CN105555257A - 微粉化的药物组合物 - Google Patents
微粉化的药物组合物 Download PDFInfo
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- CN105555257A CN105555257A CN201480025155.9A CN201480025155A CN105555257A CN 105555257 A CN105555257 A CN 105555257A CN 201480025155 A CN201480025155 A CN 201480025155A CN 105555257 A CN105555257 A CN 105555257A
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- Prior art keywords
- capsule
- powder
- colistimethate sodium
- micronized
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Classifications
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
本文描述了多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少50体积%的所述微粉化的粒子具有小于7微米但不小于3微米的直径并且所述粉末具有5重量%至10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中所述多粘菌素E甲磺酸钠未被分离成组分形式。多粘菌素E甲磺酸钠的所述微粉化的粉末粒子可用于治疗特别是罹患囊性纤维化的患者的由革兰氏阴性细菌引起的感染。
Description
相关申请的交叉引用
本申请要求2013年3月13日提交的美国临时申请61/779,057的优先权,该临时申请的内容通过引用整体并入本文。
技术领域
本公开描述了包含微粉化的粘菌素甲磺酸钠(colistinsulphomethatesodium)的药物组合物的改善或与其有关的改善。
发明背景
粘菌素是属于多粘菌素类的抗细菌性阳离子环状多肽。它以多粘芽孢杆菌粘菌素变种(Baciluspolymyxavar.colistinus)的次生代谢物形式产生。用甲醛和亚硫酸氢钠处理粘菌素基质产生粘菌素甲磺酸钠。该产物是可溶于水的结晶粉末。
粘菌素甲磺酸钠,更通常被称为多粘菌素E甲磺酸钠,是带负电的分子离子甲磺酸粘菌素与正钠离子的组合。应小心地与硫酸粘菌素区别开。这两种物质在欧洲药典中均有描述。
粘菌素在治疗由如铜绿假单胞菌(Pseudomonasaeruginosa)、大肠杆菌(Escherichiacoli)和克雷伯氏菌(Klebsielaspp)的细菌病原体引起的严重感染方面特别有益。粘菌素的一个重要性质是对药物敏感的细菌不易获得抗性。作为药物的粘菌素可被制成许多不同的制剂,例如局部外用的,膀胱灌洗液,口服的如片剂,或静脉内或肌内注射液。
多粘菌素E甲磺酸钠是白色至浅黄色的吸湿性粉末。它以质量中值直径为100-200μm的粒度被商供。该粉末高度溶于水,微溶于乙醇(96%)并且通过溶解于水中用于胃肠外施用。作为粉末,粘菌素甲磺酸钠必须储存在密封容器中,优选避光存放。粘菌素甲磺酸钠被用于治疗罹患囊性纤维化的患者的感染,囊性纤维化是一种遗传性疾病,其影响许多身体系统,且在年轻时产生。该疾病以支气管衬里中的腺体功能失常为标志。支气管的腺体不再产生正常的稀的粘液,而是产生粘稠的粘液并淤塞在支气管中。微生物能够很快地繁殖,引起严重的呼吸感染,最终导致呼吸衰竭。已知多粘菌素E甲磺酸钠可有效地治疗由这些微生物(例如,铜绿假单胞菌)引起的感染。施用的惯用形式是作为用于雾化后吸入的溶液。雾化的溶液通过如下方式制得:取装有已知剂量的多粘菌素E甲磺酸钠粉末的小瓶,向该小瓶中注入水和然后通过吸入器将溶液吸入肺中。多粘菌素E甲磺酸钠很难被吸收进血流。因此,该施用方法是优选的,因为可以在生病期间聚集在肺部的粘液中攻击细菌。
尽管粘菌素甲磺酸钠是一种治疗囊性纤维化期间发生的感染和其它细菌感染的有价值的药物,但在药物递送方面存在许多缺点,这些缺点已经阻碍了其作为囊性纤维化的治疗方案的接受性,特别是对于婴儿。已经确定由上述优选的递送输送方法,即作为雾化的液体会产生许多问题。本文所述的本发明提出并解决了本领域内的这一长久的需要。
发明概要
本公开描述了包含微粉化的粘菌素甲磺酸钠的药物组合物的改善或与其有关的改善。
在本发明的一个方面,至少约50体积%的微粉化的粒子具有小于约7微米但不小于约3微米的直径并且该粉末具有约0.1重量%至约10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中该多粘菌素E甲磺酸钠未被分离成组分形式。
在一个实施方案中,约10体积%的粒子具有小于约3微米但不小于约1.5微米的粒度。
已经发现,相比于2微米至5微米的正常尺寸使用更大的粒子用于吸入具有与该粉末在被填充至产品胶囊中时的物理稳定性有关的有利作用以及在防止粉末在该胶囊内压实方面的有利作用。更大的粒子充当更小的粒子进入肺中的载体。
该方法对于粒度的又一惊人结果是相比于更小平均尺寸的粒子,该量的多粘菌素E甲磺酸钠被非常深地递送至肺中,随后被吸收至血流中,从而显著地降低毒性,同时维持足够水平以实现期望的临床结果。
