CN1073119C - 干扰素干粉配方的方法及组合物 - Google Patents

干扰素干粉配方的方法及组合物 Download PDF

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CN1073119C
CN1073119C CN95193669A CN95193669A CN1073119C CN 1073119 C CN1073119 C CN 1073119C CN 95193669 A CN95193669 A CN 95193669A CN 95193669 A CN95193669 A CN 95193669A CN 1073119 C CN1073119 C CN 1073119C
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R·M·埔拉兹
N·凯穆拉
O·萨彤
L·C·佛斯特尔
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Abstract

本发明提供了经喷雾—干燥以干扰素为主特别是β-干扰素干粉配方的方法和组合物。该组合物可用于对干扰素治疗敏感的人类疾病的治疗，尤其是，本发明的方法基于喷雾干燥，可生产稳定高效的干扰素的干粉配方，这些干扰素包括但不限于β-干扰素。出人意外的是，人们发现可用喷雾干燥法制备干扰素的高效干粉配方。这些干粉配方可特别用于干扰素的肺部给药。

Description

干扰素干粉配方的方法及组合物
本申请为1994年5月18日提出的、未决的美国专利申请08/246,034号的部分继续。
本发明一般地涉及细胞因子，特别是干扰素干粉配方的方法和组合物。更具体讲，本发明涉及干扰素(IFNS)的喷雾干燥以生产高效干粉配方的方法。
干扰素是可用于治疗人类癌症-免疫系统增强等多种疾病的细胞因子。干扰素通常被配成非肠道给药的等渗溶液。近来，临床医师们寻找可供病人长期使用的干扰素的另一些给药途径。特别是，WO 91/16038中描述的已制备出肺部给药的干扰素的气雾剂配方。通过一种液体抛射剂的挥发使该配方分散。该专利告诉人们，通过加入表面活化剂或类似物来提高人类干扰素从氟里昂给药系统中释放的分散性。
WO 91/16038中公开了将固体多肽微粒制成药用气雾剂的方法和组合物，其中通过将IFN水溶液冻干然后喷射粉碎再冻干制成β-INF的干粉形式。美国专利4,503,035号中公开了分子量超过12,000，包括人类IFN在内的蛋白质的纯化方法。WO 89/05158号中公开了重组β-IFN低pH值的药物组合物。
由于干扰素是相当贵的化合物，有必要将其制成能在干粉吸入器中高效使用、在肺部给药能重现剂量，改进流动特性的高效价制剂。
本发明的目的是提供一种病人长期肺部给药的、含有干扰素的组合物。本发明的另一目的是提供一种无氟氯烷烃类或二氧化碳这样的液体抛射剂即可吸入给药的含有干扰素的粉状组合物。
本发明的另一目的是提供一种含有干扰素的粉状组合物，该组合物易于用能够保持干扰素高百分比活性的方法来制造。
本发明还有一个目的是提供一种比以往干扰素显示出较高稳定性的含有干扰素的组合物。
本发明的其他目的是本领域的普通技术人员通过审阅下列说明书和权利要求书就可明了的。
本发明一方面是一种肺部给药的、以干扰素为主的干粉组合物，该组合物含有治疗有效量的干扰素和药物可接受载体。
本发明的另一方面是干扰素肺部给药的单位剂量形式，该单位剂量形式包括一个含有本发明以干扰素为主的干粉组合物的单位容器。
本发明的第三方面是一种治疗对干扰素敏感的疾病的方法，该方法包括在病人的肺部给予生理有效量的以干扰素为主的干粉组合物。
本发明的另一方面是一种将以干扰素为主的干粉组合物气雾化的方法，该方法包括将一定量的干粉组合物分散到气流中形成气雾，然后将气雾捕获到有吹口的药室，随后可供病人吸入。
本发明还有一方面是制备以干扰素为主的干粉组合物的方法，该方法包括在一定条件下将干扰素与载体的湿混合物进行喷雾干燥，以制成可吸入的干粉。
