CN113368169A - 一种对化学性肝损伤有保护功能的组合物及其制备方法 - Google Patents
一种对化学性肝损伤有保护功能的组合物及其制备方法 Download PDFInfo
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Abstract
本发明属于中医药治疗肝脏疾病领域,具体涉及一种对化学性肝损伤有保护功能的组合物及其制备方法。其中,组合物的原料由以下重量份数的组分组成:葛根8‑15份、枳椇子3‑10份、五味子3‑12份、人参2‑9份和香菇2‑10份。其制备方法包括:先将人参、香菇和五味子提取挥发油,滤液酶解,药渣与葛根、枳椇子混合先醇提弱极性有效成分,然后水提过大孔树脂富集有效成分,最后将各提取液浓缩干燥制得的的干膏粉混合,即得。本发明制备方法药材利用率高,制得的组合物对化学性肝损伤保护功能疗效确切,且服用安全,质量可控。
Description
技术领域
本发明属于中医药治疗肝脏疾病领域,具体涉及一种对化学性肝损伤有保护功能的组合物及其制备方法。
背景技术
化学性肝损伤是由化学性肝毒性物质所造成的肝损伤,其临床表现为食欲不振,消化不良,肝区疼痛,恶心呕吐等。化学性肝损伤一般为慢性肝损伤,多数存在于亚健康人群中,治疗多以修复受损肝细胞、保肝护肝为主。
化学性肝损伤诱因通常表现以下几个方面:
(1)长期或间断性大量饮酒都可引起肝损伤,酒精直接毒害肝细胞,影响肝脏功能代谢紊乱,从而不能利用或贮存营养物质。进入人体的酒精有80%~90%在肝脏代谢,当长期大量饮酒时,酒精在肝内代谢产物堆积,对肝细胞有直接毒害的作用。急性酒精性肝损伤的机理为机体大量摄入乙醇后,在乙醇脱氢酶的催化下大量脱氢氧化,使三羧酸循环障碍和脂肪酸氧化减弱而影响脂肪代谢,乙醇可致α-磷酸甘油增多而促进甘油三酯合成,致使脂肪在肝细胞内沉积;同时乙醇能激活氧分子,产生氧自由基导致肝细胞膜的脂质过氧化及体内还原型谷胱甘肽的耗竭。
(2)一些亲肝毒物与其非或微毒性化学物质结合,可增加毒性,如脂肪醇类(甲醇、乙醇、异丙醇等)能增强卤代烃类(四氯化碳、氯仿等)的毒性。化学性有害物质,会通过胃肠道、血液循环进入肝脏进行转化,因此肝脏容易受到这些毒性物质的损害,造成化学性肝损伤。
(3)肝脏是药物代谢的主要场所,长期服用药物可引起肝细胞损伤,容易诱发肝脏疾病。
(4)饮食不当也会加重肝脏负担,病从口入,变质的食物和被污染的水对肝脏造成一定的损伤,如长期食用含亚硝胺的食物、霉变食物(粮食受黄曲霉素污染)、缺乏微量元素的食物及饮用藻类污染的水等都会对肝脏造成损伤,甚至导致肝癌。
目前市场上出现的对化学性肝损伤有保护功能的药品和保健品很多,化学药因长期服用不良反应明显而损害脏器,或形成药物依赖而产生耐药性,而用纯天然具有对化学性肝损伤有保护作用的中草药对人体的不良反应相对较少,且可以多靶点调节,适合长期服用。
中国发明专利CN106975069B公开了一种保肝护肝组合物及其制备方法,其组合物包括如下组份:枳椇子1~5份、葛根0.5~4份、枸杞子0.5~4份、茯苓0.1~3份、玉米低聚肽粉0.1-3份、蚌肉多糖0.5~1份以及杭白菊0.05~0.4份。该制备方法制备得到的组合物对改善化学性肝损伤有一定的治疗作用,但是对机体脂质代谢与抗自由基的效果有待研究。
中国发明专利CN110876772A公开了一种具有保肝护肝功能的中药制剂的制备方法及应用,该组合物由如下重量份数的中药原料制成:葛根3-5份、枸杞子3-5份、枳椇子2-3份、人参1-2份、五味子1-2份。但该发明对药材的利用率低,不利于药效的发挥,且对各种肝损伤的治疗效果需进一步改善。
发明内容
为了解决现有技术存在的不足,本发明提供一种对化学性肝损伤有保护功能的组合物及其制备方法,药材利用率高,生产成本低,对化学性肝损伤保护功能疗效确切,且服用安全,质量可控。
