WO2005089917A1 - 選択透過性分離膜およびその製造方法 - Google Patents
選択透過性分離膜およびその製造方法 Download PDFInfo
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- WO2005089917A1 WO2005089917A1 PCT/JP2005/004980 JP2005004980W WO2005089917A1 WO 2005089917 A1 WO2005089917 A1 WO 2005089917A1 JP 2005004980 W JP2005004980 W JP 2005004980W WO 2005089917 A1 WO2005089917 A1 WO 2005089917A1
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- hollow fiber
- separation membrane
- fiber membrane
- blood
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- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
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- 229940092253 ovalbumin Drugs 0.000 description 1
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- JCGNDDUYTRNOFT-UHFFFAOYSA-N oxolane-2,4-dione Chemical compound O=C1COC(=O)C1 JCGNDDUYTRNOFT-UHFFFAOYSA-N 0.000 description 1
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- 229920006267 polyester film Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
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- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920005749 polyurethane resin Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000131 polyvinylidene Polymers 0.000 description 1
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
- B01D69/085—Details relating to the spinneret
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
- B01D69/087—Details relating to the spinning process
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
- B01D71/68—Polysulfones; Polyethersulfones
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/24—Formation of filaments, threads, or the like with a hollow structure; Spinnerette packs therefor
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
- D01F6/88—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from mixtures of polycondensation products as major constituent with other polymers or low-molecular-weight compounds
- D01F6/94—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from mixtures of polycondensation products as major constituent with other polymers or low-molecular-weight compounds of other polycondensation products
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/02—Hydrophilization
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/12—Specific ratios of components used
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/20—Specific permeability or cut-off range
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/28—Degradation or stability over time
Definitions
- the present invention relates to a selectively permeable separation membrane that can be used for blood purification treatment. More specifically, the present invention relates to a polysulfone-based selectively permeable separation membrane having a good balance of separation characteristics, high safety and high performance stability, and excellent threading property of a module, and a method for producing the same.
- Background art
- cellulose which is a natural material, and cellulose derivatives such as cellulose diacetate, cellulose triacetate, and synthetic polymers are used.
- hemodialyzers and hemofilters that use dialysis membranes and ultrafiltration membranes using polymers such as polysulfone, polymethyl methacrylate, and polyacrylonitrile as separation materials!
- modules such as hemodiafiltration filters are widely used.
- Modules using hollow fiber membranes as separation materials are particularly important in the field of dialysis machines due to their advantages such as reduced extracorporeal blood volume, high efficiency in removing blood substances, and productivity during module production. Is high,.
- a polysulfone-based resin having high water permeability has attracted attention as the one most suited to the progress of dialysis technology.
- a semi-permeable membrane is made of polysulfone alone, since the polysulfone resin is hydrophobic, it causes an air-opening phenomenon with poor affinity for blood. Cannot be used.
- a method for solving the above-mentioned problem a method has been proposed in which a hydrophilic polymer is mixed with a polysulfone-based resin to form a film, thereby imparting hydrophilicity to the film.
- a method of blending a polyhydric alcohol such as polyethylene glycol has been disclosed (for example, see Patent Documents 1 and 2).
- Patent Document 1 Japanese Patent Application Laid-Open No. 61-232860
- Patent Document 2 JP-A-58-114702
- Patent Document 3 Japanese Patent Publication No. 5-54373
- Patent Document 4 Japanese Patent Publication No. 6-75667
- the latter method using polyvinylpyrrolidone has attracted attention from the viewpoint of safety and economy, and the above-mentioned method solves the above-mentioned problems.
- the problem arises when polyvinylpyrrolidone is eluted and mixed with purified blood during dialysis.
- the amount of polyvinylpyrrolidone elutes is increased, the accumulation of polyvinylpyrrolidone, which is a foreign substance to the human body, during long-term dialysis increases, which may cause side effects and complications.
- the amount of polyvinylpyrrolidone eluted is determined by the dialysis-type artificial kidney device manufacturing approval standard. According to the standard, the elution amount of polybutylpyrrolidone and the like is determined by UV absorbance. A technique for judging the effect of elution amount control using the criterion is disclosed (for example, see Patent Documents 5-7).
- Patent Document 5 Patent No. 3314861
- Patent Document 6 JP-A-6-165926
- Patent Document 7 JP-A-2000-350926
- the above problem is solved by the above method.
- the polyvinyl alcohol existing on the inner surface of the membrane referred to as the inner surface
- the outer surface of the membrane opposite to the blood referred to as the outer surface
- the content of pyrrolidone greatly affects the membrane performance of the permselective separation membrane, it is important to optimize the content. For example, by increasing the content of polypyrrolidone on the inner surface, it is possible to ensure blood compatibility. If the content on the surface is too high, the amount of polyvinylpyrrolidone eluted into the blood increases. The accumulation of the eluted polypyrrolidone is not preferable because side effects and complications occur during long-term dialysis.
- reducing the amount of polyvinylpyrrolidone present on the outer surface is preferable from the viewpoint of suppressing the penetration of endotoxin into the blood. Since the hydrophilicity of the outer surface is reduced while applying force, when the hollow fiber membrane dried for assembly after the assembly of the module is returned to a wet state, the affinity with the physiological saline used for wetting is reduced. For this reason, if the priming property, which is the ability to add and remove air during the wetting operation, is reduced, this leads to the generation of a problem.
- the content of polyvinylpyrrolidone present in the dense layer on the inner surface of the permselective separation membrane is specified, and the polyvinylpyrrolidone present in the dense layer on the inner surface is provided.
- a method is disclosed in which the content of is at least 1.1 times the content of polyvinylpyrrolidone present on the outer surface (see Patent Document 5).
- this technology increases the content of polybutylpyrrolidone present on the surface of the dense layer on the inner surface and improves blood compatibility, and conversely lowers the content of polybutylpyrrolidone present on the outer surface, thereby reducing the membrane.
- Patent Document 5 JP-A-6-165926
- Patent Document 7 JP-A-6-296686
- Patent Document 8 JP-A-11 309355
- Patent Document 9 JP-A-2000-157852
- endotoxin endotoxic system
- endotoxin has a hydrophobic portion in its molecule and is easily adsorbed to a hydrophobic material.
- a method using characteristics is disclosed (for example, see Patent Document 10). That is, the method relates to making the ratio of polyvinylpyrrolidone to hydrophobic polymer on the outer surface of the hollow fiber membrane 5 to 25%. Certainly, this method is preferable as a method for suppressing invasion of endotoxin into the blood side.
- Patent Document 10 JP-A-2000-254222
- hydrophilicity Since the compound acts as a foreign substance during dialysis and the hydrophilic compound is susceptible to deterioration such as light deterioration, it leads to problems such as adversely affecting the storage stability of the module. Another problem is that when the hollow fiber membrane is fixed to the module in module assembly, adhesion of the adhesive is hindered.
- Patent Document 11 JP-A-2001-190934
- Patent Document 12 Patent No. 3193262
- Patent Document 13 JP-A-2000-140589
- the polybutylpyrrolidone content on the inner surface also has a large effect on the selectivity of separation by a permselective separation membrane.
- a permselective separation membrane For example, in the treatment of blood in patients with chronic renal failure, it is necessary to actively remove other low-molecular-weight proteins while minimizing leakage of the active protein albumin.
- a polysulfone-based selective separation membrane having a transmittance of albumin of 0.5 to 0.0001% is disclosed (see Patent Document 15). Certainly, the method of the patent document is excellent in that the transmittance of albumin is suppressed to an extremely low level.
- the permselective separation membrane obtained by this method has a problem that the ⁇ 1-microglobulin removal rate is low, for example.
- dialysis complications associated with the increase in long-term dialysis patients have been attracting attention, and low molecular weights from a medium molecular weight region of around 5,000 daltons to molecular weights of 10,000 daltons or more can be obtained using only low molecular weight substances such as urea, uric acid, and creatine.
- the removal target has spread to proteins. Therefore, it is required that uremic substances having a molecular weight represented by OC 1 microglobulin present in blood can be efficiently removed.However, according to the method of Patent Document 15, the selectivity of protein separation is inferior. I can't respond.
- Patent Document 16 a polysulfone-based selective separation membrane having a sieving coefficient of ovalbumin of 0.2 or more has been disclosed (see Patent Document 16).
- the permselective separation membrane obtained in the literature is effective in that it can remove uremic substances efficiently.
- Patent Document 15 JP-A-11-309356
- Patent Document 16 JP-A-7-289863
- Patent Document 17 Japanese Patent Application Laid-Open No. 2003-175320
- Patent Document 18 JP-A-2003-175321
- Patent Document 19 JP-A-2003-175322
- the present inventors have conducted detailed studies on the dissolution behavior of polypyrrolidone.
- the extract extracted by the test method defined by the above dialysis-type artificial kidney device manufacturing approval standard contains: It has been found that hydrogen peroxide is included, which cannot be measured by conventionally known UV absorbance!
- the presence of hydrogen peroxide for example, promotes the oxidation degradation of polypyrrolidone and increases the amount of polyvinylpyrrolidone eluted during storage of the permselective separation membrane, thereby deteriorating the storage stability.
- the presence of hydrogen peroxide for example, promotes the oxidation degradation of polypyrrolidone and increases the amount of polyvinylpyrrolidone eluted during storage of the permselective separation membrane, thereby deteriorating the storage stability.
- Patent Documents 5 to 7 described above evaluate V and deviation of specific portions of the permselective separation membrane. For example, when processing such as drying the hollow fiber membrane during module assembly, etc., the above-mentioned elution amount fluctuates greatly due to fluctuations in drying conditions, etc. It turned out to be unresponsive.
- the present invention provides a blood having a high balance of separation characteristics, high safety and high performance stability, and excellent module assemblability, and high water permeability for use in the treatment of chronic renal failure. It is an object of the present invention to provide a selectively permeable separation membrane suitable for a purifier. Another object of the present invention is to provide a method for economically and stably producing a selectively permeable separation membrane having the above characteristics.
- the present invention relates to a selectively permeable separation membrane
- the permselective separation membrane mainly comprises a polysulfone-based polymer and polyvinylpyrrolidone,
- the present invention when the film forming solution and the internal solution is discharged from the tube-in-orifice type nozzle, and then coagulated in a coagulation bath through an air gap,
- the film-forming solution contains a polysulfone polymer, polybulpyrrolidone and a solvent.
- the ratio of polybulpyrrolidone to the polysulfone polymer is 10-18% by mass, and the internal solution contains an amide solvent of 30-60% by mass.
- the liquid temperature of the internal liquid is lowered by 30 to 60 ° C from the liquid temperature of the film forming solution, and the liquid temperature is discharged under the condition of SO-40 ° C.
- FIG. 1 is a schematic view of a tube in orifice nozzle that can be used in the present invention.
- FIG. 2 is a graph showing the relationship between the PVP content ratio on the inner and outer surfaces of the hollow fiber membrane and the albumin sieving coefficient.
- FIG. 3 is a graph showing the relationship between the PVP content ratio on the inner and outer surfaces of the hollow fiber membrane and the change over time in the albumin sieving coefficient.
- FIG. 4 is a view showing the relationship between the PVP content ratio on the inner and outer surfaces of a hollow fiber membrane and a1 microglobulin clearance.
- FIG. 5 is a graph showing the relationship between the PVP content ratio on the inner and outer surfaces of the hollow fiber membrane and the amount of ⁇ 1 microglobulin adsorbed.
- FIG. 6 is a view showing the relationship between the PVP content on the inner surface of the hollow fiber membrane and the amount of a1MG adsorbed.
- the permselective separation membrane of the present invention comprises a polysulfone-based resin containing polyvinylpyrrolidone.
- the polysulfone resin in the present invention is a general term for a resin having a sulfone bond, and is not particularly limited.
- a polysulfone resin having a repeating unit represented by the following formula is preferred because it is widely commercially available as a polysulfone resin and is easily available.
- the polybutylpyrrolidone used in the present invention is a water-soluble polymer compound obtained by subjecting N-bulpyrrolidone to beul polymerization.
- N-bulpyrrolidone for example, “Rubitec” from BASF, “Brasdon” from ISP, Daiichi Kogyo It is marketed by pharmaceutical companies under the brand name "Pitzcol", and there are products with various molecular weights.
- a product having a single molecular weight may be used, or a mixture of two or more products having different molecular weights may be used.
- a commercially available product may be purified, for example, one having a sharp molecular weight distribution.
- the molecular weight of polyvinylpyrrolidone those having a mass average molecular weight of 10,000 to 1,500,000 can be used. Specifically, for example, those having a molecular weight of 9,000 sold by BASF (K17), and similarly, 45,000 ( ⁇ 30), 450,000 ( ⁇ 60), 900,000 ( ⁇ 80), 1, It is preferable to use 200,000 ( ⁇ 90). These may be used alone or in appropriate combination of two or more kinds in order to obtain the intended use, characteristics and structure. In the present invention, it is most preferable to use 90 alone.
- the permselective separation membrane of the present invention is preferably produced using polyvinylpyrrolidone having a hydrogen peroxide content of 30 Oppm or less. 250 ppm or less is more preferred 20 Oppm or less is even more preferred 150 ppm or less is even more preferred.
- the content of hydrogen peroxide in the polyvinylpyrrolidone used as a raw material is 300 ppm or less, the amount of hydrogen peroxide dissolved in the permselective separation membrane can be stabilized at 5 ppm or less. This is preferable because film quality stability can be achieved.
- a method of reducing the amount of hydrogen peroxide by a recrystallization method and an extraction method is used.
- polypyrrolidone When polypyrrolidone is dissolved in a solvent, it is preferable to dissolve it at a temperature of 70 ° C. or lower. It is also a preferred embodiment that the dissolution is carried out in a state of being replaced with an inert gas.
- polybutylpyrrolidone As described above, in the present invention, it is preferable to use only the above-described polybutylpyrrolidone. However, for example, another hydrophilic polymer such as polydalicol described in Patent Document 6 is used. They may be used together within the scope of the present invention.
- the method for producing the permselective separation membrane of the present invention is not limited at all, for example, a method for producing a hollow fiber membrane type as disclosed in Japanese Patent Application Laid-Open No. 2000-300663 Is preferred.
- the following methods can be exemplified as disclosed in the patent document: 16 parts by mass of polyether sulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.) and 5 parts by mass of polybutylpyrrolidone (K-90, manufactured by BASF).
- the permselective separation membrane of the present invention is obtained by a wet membrane formation method using a membrane formation solution obtained by dissolving the above-mentioned constituent polysulfone-based polymer and polybutylpyrrolidone in a solvent.
- a solvent include dimethyl phos- phate capable of dissolving both components.
- Sulfoxide polar solvents such as amides such as lumamide, dimethylacetoamide, and N-methylpyrrolidone are preferably used. If the content is 10% by mass or less, a non-solvent for the polysulfone-based polymer such as water or alcohol may be used in combination. This makes it possible to control the phase separation of polybutylpyrrolidone from the polysulfone-based polymer.
- the permselective separation membrane of the present invention is prepared by loading a permselective separation membrane having the above composition with a module prepared by adding a hematocrit of 30%, a total protein concentration of 6 to 7gZdl, and sodium tenoate.
- a permselective separation membrane having the above composition with a module prepared by adding a hematocrit of 30%, a total protein concentration of 6 to 7gZdl, and sodium tenoate.
- the sieving coefficient [A] of albumin after 15 minutes was 0.01 or more and 0.1 or less, and albumin after 2 hours. It is preferable that the sieving coefficient [B] is not less than 0.005 and less than 0.04 (requirement 1).
- the sieving coefficient [A] of albumin after 15 minutes is more preferably from 0.01 to 0.09, and still more preferably from 0.01 to 0.08.
- the sieving coefficient [B] of albumin after 2 hours is more preferably from 0.005 to 0.035, and still more preferably from 0.005 to 0.03. If the sieving coefficient of albumin after 15 minutes and after 2 hours is too large, the permeability of albumin, a useful protein, will increase, which may increase the burden on patients. On the other hand, when the sieving of the albumin after 15 minutes and after 2 hours, the coefficient is too small, respectively, it is preferable in that the transmittance of albumin is low, but (1) there is a possibility that uremic substances such as microglobulin cannot be removed efficiently. is there.
