JP2008505919A - 精製両親媒性ペプチド組成物およびその使用 - Google Patents
精製両親媒性ペプチド組成物およびその使用 Download PDFInfo
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- JP2008505919A JP2008505919A JP2007520521A JP2007520521A JP2008505919A JP 2008505919 A JP2008505919 A JP 2008505919A JP 2007520521 A JP2007520521 A JP 2007520521A JP 2007520521 A JP2007520521 A JP 2007520521A JP 2008505919 A JP2008505919 A JP 2008505919A
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- peptide
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Abstract
Description
本発明は高純度の両親媒性ペプチド組成物に関する。
一般的に、身体は傷害を受けた組織を再生してもとの組織と同様の特性を有する新しい組織を形成することができる。例えば小型の切り傷は永久的な瘢痕を形成することなく治癒し、そして、骨の簡潔な骨折は骨の2つの切片を結合する新しい骨の形成により治癒する。しかしながら結合組織の細胞及び他の臓器の細胞は足場依存性であり、それらは正常な生理学的挙動を示すためにはスカホールドを必要とする。組織の損傷が広範であるか、又は大型の間隙が存在する場合は、創傷内に遊走した細胞は適切な足場を発見できず、創傷の両端の健常な組織の間の間隙を架橋する瘢痕組織を形成する。瘢痕組織は元の組織と同じ機械的及び生物学的特性を有していない。例えば皮膚の瘢痕組織は元の組織ほど柔軟性を有していない。骨の瘢痕組織は未傷害の骨ほど強度がなく、骨が再度破断しやすい弱点箇所を与える場合が多い。関節の軟骨のような一部の組織は自然に再生せず、そして治癒は瘢痕組織の形成により進行するのみである。
「スカホールド」とは、細胞を支持することができる三次元構造を意味する。細胞はスカホールドによりカプセル化されるか、又はスカホールドの表面上の層内に配置させてよい。スカホールドのβ−シート二次構造は標準的な円偏光二色性を用いて、約218nmにおける最小吸光度及び約195nmにおける最大吸光度を検出することを確認し得る。スカホールドはペプチドの自己組立により形成され、L−アミノ酸、D−アミノ酸、天然アミノ酸、非天然アミノ酸又はこれらの組み合わせを包含し得る。L−アミノ酸がスカホールド内に存在する場合は、スカホールドの分解により宿主組織により再利用されるアミノ酸が生じる。ペプチドは化学誘引物質又は治療活性化合物のような化合物に共有結合され得る。ペプチドは天然又は組み換えの原料から化学合成又は精製してよく、ペプチドのアミノ末端及びカルボキシ末端は保護されていても保護されていなくてもよい。ペプチドスカホールドは相互に相補であり構造的に適合性のあるペプチドの異なる分子種1つ以上から形成されてよい。隣接するペプチド由来の2つの同様に荷電した残基の反発性の対形成のようなミスマッチペアを含有するペプチドもまた、ペプチド間の安定化相互作用が破壊的な力より優位となる場合はスカホールドを形成する。スカホールドは本明細書においてはペプチド構造、ペプチドヒドロゲル構造、ペプチドゲル構造又はヒドロゲル構造とも称する。
1つの局面において、本発明は相補的であり構造的に適合し、そして自己組立によりβ−シート巨視的スカホールドとなる、交互する親水性アミノ酸及び疎水性アミノ酸を有する両親媒性のペプチド鎖を含む組成物である。ペプチド鎖は少なくとも8アミノ酸を含有し、そしてペプチド鎖の少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%又は少なくとも約99%が同じ配列を有する。
本明細書に記載した本発明の組成物は12〜16アミノ酸を有する精製された両親媒性ペプチドを包含する。ペプチドは少なくとも75%の純度である。1つの実施形態において、ペプチドは保護基に連結する側鎖内の基を含むアミノ酸を準備すること、アミノ酸を組み立てて両親媒性のペプチド鎖とすること、及び、トリフルオロ酢酸又はその塩の何れかの非存在下にアセテート塩にペプチドを反応させることにより保護基を除去することにより調製してよい。
