Polymer composition

Abstract

To provide a composition containing a novel polymer that shows biocompatibility by having a polyoxyethylene structure in part of it, the polymer composition particularly useful as a coating agent and capable of giving biocompatibility to the surfaces of various substrates.SOLUTION: A polymer composition has a urethane bond in the main chain of the polymer and includes a polyoxyethylene structure in the main chain and / or a side chain of the main chain, the polymer composition used to constitute a surface for inhibiting nonspecific absorption of protein.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to polymer compositions and the like that can be used, for example, to create a surface that is less likely to be recognized as a foreign substance by biological tissues or blood when used in contact with them. [Background technology]

[0002] Generally, when biological tissues or blood come into contact with the surface of a substance that does not originate from a living organism, the surface of the substance is recognized as a foreign object. This leads to nonspecific adsorption of proteins from the biological tissue to the surface, causing denaturation, and also to activation of the coagulation system, complement system, platelet system, etc., resulting in the adsorption of blood cells such as platelets to the surface.

[0003] In contrast, recent research has focused on the state of water molecules contained on the surface of synthetic polymers having a predetermined structure. By forming a surface capable of containing water molecules in a state called "intermediate water," it has become clear that non-specific adsorption of proteins to the surface and denaturation of adsorbed proteins can be prevented. Furthermore, it has become clear that such surfaces exhibit a lower frequency of adhesion of platelets and other substances when in contact with blood, and that inflammation caused by contact with in vivo tissues can be suppressed (see, for example, Non-Patent Document 1).

[0004] The presence of such "intermediate water" suppresses nonspecific adsorption of proteins to the surface of materials, and as a result, it can suppress various problems that occur in biological tissues or blood that come into contact with it. This state is generally described as having biocompatibility (blood compatibility).

[0005] Furthermore, in the case of medical devices such as artificial lungs, dialysis machines, blood storage bags, platelet storage bags, blood circuits, artificial hearts, indwelling needles, catheters, guidewires, stents, artificial blood vessels, and endoscopes, it is desirable to have the above-mentioned biocompatibility (blood compatibility) in order to suppress the above-mentioned phenomena that occur when in vivo tissues or blood come into contact with the surface of the medical device (see, for example, Patent Document 1).

[0006] As a method for imparting biocompatibility to the surface of a medical device that comes into contact with biological tissues or blood, for example, as described in Patent Document 2, a common method involves using a material with suitable mechanical properties for constructing the medical device as a base material, and then applying a biocompatible substance as a coating to its surface by means of a coating or other means.

[0007] Polyoxyethylene, obtained by ring-opening polymerization of ethylene oxide and represented by a structure with repeating (C2H4-O) units, is generally also called polyethylene glycol because it has hydroxyl groups at both ends of the polymerization chain. This polyethylene glycol (hereinafter sometimes referred to as "PEG") is known to exhibit excellent biocompatibility and low toxicity to living organisms, and is expected to be used as a medical material to impart biocompatibility by applying a PEG-containing coating to the surface of medical devices.

[0008] However, since PEG itself is water-soluble, in order to prevent elution when used in contact with blood or other substances as a medical material, it is necessary to form a water-insoluble substance containing PEG by means of forming a copolymer with other polymers, thereby conferring water resistance while maintaining the biocompatibility exhibited by PEG. On the other hand, because the mechanism by which PEG exhibits biocompatibility is not necessarily clear, various means are being explored to solve this problem by incorporating the structure of PEG and achieving both biocompatibility and water resistance.

[0009] For example, Patent Document 3 describes wound dressing sheets and intravascular embolization materials formed by dissolving a water-insoluble hydrophilic polymer containing PEG in an organic solvent and molding it. Patent Document 3 describes how to create a water-insoluble PEG-based polymer by forming a block copolymer of PEG and a biodegradable polymer. Patent Document 4 describes a technique for hydrophilizing a plastic surface that comes into contact with living tissue by grafting PEG onto it using gamma ray irradiation. Patent Document 5 describes a technique for forming a surface with low protein adsorption by photopolymerizing a copolymer containing PEG on the surface of a substrate.

[0010] Furthermore, Patent Document 6 describes a polymer composition that exhibits biocompatibility by introducing PEG constituent units as side chains to a (meth)acrylate main chain, and states that it can be used as a coating agent to impart biocompatibility by dissolving it in a predetermined organic solvent according to its structure. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] Japanese Patent Publication No. 2018-17720 [Patent Document 2] Japanese Patent Publication No. 2020-110638 [Patent Document 3] Japanese Patent Publication No. 2004-339497 [Patent Document 4] Special Publication No. 9-506665 [Patent Document 5] Japanese Patent Publication No. 2001-98007 [Patent Document 6] Japanese Patent Publication No. 2017-82174 [Non-patent literature]

[0012] [Non-Patent Document 1] Journal of the Adhesion Society of Japan Vol.51 No.9(2015)P.15~25

Summary of the Invention

Problems to be Solved by the Invention

[0013] There are a variety of medical devices for which imparting biocompatibility is desired, and the materials constituting such medical devices are similarly diverse. Also, depending on the type, use, etc. of the medical device, the properties that need to be ensured simultaneously with the imparting of biocompatibility vary widely. For this reason, the properties required of coating agents used to impart biocompatibility, etc. to the surface of medical devices are diverse, and there are infinite expectations especially for proposals of coating agents, etc. that exhibit biocompatibility with new characteristics.

[0014] On the other hand, the mechanism by which a substance exhibits biocompatibility is not necessarily clear, and in particular, the correlation between the structure of a specific substance and the manifestation of biocompatibility is not clear. For this reason, there is no guideline for designing coating agents, etc. that exhibit biocompatibility as described above, and it is only possible to clarify whether or not the substance exhibits biocompatibility by evaluating the actually synthesized substance, etc.

[0015] An object of the present invention is to provide a composition containing a novel polymer that exhibits biocompatibility by partially having the above PEG, and particularly a polymer composition capable of imparting biocompatibility to the surface of various substrates as a coating agent.

Means for Solving the Problems

[0016] In order to solve the above problems, the present invention provides a polymer composition having a urethane bond in the polymer main chain and containing a polyoxyethylene structure in the polymer main chain and / or in a side chain portion with respect to the polymer main chain, which is used for the purpose of constructing a surface for suppressing non-specific adsorption of proteins. The present invention also provides the above polymer composition in which the terminal of the polyoxyethylene structure contained in the polymer main chain is bonded by the above urethane bond.

[0017] The present invention also provides the above polymer composition in which the polymer main chain includes a structure derived from an aliphatic polyisocyanate. The present invention also provides the above polymer composition in which the polymer main chain includes a structure derived from a polycarbonate polyol.

[0018] The present invention also provides the above polymer composition for use in forming a surface with a low platelet adhesion frequency when used in contact with blood, and / or forming an antifouling surface by reducing the bacterial adhesion frequency, by suppressing non-specific adsorption of proteins. The present invention also provides an aqueous dispersion in which microparticles containing the above polymer composition are dispersed in an aqueous phase.

Advantages of the Invention

[0019] According to the polymer composition of the present invention, it is possible to exhibit biocompatibility derived from PEG and form a water-insoluble film at the same time.

Brief Description of the Drawings

[0020] [Figure 1] It is a graph showing the platelet adhesion characteristics of the polymer composition according to the present invention. [Figure 2] It is a graph showing the platelet adhesion characteristics of the polyurethane film according to the comparative example of the present invention. [Figure 3] It is a graph showing the mechanical strength of the polymer composition according to the present invention. [Figure 4] It is a graph showing the weight gain rate when the polymer composition according to the present invention contains water.

