JP2018521120A - 翼状片を治療するための組成物及び方法 - Google Patents
翼状片を治療するための組成物及び方法 Download PDFInfo
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- JP2018521120A JP2018521120A JP2018515193A JP2018515193A JP2018521120A JP 2018521120 A JP2018521120 A JP 2018521120A JP 2018515193 A JP2018515193 A JP 2018515193A JP 2018515193 A JP2018515193 A JP 2018515193A JP 2018521120 A JP2018521120 A JP 2018521120A
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- Prior art keywords
- pterygium
- nintedanib
- sustained
- multikinase inhibitor
- antimetabolite
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Abstract
Description
本願に記載する方法は本願に記載する手法により有効成分として同定された化合物を含有する医薬組成物の製造及び使用を含む。このような医薬組成物自体も本願に含まれる。
角膜新生血管形成に及ぼす医薬品効果を評価するためにウサギ角膜縫合糸モデルが確立されている(Ko et al.Cornea.2013;32(5):689−695;Perez−Santonja et al.Am J Ophthalmol.2010;150(4):519−528)。このモデルでニンテダニブをその抗新生血管形成活性について試験した。
10%の2−ヒドロキシプロピル−β−シクロデキストリンを添加したリン酸緩衝液(pH7.4)中に0.2%又は0.05%のニンテダニブを含有する局所組成物を調製した。また、同一基剤で0.05%のスニチニブを含有する組成物も調製し、陽性対照とした。
ニュージーランドホワイト(Zealand White)種の雌性ウサギ36羽を使用して試験を行った。要約すると、1日目に各動物の右目の角膜上皮層の5カ所に縫合糸を留置し、新生血管形成を誘発させた。表4に記載するように動物の両目に投与した。
NIH ImageJ(R)ソフトウェアを使用して目の画像を解析した。各画像をImageJ(R)で開き、写真にルーラーを使用して目盛を設定し、縫合糸の近くの角膜上の新生血管形成領域を選択ツールにより選択した。ソフトウェアの測定ツールにより面積(mm2)を計算し、エクセルで記録し、画像をキャプチャーし、保存した。両側t検定を使用し、各群の対毎に有意差があるか否かを判定した。簡単に比較できるように平均値と標準偏差のヒストグラムとして結果をプロットした。
この試験の結果を、図1A及び1B及び下表5にまとめる。この結果は、ニンテダニブはウサギ角膜に縫合糸により誘発させた新生血管形成に対して顕著な阻害効果があったことを実証した。高用量の0.2%ニンテダニブは0.05%ニンテダニブに比較して有効性の改善を示し、TID投与とした高頻度投与レジメンはBID投与に比較して有効性の改善を示した。驚くべきことに、ニンテダニブはこのモデルで新生血管面積の縮小に関して陽性対照スニチニブよりも明白な優位傾向を示した。
免疫不全マウスの角膜上のヒト翼状片成長を評価するためにヒト翼状片マウスモデルが記載されている(Lee et al.,Graefes Arch Clin Exp Ophthalmol.2014;252(4):609−18)。今回の試験では、翼状片成長に及ぼす数種の医薬品の効果を検討した。これらの医薬品はニンテダニブ、スニチニブ及びマイトマイシンCである。
10%の2−ヒドロキシプロピル−β−シクロデキストリンを添加したリン酸緩衝液(pH7.4)で試験薬を調製した。製剤の詳細な情報については後記セクションに開示する。
7週齢雄性無胸腺ヌードマウスを密閉式フィルタートップケージで無病原体条件下に順応させた。
