JP2812890B2 - Blood purifier - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a selectively permeable hollow fiber. More specifically, it is a hollow fraction having a specific porosity, has a specific dextran sieving coefficient, and has selective permeability exhibiting excellent separation performance in a dialyzer. The present invention provides a selectively permeable hollow fiber which is suitable for blood treatment such as the above, and is particularly suitable for removing harmful substances in the medium and high molecular weight regions together with harmful substances in the low molecular weight region. 2. Description of the Related Art Permselective hollow fibers have been practically used in reverse osmosis and hemodialysis. In particular, hollow fiber hemodialyzers are often used at present for purifying blood of patients with renal failure. In this method, a dialysis membrane, for example, a large number of hollow fiber membranes, is housed in a housing, a patient's blood flows in the hollow, and a dialysate flows in the outside, that is, in the hollow fiber gap, and the hollow fiber Dialysis through the membrane wall removes waste in blood and corrects electrolyte concentration,
A pressure difference is applied between the inside and the outside of the hollow fiber to remove excess water in blood by ultrafiltration. Furthermore, hollow fibers may be used to separate only plasma from blood or to remove specific components from the plasma to treat autoimmune diseases and the like. Recently, it has been confirmed that a therapeutic effect can be obtained by using hollow fibers in protein-permeable hemodialysis or protein-permeable hemofiltration dialysis. As described above, a hollow fiber for blood treatment must selectively allow a specific substance to permeate according to the purpose. The performance is determined by the material of the hollow fiber, the porosity (the size and number of holes), the film thickness, and the like. But,
Not only that, for example, how to bundle a large number of hollow fibers so that the entire membrane surface functions effectively is also an important point in determining the performance. For example, at the time of dialysis, if the hollow fibers adhere along the length direction,
In the vicinity of the portion, the dialysate is difficult to flow evenly around each hollow fiber, resulting in the formation of a certain basin, and the dialysis through the hollow fiber which does not participate in this flow is hardly performed, and as a whole, Is reduced. In a normal dialysis operation, the difference in concentration on both sides of the hollow fiber membrane becomes the driving force for mass transfer, so that the dialysate is flowed as evenly as possible into the outer space of the hollow fiber, and the part where the outer membrane resistance is greater than the surroundings is reduced as much as possible. It is necessary to devise the shape of the hollow fiber itself so that the concentration difference between the blood side (the inside of the hollow fiber) and the dialysate side (the outside of the hollow fiber) can be increased. For example, as previously proposed by some of the present inventors, a method can be used in which a projection is provided on the outer surface of a hollow fiber to exert an effect of preventing adhesion between the hollow fibers (Japanese Patent Laid-Open No. 48-1983). -75481). However, for example, a polymethyl methacrylate (PMA) membrane, an ethylene-vinyl alcohol copolymer (EVAL) membrane, or a cellulose acetate developed for use in protein permeable hemodialysis or protein permeable hemofiltration dialysis. (CA) In membranes and the like, amyloid-
Β ₂ -MG (microglobulin) (molecular weight 11,800), which is thought to be the causative agent of cis, parathyroid hormone (molecular weight of about 9,50) which is considered to be related to pruritus and hyperlipidemia
0), an erythroblast inhibitory factor (molecular weight: 1,0
00) Further, it was not possible to efficiently remove harmful substances in a low molecular weight region such as urea at a high level together with removing harmful substances in a molecular weight region such as Al related to bone pain anemia. In addition, as a thing that demonstrates relatively good removal performance,
Finned cellulose acetate hollow fibers have been proposed ("Kidney and Dialysis", separate volume, pages 16 to 19 (1986)).
However, development of a film having higher removal performance has been desired. SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems of the prior art. In particular, in hemodialysis and hemofiltration dialysis, a medium molecular weight region such as β ₂ -MG is used. It is an object of the present invention to provide a selectively permeable hollow fiber capable of sufficiently improving both the performance of removing harmful substances such as urea and the performance of removing harmful substances in a low molecular weight region such as urea. The present inventors have conducted intensive studies to achieve the above object, and as a result, a blood purifier using hollow fibers having a specific porosity, water permeability and dextran sieving coefficient has been dramatically improved. The present inventors have found that they exhibit enhanced separation performance, and have reached the present invention. That is, the present invention relates to a blood purifier assembled using hollow fibers having selective permeability, wherein the used hollow fibers have an average porosity of 50% or more in the hollow fiber membrane wall in a wet state. Water permeation performance at 37 ° C (UF
R) 6-20 ml / hr · mmHg · m ² , molecular weight 1
The dextran using an aqueous solution containing 0.1% by weight of dextran of 000 has a sieving coefficient (SC) of 0.4 to 0.4 .
