JPH0966225A - Production of hollow fiber membrane, hollow fiber membrane and dialyser - Google Patents

Abstract

PROBLEM TO BE SOLVED: To inexpensively produce a hollow fiber membrane capable of developing its effect to a membrane permeable substance, in a method for producing the hollow fiber membrane by discharging a spinning raw soln. from an annular spinning hole to coagulate the same in a coagulation soln., by adding oil-soluble vitamin to the spinning raw soln. or a core soln. SOLUTION: A spinning raw soln. and a core soln. are respectively discharged from the outer and inner pipes of a discharge nozzle 4 and the spinning raw soln. is extruded while the core part thereof is filled with the core soln. The extrudate is allowed to fall under its own wt. to be stretched and the stretched extrudate is introduced into a coagulation bath tank 5 to be coagulate dand the obtained filminent 8 is passed through a washing soln. tank 6 to be taken up by a winder 7. In this case, an oil-soluble vitamin soln. tank is disposed between the coagulation soln. tank 5 and the washing soln. tank 6. The filament 8 is introduced into this oil-soluble vitamin soln. tank to be impregnated with the vitamin soln. At this time, the content of oil-soluble vitamin is set to 0.001-10wt.% and, as oil-soluble vitamin, vitamin E, that is, α-tocopherol or α-tocopherol acetate is used.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a method for producing a hollow fiber membrane, a hollow fiber membrane and a hollow fiber membrane type dialyzer. In particular, the present invention relates to a method for producing a hollow fiber membrane excellent in biocompatibility by suppressing activation of leukocytes or platelets, a hollow fiber membrane, and a hollow fiber membrane dialyzer.

[0002]

In the field of extracorporeal blood circulation, hemodialysis, oxygenation to blood during open heart surgery, plasma separation, etc., hollow fiber type blood processors using hollow fiber membranes have been widely used in the past. In particular, in the fields of dialysis membranes, gas exchange membranes, blood component separation membranes, etc., synthetic polymer hollow fiber membranes are widely used.

However, for example, in hemodialysis, the extracorporeal blood circulation is frequently performed, and the above-described hollow fiber type blood treatment device is used for a long period of time, and the blood circulation during the extracorporeal blood circulation occurs. It is a serious problem for dialysis patients due to complications that are considered to be caused by activation of white blood cells and / or platelets.

[0004] In addition, it has been confirmed that, in patients undergoing hemodialysis for a long period of time, a decrease in blood antioxidant activity and a high level of lipid peroxides are observed. Arteriosclerotic diseases are increasing.

On the other hand, in order to solve these problems, the artificial dialysis membrane is coated with a vitamin E film having various physiological actions such as in-vivo antioxidant action, biological membrane stabilizing action and platelet aggregation inhibiting action. An organ has been proposed (see Japanese Patent Publication No. 62-41738).

However, in the above-mentioned prior art,
Vitamin E is coated after the dialysis membrane formation process and artificial organ assembly process, so the production process is complicated and costly, and for substances that can permeate through the membrane because it only requires treatment on the surface. There are problems such as not being able to fully exert the effect.

[0007]

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems of the prior art, and its object is to manufacture a hollow fiber membrane in which the membrane forming process is simple and economical. A method and a hollow fiber membrane and a hollow fiber membrane type dialyzer are provided.

Another object of the present invention is to provide a method for producing a hollow fiber membrane and a hollow fiber membrane and a hollow fiber membrane type dialyzer which are highly biocompatible and can exert their effects on a substance that can penetrate the membrane. To provide.

[0009]

The above objects are achieved by the following method for producing a hollow fiber membrane, a hollow fiber membrane and a hollow fiber membrane type dialyzer according to the present invention.

That is, the present invention is a method for producing a hollow fiber membrane by discharging a spinning dope from a ring-shaped spinning hole, extruding it linearly while filling the core liquid inside, and then introducing it into a coagulating liquid to coagulate. 3. In the method for producing a hollow fiber membrane, the stock solution for spinning or the core solution is allowed to contain a fat-soluble vitamin.

In the present invention, the content of the fat-soluble vitamin in the spinning dope or the core liquid is 0.001-1.
The production method of the hollow fiber membrane is 0 wt%.

The present invention further provides a method for producing a hollow fiber membrane, in which a spinning dope is discharged from an annular spinning hole and simultaneously extruded linearly while filling a core liquid therein, and then introduced into a coagulating liquid to coagulate. The method for producing a hollow fiber membrane is characterized in that the coagulated filament is then introduced into a fat-soluble vitamin solution and impregnated.

The present invention is also the method for producing the hollow fiber membrane, wherein the fat-soluble vitamin is vitamin E.

The present invention further provides the method for producing the hollow fiber membrane, wherein the vitamin E is α-tocopherol, α-tocopherol acetate or α-tocopherol nicotinate.

