CN109512862B - 一种用于护肝的组合物及其制备方法和质量研究 - Google Patents
一种用于护肝的组合物及其制备方法和质量研究 Download PDFInfo
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Abstract
本发明提出了一种护肝的组合物,其特征在于,以重量计,该组合物由葛根1~8份,丹参1~6份,余甘子0.5~5份,灵芝1~6份组成。实验表明,相比于原料分别提取,本发明提出的组合物提取物的提取工艺简单。此外,本组合物的配方中所用材料均容易制粒,同时本组合物显著降低小鼠血清中ALT、AST水平,明显具有保肝护肝作用。
Description
技术领域
本发明涉及药品、食品或保健品领域,特别涉及一种护肝的组合物、其制备方法及质量研究。
背景技术
肝脏是人体中最大的消化腺,能够防御、分解外来和代谢产生的毒素,对维持机体平衡和健康起着至关重要的作用。化学物质通过体循环或胃肠道门静脉进入人体的肝脏进行转化,代谢产生的化学毒性物质极易造成化学性肝损伤。
化学性肝损伤是由多种因素造成的,如受污染的空气、水、食物以及日常生活中所用到的药品、酒精等均可使人体产生大量自由基,造成肝细胞损伤,最终引起化学性肝损伤。根据毒性的强弱,这些亲肝毒物可分为三类:①剧毒类:包括磷、三硝基甲苯、四氯化碳、氯奈、丙烯醛等。②高毒类:砷、汞、锑、苯胺、氯仿、砷化氢、二甲基甲酰胺等。③低毒类二硝基酚、乙醛、有机磷、丙烯腈、铅等。一些亲肝毒物与其他非毒性化学物质结合,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。这些化学物质也包括酒精及某些药物引起的肝损伤,而且酒精肝损伤也是目前最常见的。
近年来,脂肪肝、酒精肝等化学性肝损伤成为了一种常见疾病,俨然成为国人身体健康的严重威胁。目前,脂肪肝、酒精肝的患病人数不断增加,且患病人群的年龄趋于低龄化。所以肝损伤有保护作用的产品的研制与开发已成为当今社会的一个重要课题。
专利CN104667195A公开了一种保护肝脏的组合物,由葛根提取物、丹参提取物、余甘子提取物、灵芝孢子粉和姜黄提取物,但后续研发发现该组合物制粒比较困难,同时服用该组合物会使小鼠体重下降。考虑到安全性问题和制剂质量,经过重新实验考察,将药材提取物换成原药材,并将灵芝孢子粉换成灵芝,可大大改善制粒效果;同时本申请对该组合物做进一步的筛选研究,发现在去除姜黄和进一步的调试比例后,不会引起小鼠体重下降,药效依旧保留甚至更优。
发明内容
有鉴于此,本发明意在提供一种用于护肝的组合物、药品、食品或保健品及其制备方法和质量控制的方法。具体来说,本发明提出了一种护肝的组合物,该组合物可以直接研磨成粉,也可以是经过常规手段制得的提取物或其它形态等,其特征在于,以重量计,该组合物由葛根1~8份,丹参1~6份,余甘子0.5~5份,灵芝1~6份组成。
进一步地,所述组合物由葛根2~6份,丹参2~5份,余甘子1~4份,灵芝2~5份组成。
优选地,所述组合物由葛根3份,丹参3份,余甘子2份,灵芝3份组成。
本发明还提出了一种药品、食品或保健品,其特征在于,该药品、食品或保健品由前述任一所述的组合物与药品或食品上可接受的辅料或添加剂制得。
具体地,所述辅料可以是微晶纤维素、硬脂酸镁、乳糖、交联羧甲基纤维素钠、玉米淀粉、小麦淀粉、马铃薯淀粉、二氧化硅等等。
本发明还提出了一种前述任一所述组合物的制备方法,其特征在于,包括以下步骤:
(A)取药材加入8~14倍量水煎煮提取1~3次,每次0.5~2.0小时,滤过,合并两次提取液,得到滤液;
(B)将所得滤液在60±5℃~80±5℃条件下减压浓缩,并浓缩至相对密度1.10~1.30,60±5℃~80±5℃减压干燥得干浸膏,干浸膏粉碎后过筛,即得。
本发明还提出了上述制备方法制得的组合物。
本发明还提出了前述任一所述组合物在制备护肝的药品、食品或保健品中的应用。该护肝作用优选为对化学性肝损伤有辅助保护作用。
具体地,所述药品或保健品选自胶囊剂、片剂、颗粒剂、丸剂或口服液等等。
本发明还提出了一种用于护肝的颗粒剂的制备方法,其特征在于,该方法包括:取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加10倍量水煎煮提取2次,每次1.0小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏粉碎后过筛,加入辅料适量,混合均匀,制粒、干燥、整粒、即得。
本发明还提出了一种用于护肝的片剂的制备方法,其特征在于,该方法包括:取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加10倍量水煎煮提取2次,每次1.0小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,制粒、压片、包衣,即得。
