JP6099609B2 - 肺炎症を低減するためのレボフロキサシンの吸入 - Google Patents
肺炎症を低減するためのレボフロキサシンの吸入 Download PDFInfo
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- JP6099609B2 JP6099609B2 JP2014208156A JP2014208156A JP6099609B2 JP 6099609 B2 JP6099609 B2 JP 6099609B2 JP 2014208156 A JP2014208156 A JP 2014208156A JP 2014208156 A JP2014208156 A JP 2014208156A JP 6099609 B2 JP6099609 B2 JP 6099609B2
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- levofloxacin
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Description
本出願は、2008年10月7日に出願された「Topical Use of Levofloxacin for Reducing Lung Inflammation」と題する米国仮出願第61/103,496号の優先権を主張し、これは参照により全体として本明細書に援用される。
(Blau Hら、Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2007; 292: L343〜352頁;およびDonnarumma Gら、Anti-inflammatory effects of moxifloxacin and human beta-defensin 2 association in human lung epithelial cell line (A549) stimulated with lipopolysaccharide. Peptides 2007; 28: 2286〜2292頁、参照により全体として援用される)。それらの細胞におけるIL-6およびIL-8産生は、CFおよびCOPD患者の肺液において高濃度で存在するTNFαによってまたは細菌LPSによって強力に誘導され得る(Sagel SDら、Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc 2007; 4: 406〜417頁、参照により全体として援用される)。IL-6およびIL-8はともに、CF肺における炎症応答の制御に非常に重要であり、後者は好中球の走化性を誘導する最も高い潜在能力を有する(Strieter RM. Interleukin-8: a very important chemokine of the human airway epithelium. Am J Physiol Lung Cell Mol Physiol 2002; 283: L688〜689頁、参照により全体として援用される)。レボフロキサシンは、培養されたヒト気道上皮細胞において、TNFαおよびLPSによって誘導されたIL-6およびIL-8レベルの投薬量に依存した低減を生じさせることが発見された。また、レボフロキサシンは、ヒト単球細胞にお
いて、LPSによって誘導されたIL-1β、IL-6およびIL-8の産生を低減する。さらに、レボフロキサシンはインビボにおいてIL-6およびIL-8の産生を低減する。
用語「投与」または「投与すること」とは、ある投薬量の抗炎症医薬組成物を脊椎動物に与える方法を意味する。投与の好ましい方法は、様々な因子、例えば、医薬組成物の成分、炎症の部位、および実際の炎症の重症度に依存して変化させることができる。
ある種の実施形態では、炎症を患っている動物を二価または三価の陽イオンを配合し、肺で有効性を改善したフルオロキノロン抗炎症薬を用いて治療することによって、具体的には哺乳動物を含む動物における炎症を治療するための方法が提供される。ある種の実施形態では、エアロゾル形成および吸入に続けて、フルオロキノロン抗炎症薬を投与しもよい。したがって、この治療の方法は、高い非経口投薬レベル(望ましくない副作用を引き起こす可能性がある)の必要性により、またはいずれの臨床的に有効な抗炎症薬の欠如により、非経口で送達される抗炎症薬を用いて治療することが困難である肺炎症の治療に特に適している。このような1つの実施形態では、この方法は、フルオロキノロン抗炎症薬を炎症の部位に直接投与するために用いられてもよい。このような方法は、全身曝露を低減することができ、炎症の部位への抗炎症薬の量を最大にすることができる。
