranes containing hydrophilic polymers, degradation or decomposition of hydrophilic polymers may occur due to overdrying or overheating. Therefore, it is preferable that the output is not increased too much. 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 consideration of cost increase for increasing the degree of sealing of the system. More preferably, it is 0.2 kPa or more, More preferably, it is 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 fibers = 1,000 g. At this time, it is appropriate that the microwave output is 1.5 kW and the decompression degree is 5 kPa.

  The microwave irradiation frequency is preferably 1,000 to 5,000 MHz in consideration of the 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 water in the hollow fiber membrane will be slow and it will be difficult for the hydrophilic polymer to get on the water, and it will be easy to cause movement spots, so the amount of hydrophilic polymer in each part can be controlled. There is a possibility of disappearing. 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.

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 be lowered. 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. Further, when the membrane is dried, the hydrophilic polymer existing on the outer surface of the membrane is interposed, and the hollow fiber membranes are fixed to each other, causing problems such as deterioration in module assemblability. 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 abundance ratio of the hydrophilic polymer on the outer surface of the hollow fiber membrane to the above range and a method for setting the opening ratio of the outer surface of the hollow fiber membrane to 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 composed of polyethersulfone / polyvinylpyrrolidone / dimethylacetamide / RO water = 10-25 / 0.5 to 12.5 / 52.5 to 89.5 / 0 to 10.0 at 30 to 60 ° C. When discharging from a nozzle, passing through an air gap of 100 to 1000 mm, and leading 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 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.

  The external coagulation liquid is preferably a 0 to 50% by weight DMAc aqueous solution. 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 washing 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 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 RO 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 updating the RO water to perform the cleaning process.
(2) A method of treating a hollow fiber membrane bundle immersed in excess RO water in a pressurized container at 121 ° C. for about 2 hours may 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. .
Since there is also an objective to optimize the hydrophilicity and hydrophobicity balance of the hollow fiber type membrane in the washing process, all the water used is purified tap water with an RO device and has a specific resistance of 0.3 to The thing of 2Mohmcm is preferable and the thing of 0.4-1.9Mohmcm is more preferable. 0.5 to 1.7 MΩcm is more preferable, and 0.7 to 1.5 MΩcm is even more preferable.
RO water contains almost no impurities such as metal ions, and the adsorption of ionic substances and other impurities to the hollow fiber membrane during the washing process can be ignored, so the application of charge to the hollow fiber membrane is controlled. It becomes easy to do.
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 order to have an appropriate negative charge, it is preferable to control static electricity on the film surface. There are Teflon (R), ceramic, bakelite (R), stainless steel, plastic, etc. as materials for rollers and guides, but as a result of examining various combinations, it is clear that it is good to use stainless steel for both rollers and guides. It was. Moreover, it is preferable that those shapes have a smooth curve at the contact portion with the hollow fiber. It is also preferable to attach a ground. Thus, by controlling the process so that static electricity and friction can be controlled excessively, the negative charge inherent to the hydrophobic polymer can be brought into an optimum state.

