JP3130081B2 - Permeable membrane with excellent biocompatibility - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a permeable membrane. More specifically, the present invention relates to a permeable membrane having excellent biocompatibility and high safety.

[0002]

2. Description of the Related Art In recent years, hemodialysis is a typical example in which application of a permeable membrane plays an important role in the medical field. A kidney disease patient who has lost renal function removes metabolites and excess water that should be excreted by the kidney by hemodialysis, maintains a constant electrolyte concentration in body fluids, and maintains an acid-base balance. Therefore, hemodialysis is currently synonymous with artificial kidney, but it is not limited to it, it is also used to remove drugs from the blood of patients who are drug-addicted by sleeping pills and pesticides, and to remove hepatotoxin as an artificial liver. Has become an important technology.

Hitherto, cellulose membranes such as regenerated cellulose membranes and cellulose acetate membranes have been widely used for such hemodialysis. These cellulosic membranes
Although it has excellent clearance of low molecular weight substances, it cannot be said that the clearance of medium and high molecular weight substances is sufficient, and immunological abnormalities such as complement activity and transient leukopenia may occur. In addition, blood coagulation occurs upon contact with blood, and a large amount of anticoagulant is required to prevent this.

Further, for the purpose of eliminating these drawbacks of the cellulose-based membrane, a permeable membrane made of various synthetic polymers, for example, a hydrophilic membrane such as polyvinyl alcohol, polyacrylonitrile, polysulfone, polymethyl methacrylate, polyamide, etc. And those composed of hydrophobic polymers have been proposed and developed.

[0005] Permeation membranes made of these synthetic polymers are often superior to cellulose-based ones in terms of permeability, but those made of hydrophilic polymers have sufficient mechanical strength. In addition, those made of hydrophobic polymers have the complexity of requiring a hydrophilic treatment at the time of use, and none of them are sufficient from the viewpoint of biocompatibility. Was.

Further, copolymers having a hydrophilic segment and a hydrophobic segment, such as acrylonitrile-sodium methacrylsulfonate copolymer, polycarbonate-polyether block copolymer, ethylene-vinyl alcohol copolymer, and the like (for example, Chemical special issue 84
Biomedical Polymer Chemical Dojinsha, No. 142-1
45 pages, Membrane Application Technology Handbook Koshobo, 663-
See page 713, JP-A-59-193102, and the like. ) Has also been developed. A permeable membrane made of a copolymer having these hydrophilic segments and hydrophobic segments generally has considerably excellent properties even in its biocompatibility, but it cannot be said that it is still sufficient. In addition, there remains room for improvement in aspects such as safety, thermal stability, and mechanical strength, and in properties such as water permeability and substance permeability, which are essentially required as blood permeable membranes.

[0007]

Accordingly, an object of the present invention is to provide a novel permeable membrane. Another object of the present invention is to provide a permeable membrane having excellent biocompatibility and high safety.

[0008]

The above objects are achieved by the following structural formulas (1), (2), (3) or (4).

[0009]

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[0010]

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[0011]

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[0012]

Embedded image (However, R ¹ , R ² , and R ³ each represent a linear or branched alkylene group having 2 to 4 carbon atoms, and R ⁴ , R ⁵ , and R ⁶ each represent an aliphatic, alicyclic, or Represents an aromatic hydrocarbon group, and n is 0 to 180, and m is 1 to 400.)
Having a molecular weight of 10,000 to 100,00 and having a hydrocarbon group having 1 to 22 carbon atoms at its terminal.
A polyether amide having a number of hydrocarbon groups of 5 to 100% of the total number of terminal groups of the polyether amide after melt-casting and then swelling with respect to the polyether amide. Swelling or partially dissolving the membrane by contacting it with a medium exhibiting solubility, and furthermore by a biocompatible permeable membrane obtained by contacting the polyetheramide with a non-solvent-based solution. Achieved.

The present invention also provides a permeable membrane wherein the medium exhibiting swelling or solubility with respect to the polyetheramide is mainly composed of a poor solvent for the polyetheramide. The present invention further provides a permeable membrane in which the solution mainly composed of a non-solvent for the polyetheramide is mainly composed of water. In the present invention, the medium exhibiting swelling or solubility with respect to the polyetheramide is preferably a dimethylsulfoxide / dimethylformamide mixed solution having a weight ratio of 30 to 0:70 to 100 or a weight ratio of 30 to 0:70 to 100. 1 shows a permeable membrane that is dimethyl sulfoxide / N-methylpyrrolidone.