タメタゾン、クロロプレドニゾン、シクレソニド、クロベタゾール、クロベタゾン、クロコルトロン、クロプレドノール、コルチコステロン、コルチゾン、コルチバゾール、デフラザコルト、デスシクレソニド、デソニド、デスオキシメタゾン、デキサメタゾン、ジフロラゾン、ジフルコルトロン、ジフルプレドナート、エノキソロン、フルアザコルト、フククロロニド、フルメタゾン、フルニソリド、フルオシノロンアセトニド、フルオシノニド、フルオコルチンブチル、フルオコルトロン、フルオロメトロン、フルペロロンアセテート、フルプレドニデンアセテート、フルプレドニゾロン、フルランドレノリド、フルチカゾンプロピオネート、ホルモコータル、ハルシノニド、ハロベタゾールプロピオネート、ハロメタゾン、ハロプレドンアセテート、ヒドロコルタメート、ヒドロコルチゾン、ロテプレドノールエタボネート、マジプレドン、メドリゾン、メプレドニゾン、メチルプレドニソロン、モメタゾンフロエート、パラメタゾン、プレドニカルベート、プレドニゾロン、プレドニゾロン25-ジエチルアミノアセテート、プレドニゾロンリン酸ナトリウム、プレドニゾン、プレドニバル、プレドニリデン、リメキソロン、チクソコルトール、トリアムシノロン、トリアムシノロンアセトニド、トリアムシノロンベネトニド、トリアムシノロンヘキサセトニド、任意のそれらの誘導体、類似体、ならびにそれらの組合せが挙げられる。非ステロイド性抗炎症薬の例には、COX阻害剤(COX-1またはCOX非特異的阻害剤)(例えば、サリチル酸誘導体、アスピリン、サリチル酸ナトリウム、トリサリチル酸コリンマグネシウム、サルサレート、ジフルニサル、スルファサラジンおよびオルサラジン;パラ-アミノフェノール誘導体、例えば、アセトアミノフェン;インドールおよびインデン酢酸、例えば、インドメタシンおよびスリンダク;ヘテロアリール酢酸、例えば、トルメチン、ジクロフェナクおよびケトロラク;アリールプロピオン酸、例えば、イブプロフェン、ナプロキセン、フルビプロフェン、ケトプロフェン、フェノプロフェンおよびオキサプロジン;アントラニル酸(フェナメート)、例えば、メフェナム酸およびメロキシカム;エノール酸、例えば、オキシカム(ピロキシカム、メロキシカム)およびアルカノン、例えば、ナブメトン)および選択的COX-2阻害剤(例えば、ジアリール置換フラノン、例えば、ロフェコキシブ;ジアリール置換ピラゾール、例えば、セレコキシブ;インドール酢酸、例えば、エトドラク、およびスルホンアニリド、例えば、ニメスリド)が挙げられる。
本明細書に記載される方法の目的で、二価または三価の陽イオンを配合し、肺での有効性を改善したフルオロキノロン抗炎症薬は、吸入器を用いて投与されてもよい。ある種の実施形態では、本明細書に開示されたフルオロキノロン抗炎症薬は、エアロゾル形成、良好な風味、保存安定性、ならびに患者の安全性および耐容性に適した医薬組成物として製造される。ある種の実施形態では、製造されたフルオロキノロンのアイソフォーム含量は、耐容性、抗炎症活性および安定性について最適化されてもよい。
二価または三価の陽イオンを配合し、肺での有効性を改善したフルオロキノロン抗炎症薬は、治療的有効投薬量、例えば、前述の疾患状態に対する治療をもたらすのに十分な投薬量で投与されてもよい。投与される活性化合物の量は、当然に、治療されるべき対象および疾患状態、炎症の重症度、投与の方法およびスケジュール、処方医師の判断に依存する;例えば、レボフロキサシンのエアロゾル投与のための可能な投薬量範囲は、約20〜300mg/日であり、活性薬剤は、それぞれ長期または短期の肺の半減期のために選択される。ある種の実施形態では、レボフロキサシンのエアロゾル投与のための可能な投薬量範囲は約20〜300mgのBID(1日2回)である。
肺投与について、上気道は、中気道および下気道に有利になるように避けられる。肺の薬剤送達は、口腔および咽喉を通してエアロゾルの吸入によって達成されてもよい。一般に、約5ミクロンより大きい空気動力学的中央粒子径(MMAD)を有する粒子は肺に到達しない;その代わりに、この粒子は咽喉背面に衝突し、飲み込まれ、恐らくは経口吸収される傾向にある。約2〜約5ミクロンの直径を有する粒子は、上部から中部の肺領域(誘導気道)に到達するのに十分小さいが、肺胞に到達するには大き過ぎる。より小さい粒子、すなわち、約0.5〜約2ミクロンの粒子は、肺胞領域に到達することができる。また、約0.5ミクロンよりも小さい直径を有する粒子は、堆積によって肺胞領域に沈着され得るが、非常に小さい粒子は吐き出されることがある。
本明細書に記載された方法および組成物のある種の実施形態は、炎症に関連した特定の障害および疾患の治療に関する。特定の実施形態では、炎症は、肺もしくは上気道の急性または慢性炎症であってもよい。本明細書で使用するとき、「肺炎症」とは、呼吸器の少なくとも一部、例えば、肺および上気道の急性または慢性炎症を意味し得る。肺炎症に関連したこのような障害および疾患の例には、喘息、嚢胞性線維症、肺線維症、慢性気管支炎、気管支拡張症、慢性肉芽腫症、静脈洞炎、慢性閉塞性肺疾患、および肺炎が含まれ得る。