本発明の使用に適切であるペプチド配列は、参照により本明細書に組み込まれる、米国特許第5,670,483号及び同第5,955,343号及び米国特許出願第09/778,220号に報告されているものを包含する。これらのペプチド鎖は、1価のカチオンのような電解質の存在下で自己組立して非常に安定なβ−シートの巨視的構造を形成することができる、交互する親水性アミノ酸及び疎水性アミノ酸からなる。ペプチド鎖は相補的であり、構造的に適合している。構造内のペプチド鎖の側鎖は、2つの面、即ち、荷電したイオン性側鎖を有する極性の面及びアラニン又は他の疎水性の基を有する非極性の面に分割される。これらのイオン性の側鎖は、正荷電のアミノ酸残基及び負荷電のアミノ酸残基が相補性のイオン対を形成できるという点において、相互に自己相補的である。従ってこれらのペプチド鎖はイオン性自己相補性ペプチド、又はI型自己組立ペプチドと称する。イオン性残基が1つの正荷電残基と1つの負荷電残基とで交互である場合(−+−+−+−+)、このペプチド鎖は「モジュラスI」と記載され;イオン性残基が2つの正荷電残基と2つの負荷電残基とで交互である場合(−−++−−++)は、このペプチド鎖は「モジュラスII」と記載される。本発明で使用するための例示されるペプチド配列は、表1に列挙するものを包含する。一部の実施形態においては、本発明で使用するペプチド配列は少なくとも12又は18アミノ酸残基を有する。D型及びL型の両方のアミノ酸をペプチド鎖の作製に使用してよい。それらは同じ鎖内で混合されていてよく、或いは、自身がD型及びL型のアミノ酸のみを含んでいる個々の鎖の混合物を有するペプチド組成物を調製してよい。
本発明で使用するためのペプチド鎖は、溶液相合成および固相合成を包含する、当該分野でよく知られた手法を用いて作製してよい。これらの手法は、驚くべき特性(貯蔵寿命、分解速度、溶解度及び機械的特性が挙げられるが、これらに限定されない)を最終組成物に与える純度レベルにおいて、本明細書に記載したペプチド鎖を作製するために最適化されてもよい。
形成されるまで反復する。当業者の知る通り、4量体同士の幾つかの組み合わせは16量体の迅速な形成をもたらす。
精製された生成物は粉末状態で保存するか、又は水溶液中に再溶解してよい。ペプチド産物は以前の製剤よりも水溶性が有意に高値であり、そして2%又は3%超の濃度が達成される。例えば超音波又は振とうテーブルによる攪拌を行えばペプチド鎖が溶液となり易い。溶液中のペプチドの濃度は所望の用途に応じて変動してよい。1つの実施形態において、水中のペプチド鎖の濃度は約0.25%〜約7%、例えば約0.5%、約1%、約2%、約3%、約4%、約5%又は約6%であってよい(全濃度は特段の記載が無い限り、重量%である)。別の実施形態においては、ペプチド鎖の濃度はむしろより高値となり、例えば約7%〜約10%、例えば約8%又は約9%であってよい。
ペプチド溶液を1価の塩の溶液に曝露することにより安定なスカホールドを形成してよい。十分な電解質を溶液に添加することにより、ペプチドからβ−シート巨視的構造への自己組立が開始される。本発明の特定の実施形態においては、添加される電解質の濃度は少なくとも5、10、20又は50mMである。より低濃度、例えば0.1〜1mm又はより高濃度も使用してよい。濃度の選択は部分的にはペプチドゲルの所望のイオン強度に依存しており、そしてゲル化の速度にも影響する。適当な電解質は例えばLi+、Na+、K+及びCs+を包含するがこれらに限定されない。電解質はペプチド鎖を自己組立させて機械的攪拌に対して安定なスカホールドとする。
1.酢酸アンモニウム(実験室調製)
2.クエン酸ナトリウム(実験室調製)
3.酢酸ナトリウム(実験室調製)
4.炭酸水素ナトリウム(Abbott,Inc.作製の臨床用等級)
5.HEPES(Stem Cell Technologies,Inc.作製の研究用等級)
6.Tris−HCl(実験室調製)
7.トロメタミン、別名THAM(Abbott,Inc.作製の臨床用等級)
8.Ca及びMg非含有のリン酸塩緩衝食塩水(Gibc−BRL)。
本明細書に記載したペプチドゲルは、それに細胞が結合し、その上で創傷部位の内部に遊走するマトリックスを提供する。本明細書に開示したペプチドスカホールドは固体マトリックスというよりはむしろ介入する空間を有するナノ繊維のネットワークを含む。そのような構造は、他の培養手法及び材料により可能となるものよりも身体内の細胞の環境により近似した態様において、細胞の浸潤及び細胞−細胞の相互作用を可能にする。端部から単に治癒する代わりに、細胞がスカホールドの中心にまで遊走するに従って創傷の全領域が同時に再生されるのである。
Claims (90)
- 交互する親水性アミノ酸及び疎水性のアミノ酸を各々が有する複数の両親媒性ペプチドを含む組成物であって、ここで、該ペプチド鎖は各々少なくとも8アミノ酸を含有し、相補的であり、構造的に適合し、そして、自己組立によりβ−シートの巨視的スカホールドとなり、そしてここで該ペプチド鎖の少なくとも約75%が同じ配列を有する、組成物。
- 前記ペプチド鎖の少なくとも約80%が同じ配列を有する、請求項1に記載の組成物。
