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CN1171046A - 肽和蛋白质的气雾剂 - Google Patents

肽和蛋白质的气雾剂 Download PDF

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CN1171046A
CN1171046A CN95196977A CN95196977A CN1171046A CN 1171046 A CN1171046 A CN 1171046A CN 95196977 A CN95196977 A CN 95196977A CN 95196977 A CN95196977 A CN 95196977A CN 1171046 A CN1171046 A CN 1171046A
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K·贝克斯特兰
M·德尔贝克
A·约翰森
G·卡尔斯特兰德
E·林奎维斯特
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Abstract

一种药物气雾剂包括(a)一种氢氟链烷抛射剂;(b)一种可分散在抛射剂中的药学上的活性多肽;和(c)一种表面活性剂,它是C8－C16脂肪酸或其盐,胆汁盐,磷脂,或烷基糖化物,此表面活性剂能促进下呼吸道中多肽的系统吸收。

Description

肽和蛋白质的气雾剂
本发明涉及包括医用肽和蛋白质的药物制剂，它通过气溶胶吸入器吸入。
本发明的背景技术
许多药物是以气雾剂的形式通过口或鼻给药的。给予这种气雾剂的一种通用方法包括将药物的悬浮液制剂制备成用作抛射剂的液化气体中的精细粉碎的粉剂。通常使用加压计量吸入器给予病人这种制剂。为了帮助抛射剂中药物的分散和防止被粉碎的药物颗粒的聚集，一般包括一种表面活性剂。
直到最近，包含含氯氟烃的抛射剂被用在所有药学气雾剂中。用在含氯氟烃制剂中的典型表面活性分散剂有脱水山梨糖醇三油酸盐，油酸，卵磷脂，和乙醇。由于在臭氧的破坏中包含含氯氟烃的抛射剂受到影响，新一代抛射剂便立即产生。
被认为最有希望的新的抛射剂是氢氟链烷(HFA)抛射剂例如1，1，1，2-四氯乙烷(P134a)，1，1，1，2，3，3，3-七氯丙烷(P227)和1，1-二氯乙烷(P152a)。不仅是在环境上它们可被接受，而且它们具有小的毒性和适用于气雾剂的气压。然而通常用在含氯氟烃气雾剂中的表面活性剂不是特别适用于与新一代的抛射剂同用，因此近年来建议将许多替代的表面活性剂专门与氢氟链烷抛射剂同用，其中有多乙氧基表面活性剂和氟化表面活性剂。
虽然已采用了各种气雾剂，但传统地肽类药物并不包含在那些以气雾剂形式给药的药物中。例如美国专利号5,284,656公开了一种粒性白细胞集落刺激因子制剂，它包括悬浮在抛射剂中含粒性白细胞集落刺激因子的精细粉碎的粉末，并有表面活性剂如脱水山梨糖醇三油酸盐，大豆卵磷脂或油酸的辅助。美国专利号5,364,838公开了一种胰岛素制剂，其中胰岛素干燥粉末悬浮在含赋形剂油酸的低沸点抛射剂中。
本发明的概述
目前我们意外发现能促进呼吸道中多肽吸收的各种物质也特别适用于作为与氢氟链烷抛射剂同用的表面活性剂。
