JPH1128345A - Filter membrane and filter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently remove an objective substance having hydrophobic parts on its molecule surface such as endotoxin, myoglobin or the like from a treatment liquid by applying a polymer having a glycoside derivative on its side chain to the contact surface of a hydrophobic porous membrane with the treatment liquid. SOLUTION: In a filter membrane suitable for removing and separating an objective substance from a treatment liquid such as a dialyzing liquid, a polymer having a glycoside derivative on its side chain is applied to the contact surface of the treatment liquid. At this time, as the glycoside derivative, one wherein a glycoside part is glucose, mannose or lactose is pref. used. As this filter membrane, one wherein the polymer is a copolymer of 2- methacryloyloxyethyl-D-glycoside (GEMA) and methyl methacrylate (MMA) and a wt. compsn. ratio of GEMA and MMA is (1.0-2.0):1.0 is used. Further, this filter membrane is self-crosslinked by the mutual dehydration of the hidroxyl groups of a part of GEMA.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to an endotoxin,
beta ₂ microglobulin, dialysate is treated to remove the substance having a hydrophobic moiety to the molecular surface of such myoglobin, from the processing liquid, such as hemofiltration drainage or peritoneal dialysis effluent, removing the target material, It relates to a filter membrane and a filter which can be separated.

2. Description of the Related Art Endotoxins, known as pyrogens, are constituents of the epidermis of gram-negative bacteria, and live bacteria usually exist in micelles and have a molecular weight of several million daltons. However, endotoxins produced from Gram-negative bacteria or their carcasses are small pieces with molecular weights of thousands to tens of thousands of daltons.
(Fragment), and is known to be present in facility water, tap water, and the like. From the molecular weight, fragments of endotoxin (hereinafter referred to as fragments) in the dialysate used in hemodialysis, hemodiafiltration, continuous hemodiafiltration, continuous hemodiafiltration, etc., pass through the semipermeable membrane in the above-mentioned therapy and enter the blood. Is concerned about Endotoxin is composed of O-antigen polysaccharide, core polysaccharide, and lipid A. Lipid A, which is a hydrophobic lipid moiety, is an active site that induces heat and the like. The fragment containing lipid A shows hydrophobicity.
Removal of endotoxin in facility water, tap water, or dialysate by a hydrophobic porous membrane is performed by using a filtration function utilizing the molecular weight cutoff characteristics of the hydrophobic porous membrane and an adsorption function of the hydrophobic porous membrane. Both are used at the same time and strictly depend on the adsorption function. In this case, the removal performance by the adsorption function decreases with time, and not only does the fragment easily pass (leak) through the hydrophobic porous membrane, but also the water permeability decreases with time due to endotoxin adsorption. Further, by setting the molecular weight cut-off of the hydrophobic porous membrane to be small, the probability of the fragment leaking can be reduced, but at the same time, the water permeability is reduced. Therefore, in order to obtain sufficient water permeability for the treatment, the effective membrane area must be increased, and the size of the filter module increases, so that a large work space is required and the cost increases, which is not preferable. beta ₂ microglobulin (hereinafter referred BetaMG) is a hydrophobic low molecular weight proteins of molecular weight 11,600 daltons which hydrophobic amino acids exposed on the molecular surface, is considered one of the amyloid constituents of the dialysis amyloidosis, for treatment Removal from chronic dialysis patients is considered essential. In addition, patients with acute renal failure due to crash syndrome or the like are required to remove low molecular weight proteins such as myoglobin (molecular weight 17,800). In order to efficiently remove these low-molecular-weight proteins from the patient's blood, a therapeutic means involving filtration is necessary, and a special replenisher with adjusted electrolytes, etc., was insufficient due to the large amount of filtration from the blood. It needs to be replenished from outside the body instead of liquid components. Here, the treatment involving filtration includes, for example, hemofiltration, hemodiafiltration, continuous hemofiltration, continuous hemodiafiltration, and the like. In these treatments, it is necessary to adjust the balance between the amount of the separated filtrate and the replenisher, and the operation is complicated by using a large amount of the replenisher. In order to eliminate the replenisher, a technique of removing the causative substance from the filtrate of the patient's blood (hereinafter referred to as hemofiltration effluent), adjusting the electrolyte, and returning the hemofiltration effluent to the body has been studied. Therefore, there is a need for an efficient treatment technique for hemofiltration effluent. In order to remove proteins having a hydrophobic portion, such as βMG, myoglobin, etc., from the blood filtration effluent, a 95% cut-off point (c
out-off point) molecular weight 500 to 15,000
It is preferable to use a hollow fiber membrane of 0 Dalton, but when a hydrophobic porous membrane such as porsulfone is used, the hydrophobic porous membrane is brought into contact with the protein having the hydrophobic portion by the hydrophobic porous membrane. The protein is adsorbed on the membrane surface, and the water permeability of the hydrophobic porous membrane decreases with time.

