JP2008539257A - 止血および他の生理学的活性を促進するための組成物および方法 - Google Patents
止血および他の生理学的活性を促進するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2005年4月25日に出願された米国出願第60/674,612号および2006年1月13日に出願された米国出願第60/758,827号の利益を主張する。本出願から発行され得るあらゆる米国特許の目的のために、これらの先行する出願は、それらの全体が参考として本明細書に援用される。
米国政府により、本発明の開発に利用される助成金補助(米国立衛生研究所の助成金番号EY00126)が提供された。したがって、米国政府は、本発明において一定の権利を有し得る。
血液製品が利用可能であるにもかかわらず、失血は罹病率および死亡率の主な原因である。失血の原因は数多くあり、重症な損傷および臨床状態、例えば、動脈瘤の破裂、食道または胃の潰瘍および食道の静脈瘤などが挙げられる。主要な動脈の完全性が失われると急速に死に至ることになり得、特に、医療ケアが早急な利用手段がない状況では、そのような事態が起こる。
親水性モノマーと疎水性モノマーを交互に有し、生理学的条件でこれらが自己集合することが可能なペプチドを含む組成物を、創傷への適用のために処方する。任意の所与の処方物における自己集合性(self−assembling)ペプチドの濃度は種々であり得、ほぼ0.1%(1mg/ml)〜10%(100mg/ml)(両端を含む)であり得る。例えば、自己集合性ペプチドの濃度(例えば、液状処方物中)は、ほぼ0.1〜3.0%(1〜30mg/ml)(例えば、0.1〜1.0%;1.0〜2.0%;2.0〜3.0%または1.0〜3.0%)であり得る。自己集合性ペプチドの濃度は、ストック溶液中、および固形(例えば、粉末状)の処方物においては、より高いことがあり得る。固形調製物は、100%に近い自己集合性ペプチド濃度を有するものであり得る(例えば、自己集合性ペプチドの濃度は、該組成物の95、96、97、98、99%またはそれ以上(例えば、99.99%)であり得る)。液状形態であろうと固形形態であろうと、該ペプチドは使用前に、希釈剤(例えば、水(例えば、脱イオン水))、充填剤または油の添加によって所望の濃度にされ得る。
I.処方物
A.自己集合性ペプチド
用語「ペプチド」は、本明細書で用いる場合、「ポリペプチド」、「オリゴペプチド」および「タンパク質」を含み、共有結合(例えば、ペプチド結合)によって互いに連結された少なくとも2つのα−アミノ酸残基の一連の鎖をいう。使用されるペプチドは、本明細書に記載の目的の1つ以上に有用な程度まで自己集合する能力を保持している限り、長さは種々であり得る。2つ程度の少ないα−アミノ酸残基を有するペプチドまたは約200残基ものペプチドも適切であり得、自己集合することが認識されるものは、典型的には、この範囲内の長さ(例えば、8〜200、8〜36、8〜24、8〜16、12〜20、6〜64または16〜20個のアミノ酸残基)を有する。状況に応じて、「ペプチド」は、個々のペプチドまたは同じもしくは異なる配列を有するペプチドの集合体をいうことがあり得、これらはいずれも、天然に存在するα−アミノ酸残基のみ、天然に存在しないα−アミノ酸残基のみ、または両方を含むものであり得る。また、α−アミノ酸アナログは、当該技術分野で知られており、代替的に使用され得る。特に、D型のα−アミノ酸残基が使用され得る。また、自己集合性ペプチド内のアミノ酸残基の1つ以上が、化学的実体、例えば、アシル基、炭水化物基、炭水化物鎖、リン酸基、ファルネシル基、イソファルネシル基、脂肪酸基、または結合体化もしくは官能性付与のためのリンカーなどの付加によって改変または誘導体化されたものであってもよい。また、使用されるペプチドは分枝鎖であり得、この場合、該ペプチドは、各々がペプチド結合によって接合された少なくとも3つのアミノ酸残基からなる少なくとも2種類のアミノ酸ポリマーを含有する。該2種類のアミノ酸ポリマーはそれら自体で連結されているが、ペプチド結合によってではない。
