CN110038057B - 苍芷通鼻滴雾剂及其制备方法与在防治变应性鼻炎的应用 - Google Patents
苍芷通鼻滴雾剂及其制备方法与在防治变应性鼻炎的应用 Download PDFInfo
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Abstract
本发明公开了一种苍芷通鼻滴雾剂及其制备方法与在防治变应性鼻炎的应用，苍芷通鼻滴雾剂由苍耳子、白芷、薄荷、辛夷花、川芎等七味常用内服的中药组成，经水煮醇沉提取后，在常压下采用具有喷头的塑料瓶灌装而成。本发明将苍耳子散与行气化瘀药相结合，对治疗变应性鼻炎简便、有效、复发率低，对人体无或轻微毒副作用，药品工艺稳定、质量可控、性能可靠，生产的产品自然放置3年仍符合《中国药典》质量标准要求；苍芷通鼻滴雾剂生产工艺简单，成本低廉，使用、携带方便，不需要特殊的制造设备。
Description
技术领域
本发明属于一种变应性鼻炎的治疗药剂及其制备方法，具体涉及一种苍芷通鼻滴雾剂及其制备方法与在防治变应性鼻炎的应用。
背景技术
变应性鼻炎(allergic rhinitis，AR)，即过敏性鼻炎，是机体接触变应原后主要由IgE介导的鼻粘膜非感染性炎性疾病。AR可引起变应性鼻窦炎、支气管哮喘、分泌性中耳炎、变应性咽喉炎等并发症。由于变应性鼻炎具有喷嚏、鼻涕、鼻塞、鼻痒、嗅觉减退，且病程较长，反复发作容易发展为哮喘等特点，给患者在日常生活和工作上带来诸多不便，常使患者的精神极度痛苦和造成患者沉重经济负担。遍及全球的国际耳鼻咽喉科学联合会的31个成员国对变应性鼻炎流行情况进行调查，AR流行率为10％-40％，变应性鼻炎患病率高且呈上升趋势，已成为国际关注的全球性疾病。我国针对中心城市人群的初步研究表明，平均自报患病率约为11.1％，不同地区差异很大。
目前西医治疗变应性鼻炎常用的方法有如下几种：
⒈药物疗法，包括口服/鼻内抗组胺药、鼻内类固醇激素、减充血药、白三烯受体拮抗剂、色甘酸钠、抗胆碱药等；
⒉皮下/舌下脱敏疗法；
⒊手术治疗，包括鼻腔筛前、筛后、翼管神经等阻滞术，鼻中隔矫正术，下鼻甲部分切除术，或者鼻粘膜部施以冷冻、激光照射、烧灼等方法以降低鼻粘膜敏感性。
尽管以上方法均可到达控制症状目的，但其所带来的药物毒、副作用和手术并发症等问题是不可忽视的。例如，长期服药可能存在药物的毒、副作用，特别是儿童和老年患者；另外，脱敏治疗虽然是未来的发展方向，但其存在过敏性休克的风险，以及高昂的费用和不确定的疗效使得患者难以接受；手术治疗则是一种破坏性操作，存在并发症的风险。总之，目前变应性鼻炎的临床治疗仍然非常棘手。
其中的药物疗法，大多采用西药治疗，西药主要以抗过敏内服、类固醇类药物喷雾剂外用，虽可暂缓一时，但一旦停药就会复发且更严重，如长期使用则毒副作用明显,而免疫治疗存在风险和疗效不确切，目前国内外尚无一个外用的纯中药喷鼻治疗变应性鼻炎的专用药物，
变应性鼻炎相当于中医之“鼻鼽”的范畴，其病因病机历代医家多认为系内、外因所致。内因多为脏腑功能失调，主要是肺、脾、肾之脏虚损；外因多为风寒，异气之邪侵袭肺脏所致。其治疗内服多以扶正固本为主，外治多用辛散芳香通窍的药物。
对变应性鼻炎的治疗，中医中药具有疗效较好，价格低廉，操作简便，便于推广使用，且无毒副作用或轻微，在提高自身免疫力和治疗变态反应性疾病方面有其独特的优势。2012年，在最新的《欧洲鼻-鼻窦炎诊疗指南》(EPOS)中指出：有充分证据(Ia证据)表明中草药对鼻-鼻窦炎有重要的治疗价值，推荐临床上使用(A级)。
苍耳子散是用来治疗鼻病的中医古方，其由白芷、辛夷花、苍耳子、薄荷四味药组成，其主要成分辛夷花经现代药理研究证实具很强的抗变态反应和收缩鼻粘膜血管的作用，临床上常单用本品或配合其他药物来治疗变应性鼻炎，取得较好的疗效。李氏等用白芷、辛夷花、苍耳子、防风制备得辛防白滴鼻液，治疗变应性鼻炎32例，总有效率为84％。余氏等用苍耳子、辛夷花、黄芩、青黛制备得复方苍耳子滴鼻剂，治疗变应性鼻炎423例，有效率为88％。
