CN104271112A - 包含阿福特罗和糠酸氟替卡松的药物组合物 - Google Patents
包含阿福特罗和糠酸氟替卡松的药物组合物 Download PDFInfo
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- CN104271112A CN104271112A CN201380019244.8A CN201380019244A CN104271112A CN 104271112 A CN104271112 A CN 104271112A CN 201380019244 A CN201380019244 A CN 201380019244A CN 104271112 A CN104271112 A CN 104271112A
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Abstract
本发明涉及包含阿福特罗和糠酸氟替卡松的药物组合物(优选用于每天给药一次)、用于制备此类组合物的方法以及此类述组合物用于治疗和/或预防呼吸、炎性或阻塞性气道疾病的用途。
Description
技术领域
本发明涉及包含吸入皮质类固醇(inhaled corticosteroid)和β-激动剂的用于吸入的药物组合物，以及用于制备所述组合物的方法。此外，本发明涉及所述组合物用于治疗和/或预防呼吸、炎性或阻塞性气道疾病的用途，以及使用其的治疗方法。
背景技术
哮喘是慢性发病率和死亡率的主要原因，估计全球有3亿人受累，并且每年有25万人死于该疾病。在大多数国家，所有年龄的人都受累于这种慢性疾病。
哮喘是与气道高反应性有关的慢性炎性气道病症，它会导致哮鸣、气喘、胸闷和咳嗽的反复发作。增加的炎症反应是急性哮喘的病理生理学的主要部分，并且其定期的预防性治疗非常重要。
慢性阻塞性肺疾病(COPD)是在全球范围内患病率不断增加的严重呼吸病症。在印度，估计病患约为1236万。
慢性阻塞性肺疾病(COPD)是可预防并且可治疗的疾病状态，它的特征在于不完全可逆的气流限制。气流阻塞通常是渐进性的，并且与主要由吸烟引起的肺对有害颗粒或气体的异常炎症反应有关。尽管COPD累及肺，但它也产生显著的全身性后果。COPD与粘液分泌过多、肺气肿和细支气管炎有关。
用于治疗或预防COPD和哮喘的疗法目前包括使用支气管扩张剂和类固醇。
更具体地，已知用β2-激动剂来治疗哮喘、COPD和其它相关病症，因为它们提供支气管扩张作用，从而实现气喘症状的缓解。β2-激动剂可以是用于立即缓解哮喘症状的短效型的或用于长期预防哮喘症状的长效型的。
长效β2-激动剂在患有哮喘和COPD的患者中改善肺功能，减轻症状，并且预防运动引起的呼吸困难。长效β2-激动剂通过引起气道平滑肌长时间松弛而诱导支气管扩张。除了长时间的支气管扩张以外，长效β2-激动剂(LABA)还发挥其它作用，例如抑制气道平滑肌细胞增殖和炎症介质的释放，以及非平滑肌作用，例如刺激粘膜纤毛转运、对呼吸道粘膜的细胞保护作用以及减少嗜中性粒细胞的募集和活化。
此外，长效β2-激动剂的使用降低药物的给药频率。
目前可用的长效β2-激动剂(LABA)包括沙美特罗和福莫特罗。
尽管已知β2-激动剂提供支气管收缩的症状缓解，但哮喘的另一个组成部分，即炎症，需要单独的治疗，例如类固醇。大多数的吸入皮质类固醇需要以多剂量方案给药。
皮质类固醇表现出对与呼吸病症的发病机制有关的炎症细胞和炎症介质的抑制作用。用皮质类固醇/糖皮质激素治疗被认为是目前可用于持续性哮喘的最有力和有效的疗法之一。
但皮质类固醇的使用由于潜在的副作用而受到限制。通常担心的皮质类固醇副作用包括对下丘脑-垂体-肾上腺(HPA)轴的抑制、对儿童的骨生长和中老年人的骨密度的影响、眼部并发症(白内障形成和青光眼)以及皮肤萎缩。
目前可用的皮质类固醇包括倍氯米松、布地奈德、氟替卡松、莫米松、环索奈德和曲安西龙。
目前，存在若干个批准的长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的组合。这些批准的用于治疗哮喘和慢性阻塞性肺疾病(COPD)的组合中的一些是沙美特罗/丙酸氟替卡松(Advair diskus，Advair HFA)和富马酸福莫特罗二水合物/布地奈德(Symbicort)。
