JP2005074139A - Coating composition for medical article - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a coating composition for forming a coat that satisfies mechanical strength and non-eluting property while having excellent protein adsorption preventing property, biocompatibility and antithrombogenicity for a long period of time. <P>SOLUTION: This coating composition for a medical article comprises a binder resin A and a coat surface modifying additive B. The binder resin A is at least one kind of resin selected from acrylic resin, epoxy resin, polyester resin and urethane resin. The coat surface modifying additive B is a polyoxyalkylene-silicone block alternating copolymer capable of forming a hydrophilic and/or hydrophobic domains smaller than the size of adsorbed molecules, alternately on the coat surface. Further preferably, the polyoxyalkylene-silicone block alternating copolymer is contained at 0.01 pts.wt. to 10 pts.wt. to 100 pts.wt. of the binder resin. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a coating composition for medical supplies that is excellent in protein adsorption prevention, biocompatibility and antithrombotic properties.

  In recent years, medical supplies such as artificial organs, catheters, stents, medical tubes, blood circuits, blood storage containers, permeable membranes, and syringes have been used more and more frequently as medical technology advances. Some of these medical supplies are used for filling and administration of drug solutions such as polypeptide hormones, and the non-adsorbability of the drug on the surface of these medical devices is required. In addition, medical supplies that are semi-permanently embedded in a living body or indwelled for a certain period of time are required to have compatibility with blood and living tissue, as well as the strength and durability of the material.

  In general, polyester, polysulfone, polyvinyl chloride, polystyrene, silicone resin, polyolefin, polymethacrylic acid ester, fluorine-containing resin, and the like are known as polymer materials used in the above-mentioned medical supplies. Although these polymer materials have satisfactory mechanical strength, they have a hydrophobic surface and are not satisfactory in terms of protein non-adsorbability, biocompatibility, and antithrombotic properties.

  Segmented polyurethane is well known as a material that improves biocompatibility and antithrombogenicity (see, for example, Patent Documents 1, 2, and 3). Segmented polyurethane suppresses platelet adhesion by a microphase separation structure between a rigid aromatic urethane bond site and a flexible polyether bond site. However, it reduces mechanical strength and produces eluate. Not only is there a problem, but the effect of suppressing platelet adhesion is not sufficient.

  In addition, by using a material such as 2-hydroxyethyl methacrylate (HEMA) -styrene-HEMA block copolymer and making the polymer surface a microphase separation structure of a hydrophilic part and a hydrophobic part, platelet adhesion is suppressed and antithrombotic. Is known (for example, Non-Patent Document 1). However, practical problems such as price, mechanical strength and formability are great.

In addition, a poly (alkylaryl ether) sulfone copolymer having a solubility parameter in a specific range is used, and the polymer surface has a microphase-separated structure of a hydrophilic part and a hydrophobic part to obtain antithrombogenicity. (For example, patent document 4).
JP 60-238315 A JP-A-4-144572 JP 2000-34439 A JP 2000-38488 A “Trans. ASAIO”, Volume 33, Item 596 (1987)

  The present invention has been made in order to solve the above-mentioned problems, and the problem is that it has excellent protein adsorption prevention property, biocompatibility, and antithrombotic property for a long time, and also has mechanical strength and non-eluting properties. The object is to provide a coating composition which forms a satisfactory film.

  The present inventors previously invented an antifouling composition that can be applied to products used in bathrooms, toilets, toilets, kitchens, and the like to improve antifouling properties (Japanese Patent Application Laid-Open No. 2000-1620). ). The additive (polyether-modified silicone compound) employed in the present invention exhibited good antifouling properties against a wide variety of stains generated around water. The present inventor subsequently conducted extensive research to develop the antifouling composition for medical supplies, and as a result, coated the polyether-modified silicone compound with a molecular design in consideration of the physical properties of the protein in contact with the coating surface. Adopted as an additive for surface modification, and this was mixed with a binder resin, leading to an invention to form a coating composition.

  The film formed by the coating composition according to the present invention satisfies the adhesiveness to the substrate, the mechanical strength, and the non-elution property by the binder resin, and the film surface modifying additive segregates on the surface, and In order to form a microphase separation structure composed of a hydrophilic part and a hydrophobic part having a designed size, the protein adsorption prevention property, biocompatibility and antithrombotic property are all satisfied.

