JPH0613048B2 - Selectively permeable hollow fiber - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a permselective hollow system. More specifically, it is a hollow system having a specific porosity, a specific dextran sieving coefficient, and a selective permeability that exhibits excellent separation performance in a dialyzer. The present invention provides a permselective hollow system suitable for blood treatment such as, and particularly suitable for removing harmful substances in the low molecular weight region as well as harmful substances in the medium and high molecular weight region.

<Prior Art> Hollow permselective systems have been conventionally used practically in reverse osmosis, hemodialysis and the like. In particular, hollow hemodialyzers are currently often used to purify the blood of patients with renal failure. This is a dialysis membrane in the housing, eg
A large number of hollow membranes are stored, the patient's blood is allowed to flow inside the hollow, the dialysate is allowed to flow to the outside, that is, the hollow space, and dialysis is carried out through the hollow fiber membrane wall to abolish blood. The substance is removed to correct the electrolyte concentration, and a pressure difference is applied between the inside and outside of the hollow fiber to remove excess water in blood by ultrafiltration. Further, the hollow fiber may be used for separating only plasma from blood or removing a specific component from the plasma to treat an autoimmune disease or the like. In addition, it has recently been confirmed that a therapeutic effect can be obtained by using hollow fibers for protein-permeable hemodialysis and protein-permeable hemodialysis.

As described above, the hollow fiber for treating blood must be capable of selectively permeating a specific substance according to the purpose. The performance is determined by the hollow fiber material, porosity (pore size, number, etc.), and film thickness. However, not only that, for example, how to bundle a large number of hollow fibers to effectively function the entire membrane surface is also an important point for determining the performance. For example, during dialysis, if the hollow fibers are in close contact with each other along the length direction, it becomes difficult for the dialysate to flow evenly around each hollow fiber in the vicinity of that portion, resulting in the formation of a certain basin. The dialysis effect through the hollow fiber, which is not part of the flow, is hardly performed and the overall dialysis effect is reduced. In normal dialysis operation, the difference in concentration on both sides of the hollow fiber becomes the driving force for mass transfer.Therefore, the dialysate is made to flow into the outer space of the hollow fiber as evenly as possible, and the part where the outer membrane resistance is larger than the surrounding area is reduced as much as possible. Therefore, it is necessary to devise the shape of the hollow fiber itself so that the difference in concentration between the blood side (inside the hollow fiber) and the dialysate side (outside of the hollow fiber) can be increased.

For example, as proposed by some of the inventors of the present invention, a method can be used in which protrusions are provided on the outer surface of the hollow fibers to exert the effect of preventing the adhesion between the hollow fibers.
-75481).

However, for example, polymethylmethacrylate (PMMA) membranes and ethylene-based resins developed for the purpose of being used for protein permeable hemodialysis and protein permeable hemodialysis.
In vinyl alcohol copolymer (EVAL) membrane, cellulose acetate (CA) membrane, etc., it is related to β ₂ -MG (microglobulin) (molecular weight 11,800), which is considered to be the causative substance of amyloidosis, pruritus, and hyperlipidemia. It is thought that parathyroid hormone (molecular weight of about 9,500), erythroblast inhibitory factor involved in anemia (molecular weight of 1,000), and harmful substances in the molecular weight region such as Al related to bone pain anemia are removed together with low molecular weight region such as urea. It was not possible to efficiently remove the harmful substances at high level. In addition, a cellulose acetate hollow fiber with fins has been proposed as a material that exhibits relatively good removal performance (“Kidney and Dialysis”, separate volume 16 to 19).
Page (1986)), but the development of a membrane with higher removal performance has been desired.

<Purpose of the Invention> The present invention is intended to solve such problems of the prior art, and is a harmful substance in the medium molecular weight region such as β ₂ -MG particularly in hemodialysis and hemodialysis. It is an object of the present invention to provide a selectively permeable hollow fiber capable of sufficiently enhancing both the removal performance of the above and the removal performance of harmful substances in the low molecular weight region such as urea.

<Structure of the Invention> As a result of earnest studies for achieving the above object, the present inventor has dramatically improved a blood purifier using a hollow fiber having a specific porosity, water permeability and dextran sieving coefficient. The present invention has been achieved by discovering that they exhibit excellent separation performance.

