JP2019524348A - 止血組成物及びその作製方法 - Google Patents
止血組成物及びその作製方法 Download PDFInfo
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Abstract
Description
・フィブリノゲン、トロンビン、及びORCの乾燥粉末を調製する工程、
・フィブリノゲン、トロンビン、及びORCの粉末の混合物を、周囲条件下で急速蒸発することができる非水性溶媒に懸濁させる工程、
・ノズルを通して懸濁液を基材上に噴霧する工程、
・当該非水性溶媒を蒸発させ、得られた止血材料を乾燥させる工程、
・当該基材から当該止血材料を除去/分離し、篩分けし、このようにして、粉末の形態の少なくとも部分的に一体化しているORC繊維、フィブリノゲン、及びトロンビンを形成する工程。
本発明の止血組成物の個々の成分を下記のとおり調製した。
1)当該布地を約5cm×20cm(約2”×8”)片に分割及び切断し、
2)公知の粉砕方法を用いて、当該布地を粉末粒径(D50が94マイクロメートル未満)に粉砕する。調製において使用される方法のうちの1つは次のボールミル法である。約100グラムの布地を500mLのジルコニア製ジャーに入れ、次いで、12又は13個の20mmのジルコニア製ボール(ビー玉)を同じジャーに入れ、ジャーにふたをし、Retsch遊星ボールミル(型番PM100)にジャーを固定し、当該布地を450rpmで20分間粉砕し、粉砕された粉末を直径20cm(8”)及び目開き300−マイクロメートルの篩上に移し、少し振盪することによってビー玉と粉末とを分け、粉末を回収する。
急速なゲル化及び強力なゲルの形成は、止血材にとって重要である。
・試験バイアル1は、1:1FS/ORC比の機械混合組成物を示し、
・試験バイアル2は、2:1FS/ORC比の機械混合組成物を示し、
・試験バイアル3は、5:1FS/ORC比の機械混合組成物を示し、
・試験バイアル4は、10:1FS/ORC比の機械混合組成物を示し、
・試験バイアル5は、ORC粉末を含まない(フィブリンシーラント粉末のみ)機械混合組成物を示し、
・試験バイアル6は、1:1FS/ORC比の本発明の止血組成物を示す。
インビトロにおけるいくつかの本発明の組成物、また、比較組成物による血液凝固を以下のとおり試験した。
・試験バイアル8は、2:1FS/ORC比を有する本発明の止血組成物を示し、
・試験バイアル9は、5:1FS/ORC比を有する本発明の止血組成物を示し、
・試験バイアル10は、1:1FS/ORC比を有する本発明の止血組成物を示し、
・試験バイアル11は、同時噴霧によって作製された、ORCを含まず、フィブリンシーラント粉末のみを含む比較組成物を示し、
・試験バイアル12は、10:1FS/α−セルロース重量比でα−セルロースを添加した、フィブリンシーラント粉末を含む比較組成物を示し、
・試験バイアル13は、10:1FS/トレハロース重量比でトレハロースを添加した、フィブリンシーラント粉末を含む比較組成物を示し、
・試験バイアル14は、10:1FS/PEG4000重量比でPEG4000を添加した、フィブリンシーラント粉末を含む比較組成物を示し、
・試験バイアル15は、10:1FS/マンニトール重量比でマンニトールを添加した、フィブリンシーラント粉末を含む比較組成物を示す。
・試験バイアル1は、1:1FS/ORC比の機械混合組成物を示し、
・試験バイアル2は、2:1FS/ORC比の機械混合組成物を示し、
・試験バイアル3は、5:1FS/ORC比の機械混合組成物を示し、
・試験バイアル4は、10:1FS/ORC比の機械混合組成物を示し、
・試験バイアル5は、Yi−Lan Wangによる、2015年11月6日に出願された、「Compacted Hemostatic Cellulosic Aggregates」と題された米国仮特許出願第62/251773号に記載のとおり調製された圧縮されたORC粉末凝集体を含む比較組成物(200mg)を示し、
・試験バイアル6は、同時噴霧方法によって調製された、ORCを含まず、フィブリンシーラント粉末のみを含む比較組成物を示し、
・試験バイアル7は、1:1FS/ORC比を有する本発明の止血組成物を示し、
・試験バイアル8は、2:1FS/ORC比を有する本発明の止血組成物を示し、
