CN115105480A - 一种藿香正气片及其制备方法 - Google Patents
一种藿香正气片及其制备方法 Download PDFInfo
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- CN115105480A CN115105480A CN202110292012.6A CN202110292012A CN115105480A CN 115105480 A CN115105480 A CN 115105480A CN 202110292012 A CN202110292012 A CN 202110292012A CN 115105480 A CN115105480 A CN 115105480A
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Abstract
本发明提供了一种藿香正气片及其制备方法，所述藿香正气片的组方为：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；还包括辅料，所述辅料包括崩解剂24.8‑35.2g、润滑剂8‑13g，片剂的规格为0.6‑0.7g/片。本发明所述的藿香正气片为大规格片剂，通过对辅料的用法、用量的优化以及对水提液预处理，使大规格片剂的可压性良好、药物的溶出性能有所改善；为避免药性发生变化，申请人利用有机溶剂对生半夏细粉进行萃取；结合对生半夏的预处理以及浓缩过程的优化以确保药效，止泻效果明显，疗效确切。
Description
技术领域
本发明涉及中药制剂技术领域，特别涉及一种藿香正气片及其制备方法。
背景技术
藿香正气为传统中成药，组方中的藿香味辛性微温，既解表散风寒，又芳香化湿浊，辟秽和中，升清降浊，为君药：紫苏叶和白芷辛温发散，助藿香外散风寒，芳化湿浊，为臣药；厚朴和大腹皮行气燥湿、除满消胀，半夏和陈皮燥湿和胃、降逆止呕，茯苓和白术燥湿健脾、和中止泻，桔梗理气化痰，共为佐药；甘草调和脾胃、调和药性，为使药。诸药合用，内外兼治，表里双解，风寒得解，湿滞得化，清升浊降，气机通暢，共奏解表化湿、理气和中之功；用于外感风寒，内伤湿滞，头痛昏重，胸隔痞闷，脘腹胀痛，呕吐泄泻。
目前常用剂型有口服液、丸剂、胶囊剂、片剂。其中藿香正气片为传统成方“藿香正气散”的变更剂型，于1998年收入卫生部中成药成方制剂第15册，由于其具有含量准确，稳定性好，同时克服了原有剂型中带有的刺激性气味，同时可以避免酒精的残留，安全性优而深受好评。
现有的制备方法为：以上十味，白芷粉碎成细粉，备用；陈皮提取挥发油与广藿香油、紫苏叶油混合后用乙醇适量溶解，备用；提油后的水溶液留用，药渣加水煎煮1小时，滤过，滤液备用；大腹皮、茯苓加水煎煮二次，第一次2小时，第二次1小时，滤过，合并滤液，加入提油后的水溶液和上述滤液，滤过，滤液备用；生半夏用冷水浸泡，8h换水一次，泡制透心后另加干姜，加水煎煮二次，滤过，合并滤液，加入上述滤液和甘草浸膏，浓缩至相对密度为1.2-1.3(55℃)的清膏；白芷,苍术、厚朴用60％乙醇回流提取三次，第一次6小时，第二次4小时，第三次2小时，合并上述乙醇提取液，滤过，滤液回收乙醇，浓缩成膏；合并水、醇浓缩膏，加入白芷细粉及辅料适量，混匀制粒干燥，兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液，混匀压制成片，或包薄膜衣，即得。
现有藿香正气片的组方、制法均固定，且采用小规格(0.3g/片)以确保药效；但存在服用繁琐、包装成本高等不足，开发大规格的藿香正气片具有重要意义。如CN105079362A公开了一种藿香正气片(0.5-0.6g/片)，在传统组方的基础上，用连续动态的乙醇进行提取半夏等，虽如琥珀酸等活性成分含量高，但片剂的可压性、溶出性能均有待改善，药效并不理想。
发明内容
有鉴于此，本发明旨在提出一种藿香正气片及其制备方法，以解决利用现有技术中大规格的藿香正气片存在可压性差、溶出效果不佳等不足。
