CN103732220A - 高容量二酮哌嗪微粒 - Google Patents
高容量二酮哌嗪微粒 Download PDFInfo
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- CN103732220A CN103732220A CN201280039893.XA CN201280039893A CN103732220A CN 103732220 A CN103732220 A CN 103732220A CN 201280039893 A CN201280039893 A CN 201280039893A CN 103732220 A CN103732220 A CN 103732220A
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Abstract
本发明公开了具有吸附药物或活性剂的高容量的二酮哌嗪微粒。具体来说，二酮哌嗪微粒是使用富马酰基二酮哌嗪而形成的，并且以大剂量包含药物用于通过经口吸入肺部输送来治疗疾病或失调。
Description
技术领域
本发明公开了具有携带和输送医药物质的高容量的二酮哌嗪微粒。具体来说，此微粒包含富马酰基二酮哌嗪（FDKP），富马酰基二酮哌嗪可用作肺部药物输送系统，用于治疗需要大剂量药物或活性剂的疾病或失调，例如用于治疗包括全身性或由内分泌引起的那些的疾病或失调，包括疼痛、糖尿病和肥胖症。
背景技术
多年来药物的输送已成为一个重要的问题，特别是当待输送的化合物通过口服给药给予被受试者而在到达其目标位置之前在胃肠道中所遇到的条件下不稳定时。例如，在许多情况下优选口服给药，特别是从易于给药、患者依从性和降低的成本方面来考虑。但是，口服给药时很多化合物（包括有机小分子、肽和蛋白质）不起作用或者展现出较低或多变的药效。这可能是因为药物在消化道的条件下不稳定或者因为它们未被有效吸收。
由于与口服药物输送有关的这些问题，所以开发了将药物输送至肺部的方案。例如，通常输送到肺部的药物被设计为对肺部组织起作用，例如血管扩张剂、表面活性剂、化疗剂、或者流感或其他呼吸系统疾病的疫苗。其他药物（包括核苷酸药物）已经被输送到肺部，因为肺部代表特别适合治疗的组织，例如囊性纤维化的基因治疗，其中将表达有缺陷的腺苷脱氨酶的逆转录病毒载体给药至肺部，来试图纠正缺陷的基因。
也可以将具有全身效应的试剂药物输送到肺部。将全身性试剂输送到肺部的好处包括大的表面积和易于通过肺部粘膜表面吸收。与肺部药物输送所有这些形式有关的一个问题是：由于使药物通过所有的天然屏障（例如沿气管排列的纤毛）和试图以均匀的体积和重量进行给药都很麻烦，所以难以将药物输送到肺部。此外，为了尽量减少咳嗽并防止肺部功能的任何损伤，降低输送到肺部的粉末的量对于被治疗的对象来说是有利的。随着为了输送适当剂量活性剂或增加活性剂的剂量所需要的粉末的量增加，肺部功能的损伤会是一个潜在的问题。因此，在设计并提供需要大量或大剂量活性剂来肺部输送的药物制剂时存在改善的空间，以便改善治疗和患者依从性。
发明概述
本发明提供了可以使药物输送到肺部得到改善的吸入系统、微粒和方法。本文中公开的实施方式通过提供具有药物吸附的高容量的二酮哌嗪微粒并得到具有高药物含量的粉末来实现改善的输送。由本发明的微粒制成的粉末可以以较小的粉末剂量输送更多的药物，这可以促进药物输送给患者。
在一个实施方式中，本文中的二酮哌嗪微粒在形成时具有多个结构域，每个结构域包含由多层多孔结晶材料包围的核，其中核或芯包含1至约850个体素（voxels），所述体素使用X-射线断层摄影术测得。在具体的实施方式中，微粒在每个域中平均包含大于1000个体素、或每个域中大于2000个体素。每个体素包含确定的立方体积元，其在每个边上测量约33nm，并且包含约3.6×10-23m3的体积。在一些实施方式中，二酮哌嗪微粒包含一个或多个结构域；每个域包含约2000个体素或大于2000个体素；其中对于几何尺寸从约0.5至约4μm的颗粒来说，微粒尺寸从约2000体素到约680000体素。在该实施方式中，颗粒具有约33000体素到约216000体素的质量加权平均颗粒尺寸。
在另一个实施方式中，提供了包含二酮哌嗪微粒的粉末；其中微粒具有范围从约500体素到约125000体素的数量加权（number-weighted）平均尺寸。在一个实施方式中，数量加权平均颗粒尺寸从约2000体素到100000体素；或从约40000体素到约85000体素。
在一个实施方式中，高容量颗粒是由二-3,6-(N-富马酰基-4-氨基丁基)-2,5-二酮哌嗪（富马酰基二酮哌嗪）微粒（FDKP）形成的，并且包含多个结构域；其中每个颗粒包含一个或多个结构域。在此实施方式中，肺部输送的典型的二酮哌嗪微粒包含从约1个域至约1000个域；从2至约800个域；或者从约50至约250个域。在具体的实施方式中，每个颗粒中域的数目平均为从约3至160个域，其中颗粒的几何直径为约0.5至4μm。
在一个实施方式中，FDKP微粒包含平均值从约250体素到约1370体素的数量加权域尺寸。
在一些实施方式中，高容量FDKP微粒包含体素加权（voxel-weighted）尺寸分布的域，具有范围从约300nm至约450nm或从约310nm至约445nm的平均物理尺寸，其通过Doman回转半径测得。
在一些实施方式中，二酮哌嗪微粒包含药物或活性剂，其中所述药物或活性剂是有机小分子、肽或蛋白质。内分泌激素的例子包括胰岛素、甲状旁腺激素、降钙素、胰高血糖素、胰高血糖素样肽1、胃泌酸调节素、催产素、CCK-8、PYY3-36、脑肠肽（ghrelin）和VIP（血管活性肠肽）、内分泌激素的类似物或活性片段。有机小分子的例子包括神经递质激动剂、神经递质拮抗剂、疼痛抑制剂（包括吗啡和吗啡衍生物）、曲坦（triptan）例如舒马曲坦（sumatriptan）和利扎曲坦（rizatriptan）、疫苗、抗炎剂、抗癌剂、细胞受体激动剂分子或细胞受体拮抗剂分子。
在另一个实施方式中，提供了形成富马酰基二酮哌嗪微粒的方法，其中所形成的微粒具有多个结构域，每个结构域包含由多层多孔结晶材料包围的核，并且其中域包含使用X-射线断层摄影术测得的大于500个体素。此方法包括：提供2.75重量%的富马酰基二酮哌嗪溶液；在约17℃至约22℃的温度下将等质量的约11重量%至约12重量%乙酸和约2.75重量%富马酰基二酮哌嗪溶液并且以0.05重量%浓度包含表面活性剂的溶液进料通过高剪切混合器，并收集富马酰基二酮哌嗪微粒。一些实施方式包括合成富马酰基二酮哌嗪微粒的方法，其包括：收集富马酰基二酮哌嗪微粒，其为将前体溶液进料通过高剪切混合器后的产物；其中前体溶液包含含有约11重量%至约12重量%乙酸的第一溶液、含有约2.75重量%富马酰基二酮哌嗪的第二溶液，并且前体溶液以约0.05重量%的浓度含有表面活性剂。在一个实施方式中，所使用的表面活性剂可以是例如聚山梨醇酯80。在某些实施方式中，此方法还可以包含用去离子水洗涤悬浮液的步骤以去除过量的酸。在另一个实施方式中，此方法包含向悬浮液中的微粒中加入含有活性成分（包括肽或小分子）的溶液，并用氨水溶液调节溶液的pH至约4.5，以促进活性成分吸附到颗粒上。
在另一个实施方式中，公开了给患有疾病或失调的患者输运活性剂的方法，其包括：向需要给其治疗的患者给药含有吸附到如本发明所描述的微粒上的用来治疗疾病或失调的活性剂的制剂。
