JP2004008628A - Manufacturing method for medical appliance - Google Patents
Manufacturing method for medical appliance Download PDFInfo
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- JP2004008628A JP2004008628A JP2002168385A JP2002168385A JP2004008628A JP 2004008628 A JP2004008628 A JP 2004008628A JP 2002168385 A JP2002168385 A JP 2002168385A JP 2002168385 A JP2002168385 A JP 2002168385A JP 2004008628 A JP2004008628 A JP 2004008628A
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Description
【0001】
【発明の属する技術分野】
本発明は、例えばカテーテルなど医療用具の表面において、抗血栓性の被膜を有する医療用具の製造方法に関するものである。
【0002】
【従来の技術】
医療用具技術の発展に伴って、その医療用具自体の用途は多様化しており、人工血管、カテーテル、人工心臓および人工弁など直接血液に接する部位に使用した医療用具は、血液にとって異物であるため血液凝固反応が起こり、最終的に血栓塊が形成される。この血栓形成によって、病気の治療や診断という本来の目的が果たせなくなることがあるとともに、かえって新たな合併症を作り出し、場合によっては血栓が原因で死に至ることもある。よって、医療用具に対して優れた抗血栓性も要求されている。
【0003】
このような抗血栓性を有する主な生理活性物質としては、▲1▼ヘパリン等の血液凝固因子の活性を抑制するもの、▲2▼プロスタグランジン等の血小板の活性化を抑制するもの、▲3▼ウロキナーゼ等の血栓(フィブリン塊)を溶解するものなどがあり、中でも上記▲3▼の生理活性物質は抗血栓性に非常に優れていることから、ウロキナーゼ等を用いた医療用具が提案、開発されており、その一例として、例えば特開昭63−98384号公報に開示された発明がある。
【0004】
特開昭63−98384号公報に開示された酵素の固定化方法は、ポリウレタン表面を50〜100℃の熱水で処理した後、メチルビニルエーテル無水マレイン酸共重合体で処理し、ウロキナーゼなどを含む線維素溶解活性酵素溶液を接触させて線維素溶解活性酵素(生理活性物質の一つ)を化学結合させることにより、ポリウレタン表面に線維素溶解活性(抗血栓性)を付与する方法である。
【0005】
【発明が解決しようとする課題】
上記のような従来の方法により得られた医療用具は、ポリウレタンからなる基材表面にメチルビニルエーテル無水マレイン酸共重合体を被覆し、その被覆された膜に共有結合により線維素溶解活性酵素を固定させている。しかしながら、メチルビニルエーテル無水マレイン酸共重合体からなる被膜と基材表面との密着性が弱いため、基材表面からメチルビニルエーテル無水マレイン酸共重合体からなる被膜が剥がれやすく、被膜と強固に固定されている線維素溶解活性酵素も被膜とともに剥がれてしまう。このため、基材表面から線維素溶解活性、つまり抗血栓性がなくなってしまうこととなり、上記のような医療用具は抗血栓性を維持でないという問題があった。また、剥がれた被膜は例えば血液中に溶出することになり、この血液中の被膜がかえって血液凝固を誘起するあるいは促進させる原因となってしまうおそれがあった。
【0006】
本発明は、上記のような課題を解決するためになされたもので、抗血栓性を発現する被膜の基材への密着性を向上させ、その抗血栓性を長く維持することのできる医療用具の製造方法を提供することを目的としたものである。
【0007】
【課題を解決するための手段】
本発明に係る医療用具の製造方法は、合成樹脂からなる医療用具の基材表面に、メチルビニルエーテル無水マレイン酸共重合体とポリエーテルブロックアミドとを有機溶媒に溶解した被覆用混合溶液を塗布した後、室温から80℃の範囲内の乾燥温度で乾燥処理して被膜を形成し、さらに線維素溶解活性酵素を含む溶液に浸漬して乾燥し、被膜に線維素溶解活性酵素を含ませる方法である。
