JP3541627B2 - Graft polymer and molded article for medical use using the same - Google Patents

Graft polymer and molded article for medical use using the same Download PDF

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JP3541627B2
JP3541627B2 JP19149497A JP19149497A JP3541627B2 JP 3541627 B2 JP3541627 B2 JP 3541627B2 JP 19149497 A JP19149497 A JP 19149497A JP 19149497 A JP19149497 A JP 19149497A JP 3541627 B2 JP3541627 B2 JP 3541627B2
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medical
molded article
molded product
graft
quaternary ammonium
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JPH1081717A (en
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一裕 棚橋
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Toray Industries Inc
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Toray Industries Inc
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Priority to JP19149497A priority Critical patent/JP3541627B2/en
Priority to TW086116161A priority patent/TW523522B/en
Priority to PCT/JP1997/004005 priority patent/WO1999023127A1/en
Priority to EP97909734A priority patent/EP0952168A4/en
Priority claimed from PCT/JP1997/004005 external-priority patent/WO1999023127A1/en
Publication of JPH1081717A publication Critical patent/JPH1081717A/en
Priority to US09/343,401 priority patent/US6497868B1/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F291/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/12—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group, wherein Cn means a carbon skeleton not containing a ring; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/041—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F259/00—Macromolecular compounds obtained by polymerising monomers on to polymers of halogen containing monomers as defined in group C08F14/00
    • C08F259/02—Macromolecular compounds obtained by polymerising monomers on to polymers of halogen containing monomers as defined in group C08F14/00 on to polymers containing chlorine
    • C08F259/04—Macromolecular compounds obtained by polymerising monomers on to polymers of halogen containing monomers as defined in group C08F14/00 on to polymers containing chlorine on to polymers of vinyl chloride
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/208—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Dentistry (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Polymers & Plastics (AREA)
  • Environmental Sciences (AREA)
  • Biomedical Technology (AREA)
  • Toxicology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Graft Or Block Polymers (AREA)

Description

【０００１】
【発明の属する技術分野】
本発明は、高分子基材に塗布可能なグラフトポリマー、およびそれを用いた医療用成型品に関する。
【０００２】
【従来の技術】
医療の分野においては、ポリウレタンなどの高分子材料から成る医療用具を患者の体内に挿入・留置している間に起こる感染症が合併症の一つとして問題視されている。従来、医療用具の留置に伴う感染症を防止するために、医療用具を使用直前にクロロヘキシジンやポピドンヨードなどの抗菌剤や消毒剤を含む水溶液に浸漬するなどして消毒するか、あるいは治療中に交換可能な医療用具に関しては頻繁な交換が行われてきた。しかしながら、抗菌剤・消毒剤は時間と共にカテーテル表面から消失するため消毒の効果に持続性がなく、医療用具を長期間にわたって使用する場合には徐々に効果が低下していくことは明らかである。また、医療用具の頻繁な交換も医療従事者にとっては大きな負担となる。そこで更なる感染防止の手段の一つとして、医療用具に種々の抗菌加工が施されてきた。その代表的なものとしては、クロロヘキシジンをはじめとする抗菌剤や、銀・銅をはじめとする金属またはその化合物を含有する層で表面を被覆したカテーテルがある。これらのカテーテルにおいては、抗菌作用をもつ物質を体内で一定量ずつ徐放するシステムが採用されており、カテーテルを使用直前に消毒する場合に比べて良好な効果を示す。
【０００３】
【発明が解決しようとする課題】
しかしながら、抗菌物質が徐放するシステムでは依然として使用期間に限りがあり効力が次第に低下していくことは避けられない。銀などの金属あるいはその化合物については徐放後の体内動態が不明であり、人体への害も考えられる。また、使用後の医療用具廃棄物に銀が残存している場合には、廃棄に際して回収などの特別の処置が必要になる。
【０００４】
そのため、徐放型でなく、それ自身で抗菌性のあるポリマーとして第四アンモニウム基をもつポリマーが種々提案されてきている（特公昭54-17797、特公昭5418817）。しかし、これらポリマーは加工性が悪く、単独では成型品にできないので、機械的特性の優れたポリマーを成型したものの表面にコーティングするか、あるいは、該ポリマーと混合成型することが必要になる。機械的特性のよい基材ポリマーほど他のポリマーとの相溶性が悪い。相溶性が悪いとコーティングしたポリマーが剥離したり、裂け目が生じる。現在、基材ポリマーとの相溶性が十分な抗菌性ポリマーは知られていない。
【０００５】
そこで、本発明者らはかかる従来技術の問題点に鑑み、複雑な形をした医療用具にも適用できるような柔軟な膜を形成し、かつ、種々のポリマーとの相溶性・接着性の良い抗菌性ポリマーを得るべく種々検討した結果、一般式（Ｉ）を含む成分単位を塩化ビニル含有ポリマーにグラフト重合したポリマーが、種々のポリマーとの相溶性・接着性が良く、且つ強い抗菌作用を有することを見いだし、本発明に到達した。
【０００６】
即ち、本発明は、柔軟な膜を形成可能であり、複雑な形をした基材にも好適に適用可能なポリマおよびそれを用いた医療用成型品を提供することを目的とする。
【０００７】
【課題を解決するための手段】
このような目的を達成する本発明は、以下の（１）および（２）の技術的手段から構成される。
【０００８】
「(1)一般式（Ａ）
【化４】

Figure 0003541627
（Ｒ2、Ｒ3は炭素数 1〜3のアルキル基を、Ｒ4は炭素数4〜18のアルキル基を示す。Ｘはハロゲンイオン、硫酸イオン、水酸化物イオンおよびカルボン酸イオンから選ばれる少なくとも１種を示す。）で表される第四級アンモニウム基を含む構成単位がグラフト重合されてなることを特徴とするグラフトポリマー。