为达到上述目的，本发明的技术方案是这样实现的：一种藿香正气片，组方为：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；还包括辅料，所述辅料包括崩解剂24.8-35.2g、润滑剂8-13g，片剂的规格为0.6-0.7g/片。
优选的，所述崩解剂包括低取代羟丙纤维素，还包括羧甲基纤维素钠、聚乙烯吡咯烷酮、羧甲基淀粉钠中的至少一种。优选的，所述崩解剂由低取代羟丙纤维素：羧甲基纤维素钠＝5:3组成。
优选的，所述的润滑剂为硬脂酸镁、硬脂酸富马酸钠、硅酸铝镁和二氧化硅中的一种或几种。
优选的，所述辅料还包括稀释剂8-14g，所述稀释剂为乳糖一水合物；优选的，乳糖一水合物的D90＜5μm。
优选的，所述片剂的规格为0.63-0.66g/片，如0.65g/片。
本发明还提供了一种藿香正气片的制备方法，包括下述步骤：
(1)预处理 将生半夏，白芷150g分别粉碎成细粉，过80目筛备用；陈皮提取挥发油与藿香油、紫苏子叶油混合后用0.7-1.2倍(v/v)乙醇溶解备用；所述陈皮提油工艺为现有技术，在此不进行赘述。
(2)提取 陈皮药渣投至1.8-2.2倍(v/m)沸水中煎煮1-1.5h；大腹皮、茯苓投至2.2-2.5倍(v/m)沸水中煎煮两次，每次1-2h，合并上述水煎液，过滤、浓缩成膏至相对密度1.2-1.3(50-60℃)；白芷90g、苍术、厚朴用2.5-3.0倍(v/m)60-65％乙醇回流提取三次，每次2-6h，合并上述醇提液，过滤、浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过80目筛备用；
(3)制粒 将步骤(2)制备的细粉与乳糖一水合物(D90＜5μm)混匀，再用气流粉碎机粉碎，制得微粒(D90＜10μm)；将微粒、生半夏、白芷细粉以及42-63％崩解剂混匀，按1：5-8(ml/g)加入乙醇润湿，搅拌5-10min，制粒、干燥、整粒；
(4)压片 取润滑剂、余量崩解剂与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，压片、包衣、即得。
优选的，所述包衣用包衣液的制备方法为：取硬脂酸镁15份、羟丙甲基纤维素21份、共聚维酮7份、聚乙烯醇11份、聚乙二醇3008份、胶体MCC1份、纯化水9份及乙醇(质量浓度为99％)1份，均匀混合1h，40℃干燥5h，其中胶体MCC中微晶纤维素和羧甲基纤维素钠的重量比为1.2：8.8，取中间体检测，水分的含量≤5％的即为合格；合格后，加入上述质量份的果绿色淀2份、钛白粉13份，混合0.8h后，转移至研磨机研磨4h，即得。利用胃溶性包衣，可使片剂进入胃部后逐渐释放，改善药物的生物利用度。
优选的，步骤(2)中过滤、浓缩成膏为：0.25μm滤膜过滤，浓缩至原体积的1/3后，将煎提液降至8-12℃，同时通入二氧化碳气体使溶液pH为5.4-5.6，加炭12-18g搅拌20-30min过滤，收集滤液，继续浓缩至相对密度1.2-1.3(50-60℃)膏。低温下二氧化碳的溶解度更大，利用温度与pH协同作用，降低杂质溶解度，确保除杂效果。优选的，将步骤(4)中所述润滑剂在步骤(3)浓缩成膏前加入，如收集滤液，加入4g硬脂酸镁，继续浓缩至相对密度1.2-1.3(50-60℃)膏。
优选的，步骤(3)中生半夏细粉采用下述方式提取：生半夏细粉加入3.5-4.5倍(v/m)有机溶剂，50-55℃搅拌萃取2.0-2.5h，静置1.5-3.0h分层后，分离有机相、浓干，粉碎过80目筛。优选的，所述有机溶剂为正丁醇、乙酸乙酯、环己烷中的任意一种。优选的，分离的有机相用0.2倍(v/v)饱和食盐水洗涤两次后浓干。
