JP3253861B2 - Permselective hollow fiber membrane - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a blood purification hollow fiber membrane. For example, artificial dialysis membranes for patients with renal failure, particularly β ₂ -microglobulin (β ₂₎ having a molecular weight of 10,000 or more, which has recently been attracting attention in relation to long-term complications of dialysis patients.
-MG), which is suitable for removing medium-high molecular weight substances. Also simply hemodiafiltration,
The present invention relates to a hollow fiber membrane that is also suitable for hemofiltration.

[0002]

2. Description of the Related Art In recent years, in connection with long-term complications of dialysis patients, β which is considered to be a causative substance of dialysis amyloidosis
_2- MG (molecular weight 11,800), parathyroid hormone (molecular weight of about 9,
500), molecular weight 2 thought to be related to joint pain and bone pain
The need to remove harmful substances in the relatively medium to high molecular weight region, such as ~ 40,000 substances, has been avoided. On the other hand, loss of albumin (molecular weight: 66,000), which is essential for the human body, must be avoided as much as possible.

[0003] That is, there is a demand for a permselective membrane having excellent permeability for substances having a molecular weight of 40,000 or less and 50,000 or less, and having good rejection of substances having a molecular weight of 60,000 or more and having a good sharp cut of the molecular weight. .

However, conventionally, in the case of synthetic polymers such as polysulfone, for example, Japanese Patent Publication No.
As can be seen from the publications of JP-A-54373, those which relatively satisfy the above requirements have been obtained. However, in the case of cellulose derivatives, especially cellulose triacetate, for example, liquid paraffin, as a core agent for wet spinning a hollow fiber, as shown in JP-B-58-24165.
Higher alcohols, isopropyl myristate, etc., which do not have coagulability with the triacetate spinning dope, are used. The coagulation of the spinning solution is inevitably performed by the coagulation liquid from the outer surface of the hollow fiber after spinning from the nozzle, so that a dense structure layer is formed on the outer surface of the hollow fiber.

[0005] For these reasons, the conventional cellulose derivative hollow fiber has a smaller density difference between the dense layer and the porous layer than the synthetic polymer membrane, is close to a uniform layer as a whole, and has a sufficient substance permeability. Did not.

On the other hand, JP-A-8-970 discloses a hollow fiber membrane which is triacetate and has improved permeability by using N ₂ gas as a core agent.

According to this, the ultrafiltration coefficient of pure water is 10
200 ml / m ² · mmHg · Hr, a hollow fiber membrane having a β ₂ -MG sieving coefficient of 0.2 or more,
A hemodialysis membrane is obtained, characterized in that the blood permeability of the membrane and the sieving coefficient of β ₂ -MG show 90% or more of the values at the start of hemofiltration even after a lapse of time.

However, in the spinning method of triacetate using a gas as a core agent disclosed in the publication, spinning at a low polymer concentration is difficult because spinning is difficult, and the ultrafiltration coefficient of water is shown in Examples. 10 to 120 ml /
It is difficult to obtain a hollow fiber membrane having a relatively low Hr · mmHg · m ² and a high ultrafiltration coefficient. When a gas is used as the core material, since the core material does not have coagulation properties, it is difficult to form an inner dense layer, and as a film structure, the density difference between the dense layer and the porous layer is small, and the permeability is excellent. A two-layer film like a synthetic polymer cannot be obtained. Therefore, it is difficult to significantly improve the removal of medium-high molecular weight substances represented by β ₂ -MG, which is a problem due to long-term complications in hemodialysis.

As described above, since the density difference between the dense layer and the porous layer of the membrane structure is unclear, there is still room for improvement in permeability and fractionability.

[0010]

An object of the present invention is to provide a high-performance permselective hollow fiber membrane comprising a cellulose derivative, wherein both the ultrafiltration coefficient and the β ₂ -MG sieve coefficient are large. Another object of the present invention is to provide a selectively permeable hollow fiber membrane having high water permeability retention rate and high retention rate of β ₂ -MG sieving coefficient in hemofiltration dialysis, and having little deterioration over time in filtration performance.

[0011]

Means for Solving the Problems The present inventor has conducted intensive studies to achieve the above object, and as a result, has found a hollow fiber having a two-layer structure having an extremely thin dense layer on the inner surface and a porous layer on the support layer. When the membrane has a specific water permeation performance, a low-deterioration cellulose derivative selectively permeable hollow fiber membrane excellent in water retention rate during blood treatment and retention rate of β ₂ -MG sieving coefficient can be obtained. The inventors have found that the present invention has been achieved.

