WO2016158700A1

WO2016158700A1 - Medical instrument

Info

Publication number: WO2016158700A1
Application number: PCT/JP2016/059486
Authority: WO
Inventors: 政則倉本; 崇王安齊
Original assignee: テルモ株式会社
Priority date: 2015-03-30
Filing date: 2016-03-24
Publication date: 2016-10-06

Abstract

The present invention provides a medical instrument having a lubricating layer that reduces the association of polymer brushes while ensuring hemocompatibility. This medical instrument has a base material layer and a lubricating layer comprising polymer chains that have a length of less than 10 μm present in the form of brushes on the base material layer, the polymer chains being formed from a hemocompatible copolymer of zwitterionic monomers and anionic monomers, and carrying a negative charge during contact with body fluids.

Description

Medical tools

The present invention relates to a medical device. In particular, the present invention relates to a medical device having a surface having lubricity and blood compatibility.

Medical devices such as catheters are required to have lubricity in order to reduce tissue damage such as blood vessels and improve the operability of the operator. On the other hand, a medical device inserted into a blood vessel such as a catheter is required to have blood compatibility.

Also, in a procedure using a catheter, a lesion in a peripheral blood vessel is treated, and a reduction in the diameter of the catheter is required. Accordingly, a technique for reducing the film thickness such as a lubricious coating is also required.

For example, Patent Document 1 describes that a polymer chain is grown on the surface of a medical device by radical polymerization of a deliquescent monomer, thereby imparting lubricity while reducing the film thickness. In Patent Document 1, an alkali metal-containing monomer and a zwitterionic monomer are disclosed as deliquescent monomers.

JP 2014-214226 A (equivalent to US 2014/0322468 A1)

However, when a polymer brush made of an alkali metal-containing monomer is produced, the polymer brush may be charged too negatively. In such a case, due to the negative charge of the polymer brush, the hydration between the polymer brush and water may be significantly disturbed, and blood compatibility may be reduced. In addition, when a polymer brush made of a zwitterionic monomer is prepared, the polymer brush is not charged negatively or positively (neutral), so there is no repulsive force between the polymer brushes, and the polymer brushes Tend to grow together and form aggregates. For this reason, when a polymer brush peels, there exists a possibility of having a bad influence on a human body by the magnitude | size.

Therefore, the present invention has been made in view of the above circumstances, and an object thereof is to provide a medical device having a lubricating layer in which association between polymer brushes is reduced while ensuring blood compatibility.

As a result of intensive studies to solve the above problems, the present inventors have found that a polymer brush composed of a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility is formed on a substrate of a medical device. As a result, it was learned that the above object could be achieved, and the present invention was completed.

That is, the object is a medical device having a base material layer, wherein the polymer chain has a lubricating layer in which polymer chains having a length of less than 10 μm are present in a brush shape on the base material layer. Can be achieved by a medical device which is formed from a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility and has a negative charge when contacting a body fluid.

It is a general | schematic fragmentary sectional view for demonstrating the surface of the medical device of this invention. In FIG. 1, 1 indicates a medical device; 2 indicates a polymer chain (polymer brush); 3 indicates a lubricating layer; and 4 indicates a base material layer. It is a photograph which shows the adhesion state of the thrombus of the medical devices 4, 7, and 9 in "Evaluation of blood compatibility" in an Example. It is a photograph which shows the external appearance of the solution containing the compounds 3, 5 and 6 in "Evaluation of cohesiveness (association of polymer chains)" in an Example.

The medical device of the present invention is a medical device having a base material layer, and has a lubricating layer in which polymer chains having a length of less than 10 μm are present in a brush shape on the base material layer, and the polymer The chain is formed from a copolymer of a zwitterionic monomer having an affinity for blood and an anionic monomer, and is negatively charged when contacting a body fluid. With the above configuration, blood compatibility and lubricity can be improved, and the charge amount of the polymer brush can be adjusted to effectively suppress / prevent association between the polymer brushes. In the present specification, a polymer chain having a length of less than 10 μm and existing in a brush shape on the base material layer is also simply referred to as “polymer brush according to the present invention” or “polymer brush”. Similarly, “zwitterionic monomer having blood compatibility” is also simply referred to as “zwitterionic monomer according to the present invention” or “zwitterionic monomer”.

In the present invention, (a) the polymer chain constituting the lubricating layer is formed from a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility; and (b) the lubricating layer has a length of less than 10 μm. And having a polymer chain existing in a brush shape. The medical device having the above configuration can reduce the association between polymer chains with an anionic monomer while ensuring blood compatibility with a zwitterionic monomer.

According to the configuration of (a) above, the polymer chain has a structural unit derived from a zwitterionic monomer. The constituent unit derived from this zwitterionic monomer has blood compatibility and hydrophilicity. For this reason, the lubricating layer can exhibit excellent blood compatibility and lubricity. The polymer chain has a structural unit derived from an anionic monomer in addition to a structural unit derived from a zwitterionic monomer. The structural unit derived from the anionic monomer is negatively charged when contacting a body fluid (for example, an aqueous liquid such as blood). That is, as shown in FIG. 1, in the medical device 1 of the present invention, each polymer chain 2 constituting the lubricating layer 3 is negatively charged when contacting a body fluid and repels adjacent polymer chains due to this negative charge. Ah (electrostatic repulsion). Therefore, adjacent polymer chains do not associate with each other due to electrostatic repulsion, but rather extend in parallel on the base material layer 4 in a brush shape (perpendicular to the surface of the base material layer 4) and are oriented. Therefore, the lubricating layer according to the present invention can effectively exhibit the original characteristics (blood compatibility, lubricity) of the polymer brush when contacting body fluid. In the present specification, “association” means that polymer brushes (polymer chains) according to the present invention are bonded to each other.

In addition, the polymer chain according to the present invention has a structural unit derived from an anionic monomer. By using an anionic monomer in this way, even if the polymer is peeled off, it is difficult for the polymers to associate with each other due to electrostatic repulsion. Even when the medical device of the present invention is used in blood, the anion on the blood cell surface repels the anion of the anionic monomer of the polymer chain, so that the induction of blood cell aggregation can be suppressed / prevented. In the present specification, “aggregation” or “aggregation of blood cells” means that blood cells bind to each other via a polymer chain.

As described above, according to the configuration of the above (a), blood compatibility and lubricity can be exhibited by the zwitterionic monomer. In addition, the charge amount of the polymer brush is appropriately adjusted by the anionic monomer to effectively suppress / prevent disturbance of the hydration structure of the polymer brush with water, and further decrease in blood compatibility and lubricity of the polymer brush. it can.