优选的，步骤(1)中，所述生半夏进行如下预处理：取生半夏粉碎成细粉，过80目筛，加入0.5-0.6倍(m/m)水冷冻-即室温下4.5-5min降温至4-6℃，保温20-25min；之后12-15min降温至-20～-25℃，保温15-35min，5-10min内加热至煮沸，煎煮0.5-1h后冷冻干燥。通过上述冷冻方式使细胞内形成较大冰晶，对细胞壁造成破坏，保持大粒径，避免超微粉等操作导致细胞内容物大量释放；利用快速煮沸使温度剧烈变化实现预提取，提高有机溶剂提取收率；相对于烘干而言，通过冷冻干燥可使避免生半夏细粉重新结块，提取效果佳。优选的，所述冷冻干燥采用分段冷冻干燥方法进行，所述分段冷冻干燥具体包括下述步骤：S1.将所述煎煮混合液在-60℃至-40℃的温度条件下冷冻10-25min；S2.再在-20℃至0℃和30-50Pa的温度和压力条件下冷冻10-25min；S3.之后在0℃至5℃和1000-1200Pa的温度和压力条件下冷冻30-60min；S4.以0.1-0.2℃/min的升温速率和40-100Pa/min的升压速率将温度和压力升高至20-25℃和10kPa的条件下，保持40-60min。通过分段冷冻干燥使生半夏细粉形成中空结构，便于有机溶剂提取液的浸入，提取效果佳。通过分段冻干，能够使生半夏细粉的形成细微流道，便于有机溶剂提取液的浸入。
优选的，步骤(3)中所述乳糖一水合物的用量为8-14g。优选的，步骤(3)中所述气流粉碎机的运行参数为：压力0.35-0.4MPa，进料速度为0.5-0.6g/min，环境湿度≤40％。
相对于现有技术，本发明所述的藿香正气片及其制备方法具有以下优势：
本发明所述藿香正气片通过对辅料的用法、用量的优化，使大规格片剂的可压性良好、药物的溶出性能有所改善；对水提液进行降温，同时通入CO2调pH，利用pH与温度的协同效应以降低部分杂质的溶解度，除杂效果好，改善活性成分的溶出；CO2调pH过程可逆，且不会引起局部的强酸、碱；(2)生半夏性味辛、温，有毒；归脾、胃、肺经；在上述改进的基础上，申请人利用有机溶剂萃取细粉后加入以避免药性变化引起安全性问题；(3)为了确保药效，申请人对生半夏进行预处理以提高其收率；同时，研究发现：浓缩成膏时，药液的粘度逐渐增大，易粘结在器壁上，造成浓缩时间长、收率低；申请人通过研究发现：浓缩前加入部分润滑剂，可起到抗粘剂的作用，收率高，药效进一步改善。
具体实施方式
需要说明的是，在不冲突的情况下，本发明中的实施例及实施例中的特征可以相互组合。
下面将结合实施例来详细说明本发明。
藿香正气片作为传统的中成药，具有解表化湿，理气和中之功效，疗效确切。由于传统制法中采用水煎提取，有效成分含量低，且杂质多，易粘结、片剂可压性差，通常以小规格(0.3g/片)服用以保证药效，但存在服用繁琐、包装成本高等不足；一方面，片剂规格与比表面积密切相关，影响活性成分的释放，进而影响其药效。简单的将小规格改成大规格，仅通过提取工艺改进，最终片剂的可压性较差，导致药效并不理想，如CN105079362A；另一方面，藿香正气片中含有半夏，具有一定的毒性；片剂的规格、溶出等改进对片剂的毒副作用的影响也需关注。
申请人为解决制备的大规格藿香正气片存在溶出不佳等问题进行大量研究，发现辅料的选择、用法对其溶出效果产生影响；具体的，当采用单独的羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素作为崩解剂，片剂的可压性、溶出及药效均难以满足要求；而传统水提工艺中滤液含有大量水溶性杂质，遇水易粘结，也会影响大规格片剂的溶出及药效。大规格片剂的溶出性能大幅改进后，其药性有也所变化；相关动物实验表明，处方中生半夏细粉在快速崩解时存在一定的不良作用；而随生半夏提取工艺的改变，其毒性减弱的同时，最终的药效也有所降低；需要对生半夏的提取工艺进一步优化，以改善大规格片剂的药效；此外，申请人还发现水提液浓缩成膏过程中，由于料液粘度较大，易粘附在器壁上，导致浓缩时间长，效率低、损耗较大，也是药效不佳的原因之一。
实施例1
一种藿香正气片，处方为：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；辅料：硬脂酸镁10g、乳糖一水合物14g、低取代羟丙纤维素16g、羧甲基纤维素钠9.6g；
制备方法包括：
(1)预处理 将生半夏，白芷150g分别粉碎成细粉，过80目筛备用；陈皮提取挥发油与藿香油、紫苏子叶油混合后用0.7倍(v/v)乙醇溶解备用；
