CN102083416A - 包含阿地尼亚的用于治疗哮喘和慢性阻碍性肺病的吸入式组合物 - Google Patents
包含阿地尼亚的用于治疗哮喘和慢性阻碍性肺病的吸入式组合物 Download PDFInfo
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Abstract
一种供吸入的药剂组成物,包括干粉型态的阿地尼亚(aclidinium)在药理学上可接受的盐,并与一药理学上可接受的干粉载体相混合,且提供有相当于约400微克阿地溴铵(aclidinium bromide)的阿地尼亚定量标称剂量。
Description
技术领域
本发明是有关一种阿地尼亚(aclidinium)的新颖剂量以及使用阿地尼亚以治疗呼吸***疾病(尤其是哮喘以及慢性阻塞性肺病)的新颖方法与配方。
背景技术
阿地溴铵(aclidinium bromide)为(3R)-(2-羟基-2,2-二噻吩-2-基乙酰氧基)-1-(3-苯氧丙基)-1-氮杂双环[2.2.2]辛烷溴化物(即叙述于例如WO0104118号专利案中者)。虽然该化合物已知为长效性抗胆碱药物,且对于治疗呼吸***疾病有所帮助,然而其最适当的剂量仍尚未被揭露。
发明内容
在现今研究结果中意外发现,在治疗成人的呼吸***疾病-尤其是哮喘以及慢性阻塞性肺病-方面,最有效使用阿地尼亚的方式是利用吸入方式在一次用药中,给予每一定量标称剂量(metered nominal dose)约400微克的阿地尼亚;通常于单一用药中,给予每日定量标称剂量约400微克的阿地尼亚;例如约360微克的吸入器发出剂量(emitted dose),以及约120微克的微粒剂量(Fine Particle dose)(相对应于阿地溴铵的重量)。
因此,本发明于第一实施例中提供一种供吸入的药剂组成物,包含干粉型态的阿地尼亚(aclidinium)在药理学上可接受的盐(例如阿地溴铵),并与一药理学上可接受的干粉载体(例如乳糖颗粒)相混合;其(i)包括一相当于约400微克阿地溴铵(aclidinium bromide)的阿地尼亚单一定量标称剂量,或(ii)在多剂量干粉吸入装置中,以计量提供一相当于约400微克阿地溴 铵的阿地尼亚定量标称剂量。此组成物可每日给予一次或多次,较佳每日给予一次或两次。
在第二实施例中,本发明提供一种治疗呼吸***疾病的方法,适用于有需要的病患,其中该呼吸***疾病是选自于例如哮喘或慢性阻塞性肺病;该方法包括给予一剂量,通常为每日给予一次或每日给予两次的阿地尼亚剂量,例如给予阿地溴铵(相当于约400微克定量标称剂量的阿地溴铵),例如包括给予如前文中所述的药剂组成物。本发明亦提供于制造药剂过程中阿地尼亚的使用,例如于前述方法中的使用。
阿地尼亚可当作单一治疗药物而加以给予,也可与一种或多种附加的抗发炎以及/或气管扩张药物合并使用(例如皮质类固醇、PDE IV抑制剂以及β2促效剂),例如佛莫特洛(formoterol)、沙美特洛(salmeterol)、布***(budesonide)以及莫美他松(mometasone)。本发明进一步提供有如前文所述的方法以及药剂组成物;该方法更包括给予有效量的前述附加药物,该药剂组成物则更包括前述的附加药物。
具体实施方式
一般而言,阿地尼亚是与一阴离子X相结合,而以盐的形式给予,其中X为药学上可接受的单价或多价酸的阴离子。X通常是取自于一无机酸(例如盐酸、氢溴酸、硫酸以及磷酸)或一有机酸(例如甲磺酸、醋酸、反丁烯二酸、琥珀酸、乳酸、柠檬酸或顺丁烯二酸)。前述阿地尼亚较佳为阿地溴铵的形式。
阿地尼亚较佳以干粉形式给予,并与一适当的载体(例如乳糖粉末)相结合,以适于吸入。
举例而言,在一实施例中,阿地尼亚为阿地溴铵,并与乳糖粉末相混合。
可使用本发明所述的配方与方法治疗的呼吸***疾病或病症通常为哮喘、急性或慢性支气管炎、肺气肿、慢性阻塞性肺病(COPD)、支气管性过 度敏感或鼻炎,特别是哮喘或慢性阻塞性肺病,且尤其为慢性阻塞性肺病。
关于活性药物的剂量方面,本文中所使用的“约”指落入如欧洲与美国药典所定义的加/减35%的可接受变异的正常限值内;或指落入由现今最严格要求所定义的较佳的可接受变异的正常限值内(即美国食品及药物管理局的指南草案中关于吸入器的规定的加/减25%的范围);或特别指落入用于配送***中定量剂量准确度的范围内(例如加/减10%)。因此,『约400微克』的定量标称剂量,指为400微克的一目标剂量标的,该目标剂量的变异是落入配送***中可接受的限值内(例如美国与欧洲药典所定义的可接受变异加/减35%);或较佳的指为300至500微克目标剂量(如现今最严格要求所定义的较佳的可接受变异,即美国食品及药物管理局的指南草案中关于吸入器的规定);或最佳是指为340至460微克的目标剂量(在吸入器的定量剂量准确度的范围内)。
