JP4582081B2 - Selective separation membrane for blood treatment, manufacturing method and module thereof - Google Patents

Description

  The present invention relates to a selective separation membrane comprising a hydrophobic polymer and a hydrophilic polymer, the elution of the hydrophilic polymer is suppressed, and the safety is improved. More specifically, the present invention relates to a selective separation membrane containing a hydrophilic polymer whose safety is improved by suppressing elution of the hydrophilic polymer into blood when used for blood purification.

  As a blood treatment method for patients with chronic renal failure, various techniques for improving membrane performance and dialysis methods have been developed using living kidney as a model. As membrane materials used for them, natural materials such as cellulose and cellulose derivatives and synthetic polymer materials such as polysulfone, polymethyl methacrylate, polyacrylonitrile, and ethylene vinyl alcohol copolymer are widely used. Among synthetic polymer materials, polysulfone-based resins that are excellent in biocompatibility and can exhibit high uremic substance removal performance have attracted attention. In recent years, many membranes for blood purification using polysulfone-based resins have been put on the market. . Polysulfone-based resins are thermoplastic heat-resistant engineer plastics and are widely used in various industrial fields.

  Polysulfone-based resins are relatively hydrophobic and tend to adsorb plasma proteins when in contact with blood. For this reason, when producing a blood purification membrane, a method of imparting hydrophilicity by mixing polyvinyl pyrrolidone with a polysulfone resin is generally used in order to increase affinity with blood.

  It is known that serious side effects such as anaphylactic shock that may be caused by elution of polyvinylpyrrolidone occur during hemodialysis treatment using a selective separation membrane containing a hydrophilic polymer, particularly polyvinylpyrrolidone. In Germany, there is a regulation that polyvinyl pyrrolidone having a K-18 (weight average molecular weight of 10,000) or more cannot be intravenously injected. Furthermore, it has been reported that anaphylactic symptoms are exhibited by intravenous injection of polyvinylpyrrolidone (Pilar Maiques Asuero et al., The Annals of Pharmacotherapy, pp30, January, Vol. 30, 1996). In other words, polyvinylpyrrolidone generally used as a hydrophilizing agent for polysulfone resin membranes has a safety problem, and when used for blood purification, it is necessary to suppress elution of polyvinylpyrrolidone into blood as much as possible. .

  Many methods have been proposed to suppress elution of polyvinylpyrrolidone. For example, JP-A-10-230148 discloses a method for suppressing elution of polyvinylpyrrolidone by crosslinking and insolubilizing polyvinylpyrrolidone by subjecting a polysulfone-based hollow fiber membrane containing polyvinylpyrrolidone to heat treatment or radiation treatment. Yes. Japanese Patent Laid-Open No. 10-243999 discloses a method for suppressing the elution of polyvinylpyrrolidone by making the thickness of the selective separation layer appropriate. However, although these methods are effective for suppressing the amount of elution into water or hot water, as described later, the amount of elution into a 40% ethanol aqueous solution that serves as an index of the amount of elution into blood or plasma is suppressed. Is not enough. In fact, there are still reports of the occurrence of anaphylactic shock in dialysis membranes that are said to suppress the elution amount of polyvinylpyrrolidone (for example, Nakayama et al., O-439, 43rd Annual Meeting of the Japanese Society for Dialysis Medicine, pp620, 1998). However, the problem with respect to the safety of selective separation membranes containing polyvinylpyrrolidone has not been solved.

  An object of the present invention is to provide a selective separation membrane in which a hydrophilic polymer that is recognized as a foreign substance in a living body is difficult to elute, in order to solve the above problems.

The present inventors have reached the present invention as a result of diligent research to solve the above problems and to provide a selective separation membrane having excellent safety. That is, the present invention is as follows.
(1) The hydrophilicity extracted with a 40% ethanol aqueous solution in a selective separation membrane formed from a hydrophobic polymer and a hydrophilic polymer from which a low molecular weight body having a number average molecular weight of 50,000 or less is substantially removed sex polymer Ri treated liquid contacting side membrane area 1 m ² per 10mg der following selective separation membrane, and selective separation of blood processing, characterized in that is substantially free of a number average molecular weight of 100,000 or more film.
( 2 ) The selective separation membrane for blood treatment according to ( 1 ), wherein the hydrophobic polymer is a polysulfone resin.
( 3 ) The selective separation membrane for blood treatment according to (1) or (2) , wherein the hydrophilic polymer is polyvinylpyrrolidone.
( 4 ) The hydrophilic polymer extracted with a 40% aqueous ethanol solution is selected by using the hydrophilic polymer from which the hydrophobic polymer and the low molecular weight substance having a number average molecular weight of 50,000 or less are substantially removed. A method for producing a selective separation membrane, characterized in that the membrane area is 10 mg or less per 1 m ^{2 of} membrane surface on the liquid contact side of the separation membrane and does not substantially contain a number average molecular weight of 100,000 or more .
( 5 ) A blood processing module manufactured using a selective separation membrane formed from a hydrophobic polymer and a hydrophilic polymer from which a low molecular weight substance having a number average molecular weight of 50,000 or less has been substantially removed. there are, the selective separation membrane is substantially dry, Ri hydrophilic polymer treated liquid contacting side membrane area 1 m ² per 10mg der following selective separation membranes are extracted with 40% aqueous ethanol solution, A selective separation membrane module for blood treatment , which is substantially free of those having a number average molecular weight of 100,000 or more .

