JP2024103590A - Manufacturing method of medical equipment - Google Patents
Manufacturing method of medical equipment Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 29
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- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical group OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 claims abstract description 49
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- RIIRGXOHHAMBRJ-UHFFFAOYSA-N 2-ethoxypropyl 2-methylprop-2-enoate Chemical compound CCOC(C)COC(=O)C(C)=C RIIRGXOHHAMBRJ-UHFFFAOYSA-N 0.000 description 1
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- NUXLDNTZFXDNBA-UHFFFAOYSA-N 6-bromo-2-methyl-4h-1,4-benzoxazin-3-one Chemical compound C1=C(Br)C=C2NC(=O)C(C)OC2=C1 NUXLDNTZFXDNBA-UHFFFAOYSA-N 0.000 description 1
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- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- RBEOEYUJTIEQOQ-UHFFFAOYSA-O C(C(=C)C)(=O)OCCCCCCCCCCP(=O)=C(O)C[N+](C)(C)C Chemical compound C(C(=C)C)(=O)OCCCCCCCCCCP(=O)=C(O)C[N+](C)(C)C RBEOEYUJTIEQOQ-UHFFFAOYSA-O 0.000 description 1
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- GQTUZZMVKWKMEO-UHFFFAOYSA-O C[N+](C)(C)CC(O)=P(=O)CCCCOC=CC1=CC=CC=C1 Chemical compound C[N+](C)(C)CC(O)=P(=O)CCCCOC=CC1=CC=CC=C1 GQTUZZMVKWKMEO-UHFFFAOYSA-O 0.000 description 1
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000002473 artificial blood Substances 0.000 description 1
- 230000010065 bacterial adhesion Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
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- 210000000601 blood cell Anatomy 0.000 description 1
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- MDNFYIAABKQDML-UHFFFAOYSA-N heptyl 2-methylprop-2-enoate Chemical compound CCCCCCCOC(=O)C(C)=C MDNFYIAABKQDML-UHFFFAOYSA-N 0.000 description 1
- LNCPIMCVTKXXOY-UHFFFAOYSA-N hexyl 2-methylprop-2-enoate Chemical compound CCCCCCOC(=O)C(C)=C LNCPIMCVTKXXOY-UHFFFAOYSA-N 0.000 description 1
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- NZIDBRBFGPQCRY-UHFFFAOYSA-N octyl 2-methylprop-2-enoate Chemical compound CCCCCCCCOC(=O)C(C)=C NZIDBRBFGPQCRY-UHFFFAOYSA-N 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- GYDSPAVLTMAXHT-UHFFFAOYSA-N pentyl 2-methylprop-2-enoate Chemical compound CCCCCOC(=O)C(C)=C GYDSPAVLTMAXHT-UHFFFAOYSA-N 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
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- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- KEROTHRUZYBWCY-UHFFFAOYSA-N tridecyl 2-methylprop-2-enoate Chemical compound CCCCCCCCCCCCCOC(=O)C(C)=C KEROTHRUZYBWCY-UHFFFAOYSA-N 0.000 description 1
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- Materials For Medical Uses (AREA)
- Prostheses (AREA)
Abstract
Description
本発明は、医療機器の製造方法に関する。 The present invention relates to a method for manufacturing a medical device.
ホスホリルコリン基を含有する合成高分子は、生体内の細胞膜と同様の構造を持つため、生体親和性、高潤滑特性、低摩擦特性、タンパク吸着抑制、細胞接着抑制、細菌付着抑制などの様々な優れた特性を持ち、コンタクトレンズ、カテーテル、人工関節等の医療機器や、ウェルプレートなどの検査用医療機器や診断用医療機器等、多くの医療機器の表面へ応用されている。 Synthetic polymers containing phosphorylcholine groups have a structure similar to that of cell membranes in the body, and therefore have a variety of excellent properties, such as biocompatibility, high lubricity, low friction, inhibition of protein adsorption, inhibition of cell adhesion, and inhibition of bacterial adhesion. They are used on the surfaces of many medical devices, including contact lenses, catheters, artificial joints, and testing and diagnostic medical devices such as well plates.
ホスホリルコリン基を含有する合成高分子を医療機器の表面へ応用するとき、医療機器が必要とする特性に合わせて、様々なホスホリルコリン基を含有する高分子が用いられる。例えば、特許文献１には、ホスホリルコリン基を含有する高分子の一例である２－メタクリロイルオキシエチルホスホリルコリンと、メタクリル酸エステルの共重合体が記載されている。 When applying synthetic polymers containing phosphorylcholine groups to the surface of medical devices, various polymers containing phosphorylcholine groups are used according to the characteristics required by the medical device. For example, Patent Document 1 describes a copolymer of 2-methacryloyloxyethyl phosphorylcholine, which is an example of a polymer containing phosphorylcholine groups, and a methacrylic acid ester.
例えば、コンタクトレンズなどの医療機器やウェルプレートなどの検査用医療機器には、比較的穏やかな水環境下においてタンパク質等の吸着を防ぐことを目的として、ホスホリルコリン基を含有する高分子が用いられている。したがって、疎水性のホスホリルコリン基を含有する合成高分子を溶解させた有機溶媒に基材を浸漬したり、疎水性のホスホリルコリン基を含有する合成高分子を溶解させた有機溶媒を基材に噴霧したりしたのち、乾燥して、ホスホリルコリン基を含有する高分子によるコーティングを行っている。 For example, in medical devices such as contact lenses and medical devices for testing such as well plates, polymers containing phosphorylcholine groups are used to prevent the adsorption of proteins and the like in a relatively mild aqueous environment. Therefore, a substrate is immersed in an organic solvent in which a synthetic polymer containing a hydrophobic phosphorylcholine group has been dissolved, or an organic solvent in which a synthetic polymer containing a hydrophobic phosphorylcholine group has been dissolved is sprayed onto the substrate, and then the substrate is dried to coat it with the polymer containing the phosphorylcholine group.
特許文献２には、薬剤放出ステントのような体内埋め込み型医療機器として、金属基材の表面に、２－メタクリロイルオキシエチルホスホリルコリンからなる高分子などの合成リン脂質成分をスプレー噴霧などでコーティングを行うことが記載されている。 Patent Document 2 describes coating the surface of a metal substrate with a synthetic phospholipid component, such as a polymer made of 2-methacryloyloxyethyl phosphorylcholine, by spraying, etc., to produce an implantable medical device, such as a drug-releasing stent.
人工関節には、日常生活において絶えず摺動するような過酷な使用環境において、高い潤滑特性、耐摩耗特性を獲得するために、ホスホリルコリン基を含有する合成高分子が用いられている。前出の浸漬や噴霧などによるコーティングでの表面改質では、ホスホリルコリン基を含有する高分子は基材に物理吸着しているだけなので、生体内においてホスホリルコリン基を含有する高分子が基材から容易に剥離してしまう。したがって、剥離を防止するために、人工関節では、光照射によるグラフト重合によりホスホリルコリン基を含有する合成高分子と基材を共有結合により強固に固着させている。これによりホスホリルコリン基を含有する合成高分子が基材表面を長期間にわたって保護している。また、ホスホリルコリン基を含有する合成高分子の末端が基材と共有結合することで固定されているため、ホスホリルコリン基を含有する合成高分子が高い親水性であっても、生体内に溶出しない。 Synthetic polymers containing phosphorylcholine groups are used in artificial joints to obtain high lubrication and wear resistance properties in the harsh usage environment of constant sliding in daily life. In the surface modification by coating such as immersion or spraying, the polymer containing phosphorylcholine groups is only physically adsorbed to the substrate, so the polymer containing phosphorylcholine groups easily peels off from the substrate in the body. Therefore, in order to prevent peeling, in artificial joints, the synthetic polymer containing phosphorylcholine groups and the substrate are firmly fixed by covalent bonds using graft polymerization by light irradiation. This allows the synthetic polymer containing phosphorylcholine groups to protect the substrate surface for a long period of time. In addition, since the ends of the synthetic polymer containing phosphorylcholine groups are fixed by covalent bonds with the substrate, the synthetic polymer containing phosphorylcholine groups does not dissolve in the body even if it is highly hydrophilic.
物理吸着によるコーティングで、ホスホリルコリン基を含有する合成高分子の皮膜を基材表面に形成させる方法は、皮膜を容易に形成させることが可能で、かつ、基材の材質や形状に制限がほとんどない。しかし、高い親水性を示すホスホリルコリン基を含有する合成高分子による皮膜は、水に溶解しやすく、耐水性に劣るため、生体内などの水環境下での使用が制限される。一方、疎水性のホスホリルコリン基を含有する合成高分子による皮膜は、皮膜が水和するまでの間、ぬれ性に劣り、ホスホリルコリン基を含有する合成高分子の性能が十分に発現するまでに時間を要する。 The method of forming a film of a synthetic polymer containing phosphorylcholine groups on the surface of a substrate by coating through physical adsorption allows for easy formation of the film and places almost no restrictions on the material or shape of the substrate. However, films made of synthetic polymers containing phosphorylcholine groups, which are highly hydrophilic, are easily dissolved in water and have poor water resistance, limiting their use in aqueous environments such as inside the body. On the other hand, films made of synthetic polymers containing hydrophobic phosphorylcholine groups have poor wettability until the film is hydrated, and it takes time for the performance of the synthetic polymer containing phosphorylcholine groups to be fully expressed.
