CN1638729A - 含有β2－激动剂的溶液的加压计量吸入器 - Google Patents
含有β2－激动剂的溶液的加压计量吸入器 Download PDFInfo
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- CN1638729A CN1638729A CNA038049724A CN03804972A CN1638729A CN 1638729 A CN1638729 A CN 1638729A CN A038049724 A CNA038049724 A CN A038049724A CN 03804972 A CN03804972 A CN 03804972A CN 1638729 A CN1638729 A CN 1638729A
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种用于通过吸入给药2(1H)－喹啉酮衍生物长效β2－激动剂的药剂。具体地说，本发明涉及一种通过特征在于肺渗透深的加压计量吸入器(pMDIs)给药的化学稳定的高效TA 2005 HFA溶液制剂。本发明还涉及所述制剂的制备方法及其在呼吸系统疾病如哮喘和慢性阻塞性肺疾病(COPD)中的用途。
Description
发明背景
哮喘是一种越来越普遍的疾病并且是儿童最常见的疾病。它可以通过周期性复发的喘鸣和间断的通气受限来诊断。尽管对其理解前进了许多，但是对所述病症的了解还很差并且经常是一种治疗效果差的疾病。以前，气道平滑肌的收缩被认为是哮喘最重要的特征。基于哮喘被认为是一种慢性炎性疾病的事实，最近在哮喘治疗方面有了明显的变化不可控制的气道炎症可以导致粘膜损坏和结构变化，从而使气道不可逆地变窄以及肺组织纤维化。因此治疗旨在控制症状以便可以正常生活，同时提供用于治疗这种根本炎症的基础。
全世界的发病率正稳定上升的另一种呼吸系统疾病是慢性阻塞性肺疾病(COPD)。患有COPD的大多数病人是通过吸烟患上的肺疾病。根据吸烟的趋势，全世界到2020年它将上升至最流行疾病第五位(LeckieM等人Exp Opin Invest Drugs 2000，9，3-23)。
慢性阻塞性肺疾病(COPD)定义为特征为因慢性支气管炎或肺气肿而存在气流梗阻的病态。
慢性支气管炎的特征是支气管粘液过量分泌，而肺气肿是指末端细支气管远端的气室的异常且永久性地扩大，同时其壁破坏并且没有明显的纤维化(American Toracic Society)。每一症状都是作为特定疾病治疗的。
慢性梗阻细支气管炎是由于细支气管发炎导致外周气道梗阻。
β2-肾上腺受体激动剂由于其促进支气管扩张效果而成为多年来治疗哮喘的一线药物。先前的研究还显示，β2-激动剂具有有效的抗炎性能，例如其代表是抑制致炎细胞因子释放。
第一代药物如沙丁胺醇或非诺特罗的特征是作用时间较短，已认为这对患夜间哮喘的病人特别不利。而且，它们对COPD效果有限，这是由于这种疾病涉及“不可逆”气道梗阻。因此开发较长效的β2-激动剂如福莫特罗、沙美特罗和TA 2005已宣布为治疗哮喘的主要且是新的开发趋势。根据一些作者，长效β2-激动剂(LABAs)在体内可以具有急性抗炎活性(Johnson M Clin Exp Allergy 1992，22，177-181；Stelmach I等人Ann Allergy Asthma Immunol 2002，89，67-73)。这些药物由于它们显示显著提高肺功能并控制症状的作用，因此对患慢性阻塞性肺疾病(COPD)的病人是一个新的感兴趣的治疗选择。
β2-肾上腺素激动剂也能够在几种动物内以及体外大鼠和人的肺内促动清除肺泡液。鉴于这些发现，已提出将β-肾上腺素能激动剂治疗作为一种加速患急性肺水肿的病人的肺水肿消除的可能的治疗(Sacuma T等人Am J Respir Crit Care Med 1997，155，506-512)。用β2-激动剂治疗也可以增加表面活性剂的分泌并且可以产生抗炎作用，因此有利于恢复肺的血管渗透性(Ware L等人New Eng.J Med 2000，342，1334-1349。
打算用于治疗肺疾病如哮喘和COPD的药物目前是通过依赖口和咽喉吸入气溶胶经肺递送给药以便药物可以到达肺。它们可以通过喷雾器以含水或水醇制剂给药，通过干粉吸入器或者在卤化烃推进剂中以干粉给药。这些推进剂-基体系需要合适的加压计量吸入器(pMDIs)，它通过每次促动释放计量量的药物。相关制剂可以是溶液或悬浮液形式。相对悬浮液，溶液制剂不存在悬浮颗粒的物理稳定性的问题因此可以保证更高剂量的均匀性和再现性。至于提到的推进剂的类型，氢氟链烷[(HFAs)，也称之为氢-氟-碳(HFCs)]将是必不可少的推进剂如氟氯化碳(还称之为氟利昂或CFCs)，多年来它们都是药用优选的推进剂气溶胶，在破坏臭氧层方面已暗示应停止使用它们。具体地说，1，1，1，2-四氟乙烷(HFA 134a)和1，1，1，2，3，3，3-七氟丙烷(HFA 227)已知是非-CFC推进剂的最佳候选并且已公开了许多使用这种HFA推进剂体系的药用气溶胶制剂。
