JPH05123552A - Permeable membrane excellent in biocompatibility - Google Patents

Abstract

PURPOSE:To provide a novel permeable membrane excellent in biocompatibility and enhanced in safety. CONSTITUTION:A permeable membrane excellent in biocompatibility is obtained by the wet film forming technique of terminal modified polyamide being polyetheramide with a mol.wt. of 10,000-100,000 having a 1-22C hydrocarbon group at its terminal and characterized by that the number of hydrocarbon groups is 5-100% of the total number of the terminal groups of polyetheramide.

Description

Detailed Description of the Invention

[0001]

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, keeps the electrolyte concentration in body fluid constant, and maintains an acid-base balance. Therefore, hemodialysis is currently synonymous with so-called artificial kidneys, but it is not limited to that. It has become an important technology.

Conventionally, cellulosic membranes such as regenerated cellulose membranes and cellulose acetate membranes have been widely used for such hemodialysis. These cellulosic membranes have excellent clearance for low molecular weight substances, but the clearance of medium and high molecular weight substances is not sufficient, and the activity of complement and transient leukopenia, etc. There is a high possibility that an immunological change will occur, and further, blood coagulation will occur upon contact with blood, and a large amount of anticoagulant is required to prevent this.

Further, for the purpose of eliminating the drawbacks of these cellulosic membranes, permeable membranes made of various synthetic polymers, for example, hydrophilic properties such as polyvinyl alcohol, polyacrylonitrile, polysulfone, polymethylmethacrylate and polyamide. And, those composed of hydrophobic polymers have been proposed and developed.

Many of these synthetic polymer permeable membranes are superior to the cellulosic ones in terms of permeation performance, but hydrophilic polymer ones have sufficient mechanical strength. In addition, it is not sufficient in that it is made of a hydrophobic polymer and requires hydrophilic treatment at the time of use, and in any case, it is not sufficient in terms of its biocompatibility. It was

Further, a copolymer having a hydrophilic segment and a hydrophobic segment, for example, an acrylonitrile-sodium methacryl sulfonate copolymer, a polycarbonate-polyether block copolymer, an ethylene-vinyl alcohol copolymer and the like (for example, Kagaku Special Number 84 Biomedical Polymer Kagaku Dojinsha, No. 142-14
Page 5, Membrane Utilization Technology Handbook, Koshobo, 663-7
See page 13, JP-A-59-193102 and the like. )
A permeable membrane consisting of is also being developed. The permeable membrane made of a copolymer having these hydrophilic segment and hydrophobic segment generally has considerably excellent properties even in its biocompatibility, but it cannot be said to be sufficient yet. In addition, there is room for improvement in terms of safety, thermal stability, mechanical strength, and the like, and water permeability, substance permeability, and other properties that are essentially required for blood permeable membranes.

[0007]

Therefore, the 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-mentioned objects are achieved by the following structural formulas (1), (2), (3) or (4).

[0009]

[Chemical 5]

[0010]

[Chemical 6]

[0011]

[Chemical 7]

[0012]

[Chemical 8] (However, in the formula, each of R ¹ , R ² , and R ³ has 2 to 4 carbon atoms.
Is a linear or branched alkylene group, R ⁴ , R ⁵ and R ⁶ each represent an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36 carbon atoms, and n is 0 to 180 and m is 1 ~ 400. ) Consists of the structural units shown in, and has 1 carbon atom at the end.
Molecular weight 10,000 to 10 having a hydrocarbon group of 22
10,000 polyether amides, the number of said hydrocarbon groups being 5-10 of the total number of end groups of said polyether amides.
This is achieved by a permeable membrane having excellent biocompatibility obtained by wet-forming a 0% end-modified polyamide.

In the present invention, the solvent of the 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 organic solvents such as dimethyl-2-imidazolidinone, and those obtained by adding water and / or metal salt in an amount of less than 25% by weight to these solvents, and the coagulating liquid is A permeable membrane comprising water, glycols, glycerin and a mixture thereof, or a mixture thereof containing 5% by weight or more and the solvent and / or metal salt as described above added thereto. is there. The present invention further shows 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 coagulating liquid is water / methanol / metal salt or water /
Methanol / dimethyl sulfoxide / metal salt,
Further, it shows a permeable membrane which uses at least one selected from calcium chloride, zinc chloride and lithium chloride as a metal salt.

