CN1066192A - 粒性白细胞菌落刺激因子(g-csf)的肺部给药法 - Google Patents

粒性白细胞菌落刺激因子(g-csf)的肺部给药法 Download PDF

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CN1066192A
CN1066192A CN92102497A CN92102497A CN1066192A CN 1066192 A CN1066192 A CN 1066192A CN 92102497 A CN92102497 A CN 92102497A CN 92102497 A CN92102497 A CN 92102497A CN 1066192 A CN1066192 A CN 1066192A
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R·M·普拉茨
M·A·温特斯
C·G·皮特
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Abstract

粒性白细胞菌落刺激素(G—CSF)可以应用各 种肺部传送装置包括喷雾器、计量剂量吸入器及粉剂 吸入器通过肺部给药的方式以全身性方式传送治疗 或预防有效量的G—CSF。本发明的气溶体给药法 使中性白血球水平产生与皮下注射法可比拟的显著 增加。G—CSF可通过此法给药来医学治疗中性白 细胞缺乏症，亦可治疗或预防感染。

Description

本发明涉及治疗蛋白质的肺部给药法，尤其是涉及通过呼吸系统将有效治疗剂量的粒性白细胞菌落刺激素（G-CSF）以全身性方式进行给药的方法。
G-CSF是一种类激素糖蛋白，用于调节红细胞生成并在骨髓中正常造血前体细胞的无性生长和成熟中需要它，见Welte.等.，Proc.Natl.Acad.Sci.，Vol.82，pp.1526-1530（1985）。更具体地说，当G-CSF以低浓度存在时，G-CSF亦被认为在用于体外时，能刺激嗜中性的粒性细胞菌落的产生。G-CSF亦被认为能增加中性白血球的迁移;见Gabrilove，J.;Seminars  in  Hematology.Vol.26，No.2pp.，1-4（1989）。还有，G-CSF在试管里能通过抗体调节细胞的细胞毒性显著增加嗜中性白细胞杀灭肿瘤细胞的能力，见Souza等人.，Science，Vol.232，pp.61-65（1986）。
在人体血浆中可以检测到内源性的G-CSF;见Jones等人，Bailliere′s  Clinical  Hematology.Vol.2.No.1.pp.83-111。G-CSF通过成纤维细胞、巨噬细胞、T细胞、滋养层、内皮细胞及上皮细胞产生，它是位于第十七条染色体上的由4个外显子及5个内含子组成的单独一个复制基因的表达产物。这种基因位点的转录产生被分化加工的mRNA种，导致两种形式的G-CSF的表达，一种是具有177个氨基酸的完全直链肽，另一种是具有174个氨基酸的完全直链肽。具有174氨基酸的型式发现在体内具有最大的特异生物活性。G-CSF是具有交叉反应性的生物分子。故此当人的G-CSF给予其它哺乳动物，如鼠、犬或猴子施用时，将导致持续的嗜中性白血球溶解，见Moore等人.，Proc.Natl.Acad.Sci.，Vol.84，pp.7134-7138，1987。
人的G-CSF可通过几种来源获得及纯化。天然的人的G-CSF（nhG-CSF）可从被培养的人肿瘤细胞系的上清液中分离得到。DNA重组技术的发展（见美国专利4，810，643（Souza）。包括在此引入的参考资料）已能使G-CSF以糖基化形式作为真核寄生细胞的表达产物或G-CSF亦可以非糖化形式作为原核寄主细胞表达产物的形式达到商业化生产规模。
