JPH06262046A - Transmission membrane with excellent bio-compatibility - Google Patents

Abstract

PURPOSE:To obtain a permeable membrane with excellent bio-compatibility and high safety by using a poly(etheramide) resin with a repeating structural unit of a specified structural formula and specified mean mol.wt., equivalent no. of a terminal amino group and equivalent no. of a terminal carboxylic group. CONSTITUTION:A poly(etheramide) resin with a repeating structural unit of formula I or II, a mean mol.wt. of about 10,000-100,000, an equivalent no. of the terminal amino group ([NH2]mueq/g) of at most 40 and in a range of [COOH] >=[NH2]+5 to the equivalent no. of the terminal carboxylic group ([COOB]mueq/ g) is used. In the formulas, R<1>, R<2> and R<3> are each a 2-4C linear or branched alkylene group; R<4>, R<5> and R<6> are each a 2-24C linear or branched alkylene group; n, m and X are respectively an integer of 0-180, 1-400 and 0 or 1.

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

◎

[Chemical 3] ◎

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

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 during wet film formation is formic acid, and the coagulating liquid is a hydrous alcohol with a metal salt added. 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.

[0012]

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

◎

[Chemical 5] ◎

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

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

Next, the raw material polyamide will be described. (1) A polymer having a carboxyl group and an amino group at the end.
Liamide The above polyamide can be directly obtained by ring-opening polycondensation of a lactam having 3 or more members, polycondensation of a polymerizable ω-amino acid or polycondensation of a dicarboxylic acid and a diamine.
As a specific example, for example, nylon 4, 6, 7, 8, 1
1, 12, 6.6, 6.9, 6.10, 6.11, 6.12,
6T, 6 / 6.6, 6/12, 6 / 6T and the like.

(2) A polymer having a carboxyl group at both ends
Liamides and polyamides having amino groups at both ends As the above-mentioned polyamides, polyamides having carboxyl groups at both ends are obtained by adding a dicarboxylic acid to a basic polyamide by ring-opening polycondensation of a lactam. The basic polyamide is obtained by adding a diamine to the same basic polyamide. In the case of a polyamide produced by polycondensation of a dicarboxylic acid and a diamine, by using any of the raw materials in an amount equal to or more than the theoretical amount, directly obtain as a polyamide having carboxyl groups at both ends or a polyamide having amino groups at both ends. You can

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

◎

[Chemical 7] ◎

[Chemical 8]

The structural formula (1) is a repeating structural unit obtained by condensing a polyether having amino groups at both ends and a polyamide having carboxyl groups at both terminals, and the structural formula (2) is a carboxyl group at both ends. Is a repeating structural unit obtained by condensing the above polyether and a polyamide having amino groups at both ends.

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

Further, in the above structural formulas (1) and (2), the combination of the carbon number of the alkylene group of the polyether structural unit and the polyamide structural unit is not particularly limited, but with respect to the polyether structural unit. A combination that provides a microphase-separated structure is preferable, and this provides a higher antithrombotic property. Examples of such a combination include a combination in which R ³ is an octamethylene group and R ⁴ is a hexamethylene group.

The material constituting the medical permeable membrane of the present invention is
For example, it can be obtained by carboxyl-modifying the terminal amino group with a dicarboxylic acid using the poly (ether amide) as described above. As the terminal-modifying dicarboxylic acid, various dicarboxylic acids having 2 to 24 carbon atoms described above as one kind of polyamide raw material are preferably used. In particular, when the starting polyamide for poly (ether amide) is a polyamide derived from a dicarboxylic acid, it is preferable to use the same dicarboxylic acid as the dicarboxylic acid. As the dicarboxylic acid, specifically, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanoic acid, dodecanedioic acid, tridecadioic acid, tetradecadioic acid, hexadecane. Acid, hexadecenedioic acid, octadecadionic acid, eicosandioic acid, eicosendionic acid, eicosadiendioic acid, docosandionic acid, 2,
Aliphatic dicarboxylic acids such as 2,4-trimethyladipic acid, alicyclic dicarboxylic acids such as 1,4-cyclohexanedicarboxylic acid, aromatic dicarboxylic acids such as terephthalic acid, isophthalic acid, phthalic acid, xylylenedicarboxylic acid Acid etc. are mentioned.

