CN103476412A - 用于改善呼吸系统疾病患者睡眠质量的阿地铵 - Google Patents

用于改善呼吸系统疾病患者睡眠质量的阿地铵 Download PDF

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CN103476412A
CN103476412A CN2012800186372A CN201280018637A CN103476412A CN 103476412 A CN103476412 A CN 103476412A CN 2012800186372 A CN2012800186372 A CN 2012800186372A CN 201280018637 A CN201280018637 A CN 201280018637A CN 103476412 A CN103476412 A CN 103476412A
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M·E·加西亚吉尔
G·德米克尔塞拉
M·J·萨拉佩纳多
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Abstract

本发明提供了阿地铵或其任何立体异构体或立体异构体的混合物，或其药学上可接受的盐或溶剂合物，用于改善呼吸系统疾病患者的睡眠质量的用途。

Description

用于改善呼吸系统疾病患者睡眠质量的阿地铵
技术领域
本发明涉及阿地铵（aclidinium）的新用途，其可有利地用于改善呼吸系统疾病患者的睡眠质量。
背景技术
例如哮喘和慢性阻塞性肺病(COPD)的呼吸疾病是重大的全球性健康问题，并且全世界的发病率增加。它们通常的特征是气道的炎性功能性障碍，其将导致支气管收缩。
在哮喘中，炎症是由暴露于多种触发因子引起的，所述触发因子包括过敏原和病毒，其既激活了先天性免疫应答和获得性免疫应答的组分。在COPD中，炎症主要是由于暴露于有害颗粒和气体（尤其是香烟烟雾）而发生。COPD这一术语是包括多种疾病，例如慢性支气管炎或肺气肿而不是单一的病理状态。
哮喘和COPD通常伴随严重的由肺部症状引起的身体功能损伤，所述肺部症状例如呼吸困难（呼吸急促）、疲劳、咳嗽、喘鸣、胸闷或充血以及生痰。许多呼吸系统疾病患者抱怨这些症状严重影响他们的睡眠质量。
在COPD患者中，睡眠相关的症状是继呼吸困难和疲劳后第三位的最常报告的症状（Kinsman et al,Chest,1983,83,755-761）。在哮喘中，80%的患者至少偶尔地会因夜间喘鸣和咳嗽而醒来，许多患有严重的稳定期哮喘患者事实上每天夜间都会醒来（Turner-Warwick,M.;Am,J.Med.,1988,85(suppl.1B),6-8）。
呼吸系统疾病患者经常报告的睡眠症状为，例如入睡等待时间较长、保持睡眠困难、经常激醒和觉醒、睡眠浅、总睡眠时间减少、过早醒来且不能再入睡、普遍性失眠以及总体而言非常差的睡眠质量。由早晨呼吸急促引起的日间过度嗜睡和体力活动受限也是睡眠质量下降的常见结果。
这些睡眠紊乱随着疾病的发展将趋于更加严重，并将大幅降低呼吸系统疾病患者的生活质量。
支气管扩张剂，如β-肾上腺素能激动剂或胆碱能毒蕈碱受体拮抗剂（通常称为抗胆碱能剂或抗毒蕈碱剂）通常被医生开给患有阻塞性气道疾病（例如哮喘或COPD）的呼吸系统疾病患者用于吸入。所有可市购的抗胆碱能剂均为合成的托烷衍生物，包括异丙托铵（ipratropium）、氧托铵（oxitropium）、噻托铵（tiotropium）。噻托铵是目前市场上唯一的长效抗胆碱能剂。
