CN105120843A - 超低密度的肺部粉末 - Google Patents
超低密度的肺部粉末 Download PDFInfo
- Publication number
- CN105120843A CN105120843A CN201380069936.3A CN201380069936A CN105120843A CN 105120843 A CN105120843 A CN 105120843A CN 201380069936 A CN201380069936 A CN 201380069936A CN 105120843 A CN105120843 A CN 105120843A
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- pharmaceutical compositions
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Classifications
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Abstract
本发明提供用于肺部递送的包含颗粒的药物组合物,所述颗粒含有药剂,并且具有大于约5μm的几何尺寸和小于约0.075g/cm3的振实密度。本发明还提供用于递送本发明的药物组合物至患者呼吸道的方法。
Description
相关申请
本申请要求于2012年11月9日提交的美国临时申请号61/724,781;均于2013年9月30日提交的美国临时申请号61/884,319、美国临时申请号61/884,315、美国临时申请号61/884,436的权益。本申请是2012年11月16日提交的申请号13/679,245,现在的美国专利8,545,878的部分继续申请,并且是2013年7月18日提交的美国申请号13/945,160的部分继续申请。以上申请的全部教义以引用的方式并入本文。
发明背景
通过肺部途径递送大剂量的药物是非常困难的。干粉吸入器在递送高剂量药物时提供优点。在干粉制剂中,选择具有高百分率药物和低百分率赋形剂的制剂可以帮助递送高剂量药物,但通常难以制造和使用此类粉末。申请人已经发现一种超低密度的肺部干粉,所述干粉允许高剂量的粉末被包装在递送隔室中,同时作为高度可吸入的颗粒从吸入器中释放。
发明概述
本发明提供用于肺部递送的包含颗粒的药物组合物,所述颗粒含有药剂,并且具有大于约5μm的几何尺寸和小于约0.075g/cm3的振实密度。本发明还提供用于递送本发明的药物组合物至患者呼吸道的方法。在一个实施方案中,所述药物组合物包含用于肺部递送至患有帕金森病的患者的呼吸道的含有左旋多巴的颗粒。
发明详述
在一个实施方案中,本发明为用于肺部递送的包含颗粒的药物组合物,所述颗粒含有药剂,并且具有大于约5微米(μm)的中值几何尺寸和小于约0.075g/cm3的振实密度。在本发明的一个方面,振实密度为约0.02至0.075g/cm3。在本发明的另一个方面,振实密度为约0.02至0.05g/cm3。在本发明的又一个方面,振实密度为约0.03至0.06g/cm3。在本发明的一个方面,振实密度为约0.03至0.04g/cm3。在本发明的另一个方面,中值几何尺寸为约5μm至30μm、5μm至10μm、7μm至15μm,或7μm至12μm。
在另一个实施方案中,本发明为一种递送药剂至患者的肺部系统的方法,所述方法包括如下的步骤:
向患者提供在隔室和吸入器中的粉末,其中所述粉末包含药剂的颗粒;
通过患者的呼吸致动分散粉末;
递送颗粒至患者的呼吸系统;
其中通过粉末的分散,递送至患者呼吸系统的颗粒具有小于所述隔室中含有的颗粒的中值几何直径。
在本发明的一个方面,粉末具有小于约0.75g/cm3、约0.02至0.075g/cm3,或约0.025至0.055g/cm3的振实密度。
