JP2017082174A - Polymer, polymer solution and polymer coated substrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel biocompatible polymer.SOLUTION: There is provided a polymer having a structure represented by the following formula 1 in a side chain part: -L-(CH-O)-R(Formula 1), where L is a linker connecting a side chain to a polymer main chain, n is an integer of 3 to 6, m is an integer of 1 to 3, Ris a hydrogen atom, a methyl group or an ethyl group and each n, m and Rin the side chain part may be same or different when there are a plurality of side chain parts represented by the formula 1 to the main chain.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a polymer excellent in biocompatibility, a solution in which the polymer is dissolved, and a polymer-coated substrate.

  In general, when a biological component such as blood comes into contact with the surface of various artifacts, the surface of the material is recognized as a foreign substance, and nonspecific adsorption, denaturation, multilayer adsorption, etc. of proteins in biological tissue occur on the material surface. As a result, activation of the coagulation system, complement system, platelet system, etc. occurs. For this reason, on the surface of a medical device used in contact with a living body, in order to prevent the device from being recognized as a foreign object and causing a foreign body reaction with a biological component when the device is used, It is desired to impart biocompatibility to the surface of the material.

  As means for imparting biocompatibility to the surfaces of various medical devices, attempts have been made to artificially synthesize biocompatible materials and apply them to the surfaces of medical devices. Yes. As such biocompatible materials, 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, polyethylene glycol (PEG), poly (2-methoxyethyl acrylate) (PMEA), polyalkoxyalkyl (meth) acrylamide and the like are known. ing. By applying these biocompatible materials to a site such as the surface of a medical device that comes into contact with a biological component such as blood, the surface of the medical device is prevented from being recognized as a foreign substance. As a result, the coagulation system, complement system In addition, activation of the platelet system and the like can be suppressed.

  MPC polymer, also known as Lipidure (registered trademark), is a kind of betaine that maintains electrical neutrality in the living environment. The phospholipid polar group covering the cell membrane of the living body is polymerized by vinyl groups and the like. It is a polymer produced by bonding to a functional group via an ester bond and further polymerizing the polymerizable group, and has a structure in which a phospholipid polar group is bonded as a side chain to an alkyl chain (main chain). ing. In other words, the MPC polymer is a polymer that exhibits biocompatibility by having a structure simulating a substance constituting a living body, and by applying the MPC polymer to the surface of a medical device, a cell membrane structure is formed on the surface. As a result, the adhesion of platelets is suppressed and an excellent antithrombotic property is exhibited.

On the other hand, PEG is a polymer having a chain ether structure — (C ₂ H ₄ —O) — as a repeating unit, and has a structure similar to a substance constituting a living body. It is known to have a very good biocompatibility.

PMEA has a structure in which an alkyl chain (main chain) is bonded to a side chain having a main structure of — (C ₂ H ₄ —O) —, which is a structural unit of PEG, and is biocompatible. It is known to have sex.

  Polyalkoxyalkyl (meth) acrylamide has a structure with (meth) acrylamide having an ether structure at the end of the side chain as a repeating unit, and due to its moderate hydrophilicity, it has activities such as coagulation system, complement system, and platelet system It is known that it is possible to suppress oxidization and to express excellent blood affinity.

  In addition, for example, Patent Document 1 discloses a polymer in which a side chain having a chain ether structure or a cyclic ether structure is provided on a main chain composed of a vinyl ether skeleton, and Patent Document 2 discloses a main chain having a carbonate bond or the like. A biocompatible polymer provided with a side chain having a chain ether structure or a cyclic ether structure with respect to the chain, Patent Document 3 discloses that a main chain mainly composed of a polyethylene structure has an ether bond, an ester bond, etc. as a crosslinking group. A polymer in which a side chain including a chain ether structure is introduced, Patent Document 4 discloses biocompatibility in which a side chain including a chain ether structure is introduced into a main chain having a (meth) acrylate skeleton with an ester bond as a crosslinking group. It is described that the polymer exhibits biocompatibility.

As described above, structurally completely different from the main chain of the synthetic polymer in addition to the MPC polymer or the like in which a structure imitating a substance constituting a living body is provided as a side chain— (C ₂ H ₄ —O) It has been clarified that even a polymer in which an ether structure represented by − is introduced as a side chain in various forms exhibits biocompatibility similar to a substance derived from a living body. As described above, regarding a mechanism in which biocompatibility is exhibited even in a polymer having a completely different structure from a substance derived from a living body, these polymers are commonly used as “intermediate water” (freezing-bound water, intermediate water) and It has become clear that water molecules can be hydrated in a so-called form, and using this as a clue, a mechanism for biocompatibility is being explored.

  For example, Non-Patent Document 1 describes that there is intermediate water in the vicinity of the surface where the above-mentioned PMEA is impregnated, which causes the movement of latent heat accompanying the ordering / disordering of water molecules even in the temperature range below freezing point. Has been. Such intermediate water has been found to be observed in various biological substances in addition to the above polymer, and is considered to play an important role in the expression of biocompatibility.

JP 2014-47347 A JP 2014-161675 A JP 2014-105221 A International Publication No. 2004/087228

Tanaka, M.M. et al. , Journal of Biomaterials Science Polymer Edition, 2010, 21, p. 1849-1863

As described above, it is possible to contain intermediate water by introducing a predetermined side chain into the main chain of various polymers, even if it is not a substance constituting the living body, and biocompatibility can be achieved by the intermediate water. Although it has been clarified, the mechanism by which various polymers can contain intermediate water has not yet been clarified. For this reason, it is expected to obtain a new polymer having high biocompatibility and capable of expressing various functions by optimizing the side chain structure and the like of the polymer.
Then, this invention makes it a subject to provide a novel biocompatible polymer.

In order to solve the above problems, the present invention has a polymer having a structure represented by the following formula 1 in a side chain portion:
_{-L- (C n H 2n -O)} m -R 1 ( Formula 1)
[In the formula, L is a linker that connects the side chain to the polymer main chain, n is an integer of 3 to 6, m is an integer of 1 to 3, and R ¹ is a hydrogen atom, a methyl group, or When it is an ethyl group and has a plurality of side chain portions represented by Formula 1 with respect to the main chain, each n, m and R ¹ in the side chain portion may be the same or different. ]I will provide a.
In addition, the above polymer is characterized in that it can be hydrated and releases or absorbs latent heat due to the ordering / disordering of water molecules in a temperature range below the freezing point when hydrated.
Further, the present invention provides the above polymer, wherein the main chain is composed of a carbon chain mainly composed of carbon atoms.
The above-mentioned polymer is characterized in that the linker is any one of an alkylene group, an ether bond, a thioether bond, an ester bond, an amide bond, a urethane bond or a urea bond.
Further, the present invention provides a water-containing polymer characterized by containing water in the above polymer.
Further, the present invention provides a polymer solution, wherein the polymer is dissolved in a solvent substantially composed of ethanol and water, and the ethanol ratio is 80% by volume or more.
In addition, the polymer solution is characterized in that the solvent is substantially composed of ethanol.
Also provided is a polymer-coated substrate, wherein at least a part of the substrate surface is coated with the polymer.
In addition, the polymer-coated substrate is provided, wherein the substrate is made of an inorganic material.
The present invention also provides an antifouling material characterized in that it contains a polymer containing a side chain of n = 3 as an active ingredient.

  The polymer according to the present invention exhibits biocompatibility and various characteristic properties, hardly causes a foreign body reaction when used in contact with a biological substance or a living body, and is an antifouling material or a protein recovery material. Can be used as such.

FIG. 1 is a graph showing the amount of bovine serum albumin adsorbed when bovine serum albumin (BSA) aqueous solution is brought into contact with the surfaces of various polymers. FIG. 2 is a graph showing the amount of human fibrinogen adsorbed when a human fibrinogen (hFbn) aqueous solution is brought into contact with the surfaces of various polymers. FIG. 3 is a diagram showing the amount of exposed platelet adhesion sites in human fibrinogen adsorbed when platelet-poor plasma is brought into contact with the surfaces of various polymers. FIG. 4 is a view showing a scanning electron microscope image of the surface of a glass substrate coated with a polymer solution containing various polymers.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that many of the conventionally known biocompatible polymers have a PEG structural unit in the side chain moiety thereof as — (C ₂ H ₄ —O ) - whereas has an ether structure represented by, the ether structure _{- (C n H 2n -O)} - [ where, n is an integer of 3-6] upon the substituted structure In addition, the inventors have found that a predetermined biocompatibility is expressed and various characteristics corresponding to the carbon number are expressed, and the present invention has been achieved.
As described above, biocompatibility is maintained even when the number of carbon atoms in the ether structure portion is changed. On the other hand, although the mechanism for developing various characteristics is not clear, intermediate water related to the development of biocompatibility Since it is known that the content of water is caused by the molecular mobility of the polymer, the molecular mobility of the polymer gradually changes due to the change in the carbon number, and the content and state of the intermediate water change variously. The cause is assumed.