外科的切除後に採取した検体からヒト翼状片上皮細胞(hPEC)を単離・培養した。参加者全員が試験の総合的な説明を受けた後に書面によるインフォームドコンセントを提出した。コラーゲン(ラット尾I型コラーゲン)をコーティングした表面で10%ウシ胎児血清、0.5%ジメチルスルホキシド及び1%抗生物質/抗真菌剤を添加したDMEM/F12培地にて新鮮な翼状片検体を3日間培養した処、この間に細胞は外植体から遊走した。その後、外植体を取り出し、5%BCSと1%抗生物質/抗真菌剤を添加した角化細胞用無血清培地に培地を交換し、上皮細胞増殖を更に促進した。
結膜下注入に備え、ケタミン(30mg/kg)とロンプン(2.5mg/kg)の腹腔内注射によりマウスに麻酔した。0日目に両目の鼻側結膜下スペースにhPEC1×104個を注入することによりマウスに翼状片を誘発させた。7日後に、hPECで誘発させたマウスを試験に供した。
動物を次のように処置した。
第1群:右目に基剤、左目に生理食塩水;
第2群:右目に0.2%ニンテダニブ、左目に生理食塩水;
第3群:右目に0.002%マイトマイシン、左目に生理食塩水;
第4群:右目に0.05%スニチニブ、左目に生理食塩水;
第5群:右目に0.2%ニンテダニブと0.002%マイトマイシンの混合物、左目に生理食塩水。
実験期間中、マウスを臨床毒性徴候について毎日観察した。注射の前と17日目に目を観察し、写真撮影した。疾患、診断及び治療を含む全所見を記録した。0日目、7日目、11日目、15日目及び17日目にマウスの体重を測定した。
ImageJ(R)を使用して写真の画像解析を行い、0日目、7日目、10日目、14日目及び17日目の病変の大きさを測定した。これらのデータは角膜全体に対する翼状片の比として計算した。
全マウスの目の臨床特徴を評価した。角膜新生血管形成(NV)の程度を0から3で採点し、0=NVなし、1=NVが角膜周辺に限定している、2=NVが瞳孔縁まで延びている、3=NVが瞳孔縁を越えて角膜中央まで延びているとした。
Windows用SPSSバージョン18.0(SPSS,Chicago,IL)によりデータを解析し、平均±標準偏差として表す。
結果を図2A〜B、3A〜B、4A〜B及び5A〜Bに示し、更に上記表4にまとめる。ヒト翼状片マウスモデルでは、0.2%ニンテダニブ投与の結果、14日目と17日目の翼状片面積は7日目のベースラインレベルと比較して縮小した(図2A及び2B)。対照的に、生理食塩水を投与した対照群の目は14日目と17日目に翼状片面積の増大を示した。ニンテダニブは投与期間中に角膜上の新生血管形成スコアも低下させ、17日目のレベルは7日目のベースラインに対して有意差を示した(図2A及び2B)が、対照群の目は統計的に有意ではない若干の新生血管形成の増加を示した(図2A及び2B)。このモデルでは、0.002%マイトマイシン及び0.05%スニチニブも翼状片面積の縮小傾向を示したが、どの時点でも統計的有意には達しなかった(図3A〜3B、4A〜4B)。対照的に、生理食塩水を投与した対照群の目はほぼ全時点で翼状片面積の増大を示し、増加は時間の経過に伴ってほぼ直線的である。マイトマイシンとスニチニブも新生血管形成スコアを低下させ、マイトマイシンは17日目、スニチニブは14日目と17日目に有意低下を示した(図3A〜3B、4A〜4B)。この場合も、対照群の目は投与期間中に新生血管形成の有意変化を示さなかった。ニンテダニブとマイトマイシンを併用投与した目では、翼状片面積は増大しなかったが、生理食塩水対照群では有意に増加した(図5A〜5B)。新生血管形成スコアは、この動物群では有意変化を示さなかった。
ニンテダニブ眼用溶液剤
本医薬品製剤は、2−ヒドロキシプロピル−β−シクロデキストリン又は他の同様のシクロデキストリンと、pH範囲5.5〜8.0の緩衝液で調製した等張眼用溶液剤である。製剤の機能性を高めるために他の粘度調整剤、滑沢剤、防腐剤を加えてもよい。本眼用溶液剤の組成を表6に開示する。
本医薬品製剤は、カルボキシメチルセルロースナトリウムと、pH範囲5.5〜8.0の緩衝液で調製した等張眼用懸濁剤である。原薬粒子径を40ミクロン未満まで低下させる。懸濁製剤の機能性を高めるために他の粘度調整剤、滑沢剤、溶解補助剤及び防腐剤を加えてもよい。組成を表7に開示する。
本医薬品製剤は、等張眼用乳剤である。原薬を混合油相と乳化剤に溶解させた後、乳化させ、pH範囲5.5〜8.0の水相と混合する。乳剤製剤の機能性を高めるために他の粘度調整剤、滑沢剤、溶解補助剤及び防腐剤を加えてもよい。組成を表8に開示する。
本医薬品製剤は、等張徐放性半固形製剤である。原薬をpH範囲5.5〜8.0の半固形媒体に溶解及び/又は懸濁させる。徐放性半固形製剤の機能性を高めるために他の粘度調整剤、滑沢剤、溶解補助剤及び防腐剤を加えてもよい。組成を表9に開示する。
