CN112546134A - 一种用于治疗脂肪肝和酒精性肝损伤的颗粒及制备方法 - Google Patents
一种用于治疗脂肪肝和酒精性肝损伤的颗粒及制备方法 Download PDFInfo
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Abstract
本发明涉及中药制药领域，即一种用于治疗脂肪肝和酒精性肝损伤的颗粒及制备方法。它由以下重量的原料药制成：焦山楂150g，茵陈100g，泽泻100g，车前草75g，虎杖75g，丹参100g，熟大黄45g，决明子75g，黄芪100g，柴胡75g，制何首乌75g，加常规辅料制成1000g。通过配方、工艺参数的改进，丹参酮含量提高3倍以上。产品稳定性明显增加。在用于肝炎后脂肪肝和长期酗酒形成的脂肪肝病变，起到良好的治疗及保护作用。
Description
技术领域
本发明涉及中药制药领域，即一种用于治疗脂肪肝和酒精性肝损伤的颗粒及制备方法。
背景技术
原清肝健脾颗粒：处方：山楂 150g ，茵陈（滨蒿）100g，泽泻100g，车前草 75g，虎杖 75g，丹参 100g，大黄 45g，决明子75g，黄芪 100g，柴胡75g，制何首乌 75g，加辅料制成1000g。其缺点是：1、山楂药材大多含有果核，果核为无效成分，占比大，数量不固定，造成投料数量不稳定，批与批之间存在差异。2、处方中虎杖、大黄、决明子、制何首乌中均含有葸菎类物质，泻下力强。不利于体虚者服用，不利于长期服用。
原清肝健脾颗粒制备方法：以上十一味，山楂、丹参酌予碎断，用50%乙醇加热回流提取三次，第一次加5倍量醇，回流2小时，第二次加3倍量醇，回流1.5小时，第三次加3倍量醇，回流1.5小时，分次滤过，合并滤液，回收乙醇并浓缩至相对密度为1.15（50℃），备用。药楂与茵陈等其余九味加水煎煮三次，第一次加8倍量水，煎煮2小时，第二次加5倍量水，煎煮1.5小时，第三次加5倍量水，煎煮1.5小时，分次滤过，合并滤液，与上述药液合并，浓缩至相对密度为1.30～1.35（80℃）的稠膏，与蔗糖粉按1：4的比例混匀，制粒，干燥，整粒，制成1000g，即得。
其缺点是：
1、山楂、丹参酌予碎断，用50%乙醇加热回流提取。丹参中的脂溶性有效成分不能完全提取出来，如丹参酮。
2、山楂、丹参酌予碎断，用50%乙醇加热回流提取三次，第一次加5倍量醇，第二次加3倍量醇，第三次加3倍量醇。加溶媒量少，不能充分浸渍药材，煎煮不充分。
3、山楂、丹参药楂与茵陈等其余九味加水煎煮三次，第一次加8倍量水，第二次加5倍量水，第三次加5倍量水。加溶媒量少，不能充分浸渍药材，煎煮不充分。
4、分次滤过，合并滤液，与上述药液合并，浓缩至相对密度为1.30～1.35（80℃）的稠膏。山楂和丹参的醇提取物没有处理，存在一定量的水溶性较差的成分， 在水提取工艺中，药液直接浓缩至稠膏，此稠膏中存在一定量的杂质，浓缩到相对密度为1.30～1.35（80℃），有部分药液碳化。导致发明在溶化性检测中不达标。
5、发明放置一段时间后，会出现吸潮、结块。
发明内容
本发明的目的是针对上述不足而提供一种缓和泻下作用，增加游离蒽醌类物质含量，改进方法的用于治疗脂肪肝和酒精性肝损伤的颗粒及制备方法。
本发明的技术解决方案是：一种用于治疗脂肪肝和酒精性肝损伤的颗粒，由以下重量的原料药及常规辅料制成1000g：焦山楂 150g ，茵陈（滨蒿）100g，泽泻100g ，车前草75g，虎杖75g，丹参100g，熟大黄45g，决明子75g，黄芪 100g，柴胡75g，制何首乌 75g。