That is, according to the present invention, the inner diameter is 100 to 300 μm.
m, thickness: 30 to 60 μm, porosity: 60 to 90%, ultrafiltration coefficient of pure water: 200 to 850 ml / m ² · mmH
A selectively permeable hollow fiber membrane having a g · Hr, β ₂ -microglobulin sieving coefficient of 0.5 or more, wherein the selectively permeable hollow fiber membrane retains blood permeability and β ₂ -microglobulin sieving. A permselective hollow fiber membrane consisting essentially of a cellulose derivative, characterized in that the coefficient retention rates are both 80% or more.

Hereinafter, the present invention will be described in more detail. The material forming the hollow fiber membrane in the present invention is a cellulose derivative, particularly acetyl cellulose.

Among them, those generally used are polymers substantially consisting of cellulose diacetate and cellulose triacetate. Among these, cellulose triacetate is particularly preferred. In addition, substantially means that the properties of the cellulose derivative are not impaired.
It means that other high molecular weight substances and additives may be contained.

The structure of the membrane wall of the hollow fiber membrane according to the present invention has an extremely thin dense layer for determining the separation and permeation characteristics of a substance on the inner surface, and a support layer for sharing the mechanical properties of the membrane on the outer surface. The support layer is preferably a two-layer or multilayer structure, which is a porous layer having almost no permeation resistance of the target substance.

In order to reduce the time-dependent change in blood permeability and the time-dependent change in the sieving coefficient of β ₂ -MG in hemodiafiltration, a membrane structure having a dense layer on the inner surface of the membrane is essential. At this time, while the structure of the dense layer is made more dense, the thickness of the dense layer is made extremely thin as 1 to 2 μm, so that the permeation / filtration performance is not impaired. It is possible to suppress the performance of the hollow fiber membrane over time due to clogging.

[0017] The thickness of the hollow fiber is 2 as in the present invention.
Since the layer structure has a porous layer, it needs to be 30 μm or more from the viewpoint of mechanical strength. As the film thickness increases, the number of hollow fibers that can be filled in the dialyzer decreases and the membrane area of the dialyzer decreases, so the film thickness is preferably 30 to 60 μm.

The inner diameter of the hollow fiber membrane is 100 to 300 μm.
m, particularly preferably 150 to 250 μm.

Water permeation performance (UFR) of the hollow fiber membrane of the present invention
Is 200 to 850 ml / m ² · mmHg · Hr.
It was difficult to obtain such a high level of water permeation performance with a conventional film having a relatively uniform structure. By providing such a UFR, TMP (differential pressure applied to both sides of the hollow fiber membrane) for removing a certain amount of water can be reduced, and adhesion of blood protein to the hollow fiber membrane can be suppressed. it can. In addition, the hollow fiber membrane of the present invention has a two-layer structure of a porous layer having a dense layer on the inner surface. And the change with time of the sieving coefficient of β ₂ -MG can be reduced. The thickness and density (porosity) of the inner dense layer are determined by spinning conditions, particularly the polymer concentration, the moisture content of the core agent,
It can be determined by the spinning temperature and the like.

The porosity of the hollow fiber membrane of the present invention is 60 to 90%.
It is. If the porosity is 60% or less, the desired transmission performance cannot be obtained. If it is 90% or more, the mechanical strength of the hollow fiber membrane decreases, and problems such as leakage due to handling during production occur. The porosity was measured by rinsing the hollow fiber membrane for 1 hour, removing the water on the surface of the hollow fiber and the hollow fiber tube, measuring the weight (weight W ₁ ), and then drying the hollow fiber membrane completely. The weight is measured (weight W ₂ ) and determined by the following equation. Porosity = (1−W ₂ / W ₁ ) × 100% Absolute drying refers to a state of drying in a 130 ° C. hot air dryer for 3.5 hours.

The sieving coefficient of β ₂ -MG of the hollow fiber membrane of the present invention must be 0.5 or more. Β ₂ -MG (molecular weight 11,800), a causative substance of dialysis amyloidosis, arthralgia,
Higher is preferable from the necessity of removing a harmful substance in a relatively high molecular weight region such as a substance having a molecular weight of 20,000 to 40,000, which is considered to be related to bone pain. The larger the sieve coefficient of β ₂ -MG is, the more preferable it is, but usually it is 0.95 or less.

The ultrafiltration coefficient of pure water of the hollow fiber membrane of the present invention needs to be 200 to 850 ml / m ² · mmHg · Hr. Further, when blood filtration is performed at a filtration rate of 10 ml / min per 1 m ² of a membrane area of a module manufactured using the hollow fiber membrane, the water permeability retention rate of the present invention needs to be 80% or more.
More preferably, it is 95% or more. 80 permeability retention
% Or less is not preferred because the filtration efficiency is greatly reduced due to clogging and the clearance of low molecular weight substances is reduced.

