JP5902171B2 - 高抗微生物活性および低毒性を有する材料の組成物および使用 - Google Patents
高抗微生物活性および低毒性を有する材料の組成物および使用 Download PDFInfo
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Description
本出願は、準拠法で認められた範囲内で参照により本明細書に組み入れられる2010年8月23日出願の米国仮特許出願第61/376,195号に基づく利益および優先権を主張する。
該当なし。
は、抗微生物剤として最も有効であると思われるが、皮膚刺激を引き起こしうる。全体的にみて、クロルヘキシジンは、最小量の化合物が吸収されるので、無傷の皮膚に適用する場合、比較的安全である。しかしながら、刺激性および毒性があるので、クロルヘキシジンは、眼、耳、脳組織、および髄膜の近傍での使用が禁忌である[2]。創傷洗浄剤および含嗽剤として、低濃度(たとえば、0.05%〜0.12%)が使用されることもある。低pH環境では活性が低下するので、活性はpH依存性である。それに加えて、クロルヘキシジンは、アニオン性化合物(たとえば、硬水、石鹸、アルギン酸塩)との適合性がなく、有機物質(たとえば、血液)の存在下で活性低下を呈する。
概要。使用前、窒素下でアルミナ充填カラムに通すことにより、無水テトラヒドロフラン(THF)を準備した。105、104、および103Å Phenomenex 5μmカラムで、溶出液としてDMF中の0.1M LiBrおよび約5mg/mLのポリペプチド濃度を用いて、Wyatt DAWN EOS光散乱検出器および、Wyatt Optilab DSPを備えたSSIポンプを利用して、60℃でタンデムゲル浸透クロマトグラフィー/光散乱(GPC/LS)を行うことにより、分子量(Mn)および多分散度(PDI)を得た。ポリスチレン膜を用いて校正されたPerkin Elmer RX1 FTIR分光光度計を利用して、フーリエ変換赤外スペクトル(FTIR)を記録した。Bruker AVANCE 400MHz分光計を利用して、1H NMRスペクトルを記録した。Purelab Option 560逆浸透式浄水器を用いて、脱イオン(DI)水を精製した。Millipore Milli−Q Biocel A10精製ユニットから、Millipore水を得た。
ポリ(L−グルタミン酸−Na)64−b−ポリ(rac−ロイシン)20、E64(rac−L)20。ドライボックス内で、攪拌子を備えた250mL平底フラスコ中にγ−ベンジル−L−グルタミン酸、Bzl−Glu NCA(5.00g、19mmol)を入れた。無水THF(100mL)を添加し、次いで、プラスチック栓で密封した。次いで、シリンジを介して(PMe3)4Coのアリコート(11.5mLの40mg/mL無水THF溶液、1.27mmol)を添加し、そしてフラスコを密封して1時間攪拌した。アリコート(50μL)を重合系から取り出してGPC分析に供した(Mn=13.9×103g/mol、Mw/Mn=1.27)。次いで、D,Lロイシン(L)NCAのアリコート(18.7mLの50mg/mL THF溶液、6.0mmol)を添加して一晩重合させた。次いで、THFを減圧下で除去し、次いで、無水CH2Cl2(100mL)中に溶解させた。ベンジル保護基を除去するために、シリンジを介してヨードトリメチルシラン(10.8mL、76mmol)を添加した。還流冷却器をフラスコに取り付けて、40℃で一晩還流させた。次いで、溶媒を減圧下で除去し、そして1M NaOHを添加して一晩撹拌し、次いで、濾過して沈殿物を除去し、2回/日で各溶液を交換して、5mM重亜硫酸ナトリウムおよび0.1M NaOH(3日間)、次いで、Millipore水(4日間)で透析した(6〜8,000MWCO膜)。次いで、透明溶液を凍結乾燥させて白色綿毛状固体(1.26g、36%)を得た。
付記
[1]少なくとも5個のカチオン性アミノ酸残基と、
ブロック状アミノ酸配列であって、前記ブロックの少なくとも1つが少なくとも10個の親水性アミノ酸残基を含有し、かつ前記ブロックの少なくとも1つが少なくとも5個の疎水性アミノ酸残基を含有する、ブロック状アミノ酸配列と、
微生物を阻害するまたは死滅させる能力と、
を含む合成コポリペプチド。
[2]少なくとも5個のカチオン性アミノ酸残基と、
秩序化階層構造形態への誘導自己集合を促進するアミノ酸配列と、
微生物を阻害するまたは死滅させる能力と、
を含む合成コポリペプチド。
[3]全鎖長が25アミノ酸残基以上である、[2]に記載の合成コポリペプチド。
