CN104383546B - 用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法 - Google Patents

用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法 Download PDF

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CN104383546B
CN104383546B CN201410312545.6A CN201410312545A CN104383546B CN 104383546 B CN104383546 B CN 104383546B CN 201410312545 A CN201410312545 A CN 201410312545A CN 104383546 B CN104383546 B CN 104383546B
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布赖恩·R·威尔逊
马歇尔·格兰特
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Abstract

本发明提供了用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法。具体地，本发明涉及优化二酮哌嗪干燥粉末的气动性能的方法，包括步骤：在受控温度下从溶液中沉淀二酮哌嗪以形成颗粒；基于所述温度选择干燥方法；和干燥所述颗粒。采用该方法使得颗粒中的活性剂更稳定并能更有效地输送。

Description

用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法
本申请是申请日为2007年2月22日，国家申请号为200780006438.9，发明名称为“用于改善包含二通哌嗪和活性剂的微粒的药物性质的方法”的发明专利申请的分案申请。
相关申请的交叉引用
本申请根据37CFR§119(e)要求2006年2月22日递交的美国临时专利申请No.60/776,605的优先权，通过引用将其全文结合在本文中。
技术领域
本发明涉及干燥粉末药物领域。本发明公开了获得具有改善的气动性能的颗粒的方法，或该颗粒中的活性剂更稳定并能更有效地输送。更具体地，本发明涉及干燥(特别是喷雾干燥)二酮哌嗪-胰岛素(DKP-胰岛素)颗粒的方法。本发明的干燥粉末可用于肺部输送的药物制剂。
背景技术
对于制备干燥粉末组合物形式的颗粒，本领域中使用大量不同的方法。这些方法例如包括冷冻干燥、蒸发、相分离和喷雾干燥(见PCT专利申请WO91/16038)。当制造干燥粉末药物时，有些方法始于溶液中的组分，然后通过去除溶剂来形成粉末颗粒。其它方法在先前的独立步骤(例如沉淀)中形成颗粒，并且可以得到悬浮液中的颗粒，该颗粒必须被干燥。对于干燥或从悬浮液中的颗粒去除溶剂，例如冷冻干燥和蒸发的方法是特别常用的，而喷雾干燥更普遍地用于从溶液中形成颗粒。例如，参见美国专利No.5,976,574、5,985,248、6,001,336、6,051,256、6,077,543、6,365,190、6,372,258、6,423,344、6,479,049、6,509,006、6,569406、6,572,893、6,582,728、6,838,076和6,896,906。
冷冻干燥(或冻干)包括这样一个过程：将产品冻结并置于真空中，然后使冰从固体不经过液态直接变为蒸汽，由此将溶剂(通常为水)从产品中去除。该过程包括三个独立的过程：冷冻、初级干燥(升华)和次级干燥(解吸)。在喷雾干燥过程中，通过喷嘴(例如双流体喷嘴)、转盘或等同设备将溶液(通常为水溶液)引入热气体流。溶液穿过喷嘴被雾化成精细液滴。气体流提供的热能导致水或其它溶剂蒸发，从而生成精细颗粒。
美国专利No.5,352,461、5,503,852、6,331,318、6,395,774和6,663,898中描述了使用取代的二酮哌嗪微粒来输送药物。干燥粉末形式的二酮哌嗪微粒的肺部输送描述在美国专利5,503,852、6,428,771、6,444,226和6,652,885中。形成和加载二酮哌嗪颗粒以用于药物输送的各种方法公开在美国专利No.6,444,226、2006年9月14日提交的美国专利申请No.11/532,063和11/532,065以及2005年9月14日提交的美国临时专利申请No.60/717,524中。通过引用将上述文献关于二酮哌嗪、二酮哌嗪微粒及其在药物输送中的用途的内容结合在本文中。根据这些教导制造的干燥粉末可以较好地用于肺部输送，但仍存在改善各种药物性质的空间。本发明旨在满足本领域中对于获得改善的颗粒的要求，这种颗粒具有更好的气动性，并能使活性剂输送效率更高且稳定性更强。
发明内容
本发明涉及获得改善的颗粒和/或改善的干燥粉末的方法。本发明中的颗粒和粉末包括与活性剂结合的二酮哌嗪衍生物。在本发明的具体实施方式中，颗粒是二酮哌嗪-胰岛素颗粒制剂，当用喷雾干燥工艺干燥时，该颗粒制剂比用冷冻干燥时具有改善的稳定性、气动特性和药效学特性。在其它实施方式中，提供了喷雾干燥的二酮哌嗪-胰岛素颗粒制剂或干燥粉末。
在本发明的一种具体实施方式中，制备包含二酮哌嗪的颗粒，并以悬浮液形式(通常为水悬液)提供，向该悬浮液中添加活性剂溶液。本发明的活性剂可以包括但不限于下列中的一种或更多种：胰岛素、降钙素、甲状旁腺激素1-34或甲状旁腺激素的其它生物活性片段、奥曲肽(octreotide)、亮丙瑞林(leuprolide)和RSV肽、非氨酯(felbamate)、大麻素拮抗剂和/或激动剂、蕈毒碱性(muscurinic)拮抗剂和/或激动剂、肝素(heparin)、低分子量肝素、色甘酸、西地那非、伐地那非、他达拉非(tadalafil)、生长激素、齐多夫定(zidovudine，AZT)、去羟肌苷(DDI)、粒细胞菌落刺激因子(GCSF)、拉莫三嗪(lamotrigine)、绒毛膜促性释放因子、黄体生成释放激素、β-半乳糖苷酶、GLP-1、促胰岛素分泌肽(exendins)1-4、脑肠肽、及其片段。在另一种实施方式中，活性剂是肽或例如胰岛素或其类似物的蛋白质。