在一个实施方式中，治疗的方法是针对肺部输送的。在一个具体的实施方式中，此方法用于治疗糖尿病，其包括向需要治疗的患者给药含有吸附到所形成的二酮哌嗪微粒上的胰岛素的干粉制剂，其中二酮哌嗪是富马酰基二酮哌嗪，并且微粒具有多个结构域，每个结构域包含由多层多孔结晶材料包围的核，并且其中核包含使用X-射线断层摄影术测得的大于500个体素，并且通过患者吸入所述干粉制剂来将微粒输送到肺部深处。在该实施方式和其他实施方式中，使用高阻力吸入系统来输送制剂。
在一个实施方式中，二酮哌嗪微粒具有多个结构域，每个结构域包含由多层多孔结晶材料包围的核，其中核包含使用X-射线断层摄影术测得的大于500个体素。二酮哌嗪微粒可以具有大于35m2/g的比表面积。在某些实施方式中，所提供的二酮哌嗪微粒具有大于70m2/g的高比表面积。在一个具体的实施方式中，由二-3,6-(N-富马酰基-4-氨基丁基)-2,5-二酮哌嗪（FDKP）形成的微粒具有约72m2/g至约94m2/g的比表面积。具有72m2/g至约94m2/g的高比表面积的微粒能够展现出有利于输送到肺部的特征，例如携带药物或活性物质的容量得到改善，同时药物吸附得到改善，这保持了优异的空气动力学性能。颗粒还展现出改善的稳定性。
在另一个实施方式中，二酮哌嗪微粒与药物相结合。在该实施方式中，药物是肽或蛋白质，例如激素，包括胰岛素、甲状旁腺激素、胰高血糖素、胰高血糖素样肽1等等。在另一个实施方式中，药物或活性剂可以是针对局部或全身性输送的药物，包括小分子诸如神经递质、疼痛缓解剂、血管活性剂、免疫抑制药、抗癌剂、疫苗、核酸分子和/或预防试剂。在某些实施方式中，待输送的药物可以包含曲坦，包括舒马曲坦、利扎曲坦和它们的盐。
在另一个实施方式中，二酮哌嗪微粒是在肺部输送用于治疗疾病或失调的药物或活性剂的干粉制剂中的二-3,6-(N-富马酰基-4-氨基丁基)-2,5-二酮哌嗪（富马酰基二酮哌嗪）微粒；其中药物或活性剂被吸附到预成型的颗粒上。微粒所吸附的药物的量取决于要配制的药物。
在一些实施方式中，二酮哌嗪微粒包含肽例如胰岛素，其中胰岛素含量例如对于由FDKP制成的微粒来说，大于4U/mg。在一个具体的实施方式中，FDKP微粒可以在每mg粉末制剂中包含6U/mg的胰岛素或更大量的胰岛素。在该实施方式中，包含约5U/mg胰岛素的FDKP微粒具有范围从约28m2/g至约71m2/g的比表面积，并且包含约6U/mg胰岛素的FDKP微粒具有例如范围从约19m2/g至57m2/g的比表面积。
其他实施方式涉及药物输送系统，其包括吸入器、单位剂量的干粉药剂容器、以及含有本文所公开的微粒和活性剂的粉末。
本文所公开的另一个实施方式包括给需要胰岛素的患者输送胰岛素的方法，其包括通过患者吸入干粉来给药含有本文所公开的二酮哌嗪微粒的干粉到肺部深处。在该实施方式的各个方面，指定了吸入器系统的具体特征。
在FDKP微粒的各种实施方式中，药物可以是例如肽，包括胰岛素、胰高血糖素样肽-1(GLP-1)、胰高血糖素、促胰岛素分泌肽、甲状旁腺激素、降钙素、胃泌酸调节素等。在FDKP微粒的另一个实施方式中，肽含量可以根据下游处理条件而变化。在一个具体的例子中，FDKP微粒可以制备成其药物/肽含量能够根据目标剂量或输送剂量变化。例如，其中药物是胰岛素，胰岛素组分可以在粉末制剂中大于4U/mg来降低输送给患者的粉末含量。
其他实施方式涉及药物输送系统，其包括吸入器、单位剂量的干粉药剂容器（例如药盒）、以及含有本文所公开的微粒和活性剂的粉末。在一个实施方式中，与干粉一起使用的输送系统包括含有高阻力吸入器的吸入系统，所述高阻力吸入器具有空气管道，能够将高阻力赋予经过管道的用于粉末解聚和分散的气流。在一个实施方式中，吸入系统的阻力值为例如每分钟约0.065到约0.200(√kPa)/升。在某些实施方式中，可以采用吸入系统通过吸入有效地输送干粉，其中峰值吸入压差可以在约2到约20kPa之间，这可以产生约在7和70升/分钟之间的峰值流速。在某些实施方式中，配置吸入系统从而通过使粉末作为输送给患者的粉末的连续流或者作为一个或更多个脉冲从吸入器排出而提供单次剂量。在本文公开的一些实施方式中，干粉吸入器系统包含吸入器内的预定质量流量平衡。例如，总流量约10%至70%离开吸入器并进入患者体内的流量平衡是通过一个或更多个分配端输送的，其中气流通过含有粉末制剂的区域，并且其中约30%至90%的气流是从吸入器的其他管道产生的。此外，旁通流或未进入并离开粉末容器区域（例如经过药盒）的物料流可以与离开粉末分配端的物料流在吸入器内重新组合，从而使流化粉末离开接口管之前被稀释、加速并最终解聚。在一个实施方式中，约7至70升/分钟的流速导致以l-30mg填充质量分配超过容器或药盒内容物的75%。在某些实施方式中，上述吸入系统在单次吸入中可以射出以百分比计大于40%、大于50%、大于60%或大于70%的可吸收分数/填充量的粉剂，并且可以至多约90%、95%、99%或可以接近100%。
在具体的实施方式中，所提供的吸入系统包括干粉吸入器、含有富马酰基二酮哌嗪微粒的干粉制剂，其中FDKP微粒具有多个结构域，每个结构域包含由多层多孔结晶材料包围的核，其中域包含使用X-射线断层摄影术测得的大于500个体素。在吸入系统的这个实施方式的一些方面，在用于与可重复使用的吸入器一起使用的单位剂量药盒中提供干粉制剂。或者，干粉制剂可以预加载在一次使用的一次性吸入器中。在该实施方式中，吸入系统的结构配置考虑了吸入器的解聚机理从而产生大于50%的可吸收分数；也就是说，多于一半的包含在吸入器（药盒）中的粉末作为小于5.8μm的颗粒射出。在给药期间吸入器可以排出容器内所含的大于85%的粉末药物。在某些实施方式中，吸入器可以排出单次吸入所含的大于85%的粉末药物。在某些实施方式中，吸入器可以在2kPa到5kPa的压差下以至多30mg或更多的填充质量在小于3秒的时间内排出大于约90%、或约97%至接近100%的药盒内容物或容器内容物。
在一些具体的实施方式中，描述了合成具有多个结构域的FDKP微粒的方法，每个结构域包含由多层多孔结晶材料包围的核，其中域包含使用X-射线断层摄影术测得的大于500个体素。该方法包括：提供2.75重量%的富马酰基二酮哌嗪溶液；在约17℃至约22℃的温度下等质量的约11重量%至约12重量%乙酸和约2.75重量%FDKP溶液进料通过高剪切混合器（例如Dual-feed S0N0LAT0RTM），在2000psi的压力下通过0.001-in2（平方英寸）的喷嘴来形成悬浮液。该方法还可以包括下列步骤：使微粒从溶液中沉淀出来，并在大约相同质量和温度的去离子水贮水池中收集所形成的微粒。在某些实施方式中，该方法还包括通过在例如去离子水中使用切向流过滤技术洗涤微粒来浓缩微粒悬浮液。在该实施方式和其他实施方式中，可以首先将沉淀浓缩至约4%固体，然后进一步用去离子水洗涤。在一些实施方式中，基于所用的FDKP组合物的初始质量，悬浮液通常可以浓缩至约10%固体。通过烘干法可以测定被浓缩的悬浮液的固体含量。在本文公开的实施方式中，该方法还包括在颗粒干燥之后测定颗粒的表面积。