根据本发明的一个方面,提供了一种适用于干粉吸入器的药物剂型。该剂型包含(a)多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少约50体积%的该微粉化的粒子具有小于约7微米但不小于约3微米的直径并且该粉末具有约0.1重量%至约10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中该多粘菌素E甲磺酸钠未被分离成组分形式;(b)用于多粘菌素E甲磺酸钠的该微粉化的粉末粒子的容器。根据本发明的一个实施方案,该容器是硬明胶胶囊。
在另一方面,提供了一种具有多粘菌素E甲磺酸钠的微粉化的粉末粒子的药物胶囊,其中至少约50体积%的微粉化的粒子具有小于约7微米但不小于约3微米的直径并且该粉末具有约0.1重量%至约10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中该多粘菌素E甲磺酸钠未被分离成组分形式。在本发明的一个实施方案中,药物胶囊是半透明的。在另一实施方案中,药物胶囊具有微粉化的支气管扩张药。
根据另一方面,药物胶囊具有1,500,000IU至2,000,000IU的多粘菌素E甲磺酸钠。在一个实施方案中,提供了一种包含铝箔连同多个药物胶囊的泡罩包装。
在本发明的另一方面,提供了一种治疗呼吸道的革兰氏阴性感染的方法。该方法包括向患者的呼吸道施用多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少约50体积%的微粉化的粒子具有小于约7微米但不小于约3微米的直径并且该粉末具有约0.1重量%至约10重量%的总含湿量,其中该多粘菌素E甲磺酸钠未被分离成组分形式。
根据一个实施方案,提供了一种治疗罹患呼吸道的革兰氏阴性感染的患者的方法,其中该患者是儿科患者。在另一实施方案中,革兰氏阴性感染由选自具有铜绿假单胞菌、大肠杆菌和克雷伯氏菌的组的细菌病原体引起。
在本发明的另一方面,提供了呈使用干粉吸入器的药物剂型的微粉化的多粘菌素E甲磺酸钠。该微粉化的多粘菌素E甲磺酸钠粉末具有约0.1wt%至约10wt%的含湿量。该微粉化的粉末任选地连同载体和容器一起提供被提供。在一个实施方案中,容器优选为胶囊。根据另一实施方案,微粉化的多粘菌素E甲磺酸钠的含湿量是约5wt%至约10wt%。
本发明还描述了提供了用于胶囊中的具有多粘菌素E甲磺酸钠粉末的药物组合物,其中该粉末的含湿量通过使用胶囊作为水分缓冲物来控制。根据一个实施方案,胶囊的含湿量在约0.1wt%至约16wt%的范围。
在另一实施方案中,提供了一种具有约6wt%至约16wt%的胶囊壳水含量的明胶胶囊。该明胶胶囊可以是具有约5wt%至约15wt%的胶囊壳水含量的基于PEG的明胶胶囊。在另一实施方案中,该胶囊可以是具有约0.1wt%至约10wt%的胶囊壳水含量的羟丙基甲基纤维素(HPMC)胶囊。
如本文在以下详述和附图中所述的,本公开产生了储存稳定性的改善,降低了水分转移并且增加了多粘菌素E甲磺酸钠的稳定性和可操作性。
附图简述
图1显示微粉化的粘菌素甲磺酸钠的粒度分析。
图2显示具有伴随钠离子的甲磺酸粘菌素的结构。
图3显示如美国专利5,767,068中所述的中和的粘菌素基质。
图4显示多粘菌素E甲磺酸钠随时间、相对湿度和储存条件而变化的含湿量。
图5显示明胶胶囊在各种储存和相对湿度条件下的含湿量。
图6显示明胶胶囊随时间和储存条件而变化的类别3刺穿频率。
图7显示明胶胶囊的类别3刺穿减少。
定义
术语“可呼吸的干燥粉末”是指具有细分散粒子的组合物,该细分散粒子是相对自由流动的并且能够(i)容易地分散于吸入装置中以及(ii)被受试者吸入,使得至少一部分该粒子到达肺部从而允许渗透至肺泡。干燥粉末可以是结晶的、无定形的或两者的混合物(部分结晶的)。此类粉末被认为是“可呼吸的”或“可吸入的”,更特别地,适于肺部递送。尽管优选的实施方案涉及多粘菌素E甲磺酸钠的可呼吸的干燥粉末制剂,但可针对意在用于其它施用途径如口服施用的制剂实施本发明。
术语“射出剂量”或“ED”是指该制剂在激发(firing)或分散事件后从合适的吸入器装置递送的示值。更具体地,对于多粘菌素E甲磺酸钠制剂来说,ED是从单位剂量包装中吸出并且排出吸入器装置的吸嘴的粉末的百分比的量度。
术语“气溶胶化”是指细干燥粉末或液体粒子的气态悬浮物。气溶胶化药剂可通过干燥粉末吸入器、计量剂量吸入器或雾化器生成。
术语“可分散的”粉末是具有至少约30%、优选至少约40%、更优选至少约50%、更优选至少约60%、更优选至少约70%、更优选至少约80%、更优选至少约90%的ED值的粉末。
术语“分散剂”是指占组合物的0.01重量%至99重量%、优选0.01重量%至70重量%的可呼吸的干燥粉末制剂的组分,当与无该分散剂的可呼吸的干燥粉末制剂的分散性比较时,该分散剂在存在时,可有效地将如通过射出剂量确定所确定的多粘菌素E甲磺酸钠的可呼吸的干燥粉末制剂的分散性增加至少10%。可使用本领域已知的任何合适的分散剂。
多粘菌素E甲磺酸钠的最大临界含湿量是多粘菌素E甲磺酸钠粉末开始损失其化学和物理稳定性(包括气溶胶性质)和储存稳定性的点。多粘菌素E甲磺酸钠的最小临界含湿量是多粘菌素E甲磺酸钠干燥粉末开始损失其机械完整性和/或分散性使得不利地影响干燥粉末的性能的点。临界含湿(最大或最小)量从一种多粘菌素E甲磺酸钠干燥粉末制剂至下一种可发生变化并且可由本领域技术人员使用常规实验容易地确定。最小RH和最大RH是指对应于临界吸湿点的相对湿度水平。
胶囊的最大临界含湿量是具有多粘菌素E甲磺酸钠的胶囊开始损失其化学和物理稳定性的点。胶囊的最小临界含湿量是具有多粘菌素E甲磺酸钠的胶囊开始损失其机械完整性的点。临界含湿(最大或最小)量随多粘菌素E甲磺酸钠干燥粉末制剂的不同并且随胶囊类型的不同而变化,并且可由本领域技术人员使用常规实验容易地确定。胶囊的RH是指对应于临界吸湿点的相对湿度水平。