在患有例如哮喘和COPD的呼吸病症的患者中，与单独的较高剂量的吸入皮质类固醇(ICS)相比，长效β-激动剂(LABA)与吸入皮质类固醇(ICS)的组合疗法提高肺效率，减轻炎症反应，并且提供症状缓解。
此外，它简化了治疗，降低了成本，并且还提供对呼吸病症的控制。
US6030604公开了包含糖皮质激素和β2-激动剂的干粉组合物。
WO0178745公开了含有福莫特罗和丙酸氟替卡松的组合的组合物。
US7172752公开了包含预定和恒定的比率的β2-激动剂和糖皮质激素的组合的吸入颗粒。
WO02083113公开了包含在药理学上合适的流体中的福莫特罗和类固醇抗炎剂的药物组合物。
WO2004028545公开了用在纤维化疾病的治疗中的长效β2-激动剂和糖皮质激素的组合。
US2005053553公开了通过吸入具有福莫特罗和氟替卡松的组合剂量的计量干粉的给药方法。
此外，上述现有技术中都没有公开了阿福特罗(arformoterol)和糠酸氟替卡松(fluticasone furoate)的特定组合。
大多数现有的长效β-激动剂(LABA)与吸入皮质类固醇(ICS)的组合必须每天给药两次。
即使从患者依从性的角度来看，治疗需要患者依从不同的剂量方案、不同的给药频率等。
已经通过简化药物包装、提供有效的用药提醒、改善患者的教育和限制同时处方的药物的数量来努力改善依从性。
因此，仍然需要配制用于治疗呼吸病症的药物组合物，所述药物组合物通过给药阿福特罗和糠酸氟替卡松的有效组合而简化剂量方案。
发明目的
本发明的目的是提供包含长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的药物组合物，其用于在呼吸、炎性或阻塞性气道疾病的预防或治疗中给药。
本发明的另一目的是提供用于每天给药一次的包含长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的药物组合物，其用于预防或治疗呼吸、炎性或阻塞性气道疾病。
本发明的再一个目的是提供用于制备包含长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的药物组合物的方法，所述药物组合物用于呼吸、炎性或阻塞性气道疾病的预防或治疗中给药。
本发明的又一个目的是提供用于治疗或预防哮喘、COPD或相关呼吸病症的方法，所述方法包括给药包含长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的药物组合物。
发明概述
根据本发明的一个方面，提供包含阿福特罗和糠酸氟替卡松的药物组合物。
根据本发明的另一个方面，提供用于每天给药一次的包含阿福特罗和糠酸氟替卡松的药物组合物。
根据本发明的再一个方面，提供用于制备药物组合物的方法，所述方法包括将阿福特罗和糠酸氟替卡松以及任选存在的一种或多种药学上可接受的载体和/或赋形剂组合。
根据本发明的又一个方面，提供用于治疗或预防哮喘、慢性阻塞性肺疾病(COPD)或相关病症的方法，所述方法包括向有此需要的患者给药本发明的药物组合物。
根据本发明的另一个方面，提供本发明的用于治疗或预防哮喘、COPD或相关病症的药物组合物。
根据本发明的再一个方面，提供本发明的药物组合物用于治疗或预防哮喘、慢性阻塞性肺疾病(COPD)或相关病症的用途。
发明详述
用长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的药物疗法已被推荐用于预防或治疗呼吸、炎性或阻塞性气道疾病，例如哮喘和慢性阻塞性肺疾病(COPD)。
此外，需要简化各种不同的剂量方案以及不同的药物给药频率。
另外，选择长效β2-激动剂(LABA)和吸入皮质类固醇(ICS)的组合至关重要，因为这两种药物应能够每天给药一次。其中长效β2-激动剂(LABA)需要每天给药一次而吸入皮质类固醇(ICS)需要每天给药两次的治疗方法不可用，因为每天治疗一次的目的不能实现。
此外，需要配制可每天给药一次来预防病症的组合物，所述病症对长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的给药有反应或可通过长效β-激动剂(LABA)和吸入皮质类固醇(ICS)的给药预防、改善或消除。
