CN115429845A - 一种川贝母总生物碱提取物在制备抗哮喘药物中的用途 - Google Patents
一种川贝母总生物碱提取物在制备抗哮喘药物中的用途 Download PDFInfo
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- CN115429845A CN115429845A CN202211048456.6A CN202211048456A CN115429845A CN 115429845 A CN115429845 A CN 115429845A CN 202211048456 A CN202211048456 A CN 202211048456A CN 115429845 A CN115429845 A CN 115429845A
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Abstract
本发明提供了川贝母总生物碱在制备预防或治疗哮喘的新用途。贝母总生物碱中含有的单体化合物包括西贝碱、西贝碱氮氧化物,西贝碱苷、贝母辛、贝母甲素、贝母乙素。本发明的川贝母生物碱能够显著地改善过敏性哮喘相关细胞因子在气道中的释放,降低嗜酸性粒细胞数量,改善过敏情况,并能改善哮喘小鼠肺部炎性浸润、杯状细胞化生、肺实质化等病理状况。因此,川贝母总生物碱可用于开发治疗哮喘的中药新药。
Description
技术领域
本发明属于防治哮喘药物技术领域,尤其是涉及川贝母总生物碱在制备治疗哮喘的药物中的用途,属药物领域。
背景技术
支气管哮喘(以下简称哮喘),在全球范围发病率较高,是一种严重威胁人类健康的呼吸系统疾病,是以气道炎症、气道高反应和气道重塑为表征,在临床上主要表现为反复发作的喘息、气促、胸闷和咳嗽等症状。
哮喘与免疫调节密切相关,个体易感性、病毒感染、过敏原暴露等因素导致免疫失衡引发哮喘,而且免疫细胞在哮喘的发展过程中起着关键作用。提高免疫力有助于减少病毒、过敏原引起的疾病(如流感、咳嗽等),从而减少疾病引起的哮喘,但提高免疫力的药物并不都对哮喘有效,且无法避免哮喘的复发。因此寻找到有显著抗炎消炎作用的安全有效的药物以防治哮喘的发病具有重大意义。现代药理学研究及本研究前期已证明,川贝母总生物碱有显著的抗炎活性。因此选取了川贝母总生物碱进行防治哮喘活性研究。
通过上述分析,现有技术存在的问题及缺陷为:临床用药主要是联合舒张支气管和减轻气道炎症的药物。这些药物具有较强的抑制气道炎症和松弛气道平滑肌的作用,但长期服用会产生耐药性并带来严重的不良反应,包括骨质疏松、生长发育受限、心律失常、免疫力降低、神经毒性等。因此急需开发高效低毒并能够针对哮喘发病源头(致敏和激发阶段)的药物。而贝母作为有临床应用百年历史的珍贵药材,其药效物质基础研究还在大力发展,而其活性成分生物碱有被分离得到,可对其药效应用开发进行实验验证,拓宽了贝母属植物的新应用病症范围,为安全有效的治疗哮喘新药物的开发提供了可靠的方向和基础。
发明内容
针对现有技术存在的问题,本发明提供了一种川贝母总生物碱提取物的用途。
本发明是这样实现的,一种川贝母总生物碱提取物在制备用于预防或治疗哮喘的药物中的用途。
本发明中,所述的哮喘是以气道炎症为特征的疾病,临床特征包括为喘息、咳嗽和咯痰,包括但不限于。
本发明中,所述的哮喘是肺部炎性浸润、杯状细胞化生、肺实质化,包括但不限于。
本发明中,所述的贝母总生物碱中总生物碱含量以西贝碱计为5-100%W/W。
本发明中,所述的贝母总生物碱中含有的单体化合物包括西贝碱、西贝碱氮氧化物,西贝碱苷、贝母辛、贝母甲素、贝母乙素生物碱单体。
本发明中,所述提取物是由如下方法制备的:
取川贝母粉碎,以60-95%乙醇浸润或不浸润,用60-95%乙醇提取2-3次,真空干燥,以大孔吸附树脂、离子交换树脂进行或不进行纯化而得到的川贝母总生物碱,真空干燥或冷冻干燥,即得川贝母总生物碱。