光照射によるグラフト重合で形成した親水性の高いホスホリルコリン基を含有する合成高分子による皮膜は、生体内において瞬時に高い親水性や耐摩耗特性を発現し、また安定してそれらの性能を発揮するが、光照射によるグラフト重合反応の条件などが複雑であり、コーティングをする基材の材質や形状により制限される。 A coating made of a synthetic polymer containing highly hydrophilic phosphorylcholine groups formed by graft polymerization under light irradiation instantly exhibits high hydrophilicity and abrasion resistance properties in vivo, and also stably exhibits these properties. However, the conditions for the graft polymerization reaction under light irradiation are complex, and are limited by the material and shape of the substrate to be coated.
本発明の目的は、容易にホスホリルコリン基を含有する合成高分子皮膜を形成することができ、生体内において早期に高いぬれ性を発現し、その使用環境下での高い安定性を有する医療機器の製造方法を提供することである。 The object of the present invention is to provide a method for producing a medical device that can easily form a synthetic polymer coating containing phosphorylcholine groups, exhibits high wettability in the body at an early stage, and has high stability in the environment in which it is used.
本発明は、医療機器の製造方法であって、基材を準備する準備工程と、ホスホリルコリン基を有する第１重合体および第１重合体よりも親水性が低い、ホスホリルコリン基を有する第２重合体を有機溶媒に溶解させて重合体混合溶液を調製する調製工程と、調製された重合体混合溶液に基材を浸漬させたのち、乾燥させて、基材の少なくとも一部の表面に第１重合体および第２重合体を含む親水性皮膜を形成する皮膜形成工程と、を有し、前記有機溶媒に溶解させる前記第１重合体と前記第２重合体との重量比（前記第１重合体／前記第２重合体）は、１／９以上１／４以下である、医療機器の製造方法である。 The present invention is a method for producing a medical device, which includes a preparation step of preparing a substrate, a preparation step of dissolving a first polymer having a phosphorylcholine group and a second polymer having a phosphorylcholine group, which is less hydrophilic than the first polymer, in an organic solvent to prepare a polymer mixture solution, and a film formation step of immersing a substrate in the prepared polymer mixture solution and then drying the substrate to form a hydrophilic film containing the first polymer and the second polymer on at least a portion of the surface of the substrate, and the weight ratio of the first polymer to the second polymer (the first polymer/the second polymer) dissolved in the organic solvent is 1/9 or more and 1/4 or less.
また本発明は、第１重合体および第２重合体は、光反応性を有しておらず、皮膜形成工程では、光反応を行わないことを特徴とする。 The present invention is also characterized in that the first polymer and the second polymer are not photoreactive and do not undergo photoreaction during the film formation process.
また本発明は、ホスホリルコリン基を有する第１重合体およびホスホリルコリン基を有する第２重合体は、互いに共重合比が異なる２－メタクリロイルオキシエチルホスホリルコリンとｎブチルメタクリレートとの共重合体であることを特徴とする。 The present invention is also characterized in that the first polymer having a phosphorylcholine group and the second polymer having a phosphorylcholine group are copolymers of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate having different copolymerization ratios.
また本発明は、重合体混合溶液中の第１重合体と第２重合体の含有濃度が０．１～０．５重量％であることを特徴とする。 The present invention is also characterized in that the concentration of the first polymer and the second polymer in the polymer mixture solution is 0.1 to 0.5% by weight.
また本発明は、基材は、生体適合性材料からなることを特徴とする。 The present invention is also characterized in that the substrate is made of a biocompatible material.
また本発明は、親水性皮膜が形成された基材に滅菌処理を施す滅菌工程をさらに有することを特徴とする。 The present invention is also characterized by further having a sterilization step in which a sterilization treatment is performed on the substrate on which the hydrophilic coating is formed.
また本発明は、滅菌処理が、親水性皮膜が形成された基材に高エネルギー線を照射する照射処理または親水性皮膜が形成された基材にガスプラズマを接触させるガスプラズマ処理であることを特徴とする。 The present invention is also characterized in that the sterilization treatment is an irradiation treatment in which a substrate on which a hydrophilic film is formed is irradiated with high-energy rays, or a gas plasma treatment in which a substrate on which a hydrophilic film is formed is brought into contact with gas plasma.
本発明によれば、調製工程で、ホスホリルコリン基を有する第１重合体および第１重合体と親水性が異なる、ホスホリルコリン基を有する第２重合体を有機溶媒に溶解させて重合体混合溶液を調製し、皮膜形成工程で、重合体混合溶液に基材を浸漬させたのち乾燥させて、基材の少なくとも一部の表面に第１重合体および第２重合体を含む親水性皮膜を形成することで、医療機器を製造する。 According to the present invention, in the preparation step, a first polymer having a phosphorylcholine group and a second polymer having a phosphorylcholine group, which has a different hydrophilicity from the first polymer, are dissolved in an organic solvent to prepare a polymer mixture solution, and in the film formation step, a substrate is immersed in the polymer mixture solution and then dried to form a hydrophilic film containing the first polymer and the second polymer on at least a portion of the surface of the substrate, thereby manufacturing a medical device.
上記のような第１重合体と第２重合体とを混合して溶解させた重合体混合溶液に基材を浸漬させて乾燥するだけで、容易に親水性皮膜を形成することができ、形成された親水性皮膜が、初期の濡れ性に優れ、使用環境下における高い安定性を有する。 A hydrophilic film can be easily formed by simply immersing a substrate in a polymer mixture solution in which the first polymer and the second polymer described above are mixed and dissolved, and then drying the substrate. The formed hydrophilic film has excellent initial wettability and high stability in the usage environment.
また本発明によれば、第１重合体および第２重合体は、光反応性を有しておらず、皮膜形成工程では、光反応を行わない。 Furthermore, according to the present invention, the first polymer and the second polymer are not photoreactive and do not undergo photoreaction during the film formation process.
また本発明によれば、ホスホリルコリン基を有する第１重合体およびホスホリルコリン基を有する第２重合体として、互いに共重合比が異なる２－メタクリロイルオキシエチルホスホリルコリンとｎブチルメタクリレートとの共重合体を用いることが好ましい。 Furthermore, according to the present invention, it is preferable to use a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate having different copolymerization ratios as the first polymer having a phosphorylcholine group and the second polymer having a phosphorylcholine group.
また本発明によれば、重合体混合溶液中の第１重合体と第２重合体の含有濃度は０．１～０．５重量％とすることが好ましい。 Furthermore, according to the present invention, it is preferable that the concentration of the first polymer and the second polymer in the polymer mixture solution is 0.1 to 0.5% by weight.
また本発明によれば、基材は、生体適合性材料からなるものであることが好ましい。 Furthermore, according to the present invention, it is preferable that the substrate is made of a biocompatible material.
また本発明によれば、滅菌工程によって、親水性皮膜が形成された基材に滅菌処理を施すことが好ましい。 Furthermore, according to the present invention, it is preferable to subject the substrate on which the hydrophilic coating is formed to a sterilization treatment by a sterilization process.
また本発明によれば、滅菌処理として、親水性皮膜が形成された基材に高エネルギー線照射する照射処理、親水性皮膜が形成された基材にガスプラズマを接触させるガスプラズマ処理を用いることができる。 In addition, according to the present invention, the sterilization treatment can be an irradiation treatment in which a substrate on which a hydrophilic film is formed is irradiated with high-energy rays, or a gas plasma treatment in which a substrate on which a hydrophilic film is formed is brought into contact with gas plasma.
本発明の製造方法によって製造される医療機器としては、直接生体成分と接触して用いる医療機器であり、例えば人工血管、人工弁、血液バッグ、血液透析膜、カテーテル、ステント、カプセル化材料、酵素電極、眼内レンズ、コンタクトレンズ、人工骨、細胞培養プレート、診断用マイクロチップなどが挙げられるが、これらに限定されない。 Medical devices manufactured by the manufacturing method of the present invention are medical devices that are used in direct contact with biological components, such as, but not limited to, artificial blood vessels, artificial valves, blood bags, hemodialysis membranes, catheters, stents, encapsulation materials, enzyme electrodes, intraocular lenses, contact lenses, artificial bones, cell culture plates, and diagnostic microchips.
図１は、本発明の実施形態である医療機器の製造方法を示す工程図である。
本実施形態の製造方法は、
（工程Ａ１）準備工程
（工程Ａ２）調製工程
（工程Ａ３）皮膜形成工程
の３つの工程からなる。
FIG. 1 is a process diagram showing a method for producing a medical device according to an embodiment of the present invention.
The manufacturing method of this embodiment is as follows:
The method comprises three steps: (Step A1), a preparation step (Step A2), a preparation step (Step A3), and a film-forming step.
