JP2016040313A - 眼症状を処置するための高粘度高分子組成物 - Google Patents
眼症状を処置するための高粘度高分子組成物 Download PDFInfo
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Abstract
【解決手段】かかる組成物は、治療上有効量にて存在するMAAC溶液または粒子、粘性誘導成分および水性担体成分を含む。本組成物は約25℃において0.1/秒の剪断速度にて少なくとも約10 cpsまたは約100 cpsの粘度を有する。好ましい一実施態様において、25℃における粘度は約80,000 cps〜約300,000 cpsの範囲である。
【選択図】なし
Description
本出願は2007年4月30日出願の米国特許出願11/742,350号の利益を主張する(参照によりその全体が本明細書に組み込まれる)。
一実施態様において、本発明は、例えば、黄斑浮腫、乾燥したおよびウェットな黄斑変性症、特に滲出性黄斑変性症、糖尿病性網膜症および血管新生に関する他の障害および疾患の発症において現れ得るような、眼の血管新生、特に、網膜(斑を含む);脈絡膜、強膜および眼の後区に特徴的な他の物における血管新生を処置するための、眼内(限定するものではないが、硝子体内、結膜下および網膜下)注射または配置に適する生体適合性の粘性担体中に1以上のMAACを含む製剤を提供する。好ましい一実施態様において、担体は、ヒアルロン酸成分、好ましくは少なくとも1の既定の平均分子量のポリヒアルロン酸成分を含む。
本明細書において用いる場合、以下に記載の単語または用語は以下の定義を有する。
フィブロネクチンは多数の重要な機能に関与する:例えば、創傷治癒;細胞接着;血液凝固;細胞分化および遊走;細胞の細胞骨格の保持;および腫瘍転移など。細胞分化におけるフィブロネクチンの役割は、腫瘍性形質転換が起こる際にその遺伝子の発現が顕著に減少することにより示される。細胞接着はテトラペプチドRGDSの細胞表面上のインテグリンへの結合によって媒介されることが発見されたが、関連配列も細胞接着活性を示すことができる。
本発明は、網膜黄斑浮腫などの様々な眼症状を処置するための眼内、例えば硝子体内注射または投与に特異的に設計されたMAAC含有製剤の発見に基づく。本MAAC製剤は以下を含む多くの優れた特徴および利点を有する:(1)本製剤は保存剤および再懸濁の補助剤、例えば、ベンジルアルコールおよび/またはポリソルベートを含まないように作製され得る;(2)同時に、本製剤は非常に減少した網膜および光受容細胞毒性を有する;(3)無菌であり、必要に応じて保存剤を含まないことに加え、本MAAC製剤は、製剤の粘性および製剤からMAACが比較的緩徐に拡散することにより延長された治療効果を提供することができ、粒子の懸濁液として製剤化された場合、例えばかかる製剤の硝子体内注射から数ヶ月の期間にわたる、治療量のMAACの徐放を提供することができる。よって、本粘性MAAC製剤は、徐放性の移植片として特徴付けることができる;(4)本MAAC製剤の硝子体内投与は、副作用事象、例えば、実質的に上昇した眼内圧、緑内障、白内障および/または眼内炎症の増大した発生率を実質的に伴わない;(5)本MAAC製剤の硝子体内投与は、近年用いられているまたは既知の眼内(例えば硝子体内)用途のMAAC製剤と比較して、増大した発生率の副作用事象、例えば上昇した眼内圧、緑内障、白内障および/または眼内炎症などを伴わない;(6)特定の実施形態において、本製剤はMAAC粒子または結晶が(後眼房の粘性液体中に可溶化するので)比較的離れた単位の位置から緩徐に放出され、これにより硝子体内投与時に低粘性水性製剤に特徴的なプルーム効果(素早い分散)が回避され;(7)硝子体内投与時のプルーム形成または素早い分散が回避され、これにより視野の不明瞭化が有利に減少する。