本发明还提出了一种如前所述药品、食品或保健品中丹参素的检测方法,其特征在于,该方法色谱条件为:Gimini C18色谱柱(4.6mm×250mm,5μm),流动相甲醇(A)–0.5%乙酸水溶液(B)梯度洗脱(30min,10%A;30~40min,10%~95%A;40~50min,95%~10%A;50~60min,10%A)。
进一步地,上述色谱条件中,柱温为室温,流速为1.0mL·min-1,检测波长为280nm,进样体积为10μL。
具体地,当所述药品或保健品选自片剂时,其检测方法包括如下步骤:
(1)对照品溶液的制备:取丹参素钠标准品,加甲醇溶解,并用甲醇定容至刻度,即得对照品母液,移取母液,加甲醇稀释定容,即得对照品溶液;
(2)供试品溶液的制备:取片剂除去包衣,研细,加甲醇,超声处理后,取出放冷至室温后加甲醇稀释至刻度,摇匀,经0.45μm微孔滤膜过滤,即得;
(3)分别吸取所述对照品溶液及供试品溶液按前述色谱条件进行色谱分析,并计算丹参素含量。
本发明的组合物中,葛根属于解表药,可解酒毒,能有效地拮抗酒精导致的肝组织脂质的过氧化损害,促进血液对酒精的排泄和代谢,防止酒精肝纤维化;灵芝安神,补益气血,扶正固本,在《本草纲目》中记载其有解百毒的作用;丹参活血化瘀,丹参的干燥根及根茎具有保肝消痛,安神宁心,活血通经之功效,是常用的活血化瘀中药,中医有“一味丹参饮,功同四物汤”之说;余甘子清热凉血,用于血热血瘀,可以改善肝脏对蛋白质的合成功能,对抗肝纤维化,是一种具有较高的食用和药用价值的野生植物资源,风味独特,营养丰富,保健功能强。因此本发明的组合物是针化学性肝损伤发生机理,运用中医和现代医学理论,各原料协同作用,对化学性肝损伤具有保护作用。实验表明,本发明提出的组合物能显著降低小鼠血清中ALT、AST水平,其对化学性肝损伤有良好的保护作用。
本发明组合物相比于现有技术,优势在于:
1)原有组分灵芝孢子粉含较多油性成分,在制剂过程中,制粒困难,不易成型,本发明选用灵芝药材作为替代品,并将葛根、灵芝、丹参和余甘子合并提取,提取工艺简单,相比于用各提取物混合降低了成本,且制粒质量大大提高。
2)本发明组方省去原组方的姜黄并调整其他药比例后,不会引起小鼠体重下降,保肝护肝作用依旧保留甚至更优。
附图说明
图1为丹参素测定过程对照品的HPLC图;
图2为丹参素测定过程检测条件优化前供试品HPLC图;
图3为丹参素测定过程检测条件优化后供试品HPLC图。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明提供的组合物、制剂,其制备方法及质量检测进行详细说明,本发明的保护范围不受以下实施例的限制。
药效实验部分,采用卫生部发布的《保健食品检验与评价技术规范》(2003版)中“对化学性肝损伤有辅助保护作用”(四氯化碳肝损伤模型)进行研究。
本发明所用的组分如葛根、灵芝、丹参和余甘子均为市售中药材。需要注意的是,如未注明具体条件者,均按照常规条件或制造商建议的条件进行,所用原料或辅料,以及所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。除非另外说明,否则所有的百分数、比率、比例或份数按重量计。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用与本发明。
实验1制粒调试
根据专利CN104667195A公开的一种保护肝脏的组合物,由葛根提取物、丹参提取物、余甘子提取物、灵芝孢子粉和姜黄提取物,其中,在制剂过程中,因灵芝孢子粉中含有灵芝孢子油,导致制粒困难,不易成型。据文献报道,灵芝与灵芝孢子粉在成份和功能上相近;并且,CN104667195A使用市售药材提取物使制粒不均一,难以融合,所以考虑将灵芝替换灵芝孢子粉,并与各原药材一起煎煮。结果见表1:
实施例1
取葛根提取物7重量份数、丹参提取物5重量份数、余甘子提取物4重量份数、灵芝孢子粉5重量份数和姜黄提取物6重量份数,过筛后,混合均匀,得组合物(CN104667195A最优实施例)。
实施例2
取葛根7重量份数、丹参5重量份数、余甘子4重量份数、灵芝5重量份数和姜黄6重量份数,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
表1制粒效果
由表1可知,当灵芝孢子粉换成灵芝时,且将各药材提取物换成原药材时,制粒效果有明显改善,制粒后有颗粒,且整粒时无结块。
实验2针对导致小鼠体重下降的处方研究
专利CN104667195A中的保护肝脏组合物经后续研发发现服用时会使小鼠体重下降,考虑到安全性问题,对其进行了拆方实验,研究是哪种药材使小鼠体重下降。
实施例3
取丹参5重量份数、余甘子4重量份数、灵芝5重量份数和姜黄6重量份数,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例4
