CN114848614A - 热稳定性干粉药物组合物和方法 - Google Patents

热稳定性干粉药物组合物和方法 Download PDF

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CN114848614A
CN114848614A CN202210211995.0A CN202210211995A CN114848614A CN 114848614 A CN114848614 A CN 114848614A CN 202210211995 A CN202210211995 A CN 202210211995A CN 114848614 A CN114848614 A CN 114848614A
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dry powder
oxytocin
diketopiperazine
citrate
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卡琳·法比奥
约瑟夫·J·古尔纳利
凯伦·柯利
马歇尔·L·格兰特
安德里亚·勒龙-贝
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Abstract

本发明涉及热稳定性干粉药物组合物和方法。本文公开了用作药物组合物的热稳定性干粉组合物，其包含肽或蛋白质。所述组合物在提高的温度和相对高湿度的环境下非常稳定，且旨在用于室温下贮存并具有延长的保质期。特别地，干粉旨在用于吸入，然而，当在溶液中重建时，也可以使用其它给药途径。

Description

热稳定性干粉药物组合物和方法
本申请是2014年7月18日提交的申请号为201480045133.9(PCT/US2014/047304)的发明专利申请“热稳定性干粉药物组合物和方法”的分案申请。
相关申请的交叉引用
根据35 U.S.C.§119(e)，本申请要求2013年7月18日递交的美国临时专利申请序列号61/847,981的权益，所述文献的内容通过全文引用并入本文。
技术领域
本文公开了热稳定性干粉组合物和递送生物可降解物质(包括肽和蛋白质)的方法，以及递送干粉的系统和方法。特别地，干粉优选地旨在用于通过吸入肺部递送以治疗某些病症和/或疾病，包括产后出血。
背景技术
多年来药物的递送已成为一个重要的问题，当待递送的化合物通过口服给药给予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尤其如此。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中的条件下不稳定或者因为它们未被有效吸收。对于生物制品，特别是肽和蛋白质，胃中的酸性环境对维持功能不利，因为大部分蛋白质容易降解。
分离的生物物质(包括某些蛋白质和肽)可容易且完全地丢失功能活性，例如，通过一旦将它们从20℃贮存下取出。在不添加蛋白酶抑制剂时，其它分离蛋白和肽在贮存于4℃时显著降解。大部分哺乳动物蛋白质和肽在高于43℃的温度下降解。可以确定的是：在55℃下，大部分蛋白质在约1-2小时内完全变性。在一些情况下，分离蛋白的完全变性和去稳定化也在室温下发生。
由于与药物(特别是生物衍生品)的经口药物递送有关的问题，所以开发了到肺部的药物递送。例如，递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、或者流感或其它呼吸系统疾病的疫苗。用于治疗肺部疾病例如哮喘的药物制剂可通过一些方法得到，包括，使用雾化器例如利用
Figure BDA0003533234320000021
处理，使用定量吸入器例如
Figure BDA0003533234320000022
和干粉吸入器例如ADVAIR
Figure BDA0003533234320000023
PULMICORT
Figure BDA0003533234320000024
其它药物(包括核苷酸药物)已经被递送到肺部，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，其中将表达有效的腺苷脱氨酶的逆转录病毒载体施用至肺部。
目前，使用生物制品治疗全身性疾病的制剂主要通过可注射的组合物得到。用于肺部吸入和全身性递送胰岛素的干粉组合物(包括
Figure BDA0003533234320000025
和
Figure BDA0003533234320000026
)已在临床试验中使用。然而，期望改善干粉组合物、尤其是包含生物分子(包括肽和核酸)的那些干粉组合物在室温下的保质期，以进一步延长它们的寿命、在患者使用之前易于贮存和递送，在无法使用冰箱时尤其如此。
例如，根据世界卫生组织，每天有800名妇女死于怀孕或分娩相关的并发症。死亡的主要原因是严重出血(产后出血)，这可通过使用肽激素、催产素、生物分子来预防。商业购买的催产素组合物被提供为通用类催产素或者商品名为
Figure BDA0003533234320000027
和
Figure BDA0003533234320000028
的液体制剂；溶液中的肽在环境温度下易于降解，因此使用前需要在低于25℃下贮存，并且仅通过注射给药。在可注射制剂的制备和所需的特殊贮存方面遇到了挑战，这阻止了它们在有巨大需求但冰箱和稳定化并非总能容易得到的亚热带和热带气候中的使用。
因此，在疾病治疗中，(尤其是用于肺部递送的)包含生物分子的药物制剂的开放有改进的空间。
发明内容
本公开提供用于吸入的干粉组合物，其在室温或较高温度下持续长时间保持稳定且实质上不损失它们的生物活性。在一个实施方式中，提供一种药物制剂，所述药物制剂包括含有生物分子的用于吸入的干粉，其中所述生物分子包括适合使用干粉吸入系统全身性递送的肽或蛋白质，所述干粉吸入系统包括可与单位剂量的多用途药筒或胶囊一起使用的吸入器；单用途吸入器，其具有适合单用途的整体嵌入容器；或者多剂量吸入器，其被提供时采用整体与吸入器相配的多个剂量。
在一个实施方式中，提供热稳定性药物制剂，所述制剂包括含有蛋白质或肽和一种或多种药学上可接受的载体和/或赋形剂的干粉，所述制剂在高温和高湿度下稳定。在一个实施方式中，药物制剂在多个温度，例如高于20℃、高于25℃、高于30℃、或高于35℃的温度；和相对潮湿的环境，例如相对湿度高于5％、高于10％、高于30％、高于50％、高于60％、或高于70％的环境下，持续长时间保持稳定；其中药学上可接受的载体和/或赋形剂包括，例如，缓冲剂、盐、聚合物、二酮哌嗪和/或其盐等。在一个实施方式中，干粉组合物可任选地包含表面活性剂，例如聚山梨醇酯，例如，聚山梨醇酯80和Tween。
在某些实施方式中，制剂包括干粉，干粉包含肽，包括例如催产素、催产素衍生物或催产素类似物例如卡贝缩宫素(carbotecin)；缓冲剂；和单价或二价阳离子盐；和任选地糖和/或氨基酸。在一个具体的实施方式中，制剂包含干粉，干粉包含催产素、催产素衍生物或催产素类似物；缓冲剂和/或由盐提供的二价阳离子或单价阳离子，所述盐包括柠檬酸锌、乙酸锌、酒石酸二钠、酒石酸单钠、柠檬酸钠、柠檬酸二钠、柠檬酸三钠、氯化锌、氯化钙、氯化镁、氢氧化钠等。在一个实施方式中，制剂还包含一种或多种氨基酸，包括亮氨酸、异亮氨酸、三亮氨酸(trileucine)、胱氨酸、精氨酸、赖氨酸、甲硫氨酸和/或组氨酸。在一个实施方式中，单价阳离子可包括钠、钾和锂。在替代性实施方式中，制剂可含有柠檬酸。
在一个具体的实施方式中，提供这样的干粉组合物，其包含在组合物中的量低于40％(w/w)、低于30％(w/w)、低于20％(w/w)或低于10％(w/w)的催产素、柠檬酸钠，包括单价、二价或三价形式；和含量低于35％(w/w)、低于20％(w/w)或低于10％(w/w)的氯化锌或柠檬酸锌。在一个具体的实施方式中，氯化锌的用量范围为组合物的约1％-约7％(w/w)。在替代性实施方式中，柠檬酸锌的用量范围为组合物的约9％-约35％(w/w)。
