JP2012126658A - 血小板放出促進剤および血小板放出促進方法 - Google Patents
血小板放出促進剤および血小板放出促進方法 Download PDFInfo
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- JP2012126658A JP2012126658A JP2010277325A JP2010277325A JP2012126658A JP 2012126658 A JP2012126658 A JP 2012126658A JP 2010277325 A JP2010277325 A JP 2010277325A JP 2010277325 A JP2010277325 A JP 2010277325A JP 2012126658 A JP2012126658 A JP 2012126658A
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Abstract
安全性および熱安定性が高く、安価に用いることができ、且つ高い血小板放出促進効果を示す血小板放出促進剤を提供する。
【解決手段】
下記式(1)で表される構成単位を含む重合体であって、重量平均分子量が50万〜1000万である重合体を有効成分として用いる。
−(Pro−X−Gly)− (1)
(式中、XはProまたはHypを表す。)
【選択図】 図1
Description
[1]下記式(1)で表される構成単位を含む重合体であって、平均分子量が50万〜1000万である重合体を含有する、血小板放出促進剤。
−(Pro−X−Gly)− (1)
(式中、XはProまたはHypを表す。)
[2]ゲルパーミエーションクロマトグラフィーにおいて前記重合体の分子量を測定した場合に、全ピーク面積の80%以上が分子量2万〜2000万の範囲に含まれることを特徴とする、[1]に記載の血小板放出促進剤。
[3]前記重合体が3重螺旋構造を取ることを特徴とする、[1]または[2]に記載の血小板放出促進剤。
[4]前記重合体が0.05μg/mLの濃度で血小板放出促進活性を示すことを特徴とする、[1]〜[3]のいずれかに記載の血小板放出促進剤。
[5]前記重合体が熱架橋により不溶化していることを特徴とする、[1]〜[4]のいずれかに記載の血小板放出促進剤。
[6][1]〜[5]のいずれかに記載の血小板放出促進剤に、in vitroで血小板を暴露する工程を含む、血小板放出を促進する方法。
[7][1]〜[5]のいずれかに記載の血小板放出促進剤を保持する創傷治癒材。
本発明の血小板放出促進剤は、下式(1)で表される構成単位を含む重合体(「本発明の血小板放出促進ペプチド」または「血小板放出促進ペプチド」ともいう)を含有する。−(Pro−X−Gly)− (1)
(式中、XはProまたはHypを表す。)
血小板放出促進ペプチドにおいては、全てのXがProであってもよく、全てのXがHypであってもよく、XとしてProおよびHypが任意の比率で混在していてもよい。Xについて、ProとHypの比率は特に制限されないが、3重螺旋構造の熱安定性の点で、Hyp:Pro(モル比)=100:0〜5:95が好ましく、100:0〜50:50がより好ましく、100:0〜90:10がさらに好ましい。なお、Hypは、通常、4Hyp(例えば、trans−4−ヒドロキシ−L−プロリン)残基である。
以下、血小板放出促進ペプチドの製造方法について詳述する。
血小板放出促進ペプチドの製造方法は特に制限されず、何れの方法により得られた血小板放出促進ペプチドであっても血小板放出促進剤に使用できる。
血小板放出促進ペプチドを含有する本発明の血小板放出促進剤に血小板を暴露することにより、血小板放出を促進することができる。すなわち、本発明は、本発明の血小板放出促進剤に血小板を暴露する工程を含む血小板放出の促進方法(以下、本発明の方法ともいう)を提供する。本発明の方法においては、精製された血小板を暴露してもよく、血小板を含む任意の試料を曝露してもよい。血小板を含む試料としては、全血や多血小板血漿などが挙げられる。試料に血小板が含まれる限り、血小板放出促進剤に当該試料を暴露する工程は、血小板放出促進剤に血小板を暴露する工程の範囲に含まれる。
液相法で合成したPro−Hyp−Glyで示されるトリペプチド1gを20mLの10mMリン酸塩緩衝液(pH7.4)に溶解し、4℃まで冷却した。これに4℃の473mgの1−ヒドロキシベンゾトリアゾール(HOBt)、3.35gの1−エチル−3−(3−ジメチルアミノプロピル)−カルボジイミド塩酸塩(WSCI・HCl)を加え、4℃で2時間撹拌し、その後20℃まで加温し46時間撹拌した。反応終了後、反応液に水を加えて2倍に希釈し、この溶液を透析用セルロースチューブ(ビスケース社製 UC27−32−100)に入れ、水2Lに対して48時間透析した。その際水は6時間以上の間隔を空け4回交換した。このようにして得られたポリペプチドの水溶液を血小板放出促進ペプチド溶液として以下の実験に用いた。
実験例1で調製した血小板放出促進ペプチド溶液を、ペプチド濃度0.5%の水溶液とし、テフロン(登録商標)容器に入れて凍結乾燥した。得られた乾燥物はスポンジ状で、加水により直ちに湿潤し、数分で水に溶解した。一方、得られたスポンジ状の乾燥物の一部を窒素雰囲気下180℃で2時間加熱したところ、加熱後の乾燥物は加水後1日経過しても水に溶解しなかった。