(2)提取 陈皮药渣投至2.2倍(v/m)沸水中煎煮一次，时间1h；大腹皮、茯苓投至2.5倍(v/m)沸水中煎煮两次，第一次2h，第二次1h，合并上述水煎液，0.25μm滤膜过滤、浓缩至相对密度1.2-1.3(50-60℃)的稠膏；白芷90g、苍术、厚朴用3.0倍(v/m)60％乙醇回流提取三次，第一次6h，第二次4h，第三次2h，合并上述醇提液，0.25μm过滤并浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过80目筛备用；
(3)制粒 将步骤(2)制备的细粉与乳糖一水合物(D90＜5μm)14g混匀，再用气流粉碎机(压力为0.4MPa，进料速度为0.6g/min，环境湿度≤40％)粉碎，制得微粒(D90＜10μm)；将微粒、生半夏、白芷细粉以及低取代羟丙纤维素10g、羧甲基纤维素钠6g混匀，按1：8(ml/g)加入乙醇润湿，搅拌10分钟，用16目筛制粒，70℃±5℃鼓风干燥，干颗粒过16目筛整粒；
(4)压片 再取低取代羟丙纤维素6g、羧甲基纤维素钠3.6g、硬脂酸镁10g与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，样检合格后、压制900片、包衣，规格：每片0.65g/片，即得。
实施例2
一种藿香正气片，处方为：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；辅料：硬脂酸镁12g、乳糖一水合物10g、低取代羟丙纤维素15.5g、羧甲基纤维素钠9.3g；
制备方法包括：
(1)预处理 将生半夏，白芷150g分别粉碎成细粉，过80目筛备用；陈皮提取挥发油与藿香油、紫苏子叶油混合后用1.2倍(v/v)乙醇溶解备用；
(2)提取 陈皮药渣投至1.8倍(v/m)沸水中煎煮一次，时间1h；大腹皮、茯苓投至2.4倍(v/m)沸水中煎煮两次，第一次2h，第二次1h，合并上述水煎液，0.25μm滤膜过滤，浓缩至原体积的1/3后，将煎提液降至10℃，同时通入二氧化碳气体使溶液pH为5.4，加炭15g搅拌30min过滤，收集滤液，继续浓缩至相对密度1.2-1.3(50-60℃)膏；白芷90g、苍术、厚朴用2.8倍(v/m)65％乙醇回流提取三次，第一次5h，第二次3h，第三次3h，合并上述醇提液，过滤并浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过筛备用；
(3)制粒 将步骤(2)制备的细粉与乳糖一水合物(D90＜5μm)10g混匀，再用气流粉碎机(压力为0.35MPa，进料速度为0.56g/min，环境湿度≤39％)粉碎，制得微粒(D90＜10μm)；将微粒、生半夏、白芷细粉以及低取代羟丙纤维素8g、羧甲基纤维素钠4.8g混匀，按1：5(ml/g)加入乙醇，搅拌10分钟，用16目筛制粒，70℃±5℃鼓风干燥，干颗粒过16目筛整粒；
(4)压片 再取低取代羟丙纤维素7.5g、羧甲基纤维素钠4.5g、硬脂酸镁12g与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，样检合格后、压制900片、包衣，规格：每片0.63g/片，即得。
实施例3
处方：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；辅料：硬脂酸镁8g、乳糖一水合物9g、低取代羟丙纤维素22g、羧甲基纤维素钠13.2g；
制备方法包括：
(1)预处理 将生半夏，白芷150g分别粉碎成细粉，过80目筛备用；陈皮提取挥发油与藿香油、紫苏子叶油混合后用0.9倍(v/v)乙醇溶解备用；
(2)提取 陈皮药渣投至2.2倍(v/m)沸水中煎煮一次，时间1h；大腹皮、茯苓投至2.5倍(v/m)沸水中煎煮两次，第一次2h，第二次1h，合并上述水煎液，浓缩至原体积的1/3后，将煎提液降至12℃，搅拌通入二氧化碳气体使溶液pH为5.5，加炭12g搅拌25min过滤，收集滤液，继续浓缩至相对密度1.2-1.3(50-60℃)膏；白芷90g、苍术、厚朴用3.0倍(v/m)60％乙醇回流提取三次，第一次5h，第二次4h，第三次3h，合并上述醇提液，过滤并浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过筛备用；生半夏加入3.5倍(v/m)乙酸乙酯，52℃搅拌萃取2.0h，静置1.5h分层后，分离上层有机相，浓干萃取液；
