CN117062637A

CN117062637A - Medical composition and use thereof

Info

Publication number: CN117062637A
Application number: CN202280022599.1A
Authority: CN
Inventors: 田中贤; 小林慎吾; 西村文男; 枝连未奈里; 西浦圣人
Original assignee: Dai Ichi Kogyo Seiyaku Co Ltd; Kyushu University NUC
Current assignee: Kyushu University NUC; DKS Co Ltd
Priority date: 2021-03-31
Filing date: 2022-03-30
Publication date: 2023-11-14
Also published as: JP2023026365A

Abstract

The present invention provides a medical composition which can impart biocompatibility to the surface of a medical device, etc., and uses thereof, etc. One embodiment of the present invention is a medical composition comprising a urethane resin having a urethane bond in a main chain and a polyoxyethylene structure in the main chain and/or a side chain. In another embodiment of the present invention, the urethane resin has a structural unit derived from a polycarbonate polyol and a structural unit derived from an aliphatic isocyanate, and has at least 1 or more urea bonds.

Description

Medical composition and use thereof

Technical Field

The present invention relates to a medical composition and use thereof.

Background

In general, when a surface of a substance which is not derived from a living body, such as a tissue or blood in a living body, is brought into contact with the surface, it is known that the surface of the substance is recognized as a foreign substance, a protein in the tissue of the living body is nonspecifically adsorbed to the surface and denatured, and activation of a coagulation system, a complement system, a platelet system, and the like occurs, and adhesion of blood cells such as platelets occurs on the surface. In recent years, it has been known that, focusing on the state of water molecules contained on the surface of a synthetic polymer having a predetermined structure: by forming a surface capable of containing water molecules in a state called "intermediate water", it is possible to prevent nonspecific adsorption of proteins to the surface and to prevent denaturation of the adsorbed proteins. It can be seen that: on the surface, the adhesion frequency of platelets and the like is reduced when the surface is in contact with blood and the like, and inflammation generated when the surface is in contact with tissue in a living body can be suppressed (for example, refer to non-patent document 1).

The presence of the "intermediate water" suppresses nonspecific adsorption of proteins to the substance surface, and thus can bring about biocompatibility (blood compatibility). For example, in various medical devices, it is desirable to achieve a state having the above-described biocompatibility (blood compatibility) because a phenomenon such as non-specific adsorption of proteins due to contact of a tissue, blood, or the like in a living body with a surface of a substrate of the medical device or the like is suppressed (for example, refer to patent document 1).

As a method for imparting biocompatibility to a surface of a medical device that contacts a tissue, blood, or the like in a living body, for example, as described in patent document 2, the following means are generally used: the coating is provided by coating a substance having a biological affinity on the surface of a base material which is suitable for the mechanical properties of the medical device.

Prior art literature

Non-patent literature

Non-patent document 1: japanese society of next Vol.51No.9 (2015) P.15-25

Disclosure of Invention

Technical problem to be solved by the invention

Medical devices for which biocompatibility is desired are various, and materials constituting the medical devices are also various. Further, the characteristics required to be ensured while imparting biocompatibility vary depending on the type of medical instrument, the use, and the like. Therefore, the characteristics required for a coating agent used for imparting biocompatibility or the like to the surface of a medical device are various, and there is an infinite expectation for proposals of a coating agent exhibiting biocompatibility or the like having new characteristics.

On the other hand, the mechanism by which a substance exhibits biocompatibility is unknown, and in particular, the correlation of the specific structure of the substance with the presentation of biocompatibility is unknown. Therefore, there is no policy to design a coating agent or the like exhibiting the above-described biocompatibility, and it is possible to understand whether or not a substance exhibits biocompatibility only by evaluating the substance actually synthesized or the like.

From this point of view, in the medical field, there is a strong demand for new development of medical materials capable of imparting biocompatibility to surfaces of various medical instruments and the like.

The present invention has been made in view of the above circumstances, and an object thereof is to provide a medical composition capable of imparting biocompatibility to a medical device surface or the like, and use thereof, and the like.

Means for solving the problems

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, found that: the above object can be achieved by appropriately using a urethane resin having a specific structure, and the present invention has been completed.

That is, the present invention includes the subject matter described in the following items.

Item 1

A medical composition comprising a urethane resin,

the urethane resin has a urethane bond in the main chain and a polyoxyethylene structure in the main chain and/or a side chain.

Item 2

The medical composition according to claim 1, wherein the urethane resin has a structural unit derived from a polycarbonate polyol.

Item 3

The medical composition according to claim 1, wherein the urethane resin has a structural unit derived from an isocyanate compound.

Item 4

A medical composition comprising a urethane resin,

the urethane resin has structural units derived from a polycarbonate polyol and structural units derived from an aliphatic isocyanate, and has at least 1 urea bond or more.

Item 5

The medical composition according to claim 4, wherein the urethane resin has a polyoxyethylene structure in a main chain and/or a side chain.

Item 6

The medical composition according to any one of claim 1 to 5, which is an aqueous dispersion.

Item 7

A protein adsorption inhibitor comprising the medical composition according to any one of items 1 to 6.

Item 8

A platelet adsorption inhibitor comprising the medical composition according to any one of items 1 to 6.

Item 9

A medical fiber treatment agent comprising the medical composition according to any one of items 1 to 6.

Item 10

A medical device comprising a coating film of the medical composition according to any one of items 1 to 6.

Item 11

A medical fiber comprising the medical fiber-treating agent according to claim 9.

Item 12

A method of inhibiting protein adsorption, comprising the step of forming a coating film of the medical composition according to any one of items 1 to 6 on a substrate.

Item 13

A method of inhibiting platelet adsorption, comprising the step of forming a coating of the medical composition according to any one of items 1 to 6 on a substrate.

Item 14

A method of treating a medical fiber, comprising the step of treating the medical composition according to any one of items 1 to 6 with a medical fiber.

Effects of the invention

According to the medical composition of the present invention, biocompatibility can be imparted to the surface of a medical device or the like.

Drawings

Fig. 1 is a graph showing platelet adhesion properties of a polymer composition of the present invention.

Fig. 2 is a graph showing the mechanical strength of the polymer composition of the present invention.

FIG. 3 is a graph showing the weight increase rate when the polymer composition of the present invention contains water.

Fig. 4 is a graph showing protein adhesion properties of the polymer composition of the present invention.

Detailed Description

Hereinafter, embodiments of the present invention will be described in detail. In the present specification, the expressions "including" and "comprising" include the concepts of "including", "containing", "substantially including" and "including only".

1. Medical composition

The medical composition of the present invention contains a urethane resin, and for example, contains the following medical composition a and medical composition B.

Medical composition a: the urethane resin has a urethane bond in the main chain and a polyoxyethylene structure in the main chain and/or a side chain.

Medical composition B: contains a urethane resin having a structural unit derived from a polycarbonate diol and a structural unit derived from an aliphatic isocyanate, and having at least 1 or more urea bonds.

The following describes the patterns of the medical compositions a and B.

(medical composition A)

The medical composition a contains a urethane resin. As described above, the urethane resin has a urethane bond in the main chain, and at least one of the main chain and the side chain has a polyoxyethylene structure. Hereinafter, the "urethane resin a" contained in the medical composition a will be described.

The urethane resin a is not particularly limited as long as it has the polyoxyethylene structure, and may contain the same structural unit as a known urethane resin in a molecule.

The urethane resin a may have 1 or 2 or more structural units derived from a polyol. Further, the urethane resin a may have 1 or 2 or more structural units derived from an isocyanate compound. The urethane resin a may have both of 1 or 2 or more structural units derived from a polyol and 1 or 2 or more structural units derived from an isocyanate compound. In addition, the structural unit derived from the polyol may refer to, for example: and a group in which a hydrogen atom of a hydroxyl group in the polyol is removed. Further, the structural unit derived from the isocyanate compound may refer to, for example: a group formed by adding a hydrogen atom to a nitrogen atom of an isocyanate group in an isocyanate compound.

The type of the polyol used to form the structural unit derived from the polyol is not particularly limited, and for example, known polyols used to form urethane resins can be widely exemplified. For example, as the polyol, there may be mentioned: polycarbonate polyols, polyester polyols, polyether polyols, hydrocarbon polyols, low molecular weight polyols having a molecular weight of 400 or less, and the like.

The polycarbonate polyol is not particularly limited, and for example, a known polycarbonate polyol used for forming a urethane resin can be widely used. For example, a polycarbonate polyol obtained by a reaction between a polyol compound and a carbonate compound can be mentioned. The polyol compounds include: aliphatic polyols, alicyclic polyols. Further, as the carbonate compound, there may be mentioned: carbonate derivatives such as carbonate and phosgene.

The polycarbonate polyol preferably has a structure derived from an aliphatic polyol. Examples of the aliphatic polyol include: ethylene glycol, diethylene glycol, 1, 4-butanediol, 1, 3-butanediol, 2, 3-butanediol, 1, 3-propanediol, 1, 2-propanediol, 1, 6-hexanediol, 3-methyl-1, 5-pentanediol, neopentyl glycol, etc.

The structure derived from the polyol compound contained in the polycarbonate polyol may be 1 or 2 or more. Further, the structure derived from the carbonate derivative contained in the polycarbonate polyol may be 1 or 2 or more.

