JP5861632B2 - ナノカプセル化薬物をそのために設計された医療装置を通して送り、身体のpHを用いてヒト動脈内でナノカプセル化薬物を放出させることによる遮断されたヒト動脈における血流再開 - Google Patents
ナノカプセル化薬物をそのために設計された医療装置を通して送り、身体のpHを用いてヒト動脈内でナノカプセル化薬物を放出させることによる遮断されたヒト動脈における血流再開 Download PDFInfo
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Description
本発明に従う実施形態を詳細に記載する前に、これらの実施形態が主として体腔に関連する医学的状態を処置するための医療装置の構成要素の組合せにあることを認識するべきである。従って、これらの構成要素は、本明細書の利益を有する技術分野の熟練者に容易に明らかになる詳細な開示を不明確にしないために、本発明の実施形態を理解するのに適切な特定の詳細のみを含めて記載されている。
ダイズリン脂質はLioid GMBHから入手した(バッチ番号:776114−1/906)。シロリムスはFujan Chemicals, Chinaから、99.5%を超える純度のものを入手した。用いた水、他の溶媒および試薬はHPLCグレードのものであった。Amazonia Croco(登録商標)(超薄血管形成術バルーンに取り付けたクロムコバルト冠動脈用L−605ステントシステム、以下、「ステントシステム」)は、Minvasys, Paris, Franceから入手した。
80(5mg)を加え、ダイズリン脂質水溶液を得た。このダイズリン脂質水溶液(10ml)を氷冷水浴中、20〜25分間、15000〜20000rpmで高速ホモジナイゼーションにかけ、溶液A1を得た。このようにして得られた溶液A1は、ダイズリン脂質のナノ粒子を含んでいた。次に、溶液A1に対し、Malvern ZS90(Malvern, UK)粒径検出器を用いて粒径検出分析を行った。図1は、Malvern ZS90により検出されたダイズリン脂質ナノ粒子の粒度分布を示す。ダイズリン脂質ナノ粒子の平均径は、475.79nmであることが分かった。
ステントシステムの薬物含量の検出:
コーティング済みステントシステムに付加されたシロリムスの量を、HPLC分析を用いて算出した。HPLC作動パラメーターは次のように選択した:流速は1.2ml/分(±0.01)に設定し、λ最大値は278nm(±1nm)に設定し、カラム温度は60℃(±2℃)に設定し、検出器の感度は0.02AUFSに設定し、分析時間は最大20分に設定した。
薬物の量=(サンプル面積/標準面積)*(標準濃度/サンプル濃度)
を用いて計算した。
よって、薬物の量=(683.235/3196.970)*(50/(1/10))=106.82μg。
従って、コーティング済みステントシステムに付加された薬物は106.85μgであることが分かった。
封入効率(EE):
1mlのナノ担体水溶液(実施例1)を10mlのSMFに入れた。容量を10mlに調整した。20μLのナノ担体水溶液をHPLCインジェクターに注入し、ナノ担体水溶液のクロマトグラムを得た。図5は、ナノ担体水溶液のクロマトグラムを示す。ナノ担体水溶液の保持時間は4.308分であることが分かり、ナノ担体水溶液のピークに相当する「ナノ担体水溶液の面積」は280.555であることが分かった。遊離薬物の量は下式:
遊離薬物の量=(ナノ担体水溶液の面積/標準面積)*(標準濃度/ナノ担体水溶液濃度)
を用いて計算した。
%EE=(最初の薬物重量(mg)−遊離薬物量(mg))*100/(最初の薬物重量(mg))
を用いて計算した。
%EE=(20−0.8774)*100/20=95.61%
よって、封入効率%は95.61%であることが分かった。
コーティング済みステントシステムからのシロリムスの放出を、pH6.4のリン酸緩衝生理食塩水(PBS)を用いることで、in vitroにおいて調べた。PBS溶液は、1.79gのオルトリン酸水素二ナトリウム、1.36gのオルトリン酸水素カリウムおよび7.02gの塩化ナトリウムを1000mlのHPLCグレード水に溶かすことによって調製した。この溶液を10分間超音波洗浄機内で維持して溶解させた。
4匹の動物を選択した。この4匹の各個体に3つのステントを移植した。これら3つのステントには、ステントシステム(2つ)とシロリムス不含ステントシステム1つが含まれた。移植および追跡調査のQCA結果を分析し、移植前、移植後および追跡調査28日目のステント付きセグメントの平均管腔径を求めた。QCA結果を用い、ステント/動脈比、初期獲得径(acute gain)、リコイル率%および遠隔期径損失(late