（工程Ａ１）準備工程
工程Ａ１の準備工程では、医療機器の基材を準備する工程である。基材は、製造しようとする医療機器に応じて適宜材料、形状などを選択すればよい。特に、医療機器が、体内に挿入される、もしくは、埋め込まれる機器などである場合には、基材は、生体適合性材料からなるものとすればよい。
(Step A1) Preparation Step The preparation step of step A1 is a step of preparing a substrate for the medical device. The substrate may be selected from a suitable material, shape, etc., depending on the medical device to be manufactured. In particular, when the medical device is a device to be inserted or implanted in the body, the substrate may be made of a biocompatible material.
医療機器が、生体適合性を要求されない、検査用医療機器や診断用医療機器などの場合は、基材について特に制限はなく、医療機器に要求される特性に応じた材料を用いればよい。 When the medical device is a medical device for testing or diagnosis, etc., which does not require biocompatibility, there are no particular restrictions on the base material, and a material that meets the characteristics required of the medical device may be used.
本実施形態では、基材材料として、たとえばチタン、ステンレス、コバルトクロム合金等の金属材料、アルミナ、ジルコニア、ハイドロキシアパタイト等のセラミック材料、シリコーン樹脂、ポリエチレン、ポリプロピレン、ポリ塩化ビニル、ポリアクリロニトリル、ポリスチレン、ポリメタクリル酸メチル、ポリオキシメチレン、ポリイソプレン、ポリＬ乳酸、ポリカーボネート、ポリアミド、ポリスルホン、ポリウレタン、ポリエーテルエーテルケトン、ポリパリレン、環状ポリオレフィン等の高分子材料などを用いることができる。 In this embodiment, the substrate material may be, for example, a metal material such as titanium, stainless steel, or cobalt-chromium alloy; a ceramic material such as alumina, zirconia, or hydroxyapatite; or a polymer material such as silicone resin, polyethylene, polypropylene, polyvinyl chloride, polyacrylonitrile, polystyrene, polymethylmethacrylate, polyoxymethylene, polyisoprene, poly-L-lactic acid, polycarbonate, polyamide, polysulfone, polyurethane, polyether ether ketone, polyparylene, or cyclic polyolefin.
基材の形状は、基材を構成する材料に応じて、成形および切削などの加工を施せばよい。 The shape of the substrate can be determined by processing such as molding and cutting depending on the material that constitutes the substrate.
基材は、ホスホリルコリン基を有する重合体が含まれる有機溶剤とのなじみを向上させるために、少なくとも皮膜を形成すべき表面に大気プラズマ、酸素プラズマなどをあらかじめ照射してもよい。 In order to improve compatibility with the organic solvent containing the polymer having phosphorylcholine groups, the substrate may be irradiated in advance with atmospheric plasma, oxygen plasma, or the like, at least on the surface on which the coating is to be formed.
（工程Ａ２）調製工程
次に、工程Ａ２の調製工程では、ホスホリルコリン基を有する第１重合体およびホスホリルコリン基を有する第２重合体を有機溶剤に溶解させて重合体混合溶液を調製する。第１重合体と第２重合体とは、互いに親水性が異なる重合体である。すなわち、本工程で調製する重合体混合溶液は、２種類の重合体を混合して溶解させた溶液である。
(Step A2) Preparation Step Next, in the preparation step A2, a first polymer having a phosphorylcholine group and a second polymer having a phosphorylcholine group are dissolved in an organic solvent to prepare a polymer mixture solution. The first polymer and the second polymer are polymers having different hydrophilicities. That is, the polymer mixture solution prepared in this step is a solution in which two types of polymers are mixed and dissolved.
第１重合体と第２重合体の親水性が異なるとは、第１重合体と第２重合体の骨格（主鎖）構造が異なる場合、骨格構造自体の親水性が第１重合体と第２重合体とで異なっているということである。第１重合体と第２重合体の骨格構造が同じ場合には、それぞれの重合体の側鎖の親水性が異なっているということである。 The difference in hydrophilicity between the first polymer and the second polymer means that when the skeletal (main chain) structures of the first polymer and the second polymer are different, the hydrophilicity of the skeletal structure itself is different between the first polymer and the second polymer. When the skeletal structures of the first polymer and the second polymer are the same, the hydrophilicity of the side chains of each polymer is different.
第１重合体と第２重合体の骨格（主鎖）構造が異なる場合、いずれの骨格構造にもホスホリルコリン基が含まれていればよく、第１重合体と第２重合体の骨格構造が同じ場合、当該骨格構造にホスホリルコリン基が含まれていればよい。 When the skeletal (main chain) structures of the first polymer and the second polymer are different, it is sufficient that both skeletal structures contain phosphorylcholine groups, and when the skeletal structures of the first polymer and the second polymer are the same, it is sufficient that both skeletal structures contain phosphorylcholine groups.
第１重合体および第２重合体は、２種以上のモノマーからなる共重合体であってもよい。第１重合体および第２重合体が、共重合体である場合、少なくともいずれか１種のモノマーがホスホリルコリン基を含んでいればよい。 The first polymer and the second polymer may be copolymers consisting of two or more types of monomers. When the first polymer and the second polymer are copolymers, at least one of the monomers may contain a phosphorylcholine group.
第１重合体と第２重合体とで、共重合体を構成するモノマーが異なる場合、モノマーの親水性が異なれば、第１重合体と第２重合体の親水性は異なり、第１重合体と第２重合体とで、モノマーが同じ場合、共重合比が異なれば、第１重合体と第２重合体の親水性は異なる。 When the monomers constituting the copolymer are different between the first polymer and the second polymer, if the hydrophilicity of the monomers differs, the hydrophilicity of the first polymer and the second polymer will differ. When the monomers are the same between the first polymer and the second polymer, if the copolymerization ratio is different, the hydrophilicity of the first polymer and the second polymer will differ.
第１重合体および第２重合体が、共重合体である場合、ホスホリルコリン基を含むモノマーとしては、たとえば、２－メタクリロイルオキシエチルホスホリルコリン、２－アクリロイルオキシエチルホスホリルコリン、４－メタクリロイルオキシブチルホスホリルコリン、６－メタクリロイルオキシヘキシルホスホリルコリン、１０－メタクリロイルオキシデシルホスホリルコリン、ω－メタクリロイルオキシポリ（エチレンオキシド）エチルホスホリルコリン、４－スチリルオキシブチルホスホリルコリンなどがある。これらの中でも、重合特性と原料化合物の入手の点から２－メタクリロイルオキシエチルホスホリルコリン（以下では、「ＭＰＣ」という）が特に好ましい。 When the first polymer and the second polymer are copolymers, examples of monomers containing a phosphorylcholine group include 2-methacryloyloxyethyl phosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, 4-methacryloyloxybutyl phosphorylcholine, 6-methacryloyloxyhexyl phosphorylcholine, 10-methacryloyloxydecyl phosphorylcholine, ω-methacryloyloxypoly(ethylene oxide)ethyl phosphorylcholine, and 4-styryloxybutyl phosphorylcholine. Among these, 2-methacryloyloxyethyl phosphorylcholine (hereinafter referred to as "MPC") is particularly preferred in terms of polymerization characteristics and availability of raw material compounds.
ホスホリルコリン基を含むモノマーとともに共重合体を構成する他のモノマーとしては、たとえば、メタクリル酸エステル、メタクリルアミドなどがある。これらの中でもメタクリル酸エステルが好ましい。 Other monomers that can be used to form copolymers together with the monomer containing a phosphorylcholine group include, for example, methacrylic acid esters and methacrylamides. Among these, methacrylic acid esters are preferred.
また、メタクリル酸エステルとしては、たとえば、メタクリル酸エチル、メタクリル酸プロピル、メタクリル酸ｎ-ブチル、メタクリル酸ペンチル、メタクリル酸ヘキシル、メタクリル酸ヘプチル、メタクリル酸オクチル、メタクリル酸トリデシル、メタクリル酸２－エトキシエチル、メタクリル酸２－エトキシプロピル、メタクリル酸２－フェノキシエチル、メタクリル酸２－ブトキシエチルなどがある。これらの中でもメタクリル酸ｎ-ブチル（ｎブチルメタクリレート、ＢＭＡ）が特に好ましい。 Examples of methacrylic acid esters include ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, tridecyl methacrylate, 2-ethoxyethyl methacrylate, 2-ethoxypropyl methacrylate, 2-phenoxyethyl methacrylate, and 2-butoxyethyl methacrylate. Among these, n-butyl methacrylate (n-butyl methacrylate, BMA) is particularly preferred.
以下の本実施形態では、第１重合体および第２重合体は、いずれも下記の一般式で表される２－メタクリロイルオキシエチルホスホリルコリン（ＭＰＣ）とブチルメタクリレート（ＢＭＡ）との共重合体で（以下では、「ＰＭＢ」と略称する。）ある。 In the following embodiment, the first polymer and the second polymer are both copolymers of 2-methacryloyloxyethyl phosphorylcholine (MPC) and butyl methacrylate (BMA) represented by the following general formula (hereinafter abbreviated as "PMB").
