JPH11332979A - Membrane type blood dialyzer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent the infiltration of endotoxin from a dialyzate side to a blood side by interposing an endotoxin adsorbent in dialyzate side flow passages. SOLUTION: Fibers 21 which adsorb the endotoxin are interposed between hollow fiber membranes 3 forming the dialyzate side flow passages. These fibers 21 are arranged at the hollow fiber membranes 3 or may be knitted among the hollow fiber membranes 3. The fibers may also be arranged at the plane membranes or among the plane membranes of the dialyzate flow passages. The ratio of the endotoxin adsorbent cross-sectional area to the membrane cross-sectional area is preferably specified to about 5 to about 90% in the case of the fibers 21. About 20 to about 50% is more preferable. Endotoxin adsorption efficiency is higher at about >=20% and the assembly of the blood dialyzer is easier at about <=50%. The endotoxin concn. of the dialyzate may be lowered below the detection threshold and endotoxin prohibition performance improved by this constitution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a membrane type hemodialyzer used in hemodialysis therapy and hemodiafiltration therapy.

[0002]

2. Description of the Related Art Since β-microglobulin having a molecular weight of 11,800 daltons has been referred to as a uremic substance, not only the original small and medium molecular substances but also a molecular weight of about 20,0.
For the purpose of removing low molecular weight proteins of 00 to 40,000 daltons, the high performance of the hemodialysis membrane has been promoted by increasing the diameter of the hemodialysis membrane and reducing the thickness of the active layer. Has become a concern. Endotoxin, known as a pyrogen, is a constituent of the epidermis of Gram-negative bacteria,
Live bacteria usually exist in a micelle state and have a molecular weight of several million daltons, but when the bacteria die, they are released as small fragments having a molecular weight of thousands to tens of thousands of daltons. That is, conventionally, since the membrane pore size of the hemodialysis membrane was so large that fragments of endotoxin could not pass through, in hemodialysis, the incorporation of endotoxin into the blood side by back-filtration did not pose a major problem. The invasion of endotoxin has become a problem as a result of the development. Also,
Also in hemodiafiltration, there is a concern that endotoxin may enter due to an increase in the diameter of the hemodialysis membrane. In particular, the push-pull hemodiafiltration method, a type of hemodiafiltration therapy, forcibly promotes a large amount of filtration and back-filtration from the dialysate side, so that endotoxin is largely prevented from entering the blood side. Will be an issue.

On the other hand, for the purpose of reducing the cost of hemodiafiltration, online hemodiafiltration or the like in which a dialysate is injected into a patient's body instead of a sterilized replacement liquid has been attempted. In this case, facility water, tap water, and the like are used as the dialysate, but these are problematic because they contain a large amount of endotoxin.

[0004] Conventionally, in order to remove endotoxin fragments in facility water, tap water, or dialysate, a filtration method utilizing the molecular weight cutoff characteristics of a hydrophobic porous membrane has been used. This utilizes the fact that the size of endotoxin fragments can be sieved, and the dialysate flowing into the dialyzer is filtered through a channel before the dialyzer inlet. However, in the above-mentioned method, since the filtration filter is reused, it is difficult to control the endotoxin concentration strictly low, and there is a disadvantage that the cost is high. There is also a problem that the dialysate passed through the filtration filter is re-contaminated with endotoxin at the junction between the dialysate circuit tube and the hemodialyzer. Therefore, a high-performance hemodialyzer using a large-diameter hemodialysis membrane, which can prevent invasion of endotoxin with high accuracy and is inexpensive, has been desired.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a membrane type hemodialyzer which prevents endotoxin from penetrating from the dialysate side to the blood side.

[0006]

SUMMARY OF THE INVENTION The present invention has a housing including a hollow fiber membrane, a blood-side flow path is formed inside the hollow fiber, and a dialysate-side flow path is provided outside the hollow fiber with the hollow fiber membrane interposed therebetween. The present invention provides a membrane hemodialyzer in which an endotoxin adsorbent is interposed in the dialysate-side flow path.

The present invention has a housing including a flat membrane,
In a membrane type hemodialyzer in which a blood side channel and a dialysate side channel are formed with a flat membrane interposed therebetween, a membrane type blood in which an endotoxin adsorbent is interposed between the flat membranes forming the dialysate side channel Provide a dialyzer.

[0008] It is preferable that the endotoxin adsorbent is a fiber, a mesh or a nonwoven fabric coated with an endotoxin adsorbent.