在具体的实施方式中，描述了制备具有多个结构域的二酮哌嗪微粒的方法，每个结构域包含由多层多孔结晶材料包围的核，其中域包含使用X-射线断层摄影术测得的大于500个体素，采用具有式3,6-二(N-X-4-氨基丁基)-2,5-二酮哌嗪的二酮哌嗪，其中X选自由富马酰基、琥珀酰基、马来酰基和戊二酰基组成的组。在示例性实施方式中，二酮哌嗪为二-3,6-(N-富马酰基-4-氨基丁基)-2,5-二酮哌嗪或2,5-二酮-3,6-二(N-富马酰基-4-氨基丁基)哌嗪。
本文公开的另一个实施方式包括制备包含具有多个结构域的FDKP微粒和药物或活性剂的干粉制剂的方法，每个结构域包含由多层多孔结晶材料包围的核，其中域包含使用X-射线断层摄影术测得的大于500个体素；其中微粒尺寸范围从约2000体素到约680000体素，且质量加权平均颗粒尺寸约33000体素至约216000体素。在一个实施方式中，微粒的平均尺寸可以从约500体素到约125000体素；约2000体素到约100000体素；约50000体素到约80000体素；约60000体素到约70000体素；或约60000体素到约65000体素。在该实施方式中，本方法包括向微粒悬浮液中加入含有活性剂的溶液，活性剂例如小分子（包括曲坦）或肽（包括胰岛素、胰高血糖素、胰高血糖素样肽-1、胃泌酸调节素、肽YY(3-36)、脑肠肽、血管活性肠肽、催产素、CCK等等）；向悬浮液中加入氨水以使悬浮液的pH提高至4.5；并且在液氮中将所得到的悬浮液速冻，并将所形成的粒料冻干，以产生包含FDKP微粒的干粉。
其他实施方式涉及治疗与胰岛素相关的失调的方法，其包括给需要胰岛素的人给药如上所述的干粉。在各种实施方式中，与胰岛素相关的失调可以具体包括但不限于下列中的任何一种或所有：糖尿病前期（pre-diabetes）、1型糖尿病（蜜月期、后蜜月期或二者）、2型糖尿病、妊娠期糖尿病、低血糖症、高血糖症、胰岛素抗性、内分泌功能失调、受损的胰岛素早期释放、胰腺β-细胞功能的丧失、胰腺β-细胞的减少和代谢失调。
在一个实施方式中，公开了治疗疾病或失调的方法、包括治疗与内分泌有关的疾病或失调的方法，其包含给需要其的人给药含有具有多个结构域的FDKP微粒和适合治疗所述疾病或失调的药物的干粉制剂，每个结构域包含由多层多孔结晶材料包围的核，其中域包含使用X-射线断层摄影术测得的大于500个体素；其中微粒尺寸范围从从约2000体素到约400000体素，且质量加权平均颗粒尺寸约33000体素到约216000体素。在一个实施方式中，微粒可以具有范围从约500体素到约125000体素；从2000体素到100000或从50000体素到80000体素的平均尺寸。
一个实施方式包括治疗与胰岛素相关的失调的方法，其包括：将包含上述FDKP微粒的干粉制剂给药至需要其的人。在各种实施方式中，与胰岛素相关的失调可以具体包括但不限于下列中的任何一种或所有：糖尿病前期（pre-diabetes）、1型糖尿病（蜜月期、后蜜月期或二者）、2型糖尿病、妊娠期糖尿病、低血糖症、高血糖症、胰岛素抗性、内分泌功能失调、受损的胰岛素早期释放、胰腺β-细胞功能的丧失、胰腺β-细胞的减少和代谢失调。在一个实施方式中，干粉包含胰岛素。在其他实施方式中，干粉包含胰高血糖素和促胰岛素分泌肽或GLP-1。
附图简要说明
以下附图构成本说明书的一部分，用于进一步说明本文公开的实施例的某些方面。通过参考一个或更多个附图，并结合本文所列的具体实施方式的详细描述，可以更好地理解本发明。
图1A和1B描绘了由高容量颗粒（图1A）与通过标准现有技术方法所生成颗粒（图1B）相比的X射线断层摄影术研究收集到的数据所得到的颗粒的数量加权尺寸分布的图形表示。
图2A和2B描绘了由高容量颗粒（图2A）与通过标准现有技术方法所生成颗粒（图2B）相比的X射线断层摄影术研究收集到的数据所得到的颗粒的体素加权尺寸分布的图形表示。
图3A和3B描绘了由高容量颗粒（图3A）与通过标准现有技术方法所生成颗粒（图3B）相比的X射线断层摄影术研究收集到的数据所得到的域的数量加权尺寸分布的图形表示。
图4A和4B描绘了由高容量颗粒（图4A）与通过标准现有技术方法所生成颗粒（图4B）相比的X射线断层摄影术研究收集到的数据所得到的域的体素加权尺寸分布的图形表示。
图5A描绘了通过回转半径计算得的高容量FDKP颗粒与标准现有技术FDKP颗粒（图5B）相比物理域尺寸的体素加权分布。图5C是高容量FDKP颗粒（实线）和现有技术颗粒（虚线）的叠加，其表示高容量颗粒与标准颗粒尺寸分布之间差异。
图6描绘了具有不同胰岛素含量的松散粉末的几何颗粒尺寸分布图，对于标准FDKP微粒含量为3U/mg和4U/mg，并且高容量FDKP微粒含量为6U/mg。
发明详述
如上所述，将药物输送至肺部具有很多优势。但是由于输送药物经过天然的物理屏障，所以难以将药物以均匀的体积和重量输送至肺部。本文中公开了作为药物递送剂的二酮哌嗪微粒，其具有吸附活性剂（包括小分子、核酸、肽）的高容量。在一个实施方式中，微粒具有大于约70m2/g的比表面积。公开了制备微粒的方法和使用微粒的方法。在一个示例性实施方式中，本发明微粒能够输送用于肺吸入的浓度大于4IU/mg的肽，例如胰岛素。在一些实施方式中，微粒可以包含约18重量%至约25重量%、约20重量%至约25重量%或者约21重量%至约25重量%的胰岛素。
在本文中使用吋，术语“微粒”是指直径为约0.5μm至约1000μm的颗粒，而不考虑其精确的外部或内部结构怎么样。直径小于10μm的微粒可以成功穿过大部分天然屏障到达肺部。直径需要小于约10μm来通过喉咙的转角。为了到达被认为发生最有效吸收的肺深部（或肺泡区），优选使“可吸收分数”（RF）中所含的颗粒比例最大化，通常可接受的是使用标准技术（例如Anderson Cascade Impactor）测定的空气动力学直径小于5.8μm的那些颗粒，尽管一些参考文献使用稍微不同的范围。其他冲击器也可以用于测定空气动力学颗粒尺寸，例如NEXT GENERATIONIMPACTORTM(NGITM,MSP Corporation)，对其来说，可吸收分数是通过相似的空气动力学尺寸（例如<6.4μm）来定义的。在一些实施方式中，使用激光衍射装置来测定颗粒尺寸，例如2010年3月18日递交的美国专利申请No.12/727179中公开的激光衍射装置，其相关教导通过引用全部并入本文，其中测定了颗粒的体积中值几何直径（VMGD）来评估吸入系统的性能。例如，在各种实施方式中，≥80%、85%或90%的药盒排空率和≤12.5μm、≤7.0μm或≤4.8μm的射出颗粒的VMGD可以表明越来越好的空气动力学性能。本文中公开的实施方式显示出具有多个结构域的FDKP微粒，每个结构域包含由多层多孔结晶材料包围的核，其中域包含使用X-射线断层摄影术测得的大于500个体素。在某些实施方式中，本文中所描述的FDKP微粒具有大于36m2/g或大于70m2/g的比表面积，并且展现出有利于将药物输送至肺部的特性（包括保持改善的空气动力学性能）。
基于填充量的可吸入分数（RF/填充量）表示：在用作药剂的所填充的粉末内容物排出时，从吸入器中射出的且适合呼吸的粉末占药剂的分数或百分比，即填充剂量中以适合肺部输送的尺寸射出的颗粒的百分比，其为微粒空气动力学性能的量度。如本文中所述，40%或大于40%的RF/填充量值反映出可接受的空气动力学性能特性。在本文公开的某些实施方式中，基于填充量的可吸入分数可以大于50%。在一个示例性实施方式中，基于填充量的可吸入分数可以至多约80%，其中使用标准技术测得的约80%的填充量以<5.8μm的颗粒尺寸射出。
