JP6588019B2 - 重合阻害剤を含む一成分型フィブリン糊 - Google Patents
重合阻害剤を含む一成分型フィブリン糊 Download PDFInfo
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- JP6588019B2 JP6588019B2 JP2016542749A JP2016542749A JP6588019B2 JP 6588019 B2 JP6588019 B2 JP 6588019B2 JP 2016542749 A JP2016542749 A JP 2016542749A JP 2016542749 A JP2016542749 A JP 2016542749A JP 6588019 B2 JP6588019 B2 JP 6588019B2
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- fibrin
- liquid sealant
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Description
本出願は、EFS−ウェブを介してASCIIフォーマットで本出願に付随して提出される配列表を含み、その全体は、参照文献として本願に援用されるものである。2013年12月22日に作成された前記ASCIIコピーは、「配列表(sequencelisting)」というファイル名で、サイズは8キロバイトである。
本明細書で提供されるのは、単一成分液体シーラント製剤、その調製方法、並びに、とりわけ止血、封止、癒合及び/又は外科手術のための使用方法である。特に、フィブリンモノマー及びGPRPペプチドを含む液体シーラント製剤が、本明細書にて開示される。本製剤は、安定性及び長い貯蔵寿命を示し、かつペプチドの追従阻害、中和、希釈及び/又は除去に有用である。
a)本明細書にて開示する液体シーラント製剤を提供すること、及び
b)表面でのフィブリン重合を促進する条件下にて、製剤を表面に適用すること、を含む、表面におけるシーラントの調製方法が提供される。
a)フィブリンモノマーを含む成分を提供すること、
b)GPRPペプチド又はその他の可逆性フィブリン重合ブロック剤、その誘導体又はその塩、
c)フィブリンモノマー対して、モル過剰が100倍を超える又は少なくとも340倍を超える量のGPRPを含む液体シーラント製剤を得るために、a)及びb)を混合すること、またフィブリンモノマー濃度が1〜13%(重量体積パーセント)であること、を含む方法である。
ペプチドの存在及びフィブリンモノマー重合速度におけるその濃縮の効果を評価するために、GPRPペプチドフィブリンモノマーの混合物を培養し、また凝固が形成されるまでの時間を測定した。
GPRPペプチド(Gly−Pro−Arg−Pro、Sigmaより特注製造、ペプチドを冷凍乾燥形状にて供給して(250mg)、100mMのトリ−クエン酸ナトリウム二水和物中に溶解させ、pH=7で1MのGPRPを生成)を、フィブリノーゲン溶液(EVICEL(登録商標)フィブリンシーラントにおけるようなBAC2溶液)に添加した。溶液中のペプチド終濃度が、下表1に記載されている。使用したフィブリノーゲン終濃度は1%、1.5%、3%、3.5%である。7%の凝固可能なフィブリノーゲンを含有するBAC2溶液[EVICEL(登録商標)のフィブリノーゲン成分]を、20mMの酢酸ナトリウム(Naアセテート)緩衝剤に希釈させ、pH7.0にて一覧表に記載されている終濃度を得た。
一般に、GPRPペプチドの濃度が低められたので、フィブリンモノマーは次第により高速で重合した。例えば、1%フィブリンで0.1mMのGPRP(GPRP:フィブリンが〜3.4:1モル比)ではフィブリン凝固が直ちに形成され、1%フィブリンで1mMのGPRP(〜34:1モル比)では凝固は5分未満で形成された。1%フィブリンで5mMのGPRP(〜170:1)では、溶液は液体で4時間安定であり、1%フィブリンで10mMのGPRP(〜340:1)では、溶液は液体でおよそ7〜8日で安定であり、その後、重合化して個体を形成する、ということはなかった。
1.5%のフィブリン濃度で20mMのGPRP(〜453:1)、又は3.5%フィブリンで40mMのGPRP(〜389:1)では溶液は安定し、かつ2週間後であっても室温で凝固を形成しなかった。
以下の実施例は、低分子交換機構を使用して、溶液からGPRPペプチドを希釈又は除去することにより、フィブリン凝固形成の反応開始及び/又は加速が得られることを示すことを目的とする。
(1) 1〜13%(重量体積パーセント)の濃度のフィブリンモノマー、及びGPRPペプチド又はその他の可逆性フィブリン重合ブロック剤を含む液体シーラント製剤であって、前記ブロック剤又はGPRPが、前記フィブリンモノマーに対して100倍モル過剰を超える量で前記製剤中に存在し、また、前記液体製剤が、約20、21、22、23、24及び25℃からなる群から選択される周囲温度にて、少なくとも14日間安定している、液体シーラント製剤。
(2) 前記GPRPペプチドが、前記フィブリンモノマーに対して約340倍モル過剰を超える量で存在する、実施態様1に記載の製剤。
(3) 前記GPRPペプチドが、前記フィブリンモノマーに対して約340〜460倍モル過剰の量で存在する、実施態様1に記載の製剤。
(4) 前記製剤が、付加トロンビンを実質的に含まない、実施態様1〜3のいずれかに記載の製剤。
(5) トロンビン活性化因子XIIIを更に含む、実施態様1〜4のいずれかに記載の製剤。
(7) 前記カルシウムキレート剤が、クエン酸イオンである、実施態様6に記載の製剤。
(8) 前記クエン酸イオンが、クエン酸ナトリウムにより提供される、実施態様7に記載の製剤。
(9) 約1mM〜約50mMのクエン酸ナトリウムを含む、実施態様8に記載の製剤。
(10) 前記製剤が、中性pHを有する、実施態様1〜9のいずれかに記載の製剤。
(12) 実施態様1〜10のいずれかに記載の製剤を含む容器。
(13) 実施態様12に記載の容器、及び、任意に、使用説明書を含む、キット。
(14) 表面におけるシーラントの調製方法であって、
実施態様1〜10のいずれかに記載の製剤を提供すること、及び、前記表面でのフィブリン重合を促進する条件下にて、前記製剤を前記表面に適用することを含む、方法。