The polyester polyol is not particularly limited, and examples thereof include known polyester polyols for forming urethane resins. Examples of the polyester polyol include an esterified condensate obtained by reacting a polyhydric alcohol compound with a polycarboxylic acid, and a polyester polyol having a structure terminating at the end with a hydroxyl group. The polyol compound used for forming the polyester polyol may be exemplified by the same kind as the polyol compound used for forming the polycarbonate polyol. Examples of the polycarboxylic acid include: succinic acid, glutaric acid, adipic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid, trimellitic acid, tetrahydrofuranic acid, endo-methyltetrahydrofuranic acid, or hexahydrophthalic acid, and the like.

The structure derived from the polyol compound contained in the polyester polyol may be 1 or 2 or more. The structure derived from the polycarboxylic acid contained in the polyester polyol may be 1 or 2 or more.

The polyether polyol is not particularly limited, and examples thereof include known polyether polyols for forming urethane resins. For example, polyether polyols obtained by addition polymerization of a polyol compound and an alkylene oxide can be cited. The polyol compound used for forming the polyester polyol may be exemplified by the same kind as the polyol compound used for forming the polycarbonate polyol. As the alkylene oxide, for example, there may be exemplified: alkylene oxides such as ethylene oxide, propylene oxide, and butylene oxide. In the case where the urethane resin a has a structural unit derived from a polyether polyol, the structural unit may be a polyoxyethylene structure equivalent to that in the urethane resin a.

The polyether polyol may have 1 or 2 or more structures derived from a polyol compound. The alkylene oxide-derived structure contained in the polyether polyol may be 1 or 2 or more.

The hydrocarbon polyol is not particularly limited, and examples thereof include known hydrocarbon polyols for forming urethane resins. For example, the hydrocarbon polyol is a polyol in which the terminal of a hydrocarbon chain is terminated with a hydroxyl group (translator: capping), and examples thereof include: polybutadiene polyol, polyisoprene polyol, hydrogenated polybutadiene polyol, hydrogenated polyisoprene polyol, or the like.

Examples of the low molecular weight polyol having a molecular weight of 400 or less include: ethylene glycol, diethylene glycol, triethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 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, glycerol, trimethylolpropane, and the like. In the case where the structural unit derived from the polyol in the urethane resin a is formed from a low-molecular-weight polyol having a molecular weight of 400 or less, the content ratio of the polyoxyethylene structure in the urethane resin a can be increased.

In the urethane resin a, the polyol used for forming the structural unit derived from the polyol preferably contains at least the above polycarbonate polyol. In this case, the medical composition a is likely to form a film excellent in water resistance and strength, and the film is likely to inhibit nonspecific adsorption of proteins and also is likely to inhibit adsorption of platelets.

The content ratio of the structural units derived from the polycarbonate polyol (excluding the polyoxyethylene structural units) in the urethane resin a may be 80 mass% or more, preferably 90 mass% or more, more preferably 95 mass% or more, and still more preferably 99 mass% or more with respect to the total mass of the structural units derived from the polyol. The structural unit derived from a polyol contained in the urethane resin a may be only a structural unit derived from a polycarbonate polyol.

The polyol preferably has 2 or more hydroxyl groups, and particularly preferably has 2 hydroxyl groups.

The type of the isocyanate compound used to form the structural unit derived from the isocyanate compound is not particularly limited, and for example, known isocyanate compounds used to form urethane resins can be widely used. For example, as the isocyanate compound, there may be mentioned: aliphatic isocyanates, alicyclic isocyanates, aromatic isocyanates, and the like.

The aliphatic isocyanate is not particularly limited, and examples thereof include known aliphatic isocyanates for forming urethane resins. Examples of the aliphatic isocyanate include: 1 or more of tetramethylene diisocyanate, dodecamethylene diisocyanate, hexamethylene diisocyanate (HMDI), 2, 4-trimethylhexamethylene diisocyanate, 2, 4-trimethylhexamethylene diisocyanate, lysine diisocyanate, 2-methylpentane-1, 5-diisocyanate, 3-methylpentane-1, 5-diisocyanate, and the like.

The alicyclic isocyanate is not particularly limited, and for example, zhou Zhizhi cyclic isocyanate used for forming a urethane resin can be widely exemplified. Examples of the alicyclic isocyanate include: 1 or 2 or more of isophorone diisocyanate (IPDI), hydrogenated xylene diisocyanate, 4' -dicyclohexylmethane diisocyanate (H12 MDI), 1, 4-cyclohexane diisocyanate, methylcyclohexylene diisocyanate, 1, 3-bis (isocyanatomethyl) cyclohexane, and the like.

The aromatic isocyanate is not particularly limited, and examples thereof include known aromatic isocyanates used for forming urethane resins. Examples of the aromatic isocyanate include: toluene Diisocyanate (TDI), 2 '-diphenylmethane diisocyanate, 2,4' -diphenylmethane diisocyanate, 4 '-diphenylmethane diisocyanate (MDI), 4' -dibenzyl diisocyanate, 1, 5-naphthalene diisocyanate, xylylene diisocyanate, 1, 3-phenylene diisocyanate, 1, 4-phenylene diisocyanate, or the like.

In the urethane resin a, the isocyanate compound used for forming the structural unit derived from the isocyanate compound is preferably an aliphatic isocyanate. In this case, the medical composition a is easy to form a coating film having excellent strength, and is easy to suppress an increase in weight when immersed in an aqueous phase.

The content ratio of the structural unit derived from the aliphatic isocyanate in the urethane resin a may be 80 mass% or more, preferably 90 mass% or more, more preferably 95 mass% or more, and still more preferably 99 mass% or more, relative to the total mass of the structural units derived from the isocyanate compound. The structural unit derived from the isocyanate compound contained in the urethane resin a may be only a structural unit derived from an aliphatic isocyanate.

The isocyanate compound preferably has 2 or more isocyanate groups, and particularly preferably has 2 isocyanate groups.

In addition, the isocyanate compound may have a polyoxyethylene site, and in this case, a polyoxyethylene structure may be introduced into the urethane resin a.

As described above, at least one of the main chain and the side chain of the urethane resin a may have a polyoxyethylene structure. Specifically, the urethane resin a has a polyoxyethylene unit in at least one of a main chain and a side chain. The polyoxyethylene structure is present by being covalently bonded to at least one of the main chain and the side chain of the urethane resin a.

In the urethane resin a, the number average molecular weight of the polyoxyethylene unit is not particularly limited, and is, for example, 100 to 10000, preferably 150 to 5000, more preferably 200 to 3000. In the present specification, the number average molecular weight of the polyoxyethylene unit means a value measured by GPC.

The urethane resin a having a polyoxyethylene structure can be obtained by using polyethylene glycol (PEG) or branched polyethylene glycol (PEG) as a raw material at the time of polymerization of the urethane resin, for example, as described later. Alternatively, the urethane resin a having a polyoxyethylene structure may be obtained by reacting polyethylene glycol (PEG) or branched polyethylene glycol (PEG) with a urethane resin.

In the urethane resin a, the content ratio of the polyoxyethylene structure, that is, the content ratio of the polyoxyethylene unit is not particularly limited. The content ratio of the polyoxyethylene unit in all the constituent units of the urethane resin a may be 1 mass% or more and 50 mass% or less. In this case, the coating film obtained from the medical composition a can have good biocompatibility and strength. The content ratio of the polyoxyethylene unit in all the constituent units of the urethane resin a is preferably 2% by mass or more, more preferably 3% by mass or more, and still more preferably 5% by mass or more. The content of the polyoxyethylene unit in all the constituent units of the urethane resin a is preferably 40 mass% or less, more preferably 30 mass% or less, and still more preferably 20 mass% or less. When the content of the polyoxyethylene units in all the constituent units of the urethane resin a is 20 mass% or less, the strength of the film is easily improved, and the water content when immersed in water is easily increased to the same extent as that of a urethane resin film containing no polyoxyethylene structure.

When the polyoxyethylene structure is present in the side chain of the urethane resin a, a film having excellent biocompatibility and strength can be formed even in a small amount, and an increase in water content can be easily suppressed, as compared with the case where the polyoxyethylene structure is present in the main chain. For this reason, although a definite explanation is not expected, it is presumed that: when the urethane resin a is brought into contact with water, the hydrophilic polyethylene structure introduced into the hydrophobic polyurethane skeleton is rearranged so as to be aggregated at the interface portion with the water within the degree of freedom of the molecular chain, and thus excellent biocompatibility can be exhibited even by a small amount of the introduced polyethylene structure. In particular, in view of the ease of rearrangement of the polyoxyethylene structure, if the polyoxyethylene structure is present in the polymer main chain, both ends of the polyoxyethylene are fixed, but when present in the side chain, only one end is fixed, so that the degree of freedom of rearrangement becomes large, and it is easy to exhibit biocompatibility or the like.

In addition, when the polymer main chain does not contain a polyoxyethylene structure but only a polyoxyethylene structure is contained in a side chain portion, the film obtained from the medical composition a tends to have high strength even in an aqueous state.

The method for producing the urethane resin a is not particularly limited, and for example, a known method for producing a urethane resin can be widely used. In one embodiment of the method for producing the urethane resin a, the method may further include a step of polymerizing the polyol and the isocyanate compound to obtain the urethane resin a. In the case where the polyol and the isocyanate compound do not have a polyoxyethylene unit, polyethylene glycol (PEG) and/or branched polyethylene glycol (PEG) may be used as a raw material in the above polymerization reaction. Based on this, a urethane resin a having a polyoxyethylene structure can be obtained.

The conditions for the polymerization reaction are not particularly limited, and may be, for example, the same conditions as those for the polymerization reaction of a known polyol and an isocyanate compound. The polymerization reaction temperature may be, for example, about 30 to 130 ℃ and the reaction time may be about 30 minutes to 50 hours. The polymerization reaction may be carried out using a catalyst, for example, a metal catalyst such as an amine compound, tin octoate, bismuth octoate, or the like.