An object of the present invention is to provide a, without allowed to lower the water permeability of the hydrophobic porous membrane, the substance having endotoxin, beta ₂ microglobulin, the hydrophobic moiety to the molecular surface of such myoglobin Efficient removal of the target substance from the processing liquid such as dialysate, hemofiltration drainage or peritoneal dialysis drainage that is processed to remove
An object of the present invention is to provide a filtration membrane or a filter which can be separated.

The present invention has the following features to attain the object mentioned above. That is, in the filtration membrane of the present invention, a polymer having a glycoside derivative in a side chain is provided on at least a contact surface of a processing liquid. In the filtration membrane of the present invention, the glycoside portion of the glycoside derivative is glucose, mannose, lactose, maltose, or sucrose. Further, the filtration membrane of the present invention,
The polymer is 2-methacryloyloxyethyl-D-glycoside (GEMA) and methyl methacrylate (MMA)
And the weight composition ratio of the GEMA and MMA is 1.0 to 2.0: 1.0. Further, the filtration membrane of the present invention is self-crosslinked by dehydration of a part of the hydroxyl groups of the GEMA, and the advancing contact angle of water is 80 to
It has a 95 ° treatment liquid contact surface. Further, a filter of the present invention has the above-mentioned filtration membrane.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The filtration membrane of the present invention will be described below. The filtration membrane of the present invention is characterized in that the hydrophobic porous membrane is provided with a polymer having a glycoside derivative in a side chain at least on a contact surface of the hydrophobic porous membrane in contact with the treatment liquid. Endotoxin, β from the treated liquid without reducing the water permeability of the membrane
_{2. It} can efficiently remove a target substance having a hydrophobic portion on the molecular surface, such as microglobulin and myoglobin. The treatment liquid includes a dialysate used for hemodialysis, a dialysate after hemodialysis containing a component in the blood in contact with blood through a membrane in a hemodialysis device, a hemofiltration drainage or a peritoneal dialysis drainage, and the like. Can be Applying to the contact surface of the hydrophobic porous membrane that comes into contact with the treatment liquid means that the hydrophobic porous membrane and the polymer having a glycoside derivative in the side chain have a hydrophobic bond, an ionic bond, a covalent bond, and a molecular chain. Refers to the interaction due to confounding and the like. The hydrophobic porous membrane, when the treatment liquid is filtered, the target substance is adsorbed, a decrease in water permeability is observed due to adsorption, and as a membrane substrate, polysulfone, polyether sulfone, polypropylene, polyethylene And ethylene vinyl alcohol.
The present invention is not limited to these as long as the effects of the present invention can be obtained. The membrane may be a flat membrane or a hollow fiber membrane, but a hollow fiber membrane shape is preferable because a large volume of filtration area can be obtained with a module having a limited volume. The hydrophobic porous membrane has a 95% cut-off point molecular weight of 2,000 to 60,000, preferably 3,0.
00 to 40,000, more preferably 5,000 to 2
000 daltons. Permeability rate is 50 ~ 1,0
00 ml / hr / m ² / mmHg, preferably 200 to
800 ml / hr / m ² / mmHg, more preferably 2
Is a ^{00~500ml / hr / m 2 / mmHg} . Filter of the present invention, membrane area 0.1 to 50 m ² preferably 0.5 to 20 m ^2, more preferably 0.5~8m ^2. A membrane area smaller than this is insufficient for filtration,
With a larger film area, the module becomes larger.
The form of the filter is a conventionally used hemodialyzer,
It can take the form of a blood filter, or a general filter such as a water purifier. 95% cut- of the hydrophobic porous membrane after the addition of the polymer having a glycoside derivative in the side chain.
The off point molecular weight is 1,000 to 40,00.
0, preferably 2,000 to 20,000, more preferably 3,000 to 10,000 daltons. It is preferable that the water permeation rate at this time is substantially the same as before the application of the polymer. In the filtration membrane of the present invention, a polymer having a glycoside derivative in a side chain is provided on at least a contact surface of a processing liquid. When the glycoside derivative is applied to the treatment liquid contact surface of the hydrophobic porous membrane, it becomes moderately hydrophilic, and a substance having a hydrophobic portion contained in the treatment liquid does not adsorb to the membrane.
It is possible to improve a decrease in water permeability due to adsorption. As the polymer having a glycoside derivative in the side chain, a copolymer obtained by copolymerizing a glycoside derivative and a compound copolymerizable therewith can be used. For example, a copolymer of 2-methacryloyloxyethyl-D-glycoside (GEMA) with glucose as a glycoside moiety and methyl methacrylate (MMA), which is obtained according to JP-A-5-237181. The glycoside moiety of the glycoside derivative is preferably a monosaccharide such as glucose, mannose and lactose which exists in the human body, or a disaccharide such as maltose and sucrose. Polysaccharides such as cellulose and amylose are difficult to treat and are not suitable. The membrane of the present invention is provided with a polymer having the glycoside derivative in a side chain at least on a surface to be contacted with a liquid to be treated. The method of applying the polymer to the film substrate can be performed by dissolving the polymer in a solvent, immersing the film substrate in the obtained solution, and then drying to remove the solvent. Further, the solution may be circulated on a surface of the hydrophobic porous membrane that comes into contact with the treatment liquid, and then dried. As the solvent, a mixed solvent of a polar organic solvent such as methanol, ethanol, and isopropyl alcohol and an aqueous solvent, or a mixed solvent of a nonionic polar organic solvent such as dimethyl sulfoxide (DMSO) and an aqueous solvent may be used. it can. Drying is usually performed at a temperature of about 50 to 150 ° C., and vacuum drying may be performed if necessary. The filter of the present invention can remove endotoxin from a dialysate by being provided in a hemodialyzer or a supply pipe of a dialysate supplied to the hemodialyzer. In addition, a dialysate from which endotoxin has been removed by the filter of the present invention can be used as a replacement liquid when using a blood filter. further,
Filtrate obtained by a blood filter, or a dialysate treated by a hemodialyzer or hemofiltration dialyzer, is filtered by the filter of the present invention to remove or separate unnecessary substances such as βMG and myoglobin, By preparing an electrolyte or the like, it can be reused as a replacement solution, a dialysate, or the like. It can also be combined with other purification means (adsorption, dialysis, decomposition, etc.). Next, the present invention will be described in more detail with reference to examples.

