CN100346777C - 包括罗氟斯特和福莫特罗的新的协同组合 - Google Patents
包括罗氟斯特和福莫特罗的新的协同组合 Download PDFInfo
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- CN100346777C CN100346777C CNB2003801037450A CN200380103745A CN100346777C CN 100346777 C CN100346777 C CN 100346777C CN B2003801037450 A CNB2003801037450 A CN B2003801037450A CN 200380103745 A CN200380103745 A CN 200380103745A CN 100346777 C CN100346777 C CN 100346777C
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本发明涉及罗氟斯特和福莫特罗的组合给药，用于治疗呼吸道疾病。
Description
技术领域
本发明涉及某些已知的用于治疗学目的的活性化合物的组合。本发明的组合中所用物质为已知的PDE抑制剂类活性化合物和β2肾上腺素能受体激动剂类活性化合物。在现有技术中还没有描述过它们在本发明的治疗目的意义上的组合应用。
背景技术
国际专利申请WO01/13953(美国专利6,624,181)描述了PDE抑制剂类的化合物与β2肾上腺素能受体激动剂类的化合物的组合用于治疗呼吸道疾病。-美国专利6,288,118总地描述了通过给药磷酸二酯酶-4抑制剂与β-肾上腺素能支气管扩张药治疗肺病，如慢性阻塞性肺病或哮喘。-在Current Opinion in Investigational Drugs，2002，3(8)：1165-1170中，详细地描述了PDE4-抑制剂罗氟斯特(roflumilast)。在国际专利申请WO98/35683中，描述了包含肺表面活性剂和罗氟斯特的组合物。-在综述Expert Opin.Ther.Patents(2002)12(1)：53-63中，分析了1998年1月到2001年8月期间与支气管扩张药有关的专利文献，并命名了不同物质类别的示例性化合物，特别是PDE4-抑制剂罗氟斯特。-在EurRespir J，1999，13：1103-1108中，描述了福莫特罗(formoterol)对可逆性明显较差的COPD的作用。-在国际专利申请WO02/066422和WO02/076933中，公开了某些新的β2肾上腺素能受体激动剂及其在呼吸道疾病中的应用。在国际专利申请WO00/67741中公开了福莫特罗的纯(S，R)异构体及其应用。-在国际专利申请WO02/088167中描述了某些雄甾烷衍生物及其与β2肾上腺素能受体激动剂的组合。
发明概述
本发明涉及用于预防或降低肺病症状的发作、或治疗或降低肺病的严重程度的组合物和方法。具体地，本发明涉及通过将PDE4抑制剂与另一种影响肺机能的药学活性药物一起给药，治疗由磷酸二酯酶4(PDE4)介导的肺病的组合物和方法。因此，本发明的目的是获得满足以下条件的呼吸道治疗剂：
-显著的抗炎作用
-显著的支气管松弛和支气管扩张
-至少相对于PDE4抑制剂的良好的口服利用度，
-较小的副作用
-良好的长期治疗适应性
-对支气管过度反应的有利作用。
现在已经发现，PDE4抑制剂罗氟斯特和β2肾上腺素能受体激动剂福莫特罗的组合应用显著地满足上述条件，特别是考虑到两种化合物的组合协同发挥作用的实际情况，即，该组合的效应大于各自相加的效应。
因此，本发明的第一方面涉及通过对需要治疗的患者给予有效量的罗氟斯特和福莫特罗，用于预防或减少肺病症状的发作、或治疗或降低肺病严重程度的方法，罗氟斯特和福莫特罗以单一组合形式给药、独立给药、或当顺序给药时以短时间间隔或长时间间隔独立顺序地给药。
本发明还涉及用于预防或减少肺病症状的发作、或治疗或降低肺病严重程度的组合物，其包括有效量的罗氟斯特、有效量的福莫特罗和药学可接受的赋形剂。
本发明另外涉及制备有效用于预防或减少肺病症状的发作、或治疗或降低肺病严重程度的组合物的方法，所述方法包括将有效量的罗氟斯特和有效量的福莫特罗以及药学可接受的赋形剂混合。
发明详述
作为本发明主题的组合治疗包括将福莫特罗与罗氟斯特一起给药，预防肺病的发作或治疗已有疾病。两种化合物可以以单一剂型共同给药。或者，它们可以以不同剂型给药。它们可同时给药。或者，可以以短时间间隔或长时间间隔给药，如一种药物在早晨给药，第二种药物在晚上给药。可预防性地使用或在症状已经发生之后使用该组合。在有些情况中，该组合可用于预防肺病的发展或用于抑制如肺功能的功能衰竭。
