CN1138531C - 分散性大分子组合物及其制备方法和用途 - Google Patents

分散性大分子组合物及其制备方法和用途 Download PDF

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CN1138531C
CN1138531C CNB971944709A CN97194470A CN1138531C CN 1138531 C CN1138531 C CN 1138531C CN B971944709 A CNB971944709 A CN B971944709A CN 97194470 A CN97194470 A CN 97194470A CN 1138531 C CN1138531 C CN 1138531C
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罗伯特·M·普拉茨
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托马斯·K·布鲁尔
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特伦斯·D·博德曼
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Abstract

本发明涉及生物大分子超细粉末的制备方法，该方法包括雾化大分子的液体溶液，干燥雾化步骤形成的液滴，并收集干燥所得的颗粒。通过对雾化、干燥和收集各个步骤的正确控制，可以制备出具有特别适合于肺部给药治疗和其它目的特征的超细干粉组合物。

Description

分散性大分子组合物及其制备方法和用途
本发明技术背景
1.技术领域
本发明总的来说涉及大分子组合物及其制备方法和用途。具体地，本发明涉及一种在可控条件下通过喷雾干燥来制备大分子组合物的方法，该方法保持蛋白的纯度并且得到良好的粉末分散性和其它所需的特征。
多年来，某些药物以适合形成经口吸入(肺部传递)的药物分散液的组合物出售，用以治疗人的各种病症。这种肺部传递药物组合物所设计的给药方式是患者通过吸入药物分散液，以便分散液中的活性药物可以到达肺部。据发现某些经肺部传递的药物容易通过肺泡区吸收直接进入血液循环。对其它施药途径难以给药的大分子(蛋白、多肽、高分子量多糖、和核酸)，特别依赖于肺部给药。这种经肺部传递对治疗肺部疾病的内吸传递和局部传递都是有效的。
肺部药物传递本身可以通过不同的方式实现，包括使用液体喷雾器、气溶胶基的计量吸入器(MDI’s)、和干粉分散装置。由于依赖使用含氯氟烃(CFC’s)，气溶胶基的MDI’s越来越失去人们的好感，这是因为含氯氟烃对臭氧层产生负面影响而正被禁止使用。不依赖CFC气溶胶技术的干粉分散装置使用能够配制成干粉的给药药物。许多其它不稳定的大分子可以通过冻干或喷雾干燥成粉末，或者和其它稳定粉末载体结合而稳定储存。
然而，干粉状药物组合物的传递效能存在某些方面的问题。许多药物组合物的剂量常常具有临界值，所以希望干粉传递系统能够精确、准确和可靠地传递药物所需的量。此外，许多药物组合物非常昂贵。因此，对干粉的有效配制、加工、包装和给药，同时具有最小程度的药物损失的能力提出严格要求。尽管天然大分子在肺部具有渗透性为众所周知，但低效率的大分子生产过程加上低效率的大分子传递限制了用于肺部传递的大分子干粉的商品化。
一种特别有希望的干粉药物肺部传递方式是使用手执装置，该装置具有用于提供加压气体源的手泵。加压气体通过粉末分散装置，如文丘里喷嘴，急剧释放，使分散的粉末可被患者吸入利用。尽管有许多方面的优点，但这种手执装置存在很多方面的问题。给药的颗粒通常小于5μm粒度，使得粉末的处理和分散比较大的颗粒困难。手驱动泵可利用的加压气体的体积相对较小，这样更加重了这个问题。具体说，由于手泵可利用的气体仅有较少的体积，文丘里分散装置不适用于难分散的粉末。对手执和其它粉末给药装置的另一要求是效率。在药物给药给患者的过程中设备具有肺部给药最佳粒度分布的高效性是市场产品存活的主要因素。用于给药药剂的常规技术不能达到市场所要求的给药效率。能否既达到足够的分散又达到小的分散容积是一项显著的技术课题，这个课题要求粉末状组合物的各单位剂量可以被容易和可靠地分散。
喷雾干燥是一种常规用于从各种液体和浆液起始原料中生产干固体颗粒的化学加工单元操作。使用喷雾干燥用于配制干粉药物是已知的，但通常仅限于对热降解和其它剧烈处理条件较不敏感的小分子和其它稳定的药物。使用喷雾干燥来制备生物大分子组合物，包括蛋白、多肽、大分子多糖和核酸，是存在问题的，因为这些大分子经常是不稳定的，并且当处于高温和其它喷雾干燥加工条件时发生降解。大分子的过度降解可能会导致药物制剂缺乏必要的纯度。通过喷雾干燥生产的组合物的颗粒粒度和颗粒粒度分布还难以得到控制。对肺部给药而言，关键是平均颗粒粒度保持在5μm以下，优选在0.4-5μm范围，而且组合物中目标粒度范围以外的颗粒的包含量要最少。优选，至少90％wt的粉末具有0.1-7μm范围的颗粒粒度。更优选，至少95％wt具有0.4-5μm范围的颗粒粒度。此外，最终颗粒产品物理和化学稳定所要求的所需低水分含量有时可能难以达到，特别是某种经济的方式。最后，也可能是最重要的，难以用有效方式生产出肺部传递所必须的小颗粒。对高价格的大分子药物来说，收集率(即从加工中回收的可用形式的颗粒药物的量)应当在80％wt以上，优选90％wt以上，且最好在95％wt以上。尽管喷雾干燥在如下描述的实验室规模设备中已用于制备大分子的粉末，但没有为生产肺部给药粒度范围的颗粒而设计的市售的喷雾干燥器。必须改进用于雾化、干燥粉末和收集的方法，以便经济性生产具有肺部传递所需产品特征的蛋白粉末，并且是以足够的产率和具有商业上可接受的生产率(超过30g/hr)。