本文中使用吋，术语“干粉”指的是不悬浮或不溶解在推进剂、载体或其他液体中的精细颗粒组合物。并不意味着所有水分子完全不存在。
应该理解的是具体的RF/填充量值可以取决于用于输送粉末的吸入器。粉末通常倾向于团聚并结晶成DKP微粒形式，特别是粘附性粉末。干粉吸入器的一个功能是使粉末解聚从而使所产生的颗粒包含适于通过吸入输送剂量的可吸入部分。但是，粘附性粉末的解聚通常不彻底，从而当测定通过吸入器输送的可吸收分数时所看到的颗粒尺寸分布与初始颗粒的尺寸分布不匹配，也就是说，分布曲线会向更大的颗粒偏移。吸入器的设计在其解聚效率方面变化，因此使用不同设计所观察到的RF/填充量的绝对值也将不同。
本文中使用时，术语“约”用于表示一个值包括测定该值所用的设备或方法的测量的标准偏差。
本文中使用时，术语体素（voxel，亦称三维像素）是用于定义体积元的在X-射线断层摄影术中所使用的度量单位。每体素的内容物由与每体积元中材料的线性吸收系数（LAC）成比例关系的吸光度表示。水的线性吸收系数大约为0.1μm-1(3.3x10-3/体素)。体素定义为在每个侧边或边缘上测量约33nm并且体积约3.6x10-23m3的立方体积元。
二酮哌嗪
本文中使用时，二酮哌嗪包括取代的或未取代的二酮哌嗪以及相关化合物。已经用于克服药学领域中难题（例如药物不稳定性和/或较差的吸收)的一类药物递送剂是2,5-二酮哌嗪。2,5-二酮哌嗪是由下面的通式1表示的化合物，其中E1和E2独立地为N或更具体地为NH。在其他实施方式中，E1和/或E2独立地为氧或氮，从而使E1和E2取代基中的一个为氧而另一个为氮，该式得到取代类似物二酮吗啉；或者当E1和E2都是氧时，该式得到取代类似物二酮二氧杂环己烷。
已经表明这些2,5-二酮哌嗪可用在药物输送中，特别是那些带有酸性R1和R2基团的2,5-二酮哌嗪（参见例如，标题为“Self AssemblingDiketopiperazine Drug Delivery System”的美国专利No.5352461；标题为“Method For Making Self-Assembling Diketopiperazine Drug DeliverySystem”的美国专利No.5503852；标题为“Microparticles For LungDelivery Comprising Diketopiperazine”的美国专利No.6071497和标题为“Carbon-Substituted Diketopiperazine Delivery System”的美国专利No.6331318，上述文献通过全文引用将其关于二酮哌嗪的教导和二酮哌嗪作为媒介的药物输送的教导并入本文）。在一些实施方式中，2,5-二酮哌嗪可以是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、3,6-二(马来酰基-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(柠康酰基-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(戊二酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(丙二酰-4-氨基丁基)-2,5-二酮哌嗪、3,6-二(乙二酰基-4-氨基丁基)-2,5-二酮哌嗪或3,6-二(富马酰基-4-氨基丁基)-2,5-二酮哌嗪。
二酮哌嗪可以形成混有药物的微粒或形成吸附药物的微粒。药物和二酮哌嗪的组合可以赋予改善的药物稳定性和/或吸收特性。这些微粒可以通过各种给药途径来给药。作为干粉，这些微粒可以通过吸入输送到呼吸系统的特定区域，包括肺部。
这些微粒通常是通过下列方法得到：通过游离酸（或碱)的pH沉淀法产生包含聚集的结晶板的自组装微粒。颗粒的稳定性可以通过从中沉淀出颗粒的DKP溶液中的少量表面活性剂（例如聚山梨醇酯-80）来增强（参见例如标题为“Method of drug formulation based on increasing the aifinity ofcrystalline microparticle surfaces for active agents”的美国专利申请No.2007/0059373，该文献通过全文引用将与DKP微粒及其干粉的形成和负载有关的教导全部并入本文）。最后可以除去溶剂得到干粉。除去溶剂的适当方法包括冷冻干燥和喷雾干燥（参见例如标题为“A method forimproving the pharmaceutic properties of microparticles comprisingdiketopiperazine and an active agent”的美国专利申请No.2007/0196503和标题为“Purification and stabilization of peptide and protein pharmaceuticalagents”的美国专利No.6444226，每一篇文献都通过全文引用将与DKP微粒及其干粉的形成和负载有关的教导全部并入本文）。本文中公开的微粒不同于由DKP盐组成的微粒。那些颗粒通常通过喷雾干燥而形成（而不是通过喷雾干燥来干燥），其得到无定形盐（而不是游离酸或碱）的球体和/或塌陷球，所以它们是化学、物理和形态上均不同的实体。本文中提到的FDKP理解为游离酸或溶解的阴离子。
合成二酮哌嗪的方法在例如Katchalski等的J.Amer.Chem.Soc.68,879-880(1946)和Kopple等的J.Org.Chem.33(2),862-864(1968)中有所描述，它们的教导通过引用全部并入本文。2,5-二酮-3,6-二(氨基丁基)哌嗪（Katchalski等称之为赖氨酸酸酐）也可以通过N-ε-P-L-赖氨酸在熔融苯酚中的环化二聚来制备（这与Kopple方法类似），随后采用适当的试剂和条件除去保护性的(P)-基团。例如，可以使用4.3M在乙酸中的HBr除去CBz保护基。这种方法是优选的，因为其使用可商购的起始材料，其涉及据报道用于在产物中保持起始材料立体化学性的反应条件并且所有步骤都可以很容易地按比例放大用于生产。合成二酮哌嗪的方法在标题为“Catalysisof Diketopiperazine Synthesis”的美国专利No.7709639中也有描述，其就相同方面的教导也通过引用并入本文。
富马酰基二酮哌嗪（二-3,6-(N-富马酰基-4-氨基丁基)-2,5-二酮-二酮哌嗪；FDKP）是用于肺部施用的一种优选的二酮哌嗪：
FDKP提供了一种有益的微粒基质，因为它在酸中的溶解度低但是易于溶解在中性或碱性pH中。这些性质使得FDKP能结晶，并使晶体在酸性条件下自组装成微粒。这些颗粒在pH为中性的生理条件下易于溶解。如前所述，直径在约0.5和约10微米之间的微粒可以成功穿过大部分天然屏障到达肺部。在该尺寸范围内的颗粒可以很容易地由FDKP制备。
