WO2014123077A1

WO2014123077A1 - Medical coating material and medical device

Info

Publication number: WO2014123077A1
Application number: PCT/JP2014/052322
Authority: WO
Inventors: 崇王安齊; 友恵袴谷
Original assignee: テルモ株式会社
Priority date: 2013-02-08
Filing date: 2014-01-31
Publication date: 2014-08-14
Also published as: JP2016063846A

Abstract

Provided are a medical coating material which has excellent hydrophilic properties and a medical device which is coated with said material. This medical coating material comprises a copolymer which includes a segment A having vinylimidazole-derived constitutional units and a segment B having vinyl monomer-derived constitutional units.

Description

Medical coating material and medical device

The present invention relates to a medical coating material and a medical device coated with the material. More specifically, the present invention relates to a medical coating material excellent in hydrophilicity and a medical device coated with the material.

In recent years, medical devices such as plasma separation membranes, catheters, artificial lung membranes, artificial blood vessels, and artificial organs have been used for the treatment of various diseases with the improvement of medical technology. Since these medical devices come into contact with blood, body fluids or biological tissues for a long time, affinity with blood, body fluids or biological tissues, and blood compatibility (antithrombogenicity) to prevent blood coagulation are required. ing.

Usually, imparting antithrombogenicity to a medical device is performed by a method of coating a base material constituting the medical device with an antithrombotic material or a method of fixing an antithrombotic material on the surface of the base material. For example, Patent Document 1 is a copolymer having, as monomer components, an alkoxyalkyl (meth) acrylate monomer represented by the following formula (1) and a monomer having a basic functional group that can be copolymerized with the monomer. The molar ratio of the amount of the monomer represented by the following formula (1) and the amount of the monomer having a basic functional group is 85/15 to 99.9 / 0.1, and the number average molecular weight is 5, An antithrombotic surface treatment agent comprising a copolymer having a molecular weight of 000 to 500,000 and a medical device surface-treated with the antithrombotic surface treatment agent are disclosed. Further, an antithrombotic agent in which an alkoxyalkyl (meth) acrylate and a copolymer having a basic functional group copolymerizable therewith in a specific molar ratio, and an antithrombotic material comprising the copolymer are excellent in antithrombosis It is described that it can exhibit the property and hydrophilicity.

(Wherein R ¹ represents an alkylene group having 1 to 4 carbon atoms, R ² represents an alkyl group having 1 to 4 carbon atoms, and R ³ represents a hydrogen atom or a methyl group.)

JP 2002-105136 A (corresponding to US Patent Application Publication No. 2002/0064558)

However, the above copolymer, and thus the antithrombotic surface treatment agent, has insufficient hydrophilicity, and an antithrombotic surface treatment agent having higher hydrophilicity has been demanded.

Therefore, the present invention has been made in view of the above circumstances, and an object thereof is to provide a medical coating material excellent in hydrophilicity and a medical device coated with the material.

As a result of intensive studies to solve the above problems, the present inventors have found that a copolymer of segment A having a structural unit derived from vinylimidazole and segment B having a structural unit derived from vinyl monomer has a high hydrophilicity. The present invention has been completed by finding that it exhibits the properties (hence, thrombus adhesion suppression / prevention property).

That is, the above-mentioned objects can be achieved by a medical coating material containing a copolymer having a segment A having a structural unit derived from vinylimidazole and a segment B having a structural unit derived from vinyl monomer.

FIG. 1 shows a photograph of the surface of a polypropylene film having a coating layer formed of the copolymer (3) obtained in Example 3 observed with a scanning electron microscope (SEM). FIG. 2 shows a photograph of the surface of a polypropylene film not coated with a polymer (Comparative Example 1) observed with a scanning electron microscope (SEM).

The medical coating material of the present invention comprises a segment A having a structural unit derived from vinylimidazole (also referred to herein as “segment A”) and a segment B having a structural unit derived from vinyl monomer (herein referred to as “segment A”). , Also referred to as “segment B”) (also referred to herein as “copolymer according to the invention”).

The medical coating material of the present invention is characterized by using a copolymer having segment A and segment B. Since the copolymer according to the present invention (hence, the coating layer containing the medical coating material of the present invention and the copolymer according to the present invention) has high hydrophilicity, it is excellent in antithrombogenicity (particularly, adhesion of platelets and adhesion prevention). In addition, it has excellent antibacterial properties. The mechanism by which the copolymer according to the present invention exhibits excellent antithrombogenicity (particularly platelet adhesion / adhesion prevention) and antibacterial properties is unknown, but is presumed as follows. The present invention is not limited by the following estimation. Specifically, the segment A constituting the copolymer according to the present invention has a structural unit derived from vinylimidazole. Here, vinylimidazole is a water-soluble polymer. Further, since the pKa of the imidazole group is 5.9, it is nonionic and hydrophilic under a physiological environment (pH about 7.4). For this reason, a polymer having a constitutional unit derived from vinylimidazole forms a nonionic and hydrophilic coat layer in a physiological environment. Therefore, a coat layer containing a copolymer having segment A has blood compatibility and antithrombotic properties. (Especially platelet adhesion and adhesion prevention) That is, the copolymer according to the present invention can be a thrombus adhesion suppression / prevention material. Vinyl imidazole itself has antibacterial properties. For this reason, the copolymer according to the present invention having segment A also exhibits excellent antibacterial properties, that is, the copolymer according to the present invention can also be an antibacterial material. Further, the copolymer of the present invention has a segment B, and can be firmly bonded to the substrate through the segment B. For this reason, since the copolymer according to the present invention is firmly bonded (fixed) to the base material via the segment B, peeling of the coat layer from the base material can be suppressed / prevented. Therefore, the copolymer according to the present invention having segment B can maintain the thrombus adhesion suppression / prevention (antithrombogenicity) and antibacterial properties by segment A for a long period of time.

