JP2017186482A - Polymer, protein adhesion prevention agent and medical device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polymer and a protein adhesion prevention agent capable of forming a coating layer to which protein is less likely to adhere and excellent in water resistance and durability, and a medical device having the coating layer using the protein adhesion prevention agent.SOLUTION: There is provided a polymer having a unit derived from a maleimide derivative having a polyoxyethylene group in a side chain and having glass transition temperature of 20°C or more. There is provided a medical device 1 having a substrate 2 and a coating layer 3 formed on the substrate 2, the coating layer 3 is a layer formed from a protein adhesion prevention agent consisting of the polymer.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a polymer, a protein adhesion preventing agent, and a medical device.

  Synthetic polymer materials are widely used as medical polymer materials for forming medical devices such as cell culture containers, catheters, and artificial organs. Typical synthetic polymer materials used for medical polymer materials include, for example, hydrophobic polymers such as polyvinyl chloride, polystyrene, silicone resins, polymethacrylic acid esters, fluorine-containing resins, polyvinyl alcohol, and poly (methacrylic acid). Acid 2-hydroxyethyl), and hydrophilic polymers such as polyacrylamide. However, these synthetic polymer materials tend to adsorb biological components such as proteins and blood cells to the device surface. When the biological component is adsorbed on the device surface and denatured, problems such as blood clot formation, inflammatory reaction, and other adverse effects on the living body, and deterioration of the device are caused. This problem is an important issue that must be solved fundamentally and urgently in medical polymer materials.

  As a method for suppressing protein adsorption in a device, a coating layer made of a synthetic polymer material containing 2-methacryloyloxyethyl phosphorylcholine (MPC) having a biological membrane-like structure or polyethylene glycol (PEG) is formed on the device surface. Has been proposed (for example, Non-Patent Document 1). However, since MPC and PEG are water-soluble, there is a problem that the coating layer dissolves during use only with them.

  Therefore, MPC is copolymerized with a hydrophobic monomer such as butyl methacrylate (Patent Document 1), a prepolymer having a hydroxy group and a phospholipid-like structure is reacted with a diisocyanate compound, and crosslinked with a urethane bond (Patent Document). 2) It has been proposed to improve water resistance by immobilizing a hydrophilic polymer obtained by copolymerizing an epoxy group-containing monomer on the surface of a material by reaction of an epoxy group (Patent Document 3). .

Japanese Patent No. 4774899 Japanese Patent No. 3695944 International Publication No. 2001/007097

Polymer Papers Vol. 35, pp. 423-427, 1978

  However, in the method of increasing water resistance by copolymerizing monomers such as butyl methacrylate or reacting with a diisocyanate compound after polymerization, reproducibility is difficult to obtain due to variation in the composition of the polymer, and water resistance is poor. May be sufficient. In addition, the coating layer formed using the polymer may peel off from the device surface when it comes into contact with water, and sufficient durability may not be obtained.

  The present invention provides a polymer and a protein adhesion preventive agent capable of forming a coating layer that is difficult to adsorb proteins and is excellent in water resistance and durability, and a medical device provided with a coating layer using the protein adhesion preventive agent. For the purpose.

The present invention has the following configuration.
[1] A polymer having a unit derived from a maleimide derivative having a polyoxyethylene group in the side chain and having a glass transition temperature of 20 ° C. or higher.
[2] The polymer of [1], wherein the maleimide derivative is a compound represented by the following formula (1).

(However, in the formula (1), X represents an alkylene group having 1 to 10 carbon _{atoms, - (CH 2) d -COO-} (CH 2) e - ( however, d, e from independently 0 10 Or —C ₆ H ₄ — (CH ₂ ) _c — (where c is an integer of 0 to 10), a is an integer of 2 to 50, and R ¹ is hydrogen. It is an atom or a monovalent hydrocarbon group.)
[3] The polymer according to [1] or [2], further having units derived from the compound represented by the following formula (2).

(However, in the formula (2), ^{R 2} is a hydrogen atom, a chlorine atom or a methyl group, b is an integer from 1 to 10, ^{R 3} is an alkyl group having 1 to 5 carbon atoms .R ^{The three} alkyl groups in 3 may be the same as or different from each other.
[4] A protein adhesion preventing agent comprising the polymer according to any one of [1] to [3].
[5] A medical device having a coating layer containing the polymer according to any one of [1] to [3] on at least a part of the surface.
[6] The medical device according to [5], which is a cell culture container.

If the polymer of the present invention is used, it is possible to form a coating layer that hardly adheres to proteins and is excellent in water resistance and durability.
If the protein adhesion preventing agent of the present invention is used, it is possible to form a coating layer that is less likely to adhere to proteins and is excellent in water resistance and durability.
The medical device of the present invention is provided with a coating layer that hardly adheres to proteins and is excellent in water resistance and durability.

It is the perspective view which showed an example of the medical device of this invention. It is II sectional drawing of the medical device of FIG.

The following definitions of terms apply throughout this specification and the claims.
The “glass transition temperature (Tg)” of the polymer means a midpoint glass transition temperature when changing from a rubber state to a glass state measured by a differential scanning calorimetry (DSC) method.
The “number average molecular weight (Mn)” and “mass average molecular weight (Mw)” of the polymer mean values determined in terms of polystyrene by gel permeation chromatography (GPC) method.
The “unit” means a part derived from a monomer that exists in the polymer and constitutes the polymer. The unit derived from the monomer resulting from addition polymerization of a monomer having a carbon-carbon unsaturated double bond is a divalent unit generated by cleavage of the unsaturated double bond. Moreover, what unitally converted the structure of a unit after polymer formation is also called a unit.
The “side chain” of the maleimide derivative means a chain formed by replacing a hydrogen atom bonded to a nitrogen atom in maleimide.
A “medical device” is a device used for medical purposes such as treatment, diagnosis, anatomy, or biological examination, and is a medium (blood that is inserted into or brought into contact with a living body such as a human body or taken out of a living body) Etc.) shall be included.

  In the present specification, a compound represented by the formula (1) is referred to as a compound (1). The same applies to compounds represented by other formulas.

[Polymer]
The polymer of the present invention is a polymer having a unit derived from a maleimide derivative having a polyoxyethylene group in the side chain (hereinafter also referred to as unit (a1)) and having a glass transition temperature of 20 ° C. or higher. In addition to the unit (a1), the polymer of the present invention includes units derived from the compound (2) described later (hereinafter also referred to as unit (a2)), units (a1) and units other than the unit (a2). A unit (hereinafter also referred to as a unit (a3)) may be further included.

(Unit (a1))
The unit (a1) is a unit derived from a maleimide derivative having a polyoxyethylene group in the side chain.
The side chain of the maleimide derivative only needs to have a polyoxyethylene group, and the structure of the portion other than the polyoxyethylene group is not particularly limited. In the side chain of the maleimide derivative, the polyoxyethylene group is an alkylene group having 1 to 10 carbon atoms, — (CH ₂ ) _d —COO— (CH ₂ ) _e — (where d and e are each independently 0 to 10). It is preferably a chain that is bonded to the nitrogen atom of maleimide via —C ₆ H ₄ — (CH ₂ ) _c — (where c is an integer of 0 to 10). The terminal structure of the side chain of the maleimide derivative is not particularly limited, and may be a hydroxy group or an alkoxy group.