(Side chain)
That is, the polymer according to the present invention is characterized by having a side chain represented by Formula 1.
_{-L- (C n H 2n -O)} m -R 1 ( Formula 1)
[Wherein, n is 3 to 6, m is 1 to 3, and R ₁ is any one of a hydrogen atom, a methyl group, and an ethyl group. ]

  By having the side chain of the structure shown in Formula 1, the side chain of the side chain as shown by the decrease in Tg compared to the conventionally known polymer containing a side chain having a chain ether structure having 2 carbon atoms. It is considered that an effect specific to the present invention is produced by increasing the molecular mobility.

  The polymer according to the present invention only needs to have a side chain represented by Formula 1 at a density according to the purpose of use, and in particular, has a plurality of types of side chains having different structures within the range represented by Formula 1. Is possible. Moreover, as long as it does not deviate from the gist of the present invention, a part of the side chain other than the side chain structure that is preferable in the present invention, such as a conventionally known side chain structure in which n = 2 in Formula 1 is used. A chain structure is also possible.

  In the polymer according to the present invention, about 10 carbon atoms constituting the main chain are introduced at a ratio of about 1 side chain having the structure represented by Formula 1, and thus various types caused by the side chain. These characteristics can be expressed, and the characteristics are strongly expressed as the side chain density increases. In particular, when an acrylic skeleton or the like is used, a side chain is introduced at a ratio of one to two carbon atoms constituting the main chain, and the characteristics resulting from the side chain can be strongly expressed. Further, among the polymers according to the present invention, in particular, when utilizing the characteristic characteristic of a specific structure, one side chain of the specific structure per 10 carbon atoms constituting the main chain By introducing at a certain ratio, it is possible to express various characteristics resulting from the side chain.

  In general, when the n value is 3 to 4, the content of intermediate water is high, and a surface that hardly adsorbs protein or the like when water is contained can be formed. On the other hand, when the n value is 5 to 6, the biocompatibility is maintained, and specific properties such as adsorption without denaturing proteins in the aqueous solution can be expressed.

  In addition, when the m value is set to 1, predetermined characteristics are exhibited in a wide temperature range, while when the m value is set to 2 and 3, variations in molecular motion increase due to longer side chains. It is expected to have a lower critical solution temperature (LCST), an upper critical solution temperature (UCST), etc. at which the solubility in water changes abruptly at a specific temperature.

In addition, when hydrogen is selected as R ₁ , the polymer as a whole exhibits high hydrophilicity, while substitution with a methyl group or an ethyl group is expected to cause hydrophobicity. When used in contact with water, it is effective for imparting water resistance.

(Main chain)
The structure of the main chain of the polymer according to the present invention is mainly composed of bonds between carbon atoms, and can contain intermediate water without inhibiting the molecular mobility of the side chain portion. Although not particularly limited, an alkyl chain such as a (meth) acryl skeleton or a vinyl skeleton, which is typically a linear carbon chain, can be typically used. In this case, the biocompatible polymer according to the present invention can be obtained by polymerizing a monomer in which a predetermined side chain structure is introduced into (meth) acrylic acid or a vinyl monomer by a known method. In addition, for example, by performing ring-opening polymerization using a monomer obtained by introducing a predetermined side chain portion into a cyclic compound having a carbon-carbon unsaturated bond, a polymer having an appropriately adjusted side chain density can be obtained. . That is, when the number of carbon atoms of the repeating unit constituting the main chain of the polymer is 2, the main chain is polymerized by an appropriate method using (meth) acrylic acid or the like with a later-described side chain moiety introduced as a monomer. The polymer according to the invention can be obtained. Further, when the number of carbon atoms of the repeating unit is 3 or more, for example, the present invention is carried out by performing ring-opening polymerization using a monomer obtained by introducing a predetermined side chain portion into a cyclic compound having a carbon-carbon unsaturated bond. Can be obtained.

  In addition, it is conventionally known that an intermediate water-containing polymer can be constituted, for example, a polymer having a polycarbonate skeleton as a main chain, a skeleton containing a carbon-carbon unsaturated bond, an ester bond, a urethane bond, an amide. It is also possible to use a main chain structure containing a bond, a urea bond and the like.

(Linker part)
The polymer according to the present invention has a structure in which the chain ether structure is provided on the polymer main chain via an appropriate linker moiety. As the structure of the linker (L), a divalent functional group such as an ether group, an ester group, an amide group, an amino group, a urethane group, a urea group, or an alkylene group can be typically used. The biocompatible polymer according to the present invention is considered to exhibit various characteristics due to the molecular mobility of the alkoxyalkyl structure introduced into the side chain portion. For this reason, as the linker (L) for linking the main chain and the alkoxyalkyl structure portion, it is desirable to select and use various types of structures that do not inhibit molecular mobility according to the individual structures of the alkoxyalkyl structure. Further, in order to satisfactorily contain intermediate water as a polymer and exhibit biocompatibility, it is desirable that each part of the polymer does not become hydrophobic. For this reason, as a structure of a linker (L), it is desirable that a hydrophobic structure does not become too large, and a functional group with strong polarity is not included. Moreover, it is desirable to use a linker having a structure that can easily carry out a reaction for introducing an alkoxyalkyl structure when a monomer molecule is synthesized.

  Among the divalent functional groups used as the linker shown above, when a functional group containing an N—H bond such as an amide group, an amino group, a urethane group, or a urea group is used as the linker (L) The linker portion is preferable in that it exhibits hydrophilicity, but there is a tendency that unintentional adsorption of proteins present in vivo to the polymer occurs. In addition, when an alkylene group such as methylene or ethylene is used, hydrophobicity is exhibited, and the proportion of intermediate water that can be contained in the polymer tends to decrease. On the other hand, when an ether group is used as a linker, it is difficult to generate an ether bond only between the main chain and the side chain because the starting material in the synthesis generally has an alcohol on both the main chain side and the side chain side. And the yield is expected to decrease. For this reason, it is particularly preferable to use an ester group as the linker (L) from the viewpoint of ease of production and biocompatibility.

  In the polymer according to the present invention, the density at which the side chain is introduced, the arrangement, and the like can be appropriately set depending on the use of the polymer. That is, the side chain structure does not necessarily have to exist for all the repeating units of the main chain, and by adjusting the ratio of the monomer having the structure represented by Formula 1 in the monomer used for polymerizing the polymer, The density can be adjusted. In addition, side chains having different structures can be simultaneously included in the main chain. On the other hand, from the viewpoint of ease of synthesis and ease of predicting the degree of expression of various properties from the structure of the polymer, generally a compound having a chain ether structure introduced in advance is used as the monomer compound used in the polymerization. It is preferable that a side chain containing a chain ether exists for all the repeating units of the main chain polymer. It is also possible to introduce a side chain having two chain ether structures to one carbon atom constituting the main chain via a linker.

The “alkylene group” in the linker means a saturated hydrocarbon chain represented by the general formula C _n H _{2n + 2} , and examples thereof include an alkylene group having 1 to 8 carbon atoms.
The “ether bond” in the linker means a bond represented by —O—.
The “thioether bond” in the linker means a bond represented by —S—.
The “ester bond” in the linker means a bond represented by —C (═O) O— or —OC (═O) —.
The “amide bond” in the linker means a bond represented by —NHC (═O) — or —C (═O) NH—.
The “urethane bond” in the linker means a bond represented by —NHC (═O) O— or —OC (═O) NH—.
The “urea bond” in the linker means a bond represented by —NHC (═O) NH—.

  Among the polymers according to the present invention, for example, a polymer represented by the following formula 2:

[Wherein, n, m and R ¹ are as defined above, R ² is a hydrogen atom or a methyl group, and x is a symbol indicating a repeating unit of the main chain. ], It can be preferably used in that it can be easily synthesized using polymerization of (meth) acrylic acid, etc., similarly to PMEA and the like already used.

In this specification, the term “chain ether” refers to a structure in which one or more unit structures in which one end of an alkylene group is replaced with an ether bond (—O—) are connected, and in the above formula 2, (C _n H _2n —O) The structure of the portion represented by _m is meant.

  The term “monomer” or “monomer” refers to a low molecular weight molecule that can be used interchangeably and can be a component of the basic structure of a polymer. The monomer usually has a functional group that becomes a reaction point of the polymerization reaction, such as a carbon-carbon double bond or an ester bond. The term “polymer” or “polymer” refers to a molecule having a structure composed of repeating monomer units, which can be used interchangeably and can be obtained from a monomer having a low molecular weight. The term “polymer” refers to a macromolecule formed by covalently bonding a large number of atoms, such as a protein, a nucleic acid and the like, in addition to a polymer.