ＭＰＣは、下記構造式に示すような化学構造を有しており、ホスホリルコリン基と、重合性のメタクリル酸ユニットとを有する重合性モノマーである。
ＭＰＣは、例えば、２－ヒドロキシエチルメタクリレート、トリエチルアミン、２－クロロ－２－オキソ－１，３，２－ジオキサホスホランを反応させ、２－（２－オキソ－１，３，２－ジオキサホスホロイルオキシ）エチルメタクリレート（ＯＰＥＭＡ）を得たのち、このＯＰＥＭＡを無水トリメチルアミンのアセトニトリル溶液中で反応させて得ることができる。 MPC can be obtained, for example, by reacting 2-hydroxyethyl methacrylate, triethylamine, and 2-chloro-2-oxo-1,3,2-dioxaphosphorane to obtain 2-(2-oxo-1,3,2-dioxaphosphoroyloxy)ethyl methacrylate (OPEMA), and then reacting this OPEMA in an acetonitrile solution of anhydrous trimethylamine.
また、ＢＭＡは、下記構造式に示すような化学構造を有する重合性モノマーである。
本実施形態の第１重合体と第２重合体とは、構成するモノマーが同じＰＭＢであり、第１重合体と第２重合体とで、共重合比を異ならせることによって、第１重合体と第２重合体との親水性が異なるようにしている。 In this embodiment, the first polymer and the second polymer are made of the same constituent monomer, PMB, and the copolymerization ratios of the first polymer and the second polymer are different, so that the hydrophilicity of the first polymer and the second polymer differs.
第１重合体であるＰＭＢ（第１ＰＭＢ）の共重合比（ＭＰＣ：ＢＭＡ）は、モル比で９：１～６：４である。一方、第２重合体であるＰＭＢ（第２ＰＭＢ）の共重合比（ＭＰＣ：ＢＭＡ）は、モル比で３：７～１：９である。 The copolymerization ratio (MPC:BMA) of the first polymer PMB (first PMB) is 9:1 to 6:4 in molar ratio. On the other hand, the copolymerization ratio (MPC:BMA) of the second polymer PMB (second PMB) is 3:7 to 1:9 in molar ratio.
このような第１ＰＭＢの平均分子量は、５，０００～３００，０００であり、好ましくは、１０，０００～３００，０００である。また、第２ＰＭＢの平均分子量は、３００，０００以上であり、好ましくは、３００，０００～５，０００，０００である。 The average molecular weight of the first PMB is 5,000 to 300,000, and preferably 10,000 to 300,000. The average molecular weight of the second PMB is 300,000 or more, and preferably 300,000 to 5,000,000.
第１ＰＭＢは、ＢＭＡに対してＭＰＣの比率が高く、第２ＰＭＢは、ＢＭＡに対してＭＰＣの比率が低い。ＭＰＣとＢＭＡのモノマーとしての親水性は、ＭＰＣのほうがＢＭＡよりも高いので、第１ＰＭＢと第２ＰＭＢとでは、第１ＰＭＢのほうが第２ＰＭＢよりも親水性が高い共重合体である。また、第１ＰＭＢの共重合比（ＭＰＣ：ＢＭＡ）において、ＭＰＣの比率が大きいほど、より親水性が高い共重合体である。第２ＰＭＢの共重合比（ＭＰＣ：ＢＭＡ）において、ＢＭＡの比率が大きいほど、より疎水性が高い（親水性が低い）共重合体である。 The first PMB has a high ratio of MPC to BMA, and the second PMB has a low ratio of MPC to BMA. As MPC and BMA as monomers have higher hydrophilicity than BMA, the first PMB is a more hydrophilic copolymer than the second PMB. In addition, the higher the ratio of MPC in the copolymerization ratio (MPC:BMA) of the first PMB, the more hydrophilic the copolymer. In the copolymerization ratio (MPC:BMA) of the second PMB, the higher the ratio of BMA, the more hydrophobic (less hydrophilic) the copolymer.
本実施形態で用いられる共重合体である第１ＰＭＢとしては、共重合比（ＭＰＣ：ＢＭＡ）がモル比で８：２である共重合体（以下では、ＰＭＢ８０という）が好ましく、第２ＰＭＢとしては、共重合比（ＭＰＣ：ＢＭＡ）がモル比で３：７である共重合体（以下では、ＰＭＢ３０という）が好ましい。 The first PMB, which is the copolymer used in this embodiment, is preferably a copolymer having a copolymerization ratio (MPC:BMA) of 8:2 by molar ratio (hereinafter referred to as PMB80), and the second PMB is preferably a copolymer having a copolymerization ratio (MPC:BMA) of 3:7 by molar ratio (hereinafter referred to as PMB30).
第１ＰＭＢおよび第２ＰＭＢの共重合体の製造は、重合開始剤の存在下、ＭＰＣとＢＭＡを溶媒中で反応させて得られる。反応場となる溶媒としては、ＭＰＣおよびＢＭＡが溶解すればよく、具体的には水、メタノール、エタノール、プロパノール、ｔ－ブタノール、ジメチルホルムアミド、テトラヒドロフラン、クロロホルムおよびこれらの混合物等である。重合開始剤としては、一般に用いられるラジカル開始剤ならばいずれを用いてもよく、２，２’－アゾビスイソブチロニトリル（ＡＩＢＮ）、アゾビスマレノニトリル等の脂肪族アゾ化合物や、過酸化ベンゾイル、過酸化ラウロイル、過硫酸アンモニウム、過硫酸カリウム等の有機過酸化物などがある。 The copolymer of the first PMB and the second PMB is produced by reacting MPC and BMA in a solvent in the presence of a polymerization initiator. The solvent that serves as the reaction field may be any solvent in which MPC and BMA dissolve, specifically water, methanol, ethanol, propanol, t-butanol, dimethylformamide, tetrahydrofuran, chloroform, and mixtures thereof. As the polymerization initiator, any commonly used radical initiator may be used, including aliphatic azo compounds such as 2,2'-azobisisobutyronitrile (AIBN) and azobismalenonitrile, and organic peroxides such as benzoyl peroxide, lauroyl peroxide, ammonium persulfate, and potassium persulfate.
第１ＰＭＢと第２ＰＭＢの共重合比を異ならせるためには、溶媒に溶解させるＭＰＣとＢＭＡのそれぞれの投入量（比率）を、第１ＰＭＢと第２ＰＭＢの共重合比に応じて適宜調製すればよい。 To make the copolymerization ratio of the first PMB and the second PMB different, the amounts (ratio) of MPC and BMA dissolved in the solvent may be adjusted appropriately according to the copolymerization ratio of the first PMB and the second PMB.
本工程では、上記のようにして得られた親水性が異なる２種の重合体、本実施形態では、共重合比が互いに異なる第１ＰＭＢと第２ＰＭＢを、有機溶媒に溶解させることで重合体混合溶液を調製する。 In this process, the two types of polymers with different hydrophilicity obtained as described above, in this embodiment, the first PMB and the second PMB with different copolymerization ratios, are dissolved in an organic solvent to prepare a polymer mixture solution.
重合体混合溶液に用いられる有機溶媒としては、親水性が異なる第１重合体と第２重合体とがいずれも溶解するような溶媒であればよく、具体的には、エタノール、メタノール、イソプロピルアルコール、アセトンおよびこれらの混合物等である。これらの中でもエタノールが好ましい。 The organic solvent used in the polymer mixture solution may be any solvent that dissolves both the first polymer and the second polymer, which have different hydrophilicity. Specifically, the organic solvent may be ethanol, methanol, isopropyl alcohol, acetone, or a mixture thereof. Of these, ethanol is preferred.
上記のように、第１重合体である第１ＰＭＢは、共重合比（ＭＰＣ：ＢＭＡ）が９：１～６：４（モル比）の範囲内で複数種類の共重合体を含み、第２重合体である第２ＰＭＢは、共重合比（ＭＰＣ：ＢＭＡ）が３：７～１：９（モル比）の範囲内で複数種類の共重合体を含んでいる。重合体混合溶液に溶解される２種の重合体の組み合わせは、重合比（ＭＰＣ：ＢＭＡ）が９：１～６：４（モル比）の範囲から選ばれた１種の第１ＰＭＢと、共重合比（ＭＰＣ：ＢＭＡ）が３：７～１：９（モル比）の範囲から選ばれた１種の第２ＰＭＢとの組み合わせであり、複数の組み合わせがある。 As described above, the first polymer, the first PMB, contains multiple types of copolymers with a copolymerization ratio (MPC:BMA) in the range of 9:1 to 6:4 (molar ratio), and the second polymer, the second PMB, contains multiple types of copolymers with a copolymerization ratio (MPC:BMA) in the range of 3:7 to 1:9 (molar ratio). The combination of the two polymers dissolved in the polymer mixture solution is a combination of one type of first PMB selected from the range of 9:1 to 6:4 (molar ratio) in polymerization ratio (MPC:BMA) and one type of second PMB selected from the range of 3:7 to 1:9 (molar ratio), and there are multiple combinations.
本実施形態で調製される重合体混合溶液は、これら複数の組み合わせのうち、少なくとも１つの組み合わせである第１ＰＭＢと第２ＰＭＢとが、有機溶媒に溶解されたものである。 The polymer mixture solution prepared in this embodiment is one in which at least one of these combinations, the first PMB and the second PMB, is dissolved in an organic solvent.