As described above, the copolymer itself according to the present invention having segment A and segment B has antithrombotic properties (particularly platelet adhesion / adhesion prevention properties) and antibacterial properties, and also has various high functions that constitute medical devices. A stable coating layer can be firmly bonded (immobilized) to the surface of the molecular material or metal material by a simple coating process.

Therefore, according to the present invention, a medical coating material having excellent hydrophilicity and a medical device coated with the material can be provided.

In this specification, “excellent thrombus adhesion suppression / prevention (antithrombogenicity)” or “excellent thrombus adhesion suppression / prevention (antithrombogenicity)” means that adhesion (adhesion) of platelets can be suppressed / prevented. Means. Specifically, in the “platelet adhesion test” in the following examples, it means that the number of platelet adhesion (thrombus adhesion suppression / prevention) is 130 or less (lower limit = 0). Preferably, the medical device of the present invention has a platelet adhesion number (thrombus adhesion suppression / prevention) in the “platelet adhesion test” in the following examples of 0 to 130, more preferably 0 to 50, The number is preferably 0-20. In addition, the lower limit of the platelet adhesion number (thrombus adhesion suppression / prevention property) in the “platelet adhesion test” is zero as it is preferably lower.

Hereinafter, embodiments of the present invention will be described. In addition, this invention is not limited only to the following embodiment.

In the present specification, “X to Y” indicating a range means “X or more and Y or less”, “weight” and “mass”, “weight%” and “mass%”, “part by weight” and “weight part”. “Part by mass” is treated as a synonym. Unless otherwise specified, measurements such as operation and physical properties are performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.

[Medical coating materials]
In the present invention, the medical coating material includes the copolymer according to the present invention. Here, the medical coating material may contain other additives, drugs (bioactive substances), and the like. However, the medical coating material is preferably composed only of the copolymer according to the invention.

(Copolymer according to the present invention)
The copolymer according to the present invention has a segment A having a structural unit derived from vinylimidazole and a segment B having a structural unit derived from vinyl monomer.

(Segment A)
Segment A includes:

And a structural unit derived from vinylimidazole. As described above, a segment having a structural unit derived from vinylimidazole imparts thrombus adhesion suppression / prevention and antibacterial properties to a medical device (coat layer).

The segment A may have a structural unit (other structural unit) other than the structural unit derived from vinylimidazole. Here, other structural units are not particularly limited as long as the effects (thrombus adhesion suppression / prevention, antibacterial properties, etc.) according to the present invention are not impaired. Specifically, acrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, aminoisopropyl acrylate, diaminomethyl acrylate, diaminoethyl acrylate, diaminobutyl acrylate, methacrylamide, N, N-dimethylmethacrylamide, N, N-diethylmethacrylamide, aminomethyl methacrylate, aminoethyl methacrylate, diaminomethyl methacrylate, diaminoethyl methacrylate, methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate , Isopropyl methacrylate, ethylene, propylene 2- (meth) acrylamide-2-methyl-propanesulfonic acid, vinyl sulfate, allyl sulfate, styrene sulfonic acid, sulfoethyl (meth) acrylate, sulfopropyl (meth) acrylate, glycidyl (meth) acrylate, 3,4-epoxy Cyclohexylmethyl (meth) acrylate, β-methylglycidyl methacrylate, glycidyl ether, allyl glycidyl ether, the following formula (a):

R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents a linear or branched alkylene having 1 to 4 carbon atoms, such as a methylene group, an ethylene group, a trimethylene group, a propylene group, or a tetramethylene group. R ⁶ represents a straight chain or branched chain having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Represents an alkyl group of
The structural unit derived from the alkoxyalkyl (meth) acrylate shown by these is mentioned. In addition, the said other structural unit may exist individually by 1 type, and may exist in 2 or more types of mixed forms. Here, when the segment A has other structural units, the composition (ratio) of the other structural units is particularly limited as long as the effects (thrombus adhesion suppression / prevention, antibacterial properties, etc.) according to the present invention are not impaired. Not. Specifically, the proportion of other structural units present in the segment A is preferably about 5 to 30 mol%, and more preferably about 7 to 15 mol%.

(Segment B)
Segment B has a structural unit derived from a vinyl monomer. As described above, a segment having a structural unit derived from a vinyl monomer imparts a coating property (hence, thrombus adhesion suppression / prevention maintenance property, antibacterial maintenance property, etc.) to a medical device (coat layer). Here, the structural unit derived from a vinyl monomer may exist individually by 1 type, and may exist with 2 or more types of mixed forms.

The structural unit derived from the vinyl monomer is not particularly limited as long as it has a vinyl group (CH ₂ ═C (R) —; R is a hydrogen atom or a methyl group), but is hydrophilic with a crosslinkable side chain. A vinyl monomer or a hydrophobic vinyl monomer is preferred. In particular, when a base material is coated with a coating layer containing a copolymer (medical coating material) according to the present invention to form a medical device, the constituent unit derived from the vinyl monomer has a binding property (reactivity) with the base material. It preferably has a functional group. Here, the functional group having a binding property (reactivity) with the base material is not particularly limited, and varies depending on the type of material forming the base material, but a carbonyl group, an epoxy group, an isocyanate group, an aldehyde group, and an acid. Preferred examples include a chloride group. Of these, a carbonyl group is more preferred. Segment B having a structural unit derived from a vinyl monomer having such a functional group can be strongly bonded to the base material, and has superior coating properties (hence, thrombus adhesion suppression / prevention maintenance property, antibacterial properties). Maintainability).