- Albumin is a useful protein for living organisms, and in clinical practice, it is considered that the amount of albumin leakage per hemodialysis treatment (3 L of water removal) should be 3 g or less. Excessive albumin leakage can cause disorders such as hypoalbuminemia in patients with low dietary intake. Therefore, the amount of albumin leaked per hemodialysis is preferably 2.5 g or less, more preferably 2. Og or less, and even more preferably 1.5 g or less. Conversely, the existence of a toxin that binds to albumin is also known in vivo, and even if the amount of albumin leakage is too small, various disorders may be caused. Therefore, the amount of albumin leakage per dialysis treatment is preferably 0.05 g or more, more preferably 0.1 lg or more, and still more preferably 0.15 g or more.
- the clearance of ⁇ -microglobulin (molecular weight 33,000) is 15 ml / min (lOm 2 ) or more (Requirement 4). If the clearance of ⁇ 1 microglobulin is too small, the removal amount of substances with a molecular weight of about 30,000 is small, so that it is possible to prevent dialysis complications and improve itching and pain! There may not be. Therefore, the clearance of ⁇ microglobulin is more preferably 18 ml / min (l.Om 2 ) or more, more preferably 21 ml / min (l.Om 2 ) or more, more than 24 ml / min (1 Om 2 ).
- the clearance is large.
- the alpha I microglobulin clearance 100ml / min (l. Om 2 ) or less preferably fixture 80ml / min (l. Om 2 ) or less and more preferably tool 60ml / min (l. Om 2 ) hereinafter is More preferred.
- the albumin sieving coefficient [B] is 0.015 or more and 0.1 or less and 2 hours later. It has been found that it is an optimal condition to provide a selectively permeable separation membrane having characteristics falling within the range of less than 04. In order to manufacture a separation membrane with such optimum conditions, it is important to control various materials, their specifications, the manufacturing process, drying conditions, etc. One method is to analyze the relationship between albumin and the sieving coefficient.
- FIG. 1 shows the relationship between [D] Z [C] as a relationship between the content of [D], the albumin sieving coefficient [A] after 15 minutes, and the albumin sieving coefficient [B] after 2 hours. It is. According to this, when [D] Z [C] becomes 1.1 or more, the albumin sieving coefficient [A] is set to a predetermined value of 0.01 or more and 0.1 or less in Example 13 to 13 in Example 13.
- FIG. 4 shows the power of quantitatively analyzing the relationship between [D] Z [C] and a1 microglobulin clearance.
- [D] Z [C] 1.1
- its distribution is concentrated in the stable region of 15 mlZmin (l.Om 2 ) in Example 13 of the present Example 13 in which the clearance of ⁇ ⁇ ⁇ ⁇ ⁇ microglobulin is concentrated.
- ⁇ 1 a large dispersion state of microglobulin clearance suggests that a separation membrane of unstable quality was obtained.
- FIG. 5 is a quantitative analysis of the relationship between [D] Z [C] and the amount of ⁇ microglobulin adsorbed.
- ⁇ 1 microglobulin adsorption the pore size of the membrane that can be formed only with [D] Z [C]] the structure of the blood contact surface, such as micro unevenness, and the degree of hydrophilicity of the surface affect the amount of adsorption. I can't say it.
- [D] Z [C] is 1.1 or more is one of the factors that have a significant effect in that ⁇ ⁇ microglobulin falls within a predetermined range. Can be easily understood.
- the outermost layer of the permselective separation membrane is a 20-40 mass 0/0 It is suitable.
- Many technical factors affect the performance of the separation membrane, such as the grade of polysulfone polymer, the grade of polyvinylpyrrolidone, the total blended amount of polypyrrolidone, the content on the outer surface, and the method of manufacturing the selectively permeable separation membrane.
- the content of polybutylpyrrolidone in the outermost layer on the blood contact side surface greatly affects the performance of the separation membrane of the present invention.
- the permselective separation membrane of the present invention preferably has an ⁇ 1 microglobulin (MG) adsorption amount of 2.0-20 mgZm 2 .
- FIG. 6 shows the relationship between the content (% by mass) of polybutylpyrrolidone (PVP) in the outermost layer of the inner surface and ⁇ the amount of adsorbed microglobulin. As is evident from the figure, it is important to specify the PVP content in the outermost surface of the blood contact side as 20-40% by mass as one of the factors indicating the performance of the permselective separation membrane. The figure also shows that one of the performance requirements of the permselective separation membrane, ex 1MG adsorption, is closely related to the PVP content that specifies the material or structure of the permselective separation membrane. Clarified.
- the method for imparting the above-mentioned selectivity balance of protein separation to the permselective separation membrane is not limited, but the hollow fiber membrane for blood purification in the present invention has a skin layer on the inner surface.
- the thickness of the skin layer is preferably 0.1-1.2 m (requirement 6). The thinner the skin layer, which is a substantial separation active layer, the lower the solute migration resistance. For this reason, it is more preferable that the length is 1.1 m or less, and it is even more preferable that the length is 1.0 m or less.
- the thickness of the skin layer is more preferably 0.2 ⁇ m or more, more preferably 0.3 ⁇ m or more, and particularly preferably 0.4 ⁇ m or more.
- the film-forming solution also becomes a polysulfone-based polymer, polyvinyl vinylidone and a solvent, and the ratio of polybulpyrrolidone to the polysulfone-based polymer is 10 to 18% by mass.
- the internal solution is an aqueous solution containing 30 to 60% by mass of an amide-based solvent.
- the temperature of the internal solution is 30 to 60 ° C lower than the temperature of the film forming solution, and the temperature of the solution is 0 to 40. It is also an embodiment that it is preferable to discharge under the condition of ° C.
- the polyvinylpyrrolidone ratio is more preferably from 12.0 to 17.5% by mass, and still more preferably from 13.0 to 17.5% by mass.
- the amount of the amide solvent in the internal liquid is more preferably 32 to 58% by mass, more preferably 34 to 56% by mass, and still more preferably 35 to 54% by mass.
- the temperature of the internal solution is preferably 30 to 55 ° C, more preferably 35 to 50 ° C.
- the liquid temperature of the internal liquid is more preferably 0 to 35 ° C, more preferably 5 to 30 ° C, and still more preferably 10 to 30 ° C.
- the inner surface properties such as the skin layer thickness of the permselective separation membrane, the content of polyvinylpyrrolidone on the inner surface, and the average pore size / pore size distribution are optimized, and the selectivity of the protein is improved.
- the method of giving a temperature difference between the liquid temperature of the internal liquid and the liquid temperature of the film forming solution is not limited, either.
- a tube-in orifice type nozzle the pipe from the internal liquid tank to the nozzle and the inside of the nozzle block are used. It is preferable to use an internal liquid heat medium circulation type block in which heat exchange is provided and the liquid temperature can be adjusted separately from the temperature of the film forming solution.
- the balance of protein selectivity can be imparted by the swelling effect of polyvinylpyrrolidone present in the permselective separation membrane through blood.
- protein permeability is increased, but during the dialysis process, polybulpyrrolidone in the permselective separation membrane swells with the passage of blood, thereby reducing albumin permeability.
- the polypyrrolidone When the polypyrrolidone is cross-linked, the molecular motility of the polyvinylpyrrolidone and the swelling property of the polyvinylpyrrolidone by blood are reduced, so that the action and function are reduced, and the selectivity of protein separation may be reduced.
- the content of the insoluble component is preferably 30% by mass or less based on all polyvinylpyrrolidone present in the permselective separation membrane. 25 mass% or less is more preferred 20 mass% or less is even more preferred 15 mass% or less is even more preferred 10 mass% or less is particularly preferred Less than 5 mass% is most preferred.
- the content of the insoluble component is a measure of the degree of crosslinking of polyvinylpyrrolidone, and a high content of the insoluble component means that the crosslinking of the polypyrrolidone present in the permselective separation membrane proceeds. I do.
- the permselective separation membrane of the present invention preferably keeps the moisture content after drying at 110 to 10% by mass, a certain degree of crosslinking reaction may occur due to the effect of a small amount of water present during irradiation sterilization.
- cross-linking insolubilizing
- the content of insolubles is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, even more preferably 0.3% by mass or more, more preferably 0.5% by mass or more. More preferred.
- the content of the above insoluble matter can be simply obtained from the insoluble matter in a solution obtained by immersing and dissolving the permselective separation membrane in dimethylformamide.
- the solution is obtained by dissolving 10 g of the selectively permeable separation membrane in 100 ml of dimethylformamide. If the solution is visually observed and no insoluble matter is seen! /, The solution may be determined to be non-crosslinked.
- the thickness of the permselective separation membrane is preferably 25 to 45 ⁇ m.
- the film thickness is more preferably 40 ⁇ m or less, more preferably 35 ⁇ m or less, and even more preferably 33 ⁇ m or less.
- the content of polyvinylpyrrolidone in the outermost layer on the blood contacting surface (inner surface) of the permselective separation membrane is preferably 20 to 40% by mass. Requirement 9). If the content of polypyrrolidone is too low, the hydrophilicity of the inner surface of the hollow fiber membrane is low and blood compatibility is deteriorated, and blood coagulation tends to occur on the surface of the hollow fiber membrane. Blockage of the fiber membrane may occur and the separation performance of the hollow fiber membrane may decrease, or residual blood after use in hemodialysis may increase.
- the content of polybutylpyrrolidone in the outermost layer on the inner surface of the hollow fiber membrane is more preferably 21% by mass or more, further preferably 22% by mass or more, and even more preferably 23% by mass or more.
- the content of polyvinylpyrrolidone in the outermost layer on the inner surface of the hollow fiber membrane is more preferably 38% by mass or less, and still more preferably 36% by mass or less.
- Blood compatibility is also affected by the amount of plasma protein adsorbed. That is, the plasma protein, which is a hydrophilic protein, is adsorbed on the blood-contacting surface of the permselective separation membrane, thereby increasing the hydrophilicity of the surface and improving blood compatibility.
- ⁇ 1 microglobulin (molecular weight 33,000) in plasma protein is used as an indicator for improving clinical symptoms (itching / pain) and blood compatibility of a selectively permeable separation membrane. It is preferable that the adsorption amount is 2.0 to 20 mgZm 2 (requirement 5).
- ⁇ 1 microglobulin has a property of easily binding to immunoglobulin (molecular weight of 100,000 or more) in blood (plasma).
- the removal amount is increased by the action of adsorption to the selectively permeable separation membrane. a 1 If the amount of adsorbed microglobulin is too small, blood compatibility may decrease or the effect of improving clinical symptoms may be insufficient. Therefore, the adsorption amount is more preferably 2.5 mg / m 2 or more 3. OmgZm 2 is more preferable 3.5 mgZm 2 is even more preferable.
- the adsorption amount 19MgZm 2 or less still more preferred more and more preferably tool 18MgZm 2 or less still more preferred instrument 17 mg Zm 2 is.
- the amount of adsorption is also affected by the form of the surface layer on the inner surface.
- the method for controlling the amount of adsorption to be in the above range is not limited.
- the temperature of the internal liquid can have a significant effect on the amount of adsorption. Therefore, it is important that the liquid temperature of the above-mentioned internal liquid is 30 to 60 ° C lower than the liquid temperature of the film forming solution and that the liquid is discharged under the condition that the liquid temperature is 0 to 40 ° C.
- the content of polyvinylpyrrolidone on the outermost surface of the inner surface is optimized. Furthermore, by increasing the draft ratio at the time of film formation under the above conditions, streaky micro unevenness continuous in the longitudinal direction of the hollow fiber membrane is formed on the surface layer on the inner surface. The micro unevenness increases the surface area of the inner surface and optimizes the amount of adsorption.
- the amount of ⁇ 1 microglobulin adsorbed is affected by the degree of orientation of polybutylpyrrolidone on the inner surface of the hollow fiber membrane.
- the shear stress in the nozzle is more preferably 5 ⁇ 10 4 s ⁇ 1 or more, more preferably 1 ⁇ 10 5 s ⁇ 1 or more, and still more preferably 5 ⁇ 10 5 s ⁇ 1 or more. If the shear stress is too large, crystallization of polypyrrolidone on the inner surface of the hollow fiber membrane may proceed, and the permeability of the solute may be reduced. did Therefore, the shear stress 5 X 10 7 s- 1 or less even more preferably from more preferred instrument l X 10 7 s- 1 or less and more preferably tool 5 X 10 6 s- 1 or less.
- Shear stress time 1 X 10- 5 - 0. lsec is preferred. More preferably 5 X 10- 4 - 5 X 10- 2 sec, more preferably 1 X 10- 4 - a 1 X 10- 2 sec.
- the specific nozzle shape should have a maximum outer diameter of 100 to 700 / ⁇ ⁇ and a land length of 0.1 to 5 mm. .
- the maximum outer diameter is preferably 150-600 m force, more preferably 180-550 m force S, even more preferably 200-500 m force S.
- the amount of adsorbed a1 microglobulin is also affected by the charge state of the surface of the hollow fiber membrane on the blood contact side.
- it is effective to use RO water as the water used for producing the hollow fiber membrane.
- the use of RO water makes it possible to efficiently remove the charged substance adhering to the membrane.
- RO water contains no ionic substances, so no ions are adsorbed on the membrane.
- the RO water to be used preferably has a specific resistance of 0.3 to 2 ⁇ ⁇ cm, more preferably 0.4 to 1.9 ⁇ ⁇ cm.
- the adsorbed amount of a1 microglobulin contributes not only to the improvement of blood compatibility but also to the removal of a1 microglobulin, thereby preventing dialysis complications and improving clinical symptoms such as itching and pain. Also seems to give good results.
- the content of polyvinyl pyrrolidone near the surface layer of the blood contacting surface of the permselective separation membrane is 5 20 weight 0/0 (Requirement 10). 7-18% by mass is more preferred.
- the content of polyvinylpyrrolidone in the outermost layer on the blood contact side surface of the permselective separation membrane is preferably higher from the viewpoint of blood compatibility.
- the amount of polyvinylpyrrolidone eluted into the blood increases, which is a trade-off phenomenon.
- the content of polyvinylpyrrolidone in the vicinity of the inner surface of the hollow fiber membrane is more preferably 19% by mass or less, more preferably 18% by mass or less.
- the content of polypyrrolidone near the inner surface is too low, pouring to the outermost layer will occur. Since rivulpyrrolidone is not supplied, there is a possibility that the solute removal performance and the stability over time of blood compatibility may decrease. Therefore, the content of polypyrrolidone in the vicinity of the inner surface is more preferably 6% by mass or more, more preferably 7% by mass or more.
- the above trade-off phenomenon can be overcome, and optimization of the above-mentioned phenomenon can be achieved at a very high level that cannot be achieved by the prior art. That is, it is important to set the content of polybutylpyrrolidone in the outermost layer of the permselective separation membrane that governs blood compatibility to the lowest level at which blood compatibility can be exhibited.
- polyvinylpyrrolidone present in the outermost layer gradually elutes into the blood after long-term dialysis, and as the dialysis progresses, Blood compatibility gradually decreases! / ⁇ t ⁇ ⁇ Issues occur.
- this problem has been solved by replenishing polyvinylpyrrolidone existing in the layer near the surface to the outermost layer. Therefore, when the content of polyvinylpyrrolidone in the layer near the surface on the blood contact side is too low, it may be insufficient to suppress a decrease in the persistence of blood compatibility. On the other hand, if the content is too high, the amount of polybutylpyrrolidone eluted in the blood increases, which may cause side effects and complications due to long-term dialysis.
- the content of polybutylpyrrolidone in the outermost layer on the blood non-contact side of the permselective separation membrane is 25 to 50% by mass
- the content of polyvinylpyrrolidone in the surface layer: [D]) Z (the content of polypyrrolidone in the outermost surface layer on the blood contact side: [C]) is preferably 1.1 times or more (Requirement 11). . If the content of polybutylpyrrolidone in the outermost layer of the surface on the blood non-contact side (outer surface) is too low, the amount of blood protein adsorbed to the support layer of the hollow fiber membrane will increase, resulting in poor blood compatibility and permeability. Degradation can occur.
- the priming property may be poor. Therefore, the content of polybutylpyrrolidone in the outermost surface layer is more preferably 27% by mass or more, further preferably 29% by mass or more, and still more preferably 31% by mass or more. Conversely, if the content of polyvinylpyrrolidone on the outer surface is too high, the possibility that endotoxin (endotoxin) contained in the dialysate enters the blood side increases, which may lead to side effects such as fever. Dried membrane In this case, there is a possibility that the hollow fiber membranes will adhere to each other due to the interposition of polypyrrolidone present on the surface, and problems such as poor module assemblability will be caused.
