JP2015521477A - デフィブロチドの生物学的活性を決定する為の、ユーグロブリンに基づく方法 - Google Patents
デフィブロチドの生物学的活性を決定する為の、ユーグロブリンに基づく方法 Download PDFInfo
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- JP2015521477A JP2015521477A JP2015517926A JP2015517926A JP2015521477A JP 2015521477 A JP2015521477 A JP 2015521477A JP 2015517926 A JP2015517926 A JP 2015517926A JP 2015517926 A JP2015517926 A JP 2015517926A JP 2015521477 A JP2015521477 A JP 2015521477A
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- Prior art keywords
- defibrotide
- euglobulin
- plasmin
- biological activity
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- JNWFIPVDEINBAI-UHFFFAOYSA-N [5-hydroxy-4-[4-(1-methylindol-5-yl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-propan-2-ylphenyl] dihydrogen phosphate Chemical compound C1=C(OP(O)(O)=O)C(C(C)C)=CC(C=2N(C(=O)NN=2)C=2C=C3C=CN(C)C3=CC=2)=C1O JNWFIPVDEINBAI-UHFFFAOYSA-N 0.000 title claims abstract description 107
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- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
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- 150000001413 amino acids Chemical class 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
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- 108010056926 valyl-phenylalanyl-lysine-4-nitroanilide Proteins 0.000 description 1
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6435—Plasmin (3.4.21.7), i.e. fibrinolysin
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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Abstract
Description
a) デフィブロチド、ユーグロブリン及び、プラスミンに特異的な基質を接触させる工程、ここで該基質は、プラスミンとの反応により測定可能産物を与えるものである、及び、
b) 形成された該産物の量を逐次の時点で測定する工程、
を含む。
Microsoft Excel(商標) (Microsoft Corporation、レドモンド、ワシントン、米国)
デフィブロチド(ゲンチウム)
発色性基質S-2251(Chromogenix Instrumentation Laboratory S.p.A.、ミラノ、イタリア)
トリス(ヒドロキシメチル)アミノメタン(TRIS)-NaCl(Sigma-Aldrich、ミラノ、イタリア)
1N HCl(Carlo Erba reagenti、ミラノ、イタリア)
1N NaOH (Carlo Erba reagenti、ミラノ、イタリア)
ウシ血漿(Tebu Bio Italia、マジェンタ(MI)、イタリア)
氷酢酸(Carlo Erba reagenti、ミラノ、イタリア)
TRIS-NaCl (1L調製): 1Lビーカーへ、定量的に、6.06gのTRIS-HCl及び2.2gのNaClを移す。500mLの精製水中に溶解し、そして、pHを7.4へと、約40mLのHCl 1Nにより調整する。定量的に、該溶液を1Lメスフラスコへ移し、そして、該溶液を精製水により体積へと希釈する。該溶液を冷蔵庫内(2〜8℃)で保存する。
