JP6884755B2 - ペプチド組成物および使用方法 - Google Patents
ペプチド組成物および使用方法 Download PDFInfo
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- JP6884755B2 JP6884755B2 JP2018508624A JP2018508624A JP6884755B2 JP 6884755 B2 JP6884755 B2 JP 6884755B2 JP 2018508624 A JP2018508624 A JP 2018508624A JP 2018508624 A JP2018508624 A JP 2018508624A JP 6884755 B2 JP6884755 B2 JP 6884755B2
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- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
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Description
本特許書類は、米国特許法第119条(e)の定めにより、参照により本明細書中に組み入れられる米国特許仮出願第62/155,711号(2015年5月1日出願)の出願日の利益を主張する。
本明細書中に引用されるすべての特許、特許出願および公報、ならびに他の参考文献は、その全体が参照により本明細書中に組み入れられる。これらの刊行物の開示は、その全体が、本明細書中に記載および請求される発明の日に当業者に公知である技術水準をさらに完全に説明するために、本出願中に参照により組み入れられる。
本発明は、米国国立衛生研究所(NIH)により与えられる助成金第R44EY022512号による政府の支援を用いてなされた。政府は、本発明に一定の権利を有する。
ペプチドを含む組成物、その医薬調製物、ならびにそれを用いる光受容体細胞死の予防方法およびFas媒介性またはTRAIL媒介性アポトーシスから、限定するものではないが、光受容体および網膜色素上皮をはじめとする網膜細胞を保護する方法が、本明細書中に提供される。
生物学的に活性なペプチド組成物、生物学的に活性なペプチド組成物の医薬調製物、およびペプチド組成物を用いる方法が記載される。
一部の実施形態では、組成物は、光受容体の効果的な保護および/またはアポトーシスの阻害のための1種以上の他の薬剤と一緒に共投与することができる。
化合物1ペプチド(ペプチドHis-His-Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH 2 ;配列番号1)は、複数の供給業者により、Fmoc化学を介してFmoc-アミド-AMS樹脂上で合成された。Fmoc保護アミノ酸は、GL Biochem社から購入した。カップリングおよび切断用の試薬は、Aldrich社から購入した。溶媒は、Fisher Scientific社から購入した。
後者のペプチドサンプルはまだトリフルオロ酢酸塩として合成されたが、酢酸を用いてアニオン交換を行ない、化合物1をその三酢酸塩として得た。
実施例1に記載される通りに三塩酸塩として得た化合物1を、以下のプロトコールに従ってpH滴定を行なうことにより、様々なpHでの水溶性に関してスクリーニングした。一部のケースでは、Met-12を、同じ条件下でのその溶解度pHプロフィールを決定するために、同一の実験手順に供した。複数回の事前の実験では、Met-12が2.7を超えるいずれかのpHで大部分が水性である媒体中に満足に製剤化できる条件を見い出せなかった。
化合物1のpH依存的溶解度を、共溶媒および添加剤を用いて検討し、同じ条件下でのMet-12の溶解度と比較した。
70%DMSO実験は、pH5.5付近でのゲル形成を伴ってMet-12滴定と同様であったが、この場合に、おそらくはC末端がイオン化できないせいで、ゲルはより高いpHで再溶解しなかった。
70%PEG400および70%グリセロール溶液は、有用には見えず、2種類の糖添加剤である10%マンニトールまたは10%トレハロースもまた有用には見えなかった。
