JP5668476B2 - カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 - Google Patents
カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 Download PDFInfo
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- JP5668476B2 JP5668476B2 JP2010528993A JP2010528993A JP5668476B2 JP 5668476 B2 JP5668476 B2 JP 5668476B2 JP 2010528993 A JP2010528993 A JP 2010528993A JP 2010528993 A JP2010528993 A JP 2010528993A JP 5668476 B2 JP5668476 B2 JP 5668476B2
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- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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Description
本明細書に開示された実施態様は、安定なカルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物、およびより具体的には開示組成物を使用する眼疾患および/または症状を処置する方法に関する。
眼の前面に対する疾患および損傷は、米国において医療的眼科処置のために来院する主要原因である。これらの疾患および損傷は、最も痛みが伴う眼の症状の一つに位置づけられ、障害および失明となり得る。眼表面の主な臨床的問題には、眼表面の乾燥、涙液層異常および関連合併症;病理学および瘢痕化の原因となる眼表面の創傷;角膜変性ジストロフィーおよび遺伝的疾患;炎症性疾患;および外側の眼の感染が挙げられる。眼の疾患および損傷は、痒み、涙眼から視覚障害にわたる兆候を有し得る。それ故に、なんらかの疾患が次第に悪化するか、または他の重大な問題の誘因となり得るので、眼の問題を迅速に解決することが重要である。殆どの眼疾患に関する薬理学的管理には、液滴として眼の表面へ溶液を局所適用することが挙げられる。前眼部の組織に最終的に到達する局所適用される該薬物用量が比較的少量であるにも関わらず、一般的に投与される薬物濃度が非常に高いため、局所製剤は有効性を維持する。
カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物は、本発明に開示される。本開示内容の眼科用組成物は、混合ミセルの水溶液である。本明細書に開示された眼科用組成物は生体適合性であって、眼の症状を処置するために該眼への局所適用に特に有用である。本明細書に示した局面に従って、カルシニューリン阻害剤またはmTOR阻害剤;約10を超えるHLB指数を有する第一の界面活性剤;および約13を超えるHLB指数を有する第二の界面活性剤を包含しており、ここで該第一の界面活性剤のHLB指数および該第二の界面活性剤のHLB指数との間の絶対相違が約3を超えており、該組成物が混合ミセルを形成する医薬組成物を提供するものである。
本明細書に開示した実施態様に従って、添付の図面を参照してさらに説明され、この類似した構造はいくつかの図表を通じて数字等により言及される。提示された図面は、本発明に開示された実施態様の原理を説明するために位置づけられる以外には重点をおく必要はない。
本明細書にて開示した実施態様は、混合ミセルの局所適用形態においてカルシニューリン阻害剤またはmTOR阻害剤を含む医薬組成物に関する。本開示内容の医薬組成物は、患者または被検対象における眼の症状を、処置する、減少させる、改善する、および緩和することが判った。実施態様において、該組成物を、炎症性の眼の表面疾患などの眼疾患の処置に使用できる。かかる疾患の例示には、ドライアイ症候群(DES)、シェーングレン症候群、ブドウ膜炎、結膜炎(伝染性結膜炎)、角膜炎、角結膜炎、春季角結膜炎(VKC)、アトピー性角結膜炎(AKC)、痕跡性結膜炎などの眼の表面の自己免疫障害、眼瞼炎および強膜炎等が挙げられるが、これに限定するものではない。