【０００９】
（２）医療用体内挿入用成型品に上記（１）のグラフトポリマーを被覆してなる医療用成型品。
【００１０】
（３）上記（１）のポリマーを含有してなることを特徴とする医療用成型品。」
【００１１】
【発明の実施の形態】
続いて、本発明について更に詳細に説明する。
【００１２】
本発明におけるグラフトポリマーは、上記のとおり式（Ａ）で示される官能基を有する。式（Ａ）で示される官能基を有する構成単位としては、式（Ａ）をエステル結合、アミド結合、ウレイド結合、エーテル結合で、あるいは、アルキレン基、フェニレン基を介して主鎖に結合して成る構成単位が挙げられる。中でも、式（Ａ）で示される官能基を有する構成単位としては、前駆体が入手しやすいという点で、次の式（Ｉ）で示される構成単位を有することが好ましい。
【００１３】
【化５】
Figure 0003541627
（Ｒ1は水素、メチル基およびエチル基から選ばれる少なくとも１つを、Ｒ2、Ｒ3は炭素数 1〜3のアルキル基を、Ｒ4 は炭素数4〜18のアルキル基を示す。ｎは1〜12の整数を示す。ＡはＯ，ＳまたはＮＲ5 から選ばれる少なくとも１種を示す。Ｒ5 は水素または炭素数 1〜12のアルキル基を示す。Ｘはハロゲンイオン、硫酸イオン、水酸化物イオンおよびカルボン酸イオンから選ばれる少なくとも１種を示す。）
ｎは１〜１２の整数を示すが、抗菌官能基の自由度に関与し、短すぎると官能基が自由に動けずに例えば菌体等と接触しにくく、また長すぎても疎水性が強くなるため菌体を含む水系の媒体中では抗菌官能基が菌体と接触しにくい。
【００１４】
Ｒ2 、Ｒ3 はアルキル基であり、炭素数が多いと疎水性が強くなるため抗菌官能基が菌体と接触しにくくなるので、その炭素数は 1〜 3であり、最も炭素数が少ないメチル基が最良である。
【００１５】
Ｒ4はアルキル基である。Ｒ4 は炭素数 4〜18のアルキル基であり、好ましくは、4〜12である。これらのアルキル基は、枝別れしていると動きが制限されるので直鎖状であることが望ましい。

【００１６】
Ｘはハロゲンイオン、硫酸イオン、水酸化物イオンおよびカルボン酸イオンを示す。硫酸イオンは通常２価であるが、本発明では１価分のイオンが配位していればよい。
【００１７】
又、ＡはＯ，ＳまたはＮＲ5 から選ばれる少なくとも１種を示す。
【００１８】
一般式（Ａ）で示される第四級アンモニウム基を構成単位を共重合するために用いる前駆体ビニル化合物としては、例えばジメチルアミノエチルメタクリレート、ジメチルアミノエチルアクリレート、ジエチルアミノプロピルメタクリレート、ジメチルアミノアクリルアミド、ジエチルアミノアクリルアミドが用いられるが、入手の容易さからジメチルアミノメタクリレートが好ましく用いられる。グラフトポリマー中の官能基の量は多すぎるとコーティング性が悪くなり、又その他のポリマーとのブレンドしようとした場合、相溶性が低下する傾向がある。一方、少なすぎると抗菌性能が低下する傾向がある。従って、グラフトポリマー中、グラフトポリマー１ｇに対して、一般式（Ａ）で示されるアンモニウム基を含む構成単位が 0.1ミリモル以上、４ミリモル以下、更に好ましくは、 0.5ミリモル以上、４ミリモル以下の割合で含まれることが好ましい。
【００１９】
本発明において、一般式（Ａ）以外のグラフト成分としては限定されるものではないが、材料が水溶液や体液などとなじみやすくなるという点で親水性成分を用いることが好ましく、例えばメトキシポリエチレングリコール、エトキシポリエチレングリコール、メトキシポリプロピレングリコール、エトキシポリプロピレングリコールなどが用いられる。中でも下記一般式（II）で示される成分単位が、入手しやすく、安全の点でも好ましい。
【００２０】
【化６】
Figure 0003541627
そのグラフト共重合前の前駆体であるビニル化合物の具体例としては、例えばメトキシポリエチレングリコールメタクリレート、メトキシポリエチレングリコールアクリレート、ポリエチレングリコールメタクリレートなどが挙げられる。
【００２１】
本発明におけるグラフト共重合を構成する幹ポリマーとしては、特に限定されるものではないが、ハロゲン原子、特に塩素原子を側鎖に有するものが好ましく、具体的には塩化ビニル含有ポリマーが好ましく用いられる。ポリ塩化ビニルのほかのポリマーとしては、塩化ビニルと酢酸ビニルの共重合体、さらに、第三成分として、例えば、アクリレート、メタクリレート、ビニルアルコール、スチレン、アクリロニトリルとの共重合体、エチレン−酢酸ビニル共重合体に塩化ビニルをグラフトしたポリマー、これらのポリマーの混合物、またこれらのポリマーに可塑剤や安定剤などを混合したものなど種々の共重合体や混合物を用いることができる。混合する場合、例えばポリウレタン、天然ゴム、シリコン樹脂、ポリ塩化ビニル、、ポリアミド、合成ゴムなどを混合して、医療用成型品として好ましく用いられる。これらの共重合体および混合物において、その塩化ビニル含有量は0.1〜 100％の範囲に含まれていれば良く、目的に応じて適宜選択できる。
【００２２】
本発明のグラフトポリマーの分子量としては、限定されるものではないが、数平均分子量としてほぼ３０００以上であり、好ましくは５０００〜１００万、さらに好ましくは３万〜１０万程度である。
【００２３】
本発明のグラフトポリマの製造方法は任意であるが、以下に例をあげて説明する。
【００２４】
グラフト共重合体は、主鎖となる重合体をグラフト活性化処理した後、式（Ａ）を含む構成単位の前駆体ビニル化合物を添加して適当な重合方法で重合させることにより得られる。
【００２５】
グラフト活性化処理の方法としては、例えば塩化ビニル含有重合体の塩素原子を光照射などによって、ラジカルを与えやすいジチオカルバメート基で置換する方法などが好ましく用いられる。
【００２６】
第四級アンモニウム基を得るためには、一般式（Ａ）を含む構成単位の前駆体ビニル化合物を用いてグラフト重合した後にアルキルハライドで第四級アンモニウム化しても良いが、先にアルキルハライドで第四級アンモニウム化した前駆体ビニル化合物を用いてグラフト重合しても良い。
【００２７】
本発明のグラフトポリマーは、医療用樹脂として好ましく用いられ、中でも、抗菌性に優れることから、抗菌性樹脂として好ましく用いられる。
【００２８】
抗菌能樹脂は表面コートすることによって、細菌感染の防止が必要な任意の医療用具に適用することができる。医療用具の中でも、医療用体内挿入成型品に適用した場合、特に効果的である。医療用体内挿入品の素材としては、ポリウレタン、天然ゴム、シリコン樹脂、ポリ塩化ビニル、ポリアミド、合成ゴムなどが好ましく用いられる。
【００２９】
医療用体内挿入成型品の中でも、例えば長期間にわたり体内に留置されるカテーテル、ステント、チューブ（ドレナージチューブ）、カフ、コネクター（チューブコネクター）、アクセスポート、内視鏡カバー、排液バック、血液回路などに効果的に適用することができる。徐放システムの材料に比べて、抗菌官能基がグラフト共重合体に共有結合で固定化されているため人体にとって安全で、効果が持続するためである。
【００３０】
又、本願発明のグラフトポリマと前記ポリウレタン、天然ゴム、シリコン樹脂などを混合した医療用成型品についても、上記カテーテル、ステント、チューブ等と同様の用途において、効果的に用いられる。
【００３１】
以下、実施例により本発明をさらに具体的に説明するが、本発明は当該実施例に限定されるものではない。
【００３２】
【実施例】
実施例１
重合度５５０のポリ塩化ビニル１２０ｇを２リットルのジメチルホルムアミドに溶解し、２．７０４ｇのジエチルジチオカルバミン酸ナトリウム塩を添加し、５０℃で３時間反応させ、メタノールに再沈後、乾燥させることにより、光グラフト活性化ポリ塩化ビニル（以下、ＤＴＣ化ポリ塩化ビニルと略す）を得た。
【００３３】
このＤＴＣ化ポリ塩化ビニル８０ｇを１２５０ｍｌのテトラヒドロフランに溶解し、２００ｇのメトキシポリエチレングリコールメタクリレート（ポリエチレングリコール部分の重合度２０〜２３）と８０ｇのジメチルアミノエチルメタクリレートを添加し、光源内部浸透型光反応装置中で１００Ｗ高圧水銀灯（ウシオ電機ＵＭ−１０２）を３０℃で９．５時間照射することにより光グラフト重合を行なった。このグラフト共重合体の組成は重量比で塩化ビニル５４％、メトキシポリエチレングリコールメタクリレート３０％、ジメチルアミノエチルメタクリレート１６％であった。
【００３４】
実施例２
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化ブチル 1.1mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数 4）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.15ミリモルであった。
【００３５】
実施例３
実施例２に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬してチューブに抗菌性材料を塗布して乾燥した。材料を塗布したチューブをアルコールで消毒した後、大腸菌（MC1061株）を菌濃度104 個／ｍｌになるように懸濁した生理食塩水に浸漬し、24時間静置した。24時間後にチューブに付着した菌数を測定した。対照として抗菌性材料を塗布していないポリウレタンチューブについても同様に操作した。その結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 534個、抗菌性材料を塗布したチューブでは137個であった。