术语“干燥剂(desiccant)”还被称为干燥剂(dryingagent),是吸收或吸附水并且用于去除环境水分的材料。干燥剂必定对水具有高亲和力。实例包括氧化钙、分子筛和硅胶。干燥剂主要用于保持干燥粉末足够地“干燥”(即,低于临界吸湿点)。
发明详述
虽然喷射雾化疗法已显示是成功的,但雾化技术具有若干缺陷。喷射雾化器利用压缩气体(通常为空气)将药物溶液转化为喷雾。压缩空气通过窄的文丘里孔口并且产生负压力。从流体储器吸出的液体通过进料管区段形成液滴中,并且被加速至足够速度而使得超过99%的液滴物质冲击挡板或雾化器,其中液滴凝聚并回流至流体储器中。仅1%的气溶胶物质直接离开雾化器。排出的空气被源自保留在雾化器中的液体的水饱和。这具有两个重要结果:首先,雾化器被冷却并达到低于环境温度大约10℃的平衡温度,使得患者吸入相对较冷的喷雾。其次,水的蒸发导致溶质的浓缩随时间而增加。
可利用的雾化器存在许多不同的设计,该设计使用了不同流速的压缩气体。来自这些雾化器的输出量将全部是不同的,因此对于患者来说,难以确保施用恒定剂量。因为需要压缩器,因此雾化器自身体积较大。虽然被描述为可运输的,但雾化器/压缩器系统并非真正便携的。当患者正在经受治疗时,他们需要保持与雾化器的吸嘴连接大约20分钟以完成该疗法和确保施用正确剂量。此外,需要电力供应来运行雾化器。
令人惊讶地且出乎意料地,约0.1wt%至约10wt%的微粉化的多粘菌素E甲磺酸钠的含湿量改善了粉末至肺中的流动,而不会不利地影响最终产品的稳定性。此外,还可通过改变制剂在制造和包装期间的相对湿度和/或温度条件来改善微粉化的制剂的流动性质。还可通过使多粘菌素E甲磺酸钠(干燥)粉末在填充前暴露于环境条件来改善流动性质。令人惊讶地且出乎意料地,可通过小心地控制胶囊的特性来降低胶囊的破损率和/或功能障碍率。用于改善多粘菌素E甲磺酸钠的流动性质以及阻止胶囊的破损率的上述方法被认为是本发明的个别实施方案。
为了使雾化器适当地发挥功能,必须小心地配制和分配可呼吸的多粘菌素E甲磺酸钠粉末。应当小心地控制如但不限于以下的特性:多粘菌素E甲磺酸钠粉末的含湿量、粉末的吸湿性、制造和包装期间的环境条件。多粘菌素E甲磺酸钠的含湿量的变化可影响可呼吸的粉末的流动性。具有多粘菌素E甲磺酸钠粉末的胶囊的含湿量的变化可改变胶囊的脆性,从而导致胶囊的破损和/或功能障碍。
图1显示微粉化的粘菌素甲磺酸钠的粒度分析。多粘菌素E甲磺酸钠是具有带正电的钠反荷离子的带负电的分子离子。图2显示多粘菌素E甲磺酸钠的结构。存在5个甲磺酸根基团(CH2-OS02 -)。相比之下,美国专利5,767,068公开了一种图3中所示的中性基质。美国专利5,767,068提到可变基团Rx和R2;Rx被认为是6-甲基辛酰基或6-甲基庚酰基,并且R2被认为是仲丁基、异丁基或异丙基。已经发现多粘菌素E甲磺酸钠是至少10种组分的混合物。对抗细菌防腐剂混合物实施的测试显示,在多粘菌素E甲磺酸钠中发现的组分的混合物显示针对革兰氏阴性微生物生物体的活性的协同作用。
根据本发明的微粉化的多粘菌素E甲磺酸钠是粉末,其中约90体积%的该粉末具有直径小于约10微米的粒子。优选地,约50体积%的粒子具有小于约7微米但不小于约3微米的直径,并且约10体积%的粒子具有小于约3微米但不小于约1.5微米的粒度。由于不想要吸收至血流中,因此带负电的离子优于基质粘菌素。
通过吸入施用的药剂应当具有受控粒度以实现至肺中的最大渗透。合适的粒度在约0.01-10微米、优选约1-8微米的范围。粒度可通过许多方法如激光衍射或显微分析来测量。微粉化的多粘菌素E甲磺酸钠可通过流体能量研磨、球磨、喷雾干燥或沉淀制备。
令人惊讶地,多粘菌素E甲磺酸钠的微粉化的粉末不粘在一起并且可将微粉化的粒子递送至肺泡。在正常大气条件下,微粉化的粉末对水的吸收相对较低,例如大约约0.1重量%-10重量%。当微粉化的多粘菌素E甲磺酸钠粉末以约5wt%、约5.5wt%、约6wt%、约6.5wt%、约6.75wt%、约7wt%、约7.25wt%、约7.5wt%、约7.75wt%或约8wt%的含湿量存在时,带负电的甲磺酸粘菌素离子、优选以其钠形式可被递送至肺。微粉化的多粘菌素E甲磺酸钠粉末可以约0.1wt%至约10wt%的范围的含湿量存在。实际含湿量可以该范围内的任何增量存在。
在另一方面,当微粉化的多粘菌素E甲磺酸钠粉末以约0.1wt%的最小临界含湿量和约10wt%的最大临界含湿量存在时,带负电的甲磺酸粘菌素离子、优选呈其钠形式可被递送至肺中。在一些实施方案中,最小临界含湿量是约4wt%并且最大临界含湿量是约10wt%。在其它实施方案中,最小临界含湿量是约5wt%并且最大临界含湿量是约10wt%。微粉化的多粘菌素E甲磺酸钠粉末可以约6wt%的最小临界含湿量和约10wt%的最大临界含湿量存在。在其它实施方案中,最小临界含湿量是约6.5wt%并且最大临界含湿量是约10wt%。在一些实施方案中,微粉化的多粘菌素E甲磺酸钠粉末以约5wt%的最小临界含湿量和约9wt%的最大临界含湿量存在。在其它实施方案中,最小临界含湿量是约5wt%并且最大临界含湿量是约8wt%。在另一实施方案中,微粉化的多粘菌素E甲磺酸钠粉末以约5.5wt%的最小临界含湿量和约8wt%的最大临界含湿量存在。
最小相对湿度(RH)可高于2%RH±5%RH。在某些实施方案中,在23℃±2℃下的最小相对湿度高于2%RH±5%RH,高于4%RH±5%RH,高于6%±5%RH,高于10%RH±5%RH,高于12%RH±5%RH,高于15%RH±5%RH,高于25%RH±5%RH,高于30%RH±5%RH,高于40%RH±5%RH,高于45%RH±5%RH,高于60%RH±5%RH。在其它实施方案中,最小相对湿度是在约26℃±2℃、27℃±2℃、28℃±2℃或30℃±2℃下。