Modes for Carrying Out the Invention

[0021] As described above, PEG is known to have good biocompatibility and low toxicity to organisms. Therefore, various attempts have been made as described above regarding a method of imparting properties such as water resistance while maintaining the biocompatibility exhibited by PEG by introducing PEG into a part of a polymer structure having predetermined properties.

[0022] However, due to reasons such as the relatively low chemical stability of PEG, there are few options for immobilizing PEG and making it water-insoluble. As a result, polymer compositions that exhibit water resistance and biocompatibility, and can be widely used on various substrates as coating agents, have not yet been obtained.

[0023] Furthermore, when using water-insoluble polymers, particularly those produced by incorporating PEG in various forms into the structure of other polymers, as coating agents, it is generally necessary to apply the polymer to the substrate in a state where it is dissolved in various organic solvents. Therefore, in relation to the material of the substrate to which the coating is applied, there is a need for an organic solvent that can dissolve the polymer but does not damage the substrate. This makes it difficult to obtain a polymer composition that has the desired properties and can be used on a wide range of substrates.

[0024] In order to resolve the technical challenges described above, and while maintaining the biocompatibility exhibited by PEG, the inventors diligently studied polymer compositions that exhibit properties such as water resistance and can be widely used on various substrates. They discovered that a polymer composition in which various structures are bonded together by urethane bonds, and in which a polyoxyethylene structure is introduced as part of the polymer composition, exhibits phenomena that support the existence of biocompatibility, such as the suppression of nonspecific adsorption of proteins and the frequency of platelet adhesion, on a surface coated with such a polymer composition, leading to the present invention.

[0025] Polyurethanes produced from the polymer composition according to the present invention exhibit particularly remarkable biocompatibility, as shown in the following examples. Depending on their structure, they exhibit suppression of nonspecific protein adsorption and suppression of platelet adhesion frequency to a degree comparable to or greater than that of conventionally widely used biocompatible polymers such as PMEA (poly-2-methoxyethyl acrylate) and MPC (2-methacryloyloxyethyl phosphorylcholine) polymers.

[0026] The mechanism by which the polyurethane produced from the polymer composition according to the present invention exhibits high biocompatibility is not clear. On the other hand, it is known that the expression of biocompatibility is due to the mobility of molecules such as PEG, and that the mobility of such molecules is influenced by polar functional groups present in the surroundings. Considering these circumstances, it can be inferred that the reason why the polyurethane produced from the polymer composition according to the present invention exhibits biocompatibility due to the inclusion of a polyoxyethylene structure (PEG) is that at least the degree to which the molecular mobility of the polyoxyethylene structure is inhibited by the urethane bond is low.

[0027] Furthermore, the polymer composition according to the present invention aims to exhibit biocompatibility and other properties due to the polyoxyethylene structure by introducing a highly hydrophilic polyoxyethylene structure to a polyurethane backbone that is generally hydrophobic. When a hydrophobic structure and a hydrophilic structure are adjacent to each other, a high interfacial energy is generally generated between them. It is presumed that there is a tendency to alleviate the interfacial energy within the polymer by rearranging each structure within the degrees of freedom of the molecular chain.

[0028] As shown in the following examples, even when a small amount of polyoxyethylene structure is introduced by weight into a polyurethane backbone that does not exhibit biocompatibility, the polymer composition according to the present invention exhibits biocompatibility at a level comparable to or higher than that of conventionally used biocompatible polymers such as PMEA and MPC polymers.

[0029] The above phenomenon suggests that when a polyurethane film composed of the polymer composition according to the present invention comes into contact with an aqueous phase, the interfacial energy with the aqueous phase acts as a driving force, causing the polyoxyethylene structure introduced into the polyurethane backbone to rearrange and aggregate on the surface of the polyurethane film. This suggests that the polyurethane backbone is preferable as the backbone used when making the polyoxyethylene structure water-insoluble.

[0030] The polyoxyethylene structures present on the surface of the polyurethane film in contact with the aqueous phase form what is known as a polymer brush, and it is thought that this covers the polyurethane backbone and thus prevents non-specific adsorption of proteins.

[0031] It should be noted that the name polyethylene glycol (PEG) is used when the polymerization chain of polyoxyethylene has a hydroxyl group at the end. The name PEG is not necessarily appropriate for polyoxyethylene structures introduced into a polymer through polymerization reactions involving such hydroxyl groups. However, for convenience, in this specification, following common usage, the terms polyoxyethylene and PEG are used to refer to the same substance, and polyoxyethylene structures introduced into a polymer may be described as "PEG introduced into the polymer."

[0032] Furthermore, in this specification, "biocompatibility" refers to properties that make a substance less likely to be recognized as a foreign substance when it comes into contact with a biological substance or a substance derived from a biological organism, such as nonspecific adsorption of proteins or suppression of platelet adhesion frequency. Specifically, it means, for example, that it does not cause complement activation or platelet activation and is minimally invasive or non-invasive to tissues. "Biocompatibility" also includes the aspect of "blood compatibility." "Blood compatibility" means that it does not induce blood coagulation mainly caused by platelet adhesion or activation.

[0033] Furthermore, polymer compositions containing urethane bonds are generally referred to as "polyurethanes," regardless of the structure of each part present within the polymer. Therefore, the polymer composition containing urethane bonds incorporating PEG according to the present invention can also be classified as a "polyurethane," and can be synthesized using general polyurethane synthesis methods. Hereinafter, the polymer composition according to the present invention may be referred to as "polyurethane."

[0034] One form of use for the polymer composition according to the present invention is to dissolve it in a suitable solvent and apply it to a target substrate to form a biocompatible coating. On the other hand, polyurethane is known to be able to be stably dispersed as fine particles in water by containing a hydrophilic component in its polymer chain, and to form an aqueous dispersion as a so-called aqueous polyurethane resin, and to form a polyurethane coating by applying the aqueous dispersion.

[0035] The polymer composition according to the present invention also contains a polyoxyethylene structure which is a hydrophilic group, making it possible to disperse it as fine particles in water to form an aqueous dispersion. Furthermore, by using the polymer composition according to the present invention as a coating agent in the form of an aqueous dispersion, it becomes possible to impart biocompatibility to substrate surfaces that have low resistance to organic solvents.

[0036] As described above, the polymer composition according to the present invention introduces a highly hydrophilic polyoxyethylene structure to a hydrophobic polyurethane backbone. When the polymer comes into contact with an aqueous phase, it is presumed that a rearrangement occurs, causing the polyoxyethylene structure to aggregate on the polymer surface in order to alleviate interfacial energy within the polymer. For this reason, it is considered that using the polymer composition according to the present invention in the form of an aqueous polyurethane resin dispersed in an aqueous phase makes it easier to exhibit properties such as biocompatibility due to the polyoxyethylene structure.

[0037] The polymer composition according to the present invention will be described in detail below. The polymer composition according to the present invention can be synthesized, like ordinary polyurethanes, by reacting a polyol and a polyisocyanate without the use of a solvent or in an organic solvent that does not contain active hydrogen groups. In the synthesis process, polyethylene glycol (PEG) can be used as part of the polyol constituting the polyurethane, and the composition can also be synthesized by using a polyol containing a polyoxyethylene structure. Furthermore, a polyoxyethylene structure can be introduced into the polymer composition by using a polyisocyanate that has a polyoxyethylene structure inside as the polyisocyanate constituting the polyurethane.