【００３６】
実施例４
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化ヘキシル 1.4mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数 6）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.11ミリモルであった。
【００３７】
実施例５
実施例４に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬してチューブに抗菌性材料を塗布して乾燥した。実施例３と同様に実験した結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は534個、抗菌性材料を塗布したチューブでは 125個であった。
【００３８】
実施例６
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化オクチル 1.7mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数 8）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.30ミリモルであった。
【００３９】
実施例７
実施例６に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬して、チューブに抗菌性材料を塗布して乾燥した。実施例３と同様に実験した結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 534個、抗菌性材料を塗布したチューブでは 126個であった。
【００４０】
実施例８
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化デシル 2.1mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数10）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.16ミリモルであった。
【００４１】
実施例９
実施例８に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬して、チューブに抗菌性材料を塗布して乾燥した。実施例３と同様に実験した結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 534個、抗菌性材料を塗布したチューブでは71個であった。
【００４２】
実施例１０
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化ラウリル 2.4mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数12）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.18ミリモルであった。
【００４３】
実施例１１
実施例１０に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬して、チューブに抗菌性材料を塗布して乾燥した。実施例２と同様に実験した結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 534個、抗菌性材料を塗布したチューブでは38個であった。
【００４４】
実施例１２
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化ミリスチル 2.7mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数14）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.19ミリモルであった。
【００４５】
実施例１３
実施例１２に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬して、チューブに抗菌性材料を塗布して乾燥した。実施例３と同様に実験した結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 534個、抗菌性材料を塗布したチューブでは 151個であった。
【００４６】
実施例１４
実施例１に示したグラフト共重合体5gをテトラヒドロフラン50mlに溶解後、臭化オクタデシル 3.3mlを加えて50℃で 4時間反応させた。飽和食塩水中に投じて沈殿させた後、水とエタノールで洗浄・乾燥して長鎖のアルキル基（炭素数18）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり0.24ミリモルであった。
【００４７】
実施例１５
実施例１４に示した抗菌性材料の10％溶液にポリウレタンのチューブを軸方向に浸漬して、チューブに抗菌性材料を塗布して乾燥した。実施例３と同様に実験した結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 534個、抗菌性材料を塗布したチューブでは 211個であった。
【００４８】
実施例１６
実施例１０に示した抗菌性材料の 1％溶液をカバーグラス上に滴下することによりカバーグラスに抗菌性材料あるいはポリ塩化ビニルまたはポリウレタンを塗布して乾燥した。材料を塗布した側が上になるようにカバーグラスを置き、その上に103 〜104 個／ｍｌの大腸菌または緑膿菌または黄色ブドウ球菌または表皮ブドウ球菌または腸球菌を含む血清または尿を滴下し、その上からもう一枚のカバーグラスを材料を塗布した側が下になるようにおいて菌液を挟みこんで、37℃で24時間放置した。カバーグラスを洗浄した後に寒天培地に張り付けて付着菌を転写し、培養した後にコロニーの形成の有無を判定した。その結果、ポリ塩化ビニルまたはポリウレタンを塗布したカバーグラスでは血清・尿にかかわらず全ての菌に対してコロニーが形成されたのに対し、抗菌性材料を塗布したカバーグラスでは全ての菌に対してコロニーが形成されなかった。
【００４９】
実施例１７
実施例１記載のＤＴＣ化ポリ塩化ビニル 160ｇを2500ｍｌのテトラヒドロフランに溶解し、400ｇのメトキシポリエチレングリコールメタクリレート（ポリエチレングリコール部分の平均重合度90）と 160ｇのジメチルアミノエチルメタクリレートを添加し、光源内部浸透型光反応装置中で１００Ｗ高圧水銀灯（ウシオ電機ＵＭ−１０２）を30℃で９．５時間照射することにより光グラフト重合を行なった。このグラフト共重合体の組成は重量比で塩化ビニル64％、メトキシポリエチレングリコールメタクリレート21％、ジメチルアミノエチルメタクリレート15％であった。
【００５０】
実施例１８
実施例１７に示したグラフト共重合体30ｇをジメチルホルムアミド 300mlに溶解後、臭化ラウリル40mlを加えて60℃で18時間反応させた。水メタノール混合溶媒中に投じて沈殿させた後、洗浄・乾燥して長鎖のアルキル基（炭素数１２）を含む４級アンモニウム基を有する抗菌性材料を得た。４級アンモニウム基の導入量はグラフト共重合体 1ｇあたり 1ミリモルであった。
【００５１】
実施例１９
実施例１７に示した抗菌性材料の 3％溶液にポリウレタンのチューブを軸方向に浸漬してチューブに抗菌性材料を塗布して乾燥した。材料を塗布したチューブをアルコールで消毒した後、表皮ブドウ球菌を菌濃度104 個／ｍｌになるように懸濁した生理食塩水に浸漬し、24時間静置した。24時間後にチューブに付着した菌数を測定した。対照として抗菌性材料を塗布していないポリウレタンチューブについても同様に操作した。その結果、付着菌数は、抗菌性材料を塗布していないポリウレタンチューブの場合は 967個、抗菌性材料を塗布したチューブでは 0個であった。
【００５２】
実施例２０
実施例１７に示した抗菌性材料の 3％溶液にスチレン−イソプレン合成ゴムのシートを長軸方向に浸漬してシートに抗菌性材料を塗布して乾燥した。乾燥後水中に浸して、爪で２０回擦っても剥がれることなくコーティングされていた。
【００５３】
【発明の効果】
本発明のグラフトポリマは、プラスチック製品、特に医療用具には容易に塗布でき、細菌が高濃度であっても良好な抗菌能を示し、その効果は長期間持続する。さらに、抗菌性能などを発現する官能基が共有結合されており、溶離することがないため、性能が長期間持続し、人体にも無害である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a graft polymer that can be applied to a polymer substrate, and a molded medical product using the same.
[0002]
[Prior art]
