JP6868235B2 - Polymers for medical devices, materials for medical devices and medical devices using them - Google Patents

Description

The present invention relates to polymers for medical devices and the like. More specifically, the present invention relates to a polymer for a medical device having high biocompatibility, which is suitable as a material for a medical device used in contact with a biological component or a biological tissue.

It is possible to design polymer compounds having various characteristics by selecting a monomer as a raw material, and they are widely used in various applications from industrial products to daily necessities. One of the uses of such polymer compounds is for medical devices. Medical devices are used in an environment where they come into contact with biological components such as blood and biological tissues, and when the surface of the medical device has a low affinity for biological components and tissues, the biological defense mechanism is activated and blood coagulates. This causes problems such as the formation of blood clots. For this reason, medical devices need to have at least a surface in contact with biological components and tissues made of a highly biocompatible material.

As a polymer material used in such a medical field, a coating composition for preventing adsorption of bio-related substances containing a copolymer, a cross-linking agent and a solvent obtained from a raw material monomer containing two types of specific monomers is brought into contact with each other. Anti-thrombotic property consisting of an article for bio-related substances having a film formed by heating on the surface (see Patent Document 1) and a graft copolymer obtained by graft-polymerizing a specific radically polymerizable monomer onto a thermoplastic elastomer. Materials for medical devices (see Patent Document 2), phosphorylcholine-like group-containing polymers obtained from phosphorylcholine-like group-containing monomers, etc. (see Patent Document 3) and specific copolymers on medical devices for transporting therapeutic agents A method of forming a layer by a composition containing a bound therapeutic agent (see Patent Document 4) is described.

Japanese Unexamined Patent Publication No. 2006-158961 Japanese Unexamined Patent Publication No. 7-16292 JP-A-2002-356519 Special Table 2006-519049

In the above-mentioned documents, polymers having a glycerol group are used as the polymer material, but none of them has sufficient antithrombotic properties, and the weight has more suitable performance as a polymer for medical devices. There was room for ingenuity to develop coalescence.

The present invention has been made in view of the above situation, and an object of the present invention is to provide a polymer which has high antithrombotic property as compared with a conventional polymer having a glycerol group and is more suitable as a material for medical devices. ..

The present inventor has investigated various polymers having higher antithrombotic properties than conventional polymers having a glycerol group, and found that a structural unit derived from a glycerol group-containing monomer and an ethylenically unsaturated group have 4 carbon atoms. Whether it has a structural unit derived from an unsaturated polymer having a structure in which the above organic groups are bonded and the glass transition temperature is 10 ° C. or lower, or the glass transition temperature at the time of saturated water content is -25 ° C. or lower. Whether the polymer satisfying at least one of the above or having a glycerol group at a ratio of 1 mmol or more per 1 g of the polymer and the glass transition temperature is 10 ° C. or lower, or the glass transition temperature at the time of saturated water content is -25 ° C. or lower. A polymer satisfying at least one of the above has higher antithrombotic properties than a conventional polymer having a glycerol group, and is more suitable as a material for medical devices in which adhesion and activation of platelet cells are sufficiently suppressed. The present invention was reached by finding that it is a polymer and brilliantly solving the above-mentioned problems.

That is, the present invention is a polymer used as a material for medical devices, in which a structural unit derived from a glycerol group-containing monomer and an organic group having 4 or more carbon atoms are bonded to an ethylenically unsaturated group. A medical treatment characterized by having a structural unit derived from an unsaturated monomer having a above-mentioned structure and having a glass transition temperature of 10 ° C. or lower and / or a glass transition temperature of −25 ° C. or lower at the time of saturated water content. It is a polymer for tools.
The present invention is also a polymer used as a material for medical devices, wherein the polymer has a glycerol group at a ratio of 1 mmol or more per 1 g of the polymer, a glass transition temperature of 10 ° C. or less, and / or. It is also a polymer for medical devices, characterized in that the glass transition temperature at the time of saturated water content is -25 ° C. or lower.

The polymer for medical devices of the present invention has the above-mentioned structure, has excellent antithrombotic properties, and sufficiently suppresses the occurrence of adhesion and activation of platelet cells. Therefore, it is a material for medical devices. It can be suitably used for antithrombotic coating agents and the like.

The present invention will be described in detail below.
A combination of two or more of the individual preferred embodiments of the present invention described below is also a preferred embodiment of the present invention.

The polymer for medical devices of the present invention has (1) an unsaturated monomer derived from a glycerol group-containing monomer and an unsaturated monomer having a structure in which an organic group having 4 or more carbon atoms is bonded to an ethylenically unsaturated group. Those having a structural unit of origin and having a glass transition temperature of 10 ° C. or lower and / or a glass transition temperature of -25 ° C. or lower when saturated with water, (2) 1 mmol or more of glycerol group per 1 g of polymer There are two types: those having a ratio and having a glass transition temperature of 10 ° C. or lower, and / or having a glass transition temperature of -25 ° C. or lower when saturated with water. Each of them is characterized in that the glass transition temperature and / or the glass transition temperature at the time of saturated water content is equal to or lower than a predetermined temperature.
In the following, the polymer for medical devices of (1) will be referred to as the first polymer for medical devices of the present invention, and the polymer for medical devices of (2) will be referred to as the second polymer for medical devices of the present invention. .. Further, a combination of both of these is described as a polymer for medical devices of the present invention.

<First polymer for medical devices of the present invention>
The first polymer for medical devices of the present invention is derived from an unsaturated monomer having a structural unit derived from a glycerol group-containing monomer and a structure in which an organic group having 4 or more carbon atoms is bonded to an ethylenically unsaturated group. The glass transition temperature is 10 ° C. or lower, and / or the glass transition temperature at the time of saturated water content is −25 ° C. or lower.
The first polymer for medical devices of the present invention may satisfy at least one of the requirements of a glass transition temperature of 10 ° C. or lower and a glass transition temperature of -25 ° C. or lower at the time of saturated water content, but both. It may meet the requirements.

