JP4909071B2 - 逆感熱性ポリマーを使用する一時的な塞栓形成 - Google Patents
逆感熱性ポリマーを使用する一時的な塞栓形成 Download PDFInfo
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- JP4909071B2 JP4909071B2 JP2006509225A JP2006509225A JP4909071B2 JP 4909071 B2 JP4909071 B2 JP 4909071B2 JP 2006509225 A JP2006509225 A JP 2006509225A JP 2006509225 A JP2006509225 A JP 2006509225A JP 4909071 B2 JP4909071 B2 JP 4909071B2
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- thermosensitive polymer
- poloxamer
- embolization
- polymer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Description
本出願は、2003年3月24日に出願された米国仮特許出願第60/457,148号に関して、優先権の利益を主張する。
(塞栓形成)
一般に、塞栓形成は、血管を治療上一時的または永久的に閉塞させることである。血管は、異常な出血の防止、腫瘍供給血管の閉塞、または動脈と静脈との間が異常に連通する動静脈奇形(AVM)の閉塞などのいくつかの理由で、閉塞を要する場合がある。
ポリエチレンオキシド、ポリプロピレンオキシドb−ポリエチレンオキシドa[PEOa−PPOb−PEO a]のトリブロック(ABA)コポリマーは、ポロキサマー(またはプルロニック類)とも呼ばれ、多様な工業用途に広く使用されている非イオン性界面活性剤である。「非イオン性界面活性剤:ポリオキシアルキレンブロックコポリマー」(Nonionic Surfactants:polyoxyalkylene block copolymers)、第60巻、Vol.60. Nace VM, Dekker M(編集者)、ニューヨーク、1996年、280pp。それらの界面活性剤特性は、洗浄力、分散、安定化、泡立ちおよび乳化に有用だった。カバナ A(Cabana A)、アブデルティフ AK(Abdellatif AK)、ユハス J.(Juhasz J.)、「ポリエチレンオキシド、ポリプロピレンオキシド−ポリエチレンオキシドコポリマー(ポロキサマー407)水性溶液のゲル化過程の研究」(Study of the gelation process of polyethylene oxide.polypropylene oxide−polyethylene oxide.copolymer(poloxamer407)aqueous solutions.)、コロイドおよび界面科学学会会報(Journal of Colloid and Interface Science)1997年;190:307−312。特定のポロキサミン、たとえばポロキサミン1307も逆感熱性を示す。
本発明の一態様は、哺乳動物の血管部位に一時的に塞栓形成する方法であって、逆感熱性ポリマーを含む組成物を哺乳動物の脈管構造内に導入するステップを含み、前記逆感熱性ポリマーが、前記脈管構造内においてゲル化して、前記哺乳動物の血管部位に一時的に塞栓形成する方法に関する。
次に、本発明について、付随する実施例に関してさらに詳細に説明し、実施例には、本発明の特定の好ましい実施態様を示す。しかし、本発明は、多くの異なる形態で実施することができるため、本明細書に記載する実施態様に限定されると考えるべきではなく、むしろ、これらの実施態様は、本開示が綿密かつ完全であるように提供され、本発明の範囲を当業者に完全に伝えるものである。