In the medical field, infectious diseases that occur while a medical device made of a polymer material such as polyurethane is inserted and placed in a patient's body are regarded as one of the complications. Conventionally, in order to prevent infectious diseases associated with indwelling medical devices, disinfect the medical device immediately before use by immersing it in an aqueous solution containing an antibacterial agent such as chlorohexidine or popidone iodine or a disinfectant, or replace it during treatment. Frequent changes have been made to possible medical devices. However, since the antibacterial agent / disinfectant disappears from the catheter surface over time, the effect of disinfection is not persistent, and it is clear that the effect gradually decreases when the medical device is used for a long period of time. Frequent replacement of medical equipment also places a heavy burden on healthcare workers. Therefore, various antibacterial treatments have been applied to medical devices as one of means for further preventing infection. A typical example is a catheter whose surface is coated with a layer containing an antibacterial agent such as chlorohexidine or a metal such as silver or copper or a compound thereof. In these catheters, a system for gradually releasing a substance having an antibacterial action in the body in a fixed amount is employed, which shows a better effect as compared with a case where the catheter is disinfected immediately before use.
[0003]
[Problems to be solved by the invention]
However, in systems where sustained release of antimicrobial substances occurs, the duration of use is still limited and the efficacy is inevitably reduced. The pharmacokinetics of metals such as silver and their compounds after sustained release are unknown, and harm to the human body is also considered. In addition, if silver remains in the used medical device waste, special treatment such as collection is required at the time of disposal.
[0004]
For this reason, various polymers having a quaternary ammonium group have been proposed as antibacterial polymers which are not sustained release but themselves (JP-B-54-17797 and JP-B-5418817). However, since these polymers have poor processability and cannot be formed into a single product, it is necessary to coat a polymer having excellent mechanical properties on the surface of the molded product or to mix and mold with the polymer. A base polymer having better mechanical properties has poorer compatibility with other polymers. Poor compatibility results in peeling or tearing of the coated polymer. At present, no antibacterial polymer having sufficient compatibility with the base polymer is known.
[0005]
In view of the problems of the prior art, the present inventors have formed a flexible film that can be applied to medical devices having complicated shapes, and have good compatibility and adhesion with various polymers. As a result of various studies to obtain an antibacterial polymer, a polymer obtained by graft-polymerizing a component unit containing the general formula (I) to a vinyl chloride-containing polymer has good compatibility and adhesion with various polymers and a strong antibacterial action. And have reached the present invention.
[0006]
That is, an object of the present invention is to provide a polymer which can form a flexible film and can be suitably applied to a substrate having a complicated shape, and a medical molded product using the polymer.
[0007]
[Means for Solving the Problems]
The present invention for achieving the above object is constituted by the following technical means (1) and (2).
[0008]
"(1) General formula (A)
Embedded image
Figure 0003541627
(R 2 and R 3 represent an alkyl group having 1 to 3 carbon atoms, and R 4 represents an alkyl group having 4 to 18 carbon atoms. X is selected from a halogen ion, a sulfate ion, a hydroxide ion and a carboxylate ion. At least one of which is represented by the following formula): A graft polymer comprising a constituent unit containing a quaternary ammonium group represented by the formula:
[0009]
(2) A medical molded article obtained by coating the graft polymer of the above (1) on a molded article for insertion into a medical body.
[0010]
(3) A molded medical product comprising the polymer of (1). "
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
Next, the present invention will be described in more detail.