When the first polymer for medical devices of the present invention satisfies the requirement that the glass transition temperature is 10 ° C. or lower, the glass transition temperature is preferably 0 ° C. or lower. More preferably, it is −5 ° C. or lower, and even more preferably, it is −10 ° C. or lower. The glass transition temperature has no particular lower limit, but is usually −100 ° C. or higher.
When the first polymer for medical devices of the present invention satisfies the requirement that the glass transition temperature at saturated water content is −25 ° C. or lower, the glass transition temperature at saturated water content is preferably −30 ° C. or lower. is there. More preferably, it is −35 ° C. or lower, and even more preferably, it is −40 ° C. or lower. The glass transition temperature at the time of saturated water content is not particularly limited, but is usually −150 ° C. or higher.
The glass transition temperature of the polymer for medical devices of the present invention and the glass transition temperature at the time of saturated water content can be measured by the method described in Examples.

The first polymer for medical devices of the present invention is derived from an unsaturated monomer having a structural unit derived from a glycerol group-containing monomer and a structure in which an organic group having 4 or more carbon atoms is bonded to an ethylenically unsaturated group. It has the structural units of the above, and may contain one kind of each of these structural units, or may contain two or more kinds of these structural units. In the present invention, the structure derived from the unsaturated monomer is a structure in which the carbon-carbon double bond (C = C) of the unsaturated monomer is replaced with a carbon-carbon single bond (-CC-). Is. Typically, it has a structure formed by polymerizing unsaturated monomers, and a monomer having two or more unsaturated bonds may have a structure in which a ring is formed. However, the structure is not limited to the structure actually formed by polymerizing an unsaturated monomer, but is not limited to a structure in which a carbon-carbon double bond is replaced with a carbon-carbon single bond or a structure in which a ring is formed. It corresponds to a structural unit derived from a saturated monomer.
Further, the first polymer for medical devices of the present invention is an unsaturated unit having a structural unit derived from a glycerol group-containing monomer and a structure in which an organic group having 4 or more carbon atoms is bonded to an ethylenically unsaturated group. It has at least two types of structural units derived from the body, and these plurality of structural units may be in any form of random polymerization, block polymerization, or alternating polymerization.

The structural unit derived from the glycerol group-containing monomer is not particularly limited as long as it is a structural unit derived from a monomer having a glycerol group and an ethylenically unsaturated bond site, but the following formula (1-1) and / Or (1-2);

(In the formula, R ¹ represents a hydrogen atom, a methyl group, or -R ^5- Y. R ⁵ represents -CH _2- or -CH ₂ CH _2-. X and Y represent the following formula (2). ) Or -CO-O-R ⁶ (R ⁶ is an organic group having 1 to 24 carbon atoms), and at least one of X and Y is represented by the following formula (2). It is a group.)

(In the formula, R ² represents -CH _2- , -CO- or a direct bond, and n represents a number from 0 to 20), which is preferably a structural unit.
^{As the organic group of R 6} in the above formula (1-1), a hydrocarbon group is preferable, and an alkyl group is more preferable.
In the above formula (2), n is preferably 0 to 15. It is more preferably 0 to 10, and even more preferably 0 to 5.
Among these, the structural unit derived from the glycerol group-containing monomer has a structural unit derived from glycerol (meth) acrylate, that is, the first polymer for medical devices of the present invention is derived from glycerol (meth) acrylate. Having a structural unit is one of the preferred embodiments of the first polymer for medical devices of the present invention.

The structural unit derived from the unsaturated monomer having a structure in which an organic group having 4 or more carbon atoms is bonded to the ethylenically unsaturated group preferably has an organic group having 4 or more carbon atoms bonded continuously (meth). ) A structural unit derived from acrylic acid ester. That is, the following equation (3);

(In the formula, R ³ represents a hydrogen atom or a methyl group. R ⁴ represents an organic group in which 4 or more carbons are continuously bonded.) A structural unit represented by is preferable.
The continuously organic groups bonded carbon 4 or more R ^4, preferably, it is of 4 to 15 carbon atoms, more preferably of 4-10.
The continuously organic groups bonded carbon 4 or more R ^4, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, any or part of the carboxyl groups of these groups of aralkyl groups, carboxyl salts, hydroxy Examples thereof include groups having a structure substituted with a substituent such as a group, an epoxy group, an amino group and an alkoxy group.

Examples of the monomer forming the structural unit represented by the above formula (3) include n-butyl (meth) acrylate, s-butyl (meth) acrylate, t-butyl (meth) acrylate, and (meth). N-amyl acrylate, s-amyl (meth) acrylate, t-amyl (meth) acrylate, n-hexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, isodecyl (meth) acrylate, ( Tridecyl (meth) acrylate, cyclohexyl (meth) acrylate, cyclohexylmethyl (meth) acrylate, octyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, benzyl (meth) acrylate, ( Phenyl acrylate, isobornyl (meth) acrylate, adamantyl (meth) acrylate, tricyclodecanyl (meth) acrylate, 2-hydroxybutyl (meth) acrylate, 3-hydroxybutyl (meth) acrylate, 4-Hydroxybutyl (meth) acrylate, 2-ethoxyethyl (meth) acrylate, phenoxyethyl (meth) acrylate, tetrahydrofurfuryl (meth) acrylate, β-methylglycidyl (meth) acrylate, (meth) Examples thereof include (meth) acrylic acid esters such as β-ethylglycidyl acrylate, (meth) acrylic acid (3,4-epoxycyclohexyl) methyl, and (meth) acrylic acid N, N-dimethylaminoethyl.

