JP6812436B2 - 抗ウイルス薬およびウイルス感染症の治療方法 - Google Patents
抗ウイルス薬およびウイルス感染症の治療方法 Download PDFInfo
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Description
「身体」という用語は、人間および/または動物の身体を意味する。「対象」という用語は対象であるそのような被験者を意味する。
本発明の実施形態を図面を参照して説明する:
ポリアルキレングリコール(好ましくは200〜600ダルトンの範囲での分子量のポリエチレングリコール)の弱塩基性(好ましくはpHが12.0以下、より好ましくはpHが9〜11)水溶液を提供し、
前記弱塩基性の溶液を激しく撹拌して空気を含ませ、
アクロレイン水溶液50%w/w以下の濃度の水溶液(通常は防腐剤を含む)としてアクロレインを添加し(好ましくはある期間、例えば2分間、より好ましくは少なくとも5分間にわたってゆっくりと)、
反応温度を10℃〜40℃の範囲に維持し、
前記アクロレインのモノマーが消費されたら、酸を添加して9以下、好ましくは8以下のpHを提供する。
・本発明により記載される共重合体は、共重合体と疾患細胞の外膜のタンパク質との間の非特異的な疎水性反応に依存することが判明しており、反応がより大きくなると、細胞の外膜の疎水性および代謝性活性が細胞を弱め、内部浸透圧が周囲の細胞よりも大きく上昇し、
・反応が膜を弱める、
という利点をもたらす。
実施例1および比較例1からの共重合体は抗ウイルス特性を有する。インビボで実施例1からのより低いMW500は、アクロレインおよびPEGのより高分子量のポリマーよりも常に有効であることが見出されている。
本明細書で報告されるカルボニル含有量の推定値は、確立された方法(Peters 1962; Melrose 2009)に基づいている。二重に、共重合体(1g)の試料水溶液を0.01gの精度で秤量し、水(9g)を添加し、次に0.01M塩酸または0.01M水酸化ナトリウム水溶液のいずれかを適切に添加してpHを6.00にした。
高性能液体クロマトグラフィー(HPLC)は、屈折率およびUV(268nm)検出器の両方を同時に使用してShimadzu Profinence装置で実施した。カラムは、サイズ排除による分離のために、(直列の)Waters Hydrogel 120またはWaters Hydrogel 250のいずれかまたは両方であった。
2つの別々の技術(島津科学機器(オセアニア)Pty Ltdの提供による)が実施された:
・事前クロマトグラフィーなしで、質量分析計への直接注入;
・クロマトグラフィー後の質量分析
分析のための溶液は、水(20g)に共重合体(250mg)を希釈し、場合によっては化学量論的モル当量の反応物を希釈することによって調製し、その後、Shimadzu UVmini-1240装置でUVスペクトルを取る前に、水で1:9に希釈した。
実施例1は、ポリアクロレインオリゴマーセグメントおよび分子量200ダルトンのポリエチレングリコールオリゴマーセグメントを含む約500ダルトンの分子量の本発明の共重合体の製造を記載する。この共重合体は、本明細書に記載されるような望ましくない副反応のレベルを導入することなく、信頼できる成功のために推奨される最高pHであるので、pH12.0の調製物から意図的に説明される。共重合体の抗ウイルス活性は、通常、約2500ダルトンの分子量の対応する共重合体のものと比較して高い。
水(20g)とポリエチレングリコール(60g;MW200)の溶液に、新たに蒸留したアクロレイン(5g;ハイドロキノン0.1%w/wで阻害)の水(20g)溶液を10分かけてゆっくりと添加し、1M水酸化ナトリウム水溶液の添加によりpH12にすると、10分の間に、酸化ハイドロキノンの黄色が速やかに現れ、その後消失した。このプロセスの間、組成物を連続的かつ激しく撹拌して空気との多量の接触を提供した。発熱および急速な重合が行われ、反応物の温度は約25℃〜35℃に維持された。
この実施例は、分子量2000のポリエチレングリコールセグメントを含む、より高分子量の2500ダルトンの、本発明ではない共重合体の製造を記載する。
この実施例は、分子量600ダルトンのポリエチレングリコールオリゴマーセグメントを含む約1000ダルトンの分子量の本発明の共重合体の調製を実証した。
第1部 第1にCPEアッセイ(および抗生物質の細胞傷害性)、第2にPRNT試験における、インフルエンザA TX/36/91(H1N1)に対する実施例1のインビトロ抗ウイルス評価。
実施例1の以下の2つのインビトロ活性の例は、作用が、それぞれ、予防的/細胞内部である場合、および作用が治癒的/細胞外である場合の代表例である。