驚くべきことに、検討した界面活性剤の一部は、化合物1のpH-溶解度プロフィールの顕著な改善をもたらしたが、試験した界面活性剤のいずれも、Met-12のpH-溶解度プロフィールを改善しなかった。10%チロキサポールの存在下での化合物1は、pHが5.87を超えるまで、透明なままであり、かつ許容できる粘度を有した。10%ポリソルベート80を用いる場合、透明な溶液は、pH6.36を超えるまで明らかに粘性にはならなかった。10%ポリソルベート20を用いる場合、pH3.2で線維が観察されたが、pH7.14まで、濁りまたはゲル化の徴候は見られなかった。10%ポロキサマー407は、溶液は流動性に見えるが、pH5〜9の範囲で第2の相が明らかに存在したので、不溶性の開始がいつ生じたかに関して幾分か不明瞭であった。これは、溶液中に形成された非常に大きな透明球からなるように思われた。これは、高いポロキサマー濃度のアーチファクトであると考えられ、なぜなら、15%ポロキサマー溶液は27℃で完全にゲル化する一方で、10%ポロキサマーは25℃では明らかにはゲル化しないが、種々の添加剤がゾル-ゲル臨界温度を上昇または低下させることができ、かつゲル化に関する通常の粘度測定は分離したゲル相の最初の出現を効率的に取り上げることがないであろうからである。したがって、混合物中のペプチドの溶解度は損なわれなかったが、多量のポロキサマーがゾル相とゲル相からなる2種類のポロキサマー相を形成したと考えられる。ポビドンK30は、pH3.60で粘性溶液を生じ、pH4.0超ではゲル化した。
70%PGと10%ポリソルベート80との組み合わせは、透明な溶液を生じ、この溶液はpH3.4まで粘稠になり、pH5.25でゲル化し、このことにより、この組み合わせは70%PGよりも良好ではなく、10%PS-80よりも劣っていた。
70%PGおよび3%PSを用いる場合、pH4.6で粘性が生じたが、物質はpH5.25まではゲルのままであった。
35%PGおよび3%PS-80を用いる場合、pH2.66の低pHで溶液中に線維が現われ、pH3.48の溶液で凝集物が見られた。
10%PGおよび10%PS-80はpH4.94までは低い粘度を有する透明溶液を生じ、pH5.13超で物質の沈殿が始まった。
10%PGおよび3%PS-80はpH3.16までは透明な溶液を生じたが、幾分かの沈殿がpH3.4までに起こった。
3%ポリソルベート20および10%PGはpH5.3まで透明な流動性溶液を生じたが、PS-20を1%にまで低下させると、pH3未満で線維が生成された。
in vitro有効性実験および後のin vivo有効性実験により、化合物1が、光受容体細胞でのFasL(または網膜剥離)誘導型アポトーシスを遮断する上で3〜10倍超の範囲でより強力であることが実証された。これらの驚くべき結果は、予測されるヒト用量を25〜200μg/眼の範囲まで減少させることを可能にし、製剤化された薬物の最大必要濃度を2.0mg/mLにまで低下させた。その濃度での最適製剤化条件を見い出すために、さらに低い薬物濃度を検討する数種類の実験を用いてさらなる実験セットを行なった。この実験は、すべて、界面活性剤としてポロキサマー407またはポリソルベート20のいずれかを検討した。目視できる濁りおよび粘性の視覚的評価の両方が、有用なスクリーニング観察であるが、上述の通り、それらは凝集したペプチドの存在を常に示すものではないことが見出され、後の実験の大部分では、0.2ミクロンPVDFメンブレンまたはPALL 25mm 0.2μM Ultipor Nylon 6,6フィルターを通す前後でサンプル中に存在する薬物量を測定することにより、溶解度を評価した。濁っているかまたは非常に粘稠な溶液は、一般的に、ろ過が難しいかまたは不可能であり、それらがろ過できた場合には、多くの場合には非常に低い薬物回収率をもたらした。驚くべきことに、一部の流動性の透明溶液もまたろ過時に大きな損失を示したので、満足できる製剤は、ろ過後に90%超の薬物回収率を与えるものとして定義された。線維を形成する、化合物1のような化合物を用いるすべての溶解度測定は、動的溶解度しか測定できないことに留意すべきである。線維形成は、多数の条件セットの下では非常に緩慢であり得、準安定性溶液の溶解度を測定している可能性があり、この場合、最も安定な考えられる線維形態とは異なり、真の熱力学的溶解度に完全に到達するのには数日間から数年間を要し得る。しかしながら、少なくとも製剤化後の迅速な沈殿を回避するために、製剤は、慣用的に、ろ過前に24〜72時間保持される。
