CN106176755A - 埃克替尼在制备防治特发性肺纤维化药物中的应用及其药物制剂 - Google Patents
埃克替尼在制备防治特发性肺纤维化药物中的应用及其药物制剂 Download PDFInfo
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- CN106176755A CN106176755A CN201610542646.1A CN201610542646A CN106176755A CN 106176755 A CN106176755 A CN 106176755A CN 201610542646 A CN201610542646 A CN 201610542646A CN 106176755 A CN106176755 A CN 106176755A
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- icotinib
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- idiopathic pulmonary
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Abstract
本发明属于化学医药领域,涉及药物制剂技术,具体涉及埃克替尼在制备防治特发性肺纤维化药物的应用及其药物制剂。埃克替尼在制备防治特发性肺纤维化药物中的应用,即埃克替尼用于预防和治疗肺纤维化。本发明提供了一种用于防治特发性肺纤维化的药物及其剂型。本发明公开了埃克替尼防治特发性肺纤维化的应用及其药物制剂,药效学试验证明埃克替尼雾化吸入给药能明显改善肺纤维化动物肺功能、肺组织相关生化指标及病理学的改变,从而为埃克替尼防治特发性肺纤维化提供实验依据。本发明所述药物可制成粉雾剂、气雾剂或雾化吸入溶液(混悬液)。
Description
技术领域
本发明属于化学医药领域,涉及药物制剂技术,具体涉及埃克替尼在制备防治特发性肺纤维化药物的应用及其药物制剂。
技术背景
肺纤维化(pulmonary fibrosis,PF)是以弥漫性的肺泡炎、肺间质炎症和间质纤维化为组织学特点的一组疾病群,涵盖多种疾病,多数疾病缺乏有效的治疗手段,预后极差。因此,肺纤维化目前引起世界呼吸病学界的重视。目前,对肺纤维化的临床研究主要集中在特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)方面,因其进展快、死亡率高被世界卫生组织(WHO)列为疑难疾病,也是遍及全世界的疾病。
IPF是一种组织学或影像学表现为寻常型间质性肺炎的病因不明、呈慢性进行性加重的间质性肺疾病。IPF好发于老年患者,50岁以下人群罕见,男性发病率高于女性。目前尚无关于患病率及发病率的大规模研究报道。IPF与家族基因异常有关,是一种恶性进展性间质性肺炎。其发病机制涉及多种因素如持续性损伤肺泡上皮致肺泡上皮-间充质细胞(EMT)的细胞内环境失调,转移生长因子-β(TGF-β)、Wnt、Notch等信号通路激活、上皮细胞功能障碍和细胞凋亡、疤痕组织形成等导致的肺内环境稳定破坏。由于IPF的诊断较为困难,缺乏统一标准,并且受地理、宗教及人种等影响,IPF的患病率在总人口中的估计值为2/100000~29/100 000不等。IPF目前尚无有效的治疗药物,其预后不良,IPF患者的中位生存期为3年。由于IPF病理机制复杂,病因尚未完全阐明,临床上目前多采用药物联合治疗,如泼尼松、硫唑嘌呤和环磷酰胺联合治疗方案,大剂量N-乙酰半胱氨酸联合泼尼松和硫唑嘌呤。也有单药治疗的糖皮质激素、吡非尼酮、秋水仙碱、环孢素、干扰素(IFN)-γ1b、波生坦、依那西普等药物,但疗效一般不理想。
