JP4631263B2 - Antithrombotic copolymer - Google Patents
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- JP4631263B2 JP4631263B2 JP2003348559A JP2003348559A JP4631263B2 JP 4631263 B2 JP4631263 B2 JP 4631263B2 JP 2003348559 A JP2003348559 A JP 2003348559A JP 2003348559 A JP2003348559 A JP 2003348559A JP 4631263 B2 JP4631263 B2 JP 4631263B2
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本発明は、抗血栓性共重合物、該抗血栓性共重合物を含む抗血栓性組成物及び抗血栓性共重合物で処理された医療用器具に関する。 The present invention relates to an antithrombotic copolymer, an antithrombotic composition containing the antithrombotic copolymer, and a medical device treated with the antithrombotic copolymer.
従来からカテーテル、チューブ類等の体外循環回路に用いられる医療用器具や、人工腎臓、人工肺、人工肝臓等の種々の人工臓器には、それぞれの医療用機能に加えて、抗血栓性が重要な要素として要求されている。 The catheter conventionally, and medical instruments used in the extracorporeal circulation circuit such as tubing, artificial kidneys, artificial lungs, the various artificial organs such as an artificial liver, in addition to the respective medical function, anti-thrombotic properties It is required as an important factor.
一般に、人体には、血管が破損し、血液が血管外に流出すると、血液は凝固して、血栓によって血管の破損部分を補修し、それ以上の出血の危険が防止され、或いは血流中に異物が混入されると、その表面を血栓が被覆し、その異物を生体に同化する機能が備えられている。 In general, when a blood vessel breaks and the blood flows out of the blood vessel in the human body, the blood coagulates and repairs the damaged portion of the blood vessel with a thrombus, preventing further risk of bleeding or entering the bloodstream. When a foreign substance is mixed in, the surface is covered with a thrombus, and the function of assimilating the foreign substance into a living body is provided.
従って、かかる血栓形成は、生命維持にとって必要不可欠であるが、血液と直接に接触する上記のような医療用器具や人工臓器については、かかる血栓形成は、その使用上、致命的な障害である。 Therefore, such thrombus formation is indispensable for life support. However, for the above-mentioned medical devices and artificial organs that are in direct contact with blood, such thrombus formation is a fatal obstacle in its use. .
血栓形成の機構は、非常に複雑であって、未だ必ずしも明確にはされていないが、凝固反応、線溶反応及び血小板反応が血栓形成にかかわる主要な反応であって、血液成分のうちでは、血液凝固因子と血小板とが血栓形成を支配する因子であるとされている。 The mechanism of thrombus formation is very complicated and not yet clearly defined, but coagulation reaction, fibrinolysis reaction and platelet reaction are the main reactions involved in thrombus formation. It is said that blood coagulation factors and platelets are the factors governing thrombus formation.
医療用具の抗血栓性向上の中心となって検討されてきたのが抗凝血作用を有するヘパリンまたはその誘導体を医療用具の表面上になんらかの方法で固定して、抗血栓性を得る手法である。 A method for obtaining antithrombogenicity by fixing heparin or a derivative thereof having anticoagulant action on the surface of the medical device by some method has been studied as a center for improving the antithrombogenicity of the medical device. .
例えば、ヘパリンのアミノ基と基材表面に導入したアミノ基をポリエチレングリコールジグリシジルエーテルでカップリングする共有結合方式がある（特許文献１）。 For example, there is a covalent bond method in which an amino group of heparin and an amino group introduced onto the substrate surface are coupled with polyethylene glycol diglycidyl ether (Patent Document 1).
しかし、これらの製品に用いられるヘパリンは、そのほとんどが、ウシやブタ等の生物組織から抽出される生物由来材料である。 However, most of the heparin used in these products is a biological material extracted from biological tissues such as cows and pigs.
近年、生物由来製品の汚染による健康被害が相次いだことから、生物由来製品の汚染に対する安全確保の必要性が高まり、改正薬事法が平成１５年７月３０日から適用され、その製造・使用等は、厳しく制限されている。 In recent years, due to the continual health damage caused by contamination of biological products, the need to ensure safety against contamination of biological products has increased, and the revised Pharmaceutical Affairs Law has been applied since July 30, 2003. Is strictly limited.