黄斑症/網膜変性症:黄斑変性症(加齢性黄斑変性症(ARMD)、例えば、非滲出性加齢性黄斑変性症および滲出性加齢性黄斑変性症を含む)、脈絡膜新血管新生、網膜症(糖尿病性網膜症、急性および慢性黄斑視神経網膜症、中心性漿液性網脈絡膜症を含む)および黄斑浮腫(嚢胞様黄斑浮腫および糖尿病性黄斑浮腫を含む)。ブドウ膜炎/網膜炎/脈絡膜炎:急性多発性小板状色素上皮症、ベーチェット病、散弾状網脈絡膜炎(birdshot retinochoroidopathy)、感染症(梅毒、ライム病、結核症、トキソプラズマ症)、ブドウ膜炎(中間部ブドウ膜炎(扁平部炎)および前部ブドウ膜炎を含む)、多巣性脈絡膜炎、多発消失性白点症候群(MEWDS)、眼サルコイドーシス、後部強膜炎、匐行性脈絡膜炎(serpignous choroiditis)、網膜下線維症、ブドウ膜炎症候群およびフォークト・小柳・原田症候群。血管疾患/滲出性疾患:網膜動脈閉塞性疾患、網膜中心静脈閉塞症、播種性血管内凝固障害、網膜静脈分枝閉塞症、高圧性眼底変化(hypertensive fundus change)、眼虚血症候群、網膜動脈毛細血管瘤、コーツ病、傍中心窩毛細血管拡張症、半側網膜静脈閉塞症(hemi-retinal vein occlusion)、乳頭静脈炎(papillophlebitis)、網膜中心動脈閉塞症、網膜動脈分枝閉塞症、頚動脈疾患(CAD)、霜状分枝血管炎(frosted branch angitis)、鎌状赤血球網膜症および他の異常ヘモグロビン症、網膜色素線条症、家族性滲出性硝子体網膜症、イールズ病。外傷性/外科的:交感性眼炎、ブドウ膜網膜疾患、網膜剥離、外傷、レーザー、PDT、光凝固、外科術中の低灌流、放射線網膜症、骨髄移植網膜症。増殖性障害:増殖性硝子体網膜症および網膜上膜、増殖性糖尿病性網膜症。感染性障害:眼ヒストプラズマ症、眼トキソカラ症、推定眼ヒストプラズマ症候群(POHS)、眼内炎、トキソプラズマ症、HIV感染に関連する網膜疾患、HIV感染に関連する脈絡膜疾患、HIV感染に関連するブドウ膜疾患、ウイルス性網膜炎、急性網膜壊死、進行性網膜外層壊死、真菌性網膜疾患、眼梅毒、眼結核症、片側性瀰漫性亜急性視神経網膜炎(diffuse unilateral subacute neuroretinitis)およびハエ幼虫症。遺伝障害:網膜色素変性症、網膜ジストロフィーに関連する全身性疾患、先天停止性夜盲、錐体ジストロフィー、スタルガルト病および黄色斑眼底、ベスト病、網膜色素上皮の模様ジストロフィー、X連鎖性網膜分離症、ソースビー眼底変性症、良性中心性黄斑症(benign concentric maculopathy)、ビエッティ結晶性ジストロフィー(Bietti's crystalline dystrophy)、弾力線維性仮性黄色腫。網膜裂孔/円孔:網膜剥離、黄斑円孔、巨大網膜裂孔。腫瘍:腫瘍に関連する網膜疾患、RPEの先天性肥大、後部ブドウ膜黒色腫、脈絡膜血管腫、脈絡膜骨腫、脈絡膜転移、網膜および網膜色素上皮の混合性過誤腫、網膜芽細胞腫、眼底の血管増殖性腫瘍(vasoproliferative tumor)、網膜星状細胞腫、眼内リンパ系腫瘍。その他:点状脈絡膜内層症、急性後部多発性小板状色素上皮症、近視性網膜変性症、急性網膜色素上皮炎など。
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TsT G A C U C A A A U U U U C C G U G G G。
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ここでiBは逆位塩基であり、TsTはホスホロチオエート結合により連結されたジチミジンジヌクレオチドセグメントである。これらのそれぞれの修飾はオリゴヌクレオチドにヌクレアーゼ耐性を加えると考えられている。このおよび他の関連siRNA分子は、例えば、米国特許出願公開第2005/0233344号明細書(これにより参照によりその全体が本明細書に組み込まれる)に開示されている。
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gggaauacccuucuucgaa
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gcaucagcauaagaaacuu
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gcugacauguacggucuau
配列番号6
ggaauugacaagacagcaa
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ccacuuaccugaggagcaa
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gcuccugaagaucuguaua
