JP6812511B2 - フィブリノゲン製剤 - Google Patents
フィブリノゲン製剤 Download PDFInfo
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- JP6812511B2 JP6812511B2 JP2019135198A JP2019135198A JP6812511B2 JP 6812511 B2 JP6812511 B2 JP 6812511B2 JP 2019135198 A JP2019135198 A JP 2019135198A JP 2019135198 A JP2019135198 A JP 2019135198A JP 6812511 B2 JP6812511 B2 JP 6812511B2
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- plasma
- fibrinogen
- preparation
- sealant
- precipitate
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Description
第VIII因子枯渇クリオプレシピテート(FDC)の調製:
FVIII枯渇クリオプレシピテート(FDC)は、第VIII因子(FVIII)の製造プロセスの副産物である。製造プロセス中、低い塩濃度の条件下、14〜18℃の範囲内の温度でエタノールを添加した後、遠心分離することにより、フィブリノゲン、フィブロネクチン、第XIII因子、並びにプラスミン及び/又はプラスミノゲンなどのプロテアーゼが、再懸濁クリオプレシピテートから沈殿する。遠心分離工程に先立って、上記の再懸濁中に水酸化アルミニウム[Al(OH)3]を添加することにより)、第II因子、第VII因子及び第X因子などのビタミンK依存性凝固因子が水酸化アルミニウムと共に沈殿する。水酸化アルミニウム沈殿物(即ち、FDC)を、第VIII因子含有上清から分離し、下記に記載する実験にて使用した。
凝固時間の試験によるフィブリノゲンレベルの決定(Clauss法)
試料のフィブリノゲン(mg/ml)=(較正曲線からのmg/100ml×希釈倍数)/100。
非補充及び血漿補充フィブリノゲン試料を、以下のように調製した。120ml及び90mlの再懸濁緩衝液(0.7% NaCl、0.295%クエン酸三ナトリウムpH7.4)を、それぞれ2つの異なるビーカーA及びB内で34℃に予熱した。次いで、7.5mlの2%アルハイドロゲル[Al(OH)3]及び2.25mlの、ビーズに結合したトラネキサム酸(TEA)(これは、概して国際特許出願公開第2013/001524号に開示されているように、特にFDC調製物からプラスミン及び/又はプラスミノゲンを除去する)を連続的に撹拌しながら各ビーカーに添加した。30mlのプールしたヒト血漿(クリオプア血漿)をビーカーB内の混合物に添加した。
上記の実施例1の非補充(A)及び血漿補充(B)フィブリノゲン試料を、以下のように、フィブリノゲン安定性に関して試験した。
クリオプレシピテートから得られた濃縮フィブリノゲン調製物に血漿を添加して、タンパク質安定性に対する血漿の効果(例えば、タンパク質分解の低下)を評価した。クリオプレシピテートを溶解し、水酸化アルミニウムを添加し、S/D処理に供し、油抽出及び逆相カラムによりS/D物質を除去する(概して、国際公開第93/05822号及び同第94/22503号に記載されているように)ことによって、クリオプレシピテート由来の濃縮フィブリノゲン調製物を調製した。この実施例では、濃縮フィブリノゲン調製物は、プラスミン/プラスミノゲンを除去するためのTEAに供されず、またプロテアーゼ阻害剤にも供されなかった。濃縮フィブリノゲン調製物(約30mg/ml)の2つのバッチからの試料を収集し、添加された血漿と共に又は添加された血漿なしに、37℃(又は凍結状態に維持)でインキュベートし、SDS−PAGEを使用してタンパク質の完全性に関して試験した。使用した血漿は、ドナーから血漿交換により収集した血漿単位であった。希釈緩衝液の組成は、120mM NaCl、10mMクエン酸ナトリウム、120mMグリシン、95mMアルギニン塩酸塩、1mM塩化カルシウムであった。
I.37℃保存−100μlフィブリノゲン調製物+100μl血漿。
II.37℃保存−100μlフィブリノゲン調製物+100μl希釈緩衝液。
III−80℃保存−100μlフィブリノゲン調製物+100μl血漿。
IV.−80℃保存−100μlフィブリノゲン調製物+100μl希釈緩衝液。
950ml DDWを50ml MOPS泳動緩衝液X20(Life Technologies,NP0001)で希釈することにより1リットルの泳動緩衝液を調製した。試料ローディング混合物の組成を、表2に示す。
ヒト血清血漿中のIgGクラスパルボウイルスB19抗体を検出するためにパルボウイルスB19−IgG ELISAキット(BIOTRIN)、サンドイッチELISAを用いて、B19特異的抗体の定量を行った。アッセイは製造者の指示書に従って行った。試料A及びBに関して得られた結果を、表3に要約する。
実施例1の血漿補充フィブリノゲンを、2つの直交性ウイルス不活化工程と、プラスミン及びプラスミノゲンの除去と、濃縮と、調製と、滅菌濾過とを含むように、処理した(基本的に、国際特許出願公開第2013/001524号におけるように)。最終的な製剤は、50〜90mg/mlの範囲内のフィブリノゲン濃度を含んでいた。
ラット腎臓止血モデルは、止血試験のための一般的なモデルである(Raccuia JS et al.,Comparative efficacy of topical hemostatic agents in a rat kidney model.Am J Surg.1992.163(2):234〜8)。手短には、腎臓を腹膜側から解剖して出し、その周囲にパッドを置いて血液を吸い上げた。腎臓に供給する血管上にクランプを置き、腎臓を通して横方向の切断部を作製した。血漿補充フィブリノゲン成分(実施例5のように調製)及びトロンビン成分(VICELフィブリンシーラントにおけるトロンビン成分のような)を含むシーラント製剤を、1:1の比で使用した。シーラントを適用し、クランプを除去した。出血を1時間の間評価した後、出血の総量を秤量した。続いて、シーラントを擦り落とし、出血を再開させ、低、中又は高として定量した(出血の可能性が尚存在するか否かを評価するために)。全てのラットに300IUヘパリン/kg動物体重を注入して、自発的な止血を防止した。
(1) フィブリノゲン製剤の調製方法であって、
濃縮フィブリノゲン調製物と血漿源とを混合する工程を含む、方法。
(2) 前記濃縮フィブリノゲン調製物が、血液又は血液画分に由来する、実施態様1に記載の方法。