【0008】
本発明に係る医療用具の製造方法は、メチルビニルエーテル無水マレイン酸共重合体をポリエーテルブロックアミドにより基材に密着させ、線維素溶解活性酵素を共有結合により被膜に固定化する方法である。
【0009】
本発明に係る医療用具の製造方法は、線維素溶解活性酵素をウロキナーゼとする方法である。
【0010】
本発明に係る医療用具の製造方法は、基材を構成する合成樹脂を、ポリウレタン、ポリ塩化ビニル、ナイロンまたはナイロンエラストマーとする方法である。
【0011】
【発明の実施の形態】
本発明に係る製造方法による医療用具は、合成樹脂からなる基材をメチルビニルエーテル無水マレイン酸共重合体とポリエーテルブロックアミドとを有機溶媒に溶解した被覆用混合溶液に浸漬して熱処理することにより、基材表面に被膜を形成し、その後、線維素溶解活性酵素を含む溶液に浸漬することにより、被膜中に線維素溶解活性酵素を化学的に結合させて取り込む。そして、この被膜は、抗血栓性を有して、線維素溶解活性酵素の活性を長く維持する。
【0012】
このような被膜を形成するための被覆用混合溶液および被膜を有する医療用具の製造方法は、以下の通りである。
(1)メチルビニルエーテル無水マレイン酸共重合体とポリエーテルブロックアミドとを、有機溶媒であるテトラヒドロフラン(以下、THFと記す)、アセトンあるいはそれらの混合液に溶解し、被覆用混合溶液を作製する。
(2)ポリウレタン、ポリ塩化ビニル、ナイロンまたはナイロンエラストマーの合成樹脂からなる基材の表面に、浸漬法により、被覆用混合溶液を塗布する。
(3)塗布した基材を室温から80℃の範囲内の乾燥温度で乾燥処理して溶媒を除去し、基材表面にポリエーテルブロックアミド中にメチルビニルエーテル無水マレイン酸を取り込んだポリマーアロイの被膜を形成する。
(4)その後、線維素溶解活性酵素であるウロキナーゼを含む生理食塩水に浸漬し、蒸留水で洗浄した後乾燥し、ウロキナーゼが化学的に結合(共有結合)した被膜を形成する。
【0013】
こうして得られた医療用具の被膜の抗血栓性およびその持続性について、以下に実施例を用いて説明する。
【0014】
【実施例】
[実施例1]
メチルビニルエーテル無水マレイン酸共重合体(商品名:Gantrez AN−169、ISP(INTERNATIONAL SPECIALTY PRODUCTS)社製)2%アセトン溶液と、ポリエーテルブロックアミド(商品名:Pebax 2533SA、ATOCHEM社製)2%THF溶液とを1.5:1の割合で混合した被覆用混合溶液を作製し、基材をこの被覆用混合溶液中に浸漬し、引き上げ後乾燥温度80℃で3時間乾燥し、ウロキナーゼ(持田製薬社製)を600単位/ml含む酸性生理食塩水(pH=4.6)に7℃で24時間浸漬し、引き上げ後蒸留水にて洗浄し、室温にて12時間真空乾燥させて基材表面に被膜を形成した。
なお、基材は、直径が16Gで全長が70cmのポリウレタンからなるチューブとした。
そして、表面(外周面および内腔面)に被膜が形成されたチューブに対して次のような抗血栓の持続性試験を行った。その結果を表1に示す。
【0015】
[抗血栓持続性試験]
37℃温風下でポンプを利用し、一定流速(50ml/h)でチューブの内腔に生理食塩水を24時間流して内腔面の被膜をリンスし、蒸留水10mlを流したチューブと、上記のようなリンスを行わないチューブとの各内腔に、室温にて人全血をそれぞれ封入し、所定時間毎(表1参照)に血液封入側からチューブを約2cmずつ切断し、切断したチューブの内腔の血液を生理食塩水で押し出した後、内腔の血液凝固の状態を目視により観察するとともに、内腔に血栓が形成される時間、クロッティングタイム(hr)を検出し、被膜の抗血栓持続性について調べた。血液凝固の状態は、−,+〜++++の5段階とし、+の数で形成される血栓の程度を示した(+<<++++)。
【0016】
【表1】
【0017】
なお、比較例1および比較例2は次の通りであり、比較例2は、基材の表面にいずれの被膜も形成されていないものとする。
【0018】
[比較例1]