  2-50 are preferable and, as for the repeating number of the oxyethylene group in a polyoxyethylene group, 2-25 are more preferable. If the number of repeating oxyethylene groups is not less than the lower limit, it is more difficult to adsorb cells. When the number of repeating oxyethylene groups is not more than the upper limit, it is easy to produce a maleimide derivative with high purity.

  As the maleimide derivative, the following compound (1) is preferable because it is difficult to adsorb proteins and easily exhibits excellent water resistance.

However, In the formula (1), X represents an alkylene group having 1 to 10 carbon _{atoms, - (CH 2) d -COO-} (CH 2) e - (d, e is from 0 to 10 integer) or -C ₆ H ₄ — (CH ₂ ) _c — (where c is an integer of 0 to 10), a is an integer of 2 to 50, and R ¹ is a hydrogen atom or a monovalent hydrocarbon group. is there.

  The alkylene group in X may be linear or branched. The number of carbon atoms of the alkylene group in X is preferably 1 to 10 and more preferably 1 to 5 from the viewpoint that protein is difficult to adsorb.

The phenylene group in —C ₆ H ₄ — (CH ₂ ) _c — in X may be any of o, m, or p-phenylene group. c is preferably an integer of 0 to 10 and more preferably an integer of 0 to 5 from the viewpoint that it is difficult to adsorb proteins.
X is preferably —C ₆ H ₄ — (CH ₂ ) _c — from the viewpoint of excellent heat resistance of the polymer.

  a is preferably an integer of 2 to 50, and more preferably an integer of 2 to 25. If a is more than a lower limit, protein adhesion can be prevented more. If a is at most the upper limit, the purity of the material is high and it is easy to produce a uniform compound.

Examples of the monovalent hydrocarbon group for R ¹ include an alkyl group having 1 to 10 carbon atoms, an aryl group (such as a phenyl group and a naphthyl group), and an aromatic alkyl group (such as a benzyl group). The alkyl group in R ¹ may be linear or branched. As the monovalent hydrocarbon group, an alkyl group having 1 to 10 carbon atoms is preferable, and a methyl group or an ethyl group is more preferable from the viewpoint that protein is hardly adsorbed.
R ¹ is preferably a hydrogen atom, a methyl group, or an ethyl group from the viewpoint that protein is more difficult to adsorb.

The unit (a1) possessed by the polymer of the present invention may be only one type or two or more types.
10-100 mol% is preferable, as for the ratio of the unit (a1) with respect to all the units of the polymer of this invention, 20-100 mol% is more preferable, and 30-100 mol% is further more preferable. If the ratio of the unit (a1) is at least the lower limit value, the protein is difficult to adsorb and can exhibit excellent water resistance. If the ratio of the unit (a1) is less than or equal to the upper limit value, the ratio of the unit (a2) and the unit (a3) can be relatively increased, and the adhesion of the device to the substrate or the like can be easily increased. .

(Unit (a2))
The unit (a2) is a unit derived from the following compound (2). The polymer of the present invention preferably has a unit (a2) from the viewpoint of improving the adhesion to the substrate of the device.

In the formula (2), ^{R 2} is a hydrogen atom, a chlorine atom or a methyl group, b is an integer from 1 to 10, ^{R 3} is an alkyl group having 1 to 5 carbon atoms. The ^three alkyl groups for R ³ may be the same as or different from each other.

R ² is preferably a hydrogen atom or a methyl group from the viewpoint of easy polymerization.
b is preferably an integer of 1 to 10 and more preferably an integer of 1 to 5 from the viewpoint of availability.

The alkyl group for R ³ may be linear or branched. The alkyl group for R ³ is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and particularly preferably a methyl group from the viewpoint of reaction time.

When the polymer of this invention has a unit (a2), only 1 type may be sufficient as a unit (a2), and 2 or more types may be sufficient as it.
When the polymer of this invention has a unit (a2), 0-50 mol% is preferable, as for the ratio of the unit (a2) with respect to all the units of a polymer, 0-30 mol% is more preferable, and 0-20 mol%. Is more preferable. If the ratio of the unit (a2) is at least the lower limit value, the adhesion of the device to the substrate and the like will be more excellent, and a coating layer having excellent durability can be easily formed. If the ratio of the unit (a2) is not more than the upper limit value, the ratio of the unit (a1) can be relatively increased, protein adhesion can be further prevented, and excellent water resistance can be easily obtained.

(Unit (a3))
It does not specifically limit as a monomer which forms a unit (a3), The compound shown below is mentioned.
For _{example, CH 2 = CH-COO- (} CH 2 CH 2 O) n -CH 3 (n is an integer of _{2~50.), CH 2 = CH} -COO- (CH 2 CH 2 O) n -CH ₂ CH ₃ (n is an integer of 2 to 50), CH ₂ ═C (CH ₃ ) —COO— (CH ₂ CH ₂ O) _n —CH ₃ (n is an integer of 2 to 50) _{, CH 2 = C (CH 3} ) -COO- ( where n is an integer of _{2~50.) (CH 2 CH 2} O) n -CH 2 CH 3, C (CH 3) = CH-COO- (CH _{2) 3} -CH _3, and the like.

When it is desired to impart water resistance to the polymer of the present invention, the following compounds can be used as monomers for forming the unit (a3).
_{CH 2 = CH-COO- (CH} 2) 4 -H,
_{CH 2 = CH-COO- (CH} 2) 6 -H,
_{CH 2 = CH-COO- (CH} 2) 8 -H,
_{CH 2 = CH-COO- (CH} 2) 16 -H,
_{CH 2 = CH-COO-CH} 2 CH (C 2 H 5) CH 2 CH 2 CH 2 CH 3 and the like.
Of these _{CH 2 = CH-COO- (CH} 2) 4 -H, CH 2 = CH-COO- (CH 2) 8 -H, CH 2 = CH-COO- (CH 2) 16 -H preferably, CH ₂ = CH—COO— (CH ₂ ) ₈ —H and CH ₂ ═CH—COO— (CH ₂ ) ₁₆ —H are particularly preferred.