在开发治疗用气溶胶时，吸入颗粒的空气动力学颗粒大小是定义液滴或颗粒沉积于患者的肺中的位置时的最重要的变量；简言之，它将决定药物寻靶是成功还是失败。参见P.Byron，″Aerosol Formulation，Generation，and Delivery Using Nonmetered Systems，″RespiratoryDrug Delivery，144-151，144(CRC Press，1989)。
因此，开发治疗用的气溶胶的一个先决条件是一优选的颗粒大小。
当制剂为悬浮液形式时，云状物的颗粒大小由悬浮药物的颗粒大小决定，通过磨碎/微粉化法限定。当制剂为溶液形式时，没有悬浮药物颗粒的体积分布，并且产生主要由溶液中的药物浓度限定的细得多的液滴云状物。
气溶胶制剂中的固体颗粒和/或液滴可以通过其质量中值空气动力学直径(MMAD，在该直径周围，总气体动力学直径相等地分布)表征。
颗粒在肺中的沉积主要依赖于三个物理机制：
i)碰撞，颗粒惯性的函数；
ii)重力引起的沉降；以及
iii)由精细的亚微米(＜1μm)颗粒的布朗运动产生的扩散。
颗粒的质量决定了这三个主要机制中哪一个起主导作用。
就局部作用于导气管的平滑肌的气溶胶治疗的药物而言，特别是β2-激动剂，过去已报道颗粒应优先沉积在上部至中间的肺部区域(细支气管区)，这样它们应具有约1.5(2.0)-约5.0μm，优选约3μm的MMAD(Zanen P等人Int J Pharm 1994，107，211-217；Int J Pharm 1995，114，111-115；Thorax，1996，51，977-980)。
事实上，空气动力学直径大于约5μm的颗粒通常不会到达肺，这是由于它们趋于撞击咽喉壁并吞咽，可能经口吸收，而小于1.5(2.0)μm，即约0.5-约2μm的颗粒能够到达肺泡区，已认为这是不理想的，这是由于它们可以吸收到血流中并且可能增强药物的不希望的全身效果。直径小于约0.5μm的颗粒因为它们可被呼出，所以通常认为没有治疗效果。
因此，β2-激动剂的pMDI制剂通常是能够递送颗粒大部分为2-5μm并且小于1μm的颗粒的数量非常有限的制剂，这是由于前者足够小以致它们到达上部至中间肺部区域，但是太大而不能到达肺泡。这也是传统纯药物微粒化(空气喷射粉碎)可以将药物颗粒大小降低至约2-3μm时悬浮液形式的制剂的固有颗粒大小。
另一方面，已知β-肾上腺素能受体的密度在细支气管的末端较高(Barnes P等人Am Rev Respir Dis 1983，127，758-762)，该末端是较小颗粒更好到达的区域。而且哮喘的炎症不仅仅限制在大的中心气道，而且也延伸到小的外周气道。已看到与哮喘有关的嗜曙红炎症过程既涉及支气管也涉及肺泡区(Wang S J Immunol 2001，166，2741-2749)。最近，Martin R在J Allergy Clin Immunol 2002，109(Suppl 2)，447-460中报道了末梢肺病显示增加了复发性哮喘恶化的危险性，而在末梢肺的小气道的涉及疾病的解剖学变化主要是致命性哮喘。在这方面，在其意见中，用直径为约1μm的颗粒的药物给药(称之为“超细”气溶胶)可能是有益的。末梢肺病的临床重要性使该区域成为重要的治疗目标，这样能够到达并沉积在该区域的颗粒可以更好地控制这种疾病。也已报道，在小于0.5μm的颗粒中，直径小于或等于0.3μm，优选5-300nm的颗粒，可以通过沉降沉积到肺的肺泡区。该范围内的颗粒在文献中称之为“超细”颗粒。
由癸二酸二-2-乙基己酯(DEHS)产生的“超细”颗粒，也已报道作为模型具有良好的气道渗透性(Anderson P等人Chest 1990，97，1115-1120)。Amirav I等人在J Nucl Med 2002，43，487-491中强调在治疗炎症气道疾病，特别是急性毛细支气管炎中需要用超细气溶胶寻靶窄的外周气道来改善气溶胶递送。
因此直径＜0.1μm的药用气溶胶颗粒在哮喘患者的气道梗阻的情况下可能尤为有效，其中病状与粘液分泌过多有关，它阻碍了药物分散或者在患者体内受到阻塞性肺病如COPD影响。直觉上，人们将希望粘液降低的气道腔以及永久收缩将需要更细的云状物进行灌注。
