CN111150728B - 格隆溴铵和福莫特罗组合的稳定的加压气雾剂溶液组合物 - Google Patents
格隆溴铵和福莫特罗组合的稳定的加压气雾剂溶液组合物 Download PDFInfo
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- CN111150728B CN111150728B CN202010180583.6A CN202010180583A CN111150728B CN 111150728 B CN111150728 B CN 111150728B CN 202010180583 A CN202010180583 A CN 202010180583A CN 111150728 B CN111150728 B CN 111150728B
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- formoterol
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- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 title claims abstract description 48
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Abstract
本发明涉及预期用于加压定量雾化吸入器的气雾剂溶液组合物,其包含格隆溴铵和福莫特罗或其盐或所述盐的溶剂合物、任选地与一种或多种另外的活性成分的组合,该气雾剂溶液用选择用量的无机酸稳定,且其中当储存在25℃和60%相对湿度(RH)下的罐中的加速条件下6个月时,降解产物N‑(3‑溴)‑[2‑羟基‑5‑[1‑羟基‑2‑[1‑(4‑甲氧基苯基)丙‑2‑基氨基]乙基]苯基]甲酰胺的量低于定量检测限,所述罐内部被包含氟化乙丙烯(FEP)的聚合物涂敷。任选的一种或多种活性成分可以是吸入皮质类固醇,其选自二丙酸倍氯米松、布地奈德或其22R‑表异构体、环索奈德、氟尼缩松、丙酸氟替卡松、糠酸氟替卡松、糠酸莫米松等。
Description
本申请是发明名称为“格隆溴铵和福莫特罗组合的稳定的加压气雾剂溶液组合物”的中国发明专利申请No.201480071526.7的分案申请,其申请日是2014年12月23日,优先权日是2013年12月30日。
发明领域
本发明涉及预期用于加压计量吸入器(pMDI)的气雾剂溶液组合物,其包含格隆溴铵和福莫特罗或其盐或所述盐的溶剂合物,任选地与吸入皮质类固醇(ICS)组合,该气雾剂溶液用选择用量的无机酸稳定,该组合物包含在金属罐中,所述金属罐可内部被包含氟化乙丙烯(FEP)聚合物的树脂涂敷。
更具体地,在严苛的温度和相对湿度(RH)条件下在上述的涂敷罐中长时间储存时,本发明提供上述pMDI组合物显示降解产物,特别是N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺的量充分低于定量检出限(即,相对于6μg/启喷(actuation)的理论富马酸福莫特罗含量低于0.10%w/w)。
本发明还涉及所述稳定的气雾剂溶液组合物在预防和治疗呼吸道疾病,特别是阻塞性呼吸病例如哮喘和COPD中的用途。
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病,特别是慢性阻塞性肺疾病(COPD)。该专利申请主要关注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性、炎性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;任选的抗胆碱能药中有格隆溴铵。
根据WO 2007/057223和WO 2007/057222,据报道格隆溴铵与抗炎类固醇,特别是与糠酸莫米松的组合提供了治疗炎性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)或与与抗炎类固醇,特别是与糠酸莫米松的组合。
WO 00/07567在实施例4中公开了气雾剂混悬液制剂,其中向微粉化活性成分即富马酸福莫特罗、格隆溴铵和色甘酸二钠的混合物中加入了HFA和一氧化二氮的推进剂混合物以及2%重量的乙醇。
有关格隆溴铵的专著The“Martindale.The complete drug reference”,2002年1月(467页)在有关该物质与输注水溶液和添加剂的相容性研究中显示,由于酯水解格隆溴铵的稳定性在高于pH 6时存在问题。
US 2002/025299公开了不同活性成分的加压气雾剂溶液制剂,其中活性成分是福莫特罗或其与二丙酸倍氯米松的组合,进一步被HCl酸化并且储存在指定罐中,例如不锈钢或阳极氧化的铝,或甚至衬有惰性有机涂层。
WO 2005/074900公开了抗胆碱能药与β-2模拟剂的可吸入组合产品,其用于治疗炎性或阻塞性呼吸病,在实施例中显示格隆溴铵的R,R-对映体与福莫特罗组合的制剂,作为DPI制剂或pMDI混悬液。