发出剂量以及微粒剂量(微粒剂量=发出剂量中低于5微米的截止气动临界值(cut off aerodynamic threshold)的阿地溴铵微克数)也具有相同的变异值,且与定量剂量成比例;因此,对于发出剂量来说,举例而言,约400微克的定量标称剂量(加/减35%)相当于约360微克的发出剂量(加/减35%),且相当于120微克的微粒剂量(加/减35%)。
配方的包装方式可为适用于单位剂量配送者或适用于多剂量配送者。于多剂量配送的情况下,该配方可预先定量或在使用时再定量。因此,干粉吸入器可依此分成三种类型:(a)单一剂量装置;(b)多单位剂量装置;以及(c)多剂量装置。
配方通常包括本发明中用于吸入的化合物的粉末混合物,以及一适当的粉末基底(载体物质)(例如乳糖或淀粉);其中该载体物质较佳使用乳糖。包含于每一胶囊或储存匣中的每一种有疗效的活性成份,通常介于2微克至400微克之间。或者该活性成份可能以未使用赋形剂的方式呈现。
关于第一种类型的单一剂量吸入器,制造者秤出单一剂量后,将其置入 小容器内;其中前述小容器大多为硬质胶囊。自一分离的盒体或容器内取出一颗胶囊,将胶囊***吸入器的容纳区域内。随后,利用针体或切割刀片将该胶囊打开或穿孔,使部份的吸入蒸气得以穿透胶囊而得以传送粉末,或经由吸入时所产生的离心力而将粉末由胶囊内经该穿孔排出。在吸入后,必须再次将空胶囊自该吸入器移除。通常,胶囊的***或移除都必须拆解该吸入器,而这样的操作方式对某些病患而言,是相当困难且麻烦的。此外,关于装载吸入粉末硬质胶囊的使用方面,仍具有下述其它缺点:(a)、对于周边空气中湿气的抵抗能力差;(b)、对于暴露在极端相对湿度下的胶囊而言,将胶囊打开以及穿孔都会造成胶囊的碎裂或凹陷等问题;(c)、可能会吸入胶囊碎片。此外,对于为数不少的胶囊吸入器而言,也有报告指出曾发生不完全排出的情况。
如WO92/03175专利案所述,一些胶囊吸入器是设有一匣体,个别的胶囊可自该匣体传送至一容纳室,并在该容纳室内将胶囊加以穿孔并排空。其它胶囊吸入器则设置有具有胶囊室的旋转式匣体,前述胶囊室可被带至与气道相对应的位置,而将药剂释放(例如WO91/02558以及GB2242134专利案)。这些胶囊吸入器包括多单位剂量吸入器以及泡囊吸入器,这些吸入器仅能在一盘体或条体上供给有限数量的单位剂量。
相较于胶囊吸入器而言,泡囊吸入器对于湿气的防潮能力较佳。此外,通过贯穿表面与泡箔或剥除表面泡箔,则可接触到粉末。当使用泡条体以取代一盘体时,剂量数目虽可随之增加,但对于病患而言,空条体的更换仍然不方便。因此,该类装置通常与整合于其内的剂量***都为可以是抛弃式的,其中整合在其中的剂量***则包括有运输条体以及打开泡囊的技术。
在多剂量吸入器中,并未包含有已预先测定数量的粉末配方。这些吸入器是由一较大的容器以及一必须由病患操作的剂量量测结构所组成。该容器所承载的多剂通过体积排量,从大的粉末团块分离而得。前述剂量量测结构有多种类型,包括可旋转膜(例如EP0069715专利案所述)或盘体(例如GB2041763、EP0424790、DE4239402以及EP0674533等专利案所述)、可 旋转圆筒(例如EP0166294、GB2165159以及WO92/09322等专利案所述)以及可旋转的平截头体(Frustum)(例如WO92/00771专利案所述);前述所有类型的结构都具有空腔,且必须以容器内的粉末将该空腔加以填满。其它多剂量装置则具有测量用滑道(如US5201308或WO97/00703等专利案所述)或测量用活塞;其中该活塞具有局部或环绕周围的凹陷,从而将一定容积的粉末自该容器内移转至一给药腔或一空气导管(例如EP0505321、WO92/04068以及WO92/04928等专利案所述)。
对于多剂量吸入式装置而言,剂量测量的可重复性是主要考虑点之一。一般而言,由于剂量测量杯或空腔的填入过程主要受到重力影响,因此填装的粉末配方必须能展现良好且稳定的流动性质。对于重新填装的单一剂量以及多单位剂量吸入器而言,使用者可以确保剂量量测准确度以及可重复性。然而在另一方面,对于多剂量吸入器而言,由于可包含的剂量数目较高,因此较少在操作时仅装填一剂量。
