JP6811232B2 - 生分解性シルク耳チューブ - Google Patents
生分解性シルク耳チューブ Download PDFInfo
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- JP6811232B2 JP6811232B2 JP2018503476A JP2018503476A JP6811232B2 JP 6811232 B2 JP6811232 B2 JP 6811232B2 JP 2018503476 A JP2018503476 A JP 2018503476A JP 2018503476 A JP2018503476 A JP 2018503476A JP 6811232 B2 JP6811232 B2 JP 6811232B2
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Description
ここで、シルク耳チューブは、2mm未満の長さであり、1.5mm未満の外径を有し、およびここで、シルク耳チューブは、対象によって再吸収される。一部の実施態様では、中耳炎は、急性中耳炎、浸出のある中耳炎、または慢性の化膿性中耳炎である。
本出願において、文脈からそれ以外が明らかでない限り、(i)用語「a」は、「少なくとも1つ」を意味することが理解され得て;(ii)用語「または」は、「および/または」を意味することが理解され得て;(iii)用語「含む(comprising)」および「含む(including)」は、それら自体でまたは1つまたは複数のさらなる構成要素またはステップとともに示されたかにどうかかかわらず、箇条書きされた構成要素またはステップを包含することが理解され得て;および、(iv)用語「約(about)」および「およそ(approximately)」は、等価として用いられ、当業者によって理解される標準的な変動を許容することが理解され得て;および、(v)範囲が提供される場合は、エンドポイントが含まれる。
本明細書に記載の方法および組成物において用いられるシルクフィブロイン溶液は、例えばBombyx mori由来の溶解されたカイコシルクを含む溶液から得られ得る。あるいは、シルクフィブロイン溶液は、例えばNephila clavipes由来の溶解されたスパイダーシルクを含む溶液から得られ得る。また、シルクフィブロイン溶液は、例えば、細菌、酵母、哺乳類の細胞、トランスジェニック動物またはトランスジェニック植物由来の遺伝学的に操作されたシルクを含む溶液から得ることもできる。例えば、WO97/08315および米国特許5,245,012を参照。一部の実施態様では、遺伝学的に操作されたシルクは、例えば、治療剤、例えば、サイトカイン、酵素、または任意の数のホルモンまたはペプチド系薬物、抗菌剤および関連基質との融合タンパク質を含むことができる。
提供されるシルク耳チューブの外径は、特定の適用および/または対象のニーズに従って変更することができ、例えば、約0.1mm〜約4mmまたはそれよりも大きい。本明細書に記載されるように、一部の実施態様では、シルク耳チューブまたは特定の内側ルーメン直径の構築物は、シルク耳チューブを作製する工程において、所望の直径のロッドを用いることによって準備され得る。特定のサイズは、例えば、0.1mm、0.2mm、0.3mm、0.4mm、0.5mm、0.6mm、0.7mm、0.8mm、0.9mm、1.0mm、1.2mm、1.4mm、1.6mm、1.8mm、2.0mm、2.2mm、2.4mm、2.6mm、2.8mm、3.0mm、3.2mm、3.4mm、3.6mm、および3.8mmを含む。好ましいサイズは、範囲として表現することもでき、例えば、0.1〜2.9mm、0.1〜2.5mm、0.1〜2mm、0.1〜1.5mm、0.1〜1mm、1.0〜3mm、1.0〜2mm、1.0〜1.5mmなどである。一部の実施態様では、提供される実施態様は、これらの値の1つまたは複数から、最大で20%(例えば、最大で15%、10%、5%)変化し得る。
様々な実施態様によれば、提供されるシルク耳チューブは、2以上の層を含んでよい。一部の実施態様では、それぞれの沈着された層の厚さは、とりわけ、層を形成するために用いられるシルクフィブロイン溶液中のフィブロインの濃度を調節することによって制御することもできる。例えば、提供されるシルク耳チューブが、浸漬コーティングによって形成される実施態様では、シルクフィブロイン水溶液中のフィブロインが濃縮されればされるほど、より多くのフィブロインが、ロッド上またはシルクフィブロインの以前の層上に沈着されて、よりぎっしり詰まった構造が形成される。