US 2006/0257324公开了在HFA推进剂-共溶剂系统中两种或多种溶解的药物组合的递送,该药物组合物具有基本上相同的粒度分布且由此允许共同沉积在相同肺部区域道上。这些制剂包含β-2激动剂(福莫特罗或卡莫特罗为示例)和皮质类固醇(二丙酸倍氯米松为示例)或抗胆碱能药,例如异丙托铵、氧托品、噻托溴铵或格隆溴铵,后者这些仅一般地引述在说明书中。
福莫特罗是β-2肾上腺素能激动剂药物,其能够松弛支气管中的平滑肌并且开放气道以减轻哮鸣病症。它通常用于处置哮喘和其它呼吸系统病症。
近期,包含富马酸福莫特罗和二丙酸倍氯米松(BDP)的有效联合疗法已经可以在商品名下得到。该产品被设计成可通过各种气雾剂装置,也包括加压定量雾化吸入器(pMDI)递送至肺。
在这方面,已知富马酸福莫特罗的气雾剂溶液相对不稳定并且当在储存在最适度以下条件下时具有短的贮存期限。为了避免这种缺陷,已经通过掺入适量的无机酸适当地研发了组合物,掺入适量的无机酸以便在选择的表观pH范围稳定福莫特罗成分,例如,如EP1157689中所述。
在WO 2011/076843中,申请人还公开了pMDI气雾剂溶液制剂,其包含与福莫特罗或其盐组合的格隆溴铵,任选地包括吸入皮质类固醇,例如BDP,其中加入适量的无机酸,特别是0.1-0.3μg/μl的1M HCl,使得福莫特罗和格隆溴铵成分被适当地稳定。此外,上述组合物能够将其中称作DP3的降解产物的量维持至低水平。
然而,当使用相对高用量的酸作为福莫特罗和葡萄糖吡喀成分的稳定佐剂时,在25℃和60%相对湿度(RH)下储存3个月时检测到的DP3的量实际上是显著的。
因此,正如WO 2011/076843中所公开的,由此可能需要包含从气雾剂罐顶空除去氧的另外的步骤,例如加入通过经气雾剂罐的填充工艺中的真空卷边清除氧的步骤,以便降低DP3含量。
在这类组合的制剂研发过程中,随后将降解产物DP3鉴定为N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺(参见实验部分中的分析细节)。
当对其定量明显高于鉴定/定量阈值时(相对于6μg/启喷的理论富马酸福莫特罗含量≥1.0%w/w[如ICH Guideline Q3B(R2)中所定义]),作为这种降解产物的形成,可以代表这些pMDI组合制剂的潜在问题,降低DP3含量使其低于可接受的阈值的方式可能是特别有利的,所述方式不同于已知的那些,包括除去氧和在制备期间的填充气雾剂罐过程中需要专用的清除步骤。
照此,由此期望提供临床上有用的气雾剂组合产品,其合并了福莫特罗或其盐或所述盐的溶剂合物和格隆溴铵、任选与另外的活性成分例如吸入皮质类固醇、特别是二丙酸倍氯米松的治疗有益性,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,否则的话可能需要所述条件以维持低水平的降解产物,例如DP3。
我们目前令人意外地发现,上述制剂组合一旦适当地储存在铝罐中,该铝罐在内部被包含氟化乙丙烯(FEP)聚合物的树脂涂敷并且进一步安装标准阀门,则能够将其贮存期限过程中降解产物、特别是DP3的量最小化,甚至低于检测阈值,在严苛温度和湿度条件下储存后测定。
发明概述
本发明由此提供预期用于加压计量吸入器的气雾剂溶液药物组合物,其包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷(per actuation);
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的无机酸;
该组合物包含在气雾剂罐中,所述气雾剂罐内部被包含氟化乙丙烯(FEP)聚合物的树脂涂敷。
根据本发明,在25℃和60%相对湿度(RH)下储存至少6个月时,或在40℃和75%相对湿度(RH)的加速条件下储存1个月时,下文简称为DP3的降解产物N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺的量相对于6μg/启喷的理论富马酸福莫特罗含量低于0.10%w/w(其为定量检测限)。
任选地,该组合物还包含吸入皮质类固醇,选自二丙酸倍氯米松、糠酸莫米松、布地奈德、氟尼缩松、丙酸氟替卡松、糠酸氟替卡松、环索奈德、曲安西龙、曲安奈德、甲泼尼龙和泼尼松。
在另一个方面,本发明提供内部被包含氟化乙丙烯(FEP)的树脂涂敷的气雾剂罐,该气雾剂罐与预期用于加压计量吸入器的气雾剂溶液药物组合物一起使用,该气雾剂溶液药物组合物包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的无机酸;和任选的
(f)吸入皮质类固醇。
本发明的另一个方面提供降低气雾剂溶液药物组合物贮存期限期间降解产物N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺(DP3)的量的方法,所述气雾剂溶液药物组合物预期用于加压计量吸入器,该气雾剂溶液药物组合物包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的无机酸;和任选的
(f)吸入皮质类固醇,