由于进入多剂量装置内的吸入蒸气通常直接穿过剂量测量空腔,且由于大体积刚性的多剂量吸入器的剂量测量***无法被该吸入蒸气所搅动,因此粉末团块仅自该空腔内被带出,而在排出时仅有少量粉末会自该团块脱离。
因此,有必要具有单独存在的分解装置(disintegration means)。然而,在实施时,这些分解装置并非总是被设计为吸入器的一部份。由于多剂量装置内剂量数目较多,因此在不影响到装置内剩余剂量的情形下,必须将粉末附着在空气导管与该解聚装置(de-agglomeration means)内壁上的情形降至最低,以及/或必须能定时清理这些部份。一些多剂量吸入器拥有可抛弃式药品承载容器,当攫取预定数目的剂量后,该容器将可被更换(例如WO97/000703)。对于这些具有可抛弃式药品承载容器的半永久的多剂量装置而言,须更为严格地防止药品的积聚。
在一较佳实施例中,阿地尼亚是经由一由呼吸致动、多剂量、干粉吸入器加以给予,而计量给予400微克的阿地尼亚定量标称剂量的每日剂量。为达此目的,所提供的更佳的吸入装置为Genuair (原称为Novolizer SD2FL), 或提供有如叙述于WO97/000703、WO03/000325或WO03/061742等专利案中者;前述专利案的内容在此引入本文中参考。
除使用在干粉吸入器外,本发明的组成物也可以雾气形式,利用推进气体或使用所谓雾化器(atomizer)或喷雾器(nebulizer),将含有药理学上具活性的药物的溶液或悬浮液在高压下喷洒,从而产生含有可吸入颗粒的喷雾。
供以吸入方式给予的药物的颗粒大小,较佳控制在一特定范围内。供吸入气管***内的最佳颗粒大小通常为1至10微米,较佳为2至5微米。当吸入颗粒时,大小超过20微米的颗粒将难以到达小气道内。为达到上述颗粒大小,可利用公知的方法(例如微粉化或超临界流体技术),将所产生的活性成份颗粒加以缩小。此外,可利用气流分级或筛选方式,分离出想得到的颗粒大小的部份颗粒。前述颗粒较佳为结晶状。
由于被微粉化粉末的流动性较差,且有极端聚积倾向,因此将难以使受到微粉化的粉末达到高剂量的可重复性。为增加干粉组成物的效率,在吸入器内颗粒大小应较大,但当进入呼吸道时的颗粒大小则应较小。因此,通常需要使用赋形剂(例如单、双或多醣,或醣醇),其中一般被使用者包括有乳糖、甘露醇或葡萄糖。赋形剂的颗粒大小通常远大于本发明中所述的吸入药剂的颗粒大小。当使用乳糖作为赋形剂时,其通常为乳糖颗粒,较佳为结晶阿伐(alpha)乳糖单水合物,其平均颗粒大小例如介于20至1000微米的范围内,较佳介于90至150微米范围内。中位颗粒大小(median particle size)与平均颗粒大小约略相等;前述中位颗粒大小指一直径值,其中50%颗粒具有较大的等效直径(equivalent diameter),另外50%的颗粒则具有一较小的等效直径。因此,在所属技术领域内,平均颗粒大小通常是指等效d50。颗粒大小分布对于流动性质以及块体密度等都可能造成影响。由此,为描述一颗粒大小直径的特征,除使用d50外,也可使用其它等效直径,例如d10以及d90。d10的等效直径指其中10%颗粒具有一较小的直径,因此其余90%的颗粒则较粗。d90的等效直径则指其中90%颗粒具有一较小的直径。在一 实施例中,使用于本发明配方中的乳糖颗粒,其d10为90至160微米,其d50为170至270微米,而其d90则为290至400微米。
适合使用于本发明中的乳糖物质都可以在市面上购得,例如由DMWInternacional所购得者(Respitose GR-001、Respitose SV-001、Respitose SV-003);由Meggle所购得者(Capsulac 60、Inhalac 70、Capsulac 60INH);以及由Borculo Domo所购得者(Lactohale 100-200、Lactohale 200-300以及Lactohale 100-300)。
乳糖颗粒与阿地尼亚的重量比率将视所使用的吸入装置而定,但其比率通常为5∶1至100∶1,例如25∶1至75∶1,如30-35∶1。
在一较佳实施例中,在给药时,阿地尼亚以阿地溴铵的干粉配方形式存在,并与乳糖混合,其中阿地尼亚与乳糖的重量比率为1∶50至1∶75,由此可适用于一干粉吸入器而加以给药。其中,前述阿地尼亚颗粒的平均颗粒直径为介于2至5微米,例如,其直径小于3微米;而乳糖颗粒的d10为90至160微米,d50为170至270微米,而d90则为290至400微米。