G-CSF已被发现用于治癌症作为一种刺激嗜中性白细胞产生的途径来弥补因化疗或放射治疗而致的红血球缺失。G-CSF作为一种治疗剂的有效使用方法需要给病人施用全身性剂量的这种蛋白质。目前，病人通过静脉、肌肉或皮下注射的给药方法是对人的最好给药途径，并且似乎是将有治疗作用剂量的G-CSF传递到血流中的唯一可行的方法，尽管亦作了口服传递的许多尝试;例如见Takada，等人.，Chem.Pharm.Bull.，Vol.37.No.3，pp838-839（1989）。
相对较大分子的肺部传送并非未知，尽管只有几个被定量核实的例子。乙酸促黄体生成素（leuprolide  acetate）是具有促黄体激素释放激素（LHRH）促效活性的非肽物质。具有低的口服利用率。对动物的研究表明乙酸促黄体生成素通过气溶胶配方方式吸入导致血液中有意义的含量水平;见Adjei.等人，Pharmaceutical  Research，Vol.7，No.6，pp.565-569（1990）;Adjei.等人.，International  Journal  of  Pharmaceutics，Vol.63，pp.135-144（1990）。
内皮素-1（ET-1）、一种由内皮细胞产生的具有21个氨基酸的血管收缩肽，在用气溶体对豚鼠进行给药时，发现可使动物的动脉血压降低;见Braquet等人，Journal  of  Cardiovascular  Pharmacology，Vol.13，suppl.5，S.143-146（1989）。
由Hubbard等人报道用气溶体给药法向人肺系统送入人血浆α1-抗胰蛋白酶的可行性，一些药进入体循环;见Hubbard等人.Annals  of  Internal  Medicine，Vol.Ⅲ，No.3，pp.206-212（1989）。
α1-蛋白酶抑制剂对羊及犬的肺部给药已发现是将某些这种物质送入血流的途径;见Smith等人.J.Clin.Invest.，Vol.84pp.1145-1146（1989）。
对试验动物进行的试验已表明，重组人生长激素在通过气溶胶输送时，迅速地被肺吸收，产生与皮下注射法相比更快的生长;见Oswein等人.“Aerosolization  of  Proteins”，Proceedings  of  Symposium  on  Respiratory  Drug  Delivery  Ⅱ，Keystone，Colorado，1990年3月。同样地，对重组型的细胞素γ-干扰素（IFN-γ）和肿瘤坏死因子α（TNF-α）在用气溶体对肺给药后，在血流中亦被发现;见Debs等人.，The  Journal  of  Immunology，Vol.140，pp.3482-3488（1988）。
本发明是基于发现G-CSF可通过肺途径对哺乳动物全身性给药。一般，这是通过将治疗有效量的G-CSF气流导入正在吸气的哺乳动物的口腔中实现的。重要的和令人惊异的是相当数量的G-CSF就聚集于肺部并由肺吸收进入血流中，导致血液中嗜中性白细胞水平的提高。还有，该法无需借助于特殊措施如使用吸附增强剂或专门用来改善吸附的蛋白衍生物即可完成。这样，G-CSF的肺部给药就提供了一种替代通过注射全身性输送G-CSF的非侵害的有效方法。
本发明用任何纯化的具有部分或全部初级结构组成（即氨基残基的连续片断）及一个或几个天然存在的G-CSF的生物性质的分离多肽来实施。一些文献叙述了制备G-CSF的方法，包括前面提及的Souza的专利及Welte等人和Nicola等人的文章。
一般地，本发明实践中使用的G-CSF是从哺乳动物机体分离纯化而得的天然形式或化学合成产物或通过基因组或cDNA克隆或通过基因合成而得到的外源性DNA顺序的原核生物或真核生物寄主表达的产物。合适的原核生物寄主细胞包括各种各样的细菌（如E.Coli）细胞。合适的真核生物寄主细胞包括酵母（即S.Cerevisiae）和哺乳动物（如中国仓鼠卵巢、猴）细胞。根据所使用的寄主细胞的不同，G-CSF表达产生可以是用哺乳纲或其它真核生物的碳水化合物糖基化的或是非糖基化的。G-CSF表达产物还可包括一个初始的蛋氨酸残基（在1位）。本发明的构思包括使用任何一种或全部这些型式的G-CSF，尽管重组G-CSF、尤其是用E.Coli得到的，因为具有最好的商业实用性的缘故而是最优选的。
