JP2021502404A - 線維症の治療のための組成物および方法 - Google Patents
線維症の治療のための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、参照により本明細書に組み込まれる、2017年10月11日に申請された米国仮特許出願第62/570,847号の優先的利益を主張する。
リポソームは、10年以上にわたって医薬品開発に使用されてきた。リポソームの調製は、米国特許第6,217,899号、米国特許公開第20100021531号、Lichtenberg et al.,Methods Biochem Anal.33:337−462,1988、およびG.Gregoriadis:”Liposome Technology Liposome Preparation and Related Techniques,”2nd edition,Vol.I−III,CRC Pressに記載されている。医薬用途のためのリポソームは、Mozafari,M.,Liposomes,Methods and Protocols Vol.1,Chapter 2,V.Wessing Ed.2010,Humana Press)に開示されている。
使用方法
本明細書に記載されるリポソームまたはナノ粒子を作製する方法も提供される。
本開示のリポソームまたはナノ粒子を投与するために、様々な送達システムが使用され得る。本開示の様々な実施形態では、リポソーム組成物の投与は、静脈内点滴による。いくつかの実施形態では、投与は、30分、1時間、または2時間の静脈内点滴による。
さらなる態様として、本開示は、本開示の方法を実践するためにそれらの使用を容易にする様式でパッケージ化された1つ以上のリポソームまたはナノ粒子化合物または組成物を含むキットを含む。一実施形態では、かかるキットは、密封ボトルまたは器などの容器の中にパッケージ化された、本明細書に記載される化合物または組成物(例えば、リポソームまたはナノ粒子を単独で、または抗線維症剤と組み合わせて含む組成物)を含み、本方法の実践における化合物または組成物の使用を記載するラベルが容器に貼付されているかまたはパッケージに含まれる。好ましくは、本化合物または本組成物は、単位剤形でパッケージ化されている。キットは、特定の投与経路に従う組成物の投与のため、またはスクリーニングアッセイの実践のために好適なデバイスをさらに含んでもよい。好ましくは、キットは、リポソームまたはナノ粒子組成物の使用を記載するラベルを含む。
肝疾患のマウスモデルはいくつかあるが、ヒトの肝疾患を完全に模倣するモデルは一つもない。摂食動物モデルは、例えば、高脂肪食またはアルコールを給餌することにより、対象の動物の食餌を変更し、これは、長期にわたると硬変肝につながる。四塩化炭素(CCl4)などの肝臓毒性動物モデルは、投与した薬剤の毒性作用により肝障害を引き起こし、結果として線維症になる(Trautwein et al.,J Hepatology 62:S15−S24,2015、Popov and Schuppan,Hepatology 50:1294−1305,2009)。食餌と組み合わせるとNASHをシミュレートする遺伝的動物モデルもある。マウスモデルのいずれにおいても、線維症およびまたは脂質の無秩序の測定は、疾患の指標である。現在の療法の使用は、線維症を低減し、肝酵素を減少させる。
本発明のリポソーム療法は、人間の使用のために設計されている。この療法は、NASHおよびアルコール性硬変症を含むが、これらに限定されない肝疾患を有するヒトに有用である。疾患マーカーは、線維症の増加、Fibroscanにより測定した場合の肝臓の硬化の両方で類似している。肝生検は、肝疾患の診断にも使用される。
追加のリポソーム組成物を療法的投与のために開発した。リポソーム調合物は、2つのリン脂質、コレステロールおよびアルファ−トコフェロール(ビタミンE、VITE)、ならびに任意にポリエチレングリコール(PEG)を含む。リン脂質は、1,2ジラウリル−sn−グリセロール−3−ホスホコリン(DLPC)および1,2−ジパルミトイル−sn−グリセロール−3−ホスホコリン(DPPC)である。一実施例では、リポソームの水性内部は、0.9%の正常生理食塩水を含有する。リポソームは、以下の比率の構成成分を含有し得る:
Claims (34)
- 線維症を治療するための方法であって、それを必要とする対象に、線維症を治療するためのリポソームまたはナノ粒子中の有効量のホスファチジルコリン(PC)を投与することを含む、方法。
- 前記ホスファチジルコリンが、ポリエンホスファチジルコリン(DPPC)または16個の炭素のリン脂質テールを有するコリンヘッドである、請求項1に記載の方法。
- 前記ホスファチジルコリンが、ジリノレオイルホスファチジルコリン(DLPC)またはコリンヘッドおよび12個の炭素のリン脂質テールである、請求項1に記載の方法。
- 前記リポソームまたはナノ粒子が、抗酸化剤をさらに含む、請求項1〜3のいずれか一項に記載の方法。
