JP2018149270A - Antithrombotic coating material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antithrombotic coating material that allows heparin to stably exist in antithrombotic polymer compounds (for example, PMEA).SOLUTION: An antithrombotic coating material contains heparin, an antithrombotic polymer compound that contains a constitutional unit represented by the following formula (I) and has a weight average molecular weight of 300,000 or more, and a solvent containing water and methanol. In the formula (I), Ris a hydrogen atom or a methyl group, Ris a C1-4 alkylene group, and Ris a C1-4 alkyl group.SELECTED DRAWING: None

Description

  The present invention relates to an antithrombogenic coating material. More specifically, the present invention relates to an antithrombogenic coating material having heparin, an antithrombotic polymer compound, and a specific solvent.

  In recent years, medical materials using various polymer materials have been studied, such as artificial kidney membranes, plasma separation membranes, catheters, stents, artificial lung membranes, artificial blood vessels, adhesion prevention membranes, artificial skins, etc. Is expected to be used. In these, a synthetic polymer material that is a foreign substance for a living body is used in contact with a body fluid such as a living tissue or blood. Therefore, medical materials are required to have biocompatibility. The biocompatibility required for medical materials varies depending on the purpose and method of use, but medical materials used as materials that come into contact with blood include suppression of blood coagulation system, suppression of platelet adhesion and activation, and activity of the complement system. The characteristic (antithrombogenicity) of suppression of crystallization is required.

  Usually, antithrombogenicity is imparted to medical devices by coating the base material constituting the medical device with an antithrombotic material (antithrombogenic coating material) or by fixing the antithrombotic material on the surface of the base material. By the method.

  For example, Patent Document 1 discloses that a living body having a synthetic polymer that simultaneously satisfies biocompatibility such as suppression of platelet adhesion / activation, inhibitory effect of complement system activation, and affinity with tissue in vivo. Artificial organ membranes and medical devices used in contact with tissue and blood are disclosed. Patent Document 1 discloses polymethoxyethyl acrylate (hereinafter also simply referred to as “PMEA”) and the like as a synthetic polymer that is an antithrombotic material.

  However, when the blood coagulation reaction is started first, there is a problem that PMEA cannot suppress it.

  As a solution to the above problem, the present inventor tried to make heparin having anticoagulant activity present in PMEA, but could not stably exist in PMEA. Therefore, a medical device containing this and heparin has been found using a water-insoluble blood compatible polymer having a specific water content and glass transition temperature instead of PMEA (Patent Document 2).

Japanese Patent Laid-Open No. 4-152952 JP 2004-161954 A

  However, making heparin water-insoluble can change the chemical structure of heparin in many ways, thus reducing the anticoagulant activity. Moreover, the compound used for making it water-insoluble is cationic and may have poor biocompatibility. Therefore, from the viewpoint of obtaining higher antithrombogenicity by coexisting heparin with an antithrombotic polymer without chemically modifying it, a coating layer in which heparin is stably held in the antithrombotic polymer compound is produced. There remains a need for anti-thrombogenic coating materials.

  Then, an object of this invention is to provide the antithrombogenic coating material for producing the coating layer by which heparin was stably hold | maintained at the antithrombotic polymer compound.

  The present inventor has intensively studied to solve the above problems. As a result, a coating in which heparin is stably held in the antithrombotic polymer compound by using an antithrombotic coating material containing an antithrombotic polymer compound having a weight average molecular weight of a specific value or more and heparin. The inventors have found that a layer can be produced and have completed the present invention.

  That is, the present invention comprises heparin, an antithrombotic polymer compound containing a structural unit represented by the following formula (I) and having a weight average molecular weight of 300,000 or more, and a solvent containing water and methanol. It has an antithrombogenic coating material.

In formula (I), R ³ is a hydrogen atom or a methyl group, R ¹ is an alkylene group having 1 to 4 carbon atoms, and R ² is an alkyl group having 1 to 4 carbon atoms.

  ADVANTAGE OF THE INVENTION According to this invention, the antithrombogenic coating material for producing the coating layer by which heparin was stably hold | maintained in the antithrombogenic polymer compound (for example, PMEA) is provided.

It is a photograph which shows the coatability of the sample produced in the Example and the comparative example.

According to one embodiment of the present invention, heparin, an antithrombotic polymer compound containing the structural unit represented by the above formula (I) and having a weight average molecular weight of 300,000 or more, water and methanol are included. And an anti-thrombogenic coating material having a solvent. Moreover, according to other embodiment of this invention, the manufacturing method of a medical device including coating using the antithrombogenic coating material of this invention is also provided. Furthermore, according to another embodiment of the present invention, heparin and an antithrombotic polymer compound containing the structural unit represented by the above formula (I) and having a weight average molecular weight of 300,000 or more are included. Also provided is a medical device having a layer and having a surface heparin activity of greater than 0.02 × 10 ⁻² u / cm ² .

