JP3130082B2 - 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]

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

[0009]

Embedded image

[0010]

Embedded image

[0011]

Embedded image

[0012]

Embedded image (Wherein, R ¹ , R ² and R ³ each have 2 to 4 carbon atoms)
R ⁴ , R ⁵ , and R ⁶ each represent an aliphatic, alicyclic, or aromatic hydrocarbon group having 2 to 36 carbon atoms; n is 0 to 180; ~ 400. ), Having 1 carbon atom at the terminal
Molecular weight of 10,000 to 10 having a hydrocarbon group of from 22 to 22
000 polyetheramides, wherein the number of hydrocarbon groups is 5 to 10 of the total number of terminal groups of the polyetheramides.
This is achieved by a biocompatible permeable membrane obtained by wet-forming a 0% terminal-modified polyamide.

In the present invention, the solvent of the above-mentioned polyether amide 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.

[0015]

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

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

[0017]

Embedded image

[0018]

Embedded image

[0019]

Embedded image

[0020]

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

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

The 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% by weight, preferably 15-55% by weight, is preferred in that the resulting product has good biocompatibility and can provide a balance between mechanical strength and flexibility.

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

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

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

The terminal group of the terminal-modified polyetheramide having the above-mentioned structure used in the present invention includes, in addition to the above-mentioned terminal hydrocarbon group, an amino group derived from a raw material for producing polyetheramide described later and / or Alternatively, there is a carboxyl group, but the total number of terminal groups is the sum of the numbers of the above-mentioned terminal hydrocarbon groups, amino groups and / or carboxyl groups. In the terminal-modified polyetheramide used in the permeable membrane of the present invention, the number of the terminal hydrocarbon groups is 5 to 100%, preferably 10 to 10% of the total number of the terminal groups.
95%, more preferably 10 to 90%. That is, when the number of terminal hydrocarbon groups is less than 5% of the total number of terminal groups, the thermal stability of the polyether amide is reduced, and during the melt polymerization of the polymer or the heat sterilization of the product,
This is because there is a possibility that generation of a low-molecular odor substance or a low-molecular compound may be observed. In addition, from the viewpoint of such thermal stability, it is desired that the number of hydrocarbon groups be close to 100% of the number of all terminal groups. It is desired that the degree of introduction be suppressed to some extent as described above.

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

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

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

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

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

Further, as the monocarboxylic acid used for the terminal modification, a monocarboxylic acid having about 2 to 23 carbon atoms is usually used, and specific examples thereof include acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, and enanthate. Acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid,
Such as aliphatic monocarboxylic acids such as tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, oleic acid, and linoleic acid, cyclohexanecarboxylic acid, and methylcyclohexanecarboxylic acid Alicyclic monocarboxylic acid,
Examples thereof include aromatic monocarboxylic acids such as benzoic acid, toluic acid, ethylbenzoic acid, and phenylacetic acid. In addition,
During the reaction, the corresponding derivatives that can play the same role as the acids,
For example, acid anhydrides, esters, amides and the like can be used.

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

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

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, examples of the non-solvent or poor solvent for the polyetheramide used as the coagulating liquid include water, glycols, glycerin and mixtures thereof, or the content of these non-solvents or poor solvents 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 when the cast polymer dope is brought into contact with such a coagulating liquid and coagulated depends on the composition of the coagulating liquid.
Generally, it is desirable that the temperature is -10 to 100C, preferably 3 to 35C.

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 as described above. 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 formed 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 may be composed of structural units represented by general formulas (1) to (4). 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 refers to 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 arranged and the micro phase separation structure is clarified. Presumed.

The characteristics of the permeable membrane of the present invention are not particularly limited, but typically, the water permeability is 1 to 400 m.
1 / m ² · hr · mmHg, preferably 4 to 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 at least 2.50 × 10 ⁻⁵ cm ² / min, and vitamin B ₁₂ (molecular weight 1
355) is 0.60 × 10 ⁻⁵ cm ² / min or more, preferably 0.70 × 10 ⁻⁵ cm ² / min or more.