  According to the present invention, a selective separation membrane containing a hydrophilic polymer but having little elution of the hydrophilic polymer can be provided.

In the present invention, the reason why the hydrophilic polymer extracted with 40% ethanol aqueous solution is 10 mg or less per 1 m ^{2 of the} liquid surface membrane area of the selective separation membrane is as follows. First, in a selective separation membrane composed of a hydrophobic polymer and a hydrophilic polymer, it is impossible to completely eliminate the elution of the hydrophilic polymer, so it is necessary to determine the upper limit of safety. Although allergic reactions to the eluted polyvinylpyrrolidone vary from person to person, we investigated the anaphylactic reaction when we intravenously injected polyvinylpyrrolidone using a beagle dog. Until the intravenous injection of 5 mg of polyvinylpyrrolidone per kg body weight, the anaphylactic reaction It turns out that does not cause. Taking into account individual differences, the upper limit is 1/10 of the safe dose of beagle dogs, and the upper limit of the membrane area of a dialyzer usually used for hemodialysis is approximately 2 m ^2. If 40 kg, 20 mg per dialysis is the upper limit of administration of polyvinylpyrrolidone, and it is considered that safety can be ensured by setting it to 10 mg or less per 1 m ² .

In fact, when we measured the elution amount of polyvinyl pyrrolidone by extraction test with 40% ethanol aqueous solution of polysulfone-based dialysis membrane containing polyvinyl pyrrolidone currently on the market, elution of several tens to several hundred mg per 1 m ² I found out that Therefore, in order to ensure the safety of the polysulfone-based membrane containing polyvinylpyrrolidone, it can be achieved by suppressing the elution amount to 10 mg or less per 1 m ² due to these facts.

  The reason why we chose extraction with 40% ethanol aqueous solution is as follows. That is, when the selective separation membrane is used for the purpose of blood purification, the liquid to be treated is not water but blood or plasma. Since blood or plasma contains electrolytes, plasma proteins, blood cells, and other organic components in water, it is said that the dissolving power for various solutes is considerably higher than that of water or hot water. Extraction with 40% ethanol aqueous solution is used to measure the amount of vinyl chloride additive (phthalate ester) used in blood circuits, and is said to have extractability closer to blood than water or hot water. Yes. By using this 40% ethanol aqueous solution, it was considered that the elution amount of polyvinylpyrrolidone at the time of blood contact of the selective separation membrane containing polyvinylpyrrolidone could be measured.

  In fact, we compared the elution amount of polyvinyl pyrrolidone of a selective separation membrane containing polyvinyl pyrrolidone, which is currently on the market, under the same conditions, with 70 ° C. pure water and 40% ethanol aqueous solution. It was found that the amount of extraction by 5 to 5 times the amount of 70 ° C. pure water extracted.

As a result of the above research, the hydrophilic polymer extracted with a 40% ethanol aqueous solution is 10 mg or less per 1 m ^{2 of the} membrane area to be treated of the selective separation membrane. And the present invention has been achieved.

  In the present invention, the liquid to be treated refers to a liquid to be separated by a selective separation membrane, and the liquid treatment contact side refers to the surface of the membrane on the side that is to be treated. That is, in hemodialysis, hemofiltration, hemodiafiltration, and plasma separation, the liquid to be treated is blood, and in the plasma fraction, the liquid to be treated is plasma. The blood (or plasma in the case of plasma fraction) contact surface. When the hollow fiber-shaped selective separation membrane is used for blood purification, the liquid contact side is usually the inside of the hollow fiber. In hemodialysis and hemodiafiltration, blood is allowed to flow on one side of the membrane and dialysate is allowed to flow on the other side. Thus, in such a case, in the present invention, the liquid to be treated is blood or a blood component, not a dialysate.