発色性基質S2251(CAS 63589-93-5) 3mM (15.2mL調製):約25mgの発色性基質を15.2mLの精製水により溶解する。その溶液を冷蔵庫内(2〜8℃)で保存する。
ウシユーグロブリン(10mL調製)。300mLの最小容量を有する容器中に、240mLの氷冷精製水を導入し、そして、攪拌下で、10mLウシ血漿を添加する。pHを5.3± 0.1へと酢酸1%により調整する。2〜8℃で1〜16時間沈殿させる。透明な上清溶液をサイホン吸引により除去し、そして、沈殿物を2800rpmでの5分間4℃での遠心により集める。該沈殿物を懸濁し、 (例えば実験室ガラス棒により)5mLの氷冷精製水により機械的に分散させ、約5分間振とうし、そして、沈殿物を2800rpmで5分間4℃での遠心により集める。その沈殿物を、機械的に約10mLのTRIS-NaCl中に分散させる; その沈殿物の溶解を容易にするために、該沈殿物の粒子を適切な装置(例えば実験室ガラス棒)により砕く。得られた懸濁物を2〜8℃で、その使用前に1時間以上且つ6時間以下保存する。
20mLのメスフラスコ中に、定量的に、正確に秤量された約100mgのデフィブロチド参照基準を移す。その粉末を、約10mLのTRIS-NaClで溶解し、そして、同溶媒によりその体積にする。得られた溶液を、約1.25mg/mLのデフィブロチドRS溶液を得る為に、TRIS-NaCl により1:4希釈する。
20mLのメスフラスコ中に、定量的に、正確に秤量された約100mgのデフィブロチド試料を移す。その粉末を、約10mLのTRIS-NaClで溶解し、そして、同溶媒によりその体積にする。得られた溶液を、約1.25mg/mLのデフィブロチド試料溶液を得る為に、TRIS-NaClにより1:4希釈する。
a) デフィブロチド 125ug/mL: デフィブロチドストック溶液(参照及び試料)をTRIS NaClにより1:10希釈する(プレートウェル中への50ug/mLに相当する)。エッペンドルフ中に、定量的に、500uLのその調製された溶液を移し、そして、500uLのユーグロブリンと混合する。該チューブを閉じ、そして、氷冷水中で保存する。
b) デフィブロチド 62.5ug/mL:溶液(a)をTRIS NaClにより1:2希釈する(プレートウェル中への25ug/mLに相当する)。エッペンドルフチューブ中に、定量的に500uLのその調製された溶液を移し、そして、500uLのユーグロブリンと混合する。該チューブを閉じ、そして、氷冷水中で保存する。
c) デフィブロチド 31.25ug/mL:溶液(b)をTRIS NaClにより1:2 希釈する(プレートウェル中への12.5ug/mLに相当する)。エッペンドルフチューブ中に、定量的に、500uLの該調製された溶液を移し、そして、500uLのユーグロブリンと混合する。該チューブを閉じ、そして、氷冷水中で保存する。
d) デフィブロチド 12.5ug/mL:溶液(d)をTRIS NaClにより1:2.5希釈する(プレートウェル中への5ug/mLに相当する)。エッペンドルフチューブ中に、定量的に、500uLの該調製された溶液を移し、そして、500uLのユーグロブリンと混合する。該チューブを閉じ、そして、氷冷水中で保存する。
1体積のユーグロブリンを1体積のTRIS NaCl溶液と混合する(例: 500 uL + 500 uL)。
提案された配置スキーム(以下表1参照)に従い、プレートの各ウェル中に、200uLの基準又は試料又はブランク溶液を添加する。種々の配置スキームが、自動ピペットの利用可能性及び構成に従い用いられうる。しかしながら、参照及び試料溶液のそれぞれについて4以上の配置が、アッセイの為に用いられなければならない。
マイクロプレートリーダー中でのプレートのインキュベーションの直前に、各ウェルに50uLの発色性基質を添加する。
U1、U2、U2、U5: 試料溶液配置1、配置2、配置3、配置4、
Ca、Cb、Cc等: デフィブロチド参照及び試料の濃度a、b、c等
BLK ブランク溶液
基準調製物(例.: S1_Ca、S1_Cb、S1_Cc)の動的プロット“吸収対時間”から、適切な線形範囲を同定する(例:30〜35分、図3参照)。
線形動的範囲の同定(A@405 nm対時間)。
基準及び試料の調製物夫々について、予め決められた時間範囲におけるアッセイの応答を、以下のとおりに計算する。
ここで:
Aaは、時間Taでの吸収値(上記プロットから30分)
Ab は、時間Tbでの吸収値(上記プロットから35分)
参照及び試料の3以上の逐次の系列希釈物が用いられなければならない(例えば、デフィブロチド濃度5μg/mL、12.5μg/mL、25μg/mL、50μg/mL、又は5μg/mL、12.5μg/mL、25μg/mL、又は12.5μg/mL、25μg/mL、50μg/mL)。
