JP2000300663A - Selective separation membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To substantially prevent the elution of a hydrophilic high polymer recognized as foreign matters within the living body by specifying the content of the hydrophobic high polymer to be extracted by prescribed % of an aqueous ethanol solution into a selective separation membrane consisting of the hydrophilic high polymer and a hydrophobic high polymer to a prescribed value or below per prescribed area of the liquid to the treated contact side membrane of the selective separation membrane. SOLUTION: The hydrophilic high polymer to be extracted by the 40% aqueous ethanol solution is <=10 mg per 1 m2 the area of liquid to be treated contact side membrane of the selective separation membrane. The selective separation membrane is adequately usable in applications where inconvenience is induced by the elution of the hydrophilic high polymer; for example, thickening, refining, etc., of food, beverages and physiologically active materials in addition a blood purification. The water to be treated includes food, beverages and physiologically active material- containing liquids, etc. If the selective separation membrane is applied to the blood purification application to return the water to be treated again to the human body, safety is improved and, therefore, the membrane is most effective when the blood or the component of the blood is used as the water to be treated.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a selective separation membrane comprising a hydrophobic polymer and a hydrophilic polymer, in which the elution of the hydrophilic polymer is suppressed and safety is improved. More specifically, the present invention relates to a selective separation membrane containing a hydrophilic polymer with improved safety by suppressing elution of the hydrophilic polymer into blood when used for blood purification.

[0002]

2. Description of the Related Art With regard to a method for treating blood of a patient with chronic renal failure, various techniques for improving membrane performance and dialysis methods have been developed, taking living kidney as an example. As the membrane material 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 have excellent biocompatibility and can exhibit high removal performance of uremic substances have attracted attention.
Many blood purification membranes using polysulfone-based resins are on the market. Polysulfone resins are thermoplastic heat-resistant engineering plastics, and are widely used in various industrial fields.

[0003] Polysulfone resins are relatively hydrophobic and tend to adsorb plasma proteins when in contact with blood. For this reason, when fabricating a blood purification membrane, a method of imparting hydrophilicity by mixing polyvinylpyrrolidone with a polysulfone-based resin is generally used to increase affinity with blood.

[0004] It is known that during hemodialysis treatment using a selective separation membrane containing a hydrophilic polymer, particularly polyvinylpyrrolidone, serious side effects such as anaphylactic shock caused by elution of polyvinylpyrrolidone occur. I have. Further, in Germany, there is a regulation that polyvinylpyrrolidone having K-18 (weight average molecular weight of 10,000) or more cannot be injected intravenously. In addition, it has been reported that intravenous injection of polyvinylpyrrolidone causes anaphylactic symptoms (Pilar Maiques Asuer
o et al., The Annals of Pharmacotherapy, pp30, Janua
ry, Vol.30, 1996). That is, polyvinylpyrrolidone, which is generally used as a hydrophilizing agent for a polysulfone-based resin membrane, has a problem in safety, and when used for blood purification, it is necessary to suppress the dissolution of polyvinylpyrrolidone into blood as much as possible. .

[0005] In order to suppress the elution of polyvinylpyrrolidone, many methods have been proposed so far. For example, JP-A-10-230148 discloses that a polysulfone-based hollow fiber membrane containing polyvinylpyrrolidone is subjected to heat treatment or radiation treatment to crosslink polyvinylpyrrolidone,
A method for suppressing the elution of polyvinylpyrrolidone by insolubilization is disclosed. Also, JP-A-10-24399
No. 9 discloses a method for suppressing the elution of polyvinylpyrrolidone by making the thickness of the selective separation layer appropriate.
However, although these techniques are effective in suppressing the amount of elution into water or hot water, as described later, the amount of elution into 40% ethanol aqueous solution, which is an indicator of the amount of elution into blood or plasma, is described below. Is not enough. In fact, there is still a report of the occurrence of anaphylactic shock in dialysis membranes that are said to suppress the amount of polyvinylpyrrolidone eluted (eg, Nakayama et al., O-439, 43rd Annual Meeting of the Japanese Society for Dialysis Therapy, pp620, 1998). At present, the problem on the safety of the selective separation membrane containing polyvinylpyrrolidone has not been solved.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems and to provide a selective separation membrane in which a hydrophilic polymer which is recognized as a foreign substance in a living body is hardly eluted. .

