JP2000135422A - Polysulfone-base medical separation membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a polysulfone-base medical separation membrane excellent in endotoxin adsorptivity even after radioactive-ray irradiation and capable of maintaining its effect even after storage over a long period of time. SOLUTION: The medical separation membrane is a radioactive-ray irradiated membrane consisting of a polysulfone polymer and polyvinylpyrrolidone. The membrane shows excellent endotoxin adsorptivity when the carboxyl group content of the membrane is adjusted to >=800 and <1,600 nmol/g and can maintain its effect over a long period of time when the peroxide content is suppressed to <=200 nmol/g because the deterioration of the adsorptivity due to a change with the lapse of time is not caused. The membrane is appropriately utilized in fields related to blood purification.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical separation membrane used in the field of blood purification, and more particularly to treatment by extracorporeal circulation such as hemodialysis or hemofiltration, and purification of dialysate. It can be used as an endotoxin cut filter.

[0002]

2. Description of the Related Art In recent years, many membrane separation techniques have been put to practical use, and various selective separation membranes have been used to separate a target substance from a liquid or gas mixture or remove impurities. Organic polymers are generally used as the material of the selective separation membrane, for example, cellulose as a natural polymer, polyacrylonitrile, polyamide as a synthetic polymer,
Examples include polyimide, polyolefin, polysiloxane, polysulfone, and polymethacrylate. Among them, polysulfone-based polymers are widely used as industrial separation membranes because they exhibit excellent resistance to radiation, heating, and chemicals such as acids and alkalis. In addition, because of their excellent biocompatibility and safety, they have recently attracted attention as materials for medical separation membranes, and demand has been increasing.

However, since the polysulfone-based polymer is a material having high water repellency, sufficient filtration performance cannot be ensured as it is, or thrombus formation may occur due to poor affinity with blood. Therefore, some attempts have been made to make the membrane hydrophilic by forming a membrane from a stock solution containing a small amount of highly compatible hydrophilic polymers such as polyvinylpyrrolidone and polyethylene glycol. Was also eluted from the membrane. Many attempts to remedy this drawback have been disclosed.
In 32297, the membrane is treated with a polyacid such as polycarboxylic acid or polyphenol to form an insoluble complex with the hydrophilic polymer. In JP-A-62-38205, the membrane is treated with a radical generating reagent to convert the hydrophilic polymer. Although methods for cross-linking and insolubilizing are known, it has been difficult to completely remove reagents from the membrane by these chemical means.

On the other hand, Japanese Patent Application Laid-Open No.
In 03664, the hydrophilic polymer is insolubilized and fixed to the membrane by heat-treating the membrane in a dry state. JP-A-4-3
In No. 00636, the hydrophilic polymer is irradiated with radiation in a water-containing state to insolubilize the hydrophilic polymer by crosslinking, thereby improving the elution property from the film. In the case of a blood purification membrane as in the present invention, it is preferable that the membrane has a porous structure in order to enhance the separation performance, but heat shrinkage due to the structure easily occurs,
The above dry heat treatment at a high temperature was inappropriate. On the other hand, the insolubilization treatment by irradiation with radiation can be used as a sterilization step indispensable for a medical separation membrane, and is considered to be a more rational means.

[0005] By the way, a small amount of endotoxin, which is a physiologically active substance derived from bacterial cells, may be mixed in a dialysate. Usually, endotoxin is introduced into blood by using an endotoxin cut filter and a blood purification membrane together. Blocking the transition. Endotoxin is an aggregate of structural units having a certain molecular weight, and further contains a hydrophobic portion and a negative functional group in the molecule, so that the membrane permeability is affected by the pore size and the adsorption capacity. Although the hydrophilic polymer is contained in the membrane, even if the total content is very small, it is concentrated on the membrane surface as a result of the phase separation, so that this influence cannot be ignored. Therefore, the adsorptivity to endotoxin changes as a result of the hydrophilic treatment of the membrane, and the adsorptivity may change over time due to the decomposition of unstable functional groups generated in the hydrophilic polymer as a result of irradiation. Was.