[0038] In the above reaction, especially when seeking to obtain the polymer composition according to the present invention in the form of an aqueous dispersion, the molar ratio of active hydrogen groups such as hydroxyl groups contained in the polyol to NCO groups contained in the polyisocyanate is set to 1 or more, preferably 1.1 or more, of the active hydrogen groups such as hydroxyl groups, thereby generating a so-called NCO-terminated urethane prepolymer. By dispersing this NCO-terminated urethane prepolymer in an aqueous phase and emulsifying it, the polymer composition according to the present invention can be obtained in the form of an aqueous dispersion. The PEG contained in the polymer composition according to the present invention functions as a hydrophilic segment in the aqueous phase, and can therefore be easily obtained in the form of an aqueous dispersion.

[0039] Regarding the molar ratio of active hydrogen groups such as hydroxyl groups contained in the above polyol to NCO groups contained in the polyisocyanate, it is preferable to set the ratio of NCO groups to active hydrogen groups such as hydroxyl groups to 1.2 to 3.0 times, as this allows for the acquisition of a stable emulsion and enables the reduction of viscosity of the NCO-terminated urethane prepolymer.

[0040] Furthermore, the reaction between the polyol and polyisocyanate described above can be completed in 30 minutes to 50 hours at a temperature of approximately 30 to 130°C, thereby producing the polymer composition according to the present invention. In this process, a catalyst commonly used in the synthesis of urethanes can be added to adjust the reaction, and for example, amine compounds or metal catalysts such as tin octylate or bismuth octylate can be used.

[0041] In the polymer composition according to the present invention, in particular, when seeking to obtain a polymer composition having a polyoxyethylene structure in the polymer main chain, a polymer composition having a polyoxyethylene structure with both ends linked by urethane bonds can be obtained by mixing PEG having an appropriate molecular weight as part of the polyol into the reaction system.

[0042] Furthermore, when seeking to obtain a polymer composition having a polyoxyethylene structure in the side chain portion relative to the polymer main chain, components classified as so-called branched PEGs can be used as polyols. For example, by using a polyol with a structure in which hydrogen atoms contained in an alkylene group having hydroxyl groups at both ends are replaced with a group having a polyoxyethylene structure, it is possible to produce polyurethane that does not contain a polyoxyethylene structure in the polymer main chain.

[0043] In the polymer composition according to the present invention, for example, by including a polyoxyethylene structure in the above-described form at a weight ratio of about 1 wt% relative to the entire polymer composition, it is possible to exhibit good biocompatibility and effectively suppress platelet adhesion. Furthermore, by increasing the weight ratio of the polyoxyethylene structure contained in the polymer composition, it is possible to exhibit good biocompatibility regardless of the form in which the polyoxyethylene structure is introduced into the polymer composition.

[0044] On the other hand, an increase in the weight proportion of the polyoxyethylene structure contained in the polymer composition according to the present invention tends to decrease the strength of the polyurethane film composed of the polymer composition and increase the water content when immersed in water. For this reason, it is preferable to reduce the weight proportion of the introduced polyoxyethylene structure depending on the application, such as the film formed using the polymer composition according to the present invention. For example, the strength of the polyurethane film can be maintained by setting the weight proportion of PEG, branched PEG, etc., used as the PEG component containing the polyoxyethylene structure to 40 wt% or 30 wt% or less, relative to the total mass of the polyol containing the PEG component and the polyisocyanate used when producing each polymer composition.

[0045] Furthermore, by setting the weight percentage of the PEG component in the polymer composition according to the present invention to 20 wt% or less, it is preferable that the strength of the polyurethane film composed of the polymer composition and the water content when immersed in water can be made to be on the same level as that of a polyurethane film that does not contain a polyoxyethylene structure.

[0046] The average molecular weight of PEG used in the above is preferably in the range of 200 to 3000. When synthesizing a polymer composition with a small weight proportion of PEG, using PEG with a relatively large average molecular weight of about 200 to 1000 within the above range makes it possible to suppress the decrease in strength of the polymer composition caused by the addition of PEG. On the other hand, when synthesizing a polymer composition with a large weight proportion of PEG, using PEG with a relatively large average molecular weight in relation to the molecular weight of the polyisocyanate used makes it possible to introduce PEG in a large weight ratio.

[0047] Furthermore, in polyurethane coatings composed of the polymer composition according to the present invention, compared to a structure in which polyoxyethylene structures are included in the polymer main chain, when polyoxyethylene structures are included in the side chains relative to the polymer main chain, good biocompatibility is observed even with a small amount of polyoxyethylene structure content, and a tendency is observed to suppress the decrease in strength and increase in water content when the polyoxyethylene structure content is increased.

[0048] In the polyurethane coating composed of the polymer composition according to the present invention described above, the reason why differences in biocompatibility and other properties occur depending on the location within the polymer where the polyoxyethylene structure is introduced is presumed to be as follows. As described above, when the polymer composition according to the present invention comes into contact with the aqueous phase, it is presumed that good biocompatibility is achieved even with a small amount of polyoxyethylene structure introduced, as the hydrophilic polyoxyethylene structure introduced to the hydrophobic polyurethane backbone rearranges to aggregate at the interface with the aqueous phase, within the range of freedom of the molecular chain. Furthermore, considering the ease with which this rearrangement of the polyoxyethylene structure occurs, it is thought that the polyoxyethylene structure contained in the side chain, which has only one end fixed to the polymer backbone and a smaller molecular weight compared to the backbone, has a greater degree of freedom for rearrangement compared to a polyoxyethylene structure fixed at both ends within the polymer backbone, thus making it easier to achieve biocompatibility.

[0049] Furthermore, by using a polyol as the branched PEG, particularly one in which hydrogen atoms contained in alkylene groups having hydroxyl groups at both ends are replaced with groups having a polyoxyethylene structure, a polyurethane is produced in which the polymer main chain does not contain a polyoxyethylene structure, and the polyoxyethylene structure is contained only in the side chain portion. This is particularly preferable because it makes it easier to ensure the strength of the polyurethane when it is hydrated.

[0050] In the polymer composition according to the present invention, depending on the purpose of use, a single structure and molecular weight PEG or branched PEG may be used, or PEGs with different structures and molecular weights may be mixed in appropriate proportions and used as part of the polyol. In particular, by adjusting the proportion and molecular weight of polyoxyethylene structures introduced into the polymer main chain and the side chain portions of the polymer main chain, it is possible to adjust the expression of biocompatibility and other mechanical properties according to the purpose of use.

[0051] When synthesizing the polymer composition according to the present invention, any polyol commonly used in the synthesis of polyurethanes can be used without particular limitation as the polyol used with PEG. Polycarbonate polyols, polyester polyols, polyether polyols, hydrocarbon polyols, or low molecular weight polyols with a molecular weight of 400 or less can be used individually or in combination of two or more.

[0052] Polycarbonate polyols are polyols obtained, for example, by reacting aliphatic polyols or alicyclic polyols with carbonate derivatives such as carbonate esters or phosgene. Because polycarbonate polyols have carbonate bonds inside, polyurethanes containing polycarbonate polyols are generally preferred because they tend to have superior strength.

[0053] In the present invention, polycarbonate polyols containing aliphatic polyols are particularly preferred. Examples of such aliphatic polyols include ethylene glycol, diethylene glycol, 1,4-butanediol, 1,3-butanediol, 2,3-butanediol, 1,3-propylene glycol, 1,2-propylene glycol, 1,6-hexanediol, 3-methyl-1,5-pentanediol, neopentyl glycol, and the like, which may be used individually or in combination of two or more.