In this specification, the term “intermediate water” refers to free water that exhibits the original behavior of water molecules in water molecules contained in polymers and the like, and an independent molecule that is strongly bound by molecules such as polymers. It means water molecules (and their aggregates) that exhibit intermediate behavior of antifreeze water where no behavior is observed. In other words, the term “intermediate water” refers to water molecules and aggregates that cause the release and absorption of latent heat when the water-containing polymer is subjected to temperature changes in the temperature range below the freezing point where free water freezes. means. Typically, it can be characterized by the release and absorption of unique latent heat due to the order-disorder transformation of water molecules observed in the process of cooling and heating the water-containing polymer at a temperature below the freezing point. That is, in a polymer containing intermediate water, for example, in the process of gradually cooling to about room temperature after cooling to about −100 ° C., the release of latent heat is observed at about −40 ° C., or below the freezing point of −10 ° C. or higher. In particular, the release and absorption of specific latent heat is observed, such as the absorption of latent heat is observed. The fact that the release and absorption of latent heat below the freezing point of free water is due to the ordering / disordering of water molecules will be clarified by structural analysis using X-rays and the like during the movement of latent heat. be able to. Further, the content of intermediate water contained in the polymer can be determined from the amount of the latent heat.
Intermediate water is presumed to be weakly constrained by specific effects from the molecules that make up the substance, but is also present in biological tissues because it is also contained in biological substances such as proteins and phospholipids. It is considered to be related to the function of a living body as a mechanism for preventing non-specific adsorption between various substances. At present, the mechanism by which various substances contain intermediate water to prevent protein adsorption or the like is not necessarily clarified, but conceptually, various substances present in living tissue. It is surmised that the direct contact between the substances is prevented by covering the surface with intermediate water, and an undesirable interaction between the substances is prevented, and the soundness of the living tissue is maintained.

  The properties and the like exhibited by the various polymers according to the present invention will be described below using the polymer structure represented by the following formula 3 as an example. This structure is a structure in which a chain ether is provided as a side chain by an ester bond with respect to an alkyl chain, and when n = 2, this structure corresponds to a conventionally known PMEA. The polymer structure represented by Formula 3 is an example for explaining the characteristics of the present invention, and the present invention is not limited to this.

[Wherein, n is an integer of 1 to 6, and x represents a repeating unit of the main chain. ]

(1) Concerning the inclusion of intermediate water Among the polymers having the structure represented by formula 3, the polymer represented by n = 2 is PMEA known in the art, and the intermediate water when a sufficient amount of water is contained. It is known to contain. On the other hand, as will become apparent from the following examples, even in the polymers where n = 1, 3 to 6 in the formula 3, when each of the polymers contains a sufficient amount of water, the intermediate water In contrast, no intermediate water was observed in the polymethyl acrylate corresponding to n = 0.
On the other hand, when the temperature of each polymer was changed in the temperature range below the freezing point, it was observed that the behavior of the release and absorption of latent heat, which is thought to be due to the ordering / disordering of the intermediate water, changed. It was inferred that the state of the intermediate water contained was also changed by changing the number of carbons contained in the ether unit structure in the range of n = 1 to 6.
(2) Platelet adhesion to various polymer surfaces

The presence or absence of biocompatibility of a polymer or the like and the degree thereof can be evaluated based on the frequency of platelet adhesion to the surface of the polymer or the like in contact with blood. That is, it is known that a biocompatible polymer has a low platelet adhesion frequency and a low degree of activation of the adhered platelets.
As will be apparent from the following examples, in the polymer in which n = 3 to 6 in Formula 3, platelets when compared with the surface of a PET resin, which is a general-purpose resin, as in PMEA (n = 2) It became clear that the adhesiveness was about 1/100 and exhibited excellent biocompatibility. On the other hand, in the case of n = 1 or in polymethyl acrylate, platelet adhesion is sufficiently suppressed when compared with the surface of the PET resin, but when compared with the case of n = 2 to 6, the platelet adhesion frequency. Was observed to rise significantly.

(3) Frequency of protein adsorption in blood on various polymer surfaces When a body fluid such as blood or lymph comes into contact with a foreign substance, the protein dissolved in the body fluid first comes into contact with the foreign substance surface and is adsorbed. It is known that various cells and the like adhere to the surface adsorbed on the surface, and in particular, platelets adhere and aggregate to form a thrombus. For this reason, the frequency of adsorption of proteins dissolved in blood was examined for various polymers including the polymer according to the present invention. Especially on the surface of the polymer where n = 3 in Formula 3, the evaluated albumin and fibrinogen In both cases, the adsorption frequency was found to be extremely low. On the other hand, on the polymer surface where n = 4 to 6 in Formula 3, it became clear that the protein adsorbs at the same frequency as PMEA (n = 2) or at a higher frequency than PMEA.
On the other hand, when the degree of denaturation of the protein adsorbed by the ELISA method was evaluated on the polymer surface after the above evaluation, in any of the polymers in which n = 3 to 6 in Formula 3, the protein was compared with PMEA. It has been observed that the amount of denaturation is significantly lower.
If the platelet adhesion and the results of protein adsorption and denaturation in the blood are combined, in the polymer where n = 3 and 4 in Formula 3, especially, the degree of protein adsorption and denaturation in the blood is low. It was assumed that the platelet adhesion frequency was low. In other words, the polymer having 3 or 4 carbon atoms contained in the chain ether structure contained in the side chain has a very low degree of adsorption or denaturation of proteins dissolved in water, so that it does not contact biological materials or biological tissues. Therefore, it can be used as an excellent biocompatible material.
On the other hand, in the polymer in which n = 5, 6 in Formula 3, biocompatibility is expected by showing the same level of platelet adhesion as PMEA, but the adsorption frequency of protein is significantly higher than that of PMEA. It has been observed. Such a result is considered to be due to the fact that the adsorbed protein is difficult to denature on the polymer surface of n = 5,6. Taking advantage of such properties, the polymer having 5 or 6 carbon atoms contained in the chain ether structure contained in the side chain is used as a normal biocompatible polymer in contact with blood or living tissue, In particular, it can be used as a filter for contacting a blood or the like to adsorb a specific protein or the like in the blood and separating it without denaturation.
That is, as an embodiment of the present invention, there is provided an inflammation suppressing composition containing the polymer according to the present invention as an active ingredient and capable of suppressing inflammation caused by a foreign body reaction.

(4) About the frequency of adhesion of E. coli to various polymer surfaces When various polymers including the polymer according to the present invention were subjected to an initial adhesion test of E. coli, the surface of the polymer where n = 3 in formula 3 was conventionally used. It was revealed that the adhesion frequency of Escherichia coli was significantly lower than that of PMEA and the like used in the above. When E. coli adheres to a substance surface, it is known that the protein adsorbed on the substance surface is used as a scaffold. It was assumed that the adhesion of E. coli was low.
From the results, for example, sinks for cleaning various instruments and filth using water at the medical site, general sinks, baths, toilets, etc., on the surface that comes in contact with water containing various proteins and bacteria, By using a polymer having 3 carbon atoms contained in the chain ether structure contained in the side chain, it is expected that adsorption of proteins and bacteria contained in the water will be suppressed. That is, as an embodiment of the present invention, there is provided an antifouling material containing, as an active ingredient, a polymer having 3 carbon atoms contained in a chain ether structure contained in a side chain. The antifouling material is used as an infectious disease prevention material and bacteria adhesion prevention material, as well as a part that comes into contact with water inhabited by organisms such as ship bottoms and revetments, where attachment of various organisms is a problem. By using it, it can be used as a bio-protection material that prevents the attachment of organisms.

(5) Solubility of various polymers in a solvent When the polymer according to the present invention is used, the polymer is dissolved in a predetermined solvent and cast into a mold of a predetermined shape to be attached to the shape of the target article. It can be shaped or applied to the surface of an article to be coated with the polymer according to the present invention. The solvent used at that time can be used without particular limitation as long as it can dissolve the polymer according to the present invention at a predetermined concentration.
On the other hand, in particular, when the polymer according to the present invention is used in contact with blood or living tissue, it is preferable to use a pharmaceutically acceptable alcohol or a mixed solvent of the alcohol and water as a solvent.
Here, the “pharmaceutically acceptable alcohol” means an alcohol that is allowed when a preparation or a medical device is produced, and among them, an alcohol that is less toxic to a living body is preferable. For example, the pharmaceutically acceptable alcohol can be a primary alcohol, a secondary alcohol, or a tertiary alcohol. In another aspect, pharmaceutically acceptable alcohols include, for example, acyclic alcohols, monohydric alcohols, polyhydric alcohols (also known as polyols or sugar alcohols), unsaturated aliphatic alcohols, alicyclic alcohols, Or a combination thereof. Examples of monohydric alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol and 1-hexadecanol. Examples of polyhydric alcohols include, but are not limited to, glycol, glycerol, arabitol, erythritol, xylitol, maltitol, sorbitol, mannitol, inositol, lactitol, galactitol, and isomalt.
In particular, when the surface of a medical device is coated with a polymer, it is desired to use the polymer by dissolving it in a solvent containing ethanol from the viewpoint of low toxicity to a living body and bactericidal properties. In this regard, PMEA that has been used as a biocompatible material in the past has limited variations in the solvent that can be used. In particular, ethanol does not substantially exhibit solubility, and about 30% by volume of water or 60% by volume or more. It is necessary to use a mixture of methanol and the like, and there has been a problem that drying time becomes longer due to a drop in vapor pressure during drying after coating, and uniform drying is difficult. On the other hand, the polymer according to the present invention has been confirmed to exhibit a predetermined solubility in ethanol, and can be used to coat the surface of an article using an ethanol solution of a polymer, which has been difficult in the past. It becomes possible to perform uniform drying in a short time.

