JP2017137289A - 嚢胞性線維症のためのフルオロキノロン製剤 - Google Patents
嚢胞性線維症のためのフルオロキノロン製剤 Download PDFInfo
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- JP2017137289A JP2017137289A JP2016152940A JP2016152940A JP2017137289A JP 2017137289 A JP2017137289 A JP 2017137289A JP 2016152940 A JP2016152940 A JP 2016152940A JP 2016152940 A JP2016152940 A JP 2016152940A JP 2017137289 A JP2017137289 A JP 2017137289A
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Abstract
Description
「患者」は、哺乳動物、好ましくは、ヒトを指す。いくつかの実施形態において、ヒトは、成人である。いくつかの実施形態において、ヒトは、青年である。いくつかの実施形態において、ヒトは、子供である。いくつかの実施形態において、ヒトは、幼児である。いくつかの実施形態において、患者は、嚢胞性線維症を有し、好ましくは、嚢胞性線維症を有するヒトである。
本明細書に記載される方法のために、フルオロキノロン吸入溶液、レボフロキサシン吸入溶液およびオフロキサシン吸入溶液は、吸入器を用いて投与されてもよい。ある実施形態において、フルオロキノロン(レボフロキサシンおよびオフロキサシンを含む)は、エアロゾル生成に適しており、良好な味と貯蔵安定性、患者の安全性および認容性に適した医薬組成物として作られる。ある実施形態において、製造されるフルオロキノロンのアイソフォーム内容物は、認容性、抗菌活性および安定性について最適化されてもよい。
肺投与のために、上気道は避けられ、中部および下側の軌道が好まれる。肺への薬物送達は、口および喉を介するエアロゾルの吸入によって達成されてもよい。空気力学的直径の質量中央値(MMAD)が約5ミクロンより大きな粒子は、一般的に、肺に到達しないその代わりに、喉の裏側に衝突する傾向があり、飲み込まれ、おそらく経口吸収される。直径が約2〜約5ミクロンの粒子は、上側から中部の肺領域(誘導気道)に到達するのに十分に小さいが、肺胞に到達するには大きすぎる。もっと小さな粒子(すなわち、約0.5〜約2ミクロン)は、肺胞領域に到達することができる。直径が約0.5ミクロンより小さな粒子は、沈降によって肺胞領域に堆積することもあるが、非常に小さな粒子は、吐き出される場合もある。
本明細書に記載される方法および吸入溶液を、肺感染および障害を治療するために使用することができる。このような障害の例としては、慢性気管支炎およびある種の喘息を含め、嚢胞性線維症、肺炎および慢性閉塞性肺疾患が挙げられる。いくつかの実施形態において、障害は、嚢胞性線維症である。ある実施形態は、Pseudomonas aeruginosa、Pseudomonas fluorescens、Pseudomonas acidovorans、Pseudomonas alcaligenes、Pseudomonas putida、Stenotrophomonas maltophilia、Aeromonas hydrophilia、Escherichia coli、Citrobacter freundii、Salmonella typhimurium、Salmonella typhi、Salmonella paratyphi、Salmonella enteritidis、Shigella dysenteriae、Shigella flexneri、Shigella sonnei、Enterobacter cloacae、Enterobacter aerogenes、Klebsiella pneumoniae、Klebsiella oxytoca、Serratia marcescens、Morganella morganii、Proteus mirabilis、Proteus vulgaris、Providencia alcalifaciens、Providencia rettgeri、Providencia stuartii、Acinetobacter calcoaceticus、Acinetobacter haemolyticus、Yersinia enterocolitica、Yersinia pestis、Yersinia pseudotuberculosis、Yersinia intermedia、Bordetella pertussis、Bordetella parapertussis、Bordetella bronchiseptica、Haemophilus influenzae、Haemophilus parainfluenzae、Haemophilus haemolyticus、Haemophilus parahaemolyticus、Haemophilus ducreyi、Pasteurella multocida、Pasteurella haemolytica、Helicobacter pylori、Campylobacter fetus、Campylobacter jejuni、Campylobacter coli、Borrelia burgdorferi、Vibrio cholera、Vibrio parahaemolyticus、Legionella pneumophila、Listeria monocytogenes、Neisseria gonorrhoeae、Neisseria meningitidis、Burkholderia cepacia、Francisella tularensis、KingellaおよびMoraxellaからなる群から選択される1つ以上の細菌を含む感染を治療することを含む。いくつかの実施形態において、感染は、Pseudomonas感染である。いくつかの実施形態において、感染は、Pseudomonas aeruginosa、Pseudomonas fluorescens、Pseudomonas acidovorans、Pseudomonas alcaligenesまたはPseudomonas putidaである。いくつかの実施形態において、感染は、Pseudomonas aeruginosaである。
