JP2007289299A - Medical tool - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical tool exhibiting an excellent surface slidability and antithrombogenicity during use. <P>SOLUTION: In the medical tool having a base material layer comprising a polymeric material, a covering layer covering the surface of the base material layer, the covering layer comprises a hydrophilic polymer, the polymeric material forming the base material layer has a first higher-order structure and a first functional group arranged in at least one end of the first higher-order structure in the molecule, and the hydrophilic polymer has a second higher-order structure capable of interacting with the first higher-order structure and a second functional group arranged at least one end of the second higher-order structure and capable of hydrogen-bonding with the first functional group in the molecule. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a medical device having excellent surface lubricity or antithrombogenicity.

  Conventionally, it is based on a medical device in which the surface of a base material is coated with a hydrophilic polymer in order to develop lubricity when wet, or a functional polymer having blood compatibility or biocompatibility in order to develop antithrombogenicity. Medical devices that cover the material surface have been developed and put to practical use. In such a medical device, peeling or elution of the hydrophilic polymer or the functional polymer covering the surface of the base material is a problem in terms of the sustainability of effects such as safety and lubricity. In order to prevent such a problem, Patent Document 1 discloses a high molecular weight mixture containing a mixture of a hydrophilic polymer having a reactive functional group in the molecule and a polymer having a functional group capable of reacting with the reactive functional group. A medical device is disclosed in which a surface lubricating layer is formed on the surface of a substrate by impregnating the surface of the substrate with a molecular solution and then reacting polymers to form a cross-linked structure to insolubilize the substrate.

  Even in the medical device described in Patent Document 1, the lubricating layer can be fixed to the surface of the base material firmly to some extent, but there is a coating material and coating method that can fix the lubricating layer to the surface of the base material in a larger amount and firmly. It has been demanded.

JP-A-8-24327

An object of the present invention is to solve the above-mentioned problems of the prior art and to provide a medical device that exhibits excellent surface lubricity or antithrombogenicity during use.
Another object of the present invention is to provide a medical device in which a hydrophilic polymer or a functional polymer having biocompatibility or blood compatibility is abundantly fixed on the surface of a substrate.

In order to achieve the above object, the present invention is a medical device comprising a base material layer made of a polymer material and a coating layer covering the surface of the base material layer,
The coating layer is made of a hydrophilic polymer,
The polymer material forming the base material layer has, in the molecule, a first higher-order structure and a first functional group provided at at least one end of the first higher-order structure,
The hydrophilic polymer is provided in the molecule at a second higher order structure capable of interacting with the first higher order structure and at least one end of the second higher order structure. A medical device comprising a functional group and a second functional group capable of hydrogen bonding is provided.

Further, the present invention is a medical device comprising a base material layer made of a polymer material and a coating layer covering the surface of the base material layer,
The coating layer is made of a functional polymer excellent in blood compatibility or biocompatibility,
The polymer material forming the base material layer has, in the molecule, a first higher-order structure and a first functional group provided at at least one end of the first higher-order structure,
The functional polymer is provided in the molecule at a second higher order structure capable of interacting with the first higher order structure and at least one end of the second higher order structure. And a second functional group capable of hydrogen bonding is provided.

In the medical device of the present invention, the second higher order structure is a linear alkyl group having 4 or more carbon atoms, and the first higher order structure is an alkyl group that forms the second higher order structure. It is preferably a linear alkyl group having the same or more carbon number.
More preferably, the second higher order structure is a linear alkyl group having 8 or more carbon atoms.

  In the medical device of the present invention, the first functional group is provided at both ends of the first higher-order structure, and the second functional group is provided at both ends of the second higher-order structure. It is preferable.

  In the medical device of the present invention, it is preferable that one of the first functional group and the second functional group is an amide bond and the other is an ester bond.

  In the medical device of the present invention, the polymer material forming the base layer is preferably nylon or nylon elastomer.

  In the medical device of the present invention, the coating layer may contain an antithrombotic agent.

  In addition, the medical device of the present invention has a surface on the surface of a base material by reacting two kinds of polymers having functional groups capable of reacting with each other like the medical device described in Patent Document 1 to form a crosslinked structure. It does not deny what forms the lubricating layer. In addition to such a conventional reaction mechanism, the high-order structures of the polymer material forming the base layer and the polymer material forming the coating layer The coating layer is fixed more and more firmly on the surface of the base material layer by interaction and hydrogen bonding between functional groups.

In the medical device of the present invention, since the coating layer that expresses surface lubricity or antithrombogenicity when wet is firmly fixed to the surface of the base material layer, the coating layer peels off when the medical device is used, There is no risk of elution of components (hydrophilic polymers and hydrophilic polymers excellent in blood compatibility or biocompatibility). For this reason, the medical device is excellent in safety, and desired effects, that is, surface lubricity and antithrombotic properties are maintained for a long time.
In the medical device of the present invention, the base material layer and the coating layer are fixed by the interaction between the higher-order structures of the polymer material forming them and the hydrogen bond between the functional groups of the polymer material. Therefore, the hydrophilic polymer forming the coating layer or the functional polymer excellent in blood compatibility or biocompatibility can be fixed in a large amount and firmly on the surface of the base material layer.