(15) 前記条件が、前記GPRPペプチドの除去、遮断、中和及び/又は希釈を含む、実施態様14に記載の方法。
a)フィブリンモノマーを含む成分を提供すること、
b)GPRPペプチド又はその他の可逆性フィブリン重合ブロック剤、その誘導体又はその塩を提供すること、並びに
c)前記液体シーラント製剤を得るために、a)及びb)を混合すること、を含む、方法。
(17) フィブリノーゲンの開裂を可能にする条件下で、フィブリノーゲン水溶液をトロンビン又はトロンビン様の酵素に接触させることにより、提供される前記フィブリンモノマーが得られる、実施態様16に記載の方法。
(18) 前記フィブリンモノマー成分がトロンビン活性化因子XIIIを含む、実施態様16又は17に記載の方法。
(19) 前記フィブリンモノマー成分がカルシウムキレート剤を含む、実施態様16又は17に記載の方法。
(20) 実施態様16〜19のいずれかに記載の方法に従って得ることが可能な製剤。
(22) 1〜13%(重量体積パーセント)の濃度のフィブリンモノマー、及びGPRPペプチドを含む液体シーラント製剤であって、GPRPが、前記フィブリンモノマーに対して340倍モル過剰を超える量で前記製剤中に存在し、かつ、前記液体製剤が、約20、21、22、23、24及び25℃からなる群から選択される周囲温度にて、少なくとも14日間安定している、液体シーラント製剤。
Claims (16)
- 1〜13%(重量体積パーセント)の濃度のフィブリンモノマー、及びGPRPペプチドを含む液体シーラント製剤であって、前記GPRPペプチドが、前記フィブリンモノマーに対して389倍モル以上の量で前記液体シーラント製剤中に存在し、また、前記液体シーラント製剤が、約20、21、22、23、24及び25℃からなる群から選択される周囲温度にて、少なくとも14日間安定している、液体シーラント製剤。
- 前記GPRPペプチドが、前記フィブリンモノマーに対して約389〜460倍モル過剰の量で存在する、請求項1に記載の液体シーラント製剤。
- トロンビンを実質的に含まない、請求項1又は2に記載の液体シーラント製剤。
- トロンビン活性化因子XIIIを更に含む、請求項1〜3のいずれか一項に記載の液体シーラント製剤。
- カルシウムキレート剤を更に含む、請求項1〜3のいずれか一項に記載の液体シーラント製剤。
- 前記カルシウムキレート剤が、クエン酸イオンである、請求項5に記載の液体シーラント製剤。
- 前記クエン酸イオンが、クエン酸ナトリウムにより提供される、請求項6に記載の液体シーラント製剤。
- 約1mM〜約50mMのクエン酸ナトリウムを含む、請求項7に記載の液体シーラント製剤。
- 前記液体シーラント製剤が、中性pHを有する、請求項1〜8のいずれか一項に記載の液体シーラント製剤。
- 止血、封止、癒合及び/又は手術にて使用するための、請求項1〜9のいずれか一項に記載の液体シーラント製剤。
- 請求項1〜9のいずれか一項に記載の液体シーラント製剤を含む容器。
- 請求項11に記載の容器、及び、任意に、使用説明書を含む、キット。
- 1〜13%(重量体積パーセント)の濃度のフィブリンモノマー、及びGPRPペプチドを含む、液体シーラント製剤の製造方法であって、前記GPRPペプチドが、前記フィブリンモノマーに対して約389倍モル以上の量で前記液体シーラント製剤中に存在し、かつ、前記液体シーラント製剤が、約20、21、22、23、24及び25℃からなる群から選択される周囲温度にて、少なくとも14日間安定しており、前記製造方法が、
a)前記フィブリンモノマーを含む成分を提供すること、
b)前記GPRPペプチド又はその塩を提供すること、並びに
c)前記液体シーラント製剤を得るために、a)及びb)を混合すること、を含む、方法。 - フィブリノーゲン水溶液をトロンビン又はトロンビン様の酵素に接触させることにより、提供される前記フィブリンモノマーが得られる、請求項13に記載の方法。
- 前記成分がトロンビン活性化因子XIIIを含む、請求項13又は14に記載の方法。
- 前記成分がカルシウムキレート剤を含む、請求項13又は14に記載の方法。
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IL230151A IL230151A0 (en) | 2013-12-24 | 2013-12-24 | One-component fibrin glue containing a polymerization inhibitor |
PCT/IL2014/000063 WO2015097688A1 (en) | 2013-12-24 | 2014-12-04 | One component fibrin glue comprising a polymerization inhibitor |
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IL246174B (en) | 2020-08-31 |
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US10357589B2 (en) | 2019-07-23 |
AU2014372152A1 (en) | 2016-06-30 |
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US9814799B2 (en) | 2017-11-14 |
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EP3086818B1 (en) | 2018-10-31 |
WO2015097688A8 (en) | 2016-09-15 |
BR112016014870B1 (pt) | 2021-02-02 |
WO2015097688A1 (en) | 2015-07-02 |
CN105899242B (zh) | 2020-01-14 |
US20150174289A1 (en) | 2015-06-25 |
HK1231418A1 (zh) | 2017-12-22 |
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