分散分析が、Ph Eur. Current edition and Finney DJ (1964) Statistical Method in Biological Assay 2nd edの5.3.2.3節に従い行なわれる。
1) 線形回帰関係は有意であり、すなわち計算された確率は0.05未満である。この基準が満たされないならば、95%信頼区間を計算することはできない。
2) 非平行の関係は有意でない。すなわち、計算された確率は0.05未満である。
3) 非線形の関係は有意でない。すなわち、計算された確率は0.05未満である。
4) 推定有効性(estimated potency)が、規定有効性(stated potency)の90%以上であり且つの111%以下である。
5) 推定有効性の信頼限界(P=0.95)が、規定有効性の80%以上であり且つ125%以下である。
ここで、
- R:平行ラインモデル分析により得られた試料の結果
- 規定有効性: 基準の規定有効性(乾燥物質についてのUI/mg)
- 規定濃度: 基準の濃度(乾燥物質についてのmg/mL)
- 試料濃度: 試料の濃度(乾燥物質についてのmg/mL)
上記開示されたアッセイが、2.5ml中に200mgのデフィブロチドを有し(1ml 当り80mg)且つ表3に報告されるとおりのいずれかの定量的組成を有する液状配合物の生物学的活性を決定する為に用いられた。
Claims (20)
- デフィブロチドの生物学的活性の決定方法であって、
a) デフィブロチド、哺乳類のユーグロブリン及び、プラスミンに特異的な基質を接触させる工程、ここで該基質は、プラスミンとの反応により測定可能な産物を与えるものである、;及び
b) 形成された産物の量を逐次の時点で測定し、それにより該デフィブロチドの生物学的活性を決定する工程
を含む前記方法。 - 該ユーグロブリンが、哺乳類のユーグロブリンである、請求項1に記載の方法。
- 該ユーグロブリンが、ヒト、ウサギ、又はウシのユーグロブリンである、請求項2に記載の方法。
- 該プラスミンに特異的な該基質と反応する該プラスミンが、ユーグロブリン中に含まれるプラスミノーゲンによって放出されたものである、請求項1に記載の方法。
- 該プラスミンに特異的な該基質が、発色性基質である、請求項1に記載の方法。
- 該プラスミンに特異的な該基質が、式A1-A2-A3-Xの化合物であり、ここでA1及びA2が非極性アミノ酸であり、A3がリジン又はアルギニンであり、且つ、Xが該測定可能な産物である、請求項1に記載の方法。
- 該測定可能な産物Xが、パラ−ニトロアニリン及び2−ナフチルアミンからなる群から選ばれる、請求項6に記載の方法。
- 該プラスミンに特異的な該基質が、H-D-バリル-L-ロイシル-L-リジン-p-ニトロアニリンである、請求項4に記載の方法。
- 該測定可能な産物Xが、スペクトロフォトメトリー又はスペクトロフルオリメトリーにより測定される、請求項6に記載の方法。
- 該哺乳類のユーグロブリンが、由来する血漿と同じ体積に再構成され又は適切なバッファーにより最大で1:10で希釈され、且つ、発色性/発蛍光性基質が、2.5〜3.5mM、好ましくは3mMの濃度を有する、請求項2に記載の方法。
- 該方法が、7〜8のpH、好ましくは7.4のpHに緩衝された水性溶液である反応媒体中で行なわれる、請求項1に記載の方法。
- 温度が、35〜39℃、好ましくは37℃で維持される、請求項1に記載の方法。
- 該プラスミンに特異的な該基質の濃度が、0.3〜4mM、好ましくは2.5〜3.5mM、より好ましくは3mMである、請求項1に記載の方法。
- c) 基準試料及び試験試料の両方の酵素反応の経過の間の該測定可能な産物の放出速度を決定する工程; d) 該放出速度を、対応するデフィブロチド濃度と数学的に及び/又はグラフ的に関係付けて、デフィブロチドの該試験試料の生物学的活性を得る工程を含む、請求項1に記載の方法。
- デフィブロチドの25〜35IU/mg、好ましくは27.5〜32.5IU/mg、より好ましくは28〜32IU/mgの生物学的活性を有する、デフィブロチド液状組成物。.
- 水溶液であることにより特徴付けられる、請求項15に記載のデフィブロチド液状組成物。
- 緩衝されている、好ましくは6.5〜8.5、好ましくは7〜8のpHで緩衝されていることにより特徴付けられる、請求項16に記載のデフィブロチド液状組成物。
- VODの処置及び予防における使用の為の、請求項15〜17のいずれか1項に記載のデフィブロチド液状組成物。
- デフィブロチド液状組成物を含み且つ5000〜7000IU、好ましくは5500〜6500IU、より好ましくは5600〜6400IUの生物学的活性を有する容器。
- 該デフィブロチド液状組成物が水溶液である、請求項19に記載の容器。
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