The present invention will be further described below.
The medical device of this invention is equipped with the base material layer which consists of polymeric materials, and the coating layer which coat | covers the surface of this base material layer. The coating layer is made of a hydrophilic polymer or a functional polymer having blood compatibility or biocompatibility. Hereinafter, in the present specification, the hydrophilic polymer forming the coating layer, the functional polymer having blood compatibility or biocompatibility may be collectively referred to as “functional polymer material forming the coating layer”. is there.
In the medical device of the present invention, the polymer material forming the base layer and the functional polymer material forming the coating layer have a higher-order structure capable of interacting with each other and functional groups capable of hydrogen bonding with each other. ing. The higher order structure and functional group will be described in detail later.

The medical device of the present invention is a medical device that is required to have surface lubricity and antithrombotic properties during use, and is inserted or placed in the trachea, digestive tract, urethra, blood vessel, other body cavity, or tissue. It is what is used. Specific examples of such medical devices include, for example, catheters (including catheters, balloon catheter balloons, catheter guide wires, etc.) inserted or placed in blood vessels or other body cavities as described above; wound dressings Artificial organs such as artificial blood vessels, artificial hearts, artificial lungs, artificial kidneys, and artificial livers and their circuits; blood and body fluid storage containers, various organ insertion testing and treatment instruments, contact lenses, etc. .
These medical devices (base materials) may be formed using a single polymer material, or two or more polymer materials may be laminated.
In the medical device of the present invention, the base material layer may be a base material itself formed using a single polymer material as in the former, or on a layer of another polymer material as in the latter. It may be a polymer material layer formed in the above.

  In the medical device of the present invention, the polymer material forming the base material layer is not particularly limited as long as it has properties required as a base material layer of the medical device and has a higher-order structure and a functional group described later. . However, it is preferable to use nylon or a nylon elastomer because a material having a higher-order structure and a functional group, which will be described later, can be obtained and is excellent in tensile strength, elongation, and heat sealability.

  A polymer material having different characteristics from the polymer material constituting the base material layer, such as a base material layer. In some cases, a polymer material having different rigidity and flexibility is used in combination with the polymer material forming the. Further, the medical device may include a material having a specific function, for example, a polymer material having a laser beam reflectivity. In such a case, a polymer material having different characteristics from the polymer material constituting the base material layer or a polymer material having a specific function can be used as the layer of the other polymer material described above.

Nylon is not particularly limited as long as it has a higher-order structure and a functional group, which will be described later, and aliphatic nylon such as nylon 6, nylon 66, nylon 610, nylon 612, nylon 11, nylon 12, nylon 46, and these Examples include copolymers of aliphatic nylons.
The nylon elastomer is typically a block copolymer in which nylon such as nylon 6, nylon 11 and nylon 12 is a hard segment, and a polymer such as polyether and polyester is a soft segment. It is a concept that includes a polymer alloy (polymer blend, graft polymerization, random polymerization, etc.) with a resin rich in flexibility, the above-described nylon softened with a plasticizer or the like, and a mixture thereof.

In the present specification, the hydrophilic polymer is a polymer compound having a water absorption of 1% or more when immersed in physiological saline.
The expression of surface lubricity occurs when a hydrophilic polymer absorbs an aqueous solvent such as physiological saline, a buffer solution, or blood. That is, it is considered that the water existing on the surface of the material is caused by expressing a lubricating function by fluid lubrication at the interface in contact with the blood vessel wall. Therefore, the hydrophilic polymer in the present invention preferably has a water absorption rate of 100 wt% or more in the temperature (usually 30 to 40 ° C.) region where the medical device is used in order to develop surface lubricity.

Examples of such hydrophilic polymers include polymers containing water-soluble monomers such as acrylamide and derivatives thereof, vinyl pyrrolidone, acrylic acid and derivatives thereof, and methacrylic acid and derivatives thereof as constituent components. Specific examples of the water-soluble monomer include, for example, N-methylacrylamide, N, N-dimethylacrylamide, acrylamide, acryloylmorpholine, N, N-dimethylaminoethyl acrylate, vinylpyrrolidone, 2-methacryloyloxyethylphosphine. Examples include folylcholine, 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, and vinyl methyl ether.
In the polymer containing the above-described water-soluble monomer as a constituent component, the portion derived from the water-soluble monomer exhibits surface lubricity when wet.

In this specification, the functional polymer having blood compatibility or biocompatibility widely includes a polymer that does not impair the function as a medical device even when it comes into contact with blood or biological tissue.
Examples of such functional polymers having blood compatibility or biocompatibility include alkoxyalkyl (meth) acrylate, aminoalkyl (meth) acrylate, aminoalkyl (meth) acrylamide, and quaternary ammonium salts thereof. And polymers containing monomers such as various derivatives as constituents.
In the polymer containing a monomer such as the above alkoxyalkyl (meth) acrylate as a constituent component, a site derived from the alkoxyalkyl (meth) acrylate or the like exhibits blood compatibility or biocompatibility.

