CN102665678B - 用于copd的联合治疗 - Google Patents
用于copd的联合治疗 Download PDFInfo
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- CN102665678B CN102665678B CN201080057843.5A CN201080057843A CN102665678B CN 102665678 B CN102665678 B CN 102665678B CN 201080057843 A CN201080057843 A CN 201080057843A CN 102665678 B CN102665678 B CN 102665678B
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Abstract
本发明涉及适合于通过加压定量吸入器(pMDI)对COPD患者给药的气雾剂,包含格隆氯铵与福莫特罗。该制剂还包含HFA推进剂、共溶剂和足以稳定格隆氯铵和福莫特罗成分的用量的无机酸。任选该制剂还包含丙酸倍氯米松。
Description
发明领域
本发明涉及预定与加压定量吸入器一起使用的药物气雾剂溶液,其包含格隆氯铵(glycopyrronium chloride)和福莫特罗或其盐。本发明还涉及这种制剂在预防和治疗包括COPD的呼吸性疾病(respiratory disorder)中的应用。
发明背景
格隆溴铵(也称作glycopyrrolate)是用于减少与给予一些麻醉药相关的唾液分泌并且用作消化性溃疡病的辅助疗法的毒蕈碱M3抗胆碱能药。还报道它可有效治疗哮喘症状(Hansel等人,Chest 2005;128:1974-1979)。
WO 2005/107873涉及格隆溴铵在治疗儿童哮喘中的应用。
WO 01/76575公开了用于格隆溴铵肺部递送的控释制剂。该制剂预定用于呼吸性疾病,特别是慢性阻塞性肺疾病(COPD)。本申请集中于适合于通过干粉吸入器(DPI)递送的干粉制剂。
WO 2005/074918公开了格隆溴铵与糖皮质激素药物的组合及其在治疗呼吸道疾病中的应用。
WO 2005/110402涉及用于治疗炎症或阻塞性气道疾病的格隆溴铵与茚满或苯并噻唑-2-酮衍生物类的β-2激动剂的组合。
WO 2006/105401涉及用于预防和治疗呼吸、炎症或阻塞性气道疾病的抗胆碱能药、皮质类固醇和长效β-2激动剂的组合。所述的抗胆碱能药是格隆溴铵。
根据WO 2007/057223和WO 2007/057222,格隆溴铵相应地与抗炎类固醇且特别是与糠酸莫米松的组合提供了治疗炎症和阻塞性气道疾病的治疗有益性。
WO 2007/057221和WO 2007/057219涉及葡萄糖吡咯(glycopyrronium)盐与茚满基衍生物β-2激动剂(或类似物)和相应地与抗炎类固醇且特别是与糠酸莫米松的组合。
作为葡萄糖吡咯的溴化物抗衡离子的可能的可替代选择,已经举出了其他的抗衡离子(特别包括氯离子)。WO 2006/100453提出了碘化物、乙酸盐和硫酸盐作为格隆溴铵的可替代选择的应用,原因在于与后者相关的研磨困难。
直到本说明书公开的内容为止,尚未公布格隆氯铵在临床上有效或能够以适合于对具有呼吸性疾病的患者给药的方式配制的证据。发明人已经观察到,格隆氯铵在药物制剂方面具有超过格隆溴铵的几个优点。特别地,格隆氯铵具有优于格隆溴铵的溶解度特性且还发现具有与其他活性成分尤其是与福莫特罗的更好的相容性。
福莫特罗是能够松弛支气管平滑肌并且开放气道以减轻哮鸣病症的β-2激动剂。它常用于控制哮喘和其他呼吸性疾病。