[0014]

Hereinafter, the present invention will be described in more detail based on embodiments.

The permeable membrane of the present invention has the following structural formula (1):
A polyether amide comprising a structural unit represented by (2), (3) or (4) and having a hydrocarbon group having 1 to 22 carbon atoms at a terminal and having a molecular weight of 10,000 to 100,000; The matrix is a terminal-modified polyamide whose number of groups is 5 to 100% of the total number of terminal groups of the polyether amide.

[0016]

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[0017]

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[0018]

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[0019]

Embedded image In the above general formulas (1) to (4), R ¹ , R ² , and R ³ are each a linear or branched alkylene group having 2 to 4 carbon atoms such as an ethylene group, a trimethylene group, and a tetramethylene group. And n is an integer of 0 to 180, preferably 0 to 60.

In the above general formulas (1) to (4), R ⁴ is an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36 carbon atoms, preferably 2 to 11 carbon atoms. Is the residue of a lactam or aminocarboxylic acid. R ⁵ is an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36, preferably 2 to 7 carbon atoms, and is a residue of a diamine described later. R ⁶ is an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36, preferably 2 to 11 carbon atoms, and is a residue of a dicarboxylic acid described later. M is 1
To 400, preferably an integer of 1 to 120.

Formulas (1) to (1) used in the present invention
In the polyether amide having the structural unit represented by (4), the content of the polyether segment is 5 to 5.
75% by weight, preferably 15-55% by weight, is preferred in that it provides good biocompatibility in the resulting product and provides a balance between mechanical strength and flexibility.

The terminal-modified polyether amide resin used in the present invention is represented by the general formula (1)
A polyether amide having a constitutional unit represented by (4) is obtained by introducing a fixed ratio of hydrocarbon groups to the terminal and modifying the terminal.

The hydrocarbon group (terminal hydrocarbon group) introduced as a terminal group into the polyether amide as a terminal group or a terminal group thereof has 1 to 22 carbon atoms, preferably 6 to 22 carbon atoms.
More preferably those of 12 to 22, specifically,
For example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 2-
Aliphatic carbonization such as ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, tetradecylene, pentadecyl, hexadecyl, heptadecyl, octadecyl, octadecylene, eicosyl, docosyl Examples thereof include an alicyclic hydrocarbon group such as a hydrogen group, a cyclohexyl group, a methylcyclohexyl group, and a cyclohexylmethyl group, and an aromatic hydrocarbon group such as a phenyl group, a toluyl group, a benzyl group, and a β-phenylethyl group. Among these, an aliphatic hydrocarbon group, preferably a straight-chain alkyl group, and more preferably a long-chain alkyl group having 12 to 22 carbon atoms is desirable.

These terminal hydrocarbon groups are introduced by using a monocarboxylic acid and / or a monoamine described below during the production of the polyetheramide.

The terminal group of the polyetheramide having the above-mentioned structure used in the present invention includes, in addition to the terminal hydrocarbon group, an amino group and / or a carboxyl group derived from a raw material for producing a polyetheramide described below. Although there are groups, the number of all terminal groups is the above-mentioned terminal hydrocarbon group,
It is the sum of the number of amino groups and / or carboxyl groups. In the terminal-modified polyetheramide used in the permeable membrane of the present invention, the number of the terminal hydrocarbon groups is 5 to 100%, preferably 10 to 95% of the total number of the terminal groups.
%, More preferably 10 to 90%. That is,
When the number of terminal hydrocarbon groups is less than 5% of the total number of terminal groups, the thermal stability of the polyether amide decreases, and the polymer is melt-polymerized, melt-formed or heat-sterilized. For example, there is a possibility that generation of a low-molecular odor substance or a low-molecular compound may be observed.

From the viewpoint of such thermal stability, it is desired that the number of hydrocarbon groups be close to 100% of the total number of terminal groups. For this reason, it is desired that the degree of introduction be suppressed to some extent as described above.

The average molecular weight Mn of the terminal-modified polyether amide used in the present invention is from 10,000 to
100,000, more preferably 15,000 to 50,
It is about 000.

Further, the terminal-modified polyether amide used in the present invention may contain, if necessary, a crystal nucleating agent, a plasticizer, a heat-resistant agent, an antioxidant, and other polymers. .