已经令人惊讶地发现，与糠酸氟替卡松组合的阿福特罗缓解呼吸病症，同时降低剂量给药的频率。
因此，本发明提供用于吸入的新组合，所述组合包含与糠酸氟替卡松组合的阿福特罗，用于预防或治疗呼吸、炎性或阻塞性气道疾病，同时降低剂量给药的频率。
术语“阿福特罗”在广义上使用，不仅包括“阿福特罗”本身，还包括其药学上可接受的盐、药学上可接受的溶剂合物、药学上可接受的水合物、药学上可接受的对映异构体、药学上可接受的衍生物、药学上可接受的酯、药学上可接受的多晶型物、药学上可接受的前药、药学上可接受的络合物、药学上可接受的共晶体等。阿福特罗的盐包括酸加成盐，例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸和对甲苯磺酸。优选地，本发明中使用的阿福特罗的盐是酒石酸阿福特罗或富马酸阿福特罗，尤其是富马酸阿福特罗二水合物。
阿福特罗是福莫特罗的活性(R,R)-对映异构体。它起效快，并且作用持续时间较长。此外，阿福特罗的效力是外消旋福莫特罗(它含有(S,S)-对映异构体和(R,R)-对映异构体两者)的两倍。阿福特罗似乎对β1-肾上腺素能受体具有很少影响或没有影响。
术语“糠酸氟替卡松”在广义上使用，不仅包括“糠酸氟替卡松”本身，还包括其药学上可接受的盐、药学上可接受的溶剂合物、药学上可接受的对映异构体、药学上可接受的水合物、药学上可接受的衍生物、药学上可接受的多晶型物、药学上可接受的前药、药学上可接受的络合物、药学上可接受的共晶体等。
氟替卡松目前可作为糠酸酯和丙酸酯得到。糠酸氟替卡松是基本上克服了使用常规的皮质类固醇通常产生的潜在的副作用的皮质类固醇。而且，糠酸氟替卡松所表现出的对人类糖皮质激素受体的结合亲和力是丙酸氟替卡松的1.7倍。
糠酸氟替卡松具有较长的作用持续时间，其消除半衰期为15.1小时。阿福特罗具有较长的作用持续时间，并且还表现出更快的起效。
糠酸氟替卡松和阿福特罗主要作用于哮喘的两个不同组成部分，从而表现出互补作用(complimentary action)。通常与哮喘有关的慢性炎症由糠酸氟替卡松管控，而哮喘的其它方面(例如支气管平滑肌异常)由阿福特罗改善。
因此，糠酸氟替卡松与阿福特罗的组合提供了对于哮喘和COPD患者而言具有每天给药一次的方便性的新组合。
此外，所述组合由于阿福特罗而具有的起效快的作用可增加患者的治疗信心，随后改善治疗依从性。
根据本发明，单一剂量可以包含约2mcg-约10mcg、优选约3mcg-约9mcg阿福特罗。单一剂量可以包含约3mcg、约5mcg、约7mcg或约9mcg阿福特罗。
根据本发明，单一剂量可以包含约25mcg-约800mcg、优选约50mcg到约400mcg糠酸氟替卡松。单一剂量可以包含约27.5mcg、约50mcg、约100mcg、约125mcg、约200mcg、约250mcg或约400mcg。
在本发明的组合物每天给药一次的实施方案中，单一剂量可以提供日剂量。或者，日剂量可以包含所述组合物的多个剂量(例如两个剂量)，如果每天给药一次，其可以同时服用，或者如果每天给药一次以上，其可以在不同时间服用。
在单一剂量提供每日单一剂量(single daily dose)的实施方案中，每日单一剂量可以包含5mcg糠酸氟替卡松和50mcg阿福特罗、5mcg糠酸氟替卡松和125mcg阿福特罗或10mcg糠酸氟替卡松和250mcg阿福特罗。
本发明的组合物中阿福特罗对糠酸氟替卡松的摩尔比优选为约1:10-1:100，优选1:15-1:70。
所述药物组合物可以为适于作为单一药物给药的形式。
本发明的药物组合物可以包含阿福特罗和糠酸氟替卡松以及一种或多种药学上可接受的赋形剂。
本发明的药物组合物可以通过任何合适的用于将药物递送到呼吸道的方法来给药。因此，本发明的组合物可以为适于吸入的形式。因此，所述药物组合物可以被配制成用于从定量吸入器(MDI)、干粉吸入器(DPI)、雾化器等吸入的组合物；或者，所述药物组合物可以被配制成鼻喷雾剂、滴鼻剂、令舒(respule)、鼻吸入粉末(insufflation powder)等形式的用于吸入的组合物。“令舒”是适合与雾化器一起使用的剂型；令舒是含有液体形式的药物的安瓿。令舒、鼻喷雾剂和滴鼻剂可以含有吸入用溶液或吸入用混悬液形式的本发明的药物组合物。
本发明的各种剂型可以包含适于其配制的载体/赋形剂。