该方法包含,在内部被包含氟化乙丙烯(FEP)聚合物的树脂涂敷的气雾剂罐中包含上述组合物。
在另一个方面中,本发明提供内部被包含氟化乙丙烯(FEP)的树脂涂敷的气雾剂罐作为预期用于加压计量吸入器的气雾剂溶液药物组合物的容器的用途,该气雾剂溶液药物组合物包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围在1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的无机酸;和任选的
(f)吸入皮质类固醇。
在又一个方面中,本发明提供如上所述的气雾剂组合物在预防和/或治疗阻塞性呼吸病包括哮喘和COPD中的用途。
优选实施方案的详细描述
已经令人意外地发现,在预期用于加压计量吸入器的气雾剂溶液药物组合物中,所述组合物包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的无机酸;和任选的
(f)吸入皮质类固醇,
通过使用特定的内部涂敷的金属罐,该金属罐包含氟化乙丙烯(FEP)聚合物,当在25℃和60%相对湿度(RH)加速条件下储存至少6个月时,其可以将福莫特罗和格隆溴铵相互作用形成的降解产物N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺水平维持在低于定量检测限0.10%w/w(相对于6μg/启喷的理论富马酸福莫特罗含量),与所用的计量阀门类型无关。
使用这种特定罐制造的本组合产品的加压气雾剂溶液组合物在25℃和60%RH下储存6个月后,除降解产物DP3水平低于0.10%w/w的定量检测限(相对于6μg/启喷的理论富马酸福莫特罗含量)外,还显示总福莫特罗降解产物水平在低于10%w/w的可接受的限制内(相对于6μg/启喷的理论富马酸福莫特罗含量),优选低于3%w/w,且更优选低于2%w/w,且维持组合物中最不稳定成分富马酸福莫特罗的残留水平相对于其起始含量高于90%w/w,优选高于92%,且最优选高于95%w/w。
格隆溴铵和任选的吸入皮质类固醇水平被维持维持为几乎与相应的起始水平相同。
市售可得到的内部涂敷不同聚合物或使用钝化技术的其它类型的罐不能保持控制所述特定降解产物形成和所述组合成分的相关化学稳定性。
格隆溴铵,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)溴化物,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溴铵都可以用于实施本发明。在本发明的一个实施方案中,优选定义为苏型混合物的(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溴化物外消旋混合物,也称作格隆溴铵。格隆溴铵在制剂中的存在量为0.005-0.14%(w/w),优选0.008-0.090%(w/w),更优选0.01-0.045%(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。
格隆溴铵是商购的且可以根据US2,956,062或Franko BV和Lunsford CD,J MedPharm Chem2(5),523-540,1960中所述的方法合成。
福莫特罗,通常作为外消旋混合物(R,R),(S,S)用于疗法,化学上定义为(±),(R*,R*)-N-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺,其可以为游离碱形式,或作为其盐或溶剂合物。优选地,福莫特罗以其富马酸盐的形式提供,且更优选地,福莫特罗盐的溶剂合物形式为二水合富马酸福莫特罗。例如,富马酸福莫特罗可以以0.002-0.08%w/w,优选0.005-0.02%w/w的量用于制剂。
优选组合物的药物活性成分是完全和均一地溶于推进剂和共溶剂混合物,即组合物优选是溶液制剂。
作为称作溶液制剂的本发明,其中活性成分完全溶于制剂,当本说明书一般性地引述富马酸福莫特罗时,意指富马酸福莫特罗和二水合富马酸福莫特罗形式,其为市售可得到的其溶剂合物形式。
掺入本发明制剂中的共溶剂具有高于推进剂的极性,且可以包括一种或多种物质,例如药学上可接受的醇或多元醇,其用量能够将组合物的药物活性成分(富马酸福莫特罗、格隆溴铵和任选的吸入皮质类固醇)增溶于推进剂。
有利地,醇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。
有利地,多元醇共溶剂选自甘油、丙二醇或聚乙二醇。
共溶剂的浓度根据制剂中活性成分的最终浓度的不同而变化。例如,可以使用乙醇,其浓度在5-30%(w/w),优选8-25%(w/w),更优选10-15%(w/w)。在优选的实施方案之一中,乙醇的浓度约为12%(w/w)。
组合物的推进剂组分可以是任意压力-液化的推进剂且优选是氢氟烷(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HFA 134a。HFAs可以以70-95%(w/w),优选85-90%(w/w)的量存在于组合物中。
