CN116549434A - 淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用 - Google Patents
淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用 Download PDFInfo
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Abstract
本发明公开了淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，本发明使用实验手段考察了淫羊藿素对弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病的保护作用。淫羊藿素具有显著改善弹性蛋白酶和脂多糖联合诱导的小鼠肺功能的作用；并进一步确认其药理作用是通过抑制弹性蛋白酶和脂多糖联合所致慢性阻塞性肺疾病的肺气肿和炎症实现的。基于淫羊藿素以上新性质，本发明确定了利用其制备由弹性蛋白酶和脂多糖联合诱导的慢性阻塞性肺疾病保护药物的新用途，其疗效好，毒副作用小，具有良好的前景价值。
Description
【技术领域】
本发明属于医药用途技术领域，涉及淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用。
【背景技术】
慢性阻塞性肺疾病(chronic obstructive pulmonary disease，COPD，简称慢阻肺)是一种常见的呼吸系统慢性病，与气道对慢性炎症反应增强有关，炎症主要是由有害气体和颗粒引起的。慢性阻塞性肺疾病已经成为全世界卫生事业关注的重要问题。全球呼吸健康部的研究粗略估计了全球和地区的COPD患病率和病例，2010年有3.84亿例，全球患病率约为11.7％。2019年，全球老龄化加剧，病例数较前明显增加，其中30-79岁人群中的COPD全球患病率为10.3％。随着发展中国家吸烟人数的增加，城市化的进展，以及高收入国家人口的老龄化，估计慢性阻塞性肺疾病的患病率仍将上升。慢性阻塞性肺疾病的高发病率、高致残率和高死亡率，给社会带来了巨大的经济负担和严重危害，因此研究慢性阻塞性肺疾病的发病机制，寻求新的经济高效的药物对于人类社会具有非常重要的作用。
目前，慢性阻塞性肺疾病的治疗尚无特效药，对于慢性阻塞性肺疾病的药物研究也成为热点，寻找经济有效且毒副作用小的治疗慢性阻塞性肺疾病的药物迫在眉睫。鉴于丰富的资源和低廉的成本，植物天然药物及其小分子提取物在慢性阻塞性肺疾病药物开发上具有独特的优势。
淫羊藿为小檗科植物淫羊藿、箭叶淫羊藿、粗毛淫羊藿、巫山淫羊藿或朝鲜淫羊藿的干燥地上部分。中医认为其味辛、甘，性温，归肝、肾经，主治功能：补肾阳，强筋骨，祛风湿。淫羊藿含多种黄酮类成分，如淫羊藿甘、淫羊藿次苷、淫羊藿素(Icaritin，ICT)等。淫羊藿素是淫羊藿属植物提取物淫羊藿苷的水解衍生产物，属于黄酮醇类化合物，其化学结构式如下：
目前有关淫羊藿素的药理活性研究报道较少，有报道淫羊藿素可抑制体外培养的小鼠T淋巴瘤EL-4细胞的增殖并诱导其凋亡，范双翼、余英豪，中国比较医学杂志2011年21卷06期。淫羊藿素能够诱导雌激素受体阴性肿瘤细胞凋亡和生长抑制，2009年第二军医大学硕士学位论文，张妤；导师：殷正丰、吴孟超。淫羊藿素能以浓度依赖性方式有效地抑制CML原代细胞增殖和诱导CML原代细胞凋亡，2009年中南大学博士学位论文，朱剑锋；导师：张广森。中国专利CN1869204A公开了淫羊藿素在诱导干细胞体外定向分化方面的用途。中国专利CN1194701C公开了淫羊藿素或去甲淫羊藿素在制备雌激素受体调节剂的应用。
近年来，研究者对慢性阻塞性肺疾病病理生理学的探索逐渐深入，但仍未发现有效的治疗药物。肺气肿、炎症反应在慢性阻塞性肺疾病的发生过程中起核心作用，因此抗肺气肿、抗炎是治疗的关键。迄今尚未见有关于植物天然药物小分子淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物的报道。
【发明内容】
