JP2022500500A - カベオリン−1ペプチドの乾燥粉末製剤およびその使用方法 - Google Patents
カベオリン−1ペプチドの乾燥粉末製剤およびその使用方法 Download PDFInfo
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Abstract
Description
本明細書で使用される場合、特定の構成要素に関して「本質的に含まない」とは、特定の構成要素が、組成物に意図的に配合され、および/または汚染物質としてのみもしくは微量で存在することを意味するために本明細書で使用される。したがって、組成物の任意の意図しない汚染に起因する特定の成分の総量は、0.01%をはるかに下回る。最も好ましいのは、具体的な構成成分の量が標準的な分析方法を用いて分析できない組成物である。
本開示の実施形態は、カベオリン−1(Cav−1)ペプチドの乾燥粉末製剤を提供する。カベオリン−1(Cav−1)足場ドメインまたはペプチドは、SrcキナーゼとのCav−1相互作用を妨げ、uPAおよび抗β1−インテグリン抗体の組み合わせ効果を模倣する。天然ヒトCav−1は、178アミノ酸の長さ、および22kDaの分子量を有する。Cav−1のアミノ酸配列(配列番号1)を以下に示す:
1〜10個の炭素原子を有するアルカノイル、例えば、アセチル、プロピオニル、ブチリル;
1〜10個の炭素原子を有するアルケノイル、例えば、ヘキサ−3−エノイル;
1〜10個の炭素原子を有するアルキノイル、例えば、ヘキサ−5−イノイル;
アロイル、例えば、ベンゾイルまたは1−ナフトイル;
ヘテロアロイル、例えば、3−ピロイルまたは4−キノロイル;
アルキルスルホニル、例えば、メタンスルホニル;
アリールスルホニル、例えば、ベンゼンスルホニルまたはスルファニリル;
ヘテロアリールスルホニル、例えば、ピリジン−4−スルホニル;
1〜10個の炭素原子を有する置換アルカノイル、例えば、4−アミノブチリル;
1〜10個の炭素原子を有する置換アルケノイル、例えば、6−ヒドロキシ−ヘキサ−3−エノイル;
1〜10個の炭素原子を有する置換アルキノイル、例えば、3−ヒドロキシ−ヘキサ−5−イノイル;
置換アロイル、例えば、4−クロロベンゾイルまたは8−ヒドロキシ−ナフト−2−オイル;
置換ヘテロアロイル、例えば、2,4−ジオキソ−1,2,3,4−テトラヒドロ−3−メチル−キナゾリン−6−オイル;
置換アルキルスルホニル、例えば、2−アミノエタンスルホニル;
置換アリールスルホニル、例えば、5−ジメチルアミノ−1−ナフタレンスルホニル;
置換ヘテロアリールスルホニル、例えば、1−メトキシ−6−イソキノリンスルホニル;
カルバモイルまたはチオカルバモイル;
置換カルバモイル(R’−NH−CO)または置換チオカルバモイル(R’−NH−CS)(式中、R’は、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、置換アルキル、置換アルケニル、置換アルキニル、置換アリール、または置換ヘテロアリールである);
置換カルバモイル(R’−NH−CO)および置換チオカルバモイル(R’−NH−CS)(式中、R’は、アルカノイル、アルケノイル、アルキノイル、アロイル、ヘテロアロイル、置換アルカノイル、置換アルケノイル、置換アルキノイル、置換アロイル、または置換ヘテロアロイルである)であり、すべて上記で定義されている通りである。
1〜10個の炭素原子を好ましくは有するアルケニル、例えば、プロプ−2−エニル;
1〜10個の炭素原子を好ましくは有するアルキニル、例えば、プロプ−2−イニル;
1〜10個の炭素原子を有する置換アルキル、例えば、ヒドロキシアルキル、アルコキシアルキル、メルカプトアルキル、アルキルチオアルキル、ハロゲノアルキル、シアノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、アルカノイルアルキル、カルボキシアルキル、カルバモイルアルキル;