の1つ以上に従うアミノ酸残基の配列を有するものであり得るか、または該配列を含むものであり得る。
自己集合の前に、該ペプチドを、実質的にイオン(例えば、1価のイオン)を含まない溶液、または有意な自己集合を抑制するのに充分に低い濃度のイオン(例えば、10mM未満、5mM未満、1mM未満または0.1mM未満の濃度のイオン)を含む溶液に含め得る(例えば、溶解させ得る)。自己集合は、後続の任意の時点で、ペプチド溶液へのイオン性の溶質もしくは希釈剤の添加によって、またはpHの変更によって開始または増強され得る。例えば、ほぼ5mM〜5Mの間の濃度のNaClにより、短時間内(例えば、数分以内)に巨視的構造体の集合が誘導される。また、より低い濃度のNaClでは、集合は誘導され得るが、より低速となる。あるいはまた、自己集合は、ペプチドを(乾燥状態であれ、半固形ゲル状であれ、実質的にイオンを含まない液の溶液中に溶解された状態であれ)、かかるイオンを含む液(例えば、血液もしくは胃液などの生理液)または領域(例えば、鼻もしくは口などの体腔または外科的処置によって露出させた腔)内に導入することにより開始または増強され得る。一般的に、自己集合は、ペプチドをかかる溶液に任意の様式で接触させると起こると予測される。
該処方物は、典型的には、賦形剤もしくは他の薬学的に許容され得る担体を含むか、または医療用器具もしくはコーティングの一部分として提供される。処方物はまた、他の治療剤、予防剤または診断剤を含むものであり得る。好ましい実施形態において、このような薬剤は、抗炎症薬、血管作用剤、抗感染薬、麻酔薬、増殖因子および/または細胞であり得る。
細胞を患者に送達する場合(例えば、組織治癒を促進するため)、自己由来の細胞が使用され得る。一実施形態において、該細胞は、該物質中に分散され、移植された患者由来の造血系細胞の使用であり得る。別の実施形態において、該細胞は臍帯血の赤血球であり得る。
該処方物は、薬学的に許容され得る担体を含み、医療用デバイスまたはコーティングの一部として提供される。また、該処方物は、他の治療剤、予防剤または診断剤を含むものであってもよい。
非生分解性マトリクスおよび生分解性マトリクスの両方が自己集合性ペプチドの送達に使用され得るが、生分解性マトリクスが好ましい。これらは天然または合成のポリマーであり得るが、分解および放出プロフィールの特性がより良好なため、合成ポリマーが好ましい。ポリマーは、放出が所望される期間に基づいて選択される。ある場合では線形放出が最も有用であり得るが、別の場合では、パルス放出または「バルク放出」がより有効な成績をもたらし得る。ポリマーはヒドロゲル(典型的には、約90重量%までの水分を吸収する形態)の形態であり得、任意選択で、多価イオンまたはポリマーにより架橋されたものである得る。
液状処方物は、自己集合性ペプチドを含む組成物を入れたバレルと、該組成物をシリンジまたはピペット開口先端から噴出させるための手段(例えば、プランジャーまたは弁)とを有するシリンジまたはピペットにて提供され得る。シリンジは、自己集合性ペプチドと1種類以上他の薬剤の混合が適用時に行なわれるように1つ以上の区画(例えば、シリンジバレルの長軸に沿って対称または非対称に延在する分割部によって作出される)からなるものであり得る。また、該区画は、賦形剤、例えば、ヒドロゲルまたは接着剤を形成する材料などを第1の区画内に、および自己集合性ペプチドを第2の区画内に含み得る。別の実施形態において、第1の区画は、凍結乾燥された自己集合性ペプチドまたは自己集合性ペプチド粒子を入れたものであり得、第2の区画は、該ペプチドまたは乾燥適用される粉末を溶解または水和させるための溶液を入れたものであり得る。バレル内の組成物は、本発明に記載の任意の他の非線維性因子(例えば、血管収縮薬、着色剤、麻酔剤もしくは鎮痛剤、抗菌薬(例えば、抗生物質、抗ウイルス剤もしくは抗真菌剤)または他の治療薬、コラーゲン、抗炎症剤、増殖因子または栄養素の1種類以上)をさらに含むものであり得る。また別の実施形態において、該物質はゲル化され、スパチュラなどの器具を用いて適用され得る。