In particular, when it is desired to impart water resistance, the following fluorine-containing compound can be used as a monomer for forming the unit (a3).
_{CH 2 = CH-COO- (CH} 2) 2 (CF 2) 3 CF 3,
_{CH 2 = CH-COO- (CH} 2) 2 (CF 2) 5 CF 3,
_{CH 2 = C (CH 3)} COO- (CH 2) 2 (CF 2) 3 CF 3,
_{CH 2 = C (CH 3)} COO- (CH 2) 2 (CF 2) 5 CF 3,
_{CH 2 = CH-COO- (CH} 2) 3 (CF 2) 3 CF 3,
_{CH 2 = CH-COO- (CH} 2) 3 (CF 2) 5 CF 3,
_{CH 2 = CH-COO-CH} 2 CH (OH) CH 2 (CF 2) 3 CF 3,
_{CH 2 = CH-COO-CH} 2 CH (OH) CH 2 (CF 2) 5 CF 3,
_{CH 2 = C (CH 3)} -COO- (CH 2) 3 (CF 2) 3 CF 3,
_{CH 2 = C (CH 3)} -COO- (CH 2) 3 (CF 2) 5 CF 3,
_{CH 2 = C (CH 3)} -COO-CH 2 CH (OH) CH 2 (CF 2) 3 CF 3,
_{CH 2 = C (CH 3)} -COO-CH 2 CH (OH) CH 2 (CF 2) 5 CF 3,
_{CH 2 = CHC 6 H 4 (} CF 2) 3 CF 3,
_{CH 2 = CHC 6 H 4 (} CF 2) 5 CF 3,
_{CH 2 = CH-COO-CH} 2 CH 2 N (CH 3) SO 2 (CF 2) 3 CF 3,
_{CH 2 = CH-COO-CH} 2 CH 2 N (CH 3) SO 2 (CF 2) 5 CF 3,
_{CH 2 = C (CH 3)} -COO-CH 2 CH 2 N (CH 3) SO 2 (CF 2) 3 CF 3,
_{CH 2 = C (CH 3)} -COO-CH 2 CH 2 N (CH 3) SO 2 (CF 2) 5 CF 3,
_{CH 2 = CH-COO-CH} 2 CH 2 N (C 2 H 5) SO 2 (CF 2) 3 CF 3,
_{CH 2 = CH-COO-CH} 2 CH 2 N (C 2 H 5) SO 2 (CF 2) 5 CF 3,
_{CH 2 = C (CH 3)} -COO-CH 2 CH 2 N (C 2 H 5) SO 2 (CF 2) 3 CF 3,
_{CH 2 = C (CH 3)} -COO-CH 2 CH 2 N (C 2 H 5) SO 2 (CF 2) 5 CF 3,
_{CH 2 = CH-COO- (CH} 2) 2 N (CH 2 CH 2 CH 3) SO 2 (CF 2) 3 CF 3,
_{CH 2 = CH-COO- (CH} 2) 2 N (CH 2 CH 2 CH 3) SO 2 (CF 2) 5 CF 3,
_{CH 2 = C (CH 3)} -COO- (CH 2) 2 N (CH 2 CH 2 CH 3) SO 2 (CF 2) 3 CF 3,
_{CH 2 = C (CH 3)} -COO- (CH 2) 2 N (CH 2 CH 2 CH 3) SO 2 (CF 2) 5 CF 3,
CH ₂ = CHCONHCH ₂ C ₄ F ₉ ,
CH ₂ = CHCONHCH ₂ C ₅ F ₁₁ ,
CH ₂ = CHCONHCH ₂ C ₆ F ₁₃ ,
_{CH 2 = CHCONHCH 2 CH 2 OCOC} 4 F 9,
_{CH 2 = CHCONHCH 2 CH 2 OCOC} 5 F 11,
_{CH 2 = CHCONHCH 2 CH 2 OCOC} 6 F 13,
_{CH 2 = CH-COO-CH} (CF 3) 2
_{CH 2 = C (CH 3)} -COO-CH (CF 3) 2 and the like.

  In addition to the above, examples of the monomer that forms the unit (a3) include the following compounds. For example, N, N-dimethylaminoethyl (meth) acrylate, N, N-diethylaminoethyl (meth) acrylate, N- (meth) acryloylmorpholine, N- (meth) acryloylpepyridine, N, N-dimethylaminooxide ethyl (Meth) acrylate, N, N-diethylaminooxide ethyl (meth) acrylate. Also, 2-isocyanatoethyl (meth) acrylate, 3,5-dimethylpyrazole adduct of 2-isocyanatoethyl (meth) acrylate, 3-isocyanatepropyl (meth) acrylate, 4-isocyanatobutyl (meth) acrylate, triallyl isocyania Nurate, glycidyl (meth) acrylate, polyoxyalkylene glycol monoglycidyl ether (meth) acrylate.

When the polymer of this invention has a unit (a3), only 1 type may be sufficient as a unit (a3) and 2 or more types may be sufficient as it.
The ratio of the unit (a3) to the total unit of the polymer of the present invention is preferably 50 mol% or less, and more preferably 30 mol% or less. If the ratio of the unit (a3) is not more than the upper limit value, protein adhesion can be further prevented and excellent water resistance can be easily obtained.

  The polymer of the present invention can further prevent protein adhesion, and can easily form a coating layer having both water resistance and durability, so that the polymer having only unit (a1) or unit (a1) And a polymer comprising the unit (a2) are preferred.

(Physical properties)
The polymer of the present invention has a glass transition temperature (Tg) of 20 ° C. or higher. When the Tg of the polymer of the present invention is 20 ° C. or higher, a coating layer having excellent durability that is difficult to peel off from the device surface or the like even in contact with water can be formed. The glass transition temperature of the polymer of the present invention is preferably 20 to 250 ° C, more preferably 40 to 250 ° C. If the glass transition temperature of the polymer is equal to or higher than the lower limit value, it is easy to form a coating layer having excellent durability. If the glass transition temperature of the polymer is not more than the upper limit value, it can be dissolved in a general-purpose solvent.

  The glass transition temperature of the polymer can be adjusted by adjusting the proportion of the unit (a1) in the polymer and the molecular weight of the polymer. There exists a tendency for the glass transition temperature of a polymer to become high, so that the ratio of a unit (a1) is high. Moreover, there exists a tendency for the glass transition temperature of a polymer to become high, so that the molecular weight of a polymer is high.

  The number average molecular weight (Mn) of the polymer of the present invention is preferably from 3,000 to 1,000,000, particularly preferably from 5,000 to 500,000. If the number average molecular weight of the polymer is not less than the lower limit, the durability is excellent. If the number average molecular weight of the polymer is not more than the above upper limit value, the processability is excellent.

  3000-1 million are preferable and, as for the mass mean molecular weight (Mw) of the polymer of this invention, 5000-500000 are especially preferable. If the mass average molecular weight of the polymer is not less than the lower limit, the durability is excellent. If the mass average molecular weight of the polymer is not more than the above upper limit value, the processability is excellent.

  The molecular weight distribution (Mw / Mn) of the polymer is preferably 1.0 to 5.0, and particularly preferably 1.0 to 3.0. If the molecular weight distribution of the polymer is within the above range, the water resistance is excellent and the protein is difficult to adsorb.

(Production method)
The polymer of the present invention can be obtained by performing a polymerization reaction of monomers such as a maleimide derivative and compound (2) in a polymerization solvent using a known method.
The polymerization solvent is not particularly limited. For example, ketones (acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), alcohols (methanol, 2-propyl alcohol, etc.), esters (ethyl acetate, butyl acetate, etc.), ethers, etc. (Diisopropyl ether, tetrahydrofuran, dioxane, etc.), glycol ethers (ethylene glycol, propylene glycol, ethyl ether or methyl ether of dipropylene glycol, etc.) and derivatives thereof, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated Hydrocarbons (perchloroethylene, trichloro-1,1,1-ethane, trichlorotrifluoroethane, dichloropentafluoropropane, etc.), dimethylformamide, N-methyl-2-pyrrolidone, butyroacetone Dimethyl sulfoxide (DMSO) and the like.