1、用焦山楂代替山楂。焦山楂为净山楂（除去杂质及核），照清炒法炒到色变深。目的：焦山楂代替山楂，投料更准确、可控。由于去除了占比较大的果核，因此功效明显提高。焦山楂：消食导滞作用增强。用于肉食积滞，泻痢不爽。同大黄、虎杖配伍相须、相使。
2、用熟大黄代替大黄。熟大黄为取净大黄块，照 酒炖或酒蒸法炖或蒸至内外均呈黑色。熟大黄泻下力缓。熟大黄中游离蒽醌的含量为不得少于0.5%，生药材为不得少于0.2%。目的：缓和泻下作用，增加游离蒽醌类物质含量。
用法与用量：温开水冲服，一次6g，一日2次。
方中选用了焦山楂为君药，消导和中，能消食积，行结气，助消化；茵陈清泻湿热，疏肝利胆；泽泻清热化湿，利水消肿；车前草清热解毒，渗湿化痰；决明子清肝明目，利水通便。此四者配伍，行脾湿，祛胃浊，辅助君药，可增强除脂消积之效。虎杖清热解毒，活血止痛；丹参活血祛瘀，安神宁心；熟大黄行积导滞，活血化瘀。三者配伍畅旺血行，疏肝利胆，推陈致新，辅助君药通经络，可加强消除肝积之力。佐用黄芪补气健脾，升阳益胃；何首乌补血生精，通便解毒。二者配伍可补益脾肾，滋荣气血，佐伍君臣药不但可使消而不伐，并且有标本兼顾之用。使以柴胡疏肝利胆，宣畅三焦，引使群药直达病所。诸药合用，共奏去脂消积，减肥保肝之功效。
我们的实验证明，本品能明显降低肝损伤动物血清中GPT含量及胆固醇、甘油三酯含量，从而亦充分证明了该药对肝脏的保护作用及损伤后肝功能的恢复及改善作用，说明它对脂肪肝和酒精中毒性脂肪肝的症状有一定缓解，由于我们在方中加入了黄芪、首乌等补气、补血中药，因而使该方在祛邪同时兼有补虚之功效，达到治疗与保健的双重目的。
一种用于治疗脂肪肝和酒精性肝损伤颗粒的制备方法，其步骤如下：
①以上十一味，焦山楂、丹参酌予碎断，用乙醇加热回流提取三次。改变了乙醇浓度，有利于脂溶性成分的提取。体积百分比95％乙醇。
②第一次加10倍量醇，回流2小时，第二次加8倍量醇，回流1.5小时，第三次加8倍量醇，回流1小时，分次滤过，合并滤液，回收乙醇并浓缩至相对密度为1.10（70℃），备用。增加了乙醇用量，有利于药材充分浸泡、煎煮和提取完全。
③药楂与茵陈等其余九味加水煎煮三次，第一次加10倍量水，煎煮2小时，第二次加8倍量水，煎煮1.5小时，第三次加8倍量水，煎煮1小时，分次滤过，合并滤液，浓缩至相对密度为1.10（70℃）。增加了水的用量，有利于药材充分浸泡、煎煮和提取完全。
④与上述药液合并，在搅拌下加入3倍量乙醇，静置12-16小时（0-10℃），滤过，回收乙醇并浓缩至相对密度为1.10（50℃）。新增工艺，去除不溶性杂质，有利于发明质量稳定。
⑤加入2倍量纯化水，静置12-16小时（0-10℃），离心，滤液浓缩至相对密度1.20-1.25（70℃），低温干燥。新增工艺，去除水溶性杂质，保证溶化性达标，在长期放置过程中不会出现吸潮、结块。
⑥干膏粉与蔗糖粉按1：4的比例混匀，制粒，干燥，整粒，即得。
优选，一种用于治疗脂肪肝和酒精性肝损伤颗粒的制备方法，其步骤如下：
①以上十一味，焦山楂、丹参酌予碎断，用乙醇加热回流提取三次。
②第一次加10倍量95％乙醇，回流2小时，第二次加8倍量95％乙醇，回流1.5小时，第三次加8倍量95％乙醇，回流1小时，分次滤过，合并滤液，回收乙醇并浓缩至相对密度为1.10，温度70℃，备用。
③药楂与茵陈等其余九味加水煎煮三次，第一次加10倍量水，煎煮2小时，第二次加8倍量水，煎煮1.5小时，第三次加8倍量水，煎煮1小时，分次滤过，合并滤液，浓缩至相对密度为1.10温度70℃。
④与上述药液合并，在搅拌下加入3倍量95%乙醇，静置12-16小时，温度0-10℃，滤过，回收乙醇并浓缩至相对密度为1.10，温度50℃。