Specifically, as the hydrophilic vinyl monomer having a crosslinkable side chain, the following formula (1):

However, R < ¹ > is a hydrogen atom or a methyl group,
Diacetone (meth) acrylamide represented by can be preferably used.

In said formula (1), R < ¹ > is a hydrogen atom or a methyl group. Diacetone (meth) acrylamide, which is a hydrophilic vinyl monomer having a crosslinkable side chain, exhibits room temperature crosslinkability. That is, the carbonyl group in the hydrophilic vinyl monomer having a crosslinkable side chain can be crosslinked under mild conditions in the presence of a crosslinking agent, or can form a covalent bond with the substrate. For this reason, the medical coating material containing a copolymer having a structural unit derived from a hydrophilic vinyl monomer having a crosslinkable side chain does not require heating or the like, under mild conditions that do not impair the physical properties of the substrate itself, It can be simply crosslinked or bonded (immobilized) to the surface of the substrate. From the viewpoints of coatability, thrombus adhesion suppression / prevention maintenance, antibacterial maintenance, and the like, R ¹ is preferably a hydrogen atom. That is, the structural unit derived from the vinyl monomer is preferably derived from diacetone acrylamide (DAAM).

Also, as the hydrophobic vinyl monomer, the following formula (2):

An alkyl (meth) acrylate represented by can be preferably used. Since the alkyl (meth) acrylate of the above formula (2) is hydrophobic, it can be firmly bonded (immobilized) to the surface of the substrate. For example, even if it is placed in a body fluid such as blood, It is preferable from the viewpoint of safety.

In said formula (2), R < ² > is a hydrogen atom or a methyl group. From the viewpoint of coatability, thrombus adhesion suppression / prevention maintenance, and antibacterial maintenance, R ² is preferably a methyl group. R ³ is an alkyl group having 4 to 10 carbon atoms. Here, the alkyl group is not particularly limited, but butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, 2- Examples thereof include linear or branched alkyl groups such as ethylhexyl group, nonyl group, and decyl group. Of these, a butyl group, a pentyl group, and a hexyl group are preferable, and a butyl group is more preferable, from the viewpoints of coatability, thrombus adhesion suppression / prevention maintenance property, and antibacterial maintenance property.

Here, the segment B may have a structural unit (other structural unit) other than the structural unit derived from the vinyl monomer. Here, the other structural units are not particularly limited as long as the effects (coatability, thrombus adhesion suppression / prevention maintenance property, antibacterial maintenance property, etc.) according to the present invention are not impaired, and other constitutional units described in segment A The structural unit similar to a unit can be illustrated. In addition, like the other structural units described in segment A, the other structural units may be present alone or in a mixed form of two or more. Here, when the segment B has other structural units, the effects (coating properties, thrombus adhesion inhibition / prevention maintenance properties, antibacterial maintenance properties, etc.) of the present invention are impaired in the composition (ratio) of the other structural units. Unless otherwise specified, there is no particular limitation. Specifically, the proportion of other structural units present in the segment B is preferably about 5 to 30 mol%, and more preferably about 7 to 15 mol%.

In the present invention, the composition of the copolymer (the ratio of segments A and B) is not particularly limited. Considering the effects (coatability, thrombus adhesion suppression / prevention property, thrombus adhesion suppression / prevention maintenance property, antibacterial property, antibacterial maintenance property, etc.) according to the present invention, the ratio of segment A to the total structural units constituting the copolymer is 15 It is preferable to exceed mol%. Here, when the proportion of segment A is 15 mol% or less with respect to all the structural units constituting the copolymer, thrombus adhesion suppression / prevention and antibacterial properties due to segment A cannot be sufficiently exhibited, and thrombus adhesion suppression / prevention There is a possibility that medical coating materials with excellent antibacterial properties cannot be provided. Considering further improvement of the effects (coating property, thrombus adhesion suppression / prevention property, thrombus adhesion suppression / prevention maintenance property, antibacterial property, antibacterial maintenance property, etc.) according to the present invention, the ratio of segment A to all constituent units constituting the copolymer Is more preferably from 16 to 67 mol%, even more preferably from 17 to 60 mol%, particularly preferably from 20 to 50 mol%.

Note that the types and compositions (ratio) of other structural units present in the segment A or the segment B may be the same or different. Similarly, other structural units may be present only in one of segment A or segment B, or may be present in both segments. The segment A is preferably composed only of structural units derived from vinylimidazole. Similarly, it is preferable that the segment B is comprised only from the structural unit derived from a vinyl monomer. That is, the copolymer according to the present invention is particularly preferably composed of a structural unit derived from vinylimidazole and a structural unit derived from vinyl monomer.

The composition (ratio) of the structural unit derived from the vinyl imidazole and the structural unit derived from the vinyl monomer when the copolymer according to the present invention is composed of the structural unit derived from the vinyl imidazole and the structural unit derived from the vinyl monomer is not particularly limited. Specifically, the mixing ratio of the structural unit derived from vinyl imidazole and the structural unit derived from vinyl monomer (the molar ratio of the structural unit derived from vinyl imidazole to the structural unit derived from vinyl monomer) is 1: 0.4-6. It is preferably 1: 0.5 to 5, more preferably 1: 1 to 5, still more preferably 1: 1 to 4. The copolymer having such a composition can achieve both good coatability, thrombus adhesion suppression / prevention property, thrombus adhesion suppression / prevention maintenance property, antibacterial property and antibacterial maintenance property by a simple coating process.

