CN116159114A - 一种芪斛消积饮的新型发酵制备工艺及制品 - Google Patents
一种芪斛消积饮的新型发酵制备工艺及制品 Download PDFInfo
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Abstract
本发明属于中药制剂制备技术领域,具体公开了一种芪斛消积饮的新型发酵制备工艺及制品,所述新型发酵制备工艺包括药材称取、PDA培养基配制、黑曲霉和酵母菌活化、混合发酵、回流提取步骤。本发明将双向发酵技术与抗癌经验方“芪斛消积饮”相结合,以黑曲霉和酵母菌作为药用菌,“芪斛消积饮”七位生药作为药用基质,进行组合发酵。与传统炮制的原方相比,一方面芪斛消积饮有效成分含量得到提高,更易被人体吸收,生成新的潜在药效活性成分,显著改善芪斛消积饮的生物利用度;另一方面对肿瘤细胞的杀伤力、对免疫细胞的吞噬活性以及对机体的抗炎活均得到显著提升,丰富了芪斛消积饮双向发酵的药效作用机制研究。
Description
技术领域
本发明涉及中药制剂制备技术领域,具体涉及一种芪斛消积饮的新型发酵制备工艺及制品。
背景技术
“芪斛消积饮”是上海“张氏内科”第十二代传人、“国医大师”张镜人教授的经验方,由黄芪、女贞子、石见穿、薏苡仁、野葡萄藤、藤梨根和制香附共七味药煎煮制得,具扶正祛邪、健脾补肾、活血化浊、解毒通络之功效,常用于胃肠肿瘤及术后,已临床应用近20年。
自神农尝百草时期以来便流传下了丰富的中药复方,这些复方凭借着中医“辨证施治”、“多靶点治疗”、“整体系统”的医治主旨以及上千年的临床经验,为人类的健康作出了杰出贡献。然而,中药复方存在着相当的局限性,芪斛消积饮也不例外,芪斛消积饮是由药用植物经炮制等工艺制得的生药组成,其本身还保留了大量植物细胞壁成分如纤维素、木质素等,这些物质会影响人体对复方药用成分的吸收,极大降低芪斛消积饮的生物利用度,从而影响药效。
中药发酵是指中药经发酵菌丰富的酶系统催化分解作用后,纤维素结构松散,更易于吸收,进而改善药性药效的方法。由于各微生物在发酵过程中具备着强大的生物转化潜力,同时能产生丰富的次生代谢产物,有着传统中药炮制工艺所无法比拟的优势,因此中药发酵一直是研究的热点。而双向发酵作为一种新型发酵理念,更是成为发酵领域中炙手可热的话题。双向发酵指以含有活性成分的中草药作为发酵的药性基质,以有益的药用菌作为发酵的菌种,中药基质为菌提供生长所必须的碳源、氮源等养分,药用菌的生长活动则驱动中药药性基质中的有效成分转化,相互搭配,共生共长,从而形成了这种新型(双向性)发酵工程。然而,由于中药配方的组分复杂多样,双向发酵在中药方面的应用难度比较大,目前并未有将双向发酵应用在芪斛消积饮制剂生产方面的研究,发酵菌种的选择、综合药效机制的阐明等问题,都有待于进一步的研究探索。
发明内容
基于上述问题,本发明的目的之一是提供一种芪斛消积饮的新型发酵制备工艺,采用多菌种双向发酵方式,能够有效提高芪斛消积饮的生物利用度,并丰富其双向发酵的药效机制研究。
为达到上述目的,本发明采用的具体技术方案如下:
一种芪斛消积饮的新型发酵制备工艺,包括以下步骤:
S1.称取黄芪、女贞子、石见穿、薏苡仁、藤梨根、野葡萄藤、制香附七位药材,将药材粉碎研磨成药渣后混匀,作为药用基质;
S2.称取煮烂马铃薯泥和葡萄糖,溶解于超纯水中,配制成PDA马铃薯液体培养基,高温灭菌后取出,冷却备用;
S3.取黑曲霉冻干粉、干酵母粉,分别加入PDA马铃薯液体培养基,于温控摇床在37℃下进行摇菌活化,获得黑曲霉和酵母菌的发酵母液;
