JP3236356B2 - 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 have excellent low molecular weight substance clearance, but medium and high molecular weight substance clearance is not sufficient, and complement activity and transient leukopenia etc. There is a great possibility that immunological abnormalities will occur, and 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, for example, acrylonitrile-sodium methacrylsulfonate copolymer, polycarbonate-polyether block copolymer, ethylene-vinyl alcohol copolymer and the like (for example, Chemical Special 84 Biomedical Polymer Chemical Dojinsha, 142nd-14th
5 pages, Membrane Application Technology Handbook Koshobo, 663-7
See page 13, JP-A-59-193102 and the like. )
A permeable membrane consisting of 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, mechanical strength, etc., and properties essentially required as a blood permeable membrane such as water permeability and substance permeability.

[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]

Means for Solving the Problems The above objects are to provide a polymer having a repeating structural unit represented by the following structural formula (1) or (2) and having an average molecular weight of about 10,000 to 100,000,
Equivalent number of terminal amino groups ([NH ₂ ] μeq / g) is 40
And the equivalent number of terminal carboxyl groups ([COOH]
[COOH] ≧ [NH ₂ ] +5 with respect to μeq / g), which is achieved by a permeable membrane excellent in biocompatibility characterized by comprising a poly (ether amide) resin.

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Embedded image ◎

Embedded image (Wherein, R ¹ , R ² and R ³ are linear or branched alkylene groups having 2 to 4 carbon atoms, and R ⁴ , R ⁵ and R ⁶ are linear or branched alkylene groups having 2 to 24 carbon atoms) Represents a group, n
Is 0 to 180, m is 1 to 400, and x represents an integer of 0 or 1.)

In the present invention, the solvent of the above-mentioned polyetheramide used in the wet film formation is phosphoric acid or formic acid, trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid, hexafluoroisopropanol, methanol, N-methylpyrrolidone, dimethylacetamide. , Dimethylformamide, dimethylsulfoxide, phenol, 1,3-
At least one of an organic solvent such as dimethyl-2-imidazolidinone, and water and / or a metal salt in an amount of less than 25% by weight based on the solvent. A permeable membrane which is obtained by adding water, glycols, glycerin, a mixture thereof, or a mixture thereof to a solvent and / or a metal salt as described above with a content of 5% by weight or more. is there. The present invention further provides a permeable membrane in which the solvent used in the wet film formation is formic acid and the coagulating liquid is a hydrous alcohol containing a metal salt. The invention further provides that the coagulation liquid is water / methanol / metal salt or water /
Methanol / dimethyl sulfoxide / metal salt,
In addition, it shows a permeable membrane using at least one selected from calcium chloride, zinc chloride and lithium chloride as a metal salt.

Further, the present invention is a permeable membrane having biocompatibility due to the polyetheramide having a spherulite structure.

[0012]

Hereinafter, the present invention will be described in more detail based on embodiments. The permeable membrane of the present invention has a repeating structural unit represented by the following structural formula (1) or (2), an average molecular weight of about 10,000 to 100,000, and an equivalent number of terminal amino groups ([NH ₂ ]). μeq / g) is 40 or less and the poly (ether amide) resin is in the range of [COOH] ≧ [NH ₂ ] +5 with respect to the equivalent number of terminal carboxyl groups ([COOH] μeq / g). Achieved by the characteristic biocompatible permeable membrane.

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Embedded image ◎

Embedded image (Wherein, R ¹ , R ² and R ³ are linear or branched alkylene groups having 2 to 4 carbon atoms, and R ⁴ , R ⁵ and R ⁶ are linear or branched alkylene groups having 2 to 24 carbon atoms) Represents a group, n
Is 0 to 180, m is 1 to 400, and x represents an integer of 0 or 1.)

The material constituting the medical permeable membrane of the present invention is as follows:
The main structural unit is a poly (ether amide) in which a polyether component and a polyamide component are linked. Poly (ether amide) can be easily obtained, for example, by subjecting a polyether having an amino group or a carboxyl group at both ends to a polyamide having a carboxyl group and / or an amino group at the end by an amide bond in a condensation reaction. it can. First, the raw material polyether will be described. Polyethers having an amino group or a carboxyl group at both terminals, for example, ethylene oxide, alkylene oxides such as propylene oxide or tetrahydrofuran ring-opening polymerization to obtain polyethylene oxide, polypropylene oxide, polyether such as polytetramethylene oxide, It can be easily obtained by substituting the terminal hydroxyl group with an amino group or a carboxyl group. Examples of the above-mentioned amino group substitution method include a method of direct amination or cyanoethylation of a hydroxyl group followed by reductive amination, and a method of carboxyl group substitution includes
A method by oxidative carbonylation may be mentioned.

Next, the raw material polyamide will be described. (1) Possessing carboxyl and amino groups at the end
Riamides The above polyamides can be obtained directly by ring-opening polycondensation of lactams of three or more members, polycondensation of polymerizable ω-amino acids or polycondensation of dicarboxylic acids and diamines.
As a specific example, for example, nylon 4, 6, 7, 8, 1
1, 12, 6.6, 6.9, 6.10, 6.11, 6.12,
6T, 6 / 6.6, 6/12, 6 / 6T and the like.