- 前記ペプチド鎖の少なくとも約85%が同じ配列を有する、請求項1に記載の組成物。
- 前記ペプチド鎖の少なくとも約90%が同じ配列を有する、請求項1に記載の組成物。
- 前記ペプチド鎖の少なくとも約95%が同じ配列を有する、請求項1に記載の組成物。
- 前記ペプチド鎖の少なくとも約99%が同じ配列を有する、請求項1に記載の組成物。
- 請求項1に記載の組成物を含む、水溶液。
- 前記溶液が機械的攪拌に対して安定であるヒドロゲルを形成する、請求項12に記載の水溶液。
- 前記溶液が注入可能である、請求項12に記載の水溶液。
- 前記水溶液のpHが約4.5〜約8.5の間である、請求項12に記載の水溶液。
- 前記ペプチドが自己組立を起こして前記溶液中でマトリックスとなる、請求項12に記載の水溶液。
- 前記自己組立が機械的攪拌に対して安定ではない、請求項16に記載の水溶液。
- 少なくとも約0.1mMの電解質を更に含む、請求項16に記載の水溶液。
- 前記溶液が注入可能である、請求項18に記載の水溶液。
- 前記ペプチド鎖が注入後に自己組立可能である、請求項14又は19のいずれか1項に記載の水溶液。
- 緩衝剤を更に含む、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約1重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約2重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約3重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約4重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約5重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約6重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約7重量%である、請求項12に記載の水溶液。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約8重量%である、請求項12に記載の水溶液。
- 1つ以上の生物学的に活性な物質を更に含む、請求項1又は12のいずれか1項に記載の水溶液。
- 以下の工程:
保護基に連結する側鎖内の基を含むアミノ酸を準備する工程;
該アミノ酸を組み立てて両親媒性のペプチド鎖とする工程;
該ペプチド鎖を酸と反応させることにより該保護基を除去する工程;および、
該酸を非フッ素化アセテート塩と交換する工程;
を含む、ペプチド鎖の調製方法。 - 前記非フッ素化アセテート塩が酢酸ナトリウム及び酢酸カリウムから選択される、請求項31に記載の方法。
- 前記方法は、少なくとも約75%が同じ配列番号を有する複数のペプチド鎖を調製する工程を更に含んでいる、請求項31に記載の方法。
- 前記方法は、少なくとも約80%が同じ配列番号を有する複数のペプチド鎖を調製することを更に含んでいる、請求項31に記載の方法。
- 前記方法は、少なくとも約85%が同じ配列番号を有する複数のペプチド鎖を調製することを更に含んでいる、請求項31に記載の方法。
- 前記方法は、少なくとも約90%が同じ配列番号を有する複数のペプチド鎖を調製することを更に含んでいる、請求項31に記載の方法。
- 前記方法は、少なくとも約95%が同じ配列番号を有する複数のペプチド鎖を調製することを更に含んでいる、請求項31に記載の方法。
- 前記方法は、少なくとも約99%が同じ配列番号を有する複数のペプチド鎖を調製することを更に含んでいる、請求項31に記載の方法。
- 前記酸がトリフルオロ酢酸である、請求項31に記載の方法。
- 交互する親水性アミノ酸及び疎水性のアミノ酸を有する両親媒性ペプチド鎖の2%超の水溶液であって、該ペプチド鎖各々が少なくとも8アミノ酸を含有する、水溶液
を含む組成物。 - 前記ペプチド鎖が機械的攪拌に対して安定であるヒドロゲルを形成する、請求項40に記載の水溶液。
- 前記溶液が注入可能である、請求項40に記載の組成物。
- 前記ペプチド鎖が自己組立を起こして前記溶液中でマトリックスとなる、請求項40に記載の組成物。
- 前記自己組立が機械的攪拌に対して安定ではない、請求項43に記載の組成物。
- 前記溶液が少なくとも約0.1mMの電解質を含有する、請求項43に記載の組成物。
- 前記溶液が注入可能である、請求項45に記載の組成物。
- 前記ペプチド鎖が注入後に自己組立可能である、請求項42又は46のいずれか1項に記載の組成物。
- 生物学的に活性な1つ以上の物質を更に含む、請求項40に記載の組成物。
- 前記水溶液中のペプチド鎖の濃度が少なくとも約3重量%である、請求項40に記載の組成物。
- 前記水溶液中のペプチド鎖の濃度が少なくとも約4重量%である、請求項40に記載の組成物。
