JP3498543B2 - Separation membrane and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a separation membrane having both high substance permeability and antiplatelet adhesion, and a blood purifier including the same.

[0002]

2. Description of the Related Art Currently, various polymer materials are used in the medical field, but artificial blood vessels, catheters, blood bags,
In a device such as an artificial kidney that is in direct contact with blood, the adhesion of blood components such as plasma proteins and platelets, and the formation of thrombus resulting therefrom are unavoidable problems. Particularly in the case of a membrane used in a blood purifier, the adhesion of blood components directly leads to deterioration of the membrane performance, which is an important problem.

Conventionally, as a material of a membrane for a blood purifier,
Cellulose acetate, polyolefin, polyimide,
Polymer compounds such as polycarbonate, polyarylate, polyester, polyacrylonitrile / polymethylmethacrylate / polyamide / polysulfone resin have been used. Among these, especially polysulfone-based resin,
It has been widely used in recent years due to its excellent heat resistance stability and acid / alkali resistance. But on the other hand,
Due to the hydrophobic nature of the material itself, deterioration of performance over time due to adhesion of blood components, especially plasma proteins and platelets, was unavoidable. As a means for making the membrane hydrophilic in order to solve the drawbacks of the hydrophobic membrane, a method of adding a hydrophilic polymer to a membrane-forming stock solution (for example, Japanese Patent Publication No. 2-18695).
JP-A-61-193801, JP-A-61-1980
No. 238306, JP-A No. 63-97205, etc.), but generally, the hydrophilic polymer in the stock solution for film formation also serves as a pore-forming agent for the film, and it is necessary to remove it by washing after film formation. However, only a small amount of hydrophilic polymer remains in the film after washing. Even with a membrane produced by such a method, the adhesion of blood components can be suppressed to some extent during normal use, but it is not always sufficient when the blood components of the patient to be used have high activity. It cannot be said that the adhesion of blood components can be suppressed. Further, there is a method of immobilizing a hydrophilic polymer on the surface of the material after film formation (for example, JP-A-6-238139), but this method requires immobilizing the hydrophilic polymer at a high density to some extent. There is a risk of reducing the original permeability of the membrane. further,
The mechanism of the interaction between blood components and the surface of the membrane is very complicated, and even if the composition of the membrane changes subtly, the optimal hydrophilic polymer and treatment conditions for suppressing the adhesion of blood components are different. Even when the hydrophilic polymer is actually introduced, the antiplatelet adhesion may be reduced. That is, up to now, a polysulfone-based membrane having both the high substance permeability and the high antiplatelet adhesion has not been realized.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have aimed to improve the conventional techniques, and provide a separation membrane having high substance permeability and less adhesion of blood components such as plasma proteins and platelets, and such a separation membrane. An object of the present invention is to provide a blood purifier having built-in antiplatelet adhesion.

[0005]

In order to achieve the above object, the present invention has the following constitution. That is, (1) a polysulfone-based resin containing polyvinylpyrrolidone
At least part of the surface of the film
Separation membrane for blood purification characterized by the presence of call, (2) The polyalkylene glycol is insolubilized
(1) Separation membrane for blood purification according to (1) , (3) the polyalkylene glycol is 0.01 ng / cm ² or more, 50
Characterized in that present in a proportion of 0 ng / cm ² or less (1) The
Is a separation membrane for blood purification according to (2) , (4) the polyalkylene glycol is 0.05 ng / cm ² or more, 30
Characterized in that present in a proportion of 0 ng / cm ² or less (1) The
Is (2) for blood purification separation membrane according relates.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In a separation membrane of the present invention, a polysulfone-based resin containing polyvinylpyrrolidone is used as a main component as a substrate. Polysulfone resin is
Any polymer having a sulfone group in the skeleton may be used, and a polymer having a repeating unit of the formula (1) is preferable, but a polymer containing a functional group or an alkyl group may be used.
It may be copolymerized.

[Chemical 1]

Although the molecular weight of polyvinylpyrrolidone contained in the separation membrane is not particularly limited, commercially available 1
It is possible to use 40,000, 160,000, 360,000, or a mixture thereof.

