JP5681276B2 - 肺高血圧症のための治療 - Google Patents
肺高血圧症のための治療 Download PDFInfo
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- JP5681276B2 JP5681276B2 JP2013500129A JP2013500129A JP5681276B2 JP 5681276 B2 JP5681276 B2 JP 5681276B2 JP 2013500129 A JP2013500129 A JP 2013500129A JP 2013500129 A JP2013500129 A JP 2013500129A JP 5681276 B2 JP5681276 B2 JP 5681276B2
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- inhalation
- treprostinil
- oral
- therapeutic agent
- combination
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Description
本出願は、2010年3月15日に出願された、米国仮出願第61/282,659号による優先権を主張する。
上記で説明した療法において用いられるプロスタサイクリンは、エイコサノイドファミリーのいずれかのメンバーなど、当技術分野で知られる任意の種類のプロスタサイクリン(PGI2)またはその類似体でありうる。一実施形態では、プロスタサイクリンが、PAHの症状を治療するのに適する任意のプロスタサイクリンおよび/またはその類似体でありうる。例えば、プロスタサイクリンは、エポプロステノール、イロプロスト、ベラプロスト、これらのうちのいずれかの類似体、またはこれらの組合せでありうる。ベラプロストを用いて血管拡張に効果を及ぼすことができ、これにより、血圧を降下させることができる。ベラプロストはまた、血小板の凝集を阻害することも可能である。
一実施形態では、上記で説明した通り、経口剤と吸入剤との任意の組合せによる共投与を実施することができる。例えば、経口送達剤はトレプロスチニルとすることが可能であり、吸入剤は、イロプロストまたはAviptadilとすることが可能である。一実施形態では、吸入治療剤が、Tyvasoまたはその薬学的に許容される塩もしくはエステルであり、経口送達剤が、ボセンタンまたはその薬学的に許容される塩もしくはエステルである。代替的な実施形態では、吸入治療剤が、Tyvasoまたはその薬学的に許容される塩もしくはエステルであり、経口送達剤が、シルデナフィルまたはその薬学的に許容される塩もしくはエステルである。
[実施例]
動物には、U−44069(0.5mg/mL)を、10mL/kg/時間の投与速度で、15分間にわたり施し、投与1回当たりの総用量を1.25mg/kgとした。以下で詳述する通り、動物には、セッション1回当たり3〜4回の静脈内投与を施した。
1.以下の通りに動物を治療した:
2.15分間にわたる静脈内注入
3.15分間にわたる注入の後の、可能な限り迅速な経口強制投与
4.強制投与の1時間後、15分間にわたる静脈内注入
5.強制投与の2時間後、15分間にわたる静脈内注入
以下の通りに動物を治療した:
1.15分間にわたる静脈内注入
2.15分間にわたる注入の後の、可能な限り迅速な吸入曝露
3.吸入完了の約5分間後、15分間にわたる静脈内注入
4.1時間後、15分間にわたる静脈内注入
以下の通りに動物を治療した:
1.15分間にわたる静脈内注入
2.15分間にわたる注入の後の、可能な限り迅速な経口強制投与
3.経口強制投与後の、可能な限り迅速な吸入曝露。すべての動物を低用量(5.26μg/kg)に曝露した。
4.吸入完了の約5分間後、15分間にわたる静脈内注入
5.1時間後、15分間にわたる静脈内注入
6.経口強制投与の2時間後、2匹の動物(経口低用量の1匹、および経口高用量の1匹)に15分間にわたる静脈内注入
以下の数値では、個別に遠隔測定した動物についての、個別経路または組合せによるトレプロスチニル投与からの結果をまとめる。U−44069注入時の最大PAP値を、ベースライン(非治療時)PAPからの変化百分率として表す。
・動物2001を除く、報告されるすべての場合において、U−44069の静脈内投与により、PAPが、ベースラインの少なくとも150%まで上昇した。しかし、この動物についてのベースライン圧は、他の動物より著明に高いことに注意すべきである。
・吸入(5.26、10.6、または34.1μg/kg/日):すべての投与レベルで、吸入曝露後において、PAPは、ベースラインの約120%まで低下し、15分間にわたる注入において比較的安定であった。吸入曝露の1時間後における、U−44069のさらなる静脈内注射後、PAPは、投与直後(IPD)値と比較して著明に上昇した。投与後(PD)1時間で、PAPは、IPD値と比較して著明に上昇した。