一般的に、全ての使用した試薬は購入でき、別途記載がなければさらに精製を必要とせずに使用される。ボクロスポリン(ボクロスポリン、LX211、ISA247)を、Isotechnika, Inc.(Edmonton, Alberta, Canada)から得た。Isotechnikaから入手したストックを、Lux Biosciences(the New Jersey Center for Biomaterials)により保存した;シクロスポリンAをXenos Bioresources,Inc.(Santa Barbara, CA)から得た;シロリムスおよびタクロリムスをHaorui Pharma-Cheminc.から得た。ビタミンE TPGS(NF Grade)をEastman Chemical Companyから得て、IGEPAL CA-897 (オクトキシノール-40)をRhodia, Inc.から得た。滅菌脱イオン水を、EASY Pure UV Compact Ultra Pure Water System(Barnstead、IA)を用いて研究所内で調製した。Kollidon(登録商標)30 (PVP)およびKollidon(登録商標)90 F (Povidone K 90)をBASFから得た。ヒドロキシエチルセルロース,100 cpsおよび5000 cps を、Spectrum, Methocel(登録商標)から得て、HPMCを、Colorcon, Noveon(登録商標)を得て、ポリカルボフィルをLubrizol Advanced Materialsから得た。
表1に示した基本的な2X 製剤を、実施例1に記載した第二のプロトコールに記載したとおりに調製した。該カルシニューリンまたはmTOR阻害剤が、ボクロスポリン、シクロスポリンA、シロリムスおよびタクロリムスである基本製剤を調製した。50 mLの製剤として一つの調製物では;緩衝液混合物を表2に示した成分量を脱イオン水(25 mL)に溶解して調製し、2X緩衝液を調製した。2X緩衝液混合物を、別の保存剤を含んだものと含まないものとの双方を調製した。
様々な膜の型を、0.2 wt% ボクロスポリンを含有する製剤のフィルター滅菌に使用するために試験した。0.22μm 孔サイズの膜は、様々な材、例えばナイロン、テフロン、およびポリカーボネート等であった。膜からの回収物を、上記した薬剤含量のHPLC決定により評価して、遠心分離したサンプルと比較した。濾過効率比較試験についての結果を表5Aおよび5Bに示した。一般的に、0.22 μmのナイロン、テフロン、およびポリカーボネート膜は各々、濾過滅菌のために容認出来ることが判った。
該製剤の透明度を視覚的かつUV-可視光分光光度計を用いて400nmでのサンプルの吸光度を記録することにより測定した。製剤の1mlおよび対応する薬物を含まない賦形剤をプラスチックキュベットに入れ、吸光度を400 nmで記録した。水をブランクとして使用した。好ましい局面において、該混合ミセル製剤は、400 nmで約0.1未満の吸光度を有する透明な製剤である。400nmでの吸光度を、表4Aおよび表9-14の希釈実験において様々な製剤について示した。
ボクロスポリン製剤を希釈試験にて評価した。この目的は、眼と類似した条件下で製剤を希釈に供することであった。試験した各製剤中のボクロスポリン濃度は0.2 wt%であった。表3Aに記載した製剤を、薬局の店頭で購入できる人工涙液(OTC)の様々なブランドを用いて各々1:1、1:5および1:10で混合した。Systane(登録商標)(潤滑点眼薬、Alcon, Inc.; Visine(登録商標)(潤滑点眼薬、Pfizer,Inc.; Refresh Tears(登録商標)(潤滑点眼薬), Allergan, Inc.;およびHypo Tears(登録商標)(潤滑点眼薬), Novartisを用いた。測定を周囲条件下で行った。該データ(400 nmでの吸光度)を表9から14Aに示した。結果は濁度増加がないことを示した、故に溶液からのボクロスポリンの沈殿はなかった。
表3Aに示した製剤を、0.2 wt%のボクロスポリン/容量を含む製剤および含まない製剤による解離温度を決定するために試験した。〜60℃の一定温度の水浴を準備し、薬物を含むサンプルを試験するために使用した。製剤を含有するガラスバイアルを、該製剤中に温度計を差して水浴に入れた。ある程度の濁度が視覚的に観察されると直ぐに、温度の読み取りを行った。濁った溶液を室温まで冷やし、該薬物は混合ミセルに戻り、その結果全ての溶液が再度透明となった。再安定化のための時間(視覚的な透明度の回復)を記録した。ボクロスポリンを含むサンプルについてのデータを表15に示した。ヒートブロックを用いて加熱し、類似様式で薬物を含まないサンプルを試験した。ボクロスポリンを含まないサンプルについてのデータを表16に示した。