The composition ratio of the polysulfone resin and the polyvinylpyrrolidone in the separation membrane of the present invention is not particularly limited, but in order to maintain the mechanical strength of the separation membrane, polysulfone 99 to 70%, polyvinylpyrrolidone 1 It is preferably in the range of ˜30%.

In producing the polysulfone-based membrane containing polyvinylpyrrolidone according to the present invention, for example, Japanese Examined Patent Publication No. 2-18695, Japanese Unexamined Patent Publication No. 61-93801, Japanese Unexamined Patent Publication No. 61-23
The manufacturing method disclosed in Japanese Patent No. 8306 may be used without any limitation.

The polyalkylene glycol in the present invention is a chain polymer having an oxygen atom in the main chain represented by polyethylene glycol and polypropylene glycol, for example, but may be a polymer grafted with polyalkylene glycol. The amount of polyalkylene glycol on the surface is preferably in the range of 0.01 to 500 ng / cm2, 0.05 to 300 ng / cm2.

The polyalkylene glycol is preferably insolubilized.

In order to insolubilize the polyalkylene glycol, there may be mentioned a method of irradiating the polysulfone base film containing polyvinylpyrrolidone with a polyalkylene glycol solution (preferably an aqueous solution) in a state of being in contact with the polyalkylene glycol solution by immersion.

In the present invention, by incorporating such a separation membrane in a plastic case or the like, it can be preferably used as a blood purifier. The blood purifier in the present invention is a module containing a membrane for blood treatment such as a hemodialyzer, a hemofilter, a hemofilter dialyzer, and a plasma separator. Further, in the case of making blood purifiers such as hemodialyzers, hemofilters, hemofiltration dialysers, and plasma separators containing a polysulfone-based membrane containing polyvinylpyrrolidone antiplatelet-adhesive, in the blood purifiers If the polyalkylene glycol aqueous solution is in contact with the membrane and at least all the blood-contacting portions of the membrane, not only the membrane surface but also all the blood-contacting portions such as the end of the blood purifier and the inside of the header will be treated. It can be made anti-platelet-adhesive, and for example, blood coagulation at the end of the blood purifier can be reduced.

The molecular weight of the polyalkylene glycol in the aqueous solution of polyalkylene glycol and the concentration of the aqueous solution are not particularly limited, but generally a combination of low molecular weight and low concentration has a relatively low degree of antiplatelet adhesion. The higher the molecular weight and the higher the concentration, the higher the degree of antiplatelet adhesion. However, in the production method of the present invention, by selecting the molecular weight of the polyalkylene glycol, sufficient antiplatelet adhesion can be obtained even when the concentration of the aqueous solution is relatively low at 1 to 20000 ppm, so that antiplatelet adhesion can be obtained. The cost can be kept low, which is one of the effects of the present invention. On the other hand,
In the case of a combination of high molecular weight and high concentration, not only the polyalkylene glycol chains are bonded to the film surface but also the polyalkylene glycol chains are cross-linked with each other,
The mobility of the polyalkylene glycol chain is impaired, the anti-platelet adhesion cannot be imparted as expected, and the gel permeability of the polyalkylene glycol forms a gel layer on the membrane surface, so that the substance permeation performance tends to decrease.

However, the conditions of the polyalkylene glycol aqueous solution are the content ratio of polyvinylpyrrolidone in the polysulfone type membrane, the shape and pore size of the membrane, the amount of the membrane to the polyalkylene glycol aqueous solution, the desired degree of antiplatelet adhesion. Therefore, the optimum conditions differ in each case.

The dose of radiation is not particularly limited as long as the polyalkylene glycol chain is bonded to the surface of the membrane to be antiplatelet-adhesive or the surface of the blood purifier in contact with blood. Irradiation with absorbed energy of about 15 to 35 kGy is preferably used. In addition, sterilization can be performed simultaneously with imparting antiplatelet adhesion. In this case, the radiation dose may generally be any amount as long as it is equal to or higher than the sterilization dose, but it is preferably about 25 to 35 kGy in consideration of the problem of strength deterioration of the film and economical efficiency. However, when the deterioration of the film due to radiation is in a negligible range or when it is not necessary to consider economic efficiency, the irradiation dose of radiation does not need to be in this range.