近期包含富马酸福莫特罗和丙酸倍氯米松(皮质类固醇)的有效联合治疗已经可以在商品名下得到。设计是为了使用加压定量吸入器(pMDI)通过气雾剂递送至肺部。长期以来已知富马酸福莫特罗的气雾剂溶液是相对不稳定的并且在亚最适度条件下贮存时具有短的贮存期限。制剂掺入了一定量的无机酸以稳定福莫特罗成(如EP 1157689中所述)。
期望提供临床上有用的组合气雾剂产品,其合并了福莫特罗和格隆氯铵、任选与丙酸倍氯米松的治疗有益性。这种产品可能需要以这样的方式配制,使得每种药物活性成分在延长的产品使用期限内以有效和一致的剂量被递送至肺部,且理想的情况是无需在专门温度或湿度条件下贮存。
发明内容
本发明提供了药物气雾剂制剂,包含溶于HFA推进剂和共溶剂的:
(a)格隆氯铵;和
(b)福莫特罗或其盐;
其中该制剂还包含无机酸作为稳定剂。任选该制剂还包含丙酸倍氯米松。
本发明在另一个方面中提供了包含格隆氯铵和福莫特罗或其盐的联合产品在预防或治疗COPD和其他呼吸性疾病中的应用。
在另一个方面中,本发明提供了与pMDI一起使用的罐(canister),包含溶于HFA推进剂和共溶剂的混合物的:
(a)格隆氯铵;和
(b)福莫特罗或其盐;
其中该制剂还包含无机酸作为稳定剂。
发明详述
当尝试进行配制包含格隆氯铵和福莫特罗的组合溶液产品时,令人意外地发现,福莫特罗成分在高温和高相对湿度条件下贮存时发生显著降解,达到在临床和商业上无法制成的程度。尽管在制剂中存在通常足以稳定福莫特罗成分的酸,但是上述情况仍然存在。
还发现,格隆氯铵通常在基于HFA和共溶剂的气雾剂溶液制剂中不稳定,而在制剂中包含酸的情况下稳定。
在进一步分析时显示,在格隆氯铵的存在下,福莫特罗成分发生降解成一定范围的不同产物。在亚最适度条件下,这些降解产物的量可以超过对新药物产品的鉴定和规格报道阈值(如ICH GuidelineQ3B(R2)中定义)。因此,显而易见需要改变制剂以改善福莫特罗稳定性和降低不需要的降解产物的水平。
随后的实验已经揭示出一种避免这些稳定性问题的成功手段在于在制剂中包含最佳量的酸,使得福莫特罗和格隆氯铵成分保持稳定。特别地,发明人发现在溶液中包含0.1-0.3μg/μl、优选0.15-0.28μg/μl、更优选0.18-0.26μg/μl、甚至更优选0.20-0.23μg/μl的量的1M HCl足以有利于格隆氯铵和福莫特罗在延长非最佳贮存期限内保持稳定,由此确保每次启动(actuation)包含该溶液制剂的pMDI时格隆氯铵和福莫特罗的剂量一致。在制剂中包括的酸的量便利地根据添加的酸的量而非得到的pH确定,因为后者难以在非水系统中,例如基于推进剂的溶液确定。
另一个显著的发现在于从罐的顶部空间中除去氧在所有测试浓度1M HCl下进一步稳定了福莫特罗。
格隆氯铵、化学上定义为3-[(环戊基羟基苯基乙酰基)氧基]-1,1-二甲基吡咯烷鎓(pyrrolidinium)氯化物,具有两个手性中心,相当于具有构型(3R,2'R)-、(3S,2'R)-、(3R,2'S)-和(3S,2'S)-的4种潜在不同的立体异构体。任意这些纯的对映体或非对映异构体或任意其组合形式的格隆氯铵可以用于实施本发明。在本发明的一个实施方案中,优选(3S,2'R),(3R,2'S)-3-[(环戊基羟基苯基乙酰基)氧基]-1,1-二甲基吡咯烷鎓氯化物外消旋混合物。格隆氯铵在制剂中的存在量0.005-0.83%(w/w),优选0.010-0.13%(w/w),更优选0.015-0.04%(w/w),其中%(w/w)指按重量计的成分用量,表示为相对于组合物总重的百分比。
格隆氯铵可以使用任意适合的合成技术、例如ChiesiFarmaceutici SpA提交的共同悬而未决的申请中所述的技术制备。