本发明的定量吸入器可以包含一种或多种药学上可接受的赋形剂，例如HFC/HFA抛射剂、共溶剂、填充剂、非挥发性组分、缓冲剂/pH调节剂、表面活性剂、防腐剂、络合剂或它们的组合。
抛射剂是当与共溶剂混合时形成其中可以溶解治疗有效量的药剂的均匀的抛射剂体系的那些。HFC/HFA抛射剂必须是毒理学上安全的，并且必须具有适于使药剂能够经由加压MDI给药的蒸气压。
根据本发明，所述HFC/HFA抛射剂可以包括以下中的一种或多种：1,1,1,2-四氟乙烷(HFA-134(a))和1,1,1,2,3,3,3-七氟丙烷(HFA-227)、HFC-32(二氟甲烷)、HFC-143(a)(1,1,1-三氟乙烷)、HFC-134(1,1,2,2-四氟乙烷)和HFC-152a(1,1-二氟乙烷)等或它们的组合，以及可为本领域的技术人员所知的此类其它抛射剂。
共溶剂是可以所需量混溶于组合物中并且当被添加时提供其中可溶解药剂的组合物的任何溶剂。共溶剂的作用是增加组合物中的药剂和赋形剂的溶解度。
根据本发明，所述共溶剂可以包括以下中的一种或多种：C2-C6脂族醇，例如但不限于乙醇和异丙醇；二醇，例如但不限于丙二醇、聚乙二醇、聚丙二醇、乙二醇醚以及氧化乙烯和氧化丙烯的嵌段共聚物；以及其它物质，例如但不限于甘油、聚氧乙烯醇和聚氧乙烯脂肪酸酯；烃，例如但不限于正丙烷、正丁烷、异丁烷、正戊烷、异戊烷、新戊烷和正己烷；和醚，例如但不限于乙醚等，或它们的组合。
合适的表面活性剂可以用在本发明的气溶胶溶液组合物中，其可用于稳定所述溶液组合物并且改善定量吸入器的阀门系统的性能。
根据本发明，所述表面活性剂可以包括一种或多种离子型表面活性剂和/或非离子型表面活性剂，但不限于油酸、脱水山梨糖醇三油酸酯、卵磷脂、肉豆蔻酸异丙酯、泰洛沙泊、聚乙烯基吡咯烷酮、聚山梨酯例如聚山梨酯80、维生素E-TPGS和聚乙二醇羟硬脂酸酯例如聚乙二醇-15-羟硬脂酸酯等，或它们的组合。
非挥发性组分是在蒸发溶剂后残留的所有悬浮或溶解的成分。
根据本发明，所述非挥发性组分可以包括以下中的一种或多种：糖，包括单糖(例如但不限于葡萄糖、阿拉伯糖)和二糖(例如乳糖、麦芽糖)；低聚糖和多糖，例如但不限于葡聚糖；多元醇，例如但不限于甘油、山梨糖醇、甘露醇、木糖醇等，或它们的组合；和/或盐，例如但不限于氯化钾、氯化镁、硫酸镁、氯化钠、柠檬酸钠、磷酸钠、磷酸氢二钠、碳酸氢钠、柠檬酸钾、磷酸钾、磷酸氢二钾、碳酸氢钾、碳酸钙和氯化钙等，或它们的组合。
合适的填充剂可以用在本发明的定量吸入组合物中。
根据本发明，所述填充剂可以包括一种或多种糖，包括单糖、二糖、多糖和糖醇，例如阿拉伯糖、葡萄糖、果糖、核糖、甘露糖、蔗糖、海藻糖、乳糖、麦芽糖、淀粉、葡聚糖或甘露醇等，或它们的组合。
合适的缓冲剂或pH调节剂可以用在本发明的定量吸入组合物中。
根据本发明，所述缓冲剂或pH调节剂可以包含一种或多种有机酸或无机酸，例如但不限于柠檬酸、抗坏血酸、盐酸、硫酸、硝酸或磷酸等，或它们的组合。
合适的防腐剂可以用在本发明的气溶胶溶液组合物中，以保护所述组合物免受致病菌污染。
根据本发明，所述防腐剂可以包括以下中的一种或多种：苯扎氯铵、苯甲酸、例如苯甲酸钠的苯甲酸盐等，或它们的组合，以及可为本领域的技术人员所知的此类其它防腐剂。
合适的络合剂可以用在本发明的气溶胶溶液组合物中，其能够形成配位键。
根据本发明，所述络合剂可以包括以下中的一种或多种：EDTA钠或EDTA二钠等，或它们的组合，但并不限于这些。
本发明的药物组合物也可以通过干粉吸入器(DPI)给药。
适于本发明的干粉吸入的药学上可接受的赋形剂可以选自适合的载体，包括但不限于糖，例如葡萄糖、蔗糖、乳糖和果糖，淀粉或淀粉衍生物，低聚糖，例如糊精、环糊精和其衍生物；聚乙烯吡咯烷酮、海藻酸、纤基乙酸钠(tylose)、硅酸、纤维素、纤维素衍生物(例如纤维素醚)；糖醇，例如甘露醇或山梨糖醇；碳酸钙、磷酸钙等；乳糖、乳糖醇、葡聚糖结合剂、右旋糖、麦芽糖糊精；糖，包括单糖、二糖、多糖；硬脂酸镁、甘氨酸、柠檬酸钠；糖醇，例如阿拉伯糖、核糖、甘露糖、蔗糖、海藻糖、麦芽糖、葡聚糖等，或它们的组合。
本发明的药物组合物也可以使用雾化器给药。
雾化是一种将药物直接递送或沉积到呼吸道中从而实现较高药物浓度的安全疗法。雾化易于使用，并且不需要协调或费力。它的起效也远快于口服药物。