Among the structural units derived from unsaturated monomers having a structure in which an organic group having 4 or more carbon atoms is bonded to the ethylenically unsaturated group, those other than those derived from (meth) acrylic acid ester are butyl vinyl ether and 2-. Vinyl ethers such as ethylhexyl vinyl ether, dodecyl vinyl ether, stearyl vinyl ether, diethylene glycol vinyl ether, triethylene glycol vinyl ether, N-vinyls such as N-vinylpyrrolidone, N-vinylmorpholine, N-vinylcaprolactam, N-vinylcarbazole, N-phenyl Examples thereof include N-substituted maleimides such as maleimide, N-benzylmaleimide, N-naphthylmaleimide, N-cyclohexylmaleimide, N-butylmaleimide, N-isopropulmaleimide and N-ethylmaleimide.

The first monomer component used as a raw material for the polymer for medical devices of the present invention is an unsaturated monomer having a structure in which an organic group having 4 or more carbon atoms is bonded to a glycerol group-containing monomer and an ethylenically unsaturated group. It may contain other monomers other than the polymer.
Examples of other monomers include (meth) acrylate alkyl esters of any of methyl (meth) acrylate, ethyl (meth) acrylate, and propyl (meth) acrylate; vinyl esters such as vinyl acetate and vinyl propionate. Classes; vinyl chloride, vinylidene chloride and the like; olefins such as ethylene, propylene, butene and isoprene; N-vinyl compounds such as N-vinylformamide and N-vinylacetamide; vinyl ethers such as methyl vinyl ether, ethyl vinyl ether and propyl vinyl ether; Examples thereof include methyl maleimide, and one or more of these can be used.

In the first polymer for medical devices of the present invention, the proportion of the structural unit derived from the glycerol group-containing monomer is 5 to 90% by mass with respect to 100% by mass of the total structural unit of the polymer. preferable. By having such a ratio, the first polymer for medical devices of the present invention becomes excellent in antithrombotic property and the like. The proportion of the structural unit derived from the glycerol group-containing monomer is more preferably 10 to 60% by mass, still more preferably 20 to 50% by mass.

Further, in the first polymer for medical devices of the present invention, the proportion of structural units derived from unsaturated monomers having a structure in which an organic group having 4 or more carbon atoms is bonded to an ethylenically unsaturated group is determined by the polymer. It is preferably 10 to 95% by mass with respect to 100% by mass of the total structural unit having. It is more preferably 10 to 60% by mass, and even more preferably 20 to 50% by mass.
Above all, the ratio of the structural unit represented by the above formula (3) is preferably 10 to 95% by mass with respect to 100% by mass of all the structural units of the polymer. It is more preferably 10 to 60% by mass, and even more preferably 20 to 50% by mass.

When the first polymer for medical devices of the present invention has structural units derived from the other monomers, the ratio thereof is 20% by mass with respect to 100% by mass of the total structural units of the polymer. % Or less is preferable. It is more preferably 10% by mass or less, and further preferably 5% by mass or less.

<Second polymer for medical devices of the present invention>
The second polymer for medical devices of the present invention has a glycerol group at a ratio of 1 mmol or more per 1 g of the polymer, has a glass transition temperature of 10 ° C. or lower, and / or has a glass transition temperature of -25 when saturated with water. It is characterized in that it is below ° C.
Also in the second polymer for medical devices of the present invention, the glass transition temperature is 10 ° C. or lower and / or the glass transition temperature at the time of saturated water content is -25 ° C. or lower, so that the polymer becomes surface hydrophilic. It will be excellent and will have excellent antithrombotic properties.
The glass transition temperature of the second polymer for medical devices of the present invention is such that the glass transition temperature is 10 ° C. or lower and / or the glass transition temperature at the time of saturated water content is -25 ° C. or lower, but the glass transition temperature and saturation. The preferable values of the glass transition temperature at the time of water content are when the glass transition temperature of the first polymer for medical devices of the present invention is 10 ° C. or less, and the glass transition temperature at the time of saturated water content is -25 ° C. or less. Same as the case.

The second polymer for medical devices of the present invention has a glycerol group at a ratio of 1 mmol or more per 1 g of the polymer, and the amount of the glycerol group per 1 g of the polymer is 1.5 mmol or more. preferable. By having such a ratio, the second polymer for medical devices of the present invention becomes excellent in antithrombotic property and the like. More preferably, it is 2 mmol or more. The amount of glycerol groups per 1 g of the polymer is preferably 6 mmol or less. It is more preferably 5 mmol or less, still more preferably 4 mmol or less.

The second polymer for medical devices of the present invention has a structural unit having a glycerol group.
As the structural unit having a glycerol group, the structural unit derived from the glycerol group-containing monomer contained in the first polymer for medical devices of the present invention is preferable.

The second polymer for medical devices of the present invention may have other structural units other than the structural unit having a glycerol group, and the other structural unit is represented by the above-mentioned formula (3). (meth) acrylic acid ester (provided that the number of carbon atoms of R ⁴ in the formula (3) 4 may also not higher) and structural units derived include structural units derived from other monomers mentioned above.

Represented by the aforementioned formula (3) (meth) acrylic acid ester (wherein (3) the number of carbon atoms of R ⁴ may not 4 or more) Specific examples of the above-mentioned formula (3) In addition to specific examples of monomers forming structural units represented by, methyl (meth) acrylate, ethyl (meth) acrylate, n-propyl (meth) acrylate, i-propyl (meth) acrylate, 2-Hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 2-methoxyethyl (meth) acrylate, glycidyl (meth) acrylate, α-hydroxy Examples thereof include (meth) acrylic acid esters such as methyl methyl acrylate and ethyl α-hydroxymethyl acrylate.

When the second polymer for medical devices of the present invention has a structural unit other than the structural unit having a glycerol group, it is preferable to have a structural unit derived from butyl acrylate among the above-mentioned ones.

When the second polymer for medical devices of the present invention has a structural unit other than the structural unit having a glycerol group, the ratio thereof is 10 to 95% by mass with respect to 100% by mass of the total structural unit of the polymer. Is preferable. It is more preferably 20 to 90% by mass, and even more preferably 30 to 80% by mass.

