CN113398186A - 一种紫花地丁提取物及其制备方法和应用 - Google Patents
一种紫花地丁提取物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种紫花地丁提取物及其制备方法和应用,属于生物医药技术领域。本发明使用传统的水煎处理紫花地丁药材,并结合酶解法使提取液中的苷元游离出来,再用乙醇富集其中的极性、弱极性化合物,为制剂化奠定良好的物质基础。药理试验表明,该方法得到的紫花地丁提取物可以改善病毒性心肌炎小鼠的心功能及心肌组织炎症状态,表明该提取物对病毒性心肌炎有较好的心肌保护作用,因此具有良好的实际应用之价值。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种紫花地丁提取物及其制备方法和应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
紫花地丁为堇菜科植物紫花地丁Violaye doensis Makino的干燥全草,在国内有广泛的分布,药材资源丰富。紫花地丁味苦、辛,性寒,归心、肝经,具有清热解毒、凉血消肿之功效,《要药分剂》有“《纲目》止疗外科症,但古人每用治黄疸、喉痹,取其泄热除湿之功也。大方家亦不可轻弃”之说,用于疗疮肿毒,痈疽发背,丹毒,蛇毒咬伤等。现代药理研究表明,紫花地丁具有抗菌、抗炎、免疫调节、抗氧化、抗肿瘤等作用,还有广谱抗病毒作用(崔雪等,紫花地丁化学成分和抗病毒作用的研究进展,食品与药品,2020年第3期)。
紫花地丁含黄酮类、香豆素类、甾体类、环肽化合物、酰胺类、有机酸类、萜类和木脂素类等化学成分;近年来的研究表明,香豆素类为其抗菌的主要成分;此外,针对其他成分的研究也表明,紫花地丁中的不同成分有不同的药理作用。
中药现代化的主要目的之一是结合现代技术将传统中药的“粗、大、黑”转化为精致、高效、便于携带的剂型。因此,提取有效成分或部位,最大限度的去除杂质,是中药现代化普遍研究的课题之一。对于紫花地丁药材精制研究,近年来屡见不鲜,但是受紫花地丁中化学成分的理化性质限制,均以乙醇回流为提取第一步,其目的为提取得到药材中的黄酮、香豆素类成分。比如中国专利CN105770207A、CN10341749A、CN102526357A等,以及目前可查阅到的科技文献,大多采取了上述方法,其原因多是因为其中的化学成分易溶于乙醇。
殊不知紫花地丁为全草类药材,其叶占全草的80~95%,叶片中叶绿素的含量巨大,经乙醇回流后,大部分叶绿素会析出到溶剂中,后续浓缩、过滤步骤需要考虑如何去除叶绿素。同时,经乙醇提取后,基本上都有回收乙醇浓缩的步骤,在这个步骤中,有部分的水不溶性物质会析出,反而在提取率上打了折扣。因此,上述专利中涉及的技术如果转化到大生产,需要极大的成本,并且提取率并不一定高出许多。
在传统理论中,药材处置大多选择水煎、磨粉或者绞汁等,同样能发挥较好的药效。《备急千金药方》中记载,单用紫花地丁治疗疔疮肿毒,其方法为“紫花地丁草,捣汁服”,其余方剂中,紫花地丁的用法也大多为水煎处理。
作为全草类药材,紫花地丁在方剂中的用量往往较大,如银花解毒汤、五神汤等。因此,目前仍然需要一种对紫花地丁药材进行处理的方法,既能符合传统的中医药理论,又能较好的实现精制的目的。
植物中的黄酮、甾体类化合物,大部分以苷的形式存在,因此有人提出在提取过程中使用酶将苷元游离出来,再用极性溶剂提取,可以更充分的提取有效成分,但是在提取过程中使用酶作为辅助,对提取条件(包括温度、酸碱度、时间等)有更加苛刻的要求,这种情况对最终提取物的影响如何尚未有人做出评估,而中药发挥其作用,是通过其水煎液中的各种成分发挥不同的作用而实现的,因此,对中药材水煎的过程应尽量保持不变。
发明内容
基于上述现有技术的不足,本发明提供一种紫花地丁提取物及其制备方法和应用。本发明使用传统的水煎处理紫花地丁药材,并结合酶解法使提取液中的苷元游离出来,再用乙醇富集其中的极性、弱极性化合物。此外,本发明通过动物实验,还发现了通过本发明制备得到的紫花地丁提取物具有改善病毒性心肌炎小鼠心脏功能的作用,因此具有良好的实际应用之价值。
为实现上述技术目的,本发明涉及以下技术方案:
本发明的一个方面,提供一种紫花地丁提取物的制备方法,所述制备方法包括将紫花地丁煎煮、酶解、提取的步骤;