[0045]

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

Example 1 Polyether amide obtained by polycondensing hexamethylenediamine and sebacic acid with diaminopolypropylene oxide to form an amide bond and further modifying the terminal with stearylamine (Mn: about 20,000, polyether content: 25% by weight, terminal modification rate: 31%) 99 g of formic acid (99 w / v%)
The solution was heated and dissolved in 51 g to obtain a solution having a polymer concentration of 22% by weight. This was allowed to stand at 30 ° C. for 2 hours to remove bubbles. This solution is cast to a certain thickness on the substrate in the gas phase, and immediately
dipped in a coagulation liquid controlled at 5 ° C. consisting of a mixture of aCl ₂ / methanol / water (weight ratio 1/3/5) for 5 minutes to coagulate, and then formic acid and coagulation liquid remaining in the coagulated film were added to running water And removed to obtain a sample. The obtained film has a thickness of 4 when wet.
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 an SEM photograph of the front surface of the film, FIG. 1B shows an SEM photograph of the back surface of the film, and FIG. 1C shows an SEM photograph of a 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
² / min.

[0049] Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

Further, a platelet dilatation test was performed by the method described below. Table 2 shows the results.

Example 2 Using a polyetheramide obtained in the same manner as in Example 1 except that the terminal modification rate was 47%,
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 thickness of 37 μm in a wet state.

Further, the obtained film was scanned with a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. In addition, FIG.
2B shows an SEM photograph of the back surface of the film, and FIG. 2C shows an SEM photograph of a cross section of the film.

[0053] Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

Further, a platelet dilatation test was performed by the method described below. Table 2 shows the results.

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

The obtained film was subjected to a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. In addition, FIG.
FIG. 3B shows an SEM photograph of the back surface of the film, and FIG. 3C shows an SEM photograph of the cross section of the film.

Further, the water permeability of the obtained membrane (measurement of water permeability 1) and the permeability to urea and vitamin B12 were examined by the method described later. Table 1 shows the results.

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

Further, the obtained film was subjected to a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. In addition, FIG.
FIG. 4B shows an SEM photograph of the back surface of the film, and FIG. 4C shows an SEM photograph of the cross section of the film.

[0060] Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

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

Further, the obtained film was subjected to a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. FIG. 5A shows the surface of this film,
FIG. 5B shows an SEM photograph of the back surface of the film, and FIG. 5C shows an SEM photograph of the cross section of the film. Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

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

Further, the obtained film was scanned with a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. FIG. 6A shows the surface of this film.
FIG. 6B shows an SEM photograph of the back surface of the film, and FIG. 6C shows an SEM photograph of the cross section of the film. Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

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

Further, the obtained film was subjected to a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. In addition, FIG.
FIG. 7B shows an SEM photograph of the back surface of the film, and FIG. 7C shows an SEM photograph of the cross section of the film. Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

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

Further, the obtained film was scanned with a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1. FIG. 8A shows the surface of this film,
FIG. 8B shows an SEM photograph of the back surface of the film.

[0069] Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

Example 9 The composition of the coagulating liquid was changed to 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 l ₂ / methanol / water / dimethyl sulfoxide was used. The obtained film had a thickness of 80 μm in a wet state.

The obtained film was subjected to a scanning electron microscope (S
Observation by EM) revealed that the film surface had a spherulite structure as in Example 1.

[0072] Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results.

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

[0074] Further, water permeability of the film obtained (Measurement of water permeability 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 shows the results. Further, a platelet dilatation test was performed by the method described below. Table 2 shows the results
Shown in

Example 11 The composition of the coagulating liquid was adjusted 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. The water permeability of the obtained membrane was measured by the method of measuring water permeability 1 described later, and it was 329 ml /
m was ² · hr · mmHg.

Example 12 Polyetheramide 10 obtained in the same manner as in Example 1
0 g was dissolved by heating in phosphoric acid (85% by weight aqueous solution) to obtain a solution having a polymer concentration of 20% by weight. This was defoamed by a centrifugal method. This was cast on the substrate in the gas phase at a constant thickness, and immediately CaCl ₂ / MeOH / water (weight ratio 2/5 /
7) The sample was immersed in a coagulation solution of 5 ° C., which was adjusted to a temperature of 5 ° C., for 10 minutes to coagulate, and then phosphoric acid and coagulation solution remaining in the coagulation film were removed with running water to obtain a sample. The obtained film had a 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 permeability of the obtained membrane was measured by the method of measuring water permeability 1 described later, and it was 37 ml / m ² · hr · mmHg.

Example 13 The composition of the coagulating liquid was adjusted to a weight ratio of 2/3/7 / CaCl ₂ / MeO.
A film was formed in the same manner as in Example 12 except that an H / water mixture was used. The obtained film had a 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 permeability of the obtained membrane was measured by the method of measuring water permeability 1 described later, and it was 9 ml / m ² · hr ·
mmHg.