  As described above, it is known that a polymer compound containing a structural unit represented by the formula (I) such as PMEA has antithrombotic properties. This is because, when the polymer compound comes into contact with blood, it exhibits antithrombogenicity by suppressing plasma protein adsorption denaturation, which is the initial reaction of thrombus formation. However, since such a polymer compound itself does not have anticoagulant activity, if the blood coagulation reaction starts due to other factors, it cannot be suppressed. In Patent Document 2, an attempt was made to make heparin present in PMEA, but it could not be stably present in PMEA. Therefore, instead of PMEA, water-insoluble having a specific water content and glass transition temperature was used. A medical device using a blood compatible polymer and containing heparin is disclosed. However, at this time, it is necessary to make heparin water-insoluble, but this may change the chemical structure of heparin, and thus the anticoagulant activity may be reduced. Moreover, the compound used for making it water-insoluble is cationic and may have poor biocompatibility. On the other hand, according to the present invention, there is provided an antithrombogenic coating material in which heparin that maintains water solubility, which is an original property, is stably held in an antithrombotic polymer compound. This is because the antithrombotic polymer compound whose weight average molecular weight is a specific value or more can be dissolved in a mixed solvent of water and methanol, and peels off when the antithrombotic polymer compound is exposed to the bloodstream. It is thought that this is due to the property that the anti-thrombotic polymer compound is not capable of maintaining water-soluble drugs such as heparin stably. In addition, the said mechanism is based on estimation and this invention is not limited to the said mechanism.

  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 includes X and Y, and means “X or more and Y or less”. Unless otherwise specified, measurements such as operation and physical properties are performed under the conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50% RH.

<Anti-thrombogenic coating material>
The antithrombogenic coating material of the present invention contains heparin, an antithrombotic polymer compound containing a structural unit represented by the following formula (I) and having a weight average molecular weight of 300,000 or more, water and methanol. And a solvent.

[Heparin]
The antithrombogenic coating material of the present invention essentially contains heparin. By containing heparin having anticoagulant activity, the antithrombogenicity of the antithrombogenic coating material of the present invention can be further exhibited. In the present invention, heparin can be water-soluble and a commercially available product can be used. For example, Novo Heparin (trade name) manufactured by Mochida Pharmaceutical Co., Ltd., Hepaflash (trade name, registered trademark) manufactured by Terumo Corporation, and the like can be used.

[Anti-thrombotic polymer compound]
The antithrombotic polymer compound according to the present invention (also simply referred to as “polymer compound” in the present specification) includes a structural unit represented by the following formula (I). In the present specification, the structural unit represented by the following formula (I) is also referred to as “a structural unit derived from an alkoxyalkyl (meth) acrylate”. When the antithrombotic polymer compound according to the present invention has two or more structural units represented by the following formula (I), each structural unit may be the same or different. Good. In the present specification, “(meth) acrylate” means “acrylate and / or methacrylate”.

In the above formula (I), R ¹ is a cyclic, linear or branched alkylene group having 1 to 4 carbon atoms, preferably a linear or branched alkylene group having 1 to 4 carbon atoms. Specific examples include a methylene group, an ethylene group, a trimethylene group, a propylene group, a cyclopropylene group, a tetramethylene group, and a cyclobutylene group. Among these, in view of the effect of improving antithrombogenicity, a linear or branched alkylene group having 1 to 3 carbon atoms is preferable, and a methylene group or ethylene group is particularly preferable.

In the above formula (I), R ² is a cyclic, linear or branched alkyl group having 1 to 4 carbon atoms, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a t-butyl group, a cyclopropyl group, and a cyclobutyl group. Among these, considering the effect of improving antithrombogenicity, it is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group, and a methyl group. It is particularly preferred.

In the above formula (I), R ³ is a hydrogen atom or a methyl group, and is preferably a hydrogen atom.

  The compound having the structural unit represented by the above formula (I) has antithrombotic biocompatibility (platelet adhesion / adhesion suppression / prevention effect and platelet activation suppression / prevention effect), particularly platelet adhesion / Excellent anti-adhesion effect. Therefore, by using a compound having the above structural unit, antithrombotic biocompatibility (platelet adhesion / adhesion suppression / prevention effect and platelet activation suppression / prevention effect), particularly platelet adhesion / adhesion It becomes possible to manufacture a medical device (particularly, an artificial lung) having an excellent suppression / prevention effect.

  The antithrombotic polymer compound according to the present invention may further have other structural units in addition to the structural unit represented by the above formula (I). That is, the antithrombotic polymer compound according to the present invention may be a copolymer containing the structural unit represented by the above formula (I) and other structural units. The structure of the “other structural unit” is not particularly limited as long as the desired effect of the present invention can be obtained. For example, a structure derived from “other monomer” described in detail below is preferable. When the antithrombotic polymer compound is a copolymer, its structure is not particularly limited, and may be any of a random copolymer, an alternating copolymer, a periodic copolymer, and a block copolymer.