近年来国际上采用替尼类的药物如伊马替尼、尼达尼布(nintedanib,BIBF1120)等治疗IPF病人,取得了一定的疗效,因为IPF病理过程依赖酪氨酸激酶受体激活信号通路的参与。药效试验显示,参与肺纤维化的3种酪氨酸激酶受体包括表皮生长因子受体(EGFR)、成纤维细胞生长因子受体(FGFR)、血小板衍生生长因子受体(PDGFR)和血管生长因子受体(VEGFR)均可被酪氨酸激酶抑制剂阻断。
埃克替尼(Icotinib);化学名:4-[(3-乙炔基苯基)氨基]-6,7-苯并-12-冠-4喹唑啉盐酸盐;(4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazolinehydrochloride);代 号:BPI-2009;商品名:凯美纳(Commana);结构式如下:
埃克替尼是一种高效特异性的表皮生长因子受体酪氨酸激酶抑制剂,是我国第一个具有自主知识产权的小分子靶向抗癌新药。与吉非替尼(Gifitinib)相比,在化学结构、分子作用机制、疗效等方面类似,但具有更好的安全性,适用于晚期非小细胞肺癌(NSCLC)患者的治疗。盐酸埃克替尼片于2011年6月由国家食品药品监督管理局批准用于治疗进展性非小细胞肺癌,这是我国第一个自主研发的用于癌症治疗的表皮生长因子受体酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs),除了对EGFR-TKIs作用外,对FGFR、PDGFR和VEGFR均有明显的抑制作用。然而,已有的资料并未见埃克替尼抗肺纤维化治疗作用的相关报道。我们的药效学试验证明埃克替尼灌胃给药具有很强的抗肺纤维化作用,改变给药途径,采用我们制备的埃克替尼气雾吸入剂给药,肺部的局部浓度更高,疗效更好,用量更低,系统血药浓度更低,全身不良反应更少。埃克替尼气雾吸入制剂的开发将为抗肺纤维化的治疗提供新的治疗方法和新的靶向药物。我们认为埃克替尼气雾吸入制剂的开发具有良好的社会效益和经济效益。
发明内容
本发明提供了埃克替尼的新用途。
埃克替尼在制备防治特发性肺纤维化药物中的应用,即埃克替尼用于预防和治疗肺纤维化。
本发明提供了一种用于防治特发性肺纤维化的药物及其剂型。
一种用于防治特发性肺纤维化的药物,以埃克替尼为活性成分,单独或加入一种或多种药用辅料制备而成。
所述药物的制剂是将埃克替尼用常规或特殊制剂工艺制备成吸入制剂,包括气雾剂、粉雾剂、吸入混悬液或其他吸入制剂。
其中,
所述气雾剂是由埃克替尼、助溶剂、表面活性剂和抛射剂组成。
所述粉雾剂是由埃克替尼、单独或与载体组成。
所述吸入混悬液是由埃克替尼、表面活性剂、渗透压调节剂和水组成。
本发明的另一目的是公开了埃克替尼用于防治特发性肺纤维化药物的制备方法。
用于防治特发性肺纤维化的埃克替尼气雾剂的制备方法:是将埃克替尼、助溶剂和/或表面活性剂溶解后,经一步灌装法、两步灌装法或冷灌法制备而成。
优选的,埃克替尼与乙醇(和油酸)溶解后,两步法灌装充入HFA-134a即得。
用于防治特发性肺纤维化的埃克替尼粉雾剂的制备方法包括如下步骤:
1)将埃克替尼与各辅料分别粉碎后,过筛,备用;
2)采用喷雾干燥技术、或气流粉碎技术或其他微粉化技术,使埃克替尼粒径符合
要求,直接或与适量载体混合后定量分装于胶囊内或泡囊内制得。
优选的,1)将处方量的埃克替尼、聚山梨酯80、β-环糊精溶于或混悬于100ml水中,置冷冻干燥器中进行冻干,过100目筛,得附聚物;将乳糖与甘露醇混匀后,用适量无水乙醇制软材,过30目筛制粒,置65℃烘箱约30min,取出,过40目筛,置65℃烘箱约30min,过80目筛,得载体。
2)将附聚物与载体充分混合均匀后,测含量,合格后再分装至1000粒胶囊中。
用于防治特发性肺纤维化的埃克替尼吸入混悬液的制备方法:是将无菌的微粉化埃克替尼、表面活性剂和/或渗透压调节剂溶解或混悬于水中,在无菌条件下定量灌装而成。
优选的,将二甲亚砜和吐温80(或聚山梨醇酯20和氯化钠)溶解于注射用水中,然后加入无菌的微粉化埃克替尼搅拌获得均匀分散的药物-溶剂体系,在无菌条件下定量灌装。