本发明的目的是通过以下技术方案实现的:
一种对化学性肝损伤有保护功能的组合物,所述组合物的原料由以下重量份数的组分组成:葛根8-15份、枳椇子3-10份、五味子3-12份、人参2-9份和香菇2-10份。
优选地,所述组合物的原料由以下重量份数的组分组成:葛根8-10份、枳椇子5-10份、五味子6-12份、人参4-9份和香菇5-10份。
优选地,所述组合物的原料由以下重量份数的组分组成:葛根8份、枳椇子5份、五味子6份、人参4份、香菇5份。
优选地,本发明所述组合物还包括药学上可接受的辅料;
优选地,所述辅料选自填充剂、助流剂、润滑剂、粘合剂、崩解剂或矫味剂中的一种或几种。
本发明的再一目的是提供上述组合物的制备方法,其特征在于,包括如下步骤:
(1)将人参、香菇和五味子粉碎,加水进行水蒸气蒸馏提取,得滤液1、药渣1和挥发油;用β-环糊精包合挥发油得包合物;将滤液1进行酶解,95-100℃将酶灭活,浓缩、干燥得干膏粉1;
(2)将葛根、枳椇子粉碎,和药渣1混合,加70-85%乙醇加热回流提取,过滤得滤液2和药渣2,将滤液2浓缩干燥得干膏粉2,将药渣2加水回流提取过滤,浓缩得浓缩液;
(3)将大孔吸附树脂与大孔阴离子树脂混合,湿法装柱,将浓缩液上柱吸附,然后先用6-8倍柱体积的水洗脱,再用有机溶剂梯度洗脱,合并洗脱液,浓缩干燥得干膏粉3;
(4)将包合物、干膏粉1、干膏粉2、干膏粉3和辅料混合均匀,即得。
优选地,步骤(1)中所述水的质量与人参、香菇和五味子总质量的比为5-8:1;所述提取的时间为5-7h。
优选地,步骤(1)中所述挥发油与β-环糊精的质量比为1:4.5-5.5,所述包合的时间为1.5-2.5h,所述包合的温度为50-65℃。
优选地,步骤(1)酶解所用酶为β-葡萄糖苷酶与无花果蛋白酶以质量比5-10:1组成的酶混合物,所述酶混合物的加入量为滤液1质量的0.1-0.3%,所述酶解的温度为45-60℃,所述酶解的时间为0.5-1.5h,酶解的pH为4.0-6.0。
优选地,步骤(2)中所述70-85%乙醇的质量与葛根、枳椇子和药渣1总质量的比为6-10:1;所述提取的时间为1-2h;所述水与药渣2的质量比为5-10:1,所述药渣2加水回流提取的次数为1-2次,每次提取时间为1-1.5h。
以上所述药渣均为过滤后的湿料。
优选地,步骤(4)中混合均匀后制成口服制剂。
优选地,步骤(3)中所述大孔吸附树脂与大孔阴离子树脂的质量比为3-6:1;所述用水洗脱时控制洗脱液流速为0.8-1.2mL/min;所述有机溶剂梯度洗脱为依次用3-5倍柱体积的60%乙醇与丙酮的混合溶液、6-8倍柱体积的95%乙醇与正丁醇的混合溶液洗脱。
优选地,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:3-5;
优选地,所述60%乙醇与丙酮的体积比为1:0.5-0.8;所述95%乙醇与正丁醇的体积比为1:1-3;所述有机溶剂梯度洗脱时控制洗脱流速为0.5-0.7mL/min。
本发明的再一目的是提供上述组合物或制备方法在制备治疗化学性肝损伤药物中的应用。
本发明组合物的各药材四气五味及功效:
葛根:甘、辛,凉。归脾、胃、肺经,具有解肌退热,生津止渴,透疹,升阳止泻,通经活络,解酒毒之功效。用于外感发热头痛,项背强痛,口渴,消渴,麻疹不透,热痢,泄泻,眩晕头痛,中风偏瘫,胸痹心痛,酒毒上中。葛根对肝脏的功效有:①提高肝细胞的再生能力,恢复正常肝脏机能,促进胆汁分泌,防止脂肪在肝脏堆积;②促进新陈代谢,加强肝脏解毒功能,防止酒精对肝脏的损伤;③强化肝胆细胞自身免疫功能,抵抗病毒入侵。葛根素含有皂苷类化合物,对提高机体免疫力,诱导活化肝星状细胞凋亡,有效逆转化学诱导的肝纤维化,以及对四氯化碳诱导的急性肝损伤等具有保护作用。