The above-mentioned terminal-modified poly (ether amide) can be produced by a known condensation reaction. First, obtain the target polyamide from the polyamide raw material,
Next, the above-mentioned polyether having the terminal group appropriately modified is added to this, and a condensation reaction is carried out. The dicarboxylic acid for modifying the end of poly (ether amide) can be added at any stage from the start of the condensation reaction to the start of the reaction under reduced pressure. In addition to the above production method, in the condensation reaction, use of a polyamide or polyether (compound derived from a carboxyl group) having both ends with carbonyl groups and a polyamide or polyether (compound derived from an amino group) having both ends with an amino group By reducing the ratio, it is possible to produce without using the terminal-modifying dicarboxylic acid.

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

The number average molecular weight of the poly (ether amide) according to the present invention is in the range of about 10,000 to 100,000, preferably 15,000 to 50,000. The above number average molecular weight is determined by obtaining the total number of end group equivalents (total equivalent of amino groups and carboxyl groups μeq / g), and
The value calculated by

◎

[Equation 1]

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

In the permeable membrane of the present invention, the above-mentioned polyether amide modified at the terminal with dicarboxylic acid is dissolved in a good solvent, and the obtained polyether amide solution is cast on, for example, a substrate. To obtain a desired shape by contacting it with a non-solvent, or a coagulating liquid consisting of a poor solvent,
It is obtained by coagulation by extracting and removing a good solvent.

Examples of 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 prepared 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 and mixtures thereof, or the content of these non-solvents or poor solvents 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 above good solvent 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, the mixing ratio of each component is water: methanol: metal salt (saturated liquid) in a weight ratio of 1 to 1.
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 forming 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 possible that the matrix is composed of structural units represented by the general formulas (1) and (2). 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 exhibits good antithrombotic property. It is considered to be a thing. Furthermore, the fact that such polyether amide is 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 centering on a nucleus and crystallized into one sphere, which is observed by a scanning electron microscope (SEM).
Appear as a hemispherical or similar shaped protrusion.

The principle of obtaining excellent antithrombotic properties by using spherulites is not clear, but 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 600 ml.
/ M ² · hr · mmHg, preferably 4-400 ml / m ² · hr · mmHg,
The permeability of urea (molecular weight 60) as a low molecular weight substance is 1
00 × 10 ^-4 cm / min or more, preferably 200 × 10 ^-4 c
Vitamin B as m / min or more and medium molecular weight substance
₁₂ (molecular weight 1355) has a permeability of 20 × 10 ^-4 cm / min
The above is preferably 30 × 10 ⁻⁴ cm / min or more.

[0039]

EXAMPLES Hereinafter, the present invention will be described more specifically by way of examples. (Examples 1 to 6) Table 1 was added to a 50 liter autoclave.
The sebacic acid, the nylon 610 salt and the polyether raw material described in 1 above, and water were charged, and the mixture was sealed in an N ₂ atmosphere, heated to 240 ° C. at a constant pressure (10 KG), and reacted for 4 hours with stirring. Then, the pressure was gradually released to 10 mmHg, and the reaction was continued for 2 hours. The stirring was stopped, N ₂ was introduced, the pressure was restored to normal pressure, and the strand was extracted and pelletized. The results of analyzing the obtained pellets are shown in Table 3.

(Examples 7 and 8) A 200 liter autoclave was charged with the polyamide raw materials shown in Table 2 and N
₂ Place it in an atmosphere and seal it at a constant pressure (10 KG) for 24
The temperature was raised to 0 ° C., and the reaction was performed for 2 hours with stirring. Then, the polyether raw material and the terminal modifier (dicarboxylic acid) shown in Table 2 were added, and a pressure reaction was carried out for 2 hours while stirring. Then, the pressure was gradually released to a predetermined pressure, and the reaction was continued for 2 hours. The stirring was stopped, N ₂ was introduced, the pressure was restored to normal pressure, and the strand was extracted and pelletized. The results of analyzing the obtained pellets are shown in Table 3.