That is, as one embodiment of the present invention, a polymer solution containing the polymer according to the present invention, wherein the solvent of the solution is substantially ethanol or a mixture of ethanol and water having an ethanol concentration of 80% by volume or more. A polymer solution is provided.
From the viewpoint of increasing the evaporation rate of the solvent, the ethanol concentration in the mixed solvent of ethanol and water in the polymer solution of the present invention is 80% by volume or more, more preferably 90% by volume or more, and ethanol containing substantially no water. It may be. On the other hand, it is also possible to use a mixed solvent of ethanol and water having an ethanol concentration of 65 to 75% by volume from the viewpoint of the bactericidal power exhibited by the solvent.

  “Water” used for the polymer according to the present invention is not particularly limited, but when the polymer according to the present invention is used for use in contact with a living body such as an artificial organ or a medical device. Preferred examples include distilled water and sterilized water. Giving anti-bacterial and / or anti-inflammation properties to medical devices such as catheters and artificial blood vessels that are placed in the body, and medical devices that recirculate fluid that comes into contact with the body, such as dialysis machines. Therefore, when the polymer of the present invention or the water-containing polymer is used, sterilized water or pyrogen-free water is particularly preferable.

Those skilled in the art can appropriately synthesize and use the polymer according to the present invention by a conventionally known means using commercially available materials. That is, for example, when a side chain having the structure shown in Formula 1 is introduced with the main chain as the (meth) acryl skeleton and the ester bond as the linker (L), the side chain portion is introduced in advance (meth) The polymer according to the present invention can be synthesized by polymerizing acrylic acid by an appropriate means. Also, for example, when the main chain structure is a polycarbonate skeleton or the like, a portion that becomes a side chain is introduced in advance into a cyclic compound having an appropriate structure, and this is used as a monomer for ring-opening polymerization under appropriate conditions. For example, the polymer according to the present invention can be synthesized.
According to the purpose of use, the synthesized polymer is usually dissolved in an appropriate solvent and shaped into a desired form by casting or coating. In particular, as described above, ethanol or a mixed solvent of ethanol and water can be used for the polymer according to the present invention.
In addition, compared with conventionally used PMEA and the like, the polymer according to the present invention has a high affinity for substances other than organic resins such as glass and metal, so when dissolved in an appropriate solvent and applied to glass or the like A uniform coating film can be easily produced. As a result, among medical devices and the like, metal is a structural material particularly from the viewpoint of heat exchange capability, and it can be preferably used even for places where it has been difficult to coat with a biocompatible polymer or the like so far. it can.
While the polymer according to the present invention is water-insoluble, it contains a predetermined amount of water and a part thereof as intermediate water to express biocompatibility and the like. desirable. In particular, when it is used for applications that come into contact with biological materials or tissues such as artificial organs or medical devices, it is preferable to use it in a pre-hydrated environment such as physiological saline.

  The polymer according to the present invention can be used as a composition by mixing a polymer other than the polymer of the present invention, if necessary, depending on the intended use. Further, as necessary, for example, as a composition to which additives such as a radical scavenger, a peroxide decomposer, an antioxidant, an ultraviolet absorber, a heat stabilizer, a plasticizer, a flame retardant, and an antistatic agent are added. Also good.

The polymer of the present invention exhibits excellent biocompatibility by containing a predetermined amount of water, exhibits antifouling properties, antibacterial activity, and suppresses inflammation, and is required to have biocompatibility. When an artificial organ, a medical instrument, or the like is manufactured, it can be used as a raw material or a surface coating agent to provide an artificial organ or a medical instrument to which the above action is imparted.
Here, “biocompatibility” means a characteristic that is difficult to be recognized as a foreign substance when it comes into contact with a biological material or a biological material. Specifically, for example, it means that complement activation or platelet activation does not occur, and that the tissue is minimally invasive or noninvasive. Embodiments that are “biocompatible” also include embodiments that are “blood compatible”. “Blood compatibility” means not causing blood coagulation mainly due to platelet adhesion or activation.

Examples of “artificial organs” and “medical devices” include artificial organs and medical devices that have parts that come into contact with biological substances such as blood. Specifically, blood filters, artificial lung devices, dialysis devices, blood Examples include, but are not limited to, storage bags, platelet storage bags, blood circuits, artificial hearts, indwelling needles, catheters, guide wires, stents, artificial blood vessels, and endoscopes.
The material and shape of the base material constituting the “artificial organ” or “medical device” are not particularly limited.
For example, the materials include natural polymers such as Kinishiki and hemp, nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polycarbonate, polysulfone, polyethersulfone, poly (meth) acrylate, ethylene-vinyl alcohol Copolymers, synthetic polymers such as butadiene-acrylonitrile copolymers and mixtures thereof. Moreover, a metal, ceramics, those composite materials, etc. are illustrated. Artificial organs and medical devices may be composed of a plurality of types of base materials.
For example, the polymer or water-containing polymer of the present invention can be applied to the surface of a substrate having a shape such as a porous body, fiber, nonwoven fabric, particle, film, sheet, tube, hollow fiber or powder. .
When imparting anti-bacterial and / or anti-inflammatory properties to an artificial organ or medical device, at least a part of the surface in contact with the tissue or blood in the living body, preferably almost the surface in contact with the tissue or blood in the living body It is preferable to apply the polymer of the present invention to the whole.

  The polymer of the present invention can be used as a material constituting the whole of an artificial organ or medical device used in contact with tissue or blood in a living body, or a material forming a surface portion thereof. , Extracorporeal circulation type artificial organs, surgical sutures, catheters (angiographic catheters, guide wires, PTCA catheters and other cardiovascular catheters, gastrointestinal catheters, gastrointestinal catheters, esophageal tubes and other digestive organ catheters, tubes, At least a part of the surface of the medical device such as a urinary catheter or a urinary catheter such as a urinary catheter that comes into contact with blood, preferably almost the whole surface that comes into contact with blood, is composed of the polymer of the present invention or the water-containing polymer. Is desirable. The polymer or water-containing polymer of the present invention includes a hemostatic agent, a biological tissue adhesive, a tissue regeneration repair material, a drug sustained release carrier, a hybrid artificial organ such as an artificial pancreas and an artificial liver, an artificial blood vessel, and an embolization material. Further, it may be used as a matrix material for a scaffold for cell engineering.

  In these artificial organs and medical devices, surface lubricity may be further imparted in order to facilitate insertion into a blood vessel or tissue and not damage the tissue. As a method for imparting surface lubricity, a method in which a water-soluble polymer is insolubilized to form a water-absorbing gel layer on the material surface is excellent. According to this method, a material surface having both biocompatibility and surface lubricity can be provided.

  Specifically, the polymer of the present invention may be coated on at least a part of the substrate surface constituting the blood filter. Further, the polymer of the present invention or the water-containing polymer may be coated on at least a part of the blood bag and the surface of the tube communicating with the blood bag in contact with the blood. In addition, blood in an extracorporeal circulation blood circuit composed of an instrument side blood circuit unit composed of a tube, an arterial filter, a centrifugal pump, a hemoconcentrator, a cardio pregear, etc., and an operative field side blood circuit unit composed of a tube, catheter, soccer, etc. At least a part of the surface in contact with the substrate may be coated with the polymer of the invention.

  When the polymer of the present invention is used for an indwelling needle assembly, an inner needle having a sharp needle tip at a distal end, an inner needle hub installed on the proximal end side of the inner needle, and the inner needle can be inserted. A hollow outer needle, an outer needle hub installed on the proximal end side of the outer needle, a protector attached to the inner needle and movable in the axial direction of the inner needle, the outer needle hub and the At least a part of the surface in contact with blood of the indwelling needle assembly provided with the connecting means for connecting the protector may be coated with the polymer composition of the present invention. In addition, at least a part of the surface of the long tube that is in contact with the blood of the catheter constituted by the adapter connected to the proximal end (hand side) thereof may be coated with the polymer of the present invention or the water-containing polymer.

  At least a part of the surface of the guide wire that comes into contact with blood may be coated with the polymer of the present invention or the water-containing polymer. In addition, a hollow tubular body made of a metal material or a polymer material is provided with pores on the side surface, a metal material wire or a polymer material fiber is knitted into a cylindrical shape, and the stent blood of various shapes At least a portion of the contacting surface may be coated with the polymer of the present invention or a hydrous polymer.

  When the polymer of the present invention is used for cardiopulmonary bypass, a large number of gas exchange porous hollow fiber membranes are housed in a housing, blood flows on the outer surface side of the hollow fiber membranes, and oxygen-containing gas inside the hollow fiber membranes. A hollow fiber membrane external blood perfusion type artificial lung of the type in which the flow of the air flows may be an artificial lung in which the outer surface or the outer surface layer of the hollow fiber membrane is coated with the polymer of the present invention.

  A dialysate circuit including at least one dialysate container filled with dialysate and at least one drainage container for collecting dialysate, and starting from the dialysate container, or starting from the drainage container A dialysis apparatus having a liquid feeding means for feeding dialysate, and at least a part of the surface in contact with the blood may be coated with the polymer of the present invention.