因此本发明提供了一种药物气雾剂，包括(a)一种氢氟链烷抛射剂；(b)一种可分散在抛射剂中的药学上的活性多肽；和(c)一种表面活性剂，它是C8-C16脂肪酸或其盐，胆汁盐，磷脂或烷基糖化物，此表面活性剂能促进下呼吸道中多肽的系统吸收。
本发明中使用的表面活性剂尤其适用于与氢氟链烷抛射剂同用；其促进多肽吸收的能力使它们具有特别有利于用于此多肽气雾剂中的双重功能。
在脂肪酸及其盐中，优选C8-C16脂肪酸盐。优选的脂肪酸盐的例子有辛酸(C8)，癸酸(C10)，月桂酸(C12)和肉豆蔻酸(C14)的钠，钾和赖氨酸盐。由于反荷离子的种类并不是特别重要，脂肪酸的任何盐都是很有用的。特别优选的脂肪酸盐是癸酸钠。
适合的胆汁盐可以是胆酸，鹅脱氧胆酸，甘氨胆酸，牛磺胆酸，甘氨鹅脱氧胆酸，牛磺鹅脱氧胆酸，脱氧胆酸，甘氨脱氧胆酸，牛磺脱氧胆酸，石胆酸和乌索脱氧胆酸的盐。
在胆汁盐中，优选三羟基胆汁盐。更好的优选为胆酸，甘氨胆酸和牛磺胆酸的盐，特别是其钠盐和钾盐。最佳优选的胆汁盐为牛磺胆酸钠。
适合的磷脂可以是单链磷脂，例如溶血磷脂酰胆碱，溶血磷脂酰甘油，溶血磷脂酰乙醇胺，溶血磷脂酰肌醇和溶血磷脂酰丝氨酸或双链磷脂，例如二酰基磷脂酰胆碱，二酰基磷脂酰甘油，二酰基磷脂酰乙醇胺，二酰基磷脂酰磷脂酰肌醇和二酰基磷脂酰丝氨酸。
在磷脂中，优选二酰基磷脂酰甘油和二酰基磷脂酰胆碱，例如二辛酰基磷脂酰甘油和二辛酰基磷脂酰胆碱。
适合的烷基糖化物可以是烷基葡糖苷或烷基麦芽糖苷，例如癸基葡糖苷和十二烷基麦芽糖苷。
最佳优选的表面活性剂为胆汁盐。
抛射剂可以包括一个或多个1，1，1，2-四氯乙烷(P134a)，1，1，1，2，3，3，3-七氯丙烷(P227)和1，1-二氯乙烷(P152a)，例如，混合物中可任选一个或多个其它抛射剂。优选地抛射剂包括P134a或P227，或P134a和P227的混合物，例如P134a和P227的密度匹配的混合物。
多肽可以是任何小的至中等大小的医用或诊断用的肽或蛋白质，例如小于约40千道尔顿分子量，此为系统传输所需要。虽然根据多肽的分子量和理化特性以及所使用的特殊表面活性剂的不同，多肽吸收所增加的程度可能不同，但本发明的促进多肽吸收的机理是普遍适用的，且适用于所有这种多肽。预计分子量小于30千道尔顿的多肽最适用于本发明，例如分子量小于25千道尔顿或小于20千道尔顿的多肽，特别是小于15千道尔顿或10千道尔顿。
多肽优选肽类激素，如胰岛素，胰高血糖素，胰岛素的C-肽，血管加压素，去氨加压素(desmopressin)，促肾上腺皮质激素(ACTH)，促肾上腺皮质激素释放激素(CRH)，促性腺素释放激素(GnRH)，促性腺素释放激素激动剂和拮抗剂，促性腺素黄体生成素(黄体化激素或LHRH)，降钙素，甲状旁腺素(PTH)，甲状旁腺素的生物活性部分如甲状旁腺素(34)和甲状旁腺素(38)，生长激素(GH)(例如人生长激素(hGH))，生长激素释放激素(GHRH)，抑生长素，催产素，心钠素(ANF)，促甲状激素释放激素(TRH)，脱氧核糖核酸酶(DNase)，催乳素，和促滤泡素(FSH)，以及上述的类似物。
其他可能的多肽包括生长因子，白介素，多肽疫苗，酶，内啡肽，糖蛋白，脂蛋白以及包含在凝血级联系统中的多肽，它们系统地发挥其药理作用。预计即使不都是小分子至中等大小的多肽，大多数可以通过本发明的方法有效地传输。
优选的多肽为胰岛素。