针对现有技术中治疗慢性阻塞性肺疾病的治疗尚无特效药的问题，本发明提供了淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，本申请初步证实植物天然小分子药物淫羊藿素具有抑制弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病的肺气肿和炎症的功能，并显著改善模型小鼠肺功能的作用。
本发明的目的通过以下技术方案来实现：
淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用。
进一步的，所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，所述药物组合物是以淫羊藿素为主要成分，加上药学中可接受的辅料或辅助性成分制备成临床上可接受的药物制剂。
进一步的，所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，所述药物制剂包括口服制剂和注射制剂两种剂型。
进一步的，所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，所述口服制剂为口服胶囊，所述注射制剂为静脉注射液。
通常而言，作为药物，均是在制备成制剂后才临床应用。本发明所述的药物组合物，作为药物组合物可根据本领域公知的方法制备。可通过将本发明药物组合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明所述的淫羊藿素在其药物组合物中的含量通常为0.01-95％(w/w)。
本发明药物组合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明药物组合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。为了将本发明药物组合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；润湿剂可以是水、乙醇、异丙醇等；黏合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明药物组合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明药物组合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明药物组合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明药物组合物的胶囊剂。
为将本发明药物组合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
和现有技术相比，本发明具有如下优点：
1、本发明所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，本发明使用实验手段考察了淫羊藿素对弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病的保护作用，淫羊藿素具有显著改善弹性蛋白酶和脂多糖联合诱导的小鼠肺功能的作用；并进一步确认其药理作用是通过抑制弹性蛋白酶和脂多糖联合所致慢性阻塞性肺疾病的肺气肿和炎症实现的。基于淫羊藿素以上新性质，本发明确定了利用其制备由弹性蛋白酶和脂多糖联合诱导的慢性阻塞性肺疾病保护药物的新用途，其疗效好，毒副作用小，具有良好的前景价值。
2、本发明所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，本发明采用弹性蛋白酶和脂多糖联合诱导小鼠慢性阻塞性肺疾病，利用淫羊藿素干预，探讨淫羊藿素对慢性阻塞性肺疾病的保护作用，为慢性阻塞性肺疾病的治疗提供新的线索。
【附图说明】
图1是本发明实验例中淫羊藿素对慢性阻塞性肺疾病小鼠肺功能的影响的图；
图2是本发明实验例中淫羊藿素对慢性阻塞性肺疾病小鼠肺大泡的影响的图。
图3是本发明实验例中淫羊藿素对慢性阻塞性肺疾病小鼠肺部炎症的影响的图。
【具体实施方式】
以下结合实施例对本发明的具体实施方式做进一步说明。
实施例1：
淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用：
按照现有的工艺要求，制备成硬胶囊。
实施例2：
淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用：
按照现有的工艺要求，制备成注射剂。
实验例：
淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用
1、慢性阻塞性肺疾病小鼠模型构建
将小鼠随机分为七组，先将小鼠放置于动物房，使用普通饲料饲养，适应环境1周，该实验已经通过了桂林医学院动物伦理委员会的审批。实验过程中的小鼠均在桂林医学院东城校区SPF级实验动物中心饲养，小鼠于SPF级动物房饲养，经过空气净化处理的，温度维持在22～25℃，湿度维持在40～50％。在实验过程中，小鼠自由饮水及饮食。
参照国内外文献报道及本课题组前期的造模方法，将小鼠随机分为4组，每组6只，分别为：空白对照组、模型组(弹性蛋白酶和脂多糖联合诱导慢阻肺)、低剂量淫羊藿素治疗组(弹性蛋白酶和脂多糖联合诱导慢阻肺+淫羊藿素40mg/kg)、高剂量淫羊藿素治疗组(弹性蛋白酶和脂多糖联合诱导慢阻肺+淫羊藿素80mg/kg)。
动物模型的建立：
(1)空白对照组：空白对照组，仅用PBS致敏和激发；
(2)模型组：小鼠在第1天通过气管内滴入7μg脂多糖和第4天通过气管内滴入0.6单位的弹性蛋白酶，每周1次，连续4周；
(3)低剂量淫羊藿素治疗组：在每次脂多糖和弹性蛋白酶刺激前2小时，通过灌胃注射给予小鼠淫羊藿素(40mg/kg)，最后5天连续给药；
(4)高剂量淫羊藿素治疗组：在每次脂多糖和弹性蛋白酶刺激前2小时，通过灌胃注射给予小鼠淫羊藿素(80mg/kg)，最后5天连续给药。
在实验期间持续观察小鼠的毛发、体力，定期对各组小鼠进行称重，在第35天测定小鼠肺功能后，处死小鼠，进行采血、收集各组肺组织进行分析。
2、淫羊藿素改善慢性阻塞性肺疾病小鼠的肺功能
肺功能测定方法：脂多糖和弹性蛋白酶诱导及淫羊藿素给药结束24h内，将清醒状态的小鼠予吸入异氟烷麻醉后放入双通道无创肺功能检测系统(Non-Invasive AirwayMechanics，NAM)进行肺功能评估。待小鼠清醒且呼吸稳定后，实施小鼠无创肺功能测定，连续监测各组小鼠特殊气道阻力(sRaw)、呼气流量(EF50)、呼气峰流速(PEF)等指标。仪器每2秒记录1次呼吸相关指标，随机选取3组连续数值，求其平均值，作为测定值。
实验结果发现(参见图1)：
图1：淫羊藿素对慢性阻塞性肺疾病小鼠肺功能的影响(**P<0.01)(其中：
(1)模型组(PPE+LPS)小鼠sRaw显著高于空白对照组(Control)，EF50和PEF显著低于空白对照组(Control)图1(a)；
(2)淫羊藿素治疗组(PPE+LPS+ICT40和PPE+LPS+ICT80)sRaw显著低于模型组，EF50和PEF显著高于模型组(PPE+LPS)图1(b)；
(3)淫羊藿素对肺功能sRaw、EF50和PEF的改善具有剂量依赖性(PPE+LPS+ICT40和PPE+LPS+ICT80比较)图1(c))
实验结果说明：淫羊藿素能够显著改善慢性阻塞性肺疾病小鼠的肺功能。
3、淫羊藿素减退慢性阻塞性肺疾病小鼠的肺气肿
(1)取材、固定：用小号止血钳夹闭右肺主支气管，然后将4％多聚甲醛小心缓慢的灌注左肺，左肺充盈后取出，放入已装满4％多聚甲醛的5ml离心管中固定。
(2)脱水：固定48小时后，肺组织放入包埋盒中，做好标记，在缓慢流水下小心冲洗30分钟。之后将冲洗好的包埋盒轻轻甩除部分多余的水分，置于全自动脱水机中。自动脱水机已经事先放置不同溶剂，按顺序依次脱水、透明和浸蜡，然后放入溶蜡箱保温。
(3)包埋、切片：预热包埋机，预冷冷冻台。待腊缸中腊块完全溶化后，从溶蜡箱取出肺组织，滴蜡、包埋、冷冻。取蜡块放上切片机，检查切片是否固定，然后将蜡块匀速切成6μm厚的切片。然后缓慢将切片平铺到展片箱水面展片，等切片展平之后，用载玻片小心捞片，让其平整贴在载玻片上(注意不要留有气泡)，最后将标记好的载玻片烘干。