- the content of polyvinylpyrrolidone on the outer surface is more preferably 43% by mass or less, more preferably 41% by mass or less, and still more preferably 39% by mass or less.
- the content of polypyrrolidone in the outermost layer on the surface (outer surface) on the blood non-contact side is 1.1 times the content of polyvinylpyrrolidone in the outermost layer on the surface (inner surface) on the blood contact side. It is preferable that it is above.
- the content of polypyrrolidone can affect the shrinkage of the hollow fiber membrane after the membrane formation. That is, as the content of polybutylpyrrolidone increases, the contraction rate of the hollow fiber membrane increases.
- the difference in shrinkage between the inner surface side and the outer surface side results in microscopic formation on the inner surface side. Wrinkles may occur or the hollow fiber membrane may break.
- wrinkles are formed on the inner surface side, for example, when a separation membrane is used for hemodialysis, blood proteins and the like easily accumulate on the membrane surface when the blood flows, so that the permeation performance decreases over time. This can lead to problems. For these reasons, it is preferable to increase the content of polyvinylpyrrolidone on the outer surface side.
- the hollow fiber membrane of the present invention preferably has a structure in which a dense layer is provided on the inner surface, and the pore diameter gradually increases as the outer surface is urged. That is, since the porosity is higher on the outer surface side than on the inner surface side, the outer surface side has a characteristic that the shrinkage ratio on the outer surface side is larger.
- the content of polybutylpyrrolidone in the outermost surface layer is preferably 1.1 times or more the content of polybutylpyrrolidone in the innermost surface layer. More preferably, it is 1.2 times or more, further preferably 1.3 times or more.
- the content of polyvinylpyrrolidone in the outermost surface layer is preferably high, but if it is too high, the ratio of polyvinylpyrrolidone to polysulfone polymer becomes too high, resulting in insufficient strength, adhesion between hollow fiber membranes, and hemodialysis. It may cause problems such as reverse influx of endotoxin during use and elution of polybulpyrrolidone. It is more preferably at most 1.9 times, more preferably at most 1.8 times, even more preferably at most 1.7 times.
- the difference between the two layers is described in detail.
- the pore diameter of the permselective separation membrane tends to increase from the skin layer (dense layer) on the blood contact side surface to the opposite surface, so that there is a difference in density between the outermost layer and the vicinity of the surface. It can be a layered structure.
- the thickness of each layer and its boundary line are arbitrarily changed depending on the manufacturing conditions of the permselective separation membrane, and the structure of the layer has some influence on the performance.
- the outermost layer and the near-surface layer are almost at the same time, and the two layers are formed at the same time, considering that both layers are manufactured adjacent to each other.
- the boundaries are not sharp, but they can be recognized. If you look at the distribution curve of the hydrophilic polymer content in the two layers, if you look at the distribution curve of the hydrophilic polymer content, there are many cases where there is a continuous line.Because there is a fault in the distribution curve of the hydrophilic polymer content in polyvinylpyrrolidone, In addition, it would be technically impossible to assume that there would be two discontinuous layers with different material behavior.
- the content of polypyrrolidone in the outermost layer is 20 to 40% by mass and that in the layer near the surface is 5 to 20% by mass as an optimum range.
- a design in which the outermost layer is 40% by mass and the near-surface layer is 5% by mass works sufficiently in function. It may not be.
- the difference in the polypyrrolidone content of the two layers is about 135% by mass so that the ratio of the polyvinylpyrrolidone content in the outermost layer to the polyvinylpyrrolidone content in the layer near the surface is 1.1 or more.
- the content By optimally designing the content to be about 5 to 25% by mass, the diffusion transfer of polyvinylpyrrolidone from the layer near the surface to the outermost layer can be performed smoothly.
- the outermost layer is 32% by mass
- the layer near the surface is in the range of about 7 to 27% by mass, which satisfies the requirement of about 1.1 to 10 times.
- the content of the above-mentioned polybutylpyrrolidone in the outermost layer of the permselective separation membrane was measured and calculated by the ESCA method as described later, and was determined in the outermost layer of the permselective separation membrane (depth from the surface layer). It is the absolute value of the content in number A—several tens A).
- the ESCA method can measure the content of polybutylpyrrolidone up to about 10 nm (100 A) below the surface.
- the content of polybutylpyrrolidone in the near-surface layer was measured by surface infrared spectroscopy (ATR method).
- the ATR method (layer near the surface) can measure the content of polybutylpyrrolidone up to a depth of about 1000 to 1500 nm (l-1.5 ⁇ m) from the surface.
- the content of polyvinylpyrrolidone on the blood contact side surface and the opposite side surface may be related to the molecular weight of polybutylpyrrolidone.
- polyvinylpyrrolidone having a low molecular weight of about 450,000 compared to the case of using polyvinylpyrrolidone having a high molecular weight of about 1.2 million
- solubility and elution amount of polybulpyrrolidone in coagulation are increased. , Diffusion movement becomes large.
- the ratio of polybutylpyrrolidone to polysulfone-based polymer is 11 to 20% by mass, and the outermost layer portion is 20 to 40% by mass and the surface vicinity portion is 5 to 20% by mass.
- Polyvinylpyrrolidone content tends to be produced.
- Methods for achieving the above requirements 5, 9, 10 and 11 in the present invention include, for example, setting the composition ratio of polybutylpyrrolidone to the polysulfone-based polymer to the above-mentioned range, and selectively permeating and separating. This can be achieved by optimizing the film forming conditions.
- the dense layer formed on the inner surface side of the permselective separation membrane preferably has a two-layer structure having a density difference between the outermost layer portion and the portion near the surface. That is, although the detailed reason is not sufficient, the content of the polysulfone-based polymer and polybutylpyrrolidone in the membrane forming solution and the concentration and temperature of the internal solution are set in the ranges described below, so that the hollow fiber membrane is formed. Differences occur in the solidification rate and Z or phase separation rate between the outermost layer on the inner surface and the vicinity of the surface, and differences in the solubility of the polysulfone polymer and polyvinylpyrrolidone in the solvent Z water express the characteristics described above. Do not do it.
- the porosity of the surface on the blood non-contact side of the permselective separation membrane is 25 to 35% (Requirement 12). 27-33% is more preferred. If the porosity is too small, when the permselective separation membrane is used as a hollow fiber membrane, sticking between the hollow fiber membranes in the hollow fiber membrane may easily occur. If the porosity is too large, the porosity of the permselective separation membrane will increase, making it difficult to obtain the expected burst pressure, and it may not be possible to control the leakage of albumin, a useful protein, etc.
- the method for setting the porosity in the above range is not limited !, but examples thereof include a method carried out according to the method described in Patent Document 6.
- the membrane strength may be reduced, which may lead to problems such as blood leak. Therefore, when the burst pressure of the permselective separation membrane is 0.5 MPa or more, the preferred embodiment (Requirement 13) of the present invention cannot be satisfied.
- the burst pressure of the perm-selective separation membrane is an index relating to the pressure resistance of the perm-selective separation membrane after forming a module using the perm-selective separation membrane formed of a hollow fiber membrane.
- the burst pressure is the pressure at which the inside of the hollow fiber membrane is pressurized with gas and the pressure is gradually increased, and the hollow fiber membrane bursts without being able to withstand the internal pressure.
- the higher the burst pressure the less the cutting of the hollow fiber membrane and the occurrence of pinholes during use are reduced, so 0.5 MPa or more is preferred 0.5 MPa or more is more preferred 0.6 MPa or more is more preferred .
- the burst pressure is less than 0.5MPa, it may have a potential defect. The higher the burst pressure, the better. However, if the focus is on increasing the burst pressure and the film thickness is too large or the porosity is too low, the desired film performance may not be obtained.
- the burst pressure is preferably less than 2. OMPa. More preferably, it is less than 1.7 MPa, even more preferably less than 1.5 MPa, even more preferably less than 1.3 MPa, particularly preferably less than 1. OMPa.
- the above characteristics are blood leak characteristics governed by macro characteristics such as conventionally known membrane strength. It has been found based on the knowledge that the safety of hollow fiber membranes in long-term dialysis cannot be sufficiently proved. That is, as a result of examining the physical properties of a hollow fiber type permselective separation membrane (hereinafter, simply referred to as a hollow fiber membrane) used for a blood purifier, a hollow fiber membrane used for blood purification is usually At the final stage of product production, a leak test is performed in which the inside or outside of the hollow fiber membrane is pressurized with air to check for defects in the hollow fiber membrane or blood purifier. When a leak is detected by pressurized air, the blood purifier is discarded as defective and repaired.
- macro characteristics such as conventionally known membrane strength.
- the air pressure in this leak test is often several times the guaranteed pressure of the blood purifier (normally 500 mmHg).
- the guaranteed pressure of the blood purifier normally 500 mmHg.
- minute scratches, crushing, cracks, etc. of the hollow fiber membrane which cannot be detected by a normal pressure leak test, occur after the leak test.
- this leads to the cutting of hollow fibers and the generation of pinholes.
- the present inventors have found that this is a cause of troubles such as cracks.
- the above embodiment of the present invention is based on the finding that the safety of a hollow fiber membrane cannot be sufficiently ensured with conventionally known macroscopic properties such as membrane strength. That is, in the hollow fiber membrane of the present invention, the thickness and the skin layer are made extremely thin in order to improve the permeability of a substance having a molecular weight of about 30,000 represented by a1 microglobulin. If so, the potential defects of the hollow fiber membrane (pinholes, scratches, etc.) may become apparent, especially during clinical use. In the present invention, in order to ensure safety, it is extremely important to eliminate the above-mentioned potential defects in addition to macro characteristics.
- the membrane is formed of a hollow fiber membrane having a burst pressure of 0.5 MPa or more, and has a water permeability of 150 mlZm 2 ZhrZmmHg. It is preferable that it is above. If the permeability is too low, the dialysis efficiency May drop. To increase the dialysis efficiency, 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 defects. Therefore, it is preferable that the porosity of the support layer portion be optimized by optimizing the pore diameter of the outer surface, and the solute permeation resistance and the membrane strength be balanced.
- a more preferable range of the water permeability is 200 mlZm 2 ZhrZmmHg or more, further preferably 250 mlZm 2 ZhrZmmHg or more, particularly preferably 300 mlZm 2 ZhrZmmHg or more. Further, if the coefficient of water permeability is too high, it becomes difficult to have water removal control during hemodialysis, or less preferably 2000mlZ m 2 ZhrZmmHg.
- the method of setting the burst pressure to 0.5 MPa or more is not limited, but it is also important and preferable to reduce the thickness deviation of the hollow fiber membrane, which is an embodiment (Requirement 14).
- the thickness unevenness in the present invention refers to the thickness deviation when observing a cross section of 100 hollow fiber membranes in a blood purifier, and is indicated by a ratio between a maximum value and a minimum value.
- the minimum thickness deviation of the 100 hollow fiber membranes is preferably 0.6 or more. If any one of the 100 hollow fiber membranes contains a hollow fiber membrane with a thickness deviation of less than 0.6, the hollow fiber membrane may cause a leak during clinical use.
- the thickness unevenness of the present invention represents a minimum value of 100 pieces, which is equal to the average value.
- the average pore area of the pores on the outer surface of the hollow fiber membrane is 0.3-1. This is also an effective and preferable embodiment for increasing the burst pressure.
- the average pore area is more preferably 0.4 to 0.9 m 2 . If the average pore area is too small, the pore diameter of the whole membrane becomes small, so that the water permeability and solute permeability may decrease. Further, when the membrane is dried, there is a possibility that a hydrophilic polymer existing on the outer surface of the membrane is interposed and the hollow fiber membranes are fixed to each other, thereby causing a problem such as poor module assembly. Conversely, if the average pore area is too large, the pore diameter ⁇ the porosity of the hollow fiber membrane becomes too large, and the burst pressure becomes low. It may go down.
- the method for imparting the above characteristics is not limited.
- the ratio between the maximum value and the minimum value of the nozzle slit width of the tube in orifice type nozzle is 1.00 or more and 1.11 or more. It is preferable to make the following.
- the spinning nozzle for the hollow fiber membrane generally, a tube-in-orifice type nozzle having an annular portion for discharging a film forming solution and a core liquid discharge hole inside the annular portion for forming an internal liquid is used.
- the nozzle slit width refers to the width of the outer annular portion from which the film forming solution is discharged.
- the ratio between the maximum value and the minimum value of the slit width is 1.00 or more and 1.11 or less, and the difference between the maximum value and the minimum value is 10 m or less, more preferably 7 ⁇ m or less. Is more preferably 5 m or less, particularly preferably 3 ⁇ m or less. This method makes it possible to set the thickness unevenness within a preferable range.
- the membrane forming solution is preferably filtered with a filter having a filtration accuracy of 25 ⁇ m or less.
- a filter having a filtration accuracy of 20 m or less is more preferable, and a filter of 15 m or less is more preferable.
- the filtration treatment may be performed at least once, but the filtration treatment is divided into several stages, and the pore size of the filter is reduced in the later stages, which is preferable in order to increase the filtration efficiency and the filter life.
- the filtration accuracy of the filter is measured according to JIS B8356: 1976, and the maximum particle size of the glass beads transmitted through the filter media is defined as the filtration accuracy ( ⁇ m).
- the material and structure of the filter are not limited as long as the above filtering accuracy is satisfied.
- wire mesh filters are generally used in many cases, and depending on the shape of the plain weave, twill weave, plain tatami weave, twill tatami weave, etc. The miniaturization efficiency will change.
- a metal sintered filter Apart from these wire mesh filters, there is a type called a metal sintered filter. There are roughly two types: a powder sintered type, and a type of non-woven fabric which is hardened without weaving metal.
- non-woven fabrics that have been hardened without weaving metal are made by uniformly laminating and sintering micron-order stainless steel fibers, and a myriad of contacts between fibers are joined and integrated by metal members.
- '' It has high filtration accuracy with few falling This is preferable because it has a higher foreign matter holding ability than a wire mesh / sintered metal powder filter in which the pressure loss is small due to the effect of a higher porosity than a metal filter material.
- Wire mesh filters are not excluded at all, and some of them can achieve the same or better performance by improving the weaving method and lamination method. The point of selection is to select a filter with low pressure loss and high filtration capacity.
- the uniformity of the phase separation between the polysulfone-based polymer and the polybulpyrrolidone in the permselective separation membrane can be improved, not only the contamination due to the filtration effect is suppressed.
- the uniformity of phase separation in the membrane is determined by microscopic observation of the outer surface of the hollow fiber membrane shown below.
- the uniformity of the phase separation can be evaluated using a real surface view microscope VE-7800 (manufactured by Keyence Corporation). Hollow fiber membranes are arranged on the sample table at a pitch of 3 mm, fixed with double-sided tape, and the total length of lm is checked while scanning for the presence or absence of foreign matter at a magnification of 200 times. To check for voids, cut the hollow fiber membrane obliquely with a razor, fix it on a sample table with double-sided tape so that the cut surface faces upward, and observe 30 visual fields at a magnification of 300 times. Can be done.
- the uniformity of phase separation is improved by the above method because the poorly dispersed portion of polybulpyrrolidone present in the film forming solution passes through the filter when the film forming solution is filtered by the specified filter. It is presumed that it is based on the effect of dispersing by the effect and the effect of removing the poor dispersion part.
- the uniformity of phase separation between the polysulfone-based polymer and polybulpyrrolidone in the membrane constituting the permselective separation membrane can be improved.
- the formation of a defective portion where the film strength is reduced due to non-uniform phase separation in the film is suppressed, which leads to the improvement of the burst pressure.
- the nozzle temperature is preferably 20-90 ° C. If the nozzle temperature is low, it is easily affected by the room temperature, the nozzle temperature becomes unstable, and the discharge of the film forming solution may occur. Therefore, the nozzle temperature is more preferably 30 ° C. or higher, further preferably 35 ° C. or higher, and still more preferably 40 ° C. or higher. If the nozzle temperature is high, The viscosity of the film-forming solution may be too low and the ejection may not be stable, and the thermal degradation and decomposition of polybutylpyrrolidone may proceed. Therefore, the nozzle temperature is more preferably at most 85 ° C, even more preferably at most 80 ° C.