・MDCK細胞を96ウェルプレートに播種し、一晩インキュベートした
・翌日、細胞をIFV A/TX/36/91に0.01のMOIで35℃で24時間感染させた
・翌日、実施例1の連続希釈(2倍希釈で0.1%(1000ppm)で開始)を培地中で調製した
・接種材料を細胞から除去し、連続希釈物を細胞に35℃で1時間添加した
・化合物希釈物を除去し、細胞をELISAによってウイルス抗原について評価した。
・MDCK細胞を黒色壁96ウェルプレートに播種し、一晩インキュベートした
・翌日、増殖培地を細胞から除去し、インキュベーション培地を添加した
・翌日、実施例1の連続希釈物を、CPEアッセイについて記載したように調製した
・培地を細胞から吸引し、化合物希釈物を35℃で1時間添加した。培地のみでインキュベートした細胞を0%細胞傷害性データのために使用した
・培地を吸引し、PromegaのCelltiterGloキットを用いて5日目にATP含量の評価のために細胞を溶解した
・得られたルシフェラーゼルミネセンスを定量し、4−PL曲線適合を用いてCC50を計算するのに使用した
・ベロ細胞を24ウェルプレートに播種し、一晩インキュベートした
・翌日、実施例1の連続希釈(2倍希釈で0.1%(1000ppm)で開始)および対照抗体を培地中で調製した
・段階希釈液を200PFUのIFV A/TX/36/91とともに35℃で2時間インキュベートした
・その後、接種材料を35℃で1時間細胞に添加した
・接種物を除去し、プレートを5日間インキュベートした
・ウイルス力価はイムノプラーク(immunoplaque)アッセイにより決定した
・ベロ細胞を黒色壁96ウェルプレートに播種し、一晩インキュベートした
・翌日、実施例1の連続希釈液をPRNTアッセイについて記載したように調製した
・増殖培地を細胞から吸引し、化合物の希釈物を添加した。培地のみでインキュベートした細胞を0%細胞傷害性データのために使用した
・化合物を1時間後に除去し、新鮮な培地を添加してから、プレートを35℃で5日間置いた
・培地を吸引し、PromegaのCelltiterGloキットを用いて5日目にATP含量の評価のために細胞を溶解した
・得られたルシフェラーゼルミネセンスを定量し、4−PL曲線適合を用いてCC50を計算した。結果を表1に示す。
この実施例は、ウィルス、特にインフルエンザA TX/36/91(H1N1の感染の制御における、実施例1の共重合体のインビボでの活性を調べる。
Claims (16)
- アクロレイン由来セグメントおよびポリアルキレングリコールオリゴマーセグメントを含み、1000ダルトン以下の分子量を有する共重合体を含む、対象における非経口ウイルス感染症の治療のための組成物。
- 前記アクロレイン由来セグメントは、2以上のアクロレイン残基を含むポリアクロレインオリゴマーである、請求項1に記載の組成物。
- 前記共重合体は、300〜1000ダルトンの分子量を有する、請求項1または2に記載の組成物。
- 前記ポリアルキレングリコールオリゴマーセグメントは、200〜600ダルトンの範囲の分子量を有する、請求項1から3のいずれかに記載の組成物。
- 前記ポリアルキレングリコールオリゴマーセグメントは、200〜400ダルトンの範囲の分子量を有する、請求項1から4のいずれかに記載の組成物。
- 前記ポリアルキレングリコールはポリエチレングリコールである、請求項1から5のいずれかに記載の組成物。
- 局所投与用である、請求項1から6のいずれかに記載の組成物。
- 全身投与用である、請求項1から7のいずれかに記載の組成物。
- 経口投与用、吸入用、経皮送達用、または注射用である、請求項1から8のいずれかに記載の組成物。
- 経口投与用である、請求項1から9のいずれかに記載の組成物。
- 循環系または血流への注射用である、請求項1から9のいずれかに記載の組成物。
- 0.01重量%〜20重量%の範囲の水溶液としての投与で使用される、請求項1から11のいずれかに記載の組成物。
- 錠剤、カプレット、シロップ、または液体の形態で経口投与用に使用される、請求項9に記載の組成物。
- 前記共重合体は、1日あたりに体重1kg当たり1mg〜1000mgの範囲の用量で、全身投与用に使用される、請求項1から13のいずれかに記載の組成物。
- 前記ウイルス感染症は、インフルエンザウイルス、HIV、肝炎、ロスリバー、およびヘルペスからなる群から選択される、請求項1から14のいずれかに記載の組成物。
- 前記ウイルス感染症は、インフルエンザである、請求項1から15のいずれかに記載の組成物。
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