  The antithrombotic polymer compound according to the present invention is preferably a polymer composed of the structural unit represented by the above formula (I) from the viewpoint of obtaining excellent antithrombotic biocompatibility, and moreover, one kind It is more preferable that it is a homopolymer derived from the above monomer. Specific examples of such a polymer compound are preferably poly-2-methoxyethyl (meth) acrylate (polymethoxyethyl acrylate), polymethoxymethyl (meth) acrylate, polyethoxymethyl (meth) acrylate, polyethoxyethyl. (Meth) acrylate, polybutoxymethyl (meth) acrylate, polybutoxyethyl (meth) acrylate, and the like can be mentioned. From the viewpoint of solubility in a mixed solvent of water and alcohol, polymethoxyethyl acrylate ("poly-2-methoxy More preferably, it is also referred to as “ethyl acrylate” or “PMEA”.

  The antithrombotic polymer compound according to the present invention has a weight average molecular weight of 300,000 or more. When the weight average molecular weight is less than 300,000, the cohesive force is insufficient, a tough film cannot be formed, and heparin cannot be stably retained. Further, from the viewpoints of versatility and operability, the antithrombotic polymer compound preferably has a weight average molecular weight of 500,000 or more, and further, is easy to aggregate and forms a tougher film. From the viewpoint, it is more preferably 600,000 or more, and particularly preferably 800,000 or more. On the other hand, the upper limit of the weight average molecular weight is not particularly limited, but is preferably 1,000,000 or less from the viewpoint that the polymer itself does not gel and become insoluble. In the present invention, “weight average molecular weight” is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance. Specifically, the polymer compound is dissolved in THF (tetrahydrofuran) to prepare a solution having a concentration of 1 mg / ml. A Shodex (registered trademark) GPC column LF-804 (manufactured by Showa Denko KK) is attached to a GPC system LC-20 manufactured by Shimadzu Corporation, and THF is passed as a mobile phase to measure standard polystyrene and GPC of a polymer compound. After creating a calibration curve with standard polystyrene, the weight average molecular weight of the polymer compound is calculated.

  The production method of the antithrombotic polymer compound according to the present invention is not particularly limited, and for example, the following formula (II):

It can manufacture by polymerizing the monomer shown by.

In the above formula (II), the substituents R ^{1 ′} , R ^{2 ′} and R ^{3 ′} are the same as the definitions of R ¹ , R ² and R ^{3 in} the above formula (I). Omitted.

  Specific examples of the monomer represented by the formula (II) include methoxymethyl acrylate, methoxyethyl acrylate (MEA), methoxypropyl acrylate, methoxybutyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, and ethoxypropyl acrylate. , Ethoxybutyl acrylate, propoxymethyl acrylate, propoxyethyl acrylate, propoxypropyl acrylate, propoxybutyl acrylate, butoxymethyl acrylate, butoxyethyl acrylate, butoxypropyl acrylate, butoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, methoxypropyl methacrylate, methoxy Butyl methacrylate, ethoxymethyl meta Relate, ethoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, propoxymethyl methacrylate, propoxyethyl methacrylate, propoxy methacrylate, propoxy butyl methacrylate, butoxymethyl methacrylate, butoxyethyl methacrylate, butoxyethyl methacrylate, and a butoxy butyl methacrylate. Of these, methoxymethyl acrylate, methoxyethyl acrylate (MEA), ethoxymethyl acrylate, ethoxyethyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, and ethoxyethyl methacrylate are preferred and readily available. From the viewpoint, methoxyethyl (meth) acrylate is more preferable. These monomers may be used alone or in combination of two or more.

  Further, in the present invention, in addition to the monomer represented by the above formula (II), another monomer copolymerizable with the monomer represented by the above formula (II) (hereinafter simply referred to as “others”). Also referred to as “monomer”). Examples of other monomers copolymerizable with the monomer represented by the formula (II) include acrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, amino Isopropyl 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, isopropyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate Acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, ethylene, and propylene and the like.

  The method for producing the antithrombotic polymer compound according to the present invention is not particularly limited. For example, the monomer represented by the above formula (II) is dissolved in a polymerization solvent, and the obtained solution is separately prepared. It is preferable to perform a polymerization reaction by preparing a polymerization reaction solution by mixing with a polymerization initiator solution.