Further, the present invention is a permeable membrane which is biocompatible because the polyether amide has a spherulite structure.

[0015]

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

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

[0017]

[Chemical 9]

[0018]

[Chemical 10]

[0019]

[Chemical 11]

[0020]

[Chemical 12] 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 ethylene group, trimethylene group and 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, and the production of polyamide described later. It is a residue of lactam or aminocarboxylic acid used for. R ⁵ is an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36 carbon atoms, preferably 2 to 7 carbon atoms, which is a diamine residue described later. R ⁶ is an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36 carbon atoms, preferably 2 to 11 and is a residue of a dicarboxylic acid described later. Also, m is 1
Is an integer of from 400 to 400, preferably from 1 to 120.

General 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
˜75 wt%, preferably 15-55 wt%, is preferable because it makes the resulting product good in biocompatibility and brings about a balance of mechanical strength and flexibility.

The terminal-modified polyetheramide resin used in the present invention has the general formula (1) to
A polyether amide having a constitutional unit represented by (4) is introduced with a fixed proportion of hydrocarbon groups at the ends to modify the ends.

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

These terminal hydrocarbon groups are introduced by using a monocarboxylic acid and / or a monoamine, which will be described later, during the production of the polyetheramide.

As the terminal group of the terminal-modified polyetheramide having the above-mentioned structure used in the present invention, in addition to the above-mentioned terminal hydrocarbon group, an amino group and / Alternatively, although there is a carboxyl group, the number of all terminal groups is the sum of the numbers of the above-mentioned terminal hydrocarbon group, amino group and / or carboxyl group. In this 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 10% of the total number of the terminal groups.
95%, more preferably 10 to 90%. That is, when the number of the terminal hydrocarbon groups is less than 5% of the total number of the terminal groups, the thermal stability of the polyether amide is lowered, and during the melt polymerization of the polymer or the heat sterilization of the product,
This is because there is a possibility that a low molecular odor substance or a low molecular compound may be generated. From the viewpoint of such thermal stability, it is desirable that the number of hydrocarbon groups be close to 100% of the total number of terminal groups, but from an industrial standpoint, it is not easy to manufacture. As described above, it is desirable that the degree of introduction is suppressed to some extent.

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

Further, the end-modified polyetheramide used in the present invention may be added with a crystal nucleating agent, a plasticizer, a heat-resistant agent, an antioxidant, another polymer or the like, if necessary. ..

The polyether amide having the constitutional units represented by the general formulas (1) to (4) and having a terminal modified with a hydrocarbon group is, for example, a polyether having an amino group or a carboxyl group at the terminal. When a polyamide having a carboxyl group or an amino group at the terminal is subjected to a condensation reaction according to a conventional method to form an amide bond, a monocarboxylic acid and / or a monoamine is used as a terminal modifier for the amino group and the carboxyl group which are the terminal groups of the polyetheramide. Can be prepared by reacting The monocarboxylic acid and / or monoamine used for 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 the monocarboxylic acid and the 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 is, for example, polyethylene oxide, obtained by ring-opening polymerization of alkylene oxide such as ethylene oxide or propylene oxide or tetrahydrofuran.
It can be easily obtained by obtaining a polyether such as polypropylene oxide or polytetramethylene oxide and substituting the terminal hydroxyl group thereof with an amino group and / or a carboxyl group. As the amino group substitution method,
A method of direct amination or cyanoethylation of a hydroxyl group and then a reductive amination can be mentioned, and a method of carboxyl group substitution can be a method by oxidative carbonylation.

The polyamide having a carboxyl group and an amino group at the terminal 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 specifically, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, and enanthate are used. Acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid,
Aliphatic monocarboxylic acids such as tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, oleic acid, linoleic acid, such as cyclohexanecarboxylic acid, methylcyclohexanecarboxylic acid Alicyclic monocarboxylic acid,
Examples include benzoic acid, toluic acid, ethylbenzoic acid, aromatic monocarboxylic acids such as phenylacetic acid, and the like. In addition,
During the reaction, the corresponding derivative that can play the same role as the above acid,
For example, acid anhydrides, esters, amides and the like can also be used.