在一些实施方案中,最大相对湿度小于75%RH±5%RH。例如,在23℃±2℃下的最大相对湿度可小于50%RH±5%RH,小于40%RH±5%RH,小于30%RH±5%RH,小于20%RH±5%RH,小于10%RH±5%RH,小于5%RH±5%RH。在一些实施方案中,最大相对湿度是在约26℃±2℃、27℃±2℃、28℃±2℃或30℃±2℃下。相对湿度可以约2%RH至约75%RH的范围存在。实际相对湿度可以该范围内的任何增量存在。
可对相对湿度加以选择,使得多粘菌素E甲磺酸钠粉末的平衡含湿量不超过其最大临界含湿量并且不小于最小临界含湿量,由此确保多粘菌素E甲磺酸钠粉末在室温下的流动性和储存稳定性。
本发明还提供了一种用于制备本发明的组合物的方法,其包括将微粉化的多粘菌素E甲磺酸钠和任选地载体混合在一起。多粘菌素E甲磺酸钠和载体可以在本领域已知的转鼓式、环箍式或Y-锥式掺合器中进行掺合。
多粘菌素E甲磺酸钠可以结合载体施用。载体可以是任何无毒材料,该材料是对多粘菌素E甲磺酸钠化学惰性的并且对于吸入或对于施用来说是可接受的。载体的实例包括但不限于无机盐,例如,氯化钠或碳酸钙;有机盐,例如,酒石酸钠或乳酸钙;有机化合物,例如,尿素;单糖,例如,乳糖、阿拉伯糖或右旋糖;二糖,例如,麦芽糖或蔗糖;多糖,例如,淀粉和葡聚糖。特别优选的载体是乳糖,例如结晶乳糖。
载体可具有与多粘菌素E甲磺酸钠粉末相同的粒度规格。如果使用载体,则优选该载体具有比多粘菌素E甲磺酸钠更大的粒度以利于从吸入装置中递送和不会在肺的较细微的气道中沉积。包含载体可使得容易将药物和载体制成胶囊。优选至少约50%且更优选至少约70体积%的载体粒子具有在约30微米至约150微米、优选约30微米至约80微米范围中的有效粒度。药物和载体的混合物可含有最高约75重量%、更优选最高约50重量%的载体。通常,多粘菌素E甲磺酸钠的重量比率是约5:1至1:2,优选约4:1至1:1。
除了微粉化的多粘菌素E甲磺酸钠、赋形剂和任选地载体外,药物组合物还可具有其它成分,如着色物质或调味剂如糖精,该其它成分可存在于吸入组合物中。还可添加抗静电剂,如GB2269992(Rhone-PoulencRorerLtd)中所述的。粉末制剂可具有其它药物成分,如支气管扩张剂,例如沙丁胺醇。此类其它药物成分优选具有与粘菌素粒度类似的有效粒度。支气管扩张药将以很小(毫克(mg))的量被递送。例如,胶囊可具有约50毫克至约150毫克(例如125毫克)多粘菌素E甲磺酸钠和约1毫克至约250毫克(例如200微克)沙丁胺醇。
微粉化的粉末可通过专用的粉末吸入装置被递送至肺。优选地,粉状药物在硬胶囊或泡罩包装内。胶囊或泡罩被吸入器装置裂开或钻开,从而使得能够在通过吸嘴吸入空气时将粉末吸入。
当使用吸入器装置启动胶囊时,胶囊壳的含湿量可对胶囊的刺穿和/或功能发挥具有直接影响。令人惊讶地且出乎意料地,可通过小心地控制胶囊的特性(如但不限于胶囊的含湿量、相对湿度和/或胶囊和/或泡罩被填充时的条件)来降低胶囊的破损率和/或功能障碍率。类似地,可通过小心地控制多粘菌素E甲磺酸钠粉末的物理和化学特性(如但不限于含湿量和相对湿度)来增强多粘菌素E甲磺酸钠粉末的流动性。
根据本发明的实施方案,提供了具有包含粘菌素甲磺酸钠的胶囊的剂量单位。该胶囊可由明胶或塑料材料形成。用于本发明中的优选胶囊是由基于PEG的明胶胶囊或由水溶性纤维素衍生物形成的那些。水溶性纤维素衍生物的实例包括被烷基、尤其是C1至C4低级烷基和/或羟基烷基、尤其是C1至C4羟基低级烷基取代的微晶纤维素和纤维素酯。具体实例包括但不限于羟丙基甲基纤维素(HPMC)、羟乙基纤维素、羟丙基纤维素和羟乙基甲基纤维素。优选的纤维素衍生物是羟丙基甲基纤维素(HPMC)。
胶囊材料可进一步具有聚合添加剂。对胶囊材料没有特定限制,只要其具有本文所述的必要的化学和物理特性即可。各种尺寸的胶囊均适于本发明,包括00号、1号、2号和3号胶囊。使用水溶性纤维素衍生物形成的胶囊可以不同的色彩、不透明度和等级被利用,色彩、不透明度和等级全部被涵盖用于本发明。用于本发明的粉末制剂是本领域已知的。此类制剂可包含如本领域已知的活性剂、分散剂和赋形剂。
本发明的胶囊可包含水溶性纤维素化合物和胶凝剂。被烷基和羟基烷基中的至少一种基团取代的纤维醚可作为用于本发明的可用的水溶性纤维素化合物被提到。“烷基”和“羟基烷基”是指具有1至6个碳原子且优选1至4个碳原子的直链或支链低级烷基,并且可具体地提到甲基、乙基、丁基和丙基。水溶性纤维素化合物的具体实例包括低级烷基纤维素,如甲基纤维素等;低级羟基烷基纤维素,如羟乙基纤维素、羟丙基纤维素等;和低级羟基烷基烷基纤维素,如羟乙基甲基纤维素、羟乙基乙基纤维素、羟丙基甲基纤维素等。羟丙基甲基纤维素因为在低水分条件下的成膜性和机械强度而特别合适。
角叉菜胶、罗望子籽多糖、果胶、黄原胶、槐豆胶、凝胶多糖、明胶、毛皮硒(furselenium)、琼脂、结冷胶等是可用的胶凝剂,其单独或组合存在。在上述胶凝剂中,角叉菜胶具有高胶凝强度,并且当以少量且与特定的离子组合使用时,展现出极好的胶凝能力。
取决于所用胶凝剂的种类,还可使用胶凝助剂。以下胶凝助剂可与作为胶凝剂的角叉菜胶组合使用。对于κ-角叉菜胶来说,可使用在水中产生一种或多种钾离子、铵离子和钙离子的化合物,如氯化钾、氯化铵、乙酸铵和氯化钙。对于ι-角叉菜胶来说,可使用在水中产生钙离子的化合物,如氯化钙。作为与作为胶凝剂的结冷胶组合使用的胶凝助剂,可使用在水中产生一种或多种钠离子、钾离子、离子化的钙和镁离子的化合物,如氯化钠、氯化钾、氯化钙和硫酸镁。另外,还可使用柠檬酸或柠檬酸钠作为有机酸或其水溶性盐。优选地,可使用羟丙基甲基纤维素作为水溶性纤维素化合物、角叉菜胶作为胶凝剂和胶凝助剂。