本发明至少是部分基于用本发明的喷雾干燥法制成的具有高效价和改进流动性的以干扰素为主的干粉组合物。更高的效价是指所得的以干扰素为主的干粉组合物中有比用其他方法制备的组合物更高百分比的生理活性的干扰素。本发明的组合物通过干粉吸入器给药时其可快速气雾化并通过宿主的肺快速吸收。
在用于解释本发明的各方面的权利要求书中，应考虑几个重要定义。
术语“干扰素”是指包括天然存在的或重组技术制备的、分子量约为15,000-27,000道尔顿的、具有类似干扰素活性的小分子蛋白质和糖蛋白(有时叫作细胞因子)。一般地，这种活性是通过在细胞表面与特定的细胞膜受体结合而产生的。一旦结合，不同的干扰素会引发许多系列的细胞内作用。干扰素可用于治疗人类癌症——免疫系统抑制等多种疾病，天然干扰素是在对病毒感染、合成或生物诱导体的应答过程中，由细胞产生和分泌的。有些干扰素是天然干扰素的变体，可用DNA重组技术制备。干扰素有时被缩写成“IFN”，在本申请中也缩写成“IFN”。干扰素的例子包括如重组α-2A-IFN(RofernA Roche Laboratories)，重组α-2B-IFN(IntronA Schering)，从人类白细胞得到的α-N3-IFN(AlferonN-Pur-due Frederick),γ-1B-IFN(Actimmune-Genentech)，重组β-IFN(Betaseron-Chiron,Berlex)，天然存在的β-INF(Feron-Toray,Japan)等等。1985年3月5日公布的Pestka和Rubinstein的美国专利4,503,035中给出了人类白细胞干扰素的例子。用于本发明的目的，β-IFN是优选的，特别是天然存在的β-IFN。
术语“粉”是指一种由能自由流动并易在吸入器中分散，随后可供病人吸入以使微粒到达肺部并渗透到肺泡囊中的粉细分散的微粒组成的组合物，因而该粉被说成是能被吸入的。优选的是比较均匀的球状分布的、直径平均在10微米(μm)以下的微粒。更好的是直径在7.5μm以下的微粒。最好的是直径在5.0μm以下。通常微粒大小分布约为0.1μm-5μm，特别是约为2μm-5μm。
术语“干”是指组合物中的水分能使微粒在吸入器中易于分散以形成气雾。一般地，按重量计(％W)，这些水分约为10％以下，通常为5％W以下，3％以下更好。
术语“治疗有效量”是指存在于组合物中的、病人用后能出现生理反应所需的干扰素的量。每种干扰素的用量要依具体情况而定。以下将给出用量指南。
术语“生理有效量”是指给病人服用的、能产生预期的缓解作用或疗效的量。该量对每种干扰素都是特定的，为最终被批准的剂量水平，以下将给出指南。
术语“药物可接受的载体”是指能被用于肺部并无严重不良毒理作用的载体。
本发明一方面是一种肺部给药的以干扰素为基础的干粉组合物，该组合物含有与药物可接受载体结合的治疗有效量的干扰素。
一般地，本发明的组合物比本领域已知的其他干扰素组合物的效价要高，分散性也高。IFN在干燥状态下为无定形粉末。适用于本发明组合物的IFN包括各种广泛定义的αIFN,βIFN和γIFN。优选的是αIFN和βIFN，特别是βIFN。该组合物对天然存在的βIFN特别有用，如日本Toray Industries Co.的βIFN。
组合物中IFN的治疗有效量取决于所用的IFN的生物活性和单位剂量形式中所需的量。由于IFN的高活性，应以某种单位制剂的形式制造，以使配制者和消费者便于操作。这意味着干粉组合物中单位剂量物质的总重约为0.5mg-15mg，优选的是约为2mg-10mg，一般地，组合物中IFN的量为0.05％W-5.0％W。最好是约为0.2％-2.0％W。
药物可接受载体的量是为确保在病人肺部均匀给药，组合物应具必需的稳定性、分散性、相容性和松散的特点所需的载体量。其用量取决于所用的IFN的活性，约为95.0％W-99.95％W，优选的是98％W-99.8％W。
载体可以是一种赋形剂或两种或两种以上药物赋形剂的结合体，但一般实际上不是任何“渗透促进剂”。渗透促进剂是能够增加药物通过粘膜或肺泡渗透的表面活性物质，这些物质是鼻内、直肠内和阴道内药物配方中推荐使用的。典型的渗透促进剂包括胆汁盐，如牛磺胆酸盐，甘胆酸盐和去氧胆酸盐；褐霉酸盐，如牛去氧褐霉酸盐；以及生物适合剂，如吐温，聚乙二醇单十二醚十二酸酯等。可是由于表面活性物质会对肺部上皮血屏障产生不良作用，肺部用的配方中一般不必使用渗透促进剂。