When performing blood filtration at a filtration rate of 10 ml / min per 1 m ^{2 of} a module membrane area prepared using the hollow fiber membrane of the present invention, the retention rate of the β ₂ -MG sieving coefficient of the hollow fiber membrane is as follows. 80% or more is required, and 95% or more is more preferable. When the retention rate of the sieving coefficient of β ₂ -MG is 80% or less, not only does the removal efficiency of β ₂ -MG decrease, but also the removal efficiency of harmful substances in the medium-high molecular weight region of 20,000 to 40,000 decreases.
Not preferred.

In the present invention, the retention is defined as the blood ultrafiltration coefficient and the β ₂ -MG sieving coefficient at 15 minutes after the start of blood filtration, and the blood at 4 hours after the start of blood filtration. Is the ratio of the ultrafiltration coefficient and the sieving coefficient of β ₂ -MG. Retention rate = Characteristics at 4 hours after the start of hemofiltration / Characteristics at 15 minutes after the start of hemofiltration In the production of the hollow fiber membrane of the present invention, N-methylpyrrolidone is used as a solvent for the hollow fiber spinning stock solution. , Dimethylformamide, dimethylsulfoxide, dimethylamide, dimethylacetamide and the like.

As the non-solvent, propylene glycol,
Polyhydric alcohols such as ethylene glycol, triethylene glycol, and polyethylene glycol can be used.

For the coagulation bath of the hollow fiber, an aqueous solution of the above-mentioned solvent and non-solvent is used. Further, in order to form an asymmetric membrane structure having a dense layer on the inner surface, it is necessary to use a lower concentration of an aqueous solution of a solvent and a non-solvent as a core agent to promote phase separation in the middle and outer layers.

The composition of the spinning dope is generally 10 to 20% by weight of a cellulose derivative, 55 to 75% by weight of a solvent and 10 to 30% by weight of a non-solvent, preferably 10 to 15% by weight of a cellulose derivative and 60 to 60% by weight of a solvent. 70% by weight, non-solvent 15
２５25% by weight.

The composition of the coagulation bath is generally from 30 to 55/5 to 20/30 to 65, preferably from 35 to 45/10 to 15/40 to 55 by weight of solvent / non-solvent / water.

The composition of the core agent is preferably 5 to 25/2 to 15/70 to 95, and more preferably 10 to 25 by weight in a solvent / non-solvent / water ratio.
20/3 to 10/80 to 90.

The temperature of the spinneret varies depending on the composition of the stock solution, but is 30 to 100 ° C., and the temperature of the coagulation bath is 10 to 70 ° C.
° C, preferably 30 to 60 ° C. As a spinning method, a semi-dry semi-wet spinning method is preferable.

[0031]

According to the present invention, a hollow fiber membrane having extremely high water permeability and excellent separation characteristics can be obtained, which is extremely useful in the field of hemodialysis.

[0032]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

In the examples and comparative examples, the evaluation items were measured by the following methods. That is, the measurement of the permeability retention rate of the hollow fiber membrane and the retention rate of the β ₂ -MG sieving coefficient in hemofiltration dialysis were carried out using the in vitro evaluation protocol of bovine plasma of a blood purifier by the Scientific Committee of the Japanese Society for Dialysis Medicine and the functional classification ( Based on the measurement according to '94 .11.12), it was determined by the following equation.

[0034]

(Equation 1)

UFR = ultrafiltration coefficient [ml / m ² · mmHg · Hr] P _Bi = blood side inlet pressure [mmHg] P _Bo = blood side outlet pressure [mmHg] P _F = filtration side purifier internal pressure [mmHg] ]

[0036]

(Equation 2)

SC: sieving coefficient C _F : concentration of the solution on the filtrate side C _Bi : concentration of the solution on the blood side inlet C _Bo : concentration of the solution on the blood side outlet

Examples 1 to 5 and Comparative Examples 1 and 2 13 parts of cellulose triacetate and 20 parts of triethylene glycol 20
Of a dimethylsulfoxide solution in 67 parts of dimethylsulfoxide is used as a spinning solution, and an 80 wt% aqueous solution of dimethylsulfoxide / triethylene glycol = 37/13 (wt / wt) is used as a core agent in the air (about 5 cm) from a double tube nozzle. )
And then coagulated at 40 ° C. (dimethyl sulfoxide / triethylene glycol = 37/13 (wt / wt)
50 wt% aqueous solution), solidified, washed with water,
After the glycerin adhesion treatment, it was wound up. The obtained hollow fiber membrane is dried and formed into a bundle, inserted and filled in a cylindrical container, and both ends are bonded and fixed with polyurethane, and the effective area is about 1.5 m ^2.
Was prepared and used for performance evaluation in hemofiltration. The results are shown in Table-1.