除药物抛射剂和表面活性剂外，本发明的制剂中可包括少量乙醇(一般小于5％重量百分比，但可以小于20％重量百分比)。由于乙醇可以改进计量阀的功能且某些情况下也可提高分散体的稳定性，因此气溶胶组合物中通常含有乙醇。
当然根据需要组合物中可包含其他添加剂，包括其他药学上的活性剂，辅助剂，载体，芳香剂，缓冲剂，抗氧化剂，化学稳定剂等。作为适宜的添加剂的例子可以是所述的乳糖，葡萄糖，果糖，半乳糖，海藻糖，蔗糖，麦芽糖，棉子糖，麦芽糖醇，松三糖，水苏糖，乳糖醇，直辉中基性岩，淀粉，木糖醇，甘露糖醇，肌醇等，以及其水合物，和氨基酸，例如丙氨酸，甘氨酸和甜菜碱，以及肽和蛋白质，例如白蛋白。
优选的载体为松三糖。
由于所使用的特殊表面活性剂的双重作用，本发明的制剂有特别的优势。本发明提供的表面活性剂不仅在新一代的抛射剂中能意外地产生好的分散作用，而且最为重要地，还能促进多肽的吸收。本制剂稳定，多肽的生物利用率高，且可重复性好。
本发明所用的表面活性剂可以促进多肽的吸收例如：
(1)通过引起上皮细胞间的紧密连接的结构改变增加多肽的纤维间的通透性。
(2)通过相互作用或提取膜的蛋白质或脂类成分增加多肽的细胞间的通透性。
(3)增强强化因子与多肽间的相互作用增加了多肽在水溶液中的溶解性。这一作用可以通过阻止多肽聚集体(二聚体，三聚体，六聚体)的形成，或通过增溶增强子胶束中的多肽分子而产生。
(4)通过使肺泡和肺通道粘液屏障降低粘性或溶解，暴露上皮表面以便多肽的直接吸收。
(5)通过降低肺中蛋白酶抑制剂的活性增加多肽的稳定性，增加吸收。
表面活性剂可以通过上述单一或两种或多种机理起作用。通过数种机理较一种或两种机理起作用的表面活性剂更能增加多肽的有效吸收。
“促进吸收”意思是指有表面活性剂存在时较无表面活性剂时吸收至系统循环中的多肽的数量更多。
本发明中含有的表面活性剂按表面活性剂与多肽的比例范围约1∶10-1∶0.2选用，优选1∶4-1∶1，更好的优选为1∶4-1∶2.5。本发明制剂中优选的多肽浓度为0.1mg/ml-25mg/ml。
多肽尽可能选择含有直径小于10微米的颗粒，例如0.01-10微米或0.1-6微米，如0.1-5微米。选择至少有50％多肽含有所需大小范围的颗粒。例如至少60％，优选至少70％，更好的优选为至少80％，最佳优选至少90％多肽含有所需大小范围的颗粒。
因此，为了制备所需大小范围的颗粒，用于本发明的多肽在制成制剂前须进行加工。例如可以将多肽置于适合的粉碎机如喷射粉碎机中粉碎。或者，通过喷雾干燥或控制结晶法如使用超临界流体可以得到所需颗粒范围的颗粒。
用于本发明的表面活性剂也要优选所需大小范围的颗粒。相应地，可将多肽和表面活性剂在水缓冲剂中混合，再干燥成固体粉剂，然后将它任意粉碎。再将粉碎的粉末在低温下加入一部分抛射剂(和任选的乙醇)中。药物混合后，可以加入剩余的表面活性剂和抛射剂以及任意乙醇，将悬浮液装入合适的容器中。
本发明的多肽气雾剂用于疾病的局部或系统治疗，可以通过上下呼吸道给药，包括鼻的途径。因此本发明还提供了用于治疗的上述多肽气雾剂；使用多肽气雾剂制造治疗呼吸道疾病的药物的方法；以及对需要治疗的病人进行治疗的方法，包括给予上述病人治疗上有效量的本发明多肽气雾剂。
可以用本发明多肽气雾剂治疗的疾病是任何可以用各种情况下的特殊多肽治疗的那些疾病；例如本发明的含胰岛素制剂可以用于治疗糖尿病；含促肾上腺皮质激素制剂可以用于治疗炎性疾病；含促性腺素释放激素制剂可以用于治疗男性不育症。所有上述多肽的适应症都是已知的。本发明的多肽气雾剂也可用于预防治疗。