推进剂与共溶剂在组合物中的比例在70:30-95:5(w/w)。
足以稳定格隆溴铵和福莫特罗的无机酸的稳定量为与1M盐酸(HCl)相当的酸量,其为0.1-0.3μg/μl制剂,优选0.15-0.28μg/μl,更优选0.18-0.26μg/μl,甚至更优选0.200-0.240μg/μl,最优选0.200-0.227μg/μl,且尤其是0.213-0.222μg/μl制剂。
可以用不同摩尔浓度的HCl或其它的可选无机酸(矿物酸)替代本发明组合物中的1M HCl。例如,根据本领域技术人员已知的计算步骤,使用非1M HCl浓度的酸,其用量必须与所述浓度成比例。
可选的酸可以是任意药学上可接受的一元酸或多元酸,例如(但不限于):氢卤酸(盐酸、氢溴酸、氢碘酸等)、磷酸、硝酸、硫酸和卤代酮酸。
任选地,所述气雾剂溶液组合物可以包含另外的本领域中已知的其它药物赋形剂或添加剂。尤其是,本发明的组合物可以包含一种或多种低挥发性组分。低挥发性组分可用于在吸入器喷雾时增加气雾剂颗粒的质量中位数气动粒径(MMAD)和/或改善推进剂/共溶剂混合物中活性成分的溶解度。
低挥发性组分,在存在时,在25℃下具有低于0.1kPa,优选低于0.05kPa的蒸气压。低挥发性组分的实例是: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(例如月桂酸、肉豆蔻酸、硬脂酸)或不饱和羧酸(例如油酸或抗坏血酸)。
低挥发性组分的量可以在0.1-10%w/w,优选0.5-5%(w/w),更优选1-2%(w/w)之间变化。
在另一个实施方案中,可以任选地向组合物中添加0.005-0.3%(w/w)的水量,以便有利地影响活性成分的溶解度,而不增加在喷雾时气雾剂液滴的MMAD。
有利地,本发明的组合物不含除共溶剂、推进剂和稳定量的酸之外的赋形剂(例如表面活性剂)。
本发明的药物组合物还可以包含一种或多种另外的用于单独、依次或同时应用的药物活性剂。组合物的一种或多种另外的药物活性剂包括本领域已知用于预防或治疗呼吸病及其症状的任意药物活性成分。一种或多种另外的药物活性剂的实例选自如下类型:
β-2激动剂,其选自沙丁胺醇、非诺特罗、卡莫特罗(TA2005;CHF4226)、茚达特罗、米维特罗、维兰特罗(GSK642444)、奥达特罗、abediterol、特布他林、沙美特罗、比托特罗、奥西那林及其盐,任选单一立体异构体形式或其混合物的形式;
吸入皮质类固醇,其选自二丙酸倍氯米松,布地奈德或其22R-表异构体、环索奈德、氟尼缩松、丙酸氟替卡松、糠酸氟替卡松、糠酸莫米松、布替可特、曲安奈德、曲安西龙、甲泼尼龙、泼尼松、氯替泼诺和罗氟奈德;
抗毒蕈碱药,其选自甲东莨菪碱、异丙托溴铵、氧托品、曲司氯铵(trospium)、噻托溴铵、aclidinium和芜地溴铵(umeclidinium),为溴化物盐或与任意其它药学上可接受的抗衡离子的盐;
磷酸二酯酶-4(PDE-4)抑制剂,其选自CHF 6001、西洛司特、罗氟司特、替托司特、奥米司特及其盐。
在优选的实施方案中,除了富马酸福莫特罗和格隆溴铵组分之外,本发明的组合物还包含选自二丙酸倍氯米松(BDP)、布地奈德、糠酸氟替卡松、丙酸氟替卡松和糠酸莫米松的吸入皮质类固醇。在该实施方案中,更优选的吸入皮质类固醇选自BDP和布地奈德。BDP或布地奈德以0.02-0.8%w/w,更优选0.042-0.43%w/w的量存在。最优选的吸入皮质类固醇为BDP。
本发明的组合物可以从任意适合的已知加压MDI装置中吸入。制剂各药物活性成分期望的剂量依赖于组分的特性和疾病的类型和严重性,但优选使得以一喷或两喷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/启喷,例如约1-300μg/启喷,有时约5-150μg/启喷。本领域技术人员熟知对各单个药物活性成分如何确定适合的剂量。
就涉及的二水合物形式的富马酸福莫特罗而言,优选的剂量在1-24μg/启喷,更优选约6-12μg/启喷。在具体的实施方案中,二水合富马酸福莫特罗的剂量为6或12μg/启喷。
就涉及的格隆溴铵而言,优选的剂量在约5-26μg/启喷,更优选约6-25μg/启喷。在具体的实施方案中,格隆溴铵的剂量约为6、12.5或25μg/启喷。
就涉及的任选的成分而言,当其选自吸入皮质类固醇时,优选的剂量在约20-1000μg/启喷,优选50-250μg/启喷。在具体的实施方案中,二丙酸倍氯米松和布地奈德的剂量选自50、100或200μg/启喷。
将本发明的药物制剂加注到本领域已知的pMDI装置。该装置包含安装有计量阀门的罐。剂量阀门的启喷使得一小部分喷雾剂产品释放。
部分或全部本领域已知的罐可以由金属例如铝、铝合金、不锈钢或阳极化铝制备。或者,该罐可以是塑料罐或塑料涂层的玻璃瓶。
用于pMDI的金属罐可以具有部分或全部衬有惰性有机或无机涂层或被其钝化的内表面,所述有机或无机涂层通过常规涂敷或等离子涂敷涂布。涂层材料的实例是环氧-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、全氟烯类例如聚四佛乙烯(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。其它适合的涂敷材料可以是聚酰胺、聚酰亚胺、聚酰胺亚胺、聚苯硫醚或其组合。