如前所述，直径在约0.5和约10微米之间的微粒可以成功穿过大部分天然屏障到达肺部。在该尺寸范围内的颗粒可以很容易地由带酸性基团的二酮哌嗪制备，其中酸性基团例如FDKP（以及相关的分子，如2,5-二酮-3,6-二(4-X-氨基丁基)哌嗪，其中X为琥珀酰基、戊二酰基或马来酰基）中的羧酸基团。经过酸沉淀之后，得到由结晶板的聚集体组成的自组装微粒。这些板的结构和尺寸可以通过合成微粒时的反应条件来控制，因此与颗粒的比表面积有关，颗粒的比表面积又转而对颗粒的结构、负载容量和空气动力学性能有密切的影响。
DKP微粒的比表面积（SSA）是平均晶体尺寸的量度，并且可以用于估计晶核的相对分布和微粒特性的增长。比表面积取决于微粒晶体的尺寸和微粒基质的密度（ρ），并与晶体的特性尺寸L成反比。比表面积是一群颗粒总体的性能而不是其中每一个单独颗粒的特性。本文中公开的实施方式表现出：比表面积大于36m2/g的微粒展现出比标准微粒甚至更有利于输送药物到肺部的特性，例如采用中等效率的吸入器（例如标题为“Unit Dose Cartridge and Dry Powder Inhaler”的美国专利No.7464706中公开的
吸入器，其就相同方面的教导通过引用并入本文）的气动性能得到改善。在一些实施方式中，二酮哌嗪微粒可以具有大于约70m2/g的比表面积，并且可以提高空气动力学性能并改善药物吸附容量。
在一个实施方式中，本文中形成的二酮哌嗪微粒具有多个结构域，每个结构域包含由多层多孔结晶材料包围的核，其中域或核包含使用X-射线断层摄影术测得的大于500个体素。在具体的实施方式中，微粒包含每个域中大于1000体素、或每个域中大于2000体素作为中位数。在一些实施方式中，二酮哌嗪微粒包含一个或多个含有约2000体素、或大于2000体素的核；其中微粒尺寸范围从2000体素到约680000体素并且具有约33000至约216000体素的质量加权平均颗粒尺寸。在一个实施方式中，微粒的平均尺寸范围可以从约500体素至约125000体素；约2000体素至约100000体素、约50000体素至约80000体素、约60000体素至约70000体素或约60000体素至约65000体素。在一个具体的实施方式中，作为质量的量度的平均颗粒尺寸或质量加权平均颗粒尺寸为约62000至63000体素。在一些实施方式中，微粒的体素加权颗粒尺寸可以为约50000体素至约200000体素、约75000体素至约150000体素、约100000至约150000体素或约120000体素至约130000体素。
在一个示例性实施方式中，FDKP微粒包含具有多个结构域，每个结构域包含由多层多孔结晶材料包围的域或核，其中域包含使用X-射线断层摄影术测得的大于500个体素，并且每个颗粒大于2000体素。在该实施方式或其他实施方式中，颗粒可以在域的数目上变化。在一些实施方式中，微粒和每个域可以在尺寸上变化。在一些实施方式中，每个域的数量加权平均尺寸可以在约250体素至约1400体素、约500体素至约1000体素、约700体素至约900体素、约800体素至约900体素、约800体素至约850体素或约810体素至约820体素的范围内。在该实施方式或其他实施方式中，每个域的体素加权尺寸可以为约500至约2000体素、约800体素至约1500体素、约900体素至约1300体素、约1000体素至约1300体素、约1100体素至约1200体素或约1150体素至约1200体素。
在如上所描述的实施方式中，微粒可以具有多个结构域。在一些实施方式中，肺部输送的微粒可以包含1至约1000个结构域。
在另一个实施方式中，提供了含二酮哌嗪微粒的粉末；其中微粒的数量加权平均尺寸范围为从约500体素至约125000体素。在一个实施方式中，数量加权平均颗粒尺寸范围为约2000体素至100000体素；约40000体素至约85000体素；约60000体素至约70000体素、或约60000体素至约65000体素。
在一个实施方式中，提供了包含多个结构域的高容量二酮哌嗪颗粒；其中每个颗粒包含一个或多个结构域。在该实施方式中，典型的二酮哌嗪微粒包含约1至约1000个域，并且每个域的尺寸范围为约250至约2000体素；约500至约1800体素、或约500体素至约1800体素。在该实施方式中，每个颗粒中域的数目平均为从约75至80个域，其中颗粒为约0.5至4μm。在一些实施方式中，微粒的体素加权平均域尺寸可以为约300nm至约400nm、约350nm至约400nm、或约370nm至约390nm。
为了形成具有活性剂（例如用于制备治疗糖尿病的制剂的胰岛素）的FDKP微粒（负载胰岛素的FDKP微粒），通过将胰岛素储存溶液加入到FDKP微粒悬浮液中，可以在微粒悬浮时（即在冷冻干燥之前）将胰岛素直接吸附在微粒上。在一个实施方式中，在加入胰岛素储存溶液之后还可以进行pH控制步骤。该步骤可以在进一步处理之前促进胰岛素吸附到悬浮液体中的微粒上。悬浮液的pH増大到约4.5会促进胰岛素全部吸附到悬浮液中的微粒上，而不会使FDKP从微粒基质过度溶解，并且还能改善胰岛素在散装药物产品中的稳定性。悬浮液可以在液氮中逐滴速冻（即低温粒化）并冷冻干燥以便除去溶剂，得到干粉。在可选的实施方式中，悬浮液可以被喷雾干燥从而得到干粉。
提供了用于制备含有胰岛素的FDKP微粒的制造方法。在该实施方式中，使用高剪切混合器例如DUAL-FEED SONOLATORTM在2000psi下通过0.001-in2的喷嘴，或者例如在2009年11月2日递交的第12/917611号美国专利申请（US2011/0105719，其内容通过引用全部并入本文）中公开的高剪切混合器，在约16℃±约2℃的温度下，使等质量的约10.5重量％乙酸和约2.5重量％的FDKP溶液（表1和表2）在2000psi下进料通过0.001-in2的喷嘴。可以在具有大约相等的质量和温度的去离子水（DI）贮水池中收集沉淀。所得到的悬浮液包含约0.8%的固体。通过切向流过滤技术可以浓缩并洗涤沉淀。沉淀可以首先浓缩至约4%固体，然后用去离子水洗涤。悬浮液最终可以基于FDKP的初始质量浓缩至约10%固体。通过烘干法可以分析测定被浓缩的悬浮液的固含量。
活性剂的选择和引入
只要本文所述的微粒保持大于约36m2/g的所需比表面积，它们便能采用有利于输送至肺部和/或药物吸附的其他附加特性。标题为“Methodfor Drug Delivery to the Pulmonary System”的美国专利No.6428771描述了将DKP颗粒输送至肺部，其就相同方面的教导通过引用并入本文。标题为“Purification and Stabilization of Peptide and Protein Pharmaceutical Agents”的美国专利No.6444226描述了有利于使药物吸附到微粒表面上的方法，其就相同方面的教导也通过引用并入本文。可以调节微粒表面性质来实现如标题为“Method of Drug Formulation based on Increasing the Affinity ofCrystalline Microparticle Surface for Active Agents”的美国专利申请No.7799344(其就相同方面的教导通过引用并入本文）中所述的期望特性。标题为“Method of Drug Formulation based on Increasing the Affinity of ActiveAgents for Crystalline Microparticle Surfaces”的美国专利申请No.7803404描述了促进活性剂吸附到微粒上的方法。美国专利申请No.7803404也就相同方面的教导通过引用并入本文。
