JPH10295824A - 薬剤入り多孔性金属人工器官の製造方法 - Google Patents
薬剤入り多孔性金属人工器官の製造方法Info
- Publication number
- JPH10295824A JPH10295824A JP10519498A JP10519498A JPH10295824A JP H10295824 A JPH10295824 A JP H10295824A JP 10519498 A JP10519498 A JP 10519498A JP 10519498 A JP10519498 A JP 10519498A JP H10295824 A JPH10295824 A JP H10295824A
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- stent
- therapeutic agent
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- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- 238000005496 tempering Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
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Abstract
造方法である。 【解決手段】 この方法は、ステント(12)を多孔性
金属の外に形成し、治療用薬剤を金属の孔(18)に入
れることからなる。1つの実施形態では、ステントは焼
結金属ワイヤ(30)、シート(64)又はチューブか
ら形成され、且つ被覆(100)をステントに付加する
ことを含むことができる。ステントを患者の血管系に移
植するときには、ステント内の治療薬剤は、ステントに
近位の血管系の組織へ消散する。
Description
り人工器官又は移植組織に関する。更に詳細には、本発
明は、患者の血管系内で半径方向に拡張でき且つ治療薬
剤を移植部位に投与するステントのような薬剤入り血管
内人口器官に関する。
トは、血管又は他の解剖学的構造の管腔の部分を開いた
ままにし、そしてしばしばこれを拡張するように機能す
るほぼ円筒形の人工器官の移植組織である。それらは、
裂かれた或いは傷つけられた動脈の内張りを支持し、こ
れが流体通路を閉塞するのを防止するのに特に適してい
る。血管内ステントは、冠状動脈狭窄の治療及びバルー
ン式血管形成後の再狭窄や閉鎖の発達の可能性を減少さ
せるためにますます使用されている。ステントの成功
を、血栓症、ステントの移植に続く新内壁増殖、平滑筋
細胞移動及び増殖、動脈壁損傷、管腔開通性の全損失、
血管内のステント径、ステント厚み、及びステント付き
動脈の管腔の内張りへの白血球付着のような数多くの要
因を評価することによって査定できる。しかしながら、
関心のある主な領域は早期亜急性血栓症及び内壁増殖に
よる血管の起こりうる再狭窄症である。
結果の配置を改善するように開発され、薬剤はステント
移植部位に投与される。以前は、普通の金属構造を有す
るステントは、局所的治療用の薬物学的な薬剤を、ステ
ントで治療すべき位置で血管に投与することができなか
った。薬或いは、次いで、薬剤を薬の投与のために放出
することができる他の薬物学的治療物を含む治療薬剤を
入れることができるポリマー材料がある。しかしなが
ら、特にポリマー材料に薬剤を入れる場合に、ポリマー
材料の薬の装入はポリマー材料の構造的及び機械的特性
を顕著に減少させるので、これらのポリマー材料はステ
ントの構造的及び機械的要求を満たすことはできない。
金属ステントをポリマー材料で被覆し、ポリマー材料に
薬剤を入れることは当該技術で知られてきた。変形例と
して、ポリマー材料のステントが金属構造で補強されて
きた。これらのステント設計は、金属によってもたらさ
れた補強なので、管腔を開いたままにするのに必要な強
度を有する。ポリマー材料及び金属の両方で作られたス
テントは大きな半径方向輪郭を有する。というのは、ス
テントの金属部分で占められる部分が薬を吸収すること
も保持することもできないからである。ステントによっ
て形成される管腔の生体内直径を増大させるようにする
ので、ステントの輪郭を減少させることが望ましい。か
くして、薬をステントの輪郭を実質的に増大させること
なく血管壁に投与する金属ステントを形成することが望
ましい。本発明はこれらの要望を満たす。
って、本発明は薬剤入り人工器官を製造する方法であ
る。この方法は、複数の多孔空所又は孔を有する多孔性
金属材料を準備し、材料を複数の孔を有する人工器官に
形成し、治療薬剤を人工器官の孔に入れることからな
る。1つの実施形態では、人工器官は、血管、胆管、食
道又は他の身体管腔への移植用ステントである。1つの
実施形態では、この方法は、球形粒子、フィラメント又
は繊維を含む金属粒子を、ワイヤ、シート又はチューブ
に焼結することからなる。次いで、ワイヤ、シート又は
チューブを、更に、それらからステントを形成すること
によって製造する。シート又はチューブをステントパタ
ーンに従って化学的にエッチングしたりレーザー切断す
ることによって、それをステントに形成することができ