  Examples of the alkoxyalkyl (meth) acrylate include methoxymethyl (meth) acrylate, methoxyethyl (meth) acrylate, methoxypropyl (meth) acrylate, methoxybutyl (meth) acrylate, ethoxymethyl (meth) acrylate, ethoxyethyl (meth) ) Acrylate, ethoxypropyl (meth) acrylate, ethoxybutyl (meth) acrylate, propoxymethyl (meth) acrylate, propoxyethyl (meth) acrylate, propoxypropyl (meth) acrylate, and propoxybutyl (meth) acrylate. Among these, methoxyalkyl (meth) acrylate is preferable from the viewpoint of economy and operability, and 2-methoxyethyl (meth) acrylate is particularly preferable.

  Specific examples of the aminoalkyl (meth) acrylate include aminomethyl (meth) acrylate, aminoethyl (meth) acrylate, aminoisopropyl (meth) acrylate, amino normal butyl (meth) acrylate, and N-methylaminoethyl. (Meth) acrylate, N-ethylaminoisobutyl (meth) acrylate, N-isopropylaminomethyl (meth) acrylate, N-isopropylaminoethyl (meth) acrylate, N-normalbutylaminoethyl (meth) acrylate, N-tertiary Butylaminoethyl (meth) acrylate, N, N-dimethylaminomethyl (meth) acrylate, N, N-dimethylaminoethyl (meth) acrylate, N, N-dimethylaminopropyl (meth) acrylate, N, N-di Tylaminobutyl (meth) acrylate, N-methyl-N-ethylaminoethyl (meth) acrylate, N-methyl-N-butylaminoethyl (meth) acrylate, N, N-diethylaminoethyl (meth) acrylate, N, N -Diethylaminopropyl (meth) acrylate, N, N-dipropylaminoethyl (meth) acrylate, N, N-dipropylaminopropyl (meth) acrylate, N, N-diaminobutylpropyl (meth) acrylate.

  Specific examples of the aminoalkyl (meth) acrylamide include aminomethyl (meth) acrylamide, aminoethyl (meth) acrylamide, aminoisopropyl (meth) acrylamide, amino normal butyl (meth) acrylamide, and N-methylaminoethyl. (Meth) acrylamide, N-ethylaminoisobutyl (meth) acrylamide, N-isopropylaminomethyl (meth) acrylamide, N-isopropylaminoethyl (meth) acrylamide, N-normalbutylaminoethyl (meth) acrylamide, N-tertiary Butylaminoethyl (meth) acrylamide, N, N-dimethylaminomethyl (meth) acrylamide, N, N-dimethylaminoethyl (meth) acrylamide, N, N-dimethylaminopropyl (Meth) acrylamide, N, N-dimethylaminobutyl (meth) acrylamide, N-methyl-N-ethylaminoethyl (meth) acrylamide, N-methyl-N-butylaminoethyl (meth) acrylamide, N, N-diethylaminoethyl (Meth) acrylamide, N, N-diethylaminopropyl (meth) acrylamide, N, N-dipropylaminoethyl (meth) acrylamide, N, N-dipropylaminopropyl (meth) acrylamide, N, N-diaminobutylpropyl ( And (meth) acrylamide.

  In the medical device of the present invention, the polymer material forming the base material layer and the functional polymer material forming the coating layer have a higher order structure capable of interacting with each other in the molecule. Hereinafter, in this specification, the higher order structure of the polymer material forming the base layer is referred to as “first higher order structure”, and the higher order structure of the functional polymer material forming the coating layer. Is referred to as a “second higher-order structure”.

  In the functional polymer material forming the coating layer, the second higher order structure has a specific function of the functional polymer material, specifically, surface lubricity, blood compatibility or biocompatibility. Different from the site of expression. Therefore, the functional polymer material that forms the coating layer has the second higher-order structure and the site that expresses the specific function described above. When the functional polymer material is a hydrophilic polymer, the functional polymer material has a second higher-order structure and a portion that exhibits surface lubricity when wet. When the functional polymer material is a functional polymer material having blood compatibility or biocompatibility, the functional polymer material has a second higher order structure and a site that expresses blood compatibility or biocompatibility.

The number of first higher order structures present in the molecules of the polymer material forming the base material layer is not particularly limited. Therefore, there may be one first higher order structure in the molecule, or two or more. However, in order to firmly fix the coating layer on the surface of the base material layer, it is preferably 2 or more, more preferably 10 or more, further preferably 100 or more, more preferably 1000 or more in the molecule. It is particularly preferable to do this.
The number of second higher-order structures existing in the molecule of the polymer material forming the coating layer is not particularly limited. Therefore, one second higher order structure may exist in the molecule, or two or more. However, in order to firmly fix the coating layer on the surface of the base material layer by the above-described action, it is preferably present in the molecule at least 2, more preferably at least 10, more preferably at least 50. 100 or more are particularly preferable.

  In the medical device of the present invention, the first higher-order structure and the second higher-order structure are not particularly limited as long as they can interact with each other, but a linear alkyl group is preferably exemplified. When the first higher-order structure and the second higher-order structure are linear alkyl groups, the zigzag structure formed by the linear alkyl groups fits into each other, so that the coating layer is firmly fixed on the surface of the base material layer It is thought that it is done.