上述治疗主要从疏风散寒或兼清热除湿入手，未认识到气滞血瘀之病机至始至终存在于变应性鼻炎的各证型中，故而未获得更满意疗效，而且尚未将其开发成医院内制剂和中药新药。
发明内容
本发明是为了克服现有技术中存在的缺点而提出的，其目的是提供一种苍芷通鼻滴雾剂及其制备方法与在防治变应性鼻炎的应用。
一种苍芷通鼻滴雾剂，所述滴雾剂的组分和各组分的重量份为：薄荷100～450份、牡丹皮100～450份、枳实100～450份、苍耳子50～300份、白芷50～200份、辛夷花30～300份、川芎30～250份。
所述滴雾剂的组分和各组分的重量份为：
薄荷300份、牡丹皮300份、枳实300份、苍耳子150份、白芷150份、辛夷花150份、川芎150份。
所述滴雾剂的组分和各组分的重量份为：薄荷350份、牡丹皮250份、枳实150份、苍耳子150份、白芷200份、辛夷花200份、川芎200份。
所述滴雾剂的组分和各组分的重量份为：薄荷150重量份、牡丹皮150重量份、枳实250重量份、苍耳子300重量份、白芷100重量份、辛夷花花300重量份、川芎250重量份。
苍芷通鼻滴雾剂的制备方法，包括以下步骤：
(ⅰ)提取辛夷、牡丹皮、薄荷的挥发油
取薄荷100～450份、牡丹皮100～450份、辛夷花花30～300份，辛夷、牡丹皮打粗粉，合并薄荷，利用水蒸气蒸馏法提取挥发油，备用；
(ⅱ)苍耳子、川芎、白芷、枳实醇提
取苍耳子50～300份、白芷50～200份、川芎30～200份、枳实100～450份，打粗粉，加入四者质量和6倍量的乙醇回流三次，滤过，合并滤液，回收乙醇至低于0.5wt％，置-4℃静置12～24h，取上层油层提取物即苍耳子、川芎、白芷、枳实备用，下层滤过；
(ⅲ)苍芷通鼻滴雾药液的制备
将步骤(ⅰ)所得辛夷、牡丹皮、薄荷的挥发油、步骤(ⅱ)所得的苍耳子、白芷、川芎、枳实提取油以及一定量吐温混匀，再向滤液中加入10％甘油、0.5％苯甲酸钠、0.9％氯化钠，灭菌分装，即得苍芷通鼻滴雾药液；
(ⅳ)苍芷通鼻滴雾剂
将步骤(ⅲ)得到的苍芷通鼻滴雾药液在常压下灌装至具有喷头的塑料瓶中即得。
所述步骤(ⅰ)的具体方法为：取预定量的辛夷、牡丹皮打粗粉，粗粉中加入薄荷，再加入一定量的水，进行水蒸气蒸馏，收集10～15倍溜液，重蒸馏，收集2～4倍量的溜液，获得辛夷、牡丹皮、薄荷的挥发油。
所述步骤(ⅰ)水蒸气蒸馏法提取辛夷、牡丹皮、薄荷的挥发油中水蒸气蒸馏收集13倍溜液，重蒸馏时收集3倍溜液。
所述步骤(ⅱ)中的乙醇为体积分数为80％的乙醇；所述乙醇回流提取三次，第一次两小时，第二、三次各一小时。
一种苍芷通鼻滴雾剂的应用在于将苍芷通鼻滴雾剂应用于变应性鼻炎防治。
本发明的设计原理：
本发明增加了变应性鼻炎的病因病机新理论：认为气滞血瘀贯穿于变应性鼻炎的各个阶段，故治疗上除传统的辛散芳香通窍的药外，主张佐以行气化瘀之品方能获得更好的疗效。中药鼻涕雾剂(不用氟利昂的常压下的鼻喷雾剂)是很有中医特色的实用剂型，本发明的鼻涕雾剂既继承了传统中医药辨证组方用药的优势，又发挥了细微涕雾鼻腔给药的特点，临床应用方便，疗效确切；本发明秉用喷雾剂型，能使药物黏附于鼻腔患部，可达到高效、速效的局部给药治疗变应性鼻炎的目的。
本发明的有益效果是：
本发明提供了一种苍芷通鼻滴雾剂，将苍耳子散与行气化瘀药相结合，由苍耳子、白芷、薄荷、辛夷花、川芎等七味常用内服的中药组成，经水煮醇沉提取后，在常压下采用具有喷头的塑料瓶灌装而成，实际上为带雾状的滴鼻剂型，不需要氟利昂等压缩剂，因此工艺生产简单，成本低廉，使用、携带方便，不需要特殊的制造设备，一般具有生产口服液、片剂、冲剂等剂型厂家均可以生产，对治疗变应性鼻炎简便、有效、复发率低，对人体无或轻微毒副作用，填补国内外中药喷鼻治疗变应性鼻炎的空白；药品工艺稳定、质量可控、性能可靠，生产的产品自然放置3年仍符合《中国药典》质量标准要求；苍芷通鼻滴雾剂生产工艺简单，成本低廉，使用、携带方便，不需要特殊的制造设备。