由于本发明首次公开了埃克替尼在防治特发性肺纤维化方面的作用,因此,将埃克替尼单独或与其他活性成分或药用辅料制成的制剂,只要该制剂用于防治肺纤维化,均属于本发明的保护范围。
本发明公开了埃克替尼防治特发性肺纤维化的应用及其药物制剂,药效学试验证明埃克替尼雾化吸入给药能明显改善肺纤维化动物肺功能、肺组织相关生化指标及病理学的改变,从而为埃克替尼防治特发性肺纤维化提供实验依据。本发明所述药物可制成粉雾剂、 气雾剂或雾化吸入溶液(混悬液)。
附图说明
图1为埃克替尼雾化吸入给药对肺纤维化小鼠肺组织病理结构改变的影响(HE,100×),A为空白对照(control)组,B为模型(model)组,C为口服埃克替尼低剂量(30mg/kg)组,D为口服埃克替尼低剂量(60mg/kg)组,E为雾化吸入埃克替尼低剂量(5mg/ml)组,F为雾化吸入埃克替尼低剂量(10mg/ml)组,G为口服尼达尼布(BIBF1120-60mg/kg)组。图2为埃克替尼雾化吸入给药对肺纤维化小鼠肺组织胶原沉积的影响(Masson,40×),A为空白对照(control)组,B为模型(model)组,C为口服埃克替尼低剂量(30mg/kg)组,D为口服埃克替尼低剂量(60mg/kg)组,E为雾化吸入埃克替尼低剂量(5mg/ml)组,F为雾化吸入埃克替尼低剂量(10mg/ml)组,G为口服尼达尼布(BIBF1120-60mg/kg)组。
具体实施方式
本发明结合附图说明和实施例作进一步说明,但并不限制本发明的范围。
实施例1埃克替尼对博莱霉素诱导的小鼠肺纤维化的作用
1.实验动物:
C57BL/6小鼠,70只,清洁级,雌性,6周龄。购于上海斯莱克实验动物有限责任公司,许可证号码SCXK(浙)2012-0002。购入后饲养于浙江大学实验动物中心IVC系统,温度:20~26℃,湿度40~70%;自由摄食饮水。
2.主要实验仪器:
Mettler Toledo AG245天平;PARI BOY N型压缩雾化器;BIO-TEK酶标仪;FLUKO/F6高速匀浆机;BUXCO肺功能仪;Bio-Rad荧光定量PCR仪;Olympus BX51显微镜;EppendorfCentrifuge 5804R离心机;Leica切片机包埋机。
3.主要试剂:
(1)注射用盐酸博莱霉素:15mg/瓶,批号140372,日本化药株式会社。
(2)SYBR Green、Oligo d(T)、反转录酶、RNA酶抑制剂均购于北京康为试剂生物有限公司。
(3)引物:由生工生物工程(上海)股份有限公司合成。
(4)Masson三色染色试剂盒:批号20150318,北京索莱宝科技有限公司。
(5)羟辅氨酸测试盒:批号:20150123,南京建成生物工程研究所。
(6)小鼠GRO-α(CXCL1)ELISA试剂盒:批号:1503031,上海西唐生物科技有限公司。
(7)Mouse IL-6ELISA Kit:批号:1321119324,武汉博士德生物工程有限公司。
(8)Mouse TGF-β1ELISA Kit:批号:2291131324,武汉博士德生物工程有限公司。
(9)Mouse IL-1βELISA Kit:批号:1161135324,武汉博士德生物工程有限公司。
(10)小鼠引物,生工生物工程(上海)有限公司。序列见表1。
表1.小鼠引物序列表
4.建立小鼠特发性肺纤维化模型:
乙醚麻醉小鼠,仰卧位,切开颈部皮肤,分离气管,用微量进样器向气管内喷入3mg/kg的博莱霉素(给药体积为10μl/10g体重);缝合皮肤,消毒。空白组气道内喷入相同容积的生理盐水。
5.分组给药:
小鼠随机分为7组,每组10只,分别为:
(1)空白对照(control)组,雾化吸入0.5%DMSO,给药30min;
(2)模型(model)组,雾化吸入0.5%DMSO,给药30min;
(3)口服埃克替尼低剂量(30mg/kg)组,灌胃给予埃克替尼1.5mg/ml,容积0.2ml/10g;
