CN107669689B - 一种治疗慢性阻塞性肺病的气雾剂 - Google Patents
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Abstract
本发明提供一种治疗慢性阻塞性肺病的气雾剂，由有效成分、附加剂、抛射剂组成，其中有效成分由藁本内酯、苦参碱、贝母甲素三种化合物按比例组成，三种有效成分组成的质量比每种组分均为1％～99％，有效成分占气雾剂质量比例范围为1～99％。气雾剂剂型为溶液型和混选型两种。所述的气雾剂药物，通过COPD动物模型，证明其具有抑制相关炎症因子分泌、抑制黏液高分泌相关蛋白表达、抑制上皮细胞凋亡和坏死等多种作用，能够直达患处，起效快，疗效好，经动物实验证明其具有良好抗COPD的作用，可在在制备治疗慢性阻塞性肺病药物中的应用。
Description
技术领域
本发明属医药技术领域，涉及一种治疗慢性阻塞性肺病(COPD)的气雾剂，是一种以 藁本内酯、苦参碱、贝母甲素为原料制备的具有治疗COPD药效的气雾剂。
背景技术
慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease，COPD)是以不完全可逆的气 流受限为特征的疾病，是小气道病变(闭塞性细支气管炎)和肺实质破坏(肺气肿)共同作 用的结果。COPD是世界范围内严重危害公众健康的主要病种之一，据世卫组织预测，到2030 年慢性阻塞性肺病将成为仅次于心脑血管疾病和肿瘤的全世界第三大死因。2007年我国对7 个地区20245成年人群进行的调查显示，COPD患病率在40岁以上人群中高达8.2％。COPD 不仅仅患病率高，而且病程呈进行性发展，可引起劳动力丧失、生活质量减退，最终导致的 致残、致死率也很高。
迄今为止COPD的发病机制尚未完全明了，而普遍认为COPD的发病机制主要包括气道、 肺实质和肺血管的慢性炎症、氧化应激、肺部的蛋白酶/抗蛋白酶失衡、慢性黏液高分泌以及 自主神经系统功能紊乱(如胆碱能神经受体分布异常)等。根据COPD的主要特征，改善气 流受限和控制炎症反应是目前临床上的主要治疗措施。目前临床使用的化学药物主要有以下 几类：1.支气管扩张剂：支气管扩张剂是治疗COPD的关键药物，扩张支气管是缓解症状 的主要措施。2.糖皮质激素：COPD患者长期吸入糖皮质激素的量一效关系及安全性尚不清 楚，使用激素的目的在于能减轻症状.降低死亡率。3.抗生素：近10多年的研究支持，感染 是C0PD一个主要的因素，使用抗生素可以控制炎症，但反复使用易引起耐药性。4.其它类， 如磷酸二酯酶4抑制剂、抗氧剂等。总体而言，这些药物治疗效果均有限，且有诸多副作用， 对于预防其进展和疾病恶化影响不大。
目前，获批治疗慢性支气管炎引起的COPD化学药物多是单一化学成分，其中绝大多数 为支气管扩张剂。然而大多数COPD患者都需要多种药物支持，以改善症状。
发明内容
本发明的目的是提供一种治疗慢性阻塞性肺病(COPD)的气雾剂，由有效成分、附加 剂、抛射剂组成，其中有效成分由藁本内酯、苦参碱、贝母甲素三种化合物按照一定比例组 成的。有效成分占气雾剂质量比例范围为1～99％。三种有效成分组成的质量比均为1％～99％。
所述抛射剂选用二甲醚、丙烷、正丁烷。异丁烷、异戊烷、二氟乙烷、四氟乙烷、七氟丙烷或二氯四氟乙烷中的任意一种或两种以上混合物。
所述附加剂选用无水乙醇、丙二醇、聚乙二醇、吐温-80。
气雾剂剂型为溶液型和混选型两种。
其中有效成分组成的质量比范围为：藁本内酯、苦参碱、贝母甲素每种组分均为1％～99％， 优选的组成的质量比范围为：藁本内酯10～30％，苦参碱50～70％，贝母甲素10～20％。三种 有效成分的结构式如下：
本发明的另一个目的是提供所述气雾剂的制备方法，通过以下步骤实现：
(1)溶液型气雾剂制备方法：将有效成分溶解于附加剂之中，然后灌装抛射剂至一定量。
(2)混悬型气雾剂制备方法：将有效成分混悬于辅料中，然后灌装抛射剂至一定量，即 得，其中，辅料包括固体润湿剂、表面活性剂、水分调节剂、比重矫正剂等。
其中固体润湿剂包括滑石粉、胶体二氧化硅；表面活性剂包括油酸、月桂醇、司盘85等。 水分调节剂包括无水氯化钙、无水硫酸钙、无水硫酸钠等。比重矫正剂包括氯化钠、硫酸钠、 乳糖、磷酸氢钠、亚硫酸氢钠等。
本发明的第三个目的是提供所述气雾剂在制备治疗慢性阻塞性肺病药物中的应用。所述 的气雾剂药物，通过COPD动物模型，证明其具有抑制相关炎症因子分泌、抑制黏液高分泌 相关蛋白表达、抑制上皮细胞凋亡和坏死等多种作用，具有潜在的临床应用价值。