  That is, the present invention is a coating composition for medical supplies comprising a binder resin (A) and a coating surface modifying additive (B), wherein the binder resin (A) is an acrylic resin, an epoxy resin, a polyester resin, It is at least one resin selected from urethane resins, and the coating surface modification additive (B) alternately has hydrophobic domains and / or hydrophilic domains smaller than the size of adsorbed molecules on the coating surface. It is a polyoxyalkylene-silicone block alternating copolymer that can be formed.

  Here, the polyoxyalkylene-silicone block alternating copolymer is preferably included in an amount of 0.01 to 10 parts by weight with respect to 100 parts by weight of the binder resin.

  In addition, when the molecular weight is small, the polyoxyalkylene-silicone block alternating copolymer may have a crosslinkable reactive group.

  Specifically, the polyoxyalkylene-silicone block alternating copolymer has the general formula (I)

(In the formula, R ¹ and R ² may be the same or different and each represents a divalent organic group, and X represents the following formula: —R ³ —Z or —Z
(Wherein R ³ represents a divalent hydrocarbon group having 1 to 20 carbon atoms, and Z represents an amino group-containing group, an ammonium group-containing group or an epoxy group-containing group). Y represents a methyl group or X, a is an integer of 0 to 10, b is an integer of 0 to 100, a + b is an integer of 1 to 100, m is an integer of 1 to 100, and n is 0 -30, l represents an integer of 1-50)
It is represented by

In general formula (I), a, b, and m are represented by the following formula (1):
0.15 ≦ (m + n) / (a + b + m + n) ≦ 0.80 (1)
The medical composition coating composition according to the above (1), (2) or (3), characterized by satisfying
Is to provide.

  ADVANTAGE OF THE INVENTION According to this invention, it has protein adsorption prevention property, biocompatibility, antithrombotic property over a long period of time, and is excellent in non-eluting property, mechanical strength, and adhesiveness with a base material, and for medical products Coated coatings and coated medical articles formed using the compositions can be provided.

  The coating composition for medical supplies of the present invention comprises a binder resin for improving adhesion to a base resin, mechanical strength, and non-elution of additives, and an additive for coating surface modification for modifying the surface. (Hereinafter, simply referred to as “additive”).

  The binder resin is an acrylic resin having high adhesion to hydrophobic polymers such as polyester, polysulfone, polyvinyl chloride, polystyrene, silicone resin, polyolefin, polymethacrylic acid ester and fluorine-containing resin, which are used as medical polymer materials, It is at least one resin selected from an epoxy resin, a polyester resin, and a urethane resin, and the additive is a specific polyoxyalkylene-silicone block alternating copolymer described later.

  As the acrylic resin used in the present invention, an acrylic polyurethane resin, a thermosetting acrylic resin, an ultraviolet curable acrylic resin, an electron beam curable acrylic resin, a thermoplastic acrylic resin, a normally dry acrylic resin, or the like can be used. Among these, acrylic polyurethane resins are preferable because they can achieve excellent mechanical strength by combining the rigidity of acrylic resins and the flexibility of urethane bonds.

  In addition, by using thermosetting acrylic resin, ultraviolet curable acrylic resin, electron beam curable acrylic resin, and normally-drying acrylic resin, it is not only used as a paint, but also in tubular members and plates by injection molding or other molding methods It is also possible to easily form a molded product such as a shaped member.

  When an acrylic polyurethane resin is used, the acrylic polyol is not particularly limited and can be appropriately selected from known ones. A polyisocyanate compound is used as the crosslinking agent. Examples of the polyisocyanate compound include aliphatic isocyanates such as non-yellowing hexamethylene diisocyanate (HMDI), alicyclic isocyanates such as isophorone diisocyanate (IPDI), and diphenylmethane 4,4′-diisocyanate (MDI) and hydrogenated MDI. These polyisocyanate compounds can be used. As the polyisocyanate compound, HMDI is particularly preferable.