然而，迄今为止亚微米气溶胶制剂(包括HFA制剂)仅报道为含有表面活性剂如卵磷脂的微乳剂(WO 01/78689、WO 00/27363；Dickinson P等人J Drug Target 2001，9，295-302)。
根据LABAs的固有抗炎性能，能够递送大部分细粒的相关制剂将预料到在患有支气管-肺阻塞疾病的患者内非常有益。
2(1H)-喹啉酮衍生物β2-激动剂已描述为有效且长效的化合物(EP147 719；WO 00/75114)。
具体地说，8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧基苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮已报道为高效β2-激动剂，特征还在于开始作用快，由于其特有的长的作用时间，因此可以一天给药一次。其盐酸盐以试验编号TA 2005已知。
已知通过加压计量吸入器气溶胶递送的β2-激动剂的HFA溶液制剂。
名字为Boehringer Ingelheim的WO 94/13262提供了气溶胶溶液制剂，它包括一药物、HFC推进剂、助溶剂和一无机或有机酸作为防止活性成分化学降解的稳定剂。大多数实例涉及异丙托溴铵，一种抗胆碱能药。至于提及β2-激动剂，仅仅列举了含有非诺特罗的制剂，它是一种化学上与本发明的化合物无关的作用时间短的衍生物。而且，除了异丙托溴铵之外，在WO 94/13262中没有必须加入以便稳定这些药物，同时没有破坏罐中整个组成的稳定性的酸的量的教导。唯一的暗示可以在第5页第15-16行找到，说到应加入一定量的无机酸以获得1-7的pH值，该范围太宽且为一般范围。至于所述水分含量，在该申请中描述了少量水(至多约5％重量)也可以存在于推进剂/助溶剂体系中。在为异丙托溴铵的情况下，报道加入1％水降低了因脱水而致的分解。
名字为3M的WO 98/34596涉及含有一推进剂和一生理可接受的聚合物的溶液制剂，该聚合物可有助于活性成分的溶解和稳定性。
在WO 98/56349中，申请人描述了用于气溶胶吸入器的溶液组合物，包括一活性物质、含有氢氟烷烃(HFA)的推进剂、助溶剂，并且还包括一低挥发性组分以在促动吸入器时增加气溶胶颗粒的质量中值空气动力学直径(MMAD)。在一些情况下，可以将少量水加入到该组合物中以提高活性材料和/或低挥发性组分在助溶剂中的溶解。
在EP 1157689中，申请人公开了气溶胶药用组合物，它包括β2-激动剂(属于苯基烷基氨基衍生物类)在HFA推进剂、表观pH调整至2.5-5.0的助溶剂中的溶液，以保证适宜的货架期。在本发明的一个特定实施方式中，加入作为低挥发性组分的肉豆蔻酸异丙酯(IPM)以增加气溶胶颗粒的MMAD并进一步提高制品的稳定性。至于水的作用，仅报道了湿度(在为某些活性成分的情况下)会破坏贮藏期间的化学稳定性。在EP 1 157 689中笼统地叙述了TA 2005制剂将有益地适合递送2-10μg/剂，优选3-5μg/剂。在实施例7中报道了含有12％w/w乙醇和1.0％IPM的3.5μg/剂HFA 134a制剂，以便增加递送颗粒的MMAD并改善制剂的稳定性。
基于上面的考虑，特别有益的是提供高效2(1H)-喹啉酮衍生物长效β2-激动剂制剂，它通过特征在于更深肺渗透并且全身接触低的pMDI给药。
发明概述
本发明的目的是提供一种通过pMDI给药的药用气溶胶溶液制剂，它具有药用合适的货架期，包括选自式(I)的2(1H)-喹啉酮衍生物长效β2-激动剂及其旋光对映体、盐和溶剂化物的活性成分
其中R1是甲基并且R2是氢或者R1和R2形成亚甲基桥(CH2)n
n是1或2
R3、R4、R5和R6各自独立地是氢、羟基、C1-C4直链或支链烷基、取代有一个或多个卤素和/或羟基的C1-C4直链或支链烷基、卤素、C1-C4直链或支链烷氧基；
一HFA推进剂和适量的助溶剂，其中所述活性成分完全溶解在所述推进剂-助溶剂体系中。
所述溶液在将制剂促动时能够提供至少30％的等于或小于1.1μm的颗粒分数，所述颗粒分数是相对于安徒生阶式撞击取样器的阶段S3-AF收集的细粒剂量的总量，由该撞击取样器阶段S6-AF的含量定义的。
本发明的制剂能够递送大的直径等于或小于1.1μm的颗粒分数，它既包括极细颗粒，根据Martin R在J Allergy Clin Immunol 2002，109(Suppl 2)，447-460中的定义，又包括直径等于或小于0.3μm的颗粒(超细颗粒，根据其它作者的定义)。根据这些特征，本发明的制剂在本文后面称之为超细制剂。