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gcacgaaauauccucuuau
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ACCUCACCAAGGCCAGCACdTdT(配列番号13)
GUGCUGGCCUUGGUGAGGUdTdT(配列番号14)
液体組成物中のMAACの硝子体内薬物動態
ラニビズマブ(Lucentis(登録商標);rhuFab V2e)(化合物A);ベバシズマブ(Avastin(登録商標);rhuMab-VEGF)(化合物B);ペガプタニブ(MACUGEN(登録商標))(化合物C);およびsiRNA Z(VEGF-1またはVEGF-2受容体のどちらかまたは両方に対して方向付けられている短い干渉RNA(siRNA))(化合物D)の、メスのアルビノウサギの眼への単一の硝子体内注射の後に、眼の薬物動態を測定する。動物には各化合物10μgの生理食塩水硝子体内注射100μLを投与する。硝子体液サンプル(各時点につきn=4の眼)を投与後0.5、1、2、4、8および12時間の時点に収集する。硝子体液中の各MAACの濃度を液体クロマトグラフィータンデム質量スペクトル分析法(LC-MS/MS)を用いて測定する。
黄斑浮腫の硝子体内MAAC組成物による処置
糖尿病の症候を有する64才の肥満の女性患者は、網膜中心静脈閉塞症および/または網膜静脈分枝閉塞症を伴った黄斑浮腫のために視覚の損失を示している。彼女に、化合物Dを含有する高粘度MAAC(重合ヒアルロン酸塩に基づく)溶液、例えば実施例13の製剤1 mgを硝子体内注射する。同等の注射を4ヶ月ごとに行う。
後眼部症状の硝子体内ラニビズマブ高粘度組成物による処置
後眼部症状(例えば黄斑浮腫、ブドウ膜炎または黄斑変性症)を有する患者は、化合物Aを含有する高粘度ゲル(重合ヒアルロン酸塩に基づく)中の1 mgまたは2 mgのMAAC(実施例12または13の製剤のそれと実質的に同様)の硝子体内注射によって処置することができる。あるいは、その製剤を結膜下注射によって投与して後眼部症状を処置することができる。これらの患者は、注射から3ヶ月以上後に、糖尿病性網膜症の早期治療の研究(ETDRS)視力チャートを用いて測定すると、ベースラインから15文字以上の改善された最良矯正視力を示すことができる。
黄斑変性症の硝子体内の高粘度ゲル中のベバシズマブ(AVASTIN(登録商標))による処置
79才の男性は有意な視覚の歪みおよび損失を示し;網膜の検査により両目の黄斑の領域において滲出性脈絡膜血管新生が明らかになる。患者に眼圧降下薬を局所投与し、次いで実施例15に用いられた組成物と同様に(活性物質を除いて)調製した2%ポリヒアルロン酸中ベバシズマブ1 mgの粘性組成物を左目に硝子体内注射する。右目は処置しない。52週間の期間、6週間ごとに同じ様式にて続けて注射を行う。
糖尿病性網膜症の高粘度ADNECTIN(登録商標)CT-322による処置
慢性の、アルコールにより増悪した糖尿病性網膜症に罹患した50才の男性に、実質的に実施例15に示すように調製した、2%(w/v)ヒアルロン酸ナトリウムを含有する2 mgのPEG化ADNECTIN(登録商標)CT-322調製物を含む高粘度組成物を、硝子体内注射により投与する。処置の前は、それぞれの眼の視覚の損失は1週間につき0.4文字の速度で進行している。処置を52週間の間6週間ごとに繰り返す。患者を処置の開始から56週間試験する。視覚の損失は56週間にわたって8文字未満である。
Claims (37)
- 眼症状を処置するための、眼症状を患った哺乳動物に対して治療上有効量の高分子抗血管新生成分(MAAC)を含む組成物を眼の内部に投与することを含む方法であって、該組成物は組成物の粘度を約25℃において約0.1/秒の剪断速度にて少なくとも約10 cpsの粘度にまで増加させるのに効果的な量の粘性誘導成分も含み、該粘性誘導成分は恒久的な視覚の減少を伴わずに哺乳類の眼の硝子体に注射可能である、方法。
- 前記組成物が溶液を含む、請求項1に記載の方法。
- 前記組成物がゲルを含む、請求項1に記載の方法。
- 前記組成物が懸濁液を含む、請求項1に記載の方法。
- 眼症状の症候が血管新生であり、MAACが血管内皮増殖因子(VEGF)活性の直接的なまたは間接的な阻害剤を含む、請求項1に記載の方法。
- MAACが核酸(オリゴヌクレオチド)およびポリペプチドからなる群から選択される物質を含む、請求項5に記載の方法。