  The mixing ratio of the acrylic polyol and the polyisocyanate compound in the acrylic polyurethane resin is preferably 0.8 to 1.5, particularly 1.0 to 1.2 in terms of NCO / OH ratio. When an acrylic polyurethane resin is used, a catalyst can be used at the time of crosslinking. As the catalyst, dibutyltin dilaurate is preferably used at an addition rate of about 0.005%, but is not limited thereto. When an acrylic polyurethane resin is used, it is preferable to heat-treat after film formation in order to advance curing. Heat treatment is preferably performed at 50 ° C. for 0.5 hours to 7 days.

  As other acrylic resins, homopolymers or copolymers obtained by radical (co) polymerization by solution polymerization, emulsion polymerization, dispersion polymerization, etc. alone or together with other copolymerizable monomers are used. be able to. Here, (meth) acrylic acid ester is used as the acrylic monomer, styrene compound is used as the copolymerizable monomer, carboxylic acid or dicarboxylic acid having a radical polymerizable unsaturated bond, and silane having an alkenyl group such as a vinyl group. Compounds and other vinyl monomers can be used.

  As a polyester resin, what was synthesize | combined by the polycondensation reaction of a polyol and a polybasic acid can be employ | adopted suitably. Moreover, what is obtained by the polycondensation reaction and radical polymerization reaction by the polyol and polybasic acid which have an unsaturated bond, and also the monomer copolymerizable with the unsaturated group of a polyol can also be used.

  Examples of the epoxy resin include a bisphenol A type epoxy resin, a tetraglycidyl ether type epoxy resin, a diglycidyl ether type epoxy resin, a hydrogenated bisphenol A type epoxy resin, a phenol novolak type epoxy resin, and an ortho cresol. Those obtained by a polymerization reaction of a polyepoxy compound such as a lunavolac type epoxy resin, an alicyclic novolak type epoxy resin, and a triazine type epoxy resin with a polyol, polyamine, polythiol or the like can be preferably used.

  The epoxy resin can be used in combination with a curing accelerator. Examples of the curing accelerator include quaternary phosphonium salts, and examples thereof include tetrahydrophosphonium bromide, tetrahydrophosphonium chloride, tetraphenylphosphonium bromide, ethyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide, and benzyltriphenyl. Phosphonium chloride and the like can be used.

  Examples of other curing accelerators include organic acid salts of diazabicycloundecene (DBU). Examples of DBU include 6-dimethylamino-1,8-diazabicyclo [5,4,0] undecene-7 (DMA-DBU), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU). , 6-dibutylamino-1,8-diazabicyclo [5,4,0] undecene-7 (DMA-DBU) and the like, and acids constituting the organic acid salt of DBU include phenol, octylic acid, toluene Sulfonic acid, formic acid, terephthalic acid, benzoic acid, acetic acid, nitrobenzoic acid, dinitrobenzoic acid and the like can be used.

In addition to the quaternary phosphonium salt and DBU organic acid salt as curing accelerators, tin octylate, benzyldimethylamine, triethanolamine borate, 2-ethyl-4methylimidazole, dimethyl Urea compounds, organic acid salts of diazabicyclononene (DBN), and the like can be used. An example of DBN is 1,5-diazabicyclo (4,3,0) nonene-5, and the acid described in paragraph (0024) can be used as the acid constituting the organic acid salt. The accelerator is preferably 0.1 to 10 parts by weight with respect to the epoxy resin. If the curing accelerator is less than 0.1 parts by weight with respect to the epoxy resin, the effect is not obtained. On the other hand, if it exceeds 10 parts by weight, an extreme viscosity change is caused and the moldability may be lowered.

  As the urethane resin, a polyurethane obtained by reacting a polyol other than the acrylic polyol, that is, a known polyester polyol or polyether polyol, and the above-described polyisocyanate compound can be used.

  The polyoxyalkylene-silicone block alternating copolymer used in the present invention has the general formula (I)

(In the formula, R ¹ and R ² may be the same or different and each represents a divalent organic group, and X represents the following formula: —R ³ —Z or —Z
(Wherein R ³ represents a divalent hydrocarbon group having 1 to 20 carbon atoms, and Z represents an amino group-containing group, an ammonium group-containing group or an epoxy group-containing group). Y represents a methyl group or X, a is an integer of 0 to 10, b is an integer of 0 to 100, a + b is an integer of 1 to 100, m is an integer of 1 to 100, and n is 0 -30, l represents an integer of 1-50)
It is preferable that it is a compound represented by these.