- 前記抗酸化剤が、脂溶性抗酸化剤である、請求項4に記載の方法。
- 前記リポソームまたはナノ粒子が、ビタミンEをさらに含む、請求項1〜5のいずれか一項に記載の方法。
- 前記リポソームまたはナノ粒子が、新しい細胞成長を刺激し得る因子をさらに含む、請求項1〜6のいずれか一項に記載の方法。
- 前記リポソームまたはナノ粒子が、新しい細胞成長を刺激し得るタンパク質またはペプチドをさらに含む、請求項7に記載の方法。
- 前記ペプチドが、新しい細胞成長を刺激し得るGHKペプチドである、請求項7または8に記載の方法。
- 前記ホスファチジルコリンが、LHR−1およびまたはPPARアルファに結合する、請求項1〜9のいずれか一項に記載の方法。
- 前記リポソームが、新しい細胞成長を刺激し得る因子および抗酸化剤をさらに含む、請求項1〜10のいずれか一項に記載の方法。
- 前記新しい細胞成長を刺激する因子がGHKペプチドであり、前記抗酸化剤がビタミンEである、請求項10に記載の方法。
- 前記リポソームまたはナノ粒子が、コレステロールをさらに含む、請求項1〜12のいずれか一項に記載の方法。
- 前記リポソームが、注射により、経皮的に、経口的に、デポー剤を介して、または吸入により投与される、請求項1〜13のいずれか一項に記載の方法。
- 前記リポソームが、静脈内投与される、請求項14に記載の方法。
- 前記対象が、線維性疾患、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪性肝疾患(NAFLD)、肝炎、肝硬変、肺線維症、慢性閉塞性肺疾患(COPD)、または間質性肺線維症に罹患している、請求項1〜15のいずれか一項に記載の方法。
- 前記投与が、肝線維症、肝臓の脂肪含量、硬変症の発生または進行、肝細胞癌の発生、肝アミノトランスフェラーゼレベルの増加、アラニンアミノトランスフェラーゼ(ALT)レベル、アスパラギン酸アミノトランスフェラーゼ(AST)レベル、血清フェリチンの増加、ガンマ−グルタミルトランスフェラーゼ(ガンマ−GT)のレベルの上昇、ならびに血漿インスリン、コレステロール、およびトリグリセリドのレベルの上昇からなる群から選択される線維性疾患の1つ以上の症状を寛解する、請求項16に記載の方法。
- 前記対象が、NAFLDまたはNASHに罹患している、請求項16または17に記載の方法。
- 前記リポソームまたはナノ粒子が、毎週、2週間ごとに1回、3週間ごとに1回、毎月、または2ヶ月ごとに1回投与される、請求項1〜18のいずれか一項に記載の方法。
- 前記対象が、ヒトである、請求項1〜19のいずれか一項に記載の方法。
- 前記リポソームが、薬学的に許容される賦形剤、担体、または希釈剤をさらに含む、請求項1〜20のいずれか一項に記載の方法。
- リポソームまたはナノ粒子を含む組成物であって、前記リポソーム中に1〜100mg/mlの濃度で総ホスファチジルコリン(PC)を含む。
- 前記ホスファチジルコリンが、ポリエンホスファチジルコリン(DPPC)または16個の炭素のリン脂質テールを有するコリンヘッドである、請求項22に記載の組成物。
- 前記ホスファチジルコリンが、ジリノレオイルホスファチジルコリン(DLPC)またはコリンヘッドおよび12個の炭素のリン脂質テールである、請求項22に記載の組成物。
- 前記リポソームまたはナノ粒子が、抗酸化剤をさらに含む、請求項22〜24のいずれか一項に記載の組成物。
- 前記抗酸化剤が、脂溶性抗酸化剤である、請求項25に記載の組成物。
- 前記リポソームまたはナノ粒子が、ビタミンEをさらに含む、請求項22〜26のいずれか一項に記載の組成物。
- 前記リポソームまたはナノ粒子が、新しい細胞成長を刺激し得る因子をさらに含む、請求項22〜27のいずれか一項に記載の組成物。
- 前記リポソームまたはナノ粒子が、新しい細胞成長を刺激し得るタンパク質またはペプチドをさらに含む、請求項22〜28のいずれか一項に記載の組成物。
- 前記新しい細胞成長を刺激し得るペプチドが、GHKペプチドである、請求項29に記載の組成物。
- 前記新しい細胞成長を刺激する因子がGHKペプチドであり、前記抗酸化剤がビタミンEである、請求項28〜30のいずれか一項に記載の組成物。
- 前記リポソームまたはナノ粒子が、コレステロールをさらに含む、請求項22〜31のいずれか一項に記載の組成物。
- 前記DLPCが、10重量%〜50重量%組成で前記リポソーム中にある、請求項22〜32のいずれか一項に記載の組成物。
- 前記DPPCが、10重量%〜50重量%組成で前記リポソーム中にある、請求項22〜33のいずれか一項に記載の組成物。
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CN111278441A (zh) | 2020-06-12 |
AU2018347527A1 (en) | 2020-04-23 |
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