<Polymer for medical devices of the present invention>
In the following, the contents common to both the first polymer for medical devices of the present invention and the second polymer for medical devices of the present invention will be described.

The polymer for medical devices of the present invention preferably has a weight average molecular weight of 1,000 to 1,000,000. When the weight average molecular weight is in such a range, the material has excellent durability and mechanical strength, which is preferable. The weight average molecular weight is more preferably 5,000 to 2,000,000, still more preferably 10,000 to 500,000.

Further, in the polymer for medical devices of the present invention, the proportion of components having a molecular weight of 5000 or less is preferably 5.0% or less of the total polymer. When the proportion of components having a molecular weight of 5000 or less is 5.0% or less of the total polymer, elution of low molecular weight components into blood can be suppressed even after long-term use, and the affinity with biological tissues becomes higher. It will be good. The proportion of the component having a molecular weight of 5000 or less is more preferably 1.0% or less of the whole polymer, and further preferably 0.5% or less of the whole polymer.
The weight average molecular weight of the polymer and the ratio of the components having a molecular weight of 5000 or less can be measured by gel permeation chromatography (GPC) under the measurement conditions described in Examples.

<Method for producing glycerol group-containing monomer>
Among the structural units represented by the above formula (1-1), the following ^{formula (4); which forms a structural unit in which R 1} is a hydrogen atom or a methyl group;

(In the formula, R ¹ represents a hydrogen atom or a methyl group. R ² represents -CH _2- , -CO- or a direct bond. N represents a number from 0 to 20). The method for producing the glycerol group-containing monomer is not particularly limited, but the following formula (5);

(In the formula, R ¹ , R ² , and n are the same as in the formula (4). R ³ represents a hydrogen atom, an alkali metal atom, an ammonium group, or a hydrocarbon group having 1 to 30 carbon atoms.) The represented vinyl compound and the following formula (6);

A method of reacting with the glycerol compound represented by (1) or epichlorohydrin and then reacting the obtained product with water is preferable.
The compound represented by the above formula (5) is represented by the following formula (7);

(In the formula, R ¹ and R ² are the same as those in the formula (4).) It can be produced by reacting a vinyl compound represented by the formula (4) with ethylene oxide or the like.
Of the structural units represented by the above formula (1-1), for those wherein R ¹ is -R 5 ^-Y also referring to the above reaction, it can be produced by appropriately selecting the vinyl compound.

The structural unit represented by the above (1-2) is the following formula (8);

(In the formula, R ² represents -CH _2- , -CO- or a direct bond. N represents a number from 0 to 20.) It can be formed by using a compound represented by the compound or the like. The compound represented by the above formula (8) is replaced with the vinyl compound represented by the above formula (7) by the following formula (9);

(In the formula, R ² is the same as that of the formula (8)), except that the compound represented by the formula (8) is used, which is the same as the method for producing the glycerol group-containing monomer represented by the above formula (4). Can be manufactured.
Specific examples of the compound represented by the above formula (9) include allyloxymethylacrylic acid.

The reaction between the vinyl compound represented by the above formula (5) and the glycerol compound represented by the above formula (6) or epichlorohydrin can be appropriately set in the range of −10 to 150 ° C. and can be carried out under normal pressure and pressure. It may be carried out under either pressure or depressurization conditions.
Among the above reactions, when water is reacted with the reaction product of the vinyl compound represented by the formula (5) and the glycerol compound represented by the formula (6) or epichlorohydrin, in addition to acids such as hydrochloric acid and sulfuric acid, It is preferable to use one or more kinds of acid catalysts such as an inorganic solid acid and a cation exchange resin.
Further, in the above reaction, in order to suppress the polymerization of the vinyl compound, either or both of using a polymerization inhibitor and carrying out the reaction while bubbling a gas containing oxygen into the reaction solution may be carried out. preferable.

<Manufacturing method of polymer for medical devices>
The polymer for medical devices of the present invention can be produced by appropriately selecting a monomer and carrying out a polymerization reaction so as to have the above-mentioned characteristics.
The preferable amount of these monomers used in the raw material of the polymer is the same as the preferable ratio of the structural units derived from these monomers in all the monomer units of the polymer for medical devices of the present invention.

The polymerization reaction in the method for producing a polymer for medical devices is preferably carried out in the presence of a polymerization initiator. Examples of the polymerization initiator include hydrogen peroxide; persulfates such as sodium persulfate, potassium persulfate, and ammonium persulfate; dimethyl 2,2'-azobis (2-methylpropionate), 2,2'-azobis. Azo-based compounds such as (isobutyronitrile); organic peroxides such as benzoyl peroxide, peracetic acid, and di-t-butyl peroxide are suitable. These polymerization initiators may be used alone or in the form of a mixture of two or more.
The amount of the polymerization initiator used is preferably 0.01 g or more and 10 g or less, and 0.1 g or more and 5 g or less, with respect to 1 mol of the monomer used in the polymerization reaction. Is more preferable.

The above-mentioned polymerization reaction may be carried out without using a solvent, but it is preferable to use a solvent. Examples of the solvent include acetonitrile, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol and the like. These solvents may be used alone or in the form of a mixture of two or more.
The amount of the solvent used is preferably 40 to 250% by mass with respect to 100% by mass of the monomer used in the polymerization reaction.

The polymerization reaction is usually preferably carried out at 0 ° C. or higher, and is preferably carried out at 150 ° C. or lower. More preferably, it is 40 ° C. or higher, further preferably 60 ° C. or higher, and particularly preferably 80 ° C. or higher. Further, it is more preferably 120 ° C. or lower, and even more preferably 110 ° C. or lower. The polymerization temperature does not have to be kept substantially constant in the polymerization reaction, and may fluctuate (heat or cool) once or twice or more.
The polymerization reaction may be carried out under any conditions of normal pressure, pressure and reduced pressure.