Further, according to the configuration of (b) above, the lubricating layer can be a thin film of less than 10 μm. Further, as described above, since the polymer chain according to the present invention has high blood compatibility and lubricity, the medical device can exhibit excellent blood compatibility and lubricity even with such a thin film. Therefore, the diameter of the catheter can be reduced and it can be suitably used for the treatment of a lesion in a peripheral blood vessel. In addition, even when the polymer brush is peeled off from the base material layer, the polymer brush is negative, so the polymer brushes hardly meet each other. The same. For this reason, the peeled material is in the form of fine particles of less than 10 μm, and has a size with little or no influence on the human body. Therefore, the medical device of the present invention can be safely applied in vivo.

In addition, the said mechanism is estimation and this invention is not limited to the said estimation.

Hereinafter, embodiments of the present invention will be described. In addition, this invention is not limited only to the following embodiment. In addition, the dimensional ratios in the drawings are exaggerated for convenience of explanation, and may be different from the actual ratios.

In this specification, “X to Y” indicating a range includes X and Y, and means “X or more and Y or less”. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.

[Medical equipment]
FIG. 1 is a schematic partial cross-sectional view for explaining the surface of the medical device of the present invention. As shown in FIG. 1, the medical device 1 of the present invention has a structure in which a lubricating layer 3 is formed on a base material layer 4. The lubricating layer 3 has the polymer chain 2 in a brush shape. The polymer chain 2 is negatively charged with an anionic monomer in a body fluid (for example, an aqueous liquid such as blood). For this reason, especially in the body fluid, the adjacent polymer chains 2 are appropriately separated from each other by electrostatic repulsion and are oriented substantially perpendicularly (in a brush shape) to the surface of the base material layer 4. Therefore, the lubricating layer according to the present invention can exhibit higher effects (blood compatibility, lubricity) when contacting body fluid. In the present specification, the “polymer brush” is intended to indicate a state in which the polymer chain exists in a brush shape, and the polymer brush and the polymer chain are treated as synonymous unless otherwise specified. Further, in the present specification, “the polymer chain is negatively charged when contacting body fluid” means that it is only required to be negatively charged at least when contacting body fluid, and not negatively charged when not contacting body fluid. Also good.

(Base material layer)
The base material layer constitutes a medical device. The material of the base material layer is not particularly limited and can be appropriately selected depending on the application. It is preferable that at least the surface of the base material layer is made of a polymer material. Here, the “base layer is made of a polymeric material” means that at least the surface of the base layer is made of a polymeric material, and the entire base layer (all) is made of a polymeric material. It is not limited to what is configured (formed). Therefore, on the surface of the base material core portion formed of a hard reinforcing material such as a metal material or a ceramic material, a polymer material that is more flexible than a reinforcing material such as a metal material is applied by an appropriate method (dipping or spraying). (Spray), coating / printing, etc.) (coating) or the base material core metal material and the polymer material of the surface polymer layer are combined (appropriate reaction treatment), What forms the surface polymer layer is also included in the base material layer of the present invention. Therefore, the base material core portion may be a multilayer structure in which different materials are laminated in multiple layers, or a structure (composite) in which members formed of different materials for each part of the medical device are connected. . Further, a different intermediate layer may be formed between the base material core portion and the surface polymer layer. Furthermore, with regard to the surface polymer layer, a multilayer structure in which different polymer materials are laminated in multiple layers, or a structure (composite) in which members made of different polymer materials are connected to each part of a medical device, etc. There may be.

In the said form, it does not restrict | limit especially as a material which can be used for a base-material core part, The function as an optimal base-material core part is enough according to uses, such as a catheter, a guide wire, and an indwelling needle. What is necessary is just to select the reinforcement material which can be expressed suitably. For example, various stainless steels (SUS) such as SUS304, SUS316L, SUS420J2, SUS630, gold, platinum, tantalum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, magnesium, zinc and nickel-titanium alloy, cobalt Examples include various metal materials such as chromium alloys and zinc-tungsten alloys, inorganic materials such as various ceramic materials, and metal-ceramic composites, but are not limited thereto.

The polymer material that can be used for the base material layer or the surface polymer layer is not particularly limited, and examples thereof include nylon 6, nylon 11, nylon 12, and nylon 66 (all are registered trademarks). Polyolefin resins such as polyamide resin, linear low density polyethylene (LLDPE), low density polyethylene (LDPE), high density polyethylene (HDPE), and polypropylene resin, epoxy resin, urethane resin, diallyl phthalate resin (allyl resin) ), Polycarbonate resin, fluorine resin, amino resin (urea resin, melamine resin, benzoguanamine resin), polyester resin, styrene resin, acrylic resin, polyacetal resin, vinyl acetate resin, phenol resin, polyvinyl chloride (PVC) (vinyl chloride) Block copolymer having a hard segment made of nylon resin, silicone resin (silicon resin), nylon 6, nylon 66, nylon 11 or nylon 12, and soft segment made of polyalkylene glycol, polyether or aliphatic polyester. A certain nylon elastomer etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together. What is necessary is just to select the polymeric material optimal as polymeric base materials, such as a catheter, a guide wire, and an indwelling needle which are use applications, as said polymeric material suitably.

The material that can be used for the intermediate layer is not particularly limited, and may be appropriately selected depending on the intended use. Examples include various metal materials, various ceramic materials, and organic-inorganic composites, but are not limited thereto.

(Lubrication layer)
The lubrication layer has a polymer chain in a brush shape. Preferably, the lubricating layer is composed of a polymer brush (polymer chain). The polymer chain is a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility.

Here, the polymer chain has a length of less than 10 μm. As shown in FIG. 1, the length of the polymer chain corresponds to the thickness of the lubricating layer. That is, the lubricating layer can be a thin film of less than 10 μm. Since the polymer chain according to the present invention has high blood compatibility and lubricity, the medical device can exhibit excellent blood compatibility and lubricity even with such a thin lubrication layer, and the diameter of the catheter is reduced. It can also be used suitably for the treatment of lesions in peripheral blood vessels. Even when the polymer chain (polymer brush) is peeled off from the base material layer, the polymer brush is negative and the polymer brushes are hardly associated with each other. Is substantially the same (the peeled material is in the form of fine particles of less than 10 μm) and has a size with little or no effect on the human body. Therefore, the medical device of the present invention can be safely applied to the body. The length of the polymer chain is less than 10 μm, and in consideration of a further reduction effect on the influence on the human body, it is preferably 9.999 μm or less, more preferably 8.000 μm or less, and particularly preferably 7.000 μm or less. The lower limit of the polymer chain length is not particularly limited and is a measurement limit. Considering the effect of improving lubricity, the length of the polymer chain is preferably 0.001 μm or more, more preferably 0.0051 μm or more, and particularly preferably 0.0101 μm or more. With such a length, the polymer chain can reduce the influence on the human body while ensuring high blood compatibility and lubricity. According to a preferred embodiment, the length of the polymer chain is 0.001 to 9.999 μm, more preferably 0.005 to 8.000 μm, particularly preferably 0.010 to 7.000 μm.