The present invention is also the method for producing the hollow fiber membrane, wherein a synthetic polymer having a solubility parameter δ of 13 (cal / cm ³ ) ^1/2 or less is used as the substrate.

Further, the present invention is a hollow fiber membrane in which a spinning dope is discharged from an annular spinning hole and is extruded linearly while being filled with a core liquid and then introduced into a coagulating liquid to coagulate. A hollow fiber membrane obtained by impregnating the spinning solution or core solution with a fat-soluble vitamin, or introducing the coagulated filament into a fat-soluble vitamin solution for impregnation.

The present invention is also the hollow fiber membrane, wherein the fat-soluble vitamin is vitamin E.

The present invention further provides the hollow fiber membrane wherein the vitamin E is α-tocopherol, α-tocopherol acetate or α-tocopherol nicotinate.

The present invention also provides the above hollow fiber membrane, which comprises a synthetic polymer having a solubility parameter δ of 13 (cal / cm ³ ) ^1/2 or less as a substrate.

Further, the present invention is a hollow fiber membrane in which the spinning dope is discharged from the annular spinning hole and simultaneously extruded linearly while filling the core liquid therein, and then introduced into the coagulating liquid to coagulate. A hollow fiber membrane obtained by containing a fat-soluble vitamin in the spinning stock solution or the core liquid, or by introducing the coagulated filament into a fat-soluble vitamin solution and impregnating it. It is a membrane type dialyzer.

The present invention is also a hollow fiber membrane type dialyzer in which the fat-soluble vitamin is vitamin E.

The present invention is also a hollow fiber membrane type dialyzer in which the vitamin E is α-tocopherol, α-tocopherol acetate or α-tocopherol nicotinate.

The present invention is also a hollow fiber membrane type dialyzer using a synthetic polymer having a solubility parameter δ of 13 (cal / cm ³ ) ^1/2 or less as a substrate.

[0024]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS FIG. 1 is a process chart showing an embodiment of the method for producing a hollow fiber membrane of the present invention.

FIG. 2 is a perspective view showing an embodiment of the hollow fiber membrane type dialyzer of the present invention having a partial cutaway portion.

In the method for producing a hollow fiber membrane of the present invention, the stock solution for spinning is discharged from the annular spinning hole and at the same time the core solution is filled therein and extruded linearly, and then the extrudate is introduced into the coagulating solution for coagulation. In the method for producing a hollow fiber membrane, a fat-soluble vitamin is mixed in the spinning solution or the core liquid, or the filament after coagulation is continuously dipped in the fat-soluble vitamin solution. That is, by performing the impregnation treatment of the fat-soluble vitamin on the hollow fiber membrane in the spinning process in the spinning step, it is possible to impregnate the fat-soluble vitamin up to the microporous surface inside the hollow fiber membrane, and thereby permeate the membrane. It is possible to obtain a hollow fiber membrane having an excellent effect such as exhibiting an antioxidative action even with respect to a substance that can be treated.

Various methods are known for producing the hollow fiber membrane to which the present invention is applied.
When the spinning dope is extruded from the annular spinning hole while being filled with the core liquid, the extruded product is extruded into the air and dropped below its own weight to be stretched, and then passed through the coagulating liquid for coagulation treatment, and then washed and dried. A method for producing (hereinafter referred to as "in-air dropping method"), a method in which a non-coagulating liquid is directly discharged into the non-coagulating liquid of a bath liquid obtained by filling the upper layer with the coagulating liquid in the lower layer and then passing through the coagulating liquid JP-A-57-71409), and vice versa, a method of directly discharging the coagulating liquid into the non-coagulating liquid of the bath liquid obtained by filling the upper layer with the non-coagulating liquid into the lower layer, and then passing the liquid through the coagulating liquid (JP-A-SHO-A). 57-199808) in the same manner, followed by discharging into the non-coagulating liquid and then passing through the interface between the non-coagulating liquid and the coagulating liquid (JP-A-57-71408 and 57-7).
No. 1410), a method in which it is surrounded by a non-coagulating liquid to be ejected and then passed through the coagulating liquid (JP-A-57-71411).
A method of reproducing the data is included. Of these, the air drop method is particularly preferable, and the method for producing the hollow fiber membrane of the present invention will be described below with reference to the drawings taking this as an example.

The method for producing a hollow fiber membrane of the present invention is described in, for example, US Pat. No. 3,615,024, JOURNAL OF APPLIED.
POLYMER SCIENCE VOL. 20, 2377-2394 (1976), JOURNA
L OF APPLIED POLYMER SCIENCE VOL. 21, 165-180 (197
7) is a modification of the conventional method described in 1), and as shown in FIG. 1, a spinning stock solution tank 2, a core solution tank 3, a discharge nozzle 4, a coagulating solution tank 5, a cleaning solution tank 6 and a winder 7 are provided. It is performed by the spinning device 1 including.