枳椇子:甘,平。归心、脾经,具有止咳除烦,清湿热,解酒毒之功效。用于酒精中毒,烦渴呕逆,二便不利等症;枳椇子含葡萄糖、果糖、硝酸钾、过氧化物酶等,能显著降低乙醇在血液中的浓度,促进肝脏分解代谢乙醇,消除酒后体内产生的过量自由基,从而减轻乙醇对肝组织的损伤,避免酒精中毒导致各种代谢异常,诱发肝脏疾病。
人参:甘、微苦,微温。归脾、肺、心、肾经,具有大补元气,复脉固脱,补脾益肺,生津养血,安神益智之功效。治疗体虚欲脱,肢冷脉微,脾虚食少,肺虚喘咳,津伤口渴,内热消渴,气血亏虚,久病虚赢,惊悸失眠,阳痿宫冷等症。人参富含人参皂甙类、人参多糖类、人参烯醇类、人参聚乙炔类化合物、麦芽酚、必需氨基酸、维生素以及微量元素等营养成分,可增强肝脏乙醇脱氢酶和乙醛脱氢酶的活性,促进肝脏分解代谢乙醇,并将乙醇代谢所产生的有毒物质乙醛迅速排出体外,从而有效保护肝脏。
五味子:酸,甘,温。归肺、心、肾经,具有收敛固涩,益气生津,补肾宁心。用于久咳虚喘,梦遗滑精,遗尿尿频,久泻不止,自汗盗汗,津伤口渴,内热消渴,心悸失眠等症。五味子具有保护肝脏和促进因滥用酒精、药物或肝炎而受损的肝细胞再生,从而加快肝脏功能恢复。
香菇:甘,平。归肝、胃经,具有开胃健脾助食之功效,用于佝偻病,贫血,小便失禁,痘疮,麻疹不透,高血压,扁桃体炎等症。香菇含有丰富的多糖和B族维生素,香菇多糖具有保护肝脏,增强肝脏解毒功能的作用,而B族维生素就像体内的“油库”,它能加速物质代谢,并转化成能量,不仅能给肝脏“加油”,还能修复受损肝细胞、防止肝脂肪变性,增强肝脏功能的作用。
本发明的有益效果:
(1)本发明组方基于中医肝脾相互关系理论合理配伍,脾主运化,为气血生化之源,肝主藏血,脾主生血统血,脾气健运,意在养肝,本方各药味相辅相成,共奏补气养血,益气生津,健脾养肝之功效。
(2)本发明采用特定复合酶进行酶解,使人参、五味子及香菇的多糖类及低聚肽类等有效成分浓度明显提高,对化学性肝损伤和酒精所致的急性肝损伤的治疗作用显著;
(3)本发明在制备工艺中,确立了影响药效的关键质量属性,并对关键工艺参数进行了评估,结果发现本发明环糊精的用量,包合的温度、大孔吸附树脂与大孔阴离子树脂的配比,洗脱溶剂的种类及极性及洗脱液的流速等对活性成分的提取影响明显。本发明通过特定的包合工艺参数和纯化工艺,其制备得到的组合物治疗肝损伤效果明显提高。具有很好的临床价值和广阔的市场前景。
具体实施方式
下面结合具体的实施例对本发明做进一步阐述。
实施例1
本实施例的组合物由以下重量份数的组分组成:葛根8份、枳椇子3份、五味子3份、人参2份和香菇2份。
制备方法如下:
(1)将人参、香菇和五味子粉碎,加5倍量的水进行水蒸气蒸馏提取5h,得滤液1、药渣1和挥发油;
(2)将β-环糊精中制成浓度为0.1g/mLβ-环糊***溶液,将挥发油缓慢加入β-环糊精溶液中,在65℃恒温下250r/min磁力搅拌1.5h,冷却,抽滤,沉淀用1倍量的水洗涤,干燥得包合物;其中β-环糊精与挥发油的质量比为4.5:1。
(3)将滤液1中加入0.1%酶混合物(质量比为5:1的β-葡萄糖苷酶与无花果蛋白酶混合物)45℃下酶解0.5h,期间持续调pH为4.0,然后100℃将酶灭活,浓缩、干燥得干膏粉1;β-葡萄糖苷酶购自江苏奥福生物科技有限公司;无花果蛋白酶购自陕西晨明生物科技有限公司;
(4)将葛根、枳椇子粉碎,和药渣1混合,加6倍量的70%乙醇水溶液加热回流提取1h,过滤,浓缩干燥得干膏粉2,将过滤后的药渣加5倍量的水回流提取1.5h,过滤,浓缩得浓缩液;
(5)将预处理过的大孔吸附树脂AB-8与大孔阴离子树脂D315按质量比为3:1混合,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:4,湿法装柱,柱子径高比为1:12,将浓缩液上柱吸附,然后先用6倍柱体积的水洗脱,控制洗脱液流速为0.8mL/min,收集洗脱液,再依次用5倍柱体积的60%乙醇与丙酮(体积比为1:0.5)的混合溶液、6倍柱体积的95%乙醇与正丁醇(体积比为1:1)的混合溶液洗脱,控制洗脱液流速为0.5mL/min,收集各洗脱液,合并洗脱液,浓缩、减压真空干燥得干膏粉3;