(3)制粒 将步骤(2)制备的膏粉、浓干物与乳糖一水合物(D90＜5μm)9g混匀，再用气流粉碎机(压力为0.42MPa，进料速度为0.63g/min，环境湿度≤40％)粉碎，制得微粒(D90＜10μm)；将微粒、白芷细粉以及低取代羟丙纤维素12g、羧甲基纤维素钠7.2g混匀，按1：6(ml/g)加入乙醇润湿，搅拌8分钟，用16目筛制粒，70℃±5℃鼓风干燥，干颗粒过16目筛整粒；
(4)压片 再取低取代羟丙纤维素10g、羧甲基纤维素钠6g、硬脂酸镁8g与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，样检合格后、压制900片、包衣，规格：每片0.66g/片，即得。
实施例4
处方：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；
辅料：硬脂酸镁13g、乳糖一水合物9g、低取代羟丙纤维素17.5g、羧甲基纤维素钠10.5g；
制备方法包括：
(1)预处理 取白芷150g分别粉碎成细粉，过80目筛备用；取生半夏粉碎成细粉，过80目筛，加入0.5倍(m/m)水冷冻-即室温下5min降温至4℃，保温25min；之后15min降温至-25℃，保温35min，10min内加热至煮沸，煎煮1h后冷冻干燥以去除水分；陈皮提取挥发油与藿香油、紫苏子叶油混合后用0.7倍(v/v)乙醇溶解备用；
(2)提取 陈皮药渣投至2.0倍(v/m)沸水中煎煮一次，时间1h；大腹皮、茯苓投至2.2倍(v/m)沸水中煎煮两次，第一次2h，第二次1h，合并上述水煎液，浓缩至原体积的1/3后，将煎提液降至8℃，通入二氧化碳气体使溶液pH为5.4，加炭18g搅拌20min过滤，收集滤液，继续浓缩至相对密度1.2-1.3(50-60℃)膏；白芷90g、苍术、厚朴用2.5倍(v/m)62％乙醇回流提取三次，第一次6h，第二次4h，第三次2h，合并上述醇提液，过滤并浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过筛备用；生半夏加入4倍(v/m)环己烷，50℃搅拌萃取2.5h，静置3h分层后，分离上层有机相，用0.2倍(v/v))饱和食盐水洗涤两次，干燥、浓干萃取液；
(3)制粒 将步骤(2)制备的膏粉、浓干物与乳糖一水合物(D90＜5μm)9g混匀，再用气流粉碎机(压力为0.4MPa，进料速度为0.6g/min，环境湿度≤40％)粉碎，制得微粒(D90＜10μm)；将微粒、白芷细粉以及低取代羟丙纤维素7.5g、羧甲基纤维素钠4.5g混匀，按1：8(ml/g)加入乙醇润湿，搅拌5分钟，用16目筛制粒，70℃±5℃鼓风干燥，干颗粒过16目筛整粒；
(4)压片 再取低取代羟丙纤维素10g、羧甲基纤维素钠6g、硬脂酸镁13g与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，样检合格后、压制900片、包衣，规格：每片0.66g/片，即得。
实施例5
处方：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；
辅料：硬脂酸镁13g、乳糖一水合物8g、低取代羟丙纤维素17.5g、羧甲基纤维素钠10.5g；
制备方法包括：
(1)预处理 取白芷150g分别粉碎成细粉，过80目筛备用；取生半夏粉碎成细粉，过80目筛，加入0.6倍(m/m)水冷冻-即室温下4.5min降温至6℃，保温20min；之后12min降温至-20℃，保温15min，3min内加热至煮沸，煎煮30min后进行分段冷冻干燥；陈皮提取挥发油与藿香油、紫苏子叶油混合后用0.7倍(v/v)乙醇溶解备用；