In the above formula (I), examples of the divalent organic group represented by R ¹ and R ² include —R ⁴ —, —R ⁴ —CO—, —R ⁴ —NHCO—, and —R ⁴ —NHCONHR. ^5- NHCO- or -R ⁴ -OOCNH-R ⁵ -NHCO- (wherein R ⁴ is a divalent alkylene group such as an ethylene group, propylene group, butylene group, etc., and R ⁵ is a divalent alkylene group. A group exemplified as R ⁴ or a divalent arylene group such as —C ₆ H ₄ —, —C ₆ H ₄ —C ₆ H ₄ —, —C ₆ H ₄ —CH ₂ —C ₆ H ₄ — _{, -C 6 H 4 -CH (CH} 3) -C 6 H 4 - it is, etc.).. Preferable examples of the divalent organic group include —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, —CH ₂ CH (CH ₃ ) CH ₂ —, —CH ₂ CH ₂ CH ₂ CH ₂ —, _{- (CH 2) 2 CO -} , - (CH 2) 3 NHCO -, - (CH 2) 3 NHCONHC 6 H 4 NHCO- or _{- (CH 2) 3 OOCNHC 6} H 4 is NHCO-. Among them, —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, —CH ₂ CH (CH ₃ ) CH ₂ — and the like, which are divalent alkylene groups, are particularly preferred, but —CH ₂ CH (CH ₃₎ CH ₂ - is most preferred.

R ^{3 in the} X group is a divalent hydrocarbon group having 1 to 20 carbon atoms, such as —CH ₂ —, —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, —CH (CH ₃ ). _{CH 2 -, - (CH 2} ) 4 -, - (CH 2) 6 -, - (CH 2) 8 -, - CH 2 CH 2 C 6 H 4 -, - (CH 2) 12 -, - (CH ₂ ) _16- , preferably a propylene group. Z in the X group represents an amino group-containing group, an ammonium group-containing group or an epoxy group-containing group. Specific examples of the X group include, for example, — (CH ₂ ) ₃ NH ₂ , — (CH ₂ ) ₃ NH (CH ₂ ) ₂ NH ₂ , — (CH ₂ ) ₃ N (CH ₃ ) ₂ , — (CH ₂ ) ₃ N (CH ₃ ) (CH ₂ ) ₂ N (CH ₃ ) ₂ , — (CH ₂ ) ₃ N ⁺ (CH ₃ ) ₃ Cl ⁻

Etc.

  Moreover, m is an integer of 1-100, but considering the segregation effect on the surface, dispersibility, and solubility, the preferred range is 10-50, more preferably 15-40.

  Furthermore, a represents an integer of 0 to 10, b represents an integer of 0 to 100, and a + b represents an integer of 1 to 100. When a + b is 0, an alternating copolymer of a hydrophilic domain composed of a polyoxyalkylene block and a hydrophobic domain composed of a water repellent silicone block is not formed. On the other hand, in consideration of dispersibility and solubility, a + b is preferably 100 or less.

The content of the water repellent silicone block is represented by the following formula (2) in the general formula (I):
(M + n) / (a + b + m + n) × 100 (2)
Can be represented by In consideration of the segregation effect on the surface and the protein adsorption prevention effect, the water-repellent silicone block preferably constitutes 15 to 80%, preferably 15 to 60% of the polyoxyalkylene-silicone block alternating copolymer.
n represents an integer of 0 to 30. In consideration of adhesion to the binder resin and protein adsorption preventing property, n is preferably 1-30.

  L represents an integer of 1 to 50. When l is 0, it does not become an alternating copolymer, and an alternating copolymer with l exceeding 50 is difficult to produce because an end-stopping reaction occurs.