本发明中,所述川贝母来源主要包括《中华人民共和国药典》2020年版一部中及川贝母(Fritillaria cirrhosa D.Don)、暗紫贝母(Fritillaria unibracteata Hsiao etK.C.Hsia)、甘肃贝母(Fritillaria przewalskii Maxim.)、梭砂贝母(Fritillaria delavayi Franch.)、太白贝母(Fritillaria taipaiensis P.Y.Li)和瓦布贝母(Fritillaria unibracteata Hsiao et K.C.Hsia var.wabuensis(S.Y.Tang etS.C.Yue)Z.D.Liu,S.Wang et S.C.Chen)的干燥鳞茎。
本发明中,所述的药物为为片剂、胶囊剂、丸剂、口服液、注射剂或局部给药制剂。
其中,药物的剂型不限于此,按上述药用原料与制药上常用的药用载体,如赋形剂、或辅料可以混合制成注射剂、冻干粉针剂、喷鼻剂、注射微球、脂质体、片剂、胶囊剂、水剂、 散剂、糊剂、喷雾剂、气雾剂、颗粒剂、胶囊剂、软胶囊、滴丸剂、凝胶剂、贴片、膏剂等及其可以接受的缓控释制剂。
制备含有特定活性成分的各种药物组合物的方法对本领域技术人员而言是已知的,或根据本说明书是显而易见的。
本发明提供了一种川贝母总生物碱提取物在制备预防或治疗哮喘药物的新用途。贝母生物碱中含有的单体化合物西贝碱、西贝碱氮氧化物,西贝碱苷、贝母辛、贝母甲素、贝母乙素。本发明的川贝母总生物碱能够显著地改善过敏性哮喘相关细胞因子在气道中的释放,降低嗜酸性粒细胞数量,改善过敏情况,并能改善哮喘小鼠肺部炎性浸润、杯状细胞化生、肺实质化等病理状况。本发明的川贝母生物碱质量稳定,使用安全,易于控制,且制备方法简单,便于大生产和临床使用。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对本发明实施例中所需要使用的附图做简单的介绍,显而易见地,下面所描述的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下还可以根据这些附图获得其他的附图。
图1为各组小鼠间支气管肺泡灌洗液中细胞总数及白细胞分类计数。
图2为各组小鼠肺泡灌洗液IL-4的含量结果。
图3为各组小鼠肺泡灌洗液IL-5的含量结果。
图4为各组小鼠肺泡灌洗液IL-13的含量结果。
图5为各组小鼠肺泡灌洗液IFN-γ的含量结果。
图6为各组小鼠肺组织的HE染色图(放大倍数:100×)。
图7为各组小鼠肺组织的PAS染色图(放大倍数:100×)。
图8为各组小鼠肺组织的Masson染色图(放大倍数:100×)。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1 本发明川贝母总生物碱的提取
取川贝母粉末适量,以70%乙醇浸润,用适量的溶剂进行提取直至无生物碱 ,减压浓缩, 60℃真空干燥,得粗提物。粗提物用适量酸液溶解,酸液上样于离子交换树脂上,以水洗脱除去糖类等大极性物质,后以含5%氯化钠的60%进行洗脱,除盐、浓缩干燥,得到川贝母总生物碱。
实施条例2 川贝母总生物碱提取物中总生物碱含量的测定
对照品溶液的制备
精密称取2.29mg西贝碱至25ml容量瓶中,加入三氯甲烷定容,制成浓度为0.0916mg/ml的对照品储备液。
标准曲线制备
精密量取对照品溶液0、0.1、0.2、0.4、0.6与1.0ml分别置25ml具塞试管中,分别补加三氯甲烷至10ml,精密加蒸馏水5ml,加0.05%溴甲酚绿缓冲液2.0ml,密塞,剧烈振摇后,移入至分液漏斗中,静置30分钟。分取三氯甲烷层,以干燥滤纸滤过,取续滤液,以相应试剂为空白,照紫外分光光度法,在415nm的波长处测定吸光度,绘制标准曲线。