所述分段冷冻干燥为：S1.将所述煎煮液在-40℃下冷冻15min；S2.再在-15℃、40Pa下冷冻15min；S3.之后在4℃和1000Pa下冷冻45min；S4.以0.15℃/min的升温速率升温至22℃和75Pa/min的升压速率升压至10kPa的条件下，保持50min。
所述分段冷冻干燥具体为：S1.将所述煎煮混合液在-40℃下冷冻25min；S2.再在-15℃和40Pa的温度和压力条件下冷冻15min；S3.之后在0℃和1000Pa下冷冻60min；S4.以0.1℃/min的升温速率和45Pa/min的升压速率将温度和压力升高至22℃和10kPa的条件下，保持60min；
(2)提取 陈皮药渣投至2.0倍(v/m)沸水中煎煮一次，时间1h；大腹皮、茯苓投至2.2倍(v/m)沸水中煎煮两次，第一次2h，第二次1h，合并上述水煎液，浓缩至原体积的1/2后，将煎提液降至10℃，通入二氧化碳气体使溶液pH为5.6，加炭12g搅拌20min过滤，收集滤液，加入4g硬脂酸镁，继续浓缩至相对密度1.2-1.3(50-60℃)膏；白芷90g、苍术、厚朴用2.5倍(v/m)62％乙醇回流提取三次，第一次6h，第二次4h，第三次2h，合并上述醇提液，过滤，加入4g硬脂酸镁并浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过筛备用；生半夏加入4.5倍(v/m)正丁醇，55℃搅拌萃取2.0h，静置2.5h分层后，分离上层正丁醇溶液，用0.2倍(v/v))饱和食盐水洗涤两次，浓干萃取液；
(3)制粒 将步骤(2)制备的膏粉与乳糖一水合物(D90＜5μm)8g混匀，再用气流粉碎机(压力为0.4MPa，进料速度为0.6g/min，环境湿度≤40％)粉碎，制得微粒(D90＜10μm)；将微粒、生半夏、白芷细粉以及低取代羟丙纤维素7.5g、羧甲基纤维素钠4.5g混匀，按1：8(ml/g)加入润湿剂，搅拌8分钟，用16目筛制粒，70℃±5℃鼓风干燥，干颗粒过16目筛整粒；所述润湿剂为木糖醇：90％乙醇水溶液(m/v)＝1:2；
(4)压片 再取低取代羟丙纤维素10g、羧甲基纤维素钠6g、硬脂酸镁5g与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，样检合格后、压制900片、包衣，规格：每片0.65g/片，即得。
对比例1
采用CN105079362A中实施例1的方法制备藿香正气片，规格：0.62g/片。
对比例2
市售藿香正气片(同仁堂，0.3g/片)。
实验例1辅料用量、用法的优化
申请人在研究中发现，改变片剂的规格后，片剂的可压性以及活性成分的溶出性能均有所变化；在组方不变的情况下，对辅料的用法、用量的优化至关重要。
1.1用量、配比的优化
按照下表中的崩解剂种类、用量，采用实施例1的方法制备大规格片剂，参照2010年《中国药典》一部附录中崩解时限检查法测定崩解时间。
表1崩解剂对大规格片剂的崩解时间的优化
由上表可知，大规格的藿香正气片采用低取代羟丙纤维素：羧甲基纤维素钠＝5:3作为崩解剂时，能够缩短其崩解时限，且明显低于对比例2的崩解时限，更易发挥药效。
1.2辅料用法的优化
采用实施例1的组方、方法提取原料，并按照下述工艺分别制备片剂：
实验I组：采用实施例1的方法制备片剂，规格0.65g/片；
实验Ⅱ组：与实施例1的区别在于，将微粒直接与生半夏、白芷细粉以及低取代羟丙纤维素、羧甲基纤维素钠混匀，制粒，将干颗粒与硬脂酸镁以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，制备片剂，规格0.63g/片；
实验Ⅲ组：与实施例1的区别在于，将步骤(2)制备的细粉、生半夏、白芷细粉以及低取代羟丙纤维素、羧甲基纤维素钠、硬脂酸镁兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，压片，制备片剂，规格0.63g/片；
实验Ⅳ组：采用实施例2的方法制备片剂；
观察上述组别的压片效果，取制备的藿香正气片及对比例1-2，利用上海黄海药检SY-2D型片剂四用测试仪测定硬度和脆碎度；