在本发明的一个方面,吸入器为干粉吸入器。可以使用多种吸入器,包括Aerolizer、Diskus、Flexhaler、Handihaler、Neohaler、Pressair、Rotahaler、Turbohaler和Twisthaler。可以使用的其它干粉吸入器描述于美国专利6,766,799、美国专利7,278,425和美国专利8,496,002中,所述专利中的每个以其涉及本文所述吸入装置的公开内容以引用的方式在此并入。
在本发明的一个方面,隔室为胶囊或泡罩包装。在本发明的一个方面,吸入器具有约0.05至约0.25、约0.15至约0.25、0.05至约0.15、0.2至约0.25,或约0.2的阻抗。本文所指的阻抗以厘米H2O的平方根/(升/分钟)计。
在本发明的另一个方面,所述隔室中的粉末具有大于约5μm、约5μm至约30μm、约5μm至约15μm,或约7μm至约12μm的中值几何直径。在一个具体实施方案中,所述隔室中的颗粒具有10-12μm的中值几何直径,而递送至患者呼吸道的颗粒具有8-9μm的中值几何直径。在另一个实施方案中,递送至患者呼吸道的颗粒具有比所述隔室中的颗粒小5%至20%、小5%至10%,或小8%至15%的中值几何直径。
在一个实施方案中,本发明为用于肺部递送的药物组合物,所述药物组合物包含左旋多巴颗粒,所述左旋多巴颗粒具有大于约5μm的几何尺寸和小于约0.075g/cm3的振实密度。在本发明的一个方面,颗粒包含磷脂。在本发明的另一个方面,颗粒包含盐。在本发明的又一个方面,颗粒包含表面活性剂或聚合物。
在一个实施方案中,本发明的颗粒具有大于10m2/g的外表面积。在另一个实施方案中,外表面积大于15m2/g、大于20m2/g或约10m2/g至约50m2/g。
在一个具体实施方案中,本发明为用于肺部递送的药物组合物,所述药物组合物包含左旋多巴颗粒,所述左旋多巴颗粒具有约8μm至约12μm的几何尺寸和约0.025g/cm3至约0.050g/cm3的振实密度。在一些情况下,本具体发明的特征在于,颗粒具有在约2.5μm和5μm之间的空气动力学直径,颗粒具有约10m2/g至约50m2/g的外表面积,或所述颗粒还包含盐和磷脂。在一个非常具体的实施方案中,本发明为用于肺部递送的药物组合物,所述药物组合物包含左旋多巴、二棕榈酰磷脂酰胆碱和氯化钠的颗粒,其中所述颗粒具有约8μm至约12μm的几何尺寸和约0.025g/cm3至约0.050g/cm3的振实密度。在甚至更具体的实施方案中,本发明为用于肺部递送的药物组合物,所述药物组合物包含左旋多巴、二棕榈酰磷脂酰胆碱(DPPC)和氯化钠的颗粒,其中所述颗粒具有约8μm至约12μm的几何尺寸,和约0.025g/cm3至约0.050g/cm3的振实密度,在约2.5μm和5μm之间的空气动力学直径,以及约10至约50m2/g的外表面积。
吸入粉末可以含有另外的赋形剂。赋形剂的实例包括盐,如氯化钠(NaCl)、柠檬酸钠、乳酸钠和氯化钾;以及磷脂,如二棕榈酰磷脂酰胆碱(DPPC)、二月桂酰磷脂酰胆碱(DLPC)、二饱和的磷脂酰胆碱(DSPC)。在一个实施方案中,如以在粉末中的干固体的%所测量,药物组合物含有包含90%的左旋多巴、8%的二棕榈酰磷脂酰胆碱和2%的氯化钠的粉末。在一个实施方案中,药物组合物含有具有干重比率90:8:2的左旋多巴:DPPC:NaCl的可吸入粉末。在另一个实施方案中,胶囊含有具有干重比率90:5:5的左旋多巴:DPPC:NaCl的可吸入粉末。
使用阶式冲击取样器的重量分析,是一种测量空气传播颗粒的尺寸分布的方法。Andersen阶式冲击取样器(ACI)是可以根据空气动力学尺寸将气雾剂分为九个不同级分的八平台冲击取样器。各平台的尺寸截断值取决于操作ACI时的流速。优选地,在60L/min下校准ACI。在一个实施方案中,二平台折叠ACI用于颗粒优化。二平台折叠ACI由八平台ACI的平台0、2和F构成,并且允许收集两个分开的粉末级分。在每个平台气雾剂流穿过喷嘴并且撞击表面。具有足够大惯性的气雾剂流中的颗粒将撞击到板上。不具有足够的惯性撞击到板上的较小颗粒将保留在气雾剂流中,并被携带至下一个平台。