In this specification, the length of the polymer chain (polymer brush) is defined as the length of the polymer brush and the film thickness of the polymer brush being approximately the same. Further, the film thickness of the polymer brush and the film thickness of the lubricating layer are considered to be approximately the same. The film thickness of the polymer brush on the base material layer (≈the film thickness of the lubrication layer) can be calculated from an optical measurement method using an ellipsometry or an optical interference film thickness meter, or from a micrograph. Consider it a length. In this specification, as the length of the polymer chain (polymer brush), as described in the following examples, a value measured using an optical interference film thickness meter (FILMETRIX, F40) is adopted.

The polymer chain (polymer brush) according to the present invention is formed from a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility and lubricity.

Among these, zwitterionic monomers are compounds having both a cationic group and an anionic group in one molecule. Such zwitterionic monomers are not particularly limited, and examples thereof include those having a carboxybetaine skeleton, a sulfobetaine skeleton, a phosphobetaine skeleton, and those having an amino acid skeleton. Among these, the zwitterionic monomer preferably has a betaine skeleton such as a carboxybetaine skeleton, a sulfobetaine skeleton, or a phosphobetaine skeleton. That is, according to a preferred embodiment of the present invention, the zwitterionic monomer has a betaine skeleton. By introducing a skeleton containing these zwitterions as a repeating unit, blood compatibility (for example, antithrombogenicity) and lubricity can be improved more effectively.

Here, as a zwitterionic monomer having a betaine skeleton, for example, the following formula (1):

A carboxybetaine type, sulfobetaine type, or phosphobetaine type zwitterionic monomer having the following structure is preferably used.

In the above formula (1), R ¹ is a hydrogen atom or a methyl group, and is preferably a methyl group from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity. Z is an oxygen atom or —NH—, and preferably an oxygen atom from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity.

R ² is a linear or branched alkylene group having 1 to 6 carbon atoms. The linear or branched alkylene group having 1 to 6 carbon atoms is not limited to the following, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Can be mentioned. Among these, from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity, it is preferably a linear or branched alkylene group having 1 to 3 carbon atoms, preferably a methylene group or an ethylene group. More preferably, it is particularly preferably an ethylene group.

R ³ and R ⁴ are each independently an alkyl group having 1 to 4 carbon atoms. Here, R ³ and R ⁴ may be the same or different. The alkyl group having 1 to 4 carbon atoms is not limited to the following, but for example, a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group linear or Examples include branched alkyl groups. Among these, from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity, a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and 1 or 2 carbon atoms are preferable. And more preferably an alkyl group (methyl group, ethyl group), and particularly preferably a methyl group.

R ⁵ is a methylene group, ethylene group, trimethylene group, propylene group, butylene group, isobutylene group, sec-butylene group, or tert-butylene group. Among these, a methylene group, an ethylene group, a trimethylene group, and a propylene group are preferable from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or improving lubricity. In the case of the carboxybetaine type, an alkylene group having 1 carbon atom (methylene group) is particularly preferred, and in the case of the sulfobetaine type, an alkylene group having 3 carbon atoms (trimethylene group) is particularly preferred.

X is —COO ⁻ (carboxybetaine type zwitterionic monomer), —SO ₃ ⁻ (sulfobetaine type zwitterionic monomer).

Specifically, among the zwitterionic monomers, a zwitterionic monomer having a carboxybetaine skeleton (carboxybetaine type zwitterionic monomer; X = —COO ⁻ ) includes N- (meth) acryloyloxymethyl- N, N-dimethylammonium-α-N-methylcarboxybetaine, N- (meth) acryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammonium-α-N-methylcarboxybetaine, N- (meth) acryloyloleoxymethyl-N, N-diethylammonium-α-N-methylcarboxybetaine, N- (meth) acryloyloxyethyl-N, N-diethylammonium-α-N-methylcarboxybeta And N- (meth) acryloyloxypropyl-N, N-diethylammonium-α-N-methylcarboxybetaine are preferable, and N- (meth) acryloyloxyethyl-N, N-dimethylammonium-α is preferable. -N-methylcarboxybetaine (CBA) and the like.

Among the zwitterionic monomers, a zwitterionic monomer having a sulfobetaine skeleton (sulfobetaine type zwitterionic monomer; X = —SO ₃ ⁻ ) is [2-((meth) acryloyloxy) ethyl] dimethyl. -(3-sulfopropyl) ammonium hydroxide, [2-((meth) acryloyloxy) ethyl] dimethyl- (3-sulfobutyl) ammonium hydroxide, [2-((meth) acryloyloxy) ethyl] diethyl- (3 -Sulfopropyl) ammonium hydroxide, [2-((meth) acryloyloxy) ethyl] diethyl- (3-sulfobutyl) ammonium hydroxide, and the like. Of these, [2-((meth) acryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide is preferred.

Further, as another zwitterionic monomer having a betaine skeleton, for example, the following formula (2):

A phosphobetaine-type zwitterionic monomer having the following structure is preferably used.

In the above formula (2), R ¹¹ is a hydrogen atom or a methyl group, and preferably a methyl group from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity. Z ′ is an oxygen atom or —NH—, and preferably an oxygen atom from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity.

R ¹² and R ¹³ are linear or branched alkylene groups having 1 to 6 carbon atoms. Here, R ¹² and R ¹³ may be the same or different. The linear or branched alkylene group having 1 to 6 carbon atoms is not limited to the following, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Can be mentioned. Among these, from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity, it is preferably a linear or branched alkylene group having 1 to 3 carbon atoms, preferably a methylene group or an ethylene group. More preferably, it is particularly preferably an ethylene group.

R ¹⁴ to R ¹⁶ are each independently an alkyl group having 1 to 4 carbon atoms. Here, R ¹⁴ to R ¹⁶ may be the same or different. The alkyl group having 1 to 4 carbon atoms is not limited to the following, but for example, a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group linear or Examples include branched alkyl groups. Among these, from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity, a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and 1 or 2 carbon atoms are preferable. And more preferably an alkyl group (methyl group, ethyl group), and particularly preferably a methyl group.

Among the zwitterionic monomers, zwitterionic monomers having a phosphobetaine skeleton (phosphobetaine-type zwitterionic monomers) include 2- (meth) acryloyloxyethyl phosphorylcholine, 4- (meth) acryloyloxybutylphosphorylcholine, Examples include 6- (meth) acryloyloxyhexyl phosphorylcholine, ω- (meth) acryloyloxyethylene phosphorylcholine, 4-styryloxybutyl phosphorylcholine, and the like. Of these, 2- (meth) acryloyloxyethyl phosphorylcholine is preferred.

