JPH09292394A - Filtration membrane and filtration unit for measurement of low-molecule substance concentration in blood - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a filtration unit which can be miniaturized, which reduces a priming volume, whose operability is enhanced and whose costs are lowered by a method wherein a flux is adjusted to be nearly constant during the time of an artificial dialysis. SOLUTION: A cross-linking polymerizing monomer, a monomer which comprises a hydrophylic group, a solvent-soluble polymer, a solvent and a UV polymerization initiator in respectively prescribed amounts are mixed, and a polymerizing solution is obtained. A glass plate is coated with the solution in a prescribed thickness, the glass substrate is left still inside a nitrogen current for two minutes, it is irradiated with ultraviolet rays in a prescribed quantity for about 40 seconds, an obtained gel-like coating membrane is immersed in tap water together with the glass plate, and an obtained solid membrane is stripped from the glass plate. The membrane is immersed in, e.g. ethanol for 12 hours, it is then cleaned by running water for four hours, and it is then vacuum-dried at 40 deg.C. An obtained filtration membrane is built in an ABS resin housing in such a way that the glossy side of a circular membrane in a diameter of about 7cm is directed downward, its peripheral part is ultrasonically fused to be liquid-proof, and a disk-shaped filtration unit is manufactured. Thereby, it is not required to provide the margin of a membrane area in anticipation of a reduction in a flux.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sample for concentration measurement of low molecular weight substances such as blood sodium ion, potassium ion, chloride ion, blood urea nitrogen (referred to as BUN) from extracorporeal blood circulation. And a filtration unit incorporating the filtration membrane. INDUSTRIAL APPLICABILITY The filtration membrane and filtration unit of the present invention can be used, for example, as a sampling device for monitoring the concentration of low molecular weight substances such as sodium ion, potassium ion, chloride ion, and blood urea nitrogen in blood during artificial dialysis.

[0002]

2. Description of the Related Art At the time of artificial dialysis, an attempt to continuously or intermittently obtain a sample for measuring the concentration of low molecular weight substances such as sodium ion in blood and blood urea nitrogen in blood from extracorporeal blood circulation has been carried out by, for example, Yamada. Akio et al., Artificial Organs Volume 14 No. 1
2 (1985).

[0003]

However, since the filtration flow rate may be reduced during the artificial dialysis time (usually 4 to 6 hours), the sample amount necessary for the measurement may not be secured, so that the membrane area is increased. Had to design. Therefore, the filtration unit becomes large and not only causes an increase in priming volume, but also causes inconvenience in handling.
The price increase of the filtration unit was inevitable.

[0004]

[Means for Solving the Problems] The inventors of the present invention have found that in order to reduce the priming volume of a filtration unit for measuring the concentration of low-molecular substances in blood, improve the handleability, and reduce the price, it is necessary to reduce the cost during hemofiltration. We believe that it is important to prevent the decrease of the filtration flow rate over time, and as a result of further studies on a filtration membrane and a filtration unit that do not decrease the filtration flow rate over time, the first cause of the decrease in filtration flow rate over time is It was due to fouling (dirt) due to the adsorption of albumin on the membrane, and the second cause was found to be the clogging of the membrane due to the formation of thrombus, and as a result of diligent study on the suppression method thereof, the water flux was 1. 0 x 10 ^{-4 to} 3.0 x 10 ^-3 m ³ · m
^-2 · s ⁻¹ · MPa ^-1 , albumin inhibition rate is 95% or more,
In addition, the porous membrane with a water contact angle of 60 degrees or less on the side in contact with blood fouls due to albumin adsorption (dirt).
Also, the membrane is less likely to be clogged due to the formation of thrombus, and is suitable as a filtration membrane for measuring the concentration of low-molecular substances in blood. Since it is almost constant, it is easy to handle, and it is not necessary to give a margin to the membrane area in anticipation of the reduction of flux, so the filtration unit can be downsized,
The present invention has been accomplished by finding that the priming volume can be reduced, the handling property can be improved, and the cost of the filtration unit can be reduced.

Namely, the present invention is, (1) water flux ^{1.0 × 10 -4 ~3.0 × 10 -3} m 3 · m ^over 2 · s ^-1 · M
A filtration membrane for measuring the concentration of low-molecular substances in blood, which is a porous membrane having Pa ^-1 , an albumin inhibition rate of 95% or more, and a water contact angle on the side in contact with blood of 60 degrees or less.

(2) The filtration membrane for measuring the concentration of low molecular weight substances in blood according to (1) above, wherein the water contact angle of the porous membrane on the side in contact with blood is 40 to 55 degrees.

