JP2022023994A - タンパク質-ポリマー・コンジュゲートを含む有機溶媒不含組成物および該組成物の使用 - Google Patents
タンパク質-ポリマー・コンジュゲートを含む有機溶媒不含組成物および該組成物の使用 Download PDFInfo
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Abstract
Description
実施例1:比較例:以前開示された方法にしたがって得られたフィブリノーゲン-PEG DAヒドロゲル組成物におけるアセトン残渣の決定
以前開示された方法(WO 2005/061018、WO 2008/126092およびWO 2011/073991)にしたがって調製されたヒドロゲル組成物中のアセトン含量を決定するために、化学分析を行った。
8M尿素を含む10mMリン酸緩衝生理食塩水(PBS)中の7mg/mlのウシ・フィブリノーゲン(Bovogen Biologicals Pty Ltd、オーストラリア・メルボルン)溶液を、トリス(2-カルボキシエチル)ホスフィンヒドロクロリド(TCEP-HCl)(Sigma)で調製した。TCEP-HClを、1~1.5:1 TCEP対フィブリノーゲン・システインのモル比で添加した。NaOHで溶液pHを8.0に修正した。PEG-DAを10mM PBSおよび8M尿素に溶解し(280mg/mL)、溶解したフィブリノーゲン溶液にPEG-DAを添加する前に、完全な溶解を達成した。PEG-DA対フィブリノーゲン・システインのモル比は3:1であった(直鎖PEG-DA、10kDa)。混合物を、サーモスタットジャケットを含む反応容器中、25±1℃の温度で、遮光して3時間反応させた。次いで、溶液を等体積のPBSで希釈し、そして反応容器から接線流ろ過システムの試料リザーバー内に移した。
8M尿素を含む10mMリン酸緩衝生理食塩水(PBS)中の7mg/mlのヒト・フィブリノーゲン(TESSEEL-タンパク質シーラント、Baxter、米国)溶液を、トリス(2-カルボキシエチル)ホスフィンヒドロクロリド(TCEP-HCl)(Sigma)で調製した。TCEP-HClを、1~1.5:1 TCEP対フィブリノーゲン・システインのモル比で添加した。NaOHで溶液pHを8.0に修正した。PEG-DAを10mM PBSおよび8M尿素に溶解し(280mg/mL)、溶解したフィブリノーゲン溶液にPEG-DAを添加する前に、完全な溶解を達成した。PEG-DA対フィブリノーゲン・システインのモル比は3:1であった(直鎖PEG-DA、10kDa)。混合物を、サーモスタットジャケットを含む反応容器中、25±1℃の温度で、遮光して3時間反応させた。次いで、溶液を等体積のPBSで希釈し、反応容器から接線流ろ過システムの試料リザーバー内に移した。
実施例2または3で調製したようなPEG-DA-フィブリノーゲン・コンジュゲート溶液を、次いで、滅菌のため、0.2μmフィルターを通じてろ過した。ろ過溶液を、無菌条件下でバイアル内に充填し、使用まで、-15℃未満の温度で保存した。
実施例2または3で調製したようなPEG-DA-フィブリノーゲン・コンジュゲート溶液を、IRGACURE(登録商標)2959(BASF、スイス)とさらに混合して、IRGACURE 2959の0.1%(w/v)の最終濃度を達成して、完全に溶解するまで攪拌した。光開始剤試薬を含有するPEG-DA-フィブリノーゲン・コンジュゲート溶液を、滅菌のため、0.2μmフィルターを通じてろ過した。ろ過した溶液を、無菌条件下でバイアル内に充填し、使用まで、-15℃未満の温度で保存した。
5mW/cm2の強度で、365nmで動作する紫外光源(例えばOmniCure(登録商標)S1000)に連結されたレオメータ、AR-G2;TA Instrumentsを用いて、2バイアル配合物および単一バイアル配合物の両方から得たヒドロゲル試料のレオロジー研究を行った。0.2ml試料の剪断貯蔵弾性率G’を測定し、そして記録した。Excelを用いてデータをさらに処理し、そして最大G’値(G’ Max)ならびにG’ Maxに到達するまでの時間を分析した。
(1)2バイアル配合物および単一バイアル配合物から生じたゲルの機械的安定性試験は、等しく安定なヒドロゲルであることを示した。これらの結果は、プレゲル化コンジュゲート溶液を含む単一バイアル中の光開始剤の存在が、新鮮に混合されたPEG-DA-フィブリノーゲン溶液および光開始剤に比較して、材料の架橋特性を損なわないことを確認する(図2)。さらに、凍結融解周期は、図2に示すように、どちらのゲル配合物の架橋特性にも、いかなる検出可能な影響を持たないようである。