In the above polymerization reaction, the ratio of the polyol and the isocyanate compound to be used is not particularly limited. For example, the molar ratio of isocyanate groups to hydroxyl groups may be set to 1 or more, preferably 1.1 or more, more preferably 1.2 or more, and preferably 3 or less. Based on this, the emulsion of the urethane resin a is easily stabilized, and the viscosity is easily brought into an appropriate range.

The polymerization reaction may be carried out in a solvent. As the solvent, for example, an organic solvent having no active hydrogen, which is generally used in the synthesis of polyurethane, can be widely used, and examples thereof include: dioxane, methyl ethyl ketone, dimethylformamide, tetrahydrofuran, N-methyl-2-pyrrolidone, toluene, propylene glycol monomethyl ether acetate, and the like.

In the above polymerization reaction, polyethylene glycol (PEG) and/or branched polyethylene glycol (PEG) may be used. As the polyethylene glycol, for example, a linear polyethylene glycol having a number average molecular weight of 100 to 10000, preferably 150 to 5000, more preferably 200 to 3000 can be used. Examples of the branched polyethylene glycol include polyols having the following structures: the hydrogen atom contained in the alkylene group having a hydroxyl group at both ends is substituted with a group having a polyoxyethylene structure. Polyethylene glycol (PEG) and branched polyethylene glycol (PEG) are commercially available.

The above polymerization reaction uses a linear polyethylene glycol, whereby a urethane resin a having a polyoxyethylene structure in the main chain can be produced. Specifically, a urethane resin a having a polyoxyethylene structure bonded by urethane bonds at both ends of a linear polyethylene glycol can be produced. Further, by using branched polyethylene glycol in the polymerization reaction, a urethane resin a having a polyoxyethylene structure in a side chain can be produced. In this case, the main chain of the urethane resin a does not have a polyoxyethylene structure.

The urethane resin produced by the polymerization reaction of the polyol and the isocyanate compound is, for example, one in which an isocyanate group is present at the polymer terminal. Therefore, by using the terminal isocyanate group, the chain length can be further extended as described later. The urethane resin having an isocyanate group at the end is described as a urethane prepolymer. As described later, the urethane prepolymer may be dispersed in an aqueous phase and emulsified.

The urethane prepolymer may have structural units other than the structural units derived from the polyol, the structural units derived from the isocyanate compound, and the polyoxyethylene unit. The other structural unit is, for example, 10 mass% or less, preferably 5 mass% or less, and more preferably 1 mass% or less relative to the urethane prepolymer.

(medical composition B)

The medical composition B contains a urethane resin. The urethane resin has a structural unit derived from a polycarbonate polyol and a structural unit derived from an aliphatic isocyanate, and has at least 1 urea bond or more, as described above. Hereinafter, the "urethane resin B" contained in the medical composition B will be described.

The urethane resin B may have 1 or 2 or more structural units derived from a polycarbonate polyol and 1 or 2 or more structural units derived from an aliphatic isocyanate. The structural unit derived from the polycarbonate polyol is, for example, a group in which a hydrogen atom of a hydroxyl group in the polycarbonate polyol is removed. The structural unit derived from an aliphatic isocyanate is, for example, a group formed by adding a hydrogen atom to a nitrogen atom of an isocyanate group in an aliphatic isocyanate.

The polycarbonate polyol is not particularly limited, and for example, known polycarbonate polyols for forming urethane resins can be widely used. For example, a polycarbonate polyol obtained by a reaction between a polyol compound and a carbonate compound can be mentioned. The polyol compounds include: aliphatic polyols, alicyclic polyols. Further, as the carbonate compound, there may be mentioned: carbonate derivatives such as carbonate and phosgene.

The polycarbonate polyol preferably has 2 or more hydroxyl groups, and particularly preferably has 2 hydroxyl groups.

The aliphatic isocyanate is not particularly limited, and examples thereof include known aliphatic isocyanates used for forming urethane resins. Examples of the aliphatic isocyanate include: 1 or more of tetramethylene diisocyanate, dodecamethylene diisocyanate, hexamethylene diisocyanate (HMDI), 2, 4-trimethylhexamethylene diisocyanate, 2, 4-trimethylhexamethylene diisocyanate, lysine diisocyanate, 2-methylpentane-1, 5-diisocyanate, 3-methylpentane-1, 5-diisocyanate and the like.

The aliphatic isocyanate preferably has 2 or more isocyanate groups, and particularly preferably has 2 isocyanate groups.

The urethane resin B has both structural units derived from a polycarbonate polyol and structural units derived from an aliphatic isocyanate, and thus the film obtained from the medical composition B is particularly excellent in strength, in addition to being easy to suppress non-specific adsorption of proteins and to suppress adsorption of platelets.

The urethane resin B has a urea bond. The urea bond can be formed by elongating the chain length with a chain length elongation agent using an isocyanate group at the end of a urethane prepolymer described later as a base point.

The urethane resin B may have a polyoxyethylene structure in the main chain and/or the side chain. Specifically, the urethane resin B may have a polyoxyethylene unit in at least one of a main chain and a side chain. In addition, the polyoxyethylene structure may exist by being covalently bonded to at least one of the main chain and the side chain of the urethane resin B.

In the urethane resin B, the number average molecular weight of the polyoxyethylene unit is not particularly limited, and may be, for example, 100 to 10000, preferably 150 to 5000, more preferably 200 to 3000. In the present specification, the number average molecular weight of the polyoxyethylene unit means a value measured by GPC.

The urethane resin B having a polyoxyethylene structure can be obtained by using polyethylene glycol (PEG) or branched polyethylene glycol (PEG) as a raw material at the time of polymerization of the urethane resin, for example, as described later. Alternatively, the urethane resin B having a polyoxyethylene structure may be obtained by reacting polyethylene glycol (PEG) or branched polyethylene glycol (PEG) with a urethane resin.

In the case where the urethane resin B has a polyoxyethylene structure, the content ratio of polyoxyethylene units is not particularly limited. The content of the polyoxyethylene unit in all the constituent units of the urethane resin B may be 50 mass% or less. In this case, the coating film obtained from the medical composition B can have good biocompatibility and strength. The content ratio of the polyoxyethylene unit in all the constituent units of the urethane resin B is preferably 0.1 mass% or more, more preferably 1 mass% or more, and still more preferably 3 mass% or more. The content of the polyoxyethylene unit in all the constituent units of the urethane resin B is preferably 40 mass% or less, more preferably 30 mass% or less, and still more preferably 20 mass% or less.

When the polyoxyethylene structure is present in the side chain of the urethane resin B, a film having excellent biocompatibility and strength can be formed even in a small amount as compared with the case of being present in the main chain, and the increase in water content can be easily suppressed. The reason for this can be estimated in the same manner as in the case of the urethane resin a described above.

The method for producing the urethane resin B is not particularly limited, and for example, a known method for producing a urethane resin can be widely used. As an example of the method for producing the urethane resin B, the method for producing the urethane resin B includes a step of polymerizing a polycarbonate polyol and an aliphatic isocyanate to obtain the urethane resin B.

The conditions for the polymerization reaction are not particularly limited, and may be, for example, the same conditions as those for the polymerization reaction of a known polycarbonate polyol and an aliphatic isocyanate. The polymerization reaction temperature may be, for example, about 30 to 130 ℃ and the reaction time may be about 30 minutes to 50 hours. Catalysts which may also be used in the polymerization reaction include, for example: amine compounds, tin octoate, bismuth octoate, and other metal catalysts.

In the above polymerization reaction, the use ratio of the polycarbonate polyol and the aliphatic isocyanate is not particularly limited. For example, the molar ratio of isocyanate groups to hydroxyl groups may be 1 or more, preferably 1.1 or more, more preferably 1.2 or more, and preferably 3 or less. Based on this, the emulsion of the urethane resin B is easily stabilized, and the viscosity is easily brought into an appropriate range.

The polymerization reaction may be carried out in a solvent. As the solvent, for example, an organic solvent having no active hydrogen, which is generally used for the synthesis of polyurethane, can be widely used, and examples thereof include: dioxane, methyl ethyl ketone, dimethylformamide, tetrahydrofuran, N-methyl-2-pyrrolidone, toluene, propylene glycol monomethyl ether acetate, and the like.

In the above polymerization reaction, polyethylene glycol (PEG) and/or branched polyethylene glycol (PEG) may be used. As the polyethylene glycol, for example, a linear polyethylene glycol having a number average molecular weight of 100 to 10000, preferably 150 to 5000, more preferably 200 to 3000 can be used. Examples of the branched polyethylene glycol include a polyol having the structure in which a hydrogen atom contained in an alkylene group having a hydroxyl group at both ends is substituted with a group having a polyoxyethylene structure. Polyethylene glycol (PEG) and branched polyethylene glycol (PEG) are commercially available.

By using a linear polyethylene glycol in the polymerization reaction, a urethane resin B having a polyoxyethylene structure in the main chain can be produced. Specifically, a urethane resin B having a polyoxyethylene structure synthesized by urethane bond bonds at both ends of a linear polyethylene glycol can be produced. Further, by using branched polyethylene glycol in the above polymerization reaction, a urethane resin B having a polyoxyethylene structure in a side chain can be produced. In this case, the main chain of the urethane resin B does not have a polyoxyethylene structure.