附图说明
图1是本发明实施例1应用中苍芷通鼻滴雾剂给药前变应性鼻炎大鼠各组行为学及体重；
图2是本发明实施例1应用中苍芷通鼻滴雾剂对变应性鼻炎大鼠行为学的影响(n＝11，mean±SD)；
图3是是本发明实施例1应用中苍芷通鼻滴雾剂对变应性鼻炎大鼠鼻黏膜的病理影响(均为400×)；
图4是是本发明实施例1应用中苍芷通鼻滴雾剂对变应性鼻炎大鼠炎症因子的影响(n＝6，mean±SD)；
图5是是本发明实施例1应用中苍芷通鼻滴雾剂对T-bet和GATA3的调节作用(n＝11，mean±SD)。
具体实施方式
下面结合说明书附图及实施例对本发明苍芷通鼻滴雾剂及其制备方法与在防治变应性鼻炎的应用进行详细说明：
实施例1
(1)投料提取：取薄荷300g(20％)，牡丹皮300g(20％)、枳实300g(20％)、苍耳子150g(10％)、白芷150g(10％)、辛夷花150g(10％)、川芎150g(10％)。其中取辛夷花150g、牡丹皮300g打粗粉，合并薄荷300g，加2000毫升水，利用水蒸气蒸馏法提取挥发油收集13倍流液，获得挥发油。
(2)取净选的苍耳子150g、白芷150g、川芎150g、枳实300g打粗粉，加入四者质量总和的六倍量的80％的乙醇回流三次，过滤，合并滤液，回收乙醇至滤液中乙醇质量百分比含量低于0.5％置-4℃静置2-4h，取上层油层提取物即苍耳子、白芷、川芎、枳实备用，下层过滤。弟一次回流时间为2小时、等二三次回流各1小时。加入浸膏10倍量的水洗涤二次，分出水层后，置蒸发锅中挥去残余水分，即得四味药的提取混合物。
将步骤(1)和(2)所有的提取物合并，加吐温20ml混匀加入滤液中，再加入10％甘油、5％苯甲酸钠、0.9％氯化钠，灭菌分装，所得药液在常压下灌装至具有喷头的20毫升塑料瓶中即得。
实施例2
(1)投料提取：薄荷350g(23.3％)、牡丹皮250g(16.7％)、枳实150g(10％)、苍耳子150g(10％)、白芷200g(13.3％)、辛夷花200g(13.3％)、川芎200g(13.3％)。其中取辛夷花200g、牡丹皮250g打粗粉，合并薄荷350g，加2000毫升水，利用水蒸气蒸馏法提取挥发油收集13倍流液，获得挥发油。
(2)取净选的苍耳子150g、白芷200g、川芎200g、枳实150g打粗粉，加入四者质量总和的六倍量的80％的乙醇回流三次，过滤，合并滤液，回收乙醇至滤液中乙醇质量百分比含量低于0.5％置-4℃静置2-4h，取上层油层提取物即苍耳子、白芷、川芎、枳实备用，下层过滤。等一次回流时间为2小时、等二三次回流各1小时。加入浸膏10倍量的水洗涤二次，分出水层后，置蒸发锅中挥去残余水分，即得四味药的提取混合物。
将步骤(1)和(2)所有的提取物合并，加吐温20ml混匀加入滤液中，再加入10％甘油、5％苯甲酸钠、0.9％氯化钠，灭菌分装，所得药液在常压下灌装至具有喷头的20毫升塑料瓶中即得。
实施例3
(1)投料提取：薄荷150g(10％)、牡丹皮150g(10％)、枳实250(16.7％)g、苍耳子300g(20％)、白芷100g(6.7％)、辛夷花300g(20％)、川芎250g(16.7％)。其中取辛夷花300g、牡丹皮150g打粗粉，合并薄荷150g，加2000毫升水，利用水蒸气蒸馏法提取挥发油收集13倍流液，获得挥发油。
(2)取净选的苍耳子300g、白芷100g、川芎250g、枳实250g打粗粉，加入四者质量总和的六倍量的80％的乙醇回流三次，过滤，合并滤液，回收乙醇至滤液中乙醇质量百分比含量低于0.5％置-4℃静置2-4h，取上层油层提取物即苍耳子、白芷、川芎、枳实备用，下层过滤。等一次回流时间为2小时、等二三次回流各1小时。加入浸膏10倍量的水洗涤二次，分出水层后，置蒸发锅中挥去残余水分，即得四味药的提取混合物。