る。他の実施形態では、金属繊維を織って、これを金属
ワイヤ又は金属シートに焼結することによって、シート
を形成することができる。
ートは複数の層にして形成される。大きい直径の粒子の
層を第1水平平面に配列する。2つの小さい直径の粒子
の層を平面の両側に配列する。粒子を、小さい直径の粒
子の2つの層の間に挟まれた大きい直径の粒子で形成さ
れる大きな芯を有する粒子のシートに焼結する。同様
に、焼結金属ワイヤを、大きい直径の粒子を第1軸線に
沿って配列し、次いで小さい直径の粒子を大きい直径の
粒子から半径方向外方に且つこれと同軸に配列すること
によって形成することができる。次いで、粒子を、実質
的に多孔性の中央空所及び小さい孔径をもつ外層を有す
るステントワイヤを形成するように焼結する。更に別の
実施形態では、ステントの形成方法は、粒子の2つの層
の間に中実の金属のシートを配列することからなる。次
いで、粒子をシートの両側に焼結させる。変形例とし
て、粒子を中実金属ワイヤから半径方向外方に配向し、
部分的に多孔性のワイヤに焼結することができる。部分
的に多孔性のワイヤ及びシート金属芯をもつステント
は、ステント全体の強度を改善するものと考えられる。
剤を、ステントを、治療薬剤を有する液体溶液に浸すこ
とによってステントの孔に入れることができる。治療薬
剤をステントの孔に吸収させるのに十分な時間ステント
を浸す。治療薬剤は、動脈性疾病を治療し、及び又はし
ばしばステント移植に伴う副作用を最小にし或いは中和
するように治療する或いはそのようにする任意の数の薬
又は化学的薬剤であってもよい。更に別の実施形態で
は、本方法はステントにポリマーを被覆することを含
む。ポリマー自体に、1つ又は複数の治療薬剤を入れて
もよく、薬の放出を遅らせるために或いは治療薬剤が体
内に拡散する量を調整するために塗布してもよい。本発
明のこれら及び他の特徴は、本発明の原理を例示として
示す添付図面と関連して、次のより詳細な説明から明ら
かになるであろう。
態である人工器官が、管16の壁14に向かって半径方
向に拡張可能な多孔性ステントである。治療薬剤がステ
ントの孔18(図2を見よ)内に入れられる。治療薬剤
は血管系に置かれるとき、ステントと接触する組織に投
与される。1つの好ましい実施形態であるステントは多
孔性であるステントワイヤで形成される。多孔性のステ
ントワイヤの例は焼結金属ワイヤである。図2は本発明
の1つの実施形態における使用に適した焼結ワイヤの部
分的な顕微鏡的な図を示す。ワイヤは多孔性であり、い
くつかの孔18を有する。空所は、サイズが、好ましく
は、0.01μm乃至20μmの範囲である。好ましい
1つの実施形態によれば、金属を、金属を焼結させる工
程によって多孔性にする。焼結は、粒子を互いに結合さ
せてその粒子を完全に溶解させないで凝集かたまりを形
成する製造工程である。粒子は所望の形状に一体にプレ
スされ、或いは成形される。最初に、かなりの量の圧力
を加えて、粒子を一体にプレスする。次いで、金属はそ
の融点より僅かに下の温度まで加熱する。完全に溶解す
ることなく、粒子は互いに結合する。空間が粒子の格子
間に残り、この空間は孔18を形成する。
参照して示す。図3は金属粒子24の固く圧縮された格
子の顕微鏡的な図である。粒子が加圧され且つ隣接した
粒子と接触しているにもかかわらず、ギャップ26が各
粒子間に存在する。粒子は、好ましくは、直径が0.0
2μm乃至20μmのサイズである。加熱前には、個々
の粒子間に形成される化学的な結合はない。金属がその
融点より僅かに下の温度まで加熱されると、粒子は隣り
の粒子と結合する。粒子が焼結されると、固く圧縮され
た格子のギャップは孔18を形成する。かくして図2で
は、焼結工程によって形成された金属ステントワイヤは
ワイヤ全体にわたって延びる孔18を有し、それによっ
て空所を相互に連結する。次いで、以下説明するよう
に、空所を治療薬剤で満たすことができる。特定の金属
を焼結する適当な圧力及び温度はその特定の金属に特有
のものである。金属製作の当業者は、所定の金属又は合
金を焼結する仕方を理解する。
材料部材は、ステンレス鋼、タンタル、ニッケル−チタ
ン合金、プラチナ−イリジウム合金、モリブデン−レニ
ウム合金、金、マグネシウム、又はそれらの組み合わせ
のような適当な金属で良いが、他の同様の材料も適す
る。金属を、周知の焼き戻し工程及び製造工程によって
異なる硬さ、変化した剛性を示すように修正することが
できる。本発明の1つの実施形態によるステントを製造
するときに、考慮すべき最も重要な要素の1つは金属の
多孔度である。多孔度は焼結金属の孔の全容積を金属の
全容積で除したものである。多孔度は所定寸法のステン
トに入れることのできる治療薬剤の量を決定する。高多
孔度は、ステントがより多くの治療薬剤を投与すること
ができる、或いはより密集していないのでより狭い外形
を有することができることを意味する。本発明のいくつ
かの実施形態によれば、高多孔度は、金属の強度及び弾
性に悪影響を及ぼす。その結果、一方では、ステントの
強度と、他方ではステント外形及びステント装填能力と
の間に進行中のかね合いがある。
の粒径の関数である。図3に示される本発明の1つの実
施形態では、粒子24は一般的に球形である。各孔18
の径は、特にほぼ球形の粒子では、粒径に比例する。粒