1〜10個の炭素原子を有する置換アルケニル、例えば、ヒドロキシアルケニル、アルコキシアルケニル、メルカプトアルケニル、アルキルチオアルケニル、ハロゲノアルケニル、シアノアルケニル、アミノアルケニル、アルキルアミノアルケニル、ジアルキルアミノアルケニル、アルカノイルアルケニル、カルボキシアルケニル、カルバモイルアルケニル;
1〜10個の炭素原子を有する置換アルキニル、例えば、ヒドロキシアルキニル、アルコキシアルキニル、メルカプトアルキニル、アルキルチオアルキニル、ハロゲノアルキニル、シアノアルキニル、アミノアルキニル、アルキルアミノアルキニル、ジアルキルアミノアルキニル、アルカノイルアルキニル、カルボキシアルキニル、カルバモイルアルキニル;
最大10個の炭素原子を有するアロイルアルキル、例えば、フェナシルまたは2−ベンゾイルエチル;
アリール、例えば、フェニルまたは1−ナフチル;
ヘテロアリール、例えば、4−キノリル;
1〜10個の炭素原子を有するアルカノイル、例えば、アセチルまたはブチリル;
アロイル、例えば、ベンゾイル;
ヘテロアロイル、例えば、3−キノロイル;
OR’またはNR’R’’、ここで、R’およびR’’は、独立して、水素、アルキル、アリール、ヘテロアリール、アシル、アロイル、スルホニル、スルフミル、またはSO2−R’’’’もしくはSO−R’’’’であり、R’’’は、置換または非置換のアルキル、アリール、ヘテロアリール、アルケニル、またはアルキニルである。
本開示の実施形態はまた、Cav−1ペプチドの繰り返し単位から構築されたより長いポリペプチドを含む。ポリペプチド多量体は、ポリペプチドの異なる組み合わせを含み得る。かかる多量体ポリペプチドは、本明細書で論じられる化学合成または組換えDNA技術によって作製することができる。化学合成によって生成される場合、オリゴマーは、コアポリペプチド配列の2〜5回の繰り返しを有することが好ましく、多量体中のアミノ酸の総数は、約160残基を超えてはならず、好ましくは100残基(またはリンカーまたはスペーサーを含む場合、その同等物)を超えてはならない。
Cav−1ペプチドは、天然Cav−1ポリペプチドの生物学的効果を模倣するペプチド模倣化合物であり得る。ペプチド模倣剤は、天然Cav−1ポリペプチドの結合活性および生物学的活性を有するように天然Cav−1ポリペプチドの結合要素の立体空間特性を再現する、非天然ペプチドまたは非ペプチド剤であり得る。天然Cav−1ポリペプチドまたはポリペプチド多量体と同様に、ペプチド模倣物は、結合面(天然Cav−1が結合する任意のリガンドと相互作用する)および非結合面を有する。
Cav−1ペプチドは、ポリエチレングリコールなどの異種ポリペプチドセグメントまたはポリマーとコンジュゲートし得る。ポリペプチドは、酵素の流体力学的半径を増加させ、したがって、血清持続性を増加させるために、PEGに連結され得る。ポリペプチドは、外部受容体に特異的かつ安定的に結合する能力を有するリガンドなどの任意の標的化剤にコンジュゲートすることができる(米国特許公開20090304666)。
本発明の特定の実施形態は、融Cav−1ペプチドに関する。これらの分子は、N末端またはC末端で異種ドメインに結合された実施形態のポリペプチドを有し得る。例えば、融合には他の種からのリーダー配列もまた用いて、異種宿主におけるタンパク質の組み換え発現を可能にすることができる。融合タンパク質は、半減期延長因子(half−life extender)を含むことができる。別の有用な融合としては、タンパク質親和性タグ(例えば血清アルブミン親和性タグ若しくは6個のヒスチジン残基)、または、好ましくは切断可能であり、融合タンパク質の精製を促進する免疫活性ドメイン(例えば抗体エピトープ)の付加が含まれる。非限定的な親和性タグとしては、ポリヒスチジン、キチン結合タンパク質(CBP)、マルトース結合タンパク質(MBP)、およびグルタチオン−S−トランスフェラーゼ(GST)が含まれる。
