CN101389313A - 用于吸入疗法的雾化抗生素 - Google Patents
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- CN101389313A CN101389313A CNA2007800068534A CN200780006853A CN101389313A CN 101389313 A CN101389313 A CN 101389313A CN A2007800068534 A CNA2007800068534 A CN A2007800068534A CN 200780006853 A CN200780006853 A CN 200780006853A CN 101389313 A CN101389313 A CN 101389313A
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Abstract
本发明提供适用于预防或治疗气管,如肺、支气管或鼻窦腔的感染性疾病的医药气雾剂。所述气雾剂包含选自喹诺酮类抗生素的群组的活性剂。本发明还公开了适于转化为所述气雾剂的液体和固体组合物和包含所述组合物的试剂盒。
Description
技术领域
本发明涉及适用于预防或治疗气管,如肺、支气管或鼻窦腔的感染性疾病的医药气雾剂。本发明也涉及制备所述气雾剂的固体或液体医药组合物和试剂盒。
背景技术
主要使用向支气管和肺传递治疗化合物来局部治疗呼吸系统的疾病和病状,如哮喘和支气管炎。近来,利用大表面积肺的吸收,已提出经肺投与全身性药物(如,胰岛素)并且已经在产品研发计划中积极地投入研究。
通常药物物质可以作为气雾化干粉或液体形式传递给呼吸系统,所述液体呈溶液或分散液形式,如药物悬浮液。已研发了多种使液体或固体组合物转化为气雾剂并能够被吸入的装置。对任何一种这样的装置而言,最重要的一个要求在于其能够实现气雾剂的粒子尺寸以允许沉积在靶位点,即,指定的作用或吸收位点。视将药物传递到支气管还是深肺部而定,典型配方的最佳液滴或粒子尺寸可从约10微米到低至1微米以下不等;如果其密度非常低,那么较大粒子可能是适用的。
定量吸入器传递测量剂量的呈小液体或固体粒子悬浮液形式的药物,所述药物在压力下由推进剂从吸入器中分配。将所述吸入器放在嘴中,当个体吸气时就触发吸入器释放药物。这需要一定程度的协调作用,并因此可能不适于儿童。
储雾器(spacer)或储雾装置可以与一些气雾剂吸入器一起使用,用于延长吸入器与口腔之间的距离。这会降低气雾剂行至口腔后部的速度,从而留有较多的时间供推进剂蒸发,并因此减小推进剂对口强后部的可能会引起刺激的影响并且使得较高比例的药物粒子能够被吸入。也不太需要协调吸气与吸入器的触发。吸气触发的吸入器仅当使用者将嘴放在出口上并吸气时就会以气雾剂或干粉形式传递药物。这避免了需要吸气与按下分配器之间的协调。药物的剂量仍将被测量或定量并且不取决于吸气的量。
另一方面,干粉吸入器负载数份呈粉末配方形式的药物物质。可使单位剂量容纳在小胶囊中。当通过吸气触发吸入器时,胶囊被刺破并且通过一种风扇机理分散粉末,如在称作“旋转式吸入器(Spinhaler和Rotahaler)”的市售装置中的情形。另一种称为“涡流式吸入器(Turbohaler)”的装置配备有含有测量剂量的粉末配方的药筒。
水基溶液和悬浮液通常用喷雾器吸入。市售有各种类型的喷雾器或者目前正处在研发当中。传统类型是喷射喷雾器,仍在被广泛使用。近来,已研发了超声波和振动膜型喷雾器。
虽然传统吸入疗法主要针对预防和治疗呼吸系统的过敏性和发炎性疾病和病状,包括哮喘和阻塞性支气管炎,但近来已研发出新颖的治疗方法。举例来说,已提出用抗生素局部疗法肺部感染,第一个获批用于这一用途的抗生素托普霉素(tobramycin),被成功引入对一定严重性或甚至危及生命的感染类型的治疗之中。以TobiTM供应的托普霉素是一种无菌、透明、略带黄色、无热原水溶液,而pH值和盐度经特定调整以通过由压缩空气驱动的可重复使用的喷雾器进行投与。其获批用于治疗感染铜绿假单胞菌(Pseudomonas aeruginosa)的囊性纤维化患者。
科学和专利文献中已提出其它肺抗生素疗法。举例来说,WO 02/03998公开了通过气雾化传递的大环内酯类抗生素(如红霉素胺(erythromycylamine))的可吸入配方。浓红霉素胺配方含有有效治疗由敏感(susceptible)细菌引起的感染的量的红霉素胺。也描述了具有包含大环内酯类抗生素于生理学上可接受的载剂中的配方的容器的单位剂量装置。这一文献进一步公开了由所述以质量中值空气动力学直径(mass medianaerodynamic diameter)主要介于1微米与5微米之间的气雾剂形式传递的配方治疗肺部感染的方法。
在WO 00/35461中,公开了使用浓氨基糖苷类抗生素配方治疗严重慢性支气管炎(支气管扩张)的方法。所述方法包括以质量中值直径主要介于1微米与5微米之间的气雾剂或干粉形式向肺支气管内空间(包括气泡)传递抗生素。所述方法包含投与浓度比靶生物体的最小抑制浓度高一到一万倍的抗生素。所述方法优选包含支气管内投与气雾化托普霉素来治疗严重慢性支气管炎患者的假单胞菌感染。
多种革兰氏阴性菌(gram-negative bacteria)都引起严重肺部感染,而这些细菌中有许多对常用或专用抗生素(包括托普霉素)具有或变得具有抗性,并且需要用新型抗生素治疗。由革兰氏阴性菌引起的肺部感染尤其危及免疫保护反应下降的患者,如囊性纤维化(cystic fibrosis CF)和HIV患者、患有慢性阻塞性肺病(chronic obstructive pulmonarydisease,COPD)支气管扩张的患者或机械通气的患者。因此,由抗性细菌引起的细菌呼吸道感染仍是一个重大问题,尤其是在CF、COPD和HIV患者中。举例来说,在囊性纤维化患者中铜绿假单胞菌的慢性肺部感染是高死亡率的主要病因。
为了解决对治疗由革兰氏阴性菌引起的急性和慢性肺部细菌感染(并且尤其是那些由例如洋葱伯克霍尔德菌(Burkholderia cepacia)、嗜麦芽窄食单胞菌(Stenotrophomonasmaltophilia)、木糖氧化产碱菌(Alcaligenes xylosoxidan)和多药物抗性铜绿假单胞菌引起的感染)的有效疗法的持续需要,WO 02/051356提出通过以可吸入气雾剂形式或干粉配方形式传递单环的β-内酰胺类(monobactam)抗生素氨曲南(aztreonam)的浓配方的呼吸系统局部疗法。根据这一文献,可将约1至250mg氨曲南溶解在1至5ml生理盐水或另一种水溶液中。使用能够将氨曲南溶液雾化成具有所需尺寸的液滴或粒子的喷雾器,以具有质量中值平均直径主要介于1微米与5微米之间的粒子的气雾剂向肺支气管内空间传递配方。或者,为了传递可吸入干粉,将氨曲南碾磨或喷雾干燥到粒度为1至5微米。
US 2004/0009126描述预防和治疗肺中细胞内感染的吸入系统。所述系统是包含负载有抗感染剂的胶体粒子(如,脂质体和脂质复合物)的医药配方与吸入器的组合。抗感染剂视情况为来自青霉素类、四环素类、喹诺酮类、头孢菌素类、单环的β-内酰胺类、氨基糖苷类、大环内酯类等的抗生素。吸入装置可为干粉吸入器、定量吸入器或喷雾器。
虽然这一文献提出对抗肺部感染的潜在适用的活性化合物,但其要求使用包含呈胶体粒子形式(尤其脂质体或脂质复合物)的药物物质的配方。视所选择的特定活性化合物而定,一或多个缺点可能与其教示相关。
第一方面,水溶性活性化合物可能很难与脂质基胶体药物载剂系统有效缔合。第二,出于安全原因,供吸入使用的医药组合物必须无菌,而所提出的包含脂质基胶体药物载剂系统的配方很难以无菌形式制造。第三,提出载剂粒子的尺寸范围至多2微米,这在使配方转化为粒度分布处于适于将气雾剂传递到肺的范围内的气雾剂方面存在相当大的困难。第四,相对于活性成分的含量,脂质基胶体药物载剂系统通常需要较大的赋形剂负载量;并且如果如在许多抗感染化合物的情况下,活性成分的剂量相对较高(例如,与用于吸入的皮质类固醇或倍他米美类药物(betamimetics)相比),那么任何水基液体配方中赋形剂(尤其两亲脂质)的所得含量将产生过高的粘稠度从而无法有效气雾化。另一方面,如果稀释所述配方以降低粘稠度并使得能够较有效地气雾化,那么液体体积将增加,这将使所需的吸入时间潜在延长而超出可接受的范围。
因此,对适于预防、控制或治疗气管感染并克服目前已知疗法一或多个缺点的其它医药组合物、气雾剂和治疗试剂盒存在需要。因此,本发明的一个目标在于提供所述组合物、气雾剂和试剂盒。根据以下描述和本专利的权利要求书,其它目标将变得显而易见。