(4)口服埃克替尼高剂量(60mg/kg)组,灌胃给予埃克替尼3mg/ml,容积0.2ml/10g;
(5)雾化吸入埃克替尼低剂量(5mg/ml)组,雾化吸入埃克替尼5mg/ml,给药30min,血药浓度相当于口服60mg/kg;
(6)雾化吸入埃克替尼高剂量(10mg/ml)组,雾化吸入埃克替尼10mg/ml,给药30min,血药浓度相当于口服120mg/kg;
(7)口服尼达尼布(BIBF1120-60mg/kg)组,灌胃给予尼达尼布3mg/ml,容积0.2ml/10g。各组小鼠于造模后第二天开始给药,每天1次,连续21天。
6.药物配制:
精密称取埃克替尼,口服组用0.5%CMC混匀后用于灌胃给药,雾化吸入组用0.5%DMSO混匀后雾化吸入给药。尼达尼布用0.5%CMC混匀后用于灌胃给药。
7.检测指标:
(1)肺功能测定:
末次给药结束后,将各组小鼠放入Buxco肺功能仪中,在清醒状态下测定小鼠penh值。
(2)肺组织取材与肺泡灌洗:
肺功能测定结束后,处死小鼠,分离气管,行气管插管,结扎左肺叶,行肺泡灌洗,收集灌洗液(BALF)做白细胞计数,2000rpm离心10min,上清保存于-80度冰箱用于羟脯氨酸及细胞因子测定,沉淀用于涂片做分类计数。左肺叶分两部分,上半部分于液氮速冻后保存于-80度冰箱用于测定细胞因子,下半部分福尔马林溶液中固定待病理组织学检查。
(3)BALF中羟脯氨酸含量测定:
取100μl BALF用于测定羟脯氨酸含量。测定步骤参见羟辅氨酸测试盒说明书。
(4)ELISA法测定BALF中细胞因子:
按照ELISA试剂盒说明书操作步骤检测KC、TGF-β1、IL-1β和IL-6个细胞因子,每个因子用100μl上清液测定。
(5)Q-PCR法检测小鼠肺组织中细胞因子:
取肺组织1ml TRIzon,冰上匀浆,按照常规步骤提取RNA。测定RNA浓度后进行逆转录,取逆转录好的cDNA样本2μl,根据2×UltraSYBR Mixture说明书配制25μl反应体系。混合均匀,短暂离心,放入荧光定量PCR仪中,预变性95℃×10min,变性95℃×15s,退火60℃×1min,35个循环。
(6)病理检查:
取固定于福尔马林中的肺组织样本,进行石蜡包埋切4μm薄片。H&E染色和Masson’s染色。镜下观察拍照。Masson’s染色后镜下拍照,用Image pro软件测量阳性染色部位的IOD值进行统计。
(7)统计学:
数据用SPSS 20软件包统计处理,以表示,p<0.05有统计学差异。
8.结果
(1)埃克替尼对博莱霉素诱导的肺纤维化小鼠肺功能的影响
试验结束后,BUXCO肺功能仪测定小鼠肺功能,结果显示雾化吸入埃克替尼低、高剂量组均能明显抑制博莱霉素诱导的肺纤维化小鼠气道penh值增加,且与模型组比较有显著性差异(p<0.05~0.01),而口服埃克替尼低、高剂量组和BIBF1120-60mg/kg组则无明显抑制作用(p>0.05)。见表2。
表2埃克替尼对博莱霉素诱导的肺纤维化小鼠肺功能的影响。
表注:统计学:one way ANOVA,与空白对照组比较:###p<0.001;与模型组比较:*p<0.05,**p<0.01。
(2)埃克替尼对博莱霉素诱导的肺纤维化小鼠肺泡灌洗液中炎症细胞的影响
小鼠气道滴入3mg/kg博莱霉素,21天后BALF中白细胞总数、中性粒细胞。淋巴细胞和巨噬细胞明显上升(p<0.001);口服埃克替尼低、高剂量组能明显抑制肺泡灌洗液中的中性粒细胞、淋巴细胞和巨噬细胞,且均具有统计学差异(p<0.05~0.01)。雾化吸入埃克替尼低、高剂量组能明显抑制BALF中的中性粒细胞、淋巴细胞和巨噬细胞,且均具有统计学差异(p<0.01~0.001),其抑制作用明显强于口服给药组。口服BIBF1120-60mg/kg组也能抑制BALF中的中性粒细胞、淋巴细胞和巨噬细胞的增加(p<0.05-0.01)。见表3。
表3.埃克替尼对肺纤维化小鼠BALF中炎症细胞的影响