在所述药物组合物被配制用于以鼻喷雾剂、滴鼻剂或令舒的形式吸入的实施方案中，所述组合物可以包含在合适的媒介物(例如但不限于水、盐水等)中合适的赋形剂(例如润湿剂、渗透剂、张度剂、pH调节剂、缓冲剂、络合剂等，或它们的组合)。
可以使用的张度剂包括氯化钠、氯化钾、氯化锌、氯化钙等，或它们的组合。其它张度剂还可以包括但不限于甘露糖醇、甘油和右旋糖等，或它们的组合。
pH可以通过添加药理学上可接受的酸来调节。药理学上可接受的无机酸或有机酸可以用于这个目的。优选的无机酸的实例选自盐酸、氢溴酸、硝酸、硫酸和磷酸。尤其适合的有机酸的实例选自抗坏血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、乙酸、甲酸和丙酸等，或它们的组合。
本发明的络合剂可以包括依地酸(EDTA)或其已知的盐中的一种，例如EDTA钠或EDTA二钠二水合物(依地酸钠)等，或它们的组合。
对于多剂量包装，可以添加抗微生物防腐剂。
可以将本发明的组合物包装在合适的容器中，所述容器设置有能够将所含组合物递送/沉积到呼吸道的装置。
可以将意欲通过DPI递送的用于吸入的粉末封装在明胶或羟丙基甲基纤维素(HPMC)胶囊中或泡罩中，或者，可以在单一剂量或多个剂量干粉吸入装置中用干粉填充贮库。
或者，可以将意欲通过DPI递送的用于吸入的粉末悬浮在合适的液体媒介物中，并与合适的抛射剂或它们的混合物一起包装在气溶胶容器中。
此外，也可以将意欲通过DPI递送的用于吸入的粉末分散在合适的气流中，以形成气溶胶组合物。
可以将本发明的MDI组合物包装在纯铝罐或SS(不锈钢)罐中。一些气溶胶药物倾向于粘附到MDI的内表面，即罐和阀门的壁。这可能导致患者在每次开启MDI后获得比处方量明显更少的活性剂。用合适的聚合物涂覆容器的内表面的一部分或全部可以减轻这个粘附问题。合适的涂层包括碳氟化合物的共聚物，例如FEP-PES(氟化乙烯丙烯和聚醚砜)和PFA-PES(全氟烷氧基烷烃和聚醚砜)、环氧树脂和乙烯。或者，罐的内表面可以被阳极氧化、等离子体处理或等离子体涂覆。
本领域的技术人员充分认识到，所述本发明的药物组合物可以进一步包含一种或多种活性剂，所述活性剂选自：抗胆碱能药剂、抗组胺剂、抗过敏剂或白细胞三烯拮抗剂等，或它们的组合，或它们的药学上可接受的盐、溶剂合物、互变异构体、衍生物、对映异构体、同分异构体、水合物、前药或多晶型物。
本发明还提供制造本发明的组合物的方法。
本发明提供制备定量吸入组合物的方法。所述方法包括将药学上可接受的载体或赋形剂与活性剂和抛射剂组合，并将所述组合物提供在预卷边(precrimped)的罐中。
本发明还提供制备干粉吸入组合物的方法。所述方法包括将药学上可接受的载体或赋形剂与活性剂组合，并将所述组合物提供在干粉吸入器装置中。
本发明还提供用于治疗或预防哮喘、COPD或相关病症的方法。所述治疗方法包括向有此需要的患者给药本发明的药物组合物。所述患者可以是哺乳动物，例如人类。
下列实施例仅用于说明本发明的目的，并且不旨在以任何方式限制本发明的范围。
实施例1
| 编号 | 成分 | 量/喷 |
| 1. | 糠酸氟替卡松 | 50mcg |
| 2. | 酒石酸阿福特罗 | 3mcg |
| 3. | HFA134A/HFA227 | 适量 |
方法：
1)将糠酸氟替卡松和酒石酸阿福特罗与一部分量的HFA一起均质化。
2)将在步骤1中获得的悬浮液转移到添加了剩余量的HFA的混合容器中。
3)将所得悬浮液混合，再循环并填充到预卷边的铝罐中。
实施例2
| 编号 | 成分 | 量/喷 |
| 1. | 糠酸氟替卡松 | 50mcg |
| 2. | 酒石酸阿福特罗 | 3mcg |
| 3. | 乳糖 | 药物的100％ |
| 4. | HFA134A/HFA227 | 适量 |
方法：
1)将糠酸氟替卡松和酒石酸阿福特罗与乳糖和一部分量的HFA一起均质化。
2)将在步骤1中获得的悬浮液转移到添加了剩余量的HFA的混合容器中。
3)将所得悬浮液混合，再循环并填充到预卷边的铝罐中。
实施例3
| 编号 | 成分 | 量/喷 |
| 1. | 糠酸氟替卡松 | 50mcg |
| 2. | 酒石酸阿福特罗 | 3mcg |
| 3. | 乙醇 | 总制剂的1-2％ |
| 4. | 油酸 | API的0.02-5％ |