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

The permeable membrane of the present invention uses, as a good solvent, a polyetheramide having the constitutional units represented by the general formulas (1) to (4) as described above and having a terminal modified with a hydrocarbon group. Dissolve the resulting polyetheramide solution, for example,
It is obtained by casting on a substrate or the like to form a desired shape, contacting this with a coagulating liquid composed of a non-solvent or a poor solvent, and extracting and removing a good solvent to coagulate it.

Examples of the good solvent for the polyetheramide include phosphoric acid, formic acid, trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid, hexafluoroisopropanol, methanol, N-methylpyrrolidone, dimethylacetamide, dimethylformamide and dimethylsulfonamide. Xide, phenol, 1,3-dimethyl-2-imidazolidinone and the like are used, and of these, formic acid is preferable. It is also possible to use, as a good solvent, those obtained by adding water and / or a metal salt in an amount of less than 25% by weight to these organic solvents. As the metal salt, calcium chloride, zinc chloride, lithium chloride, sodium carbonate, copper sulfate or the like is used.

The polymer concentration in the solution obtained by dissolving the polyether amide in such a good solvent is 5 to 35% by weight, more preferably 10 to 30% by weight.
It is considered as a degree.

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

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

Further, the permeable membrane of the present invention is formed by casting the polyether amide into a coagulating liquid by using, for example, a hollow fiber molding nozzle, instead of casting on the substrate to form a film as described above. It is also possible to use it as a hollow fiber by extruding it in the air or in the air.

The permeable membrane of the present invention thus obtained has a large number of fine communication holes extending from the membrane surface to the membrane back surface. Although the clear mechanism by which the permeable membrane of the present invention exhibits excellent biocompatibility such as antithrombotic property is not clear, it is presumed that the matrix is composed of structural units represented by the general formulas (1) to (4). Since it is composed of the polyether amide having, a micro phase separation structure composed of a hydrophobic polyamide segment and a hydrophilic polyether segment is formed, and this micro phase separation structure exerts good antithrombotic property. Thought to be a thing. Furthermore, the fact that such polyetheramides are terminally modified and stabilized is considered to contribute to the antithrombotic property 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 of the layer of polyetheramide (blood contact surface) is made to be spherulites (spherical crystals). Thereby, the excellent antithrombotic property is exhibited.

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

Although the principle of obtaining excellent antithrombotic properties by using spherulites is not clear, it is because the microphase-separated structure is made clear by arranging the arrangement of the crystalline portion and the amorphous portion. Presumed.

The characteristics of the permeable membrane of the present invention are not particularly limited, but the water permeability is typically 1 to 400 m.
1 / m ² · hr · mmHg, preferably 4-70 ml /
m ² · hr · mmHg, permeability of urea (molecular weight 60) as a low molecular weight substance is 2.00 × 10 ⁻⁵ cm ² / min
Or more, preferably 2.50 × 10 ⁻⁵ cm ² / min or more, and vitamin B ₁₂ (molecular weight 1
355) has a permeability of 0.60 × 10 ⁻⁵ cm ² / min or more, preferably 0.70 × 10 ⁻⁵ cm ² / min or more.

[0045]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1 Polyamide obtained by polycondensing hexamethylenediamine and sebacic acid and a condensation reaction of diamino polypropylene oxide with diamino polypropylene oxide to form an amide bond, and further modifying the end with stearylamine. (Mn approx. 20,000, polyether content 25% by weight, terminal modification rate 31%) 99 g of formic acid (99 w / v%) 3
It was heated and dissolved in 51 g to obtain a solution having a polymer concentration of 22% by weight. This was left standing at 30 ° C. for 2 hours to defoam. This solution is cast in a gas phase on a substrate to a constant thickness, and immediately C
It is immersed for 5 minutes in a coagulating liquid consisting of aCl ₂ / methanol / water mixture (weight ratio 1/3/5) and adjusted to 5 ° C. to coagulate, and then the formic acid remaining in the coagulating film and the coagulating liquid are made into running water. And removed to obtain a sample. The obtained film has a film thickness of 4 in a wet state.
It was 9 μm.

Further, the obtained film was subjected to a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure. 1A shows a SEM photograph of the surface of the film, FIG. 1B shows a back surface of the film, and FIG. 1C shows an SEM photograph of the cross section of the film.