根据本发明,所述罐在其内表面上涂敷包含FEP聚合物或FEP-PES混合物的树脂。
适合的罐可以得自制造商,例如3M、Presspart和Pressteck。
使用用于递送治疗有效剂量的活性成分的计量阀门封闭容器。一般而言,所述计量阀门组件包含带有其中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,其选自EPDM(乙烯丙烯二烯单体)、氯丁橡胶和丁基橡胶。在丁基橡胶中优选氯丁基和溴丁基橡胶。EPDM橡胶是特别优选的。
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、不锈钢或阳极化铝制备。适合的阀门购自例如Valois-Aptar、Bespak plc、V.A.R.I.、3M-Neotechnic Ltd、Rexam、Coster这样的制造商。
pMDI由能够递送25-150μl,优选50-100μl和更优选50μl或63μl/启喷的体积的计量阀门启喷。
使用前将每一加注的罐便利地装配到合适的管路装置(channelling device),以形成将药物给药进入患者肺部的定量吸入器。适合的管路装置包含例如阀门启喷器和圆柱状或圆锥样通道,通过该通道药物可以从加注的罐中通过计量阀门被递送至患者口腔,例如口腔(mouthpiece)启喷器。
在一个典型的排列中,阀杆被置于阀杆容器中,进入到喷嘴区域(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长度的启喷器(出口)孔口一般是适合的。优选使用具有0.2-0.45mm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直径的启喷器(actuator)孔口,例如WO03/053501中所述的那些。所述精细孔口的应用还可以增加尘雾(cloud)的形成的持续,且由此可以有利于尘雾的形成与患者缓慢吸入的协调性。
用于递送本发明组合物的适合的启喷器是常规的,其中所述罐的纵轴(对齐阀杆插座的纵轴)相对于一般对齐启喷器孔口接口管纵轴偏移大于或等于90°的角,而且可以使用根据WO 2012/032008的启喷器,其中该启喷器出口的纵轴对齐阀杆容器的纵轴。
用于递送本发明组合物的其它适合的启喷器(actuators)是公开在WO 2014/033057中的那些,其中喷嘴块孔口的特征在于存在管状元件,其在接口罐部件中从孔口沿对齐接口罐部件的纵轴延伸。具体地,所述管状元件定位于密封凹槽中的孔口。
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外包MDI产品。还期望将能够吸收可能从罐中渗漏的任何推进剂和共溶剂的材料加入包装(例如硅胶或分子筛)。
任选加注了本发明组合物的MDI装置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WO01/49350中报道了适合的膨胀室。
本发明的组合物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。
此外,可以通过配备本领域已知的机械或电子剂量计数器或剂量指示器的启喷器给予本发明的组合物,所述本领域已知的机械或电子剂量计数器或剂量指示器可以在外部与启喷器顶端固定或在内部与启喷器整合。这类剂量计数器或剂量指示器可以分别显示给予的剂量范围和/或仍然保留在罐中的剂量数或范围。
MDI装置的效能是沉积在肺中适合部位上的剂量的函数。沉积受制剂的空气动力学粒径分布影响,可以通过几种参数在体外表征。
本发明组合物的空气动力学粒径分布可以使用多级撞击分级取样器(cascadeimpactor)根据欧洲药典第7版2013(7.8)2.9.18部分中所述的方法表征。使用以30l/min-100l/min流速操作的装置E。通过高效液相色谱法(HPLC)测定每一级联冲击器杯上药物的沉积。
可以测定加压MDI发射的粒子的下列参数:
i)质量中位数气动粒径(MMAD)是这样的直径,在其附近发射粒子的质量气动直径等同分布;
ii)根据多级撞击分级取样器中的累积沉积除以每次实验启喷的次数计算递送剂量;
iii)可吸收剂量(细颗粒剂量=FPD)相当于颗粒直径≤5微米质量除以每次实验的启喷次数;
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”剂量的获得,来自过滤用第6个杯子(C6)的沉积量(相当于颗粒直径≤1.4微米)除以每次实验的启喷次数;
本发明的溶液能够在其中包含它们的pMDI装置启喷时提供高于25%,优选高于30%,更优选高于35%的总FPF。
此外,本发明的组合物能够在启动时提供高于或等于15%发射粒子的分数,所述的发射离子的直径等于或小于1.4微米,如根据多级撞击分级取样器的容量杯C6至过滤(C6-F)相对于该撞击器C3杯至过滤器(C3-F)中采集的总细颗粒剂量所定义。优选直径等于或小于1.4微米的发射粒子的分数高于或等于20%,更优选高于25%。