The urethane resin produced by polymerization of the polycarbonate polyol and the aliphatic isocyanate has an isocyanate group at the polymer end, for example. From this terminal isocyanate group, the chain length is further extended, thereby producing a urethane resin B. By extending the chain length, urea bonds are formed in the urethane resin B. The urethane resin having an isocyanate group at the end, that is, the urethane prepolymer, may be dispersed in an aqueous phase and emulsified as described later, and after this emulsification, the urethane prepolymer is reacted with a chain extender, whereby the urethane resin B having a urea bond formed can be obtained.

The urethane prepolymer may have structural units other than structural units derived from a polycarbonate polyol, structural units derived from an aliphatic isocyanate, and polyoxyethylene units optionally contained. The other structural unit is, for example, 10 mass% or less, preferably 5 mass% or less, and more preferably 1 mass% or less relative to the urethane prepolymer.

(aqueous dispersion)

The medical composition of the present invention includes the medical composition a and the medical composition B as described above. The mode of the medical composition of the present invention is not particularly limited, and an aqueous dispersion is preferable.

The method for producing the aqueous dispersion is not particularly limited, and for example, a known method for producing a urethane resin dispersion can be widely used. For example, the urethane prepolymer is emulsified in an aqueous phase (i.e., water) to obtain an aqueous dispersion. In this emulsification, the chain length of the urethane prepolymer can be extended by allowing the chain extender to coexist, and thus the urethane resin can be increased in molecular weight. The chain length of the urethane prepolymer is extended with a chain length extender, thereby forming urea bonds in the resulting urethane resin.

The chain extender is not particularly limited, and specifically, a known compound used for extending the chain length of the urethane prepolymer can be used. As chain length extenders, there may be exemplified: polyamines such as ethylenediamine, trimethylene diamine, piperazine, isophorone diamine, diethylenetriamine, dipropylenetriamine, triethylenetetramine, etc.; polyhydric alcohols such as ethylene glycol, diethylene glycol, 1, 4-butanediol, 1, 3-butanediol, 2, 3-butanediol, 1, 3-propanediol, 1, 2-propanediol, 1, 6-hexanediol, 3-methyl-1, 5-pentanediol, and neopentyl glycol.

As chain length extenders, water molecules can also be mentioned. Therefore, the urethane prepolymer can be increased in molecular weight by utilizing water molecules present in the aqueous phase, which is the dispersion medium used in the emulsification. On the other hand, when a chain extender having a polyfunctional property such as diethylenetriamine is used, the urethane resin may have a three-dimensional network structure, and flexibility may be imparted based on this, and thus a soft and tough urethane resin may be formed.

When the emulsification of the urethane prepolymer described above is performed, a surfactant may also be used. The surfactant is not particularly limited, and examples thereof include: nonionic surfactants, anionic surfactants, cationic surfactants, and the like. These surfactants may be used alone in an amount of 1 or in an amount of 2 or more.

Examples of the nonionic surfactant include: alcohols having 8 to 24 carbon atoms, alkylene alcohols 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, polyol fatty acid esters, oils and fats, alkylene oxide adducts of polypropylene glycol, alkylene oxide adducts of polycyclic phenols, pluronic (registered trademark) nonionic surfactants, and the like. Examples of the alkylene oxide adducts of the polycyclic phenols include: polyoxyethylene distyrylphenyl ether type nonionic surfactant, polyoxyethylene polyoxypropylene distyrylphenyl ether type nonionic surfactant, polyoxyethylene tristyrylphenyl ether type nonionic surfactant, polyoxyethylene polyoxypropylene tristyrylphenyl ether type nonionic surfactant, and the like. In the case where 2 or more alkylene oxides are added to the nonionic surfactant, the addition may be performed in a block manner or may be performed in a random manner.

Examples of the anionic surfactant include: alcohols, enols, anionic compounds of alkylene oxide adducts of the above nonionic surfactants, and the like. Examples of the cationic surfactant include: a monoalkyl trimethyl ammonium salt having 8 to 24 carbon atoms, a dialkyl dimethyl ammonium salt having 8 to 24 carbon atoms, a monoalkyl amine acetate having 8 to 24 carbon atoms, a dialkyl amine acetate having 8 to 24 carbon atoms, an alkyl imidazoline quaternary salt having 8 to 24 carbon atoms, and the like.

The surfactant is preferably a nonionic surfactant, more preferably an alkylene oxide adduct of a polycyclic phenol or a Pluronic (registered trademark) nonionic surfactant, from the viewpoint of excellent miscibility with other components.

The amount of the surfactant used is preferably 0.5 parts by mass or more, more preferably 2 parts by mass or more, and preferably 10 parts by mass or less, more preferably 8 parts by mass or less, based on 100 parts by mass of the urethane prepolymer used.

The urethane prepolymer is emulsified as described above, and chain length extension (high molecular weight) is performed as needed, whereby a urethane resin dispersed in water (polyurethane aqueous dispersion) can be obtained. The average particle diameter of the urethane resin in the aqueous dispersion is not particularly limited, and may be the same as that of a known aqueous polyurethane dispersion. For example, the average particle diameter of the urethane resin is 0.01 to 50. Mu.m, preferably 0.015 to 10. Mu.m, more preferably 0.02 to 5. Mu.m. The average particle diameter of the urethane resin is 50% of the cumulative value measured by a dynamic light scattering method, and can be measured, for example, by using "Microtrack UPA particle size distribution meter MODEL No.9340" manufactured by Nikkin Kagaku Co.

The urethane resins (urethane resin a and urethane resin B) can form fine particles in water by containing a hydrophilic component or the like in a polymer chain, and can be stably dispersed to form an aqueous dispersion, which is a so-called aqueous urethane resin. In addition, in the case where the urethane resin has a polyoxyethylene site as in the case of the urethane resin a, the site may have a function as a hydrophilic segment in the aqueous phase.

By using the medical composition as an aqueous dispersion, a coating film containing a urethane resin can be formed on various substrates. Therefore, when the medical composition is an aqueous dispersion, the aqueous dispersion can be used as a coating agent. The aqueous dispersion can be applied to the surface of a substrate even without containing an organic solvent, and therefore can be used as a base material having low resistance to an organic solvent.

The coating film formed from the medical composition (for example, the coating film formed from the aqueous dispersion liquid contains the urethane resin (specifically, the urethane resin a or the urethane resin B) and has high biocompatibility.

In the present specification, "bioaffinity" refers to a property that suppresses nonspecific adsorption of proteins, the frequency of adhesion of platelets, and the like, and is not easily recognized as a foreign substance when the foreign substance comes into contact with a living body substance or a substance derived from a living body. Specifically, for example, it means that complement activation or platelet activation does not occur, and that the composition is less invasive or noninvasive to tissues. In terms of "biocompatibility", a morphology that is "blood-compatible" is also included. "blood adaptation" means that blood clotting caused by adhesion or activation of platelets is not caused.

In the case where the urethane resin is the urethane resin a and in the case where the urethane resin B has a polyoxyethylene structure, it is presumed that: since a polyoxyethylene structure exhibiting high hydrophilicity is introduced into a hydrophobic polyurethane skeleton, when the polymer is in contact with water, a rearrangement such as aggregation of the polyoxyethylene structure on the polymer surface occurs in order to alleviate interfacial energy or the like in the polymer. Therefore, it is considered that the medical composition a including the urethane resin a easily exhibits characteristics such as biocompatibility due to the polyoxyethylene structure, and it is presumed that: the characteristics of the aqueous dispersion are remarkably exhibited in the form of the aqueous dispersion. The same applies to the medical composition B having a polyoxyethylene structure as the urethane resin B.

The reason why the bioaffinity is exhibited is that the bioaffinity is exhibited by the polyethylene structure (PEG) by incorporating the polyethylene structure (PEG) into the urethane resin is presumed to be that at least the degree of inhibition of the molecular motility of the polyethylene structure or the like is low by the urethane bond, considering that the molecular motility of the polyethylene structure is significantly affected by the polar functional group or the like present in the surroundings. Therefore, the degree of biocompatibility can be adjusted by adjusting the content ratio of the polyoxyethylene structure in the urethane resin, designing the introduction position of the polyoxyethylene structure, or the like.

In the case where the urethane resin is the urethane resin a and in the case where the urethane resin B has a polyoxyethylene structure, suppression of non-specific adsorption of proteins, suppression of the adhesion frequency of platelets, and the like, which are more than or equal to those of a polymer containing PMEA (poly-2-methoxyethyl acrylate) or MPC (2-methacryloyloxyethyl phosphorylcholine) units (for example, MPC polymer, which is a copolymer of MPC and BMA, described later), which is a polymer widely used as a polymer having biocompatibility, are observed, and particularly, significant bioaffinity is observed.

In the prior art, for reasons such as not necessarily high chemical stability of PEG, there is little option for fixing PEG to be water-insoluble, and it is not always possible to obtain a polymer composition which can be widely used as a coating agent or the like having water-solubility resistance and exhibiting biocompatibility, for various substrates.

In addition, in particular, when a water-insoluble polymer produced by incorporating PEG into a part of the structure of another polymer in various ways is used as a coating agent, it is generally necessary to apply the polymer to a substrate in a state of being dissolved in various organic solvents. Therefore, in relation to the material of the substrate to be coated, an organic solvent that can dissolve the polymer while not attacking the substrate must be present, and thus it is difficult to obtain a polymer composition having desired characteristics while being usable for a wide range of substrates.

