JP2003290340A - Blood purifier - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purifier having a very thin hollow fiber membrane with improved solute-permeability of the hollow fiber membrane because of the very thin hollow fiber and without generating damage, deformation, etc., of the hollow fiber membrane caused by impact or the like. <P>SOLUTION: In the blood purifier, the hollow fiber membranes with average thickness 50 μm or smaller and a hollow fiber bundle with solid space filaments disposed between the hollow fiber membranes are mounted inside a casing. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a blood purifier, and more particularly to a blood purifier used for hemodialysis therapy or the like and reinforced with an ultrathin hollow fiber membrane.

[0002]

2. Description of the Related Art In the medical field, blood purifiers are used for blood purification treatments such as hemodialysis therapy, hemofiltration therapy, hemodiafiltration therapy, blood adsorption therapy, and plasma exchange therapy.

For example, hollow fiber membranes used for hemodialysis therapy have conventionally used hollow fibers having an outer diameter of 280 μm and an inner diameter of about 200 μm. In order to shorten the dialysis time and reduce the burden on the dialysis therapist, a blood purifier with high solute removal efficiency is required in the medical field. In addition, in an internal filtration-accelerating blood filter that actively promotes internal filtration that occurs inside the blood purifier to improve solute removal efficiency, the hollow fibers tend to be thin. One of the methods for obtaining a blood purifier with high solute removal efficiency is to use a hollow fiber membrane with high solute permeability. In order to obtain a hollow fiber membrane having high solute permeability, there is a tendency to develop a hollow fiber membrane having a thinner average thickness than the conventional one or a thin hollow fiber membrane. However, the mechanical strength of the hollow fiber membrane is lowered by reducing the average thickness of the membrane. Then, excessive vibration of the blood purifier or accidental drop of the blood purifier causes a new problem that the hollow fiber membrane loaded in the casing is bent or damaged. As a means for increasing the mechanical strength of the hollow fiber membrane, a method of selecting a strong material as the membrane material, a method of increasing the average thickness of the hollow fiber membrane, and a method of making the membrane structure an asymmetric structure in which the pore diameters differ in the thickness direction A method of increasing the occupied cross-sectional ratio of the hollow fiber membrane to the inner cross-sectional area of the casing, that is, the filling rate of the hollow fiber membrane is known.

[0004] However, it is difficult to newly select a membrane material which has a high solute removal efficiency and can be formed into a hollow fiber membrane having a high strength, and which has good compatibility with a living body. Also, increasing the average thickness of the hollow fiber membrane increases the strength,
The solute permeability will decrease. This tendency is particularly strong in a homogeneous membrane in which the structure of the hollow fiber membrane in the thickness direction is uniform. Although the strength can be increased by making the hollow fiber membrane have an asymmetric structure, the strength alone is not sufficient. Further, if the total cross-sectional area of the hollow fiber bundle relative to the cross-sectional area in the case, that is, the filling rate of the hollow fiber membranes is increased too much, the dialysate will not reach the center of the hollow fiber bundle inside the casing, and the dialysate will be outside There is a problem that a so-called non-uniform flow occurs, and the solute removal efficiency decreases.

[0005]

Therefore, according to the present invention, in a blood purifier loaded with an ultrathin hollow fiber membrane, the solute permeability of the hollow fiber membrane is improved by having the ultrathin hollow fiber membrane. Moreover, it is an object of the present invention to provide a blood purifier that does not cause damage or deformation of the hollow fiber membrane due to impact or the like. Another object of the present invention is to improve the solute permeability of the hollow fiber membrane by having an ultrathin hollow fiber membrane, and further, without causing damage or deformation of the hollow fiber membrane due to impact, etc. An object of the present invention is to provide a blood purifier capable of capturing fine particles and the like.