2バイアルまたは単一バイアル配合物として保存されたPEG-フィブリノーゲン・ヒドロゲル溶液の長期安定性を、新鮮に調製した溶液(ゼロ時点)で得た、および-20℃で少なくとも1年間の保存(終点)後に得た、最大剪断貯蔵弾性力(G’ Max)を比較することによって、評価した。レオロジー測定値の詳細を、本明細書において、上記に記載する(実施例6)。
撹拌しながら、450mg Irgacure 2959(BASF、スイス)粉末を、450ml PEG-フィブリノーゲン溶液に添加して、0.1%(w/v)光開始剤のすぐに使える配合物を得た。粉末の完全な溶解が観察されるまで、撹拌を続けた。次いで、溶液を高剪断流体プロセッサ(Microfluidics M110-Y、米国)に通過させ、均一な粒子サイズ減少を達成し、そして0.2μmフィルター(滅菌ろ過)に通過させた。次いで、均質で無菌の混合物を3mlアリコットまたはシリンジに分割して、簡便で使いやすい容器中のすぐに使える配合物を得た。
実施例8にしたがって調製した2つの試料を、-20℃で6ヶ月の期間、保存した。6ヶ月後、試料を融解し、そしてUV光源(l=365nm、I=5mW/cm2)(IlluminOss Medical Inc、ロードアイランド州イーストプロビデンス)を利用して、1分間の期間、UVに曝露した。
有機溶媒不含法、すなわち「改善されたプロセス」、ならびにWO 2005/061018、WO 2008/126092およびWO 2011/073991に開示されるようなプロセス、すなわち「以前のプロセス」の両方から由来するヒドロゲルについて、類似条件下で、レオロジー特性およびゲル化動力学に関して研究した。
時間の関数としての剪断貯蔵弾性率(G’)のレオロジー測定は、有機溶媒の使用を伴わず、より具体的には、ゲル調製のためにアセトン沈殿またはエタノール添加を含まない、改善されたプロセスが、硬化プロセス動力学に関して、有機溶媒の使用を含むものと類似のヒドロゲル前駆体を生じることを立証した。光化学反応は、100mW/cm2のUVA光への曝露90秒間の間に起こり、測定開始の60秒後に開始された(図4)。動力学プロファイルは、類似の傾向を示し、これは、改善された有機溶媒不含ゲルが、以前開示されたゲルと同程度に機械的にロバストであるが、改善された生体適合性、および環境に優しくない大量の有機溶媒の使用を伴わない、より効率的な調製プロセスの両方を有することを示す。
Claims (13)
- タンパク質-ポリマー・コンジュゲートと少なくとも1つの重合開始剤とを含む、非架橋型の、安定なすぐに使える液体組成物であって、前記タンパク質-ポリマー・コンジュゲートは、合成ポリマーに共有結合した細胞外マトリックスタンパク質を含み、前記合成ポリマーが、少なくとも1つの重合可能な基を含有し、前記安定なすぐに使える液体組成物は極性有機溶媒を実質的に含まない、安定なすぐに使える液体組成物。
- 前記コンジュゲートは、
ECMタンパク質と前記ポリマーとの間での反応を実施することにより前記コンジュゲートを形成させるステップと;
極性有機溶媒による前記コンジュゲートの沈殿を用いることなく、前記コンジュゲートを濃縮するステップと;
を含むプロセスによって作製され、その結果、前記プロセスが極性有機溶媒を実質的に含まない、請求項1に記載の安定なすぐに使える液体組成物。 - 前記プロセスが:
(a)少なくとも1つの変性細胞外マトリックスタンパク質を含む溶液を提供する工程;
(b)重合可能な基を有する合成ポリマーを含む溶液を提供する工程;
(c)(a)の細胞外マトリックスタンパク質溶液と(b)の合成ポリマーを含む溶液とを混合して、タンパク質のスルフィドリルと重合可能な基との間での共有結合コンジュゲートを生成する工程;ならびに
(d)極性有機溶媒を利用する濃縮プロセスを伴わずに、工程(c)の未精製反応混合物を濃縮する工程
を含む、請求項2に記載の安定なすぐに使える液体組成物。 - 前記細胞外マトリックスタンパク質が、ウシまたはブタ由来のフィブリノーゲンを含む、または
前記細胞外マトリックスタンパク質が、ヒト由来の精製フィブリノーゲンまたは部分精製フィブリノーゲンを含む、または