In the above polymerization reaction, the monomer which is a raw material of the polymer for medical devices, the polymerization initiator and the like may be added to the reactor all at once or sequentially.

The method for producing a polymer for medical devices of the present invention may include steps other than the above-mentioned polymerization reaction step. Examples thereof include a aging step, a neutralizing step, a deactivation step of a polymerization initiator and a chain transfer agent, a dilution step, a drying step, a concentration step, a purification step and the like.

<Materials for medical devices, antithrombotic coating agents and medical devices>
As described above, the polymer for medical devices of the present invention has excellent biocompatibility and can be suitably used as a material for medical devices. A medical device material containing such a medical device polymer of the present invention is also one of the present inventions.
Since the medical device material of the present invention has a high affinity with biological components and tissues, it can be suitably used as an antithrombotic material that does not easily cause thrombus even when it comes into contact with blood, and can be used for various medical devices. It can also be suitably used as a material constituting a portion that comes into contact with a biological component or a biological tissue. Furthermore, the material for medical devices of the present invention can also be suitably used as a cell culture substrate.
In a medical device made of the medical device material of the present invention, at least a part of a portion of the medical device in contact with a biological component or a biological tissue is surface-treated with the medical device material of the present invention, and the medical device of the present invention is used. It can be manufactured using a method of retaining the material. As described above, the material for medical devices of the present invention can be used as a surface treatment agent for medical devices, and can be used, for example, as an antithrombotic coating agent. Such an antithrombotic coating agent using the medical device material of the present invention is also one of the present inventions.
Such a medical device made of the medical device material of the present invention or an antithrombotic coating agent, the medical device has at least a part of a portion in contact with a biological component or a biological tissue for the medical device. A medical device composed of a material or an antithrombotic coating agent is also one of the present inventions, and an antithrombotic material or a cell culture substrate made of the medical device material of the present invention is also the present invention. It is one of the inventions.
The medical device of the present invention may be composed of at least a part of a portion in contact with the biological component or biological tissue using the medical device material, but the area of the portion in contact with the biological component or biological tissue is 50. It is preferable that% or more is covered with the medical device material, more preferably 80% or more, and all the parts that come into contact with the biological component or the biological tissue are covered with the medical device material. Most preferably.
The medical device of the present invention can be used for any purpose of contact with biological components or tissues, but it is one of the preferred embodiments of the medical device of the present invention to be used for the purpose of contact with blood. Is.

As a method of holding the medical device material or antithrombotic coating agent of the present invention in a portion of various medical devices that comes into contact with a biological component or tissue, the surface of the medical device or its parts is made of the medical device material or antithrombotic property. A method of coating with a coating agent, a method of bonding the surface of a medical device with a medical device material or an antithrombotic coating agent by using graft polymerization with active energy rays such as radiation, electron beam, and ultraviolet rays, and a method of bonding the surface of the medical device. Various methods can be used, such as a method of reacting and binding the functional group of the above with a material for a medical device or an antithrombotic coating agent. When the coating method is used, any method such as a coating method, a spray method, or a dip method may be used as a method for coating the surface of the medical device or its parts with a medical device material or an antithrombotic coating agent. In addition, using a composition which requires a monomer component which is a raw material of the above-mentioned polymer for medical devices, it is coated by a coating method, a spray method, a dip method, etc. The reaction may be carried out to form a layer of the medical device material or antithrombotic coating agent of the present invention on the surface of the medical device or the material of the medical device.

The material of the medical device of the present invention and the material of the medical device that holds the antithrombotic coating agent are not particularly limited, and polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, polyvinylidene fluoride, polytetrafluoroethylene, and polyolefin halide. , Polyethylene terephthalate, polycarbonate, polyamide, acrylic resin, styrene resin, polyurethane resin, silicon resin, polysulfone, polyethersulfone, cellulose, cellulose acetate and the like. Further, metals, ceramics, composite materials thereof and the like can be exemplified, and the base material may be composed of a plurality of substrates. Examples of the metal include precious metals such as gold and silver, base metals such as copper, aluminum, tungsten, nickel, chromium and titanium, alloys of these metals, and gold-plated surfaces thereof, but are limited thereto. It's not something. The metal may be used alone, or may be used as an alloy with another metal or an oxide of the metal in order to impart functionality. From the viewpoint of price and availability, it is preferable to use nickel, copper and metals containing these as main components. Here, the main component means a component that occupies 50% by weight or more of the material forming the substrate. The form of the base material is not particularly limited, and may be any form such as a molded body, fiber, non-woven fabric, porous body, particles, film, sheet, tube, hollow fiber, and powder.

When the medical device material of the present invention is used as a cell culture base material, the medical device material may be used as it is, or may be used by coating it on a predetermined base material.
The material of the base material is not particularly limited, and natural polymers such as cotton and linen, polyester, nylon, olefin, polyamide, polyurethane, polyacrylonitrile, poly (meth) acrylate, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, etc. Synthetic polymers such as polyvinylidene fluoride, polytetrafluoroethylene, halogenated polyolefin, polycarbonate, styrol resin, and silicon resin can be used. Further, metals, ceramics, composite materials thereof and the like can be exemplified, and the base material may be composed of a plurality of substrates. Examples of the metal include precious metals such as gold and silver, base metals such as copper, aluminum, tungsten, nickel, chromium and titanium, alloys of these metals, and gold-plated surfaces thereof, but are limited thereto. It's not something. The metal may be used alone, or may be used as an alloy with another metal or an oxide of the metal in order to impart functionality. From the viewpoint of price and availability, it is preferable to use nickel, copper and metals containing these as main components. Here, the main component means a component that occupies 50% by weight or more of the material forming the substrate.
The form of the base material is not particularly limited, and may be any form such as a molded body, a fiber, a non-woven fabric, a porous body, particles, a film, a sheet, a tube, a hollow fiber, and a powder.

