TW201602260A - Ion complex material having function for preventing adherence to biological material - Google Patents

Abstract

In the present invention, a coating film is formed by a coating-film forming composition being contacted with a base and subsequently being dried. The coating-film forming composition contains a solvent and a copolymer that includes a repeat unit containing an organic group expressed by formula (a) and a repeat unit containing an organic group expressed by formula (b) (in the formula, Ua1 represents a hydrogen atom or an alkali metal atom, and Ub1 and Ub2 each independently represent a hydrogen atom, or a linear or branched alkyl group having 1-5 carbon atoms).

Description

Ion composite material with adhesion inhibiting energy of living substance

The present invention relates to an ion composite material having an adhesion inhibiting property of a living substance and a coating film using the ion composite material.

In order to suppress the adhesion of living substances such as medical instruments and equipment such as artificial dialyzers, artificial organs, and medical instruments, various coating materials having adhesion inhibiting properties of living substances have been proposed.

Among these, there is a material which inhibits adhesion of a living substance by, for example, coating a polymer having an ethylene glycol chain in a side chain. For example, in Patent Document 1, a 2-ethyl acrylate is described. The copolymer of oxyethyl ester is applied to a nonwoven fabric such as a blood filter or an artificial dialysis filter. Further, in Non-Patent Document 1, a polyvinylpyrrolidone (PVP) is prepared by a polypyrene (PS) or a polyether oxime (PES) using a substrate which is a manual dialysis membrane, and is subjected to a hydrophilic treatment. However, these materials have the desired adhesion inhibiting ability of the living substance due to effects such as hydrophilicity, and on the other hand, they inhibit the solubility of water in the polymer itself and improve the solubility to the alcohol or the organic solvent. Shear stress on the coating film caused by washing, high viscosity, and other living substances such as ethanol for sterilization (cutting The reason for the long-term use and the like is that the dissolution of the coating film itself is confirmed, and the allergies caused by the eluted matter are caused to cause further concern.

On the other hand, it is known that a material having a polymer material containing a cation or an anion in a side chain is electrostatically balanced, and the surface is maintained in electrical neutrality to prevent adsorption of a living substance (protein, cell, etc.). The role. In addition, coating materials using such functions have also been proposed, and various reports have been made regarding fixing/fixing methods for glass or polymer substrates and the like.

For example, Patent Document 2 discloses an adhesion preventing copolymer having a zwitterionic portion and a stagnation portion having a charge as a dental care product.

For example, in Patent Document 3, it has been disclosed that a copolymer comprising a negatively charged repeating unit or a positively charged repeating unit is used for the prevention of non-specific protein adhesion on the surface.

For example, Non-Patent Document 2 discloses a living substance non-adhesive hydrogel containing a monomer having a specific positive and negative charge and a crosslinking agent.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open Publication No. 2001-323030

[Patent Document 2] US2012/0128600A1

[Patent Document 3] Japanese Patent Special Publication 2010-500456

[Non-patent literature]

[Non-Patent Document 1] Artificial Organs, Vol. 39, No. 1, pp. 77 (2010)

[Non-Patent Document 2] J. Phys. Chem. B2012, 116, pp. 14346-14352

In particular, the present invention provides a coating film having an adhesion inhibiting ability of a living substance which can be easily formed only by a drying step.

That is, the present invention is as follows.

[1] A coating film which is formed by contacting a composition for forming a coating film comprising a copolymer and a solvent, and drying the composition, the copolymer comprising: the monovalent organic group represented by the following formula (a) a repeating unit of a group; and a repeating unit comprising a monovalent organic group represented by the following (formula b); (In the formula, U ^a1 represents a hydrogen atom or an alkali metal atom, and U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms).

[2] The coating film according to [1], wherein the base system is selected from the group consisting of glass, a metal-containing compound, or a semimetal-containing compound, or a resin.

[3] The coating film according to [1] or [2], which has an adhesion inhibiting ability of a living substance.

[4] The coating film according to any one of [1] to [3] wherein the copolymer comprises the following repeating units of (formula a-1) and (formula b-1); (wherein, T ^a , T ^b , U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and U ^a1 represents a hydrogen atom or an alkali metal atom, Q ^a and Q ^b each independently represents a single bond, an ester bond (-C(=O)-O- or -OC(=O)-) or a guanamine bond (-NHC(=O)- or -C(=O)NH -), R ^a and R ^b each independently represent a single bond or a straight or branched alkyl group having 1 to 5 carbon atoms which may be substituted by a halogen atom.