本发明中用作载体的药物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；盐，如氯化钠等。这些载体可以是结晶或无定形粉末或这两种的混合物。
已发现HSA是特别有用的载体，因它可使IFN在溶液中非常稳定。
特别有用的填充剂包括互容的碳水化合物，多肽，氨基酸或它们的结合体。适宜的碳水化合物包括单糖，如半乳糖D-甘露糖，山梨糖等；二糖，如乳糖，海藻糖等；环糊精，如2-羟丙基-β-环糊精；以及多糖，如棉子糖，糊精-麦芽糖复合剂，葡聚糖等；糖醇，如甘露醇，木糖醇等。优选的碳水化合物包括乳糖，海藻糖，棉子糖，糊精-麦芽糖复合剂和甘露醇。适宜的多肽包括天门冬酰苯丙氨酸甲酯。氨基酸包括丙氨酸和甘氨酸，优选的是甘氨酸。
本发明的组合物中占有较少成分的添加剂可能包括喷雾干燥过程中的稳定性助剂和粒子分散性助剂。这些添加剂包括疏水氨基酸，如包氨酸，酪氨酸，亮氨酸，苯丙氨酸等。
适宜的pH调节剂或缓冲剂包括用有机酸和有机碱制成的有机盐，如枸橼酸钠，抗坏血酸钠等，优选的是枸橼酸钠。
以下将描述本发明的单位剂量形式，治疗方法和制备方法。单位剂量形式
本发明的另一方面是干扰素肺部给药的单位剂量形式，这种剂量形式包含一个装有以干扰素为基础的干粉组合物的单位剂量容器，该组合物含有与药物可接受载体结合的治疗有效量的干扰素。
关于本发明的这一方面，是将本发明的组合物(如前所述)放入一个适宜的剂量容器中，该剂量能为病人单位剂量的治疗提供足够的IFN。剂量容器装在适宜的吸入器中，以使以干扰素为基础的干粉组合物能够气雾化，分散成气流形成气雾，随后将生成的气雾捕获到有吹口的药室，随后可供病人吸入。这一剂量容器包括本领域技术人员已知的装有组合物的任意容器，如明胶或塑料胶囊，容器具移动部分，能允许气流(如空气)直接进入容器使干粉组合物分散。这些容器的例子可参见1980年10月14日公布的美国专利4,227,522号；1980年3月11日公布的4,192,309号；和1978年8月8日公布的4,105,027，适宜的容器也包括与Glaxo′s Ventolin Rotohaler和Fi-son′s Spinhaler一起用的粉末吸入器。另一种能较好地防潮的单位剂量容器是用铝箔塑料薄片制成的。β-IFN粉末按重量或体积压缩填充到可成形的箔中并用箔-塑料薄片密封。美国专利4,778,054号中公开了这种与粉末吸入器一起使用的容器，并被Glaxo′sDiskhaler使用(美国专利4,627,432；4,811,731；5,035,237)。这些文献均为本文的参考文献。治疗疾病的方法
本发明的另一方面是对干扰素敏感的疾病的治疗方法，该方法包括在病人肺部给予生理有效量的以干扰素为基础的干粉组合物，该干扰素含有与药物可接受载体结合的治疗有效量的干扰素。
可用本发明的组合物治疗的疾病包括那些对IFN的治疗敏感的疾病。例如，αIFN可用于治疗乙肝和丙肝，毛细胞白血病，慢性非甲、非乙/非丙型肝炎和卡波济氏肉瘤；βFIN可用于治疗多发性硬化，脑瘤，皮肤癌和乙肝，丙肝；γIFN可用于治疗慢性肉芽肿病。
治疗特定病人或疾病所需的生理有效量取决于个体差异，身体条件，治疗周期，治疗规律，IFN的类型和其他因素，但可由医疗领域普通技术人员确定。每人每天的剂量范围可从0.25×106IU-50×106IU，按医生的处方量服用，例如，用重组αIFN(ReferonA-Roche Laboratonies)治疗毛细胞白血病的初始剂量可以为每天3×106IU，用16-24周，每周3次的维持剂量为3×106IU。其他剂量范围可根据临床经验并参考Physicians Desk Reference1994年增补版来确定。
相信病人对本发明的干粉干扰素的有效吸收是由于其在肺泡超薄(＜0.1fm)液层的迅速溶解所致。因而本发明的微粒平均大小以肺液层大10-50倍，使这些微粒出乎意料地被溶解，无论在局部肺还是全身治疗都能使干扰素迅速的被全身吸收。详细作用机制在此不再叙述。
