JP2017520594A - 局所用抗ウイルス薬組成物及びこれを使用する方法 - Google Patents
局所用抗ウイルス薬組成物及びこれを使用する方法 Download PDFInfo
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- JP2017520594A JP2017520594A JP2017501173A JP2017501173A JP2017520594A JP 2017520594 A JP2017520594 A JP 2017520594A JP 2017501173 A JP2017501173 A JP 2017501173A JP 2017501173 A JP2017501173 A JP 2017501173A JP 2017520594 A JP2017520594 A JP 2017520594A
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Abstract
Description
本出願は、2014年7月11日に出願された米国特許仮出願第62/023,587号、及び、2015年3月27日に出願された米国特許仮出願第62/139,176号の利益を主張するものであり、これらの各文献の開示内容は、参照によりその全体が本明細書の一部をなすものとする。
本発明は、一般的には、局所用抗ウイルス薬組成物及びこれを使用する方法に関する。局所用抗ウイルス薬組成物を使用する方法は、ウイルス感染症を治療及び/又は予防する方法を含む。
ウサギの群に、以下で表1に記載するとおりの多様な用量での抗ウイルス薬治療を受けさせた。A〜G群における抗ウイルス薬治療のための製剤を表2及び表3に示す。A〜E群用の製剤にはそれぞれ、2室式ポンプ内に別々に保存された2つの別々の組成物が入っていた。施用に先立ち、2つの組成物を分注し1:1の比率で混ぜ合わせることで合わされた組成物とし、これをウサギに施用した。合わされた組成物の標的pHは、pH8であった。
インビトロ放出試験は、多チャンネルの一酸化窒素分析器を用いて実施した。実施例1に記載されているB〜E群及びG群の被験製剤の計量には化学てんびんを用いた。それぞれの製剤の両方の相およそ20mgずつを、磁気撹拌子付きの清浄な乾燥したNO測定セルに移した。製剤からの一酸化窒素のリアルタイムでのインビトロ放出は、次に挙げる機器パラメーターを用いて、連続的な混合下にて決定した:
1.湿り窒素流速:112〜115ml/分
2.サンプル温度:37℃
3.検出:化学発光による一酸化窒素
4.データ取得周波数:1Hz、不規則でシーケンシャルな交互周波
5.継続時間:NO放出速度が線形的に低下している時間(8時間以内)
6.取得用ソフトウェア:NovanWare
十億分率(PPB)単位のNOからモル単位の一酸化窒素への換算は、ヨウ化カリウム溶液中の既知量の亜硝酸ナトリウムから発生した一酸化窒素を測定してPPBからモルへの換算係数を得ることによって達成された。多チャンネル操作の結果得られたリアルタイムでの一酸化窒素放出データに隙間があれば、線形補間プログラムを用いることにより埋めた。一酸化窒素が枯渇して測定されなかったサンプルがあった場合には、放出がゼロの部分に直前の約5000秒間の放出データの線形外挿を実施した。次いで、リアルタイムの一酸化窒素放出データを積分して、総一酸化窒素の集積曲線(total nitric oxide accumulation curve)を得た。一酸化窒素放出パラメーター、例えば、Cmax(すなわち、放出されたNOの最高濃度)、Tmax(すなわち、Cmaxに達した時間)、一酸化窒素の累積放出量(すなわち、単位時間当たりのデータ点すべての総和)、及び、総放出量の半分までの到達時間(Time to Half of Total Released)(T50)(すなわち、NO累積量の50%が放出された時間)を、一酸化窒素のリアルタイム放出曲線及び累計放出曲線の両方から計算できる。前述の計算はすべて、特注のデータ処理ソフトウェア(NovanWare)で自動的に実施された。
実施例2に記載した被験物質を、実施例1のウサギの2.5cm×2.5cm区画に施用した。0.1mLの被験物質を6.25cm2に施用した場合のインビトロアッセイによる1cm2当たりのNO放出量は、表5に示すとおりである。
ウサギの群に、以下で表7に記載するとおりの多様な用量での抗ウイルス薬治療を受けさせた。A〜F群における抗ウイルス薬治療のための製剤を表8に示す。A〜E群用の製剤にはそれぞれ、2室式ポンプ内に別々に保存されていた2つの別々の組成物が入っていた。施用に先立ち、2つの組成物を分注し1:1の比率で混ぜ合わせることで合わされた組成物とし、これをウサギに施用した。合わされた組成物の標的pHは、pH8であった。