[0009]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The configuration of the present invention will be described below with reference to the drawings.

According to a first aspect of the present invention, there is provided a housing including a hollow fiber membrane, wherein a blood-side flow path is formed inside the hollow fiber,
A membrane hemodialyzer in which a dialysate-side flow path is formed outside a hollow fiber with a hollow fiber membrane interposed therebetween, wherein an endotoxin adsorbent is interposed in the dialysate-side flow path.
A second aspect of the present invention has a housing including a flat membrane,
In a membrane type hemodialyzer in which a blood side channel and a dialysate side channel are formed with a flat membrane interposed therebetween, a membrane type blood in which an endotoxin adsorbent is interposed between the flat membranes forming the dialysate side channel It is a dialyzer.

The endotoxin adsorbent used in the present invention is a fiber, a nonwoven fabric, a mesh, or the like that can adsorb endotoxin, and is not particularly limited. be able to. Endotoxin adsorbent
For example, a cationic resin, a copolymer of chitosan, N, N-dimethylacrylamide and / or N, N-dimethylaminoalkylacrylamide and a crosslinkable monomer, a copolymer of glycidyl methacrylate and ethylene glycol dimethacrylate, aminoalkyl Copolymer of methacrylate and alkyl methacrylate or vinyl monomer, polyalkylene oxide having amino group, polyethyleneimine, copolymer of allylamine hydrochloride and diallylamine hydrochloride, silicone polymer, paraffin, polyallylamine cross-linked with glutaraldehyde Treated polymer, copolymer of allylamine hydrochloride and copolymerizable vinyl monomer, styrene-divinylbenzene copolymer having sulfonic acid group, polyarylate and polyether sulfone Polymers having a down, immobilized polymyxin include polymers of aziridine compounds. Among them, polyethyleneimine is preferred because it can be easily processed into fibers, meshes, nonwoven fabrics and the like. Materials such as fibers, meshes, and nonwoven fabrics to which the endotoxin adsorbent is fixed include, for example, polyester, tetron, glass fiber, rayon, cupra, acetate, acetate acetate, vinylon, nylon, vinylidene, acrylic, polyurethane (spandex), and cotton. , Wool, silk, polyvinyl chloride,
Examples include polyurea, polyethylene, and polypropylene. Among them, polyester having excellent heat resistance and workability is preferable. The treatment for fixing the endotoxin adsorbent to fibers, meshes, nonwoven fabrics and the like includes coating, a method of mixing as a composition, and the like, but coating is preferred. Examples of the coating treatment include chemical treatments such as immersion, heat treatment, and covalent bonding.

The endotoxin adsorbent used in the present invention may be the endotoxin adsorbent itself processed into a fiber, mesh, nonwoven fabric, or the like and molded.

Although these endotoxin adsorbents may be used alone, two or more different endotoxin adsorbents having different shapes, materials and types of endotoxin adsorbents may be used in combination.

In the first embodiment of the present invention, the endotoxin adsorbent is interposed between the hollow fiber membranes serving as the dialysate-side flow path, and in the second embodiment of the present invention, the endotoxin is located between the flat membranes of the dialysate-side flow path. An embodiment in which the adsorbent is interposed will be described below. FIG. 1 is a longitudinal sectional view schematically showing an example of a hemodialyzer 1 according to a first embodiment of the present invention in which a fiber 21 for adsorbing endotoxin, which is a preferred example of an endotoxin adsorbent, is interposed between hollow fiber membranes. FIG. The mode in which the fiber 21 is interposed may be such that the fiber 21 is arranged between the hollow fiber membranes as shown in FIG. 2 or the fiber 21 may be woven into the hollow fiber membrane as shown in FIG. Although not shown, in the second embodiment of the present invention, the fiber for adsorbing endotoxin is disposed at an appropriate position in the dialysate-side flow path itself, between the flat membranes, or at an appropriate position away from the flat membrane. can do. When the adsorbent is a fiber, the ratio of the cross-sectional area of the endotoxin adsorbent to the cross-sectional area between the membranes (dialysate flow path cross-sectional area) is preferably 5 to 90%, more preferably 20 to 50%. When it is 20% or more, the endotoxin adsorption efficiency increases, and when it is 50% or less, assembly of the hemodialyzer becomes easy.