一部の実施態様では、提供されるシルク耳チューブは、1つまたは複数のポロゲンの使用を通して、多孔性で作られ得る。任意の公知のポロゲンが、様々な実施態様による使用に適切であり得ると考えられる。一部の実施態様では、ポロゲンは、結晶(例えば、塩化ナトリウム結晶、糖結晶)、マイクロ−および/またはナノ−スフェア、ポリマー(例えば、ポリエチレンオキシド、またはPEO)、氷晶、硫酸、リン酸、アルカリ金属、ハロゲン化アルカリ土類金属、多糖類、ワックス粒子、合成ポリマー粒子、および/またはレーザーであってよく、または含んでよい。一部の実施態様では、ポロゲンは、ポアの機械的導入を含んでよい(例えば、シルク耳チューブに1回または複数回の穴をあけるための針または他の物品またはデバイスを用いる、または、シルク耳チューブ内に1つまたは複数の裂け目を導入するストレスを用いる)。
様々な実施態様によれば、提供されるシルク耳チューブは、任意の適用に適切な方法を介して形成され得る。一部の実施態様では、例えば、提供されるシルク耳チューブを作製する方法は、限定されないが、注入成形、浸漬コーティング、ゲル紡糸、3Dプリント、および機械加工、多層(layer by layer)技術、および充填成形を含む。加えて、シルク耳チューブを形成するための特定の例示的な方法は、以下の実施例に示される。
一部の実施態様では、提供されるシルク耳チューブは、1つまたは複数の治療剤を含む。一部の実施態様では、シルクフィブロイン溶液は、シルク耳チューブを形成する前に治療剤と接触され得て、または、シルク耳チューブ上にそれが(例えばコーティングとして)形成された後にローディングされ得る。一部の実施態様では、少なくとも1つの治療剤は、シルク耳チューブの形成中にシルク内にトラップされて、例えば、一部の実施態様では、ガス流による水性フィブロイン層の乾燥、例えば、N2ガスによるシルクフィブロイン層の脱水は、フィブロインの、ベータシート構造への構造変化を誘導し、それは薬剤をトラップする。一部の実施態様では、さらなる層は、それから、同一の薬剤、異なる薬剤が加えられ得て、または、薬剤が加えられ得ない。一部の実施態様では、この段階的な沈着アプローチは、様々な濃度の治療薬を各層内にトラップすることも可能にする。様々な実施態様によれば、シルク材料を溶かさない任意の製剤担体が場合により用いられ得る。一部の実施態様では、治療剤は、液体、細かく分割された固体、または任意の他の適切な物理的形状として存在し得る。
当業者は、提供されるシルク耳チューブに関するいくつかの使用を思い描くことが可能である。一部の実施態様では、本発明は、シルク耳チューブを対象の外耳道に導入するステップを含む、中耳炎を処置する方法を提供し、ここで、シルク耳チューブは、2mm未満の長さであり、1.5mm未満の外径を有し、およびここで、シルク耳チューブは、対象によって再吸収される。一部の実施態様では、中耳炎は、急性中耳炎、浸出および伝音難聴のある中耳炎、または慢性の化膿性中耳炎である。
シルク溶液の調製−シルク溶液は、以前の研究において説明される手順に従って、Bombyx moriカイコ繭から生産され得る。B.moriカイコシルクの繭は、Tajima Shoji Co(日本、横浜)によって供給され得る。手短には、繭は、沸騰した0.02MのNa2CO3(Sigma−Aldrich,St Louis,MO)溶液中で20分間練られる。それから、フィブロイン抽出物をMilli−Q水中で3回リンスして、9.3−M LiBr溶液中に溶解させて、20%(w/v)溶液を産出して、続いて、蒸留水に対して2日間透析して(MWCO 3,500)、シルクフィブロイン水溶液を得る(ca.8wt/vol%)。
この実施例では、注入成形工程を用いてシルク耳チューブを製造した。
以前に説明された方法に従ってMachinableWax.com(USA)から調製されたワックスで鋳型を作成した。鋳型は、高さが3.30cmであり、0.76cmの直径であった。鋳型は、2つのピースを有し、1mm底部ウェハの上部に置かれた2mmの厚さの上側ピースは、上側部分におけるPTFEの望ましい配置に対応する直径が0.76mmの支持となるホールを与えた。また、鋳型は、0.25cmの高さを有する、6ウェル上側ピースに取り付けられた薄いウェハを有した。シルク注入の前に、2つのピースを互いの上部に置いて、パラフィンを用いて一緒に密封して、PTFEを、ボトム−ウェルソケット中に配置することによってウェルの中央に固定した。次に、CentriVapベンチトップバキュームを用いて25〜33w/v%に濃縮された30分煮沸シルクを、鋳型の各ウェルにローディングした。ウェルにシルクを添加した後に、鋳型を−20℃中に4時間置いて、それから、完全に乾燥するまで、−30℃で、真空で凍結乾燥器内に置いた。
シルク溶液の調製−シルク溶液は、以前の研究において説明された手順に従って、Bombyx moriカイコ繭から生産され得る。B.moriカイコシルクの繭は、Tajima Shoji Co(日本、横浜)によって供給され得る。手短には、繭は、沸騰した0.02MのNa2CO3(Sigma−Aldrich,St Louis,MO)溶液中で30分間練られて、5〜7%w/vのシルク溶液が提供される。それから、溶液を、1日間、およそ8〜9%w/vのシルクの溶液に濃縮させた。続いて、CentriVAP減圧濃縮器を用いてシルク溶液をさらに濃縮して、20〜25%w/vの濃度のシルクを含むシルク溶液を得た。