仔细考虑了许多设计用来输送治疗药品到达肺部的机械装置用于本发明的实践中，包括、但并不限于喷雾器、刻度剂量吸入器及粉剂吸入器，所有这些装置都是本领域中的专业人员所熟悉的。
适用于实施本发明的在商业上可得到的装置的几种特例是Ultravent喷雾器，（Mallinckrodt，Inc.，St.Louis.Missouri制造）;AcornⅡ型喷雾器（Marquest  Medical  Products制造，Englewood，Colorado）Ventolin刻度剂量吸入器（Glaxo  Inc.，Research  Triangle  Park.North  Corolina制造），和Spinhaler粉末吸入器（FisonsCorp.，Bedford.Massachusetts制造。
所有这些装置需要使用适合于G-CSF配药的配方。经典地，每一配方对所用的装置都是独特的，并且除在G-CSF治疗中有用的一般的稀释剂、辅剂和/或载体外，还包括使用适当的推进剂。可以在实施本发明的几种最常用的肺给药装置中使用的G-CSF配方叙述如下：
喷雾器的G-CSF配方：
G-CSF适合于喷雾器、喷气式或超声型，用的配方一般包含溶解于水中的G-CSF，其浓度为0.1-25mgG-CSF/ml溶液。配方中亦可包括缓冲液及单糖（例如用于蛋白稳定和调整渗透压）。缓冲液的例子有乙酸钠、柠檬酸盐及甘氨酸。最好，缓冲液具有适合于调节溶液PH范围为3-4的一种组分和摩尔浓度。一般地，缓冲液的摩尔浓度范围为2mM-50mM即可。几种单糖的例子为甘露醇和山梨醇，通常所用的重量百分比范围为1%-10%。
喷雾器配方中亦可含有表面活性剂用来降低或阻止在形成气溶胶过程中溶液的雾化而引起的蛋白质的表面聚集。可以使用各种常用的表面活性剂，如聚氧乙烯脂肪酸酯及醇，和聚氧乙烯脱水山梨（糖）醇脂肪酸酯。占配方的重量百分比范围为0.001-4%。本发明中最发使用的表面活性剂为聚氧乙烯脱水山梨（糖）醇单油酸酯。
刻度剂量吸入器的G-CSF配方：
G-CSF用于刻度剂量吸入器装置的配方一般由一种细粉末构成。该粉末含有借助于一种表面活性剂而被悬浮于一种推进剂中的G-CSF。用于此目的的推进剂可以是任何一种常用的材料如含氯氟烃、氢氯氟化碳、氢氟化碳、或碳氢化合物，包括三氯氟代甲烷、二氯二氟甲烷、二氯四氟乙醇及1，1，1，2-四氟乙烷，或它们的混合物。适合的表面活性剂包括脱水山梨（糖）醇三油酸酯及大豆卵磷脂。油酸亦可作为表面活性剂。
粉末吸入器的G-CSF配方：
用于由粉末吸入装置给药的G-CSF配方是由含有G-CSF细粉碎的干粉组成。还可包括填充剂如乳糖、山梨醇、蔗糖或甘露醇，用量要有助于粉末从装置中发散出来，例如占配方重量的50-90%。G-CSF最好是粒子形式，平均颗粒度小于10微米，最好是1～5微米，以便最有效地传送至远端的肺。
本发明是要给予治疗量的这种蛋白质，足以使血流中的嗜中性白细胞含量升高。特定病例下的治疗有效量取决于各种各样合格的医生都会加以考虑的因素，包括患者正常的嗜中性白细胞的水平、正在治疗的症状或疾病的严重性、中性白血球缺失程度、患者的身体条件等等。一般地，剂量范围遵循如下原则：进行治疗个人要恢复正常的血液中嗜中性白血球的含量，至少在异常低或低的中性白细胞指数情况下应当如此。对人来说，正常的血液嗜中性白细胞水平为5000-6000个/μl血。一般地，白血球指数低于1000的被认为是严重的白血球缺失的标志。此时，使病人有被感染的严重危险。对由化疗而导致白血球缺乏的癌症病人的临床研究表明，每24小时一次皮下注射3-5μg/kg的剂量对迅速提高缺失的白血球水平呈1000以上是很有效的。基于下面要讲到的动物试验的初步结果，可以预期，对于大多数哺乳动物包括人，肺部给药的剂量（此处称为吸入剂量）大约是为了达到特定血液白血球水平所需的皮下注射剂量的3-10倍。