组合物的推进剂成分可以是任意压力液化的推进剂,且优选氢氟烷(HFA)或不同HFAs的混合物,更优选自HFA 134a(1,1,1,2-四氟乙烷)、HFA 227(1,1,1,2,3,3,3-七氟丙烷及其混合物。优选的HFA是HFA134a(1,1,1,2-四氟乙烷)。HFAs可以以75-95%(w/w)、优选85-90%(w/w)的量存在于制剂中。
制剂的福莫特罗成分可以是游离碱、盐或溶剂合物的形式。优选以富马酸福莫特罗的形式提供福莫特罗。例如,福莫特罗可以以0.005-0.07%w/w、优选0.01-0.02%w/w的量用于制剂中。
掺入本发明制剂的共溶剂具有高于推进剂的极性并且可以包括一种或多种物质例如药学可接受的醇,特别是乙醇;或多元醇,例如丙二醇或聚乙二醇。
有利地,所述的共溶剂选自低级支链或直链烷基(C1-C4)醇类,例如乙醇和异丙醇。优选共溶剂是乙醇。
共溶剂的浓度将根据制剂中活性成分的终浓度和推进剂的类型的不同而改变。例如,乙醇可以以5-25%(w/w)、优选8-20%(w/w)、更优选10-15%(w/w)的浓度使用。在优选实施方案之一中,乙醇的浓度为12%(w/w)。
制剂中推进剂与共溶剂之比优选在50:50-95:5(w/w)。
关注不同摩尔浓度的HCl或可替代选择的无机酸(矿物酸)可以替代本发明制剂中的1M HCl。例如,可替代选择的酸可以是任意药学可接受的一元酸或多元酸,例如(但不限于):卤化氢(盐酸、氢溴酸、氢碘酸等)、磷酸、硝酸、硫酸和卤酮酸(halogen oxoacids)。
组合物的药物活性成分优选完全和均匀地溶于推进剂和共溶剂的混合物,即组合物优选是溶液制剂。
任选该溶液制剂可以包含其他本领域公知的药物赋形剂或添加剂。特别地,本发明的组合物可以包含一种或多种低挥发性成分。低挥发性成分是有用的,以增加吸入器启动时气雾剂颗粒的总气体动力学中位数直径(MMAD)和/或改善推进剂/共溶剂混合物中活性成分的溶解度。
低挥发性成分存在时在25°C具有低于0.1kPa、优选低于0.05kPa的蒸气压。低挥发性成分的实例可以是酯类,例如肉豆蔻酸异丙酯、肉豆蔻酸抗坏血酸酯、生育酚酯类;二醇类,例如丙二醇、聚乙二醇、甘油;和表面活性剂,例如饱和有机羧酸(即月桂酸、肉豆蔻酸、硬脂酸)或不饱和羧酸(即油酸或抗坏血酸)。
低挥发性成分的量可以在0.1-10%w/w、优选0.5-5%(w/w)、更优选1-2%(w/w)之间改变。
在一个实施方案中,可以任选将占0.005-0.3%(w/w)的水的量加入到制剂中,以有利地影响活性成分的溶解度,而不会增加启动时气雾剂液滴的MMAD。
有利地,本发明的制剂除共溶剂、推进剂和稳定量的酸外不含其他赋形剂(例如表面活性剂)。
本发明的药物组合物还可以包含其他另外的用于单独、依次或同时应用的药物活性成分。组合物任选的其他药物活性成包括本领域已知用于预防或治疗呼吸性疾病及其症状的任意药物活性成分。这些活性成分的实例是:β-激动剂,例如福莫特罗、沙丁胺醇、非诺特罗、卡莫特罗(TA 2005)、茚达特罗、米维特罗、维兰特罗(GSK 642444)、特布他林、沙美特罗、比托特罗和奥西那林,其单一立体异构体形式或其混合物及其盐;皮质类固醇,例如丙酸倍氯米松、丙酸氟替卡松、布替可特、糠酸莫米松、曲安奈德、布地奈德及其22R-差向异构体、环索奈德、氟尼缩松、氯替泼诺和罗氟奈德;其他抗毒蕈碱药例如甲东莨菪碱、异丙托溴铵、氧托溴铵和噻托溴铵;磷酸二酯酶IV抑制剂,例如西洛司特、罗氟司特和替托司特。
在一个优选的实施方案中,本发明的组合物包含作为活性剂的丙酸倍氯米松(BDP)与福莫特罗和格隆氯铵成分。在该实施方案中,优选BDP以0.07-0.41%w/w、优选0.1-0.3%w/w的量存在于制剂中。