(4)H&E染色严格按照苏木素-伊红试剂盒说明操作，具体步骤如下：①选取合适的切片，使用烤片机烤片30min，再经过松节油脱蜡后进行染色；②常规脱蜡后经蒸馏水浸泡2min转入染液，苏木精染液染色8min；③染缸浸泡水洗2min，0.5～1％盐酸酒精分色片刻，在显微镜下控制染色，直到细胞染清晰为止，约10s；④把玻片架放置染缸中浸泡，流水冲洗20min，完成对细胞核的染色；⑤蒸馏水浸泡2min，0.1～0.5％伊红染液染色1～5min；⑥80％、95％、100％乙醇梯度脱水，各梯度8～10s；⑦滴加中性树脂进行封片。
(5)根据H&E染色结果测定肺大泡：测量结果显示，模型组(PPE+LPS)与空白对照组(Control)比较，肺泡壁变薄，破坏增多，肺泡腔显著扩大，表明出现肺气肿病理改变；淫羊藿素治疗组(PPE+LPS+IC40和PPE+LPS+IC80)与模型组(PPE+LPS)比较，肺泡壁变厚，破坏减少，肺泡腔显著减小，表明出现肺气肿病理改善；高剂量淫羊藿素治疗组(PPE+LPS+IC80)比低剂量淫羊藿素治疗组(PPE+LPS+IC40)对肺气肿的改善更加明显(图2)。
图2：淫羊藿素对慢性阻塞性肺疾病小鼠肺大泡的影响(**P<0.01)(其中：
图2(a)：Control组；
图2(b)：PPE+LPS组；
图2(c)：PPE+LPS+ICT40组；
图2(d)：PE+LPS+ICT80组；
图2(e)：数据分析图)；
实验结果说明：淫羊藿素能够显著改善慢性阻塞性肺疾病小鼠的肺大泡。
4、淫羊藿素减退慢性阻塞性肺疾病小鼠的肺部炎症
(1)各组小鼠肺泡灌洗液炎症细胞分类计数
处死后的小鼠使用大头针固定，仰面置于解剖板上，用75％酒精消毒毛发及皮肤；用剪刀在颈部小心缓慢剪开皮肤，注意刀口的深度，避免损伤气管；用镊子钝性分离皮肤与胸腹膜壁，逐层解剖暴露胸腔、腹腔和肺脏；颈部切开皮肤并钝性分离气管，然后插入留置管，止血钳夹闭左肺，单行右肺灌洗，每次分别以0.4、0.3、0.3ml冷PBS灌洗，获得支气管肺泡灌洗液(Bronchoalveolar lavage fluid，BALF)；回收约0.6-0.7ml BALF液，置于4℃、3000r/min条件下，离心10分钟；细胞沉淀用50ul冷PBS重新悬浮，用于细胞计数。
用吸管吸取上述细胞悬液，在盖玻片上或下侧的计数板凹槽处流出悬液，至盖玻片被液体充满为止，置于显微镜下，利用血球计数板进行炎症细胞总数量的计数；再通过吉姆萨染色进行各种炎症细胞分类的计数。实验发现：模型组(PPE+LPS)比空白对照组(Control)肺泡灌洗液炎症细胞总数、中性粒细胞数和巨噬细胞数均明显增加；淫羊藿素治疗组(PPE+LPS+IC40和PPE+LPS+IC80)与模型组(PPE+LPS)比较，肺泡灌洗液炎症细胞总数、中性粒细胞数和巨噬细胞数均明显减少；高剂量淫羊藿素治疗组(PPE+LPS+IC80)比低剂量淫羊藿素治疗组(PPE+LPS+IC40)肺泡灌洗液炎症细胞总数、中性粒细胞数和巨噬细胞数均无明显变化(图3)。
图3：淫羊藿素对慢性阻塞性肺疾病小鼠肺部炎症的影响(**P<0.01)；
实验结果说明：淫羊藿素能够显著改善慢性阻塞性肺疾病小鼠的肺部炎症。
上述说明是针对本发明较佳可行实施例的详细说明，但实施例并非用以限定本发明的专利申请范围，凡本发明所提示的技术精神下所完成的同等变化或修饰变更，均应属于本发明所涵盖专利范围。
Claims (3)
1.淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，其特征在于：所述药物组合物是以淫羊藿素为主要成分，加上药学中可接受的辅料或辅助性成分制备成临床上可接受的药物制剂，所述的淫羊藿素在其药物组合物中的含量为0.01-95％w/w。
2.根据权利要求1所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，其特征在于：所述药物制剂包括口服制剂和注射制剂两种剂型。
3.根据权利要求2所述的淫羊藿素在制备弹性蛋白酶和脂多糖联合诱导慢性阻塞性肺疾病药物组合物中的应用，其特征在于：所述口服制剂为口服胶囊，所述注射制剂为静脉注射液。
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