下面的实施例是为了举例证明而不是限定本发明。
为了评价所形成的悬浮液的质量，制备含P134a和/或P227及不同表面活性剂的胰岛素制剂。在下面的实施例中悬浮液的质量评定为“可接受的”或“好的”。一种可接受的悬浮液具有下面一种或多种特征，沉淀或分离慢，易于再分散，絮状沉淀少，以及无结晶或形态学改变，这样使得分散体非常稳定从而达到均匀给药。好的分散体更加稳定。实施例1方法
将胰岛素(25-35份，如下)加入装水的烧杯中溶解。再加入表面活性剂(65-75份，如下)溶解，调整pH至7.4。蒸发水使溶液浓缩，将得到的固体块在喷射粉碎机中压碎，筛选和粉碎。将40或50mg粉末加入塑料盖玻璃瓶中。用二氧化碳冰和异丙醇的混合物将瓶子冷却至约-40℃，加入10ml冷却的P134a(约-40℃)。用计量阀密封瓶子然后剧烈振动约30秒。实施例1g-1n另外在超声浴器中处理约10分钟。结果
 实施例号 表面活性剂  表面活性剂与胰岛素的比率   悬浮液
    1a 癸酸钠   25∶75   良好
    1b 癸酸钾   27∶73   良好
    1c 癸酸赖氨酸   35∶65   良好
    1d 肉豆蔻酸   30∶70   良好
钠
    1e 月桂酸钠     25∶75     良好
    1f 辛酸钠     25∶75     良好
    1g 牛黄胆酸钠     25∶75     良好
    1h 二辛酰基磷脂酰甘油     25∶75     良好
    1j 十二烷基麦芽糖苷     25∶75     良好
    1k 溶血棕榈酰磷脂酰甘油     25∶75   可接受的
    1m 溶血棕榈酰磷脂酰胆碱     25∶75   可接受的
    1n 二辛酰基磷脂酰胆碱     25∶75     良好
实施例2
将癸酸钠(25份)和胰岛素(75份)分别粉碎然后干燥混合，将40mg这种混合物加入塑料盖玻璃瓶中。用二氧化碳冰和异丙醇的混合物将瓶子冷却至约-40℃，再加入10ml冷却的(约-40℃)P134a。用计量阀密封瓶子然后剧烈振动约30秒。得到好的悬浮液。实施例3方法
将胰岛素(25-35份，如下)加入装水的烧杯中溶解。再加入表面活性剂(65-75份，如下)溶解，调整pH至7.4。通过蒸发水使溶液浓缩，将得到的固体块在喷射粉碎机中压碎，筛选和粉碎。将40或50mg粉末加入塑料盖玻璃瓶中。用二氧化碳冰和异丙醇的混合物瓶子冷却至约-40℃，加入10ml冷却的P227(约-40℃)。用计量阀密封瓶子然后剧烈振动约30秒。实施例3g-3n另外在超声浴器中处理约10分钟。结果
实施例号 表面活性剂    表面活性剂与胰岛素的比率   悬浮液
    3a 癸酸钠     25∶75   良好
    3b 癸酸钾     27∶73   良好
    3c 癸酸赖氨酸     35∶65   良好
    3d 肉豆蔻酸钠     30∶70   良好
    3e 月桂酸钠     25∶75   良好
    3f 辛酸钠     25∶75   良好
    3g 牛黄胆酸钠     25∶75   良好
    3h 二辛酰基磷脂酰甘油     25∶75   良好