  Here, the polymerization solvent is not particularly limited as long as it can dissolve the monomer represented by the above formula (II), but preferably contains methanol as a main component. In addition, "as a main component" means that 95% by mass or more, preferably 99% by mass or more (upper limit 100% by mass) is methanol in the total solvent used in the methanol solution. As a polymerization solvent other than methanol contained in the “methanol solution”, for example, water; ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, t-butanol, ethylene glycol, diethylene glycol, propylene glycol, Examples include, but are not limited to, alcohols such as dipropylene glycol; one or more selected from organic solvents such as chloroform, tetrahydrofuran, acetone, dioxane, and benzene. In addition, the concentration of the monomer represented by the above formula (II) contained in the polymerization solvent is not particularly limited, but by setting the concentration relatively high, the weight average molecular weight of the obtained antithrombotic polymer compound is reduced. Can be bigger. Therefore, from the viewpoint of adjusting the weight average molecular weight of the antithrombotic polymer compound according to the present invention, the monomer concentration represented by the above formula (II) in the polymerization solvent is preferably 25% by mass or more. 30% by mass or more is more preferable, and 50% by mass or more is particularly preferable. The upper limit of the monomer concentration is not particularly limited, but is, for example, a saturation concentration or less, for example, 90% by mass or less, and preferably 70% by mass or less.

  Moreover, you may deaerate the polymerization solvent which added the monomer shown by the said formula (II) under the temperature of about 30 to 70 degreeC before addition of a polymerization initiator. The deaeration process may be performed by bubbling with an inert gas such as nitrogen gas or argon gas for about 0.5 to 5 hours.

  Moreover, it does not restrict | limit especially as a polymerization initiator used when manufacturing the antithrombotic high molecular compound which concerns on this invention, A well-known thing can be used. Preferably, a radical polymerization initiator is used in terms of excellent polymerization stability. Specifically, persulfates such as potassium persulfate (KPS), sodium persulfate, ammonium persulfate; hydrogen peroxide, t-butyl Peroxides, peroxides such as methyl ethyl ketone peroxide; azobisisobutyronitrile (AIBN), 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2 , 4-Dimethylvaleronitrile), 2,2′-azobis [2- (2-imidazolin-2-yl) propane] dihydrochloride, 2,2′-azobis [2- (2-imidazolin-2-yl) propane ] Disulfate dihydrate, 2,2′-azobis (2-methylpropionamidine) dihydrochloride, 2,2′-azobis [N- ( -Carboxyethyl) -2-methylpropionamidine)] hydrate, 3-hydroxy-1,1-dimethylbutylperoxyneodecanoate, α-cumylperoxyneodecanoate, 1,1,3,3- Tetrabutylperoxyneodecanoate, t-butylperoxyneodecanoate, t-butylperoxyneoheptanoate, t-butylperoxypivalate, t-amylperoxyneodecanoate, t-amyl Examples include azo compounds such as peroxypivalate, di (2-ethylhexyl) peroxydicarbonate, di (secondary butyl) peroxydicarbonate, azobiscyanovaleric acid. Further, for example, a reducing agent such as sodium sulfite, sodium hydrogen sulfite, or ascorbic acid may be combined with the radical polymerization initiator and used as a redox initiator. The blending amount of the polymerization initiator is preferably 0.005 to 2 masses with respect to 100 mass parts of the monomer represented by the above formula (II) (when plural types of monomers are used, the whole). Part, more preferably 0.01 to 2 parts by weight. With such a blending amount of the polymerization initiator, an antithrombotic polymer compound having a desired weight average molecular weight can be produced more efficiently.

  The polymerization initiator may be mixed as it is with the monomer represented by the above formula (II) and the polymerization solvent, but in the form of a solution (initiator solution) previously dissolved in another solvent, the above formula. You may mix as it is with the monomer and polymerization solvent which are shown by (II). In the latter case, the other solvent is not particularly limited as long as it can dissolve the polymerization initiator, and examples thereof include the same solvents as the polymerization solvent. In any case, the polymerization initiator, the monomer represented by the above formula (II), and the solvent (polymerization solvent and other solvent used as needed (solvent for the initiator solution) were combined. Together with the solvent, the above “polymerization reaction solution” is obtained. The concentration of the monomer represented by the formula (II) in the polymerization reaction solution is not particularly limited, but from the viewpoint of adjusting the weight average molecular weight of the antithrombotic polymer compound according to the present invention, The monomer concentration represented by the formula (II) is preferably 25% by mass or more, more preferably 30% by mass or more, and particularly preferably 50% by mass or more. Moreover, although an upper limit in particular is not restrict | limited, For example, it is below saturation concentration, for example, is 90 mass% or less, Preferably it is 70 mass% or less. Further, the other solvent may be the same as or different from the polymerization solvent, but considering the ease of controlling the polymerization, it is preferable to use the same solvent as the polymerization solvent.

  In the present invention, alkoxyalkyl (meth) acrylate or alkoxyalkyl (meth) acrylate and other monomers are (co) polymerized by heating the polymerization reaction solution containing the monomer represented by the formula (II). can do. Here, as the polymerization method, for example, known polymerization methods such as anionic polymerization and cationic polymerization can be adopted in addition to the above-mentioned radical polymerization, and preferably radical polymerization that is easy to produce is used.