  5-60 mass% is preferable and, as for the total concentration of all the monomers in the reaction liquid in a polymerization reaction, 10-40 mass% is especially preferable.

In the polymerization reaction, it is preferable to use a polymerization initiator. Examples of the polymerization initiator include peroxides (benzyl peroxide, lauryl peroxide, succinyl peroxide, tert-butyl perpivalate, etc.), azo compounds, and the like.
As the polymerization initiator, 2,2′-azoisobutyronitrile, 2,2′-azobis-2-methylbutyronitrile, dimethyl-2,2′-azobisisobutyrate, 2,2′-azobis [2- (2-imidazolin-2-yl) propane], 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 1,1′-azobis (2cyclohexane-1-carbonitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), 1,1′-azobis (1-acetoxy-1-phenylethane), dimethylazobisisobutyrate, 4,4′-azobis (4-cyano) Valeric acid), preferably 2,2′-azoisobutyronitrile, 2,2′-azobis [2- (2-imidazolin-2-yl) propane], 4,4′-azobis (4-cyanovaleric acid) Is particularly preferred.
As for the usage-amount of a polymerization initiator, 0.1-1.5 mass parts is preferable with respect to 100 mass parts of total amounts of a monomer.

In order to adjust the polymerization degree (molecular weight) of the polymer, a chain transfer agent may be used in the polymerization reaction. By using a chain transfer agent, there is also an effect that the total concentration of monomers in the polymerization solvent can be increased.
As the chain transfer agent, alkyl mercaptan (tert-dodecyl mercaptan, n-dodecyl mercaptan, stearyl mercaptan, etc.), aminoethanethiol, mercaptoethanol, 3-mercaptopropionic acid, 2-mercaptopropionic acid, thiomalic acid, thioglycolic acid, 3,3′-dithio-dipropionic acid, 2-ethylhexyl thioglycolate, n-butyl thioglycolate, methoxybutyl thioglycolate, ethyl thioglycolate, 2,4-diphenyl-4-methyl-1-pentene, And carbon tetrachloride.
As for the usage-amount of a chain transfer agent, 0-2 mass parts is preferable with respect to 100 mass parts of total amounts of a monomer.

  The reaction temperature in the polymerization reaction is preferably in the range from room temperature to the boiling point of the reaction solution. From the viewpoint of efficiently using the polymerization initiator, the half-life temperature of the polymerization initiator or higher is preferable, and 30 to 90 ° C is more preferable.

(Function and effect)
The polymer of the present invention described above has excellent water resistance because it has the unit (a1) derived from the maleimide derivative. Moreover, since unit (a1) has a polyoxyethylene group in the side chain, it is difficult for proteins to adhere to it. In addition, since the polymer of the present invention has a glass transition temperature of 20 ° C. or higher, when a coating layer is formed on the device surface or the like, the coating layer is difficult to move even when in contact with water, and is difficult to peel off from the device surface or the like. Excellent durability is obtained. Even if the polymer of this invention is a homopolymer which consists only of a unit (a1), protein cannot adhere easily and can form the coating layer which has water resistance and durability.

Further, the polymer of the present invention, as a unit (a1), X is a phenylene group or a _-C 6 _H 4 in the formula _{(1) - (CH 2)} c - in the case of having a unit derived from the compounds wherein the A coating layer having excellent heat resistance that can sufficiently withstand sterilization can be formed. In this case, the coating layer can also be formed by dry coating by vapor deposition.

[Protein adhesion inhibitor]
The protein adhesion preventive agent of the present invention is a protein adhesion preventive agent comprising the polymer of the present invention.

(Cell adhesion inhibitor)
As a use of the protein adhesion preventing agent of the present invention, a medical device is particularly effective.
The protein adhesion preventing agent of the present invention can be used, for example, for preventing cell adhesion, that is, as a cell adhesion preventing agent. The “cell” is the most basic unit constituting a living body, and means a cell having a cytoplasm and various organelles inside a cell membrane. The nucleus containing DNA may or may not be contained inside the cell.

Animal-derived cells include germ cells (sperm, ova, etc.), somatic cells that make up the living body, stem cells, progenitor cells, cancer cells separated from the living body, acquired from the living body and acquired immortalizing ability, and are stable outside the body. Maintained cells (cell lines), cells isolated from living organisms and artificially genetically modified, cells isolated from living organisms and artificially exchanged nuclei, and the like.
The somatic cells constituting the living body include fibroblasts, bone marrow cells, B lymphocytes, T lymphocytes, neutrophils, erythrocytes, platelets, macrophages, monocytes, bone cells, bone marrow cells, pericytes, dendritic cells , Keratinocytes, adipocytes, mesenchymal cells, epithelial cells, epidermal cells, endothelial cells, vascular endothelial cells, hepatocytes, chondrocytes, cumulus cells, neural cells, glial cells, neurons, oligodendrocytes, microglia, Astrocytes, heart cells, esophageal cells, muscle cells (eg, smooth muscle cells, skeletal muscle cells), pancreatic beta cells, melanocytes, hematopoietic progenitor cells, mononuclear cells and the like are included. Somatic cells include skin, kidney, spleen, adrenal gland, liver, lung, ovary, pancreas, uterus, stomach, colon, small intestine, large intestine, bladder, prostate, testis, thymus, muscle, connective tissue, bone, cartilage, vascular tissue , Cells collected from any tissue, such as blood, heart, eye, brain, nerve tissue.
Stem cells are cells that have the ability to replicate themselves and to differentiate into other types of cells. Embryonic stem cells (ES cells), embryonic tumor cells, embryonic germ stem cells, induced pluripotency Examples include stem cells (iPS cells), neural stem cells, hematopoietic stem cells, mesenchymal stem cells, hepatic stem cells, pancreatic stem cells, muscle stem cells, reproductive stem cells, intestinal stem cells, cancer stem cells, hair follicle stem cells and the like.
A progenitor cell is a cell that is in the process of being differentiated from the stem cell into a specific somatic cell or germ cell.
Cancer cells are cells that have been derived from somatic cells and have acquired unlimited proliferative capacity.
A cell line is a cell that has acquired infinite proliferation ability by artificial manipulation in vitro, and is HCT116, Huh7, HEK293 (human embryonic kidney cell), HeLa (human cervical cancer cell line), HepG2 (human) Hepatoma 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, and the like are included.

(Uses other than cell adhesion inhibitors)
In addition, you may use the protein adhesion inhibitor of this invention with respect to marine structures, such as a ship, a bridge, a marine tank, a port facility, a submarine base, a submarine oil field drilling equipment. By using the protein adhesion preventive agent of the present invention for the marine structure, protein adsorption to the marine structure is suppressed. As a result, adhesion of aquatic organisms such as shellfish (barnacles, etc.) and seaweeds (Aonori, Aosa, etc.) is suppressed.

[Medical device]
The medical device of the present invention has a coating layer containing the polymer of the present invention on at least a part of its surface. Thereby, it can prevent that a cell adheres to the medical device surface.