The terminal of the copolymer according to the present invention is not particularly limited and is appropriately defined depending on the kind of raw material used, but is usually a hydrogen atom. The structure of the copolymer according to the present invention is not particularly limited, and may be any of a random copolymer, an alternating copolymer, a periodic copolymer, and a block copolymer. However, from the viewpoint of improving the film strength after coating on the substrate (strength of the crosslinked structure), a random copolymer in which crosslinking points are dispersed is preferable.

The weight average molecular weight of the copolymer according to the present invention is preferably 10,000 to 1,000,000, more preferably 30 from the viewpoints of coatability, thrombus adhesion suppression / prevention properties and thrombus adhesion suppression / prevention maintenance properties. 50,000 to 500,000, even more preferably 50,000 to 130,000, and particularly preferably 60,000 to 130,000. In the present invention, the “weight average molecular weight” is a value measured by gel permeation chromatography (Gel Permeation Chromatography, GPC) using polystyrene as a standard substance.

The production method of the copolymer according to the present invention is not particularly limited, and the monomer (a) constituting the segment A, the monomer (b) constituting the segment B, and other structural units if necessary. A method of copolymerizing the constituent monomer (c) with stirring and heating together with a polymerization initiator in a polymerization solvent can be used.

The polymerization initiator is not particularly limited, and known ones can be used. For example, 2,2′-azobisisobutyronitrile (AIBN), 2,2′-azobis-2-methylbutyronitrile, 2,2′-azobis (2-methylpropionic acid) dimethyl, 4,4 ′ -Azobis-4-cyanovaleric acid, azobisisovaleronitrile, 2,2'-azobis (2-amidinopropane) dihydrochloride, 2,2'-azobis [2- (5-methyl-2-imidazoline-2- Yl) propane] dihydrochloride, 2,2'-azobis (2-methylpropionamidine) disulfate, 2,2'-azobis (N, N'-dimethyleneisobutylamidine) dihydrochloride, 2,2'-azobis [N- (2-carboxyethyl) -2-methylpropionamidine] azo compounds such as hydrate (azo initiator); sodium persulfate, potassium persulfate Persulfates, such as lithium and ammonium persulfate; peroxides such as dibenzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, benzoyl oxide, tert-butyl permaleate, t-butyl hydroperoxide, hydrogen peroxide ( Peroxide-based initiators); substituted ethane-based initiators such as phenyl-substituted ethane. The said polymerization initiator can be used individually or in combination of 2 or more types. The blending amount of the polymerization initiator is not particularly limited as long as the copolymerization of the monomers (a) and (b) can proceed efficiently, but the monomer (monomer (a) and single amount The total amount of the body (b) = 100 mol%) is preferably 0.0001 to 1 mol%.

In addition, the polymerization initiator may be a redox polymerization initiator. The redox polymerization initiator is excellent in polymerization stability. Examples of such redox polymerization initiators include persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; peroxides such as hydrogen peroxide, t-butyl peroxide, and methyl ethyl ketone peroxide. A system in which a reducing agent such as sodium sulfite, sodium hydrogen sulfite, and ascorbic acid is combined with an oxidizing agent such as Also in this case, the blending amount of the polymerization initiator is 0.0001 to 1 mol% with respect to the monomer (total amount of monomer (a) and monomer (b) = 100 mol%). preferable.

Further, a polymerization accelerator may be further added to the polymerization solvent as necessary. Here, the polymerization accelerator is not particularly limited, and known ones can be used. For example, a reducing agent such as sodium bisulfite, sodium sulfite, molle salt, sodium pyrobisulfite, sodium formaldehyde sulfoxylate, or ascorbic acid; ethylenediamine, sodium ethylenediaminetetraacetate, glycine, or N, N, N ′, N ′ -Amine compounds such as tetramethylethylenediamine; and the like can be used alone or in combination of two or more. In this case, the blending amount of the polymerization accelerator is not particularly limited as long as it is an amount capable of promoting the copolymerization of the monomers (a) and (b), and the monomer (a) and the monomer (b) And it can select suitably according to the kind and addition amount of a polymerization initiator.

The polymerization solvent is not particularly limited, and can be appropriately selected depending on the types of the monomer (a), the monomer (b) and the polymerization initiator. Examples thereof include alcohol solvents such as methanol, ethanol, isopropanol and butanol, and non-proton donating organic solvents such as water, chloroform, tetrahydrofuran, acetone, dioxane and benzene. The said polymerization solvent may be used individually by 1 type, and may use 2 or more types together. The monomer concentration (solid content concentration) in the polymerization solvent is usually 10 to 90% by weight, preferably 15 to 80% by weight, and more preferably 20 to 80% by weight. The concentration of the monomer in the polymerization solvent indicates the concentration of the total weight of the monomers (a) and (b).

The polymerization temperature during copolymerization is preferably 30 to 100 ° C. from the viewpoint of controlling the molecular weight. The polymerization time is usually from 30 minutes to 24 hours.

Furthermore, a chain transfer agent, a polymerization rate adjusting agent, a surfactant, and other additives may be appropriately used as needed during copolymerization.