其中,酶解步骤中,所用的酶为纤维素酶、中性蛋白酶、木瓜蛋白酶、β-葡萄糖苷酶中的任意一种或多种。
本发明的第二个方面,提供上述制备方法制备得到的紫花地丁提取物。经试验验证,所述紫花地丁提取物具有改善病毒性心肌炎小鼠心脏功能的作用。
因此,本发明的第三个方面,提供上述紫花地丁提取物在制备炎症相关疾病的药物中的应用。
其中,所述炎症相关的疾病包括脓毒症、肺炎、肝炎、类风湿关节炎、***性红斑狼疮、哮喘、病毒性心肌炎、急性呼吸窘迫综合征、胰腺炎、败血症、溃疡性结肠炎、支气管炎和感染性心内膜炎,优选为病毒性心肌炎。
本发明的第四个方面,提供一种药物组合物,所述药物组合物其活性成分包含上述紫花地丁提取物。
进一步的,所述药物组合物还包括至少一种药物活性成分或药学上的载体。
本发明的第五个方面,提供一种治疗炎症相关疾病的方法,所述方法包括:向受试者施用有效剂量的上述紫花地丁提取物或上述药物组合物。
所述炎症相关疾病包括脓毒症、肺炎、肝炎、类风湿关节炎、***性红斑狼疮、哮喘、病毒性心肌炎、急性呼吸窘迫综合征、胰腺炎、败血症、溃疡性结肠炎、支气管炎和感染性心内膜炎,优选为病毒性心肌炎。
上述一个或多个技术方案的有益技术效果:
上述技术方案提供的紫花地丁提取物制备方法,充分考虑了传统水煎药材处理的特点,同时也结合现代理论,利用酶把苷元游离出来,进一步精制了提取物,同时为下一步的制剂更好的发挥其药理作用打下了基础。如上制备方法得到的紫花地丁提取物,能够调节病毒性心肌炎小鼠血清炎症因子水平,减少心肌组织IGF-1的表达,发挥心肌保护作用,能够作为抗病毒性心肌炎的候选药物,用以制备临床可接受的药物剂型,因此具有良好的实际应用之价值。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图 1 为本发明实验例1中模型组小鼠心肌病理组织显微观察结果。
图 2 为本发明实验例1中对照组小鼠心肌病理组织显微观察结果。
图 3 为本发明实验例1中治疗组小鼠心肌病理组织显微观察结果。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本发明使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明申请的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
本发明的一个典型具体实施方式中,提供一种紫花地丁提取物的制备方法,所述制备方法包括将紫花地丁煎煮、酶解、提取的步骤;
其中,酶解步骤中,所用的酶为纤维素酶、中性蛋白酶、木瓜蛋白酶、β-葡萄糖苷酶中的任意一种或多种。
所述煎煮步骤具体方法包括:取紫花地丁药材,加水浸泡后,煎煮2~3次,合并煎液,过滤得煎煮液;
每次煎煮加入水的量控制为每4~6g水对应紫花地丁药材为1g。
所述酶解步骤具体包括:将煎煮液经减压浓缩后,加入酶进行酶解得酶解液;
煎煮液经减压浓缩后的最终密度控制为0.60~1.10(80℃)。
加入酶的量控制为1g酶对应紫花地丁药材为80~160g,如80g、100g、120g、140g、160g,酶解处理温度为40~65℃,如40℃、45℃、50℃、55℃、60℃、65℃,酶解处理时间控制为0.5~2.5h,如0.5h、1h、1.5h、2h、2.5h,酶解pH控制为酸性,进一步控制为3.0~6.5,如pH为3.0、4.0、5.0、6.0、6.5,所述酶为β-葡萄糖苷酶。通过优化酶解条件,从而使得酶解更为充分,能够把紫花地丁药物有效成分(如苷元等)充分释放。
所述提取步骤中提取剂选用有机溶剂,进一步优选为乙醇,加入乙醇后控制溶液中的乙醇浓度为40~80%,如40%、50%、55%、60%、70%、80%,优选为55%,得到乙醇提取液。通过使用乙醇有效富集其中的极性、弱极性化合物。
本发明的又一具体实施方式中,所述制备方法还包括将制备得到的乙醇提取液进行浓缩、干燥的步骤,具体包括:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
本发明的又一具体实施方式中,提供上述制备方法制备得到的紫花地丁提取物。经试验验证,所述紫花地丁提取物具有改善病毒性心肌炎小鼠心脏功能的作用。