The material for medical equipment of the present invention is for artificial living tissues such as artificial blood vessels and artificial organs, blood filters, various catheters, various stents, etc .; as a member for tools that come into contact with living tissues, and as a cell culture substrate. , Members for hemodialysis machines, members for blood or tissue testing instruments, etc .; Can be applied as members for tools that come into contact with biological components (cells, blood, etc.).
That is, the medical device in the present invention includes a device that comes into contact with a living tissue, a tool that comes into contact with a biological component (cell, blood, etc.), and the like.
That is, the material for a medical device in the present invention refers to a material used for a medical device, a cell culture substrate, or an antithrombotic material that comes into contact with a biological tissue or a biological component (cell, blood, etc.).

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Unless otherwise specified, "part" means "part by weight" and "%" means "mass%".

The GC measurement and the weight average molecular weight in the synthesis example, the example and the comparative example were carried out by the following methods.
<GC (Gas Chromatography)>
It was measured by a capillary column DB-17HT L30m × ID0.25mm, DF0.15mm using GC-2010 (manufactured by Shimadzu Corporation).
When measuring the peak area, the left and right baselines of the peak were connected by a straight line, and the area of the portion surrounded by the baseline and the peak was measured as the peak area.
<Weight average molecular weight>
The polymer was dissolved and diluted in tetrahydrofuran and filtered through a filter having a pore size of 0.45 μm (a chromatographic disk non-aqueous type manufactured by Kurabou Co., Ltd.), which was measured by the following gel permeation chromatography (GPC) apparatus and conditions.
・ Equipment: HLC-8320GPC (manufactured by Tosoh Corporation)
・ Elution solvent: Tetrahydrofuran ・ Standard substance: Standard polystyrene (manufactured by Tosoh Corporation)
-Separation column: TSKgel SuperH5000, TSKgel SuperH4000, TSKgel SuperH3000 (manufactured by Tosoh Corporation)

<Synthesis example>
(1) A gas introduction tube, a thermometer, a cooling tube, and a distilling head connected to a distilling liquid receiver are attached to a reaction vessel containing a synthetic stirrer of GLMA (glycerol monoacrylate), and methyl acrylate is attached. 230 g, 2,2-dimethyl-1,3-dioxolan-4-methanol (DOM) 70 g was charged, and the reaction solution was stirred while blowing an oxygen / nitrogen mixed gas (oxygen concentration 7 vol%) through a gas introduction pipe, and an oil bath was used. Heating was started at (bath temperature 110 ° C.). After no water came out to the distillate, 4.5 g of titanium tetraisopropoxide was added to the reaction vessel to start the transesterification reaction. The area ratio of iPGLMA (isopyridene glyceryl acrylate) / DOM was tracked by gas chromatography (GC) analysis while azeotropically distilling off the produced methanol with methyl acrylate. By GC analysis 7 hours after the start of the reaction, it was confirmed that the area ratio of iPGLMA / DOM exceeded 9/1, the reaction was terminated, and the mixture was cooled to room temperature. 150 g of purified water and 300 g of ethyl acetate as an extraction solvent were added to the reaction mixture, and the mixture was stirred for 10 minutes. The precipitate of titanium oxide generated by the hydrolysis of the catalyst was removed by suction filtration, and the filtrate was transferred to a separatory funnel to separate the organic layer and the aqueous layer. The organic layer was washed twice with purified water and then transferred to a rotary evaporator, and residual methyl acrylate and light boiling components were distilled off to obtain 96 g of iPGLMA.

A gas introduction tube was provided in the eggplant flask containing the stirrer, and 160 ml of purified water and 80 g of iPGLMA were added to dissolve the gas. The reaction solution was stirred while blowing an oxygen / nitrogen mixed gas (oxygen concentration 7 vol%) through the introduction tube, and the deprotection reaction was started at room temperature. The area ratio of GLMA / iPGLMA was tracked by GC analysis, and it was confirmed that the area ratio exceeded 99/1, and the reaction was completed in 4 hours. The filtrate obtained by filtering the solid acid catalyst was washed with n-hexane to remove unreacted iPGLMA. The aqueous layer was concentrated under reduced pressure to obtain 53 g of the target GLMA.

(2) Synthesis of GLMM (glycerol monomethacrylate) In the synthesis example (1), the desired GLMM was obtained in the same manner except that methyl methacrylate was used instead of methyl acrylate.

(3) A reaction vessel containing a synthetic stirrer of AOMA-GL (glycerol allyloxymethylacrylic acid) is provided with a gas introduction tube, a thermometer, a cooling tube and a distilling head connected to a distilling liquid receiver. 120 g of 2,2-dimethyl-1,3-dioxolan-4-methanol, 70 g of α-allyloxymethyl acrylate (AOMA-M), and 120 g of cyclohexane were charged, and an oxygen / nitrogen mixed gas (oxygen concentration 7) was charged through a gas introduction pipe. %) Was blown in, the reaction solution was stirred, and heating was started in an oil bath (bath temperature 100 ° C.). After no water came out to the distillate, 3.0 g of titanium tetraisopropoxide was added to the reaction vessel to start the transesterification reaction. The area ratio of α-allyloxymethylacrylate isopropylidene glyceryl (AOMA-iPGL) / AOMA-M was tracked by gas chromatography (GC) analysis while azeotropically distilling off the produced methanol with cyclohexane. Titanium tetraisopropoxide (1.5 g) and cyclohexane (25 g) were added every 3 hours until the area ratio of AOMA-iPGL / AOMA-M exceeded 9/1 by GC analysis. Cyclohexane was removed under reduced pressure and then cooled to room temperature. 120 g of ion-exchanged water and n-hexane as an extraction solvent were added and stirred, and then titanium oxide, which is a hydrolyzate of the catalyst, was removed by filtration. The filtrate is transferred to a separatory funnel, the organic layer and the aqueous layer are separated, and then ion-exchanged water is added to the organic layer for washing, and the remaining 2,2-dimethyl-1,3-dioxolane-4-methanol is removed. It was transferred to the aqueous layer. The obtained organic layer was depressurized and heated to distill off n-hexane to obtain 100 g of AOMA-iPGL. To 50 g of the obtained AOMA-iPGL, 70 g of ion-exchanged water and 15 g of solid acid catalyst Amberlist 15JWET (manufactured by Organo) were added, and the mixture was stirred at room temperature for 24 hours while blowing an oxygen / nitrogen mixed gas (oxygen concentration 7%). After filtering the reaction solution, water and by-products were distilled off by reducing the pressure and heating to obtain 39 g of AOMA-GL.