因此，希望提供大分子喷雾干燥的改进方法，以便在肺部和其它药物传递中使用。具体说，希望提供能够弥补上述至少一些缺陷的改进的加工方法和组合物。
2.背景技术描述
US5,260,306、4,590,206、GB2 105 189和EP 072 046描述了喷雾干燥奈多罗米钠的方法，以形成优选为2-15μm的用于肺部传递的小颗粒。US专利5,376,386描述了用于肺部药物给药的粒状多糖载体的制备方法，其中载体包含粒度为5-1000μm并具有小于1.75粗糙度的颗粒。Mumenthaler等(1994)在Pharm.Res.11:12中描述了重组人类生长激素和重组组织型纤维蛋白溶酶原激酶。这个研究表明蛋白在喷雾干燥过程会产生降解，并因此不可能保持足够的活性用于治疗。WO 95/23613描述了使用实验室设备通过喷雾干燥制备脱氧核糖核酸酶的吸入粉末。WO 91/16882描述了喷雾干燥在脂质体载体中的蛋白和其它药物的方法。
已转让给本申请申请人的以下申请分别描述了可以使用喷雾干燥制备生物大分子的干粉：1995年4月14日提交的申请08/423,515；申请08/383,475，它是1994年3月7日提交的08/207,472的部分接续申请；1995年4月14日提交的申请08/472,563，它是1995年4月4日提交的现已放弃的08/417,507的部分接续申请，该申请是1993年4月7日提交的现已放弃的08/044,358的接续申请；1994年4月25日提交的申请08/232,849，它是现已放弃的07/953,397的接续申请。要求07/953,397优先权的WO94/07514。要求08/207,472和08/383,475优先权的WO95/24183。
本发明概述
根据本发明，通过喷雾干燥生物大分子的方法，提供了药物组合物具有改进的特征，解决了至少一些上述和先前喷雾干燥过程中的有关缺陷。本发明的方法包括，提供预定浓度的大分子和选择性存在的其它赋形剂在液体介质中的溶液、浆液、悬浮液等等，通常是在水中的含水溶液。大分子和选择性存在的相容的辅剂如糖、缓冲剂、盐和其它蛋白配制在溶液中，以便提供治疗有效的剂量，防止干燥过程中的降解，增加粉末的分散性，和达到在室温下可接受的粉末的物理和化学稳定性。在一定的选择条件下雾化液体介质，所选择的条件是能够形成平均颗粒粒度在预定值或预定值以下的液滴，然后在一定的选择条件下进行干燥，所选择的条件是能够形成水分含量低于预定界限程度的制剂颗粒。收集干燥的颗粒，并以适宜使用的形式包装，一般包装在单位剂量受器中。优选选择一定的雾化和干燥条件，以便通过单独一步干燥便能够将颗粒干燥至低于目标水分含量，并且生产出在所需粒度范围内的颗粒，这些颗粒在包装之前无需进一步分离(即粒度分级)。
在本发明方法的第一个优选方面，液体介质中的总固形物含量(包括大分子和辅剂)低于10％，通常在0.5％-10％wt之间。优选的浓度范围为约1％wt-5％wt，且液体介质包括含水溶液。据发现将总固形物浓度控制在5％以下，可明显增强获得在所需粒度范围内即5μm以下，优选在0.4μm-5μm范围的干燥颗粒的能力。
在本发明方法的第二个优选方面，将溶液雾化，生产出具有平均液滴粒度在11μm或11μm以下的液滴。将雾化器的设计和操作条件最佳化，以便将固形物含量增加至上述程度，使高强度生产实际化和经济化。优选，雾化步骤通过让溶液和雾化气流以预定的气液质流比(优选大于5)流过双流喷嘴。空气孔的上游气压保持在25psig以上。这种空气压力高于引起声速的压力，即无法继续增加超过声速的速度。已发现，较高压力雾化气的密度的增加，会降低所得液滴的粒度。
本发明方法的另一个方面，将雾化的液滴干燥至形成最终水分含量低于5％wt的颗粒。优选，通过单独一步干燥操作将颗粒干燥至这个程度，一般在单独一步喷雾干燥操作中，其中液滴和加热蒸气并行流动，所说蒸气具有足够将颗粒中的水蒸发至所得程度的热量。通常，加热气流，一般是加热空气流，具有至少90℃的入口温度，优选至少120℃，更优选至少135℃，进一步优选至少145℃，通常为175℃，或根据干燥的大分子可高至200℃。至少部分地，加热干燥蒸气的入口温度要根据所处理的生物大分子的不稳定性来确定。在胰岛素的实验例中，优选入口温度为140℃-150℃。