Zwitterionic monomers having an amino acid skeleton (amino acid type zwitterionic monomers) include, for example, (meth) acryloyl-L-lysine, (meth) acryloyl-L-serine, (meth) acryloyl-L-threonine, (meta And acryloyl-L-tyrosine.

The zwitterionic monomers may be used alone or in combination of two or more. By using such a zwitterionic monomer, high blood compatibility (for example, antithrombogenicity) can be imparted to the lubricating layer of the medical device. In the present specification, “(meth) acryl” means “acryl and / or methacryl”. Similarly, “(meth) acryloyl” means “acryloyl and / or methacryloyl”.

Among these, in the above formula (1), R ¹ is a methyl group, Z is an oxygen atom, R ² is an alkylene group having 1 to 3 carbon atoms, and R ³ and R ⁴ are each independently And an alkyl group having 1 or 2 carbon atoms, and X is preferably —COO 2 ^— or —SO ₃ ^— . In the above formula (2), R ¹¹ is a methyl group, Z ′ is an oxygen atom, R ¹² and R ¹³ are alkylene groups having 1 to 3 carbon atoms, and R ¹⁴ to R ¹⁶ are respectively Independently, an alkyl group having 1 or 2 carbon atoms is preferable. Further, the zwitterionic monomer is represented by the formula (1), wherein R ¹ is a methyl group, Z is an oxygen atom, R ² is an ethylene group (—CH ₂ CH ₂ —), R ³ and R [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB)) in which ⁴ is a methyl group, R ⁵ is a trimethylene group, and X is —SO ₃ ^— ; In (1), R ¹ is a methyl group, Z is an oxygen atom, R ² is an ethylene group (—CH ₂ CH ₂ —), R ³ and R ⁴ are methyl groups, and R ⁵ is methylene group, X is -COO ^- a is N- methacryloyloxyethyl -N, N- dimethylammonium-.alpha.-N- methyl carboxy betaine (CMB); and the above formula ^{(2), R 11} is a methyl group Yes, Z ' Is particularly preferably 2-methacryloyloxyethyl phosphorylcholine (MPC) in which R ¹² is an oxygen atom, R ¹² and R ¹³ are ethylene groups (—CH ₂ CH ₂ —), and R ¹⁴ to R ¹⁶ are methyl groups. .

An anionic monomer is a compound that is negatively charged when contacting a body fluid. In the present specification, “having a negative charge when contacting a body fluid” means having a minus charge enough to repel an anionic group (minus) present in the body fluid.

Such an anionic monomer is not particularly limited, but includes a carboxyl group (—COOH), a sulfonic acid group (—SO ₃ H), a sulfuric acid group (—OSO ₃ H), and a phosphonic acid group (—PO ₃ H ₂ ). And compounds having an anionic group such as a phosphate group (—PO ₄ H ₂ ). By using these anionic monomers, a negative charge is appropriately charged when contacting the body fluid, repelling the anionic group (minus) on the surface of the body fluid component (for example, blood cells), and more effectively suppressing the aggregation of the body fluid component・ Can be prevented. In addition, these anionic monomers are appropriately negatively charged when contacting body fluids, and also exhibit blood compatibility (for example, antithrombogenicity) due to negative charges derived from these functional groups (blood of medical devices) Compatibility can be further improved). Moreover, the anionic monomer may contain the said functional group independently, and may contain both of these.

Specifically, such anionic monomers include (meth) acrylic acid, β-carboxyethyl acrylate, 2- (meth) acrylamide-2-methyl-propanesulfonic acid (AMPS), vinyl sulfate, allyl sulfate, 4-vinylphenyl sulfate, styrene sulfonic acid, sulfoethyl (meth) acrylate, sulfopropyl (meth) acrylate, 2-methyl-2-propene-1-sulfonic acid, 2-propene-1-sulfonic acid, 2-hydroxy-3 -((Meth) acryloyloxy) propane-1-sulfonic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid, 3-((meth) acryloylamino) propane-1-sulfonic acid, phosphoric acid (meth) 2-hydroxyethyl acrylate, 2- (meth) acryloyl phosphate 2-phosphonoethyl (meth) acrylate, ((meth) acryloylaminomethyl) phosphonic acid, 2-((meth) acryloylamino) ethylphosphonic acid, 2-((meth) acryloyloxyamino) ethylphosphonic acid, 2 -((Meth) acryloyloxyamino) ethylphosphonic acid; and salts thereof. Here, the salt of the anionic monomer is not particularly limited, and examples thereof include inorganic cation salts and organic cation salts. As the salt of the inorganic cation, alkali metal salts, alkaline earth metal salts, and ammonium salts are preferable, and among them, sodium salts, potassium salts, and lithium salts are more preferable. The organic cation salt is preferably a primary to tertiary amine salt. The anionic monomers may be used alone or in combination of two or more. By using these anionic monomers, a negative charge is appropriately charged when contacting the body fluid, repelling the anionic group (minus) on the surface of the body fluid component (for example, blood cells), and more effectively suppressing the aggregation of the body fluid component・ Can be prevented. In addition, these anionic monomers are appropriately negatively charged when contacting body fluids, and also exhibit particularly excellent blood compatibility (for example, antithrombogenicity) due to the negative charge derived from these functional groups (medical treatment) The blood compatibility of the device can be further improved). In addition, by using an anionic monomer, even if the polymer is peeled off, it is difficult for the polymers to associate with each other due to electrostatic repulsion.

The copolymer according to the present invention has a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer, but the composition of the copolymer is not particularly limited. Specifically, from the viewpoint of blood compatibility, it is preferable that the proportion of zwitterionic monomers is higher than the proportion of anionic monomers. Further, from the viewpoint of the effect of suppressing association and / or aggregation due to the anionic monomer, the proportion of the anionic monomer is preferably more than 0.5 mol% with respect to the copolymer. From the above viewpoint, the composition of the copolymer (molar ratio of zwitterionic monomer: anionic monomer) is such that the copolymer contains more zwitterionic monomer than anionic monomer (molar ratio of zwitterionic monomer> anion). (Molar ratio of the functional monomer). More preferably, the composition of the copolymer (molar ratio of zwitterionic monomer: anionic monomer) is 60 to 99:40 to 1, more preferably 60 to 97:40 to 3, particularly preferably. 70-97: 30-3. Here, the sum of the molar ratio of zwitterionic monomer: anionic monomer is 100. With such a composition, the copolymer (polymer brush) can more effectively achieve both the high blood compatibility and lubricity due to the zwitterionic monomer and the inhibitory effect on association and / or aggregation due to the anionic monomer. In addition, it can confirm with a well-known method that the copolymer is negatively charged. For example, using a Zetasizer (MALVERN), 1 mL of the polymer solution is put into a cell with an electrode, and the potential of the polymer surface (zeta potential) is measured by passing an electric current. You can confirm that it is tinged.