除了上述组分外,还可根据需要添加增塑剂、着色剂例如(染料、颜料)、遮光剂或调味剂。任何增塑剂均可无限制地使用,只要它们可用于医用药物或食物产品。例如,己二酸二辛酯、聚己二酸酯、环氧化的大豆油、环氧六氢邻苯二甲酸二酯、高岭土、柠檬酸三乙酯、甘油、甘油脂肪酸酯、芝麻油、聚二甲基硅氧烷-二氧化硅混合物、D-山梨醇、中链脂肪酸甘油三酯、源于玉米淀粉的糖醇溶液、三醋精、浓缩甘油、蓖麻油、植物甾醇、邻苯二甲酸二乙酯、邻苯二甲酸二辛酯、邻苯甲酸二丁酯、丁基邻苯二甲酰基羟乙酸丁酯、丙二醇、聚氧化乙烯(105)聚氧化丙烯(5)二醇、聚山梨醇酯80、聚乙二醇1500、聚乙二醇400、聚乙二醇4000、聚乙二醇600、聚乙二醇6000、肉豆蔻酸异丙酯、棉籽油-大豆油混合物、单硬脂酸甘油酯、亚油酸异丙酯可用作增塑剂。任何着色剂均可无限制地使用,只要它们可用于医用药物或食物产品。例如,儿茶单宁酸粉、姜黄提取物、甲紫、黄色氧化铁、黄色三氧化二铁、橙香精、棕色氧化铁、炭黑、焦糖、胭脂红、胡萝卜素液体、β-胡萝卜素、光敏元素201号、甘草提取物、金叶、山白竹提取物(sasaalbomarginalaextract)、黑色氧化铁、轻质无水硅酸、血竭(kekketsu)、氧化锌、氧化钛、三氧化二铁、二重氮黄、食品蓝1号和其铝色淀、食品蓝2号和其铝色淀、食品黄4号和其铝色淀、食品黄5号和其铝色淀、食品绿3号和其铝色淀、食品红2号和铝色淀、食品红3号、食品红102号和其铝色淀、食品红104号和其铝色淀、食品红105号和其铝色淀、食品红106号和其铝色淀、氢氧化钠、滑石、叶绿素铜钠(copperchlorofinsodium)、叶绿素铜、黑麦绿叶果汁粉、黑麦绿叶提取物、酚红、荧光素钠、d-冰片、孔雀绿、肉豆蔻酸辛基十二烷基酯、亚甲蓝、药用炭、丁酸核黄素、核黄素、粉状绿茶、磷酸锰铵、核黄素磷酸钠、玫瑰油、姜黄色素、叶绿素、胭脂红酸色素、食品红40号和其铝色淀、水溶性胭脂树橙、叶绿酸铁钠、杜氏藻(dunaliella)胡萝卜素、辣椒粉色素、人参胡萝卜素、降胭脂树素钾、降胭脂树素钠、棕榈油胡萝卜素、拍红(beatred)、葡萄皮色素、红醋栗色素、红曲霉色素、红花红色素、红花黄色素、金盏花色素、核黄素磷酸钠、茜草色素、紫朱草色素、铝、马铃薯胡萝卜素、小河虾色素、磷虾色素、橙色素、可可色素、可可碳粉色素、牡蛎色素、蟹色素、角豆色素、鱼鳞箔、银、海州常山(kusagi)色素、栀子蓝色素、栀子红色素、栀子黄色素和薯蓣色素、氯膦(chlorophine)、高粱色素、骨炭色素、竹叶草色素、非洲酪脂果(sheanut)色素、紫草根(lithospermroot)色素、紫檀木(redsanders)色素、植物炭黑、苏木色素、螺旋藻色素、洋葱色素、罗望子色素、玉米色素、番茄色素、花生色素、法夫酵母(phaffia)色素、美洲山核桃果色素、红曲黄(monascusyellow)、胭脂树橙粉、苏木藻(hematococcusalgae)色素、紫甘薯色素、紫玉米色素、紫薯蓣色素、植物油烟色素、紫胶色素、芸香苷、槐花(enju)提取物、苦荞提取物、洋苏木色素、甘蓝红色素、红米色素、红色素、azuki色素、绣球叶提取物、乌贼色素、蓝靛果(uguisukagura)色素、接骨木果色素、橄榄茶、越桔色素、鹅莓色素、酸果蔓色素、美莓色素、草莓色素、黑樱桃色素、樱桃色素、香莓色素、deberry色素、菠萝汁、越桔汁、葡萄汁色素、黑醋栗色素、黑莓色素、李子色素、蓝莓色素、浆果汁、波森莓(boysenberry)色素、欧洲越桔(whortleberry)色素、桑椹色素、莫利洛黑樱桃色素、覆盆子色素、红醋栗色素、柠檬汁、罗甘莓色素、小球藻粉、可可粉、藏红花色素、紫苏色素、菊苣色素、成层(layer)色素、木槿(hibiscus)色素、麦芽提取物、辣椒粉、甜菜红汁、人参汁可用作着色剂。任何遮光剂或调味剂着色剂均可无限制地使用,只要它们可用于医用药物或食物产品。例如,作为遮光剂,氧化钛、三氧化二铁、黄色三氧化二铁、黑色氧化铁、食品蓝1号铝色淀、食品蓝2号铝色淀、食品黄4号铝色淀、食品黄5号铝色淀、食品绿3号铝色淀、食品红2号铝色淀、食品红3号铝色淀、食品红102号铝色淀、食品红104号铝色淀、食品红105号铝色淀、食品红106号铝色淀和食品红40号铝色淀可用作遮光剂。
本发明的胶囊具有低平衡含湿量。胶囊的平衡水分可由胶囊被置于特定的相对湿度条件下时胶囊膜的含湿量来评估。
水溶性纤维素化合物是约5重量%至30重量%,优选约10重量%至28重量%且更优选约16重量%至24重量%。胶凝剂是约0.01重量%至0.5重量%,优选约0.02重量%至0.45重量%且更优选约0.03重量%至0.4重量%。如果被添加,胶凝助剂是约0.01重量%至0.5重量%,优选约0.02重量%至0.45重量%且更优选约0.03重量%至0.4重量%。
如本文所述的,胶囊壳的含湿量可对胶囊的刺穿和功能发挥具有直接影响。在一个实施方案中,可通过改变胶囊的物理和化学特性(如但不限于胶囊的含湿量、相对湿度和/或胶囊和/或泡罩被填充时的条件)来控制胶囊的破损。在另一实施方案中,可通过控制多粘菌素E甲磺酸钠粉末的物理和化学特性(如但不限于含湿量和相对湿度)来控制胶囊的破损。
明胶胶囊容易吸收水分并且与环境湿度条件平衡。具有如本文所述的微粉化的多粘菌素E甲磺酸钠粉末的明胶胶囊可具有约6wt%的含湿量。在其它实施方案中,明胶胶囊可具有约7wt%、约7.25wt%、约7.5wt%、约7.7wt%、约8wt%、约8.5wt%或约9wt%的含湿量。明胶胶囊可具有在约6wt%至约16wt%的范围的含湿量。胶囊的实际含湿量可以任何增量在该范围内。
