CN104382887A - 新颖剂量与配方 - Google Patents
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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)的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,且提供有一相当于约200微克阿地溴铵(aclidinium bromide)的阿地尼亚定量标称剂量。
Description
本申请是题为“新颖剂量与配方”的第200980105118.8号发明专利申请的分案申请。母案对应国际申请PCT/EP2009/001831,申请日为2009年3月13日,优先权日为2008年3月13日。
技术领域
本发明涉及一种阿地尼亚(aclidinium)的新颖剂量以及使用阿地尼亚治疗呼吸系统疾病(尤其是气喘以及慢性阻塞性肺病)的方法与配方。
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(即描述于例如WO0104118号专利申请中)。虽然该化合物已知为长效性抗胆碱药物,且对于治疗呼吸系统疾病有所帮助,然而其最适当的剂量仍尚未被揭露。
发明内容
现今研究结果中意外发现,在治疗成人的呼吸系统疾病,尤其是气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(meterednominal dose)约200微克的阿地尼亚;通常在单一用药中,给予每日定量标称剂量约200微克的阿地尼亚;例如约180微克的吸入器发出剂量(emitted dose),以及约60微克的微粒剂量(Fine Particle dose)(相对应于阿地溴铵的重量)。
因此,本发明在第一实施例中提供了一种供吸入的药剂组成物,包含干粉型态的阿地尼亚(aclidinium)的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200微克阿地溴铵(aclidinium bromide)的阿地尼亚单一定量标称剂量,或(ii)于多剂量干粉吸入装置中,以计量提供一相当于约200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二次。
在第二实施例中,本发明提供一种治疗呼吸系统疾病的方法,适用于有需要的病患,其中该呼吸系统疾病是选自于例如气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二次的阿地尼亚剂量,例如给予阿地溴铵(相当于约200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。本发明也提供在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和/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)、布地奈德(budesonide)以及莫美他松(mometasone)。本发明也提供有如前文所述的方法以及药剂组成物;该方法还包括给予有效量的前述附加药物,该药剂组成物则还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)。所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系统疾病或病症通常为气喘、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,尤其是气喘或慢性阻塞性肺病,且主要为慢性阻塞性肺病。
关于活性药物的剂量方面,本文中所使用的“约”是指落入如欧洲与美国药典所定义的加/减35%的可接受变异变量的正常限值内;或指落入由现今最严格要求所定义的较佳的可接受变异变量的正常限值内(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);或是特别指落入用于配送系统中定量剂量准确度的范围内(例如加/减10%)。因此,“约200微克”的定量标称剂量,是指为200微克的一目标剂量标的,该目标剂量的变异变量是落入配送系统中可接受的限值内(例如美国与欧洲药典所定义的可接受变异变量加/减35%);或较佳是指为150至250微克的目标剂量(如现今最严格要求所定义的较佳的可接受变异变量,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170至230微克的目标剂量(于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)也具有相同的变量值,且与定量剂量成比例;因此,对于发出剂量来说,举例而言,约200微克的定量标称剂量(加/减35%)相当于约180微克的发出剂量(加/减35%),且相当于60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于使用时再定量。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,通常是介于2微克至400微克之间。或,该活性成份也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;其中所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,将胶囊插入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,胶囊的插入或移除都必须拆解该吸入器,而此等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)、对于暴露于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专利申请所述,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,并于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,所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专利申请)。这些胶囊吸入器包括多单位剂量吸入器以及泡囊吸入器,这些吸入器仅能于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,藉由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,剂量数目虽可随的增加,但对于病患而言,空条体的更换仍为不便。因此,该类装置通常与整合于其内的剂量系统都为可抛弃式者,其中整合于其中的剂量系统则包括有运输条体以及打开泡囊的技术。
于多剂量吸入器中,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是藉由体积排量,从大的粉末团块分离而得。所述剂量量测结构有多种类型,包括可旋转膜(例如EP0069715专利申请所述)或盘体(例如GB2041763、EP0424790、DE4239402以及EP0674533等专利申请所述)、可旋转圆筒(例如EP0166294、GB2165159以及WO92/09322等专利申请所述)以及可旋转的平截头体(Frustum)(例如WO92/00771专利申请所述);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等专利申请所述)或测量用活塞;其中该活塞具有局部或环绕周围的凹陷,藉以将一定容积的粉末自该容器内移转至一投药腔或一空气导管(例如EP0505321、WO92/04068以及WO92/04928等专利申请所述)。