The polyetheramide having the structural units represented by the general formulas (1) to (4) and having a terminal modified with a hydrocarbon group is, for example, a polyether having a terminal amino group or a carboxyl group. And a polyamide having a carboxyl group or an amino group at the end thereof by a condensation reaction in accordance with a conventional method to form an amide bond, the amino group and the carboxyl group which are the terminal groups of the polyetheramide are monocarboxylic acid and / or a terminal modifier. It can be prepared by reacting a monoamine. The monocarboxylic acid and / or monoamine used for the terminal modification can be added at any stage from the start of the condensation reaction to the start of the reaction under reduced pressure. When a monocarboxylic acid and a monoamine are used in combination, they may be added simultaneously or separately.

The polyether having an amino group or a carboxyl group at the terminal can be obtained, for example, by subjecting an alkylene oxide such as ethylene oxide or propylene oxide or a ring-opening polymerization of tetrahydrofuran to a polyether such as polyethylene oxide, polypropylene oxide or polytetramethylene oxide. It is easily obtained by obtaining an ether and substituting the terminal hydroxyl group with an amino group and / or a carboxyl group. Examples of the amino group substitution method include direct amination or cyanoethylation of a hydroxyl group followed by reductive amination, and the carboxyl group substitution method includes a method by carbonyl oxidation.

The polyamide having a terminal carboxyl group and an amino group can be directly obtained by ring-opening polymerization of a lactam having three or more members, polycondensation of a polymerizable aminocarboxylic acid or polycondensation of a dicarboxylic acid and a diamine. .

Further, as the monocarboxylic acid used for the terminal modification, a monocarboxylic acid having about 2 to 23 carbon atoms is usually used, and specific examples thereof include acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, and enanthate. Acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid,
Tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, stearic acid, arachinic acid, behenic acid, myristoleic acid, oleic acid, aliphatic monocarboxylic acids such as linoleic acid, cyclohexanecarboxylic acid, methylcyclohexanecarboxylic acid, methylcyclohexane Examples thereof include alicyclic monocarboxylic acids such as carboxylic acids, and aromatic monocarboxylic acids such as benzoic acid, toluic acid, ethylbenzoic acid, and phenylacetic acid. In the reaction, corresponding derivatives capable of playing the same role as the above-mentioned acids, for example, acid anhydrides, esters, amides and the like can also be used.

On the other hand, as the monoamine, various monoamines having about 1 to 22 carbon atoms are usually used, and specifically, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine , 2-ethylhexylamine, nonylamine, decylamine, undecylamine,
Of aliphatic monoamines such as dodecylamine, tridecylamine, tetradecylamine, pentadecylamine, hexadecylamine, heptadecylamine, octadecylamine, eicosylamine, docosylamine, octadecyleneamine, cyclohexylamine, methylcyclohexylamine Such as alicyclic monoamine, benzylamine, and aromatic monoamine such as β-phenylethylamine.

In order to obtain the permeable membrane of the present invention, first, a polyetheramide having the structural units represented by the general formulas (1) to (4) and having a terminal modified with a hydrocarbon group is used. It is melted, discharged into a desired shape such as a film shape or a hollow fiber shape from a T-die or an annular die, cooled, and formed into a film. At the time when the film is formed in this way, the film is a dense film and does not have a desired substance permeability.

Next, the polyetheramide formed as described above is brought into contact with a medium exhibiting swelling or solubility properties to swell or partially dissolve the film.

Examples of the medium exhibiting swelling or solubility for the polyetheramide include lower alcohols such as phosphoric acid, formic acid, trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid, hexafluoroisopropanol, methanol and butanol. N-methylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, phenol, 1,3-dimethyl-2-
One or a mixture of two or more solvents such as imidazolidinone, or a mixture of these with a metal salt such as calcium chloride, zinc chloride, lithium chloride, sodium carbonate, copper sulfate, and the like. For example, those obtained by adding a small amount of a non-solvent such as water, glycols, and glycerin are used. However, the medium having a swelling or solubility property with respect to the polyetheramide has such a high solubility that the membrane is completely dissolved in a short time when it is brought into contact with a melt-formed film. It is not so preferable to use such a material because it becomes difficult to control the swelling or partial dissolution of the membrane to develop the material permeability. Rather, a material that is generally called a poor solvent is desirable. Therefore, for example, when formic acid having high solubility is used, it may be used by diluting it to 90% by weight or less, more preferably 50 to 80% by weight with a non-solvent such as water to reduce the solubility. desirable. In addition, as a medium showing swelling or dissolving properties with respect to such polyetheramide, particularly, a weight ratio of 30 to 0:70 is preferable.
A dimethylsulfoxide / dimethylformamide mixture of １００100 or a dimethylsulfoxide / N-methylpyrrolidone mixture with a weight ratio of 30-0: 70-100 is preferred.