PEO溶液の調製−60mg/mLのポリ(エチレン)オキシド(PEO)を50mLの脱イオン(DI)水に加えることによって、PEOの6%wt溶液を調製した(合計300mgのPEO)。PEOを加える前に、撹拌バーを用いてホットプレート上で、約80℃で10分間、DI水を加熱した。PEOがDI水に加えられた時点で、混合物を1時間撹拌して、粘性の均質な溶液になった。同時に、20%w/vシルク溶液を調製した。
1mLの20%シルクを使用:
a.(x合計mg)*0.8=200mgのシルク
b.x合計=250mg、したがって、PEOのmg=250mg合計−200mgシルク=50mg PEO
c.50mg PEO/(60mg/mL PEO)=0.83mLのPEO
Ciprodex(例示的な活性剤)による多孔性チューブのコーティング−9mg/mLのシプロフロキサシンHCLおよび3mg/mLのデキサメタゾンを、20〜25%シルクw/vに濃縮されたシルク溶液に加えた。次に、実施例3に上述のとおりに調製された、PEOコーティングを有さないシルクチューブを、テフロンロッド上に置いた。それから、シルクチューブおよびテフロンロッドを、シルク−シプロフロキサシン−デキサメタゾン溶液中に浸漬して、それから、100%メタノールで満たされた計量ボート内に水平に1時間置いた。重要なことに、シルク−薬物浸漬コーティングからメタノール溶液中に薬物が放出されるのを防ぐために、メタノール浴を、シプロフロキサシンおよびデキサメタゾンの両方で飽和した。メタノール処理後、シルクチューブを蒸発気フード内で乾燥させた。乾燥後、エチレンオキシド滅菌を用いてシルクチューブを滅菌した。
当業者は、日常的にすぎない実験を用いて、本明細書に記載の本発明の特定の実施態様に対する多くの等価物を認識し、または確認することが可能である。本発明の範囲は、上記の説明に制限されることは意図されないが、むしろ、以下の特許請求の範囲に記載される。
Claims (17)
- 再吸収可能な耳チューブを作製する方法であって、
シルクフィブロイン溶液を提供するステップ;および
前記のシルクフィブロイン溶液からシルク耳チューブを形成するステップ、
を含み、
前記のシルク耳チューブは、約0.4mm〜約3.6mmの長さを有し、約0.08mm〜約4.8mmの外径を有し、
前記のシルク耳チューブは、再吸収可能である、
方法。 - 請求項1の方法であって、
前記のシルク耳チューブは、ゲル紡糸またはゲル沈着を介して形成される、
方法。 - 請求項1の方法であって、
前記のシルク耳チューブは、浸漬コーティングまたは溶液沈着を介して形成される、
方法。 - 請求項1の方法であって、
前記のシルク耳チューブは、マイクロ造型を介して形成される、
方法。 - 請求項1の方法であって、
前記方法は、複数のポアを前記のシルク耳チューブに導入するステップをさらに含む、
方法。 - 請求項5の方法であって、
前記ポアは、前記のシルク耳チューブを形成する前に、前記シルクフィブロイン溶液とポロゲンを関連させることによって導入される、
方法。 - 請求項6の方法であって、
前記ポロゲンは、ポリエチレンオキシド、NaCl、アルカリ金属、ハロゲン化アルカリ土類金属、リン酸、硫酸、糖結晶、水溶性マイクロスフェア、多糖類、タンパク質マイクロスフェア、ワックス粒子、および、合成ポリマー粒子から選択される、
方法。 - 請求項1から7のいずれか一項の方法であって、
前記のシルク耳チューブは、少なくとも2つの層を含む、
方法。 - 請求項1の方法であって、
前記のシルク耳チューブの形成前または形成中に、少なくとも1つの治療剤を、前記シルクフィブロイン溶液と関連させるステップをさらに含む、
方法。 - 請求項9の方法であって、
前記の少なくとも1つの治療剤は、抗生物質、鎮痛剤、およびステロイドからなる群より選択される、
方法。 - 請求項1から10のいずれか一項の方法であって、
前記のシルクフィブロイン溶液は、1%〜30%wtのシルクフィブロインを含む、
方法。 - 請求項1から11のいずれか一項の方法であって、
前記のシルク耳チューブは、1日〜1週を含めた再吸収速度を有する、
方法。 - 請求項1から11のいずれか一項の方法であって、
前記のシルク耳チューブは、8日〜2年を含めた再吸収速度を有する、
方法。 - 請求項1から13のいずれか一項の方法であって、
前記のシルク耳チューブは、1〜60%のベータシート含有量を含む、
方法。 - 請求項14の方法であって、
実質的なベータシート含有量は、オートクレービング、水蒸気アニーリング、および、メタノールによる処理の少なくとも1つによって導入される、
方法。 - 請求項1から15のいずれか一項の方法であって、
前記のシルクフィブロインは、スパイダーシルク、カイコシルク、および組み換えシルクからなる群より選択される、
方法。 - 請求項1の方法であって、
前記のシルク耳チューブは、0.5mm〜3.0mmの長さを有し、0.1mm〜4.0mmの外径を有する、
方法。
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