FIG. 4 schematically shows an example of the hemodialyzer 2 according to the first embodiment of the present invention in which a mesh and / or a nonwoven fabric 22 for adsorbing endotoxin, which is a preferred example of an endotoxin adsorbent, are interposed between hollow fibers. FIG. 3 is a longitudinal sectional view schematically shown. In a mode in which the mesh and / or nonwoven fabric 22 is interposed, the mesh and / or nonwoven fabric 22 may be wound between the hollow fiber bundle and the housing outer wall as shown in FIG. 5, or as shown in FIG. The mesh and / or the nonwoven fabric 22 may be wound into the space outside the hollow fiber. Although not shown, in the second aspect of the present invention, a mesh and / or a mesh for adsorbing endotoxin at an appropriate position in the dialysate-side flow channel itself, between the flat membranes, or at an appropriate position away from the flat membrane. Or a non-woven fabric can be arranged.

In the case where the above-described various modes of intervening the endotoxin adsorbent are employed, the endotoxin adsorbent may be uniformly distributed between the hollow fiber membranes in the dialysate-side flow path or may be locally concentrated. The distribution may be non-uniform. In particular, increasing the disposition density in the vicinity of the dialysate inlet is a preferred embodiment because it enables effective and efficient prevention of endotoxin from entering the blood side.

In the membrane type hemodialyzer of the present invention, since the endotoxin adsorbent is interposed in the dialysate-side flow path, low-concentration endotoxin which cannot be completely removed by the filtration filter and recontamination after passing through the filtration filter. The endotoxin is adsorbed by the endotoxin adsorbent, so that invasion to the blood side can be prevented with high accuracy. Further, when the endotoxin-adsorbing substance is processed into a dialysis membrane by coating or the like, the endotoxin-adsorbing substance is adsorbed on the pore surface of the membrane, and the degree of the adsorption deteriorates the substance permeability of the dialysis membrane. However, there is no such problem in the membrane hemodialyzer of the present invention.

The membrane type hemodialyzer of the present invention can prevent endotoxin from entering the blood side with high accuracy and can be suitably used for hemodialysis therapy and hemodiafiltration therapy. When used in hemodiafiltration therapy, a high-performance hemodialyzer with a large pore size can be obtained. Further, it is suitably used for a push-pull hemodiafiltration method in which back filtration is forcibly promoted.

[0019]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. (Example 1) Polyester fiber (fiber diameter: 7 µm)
Was immersed in a solution obtained by adding pyridine to a methanol solution of polyethyleneimine (number-average molecular weight 10,000 daltons), dried at 120 ° C. for 8 hours, and polyethyleneimine was fixed to polyester fibers. When bundling a polysulfone hollow fiber membrane (outside diameter: 280 μm, inside diameter: 200 μm), three polyethyleneimine-treated polyester fibers are wound together with one hollow fiber membrane. About 10,000 hollow fiber bundles (effective membrane area: 1.5 m ² ) of the embodiment of FIG. 2 existing in parallel with the yarns were produced. This bundle of hollow fiber membranes is transferred to a polycarbonate cylindrical housing (diameter 0.235 m, inner diameter 0.
0345m). Next, a polyurethane potting agent was injected into both ends of each hollow fiber membrane inserted into the cylindrical housing and cured to fix each hollow fiber membrane, and both ends were sliced to open each hollow fiber membrane. By fusing a cover with a blood inlet port and a cover with a blood outlet port to both ends of the cylindrical housing, the membrane-type hemodialyzer was obtained in a liquid-tight manner. (Example 2) Polyester mesh (70 mesh, wire diameter 120 µm, opening 243 µm, opening ratio 45
%, Mesh thickness of 182 μm) was immersed in a solution of pyridine in a methanol solution of polyethyleneimine (number average molecular weight 10,000 daltons) and dried at 120 ° C. for 8 hours to fix the polyethyleneimine to the polyester fiber. This polyethyleneimine-treated polyester mesh is bundled with about 10,000 bundles of polysulfone hollow fiber membranes (outside diameter: 280 μm, inside diameter: 200 μm) (effective membrane area: 1.5
m ² ), as shown in FIG. This bundle of hollow fiber membranes is transferred to a polycarbonate cylindrical housing (effective length 0.235 m, inner diameter 0.0
345m). Next, a membrane hemodialyzer was obtained in the same manner as in Example 1. (Comparative Example 1) A bundle of polysulfone hollow fiber membranes similar to that used in Example 2 was placed in a polycarbonate cylindrical housing (diameter 0.235) having a dialysate inlet and outlet.
m, 0.0345 m inside diameter). Next, a membrane hemodialyzer was obtained in the same manner as in Example 1.