本明細書に記載の任意の薬剤、例えば、細胞、治療用、予防用または診断用化合物(例えば、抗生物質および増殖因子など)は、インビトロまたはインビボで自己集合する前にペプチド溶液中に導入するのがよく、成形前(pre−molded)構造体は、これらの薬剤の1種類以上を含むものであり得、任意選択で、滅菌物質中に包装され得る、および/または使用のための取扱い説明書が備えられ得る。該物質は予防的に、またはさらなる薬剤の非存在下での処置として使用され得る。該生物活性薬剤は、骨格全体にほぼ均一に分布させてもよく、一領域または別の領域に濃縮してもよい(例えば、表面上もしくは表面付近、コア領域内、骨格もしくはその一領域全体に勾配的に、または内部に層状に(例えば、層状で濃縮または均一もしくは不均一に分布))。構造体内での物質のほぼ均一な分布を達成するため、前駆物質含有溶液と該物質(これはまた、自己集合開始前の溶液状であり得る)を混合してもよい。
該物質はさまざまな異なる表面に、液の通過を抑制もしくは制御するため(例えば、止血を促進するため)、またはバリアとしての機能を果たすため(例えば、汚染を低減するため)に適用され得る。自己集合性薬剤の量は、一部、液の流量の制御における該物質の機能、ならびに自己集合性ペプチドと関連する任意の他の物質または構造体(単独もしくは他の生物活性物質との組合せ)の特性によって決定される。
一般に、必要とされる物質の量は種々の要素、例えば、損傷の大きさもしくは程度(これは、同様に切開の長さ、損傷血管の内径もしくは数、火傷の程度、潰瘍の大きさおよび深さ、擦傷または他の損傷に置き換えて表示され得る)などに応じて異なる。この量は、例えば、数マイクロリットル〜数ミリリットル以上(例えば、数十または数百ミリリットル)まで種々であり得る。該物質を送達するために使用されるデバイスは、この量に従って異なる。例えば、シリンジは、少量を送達するのに簡便に使用され得、一方、チューブまたはスクイーズボトルは量が多い場合により適当であり得る。有効量(骨格、その前駆物質、または処方物中に存在する別の生物活性分子のいずれに関しても)は、改善された、または所望の生物学的応答を誘発するのに必要な量を意味する。
該組成物は、被験体の身体の表面上に提供され得る、および/または力によって(例えば、不測の外傷または外科的処置によって)生成される腔内に提供され得る。このようにして、望ましくない生体物質の移動は、広範な状況、例えば、外傷性の損傷、病状(例えば、出血と関連する慢性もしくは長期の病状)、または外科的処置(例えば、整形外科手術、歯科手術、心臓手術、眼科手術、または整形外科もしくは再構築手術)において抑制され得る。例えば、望ましくない生体物質の移動が外傷の結果である場合、被験体は、一部もしくは完全に切断された身体部分、裂傷、擦傷、刺創または火傷を有する被験体であり得る。該組成物が身体表面に適用される場合、これは、望ましくない生体物質の移動を抑制し得るだけでなく、汚染からの被験体の保護を補助し得る。例えば、自己集合性薬剤を皮膚に適用することで、創傷内への皮膚または毛髪上の望ましくない異物の移動が妨げられる。望ましくない生体物質の移動が慢性の病状に起因する場合、被験体には、再発性の出血が起こり得る。例えば、被験体は、静脈瘤、例えば、毛細血管拡張症、痔、肺内の出血(例えば、肺癌、気管支炎、または細菌性もしくはウイルス性疾患、例えば、肺炎もしくはインフルエンザによる)、または食道の静脈瘤と関連する出血が起こっている被験体であり得る。再発性の出血と関連する病状は、本明細書に記載の組成物、例えば、自己集合性ペプチドおよび血管収縮薬(例えば、フェニレフリン、これは組成物の約0.25〜0.5%を構成し得る)を含有するもので処置され得る。出血が口腔咽頭内(oropharnyx)または肺内で起こる場合、該組成物は定量吸入器により投与され得る。患者の状態が人工換気が必要とされる程度まで悪化している場合、該組成物は、レスピレータにより、または洗浄によって投与され得る。