The coating film of the present invention can be formed by subjecting a coating film-forming composition containing a copolymer having an anion represented by the formula (a) and a cation represented by the formula (b) to a substrate, followed by a drying step. The coating film of the present invention can form an ionic bond (ion complex) by using an anion represented by (formula a) and a cation represented by (formula b), without selecting a glass, a metal-containing compound or a semimetal-containing compound. Fixing in the case of a compound such as a compound or a resin (synthetic resin or natural resin), and fixing to a water-based solvent (water, phosphate buffer (PBS), ethanol, isopropyl alcohol, etc.) after fixation A coating film excellent in durability.

The coating film of the present invention is a coating film obtained by bringing a composition for forming a coating film comprising a copolymer and a solvent into contact with a substrate and drying the composition, and the copolymer comprises: a monovalent organic group represented by the following formula (a) a repeating unit, and a repeating unit comprising a monovalent organic group represented by the following formula (formula b); (In the formula, U ^a1 represents a hydrogen atom or an alkali metal atom, and U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms). The temperature at the time of drying is preferably carried out under the atmosphere or under vacuum at a temperature ranging from -200 ° C to 200 ° C.

Drying refers to the removal of the solvent in the composition for forming a coating film.

The copolymer is not particularly limited as long as it is a copolymer comprising a repeating unit containing the organic group represented by the above formula (a) and a repeating unit containing the organic group represented by the above formula (b). The polymer is preferably obtained by radically polymerizing a monomer containing the organic group represented by the above formula (a) and a monomer having the organic group represented by the above formula (b), but may be used. Polycondensation, addition polymerization reaction. Examples of the copolymer include an ethylene-based polymer obtained by reacting an olefin, a polyamide, a polyester, a polycarbonate, a polyurethane, and the like. Among them, it is particularly preferable to react an olefin. A vinyl polymer or a (meth)acrylic polymer obtained by polymerizing a (meth) acrylate compound.

Further, in the present invention, the (meth) acrylate compound means both an acrylate compound and a methacrylate compound. For example, (meth)acrylic refers to acrylic acid and methacrylic acid.

U ^a1 represents a hydrogen atom or an alkali metal atom (lithium, sodium, potassium, rubidium, cesium, cesium). These atoms form a monovalent cation and form an ionic bond with one oxygen atom (monovalent anion) of the sulfonic acid group. Among these, a hydrogen atom, sodium or potassium is particularly preferable.

Examples of the linear or branched alkyl group having 1 to 5 carbon atoms include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a second butyl group, and a t-butyl group. , n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2- Dimethylpropyl or 1-ethylpropyl.

As U ^b1 and U ^b2 , a combination of a hydrogen atom, a methyl group or an ethyl group is preferred, but in particular, it is more preferred that both are methyl groups.

Examples of the solvent contained in the composition for forming a coating film of the present invention include water, a phosphate buffer solution (PBS), and an alcohol. Examples of the alcohol include alcohols having 2 to 6 carbon atoms, such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 1-pentanol, and 2-pentane. Alcohol, 3-pentanol, 1-heptanol, 2-heptanol, third pentanol, 2,2-dimethyl-1-propanol (neopentyl alcohol), 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methyl-2-butanol (third pentanol), 3-methyl-1-butanol, 3-methyl-3-pentanol, cyclopentanol, 1-hexanol, 2-hexanol, 3-hexanol, 2,3-dimethyl-2-butanol, 3,3-dimethyl-1-butanol, 3,3-dimethyl-2 -butanol, 2-diethyl-1-butanol, 2-methyl-1-pentanol, 2-methyl-2-pentanol, 2-methyl-3-pentanol, 3-methyl- 1-pentanol, 3-methyl-2-pentanol, 3-methyl-3-pentanol, 4-methyl-1-pentanol, 4-methyl-2-pentanol, 4-methyl- 3-pentanol, 1-butoxy-2-propanol and cyclohexanol may be used singly or as a mixed solvent of the combination, but from the viewpoint of dissolution of the copolymer, water or PBS may be used alone. , ethanol, isopropyl Alcohol or a mixed solvent using a combination of these.