The water permeability of the obtained membrane was 28 ml / m.
² · hr · mmHg, urea permeability is 5.2 × 10 ⁻⁵ cm
² / min, Vitamin B ₁₂ permeability is 1.1 × 10 ^-5 cm
It was ² / min.

The water permeability (measurement of water permeability 1) and the permeability of urea and vitamin B ₁₂ of the obtained membrane were examined by the methods described below. The results are shown in Table 1.

Further, a platelet expansion ability test was carried out by the method described below. The results are shown in Table 2.

Example 2 A polyetheramide obtained in the same manner as in Example 1 except that the terminal modification rate was 47% was used, and the coagulating liquid temperature was 10%.
A film was formed in the same manner as in Example 1 except that the temperature was changed to ° C. The obtained film had a film thickness of 37 μm in a wet state.

Further, the obtained film was scanned with a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 2a,
FIG. 2b shows a SEM photograph of the back surface of the film, and FIG. 2c shows a SEM photograph of the cross section of the film.

Further, the water permeation rate (measurement of water permeation rate 1) and the permeability to urea and vitamin B ₁₂ of the obtained membrane were examined by the methods described later. The results are shown in Table 1.

Further, a platelet expansion ability test was conducted by the method described later. The results are shown in Table 2.

Example 3 A film was formed in the same manner as in Example 1 except that the coagulating liquid temperature was changed to 15 ° C. The obtained film had a film thickness of 49 μm in a wet state.

Further, the obtained film was scanned with an electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 3a,
FIG. 3b shows a SEM photograph of the back surface of the film, and FIG. 3c shows a SEM photograph of the cross section of the film.

The water permeation rate (measurement of water permeation rate 1) and the permeability to urea and vitamin B12 of the obtained membrane were examined by the methods described later. The results are shown in Table 1.

Example 4 A film was formed in the same manner as in Example 1 except that the composition of the coagulation liquid was a CaCl ₂ / methanol / water mixture having a weight ratio of 2/3/7 and the coagulation liquid temperature was changed to 10 ° C. The obtained film had a film thickness of 49 μm in a wet state.

Further, the obtained film was subjected to a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 4a,
FIG. 4b shows a SEM photograph of the back surface of the film, and FIG. 4c shows a SEM photograph of the cross section of the film.

Further, the water permeation rate (measurement of water permeation rate 1) of the obtained membrane and the permeability to urea and vitamin B ₁₂ were examined by the methods described later. The results are shown in Table 1.

Example 5 A film was formed in the same manner as in Example 4 except that the coagulating liquid temperature was changed to 15 ° C. The obtained film had a film thickness of 42 μm in a wet state.

Further, the obtained film was subjected to a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 5a,
5B shows a SEM photograph of the back surface of the film, and FIG. 5C shows a SEM photograph of the cross section of the film. Further, the water permeability (measurement of water permeability 1) of the obtained membrane and the permeability to urea and vitamin B ₁₂ were examined by the methods described below. The results are shown in Table 1.

Example 6 A film was formed in the same manner as in Example 1 except that the composition of the coagulating liquid was a CaCl ₂ / methanol / water mixture having a weight ratio of 2/3/5. The obtained film had a film thickness of 62 μm in a wet state.

Further, the obtained film was subjected to a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 6a,
FIG. 6b shows a SEM photograph of the back surface of the film, and FIG. 6c shows a SEM photograph of the cross section of the film. Further, the water permeability (measurement of water permeability 1) of the obtained membrane and the permeability to urea and vitamin B ₁₂ were examined by the methods described below. The results are shown in Table 1.

Example 7 A film was formed in the same manner as in Example 1 except that the composition of the coagulating liquid was a CaCl ₂ / methanol / water mixture having a weight ratio of 2/5/5. The obtained film had a film thickness of 56 μm in a wet state.

Further, the obtained film was subjected to a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 7a,
FIG. 7b shows a SEM photograph of the back surface of the film, and FIG. 7c shows a SEM photograph of the cross section of the film. Further, the water permeability (measurement of water permeability 1) of the obtained membrane and the permeability to urea and vitamin B ₁₂ were examined by the methods described below. The results are shown in Table 1.

Example 8 A film was formed in the same manner as in Example 1 except that the composition of the coagulating liquid was a ZnCl ₂ / methanol / water mixed liquid having a weight ratio of 2/3/5. The obtained film had a film thickness of 75 μm in a wet state.