众所周知，在呼吸系统疾病患者中，昼夜节律对气道反应性和气道阻力的影响远大于对正常受试者的影响。因此，呼吸系统疾病患者在夜间和清晨特别易于发生支气管收缩，并且这是影响他们睡眠的主要因素。因此，极度需要旨在克服或预防夜间支气管收缩的治疗。但是，Calverley等在Thorax,2003,58(10),855-860的研究表明与仅在早上给药相比，在夜间给予长效支气管扩张剂噻托铵并没有在夜间产生更强的支气管扩张。
现已令人惊讶地发现阿地铵显著地减少了呼吸系统疾病患者中常见的睡眠障碍的发生，因此提高了睡眠质量和整体生活质量。
阿地铵是3(R)-(2-羟基-2,2-二噻吩-2-基乙酰氧基)-1-(3-苯氧基丙基)-1-氮鎓二环[2.2.2]辛烷，其为Almirall开发的长效毒蕈碱受体拮抗剂，用于在呼吸系统疾病（尤其是哮喘和COPD）中通过吸入给药。其首次公开于WO01/04118。
阿地铵在人血浆中被迅速水解为两种无活性的代谢产物，因此与目前可市购的吸入型抗胆碱能治疗剂相比，其引起全身副作用的可能性降低，并且具有更宽的安全边界。其改善睡眠质量的额外效果是本发明的一个意外的发现。
发明内容
本发明提供了阿地铵，或其任何立体异构体或立体异构体混合物，或其药学上可接受的盐或溶剂合物用于改善呼吸系统疾病患者的睡眠质量的用途。
优选地，阿地铵为带有阴离子X-的盐的形式。最优选地，所述阴离子X-为溴。
在优选的实施方案中，呼吸系统疾病患者患有选自以下的疾病：急性或慢性支气管炎、肺气肿、哮喘和慢性阻塞性肺病，优选哮喘和慢性阻塞性肺病，最优选慢性阻塞性肺病。
在另一个实施方案中，阿地铵作为适于吸入的药物组合物——优选以干粉的形式——给药。所述组合物可通过任意吸入器设备，更优选通过
Figure BDA0000396079400000031
进行给药。
通常，干粉制剂包含选自单糖、二糖或多糖以及糖醇的药学上可接受的载体。优选地，所述载体为乳糖。
阿地铵至少每日给药一次，优选在早上或在夜间给药。更优选阿地铵每日给药两次。在最优选的实施方案中，阿地铵每日给药两次，一次在早上，另一次在夜间。
每次吸入所使用的阿地铵的有效剂量相当于用于吸入的干粉中计量标称剂量为100至1000微克的阿地溴铵，更优选200或400微克的阿地溴铵。
在另一个优选的实施方案中，阿地铵与另外的适于治疗呼吸系统疾病的药物共同给药，所述另外的药物选自例如以下的一种或多种：皮质类固醇、β-肾上腺素能激动剂、PDE4抑制剂、抗组胺剂、抗-IgE抗体、白细胞三烯D4抑制剂、egfr-激酶抑制剂、p38激酶抑制剂和/或NK1-受体拮抗剂。所述另外的药物可与阿地铵存在于相同的药物组合物中或者存在于不同的药物组合物中。优选地，所述另外的药物选自皮质类固醇、β-肾上腺素能激动剂和/或PDE4抑制剂。
阿地铵对呼吸系统疾病患者的睡眠质量的改善可通过观察以下一项或多项的减少和/或总睡眠时间的增加而测量：
a）入睡前的等待时间
b）觉醒总次数
b）早醒
c）维持睡眠的难度
d）浅睡眠
e）失眠
f）日间嗜睡或疲劳
g）早晨期间活动限制。
可能促进阿地铵对呼吸疾病患者睡眠质量改善的临床因素为以下一项或多项睡眠期间的呼吸系统症状的减少：
a）咳嗽严重程度和/或频率
b）生痰
c）喘鸣
d）胸闷
e）胸部充血
f）支气管收缩
g）呼吸急促
h）对救援药物的需要
本发明还提供了用于改善呼吸系统疾病患者睡眠质量的含阿地铵的药物组合物。
本发明还提供了阿地铵在制备用于改善呼吸系统疾病患者睡眠质量的药物中的用途。
本发明还提供了改善呼吸系统疾病患者的睡眠质量的方法，所述方法包括向所述患者给药如上所定义的有效量的阿地铵。
发明详述
通常，阿地铵以带有阴离子X-的盐的形式给药，其中X-为药学上可接受的单价酸或多价酸的阴离子。更常见地，X-为衍生自无机酸或有机酸的阴离子，所述无机酸例如盐酸、氢溴酸、硫酸和磷酸，所述有机酸例如甲磺酸、乙酸、富马酸、琥珀酸、乳酸、柠檬酸或马来酸。最优选地，阿地铵为阿地溴铵的形式。