The ratio of the repeating unit containing the organic group represented by (formula a) in the above copolymer is from 5 mol% to 80 mol%. It is preferably from 6 mol% to 75 mol%, more preferably from 7 mol% to 50 mol%, and even more preferably from 8 mol% to 40 mol%. Further, the copolymer according to the present invention may contain two or more kinds of repeating units containing an organic group represented by the formula (a).

In the case where the solvent of the above composition is water, the proportion of the repeating unit containing the organic group represented by (formula a) in the above copolymer is preferably from 7 mol% to 50 mol%, more preferably 8 mol%. %~40% by mole.

In the case where the solvent of the above composition is PBS, the ratio of the repeating unit containing the organic group represented by the formula (a) in the copolymer is preferably from 5 mol% to 80 mol%, more preferably 6 mol%. %~75% by mole, and then preferably 7% by mole to 70% by mole, and most preferably 8% by mole to 655% by mole.

The ratio of the repeating unit containing the organic group represented by (formula b) in the above copolymer may be any residue obtained by subtracting the above (formula a) from all the copolymers, or may be subtracted from the above (formula a) And the remainder of the total ratio of the third component described below. Further, the copolymer according to the present invention may further contain two or more kinds of repeating units containing an organic group represented by (formula b).

The concentration of the solid content in the composition for forming a coating film is preferably 0.01 to 50% by mass in order to uniformly form the coating film.

The solid content in the composition for forming a coating film means that the liquid component such as a solvent is removed from the composition.

Furthermore, the composition for forming a coating film of the present invention is in addition to the above In addition to the polymer and the solvent, other substances may be added as needed within a range that does not impair the performance of the obtained coating film. Examples of the other substance include a preservative, a surfactant, and a primer for improving the adhesion to the substrate.

The coating film-forming composition obtained in the above step is brought into contact with a substrate to form a coating film.

The substrate for forming the coating film of the present invention is preferably glass, a metal-containing compound or a semimetal-containing compound, activated carbon, or a resin.

The metal-containing compound or the semimetal-containing compound may, for example, be a ceramic whose basic component is a metal oxide and which is sintered by heat treatment at a high temperature, a semiconductor such as ruthenium, a metal oxide or a semi-metal oxide. Inorganic (such as niobium oxide, aluminum oxide, etc.), metal carbide or semi-metal carbide, metal nitride or semi-metal nitride (such as niobium nitride), inorganic compound such as metal boride or semi-metal boride Solid material, aluminum, nickel titanium, stainless steel (SUS304, SUS316, SUS316L, etc.).

As the resin, a natural resin or a synthetic resin may be used. As the natural resin, cellulose, cellulose triacetate (CTA), cellulose obtained by immobilizing dextran sulfate, and the like are preferably used as the synthetic resin. Polyacrylonitrile (PAN), polyester polymer alloy (PEPA), polystyrene (PS), polyfluorene (PSF), polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polyvinyl alcohol (PVA), polyurethane (PU), ethylene-vinyl alcohol copolymer (EVAL), polyethylene (PE), polyester (PE), polypropylene (PP), polyvinylidene fluoride (PVDF), various ion exchange resins or polyether oxime (PES). Since the coating film of the present invention can be formed by drying at a low temperature, it can also be applied to a resin having low heat resistance.

In order to form the coating film of the present invention, the coating film forming composition is brought into contact with at least a part of the surface of the substrate. The contact method is not particularly limited, and a known coating method such as usual spin coating, dip coating, or solvent casting method can be used.

The drying temperature of the coating film of the present invention is not particularly limited, but is usually carried out in the range of -200 ° C to 200 ° C under atmospheric pressure or under vacuum, whereby the copolymers of the present invention (formula a) and (formula b) are mutually An ionic bond is formed and is completely fixed to the substrate.

For example, although it can be formed by drying at room temperature (10 ° C to 35 ° C, for example, 25 ° C), in order to form the coating film more rapidly, it can be dried, for example, at 40 ° C to 50 ° C. Further, a drying step of a very low temperature to a low temperature (before and after -200 ° C to -30 ° C) by a freeze drying method can also be used. Freeze-drying is a method of vacuum freeze-drying, which is usually carried out by sublimating a solvent in a vacuum state by cooling the object to be dried with a refrigerant. Examples of the general refrigerant used in the freeze-drying include a mixed medium of dry ice and methanol (-78 ° C), liquid nitrogen (-196 ° C), and the like.

