JP2022116191A - 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 - Google Patents
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 Download PDFInfo
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- abnormal neovascularization
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- neovascularization
- nintedanib
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Abstract
Description
本願は、2016年6月2日に出願された米国仮特許出願第62/344,878号および2016年6月2日に出願された米国仮特許出願第62/344,870号の恩典を主張し、それら各々の全内容が参照により本明細書に組み入れられる。
本開示は、高リスク角膜移植患者における移植片拒絶の処置および予防のためならびに眼の前方部における異常な新生血管形成を伴う眼疾患の処置のためにニンテダニブを使用する眼用組成物および方法に関する。
異常な新生血管形成は、眼の前方部における多くの疾患に関与する。異常な新生血管形成は、高リスク角膜移植患者における移植片拒絶に関与する。これらの適応症の多くに対する現行の処置法は、改善を必要としている。本明細書に開示される方法は、現行の処置法の問題に対処し、これらの疾患に対する改善された処置を提供する。
特定の局面において、本開示は、眼の前方部における異常な新生血管形成を伴う眼疾患を処置するための方法であって、ニンテダニブまたはその薬学的に許容される塩の有効量をそのような処置を必要とする対象の眼に投与する工程を含む、方法を提供する。特定の局面において、開示される方法は、角膜移植患者において移植片拒絶を処置するか、予防するか、またはその発症を遅らせる。例えば、開示される方法は、移植片拒絶のリスクが高い角膜移植患者において移植片拒絶を処置するか、予防するか、またはその発症を遅らせる。特定の局面において、開示される方法は、高リスク角膜移植における移植片拒絶を予防するために、手術前に、手術と同時に、または手術後に実施される。
局所用点眼液の形態またはインプラントの形態のニンテダニブまたはその薬学的に許容される塩の有効量を対象の眼に投与する工程を含む、異常な新生血管形成を伴う眼の適応症を処置するための方法。
[本発明1002]
前記異常な新生血管形成を伴う適応症が、高リスク患者が角膜移植を受けた後の角膜移植片拒絶である、本発明1001の方法。
[本発明1003]
ニンテダニブが、前記対象の眼において異常な新生血管形成および炎症を阻害することにより移植片拒絶を予防するのに有効な量で投与される、本発明1001の方法。
[本発明1004]
前記異常な新生血管形成を伴う適応症が移植片対宿主病である、本発明1001の方法。
[本発明1005]
前記異常な新生血管形成を伴う適応症がアトピー性結膜炎である、本発明1001の方法。
[本発明1006]
前記異常な新生血管形成を伴う適応症が眼性酒さである、本発明1001の方法。
[本発明1007]
前記異常な新生血管形成を伴う適応症が眼類天疱瘡である、本発明1001の方法。
[本発明1008]
前記異常な新生血管形成を伴う適応症がライエル症候群である、本発明1001の方法。
[本発明1009]
前記異常な新生血管形成を伴う適応症が、ウイルス感染症、細菌感染症、真菌感染症、または寄生虫感染症により誘発される新生血管形成である、本発明1001の方法。
[本発明1010]
前記異常な新生血管形成を伴う適応症がコンタクトレンズ誘発性新生血管形成である、本発明1001の方法。
[本発明1011]
前記異常な新生血管形成を伴う適応症が潰瘍である、本発明1001の方法。
[本発明1012]
前記異常な新生血管形成を伴う適応症がアルカリによるやけどである、本発明1001の方法。
[本発明1013]
前記異常な新生血管形成を伴う適応症が幹細胞欠乏である、本発明1001の方法。
[本発明1014]
前記異常な新生血管形成を伴う適応症が瞼裂斑である、本発明1001の方法。
[本発明1015]
前記異常な新生血管形成を伴う適応症が血管新生緑内障である、本発明1001の方法。
[本発明1016]
前記異常な新生血管形成を伴う適応症がドライアイ病である、本発明1001の方法。
[本発明1017]
前記異常な新生血管形成を伴う適応症がシェーグレン症候群である、本発明1001の方法。
[本発明1018]
前記異常な新生血管形成を伴う適応症がマイボーム腺機能不全である、本発明1001の方法。
[本発明1019]
前記異常な新生血管形成を伴う適応症がスティーブン・ジョンソン症候群である、本発明1001の方法。
[本発明1020]
前記異常な新生血管形成を伴う適応症が眼における腫瘍である、本発明1001の方法。
[本発明1021]
ニンテダニブが、局所用眼用製剤の形態または眼用インプラントの形態で投与される、本発明1001の方法。
[本発明1022]
前記眼用インプラントが、半固体または固体の持続放出インプラントの形態である、本発明1021の方法。
[本発明1023]
前記インプラントが前記対象の眼に挿入される、本発明1022の方法。
[本発明1024]
前記局所用眼用製剤が局所用点眼液である、本発明1021の方法。
[本発明1025]
前記局所用眼用製剤が、溶液、懸濁液、クリーム、軟膏、ジェル、ジェル形成液、リポソームもしくはミセルを含む懸濁液、噴霧用製剤、または乳濁液である、本発明1021の方法。
本発明の他の特徴および利点は、以下の詳細な説明および図面からならびに特許請求の範囲から明らかとなるであろう。
角膜移植は、一般的な外科的手法である。角膜移植の全体的な成功率は良いものの、一部の高リスク患者においては依然として生着不全が問題となっている。これらの患者は、宿主移植部位において強い炎症および新生血管形成を有し、これらが同種移植片の免疫応答および拒絶を亢進する(Yu et al. World J Transplant. 2016; 6(1): 10-27)。生着不全のリスクを軽減するために経口免疫抑制薬が使用されることもあるが、これらは全身的な副作用を有する。開示される方法は、血管内皮成長因子(「VEGF」)および血小板由来成長因子(「PDGFR」)を介する過剰な新生血管形成を阻害し、VEGFおよび線維芽細胞成長因子(「FGF」)に関連する免疫応答を弱めることにより高リスク患者において移植片拒絶を予防する。このメカニズムは、図1に示されている。
本明細書に記載される方法は、有効成分として本明細書に記載される方法により同定される化合物を含む薬学的組成物の製造および使用を含む。薬学的組成物自体も含まれる。
新生血管形成のウサギ角膜縫合モデルは、異常な角膜新生血管形成を減少させる本方法の能力を実証する。
リン酸緩衝溶液、pH 7.4中10%の2-ヒドロキシプロピルβシクロデキストリン中に0.2%または0.05%のニンテダニブを含む局所用組成物を調製した。
13匹のメスのニュージーランドホワイト(Zealand White)種のウサギを使用して本研究を実施した。簡潔に説明すると、第1日に、新生血管形成を誘発するため、各動物の右眼の角膜上部に5本の縫合糸を設置した。これらの動物の両眼を、表1に記載されるように薬物、ビヒクル、または生理食塩水のいずれかで処置した。
BID:1日2回(およそ10~12時間間隔)。TID:1日3回(およそ6~8時間間隔)。OD=右眼。OS=左眼。
両眼に投薬し、投薬容量はおよそ40μL/眼であった。
注:第1日の生理食塩水の1回目の投薬は、縫合糸の設置から4時間後に行った。
NIH ImageJ(登録商標)ソフトウェアを用いて眼の画像を分析した。各画像をImageJ(登録商標)で開き、ルーラーを用いて写真内に目盛りをつけ、縫合糸付近の角膜上の新生血管形成領域を選択ツールによって選択した。そのmm2単位の面積を、ソフトウェア内の測定ツールによって算出し、エクセルに記録し、画像をキャプチャおよび保存した。両側T検定を用いて、グループ間で有意に相違するかどうかを決定した。その結果を、比較を容易にするために、標準偏差と共に、平均のヒストグラムとしてプロットした。
図2Aおよび2Bに示されるように、ニンテダニブは、縫合糸による誘発から12および14日後のウサギ角膜において縫合糸誘発性新生血管形成に対して顕著な阻害効果を示した。より高用量である0.2%ニンテダニブは、0.05%ニンテダニブよりも良い効果を示し、TID投薬のより高頻度の投薬レジメンは、BID投薬と比較してより高い効果を示した。
本実施例では、C57BL/6マウスの角膜を、記載されている通りにBALB/cマウス角膜に移植する(Sonoda et al. Invest Ophthalmol Vis Sci. 1995 Feb; 36(2): 427-34; Invest Ophthalmol Vis Sci. 2000 Mar; 41(3): 790-8; Yamagami et al. Invest Ophthalmol Vis Sci. 2001 May; 42(6): 1293-8)。移植後第7日に、縫合糸を除去する。マウスを2つのグループに分ける。グループ1はニンテダニブ0.2%溶液で処置し、グループ2はビヒクル溶液で処置する。処置は、移植後直ちに開始し、8週間の間のTIDで行う。記載されているように、8週間の間毎週、角膜の不透明性および移植片拒絶を評価する。
ニンテダニブ眼用溶液
この薬物製剤は、5.5~8.0のpH範囲の、2-ヒドロキシプロピルβシクロデキストリンまたは他の類似のシクロデキストリンおよび緩衝溶液を用いて調製された等張性眼用溶液である。この製剤の機能性を強化するために、他の粘性剤、滑沢剤、保存剤が添加され得る。この眼用溶液の組成が表2に示されている。
この薬物製剤は、5.5~8.0のpH範囲の、カルボキシメチルセルロースナトリウムおよび緩衝溶液を用いて調製された等張性眼用懸濁液である。薬物の粒子サイズは40マイクロメートル未満にされている。この製剤懸濁液の機能性を強化するために、他の粘性剤、滑沢剤、可溶化剤、および保存剤が添加され得る。その組成が表3に示されている。
この薬物製剤は、等張性眼用乳濁液である。薬物を混合油相および乳化賦形剤に溶解させ、次いでこれを乳化させ、5.5~8.0のpH範囲の水相と混合する。この乳濁液製剤の機能性を強化するために、他の粘性剤、滑沢剤、可溶化剤、および保存剤が添加され得る。その組成が表4に示されている。
この薬物製剤は、等張性持続放出半固体製剤である。薬物を、5.5~8.0のpH範囲の半固体媒体に溶解および/または懸濁させる。この持続放出半固体製剤の機能性を強化するために、他の粘性剤、滑沢剤、可溶化剤、および保存剤が添加され得る。その組成が表5に示されている。
この薬物製剤は、固体インプラントである。薬物を、1つまたは複数のポリマーと混合およびブレンドする。この薬物およびポリマーの混合物を、既定温度で溶解させ、既定の直径サイズを有するフィラメントになるよう押し出す。このフィラメント製剤を、眼組織に移植することができる既定サイズのセグメントに切断する。その組成が表6に示されている。
本発明は、その詳細な説明に関連して説明されているが、上記の説明は例示を意図したものであり、添付の特許請求の範囲によって定義される本発明の範囲を限定するものではないことが意図されていることが理解されるべきである。他の局面、利点、および改変も、添付の特許請求の範囲の範囲に包含される。
Claims (25)
- 局所用点眼液の形態またはインプラントの形態のニンテダニブまたはその薬学的に許容される塩の有効量を対象の眼に投与する工程を含む、異常な新生血管形成を伴う眼の適応症を処置するための方法。
- 前記異常な新生血管形成を伴う適応症が、高リスク患者が角膜移植を受けた後の角膜移植片拒絶である、請求項1に記載の方法。
- ニンテダニブが、前記対象の眼において異常な新生血管形成および炎症を阻害することにより移植片拒絶を予防するのに有効な量で投与される、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が移植片対宿主病である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がアトピー性結膜炎である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が眼性酒さである、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が眼類天疱瘡である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がライエル症候群である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が、ウイルス感染症、細菌感染症、真菌感染症、または寄生虫感染症により誘発される新生血管形成である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がコンタクトレンズ誘発性新生血管形成である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が潰瘍である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がアルカリによるやけどである、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が幹細胞欠乏である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が瞼裂斑である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が血管新生緑内障である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がドライアイ病である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がシェーグレン症候群である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がマイボーム腺機能不全である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症がスティーブン・ジョンソン症候群である、請求項1に記載の方法。
- 前記異常な新生血管形成を伴う適応症が眼における腫瘍である、請求項1に記載の方法。
- ニンテダニブが、局所用眼用製剤の形態または眼用インプラントの形態で投与される、請求項1に記載の方法。
- 前記眼用インプラントが、半固体または固体の持続放出インプラントの形態である、請求項21に記載の方法。
- 前記インプラントが前記対象の眼に挿入される、請求項22に記載の方法。
- 前記局所用眼用製剤が局所用点眼液である、請求項21に記載の方法。
- 前記局所用眼用製剤が、溶液、懸濁液、クリーム、軟膏、ジェル、ジェル形成液、リポソームもしくはミセルを含む懸濁液、噴霧用製剤、または乳濁液である、請求項21に記載の方法。
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US62/344,870 | 2016-06-02 | ||
JP2019515767A JP7082115B2 (ja) | 2016-06-02 | 2017-05-26 | 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 |
PCT/US2017/034795 WO2017210132A1 (en) | 2016-06-02 | 2017-05-26 | Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization |
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