The spinning stock solution tank 2 is filled with a spinning stock solution prepared by dissolving a base material in a solvent. In the present invention, the base material has a solubility parameter δ of 13 (cal / c
It is preferable to use a synthetic polymer having m ³ ) ^1/2 or less.
The solubility parameter δ in the present invention means, for example, “Polymer Data Handbook Basic Edition”, The Society of Polymer Science, Japan, Baifukan Co., Ltd., first edition issued January 30, 1986.
It is an index described on pages 591-593, and shows that when the solubility parameter is high, the hydrophilicity is strong, and when the solubility parameter is low, the hydrophobicity is strong, and the degree of affinity between the hollow fiber membrane material and the fat-soluble vitamin. It represents.

In the method for producing a hollow fiber membrane of the present invention,
In order to impregnate the fat-soluble vitamin into the spinning solution, or to mix it in the core liquid or after coagulation and continuously immersing it in the fat-soluble vitamin solution to impregnate the fat-soluble vitamin up to the microporous surface inside the hollow fiber membrane, Affinity is an important point. That is, the solubility parameter of the base material is 13 (c
By using a synthetic polymer of al / cm ³ ) ^1/2 or less, the affinity with fat-soluble vitamins is improved, and the hollow fiber membranes can be easily impregnated with fat-soluble vitamins during the spinning process. The fat-soluble vitamin can be impregnated into the microporous surface inside the membrane.

As such synthetic polymers, polyethylene (δ = 7.70), polymethylmethacrylate (δ
= 9.10), polystyrene (δ = 9.15), polypropylene (δ = 9.40), polysulfone (δ = 9.9).
0), polyhydroxyethyl methacrylate (δ = 1
0.00), nylon 66 (δ = 11.18) cellulose diacetate (δ = 11.35), polyacrylonitrile (δ = 12.35), polyvinyl alcohol (δ =
12.60), cellulose triacetate, ethylene-
Examples thereof include vinyl alcohol copolymers and polycarbonates, which may be used alone or in combination of two or more kinds.

Examples of the solvent used for the spinning dope include dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dimethylformamide (DMF), etc., and they are appropriately selected according to the type of substrate used. If necessary, additives such as a thickening agent and a hydrophilizing agent may be mixed in the spinning dope. Examples of such thickening agents include polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and polypropylene. Examples of the hydrophilizing agent such as glycol (PPG) include glycerin and the like.

The core liquid tank 3 is filled with a core liquid for forming a hollow core. As the core liquid, a non-solvent of the substrate or a mixed solution of a non-solvent and a solvent is used. Examples of such a non-solvent include water and methanol, and examples of the solvent include those mentioned above, which are appropriately selected according to the type of the substrate to be used.

In the method for producing a hollow fiber membrane of the present invention, a fat-soluble vitamin is mixed in either or both of the spinning solution and the core solution. Examples of such fat-soluble vitamins include vitamin A, vitamin D, vitamin E, vitamin K and ubiquinone, and among these, vitamin E is preferred. As vitamin E, α-tocopherol, α-tocopherol acetate, α
-Tocopherol nicotinate, β-tocopherol, γ
-Tocopherol, delta-tocopherol and the like. The content of the fat-soluble vitamin in the spinning dope or the core liquid is preferably 0.001 to 10% by weight, particularly preferably 0.01 to 5% by weight. If the content of the fat-soluble vitamin is less than 0.01 wt%, the effect of adding the fat-soluble vitamin cannot be obtained, and if it exceeds 10 wt%, the effect corresponding to the addition cannot be obtained, which is economically disadvantageous.

Next, the spinning stock solution fed from the spinning stock solution tank 2 is fed from an annular spinning hole (not shown) which is an outer tube of the discharge nozzle 4 having a double tube structure, and from the core liquid tank 3. The prepared core liquid is simultaneously discharged from an inner pipe (not shown) of the discharge nozzle 4, and is extruded into the air while filling the core liquid of the spinning dope with the core liquid. The extruded product is dropped as it is by its own weight to be stretched, then introduced into the coagulating liquid tank 5 and coagulated. As the coagulating liquid used in the coagulating liquid tank, the non-solvent of the base material is used, but it may contain a small amount of the solvent of the base material, a surfactant and the like. The filament 8 exiting the coagulation bath is passed through the cleaning liquid bath 6 and wound by the winder 7. Water is usually used as the cleaning liquid in the cleaning liquid tank.

In the method for producing a hollow fiber membrane of the present invention, the filament 8 after coagulation is continuously dipped in the fat-soluble vitamin solution instead of mixing the fat-soluble vitamin into the spinning solution or the core liquid. Impregnation treatment may be performed. In this case, a fat-soluble vitamin solution tank is provided between the coagulation liquid tank 5 and the cleaning liquid tank 6 or between the cleaning liquid tank 6 and the winder 7, and the filament 8 that has left the coagulation liquid tank 5 or the cleaning liquid tank 6 is provided. Then, it is introduced into a fat-soluble vitamin solution tank and impregnated.