特定の実施形態では、実施形態のポリペプチドは、二官能性架橋試薬を使用して化学的にコンジュゲートされ得るか、またはタンパク質レベルでペプチドリンカーと融合され得る。
さらに、特定の態様では、Cav−1ペプチドは、細胞結合ドメインまたは細胞透過性ペプチド(CPP)をさらに含み得る。本明細書で使用される場合、「細胞透過性ペプチド」および「膜移行ドメイン」という用語は、交換可能に使用され、ポリペプチドが細胞膜(例えば、真核細胞の場合は原形質膜)を通過することを可能にするポリペプチド配列のセグメントを指す。CPPセグメントの例には、HIV Tatに由来するセグメント(例えば、GRKKRRQRRRPPQ(配列番号23))、ヘルペスウイルスVP22、Drosophila Antennapedia ホメオボックス遺伝子産物、プロテグリンI、ペネトラチン(RQIKIWFQNRRMKWKK(配列番号24))、またはメリチン(GIGAVLKVLTTGLPALISWIKRKRQQ(配列番号25)が含まれるが、これらに限定されない。特定の態様では、CPPは、T1(TKIESLKEHG(配列番号26))、T2(TQIENLKEKG(配列番号27))、26(AALEALAEALEALAEALEALAEAAAA(配列番号28))、またはINF7(GLFEAIEGFIENGWEGMIEGWYGCG(配列番号29))CPP配列を含む。
本発明の一態様は、本明細書に記載のペプチド、およびその突然変異体、変異体、類似体、または誘導体の使用に関する。具体的には、これらの方法は、本明細書に記載のペプチドのうちのいずれか1つまたはその薬学的に許容される修飾を乾燥粉末として対象に投与すること、肺の疾患、損傷、または感染症(例えば、肺の線維性状態)を処置または予防することの処置に使用するための組成物に関し、該組成物は、薬学的に許容される担体中に実施形態のポリペプチドを含む。
本明細書で提供されるCav−1ペプチドは、細胞アポトーシスを阻害するため、ならびに肺組織の損傷の処置および予防のために、全身的または局所的に投与することができる。それらは、静脈内、皮下、筋肉内、髄腔内、および/または腹腔内に投与することができる。例えば、乾燥粉末製剤は、点滴注入(例えば、皮下点滴注入)によって対象に投与することができ、または注射前に液体で再構成し得る。特定の態様では、ペプチドは、乾燥粉末吸入器を使用して乾燥粉末製剤を投与するなど、気道に局所的に送達される。それらは、単独で、または抗線維化合物と組み合わせて投与することができる。
製剤の粒子サイズは、粉砕(milling)、粉砕(grinding)、薄膜凍結、噴霧乾燥、または破砕を含むがこれらに限定されない任意の好適な方法によって低下させることができる。粉砕は、エアジェット粉砕、ボール粉砕、湿式粉砕、媒体粉砕、高圧均質化、または低温粉砕など当該技術分野で既知である任意の方法によって行うことができる。
本発明のペプチドは、様々な肺の状態を処置するために使用することができる。処置のための肺の状態は、急性または慢性であり得る。急性の肺状態は、急性肺損傷、感染症、または化学物質誘発性であり得る。慢性の肺疾患は、損傷、感染症、または疾患の結果であり得る。
いくつかの態様では、対象は、急性肺損傷(ALI)もしくは感染症、または化学物質誘発性肺損傷を有する。特定の態様では、対象は、鋳型気管支炎、喘息、慢性閉塞性気道/肺(COPD)、急性呼吸窮迫症候群(ARDS)、吸入煙誘発性急性肺損傷(ISALI)、気管支拡張症、吸入毒素誘発性気道疾患(例えば、塩素または他の誘発性気道疾患)、マスタードガスへの曝露、粒子状物質(例えば、シリカダスト)への曝露、閉塞性細気管支炎、器質化肺炎を伴う閉塞性細気管支炎、コラーゲン血管肺疾患(例えば、ループス、強皮症、または混合結合組織疾患から)、間質性肺疾患(例えば、特発性肺線維症またはサルコイドーシス)、薬物誘発性肺疾患、および加速性肺線維症(例、ARDSを含む急性肺損傷後に発生する)を有する。慢性閉塞性肺疾患、喘息、感染症、ならびに線維症をもたらす急性および慢性肺損傷を含む肺疾患は、世界で3番目に多い死因を構成している(Murray et al.,1997;Rabe et al.,2007;Tsushima et al.,2009)。急性肺損傷(ALI)は、米軍人の間で深刻な医学的問題である。戦闘中のALIは、非常に幅広い病因から生じ得る。