When the drying temperature is -200 ° C or less, it is necessary to use a non-general refrigerant, which lacks versatility, and in order to sublimate the solvent, it takes a long time to dry and is inefficient. If the drying temperature is 200 ° C or more, the ionic bond reaction on the surface of the coating film is excessively performed, and the surface loses hydrophilicity and cannot be emitted. The body substance adhesion inhibition energy is stimulated. A more preferred drying temperature is from 10 ° C to 180 ° C, and a more preferred drying temperature is from 25 ° C to 150 ° C.

After drying, in order to remove impurities, unreacted monomers, and the like remaining on the coating film, it is preferred to wash with water, PBS, or the like by running water or ultrasonic cleaning. The water or PBS may be, for example, heated in the range of 40 ° C to 95 ° C. After the fixation, even if it is washed with water, PBS, alcohol or the like, the coating film does not elute and is firmly fixed to the substrate as it is. The formed coating film can be easily removed by washing with water or the like even after adhering to the living material, and the surface of the substrate on which the coating film of the present invention is formed has adhesion inhibiting ability.

As an application example of the coating film of the present invention, for example, there is a coating film for a filter of an artificial dialyzer, and the coating film of the present invention is durable to the coating film of a synthetic resin (for example, PES, PS, etc.) used for the filter, and durable after fixation. Sex is also good.

The form of the substrate is not particularly limited, and examples thereof include a substrate, a fiber, a particle, a gel form, and a porous form, and the shape may be a flat plate or a curved surface.

For example, in the case of forming a coating film for a filter of an artificial dialyzer, the coating film forming composition of the present invention can be passed through to the inside of the filter made of the above material and provided, for example, in the shape of a hollow fiber having a diameter of 0.1 to 500 μm. Then, it is produced by a drying step and a washing step (hot water (for example, 40° C. to 95° C.) washing).

If necessary, gamma rays, ethylene oxide, autoclave, etc. may be treated for sterilization.

Examples of the living substance include a protein, a sugar, a nucleic acid, and a cell, or a combination thereof. For example, examples of the protein include fibrinogen, bovine serum albumin (BSA), human albumin, various globulins, β-lipoprotein, various antibodies (IgG, IgA, IgM), peroxidase, various complements. , various lectins, fibronectin, lysozyme, von Willebrand's factor (vWF), serum gamma globulin, pepsin, ovalbumin, insulin, histones, ribonuclease, collagen, The cytochrome c; examples of the sugar include glucose, galactose, mannose, fructose, heparin, and hyaluronic acid; and examples of the nucleic acid include deoxyribonucleic acid (DNA) and ribonucleic acid (RNA); For example, as the cells, there may be mentioned fibroblasts, bone marrow cells, B lymphocytes, T lymphocytes, neutrophils, red blood cells, platelets, macrophages, mononuclear cells, bone cells, bone marrow cells, and pericardial cells. , dendritic cells, keratinocytes, adipocytes, mesenchymal cells, epithelial cells, epidermal cells, endothelial cells, vascular endothelial cells, hepatocytes, chondrocytes, cumulus cells Nervous system cells, glial cells, neurons, oligodendrocytes, microglia, astrocytes, heart cells, esophageal cells, muscle cells (such as smooth muscle cells or skeletal muscle cells), pancreatic beta cells, melanocytes, Hematopoietic precursor cells, monocytes, embryonic stem cells (ES cells), embryogenic tumor cells, embryogenic germ cells, artificial pluripotent stem cells (iPS cells), neural stem cells, hematopoietic stem cells, mesenchymal stem cells, hepatic stem cells, Pancreatic stem cells, muscle stem cells, germ stem cells, intestinal stem cells, cancer stem cells, hair follicle stem cells, and various cell lines (eg, HCT116, Huh7, HEK293 (human) Fetal kidney cells), HeLa (human cervical cancer cell line), HepG2 (human liver cancer cell line), UT7/TPO (human leukemia cell line), CHO (Chinese hamster ovary cell line), MDCK, MDBK, BHK, C -33A, HT-29, AE-1, 3D9, Ns0/1, Jurkat, NIH3T3, PC12, S2, Sf9, Sf21, High Five, Vero), etc., in this case, the coating system has high adhesion inhibition ability to platelets. Further, the coating film of the present invention has a particularly high adhesion inhibiting ability to serum mixed with proteins, sugars and the like.