取葛根7重量份数、余甘子4重量份数、灵芝5重量份数和姜黄6重量份数,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例5
取葛根7重量份数、丹参5重量份数、灵芝5重量份数和姜黄6重量份数,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例6
取葛根7重量份数、丹参5重量份数、余甘子4重量份数和姜黄6重量份数,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例7
取葛根7重量份数、丹参5重量份数、余甘子4重量份数、灵芝5重量份数,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
空白组:给予蒸馏水,按照0.1mL/10g体重给小鼠灌胃。
实施例组:按照小鼠每1千克体重给予组合物0.3克的标准,将组合物制备成水溶液,浓度为0.03g/mL,按照0.1mL/10g体重给小鼠灌胃。
80只ICR小鼠随机分为8组,每组10只。每日经口灌胃给予实施例1~7中的组合物,空白组给予蒸馏水。测量给药前及给药30天后的体重。
表2各组30天喂养对小鼠体重的影响
与空白组比较:+P<0.05;++P<0.01
由表2可知,空白组及实施例7组动物体重逐期增长,实施例1~6组动物体重与空白组相比增长缓慢,末期体重与空白组相比有显著差异,实施例7中动物体重增长与空白组相比无明显变化,推测姜黄是导致小鼠体重增长缓慢的原因。
实验3组方药物比例筛选实验
为避免姜黄带来可能的不良反应,在组方中考虑省去姜黄,为了使其他药材配伍达到更好的效果,特设置以下比例进行筛选。
实施例8
取葛根4重量份、丹参2重量份、余甘子1重量份、灵芝4重量份,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例9
取葛根4重量份、丹参3重量份、余甘子2.5重量份、灵芝3重量份,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例10
取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
实施例11
取葛根3重量份、丹参2重量份、余甘子1重量份、灵芝2重量份,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,得组合物。
空白组:给予蒸馏水,按照0.1mL/10g体重给小鼠灌胃。
模型组:给予蒸馏水,按照0.1mL/10g体重给小鼠灌胃。
实施例组:按照小鼠每1千克体重给予组合物0.3克的标准,将组合物制备成水溶液,浓度为0.03g/mL,按照0.1mL/10g体重给小鼠灌胃。
80只ICR小鼠随机分为8组,每组10只。每日经口灌胃给予实施例1、7~11中的组合物,空白组、模型组给予蒸馏水。30天后,各组动物隔夜禁食16h,模型组及各实验组一次灌胃给予0.5%的四氯化碳溶液0.1mL/10g体重,空白组给予植物油,各实验组继续给予组合物(与四氯化碳灌胃间隔4h以上)。给予四氯化碳24小时后处死动物,取血分离血清,测定ALT、AST值。
造模前,各组小鼠可正常饮食,皮毛光滑,活动良好,反应敏捷。
表3各组30天喂养对小鼠ALT、AST的影响
与空白组比较:+P<0.05;++P<0.01;与模型组比较:*P<0.05;**P<0.01
由表3可知,与现有技术实施例1相比,经过各药材比例调试,结果显示,实施例7-11均有一定的护肝作用,其中以实施例10的护肝效果最佳。
实验4本发明制剂的制备
实施例12片剂的制备
取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加12倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,制粒、压片、包衣、包装,得到对肝损伤有保护作用的组合物片剂。
实施例13胶囊剂的制备
取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加10倍量水煎煮提取1次,每次1.0小时,滤过,在60±5℃条件下减压浓缩,并浓缩至相对密度1.10,60±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,制粒、干燥、整粒、灌装、包装,得到对肝损伤有保护作用的组合物胶囊剂。
实施例14颗粒剂的制备
取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加14倍量水煎煮提取3次,每次2.0小时,滤过,合并三次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,制粒、干燥、整粒、包装,得到对肝损伤有保护作用的组合物颗粒剂。
实施例15丸剂的制备