  The polymerization conditions are not particularly limited as long as the monomer represented by the formula (II) can be polymerized. Specifically, the polymerization temperature is preferably 30 to 60 ° C, more preferably 40 to 55 ° C. Moreover, polymerization time becomes like this. Preferably it is 1 to 24 hours, Preferably it is 3 to 12 hours. Under such conditions, a polymer having a high molecular weight as described above can be produced more efficiently. In addition, gelation in the polymerization process can be effectively suppressed and prevented, and high production efficiency can be achieved.

  Moreover, you may use a chain transfer agent, a polymerization rate regulator, surfactant, and another additive suitably in the case of superposition | polymerization as needed.

  The atmosphere in which the polymerization reaction is performed is not particularly limited, and may be performed in an air atmosphere or an inert gas atmosphere such as nitrogen gas or argon gas. Further, the reaction solution may be stirred during the polymerization reaction.

  The polymer after polymerization can be purified by a general purification method such as a reprecipitation method, a dialysis method, an ultrafiltration method, or an extraction method. Among the above, it is preferable to perform purification by a reprecipitation method because a (co) polymer suitable for the preparation of a colloidal solution can be obtained. At this time, ethanol is preferably used as the poor solvent used for reprecipitation.

  The purified polymer (that is, the antithrombotic polymer compound according to the present invention) can be dried by any method such as lyophilization, reduced pressure drying, spray drying, or heat drying. From the viewpoint of having a small effect on lyophilization, freeze drying or reduced pressure drying is preferred.

  The antithrombotic polymer compound according to the present invention can be obtained by the above-described production method.

〔solvent〕
The antithrombogenic coating material of the present invention further includes a specific solvent together with the above-described heparin and the antithrombotic polymer compound according to the present invention. Below, a specific solvent is demonstrated in detail.

  In the present invention, water and methanol are essentially contained as a solvent contained in the antithrombogenic coating material. As a result of diligent research by the present inventors, the following has been found. That is, the present inventor can dissolve both the antithrombotic polymer compound according to the present invention and the water-soluble heparin by using a solvent containing water and methanol, and uniformly on a substrate such as polypropylene. It was found that a simple coating film (coat layer) can be formed. Furthermore, heparin physically retained by the antithrombotic polymer compound can be stably present without being eluted even in a pseudo-physiological environment.

  In the solvent, the volume ratio of water to methanol (water: methanol) is preferably 5:95 to 45:55 from the viewpoint of dissolving and dispersing both heparin and PMEA. More preferably, it is -45: 55, and it is especially preferable that it is 10: 90-30: 70.

  In the present invention, the antithrombogenic coating material can be produced by the following method.

  That is, (i) a solution obtained by dissolving the antithrombotic polymer compound of the present invention in methanol (abbreviated as “solution a”) and an aqueous solution of heparin separately prepared (abbreviated as “solution b”). And (ii) a solution obtained by dissolving the antithrombotic polymer compound of the present invention in a solvent containing water and methanol, and heparin prepared separately. It can also manufacture by mixing with the aqueous solution of these.

  For example, when the method (i) is used, the concentration of the antithrombotic polymer compound in the solution (a) is not particularly limited, and is preferably 1 to 50% by mass from the viewpoint of film formation. More preferably, it is 5-30 mass%. Moreover, the density | concentration of the heparin in the solution b is not specifically limited, For example, it is preferable that it is 100-10000 u / ml, and it is more preferable that it is 500-5000 u / ml.

  In addition, the mixing of the obtained solution a and solution b is carried out according to the concentration of heparin in the antithrombogenic coating material, the concentration of the antithrombotic polymer compound, and the solvent composition (volume ratio of water and methanol, etc.) What is necessary is just to perform by volume ratio which becomes a desired value.

  In the present invention, the concentration of heparin in the antithrombogenic coating material is not particularly limited, but is preferably 10 to 500 u / ml, and more preferably 50 to 100 u / ml.

  The concentration of the antithrombotic polymer compound according to the present invention in the antithrombogenic coating material is not particularly limited, but is preferably 0.9 to 45% by mass, and 4.5 to 27% by mass. It is more preferable.

<Application>
The antithrombogenic coating material of the present invention is extremely useful as a material for medical devices such as artificial kidney membranes, plasma separation membranes, catheters, artificial lung membranes, and artificial blood vessels.

For this reason, this invention also provides the manufacturing method of a medical device including coating using the antithrombogenic coating material of this invention mentioned above. The present invention also provides a medical device having a layer containing heparin and the antithrombotic polymer compound according to the present invention. Specifically, according to the present invention, a layer containing heparin and an antithrombotic polymer compound containing the structural unit represented by the above formula (I) and having a weight average molecular weight of 300,000 or more is provided. A medical device is provided which has a surface heparin activity of greater than 0.02 × 10 ⁻² u / cm ² . By using the antithrombogenic coating material according to the present invention to form a coat layer (coating film) on the substrate surface, a medical device having excellent antithrombogenicity can be obtained. In the present specification, the value measured by the method described in Examples is adopted as the value of “surface heparin activity”.