(6)将包合物、干膏粉1、干膏粉2和干膏粉3混合均匀得混合物,得组合物。
实施例2
本实施例的组合物由以下重量份数的组分组成:葛根15份、枳椇子10份、五味子12份、人参9份和香菇10份。
制备方法如下:
(4)将人参、香菇和五味子粉碎,加8倍量的水进行水蒸气蒸馏提取7h,得滤液1、药渣1和挥发油;
(5)将β-环糊精中制成浓度为0.1g/mLβ-环糊***溶液,将挥发油缓慢加入β-环糊精溶液中,在50℃恒温下250r/min磁力搅拌2.5h,冷却,抽滤,沉淀用1倍量的水洗涤,干燥得包合物;其中β-环糊精与挥发油的质量比为5.5:1。
(6)将滤液1中加入0.3%酶混合物(质量比为10:1的β-葡萄糖苷酶与无花果蛋白酶混合物)60℃下酶解1.5h,期间持续调pH为6.0,然后100℃将酶灭活,浓缩、干燥得干膏粉1;β-葡萄糖苷酶购自江苏奥福生物科技有限公司;无花果蛋白酶购自陕西晨明生物科技有限公司;
(4)将葛根、枳椇子粉碎,和药渣1混合,加10倍量的85%乙醇水溶液加热回流提取1h,过滤,浓缩干燥得干膏粉2,将过滤后的药渣加10倍量的水回流提取2次,每次1h,过滤,浓缩得浓缩液;
(5)将预处理过的大孔吸附树脂AB-8与大孔阴离子树脂D315按质量比为6:1混合,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:3,湿法装柱,径高比为1:12,将浓缩液上柱吸附,然后先用8倍柱体积的水洗脱,控制洗脱液流速为1.2mL/min,收集洗脱液,再依次用3倍柱体积的60%乙醇与丙酮(体积比为1:0.8)的混合溶液、8倍柱体积的95%乙醇与正丁醇(体积比为1:3)的混合溶液洗脱,控制洗脱液流速为0.7mL/min,收集各洗脱液,合并洗脱液,浓缩、减压真空干燥得干膏粉3;
(6)将包合物、干膏粉1、干膏粉2和干膏粉3混合均匀得混合物,得组合物。
实施例3
本实施例的组合物由以下重量份数的组分组成:葛根8份、枳椇子5份、五味子6份、人参4份和香菇5份。
制备方法如下:
(1)将人参、香菇和五味子粉碎,加6倍量的水进行水蒸气蒸馏提取6h,得滤液1、药渣1和挥发油;
(2)将β-环糊精中制成浓度为0.1g/mLβ-环糊***溶液,将挥发油缓慢加入β-环糊精溶液中,在55℃恒温下250r/min磁力搅拌2h,冷却,抽滤,沉淀用1倍量的水洗涤,干燥得包合物;其中β-环糊精与挥发油的质量比为5:1。
(3)将滤液1中加入0.2%酶混合物(质量比为8:1的β-葡萄糖苷酶与无花果蛋白酶混合物)50℃下酶解1.0h,期间持续调pH为5.5,然后100℃将酶灭活,浓缩、干燥得干膏粉1;β-葡萄糖苷酶购自西格玛奥德里奇(上海)贸易有限公司;无花果蛋白酶购自深圳乐芙生物科技有限公司;
(4)将葛根、枳椇子粉碎,和药渣1混合,加8倍量的80%乙醇水溶液加热回流提取1h,过滤,浓缩干燥得干膏粉2,将过滤后的药渣加8倍量的水回流提取1h,过滤,浓缩得浓缩液;
(5)将预处理过的大孔吸附树脂AB-8与大孔阴离子树脂D315按质量比为5.5:1混合,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:5,湿法装柱,径高比为1:12,将浓缩液上柱吸附,然后先用8倍柱体积的水洗脱,控制洗脱液流速为1.0mL/min,收集洗脱液,再依次用5倍柱体积的60%乙醇与丙酮(体积比为1:0.6)的混合溶液、6倍柱体积的95%乙醇与正丁醇(体积比为1:2)的混合溶液洗脱,控制洗脱液流速为0.6mL/min,收集各洗脱液,合并洗脱液,浓缩、减压真空干燥得干膏粉3;
(6)将包合物、干膏粉1、干膏粉2和干膏粉3混合均匀得混合物,得组合物。
对比例1