⑤加入2倍量纯化水，静置12-16小时温度0-10℃，离心，滤液浓缩至相对密度1.20-1.25温度70℃，低温干燥。
⑥干膏粉与蔗糖粉按1：4的比例混匀，制粒，干燥，整粒，即得。
1、山楂、丹参乙醇提取浓度的改变，原工艺为50%乙醇提取，现改变95%乙醇提取。目的：药材乙醇提取后，还要经过水提，山楂和丹参中含有大量的脂溶性有效成份，采用50%乙醇提取不能完全提取出来，采用95%乙醇可提取出的脂溶性成份明显增加，如丹参中所含有的丹参酮，采用新工艺后，提取量增加1.8-2.5倍。
2、增加山楂、丹参醇提乙醇用量。目的：药材得到充分浸渍，煎煮，保障成分提取完全。
3、增加山楂、丹参药楂与茵陈等其余九味加水煎煮的加水量。目的：保障成分提取完全。
4、增加了醇沉和水沉、静置、离心过滤工艺，降低了浓缩相对密度和温度。目的：保证质量稳定，去除不溶性杂质。
5、目的：保证发明在长期放置过程中不会出现吸潮、结块。
本发明的优点是：
1、焦山楂代替山楂，投料更准确、可控。其消食导滞的功效不仅增加且得到了有利保证。
2、熟大黄泻下力缓。熟大黄中游离蒽醌的含量为不得少于0.5%，生药材为不得少于0.2%.
熟大黄代替大黄不仅缓和了泻下作用，还增加游离蒽醌类物质含量有利于增加保肝、抗菌消炎功效。
3、保肝利胆作用：实验表明小鼠连用大黄酸 7 天后, 使CCl4 致急性肝损伤的模型中丙氨酸氨基转移酶(ALT) 由191.32μg下降至178.1μg, 使丙二醛(MDA) 由 2.209nmol/ L下降至1.194 nmol• L -1( P < 0. 01) , SOD 由 44.8 ng•mg -1 上升至47. 89ng•mg - 1( P < 0. 05) 。通过对大黄研究发现蒽醌对肝细胞色P450(CYP450) 有较强抑制作用( 每公斤体质量给予大黄素 42.4mg, 使 CYP450 下降 41.7% ; 每公斤体质量给予大黄酸47mg, 使 CYP450 下降 51.9% ; 每公斤体质量给予芦荟大黄素40 mg , 使CYP450 下降 66.3%) , 并可延缓还原型辅酶 CYP450 的还原作用 , 消除循环障碍 , 增加肝血流量 , Arosio 等发现 , 芦荟大黄素对 CCl4 所致的小鼠急 性肝损害有保护作用, 不仅能阻止肝细胞的死亡 , 而且对脂质过氧化引起的炎症反应有保护作用 。
4、抗菌消炎作用：大黄中的蒽醌类对多种细菌有不同程度的抑制作用。 大黄不仅本身具有广谱抗菌作用 , 还对其它抗菌药物有协同增效作 用 , 且不易产生耐药性。 其中主要的抗菌成分为 : 3-羧基大黄酸、 羟基芦荟大黄素 、 羟基大黄素 , 其中以芦荟大黄素最强。
5、通过制备方法步骤④、⑤的改进，丹参中的主要成份丹参酮明显增加。
6、丹参酮能改善冠状动脉循环，抑制血栓疾病发生。改善心肌收缩力，促进心肌再生的功效。同时还具有抗氧化作用，可防止LDL的氧化，从而保护EC，维持其分泌PGL2的正常功能，抗AS形成。丹参酮有明显的抗炎症作用：大白鼠经灌胃给丹参酮，在炎症第一期模型上对组织胺所致毛细血管通透性增高有明显的抑制作用；对蛋清、角叉菜胶和右旋糖酐所致急性关节肿有抑制作用；对渗出性甲醛腹膜炎有抑制作用。在炎症第二期模型上，对明胶所致小白鼠的白细胞游走有明显的抑制作用；对亚急性甲醛性关节肿有明显的抑制作用。对第三期炎症模型，棉球肉芽肿实验无抑制作用（即慢性期无作用）。丹参酮能使大白鼠血中PGF2α和PGE水平降低。