因此，本发明涉及罗氟斯特和福莫特罗在预防呼吸道疾病的症状、或治疗呼吸道疾病中的组合应用。
在本发明的意义上，术语“罗氟斯特”理解为包括罗氟斯特的药理学可接受的盐和N-氧化物，它们可根据本发明同样使用。
相应地，本发明中的术语“福莫特罗”理解为包括福莫特罗的药理学可接受的盐。
可以理解，提及的活性化合物也可以例如以其溶剂化物的形式存在，特别是以其水合物的形式存在。
适当的罗氟斯特或福莫特罗的药理学可接受的盐具体为其与酸形成的水溶性和非水溶性的酸加成盐，所述酸为诸如例如，盐酸、氢溴酸、磷酸、硝酸、硫酸、乙酸、柠檬酸、D-葡糖酸、苯甲酸、2-(4-羟基苯甲酰基)苯甲酸、丁酸、磺基水杨酸、马来酸、月桂酸、苹果酸、富马酸、琥珀酸、草酸、酒石酸、恩贝酸、硬脂酸、甲苯磺酸、甲磺酸或1-羟基-2-萘甲酸。在制备盐中所用的酸(其用量取决于所述酸是否为一元酸或多元酸并取决于所需的盐)是等摩尔的定量比例或不同比例。特别优选的福莫特罗的盐为富马酸盐。
可提及的呼吸道疾病具体为过敏原和炎症诱导的支气管疾病(支气管炎、梗阻性支气管炎、痉挛性支气管炎、过敏性支气管炎、过敏性哮喘、支气管性哮喘、COPD)，其可通过本发明的组合在长期治疗的意义上进行治疗(如果需要，可在例如需要经历季节相关性变化时适当地调整单个组分的剂量)。
本发明意义中的“组合应用”或“组合”理解为是指可根据本身已知和惯例，将单个组分同时给药(以组合药物的形式)、程度不同的同时给药(独立的包装单位)或顺序地给药(直接地顺序给药或者以相对长的时间间隔给药)。例如，一种药物可在上午服用，另一种药物在当天随后服用。或者，在另一种情况中，一种药物可每天服用两次，而另一种药物为每天服用一次，可以在每天两次给药中的一次给药的同时服用，也可独立服用。
本发明的意义中的“组合应用”或“组合”具体理解为是指两组分以协同方式共同起作用。
福莫特罗通常以口服或鼻喷雾或气雾剂形式给药、或作为吸入粉末给药。通常，福莫特罗不全身给药或注射给药。罗氟斯特可口服给药或吸入给药(口或鼻内)。本发明考虑了将两种药物以一种递送形式如吸入器，即将两种药物置于同一吸入器中进行共同给药。或者，可将罗氟斯特制成小丸并用含福莫特罗的吸入器将其包装在药物包装中。
因此，在本发明的意义上，相对于罗氟斯特，“应用”理解为主要是口服。考虑到本发明的组合应用的协同作用，有可能以较低剂量口服福莫特罗，以避免已知的在较高剂量下口服给药福莫特罗的副作用。因此，根据本发明，相对于福莫特罗的“应用”主要理解为是指口服给药，但也理解为是指以吸入剂形式的局部给药。对于吸入，优选福莫特罗以气雾剂形式给药，固体、液体或混合组合物的气溶胶粒子的直径为0.5到10μm，优选为2到6μm。
可通过例如压力驱动的喷射喷雾器或超声雾化器生产气雾剂，但优选通过推进剂驱动的计量气雾剂或来自吸入胶囊的微粒化活性化合物的无推进剂给药。
活性化合物在独立剂量通常所需的范围内进行剂量给药，更可能地是，基于独立作用进行剂量给药，活性化合物之间相互积极影响和增强，与标准剂量相比，活性化合物在组合给药时各自的剂量降低。对于吸入，福莫特罗的给药优选为每天10到50μg，每天一次、两次或三次给药。
取决于使用的吸入器系统，除活性化合物之外，给药剂型另外包含必需的赋形剂，诸如例如，推进剂(如在计量气雾剂的情况中的氟利昂)、表面活性物质、乳化器、稳定剂、防腐剂、调味品、填料(如在粉末吸入剂的情况中的乳糖)，或者，如果合适可包含另外的活性化合物。
为了吸入，可选择可产生最佳粒度的气雾剂并进行给药的许多装置，其使用尽可能适合患者的吸入技术。对于计量气雾剂，除了使用适配器(定位片、扩张器)和梨形的容器(如Nebulator、Volumatic)、和散发喷雾的自动装置(Autohaler)之外，特别是在粉末吸入剂的情况中，可选择多种技术溶液(如Diskhaler、Rotadisk、Turbohaler、或在欧洲专利申请EP 0 505 321中描述的吸入剂)，使用其可得到活性化合物的最佳给药。
在福莫特罗口服的情况中(其为本发明的组合应用的优选给药形式)，每日剂量为每天20到120μg，每天口服一次、两次或三次。
在罗氟斯特口服(其为优选的给药形式)的情况中，每日的剂量为每天100到500μg，优选每天口服一次。
在药物计划用于口服的情况中，根据本身已知的和本领域技术人员公知的方法将活性成分罗氟斯特和/或福莫特罗配制成为药物。将作为药物的活性成分优选与适当的药物赋形剂或媒介物组合应用，以片剂、包衣片剂、胶囊、乳剂、悬浮液或溶液的形式。活性化合物的含量有利地为0.1到95％，通过适当地选择赋形剂和媒介物，有可能实现精密配制活性化合物和/或所需作用发生形式(如缓释形式和肠溶形式)的药物给药形式。在罗氟斯特和福莫特罗都在口服单个单位剂型中、每天一次口服给药的情况中，优选将福莫特罗制成在持续时间内释放的方式。