The copolymer constituting the polymer chain according to the present invention essentially contains a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer, but may contain other repeating units. Preferably, the copolymer constituting the polymer chain according to the present invention is composed only of a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer.

Preferably, the copolymer constituting the polymer chain according to the present invention comprises only a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer. The form of the copolymer according to the present invention is not particularly limited, and may take any form such as a random copolymer, an alternating copolymer, a graft copolymer, and a block copolymer.

In the present invention, a method for forming a lubricating layer (a method for producing a polymer brush) is 2006-523128 (US 2004) except that a polymer chain having a length of less than 10 μm can be formed from a zwitterionic monomer and an anionic monomer. / 0191538 (corresponding to A1), Japanese Patent Application Laid-Open No. 2014-214226 (corresponding to US 2014/0322468 A1) and the like can be applied similarly or appropriately modified. Specifically, it is preferable to form a radical starting point in the base material layer and then polymerize (radical polymerization) a zwitterionic monomer and an anionic monomer to the generated radical. Hereinafter, although the said preferable form is demonstrated, this invention is not limited to the following form.

First, a radical starting point is formed in the base material layer. Here, the method for forming the radical start point on the base material layer is not particularly limited, but the method for immobilizing the polymerization initiator on the base material surface, plasma treatment, ultraviolet irradiation, laser light irradiation, corona discharge, radiation (electron) Line, gamma ray) irradiation, microwave, etc. Among these, from the standpoint that special equipment is not required, a method of immobilizing the polymerization initiator on the substrate surface is preferable. Further, from the viewpoint of not requiring an initiator and simplifying the process, radiation irradiation is preferable, and electron beam irradiation (particularly atmospheric pressure electron beam irradiation) is preferable.

Among these, the radiation graft polymerization method in which the starting point of radicals is formed in the base material layer by electron beam irradiation (particularly atmospheric pressure electron beam irradiation) has a wide range of base material shapes and materials that can be selected; use an initiator. Without the use of a catalyst, and the graft polymerization can be carried out under mild conditions. The processing conditions in this case are not particularly limited. For example, the dose of the electron beam is not particularly limited, but strongly relates to the control of the density of the polymer brush formed on the base material layer. Therefore, the electron beam dose is preferably 10 to 1000 kGy, and more preferably 50 to 500 kGy. If it is such a range, a polymer brush can be formed on a base material with a suitable density, and lubricity and blood compatibility can further be improved. Moreover, if it is the above conditions, a polymer brush will be formed on a base material with a suitable density, and the association | polymerization of polymer brushes can be suppressed and prevented more effectively. The pressure conditions for electron beam irradiation are not particularly limited, and can be under reduced pressure or atmospheric pressure. However, it is possible to realize a system configuration with low space and low cost, and it is economically superior. Therefore, it is good to carry out under atmospheric pressure. The irradiation atmosphere is not particularly limited, and examples thereof include an inert gas atmosphere such as nitrogen and helium. The electron beam irradiation time is, for example, in the range of 0.1 second to 1 hour, more preferably 0.5 second to 10 minutes. Under such conditions, the polymer brush can be formed on the substrate with an appropriate density, and the lubricity and blood compatibility can be further improved. Moreover, if it is the above conditions, a polymer brush will be formed on a base material with a suitable density, and the association | polymerization of polymer brushes can be suppressed and prevented more effectively.

Alternatively, radical initiation points may be formed in the base material layer by adsorbing a polymerization initiator on the base material layer. Here, it does not restrict | limit especially as a polymerization initiator, A well-known polymerization initiator can be used. Specific examples include carbonyl compounds such as benzophenone compounds and photoreducible dyes. Of these, carbonyl compounds, particularly benzophenone compounds, are preferred. Here, the benzophenone compound is not limited to the following, but includes benzophenone, xanthone, 9-fluorenone, 2,4-dichlorobenzophenone, methyl o-benzoylbenzoate, 4,4′-bis (dimethylamino) benzophenone, 4, Examples thereof include 4′-bis (diethylamino) benzophenone; fluorinated benzophenones such as 2,3,4,5,6-pentafluorobenzophenone and decafluorobenzophenone. Of these, benzophenone, xanthone, thioxanthone, fluorenone, acetophenone, and anthraquinone are preferable in consideration of ease of adjustment of the formation density and length of the polymer brush.

Here, the method for forming the radical starting point on the base material layer using the polymerization initiator is not particularly limited, and a known method can be applied in the same manner or appropriately modified. Specifically, a method in which a polymerization initiator is dissolved in an appropriate solvent to obtain a polymerization initiator solution, and the substrate layer is treated with this polymerization initiator solution to adsorb the polymerization initiator to the substrate layer is preferable. Can be used. Here, the solvent that can be used for preparing the polymerization initiator solution is not particularly limited as long as the polymerization initiator can be dissolved, and is appropriately selected according to the polymerization initiator to be used. Specific examples include methanol, ethanol, acetone, benzene, toluene, methyl ethyl ketone, ethyl acetate, and tetrahydrofuran (THF). Of these, acetone, THF, methanol, ethanol, and 2-propanol are preferred from the viewpoints of ease of dissolution of the polymerization initiator and boiling point (particularly when drying / evaporation described below). Here, the usage-amount of a solvent will not be restrict | limited especially if a polymerization initiator can be made to adsorb | suck to a base material layer. Specifically, the amount is such that the concentration of the polymerization initiator in the polymerization initiator solution is preferably about 75 to 0.1 g / 100 mL solvent.

Further, the method for treating the base material layer with the polymerization initiator solution is not particularly limited as long as the polymerization initiator can be present on the surface of the base material layer. For example, conventionally known methods such as coating / printing method, dipping method (dipping method, dip coating method), spraying method (spray method), spin coating method, mixed solution-impregnated sponge coating method, and the like can be applied. Of these, the dipping method (dipping method, dip coating method) is preferably used. In addition, it is not necessary to process the whole base material layer with a polymerization initiator solution, and you may process a part of base material layer surface with a polymerization initiator solution. In this case, a coating / printing method and a spraying method (spraying method) can be preferably used. Moreover, after processing the base material layer surface with the polymerization initiator solution in this way, the base material layer may be dried to remove the solvent if necessary. Thereby, a polymerization initiator can adsorb | suck more firmly by the base-material layer surface.