(実施例1)
IL-6およびIL-8の産生に対する低濃度のレボフロキサシン、シプロフロキサシンおよびモキシフロキサシンのインビトロ活性
NL20細胞およびHBE135細胞は、気道上皮のある種の特徴を保持する不死化されたヒト気道上皮細胞であり、他の抗生物質の免疫調節作用を特徴付けるために幅広く使用されている(Blau Hら、Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2007; 292: L343〜352頁;およびDonnarumma Gら、Anti-inflammatory effects of moxifloxacin and human beta-defensin 2 association in human lung epithelial cell line (A549) stimulated with lipopolysaccharide. Peptides 2007; 28: 2286〜2292頁、参照により全体として援用される)。NL20細胞およびHBE135細胞におけるIL-6およびIL-8の産生は、それぞれ緑膿菌(Pseudomonas aeruginosa)由来のTNFαまたはリポ多糖(LPS)の添加によって誘導された。サイトカインレベルに対する抗生物質の効果をELISAアッセイによって評価した。
レボフロキサシン、シプロフロキサシンおよびモキシフロキサシンのインビトロにおける細胞毒性
NL20細胞株およびHBE135細胞株に対するレボフロキサシン、モキシフロキサシンおよびシプロフロキサシンの細胞毒性をAlamar Blueアッセイを用いて測定した。抗生物質を用いて48時間のインキュベーション後、5%のAlamar Blue色素を含む新鮮な増殖培地中で細胞をインキュベートし、0時間目と4時間目で蛍光を記録し、抗生物質の細胞毒性を評価した。より高いレボフロキサシン濃度は、モキシフロキサシンおよびシプロフロキサシンと比較して、NL20細胞またはHBE135細胞のいずれかに対する細胞毒性が小さかった(図3Aおよび3B)。モキシフロキサシンおよびシプロフロキサシンは、NL20細胞に対して300μg/mlで有意に細胞毒性を示した。
IL-6およびIL-8の産生に対するレボフロキサシンのインビトロ活性
TNFαにより誘導されたNL20細胞およびLPSにより誘導されたHBE135細胞は、300μg/mlのレボフロキサシン、またはMgCl2が配合された300μg/mlのレボフロキサシンを用いて処理された。IL-6およびIL-8レベルのそれぞれ約10倍および5倍の低減が、300μg/mlのレボフロキサシン、またはMgCl2が配合された300μg/mlのレボフロキサシンを用いて処理されたNL20細胞において観察された(図4Aおよび4B)。さらに、IL-6およびIL-8レベルの低減が、300μg/mlのレボフロキサシン、またはMgCl2が配合された300μg/mlのレボフロキサシンを用いて処理されたHBE細胞において観察された(図4Cおよび4D)。レボフロキサシン、およびMgCl2が配合されたレボフロキサシンは、インビトロにおいて類似した活性を有した。
レボフロキサシンおよびトブラマイシンのインビトロ活性
TNFαにより誘導されたNL20細胞およびLPSにより誘導されたHBE135細胞を10〜300μg/mlのレボフロキサシン、またはトブラマイシンにより処理した。いずれの処理間でも細胞毒性アッセイにおける細胞生存性に有意な変化が観察されなかった(データ示さず)。
ヒト単球細胞におけるレボフロキサシンのインビトロ活性
ヒト単球細胞株のTHP-1は、ヒト単球細胞の確立されたインビトロモデルであり、NL20細胞およびHBE135細胞と比較して、非常に様々なサイトカインを分泌することができる。10%FBS、0.05mMの2-メルカプトエタノールを含むRPMI-1640培地中でTHP-1細胞を培養した。血清を含まない増殖培地中で1×106個の細胞/mlでTHP-1細胞を24ウェル組織培養プレート上に播種した。翌日、緑膿菌由来の100ng/mlのLPSおよび抗生物質を添加し、培地を回収する前に24時間、細胞をインキュベートし、その後、サイトカイン産生を評価した。IL-6、IL-8、IL-1βおよびTNFα産生の定量化は、NL20細胞について上記の通りに行われた。
IL-8のmRNA発現に対するレボフロキサシンのインビトロ活性