ワタオウサギパピローマウイルスに感染させて実施例4に記載されているとおりに治療したニュージーランドホワイトウサギの組織サンプルを、治療終了時点で得た。皮膚切片を加工してヘマトキシリン・エオシン(H&E)スライドにし、盲検的方法で顕微鏡での評価に供した。スライドを評価した後、結果を3つの主要カテゴリー:1)パピローマ、2)顕著な強度の過形成、及び3)軽微〜軽度な強度の過形成に要約した。炎症細胞の存在を定性的に決定した。定量分析は実施しなかった。しかし、定性的アセスメントにより、3つのカテゴリー間での炎症のレベルは類似しており、炎症の程度が全般的に低く同程度であることが明らかになった。H&E染色による組織学的検査の結果を表10に示す。
追加の製剤を調製し、ウイルス関連の皮膚病態、例えば、生殖器いぼなどの治療及び/又は予防における有効性を決定するために使用した。これらの製剤には、4%、8%、12%又は16%の量のNitricil(商標)NVN1をプラセボと共に含めた。各製剤は、pH4.5を有するヒドロゲルと、表11に示すとおりの組成物と、ゲルの形態であり表12に示すとおりの組成を有する第2の組成物とを含んでいた。ヒドロゲルとゲルとを混和すると、表13に示すとおりの組成を有する合わされた組成物になった。
Claims (46)
- それを必要としている対象におけるウイルス感染症を治療及び/又は予防する方法であって、
局所用組成物を対象の皮膚に投与するステップを含み、
ここで、前記局所用組成物が、前記組成物の重量に対して約0.5%から約20%までの量で一酸化窒素放出性医薬的有効成分を含み、それにより前記対象における前記ウイルス感染症を治療及び/又は予防する、方法。 - 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記組成物の重量に対して約0.05%から約6%までの量で一酸化窒素を放出する、請求項1に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記局所用組成物を前記対象の皮膚に投与後1時間の期間に、前記組成物1mg当たりのNOが約10nmolから前記組成物1mg当たりのNOが1000nmolまでの累積量で一酸化窒素を放出する、請求項1又は2に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記局所用組成物を前記対象の皮膚に投与後4時間の期間に、前記組成物1mg当たりのNOが約90nmolから前記組成物1mg当たりのNOが450nmolまでの累積量で一酸化窒素を放出する、請求項1〜3のいずれか1項に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記局所用組成物を前記対象の皮膚に投与後24時間の期間に、前記組成物1mg当たりのNOが約180nmolから前記組成物1mg当たりのNOが1000nmolまでの累積量で一酸化窒素を放出する、請求項1〜4のいずれか1項に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記局所用組成物を前記対象の皮膚に投与後少なくとも約5時間にわたり一酸化窒素を連続放出させる、請求項1〜5のいずれか1項に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、一酸化窒素の前記連続放出の期間中、平均して、前記組成物1mg当たりのNOが約1pmolから約500pmolまでの範囲のNO放出量を有する、請求項6に記載の方法。
- 前記一酸化窒素放出性医薬的有効成分が、投与後24時間の時点で決定され、かつ、リアルタイムインビトロ放出試験により測定されたNO合計放出量を基準にして、前記局所用組成物を前記対象の皮膚に投与後約9分以上で少なくとも約50%の量の一酸化窒素を放出する、請求項1〜7のいずれか1項に記載の方法。
- 前記一酸化窒素放出性医薬的有効成分が、投与後24時間時点で決定されリアルタイムインビトロ放出試験により測定されたNO合計放出量を基準にして、前記局所用組成物を前記対象の皮膚に投与後約9分から約8時間までの期間で少なくとも約50%の量の一酸化窒素を放出する、請求項1〜8のいずれか1項に記載の方法。
- それを必要としている対象におけるウイルス感染症を治療及び/又は予防する方法であって、
局所用組成物を対象の皮膚に投与するステップを含み、