However, in order to firmly fix the coating layer on the surface of the base material layer by the above action, the length of the alkyl group forming the first higher order structure is the same as the length of the alkyl group forming the second higher order structure. Alternatively, it is necessary to have a longer chain than the alkyl group having the second higher-order structure. When the alkyl group that forms the first higher-order structure is shorter than the alkyl group that forms the second higher-order structure, the zigzag structure of the alkyl group that forms the second structural structure starts from the alkyl group that forms the first higher-order structure. Since it protrudes, it becomes difficult to firmly fix the coating layer on the surface of the base material layer.
Therefore, the carbon number of the alkyl group that forms the first higher-order structure is the same as or more than the carbon number of the alkyl group that forms the second higher-order structure.
In the case where the polymer material such as nylon 66, nylon 610, or nylon 612 has two or more alkyl groups having different carbon numbers as a higher order structure in the molecule, the number of carbons among the two or more alkyl groups The number of carbon atoms of the alkyl group forming the first higher-order structure is compared with the number of carbon atoms of the alkyl group forming the second higher-order structure for the alkyl group having the largest.

In order to firmly fix the coating layer on the surface of the base material layer by the above action, the number of carbon atoms of the alkyl group forming the second higher order structure is preferably 4 or more, more preferably 8 or more, More preferably, it is 10 or more.
The upper limit of the carbon number of the alkyl group that forms the second higher-order structure is not particularly limited, but the degree of molecular freedom of the polymer material that forms the coating layer is made relatively high, and the alkyl group that forms the second higher-order structure. In consideration of the fact that the zigzag structure of the alkyl group that forms the first higher-order structure easily fits into the zigzag structure of the first higher-order structure, the alkyl group that forms the second higher-order structure preferably has 15 or less carbon atoms. The following is more preferable.

In the medical device of the present invention, the polymer material forming the base material layer and the functional polymer material forming the coating layer are provided in these molecules at at least one end of the higher-order structure, and are capable of hydrogen bonding to each other. Has a functional group. Hereinafter, in the present specification, in the polymer material forming the base material layer, a functional group provided at at least one end of the first higher-order structure is referred to as a “first functional group” and forms a coating layer. In the functional polymer material, a functional group provided at at least one end of the second higher-order structure is referred to as a “second functional group”.
When the polymer material forming the base material layer has two or more first higher-order structures in the molecule, each first higher-order structure is provided with a first functional group at at least one end. It is done. Similarly, when the functional polymer material forming the coating layer has two or more second higher-order structures in the molecule, each of the second higher-order structures has a first at least one end. Functional groups are provided.

As described above, in the medical device of the present invention, the coating layer is firmly fixed to the surface of the base material layer by the interaction between the first higher order structure and the second higher order structure. The first functional group formed on at least one end of the first higher-order structure and the second functional group formed on at least one end of the second structure are formed by hydrogen bonding to each other. The coating layer is more firmly fixed to the surface of the base material layer.
Accordingly, the first functional group is preferably formed at both ends of the first higher-order structure, and the second functional group is preferably formed at both ends of the second higher-order structure.

  When the polymer material forming the base material layer has two or more first higher-order structures in the molecule, the first higher-order structures existing in the molecule are linked by the first functional group. May be. Therefore, the first functional group is not limited to what is generally called a functional group, and may be an amide bond or an ester bond. About these points, the 2nd functional group is also the same.

  In the medical device of the present invention, the first functional group and the second functional group are not particularly limited as long as they are capable of hydrogen bonding with each other, but specifically, an amide bond or an ester bond is preferable. However, since the first functional group and the second functional group are capable of hydrogen bonding with each other, when the first functional group is an amide bond, the second functional group is an ester bond, and the first functional group When is an ester bond, the second functional group is an amide bond.

The combination of the polymer material forming the base material layer and the functional polymer material forming the coating layer in the medical device of the present invention will be described with specific examples.
When the polymer material forming the base material layer is nylon 12, the first higher-order structure is a linear alkyl group having 11 carbon atoms, and the first functional group is an amide bond. In this case, as the functional polymer material forming the coating layer, in addition to the above-described specific function (surface lubricity, blood compatibility or biocompatibility), the second higher-order structure has 11 carbon atoms. The following linear alkyl group may be used, and those having an ester bond as the second functional group at at least one terminal of the linear alkyl group may be used.

  When the functional polymer material forming the coating layer is a hydrophilic polymer, it has a linear alkyl group having 11 or less carbon atoms as the second higher order structure in addition to the portion that exhibits surface lubricity when wet. The one having an ester bond as the second functional group at the terminal of at least one of the linear alkyl groups may be used. As a method for producing a hydrophilic polymer having such a structure, water-soluble monomers such as acrylamide and derivatives thereof, vinylpyrrolidone, acrylic acid and derivatives thereof, methacrylic acid and derivatives thereof, a second higher-order structure and A monomer having a second functional group, specifically, for example, a polysiloxane having a linear alkyl group having 11 or less carbon atoms and a peroxide group bonded to both ends of the alkyl group in the molecule. What is necessary is just to copolymerize an oxide.

  On the other hand, in the case where the functional polymer material forming the coating layer is a functional polymer having blood compatibility or biocompatibility, the second higher-order structure is used in addition to the site that exhibits blood compatibility or biocompatibility. A linear alkyl group having 11 or less carbon atoms and an ester bond as a second functional group at at least one terminal of the linear alkyl group may be used. As a method for producing a functional polymer having such a structure, alkoxyalkyl (meth) acrylate, aminoalkyl (meth) acrylate, aminoalkyl (meth) acrylamide, and derivatives such as quaternary ammonium salts thereof may be used. A monomer, a monomer having a second higher-order structure and a second functional group, specifically, for example, a linear alkyl group having 11 or less carbon atoms in the molecule, and both ends of the alkyl group A polyoxide having a peroxide group bonded to the sulfur may be copolymerized.

