JP7471606B2 - 肺の炎症および線維症を予防または治療する方法 - Google Patents
肺の炎症および線維症を予防または治療する方法 Download PDFInfo
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Description
ASCIIテキストファイルとして提出した配列表を引用により本書の一部とする。
本開示は、対象に処置有効量の酸化セリウムナノ粒子(「CeO2ナノ粒子」、「ナノセリア」または「CNP」とも称する)を肺投与用製剤として投与することによって、対象における肺の疾患または状態を処置する、そのリスクを低減する、それを予防する、またはその症状を軽減する方法を提供する。本開示の製剤中のCNPは、遺伝子発現の転写後調節に関与する短いノンコーディングRNA分子であるマイクロRNA(miRまたはmiRNA)を含みうる。miRはいくつかのレベルで炎症反応を調節する。特に、miR-146a(配列ugagaacugaauuccauggguuを有する配列番号1)は、炎症反応に対する「分子ブレーキ」として作用する。
本開示は、処置を必要とする対象の肺に酸化セリウムナノ粒子製剤を投与することによって、肺の疾患または状態を治療する、そのリスクを低減する、それを予防する、またはその症状を軽減する方法、肺の炎症を軽減または抑制する方法、および肺の修復を促進する方法に関する。
本書に記載するCNP組成物、例えばCNP-146aを含む製剤は、さまざまな肺の疾患または状態を処置する、そのリスクを低減する、それを予防する、またはその症状を軽減するために適当である。肺の疾患または状態は、身体において肺または肺系に負の影響を及ぼすものである。理論による限定を意図するものではないが、本開示のCNP組成物は活性酸素種スカベンジャーであり、速やかに上皮細胞に取り込まれて、肺の透過性を低下し、および/または循環から炎症組織への白血球もしくはfibrocyteの移動を抑制する。CNP組成物はまた、肺胞レベルで細胞生存および細胞再生を改善しうる。
本開示のCNP組成物、例えばCNP-146aは、医薬製剤として投与しうる。本開示のCNP化合物および薬学的に許容しうる賦形剤を、典型的には、対象への肺または鼻投与に適した投与形態に製剤化しうる。例えば、投与形態は、エアロゾル、溶液および乾燥粉末といった吸入に適するものを包含しうる。
早産に起因する気管支肺異形成症および慢性肺疾患は、早産児の罹病および死亡の大きな原因である。気管支肺異形成症の原因の中核は、線維症をもたらす慢性の炎症である。炎症に加えて、顕著な酸化ストレスも存在する。本発明者は、炎症および酸化ストレスを標的とするCNP医薬が、そのような乳児の線維症および長期の後遺症を軽減することができるかを調べた。活性酸素種スカベンジャーであり、速やかに上皮細胞に取り込まれるので、酸化セリウムナノ粒子にマイクロRNA-146aをコンジュゲートした(CNP-146a)。本発明者は、肺の炎症およびそれに続く線維症の防止および/または軽減に対するCNP-146aの効果を調べるために、ブレオマイシン損傷時およびそれから所定の期間後の両方で、CNP-146aの気管内デリバリーを開始した。
[項1]
処置有効量の酸化セリウムナノ粒子(CNP)を対象に投与することを含む、対象における肺の疾患または状態を処置する、そのリスクを低減する、それを予防する、またはそれを軽減する方法。
[項2]
CNPが処置剤を含む、上記項1に記載の方法。
[項3]
処置剤が抗炎症剤である、上記項1または2に記載の方法。
[項4]
処置剤がマイクロRNA(miRNA)である、上記項1または2に記載の方法。
[項5]
miRNAがmiRNA-146aである、上記項1~4のいずれかに記載の方法。
[項6]
miRNAがCNPに、共有結合により結合されている、上記項4または5に記載の方法。
[項7]
miRNAがCNPと、共有結合によらずに会合されている、上記項4または5に記載の方法。
[項8]
肺の疾患または状態が、肺の炎症、肺線維症、閉塞性肺疾患(COPD)、肺気腫、喘息、特発性肺線維症、肺炎、結核、嚢胞性線維症、気管支炎、肺高血圧症(例えば、特発性肺動脈性肺高血圧症(IPAH))、間質性肺疾患、および肺がんから選択される、上記項1~7のいずれかに記載の方法。
[項9]
肺の疾患または状態が、肺の炎症、肺線維症、COPD、肺気腫、喘息、肺線維症、および嚢胞性線維症から選択される、上記項8に記載の方法。
[項10]
肺の疾患または状態が、炎症、自己免疫疾患、強皮症、関節リウマチ、急性肺損傷(ALI)、急性呼吸窮迫症候群(ARDS)、肺塞栓、うっ血性心不全、心臓弁膜症、長時間にわたる血中の低酸素レベル、薬剤、または物質の乱用によって引き起こされるものである、上記項1~7のいずれかに記載の方法。
[項11]
肺の疾患または状態が、炎症によって引き起こされるものである、上記項10に記載の方法。
[項12]
miRNA-146aと結合したCNPを処置有効量で必要とする対象の肺に投与することを含む、対象における肺の炎症を軽減または抑制する方法。
[項13]
miRNA-146aと結合したCNPを処置有効量で必要とする対象の肺に投与することを含む、対象における肺の修復を促進する方法。
[項14]
対象がヒトである、上記項1~13のいずれかに記載の方法。
[項15]
CNPが吸入により投与される、上記項1~14のいずれかに記載の方法。
[項16]
CNPがエアロゾル製剤として投与される、上記項1~15のいずれかに記載の方法。
[項17]
CNPが定量吸入剤として投与される、上記項1~15のいずれかに記載の方法。
[項18]
CNPがネブライザーから投与される、上記項1~15のいずれかに記載の方法。
[項19]
CNPが、吸入による肺への局所送達のための乾燥粉末組成物としてされる、上記項1~15のいずれかに記載の方法。
[項20]
CNPが、レザバ乾燥粉末吸入器(RDPI)、多用量乾燥粉末吸入器(MDPI)、または定量吸入器(MDI)から投与される、上記項1~15のいずれかに記載の方法。
[項21]
CNPが、プレコンプレッションポンプから対象の鼻腔に投与される、上記項1~15のいずれかに記載の方法。
[項22]
CNPが、鼻内スプレーとして投与される、上記項1~15のいずれかに記載の方法。