- the viscosity of the film forming solution is 2000 to 6000 cps. 3 000—5000 cps is more preferred.
- the stirring efficiency of the solution is improved, so that the effects such as the uniformity of the phase separation, the reduction of the discharge unevenness from the nozzle, and the ease of the defoaming are exhibited, and the burst pressure is improved. Leads to.
- Methods to reduce the occurrence of scratches include optimizing the materials and surface roughness of the rollers and guides in the hollow fiber membrane manufacturing process, as well as inserting the hollow fiber membrane into the module container when inserting the hollow fiber membrane into the module container when assembling the module. It is effective to take measures to reduce contact between the hollow fibers and the hollow fiber membranes.
- a roller having a mirror-finished surface in order to prevent the surface of the hollow fiber membrane from being damaged due to slipping of the hollow fiber membrane.
- a guide having a matte finish or a knurled guide in order to minimize contact resistance with the hollow fiber membrane.
- a film in which the contact surface with the hollow fiber membrane is embossed is wound around the hollow fiber membrane. It is preferable to use a method in which the module container is inserted into the module container, and after the film is inserted, the module container force is removed only from the film.
- the degree of decompression is too high, it may be necessary to increase the number of times of defoaming, so that the treatment may take a long time. If the degree of pressure reduction is too low, the cost for increasing the degree of sealing of the system may increase. Total processing The time is preferably 5 minutes to 5 hours. If the treatment time is too long, polyvinylpyrrolidone may decompose and deteriorate due to the effect of reduced pressure. If the treatment time is too short, the defoaming effect may be insufficient.
- the permselective separation membrane is divided into 10 pieces in the longitudinal direction, and the elution power of hydrogen peroxide when measured for each is preferably 5 ppm or less at all sites.
- Mode (Requirement 15) the elution power of hydrogen peroxide when measured for each is preferably 5 ppm or less at all sites.
- the amount of eluate from the permselective separation membrane is determined by the dialysis-type artificial kidney device manufacturing approval standard.
- the amount of eluate from the membrane is determined by UV absorbance.
- the present inventors have studied the elution behavior from the membrane in detail, and as a result, the selective permeable separation membrane mainly composed of a polysulfone-based polymer and polyvinylpyrrolidone has been determined based on the above-mentioned dialysis-type artificial kidney device manufacturing approval standard. It has been found that the extract extracted by the test method contains hydrogen peroxide, which cannot be measured by a conventionally known UV absorbance.
- the hydrogen peroxide which the present inventors have noticed even when this is present only in a specific part of the hollow fiber membrane, the degradation reaction of the hollow fiber membrane material is started from that point and the hollow fiber membrane Is propagated throughout. Therefore, it is important that the content of hydrogen peroxide in the length direction of the hollow fiber membrane used is maintained at a certain level or less over the entire region.
- the amount of hydrogen peroxide eluted from the hollow fiber membrane is preferably 5 ppm or less. 4 ppm or less is more preferred 3 ppm or less is even more preferred.
- the amount of the hydrogen peroxide eluted is too large, the storage stability is deteriorated as described above due to the deterioration of the hydrogen peroxide and the like, for example, when polyvinylpyrrolidone is stored for a long period of time. Dissolution The output may increase.
- the increase in the amount of polyvinylpyrrolidone eluted is the most remarkable phenomenon, but other factors include deterioration of the polysulfone-based polymer causing brittleness of the hollow fiber membrane and polyurethane-based adhesive used for module assembly. It also means that the deterioration of the agent is accelerated, the amount of the degraded product eluted increases, and the safety decreases.
- the amount of hydrogen peroxide eluted in the present invention is quantified using an extract extracted by a method according to the elution test method of the dialysis type artificial kidney device manufacturing approval standard. That is, the hollow fiber membrane is arbitrarily taken out from the hollow fiber membrane, and 1.Og is weighed in a dry state, 100 ml of RO water is added thereto, and the mixture is extracted at 70 ° C. for 1 hour. Obtain a liquid.
- the amount of hydrogen peroxide in polyvinylpyrrolidone used as a raw material is set to 300 ppm or less. This is an effective method.
- hydrogen peroxide is also produced during the production process of the hollow fiber membrane as described above, so it is important to strictly control the production conditions of the hollow fiber membrane.
- the optimization of the drying conditions can be an effective means particularly for reducing the fluctuation of the elution amount of the hollow fiber membrane in the longitudinal direction.
- the film-forming solution As another method for suppressing the generation of hydrogen peroxide, it is important to dissolve the film-forming solution in a short time when dissolving the film-forming solution. To that end, it is usually effective to increase the dissolution temperature and increase the Z or stirring speed. While doing so, the degradation, decomposition of polyvinylpyrrolidone tends to proceed due to the effects of temperature, stirring linear velocity, and shearing force.
- the molecular weight of polybutylpyrrolidone in the film-forming solution is such that as the dissolution temperature rises, the peak top of the molecular weight moves toward the decomposition direction (shifts to the lower molecular side) or decreases.
- the present inventors have tried to mix the raw materials at a low temperature in order to suppress the decomposition of polyvinylpyrrolidone.
- the temperature is preferably 5 ° C or more and 70 ° C or less. 60 ° C or less is preferable.
- simply lowering the dissolution temperature will lead to degradation and degradation of polybutylpyrrolidone due to prolonged dissolution time, decrease in operability, and increase in equipment size, which is problematic for industrial implementation. .
- the present inventors have studied the dissolution conditions for dissolving at low temperature without taking time, and found that it is preferable to dissolve the components constituting the spinning solution after kneading them before dissolution. Reached the present invention.
- constituent components such as a polysulfone-based polymer, polyvinylpyrrolidone, and a solvent may be kneaded at a time, or polybutylpyrrolidone and a polysulfone-based polymer may be separately kneaded.
- the degradation of polybutylpyrrolidone is accelerated by contact with oxygen, generating hydrogen peroxide.
- kneading it is important to suppress contact with oxygen, for example, in an atmosphere replaced with an inert gas, and it is preferable to perform the kneading in a separate line.
- a method in which kneading is performed using only polyvinylpyrrolidone and a solvent and the polysulfone-based polymer is directly supplied to the dissolving tank without preliminary kneading is also included in the scope of the present invention.
- Kneading may be performed by providing a kneading line separately from the dissolving tank, and then the kneaded product may be supplied to the dissolving tank! Both the kneading and the dissolving are performed in a dissolving tank having a kneading function. You can.
- the type and the type of the kneading device when the former is performed by a separate device are not limited. Either a batch type or a continuous type may be used. It may be a static method such as a static mixer or a dynamic method such as an eder or a stirring kneader. The latter is preferable for the kneading efficiency.
- the kneading method may be any type such as a pin type, a screw type, and a stirrer type, which are not limited. Screw type is preferred. The shape and rotation speed of the screw may be appropriately selected from the balance between kneading efficiency and heat generation.
- the type of the dissolving tank when using a dissolving tank having a kneading function is not limited.For example, there is a kneading dissolver of a type in which a kneading effect is exhibited by a so-called planetary motion in which two frame-type blades rotate and revolve. Recommended. For example, planetary mixers and trimixes manufactured by Inoue Manufacturing Co., Ltd. correspond to this method.
- the ratio of the resin component such as polyvinylpyrrolidone or polysulfone-based polymer to the solvent during kneading is not limited. 0.1-3 is preferable as the mass ratio of the resin Z solvent. 0.5—2 is more preferred.
- the technical point of the present invention is to suppress the deterioration of polyvinylpyrrolidone and perform efficient dissolution. Therefore, it is a preferred embodiment that the system in which at least polybutylpyrrolidone is present is kneaded and dissolved at a low temperature of 70 ° C. or lower under a nitrogen atmosphere.
- the above method may be applied to a kneading line for the polysulfone polymer.
- the efficiency of kneading and dissolving and the generation of heat are two trade-offs. The selection of a device and conditions that avoid the trade-off as much as possible is an important element of the present invention. In that sense, the cooling method in the kneading mechanism is important and needs to be considered.
- the dissolution method is not limited, but, for example, a dissolution method using a stirring-type dissolution apparatus can be applied.
- Is preferably 0.7 or more and 1.3 or less
- ⁇ is the blade rotation speed (rps)
- p density (Kg / m 3 )
- Pa 's viscosity
- d stirring blade diameter (m).
- the Froude number is more preferably 1.25 or less, further preferably 1.2 or less, and still more preferably 1.15 or less.
- the Froude number is too small, the dispersibility of the raw material is reduced due to weakening of the inertia force, and in particular, polybutylpyrrolidone becomes lumpy, which makes it difficult to dissolve it further, and it is difficult to dissolve it evenly. It may take time. Therefore, the number of flows is more preferably 0.75 or more, and further preferably 0.8 or more.
- the stirring Reynolds number is large. If it is too much, problems such as prolonged defoaming time or insufficient defoaming due to entrapment of air bubbles in the film forming solution may occur during stirring. Therefore, the stirring Reynolds number is more preferably 240 or less, further preferably 230 or less, and still more preferably 220 or less. On the other hand, if the stirring Reynolds number is too small, nonuniform dissolution may easily occur because the stirring power is small. Therefore, the stirring Reynolds number is more preferably 35 or more, more preferably 40 or more, still more preferably 55 or more, and still more preferably 60 or more.
- a hollow fiber membrane is formed with such a spinning solution
- spinnability is reduced by air bubbles and operability is reduced, and in terms of quality, air bubbles are impregnated into the hollow fiber membrane by the penetration of air bubbles into the hollow fiber membrane. It turned out to be a defect, causing problems such as a decrease in the airtightness and burst pressure of the film.
- Defoaming the spinning solution is an effective countermeasure, but careful control is required when performing defoaming because the spinning solution viscosity may be controlled and the composition of the spinning solution may change due to evaporation of the solvent. It becomes.
- polybutylpyrrolidone since polybutylpyrrolidone has a tendency to undergo oxidative decomposition under the influence of oxygen in the air, it is preferable to dissolve the spinning solution in an inert gas atmosphere.
- the inert gas include nitrogen and argon, and it is preferable to use nitrogen.
- the residual oxygen concentration in the dissolution tank is preferably 3% or less.
- the dissolution time can be shortened by increasing the nitrogen filling pressure, but the inert gas filling pressure is preferably at least atmospheric pressure and no more than 2 kgfZcm2 from the viewpoint of increasing equipment costs for forming a high pressure and work safety. No.
- the stirring blade that can be used in the present invention is a stirring blade having a shape used for dissolving a low-viscosity film forming solution, and includes a disk turbine type, a paddle type, a curved blade fan turbine type, and an arrow blade bin.
- Forces include axial flow type blades such as a radial flow type blade such as a die, a propeller type, an inclined paddle type, and a Faudler type.
- the present invention is not particularly limited to these.
- the low-temperature dissolution method as described above, it is possible to obtain a highly safe hollow fiber membrane in which the degradation and degradation of the hydrophilic polymer is suppressed.
- a spinning solution having a residence time of less than 24 hours after dissolving the raw materials for film formation. This is because thermal energy was accumulated while the film-forming solution was kept warm, and there was a tendency for raw material degradation to occur.
- the hollow fiber membrane is not completely dried. Absolute drying is not preferable because the degradation of polyvinylpyrrolidone is promoted and the production of hydrogen peroxide is greatly increased.
- the moisture content of the dried hollow fiber membrane is preferably 0.5% by mass or more, more preferably 0.7% by mass or more, and even more preferably 1.0% by mass or more.
- polyvinylpyrrolidone is substantially non-crosslinked as described above.
- sterilization treatment by gamma irradiation is performed, and the irradiation tends to crosslink polybulpyrrolidone.
- the crosslinking reaction of polypyrrolidone is affected by the water content of the hollow fiber membrane. If the water content exceeds 10% by mass, the crosslinking reaction becomes remarkable. Therefore, the water content is preferably 10% by mass or less. Less than 7% by weight is more preferred Less than 4% by weight is even more preferred.
- the hollow fiber membrane bundle is over-dried at the air inlet, and the decomposition of the hollow fiber membrane bundle material progresses, and as a result, the inlet portion is made of the constituent material of the hollow fiber membrane bundle, particularly, It was speculated that this was caused by an increase in the deterioration of polybutylpyrrolidone.
- the present inventors aimed to prevent partial overdrying of the hollow fiber membrane bundle and to dry the hollow fiber membrane evenly, and to change the air direction during drying at regular intervals (for example, every hour or every 30 minutes).
- the hollow fiber membrane bundle was dried while being inverted by 180 degrees.
- the temperature inside the dryer and the temperature of the drying air are set to By lowering the temperature to 40 ° C., the hollow fiber membrane bundle of the present invention could be obtained.
- the air volume and the air velocity in the dryer may be adjusted according to the amount of the hollow fiber membrane bundle and the total water content. Usually, the air volume is about 0.01 to 5 LZsec (one hollow fiber membrane bundle). Is enough. It is preferable to use an inert gas as the ventilation medium, but it is preferable to use dehumidified air when using ordinary air.
- the drying temperature may be 20-80 ° C, but if the temperature is increased, the damage of the hollow fiber membrane bundle will be increased, and the drying tends to be partially unbalanced. It is preferable that For example, in the state of a water content of 200 to 1000 mass%, force drying that can be dried at a relatively high temperature of 60 to 80 ° C progresses, for example, when the water content falls to about 150% by mass, It is preferable to dry at a relatively low temperature in the range of room temperature to a maximum of about 60 ° C.
- the “water content” of the hollow fiber membrane bundle here means the water content at several points, such as the central part, middle part, and outer peripheral part, of the hollow fiber membrane bundle as the basis for calculation, and This is the "average moisture content” obtained by calculating the average value of the moisture content.
- the total water content of the hollow fiber membrane bundle can be used as a basis for the calculation, but there is a disadvantage that the accuracy is reduced. Since the difference in water content at the center, middle, and outer periphery of the hollow fiber membrane bundle is small, it is an embodiment for producing a product with good quality.
- Technical considerations are given to the drying method used. For example, when using an inert gas such as nitrogen gas or argon gas as the ventilation medium, the drying is performed in a substantially oxygen-free state. It is possible.
- the air volume and the drying temperature can be determined according to the total amount of water contained in the hollow fiber membrane bundle. If the water content is high, increase the air volume relatively. For example, 0.1-5 LZsec (1 hollow fiber membrane bundle) And the temperature can be set relatively high, eg, 50-80 ° C. As drying progresses and the water content of the hollow fiber membrane bundle decreases, the air volume is adjusted to gradually decrease to, for example, 0.1 LZsec (one hollow fiber membrane bundle) or less, while the temperature is also linked to it.
- One method of drying is to adopt a drying method that allows the temperature to gradually reach room temperature.
- the hollow fiber membrane bundle In order to reduce the difference in the water content of the central portion, the intermediate portion, and the outer peripheral portion of the hollow fiber membrane bundle, it may be effective to simultaneously and uniformly dry the respective portions.
- a method of alternately reversing the direction of air flow when air-drying the hollow fiber membrane bundle is used i.e., air is alternately blown from a direction in which the airflow direction of the hollow fiber membrane bundle in the air-drying is changed by 180 degrees.
- the method can be suitably adopted.
- the reversal of the blowing direction can also be achieved by devising the apparatus so that the hollow fiber membrane bundle itself, which is the content itself, is alternately reversed by 180 degrees with respect to the ventilation direction.
- blowing means is not particularly limited.
- a device that alternately turns the hollow fiber membrane bundle itself by 180 degrees alternately functions rationally not only in design but also in operation.
- This seemingly common method of inversion including drying is found in the drying of general-purpose materials in the embodiment of the present invention, particularly for quality control for preventing a bundle from partially sticking to a special material such as a hollow fiber membrane bundle. It has been found to have no unexpected effect.
- the alternate reversal time of ventilation in drying can be changed according to factors such as the total water content of the hollow fiber membrane bundle to be dried and the wind speed, air volume, drying temperature, and the degree of dehumidification of air.However, in order to achieve uniform drying, It is preferable that the air blowing direction is frequently reversed.
- the wind reversal time which is industrially set for practical use, also affects the water content after the start of drying. For example, dry at a high temperature of about 60-80 ° C (for example, 65 ° C) for 1-4 hours and at a temperature of 25-60 ° C (for example, about 30 ° C) for 120 hours, and reduce the total drying time to 24 hours. If set to about 30 minutes, the wind direction can be reversed mechanically at intervals of about 30-60 minutes.