  According to the same idea, when the polymer material forming the base material layer is nylon 11, the first higher order structure is a linear alkyl group having 10 carbon atoms, and the first functional group is an amide bond. Therefore, the functional polymer material forming the coating layer has a carbon number of 10 as the second higher-order structure in addition to the above-described specific function (surface lubricity, blood compatibility or biocompatibility). The following linear alkyl group may be used, and those having an ester bond as the second functional group at at least one terminal of the linear alkyl group may be used.

  When the polymer material forming the base material layer is nylon 610, the first higher-order structure is a linear alkyl group having 8 carbon atoms, and the first functional group is an amide bond. The functional polymer material includes linear alkyl having 8 or less carbon atoms as the second higher-order structure in addition to the above-described specific function (surface lubricity, blood compatibility or biocompatibility). A group having an ester bond as a second functional group at the terminal of at least one of the linear alkyl groups.

  When the polymer material forming the base material layer is nylon 6, the first higher order structure is a linear alkyl group having 5 carbon atoms, and the first functional group is an amide bond. The functional polymer material includes a linear alkyl having 5 or less carbon atoms as the second higher-order structure in addition to the above-described specific function (surface lubricity, blood compatibility or biocompatibility). A group having an ester bond as a second functional group at the terminal of at least one of the linear alkyl groups.

When the polymer material forming the base layer is a block copolymer having a nylon elastomer, for example, nylon 12 as a hard segment and polytetramethylene oxide glycol (PTMG) as a soft segment, the first higher order structure is It is a linear alkyl group having 11 carbon atoms, and the first functional group is an amide bond. In this case, as the functional polymer material forming the coating layer, in addition to the above-described specific function (surface lubricity, blood compatibility or biocompatibility), the second higher-order structure has 11 carbon atoms. The following linear alkyl group may be used, and those having an ester bond as the second functional group at at least one terminal of the linear alkyl group may be used.
In the case of a nylon elastomer having a hard segment and a soft segment, the first higher order structure and the first functional group may be present in either the hard segment or the soft segment, or may be present in both. .

  The hydrophilic polymer that forms the coating layer has a ratio of the second higher-order structure in the molecule to the portion that expresses surface lubricity when wet in the range of 1: 1 to 1: A coating layer of 50 is preferable because the coating layer can be firmly fixed to the surface of the base material layer and can exhibit excellent surface lubricity when wet. If the second higher-order structure is excessive from the above ratio, the surface lubricity expressed when wet may be insufficient. On the other hand, when the second higher-order structure is less than the above ratio, the coating layer may be insufficiently fixed to the surface of the base material layer. The ratio between the second higher order structure and the portion that exhibits surface lubricity when wet is more preferably 1:10 to 1:40, and further preferably 1:20 to 1:30. .

  The functional polymer having blood compatibility or biocompatibility forming the coating layer is a ratio between the number of second higher-order structures in the molecule and the number of sites exhibiting blood compatibility or biocompatibility. However, it is preferable that the ratio is 1: 1 to 1:50 because the coating layer can be firmly fixed to the surface of the base material layer and excellent blood compatibility or biocompatibility can be expressed. If the second higher-order structure is excessive from the above ratio, blood compatibility or biocompatibility may be insufficient. On the other hand, when the second higher-order structure is less than the above ratio, the coating layer may be insufficiently fixed to the surface of the base material layer. The ratio between the second higher order structure and the site expressing blood compatibility or biocompatibility is more preferably 1:10 to 1:40, and preferably 1:20 to 1:30. Further preferred.

  The functional polymer material that forms the coating layer has a second higher-order structure, a second functional group, and a site that exhibits a specific function (surface lubricity, blood compatibility, or biocompatibility) in the molecule. It may have the structure. As a specific example of such a structure, when the coating layer contains a physiologically active substance such as an antithrombotic agent, an immunosuppressive agent, an anticancer agent, or insulin, it functions as an acceptor of these physiologically active substances. A reactive functional group is mentioned. Specific examples of the reactive functional group that functions as an acceptor include an epoxy group, an acid chloride group, and an aldehyde group.

  Examples of the method for producing such a hydrophilic polymer having a reactive functional group include alkoxyalkyl (meth) acrylate, aminoalkyl (meth) acrylate, aminoalkyl (meth) acrylamide, and quaternary ammonium salts thereof. A monomer having a second higher-order structure and a second functional group, specifically, for example, a linear alkyl group having 11 or less carbon atoms in the molecule and the alkyl What is necessary is just to copolymerize the polyoxide which has the peroxide group couple | bonded with the both terminal of group, and the monomer which has a reactive functional group, for example, glycidyl (meth) acrylate.

  Examples of the method for producing a blood-compatible or biocompatible functional polymer having such a reactive functional group include alkoxyalkyl (meth) acrylate, aminoalkyl (meth) acrylate, aminoalkyl (meth) acrylamide, and A monomer such as a derivative such as a quaternary ammonium salt and a monomer having a second higher-order structure and a second functional group, specifically, for example, having 11 or less carbon atoms in the molecule A polyoxide having a linear alkyl group, a peroxide group bonded to both ends of the alkyl group, and a monomer having a reactive functional group, for example, glycidyl (meth) acrylate, What is necessary is just to superpose | polymerize.