子24が均一な径のものでない場合は、小さいほうの粒
子が大きいほうの粒子間のギャップを満たす傾向があ
る。かくして、そのような粒子で形成された金属の多孔
度は、より均一な径の粒子が使用される場合よりも予想
できない。孔径の一般的な均一性も、薬剤をステント全
体にわたって均等に確実に分散させるのに重要である。
孔のほぼ均一な分配は、ステントと接触している組織が
治療薬剤の均等に分配された1回分を受け入れることを
保証する。
与される薬にはいくつかのタイプがある。粒子の層に結
合しうる治療薬又は治療薬剤の例は、抗血小板物質、抗
繊維素薬、抗血栓薬及び抗増殖薬を含む。血液凝固阻止
薬、抗血小板物質、抗繊維素薬及び抗血栓薬の例は、ヘ
パリンナトリウムに限られないが、低分子量のヘパリ
ン、ヒルジン、アーガトロバン、フォースコリン、バピ
プロスト、プロスタサイクリン及びプロスタサイクリン
類似物、デキストラン、D−フェ−プロ−アーグ−クロ
ロメチルケトン(合成抗血栓薬)、ジピリダモール、グ
リコプロテインIIb /IIIa血小板膜レセプター抗体、組
み換え型ヒルジン、トロンビン阻害薬(ビオゲンから利
用可能)、及びセンターコール社によって登録商標「7
E−3B」の下で販売されている抗血小板薬剤を含む。
細胞増殖抑制薬又は抗増殖薬の例は、アンギオペプチ
ン、ソマトスタチン類似物、登録商標「カプトプリル」
(スクイブ社による)、「シラザプリル」(ホフマン−
ラロシュ社による)及び「リシノプリル」(メルク&C
o社による)の下で取り扱われているもののようなアン
ジオテンシン変換酵素阻害薬、ニフェジピンのようなカ
ルシウムチャネル遮断薬、コルヒチン、繊維芽細胞成長
因子(FGF)拮抗薬、オメガ3脂肪酸のような魚油、
その1つがメルク&Co社によって登録商標「ロバスタ
チン」の下で販売されているHMG−CoA還元酵素の
阻害薬のようなコレステロール降下薬剤、メトトレキセ
ート、単クローン性ホスホジエステラーゼ阻害薬、プロ
スタグラジン阻害薬(グラクソウェルカム社から利用で
きる)、セラミン及びトリアゾロピリミジンのようなP
DGF拮抗薬、セロトニン遮断薬、ステロイド、チオプ
ロテアーゼ阻害薬、及び硝酸を含む。適当と思われる他
の治療薬剤は、例えば、アルファ−インターフェロン及
び遺伝子工学的上皮細胞を含む。
はこれを治療するのに使用されており、その各々は、本
発明の用途に等しく適用できる他の治療薬を開発するこ
とができるので、例示として認識され、そして限定とし
て認識されない。管又は身体管腔を治療するのにそのよ
うな治療薬剤を使用することは当該技術で知られてお
り、それは投薬量、投薬割合、及び適当な治療期間の計
算のようなことである。1つの実施形態の治療薬剤は、
好ましくは、液体形態であり、ステントを薬剤溶液に浸
すことによってステント内に入れられる。治療薬剤は溶
媒に溶解され、或いは液体混合物に懸濁される。もし懸
濁液が使用されるならば、ステントの孔径は治療薬剤の
懸濁粒子よりもかなり大きいことが重要である。懸濁し
た治療薬剤の粒径の10倍以上の平均孔径が適する。ス
テントを薬剤溶液に浸した後、治療薬剤はステントの孔
に吸収される。次いで、薬剤入りステントを溶液から取
り出し、患者の血管系に移植することができる。選択的
に、薬を溶解させ或いは懸濁させる流体に圧力を加える
ことによって、治療薬剤をステントに入れることを容易
にすることができる。加えられる圧力は、ステントの孔
内への薬剤流体の流入を助ける。この技術を、流体をフ
ィルターの孔に押し通す物理的工程にリンクさせても良
い。
れると、孔18を形成する粒子の外面と治療薬剤の粒子
との間の表面張力の理由により適所にとどまる。図1に
示すように、次いで、薬剤入り多孔性ステント12を動
脈閉鎖部位13に配置し、拡張させる。拡張されたステ
ントは管16の壁14に係合して、管の開通性を維持す
る。図2に示すように、ひとたび管内にはいると、治療
薬剤は孔18から散布され、ステントと接触している管
の壁組織に吸収される。従来技術の薬剤入りステントを
超える本発明のステントの利点のうちの主なものはその
輪郭及び強度である。焼結金属を含む金属は、治療薬剤
を入れることのできるポリマー混合物のような合成材料
よりも強い。かくして、薬剤入りステントが治療薬剤の
適量を投与し且つ管の開通性を構造的に維持するために
は、ステントの半径方向の輪郭は実質的に金属ステント
の半径方向の輪郭よりも大きくなければならない。治療
薬剤を有するポリマー材料を、金属ステントに被覆する
かしないか、或いはステントを完全にプラスチック材料
で作るかどうか、ということは真実ではない。
弾性を有する。焼結金属は更に、多孔性という追加の特
徴を有している。その結果、焼結金属ステントを、在来
の金属ステントの輪郭に実質的に匹敵する輪郭で作るこ
とができ、治療薬剤を孔に入れ且つ薬剤入りポリマー被
覆の助けなしにステント移植部位へ投与することができ
る。加えて、生物学的吸収性である材料を含む多くの合
成材料が部位の炎症を引き起こすことがある。ステント
の孔に治療薬剤を直接入れた薬剤入り金属ステントは、
おそらく、移植部位での炎症を引き起こしそうもない。
施例を示す。ステントは細長い粒子32、即ちフィラメ
ント及び繊維で形成される。ほぼ球形の金属粒子が焼結