为控制在喷雾干燥中生产的颗粒的最终水分含量，还需要控制气体的出口温度。气体出口温度是入口温度、产品干燥步骤中施加的热负荷(根据液体介质的入口温度、蒸发掉的水的量等等)、以及其它因素的函数。优选，气体出口温度保持在至少50℃以上，优选至少70℃，通常为60℃-80℃。
本发明方法的另一个特定方面，为增强粉末分散性，应当选择干燥条件，以便控制颗粒的形态。具体说，选择获得的颗粒粗糙度为至少2的干燥条件。粗糙度是表面卷曲的测定值，数值越高表示表面不规则程度越大。不以任何方式限制本发明范围，目前据信，以粗糙度表示的表面不规则性的增加可降低相邻颗粒之间的粘聚性。这种表面之间作用的降低反过来会改进所得粉末的分散性。颗粒粗糙度受单个液滴干燥速率和溶解固形物的组成两方面的影响。
液滴开始以相对较快的速率干燥，在液滴外部形成物料的粘层。随着干燥继续，粘层的流动不如颗粒随溶剂蒸发而缩小的那样快，造成颗粒表面皱褶(起皱)。粘层的粘度和物料的玻璃化温度有WLF方程关系(Williams，Landel，Ferry方程)，参考K.Alexander & C.J.King，干燥技术，Vol.3，No.3，1985。干燥区内的温度梯度应当控制为使颗粒干燥进行得足够快，以形成表面坍陷和皱褶，而不致快到使颗粒破裂。
根据本发明方法的另一个特定方面，收集干燥的颗粒，将干燥步骤产出的基本上全部的颗粒从蒸汽中分离出来。据发现，正确控制雾化和干燥条件可以生产出至少90％的颗粒物质在0.1μm-7μm的粒度范围内，更优选至少95％的颗粒为0.4μm-5μm的粒度，从而可以收集干燥步骤的产品，并且粉末使用时可以不需要在包装之前进行粒度分级。然后收集的粉末可以以任何常规的方式用于粉末药物中。通常来说，将一部分颗粒产品包装在合适的受器中，如干粉吸入剂适用的单位剂量受器。
在本发明方法的另一个方面，粉末分离步骤包括使全部气体蒸汽通过分离器，其中分离器将具有1μm粒度以下的至少约90％wt的所有颗粒从气体蒸汽中除掉。分离器包括一特别设计并且在一定条件下操作的高效旋风器，所说条件是能够必须高效分离本发明方法生产的超细颗粒。或者，分离器可以包括过滤部件，如金属陶瓷纤维滤器、过滤膜(如袋滤器)等等。
本发明方法对生产生物大分子的干粉是有用的，所说大分子一般适合药物用途，即用于人和兽的药物。生物大分子包括蛋白质、多肽、低聚肽、高分子量多糖(一般具有约2kD的分子量)、核酸等等。具体的生物大分子列举在下表1中。本发明方法对生产胰岛素的干粉特别有用，这是一种分子量约7.5kD或更高的多肽激素。根据本发明制备的胰岛素粉末可以来源于动物源，如牛胰岛素，或者可以是通过重组体制备的。重组体胰岛素可以具有和天然人胰岛素相同的氨基酸序列，或者可以作一些程度的修饰同时保持所需的胰岛素活性。
本发明的组合物包含旨在用于肺部给药的可分散的大分子粉末，即通过患者吸入到患者肺部的肺泡区。组合物中包含平均颗粒粒度小于10μm和粗糙度大于2的颗粒，颗粒的粗糙度优选大于3，有时大于5，通常为2-6的范围，优选3-6，有时为4-6。优选地，组合物的颗粒具有5％wt以下的水分含量，更优选3％以下，一般在2％以下。粗糙度可以通过BET或其它常规的颗粒表面分析技术来测定。优选地，组合物包含90％wt颗粒粒度为0.1μm-7μm的颗粒，更优选95％的颗粒粒度为0.4μm-5μm。组合物经常包装成单位剂量，其中单位剂量受器如水泡填塞器、明胶胶囊等中存在治疗有效量的组合物。
附图简述
图1是本发明方法的基本单元操作的方框示意图。
图2是较详细的流程图，用于说明适合本发明方法使用的系统。
图3是本发明方法中适宜的雾化步骤的优选雾化喷嘴的示意图。
图4是图2进行本发明方法分离步骤的系统的另一种装置。
优选实施方案的描述
本发明涉及包含生物大分子超细干粉的组合物的制备方法，所说的生物大分子主要用于患者的各种治疗和临床性肺部给药，其中本发明的第一个主要方面涉及粉末特征的控制，以增强粉末在所需目的中的使用。本发明的第二个主要方面涉及组合物本身以及包装的组合物，具体说包括组合物的单位剂量形式。本发明的第三个主要方面涉及以能够保证所给药物市场需要的规模生产粉末的示范性方法的能力。
术语“生物大分子”指包括已知的和具有治疗和其它有用活性的生物化合物。生物大分子一般是指蛋白、多肽、低聚肽、核酸、和分子量相对高的多糖，本发明的方法可以将这种化合物改良成具有所需特性的超细干粉，特别是有用的肺部给药的粉末。适合由本发明方法制备成超细干粉的生物大分子的一些实例在下表1中列出。根据本发明的方法，首先将这些生物大分子溶解、悬浮或分散在挥发性液体介质中，然后雾化、干燥并收集。优选的生物大分子包括胰岛素、白细胞介素-1受体、甲状旁腺激素(PTH-34)、α-1抗胰蛋白、降钙素、低分子量肝素、肝素、干扰素、和核酸。使用本发明方法制备胰岛素的详细实施例参见以下的实验部分。
                         表1
                示例性生物大分子药物
    药物     适应症