本发明的气雾化的以干扰素为基础的干粉可特别用于代替非肠道给药的干扰素。因此，本发明的方法和组合物对慢性病人自行给药的治疗方案特别有用。正如刚刚叙述的，病人通过吸入适量的干扰素得到所需的剂量。通过刚才所述的方法。干扰素全身吸收的效率范围约为15％-50％，就个人剂量而言(每次吸入量)每次吸入药量范围约为3百万-5百万IU。因此病人要吸1-5次才能达到所需剂量。粉末气雾化的方法
本发明还有一方面是将以干扰素为基础的干粉组合物的气雾化的方法，该组合物含有与药物可接受载体结合的治疗有效量的干扰素，这一方法包含将一定量的干粉组合物分散到气流中形成气雾并将气雾捕获到有吹口的药室，随后可供病人吸入。
在未决的美国专利申请07/910,048和08/207,472号中对此方法作了进一步的详述，这两篇申请均为本申请的参考文献。
制备组合物
本发明还有一方面是制备本发明的以干扰素为基础的干粉组合物的方法，该方法包括在可提供吸入干粉组合物条件下喷雾干燥干扰素与药物可接受载体的湿混合物，该混合物具有使干扰素稳定的pH。
喷雾干燥是一种将IFN与载体的湿混合物通过喷嘴(如两种液体的喷嘴)、旋转盘或相同装置送入热气流中，使溶液雾化形成精细飞沫的方法。湿混合物可能是溶液、悬浮液或类似物，必须是均匀的，以确保各组分在混合物中或在最终的粉状组合物中均匀分布。优选的湿混合物是溶液，溶剂一般为水，从飞沫中迅速蒸发，生成直径1-5μm的微粒组成的细干粉。出人意外的是。蛋白质暴露于干燥的热气中时不被降解，可制成具有足够纯度、可药用的干扰素粉末。定义的可接受的纯度为降解物和污染物的含量在5％以下，优选的是3％以下，最好为1％以下。
喷雾干燥是在能够生成具有微粒的均匀组成的无定形粉末的条件下进行，该粉末为可吸入的、低水分的、具流动特性且可气雾化。优选的最终粉末微粒的大小是约有98％以上的物质直径约为10μm或10μm以下的微粒。微粒中约90％的物质的直径在5μm以下。或者约95％的物质(更好的是95％以上)为直径10μm以下的微粒，微粒中约80％的物质(更好的是80％以上)的直径在5μm以下。
按照本发明的方法，高效价、高流动性的干扰素干粉是用喷雾干燥的方法制备的，优选的干扰素原料是β-干扰素，但也适用于其他干扰素。在该方法中，干扰素被制成按重量计浓度为0.0005％-0.02％，通常为0.001％-0.005％的溶液。该溶液可含有一种能保持干扰素在溶液中的化学稳定性的稳定剂，如HSA，其浓度按重量计为0.01％-1.0％。优选的是0.05％-0.25％，并可还含有其他化学物质，如存在于IFN原料中的盐或防腐剂。然后将溶液用常规的、从Buchi,Niro,Yamato Chemical Co.,Okawara Kakoki Co等公司买到的喷雾干燥设备进行喷雾干燥，生成实际上为无定形的微粒化的产物。
喷雾方法可用旋转喷雾，加压喷雾，二流体喷雾，这些方法中所用设备的例子包括Yamato Chemicel Co.制的GA-32型泡腾小型喷雾器，DL-41型泡腾喷雾干燥器，或Okawara Kakoki Co.制造的CL-8型喷雾干燥器，L-8型喷雾干燥器，FL-12型喷雾干燥器，FL-16型喷雾干燥器，或FL-120型喷雾干燥器，这些干燥器能用转盘雾化器进行喷雾。
在喷雾方法中对雾化器的喷嘴没有特殊的限制，建议使用能够产生微粒直径适于鼻腔、咽部或肺部给药的晶粒的喷雾干燥组合物的喷嘴。例如，由同一公司Yameto Chemical Co.制造的“1A”,“1”,“2A”,“2”,“3”型等可用于上述喷雾干燥器的喷嘴。另外，由同一公司Okawara Kakoki Co.制造的“MC-50”,“MC-65”或“MC-85”型可用于喷雾干燥器的转盘。
对用于干燥喷雾物质的气体没有特殊的限制，建议用空气、氮气或一种惰性气体。用于干燥喷雾物质的气体，其入口温度为不会使喷雾干燥物质热灭活的温度。温度范围约为50℃-200℃，优选的是约为50℃-100℃。用于干燥喷雾物质的气体，出口温度约为0℃-150℃，优选的为0℃-90℃最好为0℃-60℃。鉴于IFN在55℃开始灭活，约70℃时几乎全部灭活，出口和入口处温度均为55℃以上是出人意外的。
通过将溶液中的稳定剂减到最少量来制备高效价的IFN粉末，以减少高剂量给药的吸入次数，通常只需1次吸入。