本对比例与实施例3的区别是将组合物中的原料香菇5份调整为枸杞子5份,其余与实施例3保持一致。
本对比例的组合物由以下重量份数的组分组成:葛根8份、枳椇子5份、五味子6份、人参4份和枸杞子5份。
制备方法如下:
(1)将人参、枸杞子和五味子粉碎,加6倍量的水进行水蒸气蒸馏提取6h,得滤液1、药渣1和挥发油;
(2)将β-环糊精中制成浓度为0.1g/mLβ-环糊***溶液,将挥发油缓慢加入β-环糊精溶液中,在55℃恒温下250r/min磁力搅拌2h,冷却,抽滤,沉淀用1倍量的水洗涤,干燥得包合物;其中β-环糊精与挥发油的质量比为5:1。
(3)将滤液1中加入0.2%酶混合物(质量比为8:1的β-葡萄糖苷酶与无花果蛋白酶混合物)50℃下酶解1.0h,期间持续调pH为5.5,然后100℃将酶灭活,浓缩、干燥得干膏粉1;β-葡萄糖苷酶购自西格玛奥德里奇(上海)贸易有限公司;无花果蛋白酶购自深圳乐芙生物科技有限公司;
(4)将葛根、枳椇子粉碎,和药渣1混合,加8倍量的80%乙醇水溶液加热回流提取1h,过滤,浓缩干燥得干膏粉2,将过滤后的药渣加8倍量的水回流提取1h,过滤,浓缩得浓缩液;
(5)将预处理过的大孔吸附树脂AB-8与大孔阴离子树脂D315按质量比为5.5:1混合,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:5,湿法装柱,径高比为1:12,将浓缩液上柱吸附,然后先用8倍柱体积的水洗脱,控制洗脱液流速为1.0mL/min,收集洗脱液,再依次用5倍柱体积的60%乙醇与丙酮(体积比为1:0.6)的混合溶液、6倍柱体积的95%乙醇与正丁醇(体积比为1:2)的混合溶液洗脱,控制洗脱液流速为0.6mL/min,收集各洗脱液,合并洗脱液,浓缩、减压真空干燥得干膏粉3;
(6)将包合物、干膏粉1、干膏粉2和干膏粉3混合均匀得混合物,得组合物。
对比例2
本对比例与实施例3的区别是将香菇5份去掉,其他药材及份数为:葛根8份、枳椇子5份、五味子6份和人参4份;其余与实施例3一致。
制备方法如下:
(1)将人参和五味子粉碎,加6倍量的水进行水蒸气蒸馏提取6h,得滤液1、药渣1和挥发油;
(2)将β-环糊精中制成浓度为0.1g/mLβ-环糊***溶液,将挥发油缓慢加入β-环糊精溶液中,在55℃恒温下250r/min磁力搅拌2h,冷却,抽滤,沉淀用1倍量的水洗涤,干燥得包合物;其中β-环糊精与挥发油的质量比为5:1。
(3)将滤液1中加入0.2%酶混合物(质量比为8:1的β-葡萄糖苷酶与无花果蛋白酶混合物)50℃下酶解1.0h,期间持续调pH为5.5,然后100℃将酶灭活,浓缩、干燥得干膏粉1;β-葡萄糖苷酶购自西格玛奥德里奇(上海)贸易有限公司;无花果蛋白酶购自深圳乐芙生物科技有限公司;
(4)将葛根、枳椇子粉碎,和药渣1混合,加8倍量的80%乙醇水溶液加热回流提取1h,过滤,浓缩干燥得干膏粉2,将过滤后的药渣加8倍量的水回流提取1h,过滤,浓缩得浓缩液;
(5)将预处理过的大孔吸附树脂AB-8与大孔阴离子树脂D315按质量比为5.5:1混合,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:5,湿法装柱,径高比为1:12,将浓缩液上柱吸附,然后先用8倍柱体积的水洗脱,控制洗脱液流速为1.0mL/min,收集洗脱液,再依次用5倍柱体积的60%乙醇与丙酮(体积比为1:0.6)的混合溶液、6倍柱体积的95%乙醇与正丁醇(体积比为1:2)的混合溶液洗脱,控制洗脱液流速为0.6mL/min,收集各洗脱液,合并洗脱液,浓缩、减压真空干燥得干膏粉3;
(6)将包合物、干膏粉1、干膏粉2和干膏粉3混合均匀得混合物,得组合物。
对比例3
本对比例组合物的原料仅采用香菇28份,制备方法如下:
(1)将香菇粉碎,加6倍量的水进行水蒸气蒸馏提取,得滤液1、药渣1和挥发油;