本发明的组合物可以从本领域技术人员公知的任意适合的MDI装置中吸入。制剂各药物活性成分期望的剂量依赖于成分的特性和疾病的类型和严重性,但优选使得以一次或两次启动递送活性成分的治疗量。一般而言,活性成分的剂量在约0.5-1000μg/启动,例如约1-100μg/启动,有时约5-50μg/启动。本领域技术人员熟知对每一药物活性成分如何确定适合的剂量。
就涉及的福莫特罗而言,优选的剂量在约0.5-50μg/启动,优选约1-25μg/启动,更优选约5-15μg/启动。在具体的实施方案中,富马酸福莫特罗的剂量约为6或12μg/启动。
就涉及的格隆氯铵而言,优选的剂量在约0.5-100μg/启动,优选约1-40μg/启动,更优选约5-26μg/启动。在具体的实施方案中,格隆氯铵的剂量约为25μg/启动。
就涉及的丙酸倍氯米松而言,优选的剂量在约10-2000μg/启动,优选约20-1000μg/启动,更优选约50-250μg/启动。在具体的实施方案中,丙酸倍氯米松的剂量约约为50、100、200μg/启动。
将本发明的药物制剂灌注入本领域公知的pMDI装置。该装置包含安装有计量阀门的罐。启动剂量阀门能够使一小部分喷雾剂产品释放。
部分或全部罐可以由金属例如铝、铝合金、不锈钢或阳极化铝构成。或者,该罐可以是塑料罐或塑料涂布的玻璃瓶。
金属罐可以具有部分或全部衬有惰性有机涂敷材料(coatings)的内表面。优选的涂敷材料实例是环氧-酚醛树脂(epoxy-phenol resins)、全氟化聚合物例如全氟烷氧基烷、全氟烷氧基烯、全氟烯类例如聚四氟乙烯(特氟隆)、氟化-乙烯-丙烯(FEP)、聚醚砜(PES)或氟化-乙烯-丙烯聚醚砜(FEP-PES)混合物或其组合。其他适合的涂敷材料可以是聚酰胺、聚酰亚胺、聚酰胺酰亚胺、聚苯硫醚或其组合。
在一些实施方案中,可以优选使用具有衬FEP-PES或特氟隆的内表面的罐。
在其他具体实施方案中,可以使用不锈钢构成的罐。
使用用于递送每日治疗有效剂量的活性成分的计量阀门封闭容器。一般而言,计量阀门部件包含带有其上形成的开口的金属加固环、连接容纳计量室的金属加固环的成型体、由芯和芯的延伸部分组成的柄、围绕计量室的内-和外-密封物、围绕芯的弹簧和防止推进剂通过阀门渗漏的垫片。
围绕计量阀门的一个和多个垫片密封物可以包含弹性材料例如EPDM、氯化丁基橡胶、溴化丁基橡胶、丁基橡胶或氯丁橡胶。特别优选EPDM橡胶。使用适合的材料例如不锈钢、聚酯类(例如聚对苯二甲酸丁二酯(PBT))或缩醛类制造计量室、芯和芯延伸部分。用最终包括钛的不锈钢制造弹簧。金属加固环可以由金属例如铝、铝合金、不锈钢或阳极化铝构成。适合的阀门购自例如Valois、Bespak plc和3M-Neotechnic Ltd这样的制造商。
pMDI由能够递送25-100μl、优选40-70μl和任选约50μl或约63μl/启动的体积的计量阀门开启。
每一灌注的罐便利地配合多路传输装置,然后用于形成将药物给药入患者肺部的定量吸入器。适合的多路传输装置包含例如阀门传动装置和圆柱状或圆锥样通道,通过该通道药物可以从灌注的罐中通过计量阀门被递送至患者口腔,例如接口管(mouthpiece)传动装置。
在一个典型的排布中,阀杆固定于喷嘴区域(block),该区域具有导向膨胀室的孔口。膨胀室具有出口,它延伸入接口管。具有0.15-0.45mm直径和0.30-1.7mm长度的传动装置(出口)孔口一般是适合的。优选使用具有0.2-0.44mm直径的孔口,例如0.22、0.25、0.30、0.33或0.42mm。