(2) Polyester having carboxyl groups at both ends
Polyamide having amides at both ends and amides of the above-mentioned polyamides, polyamides having carboxyl groups at both ends are obtained by adding a dicarboxylic acid to a basic polyamide by ring-opening polycondensation of a lactam. The base polyamide is obtained by adding a diamine to the base polyamide. In the case of a polyamide obtained by polycondensation of a dicarboxylic acid and a diamine, by using any of the raw materials in a stoichiometric amount or more, it can be directly obtained as a polyamide having carboxyl groups at both terminals or a polyamide having amino groups at both terminals. Can be.

The poly (ether amide) constituting the main constituent unit of the medical permeable membrane of the present invention is preferably a polyether having an amino or carboxyl group at the terminal and a carboxyl or amino group at the terminal. Is obtained by condensation with a polyamide having the following structural formula (1) (wherein R ¹ , R ² and R ³ are straight-chains having 2 to 4 carbon atoms) Or a branched alkylene group,
R ^4, R ⁵ and R ⁶ represents a linear or branched alkylene group having 2 to 24 carbon atoms, n represents 0 to 180, m is from 1 to 40
0 and x represent an integer of 0 or 1, or the following structural formula (2) (wherein, R ¹ , R ² and R ^{3 each} have 2 to 2 carbon atoms)
4 linear or branched alkylene groups, R ⁴ , R ⁵ and R ⁶
Represents a linear or branched alkylene group having 2 to 24 carbon atoms, n is from 0 to 180, m is from 1 to 400, and x is an integer of 0 or 1).

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Embedded image

Embedded image

The above structural formula (1) is a repeating structural unit obtained by condensing a polyether having amino groups at both ends and a polyamide having carboxyl groups at both ends. Is a repeating structural unit obtained by condensing a polyether of the formula (I) with a polyamide having amino groups at both terminals.

The ratio of the polyether unit and the polyamide unit constituting the poly (ether amide) can be arbitrarily selected from a wide range, but from the viewpoint of the balance between mechanical strength and flexibility, the ratio of the polyether unit is 1 To 75% by weight, preferably 10 to 50% by weight.

In the above structural formulas (1) and (2), the combination of the carbon number of the alkylene group of the polyether structural unit and the polyamide structural unit is not particularly limited. Combinations that provide a microphase-separated structure are preferred, which result in higher antithrombotic properties. Examples of such a combination include a combination in which R ³ is an octamethylene group and R ⁴ is a hexamethylene group.

The materials constituting the medical permeable membrane of the present invention are as follows:
For example, it can be obtained by using the above-mentioned poly (ether amide) to carry out carboxyl modification of the terminal amino group with dicarboxylic acid. As the dicarboxylic acid for terminal modification, the above-mentioned various dicarboxylic acids having 2 to 24 carbon atoms are suitably used as a kind of a raw material for polyamide. In particular, when the raw material polyamide of poly (ether amide) is a polyamide derived from dicarboxylic acid, it is preferable to use the same dicarboxylic acid as the dicarboxylic acid. Specific examples of the dicarboxylic acid include malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanoic acid, dodecandionic acid, tridecadionic acid, tetradecadionic acid, and hexadecane. Acid, hexadecenedionic acid, octadecadionic acid, eicosandioic acid, eicosenedioic acid, eicosadienedioic acid, docosandioic acid, 2,
Aliphatic dicarboxylic acids such as 2,4-trimethyladipic acid, alicyclic dicarboxylic acids such as 1,4-cyclohexanedicarboxylic acid, aromatic dicarboxylic acids such as terephthalic acid, isophthalic acid, phthalic acid and xylylenedicarboxylic acid Acids and the like.

The above-mentioned terminal-modified poly (ether amide) can be produced by a known condensation reaction. First, a target polyamide is obtained from a polyamide raw material,
Next, the above-mentioned polyether whose terminal group has been appropriately modified is added thereto to carry out a condensation reaction. The dicarboxylic acid for terminal modification of poly (ether amide) can be added at any stage from the start of the condensation reaction to the start of the reaction under reduced pressure. Further, in addition to the above-mentioned production method, in the condensation reaction, use of a polyamide or polyether having amino groups at both ends with respect to a polyamide or polyether having both ends with a carbonyl group (compound derived from an amino group) is used. By reducing the ratio, it can be produced without using a dicarboxylic acid for terminal modification.

The equivalent number of terminal amino groups of the poly (ether amide) according to the present invention (value per 1 g of resin, the same applies hereinafter) ([NH ₂ ] μeq / g) must be 40 or less. When the number of equivalents of the terminal amino group exceeds 40, it is not possible to sufficiently suppress the generation of reducing impurities during the condensation reaction performed in the molten state or during the melt molding. The equivalent number of terminal amino groups is preferably 30
Hereinafter, it is more preferably 20 or less. The equivalent number of amino groups, for amino groups, dissolve the resin in phenol,
It was calculated by titration with 0.05N hydrochloric acid. For the carboxyl group, the resin was dissolved in benzyl alcohol and 0.1N
It is a value calculated by titration with caustic soda.