[0054] Polyester polyols are, for example, esterified condensates obtained by reacting the aforementioned low molecular weight polyol with a polycarboxylic acid, and have a structure terminated at one end by a hydroxyl group. Examples of the polycarboxylic acid include succinic acid, glutaric acid, adipic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid, trimellitic acid, tetrahydrofuranic acid, endomethinetetrahydrofuranic acid, or hexahydrophthalic acid.

[0055] Polyether polyols are, for example, obtained by addition polymerization of alkylene oxides such as ethylene oxide, propylene oxide, and butylene oxide to the aforementioned low molecular weight polyol. In the polymer composition according to the present invention, in addition to using PEG as part of the polyol, it is also possible to introduce the structure of PEG into the polymer composition by using a polyether polyol containing ethylene oxide.

[0056] Hydrocarbon polyols are those in which the ends of the hydrocarbon chain are terminated with hydroxyl groups. Examples include polybutadiene polyols, polyisoprene polyols, hydrogenated polybutadiene polyols, or hydrogenated polyisoprene polyols.

[0057] Low molecular weight polyols with a molecular weight of 400 or less are effectively used to increase the weight proportion of PEG in the polymer composition according to the present invention. Examples of low molecular weight polyols with a molecular weight of 400 or less include ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, neopentyl glycol, 1,3-butanediol, 1,4-butanediol, 3-methylpentanediol (MPD), 1,6-hexanediol (1,6-HD), 1,8-octanediol, 2-methyl-1,3-propanediol, bisphenol A, hydrogenated bisphenol A, cyclohexanedimethanol, glycerin, trimethylolpropane, and the like.

[0058] As a polyol used with PEG, it is preferable to include a polycarbonate polyol because it provides a coating with excellent water resistance. The amount of polycarbonate polyol is not particularly limited, but it is preferably 90 parts by mass or more, and more preferably 95 parts by mass or more, of 100 parts by mass of the polyol component excluding PEG. In synthesizing the polymer composition according to the present invention, the polyol used has terminal hydroxyl groups that react with isocyanates to form urethane bonds, and a structure derived from the polyol is introduced into the main chain portion of the polymer composition.

[0059] The polyisocyanate used in synthesizing the polymer composition according to the present invention can be any polyisocyanate commonly used in the synthesis of polyurethanes, and aliphatic polyisocyanates, alicyclic polyisocyanates, aromatic polyisocyanates, etc., can be used individually or in combination of two or more.

[0060] Examples of aliphatic polyisocyanates that can be used include tetramethylene diisocyanate, dodecamethylene diisocyanate, hexamethylene diisocyanate (HMDI), 2,2,4-trimethylhexamethylene diisocyanate, 2,4,4-trimethylhexamethylene diisocyanate, lysine diisocyanate, 2-methylpentane-1,5-diisocyanate, and 3-methylpentane-1,5-diisocyanate.

[0061] In the polymer composition according to the present invention, when an aliphatic polyisocyanate is used as the polyisocyanate, a tendency is observed for high strength to be obtained in the polyurethane film composed of the polymer composition, and a tendency is observed for weight increase to be suppressed when immersed in the aqueous phase. From the above viewpoint, when producing the polymer composition according to the present invention, aliphatic polyisocyanate is preferably used. For example, by using a ratio of 80 parts by mass or more, more preferably 90 parts by mass or more, of aliphatic polyisocyanate per 100 parts by mass of polyisocyanate used, a polyurethane film with high strength can be formed.

[0062] Examples of the alicyclic polyisocyanates that can be used include isophorone diisocyanate (IPDI), hydrogenated xylylene diisocyanate, 4,4'-dicyclohexylmethane diisocyanate (H12MDI), 1,4-cyclohexane diisocyanate, methylcyclohexylene diisocyanate, and 1,3-bis(isocyanatemethyl)cyclohexane.

[0063] Furthermore, examples of aromatic polyisocyanates include tolylene diisocyanate (TDI), 2,2'-diphenylmethane diisocyanate, 2,4'-diphenylmethane diisocyanate, 4,4'-diphenylmethane diisocyanate (MDI), 4,4'-dibenzyle diisocyanate, 1,5-naphthylene diisocyanate, xylylene diisocyanate, 1,3-phenylene diisocyanate, and 1,4-phenylene diisocyanate. The polyisocyanate used in synthesizing the polymer composition according to the present invention reacts with the hydroxyl groups of polyols and the like at its terminal ends to form urethane bonds, and a structure derived from the polyisocyanate is introduced into the main chain portion of the polymer composition.

[0064] As the organic solvent used as the reaction medium when reacting the above-mentioned polyol with polyisocyanate to form a urethane bond, any organic solvent that does not have active hydrogen groups and is generally used in the synthesis of polyurethanes can be used without restriction. For example, dioxane, methyl ethyl ketone, dimethylformamide, tetrahydrofuran, N-methyl-2-pyrrolidone, toluene, propylene glycol monomethyl ether acetate, etc. can be used.

[0065] Furthermore, when the above polymer composition is dispersed as fine particles in an aqueous phase to form an aqueous dispersion, the molecular weight can be increased using various chain extenders. While not particularly limited, specific examples of chain extenders include polyamines such as ethylenediamine, trimethylenediamine, piperazine, isophoronediamine, diethylenetriamine, dipropylenetriamine, and triethylenetetramine; and polyols such as ethyleneglycol, diethylene glycol, 1,4-butanediol, 1,3-butanediol, 2,3-butanediol, 1,3-propylene glycol, 1,2-propylene glycol, 1,6-hexanediol, 3-methyl-1,5-pentanediol, and neopentyl glycol. Additionally, the molecular weight can be increased by water molecules present in the aqueous phase.

[0066] When dispersing and emulsifying the above polymer composition in water, a surfactant may be used as an emulsifier. The surfactant is not particularly limited, but examples include nonionic surfactants, anionic surfactants, and cationic surfactants. These surfactants may be used individually or in combination of two or more.

[0067] Nonionic surfactants are not particularly limited, but examples include alcohols having 8 to 24 carbon atoms, alkenols having 8 to 24 carbon atoms, polycyclic phenols, amines having 8 to 44 carbon atoms, amides having 8 to 44 carbon atoms, fatty acids having 8 to 24 carbon atoms, polyhydric alcohol fatty acid esters, oils and fats, alkylene oxide adducts of polypropylene glycol, alkylene oxide adducts of polycyclic phenols, and Pluronic® type nonionic surfactants. Alkylene oxide adducts of polycyclic phenols are not particularly limited, but examples include polyoxyethylene distyrylphenyl ether type nonionic surfactants, polyoxyethylene polyoxypropylene distyrylphenyl ether type nonionic surfactants, polyoxyethylene tristyrylphenyl ether type nonionic surfactants, and polyoxyethylene polyoxypropylene tristyrylphenyl ether type nonionic surfactants. Here, when two or more alkylene oxides are added to the nonionic surfactant, it may be blocked addition or random addition.

[0068] The anionic surfactant is not particularly limited, but examples include alcohols, alkenols, and anionic derivatives of alkylene oxide adducts of the nonionic surfactant. Cationic surfactants are not particularly limited, but examples include monoalkyltrimethylammonium salts with 8 to 24 carbon atoms, dialkyldimethylammonium salts with 8 to 24 carbon atoms, monoalkylamine acetates with 8 to 24 carbon atoms, dialkylamine acetates with 8 to 24 carbon atoms, and alkylimidazoline quaternary salts with 8 to 24 carbon atoms.