上記の問題を解決する手段としては、人工的血栓性物質が有効である。人工的抗血栓性物質としては、例えば、糖側鎖を有するポリスチレン誘導体（ポリ（Ｎ−ｐ−ビニルベンジル−Ｄ−ラクトンアミド）：ＰＶＬＡ）が知られている（特許文献２）。 Artificial thrombotic substances are effective as means for solving the above problems. As an artificial antithrombotic substance, for example, a polystyrene derivative having a sugar side chain (poly (Np-vinylbenzyl-D-lactone amide): PVLA) is known (Patent Document 2).
ＰＶＬＡは、そのスチレン骨格によりポリスチレンに対しては強固に疎水吸着をし、良好な抗血栓性を発現する。しかし、医療機器に汎用されている他の基材、例えば、ポリ塩化ビニル、ポリウレタン、ポリカーボネート、ポリスルホン、ポリエステル、ステンレス等に対しては、適用が困難であるという問題点があった。 PVLA strongly adsorbs hydrophobicity to polystyrene due to its styrene skeleton, and exhibits good antithrombotic properties. However, there is a problem that it is difficult to apply to other base materials that are widely used in medical devices, such as polyvinyl chloride, polyurethane, polycarbonate, polysulfone, polyester, and stainless steel.
そこで、汎用基材に適用可能な、人工的抗血栓性物質の開発が待たれていた。
本発明が解決しようとする課題は、安全性に優れ、汎用基材に適用可能であることを特徴とする、新規な抗血栓性共重合物を提供することである。 The problem to be solved by the present invention is to provide a novel antithrombotic copolymer characterized by being excellent in safety and applicable to a general-purpose substrate.
本発明は、下記式：
（式中、ｍ：ｎ＝９：１〜１：９であり、ｘは、６〜１８である。）
で表される共重合物に関する。
(In the formula, m: n = 9: 1 to 1: 9, and x is 6 to 18.)
It is related with the copolymer represented by these.
また、本発明は、ｘが１４である、上記共重合物に関する。 Moreover, this invention relates to the said copolymer whose x is 14.
また、本発明は、上記共重合物を含む、抗血栓性組成物、及び上記共重合物を用いて表面の少なくとも一部が処理されていることを特徴とする、医療用器具にも関する。 The present invention also relates to an antithrombogenic composition containing the copolymer and a medical device characterized in that at least a part of the surface is treated with the copolymer.
本発明による抗血栓共重合体は、極めて低濃度での適用によって、血小板の活性化を抑制し、血栓形成を効果的に防止することができる。 The antithrombotic copolymer according to the present invention can suppress platelet activation and effectively prevent thrombus formation by application at an extremely low concentration.
本発明は、下記式：
で表される共重合物に関し、
式中、ｍ：ｎは、９：１〜１：９、好ましくは、９：１〜５：５、より好ましくは、９：１〜６：４、ｘは、６〜１８、好ましくは、１４である。
In regard to the copolymer represented by
In the formula, m: n is 9: 1 to 1: 9, preferably 9: 1 to 5: 5, more preferably 9: 1 to 6: 4, and x is 6 to 18, preferably 14 It is.
すなわち、本発明は、Ｎ−ｐ−ビニルベンジル−Ｄ−ラクトンアミドと４−ビニルベンジルヘキサデカンアミドとの共重合物に関する。 That is, the present invention relates to a copolymer of Np-vinylbenzyl-D-lactone amide and 4-vinylbenzyl hexadecanamide.