在本发明的一些实施方案中,它可以用于使用具有0.10-0.22mm、特别是0.12-0.18mm直径的传动装置孔口,例如WO 03/053501中所述的那些。所述精细孔口的应用还可以增加尘雾(cloud)的形成的期限,且由此可以有利于尘雾的形成与患者缓慢吸入的协调性。
在避免水进入制剂的情况中,期望用能够抵抗水进入的软包装材料外包装MDI产品。还期望可掺入在包装内的材料,其能够吸附可能从罐中渗漏的任意推进剂和共溶剂的材料(例如分子筛)。
任选灌注了本发明制剂的MDI可以与有利于正确利用吸入器的适合的辅助装置一起使用。所述辅助装置是商购的并且根据其形状和大小的不同,称作“隔离室”、“储器”或“膨胀室”。例如,VolumaticTM是最为广泛公知和使用的储器之一,而AerochamberTM是最为广泛使用和已知的隔离室之一。例如,在WO 01/49350中报道了适合的膨胀室。
本发明的制剂还可以与常用的加压呼吸启动的吸入器一起使用,例如已知具有注册名称为Easi-BreatheTM和AutohalerTM的那些。
MDI装置的效力是沉积在肺内适合部位上的剂量的函数。沉积受制剂空气动力学粒度分布影响,可以通过体外几种参数表征。
本发明制剂的空气动力学粒度分布可以使用Cascade冲击器、根据欧洲药典第6版2009(6.5)2.09.18部分中所述的方法表征。可以使用以30l/min-100l/min流速操作的装置E或以28.3l/min流速操作的装置D-Andersen Cascade冲击器(ACI)-。通过高效液相色谱法(HPLC)测定每一ACI板上药物的沉积。
可以测定加压MDI发射的粒子的下列参数:
i)总气体动力学中位数直径(MMAD)是近似等同分布发射粒子的总空气动力直径的直径;
ii)根据ACI中的累积沉积除以每次实验启动次数计算递送剂量;
iii)可吸收剂量(细颗粒剂量=FPD)获自,ACI的阶段3(S3)至滤器(AF)的沉积(相当于颗粒直径≤4.7微米),除以每次实验的启动次数;
iv)可吸收剂量与递送剂量之间百分比的可吸收分数(细颗粒分数=FPF);
v)“超微粉”剂量获自,阶段6(S6)至滤器的沉积(相当于颗粒直径≤1.1微米),除以每次实验的启动次数;
本发明的溶液能够在其中包含它们的pMDI装置启动时提供高于40%、优选高于50%、更优选高于60%的总FPF。
此外,本发明的制剂能够在启动时提供高于或等于30%发射粒子的分数,所述的发射离子的直径等于或小于1.1微米,正如根据Andersen Cascade冲击器的容量阶段S6-AF相对于该冲击器S3-AF阶段中采集的总细颗粒剂量所定义的。优选等于或小于1.1微米的直径的发射粒子的分数高于或等于40%、更优选高于50%、甚至更优选高于60%、最优选高于70%。
本发明的另一个方面提供了用本发明的组合物灌注气雾剂吸入器的方法。药物气雾剂制造领域普通技术人员众所周知的常规批次制备方法和机器可以用于大规模批次制备商业化生产的灌注罐。
第一种方法包含:
a)在-50至-60°C温度制备格隆氯铵和富马酸福莫特罗和(任选的丙酸倍氯米松)在任选共溶剂(例如乙醇)、矿物酸、包含HFA的推进剂和任选的低挥发性成分中的溶液,在此温度下该溶液不会蒸发;
b)用制备的溶液冷灌注吸入器;和
c)将阀门安置在空罐上并且旋紧(crimping)。
可替代选择方法包含:
a)制备格隆氯铵和富马酸福莫特罗和(任选的丙酸倍氯米松)在共溶剂(例如乙醇)、矿物酸和任选的低挥发性成分中的溶液;
b)用该总体溶液灌注开放的罐;
c)将阀门安置在罐上和旋紧;和
d)通过阀门给罐压灌HFA推进剂。
另一种可替代选择方法包含:
a)使用加压容器制备格隆氯铵、富马酸福莫特罗(和任选的丙酸倍氯米松)和无机酸在任选的共溶剂(例如乙醇)、任选的低挥发性成分和HFA推进剂中的溶液;
b)将阀门安装在空罐上并且旋紧;和
c)通过阀门给罐压灌最终的溶液制剂。
在本发明的一个实施方案中,使用常规技术从气雾剂罐的顶部空间中基本上除去氧,以便进一步稳定福莫特罗成分,尤其是在较高酸浓度下。这一目的可以以不同方式实现,视灌注容器的方法而定。可以通过真空旋紧或例如通过使用推进剂进行除净(purging)。在一个优选的实施方案中,改变上述第二种灌注方法以通过真空旋紧并入氧除净步骤(c)。
本发明的包装制剂在标准温度和湿度条件下贮存时可稳定延长的时间期限。在一个优选的实施方案中,该包装制剂在25°C和60%RH下稳定至少6个月,更优选至少1年,最优选至少2年。通过测定残留活性成分的含量评价稳定性。本文所定义的“稳定的”制剂指的是在指定时间点时保留至少约85%、优选至少约90%且最优选至少约95%的每种活性成分的残留含量的制剂,正如通过HPLC-UV VIS测定的。
最佳稳定的制剂满足ICH Guideline Q1B或CPMP/QWP/122/02Rev.1有关用于药物注册目的的药物产品稳定性测试所需的规范。
本发明的组合产品组合物可以用于广泛疾病的预防目的或其治疗目的或用于其症状缓解,因此,在本发明的一个方面中,涉及任意这些药物组合物作为药物的应用。特别地,本发明的组合产品用于预防或治疗许多呼吸性疾病,例如所有类型的哮喘和慢性阻塞性肺疾病(COPD)。
因此,本发明在另一个方面中涉及预防或治疗呼吸性疾病例如COPD的方法,包括对有这种治疗需要的患者给予治疗有效量的本发明药物组合物。
本发明还提供了本发明的药物组合物在治疗性治疗或姑息性治疗或预防呼吸性疾病及其症状中的应用。
本发明药物组合物的应用可能是有益性的其他呼吸性疾病是特征在于作为炎症和存在粘液的结果的外周气道阻塞的那些,例如慢性阻塞性毛细支气管炎、慢性支气管炎、肺气肿、急性肺损伤(ALI)、囊性纤维化、鼻炎和成人或急性呼吸窘迫综合征(ARDS)。
实施例
1)单一、双重和三重组合的气雾剂溶液制剂的稳定性
进行研究以研究富马酸福莫特罗(FF)、格隆氯铵(GLY)和丙酸倍氯米松(BDP)的组合在可变贮存条件下在罐包装中的气雾剂溶液制剂中的稳定性:
除三重组合外,本研究中还包括双重组合(FF+BDP;FF+GLY)和单一活性剂(GLY),以评价活性成分之间任意可能的相互作用是否可以影响药物的稳定性。GLY作为单一活性剂与和不与1M HCl一起配制,以评价酸的稳定效果。
将该批组合物概述在表1中:
表1
将样品批次贮存在倒置方向和如下条件下并且分析两个罐中每一检查点的含量(贮存1、2和3个月后):
+5°C
+25°C/60%相对湿度(加速贮存条件)
+30°C/75%相对湿度
+40°C/75%相对湿度
使用标准色谱方案测定活性成分残留含量。
结果
有关三重组合,BDP和GLY罐含量未受到时间和温度显著影响。相反,FF罐含量高度依赖于贮存条件:相对于0时的%残留物随时间和温度减少。
当将三重组合的制剂在25°C/60%相对湿度贮存3个月时,测定活性成分相对于其在0时相应量的各自残留量百分比并且报道在下表2中。
表2
活性成分 | 残留%量±标准偏差 | 罐的数量(N.) |
FF | 96.6±0.7 | 4 |
Gly | 96.4±1.3 | 4 |
BDP | 94.5±0.3 | 4 |
就FF+GLY的双重组合而言,GLY成分在所有测试浓度下保持稳定。正如在三重组合中那样,富马酸福莫特罗罐含量高度依赖于时间和温度。
相反,FF+BDP双重组合中的福莫特罗含量在任意不同贮存条件下未随时间快速减少。这些相反的观察结果导致如下结论:与FF的组合中存在GLY具有使富马酸福莫特罗失去稳定性的效果。