8 , the reduction rate of UFR immediately after the start of dialysis and immediately before the end of 5 hours of dialysis of the hemodialyzer is 40% or less, the removal rate of β ₂ -MG before and after dialysis is 7% or more, and the blood flow side flow rate 200
ml / min, measured at a dialysate flow rate of 500 ml / min.
The overall mass transfer coefficient (K ₀ ) of urea at 37 ° C. in a 1% by weight aqueous urea solution is 60 × 10 ^{−5 to} 90 × 10 ⁻⁵ cm /
there is provided a blood purifier, which is a se c. In the present invention, the reduction rate of the UFR is 3
Blood purifiers that are 0% or less are included. Further, the present invention includes a blood purifier wherein the dextran has a sieve coefficient (SC) of 0.5 to 0.7 . The present invention further includes a blood purifier having a removal rate of the β ₂ -MG of 30% or more. The present invention further includes a blood purifier wherein the permselective hollow fiber is substantially composed of a cellulose polymer. Further, the present invention includes a blood purifier wherein the permselective hollow fiber has at least one protrusion on the outer periphery of the hollow fiber. Hereinafter, the present invention will be described in more detail. That is, the hollow fiber in the present invention has selective permeability, and specific examples of the material include a cellulose polymer, polymethyl methacrylate, polysulfone, acrylonitrile polymer, nylon, and ethylene-vinyl alcohol copolymer. Among them, cellulose polymers are preferred. Specific examples of such a cellulose polymer include regenerated cellulose, and examples include a polymer obtained by hydrolysis of a cellulose ester and a polymer substantially composed of cellulose obtained by a copper ammonium method or a viscose method. Note that “substantially” means that other polymers may be contained as long as the properties of the cellulose polymer are not impaired. In the structure of the membrane wall of the hollow fiber of the present invention, the average porosity when wet is 50% or more, and more preferably 6%.
0% or more is preferable. Here, the porosity at the time of wetting is the percentage of the volume of water and voids in the membrane wall relative to the total volume of the membrane wall in a state of impregnation with water. The film thickness (t) when wet is 50 μm or less,
Further, it is preferably 30 μm or less, and within that range, 20 μm or more is practical. Note that such a film thickness means an average thickness of a normal film wall portion excluding a film wall portion of a fin-shaped portion when a fin-shaped protrusion or the like exists as described later. Regarding the structure inside the membrane wall, it is desirable to have pores of about 80 ° or less, preferably about 30 ° or more, and that the distribution of the pores is uniform over the entire membrane wall. Can be said to be a particularly preferred embodiment for enhancing the separation characteristics. In other words, a hollow fiber in which such fine pores are present as uniformly as possible on the membrane wall 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 μm, and more preferably about 200 to about 300 μm.
Is preferred. Further, as the 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 protrusion, any material can be used as long as the effect of preventing adhesion of the hollow fiber when filled in the blood purifier can be obtained without excessively reducing the effective membrane area of the hollow fiber membrane. Is also good. From the standpoint of ease of production, the fin-shaped projections extending continuously in the long hair direction of the hollow fiber are the most substantial, but may be spirally wound around the outer periphery, or may be continuous. You don't have to. As the shape of such a projection, the ratio h / t of the height (h) of the projection to the average film thickness (t) is preferably 0.5 to 3, and more preferably in the range of 1 to 2. preferable. The width of the base of the protrusion is preferably about 15 to 50 μm. Further, the number of protrusions may be at least one, but is preferably three or more, and the upper limit is preferably ten or less, and more preferably eight or less in order to enhance the separation efficiency. The water permeation performance (UFR) at 37 ° C. of the hollow fiber of the present invention is 6 ml / hr · mmHg · m ² or more, more preferably 10 ml / hr · mmHg · m ^2.
m ² or more. Further, the hollow fiber of the present invention has a dextran having a sieve 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 permeated through the membrane. It is characterized by.
The SC was measured under the conditions that the hollow fiber bundle to be measured was filled at a filling ratio of 46% and the effective membrane surface area was 1.5 m.