7、实验表明，新处方游离蒽醌含量明显高于原处方（见实验例1）。新工艺中丹参酮含量约为原工艺3倍以上（见实验例2）。本发明溶化性符合要求，贮存期内质量稳定（见实验例3）。清肝健脾颗粒能明显减轻由于酒精中毒所造成的肝损伤（见实验例4）。清肝健脾颗粒（新处方、新工艺）在用于肝炎后脂肪肝和长期酗酒形成的脂肪肝病变，起到良好的治疗及保护作用（见实验例4）。
下面将结合实施例、实验例对本发明的实施方式作进一步详细描述。
具体实施方式
实施例1
一种用于治疗脂肪肝和酒精性肝损伤的颗粒(下称新处方)，由以下重量的原料药制成：焦山楂 150g ，茵陈（滨蒿）100g，泽泻100g ，车前草 75g，虎杖75g，丹参100g，熟大黄45g，决明子75g，黄芪 100g，柴胡75g，制何首乌 75g，加常规辅料制成1000g。
实施例2
一种用于治疗脂肪肝和酒精性肝损伤颗粒的制备方法(下称新工艺)，其步骤如下：
①以上十一味，焦山楂、丹参酌予碎断，用乙醇加热回流提取三次。
②第一次加10倍量95％乙醇，回流2小时，第二次加8倍量95％乙醇，回流1.5小时，第三次加8倍量95％乙醇，回流1小时，分次滤过，合并滤液，回收乙醇并浓缩至相对密度为1.10，温度70℃，备用。
③药楂与茵陈等其余九味加水煎煮三次，第一次加10倍量水，煎煮2小时，第二次加8倍量水，煎煮1.5小时，第三次加8倍量水，煎煮1小时，分次滤过，合并滤液，浓缩至相对密度为1.10温度70℃。
④与上述药液合并，在搅拌下加入3倍量95%乙醇，静置12-16小时，温度0-10℃，滤过，回收乙醇并浓缩至相对密度为1.10，温度50℃。
⑤加入2倍量纯化水，静置12-16小时温度0-10℃，离心，滤液浓缩至相对密度1.20-1.25温度70℃，低温干燥。
⑥干膏粉与蔗糖粉按1：4的比例混匀，制粒，干燥，整粒，即得。
实验例1
选取相同批次检验合格的药材，分别按原处方、工艺制备三批发明（Y20191001、Y20191002、Y20191003）和新处方、工艺制备三批发明（20191001、20191002、20191003）。见实施例1、2。
照《中国药典》采用高效液相色谱法（通则0512）测定。检测芦荟大黄素（C15H10O5）大黄酸（C15H8O6）、大黄素（C15H10O5）、大黄酚（C15H10O4）和大黄素甲醚（C16H12O5）的总量。
仪器：waters高效液相色谱仪 型号：e2695/2489 ；紫外检测器。电子分析天平，型号：BS124S。电子分析天平，型号：AE240。数控超声波清洗器，型号：KQ-250DE 。
色谱条件与系统适用性试验
色谱柱：Agilent TC-C18 4.6mm×250mm 5μm。
流动相：甲醇（批号：166578 ，级别：HPLC，来源：赛默飞世尔科技有限公司）-0.1%磷酸（批号：T4901，级别：HPLC，来源：山东西亚化学工业有限公司）溶液（85 : 15）检测波长：254nm，理论板数按大黄素峰计算应不低于3000。
对照品溶液的制备
精密称取芦荟大黄素对照品（批号：110795-201710 。来源：中国食品药品检定研究院）、大黄酸对照品（批号：110757-201607。来源：中国食品药品检定研究院）、大黄素对照品（批号：110756-201913 。来源：中国食品药品检定研究院）、大黄酚对照品（批号：110796-201922 。来源：中国食品药品检定研究院）、大黄素甲醚对照品（批号：110758-201817。来源：中国食品药品检定研究院）适量，加甲醇（批号：170227， 级别：分析。来源：天津市康科德科技有限公司）分别制成每1ml含芦荟大黄素、大黄酸、大黄素、大黄酚各80μg，大黄素甲醚40μg的溶液；分别精密量取上述对照品溶液各2ml，混匀，即得（每1ml中含芦荟大黄素、大黄酸、大黄素、大黄酚各l6μg，含大黄素甲醚8μg）。