The number average molecular weight of the poly (ether amide) according to the present invention ranges from about 10,000 to 100,000, preferably 15,000 to 50,000. The number average molecular weight is determined by calculating the total number of terminal group equivalents (total equivalent of amino group and carboxyl group μeq / g),
Is a value calculated by

◎

(Equation 1)

The number of equivalents of the terminal amino group of the poly (ether amide) according to the present invention is [COO] [eq.
H] ≧ [NH ₂ ] +5.
Poly (ether amide) which does not satisfy such conditions has a problem in processability such as melt molding. The preferred range of the number of equivalents of the terminal amino group to the number of equivalents of the terminal carboxyl group is [COOH] ≧ [NH ₂ ] +10.

The permeable membrane of the present invention is obtained by dissolving the above-described polyetheramide modified with a dicarboxylic acid in a good solvent, and casting the resulting polyetheramide solution on, for example, a substrate. To the desired shape, such as by contacting the non-solvent, or a coagulating liquid consisting of a poor solvent,
It is obtained by coagulation by extracting and removing a good solvent.

Examples of good solvents for the polyether amide include phosphoric acid, formic acid, trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid, hexafluoroisopropanol, methanol, N-methylpyrrolidone, dimethylacetamide, dimethylformamide, and dimethylsulfoform. Oxide, phenol, 1,3-dimethyl-2-imidazolidinone and the like are used, and among them, formic acid is preferable. In addition, those obtained by adding water and / or a metal salt in an amount of less than 25% by weight to these organic solvents can be used as a good solvent. In addition, as a metal salt, calcium chloride, zinc chloride, lithium chloride, sodium carbonate, copper sulfate and the like are used.

The concentration of the polymer in the solution obtained by dissolving the polyetheramide in such a good solvent is 5 to 35% by weight, preferably 10 to 30% by weight.
Degree.

On the other hand, as the non-solvent or poor solvent for the polyetheramide used as the coagulating liquid, for example, water, glycols, glycerin and a mixture thereof, or the content of the non-solvent or poor solvent is 5% by weight. % Or less, and the good solvent as described above is added to alleviate the coagulation action. Further, the content of these non-solvents or poor solvents is 5% by weight or more and the above-mentioned good solvent and calcium chloride, zinc chloride, Lithium chloride,
A mixture containing a metal salt such as sodium carbonate and copper sulfate is used. Of these, a mixed solution of water / methanol / metal salt and a mixed solution of water / methanol / dimethyl sulfoxide / metal salt are preferable. At least one selected from calcium chloride, zinc chloride and lithium chloride is used. The mixing ratio of each component in the case of a water / methanol / metal salt mixed solution is such that the weight ratio of water: methanol: metal salt (saturated solution) is 1 to 1.
It is desirable that the ratio be about 90: 5 to 70: 5 to 50.
In the case of a water / methanol / dimethylsulfoxide / metal salt mixture, the mixing ratio of each component is as follows: water: methanol: dimethylsulfoxide: metal salt (saturated solution) in a weight ratio of 1-90: 5-70. : 5 to 50: desirably about 5 to 50.

Further, the temperature of the coagulating liquid at the time of bringing the cast polymer dope into contact with such a coagulating liquid to coagulate it depends on the composition of the coagulating liquid.
Generally, it is desirable that the temperature is -10 to 100C, preferably 3 to 35C.

In addition, the permeable membrane of the present invention is obtained by casting the polyether amide using, for example, a hollow fiber forming nozzle or the like instead of casting it on a substrate to form a membrane. It can be used as a hollow fiber by extrusion molding in the middle or in the air.

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 the clear mechanism by which the permeable membrane of the present invention exhibits excellent biocompatibility such as excellent antithrombotic properties is not clear, it is supposed that the matrix is composed of structural units represented by the general formulas (1) and (2). Because it is composed of polyether amide, a microphase-separated structure consisting of a hydrophobic polyamide segment and a hydrophilic polyether segment is formed, and this microphase-separated structure exhibits good antithrombotic properties It is considered something. Furthermore, the fact that such polyetheramide is terminally modified and stabilized is also considered to contribute to antithrombotic properties from the aspect of suppressing the generation of low molecular weight substances or the structural aspect. .

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 means a form of a polymer in which fibrils are grown around a nucleus and crystallized into one 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.

Although the characteristics of the permeable membrane of the present invention are not particularly limited, typically, the water permeability is 1 to 600 ml.
/ M ² · hr · mmHg, preferably 4 to 400 ml / m ² · hr · mmHg,
The permeability of urea (molecular weight 60) as a low molecular weight substance is 1
00 × 10 ⁻⁴ cm / min or more, preferably 200 × 10 ⁻⁴ c
Vitamin B as m / min and medium molecular weight substance
₁₂ (molecular weight 1355) permeability of 20 × 10 ^-4 cm / min
As described above, it is preferably 30 × 10 ⁻⁴ cm / min or more.

