JP5877787B2 - 嚢胞性線維症の治療のための組成物 - Google Patents
嚢胞性線維症の治療のための組成物 Download PDFInfo
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- JP5877787B2 JP5877787B2 JP2012523343A JP2012523343A JP5877787B2 JP 5877787 B2 JP5877787 B2 JP 5877787B2 JP 2012523343 A JP2012523343 A JP 2012523343A JP 2012523343 A JP2012523343 A JP 2012523343A JP 5877787 B2 JP5877787 B2 JP 5877787B2
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Description
本発明の課題は、プロスタサイクリンまたはそれらの類似物、誘導体または製剤学的に認容性の塩を含む組成物を、嚢胞性繊維症の予防または治療において使用するために提供することによって解決される。
意外なことに、本発明者らは、プロスタサイクリン、またはそれらの類似物または誘導体または製剤学的に認容性の塩を、嚢胞性繊維症の治療のために使用できることを見出した。合成のプロスタサイクリン類似物は、例えば、限定されずに、トレプロスチニル、イロプロスト、シカプロストまたはベラプロストであってよい。
実施例1:
IB3−1細胞を、6ウェルプレート(0.2*106細胞/ウェル)上、完全増殖培地内で平板培養した(LHC−8 +5% FCS)。次の日、アデニンヌクレオチドプールを代謝的に、[3H]アデニン(1μCi/ウェル)を用い、アデノシンデアミナーゼ(1ユニット/ml)を含有するダルベッコ変法イーグル培地(DMEM)中で4時間、培養によって標識付けした。環状AMPの形成を、20μMのフォルスコリンまたはPGI2−類似物トレプロスチニル(リモジュリン(登録商標))によって刺激した。その評価を、3重に行った。
IB3−1細胞は、突然変異されたCFTR−ΔF508のみを内因的に発現し、それは細胞内で保持される。適切な処置(例えば薬理学的シャペロンまたは低温培養)を使用して、突然変異CFTR−ΔF508を小胞体からERに転座することが可能であり、細胞表面で挿入された際、Cl−コンダクタンスはcAMPを高めることによって刺激され得る。しかしながら生じるCl−コンダクタンスは小さい。トレプロスチニルによって誘導されるcAMPの蓄積がCFTRの活性化へと変換されることを明確に証明するために、我々は野生型CFTRのGFP標識バージョンを一過的に発現した (該GFP標識は、細胞表面でタンパク質を発現する細胞の同定を可能にした)。図2からわかるように、トレプロスチニルは−40mVの保持電位から+60mVへと、脱分極によって誘導される電流の強い活性化を引き起こした。最大の効果は遅延した、即ち、それは化合物のウォッシュイン後、数秒で観察されただけであった。同様に、ターンオフ反応におけるヒステリシスもあり、電流はウォッシュアウト後、〜100秒だけで基底へと減衰した。それらの遅延した応答は、(i) 介在シグナルカスケード(即ち、受容体に依存するGsの活性化、cAMP形成のGαsに依存する活性化、および次のタンパク質キナーゼAに依存するCFTRのリン酸化反応)および(ii) ホスホジエステラーゼによる、増加されたcAMPの失活の遅延を反映する。細胞がフォルスコリン、アデニリルシクラーゼの直接の活性化剤(ポジティブコントロールとして使用された)で刺激された場合も、類似の遅延が見られた。それらの観察は、トレプロスチニルが気管支上皮細胞内でCFTRを活性化できることを証明する。
電気生理学
ホールセルパッチクランプ技術を使用して、22±1.5℃で、Axoclamp 200Bパッチクランプ用増幅器(Axon Instruments)を使用して電流の記録を行った。ピペットは、記録ピペット溶液(組成: 110mM CsCl、5mM EGTA、2mM MgCl2、1mM K2-ATP、10mM Hepes、pH CsOHを用いて7.2に調整)で充填された際、1〜2MΩの抵抗を有した。電圧固定プロトコルおよびデータ取得を、pclamp 6.0ソフトウェア(Axon Instruments)を用いて実施した。データは、2kHz(−3dB)で低域フィルタをかけられ、そして10〜20kHzでデジタル化された。細胞を連続的に外部溶液で潅流した(組成: 145mM NaCl、4.5mM KCl、2mM CaCl2、1mM MgCl2、5mM グルコース、10mM Hepes、pH NaOHを用いて7.4に調整)。指定される場合、外部溶液はトレプロスチニル(10μM)またはフォルスコリン(5μM)を含有し、溶液の切り替えは電子制御圧力バルブによって達成された。