本発明の別の態様においては、Ｎ−ｐ−ビニルベンジル−Ｄ−ラクトンアミドに代えて、Ｎ−ｐ−ビニルベンジル−Ｄ−セロビオンアミド、Ｎ−ｐ−ビニルベンジル−Ｄ−マルトンアミド、Ｎ−ｐ−ビニルベンジル−Ｄ−マルトトリオンアミド、Ｎ−ｐ−ビニルベンジル−Ｄ−マルトペンタオンアミド、又はＮ−ｐ−ビニルベンジル−Ｄ−マルトヘプタオンアミド、好ましくは、Ｎ−ｐ−ビニルベンジル−Ｄ−マルトンアミド、Ｎ−ｐ−ビニルベンジル−Ｄ−マルトトリオンアミドを用いることができる。 In another embodiment of the present invention, instead of Np-vinylbenzyl-D-lactone amide, Np-vinylbenzyl-D-cellobionamide, Np-vinylbenzyl-D-maltonamide, N -P-vinylbenzyl-D-maltotrionamide, Np-vinylbenzyl-D-maltopentanamide, or Np-vinylbenzyl-D-maltoheptanamide, preferably Np-vinylbenzyl -D-maltonamide and Np-vinylbenzyl-D-maltotrioneamide can be used.
本発明の別の態様においては、４−ビニルベンジルヘキサデカンアミドに代えて、下記式：
（式中、
Ｘは、環員数が５〜１０の飽和もしくは不飽和の単環もしくは二環、もしくは窒素、酸素を含む分子を表し、ここで、該環は、窒素、硫黄、酸素からなる群より選択される１〜３個の原子を含んでもよく、
ｎは、０又は１であり、
Ｙは、−ＮＨＣＯ−、−ＣＯＮＨ−、−ＮＨＣＯＮＨ−、−ＮＨ−、−ＣＯ−、または炭素数０以上のアルキル基であり、
Ｒは、炭素数が１〜２０の直鎖または分岐のアルキル、アルケニルまたはアルキニルであり、必要により１個もしくは２個のヒドロキシ、メルカプト、アミノ、シアノ、ヘテロシクリル、ヘテロシクリルオキシ、フェニル、ベンジル、ヘテロアリール、フェノキシ、ベンジルオキシ及びヘテロアリールオキシにより置換されていてもよい）
で表される化合物を用いることができる。
(Where
X represents a saturated or unsaturated monocyclic or bicyclic ring having 5 to 10 ring members, or a molecule containing nitrogen or oxygen, wherein the ring is selected from the group consisting of nitrogen, sulfur and oxygen May contain 1 to 3 atoms,
n is 0 or 1;
Y is -NHCO-, -CONH-, -NHCONH-, -NH-, -CO-, or an alkyl group having 0 or more carbon atoms,
R is linear or branched alkyl, alkenyl or alkynyl having 1 to 20 carbon atoms, and optionally 1 or 2 hydroxy, mercapto, amino, cyano, heterocyclyl, heterocyclyloxy, phenyl, benzyl, heteroaryl Optionally substituted by phenoxy, benzyloxy and heteroaryloxy)
The compound represented by these can be used.
また、本発明に用いることができるモノマーは、上記モノマーに限定されるものではなく、上記モノマー以外にもＶＬＡと好ましく共重合体を形成するビニル基をもった市販あるいは合成されたモノマーを用いることができる。 In addition, the monomers that can be used in the present invention are not limited to the above monomers, and in addition to the above monomers, commercially available or synthesized monomers having a vinyl group that preferably forms a copolymer with VLA are used. Can do.
本発明の共重合物であるＮ−ｐ−ビニルベンジル−Ｄ−ラクトンアミド：４−ビニルベンジルヘキサデカンアミドの共重合比率は、９：１〜１：９、好ましくは、９：１〜５：５、より好ましくは、９：１〜６：４である。 The copolymerization ratio of Np-vinylbenzyl-D-lactone amide: 4-vinylbenzyl hexadecanamide, which is the copolymer of the present invention, is 9: 1 to 1: 9, preferably 9: 1 to 5: 5. More preferably, it is 9: 1 to 6: 4.