  As a method for retaining the polymer of the present invention on the surface of "artificial organ" or "medical device", a coating method, graft polymerization by radiation, electron beam and ultraviolet ray, a chemical reaction with a functional group of a substrate is used. Well-known methods, such as a method to introduce | transduce, are mentioned. Among these, the coating method is particularly preferable in practical use because the manufacturing operation is easy. Further, there are coating methods, spraying methods, dipping methods and the like as coating methods, and any of them can be applied without any particular limitation. The film thickness is preferably 0.1 μm to 1 mm. For example, in the coating treatment by the application method of the polymer of the present invention or the water-containing polymer, the member to be coated is immersed in a coating solution in which the composition containing the biocompatible polymer composition of the present invention is dissolved in an appropriate solvent. It can be carried out by a simple operation such as removing excess solution and then air drying. In addition, in order to more firmly fix the polymer or water-containing polymer of the present invention to the member to be coated, heat can be applied after coating to further improve the adhesion with the polymer or water-containing polymer of the present invention. Moreover, you may fix | immobilize by bridge | crosslinking the surface. As a method for crosslinking, a crosslinkable monomer may be introduced as a comonomer component. Moreover, you may bridge | crosslink by an electron beam, a gamma ray, and light irradiation.

  In addition to compounds having a plurality of vinyl groups or allyl groups in one molecule such as methylene bisacrylamide, trimethylolpropane diacrylate, triallyl isocyanate, trimethylolpropane triacrylate, tetramethylolmethane tetraacrylate, etc. And polyethylene glycol diacrylate. Among these, when various functional groups are introduced using polyethylene glycol diacrylate, the introduction rate of the compound having a functional group is high, and further, by introducing a polyethylene glycol chain to make it hydrophilic, as described above This is preferable because nonspecific adsorption of cells and proteins other than the intended purpose is suppressed. In this case, the molecular weight of the polyethylene glycol chain is preferably 100 to 10,000, more preferably 500 to 6,000.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
The chemicals used in the following examples were used as they were unless otherwise noted.
About the structural analysis of the monomer and the polymer, ¹ H-NMR measurement and ¹³ C-NMR measurement were performed using an NMR measuring apparatus (JEOL 500 MHz JNM-ECX, manufactured by JEOL Ltd.). The chemical shift was based on CDCl ₃ ( ¹ H: 7.26 ppm, ¹³ C: 77.1 ppm).

[Example 1]
Synthesis of 3-methoxypropyl acrylate

Under a nitrogen stream, 15.5 g (153 mmol) of triethylamine, 13.5 g (150 mmol) of 3-methoxy-1-propanol, and 200 mL of diethyl ether were added to a three-neck eggplant flask (capacity 500 mL), and the reaction system was adjusted to 0 with an ice-water bath. Cooled to ° C. While stirring, 14.0 g (155 mmol) of acrylic acid chloride was added dropwise to the reaction system over 30 minutes, followed by stirring at room temperature for 12 hours. After the completion of the reaction was confirmed by ¹ H NMR, the reaction was stopped. A white precipitate generated as the reaction progressed was removed by suction filtration, and the reaction solvent was distilled off from the obtained filtrate by a rotary evaporator to obtain a reaction product as a liquid. The obtained reaction product was separated and purified by silica gel column chromatography (developing solvent hexane: diethyl ether = 100: 0 to 90:10), and further purified by distillation under reduced pressure in the presence of calcium hydride, 9.95 g (69.1 mmol, yield 46%) of 3-methoxypropyl acrylate (transparent liquid) was obtained. Its boiling point was 24.5 ° C. to 25.5 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 6.39 (d, J = 17.3 Hz, 1H), 6.11 (dd, J = 17.3 Hz, 10.4 Hz, 1H), 5.81 (D, J = 10.4 Hz, 1H), 4.24 (t, J = 6.4 Hz, 2H), 3.45 (t, J = 6.3 Hz, 2H), 3.33 (s, 3H) 1.93 (p, J = 6.4 Hz, 2H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 166.2, 130.6, 128.5, 69.1, 61.7, 58.7, 29.0.

[Example 2]
Synthesis of 4-methoxybutyl acrylate

(1) Synthesis of 4-methoxy-1-butanol In a nitrogen stream, 53.6 g (600 mmol) of 1,4-butanediol and 300 mL of tetrahydrofuran were added to a three-necked eggplant flask (capacity 500 mL), and cooled appropriately while stirring. While this was done, 18.1 g (450 mmol) of sodium hydride was added in small portions. After the addition of the entire amount of sodium hydride was completed, the mixture was stirred at room temperature for 1 hour, 63.4 g (450 mmol) of iodomethane was added dropwise, and the mixture was further stirred for 14 hours. After confirming the progress of the reaction by ¹ H NMR, a small amount of water was added to stop the reaction. After acidifying the solution with 2N hydrochloric acid, tetrahydrofuran was distilled off by a rotary evaporator. Diethyl ether was added to the resulting reaction mixture for dilution, and then anhydrous magnesium sulfate was added for drying. Magnesium sulfate and precipitates were removed from the dried diethyl ether solution by suction filtration, and the obtained filtrate was concentrated by a rotary evaporator. The obtained concentrated liquid was separated and purified by silica gel column chromatography (hexane, dichloromethane, and methanol were used in this order as developing solvents), and then concentrated to 18.5 g (178 mmol, yield 29. 4-methoxy-1-butanol). 6%) (transparent liquid). Its boiling point was 50.0 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 3.58 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 6.0 Hz, 2H), 3.31 (s, 3H) ), 2.20 (s, 1H), 1.61 (m, 4H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 72.8, 62.6, 58.6, 30.1, 26.7.

(2) Synthesis of 4-methoxybutyl acrylate Using 15.8 g (150 mmol) of 4-methoxy-1-butanol synthesized in (1), 17.5 g (165 mol) of triethylamine, 250 mL of diethyl ether, and acrylic acid chloride 4-Methoxybutyl acrylate was synthesized in the same manner as in Example 1 except that 14.5 g (158 mmol) was used. 11.4 g (72.2 mmol, yield 48%) of 4-methoxybutyl acrylate (transparent liquid) was obtained. Its boiling point was 50 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 6.47 (d, J = 15 Hz, 1H), 6.20 (dd, J = 8.75 Hz, 5.0 Hz, 1H), 5.89 (d , J = 10.5 Hz, 1H), 4.26 (t, J = 6.5 Hz, 2H), 3.49 (t, J = 6.5 Hz, 2H), 3.42 (s, 3H), 1 .84 to 1.75 (m, 4H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 166.3, 130.5, 128.6, 72.2, 64.6, 58.6, 26.2, 25.5.

[Example 3]
Synthesis of 5-methoxypentyl acrylate

(1) Synthesis of 5-methoxy-1-pentanol Using 31.4 g (300 mmol) of 1,5-pentanediol, 200 mL of tetrahydrofuran, 12.3 g (300 mmol) of sodium hydride, and 43.8 g (300 mmol) of iodomethane Except for the above, 5-methoxy-1-pentanol was synthesized in the same manner as in Example 2 (1). 14.4 g (122 mmol, yield 41%) of 5-methoxy-1-pentanol (transparent liquid) was obtained. Its boiling point was 60 ° C. to 64 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 3.61 (m, 2H), 3.36 (t, J = 7.5 Hz, 2H), 3.31 (s, 3H), 1.85 1.35 (m, 7H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 72.8, 62.6, 58.6, 32.5, 29.3, 22.4.

(2) Synthesis of 5-methoxypentyl acrylate Using 15.4 g (130 mmol) of 5-methoxy-1-pentanol synthesized in (1), 14.5 g (143 mol) of triethylamine, 200 mL of diethyl ether, acrylic acid chloride 5-methoxypentyl acrylate was synthesized in the same manner as in Example 1 except that 12.4 g (136.5 mmol) was used. 5.95 g (34.6 mmol, yield 27%) of 5-methoxypentyl acrylate (transparent liquid) was obtained. Its boiling point was 58 ° C. to 71 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 6.36 (d, J = 18.0 Hz, 1H), 6.11 (dd, J = 5.0 Hz, 8.8 Hz, 1H), 5.79 (D, J = 9.5 Hz, 1H), 4.17 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 3.31 (s, 3H) 1.67-1.58 (m, 4H), 1.43 (m, 2H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 166.4, 130.6, 128.6, 72.6, 64.6, 58.6, 29.3, 28.5, 22.7.

[Example 4]
Synthesis of 6-methoxyhexyl acrylate

(1) Synthesis of 6-methoxy-1-hexanol Using 35.6 g (300 mmol) of 1,6-hexanediol, 230 mL of tetrahydrofuran, 12.4 g (300 mmol) of sodium hydride, and 42.6 g (300 mmol) of iodomethane Except that, 6-methoxy-1-hexanol was synthesized in the same manner as in Example 2 (1). 10.2 g (77.2 mmol, yield 26%) of 6-methoxy-1-hexanol (transparent liquid) was obtained. Its boiling point was 94.0 ° C. to 100 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 3.62 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H) ), 1.65 to 1.36 (m, 9H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 72.8, 62.8, 58.5, 32.7, 29.6, 25.9, 25.6.