  Specific examples of the medical device include pharmaceuticals, quasi-drugs, medical instruments, and the like. The medical device is not particularly limited, and is a cell culture container, a cell culture sheet, a cell capture filter, a vial, a plastic coated vial, a syringe, a plastic coated syringe, an ampule, a plastic coated ampule, a cartridge, a bottle, a plastic coated bottle, a pouch. , Pump, nebulizer, stopper, plunger, cap, lid, needle, stent, catheter, implant, contact lens, microchannel chip, drug delivery system material, artificial blood vessel, artificial organ, hemodialysis membrane, guard wire, blood filter , Blood storage packs, endoscopes, biochips, sugar chain synthesizers, molding aids, packaging materials, and the like. Especially, it is preferably used for a cell culture container, a cell culture sheet, a cell capture filter, etc.

Specific examples of the medical device of the present invention include the medical device 1 illustrated in FIGS. 1 and 2. The medical device 1 is a petri dish that is one of cell culture containers.
The medical device 1 includes a base material 2 and a coating layer 3 formed on the base material 2. The base material 2 includes a bottom surface portion 4 having a circular shape in plan view, and a side surface portion 5 that rises from the peripheral edge of the bottom surface portion 4 over the entire circumference, and has a container shape with an open top. The coating layer 3 is formed of the polymer of the present invention on the inner surface of the substrate 2, that is, the upper surface of the bottom surface portion 4 and the inner surface of the side surface portion 5.

  The material constituting the device in the medical device of the present invention is not particularly limited, and examples thereof include resins such as polyethylene terephthalate, polystyrene, polycarbonate, polypropylene, tetrafluoroethylene-ethylene copolymer (ETFE), and glass. Generally, resin is preferable from the viewpoint of material cost and processing cost. On the other hand, for applications such as use for high-precision analysis, a glass having high transparency of the material itself, low fluorescence, chemically stable and excellent rigidity is desirable.

The content of the polymer of the present invention in the coating layer is preferably 95% by mass or more, and more preferably 99% by mass or more. As a coating layer, the layer formed only from the polymer of this invention, or the layer formed from the polymer of this invention and a crosslinking agent is mentioned.
The thickness of the coating layer is preferably 1 nm to 1 mm, particularly preferably 5 nm to 800 μm. If the thickness of the coating layer is equal to or greater than the lower limit, it is difficult for protein to be adsorbed. If the thickness of the coating layer is less than or equal to the above upper limit value, the coating layer tends to adhere to the surface of the substrate constituting the device.

  In order to improve the adhesion between the coating layer and the substrate, an adhesive layer may be provided between the substrate and the coating layer. As the adhesive for forming the adhesive layer, an adhesive that exhibits sufficient adhesion to both the coating layer and the substrate can be used as appropriate, for example, cyanoacrylate adhesive, silicone-modified acrylic adhesive, epoxy-modified silicone. An adhesive etc. are mentioned.

  As a specific example, for example, when polystyrene is used as a material for forming a substrate, a cyanoacrylate adhesive is used. In this case, on the base material side of the adhesive layer, the cyanoacrylate monomer in the cyanoacrylate adhesive reacts with moisture in the air or the surface of the base material to be cured. Since polyoxyethylene groups derived from the polymer of the present invention are present in the coating layer, moisture is present in the coating layer and in the periphery thereof. Therefore, the cyanoacrylate monomer reacts with the moisture and cures even on the coating layer side of the adhesive layer.

(Method for manufacturing medical device)
The manufacturing method of the medical device of this invention is not specifically limited, For example, the method of including the following application | coating process and a drying process is mentioned.
Coating step: A step of coating a coating solution containing the polymer of the present invention and a solvent on a substrate.
Drying step: a step of removing a solvent derived from the coating solution and obtaining a medical device having a coating layer formed on the substrate.

<Application process>
A coating solution containing the polymer of the present invention and a solvent is wet-coated on a substrate. As a coating method of the coating solution, a known method can be used, and examples thereof include a method performed using a coating apparatus such as a brush, a roller, dipping, a spray, a roll coater, a die coater, an applicator, and a spin coater.

  Examples of the solvent used for the coating solution include non-fluorinated solvents and fluorinated solvents. Examples of the non-fluorinated solvent include alcohol solvents and halogen-containing solvents. For example, ethanol, methanol, acetone, chloroform, Asahi Clin AK225 (Asahi Glass Co., Ltd.), AC6000 (Asahi Glass Co., Ltd.) and the like can be mentioned. It is preferable to select a solvent that does not dissolve the device or the like. When using polystyrene as a device, ethanol, methanol, Asahi Clin AK225 (Asahi Glass Co., Ltd.), and AC6000 (Asahi Glass Co., Ltd.) are preferable.

  The concentration of the polymer in the coating solution is preferably 0.0001 to 10% by mass, particularly preferably 0.0005 to 5% by mass. If the concentration of the polymer is within the above range, it can be applied uniformly and a uniform coating layer can be formed.

  When applying the coating solution, the coating solution may contain components other than the polymer and the solvent, such as a leveling agent and a crosslinking agent. By blending a crosslinking agent in the coating solution and adjusting the degree of crosslinking in the coating layer, it is possible to form a coating layer having superior durability in which the effect of preventing protein adhesion lasts for a longer period of time. Specifically, when the end of the side chain of the unit (a1) in the polymer of the present invention is a hydroxy group, a coating layer having excellent durability can be obtained by adding a crosslinking agent that reacts with the hydroxy group. Can be formed. When a crosslinking agent is included in the coating solution, the coating layer is a layer formed from a polymer and a crosslinking agent. When a crosslinking agent is not included in the coating solution, the coating layer is a layer formed only from a polymer.

Examples of the crosslinking agent include polyfunctional isocyanate compounds. Examples of the polyfunctional isocyanate compound include hexamethylene diisocyanate (HDI), HDI polyisocyanate, and isophorone diisocyanate (IPDI). The HDI polyisocyanate includes biuret type, isocyanurate type, adduct type, and bifunctional type for two-component type, and also includes a block type having a threshold for the curing start temperature. A commercial item can be used for HDI type polyisocyanate, and duranate (made by Asahi Kasei Co., Ltd.) etc. are mentioned.
The polyfunctional isocyanate compound to be used can be appropriately selected depending on the reaction temperature and the material of the device. For example, when polystyrene is used as a device, it can be dissolved in Asahi Clin AK225 (Asahi Glass Co., Ltd.), AC6000 (Asahi Glass Co., Ltd.), etc. The nurate type is preferred.

The degree of cross-linking in the coating layer depends on the amount of hydroxy groups in the polymer, the amount of cross-linking agent added, and the reaction rate, and can be appropriately adjusted within a range not impairing the effects of the present invention.
The amount of the crosslinking agent used is preferably from 0.01 to 10 parts by weight, particularly preferably from 0.1 to 1 part by weight, based on 100 parts by weight of the polymer. If the usage-amount of a crosslinking agent is more than the lower limit of the said range, it will be easy to form the coating layer excellent in durability. If the usage-amount of a crosslinking agent is below the upper limit of the said range, it will be easy to form the coating layer to which protein does not adhere easily.

<Drying process>
The method for removing the solvent derived from the coating solution applied on the substrate is not particularly limited, and for example, a known drying method such as air drying or drying by heating can be used.
The drying temperature is preferably 30 to 200 ° C.