- MAACが核酸を含む、請求項6に記載の方法。
- 前記核酸が、アプタマー、RNAi、リボザイムおよびアンチセンスオリゴヌクレオチドからなる群から選択される治療剤を含む、請求項7に記載の方法。
- MAACが、siRNA Z、ペガプタニブおよびCand5からなる群から選択される治療剤を含む、請求項8に記載の方法。
- MAACが配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号14、配列番号15、配列番号22および配列番号23および少なくとも1の修飾ヌクレオチドを含有するこれらのいずれかに対応するヌクレオチド配列からなる群から選択されるヌクレオチド配列に対して少なくとも80%の同一性を有する核酸配列を有する少なくとも1の核酸を含む、請求項8に記載の方法。
- 前記核酸が前記の群から選択されるヌクレオチド配列に対して少なくとも90%の同一性を有するヌクレオチド配列を有する、請求項10に記載の方法。
- 前記核酸が前記の群から選択されるヌクレオチド配列に対して少なくとも95%の同一性を有するヌクレオチド配列を有する、請求項11に記載の方法。
- 前記核酸が前記の群から選択されるヌクレオチド配列に対して少なくとも95%の同一性を有する、請求項11に記載の方法。
- MAACがタンパク質を含む、請求項6に記載の方法。
- 前記タンパク質が抗体、抗体模倣物、血管新生阻害剤および受容体阻害剤からなる群から選択される、請求項14に記載の方法。
- 前記タンパク質がADNECTIN(登録商標)CT-322、ADNECTIN(登録商標)C7S100、ADNECTIN(登録商標)C7C100、ラニビズマブ、ベバシズマブ、ウロキナーゼペプチド阻害剤A6、シスプラチン、ラパマイシン、エンドスタチン、アンギオスタチン、タムスタチン、色素上皮由来因子およびVEGF TRAP(登録商標)、IMC-18F1およびIMC-1121 Fabからなる群から選択される治療剤を含む、請求項14に記載の方法。
- 前記ペプチドが、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20および配列番号21からなる群から選択されるアミノ酸配列に対して少なくとも80%の同一性を有するアミノ酸配列を有する、請求項14に記載の方法。
- 前記ペプチドが、前記の群から選択されるアミノ酸に対して少なくとも90%の同一性を有するアミノ酸配列を有する、請求項17に記載の方法。
- 前記ペプチドが前記の群から選択されるアミノ酸配列に対して少なくとも95%の同一性を有するアミノ酸配列を有する、請求項18に記載の方法。
- 該粘性誘導成分がヒアルロン酸、架橋ヒアルロン酸、アクリル酸に由来するサブユニットを含有する架橋重合体、ポリアクリル酸、セルロース誘導体、ポリカルボフィル、ポリビニルピロリドン、ゼラチン、デキストリン、ポリサッカライド、ポリアクリルアミド、ポリビニルアルコール、ポリ酢酸ビニルおよびそれらの誘導体、混合物および共重合体からなる群から選択される化合物を含む、請求項1に記載の方法。
- 粘性誘導成分が約1万〜約2百万ダルトンの範囲の分子量を有する化合物を含む、請求項1に記載の方法。
- 粘性誘導成分が約10万〜約150万ダルトンの範囲の分子量を有する化合物を含む、請求項17に記載の方法。
- 粘性誘導成分が約20万〜約100万ダルトンの範囲の分子量を有する化合物を含む、請求項17に記載の方法。
- 粘性誘導成分が25℃において0.1/秒の剪断速度にて少なくとも約100 cpsの粘度を有する、請求項1に記載の方法。
- 粘性誘導成分が25℃において0.1/秒の剪断速度にて少なくとも約1000 cpsの粘度を有する、請求項1に記載の方法。
- 粘性誘導成分が25℃において0.1/秒の剪断速度にて少なくとも約10,000 cpsの粘度を有する、請求項1に記載の方法。
- 粘性誘導成分が25℃において0.1/秒の剪断速度にて少なくとも約70,000 cpsの粘度を有する、請求項1に記載の方法。
- 粘性誘導成分が25℃において0.1/秒の剪断速度にて少なくとも約200,000 cpsの粘度を有する、請求項1に記載の方法。
- 粘性誘導成分が25℃において0.1/秒の剪断速度にて少なくとも約250,000 cpsの粘度を有する、請求項1に記載の方法。
- 粘性誘導成分が25℃において0.1/秒剪断速度にて少なくとも約300,000 cpsの粘度を有する、請求項1に記載の方法。