降钙素血红蛋白(EPO)因子IX粒细胞集落刺激因子(G-CSF)粒细胞巨噬细胞集落刺激因子(GM-CSF)生长激素肝素肝素(低分子量)胰岛素α干扰素β干扰素γ干扰素白细胞介素-2促黄体激素释放激素(LHRH)生长激素释放抑制因子类似物加压素类似物滤泡刺激激素(FSH)淀粉不溶素睫状向神经因子生长激素释放因子(GRF)胰岛素类生长因子促胰岛素     骨质疏松预防佩吉特病血钙过多贫血血友病B中性血细胞减少骨髓接枝/移植失败身材矮小肾衰竭血结块哮喘血结块I型和II型糖尿病B型和C型肝炎毛细胞性白血病卡波济肉瘤多发性硬化慢性肉芽肿病肾癌前列腺癌子宫内膜异位胃肠癌尿崩症尿床生育力I型糖尿病Lou Gehrig疾病身材矮小骨质疏松营养不良II型糖尿病B型和C型肝炎
β干扰素γ干扰素白细胞介素-1受体拮抗剂白细胞介素-3白细胞介素-4白细胞介素-6巨噬细胞集落刺激因子(M-CSF)神经生长因子甲状旁腺激素生长激素释放抑制因子类似物α-I胸腺素IIb/IIIa抑制剂α-I抗胰蛋白酶抗-RSV抗体囊纤维化转膜调节剂(CFTR)基因脱氧核糖核酸酶(DNase)杀菌剂/渗透性增加蛋白(BPI)抗-CMV抗体白细胞介素-1受体白细胞介素-1受体拮抗剂     类风湿性关节炎类风湿性关节炎化学疗法佐剂免疫缺陷症血小板减少症真菌病癌症血胆固醇过多末梢性神经病骨质疏松不应性腹泻B型和C型肝炎不稳定咽峡炎囊纤维变性呼吸多核病毒囊纤维变性慢性支气管炎成人呼吸窘迫综合症巨细胞病毒哮喘哮喘
用语“超细干粉”指包含多种离散的、干燥颗粒的粉末组合物，所说的干燥颗粒具有以下所述的特征。具体说，干颗粒具有的平均颗粒粒度为5μm以下，优选为0.4μm-5μm，更优选0.4μm-4μm，首选0.4μm-3μm。通过常规技术测定的质量平均直径(MMD)作为粉末的平均颗粒粒度。颗粒粉末粒度技术使用离心沉降颗粒粒度分析仪(HoribaCapa 700)。粉末能够容易分散在吸入装置中并随后被患者吸入，以便颗粒能够渗透到肺部的肺泡区。
对本发明特别重要的是，由本方法生产的超细干颗粒组合物具有一定的颗粒粒度分布，从而能够使它们将肺部的肺泡区作为系统活性蛋白肺部给药的目标。这种组合物有利的是不经过进一步粒度分级而掺加到单位剂量和其它形式中。通常来说，超细干粉末具有一定的粒度分布，其中至少90％wt的粉末包含平均颗粒粒度为0.1μm-7μm的颗粒，优选至少95％wt的粉末在0.4μm-5μm的范围。此外，理想的是避免过量的颗粒具有非常小的平均直径即低于0.4μm的颗粒粒度分布。
相反，吸入治疗哮喘和慢性支气管炎的已知治疗性化合物粉末需要在气道的较中心处给药(即，不是给药到肺泡区)。这些粉末可以产生具有明显较大颗粒粒度分布的气溶胶，其颗粒的平均直径为3-10μm。相比于肺部给药的最佳颗粒粒度，这种粒度的粉末在常规喷雾干燥器中较容易收集获得高产率。
术语“干”指粉末颗粒具有使粉末在室温下储藏，物理和化学稳定且容易分散在吸入装置中形成气溶胶的水分含量。通常来说，颗粒的水分含量低于10％wt的水，通常低于5％wt，优选低于3％wt，更优选低于2％wt，并且可选择低于约1％wt或更低。水分含量通常受干燥条件的控制，以下作更详细的描述。
术语“干”指粉末颗粒具有粉末容易分散在吸入装置中形成气溶胶的水分含量。通常，颗粒的水分含量低于10％wt的水，通常低于5％wt，优选低于3％wt，更优选低于2％wt，并且可选择低于约1％wt或更低。水分含量通常受干燥条件的控制，如以下作的更详细的描述。但在某些情况下，可以使用非水溶液来分散生物大分子，这种情况下水分含量可以接近零。
术语“治疗有效量”指组合物中存在的量，这个量要求在需要治疗的患者中提供所需的药物浓度，达到预计的生理反应。每种药物的治疗有效量是在逐个病例的基础上确定出来的。术语“生理有效量”指患者的给药量达到所需的减轻或者治愈效果。每种药的生理有效量有具体的规定，且其极限量规定为剂量浓度。
根据所用生物大分子的生物活性和单位剂量形式需要的量，组合物中的活性药物的治疗有效量是不同的。由于粉末是可分散的，因此强烈优选以允许配制者和消费者容易操作的方式制造单位剂量形式的粉末。这总的来说意味着干粉末组合物的单位剂量是约0.5mg-15mg的总原料，优选约2mg-10mg。一般来说，大分子在组合物中的量为约0.05％wt-99.0wt％。首选组合物中约0.2％wt-约97.0％wt为大分子。
药学可接受的载体可以选择性掺加到颗粒中(或作为颗粒的填充载体)，以提供稳定性、分散性、稠度和/或膨胀性，增强组合物对所需患者的均匀肺部给药。术语“药学可接受的载体”指可以吸入到肺中而对肺没有明显毒理影响的载体。根据所用药物的活性，载体的含量用数值表示为约0.05％w-约99.95％w，优选使用约5％w-约95％w。
这种优选可接受的载体可以是一种或者两种或几种赋形剂的组合，但一般基本上不含“渗透增强剂”。渗透增强剂是促进药物渗透粘膜或衬里的表面活性化合物，并被提出在鼻内、直肠内和阴道内药物制剂中使用。渗透增强剂的实例包括胆酸盐，如牛磺胆酸盐、甘胆酸盐、和脱氧胆酸盐；梭链孢酸盐，如牛磺脱氢梭链孢酸盐；以及生物相容的去污剂，如吐温、月桂基醚-9，等等。但是，由于肺中的上皮血液载体受这种表面活性化合物的不利影响，因此一般不希望在用于肺的制剂中使用渗透增强剂。本发明的干粉组合物不需要使用渗透增强剂便容易在肺中吸收。