在一个具体的实施方式中，提供这样的干粉组合物，其包含在组合物中的量低于40％(w/w)、低于30％(w/w)、低于20％(w/w)或低于10％(w/w)的催产素、酒石酸钠，包括单价或二价形式；和含量低于35％(w/w)、低于20％(w/w)或低于10％(w/w)的氯化锌或柠檬酸锌。在一个具体的实施方式中，氯化锌的用量范围为组合物的约1％-约7％(w/w)。在替代性实施方式中，柠檬酸锌的用量范围为组合物的约9％-约35％(w/w)。
在一个实施方式中，干粉组合物所含柠檬酸盐的量范围为每摩尔催产素、催产素类似物或催产素衍生物的100-20当量；且在组合物中，锌盐的量可以为每摩尔催产素的50-5当量。在一些实施方式中，浓缩柠檬酸钠缓冲剂被用作柠檬酸盐的来源，其中柠檬酸钠缓冲剂的浓度至多0.1M或0.75M且pH值范围为4.0-6.5。
在一个实施方式中，干粉组合物包含催产素、催产素类似物或催产素衍生物；锌和柠檬酸盐，其中在单次可吸入剂量中催产素、催产素类似物或催产素衍生物的量至多200IU。在一些实施方式中，干粉组合物的单次可吸入剂量包含150IU、100IU、50IU、40IU、20IU、10IU、5IU、1IU、0.05IU或0.005IU的催产素、催产素类似物或催产素衍生物。
制造干粉制剂的方法包括：将包含肽或蛋白质或其类似物的溶液混合或均质化，其中所述溶液所含柠檬酸盐的量范围为每摩尔肽或蛋白质的100-20当量；且在组合物中，锌盐的量范围可以为每摩尔肽或蛋白质或其类似物的50-5当量。在一些实施方式中，浓缩的柠檬酸钠缓冲剂被用作柠檬酸盐的来源；和在氮气室中喷雾干燥溶液，所述溶液包含肽、蛋白质、肽或蛋白质的片段和/或类似物，其中干粉制剂包含肽、蛋白质、肽或蛋白质的片段和/或类似物的混合物；柠檬酸盐或酒石酸盐和pH范围为4.5-6.5的阳离子盐，且其中所述阳离子盐是二价阳离子盐。
实施方式包括治疗产后出血的方法，所述方法包括：在产后24小时内，通过吸入向需要治疗的受试者施用干粉制剂，组合物包含催产素、催产素类似物或催产素衍生物；柠檬酸盐或酒石酸盐和阳离子(包括锌)源。在一个实施方式中，治疗包括：分娩后立即施用一剂或多剂本文所述的干粉制剂。
在替代性实施方式中，预防产后出血的方法包括：在分娩后24小时内或分娩后立即向易发产后出血的受试者施用干粉制剂，所述制剂包含催产素、催产素类似物或催产素衍生物；柠檬酸盐或酒石酸盐，和阳离子(包括锌)源。
在本文所述的其它实施方式中，公开了制造热稳定和潮湿稳定的制剂的方法和在治疗疾病和/或病症时使用所述制剂的方法，在使用吸入系统的实施方式中，所述疾病和/或病症包括，例如，产后出血、孤独症、社交焦虑症；情绪障碍和其它激素相关疾病。在示例性实施方式中，吸入系统是适合单剂量使用的高阻力吸入器。
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，并结合本文所展示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是包含1％催产素、87％海藻糖、10％异亮氨酸和10％聚乙烯吡咯烷酮(PVP)的无定形干粉制剂实施方式在低倍放大(1A)和高倍放大(1B)下的扫描电镜照片。
图2A是类似于图1B的对照粉末在高倍放大下的扫描电镜照片。图2B、2C和2D是包含1％催产素、柠檬酸盐和锌盐的无定形干粉制剂实施方式在高倍放大下的扫描电镜照片，所述实施方式含有不同量的二价锌盐和柠檬酸盐。
图3提供了由包含1％催产素的干粉组合物实施方式相较于对照在40℃和75％相对湿度下在约11个月内的稳定性研究数据得到的数据图示。
图4提供了由干粉的X射线衍射研究得到的数据图示，其中通过所述干粉的特征扫描谱显示粉末的无定形含量。
图5是来自干粉样品的稳定性研究的图示，其中样品包含不同浓度的二价锌盐和柠檬酸盐。
具体实施方式
将药物输送至肺部具有很多优势。但是由于传送药物经过天然的物理屏障方面的问题，很难以相同体积和重量以及药物物理和化学特性将药物递送至肺部。本文公开了热稳定性制剂，其包含：缓冲剂，包括柠檬酸盐和单价或二价阳离子；和一种或多种药学上可接受的载体和/或赋形剂。本文公开的实施方式显示：干粉制剂在高热量和湿度下稳定，因此它们便利和克服了现有技术制剂造成的贮存和冰箱挑战。还提供了制造适合在高于20℃的温度和潮湿环境下长期贮存的干粉组合物的方法。
当在本文中使用时，术语“微粒”是指直径为约0.5μm-约1000μm的颗粒，而与精确的外部或内部结构无关。直径为约0.5μm-约10μm的微粒可以成功穿过大部分天然屏障到达肺部。要求直径小于约10μm以便通过喉咙的转角，要求直径为约0.5μm或更大以避免被呼出。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“可吸入分数”(RF，respirable fraction)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多级撞击器)测量的空气动力学直径为约0.5μm-约6μm的那些颗粒，尽管一些参考文献使用稍微不同的范围。其它撞击器也可以用于测量空气动力学颗粒尺寸，例如NextGeneration ImpactorTM(NGITM,MSP Corporation)，可吸入分数是通过相似的空气动力学尺寸(例如<6.4μm)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序列号12/727,179中公开的激光衍射装置，其中关于激光衍射的相关教导全部并入本文中，其中测量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％的药筒排空率和≤12.5μm、≤7.0μm或≤4.8μm的射出颗粒的VMGD可以指示越来越好的气动性能。
当在本文中使用时，术语“约”用于表示一个值包括确定该值所用设备或方法的测定标准偏差。
基于填充量的可吸入分数(RF/填充量)表示在用作剂型使用填充粉末内容物排出之后从吸入器射出的一个剂量/剂型(dose)中适于吸入的粉末的百分比，即从填充剂型中射出且尺寸适于肺部给药的颗粒的百分比，其为微粒气动性能的量度。如本文中所述，40％或大于40％的RF/填充量反映出可接受的气动特性。在本文中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定，所射出的填充量中约80％的颗粒尺寸<5.8μm。
当在本文中使用时，术语“干粉”指的是不悬浮或溶解在推进剂或其它液体中的精细颗粒组合物。并不意味着完全不存在水分子。
当在本文中使用时，“无定形粉末”指的是缺乏确定的重复形式、形状或结构的干粉，包括所有的非晶态粉末。
在一个实施方式中，干粉是相对粘着的粉末，其需要最佳的解聚条件。在一个实施方式中，吸入系统提供可重复使用的微型呼吸电动吸入器和包含预先计量的干粉制剂剂型的一次性药筒。
当在本文中使用时，术语“单位剂量吸入器”指的是适于接收或包含单个含有干粉制剂的容器的吸入器，并且该吸入器将单剂量的干粉制剂通过吸入从容器递送至使用者。在一些情况下，需要多个单位剂量以向使用者提供规定的剂量。在一个实施方式中，吸入器是干粉吸入器，其可以是一次性的以用于单次使用，或者可以利用单个单位剂量容器重复使用多次。
当在本文中使用时，术语“多剂量吸入器”指的是具有多个容器的吸入器，每个容器包括预先计量的干粉药物且吸入器每一次均通过吸入递送单剂量的药物粉末。
当在本文中使用时，“容器”是配置成保持或者包含干粉制剂的壳、容纳粉末的壳，并且可以是具有或者不具有盖子的结构。该容器可与吸入器分开提供或者可在结构上整合在吸入器内(例如，不可拆卸的)。此外，容器可充满干粉。药筒也可包含容器。
当在本文中使用时，“粉末块”指的是粉末颗粒的结块或者具有不规则几何形状(例如，宽度、直径和长度)的结块。
当在本文中使用时，术语“微粒”指的是直径为约0.5μm-约1000μm的颗粒，而与精确的外部或者内部结构无关。然而，通常期望四种小于10μm的肺部递送微粒，尤其是颗粒直径的平均尺寸小于约5.8μm的微粒。