[0006]

Means for solving the above-mentioned problems are as follows. (1) A hollow fiber membrane having an average thickness of 50 μm in the casing, and a solid fiber interposed between the hollow fiber membranes. (2) The hollow fiber membrane of (1) is formed from a polymer alloy containing a polyarylate resin and a polysulfone resin, and (3) ( 1) A solid spacer filament is formed of a polymer alloy containing a polyarylate resin and a polysulfone resin, and (4)
(1) The diameter of the solid spacer filament is 10 to
In the blood purifier of (5) and (1), the ratio of the number of hollow fiber membranes in the hollow fiber bundle to the number of solid spacer filaments is 10: 1 to 1: 500.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION FIG. 1 shows an example of a blood purifier using a hollow fiber membrane. The blood purifier 10 includes a cylindrical casing 1, an injection-side end cap 13 and a discharge-side end cap 14 that are detachably screwed into openings at both ends of the casing 1, and a side surface of the casing 1 that is a discharge side. It has a dialysate inlet 15 provided at the end on the end cap 14 side and a dialysate outlet 16 provided at the end on the injection side end cap 13 side. A hollow fiber bundle 4 formed by bundling the hollow fiber membranes 3 and the spacer filaments 2 is loaded in the internal space of the casing 1.

In this example, the internal space of the hollow fiber membrane 3 serves as a blood flow path, and the space outside the hollow fiber membrane formed by the casing 1 and the outer surface of the hollow fiber membrane 3 serves as a dialysate flow path. Has become. The blood injected from the injection port 17 of the injection side end cap 13 passes through the internal space of the hollow fiber membrane 3 and is discharged from the discharge port 18 of the discharge side end cap 14. The dialysate injected from the inflow port 15 flows through the space outside the hollow fiber membrane 3 to the outflow port 16, and both solutions flow countercurrently across the hollow fiber membrane 3. The hollow fiber membrane 3 has a porous structure and does not permeate proteins and the like in relatively large blood, but permeates relatively small waste products and the like in blood. Move to the dialysate side, resulting in blood purification. Contrary to this example, the inner space of the hollow fiber membrane 3 can be used as a flow path for dialysate, and the space outside the hollow fiber membrane 3 can be used as a blood flow path.

The hollow fiber membrane is a hollow cylindrical membrane having an internal space through which blood and dialysate can flow. Innumerable small holes are formed in this hollow fiber membrane, and the substance that passes through the membrane is selected depending on its size. The diameter of a typical hole is 30Å to 1 with an average pore size.
It is about 00Å (3 × 10 ⁻³ to 1 × 10 ⁻² μm). The hollow fiber membrane may be a homogeneous membrane having a uniform structure in the thickness direction or an asymmetric structure (heterogeneous) membrane having different pore sizes in the thickness direction. The asymmetric structure membrane is superior to the uniform membrane because the solute permeability does not easily decrease even if the average thickness of the membrane is increased, and the strength is increased by the support layer.

The hollow fiber membrane in the present invention is a hollow fiber membrane having an average thickness of 50 μm at most. By reducing the average thickness of the membrane, the solute permeability of the membrane is improved as compared with the conventional case. Above all, the average thickness of the film is preferably 5 to 20 μm. If the average thickness is less than 50 μm, there are no particular restrictions on the inner diameter and outer diameter of the hollow fiber membrane, but the inner diameter of the hollow fiber membrane is preferably in the range of 120 to 200 μm. The length of the hollow fiber membrane is determined by the length of the casing filled with the hollow fiber membrane.

As the hollow fiber membrane, a hydrophilic membrane represented by a cellulose membrane and a hydrophobic membrane represented by a polysulfone membrane and a polyester membrane can be selected. Among them, the polyester-based polymer alloy film containing a polyarylate resin and a polysulfone resin is not only excellent in mechanical strength, heat resistance, and chemical resistance as its original properties, but also excellent in compatibility with a living body and excellent ability to adsorb a substance. Therefore, it is preferable.

Examples of the polyester resin used for forming the polyester film include a polyarylate resin having a repeating unit represented by the following formula 1.

[0013]

[Chemical 1]

However, in the formula, R ¹ and R ² have a carbon number of 1 to
5 is a lower alkyl group. R ¹ and R ² may be the same as or different from each other. Examples of R ¹ and R ² include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group.
In the present invention, R ¹ and R ² are preferably methyl groups.

