JP3367570B2 - Antithrombotic material - Google Patents
Antithrombotic materialInfo
- Publication number
- JP3367570B2 JP3367570B2 JP28086093A JP28086093A JP3367570B2 JP 3367570 B2 JP3367570 B2 JP 3367570B2 JP 28086093 A JP28086093 A JP 28086093A JP 28086093 A JP28086093 A JP 28086093A JP 3367570 B2 JP3367570 B2 JP 3367570B2
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- JP
- Japan
- Prior art keywords
- blood
- polymer
- antithrombotic
- present
- phospholipid
- Prior art date
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Description
【０００１】[0001]
【産業上の利用分野】本発明は医療分野おいて血液や生
体と接触する場で用いられる抗血栓性を有する材料に関
する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a material having an antithrombotic property which is used in the field of contact with blood or living body in the medical field.
【０００２】[0002]
【従来の技術】近年、医療分野において、各種の合成高
分子材料が用いられている。代表的な医療用高分子材料
には、ポリ塩化ビニル、ポリスチレン、シリコーン樹
脂、ポリメタクリル酸エステル、含フッ素樹脂等の疎水
性高分子や、ポリビニルアルコール、架橋ポリアクリル
アミド、ポリ（２−ヒドロキシエチルメタクリレート）
等の親水性高分子がある。2. Description of the Related Art In recent years, various synthetic polymer materials have been used in the medical field. Typical medical polymer materials include hydrophobic polymers such as polyvinyl chloride, polystyrene, silicone resin, polymethacrylic acid ester, and fluorine-containing resin, polyvinyl alcohol, crosslinked polyacrylamide, and poly (2-hydroxyethyl methacrylate). )
And other hydrophilic polymers.
【０００３】しかし、医療技術の発展に伴い、これらの
材料と生体組織や血液とが接触して用いられる機会が多
くなり、材料と生体との親和性が問題となってきた。す
なわち、これらの材料は汎用高分子であり抗血栓性に乏
しいため、血液中のタンパク質や血球成分が材料表面に
付着し、生体の自己防衛反応である血栓形成を起こし易
い。However, with the development of medical technology, the chances of using these materials in contact with living tissue or blood have increased, and the compatibility between the materials and the living body has become a problem. That is, since these materials are general-purpose polymers and have poor antithrombotic properties, proteins and blood cell components in blood adhere to the surface of the materials, and they easily cause thrombus formation which is a self-defense reaction of the living body.
【０００４】このため、これらの材料を血液と接触する
場で用いる場合には血栓形成を防ぐため抗血液凝固剤等
が用いられる。しかし、これは生体や血液に対して好ま
しくなく、投与される患者は腎疾患や出血性疾患などの
発症の可能性があり医療用高分子材料の使用に当たって
の大きな障害となっている。Therefore, when these materials are used in contact with blood, an anticoagulant or the like is used to prevent thrombus formation. However, this is not preferable for the living body and blood, and the patient to whom it is administered may develop renal disease or hemorrhagic disease, which is a major obstacle in using the medical polymer material.
【０００５】そこで、材料表面での血栓形成を防ぐため
に材料表面に生理活性物質を固定化したりコーティング
した材料もあるが、生理活性物質による生体への影響、
コーティング剤や残留溶媒の溶出等の危険性がある。Therefore, there is a material in which a physiologically active substance is immobilized or coated on the surface of the material in order to prevent thrombus formation on the surface of the material.
There is a risk of elution of coating agent and residual solvent.
【０００６】医療用高分子材料と血液とが接触するとそ
の表面に直ちに血液中のタンパク質や、りん脂質などの
生体成分が付着され、その後、材料の性質はこの付着層
を通して間接的に現れるため、細胞成分との相互作用を
完全に無くすることが難しい。従って、血液と直接接触
する材料表面において、付着が起こらないような構造を
考えることが重要である。When the medical polymer material and blood come into contact with each other, biological components such as proteins and phospholipids in blood are immediately attached to the surface, and thereafter, the properties of the material indirectly appear through this adhesion layer. It is difficult to completely eliminate the interaction with cell components. Therefore, it is important to consider a structure in which adhesion does not occur on the material surface that is in direct contact with blood.