前記従来の技術であげた特開昭63−98384号公報に開示された酵素の固定化方法を用いたもので、例えば基材(ポリウレタン)を65℃の蒸留水に24時間浸漬、真空乾燥した後、メチルビニルエーテル無水マレイン酸共重合体の4wt%水溶液脱水アセトン溶液中に基材を入れて室温下で1時間静置し、引き上げ後アセトンで十分洗浄をし、真空乾燥によりアセトンを除去した。この基材をウロキナーゼを600単位/ml含む酸性生理食塩水(pH=4.6)に7℃で24時間静置した後、生理食塩水で洗浄し、基材表面に被膜を形成した。そして、実施例1と同様に抗血栓持続性試験を行った。
【0019】
表1からわかるように、実施例1は、リンスした場合でも22時間以上血液が凝固しなかった。これに対して、比較例1および比較例2は、2〜3時間以上で確実に血液が凝固し、比較例1のリンスしたものにおいては、0.5〜0.75時間と早くから血液が凝固した。これは、リンスなしのものがウロキナーゼにより8時間経過したときに一旦凝固した血液を溶解させたものの、リンスしたものは凝固した血液を溶解させることもなかったことから、リンスしたことによってウロキナーゼの活性が低下したためと考えられる。そして、比較例1は被膜が形成されていない比較例2よりも早く血液の凝固が始まっていることから、比較例1の基材と被膜との密着性が弱く、このために被膜が血液中に溶出して血液の凝固を誘起しあるいは促進させているものと考えられる。
【0020】
よって、実施例1は、基材と被膜との密着性が強く、その被膜に化学的に結合されたウロキナーゼにより、抗血栓性が長時間持続されるものであると言える。これは、被膜の固定にポリエーテルブロックアミドを用い、その被膜にウロキナーゼを結合させたためであり、このことによって、基材への密着性および抗血栓持続性を有する被膜が得られる。また、この被膜は、低温加熱処理で簡単な処理工程によって形成することができ、カテーテル等を含む各種の基材に対しても形成可能な製造方法である。
【0021】
なお、上述の実施例1では基材をポリウレタンで構成した場合を示したが、ポリ塩化ビニル、ナイロンあるいはナイロンエラストマーで構成してもよい。これらの場合も同様の効果を奏する。
【0022】
【発明の効果】
以上のように本発明に係る医療用具の製造方法は、合成樹脂からなる医療用具の基材表面に、メチルビニルエーテル無水マレイン酸共重合体とポリエーテルブロックアミドとを有機溶媒に溶解した被覆用混合溶液を塗布した後、室温から80℃の範囲内の乾燥温度で乾燥処理して被膜を形成し、さらに線維素溶解活性酵素を含む溶液に浸漬して乾燥し、被膜に線維素溶解活性酵素を含ませる方法であるので、被膜の基材への密着性を向上させることができ、その被膜に含まれる線維素溶解活性酵素による抗血栓性を長時間持続させることができる。また、被膜の基材への密着性が高いため、基材から被膜が剥離するのを防ぐことができ、剥離による血液凝固のおそれをなくすことができる。さらに、抗血栓性を発現する被膜を有する医療用具を簡単な処理工程で形成することができるとともに、高温処理では変形してしまうカテーテル等の各種の医療用具に対しても適用することができ、実際の大量生産製品への適用が可能である。
【0023】
本発明に係る医療用具の製造方法は、メチルビニルエーテル無水マレイン酸共重合体をポリエーテルブロックアミドにより基材に密着させ、線維素溶解活性酵素を共有結合により被膜に固定化する方法であるので、密着性の高い被膜が線維素溶解活性酵素を基材表面に保持することを可能にし、抗血栓性を長く維持することができる。
【0024】
本発明に係る医療用具の製造方法は、線維素溶解活性酵素をウロキナーゼとする方法であるので、抗血栓性が非常に優れた被膜を有する医療用具を簡単な処理工程で安定的に形成することができる。
【0025】
本発明に係る医療用具の製造方法は、基材を構成する合成樹脂を、ポリウレタン、ポリ塩化ビニル、ナイロンまたはナイロンエラストマーとしたので、ポリエーテルブロックアミドとの親和性が得られ、被膜の基材への密着性を高めることができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for manufacturing a medical device having an antithrombotic coating on the surface of a medical device such as a catheter.