In this case, the solvent used for the fat-soluble vitamin solution is one which dissolves the fat-soluble vitamin but does not dissolve the base material, and has a solubility parameter of 15 (cal / cal).
cm ³ ) ^1/2 or less is preferable. When the solubility parameter exceeds 15, a hydrophilizing agent such as glycerin (δ =
The elution of additives such as 16.5 (cal / cm3) 1/2) from the film becomes large, which may adversely affect the film performance and film characteristics. As such a solvent, for example,
Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-
Alcohols such as butanol and 2-ethylhexanol; ethers such as diethyl ether; 1,2,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane, 1,1,2,2-tetrachloro −
Chlorinated fluorohydrocarbons such as 1,2-difluoroethane; perfluorocycloalkanes such as methyl fluoride, carbon tetrafluoride, tetrafluoroethane, tetrafluoroethylene, perfluoromethylpropylcyclohexane and perfluorobutylcyclohexane, perfluoro Fluorinated hydrocarbons such as decane, perfluoromethyldecalin and perfluoroalkyltetrahydropyran; and hydrocarbons such as hexane, heptane, decane and the like can be mentioned, and they are appropriately selected depending on the kind of the substrate used. When polysulfone is used as the base material and vitamin E is used as the fat-soluble vitamin, hexane is preferably used as the solvent from the viewpoint of remaining in the hollow fiber membrane.

The concentration of the fat-soluble vitamin solution varies depending on the type of base material used, immersion time, etc.
0.01-20 w / v% is good, preferably 0.01-
10w / v% is good. The concentration of fat-soluble vitamin solution is 0.
If it is less than 01 w / v%, the effect of adding the fat-soluble vitamin cannot be obtained, and if it exceeds 20 w / v%, the effect corresponding to the addition cannot be obtained, which is economically disadvantageous.

The hollow fiber membrane of the present invention thus obtained has an inner diameter of 10 to 1000 μ, preferably 100 to 300.
[mu], the film thickness is 5 to 100 [mu], preferably 20 to 60 [mu], and the fat-soluble vitamin is impregnated into the inner microporous surface. Further, in order to achieve the remarkable effects of the present invention such that the platelet aggregation inhibitory action by the fat-soluble vitamin can be maintained for a long period of time, the amount of the fat-soluble vitamin impregnated in the hollow fiber membrane of the present invention is 1 to 5000 mg. / M
It is preferably in the range of ² , especially 10 to 1000
It is preferably in the range of mg / m ² .

Next, the hollow fiber membrane type dialyzer of the present invention will be described. As shown in FIG. 2, the hollow fiber membrane type dialyzer 10 has a dialysate inlet pipe 11 near both ends.
After inserting a large number of hollow fiber membrane bundles 14 comprising the hollow fiber membranes of the present invention into a cylindrical body 13 having a dialysate outlet tube 12, both ends of the hollow fiber membrane bundle 14 are potted with agents 15 and 16. Each part is sealed,
For example, it has a structure similar to a shell and tube type device in a heat exchanger. Headers 19 and 20 having a bodily fluid inlet 17 and a bodily fluid outlet 18 are respectively in contact with both ends of the cylindrical main body 13, and the headers 19 and 20 and the cylindrical main body 13 are respectively fixed by caps 21 and 22. ing. The body fluid inlet 17
The body fluid outlet 18 has a tube 2 connected to the human body.
3, 24 are connected. Examples of the material of the tubular body, the header and the cap include polycarbonate and polypropylene. In addition, examples of the potting agent include polyurethane.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[0042]

Embodiment 1 Preparation of spinning stock solution and core solution The spinning stock solution was polysulfone (solubility parameter δ 9.9).
0 (cal / cm ³ ) ^1/2 ) 15 wt%, PVP 9 wt
%, DMSO 45 wt%, DMA 35 wt% and water 1
It was prepared by mixing wt%. Core liquid is DMSO 30 wt
%, DMA 30 wt%, methanol 30 wt% and water 10 wt% to the core liquid, α-tocopherol 1
It was prepared by mixing wt%.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double tube discharge nozzle, respectively, and extruded into the air while filling the core portion of the spinning solution with the core solution. After passing through a filled coagulation liquid tank and coagulation, it was washed and dried to produce a hollow fiber membrane. The resulting hollow fiber membrane had an inner diameter of about 200 μm and an outer diameter of about 280 μm, and the α-tocopherol content was about 480 mg / m ² .