关于附加的活性药物,例如β2促效剂、PDE IV抑制剂、皮质类固醇、白三烯D4拮抗剂、egfr-激酶抑制剂、p38激酶抑制剂或NK1受器促效剂等,都可用于本发明的方法与配方。举例而言,在此文中所述本发明所提供的阿地尼亚配方,更包括一种或多种具有有效量附加的活性药物;例如,更包括具有有效量的β2促效剂以及/或PDE IV抑制剂以及/或皮质类固醇。本发明还提供如文中所提到的用于治疗呼吸***疾病(例如哮喘或慢性阻塞性肺病)的方法,该方法包括给予如文中所述的阿地尼亚配方,且更包括同时给予具有有效量的一种或多种附加的活性药物,例如更包括具有有效量的β2促效剂以及/或PDE IV抑制剂以及/或皮质类固醇。
适合与本发明的阿地尼亚共同使用的β2促效剂包括以下物质:例如阿福特罗(arformoterol)、班布特罗(bambuterol)、比托特罗(bitolterol)、布泽特罗(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)、异他林(isoetharine)、异丙肾上腺素(isoprenaline)、左沙丁胺醇(levosalbutamol)、玛布特罗(mabuterol)、美洛君(meluadrine)、间羟异丙基肾上腺素(metaprotenerol)、诺洛米罗(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)、里模特罗(rimoterol)、沙丁胺醇(salbutamol)、沙甲胺醇(salmefamol)、沙美特罗(salmeterol)、赛本德特(sibenadet)、索特罗特(sotenerot)、磺酰特罗(sulfonterol)、特布他林(terbutaline)、噻拉米特(tiaramide)、妥洛特-加龙省罗(tulobuterol)、GSK-597901、米维特罗(milveterol)、GSK-678007、GSK-642444、GSK-159802、HOKU-81、LAS 100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)、KUL-1248、卡莫特罗(carmoterol)、茵达特罗(indacaterol)以及5-[2-(5,6-二乙基因达-2-基氨基)-1-羟乙基]-8-羟-1H-喹啉-2-酮、4-羟-7-[2-{[2-{[3-(2-苯乙氧基)丙基]磺酰基}乙基]氨基}乙基]-2(3H)-苯骈噻唑酮、1-(2-氟-4-羟苯基)-2-[4-(1-苯并咪唑基)-2-甲基-2-丁氨基]乙醇、1-[3-(4-甲氧基芐胺基)-4-羟苯基]-2-[4-(1-苯并咪唑基)-2-甲基-2-丁氨基]乙醇、1-[2H-5-羟-3-侧氧基-4H-1,4-苯并恶嗪-8-基]-2-[3-(4-N,N-二甲氨基苯基)-2-甲基-2-丙氨基]乙醇、1-[2H-5-羟-3-侧氧基-4H-1,4-苯并恶嗪-8-基]-2-[3-(4-甲氧苯基)-2-甲基-2-丙氨基]乙醇、1-[2H-5-羟-3-侧氧基-4H-1,4-苯并恶嗪-8-基]-2-[3-(4-n-丁氧苯基)-2-甲基-2-丙氨基]乙醇、1-[2H-5-羟-3-侧氧基-4H-1,4-苯并恶嗪-8-基]-2-{4-[3-(4-甲氧基苯基)-1,2,4-***-3-基]-2-甲基-2-丁氨基}乙醇、5-羟-8-(1-羟-2-异丙基氨基丁基)-2H-1,4-苯并恶嗪-3-(4H)-酮、1-(4-氨基-3-氯-5-三氟甲基苯基)-2-三级-丁氨基)乙醇以及1-(4-乙氧甲酰氨基-3-氰基-5-氟苯基)-2-(三级-丁氨基)乙醇等物质的外消旋物、镜像异构物、非镜像异构物以及其混合物、以及上述物质在药理学上兼容的酸加成盐。
与本发明一并使用的β2促效剂较佳包括以下药物:阿福特罗、班布特 罗、比托特罗、布泽特罗、卡布特罗、克伦特罗、多培沙明、非诺特罗、福莫特罗、海索那林、异丁特罗、异丙肾上腺素、左沙丁胺醇、玛布特罗、美洛君、诺洛米罗、奥西那林、吡布特罗、丙卡特罗、(R,R)福莫特罗、瑞普特罗、利托君、里模特罗、沙丁胺醇、沙美特罗、赛本德特(sibenadet)、磺酰特罗、特布他林、妥洛特-加龙省罗、GSK-597901、米维特罗、LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)、KUL-1248、卡莫特罗以及茵达特罗等物质的外消旋物、镜像异构物、非镜像异构物以及其混合物、以及上述物质在药理学兼容的酸加成盐。
由于本发明的M3拮抗剂是为具有长效作用者,因此该M3拮抗剂较佳与长效型β2促效剂(也被称为LABA)共同使用。前述共同使用的药物可毎日给予一次或两次。