表注:统计学:one way ANOVA,与Control组比较,###p<0.001;与Model组比较,*p<0.05、**p<0.01、***p<0.001。
(3)埃克替尼对肺纤维化小鼠肺组织中细胞因子表达的影响
小鼠气道喷入3mg/kg博莱霉素,21天后,肺组织中KC、IL-1β、IL-6、TGF-βmRNA表达较空白对照组明显上升(p<0.001);结果显示,小鼠口服埃克替尼低、高剂量组能明显降低肺组织中以上细胞因子mRNA表达(p<0.05-0.01),雾化吸入埃克替尼低、高剂量组能明显降低肺组织中以上细胞因子mRNA表达(p<0.001),且抑制作用强于口服埃克替尼低、高剂量组。口服BIBF1120-60mg/kg组也能明显降低肺组织中以上细胞因子mRNA表达(p<0.05-0.01),但是作用弱于雾化吸入给药。见表4。
表4.埃克替尼对肺纤维化小鼠肺组织中细胞因子表达的影响
表注:统计学:one way ANOVA,与Control组比较,###p<0.001;与Model组比较,*p<0.05、**p<0.01、***p<0.001。
(4)埃克替尼对博莱霉素诱导的肺纤维化小鼠BALF中羟脯氨酸含量的影响
结果显示,口服埃克替尼高剂量组抑制博莱霉素诱导的小鼠BALF中羟脯氨酸含量的增加,且与模型组比较具有显著性差异(p<0.05)。雾化吸入埃克替尼低、高剂量组能明显抑制博莱霉素诱导的小鼠BALF中羟脯氨酸含量的增加,且与模型组比较具有显著性差异(p<0.05-0.01)。而口服BIBF1120-60mg/kg则无明显抑制作用(p>0.05)。该结果显 示,雾化吸入埃克替尼对肺纤维化小鼠BALF中羟脯氨酸的抑制作用强于口服给药组。见表5。
表5埃克替尼对博莱霉素诱导的肺纤维化小鼠BALF中羟脯氨酸含量的影响
表注:统计学:one way ANOVA,与Control组比较,###p<0.001;与Model组比较,*p<0.05、**p<0.01。
(5)ELISA法检测埃克替尼对肺纤维化小鼠BALF中细胞因子含量的影响
结果显示,给药结束后,模型组小鼠BALF中KC、TGF-β1、IL-1β、IL-6蛋白含量明显增加(p<0.001-0.01)。口服埃克替尼呈剂量依赖性抑制博莱霉素诱导的小鼠BALF中KC、TGF-β1、IL-1β、IL-6蛋白含量的增加,且与模型组比较具有显著性差异(p<0.05)。雾化吸入埃克替尼低、高剂量组均能明显抑制博莱霉素诱导的小鼠BALF中KC、TGF-β1、IL-1β、IL-6蛋白含量的增加,且与模型组比较具有显著性差异(p<0.05-0.01)。口服BIBF1120-60mg/kg有明显的抑制作用(p<0.05)。该结果显示,雾化吸入埃克替尼对肺纤维化小鼠BALF中细胞因子含量的抑制作用强于口服给药组。见表6。
表6埃克替尼对肺纤维化小鼠BALF中细胞因子含量的影响
表注:统计学:one way ANOVA,与Control组比较,##p<0.01、###p<0.001;与Model组比较,*p<0.05、**p<0.01。
(6)埃克替尼对肺纤维化小鼠肺组织病理结构改变的影响
小鼠气道喷入博莱霉素后,肺泡闭合,肺泡间质增生;HE染色结果显示,小鼠雾化吸入埃克替尼后,小鼠肺泡间质增生明显减轻,肺泡形态趋于完整。口服埃克替尼低、高剂量组和BIBF1120-60mg/kg组虽然也能改善肺组织形态的变化,但是作用明显弱于雾化吸入给药,见附图1。Masson’s染色可见,小鼠气道喷入博莱霉素后,肺组织中胶原沉积,半定量分析结果显示,小鼠雾化吸入埃克替尼后,能明显降低胶原沉积(p<0.01-0.001),口服埃克替尼低、高剂量组和BIBF1120-60mg/kg组灌胃给药的作用明显弱于雾化吸入给药,见表7、附图2。
表7.埃克替尼降低肺纤维化小鼠肺组织胶原沉积