本共重合物の合成に用いるモノマーＶＬＡは、一般的にはラクトースの酸化、脱水により得られるラクトースラクトンとビニルベンジルアミンの反応により得られ、もう一方のモノマーであるビニルベンジルヘキサデカンアミド（VAL）は、ビニルベンジルアミンとパルミトイルクロライドの反応により得られる。共重合物は、一般的な開始剤を用いたラジカル重合により得る事が出来る。 The monomer VLA used for the synthesis of this copolymer is generally obtained by the reaction of lactose lactone obtained by oxidation and dehydration of lactose with vinylbenzylamine, and the other monomer, vinylbenzylhexadecanamide (VAL), is obtained. It can be obtained by the reaction of vinylbenzylamine and palmitoyl chloride. The copolymer can be obtained by radical polymerization using a general initiator.
また、本発明の抗血栓性共重合物は、従来公知の薬学的に許容可能な物質、例えば、水、緩衝液、アルコール等に溶解するか又は分散させ、所要の場合には、さらにこれに乳化剤、分散剤、懸濁剤、安定剤などを添加して用いることができる。 Further, the antithrombotic copolymer of the present invention is dissolved or dispersed in a conventionally known pharmaceutically acceptable substance such as water, buffer solution, alcohol, etc., and if necessary, further added thereto. An emulsifier, a dispersant, a suspending agent, a stabilizer and the like can be added and used.
また、本発明による抗血栓性共重合物は、公知の抗血栓性物質と併用することもできる。 The antithrombotic copolymer according to the present invention can be used in combination with a known antithrombotic substance.
医療容器具の表面に本発明の共重合物を処理する方法としては、浸漬法、スプレー法、刷毛などで塗布する方法等が用いられるが、塗布後、紫外線やγ線等の高エネルギー線照射により表面への結合を強化することも可能である。これらに限定されるものではない。 As a method for treating the surface of the medical container with the copolymer of the present invention, a dipping method, a spray method, a method of applying with a brush or the like is used, but after application, irradiation with high energy rays such as ultraviolet rays and γ rays. It is also possible to strengthen the bond to the surface. It is not limited to these.
ここで、医療用器具の基材の材料としては、通常使用される全ての材料が含まれる。例えば、ポリ塩化ビニル、ポリウレタン、ポリカーボネート、ポリスルホン、ポリエーテルスルホン、ポリエステル、ポリエチレンテレフタレート、ポリエチレン、ポリプロピレン、ポリブタジエン、シリコーンゴム、ポリメチルメタクリレート、ポリフッ化ビニリデン等の樹脂及びこれらの樹脂の混合物、ステンレス、チタニウム及びアルミニウム等の金属等を挙げることができる。 Here, as a material of the base material of a medical instrument, all the materials normally used are included. For example, resins such as polyvinyl chloride, polyurethane, polycarbonate, polysulfone, polyethersulfone, polyester, polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, silicone rubber, polymethylmethacrylate, polyvinylidene fluoride, and mixtures of these resins, stainless steel, titanium And metals such as aluminum.
ＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（ＶＡＬ）の製造方法
適量のナスフラスコ中でクロロメチルスチレン １kgをＤＭＦ３．２L に溶解し、カリウムフタルイミド １．２kgを加えた。これを５０℃、４時間反応させた。エバポレーターを用いてＤＭＦを留去したのち、ベンゼン４．５Lを加えて残さを溶解した。ベンゼンを０．２N ＮａＯＨ溶液で数回洗浄した（全量３．２５L）。ベンゼンを更に水で数回洗浄し（全量３．２５L）、ＮａＳＯ４等で乾燥させた後、エバポレーターを用いて溶媒を留去した。残さをメタノールから再結晶して１．５kgのビニルベンジルフタルイミドを得た。
Method for producing VLA-co-vinylbenzylhexadecanamide (VAL) 1 kg of chloromethylstyrene was dissolved in 3.2 L of DMF in an appropriate amount of eggplant flask, and 1.2 kg of potassium phthalimide was added. This was reacted at 50 ° C. for 4 hours. After distilling off DMF using an evaporator, 4.5 L of benzene was added to dissolve the residue. Benzene was washed several times with 0.2N NaOH solution (total amount 3.25 L). Benzene was further washed several times with water (total amount 3.25 L), dried with NaSO 4 and the like, and then the solvent was distilled off using an evaporator. The residue was recrystallized from methanol to obtain 1.5 kg of vinylbenzylphthalimide.