表19. 解離温度: 5%(v/v) PEG 400の添加に関する効果
混合ミセルの平均粒子サイズおよび多分散指数を、動的光散乱技術を用いて測定し(Brookhaven 90Plus particle size analyzer、Holtsville、NY)、3つの測定値の平均をとった。様々な溶液を、使い捨てのプラスチックセル中にいれた。サンプル容量(200μL)を、粒子サイズを決定するために用いた。0.2 wt% ボクロスポリンを含む実施例2に調製したとおりの製剤について粒子サイズおよび多分散性を表21に示した。0.2 wt% ボクロスポリンおよびPVP-K-90を含む製剤は、非常に狭いサイズ分布を有する13.3nmの平均ミセル直径および0.005の多分散度を示した。これに対して、0.2 wt% ボクロスポリンおよびHECを含む製剤は、23.8の平均ミセル直径を示したが、広い二峰性の粒子サイズ分布により0.482の大きな多分散性となった。
液滴あたりに送達されるカルシニューリン阻害剤の量を決定するために、各製剤に対する該液滴重量および容量を決定した。液滴サイズは製剤の表面張力に依存するので、表3Aに記載したとおり0.2wt% ボクロスポリン/容量を含有する2つの製剤を、送達される液滴サイズおよび容量について試験した。PVP-K-90を含有する該製剤およびHPMC(各々0.5 mL)を含有する該製剤を、製造供給元により提供される0.8 mLの最大容量BFS(blow-fill-seal) 容器中に個々に充填した。ボトル材はLDPEであり、該試験を大気条件の下で行った。各製剤の10滴の液滴を風袋ディッシュ(tared dish)に入れて、秤量した。同様に、10滴の製剤の液滴を測定シリンダーに入れて、容量を記録した。データを、表24および25に示した。
安定性および製剤適合性試験を、医薬的送達のために好適な3つの異なる型の容器で行った。実施例1の6つの製剤の既知容量を、3つの異なる型の容器、即ち、LDPE、ポリプロピレンおよび塩化ポリビニルに移して、室温で貯蔵した。予め決定した時間間隔にて(0、6、24 および48時間)、該サンプルをその容器から取り出し、HPLC法により薬剤含量について分析した。様々な型の容器に貯蔵された製剤は、試験期間中に薬剤含量の低下を示さなかった。
生理食塩水に対するボクロスポリンを含有する混合ミセル製剤(1X 基本製剤、表3Aア欄1、0.2wt%または0.5 wt% ボクロスポリン、各々一匹のウサギにて)の忍容性を試験するためにウサギで研究を行った。健全な若い成体のニュージーランドの白色ウサギ(3-4 Kg)(New Zealand albino rabbit)を試験に使用した。生理食塩水の一滴(おおよそ30μL)を眼に入れ、ボクロスポリンを含む製剤の一滴をもう一方のウサギの眼に入れた。下記の観察されたパラメーター:眼の瞬き、流涙、瞳孔のサイズ、充血、眼の動き、における相違は認められなかった。
さらなる試験を、様々な混合ミセル製剤の忍容性を試験するためにウサギにおいて行った。表26および27に示した製剤F1-F16をこれらの試験に使用した。
健康な若い成体のニュージーランド白色ウサギ(3-4 Kg)をこの試験に使用した。ボクロスポリンを含む製剤(LX211)の一滴(おおよそ30μL)をウサギの眼に点眼した。各製剤を3回試験した。
局所ボクロスポリンを評価するオープンラベルの一群のパイロット効率試験を計画し、行った。該試験は、イヌ科乾性角結膜炎(KCS)の処置のために本明細書にて開示した実施態様に関する組成物中の0.2 wt% ボクロスポリンの有効性を実証することを目的とする。該試験は、涙液産生の評価[シルマー涙液試験により測定した場合(STT)]、角膜の臨床的知見の応答、および参加する眼科医の全体評価に及ぶ。
表33.様々なカルシニューリンおよびmTOR阻害剤を含有する製剤
表35: 生体適合性の人工涙液組成物
本開示内容の人工涙液組成物の成分が、眼の組織に対して本来刺激性でないことを示すために、人工涙液に関する眼の忍容性および毒性を決定するために試験を行った。
・顕微鏡の眼の評価:
顕微鏡の眼の評価方式を、青色のフィルターの挿入を含めた細隙灯生体顕微鏡の使用後の眼の所見に用いて蛍光色素染料の保持について評価した。創傷は、人工涙液組成物適用(1日あたりに8回)の投薬前および14日間後に行った間接検眼鏡検査において見られなかった。