(3) The above-mentioned (1) or (2), wherein the porous membrane is a porous membrane composed of a polymer containing a nonionic hydrophilic group and / or an anionic hydrophilic group as a covalent bond as an essential constituent component. (4) A filtration membrane for measuring the concentration of low-molecular substances in blood, wherein the porous membrane is a polymer alloy containing 10 to 40% by weight of a polymer containing a nonionic hydrophilic group and / or an anionic hydrophilic group as a covalent bond. A filtration membrane for measuring the concentration of low molecular weight substances in blood according to the above (1) or (2), which is a structured porous membrane, (5) a polymer containing a nonionic hydrophilic group and / or an anionic hydrophilic group as a covalent bond. Is a polymer of monomers and / or oligomers containing (meth) acrylic acid ester as a main component, and the filtration membrane for measuring the concentration of low molecular weight substances in blood according to the above (3) or (4), (6) The nonionic hydrophilic group and / or the anionic hydrophilic group is one or more hydrophilic groups selected from the group consisting of a polyethylene glycol group having a repeating number of 4 or more, an N, N-dimethylamide group and a sulfone group (3). , (4) or the filtration membrane for measuring the concentration of low molecular weight substances in blood according to (5), (7) The low molecular weight substance in blood according to any one of (1) to (6) above, wherein the porous membrane is a flat membrane Filtration membrane for concentration measurement,

(8) On one side of the porous membrane, a blood inlet, a blood channel for flowing extracorporeal circulation blood in contact with the porous membrane, and a blood outlet are provided, and the other side of the porous membrane is provided. A filtration unit for measuring the concentration of a low molecular weight substance in the blood, which is provided with an outlet for a sample for measuring the concentration of a low molecular weight substance in the blood that has passed through, and wherein the membrane is integrated with a housing. A filtration unit for measuring the concentration of low-molecular substances in blood, which is the filtration membrane for measuring the concentration of low-molecular substances in blood according to any one of (1) to (7), (9) a low-molecular substance in blood The effective membrane area of the concentration measuring filtration membrane is 5 × 10 ^{−4 to} 100 × 1
The filtration unit for measuring the concentration of low molecular weight substances in blood according to the above (8), which is 0 ⁻⁴ m ² , (10) The flow passage cross-sectional area of the blood flow passage is 1.0 × 10 ^{−6 to} 4.0 × 10. ^A filtration unit for measuring the concentration of low molecular weight substances in blood according to the above (8) or (9), which is ^-5 m ² , (11) The shape of the blood channel is from the peripheral portion to the central portion of the planar porous membrane. The filtration unit for measuring the concentration of a low molecular weight substance in blood according to (8), (9) or (10), which has a spiral shape.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The water flux (fla
X = permeation flux), the pressure difference is 0.1 at 25 ° C.
The permeation flux of water measured in MPa, the filtration membrane of the present invention
(Hereinafter sometimes simply referred to as "membrane") water flakes
Space is 1.0 × 10^-Four~ 3.0 × 10 ^-3m^Three・ M^{ー 2}・ S
^-1・ MPa^-1 It is. The value of this water flux is the circulation
Samples for measuring low molecular weight substances in blood are collected from blood by filtration
Although it is different from the flux in the case of
It can be used as an index of flux during use. Water flack
If this value is less than this value, sample flakes per membrane area
It is necessary to have a large membrane area that is small and has practical problems.
Become. Water flux has a low albumin inhibition rate, which will be described later.
It is preferable that it is high unless it is lowered, but even if this value is exceeded
The flux of the measurement sample hardly increases.

The membrane of the present invention does not permeate most proteins existing in blood, but permeates low molecular substances existing in blood such as sodium ion, potassium ion, chloride ion, urea nitrogen (BUN). It is a film that makes it. The molecular weight fractionation characteristic of the porous membrane is the albumin inhibition rate, that is, {1- (albumin concentration in filtrate / albumin concentration in stock solution)}.
The value of the film of the present invention is 90 to 10
It is 0%, preferably 95 to 100%. The higher the albumin inhibition rate, the less the albumin is lost from the blood during use, which is preferable. However, if the inhibition rate is too high, the flux of the measurement sample decreases. It should be noted that the albumin inhibition rate here is 0.1% by weight at pH = 7, using bovine serum albumin (BSA, molecular weight 67,000) as albumin, unless it is said that "at the time of use", or the like. % Value is the value when a filtration test is performed with a pressure difference of 0.05 MPa using an aqueous solution of albumin as a stock solution for filtration. Therefore, unlike the inhibition rate of human serum albumin (molecular weight 69000) in use (hemofiltration), in actual use, a membrane having an albumin inhibition rate of 90% or more in the present invention is 99% or more of human serum. The albumin inhibition rate, and the film having an albumin inhibition rate of 95% or more shows the inhibition rate of human serum albumin of 99.9% or more, respectively.