金属を構成するのに使用されるときには、出来た多孔度
は、典型的には、5%乃至30%の範囲である。粒子が
細長くされるとぎには、これらのフィラメント又は繊維
により、焼結させたとき30%よりも大きな多孔度をも
たらすことができる。ステントを細長いフィラメント又
は繊維で製作する技術は、球形の粒子又は粉末について
の上述した方法と同様である。フィラメント又は繊維を
型に入れて、加圧する。次いで、繊維を金属の融点より
ちょっと下の温度まで加熱する。球形粒子(図2に示さ
れているようなもの)ではなく金属フィラメント又は繊
維32で作られたステントは、粒子の不規則な形状のた
めにより大きな多孔度を示す。粒子を均一な形状の粒子
よりも低密度に詰め込むことができるが、それにもかか
わらず、不規則形状の粒子間の接触を維持して焼結を可
能にすることができる。かくして、焼結金属の空間又は
孔34は、球形粒子の焼結から生ずる孔18よりも大き
くなる傾向がある。
イヤ30の強度は改善されている。というのは、焼結し
たとき、個々の成分がより大きな表面積と容積との比を
有し、且つ球形粒子のときよりも多くの隣接する成分と
接触するからである。かくして、各フィラメント又は繊
維は、隣接したフィラメント又は繊維と結合するより大
きな表面積を有する。かくして、重なり合ったフィラメ
ント又は繊維のマトリックスが、より大きな多孔度及び
より強い粒子内結合を示して形成される。更に別の実施
例では、ワイヤ繊維36が図5に示すように組織38に
織られ或いは結び付けられている。個々のストランドは
互いに作用し合う仕方で協力して、ワイヤ強度を補強す
る。加えて、ワイヤ繊維を、改良され且つ補強された強
度を有する焼結金属シートの形態に或いは焼結金属チュ
ーブの形態に織ることができる。粒径及び粒子形状の他
の組み合わせを採用して、異なる特徴を有するステント
ワイヤを形成することができる。
ヤ42が、焼結粒子の内芯44及び外層46で形成され
る。外層は、内芯を形成する粒子の直径とは異なる直径
を有する粒子で形成される。例えば、金属の芯は10μ
m乃至20μmの範囲の直径を有する粒子で形成され
る。2μm乃至5μmの範囲の直径を有する粒子が芯を
取り囲む。大きいほうの粒子はより大きい孔52を有す
る芯を作る。これにより、高い多孔度をもたらし、かく
して高い入り込み能力をもたらす。外層の小さいほうの
粒子はより小さい孔54を形成し、これは管の組織への
薬剤の散布量を減少させる。
で形成されるステントに入れられたとき、より大きな量
をステントワイヤの芯44の大きいほうの孔52に貯え
ることができる。ステント内の治療薬剤は、ひとたびス
テントが管内に置かれると、ステントワイヤの外層46
の小さいほうの孔54によって決定される量で投与され
る。そのような構造は、多量の治療薬剤を芯に貯えるこ
とができ、且つステントワイヤの孔がより均一な径のも
のである場合に達成されるであろうよりも低流量で治療
薬剤を投与することができるものと期待される。その結
果、この設計は、低投与量で長期間の薬剤治療が望まれ
る場合にふさわしい。変形例として、図7に示す本発明
の別の実施形態によれば、ステントワイヤ56が焼結粒
子58で形成される。中実の芯を囲む焼結金属粒子間に
形成された孔62が治療薬剤を保持する。中実の芯及び
多孔性の外層を有するステントの全体の多孔度は、同様
の割合を有するが全体が焼結金属で構成されたステント
ワイヤの多孔度よりもずっと小さい。しかしながら、中
実の芯は金属ステントの引張り強度及び弾力性を補強
し、均一な粒子の焼結ステントよりかなり強い。かくし
て、最大の引張り強度及び弾力性が望しく、しかも比較
的少量の治療薬剤が必要とされるに過ぎないような適用
に対しては、中実の芯を有する焼結ステントを使用する
ことが望ましい。
ステントを、前述の球形又はフィラメント状粒子で形成
される材料で作ることができる。例えば、ステントを図
8に示すように焼結金属シートで或いは焼結金属チュー
ブで形成することができる。実施例によれば、金属粒子
66を配列し、加圧して、シートにする。次いで、シー
トを前述のように粒子の融点より低い温度まで加熱す
る。焼結金属のシートは多孔性であり、多数の孔68を
有する。ワイヤの多孔度及び孔径に適用する同じ原理
が、シート又はチューブに形成される焼結金属に等しく
適用される。金属シートからステントを形成する利点
は、ステントが拡張されたときに金属格子にかなりの歪
みを生じさせることなく半径方向に拡張することができ
ることである。焼結金属のシート又はチューブを、例え
ば、連続CO2 レーザー、パルスYAGレーザー、又は
エクサイマーレーザーのようなレーザーで、又はその代
わりに化学的なエッチング又は打ち出しによって、金属
構造メンバーを形成するように所望の形状に切断するこ
とができる。平らなシートから切断した場合、次いで、
ステントを円筒形状に丸め、長手方向の縁に沿ってレー
ザー溶接する。
トについての当該技術で知られる特定のパターンに形成
することができる。1つのそのようなパターンは巻かれ
てロックするデザインであり、図9に示す。シートを1
つ又はそれ以上のスロット74を含むヘッド部分72を
有するステント形態70にエッチングし、各スロットは
それに対応する多数のテール部分76を受け入れる。テ