目立つところでは、これらの方法は、血管内における、たとえばカテーテルを使用した経皮的血管内手順時における安全な一時的な塞栓形成のために開発された。ポロキサマーおよびポロキサミンは、急速な可逆的ゾル−ゲル遷移挙動を有する非イオン性界面活性剤である。ポリマーは、一時的な塞栓性薬剤として安全かつ有効である。最初に、ポロキサマーおよびポロキサミンのゲル化後の溶解時間は、生体外モデルで決定した。さらに、たとえば、7匹の犬の腎臓および肺動脈の一過性ポロキサマー閉塞を連続的な血管造影図により追跡した。巨視的変化および病理学的変化は、1週間後に調査した。この実験は、豚の類似の動脈および2匹のラビットの耳動脈で繰り返した。生体外ゲル化後のポロキサマー溶解は、濃度に応じて1〜20時間内に完了した。生体内ポロキサマー407(22%)の注入により完全に閉塞し、次に合併症なしで10〜90分後に完全に再疎通した。ポロキサマー閉塞の唯一の生化学的作用は、トリグリセリドレベルの一過性上昇だった。1週間で、病理的な異常はなかった。たとえば、ポロキサマー407は、一時的な閉塞のための安全かつ信頼できる塞栓形成物質として使用することができる。
血管系障害を治療するための従来の塞栓形成方法は、血流を方向付ける塞栓形成に頼っている。臨床上の慣習では、血管床を塞栓症薬剤から防護するか、または血流を目標部位にリダイレクトすることが望ましい場合がある。したがって、短期および可逆的閉塞性薬剤は、こうした手順に有用であろう。
一般に、本発明の方法に使用する逆感熱性ポリマーは、体温またはほぼ体温でゲルになり、患者の体内に液体状で注入することができる。注入される物質は、体温に達すると液体からゲルに遷移する。本発明の方法に関連して使用される逆感熱性ポリマーは、逆感熱ゲル化特性を有するブロックコポリマーを含み得る。ブロックコポリマーは、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー、たとえばポリエチレンオキシドおよびポリプロピレンオキシドの生体分解性および生体適合性コポリマーをさらに含むことができる。また、逆感熱性ポリマーは、抗血管形成薬剤などの治療薬剤を含むことができる。
塞栓形成は、物質が血管内に注入され、血管を少なくとも部分的に充填するかまたは閉塞させ、および/または凝血塊の形成を促進し、その結果、血管を通る血流が減少または停止するプロセスである。「発明の背景」を参照。血管の塞栓形成は、医療上の様々な理由で有益である可能性があり、たとえば、傷害による出血(たとえば臓器の出血、胃腸内の出血、血管の出血、および動脈瘤に関連する出血)を防止もしくは調節するか、または疾患のある組織(たとえば腫瘍、血管奇形、出血プロセス)を血液供給源の切断によりアブレートすることを含む。塞栓形成は、外科手術時または外科手術直後に、血液の損失を防止するために使用することもできる。腫瘍の塞栓形成は、腫瘍のサイズを収縮させ、腫瘍の視覚化を促進し、外科手順に関連する血液の損失を最小限にするか、または防止するために手術前に行われ得る。
上記のとおり、塞栓形成は、一般に、ガイダンスおよび監視、たとえば蛍光透視ガイダンスまたはX線ガイダンスを含む血管造影技術を使用して行われ、塞栓形成薬を血管または動脈に送達する。さらに、血管拡張薬(たとえばアデノシン)は、事前、同時または後に患者に投薬されて手順を容易にし得る。
頭部および頚部では、塞栓術は、殆どの場合、鼻出血および外傷性出血の場合に行われる。耳鼻咽喉科医は、解剖および臨床ベースで、前方と後方との鼻出血を区別する。鼻出血は、温度および湿度などの環境要因、感染症、アレルギー、外傷、腫瘍および化学的刺激を含む多くの原因から生じる。外科的結紮と比べた塞栓形成の利益は、比較的小さい分岐血管をより選択的に遮断することである。まさに出血している分岐血管に塞栓形成することにより、内部上顎配置の他の部分に対する通常の血流は維持される。塞栓形成の合併症としては、塞栓形成の意図した領域外における塞栓形成物質の逆流が挙げられ得、最悪の場合、脳梗塞または失明の原因になり得る。塞栓形成は、動脈結紮より効果的であると実証されている。しかし、塞栓形成は、小さい合併症の率が比較的高く、大きい合併症の率に差は見られなかった。外傷性出血の場合、塞栓形成技術は鼻出血の場合と同じである。頭部および頚部の動脈のサイズの点で、多くの場合は、微小カテーテルが必要である。