・試験バイアル9は、5:1FS/ORC比を有する本発明の止血組成物を示し、
・試験バイアル10は、10:1FS/ORC比を有する本発明の止血組成物を示す。
体液と接触したときの粉末状止血組成物の迅速な可溶化又は溶解性は、迅速に止血させるのに役立ち得、流体との迅速な相互作用を示す。可溶化のバイアル試験を以下のとおり実施した:1グラムの試験した止血粉末状組成物を、純水の入ったトレイ内に置かれたスポンジ材上に配置された不織布を含む湿潤基材のある領域に均等に塗布した。試験した粉末状止血組成物を湿潤基材の表面に塗布した後、組成物の溶解性の目視観測を実施し、0時間(組成物の塗布直後、試験した組成物の塗布の1分後及び2分後に結果を記録した。
本発明の止血組成物の性能に対する粒径の効果を評価した。850μm、355μm、及び250μmの開口部を有する篩に組成物を逐次通すことによって粒径を制御した。本発明の組成物の粉末を、主に850μm超、主に355〜850μm、主に250〜355μm、及び主に250μm未満のサイズ群に分けた。5:1FS/ORC比で作製された本発明の止血組成物を、溶解性について試験した。
トリスを添加した及びトリスを添加していない本発明の組成物の剥離試験を実施した。pH=7を達成するためのトリス添加の量を決定した。トリス粉末を粉砕し、150μmの篩に通した。150μm未満の粉末を回収し、所定の量を乾燥混合物に添加して、組成物のpHを調整した後、同時噴霧した。
次に、5:1FS/ORCの本発明の組成物の拡大SEM画像を示す図9を参照すると、組成物の成分が少なくとも部分的に一体化しており、すなわち、互いに付着しているか又は互いにコーティングされており、単なる機械混合では一体化していないことが明らかである。
本発明の止血組成物を用いた肝擦過傷モデルにおけるインビトロにおける止血効果の試験を、以下のとおり実施した。ブタ肝臓の表面上に3cm×3cmの滲出領域を作製することによって肝擦過傷モデルを作製した。0.5gの5:1のFS/ORC比を有する本発明の止血組成物を塗布して、全くタンポン充填を適用することなく滲出領域を覆った。2分以内に止血された。
(1) 粉末状止血組成物を形成する方法であって、
a)非水性低沸点溶媒中フィブリノゲンの粒子、トロンビン、ORC繊維を含む混合物の懸濁液を形成する工程と、
b)ノズルを通して前記懸濁液を基材上に噴霧する工程と、
c)前記非水性溶媒を蒸発させる工程と、
d)前記基材から前記組成物を分離し、前記組成物を篩分けし、
このようにして、前記粉末状止血組成物を形成する工程と、
を含む方法。
(2) 前記非水性低沸点溶媒が、ヒドロフルオロエーテルC4F9OCH3を含む、実施態様1に記載の方法。
(3) 前記非水性低沸点溶媒が、HFE7100を含む、実施態様1に記載の方法。
(4) 前記懸濁液がトリスを更に含む、実施態様1に記載の方法。
(5) 前記懸濁液が塩化カルシウムを更に含む、実施態様1に記載の方法。
(7) 前記粉末状止血組成物の、フィブリンシーラント粉末のORCに対する重量比が約1:1〜約10:1である、実施態様6に記載の方法。
(8) 前記粉末状止血組成物が、主に約250〜約850マイクロメートルの範囲の粒径を有する粉末を含む、実施態様1に記載の方法。
(9) 前記粉末状止血組成物が、主に約355〜約850マイクロメートルの範囲の粒径を有する粉末を含む、実施態様8に記載の方法。
(10) 前記粉末状止血組成物が、少なくとも部分的に一体化している、凝集したORC繊維、フィブリノゲン、及びトロンビンを含む、実施態様1に記載の方法。
(12) トリスを更に含む、実施態様11に記載の止血組成物。
(13) 塩化カルシウムを更に含む、実施態様11に記載の止血組成物。
(14) 前記組成物が、約90重量%のフィブリノゲン、約8重量%のトロンビン、及び約2.5重量%の塩化カルシウムを含むフィブリンシーラント粉末を含む、実施態様11に記載の止血組成物。
(15) フィブリンシーラント粉末のORCに対する重量比が約1:1〜約10:1である、実施態様14に記載の止血組成物。
(17) 主に約355〜約850マイクロメートルの範囲の粒径を有する粉末を含む、実施態様16に記載の止血組成物。
(18) 創傷の上及び/又は中に実施態様11に記載の止血組成物を塗布することによって創傷を治療する方法。
Claims (17)
- 粉末状止血組成物を形成する方法であって、