[0006]

SUMMARY OF THE INVENTION The present invention has no problems in the above-mentioned prior art, that is, it has excellent endotoxin adsorption even when irradiated, and can maintain its effect even after long-term storage. An object of the present invention is to provide a polysulfone-based medical separation membrane.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, in a film irradiated with radiation, the carboxyl group content and the peroxide content in the film were kept constant. When the content is controlled within the above range, it has been found that the endotoxin-adsorbing property is excellent, and that the effect can be maintained even after long-term storage, thereby completing the present invention.
That is, the polysulfone-based medical separation membrane of the present invention is a radiation-irradiated membrane comprising a polysulfone-based polymer and polyvinylpyrrolidone, and has a carboxyl group content of 800 nmol / g or more and 1600 nmol / g.
And the peroxide content is less than 200 nmol / g
It is characterized by the following.

The polysulfone polymer as the first component of the membrane of the present invention is an aromatic polysulfone polymer having a repeating structure of a unit represented by the following chemical structural formula (1) or (2). Also, so-called polysulfone derivatives in which a functional group or an alkyl group is bonded to an aromatic ring are included in the category. Ar in the formula represents a para-disubstituted phenyl group. The molecular weight of these polysulfone polymers is not particularly limited. _{-O-Ar-C (CH 3} ) 3 -Ar-O-Ar-SO 3 -Ar- (1) -O-Ar-SO 3 -Ar- (2)

The second component is polyvinylpyrrolidone (PVP), which is a linear water-soluble polymer obtained by addition polymerization of vinylpyrrolidone. The copolymer is not limited to a simple substance, and may be a copolymer with another vinyl monomer.For example, a copolymer with vinyl acetate controls the affinity with the polysulfone polymer and the hydrophilicity of the membrane surface. Can be used for purpose. Since these are commercially available according to molecular weight, they may be used. However,
In any case, the larger the molecular weight, the more it is likely to remain on the film and impart hydrophilicity. Therefore, it is desirable to use a material having a weight average molecular weight of at least 100,000 or more.

[0010] The PVP content in the membrane is one of the important parameters for achieving the present invention. First, it is closely related to the hydrophilicity of the membrane, if the content is too low,
In any case where it is too high, sufficient filtration performance cannot be achieved. In the former case, the hydrophilizing effect is not exhibited, and it is difficult to wet the aqueous medium. In the latter case, the thickness of the PVP concentrated layer on the surface of the agglomerated particles increases due to the swelling of PVP when hydrated, and the pores are narrowed. Is interpreted as The second relates to the carboxyl group content and the peroxide content in the film described below. Since the polysulfone-based polymer has high radiation resistance, it is considered that such a partial structure is generated in PVP in the membrane. Therefore, in order to obtain a desired carboxyl group content, the PVP content should be controlled within a certain range, while the PVP content should be lower from the viewpoint of peroxide. The preferred range of the PVP content satisfying both is 6.0 to 11.0% by weight, and more preferably 7.5 to 10.0% by weight.

[0011] The above-mentioned medical separation membrane receives radiation irradiation represented by γ-ray which is widely used for sterilization of medical devices, so that PVP is insolubilized and hardly eluted from the membrane. Metamorphosis has also occurred. The present inventors have focused on the carboxyl group content and the peroxide content as indices of denaturation, and that the former increases the adsorbability to endotoxin, and the latter is important for maintaining the adsorption effect during long-term storage. Was found.

Since the polysulfone-based polymer has high resistance to radiation, it is considered that the carboxyl group in the film is mainly generated by hydrolysis of the pyrrolidone ring of PVP. Although the detailed action of the carboxyl group on endotoxin adsorption is unknown, since endotoxin shows strong affinity for compounds having an amino group, a secondary amino group simultaneously formed by hydrolysis of an amide bond of a pyrrolidone ring has It is presumed that it adsorbs with an affinity for the acidic group in endotoxin. Therefore, when the carboxyl group content is too low, the secondary amino group content is also low, and as a result, the adsorbability to endotoxin decreases. Conversely, if the amount is too large, there is a possibility that the acid group becomes excessive and the blood coagulation system, particularly the kinin system, is activated, leading to the production of bradykinin, which is not preferable as a medical separation membrane.
A preferable content of the carboxyl group satisfying the above is 80.
0 nmol / g or more and less than 1600 nmol / g.