  The polyoxyalkylene-silicone block alternating copolymer of the present invention is preferably contained in an amount of 0.01 to 10 parts by weight, more preferably 0.03 to 3 parts per 100 parts by weight of the binder resin (A). It is preferable that 0.1 to 3 parts by weight is contained. If the content is less than 0.01 parts by weight, the entire surface of the film formed with the coating composition cannot be coated, and the protein adsorption preventing effect is lost. This is not preferable because the mechanical strength, water resistance and elution resistance are lowered.

  The polyoxyalkylene-silicone block alternating copolymer of the present invention preferably has a weight average molecular weight in terms of polymethyl methacrylate of 500 to 100,000. If the weight average molecular weight is less than 500, the effect of preventing protein adsorption decreases, which is not preferable, and if it exceeds 100,000, the dispersion stability and surface segregation effect decrease, which is not preferable.

  The polyoxyalkylene-silicone block alternating copolymer of the present invention is a linear block copolymer of a polyether block of hydrophilic polyethylene oxide or polypropylene oxide or a mixture thereof and a water-repellent silicone block of polydimethylsiloxane. It is. By making it linear, not only the silicone block but also a polyether block that easily enters the resin can be segregated on the coating surface when added to the binder resin.

  When a film is formed with the coating composition for medical supplies of the present invention, the polyoxyalkylene-silicone block alternating copolymer as an additive covers the entire surface of the film. That is, a small amount of the polyoxyalkylene-silicone block alternating copolymer mixed in a large amount of the binder resin is present in the solution without dissolving with the binder resin. When the coating composition is coated on a medical product, as the solvent evaporates, the polyoxyalkylene-silicone block alternating copolymers agglomerate with each other and segregate on the entire coating surface to cover the entire surface. Thereafter, the resin hardens and forms a strong bond. The surface composition can be measured using X-ray photoelectron spectroscopy.

  In this way, a microphase separation structure composed of a hydrophilic domain derived from the polyether block and a hydrophobic domain derived from the water repellent silicone block is formed on the formed surface, so that protein adsorption is suppressed. Furthermore, the hydrophilic domain and the hydrophobic domain can be made to have desired sizes by adjusting the molecular weights of the units constituting the polyether block and the water repellent silicone block, respectively. In the present invention, attention was paid to the size of protein molecules in order to suppress the adsorption of various proteins such as coagulated protein preparations and platelets.

  The protein is a polypeptide having a molecular weight of 10,000 or more and a standard of 75,000 to 200,000. For example, bovine serum albumin (BSA) is about 67,000. Although the size of the molecule varies depending on the three-dimensional structure (stretched state, folded state), it is generally said that it is 100-500 nm in the extended state and 4-8 nm in the folded state. Here, in order to prevent adsorption even in the state where BSA is minimized (= folded state), the hydrophilic domain and hydrophobic domain on the surface of the coating may be designed to be smaller than the size of the BSA molecule. Actually, BSA has a spheroid structure having a major axis of 14 nm and a minor axis of 4 nm in the smallest state, and adsorption is considered to occur from the major axis side. Therefore, a microphase separation structure having a domain of less than 14 nm may be formed. In the case of applying a protein other than BSA, the molecular design can be performed in the same manner.

  For example, fibrinogen has a spheroid structure with a major axis of 45 nm and a minor axis of 9 nm. Adsorption on a hydrophobic surface occurs from the minor axis side, and adsorption on a hydrophilic surface occurs from the major axis side. . Therefore, a microphase separation structure in which the hydrophobic domain is less than 9 nm and the hydrophilic domain is less than 45 nm may be formed. The form of the domain is not particularly limited, and examples thereof include sea-island and striped microphase separation structures.

  Examples of the substrate in the present invention include polyolefin, polyvinyl chloride, polyurethanes, polystyrene, polycarbonate, silicone, cellulose and cellulose derivatives, polyfluorocarbon, polyacrylate and polymethacrylate, polyamide, polysulfone and polyethersulfone, natural rubber and the like. be able to.

  The mixing method of the binder resin (A) and the additive (B) of the present invention is not particularly limited, and known methods and methods that will be developed in the future can be widely applied. Specifically, for example, a method in which both solids are physically mixed, a method in which both solutions are mixed, or a method in which both are poured into a soluble solvent and both are dissolved and mixed at the same time. A method of mixing liquids can be exemplified.