ヒト単球細胞株のTHP-1は、ヒト単球細胞の確立されたインビトロモデルであり、NL20細胞およびHBE135細胞と比較して、非常に様々なサイトカインを分泌することができる。NL20単層におけるIL-8のmRNA発現は、10ng/mlのTNFαによる処理によって誘導された。レボフロキサシンをTNFαと同時に添加した。24時間のインキュベーション後、細胞の単層をPBSで洗浄し、全細胞のmRNAを調製し、ヒトIL-8に特異的なプライマーおよびAmbion社(テキサス州オースティン)の「Cells-to-cDNA」キットを用いて逆転写を行った。PowerSYBR Green PCRマスタミックスおよびGeneAmp 5700機器(Applied Biosystems社;ウォリントン、英国)を用いてcDNAをリアルタイムPCR分析に供した。全てのデータは、ハウスキーピング遺伝子のβ-アクチンに対して標準化された。TNFαによるNL-20細胞の刺激は、IL-8のmRNAレベルの統計学的に有意に(p<0.005)20倍の増加を生じさせた(図8)。この増加は、TNFαによって誘導されたIL-8タンパク質の増加レベルと相関している。100μg/mlおよび300μg/mlのレボフロキサシンの添加は、IL-8のmRNA発現のレベルに有意な効果を与えなかった(図4)。これらの結果は、レボフロキサシンが、タンパク質翻訳および/またはタンパク質分泌を含むプロセスを調節することによってIL-8分泌タンパク質のレベルを低減することを示唆している。
NFκB活性に対するレボフロキサシンのインビトロ活性
NFκBおよびAP-1は、ある種の炎症性サイトカインの転写活性における重要な調節因子である。この実施例は、NFκBの転写調節活性に対するレボフロキサシンの効果に関する。
MgCl2を配合したレボフロキサシンのインビボ抗炎症活性
マウス(n=4)に50μgのLPSを腹腔内経路によって注射した。LPS処理の30分後、60mg/kgの生理食塩水対照、MgCl2を配合したレボフロキサシン、またはトブラマイシンを含むマイクロスプレーエアロゾルデバイス(フィラデルフィア州ペンセンチュリー)を用いてマウスを処理した。エアロゾル化された処理の6時間後にマウスを屠殺し、1mlの生理食塩水を用いた洗浄により気管支肺胞洗浄(BAL)液を回収した。IL-6およびMIP-2(ヒトIL-8のマウスホモログ)レベルをELISAによって決定した。
CF患者におけるMgCl2を配合したレボフロキサシンの抗炎症活性
急性または慢性の肺炎症を患っているCF患者は、MgCl2を配合したエアロゾルレボフロキサシンが投与される。処置後、急性炎症の低減が観察される。炎症性サイトカインのレベルの低減が観察される。肺におけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。痰および/またはBALにおけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。
COPD患者におけるMgCl2を配合したレボフロキサシンの抗炎症活性
急性または慢性の肺炎症を患っているCOPD患者は、MgCl2を配合したエアロゾルレボフロキサシンが投与される。処置後、急性炎症の低減が観察される。炎症性サイトカインのレベルの低減が観察される。肺におけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。痰および/またはBALにおけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。
慢性気管支炎患者におけるMgCl2を配合したレボフロキサシンの抗炎症活性
急性または慢性の肺炎症を患っている慢性気管支炎患者は、MgCl2を配合したエアロゾルレボフロキサシンが投与される。処置後、急性炎症の低減が観察される。炎症性サイトカインのレベルの低減が観察される。肺におけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。痰および/またはBALにおけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。
気管支拡張症患者におけるMgCl2を配合したレボフロキサシンの抗炎症活性
急性または慢性の肺炎症を患っている気管支拡張症の患者は、MgCl2を配合したエアロゾルレボフロキサシンが投与される。処置後、急性炎症の低減が観察される。炎症性サイトカインのレベルの低減が観察される。肺におけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。痰および/またはBALにおけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。
非CF気管支拡張症患者におけるMgCl2を配合したレボフロキサシンの抗炎症活性
急性または慢性の肺炎症を患っている非CF気管支拡張症の患者は、MgCl2を配合したエアロゾルレボフロキサシンが投与される。処置後、急性炎症の低減が観察される。炎症性サイトカインのレベルの低減が観察される。肺におけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。痰および/またはBALにおけるIL-1β、IL-6、およびIL-8のレベルの低減が観察される。
