JP2002030125A - New hydrophilized aromatic polymer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hydrophilized aromatic polymer which is applicable in the field of medical treatment or food industry and has non-adhesiveness to a protein, biocompatibility, good mechanical properties and heat resistance. SOLUTION: The hydrophilized aromatic polymer is characterized in that the main chain of the polymer is composed of repeating units having their respective aromatic rings to at least one of which a side chain having hydrophilic vinyl polymer regions is covalently bonded provided that the hydrophilic vinyl polymer regions have a total electric charge of zero. There are disclosed a method for producing the hydrophilized aromatic polymer and a use for a selective permeation membrane or a catheter.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a hydrophilic aromatic polymer. More specifically, the present invention is suitable as a material for a biological material, a catheter, a dialysis membrane, a plasma separation membrane, an ultrafiltration membrane, a microfiltration membrane, a reverse osmosis membrane, etc. The present invention relates to a hydrophilicized aromatic polymer having the following formula: The present invention also relates to a method for producing the hydrophilicized aromatic polymer, a permselective membrane using the hydrophilicized aromatic polymer, and a catheter.

[0002]

2. Description of the Related Art Aromatic polymers represented by polysulfone resins, polyetherimide resins and polyester resins have been developed in various fields because of their good mechanical properties and heat resistance. . In particular, polysulfone has been used as a material for permselective membranes such as dialysis membranes and ultrafiltration membranes because of ease of membrane formation, control of pore size and pore size distribution.

However, aromatic polymers are hydrophobic, and when used in the recovery of aqueous protein solutions, in the field of food, or in the recovery of micelles such as paints, proteins and micelles are adsorbed on the membrane surface because of their hydrophobicity ( The so-called fouling phenomenon (Higuchi et al., Membrane Science and Technology)
(Y. Osada & T. Nakagawa Ed.), Marcel Dekker, In
c., New York, chp. 8 (1992)), causing a marked decrease in membrane ultrafiltration.

[0004] Various attempts have been made to improve the disadvantage of the aromatic polymer being hydrophobic. For example, it has been reported that polysulfone hollow fiber membranes are immersed in concentrated sulfuric acid for sulfonation (JP-A-55-36296).
However, when a charged group that is hydrophilic is directly introduced into the main chain, the mechanical strength characteristic of polysulfone itself is significantly reduced. In order to prevent this, a method of introducing a hydrophilic charged group into the main chain via a spacer (joint group) has been developed. For example, sulfonated polysulfone having a spacer (joint group) introduced from the dissociation reaction of propane sultone (JP-A-62-269704), amidomethylated polysulfone (JP-A-6-500925) and the like. After preparing chloromethylated polysulfone,
A method for introducing one into the introduced side chain has also been reported (Higuchi et al., J. Appl. Polym. Sci., 46, 449 (1992)).

However, the aromatic polymer derivative prepared here has a problem in biocompatibility because it has only a simple hydroxyl group introduced or is positively or negatively charged. For example, it is known that platelets are activated on the surface of a polymer having a positive charge, and change platelets into a form in which pseudopodia are extended. It should be noted that the change to the form in which the pseudopod is extended refers to a change in the cell in which the foot extends from the cell and becomes flat, and is an expression often used in a cell system. Further, it is known that bradykinin, which is a powerful physiologically active substance that induces a decrease in blood pressure and the like, is produced on the surface of a negatively charged polymer membrane. In addition, it is known that, in a charged aromatic polymer membrane, the amount of water permeation and protein adsorption are significantly affected by pH.

Furthermore, when a simple hydroxyl group is introduced into an aromatic polymer, a remarkable immune response is caused. At present, a polymer having a hydroxyl group covalently introduced into an aromatic polymer is used. There are no examples used for permselective membranes and medical materials.

In the medical field, polysulfone has recently been used as a dialysis membrane material. The reason for this is
Serum albumin (molecular weight: 67,000 daltons) useful for a living body is retained in blood by dialysis, and a protein having a molecular weight of about 30,000 daltons or less, for example, β2
-Removal of microglobulin (molecular weight 11,500 daltons) outside the body has recently been required for dialysis membranes. To do this, control the pore size of the dialysis membrane,
Further, a dialysis membrane having a sharp pore size distribution must be prepared. Polysulfone has been widely used as a dialysis membrane material that satisfies this requirement because of its ease of membrane formation, control of pore size and pore size distribution.

However, polysulfone itself is hydrophobic and poor in biocompatibility, and polyvinylpyrrolidone and the like are blended in the polysulfone membrane in order to render the polysulfone hydrophilic and impart biocompatibility (Japanese Patent Application Laid-Open No. 61-9380).
1) Further, a method has been proposed in which polyvinylpyrrolidone itself is crosslinked using a polysulfone membrane as a matrix to prepare a polyvinylpyrrolidone gel-containing polysulfone hollow fiber membrane (JP-A-4-300636). In the case of a blend membrane of polyvinylpyrrolidone and polysulfone, the polyvinylpyrrolidone gel-containing polysulfone membrane described above was developed because polyvinylpyrrolidone flows out of the membrane.

[0009] Polyvinylpyrrolidone is an uncharged polymer known to be hydrophilic despite the absence of hydroxyl groups in the molecule. By introducing this hydrophilic polymer into a hydrophobic aromatic polymer, the problems of poor protein adsorption and biocompatibility, which are defects of the hydrophobic aromatic polymer, are overcome, and protein non-adsorption is achieved. Optimum state as a biocompatible material is imparted.

[0010] However, it has been pointed out that polyvinyl pyrrolidone is also eluted from the polyvinyl pyrrolidone gel-containing polysulfone hollow fiber membrane. For example, in the case of the polyvinylpyrrolidone gel-containing polysulfone membrane prepared in Example 1 described in JP-A-4-300636, the absorbance of the extract from the hollow fiber membrane is as high as 0.046, and the polyvinylpyrrolidone is completely discharged. Has not been completely prevented. Further, in the case of a blend membrane of polyvinylpyrrolidone and polysulfone, the absorbance of the extract from the hollow fiber membrane is higher than 0.265 to 1.020 (Comparative Examples 1 to 6 described in JP-A-4-300636). As shown, high levels of polyvinylpyrrolidone efflux from the membrane were caused.

On the other hand, as a polymer for imparting hydrophilicity and improving biocompatibility, in addition to non-charged polyvinylpyrrolidone, an amphoteric (zwitter ionic) polymer has attracted attention. For example, Ishihara et al. Developed a biocompatible phospholipid polymer (2-methacryloxyethylphosphorylcholine (MPC) polymer) as a result of mimicking the interfacial properties of the outer cell surface of red blood cells and platelets (K. Ishihara). et al., Polym. J., 23, 355
(1990)). However, MPC homopolymers are expected to have better biocompatibility than polyvinylpyrrolidone, but are water-soluble, and cannot be formed into a membrane using only MPC homopolymers. For this purpose, a copolymer of a hydrophobic methacrylate monomer and MPC has been prepared, and after being insolubilized in water, is mainly used as a coating agent or a blending agent (K. Ishih
ara et al., Biomaterials, 20, 1545 (1999)).

Japanese Patent Publication No. 6-31273 describes a phosphatidylcholine lipid which is a low molecular weight compound having a polar group which is amphoteric, and is made of glass, cellulose acetate, polyvinyl chloride or Teflon (registered trademark).
It reports that it can be modified into a biocompatible surface by reacting with the surface.

Japanese Patent Application Laid-Open No. 7-300513 describes a method of immobilizing a surface of a base material such as polyethylene, polypropylene, polyethylene terephthalate, etc. by graft polymerization of both chargeable groups using plasma irradiation.

It is impossible to introduce the vinyl monomer into the aromatic ring by irradiating the aromatic polymer with plasma or ultraviolet light. This is because radicals are trapped in the aromatic ring and the reaction does not proceed, and on the contrary, the main chain is cleaved, and the mechanical strength of the aromatic polymer is significantly reduced.