校准ACI,以便在第一平台上收集的粉末的分数在此被称为“细粒分数”或“FPF”。FPF对应于具有小于5.6μm的空气动力学直径的颗粒的百分率。通过ACI的第一平台并沉积在收集过滤器上的粉末的分数被称为“FPF(3.4)”。其对应于具有小于3.4μm的空气动力学直径的颗粒的百分率。
FPF分数已证实与沉积在患者肺部的粉末的分数相关联,而FPF(3.4)已证实与到达患者肺部深处的粉末的分数相关联。按照本发明,包含在胶囊中的标称剂量的可吸入粉末的FPF(即,包含在胶囊中的具有小于5.6μm的空气动力学直径的粉末中的颗粒的百分率)为约40%或更多。在一个实施方案中,包含在胶囊中的标称粉末剂量的可吸入粉末的FPF为约50%、60%、或70%、或80%、或90%。在一个实施方案中,包含在吸入器中的标称粉末剂量的可吸入粉末的FPF为约50%至约60%。在一个实施方案中,包含在吸入器中的标称粉末剂量的可吸入粉末的FPF为约55%至约65%。在一个实施方案中,包含在吸入器中的标称粉末剂量的可吸入粉末的FPF为约50%至约70%。在一个实施方案中,包含在吸入器中的标称粉末剂量的可吸入粉末的FPF为约57%至约62%。在一个实施方案中,包含在吸入器中的标称粉末剂量的可吸入粉末的FPF为约50%至约69%。在一个实施方案中,包含在吸入器中的标称粉末剂量的可吸入粉末的FPF为约50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%或65%。
如本文所使用的,术语“标称粉末剂量”为保持在胶囊中的粉末的总量。如本文所使用的,术语“标称药物剂量”为包含在标称粉末剂量中的药物(例如左旋多巴)的总量。标称粉末剂量通过粉末中药物的负载百分比与标称药物剂量相关。
在一个实施方案中,标称粉末剂量按干重计为25-50mg。在另一个实施方案中,标称粉末剂量按干重计为25-40mg。在又一个实施方案中,标称粉末剂量按干重计为30-35mg或按干重计32-38mg。
另一种用于测量空气传播颗粒的尺寸分布的方法是多平台液体撞击取样器(MSLI)。多平台液体撞击取样器(MSLI)与Anderson阶式冲击取样器(ACI)以相同的原理来工作,但是在MSLI中具有五个平台而非八个平台。另外,每个MSLI平台由甲醇润湿的玻璃料构成,代替每个平台由实心板构成。润湿平台用于防止使用ACI时可能发生的反弹和二次夹带。MSLI用于提供粉末的流速相关性的指示。这可以通过以下方式来实现:在30、60和90L/min下操作MSLI并且测量在平台1上和收集过滤器上收集的粉末的分数。如果在不同流速下每个平台上的分数保持相对恒定,则粉末被认为是接近流速无关性。
在一个实施方案中,本发明的可吸入粉末具有小于约0.075g/cm3的振实密度。例如,颗粒具有在0.02g/cm3和0.075g/cm3之间、在0.02g/cm3和0.05g/cm3之间、在0.03g/cm3和0.06g/cm3之间、在0.03g/cm3和0.04g/cm3之间、或小于约0.05g/cm3的振实密度,或小于约0.04g/cm3的振实密度、小于约0.03g/cm3的振实密度。可以通过使用本领域技术人员已知的仪器测量振实密度,如双平台微处理器控制的振实密度测试仪(DualPlatformMicroprocessorControlledTapDensityTester)(Vankel,N.C.)或
GEOPYCTM仪器(MicrometricsInstrumentCorp.,Norcross,GA,30093)。振实密度是对包封质量密度的标准量度。可以使用USPBulkDensityandTappedDensity,UnitedStatesPharmacopiaConvention,Rockville,Md.,第10次增刊,4950-4951,1999的方法来测定振实密度。可以有助于降低振实密度的特征包括不规则表面纹理和多孔结构。各向同性颗粒的包封质量密度被定义为,颗粒的质量除以其可以被封闭在内的最小球体包封体积。在本发明的一个实施方案中,颗粒具有小于约0.4g/cm3的包封质量密度。