将步骤(1)和(2)所有的提取物合并，加吐温20ml混匀加入滤液中，再加入10％甘油、5％苯甲酸钠、0.9％氯化钠，灭菌分装，所得药液在常压下灌装至具有喷头的20毫升塑料瓶中即得。
以下为实施例1的质量控制标准和动物模型药理实验：
苍芷通鼻滴雾剂的质量控制标准采用臣药枳实、牡丹皮、白芷中所含辛弗林、丹皮酚、欧前胡素含量进行测定。辛弗林具有血管动脉条的活性作用；丹皮酚具有抗过敏作用；欧前胡素具有抗菌消炎作用。测定方法均用高效液粗色谱法(HPLC)，该方法简单、准确、回收率高。
①辛弗林含量测定：
(ⅰ)仪器美国惠普公司HP1050A—高效液粗色谱仪；美国惠普公司6010型紫外—可见分光光度计；瑞士梅特勒公司AE—200型电子分析天平。
(ⅱ)药品辛弗林对照品由中国药品生物制剂检测所提供；苍芷通鼻滴雾剂；阴性对照品(按处方工艺缺枳实制得对照品)；甲醇为色谱醇；其它试剂均为分析纯。
(ⅲ)色谱条件Hypersil Division ODS C18分析柱(150mm×4.6mm,5um)流动相为甲醇—水(5:5),1000ml中加入磷酸二氢钾0.6，十二烷基磺酸钠1.0，冰醋酸1ml，检测波长275nm，流速1.0ml/min室温操作。
(ⅳ)辛弗林含量测定
苍芷通鼻滴雾剂样品溶液的制备：精密吸取本品1ml,置2ml容量瓶中，用蒸馏水稀释至刻度，摇匀，针孔式微孔滤膜过滤，备用。
对照品溶液的制备：精密称取辛弗林对照品适量，加甲醇配置成每1ml含0.28mg的对照品溶液。
线性关系的考察：精密吸取上述辛弗林对照品溶液2,4,6,8,10ml依次进样，按上述色谱条件测定，以进样量(x)和峰面积(y)进行回归，求得回归方程为y＝349.98x+24.35，r＝0.9994，表明辛弗林在0.56-2.80ug之间线性关系良好。
精密度实验：精密吸取上述辛弗林对照品溶液5ul，重复进样5次，测得峰面积积分分别为573.31，571.10，580.85，578.43，585.74，平均值为577.89，RSD＝1.02％。
稳定性实验：取苍芷通鼻滴雾剂样品供试液分别在0,0.5,1,2,4,6h测定，测得峰面积积分分别为442.04,453.53,457.53,455.98,456.31,441.31，平均值为451.45，RSD为1.65％。结果表明在测定条件下，在6h内测定结果稳定。
空白实验：取缺枳实的阴性对照品，依样品测定项下的测定结果在含辛弗林对照品吸收峰位置处无干扰。
重现性实验：按样品测定法，对同一批样品(即苍芷通鼻滴雾剂)依法测定5次，测定得峰面积积分平均值为447.93。辛弗林平均含量为：1.051mg/ml，RSD为1.24％。表明本法重现性良好。
加样回收率实验：精密量取已知含量的样品0.5ml，置5ml容量瓶中，再精密加入1,2,3ml溶液为每ml辛弗林0.56mg的甲醇对照溶液，用蒸馏水稀释至刻度，按样品条件测定，计算回收率。
加样含量测定：分别取对照品溶液5ul，阴性对照品5ul注入溶液相色谱仪，按上述色谱条件测定可测得含量数值。
②丹皮酚、欧前胡素含量测定
所用仪器、试药、色谱条件均同辛弗林含量测定条件；其试验和检测方法也同辛弗林含量测定。
通过辛弗林、丹皮酚、欧前胡素含量测定则可控制苍芷通鼻滴雾剂的质量标准。
③苍芷通鼻滴雾剂对变应性鼻炎大鼠模型的影响
本处方以古方《济生方》的苍耳子散为基础，其所选药物均来自国颁药典且全为常用内服中药组成，其工艺和质量标准之前的研究，我们曾严格按照国家三类新药申报办法进行。
本发明共计完成苍芷通鼻滴雾剂院内制剂的初步临床观察病例600余例，资料相对完整者125例，均获得较好的疗效，其中有效者占97％；穴位注射组共计观察治疗100余人次，均获得了显著疗效。