・経口強制投与(投与1回当たり5、10、15mg/kg):PD 1時間およびPD 2時間のいずれの評価時点でも一般に、PAPの減少が用量依存的な形で観察された。
・組合せ投与(低用量の吸入投与(5.26μg/kg/日)+低用量(投与1回当たり5mg/kg)、中用量(投与1回当たり10mg/kg)、または高用量(投与1回当たり5mg/kg)の経口強制投与):
○群1:トレプロスチニルの組合せ投与は、1時間までの持続的効果を示したが、低用量の吸入トレプロスチニルだけを投与した場合、この効果は認められなかった。動物#1001では、U−44069がPAPの上昇に対してより大きな薬理学的効果を及ぼしたため、この動物では、PAPの持続的な低下がより明らかであり、PAPをベースライン値まで低下させるトレプロスチニルの作用もより明らかであった。
○群2:組合せ投与レジメンにおける低吸入用量(5.26μg/kg/日)は、個別の中吸入用量(10.6μg/kg/日)の半分であるが、いずれの動物についても、IPD時点におけるPAPの低下は同等以上であった。動物#2002の場合、PAP低下の増大はPD 1時間まで持続し、この低下は、個別の経口投与よりさらに大きかった。動物#2001の場合、PAPの低下は、個別の中用量吸入と比較して、IPDにおいて大きく(おそらく付加的であり)、PD 1時間においてやや小さいが、PD 1時間における経口投与単独よりやや大きかった。これは、この動物におけるばらつきのためでありうるだろう。加えて、動物#2002では、U−44069が、PAPの上昇に対してより大きな薬理学的効果を及ぼし、これにより、トレプロスチニルが、PAPをベースライン値まで低下させる作用の増大が可能となった可能性が高い。
○群3:組合せ投与レジメンにおける低吸入用量(5.26μg/kg/日)は、個別の吸入条件において投与される高用量(34.1μg/kg/日)の6分の1であるが、組合せ投与レジメンがIPD時点においてPAPを低下させる能力は、個別の高用量吸入と同等(#3001)であるか、またはこれより大きく(#3002)、この効果は、PD 1時間まで持続した。動物#3002では、U−44069が、組合せ投与時のPAPの上昇に対してより大きな薬理学的効果を及ぼし、これにより、トレプロスチニルが、IPD時点において、PAPをより良好に低下させることが可能となった。
○組合せ投与の場合はまた、吸入を介するトレプロスチニルの効果が良好であるが、経口強制投与を介するトレプロスチニルの効果はそれほど良好でなかった動物(#1001および#2002)が、吸入療法時のPD 1時間において、持続的効果をより良好に示すことが可能であった。より洗練された用量範囲発見研究(PAP測定値に用量および時点を対応させる研究)は、この観察をよりよく理解する一助となるであろう。
以下に、本願の当初の特許請求の範囲に記載された発明を付記する。
[1] 肺高血圧症を治療する方法であって、それを必要とする被験体に、薬学的有効量の、肺高血圧症を治療するための経口治療剤と、薬学的有効量の、肺高血圧症を治療するための吸入治療剤とを共投与するステップを含む方法。
[2] 経口治療剤が、トレプロスチニルまたはその薬学的に許容される塩もしくはエステルである、[1]に記載の方法。
[3] 吸入治療剤が、トレプロスチニルまたはその薬学的に許容される塩もしくはエステルである、[2]に記載の方法。
[4] 被験体がヒトである、[3]に記載の方法。
[5] 吸入治療剤が、Tyvasoまたはその薬学的に許容される塩もしくはエステルである、[1]に記載の方法。
[6] 経口治療剤が、ボセンタンまたはその薬学的に許容される塩もしくはエステル、シルデナフィルまたはその薬学的に許容される塩もしくはエステル、あるいはベラプロストまたはその薬学的に許容される塩もしくはエステルである、[1]に記載の方法。
[7] 皮下送達また静脈内送達を介して投与される肺高血圧症治療の副作用を軽減する方法であって、それを必要とする被験体に、薬学的有効量の、肺高血圧症を治療するための経口治療剤と、薬学的有効量の、肺高血圧症を治療するための吸入治療剤とを共投与するステップを含む方法。
[8] 副作用が、全身性低血圧、感染症、血栓症、注入部位疼痛、死亡を結果としてもたらす突発的な注入の中断、脚部疼痛、またはこれらの組合せを含む、[5]に記載の方法。
[9] 共投与が、肺高血圧症の経口治療剤または吸入治療剤を単独で用いる療法と比較して、肺高血圧症のための非経口療法の開始までの時間を遅延させる、[4]に記載の方法。
Claims (4)
- 薬学的有効量の肺高血圧症を治療するための経口治療剤と、薬学的有効量の肺高血圧症を治療するための吸入治療剤とを含む、被験体において肺高血圧症を治療するための組合せ医薬であって、
前記経口治療剤と前記吸入治療剤とは共投与され、
前記経口治療剤が、トレプロスチニルまたはその薬学的に許容される塩もしくはエステルであり、
前記吸入治療剤が、トレプロスチニルまたはその薬学的に許容される塩もしくはエステルである