本医薬品製剤は、固形インプラントである。原薬を1種以上のポリマーと混合・ブレンドする。原薬とポリマーとの混合物を既定温度で溶融させ、既定直径寸法のフィラメント状に押し出す。眼組織に埋め込むことができる既定寸法のセグメント状に製剤フィラメントを切断する。組成を表10に開示する。
以上、本発明の詳細な説明を含めて本発明について記載したが、当然のことながら、以上の記載は本発明を具体的に説明することを目的としており、本発明の範囲を限定しようとするものではなく、本発明の範囲は以下の特許請求の範囲により定義される。他の態様、利点及び改変も以下の特許請求の範囲に含まれる。
Claims (35)
- 視軸/角膜中央からの翼状片退縮を誘導するための方法であって、処置を必要とする対象の患部の目に治療有効量の(1)マルチキナーゼ阻害薬;(2)上皮細胞増殖及び線維芽細胞増殖を阻害する代謝拮抗薬;又は(3)その組み合わせを投与することを含む、前記方法。
- 前記マルチキナーゼ阻害薬、前記代謝拮抗薬又はその組み合わせの投与の結果として、前記患部の目における翼状片の大きさが縮小する、請求項1に記載の方法。
- 前記マルチキナーゼ阻害薬、前記代謝拮抗薬又はその組み合わせの投与の結果として、前記患部の目における翼状片成長速度がマイナスとなる、請求項1に記載の方法。
- 翼状片を安定化させるための方法であって、このような処置を必要とする対象の患部の目に治療有効量の(1)マルチキナーゼ阻害薬;(2)上皮細胞増殖及び線維芽細胞増殖を阻害する代謝拮抗薬;又は(3)その組み合わせを投与することを含む、前記方法。
- 前記マルチキナーゼ阻害薬、前記代謝拮抗薬又はその組み合わせの投与の結果として、前記患部の目における翼状片の大きさが安定化する、請求項4に記載の方法。
- 前記マルチキナーゼ阻害薬、前記謝拮抗薬又はその組み合わせの投与の結果として、前記患部の目における翼状片成長速度がほぼゼロになる、請求項4に記載の方法。
- 前記マルチキナーゼ阻害薬が、EGFR、ErbB2、ErbB3、FGFR1、FGFR2、FGFR3、FGFR4、TrkA、NGFR、VEGFR(1、2、3)、PDGFR(α、β)、TGF−βR(I、II、III)、FLT3、Lck、Lyn、Src、c−Kit、c−Fms、Raf−1、B−Raf、RET、CSF−1Rから選択される1種以上の細胞内及び/又は細胞表面タンパク質キナーゼの翼状片における活性を低下させる、請求項1から6のいずれか一項に記載の方法。
- 前記マルチキナーゼ阻害薬は、
VEGFR(1、2、3)に対するIC50が<200nMであり、
PDGFR(α、β)に対するIC50が<200nMであり、及び/又は
FGFR(1、2、3)に対するIC50が<1000nMである、請求項7に記載の方法。 - 前記マルチキナーゼ阻害薬が、アファチニブ、アムバチニブ、アキシチニブ、カボザンチニブ、カネルチニブ、セジラニブ、セリチニブ、クレノラニブ、クリゾチニブ、ダブラフェニブ、ダコミチニブ、ダサチニブ、エルロチニブ、フォレチニブ、ゲフィチニブ、ゴルバチニブ、イブルチニブ、イコチニブ、イデラリシブ、イマチニブ、ラパチニブ、レンバチニブ、ネラチニブ、ニロチニブ、ニンテダニブ、パルボシクリブ、パゾパニブ、ポナチニブ、キザルチニブ、レゴラフェニブ、ルキソリチニブ、ソラフェニブ、スニチニブ、タンズチニブ、チバンチニブ、チボザニブ、トラメチニブ、バンデタニブ、バタラニブ及びベムラフェニブから構成される群から選択される、請求項1から8のいずれか一項に記載の方法。
- 前記代謝拮抗薬が、マイトマイシンC、5−フルオロウラシル、フロクスウリジン、シタラビン、6−アザウラシル、アザチオプリン、メトトレキサート、ミコフェノール酸モフェチル及びチオテパから構成される群から選択される、請求項1から6のいずれか一項に記載の方法。
- 前記マルチキナーゼ阻害薬、前記代謝拮抗薬又はその組み合わせを局所眼用製剤、軟膏、ゲル剤、徐放性半固形製剤、徐放性固形製剤又は眼内インプラントの形態で前記患部の目に投与する、請求項1から10のいずれか一項に記載の方法。
- 前記マルチキナーゼ阻害薬、前記代謝拮抗薬又はその組み合わせを局所眼用製剤の形態で前記患部の目に投与し、前記患部の目に局所投与する、請求項11に記載の方法。
- 前記局所眼用製剤が、溶液剤、懸濁剤又は乳剤である、請求項11に記載の方法。