S4.分别将黑曲霉和酵母菌的发酵母液进行离心处理,弃去上清液,收集沉淀的菌群,备用;
S5.挑取黑曲霉、酵母沉淀菌群,加入超纯水混悬均匀,作为混合发酵液;将步骤S1制备的药渣和混合发酵液加入发酵罐中,于37℃进行有氧发酵;
S6.取出发酵物,使用乙醇浸润后进行回流提取,过滤残渣,收集滤液;将滤液旋蒸浓缩至浓稠的墨绿色浸膏;将墨绿色浸膏进行真空冻干处理,制得发酵芪斛消积饮冻干粉末。
优选的,步骤S1中,称取的药材分量为:黄芪30g、女贞子15g、石见穿30g、薏苡仁30g、藤梨根30g、野葡萄藤30g、制香附10g。该配方为芪斛消积饮经验方用药配比,药效最佳。
优选的,步骤S5中,黑曲霉、酵母沉淀菌群各挑取两环,加入50ml超纯水,混悬均匀作为混合发酵液,接种到上述配方含量的芪斛消积饮药渣中;在发酵罐中将混合发酵液和药渣混合并搅拌均匀,使发酵液充分接触药渣,然后补足50-100ml的超纯水湿润药渣,使发酵体系处于一种润湿而不浸出液体的状态。
优选的,步骤S5中,有氧发酵的时间为4天,期间每日搅拌混匀,使发酵菌和药用基质充分反应。发酵4天为最佳时长,此时黑曲霉生长最为旺盛,并且发酵产物对HCT-8细胞的增殖抑制效果也最为显著。
优选的,步骤S3中,黑曲霉活化的时间为5天,酵母菌活化的时间为2天。
优选的,步骤S6中,按照w/v=1:10的比率进行回流提取;旋转蒸发的条件为60℃,50rpm。
本发明的目的之二是提供利用上述方法制备得到的芪斛消积饮制品。
与现有技术相比,本发明具有以下有益效果:
本发明将双向发酵技术与抗癌经验方“芪斛消积饮”相结合,以黑曲霉和酵母菌作为药用菌,“芪斛消积饮”七位生药作为药用基质,研究出了一种新型的多菌双向发酵复方。该发酵复方与传统炮制的原方相比,具有显著优势:一方面是有效成分含量得到提高,更易被人体吸收,生成新的潜在药效活性成分,显著改善了芪斛消积饮的生物利用度;另一方面是对肿瘤细胞的杀伤力、对免疫细胞的吞噬活性以及对机体的抗炎活均得到了显著提升,丰富了芪斛消积饮双向发酵的药效作用机制研究。
附图说明
图1:实施例1中发酵候选菌种平板混合培养实验的结果图。图中,a为黑曲霉+枯草芽孢杆菌(HQ+KC);b为康氏木霉+黑曲霉(KM+HQ);c为康氏木霉+枯草芽孢杆菌(KM+KC);d为康氏木霉+酵母菌(KM+JM);e为黑曲霉+酵母菌(HQ+JM);f为枯草芽孢杆菌+酵母菌(KC+JM)。
图2:实施例2中黑曲霉和酵母菌组合发酵分时段取样镜检图。图中,A1-E1分别为发酵第1-5天。
图3:实施例2中黑曲霉和酵母菌组合发酵产物的HCT-8细胞增殖抑制曲线。图中,D1-D7分别为发酵第1-7天。
图4:实施例3和对比例1制品对RAW264.7的吞噬活性系数。图中,FD为发酵复方;NFD为原方;CON为阴性对照组;POS为阳性对照组。
图5:实施例3和对比例1制品对RAW264.7的一氧化氮释放系数。图中,FD为发酵复方;NFD为原方;CON为阴性对照组;MOD为模型组。
图6:实施例3和对比例1制品的负离子叠加质谱图。图中,A为发酵复方,B为原方。
图7:实施例3和对比例1制品的正离子叠加质谱图。图中,A为发酵复方,B为原方。
具体实施方式
以下结合附图和具体实施例对本发明进行进一步的说明。
实施例1
本实施例为芪斛消积饮发酵菌种的筛选,具体过程如下:
一、发酵菌种的拟定
查找文献中具有提高免疫力或者抑制肿瘤细胞应用的菌种,拟定康氏木霉(KM)、黑曲霉(HQ)、枯草芽孢杆菌(KC)和酵母菌(JM)为发酵候选菌种。