发明内容
本发明提供用于经鼻、鼻窦或肺投药的医药气雾剂,其包含分散液相和连续气相。分散液相基本上由包含选自喹诺酮类抗生素的群组的活性化合物的水性液滴组成。分散相的液滴具有约1.5μm至约6μm的质量中值直径,而液滴尺寸分布显示约1.2至约3.0的几何标准偏差。
另一方面,本发明提供可制备所述气雾剂的液体和固体医药组合物。所述液体组合物在不超过约10ml且更优选小于5ml的体积中包含有效剂量的活性化合物。类似地,固体组合物可溶解或可分散于体积不超过约10ml且更优选小于5ml的水性液体溶剂中。
此外,本发明提供包含喷雾器和液体组合物的试剂盒,其中所述喷雾器被调适成将液体组合物气雾化为如上所述的气雾剂。
本发明进一步公开了制备气雾剂和向需要经鼻、鼻窦或肺抗生素治疗或预防的人传递气雾剂的方法。所述方法包含步骤:提供在不超过约10ml且更优选小于5ml体积中包含有效剂量的选自喹诺酮类抗生素的群组的活性化合物的液体医药组合物,和提供能够以至少0.1ml/min的总输出速率气雾化所述液体医药组合物的喷雾器,所述喷雾器进一步被调适成喷出包含质量中值直径约1.5μm至约6μm且几何标准偏差约1.2至约3.0的分散相的气雾剂。在随后步骤中,操作喷雾器以气雾化液体组合物,从而提供可由需要抗生素疗法的患者吸入的医药气雾剂。
在一些优选实施例中,活性化合物选自由以下各物组成的群组:左氧氟沙星(levofloxacin)、莫西沙星(moxifloxacin)和加替沙星(gatifloxacin),包括这些化合物的医药学上可接受的盐、溶剂化物、异构体、接合物、前药和衍生物。
附图说明
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具体实施方式
根据第一方面,本发明提供用于经鼻、鼻窦或肺投药的医药气雾剂,其包含分散液相和连续气相,其中分散液相基本上由包含选自喹诺酮类抗生素群组的活性化合物的水性液滴组成。分散相的特征进一步在于质量中值直径为约1.5μm至约6μm,并且液滴尺寸分布的几何标准偏差在约1.2至约3.0的范围内。
如本文中所使用,气雾剂是固相或液相于气相中的分散液。分散相,也称为不连续相,包含多种固体或液体粒子。一般来说,分散相的粒度通常(大大)小于约100μm。两种基本物理类型的气雾剂(即,于气相中的固体和液体分散液)都可用作医药气雾剂。代表于气相中的固体粒子的气雾剂实例是由干粉吸入器(dry powder inhaler,DPI)喷出的气雾剂。相反,加压定量吸入器和喷雾器传递分散相为液体的气雾剂。
根据本发明,气雾剂包含分散液相和连续气相。所述气雾剂有时称为“液体气雾剂”或者可能更恰当地称为气雾化液体。应注意,要求分散液相不排除存在固相。具体来说,分散液相本身可能就是分散液,如固体粒子于液体中的悬浮液。
连续气相可选自医药学上可接受的任何气体或气体混合物。举例来说,气相可仅为空气或压缩空气,这在使用喷雾器作为气雾剂发生器的吸入疗法中最为常见。或者,也可使用其它气体和气体混合物,如富氧空气或氮氧混合物。最优选的是使用空气作为连续气相。
活性化合物是适用于诊断、预防、控制或治疗动物(尤其人类)疾病、病状或症状的天然的、生物技术衍生的、或合成的化合物或化合物的混合物。可用作活性化合物同义词的其它术语包括(例如)活性成分、活性医药成分、治疗化合物、药物物质、药物等。
根据本发明,活性化合物是选自喹诺酮类抗生素的群组的抗生素化合物。喹诺酮类抗生素,也称为氟喹诺酮类或氟喹诺酮类抗生素,代表一类化学上或多或少与萘啶酸(nalidixic acid)相关的广谱抗生素。喹诺酮类通过抑制细菌DNA旋转酶或拓扑异构酶IV或两者起作用。因此,其抑制DNA复制并且通过杀菌起作用。
气雾剂可能包含任何喹诺酮抗生素:所谓的第一代喹诺酮,如萘啶酸、西诺沙星(cinoxacin)、氟甲喹(flumequine)、奥索利酸(oxolinic acid)、吡咯米酸(piromidic acid)或吡哌酸(pipedemic acid);或第二代喹诺酮,如环丙沙星(ciprofloxacin)、依诺沙星(enoxacin)、氟罗沙星(fleroxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、那氟沙星(nadifloxacin)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、培氟沙星(pefloxacin)、单诺沙星(danafloxacin)、二氟沙星(difloxacin)、恩氟沙星(enrofloxacin)、麻保沙星(marbifloxacin)、沙氟沙星(sarafloxacin)、阿拉曲伐沙星(altrofloxacin)或芦氟沙星(rufloxacin);或第三代喹诺酮,如巴洛沙星(balofloxacin)、加替沙星(gatifloxacin)、格帕沙星(grepafloxacin)、帕珠沙星(pazufloxacin)、司帕沙星(sparfloxacin)、替马沙星(temafloxacin)或托氟沙星(tosufloxacin);或第四代或实验性喹诺酮,如克林沙星(clinafloxacin)、吉米沙星(gemifloxicin)、莫西沙星(moxifloxacin)、西他沙星(sitafloxacin)、曲伐沙星(trovafloxacin)、伊诺沙星(ecinofloxacin)、加雷沙星(garenoxacin)或普卢利沙星(prulifloxacin)。
应注意,在本说明书中,如上所给出的这些化合物的名称应理解为包括相应盐、溶剂化物、结构异构体、立体异构体、接合物、前药和衍生物。举例来说,术语帕珠沙星必须解释为包括甲磺酸帕珠沙星(pazufloxacin mesylate)。
盐、衍生物、溶剂化物和异构体是活性要素可用作医药组合物中活性成分的形式的所有种类。盐是包含离子(即,阳离子和阴离子)的中性化合物。如果活性要素可充当酸,那么可与无机阳离子或有机阳离子形成潜在适用的盐,所述无机阳离子例如为钠、钾、钙、镁和铵,所述有机阳离子例如为由精氨酸、甘氨酸、乙二胺和赖氨酸衍生的阳离子。如果活性要素可充当碱,那么可与无机阴离子形成潜在适用的盐,所述无机阴离子例如为氯离子、磷酸根(一元或二元)、硫酸根、溴离子、碘离子、硝酸根、乙酸根、三氟乙酸根、丙酸根、丁酸根、马来酸根、富马酸根、甲烷磺酸根、乙烷磺酸根、2-羟基乙基-磺酸根、正丙基磺酸根、异丙基磺酸根、乳酸根、苹果酸根或柠檬酸根。
衍生物广义上定义为化学上和功能上与母体化合物类似的化合物。举例来说,前药可理解为活性化合物或活性要素的衍生物,其在活体内转化为(例如经化学或酶促水解或氧化)相应的药理学活性物质。衍生物的其它实例为接合物、类似物和模拟物。
溶剂化物是通过溶剂化,即活性化合物与溶剂分子结合所形成的化合物。典型溶剂的实例是水,并且水合物是医药学上可接受的溶剂化物的众所周知的实例。如本文中所使用,水合物包括半水合物、单水合物、二水合物和任何其它化学计量比水合物。
异构体是化学式相同并且通常原子之间键的类型相同、但原子排列不同的分子。许多异构体共享类似但并不总是相同的性质。如本文中所使用,异构体包括结构异构体和立体异构体。在结构异构体中,原子或官能团以不同方式结合在一起,而在立体异构体中,键结构相同,但原子和官能团在空间上的几何定位不同。立体异构体包括不同异构体相互成镜像的光学异构体(例如,对映异构体),和非对映异构体和链末端的官能团可以不同方式扭动的其它几何异构体。
在一个优选实施例中,活性化合物选自:左氧氟沙星、加替沙星和莫西沙星,同样包括这些化合物的医药学上可接受的盐、溶剂化物、异构体、接合物、前药和衍生物。
本发明的气雾剂用于经肺、鼻或鼻窦传递。鼻在解剖学上是脊椎动物容纳呼吸的进气和出气的鼻孔的突起。在人类中,如在大多数其它哺乳动物中一样,它也容纳鼻毛,用以捕捉空气中颗粒污染物并阻止其到达肺。鼻腔内和鼻腔后是嗅粘膜和副鼻窦。在鼻腔后,空气接着穿过咽部,与消化系统分享,然后进入呼吸系统其余部分。
副鼻窦由颅部与面部骨骼内的四对空气填充腔或间隙组成。它们被分成四个小区,根据其下面的骨骼命名:(1)上颌窦,也称为窦(antrum),位于眼睛下方,上颌骨内;(2)额窦,位于眼睛上方,前额骨内;(3)筛窦,位于鼻子与眼睛之间,向后伸进颅内;和(4)蝶窦,差不多位于颅底中心。虽然窦的基本功能不完全明了,但似乎它们减小颅前部的相对重量,在所吸入的空气到达肺之前温热和加湿空气,增加声音共鸣,并或许提供对面部吹气的缓冲。