    3j 十二烷基     25∶75   良好
麦芽糖苷
    3k 溶血棕榈酰磷脂酰甘油     25∶75 可接受的
    3m 溶血棕榈酰磷脂酰胆碱     25∶75 可接受的
    3n 二辛酰基磷脂酰胆碱     25∶75 良好
实施例4
将含有脱氧核糖核酸酶，表面活性剂(牛磺胆酸钠或二辛酰基磷脂酰甘油)和松三糖(脱氧核糖核酸酶∶表面活性剂∶松三糖为1∶0.33∶98.67，总重量50mg)粉碎制剂加入塑料盖玻璃瓶中，冷却至约-40℃。加入冷却的抛射剂134a或抛射剂227(约-40℃，约10ml)，用计量阀密封瓶子再在超声浴器中处理约10分钟。
在超声浴器中处理之前加入5％(w/w)乙醇得到相同的制剂。立即检测所得到的悬浮液的质量，然后在室温下储存20小时。所有情况下都观察到好的悬浮液。实施例5
将癸酸钠和胰岛素分别粉碎然后干燥混合。癸酸钠与胰岛素之比为25∶75。将80mg这种混合物加入气溶胶小瓶中。用二氧化碳冰和异丙醇的混合物将气溶胶小瓶冷却至约-40℃，加入10ml冷却的P134a(约-40℃)。用50μl计量阀密封气溶胶小瓶然后在超声浴器中处理几分钟。
用“Andersen’冲击器以28.3升/分钟测定从容器中取出的气溶胶中的胰岛素颗粒大小。取出量的41％为细颗粒部分(小于6μm)。在室温下储存两月后重复颗粒测定，没有发现改变。细颗粒部分为46％。实施例6
按如下制备50个含胰岛素和牛磺胆酸钠(比例为75∶25，8mg/ml)的气溶胶单位：将这些物质称重放在烧杯中。用二氧化碳冰和异丙醇的混合物将烧杯冷却至约-40℃。加入抛射剂(p134a，约-40℃)，用ultraturrax将混合物混合几分钟，然后注入制备容器中，再加入抛射剂(p134a，约-40℃)。(总体积500ml)用ultraturrax搅拌制剂再装入计量吸入器中，每个10ml。吸入器用计量阀密封。
气溶胶在不同条件下储存：5℃，干燥条件         2，8，和13周30℃，30％相对湿度    11周
检测悬浮液的质量。所有情况下均观察到好的悬浮液。
另外，通过使用标准的色谱技术测定降解产物脱酰胺基胰岛素和其他与胰岛素相关的杂质的浓度来评价胰岛素的稳定性。各种情况下杂质的含量都在可接受的限度内(脱酰胺基胰岛素少于5％，其他与胰岛素相关的杂质少于3％)。实施例7
打开装有实施例5的制剂的加压计量吸入器，将放出的气溶胶收集在间隔器中。使一气流(8升/分钟)通过间隔器进入传输系统，让五只狗分别在其中暴露五分钟。试验物吸入量为1单位胰岛素/kg。通过从前面研究中比较吸入后的血浆曲线和静脉内注射后的血浆曲线测定生物利用率。生物利用率为66％的药物到达肺中。实施例8
用实施例6的制剂或没有增强子的相应制剂装入加压计量吸入器中。打开每个吸入器，将放出的气溶胶收集在间隔器中。使一气流(8升/分钟)通过间隔器进入传输系统，让五只狗分别在其中暴露五分钟。试验物吸入量为1单位胰岛素/kg。给药前和开始给药后不同时间间隔至245分钟收集血样。用放射免疫测定法测定血浆胰岛素浓度。
对于无增强子的制剂，一般地吸收胰岛素相对要慢，一些动物其最大血浆胰岛素含量出现在给药后50至100分钟之间。另一些动物最大血浆胰岛素含量出现在给药后10至20分钟。
对于本发明的制剂，所有动物在给药后10分钟内达到最大血浆胰岛素含量，接着大约25分钟时达到另一个最大值。