- the total amount of water is large! During the initial drying stage! At a high temperature of, for example, about 60-80 ° C !, the air flow is relatively low, such as about 0.1-5LZsec (1 hollow fiber membrane bundle). When drying under a lot of conditions, the part that is directly hit by wind first dries relatively quickly, so it takes about 10-120 minutes. The reversal of the wind direction may be repeated for about 15 hours at intervals. In particular, in the first stage, it is preferable to reverse the wind direction at intervals of 10 to 40 minutes.
- the drying temperature is gradually brought closer to room temperature to about 30 ° C, and the reversal time is set to about 30 to 90 minutes, and the wind direction is reversed. Can be repeated. Switching of the air volume and the temperature at that time can be arbitrarily determined in consideration of the moisture content of the hollow fiber membrane bundle. More specifically, when the water content, which is based on the calculation of the water content at the center and the outer periphery of the hollow fiber membrane bundle, becomes 50-100% by mass or less, while observing the drying condition, The drying temperature and the reversal time can be appropriately changed.
- Drying can be performed by setting the wind direction reversal time mechanically at fixed time intervals. On the other hand, there are factors that rely on the situation judgment and empirical rules to determine the wind direction reversal time and total drying time while observing the degree of drying progress.
- the water content (% by mass) in the present invention is obtained by measuring the mass (a) of the hollow fiber membrane bundle before drying and the mass (b) of the hollow fiber membrane bundle after drying. ab) Zb X 100
- a method of drying by irradiating a microwave under reduced pressure is one of the effective means.
- the drying conditions of the drying method it is preferable to irradiate a 0.1 to 100 kW output of a microwave under a reduced pressure of 20 KPa or less. Further, it is preferable that the frequency of the microwave is 1,000 to 5,000 MHz and the maximum temperature of the hollow fiber membrane bundle during the drying treatment is 90 ° C. or less. Employment of decompression means that the drying of water is promoted by itself, so there is an advantage that the output of microphone mouth wave irradiation can be kept low and the irradiation time can be shortened. Since it can be kept small, the overall effect on the performance of the hollow fiber membrane bundle is small.
- drying with reduced pressure has the advantage that the drying temperature can be relatively lowered, and is particularly excellent in that the degradation and degradation of the hydrophilic polymer can be significantly suppressed.
- the drying temperature is preferably from 20 to 80 ° C, more preferably from 20 to 60 ° C, still more preferably from 20 to 50 ° C, and still more preferably from 30 to 40 ° C.
- decompression accompanies means that decompression acts uniformly on the central part and the outer peripheral part of the hollow fiber membrane bundle, the evaporation of water is promoted uniformly, and the hollow fiber membrane is dried uniformly. Therefore, it is possible to avoid the trouble of the hollow fiber membrane bundle caused by uneven drying.
- microwave the heating by the pressure acts almost equally on the entire center and the outer periphery of the hollow fiber membrane bundle, so that the uniform heating and the reduced pressure work synergistically, so that a specific effect can be obtained in drying the hollow fiber membrane bundle.
- the degree of decompression can be appropriately set according to the microwave output, the total water content of the hollow fiber membrane bundle, and the number of hollow fiber membrane bundles.
- the degree of reduced pressure is preferably 20 kPa or less, more preferably 15 kPa or less, and still more preferably 10 kPa or less. If the degree of decompression is high, the moisture evaporating efficiency decreases, and the temperature of the polymer forming the hollow fiber membrane bundle, which is loosened by force, may increase to cause deterioration.
- a low degree of pressure reduction is preferable in order to suppress the temperature rise and increase the drying efficiency, but it is preferable to use 0.1 lkPa or more because the cost for maintaining the airtightness of the apparatus increases. It is more preferably at least 0.25 kPa, even more preferably at least 0.4 kPa.
- the microwave output be high.
- the microwave output it is preferable that the microwave output be high.
- the degree of decompression and the microwave output can be determined as appropriate according to the water content of the hollow fiber membrane bundle and the number of hollow fiber membrane bundles to be processed.
- the microwave output is more preferably from 0.1 to 80 kW, and still more preferably from 0.1 to 60 kW.
- the output of the microwave is determined, for example, by the total number of hollow fiber membranes and the total water content.
- a high-output microwave is suddenly irradiated, drying may be completed in a short time, but the hollow fiber membrane may be partially denatured and deformed like shrinkage.
- the hollow fiber membrane contains a water retention agent or the like, drying at high power or using microwaves can cause loss of the water retention agent due to scattering. In the past, it has never been intended to irradiate microwaves under reduced pressure.
- the present invention microwave irradiation under reduced pressure Then, since the evaporation of the aqueous liquid becomes active even at a relatively low temperature, the damage of the hollow fiber membrane such as deterioration of the polypyrrolidone and deformation of the hollow fiber membrane due to high-power microwave and high temperature is prevented. The effect can be obtained.
- drying by microwave irradiation under reduced pressure is not limited to single-stage drying with a constant microwave output, but as another preferred embodiment, the microwave output is sequentially changed according to the progress of drying. Includes so-called multi-stage drying, which is stepwise lowered. Therefore
- the multistage drying will be described below.
- microwave drying When microwave drying is performed at a relatively low temperature of about 30 to 90 ° C under reduced pressure, the microwave output is gradually reduced in accordance with the progress of drying of the hollow fiber membrane bundle.
- Multi-stage drying methods can be an excellent method.
- the degree of decompression, temperature, microwave output and irradiation time should be determined in consideration of the total amount of the hollow fiber membrane to be dried, an appropriate industrially acceptable drying time, and the like.
- the multi-stage drying can be performed in any number of stages, for example, 2 to 6 stages, but the industrially appropriate number of stages is 2 to 4 in consideration of productivity.
- multi-stage drying is performed, for example, at a temperature of 90 ° C or less and under a reduced pressure of about 5 to 20 kPa.
- the second stage is in the range of 10-30 kW and the third stage is in the range of 0.1-10 kW, taking into account the microwave irradiation time. If the range of the microwave output is large, for example, 90 kW for the high stage and 0.1 kW for the low stage, the number of stages for reducing the output may be increased to, for example, 418 stages.
- the pressure reduction operation can be used in combination with microwave irradiation, it is advantageous in that drying can be performed even when the microwave output is relatively low.
- the first stage is about 10-100 minutes using a 10-20 kW microwave
- the second stage is about 5-10 minutes at about 3-10 kW
- the third step is about 1-160 kW at about 0.1-13 kW.
- This drying method is a very gentle drying method for the hollow fiber membrane bundle, and cannot be expected in the prior art of Patent Documents 17 to 19 described above.
- the total water content of the hollow fiber membrane bundle is relatively small! /, For example, when the water content is 400% by mass or less, irradiation with a low-output microwave of 12kW or less may be excellent.
- the total amount of water in the hollow fiber membrane bundle to be dried at a time is relatively small, about 17 kg, at a temperature of 80 ° C. or less, preferably 60 ° C.
- the microwave irradiation is stopped, and at the same time, the water pressure is reduced to 13 kPa to evaporate water. I can make it.
- the pressure reduction is returned to 3 lOkPa, and the microwave irradiation is resumed.
- the membrane bundle may be heated.
- microwave irradiation can be stopped and the pressure can be reduced to 0.5-1.5 kPa to evaporate water.
- the pressure can be raised again to 3-lOkPa, and microwaves of less than 0.1-0.5 kW can be applied for heating for about 1-240 minutes.
- drying can be performed uniformly by adjusting the irradiation output and irradiation time of the microwave according to the degree of drying.
- the degree of decompression can be set at 0.1 to 20 kPa for each stage, but the degree of decompression at each stage should be adjusted according to the situation in consideration of changes in the total water content and the water content of the hollow fiber membrane bundle. Can be set properly.
- the first stage which has a relatively high water content in the hollow fiber membrane, has a higher decompression (for example, 0.1 to 5 kPa) and a higher microwave output (for example, 10 to 30 kW).
- the eye may be irradiated with microwaves at a slightly higher pressure than the first stage (eg, 0.1-5 kW output under reduced pressure of 5-2 OkPa).
- the operation of changing the degree of decompression in each stage can further make the feature of the present invention that microwaves are irradiated under reduced pressure more significant.
- a combination of a drying method of irradiating microwaves under reduced pressure and a drying method of alternately reversing the direction of ventilation is also effective for the present invention, although the steps are complicated. It is.
- the microwave irradiation method and the alternate ventilation reverse method each have advantages and disadvantages, and when high quality is required, these can be used in combination.
- a ventilation alternate reversal method is adopted, and when the average moisture content advances to about 20-60% by mass, it is possible to dry by applying microwaves under reduced pressure in the next stage. .
- a drying method of alternately reversing the direction of ventilation after drying by irradiating microwaves may be used in combination.
- the method of combined use is a hollow fiber membrane product obtained by drying.
- the quality can be determined in consideration of the quality, particularly, the quality of the polysulfone-based selectively permeable hollow fiber membrane bundle having no partial fixation in the longitudinal direction of the hollow fiber membrane.
- these drying methods can be performed simultaneously, they are not practical because of disadvantages such as complexity and complexity of the apparatus and soaring prices.
- an effective heating method such as far infrared rays may be used in combination.
- the maximum temperature of the hollow fiber membrane bundle during drying can be checked by attaching an irreversible thermolabel to the side of the film that protects the hollow fiber membrane bundle, drying it, removing it after drying, and checking the display. Can be measured by At this time, the maximum temperature of the hollow fiber membrane bundle during drying is preferably 90 ° C or less, more preferably 80 ° C or less. More preferably, it is 70 ° C or less. If the maximum temperature is high, the film structure is liable to change, which may cause a decrease in performance or deterioration due to oxidation.
- the drying temperature is preferably lower, it is preferably 30 ° C. or higher from the viewpoint of the cost of maintaining the degree of reduced pressure and shortening the drying time.
- the irradiation frequency of the microwave is preferably 1,000 to 5, OOOMHz 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, OOOMHz, even more preferably, 2,000-3, OOOMHz.
- the film forming solution a polymer and a solvent, and if necessary, non-solvent components are used. .
- the hollow inner solution it is preferable to use a mixed solution containing the same solvent and water as used in the film-forming solution.However, a non-solvent is appropriately added to obtain the desired membrane performance and membrane characteristics. You may.
- the polysulfone-based polymer not only polysulfone and polyether sulfone, but also a mixture of two or more of these polymers can be used.
- the solvent it is preferable to use a solvent capable of dissolving both the polysulfone-based polymer and polybutylpyrrolidone.
- the non-solvent refers to a non-solvent which can be mixed with the solvent at an arbitrary ratio to some extent but has no ability to dissolve the polysulfone-based polymer.
- water, ethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, 1,3-butylene glycol, glycerin, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and the like are preferable. Water, triethylene glycol, and polyethylene glycol are more preferable in terms of work safety, availability, and cost.
- the film-forming solution is discharged from a tube-in-orifice-type double tube nozzle heated to a room temperature of 130 ° C, and a film is formed by a so-called dry-wet spinning method.
- the film-forming solution and the hollow inner solution for coagulating the film-forming solution are simultaneously extruded into the air, pass through the air that is shielded from the outside air, and then guided to the coagulation bath provided immediately below the nozzle, where the microphase A film is formed by the separation.
- excess solvent “non-solvent” polyvinylpyrrolidone is removed from the membrane.
- the width of the film forming solution discharge hole of the nozzle is preferably 100 ⁇ m or less as described above. It is more preferably at most 80 m, further preferably at most 60 m. It is preferable that the discharge hole width is small because the film thickness can be reduced. However, if the discharge hole width is too small, nozzle clogging is likely to occur, or a problem may occur when cleaning becomes difficult. Therefore, the discharge hole width is preferably 30 m or more, more preferably 20 m or more.
- the L / D value which is the ratio between the discharge outer diameter (D) and the land length (L), is preferably 2-6. By taking such measures, the orientation of polyvinylpyrrolidone on the inner surface of the hollow fiber membrane can be in a preferable range.
- the film forming conditions include optimization of the stretching conditions, the temperature of the coagulation bath, the composition ratio of the solvent and the non-solvent in the coagulation solution, and the cleaning methods include hot water cleaning, alcohol cleaning, and centrifugal cleaning. Etc. are effective.
- the stretching is not substantially performed before the hollow fiber membrane structure is completely fixed.
- Substantially no stretching means that the film-forming solution discharged from the nozzle does not excessively loosen or tension, for example, by controlling the roller speed during the spinning process. .
- Discharge linear velocity The ratio (draft ratio) of the first opening speed of the first coagulation bath per one liter (draft ratio) is preferably 0.7 to 2.0. If the draft ratio is low, the running hollow fiber membrane may be slackened, which may lead to a decrease in productivity. Therefore, the draft ratio is more preferably 0.8 or more, and 0.9 or more is even more preferable 0.95. The above is even more preferred.
- the draft ratio is more preferably 1.9 or less, and still more preferably 1.8 or less.
- the draft ratio is more preferably 1.9 or less, and still more preferably 1.8 or less.
- the hollow fiber membranes that have passed through the washing bath are entirely wound up in a wet state to form a bundle of 3,000 to 20,000.
- the obtained hollow fiber membrane is washed to remove the excess solvent, polyvinylpyrrolidone.
- the method for cleaning the hollow fiber membrane includes hot water at 70 to 130 ° C.
- the hollow fiber membrane is preferably immersed in an aqueous solution of 10-40 vol% ethanol or isopropanol at room temperature and 50 ° C. for treatment.
- the cleaning method may be performed in combination of two or more.
- the processing temperature is too low, it is necessary to increase the number of times of cleaning and the like, which may lead to an increase in cost.
- the treatment temperature is too high, the decomposition of polyvinylpyrrolidone is accelerated, and conversely, the washing efficiency may decrease.
- the content of polyvinylpyrrolidone on the outer surface is optimized, and it is possible to suppress the fixation and reduce the amount of eluted substances.
- the hollow fiber membrane when the hollow fiber membrane is stored in a dry state, it is preferable to store the hollow fiber membrane at a temperature of 20 ° C.
- an aluminum foil that can substantially block oxygen gas and water vapor is a constituent layer
- an outer layer is a polyester film
- an intermediate layer is an aluminum foil
- an inner layer is a polyethylene film.
- the moisture content of the hollow fiber membrane is less than 1% by mass, store it in a state where the relative humidity at room temperature of the atmosphere in the packaging bag is 50% RH or more, or use a water release type oxygen scavenger. Preferably packed.
- the hollow fiber membrane bundle in the case of sterilization by ⁇ -ray or electron beam irradiation, in order to suppress the crosslinking reaction of polyvinylpyrrolidone, it is preferable to sterilize the hollow fiber membrane bundle in a dry state.
- the permselective separation membrane and the blood purifier of the present invention can positively remove other low-molecular-weight proteins while minimizing leakage of albumin, which is a useful protein. It is preferable that the amount of albumin leaked from the permselective separation membrane used in the blood purifier is 3 gZ3L or less. On the other hand, the clearance of ⁇ 1 microglobulin is preferably 15 mlZm 2 or more. a 1 If the removal rate of microglobulin is reduced, the effect of preventing dialysis complications and the improvement of clinical symptoms such as itching and pain may not be obtained.
- a means for increasing the permeability of 1 microglobulin and a means for adsorbing 1 microglobulin on the surface of the permselective separation membrane are added, and a total of both means is added. Achieving a high removal rate as one of the effects of this is one of the points that broke the above trade-off phenomenon.
- the permselective separation membrane of the present invention also satisfies the following many properties that should be provided when used for a blood purifier.
- the selectively permeable separation membrane of the present invention has an extremely high quality for a blood purifier, and can be suitably applied to a blood purifier.
- Solution B 20.42 g of KH PO and 126.30 g of NaC were dissolved in 3 L of pure water.
- Solution A was added with solution B, and the pH was adjusted to 7.5 ⁇ 0.1.
- 30 g of bovine plasma albumin (manufactured by Wako Pure Chemical Industries) was dissolved in 3 L of this phosphate buffer. After dissolution, the pH was adjusted to 7.5 ⁇ 0.1 again using IN-NaOH.
- Pure water was passed through the dialysate flow path of the module at 500 mLZmin for 5 minutes, and then passed through the blood flow path at 200 mLZmin for 5 minutes.