鼻腔和副鼻窦衬有粘膜。粘膜是粘液覆盖的上皮衬里。鼻腔和副鼻窦的粘膜通常受革兰氏阳性菌与革兰氏阴性菌细菌感染的影响,并且本发明气雾剂提供向这些膜传递治疗有效的活性剂的改进方式。
在另一优选实施例中,气雾剂用于经肺传递,这优选通过经口吸入气雾剂来实现。如本文中所使用,经肺传递意思是将气雾剂传递给肺任何部件或特征(包括所谓的深肺部、肺周边、气泡、支气管和细支气管)。
使用本发明气雾剂预防、控制或治疗人类是潜在有效方式的鼻、鼻窦或肺目标区病状包括,例如:
-视情况由肺炎链球菌(Streptococcus pneumoniae)、流感嗜血杆菌(Haemophilusinfluenza)或卡他莫拉菌(Moraxella catarrhalis)所引起的有或无恶化的急性或慢性窦炎或鼻窦炎;
-慢性支气管炎或慢性阻塞性肺病中视情况由金黄色葡萄球菌(Staphylococcusaureus)、肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌(Haemophilus parainfluenza)或卡他莫拉菌所引起的急性细菌恶化;
-视情况由金黄色葡萄球菌、铜绿假单胞菌(Pseudomonas aeruginosa)、粘质沙雷菌(Serratia marcescens)、大肠杆菌(Escherichia coli)、肺炎克氏杆菌(Klebsiellapneumoniae)、流感嗜血杆菌或肺炎链球菌所引起的医院内肺炎;和
-视情况由金黄色葡萄球菌、肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌、肺炎克氏杆菌、卡他莫拉菌、肺炎衣原体(Chlamydia pneumoniae)、嗜肺军团菌(Legionellapneumophila)或肺炎支原体(Mycoplasma pneumoniae)所引起的社区获得性肺炎。
尤其在免疫受损的患者中,例如在患有人类免疫缺陷病毒(HIV)感染的人、敏感患者、接受免疫抑制药物的人或囊性纤维化患者中,本发明气雾剂可能不仅适用于治疗或控制现有细菌感染,而且适用于预防所述感染。
气雾剂的特征进一步在于其分散液相显示约1.5μm至约6μm范围内的质量中值直径,以及约1.2至约3.0范围内的液滴尺寸几何标准偏差。如本文中所使用,质量中值直径(mass median diameter,MMD)是通过激光衍射法所测量的分散液相的质量中值直径。已知并且市售有多种适于测定质量中值直径的分析仪器,如Malvern MasterSizer X或Malvern SprayTec。气雾化液体粒子或液滴的包括几何标准偏差(geometric standarddeviation,GSD)在内的几何分布可以与质量中值直径同时测定。几何标准偏差描述一组优选平均值为几何平均值的数字的散布程度。
在一个优选实施例中,气雾剂用于经肺传递并显示约2.0μm至约4.5μm范围内的MMD和约1.2至约1.8范围内的GSD。更优选地,如果本发明气雾剂被调适成经肺传递,那么其具有约2.5至约4.0范围内的MMD和约1.4至约1.6范围内的GSD。已发现,这些组的组合中每一个组都特别适用于在肺(包括支气管和细支气管)中实现相对于被气雾化的药物量的较高局部药物浓度。
在另一优选实施例中,气雾剂用于经鼻窦传递。根据这一实施例,MMD优选相应在约2.5μm至4.5μm范围内,在约3μm至约4μm或在约2.8μm至约3.5μm的范围内。对于这一实施例,也优选GSD相应在约2.3至约3.0范围内或更优选至少约2.4或至少约2.5。另外,如果气雾剂用于经窦或鼻窦传递,那么优选其以选定频率脉动(或振动)。如本文中所使用,气雾剂的脉动理解为压力的周期性改变。脉动优选为有规律的,即,压力峰值之间的时间间隔大致恒定。压力脉动的振幅也可相对恒定,至少在从气雾剂发生器产生和喷出脉动气雾剂方面相对恒定。气雾剂的压力优选以约10Hz至约90Hz范围内的频率脉动。根据一些目前优选的实施例,压力也可以约10Hz至约60Hz、或10Hz至约55Hz、或约30Hz至约60Hz范围内的频率脉动。在另一实施例中,气雾剂以约30Hz至约55Hz、如约40Hz至约50Hz、例如约44Hz的频率振动。
已发现,振动气雾剂与压力大体上恒定的常规气雾剂相比,以更高的程度在鼻吸入后进入副鼻窦,条件是选择如上所概述的适当粒度。较大粒度将产生极少的窦沉积,但大的鼻粘膜沉积,而极小粒度使得气雾剂液滴跟随压力脉冲的压力梯度进入窦,而且离开窦但不沉积于其中。
在另一优选实施例中,气雾剂以至少约0.1ml/min的速率从气雾剂发生器喷出。在另一实施例中,对那些出于实用的目的密度接近1,即在约0.95至约1.05范围内的液体气雾剂来说,(总)输出速率(描述气雾剂从气雾剂发生器喷出的速率)为至少约0.150ml/min或至少约150mg/min。在其它实施例中,输出速率相应为约200mg/min至约800mg/min,或约250mg/min至约750mg/min。
下文中将更详细地讨论适于以0.1ml/min的速率产生本文中所述的气雾剂的适当气雾剂发生器,尤其喷雾器。
气雾剂可视情况包含至少一种例如选自以下各物的其它活性化合物:非喹诺酮类抗生素、外排泵抑制剂、作用于细菌生物膜的化合物、抗真菌剂、抗病毒剂、免疫调节剂、肺表面活性剂、β激动剂、抗胆碱能药、粘痰溶解剂、类肝素、消炎药和抗过敏药。
另一方面,本发明针对用于制备如上所述的气雾剂的液体医药组合物。所述液体组合物在不超过约10ml的体积中包含单位剂量的活性化合物。
如本文中所定义,液体医药组合物是包含至少一种活性化合物和至少一种医药学上可接受的、药理学上大体惰性的赋形剂的液体物质。应注意,术语“液体组合物”不一定意味没有固体物质存在。举例来说,这一表达也涵盖是固体粒子于连续液相中的分散液的液体悬浮液。
制备气雾剂的液体组合物优选为水性组合物,这意味着水是组合物的占主导地位的液体组分。如果可能,那么应避免除水以外的溶剂和助溶剂。在另一实施例中,组合物包含至少80重量%的水。在又一实施例中,组合物的至少约90重量%的液体组分是水。
如果不能避免加入溶剂,那么应谨慎选择赋形剂并考虑其生理可接受性。举例来说,如果组合物指定用于治疗危及生命的疾病,那么使用有限量的乙醇、甘油、丙二醇或聚乙二醇作为非水性溶剂可能是可接受的。但是,根据目前更优选的实施例,组合物大体上不含这些溶剂,尤其是甘油、丙二醇或聚乙二醇。
如上所提及,包含有效剂量或单位剂量活性成分的液体组合物体积不超过约10ml。更优选,所述体积为约5ml或更少。这确保患者便利性和顺应性:超过5ml的体积与许多患者不能完全接受的相对较长吸入时间相关,或许患有特别严重的急性病状的患者例外。根据另一实施例,包含有效剂量活性化合物的液体组合物体积为约4ml或更少,而在又一实施例中,所述体积为约2.5ml或更少。另外,为将治疗有效剂量沉积到窦腔或肺中所需要的吸入治疗时间小于15min,更优选小于10min,理想地小于5分钟。
液体组合物的动力粘度对通过雾化形成的气雾剂的粒度分布和雾化效率具有影响。其优选应调整到约0.8mPas至约3mPas的范围内。根据另一实施例,动力粘度在约1.0mPas至约2.5mPas的范围内。
为了获得高度适合本文中所述的优选用途的气雾剂,本发明液体组合物的表面张力优选应调整到约25mN/m至80mN/m的范围内,优选约30mN/m至75mN/m的范围内。关于这一点,应考虑在这一范围的最小部分,可预期制剂在粘膜上具有特别好的铺展性,但气雾剂品质和雾化效率会受到不利影响。
另一方面,如果看似有必要加入表面活性剂(例如,为了稳定或溶解可溶性较差的活性剂),那么几乎不能避免表面张力将相当显著地降低而低于水或生理缓冲溶液的表面张力。因此,可能不得不在各情况下视活性化合物和预期应用而定,进行折衷。
为具有良好耐受性,气雾剂应尽可能具有生理张力或渗透压。因此,可能希望加入渗透活性的赋形剂来控制气雾剂的渗透压。应选择这一赋形剂(或使用物质的组合时的这些赋形剂)的含量以产生不偏离生理体液渗透压(即,约290mOsmol/kg)太多的气雾剂渗透压。但是,在个体病例中,不得不再折衷一方面的物理化学或药物需求与另一方面的生理要求。此外,据认为气雾剂的窦传递在渗透压方面不像(例如)气雾剂的深肺部传递中一样成问题。至多800mOsmol/kg范围内的渗透压通常是可接受的。约200mOsmol/kg至至多约600mOsmol/kg范围内的渗透压尤其优选。在其它实施例中,渗透压甚至更接近生理值,即,约220mOsmol/kg至约400mOsmol/kg。