本发明中的制剂所造成的对胰岛素的普遍较快的吸收是与健康人餐后的自然胰岛素血浆曲线比较接近的。并且，在动物之间所表现出的无差异性表明，使用本发明中的制剂能够比较容易和比较可靠地达到一个期望的胰岛素吸收水准。

Claims (46)

1.一种药物气雾剂包括(a)一种氢氟链烷抛射剂；(b)一种可分散在抛射剂中的药学上的活性多肽；和(c)一种表面活性剂，它是C8-C16脂肪酸或其盐，胆汁盐，磷脂，或烷基糖化物，此表面活性剂能促进下呼吸道中多肽的系统吸收。
2.权利要求1所述的药物气雾剂，其中表面活性剂为C8-C16脂肪酸盐。
3.权利要求2所述的药物气雾剂，其中脂肪酸盐选自辛酸(C8)，癸酸(C10)，月桂酸(C12)和肉豆蔻酸(C14)，的钠，钾和赖氨酸盐。
4.权利要求1所述的药物气雾剂，其中表面活性剂为三羟基胆汁盐。
5.权利要求4所述的药物气雾剂，其中胆汁盐选自胆酸，甘氨胆酸和牛磺胆酸的盐。
6.权利要求5所述的药物气雾剂，其中胆汁盐选自胆酸，甘氨胆酸和牛磺胆酸的钠盐和钾盐。
7.权利要求6所述的药物气雾剂，其中胆汁盐为牛磺胆酸钠。
8.权利要求1所述的药物气雾剂，其中表面活性剂为单链磷脂。
9.权利要求8所述的药物气雾剂，其中表面活性剂选自溶血磷脂酰胆碱，溶血磷脂酰甘油，溶血磷脂酰乙醇胺，溶血磷脂酰肌醇和溶血磷脂酰丝氨酸。
10.权利要求1所述的药物气雾剂，其中表面活性剂为双链磷脂。
11.权利要求11所述的药物气雾剂，其中表面活性剂选自二酰基磷脂酰胆碱，二酰基磷脂酰甘油，二酰基磷脂酰乙醇胺，二酰基磷脂酰肌醇和二酰基磷脂酰丝氨酸。
12.权利要求11所述的药物气雾剂，其中表面活性剂选自二辛酰基磷脂酰甘油和二辛酰基磷脂酰胆碱。
13.权利要求1所述的药物气雾剂，其中表面活性剂选自烷基葡糖苷和烷基麦芽糖苷。
14.权利要求13所述的药物气雾剂，其中表面活性剂选自癸基葡糖苷和十二烷基麦芽糖苷。
15.权利要求1-14任何要求所述的药物气雾剂，其中抛射剂包括1，1，1，2-四氟乙烷(P134a)，1，1，1，2，3，3，3-七氟丙烷(P227)，或1，1-二氟乙烷(P152a)。
16.权利要求15所述的药物气雾剂，其中抛射剂包括1，1，1，2-四氟乙烷(P134a)和1，1，1，2，3，3，3-七氟丙烷(P227)。
17.权利要求15或16要求所述的药物气雾剂，其中抛射剂包括1，1，1，2-四氟乙烷(P134a)和1，1，1，2，3，3，3-七氟丙烷(P227)的密度匹配的混合物。
18.任何上述权利要求所述的药物气雾剂，其中多肽分子量小于40kD。
19.权利要求18所述的药物气雾剂，其中多肽分子量小于30kD。
20.权利要求19所述的药物气雾剂，其中多肽分子量小于25kD。
21.任何上述权利要求所述的药物气雾剂，其中多肽分子量小于20kD。
22.任何上述权利要求所述的药物气雾剂，其中多肽分子量小于15kD。
23.任何上述权利要求所述的药物气雾剂，其中多肽分子量小于10kD。
24.任何上述权利要求所述的药物气雾剂，其中多肽为肽类激素。
25.任何权利要求1-17所述的药物气雾剂，其中多肽选自胰岛素，胰高血糖素，胰岛素的C-肽，血管加压素，去氨加压素，促肾上腺皮质激素，促肾上腺皮质激素释放激素，促性腺素释放激素，促性腺素释放激素激动剂和拮抗剂，促性腺素黄体生成素，降钙素，甲状旁腺素，甲状旁腺素的生物活性部分如甲状旁腺素(34)和甲状旁腺素(38)，生长激素(例如人生长激素)，生长激素释放激素，抑生长素，催产素，心钠素，促甲状激素释放激素，脱氧核糖核酸酶，催乳素和，促滤泡素，以及上述的类似物。