表注:统计学:one way ANOVA,与Control组比较,###p<0.001;与Model组比较,*p<0.05、**p<0.01、***p<0.001。
8.结论
我们通过建立博来霉素诱导的小鼠特发性肺纤维化模型,验证埃克替尼的抗肺纤维化作用,结果显示,埃克替尼雾化吸入给药能明显改善肺纤维化小鼠的肺功能;抑制肺纤维化小鼠肺泡灌洗液中炎症细胞;减少肺纤维化小鼠肺泡灌洗液中羟脯氨酸的含量;抑制肺纤维化小鼠肺泡灌洗液中KC、IL-1β、IL-6、TGF-β1蛋白的表达水平;降低肺组织中KC、IL-1β、IL-6、TGF-β1mRNA表达;改善肺纤维化小鼠肺组织病理结构改变;降低肺纤维化小鼠肺组织胶原沉积。综上结果显示,埃克替尼吸入给药有很强的抗肺纤维化作用。
实施例2埃克替尼气雾剂
将埃克替尼用乙醇溶解后,一步或两步法灌装药液和HFA-134a即得,共200揿。
实施例3埃克替尼气雾剂
将埃克替尼与乙醇和油酸溶解后,两步法灌装充入HFA-134a即得,共200揿。
实施例4埃克替尼粉雾剂
处方(以1000粒计):
工艺
将处方量的埃克替尼、聚山梨酯80、β-环糊精溶于或混悬于100ml水中,置冷冻干燥器中进行冻干,过100目筛,得附聚物。
将乳糖与甘露醇混匀后,用适量无水乙醇制软材,过30目筛制粒,置65℃烘箱约30min,取出,过40目筛,置65℃烘箱约30min,过80目筛,得载体。
将附聚物与载体充分混合均匀后,测含量,合格后再分装至1000粒胶囊中。
实施例5埃克替尼粉雾剂
处方(以1000粒计):
工艺
将处方量的埃克替尼、聚山梨酯80、β-环糊精溶于或混悬于100ml水中,置冷冻干燥器中进行冻干,过100目筛,得附聚物。
将乳糖与甘露醇混匀后,用适量无水乙醇制软材,过30目筛制粒,置65℃烘箱约30min,取出,过40目筛,置65℃烘箱约30min,过80目筛,得载体。
将附聚物与载体充分混合均匀后,测含量,合格后再分装至1000粒胶囊中。
实施例6埃克替尼吸入混悬液
处方:
工艺
将二甲亚砜和吐温80溶解于注射用水中,然后加入无菌的微粉化埃克替尼搅拌获得均匀分散的药物-溶剂体系,在无菌条件下定量灌装,每支2ml。
实施例7埃克替尼吸入混悬液
处方:
工艺
将聚山梨醇酯20和氯化钠溶解于注射用水中,然后加入无菌的微粉化埃克替尼搅拌获得均匀分散的药物-溶剂体系,在无菌条件下定量灌装,每支2ml。
Claims (10)
1.埃克替尼在制备防治特发性肺纤维化药物中的应用。
2.一种用于防治特发性肺纤维化的药物,其特征在于:以埃克替尼为活性成分,单独或加入一种或多种药用辅料制备而成。
3.根据权利要求2所述的药物,其特征在于:该药物的剂型为吸入制剂。
4.根据权利要求3所述的药物,其特征在于:剂型为气雾剂、粉雾剂、吸入混悬液或其他吸入制剂。
5.根据权利要求书4所述的药物,其特征在于:所述气雾剂是由埃克替尼、助溶剂、表面活性剂和抛射剂组成。
6.根据权利要求4所述的药物,其特征在于:所述粉雾剂是由埃克替尼、单独或与载体组成。
7.根据权利要求4所述的药物,其特征在于:所述吸入混悬液是由埃克替尼、表面活性剂和/或渗透压调节剂和水组成。
8.用于防治特发性肺纤维化的埃克替尼气雾剂的制备方法:将埃克替尼、助溶剂和/或表面活性剂溶解后,加抛射剂经一步灌装法、两步灌装法或冷灌法制备而成。
9.用于防治特发性肺纤维化的埃克替尼粉雾剂的制备方法:包括如下步骤:
1)将埃克替尼与各辅料分别粉碎后,过筛,备用;
2)采用喷雾干燥技术、或气流粉碎技术或其他微粉化技术,使埃克替尼粒径符合要求,直接或与适量载体混合后定量分装于胶囊内或泡囊内制得。
10.用于防治特发性肺纤维化的埃克替尼吸入混悬液的制备方法:将无菌的微粉化埃克替尼、表面活性剂和/或渗透压调节剂溶解或混悬于水中,在无菌条件下定量灌装而成。
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Application publication date: 20161207 |