Embodiment 1 GEM according to JP-A-5-237181
An A / MMA copolymer (GEMA: MMA = 6: 4) was prepared. A hollow fiber membrane module having a fluid inlet and an outlet at each end of the hollow fiber is prepared by a conventional method.
A small test filter having a thickness of 00 μm, a thickness of 400 μm, and 341 polysulfone hollow fibers was prepared. This polysulfone hollow fiber membrane has a 95% cut-off point molecular weight of 40,000 and a water permeation rate of 304 ml / hr / m ^2.
/ MmHg. 0.5% of the hollow fiber membrane of this test filter was adjusted with 80% ethanol as a solvent.
% GEMA / MMA polymer solution. Shortly thereafter,
Excessive 0.5% GE by air blow
The MA / MMA polymer solution was discharged and dried at 100 ° C. for 1 hour to produce a surface-treated small filter.

Comparative Example 1 In the above example, 0.5% GEMA /
A non-surface-treated small filter was prepared without performing the surface treatment step on the MMA polymer.

EXPERIMENTAL EXAMPLE 1 Using the small-sized test filters of Example 1 and Comparative Example 1, a comparative experiment was conducted on the water permeability and the membrane permeability of a hydrophobic substance in the following manner. The permeation experiment was performed by the circulation circuit shown in FIG. One end of the inlet side circuit 4 of the circulation circuit is connected to the reservoir 7, and the other end is connected to the inlet of the channel of the hollow fiber membrane lumen of the filter 2. One end of the outlet side circuit 5 is connected to the reservoir 7, and the other end is connected to the outlet of the channel of the hollow fiber membrane lumen of the filter 2. The filtrate side had one filtrate port 6 and was opened, and the filtrate was dropped into a reservoir 7. A liquid feed pump 3 is disposed in the inlet side circuit 4, and the test liquid passes through the inlet side circuit 4 by the liquid feed pump 3 and is filtered.
Is filtered by the hollow fiber membrane in the filter 2 and returned to the reservoir through the filtrate port 6. The test liquid that has not been filtered by the hollow fiber membrane is returned to the reservoir 7 through the outlet circuit 5. Chambers 81 and 82 are provided between the liquid feed pump 3 and the filter 2 in the inlet side circuit 4 and in the outlet side circuit, and pressure gauges 91 and 92 are provided in the respective chambers. The pressure is
The adjustment was performed by a clamp 94 provided at a portion downstream of the chamber 82 on the outlet side 5. Since the outer part of the hollow fiber membrane of the filter 2 was open to the atmosphere, the pressure was set to zero. In <beta ₂ microglobulin permeation experiments> BetaMG are hydrophobic low-molecular-weight protein having a molecular weight 11,600 daltons which hydrophobic amino acids are concentrated on the central surface of the molecule, an amyloid constituents of the dialysis amyloidosis, chronic dialysis patient's blood A large amount is contained in the filtrate (hereinafter referred to as hemofiltration wastewater). Using 1 L of blood filtration drainage (βMG concentration: 20 mg / l), 10 ml /
The mixture was circulated at a pressure of 100 mmHg, and circulated by filtration. 1 hour and 24 hours after the start of circulation, the inlet side chamber and the outlet side chamber of the circulation circuit,