The method of using radiation to insolubilize the polyalkylene glycol on the surface of the polysulfone-based membrane is preferable because it does not require a special reactive group for introducing the polyalkylene glycol chain. In general, introducing a reactive group into a material containing a polysulfone resin not only raises the price of the material but also limits the production method. For example, when spinning a polysulfone-based hollow fiber membrane, when a reactive group is introduced into the polysulfone-based resin, which is the raw material, since its chemical properties generally change, the solubility and film-forming properties during preparation of the stock solution greatly change, It is necessary to reexamine all manufacturing conditions. In other words, it is necessary to study all the processes from the method for adjusting the hollow fiber spinning stock solution to the conditions for the yarn making condition, the post-treatment condition, and the case assembling process, and the labor is enormous. Furthermore, the introduction of the reactive group generally weakens the bonding force between the raw material molecules and lowers the strength / elongation property of the hollow fiber, so that the stability of the yarn production is deteriorated and the productivity may be reduced. On the other hand, according to the manufacturing method described above, it is not necessary to modify the conventional manufacturing method of the film at all, it suffices to add the polyalkylene glycol aqueous solution filling process and the irradiation process to the conventional manufacturing process, Since the reaction is only on the membrane surface, there is almost no need to worry about deterioration of the strength / elongation property of the hollow fiber membrane. Further, when radiation irradiation has already been adopted as a sterilization method, it is only necessary to fill the module case with the polyalkylene glycol aqueous solution when sterilizing the product.

The blood purifier in the present invention is a module containing a separation membrane for blood treatment, such as a hemodialyzer, a hemofilter, a hemodialyzer and a plasma separator.

[0019]

EXAMPLES The present invention will be described below based on examples.

The measuring methods used are as follows.

(1) Polyethylene glycol (hereinafter PEG
(Hereinafter abbreviated)), the mini module (or small module) washed with distilled water after γ-ray irradiation described in each Example and Comparative Example was disassembled and the hollow fiber was taken out. 50 taken out hollow fiber
It was dried at 0.5 ° C. and 0.5 torr for 10 hours. Take 10 to 100 mg of dried hollow fiber in a test tube, add 2 ml of a mixed solution of acetic anhydride and p-toluenesulfonic acid, and at 120 ° C about 1
After acetylation for a period of time and cooling, the vessel wall was washed off with 2 ml of pure water, neutralized with 20% sodium carbonate solution, extracted with 5 ml of trichloromethane, and analyzed by gas chromatography (hereinafter referred to as GC).

The amount of PEG present on the membrane surface was determined from a calibration curve prepared in advance.

The surface concentration of PEG is the PEG amount determined by GC,
It was calculated by dividing by the surface area including the inside of the pores of the film obtained by the nitrogen adsorption method.

(2) In vitro Platelet Adhesion Experiment 0.57 ml / 10 ml of fresh rabbit blood containing 10% by volume of 3.8% sodium citrate aqueous solution was added to the hollow portion of the hollow fiber from the blood inlet of the mini module after washing. After flushing with min, then washing with physiological saline, fixed with glutaraldehyde, the hollow fiber separation membrane was cut out from the mini-module and freeze-dried. The inner surface of this hollow fiber was observed by FE-SEM (field emission scanning electron microscope), and 0.01 cm2
The number of attached platelets in each area was counted.

(3) In Vivo Platelet Adhesion Experiment Blood derived from the carotid artery of a rabbit weighing about 3 kg is passed through the hollow inlet of the small module after washing through the hollow fiber hollow portion, and the rabbit is discharged from the blood outlet of the small module. An extracorporeal circulation test for returning to the jugular vein was performed. Blood flow rate is 50ml / min,
Heparin as an anticoagulant was initially administered at 18 IU and then 6
Circulation was continued for 3 hours with continuous administration of 0 IU / hr. After completion of the extracorporeal circulation, the cells were washed with physiological saline and fixed with glutaraldehyde as in the in vitro platelet adhesion experiment, and the hollow fiber cut out from the module and the module header were freeze-dried. The inner surface of this hollow fiber and the inside of the module header (blood contact surface) were observed by FE-SEM, and the number of attached platelets in the area of 0.01 cm 2 was counted.