[0039]

EXAMPLES The present invention will be described more specifically with reference to the following examples. (Examples 1 to 6) Table 1 in a 50-liter autoclave
Was charged with sebacic acid, a salt of nylon 610 and a polyether raw material, and water. The atmosphere was sealed under a N ₂ atmosphere, the temperature was raised to 240 ° C. under a constant pressure (10 KG), and the reaction was carried out for 4 hours with stirring. Thereafter, the pressure was gradually released to 10 mmHg, and the reaction was further performed for 2 hours. The stirring was stopped, N ₂ was introduced, and the pressure was restored to normal pressure. The results of analyzing the obtained pellets are shown in Table 3.

(Examples 7 and 8) Polyamide raw materials shown in Table 2 were charged into a 200-liter autoclave.
₂ Close in an atmosphere and seal at a constant pressure (10KG).
The temperature was raised to 0 ° C., and the reaction was carried out for 2 hours with stirring. Subsequently, the polyether raw materials and the terminal modifier (dicarboxylic acid) shown in Table 2 were added, and a pressure reaction was performed for 2 hours with stirring. Thereafter, the pressure was gradually released to a predetermined pressure, and the reaction was further performed for 2 hours. The stirring was stopped, N ₂ was introduced, and the pressure was restored to normal pressure. The results of analyzing the obtained pellets are shown in Table 3.

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[Table 1]

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[Table 2]

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[Table 3]

Example 9 311.7 of the block copolymer obtained in Example 1 (containing polyether = 4.2%)
g was dissolved in 1105.1 g of formic acid (99 w / v%) by heating to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 30 poise (P) and 30 ° C. This at 30 ° C for 2
It was left for a while for defoaming. This is cast on a substrate in a gas phase to a constant thickness and immediately EtOH / H ₂ O (weight ratio: 3/7)
The solidified phase was immersed in a solidified phase controlled at 5 ± 1 ° C. for 5 minutes to solidify, and then the formic acid and coagulating liquid remaining on the solidified film were removed with running water to obtain a sample. The resulting membrane is 44 μm wet.
m. Further, the obtained film was scanned with a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure. FIG. 1 shows a photograph of the film surface, and FIG. 2 shows a photograph of the cross section. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results. Further, a platelet dilatation ability test was performed by the method described below. Table 5 shows the results. Further, the obtained membrane was subjected to high-pressure steam sterilization at 121 ° C. for 20 minutes and a solute test was performed by the method described later. As a result, ΔpH = −0.57,
UV absorbance = 0.027.

Example 10 The block copolymer obtained in Example 2 (containing polyether = 10.2%) 60.
0 g was dissolved by heating in 212.7 g of formic acid (99 w / v%) to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 20 poise (P) and 30 ° C. This at 30 ° C for 2
It was left for a while for defoaming. This was cast in a gas phase onto a substrate to a constant thickness, and immediately cast into a solidified phase of CaCl ₂ / MeOH / H ₂ O (weight ratio 1/3/7), which was adjusted to 5 ± 1 ° C.
Then, the sample was immersed for 3 minutes to coagulate, and then the formic acid and coagulation liquid remaining on the coagulated film were removed with running water to obtain a sample. The resulting film was 24 μm wet. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results. Further, a platelet dilatation ability test was performed by the method described below. Table 5 shows the results
Shown in

Example 11 The solidification phase composition was changed to MeOH / H
_A film was formed in the same manner as in Example 10 except that ₂ O (weight ratio: 4/6) was used. The resulting film was 27 μm wet. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results.

Example 12 Block copolymer (polyether content = 9.7%) obtained in Example 3 54.0
g in 191.5 g of formic acid (99 w / v%),
A solution having a polymer concentration of 22% by weight was obtained. Solution viscosity is 1
The temperature was 7 poise (P) and 30 ° C. This was left at 30 ° C. for 2 hours to remove bubbles. This is cast on a substrate in a gas phase to a constant thickness and immediately immersed in a coagulation phase of EtOH / H ₂ O (weight ratio: 3/7) controlled at 5 ± 1 ° C. for 5 minutes to coagulate Subsequently, the formic acid and the coagulating liquid remaining on the coagulated film were removed with running water to obtain a sample. Example 1 except that the solidification phase composition was used.
A film was formed in the same manner as in No. 3. The resulting membrane is 38 wet.
μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results.

Example 13 The composition of the solidification phase was CaCl ₂ /
A film was formed in the same manner as in Example 12 except that MeOH / H ₂ O (weight ratio 1/3/10) was used. The resulting film was 24 μm wet. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results.

Example 14 Block copolymer (polyether content = 6.69%) obtained in Example 4 63.
3 g was heated and dissolved in 224.5 g of formic acid (99 w / v%) to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 88 poise (P), 30 ° C. This at 30 ° C for 2
It was left for a while for defoaming. This is cast to a constant thickness on the substrate in the gas phase and immediately MeOH / H ₂ O (weight ratio 3/7)
The solidified phase was immersed in a solidified phase controlled at 5 ± 1 ° C. for 5 minutes to solidify, and then the formic acid and coagulating liquid remaining on the solidified film were removed with running water to obtain a sample. The resulting film is 75 μm wet.
m. Further, the obtained film was scanned with a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results. Further, a platelet dilatation ability test was performed by the method described below. Table 5 shows the results.