Since the coating film of the present invention has an adhesion inhibiting ability of a living substance, it can be suitably used as a coating film for a medical substrate. For example, a leukocyte removal filter, a blood transfusion filter, a virus removal filter, a microcoagulation removal filter, a blood purification module, an artificial heart, an artificial lung, a blood circuit, an artificial blood vessel, a blood vessel shunt, a medical treatment Tubes, prosthetic valves, cannulas, stents, catheters, intravascular catheters, balloon catheters, wires, sutures, indwelling needles, shunts, artificial joints, artificial hip joints, blood bags, blood storage containers, surgical aids, It is suitably used for the adhesion preventing film, the wound covering material, and the like. Here, the blood purification module refers to a module having a function of circulating blood to the outside of the body to remove old waste materials or harmful substances in the blood, and examples thereof include an artificial kidney, a toxin adsorption filter, and a column.

Further, the coating film of the present invention is a coating film for use as a cell culture container such as a flask, a dish, or a tray, or various research instruments for inhibiting adhesion of proteins.

In addition, the coating film of the present invention is also used as a material for cosmetics, a material for contact lens maintenance products, and a fiber for skin care. Agents, diagnostic medicinal materials for biochemical research, and blockers widely used in clinical diagnostic methods to inhibit non-specific adsorption in enzyme immunoassay (ELISA) or latex agglutination, for enzymes or antibodies A stabilizer for protein stabilization.

The copolymer contained in the coating film-forming composition of the present invention is particularly preferably a copolymer comprising repeating units of the following (formulae-1) and (formula b-1).

In the formula, T ^a , T ^b , U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms. U ^a1 represents a hydrogen atom or an alkali metal atom. Q ^a and Q ^b each independently represent a single bond, an ester bond (-C(=O)-O- or -OC(=O)-) or a guanamine bond (-NHC(=O)- or -C(= O) NH-), R ^a and R ^b each independently represent a straight or branched alkyl group having 1 to 5 carbon atoms which may be substituted by a halogen atom.

The linear or branched alkyl group having 1 to 5 carbon atoms corresponds to the divalent organic group of the above alkyl group, and examples thereof include a methylene group, an ethylidene group, a propyl group, a trimethylene group, and a tetrazene group. Methyl, 1-methylpropyl, 2-methylpropyl, dimethyl-ethyl, ethylethyl, pentamethylene, 1-methyl-tetramethylene, 2-methyl -tetramethylene, 1,1-dimethyl-trimethylene, 1,2-dimethyl-trimethylene, 2,2-dimethyl-trimethylene, 1-ethyl-trimethylene Etc., and particularly excellent ethyl, propyl or trimethylene. A part or all of the hydrogen atom of the above-mentioned ethyl, propyl or trimethylene group may be substituted with a halogen atom.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The ratio of the repeating unit containing the organic group represented by (formula a-1) contained in the above copolymer is from 5 mol% to 80 mol%. It is preferably from 6 mol% to 75 mol%, more preferably from 7 mol% to 50 mol%, and even more preferably from 8 mol% to 40 mol%. Further, the copolymer according to the present invention may contain two or more kinds of repeating units containing an organic group represented by (formula a-1).

The ratio of the repeating unit containing the organic group represented by (Formula b-1) contained in the above copolymer may be any residue obtained by subtracting the above (Formula a-1) from all the copolymers, or may be subtracted The remainder of the above-mentioned (formula a-1) and the total ratio of the third component described below is obtained. Further, the copolymer according to the present invention may contain two or more kinds of repeating units containing an organic group represented by (formula b-1).

The copolymer contained in the coating film forming composition for forming the coating film of the present invention is preferably reacted by the following compounds (formulas a-1-1) and (formula b-1-1). The reaction is carried out by polymerization (polymerization) in a solvent;

(wherein, T ^a , T ^b , U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and U ^a1 represents a hydrogen atom or an alkali metal atom, Q ^a and Q ^b each independently represents a single bond, an ester bond (-C(=O)-O- or -OC(=O)-) or a guanamine bond (-NHC(=O)- or -C(=O)NH -), R ^a and R ^b each independently represent a single bond or a straight or branched alkyl group having 1 to 5 carbon atoms which may be substituted by a halogen atom.