適量のセパラブルフラスコ中で上記ビニルベンジルフタルイミド １Kgを２．７Lのエタノールに溶解し、窒素気流下、加熱灌流させた。これに滴下ロートを用いて、８０％ヒドラジンモノハイドレート ０．３６kg／５４５ml ＥｔＯＨ溶液を滴下した（滴下時間４０分程度）。反応は、９０分間、加熱灌流させて行った。反応終了後、得られた固体を濾取し、これに、ＫＯＨ溶液（１kg／６．５L Ｈ２Ｏ）を加えて溶解したのち、エーテルにて抽出した（全量３．６L×３）。エーテル層をさらに、２％Ｋ２ＣＯ３溶液で洗浄し、さらに水で数回洗浄した。エーテル層をＮａ２ＳＯ４上で乾燥した後、エーテルを留去し、残さを減圧蒸留し０．４５kgのビニルベンジルアミンを得た。 In an appropriate amount of separable flask, 1 kg of the above vinylbenzyl phthalimide was dissolved in 2.7 L of ethanol and heated and perfused under a nitrogen stream. To this, a dropping funnel was used, and 80% hydrazine monohydrate 0.36 kg / 545 ml EtOH solution was dropped (dropping time about 40 minutes). The reaction was performed by heating and perfusion for 90 minutes. After completion of the reaction, the obtained solid was collected by filtration, dissolved in KOH solution (1 kg / 6.5 L H 2 O) and extracted with ether (total amount: 3.6 L × 3). The ether layer was further washed with 2% K 2 CO 3 solution and further several times with water. After the ether layer was dried over Na 2 SO 4 , the ether was distilled off, and the residue was distilled under reduced pressure to obtain 0.45 kg of vinylbenzylamine.
次に、ラクトース１２gをメタノール３００mlに分散させ、４０℃に加熱した。これに、ヨウ素１８gのメタノール溶液を滴下し、４０分間反応させた。これに、４NのＫＯＨメタノール溶液を、ヨウ素の着色が無くなるまで添加した。沈澱を濾取し、冷メタノールで数回洗浄後、エーテルで洗浄し、一旦秤量した。その後、得られた結晶をごく少量の水に溶解し、アンバーライト１２０Ｂのプロトン型イオン交換樹脂にアプライし、酸性分画を単離した。得られた水溶液にメタノールとエタノールを添加してエバポレーションした。完全に乾固したのち、再び、メタノールとエタノールを加えて溶解し、エバポレーションした。この操作を数回繰り返し、ラクトースラクトンを作製した。 Next, 12 g of lactose was dispersed in 300 ml of methanol and heated to 40 ° C. To this, a methanol solution of 18 g of iodine was dropped and reacted for 40 minutes. To this, 4N KOH methanol solution was added until no iodine coloration occurred. The precipitate was collected by filtration, washed several times with cold methanol, washed with ether, and once weighed. Thereafter, the obtained crystals were dissolved in a very small amount of water and applied to a proton-type ion exchange resin of Amberlite 120B, and the acidic fraction was isolated. Methanol and ethanol were added to the obtained aqueous solution for evaporation. After complete drying, methanol and ethanol were added again to dissolve and evaporate. This operation was repeated several times to produce lactose lactone.
適量のナスフラスコ中で、前記ラクトースラクトン １kgをメタノール５．４Lに７０℃で溶解したのち、これにビニルベンジルアミン ０．４kgを加え、１２０分、７０℃で反応させた。反応終了後、２１．７Lのアセトンを加えて、ＶＬＡを沈殿させた、これを４℃で数時間放置したのち濾取し、沈殿をメタノールから再結晶した。収量は、１．１kgであった。 In an appropriate amount of eggplant flask, 1 kg of the above lactose lactone was dissolved in 5.4 L of methanol at 70 ° C., 0.4 kg of vinylbenzylamine was added thereto, and reacted at 70 ° C. for 120 minutes. After completion of the reaction, 21.7 L of acetone was added to precipitate VLA. This was allowed to stand at 4 ° C. for several hours and then collected by filtration. The precipitate was recrystallized from methanol. The yield was 1.1 kg.