Example 15 Block copolymer (polyether content = 12.0%) obtained in Example 5
0.0 g was heated and dissolved in 141.8 g of formic acid (99 w / v%) to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 36 poise (P), 30 ° C. This was left at 30 ° C. for 2 hours to remove bubbles. This was cast in a gas phase onto a substrate to a constant thickness, and immediately cast into a solidified phase of CaCl ₂ / MeOH / H ₂ O (weight ratio 1/3/7), which was adjusted to 5 ± 1 ° C. Then, the sample was immersed for 3 minutes to coagulate, and then the formic acid and coagulation liquid remaining on the coagulated film were removed with running water to obtain a sample. The resulting film was 58 μm wet. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results.

Example 16 Block copolymer (polyether content = 14.5%) obtained in Example 6
4.2 g was heated and dissolved in 227.6 g of formic acid (99 w / v%) to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 25 poise (P) and 30 ° C. This was left at 30 ° C. for 2 hours to remove bubbles. This was cast on a substrate in a gas phase to a constant thickness, and immediately cast into a solidified phase of CaCl ₂ / MeOH / H ₂ O (weight ratio 2/3/10), which was adjusted to 5 ± 1 ° C. Then, the sample was immersed for 3 minutes to coagulate, and then the formic acid and coagulation liquid remaining on the coagulated film were removed with running water to obtain a sample. The obtained film was 48 μm in a wet state. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, water permeability of the film obtained (Measurement of water permeability 1), urea, was investigated by the method described below permeability to vitamin B _12. Table 4 shows the results.

Comparative Example 1 A dialysis membrane (PT-150, manufactured by ENNKA) having a thickness of 27 μm made of regenerated cellulose was used in the same manner as in Example 9 to measure the water permeability (measurement of water permeability 1), urea and vitamin B _12. Was examined by the method described below. Table 4 shows the results.

Comparative Example 2 Using a commercially available polypropylene film (FOP # 60, manufactured by Nimura Chemical Co., Ltd.),
A platelet dilatation test was performed in the same manner as described above.
Table 5 shows the results.

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[Table 4]

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[Table 5]

Example 17 1410 g of the block copolymer (containing polyether = 4.2%) prepared in Example 1 was dissolved under heat in 5000 g of formic acid (99 W / V%), and a solution having a polymer concentration of 22% by weight was dissolved. Obtained. After removing foreign matter using a filter, the mixture was depressurized and allowed to stand (30 ° C.) and defoamed.
Using a hollow fiber forming nozzle, this was mixed with MeOH / H ₂ O
(Weight ratio: 3/7) was extruded into a coagulation phase composed of MeOH / H ₂ O (weight ratio: 6/4) as an internal liquid to coagulate, and then wound around a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 15.5 ° C. The obtained hollow fiber was immersed in a 60% by weight aqueous glycerin solution at room temperature for 10 minutes to maintain the pore diameter, and then dried in a 45 ° C. oven for 10 minutes. A mini-module made by bundling the ends of the hollow fiber with urethane resin and cutting the ends is 200 μm in inner diameter and 2 μm in thickness.
The water permeability (measurement of water permeability 2) was 80 ml / m ² · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ was 57 × 10 ⁻⁴ cm / min. Was.

Example 18 1410 g of the block copolymer obtained in Example 5 (containing polyether = 6.69%)
Was heated and dissolved in 5000 g of formic acid (99 W / V%) to obtain a solution having a polymer concentration of 22% by weight. After removing foreign matter using a filter, the mixture was depressurized and allowed to stand (30 ° C.) and defoamed. Using a hollow fiber forming nozzle, the MeOH / H ₂
MeOH / H ₂ O with O (weight ratio 2/8) as the internal liquid
After being extruded into a coagulation phase (weight ratio of 4/6) and coagulated, it was wound around a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 9.5 ° C. The obtained hollow fiber was 60% by weight to maintain the pore diameter, and 10% in a glycerin aqueous solution at room temperature.
After immersion for 10 minutes, drying was performed in a 45 ° C. oven for 10 minutes. The mini-module made by bundling the ends of the hollow fiber with urethane resin and cutting the ends has an inner diameter of 250 μm and a film thickness of 20 μm. The water permeability (measurement of water permeability 2) measured by the method described later is 75 ml / m2. ^{It was 2} · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ was 52.2 × 10 ⁻⁴ cm / min.

Example 19 1410 g of the block copolymer of Example 7 (polyether content = 24.0%)
Was heated and dissolved in 5000 g of formic acid (99 W / V%) to obtain a solution having a polymer concentration of 22% by weight. After removing foreign matter using a filter, the mixture was depressurized and allowed to stand (30 ° C.) and defoamed. Using a hollow fiber forming nozzle, the MeOH / H ₂
MeOH / H ₂ O with O (weight ratio 3/7) as the internal liquid
After being extruded into a coagulation phase (weight ratio of 4/6) and coagulated, it was wound around a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 13.5 ° C. The obtained hollow fiber was immersed in a 60% by weight aqueous glycerin solution at room temperature for 10 minutes to maintain the pore diameter, and then dried in a 45 ° C. oven for 10 minutes. The mini-module produced by bundling the ends of this hollow fiber with urethane resin and cutting the ends was 250 μm in inner diameter,
The film thickness was 45 μm, the water permeability (measurement of water permeability 2) measured by the method described later was 18 ml / m ² · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ was 28.2 × 10 ^-4 cm. / min. In addition, a rabbit extracorporeal circulation experiment was performed using the hollow fiber by the method described below, and the time change of the white blood cell count and platelets was determined. The results are shown in FIG. 3 (white blood cells) and FIG. 4 (platelets).