肺憎悪は、嚢胞性線維症を有するヒトの中で重要な事象であり、将来の肺憎悪および肺の機能悪化にとって顕著なリスク因子である。レボフロキサシン吸入溶液は、トブラマイシン吸入溶液を28日間用いて3サイクル、治療の間に28日の休息を設けた非盲検試験で評価された。ここで、本願発明者らは、医療関係者に報告された肺憎悪を前年に経験した(前年の肺憎悪)患者の数によって階層化された、肺憎悪を経験し、抗生物質で治療された患者の比率を記載する。この実施例において、「レボフロキサシン吸入溶液」は、約100mg/mlのレボフロキサシンと約200mMの塩化マグネシウムとを含有する溶液のエアロゾルを指す。
この試験は、無作為二重盲検プラセボ対照試験であった。適格な患者を無作為に2:1に分け、レボフロキサシン吸入溶液240mg(100mg/mlのレボフロキサシンと塩化マグネシウムを2.4mL)を1日に2回、または0.9%生理食塩水によるプラセボ(リボフラビンで色を合わせた)のいずれかを用いた28日間の治療、その後、28日間の治療をしないフォローアップ期間を受けさせた。レボフロキサシン吸入溶液またはプラセボを、PARI治験用eFlow(登録商標)ネブライザで送達した。
レボフロキサシン吸入溶液は、3回のオン/オフサイクルの168日間の試験がトブラマイシン吸入溶液より臨床的に劣っていないことを示した後に、EMAによって承認された。レボフロキサシン吸入溶液の使用期間を延ばすことへの関心は、レボフロキサシンに感受性のPseudomonas aeruginosa単離物における有病率の減少の可能性である。本願発明者らは、レボフロキサシン吸入溶液(N=189)およびトブラマイシン吸入溶液(N=93)被験者について、ベースラインおよび試験終了時での気道細菌培養物およびPseudomonas aeruginosa単離物の抗菌剤感受性を記載する。この実施例において、「レボフロキサシン吸入溶液」は、約100mg/mlのレボフロキサシンと約200mMの塩化マグネシウムとを含有する溶液のエアロゾルを指す。
Gibson et al,American Journal of Respiratory & Critical Care Medicine,168:918〜951(2003);Hoiby et al,Scand J Respir Dis,58:65〜79(1977);Courtney et al,Pediatr Pulmonol,42:525〜532(2007);Kerem et al,Eur Respir J,43:125〜133(2014);Doring et al,J Cyst Fibros,11:461〜479(2012);Mogayzel et al,Am J Respir Crit Care Med,187:680〜689(2013);Ramsey et al,New England Journal of Medicine,340:23〜30(1999);VanDevanter et al,Med Devices(Auckl),4:179〜188(2011);Assael et al,J Cyst Fibros,12:130〜140(2013);Konstan et al,J Cyst Fibrosis,10:54〜61(2011);Schuster et al,Thorax,68:344〜350(2013);VanDevanter et al,Respir Med,105 Suppl 2:S18〜23(2011);Geller et al,Antimicrob Agents Chemother,55:2636〜2640(2011);Hankinson et al,Am J Respir Crit Care Med,159:179〜187(1999);Fuchs et al,New England Journal of Medicine,331:637〜642(1994);Konstan et al,J Cyst Fibros,13:148〜155(2014);Quittner et al,Chest,128:2347〜2354(2005);Geller et al,Am J Respir Crit Care Med,183:1510〜1516(2011);Elborn et al,J Cyst Fibros,14(4):507〜514(2015);Burns et al,Journal of Infectious Diseases,179:1190〜1196(1999);McCourt et al,J Cyst Fibros,14:90〜96(2015);VanDevanter et al,Pediatr Pulmonol,49:356(2014);VanDevanter et al,J Cyst Fibros,14(6):763〜769(2015);VanDevanter et al,Journal of Cystic Fibrosis,15(3):372〜379(2016);Block et al,Thorax,61:969〜974(2006)。
Claims (62)
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、Pseudomonas aeruginosa肺感染を治療することが必要な高リスク嚢胞性線維症患者においてPseudomonas aeruginosa肺感染を治療するための方法。
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発生を減らすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発生を減らすための方法。
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発症までの時間を延ばすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発症までの時間を延ばすための方法。