上に記載したさまざまな特徴およびプロセスは、互いに独立して使用しうる、またはさまざまに組み合わせうる。すべての可能なコンビネーションおよびサブコンビネーションを本開示の範囲に含むことが意図される。さらに、ある方法またはプロセスのブロックが、いくつかの実施形態において省略されうる。本書に記載される方法およびプロセスはまた、特定の順序に限定されず、それに関連するブロックまたは状態は他の適当な順序で実行することができる。例えば、記載されるブロックもしくは状態は、具体的に開示されるのとは異なる順序で実行されてよく、または複数のブロックもしくは状態は単一のブロックもしくは状態に組み合わされてよい。例示のブロックまたは状態は、連続して、並行して、または他のいくつかの様式で実行されうる。ブロックまたは状態は、開示される例示態様に追加され、またはそれから除外されうる。本書に記載される例示の系および成分は、記載されるのとは異なるように構成されうる。例えば、開示される例示態様に要素を追加し、もしくはそれから要素を削除し、またはそれとは異なるように要素を配置しうる。
Claims (15)
- miRNA-146aを含む酸化セリウムナノ粒子(CNP)を含む、対象における肺の疾患または状態を処置する、そのリスクを低減する、それを予防する、またはそれを軽減するための医薬組成物。
- miRNA-146aがCNPに、共有結合により結合されている、または共有結合によらずに会合されている、請求項1に記載の医薬組成物。
- 肺の疾患または状態が、肺の炎症、肺線維症、閉塞性肺疾患(COPD)、肺気腫、喘息、特発性肺線維症、肺炎、結核、嚢胞性線維症、気管支炎、肺高血圧症(例えば、特発性肺動脈性肺高血圧症(IPAH))、間質性肺疾患、および肺がんから選択される、請求項1または2に記載の医薬組成物。
- 肺の疾患または状態が、肺の炎症、肺線維症、COPD、肺気腫、喘息、肺線維症、および嚢胞性線維症から選択される、請求項3に記載の医薬組成物。
- 肺の疾患または状態が、炎症、自己免疫疾患、強皮症、関節リウマチ、急性肺損傷(ALI)、急性呼吸窮迫症候群(ARDS)、肺塞栓、うっ血性心不全、心臓弁膜症、長時間にわたる血中の低酸素レベル、薬剤、または物質の乱用によって引き起こされるものである、請求項1または2に記載の医薬組成物。
- 肺の疾患または状態が、炎症によって引き起こされるものである、請求項1~5のいずれかに記載の医薬組成物。
- miRNA-146aを含むCNPを含み、対象の肺に投与される、対象における肺の炎症を軽減または抑制するための医薬組成物。
- miRNA-146aを含むCNPを含み、対象の肺に投与される、対象における肺の修復を促進するための医薬組成物。
- 対象がヒトである、請求項1~8のいずれかに記載の医薬組成物。
- 吸入により投与される、請求項1~9のいずれかに記載の医薬組成物。
- エアロゾル製剤、鼻内スプレー、または乾燥粉末の形態である、請求項1~10のいずれかに記載の医薬組成物。
- レザバ乾燥粉末吸入器(RDPI)、多用量乾燥粉末吸入器(MDPI)、ネブライザー、プレコンプレッションポンプまたは定量吸入器(MDI)から投与される、請求項1~11のいずれかに記載の医薬組成物。
- miRNA-146aがCNPに、共有結合により結合されている、請求項1~12のいずれかに記載の医薬組成物。
- miRNA-146aがCNPに、共有結合によらずに会合されている、請求項1~12のいずれかに記載の医薬組成物。
- 鼻内スプレーの形態である、請求項1~14のいずれかに記載の医薬組成物。
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PCT/US2019/053418 WO2020069292A1 (en) | 2018-09-28 | 2019-09-27 | Methods for preventing and treating pulmonary inflammation and fibrosis |
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WO2013151698A1 (en) | 2012-04-04 | 2013-10-10 | Duke University | Methods for using cerium oxide nanoparticles to mitigate or protect against radiation injury |
WO2017091700A1 (en) | 2015-11-25 | 2017-06-01 | The Regents Of The University Of Colorado, A Body Corporate | Use of microrna-146a and nanoceria conjugate to improve wound healing and promote tissue regeneration |
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WO2013151698A1 (en) | 2012-04-04 | 2013-10-10 | Duke University | Methods for using cerium oxide nanoparticles to mitigate or protect against radiation injury |
WO2017091700A1 (en) | 2015-11-25 | 2017-06-01 | The Regents Of The University Of Colorado, A Body Corporate | Use of microrna-146a and nanoceria conjugate to improve wound healing and promote tissue regeneration |
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International Journal of Nanomedicine,2013年,Vol.8,p.4507-4520 |
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