  When the functional polymer material forming the coating layer has a reactive functional group that functions as an acceptor in the molecule, the number of reactive functional groups in the molecule is the second higher-order structure, the specific structure It is preferably 50% or less, more preferably 30% or less, and even more preferably 10% or less with respect to the total number of functional sites and reactive functional groups.

  When the coating layer contains an antithrombotic agent, the antithrombotic agent is not particularly limited, and can be widely selected from drugs that inhibit thrombus formation and substances that dissolve the generated thrombus. Examples thereof include natural and synthetic substances represented by agents, fibrinolysis accelerators and the like. Specific examples of such substances include heparin, low molecular weight heparin, dermatan sulfate, heparan sulfate, activated protein C, hirudin, thrombomodulin, DHG, plasminogen activator, streptokinase, urokinase, aprotinin, nafamostat mesylate Examples thereof include inhibitors of various coagulation proteases such as (FUT) and gabexate mesylate (FOY).

  The polymer material forming the base material layer may have a structure other than the first higher-order structure and the first functional group in the molecule. Specific examples of such a structure include, for example, a reactive functional group that functions as an acceptor of a physiologically active substance described for the functional polymer material forming the coating layer.

  The base material layer and the coating layer have the above-described polymer material, that is, the polymer material having the first higher-order structure and the first functional group, the functionality having the second higher-order structure and the second functional group. It may be composed mainly of a polymer material, and may contain other materials, such as pigments and contrast materials, to the extent that it does not affect the properties required for medical devices and the formation of coating layers. Furthermore, you may contain another polymeric material.

上記式に示す構造において、ＤＭＡＡが表面湿潤性を発現する部位であり、炭素数８の直鎖のアルキル基が第２の高次構造であり、該アルキル基の両末端に形成されたエステル結合が第２の官能基である。ＧＭＡのエポキシ基は、アクセプターとして機能する反応性官能基である。 The present invention will be further described below using examples.
Example 1
<Preparation of hydrophilic polymer used as coating layer>
After 29.7 g of triethylene glycol was added dropwise to 72.3 g of sebacic acid dichloride at 50 ° C., hydrochloric acid was removed under reduced pressure at 50 ° C. for 3 hours, and 4.5 g of methyl ethyl ketone was added to 22.5 g of the resulting oligoester. The solution was added dropwise to a solution comprising 5 g of sodium oxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of a surfactant dioctyl phosphate, and 120 g of water, and reacted at −5 ° C. for 20 minutes. The reaction product is repeatedly washed with water and methanol, and then dried, and a polyperoxide having a linear alkyl group having 8 carbon atoms and a peroxide group bonded to both ends of the alkyl group in the molecule. Got. 0.5 g of this polyperoxide as an initiator, 9.5 g of glycidyl methacrylate (GMA), and 30 g of benzene as a solvent were polymerized while stirring at 80 ° C. for 2 hours under reduced pressure. The reaction product was purified by using diethyl ether as a poor solvent and tetrahydrofuran as a good solvent, and a polyglycidyl metal having a straight-chain alkyl group having 8 carbon atoms and a peroxide group bonded to both ends of the alkyl group in the molecule. Acrylates (PPO-GMA) were obtained. Subsequently, 9.0 g of PPO-GMA was charged with 9.0 g of dimethylacrylamide and 90 g of dimethyl sulfoxide as a solvent. After sealing under reduced pressure, the mixture was heated to 80 ° C. and subjected to a polymerization reaction for 18 hours. After the reaction, the poor solvent was purified with diethyl ether and the good solvent as tetrahydrofuran to obtain a hydrophilic polymer (dimethylacrylamide (DMAA) -glycidyl methacrylate (GMA) block copolymer). It was specified by NMR and IR measurement that the obtained hydrophilic polymer had a structure represented by the following formula.

In the structure shown in the above formula, DMAA is a site that exhibits surface wettability, a straight-chain alkyl group having 8 carbon atoms is the second higher-order structure, and ester bonds formed at both ends of the alkyl group Is the second functional group. The epoxy group of GMA is a reactive functional group that functions as an acceptor.

表１に記載のナイロンエラストマーは、ナイロン１２をハードセグメントとし、ポリテトラメチレンオキシドグリコール（ＰＴＭＧ）をソフトセグメントとするブロック共重合体である。
シート状の基材を上記手順で調製した親水性高分子２．５質量部をテトラヒドロフラン９７．５質量部に溶解したコーティング溶液中に１分間浸漬し、乾燥させることにより該基材表面に親水性高分子の被覆層を形成した。 <Evaluation of surface lubricity and peeling resistance when coating layers are formed on various substrate surfaces>
Using a polymer material shown in Table 1 below, a sheet-like substrate (dimensions: 30 mm × 30 mm, thickness 0.2 mm) was prepared.