^A dextran aqueous solution was supplied at a flow rate of 200 ml / min to the hollow side of ² , and the permeate was taken out at a flow rate of 10 ml / min from the gap side of the hollow fiber, and the permeate was sampled 10 minutes after the permeate began to flow out. It is collected as. The dextran concentration in the sampling solution thus obtained is measured by, for example, an anthrone-sulfuric acid method, and C is obtained from the following equation. ## EQU1 ## The effective membrane area used for calculating UFR and SC is based on the inner wall surface of the hollow fiber of the ordinary membrane wall, including the membrane wall of the portion where the projections are present. Thus, the hollow fiber of the present invention has a UFR of 6 m.
l / hr · mmHg · m ² or more and SC is 0.4
It is characterized by the above, but the UFR is 6
In the case of less than ml / hr · mmHg · m ² , it is necessary to apply a certain degree or more of TMP (differential pressure applied to both sides of the hollow fiber membrane) in order to perform necessary water removal. It is not preferable in that the amount of permeation of a substance due to invasion of blood proteins or the like into the pores of the pores changes with time. Also S
When C is less than 0.4, the performance of removing harmful substances in the medium molecular weight region is undesirably reduced. In addition, 0.5 is more preferable as the lower limit of SC, and 0.8, more preferably 0.7 is more preferable as the upper limit. One of the features of the hollow fiber of the present invention is as follows.
In the dialyzer assembled using the hollow fiber bundle, the overall mass transfer coefficient K ₀ of urea is 60 × 10 ⁻⁵ cm / sec or more. Incidentally, as a method of measuring K ₀ , a hollow fiber bundle is loaded in a cylindrical container at a filling rate of 46%, both ends are solidified with an adhesive, cut, and the hollow portion is opened to obtain 1.5 m ² . Using a dialyzer assembled with an effective membrane surface area, a 0.01% by weight aqueous urea solution is passed at 200 ml / min at 37 ° C. to the blood side, ie, the hollow side, and water is passed to the dialysate side, ie, the hollow fiber gap side. 500 ml /
By measuring the concentration of urea in the effluent on the blood side and dialysate side when flowing in minutes, K ₀ is obtained from the following equation. ## EQU2 ## QB: flow rate on the blood side [cm ³ / sec] QD: flow rate on the dialysis side [cm ³ / sec] DA: urea dialysance
It was measured by the dialyzer performance evaluation standard by the Japan Society of Artificial Organs in September, 1998. A: Hollow fiber effective membrane area [cm ² ]; this is the membrane area based on the inner diameter of the hollow fiber in a wet state. In the case of a finned hollow fiber, the portion at the base of the fin that does not effectively function for mass transfer is excluded. The K ₀ of the hollow fiber of the present invention is more preferably 70
× 10 ⁻⁵ cm / sec or more, especially 75 × 10 ⁻⁵ cm / s
ec or more is preferable, and the upper limit is 100 × 1
0 ^-5 cm / sec, more preferably 90 × 10 ^-5 cm / sec, is practically preferable. As described above, when the hollow fiber of the present invention is filled in a hemodialyzer or a hemofiltration dialyzer, the performance of removing harmful substances in a medium molecular weight region is high, and the performance of removing harmful substances in a low molecular weight region is also high. Excellent separation performance of high is obtained. still,
The harmful substance having a medium molecular weight in the present invention is a harmful substance having a molecular weight of about 500, which is present in a body fluid such as blood and is preferably removed.
Β ₂ -MG and the like in the range of about 20,000 to about 20,000, and the harmful substances in the low molecular weight region are those having a molecular weight of about 50 to about 500 which need to be removed in a body fluid such as blood. Refers to the range of urea, nitrogen, creatinine, uric acid and the like. 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, and 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 consisting of a cellulose polymer, the hollow fiber obtained by melt-spinning a cellulose ester together with a plasticizer is used. Examples thereof include a method of saponifying a hollow fiber obtained by wet spinning a yarn or a cellulose ester solution, and a method of coagulating and solidifying a copper ammonia solution of cellulose or a viscose stock solution by wet spinning. Above all, a method by saponification of a hollow fiber obtained by melt-spinning with a plasticizer of a cellulose ester is preferable, in which case the average degree of polymerization of the cellulose polymer is 15%.
A value of 0 or more is particularly practical because the moldability of the fin-like projections is good. Hereinafter, the present invention will be described more specifically 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 obtained by adding 60 parts of polyethylene glycol (molecular weight: 400) to 100 parts of cellulose diacetate was mixed.