- 前記局所眼用製剤が、更に、安定剤、界面活性剤、ポリマーベース担体、ゲル化剤、有機補助溶媒、pH調整成分及び浸透圧調整成分から選択される1種以上の医薬的に許容される添加剤を含有し、防腐剤を含有してもしなくてもよい、請求項13に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントを前記患部の目に挿入する、請求項11に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントが、更に、医薬的に許容される添加剤を含有する、請求項15に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントが、
マルチキナーゼ阻害薬、代謝拮抗薬又はその組み合わせ;及び
ポリ乳酸(PLA)、ポリグリコール酸(PLGA)及びポリ乳酸とポリグリコール酸との共重合体から選択される生分解性ポリマー
を含有する請求項16に記載の方法。 - 翼状片患者に投与を実施する、請求項1から17のいずれか一項に記載の方法。
- 処置を必要とする患者の翼状片、瞼裂斑及び偽翼状片における充血及びその症状の軽減方法であって、対象の患部の目に治療有効量のマルチキナーゼ阻害薬を投与することを含む、前記方法。
- 処置を必要とする対象における翼状片再発の低減又は予防方法であって、対象の患部の目に治療有効量のマルチキナーゼ阻害薬を投与することを含む、前記方法。
- 翼状片の外科的除去前に投与を実施する、請求項20に記載の方法。
- 翼状片の外科的除去処置中に投与を実施する、請求項20に記載の方法。
- 翼状片の外科的除去後に投与を実施する、請求項20に記載の方法。
- 前記マルチキナーゼ阻害薬は、
VEGFR(1、2、3)に対するIC50が<50nMであり、
PDGFR(α、β)に対するIC50が<100nMであり、
FGFR(1、2、3)に対するIC50が<150nMであり
FGFR4に対するIC50が<1000nMであり、
FLT3に対するIC50が<50nMであり、
Lckに対するIC50が<50nMであり、
Lynに対するIC50が<200nMであり、
Srcに対するIC50が<200nMである、請求項19から23のいずれか一項に記載の方法。 - 前記マルチキナーゼ阻害薬が、ニンテダニブ{(3Z)−3−{[(4−{メチル[(4−メチルピペラジン−1−イル)アセチル]アミノ}フェニル)アミノ](フェニル)メチリデン}−2−オキソ−2,3−ジヒドロ−1H−インドール−6−カルボン酸メチル}、その遊離塩基、水和物、溶媒和物又は医薬的に許容される塩から構成される群から選択される、請求項24に記載の方法。
- 前記マルチキナーゼ阻害薬が、ニンテダニブ遊離塩基又はニンテダニブエシラート(エタンスルホン酸塩)である、請求項25に記載の方法。
- 前記マルチキナーゼ阻害薬を、局所眼用製剤、徐放性半固形製剤、徐放性固形製剤又は眼内インプラントの形態で前記患部の目に投与する、請求項19から26のいずれか一項に記載の方法。
- ニンテダニブを、局所眼用製剤の形態で前記患部の目に投与し、前記患部の目に局所投与する、請求項27に記載の方法。
- 前記局所眼用製剤が、溶液剤、懸濁剤又は乳剤である、請求項28に記載の方法。
- 前記局所眼用製剤におけるニンテダニブの濃度が、重量換算で前記製剤の総量の0.001%〜10%である、請求項28に記載の方法。
- 前記局所眼用製剤が、更に、安定剤、界面活性剤、ポリマーベース担体、ゲル化剤、有機補助溶媒、pH調整成分、浸透圧調整成分及び防腐剤から選択される1種以上の医薬的に許容される添加剤を含有する、請求項27に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントを、前記患部の目に挿入する、請求項27に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントが、ニンテダニブ及び医薬的に許容される添加剤を含有する、前記方法請求項32に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントにおけるニンテダニブの量が、1μg〜100mgである、請求項33に記載の方法。
- 前記徐放性半固形製剤、徐放性固形製剤又は眼内インプラントが、ニンテダニブ;及びポリ乳酸(PLA)、ポリグリコール酸(PLGA)及びポリ乳酸とポリグリコール酸との共重合体から選択される生分解性ポリマーを含有する、請求項27に記載の方法。
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