[0007]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems and to provide a selective separation membrane having excellent safety, and as a result, have reached the present invention. That is, the present invention is as follows. In selective separation membrane comprising a hydrophobic polymer and a hydrophilic polymer, the liquid to be treated contact side film of the hydrophilic polymer selected separation membranes are extracted with 40% aqueous ethanol area 1 m ² per 10
A selective separation membrane characterized in that the amount is not more than mg. The selective separation membrane according to the above, wherein the liquid to be treated is blood. The selective separation membrane described above or described for use in hemodialysis, hemodiafiltration, hemofiltration, plasma separation, plasma fractionation, or ascites concentration. The selective separation membrane according to any of the above-mentioned or the above, wherein the selective separation membrane is a hollow fiber membrane. 4. The selective separation membrane according to any one of the above items, wherein the hydrophobic polymer is a polysulfone resin. 4. The selective separation membrane according to any one of the above, wherein the hydrophilic polymer is polyvinylpyrrolidone.

In the present invention, the reason why the amount of the hydrophilic polymer extracted with a 40% aqueous ethanol solution is 10 mg or less per 1 m ^{2 of the} membrane area of the liquid to be treated 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 was necessary to determine the upper limit of safety. The allergic reaction to the eluted polyvinylpyrrolidone varies from person to person, but when we examined the anaphylactic reaction of polyvinylpyrrolidone intravenously using beagle dogs, the anaphylactic reaction was observed until the intravenous injection of 5 mg polyvinylpyrrolidone per kg body weight. Did not occur. Taking into account individual differences, the upper limit is 1/10 of the safe dose of a beagle dog, and the upper limit of the membrane area of a dialyzer usually used for hemodialysis is about 2 m ^2.
If the lower limit of the weight of a dialysis patient is 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, we have found that 40% of the polysulfone-based dialysis membranes currently containing polyvinylpyrrolidone are commercially available.
When the elution amount of polyvinylpyrrolidone was measured by an extraction test with an aqueous ethanol solution, several tens mg per 1 m ² was measured.
It was found that there was ~ 100 mg of elution. Therefore, in order to ensure the safety of polysulfone film containing polyvinylpyrrolidone it can be achieved by suppressing the elution amount of less 1 m ² per 10mg These facts.

The reason why we chose extraction with a 40% aqueous ethanol solution is as follows. That is, when a selective separation membrane is used for the purpose of blood purification, the liquid to be treated is not blood but blood or plasma. Blood or plasma is said to have much higher solubility for various solutes than water or hot water because water contains electrolytes, plasma proteins, blood cells, and other organic components. Extraction with a 40% aqueous ethanol solution is used to measure the amount of vinyl chloride additive (phthalate ester) used in the blood circuit,
Compared to water and hot water, it is said to have an extraction power closer to blood. It was thought that the amount of polyvinylpyrrolidone eluted when the selective separation membrane containing polyvinylpyrrolidone was brought into contact with blood could be measured by using this 40% ethanol aqueous solution.

In fact, when we compared the amount of polyvinylpyrrolidone eluted from a commercially available selective separation membrane containing polyvinylpyrrolidone under the same other conditions with pure water at 70 ° C. and a 40% aqueous ethanol solution, we found that 40 % Ethanol aqueous solution extraction volume is 5-5 of 70 ° C pure water extraction volume.
It turned out to be 20 times.

According to the above research, the safety was remarkably improved by reducing the amount of the hydrophilic polymer extracted with a 40% aqueous ethanol solution to 10 mg or less per 1 m ^{2 of the} membrane area of the selective separation membrane on the side of the liquid to be treated. The inventors have found that a selective separation membrane can be obtained, and have reached the present invention.

In the present invention, the liquid to be treated refers to the liquid to be separated by the selective separation membrane, and the liquid contacting side refers to the surface of the membrane on the side in contact with the liquid 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. Refers to the blood (plasma in the case of plasma fraction) contact surface. When the hollow fiber-shaped selective separation membrane is used for blood purification, the contact side of the liquid to be treated is usually the inside of the hollow fiber. In hemodialysis and hemodiafiltration, blood flows on one side of the membrane and dialysate flows on the other side, but it is clear from the purpose of improving safety by suppressing elution of hydrophilic polymers from the membrane to the liquid to be treated. As described above, in such a case, the liquid to be treated in the present invention is blood or a blood component, not a dialysate.