供试品溶液的制备
精密称取纯化后干浸膏粉适量,加浓氨试液密闭浸润1h,加甲醇-三氯甲烷 (1:4)混合溶液,混匀,80℃水浴回流2h,过滤,用甲醇-三氯甲烷 (1:4)混合溶液洗涤,洗涤液并入同一量瓶中,加甲醇-三氯甲烷 (1:4)混合溶液至刻度,摇匀。精密量取2ml,置25ml具塞试管中,水浴蒸干,精密加入三氯甲烷10ml使溶解,照标准曲线制备项下的方法,自“精密加蒸馏水 5ml”起 ,依法测定吸光度,计算出总生物碱的含量。
经含量测定,按实施例1提取方法所得到的川贝母总生物碱提取物中总生物碱含量以西贝碱计算,结果为5%-99.75%。
实施例3 川贝母总生物碱对哮喘模型的治疗作用
川贝母总生物碱的制备
本发明中所使用贝母生物碱来源:提取物按实施条例1制备得到的川贝母生物碱。
实验动物
健康SPF级Balb/c雌性小鼠90只,周龄4-5W,体重17-20g,由成都达硕实验动物中心提供,饲养于四川大学华西药学院动物房。
实验方法
如表1所示,本发明采用卵清蛋白(OVA)腹腔注射的方式建立小鼠哮喘模型,经预实验结果选择OVA给药剂量为0.05mg/kg。哮喘组和各浓度FBC组分别于第0、7、14天给予OVA混悬液 [含OVA(Grade Ⅴ)50 μg 和氢氧化铝2 mg] 0.1 ml腹腔注射致敏,共3次。正常对照组小鼠则以生理盐水代替致敏液,注射的时间、部位及剂量与用药组小鼠相同。从实验第21天起,将小鼠置于20 cm×20 cm×20 cm自制雾化箱中,由402 AI超声雾化器雾化吸入2%OVA(Grade Ⅱ)溶液,每2天1次。每次40 min,持续21 d。对照组给予等量生理盐水雾化激发。每次雾化前30 min,各FBC药物干预组给予FBC(20、40、80 mg/kg)进行灌胃,对照组、哮喘组给予等量生理盐水进行灌胃,阳性对照组给予地塞米松(0.5mg/kg)腹腔注射。
表1 川贝母总生物碱对于OVA哮喘动物实验给药分组及剂量
分组(给药/时间) | 分组缩写 | 给药量 |
空白对照组 | C组 | - |
模型组 | M组 | - |
阳性对照组 | P组 | 0.5mg/kg |
川贝母总生物碱低剂量组 | FBC-L组 | 20mg/kg |
川贝母总生物碱中剂量组 | FBC-M组 | 40mg/kg |
川贝母总生物碱高剂量组 | FBC-H组 | 80mg/kg |
支气管肺泡灌洗液的收集
将经放血处死后的小鼠进行固定,气管插管,暴露胸腔,结扎右主支气管,用预冷后的PBS(每次0.4ml,共3次)灌洗左肺,并收集BALF。回收率≥80%为合格,将BALF以3000r/min、4℃离心10min后取上清液,-80℃保存,作为因子的待测样。BALF细胞沉淀重悬后用于细胞的计数及分类。
组织标本的采集
将经过放血处死的小鼠迅速摘取肺组织,取其左肺进行固定于4%的多聚甲醛中固定48h,后续进行常规石蜡包埋、切片、HE染色、显微镜下观察其组织形态及病理状态。其余肺组织用锡箔纸包裹迅速冻于液氮中,长期保存在-80℃冰箱中用于后续指标的测定。
肺泡灌洗液的分类及计数用50μl PBS稀释BALF细胞沉淀,混匀;取10μl 细胞悬液用细胞计数板在显微镜下计数细胞总数;取细胞悬液20μl涂片做瑞氏染色,由两名检验人员分别在光学显微镜下计数200个白细胞做分类计数,依据形态学特点将细胞分为嗜酸粒细胞(Eosinophil,Eos)、中性粒细胞(Neutrophil,Neu)、淋巴细(Lymphocyte,Lym)和肺泡巨噬细胞(Macrophage,Mac)。
肺泡灌洗液(BALF)中IL-4、IL-5、IL-13和IFN-γ含量的测定。取冻存的肺泡灌洗液上清于室温下融解后,按照ELISA试剂盒说明进行操作,测定IL-4、IL-5、IL-13和IFN-γ的含量变化。