在一些实施方案中,具有微粉化的多粘菌素E甲磺酸钠粉末的明胶胶囊可具有约6wt%的最小临界含湿量和约16wt%的最大临界含湿量。在其它实施方案中,明胶胶囊具有约6wt%的最小临界含湿量和约12wt%的最大临界含湿量,或约8wt%的最小临界含湿量和约10wt%的最大临界含湿量。
存在于明胶胶囊中的微粉化的多粘菌素E甲磺酸钠粉末可具有约0.1wt%的最小临界含湿量和约16wt%的最大临界含湿量、约5wt%的最小临界含湿量和约16wt%的最大临界含湿量、或约6wt%的最小临界含湿量和约10wt%的最大临界含湿量。
在某些实施方案中,明胶胶囊在23℃±2℃下的最小RH可高于2%RH±5%RH,如例如,高于2%RH±5%RH,高于4%RH±5%RH,高于6%RH±5%RH,高于10%RH±5%RH,高于12%RH±5%RH,高于15%RH±5%RH,高于25%RH±5%RH,高于30%RH±5%RH,高于40%RH±5%RH,高于48%RH±5%RH。在一些实施方案中,胶囊的最小RH是在25℃±2℃、26℃±2℃、28℃±2℃或30℃±2℃下。
明胶胶囊在23℃±2℃下的最大RH可小于75%RH±5%RH,如例如小于50%RH±5%RH,小于40%RH±5%RH,小于30%RH±5%RH,小于20%RH±5%RH,小于10%RH±5%RH,小于5%RH±5%RH。在一些实施方案中,胶囊的最大RH是在约25℃±2℃、26℃±2℃、28℃±2℃和30℃±2℃下。相对湿度可以约2%RH至约75%RH的范围存在。实际相对湿度可以该范围内的任何增量存在。
明胶胶囊应当在约最大RH下预平衡以确保多粘菌素E甲磺酸钠粉末的水含量保持低于其最大临界含湿量。优选地,预先平衡RH被选择为低于胶囊的最大RH,使得不损害胶囊的机械性能。使胶囊填充环境在低于或处于胶囊的预平衡RH的RH下维持至少24小时。
在其它实施方案中,明胶胶囊可基于PEG。具有微粉化的多粘菌素E甲磺酸钠粉末的此类基于PEG的明胶胶囊可具有约5wt%、约5.5wt%、约5.9wt%、约6.5wt%、约7wt%、约7.5wt%、约7.75wt%、约8wt%或约9wt%的含湿量。基于PEG的明胶胶囊可具有在约5wt%至约15wt%的范围的含湿量。胶囊的实际含湿量可以任何增量在该范围内。
在某些实施方案中,具有微粉化的多粘菌素E甲磺酸钠粉末的基于PEG的明胶胶囊可具有约5wt%的最小临界含湿量和约15wt%的最大临界含湿量。在其它实施方案中,胶囊的最小临界含湿量是约6wt%并且胶囊的最大临界含湿量是约14wt%。胶囊的最小临界含湿量可以是约7wt%并且最大临界含湿量可以是约12wt%。胶囊的最大临界含湿量还可以是约10wt%。
基于PEG的明胶胶囊在23℃±2℃下的最小RH可高于2%RH±5%RH,如例如,高于2%RH±5%RH,高于4%RH±5%RH,高于6%RH±5%RH,高于10%RH±5%RH,高于12%RH±5%RH,高于15%RH±5%RH,高于25%RH±5%RH,高于35%RH±5%RH,高于45%RH±5%RH。在一些实施方案中,胶囊的最小RH是在25℃±2℃、26℃±2℃、28℃±2℃和30℃±2℃下。
胶囊在23℃±2℃下的最大RH可小于50%RH±5%RH,如例如小于50%RH±5%RH,小于40%RH±5%RH,小于30%RH±5%RH,小于20%RH±5%RH,小于10%RH±5%RH,小于5%RH±5%RH。在一些实施方案中,胶囊的最大RH是在约25℃±2℃、26℃±2℃、28℃±2℃和30℃±2℃下。相对湿度可以约2%RH至约75%RH的范围存在。实际相对湿度可以该范围内的任何增量存在。
在本发明的一个实施方案中,具有微粉化的多粘菌素E甲磺酸钠粉末的HPMC胶囊可具有约0.5wt%、约1wt%、约1.4wt%、约2wt%、约2.25wt%、约2.8wt%、约3wt%、约3.5wt%、约3.75wt%、约4wt%、约4.5wt%、约5wt%、约5.5wt%、约5.8wt%、约7wt%的含湿量。HPMC胶囊可具有在约0.1wt%至约10wt%的范围的含湿量。胶囊的实际含湿量可以任何增量在该范围内。
在其它实施方案中,胶囊可以是具有微粉化的多粘菌素E甲磺酸钠粉末的HPMC胶囊,其可具有约0.1wt%的最小临界含湿量和约10wt%的最大临界含湿量。或者,最小临界含湿量可以是约1wt%并且最大临界含湿量是约8wt%。具有微粉化的多粘菌素E甲磺酸钠粉末的HPMC胶囊的最小临界含湿量可以是约1wt%并且最大临界含湿量是约5wt%,或最小临界含湿量是约2.5wt%并且最大临界含湿量是约7wt%。
HPMC胶囊的最小临界含湿量可以是约0.5wt%、约0.75wt%、约1wt%、约2wt%或约3wt%。
HPMC胶囊的最大临界含湿量可以是约10wt%、约9wt%、约8wt%、约7wt%、约6wt%或约5wt%。
HPMC胶囊在23℃下的最小RH可高于2%RH±5%RH,如例如,高于2%RH±5%RH,高于4%RH±5%RH,高于6%RH±5%RH,高于10%RH±5%RH,高于12%RH±5%RH,高于15%RH±5%RH,高于25%RH±5%RH,高于35%RH±5%RH,高于45%RH±5%RH。在一些实施方案中,胶囊的最小RH是在25℃±2℃、26℃±2℃、28℃±2℃和30℃±2℃下。
HPMC胶囊在23℃下的最大RH可小于50%RH±5%RH,如例如小于50%RH±5%RH,小于40%RH±5%RH,小于30%RH±5%RH,小于20%RH±5%RH,小于10%RH±5%RH,小于5%RH±5%RH。在一些实施方案中,胶囊的最大RH是在约25℃±2℃、26℃±2℃、28℃±2℃和30℃±2℃下。相对湿度可以约2%RH至约75%RH的范围存在。实际相对湿度可以该范围内的任何增量存在。