[0012]
The graft polymer in the present invention has a functional group represented by the formula (A) as described above. As the structural unit having a functional group represented by the formula (A), the formula (A) may be an ester bond, an amide bond, a ureido bond, an ether bond, or a bond to the main chain via an alkylene group or a phenylene group. Constituent units. Among them, the structural unit having a functional group represented by the formula (A) preferably has a structural unit represented by the following formula (I) from the viewpoint that a precursor is easily available.
[0013]
Embedded image
Figure 0003541627
(R 1 represents at least one selected from hydrogen, methyl group and ethyl group, R 2 and R 3 each represent an alkyl group having 1 to 3 carbon atoms, and R 4 represents an alkyl group having 4 to 18 carbon atoms. Represents an integer of 1 to 12. A represents at least one selected from O, S or NR 5. R 5 represents hydrogen or an alkyl group having 1 to 12. X represents a halogen ion, a sulfate ion, water And at least one selected from oxide ions and carboxylate ions.)
n represents an integer of 1 to 12, but is involved in the degree of freedom of the antibacterial functional group. If it is too short, the functional group does not move freely and it is difficult to come into contact with, for example, cells, and also if it is too long, the hydrophobicity is strong. Therefore, the antimicrobial functional group hardly comes into contact with the cells in an aqueous medium containing the cells.
[0014]
R 2 and R 3 are alkyl groups, and when the number of carbons is large, the hydrophobicity becomes strong, so that the antibacterial functional group is hardly in contact with the cells, so the number of carbons is 1 to 3, and the number of carbons is the least. Methyl groups are best.
[0015]
R 4 is an alkyl group. R4 is an alkyl group having 4 to 18 carbon atoms, preferably 4 to 12. These alkyl groups are desirably straight-chained because movement is restricted when branched.

[0016]
X represents a halogen ion, a sulfate ion, a hydroxide ion and a carboxylate ion. Sulfate ions are usually divalent, but in the present invention, it suffices that monovalent ions are coordinated.
[0017]
Also, A is indicative of at least one selected from O, S or NR 5.
[0018]
Examples of the precursor vinyl compound used for copolymerizing a quaternary ammonium group represented by the general formula (A) with a structural unit include dimethylaminoethyl methacrylate, dimethylaminoethyl acrylate, diethylaminopropyl methacrylate, dimethylaminoacrylamide, and diethylamino. Acrylamide is used, but dimethylamino methacrylate is preferably used because of easy availability. If the amount of the functional group in the graft polymer is too large, the coating property will be poor, and if it is attempted to blend with another polymer, the compatibility tends to decrease. On the other hand, if the amount is too small, the antibacterial performance tends to decrease. Accordingly, in the graft polymer, the structural unit containing the ammonium group represented by the general formula (A) is in a proportion of 0.1 to 4 mmol, more preferably 0.5 to 4 mmol, based on 1 g of the graft polymer. Preferably, it is included.
[0019]
In the present invention, the graft component other than the general formula (A) is not limited. However, it is preferable to use a hydrophilic component in that the material is easily compatible with an aqueous solution or a body fluid. Ethoxy polyethylene glycol, methoxy polypropylene glycol, ethoxy polypropylene glycol and the like are used. Among them, the component unit represented by the following general formula (II) is preferable in terms of availability and safety.
[0020]
Embedded image
Figure 0003541627
Specific examples of the vinyl compound that is a precursor before the graft copolymerization include, for example, methoxypolyethylene glycol methacrylate, methoxypolyethylene glycol acrylate, and polyethylene glycol methacrylate.
[0021]
The trunk polymer constituting the graft copolymer in the present invention is not particularly limited, but is preferably a polymer having a halogen atom, particularly a chlorine atom in a side chain, and specifically, a vinyl chloride-containing polymer is preferably used. . Other polymers of polyvinyl chloride include a copolymer of vinyl chloride and vinyl acetate, and a third component such as a copolymer of acrylate, methacrylate, vinyl alcohol, styrene, and acrylonitrile, and ethylene-vinyl acetate copolymer. Various copolymers and mixtures such as a polymer obtained by grafting vinyl chloride to a polymer, a mixture of these polymers, and a mixture of these polymers with a plasticizer or a stabilizer can be used. In the case of mixing, for example, polyurethane, natural rubber, silicone resin, polyvinyl chloride, polyamide, synthetic rubber and the like are mixed and preferably used as a molded article for medical use. In these copolymers and mixtures, the vinyl chloride content may be in the range of 0.1 to 100%, and can be appropriately selected according to the purpose.
[0022]
Although the molecular weight of the graft polymer of the present invention is not limited, it is about 3,000 or more as a number average molecular weight, preferably about 5,000 to 1,000,000, and more preferably about 30,000 to 100,000.
[0023]
The method for producing the graft polymer of the present invention is optional, but will be described below by way of examples.
[0024]
The graft copolymer is obtained by subjecting a polymer to be a main chain to a graft activation treatment, adding a precursor vinyl compound of a structural unit containing the formula (A), and polymerizing by a suitable polymerization method.
[0025]
As a method of the graft activation treatment, for example, a method of replacing a chlorine atom of a vinyl chloride-containing polymer with a dithiocarbamate group that easily gives a radical by light irradiation or the like is preferably used.
[0026]
In order to obtain a quaternary ammonium group, it may be graft-polymerized using a precursor vinyl compound of a structural unit containing the general formula (A) and then quaternized with an alkyl halide. Graft polymerization may be performed using a quaternary ammonium-modified precursor vinyl compound.
[0027]
The graft polymer of the present invention is preferably used as a medical resin, and is particularly preferably used as an antibacterial resin because of its excellent antibacterial properties.
[0028]
The antibacterial resin can be applied to any medical device that requires prevention of bacterial infection by surface coating. Among medical devices, it is particularly effective when applied to a medical insert. Polyurethane, natural rubber, silicone resin, polyvinyl chloride, polyamide, synthetic rubber and the like are preferably used as the material of the medical insert.
[0029]
Among medical implantable products, for example, catheters, stents, tubes (drainage tubes), cuffs, connectors (tube connectors), access ports, endoscope covers, drainage bags, blood circuits It can be effectively applied to such as. This is because the antibacterial functional group is covalently immobilized on the graft copolymer as compared with the material of the sustained release system, so that it is safe for the human body and the effect is maintained.