- 前記水溶液中のペプチド鎖の濃度が少なくとも約5重量%である、請求項40に記載の組成物。
- 前記水溶液中のペプチド鎖の濃度が少なくとも約6重量%である、請求項40に記載の組成物。
- 前記水溶液中のペプチド鎖の濃度が少なくとも約7重量%である、請求項40に記載の組成物。
- 前記水溶液中のペプチド鎖の濃度が少なくとも約8重量%である、請求項40に記載の組成物。
- 両親媒性ペプチド鎖を含む巨視的スカホールドであって、ここで該ペプチド鎖は、交互する親水性アミノ酸及び疎水性のアミノ酸を有し、相補的であり構造的に適合し、そして、自己組立によりβ−シート巨視的スカホールドとなり、そしてここで両親媒性ペプチド鎖は水溶液中にあり、そしてここで該ペプチド鎖の少なくとも約75%が同じ配列を有する、巨視的スカホールド。
- 前記ペプチド鎖の少なくとも約80%が同じ配列を有する、請求項55に記載の巨視的スカホールド。
- 前記ペプチド鎖の少なくとも約85%が同じ配列を有する、請求項55に記載の巨視的スカホールド。
- 前記ペプチド鎖の少なくとも約90%が同じ配列を有する、請求項55に記載の巨視的スカホールド。
- 前記ペプチド鎖の少なくとも約95%が同じ配列を有する、請求項55に記載の巨視的スカホールド。
- 前記ペプチド鎖の少なくとも約99%が同じ配列を有する、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約1重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約2重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約3重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約4重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約5重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約6重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約7重量%である、請求項55に記載の巨視的スカホールド。
- 前記水溶液中の前記ペプチド鎖の濃度が少なくとも約8重量%である、請求項55に記載の巨視的スカホールド。
- 前記スカホールドが物理的攪拌に対して安定である、請求項55に記載の巨視的スカホールド。
- 前記両親媒性ペプチドを含有する水溶液が注入可能である、請求項69に記載の巨視的スカホールド。
- 前記スカホールドが物理的攪拌に対して安定ではない請求項55に記載の巨視的スカホールド。
- 前記ペプチド鎖が注入後に自己組立可能である、請求項70に記載の巨視的スカホールド。
- 前記両親媒性ペプチドが電解質を含有する水溶液中にあり、そして前記スカホールドが物理的攪拌に対して安定である、請求項55に記載の巨視的スカホールド。
- 前記両親媒性ペプチド鎖を含有する水溶液が注入可能である、請求項73に記載の巨視的スカホールド。
- 前記スカホールド内にカプセル化された生物学的に活性な物質を更に含む、請求項55に記載の巨視的スカホールド。
- 生物学的に活性な物質を患者に送達する方法であって、以下の工程:
請求項12に記載の水溶液を準備する工程;
該水溶液に所定量の生物学的に活性な物質を添加する工程;及び、
該水溶液に電解質の所定量を添加する工程、
を包含し、ここで該所定量を添加した後に、該水溶液がヒドロゲルを形成する、方法。 - 前記生物学的に活性な物質及び前記電解質を単一の水溶液中で組み合わせ、そして同時に前記両親媒性のペプチドの水溶液に添加する、請求項76に記載の方法。
- 前記生物学的に活性な物質が抗炎症剤、抗生物質、抗癌剤、鎮痛剤、オピオイド、薬剤、成長因子、タンパク質、アミノ酸、ペプチド、ポリヌクレオチド、ヌクレオチド、炭水化物、糖、脂質、多糖類、核タンパク質、糖タンパク質、リポタンパク質、ステロイド、化学誘引剤及びこれらの何れかの組み合わせから選択される、請求項76に記載の方法。
- 患者の所定部位に前記ヒドロゲルを注入することを更に含む、請求項76に記載の方法。
- 電解質の所定量を添加する工程の前、かつ生物学的に活性な物質の所定量を添加する工程の後に患者に水溶液を注入する工程を更に含み、ここで該電解質の所定量を添加する工程が、周囲組織から、注入された溶液内にイオンを移動させることを含む、請求項76に記載の方法。
- 電解質の所定量を添加する工程の前、かつ生物学的に活性な物質の所定量を添加する工程の後に患者の所定部位内に水溶液を注入する工程を更に含み、ここで該注入された水溶液は所定部位からの移動に関して安定である、請求項76に記載の方法。
- 以下要素:
請求項1に記載の組成物;及び、