ラットおよびハムスターの脳内の上矢状静脈洞の分枝の完全な横方向の切開を、横方向に切開した組織の上部にある頭蓋骨の一部を除去した後に行なった。動物を、ケタミン(80mg/kg)およびキシラジン(8mg/kg)のi.p.注射にて麻酔した。すべての外科的処置は手術用顕微鏡下で行なった。10匹の成体ハムスターおよび12匹の幼若成体雌Spraque−Dawleyラット(200〜250g)を含む22匹の動物を、氷冷生理食塩水または20μlの1%ペプチド溶液のいずれかで、洞分枝の横方向切開部位において処置した。該物質は、RADA16−I(n−RADARADARADARADA−c;配列番号:1)ペプチドを滅菌水に溶解することにより調製し、該ペプチド含有溶液を損傷組織に、2cc容シリンジに取り付けた31ゲージニードルを用いて適用した。
成体ラットにおいて、坐骨神経および隣接する大腿動脈を露出させ、大腿動脈を横方向に切開した。12匹のラットを、RADA16−Iペプチドの1%溶液20μlを横方向切開部位に、シリンジ本体に取り付けたガラスピペットを用いて適用することによって処置し、一方、対照は、低温生理食塩水を横方向切開部位に適用することにより処置した。すべての処置例において、止血は10秒以内に達成された。生理食塩水対照例は、実験を110秒間で終了するまで出血が継続した。これらの対照動物において、続いて低温生理食塩水をペプチド溶液に交換すると、ほぼ直後に完全な止血の達成がもたらされた。
ペプチド含有構造体が、比較的低い圧力を有する血管の出血を停止させる能力をさらに実証するため、成体ラットの腹腔を開き、肝臓を曝露させ、左外側葉(lobus sinister lateralis)に、吻側(rostral)から尾側(caudal)まで肝臓の一部を完全に離断する切開を行なった。大量の出血が起こった。1%ペプチド溶液(RADA16−I)を該切開部およびその付近に、27ゲージニードルおよび4cc容シリンジを用いて適用した。出血はすべて10秒以内に停止した。一連の写真を取得した。最初のものは、肝臓の露出を示す;第2のものでは、肝臓が分離され、大量の出血が明らかである;第3のものでは、肝臓の2つの部分を元に戻して一緒にし、出血は継続している。1%ペプチド溶液での該部位の処置後(経表面的に該切開部内に適用)、出血はすべて10秒以内に停止した。透明な領域が、左外側葉の両半分間に観察された。この手順を数回繰返し、同じ結果となった。
成体ラットの腸に、十二指腸の位置に小さな切り傷により孔を開け、腹腔内への胃液の漏出をもたらした。該部位を2%ペプチド(RADA16−I)溶液で処置すると、腸からの胃液の漏出はすべて停止した。さらなる容量の2%ペプチド溶液を十二指腸の損傷の位置に注射した。これにより、腸からの漏出はすべて1時間(手順の持続時間中)抑制された。十二指腸の位置の対照切開部では腸壁を裏返し、未処置で放置すると、胃液は損傷部位から漏出し続けた。損傷後、該部位を該ペプチド溶液で15分間処置すると、やはりペプチド処置によって、この損傷部位からの漏出はすべて停止した。また、該処置により、腸の壁の反転の進行が停止した。