◎

[Table 1]

◎

[Table 2]

◎

[Table 3]

Example 9 The block copolymer obtained in Example 1 (polyether content = 4.2%) 311.7
g was heated and dissolved in 1105.1 g of formic acid (99 w / v%) to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 30 poise (P) and 30 ° C. 2 at 30 ℃
It was left to stand for a period of time to defoam. This is cast in a gas phase on a substrate to a certain thickness and immediately EtOH / H ₂ O (weight ratio 3/7)
The sample was obtained by dipping for 5 minutes in a coagulation phase whose temperature was controlled at 5 ± 1 ° C. to coagulate, and then formic acid and coagulation liquid remaining on the coagulation film were removed with running water. The obtained film is 44μ in the wet state.
It was m. In addition, the obtained film was scanned with an electron microscope (S
When observed by EM), the film surface had a spherulite structure. A photograph of the film surface is shown in FIG. 1, and a photograph of the cross section is shown in FIG. Further, the water permeation rate (Measurement of water permeation rate 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 4. Further, a platelet expansion ability test was performed by the method described below. The results are shown in Table 5. Further, the obtained membrane was subjected to high-pressure steam sterilization at 121 ° C. for 20 minutes and subjected to a solute test by the method described below, where ΔpH = −0.57,
UV absorbance = 0.027.

Example 10 Block copolymer obtained in Example 2 (polyether content = 10.2%) 60.
0 g was heated and dissolved in 212.7 g of formic acid (99 w / v%) to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 20 poise (P) and 30 ° C. 2 at 30 ℃
It was left to stand for a period of time for defoaming. This was cast in a gas phase to a certain thickness on a substrate and immediately cast into a solidified phase composed of CaCl ₂ / MeOH / H ₂ O (weight ratio 1/3/7) at a temperature of 5 ± 1 ° C.
The sample was obtained by dipping for a minute to coagulate and then removing the formic acid and coagulation liquid remaining on the coagulation film with running water. The resulting film had a wet state of 24 μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, the water permeation rate (Measurement of water permeation rate 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 4. Further, a platelet expansion ability test was performed by the method described below. The results are shown in Table 5.
Shown in.

(Embodiment 11) The composition of the solidification phase is MeOH / H.
_A film was formed in the same manner as in Example 10 except that ₂ O (weight ratio 4/6) was used. The obtained film had a wet state of 27 μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, the water permeation rate (Measurement of water permeation rate 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 4.

Example 12 Block copolymer obtained in Example 3 (polyether content = 9.7%) 54.0
g was dissolved in 191.5 g of formic acid (99 w / v%) by heating,
A solution having a polymer concentration of 22% by weight was obtained. Solution viscosity is 1
It was 7 poise (P) and 30 ° C. This was left standing at 30 ° C. for 2 hours to defoam. This is cast in a gas phase on a substrate to a certain thickness and immediately immersed in a coagulation phase composed of EtOH / H ₂ O (weight ratio 3/7) at a temperature of 5 ± 1 ° C for 5 minutes for coagulation. Then, the formic acid and the coagulation liquid remaining on the coagulation film were removed with running water to obtain a sample. Example 1 except that the solidification phase composition was changed
A film was formed in the same manner as in 3. The membrane obtained is 38 in the wet state.
was μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, the water permeation rate (Measurement of water permeation rate 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 4.

Example 13 The solidification phase composition was changed to CaCl ₂ /
A film was formed in the same manner as in Example 12 except that MeOH / H ₂ O (weight ratio 1/3/10) was used. The resulting film had a wet state of 24 μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, the water permeation rate (Measurement of water permeation rate 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 4.

Example 14 The block copolymer obtained in Example 4 (polyether content = 6.69%) 63.
3 g was dissolved in 224.5 g of formic acid (99 w / v%) by heating to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 88 poise (P), 30 ° C. 2 at 30 ℃
It was left to stand for a period of time to defoam. This is cast in a gas phase on a substrate to a certain thickness and immediately MeOH / H ₂ O (weight ratio 3/7)
The sample was obtained by dipping for 5 minutes in a coagulation phase whose temperature was controlled at 5 ± 1 ° C. to coagulate, and then formic acid and coagulation liquid remaining on the coagulation film were removed with running water. The film obtained is 75μ in the wet state.
It was m. In addition, the obtained film was scanned with an electron microscope (S
When observed by EM), the film surface had a spherulite structure. Further, the water permeation rate (Measurement of water permeation rate 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 4. Further, a platelet expansion ability test was performed by the method described below. The results are shown in Table 5.