统计学分析SPSS 23.0 for Windows软件用于本实验数据的分析,ANOVA分析用于多组间比较,用分析实验结果,差异具有统计学意义用P<0.05表示,差异具有显著统计学意义用P<0.01表示。
实验结果
小鼠外观行为学的观察在每次雾化吸入3-5min后,哮喘组小鼠出现抓耳挠鼻、烦躁不安、呼吸加快,腹肌痉挛,大小便失禁,在雾化一周后,会出现毛发竖立,失去光泽等反应。对照组小鼠无明显得到异常反应,各浓度药物干预组小鼠上述的反应较轻。
小鼠肺泡灌洗液中细胞总数及白细胞分类计数
与空白组比较,哮喘组小鼠BALF中淋巴细胞、中性粒细胞和嗜酸性粒细胞出现了明显的增多。与哮喘组比较,川贝母总生物碱低、中、高剂量组小鼠BALF中的细胞总数、淋巴细胞、中性粒细胞和嗜酸性粒细胞明显减少。
表2 各组小鼠各组间支气管肺泡灌洗液中细胞总数及白细胞分类计数(x107/L)
组别 | 只数 | 细胞总数 | 淋巴细胞 | 中性粒细胞 | 嗜酸性粒细胞 | 巨噬细胞 |
空白对照组 | 6 | 55.25±23.82 | 12.53±6.83 | 7.25±3.29 | 0.61±0.85 | 34.86±17.64 |
哮喘组 | 6 | 125.35±38.83<sup>a</sup> | 35.28±17.84<sup>a</sup> | 21.04±8.85<sup>a</sup> | 26.25±17.84<sup>a</sup> | 42.78±28.86 |
阳性对照组 | 6 | 68.39±23.63<sup>ab</sup> | 14.25±6.85<sup>ab</sup> | 8.42±3.86<sup>ab</sup> | 5.23±1.87<sup>ab</sup> | 40.49±24.23 |
低浓度(20mg/kg) | 6 | 62.06±21.36<sup>b</sup> | 14.24±6.16<sup>b</sup> | 8.84±2.74<sup>b</sup> | 2.21±1.72<sup>b</sup> | 36.74±15.42 |
中浓度(40mg/kg) | 6 | 76.12±25.24<sup>b</sup> | 14.93±6.87<sup>b</sup> | 12.67±8.26 | 4.93±2.89<sup>b</sup> | 43.61±19.34 |
高浓度(80mg/kg) | 6 | 108.29±65.61<sup>a</sup> | 29.25±22.88<sup>a</sup> | 20.18±16.89<sup>a</sup> | 14.75±9.56<sup>ab</sup> | 44.12±22.91 |
注:与空白对照组比较,a P<0.05;与哮喘组比较,b P<0.05。
小鼠肺泡灌洗液中细胞因子的变化
与空白对照组比较,哮喘组小鼠BALF中Th2细胞因子IL-4、IL-5、IL-13浓度明显升高,而Th1细胞因子IFN-γ浓度出现了明显的减少。与哮喘组比较,川贝母总生物碱小鼠BALF中Th2细胞因子IL-4、IL-5、IL-13浓度明显减少,而Th1细胞因子IFN-γ浓度出现了明显的增多。
表3 各组小鼠支气管肺泡灌洗液中IL-4、IL-5、IL-13和IFN-γ含量比较(pg/ml)
组别 | 只数 | IL-4 | IL-5 | IL-13 | IFN-γ |
空白对照组 | 6 | 264.42±17.87 | 118.78±6.39 | 106.83±11.07 | 282.70±8.19 |
哮喘组 | 6 | 356.81±9.22<sup>a</sup> | 191.74±6.30<sup>a</sup> | 187.21±12.86<sup>a</sup> | 230.48±6.14<sup>a</sup> |