因此,本发明的又一具体实施方式中,提供上述紫花地丁提取物在制备炎症相关疾病的药物中的应用。
其中,所述炎症相关的疾病包括脓毒症、肺炎、肝炎、类风湿关节炎、***性红斑狼疮、哮喘、病毒性心肌炎、急性呼吸窘迫综合征、胰腺炎、败血症、溃疡性结肠炎、支气管炎和感染性心内膜炎,优选为病毒性心肌炎。经实验证明,本发明制备得到的紫花地丁提取物可以改善病毒性心肌炎小鼠的心功能及心肌组织炎症状态,表明该提取物对病毒性心肌炎有较好的心肌保护作用。
本发明的又一具体实施方式中,提供一种药物组合物,所述药物组合物其活性成分包含上述紫花地丁提取物。
本发明的又一具体实施方式中,所述药物组合物还包括至少一种药物活性成分或药学上的载体。其中,所述药物活性成分可以为蒲公英提取物。
本发明中含有上述紫花地丁提取物的药物组合物可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明的药物组合或药物制剂中还可以含有常用的载体,这里所述可药用载体包括但不局限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,缓冲物质如磷酸盐,甘油,山梨酯,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛酯等。载体在药物组合物中的含量可以是1%重量-98%重量,通常大约占到80%重量。为方便起见,防腐剂,缓冲剂等可直接溶于载体中。
口服片剂和胶囊可以含有赋形剂如粘合剂,如糖浆,***胶,山梨醇,黄芪胶,或聚乙烯吡咯烷酮,填充剂,如乳糖,蔗糖,玉米淀粉,磷酸钙,山梨醇,氨基乙酸,润滑剂,如硬脂酸镁,滑石,聚乙二醇,硅土,崩解剂,如马铃薯淀粉,或可接受的增润剂,如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液,溶液,乳浊液,糖浆,也可以制成干品,用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂,如悬浮剂,山梨醇,纤维素甲醚,葡萄糖糖浆,凝胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶,氢化的食用油脂,乳化剂,如卵磷脂,山梨聚糖单油酸盐,***树胶;或非水载体(可能包含可食用油),如杏仁油,油脂如甘油,乙二醇,或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯,山梨酸。如需要可添加调味剂或着色剂。
本发明的又一具体实施方式中,提供一种治疗炎症相关疾病的方法,所述方法包括:向受试者施用有效剂量的上述紫花地丁提取物或上述药物组合物。
所述炎症相关疾病包括脓毒症、肺炎、肝炎、类风湿关节炎、***性红斑狼疮、哮喘、病毒性心肌炎、急性呼吸窘迫综合征、胰腺炎、败血症、溃疡性结肠炎、支气管炎和感染性心内膜炎,优选为病毒性心肌炎。
所述受试者是指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,最优选指牛。所述“治疗有效量”是指包括本发明化合物在内的活性化合物或药剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织***、动物的生物学或医学响应,这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。必须认识到,本发明所述活性成分的最佳给药剂量和间隔是由其性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等外部条件决定的,而这一最佳给药剂量可用常规的技术确定。同时也必须认识到,最佳的疗程,可用本领域内公知的方法确定。
以下通过实施例对本发明做进一步解释说明,但不构成对本发明的限制。应理解这些实施例仅用于说明本发明而不用于限制本发明的范围。实施例中制备方法涉及的试剂、材料均为药用试剂或分析纯或化学纯试剂,药理试验涉及的试剂和材料均为化学纯或生化试剂,均可在市场中获得。药理实验涉及的实验方法为本领域技术人员所熟知的方法。
实施例1紫花地丁提取物中的黄酮类化合物和香豆素类化合物含量测定
本实施例的目的在于采用HPLC法测定紫花地丁提取物中的黄酮类化合物和香豆素类化合物的含量。具体方法如下:
(1)色谱条件:色谱柱以十八烷基硅烷键合硅胶为填充剂;进样量10μl,柱温30℃,检测波长290nm;流动相A为乙腈;流动相B为14mmol/L醋酸铵水溶液;梯度洗脱(0-10min,A10-25%;10-20min,A25-60%)。
(2)对照品溶液:分别精密称取秦皮甲素、秦皮乙素、槲皮素、木犀草素、柚皮素置同一容量瓶中,加入甲醇制成浓度分别为100μg/ml、100μg/ml、50μg/ml、50μg/ml、25μg/ml的混合溶液,作为混合对照品溶液。
(3)供试品溶液:精密称取紫花地丁提取物粉末5mg置容量瓶中,加甲醇,超声使其溶解,稀释至刻度,摇匀,滤过,取续滤液作为供试品溶液。
(4)含量测定:分别精密吸取对照溶液和供试品溶液,注入液相色谱仪,测定,得紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量,其中,黄酮类化合物包含槲皮素、木犀草素和柚皮素,香豆素类化合物包含秦皮甲素和秦皮乙素。
实施例2制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为0.8(80℃),加入β-葡萄糖苷酶进行酶解,酶解的条件为:每1g酶对应药材140g;酶解温度50℃,酶解时间1小时,酶解pH值4.5,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到55%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素15.6%、秦皮乙素18.5%、槲皮素7.6%、木犀草素9.7%、柚皮素4.2%。
实施例3制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为0.6(80℃),加入纤维素酶进行酶解,酶解的条件为:每1g酶对应药材160g;酶解温度65℃,酶解时间0.5小时,酶解pH值4,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到40%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素13.9%、秦皮乙素16.7%、槲皮素3.3%、木犀草素5.1%、柚皮素2.6%。
实施例4制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为1.1(80℃),加入中性蛋白酶进行酶解,酶解的条件为:每1g酶对应药材80g;酶解温度40℃,酶解时间2.5小时,酶解pH值6,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到80%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素14.3%、秦皮乙素16.4%、槲皮素4.1%、木犀草素5.9%、柚皮素3.3%。
实施例5制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为0.7(80℃),加入木瓜蛋白酶、β-葡萄糖苷酶(1:2)进行酶解,酶解的条件为:每1g酶对应药材100g;酶解温度45℃,酶解时间2.0小时,酶解pH值5,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到60%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素14.6%、秦皮乙素16.9%、槲皮素4.5%、木犀草素5.3%、柚皮素3.0%。
实施例6制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为1.08(80℃),加入中性蛋白酶、β-葡萄糖苷酶(1:3)进行酶解,酶解的条件为:每1g酶对应药材110g;酶解温度60℃,酶解时间1.0小时,酶解pH值6.5,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到65%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素14.2%、秦皮乙素17.5%、槲皮素5.6%、木犀草素8.3%、柚皮素3.1%。