loss)を計算した。シロリムス不含ステントシステム(BMS)の場合の遠隔期径損失は一般に約1mm〜1.5mmであった。一方、ステントシステムの場合の遠隔期径損失は0.45mm(±0.23mm)であることが分かった。ステントシステムに関連する死亡は報告されなかった。さらに、ステントシステムに関連する血栓症または再狭窄もこれらの4個体のいずれについても報告されなかった。従って、これらのステントシステムはシロリムス不含ステントシステムまたはBMSに比べて効果的かつ安全であると結論づけられた。同じ研究において、28日目の試験では、平均新生内膜厚がDESでは約150(±15)ミクロンであり、賦形剤がコーティングされたステントでは185(±50)ミクロンであることが示された。定量分析によれば、シロリムスがコーティングされた全てのステントにおいて新生内膜厚の完全な治癒が示された。
Claims (22)
- 複数の層を含む体腔に関連する医学的状態を処置するための挿入可能な薬物送達医療装置であって、該挿入可能な薬物送達医療装置が複数の平均径を有する複数のナノ担体でコーティングされた外面を含み、該複数のナノ担体のうち、あるナノ担体が封入材によって取り囲まれた薬物を含み、該封入材が生物学的薬剤、血液賦形剤およびリン脂質のうち少なくとも1つを含み、該ナノ担体が該複数の層のうち少なくとも1つの層を透過するのに適した平均径を有し、かつ、該ナノ担体の表面が該薬物を含まず、
複数のナノ担体が体腔の内膜層を透過するのに適した第一の平均径を有する第一のナノ担体セットと、体腔の中膜層を透過するのに適した第二の平均径を有する第二のナノ担体セットと、体腔の外膜層を透過するのに適した第三の平均径を有する第三のナノ担体セットをさらに含み、
該第一のナノ担体セットは、挿入可能な薬物送達医療装置が体腔内の標的部位に近接するようになった際に内膜層に透過し、
該第二のナノ担体セットは、挿入可能な薬物送達医療装置が体腔内の標的部位に近接するようになった際に、内膜層を経て、また中膜層に関連する栄養血管を経て、中膜層および内膜層に透過し、
該第三のナノ担体セットは、挿入可能な薬物送達医療装置が体腔内の標的部位に近接するようになった際に、内膜層を経て、また中膜層に関連する栄養血管を経て、また外膜層に関連する栄養血管を経て、外膜層、内膜層および中膜層に透過し、該第三のナノ担体セットのうち少なくとも1種類のナノ担体が外膜層に蓄積され、薬物が第三のナノ担体セットから経時的に放出される、
挿入可能な薬物送達医療装置。 - 挿入可能な薬物送達医療装置が該体腔内の標的部位に近接するようになった際に、前記複数のナノ担体が該外面から放出され、該複数のナノ担体のうち少なくとも1種類のナノ担体が、前記複数の層のうち少なくとも1つの層を透過する、請求項1に記載の挿入可能な薬物送達医療装置。
- 複数の平均径が1nm以上、5000nm以下の範囲である、請求項1に記載の挿入可能な薬物送達医療装置。
- 体腔の複数の層が内膜層、中膜層および外膜層を含む、請求項1に記載の挿入可能な薬物送達医療装置。
- 生物学的薬剤およびリン脂質のうち少なくとも1つが、薬物の安定化および標的部位に対する親和性からなる群から選択される少なくとも1つの効果を有する、請求項1に記載の挿入可能な薬物送達医療装置。
- 第一の平均径が800nm以上、1500nm以下の範囲であり、第二の平均径が300nm以上、800nm以下の範囲であり、第三の平均径が10nm以上、300nm以下の範囲である、請求項1に記載の挿入可能な薬物送達医療装置。
- ステント、バルーン、バルーンに取り付けられたステントおよびバルーンカテーテルの1つである、請求項1に記載の挿入可能な薬物送達医療装置。
- 挿入可能な薬物送達医療装置がバルーンに取り付けられたステントであり、ステントの近位端を超えて延長するバルーンの少なくとも一部およびステントの遠位端を超えて延長する該バルーンの少なくとも一部が複数のナノ担体でコーティングされている、請求項7に記載の挿入可能な薬物送達医療装置。
- ステントおよびバルーンが少なくとも2層の複数のナノ担体でコーティングされ、バルーンおよびステントに相当する少なくとも2層のうちの外層が、第三の平均径を有する少なくとも1種類のナノ担体を含み、これにより、体腔内の標的部位に近接時にバルーンが膨張された際に、第三の平均径を有する少なくとものナノ担体のバースト放出がもたらされる、請求項7に記載の挿入可能な薬物送達医療装置。
- ステントに相当する少なくとも2層のうちの外層が第三の平均径を有する少なくとも1種類のナノ担体を含み、ステントに相当する少なくとも2層のうちの内層が第二の平均径を有する少なくとも1種類のナノ担体および第一の平均径を有する少なくとも1種類のナノ担体を含み、ステントおよびバルーンに相当する外層が、ステントの外面からの、第三の平均径を有する少なくとも1種類のナノ担体のバースト放出をもたらし、第二の平均径を有する少なくとも1種類のナノ担体および第一の平均径を有する少なくとも1種類のナノ担体が、体腔内の標的部位に近接するようになった際に経時的に複数の層のうち少なくとも1つの層を透過する、請求項9に記載の挿入可能な薬物送達医療装置。