阳性对照组 | 6 | 302.94±11.5<sup>b</sup> | 130.13±13.56<sup>b</sup> | 156.28±6.48<sup>b</sup> | 254.69±4.03<sup>ab</sup> |
低浓度(20mg/kg) | 6 | 322.62±15.52<sup>a</sup> | 169.09±24.30<sup>ab</sup> | 151.03±14.18<sup>b</sup> | 251.29±6.97<sup>ab</sup> |
中浓度(40mg/kg) | 6 | 286.35±16.96<sup>b</sup> | 163.12±5.81<sup>ab</sup> | 157.15±15.55<sup>b</sup> | 252.70±6.13<sup>ab</sup> |
高浓度(80mg/kg) | 6 | 289.42±10.79<sup>b</sup> | 165.94±9.69<sup>ab</sup> | 162.87±6.48<sup>b</sup> | 250.78±5.84<sup>ab</sup> |
注:与空白对照组比较,a P<0.05;与哮喘组比较,b P<0.05。
肺组织病理学形态学改变
HE染色(图6)结果显示,与显微镜下拍照,观察各组小鼠肺组织的病理改变。与空白对照组相比,哮喘组小鼠肺组织支气管周围出现炎细胞浸润、气管壁增厚,肺泡壁增厚,肺实质化增加。在给予川贝母总生物碱后,肺部病理明显改善。其中以川贝母总生物碱低剂量组的改善效果最优。
PAS染色(图7)结果显示哮喘组气道出现明显的杯状细胞化生、粘液分泌的现象。相较于模型组,给予川贝母总生物碱的杯状细胞化生显著被抑制,且粘液分泌减少。其中以川贝母低剂量组的效果最为显著。
Masson染色(图8)结果表明,哮喘组出现了明显的胶原纤维组织增生、变厚的现象,相较于模型组,给予川贝母总生物碱的胶原纤维组织增生、变厚的现象出现了明显的改善。其中以川贝母总生物碱低剂量组的效果最为显著。研究结果显示,川贝母总生物碱可以显著改善了OVA哮喘小鼠肺部炎性浸润、杯状细胞化生、肺实质化、胶原纤维增多、变厚等病理状况。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,凡本发明的精神和原则之内所作的任何修改、等同替换和改进等,都应涵盖在本发明的保护范围之内。
Claims (9)
1.一种川贝母总生物碱提取物在制备用于预防或治疗哮喘的药物中的用途,其特征在于川贝母来源的总生物碱提取物。
2.根据权利要求1所述的用途,其特征在于:所述的药物是治疗支气管哮喘的药物。
3.根据权利要求1或2所述的用途,其特征在于所述的药物是治疗哮喘引发喘息、咳嗽和咯痰的药物。
4.根据权利要求1或2所述的用途,其特征在于所述的药物是改善哮喘相关细胞因子在气道中的释放和改善肺部炎性浸润、杯状细胞化生、肺实质化的药物。
5.根据权利要求1-4任意一项所述的用途,其特征在于:所述的贝母总生物碱中总生物碱含量以西贝碱计为5-100%W/W。
6.根据权利要求1-4任意一项所述的用途,其特征在于:所述的贝母总生物碱中含有的单体化合物包括西贝碱、西贝碱氮氧化物,西贝碱苷、贝母辛、贝母甲素、贝母乙素生物碱单体。
7.根据权利要求1-4所任意一项所述的用途,其特征在于:所述提取物是由如下方法制备的:
取川贝母粉碎,以60-95%乙醇浸润或不浸润,用60-95%乙醇提取2-3次,真空干燥,以大孔吸附树脂、离子交换树脂进行或不进行纯化而得到的川贝母总生物碱,真空干燥或冷冻干燥,即得川贝母总生物碱。
8.根据权利要求1-4所述的用途,其特征在于:所述的药物为为口服制剂、注射剂或局部给药制剂。
9.根据权利要求1-4所述的用途,其特征在于:所述的药物含有川贝母总生物碱,加上药学上可接受的辅料或辅助性成分制备得到的制剂。
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