Example 20 1410 g of the block copolymer obtained in Example 8 (polyether content = 25.0%)
Was heated and dissolved in 5000 g of formic acid (99 W / V%) to obtain a solution having a polymer concentration of 22% by weight. After removing foreign matter using a filter, the mixture was depressurized and allowed to stand (30 ° C.) and defoamed. Using a hollow fiber forming nozzle, the MeOH / H ₂
MeOH / H ₂ O with O (weight ratio 3/7) as the internal liquid
After extruding into a coagulation phase (weight ratio of 5/5) for coagulation, it was wound around a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 15.5 ° C. The obtained hollow fiber was immersed in a 60% by weight aqueous glycerin solution at room temperature for 10 minutes to maintain the pore diameter, and then dried in a 45 ° C. oven for 10 minutes. The mini-module made by bundling the ends of this hollow fiber with urethane resin and cutting the ends is 220 μm in inner diameter,
The water permeability (measurement of water permeability 2) measured by the method described later is 18 ml / m ² · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ is 38.4 × 10 ^-4 cm. / min.

Comparative Example 3 A rabbit extracorporeal circulation experiment was performed on a hollow fiber for dialysis made of regenerated cellulose (CL-C, manufactured by Terumo Corporation) in the same manner as in Example 19, using the method described below. The time course of platelets was determined. Fig. 3 shows the results.
(White blood cells) and FIG. 4 (platelets).

(Comparative Example 4) A rabbit extracorporeal circulation experiment was performed on a hollow fiber for dialysis (KF101-15C, manufactured by Kuraray Co., Ltd.) composed of an ethylene-vinyl alcohol copolymer in the same manner as in Example 19 by the method described below, and leukocytes were obtained. The number and platelet change over time were determined. The results are shown in FIG. 3 (white blood cells) and FIG. 4 (platelets).

Example 21 Using the hollow fiber obtained in Example 19, the amount of C3a production was measured by the method described below. The results are shown in FIG. (Comparative Example 5) Hollow fiber for dialysis composed of regenerated cellulose (C
L-SS, manufactured by Terumo Corporation), and the amount of C3a production was measured in the same manner as in Example 21 by the method described below. The results are shown in FIG. (Comparative Example 6) The production amount of C3a was measured for a hollow fiber for dialysis (KF101-15C, manufactured by Kuraray Co., Ltd.) composed of an ethylene vinyl alcohol copolymer in the same manner as in Example 21 by the method described below. The results are shown in FIG.

The measuring method and the testing method of each characteristic value shown in the present specification are as follows. Intrinsic viscosity was determined at 1% concentration in m-cresol using an Ubbelohde viscosity tube (30 ° C.). Terminal group analysis Amino groups were dissolved in phenol and measured by titration with 0.05N hydrochloric acid. The carboxyl group was measured by dissolving in benzyl alcohol and titrating with 0.1N sodium hydroxide. Eluted substance test method Cut the membrane into a suitable size, put it in a container containing ion-exchanged water of 100 times the membrane weight, heat at the processing temperature and time of high-pressure steam sterilization, take out the liquid after cooling. Use as a test solution. (1) pH Take 20 ml each of the test solution and blank test solution, add 1.0 ml of a solution prepared by dissolving 1.0 g of potassium chloride in water to 1000 ml, measure the pH of both solutions, and determine the difference. (2) UV absorbance The maximum value of absorbance at a wavelength of 220 nm to 350 nm is determined using a blank test solution as a control.

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., under an atmosphere of 37 ± 1 ° C., 100 mmHg (variation rate 1
(Within 0%). After waiting for 30 minutes in this state, the relationship between the amount of distilled water discharged and the time is obtained, and the amount of water permeation is converted from this. Measurement of Water Permeability 2 As shown in FIG. 7, the mini-module 16 was connected to tubes 17 and 18 provided with a rotary pump 14, and pressure gauges 15a and 15b were attached near both ends. 37 ±
A container 12 containing a physiological saline solution 13 controlled at 1 ° C. is immersed in a thermostatic bath 11, and a tube 17 is placed in the physiological saline solution 13.
Of the tube 18, while connecting one end of the tube 18 to the container 12.
To form a circuit. Inlet flow rate 10ml / mi
n. After setting the pressure difference between the mini-modules to 100 mmHg, physiological saline was allowed to flow through the circuit, and after waiting for steady state, the outflowing physiological saline was placed in the container 19, and the relationship between the amount of physiological saline and time was determined to determine the membrane area. Converted. Material permeability (1) Urea Distilled water and concentration 100m through a flat membrane punched in a circle
g / dl aqueous solution of urea was contacted through the membrane, and each liquid was stirred at a constant speed for 3 hours.
The respective concentrations after 0 and 150 minutes are determined. From this concentration, the substance permeability is determined based on the following equation (2).
The urea was determined by the urease indophenol method. (2) Vitamin B ₁₂ Vitamin B ₁₂ solutes, except that the solute concentration of direct absorbance measurement method at 360nm the assay and 5 mg / dl was performed as in the case of urea. ◎

(Equation 2) (Where A is the membrane area (cm ² ) and ΔC (t) is the difference in solute concentration after t minutes of the cell.)