However, as a special case, Yamagish
i and Belfort et al. (J. Membrane Sci., 105, 249 (1995); ib
id, 105 249 (1995)) irradiates a polyethersulfone ultrafiltration membrane with ultraviolet light to dissociate the sulfur-carbon bonds in the polymer backbone and break the backbone to generate radicals. A method of polymerizing a hydrophilic vinyl monomer such as hydroxyethyl methacrylate at the terminal of the main chain using this radical is reported.

Also, Pieracci and Belfort et al. (J. Membrane
Sci., 156, 223 (1999)) dissociates a sulfur atom-carbon atom bond in the polymer main chain of a polyallyl sulfone ultrafiltration membrane or a polyether sulfone ultrafiltration membrane using a similar method. This report describes a method of generating a radical and polymerizing vinylpyrrolidone monomer at the terminal of the main chain using the radical.

However, such a photodissociation reaction by irradiation with ultraviolet rays is also effective for heterogeneous reactions of a film or the like, but is not applicable to obtain a uniform hydrophilic polymer as a bulk. It is possible. Further, in order to break the main chain by irradiation with ultraviolet rays, (1) the degree of polymerization of the polymer main chain is remarkably reduced, and the mechanical strength characteristic of the aromatic polymer is reduced. Since the hydrophilic monomer polymerizes at the cleaved end, it becomes a block copolymer of a hydrophilic polymer and an aromatic polymer, and the mechanical strength, which is a characteristic of aromatic polymers, is also reduced in this case. Problems arise.

As described above, it has been hitherto known that an aromatic polymer is irradiated with plasma or ultraviolet light to introduce a vinyl monomer into an aromatic ring and to introduce a vinyl monomer polymer into a side chain of the aromatic polymer. It was impossible.

Biocompatible hydrogels such as hydroxyethyl methacrylate polymer and acrylamide polymer may be used alone as a material for soft contact lenses, but may be used as mechanical materials such as aromatic polymers. Due to lack of strength and heat resistance, industrial applications have been limited to date.

As described above, the aromatic polymer has good mechanical properties and physical properties as well as heat resistance and non-protein-adsorbing properties and biocompatibility which are the characteristics of hydrophilic polymers. , And the hydrophilic polymer does not flow out,
Hydrophilic aromatic polymers have not yet been proposed.

[0021]

DISCLOSURE OF THE INVENTION The present invention solves the problems of the prior art and provides a protein which has a small amount of eluted into water and can be used in the fields such as the medical and food industries and which is characteristic of a hydrophilic polymer. It is non-adsorbent, biocompatible and has good mechanical properties, physical properties and heat resistance which are characteristic of aromatic polymers. It provides applications such as membranes.

[0022]

DISCLOSURE OF THE INVENTION The present invention has been made to achieve the above object, and has at least a part of an aromatic ring in a polymer having an aromatic ring in a repeating unit of a polymer main chain. The present invention relates to a novel hydrophilized aromatic polymer, wherein a side chain containing a vinyl polymer site is covalently bonded, and the total chargeability of the hydrophilic vinyl polymer site is zero. Further, the present invention introduces a -NH ₂ group or -NH group to the aromatic ring of the polymer having an aromatic ring in the repeating unit of the polymer backbone, then the side chain is reacted with N- succinimidyl acrylate The present invention relates to a method for producing a hydrophilic aromatic polymer, which comprises introducing a double bond and thereafter polymerizing a hydrophilic vinyl monomer to the double bond. Furthermore, the present invention relates to the use of the above-mentioned novel hydrophilic aromatic polymer.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
I will tell. In the present invention, the repeating unit of the polymer main chain is preferably used.
A polymer having an aromatic ring is defined as a repeating unit in the polymer main chain.
It is only necessary that there be a site having an aromatic ring. Examples of aromatic polymers
(1) Aromatic nuclei having an aromatic nucleus and a sulfonyl group introduced into the main chain
Lysulfone polymer, the aromatic polysulfone polymer
An example of a body is the poly (p-f
Phenylene ether sulfone):-[(p-C₆H_Four) -SO_Two-(p-C₆H_Four)
-O-] z- and “Udel polysulfone”:-[(p-C₆H_Four)-
SO_Two-(p-C₆H_Four) -O- (p-C₆H_Four) -C (CH_Three)_Two-(p-C₆H _Four) -O] z-no
Or-[(p-C₆H_Four) -SO_Two-(p-C₆H_Four) -O- (p-C₆H_Four) -O] z-,-[(p-
C₆H_Four) -SO_Two-(p-C₆H_Four) -S- (p-C₆H_Four) -O] z-, etc.
(Z is an integer of 1 or more).
Hydrogen has been replaced by halogen compounds, hydrocarbons, etc.
May be.

Further, (2) polymers such as polyimide, polyetherimide, aromatic nylon, aramid, polyamideimide, polyarylate, polyetherketone, polyetheretherketone, polyphenylene sulfide, polyphenylene oxide, polycarbonate, polyester and the like; Hydrogen in the polymer main chain may be substituted with a halogen compound, a hydrocarbon, or the like.

The polymer of the present invention having an aromatic ring in the repeating unit of the polymer main chain may be a copolymer of the aromatic polymer with another polymer. Examples of other polymers to be copolymerized include polyurethane, polyethylene oxide, polyethylene, and polypropylene.

The aromatic polymer as the main chain has a molecular weight of 5
It is preferably from 2,000 to 2,000,000. The physical form of the aromatic polymer is (a) resin, (b) film,
(C) a porous flat membrane, (d) a porous hollow fiber membrane, (e) a tube or tube such as a catheter, (f) molded products of various forms, etc., using any of the aromatic polymers. But it is good.

The side chain of the hydrophilicized aromatic polymer of the present invention contains a hydrophilic vinyl polymer site in at least a part thereof, and the total charge amount of the hydrophilic vinyl polymer site is zero. It is. The term "total charge amount" as used in the present invention means that there are no charged sites, or there are charged sites such as sulfonic acid groups, carboxylic acid groups, and phosphate groups, and these are shown in neutral water. It means that the minus charge amount is equal to the plus charge amount indicated by charged sites such as ammonium group and amino group. The amphoteric group referred to in the present invention is a sulfonic acid group showing a negative charge in neutral water, a carboxylic acid group, a negatively charged group such as a phosphate group,
And a substituent having a positively charged group such as an ammonium group and an amino group that exhibit a positive charge in pairs, and having a total charge amount of zero.

The side chain of the hydrophilic aromatic polymer of the present invention will be described in detail. First, a hydrophilic vinyl polymer site containing at least the unit represented by the general formula (I) may be mentioned. The degree of polymerization of the unit is preferably from 1 to 3000,
1 to 200 are particularly preferred. − [CH (R ¹ ) −C (R ² ) (R ³ )] − (I)

The group represented by the general formula (I) will be described in more detail. R ¹ and R ^{2 each} represent a hydrogen atom or a methyl group,
It represents an ethyl group, a branched or unbranched propyl group, a butyl group, or a pentyl group, and R ¹ and R ² may be the same or different. These alkyl groups may be halogenated alkyl groups substituted with halogen atoms. In particular, those in which R ¹ is a hydrogen atom are readily available as vinyl monomers,
Most preferred for producing the hydrophilized aromatic polymer of the present invention.

R ³ is an uncharged substituent containing a carbonyl group, an ester group, an ether group, an amide group, or a hydroxyl group;
Alternatively, it is a substituent having a molecular weight of 500 or less containing a both-charged group, and these hydrophilic sites are sites imparting hydrophilicity to the hydrophilicized aromatic polymer.