ール部分は、円筒形ループを形成するようにスロットに
受け入れられる。各テール部分はヘッド部分のスロット
に係合するようになった複数の歯78を有する。歯がス
ロットに係合するとき、テール部分は適所に保持され、
ステント形態を拡張状態に保つ。加えて、穴80が、ス
テントの金属と空気の比率を減少させるためにステント
全体にわたって形成される。管16の壁14と接触して
いる金属が少なければ少ないほど、ステントは血液と融
和しやすい。
ール」状に収縮位置へコイル巻きする。次いで、各テー
ル部分を各スロットに通して、巻く。ステントの形態
を、ステントを送り且つ移植するための当該技術で良く
知られた原理に従ってバルーンによって拡張する。ステ
ントの形態70を配置の間中バルーンによって拡張する
ので、ステントは巻きが戻り、歯78は所望の直径でス
ロットにロックして、ステントがその最初の収縮状態に
戻るのを防止する。図9に示すコイル巻きしたステント
の利点は、ステント70を、管の壁と接触する最小の表
面積を有するようにエッチングできることである。コイ
ル巻きしたシート金属ステントを、ワイヤステントと比
べて、血管の壁との最大の表面積の接触を維持するよう
に形成することができるので、血管の壁の全領域を治療
薬剤でおおうことが望まれる場合に、これは重要な特徴
であろう。
態は、金属シート82の両側84及び86に焼結された
粒子を有するシートである。図10のステントは、構造
的に、ステントが中実の芯及び芯に焼結される多孔性の
外層を形成する粒子を有する図7のステントと同様であ
る。中実の芯は金属の強度を補強する。金属シートはま
た治療薬剤が通れない障壁をなす。かくして、シートの
上側84の孔92に入れられた治療薬剤は中実の芯から
外方に第1方向に浸透する。中実ワイヤの下側の孔94
に入れられた治療薬剤は、上側の孔に入れられた治療薬
剤の方向と反対である第2方向90にだけ浸透する。図
10に示すようなステントを円筒形態にループにして、
管内に置く場合には、半径方向外方に向けられた上側8
4だけが管の壁に係合する。下側86は半径方向内方に
面し、管の壁と接触しない。かくして、望ましくは、管
の壁の組織を治療するために、第1治療薬剤を上側に入
れることができる。管内を流れる血液の凝固を防止する
ために、第2治療薬剤を下側に入れることができる。加
えて、ステントを、ステントの片側だけに粒子焼結され
るように形成することができる。治療薬剤はステントの
多孔側の焼結金属に入れられる。ステントを1つの多孔
側だけで形成する場合には、治療薬剤をステントの壁の
組織に投与するために、その側を半径方向外方に向ける
ことができる。
たステントワイヤの断面図を示す。シートは複数の多孔
空所又は孔98を有する。治療薬剤を焼結金属の孔に入
れる。次いで、被覆100を焼結金属に塗布する。被覆
を以下に説明するようないくつかの目的のために使用す
るのがよい。図12を参照すると、本発明の他の実施例
が示され、この実施例では、ステントが、焼結の結果と
してより大きい孔を形成するより大きい径の粒子108
で形成される芯106を有する金属の焼結シート104
で形成される。芯層106は、より小さい径の粒子11
4又はより小さい孔の形成をもたらす粒子で形成される
2つの層110と112の間に挟まれる。そのようなシ
ートは、大きいほうの径の粒子108の中間層又は芯層
106をある平面に沿って配向することによって形成さ
れる。小さいほうの径の粒子の上層を、芯層と平行でそ
れよりも上の平面に配列する。粒子の下層を、芯層と平
行でそれよりも下の平面に配列する。次いで、3つの層
を一体にプレスし、単一のシートに焼結する。次いで、
シートをステントの形態に切断し或いはエッチングする
ことができる。
投与する目的のための被覆を必要としないステントを提
供することであるけれども、治療薬剤が焼結金属の孔に
入れられた後に被覆をすることは本発明の効用をくつが
えすものではない。例えば、治療薬剤がステントの孔及
びポリマー被覆にも入れられた場合には、ポリマー被覆
の輪郭を減少させることができる。そのようなポリマー
被覆が塗布されると、より多くの投与量の治療薬剤をス
テントの移植部位に投与することができる。金属の孔に
おいて治療薬剤をステントに入れ、次いで、ポリマー被
覆を更にステントに塗布することによって追加の利点を
得ることができる。たとえポリマー被覆をステントに塗
布するとしても、輪郭を減少させ、しかもステントを補
強する原理は依然として実現できる。というのは、同等
の大きさを有する被覆された、すべてがポリマーのステ
ントによって投与されるよりも多くの量の治療薬剤を、
ポリマー被覆した焼結ステントによって投与することが
できるからである。
マー材料は、好ましくは、治療薬剤を入れ、その後治療
薬剤を放出することのできる生物学的分解性、生物学的
吸収性ポリマーフィルムで構成される。ポリマー被覆
は、限るわけではないが、好ましくは、ポリカプロラク
トン(PCL)、ポリ−DL−乳酸(DL−PLA)及
びポリ−L−乳酸(L−PLA)又はラクチドから形成
される。ポリオルトエステル、ポリイミノカーボネー
ト、脂肪族ポリカーボネート及びポリフォスファゼンの
ような他の生物学的分解性、生物学的吸収性ポリマーも
適しており、治療薬剤を担持し且つ投与することができ