作为本发明的一个优选方面，提供了一种药用气溶胶制剂，它包括0.005-0.016％w/v 8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧基苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮或其一种药用可接受的盐或溶剂化物作为活性成分的液化HFA推进剂和助溶剂的溶液，所述助溶剂优选选自一种药用可接受的醇，特征在于等于或小于1.1μm的颗粒分数高于或等于30％。所述颗粒分数是相对于安徒生阶式撞击取样器的阶段S3-AF收集的细粒剂量的总量，由该撞击取样器阶段S6-AF的含量定义的。优选的活性成分是前面定义为TA 2005的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧基苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮盐酸盐。在某些制剂中，可以加入占制剂总重量至多5％w/w的适量水。有益地制剂的pH在2.5-5.0之间，它是在EP 1157689中报道的模型载体体系中测定的。
本发明的制剂还可以包括另一活性成分。具体地说，将皮质类固醇加入到长效β2-激动剂能够最佳地控制大多数患者的哮喘并且相对固定的组合越来越多地用作患有持续性哮喘的患者的方便的控制剂。还报道每一类药物提高了另一类的有益作用。事实上，皮质类固醇增加了β2-受体的表达并防止其因长效β2-激动剂接触而下调，而β2-激动剂可以提高皮质类固醇的抗炎作用(Barnes P等人Eur Respir J 2002，19，182-191)。
因此，本发明的另一目的是提供高效制剂，它含有2(1H)-喹啉酮衍生物β2激动剂作为活性成分，还含有类固醇。本发明的该制剂中高的超细颗粒分数能够使两种药物都到达小的外周气道区，这样能够在末梢肺病处产生其协同作用。而且，鉴于上述特征，通过保持相同的治疗效果，可以开发包括β2激动剂和类固醇的固定组合的制剂，其中后者可以较低剂量存在。
本发明的另一方面是提供与抗胆碱能的阿托品样衍生物如异丙托溴铵、氧托溴铵和噻托溴铵组合的高效2(1H)-喹啉酮衍生物的长效β2-激动剂制剂以便提供特别有效地治疗COPD的药物。
还提供了一种将本发明的组合物装入气溶胶吸入器的方法，该方法包括：
(a)制备溶于一种或多种助溶剂中的一种或多种活性成分的溶液；
(b)任选加入预定量的水和/或调整该溶液的pH；
(c)将所述溶液装入此装置；
(d)卷曲阀门，并充气；
(e)加入一种含有氢氟烷烃(HFA)的推进剂。
本发明的另一方面包括完全溶解在推进剂/助溶剂体系并且在促动时能够提供至少30％分数的、空气动力学直径等于或小于1.1μm的发出颗粒的β2-激动剂用于制备治疗呼吸系统病症如哮喘和COPD的药物的用途。
鉴于促动时提供空气动力学直径小于1.1μm的、颗粒分数为至少30％的技术特征，本发明的制剂可以特别有效地用于治疗哮喘、COPD以及通常的气道梗阻症状，其中该病理学伴随有阻碍药物扩散的粘液分泌过多。
而且，临床上可用作加速肺泡水肿和表面活性剂缺乏有关的疾病如急性肺损伤(ALI)和急性呼吸窘迫综合症(ARDS)消退的治疗。
发明详述
本发明的气溶胶制剂包括式(I)的2(1H)-喹啉酮衍生物长效β2-激动剂作为活性成分、一HFA推进剂和一助溶剂，其中所述活性成分完全溶解，这样这些制剂在促动时能够使得发出的等于或小于1.1μm的颗粒分数大于或等于30％，该分数是通过相对于安徒生阶式撞击取样器的阶段S3-AF收集的细粒剂量的总量，以该撞击取样器阶段S6-AF的含量定义的，其有益地高于40％，优选高于50％，更优选高于60％，甚至更优选高于70％。有益地，除了增溶剂和推进剂和任选的水之外，本发明的制剂没有其它赋形剂如表面活性剂。
该制剂可以含有至多5％w/v的活性成分，例如0.0001％-5％，0.0005％-3％，0.001％-1％，0.001-0.005％w/v。
HFA推进剂的实例包括1，1，1，2-四氟乙烷(HFA134a)和1，1，1，2，3，3，3-七氟-正丙烷(HFA227)及其混合物。优选的推进剂是1，1，1，2-四氟乙烷(HFA134a)。另一感兴趣的推进剂是1，1，1，2，3，3，3-七氟-正丙烷(HFA227)。
助溶剂选自低级烷基(C1-C4)醇、多元醇、聚亚烷基二醇及其组合。其它合适的助溶剂是(聚)烷氧基衍生物，包括聚烷氧基醇类，[例如可以商标Transcutol获得的2-(2-乙氧基乙氧基)乙醇]。
优选助溶剂是一种醇。优选是乙醇。助溶剂(例如乙醇)的浓度将根据制剂中活性成分的最终浓度和推进剂而变化。乙醇的量应不超过制剂总重量的约40％w/w。有益地它占5-30％w/w，优选10-20％w/w，甚至更优选12-15％w/w。