  In the coating composition of the present invention, other additives depending on the purpose of use, for example, pigments, antioxidants, ultraviolet absorbers, crystal nucleating agents, crystallization accelerators, stabilizers, antibacterial agents, etc. may be added. Is possible.

  The coating composition of the present invention may be coated after diluting with a solvent, if necessary. The solvent is not particularly limited, and a commercially available, synthesized, or distilled solvent can be used.

  There is no particular limitation on the film forming method for coating the substrate by applying or spraying the coating composition of the present invention, for example, spin coating method, dip coating method, flow coating method, spray coating method, roll coating method. Conventionally known coating methods such as screen printing method, bar coater method, brush coating, and sponge coating can be used.

  The film thickness of the film formed using the coating composition of the present invention is preferably 10 nm to 10 μm, more preferably 100 nm to 5 μm, including the surface segregation part and the binder resin-only layer. If the film thickness is less than 10 nm, it is difficult to uniformly coat the entire surface of the target substrate, and it is not preferable, and if it exceeds 10 μm, productivity and economical efficiency are deteriorated.

  INDUSTRIAL APPLICABILITY The present invention can be used for coating compositions for medical supplies and medical supplies that require protein adsorption prevention, biocompatibility, antithrombogenicity, safety such as non-eluting properties, and mechanical strength. Specific examples of suitable medical articles on the surface of which the coating composition of the present invention is formed at least in part include artificial organs, artificial blood vessels, connectors, catheters, stents, tubes, blood circuits, blood storage containers, and artificial dialyzers. Examples include potting agents, artificial lung housings, permeable membranes, syringes, injection needles, sutures, artificial dialyzers, cannulas, shunts and the like.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

  The polyoxyalkylene-silicone block alternating copolymer used in the present invention was produced according to the following synthesis example.

In a 1000 ml four-necked flask equipped with a stirrer, a dropping funnel and a reflux condenser, 500 g of α, ω-hydrogenpolysiloxane H (SiO (CH ₃ ) ₂ ) _m Si (CH ₃ ) ₂ H was added, and 80 ° C. After adding chloroplatinic acid heated to 5 to 10 ppm in terms of platinum, an appropriate amount of allyl glycidyl ether was slowly added. The temperature was maintained at 80-90 ° C. until no SiH was detected. Excess allyl glycidyl ether was removed under reduced pressure heating at 50 mmHg and 120 ° C. Table 1 shows the formulation and the epoxy equivalent of the resulting epoxy-terminated polysiloxane.

Next, an appropriate amount of epoxy-terminated polysiloxane (A1-A5) synthesized in a 1000 ml four-necked flask equipped with a stirrer, a dropping funnel and a reflux condenser, and an amino polyalkylene oxide H ₂ NCH (CH ₃ ) CH ₂ ( OC ₂ H ₄ ) _a (OC ₃ H ₆ ) _b OCH ₂ CH (CH ₃ ) NH ₂ (a = 5, b = 50 and a = 5, b = 100) in 5% molar excess and final The amount of 2-propanol necessary to make the copolymer formed in 50% solution was added. The temperature of the reaction mixture was adjusted to 80 ° C., and the epoxy-terminated polysiloxane was added in 3 portions at intervals of 1 to 2 hours from the dropping funnel. This reaction was completed when no epoxy group was detected by titration, and polyoxyalkylene-silicone block alternating copolymers shown in Table 2 were obtained.

  The water-repellent silicone block (m + n) / (a + b + m + n) of the polyoxyalkylene-silicone block alternating copolymer used is as shown in Table 2, respectively.

  Moreover, about the micro phase-separation structure formed in the produced test piece, the size of the hydrophilic domain and the hydrophobic domain was measured with atomic force microscope Nano ScopeIII (made by Digital Instruments). The numerical values are shown in Table 2.

In the synthesized A2B1, A2B1R was obtained by substituting the epoxy group for the crosslinking reactive group X in [Chemical Formula 1].

  In Examples 1-7, the test piece was produced as follows.