In addition, the present invention can be suitably used for blood purification and other applications in which inconvenience is caused by elution of a hydrophilic polymer, for example, concentration and purification of foods and beverages, and physiologically active substances. Examples of the liquid include foods, beverages, physiologically active substance-containing liquids, and the like. However, if the present invention is applied to a blood purification application in which the liquid to be treated is returned to the human body again, the safety is improved, so that blood or blood The present invention is most effective when the components are used as the liquid to be treated. The selective separation membrane of the present invention is preferably applied to a blood purification application for returning blood after treatment to the human body as described above, and specifically, a hemodialysis membrane, a hemodiafiltration membrane, a blood filtration membrane, and a plasma separation membrane. , A plasma fractionation membrane, an ascites concentration membrane, and the like. Possible forms of the selective separation membrane of the present invention include a flat membrane, a tubular membrane, a hollow fiber membrane and the like, and a hollow fiber membrane capable of increasing a membrane area per unit volume is preferable.

In the present invention, the hydrophobic polymer includes polyester, polycarbonate, polyurethane, polyamide,
Polysulfone, polyethersulfone, synthetic polymers such as polymethyl methacrylate and cellulose-based materials such as cellulose triacetate and cellulose nitrate include, but are not particularly limited to, polysulfone-based materials such as polysulfone and polyethersulfone, When used for blood purification, it is preferable because it has excellent biocompatibility and high removal performance of uremic substances. These may be used alone or as a mixture of two or more.

The hydrophilic polymer in the present invention is a material such as polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, starch and its derivatives, and cellulose acetate, and is preferable because of its compatibility with polysulfone resin. Is polyvinylpyrrolidone.

In the embodiment of the present invention, the molecular weight of the hydrophilic polymer is most important. In the film composed of the polysulfone-based resin and polyvinylpyrrolidone, it is considered that polyvinylpyrrolidone is present surrounded by the polysulfone-based resin. For this reason, by increasing the molecular weight of the hydrophilic polymer, it becomes difficult for the hydrophilic polymer to fall out of the film. Polyvinylpyrrolidone is commercially available in grades with different molecular weights. The grade with the highest molecular weight (K-90) has a number average molecular weight of about 360,000, and polyvinylpyrrolidone with this molecular weight falls out of the film. Is hard to imagine. However, it has a commercially available molecular weight distribution of polyvinylpyrrolidone, and contains a large amount of molecules having a molecular weight of about tens of thousands to 100,000. According to our study results, the eluted polyvinylpyrrolidone was measured by gel permeation chromatography in an extraction experiment with a 40% aqueous ethanol solution of a polysulfone-based resin membrane prepared using K-90. The molecular weight is about 20,000 to 50,000,
Polyvinylpyrrolidone having a molecular weight of 100,000 or more was hardly detected. That is, any method such as chromatographic method and reprecipitation method can be used, but commercially available polyvinylpyrrolidone
By treating K-90 to positively remove low molecular weight substances and using this in forming hollow fiber membranes, 40%
Elution of polyvinylpyrrolidone by extraction with an aqueous ethanol solution can be suppressed to 10 mg or less per 1 m ^{2 of the} membrane area on the liquid side to be treated. The low molecular weight substance to be removed usually has a molecular weight of less than 50,000, preferably less than 100,000.

Hereinafter, the present invention will be described in detail with reference to examples.

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

For measuring the concentration of polyvinylpyrrolidone, use K.Mu
eller (1968). That is, citric acid and an iodine solution were added to the sample, the absorbance was measured, and the concentration was determined by a calibration curve determined from polyvinylpyrrolidone K-90. Here, at the time of concentration measurement, it is necessary to dilute at least two times in order to eliminate the inhibition of color development by ethanol. Specifically, for example, in the case of a 2-fold dilution, 1.25 mL of a sample (a sample or an extract), 1.25 mL of water, 1.25 mL of a 0.2 M aqueous citric acid solution, and 1.25 mL of a 0.006 N iodine aqueous solution.
After 5 mL was mixed well and allowed to stand for 10 minutes, the absorbance at 470 nm was measured, and the concentration of polyvinylpyrrolidone was measured.