在示例性实施方式中，提供干粉制剂，其包含肽或蛋白质，其中所述肽或蛋白质对热降解敏感。在一个具体的实施方式中，干粉制剂包含肽，包括催产素、催产素衍生物或催产素类似物；柠檬酸盐，包括柠檬酸钠和柠檬酸锌；二价盐，包括氯化锌、氯化钙和氯化镁；和一种或多种药学上可接受的载体，所述载体选自糖，例如，单糖(saccharide)、二糖、低聚糖；氨基酸；其中糖是例如海藻糖、甘露糖、甘露醇或山梨醇，且载体是聚乙二醇、聚乙烯吡咯烷酮或能够形成微粒的二酮哌嗪，包括延胡索酰二酮哌嗪、琥珀酰二酮哌嗪、马来酰二酮哌嗪、丙二酰二酮哌嗪和乙二酰二酮哌嗪、或者其二钠或镁盐、及其衍生物。
在另一个实施方式中，制剂包含肽，所述肽包括生长激素、降钙素、胰高血糖素、甲状旁腺素、甲状旁腺素(1-34)、胰高血糖素样肽-1、干扰素、白介素、促红细胞生成素、促黄体生成激素释放激素、生长激素抑制素、加压素、脑啡肽、促肾上腺皮质激素、生长激素释放激素；生长因子，包括粒细胞集落形成刺激因子；甲状腺刺激激素、甲状腺刺激激素释放激素、抗伤害感受的肽(antinociceptive peptide)、血管紧缩素、促黄体激素、凝乳酶、肠抑胃肽(GIP)和C-肽。
在另一个实施方式中，制剂包含肽，其中所述肽是催产素、胰岛素、生长激素、降钙素、胰高血糖素、甲状旁腺素、胰高血糖素样肽-1、胰高血糖素样肽-2、甲状旁腺素(1-34)、或甲状腺刺激激素释放激素、胃泌酸调节素、肽YY、瘦素、脱氧核糖核酸酶、核糖核酸酶和促卵泡激素。
在一个实施方式中，制剂包含一种或多种肽，一种或多种氨基酸，其中所述氨基酸是异亮氨酸、亮氨酸、三亮氨酸、胱氨酸、半胱氨酸、甘氨酸、赖氨酸、精氨酸、组氨酸或甲硫氨酸；和一种或多种糖，包括乳糖、甘露醇、甘露糖、山梨醇、海藻糖等。在这个和其它实施方式中，载体可以是聚乙二醇、聚乙烯吡咯烷酮、或单糖、低聚糖、或多糖，包括乳糖、海藻糖、甘露糖、甘露醇或山梨醇；柠檬酸锌和氯化锌；其中通过喷雾干燥工艺制造制剂，其中肽在pH范围为约3.5-约7或者4.5-6.5的缓冲液中。
在一个具体的实施方式中，制剂包含浓度为约0.005IU-约40IU、1IU-约15IU或者约5IU-约20IU的催产素。在一个实施方式中，分娩后几分钟，向患者施用催产素以防止产后出血，其中在单次吸入中制剂中包含催产素的量范围为5-约40IU的。在这个实施方式中，制剂中可提供的催产素的含量为约0.1％-约50％(w/w)、约0.5％-约40％(w/w)、约0.5％-约20％(w/w)或者约1％-约10％(w/w)。在某些实施方式中，取决于要治疗的受试者的需要，催产素的量可高于40IU。
在一个实施方式中，提供了向受试者的血流有效递送制剂的方法，所述方法包括：向需要治疗的受试者提供包含吸入器的吸入系统，所述吸入器包含含制剂的药筒，所述制剂包括干粉制剂，所述干粉制剂包含肽(包括催产素)、柠檬酸盐缓冲剂或酒石酸盐缓冲剂和二价阳离子盐，其中所述二价阳离子是锌。在这个实施方式和其它实施方式中，吸入系统递送包含体积中值几何直径(VMGD)小于8μm的颗粒的粉末流。在一个示例性实施方式中，微粒的VMGD可在约4μm-6μm的范围内。在一个示例性实施方式中，在单次吸入制剂的填充质量为1mg-10mg干燥粉末时，粉末微粒的VMGD可为约3μm-6μm。在这个实施方式和其它实施方式中，吸入系统递送多于40％或多于60％的药筒中的干粉制剂。
在另一实施方式中，制剂是包含延胡索酰二酮哌嗪二钠微粒的无定形干粉，所述干粉包含催产素；柠檬酸盐缓冲剂；氯化锌；氨基酸，例如亮氨酸、异亮氨酸、三亮氨酸或胱氨酸；和甘露醇或海藻糖，或其组合。
在一个实施方式中，制剂包含无定形干粉，所述干粉包含肽，包括热敏感性肽，包括催产素；其中干粉通过下述过程形成：在调节后的pH为4.5-6.5的含柠檬酸钠或乙酸钠的缓冲液中混合催产素并加入二价阳离子盐(包括氯化锌)和任选地糖(例如海藻糖或甘露醇)，然后干燥。
在一个具体的实施方式中，制剂包含无定形干粉，所述干粉包含催产素；其中干粉通过下述过程形成：在含柠檬酸盐和/或柠檬酸的溶液中混合催产素并加入二价阳离子盐(包括氯化锌)和任选地糖(例如海藻糖或甘露醇)和任选地一种或多种载体。
其它实施方式涉及药物递送系统，所述药物递送系统包含吸入器、单位剂量干粉药物容器、包含本文所公开的热敏感性肽和柠檬酸锌的干粉。
一个实施方式公开了一种制剂，所述制剂包含催产素、催产素衍生物或催产素类似物，其中所述制剂还包含二酮哌嗪微粒，包括比表面积(SSA)小于约67m2/g的延胡索酰二酮哌嗪微粒。另一个实施方式包括这样的二酮哌嗪微粒，其中在95％的置信界限内，比表面积为约35-约67m2/g。另一个实施方式包括比表面积为约35-约62m2/g的二酮哌嗪微粒。另一个实施方式包括比表面积为约40-约62m2/g的二酮哌嗪微粒。
在替代性实施方式中，FDKP微粒包含药物或活性剂。在FDKP微粒的各种实施方式中，药物可以是，例如，肽，包括催产素、胰岛素、胰高血糖素样肽-1(GLP-1)、胰高血糖素、激动肽、甲状旁腺素、降钙素、胃泌酸调节素、其衍生物和/或类似物等。在FDKP微粒的另一个实施方式中，肽含量可因下游加工条件而异。在一个具体的实例中，FDKP微粒可被制备为其药物/肽含量可因目标剂量或要递送的剂量而异。例如，当药物是胰岛素时，包含微粒的粉末制剂中胰岛素组分可以为约3U/mg-约6U/mg，且可在形成颗粒之前向溶液中加入锌盐和柠檬酸盐。在某些实施方式中，药物被吸附到预形成微粒的表面。
其它实施方式涉及药物递送系统，所述药物递送系统包含吸入器、单位剂量干粉药物容器(例如，药筒)的组合，并包含本文公开的干粉制剂和活性剂。在一个实施方式中，与干粉一起使用的递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，能够对经过管道的气流赋予高阻力以使粉末解聚和分配。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-约0.200(√kPa)/升。在某些实施方式中，干粉可以利用吸入系统通过吸入有效地递送，其中峰值吸入压差可以在约2-约20kPa的范围内，其可以产生的所得峰值流速在约7-70升/分钟之间。在某些实施方式中，吸入系统被配置为通过使粉末作为递送给患者的粉末的连续流或者一个或更多个脉冲从吸入器排出而提供单剂量。在本文所公开的一些实施方式中，干粉吸入器系统包括吸入器内的预定质量流平衡。例如，占离开吸入器并进入患者的总流量约10％-70％的流平衡是通过一个或多个分配-端递送的，其中气流穿过包含粉末制剂的区域，并且其中约30％-90％的气流是从吸入器的其它管道产生的。此外，旁流或未进入并离开粉末容器区域(例如通过药筒)的流可以与离开吸入器内粉末分配端的流重新组合，从而使流化粉末在离开口器之前被稀释、加速并最终解聚。在一个实施方式中，约7-70升/分钟范围内的流速导致超过75％的容器或药筒内容物中被分配于1-50mg或1-30mg的填充质量中。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高于40％、高于50％、高于60％或高于70％的可吸入分数/填充量的粉末剂量。
在一个具体的实施方式中，所提供的吸入系统包括干粉吸入器和干粉制剂。在吸入系统的这种实施方式的一些方面，干粉制剂被提供在单位剂量药筒中。或者，干粉制剂可以预装载在吸入器中。在这种实施方式中，吸入系统的结构配置允许吸入器的解聚机制产生高于50％的可吸入分数；也就是说，多于一半的包含在吸入器(药筒)中的粉末作为小于5.8μm的颗粒射出。吸入器在给药期间可以排出容器内所含的高于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粉末药物的多于85％。在一个实施方式中，吸入器可以在2kPa-5kPa之间的压差下以至多30mg的填充质量在小于3秒的时间内排出高于90％的药筒内容物或容器内容物。