肺疾患には、肺線維症、肺炎症、特発性肺線維症、嚢胞性線維症、慢性閉塞性肺疾患(COPD)、気管支炎、細気管支炎、閉塞性細気管支炎、喘息、および肺感染症、ならびに線維症をもたらす急性および慢性肺損傷(Murray et al.,1997;Rabe et al.,2007;Tsushima et al.,2009)が含まれる。これらの疾患は、世界で3番目に多い死因となっている。
以下の実施例は、本発明の好ましい実施形態を示すために含まれる。後に続く実施例で開示した技術は、発明者により発見された技術が、本発明の実施に際して十分機能することを示し、それ故、その実施のための好ましい方式を構成すると考えることができるということが、当業者により理解されなければならない。しかし、当業者は、本開示の観点で、開示される具体的な実施形態では、本発明の精神および範囲から逸脱することなく、同じまたは同様の結果が依然として得られる多くの変更をなし得ることを理解するべきである。
乾燥粉末ペプチドの調製。CSP7ペプチド(配列番号2)、ロット番号:AHF66//470103は、Polypeptide Laboratories(サンディエゴ,米国)によって合成された。
走査型電子顕微鏡法。CSP7のバルク粉末試料を試料トレイにスパッタリングし、圧縮窒素を吹き付けて広げた。走査型電子顕微鏡法により、試料を画像化した(図1)。SEMは、大きな粒子(>5μm)の存在を示している。さらに、ほとんどの粒子は大きい(>5μm)ようであり、したがって呼吸可能な範囲外であるようであった。
CSP7粉末の粒子サイズ低下。粉末を肺に効果的に吸入して沈着させるために、粒子サイズは、一般に、約5μm未満の空気動力学的中央粒子径を有する必要がある。ニートの材料の粒子サイズを小さくするために、エアジェット粉砕(AJM)、ボール粉砕(BM)、極低温粉砕(CM)、薄膜凍結(TFF)、および噴霧乾燥など、様々な技術を実施した。最初に、CSP7バルク粉末の粒子サイズを小さくするためにAJMを実施し、粉砕されたCSP7を粉砕機内のいくつかの位置から収集した。示された位置から収集された粉砕粉末の最初のバッチ(バッチ171013)の収率および粒子サイズ分布を表5および6に示す。粒子サイズ分布を、Sympatecレーザー回折乾式分散(表8)またはSympatecレーザー回折湿式分散(表9)によって上記のようにして決定した。
マウスにおける線維症の誘発およびCSP7処置。ブレオマイシンによる処置により、肺線維症をマウスで誘発した。マウスに0.8U/kgのブレオマイシンを鼻腔内投与し、14日間待って、処置前に疾患を発症させた。次いで、マウスを未処理のままにするか、CSP7の乾燥粉末吸入で12分間処理するか、またはCSP7の乾燥粉末吸入で60分間処理した。処置の最終日にマウスを安楽死させ、肺を取り出し、急速冷凍し、−80℃で保存した。さらなる分析の前に、瞬間冷凍された肺の重さを測った(図29)。
1.1.20mM Tris緩衝液を調製する(pH約10.3である必要がある)
2.2.1.5%(w/w)CMCを20mM Tris緩衝液に溶解し、0.2%(w/w)ポロキサマー188を添加する。約600rpmで一晩攪拌する。
3.3.0.7%(w/w)NaClをCMC溶液に添加する。
4.4.約28.5μL/mlの1N HClを添加することにより、溶液のpHを7に調整する。
5.5.特定の量のエアジェット粉砕されたCSP7粉末(小さな粒子サイズの画分を得るために収集バッグから収集されれる)を清浄なバイアル中で計量および添加する。