| 5. | HFA134a/HFA227 | 适量 |
方法：
1)将油酸溶解于乙醇中。将酒石酸阿福特罗与一部分量的HFA一起均质化，并转移到混合容器中。
2)将油酸和乙醇的溶液与糠酸氟替卡松和一部分量的HFA一起均质化。
3)将在步骤2中获得的悬浮液转移到添加了剩余量的HFA的混合容器中。
4)随后，将所得悬浮液混合，再循环并填充到预卷边的铝罐中。
实施例4
| 编号 | 成分 | 量/单位(mg) |
| 1. | 阿福特罗 | 0.0088 |
| 2. | 糠酸氟替卡松 | 0.1000 |
| 3. | 乳糖一水合物 | 24.8912 |
| 总计 | 25.000 |
方法：
1)将筛分的乳糖与阿福特罗和糠酸氟替卡松一起共筛分。
2)掺和在步骤(1)中获得的混合物。
实施例5
| 编号 | 成分 | 量/单位(mg) |
| 1. | 阿福特罗 | 0.0088 |
| 2. | 糠酸氟替卡松 | 0.2000 |
| 3. | 乳糖一水合物 | 24.7912 |
| 总计 | 25.000 |
方法：
1)将筛分的乳糖与阿福特罗和糠酸氟替卡松共筛分。
2)掺和在步骤(1)中获得的混合物。
实施例6
| 编号 | 成分 | 量/单位(mg) |
| 1. | 阿福特罗 | 0.0088 |
| 2. | 糠酸氟替卡松 | 0.4000 |
| 3. | 乳糖一水合物 | 24.5912 |
| 总计 | 25.000 |
方法：
1)将筛分的乳糖与阿福特罗和糠酸氟替卡松一起共筛分。
2)掺和在步骤(1)中获得的混合物。
本领域技术人员显而易见的是，可以对本文所公开的发明进行各种替代和修改而不背离本发明的主旨。因此，应理解，尽管已用优选的实施方案和任选的特征具体公开了本发明，但本领域技术人员可以采取本文所公开的概念的修改和变化，并且此类修改和变化被认为在本发明的范围内。
应理解，本文所用的措辞和术语是出于描述的目的，且不应解释为限制。本文所用的“包括”、“包含”或“具有”和其变体意欲包括其后所列的项目和其等同以及其它项目。
必须注意的是，如在本说明书和所附权利要求书中所使用的，除非上下文另外明确指出，否则英文单数形式“a”、“an”和“the”包括复数个指示物。因此，例如，提及“赋形剂”则包括一种赋形剂以及两种或更多种不同的赋形剂，等等。
Claims (24)
1.药物组合物，其包含阿福特罗和糠酸氟替卡松。
2.权利要求1所述的药物组合物，其中所述组合物的单一剂量包含约2mcg-约10mcg阿福特罗。
3.权利要求1或2所述的药物组合物，其中所述组合物的单一剂量包含约25mcg-约800mcg糠酸氟替卡松。
4.权利要求1、2或3所述的药物组合物，其中阿福特罗对糠酸氟替卡松的摩尔比为约1:10-1:100。
5.前述权利要求中任一项所述的药物组合物，其进一步包含一种或多种药学上可接受的载体和/或赋形剂。
6.前述权利要求中任一项所述的药物组合物，其中所述组合物为适于吸入的形式。
7.权利要求6所述的药物组合物，其被配制成鼻喷雾剂、滴鼻剂、令舒或鼻吸入粉末形式的用于吸入的组合物，或者用于从定量吸入器(MDI)、干粉吸入器(DPI)或雾化器吸入的组合物。
8.前述权利要求中任一项所述的药物组合物，其中所述组合物为适合用于定量吸入器(MDI)中的形式。
9.权利要求8所述的药物组合物，其进一步包含抛射剂。
10.权利要求8或9所述的药物组合物，其进一步包含赋形剂，所述赋形剂选自共溶剂、抗氧化剂、表面活性剂、填充剂、pH调节剂和润滑剂或它们的组合。
11.权利要求1-7中任一项所述的药物组合物，其中所述组合物为适合用于干粉吸入器(DPI)中的形式。
12.权利要求11所述的药物组合物，其进一步包含至少一种适合用于干粉吸入制剂中的药学上可接受的载体。
13.权利要求12所述的药物组合物，其中所述载体包括糖和/或糖醇或它们的组合。
14.权利要求1-7所述的药物组合物，其中所述组合物为适合用于鼻喷雾剂、滴鼻剂或令舒中的形式。
15.权利要求14所述的药物组合物，其进一步包含提供在药学上可接受的媒介物中的赋形剂，所述赋形剂选自润湿剂、渗透剂、张度剂、pH调节剂、缓冲剂和络合剂或它们的组合。
16.前述权利要求中任一项所述的药物组合物，其中所述组合物为适于每天给药一次的形式。