本发明的可吸入粉末具有优选的颗粒尺寸,例如至少约1微米(μm)的体积中值几何直径(VMGD)。在一个实施方案中,VMGD大于5μm。在其它实施方案中,VMGD在约5μm和30μm之间、在约5μm和10μm之间、在约7μm和15μm之间,以及在约7μm和12μm之间。喷雾干燥颗粒的直径,例如VMGD,可以使用激光衍射仪测量(例如Helos,由Sympatec,Princeton,N.J.制造)。其它用于测量颗粒直径的仪器是本领域熟知的。样品中的颗粒的直径范围将取决于诸如颗粒组成以及合成方法等这些因素。可以选择样品中颗粒尺寸的分布以允许最佳沉积至呼吸道内的靶向位点。
本发明的可吸入粉末的颗粒优选具有“质量中值空气动力学直径”(MMAD),本文也称为“空气动力学直径”,其在约1μm和约5μm之间或包括在约1μm和约5μm之间的任何子区间。例如,MMAD在约1μm和约3μm之间,或MMAD在约3μm和约5μm之间。在一个实施方案中,MMAD在1.5μm和2.5μm之间。在实验上,可以通过采用重力沉降法,由此使用全部粉末颗粒沉降一定距离的时间来直接推断颗粒的空气动力学直径来确定空气动力学直径。用于测量质量中值空气动力学直径(MMAD)的间接方法是多平台液体撞击取样器(MSLI)。可以由以下公式计算空气动力学直径daer
daer=dg√ρtap
其中,dg是几何直径,例如MMGD,而ρ是粉末密度。
通常通过喷雾干燥生产用于本发明的胶囊中的粉末。在一些情况下,喷雾干燥可以产生极干燥颗粒,所述干燥颗粒可能具有差的处理特性,并且可能很难以密集方式压成胶囊。具有指定水分含量的氮源可以流过、穿过或通过干粉以为干粉增加特定水分含量。这种水分可以提供所需的粉末工作密度。根据本发明的喷雾干燥方法描述于本文的实施例和美国专利号:6,848,197和8,197,845中,所述美国专利以引用的方式并入本文。
例如,如上所述的包含左旋多巴的可吸入粉末,用于填充适用于吸入器的胶囊。本文使用的术语“胶囊材料”指的是制成用于吸入的胶囊的外壳的材料。在一个实施方案中,根据本发明的胶囊材料选自明胶、纤维素衍生物、淀粉、淀粉衍生物、壳聚糖和合成塑料。
如果使用明胶作为胶囊材料,根据本发明的实例可以选自聚乙二醇(PEG)、PEG-3350、甘油、山梨糖醇、丙二醇、PEO-PPO嵌段共聚物和其它多元醇和聚醚。如果使用纤维素衍生物作为胶囊材料,那么根据本发明的实例可以选自羟丙基甲基纤维素(HPMC)、羟丙基纤维素、甲基纤维素、羟甲基纤维素和羟乙基纤维素。如果使用合成塑料作为胶囊材料,那么根据本发明的实例可以选自聚乙烯、聚碳酸酯、聚酯、聚丙烯和聚对苯二甲酸乙二醇酯。在一个实施方案中,胶囊材料还包含二氧化钛。在一个优选实施方案中,胶囊包含HPMC和二氧化钛。在一个实施方案中,胶囊包含角叉菜胶。在另一个实施方案中,胶囊包含氯化钾。在另一个实施方案中,胶囊包含HPMC、角叉菜胶、氯化钾和二氧化钛。在一个实施方案中,胶囊尺寸选自000、00、0、1或2。在一个具体实施方案中,胶囊尺寸为00。
在一个具体实施方案中,胶囊为羟丙基甲基纤维素(HPMC)胶囊。在另一个具体实施方案中,胶囊为羟丙基甲基纤维素00尺寸胶囊。在一个具体实施方案中,胶囊材料包含HPMC和二氧化钛,并且胶囊尺寸为00。
在一个实施方案中,00胶囊含有按干重计在15和50克之间的左旋多巴。在另一个实施方案中,00胶囊含有按干重计在20和40克之间的左旋多巴。在另一个实施方案中,00胶囊含有在按干重计25和35克之间的左旋多巴。在另一个实施方案中,00胶囊含有按干重计约30、31、32、33、34、35、36、37、38、39或40克的左旋多巴。
在本发明的一个方面,粉末具有低静电荷以实现从胶囊中的高度分散。
本发明的胶囊尤其适用于向患有例如帕金森病和需要用左旋多巴治疗的患者递送包含左旋多巴的干粉组合物的干粉吸入器。需要治疗的患者可能需要针对帕金森病的维持性治疗或针对帕金森病的挽救性治疗,这例如将是在由帕金森病引起的急性和/或僵冻发作的情况下所需要的。在一个实施方案中,胶囊用于干粉吸入器以向患者递送单次呼吸有效量的干粉组合物,如以引用的方式并入文本的美国专利号6,858,199和7,556,798所述。