Specific examples of the above (formula a-1-1) include vinylsulfonic acid, sodium vinylsulfonate, potassium sulfonate, and 2-sulfonic acid ethyl (meth)acrylate. 3-chloro-2-sulfonic acid Ester, 3-sulfonic acid propyl (meth)acrylate, acid sulfonic acid methyl (meth) acrylate, sodium 3-sulfonate propyl (meth) acrylate, 3-sulfonic acid (meth) acrylate An acid propyl ester potassium salt or the like, and among them, vinyl sulfonic acid, sodium vinyl sulfonate, potassium vinyl sulfonate, sodium 3-sulfonate (meth) acrylate is preferably used. The salt and the potassium 3-sulfonate propyl (meth)acrylate are preferably potassium 3-sulfonate acrylate.

Structure of vinyl sulfonic acid, sodium vinyl sulfonate, potassium vinyl sulfonate, sodium 3-sulfonate (meth) acrylate and potassium 3-sulfonate (meth) acrylate The formula is represented by the following (Formula 3-1) and (Formula 3-2).

Specific examples of the above (formula b-1-1) include dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, and dimethyl (meth)acrylate. Aminopropyl ester, and among them, dimethylaminoethyl methacrylate is preferably used.

Dimethylaminoethyl acrylate (= 2-(dimethylamino)ethyl acrylate) (Formula 3-3), dimethylaminoethyl methacrylate (= 2-(dimethyl methacrylate) The structural formula of the formula (Ethylamino)ethyl ester (Formula 3-4) is represented by the following (Formula 3-3) and (Formula 3-4).

Further, the copolymer of the composition of the present invention may be further copolymerized with any third component.

The ratio of the compound represented by the formula (a-1-1) to the entire monomer forming the above copolymer is from 5 mol% to 80 mol%.

The ratio of the compound represented by the formula (Formula b-1-1) to the entire monomer forming the above copolymer may be any residue obtained by subtracting the ratio of the above (formula a-1-1), or may be subtracted The remainder of the above (formula a-1-1) and the total ratio of the third component described below.

The synthesis method of the copolymer of the present invention can be carried out by a method such as radical polymerization, anionic polymerization or cationic polymerization which is a synthetic method of a general acrylic polymer or a methacrylic polymer. The form may be various methods such as solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization.

The solvent for the reaction may be water, a phosphate buffer or an alcohol such as ethanol, or a mixed solvent obtained by combining these.

Furthermore, the reaction solvent can also improve the solubility of the monomer and the polymer. Heating is performed (for example, 40 ° C ~ 100 ° C).

In order to carry out the polymerization efficiently, it is preferred to use a polymerization initiator. As an example of the polymerization initiator, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(2-methylbutyronitrile), 2,2'-azobis ( 2,4-Dimethylvaleronitrile), 4,4'-azobis(4-cyanovaleric acid), 2,2'-azobis(4-methoxy-2,4-dimethyl Valeronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile), 1-[(1-cyano-1-methylethyl)azo]carbamamine, 2,2' -Azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (Wako Pure Chemical Industries, Ltd. product name; VA-044), 2,2'-azobis[2- (2-imidazolidin-2-yl)propane]disulfate dihydrate (Wako Pure Chemical Industries, Ltd. product name; VA-046B), 2,2'-azobis[2-(2-imidazoline) -2-yl)propane] (Wako Pure Chemical Industries Co., Ltd. product name; VA-061), 2,2'-azobis(2-methylpropionamidine) dihydrochloride (Wako Pure Chemical Industries Co., Ltd. Product name; V-50), 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propanamide) (Wako Pure Chemical Co., Ltd. product name; VA-086), Benzoyl benzoate (BPO), 2,2'-azobis(N-(2-carboxyethyl)-2-methylpropionamidine) n-hydrate (Wako Pure Chemical Industries, Ltd.); VA -057), 4,4'-azobis(4-cyanovaleric acid) (manufactured by Wako Pure Chemical Industries, Ltd. Name; VA-501), peroxodisulfate or tert-butyl hydroperoxide, etc., among which, in consideration of ion balance and solubility in water, 2,2'-azo is preferably used. Bis[2-methyl-N-(2-hydroxyethyl)propanamide), 2,2'-azobis(N-(2-carboxyethyl)-2-methylpropionamidine)-hydration , 4,4'-azobis(4-cyanovaleric acid), 2,2'-azobis[2-(2-imidazolidin-2-yl)propane) dihydrochloride, 2,2 '-Azobis[2-(2-imidazolidin-2-) Propane]disulfate dihydrate, 2,2'-azobis[2-(2-imidazolidin-2-yl)propane], 2,2'-azobis(2-methylpropionamidine) Any of dihydrochloride or peroxodisulfuric acid.