As a method of contacting a melt-formed film with such a medium, contact in a gas phase is also possible, but it is usually carried out by immersion treatment. In addition, the contact conditions cannot be specified unconditionally because they are influenced by the degree of swelling or solubility of the medium used, or the shape and thickness of the film, but for example, dimethyl sulfone having the above mixing ratio as the medium is used. In the case of using an oxide / dimethylformamide mixed solution or a dimethylsulfoxide / N-methylpyrrolidone mixed solution having a weight ratio of 30 to 0:70 to 100, it is preferable to soak at 20 to 150 ° C. for about 10 to 60 minutes.

After contacting the thus formed film with a medium having a swelling or solubility property with respect to polyetheramide, the film is further contacted with a solution mainly composed of a non-solvent for polyetheramide. Then, the medium remaining on the film surface and / or in the film is removed to obtain a film having a desired substance permeability. Non-solvents for the polyetheramide include, for example, water, glycols, glycerin and the like, and a solution used for removing the medium remaining on the membrane surface and / or in the membrane includes any of these non-solvents. Or a mixture of two or more thereof, or a mixture thereof to which a metal salt such as calcium chloride, zinc chloride, lithium chloride, sodium carbonate, or copper sulfate is added. Of these, a solution mainly composed of water is preferable. It is. The method of contacting the membrane with a solution mainly containing a non-solvent for polyetheramide may be performed by immersion, or by arranging the membrane in a flowing solution. Or by spraying the solution.

The thus obtained permeable membrane of the present invention has a large number of fine communication holes extending from the film surface to the film back surface. Although a clear mechanism showing biocompatibility such as excellent antithrombotic properties of the permeable membrane of the present invention is not clear,
Presumably, since the matrix is composed of polyetheramide having structural units represented by general formulas (1) to (4), a microphase-separated structure composed of a hydrophobic polyamide segment and a hydrophilic polyether segment is formed. It is considered that this microphase-separated structure is formed and exhibits good antithrombotic properties. Furthermore, the general formula (1)
The fact that the polyether amide having the structural unit represented by (4) is terminally modified and stabilized, and also from the viewpoint of suppressing the generation of low molecular weight substances or structural aspects,
It is thought to contribute to antithrombotic properties.

That is, what is important in the present invention is that
The surface (blood contact surface) of the polyetheramide layer is to be spherulite (spherical crystal). Thereby, excellent antithrombotic properties are exhibited.

Here, the spherulite refers to a form of a polymer in which fibrils are grown around a nucleus and crystallized into a single sphere, and are observed by a scanning electron microscope (SEM).
It appears as a hemispherical or similar shaped protrusion.

Although the principle of obtaining excellent antithrombotic properties by using a spherulite is not clear, it is because the arrangement of the crystal part and the non-crystal part is adjusted and the micro phase separation structure is clarified. Presumed.

The characteristics of the permeable membrane of the present invention are not particularly limited, but typically, the water permeability is 1.0 to 40.
0 ml / m ² · hr · mmHg, preferably 1.5 to 1
00 ml / m ² · hr · mmHg, permeability of urea (molecular weight 60) as a low molecular weight substance is 2.50 × 10 ⁻⁵ cm
² / min or more, preferably 2.70 × 10 ⁻⁵ cm ² /
min or more.

[0044]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1 A polyamide obtained by polycondensation of hexamethylenediamine and sebacic acid and bis (3-amidopropyl) polytetrahydrofuran are subjected to a condensation reaction to form an amide bond.
Furthermore, polyetheramide (Mn: about 20600, polyether content: 44% by weight, terminal modification rate: 31%) obtained by modifying the terminal with stearylamine is supplied to an extruder equipped with a T-die and melt-kneaded. It was extruded from a T-die, introduced into water and cooled to form a film. The conditions for the extrusion molding were as follows: a melting temperature of 230 to 240 ° C., T
Die temperature 240 ° C, screw rotation speed 52.0 rpm
m, and the number of rotation of the cooling roll was 2.5 m / min.