After melting at 10 ° C., spinning from a finned hollow fiber spinneret and an ordinary finless toroidal spinneret and cooling,
The saponification reaction was carried out by immersion in a 2% by weight aqueous solution of sodium hydroxide at 0 ° C., followed by washing with water for about 5 hours.
After immersion in a 0% by weight glycerin aqueous solution, the resultant was dried with hot air to produce hollow fibers having a fin having a shape shown in Tables 1 and 2 and circular hollow fibers having no fins. In any of these wet hollow fibers, the inner diameter of the hollow fiber is about 20 μm, the thickness of the portion without fins is about 30 μm, and when the fins are provided, the height of the fins is about 30 μm, and the root portion thereof Was about 20μ. The hollow fiber obtained as described above is inserted and filled in a cylindrical container to prepare a hemodialyzer having an effective membrane area of about 1.5 m ² , and the ultrafiltration performance in vitro ( UFR), the overall mass transfer coefficient (K ₀ ) of urea and the sieving coefficient (SC) for a dextran molecular weight of 10,000. The product was subjected to hemodialysis for 5 hours, and the β ₂ -MG removal rate before and after dialysis, that is, After the calculation, the effect of concentrating β ₂ -MG by removing water was corrected. Furthermore, the reduction rate of UFR immediately after dialysis and immediately before the end of dialysis for 5 hours, that is, Was calculated. [Table 1] [Table 2] As described above, it can be seen that the urea K ₀ and β ₂ -MG removal rates are both large and the UFR changes with time are small under the conditions defined in the claims. Comparative Examples 5, 6, 7 In the same manner as in Example 1, a spinning stock solution was used in which 100 parts by weight of polyethylene glycol (molecular weight: 400) and 40 parts by weight of diethylene glycol were added to 100 parts by weight of cellulose diacetate. After spinning the six-row modified hollow fiber with fins, the additive was extracted and removed by hot water treatment, washed with water, immersed in an aqueous glycerin solution, and dried with hot air to obtain a hollow fiber for dialysis. The inner diameter of the hollow fiber was 200 μm and the film thickness other than the fin portion was 20 μm. A dialyzer having an effective surface area of about 1.5 m ² as shown in Table 3 was prepared using such hollow fibers, and the measurement results obtained therefrom were shown. [Table 3] As described above, in the case of cellulose acetate, the dialysis performance of low molecules is not as high as that of cellulose, and cannot be said to be sufficient, even with hollow fibers having fins. The hollow fiber of the present invention can be used not only for harmful substances in the medium molecular weight region such as β ₂ -MG but also for low molecular weight such as urea when a blood purifier is assembled using the bundle. This has an excellent effect that harmful substances in the region can be removed with high efficiency.

Claims (1)

(57) [Claims] In a blood purifier assembled using hollow fibers having selective permeability, the hollow fibers used have an average porosity of 50% or more on the hollow fiber membrane wall in a wet state.
Water permeation performance (UFR) at 6 ° C. is 6 to 20 ml / hr.
· MmHg · m ^2, sieving coefficient of said dextran using an aqueous solution containing 0.1 wt% dextran of molecular weight 10,000 (SC) is from 0.4 to 0.8, and the start of the dialysis blood dialyzer Immediately after and immediately after completion of dialysis for 5 hours, the reduction rate of UFR is 40% or less, the removal rate of β ₂ -MG before and after dialysis is 7% or more, blood flow side flow rate 200 ml / min, dialysate flow rate 50
3% of a 0.01% by weight aqueous urea solution measured at 0 ml / min.
The overall mass transfer coefficient (K ₀ ) of urea at 7 ° C. is 60 ×
10 blood purifier, which is a ^{-5 ~90 × 10 -5 cm / se} c. 2. 2. The blood purifier according to claim 1, wherein the UFR reduction rate is 30% or less. 3. The dextran has a sieve coefficient (SC) of 0.5 to 0.7.
The blood purifier according to claim 1, wherein 4. The removal rate of the β ₂ -MG is 30% or more.
Blood purifier. 5. 2. The blood purifier according to claim 1, wherein said selectively permeable hollow fiber is substantially composed of a cellulose polymer. 6. The blood purifier according to claim 1, wherein the permselective hollow fiber has at least one protrusion on the outer periphery of the hollow fiber.