  As mentioned above, the coating layer formed from a polymer can be easily formed by wet-coating the coating liquid containing the polymer of this invention and a solvent on a base material. In addition, the manufacturing method of the medical device of this invention is not limited to an above-described method, When the polymer of this invention is liquid at normal temperature (20-25 degreeC), this polymer is directly on a base material. The coating layer may be formed by applying the coating. In this case, the polymer may be heated in order to improve the adhesion to the surface of the substrate. You may form a coating layer by vapor deposition using the polymer of this invention.

  Since the medical device of the present invention described above has a coating layer formed from the polymer of the present invention on the surface, it is difficult for proteins to be adsorbed, it is excellent in water resistance, and it is difficult for the coating components to elute, resulting in durability. Is also excellent.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by the following description.
[Glass transition temperature (Tg)]
The glass transition temperature of the polymer was measured by raising and lowering the temperature from −30 ° C. to 200 ° C. at a rate of 10 ° C./min by DSC (manufactured by TA Instruments). The temperature at which the temperature changed from the rubber state in the second cycle when the temperature decreased to the glass state was defined as the glass transition temperature.

[Molecular weight]
The number average molecular weight (Mn), mass average molecular weight (Mw), and molecular weight distribution (mass average molecular weight (Mw) / number average molecular weight (Mn)) of the polymer are GPC devices (HLC8220, Tosoh) using tetrahydrofuran (THF) as a solvent. The measurement was performed using

[water resistant]
10 mg of the polymer used in each example and 1 g of water were weighed in a sample tube, stirred for 1 hour at room temperature, and then visually checked for water resistance. Evaluation was performed according to the following criteria.
<Evaluation criteria>
○: The polymer remained without being dispersed.
Δ: The polymer was dispersed in water.
X: The polymer was completely dissolved and did not remain.

[Non-adsorptive protein]
<Protein non-adsorption test>
(1) Preparation of color developing solution and protein solution The color developing solution includes peroxidase color developing solution (3,3 ′, 5,5′-tetramethylbenzidine (TMBZ), manufactured by KPL) and 50 mL TMB Peroxidase Substrate (manufactured by KPL). A mixture of 50 mL was used. As the protein solution, a protein (POD-goat anti mouse IgG, manufactured by Biorad) diluted 16,000 times with a phosphate buffer solution (D-PBS, manufactured by Sigma) was used.
(2) Protein adsorption 2 mL of the protein solution was dispensed into 3 wells in a 24-well microplate having a coating layer formed on the surface of each well (2 mL was used for each well) and left at room temperature for 1 hour. As a blank, 2 μL of the protein solution was dispensed into 3 wells of a 96-well microplate (2 μL was used for each well).
(3) Well Washing Next, a 24-well microplate was added with 4 mL of a phosphate buffer solution (D-PBS, Sigma) containing 0.05% by mass of a surfactant (Tween 20, manufactured by Wako Pure Chemical Industries, Ltd.). Washed 4 times (use 4 mL per well).
(4) Coloring solution dispensing Next, 2 mL of the coloring solution was dispensed to the washed 24-well microplate (2 mL was used for each well), and a coloring reaction was performed for 7 minutes. The color reaction was stopped by adding 1 mL of 2N sulfuric acid (1 mL per well was used).
For the blank, dispense 100 μL of the coloring solution to a 96-well microplate (use 100 μL per well), perform the color reaction for 7 minutes, and add 50 μL of 2N sulfuric acid (use 50 μL per well). ) The color reaction was stopped.
(5) Preparation for absorbance measurement Next, 150 μL of liquid was taken from each well of the 24-well microplate and transferred to a 96-well microplate.
(6) Absorbance measurement and protein adsorption rate Q
Absorbance was measured at 450 nm using MTP-810Lab (Corona Electric Co., Ltd.). Here, the average absorbance of the blank (N = 3) was A _0. Absorbance was measured A ₁ for each of the 3 wells of 24-well microplate liquid has been moved to the 96-well microplates.
Respectively obtained by the following equation protein adsorption rate Q ₁ for each absorbance A _1, and the average value thereof and protein adsorption rate Q (N = 3).
Q ₁ = A ₁ / {A ₀ × (100 / amount of dispensed blank protein solution)} × 100
= A ₁ / {A ₀ × (100/2 μL)} × 100 [%]

[Durability of coating layer]
(1) Durability of the coating layer formed on the well surface of the microplate A 24-well microplate having a coating layer formed on the well surface was immersed in water at 37 ° C for 1 week and then heated at 60 ° C for 2 hours. Dried. A protein non-adsorption test was performed before and after the immersion to measure the protein adsorption rate Q, and the increase rate of the protein adsorption rate Q was calculated by the following equation.
Rate of increase in protein adsorption rate Q (%) = (protein adsorption rate after immersion in water at 37 ° C. for 1 week (%) ÷ initial protein adsorption rate (%) − 1) × 100

(2) Durability of the coating layer formed on the surface of the glass petri dish 6 mL of water was placed in a glass petri dish having a coating layer formed on the surface and allowed to stand in an oven at 40 ° C. for 24 hours. Next, after removing water, the glass petri dish was dried by heating in an oven at 100 ° C. for 1 hour. A protein non-adsorption test was performed before standing and after drying to measure the protein adsorption rate Q, and the increase rate of the protein adsorption rate Q was calculated by the following equation.
Rate of increase of protein adsorption rate Q (%) = (protein adsorption rate (%) after water was allowed to stand at 40 ° C. for 24 hours ÷ initial protein adsorption rate (%) − 1) × 100

[Synthesis Example 1]
Compound B was synthesized according to the following synthesis scheme. Specifically, 21.5 g (131 mmol) of triethylene glycol monomethyl ether, 25.0 g (131 mmol) of paratoluenesulfonic acid chloride, and 100 mL of dichloromethane were charged into a 300 mL three-necked flask. To the obtained mixture, a mixture of 18.6 g (183 mmol) of triethylamine (TEA) and 50 mL of dichloromethane was added dropwise at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The obtained reaction mixture was transferred to a 500 mL separatory funnel, and the organic phase was washed once with 1N aqueous hydrochloric acid and twice with saturated brine. The obtained organic phase was dried over sodium sulfate and concentrated, and then purified by silica gel column chromatography using a developing solvent of ethyl acetate: hexane (volume ratio) = 5: 5 to obtain a colorless transparent liquid of compound B It was. The yield of Compound B was 37.3 g, and the yield was 89.3%.

[Synthesis Example 2]
Compound C was synthesized according to the following synthesis scheme. Specifically, 29.1 g (300 mmol) of maleimide, 61.3 g (900 mmol) of furan, 22 mg (0.1 mmol) of dibutylhydroxytoluene, and 600 mL of toluene were charged into a 1 L two-necked flask. The obtained mixture was stirred at 60 ° C. under a nitrogen atmosphere for 24 hours, and the reaction solution was ice-cooled. Then, the precipitated crystals were filtered and washed with cold toluene to obtain a white powder of Compound C. The yield of Compound C was 43.5 g, and the yield was 87.6%.