The reaction conditions are carried out by heating the reaction vessel to 50 ° C to 200 ° C in an oil bath or the like, and stirring for 1 hour to 48 hours to obtain a copolymer of the present invention. The reaction environment is preferably a nitrogen environment.

In the reaction sequence, all of the reaction materials may be placed in a reaction solvent at room temperature, and then heated to the above temperature to be polymerized, or the reaction material may be dropped in a small amount in a preheated solvent. All or part of the mixture.

The molecular weight of the copolymer of the present invention may be from several thousands to several millions, preferably from 1,000 to 5,000,000. Further, a random copolymer, a block copolymer, or a graft copolymer may be used, and the copolymerization reaction for producing the copolymer itself is not particularly limited, and it may be used by radical polymerization or ion polymerization or photopolymerization. A known method of synthesizing in a solution, such as a macromer or a polymerization of emulsion polymerization. These may be used singly or in combination with any of the copolymers of the present invention, or may be used by mixing a plurality of copolymers and changing the ratio thereof.

[Examples]

Hereinafter, the present invention will be described in more detail based on Synthesis Examples and Examples, but the present invention is not limited to the Synthesis Examples and Examples.

<Synthesis Example 1 to Synthesis Example 6>

The sulfonic acid group, propyl acrylate, 3-potassium salt (KSPA; (formula 3-2) of T ^b = H (hydrogen atom), U ^a1 = K (potassium atom) of the compound, Aldrich Corporation) and 10.8 g of acrylic acid 2 -(Dimethylamino)ethylmethyl ester (DMAEMA; compound of formula (3-4), and Wako Pure Chemical Industries, Ltd.) 12.3 mL each dissolved in 100 mL of ultrapure water, then added ultrapure water The solution was made up to 200 mL. 2,2'-Azobis(N-(2-carboxyethyl)-2-methylpropionamidine) n-hydrate (product name; VA-057, manufactured by Wako Pure Chemical Industries, Ltd.) 0.304 g Dissolved in 12.3 mL of ultrapure water. The above-mentioned KSPA aqueous solution, DMAEMA aqueous solution, VA-057 aqueous solution and ultrapure water were placed in a 200 mL test tube at a ratio of Table 1, and after nitrogen replacement with nitrogen for about 60 minutes, the mixture was sealed at 70 ° C for 70 minutes. This was subjected to a polymerization reaction for 16 hours to obtain each copolymer 1 to copolymer 6. After the completion of the reaction, the reaction solution was sealed in a dialysis tube (Specrta/Por (registered trademark) 6, Dialysis Membrane) having a molecular weight of 3,500, and dialyzed for 10 days in 500 mL of ultrapure water. At this time, the ultrapure water system was replaced every 12 hours. The concentration after dialysis was determined by evaporation and drying at 100 ° C for 16 hours (Table 1). The composition ratio of the copolymer (KSPA: DMAEMA) was prepared by drying 60 μL of the aqueous polymer solution on a glass slide at 70 ° C for 3 hours, and determined by X-ray photoelectron spectroscopy (XPS) from the nitrogen/sulfur element ratio (Table) 1).

<Synthesis Example 7>

2.38 g of KSPA, 23.6 μL of DMAEMA, and 17.9 mg of VA-057 were dissolved in 80 mL of ultrapure water, placed in a test tube of 200 mL, and subjected to the same operation as in Synthesis Example 1 to Synthesis Example 6 described above. Copolymer 7. The concentration of the copolymer 7 after dialysis was 0.618% by mass. The composition of the obtained copolymer 7 was KSPA: DMAEMA = 8.0: 2.0.

<Synthesis Example 8>

0.165 g of KSPA, 2.39 mL of DMAEMA, and 25.5 mg of VA-057 were dissolved in 80 mL of ultrapure water, placed in a test tube of 200 mL, and subjected to the same operation as in Synthesis Example 1 to Synthesis Example 6 described above. Copolymer 8. The concentration of the copolymer 8 after dialysis was 0.344% by mass. The composition of the obtained copolymer 8 was KSPA: DMAEMA = 0.9: 9.1.