Example 14 90 g of a block copolymer composed 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 at 30 ° C. for 2 hours to remove bubbles. This was cast on the substrate in the gas phase with a constant thickness, and immediately MeOH / water (weight ratio 7 /
3) The sample was immersed for 5 minutes in a coagulation solution controlled at 25 ° C. and coagulated, and the coagulation solution remaining in the coagulation film was removed with running water to obtain a sample. The obtained film had a thickness of 57 μm in a wet state. Observation of the obtained film with a scanning electron microscope (SEM) revealed that the film surface was in Example 1.
And had a spherulite structure. The water permeability of the obtained membrane was measured by the method of measuring water permeability 1 described later, and it was 44 ml / m ² · hr · mmHg. Further, the obtained membrane was subjected to (1) high-pressure steam sterilization at 121 ° C. for 20 minutes and (2) γ-ray sterilization (dose of 2 M) to perform an eluate test. In (1), ΔpH = 0.32, UV absorbance = 0.005, (2), ΔpH = 0.91, UV absorbance = 0.55.

Comparative Example 1 A dialysis membrane made of regenerated cellulose having a thickness of 27 μm (PT-
0.99, ENKA Co.) to water permeation amount in the same manner as in Example 1 (a water permeability measurement 1), was investigated by the method described below a permeability to urea and vitamin B _12. Table 1 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 in Example 1 by the method described below. Table 2 shows the results.

Comparative Example 3 Nylon 610 (Mn = 20,000) 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 placed on a glass plate with a uniform thickness. Then, hexafluoroisopropanol was completely evaporated in an oven at 40 ° C., and further vacuum-dried at room temperature to form a film. The thus obtained membrane was subjected to a platelet dilatation test in the same manner as in Example 1 by the method described below. Table 2 shows the results.

[0082]

[Table 1]

[0083]

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

As is clear from Table 2, the permeable membranes of Examples 1, 2 and 10 according to the present invention have less platelet adhesion as a whole than the permeable membranes of Comparative Examples 2 and 3. Particularly, 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
00g is dissolved by heating in 3800g of formic acid (99W / V%),
A solution having a polymer concentration of 24% by weight was obtained. After removing foreign substances using a filter, the mixture was depressurized and allowed to stand (30 ° C.) to remove bubbles. Using a hollow fiber forming nozzle, this was mixed with CaCl ₂ /
A MeOH / water (weight ratio 2/3/21) mixed solution was used as an internal liquid and extruded into a coagulation phase composed of the same liquid to coagulate.
A hollow fiber was wound on a bobbin. The obtained hollow fiber was immediately washed with running water, immersed in a 40% by weight aqueous solution of glycerin at 60 ° C. for 3 minutes to maintain the pore diameter, and then the inside of the hollow fiber was washed and further dried in an oven at 80 ° C. for 5 minutes. went. The obtained hollow fiber had an inner diameter of 337 μm and a thickness of 44 μm. The end of the hollow fiber was bundled with urethane resin, and the end was cut. The water permeation was measured using a mini-module created by cutting the terminal, and the water permeation was measured at 2 to be described later.
m was ² · hr · mmHg. Further, the sieving coefficient (SC) of albumin was measured in the bovine blood system by the method described later, and it was found that SC = 0.

Example 16 400 g of a block copolymer having a polyether portion composed of polypropylene oxide, a polyamide portion composed of nylon 12 and dimer acid, and having a terminal modified with stearylamine was used as a starting material.
The polymer was dissolved in 600 g of 3-dimethyl-2-imidazolidinone by heating to obtain a polymer solution. After removing foreign substances using a filter, the mixture was depressurized and allowed to stand (30 ° C.) to remove bubbles.
This was extruded into air using a hollow fiber forming nozzle, and cooled and solidified. The obtained hollow fiber was placed in a treatment solution containing dimethylformamide as a main component and kept at 100 ° C. for 60 hours.
Soak for minutes. Thereafter, the fiber was further immersed in a water bath maintained at 20 ° C. to obtain a hollow fiber. The obtained hollow fiber has an inner diameter of 22.
The thickness was 0 μm and the film thickness was 20 μm. The amount of water permeation of the obtained hollow fiber was measured by measuring water permeation 2 described below.
It was 5 ml / m ² · hr · mmHg.

As is clear from Examples 15 and 16, the hollow fibers formed with the permeable membrane according to the present invention were prepared in Examples 1 to
As in the case of No. 14, excellent water permeability is shown.