[0030]
Also, medical molded products obtained by mixing the graft polymer of the present invention with the above-mentioned polyurethane, natural rubber, silicone resin and the like can be effectively used in the same applications as the catheters, stents, tubes and the like.
[0031]
Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the examples.
[0032]
【Example】
Example 1
By dissolving 120 g of polyvinyl chloride having a polymerization degree of 550 in 2 liters of dimethylformamide, adding 2.704 g of sodium salt of diethyldithiocarbamate, reacting at 50 ° C. for 3 hours, reprecipitating in methanol and drying, Photograft activated polyvinyl chloride (hereinafter abbreviated as DTC-modified polyvinyl chloride) was obtained.
[0033]
80 g of this DTC-modified polyvinyl chloride is dissolved in 1250 ml of tetrahydrofuran, and 200 g of methoxypolyethylene glycol methacrylate (polymerization degree of polyethylene glycol portion is 20 to 23) and 80 g of dimethylaminoethyl methacrylate are added. Photograft polymerization was carried out by irradiating a 100 W high-pressure mercury lamp (USHIO UM-102) at 30 ° C. for 9.5 hours. The composition of the graft copolymer was 54% by weight of vinyl chloride, 30% by weight of methoxypolyethylene glycol methacrylate, and 16% by weight of dimethylaminoethyl methacrylate.
[0034]
Example 2
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 1.1 ml of butyl bromide was added and reacted at 50 ° C. for 4 hours. After throwing into a saturated saline solution to precipitate, it was washed and dried with water and ethanol to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (carbon number: 4). The amount of the quaternary ammonium group introduced was 0.15 mmol per 1 g of the graft copolymer.
[0035]
Example 3
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 2 in the axial direction, and the tube was coated with the antibacterial material and dried. After the applied tube material was disinfected with alcohol, E. coli (MC1061 strain) was immersed in saline suspended at cell concentration 104 cells / ml, and allowed to stand 24 hours. Twenty-four hours later, the number of bacteria adhered to the tube was measured. As a control, the same operation was performed for a polyurethane tube to which the antibacterial material was not applied. As a result, the number of adherent bacteria was 534 in the case of the polyurethane tube not coated with the antibacterial material and 137 in the tube coated with the antibacterial material.
[0036]
Example 4
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 1.4 ml of hexyl bromide was added and reacted at 50 ° C. for 4 hours. After throwing into a saturated saline solution to precipitate, it was washed with water and ethanol and dried to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (carbon number: 6). The amount of the quaternary ammonium group introduced was 0.11 mmol per 1 g of the graft copolymer.
[0037]
Example 5
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 4 in the axial direction, and the tube was coated with the antibacterial material and dried. As a result of conducting an experiment in the same manner as in Example 3, the number of adherent bacteria was 534 in the case of the polyurethane tube not coated with the antibacterial material, and was 125 in the tube coated with the antibacterial material.
[0038]
Example 6
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 1.7 ml of octyl bromide was added and reacted at 50 ° C. for 4 hours. After being poured into a saturated saline solution to precipitate, it was washed and dried with water and ethanol to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (8 carbon atoms). The amount of the quaternary ammonium group introduced was 0.30 mmol per 1 g of the graft copolymer.
[0039]
Example 7
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 6 in the axial direction, and the tube was coated with the antibacterial material and dried. As a result of conducting an experiment in the same manner as in Example 3, the number of adherent bacteria was 534 in the case of the polyurethane tube not coated with the antibacterial material and 126 in the tube coated with the antibacterial material.
[0040]
Example 8
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 2.1 ml of decyl bromide was added and reacted at 50 ° C. for 4 hours. After being poured into a saturated saline solution to precipitate, it was washed and dried with water and ethanol to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (10 carbon atoms). The amount of the quaternary ammonium group introduced was 0.16 mmol per 1 g of the graft copolymer.
[0041]
Example 9
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 8 in the axial direction, and the tube was coated with the antibacterial material and dried. As a result of conducting an experiment in the same manner as in Example 3, the number of adherent bacteria was 534 in the case of the polyurethane tube not coated with the antibacterial material, and 71 in the tube coated with the antibacterial material.
[0042]
Example 10
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 2.4 ml of lauryl bromide was added and reacted at 50 ° C. for 4 hours. After throwing into a saturated saline solution to precipitate, it was washed and dried with water and ethanol to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (12 carbon atoms). The amount of the quaternary ammonium group introduced was 0.18 mmol per 1 g of the graft copolymer.
[0043]
Example 11
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 10 in the axial direction, and the tube was coated with the antibacterial material and dried. As a result of conducting an experiment in the same manner as in Example 2, the number of adherent bacteria was 534 in the case of the polyurethane tube to which the antibacterial material was not applied, and was 38 in the case of the tube to which the antibacterial material was applied.
[0044]
Example 12
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 2.7 ml of myristyl bromide was added and reacted at 50 ° C. for 4 hours. After throwing into a saturated saline solution to precipitate, it was washed and dried with water and ethanol to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (14 carbon atoms). The amount of the quaternary ammonium group introduced was 0.19 mmol per 1 g of the graft copolymer.
[0045]
Example 13
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 12 in the axial direction, and the tube was coated with the antibacterial material and dried. As a result of an experiment conducted in the same manner as in Example 3, the number of adherent bacteria was 534 in the case of the polyurethane tube not coated with the antibacterial material, and 151 in the tube coated with the antibacterial material.
[0046]
Example 14
After dissolving 5 g of the graft copolymer shown in Example 1 in 50 ml of tetrahydrofuran, 3.3 ml of octadecyl bromide was added and reacted at 50 ° C. for 4 hours. After being poured into a saturated saline solution to precipitate, it was washed and dried with water and ethanol to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (18 carbon atoms). The amount of the quaternary ammonium group introduced was 0.24 mmol per 1 g of the graft copolymer.
[0047]
Example 15
A polyurethane tube was immersed in a 10% solution of the antibacterial material shown in Example 14 in the axial direction, and the tube was coated with the antibacterial material and dried. As a result of conducting an experiment in the same manner as in Example 3, the number of adherent bacteria was 534 in the case of the polyurethane tube not coated with the antibacterial material, and 211 in the tube coated with the antibacterial material.