【０００７】一方、リン脂質は生体全体に広く存在し生
体膜を構成する主要成分であるが、生体膜、特に血管内
表面では血栓形成が起こらないことからリン脂質が注目
され、研究が行われている。[0007] On the other hand, phospholipids are widely present throughout the living body and are the main constituents of biological membranes. However, since phospholipids do not cause thrombus formation on biological membranes, especially on the inner surface of blood vessels, phospholipids have been attracting attention and studied. ing.
【０００８】[0008]
【発明が解決しようとする課題】本発明の目的は、材料
表面に生理活性物質を固定化したりコーティングしたり
することなく、材料表面での血球成分の付着や凝集の起
こらない、いわゆる抗血栓性を有する材料を開発しよう
とするものである。SUMMARY OF THE INVENTION An object of the present invention is to prevent so-called antithrombotic property, in which adhesion or aggregation of blood cell components does not occur on a material surface without immobilizing or coating a physiologically active substance on the material surface. It is intended to develop a material having
【０００９】[0009]
【課題を解決するための手段】そこで本発明において
は、血栓形成の問題を解決するために、血液細胞との相
互作用が極めて弱い表面性状を持つ材料を開発するとい
う考えのもとに鋭意検討した結果、材料表面に生体膜と
同様な脂質二分子膜構造を構築することにより血液細胞
との相互作用が弱くなり、血栓形成が起こらない表面が
得られることを見いだし、本発明に至った。Therefore, in the present invention, in order to solve the problem of thrombus formation, the present invention is earnestly studied based on the idea of developing a material having a surface property that has an extremely weak interaction with blood cells. As a result, they found that by constructing a lipid bilayer membrane structure similar to a biological membrane on the material surface, the interaction with blood cells was weakened, and a surface free from thrombus formation was obtained, and the present invention was accomplished.
【００１０】即ち、本発明は、ハロゲンまたはハロゲン
化アルキル基を有するポリマーに、リン脂質極性基を有
するモノマーをグラフト共重合したことを特徴とする抗
血栓性材料である。また、本発明は、グラフト共重合体
の表面におけるリン脂質極性基を有する重合体の割合が
５〜６０モル％であることを特徴とする上記の抗血栓性
材料である。さらに本発明は、リン脂質極性基を有する
重合体の重合度が２〜４０であることを特徴とする上記
の抗血栓性材料である。そして本発明は、ハロゲンまた
はハロゲン化アルキル基を有するポリマーの表面にメル
カプト基を導入し、次いで該メルカプト基を起点として
リン脂質極性基を有するモノマーをグラフト共重合させ
ることを特徴とする抗血栓性材料の製造方法である。That is, the present invention is an antithrombotic material characterized by graft-copolymerizing a monomer having a phospholipid polar group onto a polymer having a halogen or a halogenated alkyl group. Further, the present invention is the above antithrombogenic material, wherein the proportion of the polymer having a phospholipid polar group on the surface of the graft copolymer is 5 to 60 mol%. Further, the present invention is the above antithrombogenic material, wherein the polymer having a phospholipid polar group has a degree of polymerization of 2 to 40. And the present invention is characterized in that a mercapto group is introduced on the surface of a polymer having a halogen or a halogenated alkyl group, and then a monomer having a phospholipid polar group is graft-copolymerized from the mercapto group as a starting point. It is a method of manufacturing a material.
【００１１】以下、本発明を詳細に説明する。本発明で
はハロゲンまたはハロゲン化アルキル基を有するポリマ
ー（以下、「基材」と記す）の表面に化学的な方法によ
り直接親水性モノマー、特にリン脂質極性基を有するモ
ノマーをグラフト共重合することにより基材表面を分子
的に設計して改質した抗血栓性材料を得た。The present invention will be described in detail below. In the present invention, by graft-copolymerizing a hydrophilic monomer, particularly a monomer having a phospholipid polar group, directly by a chemical method on the surface of a polymer having a halogen or a halogenated alkyl group (hereinafter referred to as “base material”). An antithrombogenic material having a substrate surface molecularly designed and modified was obtained.