The copolymer after copolymerization is preferably purified by a general purification method such as a reprecipitation method, a dialysis method, an ultrafiltration method, or an extraction method.

[Medical equipment]
The copolymer according to the present invention and the medical coating material of the present invention are coated (coated, fixed) on the surface of the base material constituting the medical device and can be suitably used as a coating layer for covering the base material. . That is, according to the other one form of this invention, the medical device which has a base material and the coating layer containing the medical coating material of this invention formed on the said base material surface is provided. The coating layer containing the medical coating material of the present invention can exhibit thrombus adhesion suppression / prevention properties, thrombus adhesion suppression / prevention maintenance properties, antibacterial properties, and antibacterial maintenance properties that are excellent in medical devices.

The medical device of the present invention is used in contact with blood, body fluid, or biological tissue. For example, an implantable prosthesis or treatment tool (implant), an extracorporeal circulation prosthetic organ, a catheter, A guide wire etc. can be illustrated. Specifically, implantable medical devices such as artificial blood vessels, artificial trachea, stents, artificial skin, and artificial pericardium that are inserted or replaced into blood vessels and lumens; artificial heart systems, artificial lung systems, and artificial kidney systems Artificial organ systems such as artificial liver systems and immunoregulatory systems; indwelling needles; IVH catheters, drug solution administration catheters, thermodilution catheters, angiographic catheters, vasodilator catheters and dilators or introducers Catheters inserted or indwelled, or guide wires and stylets for these catheters; gastric catheters, nutrition catheters, tube feeding (ED) tubes, urethral catheters, urinary catheters, endotracheal suction catheters Blood vessels such as various suction catheters and drainage catheters Such catheters are inserted through placement outside the living body tissue can be exemplified. The copolymer according to the present invention having segment A is excellent in thrombus adhesion inhibition / prevention (antithrombogenicity) and antibacterial properties, and the copolymer according to the present invention having segment B is firmly fixed to the substrate via segment B. It is possible to For this reason, in the medical device of the present invention, the coat layer can exhibit excellent thrombus adhesion suppression / prevention properties, thrombus adhesion suppression / prevention maintenance properties, antibacterial properties, and antibacterial maintenance properties. Therefore, the medical device of the present invention can be suitably used for artificial blood vessels, catheters, and artificial lung systems (artificial lung membranes) that come into contact with a large amount of blood, particularly artificial lung systems (artificial lung membranes) for long-term auxiliary circulation.

(Base material)
The material and shape of the base material (base material constituting the medical device) to which the copolymer according to the present invention can be immobilized are not particularly limited. The material may be composed of any material, and the material is not particularly limited. Specific examples include metal materials, polymer materials, and ceramics.

Among these, the metal material is not particularly limited, and metal materials generally used for medical devices such as catheters, guide wires, and indwelling needles are used. Specifically, various stainless steels (SUS) such as SUS304, SUS316, SUS316L, SUS420J2, and SUS630, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, or nickel-titanium (Ni-Ti) ) Alloys, nickel-cobalt (Ni—Co) alloys, cobalt-chromium (Co—Cr) alloys, various alloys such as zinc-tungsten (Zn—W) alloys, and the like. These may be used individually by 1 type and may use 2 or more types together. What is necessary is just to select suitably the metal material optimal as base materials, such as a catheter, a guide wire, and an indwelling needle which are use uses as the said metal material.

Also, the polymer material is not particularly limited, and polymer materials generally used for medical devices such as catheters, guide wires, and indwelling needles are used. Specifically, a polyolefin resin such as a polyamide resin, a linear low density polyethylene (LLDPE), a low density polyethylene (LDPE), a high density polyethylene (HDPE), or a polypropylene resin, a modified polyolefin resin, an epoxy resin, Urethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluororesin, amino resin (urea resin, melamine resin, benzoguanamine resin), polyester resin, styrene resin, acrylic resin, polyacetal resin, vinyl acetate resin, phenol resin, chloride A vinyl resin, a silicone resin (silicon resin), a polyether resin, a polyimide resin, etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together. What is necessary is just to select suitably the polymeric material optimal as base materials, such as a catheter, a guide wire, and an indwelling needle which are use uses as the said polymeric material.

The form of the substrate is not limited to a molded body using the above-mentioned material alone, and a blend molded article, an alloyed molded article, a multilayered molded article, and the like can also be used. However, when it is desired to firmly bond (fix) the coating layer (copolymer according to the present invention) by swelling the substrate with a solvent, at least the material to be present on the surface of the substrate is used in the coating liquid described later. A material that can be satisfactorily swollen by a solvent is preferred. The shape of the substrate is not particularly limited, and various shapes such as a sheet shape and a tube shape can be used according to the type of medical device to be applied.

(Coat layer)
In the present invention, the coat layer is formed on at least one surface of the substrate and covers the substrate. Here, the “coating” is not limited to a form in which the entire surface of the substrate is completely covered with the coat layer (copolymer according to the present invention), but only a part of the surface of the substrate is coated layer (the present invention). (Copolymer according to the present invention), that is, a form in which a coat layer is formed only on a part of the surface of the substrate (the copolymer according to the present invention is attached) is also included.

Further, the coat layer includes the copolymer according to the present invention. Here, the coat layer may contain other additives, drugs (bioactive substances), and the like. However, the coat layer is preferably composed only of the copolymer according to the present invention.

Further, a polymer layer, a drug coat layer, a surface lubrication layer, or the like may be separately provided on the coat layer not in contact with the substrate or between the substrate and the coat layer. However, the medical device of the present invention preferably has a structure in which the coating layer according to the present invention is directly formed on a substrate.