前記合成ポリマーが、ポリエチレングリコール(PEG)、ヒドロキシアパタイト/ポリカプロラクトン(HA/PLC)、ポリグリコール酸(PGA)、ポリL-乳酸(PLLA)、ポリメチル-メタクリレート(PMMA)、ポリヒドロキシアルカノエート(PHA)、ポリ-4-ヒドロキシブチレート(P4HB)、ポリプロピレンフマレート(PPF)、ポリエチレングリコール-ジメタクリレート(PEG-DMA)、ポリエチレングリコール-ジアクリレート(PEG-DA)、ベータ-リン酸三カルシウム(ベータ-TCP)および非生分解性ポリテトラフルオロエチレン(PTFE)からなる群より選択される、または
前記合成ポリマーがポリエチレングリコール-ジアクリレート(PEG-DA)である、
請求項3に記載の安定なすぐに使える液体組成物。 - 同じ非コンジュゲート化合成ポリマーをさらに含み、合成ポリマー対タンパク質のモル比が40:1~400:1の間である、または
合成ポリマー対タンパク質のモル比が100:1~250:1の間である、または
合成ポリマー対タンパク質のモル比が100:1~150:1の間である、
請求項1に記載の安定なすぐに使える液体組成物。 - 前記少なくとも1つの重合開始剤が、ビス(2,4,6-トリメチルベンゾイル)フェニルホスフィンオキシド(BAPO)、2,2-ジメトキシ―2-フェニルアセトフェノン(DMPA)、カンファーキノン(CQ)、1-フェニル-1,2-プロパンジオン(PPD)、Cp’Pt(CH3)3(Cp=エータ5-C5H4CH3)、2-ヒドロキシ-1-[4-(ヒドロキシエトキシ)フェニル]-2-メチル-1-プロパノン、ジメチルアミノエチルメタクリレート(DMAEMA)、2,2-ジメトキシ-2-フェニルアセトフェノン、ベンゾフェノン(BP)、フラビン含有化合物、ならびにトリエタノールアミンとN-ビニルピロリドンとエオジンYとの組み合わせからなる群より選択される、請求項1に記載のすぐに使える液体組成物。
- 単一のバイアルアリコットまたはあらかじめ充填されたシリンジより選択される容器中に保持されている、請求項1に記載のすぐに使える液体組成物。
- 重合開始前のプレゲル化型で、UV保護条件下で保存されている、請求項1に記載のすぐに使える液体組成物。
- 重合開始前のプレゲル化型で、可視光保護条件下で保存されている、請求項1に記載のすぐに使える液体組成物。
- 光に曝露するとヒドロゲルを形成する、または
UV光に曝露するとヒドロゲルを形成する、
請求項1に記載のすぐに使える液体組成物。 - 前記組成物が、10ppm未満のアセトンを含む、または
前記組成物が、アセトンの検出可能な残渣をまったく含有しない、
請求項1に記載のすぐに使える液体組成物。 - 前記組成物が、100ppm未満のエタノールを含む、または
前記組成物が、エタノールの検出可能な残渣をまったく含有しない、
請求項1または11に記載のすぐに使える液体組成物。 - 前記細胞外マトリックスタンパク質がヒトフィブリノーゲンシーラントを含む、請求項1に記載の安定なすぐに使える液体組成物。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060233854A1 (en) * | 2003-12-22 | 2006-10-19 | Regentis Biomaterials Ltd. | Matrix composed of a naturally-occurring protein backbone cross linked by a synthetic polymer and methods of generating and using same |
WO2010064251A1 (en) * | 2008-12-04 | 2010-06-10 | Technion Research & Development Foundation Ltd | Hydrogel sponges, methods of producing them and uses thereof |
WO2014207749A1 (en) * | 2013-06-27 | 2014-12-31 | Regentis Biomaterials Ltd. | Compositions comprising a polymer-protein conjugate and an environmentally-responsive polymer and uses thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5475052A (en) * | 1988-11-21 | 1995-12-12 | Collagen Corporation | Collagen-synthetic polymer matrices prepared using a multiple step reaction |