- 前記組成物が眼の内部に27ゲージ針を通して眼の後区内に配置されることによって投与される、請求項1に記載の方法。
- 前記組成物が眼の内部に30ゲージ針を通して眼の後区内に配置されることによって投与される、請求項1に記載の方法。
- 前記症状が眼の後区の症状を含む、請求項1に記載の方法。
- 前記症状が、非滲出性加齢性黄斑変性症および滲出性加齢性黄斑変性症を含む黄斑変性症、脈絡膜新血管新生、網膜症、糖尿病性網膜症、急性および慢性黄斑視神経網膜症、中心性漿液性網脈絡膜症、黄斑浮腫、急性多発性小板状色素上皮症、ベーチェット病、散弾状網脈絡膜炎、後部強膜炎、匐行性脈絡膜炎、網膜下線維症、ブドウ膜炎症候群、フォークト・小柳・原田症候群、網膜動脈閉塞性疾患、網膜中心静脈閉塞症、播種性血管内凝固障害、網膜静脈分枝閉塞症、高圧性眼底変化、眼虚血症候群、網膜動脈毛細血管瘤、コーツ病、傍中心窩毛細血管拡張症、半側網膜静脈閉塞症、乳頭静脈炎、網膜中心動脈閉塞症、網膜動脈分枝閉塞症、頚動脈疾患(CAD)、霜状分枝血管炎、鎌状赤血球網膜症、網膜色素線条症、家族性滲出性硝子体網膜症、イールズ病、増殖性硝子体網膜症、増殖性糖尿病性網膜症、腫瘍に関連する網膜疾患、RPEの先天性肥大、後部ブドウ膜黒色腫、脈絡膜血管腫、脈絡膜骨腫、脈絡膜転移、網膜および網膜色素上皮の混合性過誤腫、網膜芽細胞腫、眼底の血管増殖性腫瘍、網膜星状細胞腫、眼内リンパ系腫瘍、近視性網膜変性症、急性網膜色素上皮炎からなる群から選択される、請求項1に記載の方法。
- 前記症状が、非滲出性加齢性黄斑変性症および滲出性加齢性黄斑変性症を含む黄斑変性症、脈絡膜新血管新生、網膜症、糖尿病性網膜症、急性および慢性黄斑視神経網膜症、中心性漿液性網脈絡膜症、黄斑浮腫、急性多発性小板状色素上皮症、ベーチェット病、散弾状網脈絡膜炎、後部強膜炎、匐行性脈絡膜炎、網膜下線維症、ブドウ膜炎症候群、フォークト・小柳・原田症候群、網膜動脈閉塞性疾患、網膜中心静脈閉塞症、播種性血管内凝固障害、網膜静脈分枝閉塞症、高圧性眼底変化、眼虚血症候群、網膜動脈毛細血管瘤、コーツ病、傍中心窩毛細血管拡張症、半側網膜静脈閉塞症、乳頭静脈炎、網膜中心動脈閉塞症、網膜動脈分枝閉塞症、頚動脈疾患(CAD)、霜状分枝血管炎、鎌状赤血球網膜症、網膜色素線条症、家族性滲出性硝子体網膜症、イールズ病、増殖性硝子体網膜症、増殖性糖尿病性網膜症、腫瘍に関連する網膜疾患、RPEの先天性肥大、後部ブドウ膜黒色腫、脈絡膜血管腫、脈絡膜骨腫、脈絡膜転移、網膜および網膜色素上皮の混合性過誤腫、網膜芽細胞腫、眼底の血管増殖性腫瘍、網膜星状細胞腫、眼内リンパ系腫瘍、近視性網膜変性症、急性網膜色素上皮炎からなる群から選択される、請求項7に記載の方法。
- 前記症状が、非滲出性加齢性黄斑変性症および滲出性加齢性黄斑変性症を含む黄斑変性症、脈絡膜新血管新生、網膜症、糖尿病性網膜症、急性および慢性黄斑視神経網膜症、中心性漿液性網脈絡膜症、黄斑浮腫、急性多発性小板状色素上皮症、ベーチェット病、散弾状網脈絡膜炎、後部強膜炎、匐行性脈絡膜炎、網膜下線維症、ブドウ膜炎症候群、フォークト・小柳・原田症候群、網膜動脈閉塞性疾患、網膜中心静脈閉塞症、播種性血管内凝固障害、網膜静脈分枝閉塞症、高圧性眼底変化、眼虚血症候群、網膜動脈毛細血管瘤、コーツ病、傍中心窩毛細血管拡張症、半側網膜静脈閉塞症、乳頭静脈炎、網膜中心動脈閉塞症、網膜動脈分枝閉塞症、頚動脈疾患(CAD)、霜状分枝血管炎、鎌状赤血球網膜症、網膜色素線条症、家族性滲出性硝子体網膜症、イールズ病、増殖性硝子体網膜症、増殖性糖尿病性網膜症、腫瘍に関連する網膜疾患、RPEの先天性肥大、後部ブドウ膜黒色腫、脈絡膜血管腫、脈絡膜骨腫、脈絡膜転移、網膜および網膜色素上皮の混合性過誤腫、網膜芽細胞腫、眼底の血管増殖性腫瘍、網膜星状細胞腫、眼内リンパ系腫瘍、近視性網膜変性症、急性網膜色素上皮炎からなる群から選択される、請求項14に記載の方法。
- 眼症状を処置するための、MAACおよび高粘度ヒアルロン酸担体を含む、硝子体内投与用の医薬組成物。
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KR20170121073A (ko) * | 2016-04-22 | 2017-11-01 | 국립암센터 | 병변 표지용 주사제 조성물 |