供试品溶液的制备
取本品10g，精密称定，置具塞锥形瓶中，加甲醇（批号：170227）回流提取2小时，提取液浓缩至干，残渣加水30 ml使溶解，过滤，滤液蒸干，残渣加甲醇25ml使溶解，滤过，取续滤液，即得。
测定法
分别精密吸取对照品溶液与供试品溶液各10μl，注入液相色谱仪，测定，即得。
含游离蒽醌以芦荟大黄素（C15H10O5）、大黄酸（C15H8O6）、大黄素（C15H10O5）、大黄酚（C15H10O4）和大黄素甲醚（C16H12O5）的总量，见表1。
表1
实验证明，新处方游离蒽醌含量明显高于原处方。
实验例2
丹参酮类 照高效液相色谱法(通则0512)测定。
色谱条件与系统适用性试验
仪器：waters高效液相色谱仪 ，型号：e2695/2489。电子分析天平，型号：BS124S。电子分析天平 ，型号：AE240。数控超声波清洗器，型号：KQ-250DE 。
色谱柱：Agilent TC-C18 4.6mm×250mm 5μm。
流动相A：乙腈（批号：191611 ，级别：HPLC ，来源：赛默飞世尔科技有限公司）。
流动相B：0.02%磷酸（批号：T4901 级别：HPLC 来源：山东西亚化学工业有限公司）溶液。
按下表中的规定进行梯度洗脱，见表2：
表2
柱温：20℃，检测波长：270nm，理论板数按丹参酮ⅡA峰计算应不低于60000。
对照品溶液的制备
取丹参酮ⅡA对照品（批号：110766-202022 ，来源：中国食品药品检定研究院）适量，精密称定，置棕色量瓶中，加甲醇（批号：170227，级别：分析，来源：天津市康科德科技有限公司）制成每1ml含20μg的溶液，即得。
供试品溶液的制备
取本品10g，加甲醇200ml，超声处理，放冷，滤过，取续滤液，即得。
测定法
分别精密吸取对照品溶液与供试品溶液各10μl，注入液相色谱仪，测定。以丹参酮ⅡA对照品为参照，以其相应的峰为S峰，计算隐丹参酮、丹参酮Ⅰ的相对保留时间，其相对保留时间应在规定值的±5%范围之内。相对保留时间及校正因子见下表3。
表3
以丹参酮ⅡA的峰面积为对照，分别乘以校正因子，计算隐丹参酮、丹参酮Ⅰ、丹参酮ⅡA的含量。
以含丹参酮ⅡA（C19H18O3）、隐丹参酮（C19H20O3）和丹参酮Ⅰ（C18H12O3）的总量计，见表4。
表4
新工艺中丹参酮含量约为原工艺3倍以上。
实验例3
通过制备方法步骤④、⑤，本发明溶化性符合要求，贮存期内质量稳定。
在温度40℃±2℃、温度75%±5%条件下对样品进行考察
原处方、原工艺三批发明（Y20191001、Y20191002、Y20191003）在考察12个月后，出现结块现象，Y20191001批溶化性不符合要求。
新处方、新工艺三批发明（20191001、20191002、20191003）。考察12个月后，无吸潮、结块现象，溶化性符合要求。
实验例4
目的：观察清肝健脾颗粒新处方、新工艺对几种动物脂肪肝模型的影响
实验材料与方法
药物：小白鼠，体重18-22g。
动物：清肝健脾颗粒（新），由通化金马药业集团股份有限公司生产提供，批号:20191001。成药规格为:6g/袋，用时供灌胃给药，对照组给水。实验所用阳性药，清肝脾颗粒（旧），由通化金马药业集团股份有限公司生产，批号:Y20191002。
实验结果
一、对CCl4肝损伤的影响
清肝健脾颗粒对CCl4中毒小鼠肝脏中总脂、糖原、MDA、血清中CPT、血脂含量的影响（`X±SD），见表5：
表5