(4) A reaction vessel containing a synthetic stirrer of MG-2GL (diglyceryl methyleneglutarate) was provided with a Dean-Stark apparatus equipped with a gas introduction tube, a thermometer, a reflux tower and a cooler, and dimethyl methyleneglutarate. 30 g of (MG-2M), 120 g of 2,2-dimethyl-1,3-dioxolan-4-methanol (DOM), and 1.8 g of dibutyltin oxide were charged, and an oxygen / nitrogen mixed gas (oxygen concentration 7%) was charged through a gas introduction pipe. The reaction solution was stirred while blowing in, heated in an oil bath (bath temperature 130 ° C.), and the transesterification reaction was started under a reduced pressure of 10 kPa. The decrease in MG-2M was followed by gas chromatography (GC) analysis while distilling off the resulting methanol, and the reaction was completed in 12 hours. After cooling to room temperature, 75 g of saturated brine and 150 g of ethyl acetate as an extraction solvent were added, and the mixture was transferred to a separatory funnel to separate the organic layer and the aqueous layer. The organic layer was washed with 75 g of water a plurality of times to remove excess raw material alcohol, and then the light boiling portion was distilled off under reduced pressure to obtain 42 g of diisopyridene glyceryl methyleneglutarate (MG-2iPGL).
After adding 300 ml of methanol and 30 g of MG-2iPGL to a flask provided with a gas introduction tube and dissolving it, 50 g of a solid acid catalyst amber list that has been immersed in water and air-dried in advance is charged, and an oxygen / nitrogen mixed gas (oxygen) is passed through the gas introduction tube. The reaction solution was stirred with a paddle blade while blowing (concentration 7%), and the deprotection reaction was started at room temperature. The disappearance of MG-2iPGL spots and the formation of intermediate and target spots were confirmed by thin layer chromatography (developing solvent; ethyl acetate), and the procedure was completed in 24 hours. The filtrate obtained by filtering the solid acid catalyst was washed with n-hexane to remove unreacted MG-2iPGL, and then the product obtained by concentration under reduced pressure was isolated on a silica gel column (mobile phase methanol / ethyl acetate). 10 g of a pale yellow transparent liquid of the target diglyceryl methyleneglutarate (MG-2GL) was obtained.

<Example>
(1) Production of PGB37 A gas introduction tube, a thermometer, and a cooling tube are attached to a reaction vessel containing a stirrer, and GLMA 1.5 g as a monomer, butyl acrylate (BA) 3.5 g, and methyl ethyl ketone 5.0 g as a solvent are attached. , 0.025 g of an azo radical polymerization initiator (manufactured by Wako Pure Chemical Industries, Ltd., trade name: V-601) was charged, and stirring and temperature raising were started while flowing nitrogen gas. Polymerization was started at an internal temperature of 80 ° C., and a 3 hr reaction was carried out.
The obtained reaction solution was diluted with acetone and reprecipitated by pouring it into a large amount of n-hexane with stirring. The precipitate was dried under reduced pressure at 80 ° C. for 3 hours under reduced pressure by a vacuum dryer to obtain a solid polymer (PGB37). The obtained polymer had a weight average molecular weight of 153,000 and a content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

(2) A solid polymer (PGB46) was obtained in the same manner as in Example (1) except that 2.0 g of GLMA and 3.0 g of butyl acrylate (BA) were used as the production monomers of PGB46. The obtained polymer had a weight average molecular weight of 134,000, and the content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the mixture was filtered with a 0.45 μm filter, and the amount of insoluble matter was determined from the increase in the weight of the filter. However, there was no polymer on the mass filtered by the filter, and the weight change of the filter was 0.1% or less. It was.

(3) A solid polymer (PGB55) was obtained in the same manner as in Example (1) except that 2.5 g of GLMA and 2.5 g of butyl acrylate (BA) were used as the production monomers of PGB55. The obtained polymer had a weight average molecular weight of 75,000, and the content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

(4) A solid polymer (PGBm46) was obtained in the same manner as in Example (1) except that 2.0 g of GLMM and 3.0 g of butyl acrylate (BA) were used as the production monomers of PGBm46. The obtained polymer had a weight average molecular weight of 218,000 and a content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

(5) A solid polymer (PAgB55) was obtained in the same manner as in Example (1) except that 2.5 g of AOMA-GL and 2.5 g of butyl acrylate (BA) were used as the production monomers of PAgB55. .. The obtained polymer had a weight average molecular weight of 300,000 and a content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

(6) Production of PM2gB46 A gas introduction tube, a thermometer, and a cooling tube are attached to a reaction vessel containing a stirrer, MG-2GL 2.0 g as a monomer, 3.0 g of butyl acrylate (BA), and methanol 5 as a solvent. .0 g and 0.025 g of an azo-based radical polymerization initiator (manufactured by Wako Pure Chemical Industries, Ltd., trade name: V-65) were charged, and the mixture was stirred while flowing nitrogen gas to start raising the temperature. Polymerization was started at an internal temperature of 50 ° C., and a 12 hr reaction was carried out.
The obtained reaction solution was diluted with acetone and reprecipitated by pouring it into a large amount of n-hexane with stirring to obtain a solid polymer (PM2gB46). The obtained polymer had a weight average molecular weight of 346,000. The content of the component having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