如本文所用,术语“有效量”意指达到期望效果或功效所需的量。药物的实际有效量可以根据所采用的具体药物或其组合、配制的特定组合物、施用方式和患者的年龄、体重和病状,以及所治疗的发作的严重程度而改变。就多巴胺前体、激动剂或其组合而言,有效量是减少了需要治疗的帕金森症状的量。用于特定患者的剂量在本文进行描述,并可由本领域的普通技术人员使用的常规考虑(例如借助于合适的、常规药理学方案)来决定。例如,口服左旋多巴的有效量范围为约50毫克(mg)至约500mg。在许多情况下,正在进行(口服)的左旋多巴治疗方案通常为每日100mg,八(8)次。
可以在时间上同时或连续地施用不止一种多巴胺前体、激动剂或其组合,特别是左旋多巴、卡比多巴、阿朴吗啡和其它药物。例如,通常施用卡比多巴或苄丝肼以确保外围羧化酶活性被完全停止。可以采用肌内、皮下、口服和其它施用途径。在一个实施方案中,这些其它药剂被递送至肺部系统。可以之前、之后或同时施用这些化合物或组合物。在优选实施方案中,施用至呼吸道的颗粒包括左旋多巴和卡比多巴。本文使用的术语“共施用”意指间或施用特定的多巴胺前体、激动剂或其组合和/或其它组合物以治疗发作以及本文所述的潜在病状。
在一个实施方案中,长期左旋多巴治疗包括使用在干粉吸入器中的用于肺部递送左旋多巴与口服卡比多巴的组合的本文所述药物组合物。在另一个实施方案中,在发作期间提供左旋多巴的肺部递送,而长期治疗可以采用左旋多巴/卡比多巴的常规口服施用。在另一个实施方案中,长期左旋多巴治疗包括使用在干粉吸入器中的用于肺部递送左旋多巴与口服苄丝肼的组合的本文所述药物组合物。在另一个实施方案中,在发作期间提供左旋多巴的肺部递送,而长期治疗可以采用左旋多巴/苄丝肼的常规口服施用。
通过参照以下非限制性实施例可进一步理解本发明。
实施例
实施例1.工艺一:粉末制备
使左旋多巴和DPPC在室温下30分钟,此后称重所需量的水和乙醇并分别转移至带夹套的水相进料容器和不带夹套的有机相进料容器中。将水相容器上的夹套设定为55℃,并且使称重的水升温至52.5℃,随后将所需量的氯化钠和左旋多巴加入至水相容器中,并且将所需量的DPPC加入至有机相容器中,并且通过搅拌使它们都溶解。用维持在70scfh的氮气吹扫水相进料容器的顶部空间。
通过发起干燥气流(设定为95kg/h)和排气来启动喷雾干燥,并且将用于干燥气体的加热器设定至125℃。打开产品过滤加热器并设定至60℃,并且打开液体滑动加热器并设定至55℃。在喷雾干燥器出口温度达到80℃后,启动雾化气体(设定为22g/min)和空白溶剂(水相流速=28mL/min并且有机相流速=42mL/min)并使其稳定,并且使得系统冷却且稳定至出口温度为52.5℃。启动产品过滤器脉冲,并且将产品过滤器的吹扫流量设定至15scfh。在系统稳定在52.5℃后,切换液体滑动入口至进料溶剂。表1总结了在整个操作期间维持的参数。
工艺参数(OC) | 目标值 |
入口温度(℃) | 125.0 |
出口温度(℃) | 52.5 |
干燥气体流速(kg/h) | 95.0 |
腔室压力("wc) | -2.0 |
雾化气体流速(g/min) | 22.0 |
水相流速(mL/min) | 28.0 |
有机相流速(mL/min) | 42.0 |
产品过滤器吹扫流量(scfh) | 15.0 |
表1:喷雾干燥的工艺参数
在20℃和15%的相对湿度的控制条件下,每小时收集喷雾干燥粉末并转移至较大的容器。进料溶剂用完后,切换液体滑动入口至空白溶剂并允许进行约10分钟,在此期间收集并合并最终粉末。在空白溶剂10分钟后,通过关闭液体管线、雾化气体、干燥气体加热器、干燥气体入口,最后是排气装置来启动系统关闭。
此过程产生含有约3.4重量%水的粉末。
实施例2.工艺二:利用特殊干燥的粉末制备