In some cases, a substance (for example, a solvent, a surfactant, etc.) used in producing the copolymer according to the present invention may remain in the coat layer. As long as the effects of the invention (coatability, thrombus adhesion inhibition / prevention, thrombus adhesion inhibition / prevention maintenance, antibacterial, antibacterial maintenance, etc.) are not impaired, such a form is acceptable. It is included in the form comprised from.

(Method for manufacturing medical devices)
In the medical device of the present invention, the coat layer is coated (fixed) on the surface of the substrate. Here, the method for coating (fixing) the copolymer (medical coating material) according to the present invention on the surface of the substrate is not particularly limited except that the copolymer according to the present invention is used, and a known method is similarly used. Or it can modify and apply suitably. For example, a method of preparing a coating solution by dissolving the copolymer according to the present invention in a solvent and coating the coating solution on a substrate of a medical device can be used. By such a method, the coat layer is firmly bonded (immobilized) to the surface of the base material, and exhibits good thrombus adhesion suppression / prevention properties, thrombus adhesion suppression / prevention maintenance properties, antibacterial properties, and antibacterial maintenance properties. Can do.

In the above method, the solvent used for dissolving the copolymer according to the present invention is not particularly limited as long as it can dissolve the copolymer according to the present invention. Specifically, water, alcohols such as methanol, ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, halides such as chloroform, olefins such as hexane, tetrahydrofuran (THF ), Ethers such as butyl ether, aromatics such as benzene and toluene, amides such as N, N-dimethylformamide (DMF), and the like, but are not limited thereto. These may be used alone or in combination of two or more.

Further, the concentration of the copolymer according to the present invention in the coating solution is not particularly limited. From the viewpoint of easy application, desired effects (for example, coatability, thrombus adhesion suppression / prevention, thrombus adhesion suppression / prevention maintenance, antibacterial property, antibacterial maintenance property), the present invention in the coating liquid is used. The concentration of the copolymer is preferably 0.01 to 20% by weight, more preferably 0.05 to 15% by weight, and still more preferably 0.1 to 10% by weight. When the concentration of the copolymer is within the above range, the coatability, thrombus adhesion suppression / prevention property, thrombus adhesion suppression / prevention maintenance property, antibacterial property, and antibacterial maintenance property of the resulting coating layer can be sufficiently exhibited. In addition, a uniform coating layer having a desired thickness can be easily obtained by a single coating operation, which is preferable in terms of production efficiency. When the copolymer concentration is less than 0.01% by weight, a sufficient amount of copolymer may not be bonded (immobilized) to the substrate surface. Also, when the copolymer concentration exceeds 20% by weight, the viscosity of the coating solution becomes too high, and a copolymer with a uniform thickness cannot be bonded (immobilized) to the substrate surface, or the substrate surface is quickly coated. May be difficult. However, even if it is out of the above range, it can be sufficiently utilized as long as it does not affect the operational effects of the present invention.

The method for coating the surface of the substrate with the coating liquid is not particularly limited, and is a coating / printing method, dipping method (dipping method, dip coating method), spraying method (spray method), spin coating method, mixed solution. Conventionally known methods such as an impregnation sponge coating method can be applied. Of these, the dipping method (dipping method, dip coating method) is preferably used.

In addition, when forming a coat layer on a thin and narrow inner surface such as an artificial lung membrane or a catheter, the base material may be immersed in the coating solution, and the inside of the system may be depressurized to be defoamed. By defoaming under reduced pressure, the coating liquid can quickly penetrate into the narrow and narrow inner surface, and the formation of the coating layer can be promoted.

In the present invention, when it is difficult to immerse only a part of the base material in the coating liquid, an appropriate member that can be attached / detached (attached / removed) on the surface portion of the base material that does not require the formation of a coating layer in advance After the substrate is dipped in the coating liquid and coated with the coating liquid after being protected with a coating material (such as coating), a protective member for the surface portion of the substrate that does not require the formation of a coating layer ( The coating layer can be formed on a desired surface portion of the substrate by removing the material) and then drying it by a heating operation or the like. However, in the present invention, the forming method is not limited to these forming methods, and the coating layer can be formed by appropriately using conventionally known methods. For example, when it is difficult to immerse only a part of the substrate in the mixed solution, instead of the immersing method, another coating method (for example, spraying the coating liquid on a predetermined surface portion of the medical device) For example, a coating method using a coating apparatus such as an apparatus, a bar coater, a die coater, a reverse coater, a comma coater, a gravure coater, a spray coater, or a doctor knife) may be applied. In addition, when both the outer surface and the inner surface of the cylindrical device need to have a coat layer due to the structure of the medical device, both the outer surface and the inner surface can be coated at once. In this respect, the dipping method (dipping method) is preferably used.

After immersing the substrate in the coating solution containing the copolymer in this way, the substrate is taken out from the coating solution and dried. Here, the drying conditions of the coating solution are not particularly limited as long as the coating layer (coating) containing the copolymer can be formed on the substrate. Specifically, the drying temperature is preferably 20 to 200 ° C, more preferably 25 to 50 ° C. The drying time is preferably 30 minutes to 24 hours, more preferably 1 to 10 hours. Under such conditions, the coat layer (coating) of the copolymer according to the present invention can be firmly fixed on the surface of the substrate.

Also, the pressure condition at the time of drying is not limited at all, and it can be performed under normal pressure (atmospheric pressure), or under pressure or reduced pressure.