(2)将β-环糊精中制成浓度为0.1g/mLβ-环糊***溶液,将挥发油缓慢加入β-环糊精溶液中,在55℃恒温下250r/min磁力搅拌2h,冷却,抽滤,沉淀用1倍量的水洗涤,干燥得包合物;其中β-环糊精与挥发油的质量比为5:1。
(3)将滤液1中加入0.2%酶混合物(质量比为8:1的β-葡萄糖苷酶与无花果蛋白酶混合物)50℃下酶解1.0h,期间持续调pH为5.5,然后100℃将酶灭活,浓缩、干燥得干膏粉1;
(4)将药渣1加8倍量的80%乙醇水溶液加热回流提取1h,过滤,浓缩干燥得干膏粉2,将过滤后的药渣加8倍量的水回流提取1h,过滤,浓缩得浓缩液;
(5)将预处理过的大孔吸附树脂AB-8与大孔阴离子树脂D315按质量比为5.5:1混合,浓缩液的质量与大孔吸附树脂AB-8与大孔阴离子树脂D315总质量的比为1:5,湿法装柱,径高比为1:12,将浓缩液上柱吸附,然后先用8倍柱体积的水洗脱,控制洗脱液流速为1.0mL/min,收集洗脱液1,再依次用5倍柱体积的60%乙醇与丙酮(体积比为1:0.6)的混合溶液、6倍柱体积的95%乙醇与正丁醇(体积比为1:2)的混合溶液洗脱,控制洗脱液流速为0.6mL/min,收集洗脱液2,合并洗脱液,浓缩干燥得干膏粉3;
(6)将包合物、干膏粉1、干膏粉2和干膏粉3混合均匀得混合物,得组合物。
对比例4
本对比例与实施例3的区别是步骤(1)中所用的酶为β-葡萄糖苷酶与木瓜蛋白酶的混合物,二者质量比为8:1,其余与实施例3一致。木瓜蛋白酶购自西格玛奥德里奇(上海)贸易有限公司。
对比例5
本对比例与实施例3的区别是步骤(3)中大孔吸附树脂AB-8与大孔阴离子树脂D315的质量比为2.0:1,其余与实施例3一致。
以上各组合物可以加入10%-50%组合物质量的填充剂(如糊精、乳糖或麦芽糊精),再加入0.05-0.2%%的硬脂酸镁,或再加入其他辅料,干法制粒或湿法制粒得颗粒剂,也可进一步制成片剂、胶囊剂等口服制剂。
试验例1本发明组合物对CCl4引起的小鼠急性肝损伤的治疗作用
1.1实验动物
清洁级雌性昆明种小鼠,体重22-25g,在室温25℃,湿度50%,12小时黑暗,12小时光照的动物室饲养,饲养方式采用立体笼式饲养,给予标准饲料,并且自由饮水,实验动物由延边大学实验动物中心提供。
1.2实验分组及给药
将上述昆明种小鼠110只随机分为11组,每组10只;分别为空白组、模型组、实施例1至实施例3组,对比例1至对比例5组,阳性对照水飞蓟素组100mg/kg。各实施例与对比例组小鼠给药剂量/kg相当于1.5g生药量,生药量为制备组合物所用的原料的质量。
实验动物每日经口灌胃给药,空白对照组和模型对照组给予等量生理盐水,共给药7天,于末次给药后4小时除空白组以外其余各组小鼠一次灌胃给予CCl4(0.4%CCl4的橄榄油溶液0.1ml/10g),空白对照组给予不含CCl4的橄榄油溶液0.1ml/10g,禁食不禁水。给予CCl420小时后颈动脉取血,分离血清,分别测定ALT、AST(根据试剂盒说明书测定ALT、AST)。剩下的部分放在液氮或低温冰箱(-80℃)里保存。
1.3实验结果及统计学分析
实验数据用GraphPad Prism程序(USA)进行统计,采用均数±标准差(means±SEM)表示,所有数据用One-way ANOVA和Tukey’s multiple comparison testes进行比较。结果见表1。
表1试验例1各组小鼠生化指标检测结果
试验组 | 小鼠数量(只) | ALT(IU/L) | AST(IU/L) |
空白组 | 10 | 49.35±9.73<sup>a</sup> | 7.34±0.95<sup>a</sup> |
模型组 | 10 | 245.01±3.17<sup>b</sup> | 61.93±5.03<sup>b</sup> |