Further, the obtained film was scanned with a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1. In addition, in FIG. 8a,
FIG. 8b shows SEM photographs of the back surface of the film, respectively.

Further, the water permeation rate (measurement of water permeation rate 1) and the permeability to urea and vitamin B ₁₂ of the obtained membrane were examined by the methods described later. The results are shown in Table 1.

Example 9 The composition of the coagulating liquid was ZnC in a weight ratio of 14/21/35/30.
A film was formed in the same manner as in Example 1 except that a mixed solution of ₁₂ / methanol / water / dimethyl sulfoxide was used. The obtained film had a film thickness of 80 μm in a wet state.

Further, the obtained film was scanned with a scanning electron microscope (S
When observed by EM), the film surface had a spherulite structure as in Example 1.

The water permeability (measurement of water permeability 1) and the permeability of urea and vitamin B ₁₂ of the obtained membrane were examined by the methods described below. The results are shown in Table 1.

Example 10 A film was formed in the same manner as in Example 1 except that the composition of the coagulating liquid was CaCl ₂ / methanol / water / mixed liquid having a weight ratio of 2/3/2. The obtained film had a film thickness of 65 μm in a wet state.

Further, the water permeation rate (measurement of water permeation rate 1) and the permeability to urea and vitamin B ₁₂ of the obtained membrane were examined by the methods described later. The results are shown in Table 1. Further, a platelet expandability test was performed by the method described below. The results are shown in Table 2.
Shown in.

Example 11 The composition of the coagulating liquid was changed to CaCl ₂ / M in a weight ratio of 3/4/2/2 /.
A film was formed in the same manner as in Example 1 except that a mixed solution of OH / water / DMSO was used. The obtained film has a thickness of 66 μm in a wet state.
Met. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure as in Example 1. Further, the water permeation rate of the obtained membrane was measured by the method of water permeation rate measurement 1 described later, and it was 329 ml /
It was m ² · hr · mmHg.

Example 12 Polyetheramide 10 obtained in the same manner as in Example 1
0 g was dissolved in phosphoric acid (85% by weight aqueous solution) by heating to obtain a solution having a polymer concentration of 20% by weight. This was defoamed by the centrifugal method. This was cast in a gas phase on a substrate with a constant thickness, and immediately CaCl ₂ / MeOH / water (weight ratio 2/5 /
7) A sample was obtained by dipping for 10 minutes in a coagulation solution of which temperature was adjusted to 5 ° C. and coagulating, and then removing phosphoric acid and coagulation solution remaining on the coagulation film with running water. The obtained film had a film thickness of 98 μm in a wet state. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure as in Example 1. The water permeation rate of the obtained membrane was measured by the method of water permeation rate measurement 1 to be described later, and it was 37 ml / m ² · hr · mmHg.

Example 13 The composition of the coagulating liquid was CaCl ₂ / MeO in a weight ratio of 2/3/7 /.
A film was formed in the same manner as in Example 12 except that the H / water mixture was used. The obtained film had a film thickness of 101 μm in a wet state.
When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure as in Example 1. Further, the water permeation rate of the obtained membrane was measured by the method of water permeation rate measurement 1 described later, and was 9 ml / m ² · hr ·
It was mmHg.

Example 14 90 g of a block copolymer consisting of polypropylene oxide in the polyether portion and nylon 12 in the polyamide portion and dimer acid was dissolved by heating in 410 g of formic acid (99 W / V%),
A solution having a polymer concentration of 18% by weight was obtained. This was left standing at 30 ° C. for 2 hours to defoam. This was cast in a gas phase on a substrate with a constant thickness, and immediately MeOH / water (weight ratio 7 /
3) A sample was obtained by dipping for 5 minutes in a coagulating liquid of which temperature was adjusted to 25 ° C., which was a mixed liquid to coagulate, and then formic acid and coagulating liquid remaining on the coagulation film were removed with running water. The obtained film had a film thickness of 57 μm in a wet state. When the obtained film was observed by a scanning electron microscope (SEM), the film surface was observed in Example 1
It also had a spherulitic structure. In addition, the water permeation rate of the obtained membrane was measured by the method of water permeation rate measurement 1 described later, and it was 44 ml / m ² · hr · mmHg. Furthermore, when the obtained membrane was subjected to (1) high-pressure steam sterilization at 121 ° C. for 20 minutes, and (2) γ-ray sterilization (dose 2M) to perform an eluate test, ΔpH = 0.32 in (1), In UV absorbance = 0.005 and (2), ΔpH = 0.91 and UV absorbance = 0.055.