[0065] As shown in module solute permeability Figure 8, connecting the mini module 37 in a tube 33 provided with a rotary pump 32. 37
± 1 ° C. The vitamin B ₁₂ solution 35 of the temperature control with saline 36 and a concentration 5 mg / dl were immersed in a thermostatic bath 38, the tube 3
Put the tip of 3,34 vitamin B ₁₂ solution 35 to form a circuit by immersing the mini module 37 in saline 36. The circulating flow rate in the mini module is 100cm linear velocity
/ min. The solute permeability coefficient was calculated according to the following equation (3). The measurement was performed at time 0 and 120 minutes. ◎

(Equation 3) (In the formula, A membrane area, CB solute solution (blood side) concentration, CD saline (dialysate side) concentration, VB, VD is the volume, t denotes time.) Platelet diastolic function test 3. 8 w / v% sodium citrate is added to 1/9 volume, and blood is collected from human elbow vein. The obtained sodium citrate-containing blood is centrifuged at 800 rpm for 5 minutes to separate PRP (platelet-rich plasma). This P
The number of plasma plates in the RP was measured using a multi-item blood tester (Sysme
x NE-6000, manufactured by Toa Medical Electronics Co., Ltd.). After the PRP is separated, it is further centrifuged at 3000 rpm for 10 minutes to collect PPP (platelet poor plasma). Was diluted to the PRP will be PPP, the platelet count 10 ⁵ /
Adjust to μl. Cut the permeable membrane sample into 8 mm square, SE
Dilution PR attached to M sample stage and adjusted for platelets as described above
200 μl of P is dropped on the sample piece. Then, the PRP layer is suppressed with a petri dish (made of polystyrene) from above so that the thickness of the PRP layer becomes 2 mm. And it is left still at room temperature for 30 minutes. Thereafter, the test piece was gently washed with a mixture of 0.01 M phosphate buffered saline, pH 7.0 (PBS) /3.8 w / v% sodium citrate (weight ratio 9/1), and then 1 w / v of glutaraldehyde. 4 ° C in a% PBS solution
(2-8 ° C) and fix overnight. After the immobilized test piece is washed with PBS, it is further washed with distilled water and freeze-dried. Then, ion sputtering (1
(2KV, 6 minutes), and photograph in 5 fields of view. Based on the obtained photographs, the classification of adhered platelets and the number of adhered plates are calculated based on the following criteria. Morphological Classification I: Inactive sticky a: Normal disk shape b: Spherical but not deformed to the point where pseudofoot is put out II: Active sticky Sticky with pseudofoot stretched

Rabbit extracorporeal circulation experiment Preparation of Module for Extracorporeal Circulation Test FIG. 9 shows a module for extracorporeal circulation of the dialyzer and will be specifically described. The dialyzer 1 was prepared by inserting the hollow fiber bundle 2 into the cylindrical main body 3, fixing both ends with polyurethane potting agents 4, 5, and further fixing headers 6, 7 on both ends with caps 8, 9. In addition, in the figure, 10 is a dialysate inlet pipe, and 11 is an outlet pipe. The film area was 300 cm ² . 2. Extracorporeal circulation test The rabbit was fixed in a dorsal position on a Kitajima-type fixed base. Next, the hair on the operative field was cut with an electric hair clipper and wiped off with alcohol wool. An incision was made along the midline from the submandibular to the collarbone with scissors, and the right (left) common carotid artery was dissected, taking care not to damage the nerves, branch vessels and surrounding tissues by opening the peritoneum. Next, the left (right) facial vein was deeply peeled off with the same care, and a Surflow indwelling catheter manufactured by Terumo Corporation equipped with a rubber cap for co-infusion filled with 1 IU / ml of heparinized saline was inserted and ligated and fixed. Similarly, a catheter was inserted into the above artery and ligated and fixed. An experimental circuit was prepared for the four rabbits thus prepared using the dialyzer. That is, as shown in FIG. 10, the catheter 21 connected to the artery of the rabbit 20 was connected to the pump 22, and the chamber 23 was connected to the vein of the rabbit 20 by the catheter 25. Pump 22 and dialyzer 1 are connected to tube 2
6. The tube 26 is connected to the manometer in 27.
Communicating with the side. Further, the dialyzer 1 and the chamber 23 communicating with the out 24 side of the manometer were communicated by a tube 28. On the other hand, the dialysate inlet and outlet of the dialyzer 1 were connected by a tube 29, and a pump 30 was installed in the tube 29 and immersed in a 37 ° C water bath. Extracorporeal blood flow rate is 100 cm / m linear velocity in fiber
Set to be in. At this time, no anticoagulant was used. 5 minutes, 10 minutes, 15 minutes, 20 minutes, 3 after circulation starts
After 0 minute, 45 minutes, 60 minutes, and 120 minutes, 1 ml of blood was collected and subjected to anticoagulation treatment with 1.5% EDTA-2Na physiological saline, and then a multi-item blood test device (Sysmex NE-60) was used.
00, manufactured by Toa Medical Electronics Co., Ltd.).
Note that the leukocyte count and platelet count were corrected for hematocrit (Ht) using order 4, and were determined as Ht values before the start of circulation. ◎