GB0323378D0 (en) * | 2003-10-07 | 2003-11-05 | Univ Leicester | Therapeutic agent |
CN100427102C (zh) * | 2006-06-14 | 2008-10-22 | 孙明 | 一种纳米阿胶粉的制备方法及其阿胶制品 |
ES2733276T3 (es) * | 2007-04-13 | 2019-11-28 | Kuros Biosurgery Ag | Sellante polimérico para tejidos |
PT2150282T (pt) * | 2007-04-16 | 2018-07-09 | Regentis Biomaterials Ltd | Composições e métodos para formação do suporte |
US20100080791A1 (en) * | 2008-09-26 | 2010-04-01 | Rousseau Robert A | Composition and Method For Treating Tissue Defects |
CN106039401A (zh) * | 2009-12-16 | 2016-10-26 | 瑞吉恩提斯生物材料有限公司 | 由聚合物‑蛋白质结合物形成的支架,产生该支架的方法及其用途 |
EP2827887A4 (en) * | 2012-03-20 | 2016-04-20 | Einstein Coll Med | METHOD FOR ENHANCING EFFICIENCY OF BLOOD TRANSFUSIONS |
US20140065121A1 (en) * | 2012-08-31 | 2014-03-06 | Board Of Regents, The University Of Texas System | Blood plasma based hydrogels for tissue regeneration and wound healing applications |
US9045596B2 (en) * | 2013-02-05 | 2015-06-02 | Phillips 66 Company | Method of purifying conjugated polymers |
-
2015
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060233854A1 (en) * | 2003-12-22 | 2006-10-19 | Regentis Biomaterials Ltd. | Matrix composed of a naturally-occurring protein backbone cross linked by a synthetic polymer and methods of generating and using same |
WO2010064251A1 (en) * | 2008-12-04 | 2010-06-10 | Technion Research & Development Foundation Ltd | Hydrogel sponges, methods of producing them and uses thereof |
WO2014207749A1 (en) * | 2013-06-27 | 2014-12-31 | Regentis Biomaterials Ltd. | Compositions comprising a polymer-protein conjugate and an environmentally-responsive polymer and uses thereof |
Non-Patent Citations (1)
Title |
---|
BIOMATERIALS, 27 (2006), PP.1496-1506, JPN6022047638, ISSN: 0005087135 * |
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