- 挿入可能な薬物送達医療装置が少なくとも2層の複数のナノ担体でコーティングされ、その少なくとも2層のうちの外層が、その少なくとも2層のうちの内層に含まれる少なくとも1種類の薬物とは異なる少なくとも1種類の薬物を含む、請求項9に記載の挿入可能な薬物送達医療装置。
- 第一のナノ担体セット、第二のナノ担体セットおよび第三のナノ担体セットが異なる薬物を含む、請求項3に記載の挿入可能な薬物送達医療装置。
- 第一のナノ担体セットが抗炎症薬および抗血栓形成薬からなる群から選択される薬物を含み、第二のナノ担体セットが抗増殖薬を含む、請求項3に記載の挿入可能な薬物送達医療装置。
- 第一のナノ担体セットが抗増殖薬を含み、第二のナノ担体セットが抗血栓薬および抗炎症薬からなる群から選択される薬物を含み、第三のナノ担体セットが治癒促進薬を含む、請求項3に記載の挿入可能な薬物送達医療装置。
- 薬物が抗増殖薬、抗炎症薬、抗新生物薬、抗凝固薬、抗フィブリン薬、抗血栓薬、抗有糸分裂薬、抗生物質、抗アレルギー薬および抗酸化薬、抗増殖薬、エストロゲン、プロテアーゼ阻害剤、抗体、免疫抑制薬、細胞増殖抑制薬、細胞傷害薬、カルシウムチャネル遮断薬、ホスホジエステラーゼ阻害剤、プロスタグランジン阻害剤、栄養補助剤、ビタミン、抗血小板凝集薬および遺伝子操作上皮細胞からなる群から選択される、請求項1に記載の挿入可能な薬物送達医療装置。
- 薬物がパクリタキセル、シロリムス、タクロリムス、クロベタゾール、デキサメタゾン、ゲニステイン、ヘパリン、17β−エストラジオール、ラパマイシン、エベロリムス、エチルラパマイシン、ゾタロリムス、ABT−578、バイオリムスA9、ドセタキセル、メトトレキサート、アザチオプリン、ビンクリスチン、ビンブラスチン、フルオロウラシル、塩酸ドキソルビシン、マイトマイシンおよびその類似体、ミオマイシン(miomycine)、ヘパリンナトリウム、低分子量ヘパリン、ヘパリノイド、ヒルジン、アルガトロバン、フォルスコリン、バピプロスト、プロスタサイクリン、プロスタサイクリン類似体、デキストラン、D−phe−pro−arg−クロロメチルケトン、ジピリダモール、糖タンパク質IIb/IIIa、組換えヒルジン、ビバリルジン、ニフェジピン、コルヒチン、ロバスタチン、ニトロプルシド、スラミン、セロトニン遮断薬、ステロイド、チオプロテアーゼ阻害剤、トリアゾロピリミジン、酸化窒素または酸化窒素供与体、スーパーオキシドジスムターゼ、スーパーオキシドジスムターゼミメティック、エストラジオール、アスピリン、アンギオペプチン、カプトプリル、シラザプリル、リシノプリル、ペルミロラストカリウム、α−インターフェロン、ならびに生物活性RGDからなる群から選択される、請求項1に記載の挿入可能な薬物送達医療装置。
- 生物学的薬剤が血液由来の賦形剤、リン脂質、類脂質、ステロイド、ビタミン、エストラジオール、エステル化脂肪酸、非エステル化脂肪酸(non estrified fatty acid)、グルコース、イノシトール、L−乳酸塩、リポタンパク質、炭水化物、リン酸三カルシウム、沈殿リン酸カルシウム、三塩基性リン酸カルシウム、ならびにヒト、卵およびダイズ由来の物質からなる群から選択される、請求項1に記載の挿入可能な薬物送達医療装置。
- 生物学的薬剤および血液賦形剤のうち少なくとも1つがpH7.4未満の媒体に溶解する、請求項1に記載の挿入可能な薬物送達医療装置。
- 医学的状態が再狭窄、体腔遮断、アテローム性動脈硬化症および体腔内のプラーク蓄積のうち少なくとも1つを含む、請求項1に記載の挿入可能な医療装置。
- 体腔内が血管を含む、請求項1に記載の挿入可能な薬物送達医療装置。
- 血管が冠動脈、末梢動脈、頚動脈、腸骨動脈、膝窩動脈および静脈からなる群から選択される、請求項20に記載の挿入可能な薬物送達医療装置。
- リン脂質がホスファチジルコリン(レシチン)、ホスファチジルグリセロール、ホスファチジルイノシトール、ホスファチジルセリン、ホスファチジン酸、カルジオリピンおよびホスファチジルエタノールアミンからなる群から選択される、請求項1に記載の挿入可能な薬物送達医療装置。
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US20060085058A1 (en) * | 2004-10-20 | 2006-04-20 | Rosenthal Arthur L | System and method for delivering a biologically active material to a body lumen |
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