(Equation 4)

C3a Experiment Using Mini-Module 3.8 w / v% sodium citrate 1/9 volume was added and blood was collected from the human elbow vein. The obtained sodium citrate-added blood was centrifuged at 3000 rpm for 10 minutes to collect PPP (platelet poor plasma). Collected PPP
Were stored on ice until used in experiments. The sample used in the experiment was a mini-module with a membrane area of 300 cm ² ,
After washing with 00 ml of physiological saline (saline), the cells were stored in a state filled with the saline until used for the experiment. However, in order to prevent movement of moisture and the like inside and outside of the dialysate, a module in which the hollow fiber portion was fixed with urethane resin was used. A syringe was connected to the mini-module, and 4 ml of PPP was sucked to completely replace the edible food in the module with PPP. Both ends of the module were closed with caps and transferred to a 37 ° C. constant temperature water bath.
Time incubation was performed. The module was then placed in ice water to stop the activation of the complement system.
Once again, a syringe was attached to the mini-module, and the PPP in the module was collected in a glass test tube containing a stabilizer (EDTA-2K) and kept frozen until measurement of C3a. The C3a measurement was performed by the RIA2 antibody method.

[0068]

As described above, the average molecular weight of the present invention modified with dicarboxylic acid is 10,000 to 100,000.
A permeable membrane obtained by wet-forming a polyetheramide having an equivalent number of terminal amino groups of 40 or less and an equivalent number of terminal carboxyl groups of (equivalent number of terminal amino groups + 5) or more is an antithrombotic. It is excellent in bioadaptability such as properties, and has sufficient water permeability and low molecular weight as well as medium and high molecular weight material permeability, and has high thermal stability and is caused by the polymer production process or overheat sterilization treatment Since the generation of harmful low molecular compounds is extremely small, it can be suitably used in applications such as hemodialysis.

[0069]

[Brief description of the drawings]

FIG. 1 shows a SEM photograph of a flat film surface of Example 9.

FIG. 2 is a SEM photograph of a cross section of a flat film of Example 9.

FIG. 3 shows rabbit extracorporeal circulation experiment white blood cell counts of Example 19 and Comparative Examples 3 and 4.

FIG. 4 shows the number of platelets in the rabbit extracorporeal circulation experiment in Example 19 and Comparative Examples 3 and 4.

FIG. 5 shows a C3a experiment of Example 21 and Comparative Example 5.6.

FIG. 6 shows a cell for measuring water permeability.

FIG. 7 shows a circuit for measuring water permeability.

FIG. 8 shows a circuit for module solute permeability.

FIG. 9 shows a module for extracorporeal circulation of a dialyzer.

FIG. 10 shows a rabbit extracorporeal circulation experiment.

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 ... Dialyzer, 2 ... Hollow fiber bundle, 3 ... Cylindrical body, 4, 5 ... Potting material, 6, 7 ... Header, 8,
9 ... cap, 10 ... inlet pipe, 11 ... outlet pipe, 20.
..Rabbit, 21 ... catheter, 22 ... pump, 23 ... chamber, 24 ... manometer out, 25 ... catheter, 26 ... tube, 27 ... manometer in, 2
8 Tube, 29 Tube, 30 Pump, 3
1 ... water bath, 32 ... rotary pump, 33 ... tube, 35 ... vitamin B ₁₂ solution, 36 ... saline, 37 ... mini module, 38 ... constant temperature Tank, 100 ...
・ Top lid, 101 ・ ・ ・ O-ring, 102 ・ ・ ・ Film (sample),
103: mesh, 100 ': lower lid

Continuation of the front page (56) References JP-A-5-123551 (JP, A) JP-A-5-123552 (JP, A) JP-A-5-161836 (JP, A) (58) Fields investigated (Int) .Cl. ⁷ , DB name) B01D 71/56

Claims (1)

(57) [Claims] An average molecular weight of about 10,000 having a repeating structural unit represented by the following structural formula (1) or (2).
0 to 100,000, the equivalent number of terminal amino groups ([N
H ₂ ] μeq / g) is 40 or less and [COO] μeq / g
OH] ≧ [NH ₂ ] +5. A permeable membrane having excellent biocompatibility, comprising a poly (ether amide) resin. ◎ [Formula 1] ◎ [Formula 2] (Wherein, R ¹ , R ² and R ³ are linear or branched alkylene groups having 2 to 4 carbon atoms, and R ⁴ , R ⁵ and R ⁶ are linear or branched alkylene groups having 2 to 24 carbon atoms) Represents a group, n
Is 0 to 180, m is 1 to 400, and x represents an integer of 0 or 1.)