为实现针对目标区内细菌的特别高的效力,增强气雾剂沉积后组合物的局部停留可能有用。举例来说,沉积于肺中的组合物延长的停留时间可能产生病原体对抗生剂的较高的连续暴露。同时,可降低所需的投药频率,并因此提高患者便利性和顺应性。
可探求多种配方策略来实现停留的延长。首先,可能以微溶性固体形式(如难溶性盐形式)加入高水溶性活性化合物。这将要求化合物以不溶形式(如微悬浮液或纳米悬浮液形式)存在于气雾剂中。气雾剂液滴沉积后,组合物的液相与生理体液(例如,粘液)结合并使药物物质溶解。
在一个优选实施例中,与高分子赋形剂一起调配活性化合物,以实现缓慢释放和局部长时间停留。潜在合适的聚合物尤其包括医药学上可接受的水溶性或水可分散性聚合物,如甲基纤维素、羟基甲基纤维素、羟基乙基纤维素、羟基丙基纤维素、羟基丁基纤维素、羟基乙基甲基纤维素、羟基丙基甲基纤维素、羧甲基纤维素、羧甲基乙基纤维素、海藻酸盐、角叉菜、半乳甘露聚糖、黄芪胶、琼脂、阿拉伯胶、瓜尔胶、黄原胶、果胶、羧甲基支链淀粉、壳聚糖、葡聚糖、聚丙烯酸酯、聚甲基丙烯酸酯、甲基丙烯酸酯共聚物、聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮乙酸乙烯酯共聚物和任何这些物质的混合物。
一种目前优选的高分子赋形剂是壳聚糖。壳聚糖是包含随机分布的β-(1-4)联结的D-葡糖胺和N-乙酰基-D-葡糖胺的线性多糖。壳聚糖是甲壳素去乙酰化后所产生,而甲壳素是甲壳类动物和其它动物的外骨骼中的结构要素。根据本发明适用的壳聚糖中去乙酰化的程度在60-100%范围内,更优选至少约75%。壳聚糖中的氨基pKa值约6.5,以致壳聚糖通常带正电并且可溶于中性或酸性水性介质中。壳聚糖与带负电表面(如,粘膜)相互作用时还具有生物粘附性质,这可能进一步促使其适用于本发明的组合物。
如果选择壳聚糖作为液体组合物中的赋形剂,那么其含量优选应足够低而不超过约3mPas的动力粘度以允许有效气雾化。赋形剂对粘度的影响将取决于就分子量和去乙酰化程度来说壳聚糖的具体等级,以及组合物的pH值和可能存在的其它赋形剂。对于大多数等级的壳聚糖,优选组合物中的含量不超过约0.5重量%。在另一实施例中,壳聚糖含量在约0.01重量%至约0.25重量%的范围内。在又一实施例中,其在约0.025重量%至约0.1重量%的范围内。
作为组合物中的优选赋形剂,另一种水溶性聚合物选自水溶性纤维素醚的群组,所述纤维素醚例如为甲基纤维素、羟基甲基纤维素、羟基乙基纤维素、羟基丙基纤维素、羟基丁基纤维素、羟基乙基甲基纤维素、羟基丙基甲基纤维素、羧甲基纤维素和羧甲基乙基纤维素。尤其优选的是羟基丙基甲基纤维素。纤维素醚可以是组合物中唯一的高分子赋形剂,或者其可与另一聚合物(如壳聚糖)组合加入。
如果选择纤维素醚(如羟基丙基甲基纤维素)作为赋形剂中的一种,那么关于选择壳聚糖含量所给出的指导同样适用:应注意所得动力粘度优选不超过约3mPas的值,否则气雾化将难以进行。同样,当计算聚合物的含量时,应考虑聚合物的确切等级和其它赋形剂的存在。通常,对于大多数等级的羟基丙基甲基纤维素,优选液体组合物中的含量不超过约1重量%。在另一实施例中,选择在约0.05重量%至0.5重量%范围内的含量。
已发现如上所述的高分子赋形剂对活性化合物从配方中的释放或对沉积在目标组织上后组合物的局部停留时间或两者具有影响。因此也影响活性化合物的局部生物利用率和微生物的暴露。
潜在地,除聚合物以外的赋形剂也可以具有这些有益作用。举例来说,络合剂可以与高分子赋形剂类似的方式延长活性化合物的释放。某些两亲化合物,尤其可形成各种类型的与活性成分相互作用并提高其在目标区停留时间的胶体结构的两亲脂质,也同样如此。
潜在合适的络合剂实例包括环糊精。环糊精(Cyclodextrin,CD)是包含(α-1,4)联结的α-D-吡喃葡萄糖单元的环状低聚糖。其包含相对疏水性的中央腔和亲水性外部区。因为单体单元在α-1,4-键联处不能自由旋转,所以分子的形状倾向于圆锥形而非圆柱形,其中伯羟基位于锥体的较小部分而仲羟基位于锥体的较大部分。
最常见的环糊精是分别具有6、7和8个吡喃葡萄糖单元的α、β和γ环糊精。对于α环糊精,腔的直径约为4.7至对于β环糊精,约为6.0至而对γ环糊精,约为7.5至非衍生环糊精在25℃下显示约145mg/ml(α环糊精)、18.5mg/ml(β环糊精)和232mg/ml(γ环糊精)的水溶性。
已知环糊精能够与较小分子形成包合络合物。如果主体分子本身水溶性很差,那么在作为所述环糊精包合络合物形式时,可能变得溶解。已将数种医药剂成功调配为加入环糊精作为增溶剂的销售药品。
潜在适用的环糊精实例包括非衍生环糊精以及其羟基被烷基化或羟基烷基化、酯化或醚化的衍生物,如2-羟基丙基-β环糊精、2-羟基丙基-γ环糊精、磺丁基-β环糊精、磺丁基-γ环糊精、麦芽糖基-β环糊精和甲基-β环糊精。目前尤其优选的是2-羟基丙基-β环糊精和磺丁基-β环糊精、α环糊精、β环糊精和γ环糊精。
其它潜在合适的络合剂包括二价或多价金属盐(尤其钙、镁和铝盐)和螯合剂(如乙二胺四乙酸,包括其盐和衍生物)。此外,二价或多价金属盐也可充当由活性化合物和聚合物(如壳聚糖)形成的复合物的稳定剂。
潜在合适的两亲赋形剂的实例尤其包括磷脂(phospholipid)。磷脂可定义为含有磷的两亲脂质。也称为磷脂(phosphatide),在自然界中发挥重要作用,尤其作为生物膜的双层形成组分。广泛存在化学上衍生自磷脂酸的磷脂并且也常用于医药目的。此酸是一种通常(双重)酰化的甘油-3-磷酸,其中脂肪酸残基可具有不同长度。磷脂酸衍生物包括例如,磷酸基又经胆碱酯化的磷酸胆碱或磷脂酰胆碱,还有磷脂酰乙醇胺、磷脂酰肌醇等。卵磷脂是多种磷脂的天然混合物,通常具有高比例的磷脂酰胆碱。视特定卵磷脂的来源和其提取和/或富集方法而定,这些混合物也可包含显著量的固醇、脂肪酸、三酸甘油酯和其它物质。
合适的磷脂也是那些鉴于生理学性质而适于通过吸入投药的磷脂。这些磷脂尤其包含以卵磷脂形式从大豆或鸡蛋黄等天然源中提取的磷脂混合物,优选为氢化形式和/或不含溶血卵磷脂;以及纯化、富集或部分合成制备的磷脂,优选为饱和脂肪酸酯类。尤其优选的是纯化、富集或部分合成制备的中到长链两性离子磷脂,其在酰基链中基本不含不饱和度并且不含溶血卵磷脂和过氧化物。在磷脂混合物中,卵磷脂尤其优选。富集或纯化合物的实例是二豆蔻酰磷脂酰胆碱(dimyristoyl phosphatidyl choline,DMPC)、二硬脂酰磷脂酯胆碱(distearoyl phosphatidyl choline,DSPC)和二棕榈酰磷脂酰胆碱(dipalmitoyl phosphatidyl choline,DPPC)。
液体组合物可视情况包含其它医药学上可接受的赋形剂,如渗透剂,尤其无机盐;调节或缓冲pH值的赋形剂,如有机或无机盐、酸和碱;填充剂和冻干助剂,如蔗糖、乳糖、甘露糖醇、山梨糖醇、木糖醇、和其它糖醇;稳定剂和抗氧化剂,如维生素E或维生素E衍生物、番茄红素和其衍生物、抗坏血酸、亚硫酸盐、亚硫酸氢盐、没食子酸酯、丁基羟基苯甲醚和丁基羟基甲苯;离子和非离子表面活性剂,包括磷脂,如以上所公开的那些表面活性剂;以及掩味剂、崩解剂、着色剂、甜味剂和调味剂。
在一个优选实施例中,在组合物中加入一或多种渗透剂(如氯化钠),以将渗透压调节到如上文中所概述的优选范围内的值。
在另一实施例中,组合物包含至少一种调节pH值的赋形剂。为提供具有良好耐受性的气雾剂,应将本发明制剂调节到良好pH值(euhydric pH value)。术语“良好(euhydric)”已暗指医药与生理要求之间可能存在差异,如此不得不拆衷,例如担保从经济角度来看制剂在储存期间恰好充分稳定,但另一方面基本上具有良好耐受性。pH值优选位于弱酸性至中性区,即约4到8的pH值。应注意,偏向弱酸性环境可比pH值移入碱性区易耐受。约4.5至约7.5范围内的pH值尤其优选。
为调节和(视情况)缓冲pH值,可使用生理学上可接受的酸、碱、盐和这些的组合。降低pH值或作为缓冲系统的酸性组分的合适赋形剂是强无机酸,尤其硫酸和盐酸。此外,可使用中等强度的无机酸和有机酸以及酸性盐,例如,磷酸、柠檬酸、酒石酸、琥珀酸、富马酸、蛋氨酸、酸性磷酸氢钠或酸性磷酸氢钾、乳酸、葡糖醛酸等。然而,硫酸和盐酸最优选。适于升高pH值或作为缓冲系统的碱性组分的尤其是无机碱,如氢氧化钠或其它碱金属和碱土金属氢氧化物和氧化物,如尤其氢氧化镁和氢氧化钙、氢氧化铵和碱性铵盐,如乙酸铵;以及碱性氨基酸,如赖氨酸;碳酸盐,如碳酸钠或碳酸镁、碳酸氢钠;柠檬酸盐,如柠檬酸钠等。