The polyarylate resin preferably has a molecular weight of, for example, about 20,000 to 50,000.
As the polyarylate, a polyarylate appropriately synthesized by polycondensing a dihydric phenol and an aromatic dicarboxylic acid may be used, or a commercially available product may be used. As a commercially available product, a product by Unitika Ltd. sold under the trade name "U polymer", trade name "AP
Examples thereof include products manufactured by Bayer AG under the trade name "E", products manufactured by Celanese under the trade name "DUREL", products manufactured by DuPont under the trade name "Arylon", and the like.

Examples of the polysulfone-based resin used for forming the polysulfone film include polyether sulfone resins having at least one of repeating units represented by the following formulas 2 to 5.

[0017]

[Chemical 2]

However, in the formula, R ³ and R ⁴ have a carbon number of 1 to
5 is a lower alkyl group. R ³ and R ⁴ may be the same as or different from each other. Examples of R ³ and R ⁴ include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. In the present invention, R ³ and R ⁴ are preferably methyl groups.

[0019]

[Chemical 3]

[0020]

[Chemical 4]

[0021]

[Chemical 5]

The polyether sulfone resin preferably has a molecular weight of, for example, about 20,000-40,000. As the polyether sulfone, appropriately synthesized polyether sulfone may be used, or a commercially available product may be used. As a commercially available product, the product name “P-350
Products manufactured by Union Carbide Co., Ltd. sold under the trade name “Sumika Excel PES” by Sumitomo Chemical Co., Ltd., and the like.

The polyester-based polymer alloy film is
Above all, a combination of a polyarylate resin and a polyethersulfone resin is preferable. In the combination of the polyarylate resin and the polyethersulfone resin, the mixing weight ratio (A / B) of the polyarylate resin (A) and the polyethersulfone resin (B) is 0.1 to 1.
It is preferably 0, preferably 0.3 to 4.

The hollow fiber membrane can be produced by a known method. For example, a polymer stock solution prepared by dissolving the above two resins in an organic solvent is extruded from a spinneret or an extrusion die that has become a double tube and introduced into a coagulating solution to give a hollow cord-shaped body. Alternatively, it can be formed as a thread.

The solid spacer filaments in the present invention are interposed in the hollow fiber bundle in which the hollow fiber membranes are bundled for the purpose of reinforcing the hollow fiber membranes. The length of the spacer filament is
It is preferably as long as the hollow fiber membrane. The outer diameter of the spacer filament is preferably 10 to 100 μm. When the outer diameter of the spacer filament is less than 10 μm, the effect of reinforcing the hollow fiber membrane is low, which is not preferable. Outer diameter of spacer filament is 100 μm
If it exceeds, the hollow fiber membrane bundle in which the hollow fiber membrane and the spacer filament are mixed becomes too thick, and as a result, the entire blood purifier becomes large, which is not preferable.

As the solid spacer filament, any fiber can be used as long as it can reinforce the hollow fiber membrane within the above diameter range. For example, the same material as the hollow fiber membrane described above can be used.
Above all, a polyester polymer alloy obtained by combining the polyarylate resin and the polyethersulfone resin is particularly preferable.

It is preferable to use hydrophobic fibers as the spacer filaments. The hydrophobic fiber has a function of adsorbing a substance contained in the dialysate, which adversely affects the human body, such as endotoxin, and thus has an advantage that endotoxin can be prevented from entering blood.

Examples of the hydrophobic fiber include polysulfone, polyether sulfone, polyarylate, polystyrene, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, 1,2-polybutadiene,
Examples thereof include 1,4-polybutadiene, polystyrene-polybutadiene block polymer, polyisoprene, polychloroprene, polyacrylonitrile, and polymethylmethacrylate. The polymers in this invention may be used alone or in combination.

The solid spacer filaments can be produced by known melt spinning, dry spinning, wet spinning methods and the like.