用于本发明的干扰素干粉实际为无定形的，基本上没有晶体结构。在喷雾干燥条件下制备的干粉干扰素，实际为微粒大小在上述范围的无定形粉末。按照本发明的方法，优选的是β-IFN，但也适用于其他干扰素，先将干扰素原料溶于pH约为2-9的生理可接受的水溶液，典型的水溶液中含有氯化钠，也可含一种缓冲剂。干扰素溶液制成重量百分比浓度为0.01％-1％，通常为0.1％-0.2％的溶液。然后用可买到的载体如Buchi,Niro Yamato Okawara Kakori等常规喷雾干燥器将溶液喷雾干燥，得到实际为无定形的微粒产物。
本发明的干扰素可与适于吸入给药或肺部给药的药物载体或赋形剂结合。当需要降低给病人服用的粉末中的干扰素的浓度时，这些载体可用作填充剂，也可用于提高干扰素组合物的稳定性，增加粉末在分散器中的分散性，以使干扰素更为有效并可重现给药，改善干扰素的操作性能，如流动性和相容性，从而加快制造和粉末填充的过程。
这些载体可在喷雾干燥前与干扰素结合，即将载体加到原料溶液中。这样，载体微粒与IFN微粒一起形成，生成均匀粉末。另一种是将载体分别制成干粉形式并与干粉干扰素混合载体粉末通常如结晶体(以避免吸收水分)，但某些情况下也可是无定形粉末，或结晶与无定形粉末的混合物。载体微粒大小是可以选择的，用以增加IFN粉末的流动性能，典型的载体微粒大小为25μm-100μm，优选的载体物质是大小为上述范围的结晶乳糖。
                     实验
                    实施例Ⅰ
本实施例阐述一种制备本发明组合物的方法
制备约50ml10mM的、含有约2mg/mlHSA的天然人类β-IFN的氯化钠溶液。
所得湿混合物在下列条件下装到Buchi Laboratory喷雾干燥器中，得到本发明的组合物。
湿混合物的温度    4℃-10℃
入口温度          115℃-125℃
进料速度          6ml/min
出口温度          60℃-70℃
一旦湿混合物耗完，由于入口温度缓慢下降，出口温度将在70℃左右维持15分钟，这使水分已在3％以下的以IFN为基础的干粉组合物得以二次干燥，水分用电量Karl Fischer法制定。本实施例的组合物组成如下(％W按固体总量计算)：
1.9％W    β-IFN
98.1％W载体(75.8％HSA,22.3％NaCl)
                       实施例Ⅱ
用实施例Ⅰ的方法，但在二次干燥阶段将出口温度增至75℃-80℃，得到水分在1％以下的本发明的组合物。
                       实施例Ⅲ
本实施例阐述一种制备本发明的组合物的方法，该组合物中的载体含有填充剂-甘露醇。
按实施例Ⅰ所述，将甘露醇溶于天然人类βIFN中。甘露醇的浓度为5.75mg/ml。
在下列条件下，将所得的湿混合物装入Buchi Laboratory喷雾干燥器中：
湿混合物的温度          4℃-10℃
入口温度                115℃-125℃
进料速度                5ml/min
出口温度                60℃-70℃
二次干燥——15分钟于    70℃
虽然已用说明书和实施例对前述发明进行了详细说明，但为了理解的更清楚显然可在后面权利要求范围内，对说明书和实施例予以修改。
                        实施例Ⅳ
本实施例阐述一种制备本发明的组合物的方法，其中无膨胀剂存在于组合物中。
制备约100ml、10mM的含有2mg/ml人血清白蛋白(HSA)(用人类正常二倍体成纤维细胞进行培养得到)(约7×104IU/ml)的天然人类干扰素的氯化钠溶液。用买到的Yamrto Chemicel Co.制造的“GA-32型泡腾小型喷雾器”进行喷雾干燥。所用喷嘴为1A喷嘴(φ0.4mm)，干燥气体入口和出口温度分别为100℃和60℃。另外，喷雾压力为1kg/cm2，热空气流量为0.40-0.42m3/min，溶液的传输速率为4.3ml/min，喷雾干燥约20分钟后，用旋风器将干粉收集到药室，回收干粉，测定IFN的活性。用含有抗人类β干扰素的抗体进行酶免疫分析法测定干扰素的活性(S.Yamazaki et al.,Im-munoassay,10,57(1989))将干粉用蒸馏水溶解，测定干粉的活性，先吸收在280nm，与喷雾干燥前的干扰素活性进行比较。所得结果列于表1。重复测定3次，用平均值进行比较。表中相对活性的误差为标准误差(±SE)。