在一个实施例中,本发明组合物含有由双组分组成的缓冲系统并且一种尤其优选的缓冲系统含有柠檬酸和柠檬酸钠。然而,其它缓冲系统也可能是合适的。
主要出于生理原因而不是医药原因,可通过其它添加剂达到组合物的化学稳定。这主要取决于其中所含的活性剂的种类。化学上所定义的活性剂在水性制剂中最常见的降解反应尤其包含可能主要受最佳pH值调节而限制的水解反应,以及氧化反应。可能经受氧化攻击的活性剂的实例是那些具有烯基、醛基、伯羟基、仲羟基、醚基、硫醚基、烯二醇基(endiol)、酮基或氨基的试剂。因此,在所述氧化敏感的活性剂情况下,视情况与增效剂组合添加抗氧化剂可能是可取的或是必要的。
抗氧化剂是防止或中断活性剂氧化的天然或合成物质。这些物质主要是自身可氧化或充当还原剂的佐剂,例如乙酸生育酚、番茄红素、还原型谷胱甘肽、过氧化氢酶、过氧化物歧化酶。协同物质例如为不在氧化过程中直接充当电抗但通过间接机理阻碍氧化的物质,例如EDTA衍生物(EDTA:乙二胺四乙酸)的情况下,络合在氧化中起催化作用的金属离子。其它合适抗氧化剂为抗坏血酸、抗坏血酸钠和抗坏血酸的其它盐和酯(例如,抗坏血酸棕榈酸酯)、富马酸和其盐、苹果酸和其盐、丁基羟基苯甲醚、没食子酸丙酯以及亚硫酸盐(如偏亚硫酸氢钠)。除EDTA和其盐外,柠檬酸和柠檬酸盐、苹果酸和其盐和麦芽酚(3-羟基-2-甲基-4H-吡喃-4-酮)也可充当螯合剂。
在一个实施例中,组合物含有至少一种抗氧化剂。在另一实施例中,其含有抗氧化剂与螯合剂。维生素E衍生物(尤其乙酸维生素E)与EDTA衍生物(尤其EDTA二钠盐)的组合尤其优选。在某些活性剂的情况下,已证明这一组合对获得组合物的高化学稳定性尤其有利。
在另一实施例中,组合物包含影响味道的赋形剂。明显较差的味道在吸入时极其令人讨厌并且有刺激性,并且会导致不顺应性,从而使疗法失败。较差的味道通过吸入期间沉淀于口腔和咽区的气雾剂部分被患者察觉。即使可通过优化气雾剂的粒度来实现小部分的制剂沉淀其中(除非口咽或鼻粘膜是待治疗的组织,否则这一部分对疗法来说是损失),目前也几乎不可能将这一部分降低到活性剂的较差味道将不再被察觉的程度。因此,可取的是改善组合物的味道或掩盖所选择的活性化合物的不良味道。
为改善味道,可加入一或多种来自糖、糖醇、盐、调味剂、络合剂(例如环糊精)、聚合物、甜味剂(例如糖精钠、天冬氨酸、精氨酸等)和表面活性剂的群组的潜在适用的赋形剂。
如以上所提及,在一个尤其优选的实施例中,活性化合物选自以下各物的群组:左氧氟沙星、加替沙星和莫西沙星,包括这两种化合物的医药学上可接受的盐、溶剂化物、异构体、接合物、前药和衍生物。
应选择活性成分的含量以确保超过目标位点的最低抑制浓度(minimum inhibitoryconcentration,MIC)。更优选地,选择含量以便相应超过MIC至少2倍或至少3倍。当然,对于已知的特定病原体来说,未必总是确切的MIC,并且可能适用于提供具有有效抵抗大量菌株的活性化合物浓度的组合物。
在一个优选实施例中,组合物的每单位剂量包含约10mg至约500mg左氧氟沙星或等效量的其盐或溶剂化物或衍生物,其中单位剂量是指定用于单次投药的组合物部分。更优选地,左氧氟沙星的剂量在约25mg至约250mg、如约50mg至约200mg的范围内。待加入的确切剂量的选择也应考虑下文将更详细讨论的气雾剂发生器的气雾化效率。
在另一实施例中,本发明的液体组合物显示约10mg/ml至约200mg/ml范围内的左氧氟沙星浓度。更优选地,浓度相应为约20mg/ml至约150mg/ml或约25mg/ml至约100mg/ml。已发现所述浓度与优选类型的气雾剂发生器非常相符,允许高效的气雾化,并且仍非常耐受。
如果选择加替沙星或莫西沙星或其盐、异构体、溶剂化物或衍生物作为活性成分,那么与左氧氟沙星情况相同的剂量和浓度视为合适的。
组合物视情况包含另一种活性化合物,例如具有补充抗菌谱的另一种抗生素或增效剂,例如外排泵或生物膜形成抑制剂或生物粘附剂或促进抗生素穿过细菌细胞膜流入细菌中的化合物。
在另一实施例中,本发明气雾剂包含选自化学上不太稳定的喹诺酮类抗生素的活性成分。在此情况下,用于气雾化的液体配方可能不具有足够长的充当合适的销售配方的保质期,而改为提供固体组合物可能是有利的。化学上不稳定的活性化合物的固体组合物通常具有较长保质期的潜能。
干燥固体组合物优选包含活性化合物和至少一种赋形剂。通常可选择与如上所述相同的赋形剂。视固体组合物的制造方法而定,一或多种另外的赋形剂可能是适用的。举例来说,如果通过冷冻干燥(冻干)(制备本发明的所述固体组合物的尤其优选方法之一)制备组合物,那么加入至少一种填充剂和/或冻干助剂(例如糖或糖醇,尤其蔗糖、果糖、葡萄糖、甘露糖醇、山梨糖醇、海藻糖、异麦芽糖醇或木糖醇)可能有用。
固体组合物的特征进一步在于其包含有效量的活性化合物的部分或单位剂量可溶解或可分散于体积不超过约10ml的水性溶剂中。在另一实施例中,其可溶解或可分散于相应不超过约5ml或不超过约4ml或甚至2ml的水性液体体积中。另外,雾化或吸入用时少于15分钟且更优选少于5分钟。
如本文中所定义,可溶解意思是固体组合物和水性液体溶剂可组合形成溶液或胶体溶液,而术语“可分散”应解释为也包括形成液体分散液,尤其乳液和微悬浮液。
水性意思是溶剂的主要液体组分是水。如果可能,应避免除水以外的溶剂和助溶剂。在另一实施例中,水性液体溶剂包含至少80重量%水。在又一实施例中,溶剂的至少约90重量%的液体组分是水。
如果不能避免加入溶剂,那么应谨慎选择赋形剂并考虑其生理可接受性。举例来说,如果气雾剂指定用于治疗危及生命的疾病,那么使用有限量的乙醇、甘油、丙二醇或聚乙二醇作为非水性溶剂可能是可接受的。但是,根据目前更优选的实施例,溶解或分散固体组合物的水性溶剂大体上不含这些溶剂,尤其是甘油、丙二醇或聚乙二醇。
用于复原(reconstitution)的固体组合物可以是医药试剂盒的一部分。所述试剂盒优选包含呈无菌形式的固体组合物。如本文中所使用,术语“无菌”将根据常用医药含义定义。应理解为不存在能够繁殖的细菌。无菌性由相关药典中所定义的合适测试确定。根据目前科学标准,10-6的无菌保证水平通常视为可为无菌制剂所接受,即一百万个单位中可能有一个单位被污染。
然后,实际中,污染率可能较高。举例来说,通常假定无菌制造的制剂的污染率总计约10-3。因为一方面根据药典用于批次质量控制的无菌测试的程度有限并且另一方面在进行测试本身时外来物质可能引起污染,所以很难要求绝对意义上的无菌或者测试特定产物绝对意义上的无菌。因此,在本文中应理解组合物的无菌应当使组合物满足相关药典关于无菌的要求。即用型液体配方的情况也如此。
如以上所提及,可通过提供与待气雾化的液体组合物类似的液体组合物,接着例如通过冻干进行干燥来制备固体组合物。类似的意思是通过干燥制备固体组合物的液体组合物可能不包含即用型液体组合物的所有固体成分,例如在设计用于复原的液体载剂包含一或多种赋形剂的情况下。这两种液体组合物中成分的浓度也未必相同。或者,可通过提供呈粉末形式的活性成分和(视情况)至少一种赋形剂,接着混合这些物质以形成粉末混合物来制备用于复原的固体组合物。
另一方面,本发明针对制备和传递用于经鼻、鼻窦或肺投药的气雾剂的医药试剂盒,其包含分散液相和连续气相,其中所述分散液相基本上由包含选自喹诺酮类抗生素的群组的活性化合物的水性液滴组成,具有约1.5μm至约6μm的质量中值直径并且液滴尺寸分布显示约1.2至约3.0的几何标准偏差。试剂盒的特征进一步在于其包含选自喷雾器和水性液体组合物的群组的气雾剂发生器,所述组合物在不超过约10ml的体积内包含有效剂量的活性化合物。
喷雾器是能够气雾化液体的装置。本发明的这一实施例的试剂盒的喷雾器优选选自喷射喷雾器、超声波喷雾器或压电喷雾器、喷射碰撞喷雾器、电流体动力喷雾器、毛细管力喷雾器、穿孔膜喷雾器和穿孔振动膜喷雾器。(M.Knoch和M.Keller:定制电子喷雾器:液体气雾剂药物传递系统的新策略(The customised electronic nebuliser:a newcategory of liquid aerosol drug delivery systems).药物传递专家意见(Expert Opin.DrugDeliv.)2005,2(2),377-390)。尤其优选的是压电型喷雾器、电流体动力型喷雾器和/或穿孔膜型喷雾器,例如MysticTM、eFlowTM、AeroNebTM、AeroNeb ProTM、Aero DoseTM。如果气雾剂待传递到支气管和/或肺,那么这些类型的喷雾器尤其适用。