3. Preparation of hollow fiber dialyzer 2. The hollow fiber membrane obtained in (4) was cut into a length of about 14 cm, and 341 of them were inserted into a polycarbonate main body having an inner diameter of 1.2 cm and a length of 14 cm. Both ends were fixed with a polyurethane potting agent, and a polycarbonate header was attached to both ends and fixed with a polycarbonate cap to produce a hollow fiber type dialyzer of the same type as in FIG. The hollow fiber dialyzer thus obtained had an in-membrane surface area of 300 cm ² .

[0045]

Embodiment 2 1. Preparation of spinning dope The spinning dope is polysulfone 15wt%, PVP9wt
%, DMSO 46 wt% and DMA 30 wt% were prepared by mixing 0.5 wt% of α-tocopherol. The viscosity of this solution was 36 poise.
The core liquid was prepared by mixing 30 wt% DMSO, 30 wt% DMA, and 40 wt% water.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double tube discharge nozzle, respectively, and extruded into the air while filling the core portion of the spinning solution with the core solution. After passing through a filled coagulation liquid tank and coagulation, it was washed and dried to produce a hollow fiber membrane. The obtained hollow fiber membrane had an inner diameter of about 200 μm and an outer diameter of about 280 μm, and the α-tocopherol content was about 580 mg / m ² .

3. Preparation of hollow fiber dialyzer 2. The hollow fiber membrane obtained in (4) was cut into a length of about 14 cm, and 341 of them were inserted into a polycarbonate main body having an inner diameter of 1.2 cm and a length of 14 cm. Both ends were fixed with a polyurethane potting agent, and a polycarbonate header was attached to both ends and fixed with a polycarbonate cap to produce a hollow fiber type dialyzer of the same type as in FIG. The hollow fiber dialyzer thus obtained had an in-membrane surface area of 300 cm ² .

[0048]

Embodiment 3 1. Preparation of spinning dope The spinning dope is polysulfone 15wt%, PVP9wt
%, DMSO 45 wt%, DMA 35 wt% and water 1
It was prepared by mixing wt%. Core liquid is DMSO 30 wt
%, DMA 30 wt% and water 40 wt% were mixed and produced.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double-tube discharge nozzle, respectively, and the core solution of the spinning stock solution is extruded into the air while filling the core solution with water. After passing through a filled coagulating liquid tank to coagulate, it was washed and dried. Further, it was passed through a 10% α-tocopherol / hexane solution tank and dried to prepare a hollow fiber membrane.
The obtained hollow fiber membrane has an inner diameter of about 200 μm and an outer diameter of about 280 μm.
and the content of α-tocopherol is about 830 mg /
m ² .

3. Preparation of hollow fiber dialyzer 2. The hollow fiber membrane obtained in (4) was cut into a length of about 14 cm, and 341 of them were inserted into a polycarbonate main body having an inner diameter of 1.2 cm and a length of 14 cm. Both ends were fixed with a polyurethane potting agent, and a polycarbonate header was attached to both ends and fixed with a polycarbonate cap to produce a hollow fiber type dialyzer of the same type as in FIG. The hollow fiber dialyzer thus obtained had an in-membrane surface area of 300 cm ² .

[0051]

Embodiment 4 1. Preparation of spinning dope The spinning dope is polysulfone 15wt%, PVP9wt
%, DMSO 45 wt%, DMA 35 wt% and water 1
It was prepared by mixing wt%. Core liquid is DMSO 30 wt
%, DMA 30 wt% and water 40 wt% were mixed and produced.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double-tube discharge nozzle, respectively, and the core solution of the spinning stock solution is extruded into the air while filling the core solution with water. After passing through a filled coagulating liquid tank to coagulate, it was washed and dried. Furthermore, α-tocopherol acetate 10% /
It was passed through a hexane solution tank and dried to produce a hollow fiber membrane. The resulting hollow fiber membrane has an inner diameter of about 200 μm and an outer diameter of about 28.
0 μm and the content of α-tocopherol acetate is about 78.
It was 0 mg / m ² .

3. Preparation of hollow fiber dialyzer 2. The hollow fiber membrane obtained in (4) was cut into a length of about 14 cm, and 341 of them were inserted into a polycarbonate main body having an inner diameter of 1.2 cm and a length of 14 cm. Both ends were fixed with a polyurethane potting agent, and a polycarbonate header was attached to both ends and fixed with a polycarbonate cap to produce a hollow fiber type dialyzer of the same type as in FIG. The hollow fiber dialyzer thus obtained had an in-membrane surface area of 300 cm ² .

[0054]

Example 5 1. Preparation of spinning dope The spinning dope is polysulfone 15wt%, PVP9wt
%, DMSO 45 wt%, DMA 35 wt% and water 1
It was prepared by mixing wt%. Core liquid is DMSO 30 wt
%, DMA 30 wt% and water 40 wt% were mixed and produced.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double-tube discharge nozzle, respectively, and the core solution of the spinning stock solution is extruded into the air while filling the core solution with water. After passing through a filled coagulating liquid tank to coagulate, it was washed and dried. Furthermore, α-tocopherol nicotinate 1
A hollow fiber membrane was produced by passing through a 0% / hexane solution tank and drying. A hollow fiber membrane was prepared. The resulting hollow fiber membrane had an inner diameter of about 200 μm and an outer diameter of about 280 μm, and the content of α-tocopherol nicotinate was about 740 mg / m ² .