本发明的另一个方面提供了用本发明的组合物加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加注罐。
第一种方法包括:
a)在-50至-60℃温度制备格隆溴铵、富马酸福莫特罗和任选的吸入皮质类固醇,优选二丙酸倍氯米松和布地奈德在共溶剂(例如乙醇)、无机酸、包含HFA的推进剂和任选的低挥发性组分中的溶液,在此温度下该组合物不会蒸发;
b)用制备的溶液冷加注罐;和
c)将阀门安置在空罐上并且卷边(crimping)。
可替代选择的方法包括:
a)制备格隆溴铵、富马酸福莫特罗和任选的吸入皮质类固醇,优选自二丙酸倍氯米松和布地奈德在共溶剂(例如乙醇)、无机酸和任选的低挥发性组分中的溶液;
b)用该本体溶液加注开放的罐;
c)将阀门安置在罐上和卷边;和
d)通过阀门给罐压注HFA推进剂。
另一种可替代选择方法包括:
a)使用加压容器制备格隆溴铵、富马酸福莫特罗和任选的吸入皮质类固醇,优选自二丙酸倍氯米松和布地奈德在任选的共溶剂(例如乙醇)、无机酸、包含HFA的推进剂和任选的低挥发性组分中的溶液;
b)将阀门安装在空罐上并且卷边;和
c)通过阀门给罐压注最终的溶液。
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组分,尤其是在较高酸浓度下。这可以以不同方式实现,视加注容器的方法而定。可以通过真空卷边或例如通过使用推进剂进行清除(purging)。在一个优选的实施方案中,改变上述第二种加注方法以通过真空卷边并入一个氧清除步骤(c)。
本发明的包装组合物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,该包装组合物在25℃和60%RH下稳定6个月以上,更优选至少9个月。通过测定残留活性成分和杂质/降解产物的含量评价稳定性。本文所定义的“稳定的”组合物意指在指定时间点时具有至少约90%w/w(为相对于其在0时的起始含量的重量百分比含量),优选至少约95%w/w的活性成分残留含量,且降解产物的总含量相对于0时的活性成分的起始含量不超过约10%重量,优选不超过约5%重量,通过HPLC/UV-VIS测定。
优化的稳定组合物满足ICH Guideline Q1A(R2)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适应症的预防目的或治疗目的或用于症状缓解,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哮喘和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还可能是有益性的其它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
三重组合气雾剂溶液组合物在25℃和60%相对湿度(RH)下储存6个月的稳定性
进行研究以研究气雾剂溶液制剂(其组成如表1中所示)中富马酸福莫特罗(FF)、格隆溴铵(GLY)和二丙酸倍氯米松(BDP)的三重组合在25℃和60%相对湿度(RH)条件下在不同种类罐中储存6个月的稳定性,所述罐用不同种类的阀门卷边。
表1:二水合富马酸福莫特罗(FF)、格隆溴铵(GLY)和二丙酸倍氯米松(BDP)三重组合的气雾剂溶液组合物的组成。含量%w/w是指每种成分相对于组合物总重的重量百分比含量。
将样品批次以倒置方向贮存,对于药物产品的稳定性被视为最差情况的条件,并且在6个月的检查点每个批次分析3个罐,分析活性成分残留含量和总的福莫特罗降解产物(其中有DP3:相当于N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺)。
DP3结构通过对气雾剂溶液制剂中富马酸福莫特罗、格隆溴铵和二丙酸倍氯米松三重组合的降解样品进行HPLC/MS/MS实验鉴定。
为了标记取代溴原子的位置,用普通铝罐制造氘代富马酸福莫特罗(N-(3-氘代)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺)、格隆溴铵和二丙酸倍氯米松的三重组合,用配备EPDM(乙烯丙烯二烯单体)橡胶密封物(RB700,来自Bespak)的阀门卷边,并且储存在40℃和75%RH下1个月。对降解产物的分析指出氘代富马酸福莫特罗的氘原子被溴原子取代,得到降解产物DP3。此外,合成了N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺标准品,并且通过1H-NMR和MS/MS分析表征。N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺标准品的MS/MS光谱显示与DP3的碎片峰相当的碎片峰。
使用经验证的HPLC/UV-VIS方法测定每种活性成分的残留含量、DP3和总的福莫特罗降解产物量。质谱检测器用于证实在每个罐中发现的检测到的降解产物的分子量。