<Medical tools>
Examples of the medical device according to the present invention include an implantable artificial organ and a therapeutic instrument, an extracorporeal circulation type artificial organ, a catheter, a guide wire, and the like. Specifically, implantable medical devices such as artificial blood vessels, artificial trachea, stent artificial skin, and artificial pericardium that are inserted or replaced into blood vessels and lumens; artificial heart systems, artificial lung systems, artificial cardiopulmonary systems, artificial Artificial organ systems such as kidney systems, artificial liver systems, immunoregulatory systems; indwelling needles, IVH catheters, medicinal solution administration catheters, thermodilution catheters, angiographic catheters, vasodilator catheters and dilators or introducers Catheters inserted or placed in blood vessels; or guide wires and stylets for these catheters; gastric catheters, nutrition catheters, tube feeding (ED) tubes, urethral catheters, urinary catheters, balloon catheters , Each intratracheal suction catheter Catheters are inserted or indwelled in the living body tissues other than blood vessels, such as the suction catheter and drainage catheter; can be exemplified. In particular, the above-mentioned antithrombogenic coating material is suitably used for an artificial lung system that contacts a large amount of blood or an artificial cardiopulmonary system. That is, preferred embodiments of the medical device according to the present invention include an artificial lung and an artificial heart lung. For example, when forming a coating layer made of a coating of an antithrombotic coating material on a hollow fiber membrane of a hollow fiber membrane external blood perfusion type artificial lung, the thickness of the hollow fiber membrane (film thickness, inner surface of the hollow fiber membrane and The thickness between the outer surface and the outer surface is, for example, 20 μm to 100 μm.

〔Base material〕
The material for the base material of the medical device is not particularly limited, and examples thereof include polyolefins such as polyethylene, polypropylene, and ethylene-α-olefin copolymers, and modified polyolefins; polyamides; polyimides; polyurethanes; polyethylene terephthalate (PET), polybutylenes. Polyesters such as terephthalate (PBT), polycyclohexane terephthalate, polyethylene-2,6-naphthalate; polyvinyl chloride; polyvinylidene chloride (PVDC); polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer (ETFE) Examples thereof include various polymer materials such as fluororesins, metals, ceramics, carbon, and composite materials thereof. The above polymer material may be subjected to a stretching treatment (for example, ePTFE).

  The shape of the base material is appropriately selected according to the use of the medical device, and can be, for example, a tube shape, a sheet shape, or a rod shape. The form of the base material is not limited to a molded body using the above-mentioned material alone, and a blend molded product, an alloyed molded product, a multilayered molded product, and the like can also be used. The substrate may be a single layer or may be laminated. At this time, when the base material is laminated, the base material of each layer may be the same or different.

  In the present invention, the “base material surface” is a base material surface for a body fluid such as a biological tissue or blood. By forming a coat layer having heparin and an antithrombotic polymer compound on the substrate surface, the antithrombogenicity of the substrate surface is improved. In a medical device, a coating layer having heparin and an antithrombotic polymer compound may be formed on the base material surface for body fluid such as biological tissue or blood, but the coating layer is also formed on the other surface. It does not prevent it.

  In order to enhance the stability of the coat layer to the substrate surface, the substrate may be surface-treated before forming the coat layer on the substrate surface. Examples of the surface treatment method of the substrate include a method of irradiating active energy rays (electron beam, ultraviolet ray, X-ray, etc.), a method using plasma discharge such as arc discharge, corona discharge, glow discharge, etc., and a high electric field. Examples thereof include a method of applying, a method of applying ultrasonic vibration via a polar liquid (water or the like), a method of treating with ozone gas, and the like.

[Coat layer]
In the medical device, a coating layer made of a coating film of the antithrombogenic coating material according to the present invention is formed on the surface of the substrate.

  Formation of the coating layer on the substrate surface covers the substrate surface by applying the antithrombogenic coating material according to the present invention. “Coating” is not only a form in which the entire surface of the substrate is completely covered with the coat layer, but also a form in which a part of the surface of the substrate is covered with the coat layer, that is, the surface of the substrate. A form in which a coat layer is attached to a part of the film is also included.

  The method for applying the antithrombogenic coating material according to the present invention to the surface of the substrate can employ a known method, and is not particularly limited. For example, filling, dip coating (dipping method), spraying, Examples include spin coating, dripping, doctor blade, brush coating, roll coating, air knife coating, curtain coating, wire bar coating, and gravure coating.

  Further, the thickness of the coat layer having heparin and the antithrombotic polymer compound may be appropriately adjusted depending on the use of the medical device, and is not particularly limited, but is formed to be thinner than 1000 μm, for example.