【００１２】本発明で用いられる基材の代表的なものと
しては、ポリ塩化ビニル、塩素化ポリエチレン、ポリク
ロロプレン、クロロスルホン化ポリエチレン等が挙げら
れる。Representative examples of the substrate used in the present invention include polyvinyl chloride, chlorinated polyethylene, polychloroprene, chlorosulfonated polyethylene and the like.
【００１３】本発明の抗血栓性材料の合成は、先ず、基
材を水硫化物で処理し、基材中のハロゲンをメルカプト
基と置換する。ここで使用する水硫化物としては水硫化
カリウム、水硫化ナトリウムなどが挙げられる。In the synthesis of the antithrombotic material of the present invention, first, the base material is treated with hydrosulfide to replace the halogen in the base material with a mercapto group. Examples of hydrosulfides used here include potassium hydrosulfide and sodium hydrosulfide.
【００１４】続いてメルカプト基を導入した基材に、親
水性、特にリン脂質を有するモノマーをラジカル重合に
よりメルカプト基を起点として直接グラフト共重合させ
る。リン脂質モノマーの導入量は、グラフト共重合体の
表面におけるリン脂質極性基を有する重合体の割合が５
〜６０モル％、好ましくは２０〜４０モル％である。導
入するリン脂質モノマーが５モル％より少ない場合には
抗血栓性の効果が乏しく、６０モル％より多い場合には
基材の性能が損なわれる。Subsequently, a monomer having hydrophilicity, particularly phospholipid, is directly graft-copolymerized from the mercapto group as an origin by a radical polymerization on the substrate having the mercapto group introduced. The amount of phospholipid monomer introduced depends on the graft copolymer.
The ratio of polymer having phospholipid polar groups on the surface is 5
-60 mol%, preferably 20-40 mol%. If the amount of phospholipid monomer to be introduced is less than 5 mol%, the antithrombotic effect is poor, and if it is more than 60 mol%, the performance of the base material is impaired.
【００１５】本発明におけるグラフト部分のリン脂質極
性基を有する重合体は、リン脂質極性基を有するモノマ
ーのくりかえし単位として２〜４０程度が好ましい。こ
れにより基材表面に親水性、特にリン脂質を有する重合
体を配向させることができ、血液と材料とが接触した際
に表面に固定化されたリン脂質部分と血液中のリン脂質
との複合効果により材料表面への血球成分の付着が全く
起こらず抗血栓性を持つ材料が得られる。The polymer having a phospholipid polar group in the graft moiety in the present invention is preferably about 2 to 40 as a repeating unit of a monomer having a phospholipid polar group. As a result, a polymer having hydrophilicity, particularly phospholipids, can be oriented on the surface of the base material, and when the blood and the material come into contact with each other, the complex of the phospholipid part immobilized on the surface and the phospholipid in the blood Due to the effect, adhesion of blood cell components to the material surface does not occur at all, and a material having antithrombotic properties can be obtained.
【００１６】本発明で用いられるリン脂質極性基を有す
るモノマーとしては現在のところ数種類が知られている
が( 表面,vol.28 、No.9,720-)、その一例を挙げれば、
２−メタクリロイルオキシエチルホスホリルコリンが例
示できる。Several kinds of monomers having a phospholipid polar group used in the present invention are known at present (Surface, vol.28, No.9,720-).
2-methacryloyloxyethyl phosphoryl choline can be illustrated.
【００１７】またラジカル重合の開始剤としては、通常
のラジカル開始剤であればいずれを用いても良く、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等を例示することができ
る。As the radical polymerization initiator, any ordinary radical initiator may be used.