- the above phosphate buffer solution was passed through the dialysate side flow path of the module at 500 mLZmin for 5 minutes, and then passed through the blood side flow path at 200 mLZmin for 5 minutes. Thereafter, the solution was passed for 3 minutes while filtering from the blood side to the dialysate side.
- the circuit was connected to the blood side, and the priming solution (phosphate buffer) on the dialysate side was discarded. Place the module in a 37 ° C constant temperature bath, seal the dialysate side, and set the blood side at 200 mL Zmin. The solution was passed for 1 minute to remove the priming solution remaining on the blood side.
- a circuit was connected to the dialysate inlet, the flow rate on the blood side was set to 200 mLZmin, the flow rate of the filtration circuit connected to the dialysate inlet was set to 30 mLZmin, and both the blood-side permeate and filtrate were returned to the test solution. The test was carried out.
- the test solution, the blood-side permeate, and the filtrate were collected 15 minutes after the start of circulation.
- the collected sample was diluted 10-fold with pure water (the filtrate was preferably not diluted), and the absorbance was measured with a spectroscope at a wavelength of 280 nm.
- the sieving coefficient of albumin was calculated from the respective absorbances using the following equation.
- Cf is the absorbance of the filtrate
- Cb is the absorbance of the test solution
- Co is the absorbance of the blood-side permeate. If diluted, multiply by the respective dilution factor.
- both ends were sealed with urethane resin, and the measurement was performed using a hollow fiber membrane module in which the hollow portions were opened at both ends by cutting.
- the sample may or may not be gamma sterilized.
- Solution A Na HPO ⁇ 12 ⁇ 053.72 g and NaC126.30 g were dissolved in 3 L of pure water.
- Solution B 20.42 g of KHPO and 126.30 g of NaC were dissolved in pure water.
- 300 mg of bovine plasma albumin (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 3 L of this phosphate buffer. After dissolution, the pH was adjusted to 7.5 ⁇ 0.1 again using IN-NaOH.
- Pure water was passed through the dialysate flow path of the module at 500 mL / min for 5 minutes, and then passed through the blood flow path at 200 mL / min for 5 minutes.
- the phosphate buffer solution was passed through the dialysate flow path of the module at 500 mL / min for 5 minutes, and then passed through the blood flow path at 200 mL / min for 5 minutes. Thereafter, the solution was passed for 3 minutes while filtering the dialysate side from the blood side.
- the measurement solution circuit was connected to the blood side, and the priming solution (phosphate buffer) on the dialysate side was discarded.
- the module was placed in a thermostat at 37 ° C, the dialysate side was sealed, and the blood side was passed at 200 mL / min for 1 minute to remove the priming solution remaining on the blood side.
- a circuit was connected to the dialysate inlet, and the flow rate on the blood side was set to 200 mL / min, and the flow rate of the filtration circuit connected to the dialysate inlet was set to 30 mL / min.
- the test was carried out in a circulation system that returns to. Test liquids were collected at the start of circulation and 15 minutes later, respectively. The concentration of the collected sample was determined by the eraser method, and the amount of adsorption was determined.
- a 1MG adsorption amount (mg) CbO X test solution volume Cbl5 X test solution volume
- CbO and Cbl5 represent the concentration of the test solution at the start of circulation and 15 minutes after, respectively, and when diluted, multiply by the respective dilution ratio.
- the flow in the blood outlet circuit (outlet side from the pressure measurement point) of the dialyzer was stopped with forceps, and the whole filtration was performed. Pure water kept at 37 ° C is placed in a pressurized tank, and while controlling the pressure with a regulator, the pure water is sent to the dialyzer kept in a 37 ° C high-temperature bath, and the filtrate flowing out from the dialysate side is measured with a graduated cylinder. It was measured.
- TMP transmembrane pressure difference
- TMP (Pi + Po) / 2 And Where Pi is the dialyser inlet pressure and Po is the dialyser outlet pressure.
- the filtration flow rate was measured by changing the TMP at four points, and the water permeability (mLZhrZmmHg) was calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and filtration flow rate must be greater than 0.999. TMP was measured within the range of 100 mmHg or less to reduce the pressure loss error due to the circuit. For the water permeability of the hollow fiber membrane, the membrane area and the water permeability of the dialyzer were also calculated.
- UFR (H) is the water permeability of the hollow fiber membrane (mLZm 2 ZhrZmmHg)
- UFR (D) is the water permeability of the dialyzer (mLZhrZmmHg)
- A is the membrane area (m 2 ) of the dialyzer.
- the membrane area of the dialyzer was determined based on the inner diameter of the hollow fiber.
- n is the number of hollow fibers in the dialyzer
- ⁇ is the pi
- d is the inner diameter of the hollow fibers (m)
- L is the effective length of the hollow fibers in the dialyzer (m).
- the dialysate side of the module loaded with about 10,000 hollow fiber membranes was filled with water and plugged. Dry air or nitrogen was supplied from the blood side at room temperature and pressurized at a rate of 0.5 MPa per minute. The pressure was increased, and the air pressure when the hollow fiber membrane burst (burst) with pressurized air and bubbles were generated in the liquid filled on the dialysate side was defined as the burst pressure.
- a cross section of 100 hollow fiber membranes was observed with a 200 ⁇ projector.
- the thickness of the thickest portion, the portion and the thinnest portion, and the thickness of the portion were measured for one yarn cross section having the largest film thickness difference in one visual field.
- the film thickness is perfectly uniform.
- Bovine blood at 37 ° C with quenched acid added to suppress coagulation was sent to a blood purifier at 200 mLZmin, and the blood was filtered at a rate of 20 mLZmin. At this time, the filtrate was returned to the blood to form a circulation system. After 60 minutes, the filtrate from the blood purifier was collected, and the red color caused by red blood cell leak was visually observed.
- This blood leak test was performed for 30 blood purification samples in each of the Examples and Comparative Examples. The test was carried out using a device, and the number of modules that leaked blood was examined.
- hydrophilic polymers such as polyvinylpyrrolidone (PVP) was determined by X-ray photoelectron spectroscopy (ESCA method).
- One hollow fiber membrane was affixed to a sample stage and measured by ESCA.
- the measurement conditions are as follows.
- Photoelectron escape angle 45 °
- Vacuum about 10- 7 Pa or less
- the sample was dried at 80 ° C for 48 hours using a vacuum dryer, and its lOmg was analyzed using a CHN coder (manufactured by Janaco Analytical Industry Co., Ltd., MT-6), and the nitrogen content
- CHN coder manufactured by Janaco Analytical Industry Co., Ltd., MT-6
- PVP content Nitrogen content (% by mass) X111 / 14
- the ratio ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ s of the peak position ⁇ ⁇ (wave number) of V s and PVP was multiplied by the actually measured value.
- the content of the hydrophilic polymer (for example, PVP) in the layer near the blood contact surface was calculated according to the following equation.
- Cav is the content (% by mass) of the hydrophilic polymer (for example, PVP) determined in 10 above.
- the outer surface of the hollow fiber membrane was observed with an electron microscope at 10,000 magnification, and a photograph (SEM photograph) was taken.
- the image was processed by image analysis processing software to determine the porosity of the outer surface of the hollow fiber membrane.
- the measurement was performed using, for example, Image Pro Plus (Media Cybernetics, Inc.) as image analysis processing software.
- An emphasis' filter operation was performed on the captured image so that holes and occlusions were identified. Thereafter, the holes were counted. At this time, when the lower polymer chain was found inside the pore, the counting was performed ignoring the lower polymer chain.
- the scale setting is to be performed as an initial operation, and holes at the boundary of the measurement range are not excluded at the time of counting.
- the holes were counted in the same manner as in the previous section, and the area of each hole was determined.
- the measurement range Holes on the border of the enclosure were excluded. This was performed for 10 visual fields, and the average of all pore areas was determined.
- the cross section of the hollow fiber membrane was projected using a 200 ⁇ magnification projector, and the inner diameter (A) and outer diameter (B) of the maximum, minimum, and medium-sized hollow fibers were measured in each field of view.
- the film thickness of each hollow fiber is determined according to the following equation,
- the average of the film thickness of five hollow fibers per one visual field was calculated.
- the thickness of the skin layer of the hollow fiber membrane was determined as follows. That is, the cross section of the hollow fiber membrane was observed with a scanning electron microscope (SEM) at a magnification of 3000 times, and a portion where no pore was clearly observed was defined as a skin layer, and its thickness was measured.
- SEM scanning electron microscope
- a dialysate having an endotoxin concentration of 200 EUZL was sent from the dialysate inlet of the module at a flow rate of 500 mlZmin, and the dialysate containing endotoxin was filtered from the outside to the inside of the hollow fiber membrane at a filtration rate of 15 mlZmin for 2 hours.
- the filtered dialysate was stored from the outside of the hollow fiber membrane to the inside of the hollow fiber membrane, and the endotoxin concentration of the stored solution was measured.
- the endotoxin concentration was analyzed using Limulus ESII Test Co., Ltd. (manufactured by Wako Pure Chemical Industries, Ltd.) according to the method described in the manual (gelling method).
- the dialysate side of the module with a membrane area of 1.5 m 2 was filled with physiological saline, and 200 ml of heparin cider blood collected from a healthy person was packed in a blood bag.
- the blood bag and the module were connected by a tube and circulated at 37 ° C for 1 hour at a blood flow rate of 100 mlZmin. Blood was sampled before and 60 minutes after the start of circulation, and the numbers of white blood cells and platelets were measured. The measured value is Corrected by the value of Tocrit.
- Rate of change correction value (60 minutes) Z value before circulation start X 100
- the blood was returned with physiological saline, the number of remaining blood threads was counted, and the evaluation was made according to the following criteria.
- distilled water for injection was flowed at 200 mL / min from the blood side inlet port. After the distilled water for injection reached the outlet port, the module case was lightly squeezed five times for 10 seconds for 10 seconds to defoam, and the number of air bubbles per minute was visually confirmed. Judgment was made based on the following criteria.
- the insolubility due to crosslinking of polyvinylpyrrolidone in the present invention is determined by the solubility of dimethylformamide in the crosslinked film. That is, 10 g of the membrane after cross-linking was taken, a solution dissolved in 100 ml of dimethylformamide was separated by a centrifuge at 1500 rpm for 10 minutes, and the supernatant was removed. Once again, add 100 ml of After adding methylformamide and stirring, centrifuge under the same conditions.
- An extract was obtained according to the method defined in the dialysis-type artificial kidney device manufacturing standard, and hydrogen peroxide in the extract was quantified by a colorimetric method. The quantification was performed on each part by dividing the hollow fiber membrane into ten pieces each of 2.7 cm in the longitudinal direction.
- 0.2 ml of a coloring reagent prepared at 0.4 mM from a mixed solution with an aqueous salt solution was prepared, heated at 50 ° C. for 5 minutes, cooled to room temperature, and the absorbance at 508 nm was measured.
- the amount of hydrogen peroxide eluted was quantified using a calibration curve obtained by performing the same measurement using a sample.
- a physiological saline solution was passed through the dialysate-side flow path of the module at 500 mLZmin for 5 minutes, and then passed through the blood-side flow path at 200 mLZmin. After that, the solution was passed through the blood side to the dialysate side for 3 minutes while being filtered at 200 ml Zmin, followed by freeze drying to obtain a dried membrane. The quantification was performed using the dried film.
- Bovine blood at 37 ° C to which coagulation was added to inhibit coagulation was used. Hematocrit was adjusted to 30% by dilution with bovine plasma.
- the blood was sent to the blood purifier at 200 mL Zmin, and the blood was filtered at a rate of 20 mLZmin. At this time, the filtrate was returned to blood to form a circulatory system.
- the blood purifier was sufficiently replaced with physiological saline in advance. Circulation Five minutes after the start, it was confirmed that a predetermined filtration flow rate was obtained. From 15 minutes after the start, the filtrate was sampled by about lcc every 15 minutes.
- Cf indicates the albumin concentration in the filtrate
- Ci indicates the albumin concentration in the blood 'plasma at the inlet of the blood purifier
- Co indicates the albumin concentration in the blood' plasma at the outlet of the blood purifier.
- the amount of albumin leak equivalent to 3 L of water removal was determined as follows. That is, the samples were sampled at 30, 45, 60, 75, 90, 105, and 120 minutes, and the albumin concentration in the filtrate was calculated by the A / GB-Testco's BCG method. . Using these data, take the albumin leak (TAL [mgZdL]) on the vertical axis and In (time [min]) (InT) on the horizontal axis, and use spreadsheet software (for example, Microsoft EXCEL- ⁇ ).
- TAL aXlnT + b
- the water content of the permselective separation membrane in the present invention was calculated by the following equation.
- Ww is the weight (g) of the permselective separation membrane
- Wd is the weight (g) of the permselective separation membrane after drying in a dry heat oven at 120 ° C for 2 hours (after absolute drying).
- Ww is the weight (g) of the permselective separation membrane after drying in a dry heat oven at 120 ° C for 2 hours (after absolute drying).
- Polyethersulfone manufactured by Sumika Chemtex Co., Sumikaetaseru 5200P
- poly Bulle pyrrolidone BASF Corp. Kollidon K 90
- DM Ac dimethyl ⁇ Seto amide
- the dissolution tank was immediately sealed and left for 15 minutes so that the solvent and the like did not evaporate and the composition of the film-forming solution did not change. This operation was repeated three times to defoam the film forming solution.
- the ratio of polyvinylpyrrolidone to polysulfone polymer in the film-forming solution was 16.7% by mass, and the hydrogen peroxide content of polybutylpyrrolidone was 100 ppm.
- the supply tank of the raw material supply system and the inside of the above-mentioned dissolution tank were replaced with nitrogen gas. At this time, the oxygen concentration in the dissolution tank was 0.06%.
- the Froude number and the stirring Reynolds number at the time of dissolution were 1.1 and 120, respectively.
- the obtained film forming solution was passed through a two-stage sintered filter of 15 / zm10 / zm in order. After that, discharge from the tube in orifice nozzle heated to 70 ° C at a discharge rate of 2.3 ccZmin, and at the same time discharge a 46% by mass aqueous DMAc solution at 25 ° C at 25 ° C, which was previously degassed at -700 mm Hg for 30 minutes as an internal liquid. did.
- the ejected material was passed through a dry section (air gap) of 700 mm, which was cut off from the outside air by a spinning tube, then solidified in a 20% by mass aqueous DMAc solution at 70 ° C, and wound up entirely in a wet state .
- the average slit width was 60 m
- the maximum was 61 ⁇ m
- the ratio of the maximum and minimum slit width was 1.03.
- the pressure loss in the nozzle was 2.9 ⁇ 10 8 Pa 's
- the shear stress in the film forming solution flow path was 1.5 ⁇ 10 6 s- 1
- the flow path passage time was 1.3 It was calculated to be X 10- 3 sec.
- the draft ratio was 1.3.
- the rollers used for changing the yarn path during the spinning process used mirror-finished surfaces, and the fixed guides used were matte-finished surfaces.
- a polyethylene film was wound around the bundle of about 10,000 hollow fiber membranes, and immersed and washed twice in a 40 vol% aqueous solution of isopropanol at 30 ° C for 30 minutes.
- the hollow fiber membrane bundle after the washing treatment is lightly rinsed with RO water, and isopropanol is replaced with water. At 600 rpm for 5 min.
- the obtained bundle of wet hollow fiber membranes was set on a rotating table in a drying device in a 12-piece ⁇ 2 stage, and was subjected to a drying treatment under the following conditions.
- the microwave irradiation was stopped, and at the same time, the degree of reduced pressure was reduced to 1.5 kPa and maintained for 3 minutes. Subsequently, the pressure reduction degree was returned to 7 kPa, and at the same time, the hollow fiber membrane bundle was heated at a power of 0.5 kW for 10 minutes by irradiating the microwave, then the microwave was cut, and the pressure reduction degree was reduced to 0.7 kPa for 3 minutes. Maintained. The degree of pressure reduction was returned to 7 kPa, and microwave irradiation was performed for 8 minutes at an output of 0.2 kW to heat the hollow fiber membrane bundle.
- the degree of vacuum was reduced to 0.5 kPa and maintained for 5 minutes to condition the hollow fiber membrane bundle and finish drying.
- the highest temperature reached on the surface of the hollow fiber membrane bundle was 65 ° C.