The most important feature of the membrane of the present invention is that the water contact angle (contact angle with water) on the side in contact with blood is 60 degrees or less. The water contact angle can be measured by a droplet method, for example, a method using a CA-D type contact angle meter manufactured by Kyowa Interface Science Co., Ltd. Water contact angle is 60
If the degree is higher, it will filter ions such as ions from blood,
The decrease of the flux over time becomes large. The lower limit of the water contact angle may be 0 degree, but a film having a small water contact angle tends to have a low flux, so that the water contact angle is preferably 40 to 55 degrees. Further, when the water contact angle of the film is small, water may be absorbed by the film, depending on the porous structure of the film, and the water contact angle may not be measured. In such a case, measurement is performed using a non-porous film formed of the same material as the membrane.

A method for preparing a membrane having a water contact angle of 60 degrees or less is arbitrary, and a method of coating the porous membrane with a hydrophilic polymer, a method of chemically modifying the porous membrane with a hydrophilic group, and a method of containing a hydrophilic group-containing polymer are included. And a method of forming a film of a polymer alloy containing a hydrophilic group-containing polymer, a method of forming a film using a polymer containing a hydrophilic group, and the like. It should be noted that these hydrophilic groups are bound to the polymer constituting the membrane by a covalent bond,
It is preferable in maintaining the water contact angle of the membrane. Another method is to coat the membrane with a low molecular weight compound such as a surfactant, but these may elute during use.

The hydrophilic group which can be introduced into the membrane is arbitrary, and examples thereof include polyethylene glycol group, polyoxymethylene group,
Hydroxyl group, sugar-containing group, N, N-dimethylamide group, nonionic hydrophilic group such as N-methylpyrrolidone group, anionic hydrophilic group such as carboxyl group, sulfone group, phosphoric acid group and phosphorous acid group, amino group, amide group Examples thereof include a cationic hydrophilic group such as ammonium group, an amino acid-containing group, and a zwitterionic group such as ammonium phosphate-containing group. Among them, the nonionic hydrophilic group and / or the anionic hydrophilic group are preferable from the viewpoint of suppressing the deterioration of the flux over time and biocompatibility.
The nonionic hydrophilic group is particularly preferably a polyethylene glycol group having a repeating number of 4 or more and / or an N, N-dimethylamide group, and the anionic hydrophilic group is particularly preferably a sulfone group. Of course, it is also possible to mix and use these.

From the balance of physical properties such as the strength of the membrane and hydrophilicity, the content is 7 to 80% by weight in the case of a polyethylene glycol group having a repeating number of 4 or more, and 7 in the case of an N, N-dimethylamide group. The porous membrane is preferably composed of a polymer containing a hydrophilic group as a covalent bond in an amount of ˜65% by weight and, in the case of a sulfone group, 2 to 50% by weight.

Further, among these, a porous membrane composed of a polymer alloy containing 10 to 40% by weight of a polymer containing a hydrophilic group as a covalent bond is particularly preferable.

The polymer alloy is formed by, for example, forming a uniform solution of a cross-linking polymerizable vinyl-based monomer and / or oligomer, a monomer and / or oligomer having a hydrophilic group, a solvent-soluble polymer, and a solvent for dissolving them into a film shape, and energizing them. It can be produced by a method of irradiating with rays to polymerize. This film is composed of a cross-linkable vinyl-based monomer and / or oligomer, a cross-linked copolymer of a monomer and / or oligomer having a hydrophilic group, and another solvent-soluble polymer (ie, linear polymer).
And a polymer alloy having a semi-interpenetrating polymer network (semi-IPN) structure, and having physical properties such as strength, rigidity, flexibility, and heat resistance, and sufficient hydrophilicity. Is preferred, which is preferable.

The crosslinkable vinyl-based monomer and / or oligomer means a bifunctional or higher functional monomer and / or oligomer having a vinyl-polymerizable functional group such as a vinyl group, a vinylidene group, an acryl group and a methacryl group. The vinyl-based oligomer is an oligomer having a polymerizable vinyl-based functional group. Further, the monomer and / or oligomer having a hydrophilic group used here may be monofunctional or polyfunctional.

The crosslinkable polymerizable monomer and / or oligomer and the hydrophilic group-containing monomer and / or oligomer are preferably those having a high polymerization rate, and those capable of energy beam curing are preferred. Therefore, these are an acryloyl group and / or a methacryloyl group [hereinafter, these are collectively referred to as "(meth) acryloyl group". The same applies to similar compounds]. The one having a (meth) acryloyl group means (meth) acrylic acid, (meth) acrylic acid ester, (meth) acrylonitrile, (meth) acrylamide, and derivatives thereof. Among these, (meth) acrylic acid ester is particularly preferable as the crosslinkable polymerizable monomer and / or oligomer, and it is preferable to use this as the main component. The main component means a cross-linking polymerizable monomer and /
Alternatively, the content in the oligomer is 50% by weight or more.