Comparative Example 1 A dialysis membrane (PT-
150, manufactured by ENKA), water permeability (measurement of water permeability 1) and permeability to urea and vitamin B ₁₂ were examined in the same manner as in Example 1 by the method described below. The results are shown in Table 1.

Comparative Example 2 Using a commercially available polypropylene film (FOP # 60, manufactured by Nimura Chemical Co., Ltd.), a platelet expansion ability test was conducted by the method described below in the same manner as in Example 1. The results are shown in Table 2.

Comparative Example 3 Nylon 610 (Mn = 20000) was dissolved in hexafluoroisopropanol to prepare a polymer solution having a polymer concentration of 5% by weight at 40 ° C., and the obtained dope solution was applied to a glass plate at a uniform thickness. The resulting product was cast into a cup, the hexafluoroisopropanol was completely evaporated in an oven at 40 ° C., and vacuum drying was performed at room temperature to form a film. The membrane thus obtained was subjected to a platelet expansion test by the method described below in the same manner as in Example 1. The results are shown in Table 2.

[0082]

[Table 1]

[0083]

[Table 2] As is clear from the results shown in Table 1 and Examples 11 to 14, in the permeable membranes of Examples 1 to 14 according to the present invention, the water permeation rate and the medium molecular weight are higher than those of the conventionally used regenerated cellulose permeable membranes. The material has improved permeability.

As is clear from Table 2, in the permeable membranes of Examples 1, 2 and 10 according to the present invention, as compared with the permeable membrane of Comparative Example 2 or 3, the adhesion of platelets was generally less, In particular, since the adhesion (type 2) in the activated state is extremely small, it can be said that it has excellent antithrombotic properties.

Example 15 Polyetheramide 12 obtained in the same manner as in Example 1
Dissolve 00g in 3800g of formic acid (99W / V%) by heating,
A solution having a polymer concentration of 24% by weight was obtained. After removing foreign matters using a filter, degassing was performed by depressurizing and standing (30 ° C.). Using a hollow fiber molding nozzle, this was CaCl ₂ /
After using a MeOH / water (weight ratio 2/3/21) mixture as an internal liquid and extruding it into a solidification phase consisting of the same liquid to solidify,
A hollow fiber was obtained which was wound on a bobbin. The obtained hollow fiber was immediately washed with running water, immersed in a 40 wt% aqueous solution of glycerin at 60 ° C. for 3 minutes to maintain the pore size, then washed inside the hollow fiber, and further dried in an oven at 80 ° C. for 5 minutes. went. The hollow fiber obtained had an inner diameter of 337 μm and a film thickness of 44 μm. The hollow fiber ends were bundled with urethane resin, and the water permeability was measured by the water permeability measurement 2 described below using a mini module prepared by cutting the ends.
It was m ² · hr · mmHg. Furthermore, when the sieving coefficient (SC) of albumin was measured by a method described below in a bovine blood system, SC = 0.

Example 16 400 g of a block copolymer in which the polyether portion was polypropylene oxide, the polyamide portion was nylon 12 and dimer acid, and the terminal was modified with stearylamine
It was heated and dissolved in 600 g of 3-dimethyl-2-imidazolidinone to obtain a polymer solution. After removing foreign matters using a filter, degassing was performed by depressurizing and standing (30 ° C.).
This was extruded into the air using a hollow fiber forming nozzle to be cooled and solidified. The obtained hollow fiber was added to a treatment liquid containing dimethylformamide as a main component, which was kept at 100 ° C.
Soaked for a minute. Then, it was further immersed in a water bath maintained at 20 ° C. to obtain a hollow fiber. The hollow fiber obtained has an inner diameter of 22.
The thickness was 0 μm and the film thickness was 20 μm. The water permeability of the obtained hollow fiber was measured by the water permeability measurement 2 described below, and the result was 1
It was 5 ml / m ² · hr · mmHg.

As is clear from Examples 15 to 16, the hollow fibers molded from the permeable membrane according to the present invention are
Similar to No. 14, the water permeability is excellent.