Further, the conditions for treating the base material layer with the polymerization initiator solution are not particularly limited as long as the polymerization initiator can be present on the surface of the base material layer. For example, the contact temperature of the base material layer with the polymerization initiator solution (for example, when the base material layer is immersed in the polymerization initiator solution) is preferably 10 to 100 ° C., more preferably Is 20 to 80 ° C. The immersion time is preferably 0.5 minutes to 30 minutes, more preferably 1 minute to 10 minutes.

Next, a zwitterionic monomer and an anionic monomer are supplied to the radical generated as described above to perform polymerization (radical polymerization). Here, the supply form of the monomer is not particularly limited. Preferably, a method of polymerizing a monomer by immersing a base material layer having a radical start point formed on the surface thereof in a monomer solution containing a zwitterionic monomer and an anionic monomer, and, if necessary, another monomer, and a radical A method of polymerizing the monomer by supplying a zwitterionic monomer and an anionic monomer and, if necessary, other monomers in a gaseous form to the base material layer having the starting point of the surface formed on the surface is preferred.

Among the above methods, in the radiation graft polymerization method in which radical starting points are formed in the base material layer by electron beam irradiation (particularly atmospheric pressure electron beam irradiation), it is more preferable to immerse the base material layer in the monomer solution. Here, the solvent used for the preparation of the monomer solution is not particularly limited as long as it can dissolve the zwitterionic monomer and the anionic monomer. For example, water, methanol, ethanol, propanol, n-butanol and the like can be used. Alcohols, polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, acetic acid, tetrahydrofuran (THF), 1,4-dioxane, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, hexamethylphosphoric triamide, triethylamine , A solvent miscible with water such as pyridine and dimethyl sulfoxide, or a solvent soluble in water such as diethyl ether and ethyl acetate. These solvents may be used alone or in the form of a mixture of two or more. Further, the mixing ratio of the zwitterionic monomer and the anionic monomer in the monomer solution is not particularly limited, but the preferred composition of the copolymer (molar amounts of zwitterionic monomer and anionic monomer, and other monomers if necessary). Ratio) is preferably adjusted. Further, the concentration of the zwitterionic monomer and the anionic monomer in the monomer solution and, if necessary, the concentration of other monomers (monomer concentration) are not particularly limited, but the density of the polymer brush on the base material layer, the polymer Considering the length of the brush and the like, the total monomer concentration is preferably 0.01 to 20 mol, more preferably 0.05 to 10 mol, per liter of the monomer solution. The monomer concentration is the total concentration of zwitterionic monomer and anionic monomer and, if necessary, other monomers. Further, the monomer solution may be bubbled with an inert gas such as nitrogen or helium when the base material layer is immersed. The conditions for immersing the base material layer in the monomer solution are also not particularly limited. For example, the immersion temperature (liquid temperature of the monomer solution) is preferably 10 to 200 ° C., more preferably room temperature (25 ° C.) to 100 ° C. The immersion time is preferably 1 minute to 24 hours, more preferably 5 minutes to 12 hours. Under such conditions, a polymer brush having a predetermined length can be efficiently formed. In particular, since the immersion time of the base material layer in the monomer solution is strongly related to the length of the polymer brush formed on the base material layer, the polymer brush having a predetermined length can be obtained by adjusting the immersion time as described above. It can be formed efficiently.

In addition, when the radical starting point is formed on the base material layer by adsorbing the polymerization initiator, after the base material layer adsorbed with the polymerization initiator is immersed in the monomer solution, the starting point of the base material layer surface is set. It is preferable to radically polymerize monomers (zwitterionic monomers and anionic monomers and, if necessary, other monomers) as a starting point. Thereby, a polymer brush is formed on the substrate layer surface. Here, the solvent used for the preparation of the monomer solution and the concentration of the monomer (monomer concentration) are not particularly limited and are the same as those in the above-described radiation graft polymerization method, and thus the description thereof is omitted here. Further, the monomer solution may be bubbled with an inert gas such as nitrogen or helium when the base material layer is immersed. The conditions for immersing the base material layer in the monomer solution are also not particularly limited.

In this method, the radical polymerization method is not particularly limited, and known radical polymerization methods can be applied in the same manner or appropriately modified. Specifically, a method of irradiating ultraviolet rays (200 to 400 nm, particularly a high pressure mercury lamp having a wavelength of 300 to 400 nm) is preferable. Thereby, radical polymerization (photo radical polymerization) proceeds more efficiently, and a polymer brush having a desired length can be grown on the base material layer. The radical polymerization conditions are not particularly limited as long as a polymer brush having a desired length can be grown on the base material layer. Specifically, the illuminance of the ultraviolet rays is preferably 70 ~ 0.1mW / cm ^2, more preferably 30 ~ 0.5mW / cm ^2. The irradiation time is preferably 0.1 to 12 hours, more preferably 0.5 to 6 hours. Under such conditions, radical polymerization (photo radical polymerization) proceeds more efficiently, and a polymer brush having a desired length can be grown on the base material layer.

By the above method, a lubricating layer in which the polymer chain according to the present invention is present in a brush shape can be formed on the base material layer. In addition, after the completion of the polymerization reaction, the base material layer on which the lubricating layer is formed may be washed (for example, washed with water). Here, the density of the polymer brush is not particularly limited, but is preferably about 0.1 to 1 μg / cm ² in consideration of lubricity and the like. In addition, in this specification, the value which remove | divided the weight difference before and behind the polymerization measured by the ultramicro balance (Sartorius) by the area is used for the density of the polymer brush. In addition, the molecular weight of the copolymer (polymer chain, polymer brush) of the zwitterionic monomer and the anionic monomer is not particularly limited, but the length of the polymer is not limited from the viewpoint of lubricity and safety of the peeled fine particles. It is preferable that the length is adjusted so as to be as described above.

Examples of the medical device according to the present invention include, for example, an implantable artificial organ and a therapeutic instrument, an extracorporeal circulation artificial organ, a catheter, a guide wire, and the like. Specifically, an artificial blood vessel, an artificial trachea, a stent, or an implantable medical device such as an artificial skin or an artificial pericardium, or an artificial heart system, an artificial lung system, an artificial heart lung or the like inserted into or replaced into a blood vessel or a lumen. Systems, artificial kidney systems, artificial liver systems, artificial organ systems such as immune regulation systems, indwelling needles, IVH catheters, drug solution catheters, thermodilution catheters, angiographic catheters, vasodilator catheters and dilators or Catheters inserted or placed in blood vessels such as introducers, guide wires for these catheters, stylets, gastric catheters, nutritional catheters, tube feeding (ED) tubes, urinary catheters, guides Urine catheter, balloon catheter, endotracheal suction catheter Catheters are inserted or indwelled in various suction catheter and drainage catheter vessels other than living tissue, such that the can be exemplified. In particular, the medical device according to the present invention is excellent in blood compatibility and can suppress the formation of thrombus on the surface of the medical device, so that the medical device to be inserted into a blood vessel, specifically, cardiovascular, cerebral blood vessel, etc. It is preferably applied to various catheters used for endovascular treatment. In particular, in heart and cerebrovascular treatment, since blood vessels are thin and blood vessels meander, advanced techniques are required. Therefore, medical devices in these fields are particularly required to have lubricity and blood compatibility (antithrombogenicity to prevent thrombus formation) for improving operability.