Examples include aliphatic azo compounds such as 2′-azobisisobutyronitrile (AIBN) and azobismalenonitrile, and organic peroxides such as benzoyl peroxide, lauroyl peroxide, ammonium persulfate and potassium persulfate. You can
【００１８】[0018]
【作用】本発明の抗血栓性材料は、材料表面に親水性
基、特に血液中に多く存在するリン脂質をもち、生体内
由来のリン脂質分子と強く相互作用し、生体膜類似の配
向したリン脂質層を安定に形成するため、優れた生体適
合性を獲得できるという概念により分子設計されてい
る。したがって、タンパク質や血液細胞などの生体成分
の付着が極めて少なく、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。The antithrombotic material of the present invention has hydrophilic groups on the surface of the material, especially phospholipids that are abundant in blood, and strongly interacts with phospholipid molecules derived from the living body, and is oriented like biological membranes. The molecular design is based on the concept that excellent biocompatibility can be obtained because the phospholipid layer is stably formed. Therefore, the adhesion of biological components such as proteins and blood cells is extremely small, and the activation of platelets that induces thrombus formation can be suppressed.
【００１９】本発明の抗血栓性材料は、医用材料、臨床
検査用材料、製剤用材料、光学材料など直接生体成分と
接触して用いる分野、たとえば血液バッグ、カテーテ
ル、血液導流管等に利用することができる。The antithrombotic material of the present invention is used in the fields of direct contact with biological components such as medical materials, clinical test materials, pharmaceutical materials, and optical materials, for example, blood bags, catheters, blood flow conduits, etc. can do.
【００２０】[0020]
【実施例】以下に、本発明の実施例を記載するが、本発
明はこれらの実施例に限定されるものではない。EXAMPLES Examples of the present invention will be described below, but the present invention is not limited to these examples.
【００２１】実施例１
医療用無可塑ポリ塩化ビニルシート１０ｇを水硫化ナト
リウム濃度０．０５ｍｏｌ／ｌのエチルアルコール溶液
１０００ｍｌに加え、７９℃、２時間加熱処理して無可
塑ポリ塩化ビニルシートの塩素をメルカプト基で置換し
た。Example 1 10 g of a non-plasticized polyvinyl chloride sheet for medical use was added to 1000 ml of an ethyl alcohol solution having a sodium hydrosulfide concentration of 0.05 mol / l, and heat-treated at 79 ° C. for 2 hours to give chlorine of the non-plasticized polyvinyl chloride sheet. Was replaced with a mercapto group.
【００２２】次に、メルカプト基で置換した該ポリ塩化
ビニルシートの半分を採取して６０ｍｌのシクロヘキサ
ノンと４０ｍｌのエチルメチルケトンから成る混合溶媒
に溶解し、０．０５ｍｏｌ／ｌのヨウ素エタノール溶液
１０ｍｌを加え充分に反応させた後、０．０５規定のチ
オ硫酸ナトリウム水溶液で滴定し、シート上のメルカプ
ト基の量を求めた。シートに導入されたメルカプト基は
１ｃｍ2 あたり８．１３×１０-5ｍｏｌであった。Next, half of the polyvinyl chloride sheet substituted with mercapto groups was sampled and dissolved in a mixed solvent consisting of 60 ml of cyclohexanone and 40 ml of ethyl methyl ketone, and 10 ml of a 0.05 mol / l iodine-ethanol solution was added. After sufficient addition and reaction, the amount of mercapto groups on the sheet was determined by titration with a 0.05 N sodium thiosulfate aqueous solution. The mercapto group introduced into the sheet was 8.13 × 10 -5 mol / cm 2 .
【００２３】次に、メルカプト基で置換した該ポリ塩化
ビニルシートの残りの半分について脱気水およびエチル
アルコールで洗浄した後、２−メタクリロイルオキシエ
チルホスホリルコリン（以下、ＭＰＣと記す）０．１ｍ
ｏｌ／ｌのエチルアルコール溶液５００ｍｌ中で、開始
剤としてＡＩＢＮをモノマーに対して０．１ｍｏｌ％使
用して窒素雰囲気下で８時間反応させ、表面にリン脂質
極性基を配向させて抗血栓性材料を得た。Next, the remaining half of the polyvinyl chloride sheet substituted with mercapto groups was washed with deaerated water and ethyl alcohol, and then 0.1 m of 2-methacryloyloxyethylphosphorylcholine (hereinafter referred to as MPC).