如果气雾剂待传递到鼻或鼻窦腔或区,那么优选喷雾器选自能够喷出脉动(或振动)气雾剂的喷射喷雾器的群组。最近已经有了可用的能够比先前更好地到达鼻窦的改进喷射喷雾器。这些喷雾器具有喷嘴(nose piece),用以引导气雾剂流入鼻中。如果仅一个鼻孔用来吸入气雾剂,那么必须用合适的限流器封闭另一个鼻孔。此外,这些喷雾器的特征在于其以脉动压力释放气雾剂。脉动压力波达成更强烈的鼻窦通气,以致伴随吸入的气雾剂能更好地散布到这些腔中。所述喷雾装置的实例公开于DE 102 39 321 B3中。
优选应选择或调适喷雾器以能够以至少约0.1ml/min的速率或(假定组合物的相对密度通常会在1左右)以至少约100mg/min的速率气雾化单位剂量,即包含单次投药期间指定待投与的有效量活性化合物的液体组合物的体积。更优选地,喷雾器能够使输出速率相应为至少约0.15ml/min或150mg/min。在其它实施例中,喷雾器的输出速率相应为至少约0.2、0.3、0.4或0.5ml/min。
此外,应选择喷雾器的输出速率以实现短的液体组合物雾化时间。显然,雾化时间将视待喷雾的组合物的体积和输出速率而定。优选地,应选择或调适喷雾器以能够在不超过约20分钟内气雾化包含有效剂量活性化合物的液体组合物体积。更优选地,单位剂量的雾化时间不超过约10分钟。在其它实施例中,选择或调适喷雾器以使每剂量单位的雾化时间能够不超过约8分钟或不超过约5分钟。目前最优选的是约1分钟至约8分钟范围内的雾化时间。
优选也应选择喷雾器以能够喷出相当大部分的分散相具有不大于5μm的液滴尺寸的气雾剂。这一部分通常称为可呼吸部分,因为与较大液滴相反,这些液滴具有沉积于肺而不是气管和咽中的高概率。在一个实施例中,选择喷雾器以喷出至少约50重量%的气雾剂为可呼吸部分的气雾剂。更优选地,可呼吸部分为至少约70重量%。尤其优选的是被调适成从上述液体组合物产生相应具有约80重量%或更高或甚至约90重量%或更高的可呼吸部分的气雾剂的喷雾器。
根据另一优选实施例,喷雾器被调适成以气雾剂形式传递主要部分的负载剂量的液体组合物,例如至少约50重量%的负载剂量。更优选,实际上从装置中喷出至少60重量%的填充于喷雾器中的剂量,这通过使用基于振动穿孔膜设计的现代的视情况定制的电子喷雾器得以最佳实现。根据另一实施例,气雾化至少约70重量%的负载剂量或甚至相应至少约75重量%或95重量%。
本发明也提供制备和传递气雾剂的方法,所述方法包含以下步骤:提供在不超过约10ml且更优选小于5ml的体积中包含有效剂量的选自喹诺酮类抗生素的群组的活性化合物的液体医药组合物;提供能够以至少0.1ml/min的总输出速率气雾化所述液体医药组合物的喷雾器,所述喷雾器进一步被调适成喷出包含质量中值直径约1.5μm至约6μm且几何标准偏差约1.2至约3的分散相的气雾剂;和操作喷雾器以气雾化液体组合物。组合物的雾化优选在不超过约15分钟且更优选小于5分钟的时间内进行。
无论是液体或最初为固体,本发明组合物或包含所述组合物的试剂盒都适用于预防、控制或治疗:
-视情况由肺炎链球菌、流感嗜血杆菌或卡他莫拉菌所引起的有或无恶化的急性或慢性窦炎或鼻窦炎;
-慢性支气管炎或慢性阻塞性肺病中视情况由金黄色葡萄球菌、肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌或卡他莫拉菌所引起的急性细菌恶化;
-视情况由金黄色葡萄球菌、铜绿假单胞菌、粘质沙雷菌、大肠杆菌、肺炎克氏杆菌、流感嗜血杆菌或肺炎链球菌所引起的医院内肺炎;和
-视情况由金黄色葡萄球菌、肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌、肺炎克氏杆菌、卡他莫拉菌、肺炎衣原体、嗜肺军团菌或肺炎支原体所引起的社区获得性肺炎。
尤其在免疫受损的患者中,例如在患有HIV感染的人、敏感患者、接受免疫抑制药物的人或囊性纤维化患者中,本发明的组合物或试剂盒可能不仅适用于治疗或控制现有细菌感染,而且适用于预防所述感染。
优选在至少约1周的时程内使用重复投药方案投与组合物。方案的持续时间视情况为约10天或约2周。在其它实施例中,持续时间为约3周至约3个月。此外,方案优选包含每日吸入一或两次;最优选的是在疗法过程中每日投药一次。
以下实例用于说明本发明;然而,这些实例不应理解为限制本发明的范围。
实例
实例1:
将半水合左氧氟沙星(2.5g)、壳聚糖(0.06g)、羟丙基甲基纤维素(0.20g)、六水合硫酸镁(0.13g)和氯化钠(0.71g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤溶液,并在无菌条件下在层流气流罩中将每1.5ml装入2ml预成形无菌吹填密封小瓶中,此后加热密封小瓶。
液体组合物具有2.1mPas的动力粘度。表面张力为47.8mN/m。pH值在22℃下为6.73,并且渗透压为332mOsmol/kg。
实例2:
将半水合左氧氟沙星(3.5g)、2-HP-β环糊精(5g)、六水合硫酸镁(0.15g)和氯化钠(0.25g)溶解于注射用水中,总重量达100g。使用0.22μm滤纸无菌过滤所得溶液,并且在无菌条件下将10ml装入15ml玻璃小瓶中。溶液具有292mOsmol/kg的渗透压。
实例3:
将半水合左氧氟沙星(4g)、托普霉素(6g)、2-HP-β环糊精(10g)、六水合硫酸镁(0.15g)和氯化钠(0.25g)溶解于注射用水中,总重量达100g。在无菌条件下在层流气流罩中将每1ml装入2ml预成形吹填密封小瓶中,此后加热密封小瓶。
实例4:
将半水合左氧氟沙星(5g)、肝素钠(1g)、γ环糊精(15.0g)、六水合硫酸镁(0.15g)、卵磷脂(0.25g)和氯化钠(0.25g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤这两种溶液并装入5ml无菌琥珀色玻璃小瓶中。这两种溶液具有290-350mOsmol/kg范围内的渗透压值。
实例5:
将科利当SR(Kollidon SR)(0.3g)溶解于乙醇中。将半水合左氧氟沙星(1.0g)、聚山梨酸酯80(0.5g)和氯化钠(0.25g)溶解于注射用水中。将乙醇聚合物溶液倾入水基左氧氟沙星溶液中,并将总重量添加到100.0g的重量。胶体粒子因这一过程而沉淀,产生187.9nm±1.4的平均粒径,多分散指数为0.14±0.09。使用0.22μm滤纸无菌过滤所得悬浮液,并将每4ml装入5ml琥珀色玻璃小瓶中。
实例6:
将加替沙星(8g)、γ环糊精(13g)、六水合硫酸镁(0.13g)和氯化钠(0.25g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤所得溶液,并在无菌条件下将每4ml装入5ml无菌玻璃小瓶中。
实例7:
将加替沙星(4g)、两性霉素B(1g)、γ环糊精(8g)和L-精氨酸(0.55g)、维生素E-TPGS(0.1g)和氯化钠(0.25g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤所得溶液,并在无菌条件下将3ml装入5ml无菌玻璃小瓶中。
实例8:
将半水合左氧氟沙星(2g)、两性霉素B(1g)、γ环糊精(6g)、壳聚糖(0.06g)、羟丙基甲基纤维素(0.20g)、六水合硫酸镁(0.15g)和氯化钠(0.5g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤溶液,并在无菌条件下在层流气流罩中将每2ml装入2.5ml预成形无菌吹填密封小瓶中,此后加热密封小瓶。
实例9:
将加替沙星(2g)、氨溴素(Ambroxol)(1g)、γ环糊精(5g)、六水合硫酸镁(0.12g)、木糖醇(0.5g)和氯化钠(0.4g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤所得溶液,并在无菌条件下在层流气流罩中将每2ml装入2.5ml预成形无菌吹填密封小瓶中,此后加热密封小瓶。
实例10:
将莫西沙星(5g)、丙酸氟替卡松(Fluticasone-propionate)(0.02g)、γ环糊精(7.5g)、六水合硫酸镁(0.2g)、L-精氨酸(0.5g)和氯化钠(0.3g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤所得溶液,并在无菌条件下在层流气流罩中将0.5ml装入1ml预成形无菌吹填密封小瓶中,此后加热密封小瓶。