In this specification, blood compatibility can be evaluated by, for example, a blood coagulation test or a protein adsorption test.

The effect of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In the following examples, the operation was performed at room temperature (25 ° C.) unless otherwise specified. Unless otherwise specified, “%” and “part” mean “% by weight” and “part by weight”, respectively.

Example 1
A base material 1 was prepared by irradiating the surface of a polypropylene (PP) film (thickness: 60 μm) with an electron beam of 70 kGy / sec for 5 seconds in a nitrogen atmosphere.

Separately, ([2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB)) as a zwitterionic monomer having blood compatibility, and acrylic acid (AAc) as an anionic monomer, 95 : The monomer solution (1) was prepared by dissolving in water so that the molar ratio was 5. Here, the total monomer concentration (molar concentration) of the monomer solution was adjusted to be 1 mol / L monomer solution.

Next, the base material 1 prepared above is immersed in the monomer solution (1) prepared above while nitrogen bubbling, and a polymerization reaction is performed at 50 ° C. (monomer solution temperature) for 1 hour, thereby forming a lubrication comprising a polymer brush. A layer was formed on substrate 1 (substrate 2). This base material 2 was washed with water to produce a medical device 1. About the lubricating layer formed in this way, the film thickness (dry film thickness) was measured using an optical interference type film thickness meter (F40 manufactured by FILMETRIX). As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 95: 5 (molar ratio)).

When the obtained medical device 1 was rubbed with a finger, it exhibited excellent lubricity and durability.

Example 2
A medical device 2 was produced in the same manner as in Example 1 except that a nylon elastomer sheet (thickness: 1 mm) was used instead of the polypropylene film (thickness: 60 μm). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 95: 5 (molar ratio)).

When the obtained medical device 2 was rubbed strongly with a finger, as in Example 1, excellent lubricity and durability were exhibited.

Example 3
As a zwitterionic monomer having blood compatibility ([2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB)) 3.27 g (11.7 mmol), acrylic acid (AAc) 0 0.09 g (1.3 mmol) and water were added to prepare 13 mL of an aqueous monomer solution (3) [total monomer concentration (molar concentration) = 1 mol / L]. At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 90:10.

Next, 0.05 g of benzophenone is dissolved in 10 mL of acetone, a high-density polyethylene (HDPE) sheet (thickness: 1 mm) is immersed in it for 1 minute, and then pulled up and dried at room temperature (25 ° C.). The HDPE sheet | seat (base material 3) which removed and adsorb | sucked the benzophenone was obtained.

Further, the HDPE sheet (base material 3) adsorbed with benzophenone thus obtained was immersed in the monomer aqueous solution and subjected to nitrogen bubbling for 1 minute, and then sealed and irradiated with ultraviolet rays (illuminance 2.5 mW / cm ² , (Wavelength 365 nm) was irradiated for 2 hours, a copolymer of SPB and AAc was grafted onto the surface of the HDPE sheet, and a lubricating layer composed of a polymer brush was formed on the substrate 3 (substrate 4). This base material 4 was washed with water to produce a medical device 3. With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 90: 10 (molar ratio)).

When the obtained medical device 3 was rubbed strongly with a finger, it exhibited excellent lubricity and durability.

Example 4
2.91 g (10.4 mmol) of SPB, 0.19 g (2.6 mmol) of AAc, and water were added to prepare 13 mL of an aqueous monomer solution (4). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 80:20.

In Example 3, the medical device 4 was produced in the same manner as in Example 3 except that the monomer aqueous solution (4) thus prepared was used instead of the monomer aqueous solution (3). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 80: 20 (molar ratio)).

When the obtained medical device 4 was rubbed strongly with a finger, it exhibited excellent lubricity and durability.

Example 5
SPB 2.54 g (9.1 mmol), AAc 0.28 g (3.9 mmol), and water were added to prepare 13 mL of an aqueous monomer solution (5). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 70:30.

In Example 3, the medical device 5 was produced in the same manner as in Example 3 except that the monomer aqueous solution (5) thus prepared was used instead of the monomer aqueous solution (3). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 70: 30 (molar ratio)).

When the obtained medical device 5 was rubbed strongly with a finger, it exhibited excellent lubricity and durability.

Example 6
SPB 2.18 g (7.8 mmol), AAc 0.37 g (5.2 mmol), and water were added to prepare 13 mL aqueous monomer solution (6). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 60:40.

In Example 3, a medical device 6 was produced in the same manner as in Example 3 except that the monomer aqueous solution (6) thus prepared was used instead of the monomer aqueous solution (3). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 60: 40 (molar ratio)).

When the obtained medical device 6 was rubbed with a finger, it exhibited excellent lubricity and durability.

Example 7
SPB 1.82 g (6.5 mmol), AAc 0.47 g (6.5 mmol), and water were added to prepare a 13 mL aqueous monomer solution (7). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 50:50.

In Example 3, the medical device 7 was produced in the same manner as in Example 3 except that the monomer aqueous solution (7) thus prepared was used instead of the monomer aqueous solution (3). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm. The polymer brush is composed of an SPB-AAc copolymer (SPB: AAc = 50: 50 (molar ratio)).

When the obtained medical device 7 was rubbed strongly with a finger, it exhibited excellent lubricity and durability.

Comparative Example 1
SPB 3.63g (13.0mmol) and water were added, and 13 mL monomer aqueous solution (8) was prepared. At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 100: 0.

In Example 3, the medical device 8 was produced in the same manner as in Example 3 except that the monomer aqueous solution (8) thus prepared was used instead of the monomer aqueous solution (3). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this comparative example is estimated to be in the range of 10 nm to 100 nm.

When the obtained medical device 8 was rubbed with a finger, it exhibited excellent lubricity and durability.

Comparative Example 2
No monomer was added and only 13 mL of water was added. At this time, the charge ratio of SPB and AAc (SPB: AAc (molar ratio)) is 0: 0.

In the above Example 3, a medical device 9 was produced in the same manner as in the above Example 3 except that this water was used in place of the monomer aqueous solution (3).

The obtained medical device 9 was strongly rubbed with a finger, but no lubricity was exhibited.