胸部では、出血に関連する塞栓形成の2つの主な適応症は、(1)肺動静脈奇形(PAVM);および(2)喀血。PAVMは、通常は先天的外傷だが、外科手術または外傷後に生じる場合もある。先天的形態は、一般に、ランデュ−オースラ−ウェバー症候群とも呼ばれる遺伝的出血性毛細血管拡張症に関連する。この状態には、遺伝性素因がある。PAVMは1つまたは複数であり得、十分に大きい場合、生理的な右左心臓短絡を生じる可能性がある。こうした短絡の臨床上の発現としては、チアノーゼおよび赤血球増加症が挙げられる。脳梗塞および脳膿瘍は、奇異性塞栓から生じる可能性がある。PAVMも、出血して喀血を生じる場合もある。
腹部および骨盤では、塞栓形成の多くの適応症が存在する。出血の塞栓形成の場合、最も一般的な適応症は急性GI出血である。一般に肝臓および脾臓に対する固形臓器傷害は、塞栓形成で容易に治療することができる。その他の適応症が存在し、たとえば、婦人科/産科関連出血および骨盤環骨折などがある。
薬物送達および製薬業界では、薬物を正しい時に、管理されたやり方で送達し、副作用が最小限であり、投与量当たりの効力が大きい新たな方法が求められている。本発明の塞栓形成法に使用される可逆的ゲル化ポリマーは、従来の小分子薬物、および新しい大分子(たとえば、ペプチド)薬物またはその他の治療用生成物に適する送達媒体にする物理化学特性を有する。したがって、感熱性ポリマーを含む組成物は、さらに予め選択された製剤効果を提供するように選択された製剤をさらに含み得る。製剤効果は、疾病または身体疾患の源または症状を治療するために求められる効果の1つである。製剤は、FDA製薬ガイドラインに基づく規則の対象となる製品、および消費製品を含む。重要なことに、本発明の塞栓形成法に使用される組成物は、生物活性物質を可溶化して排出することが可能である。可溶化は、大量の水相中における溶解の結果として、またはポロキサマーの疎水性領域により形成されるミセル中に溶質を含むことにより生じると予想される。薬物の放出は、拡散または網状組織浸食のメカニズムにより生じる。
本発明の方法は、たとえばポロキサマー407を含む塞栓形成キットを使用して行うこともできる。こうしたキットは、減菌形態の感熱性ポリマーを含み得、許容可能な再構成液体の減菌容器を含み得る。適切な再構成液体は、「レミントン薬学」(Remington’s Pharmaceutical Sciences)、米国薬局方(The United States Pharmacopia)−国民医薬品集(The National Formulary)に開示されている。こうしたキットは、別法によると、たとえばポロキサマー407の組成物の減菌容器を含み得る。こうしたキットは、必要な場合、その他の従来のキットの構成要素、たとえば1個または複数の担体、1個または複数の追加の混合用バイアルを含むこともある。塞栓性組成物および担体の量、これらの成分を混合するためのガイドライン、投与手順を指示する折込みまたはラベルなどの説明書もキットに含まれ得る。キットに含まれる容器および任意の材料の減菌、および塞栓性組成物の凍結乾燥方法(フリーズドライとも呼ばれる)は、当業者に公知の従来の減菌および凍結乾燥方法を使用して行うことができる。
便宜上、本明細書、実施例および添付の請求の範囲で使用する特定の用語を以下に記載する。
特定の実施態様では、本発明は、哺乳動物の血管部位に一時的に塞栓形成する方法であって、
哺乳動物の脈管構造に、逆感熱性ポリマーを含む組成物を導入するステップで、前記逆感熱性ポリマーが、前記脈管構造内でゲル化し、その結果、前記哺乳動物の血管部位に一時的に塞栓形成するステップを含む方法に関する。
本発明について一般的に説明したが、以下の実施例を参照すると、さらに理解しやすいであろう。以下の実施例は、単に本発明の特定の態様および実施態様を具体的に示すために含まれるのであり、本発明を制限する意図はない。
(ポリマーの処方)
精製したポロキサマー407(多分散性指数1.06)(ヒンズバー・ラボラトリーズ(Hinsbar Laboratories、クローソン、ミシガン州、米国)を、最終処方物の所望の濃度の2倍で攪拌しながら、氷温の生理食塩水に徐々に添加した。ポロキサマーが溶解し始めると、氷温の造影剤(オムニパーク(商標)300、アマシャム・ヘルス(Amersham Health)、プリンストン、ニュージャージー州、米国)を最終量まで添加した。最初のスラリーを、氷槽内で一晩中攪拌し、次に濾過して殺菌した。生体外実験の場合、溶解を視覚的に評価するのを補助するために、1滴の食品着色料を添加した。