細胞培養:661W光受容体細胞株は、Muayyad Al-Ubaidi氏(Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK)により寛大に提供された。661W細胞株は光受容体細胞株であり、SV40-T抗原をヒト光受容体間レチノール結合性タンパク質(IRBP)プロモーターの制御下に発現させることにより不死化されている(AI-Ubaidi et al., J Cell Biol., 119(6):1681-1687 (1992)、その全体が参照により本明細書中に組み入れられる)。661W細胞は、青色および緑色錐体色素、トランスデューシン、および錐体アレスチンをはじめとする錐体光受容体マーカーを発現し(Tan et al., Invest Ophthalmol Vis Sci., (3):764-768 (2004)、その全体が参照により本明細書中に組み入れられる)、カスパーゼ媒介性細胞死を生じ得る(Kanan et al., Invest Ophthalmol Vis Sci., 48(1):40-51 (2007)、その全体が参照により本明細書中に組み入れられる)。
本試験は、雄性ダッチベルテッド種ウサギの硝子体内注入後の、硝子体液(VH)および網膜組織中の化合物1の濃度を測定するために行なった。濃度は、50μL両側硝子体内(IVT)用量の投与から24時間、72時間、168時間および240時間の組織中で測定した。
試験設計を、表1にまとめる。
動物種/系統/性別:雄性ダッチベルテッド種ウサギ
供給業者:Covance Research Products社
月齢範囲:4〜5ヵ月齢
受け取り時の体重(体重範囲):1.51〜1.85kg
投与経路:硝子体内(IVT)注入
処置期間:単回投与/眼
製剤濃度:2.0、1.0、および0.5mg/mL 化合物1三酢酸塩
投与体積:50μL/眼
変動係数(%):精度の推定値として用いた:
変動係数(%CV)=(標準偏差/平均値)×100
二次最小二乗分析:標準曲線フィッティングを、1/x2重み付けを用いた二次方程式を用いて決定した:
y=ax2+bx+c
[式中、y=内部標準に対する較正標準のピーク面積比率
x=較正標準の濃度
a=x2の二次係数(quadratic coefficient)
b=xの二次係数
c=較正曲線のy切片としての定数]
二次アナライト濃度:アナライトの濃度は、上記で算出される較正曲線パラメータを用い、次にxの値について方程式を解くことにより算出される。
網膜濃度およびVH濃度は、以下の表2および表3に見出され、図1および図2に図示される。薬物動態パラメータを必要に応じて算出し、以下の表4および表5にまとめる。
本試験は、ブラウンノルウェー種ラットの硝子体内注入後の硝子体液および網膜組織での化合物1三塩酸塩の濃度を測定するために行なった。5μL両側硝子体内(IVT)用量の投与から24時間後(群1)、および72時間後(群1および2)の組織で濃度を測定した。
試験を、表6にまとめる。
動物種/系統/性別:ノルウェーブラウン種ラット
供給業者:Charles River社
月齢範囲:1〜2ヵ月齢
受け取り時の体重(体重範囲):165.9〜181.2g
投与経路:硝子体内(IVT)注入
処置期間:単回投与/眼
製剤濃度:0.06mg/mL ONL-1204三酢酸塩
投与体積:5μL/眼
静脈内バルビツール酸過剰投与によりラットを安楽死させ、眼を摘出して急速凍結した。硝子体液(VH)および網膜をすべての動物から回収し、LC-MS/MSにより化合物1について分析した。
眼組織濃度
未知ブラウンノルウェー種ラット網膜および硝子体液での化合物1三塩酸塩濃度