阳性组 | 10 | 120.82±13.58<sup>c</sup> | 38.93±3.73<sup>c</sup> |
实施例1 | 10 | 79.01±16.69<sup>d</sup> | 29.36±6.95<sup>d</sup> |
实施例2 | 10 | 77.83±13.82<sup>d</sup> | 29.08±5.58<sup>d</sup> |
实施例3 | 10 | 76.95±12.87<sup>d</sup> | 28.89±2.97<sup>d</sup> |
对比例1 | 10 | 95.25±15.93<sup>e</sup> | 35.92±4.25<sup>c</sup> |
对比例2 | 10 | 101.53±17.15<sup>e</sup> | 40.15±7.68<sup>c</sup> |
对比例3 | 10 | 176.80±11.94<sup>f</sup> | 49.93±9.54<sup>e</sup> |
对比例4 | 10 | 83.04±16.81<sup>e</sup> | 33.26±8.41<sup>c</sup> |
对比例5 | 10 | 89.17±13.46<sup>e</sup> | 35.83±6.75<sup>c</sup> |
注:同一列不同字母之间表示相应组之间比较,P<0.05。
结果分析:模型组的血清ALT、AST与正常组相比均具有显著性(p<0.001),说明CCl4致小鼠急性肝损伤造模成功;本发明组合物血清ALT、AST水平与模型组和对比例组比较显著下降(P<0.05),阳性对照组水飞蓟素组血清ALT,AST含量与模型组比较也显著下降。其中各药味的配伍及纯化工艺步骤对药效结果的影响较大,且具有显著的统计学意义。
试验例2本发明组合物对乙醇引起的小鼠急性肝损伤的治疗作用
2.1实验动物
清洁级雌性昆明种小鼠,体重22-25g,在室温25℃,湿度50%,12小时黑暗,12小时光照的动物室饲养,饲养方式采用立体笼式饲养,给予标准饲料,并且自由饮水。
2.2实验分组及给药
将上述昆明种小鼠110只随机分为11组,每组10只;分别为空白组、模型组、实施例1至实施例3组,对比例1至对比例5组,阳性对照水飞蓟素组100mg/kg。各实施例与对比例组小鼠单次给药剂量为1.5g生药量/kg。
实验动物每日经口灌胃给药,空白对照组和模型对照组给予等量生理盐水,共给药7天,于末次给药后4小时除空白组以外其余各组小鼠一次灌胃给予50%乙醇(12ml/kg),空白对照组给蒸馏水,同时禁食不禁水。给予乙醇12小时后颈动脉取血,分离血清,测定ALT。处死小鼠,取肝脏待测。
肝匀浆生物化学指标测定:取部分肝脏组织,以4℃生理盐水制成10%肝匀浆,3500rpm离心15min,取上清备测肝组织TG、MDA、GSH含量,剩下的部分放在低温冰箱(-80℃)里保存。
2.3实验结果及统计学分析
实验数据用GraphPad Prism程序(GraphPad Software,Inc.,San Diego,USA)进行统计,采用均数±标准差(means±SEM)表示,所有数据用One-way ANOVA和Tukey’smultiple comparison testes进行比较,结果见表2。
表2试验例2各组小鼠生化指标检测结果
注:同一列不同字母之间表示相应组之间比较,P<0.05。
结果分析:脂质代谢紊乱是酒精性肝损伤出现的早期征兆,过量酒精摄入还可导致肝细胞线粒体功能受损,抑制肝脏脂类的氧化利用,导致肝脏甘油三酯(TG)沉积。
本发明组合物对乙醇引起的的小鼠急性肝损伤模型的保护作用,由小鼠肝匀浆中TG、MDA、GSH含量和血清ALT变化评价。模型组的肝匀浆中TG、MDA、GSH含量和血清ALT变化与正常组比较都具有显著性(p<0.001);阳性对照组水飞蓟素组肝匀浆中TG、MDA、GSH含量、ALT水平与模型组比较有显著差异;其中本发明实施例组肝匀浆中TG、GSH含量与阳性组具有显著性差异;MDA的下降与阳性组具有相当的治疗作用。由结果可知,本发明物组合物对改善肝脏生理功能作用显著。