(4) Measurement of in vitro β2-microglobulin (hereinafter β2-MG) removal performance Human β2-M was added to 30 ml of filter-treated bovine serum.
G was dissolved at a concentration of 5 mg / ml and perfused at 1 ml / min into the hollow fiber hollow part from the blood inlet of the washed mini module, and 140 ml of PBS kept at 37 ° C was 20 ml / min outside the hollow fiber.
Was perfused in closed form at a rate of. Inside the hollow fiber after 4 hours of perfusion
The outer perfusate was collected and the clearance was calculated. The clearance was calculated by the formula (2).

[Equation 1] Where CL: clearance (ml / min), CBi: module inlet side concentration (mg / ml), CBo: module outlet side concentration (mg / m)
l), QB: Module supply liquid amount (ml / min).

The sample hollow fibers used in Examples and Comparative Examples were prepared as follows.

Examples 1 to 11, Comparative Examples 1 to 3 18 parts of polysulfone (Udel P-3500) and 2 parts of polyvinylpyrrolidone (K30) were added to 80 parts of N, N-dimethylacetamide (hereinafter referred to as DMAc). , Heated and melted.
This stock solution for film formation was discharged from an orifice type double cylinder type die, passed through 200 mm in air, and then introduced into a coagulation bath of 100% water to obtain a hollow fiber. At this time, DMAc50 is used as the internal injection liquid.
And 50 parts of water were used. The inner diameter of the hollow fiber is 0.
The thickness was 2 mm and the film thickness was 0.04 mm.

40 polysulfone hollow fiber separation membranes prepared in this way were bundled, and both ends were fixed to a glass tube module case with an epoxy potting agent so as not to block the hollow portions of the hollow fibers, and the mini module shown in FIG. It was created. The mini-module has a diameter of about 7 mm and a length of about 10
cm.

The blood inlet and the dialysate outlet of the mini-module are connected by a silicone tube, and 100 ml of an aqueous solution of various kinds of polyethylene glycol or polyvinylpyrrolidone is flown from the blood outlet at a flow rate of 100 ml / min, and air is introduced into the mini-module. Cap it to prevent it from entering
Irradiation with γ rays at kGy. Table 1 shows the number average molecular weights and aqueous solution concentrations of the solutes of the polyethylene glycol aqueous solution and the polyvinylpyrrolidone aqueous solution filled in the mini-module. After γ-irradiation, the blood inlet and dialysate outlet of the mini module are connected with a silicon tube, and 500 ml of distilled water is flown from the blood outlet at a flow rate of 100 ml / min to wash the hollow fiber and the inside of the module, and in vitro platelet adhesion Experiments and in vitro β2-MG removal performance were measured. The measurement result of each mini-module is shown in Table 1 as a relative value with the result of Comparative Example 1 filled with distilled water and irradiated with γ-ray as 100.

Example 12 and Comparative Example 4 3,500 polysulfone hollow fiber separation membranes spun in the same manner as in Example 1 were bundled and both hollow fiber separation membranes were covered with a urethane-based potting agent so as not to block the hollow portions of the hollow fibers. The ends were fixed to a polystyrene module case, and polystyrene module headers were attached to both ends of the module case to prepare a small module shown in FIG. The body diameter of the small module is about 3 cm and the length is about 15 cm.
The blood inlet and dialysate outlet of this small module are connected with a silicon tube, and 500 ml of distilled water or an aqueous solution of polyethylene glycol having a molecular weight of 6000 and a concentration of 2000 ppm is flown at a flow rate of 100 ml / min from the blood outlet, and air is introduced into the small module. Cap it to prevent it from entering
Irradiation with γ rays of kGy. Connect the blood inlet and dialysate outlet of the small module after γ-ray irradiation with a silicone tube,
1000 ml of distilled water was flown from the blood outlet at a flow rate of 100 ml / min to wash the hollow fiber and the inside of the module.
ivo Platelet adhesion experiments were performed. In addition, a small module treated in the same manner was disassembled, and a mini module was prepared in the same manner as in Example 1 using the hollow fiber taken out, and in vitro β2-MG
The removal performance was measured. Further, the membrane surface binding density of polyethylene glycol was measured using the hollow fiber taken out after disassembly. The measurement result of Example 12 was filled with distilled water to obtain γ.
Table 6 is a relative value in which the result of Comparative Example 4 in which the linear irradiation is performed is 100.
Shown in.