In contrast, the present inventors have found that, as in the case of the medical composition a, introduction of a polyoxyethylene structure into a urethane resin can maintain the bioaffinity exhibited by PEG, exhibit water-solubility and other properties, and can suppress the nonspecific adsorption of proteins and the frequency of platelet adhesion, thereby ensuring the presence of bioaffinity. In addition, in the case where the urethane resin B has a polyoxyethylene structure in the medical composition B, the present inventors have found that the same phenomenon occurs.

By introducing a polyoxyethylene structure exhibiting high hydrophilicity into a polyurethane skeleton exhibiting hydrophobicity, biocompatibility and the like due to the polyoxyethylene structure can be exhibited. It is assumed that when a structure showing hydrophobicity is adjacent to a structure showing hydrophilicity, a high interfacial energy is generally generated between the two, and thus, the rearrangement of each structure occurs within the range of the degree of freedom of the molecular chain, and there is a tendency to alleviate the interfacial energy and the like in the polymer.

It is assumed that when the urethane resin has a polyoxyethylene structure, the interface energy with the aqueous phase becomes a driving force when the polyurethane film is in contact with the aqueous phase, and the rearrangement occurs, so that the polyoxyethylene structure introduced into the polyurethane skeleton is accumulated on the surface of the polyurethane film. Thus, it can be considered that: as the skeleton used when rendering the polyoxyethylene structure water insoluble, a polyurethane skeleton is preferable. It can be considered that: the polyethylene structure present on the surface of the polyurethane film in contact with the water is in a state of a so-called polymer brush (brush) or the like, and the polyurethane skeleton or the like is covered with the polyethylene structure, thereby preventing the nonspecific adsorption of the protein.

In the present invention, the urethane resin does not necessarily need to have a polyoxyethylene structure, as in the urethane resin B contained in the medical composition B. According to the medical composition B containing the urethane resin B, a film exhibiting biocompatibility can be formed even in the absence of a polyoxyethylene structure, and the film can suppress nonspecific adsorption of proteins or can suppress the frequency of adhesion of platelets (i.e., exhibit antithrombotic property).

In the case where the urethane resin B does not have a polyoxyethylene structure, the adhesion frequency of platelets can be suppressed in addition to the remarkably high strength of the film as compared with the case where the urethane resin B has a polyoxyethylene structure. In addition, when the urethane resin B does not have a polyoxyethylene structure, the water content of the film can be reduced, and therefore the water resistance is high, and as a result, the dimensional stability is high even when used in a wet environment, and the film is excellent in practical use. In addition, when the urethane resin B has a polyoxyethylene structure, the biocompatibility is further improved, and the dispersibility to water is also easily improved.

As described above, the medical composition of the present invention (specifically, medical composition a and medical composition B) can form a coating film having excellent biocompatibility, and is therefore suitable for various medical applications described below. Since the coating film formed from the medical composition of the present invention contains a specific urethane resin (urethane resin a and urethane resin B), it is presumed that: the intermediate water may be formed in the coating film. Although a limited explanation is not necessarily expected, the excellent biocompatibility described above can be exhibited by providing the coating film with intermediate water.

2. Method for using medical composition and use thereof

The medical composition of the present invention contains a urethane resin having a high biocompatibility (specifically, the urethane resin a or the urethane resin B described above), and therefore is suitable for various medical uses.

The use of the medical composition of the present invention can form a coating film. The coating may be formed on various substrates such as various medical instruments and artificial organs, or may be formed on various medical fibers, for example. In the case of forming a coating film using the medical composition of the present invention, the medical composition is the aqueous dispersion.

Since the medical device having a coating film formed from the medical composition of the present invention contains the urethane resin, a biocompatible property can be imparted to the medical device or an artificial organ. That is, a medical device or artificial organ having a coating formed from the medical composition of the present invention can suppress nonspecific adsorption of proteins or can suppress the frequency of adhesion of platelets.

Examples of the "artificial organ" or "medical device" include an artificial organ or medical device having a portion in contact with a biological substance such as blood, and specifically include, but are not limited to, a blood filter, an artificial lung device, a dialysis device, a blood storage bag, a platelet storage bag, a blood circuit, an artificial heart, an indwelling needle, a catheter, a guide wire, a stent, an artificial blood vessel, and an endoscope.

The material or shape of the base material such as "artificial organ" or "medical device" is not particularly limited. For example, as the material, there may be mentioned: natural polymers such as brocade and hemp, nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyurethane, polyamide, polycarbonate, polysulfone, polyethersulfone, poly (meth) acrylate, synthetic polymers such as ethylene-vinyl alcohol copolymer, butadiene-acrylonitrile copolymer, and mixtures thereof. Also, metals, ceramics, composite materials thereof, and the like can be exemplified. Artificial organs or medical devices may also be constructed from a variety of substrates. Examples of the shape of the substrate include porous bodies, fibers, nonwoven fabrics, particles, membranes, sheets, hoses, hollow fibers, and powders.

When the bacteria adhesion preventing property and/or the inflammation suppressing property are provided to an artificial organ, a medical device, or the like, a coating is preferably formed on at least a part of the surface in contact with the tissue or blood in the living body, more preferably on substantially the entire surface in contact with the tissue or blood in the living body.

The medical composition of the present invention can be used as all materials constituting an artificial organ or medical device to be used in contact with tissue or blood in a living body, or as materials constituting a surface portion thereof, and it is desirable that at least a part of a surface of a medical device such as an in-vivo-embedded artificial organ or a therapeutic device, an artificial organ of extracorporeal circulation type, an operation suture wire, a catheter (a catheter for angiography, a guide wire, a catheter for circulation such as a catheter for PTCA, a catheter for stomach tube, a gastrointestinal catheter, a catheter for urologic such as an esophageal tube, a catheter for flexible tube, a urinary catheter such as a urinary catheter, etc.), preferably substantially all of a surface to be contacted with blood is constituted by a coating formed of the medical composition of the present invention. The coating film may be used as a hemostatic agent, an adhesive material for living tissue, a repair material for tissue regeneration, a carrier for a drug delivery system, a hybrid artificial organ such as an artificial pancreas or an artificial liver, an artificial blood vessel, an embolic material, a matrix material for a scaffold for cell engineering, or the like. In these artificial organs or medical devices, surface lubricity may be further provided in order to facilitate insertion into blood vessels or tissues without damaging the tissues.

The medical composition of the present invention may be applied to at least a part of the surface of a substrate constituting a blood filter. The polymer composition of the present invention may be applied to at least a part of the blood bag and the surface of the tube communicating with the blood bag, which surface is in contact with blood. Further, at least a part of the blood-contacting surface of the extracorporeal circulation blood circuit including the device-side blood circuit portion including a tube, arterial filter, centrifugal pump, blood concentrator, heart front gear, and the like, and the operation-side blood circuit portion including a tube, catheter, suction tube, and the like may be coated with the medical composition of the present invention.

When the medical composition of the present invention is used in an indwelling needle assembly, the medical composition may be applied to at least a part of a blood-contacting surface of the indwelling needle assembly, and the indwelling needle assembly includes: an inner needle having an sharp needle tip at a distal end, an inner needle hub provided on a proximal end side of the inner needle, a hollow outer needle into which the inner needle is inserted, an outer needle hub provided on a proximal end side of the outer needle, a protector to which the inner needle is attached and which is movable in an axial direction of the inner needle, and a connecting means for connecting the outer needle hub and the protector. Further, at least a part of the blood-contacting surface of the catheter constituted by the long tube and the adapter connected to the base end (hand side) thereof may be coated with the medical composition of the present invention.

At least a portion of the blood-contacting surface of the lead may also be coated with the medical composition of the present invention. Further, at least a part of the blood-contacting surface of a stent of various shapes, such as a stent having pores formed in the side surface of a hollow tubular body made of a metal material or a polymer material, or a stent formed by braiding a wire of a metal material or a fiber of a polymer material into a cylindrical shape, may be coated with the medical composition of the present invention.

When the medical composition of the present invention is used for artificial heart and lung, the outer surface or outer surface layer of the hollow fiber membrane-external blood perfusion type artificial lung in which a plurality of porous hollow fiber membranes for gas exchange are housed in a case, blood flows on the outer surface side of the hollow fiber membrane, and an oxygen-containing gas flows in the hollow fiber membrane may be used as an artificial lung coated with the polymer composition of the present invention.

The medical composition of the present invention may be coated on at least a part of the blood-contacting surface of a dialysis apparatus comprising: a dialysate circuit comprising at least one dialysate container filled with dialysate and at least one drain container for recovering dialysate; and a liquid feeding means for feeding the dialysate from the dialysate container or from the drain container.

As a method for holding the film of the medical composition of the present invention on the surface of an "artificial organ" or "medical device" or the like, a known method such as a method of introducing by graft polymerization by radiation, electron beam or ultraviolet ray or chemical reaction with a functional group of a base material may be used in addition to the coating by a usual coating method. Among them, the coating method is particularly preferable in practice because the manufacturing operation is particularly easy. The coating method is not particularly limited, and a coating method, a spray method, a dipping method, or the like may be used depending on the purpose. The film thickness of the film formed from the polymer composition of the present invention is not particularly limited, and for example, a film having a film thickness of about 0.1 μm to 1mm can be used.

The coating treatment of the medical composition of the present invention by the coating method may be carried out by a simple operation such as immersing the coated member in a solution obtained by dissolving the composition containing the biocompatible polymer composition of the present invention in an appropriate solvent, removing the excess solution, and then air-drying the solution, in addition to using the medical composition of the present invention. In order to more firmly fix the medical composition of the present invention to the member to be coated, the medical composition of the present invention may be further improved in adhesion to the medical composition of the present invention by heating after coating. Furthermore, the surface may be fixed by crosslinking. As a method of crosslinking, a crosslinkable monomer may be introduced as a comonomer component. Further, the crosslinking may be performed by electron beam, gamma ray, or light irradiation.