本发明的化合物既可以未溶剂化的形式存在也可以溶剂化的形式存在。本文中使用术语溶剂合物来描述含有本发明的化合物和一定量一种或多种药学上可接受的溶剂分子的分子配合物。当所述溶剂为水时，使用术语水合物。溶剂合物形式的实例包括但不限于，与水、丙酮、二氯甲烷、2-丙醇、乙醇、甲醇、二甲基亚砜（DMSO）、乙酸乙酯、乙酸、乙醇胺或其混合物结合的本发明化合物。尤其考虑在本发明中的是，一个溶剂分子可与本发明化合物的一个分子结合，例如水合物。
术语“治疗”应理解为包括疾病或病症的症状缓解和/或疾病或病症的病因的消除和/或预防疾病或其症状的出现。
术语“治疗有效量”是指当向需要治疗的患者给药时，足以使治疗起效的量。
阿地铵还可与已知对治疗上述疾病或病症有效的其他药物结合使用。例如，阿地铵可与皮质类固醇或糖皮质激素、β-肾上腺素能激动剂、PDE4抑制剂、抗组胺剂、抗-IGE抗体、白细胞三烯D4拮抗剂、egfr-激酶抑制剂、p38激酶抑制剂和/或NK-1受体激动剂结合。
在本发明中可与阿地铵结合的皮质类固醇具体包括适于在治疗呼吸系统疾病或病症中通过吸入给药的那些，例如，泼尼松龙（prednisolone）、甲泼尼龙（methylprednisolone）、地塞米松、萘非可特（naflocort）、地夫可特（deflazacort）、醋酸卤泼尼松（halopredone acetate）、布地奈德（budesonide）、二丙酸倍氯地米松（beclomethasone dipropionate）、氢化可的松（hydrocortisone）、曲安奈德（triamcinolone acetonide）、氟轻松（fluocinolone acetonide）、醋酸氟轻松（fluocinonide）、氯可托龙（clocortolone Pivalate）、醋丙甲泼尼龙（methylprednisolone aceponate）、软脂酸地塞米松（dexamethasone palmitoate）、替泼尼旦（tipredane）、醋丙氢可的松（hydrocortisone aceponate）、泼尼卡酯（prednicarbate）、双丙酸阿氯米松（alclometasone dipropionate）、卤米松（halometasone）、磺庚甲泼尼龙（methylprednisolone suleptanate）、糠酸莫米松（mometasone furoate）、利美松龙（rimexolone）、法尼基泼尼松龙（prednisolone farnesylate）、环索奈德（ciclesonide）、地泼罗酮丙酸酯（deprodone propionate）、丙酸氟替卡松（fluticasone propionate）、卤倍他索丙酸酯（halobetasol propionate）、依碳氯替泼诺（loteprednoletabonate）、倍他米松丁酸丙酯（betamethasone butyrate propionate）、氟尼缩松（flunisolide）、泼尼松（prednisone）、地塞米松磷酸钠（dexamethasone sodium phosphate）、曲安西龙（triamcinolone）、倍他米松17-戊酸酯（betamethasone17-valerate）、倍他米松（betamethasone）、二丙酸倍他米松（betamethasone dipropionate）、醋酸氢化可的松（hydrocortisone acetate）、氢化可的松琥珀酸钠（hydrocortisone sodiumsuccinate）、泼尼松龙磷酸钠(prednisolone sodium phosphate)和丙丁酸氢化可的松（hydrocortisone probutate）。特别优选布地奈德和莫米松（mometasone）。