The film thus obtained (film thickness 80 μm)
m) in a 10/90 by weight dimethylsulfoxide / dimethylformamide mixture maintained at 100 ° C.
The immersion treatment was performed for minutes. Thereafter, the sample was further immersed in a water bath maintained at 20 ° C. to obtain a sample.

The surface of the obtained film was scanned with a scanning electron microscope (S
When observed by EM), it had a spherulite structure as shown in FIG.

The water permeability (measurement of water permeability 1) of the obtained membrane was 3.0 ml / m ² · hr · mmHg, and the urea permeability was 4.29 × 10 ⁻⁵ cm ² / min.

Further, a platelet dilatation test was performed by the method described below. Table 1 shows the results. Example 2 A sample was obtained in the same manner as in Example 1 except that a 5/95 weight ratio of dimethylsulfoxide / dimethylformamide was used instead of a 10/90 weight ratio of dimethylsulfoxide / dimethylformamide mixed solution.

The water permeability of the obtained membrane (measurement of water permeability 1) was 16.1 ml / m ² · hr · mmHg, and the urea permeability was 5.92 × 10 ⁻⁵ cm ² / min.

Example 3 The procedure of Example 1 was repeated, except that a mixture of dimethylsulfoxide / N-methylpyrrolidone at a weight ratio of 20/80 was used instead of the dimethylsulfoxide / dimethylformamide mixture at a weight ratio of 10/90. A sample was obtained.

The water permeability (measurement 1 of water permeability) of the obtained membrane was 4.3 ml / m ² · hr · mmHg, and the urea permeability was 7.
It was 27 × 10 ⁻⁵ cm ² / min.

Example 4 Same as Example 3 except that a 10/90 weight ratio dimethylsulfoxide / N-methylpyrrolidone mixture was used instead of the 20/80 weight ratio dimethylsulfoxide / N-methylpyrrolidone mixture. To obtain a sample.

The water permeability (measurement of water permeability 1) of the obtained membrane was 7.9 ml / m ² · hr · mmHg, and the urea permeability was 1
It was 0.3 × 10 ⁻⁵ cm ² / min.

Example 5 Same as Example 3 except that a 5/95 weight ratio dimethylsulfoxide / N-methylpyrrolidone mixture was used instead of a 20/80 weight ratio dimethylsulfoxide / N-methylpyrrolidone mixture. To obtain a sample.

The water permeability (measurement of water permeability 1) of the obtained membrane was 1.8 ml / m ² · hr · mmHg, and the urea permeability was 3.
It was 48 × 10 ⁻⁵ cm ² / min.

Example 6 A block copolymer consisting of polypropylene oxide in the polyether portion and nylon 12 and dimer acid in the polyamide portion was melt-kneaded by an extruder equipped with a hollow fiber forming nozzle, extruded from the hollow fiber forming nozzle and into water. It was introduced, cooled and solidified. The obtained hollow fiber was placed in a treatment solution containing dimethylformamide as a main component and kept at 100 ° C. for 60 hours.
Soak for minutes. Thereafter, the fiber was further immersed in a water bath maintained at 20 ° C. to obtain a hollow fiber. The obtained hollow fiber has an inner diameter of 31.
The thickness was 0 μm and the film thickness was 24 μm. When the water permeability of the obtained hollow fiber was measured by the water permeability measurement 2 described below,
It was 7.0 ml / m ² · hr · mmHg.

Comparative Example 1 Film thickness 27 made of regenerated cellulose
The water permeability and urea permeability of a μm dialysis membrane (PT-150, manufactured by ENKA) were measured in the same manner as in Example 1 by the methods described later. The water permeability of the membrane was 3.0 ml / m ² ··· hr · mmHg, urea permeability is 2.
It was 70 × 10 ⁻⁵ cm ² / min.

Comparative Example 2 A platelet dilatation test was carried out in the same manner as in Example 1 using a commercially available polypropylene film (FOP # 60, manufactured by Nimura Chemical Co., Ltd.). Table 1 shows the results.