前述LABA较佳为福莫特罗、沙美特罗以及GSK-597901、米维特罗、LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)、KUL-1248、卡莫特罗以及茵达特罗等物质的外消旋物、镜像异构物、非镜像异构物以及其混合物、以及上述物质在药理学上兼容的酸加成盐。更佳为沙美特罗、福莫特罗、LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)以及茵达特罗。最佳为沙美特罗、福莫特罗以及LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮),尤其为沙美特罗羟萘甲酸盐(salmeterol xinafoate)、富马酸福莫特罗(formoterol fumarate)以及LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)。
举例来说,本发明提供有一供吸入的药剂组成物,其包含干粉型态阿地尼亚在药理学上可接受的盐(例如溴盐),并与一药理学上可接受的干粉载体(例如乳糖颗粒)以及富马酸福莫特罗相混合,(i)包括一相当于约400微克阿地溴铵的阿地尼亚单一定量标称剂量以及约5至25微克(如6、8.5、 12、18或24微克,例如12微克)富马酸福莫特罗的单一定量标称剂量,或(ii)在一多剂量干粉吸入装置,以计量提供一相当于约400微克阿地溴铵的阿地尼亚定量标称剂量以及约5至25微克(例如6、8.5、12、18或24微克,例如12微克)富马酸福莫特罗的定量标称剂量。
供吸入方式给予的药剂组成物包括阿地尼亚以及一β2促效剂,毎日可给予一次或多次;其中该β2促效剂例如为福莫特罗或LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)。较佳毎日给予一次或两次。
适合与本发明阿地尼亚共同使用的PDE4抑制剂包括以下物质:苯芳群二马来酸盐(benafentrine dimaleate)、依他唑酯(etazolate)、登布茶碱(denbufylline)、洛利普南(rolipram)、西潘茶碱(cipamfylline)、札达维林(zardaverine)、阿罗茶碱(arofylline)、非明司特(filaminast)、泰鲁斯特(tipelukast)、妥非司特(tofimilast)、吡拉米司特(piclamilast)、托拉芬群(tolafentrine)、美索普南(mesopram)、盐酸屈他维林(drotaverine hydrochloride)、利米斯特(lirimilast)、罗氟司特(roflumilast)、西洛司特(cilomilast)、欧果米司特(oglemilast)、艾朴瑞米司特(apremilast)、6-[2-(3,4-二乙氧苯基)噻唑-4-基]砒啶-2-羧酸(替托米司特、Tetomilast)、(R)-(+)-4-[2-(3-环戊氧基-4-甲氧基苯基)-2-苯乙基]砒啶(CDP-840)、N-(3,5-二氯-4-砒啶基)-2-[1-(4-氟芐基)-5-羟基-1H-吲哚-3-基]-2-含氧乙酰胺(GSK-842470)、9-(2-氟芐基)-N6-甲基-2-(三氟甲基)腺嘌呤(NCS-613)、N-(3,5-二氯-4-砒啶基)-8-甲氧基喹啉-5-甲酰胺(D-4418)、N-[9-甲基-4-侧氧基-1-苯基-3,4,6,7-四氢吡咯[3,2,1-jk][1,4]苯重氮基-3(R)-基]砒啶-4-甲酰胺、3-[3-(环戊氧基)-4-甲氧基苯基]-6-(乙氨基)-8-异丙基-3H-嘌呤氯化氢(V-11294A)、6-[3-(N,N-二甲基胺甲酰基)苯磺酰基]-4-(3-甲氧基苯氨基)-8-甲基喹啉-3-甲酰胺氯化氢(GSK-256066)、4-[6,7-二乙氧基-2,3-二(羟甲基)奈-1-基]-1-(2-甲氧基乙基)砒啶-2(1H)-酮(T-440)、(-)-反式-2-[3′-[3-(N-环丙基胺甲酰基)-4-侧氧基-1,4-二 氢-1,8-奈啶-1-基]-3-氟联苯-4-基]环丙甲酸(MK-0873)、CDC-801、UK-500001、BLX-914、2-甲氧羰基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷1-酮、顺[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-醇、5(S)-[3-(环戊氧基)-4-甲氧基苯基]-3(S)-(3-甲基芐基)哌啶-2-酮(IPL-455903)、ONO-6126(Eur Respir J 2003,22(Suppl.45):Abst 2557)以及PCT专利申请案号为WO03/097613、WO2004/058729、WO 2005/049581、WO 2005/123693与WO 2005/123692的专利案中所要求保护的化合物。