The nylon elastomer described in Table 1 is a block copolymer having nylon 12 as a hard segment and polytetramethylene oxide glycol (PTMG) as a soft segment.
A sheet-like base material prepared by the above procedure was immersed in a coating solution prepared by dissolving 2.5 parts by weight of a hydrophilic polymer in 97.5 parts by weight of tetrahydrofuran and dried to make the surface of the base material hydrophilic. A polymer coating layer was formed.

The following evaluation was performed using the sheet in which the coating layer was formed by the above procedure and the sheet in which the coating layer was not formed as a comparison.
The surface lubricity surface lubricity evaluation sheet to form a coating layer by the above procedure, and the sheet does not form a coating layer as a comparative, those coating layer adhered on a plastic plate so as to be exposed to the outside used. As shown in FIG. 1, the sheet (3) adhered to the plastic plate was placed in the water (1) so as to be inclined at an angle of 30 °. A brass column weight (2) having a mass of 1 kg was gently put on the covering layer of the sheet (3) (when the covering layer was not formed, the exposed surface of the sheet). In this state, the weight (2) was moved up and down by repeating the width of 1 cm 100 times at a speed of 100 cm / min.
The final friction resistance value after 100 times of repetition was evaluated as a surface lubricity index, and the change in frictional resistance value (Δ friction resistance value) obtained by the following equation as a durability index of surface lubricity was evaluated.
ΔFriction resistance value = (Final friction resistance value)-(Initial friction resistance value)

The peel resistance of the coating layer formed on the peel resistant sheet was evaluated by the peeled state by tactile sensation.

The swelling property of the coating layer formed on the swellable sheet was evaluated by determining the swelling rate of the coating layer according to the following procedure.
(1) A 20 mm × 30 mm × 0.2 mm sheet piece was cut from the sheet after the coating layer was formed (the mass at this point is W ₀ ), and immersed in 25 ml of a solvent (tetrahydrofuran).
(2) After immersion, the solvent present on the surface was immediately wiped off, and the mass change (ΔW) before and after immersion was calculated.
(3) The swelling ratio was calculated based on the following formula 1.

The evaluation results are shown in Table 2.

As is apparent from the results in Table 2, when the nylon 12 and nylon 11 having the first higher-order structure and the first functional group are used as the polymer material for forming the base material layer, surface lubricity and resistance The peelability was good.
On the other hand, in the case of nylon 6, polypropylene, polyethylene, and modified polyethylene (PE) not having the first higher-order structure, the surface lubricity and the peel resistance are inferior.
Nylon elastomer has the same first higher-order structure as nylon 12, but the proportion of the first higher-order structure occupying in the molecule is nylon alone (nylon 12 homopolymer) due to the presence of soft segments. ) Less. For this reason, since the ratio of the first higher-order structure in the polymer material constituting the base material layer is smaller than that of nylon 12 and nylon 11, the surface lubricity and peel resistance are inferior to those of nylon 12 and nylon 11. . However, the surface lubricity and the peel resistance are excellent as compared with nylon 6 or the like not having the first higher-order structure.
Nylon 610 also has a proportion of the first higher order structure (nylon 10 segment) in the molecule compared to nylon 12 and nylon 11 because of the presence of the nylon 6 segment not having the first higher order structure. And few. For this reason, since the ratio of the 1st higher order structure to the polymeric material which comprises a base material layer is few compared with nylon 12 and nylon 11, it is inferior to surface lubricity and peeling resistance compared with nylon 12 and nylon 11. . However, the surface lubricity and the peel resistance are excellent as compared with nylon 6 or the like not having the first higher-order structure.

上記式に示す構造において、ＭＥＡが血液適合性を発現する部位であり、炭素数８の直鎖のアルキル基が第２の高次構造であり、該アルキル基の両末端に形成されたエステル結合が第２の官能基である。ＧＭＡのエポキシ基は、アクセプターとして機能する反応性官能基である。 (Example 2)
<Preparation of functional polymer having blood compatibility to be used as coating layer>
After 29.7 g of triethylene glycol was added dropwise to 72.3 g of sebacic acid dichloride at 50 ° C., hydrochloric acid was removed under reduced pressure at 50 ° C. for 3 hours, and 4.5 g of methyl ethyl ketone was added to 22.5 g of the resulting oligoester. The solution was added dropwise to a solution comprising 5 g of sodium oxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of a surfactant dioctyl phosphate, and 120 g of water, and reacted at −5 ° C. for 20 minutes. The reaction product is repeatedly washed with water and methanol, and then dried to obtain a polyperoxide having a linear alkyl group having 8 carbon atoms and a peroxide group bonded to both ends of the alkyl group in the molecule. Obtained. 0.5 g of this polyperoxide as an initiator, 9.5 g of glycidyl methacrylate (GMA), and 30 g of benzene as a solvent were polymerized while stirring at 80 ° C. for 2 hours under reduced pressure. The reaction product was purified by using diethyl ether as a poor solvent and tetrahydrofuran as a good solvent, and a polyglycidyl metal having a straight-chain alkyl group having 8 carbon atoms and a peroxide group bonded to both ends of the alkyl group in the molecule. Acrylates (PPO-GMA) were obtained. Subsequently, 1.0 g of PPO-GMA was charged with 9.0 g of 2-methoxyethyl acrylate and 90 g of dimethyl sulfoxide as a solvent, which was sealed under reduced pressure, and then heated to 80 ° C. to carry out a polymerization reaction for 18 hours. After the reaction, the poor solvent was purified with diethyl ether and the good solvent as tetrahydrofuran, and a functional polymer having blood compatibility (2-methoxyethyl acrylate (MEA) -glycidyl methacrylate (GMA) block copolymer (P (MEA -B-GMA))) was obtained. By NMR and IR measurements, it was identified that the obtained functional polymer had a structure represented by the following formula.