The medical composition of the present invention can be used for the purpose of forming an antifouling surface for preventing various biological contamination by reducing the adhesion frequency of bacteria, by suppressing nonspecific adsorption of proteins to the polyurethane surface formed from the medical composition of the present invention, denaturation thereafter, and multi-layer adsorption. That is, it is known that when Escherichia coli or the like adheres to the surface of a substance, the adhesion frequency of Escherichia coli is expected to be reduced on the surface where the adsorption frequency of proteins is low, such as in the medical composition of the present invention, by using proteins or the like adsorbed to the surface of the substance as a scaffold.

As an application for forming an antifouling surface, for example, a sink or the like in washing various instruments or dirt with water at a medical site, adsorption of proteins or bacteria contained in water can be expected to be suppressed by using the composition for medical treatment of the present invention to a surface contacted with water containing various proteins or bacteria such as a general wash stand, bathroom, toilet, or the like. The antifouling material can be used as a material for preventing infection or a material for preventing bacterial adhesion, and can be used as a biological protective material for preventing adhesion of organisms by being used in a portion of a ship bottom, a shore protection, or the like which is in contact with water in which organisms depend, that is, a portion where adhesion of various organisms is a problem.

As described above, the coating film of the medical composition (in particular, the aqueous dispersion) of the present invention is formed on a medical device or the like, and excellent biocompatibility can be imparted to the medical device or the like. Therefore, the step of forming the coating film of the medical composition of the present invention on the medical device is applicable to a protein adsorption inhibition method or a platelet adsorption inhibition method. The step of treating the medical composition of the present invention with a medical fiber is suitable as a treatment method for a medical fiber.

The medical composition of the present invention can be suitably used in various applications such as protein adsorption inhibitors, platelet adsorption inhibitors, and medical fiber treatment agents.

The coating agent, the protein adsorption inhibitor, the platelet adsorption inhibitor and the medical fiber treatment agent may contain other components as long as they contain the medical composition of the present invention, or may be formed of only the medical composition of the present invention. The method for producing the coating agent, the protein adsorption inhibitor, the platelet adsorption inhibitor and the medical fiber treatment agent containing the medical composition of the present invention is not particularly limited, and the medical composition of the present invention can be used to produce the medical composition by an appropriate method.

Examples

The present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Preparation and evaluation of medical composition A

[ Synthesis of aqueous polyurethane Dispersion ]

Example 1

Aqueous polyurethane dispersions were prepared according to the respective raw material components and the amounts (parts by mass) shown in table 1. A four-necked flask equipped with a stirrer, a cooling reflux tube, a thermometer and a nitrogen-blowing tube was used, and 49.9 parts by mass of a polycarbonate diol (PCD (1, 6-HD) of 1, 6-hexanediol as a polyol component (component A), manufactured by Yuxiangzhi Co., ltd., product name: ETERNACOL UH-100, number average molecular weight of about 1000, average hydroxyl value of 110mg KOH/g), 33.3 parts by mass of a polyethylene glycol (manufactured by first industry Co., ltd., product name; PEG-1000, number average molecular weight of about 1000, average hydroxyl value of 110mg KOH/g), and 16.8 parts by mass of Hexamethylenediisocyanate (HMDI) (Duranate 50MS, manufactured by Asahi chemical Co., ltd.), 0.0035 parts by mass of an organotin compound (bis (neodecanoyloxy) dioctylstannane as a reaction catalyst, songwon Industrial Co., ltd.) were added to 90 parts by mass of methyl ethyl ketone as a reaction medium, and a methyl urethane prepolymer was produced at 75℃to dissolve the urethane prepolymer.

The solution was cooled to 45℃and 1408 parts by mass of water was slowly added to 6.0 parts by mass of a surfactant (product name: noigen EA-157, manufactured by first Industrial pharmaceutical Co., ltd.) and 0.05 parts by mass of a silicon-based antifoaming agent, and a urethane prepolymer was emulsified and dispersed in a liquid phase by using a homogenizer to obtain an aqueous dispersion. After the chain extension reaction was carried out with water for 1 hour, the reaction medium methyl ethyl ketone was evaporated and removed by maintaining the reaction medium under reduced pressure at 50℃to obtain an aqueous polyurethane dispersion containing about 7.3% of nonvolatile components.

Examples 2 to 10

As shown in table 1, polyurethane aqueous dispersions were produced in the same manner as in example 1, except that the amount ratio of PCD (1, 6-HD), HMDI, the amount ratio of PEG used, the average molecular weight, the structure, and the like were changed variously.

In Table 1, PEG-600 (manufactured by first Industrial pharmaceutical Co., ltd., product name: PEG-600S, number average molecular weight: about 600, average hydroxyl value: 187mg KOH/g) and PEG-2000 (manufactured by first Industrial pharmaceutical Co., ltd., product name: PEG-2000, number average molecular weight: about 2000, average hydroxyl value: 56mg KOH/g) were polyethylene glycols. The branched PEG is a diol and has a structure in which a hydrogen atom of an alkylene chain having hydroxyl groups at both ends thereof is substituted with a group containing a polyoxyethylene structure or the like (Ymer N120, manufactured by Perston Co., ltd.) and has a number average molecular weight of about 1020 and an average hydroxyl value of 110mg KOH/g.

TABLE 1

Examples 11 to 17

According to the respective raw material components and the blending amounts (parts by mass) shown in table 2, the types and the amount ratios of the polyol component (a component) and the polyisocyanate component (B component), and the amount ratio, the average molecular weight, the structure, and the like of PEG used were variously changed, and a polyurethane aqueous dispersion was produced in the same manner as in example 1.

In Table 2, polyester polyol (MPD/AA: 3-methyl-1, 5-pentanediol/adipic acid) was used with a number average molecular weight of about 1000 (Kurapol P-1010; manufactured by Kurapay). In addition, polytetramethylene glycol (PTMG) was used, which had a number average molecular weight of about 1000 (Ploy THF 1000S: manufactured by BASF Japan).

TABLE 2

In the above examples 1 to 17, the free isocyanate group content with respect to the nonvolatile matter was measured in accordance with JIS K7301 for the methyl ethyl ketone solution of the synthesized urethane prepolymer, and the results are shown in tables 3 to 4. Further, the weight of the nonvolatile matter in each aqueous polyurethane dispersion was determined in accordance with JIS K6828-1: 2003 (weight of nonvolatile matter of polyurethane aqueous dispersion) was measured, and the results are shown in tables 3 to 4.

TABLE 3

TABLE 4

[ evaluation of protein adsorption ]

The polymer compositions of example 5 and example 13 were evaluated for protein (fibrinogen) adsorptivity according to the following method.

In order to form a polyurethane film on a 96-well plate made of polypropylene using the above polymer compositions, the aqueous dispersion of each polymer composition was freeze-dried to isolate each polymer, and then dissolved in methylene chloride (CH ₂ Cl ₂ ) The solution forming 0.2 (wt/v%) was dropped into a 96-well plate and dried, and each polyurethane film was formed at the bottom thereof as a sample. For comparison, various films of PP (polypropylene) showing no biocompatibility, PMEA showing high biocompatibility, and a polymer obtained by copolymerizing MPC (2-methacryloyloxyethyl phosphorylcholine) and BMA (butyl methacrylate) and making them insoluble (referred to as "MPC polymer" in the examples) were formed and used in the same manner. In the MPC polymer, the molar ratio of MPC to BMA "MPC: BMA "is 3:7.

for each sample, the fibrinogen amount per unit area was adjusted to 156 (. Mu.g/cm) ² ) After incubation at 37℃for 1 hour, the aqueous solution was removed and each well was washed with PBS (-). Then, in order to recover fibrinogen adsorbed to each well into the aqueous phase, 30. Mu.L of 0.5% SDS+1N NaOH aqueous solution was added, and incubated for 2 hours. Then, protein was quantified using a Micro BCA protein assay kit (Micro BCA Protein Assay Kit (manufactured by Thermo Fischer Scientific).

The results of the above measurement are shown in Table 5. It was observed that adsorption of 3.8 (. Mu.g/cm) on PP surfaces showing no bioaffinity was observed ² ) On the other hand, on the surface of PMEA and MPC polymers known to exhibit bioaffinity, 0.8 (. Mu.g/cm) was adsorbed, respectively ² )、1.7(μg/cm ² ) Is a fibrinogen of (a).

In contrast, in examples 5 and 13 of the present invention, it was observed that each of the two components was 1.7 (. Mu.g/cm) ² )、0.8(μg/cm ² ) The protein adsorption on the polyurethane film surface of examples 5 and 13 showed the same extent as that of PMEA and MPC polymers.

From the above results, it has been shown that the urethane resin having a urethane bond in the main chain and a polyoxyethylene structure in the main chain and/or the side chain can inhibit the adsorption of proteins.

TABLE 5

[ evaluation of polyurethane film produced Using polyurethane aqueous Dispersion ]

The aqueous dispersion solutions of the respective polymer compositions obtained in examples 1 to 17 were put into a teflon (registered trademark) coated petri dish under the condition that the film thickness after drying was 200 μm, dried at 20 ℃ for 3 days, dried at 80 ℃ for 1 hour, and further dried at 120 ℃ for 30 minutes, and urethane prepolymers dispersed in the aqueous dispersion solutions were fused with each other to form a polyurethane film, and the following tests were performed.