适合与本发明的阿地尼亚共同使用的皮质类固醇以及糖质肾上腺皮质素包括以下物质:***龙(prednisolone)、甲基***龙(methylprednisolone)、德沙美松(dexamethasone)、西贝酸德沙美松(dexamethasone cipecilate)、奈非可特(naflocort)、地夫可特(deflazacort)、乙酸卤***(halopredone acetate)、布***(budesonide)、二丙酸贝克美松(beclomethasone dipropionate)、氢化可体松(hydrocortisone)、醋酸曲安缩松(triamcinolone acetonide)、醋酸氟轻松(fluocinolone acetonide)、氟轻松(fluocinonide)、新戊酸氯可托龙(clocortolone pivalate)、甲基***龙乙丙酸酯(methylprednisolone aceponate)、软脂酸德沙美松(dexamethasone palmitoate)、替利坦松(tipredane)、氢化可体松醋丙酯(hydrocortisone aceponate)、波尼卡酯(prednicarbate)、二丙酸阿氯米松(alclometasone dipropionate)、丙酸布替可特酯(Butixocort propionate)、RPR-106541、卤美他松(halometasone)、磺庚甲基***龙(methylprednisolone suleptanate)、莫美他松糠酸酯(mometasone furoate)、利美索龙(rimexolone)、法呢酸***龙酯(prednisolone farnesylate)、环索奈德(ciclesonide)、迪普罗酮丙酸酯(deprodone propionate)、丙酸氟替卡松(fluticasone propionate)、糖酸氟替卡松(fluticasone furoate)、卤倍他索丙酸酯(halobetasol propionate)、氯替泼诺(loteprednol etabonate)、倍他米松丁酸丙酸酯(betamethasone butyrate propionate)、氟尼缩松(flunisolide)、***(prednisone)、德沙美松磷酸钠(dexamethasone sodium phosphate)、曲安奈德(triamcinolone)、倍 他米松戊酸酯(betamethasone 17-valerate)、倍他米松(betamethasone)、倍他米松二丙酸酯(betamethasone dipropionate)、21-氯-11贝他-羟-17阿尔发-[2-(甲基巯基)乙酰氧基]-4-孕烯-3,20-双酮、去异丁酰基环所奈德(Desisobutyrylciclesonide)、醋酸氢化可体松(hydrocortisone acetate)、氢化可体松琥珀酸钠(hydrocortisone sodium succinate)、NS-126、***龙磷酸钠(prednisolone sodium phosphate)、普酸氢化可体松(hydrocortisone probutate)、***龙间磺基苯甲酸钠(prednisolone sodium metasulfobenzoate)以及丙酸氯倍他索(clobetasol proprinate),尤其为布***以及莫美他松。
举例来说,本发明提供有一供吸入的药剂组成物,其包含干粉型态阿地尼亚在药理学上可接受的盐(例如溴盐),并与一药理学上可接受的干粉载体(例如乳糖颗粒)以及富马酸福莫特罗相混合,(i)包括一相当于约400微克阿地溴铵的阿地尼亚单一定量标称剂量以及约100至900微克(例如100、110、200、220、300、330、400、440、800或880微克,例如200至450微克,如220或440微克)的莫美他松糠酸酯单一定量标称剂量,或(ii)在一多剂量干粉吸入装置,以计量提供一相当于约400微克阿地溴铵的阿地尼亚定量标称剂量以及约100至900微克(例如100、110、200、220、300、330、400、440、800或880微克,例如200至450微克,如220或440微克)的莫美他松糠酸酯定量标称剂量。