ここで、前記局所用組成物が、一酸化窒素を前記対象の皮膚に放出する一酸化窒素放出性医薬的有効成分を含み、リアルタイムインビトロ放出試験により測定した場合、前記組成物1mg当たりのNOが少なくとも約7pmolの一酸化窒素リアルタイム濃度を投与後少なくとも1時間にわたり維持し、それにより前記対象における前記ウイルス感染症を治療及び/又は予防する、方法。 - 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記組成物1mg当たりのNOが少なくとも約6pmolの一酸化窒素リアルタイム濃度を、投与後少なくとも2時間にわたり維持する、請求項10に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記組成物1mg当たりのNOが少なくとも約5pmolの一酸化窒素リアルタイム濃度を、投与後少なくとも4時間にわたり維持する、請求項10又は11に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記組成物1mg当たりのNOが約12pmolから前記組成物1mg当たりのNOが約3500pmolまでの範囲で一酸化窒素の最高濃度を有する、請求項10〜12のいずれか1項に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、投与後24時間で、前記組成物1mg当たりのNOが約300nmolから前記組成物1mg当たりのNOが約1000nmolまでの累積量の一酸化窒素を放出する、請求項10〜13のいずれか1項に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、約9分から約420分までの範囲の半減期を有する、請求項10〜14のいずれか1項に記載の方法。
- それを必要としている対象におけるウイルス感染症を治療及び/又は予防する方法であって、
局所用組成物を対象の皮膚に投与するステップを含み、
ここで、前記局所用組成物が、一酸化窒素を前記対象の皮膚に放出する一酸化窒素放出性医薬的有効成分を含み、リアルタイムインビトロ放出試験により測定した場合、1cm2当たりのNOが少なくとも約104pmolの一酸化窒素リアルタイム濃度を、前記組成物を前記対象の皮膚に投与後少なくとも1時間の期間にわたって維持し、それにより前記対象におけるウイルス感染症を治療及び/又は予防する、方法。 - 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、1cm2当たりのNOが少なくとも約89pmolの一酸化窒素リアルタイム濃度を、前記組成物を前記対象の皮膚に投与後少なくとも2時間の期間にわたって維持する、請求項16に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、1cm2当たりのNOが少なくとも約74pmolの一酸化窒素リアルタイム濃度を、前記組成物を前記対象の皮膚に投与後少なくとも4時間の期間にわたって維持する、請求項16又は17に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記組成物を前記対象の皮膚に投与後約4時間の期間に1cm2当たりのNOが約1300nmolから1cm2当たりのNOが約14000nmolまでの累積量で一酸化窒素を放出する、請求項16〜18のいずれか1項に記載の方法。
- 前記局所用組成物が、リアルタイムインビトロ放出試験により測定した場合、前記組成物を前記対象の皮膚に投与後約24時間の期間に1cm2当たりのNOが約4500nmolから1cm2当たりのNOが約14000nmolまでの累積量で一酸化窒素を放出する、請求項16〜19のいずれか1項に記載の方法。
- 前記局所用組成物を前記対象の皮膚に投与後の前記局所用組成物のNOリアルタイム濃度が、リアルタイムインビトロ放出試験により測定した場合、投与後0.5時間時点で1cm2当たりのNOが少なくとも100pmol、投与後1時間時点で1cm2当たりのNOが少なくとも50pmol、投与後2時間時点で1cm2当たりのNOが少なくとも40pmol、投与後3時間時点で1cm2当たりのNOが少なくとも25pmol、及び/又は、投与後4時間時点で1cm2当たりのNOが少なくとも20pmolである、請求項16〜20のいずれか1項に記載の方法。
- 前記局所用組成物が、酸性化された亜硝酸塩を含まない、請求項1〜21のいずれか1項に記載の方法。
- 前記ウイルス感染症が、サイトメガロウイルス(CMV)、エプスタイン・バーウイルス、水痘帯状疱疹ウイルス(VZV)、ワクシニアウイルス、牛痘ウイルス、サル痘ウイルス、単純ヘルペスウイルス(HSV)、帯状ヘルペス、ヒトヘルペスウイルス6(HHV−6)、ヒトヘルペスウイルス8(HHV−8)、パピローマウイルス、伝染性軟属腫、羊鵞口瘡、天然痘、及び/又はコクサッキーウイルスが原因で生じるものである、請求項1〜22のいずれか1項に記載の方法。
- 前記ウイルス感染症が、パピローマウイルスが原因で生じるものである、請求項1〜23のいずれか1項に記載の方法。
- 前記ウイルス感染症が、単純ヘルペス1型及び/又は単純ヘルペス2型が原因で生じるものである、請求項1〜24のいずれか1項に記載の方法。