Example 15 Block copolymer (polyether content = 12.0%) 4 obtained in Example 5
0.0g was dissolved in 141.8 g of formic acid (99w / v%) by heating to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 36 poise (P), 30 ° C. This was left standing at 30 ° C. for 2 hours to defoam. This was cast in a gas phase to a certain thickness on a substrate and immediately cast into a solidified phase composed of CaCl ₂ / MeOH / H ₂ O (weight ratio 1/3/7) at a temperature of 5 ± 1 ° C. The sample was obtained by dipping for a minute to coagulate and then removing the formic acid and coagulation liquid remaining on the coagulation film with running water. The obtained film had a wet state of 58 μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. 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 4.

Example 16 The block copolymer (polyether content = 14.5%) 6 obtained according to Example 6
4.2 g of formic acid (99 w / v%) was dissolved in 227.6 g by heating to obtain a solution having a polymer concentration of 22% by weight. The viscosity of the solution was 25 poise (P) and 30 ° C. This was left standing at 30 ° C. for 2 hours to defoam. This was cast in a gas phase on a substrate to a certain thickness and immediately cast into a solidified phase of CaCl ₂ / MeOH / H ₂ O (weight ratio 2/3/10) controlled at 5 ± 1 ° C. The sample was obtained by dipping for a minute to coagulate and then removing the formic acid and coagulation liquid remaining on the coagulation film with running water. The obtained membrane had a wet state of 48 μm. When the obtained film was observed with a scanning electron microscope (SEM), the film surface had a spherulite structure. Further, the water permeation rate (Measurement of water permeation rate 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 4.

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

Comparative Example 2 A commercially available polypropylene film (FOP # 60, manufactured by Nimura Kagaku) was used in Example 1.
Similarly to the above, a platelet expansion ability test was performed by the method described below.
The results are shown in Table 5.

◎

[Table 4]

◎

[Table 5]

Example 17 1410 g of the block copolymer (polyether content = 4.2%) of Example 1 was dissolved in 5000 g of formic acid (99 W / V%) by heating to give a solution having a polymer concentration of 22% by weight. Obtained. After removing foreign matters using a filter, decompression was performed by depressurizing and standing (30 ° C.).
Using a hollow fiber molding nozzle, MeOH / H ₂ O
(Weight ratio 3/7) was extruded as an internal liquid into a solidification phase consisting of MeOH / H ₂ O (weight ratio 6/4) to solidify, and then wound on a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 15.5 ° C. The obtained hollow fiber was immersed in a glycerin aqueous solution at 60% by weight and room temperature for 10 minutes to maintain the pore size, and then dried in an oven at 45 ° C. for 10 minutes. The mini-module made by bundling the hollow fiber ends with urethane resin and cutting the ends has an inner diameter of 200μ and a film thickness of 2
The water permeability (measurement 2 of water permeability) measured by the method described below is 80 ml / m ² · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ is 57 × 10 ⁻⁴ cm / min. It was

(Example 18) 1410 g of the block copolymer (polyether content = 6.69%) of Example 5
Was dissolved in 5000 g of formic acid (99 W / V%) by heating to obtain a solution having a polymer concentration of 22% by weight. After removing foreign matters using a filter, decompression was performed by depressurizing and standing (30 ° C.). Using a hollow fiber molding nozzle, MeOH / H ₂
MeOH / H ₂ O with O (weight ratio 2/8) as internal liquid
After extruding into a coagulation phase consisting of (weight ratio 4/6) to coagulate, it was wound on a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 9.5 ° C. The obtained hollow fiber is 60% by weight for maintaining the pore size, and 10% in a room temperature glycerin aqueous solution.
After soaking for a minute, it was dried in an oven at 45 ° C. for 10 minutes. The mini module produced by bundling the ends of the hollow fibers with urethane resin and cutting the ends had an inner diameter of 250μ and a film thickness of 20μ, and the water permeation amount (water permeation amount measurement 2) measured by the method described later was 75 ml / m 2. ^{It was 2} · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ was 52.2 × 10 ⁻⁴ cm / min.