The solvent-soluble polymer may be of any type, but polysulfone-based polymers such as polysulfone and polyether sulfone, amide-based polymers such as aliphatic polyamide, aromatic polyamide and alicyclic polyamide, acetyl cellulose, nitrocellulose and ethyl cellulose. Cellulosic polymers such as (meth) acrylic acid ester,
(Meth) acrylic polymers such as acrylonitrile,
An imide-based polymer such as an aromatic polyimide, a styrene-based polymer, a polycarbonate-based polymer and the like are preferable, and among them, an aromatic polyamide is particularly preferable because it can achieve excellent physical properties and can easily control the molecular weight cutoff.

The membrane of the present invention preferably has a pore size distribution in the thickness direction from the membrane surface, that is, an asymmetric structure, because it is easy to achieve both flux and albumin rejection. In this case, a method of bringing blood into contact with the layer having a small pore size (dense layer) is preferable. The membrane shape is preferably a flat membrane or a hollow fiber membrane (including a capillary membrane), and a flat membrane is particularly preferable because it can constitute a low-cost filtration unit. The flat membrane may be formed on a porous support such as a nonwoven fabric.

In the filtration unit for measuring the concentration of low molecular weight substances in blood of the present invention, the porous membrane incorporated as a filtration membrane is the filtration membrane for measuring the concentration of low molecular weight substances in blood as described above. It is a filtration unit for measuring the concentration of medium and low molecular weight substances. The filtration unit is composed of a porous membrane and a housing, and on one side of the membrane is a blood flow path for flowing extracorporeal circulation blood in contact with the porous membrane. And a blood outlet is provided. on the other hand,
On the other side of the porous membrane, there is provided a flow channel for guiding the permeated sample for measuring the concentration of low molecular weight substances in blood to the sample outlet provided in the housing. When the membrane is a flat membrane, the present filtration unit is provided with a blood flow path for allowing extracorporeal blood to flow in contact with the porous membrane in the space formed on one side of the membrane and inside the housing. In the space composed of the membrane on the other side of the porous membrane and the inside of the housing, the sample for measuring the blood ion concentration that has passed through the membrane is introduced into the sample outlet provided in the housing. There is a road. In both cases, the membrane and the housing are liquid-tightly integrated.

The method of integrating the membrane and the housing may be adhesion, fusion (welding), fitting, screwing, screwing or the like, but adhesion or fusion is preferable. It is also possible to use an O-ring or the like to make it liquid-tight. The material of the housing is arbitrary, but plastics such as polystyrene, polymethylmethacrylate, polyacrylonitrile, polycarbonate, polysulfone, polyethersulfone, polyethylene, polypropylene, polymethylpentene or a copolymer containing them are preferable.

In order to prevent coagulation and hemolysis in the filtration unit, the value of the pressure drop (blood pressure loss) between the blood inlet and the blood outlet when using the present filtration unit is properly designed. This is very important. Excessive pressure loss results in hemolysis and too small pressure loss results in coagulation.
The largest factors that determine the magnitude of pressure loss are the channel cross-sectional area and channel length. In the filtration unit of the present invention, the blood flow passage has a cross-sectional area of 1.0 × 10 ^{−6 to} 4.0 × 10 ^−5.
m ² is preferred and 3.0 × 10 ^{−6 to} 1.5 ×
More preferably, it is 10 ⁻⁵ m ² .

When the membrane is a flat membrane, the filtration unit may be a spiral type, a flat type, a flat laminated type or the like, but a single-layer flat type is preferable because it is easy to manufacture. The shape of the blood channel in the case of the one-layer plane type may be a zigzag type, a spiral type, a linear type, a radial type, etc., but the spiral type is preferable. That is, a spiral shape from the peripheral portion to the central portion of the membrane held flat is preferable because hemolysis and coagulation can be suppressed by minimizing the curvature of the blood channel. A plurality of blood channels may be provided in parallel. At this time, the direction of blood flow may be from the peripheral portion of the membrane to the central portion or vice versa.

The present filtration unit is used by being incorporated in an extracorporeal blood circuit. For example, when used as a monitor for the concentration of ions such as sodium and blood urea nitrogen in a patient undergoing dialysis treatment, the blood taken from the patient's vein is pressurized with a blood pump and then filtered by the filtration unit. After entering and flowing through the blood channel in the filtration unit in contact with one side of the porous membrane, it flows out of the filtration unit, passes through the dialysis module, and is returned to the patient's vein. The higher the blood pressure in the filtration unit, the more the flux increases, but if it is too high, hemolysis occurs. Therefore,
The blood pressure at the blood inlet of the filtration unit is 100 to 30.
0 mmHg is preferred, 150-200 mm
Hg is more preferred. Further, the pressure loss on the blood side of the present filtration unit is preferably 20 to 150 mmHg, 40
-100 mmHg is more preferable. If the pressure loss is too large, hemolysis occurs, and if it is too small, blood clotting occurs. The extracorporeal blood flow rate in dialysis treatment is usually 150 to 200 ml / min, and an appropriate pressure loss value can be obtained by setting the blood flow passage cross-sectional area of the filtration unit to the above value.