                        表1
天然人类β干扰素在喷雾干燥前后的活性
       相对活性(IU/A280单位)    剩余活性(％)喷雾干燥前    4.11±0.11              100％喷雾干燥后    3.14±0.04              74.8％
喷雾干燥后，天然人类β干扰素的活性为喷雾干燥前的74.8％，表明在喷雾干燥过程中是能保持活性的。这一结果是出人意外的，因为另一种含有相似量HSA的类似天然人类β干扰素的溶液在约55℃时开始灭活，70℃时全部灭活。将本发明的方法得到的干粉涂铂，用场致发射扫描电子显微镜(Hitachi Co.生产，型号S-8000)查看晶粒形状。观察到约90％的晶粒相对光滑，晶粒表面有大的凹痕和突起，晶粒直径约为10μm。另外，用Karl fischer法(MitsubishiKasei Co.生产，CA-06型电量滴定水分仪)测定所得干粉水分为5.6wt％。
                    实施例Ⅴ
本实施例阐述一种制备IFN/HSA/甘露醇组合物的方法。
制备约100ml、10mM的含有150mg/ml甘露醇和约2mg/ml人血清白蛋白(HSA)的天然人类干扰素的氯化钠溶液。在该溶液组成中，甘露醇约占总溶质量的90wt％。
用与实施例Ⅳ相同的方法和条件将上述溶液喷雾干燥，用与实施例Ⅳ相同的方法测定所得干粉的干扰素活性。所得结果列于表2中。
                    表2
天然人类β干扰素喷雾干燥前后的活性
       相对活性(IU/A280单位)    剩余活性(％)喷雾干燥前    5.59±0.51              100％喷雾干燥后    4.53±0.13              81.0％
喷雾干燥后，天然人类β干扰素的活性与喷雾干燥前比为81.0％，正如实施例Ⅳ中所述，这一结果是出人意外的，因为类似的含有相同量的天然人类β干扰素、HSA和甘露醇的溶液在约55℃时开始灭活，70℃时几乎全部灭活。
用实施例Ⅳ和Ⅴ制得的从IFN为基础的粉末是分散的，实施例Ⅴ制得的粉末比实施例Ⅳ更分散。
粉末涂铂，并用场致发射扫描电子显微镜(Hitachi公司制造，型号S-8000)查看晶粒形状时，发现晶粒大小与实施例Ⅳ中相似，但其形状比实施例Ⅳ中的更圆。另外，将粉末分散到无水乙醇中，用颗粒分析器(Nikkiso Co.制造，Microtrac FRA)查看晶粒直径分布时，发现约有90％的晶粒分布在1.6-9.3μm范围。用实施例Ⅳ中的Karl Fischer法测定水分为0.74％wt。
本发明中提到的所有出版物和专利申请文献在同等程度上，即使每一公开物和专利申请特指作为本申请的对比文献。
由于已对本发明进行了完全的描述，显然，本领域的任何普通技术人员都能按后面权利要求书的范围或精神对其进行改变和修改。

Claims (33)

1．一种用于肺部给药的喷雾干燥的以干扰素为基础的干粉组合物，所述组合物是由干扰素水溶液制备的并含有与药物可接受的载体结合的治疗有效量的干扰素。
2．权利要求1的组合物，该组合物实际不含渗透促进剂。
3．权利要求2的组合物，其中的载体含有人血清白蛋白。
4．权利要求3的组合物，其中的载体可进一步含有一种碳水化合物填充剂。
5．权利要求4的组合物，其中的载体为甘露醇。
6．权利要求4的组合物，其中的载体为棉子糖。
7．权利要求1的组合物，其中的干粉组合物中95％的物质为大小在10μm以下的微粒。
8．权利要求7的组合物，其中的干粉组合物中80％的物质为大小在5μm以下的微粒。
9．权利要求1的组合物，其中的干扰素为天然存在的。
10．权利要求1的组合物，其中的干扰素为β干扰素。
11．一种肺部给药的干扰素的单位剂量形式，该剂量形式含有一个装有喷雾-干燥的、以干扰素为基础的干粉组合物的单位剂量容器，该组合物是由干扰素水溶液制备的并含有与药物可接受的载体结合的治疗有效量的干扰素。