  By drying the substrate surface to which the antithrombogenic coating material according to the present invention is applied, a coat layer is formed on the substrate surface. The drying step may be appropriately set in consideration of the glass transition temperature of the base material and the like, and can be performed for 0.5 to 20 hours by heating in an oven or the like at 20 to 80 ° C., for example. The atmosphere in the drying step is not particularly limited, and can be performed in the air or in an inert gas atmosphere such as nitrogen gas or argon gas.

The coat layer formed as described above has high antithrombogenicity. Specifically, the medical device according to the present invention has a surface heparin activity exceeding 0.02 × 10 ⁻² u / cm ² . Preferably, the surface heparin activity is greater than 0.10 × 10 ⁻² u / cm ² , more preferably greater than 0.15 × 10 ⁻² u / cm ² , and even more preferably 0.20 × 10 greater than ^-2 u / cm ^2. On the other hand, the upper limit of surface heparin activity is preferably as high as possible and is not particularly limited, but is substantially about 0.5 × 10 ⁻² u / cm ² .

[Application example]
An artificial lung can be produced using the antithrombogenic coating material according to the present invention.

The oxygenator is an oxygenator having a plurality of gas exchange porous hollow fiber membranes having an outer surface and an inner surface that forms a lumen, and an opening that communicates the outer surface and the inner surface, A material mainly comprising an antithrombotic polymer compound containing a structural unit represented by the above formula (I) and having a weight average molecular weight of 300,000 or more on either one of the outer surface and the inner surface ( It can be an oxygenator with a layer containing an antithrombotic material) and a water soluble drug (especially heparin). Moreover, it is preferable that the surface heparin activity of such an artificial lung exceeds 0.02 × 10 ⁻² u / cm ² .

  The effects 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. Unless otherwise specified, the operation was performed at room temperature (25 ° C.).

[Production Example 1 Production of PMEA having a weight average molecular weight of 800,000]
100 g (0.77 mol) of methoxyethyl acrylate (MEA) was dissolved in 95 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.1 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 50% by mass). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer (PMEA) had a weight average molecular weight of 800,000.

  The weight average molecular weight was measured by gel permeation chromatography (GPC) using polystyrene as a standard substance. Specifically, the produced polymer is dissolved in THF (tetrahydrofuran) to prepare a solution having a concentration of 1 mg / ml, and Shodex (registered trademark) GPC column LF-804 is added to Shimadzu Corporation GPC system LC-20. (Manufactured by Showa Denko KK) was attached, THF was flowed as a mobile phase, and GPC of standard polystyrene and a polymer (antithrombotic polymer compound) was measured. After creating a calibration curve with standard polystyrene, the weight average molecular weight of the polymer was calculated. The same applies to the following production examples.

[Production Example 2 Production of PMEA having a weight average molecular weight of 320,000]
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 30 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). . Thereafter, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 30% by mass). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer (PMEA) had a weight average molecular weight of 320,000.

[Production Example 3 Production of PMEA having a weight average molecular weight of 90,000]
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 55 g of toluene, put into a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of dimethyl 2,2′-azobis (2-methylpropionate) (V-601, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 66 ° C.) was dissolved in 5 g of toluene. The agent solution was added to a toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 20% by mass). While stirring the reaction solution, polymerization was performed at 80 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into normal hexane, and the precipitated polymer was recovered. The recovered polymer (PMEA) had a weight average molecular weight of 90,000.

<Example 1>
PMEA having a weight average molecular weight of 800,000 produced above was dissolved in methanol to prepare a 20% by mass solution. Heparin aqueous solution (Novo heparin 1000 u / ml, manufactured by Mochida Pharmaceutical Co., Ltd.) 1 ml and the above PMEA solution 9 ml were mixed to obtain a colorless and transparent solution (water: methanol volume ratio = 10: 90 in the solution). . A biaxially stretched polypropylene film (FOP50, manufactured by Futamura Chemical Co., Ltd.) having a width of 1 cm, a total length of 10 cm, and a thickness of 50 μm is dipped in the coating solution for 10 seconds, then pulled up and dried by heating in an oven set at 50 ° C. for 12 hours or more. Then, a sample of Example 1 (coat film 1) was produced.

<Example 2>
PMEA having a weight average molecular weight of 320,000 produced above was dissolved in methanol to prepare a 20% by mass solution. Heparin aqueous solution (Novo heparin 1000 u / ml, manufactured by Mochida Pharmaceutical Co., Ltd.) 1 ml and the above PMEA solution 9 ml were mixed to obtain a colorless and transparent solution (water: methanol volume ratio = 10: 90 in the solution). . A biaxially stretched polypropylene film (FOP50, manufactured by Futamura Chemical Co., Ltd.) having a width of 1 cm, a total length of 10 cm, and a thickness of 50 μm is dipped in the coating solution for 10 seconds, then pulled up and dried by heating in an oven set at 50 ° C. for 12 hours or more. Then, a sample of Example 2 (coat film 2) was produced.