  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-described blood purifier, it is a blood purifier comprising 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 water permeability range 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, still 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 that the thickness deviation when observing the cross section of 100 hollow fiber membranes in the hollow fiber membrane module is small, and the thickness deviation shown by the ratio between the maximum value and the minimum value is small. 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 film uniformity, suppresses the generation of latent defects, and improves the burst pressure. Therefore, the thickness is more preferably 0.7 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 diameter of the filter as it is in the latter stage in order to extend the filtration efficiency and the filter life. The pore size 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. The pure water is sent to a 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. The TMP is changed at four points, the filtration flow rate is measured, and the water permeability (mL / hr / mmHg) is calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and the filtration flow rate must be 0.999 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100 mmHg 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
Here, 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 (mL 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 so that 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 water 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. Abundance ratio of hydrophilic polymer in outermost surface of inner and outer surfaces The abundance ratio 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.
A hollow fiber membrane, which was cut obliquely with a razor blade so that the inner surface was exposed, was attached to a sample stage and measured 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. Presence ratio of hydrophilic polymer in surface vicinity layer of blood contact surface of hollow fiber membrane An example of a measurement method when PVP is used as the hydrophilic polymer is illustrated. Measurement was performed by infrared absorption analysis. The measurement was performed using a sample prepared by the same method as that used for measuring the abundance of the hydrophilic polymer in the outermost layer on the inner and outer surfaces. The vicinity of the surface was measured 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 measurement, IRμs / SIRM manufactured by SPECTRA TECH was used. In the infrared absorption spectrum, the ratio Ap / As of the absorption intensity Ap of the peak derived from C═O of PVP near 1675 cm ⁻¹ and the absorption intensity As of the peak derived from the polysulfone 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 as a correction value to the actually measured value. The presence ratio of PVP in the blood contact surface vicinity layer was calculated by the following formula.
Presence ratio (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. Evaluation of blood compatibility (1) A bundle of 10 hollow fiber membranes cut to 20 cm, both ends are inserted into a silicon tube, and a micromodule fixed with an adhesive is prepared.
(2) The hollow fiber membrane part of the micromodule is immersed in a kinderly solution.
(3) Fill the micromodule lumen with (ACD) bovine blood to which citric acid has been added using a syringe.
(4) After filling, close both ends of the micromodule with forceps.
(5) After 10 minutes of blood filling, the forceps are removed, and the blood sealed with a syringe is pushed out from one end of the micromodule into a petri dish filled with physiological saline.
(6) The case where the encapsulated blood does not come out at the time of extruding the blood in (5) is defined as “that is”.
(7) The blood extruded into the petri dish is not uniform in physiological saline but is agglomerated, and is referred to as “coagulation”.
(8) If the blood pushed out in the petri dish becomes uniform in physiological saline, “no coagulation reaction” is set.

10. 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 areas of the pores within the measurement range were determined, and the area ratio (%) = B / A × 100. This was carried out for 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.

11. The average pore area of the apertures on the outer surface of the hollow fiber membrane was 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.

12. Blood Leak Test A 37 ° C. bovine blood to which citrate was added and coagulation was suppressed was fed to a blood purifier at 200 mL / min, and the blood was filtered at a rate of 20 mL / min. 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 and loaded in 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 performed at five levels for each level, and the number of modules that caused leaks due to poor sealing of the urethane resin was counted.

14. Residual blood of the hollow fiber membrane Fill the dialysate side of the module with a membrane area of 1.5 m ² with physiological saline, fill the blood bag with 200 ml 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.
Change rate = correction value (60 minutes) / value before circulation start × 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. Measurement of specific resistance of water The specific resistance of water is calculated from the electrical conductivity measured with an electric conductivity meter (CM-40V, manufactured by Toa Radio Industry Co., Ltd.).
(Resistivity) [MΩcm] = 1 / (Electric conductivity)

16, Priming property With the dialysate side port of the module covered, distilled water for injection is allowed to flow from the blood side inlet port at 200 mL / min until 10 seconds elapse 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: ×

Example 1
17.6% by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (R) 4800P), 4.8% by mass of polyvinylpyrrolidone (Collidon (R) K-90, manufactured by BASF), 74% dimethylacetamide (DMAc). 6% by mass and 3% by mass of RO water are uniformly dissolved at 50 ° C., and then the system is decompressed to −500 mmHg using a vacuum pump. The system was sealed and left for 15 minutes. This operation was repeated three times to degas the film forming solution. The membrane-forming solution was 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 65 ° C., and at the same time, degassed as an internal coagulating liquid at −700 mmHg for 60 minutes. The treated 45% by weight DMAc aqueous solution at 15 ° C. is discharged from the inner liquid discharge hole, passes through a 450 mm dry part cut off from the outside air by a spinning tube, and then solidifies in a 20% DMAc 20% by weight aqueous solution at 60 ° C. I whispered to the wall. The nozzle slit width of the tube-in-orifice nozzle used was an average of 60 μm, the maximum 61 μm, the minimum 59 μm, the ratio of the maximum and minimum slit widths was 1.03, and the draft ratio of the film forming solution was 1.2. . The discharge rate was adjusted so that the lumen forming agent discharge linear velocity immediately after discharge was 25000 cm / min and the dope discharge linear velocity was 5000 cm / min.