本发明的苍芷通鼻滴雾剂为中药经水煮醇沉提取获得，将其在常压下采用具有喷头的塑料瓶灌装，即可得到“喷雾剂”，实际上为带雾状的滴雾剂型，不需要氟利昂等压缩剂，该药因此工艺生产简单，成本低廉，使用、携带方便，不需要特殊的制造设备。一般具有生产口服液、片剂、冲剂等剂型厂家均可以生产。故更名后更符合实际。
本发明将苍芷通鼻滴雾剂应用于防治变应性鼻炎，并在动物模型上进行了药理药效的随机对照实验，结果证实苍芷通鼻滴雾剂对大鼠变应性鼻炎的症状有明显的改善作用，对其鼻粘膜的损伤有修复作用。通过抑制变应性鼻炎发生过程中促炎因子表达，增强抑炎因子的表达发挥治疗作用。由此更进一步证实了临床上治疗变应性鼻炎获得良好疗效的药理药效机理。
本发明将苍芷通鼻滴雾剂应用于防治变应性鼻炎，并对该中药组合物的药理作用进行了动物模型上的药理药效的随机对照实验，结果证实苍芷通鼻滴雾剂对大鼠变应性鼻炎的症状有明显的改善作用，对其鼻粘膜的损伤有修复作用。通过抑制变应性鼻炎发生过程中促炎因子表达，增强抑炎因子的表达发挥治疗作用。由此更进一步证实了临床上治疗变应性鼻炎获得良好疗效的药理药效机理。本发明的中药组合物经发明人几十上百次的实验证明：只有在一定的重量份配比下制备得到的苍芷通鼻滴雾剂才具有非常好的治疗变应性鼻炎的作用。
动物模型的药理药效的随机对照实验方法：
将60只SD大鼠随机分为空白对照组，模型组，苍芷通鼻滴雾剂低剂量组，苍芷通鼻滴雾剂高剂量组，阳性组(丙酸倍氯米松)。除对照组外，其余各组腹腔注射1ml含0.3mg卵清蛋白蛋白的氢氧化铝佐剂溶液致敏，隔天一次，14天共7次。造模第15天开始，用10μl 10％的卵清蛋白生理盐水滴鼻激发，每天一次共8天。第23天开始，继续用10μl 10％的卵清蛋白生理盐水滴鼻维持，每天一次。维持期同时给予观察药物，给药8天。从造模第15天开始，持续观察大鼠AR行为学指标。给药结束后取材，HE、AB-PAS、Masson染色观察鼻黏膜的病理改变，Elisa法检测大鼠血清中ECP,IgE,IL-4,IL-5,IL-13,TGF-β1,TGFβ2的含量，Westernblot方法检测大鼠鼻黏膜中T-bet和GATA3的表达。
实验结果：OVA致敏后，大鼠行为学分数明显升高，给药之后显著降低。OVA造模后模型组黏膜充血，水肿，炎细胞浸润明显，基底层胶原增多，杯状细胞明显增多。给药后充血，水肿程度降低，炎症浸润有一定程度降低，胶原减少，杯状细胞数量有所下降。造模后IL-4，IL-5明显升高，给药后显著降低。IFN-γ、TGF-β2造模之后显著降低，在给药之后显著升高。T-bet和GATA3造模后显著升高，给药后显著降低。
实验结论：苍芷通鼻滴雾剂对大鼠变应性鼻炎的症状有改善作用，对其鼻粘膜的损伤有修复作用。苍芷通鼻滴雾剂通过抑制变应性鼻炎发生过程中促炎因子表达，增强抑炎因子的表达发挥治疗作用。
具体实验方法及结果分析如下：
1、实验材料
1.1受试药物
苍芷通鼻滴雾剂，由广州天河区中医院提供，批号201703；配制方法：加蒸馏水配制至所需浓度(高剂量组为100％，低剂量组为50％)，使各组给药体积为108μl，分两次滴鼻给药。
丙酸倍氯米松(源叶生物，Lot:Y15F7X9688)，浓度：0.33mg/ml。
1.2实验试剂