Comparative Example 3 Ethylene-vinyl alcohol copolymer (ethylene content 3
3 mol%, manufactured by Kuraray Co., Ltd.) was dissolved in dimethyl sulfoxide (DMSO) at 75 ° C. so as to have a concentration of 5% by weight, and the obtained dope solution was formed into a uniform thickness on a glass plate. It was cast and immediately vacuum dried at 75 ° C. to obtain a comparative sample. The membrane thus obtained was subjected to a platelet dilatation test in the same manner as in Example 1. Table 1 shows the results.

[0061]

[Table 1] As is clear from Table 1, in the permeable membrane of Example 1 according to the present invention, compared with the permeable membrane of Comparative Example 2 or 3,
Platelet adhesion is low overall, and especially in the activated state (type 2), which is extremely low, indicating that it has excellent antithrombotic properties.

The measuring method and test method of each characteristic value shown in the present specification are as follows.

Measurement of Water Permeability 1 A flat membrane punched to a diameter of 43 mm is set in a cell as shown in FIG. Then, using distilled water adjusted to 37 ± 1 ° C., in an atmosphere of 37 ± 1 ° C., 250 mmHg (variation rate 1
(Within 0%). After a steady waiting in this state for 30 minutes, the relationship between the amount of effluent distilled water and time is obtained, and the amount of water permeation is converted from this.

Measurement of Water Permeability 2 As shown in FIG. 3, the mini-module 16 was connected to the tubes 17 and 18 provided with the rotary pump 14, and pressure gauges 15a and 15b were attached near both ends. 37 ° C
A container 12 containing a physiological saline solution 13 whose temperature is controlled to ± 1 ° C. is immersed in a thermostatic bath 11, and a tube 1 is placed in the physiological saline solution 13.
7 while inserting one end of tube 18 into container 1
2 to form a circuit. Inlet flow rate 10ml / m
in, the physiological module was set to a pressure difference between mini-modules of 100 mmHg, and physiological saline was allowed to flow through the circuit. After waiting for steady state, the physiological saline outflow was placed in the container 19, and the relationship between the physiological saline amount and time was determined. Was converted.

Substance-permeable urea Distilled water and a concentration of 100 m
Using a cell in which a g / dl aqueous urea solution (each 50 ml) is in contact with each other via a membrane, the respective concentrations are determined at 30 minutes and 50 minutes while each liquid is stirred at a constant speed. From this concentration and the thickness of the flat film, the substance permeability is determined based on the following equation.

Material permeability P = P ′ · L (cm ² / mi)
n), where L = film thickness (cm)

[0067]

(Equation 1) C ₁ , C ₂ : solute concentration in each cell after t minutes V ₁ , V ₂ : solute volume t: measurement time The urease indophenol method was used for quantification of urea.

The procedure was the same as in the case of urea, except that the vitamin B ₁₂ solute was vitamin B ₁₂ , the solute concentration was 5 mg / dl, and the quantitative method was a direct absorbance measurement method at 360 nm.

Platelet dilatation ability test 3.8 w / v% sodium citrate was added to 1/9 volume, and blood was collected from human elbow vein. The obtained sodium-citrated blood is centrifuged at 800 rpm for 5 minutes to separate PRP (platelet-rich plasma). This PR
The number of platelets in P was measured using an eight-item blood test device (ELT-8,
Ortho Instruments). After the PRP is separated, it is further centrifuged at 3000 rpm for 10 minutes.
Collect PPP (platelet poor plasma). Was diluted to the PRP will be PPP, to adjust the number of platelets to 10 ⁵ / [mu] l.

A permeable membrane sample was cut into an 8 mm square, attached to an SEM sample table, and diluted P was adjusted for platelet count as described above.
200 μl of RP is dropped on the sample piece. Then, the PRP layer is pressed with a petri dish (made of polystyrene) from above so that the thickness of the PRP layer becomes 2 mm. Then, as it is at room temperature (25 ±
(2 ° C.) for 30 minutes. After that, the test piece was
1 M phosphate buffered saline, pH 7.0 (PBS) /3.8
Wash lightly with a w / v% sodium citrate mixture (weight ratio 9/1), and then glutaraldehyde 1 w / v% P
Fix overnight at 4 ° C. (2-8 ° C.) in BS solution. After the immobilized sample piece is washed with PBS, it is further washed with distilled water and freeze-dried. Then, after performing ion sputtering (12 kV, 8 minutes) on the sample piece, SE
Photographs are taken with M at 1000 times magnification in 5 fields of view. Then, from the obtained photograph, the morphological classification of the adhered platelets and the calculation of the number of adhered platelets are performed based on the following criteria.