- the moisture content of the hollow fiber membrane bundle before drying is 310% by mass
- the moisture content of the hollow fiber membrane bundle after the first stage is 38% by mass
- the moisture content of the hollow fiber membrane bundle after the second stage is 14% by mass.
- the water content of the hollow fiber membrane bundle was 2.3% by mass.
- the inner diameter of the obtained hollow fiber membrane was 198 m
- the film thickness was 27 ⁇ m
- the skin layer thickness was 0.9 ⁇ m. Table 1 shows the characteristic values of the obtained hollow fiber membrane.
- the obtained hollow fiber membrane was divided into 10 pieces of 2.7 cm each in the longitudinal direction, and the hollow fiber membrane lg in a dry state was weighed from each site, and the amount of hydrogen peroxide eluted was quantified. The eluted amount of hydrogen peroxide was stable at a low level at all sites. The quantitative values are shown in Table 2.
- the hollow fiber membrane bundle prepared by the above method was inserted into a polycarbonate module case. Both ends are fixed with urethane resin, the resin ends are cut to open the hollow fiber membrane hollow, and a cap with an inlet is attached.
- the effective length of the hollow fiber membrane is 115 mm and the membrane area is 1.
- An Om 2 hollow fiber membrane mini-module was fabricated. This module was sterilized by irradiating 25 kgy of ⁇ -rays in an oxygen-free environment. The priming property of the obtained module was good.
- the obtained module was used to evaluate the sieving coefficient of albumin, a1 microglobulin talliance, a1 microglobulin adsorption amount, blood leak, endotoxin permeability, residual blood and burst pressure. .
- the hollow fiber membrane after ⁇ -ray sterilization was cut out and subjected to an eluate test.
- the elution amount of polybutylpyrrolidone was 5 ppm
- the maximum elution amount of hydrogen peroxide was 2 ppm.
- Table 1 shows the results of these evaluations.
- Example 1 Te film the composition of the solution polyethersulfone (Sumika Chemical Kemutetsu task Co., Sumikaetaseru 5200P) 18. 0 Weight 0/0, poly Bulle pyrrolidone (BASF Corp. coli pyrrolidone K 90) 0.5 mass%, dimethylacetamide (DMAc) 77.0 mass%, RO water 4.5 mass%, except for changing the internal solution temperature to 50 ° C and the coagulation solution to RO water
- the hollow fiber membrane and the module of Comparative Example 1 were obtained in the same manner as in Example 1.
- the ratio of polyvinylpyrrolidone to polysulfone-based polymer in the film-forming solution was 2.8% by mass, and the temperature difference between the film-forming solution temperature and the internal solution at the time of nozzle discharge was 20 ° C. These characteristics are shown in Table 1 and Table 2.
- the hollow fiber membrane obtained in this comparative example is inferior in permselectivity for proteins because the content of polyvinyl bilidone in the outermost surface layer of the hollow fiber membrane is too low and the skin layer is thick. Was.
- the residual blood content was poor because the content of polyvinylpyrrolidone on the inner surface was too low.
- the priming property was improved because the content of polybulpyrrolidone on the inner and outer surfaces of the hollow fiber membrane was low. Therefore, the hollow fiber membrane obtained in this comparative example was of low practicality for blood purifiers.
- Example 1 Te film the composition of the solution polyethersulfone (Sumika Chemical Kemutetsu task Co., Sumikaetaseru 5200P) 18. 0 Weight 0/0, poly Bulle pyrrolidone (BASF Corp. coli pyrrolidone K 90) 10.0 mass%, dimethylacetamide (DMAc) 67.5 mass%, RO water 4.5 mass%, except that the concentration of the internal solution was changed to 65 mass% and the liquid temperature was changed to 45 ° C.
- a hollow fiber membrane and a module of Comparative Example 1 were obtained in the same manner as in Example 1.
- the ratio of polyvinylpyrrolidone to polysulfone-based polymer in the film-forming solution was 55.5% by mass. Tables 1 and 2 show these characteristics.
- the hollow fiber membrane obtained in this comparative example had a high content of polyvinylpyrrolidone on the inner surface of the hollow fiber membrane, and had a large pore diameter, and thus was inferior in permselectivity for proteins. Ma In addition, the elution amount of polybulpyrrolidone was high. Regarding the low selectivity of the protein, other than the fact that the content of polybutylpyrrolidone on the inner surface is high, there are other factors that affect the permeability of the protein, such as the average pore size / pore size distribution on the inner surface. Are different from those of the hollow fiber membrane of Example 1, and it is presumed that this also has an effect. In addition, since the content of polyvinylpyrrolidone on the outer surface of the hollow fiber membrane was high, sticking between the hollow fiber membranes occurred. In addition, permeation of endotoxin was observed.
- a blood purifier was assembled using the hollow fiber membrane thus obtained, and an air leak test was performed. As a result, bubbles were generated from the module bonding portion. It is probable that poor adhesion was caused by the adhesion of the hollow fiber membranes. Therefore, the hollow fiber membrane obtained in this comparative example was of low practicality for a blood purifier.
- a hollow fiber membrane and a module of Comparative Example 3 were obtained in the same manner as in Comparative Example 2, except that the number of washings with a 50 vol% aqueous solution of isopropanol was changed to six.
- Tables 1 and 2 show the properties of the obtained hollow fiber membrane and module.
- the hollow fiber membrane obtained in the present comparative example has a high hydrophobicity due to a decrease in the content of polybulpyridone in the outer surface due to enhanced washing. Therefore, the problem of permeation of endotoxin, which is one of the problems of the hollow fiber membrane obtained in Comparative Example 2, is solved, but the priming property is poor. In addition, since the state of the inner surface did not change, the problem of Comparative Example 2 which had the permselective separation membrane of Example 2 due to the inner surface characteristics was not improved.
- polyethersulfone manufactured by Sumika Chemtex Co., Sumikaeta cells 5200P
- Poly Bulle pyrrolidone BASF Corp. Kollidon K-90
- DMAc dimethyl ⁇ Seto amide
- RO water 1.
- film soluble liquid consisting of 0 wt 0/0.
- the ratio of polybutylpyrrolidone to polysulfone-based polymer in the film forming solution was 27.7 mass 0 /. Met.
- the polypyrrolidone one having a hydrogen peroxide content of 100 ppm was used.
- the film forming solution was passed through a two-stage sintered filter of 15 m and 10 m in order. Then, using a tube-in orifice nozzle heated to 70 ° C, a 46% by mass aqueous DMAc solution at 25 ° C that had been degassed at -700 mmHg for 30 minutes in advance was used as the internal solution.
- the liquid was discharged at a spinning speed of 50 mZ, and passed through a dry section (air gap section) of 700 mm, which was isolated from the outside air by a spinning tube. Thereafter, it was coagulated in a 20 wt% DMAc aqueous solution at 35 ° C., and was entirely wound up in a wet state.
- the average nozzle slit width of the tube-in-orifice nozzle used was 60 m, the maximum was 61 ⁇ m, the minimum was m, the ratio of the maximum and minimum slit widths was 1.03, and the draft ratio was 1.15. .
- the hollow fiber membrane whose coagulation bath power was also lifted was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up.
- Example 1 After the same polyethylene film as in Example 1 was wound around the bundle of about 10,000 hollow fiber membranes, a reflector was placed in an oven without washing, and uniform heating was possible. It was introduced into a microwave irradiation type dryer having such a structure, and dried under the following conditions. Under reduced pressure of 7 KPa, microwave irradiation is performed for 30 minutes at 1.5 kW output, 10 minutes at 0.5 kW output, and 8 minutes at 0.2 kW output, and the water content becomes 2.9% by mass. Dried to dryness. At this time, the highest temperature reached on the surface of the hollow fiber membrane was 65 ° C.
- a roller having a mirror-finished surface was used as a roller for changing the yarn path during the spinning process, and a surface-finished roller was used as a fixing guide.
- the inner diameter of the obtained hollow fiber membrane was 200 m, and the membrane thickness was 35 ⁇ m.
- the skin layer thickness was 1.7 ⁇ m. Table 1 shows the characteristic values of the obtained hollow fiber membrane.
- the obtained hollow fiber membrane was divided into 10 pieces of 2.7 cm each in the longitudinal direction, and the dried hollow fiber membrane lg was weighed from each site, and the amount of hydrogen peroxide eluted was quantified. The eluted amount of hydrogen peroxide was stable at a low level at all sites. The quantitative values are shown in Table 2. However, the hollow fiber membrane obtained in this comparative example was observed to adhere to the dried hollow fiber membrane bundle, and the end adhesive resin did not enter between the hollow fiber membranes when assembling the blood purification device. In many cases, blood purifiers could not be assembled.
- the filter used for filtration of the film-forming solution was changed to a sintered filter with a filter accuracy of 30 ml, and the tube in orifice nozzle was used with a nozzle slit width of 60 m on average, maximum m, minimum m, and slit.
- a hollow fiber membrane and a module were obtained.
- Tables 1 and 2 show the properties of the obtained hollow fiber membrane and module.
- the hollow fiber membrane and the module obtained in this comparative example had the same problems as the product obtained in comparative example 1.
- blood cell leaks were observed in 5 out of 30 modules in a blood leak test using bovine blood with a low burst pressure due to a decrease in wall thickness unevenness and phase separation uniformity of the hollow fiber membrane.
- the hollow fiber membrane obtained in this comparative example was of low practicality for a blood purifier.
- a hollow fiber membrane and a module were obtained in the same manner as in Comparative Example 1 except that the method of Comparative Example 1 was changed as follows.
- a product having a hydrogen peroxide content of 500 ppm was used as polybutylpyrrolidone used in the film forming solution.
- the nos and the nore slit width are 80 ⁇ m on average, 81 ⁇ m at maximum, 79 / ⁇ minimum, the ratio of the maximum and minimum slit width is 1.03, and the flow of the film forming solution A nozzle with an L ZD of 2.5 was used.
- Tables 1 and 2 show the properties of the obtained hollow fiber membrane and module.
- the hollow fiber membrane and the module obtained in this comparative example had the same problems as the product obtained in comparative example 1, and also had a large amount of hydrogen peroxide dissolved out.
- the dried sample used for the measurement of hydrogen peroxide in the hollow fiber membrane obtained in this comparative example was placed in a dry box conditioned at a humidity of 50% RH (atmosphere: air) at room temperature for 3 times. After storage for a month, extraction was performed by the method specified in the dialysis-type artificial kidney device manufacturing standard, and UV (220-350 nm) absorbance was measured. The UV (220-350 nm) absorbance at the start of storage was less than the approval standard of 0.1 at all sites, but after storage, all sites exceeded the approval standard of 0.1. The storage stability was poor.
- polyethersulfone manufactured by Sumika Chemtex Co., Sumikaeta cells 4800P
- Polyethersulfone manufactured by Sumika Chemtex Co., Sumikaeta cells 4800P
- Poly Bulle pyrrolidone BASF Corp. Kollidon K-90
- 5 Weight 0 / 0, dimethyl ⁇ Seto amide (DMAc) 74.
- 5 mass 0/0, RO water 5.
- film soluble liquid consisting of 0 wt 0/0 were prepared.
- the ratio of polyvinylpyrrolidone to polysulfone-based polymer in the film forming solution was 13.8% by mass.
- the hydrogen peroxide content of the starting polyvinylpyrrolidone was 100 ppm.
- the obtained film-forming solution was passed through a two-stage sintering filter of 15 m and 10 m in order, and then discharged at a tube-in-orifice nozzle power heated to 70 ° C with a film-forming stock solution discharge rate of 2.lccZmin. .
- a 50% by mass DMAc aqueous solution at 30 ° C which was previously degassed at -700 mmHg for 30 minutes, was discharged as an internal solution, and after passing through a 75 Omm air gap that was shut off from the outside air by the spinning tube, Was coagulated in a 25% by mass aqueous solution of DMAc, and the whole was wound up in a wet state.
- the average nozzle slit width was 60 m, the maximum was 61 ⁇ m, and the minimum was 59 / zm.
- the ratio between the maximum and the minimum slit width was 1.03.
- the draft ratio was 1.3.
- Pressure loss of the membrane forming solution in the nozzle 2. a 15 X 10 8 Pa 's, shear stress 1. 1 X Pass the passage time 1. was 2 X 10- 3 sec.
- the hollow fiber membrane pulled out of the coagulation bath was passed through a water washing tank at 85 ° C for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up.
- a roller having a mirror-finished surface was used as a roller for changing the yarn path during the spinning process, and a surface-finished roller was used as a fixed guide.
- a polyethylene film similar to that in Example 1 was wound around the bundle of about 10,000 hollow fiber membranes. Thereafter, the substrate was immersed and washed three times in a 30 vol% ethanol aqueous solution at 30 ° C. for 30 minutes, and the hollow fiber membrane bundle after the washing treatment was lightly rinsed with RO water to replace ethanol with water. afterwards Then, the liquid was removed with a centrifugal separator at 600 rpm for 5 minutes.
- the obtained wet hollow fiber membrane bundle is dried at 65 ° C for 3 hours at a flow rate of 0.3 LZsec using a draft dryer having a flow path in the longitudinal direction, and then at 35 ° C and a flow rate of 0.05 LZsec. For 20 hours.
- the drying start force was changed every 20 minutes for the first 3 hours and every hour for the next 20 hours until the end of drying, and the drying direction was reversed by 180 degrees.
- the moisture content of the hollow fiber membrane bundle before drying is 290% by mass
- the moisture content of the hollow fiber membrane bundle after 3 hours of drying is 67% by mass
- the moisture content of the hollow fiber membrane bundle after drying is 2.4% by mass.
- nitrogen gas was used as a ventilation medium.
- the inner diameter of the obtained hollow fiber membrane was 200 ⁇ m
- the film thickness was 29 ⁇ m.
- the thickness of the skin layer was 0.7 ⁇ m. Table 1 shows the characteristic values of the obtained hollow fiber membrane.
- the obtained hollow fiber membrane was divided into 10 pieces of 2.7 cm each in the longitudinal direction, and the dried hollow fiber membrane lg was weighed from each site, and the amount of eluted hydrogen peroxide was quantified. The eluted amount of hydrogen peroxide was stable at a low level at all sites. The quantitative values are shown in Table 2.
- the hollow fiber membrane bundle adjusted by the above method is inserted into a polycarbonate module case, both ends are fixed with urethane resin, cut and opened, and a cap having an inflow port is attached.
- a hollow fiber membrane module with an effective length of 115 mm and a membrane area of 1. Om 2 was produced. This module was sterilized by irradiating it with 25 kgy of ⁇ -rays in an oxygen-free environment. The priming property of the obtained module was good.
- the obtained module was used to evaluate the sieving coefficient of albumin, a1 microglobulin talliance, a1 microglobulin adsorption amount, blood leak, endotoxin permeability, residual blood and burst pressure. .
- the hollow fiber membrane after ⁇ -ray sterilization was cut out and subjected to an eluate test. As a result, the elution amount of polybutylpyrrolidone was 5 ppm, and the elution amount of hydrogen peroxide was 3 ppm.
- Example 2 In the same manner as in Example 1, a polysulfone (Amoko Co. P- 3500) 18. 5 wt%, polyvinyl - Rupiroridon (BASF Corp. Kollidon K 60) 3. 0 mass 0/0, dimethyl ⁇ Seto amide (DMAc 74.5% by mass and 4.0% by mass of RO water were obtained.
- the ratio of polypyrrolidone to polysulfone polymer in the film forming solution was 16.2% by mass, and the content of hydrogen peroxide in the starting polypyrrolidone was 150 ppm.
- the resulting film-forming solution was passed through a two-stage sintering filter of 15 / ⁇ , 10 m in order, and then discharged at a discharge rate of 2.4 cc / min from a tube-in orifice nozzle heated to 50 ° C.
- a 35% by mass aqueous solution of DMAc at 15 ° C which was previously degassed at 700 mmHg for 30 minutes, was discharged as an internal solution, and after passing through a 650 mm air gap blocked from the outside air by a spinning tube, the temperature was raised to 60 ° C.
- Coagulation was carried out in a 15% by mass aqueous solution of DMAc, and the whole was wound up in a wet state.
- the tube in orifice nozzle used had a nosed and knurled slit width of 60 ⁇ m on average, a maximum of 61 ⁇ m, and a minimum of 59 ⁇ m, and the ratio between the maximum and minimum slit widths was 1.03.