人工涙液組成物の適用の試験前および14日後に行ったウサギの内部眼圧(IOP)の平均眼圧測定法(Tono-pen)による測定値は11-17 mm/Hg圧の間であり、正常な生理学的範囲(10-20/mm Hg)内であった。要するに、IOP効果は、投与した局所処置(1日あたりに8回)との関連においては観察されなかった。
両眼フラッシュERGを、ISCEVプロトコールおよびHMsERGユニットを用いてウサギにおいて行った。双方暗順応条件下で10cd.s/m2および30Hzフリッカー刺激による、また10cd.s/m2を用いる高強度の刺激に対する最大のa波およびb波の振幅の予備的評価は、人工の涙液組成物の適用(1日あたりに8回)の14日間後にいずれかの所見も示さなかった。
人工の涙液組成物の適用(1日あたりに8回)の14日後に組織学的所見はなかった。
糖付加剤、例えばトレハロース、マンノース、D-ガラクトースおよびラクトースを、本開示の多様な製剤に添加し、安定性試験を様々な温度で行った。糖を再水和(rehydration)工程中に該製剤に添加するか(外部に)、または薄いフィルムの作成前に添加した(内部に)。該製剤は、アジュバントの糖の存在下では安定となることが判った。
製剤(100 mL)に必要とされる薬物(約0.2%、即ち200mg)、ビタミンE TPGS (約2.5%、即ち2.5g)およびオクトキシノール-40(約0.05/0.1%、即ち50/100 mg)の算出量を秤量した。薬物(200mg)、TPGS(約2.5g)およびオクトキシノール-40(約50/100 mg)を、約2ml、約1mlおよび約50/100μLの95%エタノールの各々に溶解した。糖について、約1gのトレハロースを、約4.5 mlの水/エタノール混合物(約2.5 ml 水+約2.0 ml エタノール)に別々に溶解し、他の含有物と混合した。同じ水:エタノールの比率を、異なる糖含量を含む製剤を調製するために使用した。該混合物を、薄いフィルムを形成するように終夜真空下にて蒸発させた。該薄いフィルムを脱イオン水(約45 mL)に溶解させて、混合ミセルの完全な形成を確実にするためにおおよそ45分間超音波処理を行った。
該製剤は、安定性試験の開始前の室温では澄んでおり、透明であることが判った。観察されたミセルサイズは12−14nmの範囲であった。オクトキシノール-40およびトレハロースを含む製剤の例示は次のとおりである:
この試験の目的は、眼の適用後の本開示内容の0.2%14C-放射性色素ボクロスポリン組成物(眼科用溶液)の反復投与による経時的分布および蓄積可能性、性別の相違、およびメラニン色素結合の可能性を、ニュージーランド白色ウサギ(NZW)およびダッチ・ベルト(Dutch Belted)ウサギ(DB)の眼の組織、涙および血液中の放射性活性を決定することにより評価することであった。
NZWウサギ (30匹雌/8匹雄)を、単回用量(SD)にておよび7日間の反復用量(RD)試験(表38を参照されたい)に使用した。DBウサギ(16匹雌)を、単回用量試験(表39を参照されたい)に使用した。動物は、処理されない(コントロール)か、または7日間の間に1回または毎日の局所眼用量(混合ミセル製剤中に0.2% 14C-ボクロスポリン(35μL)、片方または両眼に)が投与された。血液および眼の組織の放射活性レベルを、燃焼の後の液体シンチレーション計測により計画された時点で評価した。死亡、罹患または臨床的刺激の兆候は、いずれのウサギにおいてもおこらなかった。
b 処置群2(SD群)に対する投与前濃度として使用した。
c 薬物動態評価(SD群)に使用した。
d 処置群5(RD群)に対する投与前濃度として使用した。
e 薬物動態評価(MD群)に使用した。
b. 処置群2(SD群)に対する投与前濃度として使用した。
c. 薬物動態評価(MD群)に使用した。
14Cボクロスポリン-誘導放射活性について選択した薬物動態パラメーター(Cmax、AUC、Tmaxおよびt1/2)を、NZWおよびDBウサギ各々について表40および41にまとめた。単回用量投与後に、眼の組織内へ薬物の迅速な浸透(放射活性として測定した)が、最も高い濃度(>1mg eq/g組織)にて、瞼、結膜、角膜、瞬膜および涙内で起こり、最も低い濃度(1-11 ng eq/g組織)にて、房水および硝子体液、および水晶体で起きた。他の眼の組織は、ボクロスポリンおよび/または関連残留物の様々なレベル(20-223ng eq/g組織)に達した。図2は、雌のニュージーランド白色ウサギへの0.2%14C-ボクロスポリン混合ミセル製剤の1回(1日)の局所適用の後の14C-ボクロスポリンの組織レベルを示す。ボクロスポリンの治療レベルを24時間の基準で注目すると、一日に一回(QD)の投薬が本発明に開示した実施態様の水性混合ミセル組成物を用いて可能であることを支持するものであった。