在一种具体实施方式中，活性剂是胰岛素或其类似物。
本发明公开了获得具有改善的气动性能并且其中活性剂更稳定且能更有效地输送的颗粒的方法。更具体地，本发明涉及干燥(特别是喷雾干燥)二酮哌嗪-胰岛素颗粒的方法。干燥粉末可用作肺部输送的药物制剂。在其它实施方式中，二酮哌嗪-胰岛素干燥粉末可用于鼻腔输送。
因此，本发明的具体实施方式提供了一种制备具有改善的药物性质的干燥粉末的方法，包括步骤：(a)提供二酮哌嗪溶液；(b)提供活性剂溶液；(c)形成颗粒；和(d)将二酮哌嗪与活性剂结合；然后(e)通过喷雾干燥去除溶剂以得到干燥粉末，其中所述干燥粉末与通过冷冻干燥去除溶剂得到的干燥粉末相比具有改善的药物性质。
在另一种实施方式中，改善的药物性质选自改善的活性剂稳定性、增大的干燥粉末密度和改善的干燥粉末气动性能。在另一种实施方式中，改善的干燥粉末气动性能通过从吸入器输送的可吸入范围内的颗粒的百分比(可吸入分数)来测定。本发明中的可吸入分数可大于约40％或大于约50％或大于约60％，但不限于此。
在本发明的其它实施方式中，微粒中的胰岛素含量相对于干燥粉末制剂的重量在约3％至约50％的范围内。在其它场合，胰岛素浓度在约7重量％至约25重量％的范围内。在优选实施方式中，胰岛素含量为约19.0、19.1、19.219.3、19.4、19.5、19.6、19.7、19.8或19.9重量％。在另一种优选实施方式中，胰岛素浓度为约11重量％。在其它优选实施方式中，胰岛素含量为约10、12、13、14、15、16、17或18wt％。在各种实施方式中，“约”被定义为±0.1、0.2、0.5、1或2％，只要不确定程度不超过胰岛素含量的10％。
在另一种实施方式中，本发明提供了由式2，5-二酮-3，6-二(4-X-氨基丁基)哌嗪表示的二酮哌嗪，其中X选自琥珀酰基、戊二酰基、马来酰基和富马酰基。在一种优选实施方式中，二酮哌嗪是富马酰基二酮哌嗪。
在本发明的另一种具体实施方式中，提供了一种根据制备具有改善的药物性质的干燥粉末药物的方法制备的干燥粉末，其中所述方法包括步骤：(a)提供二酮哌嗪溶液；(b)提供活性剂溶液；(c)形成颗粒；和(d)将二酮哌嗪与活性剂结合；然后(e)通过喷雾干燥去除溶剂以得到干燥粉末，其中所述干燥粉末与通过冷冻干燥去除溶剂得到的干燥粉末相比具有改善的药物性质。在另一种实施方式中，所述干燥粉末包含活性剂，所述活性剂例如但不限于胰岛素或其类似物。
在另一种具体实施方式中，本发明提供了一种将胰岛素输送给患者的方法，包括给予患者有效量的干燥粉末。
本发明还提供了一种具有改善的药物性质的干燥粉末，其中改善的性质是改善的活性剂输送性，从而获得更大的葡萄糖代谢清除率(glucose disposal)。
在本发明的另一种具体实施方式中，提供了一种制备具有改善的药物性质的干燥粉末药物的方法，包括：(a)提供二酮哌嗪溶液；(b)形成包含二酮哌嗪的颗粒的步骤；和(c)通过喷雾干燥去除溶剂以得到干燥粉末，其中所述干燥粉末与通过冷冻干燥去除溶剂得到的干燥粉末相比具有改善的药物性质。还提供了另一个包括在溶剂去除步骤之前在颗粒中加入活性剂的步骤。
本发明的另一种具体实施方式提供了一种优化二酮哌嗪干燥粉末的气动性能的方法，包括步骤：(a)在受控温度下使二酮哌嗪从溶液中沉淀以形成颗粒；(b)基于所述温度选择干燥方法；和(c)干燥颗粒。还可以包括另一个在颗粒中加入活性剂的步骤。
在具体实施方式中，喷雾干燥时的进口温度为105℃、110℃、120℃、130℃、140℃或由这些值中的任何两个构成上下限的范围。在其它具体实施方式中，雾化压力为0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1bar或由这些值中的任何两个构成上下限的范围。在其它具体实施方式中，喷雾速率为4.4、7.6、12.2g/min或由这些值中的任何两个构成上下限的范围。在本发明的另一种具体实施方式中，出口温度为75℃。
在另一种实施方式中，二酮哌嗪是富马酰基二酮哌嗪，其中受控温度为约15-18℃，所选的干燥方法是喷雾干燥。在其它实施方式中，受控温度为17℃。在其它实施方式中，受控温度小于或等于约13℃，或大于或等于约19℃。
在另一种具体实施方式中，颗粒可以包含约11.0％、11.1％、11.2％、11.3％、11.4％、11.5％、11.6％、11.7％、11.8％、11.9％、12.0％、12.1％、12.2％、12.3％、12.4％、12.5％、12.6％、12.7％、12.8％、12.9％、13.0％、13.1％、13.2％、13.3％、13.4％、13.5％、13.6％、13.7％、13.8％、13.9％、14.0％、14.1％、14.2％、14.3％、14.4％、14.5％、14.6％、14.7％、14.8％、14.9％、15.0％、15.1％、15.2％、15.3％、15.4％、15.5％、15.6％、15.7％、15.8％、15.9％、16.0％或更多的胰岛素(重量比)。在本发明的一种具体实施方式中，提供了一种包含约11.4重量％的胰岛素的颗粒。在另一种具体实施方式中，颗粒可以包含至多50重量％的胰岛素。
活性剂(例如但不限于包含在溶液或悬浮液中的胰岛素)与二酮哌嗪悬浮液混合，其中，溶液或悬浮液是在对于活性剂和二酮哌嗪都适合的溶剂中。
在某些实施方式中，本发明提供了一种获得干燥粉末的方法，所述干燥粉末包含二酮哌嗪和例如胰岛素的活性剂，具有改善的药物性质，所述方法通过在约15-18℃的受控温度下使颗粒从溶液中沉淀来实现。在其它实施方式中，受控温度为约17℃。在其它实施方式中，受控温度小于或等于约13℃或大于或等于约19℃。
在本发明的其它实施方式中，所用术语“药盒填充重量”是指，吸入器药盒中包含的药品的量，通常为5-10mg或更多。在其它实施方式中，药盒填充重量可为约2.5-15mg、10-20mg或5-30mg。