二、发酵菌种的筛选
(1)平板混合培养实验
将发酵候选菌两两组合,共得到KM+HQ、KM+KC、KM+JM、HQ+KC、HQ+JM、KC+JM六组,经六组混合菌种分别在平板上进行混合培养,结果如图1所示,除黑曲霉和枯草芽孢杆菌之间菌落间有明显分隔线,其它组合均未显示出菌种间的生长拮抗关系。另外,酵母菌进入生长对数期较快,菌群聚集紧凑,不形成辐射态,对其他菌的生长影响小。
(2)CCK-8增殖抑制率实验
基于单菌种发酵和多菌种混合发酵(包括两菌种组合发酵和三菌种组合发酵)筛选发酵菌种,共计14组(具体组合如下表1所示),菌种活化后进行菌液混合制成混合发酵液,与芪斛消积饮七位生药药渣混合,37℃下发酵3天,所得产物经旋蒸、浓缩冻干,进行HCT-8结肠癌细胞株的CCK-8增殖抑制率实验,评价候选菌各组合的优劣。
结果如表1所示,酵母菌单菌种发酵产物对HCT-8不存在增殖抑制作用,其余候选菌种发酵产物对HCT-8均存在不同程度的增殖抑制作用,贡献率依次为黑曲霉>康氏木霉>>枯草芽孢杆菌。各发酵组合所得产物相较于不发酵的生药对照组,对HCT-8的增殖抑制作用均具有显著性。两菌种组合发酵与单菌种发酵结果相比,趋势基本吻合,但黑曲霉和酵母菌组合的发酵产物对HCT-8的增殖抑制作用得到增强,显示为最优组合。三菌种组合发酵的结果较复杂,酵母菌的加入提高了黑曲霉+康氏木霉、康氏木霉+枯草芽孢杆菌组合所得发酵产物的HCT-8的增殖抑制作用,而枯草芽孢杆菌的加入则削弱了黑曲霉+康氏木霉、酵母菌+黑曲霉发酵组合所得发酵产物的HCT-8的增殖抑制作用,进一步说明酵母菌尽管单菌种发酵产物对HCT-8不存在增殖抑制作用,但是在多菌种组合发酵中存在独特的贡献,此外,黑曲霉和康氏木霉均为发酵优势菌,但康氏木霉在多菌种组合发酵中表现不如黑曲霉菌。综合来看,黑曲酶和酵母的组合抑制增殖效果最佳,结合平板培养结果,选择该组合为发酵菌种。
表1发酵候选菌种不同组合所得发酵产物对HCT-8结肠癌细胞的半数增殖抑制率IC50
注:生药对照组为未经发酵处理的实验组。表中↑、‖、↓分别表示在原发酵组合(下划线)基础加入新菌种后所得发酵产物对HCT-8的增殖抑制效果得到提升、无显著变化、下降。
实施例2
本实施例为芪斛消积饮发酵条件的优化,具体过程如下:
(1)镜检形态观察
为确定最佳发酵时间,在总发酵时段7天(依次以D1-D7表示)的基础上,对发酵产物进行分时段取样分析,在光学显微镜下观察发酵菌种形态。结果如图2所示,对于黑曲霉+酵母菌发酵组合,D1以酵母菌为主,未见黑曲霉,D2开始可见黑曲霉若干,D3可见大量黑曲霉,D4黑曲霉数量减少,细胞出现皱缩,D5开始几乎不见黑曲霉,因此最佳发酵时长为3-4天。
(2)CCK-8增殖抑制率实验
利用CCK-8增殖抑制率实验,分析发酵时间对发酵产物药理活性的影响。结果如图3和下表2所示,黑曲霉和酵母菌两菌种组合发酵所得产物在发酵初期(1-2D)对于HCT-8细胞的增值抑制率均不明显,至发酵中期(3-5D),黑曲霉达到对数生长期,对药材基质的发酵作用达到高峰,可能形成新的抗肿瘤活性成分,展现出对HCT-8细胞增殖抑制的最佳效果,而发酵后期(5-7D),黑曲霉进入分生孢子繁殖期,发酵活力下降,同时菌丝体表面产生疏水层物质,进一步阻碍其与药材基质发生相互作用,使得发酵产物对HCT-8细胞的增殖抑制效果减弱。综合来看,发酵4天增殖抑制效果最强,结合镜检结果,确定最佳发酵时长为4天。