組合せ医薬。 - 前記被験体がヒトである、請求項1に記載の組合せ医薬。
- 前記組合せ医薬が、肺高血圧症の経口治療剤または吸入治療剤を単独で用いる療法と比較して、肺高血圧症のための皮下投与または静脈内投与による治療の開始までの時間を遅延させる、請求項2に記載の組合せ医薬。
- 前記経口治療剤がトレプロスチニルのジエタノールアミン塩であり、前記吸入治療剤がトレプロスチニルのナトリウム塩である請求項1に記載の組合せ医薬。
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US20090036465A1 (en) | 2006-10-18 | 2009-02-05 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
WO2008098196A1 (en) * | 2007-02-09 | 2008-08-14 | United Therapeutics Corporation | Treprostinil treatment for interstitial lung disease and asthma |
CA2698721A1 (en) | 2007-09-07 | 2009-03-12 | United Therapeutics Corporation | Buffer solutions having selective bactericidal activity against gram negative bacteria and methods of using same |
CA2723540C (en) | 2008-05-08 | 2016-01-05 | United Therapeutics Corporation | Treprostinil monohydrate |
CN102164487A (zh) | 2008-09-25 | 2011-08-24 | 阿拉迪姆公司 | 曲前列素的深肺部递送 |
KR101544246B1 (ko) | 2009-05-07 | 2015-08-12 | 유나이티드 세러퓨틱스 코오포레이션 | 프로스타시클린 유사체의 고체 제제 |
EP2547341B1 (en) | 2010-03-15 | 2016-09-14 | United Therapeutics Corporation | Treatment for pulmonary hypertension |
US20120010159A1 (en) | 2010-07-09 | 2012-01-12 | United Therapeutics Corporation | Combination therapies with cox-2 inhibitors and treprostinil |
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US20110224236A1 (en) | 2011-09-15 |
KR20160132501A (ko) | 2016-11-18 |
WO2011115922A1 (en) | 2011-09-22 |
JP2018135383A (ja) | 2018-08-30 |
US8609728B2 (en) | 2013-12-17 |
CA2892104C (en) | 2016-08-30 |
ES2790859T3 (es) | 2020-10-29 |
US20130253049A1 (en) | 2013-09-26 |
CN102883722A (zh) | 2013-01-16 |
KR20130038835A (ko) | 2013-04-18 |
EP2547341B1 (en) | 2016-09-14 |
EP3108888A1 (en) | 2016-12-28 |
JP2016153413A (ja) | 2016-08-25 |
CA2791081A1 (en) | 2011-09-22 |
EP3108888B1 (en) | 2020-02-12 |
CN102883722B (zh) | 2014-11-05 |
KR101508047B1 (ko) | 2015-04-06 |
JP2015129129A (ja) | 2015-07-16 |
US8969409B2 (en) | 2015-03-03 |
EP2547341A1 (en) | 2013-01-23 |
CA2892104A1 (en) | 2011-09-22 |
KR20150027846A (ko) | 2015-03-12 |
JP2013522303A (ja) | 2013-06-13 |
ES2611187T3 (es) | 2017-05-05 |
CA2791081C (en) | 2015-08-25 |
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