る他の非分解性ポリマーも同様に適当であろう。非分解
性合成ポリマーの例は、ポリウレタン、ポリエチレン、
ポリエチレンテラフタレート、エチレンビニルアセテー
ト、シリコン及びポリエチレンー酸化物(PEO)であ
る。1つの実施形態によれば、ポリマー層に、局所の薬
物治療に使用される薬物学的薬剤を入れる。この説明で
使用されるように、生物学的分解性、生物学的吸収性、
再吸収性、分解性及び吸収性の用語は、これらの過程が
加水分解の新陳代謝過程であろうと容積又は表面浸食で
あろうと、集合的に、壊れて、人体によって徐々に吸収
され又は除去される材料を取り囲むことを意味する。前
述の実施例の各々では、1つのポリマー層は、好ましく
は、約0.025mm乃至0.051mm(0.000
1インチ乃至0.002インチ)の厚さである。
めに使用される薄いポリマーフィルムを、投与すべき薬
と混合し、次いで典型的には、金属構造部材の表面に積
層させ又は溶媒注型される。積層工程法及び温度は、使
用されるポリマー及び入れるた薬剤の温度感度に応じて
広範囲に変えることができる。変形例として、ステント
の金属構造を、溶媒注型、溶融工程、挿入成形及び浸液
被覆によってポリマー材料層に包み込むことができる。
本発明の1つの実施形態では、膜は生物学的吸収性であ
るが、治療薬剤はポリマーに装入させない。被覆は移植
後に溶解し、そしてこれは治療薬剤を患者の血管系に放
出する時間を遅らせる。被覆の厚さ並びに被覆が生物学
的に吸収される量は、治療薬剤をステントの孔から投与
する前にステントを血管に位置決めする時間の長さを決
定する。ひとたび生物学的吸収性材料が完全に溶解され
ると、孔内の治療薬剤を孔径及び多孔度によって決定さ
れた量で投与することができる。
収性であることが好ましい。そのような状況では、薬剤
が組織に浸透する量を、選ばれた特定の被覆の物理的特
性によって調節する。加えて、被覆を、再狭窄、血栓症
又は他の組織炎症を減ずるように選択しても良い。例え
ば、血液凝固を減少させるためのヘパリン被覆が当該技
術で知られている。ヘパリンは、ステントに被覆される
と、ステント表面の血液凝固を減少させる。ヘパリン被
覆を、イオン結合、端点付着により或いはヘラピンを光
結合させることによってステント表面に付着させる。更
に別の実施形態では、第1治療薬剤が被覆内に入れら
れ、第2治療薬剤がステントの孔内に入れられる。これ
は、一連の薬剤投与量又は濃度を必要とする場合であろ
う。そのようなステントが血管系に置かれると、最初に
第1治療薬剤がステントによって吸収され、遅れて第2
治療薬剤が血管系によって吸収される。この変化は、ス
テント配置部位での連続的な薬物治療を可能にする薬物
治療に更なる特質を加える。
けれども、様々な変更を本発明の精神及び範囲から逸脱
することなく行うことができることは、前述より明らか
であろう。更に、請求項によるものを除き、発明を限定
することを意図しない。
製作されたステントを備えた血管の長手方向の断面図で
ある。
製造された多孔性ステントワイヤ又はストラットの部分
拡大、部分切除の斜視図である。
拡大断面図である。
製造された多孔性ステントワイヤ又はストラットの部分
拡大、部分切除の斜視図である。
製造された多孔性ステントワイヤ又はストラットの部分
拡大、部分切除の斜視図である。
製造されたステントワイヤ又はストラットの断面図であ
る。
製造されたステントワイヤ又はストラットの断面図であ
る。
製造された焼結ステントシートである。
焼結金属シートで形成されたステントである。
に従って製造された焼結金属シートの断面の部分切除の
図である。
に従って製造されたステントワイヤ又はストラットの断
面図である。
に従って製造された焼結金属シートを部分切除の断面図
である。
Claims (41)
- 【請求項1】 複数の孔を有する多孔性金属材料を準
備し、 前記材料を複数の孔を有するステントに形成し、 前記ステントの前記孔に治療薬剤を入れる、ことからな
る人工器官の製造方法。 - 【請求項2】 前記準備段階で準備される前記多孔性
金属材料は、焼結金属材料である、請求項1に記載の方
法。 - 【請求項3】 前記準備段階は、金属繊維を織り、且
つ金属繊維を焼結して焼結金属材料を形成することから
なる、請求項1に記載の方法。 - 【請求項4】 前記準備段階で形成される前記多孔性
金属材料は、更にシート材料の形態であり、 前記形成段階は、前記多孔性の金属材料のシートを拡張
可能なステントの形態に化学的にエッチングすることか
らなる、請求項1に記載の方法。 - 【請求項5】 前記準備段階は、更に、金属粒子を前
記多孔性金属材料のシートに焼結することからなる、請
求項4に記載の方法。 - 【請求項6】 前記準備段階は、更に、金属繊維を多
孔性金属材料のシートに織り、且つ前記織られた金属繊
維を前記シートに焼結することからなる、請求項5に記
載の方法。 - 【請求項7】 前記準備段階で準備される前記多孔性
金属材料はシートの形態であり、 前記形成段階は、更に、前記シートをレーザーでステン
トの形態に切断することからなる、請求項1に記載の方
法。 - 【請求項8】 前記準備段階は、更に、金属粒子を前
記多孔性金属材料のシートに焼結することからなる、請
求項7に記載の方法。 - 【請求項9】 前記準備段階は、更に、金属繊維を多