通过小心地控制胶囊被填充时的条件,可使多粘菌素E甲磺酸钠粉末的最终水分水平保持至低于约15wt%,优选约0.1wt%至约10wt%。湿度水平优选低于约45%RH,更优选低于约35%RH,最优选低于约30%RH。低水分水平对于产品稳定性至关重要,因为它使得该产品能够以最低静电效应被填充。
胶囊中所含组合物的量将取决于期望的剂量。优选地,胶囊具有约10毫克至约200毫克、更优选约30毫克至约150毫克的粘菌素甲磺酸钠,最优选约120毫克至约130毫克。多粘菌素E甲磺酸钠可在有载体或无载体的情况下被递送。如果使用载体,则需要更大量的载体和药物的混合物。优选地,胶囊应当具有比将被实际递送至肺的量更大的剂量的药物。
剂量通常以“国际单位”或“IU”表示。80mg甲磺酸粘菌素等同于大约1百万IU的甲磺酸粘菌素。1单位甲磺酸粘菌素被包含于0.00007874mg的甲磺酸粘菌素的第一国际参考制剂(1966)中。患有囊性纤维化的儿童可以利用500,000单位水平的雾化多粘菌素E甲磺酸钠,每天两次进行治疗。来自常规的雾化器(CR50系统22)的可呼吸的部分是来自500,000单位剂量的大约9mg的多粘菌素E甲磺酸钠。这可使用多级碰撞取样器(multistageimpinger)并测量在第3级和第4级收集的质量进行测试。
用于递送根据本发明的药物组合物的优选装置是来源于PH&T的该装置使用明胶胶囊,该胶囊在其底部被一根金属针刺穿。当患者通过吸嘴吸入时,空气通过药室周围正切排列的狭缝被吸引。这使胶囊旋转并使胶囊中的内含物释放至空气流中。装置上的可轻按的顶部允许储存最多3个备用胶囊。
用于递送药物组合物的另一优选装置是来自BoehringerIngelheim的该装置使用硬明胶胶囊,在该胶囊在其侧面被两根金属针刺穿。当患者通过吸嘴吸入时,空气进入药室的底部,引起胶囊旋转并使胶囊中的内含物释放至空气流中。该单元的圆盘传送带药筒中装有六个胶囊。当全部六个胶囊已被使用时,单元被锁定并且必须重新对其进行加载。可使用本领域已知用于通过吸入递送封装粉末的其它装置。
胶囊使粉末保持优选的含湿量和可流动的形式。胶囊应当优选地被设计成使其内含物避光,例如它们应当是不透明的或胶囊可以是半透明的并且被包装和/或储存在不透明的容器(例如有颜色的或有盖子的容器)或金属箔中。
胶囊适当放置在装置中,以及该装置使用的刺穿方式可包括例如成角度刺穿、首先放置胶囊头、首先放置胶囊的平直端、在平直端上刺穿可降低胶囊的破损率。各实施例是本发明的单独实施方案。
在传统上,多粘菌素E甲磺酸钠必须被储存在气密容器中并且没有水分。然而,现已发现水分的临界水平改善了流动并且不影响化合物稳定性。根据欧洲药典(第7版,2013年,第1762-1763页),对多粘菌素E甲磺酸钠原始非微粉化的材料的含湿量有约5.0wt%的最大极限。测试已显示,经5年时期以约0.1wt%至约10wt%的含湿量储存的根据本发明的微粉化的粉末产品没有活性损失并且保持稳定。
通过参考以下实施例进一步描述本发明,通过下文的附图来说明本发明。以下实施例仅仅是说明性的,而不应当被解释为以任何方式限制实施方案的范围,因为本领域技术人员在阅读本公开后,将明白这些实施方案所涵盖的许多变化和等同物。
实施例
实施例1
通过使用HosokawaAlpine磨机流化能量研磨由DumexPharmaceuticals供应的具有大约100微米的平均粒度的粉状多粘菌素E甲磺酸钠来产生微粉化的多粘菌素E甲磺酸钠。将微粉化的多粘菌素E甲磺酸钠的样品悬浮在氯仿中并且通过激光计数器进行粒度分析。图1显示微粉化的粘菌素的粒度范围。
实施例2
从ShionogiQualicaps获得明胶药物胶囊(标准尺寸2)。使用标准的加药机(dosator)(ZanassiLZ64)在受控的温度和湿度条件(17℃,10%-15%RH)下填充胶囊。将多粘菌素E甲磺酸钠以纯的微粉化的粉末形式或与乳糖载体(乳糖一水合物,来自BorculoWheyProducts的lactochem药物级)一起填充至胶囊中。填充物如表1中所示。
表1
当单独使用多粘菌素E甲磺酸钠时,它很好地流动。填充重量是标准的。如果使用如在操作2中的粘菌素与乳糖的混合物,则混合的粉末很好地流过机器,但胶囊填充机中的组分会粘着。在操作3和4中粘着减少。测试表明可呼吸的部分在16毫克至20毫克区间。这是多级液体碰撞取样器的第3级和第4级收集到的多粘菌素E甲磺酸钠的质量且相当于具有小于约3微米至4微米的尺寸的粒子。
实施例3
将上述操作1至4所产生的填充的胶囊在各种湿度条件下储存9个月。粘菌素甲磺酸钠没有发生降解或结块。在胶囊壁上没有显著的多粘菌素E甲磺酸钠的结块。
实施例4
将微粉化的多粘菌素E甲磺酸钠粉末在25℃和60%RH与8wt%含湿量的密封条件下储存5年。游离粘菌素(一种毒性降解产物)的水平低于约5wt%,表明降解水平非常低。
实施例5
在环境温度条件下在约20%RH至约80%RH范围的相对湿度中储存封装在明胶胶囊中的多粘菌素E甲磺酸钠的等分试样。在若干时间点测试封装的多粘菌素E甲磺酸钠的含湿量和刺穿性能。例如,在23℃于30%RH、23℃于40%RH、23℃于48%RH、23℃于75%RH下,在不同时间点如1小时、2小时、4小时和24小时测试胶囊。使用目标温度设定在23℃±2℃且相对湿度±5%RH的合格的稳定性药室生成储存条件。环境实验室条件被确定为在约23℃±2℃于48%RH下。使用校准的NIST温湿度计验证环境条件。利用卡尔-费歇尔(Karl-Fisher)确定来确定多粘菌素E甲磺酸钠的平均含湿量以及明胶胶囊的含湿量。