Albumin from chicken egg white(OVA)(Sigma，Lot#SLBQ9036V)；大鼠嗜酸性粒细胞阳离子蛋白(ECP)ELISAKit(武汉华美，Lot：A03348524)；大鼠白介素4(IL-4)ELISAKit(武汉华美，Lot:Y13017052)；大鼠白介素5(IL-5)ELISA Kit(武汉华美，Lot:Z12018228)；大鼠转化生长因子β1(TGF-β1)ELISA kit(武汉华美，Lot:Y13010537)；大鼠转化生长因子β2(TGF-β2)ELISA Kit(武汉华美,Lot:Y13357452)；大鼠白介素13(IL-13)ELISA KIT(武汉华美，Lot:A03018902)；大鼠免疫球蛋白E(IgE)ELISAKit(武汉华美，Z130235228)；大鼠卵清蛋白特异性IgE(OVA sIgE)ELISAKit(武汉华美，Y1915683)；大鼠IFN-γElisa kit(RayBio，Lot：090718 0732)；Anti T-bet小鼠单克隆抗体(abcam，Lot:GR21130-13)；Anti GATA3兔多克隆抗体(abcam,Lot:GR3190040-5)；山羊抗小鼠HRP二抗(abcam，Lot：GR3196451-6)；山羊抗兔HRP二抗(CST,Lot:102118S)
1.3试验仪器
1510型全波长酶标仪(Thermo Fisher Scientific)；T10电动匀浆器(德国IKA)；DYY-7C电泳仪(北京六一生物科技有限公司)；DYY-7C转膜仪(北京六一生物科技有限公司)；Tanon-5200曝光仪(上海天能科技有限公司)；D3024R高速冷冻离心机(美国SCILOGEX)；STP120组织脱水机(Thermo Fisher Scientific)；HistoStar组织包埋机(Thermo Fisher Scientific)；HM340E石蜡切片机(Thermo Fisher Scientific)；GeminiAS自动染色机(Thermo Fisher Scientific)；BX53荧光正置显微镜(OLYMPUS公司)
1.4实验动物
SD大鼠，体重160-180g，60只，SPF级，由广东省医学实验动物中心提供，，许可证号：SCXK(粤)2013-0002，适应性饲养3天后实验。经过广州中医药大学伦理学审查批准进行实验。
2、实验方法及结果
2.1动物分组、造模及给药方法
所有大鼠适应性喂养3天后，根据体重随机分成对照组和药物组。药物组腹腔注射1ml含0.3mg卵清蛋白蛋白的氢氧化铝佐剂溶液致敏，对照组腹腔注射等量生理盐水，隔天一次，14天共7次。第15天开始，用10μl10％的卵清蛋白生理盐水溶液滴鼻激发，每天1次共8天，并对药物组的AR行为学进行打分。根据AR行为学分值和体重，将药物组随机分为模型组，阳性组，低剂量组，高剂量组。第23天开始，继续用10μl10％的卵清蛋白生理盐水滴鼻维持，每天一次。维持期同时给予观察药物，阳性组给予丙酸倍氯米松，根据AR行为学分值确定最后取材时间为给药8天。
2.2行为学观察
每组大鼠分成两笼饲养，从第15天激发开始，每天观察大鼠AR行为学，每只老鼠由四人单独评分，评分标准如表1，总分大于5分则造模成功。
表1行为学评分标准
2.3取材方法
1.腹主动脉取血
麻醉后腹主动脉取血，使用10ml无添加剂真空采血管，取好后室温(24℃)静置1.5小时后于室温、3800RPM、15min离心，吸取血清分装成8管，-80℃冻存。
2.取鼻中隔和周围组织
先取5mm以上鼻中隔放入10％中性福尔马林中固定做病理切片观察；另刮下鼻腔两侧鼻黏膜放入EP管置于液氮冻存。
3.取肺，肝，脾
取右肺，生理盐水清洗后滤纸吸干，称重，分成气管连接部分和其他部分，均液氮冻存。取肝，生理盐水清洗后滤纸吸干，取最大叶3部分，第一部分长宽5mm，放入10％中性福尔马林固定并标号，第2、3部分超过100mg液氮冻存。取脾，生理盐水清洗后滤纸吸干，称重，分装成两部分，每部分要多于100mg液氮冻存。
2.4各项指标的检测
2.4.1病理学染色
鼻中隔组织在4℃固定24小时后，EDTA脱钙一周，经病理学专家判断到达脱钙终点后，脱水，石蜡包埋，切片，进行常规HE、Masson和AB-PAS染色。
2.4.2 Elisa检测