在本发明中可与阿地铵结合的β-肾上腺素能激动剂具体包括可用于治疗呼吸系统疾病或病症的β2肾上腺素能激动剂，例如，其选自游离形式或药学上可接受的盐形式的阿福特罗（arformoterol）、班布特罗（bambuterol）、比托特罗（bitolterol）、溴沙特罗（broxaterol）、卡布特罗（carbuterol）、克伦特罗（clenbuterol）、多培沙明（dopexamine）、非诺特罗（fenoterol）、福莫特罗（formoterol）、海索那林（hexoprenaline）、异丁特罗（ibuterol）、异丙肾上腺素（isoprenaline）、马布特罗（mabuterol）、美卢君（meluadrine）、诺罗米罗（nolomirole）、奥西那林（orciprenaline）、吡布特罗（pirbuterol）、丙卡特罗（procaterol）、瑞普特罗（reproterol）、利托君（ritodrine）、利米特罗（rimoterol）、沙丁胺醇（salbutamol）、沙美特罗（salmeterol）、西贝奈迪（sibenadet）、磺酰特罗（sulfonterol）、特布他林（terbutaline）、妥洛特罗（tulobuterol）、维兰特罗（vilanterol）、殴达特罗（olodaterol）、KUL-1248、LAS-100977、卡莫特罗（carmoterol）和茚达特罗（indacaterol）。优选地，所述β2肾上腺素能激动剂为长效β2肾上腺素能激动剂，例如，其选自游离形式或药学上可接受的盐的形式的福莫特罗、沙美特罗、卡莫特罗、卡莫特罗、殴达特罗、LAS-100977和茚达特罗。
可与本发明的阿地铵结合的PDE4抑制剂包括登布茶碱（denbufylline）、咯利普兰（rolipram）、西潘茶碱（cipamfylline）、阿罗茶碱（arofylline）、非明司特（filaminast）、吡拉米司特（piclamilast）、美索普兰（mesopram）、盐酸屈他维林（drotaverinehydrochloride）、利米司特（lirimilast）、罗氟司特（roflumilast）、西洛司特（cilomilast）、6-[2-(3,4-二乙氧基苯基)噻唑-4-基]吡啶-2-羧酸、(R)-(+)-4-[2-(3-环戊氧基-4-甲氧基苯基)-2-苯乙基]吡啶、N-(3,5-二氯-4-吡啶基)-2-[1-(4-氟苄基)-5-羟基-1H-吲哚-3-基]-2-氧代乙酰胺、9-(2-氟苄基)-N6-甲基-2-(三氟甲基)腺嘌呤、N-(3,5-二氯-4-吡啶基)-8-甲氧基喹啉-5–羧酰胺、N-[9-甲基-4-氧代-1-苯基-3,4,6,7-四氢吡咯[3,2,1-jk][1,4]苯二氮-3(R)-基]吡啶-4-羧酰胺、3-[3-(环戊氧基)-4-甲氧基苄基]-6-(乙氨基)-8-异丙基-3H-嘌呤盐酸盐、4-[6,7–二乙氧基-2,3-双(羟甲基)萘-1-基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮、2-甲酯基-4-氰基-4-(3–环丙基甲氧基-4-二氟甲氧基苯基)环己-1-酮、顺[4-氰基-4-(3–环丙基甲氧基-4-二氟甲氧基苯基)环己-1-醇、ONO-6126（Eur Respir J2003,22(Suppl.45):Abst2557）及PCT专利申请WO03/097613和PCT/EP03/14722和西班牙专利申请P200302613中要求保护的化合物。
用于本发明的阿地铵可通过任何适宜的途径给药以提供局部抗毒蕈碱作用。其优选以例如粉末、喷雾或气雾形式，优选以干粉形式通过吸入给药。包含阿地铵的药物组合物可用医学领域中已知的常规稀释剂或赋形剂和技术来制备。
用于以干粉形式通过吸入给药的药剂需具有受控的粒径。吸入至支气管系统的最佳粒径通常为1-10μm、优选2-5μm。粒径超过20μm的颗粒被吸入时通常太大以致于不能达到小的气道。为了达到所述粒径，可通过常规方法，例如通过微粉化或超临界流体技术来减小所产生的活性成分的尺寸。所需级分可以通过风选或风筛而分离。优选地，所述颗粒为晶体。