[0002]
[Prior art]
With the development of medical device technology, the applications of the medical device itself are diversifying, and medical devices used for parts that directly contact blood such as artificial blood vessels, catheters, artificial hearts and artificial valves are foreign substances to blood. A blood clotting reaction takes place, eventually forming a thrombus clot. This thrombus formation may not fulfill its intended purpose of treating or diagnosing the disease, but may also create new complications, and in some cases may result in death due to thrombus. Therefore, medical devices are also required to have excellent antithrombotic properties.
[0003]
The main physiologically active substances having such antithrombotic properties include (1) those that inhibit the activity of blood coagulation factors such as heparin, (2) those that inhibit the activation of platelets such as prostaglandin, and 3) There are substances that dissolve thrombus (fibrin clots) such as urokinase. Above all, since the physiologically active substance of the above (3) is extremely excellent in antithrombotic properties, medical devices using urokinase and the like have been proposed. One example is the invention disclosed in JP-A-63-98384.
[0004]
The method for immobilizing an enzyme disclosed in JP-A-63-98384 is to treat a polyurethane surface with hot water at 50 to 100 ° C., then treat with a methyl vinyl ether maleic anhydride copolymer, and include urokinase and the like. This is a method of imparting fibrinolytic activity (antithrombotic) to the polyurethane surface by contacting a fibrinolytic active enzyme solution to chemically bond fibrinolytic active enzyme (one of the physiologically active substances).
[0005]
[Problems to be solved by the invention]
The medical device obtained by the conventional method as described above coats a base material made of polyurethane with a methylvinyl ether-maleic anhydride copolymer, and immobilizes a fibrinolytic active enzyme to the coated membrane by covalent bonding. Let me. However, since the adhesion between the film made of the methyl vinyl ether maleic anhydride copolymer and the substrate surface is weak, the film made of the methyl vinyl ether maleic anhydride copolymer is easily peeled off from the substrate surface, and is firmly fixed to the film. The active fibrinolytic enzyme is also peeled off with the coating. Therefore, the fibrinolytic activity, that is, the antithrombotic property is lost from the surface of the base material, and there is a problem that the medical device as described above does not maintain the antithrombotic property. In addition, the peeled film is eluted in blood, for example, and the film in blood may instead induce or promote blood coagulation.
[0006]
The present invention has been made in order to solve the above-described problems, and is a medical device capable of improving the adhesion of a film exhibiting antithrombotic properties to a substrate and maintaining the antithrombotic properties for a long time. It is an object of the present invention to provide a production method of
[0007]
[Means for Solving the Problems]
In the method for manufacturing a medical device according to the present invention, a coating mixed solution obtained by dissolving a methyl vinyl ether maleic anhydride copolymer and a polyether block amide in an organic solvent is applied to the surface of a medical device device made of a synthetic resin. Thereafter, a film is formed by drying at a drying temperature in the range of room temperature to 80 ° C., and further immersed in a solution containing fibrinolytically active enzyme and dried, and the film is coated with fibrinolytically active enzyme. is there.
[0008]
The method for producing a medical device according to the present invention is a method in which a methyl vinyl ether / maleic anhydride copolymer is closely adhered to a substrate with a polyether block amide, and a fibrinolytic active enzyme is immobilized on the coating by a covalent bond.
[0009]
The method for producing a medical device according to the present invention is a method using urokinase as a fibrinolytic active enzyme.
[0010]
The method for producing a medical device according to the present invention is a method in which the synthetic resin constituting the base material is polyurethane, polyvinyl chloride, nylon, or a nylon elastomer.