概括在下表2中的结果显示,在25℃/60%相对湿度(RH)下6个月后,就较高活性成分含量(特别是格隆溴铵和福莫特罗)、最低总降解产物水平(相对于理论富马酸福莫特罗含量6μg/启喷)和,令人意外地,在降解产物DP3中低于0.10%w/w的定量检测限(相对于6μg/启喷的理论富马酸福莫特罗含量)而言,实现最佳结果的构造是这样的构造,其中将所述组合物储存在铝罐中,该铝罐内部被包含氟化乙丙烯(FEP)聚合物的树脂涂敷。
尽管从上文引述的WO 2011/076843中已知,但是真空卷边(vacuum crimping)通过从气雾剂罐中除去氧改善了组合物的稳定性;通过使用FEP涂敷的罐确实获得了对稳定性的令人意外的改善。
包装在内部用包含氟化乙丙烯(FEP)聚合物的树脂涂敷的罐中的本发明的组合物显示降解产物DP3水平低于0.10%w/w的定量检测限(相对于6μg/启喷的理论富马酸福莫特罗含量),总的福莫特罗降解产物水平低于2%w/w(相对于6μg/启喷的理论富马酸福莫特罗含量)且组合物中最不稳定成分富马酸福莫特罗的残留水平在本条件下储存后维持高于95%w/w。
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实施例2
三重组合气雾剂溶液组合物在40℃和75%相对湿度(RH)下储存1个月的稳定性
进行进一步研究,使用不同种类罐研究组成与实施例1表1中所示的相同且在更严苛条件下且特别是在40℃和75%相对湿度(RH)条件下储存1个月的气雾剂溶液制剂中富马酸福莫特罗(FF)、格隆溴铵(GLY)和二丙酸倍氯米松(BDP)的三重组合的稳定性,所述罐用不同种类的阀门卷边。
将样品批次以倒置方向贮存,对于药物产品的稳定性被视为最差情况的条件,并且在1个月的检查点每个批次分析3个罐,分析活性成分的残留含量和总的福莫特罗降解产物(其中有DP3:相当于N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺)。
使用经验证的HPLC/UV-VIS方法测定每种活性成分的残留含量、DP3和总的福莫特罗降解产物量。MS检测器用于证实在每个罐中发现的检测到的降解产物的分子量。
概括在下表3中的结果证实了在25℃和60%RH下储存6个月后得到的那些结果。
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实施例3
三重组合气雾剂溶液组合物在25℃和60%相对湿度(RH)下在不同的HCl浓度下储
存6个月的稳定性
进行进一步研究以便研究在本发明的FEP涂敷的铝罐(如上述所定义)中相应于实施例1(表1)的气雾剂溶液制剂中富马酸福莫特罗(FF)、格隆溴铵(GLY)和二丙酸倍氯米松(BDP)的三重组合的稳定性,其中1M盐酸的量在0.200-0.240μg/μL的范围变化,并且在25℃和60%相对湿度(RH)下储存6个月,所述罐用EPDM阀门(第2类,相应于Bespak BK700)卷边。
将样品批次以倒置方向贮存,对于药物产品的稳定性被视为最差情况的条件,并且在6个月的检查点每个批次分析3个罐,分析活性成分的残留含量和总的福莫特罗降解产物(其中有DP3:相应于N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺)。
使用经验证的HPLC/UV-VIS方法测定每种活性成分的残留含量、DP3和总的福莫特罗降解产物量。MS检测器用于证实在每个罐中发现的检测到的降解产物的分子量。
概括在下表4中的结果证实了在25℃和60%RH下储存6个月后得到的那些结果,在FEP涂敷的罐中储存的制剂中存在更具体范围的用量的1M HCl。
实施例4
另一种三重组合气雾剂溶液组合物在25℃和60%相对湿度(RH)下储存6个月的稳
定性
进行研究以便研究气雾剂溶液制剂中富马酸福莫特罗(FF)、格隆溴铵(GLY)和布地奈德的三重组合的稳定性,所述气雾剂溶液的组成如表5中所示,且该制剂在25℃和60%相对湿度(RH)下在不同种类的罐中储存6个月,所述罐用不同种类的阀门卷边。
表5:二水合富马酸福莫特罗(FF)、格隆溴铵(GLY)和布地奈德的气雾剂溶液组合物的组成。含量%w/w是指每种成分相对于组合物总重的按重量计的百分比含量。
将样品批次以倒置方向贮存,对于药物产品的稳定性被视为最差情况的条件,并且在6个月的检查点每个批次分析3个罐,分析活性成分的残留含量和总的福莫特罗降解产物(其中有DP3:相当于N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺)。
使用经验证的HPLC/UV-VIS方法测定每种活性成分的残留含量、DP3和总的福莫特罗降解产物量。MS检测器用于证实在每个罐中发现的检测到的降解产物的分子量。
概括在下表6中的结果证实,在25℃和60%RH下储存6个月后,就较高活性成分含量(特别是格隆溴铵和福莫特罗)、最低总降解产物水平(相对于理论富马酸福莫特罗含量6μg/启喷)和主要在降解产物DP3中低于0.10%w/w的定量检测限(相对于6μg/启喷的理论富马酸福莫特罗含量)而言,实现最佳结果的构造是这样的构造,其中将组合物储存在铝罐中,该铝罐内部被包含氟化乙丙烯(FEP)聚合物的树脂涂敷。