The solid spacer filaments have a function of reinforcing the hollow fiber membranes and a function of preventing the dialysate from flowing easily to the outer surface of the hollow fibers due to the close contact of the hollow fiber membranes. As a result, the solute permeability of the hollow fiber membrane is enhanced.

FIG. 2 shows an example in which a solid spacer filament is interposed between the hollow fiber bundles. FIG. 2 is a cross-sectional view of a casing filled with a hollow fiber bundle in a direction orthogonal to the long axis direction of the hollow fiber membrane. In this example, the hollow fiber membranes 3 and the spacer filaments 2 are arranged in the casing 1 in a substantially uniformly dispersed manner. As shown in FIG. 2, in the cross-sectional distribution state of the hollow fiber membranes and the spacer filaments in the hollow fiber bundle, it is desirable that the spacer filaments are uniformly distributed in the bundle of hollow fiber membranes. By evenly distributing the spacer filaments, the hollow fiber membrane can be reinforced more and the strength of the blood purifier can be further increased. The ratio of the number of spacer filaments (solid fibers) to the number of hollow fiber membranes (hollow fibers) (hollow fiber: solid yarn) varies depending on the diameter of the spacer filament, but is 10:
It is preferably from 1 to 1: 500, and particularly preferably from 5: 1 to 1: 100.

As a method for interposing spacer filaments in the hollow fiber bundle, there can be mentioned a method in which spacer filaments cut to the same length as the hollow fiber membrane are bundled together with the hollow fiber membrane.

[0033]

EXAMPLES Example 1 Polyarylate Resin Co., Ltd. having the structural formula shown in the above formula (1) in N-methylpyrrolidone
Unitika U.S.A., trade name U Polymer, and polyether sulfone resin (Sumitomo Chemical Co., Ltd., trade name Sumika Excel PES) having the structural formula shown in the above formula (3) are dissolved so as to each be 17% by weight. , A solid spacer filament (hereinafter referred to as a solid fiber) and a hollow fiber spinning dope. A 50% by weight aqueous solution of N-methylpyrrolidone was used as a core liquid and a coagulating liquid, respectively, and a polyester polymer alloy (hereinafter referred to as PEPA) solid yarn and hollow fiber were spun. 2,000 solid yarns, which are monofilaments with an outer diameter of 100 μm, and formed with PEPA,
A hollow fiber bundle was prepared by bundling 8000 hollow fibers having an inner diameter of 210 μm and an average membrane thickness of 30 μm with solid fibers interposed between the hollow fibers. Subsequently, this hollow fiber bundle was loaded into a cylindrical casing, and the ends were adhered with urethane resin to form a module. A blood purifier was created by connecting blood ports to both ends of this module.

(Example 2) A solid yarn (2,000 yarns) of the same material and shape as in Example 1 and the same material as in Example 1 were used. The inner diameter was 170 μm and the average thickness of the film was 20μ
m hollow fiber 9800 fibers were bundled to form a hollow fiber bundle in which solid fibers are interposed between the hollow fibers. Then, a blood purifier was prepared in the same manner as in Example 1.

Comparative Example 1 A hollow fiber bundle was prepared using only the same materials and hollow fibers as in Example 1, and a blood purifier was prepared in the same manner as in Example 1. (Comparative Example 2) Made of the same material as that of the example and having an inner diameter of 210
A hollow fiber bundle was prepared using only hollow fibers having a thickness of 80 μm and an average membrane thickness of 80 μm, and a blood purifier was prepared in the same manner as in Example 1. The hollow fiber bundle of Comparative Example 2 is a hollow fiber bundle used in a conventional general blood purifier. Table 1 shows the specifications of Example 1, Example 2, Comparative Example 1 and Comparative Example 2.