100mg肺组织加1mlPBS，匀浆后-20℃过夜，反复冻融2次后，5000×g，4℃离心5分钟，上清分装后-20℃保存。根据预实验结果及试剂盒特异性，选择血清或肺组织匀浆按照试剂盒说明书检测。
2.4.3 Western Blot检测
将鼻黏膜组织加入RIPA裂解液，使用电动匀浆器进行匀浆。上清蛋白定量后加入上样缓冲液，煮沸变性。使用8％分离胶，10μg上样，150V，60分钟电泳，300mAh湿法转膜，BSA封闭一小时，一抗4℃过夜，二抗室温孵育1小时后显影。通过ImageJ软件，测量条带灰度值，与内参比对计算蛋白相对表达量。
2.4.4统计学方法
使用Prism 7进行单因素方差分析，组间比较使用多重T检验。
2.5实验结果
2.5.1苍芷通鼻滴雾剂对变应性鼻炎大鼠行为学的影响
第23天开始给药前，药物组各组行为学分值均大于5，提示变应性鼻炎模型复制成功，各给药组之间，行为学分值与体重均无统计学差异(图1)，提示给药前各组的个体差异不大。给药第8天，低剂量、高剂量和阳性组的行为学分值显著下降(图2)，提示苍芷通鼻滴雾剂对变应性鼻炎大鼠的喷嚏、流涕及鼻痒的症状有改善作用。
2.5.2苍芷通鼻滴雾剂对变应性鼻炎大鼠鼻粘膜结构的影响
OVA造模后，HE染色显示，大鼠鼻黏膜水肿、充血明显，炎细胞浸润，杯状细胞化生明显(图3第一排箭头所示)，Masson染色显示模型组胶原沉积增多，(图3第二排箭头所示)，AB-PAS染色显示，模型组杯状细胞出现增生(图3第三排箭头所示)；给药组上述各指标均有明显改善。提示苍芷通鼻滴雾剂变应性鼻炎大鼠鼻黏膜的病理改变有改善作用。第一排箭头指示黏膜水肿、充血及炎症浸润；第二排箭头指示:胶原沉积；第三排箭头指示：杯状细胞
2.5.3苍芷通鼻滴雾剂对变应性鼻炎大鼠炎症因子的变化
造模后，OVAsIgE造模后显著升高(图4A)，提示OVA造模成功。
造模后，血清IL-4及肺IL-5显著升高，IFN-γ、TGF-β2显著降低；给药后各组IL-4、IL-5均显著降低；IFN-γ、TGF-β2显著升高(图4B-E)。提示苍芷通鼻滴雾剂能抑制变应性鼻炎大鼠的促炎因子(IL-4、IL-5)表达、增强抑炎因子(IFN-γ)的表达发挥抗炎作用；通过促进TGF-β2表现出对于粘膜修复作用。
造模后血清中总IgE、ECP、IL-13、TGF-β1与正常组比较无差异(图4F-I)。
2.5.4苍芷通鼻滴雾剂对变应性鼻炎大鼠T-bet和GATA3表达的影响
OVA造模后，大鼠鼻黏膜中T-bet和GATA3显著上升，给药后显著下降(图5)。提示苍芷通鼻滴雾剂通过抑制GATA3以抑制变应性鼻炎大鼠促炎因子的表达。
结论：
变应性鼻炎(allergic rhinitis,AR)，是由IgE介导、Th2细胞免疫反应增强以及Th2细胞因子IL-4、IL-5等增加所致的嗜酸性粒细胞浸润为主的鼻黏膜Ⅰ型超敏反应。GATA3可以促进Th细胞向Th2细胞分化，诱导IL-4、IL-5上调。IL-4、IL-5这类Th2炎症因子可以作用于嗜酸性粒细胞、嗜碱性粒细胞和肥大细胞后产生多种效应，并可以促进B细胞合成特异性sIgE，释放组胺，前列腺素，白三烯等炎症介质，产生过敏症状。
T-bet可以介导Th细胞向Th1细胞分化，诱导抗炎因子IFN-γ的产生。IFN-γ能抑制Th细胞向Th2细胞分化，减少促炎因子IL-4、IL-5的产生。从而抑制IgE，减轻变应性鼻炎。
TGF-β2可以促进气管中上皮细胞的增殖，修复损伤粘膜。
本研究采用OVA诱导的大鼠变应性鼻炎模型，通过观察行为学、病理改变、炎症因子及相关免疫蛋白的表达，研究苍芷通鼻滴雾剂对变应性鼻炎大鼠的治疗效果及初步机制。