包装在内部涂敷包含氟化乙丙烯(FEP)聚合物的树脂的罐中的本发明组合物,甚至在不同吸入皮质类固醇(布地奈德替代BDP)的存在下,也显示降解产物DP3水平低于0.10%w/w的定量检测限(相对于6μg/启喷的理论富马酸福莫特罗含量),总的福莫特罗降解产物水平低于2%w/w(相对于6μg/启喷的理论富马酸福莫特罗含量)且组合物中最不稳定成分富马酸福莫特罗的残留水平在本条件下储存后维持高于95%w/w。
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Claims (17)
1.预期用于加压定量雾化吸入器的气雾剂溶液药物组合物,包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)吸入皮质类固醇,所述吸入皮质类固醇选自50-250μg/启喷的量的二丙酸倍氯米松和50-250μg/启喷的量的布地奈德;
(d)HFA推进剂;
(e)共溶剂;
(f)稳定量的药学上可接受的一元酸,所述药学上可接受的一元酸为盐酸;
该组合物包含在气雾剂罐中,所述气雾剂罐内部被包含氟化乙丙烯聚合物的树脂涂敷。
2.权利要求1的气雾剂溶液药物组合物,其特征在于当在25oC和60%相对湿度的加速条件下储存至少6个月时,降解产物N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺的量相对于6μg/启喷的理论富马酸福莫特罗含量低于0.10%w/w。
3.权利要求1或2的气雾剂溶液药物组合物,其中药学上可接受的一元酸的稳定量为与0.15-0.28μg/μl的1M盐酸相当的酸用量。
4.权利要求3的气雾剂溶液药物组合物,其中药学上可接受的一元酸的稳定量为与0.200-0.240μg/μl的1M盐酸相当的酸用量。
5.权利要求4的气雾剂溶液药物组合物,其中药学上可接受的一元酸的稳定量为与0.200-0.227μg/μl的1M盐酸相当的酸用量。
6.权利要求1-2和4-5中任一项的气雾剂溶液药物组合物,其中共溶剂是乙醇。
7.权利要求3的气雾剂溶液药物组合物,其中共溶剂是乙醇。
8.权利要求1的气雾剂溶液药物组合物,其中福莫特罗盐是富马酸福莫特罗。
9.权利要求1的气雾剂溶液药物组合物,其中福莫特罗盐的溶剂合物形式是二水合富马酸福莫特罗。
10.权利要求1的气雾剂溶液药物组合物,还包含一种或多种药物活性成分,其选自β-2激动剂、吸入皮质类固醇、抗毒蕈碱药和磷酸二酯酶-4抑制剂。
11.权利要求1的气雾剂溶液药物组合物,其中总的福莫特罗降解产物水平相对于6μg/启喷的理论富马酸福莫特罗含量低于10%w/w,且富马酸福莫特罗的残留水平相对于其起始含量高于90%w/w。
12.权利要求11的气雾剂溶液药物组合物,其中总的福莫特罗降解产物水平相对于6μg/启喷的理论富马酸福莫特罗含量低于2%w/w,且富马酸福莫特罗的残留水平相对于其起始含量高于95%w/w。
13.内部被包含氟化乙丙烯聚合物的树脂涂敷的与气雾剂溶液药物组合物一起使用的气雾剂罐,所述气雾剂溶液药物组合物预期用于加压计量吸入器,该气雾剂溶液药物组合物包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的药学上可接受的一元酸,所述药学上可接受的一元酸为盐酸;和
(f)吸入皮质类固醇,所述吸入皮质类固醇选自50-250μg/启喷的量的二丙酸倍氯米松和50-250μg/启喷的量的布地奈德。
14.降低气雾剂溶液药物组合物贮存期限期间降解产物N-(3-溴)-[2-羟基-5-[1-羟基-2-[1-(4-甲氧基苯基)丙-2-基氨基]乙基]苯基]甲酰胺的量的方法,所述气雾剂溶液药物组合物预期用于加压计量吸入器,该气雾剂溶液药物组合物包含:
(a)格隆溴铵,其剂量范围为5-26μg/启喷;
(b)福莫特罗或其盐或所述盐的溶剂合物,其剂量范围为1-25μg/启喷;
(c)HFA推进剂;
(d)共溶剂;
(e)稳定量的药学上可接受的一元酸,所述药学上可接受的一元酸为盐酸;和
(f)吸入皮质类固醇,所述吸入皮质类固醇选自50-250μg/启喷的量的二丙酸倍氯米松和50-250μg/启喷的量的布地奈德,
其特征在于该方法包括在内部被包含氟化乙丙烯聚合物的树脂涂敷的气雾剂罐中包含上述组合物。
15.权利要求14的方法,其进一步特征还在于如下事实:总的福莫特罗降解产物水平相对于6μg/启喷的理论富马酸福莫特罗含量低于10%w/w,且富马酸福莫特罗的残留水平相对于其起始含量高于90%w/w。
16.权利要求14或15的方法,其特征还在于如下事实:总的福莫特罗降解产物水平相对于6μg/启喷的理论富马酸福莫特罗含量低于2%w/w,且富马酸福莫特罗的残留水平相对于其起始含量高于95w/w。
17.如权利要求1-12任一项中所定义的气雾剂溶液药物组合物在制备药物中的用途,所述药物用于预防和/或治疗选自哮喘和慢性阻塞性肺疾病的阻塞性呼吸病。
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