表2HQ+JM两菌种组合发酵第1-7天所得产物对HCT-8细胞的半数抑制率(IC50)
实施例3
本实施例为一种新型芪斛消积饮的新型发酵制备工艺,具体包括以下步骤:
S1.称取黄芪30g、女贞子15g、石见穿30g、薏苡仁30g、藤梨根30g、野葡萄藤30g、制香附10g,将上述共175g药材粉碎研磨成药渣后混匀,作为药用基质;
S2.称取煮烂马铃薯泥200g、葡萄糖20g溶解于1000ml超纯水中,配制成PDA马铃薯液体培养基,置于高压灭菌锅于121℃灭菌30min后取出,冷却备用;
S3.取黑曲霉冻干粉、干酵母粉,分别倒入两只250ml烧瓶中,各加入150ml的PDA马铃薯液体培养基,使用透气膜封好瓶口,于温控摇床下在37℃、200rpm的条件下进行摇菌活化,黑曲霉活化5天,酵母菌活化2天,获得黑曲霉和酵母菌的发酵母液;
S4.分别将黑曲霉和酵母菌的发酵母液收集到50ml离心管中,于15℃、1200rpm条件下进行高速离心,弃去上清液,收集沉淀的菌群,于4℃下保存备用;
S5.用接种环挑取黑曲霉、酵母沉淀菌群各两环于离心管中,加入50ml超纯水,混悬均匀作为混合发酵液;步骤S1中175g药渣置于容量1L的发酵罐中后,倒入混合发酵液,搅拌均匀,使发酵液充分接触药渣,并补足50-100ml的超纯水湿润药渣,使得发酵体系处于一种润湿而不浸出液体的状态;使用透气封口膜封好发酵罐瓶口,将发酵罐置于温控培养箱中,于37℃下有氧发酵4天,期间每日搅拌混匀,使发酵菌和药用基质充分反应;
S6.取出发酵物,用95%的乙醇浸润,并按照w/v=1:10的比率回流提取2h后过滤残渣,收集滤液;滤液通过旋转蒸发仪于60℃,50rpm下旋蒸浓缩至浓稠的墨绿色浸膏;收集浸膏置于-80℃冰箱中预冷一晚后进行真空冻干处理,制得发酵芪斛消积饮冻干粉末。
对比例1
本对比例为传统的芪斛消积饮炮制工艺,与实施例3所述的制备工艺相比,无发酵过程,药渣直接经回流提取、旋蒸浓缩、真空冻干,得到制品。
性能测试:用实施例3和对比例1制备得到的芪斛消积饮制品(分别记作发酵复方和原方)进行以下试验。
一、抗肿瘤活性测试
使用发酵复方和原方对人源结直肠癌细胞株HCT-8进行CCK-8细胞增殖活性实验,结果为发酵复方的半数抑制率IC50为27.855ug/ml,原方IC50为729.815ug/ml。因此,发酵复方相较于原方具有更好的抗肿瘤活性。
二、免疫促进活性测试
使用发酵复方和原方对小鼠巨噬细胞RAW264.7进行吞噬活性实验,结果如图4所示,发酵复方与原方相较于阴性对照组(培养基处理)均显著提升了巨噬细胞的吞噬活性,且发酵复方相较于原方在提升巨噬细胞吞噬活性方面具有显著性,此外发酵复方在100-400ug/ml浓度梯度下相较于阳性对照组(脂多糖5ug/ml)也具有显著性。因此,发酵复方相较于原方具有更好的免疫促进活性。
三、抗炎活性测试
使用发酵复方和原方对小鼠巨噬细胞RAW264.7进行NO释放率实验,结果如图5所示,发酵复方与原方相较于模型组(脂多糖5ug/ml)均能抑制LPS导致的炎症因子NO释放升高,而发酵复方相较于原方在抑制LPS所介导的炎症因子NO释放升高方面具有显著性。因此,发酵复方相较于原方具有更好的抗炎活性。
四、成分检测