14C-ボクロスポリンの眼の暴露に対する眼の暴露は、14Cボクロスポリン(35μL、70ng)の一日に1回の両眼投与7日間後に角膜、涙腺、虹彩/毛様体および水晶体中で2.8から6.7倍増加した(表40を参照されたい)。複数回の投薬後に(表40-43および図3-7を参照されたい)、Cmax-反復用量:Cmax-単回用量の比率が選択された組織内で上昇したとしても、ボクロスポリンの全体レベルは、最小の組織蓄積を示す表面組織レベルを十分に下回る。また、単回または反復投薬後の同程度のt1/2は、最小の組織蓄積を強く示唆した。
14C-ボクロスポリンのDBウサギへの単回投薬後の、眼の組織濃度(例えば、Cmax)は、NZWウサギとは有意に相違せず、メラニン結合がないことを示唆している(表42を参照されたい)。
Claims (24)
- 下記のものを含んでいる医薬組成物:
ボクロスポリン、シクロスポリンA、ピメクロリムス、タクロリムス、シロリムス、テムシロリムス、エベロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択されるカルシニューリン阻害剤または哺乳類ラパマイシン標的(mTOR)阻害剤;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで、該組成物は混合ミセルを形成する。 - 下記のものを含んでいる医薬組成物:
ボクロスポリン、シクロスポリンA、ピメクロリムス、タクロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択されるカルシニューリン阻害剤;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 該カルシニューリン阻害剤が、ボクロスポリンである、請求項2記載の医薬組成物。
- 下記のものを含んでいる医薬組成物:
シロリムス、テムシロリムス、エベロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択される哺乳類ラパマイシン標的(mTOR)阻害剤;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物が眼組織への局所適用に好適である。 - 混合ミセルを形成する、請求項2または4記載の医薬組成物。
- 光学的に透明な混合ミセルを形成する、請求項2または4記載の医薬組成物。
- 下記工程を含む、混合ミセル組成物を調製する方法:
カルシニューリン阻害剤または哺乳類ラパマイシン標的(mTOR)阻害剤を、ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS)およびオクトキシノール-40と混合して、溶媒を形成する工程(ここで、カルシニューリン阻害剤またはmTOR阻害剤は、ボクロスポリン、シクロスポリンA、ピメクロリムス、タクロリムス、シロリムス、テムシロリムス、エベロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択される)、
該溶媒溶液を蒸発させて、固体様物質を形成させる工程、
該固体様物質を、水溶液を用いて水和する工程、および
該固体様混合物を溶解して、混合ミセル組成物を生成する工程、
ここで該混合ミセル組成物は光学的に透明である。 - 該水溶液中で生体接着性ポリマーを混合する工程をさらに含んでおり、該生体接着性ポリマーがPVP-K-30、PVP-K-90、HPMC、HEC、およびポリカルボフィルからなる群から選択される、請求項7記載の方法。
- 該カルシニューリン阻害剤がボクロスポリンである、請求項7記載の方法。
- 該ボクロスポリンが、混合ミセル組成物中に0.01%〜10%で存在する、請求項9記載の方法。
- 下記のものを含んでいる医薬組成物:
ボクロスポリン;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 下記のものを含んでいる医薬組成物:
シクロスポリンA;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 下記のものを含んでいる医薬組成物:
タクロリムス;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 下記のものを含んでいる医薬組成物:
シロリムス;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - カルシニューリン阻害剤またはmTOR阻害剤が、眼底に到達できる、請求項1、2および4のいずれかに記載の医薬組成物。
- カルシニューリン阻害剤またはmTOR阻害剤が、医薬組成物の全容量の0.01重量パーセントから10重量パーセントの範囲である、請求項1、2および4のいずれかに記載の医薬組成物。
- ビタミンE TPGSが、医薬組成物の全容量の0.01重量パーセントから20重量パーセントの範囲である、請求項1-6および11-14のいずれかに記載の医薬組成物。
- オクトキシノール-40が、該組成物の全容量の0.01重量パーセントから10.0重量パーセントの範囲にある、請求項1-6および11-14のいずれかに記載の医薬組成物。
- 1以上のPVP-K-30、PVP-K-90、HPMC、HEC、およびポリカルボフィルからなる群から選択される生体接着性ポリマーをさらに含んでいる、請求項1-6および11-14のいずれかに記載の医薬組成物。
- 1以上のトレハロース、マンノース、D-ガラクトースおよびラクトースから選択される添加剤をさらに含んでいる、請求項1-6および11-14のいずれかに記載の医薬組成物。
- 眼疾患を処置するための、請求項1-6および11-20のいずれかに記載の医薬組成物。
- 該眼疾患が、ドライアイ症候群(DES)、シェーングレン症候群、ブドウ膜炎、結膜炎(伝染性結膜炎)、角膜炎、角結膜炎、春季角結膜炎(VKC)、アトピー性角結膜炎(AKC)、痕跡性結膜炎などの眼の表面の自己免疫障害、眼瞼炎および強膜炎からなる群から選択される炎症性の眼の表面疾患である、請求項21記載の医薬組成物。
- 眼底症状または障害を処置するための、請求項1-6および11-20のいずれかに記載の医薬組成物。
- 該眼底症状または障害が、糖尿病性網膜症(「DR」)、加齢性黄斑変性症(「AMD」)、糖尿病性黄斑浮腫(「DME」)、後部ブドウ膜炎、およびその組合せからなる群から選択される、請求項23記載の医薬組成物。
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CN101918019A (zh) | 2010-12-15 |
JP2010540682A (ja) | 2010-12-24 |
WO2009048929A1 (en) | 2009-04-16 |
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CA2701482A1 (en) | 2009-04-16 |
US20130345185A1 (en) | 2013-12-26 |
AU2008310956B2 (en) | 2014-08-07 |
JP2015086226A (ja) | 2015-05-07 |
CN101918019B (zh) | 2014-11-26 |
US10973871B2 (en) | 2021-04-13 |
US20210338769A1 (en) | 2021-11-04 |
US20090092665A1 (en) | 2009-04-09 |
JP5836473B2 (ja) | 2015-12-24 |
MX2010003364A (es) | 2010-07-06 |
EP2197461B1 (en) | 2018-02-21 |
US20110300195A1 (en) | 2011-12-08 |
US8435544B2 (en) | 2013-05-07 |
CA3014633C (en) | 2022-05-17 |
CA3014633A1 (en) | 2009-04-16 |
ES2667945T3 (es) | 2018-05-16 |
AU2008310956A1 (en) | 2009-04-16 |
EP2197461A1 (en) | 2010-06-23 |
US8535694B2 (en) | 2013-09-17 |
EP2197461A4 (en) | 2013-10-02 |
US20200009217A1 (en) | 2020-01-09 |
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