  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 water used for washing is RO water having a specific resistance of 1.4 MΩcm. The obtained wet bundle is centrifugally drained for 600 rpm × 5 min, 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. Furthermore, 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% by mass. The resulting hollow fiber membrane had an inner diameter of 201 μm and a film thickness of 28 μm. During the spinning process, the roller with which the hollow fiber membrane comes into contact was made of stainless steel whose surface was mirror-finished, and the guide was made of stainless steel.

  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 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, blood coagulation was not observed in the blood encapsulation test. 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. 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.

(Comparative Example 1)
The spinning dope was changed to 2.4% by mass of polyvinylpyrrolidone (BASF Koridone (R) K-90) and DMAc 77% by mass, the dry part length was changed to 700 mm, and the hollow fiber membrane was in contact during the spinning process. A wet hollow fiber membrane was obtained in the same manner as in Example 1 except that the roller was made of stainless steel whose surface was not mirror-finished, and the guide was made of Teflon (R). The obtained hollow fiber membrane was subjected to a washing treatment in the same manner as in Example 1 except that the water used for washing was tap water, and was dried in a hot air dryer at 60 ° C. The resulting hollow fiber membrane had a moisture content of 3.4% by mass, an inner diameter of 199 μm, and a film thickness of 29 μm. The properties of the obtained hollow fiber membrane bundle and blood purifier are shown in Table 1. The hollow fiber membrane of Comparative Example 1 was poor in both the blood entrapment test and the residual blood property, but this is presumed that the hydrophilic / hydrophobic balance was not appropriate due to the low proportion of PVP in the vicinity of the inner surface.

(Comparative Example 2)
In Example 1, the charged amount of PVP (Collidon (R) K-90 manufactured by BASF) was set to 12.0% by mass, DMAc was set to 67.4% by mass, and the lumen forming agent discharge linear velocity immediately after discharge was The discharge amount was adjusted to 14000 cm / min and the dope discharge linear velocity was 5000 cm / min. During the spinning process, the roller with which the hollow fiber membrane comes into contact was made of stainless steel, and the guide was made of Teflon (R). A spinning dope was obtained in the same manner as in Example 1 except that. In addition, the hollow fiber was the same as in Example 1 except that the temperature control of the hollow forming agent was not performed, the cleaning process was not performed, and the drying process of the hollow fiber membrane bundle 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 existing ratio in the outermost layer on the inner surface and a high PVP elution amount. Further, since the hydrophilic polymer content on the outer surface of the hollow fiber membrane is large, permeation of endotoxin to the blood side was observed. The reason why the blood inclusion test was not good is presumed that the hydrophilicity / hydrophobicity balance was not appropriate.

(Comparative Example 3)
In Comparative Example 2, the number of hot water washings was changed to 6 hrs, except that the discharge rate was adjusted so that the lumen forming agent discharge linear velocity immediately after discharge was 25000 cm / min, and the dope discharge linear velocity was 5000 cm / min. In the same manner as in Example 2, a hollow fiber membrane bundle and a 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 bundle obtained in this comparative example had a low priming property because the outermost surface PVP content on the outer surface was low and the hydrophilicity on the outer surface was low.

(Example 2)
Polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (R) 4800P) 18.8% by mass, polyvinyl pyrrolidone (BASF Koridone (R) K-90) 5.2% by mass, DMAc 71.0% by mass, water Dissolve 5% by mass at 50 ° C., and then reduce the pressure in the system to −700 mmHg using a vacuum pump. Immediately seal the system and leave it for 10 minutes so that the composition of the film forming solution does not change due to evaporation of the solvent. did. 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% by mass DMAc aqueous solution at 10 ° C. was discharged from the inner liquid discharge hole, passed through a 330 mm air gap portion cut off 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 maximum and minimum slit width ratio is 1.02, the draft ratio is 1.15, and the dry type The absolute humidity of the part was 0.12 kg / kg dry air. The discharge rate was adjusted so that the lumen forming agent discharge linear velocity immediately after discharge was 25000 cm / min and the dope discharge linear velocity was 5000 cm / min. 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 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 water used for washing is RO water having a specific resistance of 1.2 MΩcm.