本工程で調製される重合体混合溶液は、第１重合体の含有量（Ｐ１）と第２重合体の含有量（Ｐ２）との比（Ｐ１／Ｐ２）が、重量比で１／９～４／６である。 The polymer mixture solution prepared in this process has a ratio (P1/P2) of the content of the first polymer (P1) to the content of the second polymer (P2) of 1/9 to 4/6 by weight.
特に、第１重合体がＰＭＢ８０であり、第２重合体がＰＭＢ３０である組み合わせの場合、ＰＭＢ８０の含有量とＰＭＢ３０の含有量との比（ＰＭＢ８０／ＰＭＢ３０）は、重量比で１／９～３／７が好ましく、より好ましくは、１／９～２／８である。 In particular, in the case of a combination in which the first polymer is PMB80 and the second polymer is PMB30, the ratio of the PMB80 content to the PMB30 content (PMB80/PMB30) is preferably 1/9 to 3/7 by weight, and more preferably 1/9 to 2/8.
本実施形態において、重合体混合溶液中の、第１重合体および第２重合体の混合物の濃度は、濡れ性に影響を与えないので、特に限定されないが、たとえば、０．１～０．５重量％とすればよい。 In this embodiment, the concentration of the mixture of the first polymer and the second polymer in the polymer mixture solution is not particularly limited because it does not affect the wettability, but may be, for example, 0.1 to 0.5% by weight.
このようにして調製された重合体混合溶液は、次の皮膜形成工程で使用される。 The polymer mixture solution prepared in this way is used in the next film formation process.
（工程Ａ３）皮膜形成工程
次に、工程Ａ３の皮膜形成工程では、調製された重合体混合溶液に基材を浸漬させたのち乾燥させる方法、調製された重合体混合溶液を噴霧する方法またはスピンコーティング法を用いて、基材の少なくとも一部の表面に第１重合体および第２重合体を含む親水性皮膜を形成する。
(Step A3) Film-forming step Next, in the film-forming step A3, a hydrophilic film containing the first polymer and the second polymer is formed on at least a portion of the surface of the substrate by using a method of immersing the substrate in the prepared polymer mixed solution and then drying it, a method of spraying the prepared polymer mixed solution, or a spin coating method.
本工程では、浸漬および乾燥という簡単な処理操作、いわゆるディッピングによって基材の少なくとも一部の表面に親水性皮膜を形成することができる。本工程で形成された親水性皮膜には、重合体混合溶液に溶解されていた第１重合体と第２重合体とが含まれている。 In this process, a hydrophilic film can be formed on at least a portion of the surface of the substrate by a simple process of immersion and drying, known as dipping. The hydrophilic film formed in this process contains the first polymer and the second polymer that were dissolved in the polymer mixture solution.
親水性皮膜が第１重合体および第２重合体であるＰＭＢを含むことにより、医療機器の表面に、ＭＰＣ由来のリン脂質極性基が存在するため、細胞膜類似となる。このような医療機器の表面には、タンパク質や血球などの生体成分の吸着が極めて少なく、また血栓形成を誘引する血小板の活性化を抑制することができるという効果もある。 By containing the first polymer and the second polymer PMB, the hydrophilic coating has phospholipid polar groups derived from MPC on the surface of the medical device, making it similar to a cell membrane. The surface of such a medical device has very little adsorption of biological components such as proteins and blood cells, and also has the effect of suppressing the activation of platelets that induce thrombus formation.
さらに、親水性皮膜が、親水性が異なる２種の、ホスホリルコリン基を有する重合体を含むことにより、初期の水濡れ性に優れ、使用環境下における高い安定性を有する医療機器を製造することができる。 Furthermore, by containing two types of polymers with phosphorylcholine groups that differ in hydrophilicity, the hydrophilic coating can produce medical devices that have excellent initial water wettability and high stability in the usage environment.
本発明における安定性とは、水または水性媒体中に医療機器を浸漬させたときに、皮膜を構成する重合体の水または水性溶媒への溶出のし難さであり、溶出し難いほど安定性が高い。 In the present invention, stability refers to the resistance of the polymer that constitutes the coating to dissolution into water or an aqueous medium when the medical device is immersed in water or an aqueous medium, and the more difficult it is to dissolve, the higher the stability.
親水性皮膜が、比較的親水性の高い１種の重合体、たとえばＰＭＢ８０のみで構成される場合、初期の水濡れ性は十分に高いが、安定性が低いので、水中に重合体が溶出して皮膜の一部または全部が失われる。また、医療機器が、ウェルプレートなどの検査用器具やマイクロチップなどの診断用器具である場合、検体液中に重合体が混入し、検査結果または診断結果に影響を及ぼしてしまう。 When the hydrophilic coating is composed of only one type of polymer with relatively high hydrophilicity, such as PMB80, the initial water wettability is sufficiently high, but the stability is low, so the polymer dissolves in water and the coating is lost in part or in whole. In addition, when the medical device is a testing tool such as a well plate or a diagnostic tool such as a microchip, the polymer gets mixed into the sample liquid, affecting the test or diagnostic results.
親水性被膜が、比較的親水性の低い１種の重合体、たとえばＰＭＢ３０のみで構成される場合安定性は高いが、初期の水濡れ性に劣るので、応用される医療機器が限定される。 When the hydrophilic coating is made of only one type of polymer with relatively low hydrophilicity, such as PMB30, it is highly stable, but has poor initial water wettability, so the medical devices to which it can be applied are limited.
さらに、本発明のように第１重合体と第２重合体とを含む混合溶液を用いず、親水性の高い１種の重合体（たとえばＰＭＢ８０）のみを溶解させた第１溶液と、親水性の低い１種の重合体（たとえばＰＭＢ３０）のみを溶解させた第２溶液とをそれぞれ調製し、第１溶液に浸漬させて第１皮膜を形成したのち第２溶液に浸漬させて第１皮膜上に第２皮膜を形成していわゆる２層型の親水性皮膜を形成した場合、表面層がＰＭＢ３０からなるので、初期の水濡れ性は改善されない。また、浸漬の順序を入れ替えて、２層型の親水性皮膜を形成した場合、表面層がＰＭＢ８０からなるので、表面層が水中に溶出する問題が残る。 Furthermore, instead of using a mixed solution containing a first polymer and a second polymer as in the present invention, a first solution in which only one type of polymer with high hydrophilicity (e.g., PMB80) is dissolved and a second solution in which only one type of polymer with low hydrophilicity (e.g., PMB30) is dissolved are prepared, and the first film is formed by immersion in the first solution, and then the second film is formed on the first film by immersion in the second solution to form a so-called two-layer hydrophilic film. Since the surface layer is made of PMB30, the initial water wettability is not improved. Furthermore, if the order of immersion is reversed to form a two-layer hydrophilic film, the surface layer is made of PMB80, so the problem of the surface layer dissolving in water remains.
これに対して、第１重合体と第２重合体とを含む混合溶液を用いて、ディッピングによって親水性皮膜を形成した場合、形成される皮膜は１層型であり、初期の水濡れ性に優れ、高い安定性を有する医療機器が得られる。ただし、この１層型の第１皮膜上を形成させたのちであれば、第１重合体と第２重合体とを含む混合溶液を用いず、親水性の高い１種の重合体（たとえばＰＭＢ８０）のみを溶解させた溶液による第２皮膜を形成していわゆる２層型の親水性を高めた皮膜を作製してもよい。 In contrast, when a hydrophilic coating is formed by dipping using a mixed solution containing the first polymer and the second polymer, the coating formed is a single-layer type, and a medical device with excellent initial water wettability and high stability is obtained. However, after forming this single-layer type first coating, a second coating may be formed from a solution in which only one highly hydrophilic polymer (e.g., PMB80) is dissolved, without using the mixed solution containing the first polymer and the second polymer, to produce a so-called two-layer type coating with enhanced hydrophilicity.
浸漬条件は、基材の大きさ、基材の形状、親水性皮膜を形成する表面部分の大きさ、親水性皮膜の厚みなど製造すべき医療機器の仕様に従い、適宜決定すればよい。浸漬条件としては、たとえば、基材を重合体混合溶液に浸漬させる時間、重合体混合溶液の液温などである。 The immersion conditions may be appropriately determined according to the specifications of the medical device to be manufactured, such as the size of the substrate, the shape of the substrate, the size of the surface portion on which the hydrophilic coating is to be formed, and the thickness of the hydrophilic coating. Examples of the immersion conditions include the time for which the substrate is immersed in the polymer mixture solution and the temperature of the polymer mixture solution.
基材を重合体混合溶液に浸漬させた直後の状態では、基材の表面には、有機溶媒を含む混合溶液が付着した状態であるので、基材の表面には第１重合体と第２重合体にさらに有機溶媒を含んだ状態である。有機溶媒を除去するために、乾燥を行う。 Immediately after the substrate is immersed in the polymer mixture solution, the substrate surface is in a state where the mixture solution containing the organic solvent is adhered to the substrate surface, so the substrate surface contains the first polymer, the second polymer, and the organic solvent. Drying is performed to remove the organic solvent.