由于微粉化粉末的流动性差且极易团聚，因此难以使用微粉化粉末实现高剂量重复性。为了提高干粉组合物的效能，所述颗粒在吸入器中时应当较大，但是当其被送至呼吸道时应当较小。因此，一般使用赋形剂，例如单糖、二糖、多糖或者糖醇，例如乳糖、甘露醇或葡萄糖。所述赋形剂的粒径通常会远大于本发明吸入药剂的粒径。当所述赋形剂是乳糖时，其通常会以例如平均粒径为20-1000μm，优选90-150μm的乳糖颗粒存在，优选为晶体α-乳糖一水合物。在一个实施方案中，用于本发明的制剂的乳糖颗粒的d10为90-160μm，d50为170-270μm且d90为290-400μm。
适合用于本发明的乳糖材料可市购自，例如DMW Intemacional(Respitose GR-001、Respitose SV-001、Respitose SV-003)；Meggle(Capsulae60、Inhalac70、Capsulae60INH)；和Borculo Domo(Lactohale100-200、Lactohale200-300、Lactohale100-300)。
乳糖颗粒与阿地铵的重量比取决于所使用的吸入装置，但是其通常为例如5:1至200:1，例如50:1至150:1，例如60-70:1。
在优选的实施方案中，阿地铵以适于通过干粉吸入器给药的、阿地溴铵与乳糖混合的干粉制剂形式给药，阿地溴铵与乳糖的重量比为1:50至1:150，其中阿地铵颗粒的平均粒径为直径2至5μm，例如直径小于3μm；乳糖颗粒的d10为90-160μm，d50为170-270μm且d90为290-400μm。
通过吸入局部递送至肺的干粉组合物可以存在于例如明胶胶囊和药筒中或存在于例如层压铝箔的泡罩中，以用于在吸入器或吹入器中使用。每个胶囊或药筒一般可含有0.001-50mg，更优选0.01-5mg的活性成分或等同量的其药学上可接受的盐。或者，所述活性成分可以以无赋形剂的形式存在。
制剂的包装可以适用于单位剂量给药或多剂量递送。对于多剂量递送的情况，所述制剂可被预计量或在使用时计量。因此，干粉吸入器被分为三类：（a）单剂量装置；（b）多个单位剂量装置和（c）多剂量装置。
阿地铵优选用多剂量吸入器给药，更优选用
Figure BDA0000396079400000081
（正式名称为Novolizer SD2FL）给药，其描述于以下专利申请中：WO97/000703、WO03/000325和WO2006/008027。
剂量会根据例如个体、给药方式和给药频率、待治疗的病症的性质和严重程度而变化。对于70kg的成年人，其每日剂量通常可以为例如约100-1000微克用于吸入的干粉形式的活性试剂的量级。
实施例1
在IIa期的随机、双盲、交叉试验中，中度至重度COPD患者接受400微克阿地铵，每日两次（早上9点；夜间9点）和安慰剂15天，在治疗期之间有9-15天的清洗期（washout）。
睡眠质量根据患者日志卡上的每日记录，按照如下标准使用0-4分进行评估：
0 无觉醒
1 早醒或在夜间醒来一次
2 早醒或在夜间醒来两次或多于两次
3 在夜间大多时候是醒着的
4 患者根本不能入睡
用阿地铵治疗的患者与未经治疗的患者相比显示出睡眠质量的显著改善。
实施例2
在双盲、随机、安慰剂对照的III期试验中，在COPD患者的每日进行两次阿地溴铵治疗期间，评估了睡眠质量和救援药物的使用。
向FEV1/FVC<70%的COPD患者随机（1:1:1）给药阿地铵200微克、400微克或安慰剂。使用电子日志和调查问卷每日报告睡眠质量，其评估了症状频率和严重程度及其对晨间活动的影响。还评估了救援药物的使用。
在第12周，阿地铵与安慰剂相比显著改善了睡眠质量。200微克和400微克阿地铵显著地降低了夜间呼吸急促和咳嗽的严重程度、醒来频率和再次入睡的困难程度。此外，还减少了痰液的产生和救援药物的使用。