  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 maximum temperature reached on the surface of the hollow fiber membrane bundle during the drying treatment was 65 ° C., and the water content averaged 2.8% by mass. The roller for changing the yarn path during the spinning process was made of stainless steel with a mirror-finished surface, and the guide was made of stainless steel. The resulting hollow fiber membrane had an inner diameter of 201 μm and a film thickness of 27 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 subjected to the subsequent analysis without performing the crosslinking treatment of the hydrophilic polymer. When the hollow fiber membrane was cut out from the blood purifier not irradiated with γ-rays and subjected to the eluate test, the elution amount of PVP was as good as 7 ppm. Further, when the outer surface was observed with a microscope, no defects such as scratches were observed.

  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. Both blood inclusion test and residual blood property were good. The other analysis results are shown in Table 1.

(Comparative Example 4)
Polyethersulfone (Sumika Chemtex, Sumika Excel (R) 7800P) 23% by mass, PVP (BASF Kollidon (R) K-30) 7% by mass, DMAc 67% by mass, water 3% by mass at 50 ° C. After dissolution, the pressure in the system was reduced to −500 mmHg using a vacuum pump, and the system was immediately sealed and left for 30 minutes so that the solvent and the like were volatilized and the film forming solution composition did not change. This operation was repeated twice to degas the film forming solution. The obtained film-forming solution is passed through a two-stage filter of 30 μm and 30 μm, and then discharged from the outer slit of the tube-in orifice nozzle heated to 50 ° C., and at the same time, the inner solidification from the inner liquid discharge hole of the tube-in orifice nozzle A 50% by mass DMAc aqueous solution at 50 ° C. that had been degassed under reduced pressure in advance was discharged as a liquid, and after passing through a 350 mm air gap portion that was blocked from outside air by a spinning tube, the solution was solidified in 50 ° C. water. 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 1.17, and the dry type The absolute humidity of the part was 0.07 kg / kg dry air. The discharge rate was adjusted so that the lumen forming agent discharge linear velocity immediately after discharge was 25000 cm / min and the dope discharge linear velocity was 5000 cm / min. 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. The roller for changing the yarn path during the spinning process was made of stainless steel with a mirror-finished surface, and the guide was made of Teflon (R). The resulting 10,000 hollow fiber membrane bundles were not washed and dried at 60 ° C. for 18 hours. Adherence was observed in the dried hollow fiber membrane bundle, and when assembling the blood purifier, there were many cases where the end adhesive resin did not enter between the hollow fiber membranes and the blood purifier could not be assembled. The analysis results are shown in Table 1.

(Comparative Example 5)
20% by mass of polyethersulfone (Suika Chemtex Co., Ltd. Sumika Excel (R) 4800P), 40% by mass of triethylene glycol (Mitsui Chemicals), and 40% by mass of N-methyl 2-pyrrolidone (Mitsubishi Chemical) A uniform transparent film forming solution was prepared by mixing and stirring. Using this membrane-forming solution, N-methyl 2-pyrrolidone / triethylene glycol / water = 5/5/90 was used as a hollow forming material, the water used for washing was tap water, and the guide was made of Teflon ( A hollow fiber membrane was obtained in the same manner as in Example 2 except that it was changed to one made of R). The hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 51 μm. The water content was 0.4% by mass, and the mass ratio of the hydrophilic polymer was 0% by mass.

  Although there were no problems such as sticking of the hollow fiber membrane and backflow of endotoxin, it could not be used as a hemodialysis membrane. This is probably because the hollow fiber membrane does not contain a hydrophilic polymer and thus has strong hydrophobicity, and blood proteins and the like are clogged in the pores and deposited on the membrane surface.

(Example 3)
Polysulfone (Amoco P-3500) 18.5% by mass, polyvinylpyrrolidone (BASF K-60) 9% by mass, DMAc 67.5% by mass, water 5% by mass dissolved at 50 ° C. After the pressure inside the system was reduced to −300 mmHg, the system was immediately sealed and left for 15 minutes so that the solvent and the like would volatilize and the film forming solution composition would not change. This operation was repeated three times to degas the film forming solution. After passing the obtained film-forming solution through a two-stage filter of 15 μm and 15 μm, it was discharged from the outer slit of a tube-in orifice nozzle heated to 40 ° C., and at the same time, 0 ° C. was degassed in advance as a hollow forming agent, A 35 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, the solution was solidified in water at 50 ° C. The nozzle slit width of the tube-in-orifice nozzle used is an average of 60 μm, the maximum is 61 μm, the minimum is 59 μm, the maximum and minimum slit width ratio is 1.03, the draft ratio is 1.22, the absolute humidity of the dry section Was 0.06 kg / kg dry air. The discharge rate was adjusted so that the lumen forming agent discharge linear velocity immediately after discharge was 25000 cm / min and the dope discharge linear velocity was 5000 cm / min. 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. The bundle of 10,500 hollow fiber membranes was immersed in RO water having a specific resistance of 1.2 MΩcm, and washed with an autoclave at 121 ° C. for 1 hour. A polyethylene film similar to that in Example 1 was wound around the hollow fiber membrane bundle after washing, and then dried in the same manner as in Example 1. The roller for changing the yarn path during the spinning process was made of stainless steel with a mirror-finished surface, and the fixing guide was made of stainless steel. The resulting hollow fiber membrane had an inner diameter of 199 μm and a film thickness of 44 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 8 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 2.