本发明实施例的用途仅用于说明本发明,而非意欲限制本发明的保护范围。此外,在阅读了本发明的技术内容之后,本领域技术人员可以对本发明作各种改动、修改或变型,所有的这些等价形式同样属于本发明申请所附权利要求书所限定的保护范围之内。
Claims (10)
1.一种对化学性肝损伤有保护功能的组合物,其特征在于,所述组合物的原料由以下重量份数的组分组成:葛根8-15份、枳椇子3-10份、五味子3-12份、人参2-9份和香菇2-10份。
2.根据权利要求1所述的组合物,其特征在于,所述组合物的原料由以下重量份数的组分组成:葛根8-10份、枳椇子5-10份、五味子6-12份、人参4-9份和香菇5-10份;
优选地,所述组合物的原料由以下重量份数的组分组成:葛根8份、枳椇子5份、五味子6份、人参4份、香菇5份;
优选地,所述组合物还包括药学上可接受的辅料;优选地,所述辅料选自填充剂、助流剂、润滑剂、粘合剂、崩解剂或矫味剂中的一种或几种。
3.一种根据权利要求1-2任意一项所述的组合物的制备方法,其特征在于,包括如下步骤:
(1)将人参、香菇和五味子粉碎,加水进行水蒸气蒸馏提取,得滤液1、药渣1和挥发油;用β-环糊精包合挥发油得包合物;将滤液1进行酶解,95-100℃将酶灭活,浓缩、干燥得干膏粉1;
(2)将葛根、枳椇子粉碎,和药渣1混合,加70-85%乙醇加热回流提取,过滤得滤液2和药渣2,将滤液2浓缩干燥得干膏粉2,将药渣2加水回流提取过滤,浓缩得浓缩液;
(3)将大孔吸附树脂与大孔阴离子树脂混合,湿法装柱,将浓缩液上柱吸附,然后先用6-8倍柱体积的水洗脱,再用有机溶剂梯度洗脱,合并洗脱液,减压浓缩干燥得干膏粉3;
(4)将包合物、干膏粉1、干膏粉2、干膏粉3和辅料混合均匀,即得。
4.根据权利要求3所述的制备方法,其特征在于,步骤(1)中所述水的质量与人参、香菇和五味子总质量的比为5-8:1;所述提取的时间为5-7h。
5.根据权利要求3所述的制备方法,其特征在于,步骤(1)中所述挥发油与β-环糊精的质量比为1:4.5-5.5,所述包合的时间为1.5-2.5h,所述包合的温度为50-65℃。
6.根据权利要求3所述的制备方法,其特征在于,步骤(1)酶解所用酶为β-葡萄糖苷酶与无花果蛋白酶以质量比5-10:1组成的酶混合物,所述酶混合物的加入量为滤液1质量的0.1-0.3%,所述酶解的温度为45-60℃,所述酶解的时间为0.5-1.5h,酶解的pH为4.0-6.0。
7.根据权利要求3所述的制备方法,其特征在于,步骤(2)中所述70-85%乙醇的质量与葛根、枳椇子和药渣1总质量的比为6-10:1;所述提取的时间为1-2h;所述水与药渣2的质量比为5-10:1;所述药渣2加水回流提取的次数为1-2次,每次提取时间为1-1.5h;步骤(4)中混合均匀后制成口服制剂。
8.根据权利要求3所述的制备方法,其特征在于,步骤(3)中所述大孔吸附树脂与大孔阴离子树脂的质量比为3-6:1;所述用水洗脱时控制洗脱液流速为0.8-1.2mL/min;所述有机溶剂梯度洗脱为依次用3-5倍柱体积的60%乙醇与丙酮的混合溶液、6-8倍柱体积的95%乙醇与正丁醇的混合溶液洗脱。
9.根据权利要求8所述的制备方法,其特征在于,所述60%乙醇与丙酮的体积比为1:0.5-0.8;所述95%乙醇与正丁醇的体积比为1:1-3;所述有机溶剂梯度洗脱时控制洗脱液流速为0.5-0.7mL/min。
10.一种权利要求1-2任意一项所述的组合物或权利要求3-9任意一项所述的制备方法制备得到的组合物在制备治疗化学性肝损伤药物中的应用。
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