(3) 前記濃縮フィブリノゲン調製物中のフィブリノゲン濃度が、約10mg/ml〜200mg/mlの範囲内である、実施態様1又は2に記載の方法。
(4) 前記濃縮フィブリノゲン調製物中のフィブリノゲン濃度が、約10mg/ml〜150mg/mlの範囲内である、実施態様1又は2に記載の方法。
(5) 前記濃縮フィブリノゲン調製物がクリオプレシピテートである、実施態様1〜4のいずれかに記載の方法。
(7) 前記濃縮フィブリノゲン調製物と前記血漿とが、約1:1の比で混合される、実施態様1〜6のいずれかに記載の方法。
(8) 血漿補充フィブリノゲン製剤。
(9) 実施態様1〜7のいずれかに記載の方法に従って得ることが可能なフィブリノゲン製剤。
(10) フィブリンシーラントの成分として使用するための、実施態様8又は9に記載のフィブリノゲン製剤。
(12) 血漿補充フィブリノゲン成分及びトロンビン成分を表面に適用することを含む、前記表面におけるシーラントの調製方法。
(13) 血漿補充フィブリノゲンから調製されたフィブリンモノマーを含む、シーラント製剤。
(14) 実施態様8、9、11又は13のいずれかに記載の製剤を含む容器。
(15) 実施態様14に記載の容器及び任意に使用説明書を含む、キット。
(17) 有効量の実施態様8、9又は11のいずれかに記載の製剤を、トロンビン製剤と共に前記対象に適用することを含む、実施態様16に記載の方法。
(18) フィブリンモノマーを含む血漿補充製剤。
Claims (5)
- 血漿源を補充してなる、少なくとも5日間の保存のために安定化された、フィブリノゲン製剤であって、
前記フィブリノゲン製剤が、血漿クリオプレシピテート、血漿酸沈殿物、血漿冷却沈殿物、血漿水酸化アルミニウム沈殿物、血漿グリシン沈殿物、血漿エタノール沈殿物、血漿ヘパリン沈殿物、及びこれらの組み合わせからなる群から選択される濃縮フィブリノゲン調製物を含有し、
前記血漿源が、動物血漿、クリオプア血漿、回収された血漿、トロンビン枯渇血漿、因子枯渇血漿、血漿交換により収集された血漿、及びこれらの組み合わせからなる群から選択されるプールした血漿源であり、
前記濃縮フィブリノゲン調製物と前記血漿源との比が、約3:1〜約1:3であり、
前記フィブリノゲン製剤は、血小板に富んだ血漿を含有せず、
前記血漿源が前記クリオプア血漿である、
フィブリンシーラントの成分として使用するための、フィブリノゲン製剤。 - 請求項1に記載のフィブリノゲン製剤を含む、シーラント製剤。
- 請求項1に記載のフィブリノゲン製剤を含む、容器。
- 請求項2に記載のシーラント製剤を含む、容器。
- 請求項3又は4に記載の容器、及び任意に使用説明書を含む、キット。
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DE2916711A1 (de) | 1979-04-25 | 1980-11-06 | Behringwerke Ag | Blutgerinnungsfaktoren und verfahren zu ihrer herstellung |
US4455300A (en) | 1980-03-05 | 1984-06-19 | Cutter Laboratories, Inc. | Fibronectin compositions |
US4341764A (en) | 1980-03-05 | 1982-07-27 | Cutter Laboratories, Inc. | Method of preparing fibronectin and antihemophilic factor |
US4627879A (en) * | 1984-09-07 | 1986-12-09 | The Trustees Of Columbia University In The City Of New York | Fibrin adhesive prepared as a concentrate from single donor fresh frozen plasma |
DE3622642A1 (de) | 1986-07-05 | 1988-01-14 | Behringwerke Ag | Einkomponenten-gewebekleber sowie verfahren zu seiner herstellung |
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-
2014
- 2014-02-27 IL IL231230A patent/IL231230A0/en unknown
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2015
- 2015-02-25 CN CN201580010752.9A patent/CN106061519A/zh active Pending
- 2015-02-25 EP EP15717659.5A patent/EP3110842A1/en not_active Withdrawn
- 2015-02-25 WO PCT/IL2015/000010 patent/WO2015128858A1/en active Application Filing
- 2015-02-25 CA CA2939555A patent/CA2939555A1/en not_active Abandoned
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JP2019196388A (ja) | 2019-11-14 |
AU2019208251A1 (en) | 2019-08-15 |
US10806755B2 (en) | 2020-10-20 |
WO2015128858A1 (en) | 2015-09-03 |
IL231230A0 (en) | 2014-08-31 |
AU2015221786B2 (en) | 2019-05-02 |
AU2015221786A1 (en) | 2016-09-08 |
AU2019208251B2 (en) | 2020-10-22 |
JP2017506657A (ja) | 2017-03-09 |
JP6563412B2 (ja) | 2019-08-21 |
US20150238529A1 (en) | 2015-08-27 |
CA2939555A1 (en) | 2015-09-03 |
WO2015128858A8 (en) | 2017-03-16 |
EP3110842A1 (en) | 2017-01-04 |
CN106061519A (zh) | 2016-10-26 |
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