6.6.清浄なロッドを使用して最初に粉末を粉砕し、目視可能な凝集粒子がないことを確認する。
7.7.ロッドを用いた粉砕(milling)/粉砕(grinding)により、調製した溶液をバイアルに徐々に添加する。
8.8.粉末が完全に湿り、目視可能な凝集粒子が見出される場合、適量添加して標的体積にする。
結果
調製について:
1.1.20mM Tris緩衝液を調製する(pH約10.3である必要がある)
2.2.1.5%(w/w)CMCを20mM Tris緩衝液に溶解し、0.2%(w/w)ポロキサマー188を添加する。約600rpmで一晩攪拌する。
3.3.0.7%(w/w)NaClをCMC溶液に添加する。
4.4.1.2〜1.4mg/ml CSP7(未処理の粉末)を溶液に添加し、ボルテックスして溶解する。pHは約9である必要があり、次いで、−50μL1N HClを添加してpHを8.2〜8.5に調整する。
変異体粉末を5mg/mlの濃度で溶媒に添加し、次いで3分間ボルテックスすることにより、変異体の溶解度研究を行った。5分で溶液の外観を観察する。さらに粉末を添加し(毎回約5mg/ml)、ボルテックスを繰り返し、沈殿またはゲル化が発生するまで観察する。
結果:
ニートの(すなわち、粉砕されていない)CSP7アンモニウム対イオン形態(表35)の溶解は、過剰量のペプチド粉末を3mLの異なるpH緩衝液に添加し(表36)、オービタルシェーカー上で、100rpmで24分間混合することによって行った。
モデル00Jet−O−Mizer(商標)(Aljet millとしても既知,Fluid Energy,ペンシルベニア州テルフォード)を使用して、CSP7ペプチドを粉砕した。供給速度、押し出し圧力、および粉砕圧力は、それぞれ1g/分、60psi、70psiである(表37)。バッチサイズは20gであり、粉砕された粉末は、粉砕チャンバー後のチューブ(bfC)、サイクロン(C)、収集容器アダプター(D)、収集バッグアダプター(E)、収集バッグ(H)、および収集容器(G)を含む、ジェット粉砕の様々な区域から収集される。Turbulaミキサー(Glen Mills Inc.,Clifton,米国ニュージャージー州)を使用して、収集した粉末を10分間混合した。
参考文献
Carvalho et al.,“Influence of particle size on regional lung deposition − What evidence is there?”Int.J.Pharma.406:1−10,2011.
Huebner,R.−H.;Gitter,W.;El Mokhtari,N.E.;Mathiak,M.;Both,M.;Bolte,EL;Freitag−Wolf,S.;Bewig,B.Standardized quantification of pulmonary fibrosis in histological samples.Biotechniques,44,507−11,514−7,2008.
Surasarang et al.,“Optimization of Formulation for a Novel Inhaled Candidate Therapeutic for Idiopathic Fibrosis,”Drug Development and Industrial Pharmacy,44(2):184−198,2017.
Tepper,J.S.;Kuehl,P.J.;Cracknell,S.;Nikula,K.J.;Pei,L.;Blanchard,J.D.Symposium Summary:“breathe In,Breathe Out,Its Easy:What You Need to Know about Developing Inhaled Drugs.”Int.J.Toxicol.35,376−392,2016.