3. Preparation of hollow fiber dialyzer 2. The hollow fiber membrane obtained in (4) was cut into a length of about 14 cm, and 341 of them were inserted into a polycarbonate main body having an inner diameter of 1.2 cm and a length of 14 cm. Both ends were fixed with a polyurethane potting agent, and a polycarbonate header was attached to both ends and fixed with a polycarbonate cap to produce a hollow fiber type dialyzer of the same type as in FIG. The hollow fiber dialyzer thus obtained had an in-membrane surface area of 300 cm ² .

[0057]

Embodiment 6 Preparation of spinning dope The spinning dope was a polyacrylonitrile copolymer (solubility parameter δ 12.35 (cal / cm 3) 1 consisting of 91.5 wt% acrylonitrile, 8 wt% methyl acrylate, and 0.5 wt% sodium methallylsulfonate. /
2) It was produced by mixing DMF 82.8 wt% and zinc chloride 4.8 wt% with 12.4 wt%.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double-tube discharge nozzle, respectively, and the core solution of the spinning stock solution is extruded into the air while filling the core solution with water. After passing through a filled coagulating liquid tank to coagulate, it was washed and dried. Further, it was passed through a 10% α-tocopherol / hexane solution tank and dried to prepare a hollow fiber membrane.
The resulting hollow fiber membrane has an inner diameter of about 200 μm and an outer diameter of about 300 μm.
and the content of α-tocopherol is about 50 mg / m
^{Was 2} .

[0059]

Comparative Example 1 1. Preparation of spinning dope The spinning dope is polysulfone 15wt%, PVP9wt
%, DMSO 45 wt%, DMA 35 wt% and water 1
It was prepared by mixing wt%. Core liquid is DMSO 30 wt
%, DMA 30 wt% and water 40 wt% were mixed and produced.

2. Production of hollow fiber membrane The spinning stock solution and the core solution prepared in step 2 are simultaneously discharged from the outer tube (annular spinning hole) and the inner tube of the double tube discharge nozzle, respectively, and extruded into the air while filling the core portion of the spinning solution with the core solution. After passing through a filled coagulation liquid tank and coagulation, it was washed and dried to produce a hollow fiber membrane. The resulting hollow fiber membrane had an inner diameter of about 200 μm and an outer diameter of about 280 μm.

3. Preparation of hollow fiber dialyzer 2. The hollow fiber membrane obtained in (4) was cut into a length of about 14 cm, and 341 of them were inserted into a polycarbonate main body having an inner diameter of 1.2 cm and a length of 14 cm. Both ends were fixed with a polyurethane potting agent, and a polycarbonate header was attached to both ends and fixed with a polycarbonate cap to produce a hollow fiber type dialyzer of the same type as in FIG. The hollow fiber dialyzer thus obtained had an in-membrane surface area of 300 cm ² .

[Experimental Example 1] Measurement of lipid peroxide Using the hollow fiber type dialyzers of Examples 1 to 5 and Comparative Example 1, lipid peroxide was examined according to the following procedure.

After priming the hollow fiber dialyzer with 10 ml of saline, blood (10 U heparinized blood) 4
The ml was gently sucked to completely replace the saline in the mini-module with blood. This was incubated at 37 ° C. for 2 hours to collect blood from the mini module. Table 1 shows the results of measuring the collected blood with the lipid peroxide test Wako (Yagi method: Wako Pure Chemical Industries, Ltd.). In this case, malondialdehyde (MDA) was used as an indicator substance of lipid peroxide.

[0064]

[Table 1]

From Table 1 above, the polysulfone membrane of Comparative Example 1 produced a large amount of lipid peroxide, whereas Examples 1 to 5 according to the present invention produced a slight amount of the active oxygen, showing an effect of suppressing active oxygen. It was confirmed that the biocompatibility was improved.

[Experimental Example 2] Measurement of Vitamin E Elution Amount Using the hollow fiber dialyzer of Examples 1 to 5 and Comparative Example 1, the elution of vitamin E was examined according to the following procedure.

First, 500 ml of bovine blood was dispensed into a 50 ml polypropylene test tube and centrifuged at 3000 rpm for 15 minutes to obtain 200 ml of bovine plasma. In addition, 50
50 ml of bovine plasma was dispensed into a polypropylene test tube of ml, and the test tube containing bovine plasma was connected via a pump to the blood inlet 8 of the hollow fiber type dialyzer 1 with a vinyl chloride tube 14 and further a hollow fiber type tube. The blood outlet 9 of the dialyzer 1 and the test tube containing bovine plasma were connected by a vinyl chloride tube 15 to prepare an experimental circuit.