12．权利要求11的单位剂量形式，其中的载体含有人血清白蛋白或人血清白蛋白和碳水化合物填充剂，该组合物实际不含渗透促进剂，并且干粉组合物中的95％的物质为大小约在10μm以下的微粒。
13．一种将权利要求1-12任一要求的喷雾-干燥的、以干扰素为基础的干粉组合物气雾化的方法，该方法包含：
将一定量的权利要求1-12任一要求的干粉组合物分散到气流中以形成气雾，并且
将气雾捕获到药室。
14．权利要求13的方法，其中的载体含有HSA和碳水化合物填充剂，该组合物实际不含渗透促进剂，并且干粉组合物中95％的物质为大小在10μm以下的微粒。
15．一种制备用于肺部给药的喷雾-干燥的、以干扰素为基础的干粉组合物的方法，该方法包括：
(ⅰ)制备干扰素和药用载体的均匀水性混合物；
(ⅱ)将(ⅰ)中均匀水性混合物气雾化形成细液滴；和
(ⅲ)将所述液滴暴露于热汽流中以蒸发液滴中水，从而形成含干扰素和药用载体的喷雾干燥粉。
16．权利要求15的方法，其中的组合物实际不合渗透促进剂。
17．权利要求16的方法，其中的载体含有HSA。
18．权利要求17的方法，其中的载体可进一步含有碳水化合物填充剂。
19．权利要求18的方法，其中的填充剂为甘露醇。
20．权利要求18的方法，其中的填充剂为棉子糖。
21．权利要求15的方法，其中的喷雾-干燥组合物中有95％的物质为大小在10μm以下的微粒。
22．一种喷雾干燥的、肺部给药的以干扰素为基础的干粉组合物，所述组合物是由干扰素水溶液制备的并含有与药物可接受载体结合的治疗有效量的天然存在的β干扰素，该药物可接受载体含有人血清白蛋白或人血清白蛋白和碳水化合物填充剂，组合物中实际不合渗透促进剂，并且干粉组合物中有95％的物质为大小在10μm以下的微粒。
23．权利要求22的组合物，其中的填充剂为甘露醇。
24．权利要求22的组合物，其中的填充剂为棉子糖。
25．权利要求1的组合物，其中载体选自碳水合物，氨基酸和多肽。
26．权利要求25的组合物，其中载体是选自单糖，二糖，多糖和糖醇的碳水合物。
27．权利要求26的组合物，其中载体是二糖。
28．权利要求25的组合物，其中载体是氨基酸。
29．权利要求28的组合物，其中氨基酸是疏水氨基酸
30．权利要求29的组合物，其中疏水氨基酸选自色氨酸，酪氨酸，亮氨酸和苯丙氨酸。
31．权利要求25的组合物，其中所述载体包括碳水合物和氨基酸的混合物。
32．权利要求31的组合物，其中所述载体包括二糖和疏水性氨基酸。
33．权利要求32的组合物，其包括β-干扰素，二糖和亮氨酸。
CN95193669A 1994-05-18 1995-05-15 干扰素干粉配方的方法及组合物 Expired - Fee Related CN1073119C (zh)

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US6123936A (en) 2000-09-26
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NZ285664A (en) 1998-07-28
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EP0759939B1 (en) 2005-07-20
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US6479049B1 (en) 2002-11-12
US20030072718A1 (en) 2003-04-17
DE69534318D1 (de) 2005-08-25
AU696387B2 (en) 1998-09-10
AU2514295A (en) 1995-12-05
US6231851B1 (en) 2001-05-15
JPH10500672A (ja) 1998-01-20
CN1151168A (zh) 1997-06-04
DE69534318T2 (de) 2006-04-20
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