当将双重组合的制剂在25°C/60%相对湿度贮存3个月时中时,测定活性成分相对于其在0时相应量的各自残留百分比量并且报道在下表3中。
表3
组合 | 活性成分 | 残留%量±标准偏差 | 罐的数量(N.) |
FF+Gly | FF | 96.7±0.2 | 4 |
FF+Gly | Gly | 96.0±0.1 | 4 |
FF+BDP | FF | 97.0±0.7 | 4 |
FF+BDP | BDP | 98.9±0.6 | 4 |
发现包含GLY的单一活性剂制剂在1M HCl的存在下维持恒定含量,但如果不使用酸,则高度依赖于贮存时间和温度。参见下表4当将单一活性剂制剂在25°C/60%相对湿度与或不与相同量的酸一起贮存3个月时的数据。
表4
活性成分 | 残留%量±标准偏差 | 罐的数量(N.) |
Gly(无酸) | 90.4±1.2 | 4 |
Gly(有酸) | 94.4±0.2 | 4 |
2)杂质/降解产物的分析
通过标准HPLC/UV VIS方法测试在25°C/60%RH下保护的所有制剂的非手性杂质和活性成分的降解产物。MS检测器用于证实在FF+BDP和FF+GLY+BDP罐中发现的检测杂质/降解产物的分子量。
结果:
通过HPLC/UV方法分析的那些包含福莫特罗和GLY二者的制剂具有涉及富马酸福莫特罗的高降解产物水平。还观察到每种降解产物的量随温度而增加。
当将三重组合的制剂在25°C/60%相对湿度贮存3个月时,测定相对于相应活性成分起始量表示的杂质和/或降解产物的总百分比量并且报道在下表5中:
表5
活性成分 | 相对于活性成分的总杂质% | 罐的数量(N.) |
FF | 1.1 | 2 |
Gly | 0.75 | 2 |
BDP | 0.21 | 2 |
当将双重组合的制剂在25°C/60%相对湿度贮存3个月时,测定相对于相应活性成分起始量表示的杂质和/或降解产物的总百分比量并且报道在下表6中:
表6
组合 | 活性成分 | 相对于活性成分的总杂质% | 罐的数量(N.) |
FF+Gly | FF | 1.3 | 2 |
FF+Gly | Gly | 0.48 | 2 |
FF+BDP | FF | 0.80 | 2 |
FF+BDP | BDP | 0.20 | 2 |
发现包含GLY的单一活性剂制剂在1M HCl的存在下维持恒定含量,但如果不使用酸,则高度依赖于贮存时间和温度。参见下表7当将单一活性剂制剂在40°C/75%相对湿度与或不与相同量的酸一起贮存3个月时,相对于活性成分起始量表示的杂质和/或降解产物的总百分比的量的数据。
表7
活性成分 | 相对于活性成分的总杂质% | 罐的数量(N.) |
Gly(无酸) | 14.2 | 2 |
Gly(有酸) | 1.0 | 2 |
3)酸含量的滴定
由于稳定性和杂质测试结果指向酸在格隆氯铵存在下的制剂中稳定富马酸福莫特罗的重要性,所以添加0.191μg/μl-0.254μg/μl之间可变的1M HCl制备一系列三重组合制剂。在每一测试样品对中,一个罐使其中的氧通过真空旋紧除去,以研究氧对降解方法的影响。
在25°C/60%RH 3个月后,分析样品的活性成分和主要杂质/降解产物的罐含量。GLY和BDP成分在3个月内保持稳定且几乎不发生降解。
比较已经除去氧的那些样品,观察到当酸含量从0.191μg/μl升至0.222和0.234μg/μl时,FF降解的减少具有一致性。在这些酸值下的%降解产物低于药物注册的鉴定/规格水平。