Morphological Classification Type 1: Inactive sticking a: Normal disk shape. b: Spherical but not deformed to the point where pseudo feet are produced.

Type 2: Active Adhesion An object that has been stretched and adhered.

[0073]

As described above, the permeable membrane of the present invention comprises a structural unit represented by the structural formula (1), (2), (3) or (4), and has a terminal having 1 to 22 carbon atoms. A polyetheramide having a hydrocarbon group and a molecular weight of 10,000 to 100,000, wherein the number of the hydrocarbon groups is 5 to 100% of the total number of the terminal groups of the polyetheramide, After forming the film, the film is swelled or partially dissolved by contacting with a medium exhibiting swelling or solubility with respect to the polyetheramide, and further contacted with a solution mainly containing a nonsolvent for the polyetheramide. It has excellent biocompatibility, such as antithrombotic properties, and has sufficient water permeability and substance permeability, and has high thermal stability and a polymer production process, and melt film formation. Process There is a also a very small occurrence of adverse low molecular compounds due to heat sterilization, it is suitably used in applications hemodialysis or the like. Further, in the permeable membrane of the present invention, the medium exhibiting swelling or solubility with respect to the polyetheramide is mainly composed of a poor solvent with respect to the polyetheramide. Dimethyl sulfoxide / dimethylformamide mixed solution or weight ratio 30 to
0: 70-100 dimethylsulfoxide / N-methylpyrrolidone mixed solution, wherein the above-mentioned solution mainly composed of a non-solvent for polyetheramide is mainly composed of water, and the above-mentioned properties are more excellent. It will be.

[Brief description of the drawings]

FIG. 1 is a photograph (scanning electron microscope photograph (2000-fold magnification)) of a thin film obtained according to an example of the present invention.

FIG. 2 is a perspective view showing a configuration of an apparatus for measuring a water permeability (measurement 1 of water permeability).

FIG. 3 is a schematic diagram showing a configuration of an apparatus for measuring a water permeability (measurement of water permeability 2).

[Brief description of reference numerals]

1, 1 ': Permeability evaluation cell, 2: O-ring, 3: Flat membrane, 4: Supporting glass filter, 14: Rotary pump, 15a, 15b: Pressure gauge, 16: Mini module, 17, 18: Tube .

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Mitsuhide Nakagawa 1500 Inoguchi, Nakai-machi, Ashigara-gun, Kanagawa Prefecture Inside Terumo Corporation (56) References JP-A-5-123552 (JP, A) (58) Fields investigated ( Int.Cl. ⁷ , DB name) B01D 71/56

Claims (5)

(57) [Claims] 1. The following structural formula (1), (2), (3) or (4) Embedded image Embedded image Embedded image (However, R ¹ , R ² , and R ³ each represent a linear or branched alkylene group having 2 to 4 carbon atoms, and R ⁴ , R ⁵ , and R ⁶ each represent an aliphatic, alicyclic, or Represents an aromatic hydrocarbon group, and n is 0 to 180, and m is 1 to 400.)
Having a molecular weight of 10,000 to 100,00 and having a hydrocarbon group having 1 to 22 carbon atoms at its terminal.
A polyether amide having a number of hydrocarbon groups of 5 to 100% of the total number of terminal groups of the polyether amide after melt-casting and then swelling with respect to the polyether amide. A permeable membrane excellent in biocompatibility obtained by contacting with a medium exhibiting solubility, swelling or partially dissolving the membrane, and further contacting the polyetheramide with a solution mainly containing a non-solvent. 2. The permeable membrane according to claim 1, wherein the medium exhibiting swelling or solubility with respect to the polyetheramide is mainly composed of a poor solvent for the polyetheramide. 3. The polyetheramide-based solution mainly composed of a non-solvent is mainly composed of water.
Or the permeable membrane according to 2. 4. A medium exhibiting solubility in the polyether amide is a mixed solution of dimethyl sulfoxide / dimethylformamide having a weight ratio of 30 to 0: 70 to 100 or dimethyl sulfoxide having a weight ratio of 30 to 0: 70 to 100. Oxide /
The permeable membrane according to any one of claims 1 to 3, which is a mixture of N-methylpyrrolidone. 5. The permeable membrane according to claim 1, which exhibits excellent antithrombotic properties.