する。
Claims (34)
炎症性サイトカインがIL-1β、IL-6およびIL-8から選択され、
前記溶液が、90mg/ml〜110mg/mlのレボフロキサシン、175mM〜225mMの塩化マグネシウムを含み、300mOsmol/kg〜500mOsmol/kgのオスモル濃度、及び5〜8のpHを有する、エアロゾル。
前記溶液が、90mg/ml〜110mg/mlのレボフロキサシン、175mM〜225mMの塩化マグネシウムを含み、300mOsmol/kg〜500mOsmol/kgのオスモル濃度、及び5〜8のpHを有する、エアロゾル。
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US10987357B2 (en) | 2005-05-18 | 2021-04-27 | Horizon Orphan, LLC | Aerosolized fluoroquinolones and uses thereof |
JP2017025106A (ja) * | 2008-10-07 | 2017-02-02 | ラプター・ファーマシューティカルズ・インコーポレーテッド | 肺炎症を低減するためのレボフロキサシンの吸入 |
US10149854B2 (en) | 2008-10-07 | 2018-12-11 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US10722519B2 (en) | 2008-10-07 | 2020-07-28 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US11020481B2 (en) | 2008-10-07 | 2021-06-01 | Horizon Orphan Llc | Topical use of levofloxacin for reducing lung inflammation |
US10231975B2 (en) | 2009-09-04 | 2019-03-19 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US10792289B2 (en) | 2009-09-04 | 2020-10-06 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
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WO2010042549A1 (en) | 2010-04-15 |
US11020481B2 (en) | 2021-06-01 |
HUE050147T2 (hu) | 2020-11-30 |
US20140105985A1 (en) | 2014-04-17 |
US20100087386A1 (en) | 2010-04-08 |
EP2346509A1 (en) | 2011-07-27 |
HRP20201150T1 (hr) | 2021-01-22 |
SI2346509T1 (sl) | 2020-08-31 |
PL2346509T3 (pl) | 2021-03-08 |
PT2346509T (pt) | 2020-08-05 |
US20180085462A1 (en) | 2018-03-29 |
CN102325532A (zh) | 2012-01-18 |
EP2346509B1 (en) | 2020-05-13 |
DK2346509T3 (da) | 2020-08-03 |
US8629139B2 (en) | 2014-01-14 |
CA2739893C (en) | 2016-10-04 |
CN102325532B (zh) | 2015-06-17 |
IL212189A0 (en) | 2011-06-30 |
JP2015044825A (ja) | 2015-03-12 |
JP2012505222A (ja) | 2012-03-01 |
JP2014159461A (ja) | 2014-09-04 |
HRP20201150T8 (hr) | 2021-06-25 |
ES2809177T3 (es) | 2021-03-03 |
CA2739893A1 (en) | 2010-04-15 |
US20220080047A1 (en) | 2022-03-17 |
JP2017025106A (ja) | 2017-02-02 |
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