In 500 ml of an ethyl alcohol solution of ol / l, AIBN was used as an initiator in an amount of 0.1 mol% with respect to the monomer and reacted for 8 hours in a nitrogen atmosphere to orient the phospholipid polar groups on the surface to form an antithrombogenic material. Got
【００２４】次に、該抗血栓性材料に含まれるリンの含
量をリン脂質テストワコー（和光純薬工業社製）で測定
し、含有されるＭＰＣ量を求めた。該抗血栓性材料に含
有されるＭＰＣは１ｃｍ2 あたり２．７１×１０-3ｍｏ
ｌであった。また、シート１ｃｍ2 に導入されたメルカ
プト基の数と抗血栓性材料に含有されるＭＰＣ量より求
めたＭＰＣの重合度は３２であった。Next, the content of phosphorus contained in the antithrombotic material was measured with a phospholipid test Wako (manufactured by Wako Pure Chemical Industries, Ltd.) to determine the amount of MPC contained. MPC contained in the antithrombotic material is 2.71 × 10 −3 mo / cm 2.
It was l. The degree of polymerization of MPC determined from the number of mercapto groups introduced into 1 cm 2 of the sheet and the amount of MPC contained in the antithrombotic material was 32.
【００２５】抗血栓性試験
上記で合成した抗血栓性材料シートを直径１．５ｃｍの
大きさに打ち抜き試料膜としてファルコンシャーレにセ
ットし、ウサギより採血した全血を試料膜表面に流し込
み、３７℃で６０分および１８０分間ウサギ全血を直接
接触させ、その後表面に付着した血球成分の様子を走差
型電子顕微鏡で観察し、材料表面に付着した血球数とそ
の凝集（血栓形成の進行度合い）に分けて評価し、材料
の抗血栓性の判断を行った。Anti-thrombogenicity test The anti-thrombogenic material sheet synthesized above was punched out to a size of 1.5 cm and set as a sample film on a Falcon Petri dish, and whole blood collected from a rabbit was poured onto the surface of the sample film at 37 ° C. Rabbit whole blood is brought into direct contact for 60 minutes and 180 minutes, then the state of blood cell components attached to the surface is observed with a scanning electron microscope, and the number of blood cells attached to the surface of the material and its aggregation (progress of thrombus formation) The antithrombotic properties of the materials were evaluated by dividing the evaluation into two.
【００２６】比較例１〜３
医療用として用いられているエスメディカ製無可塑ポリ
塩化ビニル（比較例１）、サンプラスチック製ポリエチ
レンシート８０５０−ＢＱ（比較例２）および疎水性材
料としてアルドリッチ社製ポリブチルメタクリレート
（比較例３）の各試料膜について同じように試験を行っ
た。表１に示す通り、以上の結果から本発明の抗血栓性
材料はその表面に血球成分の付着が認められず、凝集物
も認められないのに対して、表面にリン脂質極性基構造
を持たない他の材料では付着も凝集も認められた。Comparative Examples 1 to 3 Non-plasticized polyvinyl chloride made by Smedica (Comparative Example 1), polyethylene sheet 8050-BQ (Comparative Example 2) made of Sunplastic used for medical purposes and Aldrich made as a hydrophobic material. The same test was conducted for each sample film of polybutyl methacrylate (Comparative Example 3). As shown in Table 1, from the above results, the antithrombotic material of the present invention has no adherence of blood cell components and no aggregates on its surface, whereas it has a phospholipid polar group structure on the surface. Adhesion and agglomeration were observed with the other materials which were not present.