(Example 19) 1410 g of the block copolymer (polyether content = 24.0%) of Example 7
Was dissolved in 5000 g of formic acid (99 W / V%) by heating to obtain a solution having a polymer concentration of 22% by weight. After removing foreign matters using a filter, decompression was performed by depressurizing and standing (30 ° C.). Using a hollow fiber molding nozzle, MeOH / H ₂
MeOH / H ₂ O with O (weight ratio 3/7) as internal liquid
After extruding into a coagulation phase consisting of (weight ratio 4/6) to coagulate, it was wound on a bobbin to obtain a hollow fiber. The solidification phase temperature at this time was 13.5 ° C. The obtained hollow fiber was immersed in a glycerin aqueous solution at 60% by weight and room temperature for 10 minutes to maintain the pore size, and then dried in an oven at 45 ° C. for 10 minutes. A mini module produced by bundling this hollow fiber end with urethane resin and cutting the end has an inner diameter of 250μ,
The film thickness is 45μ, and the water permeability (water permeability measurement 2) measured by the method described later is 18 ml / m ² · hr · mmHg, and the solute permeability coefficient of vitamin B ₁₂ is 28.2 × 10 ⁻⁴ cm. It was / min. In addition, using the above hollow fiber, an extracorporeal rabbit experiment was carried out by the method described below, and the changes in white blood cell count and platelets over time were determined. The results are shown in FIG. 3 (white blood cells) and FIG. 4 (platelets).

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

Comparative Example 3 A rabbit extracorporeal circulation experiment was conducted on a dialysis hollow fiber (CL-C, manufactured by Terumo Co., Ltd.) composed of regenerated cellulose by the method described below in the same manner as in Example 19 to determine the white blood cell count. The time change of platelets was calculated. The result is shown in Figure 3.
(White blood cells) and FIG. 4 (platelets).

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

(Example 21) Using the hollow fiber obtained in Example 19, the amount of C3a produced was measured by the method described below. Results are shown in FIG. (Comparative Example 5) Hollow fiber for dialysis (C
(L-SS, manufactured by Terumo Corp.), the amount of C3a produced was measured by the method described below as in Example 21. Results are shown in FIG. (Comparative Example 6) The production amount of C3a was measured by the method described below in the same manner as in Example 21 with respect to a dialysis hollow fiber (KF101-15C, manufactured by Kuraray) made of an ethylene vinyl alcohol copolymer. Results are shown in FIG.

The measuring methods and testing methods of the respective characteristic values shown in this specification are as follows. Intrinsic Viscosity Using an Ubbelohde viscosity tube, it was determined at 1% concentration in m-cresol (30 ° C.). Terminal group analysis Amino groups were dissolved in phenol and titrated with 0.05N hydrochloric acid for measurement. The carboxyl group was dissolved in benzyl alcohol and titrated with 0.1N caustic soda for measurement. Eluate test method Cut the membrane into an appropriate size, put it in a container containing 100 times the weight of the ion-exchanged water, heat it at the treatment temperature and time of high-pressure steam sterilization, and remove the contents after cooling. Use the test solution. (1) △ pH Take 20 ml each of the test solution and blank test solution, add 1.0 ml of a solution prepared by dissolving 1.0 g of potassium chloride in water to 1000 ml, measure the pH of both solutions, and determine the difference. (2) UV Absorbance Using the blank test solution as a control, determine the maximum absorbance at wavelengths of 220 nm to 350 nm.

Measurement of Water Permeability 1 A flat membrane punched out to a diameter of 43 mm is set in a cell as shown in FIG. Then, using distilled water adjusted to 37 ± 1 ° C., 100 mmHg (variation rate 1
Apply air pressure (within 0%). In this state, after standing by for 30 minutes, the relationship between the amount of distilled water flowing out and time is obtained and the amount of water permeation is converted from this. Measurement of Water Permeability 2 As shown in FIG. 7, the mini-module 16 was connected to 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 was adjusted to 1 ° C. was immersed in a constant temperature bath 11, and a tube 17 was placed in the physiological saline solution 13.
The end of the tube 18 while inserting one end of the tube 18 into the container 12
To form a circuit. Inlet side flow rate 10 ml / mi
n. , The pressure difference between the mini-modules was set to 100 mmHg, the physiological saline was circulated in the circuit, and after waiting for a steady state, the outflowing physiological saline was taken in the container 19 and the relationship between the amount of physiological saline and the time was calculated to determine the membrane area. Converted. Material permeability (1) Urea Distilled water and concentration 100m through a flat membrane punched out in a circle
Using a cell in which g / dl aqueous urea solution is in contact through the membrane, each liquid is stirred at a constant speed.
The respective concentrations after 0 minutes and after 150 minutes are obtained. From this concentration, the substance permeability is determined based on the following equation (2).
The urease indophenol method was used to quantify urea. (2) Vitamin B ₁₂ was carried out in the same manner as for urea, except that the 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. ◎

[Equation 2] (In the formula, A represents a membrane area (cm ² ), and ΔC (t) represents a difference in solute concentration after t minutes in the cell.)