[4]前記階層構造が、ミセル、ベシクル、シート、およびフィブリルよりなる群から選択される、[2]に記載の合成コポリペプチド。
[5]前記微生物が、細菌、ウイルス、菌類、および原生動物よりなる群から選択される、[1]または[2]に記載の合成コポリペプチド。
[6]少なくとも20個の連続した親水性アミノ酸残基を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[7]少なくとも50個の連続した親水性アミノ酸残基を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[8]少なくとも80個の連続した親水性アミノ酸残基を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[9]少なくとも100個の連続した親水性アミノ酸残基を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[10]少なくとも120個の連続した親水性アミノ酸残基を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[11]少なくとも5個の連続した疎水性アミノ酸残基を有する少なくとも1つブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[12]少なくとも10個の連続した疎水性アミノ酸残基を有する少なくとも1つブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[13]少なくとも15個の連続した疎水性アミノ酸を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[14]少なくとも20個の連続した疎水性アミノ酸を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[15]少なくとも30個の連続した疎水性アミノ酸を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[16]少なくとも40個の連続した疎水性アミノ酸を有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[17]疎水性アミノ酸残基が前記コポリペプチドのアミノ酸残基の30%以下を構成する、[1]または[2]に記載の合成コポリペプチド。
[18]疎水性アミノ酸残基が前記コポリペプチドのアミノ酸残基の20%以下を構成する、[1]または[2]に記載の合成コポリペプチド。
[19]疎水性アミノ酸残基が前記コポリペプチドのアミノ酸残基の10%以下を構成する、[1]または[2]に記載の合成コポリペプチド。
[20]少なくとも3つのブロックを含むアミノ酸配列をさらに含む、[1]または[2]に記載の合成コポリペプチド。
[21]前記合成コポリペプチドの臨界凝集濃度が、前記合成コポリペプチドと同一のアミノ酸残基組成を有するランダム配列合成コポリペプチドの臨界凝集濃度よりも少なくとも20%低い、[1]または[2]に記載の合成コポリペプチド。
[22]階層構造形態への前記合成コポリペプチドの会合の速度が、前記合成コポリペプチドと同一のアミノ酸残基組成を有するランダム配列合成コポリペプチドの会合の速度よりも少なくとも20%高い、または前記合成コポリペプチドにより形成された階層構造の解離の速度が、前記合成コポリペプチドと同一のアミノ酸残基組成を有するランダム配列合成コポリペプチドにより形成された階層構造の解離の速度よりも少なくとも20%低い、[1]または[2]に記載の合成コポリペプチド。
[23]前記合成コポリペプチドが、少なくとも50Paの貯蔵弾性率を有するヒドロゲルを形成する、[1]または[2]に記載の合成コポリペプチド。
[24]前記合成コポリペプチドが、0.01%(w/w)程度の低い濃度でヒドロゲルを形成する、[1]または[2]に記載の合成コポリペプチド。
[25]前記合成コポリエプチドが、非混和性相の組合せを有する混合物中に組み込まれて、分散混合物またはエマルジョンを形成する、[1]または[2]に記載の合成コポリペプチド。
[26]前記非混和性相が、油混和性相および水混和性相から選択される、[25に記載の合成コポリペプチド。
[27]前記分散混合物またはエマルジョンが、水中油、油中水、水中油中水、および油中水中油から選択される、[26に記載の合成コポリペプチド。
[28]前記合成コポリペプチドが哺乳動物細胞を死滅させるよりも低い濃度で微生物を死滅させるまたは阻害する能力をさらに含む、[1]または[2]に記載の合成コポリペプチド。