本领域技术人员根据其专业知识知道哪些赋形剂或媒介物适合于所需的药物剂型。除了溶剂、胶凝剂、片剂赋形剂和其它活性化合物载体之外，有可能使用例如抗氧化剂、分散剂、乳化剂、消泡剂、矫味剂、防腐剂、增溶剂、着色剂或渗透增强剂和络合剂(如环糊精)。
药理
模型
在卵清蛋白敏化/处理的褐色挪威大鼠中的晚期炎症性气管反应
在卵清蛋白(OVA)敏化的和OVA激发的褐色挪威大鼠中测定罗氟斯特和福莫特罗的抗炎活性。通过在敏化开始之后的第1、14、和21、28天同时静脉注射百日咳博德特杆菌悬浮液和皮下注射OVA/AHG悬浮液进行敏化。通过吸入气雾化的OVA溶液激发褐色挪威大鼠1h(～20ml/h)。使用未激发而只经过敏化的动物作为基线对照。在OVA激发之前1h，将药物(与乳糖充分混合)或安慰剂对照(乳糖)作为干粉气管内给药(i.t.)。在48h之后，将OVA激发或未激发的动物麻醉并使用3×4ml BAL缓冲液对每只动物进行支气管肺泡灌洗(BAL)。测定BAL液中总的细胞和嗜酸性粒细胞数、和无细胞的BAL液中的蛋白质浓度。通过Jonckheere Terpstra试验计算药物诱导的相对变化并进行统计学分析。
结果
| 化合物 | 剂量[μmol/kg] | 给药途径 | N | 平均抑制％ | |
| 嗜酸性粒细胞 | 蛋白质 | ||||
| 罗氟斯特 | 1.0 | p.o. | 8 | 0 | 15 |
| 福莫特罗 | 3.0 | p.o. | 16 | 35 | 46 |
| 罗氟斯特、福莫特罗 | 1.0+3.0 | p.o. | 8 | 60 | 68 |
总结
以0.3μmol/kg剂量i.t.给药的PDE抑制剂罗氟斯特(PDE4抑制剂)对于细胞浸润和蛋白质积聚没有表现出任何明显的作用。得到的负值(趋势：炎症扩大)在模型的生物差异范围内，因此，这些数据不必附加显著性。
相比之下，以3μmol/kg剂量i.t.给药的长效β2肾上腺素能受体激动剂福莫特罗对于流入肺泡腔的总的细胞和嗜酸性粒细胞数和BAL液中的蛋白水平表现出抑制作用。然而，数据没能达到显著性。
PDE抑制剂罗氟斯特与福莫特罗的共同给药产生了与每种化合物单独给药相比较的协同作用，即，PDE抑制剂与β2激动剂组合表现出对于嗜酸细胞的显著抑制和BAL液中蛋白质浓度降低。
Claims (19)
1.一种固定或自由组合的药物，包括罗氟斯特、罗氟斯特的药学可接受的盐或罗氟斯特的N-氧化物和福莫特罗或福莫特罗的药学可接受的盐。
2.如权利要求1所述的药物，包括罗氟斯特和福莫特罗或福莫特罗的药学可接受的盐。
3.如权利要求1或2任一项所述的药物，其是固定的组合。
4.如权利要求3所述的药物，其是固定的口服组合。
5.如权利要求3所述的药物，其是适于吸入给药的固定的组合。
6.如权利要求1和2任一项所述的药物，其是自由的组合。
7.如权利要求4所述的药物，其是包含日剂量为100至500μg罗氟斯特和日剂量为10至120μg福莫特罗或福莫特罗的药学可接受的盐的固定的口服组合。
8.如权利要求6所述的药物，其是包含口服制剂的罗氟斯特和适于通过吸入给药的制剂的福莫特罗或福莫特罗的药学可接受的盐的自由组合。
9.如权利要求6所述的药物，其是包含日剂量为100至500μg的口服制剂的罗氟斯特和日剂量为10至50μg适于通过吸入给药的制剂的福莫特罗或福莫特罗的药学可接受的盐的自由组合。
10.如权利要求1所述的药物，其是包含两种包装单位的药物包装，罗氟斯特、罗氟斯特的药学可接受的盐或罗氟斯特的N-氧化物处于口服制剂中和福莫特罗或福莫特罗的药学可接受的盐处于适于通过吸入给药的制剂中。
11.如权利要求1所述的药物，其是包含两种包装单位的药物包装，罗氟斯特处于口服制剂中和福莫特罗或福莫特罗的药学可接受的盐处于适于通过吸入给药的制剂中。
12.罗氟斯特、罗氟斯特的药学可接受的盐或罗氟斯特的N-氧化物和福莫特罗或福莫特罗的药学可接受的盐在制备用于预防或减少呼吸道疾病的症状发作或用于治疗或降低呼吸道疾病的严量程度的固定或自由组合的药物中的应用。
13.罗氟斯特和福莫特罗或福莫特罗的药学可接受的盐在制备用于预防或减少呼吸道疾病的症状发作或用于治疗或降低呼吸道疾病的严重程度的固定或自由组合的药物中的应用。
14.如权利要求12和13任一项所述的应用，其中所述药物是固定的组合。
15.如权利要求12和13任一项所述的应用，其中所述药物是自由的组合。