在其它实施方式中，与冷冻干燥的类似粉末相比，喷雾干燥的粉末的体积密度或震实(tapped density)密度增大。在一种这样的实施方式中，密度增加到约2倍(1.7-2.3倍)。其它具体实施方式包括那些限于实施例中公开的值或由这些值中的任何两个构成上下限的范围。在各种实施方式中，喷雾干燥粉末的体积密度为0.150-0.200g/cc。具体实施方式包括那些限于实施例中公开的值或由这些值中的任何两个构成上下限的范围。在各种实施方式中，喷雾干燥粉末的震实密度(tapped density)为0.250-0.300g/cc。具体实施方式包括那些限于实施例中公开的值或由这些值中的任何两个构成上下限的范围。
在本发明的另一种实施方式中，所用术语“药盒排空率(Cartridge Emptying)”是指活化(或排放)时从吸入器排出的粉末的百分比(％)。该值通常通过在排放前后对药盒进行称重来获得。具体实施方式包括那些限于实施例中公开的值或由这些值中的任何两个构成上下限的范围。
在本发明的另一种实施方式中，所用术语“可吸入分数(RF)”是指可吸入范围(0.5-5.8μm)内的颗粒的百分比(％)。“输送的可吸入分数(RF)”是指能够达到发挥药效的肺部气管的活性成分的百分比。具体实施方式包括那些限于实施例中公开的值或由这些值中的任何两个构成上下限的范围。
在本发明的另一种实施方式中，所用术语“基于填充量的可吸入分数”(“基于填充量的RF”、“填充量RF％”或“RF％/填充量”)是指，用吸入器中的粉末量来标准化的可吸入范围内的粉末的百分比(％)。具体实施方式包括那些限于实施例中公开的值或由这些值中的任何两个构成上下限的范围。
附图说明
以下附图构成本说明书的一部分，用于进一步说明本实施例的特定方面。通过以下附图，并结合具体实施方式的详细描述，可以更好地理解本发明。
图1示出了增大的雾化压力有利于二酮哌嗪-胰岛素制剂的气动性质。进口温度为110-140℃，出口温度保持75℃不变。
图2A-2E示出了二酮哌嗪-胰岛素制剂的加速稳定性平价。加速稳定性条件为维持40℃和75％RH(相对湿度)10天。图2A示出了喷雾干燥制剂中的胰岛素损失的减少。图2B示出了相应的A-21(胰岛素在这些条件下的主要降解产物)形成的减少。图2C-2E示出了当雾化压力从0.4bar(图2C)增至0.6bar(图2D)再增至0.7bar(图2E)时，初始颗粒呈现出降低的团聚趋势。测量结果通过激光衍射法获得。
图3示出了温度对二酮哌嗪-胰岛素制剂的气动性的影响。出口温度保持在75℃，雾化压力保持在0.6bar。填充量RF％(基于药盒填充量的可吸入分数百分比)在温度范围内保持相对一致。
图4A-4F示出了提高的进口温度(干燥速率)对制剂的稳定性没有不利的影响。加速稳定性条件是保持40℃和75％RH10天。图4A示出了胰岛素的损失百分比。图4B示出了最普遍的降解产物A-21的形成。图4C-4F示出了当进口温度从105℃(图4C)升至120℃(图4D和4E)再升至140℃(图4F)时，初始颗粒团聚的趋势增大(以激光衍射法得到的颗粒尺寸分布表示)。
图5A-5E示出了胰岛素分布和颗粒形态。图5A示出了胰岛素在整个制剂中平均分布，而与颗粒尺寸无关。图5B-5E示出了喷雾干燥颗粒的形态(图5C和5E)和冷冻干燥颗粒的形态(图5B和5D)。
图6A-6B示出了颗粒气动性和胰岛素稳定性的改善。图6A示出了基于填充量的RF％随着雾化压力增大(0.7、0.9和1.1bar)而增加。图6B示出了基于填充量的RF％随着进口温度升高(110℃、120℃和130℃)而不发生变化。
图7A-7K示出了胰岛素稳定性在较高的进口温度和雾化压力下提高。图7A示出了以粉末的胰岛素损失百分比表示的加速稳定性的测量结果，其中所述粉末是在0.7bar的压力和110℃、120℃和130℃的进口温度下喷雾干燥的。图7B示出了以粉末的胰岛素损失百分比表示的加速稳定性的测量结果，其中所述粉末是在1.1bar的压力和110℃、120℃和130℃的进口温度下喷雾干燥的。图7C-7K示出了当雾化压力从0.7bar到1.1bar变化并且进口温度分别为110℃、120℃和130℃时，初始颗粒的最小团聚趋势(以激光衍射法得到的颗粒尺寸分布表示)，
图8示出了将11.4％的冷冻干燥的FDKP/胰岛素和11.4％的喷雾干燥的FDKP/胰岛素吹入大鼠体后的药效性(血糖降低)比较。每只大鼠接受3mg的包含11.4重量％胰岛素的粉末。每组包括4只大鼠。
图9示出了喷雾干燥或冷冻干燥的FDKP/胰岛素粉末的气动性能。对两组悬浮液(以方块和圆圈表示)进行测试。空心符号表示喷雾干燥粉末，实心符号表示冷冻干燥粉末。
图10A-10B示出了稳定性数据，数据表明，与冷冻干燥粉末相比，喷雾干燥粉末中的胰岛素损失(图10A)和A-21形成(图10B)均减少。两种粉末均在干燥之前调节至pH为4.5。
具体实施方式
任何药物颗粒的成功不仅仅取决于它在治疗疾病或病症时的效果，还必须具有超过其它已知治疗方法的药物性质。对于干燥粉末颗粒，期望的药物性质包括改善的气动性、药效性和稳定性。然而，制造具有这些性质的颗粒目前在本领域中是一个挑战。实现此目标的一种途径涉及制造颗粒所使用的方法。
因此，本发明提供了新颖且出乎意料的发现：通过优先使用喷雾干燥而非冷冻干燥，将溶剂从颗粒中去除，通常可以改善干燥粉末的药物性质。
本发明可以克服现有技术的缺点，这通过提供与活性剂结合的二酮哌嗪(DKP)颗粒来实现，所述颗粒通过使干燥粉末具有改善的药物性质的工艺来加载和/或干燥。在具体实施方式中，本发明提供了一种颗粒，该颗粒包含结合胰岛素的二酮哌嗪，并通过喷雾干燥来干燥。本发明还提供了一种喷雾干燥粉末，与先前公开的冷冻干燥粉末相比，本发明的粉末具有改善的稳定性、气动性或较大的密度，同时保持至少类似的药效性，其中所述冷冻干燥粉末参见名称为“Purification and Stabilization of Peptide and ProteinPharmaceutical Agents”的美国专利US6,444,226以及名称均为“Method of DrugFormulation Based on Increasing the Affinity of Active Agents for CrystallineMicroparticle Surfaces”、分别于2005年9月14日和2006年9月14日提交的美国专利申请No.60/717,524和11/532,063，通过引用将这些文献中关于二酮哌嗪微粒组合物的内容结合在本文中。