As the drying means (apparatus), for example, an oven or a vacuum dryer can be used. However, in the case of natural drying, the drying means (apparatus) is not particularly required.

The cross-linking reaction may be further performed before or after forming the coat layer (coating) of the copolymer according to the present invention on the substrate surface by the above method. Thereby, a stronger coating layer that does not easily peel from the substrate can be formed. In addition, the medical device according to the present invention has a coat layer (film) formed of the copolymer according to the present invention on the surface. For this reason, the medical device by this invention can exhibit the outstanding thrombus adhesion suppression / prevention property, thrombus adhesion suppression / prevention maintenance property, antibacterial property, and antibacterial maintenance property.

Here, for example, in the case of a hydrophilic vinyl monomer having a crosslinkable side chain of the formula (1), the crosslinking reaction is performed under mild conditions in which the carbonyl group in the hydrophilic vinyl monomer is present in the presence of a crosslinking agent. Yes. For this reason, the medical coating material containing a copolymer having a structural unit derived from a hydrophilic vinyl monomer having a crosslinkable side chain does not require heating or the like, under mild conditions that do not impair the physical properties of the substrate itself, It can be simply crosslinked or bonded (immobilized) to the surface of the substrate.

Here, the crosslinking agent can be appropriately selected depending on the type of hydrophilic vinyl monomer to be used. For example, the hydrophilic vinyl monomer having a crosslinkable side chain of the formula (1) is not particularly limited as long as it can react with a carbonyl group in the hydrophilic vinyl monomer to form a covalent bond. It is preferable that the hydrazide compound has at least two hydrazine residues. That is, the coat layer is formed of a reaction product of the copolymer according to the present invention (or the hydrophilic vinyl monomer of the formula (1)) and a hydrazide compound having at least two hydrazine residues per molecule. preferable. The hydrazine residue forms a covalent bond with the carbonyl group under mild conditions, particularly at room temperature, thereby strengthening the copolymer according to the present invention without impairing the physical properties originally required for the substrate itself. It becomes possible to fix to the substrate surface. In such a reaction, a proton-donating solvent can also be used, and it is not necessary to perform strict moisture management in the work area during the reaction.

Examples of the hydrazide compound include adipic acid dihydrazide, carbohydrazide, 1,3-bis (hydrazinocarboethyl) -5-isopropylhydantoin, and the like. In addition, a polymer or copolymer obtained by treating a poly (meth) acrylic ester with a hydrazine residue after polymerization, or a polymer of a monomer previously treated with a hydrazine residue at the time of the monomer, or Copolymers are also included. Among these, adipic acid dihydrazide is preferable from the viewpoint of solubility in water.

The crosslinking reaction between the hydrazide compound and the copolymer according to the present invention (or the hydrophilic vinyl monomer of the formula (1)) proceeds at room temperature as described above, and usually no addition of a catalyst is necessary. It can be accelerated by adding a water-soluble metal salt such as zinc sulfate, manganese sulfate, cobalt sulfate or the like, or by heating and drying. The heating temperature for the heat drying is preferably 40 to 150 ° C., more preferably 40 to 60 ° C., from the viewpoint of not deteriorating the physical properties of the substrate.

These crosslinking agents are applied at a ratio of 1 to 200 parts by weight, preferably 10 to 100 parts by weight, based on 100 parts by weight of the copolymer according to the present invention (or the hydrophilic vinyl monomer of the formula (1)). It is desirable.

The effect of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In addition, the weight average molecular weight of the polymer was measured using GPC (manufactured by Showa Denko KK, apparatus: SHODEX (registered trademark) GPC system; standard material: polystyrene). The composition of each copolymer was measured by neutralization titration.

In addition, in the examples, “part” or “%” may be used, but “part by weight” or “% by weight” is indicated unless otherwise specified. Unless otherwise specified, each operation is performed at room temperature (25 ° C.).

Example 1
Vinylimidazole (VIm) 3.57 g (38 mmol) and diacetone acrylamide (DAAM) 6.43 g (38 mmol) were dissolved in 40 g of dioxane, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour. It was. Separately, a solution obtained by dissolving 0.1 g of azobisisobutyronitrile (AIBN) in 1 mL of dioxane was added to the obtained mixed solution, and polymerization was performed at 80 ° C. for 5 hours. The obtained polymerization solution was dropped into hexane, and the precipitated polymer was collected. As a result, a copolymer (1) (VIm: DAAM = 1: 1 (molar ratio)) composed of vinylimidazole and diacetone acrylamide as structural units was obtained. The weight average molecular weight of the obtained copolymer (1) was 65,000.

Example 2
2.17 g (23 mmol) of vinylimidazole (VIm) and 7.82 g (46 mmol) of diacetone acrylamide (DAAM) were dissolved in 40 g of dioxane, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour. . Separately, a solution obtained by dissolving 0.1 g of azobisisobutyronitrile (AIBN) in 1 mL of dioxane was added to the obtained mixed solution, and polymerization was performed at 80 ° C. for 5 hours. The obtained polymerization solution was dropped into hexane, and the precipitated polymer was collected. As a result, a copolymer (2) (VIm: DAAM = 1: 2 (molar ratio)) composed of vinylimidazole and diacetone acrylamide as structural units was obtained. The weight average molecular weight of the obtained copolymer (2) was 81,000.