乾燥は、第１重合体と第２重合体に影響を与えずに有機溶媒を除去できる操作であればよく、常温常圧下に浸漬後の基材を放置する風乾、浸漬後の基材に高温の熱風を吹き付ける熱風乾燥、常温下、真空雰囲気内に基材を放置する真空乾燥などであってもよい。 The drying may be any operation capable of removing the organic solvent without affecting the first polymer and the second polymer, and may be air drying in which the substrate is left at room temperature and pressure after immersion, hot air drying in which high-temperature hot air is blown onto the substrate after immersion, or vacuum drying in which the substrate is left in a vacuum atmosphere at room temperature.
乾燥条件も浸漬条件と同様に製造すべき医療機器の仕様に従い、適宜決定すればよい。 As with the soaking conditions, the drying conditions should be determined appropriately according to the specifications of the medical device to be manufactured.
このような乾燥を経て、基材表面に第１重合体と第２重合体とを含む親水性皮膜が形成された医療機器が製造される。 After this drying process, a medical device is manufactured in which a hydrophilic coating containing the first polymer and the second polymer is formed on the surface of the substrate.
（工程Ａ４）滅菌工程
本実施形態の製造方法は、さらに、工程Ａ４として、親水性皮膜が形成された基材に滅菌処理を施す滅菌工程を有していてもよい。工程Ａ４の滅菌工程では、滅菌処理として、たとえば親水性皮膜が形成された基材に高エネルギー線を照射する照射処理、親水性皮膜が形成された基材にガスプラズマを接触させるガスプラズマ処理などがある。
(Step A4) Sterilization Step The manufacturing method of this embodiment may further include, as step A4, a sterilization step of subjecting the substrate on which the hydrophilic coating is formed to a sterilization treatment. In the sterilization step of step A4, the sterilization treatment may be, for example, an irradiation treatment of irradiating the substrate on which the hydrophilic coating is formed with high-energy rays, or a gas plasma treatment of contacting the substrate on which the hydrophilic coating is formed with gas plasma.
照射処理またはガスプラズマ処理によって、得られる医療機器に滅菌処理を施すことができるとともに、さらに初期の濡れ性を向上させることができる。 By irradiation or gas plasma treatment, the resulting medical device can be sterilized and its initial wettability can be improved.
照射処理において、照射する高エネルギー線は、滅菌処理に用いられるものであれば、限定されないが、たとえば、ガンマ線、電子線、紫外線などを用いることができる。ガンマ線または電子線を照射する場合、その吸収線量は、たとえば２０～１００ｋＧｙとすることが好ましい。紫外線を照射する場合、その照射量は、たとえば８，０００～１００，０００ｍＪ／ｃｍ２とすることが好ましい。 In the irradiation process, the high energy rays to be irradiated are not limited as long as they are used in sterilization processes, and for example, gamma rays, electron beams, ultraviolet rays, etc. can be used. When irradiating with gamma rays or electron beams, the absorbed dose is preferably, for example, 20 to 100 kGy. When irradiating with ultraviolet rays, the dose is preferably, for example, 8,000 to 100,000 mJ/ cm2 .
ガスプラズマ処理において、接触させるガスプラズマは、滅菌処理に用いられるものであれば、限定されないが、たとえば、過酸化水素ガスプラズマなどを用いることができる。 In gas plasma treatment, the gas plasma to be contacted is not limited as long as it is used in sterilization treatment, but for example, hydrogen peroxide gas plasma can be used.
（実施例１）
・準備工程
準備工程では、たて１０ｍｍ×よこ１０ｍｍ×厚み３ｍｍの平板形状であり、ポリカーボネート（ＰＣ）からなる基材、環状ポリオレフィン（ＣＯＰ）からなる基材、シリコン（Ｓｉ）からなる基材、クロスリンクポリエチレン（ＣＬＰＥ）からなる基材、コバルトクロム合金（ＣＣＭ）からなる基材、チタン（Ｔｉ）から成る基材およびステンレス鋼（ＳＵＳ）から成る基材をそれぞれ準備した。
Example 1
Preparation Step In the preparation step, substrates each having a flat plate shape measuring 10 mm in length × 10 mm in width × 3 mm in thickness, including a substrate made of polycarbonate (PC), a substrate made of cyclic polyolefin (COP), a substrate made of silicon (Si), a substrate made of cross-linked polyethylene (CLPE), a substrate made of cobalt chromium alloy (CCM), a substrate made of titanium (Ti), and a substrate made of stainless steel (SUS) were prepared.
・調製工程
調製工程では、実施例として、第１重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で８：２であるＰＭＢ８０（重量平均分子量３５０，０００）とし、第２重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で３：７であるＰＭＢ３０（重量平均分子量２００，０００）とし、有機溶媒をエタノールとした。
Preparation Step In the preparation step, as an example, the first polymer was PMB80 (weight average molecular weight 350,000) having a copolymerization ratio (MPC:BMA) of 8:2 in molar ratio, the second polymer was PMB30 (weight average molecular weight 200,000) having a copolymerization ratio (MPC:BMA) of 3:7 in molar ratio, and the organic solvent was ethanol.
エタノールに、ＰＭＢ８０とＰＭＢ３０の混合物濃度が０．２重量％となるよう溶解させて重合体混合溶液を調製した。混合物の含有量比（ＰＭＢ８０／ＰＭＢ３０）は、重量比で１／９となるように混合した。 A polymer mixture solution was prepared by dissolving PMB80 and PMB30 in ethanol so that the mixture concentration was 0.2% by weight. The mixture was mixed so that the content ratio (PMB80/PMB30) was 1/9 by weight.
また、比較例として、ＰＭＢ８０を用いず、ＰＭＢ３０のみを、エタノールに、ＰＭＢ３０の濃度が０．２重量％となるように溶解させて重合体溶液を調製した。 As a comparative example, a polymer solution was prepared by dissolving only PMB30 in ethanol without using PMB80, so that the concentration of PMB30 was 0.2% by weight.
・皮膜形成工程
皮膜形成工程では、実施例の重合体混合溶液に、各基材を１０秒間浸漬し、これを２回繰り返したのち、真空乾燥によって乾燥させ、各基材の表面に親水性皮膜を形成し、実施例の試験片を得た。また、比較例の重合体溶液に各基材を１０秒間浸漬し、これを２回繰り返したのち、真空乾燥によって乾燥させ、各基材の表面に親水性皮膜を形成し、比較例の試験片を得た。
In the film-forming step, each substrate was immersed in the polymer mixture solution of the example for 10 seconds, and this was repeated twice, and then dried by vacuum drying to form a hydrophilic film on the surface of each substrate, thereby obtaining a test piece of the example. Also, each substrate was immersed in the polymer solution of the comparative example for 10 seconds, and this was repeated twice, and then dried by vacuum drying to form a hydrophilic film on the surface of each substrate, thereby obtaining a test piece of the comparative example.
試験片表面の水濡れ性は、実施例および比較例の各試験片の親水性皮膜の表面に純水を滴下したときの接触角を測定することで評価した。水の静的接触角は、表面接触角測定装置（協和界面科学社製 ＤＭ３００）を用い、液滴法により評価した。液滴法による静的表面接触角の測定は、ＩＳＯ１５９８９規格に準拠し、液滴量１μＬの純水を試料表面に滴下し、６０秒後に測定した。結果を図２のグラフに示す。 The water wettability of the test piece surface was evaluated by measuring the contact angle when pure water was dropped onto the surface of the hydrophilic coating of each test piece in the examples and comparative examples. The static contact angle of water was evaluated by the sessile drop method using a surface contact angle measuring device (DM300 manufactured by Kyowa Interface Science Co., Ltd.). The static surface contact angle was measured by the sessile drop method in accordance with the ISO15989 standard, where a 1 μL drop of pure water was dropped onto the sample surface and measured 60 seconds later. The results are shown in the graph in Figure 2.
図２からわかるように、実施例の試験片は、比較例の試験片に比べていずれも小さな接触角を示した。すなわち、実施例の試験片表面は、比較例の試験片表面よりも親水性が高く、初期の濡れ性に優れていることがわかった。 As can be seen from Figure 2, the test pieces of the Examples all showed smaller contact angles than the test pieces of the Comparative Examples. In other words, it was found that the surfaces of the test pieces of the Examples were more hydrophilic and had better initial wettability than the surfaces of the test pieces of the Comparative Examples.
（実施例２）
・準備工程
準備工程では、たて１０ｍｍ×よこ１０ｍｍ×厚み３ｍｍの平板形状であり、ポリカーボネート（ＰＣ）からなる基材、環状ポリオレフィン（ＣＯＰ）からなる基材およびステンレス鋼（ＳＵＳ）から成る基材をそれぞれ準備した。
Example 2
Preparation Step In the preparation step, a substrate made of polycarbonate (PC), a substrate made of cyclic polyolefin (COP), and a substrate made of stainless steel (SUS) were prepared, each having a flat plate shape with a length of 10 mm, a width of 10 mm, and a thickness of 3 mm.