实验结果显示，苍芷通鼻滴雾剂能够减轻变应性鼻炎大鼠鼻痒，流涕和喷嚏的症状，且具有剂量依赖性；病理染色显示苍芷通鼻滴雾剂能够改善鼻黏膜水肿和充血，减轻胶原沉积，减少杯状细胞的化生；同时能够降低促炎因子IL-4，IL-5，及GATA3的表达，增加抗炎因子IFN-γ的分泌，上调TGF-β2。提示苍芷通鼻滴雾剂可能是通过降低GATA3的表达，增加IFN-γ的分泌，从而减少Th细胞向Th2分化，进而减少IL-4、IL-5的产生，减少IgE的生成，增加TGF-β2的分泌，从而减小下游炎症效应，增强上皮的修复，从而改善鼻黏膜炎症，起到预防和治疗变应性鼻炎的作用。
T-bet的表达情况与文献中记录不一致，但从T-bet蛋白下游的抗炎因子IFN-γ的变化可以看出，苍芷通鼻滴雾剂可以上调OVA造模后减少的IFN-γ，IFN-γ的变化与文献报道相符[5]。实验中T-bet模型组的过度升高可能是因为OVA致敏过程中的短时间动态变化，后期可考虑增加观察时间点，从而得到更准确的T-bet变化情况。
Claims (5)
1.一种苍芷通鼻滴雾剂，其特征在于：所述滴雾剂的组分和各组分的重量份为：薄荷300份、牡丹皮300份、枳实300份、苍耳子150份、白芷150份、辛夷花150份、川芎150份；
所述苍芷通鼻滴雾剂的制备方法，包括以下步骤：
（ⅰ）提取辛夷花、牡丹皮、薄荷的挥发油
取预定量的薄荷、牡丹皮、辛夷花，辛夷花、牡丹皮打粗粉，合并薄荷，利用水蒸气蒸馏法提取挥发油，备用；
（ⅱ）苍耳子、川芎、白芷、枳实醇提
取预定量苍耳子、白芷、川芎、枳实，打粗粉，加入四者质量总和的六倍量的80％的乙醇回流三次，过滤，合并滤液，回收乙醇至滤液中乙醇质量百分比含量低于0.5％，置-4℃静置2-4h，取上层油层提取物即苍耳子、白芷、川芎、枳实备用，下层过滤；加入浸膏10倍量的水洗涤二次，分出水层后，置蒸发锅中挥去残余水分，即得四味药的提取混合物；
（ⅲ）苍芷通鼻滴雾药液的制备
将步骤（ⅰ）和（ⅱ）所有的提取物合并，加入一定量吐温混匀，再向滤液中加入10%甘油、0.5%苯甲酸钠、0.9%氯化钠，灭菌分装，即得苍芷通鼻滴雾药液；
（ⅳ）苍芷通鼻滴雾剂
将步骤（ⅲ）得到的苍芷通鼻滴雾药液在常压下灌装至具有喷头的塑料瓶中即得。
2.根据权利要求1所述的苍芷通鼻滴雾剂的制备方法，其特征在于：包括以下步骤：
（ⅰ）提取辛夷花、牡丹皮、薄荷的挥发油
取预定量的薄荷、牡丹皮、辛夷花，辛夷花、牡丹皮打粗粉，合并薄荷，利用水蒸气蒸馏法提取挥发油，备用；
（ⅱ）苍耳子、川芎、白芷、枳实醇提
取预定量的苍耳子、白芷、川芎、枳实，打粗粉，加入四者质量总和的六倍量的80％的乙醇回流三次，过滤，合并滤液，回收乙醇至滤液中乙醇质量百分比含量低于0.5％，置-4℃静置2-4h，取上层油层提取物即苍耳子、白芷、川芎、枳实备用，下层过滤；加入浸膏10倍量的水洗涤二次，分出水层后，置蒸发锅中挥去残余水分，即得四味药的提取混合物；
（ⅲ）苍芷通鼻滴雾药液的制备
将步骤（ⅰ）和（ⅱ）所有的提取物合并，加入一定量吐温混匀，再向滤液中加入10%甘油、0.5%苯甲酸钠、0.9%氯化钠，灭菌分装，即得苍芷通鼻滴雾药液；
（ⅳ）苍芷通鼻滴雾剂
将步骤（ⅲ）得到的苍芷通鼻滴雾药液在常压下灌装至具有喷头的塑料瓶中即得。
3.根据权利要求2所述的苍芷通鼻滴雾剂的制备方法，其特征在于：所述步骤（ⅰ）的具体方法为：取预定量的辛夷花、牡丹皮打粗粉，粗粉中加入薄荷，再加入一定量的水，进行水蒸气蒸馏，收集10~15倍馏液，重蒸馏，收集2~4倍量的馏液，获得辛夷花、牡丹皮、薄荷的挥发油；所述步骤（ⅱ）乙醇回流提取三次，第一次两小时，第二、三次各一小时。
4.根据权利要求3所述的苍芷通鼻滴雾剂的制备方法，其特征在于：所述步骤（ⅰ）水蒸气蒸馏法提取辛夷花、牡丹皮、薄荷的挥发油中水蒸气蒸馏收集13倍馏液，重蒸馏时收集3倍馏液。
5.一种权利要求1所述苍芷通鼻滴雾剂在制备防治变应性鼻炎药物中的应用。
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