As specific examples of the non-chargeable group for the substituent R ³ , general formula (I) is represented by —OCH ₂ OH group, —OCH ₂ CH ₂ OH group, —OCH ₂ CH ₂ CH ₂ OH group, CON
H ₂ group, -CON (CH ₃₎ CH _{3 group, -CON (CH 2 OH) CH} 2 OH group, -CON (CH ₂ C
H ₃ ) CH ₂ CH ₃ group, -CON (CH ₂ CH ₂ OH) CH ₂ CH ₂ OH group, -CON (CH ₂ CH ₂ CH ₃ ) CH ₂ CH ₂ C
H _{3 group, -CON (CH 2 CH 2 CH} 2 OH) CH 2 CH 2 CH 2 OH _{group, -CON (CH 2 CH 2 CH} 2 CH 3) CH 2 CH 2 CH 2 CH 3 group, -CON (CH ₂ CH ₂ CH ₂ CH ₂ OH) CH ₂ CH ₂ CH ₂ CH ₂ OH group, -COOCH ₂ CH (OH) CH ₂ NH ₂ group, -COOCH ₂ CH (OH) CH ₂ N (CH ₃ ) CH _{3
Group, -COOCH 2 CH (OH) CH} 2 N (CH 2 OH) CH 2 OH _{group, -COOCH 2 CH (OH) CH} 2 N (CH 2 CH 3) CH 2 CH 3 group, -COOCH ₂ CH (OH ) CH ₂ N (CH ₂ CH ₂ OH) CH ₂ CH ₂ OH group, -COOCH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ CH ₃ ) CH ₂ CH ₂ CH ₃ group, -COOCH ₂ CH (OH ) CH ₂ N (CH ₂ CH ₂ CH ₂ OH) CH ₂ CH ₂ CH ₂ OH group, -COOCH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ CH ₂ CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ Group, -COOCH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ CH ₂ CH ₂ OH) CH ₂ CH ₂ CH ₂ CH ₂ OH
Group, etc. The hydrogen of the methyl group and the methylene group contained in these groups may be substituted with a halogen atom.

Further, as a specific example in which the substituent R ³ is an amphoteric group, a — (CO) OCH ₂ CH ₂ N (CH ₃ ) ₂ ⁺ CH ₂ CH ₂ CH ₂ SO ₃ ^— group, CO) NH CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ⁺ CH ₂ CH ₂ CH ₂ SO ₃ ^- group,-(CO) OCH ₂ CH ₂ OPOO ^- CH ₂ CH ₂ N (CH ₃ ) ₃ ⁺ group, etc. And the like. The hydrogen of the methyl group and the methylene group contained in these groups may be substituted with a halogen atom. In particular, when the general formula (I) is 2-methacryloxyethyl phosphorylcholine
("MPC"), N, N-dimethyl-N-methacryloxyethyl-N
-(3-sulfopropyl) ammonium betaine is preferable for producing the hydrophilic aromatic polymer of the present invention because the vinyl monomer is easily available.

Next, the unit is represented by the general formula (II)

Embedded image Examples thereof include N-vinylpyrrolidone where p is 3 and N-vinylcaprolactam where p is 4. The degree of polymerization of the unit is preferably from 1 to 3000,
1 to 200 are particularly preferred. In particular, vinylpyrrolidone is preferable for producing the hydrophilic aromatic polymer of the present invention because the vinyl monomer is easily available.

Next, as a side chain of the hydrophilicized aromatic polymer of the present invention, a hydrophilic vinyl polymer site containing at least a unit represented by the general formula (III) may be mentioned.
The polymerization degree of the unit is preferably from 1 to 3,000,
200 is particularly preferred. − [CH ₂ −C (R ⁴ ) (R ⁵ )] − (III)

In explaining the group represented by the general formula (III), R ⁴ represents a hydrogen atom or a methyl group, an ethyl group, a branched or unbranched propyl group, a butyl group, a pentyl group, R ⁵ represents a —COO—R ⁶ —OH group, and R ⁶ represents a methylene group, an ethylene group, a branched or unbranched propylene group, a butylene group, or a pentylene group. The alkyl group or alkylene group in R ⁴ , R ⁵ and R ⁶ may be substituted with a halogen atom. In particular, those in which the general formula (III) is hydroxyethyl methacrylate are preferable for producing the hydrophilic aromatic polymer of the present invention because vinyl monomers are easily available.

Next, as a side chain of the hydrophilicized aromatic polymer of the present invention, a hydrophilic vinyl polymer site containing at least a unit represented by the general formula (IV) may be mentioned. The polymerization degree of the unit is preferably from 1 to 3,000,
00 is particularly preferred. − [CH ₂ −C (R ⁷ ) (CON (R ⁸ ) R ⁹ )] − (IV)

When explaining the group represented by the general formula (IV),
In the formula, R ⁷ represents a hydrogen atom or a methyl group, an ethyl group, a branched or unbranched propyl group, a butyl group, a pentyl group, R 8 represents a hydrogen atom or a-(CH ₂ ) x R ¹⁰ group, R ⁹
Represents a-(CH ₂ ) yR ¹¹ group, R ¹⁰ represents a hydrogen atom or a hydroxyl group, R ¹¹ represents a hydrogen atom or a hydroxyl group, and n is an integer of 1 or more. x and y are integers of 1 or more,
If the value is too large, the hydrophobicity increases, so a value of 5 or less is preferable. The alkyl group or alkylene group in R ⁷ , R ⁸ and R ⁹ may be a halogenated alkyl group or a halogenated alkylene group in which a halogen atom is substituted. In particular, when the general formula (IV) is
Certain N, N'-acrylamides are preferred for producing the hydrophilized aromatic polymer of the present invention because vinyl monomers are readily available.

In addition, examples of the side chain of the hydrophilic aromatic polymer of the present invention include a hydrophilic vinyl polymer moiety represented by the following general formula (V).

The group represented by the general formula (V) is explained as follows.
¹² and R ¹³ represent a hydrogen atom or a methyl group, an ethyl group, a branched or unbranched propyl group, a butyl group, or a pentyl group, and R ¹² and R ¹³ may be the same or different. These alkyl groups may be halogenated alkyl groups substituted with halogen atoms. In particular, those in which R ¹² is a hydrogen atom are readily available as vinyl monomers,
Most preferred for producing the hydrophilized aromatic polymer of the present invention.

R ¹⁴ is an uncharged substituent containing a carbonyl group, an ester group, an ether group, an amide group, or a hydroxyl group, or a substituent having a molecular weight of 500 or less containing a bicharged group. Is a site that imparts hydrophilicity to the hydrophilicized aromatic polymer.

The substituent Specific examples of uncharged groups R ^14, annular _{-NCH 2 CH 2 CH 2 C =} O where some of the general formula (V) is vinylpyrrolidone polymer
-NCH ₂ CH ₂ CH ₂ CH which becomes a vinylcaprolactam polymer
₂ CH ₂ C = O group, -OCH ₂ OH group, -OCH ₂ CH ₂ OH group, -OCH ₂ CH ₂ CH ₂ OH group, -CON
H ₂ group, -CON (CH ₃₎ CH _{3 group, -CON (CH 2 OH) CH} 2 OH group, -CON (CH ₂ C
H ₃ ) CH ₂ CH ₃ group, -CON (CH ₂ CH ₂ OH) CH ₂ CH ₂ OH group, -CON (CH ₂ CH ₂ CH ₃ ) CH ₂ CH ₂ C
H _{3 group, -CON (CH 2 CH 2 CH} 2 OH) CH 2 CH 2 CH 2 OH _{group, -CON (CH 2 CH 2 CH} 2 CH 3) CH 2 CH 2 CH 2 CH 3 group, -CON (CH ₂ CH ₂ CH ₂ CH ₂ OH) CH ₂ CH ₂ CH ₂ CH ₂ OH group, -COOCH ₂ CH (OH) CH ₂ NH ₂ group, -COOCH ₂ CH (OH) CH ₂ N (CH ₃ ) CH _{3
Group, -COOCH 2 CH (OH) CH} 2 N (CH 2 OH) CH 2 OH _{group, -COOCH 2 CH (OH) CH} 2 N (CH 2 CH 3) CH 2 CH 3 group, -COOCH ₂ CH (OH ) CH ₂ N (CH ₂ CH ₂ OH) CH ₂ CH ₂ OH group, -COOCH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ CH ₃ ) CH ₂ CH ₂ CH ₃ group, -COOCH ₂ CH (OH ) CH ₂ N (CH ₂ CH ₂ CH ₂ OH) CH ₂ CH ₂ CH ₂ OH group, -COOCH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ CH ₂ CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ Group, -COOCH ₂ CH (OH) CH ₂ N (CH ₂ CH ₂ CH ₂ CH ₂ OH) CH ₂ CH ₂ CH ₂ CH ₂ OH
Group, etc. The hydrogen of the methyl group and the methylene group contained therein may be substituted by a halogen atom. In particular, those in which a part of the general formula (V) is a polyvinylpyrrolidone polymer are preferable for producing the hydrophilic aromatic polymer of the present invention because the vinyl monomer is easily available.