It is considered that the peroxide in the film, like the carboxyl group, is formed in the main chain of PVP by irradiation, and decomposes during long-term storage due to its chemical instability. In addition, peroxide may already be contained in PVP at the stage of the production raw material, and may be taken into the film as it is.
When irradiation is performed in this state, the radicals generated by the irradiation trigger to cause decomposition. As a result, PV that has been reduced in molecular weight by molecular cleavage starting from peroxide
P is detached from the membrane, and the adsorbability of endotoxin decreases. In order to virtually eliminate the influence of the decomposition, it is necessary to suppress the peroxide content in the film to 200 nmol / g or less, and more preferably 100 nmol / g or less.

The shape of the above-mentioned membrane is preferably hollow in consideration of the strength and practicality of blood purification-related applications. The structure of the hollow fiber is composed of a hollow part having an inner diameter of 80 to 400 μm and a film part having a thickness of 35 to 85 μm. If the inner diameter is smaller than this, the fluid resistance increases and the operability decreases. On the other hand, if it is larger than necessary, the film thickness must be increased to maintain the strength, and the mass transfer efficiency is reduced. On the other hand, if the film thickness is too small, the strength cannot be maintained and the film may be crushed at the time of handling. If the film thickness is too large, the mass transfer resistance in the film increases, and the permeation performance deteriorates.

Furthermore, when the membrane of the present invention is actually used,
After assembling the membrane into the housing, both ends are potted to form a separation module having a predetermined membrane area.
The shape of the module may be a known one, and is not particularly limited.Each of the potting portions has a header with a nozzle for introducing and discharging blood, and a dialysis solution is introduced near both ends of the housing. Any structure having a nozzle for discharging may be used. When used as an endotoxin cut filter, there is no problem with the same structure. The materials of the housing and the potting material are not particularly limited.

The packing density of the hollow fiber membrane in the module is:
It is sufficient that the dialysis efficiency is not reduced due to the uneven flow of the dialysate or the membrane is not damaged when inserted into the housing. The membrane area is the total surface area assuming that the inner surface of the hollow fiber is a uniform plane,
The range of 0.01 to 2.5 m ² is preferred. If it is smaller than this, the therapeutic effect of the separation module is not exhibited, and if it is too large, the amount of blood taken out of the body increases, which is not preferable. The module may be either a dry type or a wet type in which an aqueous medium is filled in the module. As described later, the membrane is preferably in a wet state containing at least 100% by weight or more of an aqueous medium.

Next, an embodiment of the polysulfone-based medical separation membrane having the above characteristics will be described in detail. The stock solution is composed of a polysulfone polymer, PVP, and a common solvent thereof. Solvents are N, N-dimethylacetamide, N, N-dimethylformamide, N-methyl-2-
Pyrrolidone and dimethyl sulfoxide can be mentioned, and these can be used alone or in a mixture at an arbitrary ratio. Further, a small amount of water or salt may be added as an additive for the purpose of controlling the solidification rate. In order to form a hollow film, an appropriate viscosity is required. For this purpose, a preferable composition is 15 to 18% by weight of a polysulfone-based polymer,
PVP is 5 to 9% by weight, the balance being solvent.

The composition of the hollow agent is important not only for forming the film into a hollow fiber shape but also for controlling the permeability of the film. In order to obtain a permeability that can be suitably used for the medical separation membrane of the present invention, it is preferable to use a mixture of water and a solvent, and the solvent may be N, N-dimethylacetamide, N, N-dimethylformamide, N -Methyl-2-
It is selected from pyrrolidone and dimethyl sulfoxide. The preferred composition of the hollow agent is 10 to 60% by weight of a solvent and the rest is water. If the proportion of the solvent is higher than this, the hollow shape cannot be maintained until solidification, which causes a production trouble such as thread breakage. On the other hand, if it is lower, sufficient permeability cannot be achieved as a membrane. A more preferred range is 15 to
40% by weight.