(evaluation of platelet adhesion index)

The platelet adhesion test was performed according to the following method. Human whole blood, which was purchased for testing in the united states of america for blood collection, was used for testing within 5 days after blood collection. Human whole blood in a refrigerated state was left at room temperature for about 30 minutes to return to normal temperature. Then, 3 tumbling mixing was performed at 1500r by a centrifuge (tabletop centrifuge 2420, KUBOTA)pm was centrifuged for 5 minutes. The supernatant (pale yellow translucent) at this time was collected as about 500. Mu.L and used as platelet rich plasma (Platelet Rich Plasma; PRP). After collection, the supernatant (pale yellow transparent) was collected as platelet poor plasma (Platelet Poor Plasma; PPP) in about 2mL by centrifugation at 4000rpm for a further 10 minutes. Platelets in PRP diluted to 800-fold with PBS (-) were counted using a hemocytometer tray, and the platelet concentration in PRP was calculated so that the seeding concentration was 4.0X10 × ⁷ Individual cells/cm ² PRP was diluted with PPP to prepare platelet suspensions.

The above procedure was followed, and the resulting product was peeled off from the petri dish to carry 450. Mu.L (about 300. Mu.L/cm) of each polyurethane film surface sufficiently wetted with physiological saline in advance ² ) Platelet suspensions prepared as described above were incubated at 37℃for 1 hour to allow platelets to adhere. Then, the platelet suspension was removed, washed 2 times with PBS, immersed in a 1% glutaraldehyde (25% glutaraldehyde, polyscience, inc.01909, diluted 1/25 with PBS (-)) solution, and incubated at 37℃for 2 hours to fix the adhered platelets to the substrate. After fixation, the samples were immersed in PBS (-) (10 min), PBS (-): water = 1:1 (8 minutes) and water (8 minutes, 10 minutes) 1 time each, thereby performing washing. After washing, the mixture was air-dried for 3 hours, and then dried in a container containing a silicone gel for 1 day or more. After drying, the substrate surface was observed using a scanning electron microscope (Scanning Electron Microscope; SEM, KEYENCE,3D real surface view microscope VE-9800) to calculate the number of platelets adhered to each polyurethane film surface.

On the other hand, the number of platelets adhered to the surface of a PET (polyethylene terephthalate (Polyethylene Terephthalate)) film known not to exhibit blood compatibility was calculated as a negative control in the same manner as described above, and a value normalized by dividing the count on the PET surface by the number of platelets adhered to the surface of each polyurethane film was used as a "platelet adhesion index". By this platelet adhesion index, the difference in platelet adhesion frequency derived from the state of blood used in the evaluation is eliminated, and the degree of blood adaptation shown on the sample surface can be appropriately evaluated.

In order to clearly show the degree of platelet adhesion on the surface exhibiting biocompatibility, a positive control was also obtained by copolymerizing PMEA known to exhibit high biocompatibility and the above-mentioned polymer (MPC polymer) obtained by copolymerizing MPC and BMA (butyl methacrylate) and nonaqueous-dissolving the copolymer, and performing a platelet adhesion test simultaneously with the above-mentioned polymerization.

(measurement of Water resistance)

Each polyurethane film prepared above was peeled off from the petri dish and cut into a predetermined size (2 cm×4 cm) to obtain an evaluation sample. The evaluation sample was immersed in tap water (20 ℃) as a test solution for 4 hours, the weight before and after measurement, and the weight increase ratio was obtained according to the following formula, whereby the water resistance of each polyurethane film was evaluated.

Weight increase ratio = (weight after impregnation-weight before impregnation)/weight before impregnation×100 (%)

(measurement of mechanical Properties)

Each polyurethane film prepared above was peeled off from a petri dish, and a bar of Cheng Kuandu mm and 100mm in length was cut according to JIS K6301 (2010) to obtain an evaluation sample for tensile test. The test was performed using a tensile tester [ product name "Tensilon UTM-III-100" manufactured by Orientec Co., ltd ] "]The maximum tensile stress shown in each sample was measured by performing a tensile test at a distance of 50mm between chucks, a tensile speed of 500 mm/min and a temperature of 23 ℃ (relative humidity 55%), and the maximum tensile stress was divided by the initial sectional area of the sample to obtain the maximum point strength (N/mm ² )。

The results of each of the above experiments are collated and shown in tables 6 to 7.

TABLE 6

TABLE 7

[ evaluation results ]

(1) Platelet adhesion test

Fig. 1 shows the results of plotting the platelet adhesion index of the surface of each polyurethane film composed of the polymer composition of the present invention, with respect to the amount of the polyoxyethylene structure introduced into the polymer composition. In fig. 1, 3 and 4, the mass ratio of PEG and branched PEG used as the PEG component to the total mass of the polyol and polyisocyanate containing the PEG component used for producing each polymer is referred to as "PEG incorporation amount (wt%)".

In fig. 1, the number of platelet adhesion observed on the PET surface is regarded as 100, and the degree of the number of platelet adhesion (platelet adhesion index) observed on each sample surface is shown. In fig. 1 and the like, the "o" indicates a structure having a polyoxyethylene group in the main chain of the polymer, and the "o" indicates a structure having a polyoxyethylene group in a side chain portion of the polymer.

As shown in fig. 1, the films containing urethane resin having urethane bonds in the main chain and having a polyoxyethylene structure in the main chain and/or side chains have a difference in platelet adhesion index depending on the polymer structure and the amount of PEG introduced, and on the other hand, each film shows a platelet adhesion index of 40 or less.

Further, as shown in Table 7, the PMEA or MPC polymer exhibiting high bioaffinity showed a platelet adhesion index of about 15 or less (gray scale in FIG. 1), whereas the polymer composition of the present invention having a predetermined composition showed high bioaffinity because it gave a platelet adhesion index of about the same degree or less as the polymer.

In particular, in the case where the amount of the polyoxyethylene structure introduced into the polymer (block) is 3.0wt% (example 7), the platelet adhesion index was equal to or lower than that of PMEA or the like, and it was presumed that the high biocompatibility was exhibited by introducing a small amount of the polyoxyethylene structure.

(2) Strength test of polyurethane skin film

Fig. 2 shows the relationship between the maximum point strength exhibited by each polyurethane film composed of the polymer composition of the present invention and the amount of PEG (polyoxyethylene structure) incorporated into the polyurethane (wt%). As shown in fig. 2, the maximum point strength generally tends to decrease with an increase in the amount of polyoxyethylene structure introduced. On the other hand, it was revealed that setting the amount of PEG introduced to 30wt% or less maintains the same strength as the polyurethane film into which the polyethylene structure was not introduced.

In addition, in particular, in a polymer using a polycarbonate polyol as a polyol other than the PEG component and an aliphatic polyisocyanate as a polyisocyanate, or a polymer having a polyoxyethylene structure introduced into a side chain portion of the polymer, a tendency of a high maximum point strength was observed.

(3) Evaluation test of Water resistance

Fig. 3 shows the relationship between the weight increase rate and the amount of PEG (wt%) introduced into each polyurethane film made of the polymer composition of the present invention when the polyurethane film contains water, which is caused by immersion in water. As shown in fig. 3, it can be observed that: generally, as the amount of PEG introduced increases, the water content increases and the water resistance tends to decrease due to immersion in water. On the other hand, by setting the amount of PEG introduced to 30wt% or less, the weight increase rate can be suppressed, and the water resistance can be maintained. Furthermore, no dissolution in the aqueous phase was observed for any polymer composition, showing no water solubility.

In particular, a polymer using a polycarbonate polyol as a polyol other than the PEG component and an aliphatic polyisocyanate as a polyisocyanate has a small weight increase rate due to water content compared to a polymer using a polyol/polyisocyanate having another structure.

In particular, in the polymer having a polyoxyethylene structure introduced into the side chain portion of the polymer (example 5), it was observed that: the increase in the weight increase rate associated with the increase in the amount of the polyoxyethylene structure tends to be suppressed.

Preparation and evaluation of medical composition B

Example 18

Aqueous polyurethane dispersions were prepared according to the respective raw material components and the amounts (parts by mass) shown in table 8. A four-necked flask equipped with a stirrer, a cooling reflux tube, a thermometer and a nitrogen gas blowing tube was set at 45.41: 54.59A polycarbonate diol (PCD (1, 6-HD), available from Yujingcheng Co., ltd., product name: ETERNACOLL UH-100, number average molecular weight about 1000, average hydroxyl value 110mg KOH/g) and hexamethylene diisocyanate (HMDI) (Duranate 50MS, manufactured by Asahi chemical Co., ltd.) were added as the polyol component (component A), followed by Methyl Ethyl Ketone (MEK) to make the solid content 80% by mass, to obtain a uniform raw material liquid. To this raw material liquid, an organotin compound (bis (neodecanoyloxy) dioctylstannane, songwon Industrial co., ltd.) was added as a reaction catalyst so as to be 0.002 mass% with respect to the total mass of 1,6-HD and HMDI, the temperature was raised to 65 ℃, the reaction was started at this temperature, and after confirming that the reaction was carried out between 70 and 77 ℃ until a predetermined free isocyanate group content (%), the solution was cooled.