1つ以上の電解質、緩衝剤、送達装置、他の薬剤1つ以上と該組成物とを混合するために適する容器、使用のための組成物を調製するための説明書、他の物質と組成物とを混合するための説明書、および、対象内に該組成物を導入するための説明書、
を備える、患者に物質を送達するためのキット。 - 前記組成物が乾燥形態又は水溶液である、請求項82に記載のキット。
- 前記水溶液が所定の条件下で少なくとも9週間の貯蔵寿命を有する、請求項83に記載のキット。
- 前記水溶液が更に電解質を含む、請求項83に記載のキット。
- 前記送達装置が1つ以上のカテーテル、針及びシリンジを含む、請求項82に記載のキット。
- 生物学的に活性な物質を更に含む、請求項82に記載のキット。
- 前記生物学的に活性な物質が前記組成物と予備混合される、請求項87に記載のキット。
- 前記生物学的に活性な物質がナノスフェア又はマイクロスフェアの形態である、請求項87に記載のキット。
- 前記キットを用いて送達されるべき細胞の調製に関する説明書を更に含む、請求項82に記載のキット。
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JPWO2007000979A1 (ja) * | 2005-06-27 | 2009-01-22 | 株式会社メニコン | 自己組織化ペプチドおよびそれより得られるゲル |
JP2010001238A (ja) * | 2008-06-19 | 2010-01-07 | Nagoya Institute Of Technology | 二次元微細薄膜の作製方法 |
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KR20190084286A (ko) | 2016-11-17 | 2019-07-16 | 지호우도쿠리츠교우세이호우징 도쿄토리츠 산교기주츠켄큐센타 | 생체 조직 구멍 폐쇄용, 궤양 보호용 및 혈관 색전 치료술용 졸 |
US11559602B2 (en) | 2016-11-17 | 2023-01-24 | Tokyo Metropolitan Industrial Technology Research Institute | Sol for tissue perforation closure, ulcer protection, and vascular embolization |
US11324703B2 (en) | 2017-12-15 | 2022-05-10 | 3-D Matrix, Ltd. | Surfactant peptide nanostructures and uses thereof in drug delivery |
WO2020171161A1 (ja) * | 2019-02-20 | 2020-08-27 | 国立大学法人東京農工大学 | 自己組織化ペプチド |
JP7466876B2 (ja) | 2019-02-20 | 2024-04-15 | 国立大学法人東京農工大学 | 自己組織化ペプチド |
US12006085B2 (en) | 2022-06-04 | 2024-06-11 | 3-D Matrix, Ltd. | Fill-finish process for peptide solutions |
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WO2006014570A3 (en) | 2006-04-06 |
EP1843776A2 (en) | 2007-10-17 |
EP3031466A1 (en) | 2016-06-15 |
JP5255274B2 (ja) | 2013-08-07 |
US20060084607A1 (en) | 2006-04-20 |
JP5730828B2 (ja) | 2015-06-10 |
EP3031466B1 (en) | 2018-11-28 |
US20160317607A1 (en) | 2016-11-03 |
CA2572964C (en) | 2018-03-06 |
US20230190864A1 (en) | 2023-06-22 |
WO2006014570A2 (en) | 2006-02-09 |
EP1843776A4 (en) | 2011-05-11 |
JP2012250988A (ja) | 2012-12-20 |
CA2572964A1 (en) | 2006-02-09 |
US20130281547A1 (en) | 2013-10-24 |
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EP4049671A1 (en) | 2022-08-31 |
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