The above-mentioned stock solution and the hollow agent are mixed at 30 to 60 ° C.
Is discharged simultaneously from a double spinneret kept warm, and introduced into a coagulation bath through aerial traveling to form a hollow fiber membrane. The coagulation bath may use water kept at 30 to 60 ° C. After winding the solidified hollow fiber membrane into a scalpel, the bundle is cut and hot water is allowed to flow from above the cut surface to remove residual solvent and excess PV.
Wash P. A glycerin aqueous solution is adhered to the membrane as a pore diameter retaining agent, and a drying treatment is performed at 70 to 80 ° C. for 10 hours or more to obtain a dried membrane. The membrane obtained under such controlled conditions achieves the desired PVP content and also has adequate permeation performance as a medical separation membrane.

Next, radiation is applied for the purpose of insolubilizing PVP and sterilizing the membrane. In irradiation, it is preferable to irradiate after modularization by a known method, but in order to insolubilize PVP, the film is desirably in a wet state impregnated with an aqueous medium, and at a water content of at least 100% by weight or more. Irradiation is preferred. Of course, the irradiation may be performed in a so-called wet state in which the inside of the module is filled with an aqueous medium. The water content here is defined as the weight percentage of the aqueous medium contained in the wet membrane. Further, the composition of the aqueous medium is
There is no particular limitation as long as it does not significantly hinder the γ-ray irradiation efficiency, distilled water, pH-controlled acid / alkali aqueous solution,
And a buffer. There is no particular limitation on the type of radiation source when irradiating, but γ-rays using cobalt 60 are commonly used for irradiation sterilization of medical devices. In addition, X-rays and electron beams can be used, but it is most preferable to use γ-rays from the viewpoint of material permeability. Irradiation may be performed continuously or divided into several times, and a total dose of 20 to 100K
Gy irradiation may be performed. By the above method, the polysulfone-based medical separation membrane of the present invention can be obtained.

[0021]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. The various numerical values used in the examples were measured according to the following procedures. (Measurement of Carboxyl Group Content in Membrane) A membrane washed with water and freeze-dried was cut into a length of about 1 cm, and 0.75 g was weighed. This film was immersed in 25 cc of a methanol solution containing 0.01% by weight of 9-anthryldiazomethane (manufactured by Funakoshi Co., Ltd.), allowed to stand at room temperature for 1 hour, and then the film was separated by filtration. The reagent was washed off.
Next, the membrane was immersed in 25 cc of methanol containing 1N caustic soda and hydrolyzed at room temperature for 2 hours. The fluorescence intensity of the supernatant was measured at an excitation wavelength of 365 nm and an emission wavelength of 412 nm, and the content in the membrane was calculated using anthracene methanol as a standard.

(Measurement of Peroxide Content in Membrane) A membrane washed with water and freeze-dried was cut into a length of about 5 cm, and 0.3 g
Weighed. This film is filled in a glass test tube, and a color reagent solution 4
The reaction mixture was reacted at 37 ° C. for 8 hours under light shielding. The color reagent is a commercially available peroxide measurement kit (Determiner LPO:
A solution prepared by dissolving the color former attached to Kyowa Medix Co., Ltd.) with a special solution was used. After the completion of the reaction, the membrane was separated by filtration, the absorbance of the filtrate was measured at a wavelength of 675 nm, and the content in the membrane was calculated using cumene hydroperoxide as a standard.

(Measurement of PVP Content in Membrane) A membrane washed with water and freeze-dried was weighed to a constant weight, and the PVP content was calculated from the total nitrogen content measured using an elemental analyzer.