The above solution was cooled to 45℃and a surfactant (product name: noigen EA-157, manufactured by first Industrial pharmaceutical Co., ltd.) was added to the solution so as to be 20% by mass relative to the total mass of 1,6-HD and HMDI, and the mixture was sufficiently mixed, and then 400% by mass of water as a chain length extender was added thereto, followed by stirring at high speed for 1 hour by a homomixer, whereby the chain extension reaction was carried out, to obtain an aqueous dispersion. After adding a silicon-based antifoaming agent (silicone emulsion, dow Corning Toray) to the aqueous dispersion obtained, MEK was distilled off by heating under reduced pressure in an evaporator, thereby obtaining an aqueous urethane. After adding 0.01 mass% to the total mass of 1,6-HD and HMDI, the mixture was kept in an environment at 50 ℃ under reduced pressure, and methyl ethyl ketone as a reaction medium was evaporated to remove the methyl ethyl ketone, thereby obtaining a polyurethane aqueous dispersion.

TABLE 8

Example 19

Aqueous polyurethane dispersions were prepared according to the compounding compositions shown in table 8. A urethane prepolymer was prepared by adding 49.59 parts by mass of a polycarbonate diol (PCD (1, 6-HD) of 1, 6-hexanediol as a polyol component (component A), manufactured by Yuxiangzhi Kogyo Co., ltd., product name: ETERNACOL UH-100, number average molecular weight about 1000, average hydroxyl value 110mg KOH/g), 33.73 parts by mass of polyethylene glycol (manufactured by first industry Co., ltd., product name: PEG-1000, number average molecular weight about 1000, average hydroxyl value 110mg KOH/g) and 16.68 parts by mass of hexamethylene diisocyanate (HMDI) (Duranate 50MS, manufactured by Asahi chemical Co., ltd.) as a polyisocyanate component (component B) and 0.003 parts by mass of an organotin compound (bis (neodecanoyloxy) dioctylstannane, songwon Industrial, ltd.) as a reaction catalyst to 90 parts by mass of methyl ethyl ketone as a reaction medium, and reacting the resultant prepolymer at 75℃to give a urethane prepolymer. In addition, branched PEG uses a diol having the following structure: the hydrogen atom of the alkylene chain having hydroxyl groups at both ends was substituted with a group containing a polyoxyethylene structure or the like (Ymer N120, manufactured by Perston Co., ltd.), and the number average molecular weight was about 1020, and the average hydroxyl value was 110mg KOH/g of PEG.

The raw material liquid was cooled to 45 ℃, and 300 parts by mass of water and 1.02 parts by mass of Diethylenetriamine (DETA) were slowly added to the mixture, which corresponds to 0.01 parts by mass of a silicon-based antifoaming agent (silicone emulsion, dow Corning Toray), while emulsifying and dispersing the urethane prepolymer in a liquid phase using a homogenizer, to form an aqueous dispersion. Then, after the DETA-based chain extension reaction was carried out for 1 hour, it was kept under reduced pressure at 50 ℃ to evaporate methyl ethyl ketone as a reaction medium, thereby obtaining a polyurethane aqueous dispersion containing about 26.5 mass% of nonvolatile components.

Examples 20 to 21

An aqueous polyurethane dispersion was produced in the same manner as in example 19, except that the amount ratio of PCD (1, 6-HD), HMDI, the amount ratio of branched PEG used, the type and amount ratio of chain extender used, the average molecular weight, the structure, and the like were changed variously. Table 8 shows details (parts by mass) of the raw material components used in examples 19 to 21.

Fig. 4 shows the results of the protein adsorption test, (a) shows the albumin adsorption test, (b) shows the fibrinogen adsorption test, and (c) shows the results of the fibronectin adsorption test. Further, the aqueous polyurethane dispersion obtained in example 18 was dried to prepare a urethane resin, and then the urethane resin was dissolved in methylene chloride to prepare a methylene chloride dispersion having a concentration of 7 mass%, and the methylene chloride dispersion was used to prepare a polyurethane film. In fig. 4, the results of the protein adsorption test of PMEA, MPC polymer, and PET are also shown together as references.

Table 8 shows the measurement results of various analysis values of the aqueous polyurethane dispersions obtained in examples 18 to 21, and various physical properties and platelet adhesion index of the coating film of the urethane resin formed from the dispersions. In Table 8, the results of the platelet adhesion index of PMEA, MPC polymer, and PET are also disclosed together as references.

As is clear from the results shown in table 8 and fig. 4, the coating film comprising the urethane resin having the structural unit derived from the polycarbonate polyol and the structural unit derived from the aliphatic isocyanate and having at least 1 urea bond has excellent mechanical strength and can inhibit the adsorption of platelets and the adsorption of various proteins, that is, has excellent mechanical strength and biocompatibility.

Comparative example 1

In a four-necked flask equipped with a stirrer, a cooling reflux tube, a thermometer and a nitrogen gas blowing tube, 45.46:54.54 molar ratio of 1, 6-hexanediol (PCD (1, 6-HD), manufactured by Yu Kogyo Co., ltd., product name: ETERNACOLL UH-100, number average molecular weight about 1000, average hydroxyl value 110 mgKOH/g) and Toluene Diisocyanate (TDI), and Methyl Ethyl Ketone (MEK) were added so that the solid content became 80 mass%, to obtain a uniform raw material liquid. To this raw material liquid, an organotin compound (bis (neodecanoyloxy) dioctylstannane, songwon Industrial co., ltd.) was added as a reaction catalyst in an amount of 0.002 mass% relative to the total mass of the above mixture, the temperature was raised to 65 ℃, the reaction was started at this temperature, and then the reaction was carried out at 70 to 77 ℃ until it was confirmed that the predetermined free isocyanate group content (%) was reached, and then the solution was cooled to obtain a solution.

The solution was cooled to 45℃and a surfactant (product name: noigen EA-157, manufactured by first Industrial pharmaceutical Co., ltd.) was added to the solution in an amount corresponding to 20% by mass of the total mass of the mixture, and after sufficiently mixing, a chain length extender (water) was added in an amount of 400% by mass, and the mixture was stirred at a high speed for 1 hour by a homomixer, whereby a chain extension reaction was carried out to obtain an aqueous dispersion. After adding a silicon-based antifoaming agent (silicone emulsion, dow Corning Toray) to the aqueous dispersion obtained, MEK was distilled off by heating under reduced pressure using an evaporator, thereby obtaining an aqueous urethane. After 0.01 mass% based on the total mass of 1,6-HD and HMDI was added, the mixture was kept under reduced pressure at 50 ℃ to evaporate methyl ethyl ketone as a reaction medium, thereby obtaining an aqueous polyurethane dispersion.

Comparative example 2

An aqueous polyurethane dispersion was obtained in the same manner as in comparative example 1, except that the mixture was changed to a mixture (molar ratio: 45.45:54.55) of a polyester polyol (MPD/AA: 3-methyl-1, 5-pentanediol/adipic acid) and isophorone diisocyanate (IPDI), and the amount of the organotin compound used was changed to 0.004 mass% relative to the total mass of the mixture.

Comparative example 3

An aqueous polyurethane dispersion was obtained in the same manner as in comparative example 1, except that the mixture was changed to a mixture (molar ratio: 45.44:54.56) composed of a polyester polyol (MPD/AA: 3-methyl-1, 5-pentanediol/adipic acid) and Toluene Diisocyanate (TDI), and the amount of the organotin compound used was changed to 0.0035 mass% based on the total mass of the mixture.

Comparative example 4

An aqueous polyurethane dispersion was obtained in the same manner as in comparative example 1, except that the mixture was changed to a mixture (molar ratio: 45.44:54.56) composed of polytetramethylene glycol (PTMG) and Toluene Diisocyanate (TDI), and the amount of the organotin compound used was changed to 0.006 mass% based on the total mass of the mixture.

(evaluation of aqueous polyurethane Dispersion obtained in comparative examples)

The polyurethane aqueous dispersion obtained in comparative examples 1 to 4 was used to prepare a polyurethane film in the same manner as described above, but the polyurethane film was not obtained as a target, although both were in a syrup form. Therefore, the aqueous polyurethane dispersions obtained in comparative examples 1 to 4 are not suitable as a coating agent for medical use.

Claims

1. A medical composition, characterized in that,

Is a medical composition comprising a urethane resin,

the urethane resin has a urethane bond in a main chain and a polyoxyethylene structure in the main chain and/or a side chain.

2. The medical composition according to claim 1, wherein,

the urethane resin has structural units derived from a polycarbonate polyol.

3. The medical composition according to claim 1, wherein,

the urethane resin has a structural unit derived from an isocyanate compound.

4. A medical composition, characterized in that,

is a medical composition comprising a urethane resin,

the urethane resin has structural units derived from a polycarbonate polyol and structural units derived from an aliphatic isocyanate, and has at least 1 or more urea bonds.

5. The medical composition according to claim 4,

the urethane resin has a polyoxyethylene structure in a main chain and/or a side chain.

6. The medical composition according to claim 1 to 5,

the medical composition is an aqueous dispersion.

7. A protein adsorption inhibitor, characterized in that,

a medical composition according to any one of claims 1 to 6.

8. A platelet adsorption inhibitor is characterized in that,

a medical composition according to any one of claims 1 to 6.

9. A medical fiber treating agent, characterized in that,

a medical composition according to any one of claims 1 to 6.

10. A medical apparatus, which is characterized in that,

a coating comprising the medical composition according to any one of claims 1 to 6.

11. A medical fiber, which is characterized in that,

a medical fiber-treating agent according to claim 9.

12. A method for inhibiting protein adsorption, characterized in that,

comprising a step of forming a coating of the medical composition according to any one of claims 1 to 6 on a substrate.

13. A platelet adsorption inhibition method is characterized in that,

14. A method for treating a medical fiber, characterized by comprising the steps of,

comprising a step of treating the medical composition according to any one of claims 1 to 6 with a medical fiber.