・調製工程
調製工程では、実施例として、第１重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で８：２であるＰＭＢ８０（重量平均分子量３５０，０００）とし、第２重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で３：７であるＰＭＢ３０（重量平均分子量２００，０００）とし、有機溶媒をエタノールとした。
Preparation Step In the preparation step, as an example, the first polymer was PMB80 (weight average molecular weight 350,000) having a copolymerization ratio (MPC:BMA) of 8:2 in molar ratio, the second polymer was PMB30 (weight average molecular weight 200,000) having a copolymerization ratio (MPC:BMA) of 3:7 in molar ratio, and the organic solvent was ethanol.
エタノールに、ＰＭＢ８０とＰＭＢ３０の混合物濃度が０．１重量％、０．２重量％、０．５重量％となるよう溶解させて３種の重合体混合溶液を調製した。混合物の含有量比（ＰＭＢ８０／ＰＭＢ３０）は、重量比で１／９となるように混合した。 Three types of polymer mixture solutions were prepared by dissolving PMB80 and PMB30 in ethanol to a mixture concentration of 0.1 wt%, 0.2 wt%, and 0.5 wt%. The mixture content ratio (PMB80/PMB30) was 1/9 by weight.
・皮膜形成工程
皮膜形成工程では、３種の重合体混合溶液それぞれに、各基材を１０秒間浸漬し、これを２回繰り返したのち、真空乾燥によって乾燥させ、各基材の表面に親水性皮膜を形成し、実施例の試験片を得た。
In the film-forming step, each substrate was immersed in each of the three polymer mixture solutions for 10 seconds, and this was repeated twice. After that, the substrate was dried by vacuum drying to form a hydrophilic film on the surface of each substrate, and a test piece for the example was obtained.
試験片表面の濡れ性は、実施例の各試験片の親水性皮膜の表面に純水を滴下したときの接触角を測定することで評価した。水の静的接触角は、表面接触角測定装置（協和界面科学社製 ＤＭ３００）を用い、液滴法により評価した。液滴法による静的表面接触角の測定は、ＩＳＯ１５９８９規格に準拠し、液滴量１μＬの純水を試料表面に滴下して、６０秒後に測定した。結果を図３のグラフに示す。 The wettability of the test piece surface was evaluated by measuring the contact angle when pure water was dropped onto the surface of the hydrophilic coating of each test piece in the examples. The static contact angle of water was evaluated by the sessile drop method using a surface contact angle measuring device (DM300 manufactured by Kyowa Interface Science Co., Ltd.). The static surface contact angle was measured by the sessile drop method in accordance with the ISO15989 standard, where a 1 μL drop of pure water was dropped onto the sample surface and measured 60 seconds later. The results are shown in the graph in Figure 3.
図３からわかるように、実施例の試験片の水の静的接触角は、重合体混合溶液の第１重合体および第２重合体の濃度には影響を受けず、０．１～０．５重量％の範囲で一定であることがわかった。 As can be seen from Figure 3, the static water contact angle of the test specimen of the example was not affected by the concentration of the first polymer and the second polymer in the polymer mixture solution, and was found to be constant in the range of 0.1 to 0.5 wt.%.
（実施例３）
・準備工程
準備工程では、たて１０ｍｍ×よこ１０ｍｍ×厚み３ｍｍの平板形状であり、ポリカーボネート（ＰＣ）からなる基材、環状ポリオレフィン（ＣＯＰ）からなる基材およびステンレス鋼（ＳＵＳ）から成る基材をそれぞれ準備した。
Example 3
Preparation Step In the preparation step, a substrate made of polycarbonate (PC), a substrate made of cyclic polyolefin (COP), and a substrate made of stainless steel (SUS) were prepared, each having a flat plate shape with a length of 10 mm, a width of 10 mm, and a thickness of 3 mm.
・調製工程
調製工程では、実施例として、第１重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で８：２であるＰＭＢ８０（重量平均分子量３５０，０００）とし、第２重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で３：７であるＰＭＢ３０（重量平均分子量２００，０００）とし、有機溶媒をエタノールとした。
Preparation Step In the preparation step, as an example, the first polymer was PMB80 (weight average molecular weight 350,000) having a copolymerization ratio (MPC:BMA) of 8:2 in molar ratio, the second polymer was PMB30 (weight average molecular weight 200,000) having a copolymerization ratio (MPC:BMA) of 3:7 in molar ratio, and the organic solvent was ethanol.
エタノールに、ＰＭＢ８０とＰＭＢ３０の混合物濃度が０．２重量％となるよう溶解させて重合体混合溶液を調製した。混合物の含有量比（ＰＭＢ８０／ＰＭＢ３０）は、重量比で１／９となるように混合した。 A polymer mixture solution was prepared by dissolving PMB80 and PMB30 in ethanol so that the mixture concentration was 0.2% by weight. The mixture was mixed so that the content ratio (PMB80/PMB30) was 1/9 by weight.
・皮膜形成工程
皮膜形成工程では、実施例の重合体混合溶液に、各基材を１０秒間浸漬し、これを２回繰り返したのち、真空乾燥によって乾燥させ、各基材の表面に親水性皮膜を形成し、未滅菌の実施例の試験片を得た。
In the film-forming process, each substrate was immersed in the polymer mixture solution of the example for 10 seconds, and this was repeated twice. After that, the substrate was dried by vacuum drying to form a hydrophilic film on the surface of each substrate, and a non-sterile test piece of the example was obtained.
・滅菌工程
滅菌工程では、親水性皮膜が形成された乾燥後の試験片に吸収線量２５～４０ｋＧｙの条件でガンマ線を照射する照射処理を施した滅菌済み実施例の試験片および親水性皮膜が形成された乾燥後の試験片にガスプラズマ処理を施した滅菌済み実施例の試験片を得た。
Sterilization step In the sterilization step, the dried test specimens on which the hydrophilic coating was formed were subjected to an irradiation treatment of irradiating them with gamma rays at an absorbed dose of 25 to 40 kGy to obtain sterilized example test specimens, and the dried test specimens on which the hydrophilic coating was formed were subjected to a gas plasma treatment to obtain sterilized example test specimens.
試験片表面の濡れ性は、実施例の各試験片の親水性皮膜の表面に純水を滴下したときの接触角を測定することで評価した。水の静的接触角は、表面接触角測定装置（協和界面科学社製 ＤＭ３００）を用い、液滴法により評価した。液滴法による静的表面接触角の測定は、ＩＳＯ１５９８９規格に準拠し、液滴量１μＬの純水を試料表面に滴下して６０秒後に測定した。結果を図４のグラフに示す。図４のグラフにおいて、基材ごとに左から未滅菌、ガンマ線滅菌、ガスプラズマ滅菌の順に示している。 The wettability of the test piece surface was evaluated by measuring the contact angle when pure water was dropped onto the surface of the hydrophilic coating of each test piece in the examples. The static contact angle of water was evaluated by the sessile drop method using a surface contact angle measuring device (DM300 manufactured by Kyowa Interface Science Co., Ltd.). The static surface contact angle was measured by the sessile drop method in accordance with the ISO15989 standard, where a 1 μL drop of pure water was dropped onto the sample surface and measured 60 seconds later. The results are shown in the graph in Figure 4. In the graph in Figure 4, the order of non-sterilization, gamma ray sterilization, and gas plasma sterilization is shown from the left for each substrate.
図４からわかるように、実施例の試験片の水の静的接触角は、いずれの基材においてもガンマ線滅菌およびガスプラズマ滅菌を施すことで未滅菌のものよりも低くなることがわかった。すなわち、ガンマ線滅菌のように高エネルギー線を照射したり、ガスプラズマ滅菌のようにガスプラズマを接触させることで、照射前よりも初期の水濡れ性が優れることがわかった。 As can be seen from Figure 4, the static contact angle of water on the test specimens of the examples was found to be lower for all substrates after gamma ray sterilization and gas plasma sterilization than for unsterilized specimens. In other words, it was found that exposure to high-energy rays, as in gamma ray sterilization, or contact with gas plasma, as in gas plasma sterilization, resulted in better initial water wettability than before irradiation.
（実施例４）
・準備工程
準備工程では、たて１０ｍｍ×よこ１０ｍｍ×厚み３ｍｍの平板形状であり、シリコン（Ｓｉ）から成る基材をそれぞれ準備した。
Example 4
Preparation Step In the preparation step, a substrate having a flat plate shape with a length of 10 mm, a width of 10 mm, and a thickness of 3 mm and made of silicon (Si) was prepared.
・調製工程
調製工程では、実施例として、第１重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で８：２であるＰＭＢ８０（重量平均分子量３５０，０００）とし、第２重合体を、共重合比（ＭＰＣ：ＢＭＡ）がモル比で３：７であるＰＭＢ３０（重量平均分子量２００，０００）とし、有機溶媒をエタノールとした。
Preparation Step In the preparation step, as an example, the first polymer was PMB80 (weight average molecular weight 350,000) having a copolymerization ratio (MPC:BMA) of 8:2 in molar ratio, the second polymer was PMB30 (weight average molecular weight 200,000) having a copolymerization ratio (MPC:BMA) of 3:7 in molar ratio, and the organic solvent was ethanol.