实施例7制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为1.02(80℃),加入β-葡萄糖苷酶进行酶解,酶解的条件为:每1g酶对应药材120g;酶解温度50℃,酶解时间1小时,酶解pH值4.0,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到50%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素14.9%、秦皮乙素17.3%、槲皮素6.8%、木犀草素9.2%、柚皮素3.9%。
实施例8制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为0.94(80℃),加入β-葡萄糖苷酶、纤维素酶、中性蛋白酶(4:1:1)进行酶解,酶解的条件为:每1g酶对应药材150g;酶解温度55℃,酶解时间1.5小时,酶解pH值5.5,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到55%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素15.1%、秦皮乙素17.7%、槲皮素5.4%、木犀草素7.9%、柚皮素3.6%。
实施例9制备紫花地丁提取物:
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为0.90(80℃),加入β-葡萄糖苷酶、纤维素酶、木瓜蛋白酶(4:1:2)进行酶解,酶解的条件为:每1g酶对应药材110g;酶解温度50℃,酶解时间1.0小时,酶解pH值5.0,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到65%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素14.6%、秦皮乙素17.3%、槲皮素4.7%、木犀草素6.2%、柚皮素2.8%。
对比例1制备紫花地丁提取物:
本对比例参考了CN102462701A所公开的技术。
(1)煎煮:取紫花地丁药材,加水浸泡30min,煎煮3次,每次用水为5倍药材量,煎煮时间分布为1h、1h、0.5h,合并煎液,过滤,得水煎液;
(2)酶解:煎液适度减压浓缩至密度为1.04(80℃),加入纤维素酶,酶解的条件为:加入酶的量为水煎浓缩液的0.8重量%;酶解温度50℃,酶解时间2小时,酶解pH值4,酶解过程中适时搅拌,得酶解液;
(3)提取:酶解液加入乙醇,使溶液的乙醇浓度达到55%,充分搅拌后静止过夜,过滤,得乙醇提取液;
(4)浓缩、干燥:乙醇提取液回收乙醇,得浸膏,浸膏干燥后即得紫花地丁提取物。
(5)含量测定:依据实施例1所描述的方法,测定紫花地丁提取物中黄酮类化合物和香豆素类化合物的含量分别为:秦皮甲素10.7%、秦皮乙素12.5%、槲皮素1.8%、木犀草素2.6%、柚皮素0.6%。
实验例1
紫花地丁提取物对病毒性心肌炎小鼠的影响实验
本实施例探讨了紫花地丁提取物对病毒性心肌炎模型小鼠死亡率、血清肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)、天门冬氨酸氨基转移酶(AST)、炎症因子(IL-6、IL-10、TNF-α),以及心肌病理的影响,以初步评价紫花地丁提取物对病毒性心肌炎的作用。具体如下:
(1)模型制备:选取60只BALC/c小鼠,按体重随机分组,分为模型组(20只)、治疗组(20只)、对照组(20只)。
其中,模型组和治疗组小鼠,每只腹腔注射含柯萨奇病毒B3(CVB3)100TTCID50/0.1ml的CNB3病毒液0.1ml,连续注射3次,建立小鼠病毒性心肌炎模型。
对照组同时注射等量生理盐水。
(2)药物制备:取实施例2(最佳实施例)所得紫花地丁提取物适量,临用时加蒸馏水充分搅拌成混悬液使用。
(3)给药:首次注射病毒液后,2h开始灌胃给药。其中治疗组给予紫花地丁提取物6g/kg体重;模型组和对照组同时给予等体积蒸馏水灌胃。每日给药1次,连续给药14d。
(4)日常观察:一般状况和死亡率