可以通过各种方法形成用于药物输送的二酮哌嗪颗粒并加载活性剂。二酮哌嗪溶液可以与活性剂的溶液或悬浮液混合，然后沉淀以形成包含活性剂的颗粒。或者，DKP可沉淀形成颗粒，然后与活性剂溶液混合。颗粒与活性剂之间的缔合可自发产生，或通过去除溶剂来驱动或在干燥之前可包括一个特定步骤，或者这些促进缔合的机制的任意组合。
在一种具体方案中，将沉淀的二酮哌嗪颗粒洗涤，添加胰岛素溶液，通过向液氮中逐滴添加使混合物冻结，然后将得到的冻结微滴(微粒)冷冻干燥，以得到二酮哌嗪-胰岛素干燥粉末。在其它实施方式中，可以通过其它方法(例如，喷雾)将混合物分散到液氮中。在其它方案中，将本发明的沉淀二酮哌嗪颗粒洗涤，添加胰岛素溶液，调节溶液的pH以促进胰岛素吸附在颗粒上，然后通过喷雾干燥或冷冻干燥去除溶剂，以得到二酮哌嗪-胰岛素干燥粉末。以前，冷冻干燥被用于去除溶剂，并且人们期望使用喷雾干燥可以得到类似的结果。如本文所公开，令人惊讶地发现，喷雾干燥的干燥粉末具有改善的药物特性。具体地，喷雾干燥粉末具有改善的可吸入分数(RF％)，颗粒中包含的胰岛素具有更大的对降解的稳定性，并且颗粒具有更大的密度以使更高的剂量被加载到任何特定的体积。在肺部给药之后，至少相当量的胰岛素被输送到血流中，这通过至少相当的血糖减少来证实。喷雾干燥粉末的性能优于冷冻干燥粉末，无论冷冻干燥样品的制备是否包括pH调节以促进药物与颗粒缔合。
在另一种改进方法中，对DKP从其中沉淀的溶液的温度进行控制。令人惊讶地，FDKP颗粒在小于约13℃或大于约19℃的温度下从溶液中沉淀，使用冷冻干燥去除溶剂，得到具有较大RF％的干燥粉末。对于在约17℃下从溶液中沉淀的FDKP颗粒，使用喷雾干燥去除溶剂，得到具有较大RF％的干燥粉末。对于测试范围的其它部分，两种干燥方法得到的气动性能类似。因此，通过基于颗粒从其中沉淀的溶剂的温度选择溶剂去除方法，可以优化DKP颗粒的气动性能。如本文提供的实施例中所述，得到的干燥粉末由其气动性质(RF％、药盒排空率、RF％/填充量、质量中位气动直径[MMAD]、几何标准差[GSD])和物理化学性质(胰岛素含量[％加载量]、产率、密度)来表征。
令人惊讶地，喷雾干燥颗粒的密度约为冷冻干燥颗粒的密度的两倍。这对于提供较高的剂量是有利的。干燥粉末吸入器通常施加的粉末体积有限，因此单次操作可输送的活性剂的剂量也有限。密度较高的粉末(至少可吸入分数相似)可使单次操作施加的剂量更大，而不必每次服药进行更多次操作，也无需活性剂加载量％较高的制剂，或者设计吸入器或吸入器药盒以容纳各种体积的粉末。这些替代性方法具有较大的开发和/或生产成本，并且引起了产品复杂性的问题。产品复杂性和每次服药需要多次操作的要求额外产生了产品可接受性和患者依从性的问题。因此，出乎意料的粉末密度的增加对于使用喷雾干燥粉末作为药物产品来说具有多种优点。
1.通过喷雾干燥制备预成形颗粒
本发明中使用的喷雾干燥是一种热处理方法，用于在液体介质(溶剂)的悬浮液中加载和/或干燥颗粒。如实施例中所公开，将二酮哌嗪的悬浮液与胰岛素溶液混合。然后，一些或全部的胰岛素分子结合到二酮哌嗪颗粒上。在各种实施方式中，然后通过喷雾干燥将二酮哌嗪-胰岛素颗粒加载和/或干燥，得到干燥粉末。在另一种实施方式中，在颗粒沉淀之前将活性剂加入二酮哌嗪溶液。
在喷雾干燥过程中，通过喷嘴(例如双流体喷嘴或高压喷嘴)、转盘或等同设备将二酮哌嗪颗粒或二酮哌嗪-胰岛素颗粒的水性混合物引入加热气体流。在穿过加热气体流之前，溶液或悬浮液被雾化成精细微滴。气体流供应的热能造成其中悬浮有颗粒的水或其它溶剂蒸发，从而制备出干燥粉末组合物。
在本发明的实施方式中，在获得包含结合有胰岛素的二酮哌嗪的干燥粉末时，本发明人发现，与通过冷冻干燥得到的类似颗粒相比，喷雾干燥方法得到的颗粒通常具有更好的药物性质。在获得颗粒时，本发明人考虑了多个参数。这些参数包括温度、雾化压力、悬浮液的固体含量、胰岛素损失百分比、A-21的形成、颗粒的团聚以及气动和生物性能。
进口温度是离开气体源的气体流的温度。出口温度是粉末制剂最终温度的度量，并且是用于干燥的进口空气的能量利用率的指示，其为进口温度和干燥产品所需热负荷以及其它因素的函数。基于被处理的大分子的不稳定性来选择出口温度。
二酮哌嗪/活性剂混合物可以是悬浮液。溶剂(通常为水)迅速从微滴中蒸发，得到精细的干燥粉末。
喷雾干燥在可得到组成均匀的粉末的条件下进行，所述粉末具有可吸入的颗粒尺寸、低水分含量并且具有适合烟雾化的其它特性。优选地，所得粉末的颗粒尺寸可使超过约98质量％的颗粒的直径为约10μm或更小，并且约90质量％的颗粒的直径小于5μm。或者，约95质量％的颗粒的直径小于10μm且约80质量％的颗粒的直径小于5μm。在某些实施方式中，干燥粉末的以直径表示的平均颗粒尺寸为1-5μm。上述实施方式特别涉及将粉末用于肺部输送。平均颗粒尺寸可以影响颗粒沉积在呼吸道中的位置，并且还可以影响颗粒的整体操作性质。例如，对于平均直径大于20μm的颗粒，鼻腔沉积是有利的。在其它实施方式中，粉末可用于形成药片、封装在胶囊中或重新悬浮以用于口服或注射。因此，在各种实施方式中，干燥粉末包含的颗粒的平均颗粒尺寸可大于约10μm、20μm、30μm、40μm、50μm、60μm、70μm、80μm、90μm、100μm。在另一种实施方式中，干燥粉末包含的颗粒的平均颗粒尺寸可为约100-500μm。在其它实施方式中，干燥粉末包含的颗粒的平均颗粒尺寸可小于约1mm。