26.权利要求25所述的药物气雾剂，其中多肽为胰岛素。
27.任何上述权利要求所述的药物气雾剂，包括占抛射剂和表面活性剂重量20％以下的乙醇。
28.任何上述权利要求所述的药物气雾剂，包括占抛射剂和表面活性剂重量5％以下的乙醇。
29.任何上述权利要求所述的药物气雾剂，包括选自辅助剂，载体，芳香剂，缓冲剂，抗氧化剂和化学稳定剂分的添加剂。
30.权利要求29所述的药物气雾剂，其中辅助剂选自乳糖，葡萄糖，果糖，半乳糖，海藻糖，蔗糖，麦芽糖，棉子糖，麦芽糖醇，松三糖，水苏糖，乳糖醇，直辉中基性岩，淀粉，木糖醇，甘露糖醇，肌醇等，以及其水合物，丙氨酸，甘氨酸和甜菜碱，和白蛋白。
31.权利要求30所述的药物气雾剂，其中载体为松三糖。
32.任何上述权利要求所述的药物气雾剂，其中表面活性剂是按表面活性剂：多肽为1∶10-1∶0.2的范围选用。
33.权利要求32所述的药物气雾剂，其中表面活性剂是按表面活性剂：多肽为1∶4-1∶1的范围选用。
34.任何上述权利要求所述的药物气雾剂，其中多肽包括直径为0.01-10微米的颗粒。
35.权利要求34所述的药物气雾剂，其中多肽包括直径为0.1-6微米的颗粒。
36.权利要求34所述的药物气雾剂，其中多肽包括直径为0.1-5微米的颗粒。
37.任何权利要求34-36所述的药物气雾剂，其中至少50％多肽含有上述大小范围的颗粒。
38.任何权利要求34-36所述的药物气雾剂，其中至少60％多肽含有上述大小范围的颗粒。
39.任何权利要求34-36所述的药物气雾剂，其中至少70％多肽含有上述大小范围的颗粒。
40.任何权利要求34-36所述的药物气雾剂，其中至少80％多肽含有上述大小范围的颗粒。
41.任何权利要求34-36所述的药物气雾剂，其中至少90％多肽含有上述大小范围的颗粒。
42.任何上述权利要求所述的药物气雾剂，其中多肽的浓度为0.1mg/ml-25mg/ml。
43.制备任何权利要求1-42所述的多肽气雾剂的方法，包括以下步骤：在水混合物中混合多肽和表面活性剂；干燥得到固体粉剂；任意粉碎固体粉剂；在低温下将任意粉碎的粉剂，抛射剂和任意乙醇加入容器中；混合；再加入抛射剂和任意乙醇。
44.任何权利要求1-42所述的多肽气雾剂，可用于治疗。
45.任何权利要求1-42所述的多肽气雾剂可用于制备治疗呼吸道疾病的药物。
46.对于需要治疗的病人的治疗方法，包括给予上述病人治疗上有效量的任何权利要求1-42所述的多肽气雾剂。
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* Cited by examiner, † Cited by third party
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CN107096012A (zh) * 2008-05-07 2017-08-29 诺和诺德股份有限公司 肽的组合物及其制备方法

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