由表5结果可见，清肝健脾颗粒能明显降低肝脏中MDA、总脂含量，增加糖原含量，使GPT和血脂有降低的趋势。
二、对乙肝损伤的影响
清肝健脾颗粒对乙醇中毒小鼠肝脏中MDA、血清中CPT、血脂、胆固醇、三油酸甘油酯含量的影响（`X±SD）见表6：
表6
清肝健脾颗粒对乙醇中毒小鼠肝脏的影响，表7：
表7
由表7结果可见，清肝健脾颗粒可明显降低GPT、血脂、胆固醇、三油酸甘油酯含量，使肝脏中MDA含量亦明显降低，P＜0.001。表3病理检查结果表明，清肝健脾颗粒能明显减轻由于酒精中毒所造成的肝损伤。
三、对急性高脂模型动物的影响
清肝健脾颗粒对急性高脂小鼠肝糖原和血清中三油酸甘油酯含量的影响（`X±SD），见表8 ：
表8
由表8结果可见，清肝健脾颗粒能明显增加肝脏中糖原含量，使血清中三油酸甘油酯含量有降低趋势。
由于肝炎病毒在肝细胞内复制，使肝细胞内的超微结构尤其是线粒体受损伤，导致脂类在肝内代谢发生紊乱而积累，形成肝炎后脂肪肝，另外由于乙醇的代谢造成能量的浪费，甘油三酯沉积，蛋白质合成减少，并增加了脂质过氧化，进而造成肝损伤[5]，最直接的表现即为脂肪肝，我们的实验结果表明，由CCl4和乙醇造成的肝损伤后，肝脏中总酯和MDA明显升高，血清中GPT、 血脂、胆固醇、三油酸甘油酯均高于正常组，经灌胃清肝健脾颗粒后，能明显降低肝脏中总酯和MDA含量，血清中GPT和 血脂、胆固醇、三油酸甘油酯也显著降低，表现出了明显的降脂、抗氧化和恢复肝功的作用。经乙醇中毒后，若出现肝脂变，则表现为肝细胞气球样变，小坏死灶并伴有炎细胞浸润 。[6]上述实验结果证明，乙醇中毒后小鼠肝脏确出现空泡状变性，炎细胞浸润和坏死灶，说明出现脂肪肝症状，而给动物灌服清肝健脾颗粒后，上述病变程度减轻，表明清肝健脾颗粒可使肝脂变恢复或消失。同时对于急性高脂模型动物，清肝健脾颗粒可明显增加其肝脏中糖原含量，积蓄能量，在治愈病变的同时，亦发挥其保护肝脏的作用。
综上所述，清肝健脾颗粒（新处方、新工艺）在用于肝炎后脂肪肝和长期酗酒形成的脂肪肝病变，起到良好的治疗及保护作用。
上面描述，只是本发明的具体实施方式，各种举例说明不对本发明的实质内容构成限制。
Claims (2)
1.一种用于治疗脂肪肝和酒精性肝损伤的颗粒，由以下重量的原料药及常规辅料制成1000g：焦山楂 150g ，茵陈100g，泽泻100g ，车前草 75g，虎杖75g，丹参100g，熟大黄45g，决明子75g，黄芪 100g，柴胡75g，制何首乌 75g。
2.一种如权利要求1所述的用于治疗脂肪肝和酒精性肝损伤的颗粒的制备方法，其特征在于步骤如下：
①以上十一味，焦山楂、丹参酌予碎断，用95%乙醇加热回流提取三次；
②第一次加10倍量95％乙醇，回流2小时，第二次加8倍量95％乙醇，回流1.5小时，第三次加8倍量95％乙醇，回流1小时，分次滤过，合并滤液，回收乙醇并浓缩至相对密度为1.10，温度70℃，备用；
③药楂与茵陈等其余九味加水煎煮三次，第一次加10倍量水，煎煮2小时，第二次加8倍量水，煎煮1.5小时，第三次加8倍量水，煎煮1小时，分次滤过，合并滤液，浓缩至相对密度为1.10温度70℃；
④与上述药液合并，在搅拌下加入3倍量95%乙醇，静置12-16小时，温度0-10℃，滤过，回收乙醇并浓缩至相对密度为1.10，温度50℃；
⑤加入2倍量纯化水，静置12-16小时温度0-10℃，离心，滤液浓缩至相对密度1.20-1.25温度70℃，低温干燥；
⑥干膏粉与蔗糖粉按1：4的比例混匀，制粒，干燥，整粒，即得。
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