Claims (80)
- ペプチドの乾燥粉末を含む医薬組成物であって、前記ペプチドは、配列番号2〜20のうちのいずれか1つの配列を含む、医薬組成物。
- 前記ペプチドが、7〜20のアミノ酸長である、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号2のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号2のペプチドのN末端に付加された少なくとも1つのアミノ酸を含む、請求項3に記載の医薬組成物。
- 前記ペプチドが、配列番号2のペプチドのC末端に付加された少なくとも1つのアミノ酸を含む、請求項3に記載の医薬組成物。
- 前記ペプチドが、配列番号2のペプチドのN末端およびC末端に付加された少なくとも1つのアミノ酸を含む、請求項3に記載の医薬組成物。
- 前記ペプチドが、L−アミノ酸を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、D−アミノ酸を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、L−アミノ酸およびD−アミノ酸の両方を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、少なくとも1つの重水素化残基を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、少なくとも1つの非標準アミノ酸を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、2つの非標準アミノ酸を含む、請求項11に記載の医薬組成物。
- 前記非標準アミノ酸が、オルニチンである、請求項11に記載の医薬組成物。
- 前記ペプチドが、N末端修飾を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、C末端修飾を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、N末端修飾およびC末端修飾を含む、請求項1に記載の医薬組成物。
- 前記N末端修飾が、アシル化である、請求項14に記載の医薬組成物。
- 前記C末端修飾が、アミド化である、請求項15に記載の医薬組成物。
- 前記ペプチドが、配列番号3のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号4のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号6のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号9のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号5のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号7のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号8のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号11のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号12のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号13のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号14のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号15のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号16のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号17のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号18のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号19のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号10のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 前記ペプチドが、配列番号20のアミノ酸配列を含む、請求項1に記載の医薬組成物。
- 細胞透過性ペプチド(CPP)をさらに含む、請求項1に記載の医薬組成物。
- 前記CPPが、GRKKRRQRRRPPQ(配列番号23)、RQIKIWFQNRRMKWKK(配列番号24)、およびGIGAVLKVLTTGLPALISWIKRKRQQ(配列番号25)を含む群から選択されるアミノ酸配列を含む、請求項37に記載の医薬組成物。
- 前記ペプチドが、配列番号2〜20のうちのいずれか1つの配列の少なくとも2つの反復を含む、請求項1に記載の医薬組成物。
- 前記少なくとも2つの反復が、同一のアミノ酸配列を有する、請求項39に記載の医薬組成物。
- 前記少なくとも2つの反復が、異なるアミノ酸配列を有する、請求項39に記載の医薬組成物。
- 前記乾燥粉末が、粉砕プロセスによって製造される、請求項1に記載の医薬組成物。
- 前記乾燥粉末が、噴霧乾燥プロセスによって製造される、請求項1に記載の医薬組成物。
- 前記乾燥粉末が、エアジェット粉砕によって製造される、請求項1に記載の医薬組成物。
- 前記乾燥粉末が、ボール粉砕によって製造される、請求項1に記載の医薬組成物。
- 前記乾燥粉末が、湿式粉砕によって製造される、請求項1に記載の医薬組成物。
- 前記乾燥粉末が、10(重量)%未満の水を含む、請求項1に記載の医薬組成物。
- 前記乾燥粉末が、1(重量)%未満の水を含む、請求項1に記載の医薬組成物。
- 前記医薬組成物が、本質的に賦形剤を含まない、請求項1に記載の医薬組成物。
- 前記医薬組成物が、賦形剤を含まない、請求項49に記載の医薬組成物。
- 前記医薬組成物が、肺送達用に製剤化されている、請求項1に記載の医薬組成物。
- 前記医薬組成物が、乾燥粉末吸入用に製剤化されている、請求項51に記載の医薬組成物。
- 前記医薬組成物が、吸入加圧式定量吸入用に製剤化されている、請求項51に記載の医薬組成物。
- 前記医薬組成物が、経口投与用、局所投与用、または注射用に製剤化されている、請求項1に記載の医薬組成物。
- 請求項1〜51に記載の医薬組成物を含む、ネブライザーデバイス。
- 対象を治療する方法であって、前記対象に有効量の請求項1〜51に記載の医薬組成物を前記対象に投与することを含む、方法。
- 前記対象が、炎症性障害を有する、請求項56に記載の方法。
- 前記対象が、線維性状態を有する、請求項56に記載の方法。
- 前記対象が、肺炎症、急性肺傷害、肺感染症、または肺を有する、請求項56に記載の方法。