自己集合性ペプチドが創傷治癒を増強する能力を実証するため、動物を、皮膚および皮下組織のパンチ生検に供した。生検材料を採取した領域を、自己集合性ペプチド(RADA16−I)溶液の単回適用によって処置するか、または未処置で放置するかのいずれかとした。創傷には包帯をしないで放置した。損傷させた動物を自己集合性ペプチドで処置し、処置なしの対応する例と比較した4mmパンチ生検治癒試験の一連の写真に結果が示される。創傷は、第0日、第1日、第4日、および第7日に写真撮影した。処置された創傷は、早くも第1日での創傷部位の収縮によって示されるように、3つの穿孔すべてにおいてずっと速く治癒した。該ペプチドでの処置により、治癒は、場合によっては5日間も加速されるようであった。すべての例において、創傷部位の収縮は処置例で速く起こった。
RADA16(モジュラスI)をリドカイン(5%)と混合し、ピン痛覚を与える前に混合物を成体ラットの皮膚に適用した。自己集合性ペプチドと混合した場合、ピン痛覚に対する応答は、リドカイン単独を用いた応答の減弱よりも4倍長く減弱された。また、腸の手術を行なう際に、2匹のラットの腸に自己集合性ペプチドとリドカインの溶液を適用した。該溶液により、手術の持続時間中、動物に対する明白な副作用なく蠕動が低減された。
Claims (27)
- 必要部位に投与された場合、体液の移動を抑制もしくは制限するか、組織もしくは細胞を安定化するか、または汚染を抑制するのに有効な量の自己集合性ペプチドを含む処方物。
- 身体上もしくは体内への投与のための薬学的に許容され得る担体および/または非線維性因子をさらに含む、請求項1に記載の処方物。
- 前記処方物が、乾燥粉末、オブラート、ディスク、錠剤、カプセル、液体、ゲル、クリーム、気泡、軟膏、乳剤、ステント、カテーテルもしくは他の医療用インプラント上のコーティング、微粒子内に組み込まれたペプチド、ポリマーマトリクス、ヒドロゲル、織物、包帯、縫合糸またはスポンジを含む、請求項2に記載の処方物。
- 前記自己集合性ペプチドを含む処方物が第1の保存または投与手段に提供され、前記薬学的に許容され得る担体が第2の保存または投与手段に提供される、請求項2に記載の処方物。
- 前記自己集合性ペプチドが、式IIIまたは式IVに従うアミノ酸残基の配列を含む、請求項5に記載の処方物。
- Xaaneuがアラニンを表し;Xaa+がアルギニンまたはリシンを表し;そしてXaa−がアスパラギン酸またはグルタミン酸を表す、請求項5に記載の処方物。
- 前記組成物が、アミノ酸配列RADARADARADAを含む自己集合性ペプチドを含む、請求項5に記載の処方物。
- 前記アミノ酸残基が天然に存在するアミノ酸残基である、請求項5に記載の処方物。
- 自己集合性ペプチドの濃度が、包括的に、0.1%(1mg/ml)〜99%(99mg/ml)との間である、請求項1に記載の処方物。
- 前記自己集合性ペプチドがキット内に、使用のための取扱い説明書、および任意選択で投与のための手段とともに提供される、請求項1に記載の処方物。
- 前記自己集合性ペプチドを入れた第1の区画、および任意選択で、患者への投与前に該自己集合性ペプチドと混合され得る担体または非線維性因子を入れた第2の区画を備える容器(container/vessel)内の、請求項1に記載の処方物。
- 血管収縮薬、着色剤もしくは麻酔剤および/または生体細胞、抗菌剤、コラーゲン、抗炎症剤、増殖因子もしくは栄養素をさらに含む、請求項1に記載の処方物。
- 必要部位における体液の移動の制限または汚染の低減のための医薬の調製のための請求項1〜13いずれか1項に記載の処方物の使用。
- 前記体液が血液である、請求項14に記載の使用。
- 汚染のリスクを低減するため、または汚染を制限するために前記処方物を投与することを含む、請求項14に記載の使用。
- 前記体液が間質液または脳脊髄液である、請求項14に記載の使用。
- 前記細胞または生体液中のタンパク質を安定化させるために、組織、細胞または生体液に前記処方物を投与することを含む、請求項14に記載の使用。
- 汚染または腫瘍細胞、感染、膿、漿液性滲出液、胆汁、膵液、胃、腸もしくは尿路内に通常含まれている物質の拡散を制限するために、手術の際に前記処方物を投与することを含む、請求項14に記載の使用。