可用于本发明的气溶胶组合物中的活性成分是式(I)的2(1H)-喹啉酮衍生物长效β2肾上腺素能激动剂及其立体异构体、生理可接受的盐和溶剂化物。
优选的活性成分是8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧基苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮，为盐酸盐形式(TA2005)。
所述活性成分可以单独使用或者可以与类固醇如二丙酸倍氯米松(BDP)、氟尼缩松、糠酸莫米他松、丙酸氟替卡松、环索奈德、布地奈德及其22R-表异构物，以及与抗胆碱能的阿托品样衍生物如异丙托溴铵、氧托溴铵、噻托溴铵或者与可用于控制呼吸系统疾病的药物如甲基黄嘌呤、抗白三烯类和磷酸二酯酶抑制剂联合使用。
该活性成分在HFA制剂中的浓度将取决于优选在一次或两次促动中递送的药物量。
在前述中，制剂是针对TA 2005提供的，药物浓度以w/v给出。相应的百分比(w/w)可以通过测定载体的密度来计算。
这些制剂将装入配备有适宜计量阀的罐中。优选制剂通过一能够递送25μl-100μl，例如50μl或63μl的体积的计量阀促动。100μl也是合适的。
TA 2005浓度将在0.0005-0.024％w/v之间变化以便每次促动递送0.5-6μg，优选在0.001-0.016％w/v之间变化以便每次促动递送1-4μg，更优选在0.001-0.008％w/v之间变化以便每次促动递送1或2μg。如果需要的话，可以使药物过量。例如，就一1和2μg/剂而言，其中使用一63μl计量容量，每次促动递送的TA 2005盐酸盐的最终浓度分别是0.0016％和0.0032％w/v。
所需的剂量方案对TA 2005而言是每天2次或1次，优选每天1次，其中适宜的每日剂量可以至多8μg，有益地在0.5-6μg的范围内，优选在1-6μg的范围内，更优选在2-4μg的范围内。
表观pH范围在2.5-5.0之间是有利的，优选在2.8-4.0之间。优选应用例如盐酸、硝酸、磷酸的强无机酸调节表观pH，更优选盐酸。
将在EP 1157689报告的模型载体中预测达到所需表观pH需要加入酸的量，该量取决于活性成分的类型和浓度以及助溶剂的量。
就在HFA 134a和15％w/w乙醇中的0.001-0.008％w/v TA 2005而言，以制剂的总重量计，优选加入浓度在0.01％-0.05％，优选0.01％-0.03％的0.1M盐酸。
当制剂还含有其它活性成分如类固醇时，水的存在特别有益。
在这些情况下，以制剂的总重量计，可以存在的水的量至多5.0％w/w，优选0.05％-3％w/w，甚至更优选1％-2％w/w。
本发明的制剂将装入适合递送药用气溶胶制剂的罐中，例如塑料或塑料涂布的玻璃瓶，或者优选金属罐，例如铝罐。制剂也可以装入部分或全部内表面由阳极化铝、不锈钢制成或者衬有一惰性有机涂层的罐中。优选涂层的实例是环氧-苯酚树脂、全氟化聚合物如全氟烷氧基链烷、全氟烷氧基链烯、全氟链烯如聚-四氟乙烯(Teflon)、氟化-乙烯-丙烯、聚醚砜和氟化-乙烯-丙烯聚醚砜共聚物。其它合适的涂层可以是聚酰胺、聚酰亚胺、聚酰胺酰亚胺、聚苯硫醚或其组合。
对TA 2005制剂而言可以优选内表面衬有Teflon的罐。
为了进一步提高稳定性，根据WO 02/72448的教导，可以使用带圆边边缘，优选包金箔颈或包金箔内边、部分或完全翻转边的罐。
罐用计量阀密封。该计量阀设计成每次促动递送计量量的制剂并且加入垫圈防止推进剂通过阀泄漏。
垫圈可以包括任何适宜的弹性材料如低密度聚乙烯、氯丁基、黑和白丁二烯-丙烯腈橡胶、丁基橡胶、氯丁橡胶、EPDM(乙烯丙二烯单体的聚合物)和TPE(热塑性弹性体)。优选EPDM和TPE橡胶。特别优选EPDM橡胶。合适的阀可从气溶胶工业公知的厂商商购获得，例如从Valois，France(例如DF10、DF30、DF60)、Bespak plc，UK(例如，BK300、BK356、BK357)和3M-Neotechnic Ltd，UK(例如Spraymiser)。法国Valois的DF31阀也是合适的。阀密封，特别是垫圈密封，以及围绕计量室的密封，优选是由对制剂的内容物，特别是当内容物包括乙醇时为惰性并且耐萃取到制剂的内容物内的材料制成。
阀材料，特别是制备计量室的材料，优选由对制剂的内容物，特别是当内容物包括乙醇时为惰性并且耐变形的材料制成。用于制备计量室的特别合适的材料包括聚酯如聚对苯二甲酸丁二酯(PBT)和缩醛类，特别是PBT。
制备计量室和/或阀干的材料可以经过氟化，部分氟化或者浸渗有含氟物质，以便防止药物沉积。