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺細菌感染を治療することが必要な高リスク嚢胞性線維症患者において肺細菌感染を治療するための方法。
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪を治療することが必要な高リスク嚢胞性線維症患者において肺憎悪を治療するための方法。
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、嚢胞性線維症を治療することが必要な高リスク嚢胞性線維症患者において嚢胞性線維症を治療するための方法。
- 治療上有効な量のレボフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、唾液のPseudomonas aeruginosa密度を減らすことが必要な高リスク嚢胞性線維症患者において唾液のPseudomonas aeruginosa密度を減らすための方法。
- 前記高リスク患者が、前年に少なくとも3回肺憎悪を発生したものである、請求項1〜7のいずれか一項に記載の方法。
- 前記高リスク患者が、前年に少なくとも4回肺憎悪を発生したものである、請求項1〜7のいずれか一項に記載の方法。
- 前記高リスク患者が、前年に少なくとも5回肺憎悪を発生したものである、請求項1〜7のいずれか一項に記載の方法。
- 前記肺憎悪が、(i)唾液の変化;(ii)新しい喀血または喀血の増加;(iii)咳の増加;(iv)呼吸困難の増加;(v)不快感、疲労感または無気力;(vi)38℃以上の体温;(vii)食欲不振または体重減少;(viii)副鼻腔痛または圧痛;(ix)洞排泄物の変化;(x)胸部の身体検査での変化;(xi)以前記録した値からの10%以上の肺機能低下;および(xii)肺感染の指標となるレントゲン写真の変化のうち少なくとも4つを含む、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記肺憎悪が肺細菌感染である、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記肺憎悪がPseudomonas aeruginosa肺感染である、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記肺憎悪がPseudomonas肺感染である、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記肺憎悪がStaphylococcus aureus肺感染である、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記肺憎悪がStaphylococcus肺感染である、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記肺憎悪が、Hankinson/NHANES III参照式を用いた予測値のFEV1の10%以上の低下である、請求項2、3、5および8〜10のいずれか一項に記載の方法。
- 前記高リスク患者が、1秒間の努力呼気肺活量(FEV1)について、Hankinson/NHANES III参照式を用いた予測値の25〜85%を示すものである、請求項1〜17のいずれか一項に記載の方法。
- 前記高リスク患者が、Pseudomonas aeruginosaによる慢性気道感染にかかっており、前年にトブラマイシン製剤の28日間の吸入を少なくとも3回受けている、請求項1〜17のいずれか一項に記載の方法。
- 前記高リスク患者が、Pseudomonas aeruginosaによる慢性気道感染にかかっており、前年にアミノグリコシド製剤、モノバクタム製剤、ポリミキシン製剤、またはこれら2つ以上の製剤の組み合わせの28日間の吸入を少なくとも3回受けている、請求項1〜17のいずれか一項に記載の方法。
- 前記溶液が、レボフロキサシンまたはオフロキサシンと、二価カチオンまたは三価カチオンとを含む、請求項1〜20のいずれか一項に記載の方法。
- 前記三価カチオンがアルミニウムまたは鉄である、請求項21に記載の方法。
- 前記溶液が、レボフロキサシンと二価カチオンとを含む、請求項1〜20のいずれか一項に記載の方法。
- 前記二価カチオンが、マグネシウム、カルシウム、亜鉛、銅または鉄である、請求項23に記載の方法。
- 前記二価カチオンがマグネシウムである、請求項23に記載の方法。
- 前記溶液が、約75mg/ml〜約150mg/mlのレボフロキサシンと、約150mM〜約250mMの二価カチオンとを含む、請求項1〜20のいずれか一項に記載の方法。
- 前記二価カチオンが、マグネシウム、カルシウム、亜鉛、銅または鉄である、請求項26に記載の方法。
- 前記二価カチオンがマグネシウムである、請求項26に記載の方法。
- 前記溶液が、約90mg/ml〜約110mg/mlのレボフロキサシンと、約190mM〜約210mMの二価カチオンとを含む、請求項1〜20のいずれか一項に記載の方法。
- 前記二価カチオンが、マグネシウム、カルシウム、亜鉛、銅または鉄である、請求項29に記載の方法。
- 前記二価カチオンがマグネシウムである、請求項29に記載の方法。
- 前記溶液が、約80mg/ml〜約120mg/mlのレボフロキサシンと、約180mM〜約220mMの二価カチオンとを含む、請求項1〜20のいずれか一項に記載の方法。
- 前記二価カチオンが、マグネシウム、カルシウム、亜鉛、銅または鉄である、請求項32に記載の方法。
- 前記二価カチオンがマグネシウムである、請求項32に記載の方法。