(Endotoxin adsorption test on membrane) 0.1 g of membrane washed and freeze-dried was placed in a sterilized glass test tube, and a dialysate containing 100 EU / liter of purified endotoxin (derived from Escherichia coli 026: B6, manufactured by Funakoshi) was used. 5cc
Was added and shaken at 37 ° C. for 1 hour. The dialysate used was a mixture of 1 volume of A solution of AK Solita DL (manufactured by Shimizu Pharmaceutical Co., Ltd.) and 34 volumes of a 26-fold diluted solution of B solution. The endotoxin concentration in the test solution was determined using a commercially available colorimetric kit (Endospecy E
S-50: manufactured by Seikagaku Corporation), and the residual ratio was calculated from the following equation (3). Residual rate (%) = (C1 / C0) × 100 (3) C0: Endotoxin concentration in dialysate before addition C1: Endotoxin concentration in dialysate 1 hour after addition

(Test for Bradykinin Production by Membrane) From 250 hollow fiber membranes washed and freeze-dried, a membrane area of 0.0
A small module of 3 m ² was made. ACD-added human plasma was sucked into the hollow portion of the module, allowed to stand at 37 ° C. for 20 minutes, and then centrifuged to collect the plasma. The concentration of bradykinin in plasma was measured using a commercially available EIA kit (Merkit M
Bradykinin: manufactured by Dainippon Pharmaceutical Co., Ltd.), and evaluated by the rate of increase after filling the module before filling the module.

[0026]

Example 1 Polysulfone (P-170 manufactured by Amoco)
0) 17 parts and 7 parts of PVP (manufactured by BASF: K90, weight average molecular weight: 360,000) were added to 76 parts of N, N-dimethylacetamide (hereinafter, referred to as DMAC), and the mixture was stirred and dissolved at 50 ° C. to form a stock solution. I got As the hollow agent, a mixed solution of 15 parts of DMAC and 85 parts of water was used. This film forming stock solution and the hollow agent were discharged from a double spinneret kept at 45 ° C., and wound around a scab through a coagulation bath. After the bundle was washed with hot water, a 20% by weight aqueous glycerin solution was applied thereto and dried at 70 ° C. for 10 hours. The PVP content in this film was 8.7% by weight. Next, the dried film was molded into a 1.5 m ² module,
When filled with distilled water for injection and irradiated with γ-rays at 75 KGy, the carboxyl group content in the film was 1384 nmol /
g, peroxide content was 128 nmol / g. After the membrane was immersed and shaken for one hour, the endotoxin concentration was below the detection limit (9 EU / liter), indicating excellent adsorption. The residual endotoxin ratio of the module prepared in the same manner after storage at 60 ° C. for 2 weeks was below the detection limit. The increase rate of bradykinin was as low as 1.2.

[0027]

Example 2 The dry film obtained in Example 1 was molded into a module of 1.5 m ² , and the pH was adjusted to 7.8 and adjusted to 0.1 m.
ol / liter of a phosphate buffer and 55 gamma rays
After irradiation with y, the carboxyl group content in the film was 92
3 nmol / g and the peroxide content was 98 nmol / g. The endotoxin residual rate of this membrane was below the detection limit, and was the same after storage of the similarly prepared module at 60 ° C. for 2 weeks.

[0028]

Example 3 Polysulfone (P-170 manufactured by Amoco)
0) 18 parts and 4 parts of PVP (manufactured by BASF: K90, weight average molecular weight 360,000) were added to 78 parts of DMAC, and the mixture was heated at 50 ° C.
Was dissolved by stirring to obtain a film forming stock solution. Hollowing agent is DMAC15
And a mixture of 85 parts of water and 85 parts of water. The film forming stock solution and the hollow agent were discharged from a double spinneret kept at 30 ° C., and wound around a scab through a coagulation bath. After the bundle was washed with hot water, a 50% by weight aqueous glycerin solution was applied thereto, and dried at 70 ° C. for 12 hours. The PVP content in this membrane was 6.7% by weight. Next, the dried film was formed into a 1.5 m ² module, filled with distilled water for injection, and irradiated with 50 KGy of γ-ray. The carboxyl group content in the film was 825 nm.
ol / g and the peroxide content was 78 nmol / g. The endotoxin residual rate of this membrane was lower than the detection limit (9 EU).
/ Liter). The residual rate of the module prepared in the same manner at 60 ° C. for 2 weeks was below the detection limit, and the module retained endotoxin adsorption.