次にもう一方のモノマーであるビニルベンジルヘキサデカンアミド（ＶＡＬ）の合成を示す。上記で得られたビニルベンジルアミン１０gを無水クロロフォルム１５０mlに溶解し、ピリジン７gを加えて、冷却した後、パルミトイルクロリド２４gを溶解した無水クロロフォルム５０mlを滴下漏斗より３０分間かけて滴下した。反応終了後、クロロフォルム溶液を水で洗浄した後、乾燥させ、溶媒を減圧留去した。残さをエタノールから再結晶して、ＶＡＬ２０gを得た。 Next, synthesis of another monomer, vinylbenzylhexadecanamide (VAL), is shown. 10 g of vinylbenzylamine obtained above was dissolved in 150 ml of anhydrous chloroform, 7 g of pyridine was added and cooled, and then 50 ml of anhydrous chloroform in which 24 g of palmitoyl chloride was dissolved was added dropwise over 30 minutes from the dropping funnel. After completion of the reaction, the chloroform solution was washed with water and then dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 20 g of VAL.
ポリマーの合成のために、ＶＬＡとＶＡＬをモル比９：１、８：２，７：３等の割合で秤量し、真空反応管に分注した。ＤＭＳＯあるいはＤＭＳＯ−トルエンの混合溶媒を加えて完全に溶解した後、凍結−脱気−融解を繰り返して、酸素を溶液中から取り除いた。これに１００分の１モルのアゾイソブチロニトリル（ＡＩＢＮ）を添加して、溶解したのち、減圧密閉した。６０℃で５時間反応させてポリマーを合成した。 For polymer synthesis, VLA and VAL were weighed at a molar ratio of 9: 1, 8: 2, 7: 3, etc., and dispensed into a vacuum reaction tube. After DMSO or a mixed solvent of DMSO-toluene was added and completely dissolved, freeze-deaeration-thawing was repeated to remove oxygen from the solution. To this, 1/100 mol of azoisobutyronitrile (AIBN) was added and dissolved, and then sealed under reduced pressure. The polymer was synthesized by reacting at 60 ° C. for 5 hours.
得られた溶液を大過剰のメタノールに滴下して、ポリマーを沈澱させた。これを適当な溶媒に溶解し、再びメタノールに滴下してポリマーを沈澱させる操作を３回繰り返した。 The resulting solution was added dropwise to a large excess of methanol to precipitate the polymer. The operation of dissolving this in an appropriate solvent and dropping it again into methanol to precipitate the polymer was repeated three times.
最終的に得られたポリマーを蒸留水に溶解し、大過剰の水に対して透析した。その後、凍結乾燥により目的のポリマーを得た。 The finally obtained polymer was dissolved in distilled water and dialyzed against a large excess of water. Then, the target polymer was obtained by freeze-drying.
上記で調製したＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１）のポリスチレン板に対するコーティング性を従来のＰＶＬＡと比較した。 The coating properties of the VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1) prepared above on polystyrene plates were compared with conventional PVLA.
媒体として７０％（v/v）エタノール水溶液を用いコーティング用溶液を調製した。コーティング用溶液の濃度は、両者ともに０．３mg/mlとした。 A coating solution was prepared using 70% (v / v) aqueous ethanol as a medium. The concentration of the coating solution was 0.3 mg / ml in both cases.
ポリスチレン板上８８４（mm2）にコーティング溶液５０μLを均一に塗布し、コーティング溶液のポリスチレン板上における挙動を経時的に観察した。 50 μL of the coating solution was uniformly applied to 884 (mm 2 ) on the polystyrene plate, and the behavior of the coating solution on the polystyrene plate was observed over time.
ＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１）溶液では、６分３０秒後においても溶液は、ポリスチレン板状に均一に広がっていた。これに対して、ＰＶＬＡ溶液は、約３０秒後から分布が不均一となり、２分３０秒後には、ポリスチレン板上に水滴状に散在していた。 In the VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1) solution, the solution spread evenly in a polystyrene plate shape even after 6 minutes and 30 seconds. On the other hand, the distribution of the PVLA solution was uneven after about 30 seconds, and after 2 minutes and 30 seconds, the PVLA solution was scattered in the form of water droplets on the polystyrene plate.
また、処理後のポリスチレン板を風乾し、これに水を滴下したところ、ＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１）溶液処理では、均一に水が拡がったのに対し、ＰＶＬＡ溶液処理では、ＰＶＬＡ溶液が局在した部分にのみ水が局在した。 Moreover, when the polystyrene plate after the treatment was air-dried and water was added dropwise thereto, in the VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1) solution treatment, the water spread uniformly. In the PVLA solution treatment, water was localized only in the portion where the PVLA solution was localized.
これらの結果から、ＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１）溶液は、ＰＶＬＡに比べて優れたコーティング性を有していることが明らかとなった。 From these results, it became clear that the VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1) solution has a coating property superior to that of PVLA.
平均直径２０７μmのガラスビーズに、医療用軟質ポリ塩化ビニル樹脂（以下ＰＶＣ）の０．３％（w/v）テトラヒドロフラン溶液を用いＰＶＣをコーティングした後、ＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１および８：２）の９５％（vol.）メタノール水溶液を用い更にコーティング行なった。純水で充分リンスののち乾燥させ、内径２．１mmのテフロンチューブ内に細密充填し血小板粘着評価用カラムとした（図１）。 A glass bead having an average diameter of 207 μm was coated with PVC using a 0.3% (w / v) tetrahydrofuran solution of soft polyvinyl chloride resin (hereinafter PVC) for medical use, and then VLA-co-vinylbenzylhexadecanamide (copolymerization). Further coating was performed using a 95% (vol.) Aqueous methanol solution in a ratio = 9: 1 and 8: 2). After thoroughly rinsing with pure water, it was dried and packed finely in a Teflon tube having an inner diameter of 2.1 mm to obtain a platelet adhesion evaluation column (FIG. 1).
比較対照とし、未コートビーズ（ＰＶＣコーティングのみ）、ＰＶＬＡコーティングビーズ、市場流通品と同等のヘパリン化合物コーティングビーズを用い同様のカラムを作製した。 As a comparative control, similar columns were prepared using uncoated beads (PVC coating only), PVLA coated beads, and heparin compound coated beads equivalent to those on the market.
これらカラムに生理食塩水を充填後、３．８（ＩＵ／mL）の濃度となるように前もってヘパリンナトリウムを入れたシリンジを用い、家兎心臓直接穿刺による採血を行った。直ちにペリスターポンプを用いて毎分１mLの流速で上記カラムへ送血し、カラム入口側と出口側の血液サンプリングを行い、両血液中の血小板数を微粒子カウンターで測定した。両血小板数より血小板流出率（％）（出口側血小板数／入口側血小板数×１００）を求めた。結果を表１に示す。 After these columns were filled with physiological saline, blood was collected by direct puncture of the rabbit heart using a syringe containing heparin sodium in advance so as to obtain a concentration of 3.8 (IU / mL). Immediately using a peristaltic pump, blood was sent to the column at a flow rate of 1 mL per minute, blood sampling was performed on the inlet and outlet sides of the column, and the number of platelets in both blood was measured with a fine particle counter. Platelet outflow rate (%) (exit side platelet count / inlet side platelet count × 100) was determined from both platelet counts. The results are shown in Table 1.
表１中、9:1及び8:2は、それぞれ、共重合比率が、９：１及び８：２のＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミドを表す。また、Hepは、ヘパリンを表す。 In Table 1, 9: 1 and 8: 2 represent VLA-co-vinylbenzylhexadecanamide having a copolymerization ratio of 9: 1 and 8: 2, respectively. Hep represents heparin.