That is, in the present invention, in the hollow fiber having selective permeability, the average porosity of the hollow fiber membrane wall in the wet state is 50% or more, and the water permeation performance (UFR) at 37 ° C. is 6 ml / hr.
Sieving coefficient (S) of the dextran using an aqueous solution containing 0.1% by weight of dextran having a molecular weight of 10,000 mmHg · m ² or more
C) is 0.4 or more, and the hollow system is assembled as a dialyzer, and a 0.01 wt% urea aqueous solution measured at a blood flow side flow rate of 200 ml / min and a dialysate flow rate of 500 ml / min. A permselective hollow system having a mass transfer coefficient (K ₀ ) of 60 × 10 ⁻⁵ cm / sec or more.

The present invention will be described in more detail below. That is, the hollow fiber in the present invention has selective permeability, and specific examples of the material thereof include cellulose polymer, polymethylmethacrylate, polysulfone, acrylonitrile polymer, nylon, ethylene-vinyl alcohol copolymer and the like. Among them, cellulose polymers are preferable. Specific examples of such a cellulose polymer include regenerated cellulose, and polymers obtained by hydrolysis of cellulose ester and polymers substantially composed of cellulose obtained by the copper ammonium method and the viscose method are mentioned.
In addition, "substantially" means that other polymer may be contained within a range not impairing the characteristics of the cellulose polymer.

Regarding the structure of the membrane wall of the hollow fiber of the present invention, the average porosity when wet is 50% or more, more preferably 60% or more. Here, the porosity when wet is a percentage of the volume of water and voids in the membrane wall with respect to the volume of the entire membrane wall when impregnated with water. The wet film thickness (t) is preferably 50 μm or less, more preferably 30 μm or less, and within that range, 20 μm or more is practical. Incidentally, such a film thickness means an average thickness of a normal film wall portion excluding the film wall portion of the fin-shaped portion when a fin-shaped projection portion is present as described later. Regarding the internal structure of the membrane wall, it is desirable that the pores have a size of about 80Å or less, preferably about 30Å or more, and the distribution of the pores is uniform over the entire membrane wall. Can be said to be a particularly preferable mode for improving the separation characteristics. In other words, a hollow fiber in which such fine pores are present in the membrane wall in a state as uniform as possible, and the average occupancy of the pores is 50% or more is a preferred embodiment of the hollow fiber of the present invention. . The outer diameter of the hollow fiber is preferably about 100 to about 400 µ, more preferably about 200 to about 300 µ.

Further, as a form of the hollow fiber of the present invention, it is preferable to have at least one protrusion on the outer periphery thereof. As such a protruding portion, any one can be used as long as it does not excessively reduce the effective membrane area of the hollow fiber membrane and can obtain the adhesion preventing effect of the hollow fiber threading when it is filled in the blood purifier. Good. From the viewpoint of easiness of production, the fin-shaped protrusions that are continuously extended in the long hair direction of the hollow fiber are the most practical, but other than that, they may be spirally wound around the outer periphery, or continuous. You don't have to. The shape of such protrusions is the height (h) of the protrusions and the average film thickness.
The ratio h / t of (t) is preferably 0.5 to 3, and more preferably in the range of 1 to 2 for practical use. Further, the width of the root of the protrusion is preferably about 15 to 50 μm. Further, the number of protrusions may be at least one, but in order to enhance the separation efficiency, it is preferably three or more, and the upper limit is preferably 10 or less, more preferably 8 or less.

In addition, the hollow fiber of the present invention has a water permeability (UF) at 37 ° C.
R) is 6 ml / hr · mmHg · m ² or more, more preferably 10 ml / hr · mmHg · m ² or more. Further, the hollow fiber of the present invention is characterized in that the dextran has a sieving coefficient (SC) of 0.4 or more when a part of an aqueous solution containing 0.1% by weight of dextran having a molecular weight of 10,000 is passed through the membrane. I am trying. The SC measurement conditions were as follows: a hollow fiber hemodialyzer with an effective membrane surface area of 1.5 m ² assembled by filling the hollow fiber bundle to be measured at a filling rate of 46%, and the hollow fiber hollow at 37 ° C. The dextran aqueous solution is supplied to the part side at a flow rate of 200 ml / min, the permeate is taken out from the hollow fiber gap side at a flow rate of 10 ml / min, and the permeate 10 minutes after the permeate begins to flow out is collected as a sampling liquid. It is a thing. The dextran concentration in the sampling liquid thus obtained is measured by, for example, the anthrone-sulfuric acid method, and SC is obtained from the following equation.