在本发明中可作为载体使用的药学可接受的赋形剂的类型包括稳定剂，如人血清白蛋白(HSA)，填充剂，如碳水化合物、氨基酸和多肽；pH调节剂或缓冲剂；诸如氯化钠的盐；等等。这些载体可以是结晶或无定形的形式，或者是两者的混合物。
据发现HSA是特别具有价值的载体，在于它提供改进的分散性。
可以和本发明的粉末混合的填充剂包括可相容的碳水化合物、多肽、氨基酸或其混合物。合适的碳水化合物包括单糖，如半乳糖、D-甘露糖、山梨糖等等；双糖，如乳糖、海藻糖等等；环糊精，如2-羟丙基-β-环糊精；以及多糖，如棉子糖、麦芽糖糊精、葡聚糖等等；糖醇，如甘露糖醇、木糖醇等等。优选的碳水化合物包括乳糖、海藻糖、棉子糖、麦芽糖糊精和甘露糖醇。适宜的多肽包括天冬酰苯丙氨酸甲酯。氨基酸包括丙氨酸和甘氨酸，优选甘氨酸。
用于在喷雾干燥中使构象稳定和用于改进粉末分散性的添加剂，可以作为次要组分包含在本发明的组合物中。这些添加剂包括疏水氨基酸，如色氨酸、酪氨酸、亮氨酸、苯丙氨酸等等。
适宜的pH调节剂或缓冲剂包括由有机酸和碱制备的有机盐，如柠檬酸钠、抗坏血酸钠等等，优选柠檬酸钠。
已发现，本发明的方法提供的颗粒具有分散性，并且在处理和包装操作中耐附聚作用和不希望有的压紧作用。已发现，直接关系到这种改进的分散性和操作性的颗粒特征是产品的粗糙度。假设对非多孔球形颗粒而言，粗糙度是比面积(通过BET、分子表面吸附、或其它常规技术测定)与从颗粒粒度分布(通过离心沉降颗粒粒度分析仪，Horiba Capa700测定)和颗粒密度(通过比重瓶测定)中计算出来的表面积之比。如果已知颗粒在喷雾干燥中一般为结节形状，则粗糙度是表面皱褶和褶合程度的测定值。这可以通过SEM分析来验证本发明制造的粉末。粗糙度为1说明颗粒表面是球形且非多孔性。粗糙度值大于1说明颗粒表面不均匀并且具有至少一些程度的皱褶，粗糙度值越高说明不均匀性程度越大。对本发明的粉末来说，优选具有至少为2的粗糙度，更优选至少为3，通常为2-6，优选3-6，更优选4-6。
可分散性干粉生物大分子的肺部给药的单位剂量形式包括，如上所述的包含干粉的单位剂量受器。将足够量的粉末放在适宜的剂量受器之内，以便将剂量治疗的药物提供给患者。剂量受器适配在适宜的吸入装置内，在吸入装置中分散在气体蒸汽中形成气溶胶而使干粉组合物气溶胶化，然后这样产生的气溶胶被捕获在具有接口管的小室中，随后由需要治疗的患者连接接口管吸入。这种剂量受器包括本领域中任何已知的用来密封组合物的容器，如明胶胶囊和塑料胶囊，所说容器具有可去掉的部分并允许气体(如空气)蒸汽直接进入容器分散干粉组合物。这些容器的实例可见1980.10.14授权的US专利4,227,522；1980.3.11授权的4,192,309；和1978.8.8授权的4,105,027。适宜的容器还包括那些和Glaxo’s Ventolin Rotohaler牌粉末吸入器或Fison’s Spinhaler牌粉末吸入器连接使用的容器。另一种提供卓越水分载体的适宜的单位剂量容器由铝箔塑性层压片制成。将药物基的粉末按重量或体积填装在可成型性箔的凹陷处，并且用覆盖箔塑性层压片密封。这种在粉末吸入装置中使用的容器在US专利4,778,054中所有描述并且被Glaxo’s Diskhaler使用(US专利4,627,432；4,811,731和5,035,237)。优选的干粉吸入器为本发明申请人申请的US专利系列申请08/309,691和08/487,184中描述的吸入器。后者申请公开为WO 96/09085。
现在参见图1，本发明制备生物大分子分散性干粉的方法包括雾化操作10，用来生产液体介质的液滴，该液滴通过干燥操作20干燥。液滴干燥到离散颗粒的形式，从而形成干粉组合物，然后通过分离操作30收集。以下将详细描述这些单元操作的每一步。
雾化操作10可以使用任何一种常规形式的雾化器，雾化过程增加了起始原料的表面积。这要求液体的表面能、其量度的增加与面积的增加直接成正比，反过来与液滴直径的平方成反比。这个能量增加的源取决于所用雾化器的类型。任何一种能够生产物质平均直径小于约11μm颗粒的雾化器(离心、声速、压力、双流)均可以使用。本发明优选使用双流雾化器，其中液体介质和高压气体蒸汽并行通过喷嘴传递。特别优选使用能够生产平均直径低于10μm的颗粒的双流雾化喷嘴，以下将作详细描述。
雾化气体通常是经过过滤等清除掉灰粒和其它污染物的空气。或者是其它气体，如可以使用氮气。将通过雾化嘴传递的雾化气加压，一般达到约25psig，优选50psig以上。虽然雾化气的流速一般要限制为声速，但传递的压力越高，雾化气密度越增加。据发现气体密度增加可降低雾化操作中形成的液滴的粒度。反过来，液滴粒度越小，所得的颗粒粒度越小。控制雾化条件，包括雾化气流速、雾化气压力、液体流速等等，以便得到平均直径低于11μm的液滴，通过多普勒相速度计进行测定。在确定优选的雾化器设计和操作条件中，使用Aerometric’s多普勒相颗粒粒度分析仪来测定液滴的粒度分布。液滴粒度分布还可以从测得的干颗粒粒度分布(Horiba Capa 700)和颗粒密度中计算出来。两种方法测得的结果彼此具有良好的一致性。优选，雾化的液滴具有5μm-11μm的平均直径，更优选6μm-8μm。气液质流之比优选保持在大于5，更优选8-10。将气液质量之比控制在这些范围内对控制颗粒的液滴粒度是特别重要的。