17.前述权利要求中任一项所述的药物组合物，其进一步包含一种或多种额外的活性剂，所述额外的活性剂选自抗胆碱能药剂、抗组胺剂、抗过敏剂或白细胞三烯拮抗剂。
18.制备前述权利要求中任一项所述的药物组合物的方法，所述方法包括将阿福特罗和糠酸氟替卡松以及任选存在的与一种或多种药学上可接受的载体和/或赋形剂组合。
19.治疗或预防哮喘、慢性阻塞性肺疾病(COPD)或相关病症的方法，所述方法包括给药权利要求1-17中任一项所述的药物组合物。
20.权利要求1-17中任一项所述的药物组合物，其用于治疗或预防哮喘、COPD或相关病症。
21.权利要求1到17中任一项所述的药物组合物用于治疗或预防哮喘、慢性阻塞性肺疾病(COPD)或相关病症的用途。
22.药物组合物，其基本上如本文中参照实施例所述。
23.制备药物组合物的方法，其基本上如本文中参照实施例所述。
24.治疗或预防哮喘、慢性阻塞性肺疾病或相关病症的方法，其如本文中参照实施例所述。
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| EP (1) | EP2836198A2 (zh) |
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| CN (1) | CN104271112A (zh) |
| AU (2) | AU2013246692A1 (zh) |
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| WO2001070198A1 (en) * | 2000-03-20 | 2001-09-27 | Dura Pharmaceuticals, Inc. | Stabilized dry powder formulations |
| CN1339965A (zh) * | 1999-02-18 | 2002-03-13 | 诺瓦提斯公司 | 福莫特罗和氟替卡松丙酸酯联合用于哮喘 |
| WO2011136753A1 (en) * | 2010-04-26 | 2011-11-03 | Mahmut Bilgic | Combination of carmoterol and fluticasone for use in the treatment respiratory diseases |
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| SE9700135D0 (sv) | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
| US6458338B1 (en) * | 1998-09-22 | 2002-10-01 | Aeropharm Technology Incorporated | Amino acid stabilized medicinal aerosol formulations |
| DE19847969A1 (de) * | 1998-10-17 | 2000-04-20 | Boehringer Ingelheim Pharma | Lagerfähig flüssige Formulierung mit Formoterol |
| GB0009591D0 (en) | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medical combinations |
| FI20002216A0 (fi) | 2000-10-06 | 2000-10-06 | Orion Yhtymae Oyj | Yhdistelmäpartikkelit astman hoitoon |
| US20030055026A1 (en) | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
| DE10228103A1 (de) | 2002-06-24 | 2004-01-15 | Bayer Cropscience Ag | Fungizide Wirkstoffkombinationen |