本文公开的另一个实施方式包括制造适合作为干粉制剂肺部给药的微粒的方法，所述干粉制剂包含载体颗粒，包括二酮哌嗪微粒。在这个实施方式和其它实施方式中，干粉制剂是通过喷雾干燥含肽的溶液得到的，其中将一种或多种赋形剂溶解在含锌盐和柠檬酸盐的水性溶液中并混合，随后加入一定量的肽并混合以形成料液；然后在入口温度约120℃-150℃且出口温度约60℃-65℃、或50℃-75℃、或40℃-85℃等的干氮气流中使溶液流雾化。
在一些实施方式中，涉及制造比表面积小于约67m2/g且/或反式异构体比率为约45％-65％的二酮哌嗪微粒的方法，所述方法利用具有式2,5-二酮-3,6-双(N-4-X-氨基丁基)哌嗪二钠盐或镁盐的二酮哌嗪，其中X选自由延胡索酰基、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，二酮哌嗪具有式双-3,6-(N-延胡索酰基-4-氨基丁基)-2,5-二酮哌嗪或2,5-二酮-3,6-双(N-延胡索酰基-4-氨基丁基)哌嗪。
本文公开的另一个实施方式包括将药物(例如，肽诸如胰岛素)递送至有此需要的患者的方法，所述方法包括：通过患者对干粉的吸入，将干粉施用至肺深部，其中所述干粉包含含有胰岛素、锌盐和柠檬酸盐的二酮哌嗪微粒；其中所述微粒由二酮哌嗪微粒形成，并且具有约35-约67m2/g或者约40-约67m2/g的SSA且/或在微粒具有约45％-约65％的反式异构体比率。在这种实施方式的一些方面中，吸入器系统的具体特征是指定的。其它实施方式涉及治疗胰岛素相关病症的方法，所述方法包括将上文所述的干粉施用至有此需要的人。在各种实施方式中，胰岛素相关病症可具体包括或排除前期糖尿病、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、胰岛素抵抗、分泌功能障碍、受损的胰岛素早期释放、胰腺β-细胞功能损失、胰腺β-细胞损失和代谢病症中的任何或所有。
一种实施方式包括治疗内分泌相关疾病或病症的方法，所述方法包括将干粉制剂施用至有此需要的人，所述干粉制剂包含肽激素，包括催产素、GLP-1等、柠檬酸盐和二价阳离子盐。在一个实施方式中，干粉制剂可包含比表面积小于约67m2/g的FDKP二钠微粒或FDKP微粒和适合治疗所述疾病或病症的药物。其它实施方式包括治疗胰岛素相关疾病的方法，所述方法包括将干粉施用至有此需要的人，所述干粉包含FDKP二钠微粒或FDKP微粒、柠檬酸盐、乙酸盐或酒石酸盐缓冲剂和二价阳离子(包括锌、镁和钙)或单价阳离子(包括钠、钾和锂)。方法可包括向受试者施用干粉制剂。在各种实施方式中，可利用包含催产素的制剂治疗激素相关病症例如产后出血、或者任何其它催产素相关疾病。在将要治疗胰岛素相关病症的实施方式中，将要用包含胰岛素的制剂治疗的受试者可具体包括或排除前期糖尿病、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、胰岛素抵抗、分泌功能障碍、受损的胰岛素早期释放、胰腺β-细胞功能损失、胰腺β-细胞损失和代谢病症中的任何或所有。在一种实施方式中，干粉包含胰岛素。在其它实施方式中，干粉包含胰高血糖素、激动肽、或GLP-1、PTH、PTHrP、其组合等。
在本文的实施方式中，具体的RF/填充量值可取决于用于递送粉末的吸入器。粉末通常倾向于团聚且结晶的DKP微粒特别形成粘着性粉末。干粉吸收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递送剂量的可吸入分数。但是，粘着性粉末的解聚通常不彻底，使得当测量通过吸入器递送的可吸入分数时，所看到的颗粒尺寸分布与最初的颗粒尺寸分布不匹配，也就是说，分布曲线向较大的颗粒偏移。吸入器的设计在其解聚效率方面变化，因此使用不同设计观察到的RF/填充量的绝对值也将不同。但是，不同吸入器之间作为比表面积的函数的最佳RF/填充量是类似的。
已被用于克服药物领域中的问题例如药物不稳定性和/或吸收差的一类药物递送剂是2,5-二酮哌嗪。2,5-二酮哌嗪可形成混有药物的微粒或形成其上吸附药物的微粒。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被递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：通过基于pH的游离酸(或碱)沉淀法产生由聚集的结晶板构成的自组装微粒。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 drugformulation based on increasing the affinity of crystalline microparticlesurfaces 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)。最后可以除去溶剂以得到干粉。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 pharmaceutical agents”的美国专利No.6,444,226，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)。本文公开的微粒可由DKP游离酸或碱组成或者由DKP盐组成。这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)，从而得到无定形盐(而不是游离酸或碱)的球体和/或塌陷球，使得它们是在化学、物理和形态上均不同的实体。在各实施方式中，本公开的内容涉及作为游离酸或溶解的阴离子的FDKP。在本文的实施方式中，示例性实施方式包括美国专利Nos.7,820,676和8,278,308中公开和预期的FDKP二钠盐，上述文献通过全文引用并入本文。
合成二酮哌嗪的方法在例如Katchalski等人,J.Amer.Chem.Soc.68,879-880(1946)和Kopple等人,J.Org.Chem.33(2),862-864(1968)中有所描述，它们中关于二酮哌嗪合成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等人称之为赖氨酸酸酐)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)，随后利用适当的试剂和条件除去保护(P)-基团。例如，可以使用乙酸中的4.3MHBr除去CBz保护基。这种途径可以是优选的，因为它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“Catalysis of DiketopiperazineSynthesis”的美国专利No.7,709,639中也有描述，其就相同方面的教导也通过引用并入本文。
对于肺部应用而言，延胡索酰二酮哌嗪(双-3,6-(N-延胡索酰基-4-氨基丁基)-2,5-二酮哌嗪；FDKP)是一种优选的二酮哌嗪：
Figure BDA0003533234320000141
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在中性或碱性pH下易于溶解。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-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容易地由FDKP制备。
如前所述，直径在约0.5-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，例如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。这些板的尺寸与颗粒的比表面积有关，颗粒的比表面积又转而影响颗粒的结构、负载容量和气动性能。