(一時的な塞栓形成の生体外モデル)
生体外モデルを、ポロキサマー407の様々な濃度(14〜24%(w/w))のゲルの溶解時間を調査するために使用した。生体外モデルは、サイズが200〜400μで、毛細血管床を模倣したガラスビーズを充填した5mLのカラムから構成された(図1a)。カラムは、38℃の加熱水槽中に浸漬し、ハーバードポンプを使用して、毎分400mLの流量で潅流させた。カラム周囲のバイパスを、閉塞周囲で流れを迂回させるために使用した。代表的な実験では、ガラスカラムの上部から2cmの同軸カテーテルを介して、1mLのポリマー溶液を注入した。溶解時間を、ゲルの消滅、およびカラムを通る流れの再確立により視覚的に決定した。濃度に応じたポロキサマー407の溶解時間を図1bに示す。原則として、生体外の溶解は、生体内の実験に比べて非常に遅延した。たとえば、22%(w/w)の濃度は、生体内動脈を10〜90分間閉塞させることが分かったが、生体外閉塞は8時間を超えて持続した。
(生体内の一時的な塞栓形成)
(生体内血管閉塞)
動物実験の計画は、カナダ動物管理委員会(the Canadian Council on Animal Care)のガイドラインに従って、所内動物管理委員会(Institutional Animal Care Committee)で承認された。すべての血管内手順は、全身麻酔状態で実施した。重量10〜15kgの8匹のビーグル犬は、アセプロマジン(0.1mg/kg)、グリコピロレート(0.01mg/kg)およびブトルファノール(0.1mg/kg)の筋肉注射により鎮静させて、静脈内チオペンタール(15mg/kg)で麻酔した。動物は、人為的に肺換気され、2%のイソフルランによる手術麻酔状態に維持した。ポロキサマー407(22%)は、介入を行っている間、氷上に維持した。生理食塩水を含むシリンジも氷上に維持して、ポロキサマーを注入する直前にカテーテルを冷却した。
大動脈および末端器官の巨視的写真を、検視解剖時に作成した。病理学的調査は、任意の可視的な異常のサンプルからの組織ブロック、および異常を示さない臓器の無作為サンプルに関して実施した。スライドは、ヘマトキシリン−フロキシン−サフランおよびモヴァット(Movat)のペンタクロームステインで着色した。各々のスライドを、ポロキサマーを注入した対側の動脈、静脈または末端臓器から作成した対比スライドと同時に調査した。
(血管内の一時的な塞栓形成)
追跡血管造影図の時点で、潜在的な血管内における応用を調査した。シアノアクリレートを、ポロキサマー407閉塞の近位に配置した2F微小カテーテル(ターゲット・セラピューティックス・インク(Target Therapeutics Inc.)、ボストンサイエンティフィック・コーポレーション(Boston Scientific Corporation)、フレモント、カリフォルニア州、米国)を通して注入し、膠がポロキサマーに浸潤し得たか、またはポロキサマーと血管壁(n=4)との間に浸透し得たかを試験した。完全かつ永久的な動脈閉塞は、1本の肝臓動脈、1本の腰動脈、1本の回旋枝静脈および1本の頚動脈におけるポロキサマー407に近接して注入したシアノアクリレートにより生成された。シアノアクリレートは、ポロキサマーゲルを越えて侵入し得ず、ポロキサマー407キャストと血管壁との間に浸潤することもできなかった。
(カテーテル血管造影後の大腿部動脈の一時的な塞栓形成)
大腿部動脈も、カテーテルの回収時に一時的に閉塞させて(n=3)、血管造影後の大腿部閉鎖薬剤としてのポロキサマー407の可能性を調査した。カテーテルは、ポロキサマー407を大腿部閉鎖に使用した時に圧迫も出血もせずに、大腿部動脈から回収され得た。しかし、15〜32分後、創傷はすべての事例で突然開通し、止血のための通常の圧迫が必要だった。ポロキサマー407の注入は、凝固時間の変化を生じなかった。通常の血液学的および生化学的試験の結果を表1にまとめる。