<Comparison example>
(1) Production of PGS46 A gas introduction tube, a thermometer, and a cooling tube are attached to a reaction vessel containing a stirrer, and GLMA 2.0 g as a monomer, styrene (ST) 3.0 g, and dioxane 5.0 g as a solvent. 0.01 g of organic peroxide (manufactured by Kayaku Akzo Corporation, trade name: Luperox 575) was charged, and stirring and heating were started while flowing nitrogen gas. Polymerization was started at an internal temperature of 90 ° C., and an 8 hr reaction was carried out.
The obtained reaction solution was diluted with acetone and reprecipitated by pouring it into a large amount of n-hexane with stirring. The precipitate was dried under reduced pressure at 80 ° C. for 3 hours under reduced pressure by a vacuum dryer to obtain a solid polymer (PGS46). The obtained polymer had a weight average molecular weight of 74,000, and the content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

(2) Production of PGBm46 A gas introduction tube, a thermometer, and a cooling tube are attached to a reaction vessel containing a stirrer, and GLMA 2.0 g as a monomer, butyl methacrylate (BMA) 3.0 g, and dioxane 5.0 g as a solvent are attached. , 0.01 g of organic peroxide (manufactured by Kayaku Akzo Corporation, trade name: Luperox 575) was charged, and stirring and heating were started while flowing nitrogen gas. Polymerization was started at an internal temperature of 90 ° C., and an 8 hr reaction was carried out.
The obtained reaction solution was diluted with acetone and reprecipitated by pouring it into a large amount of n-hexane with stirring. The precipitate was dried under reduced pressure at 80 ° C. for 3 hours under reduced pressure by a vacuum dryer to obtain a solid polymer (PGBm46). The obtained polymer had a weight average molecular weight of 218,000 and a content of components having a molecular weight of 5000 or less was 0.5% or less. The polymer was dissolved in methanol to make a 1% solution, but no insoluble matter was visually observed. Further, the filter was filtered with a 0.45 μm filter (Kurabo Industries chromatographic disk non-aqueous type), and the amount of insoluble matter was determined from the increase in the weight of the filter. The weight change was 0.1% or less.

For the polymers produced in Examples (1) to (6) and Comparative Examples (1) and (2), the glass transition temperature, the glass transition temperature when water was contained, and the amount of glycerol groups were measured by the following methods. Biocompatibility (antithrombotic property) was evaluated by a platelet adhesion test. The results are shown in Table 1.
<Measurement method of Tg>
The glass transition temperature (Tg) was determined by the midpoint method by measuring with the following differential scanning calorimeter and conditions according to JIS K7121.
・ Equipment: DSC3100 (manufactured by Bruker AXS Co., Ltd.)
・ Temperature rise rate: 10 ℃ / min ・ Nitrogen flow: 50mL / min <Measurement method of Tg when water content>
The same amount of pure water as the polymer was added to the pressure-resistant aluminum pan, and after sealing, the mixture was allowed to stand for one day and night, and then the temperature was raised from −100 ° C. to 40 ° C. at a heating rate of 5 ° C./min for measurement.
<Amount of glycerol group>
The composition of the polymer was calculated and determined from the reaction rate of the monomer determined by GC (gas chromatography).

<Platelet adhesion test>
The antithrombotic property was evaluated by a platelet adhesion test. Each material to be tested was prepared as a 0.2% methanol solution, coated on a PET film by spin coating, and dried as a sample. 0.2 mL of fresh human platelet-rich plasma anticoagulated with sodium citrate was added dropwise to the sample with a pipette, and the mixture was allowed to stand at 37 ° C. for 60 minutes. Subsequently, after rinsing with a phosphate buffer solution and fixing with glutaraldehyde, the substrate was observed with a scanning electron microscope, and the number of platelets adhering to an area of ^{1 × 10 4} μm ^{2 was counted.} According to the degree of morphological change of platelets, it is classified into 3 types, type 1 (normal), type 2 (pseudopodia formation), and type 3 (extension), and MS (morphological score) is defined and calculated as follows. did. From the calculated MS, biocompatibility was evaluated on a 5-point scale.
MS = n ₁ x 1 + n ₂ x 2 + n ₃ x 3
(In the formula, n ₁ represents the number of type 1 platelets, n ₂ represents the number of type 2 platelets, and n ₃ represents the number of type 3 platelets.)
A: MS = 0 or more and less than 100 B: MS = 100 or more and less than 300 C: MS = 300 or more and less than 600 D: MS = 600 or more and less than 1000 E: MS = 1000 or more The smaller the MS, the more difficult it is for platelets to adhere. Shows excellent biocompatibility.
The MS of the PET film performed as a control experiment was E.

From the results in Table 1, it was confirmed that the polymer satisfying the predetermined requirements of the present invention has excellent antithrombotic properties and is suitable as a material for medical devices.

Claims (5)

An antithrombotic coating agent containing a polymer used as a material for medical devices.
The polymer has a structural unit derived from a glycerol group-containing monomer and a structural unit derived from an unsaturated monomer having a structure in which an organic group having 4 or more carbon atoms is bonded to an ethylenically unsaturated group.
An antithrombotic coating agent characterized in that the glass transition temperature is 10 ° C. or lower and / or the glass transition temperature at the time of saturated water content is −25 ° C. or lower. An antithrombotic coating agent containing a polymer used as a material for medical devices.
The polymer has a glycerol group at a ratio of 1 mmol or more per 1 g of the polymer, and has a glass transition temperature of 10 ° C. or lower and / or a glass transition temperature of −25 ° C. or lower when saturated with water. Antithrombotic coating agent. The antithrombotic coating agent according to claim 1 or 2, wherein the polymer has a structural unit derived from glycerol (meth) acrylate. A medical device coated with the antithrombotic coating agent according to any one of claims 1 to 3.
The medical device, medical device and at least a part of the portion in contact with the biological components or biological tissue has been coated by the antithrombogenic coatings. The medical device according to claim 4, wherein the medical device is used for an application of contact with blood.