本発明によれば、ＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１および８：２）を用いることにより、既知のＰＶＬＡや既存のヘパリン化合物より優れた血液適合性表面を得ることができる。 According to the present invention, by using VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1 and 8: 2), a blood compatible surface superior to known PVLA and existing heparin compounds is obtained. Can do.
また別基材として平均直径１９９（μm）のステンレスビーズにＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１）のメタノール水溶液を用いコーティングし同様の評価を行った結果を表２に示す。 In addition, Table 2 shows the results of coating the stainless steel beads having an average diameter of 199 (μm) with a methanol aqueous solution of VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1) as another base material and conducting the same evaluation. Show.
本発明によればＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１）を用いることにより、ステンレス表面の血液適合性を著しく高めることができる。 According to the present invention, by using VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1), blood compatibility on the stainless steel surface can be remarkably enhanced.
また、別基材として１，２−ポリブタジエンの０．３％（w/v）シクロヘキサン溶液によりコーティングを行なった上記ガラスビーズへＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝６：４）のジメチルスルホキシド（ＤＭＳＯ）０．５％（ｗｔ．／ｖｏｌ．）溶液を用い更にコーティングを行なった後、５Wの紫外線照射を行なった試料の評価結果を下記表３に示す。 In addition, VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 6: 4) was applied to the glass beads coated with a 0.3% (w / v) cyclohexane solution of 1,2-polybutadiene as another substrate. Table 3 below shows the evaluation results of samples subjected to 5 W ultraviolet irradiation after further coating with a dimethyl sulfoxide (DMSO) 0.5% (wt./vol.) Solution.
本発明によればＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝６：４）を用いることにより、ポリブタジエン表面の血液適合性を著しく高めることができる。 According to the present invention, the blood compatibility of the polybutadiene surface can be remarkably enhanced by using VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 6: 4).
更に別基材として、ポリウレタンの０．３％（w/v）テトラヒドロフラン溶液によりコーティングを行なった上記ガラスビーズへＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１及び８：２）の９５％（vol.）メタノール水溶液、および共重合比率＝６：４の９５％（vol.）1−プロパノール水溶液を用い更にコーティングを行なった試料の評価結果を表４に示す。 Further, as another substrate, VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1 and 8: 2) was applied to the glass beads coated with a 0.3% (w / v) tetrahydrofuran solution of polyurethane. Table 4 shows the evaluation results of samples further coated with a 95% (vol.) Aqueous methanol solution and a 95% (vol.) 1-propanol aqueous solution having a copolymerization ratio of 6: 4.
本発明によればＶＬＡ−ｃｏ−ビニルベンジルヘキサデカンアミド（共重合比率＝９：１〜６：４）を用いることにより、ポリウレタン表面の血液適合性を著しく高めることができる。 According to the present invention, the blood compatibility of the polyurethane surface can be remarkably enhanced by using VLA-co-vinylbenzylhexadecanamide (copolymerization ratio = 9: 1 to 6: 4).
本発明の共重合物は、血小板の活性化を抑制し、血栓形成を効果的に予防することができる。また、血液と接触する可能性がある医療用器具の血液接触面の少なくとも一部を本発明の共重合物で処理することによって、当該医療用器具の使用による血栓形成を防止することができる。 The copolymer of the present invention can inhibit platelet activation and effectively prevent thrombus formation. In addition, by treating at least part of the blood contact surface of a medical device that may come into contact with blood with the copolymer of the present invention, thrombus formation due to the use of the medical device can be prevented.
Claims (4)
（式中、ｍ：ｎ＝９：１〜１：９であり、ｘは、６〜１８である。）
で表される共重合物。 Following formula:
(In the formula, m: n = 9: 1 to 1: 9, and x is 6 to 18.)
A copolymer represented by
A medical device, wherein at least a part of the surface is treated with the copolymer according to claim 1.
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| JPH08253495A (en) * | 1995-03-17 | 1996-10-01 | Kanagawa Kagaku Gijutsu Akad | Mannose structure-containing styrene derivative and polystyrene derivative and their production |
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