  According to the formulation shown in Table 3, 100 g of acrylic polyol (“Olestar” manufactured by Mitsui Chemicals, Inc.), 10 g of polyisocyanate as a curing agent (manufactured by Nippon Polyurethane Industry Co., Ltd.), dibutyltin dilaurate as a curing catalyst 0.5 mg of a polyoxyalkylene-silicone block alternating copolymer (formulation described in Table 1) was dissolved in a mixed solvent of 210 g of toluene and 90 g of ethyl acetate to obtain a coating agent.

  Next, a 100 mm square, 2 mm thick acrylic plate is prepared as a substrate, and the above coating agents are rotated at two stages of 1) 500 rpm for 20 seconds and 2) 1000 rpm for 20 seconds so that the dry film thickness is about 1 μm. Spin coating was performed. Thereafter, the test piece was left standing for one day and heat-treated at 50 ° C. for 3 days to complete the preparation of the test piece.

  “Olestar” manufactured by Mitsui Chemicals, Inc. is an acrylic polyol for polyurethane resins, and the brand and OH value used are 30 for Olester Q166 (unit: KOHmg / g) and 45 for Olester Q182. Olester Q193 is 20.

  Moreover, the following two were used as the curing agent polyisocyanate manufactured by Nippon Polyurethane Industry Co., Ltd. One is coronate HX, which is a non-yellowing polyisocyanate having an isocyanurate bond made from hexamethylene diisocyanate (HDI). The other is Coronate L, which is an ethyl acetate solution of a polyisocyanate compound obtained from a polyisocyanate compound obtained from tolylene diisocyanate (TDI) and a polyhydric alcohol.

  The curing catalyst dibutyltin dilaurate was added by a method of adding 10 mg of dibutyltin dilaurate in 20 ml of n-butyl acetate and the addition amount was 1 ml.

  The polyoxyalkylene-silicone block alternating copolymer in the present invention is a linear polyoxyalkylene-silicone block alternating copolymer manufactured by Nippon Unicar Co., Ltd. in addition to those described above, and the water repellent silicone block content rate. 0.15-0.8 can be used, and F1-009-15 (content 0.15), F1-009-11 (content 0.4), F1-009-03 ( Content rate 0.5), FZ-222-2 (content rate 0.6), F1-009-02 (content rate 0.8), etc. can be used.

  As a comparative example, a material in which a polyoxyalkylene-silicone block alternating copolymer was added to the above binder (Comparative Example 1) was used. Moreover, the material (Comparative Example 2) which added polyoxyalkylene to said binder was used.

  Also, polypropylene (Comparative Example 3), which is a material generally used as a pharmaceutical product, was used.

  The protein adsorption test was performed by the following method.

  The test piece was immersed in a phosphate buffer solution (pH 6.8) of 1-10 mg / L bovine serum albumin (BSA), and extracted with SDS-PAGE Sample Buffer. The extracted BSA was dried and mixed with potassium bromide, and the BSA adsorption property to the test piece was evaluated from the FT-IR transmission absorption spectrum. However, an adsorption amount calibration curve was prepared in advance by measuring the spectrum of an appropriate amount of BSA. The apparatus used for the measurement is SPECTRUM2000 (manufactured by PERKINELMER).

In the elution test, according to the Japanese Pharmacopoeia / Plastic Drug Container Test Method, the test piece is cut so that the coating area is 0.12 m ^2, and the eluate is extracted by immersion in 200 ml of water at 70 ° C. for 24 hours. did. This test solution was treated by the following two methods to evaluate non-eluting properties.
(1) Add 0.002 mol / L potassium permanganate solution and 1 ml of dilute hydrochloric acid to 20 ml of test solution, boil for 3 minutes, cool, add 0.10 g of potassium iodide, and titrate with 0.01 mol / L sodium thiosulfate solution. Do. The required specification is that the difference in consumption of potassium permanganate solution is 1.0 ml or less with respect to the blank test solution.
(2) 20 ml of the test solution is evaporated to dryness on a water bath, and the mass of the residue is measured. The required specification is that the evaporation residue is 1.0 mg or less.

  Moreover, the mechanical strength of the coating film formed on the test piece was evaluated by a pencil scratch test and a cross-cut peel test.

  The pencil scratch test was performed according to JIS K 5600-5-4. A scratch test was performed with a pencil having a pencil hardness of 2H, and scratches and peeling of the coating film were observed.