[0029]

Comparative Example 1 Polysulfone (P-170 manufactured by Amoco)
0) 18 parts and 3 parts of PVP (manufactured by BASF: K90, weight average molecular weight: 360,000) were added to 79 parts of DMAC, and stirred and dissolved at 50 ° C. to obtain a stock solution for film formation. As the hollow agent, a mixed solution of 25 parts of DMAC and 75 parts of water was used. The film forming stock solution and the hollow agent were discharged from a double spinneret kept at 40 ° C., and wound around a scab through a coagulation bath. After the bundle was washed with hot water, a 50% by weight aqueous glycerin solution was adhered and dried at 70 ° C. for 12 hours. The PVP content in this film was 5.3% by weight. Next, the dried film was molded into a 1.5 m ² module,
Filled with distilled water for injection and irradiated with 50 KGy of γ-ray, the carboxyl group content in the film was 672 nmol /
g, peroxide content was 94 nmol / g. The endotoxin residual ratio of this membrane was 26.5%, and the adsorptivity was insufficient.

[0030]

Comparative Example 2 After the dried film obtained in Example 1 was molded into a 1.5 m ² module and irradiated with γ-rays at 30 KGy, the carboxyl group content in the film was 1154 nmol /
g, peroxide content was 402 nmol / g. Although the residual ratio of endotoxin of this membrane was below the detection limit, the residual ratio of endotoxin after storage for 2 weeks at 60 ° C. of the module prepared in the same manner was 21.3%, and the adsorptivity was reduced.

[0031]

Comparative Example 3 Polysulfone (P-170 manufactured by Amoco)
0) 16 parts and 9.5 parts of PVP (manufactured by BASF: K90, weight average molecular weight: 360,000) were added to 74.5 parts of DMAC, and the mixture was stirred and dissolved at 50 ° C. to obtain a stock solution for film formation. The hollow agent is D
A mixed solution of 15 parts of MAC and 85 parts of water was used. This film forming stock solution and the hollow agent were discharged from a double spinneret kept at 60 ° C., and wound around a cassette through a coagulation bath. After washing the bundle with hot water, a 20% by weight aqueous glycerin solution was adhered to
For 10 hours. The PVP content in this membrane is 1
It was 3.6% by weight. After forming this membrane into a 1.5 m ² module, it was filled with distilled water for injection and gamma rays were irradiated at 75 KGy.
Upon irradiation, the carboxyl group content in the film was 184
1 nmol / g, peroxide content 188 nmol / g
Met. The rate of increase in bradykinin by the membrane was increased to 4.6.

[0032]

Industrial Applicability The polysulfone medical separation membrane of the present invention has excellent endotoxin adsorption even when irradiated, and can maintain its effect even when stored for a long period of time. Therefore, it is suitable for the field of blood purification. Available.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C077 AA05 BB01 BB02 BB03 KK04 KK13 LL05 LL23 MM09 NN20 PP15 PP18 PP28 4D006 GA13 HA02 JA02B MA01 MA31 MA33 MB14 MB20 MC32 MC40X MC62X MC75X MC78X MC83 MC88 MC89 NA90 NA05 NA05 PA01 PB09 PB54 PC41 PC44

Claims (3)

[Claims] 1. A radiation-irradiated membrane comprising a polysulfone-based polymer and polyvinylpyrrolidone, wherein the membrane has a carboxyl group content of 800 nmol / g or more,
Less than 00 nmol / g and a peroxide content of 2
A polysulfone-based medical separation membrane having a molecular weight of 00 nmol / g or less. 2. The polysulfone-based medical separation membrane according to claim 1, wherein the content of polyvinylpyrrolidone in the membrane is 6.0 to 11.0% by weight. 3. A separation membrane comprising a polysulfone polymer and polyvinylpyrrolidone having a membrane area of 0.01 to 2.5 m ^2.
A separation module incorporated so that the carboxyl group content in the separation membrane is at least 800 nmol / g by irradiating the module with radiation.
Less than 100 nmol / g and a peroxide content of 200
A separation module characterized by having a concentration of not more than nmol / g.