(2) Synthesis of 6-methoxyhexyl acrylate Using 6.25 g (70.0 mmol) of 6-methoxy-1-hexanol synthesized in (1), 6.65 g (73.5 mol) of triethylamine, 200 mL of diethyl ether, 6-methoxyhexyl acrylate was synthesized in the same manner as in Example 1 except that 6.65 g (73.5 mmol) of acrylic acid chloride was used. 6.77 g (31.0 mmol, yield 44%) of 6-methoxyhexyl acrylate (transparent liquid) was obtained. Its boiling point was 99 ° C. to 103 ° C./0.08 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 6.36 (d, J = 18.0 Hz, 1H), 6.09 (dd, J = 5.3 Hz, 8.8 Hz, 1H), 5.79 (D, J = 12.0 Hz, 1H), 4.13 (t, J = 7.0 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H) 1.66 to 1.56 (m, 4H), 1.37 (m, 4H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 166.4, 130.5, 128.6, 72.7, 64.6, 58.6, 29.6, 26.8, 25.8.

[Example 5]
Production of 3-methoxypropyl acrylate polymer

In a three-necked eggplant flask (capacity 100 mL), 7.50 g (52.0 mmol) of 3-methoxypropyl acrylate obtained in Example 1, 30.2 g of 1,4-dioxane, and 7.5 mg of azobisisobutyronitrile were obtained. (0.047 mmol) was added. The mixture was stirred for 30 minutes while passing dry nitrogen gas through the reaction solution, and the reaction system was purged with nitrogen. Polymerization was carried out by setting the temperature of the oil bath to 75 ° C. and stirring for 6 hours under a nitrogen stream. The progress of the polymerization reaction was confirmed by ¹ H NMR, and after confirming that the reaction conversion rate was sufficiently high (around 90%), the reaction was stopped by allowing the polymerization system to cool to room temperature. The polymer was precipitated by dropping the polymerization solution into hexane, the supernatant was removed by decanting, and the precipitate was dissolved in tetrahydrofuran and collected. The obtained 3-methoxypropyl acrylate polymer was dissolved in tetrahydrofuran and purified by repeating the operation of reprecipitation with hexane twice. The resulting precipitate was further stirred in water for 24 hours. Water was removed by decanting, and the precipitate was dissolved in tetrahydrofuran and collected. After the solvent was distilled off under reduced pressure, the residue was dried with a vacuum dryer to obtain 6.47 g (yield 86%) of 3-methoxypropyl acrylate polymer.
When a molecular weight was measured by the following method using a part of the obtained polymer, the number average molecular weight (Mn) was 31000 g / mol and the molecular weight distribution (Mw / Mn) was 2.5. These results are shown in Table 1. Moreover, when the glass transition temperature of this polymer was measured by the following method, it was -48.0 degreeC as shown in Table 1.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 4.10 (br, 2H), 3.41 (brt, 2H), 3.31 (s, 3H), 2.26 (s, 1H), 1 .86-1.62 (m, 4H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 174.3, 69.1, 62.0, 58.6, 41.5, 29.0, 0.07.

[Example 6]
Production of 4-methoxybutyl acrylate polymer

Using 9.41 g (59.5 mmol) of 4-methoxybutyl acrylate obtained in Example 2, 41.2 g of 1,4-dioxane, and 10 mg (0.061 mmol) of azobisisobutyronitrile, the polymerization time was 8 hours. A 4-methoxybutyl acrylate polymer was synthesized in the same manner as in Example 5 except that. Thus, 7.21 g (yield 77%) of 4-methoxybutyl acrylate polymer was obtained.
When molecular weight was measured by the following method using a part of the obtained polymer, it was number average molecular weight (Mn) 29000 g / mol and molecular weight distribution (Mw / Mn) 2.2. These results are shown in Table 1. When the glass transition temperature of this polymer was measured by the following method, it was −64.6 ° C. as shown in Table 1.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 4.03 (br, 2H), 3.37 (t, J = 6.0 Hz, 2H), 3.30 (s, 3H), 2.24 ( s, 1H), 1.87-1.59 (m, 6H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 174.3, 72.1, 64.4, 58.5, 41.4, 35.0, 26.1, 25.4.

[Example 7]
Production of 5-methoxypentyl acrylate polymer

Using 5.01 g (32.1 mmol) of 5-methoxypentyl acrylate obtained in Example 3, 20 g of 1,4-dioxane, and 5 mg (0.030 mmol) of azobisisobutyronitrile, the polymerization time was 8 hours. Except for the above, 5-methoxypentyl acrylate was synthesized in the same manner as in Example 5. 3.64 g (yield 73%) of 5-methoxypentyl acrylate polymer was obtained.
When a molecular weight was measured by the following method using a part of the obtained polymer, the number average molecular weight (Mn) was 50000 g / mol and the molecular weight distribution (Mw / Mn) was 2.3. These results are shown in Table 1. When the glass transition temperature of this polymer was measured by the following method, it was −77.6 ° C. as shown in Table 1.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 4.00 (br, 2H), 3.36 (t, J = 6.5 Hz, 2H), 3.31 (s, 3H), 2.24 ( m, 1H), 1.87-1.38 (m, 8H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 174.3, 72.5, 64.6, 58.6, 41.5, 29.3, 28.5, 23.5.

[Example 8]
Production of 6-methoxyhexyl acrylate polymer

The polymerization time was determined using 5.05 g (28.0 mmol) of 6-methoxyhexyl acrylate obtained in Example 4, 25.1 g of 1,4-dioxane, and 5.03 mg (0.030 mmol) of azobisisobutyronitrile. A 6-methoxyhexyl acrylate polymer was synthesized in the same manner as in Example 5 except that the time was 8 hours. 3.75 g (yield 74%) of 6-methoxyhexyl acrylate polymer was obtained.
When molecular weight was measured by the following method using a part of the obtained polymer, it was number average molecular weight (Mn) 29000 g / mol and molecular weight distribution (Mw / Mn) 2.5. These results are shown in Table 1. Moreover, when the glass transition temperature of this polymer was measured by the following method, it was -77.4 degreeC as shown in Table 1.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 3.99 (br, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.31 (s, 3H), 2.24 ( m, 1H), 1.58-1.35 (m, 10H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 174.7, 72.7, 64.6, 58.6, 41.5, 35.4, 29.6, 28.6, 25.9, 25 .8.

[Comparative Example 1]
Synthesis of methoxymethyl acrylate

To a three-necked eggplant flask (capacity 500 mL), 10.8 g (150 mmol) of acrylic acid, 18.2 g (180 mmol) of triethylamine and 150 mL of dichloromethane were added and stirred. To the reaction system, 12.9 g (160 mmol) of chloromethyl methyl ether was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was confirmed by ¹ H NMR, and the reaction was stopped. The deposited precipitate was removed by suction filtration, and the filtrate was concentrated to obtain a crude product. The obtained crude product was purified by distillation under reduced pressure in the presence of calcium hydride to obtain 7.37 g (70.8 mmol, yield 44%) (transparent liquid) of methoxymethyl acrylate. Its boiling point was 50.0 ° C. to 68 ° C./35 mmHg.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 6.49 (d, J = 17.5 Hz, 1H), 6.15 (dd, J = 5.5 Hz, 8.8 Hz, 1H), 5.88 (D, J = 12 Hz, 1H), 5.33 (s, 2H), 3.49 (s, 3H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 165.6, 131.7, 128.2, 90.6, 57.7.

[Comparative Example 2]
Production of methoxymethyl acrylate polymer

Using 7.01 g (116 mmol) of methoxymethyl acrylate obtained in Comparative Example 1, 28.1 g of 1,4-dioxane, and 7.3 mg (0.043 mmol) of azobisisobutyronitrile, the polymerization time was 7.5. A methoxymethyl acrylate polymer was synthesized in the same manner as in Example 5 except that the time was used. 5.78 g (yield 83%) of methoxymethyl acrylate polymer was obtained.
When molecular weight was measured by the following method using a part of the obtained polymer, it was number average molecular weight (Mn) 20000 g / mol and molecular weight distribution (Mw / Mn) 2.6. These results are shown in Table 1. Moreover, when the glass transition temperature of this polymer was measured by the following method, as shown in Table 1, it was -27.3 degreeC.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 5.20 (s, 2H), 3.45 (s, 3H), 2.39-1.73 (m, 3H).
¹³ C-NMR (125 MHz, CDCl ₃ ): δ = 173.9, 90.8, 57.8, 41.6, 30.2.

[Comparative Example 3]
Production of 2-methoxyethyl acrylate polymer

Example 1 except that 15.2 g (117 mmol) of 2-methoxyethyl acrylate, 60.5 g of 1,4-dioxane, 15.4 mg (0.094 mmol) of azobisisobutyronitrile were used, and the polymerization time was 6 hours. In the same manner as in No. 5, a methoxymethyl acrylate polymer was synthesized. 13.8 g (yield 92%) of a methoxymethyl acrylate polymer was obtained.
When a molecular weight was measured by the following method using a part of the obtained polymer, the number average molecular weight (Mn) was 33000 g / mol and the molecular weight distribution (Mw / Mn) was 3.2. These results are shown in Table 1. Moreover, when the glass transition temperature of this polymer was measured by the following method, it was -35 degreeC as shown in Table 1.