本文所述的微粒可以包含一种或更多种活性剂。在本文中使用时，可与“药物”互换使用的“活性剂”指的是医药物质，包括小分子药物、生物制剂和生物活性剂。活性剂可以是天然存在的、重组的或合成来源的，包括蛋白质、多肽、肽、核酸、有机大分子、合成有机化合物、多糖和其他糖、脂肪酸和脂质，以及抗体及其片段，所述抗体及其片段包括但不限于人源化抗体或嵌合抗体、F(ab)、F(ab)2、单独的单链抗体或与其他多肽混合的单链抗体、或对抗癌抗原的治疗性或诊断性单克隆抗体。活性剂可以涵盖多种生物活性和种类，例如血管活性剂、神经活性剂、激素、抗凝血剂、免疫调节剂、细胞毒性剂、抗菌素、抗病毒剂、抗原、传染物、炎症介质、激素和细胞表面抗原。更具体地，活性剂以非限制性方式包括细胞因子、脂质因子（lipokine）、脑啡肽、炔、环孢菌素、抗-IL-8抗体、包括ABX-IL-8的IL-8拮抗剂；包括PG-12的前列腺素，包括LY29311、BIIL284和CP105696的LTB受体阻滞剂；诸如舒马曲坦的曲坦和棕榈油酸酯、胰岛素及其类似物、生长激素及其类似物、甲状旁腺激素（PTH)及其类似物、甲状旁腺激素相关肽(PTHrP)、催产素、亮丙瑞林、α-干扰素、RGD肽、DDAVP肽、GHR肽、Detirelex人生长激素、白蛋白、免疫球蛋白G、环孢菌素、脑肠肽、肥胖抑制素（obestatin）、肠抑素（enterostatin)、粒细胞巨噬细胞集落刺激因子（GM-CSF）、粒细胞集落刺激因子（GCSF）、淀粉不溶素、淀粉不溶素类似物、胰高血糖素样肽1(GLP-1)、氯吡格雷（clopidogrel）、PPACK（D-苯基丙氨酰基-L-丙基-L-精氨酸氯甲基酮）、胃泌酸调节素（OXM）、肽YY(3-36)（PYY）、脂联素（adiponectin)、胆囊收缩素（CCK）、胰泌素、胃泌素、胰高血糖素、促胃动素、促生长素抑制素、脑钠肽(BNP)、心钠肽(ANP)、IGF-1、生长激素释放因子（GHRF）、整合素β-4前体(ΙΤΒ4)受体拮抗剂、孤啡肽（nociceptin）、痛稳素（nocistatin）、孤啡肽FQ2(orphanin FQ2)、降钙素、CGRP、血管紧张素（angiotensin）、P物质、神经激肽A(neurokininA)、胰多肽、神经肽Y、δ-促睡眠肽和血管活性肠肽。
在某些实施方式中，颗粒的药物含量可以根据要输送的药物的形式和尺寸而变化。要输送的药物的负载的范围通常在约0.01%和约20%之间、约25%、或更大，这通常取决于要输送的药物的形式和尺寸。对于胰岛素来说，优选的负载可以大于15%、约18%至约25%、约20%至约25%、或者约21%至约25%。在具体实施方式中，可以以大于4U/mg用于肺部输送的干粉末制剂的量将胰岛素负载到FDKP微粒上。在一些实施方式中，在用于吸入的干粉制剂中，本发明的FDKP微粒的胰岛素含量可以是5U/mg、6U/mg或更大。在一个具体实施方式中，采用本文中所描述的吸入系统，在单次吸入中可以给药于患者的胰岛素的剂量可以是约60U或更高。
实施例
以下实施例用于说明所公开的微粒的实施方式。本领域技术人员应当认识到，按照本发明人发现的代表性技术的实施例所公开的技术可以有效地用于实施本发明，并且因此这些公开的技术可以认为构成了实施本发明的优选方式。然而，根据本发明的说明书，本领域技术人员应当认识到，可以对公开的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
用于制备含有或不含有胰岛素的标准FDKP微粒的制造过程
在FDKP微粒的制造中第一步是微粒的形成，其通过pH-诱导FDKP结晶并将FDKP晶体自组装形成具有整体球形形态的微粒来实现。因此，微粒的制造实质上是一个结晶过程。可以通过反复离心、倾析并重新悬浮或者通过渗滤，来去除过量的溶剂。合成FDKP微粒的标准方法的例子如上所述，也描述于国际PCT专利申请No.PCT/US2010/038298(WO2010/144789)中，其通过引用全部并入本文。
由FDKP和胰岛素制造微粒。FDKP溶解于NH4OH水溶液中以形成溶液。该溶液的进料流与HOAc水溶液的进料流在高剪切混合器中合并，以形成微粒的水性悬浮液。
FDKP进料溶液是由约2.5重量%FDKP、约1.6重量%浓缩的NH4OH(约28至约30重量%NH3)和约0.05重量%聚山梨醇酯80制备的。乙酸进料溶液是由约10.5重量%冰醋酸和约0.05重量%聚山梨醇酯80制备的。在使用之前，两种进料溶液均通过约0.2μm膜过滤。
将等量（质量）的每种进料溶液通过配备有#5喷嘴（0.0011平方英寸）的DUAL-FEED SONOLATORTM泵入。为了使每一个进料流的流速相等，最小泵被设为50%，进料压力为约2000psi。接收容器含有与每一种进料流质量相等的DI水（例如4kg FDKP进料溶液和4kg HOAc进料溶液将通过SONOLATORTM泵入含有4kg DI水的接收容器中）。
通过使用0.2m2PES膜的切向流过滤方式来浓缩并洗涤所产生的悬浮液。悬浮液首先被浓缩至约4%固体，然后用DI水渗滤，最终浓缩至约16%名义（nominal）固体含量。洗涤过的悬浮液的实际固体百分数是通过“干燥失重法”测定的。也可以使用其他方法来测定悬浮液的固体百分数，例如在2011年5月4日递交的标题为“Determine Percent Solids inSuspension Using Raman Spectroscopy”的PCT专利申请No.PCT/US2011/035112(WO2011/140175)中公开的方法，其公开的教导内容通过引用并入本文。
制备胰岛素储存溶液，其含有约10重量％的胰岛素（原样使用），溶剂为在DI水中含有约2重量％的HOAc，然后将胰岛素储存溶液过滤除菌。基于悬浮液的固体含量，向混合的悬浮液中添加适量的储存溶液。然后使用氨水将所得到的微粒/胰岛素悬浮液的pH从约3.6的pH调节至约4.5的pH。
将包含含胰岛素的FDKP微粒的悬浮液转移到冷冻制粒机/造粒机（例如在美国专利申请No.12/917623(US2011/0100028)中公开的，其内容通过引用全部并入本文且其教导附属于本文中）中，在液氮中通过速冻。将冰粒冷冻干燥来生产干粉。
B.高容量FDKP微粒的形成
与A中和WO201/144789中所描述的类似，在两组条件（表1）下制备FDKP微粒。
表1颗粒形成条件
使用表中所示的标准条件（条件1）来制备标准FDKP微粒。与条件1类似，在制造过程中使用表1中所示的两种进料溶液来制备示例性高容量FDKP微粒（条件2）。在条件2中，制造过程包括以下步骤：在22℃的温度下2000psi的压力下将等质量的约11.5重量%乙酸溶液和约2.75重量%FDKP溶液进料通过高剪切混合器(Dual-feed SONOLATORTM)并通过0.001-in2的喷嘴，以形成悬浮液。FDKP微粒从溶液中沉淀出来，并且在具有大约相同质量和温度的去离子水贮水池中收集所形成的微粒。冲洗颗粒以去除过量的酸并干燥，通过X射线断层摄影术分析粉末样品。