  In addition to blood purification, the present invention can be suitably used for applications that cause inconvenience due to elution of hydrophilic polymers, such as foods and beverages, concentration and purification of physiologically active substances, etc. Food, beverages, physiologically active substance-containing liquids, etc. can be mentioned, but if the present invention is applied to blood purification for returning the liquid to be treated to the human body again, the safety is improved. The present invention is most effective when used as a treatment liquid. The selective separation membrane of the present invention is preferably applied to blood purification applications for returning treated blood to the human body as described above. Specifically, hemodialysis membrane, hemodiafiltration membrane, blood filtration membrane, plasma separation membrane , Plasma fractionation membrane, ascites membrane and the like. Examples of forms that the selective separation membrane of the present invention can take include a flat membrane, a tubular membrane, and a hollow fiber membrane. A hollow fiber membrane that can take a large membrane area per unit volume is preferable.

  The hydrophobic polymer in the present invention includes synthetic polymers such as polyester, polycarbonate, polyurethane, polyamide, polysulfone, polyethersulfone, and polymethyl methacrylate, and cellulosic materials such as cellulose triacetate and cellulose nitrate, and is particularly limited. Although not intended, polysulfone-based materials such as polysulfone and polyethersulfone are preferable because they are excellent in biocompatibility when used for blood purification and can provide high uremic substance removal performance. These may be used alone or in combination of two or more.

  The hydrophilic polymer in the present invention is a material such as polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, starch and derivatives thereof, and cellulose acetate, but is preferably polyvinyl because it has compatibility with a polysulfone resin. Pyrrolidone.

In the embodiment of the present invention, the molecular weight of the hydrophilic polymer is most important. In a film composed of a polysulfone resin and polyvinyl pyrrolidone, it is considered that the polyvinyl pyrrolidone is surrounded by the polysulfone resin. Therefore, by increasing the molecular weight of the hydrophilic polymer, it becomes difficult to fall out of the film. Polyvinylpyrrolidone is commercially available different grades of molecular weight, most higher molecular weight grade (K-90) has a number average molecular weight of about 360,000, polyvinylpyrrolidone having a number average molecular weight of this level, from the film It is unlikely that it will fall out. However, commercially available polyvinylpyrrolidone has a molecular weight distribution and contains a large amount of molecules having a number average molecular weight of about tens of thousands to 100,000. As a result of our study, the polyvinyl pyrrolidone eluted was measured by gel permeation chromatography in an extraction experiment using 40% ethanol aqueous solution of polysulfone resin membrane prepared using K-90. The number average molecular weight is about 20,000 to 50,000, and polyvinylpyrrolidone having a number average molecular weight of 100,000 or more was hardly detected. In other words, any method such as chromatographic method or reprecipitation method may be used, but it is used when a commercially available polyvinylpyrrolidone K-90 is treated to actively remove low molecular weight substances and form a hollow fiber membrane. This makes it possible to suppress elution of polyvinylpyrrolidone by extraction with a 40% ethanol aqueous solution to 10 mg or less per 1 m ^{2 of} membrane surface area to be treated. The low molecular weight substance to be removed usually has a number average molecular weight of less than 50,000, preferably less than 100,000.

  Details of the present invention will be described below by way of examples.

The 40% ethanol extraction test was performed according to the following procedure. After flushing by flowing 400 mL of pure water inside the hollow fiber membrane module (to the liquid to be treated), the inside of the hollow fiber was replaced with 40 vol% ethanol aqueous solution. The inside of the module case outside the hollow fiber was also filled with 40 vol% ethanol and sealed. Next, 200 mL of 40 vol% ethanol aqueous solution was circulated inside the hollow fiber for 1 hour at a flow rate of 150 mL / min and 40 ° C., and then the polyvinylpyrrolidone concentration in the circulated 40 vol% ethanol aqueous solution was measured. From the total volume of the extract and the concentration of polyvinyl pyrrolidone in the extract obtained by adding 200 mL to the inner volume of the hollow fiber of the module and the volume of the header portion at the inlet and outlet of the module, that is, the priming volume, From the membrane area of the hollow fiber membrane module (with reference to the inner diameter of the hollow fiber), the amount of polyvinylpyrrolidone extracted per 1 m ^{2 of} membrane area on the contact side of the liquid to be treated is determined.

  The method of K. Mueller (1968) was used to measure the concentration of polyvinylpyrrolidone. That is, citric acid and iodine solution were added to the specimen, the absorbance was measured, and the concentration was determined using a calibration curve obtained from polyvinylpyrrolidone K-90. Here, when measuring the concentration, it is necessary to dilute it twice or more in order to eliminate the inhibition of color development by ethanol. Specifically, for example, in case of 2-fold dilution, 1.25 mL of sample (standard or extract), 1.25 mL of water, 1.25 mL of 0.2 M citric acid aqueous solution, and 0.5 mL of 0.006 N iodine aqueous solution are sufficient. After mixing and allowing to stand for 10 minutes, the absorbance at 470 nm was measured, and the concentration of polyvinylpyrrolidone was measured.