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
The medical device according to the manufacturing method according to the present invention, by immersing a base material made of a synthetic resin in a coating mixed solution obtained by dissolving a methyl vinyl ether maleic anhydride copolymer and a polyether block amide in an organic solvent, and performing heat treatment. Then, a film is formed on the surface of the base material, and thereafter the fibrinolytically active enzyme is chemically bound and taken into the film by dipping in a solution containing fibrinolytically active enzyme. This coating has antithrombotic properties and maintains the activity of the fibrinolytically active enzyme for a long time.
[0012]
A method for producing a coating mixed solution for forming such a coating and a medical device having the coating is as follows.
(1) A methyl vinyl ether maleic anhydride copolymer and a polyether block amide are dissolved in an organic solvent, tetrahydrofuran (hereinafter, referred to as THF), acetone, or a mixture thereof to prepare a mixed solution for coating.
(2) A coating solution is applied to the surface of a substrate made of a synthetic resin of polyurethane, polyvinyl chloride, nylon or nylon elastomer by a dipping method.
(3) The applied base material is dried at a drying temperature in the range of room temperature to 80 ° C. to remove the solvent, and the surface of the base material is coated with a polymer alloy in which methyl vinyl ether maleic anhydride is incorporated into polyether block amide. To form
(4) Then, it is immersed in a physiological saline solution containing urokinase, which is a fibrinolytic active enzyme, washed with distilled water, and dried to form a film to which urokinase is chemically bonded (covalently bonded).
[0013]
The antithrombotic properties of the coating of the medical device thus obtained and its durability are described below using examples.
[0014]
【Example】
[Example 1]
Methyl vinyl ether maleic anhydride copolymer (trade name: Gantrez AN-169, manufactured by ISP (INTERNATIONAL SPECIALTY PRODUCTS)) 2% acetone solution and polyether block amide (trade name: Pebax 2533SA, manufactured by ATOCHEM) 2% THF A solution for coating was prepared by mixing the solution with the solution at a ratio of 1.5: 1, the substrate was immersed in the solution for coating, pulled up, dried at a drying temperature of 80 ° C. for 3 hours, and then urokinase (Mochida Pharmaceutical Co., Ltd.) (Manufactured by K.K.) at 600 ° C. for 24 hours at 7 ° C., washed with distilled water, vacuum-dried at room temperature for 12 hours, and dried. A film was formed on the substrate.
The base material was a tube made of polyurethane having a diameter of 16 G and a total length of 70 cm.
Then, the following antithrombotic persistence test was performed on a tube having a coating formed on the surface (outer peripheral surface and lumen surface). Table 1 shows the results.
[0015]
[Anti-thrombotic persistence test]
Using a pump under warm air at 37 ° C., a saline solution was allowed to flow through the lumen of the tube at a constant flow rate (50 ml / h) for 24 hours to rinse the coating on the inner surface of the tube, and the tube was flushed with 10 ml of distilled water. The human whole blood is sealed at room temperature in each lumen with a tube not rinsed as described above, and the tube is cut by about 2 cm from the blood sealing side at predetermined time intervals (see Table 1). After the blood in the lumen was extruded with physiological saline, the state of blood coagulation in the lumen was visually observed, and the time during which a thrombus was formed in the lumen and the clotting time (hr) were detected. The antithrombotic persistence was examined. The state of blood coagulation was made into five stages of-, + to +++, and the number of + indicated the degree of thrombus formed (+ << ++++).
[0016]
[Table 1]
[0017]
In addition, Comparative Example 1 and Comparative Example 2 are as follows, and Comparative Example 2 assumes that no coating is formed on the surface of the base material.
[0018]
[Comparative Example 1]
A method using the enzyme immobilization method disclosed in Japanese Patent Application Laid-Open No. 63-98384 described in the above prior art, for example, a substrate (polyurethane) was immersed in distilled water at 65 ° C. for 24 hours and vacuum dried. Thereafter, the base material was placed in a 4 wt% aqueous solution of methyl vinyl ether maleic anhydride copolymer in dehydrated acetone, allowed to stand at room temperature for 1 hour, pulled up, sufficiently washed with acetone, and vacuum-dried to remove acetone. This substrate was allowed to stand at 7 ° C. for 24 hours in an acidic physiological saline solution (pH = 4.6) containing urokinase at 600 units / ml, and then washed with physiological saline to form a film on the surface of the substrate. Then, an antithrombotic persistence test was performed in the same manner as in Example 1.