Example 3
Vinylimidazole (VIm) 1.0 g (10 mmol) and diacetone acrylamide (DAAM) 9.0 g (50 mmol) were dissolved in 40 g of dioxane, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour. . Separately, a solution obtained by dissolving 0.1 g of azobisisobutyronitrile (AIBN) in 1 mL of dioxane was added to the obtained mixed solution, and polymerization was performed at 80 ° C. for 5 hours. The obtained polymerization solution was dropped into hexane, and the precipitated polymer was collected. As a result, a copolymer (3) (VIm: DAAM = 1: 5 (molar ratio)) composed of vinylimidazole and diacetone acrylamide as structural units was obtained. The weight average molecular weight of the obtained copolymer (3) was 103,000.

Example 4
12.1 g (130 mmol) of vinylimidazole (VIm) and 7.9 g (60 mmol) of butyl methacrylate (BMA) were dissolved in 80 g of dioxane, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour. Separately, a solution obtained by dissolving 0.2 g of azobisisobutyronitrile (AIBN) in 1 mL of dioxane was added to the obtained mixed solution, and polymerization was performed at 80 ° C. for 5 hours. The obtained polymerization solution was dropped into hexane, and the precipitated polymer was collected. As a result, a copolymer (4) (VIm: BMA = 2: 1 (molar ratio)) composed of vinylimidazole and butyl methacrylate as structural units was obtained. The weight average molecular weight of the obtained copolymer (4) was 54,000.

Example 5
8.5 g (90 mmol) of vinylimidazole (VIm) and 13 g (90 mmol) of butyl methacrylate (BMA) were dissolved in 80 g of dioxane, put into a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour. Separately, a solution obtained by dissolving 0.2 g of azobisisobutyronitrile (AIBN) in 1 mL of dioxane was added to the obtained mixed solution and polymerized at 80 ° C. for 5 hours. The obtained polymerization solution was dropped into hexane, and the precipitated polymer was collected. As a result, a copolymer (5) (VIm: BMA = 1: 1 (molar ratio)) composed of vinylimidazole and butyl methacrylate as structural units was obtained. The weight average molecular weight of the obtained copolymer (5) was 83,000.

Example 6
0.9 g (10 mmol) of vinylimidazole (VIm) and 9.0 g (53 mmol) of diacetone acrylamide (DAAM) were dissolved in 40 g of dioxane, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour. It was. Separately, a solution obtained by dissolving 0.1 g of azobisisobutyronitrile (AIBN) in 1 mL of dioxane was added to the obtained mixed solution, and polymerization was performed at 80 ° C. for 5 hours. The obtained polymerization solution was dropped into hexane, and the precipitated polymer was collected. As a result, a copolymer (6) (VIm: DAAM = 3: 17 (molar ratio)) composed of vinylimidazole and diacetone acrylamide as structural units was obtained. The weight average molecular weight of the obtained copolymer (6) was 135,000.

Test: Platelet adhesion test The number of platelet adhesion (thrombosis) was measured according to the following method for the substrate coated with the copolymers (1) to (6) obtained in Examples 1 to 6 and the uncoated substrate (Comparative Example 1). Adhesion suppression / prevention) was evaluated.

That is, each polymer was dissolved in acetone at a concentration of 0.5% by weight. In this solution, a polypropylene film (FOP50, manufactured by Nimura Chemical) (size: 20 mm × 50 mm) as a base material is immersed for 1 minute at room temperature (25 ° C.) and then dried at room temperature (25 ° C.) for 120 minutes. Thus, a coating layer of each polymer was formed on the substrate. In addition, the thing which is not coat | covered with a polymer (uncoated polypropylene film) was made into the comparative example 1.

The base material on which the coat layer of each polymer is formed or an uncoated polypropylene film and human fresh platelet-rich plasma anticoagulated with sodium citrate are contacted for 30 minutes, rinsed with physiological saline, and glutaraldehyde Then, the number of adhered platelets was measured under an electron microscope. The total number of platelet adhesion in 1000 times 5 visual fields was calculated. The results are shown in Table 1. Further, after the platelet adhesion test, the surfaces of the polypropylene film on which the coating layer of the copolymer (3) obtained in Example 3 was formed and the uncoated polypropylene film (Comparative Example 1) were scanned with a scanning electron microscope (SEM). The results are shown in FIGS. 1 and 2, respectively.

From Table 1 and FIGS. 1 and 2, the base material (medical device) having the coating layer of the copolymer according to the present invention significantly adheres to platelets (adhesion) as compared to the uncoated base material (Comparative Example 1). ) Is suppressed.

This application is based on Japanese Patent Application No. 2013-023693 filed on February 8, 2013, the disclosure of which is referenced and incorporated as a whole.

Claims

A medical coating material comprising a copolymer having a segment A having a structural unit derived from vinylimidazole and a segment B having a structural unit derived from vinyl monomer.
The medical coating material according to claim 1, wherein a ratio of the segment A to all structural units constituting the copolymer exceeds 15 mol%.
The medical coating material according to claim 1 or 2, wherein the vinyl monomer is a hydrophilic vinyl monomer or a hydrophobic vinyl monomer having a crosslinkable side chain.
The hydrophilic vinyl monomer having a crosslinkable side chain is represented by the following formula (1):

However, R < 1 > is a hydrogen atom or a methyl group,
Diacetone (meth) acrylamide represented by the formula (2):

Where R 2 is a hydrogen atom or a methyl group, and R 3 is an alkyl group having 4 to 10 carbon atoms,
The medical coating material of Claim 3 which is alkyl (meth) acrylate shown by these.
A substrate;
A medical device comprising: a coating layer containing the medical coating material according to any one of claims 1 to 4 formed on the surface of the substrate.