<Comparative Example 1>
PMEA having a weight average molecular weight of 90,000 produced above was dissolved in methanol to prepare a 20% by mass solution. Heparin aqueous solution (Novo heparin 1000 u / ml, manufactured by Mochida Pharmaceutical Co., Ltd.) 1 ml and the above PMEA solution 9 ml were mixed to obtain a colorless and transparent solution (water: methanol volume ratio = 10: 90 in the solution). . A biaxially stretched polypropylene film (FOP50, manufactured by Futamura Chemical Co., Ltd.) having a width of 1 cm, a total length of 10 cm, and a thickness of 50 μm is dipped in the coating solution for 10 seconds, then pulled up and dried by heating in an oven set at 50 ° C. for 12 hours or more. A sample of Comparative Example 1 (coat film 3) was produced.

<Evaluation 1: Coatability>
A confirmation test was performed on the coatability (coatability of the antithrombogenic coating material) in the samples prepared in each of the above Examples and Comparative Examples.

  Each coated film of Example 1, Example 2 and Comparative Example 1 was immersed in a 0.5% by weight aqueous solution of toluidine blue for 30 seconds, then washed with water, placed in physiological saline, and the coated state was observed. The test results of Example 1 (left side) and Comparative Example 1 (right side) are shown in FIG. As for the coat film 1 of Example 1, the whole coating surface was dye | stained blue and it has confirmed that the uniform coating layer which consists of PMEA and heparin was formed. The stained state was maintained after 3 hours. On the other hand, the coated film 3 of Comparative Example 1 was repelled by the coated PMEA and was in a non-uniform point-like dyeing state. Moreover, although not shown in figure, the coated film 2 of Example 2 was the same as the coated film 1 of Example 1, and the whole coated surface was dyed blue.

<Evaluation 2: Surface heparin activity (anti-FXa activity)>
Each coated film of Example 1, Example 2 and Comparative Example 1 was placed in physiological saline and allowed to stand at room temperature (25 ° C.) for 6 hours. Each film was taken out from physiological saline, washed with distilled water, and dried at room temperature (25 ° C.) for 12 hours or more. Each dried film was cut to 0.5 cm square to produce a film piece, and a film piece corresponding to 2 cm ² was placed in a plastic test tube. Surface heparin activity (anti-FXa activity) was measured using a “Test Team (registered trademark) Heparin S” kit (manufactured by Sekisui Medical Co., Ltd.) according to the attached instructions.

  Specifically, the measurement was performed as follows. First, a calibration curve (standard straight line) was prepared by plotting the relationship between each heparin concentration and absorbance for the standard solution of the substrate using the endpoint method. The standard straight line equation (1) is shown below. The absorbance was measured by measuring the absorbance at a wavelength of 405 nm using a Hitachi U4000 spectrophotometer. Next, the absorbance was similarly measured for each sample (each film piece), and the heparin activity was calculated based on the standard line. The measurement results of the surface heparin activity for each sample are shown in Table 1 below.

  As is apparent from the above test results, in the coated film of the example, the coat layer composed of PMEA and heparin is uniformly formed, and heparin is physiological saline by physical entanglement with PMEA. It was confirmed that the film was stably held on the surface of the coated film without being eluted. Moreover, it was confirmed that the coat film of an Example has high surface heparin activity. Therefore, according to the antithrombogenic coating material according to the present invention, a coating layer having excellent antithrombogenicity can be formed, and a medical device having excellent antithrombogenicity can be obtained.

Claims (6)

An antithrombogenic coating comprising heparin, an antithrombotic polymer compound containing a structural unit represented by the following formula (I) and having a weight average molecular weight of 300,000 or more, and a solvent containing water and methanol Material;
In formula (I), R ³ is a hydrogen atom or a methyl group, R ¹ is an alkylene group having 1 to 4 carbon atoms, and R ² is an alkyl group having 1 to 4 carbon atoms.   The antithrombogenic coating material according to claim 1, wherein the antithrombotic polymer compound has a weight average molecular weight of 500,000 or more.   The antithrombogenic coating material according to claim 1, wherein the antithrombotic polymer compound is polymethoxyethyl acrylate.   The antithrombogenic coating material according to any one of claims 1 to 3, wherein in the solvent, a volume ratio of water and methanol (water: methanol) is 5:95 to 45:55.   The manufacturing method of a medical device including coating using the antithrombogenic coating material of any one of Claims 1-4. A layer containing heparin and an antithrombotic polymer compound containing a structural unit represented by the following formula (I) and having a weight average molecular weight of 300,000 or more, and the surface heparin activity is 0.02 A medical device exceeding × 10 ⁻² u / cm ² ;
In formula (I), R ³ is a hydrogen atom or a methyl group, R ¹ is an alkylene group having 1 to 4 carbon atoms, and R ² is an alkyl group having 1 to 4 carbon atoms.