下表2显示多粘菌素E甲磺酸钠粉末和明胶胶囊在各种储存条件下的水含量(KF)。图4显示多粘菌素E甲磺酸钠随时间、相对湿度和储存条件而变化的含湿量的示例。图5显示明胶胶囊在各种储存和相对湿度条件下的含湿量的示例。
表2
测试明胶胶囊以确定胶囊壳刺穿。将观察到的胶囊壳刺穿以三个等级进行分类。在类别1中,将胶囊刺穿以表示在刺激期间在囊体中或头部上形成的两个规整(neat)的孔,同时保持胶囊的机械完整性。在类别2中,将胶囊刺穿成具有带微小裂纹的两个明显孔。在类别3中,将胶囊刺穿以引起胶囊的大孔或碎裂。一旦胶囊被装置(例如,TurbospinTM装置)刺穿,胶囊即被打开,目视检测并且基于本文所述的分类的评定量表进行分级。表3显示通过时间点和条件得到的胶囊的刺穿类别。图6显示明胶胶囊随时间和相对湿度而变化的类别3刺穿频率的示例。
表3
下表4显示基于类别3刺穿的减少程度和多粘菌素E甲磺酸盐水含量的每种储存条件的平衡时间。
表4
实施例6
如实施例5中所说明并且如图4-6中所示,胶囊壳的含湿量可对具有多粘菌素E甲磺酸钠粉末的明胶胶囊的胶囊壳刺穿具有直接影响。图7显示其中在明胶胶囊中观察到类别3刺穿的最大减少的范围的示例。图7还显示了相对于类别3刺穿频率的胶囊的含湿量。明胶胶囊水含量是大约12wt%,高于12wt%时,胶囊壳足够柔性以耐受启动针的力并且不可能观察到类别3刺穿。如图7中所示,在低于约10.5wt%的含湿量下,类别3刺穿的频率增加。
实施例7
确定了三种不同类型的胶囊的胶囊破损率。表5显示胶囊的胶囊壳水含量和平均破损率。
表5
使胶囊暴露于不同的相对湿度和储存条件。例如,使胶囊暴露于11%RH至43%RH(25℃)范围的条件。确定了每种类型的胶囊的胶囊壳含湿量。
在相同条件下,明胶胶囊中的胶囊壳水含量最高,其次是基于PEG的明胶胶囊和HPMC胶囊。对于大约相同的水含量,明胶胶囊的破损率高于基于PEG的明胶胶囊。HPMC胶囊展现在很低的水含量下如表5中所示的低破损。
实施例8
在一次临床试验中,测量粉状多粘菌素E甲磺酸钠至肺的气道中的吸收(特定的气道传导性)。发现吸入微粉化的粘菌素甲磺酸钠干燥粉末的患者中有80%能够调动80毫克(即1百万单位)的药物。这是很高的摄取量,并且高于从粉状药物所预期的。粉末不会引起肺部刺激,因而不会影响其构造。在第二次试验中,向患者给予200微克术前用药剂量的沙丁胺醇。这似乎改善了气道的传导性。在可选择的药疗方案中,沙丁胺醇与粘菌素甲磺酸钠一样可以被混合至胶囊中。进一步的试验比较了如通过整个身体体积描记法测得的传统的雾化多粘菌素E甲磺酸钠和干燥粉末的特定气道传导性,并且该试验未显示任何显著的差异。
等同物
虽然已通过参考示例性实施方案描绘和描述了实施方案,但此类参考并不暗示对范围的限制,且不应推断有此限制。如受益于本公开的相关领域的普通技术人员将会想到的,该实施方案能够在形式和功能方面具有相当多的修改、改变和等同物。
所描绘和描述的实施方案仅仅是示例性的,且并未穷举范围。
本文所引用的所有参考文献在此通过引用整体并入。
Claims (12)
1.多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少50体积%的所述微粉化的粒子具有小于7微米但不小于3微米的直径并且所述粉末具有5重量%至10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中所述多粘菌素E甲磺酸钠未被分离成组分形式。
2.根据权利要求1所述的多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中10体积%的所述粒子具有小于3微米但不小于1.5微米的粒度。
3.一种适用于干粉吸入器的药物剂型,其包含
(a)多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少50体积%的所述微粉化的粒子具有小于7微米但不小于3微米的直径并且所述粉末具有5重量%至10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中所述多粘菌素E甲磺酸钠未被分离成组分形式;
(b)用于多粘菌素E甲磺酸钠的所述微粉化的粉末粒子的容器。
4.根据权利要求3所述的药物剂型,其中所述容器是硬明胶胶囊。
5.药物胶囊,其装有多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少50体积%的所述微粉化的粒子具有小于7微米但不小于3微米的直径并且所述粉末具有5重量%至10重量%的总含湿量,用于通过粉末吸入治疗肺部感染,其中所述多粘菌素E甲磺酸钠未被分离成组分形式。
6.根据权利要求5所述的药物胶囊,其中所述胶囊是半透明的。
7.根据权利要求5所述的药物胶囊,其中所述胶囊另外装有微粉化的支气管扩张药。
8.根据权利要求5所述的药物胶囊,其装有1,500,000IU至2,000,000IU的多粘菌素E甲磺酸钠。
8.一种泡罩包装,其包含铝箔连同多个根据权利要求5所述的药物胶囊。
9.一种治疗性治疗呼吸道的革兰氏阴性感染的方法,其包括向患者的呼吸道施用多粘菌素E甲磺酸钠的微粉化的粉末粒子,其中至少50体积%的所述微粉化的粒子具有小于7微米但不小于3微米的直径并且所述粉末具有5重量%至10重量%的总含湿量,其中所述多粘菌素E甲磺酸钠未被分离成组分形式。
10.根据权利要求9所述的方法,其中具有所述革兰氏阴性感染的所述患者是儿科受试者。
11.根据权利要求9所述的方法,其中所述革兰氏阴性感染由选自由铜绿假单胞菌、大肠杆菌和克雷伯氏菌组成的组的细菌病原体引起。
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