- 前記対象が、肺炎症を有する、請求項59に記載の方法。
- 前記対象が、慢性閉塞性肺障害(COPD)を有する、請求項56に記載の方法。
- 前記対象が、急性肺傷害または感染症を有する、請求項56に記載の方法。
- 前記対象が、肺感染症を有する、請求項56に記載の方法。
- 前記対象が、化学物質誘発性肺傷害を有する、請求項56に記載の方法。
- 前記対象が、鋳型気管支炎を有する、請求項56に記載の方法。
- 前記対象が、喘息を有する、請求項56に記載の方法。
- 前記対象が、急性呼吸窮迫症候群(ARDS)を有する、請求項56に記載の方法。
- 前記対象が、吸入煙誘発性急性肺傷害(ISALI)を有する、請求項56に記載の方法。
- 前記対象が、細気管支炎を有する、請求項56に記載の方法。
- 前記対象が、閉塞性細気管支炎を有する、請求項56に記載の方法。
- 前記肺疾患が、肺の線維性状態である、請求項56に記載の方法。
- 前記肺疾患が、間質性肺疾患である、請求項56に記載の方法。
- 前記肺疾患が、特発性肺線維症(IPF)または肺瘢痕化である、請求項56に記載の方法。
- 前記投与が、乾燥粉末吸入を含む、請求項56に記載の方法。
- 前記投与が、変異体ポリペプチドを含む溶液を霧化することを含む、請求項56に記載の方法。
- 少なくとも1つの追加の抗線維化治療薬を投与することをさらに含む、請求項56に記載の方法。
- 前記少なくとも1つの追加の抗線維症薬が、NSAID、ステロイド、DMARD、免疫抑制剤、生物学的応答モジュレーター、または気管支拡張剤である、請求項76に記載の方法。
- 前記対象が、ヒトである、請求項56に記載の方法。
- 呼吸可能な粒子サイズを有する、粉砕された乾燥粉末として製剤化された、配列番号2〜20のペプチドを含む、医薬組成物。
- 対象を治療する方法であって、有効量の請求項79に記載の組成物を吸入により前記対象に投与することを含む、方法。
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PCT/US2019/050349 WO2020055824A1 (en) | 2018-09-10 | 2019-09-10 | Dry powder formulation of caveolin-1 peptides and methods of use thereof |
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EP2970383B1 (en) | 2013-03-15 | 2021-04-21 | Board of Regents, The University of Texas System | Method of treating fibrosis |
CA2977519A1 (en) * | 2015-02-27 | 2016-09-01 | Board Of Regents, The University Of Texas System | Nebulized cav-1 polypeptide therapeutics and uses thereof |
AU2019339260A1 (en) | 2018-09-10 | 2021-03-25 | Lung Therapeutics, Inc. | Modified peptide fragments of Cav-1 protein and the use thereof in the treatment of fibrosis |
US20240082342A1 (en) * | 2018-11-21 | 2024-03-14 | Board Of Regents, The University Of Texas System | Peptide therapeutics for increasing lung cell viability |
EP3937966A4 (en) * | 2019-03-11 | 2022-11-30 | Lung Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR PROTECTING ALVEOLAR REPITHAL CELLS TYPE 2 (AEC2) |
US20220023204A1 (en) * | 2020-04-20 | 2022-01-27 | Board Of Regents, The University Of Texas System | Biologically active dry powder compositions and method of their manufacture and use |
WO2021216659A1 (en) * | 2020-04-21 | 2021-10-28 | Lung Therapeutics, Inc. | Modified peptide fragments of cav-1 protein and uses thereof |
EP4168031A2 (en) * | 2020-06-19 | 2023-04-26 | Lung Therapeutics, Inc. | Modified caveolin-1 peptides for the treatment of pathogen-induced lung injury |
WO2022266410A1 (en) * | 2021-06-17 | 2022-12-22 | Lung Therapeutics, Inc. | Modified caveolin-1 peptides for the treatment of post-acute covid-19 |
AU2022371643A1 (en) * | 2021-10-22 | 2024-05-02 | Lung Therapeutics, Llc | Modified caveolin-1 peptides for the treatment of chronic kidney disease |
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JP2018507867A (ja) * | 2015-02-27 | 2018-03-22 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | ポリペプチド治療及びその使用 |
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WO2020055824A1 (en) | 2020-03-19 |
EP3849581A4 (en) | 2022-07-06 |
WO2020055824A8 (en) | 2020-05-14 |
CA3109982A1 (en) | 2020-03-19 |
US20210260150A1 (en) | 2021-08-26 |
BR112021004420A2 (pt) | 2021-06-01 |
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