Comparative Example 3 Cellulose Triacetate 2
0 part and 23 parts of propylene glycol are uniformly dissolved in 57 parts of N-methylpyrrolidone to obtain a spinning dope, and liquid paraffin is used as a core agent and discharged into the air from a double tube nozzle. : N-methylpyrrolidone = 25 ° C mixed at a weight ratio of 80: 8: 12
And solidified, washed with water, treated with glycerin, and wound up. Remove the core agent in the obtained hollow fiber membrane,
After washing, the obtained hollow fiber membrane is inserted and filled in a cylindrical container, and after drying, both ends are adhered and fixed with polyurethane to produce a hemodialyzer having an effective area of about 1.5 m ^2. For performance evaluation. The results are shown in Table-1.

[0040]

[Table 1]

In Examples 1 to 3, as shown in the electron micrograph of the cross section of the hollow fiber membrane of Example 1, a two-layer structure having an extremely thin dense layer of about 1 μm on the inner surface and a support layer of a porous layer was used. The membrane has an ultrafiltration coefficient of pure water of 205.2 to 812.4 ml / m ^2.
In the range of mmHg · Hr, the ultrafiltration coefficient of blood and β
The retention rate of the _2- MG sieving coefficient is 80% or more, and the filtration performance of the hollow fiber membrane is extremely low.

In Examples 4 and 5, the ultrafiltration rate was 10 ml.
/ Min from 20/40 ml / min, the ultrafiltration coefficient of blood and the retention rate of the sieving coefficient of β ₂ -MG are both 80% or more, and the deterioration of the filtration performance of the hollow fiber membrane is extremely small. .

In Comparative Examples 1 and 2, when the ultrafiltration coefficient of pure water is 200 ml / m ² · mmHg · Hr or less, the retention of filtration performance in blood filtration is 80% or less, and the decrease is large.

Comparative Example 3 shows the ultrafiltration coefficient of blood and the retention rate of the β ₂ -MG sieving coefficient of a hollow fiber having a uniform dense membrane structure according to the prior art using liquid paraffin as a core agent. The retention rate of the filtration coefficient in hemofiltration is as large as 68.2%.

[0045]

The hollow fiber membrane of the present invention, when used for hemodialysis, has very little change over time in filtration performance due to clogging of the membrane, and causes dialysis amyloidosis in connection with long-term complications of dialysis patients. It is a permselective hollow fiber membrane excellent in removing the substance β ₂ -MG. Since the membrane of the present invention has an ultrafiltration coefficient of blood much higher than that of a conventional hollow fiber membrane and a high β ₂ -MG sieving coefficient, it has a molecular weight of 20,000 to 40,000, which is considered to be involved in bone pain and joint pain. It can also be expected to remove harmful substances in the relatively medium-high molecular weight region.

[Brief description of the drawings]

FIG. 1 is an electron micrograph (× 20,000) of a cross section of a hollow fiber membrane (including a dense layer and a porous layer) obtained in Example 2.

FIG. 2 is an electron micrograph (× 20,000) of a cross section of a hollow fiber membrane layer obtained in Comparative Example 3.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-211229 (JP, A) JP-A-7-148252 (JP, A) JP-A-7-278948 (JP, A) JP-A 8- 38598 (JP, A) JP-A-8-970 (JP, A) JP-A-9-70525 (JP, A) JP-B3-76970 (JP, B2) JP-B 8-29231 (JP, B2) (58) Field surveyed (Int.Cl. ⁷ , DB name) A61M 1/16-1/18 B01D 69 / 02,69 / 08,71 / 16

Claims (3)

(57) [Claims] 1. A two-layer structure having an extremely thin dense layer on an inner surface and a porous layer on a support layer, and having an inner diameter of 100 to 300 μm.
m, thickness: 30 to 60 μm, porosity: 60 to 90%, ultrafiltration coefficient of pure water: 200 to 850 ml / m ² · mmH
A selectively permeable hollow fiber membrane having a g · Hr, β ₂ -microglobulin sieving coefficient of 0.5 or more, wherein the selectively permeable hollow fiber membrane has a blood water permeability retention rate and a β ₂ -microglobulin sieve. Hemodialysis consisting essentially of cellulose triacetate , wherein the retention rates of the coefficients are both 80% or more.
Permeable hollow fiber membranes for use . 2. The permselective hollow fiber membrane according to claim 1, wherein the β ₂ -microglobulin sieve coefficient of the permselective hollow fiber membrane is 0.5 or more and 0.95 or less. 3. The selective permeation according to claim 1, wherein both the retention rate of blood permeability and the retention rate of β ₂ -microglobulin sieving coefficient of the permselective hollow fiber membrane are 90% or more. Hollow fiber membrane.