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

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

Measurement of Water Permeation Rate 2 As shown in FIG. 10, the mini-module 16 was connected to the tubes 17 and 18 equipped with the rotary pump 14, and the pressure gauges 15a and 15b were attached near both ends thereof. 37
A container 12 containing a physiological saline solution 13 whose temperature is controlled to ℃ ± 1 ℃
Was immersed in a constant temperature bath 11, the tip of a tube 17 was inserted into the physiological saline solution 13, while one end of the tube 18 was connected to the container 12 to form a circuit. Inlet flow rate 10ml /
After setting the min and the pressure difference between the mini-modules to 100 mmHg, the physiological saline is circulated in the circuit, and after waiting for a steady state, the outflowing physiological saline is placed in the container 19 and the relationship between the amount of physiological saline and the time is obtained to determine the membrane area. Converted in.

Substance-permeable urea Distilled water and a concentration of 100 m were passed through a flat membrane punched out in a circle.
Using a cell in which a g / dl aqueous urea solution (50 ml each) is in contact through the membrane, the respective concentrations are obtained at 30 minutes and 50 minutes while the respective liquids are stirred at a constant speed. From this concentration and the film thickness of the flat film, the substance permeability is calculated based on the following formula.

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

[0093]

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

Vitamin B _{12 The} solute was vitamin B ₁₂ , the solute concentration was 5 mg / dl, and the quantification method was the same as that for urea except that the direct absorbance was measured at 360 nm.

Platelet dilatability test 3.8 w / v% sodium citrate was added at a volume of 1/9 to collect blood from a human cubital vein. The obtained sodium citrate-added blood is centrifuged at 800 rpm for 5 minutes to separate PRP (platelet-rich plasma). This PR
The number of platelets in P is 8 item blood test device (ELT-8,
Ortho Instruments Co., Ltd.). After separating the PRP, centrifuge at 3000 rpm for 10 minutes,
Collect PPP (platelet poor plasma). The PRP is diluted with the obtained PPP to adjust the platelet count to 10 ⁵ cells / μl.

A permeable membrane sample was cut into 8 mm squares, attached to an SEM sample table, and diluted P in which the number of platelets was adjusted as described above.
200 μl of RP is dropped on the sample piece. Then, the PRP layer is pressed with a lid of a petri dish (made of polystyrene) so as to have a thickness of 2 mm. Then, at room temperature (25 ±
Let stand for 30 minutes at 2 ° C. Then, the test piece is 0.0
1M phosphate buffered saline, pH 7.0 (PBS) /3.8
Lightly wash with w / v% sodium citrate mixture (weight ratio 9/1), and then add 1 w / v% P of glutaraldehyde.
Fix in a BS solution at 4 ° C (2-8 ° C) overnight. After the immobilized sample piece is washed with PBS, it is further washed with distilled water and freeze-dried. Then, after subjecting the sample piece to ion sputtering (12 kV, 8 minutes), SE
Photograph in 5 fields with M at 1000x magnification. Then, from the obtained photographs, the morphological classification of the adhered platelets and the calculation of the adherence number are performed based on the following criteria.

Morphological classification Type 1: Inactive adhesion a: Disc shape in a normal state. b: Spherical shape, but not deformed to the point where it gives false legs. Type 2: Active adhesion One that stretches its false legs and adheres.

The solute test membrane was cut into an appropriate size, placed in a container containing ion-exchanged water having a membrane weight of 100 times, the treatment solution and time in the high-pressure steam sterilization method, and 70 in the line sterilization method. After heating at ± 5 ° C for 1 hour and cooling, the content liquid is taken out and used as a test liquid.

(1) Measurement of ΔpH 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 1,000 ml, and add pH of both solutions. And measure the difference.

(2) UV Absorbance Using a blank test solution as a control, the maximum absorbance at a wavelength of 220 to 350 nm is determined.