A part of the blood is filtered in the present filtration unit, and only the component that permeates the filtration membrane, that is, plasma water, permeates to the other side of the membrane and flows out from the outlet of the blood ion concentration measurement sample. . The flow-out sample is continuously or intermittently measured by an ion concentration or urea nitrogen measuring device. The outflow of the measurement sample from the outlet may be left to the natural outflow, or may be collected by suction. Alternatively, an open / close valve may be provided to intermittently collect the sample. Suctioning the measured solution sample outlet is preferable because it has the effect of increasing the pressure difference between the front and back of the membrane and increasing the flux.

In the filtration unit of the present invention, leakage of protein from blood can be neglected at the time of its use, so that even if the sampled amount is large, there is no burden on the patient. Therefore, the flux of the sample for measurement, that is, the sampled amount is arbitrary, but for the purpose of reducing the film area, it is desirable to set the minimum amount necessary for the measurement. Based on the performance of recent measuring instruments, if it is sampled at 1 ml / min, it can be measured at 1-minute intervals. Therefore, in order to obtain this measurement sample amount,
The membrane area to be incorporated in the filtration unit is preferably 5 × 10 ^{−4 to} 100 × 10 ⁻⁴ m ² in terms of effective membrane area, and 10 × 10 ⁻⁴ to 30 × 10 ⁻⁴ m ² . Is more preferred.

Items measured by a measuring instrument from the collected sample are low-molecular substances that can be passed through the filtration membrane of the present invention, for example, ions such as sodium ion, potassium ion, calcium ion and chlorine ion, urea, uric acid and the like. Amino acids and metabolites such as urea nitrogen (BUN), creatine, creatinine, and pyrilbin, phosphorus, oxygen, and carbon dioxide, but are not limited thereto.

The measured sample to be measured may be discarded and need not be returned to the patient's body.

[0030]

The present invention will be described in detail below with reference to examples and comparative examples, but the scope of the present invention is not limited to these examples. The parts in the examples are on a weight basis.

Example 1 (Preparation of Polymerizable Solution 1) Diethylene oxide-modified bisphenol A diacrylate [New Frontier BPE-4, Daiichi Kogyo Seiyaku Co., Ltd.] as a cross-linking polymerizable monomer
2 parts, as a monomer having a hydrophilic group, methoxynonaethylene glycol acrylate [NK ester AM-
90 G, Shin-Nakamura Chemical Co., Ltd.] 5 parts, aromatic polyamide as a solvent-soluble polymer [Conex, Teijin Ltd.]
18 parts, 85 parts of N, N-dimethylacetamide (DMAC) as a solvent, and 2 parts of Irgacure-184 (manufactured by Ciba-Geigy) as an ultraviolet polymerization initiator were mixed to obtain a polymerizable solution 1.

(Preparation of Filter Membrane 1) The polymerizable solution 1 having a thickness of 200 μm was formed on a glass plate with a film applicator.
The coating solution was applied so as to have a thickness of m, and the solvent was partially volatilized by allowing it to stand in a nitrogen stream for 2 minutes, and then an ultraviolet ray having an intensity of 10 W / m ² at 360 nm was irradiated for 40 seconds by a metal halide lamp. When the transparent gel-like coating film, which had lost fluidity and was obtained by irradiation with ultraviolet rays, was immersed in tap water of the coagulating liquid together with the glass plate, the coating film became milky white and coagulated. The obtained film was peeled off from the glass plate and placed in ethanol 1
After cleaning by immersion for 2 hours and immersion for 4 hours in running water,
It was vacuum dried at 40 ° C. to obtain a filtration membrane 1 for measuring the concentration of low molecular weight substances in blood according to the present invention.

(Evaluation of Characteristics of Filtration Membrane 1) Filtration membrane 1 was a porous membrane, and had a gloss on the side in contact with the nitrogen stream and no gloss on the side in contact with the glass plate. Filtration membrane 1
As a result of observing with a scanning electron microscope (SEM), pores having a pore diameter of about 0.5 μm were observed on the side in contact with the glass plate (hereinafter, also referred to as “non-gloss side”), and nitrogen flow was observed. No pores were observed on the side in contact with (hereinafter, sometimes referred to as “glossy side”). Further, in the observation of the cross section, the portion having a small pore size was only the surface layer on the gloss side, and the thickness thereof was 1 μm or less. The cross section has a hole diameter of 10
There were so-called macropores of -50 μm.

The contact angle of water on the glossy side of the filtration membrane 1 measured with a CA-D type contact angle meter manufactured by Kyowa Interface Science Co., Ltd. is 4
8 degrees.