エタノールに、ＰＭＢ８０とＰＭＢ３０の混合物濃度が０．２重量％となるよう溶解させて重合体混合溶液を調製した。混合物の含有量比（ＰＭＢ８０／ＰＭＢ３０）は、重量比で１／９となるように混合した。 A polymer mixture solution was prepared by dissolving PMB80 and PMB30 in ethanol so that the mixture concentration was 0.2% by weight. The mixture was mixed so that the content ratio (PMB80/PMB30) was 1/9 by weight.
また、比較例として、ＰＭＢ８０を用いず、ＰＭＢ３０のみを、エタノールに、ＰＭＢ３０の濃度が０．２重量％となるように溶解させて重合体溶液を調製した。 As a comparative example, a polymer solution was prepared by dissolving only PMB30 in ethanol without using PMB80, so that the concentration of PMB30 was 0.2% by weight.
・皮膜形成工程
皮膜形成工程では、実施例の重合体混合溶液に、各基材を１０秒間浸漬し、これを２回繰り返したのち、真空乾燥によって乾燥させ、各基材の表面に親水性皮膜を形成し、実施例の試験片を得た。また、比較例の重合体溶液に各基材を１０秒間浸漬し、これを２回繰り返したのち、真空乾燥によって乾燥させ、各基材の表面に親水性皮膜を形成し、比較例の試験片を得た。
In the film-forming step, each substrate was immersed in the polymer mixture solution of the example for 10 seconds, and this was repeated twice, and then dried by vacuum drying to form a hydrophilic film on the surface of each substrate, thereby obtaining a test piece of the example. Also, each substrate was immersed in the polymer solution of the comparative example for 10 seconds, and this was repeated twice, and then dried by vacuum drying to form a hydrophilic film on the surface of each substrate, thereby obtaining a test piece of the comparative example.
耐水性は、水温３７℃の純水に実施例および比較例の試験片を浸漬させ、浸漬時間の経過に従って、リン原子濃度を測定し、その変化によって評価した。 Water resistance was evaluated by immersing test pieces of the examples and comparative examples in pure water at a temperature of 37°C, measuring the phosphorus atom concentration over the immersion time, and observing the change in the concentration.
リン原子濃度は、ＸＰＳ分析装置（島津／ＫＲＡＴＯＳ製 ＡＸＩＳ－ＨＳｉ１６５）を用い、Ｘ線源をＭｇ－Ｋα線、印加電圧を１５ｋＶ、光電子の放出角度を９０°として測定した。結果を図５のグラフに示す。 The phosphorus atom concentration was measured using an XPS analyzer (AXIS-HSi165 manufactured by Shimadzu/KRATOS) with an X-ray source of Mg-Kα radiation, an applied voltage of 15 kV, and a photoelectron emission angle of 90°. The results are shown in the graph in Figure 5.
図５からわかるように、実施例の試験片は、浸漬時間が経過してもリン原子の濃度が殆んど低下せず、一定濃度を維持した。これに対して、比較例の試験片は、同じ浸漬時間において、実施例よりもリン原子の濃度が低く、浸漬時間の経過に伴い、リン原子の濃度も低下した。 As can be seen from Figure 5, the phosphorus atom concentration of the test piece of the embodiment hardly decreased even with the immersion time, and maintained a constant concentration. In contrast, the test piece of the comparative example had a lower phosphorus atom concentration than the embodiment at the same immersion time, and the phosphorus atom concentration also decreased as the immersion time increased.
すなわち、実施例では、親水性皮膜からの重合体の溶出は殆んど無かったのに対して、比較例は、親水性皮膜から重合体が溶出し、実施例のほうが水中での安定性に優れていると判断できる。
本開示は、次の実施形態が可能である。
（１）医療機器の製造方法であって、
基材を準備する準備工程と、
ホスホリルコリン基を有する第１重合体および第１重合体と親水性が異なる、ホスホリルコリン基を有する第２重合体を有機溶媒に溶解させて重合体混合溶液を調製する調製工程と、
調製された重合体混合溶液に基材を浸漬させたのち乾燥させて、基材の少なくとも一部の表面に第１重合体および第２重合体を含む親水性皮膜を形成する皮膜形成工程と、を有することを特徴とする医療機器の製造方法。
（２）第１重合体および第２重合体は、光反応性を有しておらず、
皮膜形成工程では、光反応を行わないことを特徴とする（１）に記載の医療機器の製造方法。
（３）ホスホリルコリン基を有する第１重合体およびホスホリルコリン基を有する第２重合体は、互いに共重合比が異なる２－メタクリロイルオキシエチルホスホリルコリンとｎ－ブチルメタクリレートとの共重合体であることを特徴とする（１）または（２）に記載の医療機器の製造方法。
（４）重合体混合溶液中の第１重合体および第２重合体の混合物の含有濃度が、０．１～０．５重量％であることを特徴とする（３）に記載の医療機器の製造方法。
（５）基材は、生体適合性材料からなることを特徴とする（１）～（４）のいずれか１つに記載の医療機器の製造方法。
（６）親水性皮膜が形成された基材に滅菌処理を施す滅菌工程をさらに有することを特徴とする（１）～（５）のいずれか１つに記載の医療機器の製造方法。
（７）滅菌処理が、親水性皮膜が形成された基材に高エネルギー線を照射する照射処理または親水性皮膜が形成された基材にガスプラズマを接触させるガスプラズマ処理であることを特徴とする（６）に記載の医療機器の製造方法。
That is, in the Examples, there was almost no elution of the polymer from the hydrophilic film, whereas in the Comparative Examples, the polymer eluted from the hydrophilic film, and it can be determined that the Examples have superior stability in water.
The present disclosure may have the following embodiments.
(1) A method for manufacturing a medical device, comprising:
A preparation step of preparing a substrate;
a preparation step of dissolving a first polymer having a phosphorylcholine group and a second polymer having a phosphorylcholine group, the second polymer having a hydrophilicity different from that of the first polymer, in an organic solvent to prepare a polymer mixture solution;
and a coating formation step of immersing a substrate in the prepared polymer mixture solution and then drying the substrate to form a hydrophilic coating containing a first polymer and a second polymer on at least a portion of the surface of the substrate.
(2) the first polymer and the second polymer are not photoreactive;
The method for producing a medical device according to (1), wherein no photoreaction is carried out in the coating formation step.
(3) A method for producing a medical device according to (1) or (2), characterized in that the first polymer having a phosphorylcholine group and the second polymer having a phosphorylcholine group are copolymers of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate having different copolymerization ratios.
(4) The method for producing a medical device according to (3), characterized in that the concentration of the mixture of the first polymer and the second polymer in the polymer mixture solution is 0.1 to 0.5% by weight.
(5) A method for producing a medical device according to any one of (1) to (4), characterized in that the substrate is made of a biocompatible material.
(6) A method for producing a medical device according to any one of (1) to (5), further comprising a sterilization step of subjecting the substrate on which the hydrophilic coating is formed to a sterilization treatment.
(7) The method for producing a medical device according to (6), wherein the sterilization treatment is an irradiation treatment in which the substrate on which the hydrophilic coating is formed is irradiated with high-energy rays, or a gas plasma treatment in which the substrate on which the hydrophilic coating is formed is brought into contact with gas plasma.
Claims (11)
ホスホリルコリン基を有する第１重合体および第１重合体よりも親水性が低い、ホスホリルコリン基を有する第２重合体を有機溶媒に溶解させて重合体混合溶液を調製する調製工程と、
調製された重合体混合溶液に基材を浸漬させたのち乾燥させて、基材の少なくとも一部の表面に第１重合体および第２重合体を含む親水性皮膜を形成する皮膜形成工程と、を有し、
前記有機溶媒に溶解させる前記第１重合体と前記第２重合体との重量比（前記第１重合体／前記第２重合体）は、１／９以上１／４以下であることを特徴とする医療機器の製造方法。 A preparation step of preparing a substrate;
a preparation step of dissolving a first polymer having a phosphorylcholine group and a second polymer having a phosphorylcholine group, which is less hydrophilic than the first polymer, in an organic solvent to prepare a polymer mixture solution;
a film-forming step of immersing a substrate in the prepared polymer mixture solution and then drying the substrate to form a hydrophilic film containing a first polymer and a second polymer on at least a part of the surface of the substrate;
A method for producing a medical device, characterized in that a weight ratio of the first polymer to the second polymer dissolved in the organic solvent (the first polymer/the second polymer) is 1/9 or more and 1/4 or less.
水温３７℃の純水に浸漬させた場合に、前記親水性皮膜表面のリン原子濃度が浸漬時間の経過に伴い低下しないことを特徴とする医療機器。 A medical device manufactured by the manufacturing method of claims 1 to 9,
A medical device characterized in that, when immersed in pure water at a temperature of 37°C, the phosphorus atom concentration on the surface of the hydrophilic coating does not decrease with the lapse of immersion time.
前記基材がポリカーボネート、コバルトクロム合金、またはチタンからなり、
前記親水性皮膜の表面に純水を滴下したときの接触角が９０度以下であることを特徴とする医療機器。 A medical device manufactured by the manufacturing method of claims 1 to 9,
the substrate is made of polycarbonate, cobalt chromium alloy, or titanium;
A medical device characterized in that the contact angle of pure water dropped on the surface of the hydrophilic coating is 90 degrees or less.
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