Measurement of sieving coefficient (SC) of albumin Using the same circuit as in the measurement of water permeation amount 2, the outlet of the tube 18 was changed to a single pass in the circuit of FIG. 10 so as not to recirculate, and a container was placed at the outlet. Place the tubes 17 and 18 with the rotary pump 14 on the mini module 16
Was connected, and pressure gauges 15a and 15b were attached near both ends thereof. Hematrix 30 temperature-controlled to 37 ° C ± 1 ° C
%, The total protein was adjusted to about 6.0 g / dl, and the container 12 containing the bovine blood 13 was immersed in the thermostatic chamber 11, and the tip of the tube 17 was inserted into the bovine blood 13 while one end of the tube 18 was inserted. A circuit was formed by connecting to the outlet container. Inlet flow rate 1
0 ml / min, pressure difference between mini modules 100 mmH
After setting the g to allow the bovine blood to circulate in the circuit and waiting for a steady state, the filtrate at the inlet, the outlet and the container 19 was taken, and SC was obtained from the concentration of each liquid (BCG method) by the following formula. SC = C _F / {(C _Bi + C _Bo ) / 2} where C _F : filtrate concentration C _Bi : inlet side liquid concentration C _Bo : outlet side liquid concentration.

[0102]

As described above, the permeable membrane of the present invention comprises the structural unit represented by the structural formula (1), (2), (3) or (4), and has 1 to 22 carbon atoms at the terminal. End-modified polyamide having a hydrocarbon group and having 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 end groups of the polyether amide is manufactured by a wet method. Since it is obtained as a membrane, it has excellent biocompatibility such as antithrombogenicity, and its water permeability, low molecular weight, and medium / high molecular weight substance permeability are sufficient, and it is more stable to heat. Since it is highly active and the generation of harmful low molecular weight compounds due to the polymer production process or heat sterilization treatment is extremely small, it is preferably used in applications such as hemodialysis.

[Brief description of drawings]

1 to 8 are scanning electron micrographs (magnification: 1000 times) showing the fine structure of one example of the permeable membrane of the present invention, wherein a figure shows the membrane surface and b figure shows the membrane back surface. ,
Further, FIG. 9C shows a cross section of the film, and FIG.
FIG. 10 is a perspective view showing a device configuration for measuring the amount of water permeation (measurement 1 of the amount of water permeation), and FIG.

[Simple explanation of symbols]

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

[Procedure amendment]

[Submission date] December 25, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Brief description of the drawing

[Correction method] Change

[Correction content]

[Brief description of drawings]

FIG. 1 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 2 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 3 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 4 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 5 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 6 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 7 is a photograph (scanning electron microscope photograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 8 is a photograph (scanning electron micrograph (magnification: 1000 times)) of a thin film obtained according to an example of the present invention,
1a shows the front surface of the film, FIG. 1b shows the back surface of the film, and FIG. 1c shows the cross section of the film.

FIG. 9 is a perspective view showing an apparatus configuration for measuring the amount of water permeation (measurement 1 of the amount of water permeation),

FIG. 10 is a schematic diagram showing an apparatus configuration for measuring the amount of water permeation (measurement 2 of the amount of water permeation).

[Short description of reference numerals] 1,1 '... Cell for water permeability evaluation, 2 ... O ring, 3 ... Flat membrane, 4 ... Supporting glass filter, 14 ... Rotary pump, 15a, 15b ... Pressure gauge, 16 ... Mini Modules, 17, 18 ... tubes.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mitsuhide Nakagawa 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Terumo Corporation

Claims (3)

[Claims] 1. The following structural formula (1), (2), (3) or (4): [Chemical 2] [Chemical 3] [Chemical 4] (However, in the formula, each of R ¹ , R ² , and R ³ has 2 to 4 carbon atoms.
Is a linear or branched alkylene group, R ⁴ , R ⁵ and R ⁶ each represent an aliphatic, alicyclic or aromatic hydrocarbon group having 2 to 36 carbon atoms, and n is 0 to 180 and m is 1 ~ 400. ) Consists of the structural units shown in, and has 1 carbon atom at the end.
Molecular weight 10,000 to 10 having a hydrocarbon group of 22
10,000 polyether amides, the number of said hydrocarbon groups being 5-10 of the total number of end groups of said polyether amides.
A permeable membrane having excellent biocompatibility obtained by wet-forming a 0% terminal-modified polyamide. 2. When the polyether portion of the polyether amide is polypropylene oxide, its content is 1
The permeable membrane according to claim 1, wherein the content is 5 to 30% by weight, and the content of polytetramethylene glycol is 30 to 55% by weight. 3. The permeable membrane according to claim 1, wherein the polyether amide has biocompatibility by having a spherulite structure.