Example 1
Polyvinylpyrrolidone (K-90, manufactured by BASF) 0.025g / mL aqueous solution is dropped into acetone, which is a poor solvent with a bath ratio of the aqueous solution to water of 2.5 to 3.0 times. Polyvinylpyrrolidone from which the body was removed was obtained in a yield of 90%. This is hereinafter referred to as purified polyvinyl pyrrolidone. FIG. 1 and FIG. 2 show the gel permeation chromatography profiles of polyvinylpyrrolidone before purification and fractions excluded during purification. As is clear from the figure, it can be seen that only the low molecular fraction (in the direction where the permeation time is long) is selectively excluded during purification. 16% by weight of polyethersulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.) and 5 parts by weight of purified polyvinylpyrrolidone were mixed and dissolved in 74 parts by weight of dimethylacetamide and 5 parts by weight of water. Used as a liquid, discharged from a double-tube orifice, passed through a 50 cm idling part, led into a water coagulation bath at 75 ° C. to form a hollow fiber membrane, scraped after washing with water, and dried at 60 ° C. for 20 hr. did. Using this hollow fiber membrane, a module having a hollow fiber inner diameter reference membrane area of 1.5 m ² was obtained. As a result of a 40% ethanol extraction test using this module, the elution of polyvinylpyrrolidone was 1.0 mg per 1 m ² of hollow fiber inner membrane area.

(Example 2)
A 45% dimethylacetamide aqueous solution was used as a core solution as a spinning stock solution in which 20 parts by weight of polysulfone (P-1700, manufactured by AMOCO), 6 parts by weight of purified polyvinylpyrrolidone and 74 parts by weight of dimethylacetamide were mixed and dissolved and degassed. Was discharged from a double tube orifice, passed through a 70 cm idling portion, led to a water coagulation bath at 50 ° C. to form a hollow fiber membrane, scraped after washing with water, and dried at 60 ° C. for 20 hours. Using this hollow fiber, a module having a hollow fiber inner diameter reference membrane area of 1.5 m ² was obtained. As a result of a 40% ethanol extraction test using this module, the elution of polyvinylpyrrolidone was 1.3 mg per 1 m ² of hollow fiber inner membrane area.

(Comparative example)
A hollow fiber membrane was spun in the same manner as in Example 2 except that unpurified K-90 (manufactured by BASF) was used as polyvinylpyrrolidone, and the hollow fiber inner diameter reference membrane area 1 was obtained using the obtained hollow fiber. A module of 5 m ² was obtained. As a result of conducting a 40% ethanol extraction test with this module, the elution of polyvinylpyrrolidone was 15.2 mg per 1 m ² of the hollow fiber inner membrane area.

The profile of the gel permeation chromatography of polyvinylpyrrolidone (K-90) is shown. The gel permeation chromatography profile of the fraction excluded during the purification of polyvinylpyrrolidone is shown. The gel permeation chromatography profile of the polyvinylpyrrolidone from which elution was detected by 40% ethanol extraction is shown.

Claims (3)

In polysulfone resin and a number average molecular weight of 50,000 or less at a certain low molecular weight material is substantially removed polyvinyl selective separation membrane formed from Don, is the selection separation membrane polyvinylpyrrolidone extracted with 40% aqueous ethanol solution A selective separation membrane for blood treatment which is 10 mg or less per 1 m ^{2 of} membrane area on the treatment liquid contact side and substantially free of a number average molecular weight of 100,000 or more. In polysulfone resin and a number average molecular weight of 50,000 or less at a certain low molecular weight material is substantially removed polyvinyl selective separation membrane formed from Don, is the selection separation membrane polyvinylpyrrolidone extracted with 40% aqueous ethanol solution A method for producing a selective separation membrane for blood treatment , characterized in that the treatment liquid contact side membrane area is 10 mg or less per 1 m ² and contains substantially no number average molecular weight of 100,000 or more. A blood treatment module produced using a selective separation membrane formed from a polysulfone-based resin and a polyvinylpyrrolidone from which a low molecular weight substance having a number average molecular weight of 50,000 or less has been substantially removed. The membrane is substantially dry, polyvinyl pyrrolidone extracted with 40% ethanol aqueous solution is 10 mg or less per 1 m ^{2 of} membrane surface area on the liquid contact side of the selective separation membrane, and has a number average molecular weight of 100,000 or more A selective separation membrane module for blood treatment, which is substantially free of blood.