The blood compatibility of the medical devices 3 to 9 obtained above was evaluated according to the following method. The results are shown in Table 1 below.

(Evaluation of blood compatibility)
Prepare 4 mL of human blood containing 0.5 unit / mL heparin, immerse the pre-weighed medical devices 3 to 9 and let it stand at room temperature (25 ° C.) for 2 hours. Tools 3-9 were withdrawn from the blood and rinsed 10 times in phosphate buffered saline (PBS, pH 7.4). When the appearance was observed, adhesion of thrombus was observed on the medical device 6, the medical device 7, and the medical device 9. Here, the attached state of the thrombus of the medical devices 4, 7 and 9 is shown in FIG.

Next, the medical devices 3 to 9 are immersed in a 1% glutaraldehyde PBS solution and allowed to stand at room temperature (25 ° C.) for 3 hours, and then the medical devices 3 to 9 are pulled up from the glutaraldehyde PBS solution and washed three times with RO water. Washed and dried under reduced pressure for 48 hours.

The amount of thrombus attached was calculated from the change in weight before and after contact with blood. The results are shown in Table 1 below. Here, the evaluation of blood compatibility is regarded as one point for every 0.0001 g of increased weight of clot adhesion, and the smaller the score, the better the blood compatibility. Further, if the score is 1.5 points or less, it is determined to be acceptable, if the score is 1.0 points or less, it is determined that the blood compatibility is excellent, and if the score is 0.5 points or less, Judged to be very excellent in blood compatibility.

From the results of Table 1 above, it can be seen that the medical device of the present invention exhibits blood compatibility. In particular, when the introduction rate of acrylic acid, which is an anionic monomer, is 30 mol% or less in the copolymer, it is suggested that particularly excellent blood compatibility can be exhibited.

Example 8
1.11 g (4.0 mmol) as a zwitterionic monomer having blood compatibility ([2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB)), anionic Acrylic acid (AAc) 1.40 mg (19 μmol) and 5 mL of water were added as monomers, and after 2 minutes of nitrogen bubbling, 27.4 mg (0.12 mmol) of ammonium persulfate and N, N, N ′, N′-tetramethylethylenediamine (27.8 mg, 0.24 mmol) was added, sealed, and allowed to stand overnight at room temperature (25 ° C.) for copolymerization. A copolymer of SPB and AAc (SPB: AAc) = 99.5: 0.5 (molar ratio)).

Next, this polymerization solution is put into a dialysis membrane (fractionated molecular weight (MWCO) = 1,000), dialyzed against RO water for 3 days, freeze-dried, and SPB-AAc copolymer (SPB: AAc = 99). .5: 0.5 (molar ratio)) (compound 1) was obtained.

Example 9
An SPB-AAc copolymer was prepared in the same manner as in Example 8, except that the addition amounts of SPB and AAc were changed to 1.08 g (3.9 mmol) and 8.60 mg (0.12 mmol), respectively. (SPB: AAc = 97: 3 (molar ratio)) (Compound 2) was obtained.

Example 10
An SPB-AAc copolymer was prepared in the same manner as in Example 8, except that the addition amounts of SPB and AAc were changed to 1.06 g (3.8 mmol) and 14.4 mg (0.20 mmol), respectively. (SPB: AAc = 95: 5 (molar ratio)) (Compound 3) was obtained.

Example 11
An SPB-AAc copolymer was prepared in the same manner as in Example 8, except that the addition amounts of SPB and AAc were changed to 0.89 g (3.2 mmol) and 57.6 mg (0.80 mmol), respectively. (SPB: AAc = 80: 20 (molar ratio)) (Compound 4) was obtained.

Comparative Example 3
In Example 8, only 0.288 g (4.0 mmol) of AAc was added to the centrifuge tube without adding SPB, and 5 mL of a 10.0 wt% saturated aqueous sodium hydrogen carbonate solution was further added to the polymerization solution, followed by dialysis. An AAc polymer (SPB: AAc = 0: 100 (molar ratio)) (Compound 5) was obtained in the same manner as in Example 8 except for carrying out.

Comparative Example 4
In Example 8, the SPB polymer (SPB: AAc = 100: 0) was added in the same manner as in Example 8 except that only 1.12 g (4.0 mmol) of SPB was added to the centrifuge tube without adding AAc. (Molar ratio)) (Compound 6) was obtained.

For the compounds 1 to 6 obtained above, the cohesiveness (association of polymer chains) was evaluated according to the following method. The results are shown in Table 2 below.

(Evaluation of cohesiveness (association of polymer chains))
Compounds 1 to 6 were each dissolved in 10 mM Tris-HCl so as to have a concentration of 10 mg / mL, the appearance of the solution was observed with the naked eye, and the presence or absence of turbidity (white turbidity) was evaluated. Here, the appearance of a solution containing the compounds 3, 5 and 6 is shown in FIG.

From the results shown in Table 2, it can be seen that the solutions containing the compounds 2 to 5 according to the present invention are transparent, that is, the association between the polymer chains is significantly reduced and no aggregate is formed. In particular, when the introduction rate of acrylic acid, which is an anionic monomer, is 3 mol% or more in the copolymer, it is suggested that the effect of suppressing association (aggregation) can be exhibited. In contrast, the compound 6 consisting only of SPB, which is a zwitterionic monomer having blood compatibility, is excellent in blood compatibility (Table 1), but the polymer chains associate to form an aggregate. .

From the results of Tables 1 and 2 above, it is considered that the lubrication layer made of the polymer brush according to the present invention exhibits excellent blood compatibility and lubricity, and the association between the polymer chains does not occur or hardly occurs. .

This application is based on Japanese Patent Application No. 2015-68760 filed on Mar. 30, 2015 and Japanese Patent Application No. 2015-247916 filed on Dec. 18, 2015. , Referenced and incorporated in its entirety.

1 ... medical equipment,
2 ... polymer chain (polymer brush),
3 ... Lubrication layer,
4 ... Base material layer.

Claims

A medical device having a base material layer,
On the base material layer, there is a lubricating layer in which polymer chains having a length of less than 10 μm are present in a brush shape,
The medical device, wherein the polymer chain is formed from a copolymer of a zwitterionic monomer having blood compatibility and an anionic monomer, and has a negative charge when contacting a body fluid.
The medical device according to claim 1, wherein the zwitterionic monomer has a betaine skeleton.
The medical device according to claim 1 or 2, wherein the copolymer contains more zwitterionic monomers than anionic monomers.
The molar ratio of the zwitterionic monomer to the anionic monomer is 60 to 99:40 to 1 (provided that the total molar ratio of the zwitterionic monomer and the anionic monomer is 100). 4. The medical device according to any one of 3 above.