[Comparative Example 4]
Production of methyl acrylate polymer

Example 5 was used except that 15.0 g (175 mmol) of methyl acrylate, 60 g of 1,4-dioxane, 15 mg (0.091 mmol) of azobisisobutyronitrile were used, and the polymerization time was 7.5 hours. A methyl acrylate polymer was synthesized. 12.2 g of methyl acrylate polymer (yield 83%) was obtained.
When molecular weight was measured by the following method using a part of the obtained polymer, it was number average molecular weight (Mn) 29000 g / mol and molecular weight distribution (Mw / Mn) 2.5. These results are shown in Table 1. Moreover, when the glass transition temperature of this polymer was measured by the following method, as shown in Table 1, it was -10.5 degreeC.

The following evaluation was performed about each polymer synthesize | combined by the said Example and comparative example.
(1) Number average molecular weight ([Mn], unit: g / mol)
Gel permeation chromatography (GPC) calibrated with the standard polystyrene having a known peak molecular weight (“HLC-8220” manufactured by Tosoh Corporation, column configuration: Tosoh TSK-gels super AW5000, super AW4000, super AW3000) Used to measure the number average molecular weight (Mn) and weight average molecular weight (Mw) of the polymer. (Solvent: tetrahydrofuran, temperature: 40 ° C., flow rate: 1.0 mL / min).

(2) Molecular weight distribution ([Mw / Mn])
It calculated | required as the ratio (Mw / Mn) using the value of the weight average molecular weight (Mw) and the number average molecular weight (Mn) calculated | required by the method of said (1).

(3) Glass transition temperature ([Tg], unit: ° C)
Using a DSC apparatus (SII Nano Technologies, Inc., “EXSTAR X-DSC7000”), the measurement was performed under conditions of a nitrogen flow rate of 50 mL / min and 5.0 ° C./min. The temperature program was (i) cooling from 30 ° C. to −100 ° C., (ii) holding at −100 ° C. for 5 minutes, and (iii) heating from −100 ° C. to 30 ° C. The glass transition temperature observed in (iii) above is shown.

(4) Contact angle A polymer solution in which various polymers were dissolved at a concentration of 0.2 g / mL was prepared, and the sample was coated on the PET substrate by spin coating to prepare a sample. After coating and air-drying for 24 hours, 2 μL of ultrapure water was dropped at 3 locations on each substrate, the contact angle θ / 2 after 30 seconds was measured, and the average value of θ was calculated.

(5) Confirmation of the presence or absence of intermediate water Using a DSC apparatus (SII NanoTechnologies Corporation, “EXSTAR X-DSC7000”), measurement was performed under conditions of a nitrogen flow rate of 50 mL / min and 5.0 ° C./min. The temperature program is as follows: (i) cooling from 30 ° C. to −100 ° C., (ii) holding at −100 ° C. for 5 minutes, and (iii) heating from −100 ° C. to 30 ° C. It was. In the process of (i) or (iii) above, the presence or absence of intermediate water was confirmed assuming that the polymer in which an exothermic peak or endothermic peak was confirmed in a temperature range of 0 ° C. or lower was intermediate water.

  In Table 1, each measured value etc. which were calculated | required above are described collectively.

  As shown in Table 1, in the various polymers synthesized above, in the range of n = 0 to 6, a tendency that the glass transition temperature decreases as the carbon number (n) increases is observed, and the molecular mobility of the polymer is observed. It was guessed that In order for the water molecules contained in the polymer or the like to behave as intermediate water, it is necessary that the molecular mobility of the polymer or the like is high. Therefore, the polymer in the range of n = 3 to 6 according to the present invention is intermediate. This was thought to be one of the reasons that water can be contained and shows good biocompatibility. On the other hand, as compared with PMEA (n = 2) shown in Comparative Example 3, the contact angle of water increases as the carbon number (n) increases, and the polymer becomes hydrophobic (lipophilic) by increasing the carbon number. A tendency to be observed was observed. From these results, it is inferred that both the amount and quality of intermediate water change as the number of carbons increases, and in comparison with PMEA (Comparative Example 3), the polymer in the range of n = 3 to 6 according to the present invention. Is hydrophobized while maintaining biocompatibility, and it is presumed that water resistance in a living environment used in contact with water is improved.

(6) Solubility test Water, ethanol, a water-ethanol mixed solvent (50:50 by volume), and methanol are prepared in a glass vial as a solvent, and synthesized in the above examples and comparative examples in each solvent. Each polymer was charged to 0.2 g per 1 mL of each solvent, sealed, and then kept at 37 ° C. for 10 minutes. The solubility of the polymer was visually confirmed, and the results are shown in Table 2. Indicated. In Table 2, those that produced precipitation or cloudiness were rated as x (insoluble), and those that became a completely transparent solution were marked as ○ (dissolved).

  As shown in Table 2, PMEA (Comparative Example 3) does not substantially dissolve in ethanol or the like, whereas any polymer in the range of n = 3 to 6 according to the present invention is ethanol or ethanol and water. It was confirmed that it was dissolved in the mixed solvent at a concentration required for coating. This is presumed to be due to the occurrence of hydrophobicity (lipophilicization) due to the increase in the number of carbon atoms, and the polymer according to the present invention can be coated using a solvent mainly containing ethanol as an organic solvent.

(7) Platelet adhesion test About each polymer synthesize | combined by said each Example and comparative example, the platelet adhesion test was done with the following method and platelet adhesion frequency was compared. In the test, each polymer was added to 0.2 g per 1 mL of methanol (THF in Example 8 and Comparative Examples 2 and 4) and spin-coated on a PET substrate using a polymer solution in which the entire amount was dissolved. The sample was cut into an 8 mm square and fixed to a sample table for a scanning electron microscope (SEM). Human blood was centrifuged at 1500 rpm for 5 minutes, and the supernatant was collected as platelet rich plasma (PRP). The remaining blood was further centrifuged at 4000 rpm for 10 minutes, and the supernatant was recovered as platelet low plasma (PPP). Platelet solution with a platelet concentration of 4 × 10 ⁷ cells / mL while diluting PPP 800-fold with a phosphate buffered saline (PBS) solution, further diluting PRP, and confirming the platelet count with a microscope Was prepared. 200 μL of this platelet solution was dropped on each sample and allowed to stand at 37 ° C. for 1 hour. Thereafter, each substrate was washed twice with a PBS solution, immersed in a 1% glutaraldehyde solution, and fixed at 37 ° C. for 2 hours. The immobilized sample was washed by dipping for 10 minutes in PBS solution, 8 minutes in PBS: water = 1: 1, 8 minutes in water, and 8 minutes in water, and then air-dried at room temperature. Platelets were adhered to the uncoated PET substrate by the same treatment. The number of platelet adhesion within 3 fields of view is measured for each sample by SEM, and the average value is shown in Table 3.

  As shown in Table 3, in the substrate coated with n = 3-6 polymer (Examples 5-8) according to the present invention, compared to the PET substrate surface not coated with the polymer, The number was about 1/100, and the platelet adhesion number was as low as PMEA (n = 2). On the other hand, in the case of n = 1 or in polymethyl acrylate corresponding to n = 0, it was observed that platelets adhere more frequently than in the case of n = 2-6.

(8) Protein adsorption test About each polymer synthesize | combined by said each Example and comparative example, the adsorption amount of the protein to a polymer surface was measured and compared with the following method.
As a sample used for the test, a polymer solution in which each polymer was added and dissolved at a rate of 0.2 g per 1 mL of the solvent in the same manner as above was used in a well of a polypropylene (PP) 96 well plate. Dropped to 2 μL / cm ² , covered and suppressed by evaporating the solvent, left to stand in a 37 ° C. constant temperature bath for 3 days to dry, and the bottom of the well was cast coated with each polymer It was used. For comparison, a well-cast poly (2-phosphorylcholine ethyl methacrylate) (PMPC) cast on the bottom surface of the well was also used.
50 μL of bovine serum albumin solution (BSA) or human fibrinogen solution (hFbn) adjusted to 1 mg / mL was added to each well cast-coated with each polymer, and incubated at 37 ° C. for 10 minutes. Washed. Next, 30 μL of 0.5% SDS + 1N NaOH aqueous solution was added and incubated at 37 ° C. for 2 hours in order to recover the protein adhered to each polymer in the well in the aqueous phase. Then, after adding 150 μL of micro BCA reagent and incubating at 37 ° C. for 2 hours to confirm that color development was sufficiently performed, the solution in the well was transferred to a 96-well TCPS plate, and the absorbance was measured with a microplate reader. Absorbance was measured by performing (540 nm), and converted to the amount of protein adsorbed on the polymer surface of a unit area using a calibration curve.
FIG. 1 shows the amount of bovine serum albumin (BSA) adsorbed, and FIG. 2 shows the amount of human fibrinogen (hFbn) adsorbed. When an aqueous solution in which each protein is dissolved is dropped onto each polymer in the well, a dry polymer (Dry) and a polymer pretreated with physiological saline (Wet) for 1 hour are used. The results are also shown in FIGS.
As shown in FIGS. 1 and 2, when either bovine serum albumin or human fibrinogen is added dropwise, in the polymers of n = 3,4 according to the present invention (Examples 5 and 6), PMEA (n = 2) On the other hand, in the polymers with n = 5 and 6 (Examples 7 and 8), an adsorption amount larger than that of PMEA was observed. In particular, for n = 3 polymers, it is clear that the amount of protein adsorbed is small even when compared with PMEA and PMPC, which is known to have less protein adsorption than before, and forms a surface that is extremely difficult to adsorb proteins. became.