本发明三个化合物中，其中藁本内酯具有很强的解痉、平喘、镇定作用，对平滑肌有明 显松弛作用(汪程远；杜俊蓉；钱忠明。藁本内酯的研究进展，中国药学杂志，2006,41(12)， 889-891.)，与支气管扩张剂作用类似；苦参碱具有抗菌、抗炎作用(何雄，韦星船，田裕 昌，赖家雄。苦参碱及其衍生物合成及生物活性研究进展.中国现代应用药学.2011，28(9)， 816-823)、抗哮喘作用(Fu,Q.；Wang.J.；Ma,Z.Q.；Ma,S.P.Anti-asthmatic effectsof matrine in a mice model of allergic astnma.Fitoterapia.2014,94,183-189.)，可视为天然抗生素；而贝母 具有较强的止咳、化痰作用，其中贝母甲素是主要的活性成分。三个成分组成的复方气雾剂， 对有效治疗COPD发挥了很好的协同作用。
本发明气雾剂通过COPD动物模型评价，证明其能够抑制相关炎症因子分泌、抑制黏液 高分泌相关蛋白表达、抑制上皮细胞凋亡和坏死等作用，具有潜在的临床应用价值。本发明 借助中医药多途径、多靶点治疗COPD的优势，经过多年研究，发现多种天然产物具有支气 管舒张、抗菌、抗炎功效，进一步研究发现，以三种类型的有效成分组方，不仅可以发挥更 好的对症治疗药效，而且可以有效改善肺部及支气管部位病变。在此基础上，通过制剂处方 筛选和工艺优化制备了定量吸入气雾剂，能够使得药物直达起效部位，发挥良好的药效，同 时避免了中药成分复杂带来的临床风险。经文献检索，目前含有两种以上药物成分，以不同 的作用方式来改善肺功能的药物尚未在临床使用。
附图说明
图1是药物对COPD模型大鼠Muc5AC的mRNA表达的影响。
图2是药物对COPD模型大鼠肺上皮细胞凋亡的影响。
具体实施方式
本发明结合具体实施例作进一步的说明。
实施例1
将藁本内酯：苦参碱：贝母甲素按照质量比1％:5％:94％混合，共8000mg，加入附加剂 无水乙醇、丙二醇、吐温-80各80mL、20mL和1g，形成100mL溶液，平均灌入100瓶 25mL气雾剂压力瓶中，每瓶1mL，用气雾剂灌装机每瓶压入12g抛射剂R134a，共计100 瓶。
实施例2
将藁本内酯：苦参碱：贝母甲素按照质量比55％:20％:25％混合，共4000mg，加入附加 剂无水乙醇、丙二醇、聚乙二醇各70mL、30mL和0.5g，形成100mL溶液，平均灌入100 瓶20mL气雾剂压力瓶中，每瓶1mL，用气雾剂灌装机每瓶压入10g抛射剂二甲醚，共计 100瓶。
实施例3
将藁本内酯：苦参碱：贝母甲素按照质量比63％:18％:19％混合，共10g，加入滑石粉1.2g、 油酸5g，无水氯化钙10g，乳糖20g，上述固体混合均匀，过400～500目筛，分装至100瓶， 用气雾剂灌装机每瓶压入11g抛射剂七氟丙烷，共计100瓶。
实施例4中试制备溶液型气雾剂
将藁本内酯：苦参碱：贝母甲素按照按照质量比50％:35％:15％混合，共100g，加入附 加剂无水乙醇、丙二醇、吐温-80各900mL、100mL和10g，形成1000mL溶液，平均灌入1000瓶25mL气雾剂压力瓶中，每瓶1mL，用气雾剂灌装机每瓶加入13g抛射剂R134a， 压制而成，共计1000瓶。
实施例5中试制备混选型气雾剂
将藁本内酯：苦参碱：贝母甲素按照质量比20％:60％:20％混合，共100g，加入胶体二氧 化硅15g、月桂醇11g，无水硫酸钠100g，亚硫酸氢钠200g，上述固体混合均匀，过400～500 目筛，分装至1000瓶，用气雾剂灌装机每瓶加入60g正丁烷和120g七氟丙烷抛射剂，压制 而成，共计1000瓶。
实施例6气雾剂药物对COPD模型大鼠BALF中细胞因子的影响
用烟熏法建立COPD大鼠模型，设空白对照组、模型组、地塞米松组和气雾剂低、高两 个剂量组(按实施例4配方)。最后一次给药完毕15小时后，取肺泡灌洗液(BALF)进行TNF-α、 KC、MIP-2表达量检测。结果表明BALF中TNF-α、KC及MIP-2含量明显上升，与空白对照组比，差异极显著(***P<0.001，n≥6)。气雾剂高、低剂量组能显著降低KC、MIP-2、TNF-α含量。与阳性对照药地塞米松(Dex)相比较，作用相当，在TNF-α、KC的分泌上，高剂量 组抑制作用还优于Dex组。结果参见表1。
表1气雾剂对急性吸烟模型小鼠BALF液中细胞因子分泌的影响
| 组别 | n | TNF-α(pg/ml) | KC(pg/ml) | MIP-2(pg/ml) |