取上述方法制备的片剂2g，以0.1mol/L盐酸500ml为溶剂，50rpm磁力搅拌10分钟时，取溶液5ml，滤过，取续滤液作为供试品溶液；利用高效液相检测百秋李醇(为藿香的代表成分)、琥珀酸(为生半夏的代表成分)、苍术醇(苍术经醇提后的代表成分)、茯苓酸(为茯苓经水提后的代表成分)的溶出度，计算4个数据的平均值作为片剂的溶出度。其中茯苓酸的检测条件为：色谱条件为：Diamonsil C18(2)色谱柱，其规格为250mm×4.6mm，粒径5μm；流动相：乙腈-0.1％甲酸(80％：20％)；柱温：30℃，流速：1.0mL/min，检测波长：210nm；其他检测方法均为现有技术，在此不进行赘述，测定结果见表2。
表2工艺条件对大规格片剂的影响
由表2可知，对比例1中由于生半夏采取连续动态提取工艺，且最终片剂的硬度低、脆碎度高(高于1％)，因此片剂的溶出度高；本申请通过优化辅料的用法、用量，制备大规格的藿香正气片具有可压性好，药物释放性更优。
实验例2片剂的药性研究
传统组方中，生半夏作为佐药之一，具有燥湿和胃、降逆止呕之功效；虽然有毒，但其成药后药性稳定，且单次口服剂量极少，通常被认为是安全、无毒的；申请人研究发现：在制备大规格藿香正气片时，对辅料的用法、用量经优化后，片剂的可压性、溶出性能明显改善，同时其药性有所变化。
取80只Wistar大白鼠(体重70～110g，雌雄兼用)，在20～22℃，相对湿度50％～70％，自然光照下暂养一周，期间可自由取食，自由饮用自来水。
将实验前随机分成8组，各组10只，分别取实施例1-5以及对比例1-2制备的片剂，每日灌胃(15g/kg)给药2次，对照组给与相等剂量的蒸馏水，连续给药40d，记录动物一般行为、状态、食欲、毛色、粪便有无异常，每20d测体重1次，末次给药后16h处死动物，断头、摘取肝、心、肾、胸腺，腺以10％福尔巴林固定，做石蜡切片，HE染色光镜检查。
表3片剂对灌胃大鼠体重的影响
观察发现：第1、2组大鼠在饲喂后期活动有所减少，其中第2组的部分白鼠存在蜷伏、竖毛等症状；相应的，实验1、2组大鼠的体重增加量较对照组有所下降，可能与片剂工艺参数改变后，片剂的溶出性、可压性改善，但药性改变有关，生半夏对白鼠存在一定的刺激性；由表3可知，实施例3-5通过极性小的有机溶剂提取生半夏，最终大鼠体重与对比例2(小规格片剂)无差别，能够改善药性并减小生半夏的刺激性，结果与对照组相当；而对比例1中生半夏采用乙醇动态提取工艺，相对于传统工艺中生半夏细粉直接入药而言，对大鼠的刺激性更强；但对上述白鼠进行切片镜检，均未见明显异常。
实验例3治疗效果
藿香正气片具有解表化湿，理气和中的功效。用于暑湿感冒，头痛身重胸闷，或恶寒发热，脘腹胀痛，呕吐泄泻。一般来说，藿香正气片主要适用于以下几种情况：胃肠型感冒、病毒性感冒和部分类型的流感，腹泻、急慢性胃炎、功能性胃病，夏季受寒引起的胃肠不适，或因饮食不节所致的腹泻、急慢性胃炎、功能性胃病等，通过评价对番泻叶腹泻模型大鼠的止泻作用检验本发明制备的藿香正气片的药效。
3.1实验动物与分组
取健康清洁级Wistar大白鼠100只(体重150±8g，雄性)，适应性饲养7天后实验；单只单笼饲养在恒温(25℃)的动物房中，光照12h，食水随意，每日换笼1次，换水2次。
将大鼠按体重随机分为正常组、治疗1-7组、对照组、模型组共10组，每组10只；治疗组于造模后分别灌胃实施例1-5、对比例1-2制备的片剂，0.9g/150g/次/d，连续3天；对照组于造模后灌胃盐酸小檗碱溶液(0.2g/ml)，3.5ml/150g/次/d，连续3天；模型组灌胃等量生理盐水。
3.2动物模型制备
采用番泻叶诱导大鼠腹泻模型；除正常组外,其余组动物都用番泻叶浓缩液灌胃(3.5ml/150g/次/天)，连续7天造成严重腹泻模型。正常组灌胃等量生理盐水，7天后除去正常组，治疗组大鼠在分别灌胃实施例1-5及对比例1-2制备的片剂(0.9g/150g/次/天)进行干预。
3.3结果
观察灌服番泻叶后6h内的大便情况和治疗后各组大鼠腹泻情况(包括稀便数、总便数、稀便级)，并计算腹泻指数，结果见表4。