[0069] As for the surfactant, nonionic surfactants are preferred from the viewpoint of excellent miscibility with other components, and alkylene oxide adducts of polycyclic phenols and Pluronic® type nonionic surfactants are more preferred. The amount of surfactant used is preferably 0.5 parts by mass or more, more preferably 2 parts by mass or more, per 100 parts by mass of the solid content of the polymer composition. Furthermore, it is preferably 10 parts by mass or less, and more preferably 8 parts by mass or less.

[0070] The polymer composition according to the present invention can be used as a coating agent by first dispersing the polymer composition as a fine dispersion in an aqueous phase, and then applying this aqueous dispersion to the surface of a substrate on which a film is to be formed. Using the polymer composition according to the present invention as an aqueous dispersion makes it possible to apply it to the surface of a substrate without using an organic solvent as a solvent, which is particularly preferable as it allows it to be used even on substrates with low resistance to organic solvents.

[0071] The method for obtaining an aqueous dispersion of the polymer composition according to the present invention is not particularly limited. For example, the polymer composition according to the present invention can be obtained by reacting the polyol and polyisocyanate in an organic solvent that does not have active hydrogen groups to form urethane bonds, and then dispersing and emulsifying them by mixing with water and stirring.

[0072] As shown in the following examples, suppression of nonspecific protein adsorption is observed on the surface of a coating formed with the polymer composition according to the present invention, and a decrease in platelet adhesion frequency is observed in the presence of a predetermined plasma protein. Therefore, the polymer composition according to the present invention is suitably usable for the purpose of constructing a surface that suppresses nonspecific protein adsorption, and can be used as a material for constructing the surface of artificial organs, medical devices, etc., in particular, where biocompatibility is required.

[0073] 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, these include, but are not limited to, blood filters, artificial lungs, dialysis machines, blood storage bags, platelet storage bags, blood circuits, artificial hearts, indwelling needles, catheters, guidewires, stents, artificial blood vessels, and endoscopes.

[0074] The material and shape of the substrate that constitutes an "artificial organ" or "medical device" and on which a film is formed on the surface by the polymer composition according to the present invention are not particularly limited. For example, examples of materials include natural polymers such as brocade and hemp, synthetic polymers such as nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polycarbonate, polysulfone, polyethersulfone, poly(meth)acrylate, ethylene-vinyl alcohol copolymer, butadiene-acrylonitrile copolymer, and mixtures thereof. Metals, ceramics, and composite materials thereof are also examples. The artificial organ or medical device may be composed of multiple types of substrates. For example, the polymer composition according to the present invention can be applied to the surface of a substrate having shapes such as porous materials, fibers, nonwoven fabrics, particles, films, sheets, tubes, hollow fibers, or powders to form a coating.

[0075] When imparting antibacterial properties and / or anti-inflammatory properties to artificial organs, medical devices, etc., it is preferable to apply the polymer composition according to the present invention to at least a portion, preferably substantially the entire surface, of the surface that comes into contact with in vivo tissue or blood to form a coating.

[0076] The polymer composition according to the present invention can be used as a material constituting the entirety or surface portion of artificial organs and medical devices used in contact with biological tissues or blood. It is desirable that at least a portion, preferably almost the entire surface constituting the surface constituting the polymer composition according to the present invention, of medical devices such as implantable artificial organs and treatment devices, extracorporeal circulation artificial organs, surgical sutures, catheters (cardiovascular catheters such as angiography catheters, guidewires, and PTCA catheters; digestive catheters such as gastric tubes, gastrointestinal catheters, and esophageal tubes; and urological catheters such as urethral catheters and ureteral catheters) that come into contact with blood be covered with a polyurethane coating composed of the polymer composition according to the present invention. Furthermore, the polyurethane coating composed of the polymer composition according to the present invention may be used as a hemostatic agent, an adhesive for biological tissues, a repair material for tissue regeneration, a carrier for drug sustained-release systems, a hybrid artificial organ such as an artificial pancreas or artificial liver, an artificial blood vessel, an embolizing material, and a matrix material for scaffolds in cell engineering. These artificial organs and medical devices may be further given surface lubrication to facilitate insertion into blood vessels and tissues and to prevent tissue damage.

[0077] Specifically, the polymer composition according to the present invention may be coated on at least a portion of the surface of a substrate constituting a blood filter. Alternatively, the polymer composition according to the present invention may be coated on at least a portion of the surface of a blood bag and a tube communicating with the blood that comes into contact with blood. Furthermore, at least a portion of the surface of an extracorporeal circulation blood circuit that comes into contact with blood, consisting of an instrument-side blood circuit section comprising tubes, arterial filters, centrifugal pumps, hemoconcentrators, cardioplegia, etc., and a surgical field-side blood circuit section comprising tubes, catheters, suction devices, etc., may be coated with the polymer composition according to the present invention.

[0078] When using the polymer composition according to the present invention in an indwelling needle assembly, at least a portion of the surface of the indwelling needle assembly that comes into contact with blood may be coated with the polymer composition of the present invention. The assembly comprises an inner needle having a sharp needle tip, an inner needle hub installed on the proximal end side of the inner needle, a hollow outer needle into which the inner needle can be inserted, 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, and a connecting means for connecting the outer needle hub and the protector. Furthermore, at least a portion of the surface of a catheter, which consists of a long tube and an adapter connected to its proximal end (proximal side), that comes into contact with blood may be coated with the polymer composition according to the present invention.

[0079] At least a portion of the surface of the guidewire that comes into contact with the blood may be coated with the polymer composition according to the present invention. Furthermore, at least a portion of the surface of various stents that come into contact with the blood may be coated with the polymer composition according to the present invention, such as hollow tubular bodies made of metal or polymer materials with pores on their sides, or stents made by weaving metal wires or polymer fibers together to form a cylindrical shape.

[0080] When the polymer composition according to the present invention is used in a cardiopulmonary bypass machine, it may be an artificial lung of the type in which a large number of porous hollow fiber membranes for gas exchange are housed in a housing, blood flows on the outer side of the hollow fiber membranes, and oxygen-containing gas flows inside the hollow fiber membranes, and the polymer composition according to the present invention is coated on the outer surface or outer layer of the hollow fiber membranes. A dialysis apparatus comprising a dialysis circuit including at least one dialysis fluid container filled with dialysis fluid and at least one drainage container for collecting dialysis fluid, and a fluid delivery means for delivering dialysis fluid starting from the dialysis fluid container or ending at the drainage container, wherein at least a portion of the surface in contact with blood may be coated with the polymer composition according to the present invention.

[0081] As a method for retaining the polymer composition according to the present invention on the surface of "artificial organs" or "medical devices," in addition to coating by conventional application methods, known methods such as graft polymerization using radiation, electron beams, and ultraviolet light, and methods for introduction using chemical reactions with functional groups of a substrate may be used. Among these, the coating method is particularly preferred in practice because it is easy to manufacture. Furthermore, the coating method is not particularly limited and can be applied according to the purpose, such as application, spraying, and dipping. The film thickness of the film formed by the polymer composition according to the present invention is not particularly limited; for example, it can be used as a film with a film thickness of about 0.1 μm to 1 mm.

[0082] The coating treatment using the polymer composition according to the present invention can be carried out by simple operations such as using an aqueous dispersion of the polymer composition according to the present invention, immersing the member to be coated in a solution obtained by dissolving a composition containing the biocompatible polymer composition according to the present invention in a suitable solvent, removing the excess solution, and then air-drying. Furthermore, in order to more firmly fix the polymer composition according to the present invention to the member to be coated, heat can be applied after coating to further enhance the adhesion with the polymer composition according to the present invention. Alternatively, the surface may be crosslinked to achieve fixation. As a method of crosslinking, a crosslinkable monomer may be introduced as a comonomer component. Crosslinking may also be performed by electron beam, gamma ray, or light irradiation.