实例11:
将莫西沙星(2.5g)、色甘酸二钠(5g)、γ环糊精(7.5g)、六水合硫酸镁(0.5g)、L-精氨酸(0.5g)、糖精钠(0.5g)和氯化钠(0.25g)溶解于注射用水中,总重量达100.0g。使用0.22μm滤纸无菌过滤所得溶液,并在无菌条件下在层流气流罩中将0.5ml装入1ml预成形无菌吹填密封小瓶中,此后加热密封小瓶。
细胞耐受性测试:
除药物配方的物理化学性质和其呈溶液或分散系统的稳定性外,研究所述药物配方在细胞培养测试系统中的细胞耐受性是有益的。出于此目的,使用支气管细胞系Calu-3作为毒性评定的活体外模型。Calu-3是一种人类粘膜下腺癌细胞系,形成具有顶端微绒毛和紧密结合复合体的致密的、极化的、高度分化的单层。与其它细胞系相反,Calu-3细胞产生细胞外粘液。已发现Calu-3细胞是活体外研究肺药物传递的合适模型。已证实这一细胞系的单层具有约1000-1300Ω·cm2的高跨上皮电阻(transepithelial electricalresistance,TEER)。另外,已证实单层完整性丧失的同时TEER降低至600Ω·cm2以下的值并且渗透性增加。内部数据显示200Ω·cm2以下的TEER值促使低渗透性分子的渗透性增加。因为具有毒性的同时单层完整性丧失,所以超过50%的TEER的增加指示测试化合物具有毒性。代表上呼吸道支气管细胞的Calu-3细胞通常是研究药物渗透以及药物、配方和/或选择用于吸入配方中的常见赋形剂的刺激或毒性作用的有效工具。Calu-3细胞测试提供了研究药物物质潜在作用以及赋形剂或配方组分的影响的可能性。
如Keller等人(药物和赋形剂对Calu-3细胞的适用性和耐受性的评估,一种支气管上皮细胞模型(Assessment of applicability and tolerability of drugs and excipients onCalu-3cells,a bronchial epithelial cell model),肺药物传递论文汇编XV(ProceedingsDrug Delivery to the Lungs XV),2005年12月7日和9日,2005,第161-164页)所详述,在Calu3细胞中测试根据实例1的组合物。在施用不同配方或赋形剂后两小时内,在生理学克雷布斯林格氏缓冲液(Krebs Ringer buffer,KRB)中测定TEER。测量电阻的减小指示完整上皮细胞间接触(紧密结合)的影响,这是确定毒性作用的极灵敏参数。为评定所述细胞损伤是否可逆,在与测试配方一起培育之后,在细胞培养物中培育细胞24小时。根据这一测试设计,确定具有毒性潜能的配方和赋形剂之间的差异。部分测试赋形剂或配方列于下表1中。
表1
由上表1中所概述的数据显而易见,为溶解和/或络合和/或胶囊化和/或掩蔽令人不愉快的味道而提出的赋形剂不影响Calu-3细胞的生活力。对于其它赋形剂(例如,缓冲盐、螯合剂、聚合物(壳聚糖、HPMC))和表面活性剂和药物(例如,托普霉素、可与氟喹诺酮类(例如左氧氟沙星)有利组合的两性霉素B)也没观察到破坏作用。但是,含有25mg/ml而不是安慰剂的左氧氟沙星配方与Calu 3细胞表面的直接接触影响所述细胞的生活力,而1:5稀释液与缓冲溶液相当。由以上结果可推断,>25ml/ml的浓度可能对Calu-3细胞有害。但是,必须考虑药物配方在被上皮衬里流体(epithelial liningfluid)吸入后将立即稀释,并且以上评定仅是配方耐受性的粗略指示。
气雾化实验:
由通过具有不同直径的孔的穿孔振动网产生气雾剂的eFlow电子喷雾器(35L配置)雾化实例1的配方组合物(R.Stangl:喷雾器产品平台的研发(Development of a nebuliserproduct platform):肺药物传递论文汇编XV(Proceedings Drug Delivery to the Lungs XV),2005年12月7日和9日,第242-245页)。如Tservistas等人(吸气流速对通过利用呼吸模拟的喷雾器系统和下一代冲击器传递的托普霉素传递剂量和液滴尺寸分布的影响(Influence of inspiratory flow rate on the delivered dose and droplet size distribution oftobramycin delivered by nebuliser systems utilizing breath simulation and the nextgeneration impactor).肺药物传递论文汇编XV(Proceedings Drug Delivery to the LungsXV),2004年12月9日和10日,第220-223页)所述通过呼吸模拟,和如M.Knoch和E.Sommer(喷射喷雾器设计与功能(Jet nebuliser design and function).欧洲呼吸评论(Eur.Respiratory Rev.)2000;10:72,183-186)所述通过关于液滴尺寸分布模式的激光衍射法,评定药物传递效率。结果如表2中所示。
表2
表2显示三种eFlow电子喷雾器雾化1.5ml根据实例1的左氧氟沙星(25mg/ml)配方后各自的传递效率。结果为使用三种eFlow电子喷雾器一式两份进行6次实验的平均值。由上表2中的结果显而易见,根据实例1中所概述的组合物含有25mg/ml的左氧氟沙星吸入溶液可被eFlow非常有效地雾化。令人惊讶地,传递性能几乎与所应用的呼吸模式无关,并且潮气量和呼吸次数和吸气与呼气比都不对67.1-70.3%总负载左氧氟沙星剂量(36mg)范围内的传递剂量产生显著影响。因此,与已知具有流动依赖性传递性能的喷射喷雾器(M.Tservistas等人:肺药物传递论文汇编XV(Proceedings DrugDelivery to the Lungs XV),2004年12月9日和10日,第220-223页)相比,eFlow更适合向肺传递氟喹诺酮。此外,1.5ml体积约3min的短雾化时间将有助于改善患者顺应性。
Claims (25)
1.一种用于经鼻、鼻窦或肺投药的医药气雾剂,其包含分散液相和连续气相,其中所述分散液相
(a)基本上由包含选自喹诺酮类抗生素的群组的活性化合物的水性液滴组成;
(b)具有约1.5μm至约6μm的质量中值直径;且
(c)具有显示约1.2至约3.0的几何标准偏差的液滴尺寸分布。
2.根据权利要求1所述的气雾剂,其中所述活性化合物选自:左氧氟沙星(levofloxacin)、莫西沙星(moxifloxacin)和加替沙星(gatifloxacin),包括其医药学上可接受的盐、溶剂化物、异构体、接合物、前药和衍生物。
3.根据权利要求1或2所述的气雾剂,其包含至少一种视情况选自以下各物的其它活性化合物:非喹诺酮类抗生素、外排泵抑制剂、作用于细菌生物膜的化合物、抗真菌剂、抗病毒剂、免疫调节剂、肺表面活性剂、β激动剂、抗胆碱能药、类固醇、粘痰溶解剂、类肝素、消炎药和抗过敏药。
4.根据权利要求1至3中任一权利要求所述的气雾剂,其以每分钟至少约0.1ml分散液相的速率从气雾剂发生器喷出。
5.一种制备根据权利要求1至4中任一权利要求所述的气雾剂的液体医药组合物,其中所述组合物的不超过约10ml且更优选小于约5ml体积包含有效剂量的所述活性化合物。
6.根据权利要求5所述的组合物,其具有在约0.8mPas至约3mPas范围内的动力粘度。
7.根据权利要求5或6所述的组合物,其具有在约25mN/m至80mN/m范围内的表面张力。
8.根据权利要求5至7中任一权利要求所述的组合物,其包含至少一种能够影响所述活性化合物在气雾剂沉积位点处的局部生物利用率、释放和/或局部停留时间的赋形剂。
9.根据权利要求8所述的组合物,其中所述能够影响所述活性化合物的局部生物利用率、释放和/或局部停留时间的赋形剂选自由络合剂、聚合物和两亲化合物组成的群组。
10.根据权利要求5至9中任一权利要求所述的组合物,其包含至少一种改味赋形剂,优选选自调味剂、甜味剂、络合剂和掩味剂,如环糊精、糖、糖醇、糖精钠、阿斯巴甜(aspartame)或精氨酸。
11.根据权利要求5至10中任一权利要求所述的组合物,其包含至少一种选自二价或多价金属离子的群组的赋形剂。