DKP微粒的SSA是平均晶体尺寸的量度，并且可以用于评估晶核的相对分布和微粒特性的增长。SSA取决于微粒晶体的尺寸和微粒基质的密度(ρ)，并与晶体的特征尺寸L成反比。本文中公开的实施方式显示：比表面积小于约67m2/g的微粒展示出有益于递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 DryPowder Inhaler”的美国专利No.7,464,706中公开的
Figure BDA0003533234320000151
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。比表面积小于约62m2/g的替代性实施方式提供更高水平的保证：一批颗粒将满足最低气动性能标准。因为SSA也影响药物负载/含量能力，所以对于改进的药物吸附能力，不同实施方式要求SSA≥35、40或45m2/g。此外，当SSA降至低于约35m2/g时，观察到不一致的药筒排空率，即使利用高效吸入器亦如此，例如2009年6月12日递交的标题为“A Dry Powder Inhaler and System for Drug Delivery”的美国专利申请No.12/484,125(现在的美国专利No.8,499,757)和2010年3月4日递交的标题为“Improved Dry Powder Drug Delivery System”的美国专利申请No.12/717,884(现在的美国专利No.8,485,180)中公开的那些，所述公开内容就相同方面的教导通过引用并入本文。
FDKP微粒形成
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(图2)。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、倾析并重新悬浮来洗涤悬浮液或者通过渗滤，以除去过量的溶剂。
在一个实施方式中，为了形成载有肽的FDKP微粒，例如，可以通过将胰岛素储液加入包含柠檬酸盐缓冲剂的FDKP微粒悬浮液中，使胰岛素在悬浮期间(即：在冷冻干燥之前)可以直接吸附在微粒上。在实施方式中，还可以在加入胰岛素储液之后进行pH控制步骤。该步骤可以在进一步处理前促进胰岛素吸附到悬浮液中的微粒上。悬浮液的pH增加到约4.5促进全部胰岛素吸附悬浮液中的微粒上，而不会使来自微粒基质的FDKP过度溶解，并且还改善胰岛素在原料药品中的稳定性。悬浮液可以在液氮中逐滴速冻(即：低温粒化)并冷冻干燥以除去溶剂和得到干粉。在替代性实施方式中，悬浮液可以被喷雾干燥以得到干粉。
在一个实施方式中，提供了制备含有胰岛素的本发明的FDKP微粒的制造方法。概括地说，使用高剪切混合器，例如Dual-feed SONOLATORTM，在2000psi下通过0.001-in2的孔；或例如在2009年11月2日递交的美国临时专利申请No.61/257,311(其公开内容就DKP微粒生产方面的教导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，在2000psi下使等质量的约10.5重量％的乙酸和约2.5重量％的FDKP溶液通过0.001-in2的孔。在质量和温度大致相等的去离子水(DI)贮水池中可以收集到沉淀物。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物。沉淀物可以首先浓缩至约4％固体，然后用去离子水洗涤。悬浮液最终可以浓缩至基于FDKP的初始质量约10％固体。通过烘干法可以测定浓缩的悬浮液的固体含量。在该实施方式中，将悬浮的FDKP微粒与含胰岛素的柠檬酸盐溶液和锌均质化以形成粉末颗粒，然后喷雾干燥或冻干。
本文所述的微粒可包含一种或多种活性剂。当在本文中使用时，“活性剂”可与“药物”交换使用，其指的是药学物质，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、多糖和其它糖、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它多肽融和的单链抗体、或抗癌抗原的治疗性或诊断性单克隆抗体。活性剂可以被归入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、传染剂、炎症介质、激素和细胞表面抗原。更具体地，活性剂可以包括但不限于细胞因子；脂质因子(lipokine)；脑啡肽；炔烃；环孢菌素；抗-IL-8抗体；IL-8拮抗剂，包括ABX-IL-8；前列腺素，包括PG-12；LTB受体阻滞剂，包括LY29311、BIIL284和CP105696；曲普坦类例如舒马曲坦；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)；胃饥饿素(ghrelin)；肥胖抑制素(obestatin)；肠抑素(enterostatin)；粒细胞集落刺激生物因子(GM-CSF)；糊精；糊精类似物；胰高血糖素样肽-1(GLP-1)；德克萨斯红(Texas Red)；氯吡格雷(clopidogrel)；PPACK(D-苯丙氨酰基-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(secretin)；促胃液素(gastrin)；胰高血糖素；胃动素(motilin)；生长抑制素(somatostatin)；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(ITB4)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。
将要递送的药物含量取决于受试者的需要和药物的效能。在某些实施方式中，使用的由反式异构体含量为45％-65％的FDKP形成的微粒的药物含量通常高于0.01％。在一个实施方式中，将要用具有上述反式异构体含量的微粒递送的药物含量可以在约0.01％-约20％的范围内，这通常是对于肽(例如胰岛素)来说的。例如，如果药物是胰岛素，则本发明的微粒通常含有3-6U/mg(约10-15％)的胰岛素。在某些实施方式中，颗粒的药物含量可因待递送药物的形式和尺寸而异。
待递送药物的负载范围通常为约0.01％-约90％，这取决于待递送药物的形式和尺寸以及所需剂量的效能。对于催产素，优选的载量为约0.5％-约50％(w/w)；或者约0.5％(w/w)-约20％(w/w)。
只要本文所述的DKP微粒保持所需的异构体含量，它们便能采用有益于递送至肺部和/或药物吸收的其它附加特性。标题为“Method for Drug Delivery to thePulmonary System”的美国专利No.6,428,771描述了将DKP颗粒递送至肺部，其就相同方面的教导通过引用并入本文中。标题为"Purification and Stabilization of Peptide andProtein Pharmaceutical Agents”的美国专利No.6,444,226描述了有益于将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中。可以利用微粒表面性能来实现如标题为“Method of Drug Formulation based on Increasing the Affinity ofCrystalline Microparticle Surface for Active Agents”的美国专利申请No.11/532,063(现在的美国专利No.7,799,344)中所述的期望特性，所述文献就相同方面的教导也通过引用并入本文中。标题为"Method of Drug Formulation based on Increasing theAffinity of Active Agents for Crystalline Microparticle Surfaces”的美国专利申请No.11/532,065描述了促进活性剂吸附到微粒上的方法。美国专利申请No.11/532,065(现在的美国专利No.7,803,404)也就相同方面的教导通过引用并入本文中。
为了进一步举例说明本发明的某些方面，本发明还具体地提供了如下的一些非限制性实施方式：