[29]食品保存、溶液保存、手指衛生、局所抗感染、補綴具およびインプラントの被覆、創傷治療、手術部位治療、火傷治療、糖尿病性足部潰瘍治療、ならびに外傷治療から選択される用途で使用される、[1]または[2]に記載の合成コポリペプチド。
[30]ステロイド剤、炎症誘発剤、抗炎症剤、抗座瘡剤、保存剤、止血剤、血管新生剤、創傷治癒剤、および抗癌剤から選択される追加の活性医薬成分(API)をさらに含む、[1]または[2]に記載の合成コポリペプチド。
[31]前記コポリペプチドが、前記階層構造の形成または強度に寄与する1つ以上の他の材料の存在下で複合階層構造形態に製剤化される、[1]または[2]に記載の合成コポリペプチド。
[32]前記コポリペプチドが修飾単量体アミノ酸を用いて合成される、または前記アミノ酸残基が重合後に修飾される、[1]または[2]に記載の合成コポリペプチド。
[33]リシン、アルギニン、ホモアルギニン、およびオルニチンよりなる群から選択される荷電アミノ酸を含む親水性ブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[34]セリンおよびチロシンよりなる群から選択される非荷電極性アミノ酸を含む親水性ブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[35]ロイシン、バリン、フェニルアラニン、イソロイシン、アラニン、およびそれらの混合物組合せよりなる群から選択される非極性疎水性アミノ酸を含む親水性ブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[36]1個以上のβ−アミノ酸残基をさらに含む、[1]または[2]に記載の合成コポリペプチド。
[37]前記合成ポリペプチドが病原性微生物を選択的に標的にする、[1]または[2]に記載の合成コポリペプチド。
[38]共有結合修飾側鎖を有するアミノ酸残基を含有する少なくとも1つのブロックを含む、[1]または[2]に記載の合成コポリペプチド。
[39]前記共有結合修飾側鎖が、PEG側鎖およびN−四級化側鎖よりなる群から選択される、[38に記載の合成コポリペプチド。
[40]親水性ブロックが、「クリックケミストリー」という手段またはインドール、グリコール、マロネート、ジカルボキシレート、トリアゾール、およびPEGよりなる群から選択されるスペーサーを含有する手段により共有結合される、[1]または[2]に記載の合成コポリペプチド。
[41]1つ以上のブロックがアミノ残基のL−、D−、ラセミ混合物または異なる光学純度の混合物を含有することを含む、[1]または[2]に記載の合成コポリペプチド。
[42]0.1%(w/w)未満の濃度でインビトロで微生物を阻害するまたは死滅させる能力を備える、[1]または[2]に記載の合成コポリペプチド。
[43]抗微生物活性および止血性を示す、[1]または[2]に記載の合成コポリペプチド。
[44]上記[1]または[2]に記載の2つ以上の合成コポリペプチドの混合物。
[45]上記[1]または[2]に記載の1つ以上の抗微生物合成コポリペプチドと他のポリマーまたはコポリマーとの混合物。
[46]前記ポリマーまたはコポリマーが、アルギネート、キトサン、PEG、変性セルロース、および他のポリサッカリドよりなる群から選択される、[45に記載の混合物。
[47]上記[1]または[2]に記載の1つ以上の抗微生物合成コポリペプチドと他の抗微生物剤との混合物。
[48]前記他の抗微生物剤が、アルコール、塩素系化合物、第四級アンモニウム化合物、フェノール化合物、クロルヘキシジン、抗生物質、および抗体よりなる群から選択される、[47]に記載の混合物。
[49]1つ以上の8アミノ酸以上のペプチドブロックと1つ以上の非ペプチドブロックとを含有する合成コポリペプチド−ポリマーハイブリッド。
[50]抗微生物活性、および止血材料、創傷治癒を支援する増殖因子、炎症誘発剤および抗炎症剤、及び免疫モジュレーターよりなる群から選択されるさらなる活性を提供するための、抗微生物合成コポリペプチドとポリマーまたはコポリマーと生体活性材料または他の活性医薬成分(API)との混合物。
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Claims (17)
- 少なくとも5個の隣接するカチオン性アミノ酸残基を含有する少なくとも1つの親水性セグメントと
少なくとも5個の隣接する疎水性アミノ酸残基を含有する少なくとも1つの疎水性セグメントと