Further, as a specific example of a zwitterionic group substituents ^{R 14, - (CO) OCH} 2 CH 2 N (CH 3) 2 + CH 2 CH 2 CH 2 SO 3 - group, - (CO ) NH CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ ⁺ CH ₂ CH ₂ CH ₂ SO ₃ ^- group,-(CO) OCH ₂ CH ₂ OPOO ^- CH ₂ CH ₂ N (CH ₃ ) ₃ ⁺ group, etc. Is mentioned. The hydrogen of the methyl group and the methylene group contained in these groups may be substituted with a halogen atom. In particular, when the general formula (V) is 2-methacryloxyethyl phosphorylcholine
("MPC"), N, N-dimethyl-N-methacryloxyethyl-N
Polymers prepared from monomers such as-(3-sulfopropyl) ammonium betaine are easy to obtain vinyl monomers,
This is preferable since the bicharged hydrophilic aromatic polymer of the present invention can be easily produced.

If n and m in the general formula (V) are too large, the physical properties of the obtained hydrophilic aromatic polymer tend to be low.
00 is preferred. This hydrophilic vinyl polymer may be partially branched. These groups may be present alone or in combination depending on the purpose of use.

In the hydrophilic vinyl polymer of the present invention, an appropriate amount of the groups represented by the general formulas (I), (II), (III), (IV), and (V), that is, the density is a value of the base polymer. Although it depends on the chemical structure and application of the compound, if the amount is too small, the function is hardly exhibited.On the other hand, if the amount is too large, it tends to be difficult to form a tough film.
0001 to 2, especially 0.001 to 1, are preferred.

The hydrophilicized aromatic polymer of the present invention can also be prepared by introducing a hydrophilicized vinyl polymer onto the surface of a film, film or molded article comprising the aromatic polymer by a surface reaction. is there. In this case, the introduction ratio with respect to the aromatic polymer in the surface portion is 0.0001 to 2, especially 0.001 to 1 per repeating unit.
Are preferred.

An example of the method for producing a hydrophilic aromatic polymer of the present invention will be described. Aromatic polymers are subjected to chloromethylation in the presence of Friedel-Crafts catalyst (for example, Nakagawa, Higuchi et al., Polymers, 46, 37 (1989); Higuchi et al.
J. Appl. Polym. Sci., 46, 449 (1992)), and then reacted with ethylenediamine to form -CH _{2 on} the aromatic ring of the aromatic polymer.
An NHCH ₂ CH ₂ NH ₂ group is introduced. Then, N
-Succinimidyl acrylate (NSA)

Embedded image Reacts with NH ₂ groups of the terminal and (reaction between NSA and -NH ₂ are Miyata et al, Nature, 399, 766 (1999) and references) and are allowed, -CH ₂ NHCH ₂ CH in aromatic ring of the aromatic polymer ₂ NHCOCH = CH ₂ is introduced.
Thereafter, the aromatic polymer of the present invention can be obtained by polymerizing the aromatic polymer with a hydrophilic vinyl monomer using a double bond covalently introduced into the aromatic polymer.

If this reaction route is described using polysulfone as the aromatic polymer and polyvinylpyrrolidone as the hydrophilic vinyl polymer, the following reaction formula is obtained.

Embedded image

In the above formula, the hydrophilic vinyl polymer is
The form bonded to the carbon atom at the β-position of NHCO—CH ＝ CH ₂ is shown. However, in the present invention, the bonding position of the hydrophilic vinyl polymer is not specified, but is bonded to the carbon atom at the α-position. May be combined with both. When attached to both, it will have the side chain of formula (V).

As an example of another production method, chloromethyl
Phthalimide is converted to aromatic polymer using tin chloride as catalyst.
Phthalimide methylated aromatic polymer
Can be obtained. Next, phthalimide methylated aromatic
Dissolve polymer in tetrahydrofuran / ethanol solution
And add hydrazine hydrate
A chilled aromatic polymer can be obtained. Ie this
-CH by reaction_TwoNH_TwoGroups can be introduced into aromatic polymers
Yes (N. Kahana et al., J. Polym. Sci .: PartA: Polym.
 Chem., 28, 3303 (1990); F. H. Roos et al., Pure Appl.
Chem., A33, 275 (1996)). In addition, N-succin
Midyl acrylate (NSA) and terminal NH _TwoGroup or NH group
With NSA and -NH_TwoOr the reaction with the NH group, Miyata et al.
Nature, 399, 766 (1999)).
-CH on the aromatic ring of the child_TwoNHCH_TwoCH_TwoNHCOCH = CH_TwoIntroduce a group. So
After that, the double bond introduced into the aromatic polymer by covalent bond
By polymerizing with a hydrophilic vinyl monomer
The hydrophilized aromatic polymer of the present invention can be obtained.
You.

The inventor of the present invention has intensively studied for many years a desire to make a hydrophilic vinyl monomer polymer covalently bond to an aromatic polymer in terms of molecular design. The best reaction route to obtain has not been obtained so far. However, by using a reaction between N-succinimidyl acrylate and a terminal NH ₂ group, a double bond is introduced into the aromatic polymer (-CH ₂ NHCH ₂ CH _{2 is} added to the aromatic ring of the aromatic polymer). The reaction of introducing an NHCOCH = CH ₂ group) is performed by introducing a double bond into an antibody (Miyata et al., Nature,
399, 766 (1999)), which has led to the present invention.

The above reaction can be carried out either by dissolving the aromatic polymer in an organic solvent and performing the reaction in a homogeneous system, or in a heterogeneous system in which the aromatic polymer is reacted in a solid state such as a film. It may be a method.

The hydrophilized aromatic polymer obtained in the present invention is biocompatible and non-protein-adsorbing, so that it can be used for various uses such as medical and food industries. In particular, since they have good mechanical properties in addition to their biocompatibility and non-protein-adsorbing properties, they can be suitably used for permselective membranes and catheters.

Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. In the following, the contact angle with water was measured using a Langmuir-Blodget monomolecular film manufacturing apparatus. More specifically, a hollow fiber was vertically mounted on a water surface of a substrate mounting portion using a Langmuir-Blodget film forming apparatus (NL-LB200S-NWC) manufactured by Nippon Laser Electronics. First, the hollow fiber was immersed in the aqueous phase at a speed of 1 mm / min, and the angle between the surface of the hollow fiber and the water surface observed when the tip of the hollow fiber entered the 1 cm aqueous phase was measured as the advancing contact angle.
Thereafter, the tip of the hollow fiber was immersed in a 2 cm aqueous phase. The receding contact angle is obtained by extracting the hollow fiber from the aqueous phase at a speed of 1 mm / min, and receding the angle between the hollow fiber surface and the water surface observed when the tip of the hollow fiber is immersed 1 cm below the water surface. It was measured as a contact angle. The degree of polymerization of the hydrophilic vinyl polymer according to the present invention is, for example, in the case of the reaction represented by Formula 2,
It is calculated by measuring the consumed molar amount of N-vinylpyrrolidone, which is a hydrophilic vinyl monomer, with an ultraviolet-visible spectrophotometer, and dividing this value by the amount of chloromethyl groups introduced into the aromatic polymer of the base material. Value.