正如本领域专业人员知道的那样，用于传送适当吸入剂量的操作条件根据所使用的机械装置的类型不同而不同。对于某些气溶胶传送系统如喷雾器，给药的频率和操作持续时间主要取决于气溶胶中单位体积中G-CSF的量。一般，喷雾器溶液中蛋白浓度愈高，相应地，气溶胶需要的操作时间愈短。如刻度剂量吸入器这样的装置可产生比其它装置更高的气溶胶浓度，因此只需较短的操作时间即可达到所需结果。
其它装置如粉末吸入器设计用来将装置中的某一给定量的活性物质传送完毕。装置中的装载物被适当地配制，以便含有在一次给药中递送适当剂量的G-CSF。
虽然发现用G-CSF在治疗如化疗导致的中性白细胞缺失这样的嗜中性白细胞缺管症中有效，预计G-CSF在消除感染及治疗其它增加血液中中性白细胞会产生医学价值的疾病时，也会有效。随着进行进一步的研究，有关这后一些情况中适当的G-CSF给药剂量水平的信息将会出现。预期在大多数使用注射法进行G-CSF给药的情况中，本发明作为一种非侵害性的替代方法都是适用的。
图1表示γhG-CSF皮下注射给药对仓鼠血液中的中性白血球水平影响的图形，
图2表示用不同浓度的γhG-CSF水溶液用AcornⅡ喷雾器或Ul
travent喷雾器产生的气溶胶接触给药后仓鼠血液中中性白血球
水平的条形图，
图3是γhG-CSF皮下注射和气溶胶给药引起的血液中中性白血球水平的比较图。
如上所述，已知G-CSF的非肠胃道给药引起周边血液中中性白血球数目的增加。所进行的研究表明，气溶胶吸入重组人G-CSF亦引起血液中中性白血球数的增加。所用的γhG-CSF是由大肠杆菌（E.Coli）产生的重组表达产物，具有前述souza专利图7所示的氨基酸序列，由具有氨基端的蛋氨酸基团的完全hG-CSF多肽组成。它可由此文中所述的同一工艺过程制得。
仓鼠的皮下给药
最初的实验是用来测量4-6周龄的雄性Golden  syrian仓鼠（Charles  River实验室，Wilmington，Massachusetts）在用不同剂量的γhG-CSF皮下注射后血液中中性白血球数的变化。γhG-CSF用灭菌蒸馏水配成4mg/ml溶液，用0.9%的灭菌生理盐水稀释，然后将不同体积的溶液立即皮下注射进每组试验3-5只的仓鼠的背下部，24小时后，通过心脏穿刺法在卤代烷麻醉下对每一只试验动物采集血样。血液中的中性白细胞数进行不同的和完全的血细胞计数来测定。这些如图1的实验结果表明直至大约每千克体重100微克（μg/kg）的剂量，注射γhG-CSF24小时后中性白细胞数的增加剂量响应曲线在较大剂量时似乎变平。
气溶胶特点及给药
用由In-Tox  Products（Albuquerque，NM）生产的小动物辐照箱进行含γhG-CSF的气溶体的吸入接触试验。只利用小动物箱中中间的12个孔，动物箱中气溶体分配管的周边孔则被密封。用这种改进了的小动物箱，一个喷雾器所提供的空气在气溶体接触中足够维持10只仓鼠生存。从动物口中的一个及从气体排出口处取出过滤器样品来测定接触箱中气溶胶的浓度。可从其余可利用的动物口对气溶体取样，而颗粒大小分布则用QCM（石英晶体监测器）级联嵌入器（Cascade  impactor）（California  Instrments  Inc.，Sierra  Madre，CA）在整个接触过程中进行周期性测量。这种级联嵌入器只抽走240ml/min，这样的量既允许测量气溶体颗粒大小的分布又不破坏接触箱中气流结构。
在进行动物接触试验之前，先在接触箱中测量由20mg/ml白蛋白溶液产生的气溶体浓度和颗粒大小分布，这种气溶体由Ultravent喷雾器或AcornⅡ型喷雾器（都为喷气式）产生。表1表示在箱子（出口和入口）两个位置处测得的粒子大小分布和气溶体中的平均白蛋白浓度。Ultravent产生的气溶胶粒子比AcornⅡ型的小，而AcornⅡ产生的气溶胶浓度较高。发现当这二种装置操作到将5ml的装载量全部输送完并且气溶体不再稳定产生为止，两种喷雾器给动物输送大至相同数量的蛋白质。（取决于工作气流的速率，AcornⅡ型需10-15分钟而Ultravent需20分钟）。