药用气溶胶制备领域的技术人员公知的常规大批量制备方法和机械可用于填充罐的工业大规模制备。因此，例如在一个大批量制备方法中，将计量阀卷曲到铝罐上以形成一空罐。将药物加入到加料容器并将乙醇、任选水和液化推进剂的混合物经加料容器加压装入一加工容器中。然后将等分量的制剂经计量阀装入罐中。
在另一方法中，在足够冷使得制剂不蒸发的条件下将等分量的液化制剂加入到一开放罐中，然后将一计量阀卷曲到罐上。
在另一方法中，将等分量的溶解在增溶剂中的药物分散到一空罐中，将计量阀卷曲其上，然后将推进剂经阀装入罐中。该方法可以在惰性环境下进行，例如通过吹入氮气，以免吸入空气中的水分。
在使用之前将每个装满的罐方便地装入合适通道设备中，以便形成向患者肺中施用药物的计量吸入器。合适的通道设备包括例如阀促动器和圆柱形或圆锥形通道，由此可以将药物从填充罐经计量阀递送到患者的嘴中，例如口罩促动器。
在一典型配置中，阀干位于喷嘴块，所述喷嘴块有一导向膨胀室的孔口。膨胀室有一延伸到口罩的出口。促动器(出)口直径在0.15-0.45mm的范围内，特别是在0.2-0.45mm的范围内通常是合适的，例如0.25、0.30、0.33或0.42mm。0.22mm也是合适的。就某些制剂而言，利用直径在0.10-0.22mm，特别是0.12-0.18mm的范围内的激光打孔的促动器孔口将是有用的，如待审申请号EP 1130521.6中所述的那些。
使用这些细孔还增加了云状物的产生时间并降低了其速度。这些变化便于协调云状物产生和患者的慢的吸入。
本发明的每个待测制剂的空气动力学颗粒大小分布可以用多级阶式撞击取样器按照European Pharmacopoeia 2nd edition，1995，partV.5.9.1，pages 15-17中所述的步骤表征。在该特定情况下，使用一安徒生阶式撞击取样器(ACI)在28.3l/min的流速下操作。通过高压液相色谱法(HPLC)测定药物在每一ACI板上的沉积。由ACI中的累积沉积计算平均递送剂量。平均可吸入剂量(细粒剂量)是由阶段3(S3)到过滤器(AF)的沉积(相当于颗粒大小≤4.7μm)除以每次试验促动的次数获得的，而平均“超细”剂量是由阶段6到过滤器上的沉积(相当于颗粒≤1.1μm)获得的。
本发明制剂的给药可以指示用于治疗轻度、中度或重度、急性或慢性症状或者用于预防性治疗呼吸系统疾病如哮喘和慢性阻塞性肺疾病(COPD)。因炎症并存在粘液引起的外周气道梗阻的特征的其它呼吸系统病症如慢性梗阻性细支气管炎和慢性支气管炎也可以用这种制剂受益。
下面参照实施例描述本发明。
实施例1-超细TA 2005 HFA制剂
用以下组成制备每次促动递送活性成分1μg标称剂量的制剂：
| 组成 | 量 | ||
| TA 2005乙醇HCl 0.1MHFA 134a(适量至9.45ml) | 每单位 | 标称剂量 | |
| mg0.1516502.0*9347.85 | ％0.0016w/v15w/w0.018w/w- | μg1--- | |
*相当于2.0μl
将该制剂(120次促动/罐，超过30次促动)装入内表面涂布有Teflon(两阶段压力填充)并配备有63μl计量室的计量阀的铝罐。使用一个孔径为0.22mm的促动器。以2个罐的平均值获得结果。
类似地，可以制备每次促动递送活性成分2、3或4μg标称剂量的制剂。通过ACI按照第16页第10-18行测定空气动力学颗粒大小分布，并根据以下参数测定每一制剂的递送特性：i)标称剂量：单次促动的理论剂量；ii)递送剂量：沉积到所有ACI阶段的活性颗粒的量；iii)可吸入剂量(细粒剂量)：颗粒大小小于4.7μm(S3-AF)的活性颗粒的量；iv)可吸入分数(细粒分数)：可吸入剂量与递送剂量之比；v)“超细”剂量：等于或小于1.1μm(S6-AF)的活性颗粒的量；iv)“超细”分数：“超细”剂量与可吸入剂量之比。
本发明的制剂在促动之后产生直径小于1.1μm的颗粒的非常高的百分比。就某些制剂而言，根据活性成分的百分比和助溶剂的量，可以获得大于80％的超细分数。
尽管制剂中存在这么高的直径等于或小于1.1μm的颗粒分数，但是在该治疗剂量下该药物也已被很好地耐受。
将这些罐于5℃直立贮藏下对每次促动时能够递送4μg的制剂的稳定性进行了研究。
9个月后，TA 2005测定高于95％，因此满足the ICH guideline Q1A提及的″Stability Testing of new Active Substances(and MedicinalProducts)″的要求。
实施例2-含有TA 2005和22R-布地奈德的超细HFA制剂
用以下组成制备每次促动时分别递送1μg标称剂量的TA 2005和80μg的22R-布地奈德的制剂：