取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加10倍量水煎煮提取2次,每次0.5小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,制丸、打光、包衣、包装,得到对肝损伤有保护作用的组合物丸剂。
实施例16口服液的制备
取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加12倍量水煎煮提取2次,每次3.0小时,滤过,合并两次提取液,在80±5℃条件下减压浓缩,并浓缩至相对密度1.30,80±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,配制、灌装、包装,得到对肝损伤有保护作用的组合物口服液。
实验5本发明制剂质量研究
针对实施例12所得的组合物片剂,本发明还优化了组合物片剂中丹参素的检测方法。
《保健食品功效成分检测方法》(主编:白鸿)是保健食品检测的主要参考标准,按照其中“丹参素钠的高效液相色谱测定法”对实施例12所得组合物片剂中丹参素的含量进行测定,结果表明峰形差,无法准确计算出丹参素含量;故对该方法进行优化,经方法学验证,优化后的方法适用于实施例12所得组合物片剂中丹参素的含量测定。
1、优化前色谱条件
Gimini C18色谱柱(4.6mm×250mm,5μm),流动相甲醇(A)–1%乙酸水溶液(B)(10+90,V/V)等度洗脱,洗脱时间60min,柱温为室温,流速为1.0mL·min-1,检测波长为280nm,进样体积为10μL。
2、优化后色谱条件
Gimini C18色谱柱(4.6mm×250mm,5μm),流动相甲醇(A)–0.5%乙酸水溶液(B)梯度洗脱(30min,10%A;30~40min,10%~95%A;40~50min,95%~10%A;50~60min,10%A),柱温为室温,流速为1.0mL·min-1,检测波长为280nm,进样体积为10μL。
3、对照品溶液的制备
取丹参素钠标准品10mg于100mL棕色量瓶中,精密称定,加甲醇溶解,超声助溶,并用甲醇定容至刻度,即得100μg/mL的对照品母液。移取母液1mL于2mL量瓶中,加甲醇稀释定容,即得对照品溶液。
4、供试品溶液的制备
取实施例12制备的片剂20片,除去包衣,研细混匀,取1.0g,精密称定,置于50mL棕色量瓶中,加甲醇40mL,超声处理30min,取出,放冷至室温后加甲醇稀释至刻度,摇匀,经0.45μm微孔滤膜过滤,清液待分析。
5、结果分析
分别吸取对照品溶液及供试品溶液10μL,分别按照优化前色谱条件和优化后的色谱条件进行色谱分析,结果表明优化前供试品中目标峰的峰形差,无法与基线分离,积分得到的峰面积偏大,导致计算得到的丹参素含量偏高;优化后的供试品中目标峰的峰形较好,且能够进行有效积分,能够准确计算。色谱图见图1、图2和图3。实施例12所得片剂中丹参素通过条件优化使分离梯度加大,杂质峰被分离出来,最终检测结果更精确,丹参素含量优化前后测量数值下降50%,从而更准确的对产品进行质量控制。优化前与优化后产品中丹参素测量值见表4。
表4优化前与优化后产品中丹参素测量值(g/100g)
以上实施例份说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通季度人员来说,在不脱离本发明原理的前提下,还可以对本发明进场若干修改和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (6)
1.一种护肝的组合物,其特征在于,所述组合物由葛根3份,丹参3份,余甘子2份,灵芝3份组成。
2.一种如权利要求1所述组合物的制备方法,其特征在于,包括以下步骤:
(A)取药材加入8~14倍量水煎煮提取1~3次,每次0.5~2.0小时,滤过,合并提取液,得到滤液;
(B)将所得滤液在60±5℃~80±5℃条件下减压浓缩,并浓缩至相对密度1.10~1.30,60±5℃~80±5℃减压干燥得干浸膏,干浸膏粉碎后过筛,即得。
3.如权利要求2所述制备方法制得的组合物。
4.权利要求1或3任一项所述的组合物在制备护肝的药品、食品或保健品中的应用。
5.一种药品、食品或保健品,其特征在于,该药品、食品或保健品由权利要求1或3任一所述的组合物与药学或食品上可接受的辅料或添加剂制得。
6.一种用于护肝的片剂的制备方法,其特征在于,该方法包括:取葛根3重量份、丹参3重量份、余甘子2重量份、灵芝3重量份,加10倍量水煎煮提取2次,每次1.0小时,滤过,合并两次提取液,在70±5℃条件下减压浓缩,并浓缩至相对密度1.20,70±5℃减压干燥得干浸膏,干浸膏用万能粉碎机粉碎后过筛,加入辅料适量,混合均匀,制粒、压片、包衣,即得。
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