| WO2004028545A1 (en) | 2002-09-25 | 2004-04-08 | Astrazeneca Ab | A COMBINATION OF A LONG-ACTING β2-AGONIST AND A GLUCOCORTICOSTEROID IN THE TREATMENT OF FIBROTIC DISEASES |
| SE527200C2 (sv) | 2003-06-19 | 2006-01-17 | Microdrug Ag | Inhalatoranordning samt kombinerade doser av formaterol och fluticason |
| AU2009253877B2 (en) * | 2008-06-02 | 2013-09-12 | Cipla Limited | Process for the synthesis of arformoterol |
| GB0918150D0 (en) * | 2009-10-16 | 2009-12-02 | Jagotec Ag | Improved formulations |
| WO2012010854A1 (en) * | 2010-07-23 | 2012-01-26 | Cipla Limited | Inhalation formulations comprising carmoterol in combination with a corticosteroid |
| CN104271112A (zh) | 2012-04-11 | 2015-01-07 | 希普拉有限公司 | 包含阿福特罗和糠酸氟替卡松的药物组合物 |
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| CN1339965A (zh) * | 1999-02-18 | 2002-03-13 | 诺瓦提斯公司 | 福莫特罗和氟替卡松丙酸酯联合用于哮喘 |
| WO2001070198A1 (en) * | 2000-03-20 | 2001-09-27 | Dura Pharmaceuticals, Inc. | Stabilized dry powder formulations |
| WO2011136753A1 (en) * | 2010-04-26 | 2011-11-03 | Mahmut Bilgic | Combination of carmoterol and fluticasone for use in the treatment respiratory diseases |
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| CN111467498A (zh) * | 2020-05-14 | 2020-07-31 | 王兆霖 | 药物组合物制剂 |
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| IN2014MN02133A (zh) | 2015-10-09 |
| EP2836198A2 (en) | 2015-02-18 |
| RU2678992C2 (ru) | 2019-02-05 |
| US20150080358A1 (en) | 2015-03-19 |
| MX2014011576A (es) | 2014-11-21 |
| RU2014144145A (ru) | 2016-06-10 |
| WO2013153349A2 (en) | 2013-10-17 |
| WO2013153349A3 (en) | 2014-01-30 |
| AU2017276321A1 (en) | 2018-01-18 |
| KR20150002774A (ko) | 2015-01-07 |
| CA2869355A1 (en) | 2013-10-17 |
| JP2018058881A (ja) | 2018-04-12 |
| US9402854B2 (en) | 2016-08-02 |
| JP2015512929A (ja) | 2015-04-30 |
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