通过X射线断层摄影术表征标准颗粒和高容量颗粒。颗粒的三维表示方式离散成在每个侧边33nm的立方体积元。体积元称为体素，以类似于图像元素的像素的方式来命名。每个体素的内容物通过与每体积元中材料的线性吸收系数（LAC）成比例关系的吸光度表示。水的线性吸收系数大约为0.1μm-1(3.3×10-3/体素)，并且对于密度为1.4g/cm3的FDKP晶体来说所计算得到的线性吸收系数为1.3μm-1(43×10-3/体素)。
通过先排除LAC<14×10-3/体素（对应约33%FDKP固体）的任何体素来识别颗粒。从任何剩余的体素开始，加入LAC>14×10-3/体素的相邻体素。然后进而加入与这些体素相邻的体素，直到所有的相邻体素已经并入到颗粒中。使用其他体素重复本过程来定义随后的颗粒。
颗粒结构解释为相邻域的集合，域由“芯”（cores）和“壳”组成。芯由体素密度（LAC）为局部最大值时的区域中的相邻体素组成，而壳为围绕芯的较低密度体素。在分析时仅包括含有大于一个“芯”和至少2000个体素的颗粒。
图1A和1B描绘了由高容量颗粒（图1A）与通过标准现有技术方法所生成颗粒（图1B）相比的X射线断层摄影术研究收集到的数据所得到的颗粒的数量加权尺寸分布的图形表示。这些数据说明高容量颗粒的数量加权平均尺寸为62347体素，标准偏差为62702体素，而标准颗粒的平均尺寸108135且标准偏差为140444体素，标准颗粒几乎是高容量颗粒的两倍。
也表征了颗粒的包膜（envelope）密度。围绕颗粒的包膜是完全包围颗粒的凸起的壳。通过用颗粒的尺寸（组成颗粒的体素的体积）除以包膜的体积来计算每个包膜的固体分数。图2A和2B示出了所得到的并进行该颗粒特征的相关性分析的数据，其中图2B描述了采用标准条件（条件1）制得的微粒的结果，并且图2A示出了由采用条件2制得的微粒所得到的数据。结果表明高容量颗粒比标准颗粒更紧凑或者凹处更少。此外，在通过X-射线断层摄影程序测量的体积方面，这些数据表明所测量的高容量微粒比标准现有技术微粒小大约二分之一到三分之一。与标准颗粒相比，本发明的微粒还具有少约四分之一的域。
图2A和2B描绘了由高容量颗粒（图2A）与通过标准现有技术方法所生成颗粒（图2B）相比的X射线断层摄影术研究收集到的数据所得到的颗粒的体素/质量加权尺寸分布的图形表示。这些数据说明标准颗粒（图1B）平均来说比高容量颗粒（图1A）大，无论是数量加权分布还是质量（体素）加权分布（图2A和2B）。
表2和图3A和3B描绘了由高容量FDKP颗粒（图3A）与通过标准现有技术方法所生成FDKP颗粒（图3B）相比的X射线断层摄影术研究收集到的数据所得到的域的数量加权尺寸分布的图形表示。图4A和4B描绘了由高容量FDKP颗粒（图4A）与通过标准现有技术方法所生成FDKP颗粒（图4B）相比的X射线断层摄影术研究收集到的数据所得到的域的质量（体素）加权尺寸分布的图形表示。图3A和4A中的代表性数据也表明高容量颗粒更小，因为1）构成高容量颗粒的域比标准颗粒中的那些更小（图3B和4B），并且2）组成高容量颗粒的域更少（表2）。在等尺寸颗粒例如直径2μm的颗粒的比较中，高容量颗粒会包含大约158个平均尺寸为780体素的域，而标准颗粒会包含大约112个平均尺寸为1050体素的域。
表2：HC（高容量）颗粒和标准颗粒的比较
也表征了两种类型的FDKP颗粒的回转半径。回转半径Rg=(R2 g)1/2，其是域的物理尺寸的一个量度。对于颗粒的样品群体，采用下列公式计算每个域：
其中(xi,yi,zi)是体素i的中心，(xc,yc,zc)是域的质心，并且c为体素的尺寸(33nm)。图5A、5B和5C是由高容量颗粒(5A)和标准颗粒(5B)所得到的数据的图形表示。平均来说，高容量颗粒的域更小(378nm)，并且具有范围从312nm到444nm的平均尺寸分布，比标准颗粒的平均尺寸分布更窄。标准颗粒的域具有426nm的平均尺寸，并且具有范围从340nm到512nm的平均尺寸分布。这表明高容量颗粒的成核与生长之间的平衡比标准颗粒更靠近成核。
实施例2
通过体积中值几何直径（VMGD）表征来对射出的制剂进行几何颗粒尺寸分析
从干粉吸入器射出的干粉制剂的激光衍射是用来表征粉末经受的解聚水平所采用的通用方法。该方法表示几何尺寸的量度，而非空气动力学尺寸的量度（在工业标准冲击法中提供）。通常，射出的粉末的几何尺寸包括通过中值颗粒尺寸（VMGD）表征的体积分布。重要的是，可以看出，射出颗粒的几何尺寸与通过冲击法提供的空气动力学粒径相比具有较高的分辨率。较小的尺寸是优选的，能产生单个颗粒被输送到肺气管的更大可能性。因此，吸入器解聚能力和最终性能的差异更易于通过衍射来解决。在这些实验中，在与实际病人吸气量类似的压力下，采用激光衍射来测试吸入器，从而确定吸入系统使粉末制剂解聚的效率。特别地，这些制剂包含负载了和未负载活性胰岛素成分的粘着性二酮哌嗪粉末。用3U/mg和4U/mg（不损失肺部递送的空气动力学性能的最大胰岛素容量）的胰岛素含量来负载采用条件1所制得的FDKP微粒，并且也制备并测试采用条件2所制得的FDKP微粒。图6报道的是采用如美国专利申请No.12/484,129(US2009/0308391)中所描述的干粉吸入器测试的各种粉末的VMGD的图形表示。
图6描绘了具有不同胰岛素含量的松散粉末的几何颗粒尺寸分布的图形表示，对于标准FDKP微粒胰岛素含量为3U/mg和4U/mg（最大的），并且高容量FDKP微粒胰岛素含量为6U/mg。图6中数据表明胰岛素含量6U/mg的微粒表现出VMGD轻微增加，然而，与3U/mg或4U/mg粉末相比，VMGD的提高并不改变肺部递送的性能。这在表3中得到证明，在表3中将粉末在临床试验中给药于健康正常的志愿者。
表3：精细颗粒剂量和胰岛素AUC
数据表明采用条件2制得的6U/mg FDKP/胰岛素的粉末制剂有效地输送比标准颗粒(3U/mg和4U/mg)更大剂量的胰岛素，其通过在各种剂量下的精细颗粒剂量（FPD）和曲线下的面积（AUC）来测得。高容量颗粒还可以用于输送较小量的活性剂例如胰岛素，因此给药于患者的粉末更少。
这些数据表明，与在条件1下所制得的颗粒相比，在条件2下所制得的颗粒展现出明显更高的容量来吸附溶液中的胰岛素。
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值参数都是约数，它们可以根据本发明想要获得的性质而变动。最起码且并非对权利要求书范围应用等同原则的限制，每个数值参数至少应按照报道的有效数字的数、并通过应用普通的数值舍入法来解释。虽然示出本发明宽广范围的数字范围和参数是约数，但是具体实施例中所示的数值是尽可能精确地报道的。然而，任何数值必然含有一定误差，这是它们各自的试验测量中发现的标准偏差必然导致的。
除非本文另有指明或者与上下文明显矛盾，在描述本发明（特别是在所附权利要求书的上下文中）的上下文中使用的不定冠词（“a”、“an”）和术语“该”以及类似提法应当被理解为既包括单数又包括复数。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法。除非本文另有指明，每个单独的值包括于说明书中，就像与本文中进行单个叙述一样。