a)非水性低沸点溶媒中フィブリノゲンの粒子、トロンビン、ORC繊維を含む混合物の懸濁液を形成する工程と、
b)ノズルを通して前記懸濁液を基材上に噴霧する工程と、
c)前記非水性溶媒を蒸発させる工程と、
d)前記基材から前記組成物を分離し、前記組成物を篩分けし、
このようにして、前記粉末状止血組成物を形成する工程と、
を含む方法。 - 前記非水性低沸点溶媒が、ヒドロフルオロエーテルC4F9OCH3を含む、請求項1に記載の方法。
- 前記非水性低沸点溶媒が、HFE7100を含む、請求項1に記載の方法。
- 前記懸濁液がトリスを更に含む、請求項1に記載の方法。
- 前記懸濁液が塩化カルシウムを更に含む、請求項1に記載の方法。
- 前記懸濁液が、約90重量%のフィブリノゲン、約8重量%のトロンビン、及び約2.5重量%の塩化カルシウムを含むフィブリンシーラント粉末を含む、請求項1に記載の方法。
- 前記粉末状止血組成物の、フィブリンシーラント粉末のORCに対する重量比が約1:1〜約10:1である、請求項6に記載の方法。
- 前記粉末状止血組成物が、主に約250〜約850マイクロメートルの範囲の粒径を有する粉末を含む、請求項1に記載の方法。
- 前記粉末状止血組成物が、主に約355〜約850マイクロメートルの範囲の粒径を有する粉末を含む、請求項8に記載の方法。
- 前記粉末状止血組成物が、少なくとも部分的に一体化している、凝集したORC繊維、フィブリノゲン、及びトロンビンを含む、請求項1に記載の方法。
- 少なくとも部分的に一体化している、凝集したORC繊維、フィブリノゲン、及びトロンビンを含む止血組成物。
- トリスを更に含む、請求項11に記載の止血組成物。
- 塩化カルシウムを更に含む、請求項11に記載の止血組成物。
- 前記組成物が、約90重量%のフィブリノゲン、約8重量%のトロンビン、及び約2.5重量%の塩化カルシウムを含むフィブリンシーラント粉末を含む、請求項11に記載の止血組成物。
- フィブリンシーラント粉末のORCに対する重量比が約1:1〜約10:1である、請求項14に記載の止血組成物。
- 主に約250〜約850マイクロメートルの範囲の粒径を有する粉末を含む、請求項11に記載の止血組成物。
- 主に約355〜約850マイクロメートルの範囲の粒径を有する粉末を含む、請求項16に記載の止血組成物。
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US15/258,549 US11229720B2 (en) | 2016-08-15 | 2016-09-07 | Hemostatic compositions and methods of making thereof |
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BR112019003015A2 (pt) | 2019-05-14 |
RU2019107165A (ru) | 2020-09-15 |
JP6968870B2 (ja) | 2021-11-17 |
MA53939A (fr) | 2021-09-15 |
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RU2756891C2 (ru) | 2021-10-06 |
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US20180043054A1 (en) | 2018-02-15 |
US11229720B2 (en) | 2022-01-25 |
CA3033932A1 (en) | 2018-02-22 |
BR112019003015B1 (pt) | 2022-10-11 |
AU2017311658A1 (en) | 2019-02-07 |
IL264613A (en) | 2019-02-28 |
EP3766526A1 (en) | 2021-01-20 |
US11998656B2 (en) | 2024-06-04 |
EP3496769A1 (en) | 2019-06-19 |
WO2018033835A1 (en) | 2018-02-22 |
US20220096708A1 (en) | 2022-03-31 |
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