Sampling was performed from each of three places of the filtrate port. βMG
The concentration was measured by an enzyme immunoassay. βMG sieving coefficient (SC) and hemofiltration effluent ultrafiltration rate (UF
R) was calculated by Equations 1 and 2. S. C. _{= C F × 2 / (C} i + C o) ·· formula ^{1 UFR (ml / hr / m} 2 / mmHg) = Q F / TMP ·· formula 2 C _i: inlet concentration, _{C o:} outlet concentration, C _F : Filtrate concentration Q _F : Filtration flow rate per unit area (ml / hr / m ² ) A permeation experiment was performed on the non-surface-treated small filter of Comparative Example 1 in the same manner as described above. As a result of the experiment, the sieving coefficient of βMG of the non-surface-treated small-sized filter of Comparative Example 1 was 0.1 mg after 1 hour.
It was 0.8 after 7, 24 hours. The ultrafiltration rate is 1
After time, it was 280 ml / hr / m ² / mmHg, but 2
After 4 hours, it decreased to 197 ml / hr / m ² / mmHg. On the other hand, βMG of the surface-treated small filter of Example 1
The sieving coefficient was 0.3 after 1 hour and 24 hours, and a low transmittance was maintained for a long time. The ultrafiltration rate is
After 1 hour ^{310ml / hr / m 2 / mmHg} , and after 24 hours ^{314ml / hr / m 2 / mmHg} , a significant time reduction was observed. <Endotoxin permeation experiment> An endotoxin permeation experiment was performed in the same manner as the βMG permeation experiment, except that 1 L of tap water (endotoxin concentration 1,200 EU / l) was used for the reservoir. Endotoxin concentration was measured by the endospace method. As a result of the experiment, the concentration of endotoxin in the filtrate of the non-surface-treated small filter of Comparative Example 1 was below the detection limit after 1 hour, and was 15 EU / l after 24 hours. The ultrafiltration rate is 304 ml / hr / m ² / mmHg after 1 hour
234 ml / hr / m ² / m after 24 hours
mHg. On the other hand, the surface-treated small filter of Example 1 did not detect endotoxin in the filtrate after 1 hour and 24 hours, and 312 ml / h after 1 hour.
r / m ² / mmHg, 309 ml / hr / m after 24 hours
² / mmHg, and no significant decrease over time was observed.

Embodiment 2 GEM according to JP-A-5-237181
An A / MMA copolymer (GEMA: MMA = 6: 4) was prepared. A hollow fiber membrane module having a fluid inlet and an outlet at each end of the hollow fiber is prepared by a conventional method.
00 μm, film thickness 40 μm, 341 polysulfone hollow fibers,
A small test filter having a membrane area of 300 cm ² was prepared. 95% cut-off of this polysulfone hollow fiber membrane
The point molecular weight is 15,000 and the water permeability is 10
It was 0 ml / hr / m ² / mmHg. A 0.5% GEMA / MMA polymer solution prepared using 80% ethanol as a solvent was filled into the hollow fiber membrane cavity of the test small filter. Immediately thereafter, the excess 0.5% GEMA / MMA polymer solution is discharged by air blowing,
Drying at 100 ° C for 1 hour to produce a surface-treated small filter

Comparative Example 2 The same procedure as in Example 2 was repeated except that 0.5% GEMA was used.
The non-surface-treated microfilter was not subjected to the surface treatment step of the / MMA polymer.