[0083] Furthermore, by utilizing the fact that non-specific adsorption of proteins to the polyurethane surface produced from the polymer composition according to the present invention, as well as subsequent denaturation and multilayer adsorption, can be suppressed, the polymer composition according to the present invention can also be used to form an antifouling surface for preventing various types of biological contamination by reducing the frequency of bacterial adhesion. In other words, it is known that when E. coli and other bacteria adhere to a material surface, they use proteins and other substances adsorbed on that surface as a scaffold, and it is expected that the frequency of E. coli adhesion will decrease on a surface with a low frequency of protein adsorption, such as the polymer composition according to the present invention.

[0084] For applications forming anti-fouling surfaces, for example, by using the polymer composition according to the present invention on surfaces that come into contact with water containing various proteins and bacteria, such as sinks used in medical settings for washing various instruments and waste with water, as well as general-purpose sinks, baths, and toilets, it is expected that the adsorption of proteins and bacteria contained in the water will be suppressed. This antifouling material can be used as a material for preventing infectious diseases and bacterial adhesion, as well as as a biodeposition prevention material for parts of ships, seawalls, and other areas that come into contact with water where organisms live and where the attachment of various organisms is a problem. The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. [Examples]

[0085] [Synthesis of polyurethane aqueous dispersions] (Example 1) Using a four-necked flask equipped with a stirrer, reflux condenser, thermometer, and nitrogen blowing tube, the following mixtures were used: 90 parts by mass of methyl ethyl ketone as the reaction medium; 49.9 parts by mass of polycarbonate diol of 1,6-hexanediol (PCD(1,6-HD), manufactured by Ube Industries, Ltd., product name: ETERNACOLL UH-100, number average molecular weight approximately 1000, average hydroxyl value 110 mgKOH / g) as the polyol component (component A); 33.3 parts by mass of polyethylene glycol (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., product name: PEG-1000, number average molecular weight approximately 1000, average hydroxyl value 110 mgKOH / g); 16.8 parts by mass of hexamethylene diisocyanate (HMDI) (Duranate 50MS, manufactured by Asahi Kasei Chemicals) as the polyisocyanate component (component B); and an organotin compound (bis) as the reaction catalyst. 0.0035 parts by mass of (neodecanoyloxy) dioctylstannane (Songwon Industrial Co., Ltd.) were added and reacted at 75°C for 4 hours to produce a urethane prepolymer, and a solution was obtained in which the urethane prepolymer dissolved in methyl ethyl ketone.

[0086] The above solution was cooled to 45°C, and 6.0 parts by mass of a surfactant (product name: Neugen EA-157, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) and 0.05 parts by mass of a silicone-based defoaming agent were added. 1408 parts by mass of water were then gradually added while using a homogenizer to emulsify and disperse the urethane prepolymer in the liquid phase to obtain a dispersion. Subsequently, a chain extension reaction with water was carried out for 1 hour. After that, the mixture was maintained under reduced pressure at 50°C to evaporate and remove the methyl ethyl ketone reaction medium, thereby obtaining a polyurethane aqueous dispersion containing approximately 7.3% nonvolatile components.

[0087] (Examples 2-10) Polyurethane aqueous dispersions were produced in the same manner as in Example 1 by varying the ratio of PCD(1,6-HD) and HMDI, as well as the ratio of PEG used, average molecular weight, structure, etc. Table 1 shows the breakdown (parts by mass) of each raw material component used in Examples 2 to 10, along with that of Example 1.

[0088] In Table 1, PEG-600 (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., product name: PEG-600S, number average molecular weight: approximately 600, average hydroxyl value: 187 mgKOH / g) and PEG-2000 (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., product name: PEG-2000, number average molecular weight: approximately 2000, average hydroxyl value: 56 mgKOH / g) are polyethylene glycols. Branched PEG is a diol (YmerN120, manufactured by Perstorp) having a structure in which hydrogen atoms of an alkylene chain with hydroxyl groups at both ends are substituted with groups containing polyoxyethylene structures, etc., with a number average molecular weight of approximately 1020 and an average hydroxyl value of 110 mgKOH / g.

[0089] [Table 1]

[0090] (Examples 11-17) Polyurethane aqueous dispersions were produced in the same manner as in Example 1 by varying the types and quantities of the polyol component (component A) and polyisocyanate component (component B), as well as the quantity ratio, average molecular weight, and structure of the PEG used. Table 2 shows the breakdown (parts by mass) of each raw material component used in Examples 11 to 17. In Table 2, the polyester polyol (MPD / AA; 3-methyl-1,5-pentanediol / adipic acid) used had a number average molecular weight of approximately 1000 (Kurapol P-1010: manufactured by Kuraray). The polytetramethylene glycol (PTMG) used had a number average molecular weight of approximately 1000 (PloyTHF 1000S: manufactured by BASF Japan).

[0091] [Table 2]

[0092] (Comparative Example 1) A polyurethane aqueous dispersion in which a PEG-free urethane prepolymer was dispersed in the aqueous phase was obtained as follows. Using a four-necked flask equipped with a stirrer, reflux condenser, thermometer, and nitrogen blowing tube, 90 parts by mass of methyl ethyl ketone as the reaction medium were mixed with 70.1 parts by mass of 1,6-hexanediol polycarbonate diol (PCD(1,6-HD), manufactured by Ube Industries, Ltd., product name: ETERNACOLL UH-100, number average molecular weight approximately 1000, average hydroxyl value 110 mgKOH / g) as the polyol component (component A), 6.3 parts by mass of dimethylolpropionic acid (DMPA), and 23.6 parts by mass of hexamethylene diisocyanate (HMDI) as the polyisocyanate component (component B). The mixture was reacted at 75°C for 4 hours to produce a urethane prepolymer, and a solution was obtained in which the urethane prepolymer dissolved in methyl ethyl ketone. In this solution, the content of free isocyanate groups relative to the nonvolatile content was estimated to be 1.97%.

[0093] The above solution was cooled to 45°C, neutralized by adding 4.7 parts by mass of triethylamine (TEA), and then emulsified and dispersed using a homogenizer while gradually adding 354.5 parts by mass of water to obtain a dispersion. Subsequently, a chain extension reaction was carried out with water for 1 hour, and then the dispersion was maintained under reduced pressure and at 50°C to evaporate and remove the methyl ethyl ketone reaction medium, thereby obtaining a polyurethane aqueous dispersion containing approximately 26.4% nonvolatile components.

[0094] (Comparative Examples 2-4) Table 3 shows the breakdown (parts by mass) of each raw material component used in Comparative Examples 2 to 4, along with Comparative Example 1. In Comparative Examples 2 to 4, polyurethane aqueous dispersions were produced in the same manner as in Comparative Example 1, except that the ratio of PCD(1,6-HD) to HMDI and the use of dimethylolpropionic acid (DMPA) as the polyol component (component A) were as shown in Table 3.