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JP2019517578A (ja) * | 2016-06-02 | 2019-06-24 | クラウドブレイク セラピューティクス リミテッド ライアビリティ カンパニー | 異常な新生血管形成を伴う眼疾患を処置するためにニンテダニブを使用する組成物および方法 |
US11246864B2 (en) | 2016-06-02 | 2022-02-15 | Ads Therapeutics Llc | Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization |
JP7082115B2 (ja) | 2016-06-02 | 2022-06-07 | エイディーエス セラピューティクス リミテッド ライアビリティ カンパニー | 異常な新生血管形成を伴う眼疾患を処置するためにニンテダニブを使用する組成物および方法 |
JP2022116191A (ja) * | 2016-06-02 | 2022-08-09 | エイディーエス セラピューティクス リミテッド ライアビリティ カンパニー | 異常な新生血管形成を伴う眼疾患を処置するためにニンテダニブを使用する組成物および方法 |
US11911379B2 (en) | 2016-06-02 | 2024-02-27 | Ads Therapeutics Llc | Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization |
JP7475395B2 (ja) | 2016-06-02 | 2024-04-26 | エイディーエス セラピューティクス リミテッド ライアビリティ カンパニー | 異常な新生血管形成を伴う眼疾患を処置するためにニンテダニブを使用する組成物および方法 |
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AU2008245503B2 (en) | 2014-01-23 |
KR20160103174A (ko) | 2016-08-31 |
US11078262B2 (en) | 2021-08-03 |
BRPI0810715A2 (pt) | 2016-07-26 |
AU2008245503A1 (en) | 2008-11-06 |
EP2606899A1 (en) | 2013-06-26 |
ES2386847T3 (es) | 2012-09-03 |
EP2606899B1 (en) | 2015-04-15 |
EP2446890A1 (en) | 2012-05-02 |
BRPI0810715B1 (pt) | 2021-01-19 |
JP2010526780A (ja) | 2010-08-05 |
ES2436203T3 (es) | 2013-12-27 |
EP2146727A1 (en) | 2010-01-27 |
BRPI0810715B8 (pt) | 2021-05-25 |
JP6247272B2 (ja) | 2017-12-13 |
JP5775301B2 (ja) | 2015-09-09 |
ES2541292T3 (es) | 2015-07-17 |
WO2008134644A1 (en) | 2008-11-06 |
US20220106388A1 (en) | 2022-04-07 |
EP2446890B1 (en) | 2013-09-18 |
EP2146727B1 (en) | 2012-04-25 |
HK1184683A1 (en) | 2014-01-30 |
KR20100022964A (ko) | 2010-03-03 |
JP2014005288A (ja) | 2014-01-16 |
US20080268051A1 (en) | 2008-10-30 |
CA2685522A1 (en) | 2008-11-06 |
CA2685522C (en) | 2018-06-12 |
KR101800570B1 (ko) | 2017-11-22 |
JP6165565B2 (ja) | 2017-07-19 |
KR101652114B1 (ko) | 2016-09-06 |
ATE554747T1 (de) | 2012-05-15 |
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