未知硝子体液(VH)のホモジナイゼーションについての指示
各未知VHまたは対照ブランクに関して:VHをホモジナイゼーションチューブに量り入れる。VH重量(mg)の4倍のACN:水:1M塩酸(70:20:10、v/v/v)(μL)をホモジナイゼーションチューブに加える。2.8mmおよび1.4mmのサイズの酸化ジルコニウムビーズを加える。Precellys(登録商標)を用いて、すべてのサンプルをホモジナイズする:5500rpm、3×30秒サイクル、サイクル間は20秒間、−10〜0℃の温度。
各網膜標準に関して:
ブランク網膜組織をホモジナイゼーションチューブに量り入れる。
組織重量(mg)の0.5倍の網膜作業用較正標準(μL)をホモジナイゼーションチューブに加える。
組織重量(mg)の3.5倍のACN:水:1M塩酸(70:20:10、v/v/v)(μL)をホモジナイゼーションチューブに加える。
1.4mmのサイズの酸化ジルコニウムビーズを加える。
Precellys(登録商標)を用いて、すべてのサンプルをホモジナイズする:5500rpm、3×30秒サイクル、サイクル間は20秒間、−10〜0℃の温度。
各未知網膜または対照ブランクに関して:
網膜組織をホモジナイゼーションチューブに量り入れる。
組織重量(mg)の4倍のACN:水:1M塩酸(70:20:10、v/v/v)(μL)をホモジナイゼーションチューブに加える。
1.4mmのサイズの酸化ジルコニウムビーズを加える。
Precellys(登録商標)を用いて、すべてのサンプルをホモジナイズする:5500rpm、3×30秒サイクル、サイクル間は20秒間、−10〜0℃の温度。
較正ストック用標準および作業用標準の調製
ストック用較正標準は、ONL-1204について500μg/mLの濃度でジメチルスルホキシド(DMSO)中に調製した。
ポリプロピレンチューブ中で、10μL(20μL STD11)の作業用較正標準またはストックを、90μL(80μL STD11)対照ブランク硝子体液に加えた。ブランクおよび内部標準を含むブランクに関しては、100μLの対照ブランクウシ硝子体液を加えた。400μLのACN:水:1M塩酸(70:20:10、v/v/v)を、各標準またはブランクに加えた。
ポリプロピレンチューブ中で、50μLのブラウンノルウェー種ラット未知ホモジネート、ウシ対照ブランクまたは較正標準ウシホモジネートを加えた。50μLのDMSO:水:ギ酸(50:40:10)を各サンプルに加えた。次に、サンプルをボルテックス混合し、14,000rpmで10分間(4℃)遠心分離した。続いて、80μLの各サンプル上清を96ウェルオートサンプラープレートへとアリコートに分けた。40μLの作業用内部標準(5,000ng/mL APi1887、水中)(内部標準を含まないブランクについては水)、および120μLの水を加えた。次に、サンプルを、マルチチャンネルピペットを用いて混合し、分析した。
変動係数(%):精度の推定値として用いた:
変動係数(%CV)=(標準偏差/平均値)×100
二次最小二乗分析:標準曲線フィッティングを、1/x2重み付けを用いた二次方程式を用いて決定した:
y=ax2+bx+c
[式中、y=内部標準に対する較正標準のピーク面積比率
x=較正標準の濃度
a=x2の二次係数(quadratic coefficient)
b=xの二次係数
c=較正曲線のy切片としての定数]
二次アナライト濃度:アナライトの濃度は、上記で算出される較正曲線パラメータを用い、次にxの値について方程式を解くことにより算出される。
包括的に平均された結果を図7に示す。群1に関して、各動物由来の両方の眼を1回の分析のために組み合わせた。群2では、4頭の動物由来の両眼を組み合わせてサンプルを作製した。群2でのプールされた網膜についての濃度は、A〜DサンプルおよびE〜Hサンプルについてそれぞれ462ng/gおよび1310ng/gであった。化合物1についての硝子体液の分析は、群1および群2の各動物由来のそれぞれの眼からの組み合わされたサンプルを用いて行なった。回収されたVHの重量によって標準化して、化合物1の理論的総量を算出した。各ラットの眼に注入された化合物1の総量は0.3μg(0.06mg/mL×5μL)であった。