(5)小鼠心功能测定:腹腔注射水合氯醛麻醉小鼠,用局部脱毛剂去毛,采用小动物超声***进行经胸超声心动图检查。采用胸骨旁长轴和短轴切面分析左心室结构及功能,M模式下显示舒张末期左心室内径(LVEDD)、左心室后壁厚度(LVPWs)、左心室前壁厚度(LVAWs),计算出左心室射血分数(EF)、左心室缩短率(FS)。
(6)血清心肌酶和炎症因子检测:末次给药后禁食禁水12h,称重,眼动脉取血,4000r/min离心6min,取上清液,ELISA法测定血清中CK-MB、AST、LDH活性以及IL-6、IL-10、TNF-α含量。
(7)心肌组织病理学变化:小鼠取血后分离心脏,取心脏用4%多聚甲醛固定,脱水,石蜡包埋,常规切片,HE染色,显微镜下观察心肌病理学改变。
(8)结果:
①小鼠的一般状况、死亡情况:
对照组小鼠实验期间进食、活动等正常,毛色光泽,反应灵敏,体重正常,实验期间小鼠未见死亡;
模型组小鼠摄食量和活动减少,耸毛蜷缩,毛发无光泽,对刺激反应迟钝,消瘦,实验期间死亡8只(死亡率40%);
治疗组小鼠一般情况较模型组明显改善,实验期间死亡2只(死亡率10%)。
3组小鼠死亡率比较,差异有统计学意义(P<0.05)。
②小鼠心功能检测结果:见表1
注:*P<0.05,与对照组比较;**P<0.05,与模型组比较
由上表可知,
模型组小鼠的EF、FS较对照组显著降低(P<0.05),经紫花地丁提取物治疗后心功能有效改善(P<0.05)。
③血清心肌酶水平检测结果:见表2
注:*P<0.05,与对照组比较;**P<0.05,与模型组比较
由上表可知,与对照组比较,模型组小鼠血清CK-MB、AST和LDH水平显著升高(P<0.05);与模型组比较,治疗组小鼠血清CK-MB、AST和LDH水平显著降低,差异有统计学意义(P<0.05)。
④小鼠血清炎症因子检测结果:见表3
注:*P<0.05,与对照组比较;**P<0.05,与模型组比较
由上表可知,与对照组比较,模型组小鼠血清IL-6和TNF-α水平显著升高,IL-10含量显著降低(P<0.05);与模型组比较,治疗组小鼠血清IL-6和TNF-α水平显著降低,IL-10含量显著升高,差异有统计学意义(P<0.05)。
⑤心肌组织病理学变化,详见图1~3。
由附图分析可知,对照组小鼠心肌细胞排列整齐,未见间质纤维及炎症细胞增生;模型组小鼠心肌细胞肿大,心肌纤维排列紊乱,心肌间质水肿,可见大量炎症细胞浸润,并伴有多灶性坏死;治疗组小鼠病理病变程度相对模型组有所改善。
应注意的是,以上实例仅用于说明本发明的技术方案而非对其进行限制。尽管参照所给出的实例对本发明进行了详细说明,但是本领域的普通技术人员可根据需要对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围。
Claims (7)
1.一种紫花地丁提取物的制备方法,其特征在于,所述制备方法包括将紫花地丁煎煮、酶解、提取的步骤;
其中,酶解步骤中,所用的酶为β-葡萄糖苷酶;
所述酶解步骤具体包括:将煎煮液经减压浓缩后,加入酶进行酶解得酶解液;煎煮液经减压浓缩后的最终密度控制为0.60~1.10,80℃;加入酶的量控制为1g酶对应紫花地丁药材为80~160g,酶解处理时间控制为0.5~2.5h,酶解pH控制为3.0~6.5;
所述提取步骤中提取剂选用有机溶剂;
所述有机溶剂为乙醇,加入乙醇后控制溶液中的乙醇浓度为40~80%。
2.如权利要求1所述的制备方法,其特征在于,所述煎煮步骤具体方法包括:取紫花地丁药材,加水浸泡后,煎煮2~3次,合并煎液,过滤得煎煮液;
每次煎煮加入水的量控制为每4~6g水对应紫花地丁药材为1g。
3.如权利要求1所述的制备方法,其特征在于,所述制备方法还包括将制备得到的提取液进行浓缩、干燥的步骤。
4.权利要求1-3任一项所述制备方法制备得到的紫花地丁提取物。
5.权利要求4所述紫花地丁提取物在制备病毒性心肌炎的药物中的应用。
6.一种药物组合物,其特征在于,所述药物组合物其活性成分包含权利要求4所述紫花地丁提取物。
7.如权利要求6所述药物组合物,其特征在于,所述药物组合物还包括至少一种药物活性成分或药学上的载体。
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