本发明的包含活性剂和二酮哌嗪的悬浮液可在常规喷雾干燥设备被喷雾干燥，从而得到由这种颗粒组成的干燥粉末，其中所述设备例如是本领域公知且可从供应商(NiroInc.、Columbia、MD)购得的PHARMASDTM PSD-1喷雾干燥器或SD-MicroTM喷雾干燥器。应当注意还可以使用其它常规的喷雾干燥设备。
在进行喷雾干燥实验时，可以采用诸如旋转雾化、加压雾化和双流体雾化(例如并流双流体喷嘴和/或自流双流体喷嘴)的方法。喷雾干燥法中使用的设备是本领域技术人员公知的。
尽管对喷雾工艺中使用的雾化器的喷嘴没有特殊限制，但对于可以制造具有适合鼻腔、咽喉或肺部给药的颗粒直径的喷雾干燥组合物的喷嘴，本领域中建议使用以下实例中的喷嘴。例如，喷雾干燥器可以使用1A、1、2A、2、3型喷嘴(Yamaμo Chemical Co.生产)或SB系列
Figure BDA0000531887650000121
喷嘴(Spraying Systems Co.生产)。此外，可以使用MC-50、MC-65或MC-85型盘(Okawara Kakoki Co.生产)作为喷雾干燥器雾化器的转盘。
在其它实施方式中，用于干燥被喷雾材料的进口气体温度不能导致活性剂热失活。进口温度的范围可在约50-200℃之间变化，优选在约110-160℃之间变化。对于很稳定的试剂，进口温度可超过200℃。用于干燥被喷雾材料的出口气体的温度可在约35-100℃、优选55-85℃之间变化。在其它实施方式中，出口温度可优选为75℃。在本发明的另一种实施方式中，进口和出口温度可分别保持在120℃和75℃。
在本文中，本发明的方法和组合物适用的术语如下：
术语“粉末”是指一种组合物，该组合物由能够分散在吸入装置中并可被患者吸入的精细固体颗粒组成。在优选实施方式中，颗粒到达肺或肺泡。这样的粉末被称作是“可吸入”的。优选地，在相对均匀的球形分布下，以直径表示的平均颗粒尺寸小于约10微米(μm)。更优选地，直径小于约7.5μm，最优选小于约5.0μm。通常，以直径表示的粒尺寸分布为约0.1-8μm，特别为约0.3-5μm。
术语“干燥”是指粉末组合物不悬浮或溶解在推进剂、载体或其它液体中。但这并不意味着完全不含水。组合物可以具有一定的水分含量，以使颗粒易于分散在吸入装置中以形成气溶胶。该水分含量通常小于约10重量％，往往小于约5重量％，优选小于约3重量％。
术语“有效量”是引起待治疗患者的期望响应所需的量。精确剂量根据各种因素会有所不同，这些因素包括但不限于，患者的年龄和尺寸大小、疾病类型和治疗方法。“有效量”还取决于预期的药效学响应或生物有效性。
2.二酮哌嗪
二酮哌嗪可被形成为结合活性剂的颗粒或活性剂吸附于其上的颗粒。本发明的二酮哌嗪包括但不限于，3，6-二(富马酰基-4-氨基丁基)-2，5-二酮哌嗪，也称为(E)-3，6-二[4-(N-羧基-2-丙烯基)酰胺基丁基]-2，5-二酮哌嗪(还可被称为富马酰基二酮哌嗪或FDKP)。
本发明中可用的其它二酮哌嗪包括3，6-二(4-氨基丁基)-2，5-二酮哌嗪、3，6-二(琥珀酰基-4-氨基丁基)-2，5-二酮哌嗪(琥珀酰基二酮哌嗪或SDKP)、3，6-二(马来酰基-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康基-4-氨基丁基)-2-5-二酮哌嗪、3，6-二(戊二酰基-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰基-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰基-4-氨基丁基)-2，5-二酮哌嗪及其衍生物。
简言之，二酮哌嗪可通过氨基酸酯衍生物的环二聚化来形成，如Katchalski等所述(J.Amer.Chem.Soc.68：879-80；1946)；或通过氨基酸衍生物在高沸点溶剂中加热脱水来形成，如Kopple等所述(J.Org.Chem.33(2)：862-64；1968)，将上述文献的教导结合在本文中。
合成和制备二酮哌嗪的方法对于本领域普通技术人员来说是公知的，描述在美国专利US5,352,461、5,503,852、6,071,497、6,331,318和6,428,771以及美国专利申请No.11/208,087中，通过引用将上述文献中关于二酮哌嗪的全部内容结合在本文中。美国专利No.6,444,226描述了制备二酮哌嗪微粒、提供二酮哌嗪微粒的水悬浮液、并将活性剂溶液添加到其水悬浮液中，通过引用将该专利关于二酮哌嗪微粒的全部内容结合在本文中。该专利还描述了一种通过冷冻干燥去除液体介质的方法，从而得到包含活性剂的微粒。另外参见美国专利No.6,440,463和2006年9月14日提交的美国专利申请No.11/532,063和11/532,025以及2005年9月14日美国临时专利申请No.60/717,524，通过引用将上述文献中关于二酮哌嗪微粒的全部内容结合在本文中。
本发明的二酮哌嗪-胰岛素颗粒制剂可通过各种给药途径来给药。作为干燥粉末，依赖于颗粒尺寸，这些颗粒可通过吸入被输送到呼吸系统的特定区域。另外，颗粒可被制成足够小，用于结合到静脉悬浮液剂型中。当颗粒结合到悬浮液、药片或胶囊中时，也可以采用口腔输送。
3.活性剂
本发明的实施方式使用活性剂与二酮哌嗪结合的颗粒。本文中的术语“活性剂”是指将封装、缔合、结合、复合或夹带在本发明的二酮哌嗪中的治疗剂或分子(例如蛋白质、肽或生物分子)。一般来说，任何形式的活性剂均可与本发明的二酮哌嗪结合。本发明的活性剂可以带电或不带电。
可用于本文所述的组合物和方法中的活性剂可包括任何聚合物或有机大分子，最优选肽和蛋白质。实例包括具有治疗、预防或诊断活性的合成有机化合物、蛋白质和肽、多糖和其它糖、脂质和核酸序列。活性剂还可包括小分子和维生素。本发明的活性剂还可以是血管活性剂、神经活性剂、激素、调节新陈代谢、重量或血糖水平的试剂、抗凝血剂、免疫调节剂、细胞毒性剂、抗菌素、抗病毒剂、反义分子或抗体。