72時間データを収集した方法が異なっていたので、標準誤差は算出しなかった。濃色バーは各眼の硝子体液中の化合物1三酢酸塩の量を表わし、t=0のバーは300ngの意図された用量を示し、淡色バーはng/gで表わされる網膜での化合物1の濃度を示す。終末相半減期は明らかに数日間の桁であるが、最初の24時間で、薬物のうちの約半分がVHからなくなった。一方で、網膜濃度は24時間で1μg/g超であり、72時間までは約40%しか有しない。このことは、ラット網膜が、少なくとも1週間は、容易に検出可能な量の薬物に曝露されるであろうことを示唆する。
簡潔には、げっ歯類を、ケタミン(100mg/mL)とキシラジン(20mg/mL)の50:50ミックスを用いて麻酔し、フェニレフリン(2.5%)およびトロピカミド(1%)の局所投与により散瞳させた。20ゲージの硝子体網膜微細手術用の刃(Walcott Scientific, Marmora, NJ)を用いて、レンズを損傷しないように注意深く、縁から2mm後方に強膜切開部を作製した。
実施例10と同じげっ歯類網膜剥離モデルを用いて、DMSO中の化合物1の非常に効果的な5μg用量を、2種類の製剤中の化合物1の同じ用量、および1μg用量と比較した。
付着対照網膜はアポトーシス細胞を示さず、未処置剥離サンプルは、この時点で測定して約6.5%のアポトーシス細胞を示した。
実施例10と同じげっ歯類網膜剥離モデルを用いて、DMSO中の化合物1三塩酸塩(1μg)を陽性対照として用いた。陰性対照は、評価対象の試験ビヒクル(0.4%ポロキサマー、4.5%マンニトール、10mM酢酸、pH4.5)とした。DMSO中の化合物1三酢酸塩(1μg)を、同じ用量の三塩酸塩と比較した。
Claims (21)
- ポリアセテート塩又は三酢酸塩である、請求項1に記載の式Iの化合物の塩。
- 眼の光受容体でのFas媒介性またはTRAIL媒介性アポトーシスを予防するための医薬製剤、
眼の網膜色素上皮の細胞でのアポトーシスまたはネクロプトーシスを予防するための医薬製剤、
網膜剥離の治療のための医薬製剤、および/または
網膜神経節細胞の疾患または症状(conditions)を予防するための医薬製剤
での使用のための、請求項1または2に記載の化合物またはその塩。 - 請求項1〜3のいずれか1項に記載の化合物、および眼への送達用につくられた製薬用担体を含有する組成物。
- 眼内、硝子体内、または眼周囲投与用に製剤化され、眼に対して無毒である、請求項4に記載の組成物。
- 前記組成物中の前記化合物が、剥離した網膜光受容体細胞を保護する、請求項4または5に記載の組成物。
- 前記組成物中の前記化合物が、眼の網膜色素上皮の細胞でのアポトーシスまたはネクロプトーシスを予防する、請求項4または5に記載の組成物。
- 前記組成物中の前記化合物が、眼の網膜神経節の細胞でのアポトーシスまたはネクロプトーシスを予防する、請求項4または5に記載の組成物。
- ポリソルベート80、ポリソルベート20、ポロキサマー407、およびチロキサポールからなる群より選択される少なくとも1種の非イオン性界面活性剤をさらに含む、請求項4〜8のいずれか1項に記載の組成物。
- 前記少なくとも1種の非イオン性界面活性剤が、前記組成物の約0.01%〜20%(w/w)、前記組成物の約0.05%〜10%(w/w)または前記組成物の約0.25%〜3%(w/w)を形成する、請求項9に記載の組成物。
- 急性か慢性かにかかわらず、治療対象である徴候に合う硝子体または網膜薬物動態などのパラメータを最適化する比率で、2種類以上の非イオン性界面活性剤が用いられ、添加される非イオン性界面活性剤の総量が前記組成物の0.01%〜20%(w/w)である、請求項9または10に記載の組成物。
- 有機共溶媒をさらに含む、請求項4〜11のいずれか1項に記載の組成物。
- プロピレングリコールおよびジメチルスルホキシドのうちの少なくとも1種をさらに含む、請求項4〜12のいずれか1項に記載の組成物。
- 前記有機共溶媒が前記組成物の約1%〜50%(w/w)、前記組成物の約1%〜20%(w/w)、または前記組成物の約1%〜5%(w/w)を形成する、請求項12に記載の組成物。
- 2.5〜6.0の範囲のpHを有する、請求項4〜14のいずれか1項に記載の組成物。
- 被験体における眼の症状、疾患、または眼の健康に影響を及ぼす症状もしくは疾患を治療するための、請求項4〜15のいずれか1項に記載の組成物。
- 前記眼の症状、疾患、または眼の健康に影響を及ぼす症状もしくは疾患が、網膜剥離、黄斑変性、加齢黄斑変性、非滲出型加齢黄斑変性、滲出型加齢黄斑変性、脈絡膜血管新生、網膜症、糖尿病性網膜症、急性および慢性黄斑性視神経網膜症(acute and chronic macular neuroretinopathy)、中心性漿液性脈絡網膜症、黄斑浮腫、類嚢胞黄斑浮腫、糖尿病性黄斑浮腫、ブドウ膜炎/網膜炎/脈絡膜炎、多発性小板状色素上皮症、ベーチェット病、バードショット網脈絡膜症、感染(梅毒、ライム病、結核、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)、前部ブドウ膜炎、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、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、高血圧性眼底変化(hypertensive fundus changes)、眼部虚血症候群、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、頸動脈疾患(CAD)、樹氷状血管炎(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、家族性滲出性硝子体網膜症、イールズ病(Eales disease)、交感性眼炎、ブドウ膜性網膜疾患(uveitic retinal disease)、網膜剥離、外傷、レーザー、PDT、光凝固、手術中の血流低下、放射線網膜症、骨髄移植網膜症、増殖性硝子体網膜症および網膜上膜、増殖性糖尿病網膜症、眼ヒストプラスマ症、眼トキソカラ症、眼ヒストプラスマ症候群(OHS)、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、進行性外側網膜壊死、真菌性網膜疾患、眼梅毒、眼結核、びまん性片側性亜急性神経網膜炎、ハエ幼虫症、網膜色素変性、網膜ジストロフィーに伴う全身性障害、先天性停止性夜盲、錐体ジストロフィー、スタルガルト病、黄色斑眼底、ベスト病、網膜色素上皮のパターンジストロフィー(pattern dystrophy)、X連鎖網膜分離、ソースビー眼底ジストロフィー、良性中心性黄斑変性(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、網膜剥離、黄斑円孔、巨大網膜裂孔、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、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、網膜色素上皮ホメオスタシス異常、急性網膜色素上皮炎、緑内障、角膜ジストロフィーまたは異形成などからなる群より選択される、請求項16に記載の組成物。
- 前記被験体が網膜剥離、黄斑変性、網膜RPE(網膜色素上皮)ホメオスタシス異常の少なくとも1種に罹患している、請求項16に記載の組成物。
- 前記組成物が、被験体体内での光受容体、RPE細胞、網膜神経節細胞、もしくはは視神経細胞の少なくとも1種における細胞死を軽減させるために十分な量で、または被験体体内での光受容体生存率を高めるために十分な量で投与される、請求項16に記載の組成物。
- 光受容体細胞死のリスクを有する被験体における光受容体細胞死を予防するための、請求項4〜15のいずれか1項に記載の組成物であって、被験体に、眼内投与、硝子体内投与、または眼周囲投与される、上記組成物。
- 光受容体細胞死がFas媒介性またはTRAIL媒介性の光受容体アポトーシスである、請求項20に記載の組成物。
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