The polysulfone membranes used in Examples 1 and 2 and Comparative Example 1 had a pore radius of 5.8 nm. The pore radius was determined from the coefficient of restitution by the following method (the reference is described below. Journal of Chem.).
Ial Engineering of Japan
n, 20 (1987) Sakai K, Takesaw.
a S, Miura R, Ohashi H, Stru
ctual analysis of Hollow
fiber dialysis members
for clinical use. p. 351-35
6, Desalination, 1 (1966) Sp
iegler KS, Kedem O, Thermo
dynamics of hyperfiltrati
on (reverse osmosis): write
ria for efficient membrane
es. p. 311-326, Desalinatio
n, 1 (1966) Jagur-Grondzinsk
iJ, Kedem O, Transport coe
ffficient and saltrejectio
n in unchanged hyperfiltr
ation members. p. 327-34
1.Journal of MembraneSci
ence, 5 (1979) Wendt RP, Kle
in E, Bresler E H, Holland
FF, Serino RM, Villa H, Si
evening coefficient of hemo
dialysis members. p. 23-4
9).

The solution for measuring the coefficient of restitution was adjusted to a blood flow rate of 1
4 ~ 5 point dialyzer of 00 ~ 500ml / min
Led to. For each blood-side flow rate,
Perform a 5-point constant speed filtration experiment with 5 to 30 ml / min
Was. Sampling from blood side inlet, outlet and filtration side outlet
And a sieve coefficient SC was determined from equation (1). Each flow rate
After changing, the stationary waiting was performed for 30 minutes or more. Dissolution
The quality is lysozyme (weight average molecular weight 14,400 dal
Ton, Stokes radius 19.3 nm) 10 mg / dl,
Myoglobin (weight average molecular weight 17,000 daltons,
Stokes radius 19.5 nm) 10 mg / dl and α
Chymotrypsinogen (weight average molecular weight 25,700
Dalton, Stokes radius 23.2 nm) 10-20 m
g / dl was used. SC = 2 × C_Fo/ (C_Bi+ C_Bo(1) where C: concentration, subscript Bi: blood side inlet, Bo: blood
Mold outlet, Fo: filtration side outlet. Calculation method of coefficient of restitution
Is shown below. The following equation holds in the concentration boundary layer. Js = c × Jv−D × (dc / dx) = c_P× Jv (2) where c: solute concentration, D: diffusion coefficient of solute, Js:
Quality flux, Jv: volume flux, x: boundary layer thickness
Direction variable, subscript P: transmission side. Equation (2) is equal to Jv
Equation (5) is obtained by integrating under the following boundary conditions
It is. x = 0; c = c_F (3) x = δ; c = c_M (4) Jv = k × ln ｛(c_M-C_P) / (C_F-C_P)｝ (5) where, k: mass transfer coefficient = D / δ, δ: boundary layer thickness,
Subscript F: supply side, M: membrane surface. True rejection rate Rint
And the apparent rejection Robs is given by the following equation:
Equation (8) is derived from equations (6) and (7). Rint = 1-c_P/ C_M (6) Robs = 1-c_P/ C_F (7) In {(1-Robs) / Robs} = ln {(1-Rint) / Rint} + Jv / k (8) In the laminar flow region of the tubular module, k is Colb.
Since the dimensionless correlation equation of urn holds, k
Rint at the permeation flux Jv is calculated,
The average of those values was defined as Rint. Sh = 1.62 × (Sc × Re × d / L)^0.333 (9) Here, Sh: Sherwood number, Sc: Schmidt number,
Re: Reynolds number, d: hollow fiber inner diameter, L: hollow fiber length
It is. Furthermore, Jagur-Grandzinski
And Kedem, the coefficient of restitution σ of the two-layer film and the true
It is derived that the following equation holds between the rejection rates Rint.
I have. Rint = ｛(1-f_sk) × (1-σ)_sp) + F_sk× (1-σ_sk) × (1-f_sp × σ_sp)-(1-σ_sk) × (1-σ)_sp)｝ / ｛(1-f_sk) × (1-σ)_sp) + F _sk × (1-σ_sk) (1-f_sp× σ_sp)｝ (10) f = exp ｛− (1−σ) × Jv / Pm｝ (11) where Pm: solute permeability coefficient, suffix sk: dense layer, s
p: It is a support layer. Also, σ_sp= 0
Equation (10) is represented by the following equation. Rint = σ_sp× (1-f_sk) / (1-σ)_sk× f_sk(12) Thus, the true rejection rate Rint versus the inverse of the permeation flux 1 / Jv
And the least squares method is used to calculate the coefficient of restitution σ_skDetermine
Was. From this coefficient of restitution, a trial and error method based on the pore theory
Using the pore radius r_skIt was determined.