The test tube containing bovine plasma was maintained in a constant temperature bath at 37 ° C., and bovine plasma was circulated in the hollow fiber dialyzer at a flow rate of 10 ml / min for 4 hours by a pump, and the bovine plasma was fed to the bovine plasma after 4 hours. The elution amount of vitamin E was measured.

The amount of vitamin E eluted in plasma was measured as follows. First, 1 ml of bovine plasma after the end of circulation was collected, and 1 ml of ethanol was added thereto and mixed for 30 seconds to remove proteins in bovine plasma. Next, 5 ml of hexane was added and mixed for 1 minute to transfer vitamin E in bovine plasma to the hexane layer. This was centrifuged at 1500 rpm for 10 minutes, and the amount of vitamin E in the upper hexane layer was quantified by liquid chromatography.

The liquid chromatography was measured under the following conditions: column: Amide-80, 4.6 × 25 cm (Toso TSK gel), n-hexane: i-propanol = 98: 2 as moving layer, flow rate: 1. 5 ml / min, injection amount: 10 μl, detection: UV monitor 292
nm.

Table 2 shows the measurement results of the amount of vitamin E eluted in plasma of Experimental Example 2.

[0072]

[Table 2]

From Table 2 above, plasma vitamin E after circulation
The amounts of Comparative Example 1 not treated with vitamin E and Examples 1 to 5 according to the present invention are almost the same, and it is clear that they are not eluted.

[Experimental Example 3] Evaluation of biocompatibility In order to evaluate the biocompatibility of vitamin E using the hollow fiber type dialyzer of Examples 1 to 5 and Comparative Example 1,
An extracorporeal circulation experiment was carried out in rabbits, and the number of hollow fibers in which blood remained in the hollow fibers after completion of extracorporeal circulation was examined.

First, the rabbit was fixed on its back on a Kitajima type fixed base, the hair of the surgical field was shaved with an electric hair clipper, and wiped with a cotton swab. Then, make an incision along the midline from below the jaw to the clavicle with scissors and open the fascia, taking care not to damage the nerves, branch vessels, and surrounding tissues.
The common carotid artery was dissected. The left (right) facial vein was then carefully removed as well. Then, while the blood vessel was clamped, an indwelling needle equipped with a mixed injection rubber cap filled with physiological saline was inserted into the vein and fixed by ligation. Further, one side (venous side) of the circuit was connected to the venous side of the hollow fiber dialyzer filled with physiological saline by a vinyl chloride tube filled with physiological saline. Similarly, an indwelling needle was inserted into the artery, fixed by ligation, and then connected to the artery side of the hollow fiber dialyzer via a pump using a vinyl chloride tube filled with physiological saline.

Using the rabbit extracorporeal circuit, an extracorporeal circulation experiment was conducted as follows. First, unclamp the blood vessel and pump 10 ml /
The extracorporeal circulation was performed for 2 hours while keeping the flow rate at min. After the circulation was completed, the arteriovenous blood vessel was clamped again, and the arterial side circuit and the venous side circuit were cut at a portion near the indwelling needle. And
50 ml of physiological saline was single-passed by a pump at a flow rate of 10 ml / min to wash the inside of the circuit and the hollow fiber type dialyzer. After washing, cut the hollow fibers at the center of the hollow fiber type dialyzer, count the number of hollow fibers with residual blood by microscope, and count the total number of hollow fibers in the hollow fiber type dialyzer and the number of hollow fibers with residual blood. The residual blood rate was calculated by.

Table 3 shows the calculation results of the residual blood rate after the end of extracorporeal circulation in Experimental Example 3.

[0078]

[Table 3]

From Table 3 above, the residual blood rate of the polysulfone membrane not treated with vitamin E of Comparative Example 1 was 29.9%, whereas the residual polysulfone membrane of Example 1 according to the present invention remained. The blood rate is 14.9%, and the residual blood rate after extracorporeal circulation in rabbits is clearly reduced by the platelet aggregation inhibitory effect of vitamin E, which shows excellent biocompatibility.

[0080]

As described above in detail, according to the method for producing a hollow fiber membrane of the present invention, a fat-soluble vitamin solution is mixed in a spinning stock solution or a core solution, or a filament after coagulation is continuously prepared in a fat-soluble vitamin solution. Since the hollow fiber membranes are immersed in the hollow fiber membranes and impregnated with the fat-soluble vitamins in the membrane-forming step, the fat-soluble vitamins can be impregnated into the microporous surface inside the hollow fiber membranes. Therefore, as compared with the conventional one in which only the surface contacting with blood is coated with vitamin E after the dialysis membrane forming step and the artificial organ assembling step, fat-soluble vitamins are used for substances that can pass through the hollow fiber membrane. It is possible to obtain a hollow fiber membrane and a hollow fiber membrane type dialyzer capable of exerting an effect of an antioxidant action. In particular, the hollow fiber membrane and the hollow fiber membrane type dialyzer of the present invention are superior in biocompatibility to conventional ones, the residual blood rate is reduced, the production of active oxygen is suppressed, and active oxygen is the cause. It is possible to alleviate various diseases.