Module Solute Permeability As shown in FIG. 8, mini-module 37 was connected to tubes 33 and 34 equipped with rotary pump 32. 37
The physiological saline 36 adjusted to ± 1 ° C. and the vitamin B ₁₂ aqueous solution 35 having a concentration of 5 mg / dl were immersed in a thermostatic bath 38, and the tube 3
The tips of 3, 34 were put in an aqueous solution of vitamin B ₁₂ 35, and the mini-module 37 was dipped in physiological saline 36 to form a circuit. Circulation flow rate in the mini module has a linear velocity of 100 cm
It was set to be / min. The solute permeability coefficient was calculated according to the following equation 3. The measurement was performed at time 0 and 120 minutes. ◎

[Equation 3] (In the formula, A is a membrane area, CB is a solute aqueous solution (blood side) concentration, CD is a physiological saline (dialysis solution side) concentration, VB and VD are volumes, and t is time.) Platelet dilatability test 3. 8 w / v% sodium citrate is added so as to have a volume of 1/9, and blood is collected 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 P
The number of plasma plates in the RP is determined by the multi-item blood test apparatus (Sysme
x NE-6000, manufactured by Toa Medical Electronics Co., Ltd. After separating the PRP, it is further centrifuged at 3000 rpm for 10 minutes to collect PPP (platelet poor plasma). The PRP was diluted with the obtained PPP to obtain a platelet count of 10 ⁵ /
Adjust to μl. Cut the permeable membrane sample into 8mm squares and
Diluted PR with platelets adjusted as described above by attaching to M sample table
P200 μl is dropped on the sample piece. Then, the PRP layer is pressed down from above by a lid of a petri dish (made of polystyrene) so that the thickness of the PRP layer becomes 2 mm. Then, it is allowed to stand at room temperature for 30 minutes. Then, the test piece was lightly washed with 0.01 M phosphate buffered saline, pH 7.0 (PBS) /3.8 w / v% sodium citrate mixed solution (weight ratio 9/1), and then 1 w / v of glutaraldehyde. 4% in PBS solution
Fix at (2-8 ° C) overnight. After the immobilized test piece is washed with PBS, it is further washed with distilled water and freeze-dried. Then, ion sputtering (1
After performing 2 KV, 6 minutes), photographs are taken in 5 fields of view. From the obtained photographs, the adhered platelets are classified based on the following criteria, and the number of adhered cells is calculated. Morphological classification I: Inactive adhesion a: Disk shape in a normal state b: Spherical shape but not deformed to the point where it gives false feet II: Active adhesion

Extracorporeal Rabbit Circulation Experiment 1. Preparation of Module for Extracorporeal Circulation Test FIG. 9 shows a module for extracorporeal circulation of a dialyzer, which will be specifically described. The dialyzer 1 was prepared by inserting the hollow fiber bundle 2 into the cylindrical main body 3, fixing both ends with the polyurethane potting agents 4, 5, and further fixing the headers 6, 7 with the caps 8, 9 at both ends. In the figure, 10 is a dialysate inlet pipe, and 11 is an outlet pipe. The film area was 300 cm ² . 2. Extracorporeal circulation test Rabbits were fixed on the Kitajima type fixed base in the dorsal position. Then, the hair of the surgical field was cut with an electric hair clipper and wiped with alcoholic cotton. An incision was made with scissors from the submandibular region to the clavicle along the midline, and the right (left) common carotid artery was dissected, taking care not to damage the nerve, branch vessels and surrounding tissues by opening the peritoneum. Then, the left (right) facial vein was similarly deeply peeled off with care, and a SURFLOW indwelling catheter manufactured by Terumo Co., Ltd. equipped with a mixed injection rubber cap filled with 1 IU / ml heparinized saline was inserted and fixed by ligation. Similarly, a catheter was inserted into the artery and ligated and fixed. An experimental circuit was prepared using the above dialyzer for the four rabbits thus prepared. That is, as shown in FIG. 10, the catheter 21 connected to the artery of the rabbit 20 was connected to the pump 22, and the chamber 23 and the vein of the rabbit 20 were connected to each other by the catheter 25. Pump 22 and dialyzer 1 are tubes 2
6 and the tube 26 is a manometer in 27.
It communicates with the side. Further, a tube 28 was used to connect the dialyzer 1 and the chamber 23, which was connected to the out 24 side of the manometer. On the other hand, the dialysate inlet / outlet of the dialyzer 1 was connected by a tube 29, a pump 30 was installed in the tube 29, and the dialyzer 1 was immersed in a 37 ° C. water bath. The extracorporeal blood flow has a linear velocity of 100 cm / m in the fiber.
It was set to be in. At this time, no anticoagulant was used. 5 minutes, 10 minutes, 15 minutes, 20 minutes, 3 after starting circulation
After 0 minutes, 45 minutes, 60 minutes, and 120 minutes, 1 ml of blood was collected and anticoagulated with 1.5% EDTA-2Na physiological saline, and then a multi-item blood test apparatus (Sysmex NE-60) was used.
00, manufactured by Toa Medical Electronics Co., Ltd., to count blood cells.
The hematocrit (Ht) correction was performed using the order of 4 for the white blood cell count and the platelet count, and the values were the Ht values before the start of circulation. ◎