腹泻指数的测定：统计稀便数、总便数、稀便级，计算腹泻指数。
腹泻率：一组动物中排稀便的动物数与该组动物总数之百分比。
稀便率：每只动物所排的稀便数与总便数之比。
稀便级：表示稀便的程度。以稀便污染滤纸形成污迹面积的大小定级；分为4级，标准如下：
统计时先逐个统计每一堆稀便的级数，然后将该鼠所有稀便级数相加除以
稀便次数得稀便的平均级数，简称稀便级。
腹泻指数：稀便率与稀便级的乘积。
表4不同组别的腹泻指数
在腹泻模型中应用腹泻指数这一指标可同时考虑稀便量的变化以及质的因素，能够更准确的反应稀便程度；由表4可知，本申请制备的大规格藿香正气片能有效降低大鼠排便次数，稀便程度和数量，有效降低腹泻指数，止泻效果明显，疗效确切。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种藿香正气片，其特征在于，组方为：苍术160g，陈皮160g，厚朴(姜制)160g，白芷240g，茯苓240g，大腹皮240g，生半夏160g，甘草浸膏20g，广藿香油1.6ml，紫苏叶油0.8ml；还包括辅料，所述辅料包括崩解剂24.8-35.2g、润滑剂8-13g，片剂的规格为0.6-0.7g/片。
2.根据权利要求1所述的藿香正气片，其特征在于，所述崩解剂包括低取代羟丙纤维素，还包括羧甲基纤维素钠、聚乙烯吡咯烷酮、羧甲基淀粉钠中的至少一种。
3.根据权利要求2所述的藿香正气片，其特征在于，所述崩解剂由低取代羟丙纤维素：羧甲基纤维素钠＝5:3组成。
4.根据权利要求1所述的藿香正气片，其特征在于，所述的润滑剂为硬脂酸镁、硬脂酸富马酸钠、硅酸铝镁和二氧化硅中的一种或几种。
5.根据权利要求1所述的藿香正气片，其特征在于，所述片剂的规格为0.63-0.66g/片。
6.一种如权利要求1-5任一项所述藿香正气片的制备方法，其特征在于，包括下述步骤：
(1)预处理将生半夏，白芷150g分别粉碎成细粉，过80目筛备用；陈皮提取挥发油与藿香油、紫苏子叶油混合后用0.7-1.2倍(v/v)乙醇溶解备用；
(2)提取陈皮药渣投至1.8-2.2倍(v/m)沸水中煎煮1-1.5h；大腹皮、茯苓投至2.2-2.5倍(v/m)沸水中煎煮两次，每次1-2h，合并上述水煎液，过滤、浓缩成膏至相对密度1.2-1.3(50-60℃)；白芷90g、苍术、厚朴用2.5-3.0倍(v/m)60-65％乙醇回流提取三次，每次2-6h，合并上述醇提液，过滤、浓缩成膏，将上述膏状物与甘草浸膏合并、烘干、粉碎成细粉，过80目筛备用；
(3)制粒将步骤(2)制备的细粉与乳糖一水合物(D90＜5μm)混匀，再用气流粉碎机粉碎，制得微粒(D90＜10μm)；将微粒、生半夏、白芷细粉以及42-63％崩解剂混匀，按1：5-8(ml/g)加入乙醇润湿，搅拌5-10min，制粒、干燥、整粒；
(4)压片取润滑剂、余量崩解剂与干颗粒以及兑入广藿香油、紫苏叶油和陈皮油的乙醇溶液充分混匀，压片、包衣、即得。
7.根据权利要求6所述藿香正气片的制备方法，其特征在于，步骤(2)中过滤、浓缩成膏为：0.25μm滤膜过滤，浓缩至原体积的1/3后，将煎提液降至8-12℃，同时通入二氧化碳气体使溶液pH为5.4-5.6，加炭12-18g搅拌20-30min过滤，收集滤液，继续浓缩至相对密度1.2-1.3(50-60℃)膏。
8.根据权利要求6所述藿香正气片的制备方法，其特征在于，步骤(3)中生半夏细粉采用下述方式提取：生半夏细粉加入3.5-4.5倍(v/m)有机溶剂，50-55℃搅拌萃取2.0-2.5h，静置1.5-3.0h分层后，分离有机相、浓干、粉碎过80目筛。
9.根据权利要求6所述藿香正气片的制备方法，其特征在于，步骤(3)中所述乳糖一水合物的用量为8-14g。
10.根据权利要求6所述藿香正气片的制备方法，其特征在于，步骤(3)中所述气流粉碎机的运行参数为：压力0.35-0.4MPa，进料速度为0.5-0.6g/min，环境湿度≤40％。
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