孔性金属材料のシートに織ることからなる、請求項7に
記載の方法。 - 【請求項10】 前記準備段階は、更に、前記織られた
金属繊維を前記シートに焼結することからなる、請求項
9に記載の方法。 - 【請求項11】 前記準備段階で準備される前記多孔性
金属材料は、多孔性金属ワイヤの形態である、請求項1
に記載の方法。 - 【請求項12】 前記準備段階の前記ワイヤは、粒子を
一体に焼結することによって形成される、請求項11に
記載の方法。 - 【請求項13】 前記準備段階は、更に、金属繊維を多
孔性金属のシートに織ることからなる、請求項11に記
載の方法。 - 【請求項14】 前記準備段階は、更に、前記金属繊維
を一体に焼結することからなる、請求項13に記載の方
法。 - 【請求項15】 前記準備段階は、更に、 大きい径の粒子を第1水平平面に配列し、 小さい径の粒子を前記平面の両側に配列し、 前記大きい径の粒子及び前記小さい径の粒子をシートに
焼結する、段階からなる、請求項13に記載の方法。 - 【請求項16】 前記準備段階は更に、 大きい径の金属粒子を第1軸線に配列し、 小さい径の金属粒子を、前記大きい径の粒子から半径方
向外方に且つそれと同軸に配列し、 且つ前記大きい径の粒子及び前記小さい径の粒子をワイ
ヤに焼結する、段階からなる、請求項1に記載の方法。 - 【請求項17】 前記治療薬剤を入れる段階は、前記ス
テントを前記治療薬剤を有する液体溶液に浸すことから
なる、請求項1に記載の方法。 - 【請求項18】 前記治療薬剤を前記ステントの前記孔
に吸収させるのに十分な時間前記ステントを前記液体溶
液に浸すことからなる、請求項17に記載の方法。 - 【請求項19】 前記治療薬剤は抗繊維素薬である、請
求項1に記載の方法。 - 【請求項20】 前記治療薬剤は抗血栓薬である、請求
項1に記載の方法。 - 【請求項21】 前記治療薬剤は抗増殖薬である、請求
項1に記載の方法。 - 【請求項22】 前記治療薬剤は血液凝固阻止薬であ
る、請求項1に記載の方法。 - 【請求項23】 前記治療薬剤はGPIIbIIIa 遮断薬で
ある、請求項1に記載の方法。 - 【請求項24】 前記治療薬剤は、フォースコリン、ア
スピリン、ジピリダモール、クマジン、チクロポジン及
びヘパリンからなるグループから選択される、請求項1
に記載の方法。 - 【請求項25】 前記治療薬剤は血管活性薬である、請
求項1に記載の方法。 - 【請求項26】 前記治療薬剤は抗炎症薬である、請求
項1に記載の方法。 - 【請求項27】 前記治療薬剤は内皮化を助長する、請
求項1に記載の方法。 - 【請求項28】 更に、前記ステントにポリマーを被覆
する段階からなる、請求項1に記載の方法。 - 【請求項29】 前記被覆段階は、入れる段階の後に行
われる、請求項28に記載の方法。 - 【請求項30】 前記ポリマーは、前記治療薬剤を実質
的に一定の流量で放出するように形成される、請求項2
8に記載の方法。 - 【請求項31】 前記ポリマーは生物学的ポリマーであ
る、請求項28に記載の方法。 - 【請求項32】 前記ポリマーはポリ−乳酸又はフィブ
リンである、請求項31に記載の方法。 - 【請求項33】 前記ポリマーは合成ポリマーである、
請求項28に記載の方法。 - 【請求項34】 前記ポリマーは、ポリウレタン、ポリ
エチレンテレフタレートテトラフロライド、ポリエチレ
ン、ポリエチレンオキサイド(PEO)、又はシリコン
からなるグループから選択される、請求項32に記載の
方法。 - 【請求項35】 前記ポリマーはヒドロゲルである、請
求項33に記載の方法。 - 【請求項36】 前記ポリマーはヘパリン被覆からな
る、請求項28に記載の方法。 - 【請求項37】 前記ポリマーは治療薬剤と混合され
る、請求項28に記載の方法。 - 【請求項38】 前記ポリマーは分解できる、請求項2
8に記載の方法。 - 【請求項39】 金属繊維を焼結して、焼結ステント材
料にし、 前記焼結ステント材料をステントに形成し、 治療薬剤を前記焼結金属ステントの孔に入れる、ことか
らなるステント製造方法。 - 【請求項40】 金属粒子をシートに焼結し、 前記シートを多孔性金属ステントに切断し、 薬剤を前記金属ステントの孔に入れる、ことからなる焼
結したステントの製造方法。 - 【請求項41】 前記焼結段階は、金属繊維を多孔性金
属のシートに織り、且つ前記織られた金属繊維を焼結す
ることからなる、請求項40に記載の方法。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/837993 | 1997-04-15 | ||
| US08/837,993 US6240616B1 (en) | 1997-04-15 | 1997-04-15 | Method of manufacturing a medicated porous metal prosthesis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10295824A true JPH10295824A (ja) | 1998-11-10 |
Family
ID=25275988