供吸入方式给予的药剂组成物包括阿地尼亚以及一皮质类固醇(例如莫美他松糠酸酯),毎日可给予一次或多次。较佳毎日给予一次或两次。
本发明亦提供有一药剂组成物,包括阿地尼亚、如前文所定义的β2促效剂以及如前文所定义的皮质类固醇。其中,β2促效剂最佳为LAS100977(5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1(R)-羟乙基)-8-羟基喹啉-2(1H)-酮)以及福莫特罗;而皮质类固醇则最佳为莫美他松糠酸酯。由此三者合并的组成物适于毎日给予一或两次。
实例1
方法:对于患有中度至重度的长期COPD的病患中,在四周内随机接受双盲试验(double blind)、毎日给予一次阿地尼亚(25、50、100、200或400微克)加以治疗、给予安慰剂或给予公开标识的噻托(tiotropium)18微克。肺功能测量(spirometric measurement)的实施如下:在第一次给药后22至24小时以及随后每周实施,以及在第1天给药后0.5至6小时以及第四周(第29天)实施。
结果:ITT母体包括有460位病患。在第29日,在下表中列有与阿地尼亚剂量呈相关性增加的FEV1谷值(trough FEV1)。
第29日FEV1谷值基准值平均改变
*p<0.05vs安慰剂
与噻托不同处在于,阿地尼亚在第29日给药后最初6小时内,仍具有可与第1日相比拟的支气管扩张效果(对所有剂量而言)。对于给予100至400微克的阿地尼亚而言,给药后3小时可达到FEV1的峰值(peak FEV1)。阿地尼亚的耐受度良好,且对于ECG、实验参数以及不良事件而言,阿地尼亚的使用并不会产生呈剂量相关性的影响。
结论:阿地尼亚可产生超过24小时的持续性支气管扩张作用,且耐受度良好。相较于公开标识的18微克噻托,200微克以及400微克的阿地尼亚具有可与其相比拟的支气管扩张效果。基于效能以及耐受度的数据,400微克的阿地尼亚将被选作为未来关于COPD长期临床试验的试验剂量。
Claims (26)
1.一种供吸入的药剂组成物,包含干粉型态阿地尼亚(aclidinium),在药理学上可接受的盐,并与一药理学上可接受的干粉载体相混合,提供有一相当于约400微克阿地溴铵(aclidinium bromide)的阿地尼亚定量标称剂量。
2.如权利要求1所述的药剂组成物,为单一剂量干粉配方样态,包括一相当于约400微克阿地溴铵的阿地尼亚单一定量标称剂量。
3.如权利要求1所述的药剂组成物,为多剂量干粉配方样态,供以一多剂量干粉吸入装置给药,从而计量提供一相当于约400微克阿地溴铵的阿地尼亚定量标称剂量。
4.如前述权利要求中任一项所述的药剂组成物,其中所述阿地尼亚在药理学上可接受的盐为阿地溴铵。
5.如前述权利要求中任一项所述的药剂组成物,其中所述药理学上可接受的载体为乳糖颗粒。
6.如前述权利要求中任一项所述的药剂组成物,其中所述阿地尼亚与所述载体的重量比率为1∶25至1∶75。
7.如权利要求6所述的药剂组成物,其中所述阿地尼亚与所述载体的重量比率为1∶50至1∶75。
8.如前述权利要求中任一项所述的药剂组成物,其中所述阿地尼亚的平均颗粒直径介于2至5微米。
9.如前述权利要求中任一项所述的药剂组成物,其中所述载体颗粒的d10为90至160微米,d50为170至270微米,以及d90为290至400微米。
10.如前述权利要求中任一项所述的药剂组成物,更包括:具有一有效量的一种或多种附加的活性物质,所述活性物质选自β2促效剂、PDE IV抑制剂以及皮质类固醇中的一种或多种。
11.如权利要求10所述的药剂组成物,其中所述附加的活性物质选自自由态或为药理学上可接受的盐的形态的佛莫特洛(formoterol)、沙美特洛(salmeterol)、布***(budesonide)和莫美他松(mometasone)中的一种或多种。
12.如权利要求11所述的药剂组成物,其中该附加的活性物质为富马酸福莫特罗(formoterol fumarate),其在每一剂量中的含量约为5至25微克。
13.如权利要求11所述的药剂组成物,其中该附加的活性物质为莫美他松糠酸酯(mometasone furoate),其在每一定量标称剂量中的含量约为100至900微克。