In the present invention, by using a synthetic polymer having a solubility parameter δ of 13 (cal / cm ³ ) ^1/2 or less as the base material, the affinity between the hollow fiber membrane base material and the fat-soluble vitamin is improved. Can be improved, and the above effects can be made more prominent.

Further, in the present invention, since the hollow fiber membrane in the membrane forming step is impregnated with a fat-soluble vitamin,
The film forming process is simpler and the cost can be reduced as compared with the conventional method in which the process is performed after the film forming process and the assembling process.

[Brief description of drawings]

FIG. 1 is a process drawing showing an embodiment of a method for producing a hollow fiber membrane of the present invention.

FIG. 2 is a perspective view showing a hollow fiber membrane type dialyzer according to an embodiment of the present invention, which has a partial cutaway portion.

[Explanation of symbols]

 1 Spinning device 2 Spinning stock solution tank 3 Core solution tank 4 Discharge nozzle 5 Coagulating solution tank 6 Cleaning solution tank 7 Winder 10 Dialyzer 11 Dialysate inlet tube 12 Dialysate outlet tube 13 Cylindrical body 14 Hollow fiber membrane bundle 15, 16 Potting Agent 17 Body fluid inlet 18 Body fluid outlet 19, 20 Header 21, 22 Cap 23, 24 Connection tube

Claims (14)

[Claims] 1. A method for producing a hollow fiber membrane, in which a spinning dope is discharged from an annular spinning hole and is extruded linearly while being filled with a core liquid, and then introduced into a coagulating liquid to coagulate to produce a hollow fiber membrane. A method for producing a hollow fiber membrane, characterized in that a stock solution or the core solution contains a fat-soluble vitamin. 2. The method for producing a hollow fiber membrane according to claim 1, wherein the content of the fat-soluble vitamin in the spinning dope or the core liquid is 0.001 to 10 wt%. 3. A method for producing a hollow fiber membrane, in which a spinning dope is discharged from an annular spinning hole and is extruded linearly while being filled with a core liquid and then introduced into a coagulating liquid to coagulate the hollow fiber membrane. Then, the filament is introduced into a fat-soluble vitamin solution for impregnation treatment, and a method for producing a hollow fiber membrane. 4. The method for producing a hollow fiber membrane according to claim 1, wherein the fat-soluble vitamin is vitamin E. 5. The vitamin E is α-tocopherol,
The method for producing a hollow fiber membrane according to claim 4, which is α-tocopherol acetate or α-tocopherol nicotinate. 6. A substrate having a solubility parameter δ of 13
The method for producing a hollow fiber membrane according to claim 1, wherein a synthetic polymer having (cal / cm ³ ) ^1/2 or less is used. 7. A hollow fiber membrane produced by linearly extruding a spinning dope from a ring-shaped spinning hole while at the same time filling a core liquid therein, and then introducing it into a coagulating liquid to coagulate it.
A hollow fiber membrane that can be obtained by containing a fat-soluble vitamin in the spinning solution or the core liquid, or by introducing the coagulated filament into a fat-soluble vitamin solution and impregnating the filament. 8. The hollow fiber membrane according to claim 7, wherein the fat-soluble vitamin is vitamin E. 9. The vitamin E is α-tocopherol,
The hollow fiber membrane according to claim 8, which is α-tocopherol acetate or α-tocopherol nicotinate. 10. A substrate having a solubility parameter δ of 13
The hollow fiber membrane according to claim 7, which comprises a synthetic polymer having (cal / cm ³ ) ^1/2 or less. 11. A hollow fiber membrane which is produced by linearly extruding a spinning dope from a ring-shaped spinning hole while at the same time filling a core liquid therein, and then introducing it into a coagulating liquid to coagulate it. A hollow fiber membrane type dialyzer comprising a hollow fiber membrane obtained by containing a fat-soluble vitamin in the stock solution or the core solution, or by introducing the coagulated filament into a fat-soluble vitamin solution and impregnating it. 12. The hollow fiber membrane type dialyzer according to claim 11, wherein the fat-soluble vitamin is vitamin E. 13. The hollow fiber membrane type dialyzer according to claim 12, wherein the vitamin E is α-tocopherol, α-tocopherol acetate or α-tocopherol nicotinate. 14. A substrate having a solubility parameter δ of 13
The hollow fiber membrane type dialyzer according to claims 11 to 13, which comprises a synthetic polymer having (cal / cm ³ ) ^1/2 or less.