- 前記ウイルス感染症が、前記対象の皮膚を感染させるものである、請求項1〜25のいずれか1項に記載の方法。
- 前記対象におけるウイルス感染症を予防する、請求項1〜26のいずれか1項に記載の方法。
- 前記対象におけるウイルス感染症を治療する、請求項1〜27のいずれか1項に記載の方法。
- 良性病変(例えば、いぼ)の出現及び/又はサイズを予防する及び/又は低減させる、請求項1〜28のいずれか1項に記載の方法。
- 悪性病変の出現及び/又はサイズを予防する及び/又は低減させる、請求項1〜29のいずれか1項に記載の方法。
- 前記対象がヒトである、請求項1〜30のいずれか1項に記載の方法。
- 前記投与するステップが、前記局所用組成物を前記対象のウイルス感染皮膚に施用するステップを含む、請求項1〜31のいずれか1項に記載の方法。
- 前記ウイルス感染皮膚が良性病変を含む、請求項32に記載の方法。
- 前記ウイルス感染皮膚が、いぼ、ただれ、パピローマ、水疱及び/又は発疹を含む、請求項33に記載の方法。
- 前記ウイルス感染皮膚が、いぼを含み、前記方法が、前記局所用組成物を前記対象の皮膚に投与するステップの前に、前記いぼを創傷清拭するステップをさらに含む、請求項33に記載の方法。
- 前記ウイルス感染皮膚が、いぼを含み、前記方法が、前記局所用組成物を前記対象の皮膚に投与するステップの前に、前記いぼを創傷清拭するステップを含まない、請求項33に記載の方法。
- 前記一酸化窒素放出性医薬的有効成分が、ジアゼニウムジオレート官能基を有する一酸化窒素放出性化合物を含む、請求項1〜36のいずれか1項に記載の方法。
- 前記一酸化窒素放出性化合物が、NO放出性の共縮合されたシリカ粒子を含む、請求項37に記載の方法。
- 前記局所用組成物が、約5から約10までの範囲のpHを有する、請求項1〜38のいずれか1項に記載の方法。
- 前記局所用組成物が、約6から約8までの範囲のpHを有する、請求項1〜39のいずれか1項に記載の方法。
- 前記局所用組成物が、
第1の粘度増加剤、
少なくとも1つの多価アルコール、
少なくとも1つの緩衝剤、
第2の粘度増加剤、
少なくとも1つの有機溶媒、
少なくとも1つの湿潤剤、
少なくとも1つの医薬品有効成分、及び
水
を含む、請求項1〜40のいずれか1項に記載の方法。 - 前記局所用組成物が、前記投与するステップの前及び/又は途中に混ぜ合わされる2つの組成物を含む、請求項1〜41のいずれか1項に記載の方法。
- 治療に有効な量及び/又は予防に有効な量の一酸化窒素が、対象の上皮の基底層及び/又は基底膜に投与される、請求項1〜42のいずれか1項に記載の方法。
- 約1×10−5Mから約1×10−7Mまでの量の一酸化窒素が、対象の上皮の基底層及び/又は基底膜に投与される、請求項1〜43のいずれか1項に記載の方法。
- 一酸化窒素が、ウイルス感染細胞においてアポトーシスを誘導するのに十分な量で投与される、請求項1〜44のいずれか1項に記載の方法。
- それを必要としている対象におけるウイルス感染症を治療及び/又は予防するための、一酸化窒素放出性医薬的有効成分を局所用組成物の重量に対して約0.5%から約20%までの量で含む局所用組成物の使用。
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KR102495101B1 (ko) | 2023-02-02 |
AU2015287674B2 (en) | 2019-11-21 |
US10322081B2 (en) | 2019-06-18 |
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EP3166593A1 (en) | 2017-05-17 |
CA2954061A1 (en) | 2016-01-14 |
WO2016007834A1 (en) | 2016-01-14 |
EP3698775A1 (en) | 2020-08-26 |
CN106659675B (zh) | 2023-07-04 |
ES2807200T3 (es) | 2021-02-22 |
AU2015287674A1 (en) | 2017-01-19 |
CN106659675A (zh) | 2017-05-10 |
US20170216197A1 (en) | 2017-08-03 |
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JP6651499B2 (ja) | 2020-02-19 |
EP3166593B1 (en) | 2020-05-20 |
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