14.一种用于治疗患有呼吸***疾病且需要被治疗的病患的方法,其中所述呼吸***疾病为哮喘或慢性阻塞性肺病,所述方法包括:每日给予一次相当于约400微克阿地溴铵的阿地尼亚定量标称剂量。
15.一种用于治疗具有呼吸***疾病且需要被治疗的病患的方法,其中所述呼吸***疾病为哮喘或慢性阻塞性肺病,所述方法包括:每日给予两次相当于约400微克阿地溴铵的阿地尼亚定量标称剂量。
16.如权利要求14或15所述的方法,包括给予如权利要求1至13任一项所述的药剂组成物。
17.如权利要求14至16任一项所述的方法,更包括:给予具有一有效量的一种或多种附加的活性物质,该活性药物选自β2促效剂、PDE IV抑制剂以及皮质类固醇中的一种或多种。
18.如如权利要求17所述的方法,其中所述附加的活性物质选自自由态或为药理学上可接受的盐的形态的佛莫特洛(formoterol)、沙美特洛(salmeterol)、布***(budesonide)以及莫美他松(mometasone)中的一种或多种。
19.如如权利要求18所述的方法,其中所述附加的活性物质为富马酸福莫特罗(formoterol fumarate),其在每一定量标称剂量中的含量约为5至25微克。
20.如如权利要求18所述的方法,其中该附加的活性物质为莫美他松糠酸酯(mometasone furoate),其于每一定量标称剂量中的含量约为100至900微克。
21.为自由态或为药理学上可接受的盐的形态的阿地尼亚的使用,其用于制造如如权利要求14至20任一项所述的方法中所给予的用药。
22.为自由态或为药理学上可接受的盐的形态的阿地尼亚的使用,其用于制造如如权利要求1至13任一项所述的药剂组成物。
23.为自由态或为药理学上可接受的盐的形态的阿地尼亚,供使用于如如权利要求14至20项任一项所述方法中。
24.根据如权利要求1至13任一项所述的配方,供使用于如权利要求14至20任一项所述的方法中。
25.根据如权利要求1至13任一项中所述的配方,供使用于治疗选自于哮喘以及慢性阻塞性肺病之一的呼吸***疾病。
26.一种多剂量干粉吸入装置,在致动时,供计量给予一相当于约400微克阿地溴铵的阿地尼亚定量标称剂量。
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- 2014-04-07 JP JP2014078703A patent/JP6170460B2/ja active Active
- 2014-10-08 RU RU2014140674A patent/RU2014140674A/ru unknown
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2015
- 2015-11-10 CY CY20151101008T patent/CY1116926T1/el unknown
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2016
- 2016-03-16 JP JP2016052576A patent/JP2016130248A/ja active Pending
- 2016-11-20 IL IL249072A patent/IL249072A0/en unknown
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2018
- 2018-06-27 US US16/019,855 patent/US11000517B2/en active Active
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2019
- 2019-01-11 RU RU2019100425A patent/RU2019100425A/ru not_active Application Discontinuation
- 2019-12-03 IL IL271132A patent/IL271132A/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104349776A (zh) * | 2012-05-25 | 2015-02-11 | 阿尔米雷尔有限公司 | 新的剂量和制剂 |
CN104869996A (zh) * | 2012-12-17 | 2015-08-26 | 阿尔米雷尔有限公司 | 阿地铵的新用途 |
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