| 组成 | 量 | ||
| 每单位 | 标称剂量 | ||
| mg | ％ | μg | |
| TA 2005 | 0.15 | 0.0016w/v | 1 |
| 22R-布地奈德 | 12.00 | 0.127w/v | 80 |
| 乙醇 | 1650 | 15w/w | - |
| HCl 0.1M | 3.3* | 0.03w/w | - |
| 水 | 220.05 | 2.0w/w | - |
| HFA 134a(适量至9.45ml) | 9114.5 | - | - |
*相当于3.3μl
将该制剂(120次促动/罐，超过30次促动)装入内表面涂布有Teflon(两阶段压力填充)并配备有63μl计量室的计量阀的铝罐。
Claims (19)
1、一种通过加压计量吸入器给药的药用气溶胶制剂，包括选自下式2(1H)-喹啉酮衍生物长效β2-激动剂及其立体异构体、生理可接受的盐和溶剂化物的活性成分，在液化HFA推进剂、助溶剂以及任选以制剂的总重量计最多5％的水的溶液中，
其中R1是甲基并且R2是氢或者R1和R2形成亚甲基桥(CH2)n
n是1或2
R3、R4、R5和R6各自独立地是氢、羟基、C1-C4直链或支链烷基、取代有一个或多个卤素和/或羟基的C1-C4直链或支链烷基、卤素、C1-C4直链或支链烷氧基。
2、如权利要求1的药剂，其中根据说明书第16页第10-18行提到的方法，相对于安徒生阶式撞击取样器的阶段S3-AF的量，由该撞击取样器的阶段S6-AF的量定义，在促动吸入器时递送的等于或小于1.1μm的颗粒分数大于或等于30％。
3、如权利要求1-2的药剂，其中超细分数大于50％。
4、如权利要求1-3的药剂，其中活性成分是8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧基-苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮、或其生理可接受的盐或溶剂化物。
5、如权利要求1-3的药剂，其中活性成分是8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧基-苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮盐酸盐。
6、如权利要求5的药剂，其中活性成分的浓度为0.0005-0.024％w/v。
7、如权利要求5的药剂，其中活性成分的浓度为0.001-0.008％w/v。
8、如任意前述权利要求的药剂，其中pH在2.5-5.0之间。
9、如任意前述权利要求的药剂，其中pH在2.8-4.0之间。
10、如权利要求8和9的药剂，其中pH是通过加入盐酸调节的。
11、如任意前述权利要求的药剂，其中推进剂包括一种或多种选自HFA 134a和HFA 227的氢氟烷烃[HFAs]。
12、如任意前述权利要求的药剂，其中助溶剂选自低级烷基(C1-C4)醇类、多元醇、聚亚烷基二醇、(聚)烷氧基衍生物及其组合。
13、如权利要求12的药剂，其中助溶剂是乙醇。
14、如权利要求6的药剂，还包括15％w/w乙醇、0.01％-0.05％w/wHCl 0.1M和HFA 134a。
15、如任意前述权利要求的药剂，将其装入部分或全部金属内表面衬有一惰性有机涂层的罐中。
16、如权利要求15的药剂，其中所述罐衬有一选自如下的惰性有机涂层：环氧-苯酚树脂、全氟烷氧基链烷、全氟烷氧基链烯、全氟链烯如聚四氟乙烯、氟化-乙烯-丙烯、聚醚砜和氟化-乙烯-丙烯聚醚砜共聚物。
17、如权利要求16的药剂，所述惰性有机涂层是聚四氟乙烯(Teflon)。
18、如任意前述权利要求的药剂，还包括选自如下的另一活性成分：类固醇类如二丙酸倍氯米松、丙酸氟替卡松、环索奈德、布地奈德及其22R-表异构物，或抗胆碱能的阿托品样衍生物如异丙托溴铵、氧托溴铵和噻托溴铵。
19、一种制备权利要求1-18的药剂的方法，该方法包括：
(a)制备溶于一种或多种助溶剂中的一种或多种活性成分的溶液；
(b)任选加入预定量的水和/或调整该溶液的pH；
(c)将所述溶液装入此装置；
(d)卷曲阀门，并充气；
(e)加入含有氢氟烷烃(HFA)的推进剂。
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| EP02004786A EP1340492A1 (en) | 2002-03-01 | 2002-03-01 | Aerosol formulations for pulmonary administration of medicaments having systemic effects |