[0054]

[Example 1] Polysulfone (trade name: UDEL P-1700 repeating unit-[(pC ₆ H ₄ ) -S) manufactured by Amoco Japan Limited
0 _2- (pC ₆ H ₄ ) -O- (pC ₆ H ₄ ) -C (CH ₃ ) _2- (pC ₆ H ₄ ) -O-] _Z -The molecular weight of 59,000 daltons was obtained by the usual method (Noda, Chloromethylation was carried out according to Kagawa, Journal of Industrial Chemistry, 66, 120 (1963); Nakagawa, Higuchi et al., Journal of Polymers, 46, 37 (1989)).
That is, 0.5 g of zinc oxide (manufactured by Tokyo Chemical Industry) suspended in 21 mL (0.28 mol, manufactured by Tokyo Chemical Industry) of chloromethyl methyl ether in a solution of 12 g (0.027 unit mol) of polysulfone dissolved in dichloroethane (180 mL). ; Used as a catalyst) at 30 ° C. while stirring. After stirring this solution for 15 minutes, the reaction solution was dropped into 5 L of methanol, and the reaction was stopped by reprecipitation. The obtained chloromethylated polysulfone was washed with methanol, 2N hydrochloric acid and methanol in that order, and dried in vacuum at room temperature. Then, 5 wt% in tetramethylfuran
Was dissolved so as to be a polymer solution, and then reprecipitated with methanol for purification. From this infrared absorption spectrum, infrared absorption based on a C-Cl bond was observed at 760 cm ^-1 . Further, a peak based on the ¹ H-NMR spectrum from methylene sites chloromethyl group protons 4.
Observed at 5 ppm. From the elemental analysis, 0.34 chloromethyl groups were introduced per repeating structural unit of the polysulfone.

Next, 8 g of chloromethylated polysulfone was dissolved in 160 mL of tetrahydrofuran. Ethylenediamine (Tokyo Kasei Co., special grade reagent)
Was added dropwise while stirring at 30 ° C. in 90 mL. After stirring for 24 hours, the reaction solution was dropped into 4 L of methanol, and the reaction was stopped by reprecipitation. The obtained ethylenediamine-modified polysulfone was washed with a large amount of methanol and dried in vacuum at room temperature. At this time, the ethylenediamine-modified polysulfone was subjected to reprecipitation purification so as to be as powdery as possible. From this infrared absorption spectrum, infrared absorption based on an NH ₂ group was observed at 3300 cm ⁻¹ . 4.5 ppm from the ¹ H-NMR spectrum
The peak attributable to the proton at the methylene site of the chloromethyl group, which was observed in the above, almost disappeared.

A 0.02 mol / L phosphate buffer (pH 7.4) was prepared using potassium dihydrogen phosphate (Wako Pure Chemical Industries, special grade) and disodium hydrogen phosphate (Wako Pure Chemical Industries, special grade). . To 200 mL of this solution, 7 g of powdery ethylenediamine-modified polysulfone was added, and the mixture was stirred at 37 ° C. for 15 minutes. N-succinimidyl acrylate (2 g, manufactured by Sigma-Aldrich) was dissolved in 100 mL of the above phosphate buffer solution, and then added to the aqueous solution of ethylenediamine-modified polysulfone. The reaction was carried out with stirring at 37 ° C. for 6 hours. After the reaction, the acryloylated polysulfone obtained in a phosphate buffer solution and then in ultrapure water was washed. When the ¹ H-NMR spectrum of this polymer was measured, a proton peak based on a vinyl group was observed from 6.1 ppm to 6.7 ppm.

Next, 6 g of acryloylated polysulfone was added to 200 mL of a 0.02 mol / L phosphate buffer (pH 7.4), and the mixture was stirred at 37 ° C. for 15 minutes. Further, N-vinylpyrrolidone (0.1 mol, Wako Pure Chemical Industries, Ltd.) was added at 0.02 mol / mol.
An aqueous solution of N-vinylpyrrolidone dissolved in 200 mL of L phosphate buffer (pH 7.4) was added to the above acryloylated polysulfone suspension. Furthermore, 0.1 mol / L ammonium peroxodisulfate (Wako Pure Chemical Industries, special grade) 0.5 m
After adding 0.5 mL of L and 0.8 mol / L of N, N, N ', N'-tetramethylethylenediamine, the mixture was reacted at 25 ° C for 3 hours. After the reaction, the polyvinyl pyrrolidone-modified polysulfone obtained in a phosphate buffer solution and then in ultrapure water was washed. In the infrared absorption spectrum of this polymer, infrared absorption based on C ＝ O groups was observed at 1600 cm ⁻¹ attributable to polyvinylpyrrolidone. FIG. 1 shows an infrared absorption spectrum of the obtained polyvinylpyrrolidone-modified polysulfone. Average degree of polymerization (n) of polyvinylpyrrolidone which is a hydrophilic vinyl polymer
Was 2.7.

2 g of this polyvinylpyrrolidone-modified polysulfone was dissolved in 40 mL of N-methyl-2-pyrrolidone and cast on a flat petri dish. The solvent was evaporated under reduced pressure of 60 mmHg for 6 hours. Thereafter, the solvent was completely removed under vacuum at 50 ° C. to prepare a uniform polyvinylpyrrolidone-modified polysulfone membrane. When the advancing contact angle of this film with water was measured, it was 55 ± 2 °.

[0059]

Example 2 6 g of acryloylated polysulfone obtained in the same manner as in Example 1 was added to 200 mL of a 0.02 mol / L phosphate buffer (pH 7.4) and stirred at 37 ° C. for 15 minutes. I let it. In addition, sulfobetaine (N, N-dimethyl-Nm
ethacryloxyethyl-N- (3-sulfopropyl) ammonium betain
e, 0.1 mol, manufactured by Lashing Chemical Co., Ltd.) in 200 mL of a 0.02 mol / L phosphate buffer (pH 7.4) was added to the above acryloylated polysulfone suspension. Further, 0.5 mL of 0.1 mol / L ammonium peroxodisulfate (Wako Pure Chemical Industries, special grade) and 0.8 mL
mol / L N, N, N ', N'-tetramethylethylenediamine
After adding 5 mL, the mixture was reacted at 25 ° C. for 3 hours. After the reaction,
The polysulfobetainated polysulfone obtained in a phosphate buffer solution and then in ultrapure water was washed. This polymer shows that 1 is attributable to polysulfobetaine from the infrared absorption spectrum.
At 670 cm ^-1 and 1740 cm ^-1 , infrared absorption based on the CＯO group was observed. FIG. 2 shows an infrared absorption spectrum of the obtained polysulfobetainated polysulfone. The average degree of polymerization (n) of polysulfobetaine, which is a bicharged vinyl polymer, was 52.

This polysulfobetainated polysulfone 2
g was dissolved in 40 mL of N-methyl-2-pyrrolidone and cast on a flat petri dish. The solvent was evaporated under reduced pressure of 60 mmHg for 6 hours. Thereafter, the solvent was completely removed under vacuum at 50 ° C. to prepare a uniform polysulfobetainated polysulfone membrane. The advancing contact angle of this film with water was measured and found to be 53 ± 2 °.

[0061]

Comparative Example 1 Polysulfone (trade name: UDEL P-170) manufactured by Acomo Japan Limited, which is the same as the raw material of Example 1
0) 2 g was dissolved in 40 mL of N-methyl-2-pyrrolidone and cast on a flat petri dish. The solvent was evaporated under reduced pressure of 60 mmHg for 6 hours. Thereafter, the solvent was completely removed under vacuum at 50 ° C. to prepare a uniform polysulfone membrane. When the advancing contact angle of this film with water was measured, it was 90 ± 2 °.