实施方式1.干粉药物制剂，其包含肽、蛋白质、所述肽或蛋白质的衍生物或类似物；柠檬酸盐或酒石酸盐、阳离子盐、氨基酸、和/或药学上可接受的载体或赋形剂。
实施方式2.根据实施方式1所述的干粉药物制剂，其中所述肽、蛋白质、所述肽或蛋白质的衍生物或类似物是催产素、催产素衍生物或催产素类似物。
实施方式3.根据实施方式1所述的干粉药物制剂，其中所述柠檬酸盐是柠檬酸钠或柠檬酸锌。
实施方式4.根据实施方式1所述的干粉药物制剂，其中所述阳离子盐是二价阳离子盐，所述二价阳离子盐是氯化锌、柠檬酸锌、乙酸锌、氯化镁或氯化钙。
实施方式5.根据实施方式1所述的干粉药物制剂，其中所述药学上可接受的载体或赋形剂是糖，所述糖选自甘露糖、甘露醇、海藻糖或山梨醇。
实施方式6.根据实施方式1所述的干粉药物制剂，其中所述药学上可接受的载体或赋形剂是聚乙烯吡咯烷酮、聚乙二醇或二酮哌嗪。
实施方式7.根据实施方式6所述的干粉药物制剂，其中所述二酮哌嗪是延胡索酰二酮哌嗪或琥珀酰二酮哌嗪。
实施方式8.根据实施方式1所述的干粉药物制剂，其中所述柠檬酸盐的量为每摩尔催产素、催产素衍生物或催产素类似物的100-20当量。
实施方式9.根据实施方式1所述的干粉药物制剂，其中所述阳离子盐的量为组合物中的每摩尔催产素的50-5当量。
实施方式10.根据实施方式1所述的干粉药物制剂，其中所述肽是内分泌激素、生长因子或伤害感受肽。
实施方式11.根据实施方式10所述的干粉药物制剂，其中所述内分泌激素是胰岛素、甲状旁腺素、降钙素、胰高血糖素、胰高血糖素样肽-1、胃泌酸调节素、所述内分泌激素的类似物或活性片段。
实施方式12.根据实施方式10所述的干粉药物制剂，其中所述氨基酸是亮氨酸、异亮氨酸、三亮氨酸、胱氨酸、赖氨酸、甘氨酸、精氨酸、甲硫氨酸或组氨酸。
实施方式13.制造干粉制剂的方法，所述方法包括：在氮气室中喷雾干燥溶液，所述溶液包含肽、蛋白质、肽或蛋白质的片段和/或类似物，其中所述干粉制剂包含如下物质的混合物：肽、蛋白质、肽或蛋白质的片段和/或类似物；柠檬酸盐或酒石酸盐和pH范围为4.5-6.5的阳离子盐，且其中所述阳离子盐是二价阳离子盐。
实施方式14.根据实施方式13所述的方法，其中所述干粉制剂包含催产素。
实施方式15.根据实施方式13所述的方法，其中所述柠檬酸盐是柠檬酸钠。
实施方式16.根据实施方式13所述的方法，其还包含氨基酸或糖。
实施方式17.根据实施方式16所述的方法，其中所述氨基酸是亮氨酸、异亮氨酸、三亮氨酸、胱氨酸、赖氨酸、甘氨酸、精氨酸、甲硫氨酸或组氨酸。
实施方式18.根据实施方式16所述的方法，其中所述糖是海藻糖或甘露醇。
实施方式19.根据实施方式13所述的方法，其中所述酒石酸盐是酒石酸钠。
实施方式20.用于吸入的药物干粉制剂，所述药物干粉制剂包含催产素、催产素类似物或催产素衍生物；柠檬酸钠、氯化锌和药学上可接受的赋形剂。
实施方式21.根据实施方式20所述的药物干粉制剂，其中在所述干粉制剂中，柠檬酸钠多于0.5％(w/w)；多于5％(w/w)；多于10％(w/w)或多于20％(w/w)。
实施方式22.根据实施方式13所述的方法，其中所述喷雾干燥包括：在入口温度约120℃-150℃的干氮气流中使溶液流雾化。
实施方式23.治疗或预防产后出血的方法，所述方法包括：向需要治疗的受试者施用根据实施方式1所述的干粉药物制剂，所述干粉药物制剂包含至多200IU的催产素。
实施方式24.根据实施方式17所述的方法，其中所述氨基酸是异亮氨酸。
实施例
以下实施例用于展示所公开微粒的实施方式。本领域技术人员应当理解，以下实施例中公开的技术代表发明人发现的在本发明的实践中很好发挥作用的技术，因此这些技术可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，可以对公开的具体实施方式进行许多改变并仍然获得类似或相似的结果。
实施例1
催产素喷雾干燥粉末的制备、表征和稳定性
如下表2中所示，以7g的规模制备14种粉末，所述粉末包含1％(w/w)催产素和不同量的得自如下表1中所述的各种供应商的缓冲剂、盐、载体、赋形剂，包括海藻糖、PVP、异亮氨酸、胱氨酸、三亮氨酸、FDKP、柠檬酸钠和锌盐。如下制备样品：称量如表2中所述需要的量并溶解在去离子水中以形成溶液或悬浮液，加入催产素并混合，然后喷雾干燥。在使用柠檬酸盐缓冲剂和二价阳离子的样品中，将催产素溶解在柠檬酸盐缓冲剂中，然后将剩余成分加入混合物中。然后利用如下表3中所述的参数将溶液或悬浮液喷雾干燥。喷雾干燥之前，在高剪切混合器中将悬浮液均质化。喷雾干燥之前，通过0.2μm的膜过滤溶液。
收集干粉并用于下述实验中。利用多种技术进行实验以表征得到的粉末，包括测量各样品在温育前后的催产素含量以确定产率、并评估干燥损失(LOD)、气动性能、颗粒尺寸和颗粒形态。使用来自每种制备的干粉样品的等份进行稳定性研究，所述样品在置于热密封的铝袋中的用氟聚合物树脂内衬螺旋盖密封的闪烁管中在40℃、75％的相对湿度(40℃/75％RH)下温育持续所研究的时间段。在实验开始时直至实验开始后约7个月的不同时间采集经温育材料的样品。通过高效液相色谱(HPLC)试验评估样品(参见下文所述的制备)以测定样品和降解产物中催产素的存在。对于某些粉末，包括表2中的样品ID Nos.4、6和13，催产素稳定性研究进行长达11个月。
表1.制剂组分
Figure BDA0003533234320000211
Büchi迷你喷雾干燥器B 290
过滤单元快速PES膜(0.2μm)150mL系统(Nalgene)
均化器(Tekmar Tissumizer)
表2.样品制剂含量
Figure BDA0003533234320000221
*ILE:异亮氨酸，TLE:三亮氨酸，CYS:胱氨酸
制备目标催产素的含量为1％的喷雾干燥粉末。表2中详述了制剂含量。海藻糖：异亮氨酸：PVP的重量比率为87:10:2的混合物用作样品ID Nos.1-6的对照制剂的基质。向该混合物中加入柠檬酸钠和锌。柠檬酸盐的量从每摩尔催产素的100-20当量不等(总重量的24-4.8％)。锌盐的量从每摩尔催产素的50-10当量不等(总重量的6.7-1.3％)。浓缩柠檬酸钠缓冲剂(75mM，pH＝4.5和6.5)被用作柠檬酸盐的来源。
进料溶液的固体含量恒定保持在5％。在喷雾干燥之前过滤进料溶液。一种含FDKP的制剂显示为混浊且未被过滤(样品ID No.7)；含三亮氨酸、胱氨酸和柠檬酸锌(样品IDNo.11、12和13)的混合物需要均质化并使产生的悬浮物在喷雾干燥工艺期间保持连续搅拌。含柠檬酸锌和柠檬酸盐缓冲剂的悬浮液被制备成进料溶液并在高剪切混合(Tissumizer均质器)中均质化。将含有在水中的催产素和剩余赋形剂的第二溶液加入到悬浮液中并利用去离子水将最终重量调节为140g。
表3.喷雾干燥条件
入口： 130℃
出口： 63℃
干燥气流： 60mbar(氮气)
雾化流： ～59.9g/h
抽吸器 80％
泵 5％
下表4中显示了催产素稳定性研究结果。数据被展示为样品中剩余的催产素相较于所用材料的起始量的百分比(％)。在表4和图3中可以看出，温育32周之后分析时，所检测的粉末制剂中有3种(样品ID No.4、6和13)保持多于约90％的催产素。数据还显示：柠檬酸钠和锌盐的组合在固体或干粉形式(约100％，样品ID No.6)下导致最高的稳定性(较少的催产素降解)。此外，添加柠檬酸钠和锌还导致较高的所用粉末单位填充量的可吸入分数(RF/填充量)，其中对于含12％(w/w)柠檬酸钠、3.4％(w/w)氯化锌、73.5％(w/w)海藻糖、8.4％(w/w)异亮氨酸和1.69％(w/w)PVP的粉末，最高RF/填充量为60.2％。不利用锌和柠檬酸盐配制的对照粉末的RF/填充量为40.9％(样品ID No.1)，但其催产素降解速率更高，因为温育32周之后，样品中剩余仅51.6％催产素。
研究样品对照粉末的扫描电镜照片(SEM)并显示于图1A(低倍放大)和图1B(高倍放大)中。SEM展示了形状规则、大体上为球形的颗粒，其大体上显示出尺寸大体均匀、具有小的表面凹陷且通常为无定形粉末。