上面列出了活性剂的具体实例。在本发明的具体实施方式中，活性剂是胰岛素或其类似物。本领域已知具有较快、较慢、较短或较长的作用形态的类似物。这种类似物包括具有改变的氨基酸序列的那些和用其它基团(例如聚乙二醇)或其它氨基酸(例如在融合蛋白中)共价改性的那些。最终，活性剂包括具有野生型胰岛素分子的实质部分和生理学相关的胰岛素活性的任何分子。
在本发明中，蛋白质被定义为由100或更多个氨基酸残基构成；此外，本发明中的肽具有少于100个的氨基酸残基。
3.本发明中的稳定剂
在其它实施方式中，本发明可以使用稳定剂，该稳定剂可包含在悬浮液或溶液中，所述悬浮液或溶液包含二酮哌嗪和可结合到颗粒制剂中的活性剂。
为了干燥工艺时的构象稳定性，可以引入稳定剂。此外，这些稳定剂还可改善本发明的二酮哌嗪-胰岛素颗粒制剂干燥粉末的气动性或生物有效性。这样的稳定剂可包括但不限于，糖、表面改性剂、表面活性剂、例如色氨酸、酪氨酸、亮氨酸、苯丙氨酸的疏水性氨基酸、药物载体或赋形剂等。
本发明的稳定剂优选适合呼吸和肺部给药的那些。在某些实施方式中，优选稳定剂同时结合到二酮哌嗪-胰岛素颗粒中，以形成均相粉末。或者，稳定剂可独立地制备成干燥粉末形式，然后通过混合与喷雾干燥二酮哌嗪-胰岛素颗粒结合。
在其它实施方式中，可以使用粉末载体，例如但不限于，碳水化合物，例如单糖，如果糖、半乳糖、葡萄糖、D-甘露糖、山梨糖等；二糖，例如乳糖、海藻糖、纤维二糖等；环糊精、2-羟丙基-β-环糊精；多糖，例如蜜三糖、麦芽糊精、葡聚糖等；氨基酸，例如甘氨酸、精氨酸、天冬氨酸、谷氨酸、半胱氨酸、赖氨酸等；由有机酸和碱制备的有机盐，例如柠檬酸钠、抗坏血酸钠、葡糖酸镁、葡糖酸钠、氨基丁三醇盐酸等；肽和蛋白质，例如阿斯巴甜(Aspartame)、人血清白蛋白、明胶等；多羟糖醇，例如木糖醇等。优选的一组载体包括海藻糖、蜜三糖、麦芽糊精、甘氨酸、柠檬酸钠、氨基丁三醇盐酸、人血清白蛋白和甘露醇。这样的粉末载体通常为晶体(以避免吸收水)，但在某些情况下可以是晶体和非晶体的混合物。稳定剂颗粒的尺寸可被选择以改善喷雾干燥粉末产品的流动性。
本发明中的糖包括但不限于葡萄糖、乳糖和甘露糖。
本发明中的表面活性剂包括但不限于聚山梨醇酯80(PS80)、卵磷脂(lecithin)、卵磷脂(phosphatidylcholine)、磷脂胆碱、DPPC、十二烷基磺酸钠和离子型除垢剂。
实施例
以下实施例用于说明本发明的实施方式。本领域技术人员应当理解，实施例中与本发明人发现的代表性技术一起公开的技术可以有效地用于实施本发明，因此这些技术被认为构成了实施本发明的优选方式。然而，根据本说明书，本领域技术人员应当认识到，在不脱离本发明的精神和范围的前提下，还可以对具体实施方式进行许多改变，同时获得相同或类似的效果。
实施例1
雾化压力对气动性、稳定性和团聚性的影响
将二酮哌嗪衍生物3，6-二[N-富马酰基-N-(正丁基)氨基]-2，5-二酮哌嗪(也称为3，6-二(富马酰基-4-氨基丁基)-2，5-二酮哌嗪、富马酰基二酮哌嗪或FDKP；还被称为(E)-3，6-二[4-(N-羧基-2-丙烯基)酰胺基丁基]-2，5-二酮哌嗪)沉淀并洗涤。通过将pH调节到约4.45，将胰岛素加载到FDKP颗粒上，然后将FDKP-胰岛素颗粒喷雾干燥以得到FDKP-胰岛素干燥粉末。如2006年9月14日提交的美国专利申请No.11/532,063和11/532,025以及2005年9月14日提交的美国临时专利申请No.60/717,524所公开，约4.45的pH被发现可以提高胰岛素与FDKP颗粒的结合能力。
干燥粉末由各种气动性质(RF％、药盒排空率、RF％/填充量、质量中位气动直径[MMAD]和几何标准差[GSD])来表征。
表1和图1表明了雾化(喷嘴)压力对颗粒气动性能的影响。喷嘴压力范围为0.4-1.1bar(表1)。随着雾化压力从0.4bar升至1.1bar，基于填充量的可吸入分数(填充量RF％)提高。
表1.雾化压力对气动性的影响(出口温度为75℃)
Figure BDA0000531887650000161
Figure BDA0000531887650000171
胰岛素的稳定性被评价为胰岛素损失百分比(图2A)以及在应力条件(在40℃，75％RH下10天)下转化成胰岛素降解产物A21脱酰氨胰岛素的百分比(A21％)(见图2B)。为了比较，每个图中的最下方数据条代表冷冻干燥颗粒得到的数据。数据表明，随着雾化压力上升，二酮哌嗪-胰岛素颗粒中的胰岛素的稳定性存在增大的一般趋势。与冷冻干燥颗粒相比，对于所有的喷雾干燥颗粒，观察到形成的A21胰岛素降解产物较少(图2B)。
为了评估初始颗粒的团聚性，使用Malvem Mastersizer2000对喷雾干燥颗粒的悬浮液进行激光衍射，从而确定颗粒尺寸分布。在上述实验条件下，随着雾化压力升高，观察到初始二酮哌嗪-胰岛素颗粒团聚减少的趋势(图2C-2E)。随着雾化压力从0.4bar(图2C)升至0.6bar(图2D)再升至0.7bar(图2E)，观察到右侧峰(代表团聚颗粒)的尺寸减小。
实施例2
进口温度对气动性、稳定性和颗粒团聚性的影响
使用如上制备的颗粒，评价喷雾干燥器进口温度和工艺规模，如下表2所示。在这些实验中，进口温度从105℃到140℃变化，出口温度保持75℃不变。喷嘴压力保持0.6bar不变。
注意到，为了保持出口温度稳定，进口温度升高需要喷雾速率增大(表2)。增大的喷雾速率以更大的生产率制造干燥颗粒。评价喷雾干燥颗粒的气动性(表2)。在实验采用的温度范围内，基于填充量的RF％保持稳定(图3)。
表2.进口温度对颗粒气动性的影响(喷嘴压力保持在0.6bar，出口温度为75℃)
Figure BDA0000531887650000181
此外，数据表明，升高进口温度(干燥速率)对颗粒上的胰岛素的稳定性没有不利影响。随着进口温度升高，存在胰岛素稳定性增大的趋势。以在40℃/75％RH下10天后的胰岛素损失和形成的A21(图4A和4B)来测定稳定性。然而，在上述实验条件下，随着进口温度升高，观察到初始二酮哌嗪-胰岛素颗粒存在团聚增多的趋势(图4C-4F)。
实施例3
胰岛素回收率和分布