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

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

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

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

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

[0093]

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

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

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

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

Morphological Classification Type 1: Non-active Adhesion a: Normal disk shape. b: Spherical but not deformed to the point where pseudo feet are produced. Type 2: Active adhesion An object that has been stretched and sticky.

[0098]Dissolution test  Cut the membrane to a suitable size, and ion exchange 100 times the membrane weight.
Place the container in a water-filled container and treat it by autoclaving.
Liquid and time, and at 70 ± 5 ° C for gamma sterilization, 1
After heating and cooling for a time, the content solution is taken out and used as a test solution.

(1) Measurement of ΔpH Take 20 ml of each of the test solution and blank test solution, add 1.0 ml of a 1,000 ml solution prepared by dissolving 1.0 g of potassium chloride in water. And determine the difference.

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

[0101]Measurement of sieving coefficient (SC) of albumin  Using the same circuit as in the measurement 2 of water permeability, the circuit of FIG.
So that the outlet of the tube 18 is not recirculated
Change to pass, place container at outlet, rotary pump
Mini modules 16 in tubes 17, 18 with 14
And pressure gauges 15a and 15b near both ends.
Attached. Hematocrit 30 controlled to 37 ° C ± 1 ° C
%, Bovine blood 13 adjusted to a total protein of about 6.0 g / dl.
Immersed container 12 in constant temperature bath 11,
Insert the tip of tube 17
The end was connected to an outlet vessel to form a circuit. Inlet flow 1
0ml / min, pressure difference between mini-modules 100mmH
g and let the bovine blood flow through the circuit
After waiting, drain the filtrate from the inlet, outlet and vessel 19
SC from the concentration of each solution (BCG method)
Was. SC = C_F / ｛(C_Bi+ C_Bo) / 2｝ where C_F : Filtrate concentration C_Bi： Inlet side liquid concentration C_Bo: Outlet liquid concentration.

[0102]

As described above, the permeable membrane of the present invention comprises a structural unit represented by the structural formula (1), (2), (3) or (4), and has a terminal having 1 to 22 carbon atoms. A polyetheramide having a hydrocarbon group and a molecular weight of 10,000 to 100,000, wherein the number of the hydrocarbon groups is 5 to 100% of the total number of the terminal groups of the polyetheramide, and a terminal-modified polyamide is produced by a wet process. Because it is obtained as a membrane, it is excellent in biocompatibility such as antithrombotic properties, and has sufficient water permeability and low molecular weight as well as medium and high molecular weight material permeability, and is also heat stable Since it is highly resistant and generates very little harmful low molecular weight compounds due to the polymer production process or the heat sterilization treatment, it is suitably used in applications such as hemodialysis.

[Brief description of the drawings]

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

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

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

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

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

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

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

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

FIG. 9 is a perspective view showing a configuration of an apparatus for measuring a water permeability (measurement 1 of water permeability);

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

[Brief description of reference numerals]

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

Continued on the front page (72) Inventor Mitsuhide Nakagawa 1500 Inoguchi, Nakai-machi, Ashigara-gun, Kanagawa Prefecture Inside Terumo Corporation (56) References JP-A-5-123551 (JP, A) (58) Fields investigated (Int. . ^7, DB name) B01D 71/56

Claims (3)

(57) [Claims] 1. The following structural formula (1), (2), (3) or (4) Embedded image Embedded image Embedded image (Wherein, R ¹ , R ² and R ³ each have 2 to 4 carbon atoms)
R ⁴ , R ⁵ , and R ⁶ each represent an aliphatic, alicyclic, or aromatic hydrocarbon group having 2 to 36 carbon atoms; n is 0 to 180; ~ 400. ), Having 1 carbon atom at the terminal
Molecular weight of 10,000 to 10 having a hydrocarbon group of from 22 to 22
000 polyetheramides, wherein the number of hydrocarbon groups is 5 to 10 of the number of all terminal groups of the polyetheramides.
A permeable membrane excellent in biocompatibility obtained by wet-forming a terminally modified polyamide of 0%. 2. When the polyether part of the polyether amide is polypropylene oxide, the content thereof is 1
The permeable membrane according to claim 1, wherein the content is 5 to 30% by weight, and in the case of polytetramethylene glycol, the content is 30 to 55% by weight. 3. The permeable membrane according to claim 1, wherein the polyetheramide has biocompatibility by having a spherulite structure.