表4.催产素粉末在40℃/75％RH下的稳定性结果
Figure BDA0003533234320000231
Figure BDA0003533234320000241
干粉表征：LOD、RF/填充量、SEM和催产素试验
利用加热和保持方法(20℃/分，110℃等温线持续30分钟)通过热重量分析(TGA)测量干燥损失(LOD)。获得的粉末的平均产率为73.8％且最低LOD为4.63％。
利用Gen2C吸入器(30Lpm,8s,MannKind Corp.)通过Andersen多级撞击(AndersenCascade Impaction)测量喷雾干燥粉末的气动性能，结果显示于表5中。利用SympatecRODOS M粉末分散器(分散压强设置为0.5bar和3bar)通过激光衍射测定几何颗粒尺寸。通过电场发射扫描电镜评估颗粒形态。表5显示：在所检测的0.5bar和3bar大气压强下，颗粒的尺寸范围为约3.8-5.6μm，且FR/填充量％为约40-约60％。在表5中可以看出，含柠檬酸盐和锌的样品(样品ID No.2、3和4)表现最好，如药筒排空率数据(>70％)和56％-60％的射出剂量所示。轻击3000次之后，利用振实密度分析仪(Autotap)评估粉末的密度。无论盐含量如何，粉末块的密度不超过0.5g/ml。
利用HPLC方法评估催产素含量。制备的催产素标准溶液为在pH＝9.5的0.1M碳酸氢钠中约250μg/mL(25.0mL中6.25mg催产素原料)。制备过程如下：将10±1.0mg粉末溶解在pH＝9.5的0.1M碳酸氢钠中以产生0.250mg/mL的最终催产素浓度。检测初始药物含量以确定起始材料。所制备粉末的目标药物含量为1％，试验证实催产素含量为0.92-1.13％。
粉末形式的催产素的稳定性
称量粉末加入20mL玻璃小瓶中，然后闭合玻璃小瓶，用箔包裹并热封。将箔袋放在40℃/75％RH的稳定性室中。在第2周和第4周时拉出样品；然后每间隔4周拉出样品直至温育后32周。冻存样品(-20℃)直至如上所述通过HPLC分析。
表5.气动性能、颗粒尺寸和密度表征
Figure BDA0003533234320000251
气动性能、颗粒尺寸和形态
所选粉末的气动试验强调了柠檬酸钠和锌与海藻糖、异亮氨酸和PVP的组合的有益效果。柠檬酸盐和锌的含量分别低至4.8％和1.3％时观察到了效果(表5，样品ID No.4)。利用12％柠檬酸盐和3.4％锌的含量时观察到了最大效果(60.3％RF/填充量)。利用2倍量的柠檬酸盐和锌制备的粉末样品ID No.2的RF/填充量为59.1％。当在吸入器中检测时，粉末样品ID Nos.2和4的原始含量的约77％被递送出吸入器。利用海藻糖、异亮氨酸和PVP(87/10/2)配制的对照粉末(样品ID No.1)的RF/填充量为40.9％且其速率低于含锌和柠檬酸盐的样品的速率。
通过扫描电镜研究的颗粒形态显示：含海藻糖、PVP和异亮氨酸的对照制剂(样品ID No.1)的喷雾干燥产生稍微起皱的球形颗粒，这对含亮氨酸的粉末是典型的(图2A)。利用向含海藻糖、PVP和异亮氨酸的混合物中加入盐(锌和柠檬酸盐)来维持起皱、大体为球形的形态(图2B、2C和2D)。然而，含锌和柠檬酸盐的颗粒不同于对照，因为它们显示出略微更加起皱且不太像球形。如SEM中所示，利用锌和/或柠檬酸盐形成的颗粒显示出大体为球形且具有略微更多凹陷、起皱表面或皱纹外观，和不太规则的图案。已观察到：在制备期间，尤其是在真空干燥步骤期间，含催产素、锌和柠檬酸盐的颗粒显示出比对照更加易碎或更容易崩散。
图4提供了由干粉的X射线衍射研究得到的数据图示，其中通过所述干粉的特征扫描谱显示粉末的无定形含量。数据显示：X射线衍射分析证实了喷雾干燥粉末均显示为均一无定形粉末，其含量如图4中所示的数据扫描所展示。
数据还显示：向含FDKP(样品ID No.7)(19.5％w/w)、海藻糖(38.4％w/w)和异亮氨酸(6.5％w/w)的粉末中加入柠檬酸盐/锌产生相较于不含柠檬酸盐和锌的粉末具有改良性质(42％RF/填充量)的粉末。相较于不利用柠檬酸盐/锌(25.6％填充量,78.4％CE)配制的粉末，含柠檬酸盐的粉末导致RF/填充量提高17％。
本发明的粉末不过度粘着，因为它们的中值几何颗粒尺寸在0.5bar和3bar RODOS分散压力下相似。在0.5bar和3bar下，平均值为4.34和4.18μm。
表5中的数据显示了粉末的气动性能。表5显示：含柠檬酸盐和锌的粉末产生高的可吸入分数(＞70％)和药筒排空率数据，在一些情况下，高于＞90％(数据未示出)。在解剖学上正确的气道模型中的样品试验显示：含粉末的吸入器中约73％的剂量被递送至肺部。
催产素稳定性研究
数据显示：在40℃/75％RH下温育32周之后，制备的14种粉末中有3种维持得到的原始总催产素含量的多于89％(表4)。对于最稳定的粉末，降解速率在停滞期前4周时显示最高(图3)；这种早发的降解很可能是由于粉末中高的残余水含量。由pH＝6.5的柠檬酸盐缓冲液和作为锌二价阳离子来源的氯化锌制备最稳定的粉末。总而言之，在柠檬酸盐和锌盐二者的存在下制备的粉末展示出最高的稳定性。甚至在低盐含量时也观察到了这种组合的稳定化效果(样品ID No.1相对于样品ID Nos.2、3、4)。在“未缓冲的”制剂中，加入FDKP二钠或者用三亮氨酸或胱氨酸替代异亮氨酸增强了粉末的稳定性。
实施例2
替代性的催产素喷雾干燥粉末实施方式的制备、表征和稳定性
如上文实施例1中所述制备催产素喷雾干燥粉末。在这些实验中，如下表1中所示，以2.5g的规模制备14种粉末，所述粉末包含1％(w/w)催产素和不同量的得自如下表6中所述的各种供应商的缓冲剂、盐、载体、赋形剂，包括海藻糖、PVP、异亮氨酸、柠檬酸钠、柠檬酸、酒石酸钠、酒石酸和锌盐。在这些实验中，使用得自Alfa Aesar的L-(+)-酒石酸和L-(+)-酒石酸钠二水合物。与实施例1中不同，块状固体柠檬酸钠和柠檬酸被用作柠檬酸钠的来源。如实施例1中所述制备含1％(w/w)催产素的样品，然后利用下表6中所述的参数将溶液或悬浮液喷雾干燥。
收集干粉并用于下述实验中。获得了用样品号ID Nos.14-28标示的粉末，平均产率为76.7％且最小干燥损失(LOD)为5.73％(通过Karl Fisher滴定法测量)。使粉末IDNos.14-28在真空泵下经受附加的干燥步骤，这导致最小LOD为2.90％。
分析目标催产素的含量为1％的喷雾干燥粉末，数据证实了催产素的值在0.87-1.01％范围内。表7中详述了所制备制剂的组分，其显示了制备和检测的每种样品的含量。在某些实施方式中，海藻糖：异亮氨酸：PVP的重量比率为87:10:2的混合物用作除样品IDNo.20和21之外的所有制剂的基质。向该混合物中加入柠檬酸钠、柠檬酸和锌。柠檬酸盐的量从每摩尔催产素的100-50当量不等(总重量的29.2-14.6％)。锌盐的量从每摩尔催产素的50-5当量不等(总重量的30.3-0.7％)。在一些实施方式中，锌阳离子显示出对于组合物的特征是至关重要的，这通过单独使用氯化锌(样品ID No.22)也能提供改善的粉末稳定性而被例证。
表6.干燥条件
入口： 150℃
出口： 70
干燥气流： 60mbar(氮气)
雾化流： ～59.9g/h
抽吸器 80％
泵 5％
表7.催产素样品组成
Figure BDA0003533234320000281
干粉的气动性能
利用Gen2C吸入器(21.6Lpm,4s,MannKind Corp.)通过Andersen多级撞击测量喷雾干燥粉末的气动性能，结果显示于表8中。即便在低吸气峰压下也得到了高RF/填充量％(>50％)。表8中的数据显示：RF/填充量％在约20-约60％范围内且全部内容物的药筒排空率高达77％(样品ID No.22)。对于含柠檬酸锌、氯化锌且含或者不含PVP的粉末，获得了最高的RF/填充量％。在表8中可以看出，添加异亮氨酸(样品ID No.14和20)提高了RF/填充量％。含单独的柠檬酸锌或氯化锌的样品(样品ID Nos.22、23和24)具有约50％-60％的高RF/填充量％和高于70％的药筒排空率。