对于多剂量吸入式装置而言,剂量测量的可重复性为主要考虑点的一。一般而言,由于剂量测量杯或空腔的填入过程主要是受到重力的影响,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。然而于另一方面,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是直接穿过剂量测量空腔,且由于为大体积刚性的多剂量吸入器的剂量量测系统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,而于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(disintegrationmeans)。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。由于多剂量装置内的剂量数目较多,因此在不影响到装置内的剩余剂量的情形下,必须将粉末附着于空气导管与该解聚装置(de-agglomeration means)的内壁上的情形降至最低,和/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200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(原称为Novolizer SD2FL),或提供有如描述于WO97/000703、WO03/000325或WO03/061742等专利申请中者;前述专利申请的内容于此引入本文中参考。
除使用于干粉吸入器外,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于高压下喷洒,藉以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,较佳控制于一特定范围内。供吸入气管系统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,可利用习知的方法(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,分离出为要求的颗粒大小的部份颗粒。所述颗粒较佳为结晶状。
由于被微粉化的粉末的流动性较差,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,于吸入器内的颗粒大小应较大,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微米的范围内。中位颗粒大小(median particle size)与平均颗粒大小约略相等;所述中位颗粒大小是指一直径值,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,于所属技术领域内,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的等效直径是指其中10%颗粒具有一较小的直径,因此其余90%的颗粒则较粗。d90的等效直径则是指其中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在市面都可购得,例如由DMW Internacional所购得者(Respitose GR-001、RespitoseSV-001、Respitose SV-003);由Meggle所购得者(Capsulac 60、Inhalac 70、Capsulac 60INH);以及由BorculoDomo所购得者(Lactohale 100-200、Lactohale 200-300以及Lactohale100-300)。
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200∶1,例如50∶1至150∶1,如60-70∶1。
在一较佳实施例中,在投药时,阿地尼亚是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∶100至1∶150,藉此可适用于一干粉吸入器而加以投药。其中,所述阿地尼亚颗粒的平均颗粒直径为介于2至5微米,其直径例如小于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受体促效剂等,都可使用于本发明的方法与配方。举例而言,在此文中所述的本发明所提供的阿地尼亚配方,还包括一种或多种具有有效量的附加的活性药物;例如,还包括具有有效量的β2促效剂和/或PDE IV抑制剂和/或皮质类固醇。本发明也提供如文中所提到的用于治疗呼吸系统疾病(例如气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,且还包括同时给予具有有效量的一种或多种附加的活性药物,例如还包括具有有效量的β2促效剂和/或PDE IV抑制剂和/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)、sibenadet、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、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)、HOKU-81、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-苯基乙氧基)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-甲氧基苄胺基)-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-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)-1,2,4-三唑-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、以及上述物质于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:例如阿福特罗、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、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、以及上述物质于药理学上兼容的酸加成盐。
由于本发明的M3拮抗剂为具有长效作用者,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。所述共同使用的药物可每日给予一次或二次。
所述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、以及上述物质于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QAB-149。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(formoterolfumarate)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的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200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(例如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)于一多剂量干粉吸入装置,以计量提供一相当于约200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,每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)。较佳每日给予一次或两次。
适合与本发明的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-氟苄基)-5-羟基-1H-吲哚-3-基]-2-含氧乙酰胺(GSK-842470)、9-(2-氟苄基)-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-甲基苄基)哌啶-2-酮(IPL-455903)、ONO-6126(Eur Respir J 2003,22(Supp1.45):Abst 2557)以及于PCT专利申请公布号为WO03/097613、WO2004/058729、WO 2005/049581、WO 2005/123693与WO 2005/123692的专利申请中所主张的化合物。