The effective membrane area used for calculating UFR and SC is based on the hollow fiber inner wall surface of the normal membrane wall portion including the membrane wall portion where the protrusion exists.

Thus, the hollow fiber of the present invention has a UFR of 6 ml / hr · mmHg ·
It is characterized in that it is m ² or more and SC is 0.4 or more, but when the UFR is less than 6 ml / hr · mmHg · m ² , it is above a certain level to remove water as necessary. TMP
It is necessary to apply (differential pressure applied to both sides of the hollow fiber membrane),
In that case, it is not preferable in that the permeation amount of the substance due to the infiltration of blood protein into the pores in the hollow fiber membrane will change significantly with time. On the other hand, when SC is less than 0.4, the ability to remove harmful substances in the medium molecular weight region is lowered, which is not preferable. The lower limit of SC is more preferably 0.5,
On the other hand, the desirable upper limit is 0.8, more preferably 0.
7 is mentioned.

Further, one of the features of the hollow fiber of the present invention is that the overall mass transfer coefficient K ₀ of urea in the dialyzer assembled using the hollow fiber bundle is 60 × 10 ⁻⁵ cm / sec or more. In addition, as a method of measuring K ₀ , a cylindrical container is used.
1.5% by filling the hollow fiber bundle at a filling rate of 10%, sealing and solidifying both ends with an adhesive, and then cutting to open the hollow portion.
Using an assembled dialyzer with an effective membrane surface area of m ² ,
At 37 ° C, 0.01 wt% urea aqueous solution was flown at 200 ml / min on the blood side, that is, on the hollow side, and at the dialysate side, that is, on the hollow fiber gap side, water was passed at 500 ml / min. By measuring the urea concentration in the effluent, K ₀ can be obtained by the following formula.

QB: Blood flow rate [cm ³ / sec] QD: Dialysis flow rate [cm ³ / sec] QA: Urea dialysance measurement method
It was measured according to the dialyzer performance evaluation standard by the Japanese Society for Artificial Organs in September, 2013.

A: Hollow fiber effective membrane area [cm ² ]; This is the membrane area of the hollow fiber based on the inner diameter in the wet state, and in the case of a hollow fiber with fins, the fin root portion that does not effectively function for mass transfer is excluded.

As K ₀ of the hollow fiber of the present invention, further 70 × 10 ⁻⁵ cm / sec
Or more, particularly 75 × 10 ^-5 cm / sec or more is preferable, and the upper limit is 100 × 10 ^-5 cm / sec, further 90 × 10 ^-5 cm / se
c is practically preferable.

Thus, the hollow fiber of the present invention has an excellent performance of removing harmful substances in the medium molecular weight region and a high performance of removing harmful substances in the low molecular weight region when filled in a hemodialyzer or hemodialysis. Separation performance is obtained. In addition, the harmful substance in the medium molecular weight range referred to in the present invention means a substance such as β ₂ -MG having a molecular weight of about 500 to about 20,000 in a body fluid such as blood, which is desirable to be removed, Hazardous substances in the low molecular weight range are urea, nitrogen, creatinine, uric acid, etc. in the body fluids such as blood, the molecular weight of which needs to be removed is about 50 to about 500. When the hollow fiber of the present invention is used in a blood purifier, the filling rate is preferably about 40% or more and about 60% or less, more preferably about 55% or less because filling is easy.

The method for producing the hollow fiber of the present invention is not particularly limited. For example, in the case of a hollow fiber substantially composed of a cellulose polymer, a hollow system or cellulose obtained by melt spinning a cellulose ester together with a plasticizer. Examples thereof include a method in which a hollow fiber obtained by wet spinning an ester solution is saponified, a method in which a copper ammonia solution of cellulose, or a viscose stock solution is solidified and solidified by wet spinning. Among them, a method by saponification of a hollow fiber obtained by melt spinning with a plasticizer of cellulose ester is preferable, in which case the average degree of polymerization of the cellulose polymer is 150 or more, particularly the moldability of the fin-shaped protrusions. Good and practically advantageous.