を含み、前記親水性セグメントが前記疎水性セグメントよりも多数のアミノ酸残基を含有する、少なくとも40のアミノ酸残基の少なくとも1種の合成コポリペプチドと、
水と、
を含む抗微生物組成物であって、
前記少なくとも1種の合成コポリペプチドが水性媒体中で多量体構造を形成し、
前記少なくとも1種の合成コポリペプチドが水性媒体中で微生物を阻害するかまたは死滅させ、かつ、
前記組成物が微生物を阻害するまたは死滅させる、
抗微生物組成物。 - 前記少なくとも1種の合成コポリペプチドが実質的に天然アミノ酸のみを含む、請求項1に記載の組成物。
- 前記少なくとも1種の合成コポリペプチドが40%以下の疎水性残基含量を有する、請求項1に記載の組成物。
- 水性媒体中で形成される前記構造が、溶液中の多量体、ミセル、シート、ベシクル、およびフィブリルよりなる群から選択される、請求項1に記載の組成物。
- 前記少なくとも1種の合成コポリペプチドが、同一のアミノ酸組成物のランダム配列コポリペプチドよりも少なくとも1 log低い水中臨界凝集濃度(CAC)を有する、請求項1に記載の組成物。
- インビトロで哺乳動物細胞を死滅させるよりも低い濃度でインビトロの微生物を死滅させるかまたは阻害することを特徴とする、請求項1に記載の組成物。
- 組織に対して低毒性を示す濃度でインビボで哺乳動物組織中または哺乳動物組織上で微生物を死滅させるかまたは阻害することを特徴とする、請求項1に記載の組成物。
- 100μg/mL以下の少なくとも1種の合成コポリペプチドの濃度で、スタフィロコッカス・エピデルミディス(Staphylococcus epidermidis)または大腸菌の3log超の減少により測定されるようにインビトロで微生物を死滅させるかまたは阻害することを特徴とする、請求項1に記載の組成物。
- 前記組成物は、少なくとも50Paの貯蔵弾性率を有するヒドロゲルを形成する、請求項1に記載の組成物。
- 前記少なくとも1種の合成コポリペプチドが血小板凝集を促進する、請求項1に記載の組成物。
- 前記少なくとも1種の合成コポリペプチドがフィブリン溶解を阻害する、請求項1に記載の組成物。
- 分散混合物またはエマルジョン中の非混和性相の組合せをさらに含む、請求項1に記載の組成物。
- ステロイド剤、炎症誘発剤、抗炎症剤、抗座瘡剤、保存剤、止血剤、血管新生剤、創傷治癒剤、抗癌剤、および他の抗微生物剤から選択されるさらなる活性医薬成分(API)をさらに含む、請求項1に記載の組成物。
- 感染症の予防または治療のための、局所抗感染のための、微生物コロニー除去のための、創傷治療のための、手術部位治療のための、外傷治療のための、火傷治療のための、糖尿病性足部潰瘍治療のための、手指衛生のための、補綴具およびインプラントを被覆するための、食品保存のための、および溶液保存のための、薬品の製造における、請求項1〜13の何れか一項に記載の組成物の使用。
- 哺乳類における感染症の予防又は治療のための医薬の製造における抗微生物組成物の使用であって、前記組成物は、少なくとも5個の隣接するカチオン性アミノ酸残基を含有する少なくとも1つの親水性セグメントと
少なくとも5個の隣接する疎水性アミノ酸残基を含有する少なくとも1つの疎水性セグメントと
を含み、前記親水性セグメントが前記疎水性セグメントよりも多数のアミノ酸残基を含有する、少なくとも40のアミノ酸残基の少なくとも1種の合成コポリペプチドと、
水と、
を含み、
前記少なくとも1種の合成コポリペプチドが水性媒体中で多量体構造を形成し、
前記少なくとも1種の合成コポリペプチドが水性媒体中で微生物を阻害または死滅させ、かつ、
前記組成物が微生物を阻害又は死滅する、使用。 - 哺乳類における止血を促進するための医薬の製造における、止血組成物の使用であって、前記組成物は、
少なくとも5個の隣接するカチオン性アミノ酸残基を含有する少なくとも1つの親水性セグメントと
少なくとも5個の隣接する疎水性アミノ酸残基を含有する少なくとも1つの疎水性セグメントと
を含み、前記親水性セグメントが前記疎水性セグメントよりも多数のアミノ酸残基を含有する、少なくとも40のアミノ酸残基の少なくとも1種の合成コポリペプチドと、
水と、
を含み、
前記少なくとも1種の合成コポリペプチドが水性媒体中で多量体構造を形成し、
前記少なくとも1種の合成コポリペプチドが水性媒体中で微生物を阻害または死滅させ、かつ、
前記組成物が止血を促進する、使用。 - 前記組成物が一以上のさらなる止血剤を含む、請求項16に記載の使用。
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