两种阿地铵剂量还显著地降低了清晨呼吸急促的严重程度并降低了呼吸急促和咳嗽对晨间活动的影响。
实施例3
在IIa期的随机、双盲、双模拟、交叉试验中，中度至重度COPD患者接受吸入型阿地铵400μg BID（每日两次）、噻托铵18μg QD和安慰剂15天，在治疗期之间具有9-15天清洗期。
在患者日志卡上每日记录睡眠困难的发生率。与实施例1相同，分数从代表无睡眠困难的0分至代表睡眠困难严重程度递增的1-4分。然后测量由每种治疗所产生的相对于本底值的分数变化。
用噻托铵治疗的患者的平均分（+/-SEM）为-0.011（0.091），该分数实际上与本底值相同并且非常接近用安慰剂治疗的患者中观察到的分数0.061（0.088）。这两组分数在统计学上没有显著性差异（p>0.05）。相对而言，用阿地铵治疗的患者的分数为-0.123（0.089）。此情况下，在与安慰剂相比存在统计学上的显著差异（p<0.05）。
这些第IIa期结果证明，当用目前市场上的对照抗胆碱能药物噻托铵治疗患者时，未观察到由阿地铵产生的睡眠质量的显著改善。因此，阿地铵这种预料不到的效果是非显而易见的，具备创造性。

Claims (15)

1.阿地铵或其任何立体异构体或立体异构体混合物或其药学上可接受的盐或溶剂合物用于改善呼吸系统疾病患者的睡眠质量的用途。
2.权利要求1所用的阿地铵，其中所述阿地铵为阿地溴铵的形式。
3.权利要求1或2所用的阿地铵，其中所述呼吸系统疾病患者患有哮喘或慢性阻塞性肺病（COPD）。
4.前述权利要求中任一项所用的阿地铵，其中所述阿地铵为适于吸入的干粉制剂形式。
5.权利要求4的干粉制剂中所用的阿地铵，每次吸入提供计量标称剂量相当于100至1000微克阿地溴铵、更优选200或400微克阿地溴铵的阿地铵。
6.前述权利要求中任一项所用的阿地铵，其中阿地铵为每日给药一次或多次，优选每日给药两次。
7.前述权利要求中任一项所用的阿地铵，其中阿地铵与治疗有效量的皮质类固醇、β-肾上腺素能激动剂和/或PDE4抑制剂共同给药。
8.前述权利要求中任一项所用的阿地铵，其中睡眠质量通过减少以下一项或多项和/或通过增加总睡眠时间来改善：
a）入睡前的等待时间
b）觉醒总次数
b）早醒
c）维持睡眠的难度
d）浅睡眠
e）失眠
f）日间嗜睡或疲劳
g）早晨期间活动限制。
9.药物组合物，包含如前述权利要求中任一项所定义的用于改善如前述权利要求中任一项所限定的呼吸系统疾病患者的睡眠质量的阿地铵。
10.前述权利要求中任一项所定义的阿地铵在制备用于改善前述权利要求中任一项所限定的呼吸系统疾病患者的睡眠质量的药物中的用途。
11.一种改善呼吸系统疾病患者的睡眠质量的方法，所述方法包括给予所述患者有效量的前述权利要求任一项中所定义的阿地铵。
12.权利要求1或2所定义的阿地铵，用于在患有睡眠障碍的患者中治疗呼吸系统病症，优选哮喘或慢性阻塞性肺病。
13.用于权利要求12的阿地铵，其中所述睡眠障碍包括以下一项或多项：
a）入睡延迟，
b）在夜间醒来一次或多次、优选2次或多于2次、更优选3次或多于3次，
b）早醒，
c）维持睡眠困难，
d）浅睡眠，
e）失眠，
f）日间嗜睡或疲劳，和
g）早晨期间活动受限。
14.权利要求1或2中所定义的阿地铵在制备用于在患有睡眠障碍的患者中治疗呼吸系统疾病的药物的用途，所述呼吸系统疾病优选哮喘或慢性阻塞性肺病。
15.权利要求14的用途，其中所述睡眠障碍包括以下一项或多项：
a）入睡延迟，
b）在夜间醒来一次或多次、优选2次或多于2次、更优选3次或多于3次，
b）早醒，
c）维持睡眠困难，
d）浅睡眠，
e）失眠，
f）日间嗜睡或疲劳，和
g）早晨期间活动受限。
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