所选粉末的气动试验强调了柠檬酸钠和氯化锌与海藻糖、异亮氨酸和PVP或无PVP的组合的有益效果，这通过样品ID No.18、19、20和21而被例证。柠檬酸盐和锌的含量分别低至14.6％和1.4％时观察到了改善的粉末性能(样品ID Nos.16和18)。利用14.6％柠檬酸钠和6.8％锌的含量时(样品ID No.18)获得了最大效果(53.0％RF/填充量)。柠檬酸锌与海藻糖、异亮氨酸和PVP的组合的有益效果通过粉末样品ID Nos.23和24的性能而被例证，其中粉末样品ID Nos.23和24产生高于50％的RF/填充量％和约73％的药筒排空率。
表8.通过Andersen多级撞击器的气动性能
Figure BDA0003533234320000291
催产素制剂稳定性研究
如上文实施例1中所述进行催产素喷雾干燥粉末的稳定性研究。稳定性试验进行长达40周。来自试验的催产素稳定性研究结果显示于下表9和图5中。数据被显示为剩余的样品相较于所用起始材料的百分比(％)。从表9中可以看出，当温育40周后分析样品份时，所检测的粉末制剂中仅有3种(样品ID No.16、27和28)保持少于约90％的催产素。柠檬酸盐和锌盐的组合在固态时导致最高的稳定性(高于约90％)。利用含14.6％柠檬酸钠和6.8％氯化锌的组合获得了最高稳定性(样品ID No.18)。温育40周后，含最低9.4％含量的柠檬酸锌并包含或者不含柠檬酸钠的粉末维持多于97％的催产素。图5是干粉样品稳定性研究的图示，其中包含不同浓度的二价锌盐和柠檬酸盐的样品在40周的时期内显示出催产素缓慢降解；其中所检测的样品保留高于90％的催产素含量。
在使用酒石酸盐的替代性实施方式中，温育24周后，含锌和酒石酸盐的粉末同样维持约90％的催产素含量；温育样品32周后，含锌和酒石酸盐的粉末维持高于85％的催产素含量
表8.催产素粉末在40℃/75％RH下的稳定性结果
Figure BDA0003533234320000301
向催产素制剂中加入柠檬酸盐或酒石酸盐和锌盐显示出有益于气动性能和催产素稳定性。
实施例3
一位第二次怀孕的35岁孕妇具有在第一次怀孕时轻微产后出血的病史，她在怀孕40周时获准进入医院并临产。主治的产科医生监测到宫缩间隔5分钟发生一次。注意到该孕妇出血，其生下了一个健康的婴儿。在手术室中，分娩后立即通过经口吸入向该妇女施用干粉制剂，其中单次吸入的干粉制剂含有单一剂量的100IU催产素、28％(w/w)柠檬酸盐和7％(w/w)氯化锌，其中使用包含如美国专利No.8,484,129中所述的高阻力吸入器的吸入系统，所述文献中关于相关主题的公开内容通过引用全部并入本文中。该妇女留在医院中3天，其并未遭受任何严重出血，然后和其新生婴儿一起出院。
除非另有说明，否则说明书和权利要求书中所用的所有表示成分的数量、特性(如分子量)、反应条件等的数字都应理解为在所有的情况下均被术语“约”修饰。因此，除非指出相反情况，否则在说明书和所附的权利要求书中所述的数字参数是可根据本发明寻求得到的所需特性而改变的近似值。至少，并且不意欲限制等同原则在权利要求的范围中的适用，每个数字参数应至少按照所报道的有效位数并且应用常规舍入方法解释。尽管详尽解释本发明的大范围的数值范围和参数是近似值，在具体实施例中所述的数值是尽可能精确地报道的。但是，任何数值不可避免地包含必然地由标准偏差导致的某些误差，所述标准偏差存在于其各自的测试测量中。
在描述本发明的上下文中(特别是以下的权利要求书的上下文中)所使用的术语“一个”、“一种”、“该”和类似的指代对象和不使用术语应被解释为同时包括单数和复数，除非在本文中另有说明或上下文明显地否定。本文中数值范围的列举仅意欲作为分别指每个落入所述范围内的单独数值的简略表达方法。除非本文另有说明，每个单独的数值均如其在本文中被单独地引用一样纳入本说明书。本文描述的所有方法可以任意合适的顺序进行，除非本文另有说明或上下文明确地否定。本文提供的任意和所有实施例，或示例性用语(例如，“诸如”)的使用仅意欲更好地说明本发明并且不限制本发明原本要求保护的范围。本说明书中的用语不应被解释为指示实施本发明所必需的任何未要求保护的元素。
权利要求书中所用的术语“或”用来表示“和/或”，除非明确指出其指代的仅仅是替代性方式或者互相排斥的替代性方式，尽管公开的内容支持仅仅为替代性方式和“和/或”这两种定义。
对本文所公开的本发明的可选元素或实施方式的分组不应被解释为限制。每个组成员都可被单独地或者与组内其它成员或在本文中发现的其它元素组合地被提及或被要求保护。预期一个组中的一个或多个成员可因便利和/或专利性的原因被纳入一个组中或从一个组中删除。当出现任意此类纳入或删除时，本说明书被认为包含修改过的组，因而满足在所附权利要求书使用的对所有马库什组的书面说明。
在本文中描述了本发明的优选实施方式，包括本发明人已知的实行本发明的最好方式。当然，在阅读上述说明后，这些所述实施方式的变化方案对本领域技术人员来说是显而易见的。本发明人预期技术人员会恰当地应用此类变化方案，并且本发明人打算按照本文所具体地描述方式之外的其它方式来实行本发明。因此，本发明包括所附权利要求书中所记载主题的由适用法律批准的所有修改和等同。此外，除非本文另有说明或者上下文明确地否定，否则本发明包括所有可能变化方案中的上述元素的任意组合。
在权利要求中可使用“由...组成”和“基本由...组成”的用语进一步限制本文公开的具体实施方式。当在权利要求中使用时，无论是提交时的或是在每次修改时加入的过渡术语(transition term)“由...组成”均排除未在权利要求中具体列举的任何元素、步骤或成分。过渡术语“基本由...组成”将权利要求的范围限制至具体列举的材料或步骤以及不对基本的和新的特点产生重大影响的那些材料或步骤。如此要求保护的本发明的实施方式在本文中得到根本地或明确地描述，并且能够实现。
此外，本发明书通篇中对专利和印刷出版物做出了很多引用。每篇上面所引用的参考文献和印刷出版物被分别地以引用的方式全文并入本文中。
另外，应理解本文公开的本发明的实施方式是用来说明本发明的基本原理的。可应用的其它修改方案在本发明的范围内。因此，通过示例而非限制的方式，可按照本文中的教导使用本发明的可选配置。因此，本发明不被限制于正如显示的和描述的发明。

Claims (11)

1.干粉药物制剂，其包含二酮哌嗪的可吸入微粒，所述可吸入微粒包含催产素、催产素衍生物或催产素类似物，和柠檬酸锌或氯化锌，和/或药学上可接受的载体或赋形剂，其中所述制剂在40℃和75％的相对湿度下稳定至少40周。
2.根据权利要求1所述的干粉药物制剂，其包含柠檬酸锌。
3.根据权利要求1所述的干粉药物制剂，其中所述药学上可接受的载体或赋形剂是糖，所述糖选自甘露糖、甘露醇、海藻糖或山梨醇。
4.根据权利要求1所述的干粉药物制剂，其中所述药学上可接受的载体或赋形剂是聚乙烯吡咯烷酮或聚乙二醇或二酮哌嗪。
5.根据权利要求1所述的干粉药物制剂，其中所述二酮哌嗪是延胡索酰二酮哌嗪或琥珀酰二酮哌嗪。
6.根据权利要求1所述的干粉药物制剂，其中所述柠檬酸锌的量为每摩尔催产素、催产素衍生物或催产素类似物的100-20当量。
7.用于吸入的药物干粉制剂，所述药物干粉制剂包含二酮哌嗪的可吸入微粒，所述可吸入微粒包含催产素、催产素衍生物或催产素类似物；用量范围为所述制剂的约1％-约7％(w/w)，和药学上可接受的赋形剂，其中药物制剂在40℃和75％的相对湿度下稳定至少40周。
8.根据权利要求5所述的干粉药物制剂，其中所述二酮哌嗪是延胡索酰二酮哌嗪。
9.根据权利要求1所述的干粉药物制剂，其中二酮哌嗪的所述微粒包含直径为约0.5μm至约10μm的微粒。
10.根据权利要求7所述的干粉药物制剂，其中所述二酮哌嗪是延胡索酰二酮哌嗪。
11.根据权利要求7所述的干粉药物制剂，其中二酮哌嗪的所述微粒包含直径为约0.5μm至约10μm的微粒。
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