[Synthesis Example 3]
Compound D was synthesized according to the following synthesis scheme. Specifically, 9.55 g (30 mmol) of Compound B, 4.95 g (30 mmol) of Compound C, 20.7 g (150 mmol) of potassium carbonate, and 200 mL of acetonitrile were charged into a 300 mL two-necked flask. The resulting mixture was stirred at 50 ° C. under a nitrogen atmosphere for 16 hours, and potassium carbonate was removed by filtration. The obtained reaction mixture was concentrated and purified by silica gel column chromatography using a developing solvent of ethyl acetate: methanol (volume ratio) = 20: 1 to obtain a colorless transparent liquid of compound D. The yield of Compound D was 3.83 g, and the yield was 41.0%.

[Synthesis Example 4]
The compound (1-1), which is a maleimide derivative having a polyoxyethylene group in the side chain, was synthesized according to the following synthesis scheme. Specifically, 3.5 g (11.2 mmol) of Compound D, 2.2 mg (0.01 mmol) of dibutylhydroxytoluene, and 50 mL of toluene were added to a 100 mL flask and stirred at reflux for 4 hours. The obtained reaction mixture was concentrated and then purified by silica gel column chromatography using ethyl acetate as a developing solvent to obtain a colorless transparent liquid of compound (1-1). The yield of compound (1-1) was 1.87 g, and the yield was 68.4%.

[Synthesis Example 5]
Compound E was synthesized according to the following synthesis scheme. Specifically, 13.5 g (120 mmol) of potassium-t-butoxide (t-BuOK) and 200 mL of tetrahydrofuran (THF) were charged into a 1 L three-necked flask. To the obtained mixture, a mixture of 10.9 g (100 mmol) of p-aminophenol and 300 mL of tetrahydrofuran was added dropwise at 0 ° C. in a nitrogen atmosphere, and the mixture was stirred at 60 ° C. for 30 minutes. A mixture of 31.8 g (100 mmol) of Compound B and 100 mL of tetrahydrofuran was added dropwise to the obtained reaction solution at 60 ° C. in a nitrogen atmosphere, and the mixture was stirred at reflux for 2 hours. After concentration of the resulting reaction mixture, 500 mL of chloroform was added, transferred to a 1 L separatory funnel, and the organic phase was washed once with 1N aqueous hydrochloric acid and twice with saturated brine. The obtained organic phase was dried over sodium sulfate and concentrated, and then purified by silica gel column chromatography using a developing solvent of ethyl acetate: hexane (volume ratio) = 7: 3 to obtain a colorless transparent liquid of compound E It was. The yield of Compound E was 13.8 g, and the yield was 54%.

[Synthesis Example 6]
Compound F was synthesized according to the following synthesis scheme. Specifically, 12.8 g (50 mmol) of Compound E and 100 mL of acetone were charged into a 300 mL three-necked flask. To the resulting mixture, a mixture of 4.9 g (50 mmol) of maleic anhydride and 50 mL of acetone was added dropwise at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The obtained reaction mixture was concentrated, recrystallized with a mixed solution of toluene: hexane (volume ratio) = 3: 2, and purified to obtain a yellow powder of compound F. The yield of compound F was 9.14 g, and the yield was 51.8%.

Compound F was identified by ¹ H-NMR (300 MHz, solvent: CDCl ₃ , standard: TMS). The NMR spectrum of Compound F is as follows.
σ = 9.78 (1H, COOH), 7.54 (2H, Ar—H), 6.79 (2H, Ar—H), 6.65 (1H, CHCONH), 6.36 (1H, CHCOOH) _{, 4.02-3.53 (12H, OCH 2 CH} 2 O), 3.32 (3H, OCH 3).

[Synthesis Example 7]
The compound (1-2), which is a maleimide derivative having a polyoxyethylene group in the side chain, was synthesized according to the synthesis scheme shown below. Specifically, in a 300 mL flask, 8.84 g (25 mmol) of Compound F, 8.8 mg (0.04 mmol) of dibutylhydroxytoluene, 112 mg (1.1 mmol) of concentrated sulfuric acid, and 0.8 mg of dimethylformamide (DMF) were added. 4 mL and 180 mL of toluene were charged. The resulting mixture was stirred at reflux for 3 hours, and water azeotroped with toluene was withdrawn in a timely manner. The obtained reaction mixture was transferred to a 1 L separatory funnel, 300 mL of chloroform was added, and the organic phase was washed 3 times with saturated brine. The obtained organic phase was dried over sodium sulfate and concentrated, and then purified by silica gel column chromatography using a developing solvent of ethyl acetate: hexane (volume ratio) = 9: 1 to give compound (1-2) yellow A powder was obtained. The yield of compound (1-2) was 6.14 g, and the yield was 73.2%.

^The compound (1-2) was identified by ¹ H-NMR (300 MHz, solvent: CDCl ₃ , standard: TMS). The NMR spectrum of the compound (1-2) is as follows.
σ = 7.22 (2H, Ar—H), 6.99 (2H, Ar—H), 6.84 (2H, O = CCHCHC═O), 4.17-3.55 (12H, OCH ₂ CH _{2 O), 3.38 (3H,} OCH 3).

[Example 1]
In a 100 mL flask, 0.70 g (2.88 mmol) of compound (1-1) as a monomer, 7 mg (0.043 mmol) of azobisisobutyronitrile (AIBN) as a polymerization initiator, and dichloroethane as a polymerization solvent 2.8 g of was added. The monomer concentration in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The obtained mixture was stirred at 75 ° C. under a nitrogen atmosphere for 16 hours, and the reaction solution was ice-cooled and then dropped into hexane to precipitate a polymer. The obtained polymer was sufficiently washed with hexane and then dried under reduced pressure to obtain a white powdery polymer (A-1). The yield of the polymer (A-1) was 0.60 g, and the yield was 85.7%.
The obtained polymer (A-1) was dissolved in ethanol so that the concentration thereof was 0.05% by mass to prepare a coating solution. 2.2 mL of the coating solution was dispensed onto a polystyrene 24-well microplate and allowed to stand for 3 days to evaporate the solvent, thereby forming a coating layer on the well surface. In addition, 2.2 mL of the coating solution was poured into a glass petri dish and allowed to stand for 3 days to evaporate the solvent, thereby forming a coating layer on the petri dish surface.

[Example 2]
2.19 g (9.0 mmol) of the compound (1-1) as a monomer and 0.02 of the compound (2-1) (trimethoxysilylpropyl methacrylate, trade name “KBM-503”, manufactured by Shin-Etsu Silicone). 25 g (1.0 mmol) was weighed into a 300 mL three-necked flask, and 0.244 g of AIBN as a polymerization initiator and 13.4 g of toluene as a polymerization solvent were added. The charged molar ratio of the compound (1-1) and the compound (2-1) was compound (1-1) / compound (2-1) = 90/10. The total concentration of monomers in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The flask was sufficiently purged with argon and sealed, and the polymerization reaction was carried out by heating to 75 ° C. for 16 hours. The reaction solution was ice-cooled and then dropped into hexane to precipitate a polymer. The obtained polymer was sufficiently washed with hexane and then dried under reduced pressure to obtain a white powdery polymer (A-2). The yield of the polymer (A-2) was 2.05 g, and the yield was 84.2%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (A-2) was used instead of the polymer (A-1).