【００２７】実施例２および比較例４
実施例１と同様に処理を行い表面にリン脂質極性基構造
を導入したチューブ（実施例２）、およびエスメディカ
製無可塑ポリ塩化ビニルチューブ（比較例４）につい
て、直径２ｍｍ、長さ３０ｃｍのチューブに血液を流速
２ｍｌ／ｍｉｎ、３７℃で循環させた時の血栓形成によ
るチューブの閉塞時間を測定した。その結果を表２に示
す。本発明の抗血栓性材料でできたチューブでは４５ｍ
ｉｎ経過後もチューブの閉塞が認められないのに対し
て、表面にリン脂質極性基構造を持たないチューブでは
１５ｍｉｎで閉塞が起きた。Example 2 and Comparative Example 4 A tube treated in the same manner as in Example 1 to introduce a phospholipid polar group structure on the surface (Example 2), and an Esmedica non-plasticized polyvinyl chloride tube (Comparative Example 4) For (1), the blockage time of the tube due to thrombus formation was measured when blood was circulated in a tube having a diameter of 2 mm and a length of 30 cm at a flow rate of 2 ml / min at 37 ° C. The results are shown in Table 2. 45 m for a tube made of the antithrombotic material of the present invention
Although the tube was not blocked even after the passage of in, the tube having no phospholipid polar group structure on the surface was blocked in 15 minutes.
【００２８】[0028]
【表１】 [Table 1]
【００２９】[0029]
【表２】 [Table 2]
【００３０】[0030]
【発明の効果】以上の通り本発明の抗血栓性材料は血球
成分による表面への付着も凝集も起こらず医療用材料と
して有望である。INDUSTRIAL APPLICABILITY As described above, the antithrombotic material of the present invention is promising as a medical material because neither adhesion nor aggregation of blood cell components on the surface occurs.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭54−63025（ＪＰ，Ａ) 特開 平５−220218（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C08F 259/00 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP 54-63025 (JP, A) JP 5-220218 (JP, A) (58) Fields investigated (Int.Cl. 7 , DB name) C08F 259/00
Claims (4)
有するポリマーに、リン脂質極性基を有するモノマーを
グラフト共重合したことを特徴とする抗血栓性材料。1. An antithrombogenic material, which is obtained by graft-copolymerizing a monomer having a phospholipid polar group with a polymer having a halogen or a halogenated alkyl group.
質極性基を有する重合体の割合が５〜６０モル％である
ことを特徴とする請求項１記載の抗血栓性材料。2. The antithrombotic material according to claim 1, wherein the proportion of the polymer having a phospholipid polar group on the surface of the graft copolymer is 5 to 60 mol%.
重合体の重合度が２〜４０であることを特徴とする請求
項２記載の抗血栓性材料。3. The antithrombotic material according to claim 2, wherein the polymer having a phospholipid polar group in the graft portion has a degree of polymerization of 2 to 40.
有するポリマーの表面にメルカプト基を導入し、次いで
該メルカプト基を起点としてリン脂質極性基を有するモ
ノマーをグラフト共重合させることを特徴とする抗血栓
性材料の製造方法。4. An antithrombotic property, which comprises introducing a mercapto group onto the surface of a polymer having a halogen or a halogenated alkyl group, and then graft-copolymerizing a monomer having a phospholipid polar group from the mercapto group as a starting point. Material manufacturing method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28086093A JP3367570B2 (en) | 1993-11-10 | 1993-11-10 | Antithrombotic material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28086093A JP3367570B2 (en) | 1993-11-10 | 1993-11-10 | Antithrombotic material |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07133327A JPH07133327A (en) | 1995-05-23 |
| JP3367570B2 true JP3367570B2 (en) | 2003-01-14 |
Family
ID=17630984
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28086093A Expired - Fee Related JP3367570B2 (en) | 1993-11-10 | 1993-11-10 | Antithrombotic material |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3367570B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009130233A1 (en) * | 2008-04-25 | 2009-10-29 | Basf Se | Modified halogenated polymer surfaces |
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1993
- 1993-11-10 JP JP28086093A patent/JP3367570B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07133327A (en) | 1995-05-23 |
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