EXPERIMENTAL EXAMPLE 2 Using Example 2 and Comparative Example 2, similar to Experimental Example 1, a comparative experiment was conducted on the water permeability and the membrane permeability of a hydrophobic substance. <Β ₂ microglobulin permeation experiment> Hemofiltration drainage (βM
Using 1 L of G concentration: 20 mg / l), the mixture was circulated at a rate of 10 ml / min in the surface-treated small-sized filter of Example 2, and the membrane was filtered and circulated at a transmembrane pressure difference (TMP) of 100 mmHg. One hour and 24 hours after the start of the circulation, sampling was performed from three places of the inlet side chamber, the outlet side chamber and the filtrate port of the circulation circuit. As a result of the experiment, the sieving coefficient of βMG of the non-surface-treated small filter of Comparative Example 2 was 0.1 after 1 hour and 0.2 after 24 hours. The ultrafiltration rate was 90 ml / hr / m ² / mmHg after 1 hour, but dropped to 64 ml / hr / m ² / mmHg after 24 hours. On the other hand, the βM of the surface-treated small filter of Example 2
The sieving coefficient of G is 0.03 after 1 hour and 24 hours.
, A low transmittance was maintained for a long time. The ultrafiltration rate was 108 ml / hr / mmHg after 1 hour and 110 ml / hr / mmHg after 24 hours, and no significant decrease with time was observed. <Endotoxin permeation experiment> As a result of the experiment, the non-surface-treated small-sized filter of Comparative Example 2 had an endotoxin concentration in the filtrate of 1
It was below the detection limit after 24 hours and 10 EU / l after 24 hours. The ultrafiltration rate after 1 hour was 96 ml / hr / m ² /
mmHg, but after 24 hours 88 ml / hr / m
² / mmHg. On the other hand, the surface-treated small filter of Example 2 did not detect endotoxin in the filtrate after 1 hour and after 24 hours, and 105 m after 1 hour.
1 / hr / m ² / mmHg, 104 ml / h after 24 hours
r / m ² / mmHg, and no significant decrease over time was observed.

As described above, in the filtration membrane of the present invention, since a polymer having a glycoside derivative in the side chain is provided at least on the contact surface of the processing liquid, endotoxin, βMG, myoglobin, etc. The substance having a hydrophobic part is not adsorbed, the water permeability is not reduced, and the substance having a hydrophobic part contained in the treatment liquid can be efficiently removed and separated. Further, in the filtration membrane of the present invention, the glycoside portion of the glycoside derivative is glucose, mannose, lactose, maltose,
Since it is sucrose, it is excellent in biocompatibility and the above-mentioned effects can be obtained. Further, in the filtration membrane of the present invention, the polymer is 2-methacryloyloxyethyl-
D-glycoside (GEMA) and methyl methacrylate (M
MA) and the weight composition ratio of the GEMA and MMA is 1.0 to 2.0: 1.0, so that the above-mentioned higher effect can be obtained. Further, the filtration membrane of the present invention is self-crosslinked by dehydration of a part of the hydroxyl groups of the GEMA, and the advancing contact angle of water is 80 to
It has a 95 ° treatment liquid contact surface. Further, since the filter of the present invention has the above-mentioned filtration membrane, the above-mentioned effects can be obtained. Further, even in a treatment means involving hemofiltration, the replenishment of a special replenisher from the outside is eliminated, thereby enabling efficient treatment.

[Brief description of the drawings]

FIG. 1 is a schematic view of a circulation circuit for a permeation experiment.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Circulation circuit 2 Filter 3 Liquid feed pump 4 Inlet circuit 5 Outlet circuit 6 Filtrate port 7 Reservoir 81, 82 Chamber 91, 92 Pressure gauge 94 Cleanme 10 Test liquid

Claims (5)

[Claims] 1. A filtration membrane wherein a polymer having a glycoside derivative in a side chain is provided at least on a contact surface of a treatment liquid. 2. The filtration membrane according to claim 1, wherein the glycoside portion of the glycoside derivative is glucose, mannose, lactose, maltose, or sucrose. 3. The polymer according to claim 1, wherein the polymer is a copolymer of 2-methacryloyloxyethyl-D-glycoside (GEMA) and methyl methacrylate (MMA).
3. The filtration membrane according to claim 1, wherein the weight composition ratio of A is 1.0 to 2.0: 1.0. 4. 4. A part of the GEMA is self-crosslinked by dehydration of a part of the hydroxyl groups.
The filtration membrane according to claim 3, wherein the filtration membrane has a contact surface of the treatment liquid of ~ 95 °. 5. A filter having the filtration membrane according to claim 1.