从喷雾器产生的气溶胶在吸入接触期间通过气溶胶输送给动物的G-CSF的大致量可由以下的表达式确定：
D＝ηVC△t
其中D为吸入剂量，η为沉积分数，V为换气速度，C为气溶胶浓度，△t为给药时间。
表 1 利用20mg/ml的白蛋白溶液用二种喷射型喷雾器产生的气溶体浓度和吸入剂量估算值
喷雾器（气流） 气溶体浓度（μg/L±SEM) MMAD(μm)*GSD 持续时间（分） 递送剂量（μg±SEM）
Ultravent10L/minAcorn Ⅱ8L/min 出口    126±13鼻子    141±17出口    239±48鼻子    297±2 0.933.62.82.9 20201515 76±885±10107±29133±3
10L/min 出口    362 － 10 109
＊MMAD＝质量空气动力学直径中值;GSD＝几何标准偏差;
SEM＝3次测量平均值的标准偏差。
利用测量到的气溶体的浓度（C）和喷雾器的操作时间（△t）以及对于成年仓鼠固定的换气速率（V  30ml/min，沉积分数（η）0.5，确定出喷雾溶液的G-CSF浓度为5-10mg/ml时，产生100μg/kg的吸入剂量（例如每一个100g仓鼠吸入10μg的G-CSF）。这是被估计通过肺部输而产生的最大中性白血球应答的剂量。
对仓鼠的G-CSF气溶体给药
用于进行气溶体接触的溶液是将冷冻干燥的γhG-CSF复溶于无菌的蒸馏水平，含有1mg/ml的非离子表面活性剂聚氧乙烯脱水山梨醇单油酸酯。应用于喷雾器产生接触气溶体的溶液用G-CSF配成浓度为1-15mg/ml。
十只仓鼠（成熟、雄性Golden  Syrian）与含γhG-CSF的气溶体接触。仓鼠被限制在管子中并允许适应大约5分钟。然后将管子插入接触箱中开始与气溶体接触。接触后，仓鼠放回到饲养笼中并可自由地取得食物和水。接触24小时后采集血样、用评价皮下注射后血样的同样方法测量血液中性白细胞的浓度。
每一次接触中都测空气溶体的浓度和粒子大小的分布。通过利用喷雾器溶液中不同的浓度改变各次接触的G-CSF剂量。
未处理的动物和与仅含水及表面活性剂（聚氧乙烯脱水山梨醇单油酸酯）的气溶体接触的仓鼠相比，暴露于含有G-CSF的气溶体的具有更高的中性白细胞浓度。图2表明暴露于所述浓度范围的γG-CSF喷雾器溶液产生气溶体的动物中所观察到的中性白血球计数的增加。从中可见，由与G-CSF气溶体接触、即使低到1mg/ml（用Ultrarent喷雾器）的浓度，其所产生的正在循环的中性白细胞水平亦比与没有G-CSF的气溶体接触的组有明显的增加（P＜0.05）。对所有其它动物组，中性白血球水平比对照组增加的统计意义为P＜0.001。血液中性白血球水平的增加直到5mg/ml、随喷雾器溶液中G-CSF浓度的增加而增加。其中最大的应答是15，000白血球/μL血液是由更高浓度的G-CSF喷雾液引起的，这与皮下注射大于50μg/kg剂量的G-CSF所得的结果相似。利用例如低于5mg/ml的低G-CSF溶液浓度时，两种喷雾器所得到的中性白细胞的应答实际上没有什么差别。对于大于5mg/ml的G-CSF溶液浓度而言，AcornⅡ型喷雾器产生的白细胞应答的增加比Ultravent要高。
与不含有表面活性剂的5mg/mlG-CSF溶液所产生的气溶体吸入接触在仓鼠中所产生的中性白细胞应答（9，910±960个中性白血球/μL）与含有表面活性剂的皮下注射50μg/kg（10，935±1.390中性白血球/μL）及不含表面活性剂皮下注射50μg/kg（10，270±430中性白血球/μL）所产生应答无显著差异。这些数据是对10只仓鼠进行气溶体试验及5只仓鼠进行皮下注射时所得的平均值及标准偏差。从本实验中可得出结论：表面活性剂在水相气溶体配方中并不是必不可少的组分。
在仓鼠肺部G-CSF的沉积分数