| EP02023589A EP1415647A1 (en) | 2002-10-23 | 2002-10-23 | "Long-acting beta-2 agonists ultrafine formulations" |
| EP02023589.1 | 2002-10-23 |
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| CNA2009100074339A Division CN101502500A (zh) | 2002-03-01 | 2003-02-27 | 含有β2-激动剂的溶液的加压计量吸入器 |
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| CNA038049724A Pending CN1638729A (zh) | 2002-03-01 | 2003-02-27 | 含有β2－激动剂的溶液的加压计量吸入器 |
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| IT1318514B1 (it) * | 2000-05-12 | 2003-08-27 | Chiesi Farma Spa | Formulazioni contenenti un farmaco glucocorticosteroide per iltrattamento di patologie broncopolmonari. |
| UA73986C2 (uk) * | 2000-05-22 | 2005-10-17 | К'Єзі Фармачеутічі С.П.А. | АЕРОЗОЛЬНА КОМПОЗИЦІЯ, ЩО МІСТИТЬ <font face="Symbol">b</font>2-АДРЕНЕРГІЧНИЙ АГОНІСТ ТРИВАЛОЇ ДІЇ, ДОЗУЮЧИЙ ІНГАЛЯТОР ПІД ТИСКОМ ТА СПОСІБ ЙОГО ЗАПОВНЕННЯ |
| EP1241113A1 (en) | 2001-03-12 | 2002-09-18 | CHIESI FARMACEUTICI S.p.A. | Inhaler with means for improving chemical stability of medicinal aerosol solution contained therein |
| ES2222294T3 (es) * | 2001-07-02 | 2005-02-01 | Chiesi Farmaceutici S.P.A. | Formulacion optimizada de tobramicina para administracion en forma de aerosol. |
| SI3494995T1 (sl) * | 2002-03-01 | 2020-08-31 | Chiesi Farmaceutici S.P.A. | Superfina formulacija formoterola |
| EP1340492A1 (en) * | 2002-03-01 | 2003-09-03 | CHIESI FARMACEUTICI S.p.A. | Aerosol formulations for pulmonary administration of medicaments having systemic effects |
| EP1595531A1 (en) * | 2004-05-13 | 2005-11-16 | CHIESI FARMACEUTICI S.p.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
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2003
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2020
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103096897A (zh) * | 2010-07-16 | 2013-05-08 | 希普拉有限公司 | 包含r(+)布地奈德和一种或多种支气管扩张剂的药物组合物 |
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