从前，一般认为喷雾干燥器的常规雾化设备不适合于生产如本发明所用的非常细的液滴(＞11μm)。例如参见Handbook of Spray Drying，4thed.，Wiley & Sons 1985。然而据发现，在上述条件参数下操作双流喷嘴可以信服地获得具有所需粒度范围的喷雾液滴。
液体介质可以是生物大分子在适宜液体载体中的溶液、悬浮液或者分散液。优选，生物大分子存在于液体溶剂以及药学可接受的液体载体中，成为溶液，且液体载体是水。也可以使用其它液体溶剂，如有机液体、乙醇等等。可以包含较宽浓度范围的溶解的固形物(包括最终干燥颗粒中可能存在的大分子和其它载体、赋形剂等等)，一般包含0.1％wt-10％wt。但通常希望包含最大浓度的固形物，所说的固形物能够产生吸入粒度范围内的颗粒并具有所需的分散特性，一般固形物浓度为0.5％-10％，优选1.0％-5％。包含相对低浓度的生物大分子的液体介质将得到相对较小粒径的干燥颗粒，以下作更详细描述。
接下来进行干燥操作20，从雾化操作10获得的液滴中蒸发掉液体。通常，干燥需要将能量引入液滴，一般是通过将液滴和引起水分或气体液体介质蒸发的热气体混合。优选，在引入了热气体蒸气的喷雾干燥器或等价干燥室中进行混合。优选，热气体蒸气和雾化的液体并行流动，但还可以使用逆向流动、交叉流动或者其它流动方式。
控制干燥操作，以便提供具有上述特定特征的干燥颗粒，如大于2的粗糙度。大于2的粗糙度可以通过控制干燥速率以便在液滴外部快速形成物料粘层来获得。此后，干燥速率应当足够迅速以便水分通过物料外层而被去掉，造成外层塌陷和皱褶，成为极度不规则的外表面。但干燥不应当快到使物料外层破裂。干燥速率可以根据许多变量进行控制，包括液滴粒度分布、气体蒸气的入口温度、气体蒸气的出口温度、液体液滴的入口温度、和雾化喷雾和热气体混合的方式。优选，干燥气体蒸气具有至少90℃的入口温度，更优选为前述的范围内。出口温度通常至少约70℃，优选在前述的范围内。干燥气体通常是经过过滤或者处理掉灰粒和其它污染物的空气。使用常规吹风机或压缩机使空气移动通过系统。
选择分离操作30，以便非常高效地收集到干燥操作20获得的超细颗粒。可以使用常规的分离操作，在某些情况下应当作出改进以便保证收集到亚微颗粒。在举例性的实施方案中，使用过滤介质实现分离，如膜介质(过滤袋)、烧结纤维滤器等等。或者，经常优选使用旋风分离器达到分离，但通常希望通过高能分离，以确保有效收集到亚微颗粒。分离操作应当收集到平均颗粒粒度大于1μm的至少80％的所有颗粒，优选85％以上，更优选90％以上，更优选95％以上的收集率。
在某些情况下，使用旋风分离器可以从最终收集的颗粒中分离掉非常细的颗粒，如0.1μm。可以选择旋风分离操作的参数，以便达到近似的截止，其中0.1μm以上的颗粒被收集同时0.1μm以下的颗粒被带出到上部的排气中。不希望肺部药物粉末中存在0.1μm以下的颗粒，因为这些颗粒一般不会沉积在肺部的肺泡区，而是被呼出。
本发明方法的具体优点在于，在干燥操作中生产且在分离操作中收集的颗粒可以用于包封在所需的药物包装中，而不必将颗粒进一步分离或者分级成所需的粒度范围。这个效果是雾化和干燥条件结合形成的，通过这些条件生产出含有粒度在肺部给药所需范围内的单个颗粒的干粉组合物。因此，分离操作30仅需要从干燥气体蒸气(具有可选择的0.40μm的截止)中分离出颗粒，其中由于基本上所有收集到的物料均适合在药物制剂中使用，分离达到了尽可能高的效率。
现在参见图2，它描述了本发明方法的示例性工艺流程图。该工艺流程图包括喷雾干燥器50，它可以是市售的喷雾干燥器(适合本发明的方法)，如可从Buchi，Niro，APV，Yamato Chemical Company，OkawaraKakoki Coinpany等供应商中获得的干燥器。上述液体介质的溶液进料到喷雾干燥器中(溶液进料)，通过供料泵52、过滤器54和供料线56。如以下结合图3的描述，供料线连接到双流雾化喷嘴57。雾化空气从压缩机58、过滤器60和管线62提供给喷嘴57。干燥空气通过加热器65和过滤器66也提供给喷雾干燥器50。
经过干燥的颗粒从喷雾干燥器中被空气流通过管道70带到过滤器72。过滤器72包括数个内部过滤元件74，它可以是过滤袋或金属陶瓷纤维滤器，如Smale，Manufacturing Chemist，P.29，1992.4中描述类型的不锈钢陶瓷纤维滤器。另一种过滤介质包括过滤袋、过滤布和过滤筒。在所有情况中，载有干燥颗粒的气体蒸气流动进入分离器72的壳体中，且载气穿过过滤元件74。但是，干燥颗粒的穿行将受到过滤元件的阻截，且干燥颗粒因重力而落到器72的底部，其中它们将收集在颗粒收集器76中。收集器76可以周期性取下和更换，且将收集器中的干粉以单位剂量或其它形式进行包装。载气从分离器72顶部通过管线80和排风扇84排出。过滤器82将收集任何没有通过过滤介质74的颗粒。设置一高压空气源90，用于间歇产生逆向穿过过滤介质74的空气脉冲流。这种沿相反方向的脉冲空气流将除去粘在过滤介质入口侧的颗粒，以防止结块。根据本发明方法和使用图2的工艺流程生产胰岛素的示例性系统在下面的实验部分中呈现。