Ultrafiltration tester UHP manufactured by Toyo Roshi Kaisha, Ltd.
-90K, the water (distilled water) flux by the filtration membrane 1 and bovine serum albumin (BSA) (molecular weight 6700
A filtration test was performed on a 0.1% by weight aqueous solution of 0) (pH = 7.0 buffer solution). The filtration pressure for water flux measurement is 0.1
MPa, the filtration pressure for measuring the rejection rate was 0.05 MPa, and the filtration temperature was 25 ° C. for both. The resulting aqueous flux ^{9.2 × 10 - 4 m 3 ·} m ^over 2 · s ^-1 · MPa
^-1 (325 l / m ² · h · kg · cm ^-2 ), the BSA inhibition rate was 99%.

Further, using the filtration membrane 1, bovine serum albumin
(BSA) adsorption test. That is, concentration 500g
/ M^Three BSA aqueous solution (pH = 7.0 buffer solution) 1 × 10
^-Fourm ^Three BSA before and after immersion in 1g of water for 24 hours
By measuring the concentration change by optical measurement,
The amount of BSA deposited was calculated to be 2.9 mg / g.
Was.

(Preparation of Filtration Unit) The circular filtration membrane 1 having a diameter of 7 cm was placed on the AS side with the gloss side (dense layer side) facing down.
It was incorporated in a resin (acrylonitrile-styrene copolymer) housing and liquid-tightly ultrasonically fused at the periphery of the membrane to produce a disc-shaped filtration unit.

On the lower surface of this filtration unit, 1
One blood outlet is provided in the center, and one blood outlet is provided in the center. In the space defined by the membrane and the inside of the housing, a swirl extends from the blood inlet to the blood outlet in the center of the membrane. A blood flow path is formed with a partition. On the other hand, a measurement sample outlet is provided in the center of the upper surface of the filtration unit, and a large number of grooves are dug inside the top surface of the housing to allow the measurement sample that has permeated the membrane to flow to the center sample outlet. It is shaped accordingly.

The effective membrane area of this filtration unit is 17.5.
× 10 ^-4 m ² , the cross-sectional area of the blood channel is 6.55 × 10 ^-6
m ² .

(Measurement Sample Collection Test) As a model of a filtration collection test of a sample for measuring a low molecular weight substance concentration in blood in a human body,
A test using bovine whole blood was performed. Hematocrit (He)
Bovine whole blood adjusted to a value of 35% by weight and total protein (TP) of 70 kg / m ³ is passed through a blood flow pump (tube pump) through a transparent soft vinyl chloride tube from a container adjusted to 36 ° C., and then main filtration is performed. It was connected to the blood inlet of the unit.
At the blood outlet of the filtration unit, with the same tube,
Piping was performed so that the blood could be returned to the original blood container via the control valve. A pressure gauge was connected to the blood inlet and the blood outlet.

The blood flow rate is adjusted to 200 by adjusting the blood flow pump.
The pressure at the blood inlet of the filtration unit was adjusted to 200 mmHg by a control valve provided at the blood outlet of the filtration unit, and the pressure at the blood outlet was 140 mmHg. The blood flow rate was measured by receiving blood returning to the blood container in a graduated cylinder.

At this time, the flux of the measurement sample flowing out from the sample outlet of the filtration unit was 0.50 ml / min on average for 5 minutes from the start of outflow, and 0.45 ml / min after 4 hours from the start of outflow. It was The albumin inhibition rate during this use test, which was measured by subjecting the used whole blood of bovine and these effluents to liquid chromatography, was 99.94%.
The obtained filtrate could be used as a sample for measuring sodium ion concentration, potassium ion concentration, and BUN concentration without any problem.

Example 2 (Preparation of Polymerizable Solution 2 and Preparation of Filter Membrane 2) Instead of aromatic polyamide as solvent-soluble polymer, polyether sulfone (RADEL 5000NT, Amoco P) was used.
information Products Inc.
18 parts), 102 parts of N, N-dimethylacetamide (DMAC) as a solvent,
Further, a polymerizable solution 2 was obtained in the same manner as in Example 1 except that 5.4 parts of lithium chloride was newly added as an additive, and in the same manner, a filtration membrane 2 for measuring the concentration of low molecular weight substances in blood according to the present invention was obtained. Got

(Evaluation of Characteristics of Filter Membrane 2) The obtained filter membrane 2 has the same structure as in Example 1, and the water contact angle on the gloss side measured in the same manner as in Example 1 is 49 degrees and BSA. Adsorption amount is 0.1 mg / g or less, water flux is 10.0 × 10
^-4 m ³ · m ⁻² · s ^-1 · MPa ^-1 , BSA rejection rate is 90%
Met.