12.一种制备根据权利要求5至11中任一权利要求所述的液体组合物的固体医药组合物,其中所述组合物包含有效剂量的所述活性化合物,并且其中所述固体组合物可溶解或可分散于体积不超过约10ml且更优选小于5ml的水性液体溶剂中。
13.一种制备和传递用于经鼻、鼻窦或肺投药的医药气雾剂的试剂盒,其包含分散液相和连续气相,其中所述分散液相
(a)基本上由包含选自喹诺酮类抗生素的群组的活性化合物的水性液滴组成;
(b)具有约1.5μm至约6μm的质量中值直径;且
(c)具有显示约1.2至约3.0的几何标准偏差的液滴尺寸分布,
其中所述试剂盒包含喷雾器和水性液体组合物,所述组合物在不超过约10ml且更优选小于5ml的体积内包含有效剂量的所述活性化合物。
14.根据权利要求13所述的试剂盒,其中所述喷雾器选自由喷射喷雾器、超声波喷雾器、喷射碰撞喷雾器、电流体动力喷雾器、毛细管力喷雾器、穿孔膜喷雾器和穿孔振动膜喷雾器组成的群组。
15.根据权利要求13或14所述的试剂盒,其中所述喷雾器被调适成能够以至少约0.1ml/min的速率气雾化所述液体组合物。
16.根据权利要求13至15中任一权利要求所述的试剂盒,其中所述喷雾器被调适成能够在不超过约20分钟且更优选小于约5分钟内气雾化所述液体组合物的包含有效剂量所述活性化合物的体积。
17.根据权利要求13至16中任一权利要求所述的试剂盒,其中所述喷雾器被调适成能够以气雾剂形式喷出至少约50重量%的所述水性液体组合物。
18.根据权利要求13至17中任一权利要求所述的试剂盒,其中至少约40重量%的所负载剂量包含直径不超过约5μm的液滴。
19.一种制备气雾剂和向需要经鼻、鼻窦或肺抗生素治疗或预防的人传递气雾剂的方法,所述方法包含以下步骤:
(a)提供在不超过约10ml且更优选小于5ml的体积中包含有效剂量的选自喹诺酮类抗生素群组的活性化合物的液体医药组合物;
(b)提供能够以至少0.1ml/min的总输出速率气雾化所述液体医药组合物的喷雾器,所述喷雾器进一步被调适成喷出包含质量中值直径约1.5μm至约6μm且几何标准偏差约1.2至约3的分散相的气雾剂;和
(c)操作所述喷雾器以气雾化所述液体组合物。
20.根据权利要求19所述的方法,其中进行步骤(c)持续不超过约20分钟且更优选小于约5分钟。
21.一种根据权利要求1所述的气雾剂或根据权利要求5所述的液体组合物或根据权利要求13所述的试剂盒的用途,其用于制备预防或治疗以下疾病的药物:视情况由肺炎链球菌(Streptococcus pneumoniae)、流感嗜血杆菌(Haemophilus influenza)或卡他莫拉菌(Moraxella catarrhalis)所引起的有或无急性恶化的急性或慢性窦炎或鼻窦炎、支气管炎、肺炎、慢性阻塞性肺病、防止肺移植后移植排斥的预防性治疗、实质性和/或纤维化疾病或病症,包括囊性纤维化;慢性支气管炎或慢性阻塞性肺病中视情况由金黄色葡萄球菌(Staphylococcus aureus)、肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌或卡他莫拉菌所引起的急性细菌恶化;视情况由金黄色葡萄球菌、铜绿假单胞菌(Pseudomonas aeruginosa)、粘质沙雷菌(Serratia marcescens)、洋葱伯克霍尔德菌(Burkholderia cepacia)、大肠杆菌(Escherichia coli)、肺炎克氏杆菌(Klebsiellapneumoniae)、流感嗜血杆菌或肺炎链球菌所引起的医院内肺炎;或视情况由金黄色葡萄球菌、肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌、肺炎克氏杆菌、卡他莫拉菌、肺炎衣原体(Chlamydia pneumoniae)、嗜肺军团菌(Legionella pneumophila)或肺炎支原体(Mycoplasma pneumoniae)所引起的社区获得性肺炎(community acquiredpneumonia,CAP)或医院获得性肺炎(hospital acquired pneumonia,HAP)或通气机相关肺炎(ventilator associated pneumonia,VAP)。
22.根据权利要求21所述的用途,其中所述药物被调适成每日两次或一次投药。
23.根据权利要求21或22所述的用途,其中所述药物的单位剂量的投药用时不超过约20分钟且更优选小于约5分钟。
24.一种高分子化合物的用途,其用作制备气雾剂的医药组合物中的赋形剂,其中所述组合物包含选自喹诺酮类抗生素群组的活性化合物。
25.根据权利要求24所述的用途,其中所述高分子化合物选自壳聚糖、纤维素衍生物、葡聚糖和环糊精。
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- 2007-02-08 BR BRPI0707641-0A patent/BRPI0707641A2/pt not_active IP Right Cessation
- 2007-02-08 PT PT77033553T patent/PT1991201T/pt unknown
- 2007-02-08 TR TR2018/07714T patent/TR201807714T4/tr unknown
- 2007-02-08 US US12/223,735 patent/US20090025713A1/en not_active Abandoned
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CN107669636A (zh) * | 2016-09-30 | 2018-02-09 | 青岛大学 | 一种氨溴索喷雾剂 |
CN109260180A (zh) * | 2017-07-17 | 2019-01-25 | 北京盈科瑞创新药物研究有限公司 | 一种盐酸莫西沙星雾化吸入用溶液制剂及其制备方法 |
CN109419785A (zh) * | 2017-08-31 | 2019-03-05 | 正大青春宝药业有限公司 | 一种鱼腥草提取物制剂及其应用 |
CN112569211A (zh) * | 2019-09-27 | 2021-03-30 | 盈科瑞(天津)创新医药研究有限公司 | 一种吸入用加替沙星溶液及其制备方法 |
CN114948914A (zh) * | 2022-06-30 | 2022-08-30 | 北京新领先医药科技发展有限公司 | 一种盐酸莫西沙星雾化吸入用溶液剂及其制备方法 |
CN114948914B (zh) * | 2022-06-30 | 2024-04-02 | 北京新领先医药科技发展有限公司 | 一种盐酸莫西沙星雾化吸入用溶液剂及其制备方法 |
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PT1991201T (pt) | 2018-06-12 |
MX2008010222A (es) | 2008-10-17 |
HUE037773T2 (hu) | 2018-09-28 |
US20090025713A1 (en) | 2009-01-29 |
PL1991201T3 (pl) | 2018-09-28 |
AU2007213983A1 (en) | 2007-08-16 |
TR201807714T4 (tr) | 2018-06-21 |
ES2671342T3 (es) | 2018-06-06 |
BRPI0707641A2 (pt) | 2011-05-10 |
EP1991201A1 (en) | 2008-11-19 |
AU2007213983B2 (en) | 2012-09-20 |
EP1991201B1 (en) | 2018-03-28 |
SI1991201T1 (en) | 2018-08-31 |
DK1991201T3 (en) | 2018-06-14 |
LT1991201T (lt) | 2018-07-25 |
JP2009526003A (ja) | 2009-07-16 |
CA2641827A1 (en) | 2007-08-16 |
RU2008136460A (ru) | 2010-03-20 |
CY1120284T1 (el) | 2019-07-10 |
WO2007090646A1 (en) | 2007-08-16 |
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