I3B−1細胞を、フィブロネクチン(10μg/mL)、ラットコラーゲンI(30μg/mL)、およびBSA(10μg/mL) (5%のウシ胎児血清(FCS)を含有するLHC−8培地(Gibco)内)で被覆された皿(Nunc、3.5cm 直径)の上で増殖させた。製造元の指示書に従って、細胞を、ヒトのGFP標識野生型CFTRの発現を駆り立てるプラスミドで、Lipofectamine plus(登録商標)(Invitrogen)を使用して一過的にトランスフェクションした。
Claims (10)
- 嚢胞性線維症の予防または治療において使用するための、トレプロスチニルまたはその製剤学的に認容性の塩を含む組成物。
- 静脈内投与のための、請求項1に記載の組成物。
- 吸入のための、請求項1に記載の組成物。
- 前記組成物が、錠剤またはカプセルの群から選択される経口的に利用可能な形態である、請求項1に記載の組成物。
- 効果的な量のトレプロスチニルまたはその製剤学的に認容性の塩が、少なくとも1.0ng/体重1kg/分である、請求項1に記載の組成物。
- (i) 効果的な量のトレプロスチニルまたはその製剤学的に認容性の塩、(ii) 1つまたはそれより多くの製剤学的に認容性の担体および/または添加剤、および(iii) 嚢胞性線維症の治療または予防において使用するための指示書を含む、嚢胞性線維症の予防または治療用キット。
- 成分(i)が、トレプロスチニルの製剤学的に認容性の塩である、請求項6に記載のキット。
- 成分(i)が、静脈内投与のために適した形態である、請求項6または7に記載のキット。
- 成分(i)が、吸入のために適した形態である、請求項6または7に記載のキット。
- 成分(i)が、経口投与のために適した形態である、請求項6または7に記載のキット。
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SI2672957T1 (sl) * | 2011-02-07 | 2017-03-31 | Scipharm Sarl | Nova sestava za zdravljenje cistične fibroze |
JP6542128B2 (ja) | 2013-01-11 | 2019-07-10 | コルセア ファーマ インコーポレイテッド | トレプロスチニルのプロドラッグ |
US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
ES2754388T3 (es) | 2013-03-15 | 2020-04-17 | Mannkind Corp | Composiciones y métodos de dicetopiperazina microcristalina |
BR122019026637B1 (pt) | 2013-07-18 | 2023-09-26 | Mannkind Corporation | Formulações farmacêuticas de pó seco e método para a fabricação de uma formulação de pó seco |
CA2927788C (en) | 2013-10-25 | 2022-09-06 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
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US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
WO2017192993A1 (en) | 2016-05-05 | 2017-11-09 | Liquidia Technologies, Inc. | Dry powder treprostinil for the treatment of pulmonary hypertension |
EP3515430A1 (en) | 2016-09-26 | 2019-07-31 | United Therapeutics Corporation | Treprostinil prodrugs |
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EP4017588A1 (en) | 2019-08-23 | 2022-06-29 | United Therapeutics Corporation | Treprostinil prodrugs |
CN115916212A (zh) | 2020-04-17 | 2023-04-04 | 联合治疗公司 | 曲前列尼尔用于治疗间质性肺病 |
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US20010006979A1 (en) * | 1998-07-08 | 2001-07-05 | Richard Stratton | Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives |
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