(Preparation of Filtration Unit and Collection Test of Measurement Sample) A filtration unit was prepared in the same manner as in Example 1 except that the filtration membrane 2 was used, and a collection test of a measurement sample from circulating blood was conducted in the same manner. went. The circulating hemofiltration flux was 0.51 ml / min at the start of measurement and 0.48 ml / min 4 hours after the start of measurement. The albumin inhibition rate during this use test was 99.1%. The obtained filtrate could be used as a sample for measuring sodium ion concentration, potassium ion concentration, and BUN concentration without any problem.

Example 3 (Preparation of Polymerizable Solution 3 and Preparation of Filter Membrane 3) Tetraethylene glycol diacrylate [NK Ester A-200, manufactured by Shin-Nakamura Chemical Co., Ltd.] as a cross-linking polymerizable monomer.
4.5 parts, N, N-dimethylacrylamide [manufactured by Kojin Co., Ltd.] as a monomer having a hydrophilic group 2.5 parts, and polysulfone (Udel Polysulfone P1700, AmocoPerformance P) as a solvent-soluble polymer.
products Inc. 18 parts, DM as solvent
67 parts AC, Irgacure-1 as an ultraviolet polymerization initiator
842 parts were mixed to obtain a polymerizable solution 3, and in the same manner as in Example 1 except that this polymerizable solution 3 was used, a blood filtration membrane 3 for measuring a low molecular weight substance concentration of the present invention was obtained.

(Evaluation of Characteristics of Filtration Membrane 3) The obtained filtration membrane 3 had the same structure as in Example 1, and the water contact angle on the gloss side measured in the same manner as in Example 1 was 47 degrees and BSA. Adsorption amount is 1.6 mg / g, water flux is 9.79 × 10 ^-4 m
³ · m ⁻² · s ⁻¹ · MPa ⁻¹ , BSA blocking rate was 90%.

(Preparation of Filtration Unit and Collection Test of Measurement Sample) A filtration unit was prepared in the same manner as in Example 1 except that the filtration membrane 3 was used, and a collection test of a measurement sample from circulating blood was carried out in the same manner. went. The circulating hemofiltration flux was 0.60 ml / min at the start of measurement and 0.56 ml / min 4 hours after the start of measurement. The albumin inhibition rate during this use test was 99.1%. The obtained filtrate could be used as a sample for measuring sodium ion concentration, potassium ion concentration, and BUN concentration without any problem.

Example 4 (Preparation of Polymerizable Solution 4 and Preparation of Filter Membrane 4) Caprolactone Modified Tris (acryloyl-t-oxyethyl) isocyanate [Aronix M
-325, manufactured by Toagosei Co., Ltd.] 2.0 parts, as a hydrophilic group-containing monomer, sodium sulfonic acid sulfonate [Antox-MS-2N, manufactured by Nippon Emulsifier Co., Ltd.] 1.
1 part, 18 parts of cellulose acetate [Kanto Chemical Co., Inc.] as a solvent-soluble polymer (D), 9 parts of DMAC as a solvent
0 parts, Irgacure-1842 as an ultraviolet polymerization initiator
The parts were mixed to obtain a polymerizable solution 4. In the same manner as in Example 1 except that the polymerizable solution 4 was used, a blood low molecular weight substance concentration measuring filtration membrane 4 of the present invention was obtained.

(Evaluation of Characteristics of Filtration Membrane 4) The obtained filtration membrane 4 had the same structure as that of Example 1, and the water contact angle on the gloss side measured in the same manner as in Example 1 was 46 degrees and BSA. The adsorption amount is 2.5 mg / g, and the water flux of the porous membrane 4 is 2.8.
It was 3 × 10 ⁻⁴ m ³ · m ⁻² · s ⁻¹ · MPa ⁻¹ and the BSA blocking rate was 99%.

(Preparation of Filtration Unit and Collection Test of Measurement Sample) A filtration unit was prepared in the same manner as in Example 1 except that the porous membrane 4 was used, and a collection test of a measurement sample from circulating blood was carried out in the same manner. I went. The circulating hemofiltration flux was 0.33 ml / min at the start of measurement and was 0.31 ml / min 4 hours after the start of measurement. The albumin inhibition rate during this use test was 99.99% or more. The obtained filtrate could be used as a sample for measuring sodium ion concentration, potassium ion concentration, and BUN concentration without any problem.

Comparative Example 1 In this comparative example, an example of a polysulfone porous membrane will be described. (Evaluation of characteristics of filtration membrane) As a filtration membrane, polysulfone ultrafiltration membrane UK-50 manufactured by Toyo Roshi Kaisha, Ltd. was used. As a result of observing this film with a scanning electron microscope (SEM), no pores were observed on the glossy side, and a structure considered to be a nonwoven fabric was seen on the non-glossy side. In the observation of the cross section, the portion with a small pore size was only the surface layer on the gloss side, and the thickness was 1 μm or less. In the cross section, the presence of so-called macropores having a pore diameter of 10 to 100 µm was recognized.