(9) Evaluation of adsorbed protein As described above, in order to evaluate the degree of denaturation of protein adsorbed on each polymer surface, when contacting platelet-poor plasma (PPP), human fibrinogen adsorbed on each polymer surface The amount of exposure of the platelet adhesion site was measured by ELISA measurement.
In the same manner as described above, using each polymer cast-coated on the bottom of the well, 50 μL of platelet-poor plasma (PPP) was dropped at a time and incubated at 37 ° C. for 10 minutes to adsorb plasma proteins to the substrate. The wells were washed 7 times with PBS to completely remove the PBS water droplets. Next, in order to prevent nonspecific adsorption of FNG such as antibody added later to other than the adsorption site, Blocking One (Nacalai Tex) is dropped into each well by 100 μL and left in an incubator for 30 minutes. After the blocking operation, the plate was washed 7 times with PBS. Anti-Fibrinogen γ ′, CT, clone, which is an antibody that specifically recognizes and binds to a cell adhesion site in FNG after washing. G2. 50 μL of H9 (Merck Millipore) diluted 200-fold with Blocking One was added dropwise to each well, reacted at room temperature for 2 hours, and washed 7 times with PBS. Furthermore, a peroxidase-labeled secondary antibody Goat anti mouse IgG1 (Abcam) diluted 1000-fold with Blocking One was added dropwise to each well in an amount of 50 μL, adsorbed at room temperature for 1 hour, and reacted with PBS 7 times. Washed. After washing, 100 μL of 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) ammonium salt (ABTS) solution, which is a substrate that reacts with the enzyme and develops color, is dropped into each well. Then, the solution in each well was transferred to a 96-well TCPS plate, and absorbance was measured at a wavelength of 405 nm with a microplate reader to obtain a denatured amount of human fibrinogen.
FIG. 3 shows the exposure amount of the platelet adhesion site in human fibrinogen measured by ELISA. The vertical axis is the relative ratio. As shown in FIG. 3, in the polymers of n = 3 to 6 (Examples 5 to 8) according to the present invention, the exposed amount of the platelet adhesion site is smaller than that of PMEA (n = 2) or PMPC. It can be seen that human fibrinogen is hardly denatured by adsorption to these polymers. In particular, for the polymers of n = 3 and 4, the exposure amount of the platelet adhesion site was below the lower limit of measurement, and it was speculated that human fibrinogen denaturation would not occur substantially.

(10) Escherichia coli adhesion test In order to evaluate the adhesiveness of bacteria on the surface of each polymer synthesized in each of the above Examples and Comparative Examples, Escherichia coli was seeded by the following method to evaluate the adhesion amount.
Made by dissolving 1 w / v% tryptone (SIGMA-ALDRICH), 0.5 w / v% yeast extract (SIGMA-ALDRICH), and 0.5 w / v% sodium chloride (SIGMA-ALDRICH) in sterile milliQ water. The LB medium thus prepared was sterilized by an autoclave, and agar (SIGMA-ALDRICH) was added to 1.5 w / v% to prepare an LB plate. Escherichia coli DH5α Competent Cells (Takara Bio) was smeared on an LB plate and cultured overnight in an incubator at 37 ° C. One colony on the plate was scraped and inoculated into 80 mL of LB medium, and shaking culture was performed overnight in a 37 ° C. incubator at a rate of 230 times / minute (primary culture). 200 μL of the primary culture solution was added to 80 mL of LB medium, and shaking culture was performed at 37 ° C. and 230 times / min (secondary culture). Secondary culture was performed by measuring the absorbance at a wavelength of 600 nm over time with a visible photometer until the absorbance reached 0.4 or more.
Using the same method as above, each polymer synthesized in Examples 5 and 6 and Comparative Example 3 and a commercially available polymer solution in which PMPC was dissolved were cast coated on the bottom of a well of a 24-well culture plate (IWAKI). did. Thereafter, the lid of the culture plate was opened and allowed to stand in a clean bench, and sterilization was performed by irradiation with ultraviolet rays for 30 minutes. Then, each well was washed once with phosphate buffered saline (PBS, Takara Bio) sterilized by autoclave, then immersed in LB medium, and incubated in a 37 ° C. incubator for 1 hour to precondition each polymer. Went. After preconditioning, Escherichia coli that had been subjected to secondary culture was inoculated to a bacterial density of 7.5 × 10 ⁷ cells / cm ² and cultured in a 37 ° C. incubator for 20 minutes. After cultivation, non-adherent bacteria were removed by washing twice with PBS. E. coli adhering to each polymer was fixed by immersing in PBS containing 1% glutaraldehyde (Wako Pure Chemical Industries) overnight at room temperature. Next, remove the milliQ water by immersing the culture plate in PBS solution for 10 minutes, in PBS diluted twice with milliQ water for 8 minutes, in milliQ water for 8 minutes, and then in milliQ water for 8 minutes. The fixing solution was washed by After the washed culture plate is dried at room temperature overnight, platinum palladium is vacuum-deposited on the surface with an ion coater (JFC-1200 FINE COATER, JEOL), and observed with a 3D real surface view microscope (VE-9800, KEYENCE). The E. coli adhering to each polymer surface was counted.
Table 4 shows the number of E. coli adhesion on each polymer surface.

  As shown in Table 4, it was revealed that the settled density of Escherichia coli was particularly low particularly in the polymer synthesized in Example 5 (n = 3). Since proteins such as Escherichia coli are required to be adsorbed on the surface of a substance such as Escherichia coli, the above results show that protein adhesion is remarkable in the polymer synthesized in Example 5 (n = 3). It was inferred to be due to the low amount.

(11) Coating property test of polymer solution In order to evaluate the coating property on the glass substrate surface by the polymer solution in which each polymer synthesized in each of the above Examples and Comparative Examples was dissolved, the coating was performed by the following method and the surface was observed. did.

Polymer solutions in which the polymers synthesized in Examples 5 and 6 (n = 3,4) and Comparative Example 3 (n = 2) were added in an amount of 0.2 g per 1 mL of methanol to dissolve the total amount. Was used. The glass substrate was washed overnight with methanol and dried overnight. For coating, 40 μL of polymer solution is dropped onto a glass substrate, the substrate is rotated at a maximum of 4000 rpm, the polymer solution is uniformly coated, dried for about 10 minutes, then coated again under the same conditions, and dried for one day. It was.
FIG. 4 shows a scanning electron microscope image of the surface of each substrate after coating as described above. As shown in FIG. 4, the polymers synthesized in Examples 5 and 6 form a smooth surface by coating, whereas the PMEA polymer synthesized in Comparative Example 3 produces island-like spots. The spots observed in the PMEA polymer are presumed to be related to the non-uniformity when the solvent of the polymer solution evaporates from the fact that it is not observed in the coating on the resin substrate and its shape, and the PMEA polymer and the glass substrate Therefore, it is inferred that the PMEA polymer also aggregated during the process of evaporation of the solvent. On the other hand, since the polymers synthesized in Examples 5 and 6 have low affinity with the glass substrate, it is presumed that the polymer is adsorbed on the substrate during the evaporation of the solvent to form a uniform coating film.

Claims (10)

A polymer having a structure represented by the following formula 1 in a side chain portion:
_{-L- (C n H 2n -O)} m -R 1 ( Formula 1)
[In the formula, L is a linker that connects the side chain to the polymer main chain, n is an integer of 3 to 6, m is an integer of 1 to 3, and R ¹ is a hydrogen atom, a methyl group, or When it is an ethyl group and has a plurality of side chain portions represented by Formula 1 with respect to the main chain, each n, m and R ¹ in the side chain portion may be the same or different. ].   2. The polymer according to claim 1, wherein the polymer can be hydrated, and releases or absorbs latent heat due to ordering / disordering of water molecules in a temperature range below freezing point when hydrated.   The polymer according to claim 1 or 2, wherein the main chain consists of a carbon chain mainly composed of carbon atoms.   The polymer according to any one of claims 1 to 3, wherein the linker is an alkylene group, an ether bond, a thioether bond, an ester bond, an amide bond, a urethane bond or a urea bond.   A water-containing polymer, wherein water is contained in the polymer according to any one of claims 1 to 4.   The polymer according to any one of claims 1 to 4, which is a solvent substantially composed of ethanol and water, wherein the polymer is dissolved in a solvent of 80% by volume or more. Polymer solution.   The polymer solution according to claim 6, wherein the solvent consists essentially of ethanol.   A polymer-coated substrate, wherein at least a part of the substrate surface is coated with the polymer according to claim 1.   The polymer-coated substrate according to claim 8, wherein the substrate is made of an inorganic substance.   An antifouling material comprising the polymer according to any one of claims 1 to 4, wherein the polymer contains a side chain of n = 3 as an active ingredient.