[Example 3]
A 100 mL two-necked flask was charged with 2.0 g (6.0 mmol) of compound (1-2) as a monomer, 20 mg (0.12 mmol) of AIBN as a polymerization initiator, and 8.0 g of dichloroethane as a polymerization solvent. The monomer concentration in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The obtained mixture was stirred at 75 ° C. under a nitrogen atmosphere for 16 hours, and the reaction solution was ice-cooled and then dropped into hexane to precipitate a polymer. The obtained polymer was sufficiently washed with hexane and then dried under reduced pressure to obtain a white powdery polymer (A-3). The yield of the polymer (A-3) was 1.64 g, and the yield was 82.0%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (A-3) was used instead of the polymer (A-1).

[Example 4]
1.59 g (4.75 mmol) of compound (1-2) as a monomer and 62 mg of compound (2-1) (trimethoxysilylpropyl methacrylate, trade name “KBM-503”, manufactured by Shin-Etsu Silicone) 0.25 mmol) was weighed into a 100 mL two-necked flask, and 16.5 mg (0.10 mmol) of AIBN as a polymerization initiator and 6.6 g of dichloroethane as a polymerization solvent were added. The charged molar ratio of the compound (1-2) and the compound (2-1) was set to compound (1-2) / compound (2-1) = 90/10. The monomer concentration in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The obtained mixture was stirred at 75 ° C. under a nitrogen atmosphere for 16 hours, and the reaction solution was ice-cooled and then dropped into hexane to precipitate a polymer. The obtained polymer was sufficiently washed with hexane and then dried under reduced pressure to obtain a white powdery polymer (A-4). The yield of the polymer (A-4) was 0.93 g, and the yield was 58.5%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (A-4) was used instead of the polymer (A-1).

[Comparative Example 1]
In a 100 mL flask, 0.70 g (2.88 mmol) of 2- (2- (2-ethoxyethoxy) ethoxy) ethyl acrylate (PEGA) as a monomer, 7 mg (0.043 mmol) of AIBN as a polymerization initiator, and As a polymerization solvent, 2.8 g of dichloroethane was added. The monomer concentration in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The resulting mixture was stirred at 75 ° C. under a nitrogen atmosphere for 16 hours and dried under reduced pressure to obtain a viscous liquid of polymer (G-1). The yield of the polymer (G-1) was 0.69 g, and the yield was 98.7%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (G-1) was used instead of the polymer (A-1).

[Comparative Example 2]
As a monomer, 2.09 g (9.0 mmol) of PEGA and 0.25 g (1.0 mmol) of compound (2-1) (trimethoxysilylpropyl methacrylate, trade name “KBM-503”, manufactured by Shin-Etsu Silicone Co., Ltd.) ) In a 300 mL three-necked flask, and 0.234 g of AIBN as a polymerization initiator and 12.9 g of toluene as a polymerization solvent were added. The charged molar ratio of PEGA to compound (2-1) was set to PEGA / compound (2-1) = 90/10. Further, the total concentration of the monomers in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The flask was sufficiently purged with argon and sealed, and the polymerization reaction was carried out by heating to 75 ° C. for 16 hours. The reaction solution was ice-cooled and then dried under reduced pressure to obtain a viscous liquid of polymer (G-2). The yield of the polymer (G-2) was 2.30 g, and the yield was 98.5%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (G-2) was used instead of the polymer (A-1).

[Comparative Example 3]
In a 100 mL flask, 0.70 g (2.88 mmol) of 2- (2- (2-ethoxyethoxy) ethoxy) ethyl methacrylate (PEGMA) as a monomer, 7 mg (0.043 mmol) of AIBN as a polymerization initiator, And 2.8 g of ethanol was added as a polymerization solvent. The monomer concentration in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The obtained mixture was stirred at 75 ° C. under a nitrogen atmosphere for 16 hours and dried under reduced pressure to obtain a viscous liquid of polymer (G-3). The yield of the polymer (G-3) was 0.69 g, and the yield was 99.1%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (G-3) was used instead of the polymer (A-1).

[Comparative Example 4]
2.19 g (9.0 mmol) of PEGMA as a monomer and 0.25 g (1.0 mmol) of compound (2-1) (trimethoxysilylpropyl methacrylate, trade name “KBM-503”, manufactured by Shin-Etsu Silicone) ) Was weighed into a 300 mL three-necked flask, and 0.244 g of AIBN as a polymerization initiator and 13.4 g of toluene as a polymerization solvent were added. The charged molar ratio of PEGMA to compound (2-1) was PEGMA / compound (2-1) = 90/10. Further, the total concentration of the monomers in the reaction solution was 20% by mass, and the initiator concentration was 1% by mass. The flask was sufficiently purged with argon and sealed, and the polymerization reaction was carried out by heating to 75 ° C. for 16 hours. The reaction solution was ice-cooled and then dried under reduced pressure to obtain a viscous liquid of polymer (G-4). The yield of the polymer (G-4) was 2.42 g, and the yield was 99.0%.
A coating layer was formed on each of the well surface and the petri dish surface in the same manner as in Example 1 except that the polymer (G-4) was used instead of the polymer (A-1).

  Table 1 shows the measurement results and evaluation results of Mn, Mw, Mw / Mn, and Tg of the polymers in Examples and Comparative Examples. “× ˜Δ” in water resistance means that the evaluation is between “×” and “Δ”, that is, a part of the polymer is dissolved and the remainder is dispersed.

  As shown in Table 1, the coating layers of Examples 1 to 4 formed using the polymer of the present invention were excellent in water resistance, hardly adhered to proteins, and excellent in durability. On the other hand, the coating layers of Comparative Examples 1 to 4 which are formed using a polymer having no unit (a1) and having a glass transition temperature of less than 20 ° C. are water-resistant and durable. It was inferior to.

  DESCRIPTION OF SYMBOLS 1 Medical device, 2 base material, 3 coating layer, 4 bottom part, 5 side part.

Claims (6)

  A polymer having a unit derived from a maleimide derivative having a polyoxyethylene group in the side chain and having a glass transition temperature of 20 ° C. or higher. The polymer according to claim 1, wherein the maleimide derivative is a compound represented by the following formula (1).

(However, in the formula (1), X represents an alkylene group having 1 to 10 carbon _{atoms, - (CH 2) d -COO-} (CH 2) e - ( however, d, e from independently 0 10 Or —C ₆ H ₄ — (CH ₂ ) _c — (where c is an integer of 0 to 10), a is an integer of 2 to 50, and R ¹ is hydrogen. It is an atom or a monovalent hydrocarbon group.) The polymer according to claim 1 or 2, further comprising a unit derived from a compound represented by the following formula (2).

(However, in the formula (2), ^{R 2} is a hydrogen atom, a chlorine atom or a methyl group, b is an integer from 1 to 10, ^{R 3} is an alkyl group having 1 to 5 carbon atoms .R ^{The three} alkyl groups in 3 may be the same as or different from each other.   The protein adhesion prevention agent which consists of a polymer as described in any one of Claims 1-3.   The medical device which has a coating layer containing the polymer as described in any one of Claims 1-3 in at least one part of the surface.   The medical device according to claim 5, which is a cell culture container.

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