Using this film, measurement was carried out in the same manner as in Example 1.
The contact angle with water on the glossy side was 69 degrees, and the amount of BSA adsorbed was 1
7 mg / g, water flux is 8.5 × 10^-Fourm^Three・ M^{ー 2}
・ S ^-1・ MPa^-1 , BSA inhibition rate was 98%.

(Preparation of filtration unit and test for collecting measurement sample) A filtration unit was prepared in the same manner as in Example 1 except that the above polysulfone ultrafiltration membrane UK-50 was used instead of the filtration membrane 1. Then, a test for collecting a measurement sample from the circulating blood was conducted. Circulating hemofiltration flux is
It was 0.48 ml / min at the start of the measurement, but it decreased to 0.26 ml / min 4 hours after the start. From this, it can be seen that when the low molecular weight substance measurement sample is collected from blood by filtration, the flux of the measurement sample is reduced to about 54% of the initial value 4 hours after the start of filtration.

[0055]

EFFECTS OF THE INVENTION The filtration membrane of the present invention is excellent in handleability because the flux is almost constant during the artificial dialysis time, and it is not necessary to allow a sufficient membrane area in anticipation of reduction of the flux. The size can be reduced, the priming volume can be reduced, the handleability can be improved, and the cost of the filtration unit can be reduced.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location B01D 71/82 B01D 71/82 G01N 33/84 G01N 33/84 (72) Inventor Sachi Miyajima Chiba Prefecture 3-36-6 Goihigashi, Ichihara City (72) Inventor Takanori Anasawa 4-35-4 Osakidai, Sakura City, Chiba Prefecture

Claims (11)

[Claims] 1. A water flux of 1.0 × 10 ^{−4 to} 3.
0 × 10 ^-3 m ³ · m ^{over 2} · s ^-1 · MPa ^-1, albumin blocking rate of 90% or more, and the water contact angle on the side in contact with blood is a porous membrane of 60 degrees or less A characteristic filtration membrane for measuring low-molecular weight substances in blood. 2. The filtration membrane for measuring low molecular weight substances in blood according to claim 1, wherein the water contact angle of the porous membrane on the side in contact with blood is 40 to 55 degrees. 3. The porous membrane comprises a nonionic hydrophilic group and / or
The filtration membrane for measuring the concentration of a low molecular weight substance in blood according to claim 1 or 2, which is a porous membrane composed of a polymer containing an anionic hydrophilic group as a covalent bond as an essential component. 4. The porous membrane comprises a nonionic hydrophilic group and / or
The filtration membrane for measuring low molecular weight substances in blood according to claim 1 or 2, which is a porous membrane composed of a polymer alloy containing 10 to 40% by weight of a polymer containing an anionic hydrophilic group as a covalent bond. 5. A polymer containing a nonionic hydrophilic group and / or an anionic hydrophilic group as a covalent bond is (meth).
The filtration membrane for measuring the concentration of low molecular weight substances in blood according to claim 3 or 4, which is a polymer of a monomer and / or an oligomer whose main component is an acrylate ester. 6. The nonionic hydrophilic group and / or the anionic hydrophilic group is one or more hydrophilic groups selected from the group consisting of polyethylene glycol groups having a repeating number of 4 or more, N, N-dimethylamide groups and sulfone groups. The filtration membrane for measuring a low molecular weight substance concentration in blood according to claim 3, 4 or 5. 7. The filtration membrane for measuring the concentration of low molecular weight substances in blood according to claim 1, wherein the porous membrane is a flat membrane. 8. A blood inflow port, a blood flow path for allowing extracorporeal circulation blood to flow in contact with the porous membrane, and a blood outflow port are provided on one side of the porous membrane, and the other side of the porous membrane is provided. A filtration unit for measuring the concentration of low-molecular-weight substances in blood, which is provided with an outlet for a sample for measuring the concentration of low-molecular-weight substances in blood, which is integrated with a membrane, wherein the porous membrane is a porous membrane. 1 to
7. A filtration unit for measuring the concentration of low-molecular substances in blood, which is the filtration membrane for measuring the concentration of low-molecular substances in blood according to any one of 7. 9. The filtration unit for measuring the concentration of low molecular weight substances in blood according to claim 8, wherein the effective membrane area of the filtration membrane for measuring the concentration of low molecular weight substances in blood is 5 × 10 ^{−4 to} 100 × 10 ⁻⁴ m ^2. . 10. The cross-sectional area of the blood channel is 1.0 × 1.
0^-6~ 4.0 x 10 ^-Fivem^Two 10. The method according to claim 8 or 9,
Filtration unit for measuring low molecular weight substances in blood. 11. The blood channel has a spiral shape extending from the peripheral portion to the central portion of the planar porous membrane.
Alternatively, the filtration unit for measuring the concentration of low-molecular substances in blood according to 10.