Example 4
Polysulfone (Amoco P-1700) 17% by mass, polyvinylpyrrolidone (BASF K-60) 4.8% by mass, DMAc 73.2% by mass, water 5% by mass were dissolved at 50 ° C., and then a vacuum pump was used. After the pressure inside the system was reduced to −400 mmHg, the inside of the system was immediately sealed and left for 30 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 the tube-in orifice nozzle heated to 40 ° C., and at the same time, the 0 ° C. A 35 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, the solution was solidified in water at 50 ° C. The nozzle slit width of the tube-in-orifice nozzle used is an average of 60 μm, maximum 61 μm, minimum 59 μm, maximum / minimum slit width ratio is 1.03, draft ratio is 1.20, absolute humidity of the dry section Was 0.07 kg / kg dry air. The discharge rate was adjusted so that the lumen forming agent discharge linear velocity immediately after discharge was 25000 cm / min and the dope discharge linear velocity was 5000 cm / min. 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. The bundle of 10,700 hollow fiber membranes was immersed in RO water having a specific resistance of 1.2 MΩcm, and washed with 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 made of stainless steel with a mirror-finished surface, and the fixing guide was made of stainless steel. The resulting hollow fiber membrane had an inner diameter of 201 μm and a film thickness of 42 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 2.

The polysulfone-based hollow fiber membrane of the present invention has high safety and performance stability, is excellent in module assembly, and is suitable for a hollow fiber blood purifier having high water permeability used for the treatment of chronic renal failure. It is important to contribute to the industry.

Claims (6)

A polysulfone-based hollow fiber membrane comprising a polysulfone-based resin and polyvinylpyrrolidone as main components and satisfying the following (a) to (c) simultaneously:
(A) The abundance of polyvinylpyrrolidone in the polysulfone-based hollow fiber membrane is 20 to 40% by mass in the outermost layer portion with a depth of 10 nm from the blood contact side surface, and 25 to 50 in the outermost layer portion on the surface opposite to the blood contact side. The amount of polyvinyl pyrrolidone relative to the polysulfone resin is 5 to 20% by mass in the vicinity of the surface layer having a depth of 1000 to 1500 nm from the blood contact side surface.
(B) The amount of polyvinyl pyrrolidone in the outermost layer on the surface opposite to the blood contact side in the polysulfone-based hollow fiber membrane is 1.1 times or more than the amount of polyvinyl pyrrolidone in the outermost layer on the blood contact side surface.
(C) Clotted cow blood is encapsulated in the lumen of a polysulfone-based hollow fiber membrane, and the hollow blood membrane resulting from coagulation and coagulation in the encapsulated blood after being immersed in an isotonic solution containing calcium for 10 minutes Does not occur. The polysulfone-based selectively permeable hollow fiber membrane according to claim 1 , comprising 99 to 80% by mass of a polysulfone-based resin and 1 to 20% by mass of polyvinylpyrrolidone . The polysulfone-based permselective hollow fiber membrane according to claim 1 or 2 , wherein the amount of polyvinylpyrrolidone eluted from the hollow fiber membrane is 10 ppm or less. The polysulfone-based selectively permeable hollow fiber membrane according to any one of claims 1 to 3, 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 4 , wherein the polyvinyl pyrrolidone is crosslinked and insolubilized in water. The polysulfone-based selectively permeable hollow fiber membrane according to any one of claims 1 to 5 , which is used for a blood purifier.