[0019]
As can be seen from Table 1, in Example 1, blood did not coagulate for 22 hours or more even when rinsed. On the other hand, in Comparative Example 1 and Comparative Example 2, blood clotted reliably in 2 to 3 hours or more, and in the rinsed product of Comparative Example 1, blood clotted as early as 0.5 to 0.75 hour. did. This was because rinsing did not lyse coagulated blood, although rinsing did not lyse coagulated blood after 8 hours had passed with urokinase without rinsing. It is considered that this has decreased. Since blood coagulation started earlier in Comparative Example 1 than in Comparative Example 2 in which no film was formed, the adhesion between the substrate of Comparative Example 1 and the film was weak. To induce or promote blood coagulation.
[0020]
Therefore, in Example 1, it can be said that the adhesion between the substrate and the coating is strong, and the antithrombotic property is maintained for a long time by urokinase chemically bonded to the coating. This is because polyether block amide was used to fix the coating and urokinase was bound to the coating, whereby a coating having adhesion to the substrate and antithrombotic persistence was obtained. Further, this film can be formed by a simple processing step by a low-temperature heat treatment, and is a manufacturing method that can be formed on various base materials including a catheter and the like.
[0021]
In the first embodiment, the base material is made of polyurethane, but may be made of polyvinyl chloride, nylon or nylon elastomer. In these cases, a similar effect is obtained.
[0022]
【The invention's effect】
As described above, the method for producing a medical device according to the present invention is a method for coating a medical device made of a synthetic resin, in which a methyl vinyl ether maleic anhydride copolymer and a polyether block amide are dissolved in an organic solvent. After applying the solution, a drying treatment is performed at a drying temperature in the range of room temperature to 80 ° C. to form a film, and the film is further immersed in a solution containing fibrinolytically active enzyme and dried. Since it is a method of including the coating, the adhesion of the coating to the substrate can be improved, and the antithrombotic effect of the fibrinolytically active enzyme contained in the coating can be maintained for a long time. In addition, since the adhesion of the coating to the substrate is high, it is possible to prevent the coating from peeling off from the substrate, and to eliminate the risk of blood coagulation due to the peeling. Furthermore, a medical device having a coating exhibiting antithrombotic properties can be formed in a simple processing step, and can be applied to various medical devices such as catheters that are deformed by high-temperature treatment, It can be applied to actual mass-produced products.
[0023]
The method for producing a medical device according to the present invention is a method in which a methyl vinyl ether maleic anhydride copolymer is adhered to a substrate with a polyether block amide, and a fibrinolytic active enzyme is immobilized on a coating film by a covalent bond. The highly adherent coating enables the fibrinolytically active enzyme to be retained on the surface of the substrate, and the antithrombotic properties can be maintained for a long time.
[0024]
Since the method for producing a medical device according to the present invention uses urokinase as a fibrinolytic active enzyme, it is possible to stably form a medical device having a coating with extremely excellent antithrombotic properties in a simple processing step. Can be.
[0025]
In the method for producing a medical device according to the present invention, since the synthetic resin constituting the base material is made of polyurethane, polyvinyl chloride, nylon or nylon elastomer, affinity for polyether block amide is obtained, and the base material of the coating film is obtained. Adhesion to the substrate can be improved.
Claims (4)
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Cited By (2)
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US9681833B2 (en) | 2014-04-18 | 2017-06-20 | Tekni-Plex, Inc. | Coextruded plastic capillary tube |
CN115975238A (en) * | 2023-02-10 | 2023-04-18 | 中南大学湘雅医院 | Ethylene diamine tetraacetic acid modified membrane type artificial organ material and preparation method thereof |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US9681833B2 (en) | 2014-04-18 | 2017-06-20 | Tekni-Plex, Inc. | Coextruded plastic capillary tube |
CN115975238A (en) * | 2023-02-10 | 2023-04-18 | 中南大学湘雅医院 | Ethylene diamine tetraacetic acid modified membrane type artificial organ material and preparation method thereof |
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