[0032]

[Table 1]

[0033]

[Table 2]

As shown by the results of Examples 1 to 11, it is understood that the number of adhered platelets is decreased and the antiplatelet adhesion is improved by binding polyethylene glycol to the membrane surface. Further, as can be seen from the results of Example 12, since the number of platelets attached to the inner surface of the header is also reduced, it can be seen that antiplatelet adhesion can be achieved on the entire blood contact surface of the blood purifier. Further, the β2-MG removing ability almost maintains the performance of the separation membrane in which polyethylene glycol is not insolubilized on the membrane surface, and it is understood that the substance permeation performance is hardly deteriorated.

In Comparative Examples 2 and 3, even if polyvinylpyrrolidone, which is generally known as a hydrophilic polymer, is insolubilized on the membrane surface, the polysulfone membrane containing polyvinylpyrrolidone has no antiplatelet adhesion effect. Not only that, but platelets are more likely to adhere. From this, it cannot be said that any hydrophilic polymer may be used in order to make the polysulfone film containing polyvinylpyrrolidone anti-platelet adherence, and it is important to adhere polyalkylene glycol to the film surface. It can be seen that it is.

Example 13 The small module after γ-ray irradiation which was treated in the same manner as in Example 12 was disassembled and the hollow fiber was taken out.
It was dried at 0.5 torr for 10 hours. 20 g of dried hollow fiber
Was added to 200 ml of DMAc and stirred at room temperature for 2 hours, then D
MAc insoluble matter was filtered off. This DMAc insoluble matter is replaced with new DMA
It was charged again into c200 ml and stirred at room temperature for 2 hours. This operation was repeated 3 times, and the obtained DMAc insoluble matter was washed with distilled water and dried at 50 ° C. and 0.5 torr for 10 hours. The dried insoluble matter was subjected to IR measurement by the KBr method. At the same time, 10 to 100 mg of this insoluble matter was taken into a test tube, and 2 ml of a mixed solution of acetic anhydride and paratoluenesulfonic acid was added to
The mixture was acetylated at 20 ° C. for about 1 hour, and after cooling, the vessel wall was washed off with 2 ml of pure water, neutralized with 20% sodium carbonate solution, extracted with 5 ml of trichloromethane, and analyzed by GC.

As a result of IR measurement, the measurement chart shows that the absorption of 1585 cm −1 derived from the benzene ring of polysulfone, the absorption of 1150 cm −1 derived from the sulfonyl group, and the absorption of 1690 cm −1 derived from the third amide group of polyvinylpyrrolidone. Was recognized. GC
From the result, a peak derived from polyethylene glycol was recognized. From the above results, it was found that three components of polysulfone, polyvinylpyrrolidone and polyethylene glycol were cross-linked with each other by irradiating a polysulfone film containing polyvinylpyrrolidone in a polyethylene glycol aqueous solution with gamma rays.

[0038]

As described above, the separation membrane according to the present invention is a separation membrane having high antiplatelet adhesion and high substance permeability, and is effective for blood purification.

[Brief description of drawings]

FIG. 1 is a schematic diagram of mini-modules used in Examples 1 to 11 of the present invention and Comparative Examples 1 to 3.

2 is a schematic view of a small module used in Example 12 of the present invention and Comparative Example 4. FIG.

[Explanation of symbols]

1. Blood inlet 2. Potting section 3. Dialysate inlet 4. Hollow fiber separation membrane 5. Glass tube module case 6. Dialysate inlet 7. Blood outlet 8. Module header 9. Module case

Claims (4)

(57) [Claims] 1. A separation membrane for blood purification, wherein polyalkylene glycol is present on at least a part of the surface of a membrane made of polysulfone-based resin containing polyvinylpyrrolidone. 2. The separation membrane for blood purification according to claim 1, wherein the polyalkylene glycol is insolubilized. 3. The polyalkylene glycol is 0.01 ng / cm ²
The separation membrane for blood purification according to claim 1 or 2 , wherein the separation membrane is present at a ratio of 500 ng / cm ² or less. 4. The polyalkylene glycol is 0.05 ng / cm ²
The separation membrane for blood purification according to claim 1 or 2 , wherein the separation membrane is present at a ratio of 300 ng / cm ² or less.