Endotoxin Inhibition Performance Test The endotoxin inhibition performance tests of the membrane hemodialyzers of Examples 1 and 2 and Comparative Example 1 were conducted according to the guidelines for the safety and performance test of endotoxin cut filters for dialysis specified by the Japan Society of Artificial Organs (draft). (Dialysis fluid endotoxin is well understood book, edited by Shingo Takezawa, 1995, Tokyo Medical Co., Ltd., p. 149-150). As shown in FIG. 7, a prepared dialysate 8 adjusted to an endotoxin concentration of 100 to 250 EU / L is supplied from a dialysate port (inlet) 41 at a dialysate flow rate of 500 ml / min, and from a blood port (inlet) 51. A permeation filtration experiment was performed.
During the experiment, dialysate port (outlet) 42 and blood port (outlet) 52 were closed. In addition, regular waiting is 15
Went for more than a minute. The endotoxin concentrations of the feed solution (before total filtration) and the permeate solution (after total filtration) were measured by the Endospecy method (Seikagaku Corporation), and the endotoxin transmittance was calculated using equation (13). The results are shown in Table 1. (Endotoxin permeability) = (Permeate endotoxin concentration) / (Feed solution endotoxin concentration) (13)

[0023]

In Examples 1 and 2, the endotoxin concentration of the permeate was below the detection limit, indicating that the endotoxin-blocking performance was superior to that of Comparative Example 1.

[0025]

As described above, the membrane hemodialyzer of the present invention can be a high-performance hemodialyzer using a large-diameter hemodialysis membrane. From the blood side is effectively prevented. Therefore, it can be suitably used for hemodialysis therapy and hemodiafiltration therapy. Further, it can be suitably used in a push-pull hemodiafiltration method in which back filtration is promoted, and in an on-line hemodiafiltration method in which a dialysate is injected into a patient's body.

[Brief description of the drawings]

FIG. 1 is a diagram schematically showing an example in which fibers for adsorbing endotoxin according to the present invention are provided.

FIG. 2 is a cross-sectional view showing an example in which fibers for adsorbing endotoxin according to the present invention are provided.

FIG. 3 is a diagram showing an example in which a fiber for adsorbing endotoxin according to the present invention is wound around a membrane.

FIG. 4 is a diagram schematically showing an example in which a mesh and / or a nonwoven fabric for adsorbing endotoxin according to the present invention are provided.

FIG. 5 is a cross-sectional view showing an example in which a mesh and / or a nonwoven fabric for adsorbing endotoxin according to the present invention are provided.

FIG. 6 is a cross-sectional view showing an example in which a mesh and / or a nonwoven fabric for adsorbing endotoxin according to the present invention are provided.

FIG. 7 is a diagram showing a measurement device for an endotoxin inhibition performance test of a membrane hemodialyzer.

[Explanation of symbols]

 1: outer cylinder housing 3: hollow fiber membrane 6: pump 8: adjusted dialysate 10: membrane type hemodialyzer 21: endotoxin-adsorbed fiber 22: endotoxin-adsorbed mesh or non-woven fabric 41: dialysate port (inlet) 42: dialysate port (Outlet) 51: Blood port (inlet) 52: Blood port (outlet) 71: Dialysate inlet circuit (supply liquid circuit) 72: Blood inlet circuit (permeate circuit)

Claims (3)

[Claims] 1. A membrane blood having a housing containing a hollow fiber membrane, a blood-side flow path formed inside the hollow fiber, and a dialysate-side flow path formed outside the hollow fiber with the hollow fiber membrane interposed therebetween. A dialyzer, wherein an endotoxin adsorbent is interposed in the dialysate-side flow path. 2. In a membrane hemodialyzer having a housing including a flat membrane, wherein a blood-side flow path and a dialysate-side flow path are formed with a flat membrane interposed therebetween, the dialysate-side flow path is formed. Membrane hemodialyzer with endotoxin adsorbent interposed between flat membranes. 3. The membrane hemodialyzer according to claim 1, wherein the endotoxin adsorbent is a fiber, a mesh or a nonwoven fabric coated with an endotoxin adsorbent.