使左旋多巴和DPPC在室温下30分钟,此后称重所需量的水和乙醇并分别转移至带夹套的水相进料容器和不带夹套的有机相进料容器中。将水相容器上的夹套设定为55℃,并且使称重的水升温至52.5℃,随后将所需量的氯化钠和左旋多巴加入至水相容器中,并且将所需量的DPPC加入至有机相容器中,并且通过搅拌使它们都溶解。用维持在70scfh的氮气吹扫水相进料容器的顶部空间。
通过发起干燥气流(设定为95kg/h)和排气来启动喷雾干燥,并且将用于干燥气体的加热器设定至125℃。打开产品过滤器和优化的吹扫气体加热器并设定至60℃,并且打开液体滑动加热器并设定至55℃。在喷雾干燥器出口温度达到80℃后,启动雾化气体(设定为22g/min)、空白溶剂(水相流速=28mL/min并且有机相流速=42mL/min)和优化的干燥气体(设定为70kg/h)并使其稳定,并且使得系统冷却且稳定至出口温度为52.5℃。启动产品过滤器脉冲,并且将产品过滤器的吹扫流量设定至15scfh。在系统稳定在52.5℃后,切换液体滑动入口至进料溶剂。表2总结了在整个操作期间维持的参数。
表2:喷雾干燥的工艺参数
在20℃和15%的相对湿度的控制条件下,每小时收集喷雾干燥粉末并转移至较大的容器。进料溶剂用完后,切换液体滑动入口至空白溶剂并允许进行约10分钟,在此期间收集并合并最终粉末。在空白溶剂10分钟后,通过关闭液体管线、优化的干燥气体、雾化气体、干燥气体加热器、干燥气体入口,最后是排气装置来启动系统关闭。
此工艺产生包含约2.2重量%水的粉末。水含量的这种1%的降低使得产品稳定性显著改善。
样品1:基于松散粉末(预先填充):
VMGD=10.2μm;并且
振实密度=0.033g/cm3。
样品2:相同但是使用在填充批次(60031)上测量的VMGD:
VMGD=8.6μm;并且
振实密度=0.033g/cm3。
样品1.由阻抗为0.2的干粉吸入器发射的粉末(28.3LPM):
VMGD=9.4μm;并且
振实密度=0.048g/cm3。
样品2.由阻抗为0.2的干粉吸入器发射的粉末(60LPM):
VMGD=8.8μm;并且
振实密度=0.042g/cm3。
上述颗粒对于肺部产品是非常低密度的。这些非常低密度的颗粒对于包装到胶囊中是有利的。由于低密度,从吸入器发射之前这些颗粒可以被解聚或剪切。这些解聚/剪切的颗粒具有良好的流动特性和至肺部的预期沉积。
虽然本发明已参考其优选实施方案进行具体显示和描述,但是本领域技术人员应了解,可在不脱离由随附权利要求书所涵盖的本发明的范围的情况下在形式和细节方面在其中做出各种改变。还应理解本文所述的实施方案不是相互排斥的,而且根据本发明,来自各种实施方案的特征可全部或部分地组合。
Claims (41)
1.一种用于肺部递送的药物组合物,其包含含有药剂的颗粒,其中所述颗粒具有大于约5μm的几何尺寸和小于约0.075g/cm3的振实密度。
2.如权利要求1所述的药物组合物,其中所述振实密度为约0.02g/cm3至0.075g/cm3。
3.如权利要求1所述的药物组合物,其中所述振实密度为约0.02g/cm3至0.05g/cm3。
4.如权利要求1所述的药物组合物,其中所述振实密度为约0.03g/cm3至0.06g/cm3。
5.如权利要求1所述的药物组合物,其中所述振实密度为约0.03g/cm3至0.04g/cm3。
6.如权利要求1所述的药物组合物,其中几何尺寸为约5μm至30μm。
7.如权利要求1所述的药物组合物,其中中值几何尺寸为约5μm至10μm。
8.如权利要求1所述的药物组合物,其中中值几何尺寸为约7μm至15μm。
9.如权利要求1所述的药物组合物,其中中值几何尺寸为约7μm至12μm。
10.一种递送药剂至患者的肺部系统的方法,其包括如下的步骤:
向患者提供在隔室和吸入器中的粉末,其中所述粉末包含药剂的颗粒;
通过所述患者的呼吸致动来分散所述粉末;
递送所述颗粒至所述患者的呼吸系统;并且
其中通过所述粉末的分散,递送至所述患者呼吸系统的所述颗粒具有小于所述隔室中含有的颗粒的中值几何直径。
11.如权利要求10所述的方法,其中所述粉末具有小于约0.75g/cm3的振实密度。