总之,基于目前的结果,通过在已经除净氧的溶液制剂中包含0.191-0.254μg/μl、优选0.22-0.23μg/μl的量的1M HCl,使得包含格隆氯铵和富马酸福莫特罗(和任选的丙酸倍氯米松)的双重或三重组合可以最佳地稳定用于临床和商业化目的。
Claims (12)
1.药物组合物,包含溶于HFA推进剂与共溶剂的混合物中的:
(a)剂量在0.5-100μg/启动的格隆氯铵;和
(b)剂量在1-25μg/启动的福莫特罗或其盐;
已经向该组合物中加入0.191-0.254μg/μl组合物用量的1M HCl,其中所述的共溶剂是乙醇。
2.权利要求1的药物组合物,还包含一种或多种选自β激动剂、皮质类固醇、抗毒蕈碱药和磷酸二酯酶IV抑制剂的药物活性成分,所述β激动剂选自沙丁胺醇、非诺特罗、卡莫特罗、茚达特罗、米维特罗、维兰特罗、特布他林、沙美特罗、比托特罗、奥西那林及它们的盐。
3.权利要求2的药物组合物,所述皮质类固醇是丙酸倍氯米松。
4.权利要求1-3中任一项的药物组合物,包含:
(a)剂量在5-26μg/启动的格隆氯铵;和
(b)剂量在5-15μg/启动的福莫特罗或其盐。
5.权利要求1-3中任一项的药物组合物,包含:
(a)剂量在25μg/启动的格隆氯铵;和
(b)剂量在6或12μg/启动的福莫特罗或其盐。
6.权利要求3的药物组合物,其中所述丙酸倍氯米松的剂量在50-250μg/启动。
7.权利要求1的药物组合物,其已经除净了氧。
8.气雾剂罐,包含权利要求1-7中任一项的药物组合物。
9.权利要求8的罐,其顶部空间的氧已经被除去。
10.灌注权利要求8或权利要求9的罐的方法,包括下列步骤:
(a)制备格隆氯铵、富马酸福莫特罗和任选的丙酸倍氯米松在共溶剂中的溶液,已经向其中加入了0.191-0.254μg/μl最终溶液的量的1MHCl,其中所述的共溶剂是乙醇;
(b)用该溶液灌注气雾剂罐;
(c)将阀门安置在罐上并且真空旋紧;和
(d)通过阀门给罐压灌HFA推进剂。
11.套盒,包含权利要求1-7任一项的药物组合物且还包含一种或多种用于单独、依次或同时给药的药物活性成分,其中所述的药物活性成分选自β激动剂、皮质类固醇、抗毒蕈碱药和磷酸二酯酶IV抑制剂,所述β激动剂选自沙丁胺醇、非诺特罗、卡莫特罗、茚达特罗、米维特罗、维兰特罗、特布他林、沙美特罗、比托特罗、奥西那林及它们的盐。
12.权利要求1-7中任一项的药物组合物在制备用于预防或治疗哮喘和慢性阻塞性肺疾病的药物中的用途。
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US20150202297A1 (en) * | 2012-07-05 | 2015-07-23 | Arven Ilac Sanayi Ve Ticaret Anonim Sirketi | Dry powder inhalers comprising a carrier other than lactose and a ternary component |
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CN107233311B (zh) * | 2017-06-27 | 2020-12-04 | 长风药业股份有限公司 | 一种以阿福特罗和格隆溴铵为活性成分的雾化剂及其制备方法 |
AU2019477296A1 (en) * | 2019-12-02 | 2022-04-14 | Chiesi Farmaceutici S.P.A. | Stainles steel can for pressurised metered dose inhalers |
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