[0048]
Example 16
A 1% solution of the antibacterial material shown in Example 10 was dropped on the coverglass to apply the antibacterial material or polyvinyl chloride or polyurethane to the coverglass and dried. Place the cover glass so that the side coated with the material is on the top, and drop serum or urine containing 10 3 to 10 4 cells / ml containing Escherichia coli or Pseudomonas aeruginosa or Staphylococcus aureus or Staphylococcus epidermidis or Enterococci. Then, the bacterial solution was sandwiched with another cover glass from above with the side coated with the material facing down, and left at 37 ° C. for 24 hours. After washing the cover glass, the adherent bacteria were transferred onto the agar medium, and after culturing, the presence or absence of colony formation was determined. As a result, colonies were formed for all bacteria regardless of serum or urine on cover glasses coated with polyvinyl chloride or polyurethane, whereas cover glasses coated with antibacterial materials were resistant to all bacteria. No colonies were formed.
[0049]
Example 17
160 g of the DTC-modified polyvinyl chloride described in Example 1 was dissolved in 2500 ml of tetrahydrofuran, and 400 g of methoxypolyethylene glycol methacrylate (average degree of polymerization of the polyethylene glycol portion of 90) and 160 g of dimethylaminoethyl methacrylate were added. Photograft polymerization was performed by irradiating a 100 W high-pressure mercury lamp (USHIO UM-102) at 30 ° C. for 9.5 hours in a photoreactor. The composition of this graft copolymer was 64% by weight of vinyl chloride, 21% by weight of methoxypolyethylene glycol methacrylate, and 15% by weight of dimethylaminoethyl methacrylate.
[0050]
Example 18
After dissolving 30 g of the graft copolymer shown in Example 17 in 300 ml of dimethylformamide, 40 ml of lauryl bromide was added and reacted at 60 ° C. for 18 hours. After throwing into a water-methanol mixed solvent to precipitate, the precipitate was washed and dried to obtain an antibacterial material having a quaternary ammonium group containing a long-chain alkyl group (carbon number: 12). The amount of the quaternary ammonium group introduced was 1 mmol per 1 g of the graft copolymer.
[0051]
Example 19
A polyurethane tube was immersed in a 3% solution of the antibacterial material shown in Example 17 in the axial direction, and the tube was coated with the antibacterial material and dried. After the applied tube material was disinfected with alcohol, Staphylococcus epidermidis was immersed in saline suspended at cell concentration 104 cells / ml, and allowed to stand 24 hours. Twenty-four hours later, the number of bacteria adhered to the tube was measured. As a control, the same operation was performed for a polyurethane tube to which the antibacterial material was not applied. As a result, the number of adherent bacteria was 967 in the case of the polyurethane tube to which the antibacterial material was not applied, and was 0 in the case of the tube to which the antibacterial material was applied.
[0052]
Example 20
A styrene-isoprene synthetic rubber sheet was dipped in a 3% solution of the antibacterial material shown in Example 17 in the longitudinal direction, the antibacterial material was applied to the sheet, and dried. After drying, it was immersed in water and rubbed with a nail for 20 times, so that it was coated without peeling off.
[0053]
【The invention's effect】
The graft polymer of the present invention can be easily applied to a plastic product, especially a medical device, shows good antibacterial activity even at a high concentration of bacteria, and its effect is long-lasting. Furthermore, since a functional group expressing antibacterial performance and the like is covalently bonded and does not elute, the performance lasts for a long time and is harmless to the human body.

Claims (25)

一般式（Ａ）
Figure 0003541627
（Ｒ2、Ｒ3は炭素数 1〜3のアルキル基を、Ｒ4は炭素数4〜18のアルキル基を示す。Ｘはハロゲンイオン、硫酸イオン、水酸化物イオンおよびカルボン酸イオンから選ばれる少なくとも１種を示す。）で表される第四級アンモニウム基を含む構成単位がグラフト重合されてなることを特徴とするグラフトポリマー。General formula (A)
Figure 0003541627
 (R 2 and R 3 represent an alkyl group having 1 to 3 carbon atoms, and R 4 represents an alkyl group having 4 to 18 carbon atoms. X is selected from a halogen ion, a sulfate ion, a hydroxide ion and a carboxylate ion. At least one of which is represented by the following formula): A graft polymer comprising a constituent unit containing a quaternary ammonium group represented by the formula: 一般式（Ｉ）
Figure 0003541627
（Ｒ1は水素、メチル基およびエチル基から選ばれる少なくとも１つを、Ｒ2、Ｒ3は炭素数 1〜3のアルキル基を、Ｒ4 は炭素数4〜18のアルキル基を示す。ｎは1〜12の整数を示す。ＡはＯ，ＳまたはＮＲ5 から選ばれる少なくとも１種を示す。Ｒ5 は水素または炭素数 1〜12のアルキル基を示す。Ｘはハロゲンイオン、硫酸イオン、水酸化物イオンおよびカルボン酸イオンから選ばれる少なくとも１種を示す。）で表される第四級アンモニウム基を含む構成単位がグラフト重合されてなることを特徴とする請求項１記載のグラフトポリマー。General formula (I)
Figure 0003541627