| 空白对照组 | 6 | 96.51±29.99*** | 146.52±38.91*** | 232.68±112.79*** |
| 模型组 | 6 | 204.20±28.99 | 308.44±52.45 | 587.91±137.17 |
| 气雾剂低剂量组 | 6 | 180.39±11.45 | 211.15±91.18* | 401.98±98.20* |
| 气雾剂高剂量组 | 6 | 122.08±21.90*** | 180.87±47.06*** | 360.63±55.60** |
| 地塞米松组 | 6 | 162.85±40.39* | 236.12±112.91 | 351.25±142.23** |
注：***P<0.001、**P<0.01、*P<0.05vs Smoke，n≥6
实施例7气雾剂药物对COPD模型大鼠Muc5AC的mRNA表达的影响
动物建模和分组方法同实例6，另加无药气雾剂空白对照组，采用TRIzol试剂一步法提 取左上肺组织总RNA。取左上肺组织在l ml TRIzol裂解液中，匀浆后在4℃、12000rpm离 心l0min；取上清加入200ml氯仿，振荡15s后的粉红色浑浊液体，室温静置5min后在4℃、12000rpm离心15min，离心管分上中下三层；小心取出无色上清，加入500ml异丙醇，轻 轻摇匀室温静置5min，4℃、12000rpm离心l0min；小心取上清，沿壁加入75％乙醇l ml， 4℃、7500rpm离心5min；吸取上清室温干燥沉淀2.5min，加30μl无RNase水溶解RNA沉 淀。取RNA样品稀释100倍，在260nm和280nm测OD260/OD280比值以判断RNA的纯度 和浓度。
荧光定量PCR中，检测CT值，将目的基因与内参照β-actin的比值作为其mRNA表达水平的指标，引物详见表2(均由上海生工生物技术有限公司合成)。
表2Muc5AC和β-actin引物序列
结果表明：气雾剂高、低剂量组(按实施例5配方)对Muc5AC的mRNA表达均有明显抑制作用(*P<0.05vs smoke，n≥6)，作用与阳性药地塞米松Dex组相当。结果参见图1。
实施例8气雾剂药物对COPD模型大鼠肺上皮细胞凋亡的影响
动物建模方法同实例6，设空白对照组、模型组和气雾剂低、高两个剂量组(按实施例3 配方)，取肺上皮细胞，处理后进行流式细胞仪检测，结果表明，气雾剂高、低剂量组均能 明显抑制COPD模型大鼠肺上皮细胞凋亡和坏死，证明其具有抗COPD的潜在用途。结果参见图2。
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Claims (3)
1.一种治疗慢性阻塞性肺病的气雾剂，其特征在于，由有效成分、附加剂、抛射剂组成，其中有效成分由藁本内酯、苦参碱、贝母甲素三种化合物按比例组成，其中有效成分组成的质量比范围为：藁本内酯:苦参碱:贝母甲素为10~30%: 50~70%:10~20%，有效成分占气雾剂质量比例范围为1~99%；所述抛射剂选用二甲醚、丙烷、正丁烷、异丁烷、异戊烷、二氟乙烷、四氟乙烷、七氟丙烷或二氯四氟乙烷中的任意一种或两种以上混合物，所述附加剂选用无水乙醇、丙二醇、聚乙二醇、吐温-80；
所述气雾剂剂型为溶液型，通过以下步骤实现：将有效成分溶解于附加剂之中，然后灌装抛射剂，即得。
2.一种治疗慢性阻塞性肺病的气雾剂，其特征在于，由有效成分、辅料、抛射剂组成，其中有效成分由藁本内酯、苦参碱、贝母甲素三种化合物按比例组成，其中有效成分组成的质量比范围为：藁本内酯:苦参碱:贝母甲素为10~30%: 50~70%:10~20%，有效成分占气雾剂质量比例范围为1~99%；所述抛射剂选用二甲醚、丙烷、正丁烷、异丁烷、异戊烷、二氟乙烷、四氟乙烷、七氟丙烷或二氯四氟乙烷中的任意一种或两种以上混合物；
所述气雾剂剂型为混悬型，通过以下步骤实现：将有效成分混悬于辅料中，然后灌装抛射剂，即得，所述辅料选用固体润湿剂、表面活性剂、水分调节剂、比重矫正剂，其中固体润湿剂包括滑石粉、胶体二氧化硅；表面活性剂选用油酸、月桂醇、司盘85；水分调节剂选用无水氯化钙、无水硫酸钙、无水硫酸钠；比重矫正剂选用氯化钠、硫酸钠、乳糖、磷酸氢钠、亚硫酸氢钠。
3.根据权利要求1或2所述的气雾剂在制备治疗慢性阻塞性肺病药物中的应用。
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