[0062]

Example 3 Polyetherimide (trade name: Ultem 1000) manufactured by GE Plastics Co., Ltd. (repeat unit-[O-
(pC ₆ H ₄ ) -C (CH ₃ ) _2- (pC ₆ H ₄ ) -O- (C ₆ H ₃ (CO) ₂ ) -N- (mC ₆ H ₄ )
-N-((CO) ₂ -C ₆ H ₃ )] _Z -molecular weight 55,000 daltons, except that hydrophilized polyetherimide was prepared in the same manner as in Example 1. Elemental analysis of the chloromethylated product showed that 0.2 per repeating structural unit of the polyetherimide.
Zero chloromethyl groups are introduced, and the average degree of polymerization of polyvinylpyrrolidone, which is a hydrophilic vinyl polymer, is (n):
3.5.

2 g of the polyvinyl pyrrolidone-modified polyetherimide was dissolved in 40 mL of N-methyl-2-pyrrolidone and cast on a flat petri dish. The solvent was evaporated under reduced pressure of 60 mmHg for 6 hours. Thereafter, the solvent was completely removed under vacuum at 50 ° C. to prepare a uniform polyvinylpyrrolidone-modified polyetherimide film. When the advancing contact angle of this film with water was measured, it was 57 ± 3 °.

[0064]

Example 4 A polysulfobetainated polyetherimide was prepared in the same manner as in Example 3 except that the sulfobetaine used in Example 2 was used instead of N-vinylpyrrolidone. The intermediate chloromethylated product, according to elemental analysis, had a content of 0.1 per repeating structural unit of the polyetherimide.
The average degree of polymerization (n) of polysulfobetaine, which is a double-charged vinyl polymer into which 20 chloromethyl groups are introduced, is as follows:
48. 2 g of this polysulfobetainated polyetherimide was dissolved in 40 mL of N-methyl-pyrrolidone, and cast on a flat petri dish. 60mmHg
The solvent was evaporated under reduced pressure for 6 hours. Thereafter, the solvent was completely removed under vacuum at 50 ° C. to prepare a uniform polysulfobetainated polyetherimide film. When the advancing contact angle of this film with water was measured, it was 54 ± 3 °.

[0065]

Example 5: Dry polysulfone hollow fiber membrane (SI-1, nominal molecular weight cut-off 6000, polysulfone repeating unit-[(pC
_{6 H 4) -S0 2 - (} pC 6 H 4) -O- (pC 6 H 4) -C (CH 3) 2 - (pC 6 H 4) -O-] Z
-Asahi Kasei Corporation) was immersed in a 100% ethanol solution for 1 hour. Thereafter, the hollow fiber was immersed in a 50% ethanol + 50% hexane solution for 1 hour. In addition, 10
The hollow fiber was immersed in a 0% hexane solution for 1 hour. Glycerin contained in the hollow fiber membrane was removed by the above treatment.

The above polysulfone hollow fiber membrane (3 m) was converted to chloromethyl methyl ether (7.72 manufactured by Tokyo Chemical Industry Co., Ltd.).
g), stannic chloride (manufactured by Wako Pure Chemical, 25 g), and hexane (Wako Pure Chemical, 228 mL) in a mixed solution (molar ratio of the above reagents is 5: 5: 90). The reaction was performed for 6 hours. In the chloromethylated porsulfone hollow fiber membrane, infrared absorption based on CCl bond was observed at 760 cm ^-1 from the infrared absorption spectrum. Further, the chloromethylated porsulfone hollow fiber membrane prepared above was dissolved in deuterated chloroform, and the ¹ H-NMR spectrum was measured. ¹ H-NMR
From the spectrum, a peak based on the proton at the methylene site of the chloromethyl group was observed at 4.5 ppm. From the elemental analysis, it was confirmed that 0.43 chloromethyl groups were introduced per repeating unit of the polysulfone.

Next, the chloromethylated porsulfone hollow fiber membrane was immersed in 200 mL of an ethylenediamine solution, and an ethylenediamine conversion reaction was performed with gentle stirring for 20 minutes. In the ethylenediamine-modified polysulfone hollow fiber membrane, infrared absorption based on NH2 groups was observed at 3300 cm ^-1 from the infrared absorption spectrum. Also, from the ¹ H-NMR spectrum, 4.
The peak due to the proton at the methylene site of the chloromethyl group, which was observed at 5 ppm, almost disappeared. From the ion exchange capacity of the ethylenediamine-modified polysulfone hollow fiber membrane, it was confirmed that 0.06 ethylenediamine groups were introduced per repeating unit of polysulfone.

A phosphate buffer (pH 7.4) of 0.02 mol / L was prepared using potassium dihydrogen phosphate (manufactured by Wako Pure Chemical Industries, special grade) and disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, special grade). . An ethylenediamine-modified polysulfone hollow fiber membrane (50 cm) was immersed in 100 mL of this solution and immersed at 37 ° C. for 5 minutes. N-succinimidyl acrylate (0.327
g, Sigma-Aldrich) was dissolved in 50 mL of a phosphate buffer (pH 7.4), and then added to the aqueous solution containing the ethylenediamine-modified polysulfone hollow fiber membrane. 37 ° C for 1 hour
The reaction was carried out while stirring. After the reaction, the acryloylated polysulfone hollow fiber membrane obtained in a phosphate buffer solution and then in ultrapure water was washed. When the ¹ H-NMR spectrum of this hollow fiber membrane was measured, a proton peak based on a vinyl group was observed from 6.1 ppm to 6.7 ppm. From this peak area, it was determined that an acryloyl group (double bond group) was contained in the hollow fiber membrane at a rate of 7.2 mmol / m (length of the hollow fiber membrane).

Next, the acryloylated polysulfone hollow fiber membrane (30 cm) was treated with N-vinylpyrrolidone (2.16 mmol,
0.02 mol / L phosphate buffer (pH 7.0) containing Wako Pure Chemical Industries, Ltd.
4) It was immersed in 150 mL. Further, 0.1 mol / L ammonium peroxodisulfate (special grade, manufactured by Wako Pure Chemical Industries) is used.
After adding 2 mL and 0.2 mL of 0.8 mol / L N, N, N ', N'-tetramethylethylenediamine, the mixture was reacted at 25 ° C for 3 hours. After the reaction, the polyvinyl pyrrolidone-modified polysulfone hollow fiber membrane obtained in a phosphate buffer solution and then in ultrapure water was washed. In the infrared absorption spectrum of this polymer, infrared absorption based on C ＝ O groups was observed at 1600 cm ⁻¹ attributable to polyvinylpyrrolidone. The average degree of polymerization (n) of polyvinylpyrrolidone, which is a hydrophilic vinyl polymer, was 100. When the advancing contact angle of the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane with water was measured, it was 53 ± 2.
°. The receding contact angle was 26 ± 2 °.

[0070]

Example 6 An acryloylated polysulfone hollow fiber membrane (1 m) obtained in the same manner as in Example 5 was treated with sulfobetaine (N, N-dimethyl-N-methacryloxyethyl-N- (3-sulfopropy).
l) 50 m of 0.02 mol / L phosphate buffer (pH 7.4) containing ammonium betaine (0.94 mmol, manufactured by Lashing Chemical Co.)
It was immersed in L. Furthermore, 0.2 mol / L of 0.1 mol / L ammonium peroxodisulfate (Wako Pure Chemical Industries, special grade)
mol / L N, N, N ', N'-tetramethylethylenediamine
After adding 2 mL, the mixture was reacted at 25 ° C. for 3 hours. After the reaction,
The polysulfobetainated polysulfone hollow fiber membrane obtained in a phosphate buffer solution and then in ultrapure water was washed. This polymer, an infrared absorption based on C = O group was observed at 1670 cm ^-1 and 1740 cm ^-1 attributable to poly sulfobetaine infrared absorption spectrum. The average degree of polymerization (n) of polysulfobetaine, which is a bicharged hydrophilic vinyl polymer,
Was 25.6. When the advancing contact angle of the polysulfobetainated polysulfone hollow fiber membrane with water was measured, it was 51 ± 2 °. The receding contact angle is 24 ±
2 °.