(Modulation of composition for coating film formation)

The copolymer 1 to the copolymer 8 were each dissolved in a manner of 0.05% by mass. The coating film-forming compositions 1 to 8 (solvent: aqueous solution) and the coating film-forming composition 9 to 16 (solvent: PBS) were prepared by dissolving in ultrapure water or PBS (pH = 7.4).

<Example 1 to Example 16>

The coating films of Examples 1 to 16 were produced on the glass substrate using the above compositions 1 to 16.

(1) The composition is brought into contact with the surface of the glass substrate.

(2) Washing 3 times with ultrapure water (Examples 1 to 8) or PBS (Examples 9 to 16)

(3) air drying

The glass substrate was produced in the following manner.

[Performed glass treated with steam plasma (SiOH surface)]

A 60-second steam plasma treatment was carried out on a high water-repellent printing slide (manufactured by Matsuron Glass Industry Co., Ltd., TF2404 (Non-Coat type)) having a window of 24 mm in diameter and 4 mm. The surface of the sample was formed into a SiOH surface by a glass surface having a diameter of 4 mm which was not subjected to water repellent treatment.

[Water droplet contact angle]

The contact angle of the water droplets was determined by a liquid-adapted method using a contact angle meter (manufactured by Kyowa Interface Science Co., Ltd., model: CA-D).

The results of measuring the water contact angles of the glass substrates of Examples 1 to 16 are shown in [Table 2].

The measured values are the average values performed with n=10.

Regardless of the composition ratio of the polymers 1 to 8, the contact angle was 13.0 to 45.0 degrees, and the formation of the coating film was confirmed.

[Protein attachment properties]

In the protein adhesion system, bovine serum albumin (FITC-BSA, pI (isoelectric point) = 4.7) was used, and the amount of adhesion (fluorescence intensity) on the surface of the SiOH was measured with respect to glass (comparative example). Relative evaluation. The measurement results are shown in [Table 3].

(condition)

FITC-BSA solution: 1.0 mg/mL in PBS

Culture conditions: 5% CO ₂ , 37 ° C

Contact time: 6 hours

Washing conditions: use 15 μL of PBS twice, then use ultrapure water twice

[Cell adhesion assessment]

Evaluation was performed by the fibrocyte adhesion characteristics. Cell line V79 cells (fiber bud cells derived from Chinese hamster lung) were inoculated on the above glass substrate, and the adhesion number was divided into stretched cells and unstretched cells after culturing at 37 ° C for 48 hours in a 5% CO ₂ atmosphere. Evaluation. The results are shown in [Table 4].

[Industrial availability]

The coating film using the ionic composite of the present invention is firmly fixed to all the substrates by a simple drying step, and the film has a living substance adhesion inhibiting ability.

The application can be expected to be a coating film for inhibiting the adhesion of living substances such as artificial dialyzers, artificial organs, and medical instruments.

Claims (4)

A coating film comprising a composition for forming a coating film comprising a copolymer and a solvent, which is formed by contacting a substrate, and comprising: a repeat comprising a monovalent organic group represented by the following formula (a) a unit, and a repeating unit comprising a monovalent organic group represented by the following (formula b); (In the formula, U ^a1 represents a hydrogen atom or an alkali metal atom, and U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms). The coating film of claim 1, wherein the base system is selected from the group consisting of glass, a metal-containing compound or a semimetal-containing compound, or a resin. The coating film of claim 1 or 2 which has an adhesion inhibiting ability of a living substance. The coating film according to any one of claims 1 to 3, wherein the copolymer comprises at least one repeating unit selected from the group consisting of the following (formulae-1) and (formula b-1); (wherein, T ^a , T ^b , U ^b1 and U ^b2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and U ^a1 represents a hydrogen atom or an alkali metal atom, Q ^a and Q ^b each independently represents a single bond, an ester bond (-C(=O)-O- or -OC(=O)-) or a guanamine bond (-NHC(=O)- or -C(=O)NH -), R ^a and R ^b each independently represent a single bond or a straight or branched alkyl group having 1 to 5 carbon atoms which may be substituted by a halogen atom.