除非本文另有指明或者与上下文明显矛盾，本文所述的所有方法均可以以任何合适的顺序来进行。除非另有指明，本文提供的任何例子以及所有例子，或者示例性的语言（例如，“例如”）仅用来更好地阐述本发明，而非对发明范围加以限制。说明书中任何语句都不应被解释为：表示对本发明的实施来说必要的、不要求保护的要素。
除非明确指出仅仅有某个可选方式或者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”。
本文公开的本发明的替换性要素或实施方式的分组不应被理解为限制。每个组成员可以单个地被采用和单个地被要求保护，或可以与该组其它成员或本文中找到的其它要素的任意组合和被要求保护。可以预见到，为了方便起见和/或可专利性的原因，组中的一个或多个成员可被包括于组中或从中删除。当任何此类包括或删除发生时，说明书在此被看作为包含经过改动的组，因此满足对所附权利要求书中所用的任何和全部马库什组的支持。
本文中描述了本发明的优选实施方式，其包括发明人已知用来实施本发明的最佳方式。当然，在阅读前述说明书的基础上，对那些优选实施方式的改动对于本领域普通技术人员来说将是明显的。本发明的发明人预见了本领域技术人员合适地采用此类改动，发明人预期本发明可以以除本文具体描述的方式之外的方式来被实现。因此，只要适用法律允许，本发明包括对所附权利要求中提到的主题进行的所有改动和等同物。此外，除非本文另有指明或者与上下文明显矛盾，在其所有可能的变化中上面提到的要素的任何组合都被包括于本发明中。
本文公开的具体实施方式可以进一歩使用“由…组成”或者“基本由…组成”的语言表达而被限制在权利要求书中。当用在权利要求书中时，不管是递交的或根据修改增加的权利要求书，过渡术语“由…组成”排除了未在权利要求中指定的任何要素、步骤或者成分。过渡术语“基本由…组成”将权利要求的范围限制到特定材料或步骤以及实质上不会影响基本特性和新颖特性的那些材料和步骤。要求保护的本发明的实施方式在此处固有地或者清楚地描述和应用。
此外，本说明书中提到了大量参考文献，包括专利和印刷公开物。上述参考文献和印刷公开物中的每种在此都通过引用被分别地整体并入本文。
此外，应当理解，本文公开的本发明的实施方式是为了阐述本发明的原理。可以进行的其它改动也落在本发明的范围内。因此，举例而言，而非限制，可按照本文的教导来使用本发明的替代性构造。因此，本发明不被限制为仅仅是本文所示和所述的。
Claims (23)
1.包含药物或活性剂和多个二酮哌嗪微粒的组合物；其中每个所述二酮哌嗪微粒均包含多个结构域；对于几何直径从约0.5至约4μm的测量颗粒尺寸来说，所述二酮哌嗪微粒具有约33000至约216000体素的质量加权平均颗粒尺寸，所述质量加权平均颗粒尺寸是通过X-射线断层摄影术测得的。
2.如权利要求1所述的组合物，其中所述二酮哌嗪微粒包含约140至约170个结构域。
3.如权利要求1或2所述的组合物，其中所述二酮哌嗪微粒包含数量加权尺寸范围为约250体素至约1400体素的结构域。
4.如前面权利要求中任意一项所述的组合物，其中所述二酮哌嗪微粒包含体素加权尺寸范围为约500体素至约2000体素的结构域。
5.如前面权利要求中任意一项所述的组合物，其中每个所述二酮哌嗪微粒均具有大于35m2/g的比表面积。
6.如前面权利要求中任意一项所述的组合物，其中每个所述二酮哌嗪微粒均具有大于70m2/g的比表面积。
7.如前面权利要求中任意一项所述的组合物，其中所述多个结构域具有约300nm至约450nm的平均尺寸，其通过回转半径测得。
8.如前面权利要求中任意一项所述的组合物，其中所述药物或活性剂是有机小分子、肽或蛋白质、或核酸分子或其组合。
9.如权利要求8所述的组合物，其中所述肽为内分泌激素。
10.如权利要求8所述的组合物，其中所述肽或蛋白质是胰岛素、甲状旁腺激素、降钙素、胰高血糖素、胰高血糖素样肽1、胃泌酸调节素、催产素、CCK-8、PYY3-36、脑肠肽、血管活性肠肽、亮丙瑞林、生长激素、RGD(Arg-Gly-Assp)肽、生长激素释放肽、DDAVP(脱氨基-Cys-1,D-arg8)血管加压素肽、环孢菌素、Detirelex、促生长素抑制素、α-干扰素、粒细胞集落刺激因子、IgG、它们的类似物或活性片段。
11.如权利要求8所述的组合物，其中所述有机小分子是神经递质激动剂、神经递质拮抗剂、疼痛抑制剂、疫苗、抗炎剂、抗癌剂、细胞受体激动剂分子、细胞受体拮抗剂分子、免疫抑制剂、他汀或抗感染剂。
12.如前面权利要求中任意一项所述的组合物，其中所述二酮哌嗪是富马酰基二酮哌嗪（二-3,6-(N-富马酰基-4-氨基丁基)-2,5-二酮哌嗪）或其盐。
13.如前面权利要求中任意一项所述的组合物，其以干粉形式存在。
14.如权利要求13所述的组合物，其还以每毫克干粉中大于4单位的量包含胰岛素。
15.如权利要求14所述的组合物，其中胰岛素的量为每毫克干粉中6单位。
16.如权利要求15所述的组合物，其中所述干粉包含含有60单位或更多胰岛素的胰岛素剂量，所述胰岛素用于在单次吸入中使用干粉吸入器输送给患者。
17.合成富马酰基二酮哌嗪微粒的方法，所述方法包括：
在约17℃至约22℃的温度下将等质量的含约11重量%至约12重量%乙酸的第一溶液和含约2.75重量%富马酰基二酮哌嗪溶液且以0.05重量%浓度包含表面活性剂的第二溶液进料通过高剪切混合器，以及
收集所述富马酰基二酮哌嗪微粒。
18.合成富马酰基二酮哌嗪微粒的方法，其包括：
收集富马酰基二酮哌嗪微粒，其为将前体溶液进料通过高剪切混合器后的产物；其中所述前体溶液包含含有约11重量%至约12重量%乙酸的第一溶液、含有约2.75重量%富马酰基二酮哌嗪的第二溶液，并且所述前体溶液以约0.05重量%的浓度含有表面活性剂。
19.如权利要求17或18所述的方法，其中所述表面活性剂是聚山梨醇酯80。
20.如权利要求17-19中任意一项所述的方法，其还包括用去离子水洗涤悬浮液的步骤以去除过量的酸。
21.如权利要求17-19中任意一项所述的方法，其还包括向所述悬浮液中加入含有活性剂的溶液、以及用氨水溶液调节溶液的pH至约4.5的步骤。
22.给需要胰岛素的患者输送胰岛素的方法，其包括向受试者给药如权利要求1-16中任意一项所述的干粉组合物到肺部深处，其通过所述患者吸入所述干粉制剂来实现。
23.二酮哌嗪微粒，其包含多个结构域，且对于几何尺寸从约0.5至约4μm的测量颗粒尺寸来说，其质量加权平均颗粒尺寸为约33000至约216000体素，所述质量加权平均颗粒尺寸是通过X-射线断层摄影术测得的。
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| HK1197017A1 (zh) | 2015-01-02 |
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| US20200147221A1 (en) | 2020-05-14 |
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| US20230016875A1 (en) | 2023-01-19 |
| WO2012174472A1 (en) | 2012-12-20 |
| JP2014517043A (ja) | 2014-07-17 |
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