12.如权利要求10所述的方法,其中所述粉末具有约0.02g/cm3至0.075g/cm3的振实密度。
13.如权利要求10所述的方法,其中所述粉末具有约0.025g/cm3至0.055g/cm3的振实密度。
14.如权利要求10所述的方法,其中所述吸入器具有约0.05√cmH2O/(L/min)至约0.25√cmH2O/(L/min)的阻抗。
15.如权利要求10所述的方法,其中所述吸入器具有约0.15√cmH2O/(L/min)至约0.25√cmH2O/(L/min)的阻抗。
16.如权利要求10所述的方法,其中所述吸入器具有约0.05√cmH2O/(L/min)至约0.15√cmH2O/(L/min)的阻抗。
17.如权利要求10所述的方法,其中所述吸入器具有约0.2√cmH2O/(L/min)至约0.25√cmH2O/(L/min)的阻抗。
18.如权利要求10所述的方法,其中所述吸入器具有约0.2√cmH2O/(L/min)的阻抗。
19.如权利要求10所述的方法,其中在所述隔室中的所述粉末具有大于约5μm的中值几何直径。
20.如权利要求10所述的方法,其中在所述隔室中的所述粉末具有约5μm至约30μm的中值几何直径。
21.如权利要求10所述的方法,其中在所述隔室中的所述粉末具有约5μm至约15μm的中值几何直径。
22.如权利要求10所述的方法,其中在所述隔室中的所述粉末具有约7μm至约12μm的中值几何直径。
23.如权利要求10所述的方法,其中在所述隔室中的所述颗粒具有10-12μm的中值几何直径,而递送至所述患者呼吸道的所述颗粒具有8-9μm的中值几何直径。
24.如权利要求10所述的方法,其中递送至所述患者呼吸道的所述颗粒具有比在所述隔室中的所述颗粒小5%至20%的中值几何直径。
25.如权利要求10所述的方法,其中递送至所述患者呼吸道的所述颗粒具有比在所述隔室中的所述颗粒小5%至10%的中值几何直径。
26.如权利要求10所述的方法,其中递送至所述患者呼吸道的所述颗粒具有比在所述隔室中的所述颗粒小8%至15%的中值几何直径。
27.一种用于肺部递送的药物组合物,其包含左旋多巴颗粒,所述左旋多巴颗粒具有大于约5μm的几何尺寸和小于约0.75g/cm3的振实密度。
28.如权利要求1或27所述的药物组合物,其中所述颗粒包含磷脂。
29.如权利要求1或27所述的药物组合物,其中所述颗粒包含盐。
30.如权利要求1或27所述的药物组合物,其中所述颗粒包含表面活性剂。
31.如权利要求1或27所述的药物组合物,其中所述颗粒包含聚合物。
32.如权利要求1或27所述的药物组合物,其中所述颗粒包含糖。
33.如权利要求1或27所述的药物组合物,其中所述颗粒具有大于约10m2/g的外表面积。
34.如权利要求1或27所述的药物组合物,其中所述颗粒具有大于约15m2/g的外表面积。
35.如权利要求1或27所述的药物组合物,其中所述颗粒具有大于约20m2/g的外表面积。
36.如权利要求1或27所述的药物组合物,其中所述颗粒具有约10m2/g至约50m2/g的外表面积。
37.一种用于肺部递送的药物组合物,其包含左旋多巴颗粒,所述左旋多巴颗粒具有:
约8μm至约12μm的几何尺寸;以及
约0.025g/cm3至约0.050g/cm3的振实密度。
38.如权利要求37所述的药物组合物,其中所述颗粒具有在约2.5μm和5μm之间的空气动力学直径。
39.如权利要求37所述的药物组合物,其中所述颗粒具有约10m2/g至约50m2/g的外表面积。
40.如权利要求37所述的药物组合物,其中所述颗粒还包含盐和磷脂。
41.一种用于肺部递送的药物组合物,其包含左旋多巴颗粒,所述左旋多巴颗粒具有:
约8μm至约12μm的几何尺寸;
约0.025g/cm3至约0.050g/cm3的振实密度;
在1.90重量%和2.90重量%之间的水含量。
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