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

Examples 1 to 10 and Comparative Examples 1 to 4 A mixture of 100 parts of cellulose diacetate and 60 parts of polyethylene glycol (molecular weight 400) was mixed, and the mixture was melted at 210 ° C. to spin a hollow fiber with fins. After preventing and cooling with a spinneret and an ordinary finless ring-shaped spinneret, the saponification reaction is carried out by immersing in a 2 wt% sodium hydroxide aqueous solution at 50 ° C., followed by washing with water and about 50 wt% glycerin aqueous solution. Then, the hollow fiber having a circular shape having fins shown in Tables 1 and 2 and the circular hollow fiber having a shape having no fins were manufactured by hot air drying. Each of these hollow fibers when wet has an inner diameter of about 20μ, the thickness of the part without fins is about 30μ, and with fins, the height of the fins is about 30μ, and its root part is about 30μ. Width was about 20μ.

The hollow fiber obtained as described above was inserted and filled into a cylindrical container to prepare a hemodialyzer having an effective membrane area of about 1.5 m ^{2, and} an ultraviability (UFR) in vitro, The overall mass transfer coefficient (K ₀ ) of urea and the sieving coefficient (SC) of dextran molecular weight 10,000 were measured. In addition, the commercialized product was subjected to hemodialysis for 5 hours to obtain β ₂ -MG before and after dialysis.
Removal rate of Then, the concentration effect of β ₂ -MG by removing water was corrected. UF immediately after dialysis and just before the end of dialysis for 5 hours
The rate of decrease of R, ie Was calculated.

As mentioned above, under the conditions of the claims, K of urea
_It can be seen that both the ₀ and β ₂ -MG removal rates are large, and the changes in UFR with time are also small.

Comparative Examples 5, 6 and 7 In the same manner as in Example 1, 100 parts by weight of cellulose diacetate was mixed with 100 parts of polyethylene glycol (molecular weight 400).
Parts and 40 parts by weight of diethylene glycol were added to the spinning stock solution to prevent deformed hollow fibers with 6 fins, the additives were extracted and removed by hot water treatment, washed with water, and then immersed in an aqueous glycerin solution, followed by hot air. It was dried to obtain a hollow fiber for dialysis. The inner diameter of the hollow fiber was 200μ and the film thickness other than the fin portion was 20μ. Using these hollow fibers, a dialyzer with an effective surface area of about 1.5 m ² as shown in Table 3 was prepared, and the measurement results obtained for it were shown.

As described above, in the case of cellulose acetate, the dialysis performance of low-molecular weight is not as high as that of cellulose, and it cannot be said that the hollow fiber with fins is sufficient.

<Effects of the Invention> The hollow fiber of the present invention is not only a harmful substance in the medium molecular weight region such as β ₂ -MG but also a harmful substance in the low molecular weight region such as urea when a blood purifier is assembled using the bundle. The substance also has an excellent effect that it can be removed with high efficiency.

Claims (3)

[Claims] 1. A hollow system having selective permeability, wherein the average porosity of the wall of the hollow fiber membrane in a wet state is 50% or more and the water permeability (UFR) at 37 ° C. is 6 ml / hr · mm.
Sieving coefficient (SC) of dextran using an aqueous solution containing 0.1% by weight of dextran having a molecular weight of Hg · m ² or more and 10,000.
Is 0.4 or more, and the hollow system is assembled as a dialyzer, and the overall mass transfer of urea at 37 ° C. in a 0.01 wt% urea aqueous solution measured at a blood flow side flow rate of 200 ml / min and a dialysate flow rate of 500 ml / min. A permselective hollow system having a coefficient (K ₀ ) of 60 × 10 ⁻⁵ cm / sec or more. 2. The selectively permeable hollow system according to claim 1, wherein the selectively permeable hollow system consists essentially of a cellulose polymer. 3. The selectively permeable hollow system according to claim 1, wherein the selectively permeable hollow system has at least one protrusion on the outer periphery of the hollow system.