- 前記溶液が、約100mg/mlのレボフロキサシンと、約200mMの塩化マグネシウムとを含む、請求項1〜20のいずれか一項に記載の方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、Pseudomonas aeruginosa肺感染を治療することが必要な高リスク嚢胞性線維症患者においてPseudomonas aeruginosa肺感染を治療するための方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発生を減らすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発生を減らすための方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発症までの時間を延ばすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発症までの時間を延ばすための方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺細菌感染を治療することが必要な高リスク嚢胞性線維症患者において肺細菌感染を治療するための方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪を治療することが必要な高リスク嚢胞性線維症患者において肺憎悪を治療するための方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、嚢胞性線維症を治療することが必要な高リスク嚢胞性線維症患者において嚢胞性線維症を治療するための方法。
- 治療上有効な量のオフロキサシンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、唾液のPseudomonas aeruginosa密度を減らすことが必要な高リスク嚢胞性線維症患者において唾液のPseudomonas aeruginosa密度を減らすための方法。
- 前記高リスク患者が、前年に少なくとも3回肺憎悪を発生したものである、請求項36〜42のいずれか一項に記載の方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、Pseudomonas aeruginosa肺感染を治療することが必要な高リスク嚢胞性線維症患者においてPseudomonas aeruginosa肺感染を治療するための方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発生を減らすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発生を減らすための方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発症までの時間を延ばすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発症までの時間を延ばすための方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、唾液のPseudomonas aeruginosa密度を減らすことが必要な高リスク嚢胞性線維症患者において唾液のPseudomonas aeruginosa密度を減らすための方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺細菌感染を治療することが必要な高リスク嚢胞性線維症患者において肺細菌感染を治療するための方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、肺憎悪を治療することが必要な高リスク嚢胞性線維症患者において肺憎悪を治療するための方法。
- 治療上有効な量のフルオロキノロンを含む溶液のエアロゾルを高リスク嚢胞性線維症患者に投与することを含む、嚢胞性線維症を治療することが必要な高リスク嚢胞性線維症患者において嚢胞性線維症を治療するための方法。
- 前記フルオロキノロンが、シプロフロキサシン、エノキサシン、ガチフロキサシン、ゲミフロキサシン、ロメフロキサシン、モキシフロキサシン、ノルフロキサシン、ペフロキサシン、スパルフロキサシン、ガレノキサシン、シタグロキサシン(sitagloxacin)またはDX−619である、請求項44〜50のいずれか一項に記載の方法。
- 前記高リスク患者が、前年に少なくとも3回肺憎悪を発生したものである、請求項44〜50のいずれか一項に記載の方法。
- 治療上有効な量の抗生物質を含む医薬組成物を高リスク嚢胞性線維症患者に投与することを含む、Pseudomonas aeruginosa肺感染を治療することが必要な高リスク嚢胞性線維症患者においてPseudomonas aeruginosa肺感染を治療するための方法。
- 治療上有効な量の抗生物質を含む医薬組成物を高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発生を減らすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発生を減らすための方法。
- 治療上有効な量の抗生物質を含む医薬組成物を高リスク嚢胞性線維症患者に投与することを含む、肺憎悪の発症までの時間を延ばすことが必要な高リスク嚢胞性線維症患者において肺憎悪の発症までの時間を延ばすための方法。
- 治療上有効な量の抗生物質を含む医薬組成物を高リスク嚢胞性線維症患者に投与することを含む、肺細菌感染を治療することが必要な高リスク嚢胞性線維症患者において肺細菌感染を治療するための方法。
- 治療上有効な量の抗生物質を含む医薬組成物を高リスク嚢胞性線維症患者に投与することを含む、肺憎悪を治療することが必要な高リスク嚢胞性線維症患者において肺憎悪を治療するための方法。
- 治療上有効な量の抗生物質を含む医薬組成物を高リスク嚢胞性線維症患者に投与することを含む、嚢胞性線維症を治療することが必要な高リスク嚢胞性線維症患者において嚢胞性線維症を治療するための方法。
- 前記高リスク患者が、前年に少なくとも3回肺憎悪を発生したものである、請求項53〜58のいずれか一項に記載の方法。
- 前記抗生物質がトブラマイシンである、請求項53〜59のいずれか一項に記載の方法。
- 前記抗生物質がアズトレオナムである、請求項53〜59のいずれか一項に記載の方法。
- 前記アズトレオナムが、アズトレオナムリジンである、請求項61に記載の方法。
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