(実験室における調査)
日常の血液学的および生化学的マルチ分析を、手順の直前および直後、24時間および1週間後に4匹の犬に関して実施した。多くの生理的値は、絶食、麻酔状態、血管造影および回復期間により妨げられるので、通常の実験室における試験は、プラチナコイル塞栓形成を施したさらに6匹の犬と比較した。統計的比較を、独立サンプルT検定で行った。ポロキサマー試験では、ポロキサマー407を使用した。
(犬の動脈の一時的な塞栓形成 − 塞栓の急速な溶解)
犬の肺動脈をポロキサマー407で閉塞させた。閉塞直後、カテーテルを交換し、低温の生理食塩水を閉塞部位に近接して注入した。ポロキサマー407は溶解し、動脈は閉塞が生じなかった。この実験は、塞栓形成の必要に応じた可逆性を実証した。
(ラビットにおける一時的な塞栓形成)
2匹のラビットで、中耳動脈にカテーテルを挿入し、ポロキサマー407(22%)で塞栓形成した。閉塞時間は、両方の動物とも約90分間だった。再疎通は、直接的な観察および拡大により直接証明された(図5)。物質の溶解は、付随分岐血管により供給される動脈セグメントレベルで逆行的に開始した。内腔は、最初に、セグメント化された経路に沿って再疎通した。このプロセスが開始すると、溶解は加速し、さらに30分以内に完了した。ある期間の一過性虚血後、耳は正常を呈した。カテーテルの先端における一過性痙攣は、両側におけるポロキサマー407閉塞より長時間持続した。ラビットを1週間追跡したが、耳または中耳動脈レベルで可視的な合併症はなかった。
(溶解性ポロキサマーの薬動力学的調査)
溶解後の生体内におけるポロキサマー407の半減期を決定するために、3mLのポロキサマー407(22%)(w/w)を使って右下葉肺動脈を閉塞させてから15分から120時間後に、1匹の犬の血液を収集した。ポロキサマー407の血漿濃度は、HPLCにより決定した。簡潔に述べると、テトラヒドロフランを使って繰り返し抽出することにより、ポロキサマー407を血漿アリコートから定量的に回収した。抽出物を合わせ、減圧状態で蒸発させて溶剤を除去した。残留物は、既知の体積のテトラヒドロフラン中で再溶解させ、UV吸収発色団を含む誘導体化試薬を添加して、反応が完了するように進行させた。ポロキサマー407誘導体を、ゲル透過クロマトグラフィ(GPC−HPLC)により、過剰な誘導体化試薬および血漿成分から分離し、UV検出を使用して視覚化した。血漿中に存在するポロキサマー407の量は、ポロキサマー誘導体ピーク面積と、同様に調製された一連の外部標準のピーク面積とを比較することにより定量化した。検出限度は、1mLの血漿当たり約2μgのポロキサマー407だった。
(ポロキサマー338を使用する塞栓形成)
上記の実験計画を使用して、ビーグル犬の肝臓動脈を、18重量%のポリマーおよび50%の放射線不透過造影剤オムニパーク(商標)を含む約6mLの冷却分画ポロキサマー338(多分散性指数、1.08)溶液で閉塞させた。動脈は、45分間閉塞状態を保ち、低温生理食塩水の注入により再び開通した。右肺動脈は、約4mLの同じポロキサマー338溶液で約20分間閉塞させたが、その後ポリマーが溶解し、動脈が再び開通した。
(ポロキサミン1107を使用した塞栓形成)
上記の実験計画を使用して、ビーグル犬の肝臓動脈を、20重量%のポリマーおよび50%の放射線不透過造影剤オムニパーク(商標)を含む約6mLの冷却分画ポロキサミン1107溶液で閉塞させた。動脈は、約20分間閉塞状態を保ち、ポリマーの溶解により開通した。右腎臓動脈は、約3mLの同じポロキサミン1107溶液で閉塞させたが、約5分後に再び開通した。
(ポロキサミン1307を使用する塞栓形成)
上記の実験計画を使用して、ビーグル犬の肝臓動脈に、21重量%のポリマーおよび50%の放射線不透過造影剤オムニパーク(商標)を含む約5mLの冷却ポロキサミン1307溶液で塞栓形成した。血流は、10分で部分的に再度確立され、15分で完全に再度確立された。肩動脈の部分は、同じポロキサミン1307溶液を使用して閉塞させ、約10分間閉塞状態を保ち、血流はその後再度確立された。