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:泼尼松龙(prednisolone)、甲基泼尼松龙(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)、乙酸卤泼尼松(halopredone acetate)、布地奈德(budesonide)、二丙酸贝克美松(beclomethasone dipropionate)、氢化可体松(hydrocortisone)、醋酸曲安缩松(triamcinoloneacetonide)、醋酸氟轻松(fluocinolone acetonide)、氟轻松(fluocinonide)、新戊酸氯可托龙(clocortolone pivalate)、甲基泼尼松龙乙丙酸酯(methylprednisolone aceponate)、软脂酸德沙美松(dexamethasone palmitoate)、替利坦松(tipredane)、氢化可体松醋丙酯(hydrocortisoneaceponate)、波尼卡酯(prednicarbate)、二丙酸阿氯米松(alclometasonedipropionate)、丙酸布替可特酯(Butixocortpropionate)、RPR-106541、卤美他松(halometasone)、磺庚甲基泼尼松龙(methylprednisolone suleptanate)、莫美他松糠酸酯(mometasone furoate)、利美索龙(rimexolone)、法呢酸泼尼松龙酯(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(halobetasolpropionate)、氯替泼诺(loteprednol etabonate)、倍他米松丁酸丙酸酯(betamethasone butyrate propionate)、氟尼缩松(flunisolide)、泼尼松(prednisone)、德沙美松磷酸钠(dexamethasone sodium phosphate)、曲安奈德(triamcinolone)、倍他米松戊酸酯(betamethasone17-valerate)、倍他米松(betamethasone)、倍他米松二丙酸酯(betamethasonedipropionate)、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、泼尼松龙磷酸钠(prednisolone sodium phosphate)、普酸氢化可体松(hydrocortisone probutate)、泼尼松龙间磺基苯甲酸钠(prednisolone sodium metasulfobenzoate)以及丙酸氯倍他索(clobetasol proprinate),尤其为布地奈德以及莫美他松。
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的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200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)于一多剂量干粉吸入装置,以计量提供一相当于约200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),每日可给予一次或多次。较佳每日给予一次或两次。
本发明也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促效剂较佳为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;而皮质类固醇则较佳为莫美他松糠酸酯。由此三者合并的组成物适于每日给予一或二次。
实施例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)、每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:于第一次投药后22至24小时以及随后每周实施,以及于第1天投药后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。于第29日,于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,阿地尼亚于第29日投药后最初6小时内,仍具有可与第1日相比拟的的支气管扩张效果(对所有剂量而言)。对于给予100至400微克的阿地尼亚而言,投药后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,200微克的阿地尼亚将可选作为未来关于COPD长期临床试验的试验剂量。
Claims (17)
1.一种供吸入的药剂组成物,包含干粉阿地溴铵型态的阿地尼亚(aclidinium),并与一药理学上可接受的干粉载体相混合,提供有(a)一相当于约200微克阿地溴铵(aclidiniumbromide)的阿地尼亚定量标称剂量,或(b)相当于180微克(加/减35%)阿地溴铵的阿地尼亚发出剂量,或(c)相当于60微克(加/减35%)阿地溴铵的阿地尼亚微粒剂量。
2.根据权利要求1所述的药剂组成物,为单一剂量干粉配方样态,包括有一相当于约200微克阿地溴铵的阿地尼亚单一定量标称剂量。
3.根据权利要求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投药,而计量提供一相当于约200微克阿地溴铵的阿地尼亚定量标称剂量。
4.根据前述任一项权利要求所述的药剂组成物,其中该药理学上可接受的载体为乳糖颗粒。
5.根据前述任一项权利要求所述的药剂组成物,其中阿地尼亚与载体的重量比率为1∶50至1∶150。
6.根据权利要求5所述的药剂组成物,其中阿地尼亚与载体的重量比率为1∶100至1∶150。
7.根据前述任一项权利要求所述的药剂组成物,其中该阿地尼亚的平均颗粒直径是介于2至5微米。
8.根据前述任一项权利要求所述的药剂组成物,其中该载体颗粒的d10为90160微米,d50为170270微米,d90则为290400微米。
9.根据前述任一项权利要求所述的药剂组成物,还包括具有一有效量的一种或多种附加的活性物质,该活性物质是选自于由以下物质所组成的群组:β2促效剂、PDE IV抑制剂以及皮质类固醇。
10.根据权利要求9所述的药剂组成物,其中该附加的活性物质是选自于由以下物质所组成的群组: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)、布地奈德(budesonide)以及莫美他松(mometasone)。
11.根据权利要求10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),其于每一剂量中的含量约为5至25微克。
12.根据权利要求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,且其于每一剂量中的含量约为6微克。
13.根据权利要求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,且其于每一剂量中的含量约为12微克。
14.根据权利要求10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),其于每一定量标称剂量中的含量约为100900微克。
15.阿地溴铵形态的阿地尼亚的使用,其是使用于制造根据权利要求1至14中任一项所述的药剂组成物。
16.根据权利要求1至14项中任一项中所述的药剂组成物,供使用于治疗选自于气喘以及慢性阻塞性肺病的一的呼吸系统疾病。
17.一种多剂量干粉吸入装置,被配置为:当被致动时,(a)计量地给予一相当于约200微克阿地溴铵的阿地尼亚定量标称剂量,或(b)相当于180微克(加/减35%)阿地溴铵的阿地尼亚发出剂量,或(c)相当于60微克(加/减35%)阿地溴铵的阿地尼亚微粒剂量。
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Application publication date: 20150304 |