雌性ICRマウス(体重25〜35g,Slc)の腹部大動脈より3.8%クエン酸ナトリウム1/10容にて0.8ml採血し、よく混和して抗凝固処理を行った。これに、実験例1で調製した血小板放出促進ペプチド溶液を、ペプチドの終濃度が0.005〜5μg/mlになるように添加し、37℃で5分間振盪した。その後、800Gで遠心して血球を除去した後、血清に含まれるPDGFをR&D System社のQuantikine Mouse/Rat PDGF−BB Immunoassay(Cat.No.MBB00)を用いて測定した。結果を図1に示す。実験例1で調製した血小板放出促進ペプチドは、0.05μg/mLにおいて、顕著なPDGFの放出促進活性を示した。
血小板放出促進ペプチドの代わりに市販のブタI型コラーゲンを用いた以外は実施例1と同様の方法でPDGFの放出活性を測定した。結果を図2に示す。ブタI型コラーゲンは、5μg/mLでも顕著なPDGFの放出促進活性を示さなかった。
実験例2で調製した熱架橋ペプチドを、20mM酢酸に湿潤させ、5分間ホモジナイズした。この懸濁液をpH6.8の燐酸バッファーにて適宜稀釈し、実施例1に記載の方法に準じてPDGF放出活性の評価を行なった。結果を図3に示す。実験例2で調製した熱架橋ペプチドは、0.025μg/mLからPDGFの放出促進活性を示し始め、0.05μg/mLでPDGFの放出促進活性がほぼ飽和した。
実験例2で調製した熱架橋ペプチドの代わりに市販の熱架橋されたウシ真皮由来コラーゲンを用いた以外は、実施例2と同様の方法でPDGFの放出活性を測定した。結果を図4に示す。ウシ真皮由来コラーゲンは、5μg/mLからPDGFの放出促進活性を示し始め、25μg/mLでPDGFの放出促進活性がほぼ飽和した。
Claims (7)
- 下記式(1)で表される構成単位を含む重合体であって、重量平均分子量が50万〜1000万である重合体を含有する、血小板放出促進剤。
−(Pro−X−Gly)− (1)
(式中、XはProまたはHypを表す。) - ゲルパーミエーションクロマトグラフィーにおいて前記重合体の分子量を測定した場合に、全ピーク面積の80%以上が分子量2万〜2000万の範囲に含まれることを特徴とする、請求項1に記載の血小板放出促進剤。
- 前記重合体が3重螺旋構造を取ることを特徴とする、請求項1または2に記載の血小板放出促進剤。
- 前記重合体が0.05μg/mLの濃度で血小板放出促進活性を示すことを特徴とする、請求項1〜3のいずれか1項に記載の血小板放出促進剤。
- 前記重合体が熱架橋により不溶化していることを特徴とする、請求項1〜4のいずれか1項に記載の血小板放出促進剤。
- 請求項1〜5のいずれか1項に記載の血小板放出促進剤に、in vitroで血小板を暴露する工程を含む、血小板放出を促進する方法。
- 請求項1〜5のいずれか1項に記載の血小板放出促進剤を保持する創傷治癒材。
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JP2005058499A (ja) * | 2003-08-13 | 2005-03-10 | Masao Tanihara | 生体材料 |
JP2005074079A (ja) * | 2003-09-02 | 2005-03-24 | Masao Tanihara | 止血材 |
WO2008075589A1 (ja) * | 2006-12-21 | 2008-06-26 | Chisso Corporation | 血小板凝集惹起物質 |
WO2009035092A1 (ja) * | 2007-09-13 | 2009-03-19 | National University Corporation NARA Institute of Science and Technology | 新規なポリペプチドおよびその製造方法 |
WO2009123903A1 (en) * | 2008-04-03 | 2009-10-08 | Zymogenetics, Inc. | Hemostatic microspheres |
WO2010034718A1 (fr) * | 2008-09-24 | 2010-04-01 | Centre Hospitalier Universitaire De Dijon | Proteines recombinantes a activite hemostatique capables d'induire l'agregation plaquett aire |
WO2010052694A2 (en) * | 2008-11-06 | 2010-05-14 | Innocoll Technologies Limited | Drug delivery implants and processes for their preparation |
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JP2005058499A (ja) * | 2003-08-13 | 2005-03-10 | Masao Tanihara | 生体材料 |
JP2005074079A (ja) * | 2003-09-02 | 2005-03-24 | Masao Tanihara | 止血材 |
WO2008075589A1 (ja) * | 2006-12-21 | 2008-06-26 | Chisso Corporation | 血小板凝集惹起物質 |
WO2009035092A1 (ja) * | 2007-09-13 | 2009-03-19 | National University Corporation NARA Institute of Science and Technology | 新規なポリペプチドおよびその製造方法 |
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