In the structure shown in the above formula, MEA is a site that expresses blood compatibility, a linear alkyl group having 8 carbon atoms is the second higher-order structure, and ester bonds formed at both ends of the alkyl group Is the second functional group. The epoxy group of GMA is a reactive functional group that functions as an acceptor.

<Evaluation of tolerance and platelet adhesion inhibiting ability of coating layers formed on various substrate surfaces>
Using the polymer material shown in Table 1, a sheet-like base material (dimensions: 30 mm × 30 mm, thickness 0.2 mm) was prepared.
A base material in the form of a sheet was immersed in a coating solution prepared by dissolving 2.5 parts by weight of a blood-compatible functional polymer prepared in the above-described procedure in 97.5 parts by weight of tetrahydrofuran and dried. A functional polymer coating layer having blood compatibility was formed on the surface of the material.
A sheet having a coating layer formed by the above procedure, and a sheet having a coating layer formed of 2-methoxyethyl acrylate homopolymer (Homo-PMEA) having no second higher order structure and second functional group as a comparison. The following evaluation was carried out.

A test for platelet adhesion suppression ability was performed using each sheet after the vertical movement of the weight (2) was repeated 50 times by the method shown in FIG.
Platelet adhesion test method The surface of the coating layer formed by the above procedure was contacted with human fresh platelet-rich plasma anticoagulated with sodium citrate for 30 minutes, rinsed with physiological saline, fixed with glutaraldehyde, and 0.5 mm ² The number of platelets adhering to the range was observed with an electron microscope. The results are shown in Table 3.

In the case of a sheet in which a coating layer is formed of Homo-PMEA not having the second higher-order structure and the second functional group, the first higher-order structure and the first functionality are used as the polymer material for forming the base material layer. Even when Nylon 12, Nylon 11, Nylon 610 and Nylon Elastomer having a group are used, the coating layer is peeled off from the base material due to the vertical movement of the weight (2), so the platelet adhesion number is different from the positive control. No value.
About the sheet | seat in which the coating layer was formed with P (MEA-b-GMA) which has a 2nd higher-order structure and a 2nd functional group, as a polymeric material which forms a base material layer, 1st higher-order structure and When nylon 12, nylon 11, nylon 610 and nylon elastomer having the first functional group were used, the platelet adhesion number was remarkably reduced, and it was confirmed that the blood compatibility was excellent. However, since nylon 610 and nylon elastomer have a segment that does not have the first higher-order structure in the polymer, the ratio of the first higher-order structure to the polymer material forming the base layer is nylon 12 and Less than nylon 11. For this reason, compared with nylon 12 and nylon 11, the platelet adhesion number is slightly higher.
On the other hand, in the case of nylon 6, polypropylene, polyethylene and modified polyethylene (PE) having no first higher order structure, the platelet adhesion number was not so low, and it was confirmed that the blood compatibility was poor.

FIG. 1 is an explanatory diagram of a method for evaluating surface lubricity in Examples.

Explanation of symbols

1: Water 2: Brass cylindrical weight 3: Evaluation sheet

Claims (8)

A medical device comprising a base material layer made of a polymer material, and a coating layer that covers the surface of the base material layer,
The coating layer is made of a hydrophilic polymer,
The polymer material forming the base material layer has, in the molecule, a first higher-order structure and a first functional group provided at at least one end of the first higher-order structure,
The hydrophilic polymer is provided in the molecule at a second higher order structure capable of interacting with the first higher order structure and at least one end of the second higher order structure. A medical device comprising a functional group and a second functional group capable of hydrogen bonding. A medical device comprising a base material layer made of a polymer material, and a coating layer that covers the surface of the base material layer,
The coating layer is made of a functional polymer excellent in blood compatibility or biocompatibility,
The polymer material forming the base material layer has, in the molecule, a first higher-order structure and a first functional group provided at at least one end of the first higher-order structure,
The functional polymer is provided in the molecule at a second higher-order structure capable of interacting with the first higher-order structure and at least one end of the second higher-order structure. And a second functional group capable of hydrogen bonding.   The second higher-order structure is a linear alkyl group having 4 or more carbon atoms, and the first higher-order structure has the same or more carbon number as the alkyl group forming the second higher-order structure. The medical device according to claim 1, wherein the medical device is a linear alkyl group.   The medical device according to claim 3, wherein the second higher-order structure is a linear alkyl group having 8 or more carbon atoms.   The first functional group is provided at both ends of the first higher-order structure, and the second functional group is provided at both ends of the second higher-order structure. The medical device in any one of.   The medical device according to any one of claims 1 to 5, wherein one of the first functional group and the second functional group is an amide bond and the other is an ester bond.   The medical device according to any one of claims 1 to 6, wherein the polymer material forming the base material layer is nylon or nylon elastomer.   The medical device according to any one of claims 1 to 7, wherein the coating layer contains an antithrombotic agent.

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