为了肯定是否能够通过肺部有效而经济地将治疗量的G-CSF输送给动物，对暴露过程中输送给动物的G-CSF剂量进行了测定。输送或沉淀的剂量是动物吸入的药物量及气溶胶微粒沉积于肺部的有效系数（沉积分数）的乘积。后者通过与气溶胶暴露后通过测定仓鼠肺中得到的G-CSF而被确定。
沉积在仓鼠肺上的G-CSF是对两组（每组由4个动物组成的）暴露于由AcornⅡ喷雾器产生的气溶体中的仓鼠进行测定。与气溶胶接触后，立即将四个仓鼠的肺取出，放入含有3mL冷生理缓冲盐水的玻璃的组织研磨机中研磨，均化。然后将均化物两次离心，将最终的上清液转移入一干净的试管中，采用放射免疫分析法分析（Amgen  Inc.，Thousand  Oaks，CA）G-CSF的含量。在用此过程进行的对照试验中，测定出从带已知量G-CSF的肺均化物中可以回收75%的G-CSF。在这些与气溶体接触后的肺中所测量到的G-CSF值者表明从肺组织中回收G-CSF的这个分数回收率是正确的。
在5mg/ml该蛋白质溶液所产生的气溶体中暴露11分钟的动物组的肺上沉积了平均值为3.1±0.3μgG-CSF。在0.20mg/ml溶液产生的气溶体暴露11分钟时，动物肺上沉积20±4.0μg平均值的G-CSF。基于接触期间测定的气溶体中的G-CSF浓度及一定的通风速度（30ml/min），5mg/ml组的动物在暴露期间吸入22μg的G-CSF（68μg/L×0.030L/min×11min），而20mg/ml组吸进69μg的G-CSF（208μg/L×0.030L/min×11min）。利用这个吸入的G-CSF量和肺中回收的G-CSF的量即可计算出肺中G-CSF的沉积效率（沉积分数×100%）对5mg/ml组为14%，对20mg/ml组为29%。
由与气溶体接触后测得的G-CSF所确定的沉积分数然后被用于估计用气溶体给药的G-CSF剂量，以便将气溶体剂量与血液白细胞浓度的增加建立起一定的联系。
表2包含了用各种G-CSF的浓度喷雾溶液时接触气溶体期间估算得到的G-CSF的吸入量及沉积量。气溶体的G-CSF浓度通过收集暴露期间的过滤样品用称重法测量，并根据溶液中表面活性剂1mg/ml与G-CSF的比例校正该重量。吸入剂量可由气溶体的浓度、固定的通气速率（30ml/min）及接触时间（对AcornⅡ为11分钟而Ultravent为20分钟）确定。沉积剂量由吸入剂量及测得的沉积分数（0.29）计算而得。
图3表示皮下注射及气溶体给药按上述计算所得剂量水平后中性白细胞的应答。由气溶体和皮下注射所引起的中性白细胞应答之间的比较可知，对治疗上重要的剂量范围1-100μg/kg而言，沉积剂量与注射情况下的大致相同。
表 2 与气溶体接触期间传送到肺部的G－CSF估算值
溶液浓度（mg/ml) [C]＊(μg/l) 吸入剂量（μg） 沉积剂量（μg） 平均体重（g） 估算的单位体重的剂量（μg/kg）
AcornII喷雾器1          8        2.6        0.75        66.7            112         10        3.3        0.96        76.3            135         73        24         7.0         92.2            7610        109        36         10          83.3            12515        188        62         18          86.1            209Ultravent喷雾器1        2.5       1.5        0.44        63.3            6.92        2.7       1.6        0.46       77.1             6.15        33        20         5.7        91.2             6310        41        25         7.1       84.8              8415        38        23         6.6       81.6              81