[0036]

[Table 1]

(Impact resistance test) A drop test was conducted using the blood purifiers of Example 1, Example 2, Comparative Example 1 and Comparative Example 2, and the leak rate after that was examined. Drop test is JIS Z
202 Packaged cargo-Free fall from a height of 80 cm according to the drop test method. Leakage is detected by filling the dialysate-side channel of the blood purifier with water, applying a pressure of 1 kgf / cm ² with air to the blood-side channel of the blood purifier, and confirming the leakage of air into the dialysate-side channel. It was judged by the presence or absence. The leak rate was calculated by the number of leaks / total number of tests × 100.

(Solute Permeability Test) Example 1, Example 2,
The blood plasma purifiers of Comparative Example 1 and Comparative Example 2 were measured for bovine plasma system clearance. The measuring method is as follows. Bovine plasma with a total protein concentration adjusted to 6.5 ± 0.5 g / dl was passed through the blood-side channel of the blood purifier at a flow rate of 200 m.
Flowed at 1 / min. In addition, the dialysate was passed through the dialysate-side channel of the blood purifier at a flow rate of 500 ml / min. The bovine plasma and the dialysate were counterflowed. 60 minutes after the start of dialysis, bovine plasma on the blood inlet side and the blood outlet side was taken out and the concentration of each solute was measured. The clearance was calculated by the following formula (6). The solutes to be measured were urea and β ₂ -microglobulin (hereinafter referred to as β 2 -MG).

[0039]

[Equation 1] Here, CL is clearance (ml / min), C _Bi
Is the solute concentration on the blood inlet side, C _Bo is the solute concentration on the blood outlet side,
Q _Bi is the blood inlet side plasma flow rate.

The results of the impact resistance test and the solute permeability test are shown in Table 2. In Example 1 in which the solid yarn was interposed, the film thickness was 30 μm, which was half or less as compared with Comparative Example 2, but showed the leakage rate of (Comparative / less than) Comparative Example 2.
Moreover, Example 1 showed (higher urea clearance and β2-MG clearance) than Comparative Example 2. on the other hand,
Comparative Example 1 in which the thickness of the hollow fiber was 30 μm without interposing the solid fiber showed the same high urea clearance and β2-MG clearance as Example 1, but the leak rate was high,
Poor mechanical strength. Example 2 having a smaller film thickness than Example 1 exhibited even higher urea clearance and β2-MG clearance than Example 1. Example 2 showed a leak rate (equivalent / less than that) to Comparative Example 2.

[0041]

[Table 2]

[0042]

By interposing the solid fiber in the hollow fiber bundle, the mechanical strength of the blood purifier can be improved. Furthermore, since the mechanical strength can be maintained, a thinner or thinner hollow fiber membrane than before can be used, and the solute removal performance can be significantly improved.

[Brief description of drawings]

FIG. 1 is a side view showing an example of a blood purifier according to the present invention.

FIG. 2 is a cross-sectional view showing an example of the blood purifier of the present invention.

[Explanation of symbols]

1 casing 2 Spacer filament 3 hollow fiber membranes

Continued front page    F-term (reference) 4C077 AA05 BB01 BB02 CC06 KK21                       LL05 PP15 PP18                 4D006 GA06 GA13 HA01 JA02B                       JA03C JA04B MA01 MA31                       MB09 MB10 MB11 MB15 MB16                       MC48X MC62X MC83 NA05                       NA10 NA13 PA01 PB09 PB42                       PB52 PC47

Claims (5)

[Claims] 1. A hollow fiber bundle having a hollow fiber membrane having an average membrane thickness of at least 50 μm and a solid spacer filament interposed between the hollow fiber membranes is loaded in a casing. And blood purifier. 2. The blood purifier according to claim 1, wherein the hollow fiber is formed of a polymer alloy containing a polyarylate resin and a polysulfone resin. 3. The solid spacer filament is formed of a polymer alloy containing a polyarylate resin and a polysulfone resin.
The blood purifier described in. 4. The solid spacer filaments have a diameter of 10 to 200 μm.
The blood purifier according to any one of 3 above. 5. The ratio of the number of hollow fiber membranes in the hollow fiber bundle to the number of solid spacer filaments is 10:
The blood purifier according to claim 1, wherein the blood purifier has a ratio of 1 to 1: 500.