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本明細書に引用するすべての特許および刊行物は、引用することにより本願に援用する。
当業者は、せいぜい通常の実験を用いて、本明細書に記載する本発明の特定の実施態様と等価な多くのものを認識するか、または確かめることができるであろう。こうした等価なものは、以下の請求の範囲により本発明に包含されることを意図する。
Claims (26)
- 哺乳動物の血管部位に一時的に塞栓形成するための、12%〜40%(w/w)の逆感熱性ポリマーを含む水性溶液からなる組成物であって、該組成物は、哺乳動物の脈管構造内に導入するのに適しており、該逆感熱性ポリマーはポリオキシアルキレンブロックコポリマーであり、そして該逆感熱性ポリマーは、脈管構造内においてゲル化し、その結果、前記哺乳動物の血管部位に一時的に塞栓形成し、逆感熱性ポリマーを含む該組成物は、約12時間未満にわたって、該血管部位に塞栓形成するのに適している、組成物。
- 前記哺乳動物がヒトである、請求項1に記載の組成物。
- 前記逆感熱性ポリマーの遷移温度が約10℃と約40℃との間である、請求項1に記載の組成物。
- その遷移温度と生理的温度との間の逆感熱性ポリマーの体積が、その遷移温度未満の逆感熱性ポリマーの体積の約80%と約150%との間である、請求項1に記載の組成物。
- 前記逆感熱性ポリマーがポロキサマーまたはポロキサミンである、請求項1に記載の組成物。
- 前記逆感熱性ポリマーがポロキサマーである、請求項1に記載の組成物。
- 前記逆感熱性ポリマーがポロキサマー407、ポロキサマー338、ポロキサマー188、ポロキサミン1107またはポロキサミン1307である、請求項1に記載の組成物。
- 前記逆感熱性ポリマーがポロキサマー407またはポロキサマー338である、請求項1に記載の組成物。
- 前記逆感熱性ポリマーの遷移温度が約10℃と約40℃との間であり、その遷移温度と生理的温度との間の逆感熱性ポリマーの体積が、その遷移温度未満の逆感熱性ポリマーの体積の約80%と約150%との間である、請求項1に記載の組成物。
- 前記逆感熱性ポリマーの遷移温度が約10℃と約40℃との間であり、その遷移温度と生理的温度との間の逆感熱性ポリマーの体積が、その遷移温度未満の逆感熱性ポリマーの体積の約80%と約150%との間であり、前記逆感熱性ポリマーがポロキサマーまたはポロキサミンである、請求項1に記載の組成物。
- 前記逆感熱性ポリマーの遷移温度が約10℃と約40℃との間であり、その遷移温度と生理的温度との間の逆感熱性ポリマーの体積が、その遷移温度未満の逆感熱性ポリマーの体積の約80%と約150%との間であり、前記逆感熱性ポリマーがポロキサマーである、請求項1に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、カテーテルを使用して前記哺乳動物の脈管構造内に導入するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 前記脈血管部位が外科的切開、出血、癌組織、子宮筋腫、腫瘍または臓器に隣接する、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、約9時間未満にわたって、前記血管部位に塞栓形成するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、約6時間未満にわたって、前記血管部位に塞栓形成するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、約3時間未満にわたって、前記血管部位に塞栓形成するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、約2時間未満にわたって、前記血管部位に塞栓形成するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、約1時間未満にわたって、前記血管部位に塞栓形成するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、約30分未満にわたって、前記血管部位に塞栓形成するのに適している、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーが、約1.5〜約1.0の多分散性指数を有する、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーが、約1.2〜約1.0の多分散性指数を有する、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーが、約1.1〜約1.0の多分散性指数を有する、請求項1、2、5、6、7または8に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が造影剤をさらに含む、請求項1に記載の組成物。
- 前記造影剤が放射線不透過物質、常磁性物質、重原子、遷移金属、ランタニド、アクチニド、染料および放射性核種含有物質から成る群から選択される、請求項23に記載の組成物。
- 逆感熱性ポリマーを含む前記組成物が、生物活性薬剤をさらに含む、請求項1に記載の組成物。
- 前記生物活性薬剤が、抗炎症性物質、抗生物質、抗菌薬、抗ウィルス薬、鎮痛薬、抗増殖性物質および化学療法薬から成る群から選択される、請求項25に記載の組成物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2010246953A (ja) * | 2003-03-24 | 2010-11-04 | Biosphere Medical Inc | 逆感熱性ポリマーを使用する一時的な塞栓形成 |
JP2014039882A (ja) * | 2003-03-24 | 2014-03-06 | Pluromed Inc | 逆感熱性ポリマーを使用する一時的な塞栓形成 |
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BRPI0408773A (pt) | 2006-03-28 |
CA2519946A1 (en) | 2004-10-07 |
MXPA05010002A (es) | 2006-03-10 |
EP2724719A1 (en) | 2014-04-30 |
JP2016093659A (ja) | 2016-05-26 |
CA2519946C (en) | 2011-09-06 |
JP2017131792A (ja) | 2017-08-03 |
CN1794980A (zh) | 2006-06-28 |
KR20060023112A (ko) | 2006-03-13 |
KR101425385B1 (ko) | 2014-07-31 |
US20050008610A1 (en) | 2005-01-13 |
JP2010246953A (ja) | 2010-11-04 |
JP2006521177A (ja) | 2006-09-21 |
AU2004224439A1 (en) | 2004-10-07 |
EP1605922A2 (en) | 2005-12-21 |
CN106215226A (zh) | 2016-12-14 |
AU2004224439B2 (en) | 2010-07-15 |
HK1197032A1 (en) | 2015-01-02 |
US20110076231A1 (en) | 2011-03-31 |
JP2014039882A (ja) | 2014-03-06 |
US20130195753A1 (en) | 2013-08-01 |
WO2004084703A2 (en) | 2004-10-07 |
US20170290948A1 (en) | 2017-10-12 |
WO2004084703A3 (en) | 2005-05-12 |
KR101198550B1 (ko) | 2012-11-06 |
EP1605922A4 (en) | 2011-03-16 |
CN102813967A (zh) | 2012-12-12 |
KR20120087912A (ko) | 2012-08-07 |
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