＊  过滤器重量对1mg/ml表面活性剂进行修正得到气溶体中的G-CSF浓度。
虽然此发明仅用气溶体化的溶液及喷雾器来具体描述，可以理解，任何一种对生物物质进行肺部给药的合适方法都可用来作本发明的G-CSF的给药。实际上，还有好多情况下，刻度剂量吸入器，或粉末吸入器或其它装置是优选的或最适合特殊的要求。前面的叙述为这些装置的实际使用提供了一个指导。此法的其它应用是在技术人员的能力范围内。因此，本发明不应被看作仅限于在已描述过的具体实施例中应用。

Claims (22)

1、一种使用方法，包括对哺乳动物进行G-CSF的肺部给药。
2、一种根据权利要求1的方法，包括在哺乳动物正在吸气时将一束具医疗有效量的G-CSF流导入哺乳动物口腔中。
3、一种根据权利要求2的方法，其特征在于G-CSF是以一种药物组合物型式给药，该组合物由在药学上隋性的载体中的G-CSF组成。
4、一种根据权利要求3的方法，其特征在于该组合物是在一种含水介质中的溶液型式或在一种无水介质中的悬浮液型式。
5、一种根据权利要求3的方法，其中该组合物是干燥粉末形式。
6、一种根据权利要求5的方法，其中G-CSF颗粒大小小于10微米。
7、一种根据权利要求5的方法，其中G-CSF颗粒大小在1-5微米之间。
8、一种根据权利要求2的方法，其中G-CSF是人G-CSF。
9、一种根据权利要求8的方法，其中该人G-CSF是重组体人G-CSF。
10、一种根据权利要求9的方法，其中重组体人G-CSF是一种转化的原核生物寄主细胞或真核生物寄主细胞的表达产物。
11、一种根据权利要求10的方法，其中该寄主细胞为原核生物寄主细胞。
12、一种根据权利要求11的方法，其中寄主细胞是大肠杆菌（E.Coli）。
13、一种根据权利要求2的方法，其中G-CSF是由一种适合于肺部给药并能够将G-CSF沉积于哺乳动物肺部的机械装置输送的。
14、一种根据权利要求13的方法，其中该装置是一个喷雾器，计量剂量吸入器或粉剂吸入器。
15、一种根据权利要求14的方法，其中该装置是一种喷射式喷雾器。
16、一种根据权利要求14的方法，其中该装置是一种超声波喷雾器。
17、一种根据权利要求2的方法，其中该哺乳动物是人。
18、一种根据权利要求17的方法，其中该给药方法使每μl血液中白细胞水平超过1000个白细胞。
19、一种根据权利要求17的方法，其中该给药方法使每μl血液中白细胞水平超过5000到6000个白细胞。
20、一种根据权利要求1的方法，其特征在于用来治疗嗜中性白细胞减少症。
21、一种根据权利要求1的方法，其特征在于用来治疗感染。
22、一种根据权利要求1的方法，其特征在于用来预防感染。
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ATE147270T1 (de) 1997-01-15
US5284656A (en) 1994-02-08
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IL101235A (en) 1998-10-30
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AU643141B2 (en) 1993-11-04
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DE69216450D1 (de) 1997-02-20
FI925163A (fi) 1992-11-13

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