- the pressure drop of the casting solution in the nozzle is 2.3 X 10 8 Pa's and the shear stress is 1.2 X Pass the passage time was 1. 5 X 10- 3 sec.
- the draft ratio was 1.3.
- Mirror-finished rollers were used as rollers for changing the yarn path during the spinning process, and satin-finished surfaces were used as fixed guides.
- Example 2 The same polyethylene film as in Example 1 was wound around the bundle of about 10,000 hollow fiber membranes. Thereafter, the substrate was washed by immersion in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes ⁇ 2 times, and the hollow fiber membrane bundle after the washing treatment was lightly rinsed with RO water to replace isopropanol with water. Thereafter, the liquid was removed using a centrifugal separator at 600 rpm for 5 minutes. The obtained wet hollow fiber membrane bundle was set on a rotating table in a drying device provided with a microwave reflecting plate in a device so as to be able to perform uniform heating, and was set in two stages of 48 tubes and dried under the following conditions.
- Microwave irradiation was performed at a reduced pressure of 7 kPa at an output of 12 kW to perform a heat treatment for 15 minutes. Subsequently, the microwave irradiation was stopped and the degree of vacuum was reduced to lkPa, and the water was evaporated by maintaining the pressure for 3 minutes. Next, the degree of pressure reduction was returned to 7 kPa, microwave irradiation was performed, and heat treatment was performed for 7 minutes at an output of 3.5 kW. After the heating, the microwave irradiation was stopped, and the degree of reduced pressure was reduced to 0.7 kPa and maintained for 3 minutes.
- the pressure reduction was returned to 7 kPa, and microwave irradiation was restarted.
- the output was reheated at 2.5 kW for 6 minutes, then the microwave irradiation was stopped, the pressure reduction was reduced to 0.5 kPa, and drying was performed for 7 minutes. Processing was performed.
- the hollow fiber membrane bundle was subjected to a moisture content equalization treatment at 35 ° C. for 3 hours in a ventilation dryer.
- the water content of the hollow fiber membrane bundle before microwave drying was 306 %,
- the moisture content after the first stage is 33% by mass
- the moisture content after the second stage is 16% by mass
- the moisture content after the third stage is 6% by mass
- the moisture content after the ventilation drying is It was 1.7% by mass.
- the maximum temperature of the hollow fiber membrane bundle during the drying treatment was 54 ° C.
- the inner diameter of the obtained hollow fiber membrane was 197 ⁇ m, and the film thickness was 30 ⁇ m.
- the thickness of the skin layer was 0.7 ⁇ m. Table 1 shows the characteristic values of the obtained hollow fiber membrane.
- the obtained hollow fiber membrane was divided into 10 pieces of 2.7 cm each in the longitudinal direction, and the hollow fiber membrane lg in a dry state was weighed from each site, and the elution amount of hydrogen peroxide was quantified. The eluted amount of hydrogen peroxide was stable at a low level at all sites. The quantitative values are shown in Table 2.
- the hollow fiber membrane bundle adjusted by the above method is inserted into a polycarbonate module case, both ends are fixed with urethane resin, cut and opened, and a cap having an inflow port is attached.
- a hollow fiber membrane mini-module with an effective length of 115 mm and a membrane area of 1. Om 2 was prepared.
- This module was sterilized by irradiating 25 kgy of ⁇ -rays in an oxygen-free environment.
- the priming property of the obtained module was good.
- the sieving coefficient of albumin, a1 microglobulin talliance, a1 microglobulin adsorption amount, blood leak property, endotoxin permeability, residual blood property, and burst pressure were evaluated.
- the hollow fiber membrane after gamma ray sterilization was cut out and subjected to an elution test.
- the elution amount of polyvinylpyrrolidone was 4 ppm, and the elution amount of hydrogen peroxide was 2 ppm.
- the selectively permeable separation membrane of the present invention has a good balance of separation characteristics, high safety and high performance stability, and is excellent in module assemblability. Therefore, it is suitable for use as a hollow fiber type blood purifier by hemodialysis, which has high water permeability and is used for treatment of chronic renal failure. Further, according to the production method of the present invention, a selectively permeable separation membrane having the above characteristics can be produced economically and stably.
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Abstract
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Priority Applications (2)
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EP05721144.3A EP1733783B1 (en) | 2004-03-22 | 2005-03-18 | Separation membrane with selective permeability and process for producing the same |
US10/599,128 US7922007B2 (en) | 2004-03-22 | 2005-03-18 | Separation membrane with selective permeability and process for producing the same |
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JP2004083712A JP3642065B1 (ja) | 2004-03-22 | 2004-03-22 | 選択透過性分離膜および選択透過性分離膜の製造方法 |
JP2004-083712 | 2004-03-22 |
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EP (1) | EP1733783B1 (ja) |
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Cited By (1)
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Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06165926A (ja) * | 1992-04-29 | 1994-06-14 | Kuraray Co Ltd | ポリスルホン系中空繊維膜とその製造方法 |
JPH06296686A (ja) * | 1993-04-19 | 1994-10-25 | Asahi Chem Ind Co Ltd | 医療用ポリスルホン中空糸膜 |
JPH07289863A (ja) | 1994-04-27 | 1995-11-07 | Asahi Medical Co Ltd | ポリスルホン系中空糸膜及びその製造方法 |
JPH07289866A (ja) * | 1994-04-27 | 1995-11-07 | Asahi Medical Co Ltd | ポリスルホン系選択透過膜 |
US5762798A (en) | 1991-04-12 | 1998-06-09 | Minntech Corporation | Hollow fiber membranes and method of manufacture |
JPH10180058A (ja) * | 1996-12-24 | 1998-07-07 | Toyobo Co Ltd | 中空糸膜 |
JPH11169690A (ja) * | 1997-12-15 | 1999-06-29 | Nikkiso Co Ltd | 血液浄化膜 |
JPH11309355A (ja) * | 1998-04-28 | 1999-11-09 | Asahi Medical Co Ltd | ポリスルホン系中空糸型血液浄化膜とその製造方法 |
JP2000157852A (ja) * | 1998-11-25 | 2000-06-13 | Asahi Medical Co Ltd | ポリスルホン系血液処理膜 |
JP2000210544A (ja) * | 1999-01-26 | 2000-08-02 | Toray Ind Inc | 半透膜の製造方法 |
JP2000254222A (ja) * | 1999-03-12 | 2000-09-19 | Terumo Corp | 血液浄化用中空糸膜および中空糸膜型人工腎臓 |
KR20010012689A (ko) | 1997-05-19 | 2001-02-26 | 아사히 메디칼 가부시키가이샤 | 혈액 정제용 폴리술폰형 중공사막 및 그의 제조 방법 |
JP2001190934A (ja) | 2000-01-12 | 2001-07-17 | Toyobo Co Ltd | 溶出物の少ない中空糸膜モジュール |
JP3193262B2 (ja) | 1995-05-12 | 2001-07-30 | 帝人株式会社 | 血液処理器の製造方法及び血液処理器 |
JP2003175322A (ja) | 2001-10-05 | 2003-06-24 | Asahi Medical Co Ltd | 中空糸状膜の製造方法 |
JP2003175321A (ja) | 2001-10-05 | 2003-06-24 | Asahi Medical Co Ltd | 中空糸状膜の製造方法 |
JP2003175320A (ja) | 2001-10-05 | 2003-06-24 | Asahi Medical Co Ltd | 中空糸状膜の製造方法 |
JP3551971B1 (ja) * | 2003-11-26 | 2004-08-11 | 東洋紡績株式会社 | ポリスルホン系選択透過性中空糸膜 |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US199891A (en) * | 1878-02-05 | Improvement in refrigerators | ||
US4976A (en) * | 1847-02-20 | Improvement in plows | ||
JPS58114702A (ja) | 1981-12-28 | 1983-07-08 | Kuraray Co Ltd | ポリスルホン中空繊維膜 |
US4906375A (en) * | 1984-07-14 | 1990-03-06 | Fresenius, Ag | Asymmetrical microporous hollow fiber for hemodialysis |
JPS61232860A (ja) | 1985-04-08 | 1986-10-17 | 鐘淵化学工業株式会社 | 血漿分離用ポリスルホン中空糸 |
JP3334705B2 (ja) | 1991-03-28 | 2002-10-15 | 東レ株式会社 | ポリスルホン系選択透過性中空糸膜 |
JPH0554373A (ja) | 1991-08-27 | 1993-03-05 | Sumitomo Metal Mining Co Ltd | 磁気記録媒体 |
US5340480A (en) * | 1992-04-29 | 1994-08-23 | Kuraray Co., Ltd. | Polysulfone-based hollow fiber membrane and process for manufacturing the same |
JPH0675667A (ja) | 1992-08-26 | 1994-03-18 | Nec Corp | 電源供給方式 |
JPH06339620A (ja) | 1993-11-29 | 1994-12-13 | Toray Ind Inc | ポリスルホン系樹脂半透膜の処理方法 |
DE69634352T2 (de) * | 1995-06-30 | 2006-01-12 | Toray Industries, Inc. | Methode zur Herstellung einer teildurchlässigen Hohlfasermembran aus Polysulfon |
US6355730B1 (en) * | 1995-06-30 | 2002-03-12 | Toray Industries, Inc. | Permselective membranes and methods for their production |
JP4003982B2 (ja) | 1995-06-30 | 2007-11-07 | 東レ株式会社 | ポリスルホン系選択透過性分離膜 |
JP3617194B2 (ja) | 1995-06-30 | 2005-02-02 | 東レ株式会社 | 選択透過性分離膜及びその製造方法 |
JP3651121B2 (ja) | 1995-06-30 | 2005-05-25 | 東レ株式会社 | 選択透過性分離膜 |
DE69629042T2 (de) * | 1995-10-09 | 2004-04-22 | Asahi Kasei Kabushiki Kaisha | Polysulfon-membran zur reinigung von blut |
JPH1057476A (ja) * | 1996-08-26 | 1998-03-03 | Toray Ind Inc | 膜分離装置 |
JP2713294B2 (ja) | 1996-09-30 | 1998-02-16 | 東レ株式会社 | ポリスルホン系樹脂半透膜の製造方法 |
JP3966481B2 (ja) | 1997-02-18 | 2007-08-29 | 東レ株式会社 | 半透膜 |
JP3132415B2 (ja) | 1997-04-28 | 2001-02-05 | 東レ株式会社 | 親水化透析膜 |
KR100289413B1 (ko) | 1997-12-30 | 2001-05-02 | 구광시 | 폴리설폰계 중공사 막 및 그의 제조 방법 |
JP3933300B2 (ja) | 1998-04-28 | 2007-06-20 | 旭化成メディカル株式会社 | ポリスルホン系選択分離膜 |
JP4265701B2 (ja) | 1998-11-16 | 2009-05-20 | 旭化成クラレメディカル株式会社 | ポリスルホン系多孔質膜 |
JP2000300663A (ja) | 1999-04-19 | 2000-10-31 | Toyobo Co Ltd | 選択分離膜 |
JP3293069B2 (ja) * | 1999-05-28 | 2002-06-17 | エリー株式会社 | 被加熱物の加熱方法及びその装置 |
JP2001038170A (ja) | 1999-08-03 | 2001-02-13 | Toyobo Co Ltd | 中空糸膜 |
JP4211168B2 (ja) * | 1999-12-21 | 2009-01-21 | 東レ株式会社 | 透析器の製造方法および滅菌法 |
JP4061798B2 (ja) | 1999-12-21 | 2008-03-19 | 東レ株式会社 | 血液処理用半透膜およびそれを用いた血液処理用透析器 |
KR20010112689A (ko) | 2000-06-10 | 2001-12-21 | 최영민 | 인터넷 포탈 asp서비스 분산처리 시스템 구성 방법 |
JP4214750B2 (ja) | 2001-10-04 | 2009-01-28 | 東レ株式会社 | 材料およびそれを用いた血液浄化用モジュール |
JP4453248B2 (ja) | 2001-12-19 | 2010-04-21 | 東レ株式会社 | 中空糸膜および中空糸膜モジュールの製造方法 |
JP4325904B2 (ja) | 2002-03-27 | 2009-09-02 | 旭化成クラレメディカル株式会社 | 中空糸膜の乾燥装置 |
JP3642065B1 (ja) | 2004-03-22 | 2005-04-27 | 東洋紡績株式会社 | 選択透過性分離膜および選択透過性分離膜の製造方法 |
-
2004
- 2004-03-22 JP JP2004083712A patent/JP3642065B1/ja not_active Expired - Lifetime
-
2005
- 2005-03-18 EP EP05721144.3A patent/EP1733783B1/en active Active
- 2005-03-18 WO PCT/JP2005/004980 patent/WO2005089917A1/ja active Application Filing
- 2005-03-18 US US10/599,128 patent/US7922007B2/en active Active
Patent Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5762798A (en) | 1991-04-12 | 1998-06-09 | Minntech Corporation | Hollow fiber membranes and method of manufacture |
JPH06165926A (ja) * | 1992-04-29 | 1994-06-14 | Kuraray Co Ltd | ポリスルホン系中空繊維膜とその製造方法 |
JPH06296686A (ja) * | 1993-04-19 | 1994-10-25 | Asahi Chem Ind Co Ltd | 医療用ポリスルホン中空糸膜 |
JPH07289863A (ja) | 1994-04-27 | 1995-11-07 | Asahi Medical Co Ltd | ポリスルホン系中空糸膜及びその製造方法 |
JPH07289866A (ja) * | 1994-04-27 | 1995-11-07 | Asahi Medical Co Ltd | ポリスルホン系選択透過膜 |
JP3193262B2 (ja) | 1995-05-12 | 2001-07-30 | 帝人株式会社 | 血液処理器の製造方法及び血液処理器 |
JPH10180058A (ja) * | 1996-12-24 | 1998-07-07 | Toyobo Co Ltd | 中空糸膜 |
KR20010012689A (ko) | 1997-05-19 | 2001-02-26 | 아사히 메디칼 가부시키가이샤 | 혈액 정제용 폴리술폰형 중공사막 및 그의 제조 방법 |
JPH11169690A (ja) * | 1997-12-15 | 1999-06-29 | Nikkiso Co Ltd | 血液浄化膜 |
JPH11309355A (ja) * | 1998-04-28 | 1999-11-09 | Asahi Medical Co Ltd | ポリスルホン系中空糸型血液浄化膜とその製造方法 |
JP2000157852A (ja) * | 1998-11-25 | 2000-06-13 | Asahi Medical Co Ltd | ポリスルホン系血液処理膜 |
JP2000210544A (ja) * | 1999-01-26 | 2000-08-02 | Toray Ind Inc | 半透膜の製造方法 |
JP2000254222A (ja) * | 1999-03-12 | 2000-09-19 | Terumo Corp | 血液浄化用中空糸膜および中空糸膜型人工腎臓 |
JP2001190934A (ja) | 2000-01-12 | 2001-07-17 | Toyobo Co Ltd | 溶出物の少ない中空糸膜モジュール |
JP2003175322A (ja) | 2001-10-05 | 2003-06-24 | Asahi Medical Co Ltd | 中空糸状膜の製造方法 |
JP2003175321A (ja) | 2001-10-05 | 2003-06-24 | Asahi Medical Co Ltd | 中空糸状膜の製造方法 |
JP2003175320A (ja) | 2001-10-05 | 2003-06-24 | Asahi Medical Co Ltd | 中空糸状膜の製造方法 |
JP3551971B1 (ja) * | 2003-11-26 | 2004-08-11 | 東洋紡績株式会社 | ポリスルホン系選択透過性中空糸膜 |
Non-Patent Citations (2)
Title |
---|
L.M. WIENK ET AL., JOURNAL OF MEMBRANE SCIENCE, vol. 10, no. 6, 1995, pages 233 - 243 |
See also references of EP1733783A4 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008291398A (ja) * | 2007-05-25 | 2008-12-04 | Toyobo Co Ltd | チューブインオリフィス型ノズルの検査方法および中空糸膜の製造方法および中空糸膜 |
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Publication number | Publication date |
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EP1733783A4 (en) | 2007-09-26 |
EP1733783B1 (en) | 2017-06-14 |
JP3642065B1 (ja) | 2005-04-27 |
US7922007B2 (en) | 2011-04-12 |
US20070199891A1 (en) | 2007-08-30 |
EP1733783A1 (en) | 2006-12-20 |
JP2006345876A (ja) | 2006-12-28 |
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