在这些实验中，将已知质量的二酮哌嗪颗粒悬浮在水中。向悬浮液中添加已知浓度的足量胰岛素溶液，以使胰岛素的理论含量为11.4％。在喷雾干燥之前，将富马酰基二酮哌嗪-胰岛素浆液滴定到pH约为4.45。
如图5A所示评价胰岛素在颗粒上的分布。这些实验使用Andersen级联采样器进行。将粉末填充到药盒中，并通过
Figure BDA0000531887650000182
吸入器排出到Andersen级联采样器中(
Figure BDA0000531887650000183
吸入器描述在名称为“Unit Dose Cartridge and Dry Powder Inhaler”的美国专利申请No.10/655,153中，通过引用将其关于吸入器装置的内容结合在本文中)。该采样器根据空气动力学尺寸将颗粒分类。在排出之后，从每一级回收粉末并分析胰岛素含量(加载量)。得知胰岛素均匀分布在制剂中。如表2所示，将规模(粉末克数)增大4倍，结果也是可以接受的。
利用扫描电子显微镜(SEM)比较喷雾干燥和冷冻干燥颗粒的颗粒形态。图5B-5E表明，冷冻干燥制剂的颗粒形态(图5B和5D)与喷雾干燥制剂的颗粒形态(图5C和5E)相当。
实施例1-3总结
以上数据表明：1)提高雾化压力，降低了初始颗粒的团聚性；2)升高进口温度，对颗粒气动性几乎无影响；3)升高进口温度，未观察到对胰岛素稳定性有不利影响；4)升高进口温度，导致初始颗粒更多地团聚；5)与组成相同的冷冻干燥颗粒相比，喷雾干燥颗粒具有更高的胰岛素稳定性；6)喷雾干燥颗粒的形态与冷冻干燥颗粒类似。
实施例4
确定喷雾干燥参数以使气动性能最优化
进一步评价进口温度和雾化压力，采用110、120和130℃的进口温度和0.7、0.7和1.1bar的雾化压力(表3)。
表3.喷雾干燥参数对颗粒气动性的影响
Figure BDA0000531887650000191
图6A示出了表3的结果，其为基于填充量的RF％与雾化压力的关系图。图6B为填充量RF％与进口温度的关系图。该数据表明，增大雾化压力可改善气动性能，而进口温度对气动性能无影响。
实施例5
进口温度和雾化压力对稳定性和团聚性的影响
分析表3所列样品的胰岛素稳定性和颗粒团聚性。如图7A和7B所示，结果与实施例1-3的结果一致：喷雾干燥样品比冷冻干燥粉末损失的胰岛素更少(图7A和7B的下方数据条；冷冻干燥样品中使用的颗粒的加载包括调节pH至4.5，如实施例1中所讨论，这增强了胰岛素与FDKP颗粒之间的结合)。
在升高进口温度和提高雾化压力的条件下评价初始二酮哌嗪-胰岛素颗粒的团聚性(图7C-7K)。在本实施例涵盖的范围内，通过激光衍射测得的颗粒尺寸分布一般对雾化压力和温度不敏感。在0.7bar和110℃和120℃的进口温度下观察到小程度的团聚，而在所有其它条件下均得到单峰分布。
与冷冻干燥样品对比，喷雾干燥样品的结果表明：1)提高雾化压力可以改善气动性；2)进口温度对填充量RF％的影响可忽略；3)胰岛素稳定性随进口温度升高而增大；4)进口温度和雾化压力升高，可减少初始胰岛素颗粒的团聚。
实施例6
喷雾干燥颗粒中的胰岛素的药效性
大鼠吹入研究得到的数据表明，喷雾干燥FDKP-胰岛素粉末具有至少与冷冻干燥材料相当的葡萄糖代谢清除率。图8示出了对大鼠吹入11.4％的冷冻干燥和喷雾干燥的FDKP-胰岛素颗粒后的药效曲线比较。可以看出，喷雾干燥FDKP-胰岛素粉末的葡萄糖下降空间与冷冻干燥FDKP-胰岛素粉末相当。
实施例7
喷雾干燥FDKP-胰岛素粉末的气动性和稳定性
以与上述类似的方式制备富马酰基二酮哌嗪(FDKP)-胰岛素颗粒。即，将颗粒与胰岛素溶液混合，得到包含11.4重量％胰岛素的颗粒，然后调节pH以促进胰岛素吸附在颗粒上。通过喷雾干燥或冷冻干燥将得到的颗粒悬浮液干燥。表4示出了使用商业规模的喷雾干燥器制备的两个200g的批量与类似的冷冻干燥样品的对比。测试整体粉末的气动性能。在评价胰岛素损失和A21(脱酰氨胰岛素)的形成之前，将另外的粉末样品在40℃/75％RH下保存15天。喷雾干燥粉末呈现出62％的基于填充量的平均可吸入分数(RF％/填充量)，而冷冻干燥粉末的平均值为54％。喷雾干燥粉末还表现出更好的稳定性。喷雾干燥粉末的胰岛素损失和A21形成约为冷冻干燥粉末的一半。
表4.喷雾干燥FDKP-胰岛素粉末的气动性和稳定性
Figure BDA0000531887650000211
*每个批量均以类似方式制备
实施例8
喷雾干燥和冷冻干燥FDKP-胰岛素粉末的表征
在另一种改进工艺中，FDKP溶液的进料温度被控制。制备富马酰基二酮哌嗪(FDKP)的原料溶液并冷却至11℃、13℃、15℃、17℃或19℃，然后沉淀FDKP颗粒。采用两种不同的方法来加载和干燥颗粒。在一种方法中，将沉淀的二酮哌嗪颗粒洗涤，添加胰岛素溶液，并调节pH以促进胰岛素吸附在颗粒上，通过逐滴添加到液氮中将混合物冻结，然后将所得颗粒冷冻干燥(冻干)以得到二酮哌嗪-胰岛素干燥粉末。在另一种方法中，将沉淀的二酮哌嗪颗粒洗涤，添加胰岛素溶液，调节pH，然后将二酮哌嗪-胰岛素颗粒悬浮液喷雾干燥，得到二酮哌嗪-胰岛素干燥粉末。
制备两组重复样品，干燥粉末由气动性能(RF％/填充量、药盒排空率、质量中位气动直径[MMAD]和几何标准差[GSD])来表征。这些数据列于表5。这些样品的RF％/填充量示于图9。图10A和10B中比较了粉末的稳定性。如上所述，喷雾干燥粉末比冷冻干燥样品呈现出较少的胰岛素损失和较少的A21(脱酰氨胰岛素)形成。
评价喷雾干燥和冷冻干燥的FDKP-胰岛素粉末的体积密度和震实密度。用体积密度和震实密度来表征这两组重复样品。表5示出了，喷雾干燥粉末的密度比冷冻干燥粉末大(倍数约为2)。喷雾干燥材料的平均体积密度和震实密度分别为0.2g/cc和0.29g/cc。冷冻干燥FDKP-胰岛素的平均体积和震实密度分别为0.09g/cc和0.13g/cc。这些结果是出乎意料和令人惊讶的。密度的增加使得单个药盒可装有更多的粉末，从而提供更高的剂量。
表5.溶液温度对喷雾干燥和冷冻干燥FDKP-胰岛素颗粒的影响
Figure BDA0000531887650000221