[Equation 4]

C3a experiment by mini-module 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 was centrifuged at 3000 rpm for 10 minutes to collect PPP (poor platelet plasma). PPP recovered
Were stored on ice until used in the experiment. The sample used in the experiment was a mini module with a membrane area of 300 cm ² ,
After washing with 00 ml of physiological saline (saline), it was stored in a state of being filled with a saline until it was used in the experiment. However, in order to prevent the movement of water and the like inside and outside the dialysate, a hollow fiber portion of the module fixed with urethane resin was used. Connect a syringe to the mini module, suck 4 ml of PPP to completely replace the saline in the module with PPP, close both ends of the module with caps, and transfer to a 37 ° C constant temperature water bath.
A time incubation was performed. Then, the module was immersed in ice water to stop the activation reaction of the complement system.
Once again, a syringe was attached to the mini-module, the PPP in the module was collected in a glass test tube containing a stabilizer (EDTA-2K), and stored frozen until C3a measurement. C3a measurement was performed by the RIA2 antibody method.

[0068]

As described above, the average molecular weight of the present invention modified with a dicarboxylic acid at the end is 10,000 to 100,0.
No. 00, the equivalent number of terminal amino groups is 40 or less, and the equivalent number of terminal carboxyl groups is (equal number of terminal amino groups +5) or more, the permeable membrane obtained by wet film formation is antithrombogenic. It has excellent biocompatibility such as properties, and also has sufficient water permeability, low molecular weight, and medium and high molecular weight substance permeability. Furthermore, it has high thermal stability and is caused by the polymer manufacturing process or overheat sterilization treatment. Since the generation of harmful low-molecular compounds is extremely small, it can be preferably used in applications such as hemodialysis.

[0069]

[Brief description of drawings]

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

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

FIG. 3 shows the numbers of white blood cells in the rabbit extracorporeal circulation experiment of Example 19 and Comparative Examples 3 and 4.

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

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

FIG. 6 shows a cell for measuring water permeability.

FIG. 7 shows a circuit for measuring water permeability.

FIG. 8 depicts a circuit for module solute permeability.

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

FIG. 10 shows a rabbit extracorporeal circulation experiment.

[Explanation of symbols]

1 ... dialyzer, 2 ... hollow fiber bundle, 3 ... cylindrical body, 4,5 ... potting material, 6,7 ... header, 8,
9 ... Cap, 10 ... Inlet pipe, 11 ... Outlet pipe, 20 ...
..Rabbits, 21 ... Catheter, 22 ... Pump, 23 ... Chamber, 24 ... Manometer out, 25 ... Catheter, 26 ... Tube, 27 ... Manometer in, 2
8 ... Tube, 29 ... Tube, 30 ... Pump, 3
1 ... Water bath, 32 ... Rotary pump, 33, 34 ... Tube, 35 ... Vitamin B ₁₂ aqueous solution, 36 ... Saline solution, 37 ... Mini module, 38 ... Constant temperature Tank, 100 ...
・ Upper lid, 101 ... O-ring, 102 ... Membrane (sample),
103 ... Mesh, 100 '... Lower lid

Front page continuation (72) Inventor Toshio Nakajima 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Terumo Corporation

Claims (1)

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