[0021]

【Example】

Example 1 Polyvinylpyrrolidone (K-90, manufactured by BASF) 0.025 g / m
The aqueous solution of L was dropped into acetone, a poor solvent having a bath ratio of 2.5 to 3.0 times that of the aqueous solution, to obtain polyvinylpyrrolidone in a yield of 90% from which low-molecular-weight substances were positively removed by the reprecipitation method. . This is hereinafter referred to as purified polyvinylpyrrolidone. FIGS. 1 and 2 show the profiles of polyvinylpyrrolidone before purification and the fraction excluded during purification by gel permeation chromatography. As is clear from the figure, it can be seen that only the low molecular fraction (in the direction of longer permeation time) was selectively excluded during purification. A mixture of 16 parts by weight of polyether sulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.), 5 parts by weight of purified polyvinylpyrrolidone, 74 parts by weight of dimethylacetamide and 5 parts by weight of water was dissolved and defoamed. Liquid and discharge it from the double pipe orifice.
A hollow fiber membrane was formed at 75 ° C. in a coagulation bath of water through a free running section of 0 cm, washed with water, washed, and dried at 60 ° C. for 20 hours. Using this hollow fiber membrane, a module having a hollow fiber inner diameter reference membrane area of 1.5 m ² was obtained. 40% with this module
Result of the ethanol extraction test, elution of polyvinylpyrrolidone were hollow fiber within the membrane area 1 m ² per 1.0 mg.

Example 2 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 a 45% aqueous solution of dimethylacetamide was used as a defoaming spinning solution. Used as a liquid and discharged from the double pipe orifice, 70 cm
The hollow fiber membrane was formed at 50 ° C. in a coagulation bath of water, washed, washed with water, and dried at 60 ° C. for 20 hours. By using this hollow fiber, the inner diameter of the hollow fiber is 1.5
m ² modules were obtained. 40% ethanol extraction test The result of this module, the elution of polyvinylpyrrolidone were hollow fiber within the membrane area 1 m ² per 1.3 mg.

Comparative Example K-90 not purified as polyvinylpyrrolidone
A hollow fiber membrane was spun in the same manner as in Example 2 except that (manufactured by BASF) was used, and a module having a hollow fiber inner diameter reference membrane area of 1.5 m ² was obtained using the obtained hollow fiber. As a result of conducting a 40% ethanol extraction test with this module, the dissolution of polyvinylpyrrolidone was 15.2 m per 1 m ² of hollow fiber inner membrane area.
g.

[0025]

[Table 1]

[0026]

According to the present invention, it is possible to provide a selective separation membrane which contains a hydrophilic polymer but has little elution of the hydrophilic polymer.

[Brief description of the drawings]

FIG. 1 shows the profile of gel permeation chromatography of polyvinylpyrrolidone (K-90).

FIG. 2 shows a gel permeation chromatography profile of a fraction excluded during purification of polyvinylpyrrolidone.

FIG. 3 shows a gel permeation chromatography profile of polyvinylpyrrolidone in which elution was detected by 40% ethanol extraction.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) B01D 71/68 B01D 71/68 F-term (Reference) 4C077 AA05 AA09 AA20 BB01 BB02 KK30 LL05 LL12 NN03 NN04 PP15 PP18 PP27 4D006 GA13 HA02 MA01 MB20 MC10 MC16 MC18 MC19 MC32 MC33 MC37 MC40X MC48 MC49 MC53 MC54 MC62X MC63X MC88 NA04 NA64 PB09 PB42 PC47

Claims (6)

[Claims] 1. A selective separation membrane comprising a hydrophobic polymer and a hydrophilic polymer, wherein the hydrophilic polymer extracted with a 40% aqueous ethanol solution has a membrane area of 1 m on the side of the selective separation membrane contacting the liquid to be treated.
A selective separation membrane characterized by being 10 mg or less per ² . 2. The selective separation membrane according to claim 1, wherein the liquid to be treated is blood. 3. The selective separation membrane according to claim 1, which is used for hemodialysis, hemodiafiltration, hemofiltration, plasma separation, plasma fractionation, or ascites concentration. 4. The selective separation membrane according to claim 1, wherein the selective separation membrane is a hollow fiber membrane. 5. The selective separation membrane according to claim 1, wherein the hydrophobic polymer is a polysulfone resin. 6. The selective separation membrane according to claim 1, wherein the hydrophilic polymer is polyvinylpyrrolidone.