  The cross cut test was conducted according to JIS K 5600-5-6. The adhesion of the coating film was evaluated by evaluating the tape peeling portion after the cross cut.

  Table 3 shows the results of the protein adsorption test, the eluate test, and the mechanical strength test of each Example and Comparative Example.

From the above results, it can be seen that the coating material in the present invention is excellent in protein low adsorptivity with respect to protein adsorptivity, and preferably exhibits low protein adsorptivity at an addition amount of 0.01 parts by weight or more and 10 parts by weight or less. . From the results of Example 4, it is more preferable to add a reactive group with the binder resin to the additive because non-eluting properties are improved.

  In the case where the additive does not sufficiently segregate on the surface as in Comparative Example 2, sufficient mechanical strength cannot be obtained. As can be seen from Examples 1 to 4, the mechanical strength can be improved by causing the additive to segregate on the surface and lowering the addition amount.

In the linear polyoxyalkylene-silicone block alternating copolymer shown in the examples, the protein adsorption property, non-eluting property, and mechanical strength were equivalent, and the water repellent silicone block content was 15% to 80%. Case is desirable.
(result)
From the above results, it can be seen that the examples of the present invention satisfy the excellent protein adsorption prevention property, non-eluting property, and mechanical strength at the same time.

  The present invention relates to a coating composition for medical supplies, a coating film for medical supplies, and a medical coating that require protein adsorption prevention, biocompatibility, antithrombotic properties, safety such as non-eluting properties, and mechanical strength. Used for supplies. Specific examples of medical articles that are formed on the surface with at least part of the coating composition of the present invention include artificial organs, artificial blood vessels, connectors, catheters, stents, tubes, blood circuits, blood storage containers, artificial dialyzer potting agents Examples thereof include an artificial lung housing, a permeable membrane, a syringe barrel, a syringe needle, a suture thread, an artificial dialyzer, a cannula, and a shunt.

Claims (7)

A medical composition coating composition comprising a binder resin (A) and a coating surface modifying additive (B), wherein the binder resin (A) is at least selected from an acrylic resin, an epoxy resin, a polyester resin, and a urethane resin One or more types of resin, and the coating surface modifying additive (B) can form a hydrophilic and / or hydrophobic domain smaller than the size of the adsorbing molecule in contact with the surface of the coating alternately. A coating composition for medical supplies, which is an oxyalkylene-silicone block alternating copolymer. 2. The coating composition for medical supplies according to claim 1, wherein the adsorbing molecule to be contacted is bovine serum albumin. The coating composition for medical supplies according to claim 1, wherein the polyoxyalkylene-silicone block alternating copolymer is contained in an amount of 0.01 to 10 parts by weight with respect to 100 parts by weight of the binder resin. A coating composition for medical supplies. The coating composition for medical supplies according to claim 1, wherein the polyoxyalkylene-silicone block alternating copolymer has a crosslinkable reactive group. The coating composition for medical supplies according to any one of claims 1 to 4, wherein the polyoxyalkylene-silicone block alternating copolymer has the general formula (I).
(Wherein R ¹ and R ² may be the same or different and each represents a divalent organic group, and X represents the following formula:
-R ³ -Z or -Z
(Wherein R ³ represents a divalent hydrocarbon group having 1 to 20 carbon atoms, and Z represents an amino group-containing group, an ammonium group-containing group or an epoxy group-containing group). Y represents a methyl group or X, a is an integer of 0 to 10, b is an integer of 0 to 100, a + b is an integer of 1 to 100, m is an integer of 1 to 100, and n is 0 -30, l represents an integer of 1-50)
It is represented by the coating composition for medical supplies characterized by these. The coating composition for medical supplies according to any one of claims 1 to 5, wherein a, b and m are represented by the following formula (1):
0.15 ≦ (m + n) / (a + b + m + n) ≦ 0.80 (1)
A coating composition for medical supplies characterized by satisfying The medical composition according to any one of claims 1 to 6, wherein hydrophilic and / or hydrophobic domains of less than 14 nm can be alternately formed on the surface of the coating. Coating composition for supplies.