 (R 1 represents at least one selected from hydrogen, methyl group and ethyl group, R 2 and R 3 each represent an alkyl group having 1 to 3 carbon atoms, and R 4 represents an alkyl group having 4 to 18 carbon atoms. Represents an integer of 1 to 12. A represents at least one selected from O, S or NR 5. R 5 represents hydrogen or an alkyl group having 1 to 12. X represents a halogen ion, a sulfate ion, water The graft polymer according to claim 1, wherein a constituent unit containing a quaternary ammonium group represented by at least one selected from an oxide ion and a carboxylate ion is graft-polymerized. 該第四級アンモニウム基を含むモノマーが、０．１ミリモル以上含有されることを特徴とする請求項１または２記載のグラフトポリマー。The graft polymer according to claim 1 or 2, wherein the monomer containing a quaternary ammonium group is contained in an amount of 0.1 mmol or more. 塩化ビニル含有ポリマーに、該第四級アンモニウム基を含む構成単位がグラフト重合されてなることを特徴とする請求項１〜３のいずれかに記載のグラフトポリマー。The graft polymer according to any one of claims 1 to 3, wherein a constituent unit containing the quaternary ammonium group is graft-polymerized to a vinyl chloride-containing polymer. 該第四級アンモニウム基を含むモノマーおよび一般式（II）
Figure 0003541627
（Ｒ1 は水素またはメチル基、ｎは 1〜 100 の整数を示す。Ｒ2 はＨ、ＣＨ3、ＣＨ2ＣＨ3から選ばれる少なくとも１つを示す。ＡはＯ，ＳまたはＮＲ5 から選ばれる少なくとも１種を示す（Ｒ5 は水素または炭素数 1〜12のアルキル基を示す））で表される成分単位を含む構成単位がグラフト重合されてなることを特徴とする請求項１〜４のいずれかに記載のグラフトポリマー。Monomer containing quaternary ammonium group and general formula (II)
Figure 0003541627
 (R 1 is hydrogen or a methyl group, n is an integer of 1 to 100. R 2 is at least one selected from H, CH 3, CH 2 CH 3. A is selected from O, S or NR 5. The structural unit containing a component unit represented by at least one of the following (R 5 represents hydrogen or an alkyl group having 1 to 12 carbon atoms) is obtained by graft polymerization. The graft polymer according to any one of the above. 該Ｒ4が、炭素数8〜12であることを特徴とする請求項１〜５のいずれかに記載のグラフトポリマー。The R 4 is a graft polymer according to any of claims 1 to 5, characterized in that 8 to 12 carbon atoms. 請求項１〜６のいずれかに記載のポリマーを含有してなることを特徴とする医療用樹脂。A medical resin comprising the polymer according to claim 1. 請求項１〜６のいずれかに記載のポリマーを含有してなることを特徴とする抗菌性樹脂。An antibacterial resin comprising the polymer according to claim 1. 医療用体内挿入用成型品に請求項１〜８のいずれかに記載のグラフトポリマーを被覆してなる医療用成型品。A medical molded product obtained by coating the graft polymer according to any one of claims 1 to 8 on a medical molded product. 該医療用体内挿入用成型品がポリウレタンからなる成型品であることを特徴とする請求項９記載の医療用成型品。10. The molded article for medical use according to claim 9, wherein the molded article for insertion into a medical body is a molded article made of polyurethane. 該医療用体内挿入用成型品が天然ゴムからなる成型品であることを特徴とする請求項９記載の医療用成型品。The medical molded article according to claim 9, wherein the molded article for insertion into the medical body is a molded article made of natural rubber. 該医療用体内挿入用成型品がシリコン樹脂からなる成型品であることを特徴とする請求項９記載の医療用成型品。The medical molded article according to claim 9, wherein the molded article for insertion into a medical body is a molded article made of silicone resin. 該医療用体内挿入用成型品がポリ塩化ビニルからなる成型品であることを特徴とする請求項９記載の医療用成型品。The medical molded article according to claim 9, wherein the molded article for insertion into a medical body is a molded article made of polyvinyl chloride. 該医療用体内挿入用成型品がポリアミドからなる成型品であることを特徴とする請求項９記載の医療用成型品。The medical molded article according to claim 9, wherein the molded article for insertion into a medical body is a molded article made of polyamide. 該医療用体内挿入用成型品が合成ゴムからなる成型品であることを特徴とする請求項９記載の医療用成型品。The medical molded article according to claim 9, wherein the molded article for insertion into a medical body is a molded article made of synthetic rubber. 該医療用成型品がカテーテル、チューブ、シース、ステント、カフ、チューブコネクター、アクセスポート、排液バック、内視鏡カバーおよび血液回路から選ばれることを特徴とする請求項９〜１５のいずれかに記載の医療用成型品。The medical molded product is selected from a catheter, a tube, a sheath, a stent, a cuff, a tube connector, an access port, a drainage bag, an endoscope cover, and a blood circuit. The molded article for medical use as described. 該医療用成型品が、抗菌性成型品であることを特徴とする請求項９〜１６のいずれかに記載の医療用成型品。The medical molded product according to any one of claims 9 to 16, wherein the medical molded product is an antibacterial molded product. 請求項１〜６のいずれかに記載のポリマーを含有してなることを特徴とする医療用成型品。A molded article for medical use, comprising the polymer according to any one of claims 1 to 6. ポリウレタンを混合してなる請求項１８記載の医療用成型品。19. The medical molded product according to claim 18, which is obtained by mixing polyurethane. 天然ゴムを混合してなる請求項１８記載の医療用成型品。The medical molded article according to claim 18, wherein natural rubber is mixed. シリコン樹脂を混合してなる請求項１８記載の医療用成型品。19. The medical molded product according to claim 18, wherein a silicone resin is mixed. ポリ塩化ビニルを混合してなる請求項１８記載の医療用成型品。19. The medical molded product according to claim 18, which is obtained by mixing polyvinyl chloride. ポリアミドを混合してなる請求項１８記載の医療用成型品。19. The medical molded product according to claim 18, wherein a polyamide is mixed. 合成ゴムを混合してなる請求項１８記載の医療用成型品。19. The medical molded product according to claim 18, wherein a synthetic rubber is mixed. 該医療用成型品がカテーテル、チューブ、シース、ステント、カフ、チューブコネクター、アクセスポート、排液バック、内視鏡カバーおよび血液回路から選ばれることを特徴とする請求項１８〜２４のいずれかに記載の医療用成型品。The medical molded product is selected from a catheter, a tube, a sheath, a stent, a cuff, a tube connector, an access port, a drainage bag, an endoscope cover and a blood circuit. The molded article for medical use as described.
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WO2009113438A1 (en) 2008-03-10 2009-09-17 東レ株式会社 Antibacterial composition for medical use and medical device
JP6353923B2 (en) * 2014-10-29 2018-07-11 富士フイルム株式会社 Biological substance non-adhesive material, curable composition, prosthesis and medical device using the same
KR20230151510A (en) * 2021-03-02 2023-11-01 도레이 카부시키가이샤 Covered medical device and method of manufacturing the same
CN115260411A (en) * 2022-09-20 2022-11-01 南通为华创新材料科技有限公司 Medical composite material and preparation method thereof

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