NM-未测量
除非另有指明，本说明书和权利要求书中使用的表示成分数量，以及分子量、反应条件等性质的所有数字都应当被理解为：在所有情况下，用术语“约”加以了修饰。因此，除非有相反含义的说明，本说明书和所附权利要求书中示出的数量参数都是约数，它们可以根据本发明想要获得的性质而变动。至少，并且并非对权利要求书范围等同原则的应用加以限制，每个数量参数至少应按照报道的有效数字的数，以及应用普通的凑整技术来解释。虽然示出本发明宽广范围的数字范围和参数是约数，但是特别实施例中所示的数值却被尽可能地精确报道。但是，任何数值，必然含有一定误差，这是它们各自的检验测量方法中发现的标准偏差必然导致的。
本领域技术人员容易理解，在不脱离本发明的范围和精神的前提下，可对本发明进行各种改进。
在本文中，在权利要求书和/或说明书中与“包括”一起使用的“一个”一般表示“一个”，但其表示的意思与“一个或多个”、“至少一个”和“一个或多于一个”也是一致的(除非另有明示)。
本文中数值范围的叙述仅仅用作该范围内每个单独的值的速记方法。除非本文另有指明，每个单独的值被包括进说明书，这与在本文个别叙述一样。
本文所述的任何方法或组合物可通过本文所述的任何其它方法或组合物来实现。
除非明确指出某个可选方式或可选方式之间互相排斥，尽管说明书支持某个可选方式和“和/或”的表述，但是权利要求中所用术语“或”是指“和/或”。
在本文中，术语“约”所表示的值包括确定该值所用设备或方法的标准偏差。
根据本文提供的具体描述，可以清楚地看出本发明的其它目的、特征和优点。然而应当理解，详细描述和具体实施例仅为示例性，而本领域技术人员根据这些详细描述在本发明的精神和范围内可以作出各种改变和改进。

Claims (34)

1.一种制备具有优化的气动性能的组合物的方法，所述组合物包含二酮哌嗪干燥粉末，所述方法包括步骤：
在15℃-18℃的受控温度下从溶液中沉淀富马酰基二酮哌嗪以形成颗粒；
在悬浮液中对所述颗粒加载胰岛素；并且
在105℃-140℃的进口温度下将所述悬浮液喷雾干燥，以形成干燥粉末。
2.如权利要求1的方法，其中所述受控温度为17℃。
3.如权利要求1的方法，其中所述胰岛素占干燥粉末制剂的重量比为3-50％。
4.如权利要求3的方法，其中所述胰岛素占干燥粉末制剂的重量比为7-19％。
5.如权利要求4的方法，其中所述胰岛素占干燥粉末制剂的重量比为11％。
6.如权利要求4的方法，其中所述胰岛素占干燥粉末制剂的重量比为15％。
7.由权利要求1-6中任意一项的方法制造的干燥粉末。
8.如权利要求7的干燥粉末，其具有0.25-0.30g/cc的震实密度。
9.如权利要求7的干燥粉末，其具有0.15-0.20g/cc的体积密度。
10.如权利要求7的干燥粉末，其用于制造将胰岛素输送至需要的患者的药物。
11.一种制备具有改善的药物性质的干燥粉末药物的方法，包括步骤：
提供富马酰基二酮哌嗪溶液；
提供活性剂的溶液，其所述活性剂包含胰岛素或具有野生型胰岛素分子的实质部分和生理学相关的胰岛素活性的任何分子；
通过在15-18℃的受控温度下从所述富马酰基二酮哌嗪溶液中沉淀富马酰基二酮哌嗪以形成二酮哌嗪颗粒；和
将二酮哌嗪颗粒与所述活性剂的溶液结合；然后
通过在105℃-140℃的进口温度下喷雾干燥去除溶剂以得到干燥粉末，
其中所述干燥粉末与通过冷冻干燥去除溶剂得到的干燥粉末相比具有改善的药物性质。
12.如权利要求11的方法，其中所述改善的药物性质选自改善的活性剂稳定性、提高的粉末密度以及改善的干燥粉末气动性能。
13.如权利要求11的方法，其中所述活性剂是胰岛素。
14.如权利要求13的方法，其中所述胰岛素占干燥粉末制剂的重量比为3-50％。
15.如权利要求14的方法，其中所述胰岛素占干燥粉末制剂的重量比为7-19％。
16.如权利要求15的方法，其中所述胰岛素占干燥粉末制剂的重量比为11％。
17.如权利要求15的方法，其中所述胰岛素占干燥粉末制剂的重量比为15％。
18.如权利要求11的方法，其中所述改善的药物性质是改善的颗粒的活性剂的稳定性。
19.如权利要求11的方法，其中所述改善的药物性质是改善的颗粒的气动性能。
20.如权利要求11的方法，其中所述改善的药物性质是增大的粉末密度。
21.如权利要求19的方法，其中所述气动性能通过基于药盒填充量的可吸入分数百分比来测定。
22.如权利要求21的方法，其中可吸入分数百分比大于40％。
23.如权利要求21的方法，其中可吸入分数百分比大于50％。
24.如权利要求21的方法，其中可吸入分数百分比大于60％。
25.根据权利要求11的方法制备的干燥粉末。
26.如权利要求25的干燥粉末，其中所述活性剂是胰岛素或具有野生型胰岛素分子的实质部分和生理学相关的胰岛素活性的任何分子。
27.一种制备具有改善的药物性质的干燥粉末药物的方法，包括步骤：
在溶液中提供富马酰基二酮哌嗪；
通过在15-18℃的受控温度下从所述溶液中沉淀富马酰基二酮哌嗪以形成包含二酮哌嗪的颗粒的步骤；
对所述颗粒加载胰岛素；和
通过在105℃-140℃的进口温度下喷雾干燥去除溶剂以得到干燥粉末，
其中所述干燥粉末与通过冷冻干燥去除溶剂得到的干燥粉末相比具有改善的药物性质。
28.有效量的如权利要求25的干燥粉末在制造药物中的应用，所述药物用于将胰岛素输送到需要的患者。
29.如权利要求27的方法，其中所述改善的药物性质是增大的粉末密度。
30.如权利要求29的方法，其中所述增大的粉末密度是通过冷冻干燥去除溶剂获得的干燥粉末的密度的1.7-2.3倍。
31.如权利要求20或29的方法，其中所述增大的粉末密度包括增大的震实密度。
32.如权利要求31的方法，其中所述增大的粉末密度包括增大的体积密度。
33.如权利要求31的方法，其中所述增大的震实密度是0.25-0.30g/cc。
34.如权利要求32的方法，其中所述增大的体积密度是0.15-0.20g/cc。
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