现在参见图3，举例来说明双流喷嘴。流程线56包括内管道100和外管道102。内管道100运载溶液进料并在喷口104处中止，喷口直径根据液体流动速度为0.015-0.075英寸、优选0.025-0.05英寸。外管道102和内管道共轴配置，并且运载来自管线62的雾化气体。管道62在喷口110处中止，喷口110和管道100的喷口104基本上同轴。喷口110的直径一般大于喷口104，通常具有足以产生所需空气物质流速的截面积，所说的空气具有所需的上游压力。
选择性地，喷雾嘴周围安装冷却夹套120(或者在雾化气体和溶液进料之间)，以便在溶液进料进入喷雾干燥器50时保持溶液进料的相对低温。冷却夹套120一般运载一定温度和一定足量的冷却水，以保持溶液进料温度低于生物大分子可能降解的温度，通常为4-45℃。冷却一般仅对热敏感型大分子是必要的。溶液进料温度越高，造成粘度越低，其中较低的粘度可以降低通过雾化操作形成的液滴的粒度。
现在参见图4，用旋风器150替换使用图2所述的过滤分离器72，来进行收集操作。旋风器150接收通过管道70的干燥颗粒，且载气以图2所述的类似方式向上通过管线80。旋风器150需按一定方式设计和操作，保证以非常高的收集率收集本发明生产的超细颗粒。使用旋风器将导致一些极细的颗粒通过上部出口80带出。但在一些情况下这可以是不需要的，而可以依赖进一步分离来除去太小以致不能到达肺部肺泡区的颗粒，例如7μm以下的颗粒。
以下实施例将以举例说明的方式给出，不是限制的方式。试验实施例
实施例1
喷雾干燥装置的结构在图2和4中所示。在运行中加工总共20升的溶液。溶液包含250g(1.25％wt)的总固形物，其中20％为胰岛素。固形物的其余部分是甘露糖醇、柠檬酸钠和甘油。使用Watson Marlow蠕动泵和硅氧烷管将溶液以约44ml/min的速率在4℃下送入雾化器中。通过PID回路使用喷雾干燥器出口温度作为控制变量来控制实际的进料速率。雾化器温度控制装有4℃水的循环夹套围绕其循环。使雾化器空气流动，并且使用针阀和玻璃转子流量计控制和测定在12scfm和38psig下。空气和液体均在进入雾化器(管线气体滤器中的Millipak 60和Millipore Wafergard II F-40)之前通过抛光滤器。粉末在高效旋风分离器中收集，在55英寸H2O的压降下进行操作。通过吹风机驱动马达上的AC速度控制系统将干燥空气的流速控制在100scfm，并且使用孔板和差压转换器在吹风机的鼓风下测定。使用时间比例PID回路和7.5KW加热器控制干燥空气温度在130℃。在四级分离器中回收到总共225g粉末，总产率90％。分析各收集器中的粉末并示于表2中。
                                        表2
  属性/方法   单位  收集器1  收集器2 收集器3 收集器4
水分Karl Fisher  H2Owt％   3.4％  2.8％  2.8％  3.0％
颗粒粒度Horiba Capa 700  MMD％＜5微米   1.80m100  1.4μm100  1.6μm100  1.40μm100
气溶胶颗粒粒度Cascade impactor  MMAD   3.3μm68％  ND  ND  ND
给药剂量效率吸入装置，重力  ％±SD   83±3  84±5  84±4  81±6
表面积  m2/g   11.3  11.7  ND  ND
粗糙度   3.8  3.9  ND  ND
实施例2
加工总共2.4升的溶液。溶液包含100g(4.0％wt)的总固形物，其中20％为胰岛素。固形物的其余部分是甘露糖醇、柠檬酸钠和甘油。本实验使用实验实施例1中使用的喷雾干燥器。使用Watson Marlow蠕动泵和硅氧烷管将溶液以随出口温度变化的速率在4℃下送入雾化器中。通过PID回路使用喷雾干燥器出口温度作为控制变量来控制实际的进料速率。雾化器温度控制装有45℃水的循环夹套围绕其循环。使雾化器空气流动，并且使用针阀和玻璃转子流量计控制和测定在13.8scfm和70psig下。空气和液体均在进入雾化器(管线气体滤器中的Millipak 60和Millipore Wafergard II F-40)之前通过抛光滤器。通过吹风机驱动马达上的AC速度控制系统将干燥空气的流速控制在95scfm，并且使用孔板和差压转换器在吹风机的鼓风下测定。使用时间比例PID回路和7.5KW加热器控制干燥空气温度在150℃。干燥出口空气不同，为70、75和80℃。粉末收集器交换各自的温度设定点。分析各收集器中的粉末并示于表3中。
                                     表3
  属性/方法   单位   收集器1人口空气70℃   收集器2人口空气75℃   收集器3人口空气80℃
水分Karl Fisher  H2Owt％  2.28   2.02   1.63