[0095] [Table 3]

[0096] (Comparative Example 5) A polyol component (component A) and a polyisocyanate component (component B) were mixed according to the composition shown in Table 3. In particular, in Comparative Example 5, 0.02 parts by mass of an organotin compound (bis(neodecanoyloxy) dioctylstannane, Songwon Industrial Co., Ltd.) was added as a reaction catalyst to obtain a methyl ethyl ketone solution of urethane prepolymer in the same manner as in Comparative Example 1. Subsequently, the solution was cooled to 45°C, 5.9 parts by mass of dimethyl sulfate was added, and a quaternization reaction was carried out. Then, 455.5 parts by mass of water was gradually added while emulsifying and dispersing using a homogenizer to obtain a dispersion. After that, a chain extension reaction with water was carried out for 1 hour, and then the mixture was kept under reduced pressure and at 50°C to evaporate and remove the methyl ethyl ketone reaction medium, thereby obtaining a polyurethane aqueous dispersion with a non-volatile content of approximately 18.6%.

[0097] (Comparative Example 6) Except for not using a reaction catalyst, a polyurethane aqueous dispersion with a non-volatile content of approximately 26.5% was obtained by performing the same procedure as in Comparative Example 5 with the composition shown in Table 3.

[0098] Tables 4-6 show the results of measuring the content of free isocyanate groups relative to the nonvolatile content in the methyl ethyl ketone solution of the synthesized urethane prepolymer, in accordance with JIS K 7301, for Examples 1-17 and Comparative Examples 1-6. Tables 4-6 also show the results of measuring the weight of the nonvolatile content in each polyurethane aqueous dispersion, in accordance with JIS K 6828-1:2003 (Weight of nonvolatile content in polyurethane aqueous dispersions).

[0099] [Table 4]

[0100] [Table 5]

[0101] [Table 6]

[0102] [Evaluation of protein adsorption] The adsorption properties of the polymer compositions described in Example 5, Example 13, and Comparative Example 3 for protein (fibrinogen) were evaluated using the following method. To form polyurethane coatings on a 96-well polypropylene plate using the above polymer compositions, each polymer was isolated by freeze-drying an aqueous dispersion of each polymer composition. These polymers were then dissolved in dichloromethane (CH2Cl2) to obtain a 0.2 (wt / v%) solution, which was then dropped into the 96-well plate and dried to form the polyurethane coatings at the bottom of the plate, which were used as samples. For comparison, coatings were also prepared using PP (polypropylene), which does not exhibit biocompatibility, PMEA, which is known to exhibit high biocompatibility, and a polymer obtained by copolymerizing MPC (2-Methacryloyloxyethyl phosphorylcholine) with BMA (butyl methacrylate) to make it insoluble in water, all of which were formed in the same manner.

[0103] For each of the above samples, the amount of fibrinogen per unit area was 156 μg / cm². 2 After supplying an aqueous solution adjusted to the specified ratio, the mixture was incubated at 37°C for 1 hour. The aqueous solution was then removed, and the wells were washed with PBS(-). Subsequently, 30 μL of a 0.5% SDS+1N NaOH aqueous solution was added to each well to recover the fibrinogen adsorbed in the aqueous phase, and the mixture was incubated for 2 hours. Protein quantification was then performed using the Micro BCA Protein Assay Kit (Thermo Fischer Scientific). The results of the above measurements are shown in Table 7. 3.8 (μg / cm³) on a PP surface that does not exhibit biocompatibility. 2 While a fibrinogen amount of 0.8 (μg / cm³) is adsorbed, the surface of PMEA and MPC polymers, which are known to exhibit biocompatibility, contains 0.8 (μg / cm³) each. 2 ), 1.7 (μg / cm³) 2 It was observed that fibrinogen from ) was adsorbed.

[0104] In contrast to the above, in Examples 5 and 13 according to the present invention, the values ​​were 1.7 (μg / cm³) respectively. 2 ), 0.8 (μg / cm³) 2Adsorption of fibrinogen was observed, indicating that the protein adsorption capacity on the polyurethane film surface in Examples 5 and 13 was comparable to that of PMEA and MPC polymers. On the other hand, the amount of fibrinogen adsorbed on the polyurethane film surface in Comparative Example 5, which did not have a polyoxyethylene structure, was 3.0 μg / cm³. 2 ) and it was shown to exhibit protein adsorption properties similar to PP. The above results demonstrate that, in the present invention, it is possible to suppress protein adsorption by introducing a polyoxyethylene structure into the polyurethane backbone.

[0105] [Table 7]

[0106] [Evaluation of polyurethane coatings created using polyurethane aqueous dispersions] The aqueous dispersions of each polymer composition obtained in Examples 1 to 17 and Comparative Examples 1 to 6 were placed in Teflon® coated petri dishes so that the film thickness after drying would be 200 μm. After drying at 20°C for 3 days and 80°C for 1 hour, they were further dried at 120°C for 30 minutes to fuse the urethane prepolymers dispersed in the aqueous dispersions together, thereby forming polyurethane films, which were then subjected to the following tests.

[0107] (Evaluation of platelet adhesion index) The platelet adhesion test was conducted as follows. Human whole blood, which was purchased experimental blood collected in the United States, was used in the experiment within 5 days after collection. The refrigerated human whole blood was returned to room temperature by leaving it at room temperature for about 30 minutes. Then, inversion mixing was performed 3 times, and centrifugation was carried out at 1500 rpm for 5 minutes using a centrifuge (tabletop centrifuge 2420, KUBOTA). Approximately 500 μL of the supernatant (light yellow semi-transparent) at this time was collected and used as platelet-rich plasma (PRP). After collection, centrifugation was further carried out at 4000 rpm for 10 minutes, and approximately 2 mL of the supernatant (light yellow transparent) was collected and used as platelet-poor plasma (PPP). The platelet concentration in PRP was calculated by counting the platelets in PRP diluted 800-fold with PBS(-) using a hemocytometer, and PRP was diluted with PPP so that the seeding concentration became 3.0×10 7 cells / cm 2 to prepare a platelet suspension.

[0108] The platelet suspension prepared above was placed on the surface of each polyurethane film that had been created and peeled off from the petri dish and sufficiently moistened with physiological saline in advance, at 450 μL (about 300 μL / cm 2 ), and incubated at 37°C for 1 hour to adhere the platelets. Then, the platelet suspension was removed, washed twice with PBS, and then immersed in a 1% glutaraldehyde (25% glutaraldehyde, polyscience, Inc. 01909 diluted 1 / 25 with PBS(-)) solution and incubated at 37°C for 2 hours to immobilize the adhered platelets on the substrate. After immobilization, washing was performed by immersing in PBS(-) (10 minutes), PBS(-):water = 1:1 (8 minutes), and water (8 minutes, 10 minutes) once each. After washing, it was air-dried for 3 hours and then dried in a container containing silica gel for more than 1 day. After drying, the number of platelets adhered to the surface of each polyurethane film was counted by observing the substrate surface with a scanning electron microscope (SEM, KEYENCE, 3D real surface view microscope VE-9800).

[0109] On the other hand, for PET (Polyethylene Terephthalate) membrane surfaces, which are known to be incompatible with blood, the number of platelets adhered to these surfaces using the same method as described above was counted and used as a negative control. The "platelet adhesion index" was standardized by dividing the number of platelets adhered to each polyurethane membrane surface by the count on the PET surface. According to this platelet adhesion index, differences in platelet adhesion frequency due to the condition of the blood used for evaluation are excluded, and the degree of blood compatibility exhibited by the sample surface can be appropriately evaluated.

[0110] Furthermore, in order to clarify the degree of platelet adhesion on biocompatible surfaces, platelet adhesion tests were also performed simultaneously on PMEA, which is known to exhibit high biocompatibility, and on a non-aqueous polymer obtained by copolymerizing MPC with BMA (butyl methacrylate), and these were used as positive controls.