[0071]

Comparative Example 2 Polysulfone hollow fiber membrane used in Example 5,
The contact angle (advance contact angle and receding contact angle) of the ethylenediamine-modified polysulfone hollow fiber membrane prepared in Example 5 with water was measured. The results are shown in Table 1 below together with the values for the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane of Example 5 and the polysulfobetainated polysulfone hollow fiber membrane of Example 6.

[0072]

[Table 1] From the results in Table 1, it can be seen that the hydrophilicity of the polysulfone hollow fiber membrane is significantly improved by modification with polyvinylpyrrolidone or polysulfobetaine.

[0073]

Example 7 A platelet adsorption experiment was performed to examine whether a hydrophilic polysulfone hollow fiber membrane had biocompatibility. Using a blood collection tube (Benoject II, manufactured by Terumo Corporation, 7 mL) containing EDTA · 2Na, which is a blood anticoagulant, 35 mL (five) of blood was collected from the elbow vein (female, 30 years old) of the upper arm. After blood collection, the anticoagulant and the blood were gently shaken and mixed. Thereafter, the blood was transmitted into the plastic centrifuge tube (Iwaki Glass Co., Ltd., 15 mL) through the tube wall and gently divided into four tubes and injected. A blood-containing centrifuge tube was set in a centrifuge, and centrifuged at 1000 rpm for 10 minutes. The separated yellow cloudy liquid (platelet-rich plasma) was gently transferred to a new centrifuge tube with a plastic Pasteur pipette. At this time, about 12 mL of platelet-rich plasma was collected from 35 mL of blood.

The ethylenediamine-modified polysulfone hollow fiber membrane prepared in Example 5, the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane, the polysulfobetainated polysulfone hollow fiber membrane prepared in Example 6, and the unmodified polysulfone hollow fiber used in Example 5 Cut the fiber membrane to about 1cm each,
Five cells were introduced into a well cell culture plate (Iwaki Glass).
Add 1 mL per well of the platelet-rich plasma prepared above, 3
Incubation was carried out for 2 hours in a constant temperature bath at 7 ° C. Two hours later, each hollow fiber membrane was washed with physiological saline to remove blood components other than the adsorbed and adhered substances. It was immersed in a physiological saline solution containing 3% by weight of glutaraldehyde (manufactured by Kanto Chemical Co., Ltd., special grade) in a refrigerator (4 ° C.) for 2 days to immobilize adhered blood components. Thereafter, the immobilized hollow fiber membrane was washed with physiological saline and then with ultrapure water, and then lyophilized for 10 hours.
After gold deposition on the dried hollow fiber membrane, scanning electron microscope (JS
M-5200, manufactured by JEOL) and the number and morphology of platelets adsorbed. The results are shown in Table 2, FIG. 3, and FIG.
FIG. 3 is an electron micrograph of the surface of the unmodified polysulfone hollow fiber membrane, the ethylenediamine-modified polysulfone hollow fiber membrane, and the surface of the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane. FIG. 4 is an electron microscope of the surface of the polysulfobetainated polysulfone hollow fiber membrane. It is a photograph. From FIG. 3, it can be seen that platelets are aggregated and attached to the surface of the unmodified polysulfone hollow fiber membrane.
It can be seen that platelets are flattened and aggregated on the surface of the ethylenediamine-modified polysulfone hollow fiber membrane to produce pseudopodia. On the other hand, platelets did not adhere to the surface of the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane of FIG. 3 and the surface of the polysulfobetainated polysulfone hollow fiber membrane of FIG.

[0075]

[Table 2] It was clarified that the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane and the polysulfobetainated polysulfone hollow fiber membrane did not adsorb platelets and had biocompatibility.

[0076]

Example 8 A fibrinogen adsorption experiment was performed to examine whether the hydrophilic polysulfone hollow fiber membrane has a non-protein-adsorbing property. 0.015 g of fibrinogen (from Tokyo Kasei Kogyo, bovine, fraction 1) was dissolved in 50 mL of a 1/15 mole / l phosphate buffer solution (pH 7.4) containing 0.15 mol / L NaCl, and dissolved in 30 mL.
A 0 ppm aqueous fibrinogen solution was prepared. Each 1 mL of the aqueous fibrinogen solution was introduced into a 24-well cell culture plate (manufactured by Iwaki Glass Co., Ltd.) and kept at 37 ° C. The ethylenediamine-modified polysulfone hollow fiber membrane prepared in Example 5, the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane, the polysulfobetainated polysulfone hollow fiber membrane prepared in Example 6, and the unmodified polysulfone hollow fiber membrane used in Example 5 were used. Each was cut to about 1 cm, and placed in a 24-well cell culture plate (manufactured by Iwaki Glass Co., Ltd.) containing aqueous fibrinogen solution.
It was introduced one by one. After keeping the temperature at 37 ° C. for 1 hour, each hollow fiber membrane was sufficiently washed with a 1/15 mol / L phosphate buffer solution (pH 7.0). Thereafter, each hollow fiber membrane was immersed in 1 mL of 1% aqueous sodium dodecyl sulfate solution,
Shake at 25 ° C. for 1 hour. After shaking, 100 μl of each aqueous solution for protein desorption and 100 μl of a solution of a micro BCA protein quantification kit (MR, manufactured by Pierce) were introduced into a 98-well plate, and kept at 37 ° C. for 2 hours. After returning the 98-well plate to room temperature, the absorbance at 570 nm was measured with a microplate reader, and the amount of fibrinogen adsorbed on each hollow fiber membrane was measured from a calibration curve prepared in advance. The results are shown in Table 3 below.
Shown in Polyvinylpyrrolidone-modified polysulfone hollow fiber membrane and polysulfobetainated polysulfone hollow fiber membrane are:
It was clarified that the amount of fibrinogen adsorbed was small and the protein had non-adsorbed properties.

[0077]

Example 9 A plasma protein adsorption experiment was performed in order to examine whether the hydrophilic polysulfone hollow fiber membrane has a non-protein-adsorbing property. After collecting human blood in the same manner as in Example 7, a centrifuge was provided with a blood-containing centrifuge tube and centrifuged at 2800 rpm for 15 minutes. The yellow cloudy liquid (platelet poor plasma) obtained by separation was gently transferred to a new centrifuge tube with a plastic Pasteur pipette.
At this time, about 12 mL of platelet poor plasma was collected from 35 mL of blood. The separated platelet poor plasma was diluted 2-fold with a 0.15 mol / L phosphate buffer solution. A plasma protein adsorption experiment was performed in the same manner as in Example 8, except that this platelet poor plasma solution was used instead of the aqueous fibrinogen solution. The results are shown in Table 3. It was clarified that the polyvinylpyrrolidone-modified polysulfone hollow fiber membrane and the polysulfobetainated polysulfone hollow fiber membrane had a small amount of plasma protein adsorbed and had a non-protein-adsorbing property.

[0078]

[Table 3]

[0079]

Example 10 Instead of N-vinylpyrrolidone,
A polyhydroxyethyl methacrylated polysulfone hollow fiber membrane was prepared in the same manner as in Example 5, except that hydroxyethyl methacrylate (2.16 mmol, manufactured by Aldrich) was used. The contact angle (advance angle) of this polyhydroxyethyl methacrylated polysulfone hollow fiber membrane to water was 55 ± 2 °. Further, the receding angle was 26 ± 2 °, indicating that the unmodified polysulfone hollow fiber membrane was hydrophilized (see Table 1).

[0080]

Example 11 Instead of N-vinylpyrrolidone, N, N-
A polyacrylamidated polysulfone hollow fiber membrane was prepared in the same manner as in Example 5, except that dimethylacrylamide (2.16 mmol, manufactured by Aldrich) was used. When the contact angle (advance angle) of this polyacrylamidated polysulfone hollow fiber membrane to water was measured, it was 56
± 2 °. In addition, the receding angle was 28 ± 2 °, indicating that the unmodified polysulfone hollow fiber membrane was hydrophilized (Table 1).
reference).