颗粒粒度Horiba Capa 700  MMD％＜5微米  2.41μm100   2.69μm82.3   2.43μm100
给药剂量效率  ％±SD  71±3   73±3   71±2
平均表面积测微计Gemini  m2/g±SD  6.76±.19   6±.02   8.07±.12
粗糙度  3.6   3.9   3.8
实施例3
用装配不锈钢陶瓷纤维过滤元件(Fairey Microfiltrex)的过滤袋器重新构造喷雾干燥器。装置结构示于图2。
通过运转加工总共8升的溶液。溶液包含100g(1.25％wt)的总固形物，其中20％为胰岛素。固形物的其余部分是甘露糖醇、柠檬酸钠和甘油。使用Watson Marlow蠕动泵和硅氧烷管将溶液在4℃下以55ml/min的速率送入雾化器中。通过PID回路使用喷雾干燥器出口温度作为控制变量来控制实际的进料速率。雾化器温度控制装有4℃水的循环夹套围绕其循环。使雾化器空气流动，并且使用针阀和玻璃转子流量计控制和测定在12scfm和42psig下。空气和液体均在进入雾化器(管线气体滤器中的Millipak 60和Millipore Wafergard II F-40)之前通过抛光滤器。通过吹风机驱动马达上的AC速度控制系统将干燥空气的流速控制在100scfm，并且使用孔板和差压转换器在吹风机的鼓风下测定。用Niro7.5KW加热器将干燥空气温度控制在145℃。颗粒的收集在改装的Pacific Engineering(Anaheim，CA)自身清洁室(过滤袋或过滤器)中进行。将过滤袋放在器中并且改装成允许许多不同的滤器。用两个FaireyMicrofiltrex(Hampshire，UK)金属陶瓷纤维滤器取代过滤笼和织物滤器在过滤袋器顶部建立使过滤元件反相脉冲(用高压空气使过滤袋反向)的系统，以帮助回收。每20秒使脉冲活动1秒以下。脉冲压力为110psig。粉末在重力和机械帮助下(振动)落在过滤袋器的底部。分析收集器中的粉末，示于表4。
                         表4
    属性/方法     单位     收集器
    水分Karl Fisher     H2Owt％     4.8％
    颗粒粒度Horiba Capa 700     MMD％＜5微米％＜1.4微米％＜1.0微米     1.34μm100％62％44％
    给药剂量效率干粉装置，重力     ％±SD     73±2
虽然出于理解清楚的目的，对前述发明通过举例和实施例的方式进行了较详细的描述，但显而易见在所附权利要求书限定的保护范围内可以作出某些改变和改进。

Claims (15)

1.可分散性生物大分子干粉的制备方法，所说方法包括：
提供包含预定浓度的分子量大于2KD的生物大分子的挥发性液体介质；
雾化液体介质，其中所述雾化条件经选择以形成具有平均粒径低于11μm的液滴；
在加热气流中干燥液滴以制备颗粒，该颗粒具有以空气渗透性为量度的至少2.0的粗糙度，水分含量低于10wt％，并且粒径小于10μm。
2.权利要求1的方法，其中液体介质的总固形物含量小于10wt％。
3.权利要求2的方法，其中固体含量低于5wt％。
4.权利要求1的方法，进一步包括收集所述颗粒。
5.权利要求1的方法，其中分散性粉体的90％质量由直径为0.1μm-7μm的颗粒组成。
6.权利要求1的方法，其中分散性粉体的90％质量由直径为0.4μm-5μm的颗粒组成。
7.权利要求1的方法，其中液滴与加热气流同向流动，并且其中该气流的入口温度高于90℃。
8.权利要求7的方法，其中入口温度为120-200℃。
9.权利要求7的方法，其中该气流具有高于120℃的入口温度和高于50℃的出口温度。
10.权利要求9的方法，其中该出口温度为60-80℃。
11.权利要求4的方法，进一步包括在收集步骤之后将至少一些颗粒封装在容器中，其中颗粒在封装之前未进行粒度分级。
12.权利要求11的方法，其中颗粒封装于单位剂量容器中。
13、权利要求1的方法，其中大分子选自：降钙素、血红蛋白、因子IX、粒细胞集落刺激因子、粒细胞巨噬细胞集落刺激因子、生长激素、胰岛素、α干扰素、β干扰素、γ干扰素、白细胞介素-2、促黄体激素释放激素(LHRH)、生长激素释放抑制因子、加压素类似物、滤泡刺激激素(FSH)、淀粉不溶素、睫状向神经因子、生长激素释放因子、胰岛素类生长因子、促胰岛素、β干扰素、γ干扰素、白细胞介素-1受体拮抗剂、白细胞介素-3、白细胞介素-4、白细胞介素-6、巨噬细胞集落刺激因子、神经生长因子、甲状旁腺激素、α-I胸腺素、IIb/IIIa抑制剂、α-I抗胰蛋白酶、抗-RSV抗体、脱氧核糖核酸酶(DNase)、杀菌剂/渗透性增加蛋白(BPI)、抗-CMV抗体、白细胞介素-1受体、白细胞介素-1受体拮抗剂。
14.权利要求1的方法，其中颗粒具有以空气渗透性为量度的3-6的粗糙度。
15.权利要求1-3和5-14中任一所述方法制备的大分子组合物。
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