16.如权利要求12所述的应用，其中所述药物是权利要求1-11任一项的药物。
17.如权利要求12-16任一项所述的应用，其中所述呼吸道疾病选自支气管炎、阻塞性支气管炎、痉挛性支气管炎、过敏性支气管炎、过敏性哮喘、支气管哮喘和慢性阻塞性肺病。
18.如权利要求17所述的应用，其中所述呼吸道疾病是支气管哮喘。
19.如权利要求17所述的应用，其中所述呼吸道疾病是慢性阻塞性肺病。
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| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| PT1606261E (pt) | 2003-03-10 | 2010-01-11 | Nycomed Gmbh | Novo processo para a preparação de roflumilast |
| EP2258350B1 (en) * | 2005-03-16 | 2014-12-24 | Takeda GmbH | Taste masked dosage form containing roflumilast |
| DE102005030733A1 (de) * | 2005-07-01 | 2007-01-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkombinationen zur Behandlung von Atemwegserkrankungen enthaltend langwirksame Beta-2-Agonisten und wenigstens einen weiteren Wirkstoff |
| KR101433394B1 (ko) * | 2006-07-05 | 2014-08-26 | 다케다 게엠베하 | 염증성 폐질환의 치료를 위한 ＨＭＧ-ＣｏＡ 리덕타제 억제제와 포스포디에스터라제 4 억제제의 병용 |
| WO2013077830A1 (en) * | 2011-11-25 | 2013-05-30 | Mahmut Bilgic | Synergistilly active combinations of roflumilast and carmoterol |
| US20130172303A1 (en) * | 2012-01-03 | 2013-07-04 | Forest Laboratories Holdings Ltd. | Roflumilast compositions for the treatment of copd |
| CN104800214A (zh) * | 2014-01-27 | 2015-07-29 | 成都英诺新科技有限公司 | 一种罗氟司特吸入气雾剂复方及制备方法 |
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| PT975347E (pt) * | 1997-02-28 | 2008-05-23 | Nycomed Gmbh | Combinação sinérgica de inibidores da pde e agonistas da adenilato ciclase ou agonistas da guanil ciclise |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1370081A (zh) * | 1999-08-21 | 2002-09-18 | 比克·古尔顿·劳姆贝尔格化学公司 | 增效组合物 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104994854A (zh) * | 2013-01-28 | 2015-10-21 | 理森制药股份公司 | 通过吸入罗氟司特n-氧化物治疗自身免疫、呼吸和/或炎性病症的方法 |
| CN110403922A (zh) * | 2013-01-28 | 2019-11-05 | 理森制药股份公司 | 通过吸入罗氟司特n-氧化物治疗自身免疫、呼吸和/或炎性病症的方法 |
| CN110464724A (zh) * | 2013-01-28 | 2019-11-19 | 理森制药股份公司 | 通过吸入罗氟司特n-氧化物治疗自身免疫、呼吸和/或炎性病症的方法 |
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