[0081]

Example 12 A nonwoven fabric made of polyvinylpyrrolidone-polyester was prepared in the same manner as in Example 5, except that a nonwoven fabric made of polyethylene terephthalate (fiber diameter 1.2 μm, basis weight 40 g / m2) was used. The average degree of polymerization (n) of polyvinylpyrrolidone was 68. A platelet adsorption experiment was performed in the same manner as in Example 7. As a result, the adsorbed platelets were not observed from the electron microscope measurement.

[0082]

Example 13 Instead of N-vinylpyrrolidone, 2-me
thacryloxyethyl phosphorylcholine (2.16 mmol,
A poly-MPC polysulfone hollow fiber membrane was prepared in the same manner as in Example 5 except that Nippon Yushi Co., Ltd.) was used. The contact angle (advance angle) of this poly MPC-formed polysulfone hollow fiber membrane to water was 57 ± 2 °. Further, the receding angle was 28 ± 2 °, indicating that the unmodified polysulfone hollow fiber membrane was hydrophilized (see Table 1).

[0083]

The effects of the present invention are listed below. 1) The hydrophilized aromatic polymer of the present invention has biocompatibility, is non-protein-adsorbing, and has good mechanical strength. 2) Therefore, the hydrophilized aromatic polymer of the present invention can be suitably used in medical or food industries such as permselective membranes and catheters. 3) According to the present invention, a hydrophilic aromatic polymer membrane having biocompatibility can be easily obtained.

[Brief description of the drawings]

FIG. 1 shows an infrared absorption spectrum of polyvinylpyrrolidone-modified polysulfone produced in Example 1.

FIG. 2 shows an infrared absorption spectrum of the polysulfobetainated polysulfone produced in Example 2.

FIG. 3 shows electron micrographs of the surfaces of an unmodified polysulfone hollow fiber membrane, an ethylenediamine-modified polysulfone hollow fiber membrane, and a polyvinylpyrrolidone-modified polysulfone hollow fiber membrane by a platelet adsorption experiment.

FIG. 4 shows an electron micrograph of the surface of a polysulfobetainated polysulfone hollow fiber membrane obtained by a platelet adsorption experiment.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) B01D 71/64 B01D 71/64 71/68 71/68 C08F 283/00 C08F 283/00 283/02 283 / 02 283/04 283/04 D04H 1/42 D04H 1/42 Q // A61M 1/16 500 A61M 1/16 500 1/18 500 1/18 500 B01D 61/02 B01D 61/02 61/14 61/14 500 500 61/24 61/24 F-term (reference) 4C077 AA05 AA06 BB01 BB02 EE01 EE03 KK01 KK10 NN03 PP07 PP08 PP14 PP15 4C081 AC08 BA03 CA23 CA28 CC03 DA03 4D006 GA03 GA06 GA07 GA13 MA01 MA03 MB05 MB59 MC14 MC20 MC47 MC48 MC48 MC47 MC61 MC62X MC88 NA54 NA59 PA01 PB09 PB42 PC47 4J026 AB07 AB08 AB17 AB22 AB26 AB28 AB29 AB30 AB33 AB34 AB40 AB41 AC22 AC26 BA29 BA30 BA32 BA40 BB01 BB09 CA02 CA04 CA06 DB14 DB16 GA01 GA02 4L047 AA22 AA26 AB10 CB01 CB10 CC03 CC12

Claims (13)

[Claims] 1. A side chain containing a hydrophilic vinyl polymer site is covalently bonded to at least a part of an aromatic ring in a polymer having an aromatic ring in a repeating unit of the polymer main chain. A hydrophilized aromatic polymer characterized in that the total charge at the coalescing site is zero. 2. The hydrophilic vinyl polymer part contains at least a unit represented by the formula (I), and has a polymerization degree of 1 to 3,
2. The hydrophilic aromatic polymer according to claim 1, wherein the molecular weight is 000. -[CH (R ¹ ) -C (R ² ) (R ³ )]-(I) (wherein, R ¹ is a hydrogen atom or a branched or unbranched C 1-5 carbon atom) R ² represents a hydrogen atom or a branched or unbranched alkyl group having 1 to 5 carbon atoms or a halogenated alkyl group; R ³ represents a carbonyl group, an ester group, an ether group, an amide group; Represents a substituent having a molecular weight of 500 or less containing a group, a hydroxyl group or an amphoteric group.) 3. The method according to claim 1, wherein the hydrophilic vinyl polymer moiety has the following formula (I)
It contains at least the unit represented by I) and has a degree of polymerization of 1
2. The hydrophilic aromatic polymer according to claim 1, wherein the number of the aromatic polymer is from 3,000 to 3,000. Embedded image (In the formula, p represents an integer of 3 to 5.) 4. The method according to claim 1, wherein the hydrophilic vinyl polymer moiety has the following formula (II)
It contains at least the unit represented by I) and has a degree of polymerization of 1
2. The hydrophilic aromatic polymer according to claim 1, wherein the number of the aromatic polymer is from 3,000 to 3,000. -[CH ₂ -C (R ⁴ ) (R ⁵ )]-(III) (wherein R ⁴ is a hydrogen atom or a branched or unbranched alkyl group having 1 to 5 carbon atoms or a halogenated group) Represents an alkyl group, R ⁵ represents a —COO—R ⁶ —OH group, and R ⁶ represents a branched or unbranched alkylene group having 1 to 5 carbon atoms or a halogenated alkylene group.) 5. The method according to claim 1, wherein the hydrophilic vinyl polymer moiety has the following formula (I)
V) containing at least the unit represented by V) and having a degree of polymerization of 1
2. The parent according to claim 1, wherein the number is from 3,000 to 3,000.
A hydrated aromatic polymer. − [CH_Two−C (R⁷) (CON (R⁸) R⁹)]-(IV) (where R⁷Represents a hydrogen atom or a branched or branched
An alkyl group having 1 to 5 carbon atoms or halogenated
Represents a alkyl group, R⁸Is a hydrogen atom or-(CH_Two) xR ^TenBase
Indicates, R⁹Is-(CH_Two) yR¹¹Represents a group, R^TenIs a hydrogen atom or
Represents a hydroxyl group, R¹¹Represents a hydrogen atom or a hydroxyl group;⁸
Or R⁹The alkylene group in is replaced with a halogen atom
And x and y represent an integer of 1 to 5. ) 6. The hydrophilized aromatic polymer according to claim 1, wherein the polymer having an aromatic ring in a repeating unit of the polymer main chain is an aromatic polysulfone. 7. The hydrophilic aromatic polymer according to claim 1, wherein the polymer having an aromatic ring in the repeating unit of the polymer main chain is polyetherimide. 8. The hydrophilized aromatic polymer according to claim 1, wherein the polymer having an aromatic ring in the repeating unit of the polymer main chain is an aromatic polyester. 9. The polymer having an aromatic ring in a repeating unit of the polymer main chain has a molecular weight of 50,000 to 2,000,000.
The hydrophilic aromatic polymer according to any one of claims 1 to 8, wherein the aromatic polymer is 0. 10. A —NH ₂ group or —NH group is introduced into an aromatic ring of a polymer having an aromatic ring in a repeating unit of the polymer main chain, and then reacted with N-succinimidyl acrylate to form a side chain. The method for producing a hydrophilic aromatic polymer according to any one of claims 1 to 9, wherein a double bond is introduced, and thereafter, a hydrophilic vinyl monomer is polymerized on the double bond. 11. The hydrophilic aromatic polymer according to claim 1, wherein the polymer is in the form of a membrane, a hollow fiber, or a nonwoven fabric. 12. A permselective membrane comprising the hydrophilicized aromatic polymer according to claim 1. 13. A catheter comprising the hydrophilicized aromatic polymer according to claim 1.