使用HPLC/MS/MS-Q-TOF对发酵复方和原方中所含化合物进行检测,并通过PCDLManager B.08.00、Qualitative Navigator B.08.00、Qualitative Workflows B.08.00软件对数据进行定性对比分析,结果如下表3-7以及图6-7所示。如图6-7所示,根据出峰对比可以明显看出,发酵复方相较于原方,汉黄芩素、皂苷等多种物质含量有了明显提升;并且,发酵复方相较于原方,还产生了具有潜在药效的新化合物(图7中标记出的a峰);更加具体的,如表3-6所示,发酵复方相较于原方,药效化合物含量(汉黄芩素)得到显著提升;如表7所示,发酵复方相较于原方,大部分具有药理活性的皂苷含量得到显著提升。由此可见,经发酵后芪斛消积饮的生物利用度得到显著改善。
表3发酵复方正离子模式主要成分(>4%)
表4原方正离子模式主要成分(>4%)
化合物归属 | 化合物 | 含量百分比 |
黄芪 | 汉黄芩素 | 0.11649294 |
黄芪 | 脯氨酸 | 0.099182265 |
黄芪 | 毛蕊异黄酮苷 | 0.070759996 |
藤梨根 | 秦皮素 | 0.06171834 |
黄芪 | 芒柄花苷 | 0.041094812 |
表5发酵复方负离子模式主要成分(>4%)
表6原方负离子模式主要成分(>4%)
表7发酵复方与原方皂苷含量对比
本具体实施方式仅仅是对本发明的解释,并不是对本发明的限制,本领域技术人员在阅读了本发明的说明书之后所做的任何改变,只要在本发明权利要求书的范围内,都将受到专利法的保护。
Claims (7)
1.一种芪斛消积饮的新型发酵制备工艺,其特征在于:包括以下步骤:
S1.称取黄芪、女贞子、石见穿、薏苡仁、藤梨根、野葡萄藤、制香附七位药材,将药材粉碎研磨成药渣后混匀,作为药用基质;
S2.称取煮烂马铃薯泥和葡萄糖,溶解于超纯水中,配制成PDA马铃薯液体培养基,高温灭菌后取出,冷却备用;
S3.取黑曲霉冻干粉、干酵母粉,分别加入PDA马铃薯液体培养基,于温控摇床在37℃下进行摇菌活化,获得黑曲霉和酵母菌的发酵母液;
S4.分别将黑曲霉和酵母菌的发酵母液进行离心处理,弃去上清液,收集沉淀的菌群,备用;
S5.挑取黑曲霉、酵母沉淀菌群,加入超纯水混悬均匀,作为混合发酵液;将步骤S1制备的药渣和混合发酵液加入发酵罐中,于37℃进行有氧发酵;
S6.取出发酵物,使用乙醇浸润后进行回流提取,过滤残渣,收集滤液;将滤液旋蒸浓缩至浓稠的墨绿色浸膏;将墨绿色浸膏进行真空冻干处理,制得发酵芪斛消积饮冻干粉末。
2.根据权利要求1所述的芪斛消积饮的新型发酵制备工艺,其特征在于:步骤S1中,称取的药材分量为:黄芪30g、女贞子15g、石见穿30g、薏苡仁30g、藤梨根30g、野葡萄藤30g、制香附10g。
3.根据权利要求2所述的芪斛消积饮的新型发酵制备工艺,其特征在于:步骤
S5中,黑曲霉、酵母沉淀菌群各挑取两环,加入50ml超纯水,混悬均匀作为混合发酵液;在发酵罐中将混合发酵液和药渣混合并搅拌均匀,然后补足50-100ml的超纯水湿润药渣,使发酵体系处于一种润湿而不浸出液体的状态。
4.根据权利要求3所述的芪斛消积饮的新型发酵制备工艺,其特征在于:步骤
S5中,有氧发酵的时间为4天,期间每日搅拌混匀。
5.根据权利要求1所述的芪斛消积饮的新型发酵制备工艺,其特征在于:步骤S3中,黑曲霉活化的时间为5天,酵母菌活化的时间为2天。
6.根据权利要求1所述的芪斛消积饮的新型发酵制备工艺,其特征在于:步骤S6中,按照w/v=1:10的比率进行回流提取;旋转蒸发的条件为60℃,50rpm。
7.利用权利要求1-6任一所述的芪斛消积饮的新型发酵制备工艺制备得到的芪斛消积饮制品。
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