- 目または目に隣接する領域もしくは目の内部領域に前記処方物を投与することを含む、請求項14に記載の使用。
- 再付着時の血管内膜または血管の外面に対する損傷を制限するために血管に前記処方物を投与することを含む、請求項14に記載の使用。
- 切開部位における外科的処置前または該処置中に前記処方物を投与することを含む、請求項14に記載の使用。
- 外科的処置を受けている患者、または該処置を受ける準備がなされた患者に、汚染を封じ込めるか、もしくは抑制するため、または手術野内の組織を支持するためのコーティングとして前記処方物を投与することを含む、請求項14に記載の使用。
- 前記処方物が口腔または口腔内の領域に適用される、請求項14に記載の使用。
- 前記処方物が、尿生殖器領域内の部位または該領域に隣接する部位に適用される、請求項14に記載の使用。
- 内視鏡または腹腔鏡の補助により前記処方物を投与することを含む、請求項14に記載の使用。
- 火傷した領域に前記処方物を投与することを含む、請求項14に記載の使用。
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KR20100102750A (ko) | 2010-09-24 |
EP1879606B1 (en) | 2013-06-12 |
JP5204646B2 (ja) | 2013-06-05 |
EP1879606A1 (en) | 2008-01-23 |
WO2006116524A1 (en) | 2006-11-02 |
CA2609656C (en) | 2016-02-02 |
DK1879606T3 (da) | 2013-09-23 |
KR20080007380A (ko) | 2008-01-18 |
IL250767A0 (en) | 2017-04-30 |
JP5629241B2 (ja) | 2014-11-19 |
ES2427565T3 (es) | 2013-10-31 |
US20090111734A1 (en) | 2009-04-30 |
US20070203062A1 (en) | 2007-08-30 |
IL250767B (en) | 2019-02-28 |
CN101267831B (zh) | 2013-04-24 |
US20160296660A1 (en) | 2016-10-13 |
IL245530A0 (en) | 2016-06-30 |
HK1112847A1 (en) | 2008-09-19 |
IL186779A0 (en) | 2008-03-20 |
AU2006241123B2 (en) | 2013-10-03 |
EP2283851A3 (en) | 2011-06-08 |
JP2011168623A (ja) | 2011-09-01 |
EP2283851B1 (en) | 2023-06-07 |
CN101267831A (zh) | 2008-09-17 |
EP2283851A2 (en) | 2011-02-16 |
IL186779A (en) | 2016-05-31 |
AU2006241123A1 (en) | 2006-11-02 |
IL245530A (en) | 2017-03-30 |
US9364513B2 (en) | 2016-06-14 |
JP2014221830A (ja) | 2014-11-27 |
US11839694B2 (en) | 2023-12-12 |
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US9327010B2 (en) | 2016-05-03 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |