JP6466504B2 - 長時間の眼圧低下効果を有するアルファ−2アドレナリンアゴニスト - Google Patents
長時間の眼圧低下効果を有するアルファ−2アドレナリンアゴニスト Download PDFInfo
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- JP6466504B2 JP6466504B2 JP2017086952A JP2017086952A JP6466504B2 JP 6466504 B2 JP6466504 B2 JP 6466504B2 JP 2017086952 A JP2017086952 A JP 2017086952A JP 2017086952 A JP2017086952 A JP 2017086952A JP 6466504 B2 JP6466504 B2 JP 6466504B2
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Description
本出願は、2010年1月21日に出願された米国特許仮出願第61/296、912号の利益を主張し、この開示は、その全体が参照により本明細書中に組み込まれる。
アルファ-2アドレナリン受容体アゴニストは、眼房水形成調節および房水流出促進に重要な役割を果たす;結果として、これらの化合物は、緑内障患者の眼圧を低下させる。緑内障は一般に眼内の圧力の上昇により、視神経の損傷および視覚の消失を引き起こし得る状態である。眼圧低下のために処方されるアルファ‐2アドレナリン薬は2つしかない。一般的に酒石酸ブリモニジンとして知られ、ALPHAGAN(登録商標)Pの商標で販売される(Allergan、 Inc.より入手可能)化合物(5-ブロモ-キノキサリン-6-イル)-イミダゾリジン-2-イリデン-アミンが、現在、緑内障患者の長期間の治療に処方される。酒石酸ブリモニジンは、上昇した眼圧を低下させるのに有効ではあるが、緑内障患者の眼圧を効果的に管理するために、1日に3回の投与計画のみが認められている。高齢の緑内障患者の人口を考慮すると、1日に3回の投与頻度は、最適とは言い難く、患者コンプライアンスが悪くなり得る。
本発明の一態様において、それを必要とする患者の眼圧を低下させる方法(その方法は、治療上有効な量の4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンまたはその塩を含むか、本質的にそれからなるか、または、それからなる治療上有効な量の医薬組成物を、前記患者の患眼に単一用量として投与することを含むか、本質的にそのことからなるか、または、そのことからなる)の提供があり、患眼は、投与の時間から少なくとも8時間、好ましくは少なくとも10時間、さらに好ましくは少なくとも12時間、ベースライン眼圧より低い眼圧を維持する。
本実施例は、ブリモニジンを含む組成物と比較する際の、4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンを含む組成物の眼圧低下効果を示す。4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンの遊離塩基を滅菌蒸留水に溶解し、塩酸を添加し、化合物の塩酸塩をin situで形成させた。溶液のpHが8.0に達するまで、溶液を水酸化ナトリウムで滴定した。4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンの最終濃度は1重量%である。使用された実験用動物は正常血圧のダッチベルテッド系のオスのウサギであった。薬物製剤の一滴(50μl)を、およそ午前7時に右眼(治療される眼)にピペットで局所的に投与した。ウサギ(治療される眼および治療されない眼)の眼圧を局所的な点眼薬の単回投与0時間前、および0.5、1、2、3、4、6および8時間後に測定した。点眼薬の投与の前(0時間)にとられた眼圧をベースライン値として使用した。眼圧検査の測定の前に、0.05%のプロパラカイン(50μl)を各眼に投与した。眼圧検査の眼圧測定をMentor Pneumontonmeterで得た。加えて、すべての研究をマスクした。すべての動物を鎮静作用、眼球の刺激作用、および瞳孔径の変化について、実験の過程を通して試験した。これらの効果は化合物の高投与量で観察されなかった。従って、全身性の効果の欠如が確認された。薬物動態学的研究は、4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンの血漿レベルは低いことを示し、この化合物の全身性暴露が低いことを確認した。
本実施例は、ブリモニジンを含む組成物と比較する際の、4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンを含む組成物の眼圧低下効果を示す。4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンの遊離塩基を滅菌蒸留水に溶解し、塩酸を添加し、化合物の塩酸塩をin situで形成させた。溶液のpHが8.0に達するまで、溶液を水酸化ナトリウムで滴定した。4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンの最終濃度は0.2重量%である。使用された実験用動物は正常血圧のダッチベルテッド系のオスのウサギであった。薬物製剤の一滴(50μl)を、およそ午前7時に右眼(治療される眼)にピペットで局所的に投与した。ウサギ(治療される眼および治療されない眼)の眼圧を局所的な点眼薬の単回投与0時間前、および、2、4、6時間後に測定した。点眼薬の投与の前(0時間)にとられた眼圧をベースライン値として使用した。眼圧検査の測定の前に、0.05%のプロパラカイン(50μl)を各眼に投与した。眼圧検査の眼圧測定をMentor Pneumontonmeterで得た。加えて、すべての研究をマスクした。すべての動物を鎮静作用、眼球の刺激作用、および瞳孔径の変化について実験の過程を通して試験した。これらの効果は化合物の高投与量では観察されなかった。従って、全身性の効果の欠如が確認された。
本実施例は、眼房水中の4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンのレベルが、ブリモニジンとは異なり、延長された時間、容易に維持されることを示す薬物動態学的分析を記載する。
本実施例は、4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンが角膜上皮細胞を浸透しにくいが、ブリモニジンは中程度に浸透することを示す、角膜浸透アッセイを記載する。これらの結果は以下の表1に報告される。
本実施例は、プラセボと比較する際の、実施例1の4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンを含む組成物の眼圧低下効果を示す。結果は、図4に報告される。図4に示されるように、組成物を含む4-ブロモ-N-イミダゾリジン-2-イリデン-1-H-ベンズイミダゾール-5-アミンで治療したサルの眼圧は、24時間に至るまで、眼圧の低下を維持する。
Claims (14)
- 4-ブロモ-5-(2-イミダゾリン-2-イルアミノ)ベンズイミダゾールまたはその塩を含む医薬組成物であって、患者の患眼に1日1回又は2回、単一用量として直接注入により投与することにより、眼圧を低下し、患眼の眼圧を少なくとも6時間、ベースライン眼圧よりも低く維持するための医薬組成物。
- 患眼の眼圧を少なくとも8時間、ベースライン眼圧よりも低く維持するための、請求項1記載の医薬組成物。
- 患眼の眼圧を少なくとも10時間、ベースライン眼圧よりも低く維持するための、請求項1記載の医薬組成物。
- 患眼の眼圧を少なくとも12時間、ベースライン眼圧よりも低く維持するための、請求項1記載の医薬組成物。
- 前記組成物が0.01〜5重量%の4-ブロモ-5-(2-イミダゾリン-2-イルアミノ)ベンズイミダゾールまたはその塩を含む、請求項1記載の医薬組成物。
- 前記組成物が0.15〜1重量%の4-ブロモ-5-(2-イミダゾリン-2-イルアミノ)ベンズイミダゾールまたはその塩を含む、請求項1記載の医薬組成物。
- 前記組成物がさらに0.001〜1重量%の保存料を含む、請求項1記載の医薬組成物。
- 前記組成物がさらに0.01〜0.5重量%の保存料を含む、請求項1記載の医薬組成物。
- 前記組成物がさらに0.001〜0.01重量%の保存料を含む、請求項1記載の医薬組成物。
- 前記組成物がさらに0.01〜1重量%の補助溶媒を含む、請求項1記載の医薬組成物。
- 前記組成物がさらに0.01〜2重量%の増粘剤を含む、請求項1記載の医薬組成物。
- 4-ブロモ-5-(2-イミダゾリン-2-イルアミノ)ベンズイミダゾールが投与後、全身循環中に検出不能である、請求項1記載の医薬組成物。
- 4-ブロモ-5-(2-イミダゾリン-2-イルアミノ)ベンズイミダゾールが少なくとも10時間、眼房水に維持される、請求項1記載の医薬組成物。
- 1日に1回投与される、請求項4記載の医薬組成物。
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US20050244463A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular vasculopathies |
JP2009500409A (ja) * | 2005-06-29 | 2009-01-08 | アラーガン、インコーポレイテッド | 痛みを処置するためのα2アドレナリン作動剤 |
JP2009525970A (ja) * | 2006-02-06 | 2009-07-16 | ニコックス エス エイ | α2−アドレナリン受容体アゴニストとしてのアプラクロニジンおよびブリモドニジンのニトロオキシ含有誘導体 |
US8821870B2 (en) * | 2008-07-18 | 2014-09-02 | Allergan, Inc. | Method for treating atrophic age related macular degeneration |
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WO2011091225A2 (en) | 2011-07-28 |
JP2017125074A (ja) | 2017-07-20 |
CL2012002038A1 (es) | 2012-11-16 |
ZA201205470B (en) | 2013-05-29 |
TW201141477A (en) | 2011-12-01 |
US20110178145A1 (en) | 2011-07-21 |
IL221030A0 (en) | 2012-09-24 |
EP2525793B1 (en) | 2018-09-05 |
JP2016026206A (ja) | 2016-02-12 |
AU2011207301A1 (en) | 2012-08-09 |
MX2012008516A (es) | 2012-10-15 |
JP2013518051A (ja) | 2013-05-20 |
RU2012134065A (ru) | 2014-02-27 |
KR20120125305A (ko) | 2012-11-14 |
US9889088B2 (en) | 2018-02-13 |
EP2525793A2 (en) | 2012-11-28 |
WO2011091225A3 (en) | 2012-05-18 |
BR112012018154A2 (pt) | 2016-04-05 |
CN102770135A (zh) | 2012-11-07 |
CO6592108A2 (es) | 2013-01-02 |
CA2787573A1 (en) | 2011-07-28 |
SG182637A1 (en) | 2012-08-30 |
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