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10519498A Ceased JPH10295824A (ja) | 1997-04-15 | 1998-04-15 | 薬剤入り多孔性金属人工器官の製造方法 |
Country Status (4)
| Country | Link |
|---|---|
| US (6) | US6240616B1 (ja) |
| EP (1) | EP0875217A3 (ja) |
| JP (1) | JPH10295824A (ja) |
| CA (1) | CA2234787A1 (ja) |
Cited By (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003094109A (ja) * | 2001-09-21 | 2003-04-02 | Hideo Nakajima | 金属線または金属板および医療機器用細線および医療機器用薄板 |
| JP2004500167A (ja) * | 1999-11-19 | 2004-01-08 | アドバンスト・バイオ・プロスゼティック・サーフィスズ・リミテッド | 改良された内皮化を提供する管腔内装置及びその製造方法 |
| JP2005296450A (ja) * | 2004-04-14 | 2005-10-27 | Masahiko Chiba | 生体用多孔質体の製造方法 |
| JP2007505703A (ja) * | 2003-09-16 | 2007-03-15 | ボストン サイエンティフィック リミテッド | 医療装置 |
| JP2008501456A (ja) * | 2004-06-09 | 2008-01-24 | イェー・アー・ツェー・ツェー・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | インプラント可能な装置 |
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- 1998-04-15 JP JP10519498A patent/JPH10295824A/ja not_active Ceased
- 1998-04-15 EP EP98302904A patent/EP0875217A3/en not_active Withdrawn
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2001
- 2001-03-01 US US09/797,313 patent/US20010013166A1/en not_active Abandoned
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2002
- 2002-09-03 US US10/235,033 patent/US6723120B2/en not_active Expired - Lifetime
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2004
- 2004-01-28 US US10/767,296 patent/US7699890B2/en not_active Expired - Fee Related
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2007
- 2007-08-16 US US11/840,147 patent/US7931931B2/en not_active Expired - Fee Related
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2008
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Also Published As
| Publication number | Publication date |
|---|---|
| US7931931B2 (en) | 2011-04-26 |
| CA2234787A1 (en) | 1998-10-15 |
| EP0875217A3 (en) | 2000-08-30 |
| US20010013166A1 (en) | 2001-08-16 |
| US20020197178A1 (en) | 2002-12-26 |
| US20080288058A1 (en) | 2008-11-20 |
| US6723120B2 (en) | 2004-04-20 |
| US20070282427A1 (en) | 2007-12-06 |
| EP0875217A2 (en) | 1998-11-04 |
| MX9802937A (es) | 1998-11-29 |
| US8007529B2 (en) | 2011-08-30 |
| US6240616B1 (en) | 2001-06-05 |
| US7699890B2 (en) | 2010-04-20 |
| US20040186553A1 (en) | 2004-09-23 |
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