[0111] (Measurement of water resistance) Each polyurethane film prepared as described above was peeled from the petri dish and cut into pieces of a predetermined size (2 cm x 4 cm) to be used as an evaluation sample. The weight of each evaluation sample was measured before and after immersion in tap water (20°C) for 4 hours, and the water resistance of each polyurethane film was evaluated by calculating the weight increase rate using the following formula. Weight increase rate = (Weight after immersion - Weight before immersion) / Weight before immersion × 100 (%)

[0112] (Measurement of mechanical properties) Each polyurethane coating prepared as described above was peeled from the petri dish and cut into strips 10 mm wide and 100 mm long in accordance with JIS K6301 (2010) to be used as evaluation samples for tensile testing. The test was conducted using a tensile testing machine (Orientec Co., Ltd., product name "Tensilon UTM-III-100") with a chuck distance of 50 mm, a tensile speed of 500 mm / min, and a temperature of 23°C (relative humidity 55%). The maximum tensile stress shown by each sample was measured, and the maximum point strength (N / mm²) was calculated by dividing this maximum tensile stress by the initial cross-sectional area of ​​the sample. 2 ) The results of each of the above tests are summarized in Tables 8-10.

[0113] [Table 8]

[0114] [Table 9]

[0115] [Table 10]

[0116] [Evaluation Results] (1) Platelet adhesion test Figure 1 shows the results of plotting the platelet adhesion index on the surface of each polyurethane film composed of the polymer composition according to the present invention against the amount of polyoxyethylene structure introduced into the polymer composition. In Figures 1, 3, and 4, the "PEG introduction amount (wt%)" is indicated as the mass percentage of PEG and branched PEG used as the PEG component relative to the total mass of the polyol containing the PEG component and the polyisocyanate used in the production of each polymer.

[0117] Figure 2 also shows the platelet adhesion count on each polyurethane film surface for Comparative Examples 1 to 6, which do not contain PEG. In Figures 1 and 2, the degree of platelet adhesion (platelet adhesion index) observed on each sample surface is shown, with the platelet adhesion count observed on the PET surface set to 100. In Figure 1, etc., "○" indicates a polymer with a polyoxyethylene structure in the main chain, and "▲" indicates a polymer with a polyoxyethylene structure in the side chain portion.

[0118] As shown in Figure 1, in each polyurethane coating composed of the polymer composition according to the present invention with introduced PEG, differences in platelet adhesion index occurred depending on the difference in polymer structure and the amount of introduced PEG. However, all coatings showed a platelet adhesion index of 40 or less, and in particular, it was shown that biocompatibility was improved compared to polyurethane without the introduced polyoxyethylene structure shown in Figure 2 (Comparative Examples 1-6).

[0119] Furthermore, as shown in Table 9, while PMEA and MPC polymers, which exhibit high biocompatibility, showed a platelet adhesion index of approximately 15 or less (gray area in Figure 1), the polymer composition according to the present invention, having a predetermined composition, obtained a platelet adhesion index of the same or lower level as those polymers. Therefore, it was inferred that the polymer composition according to the present invention exhibits high biocompatibility.

[0120] In particular, in the polymer in which a polyoxyethylene structure was introduced into the side chain portion of the polymer (▲), even when the amount of polyoxyethylene structure introduced was 3.0 wt% (Example 7), it showed a platelet adhesion index at or below that of PMEA, etc., suggesting that high biocompatibility can be achieved by introducing a small amount of polyoxyethylene structure. On the other hand, as shown in Figure 2, it was found that the surfaces of each polyurethane coating without PEG (Comparative Examples 1-6) exhibited crystalline plate adhesion comparable to that of PET, which does not exhibit biocompatibility, regardless of the microstructure of the polyurethane. This result suggests that the biocompatibility exhibited by the polyurethane coating according to the present invention is not due to the structure of the polyurethane itself, but rather to the polyoxyethylene structure (PEG) introduced into the polyurethane in the present invention.

[0121] (2) Strength test of polyurethane coating Figure 3 shows the relationship between the maximum point strength exhibited by each polyurethane film composed of the polymer composition according to the present invention and the amount (wt%) of PEG (polyoxyethylene structure) introduced into the polyurethane. As shown in Figure 3, a tendency was generally observed for the maximum point strength to decrease as the amount of polyoxyethylene structure introduced increased. On the other hand, it was shown that by keeping the amount of PEG introduced to 30 wt% or less, a strength comparable to that of a polyurethane film without polyoxyethylene structure (Comparative Example 1) could be maintained.

[0122] Furthermore, a tendency for higher maximum point strength was observed, particularly in polymers using polycarbonate polyols as polyols other than the PEG component and aliphatic polyisocyanates as polyisocyanates, as well as in polymers in which polyoxyethylene structures were introduced into the side chain portion of the polymer.

[0123] (3) Water resistance evaluation test Figure 4 shows the relationship between the weight increase rate of each polyurethane film composed of the polymer composition according to the present invention when immersed in water and the amount of PEG (wt%) introduced into the polyurethane. As shown in Figure 4, generally, as the amount of PEG introduced increases, the water content upon immersion in water increases, and a tendency for water resistance to decrease is observed. On the other hand, by keeping the amount of PEG introduced to 30 wt% or less, a weight increase rate similar to that of a polyurethane film without a polyoxyethylene structure (Comparative Example 1) was maintained, demonstrating that it possessed the desired water resistance. Furthermore, no elution into the aqueous phase was observed in any of the polymer compositions, indicating that they were not water-soluble.

[0124] Furthermore, it was shown that polymers using polycarbonate polyols as polyols other than the PEG component, and aliphatic polyisocyanates as polyisocyanates, exhibit a smaller weight increase due to water content compared to polymers using polyols / polyisocyanates of other structures. Furthermore, in particular, in polymers in which a polyoxyethylene structure was introduced into the side chain portion of the polymer (Example 5), a tendency was observed to suppress the increase in the weight increase rate associated with an increase in the amount of polyoxyethylene structure introduced. [Industrial applicability]

[0125] According to the polymer composition of the present invention, biocompatibility derived from polyoxyethylene structures such as PEG is exhibited, and it is possible to form a water-insoluble film, making it possible to easily form a biocompatible surface.

Claims

1. A polymer composition comprising a polymer having urethane bonds in the polymer main chain and a polyoxyethylene structure in the side chain portion relative to the polymer main chain, The polymer main chain includes structures derived from at least one of the polyisocyanates tetramethylene diisocyanate, dodecamethylene diisocyanate, hexamethylene diisocyanate (HMDI), 2,2,4-trimethylhexamethylene diisocyanate, 2,4,4-trimethylhexamethylene diisocyanate, lysine diisocyanate, 2-methylpentane-1,5-diisocyanate, and 3-methylpentane-1,5-diisocyanate, as well as structures derived from polycarbonate polyols. The mass proportion of the structure derived from the polycarbonate polyol is 90 parts by mass or more out of 100 parts by mass of the structure derived from polyols other than polyethylene glycol. A polymer composition characterized by being used for the purpose of forming a surface that suppresses nonspecific adsorption of proteins.

2. The polymer composition according to claim 1, characterized in that it is used for the purpose of forming a surface with a low frequency of platelet adhesion when used in contact with blood, by suppressing non-specific adsorption of proteins.

3. The polymer composition according to claim 1, characterized in that it is used for the purpose of forming an antifouling surface by reducing the frequency of bacterial adhesion through the suppression of nonspecific adsorption of proteins.

4. An aqueous dispersion characterized by dispersing fine particles containing the polymer composition described in any one of claims 1 to 3 in an aqueous phase.

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