CN116531429B - 岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用 - Google Patents
岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用 Download PDFInfo
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Abstract
本发明提供了岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用,属于中医药技术领域。本发明首次提出岩黄连总生物碱具有治疗溃疡性结肠炎的作用,而且本发明提供的所述岩黄连总生物碱制备方法与本领域目前已有的岩黄连总生物碱制备方法相比,本发明制备方法更加简单,但是仍可以得到含量达到50%以上的岩黄连总生物碱。
Description
技术领域
本发明属于中医药技术领域,尤其涉及岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用。
背景技术
溃疡性结肠炎(ulcerative colitis,UC)是一种常见的炎症性肠道疾病,临床表现为腹泻、腹痛、便血、体重减轻、呕吐等症状。近年来,UC在新兴工业化国家的发病率逐年上升,由于其病因复杂,症状反复发作,持续周期长,所以治愈难度大。目前针对UC最常见的治疗方法主要为药物治疗,包括糖皮质激素、氨基水杨酸类、免疫抑制剂类和生物制剂类等,但许多药物在临床应用中受到限制,且临床疗效不稳定,甚至可能带来一系列如肝肾毒性、药物依赖性以及撤减药物后病情反复发作等问题,并且有些生物制剂价格昂贵,普通患者难以承受,故寻求疗效确切、副作用少、价格适宜的UC治疗新药成为临床的迫切需求。
石生黄堇Corydalis saxicola Bunting(C.saxicola)为罂粟科紫堇属多年生草本植物,其干燥全草入药称为岩黄连,主要分布于贵州、广西、云南等地区,是国家二级保护植物,同时也是著名壮瑶民族药。其性凉、味苦;功效:清热解毒、利湿、止痛止血;具有抗炎、利胆、抗病毒、杀菌、镇痛、增强免疫功能、抗肿瘤的作用。现代研究表明岩黄连主要含有脱氢卡维丁、白屈菜红碱、巴马丁、原阿片碱等多种生物碱成分。目前岩黄连生物碱的制备方法及相关应用较多,但是在中药化学领域,不同的制备方法与步骤,所得到制备物的成分及其药理作用也存在差异。
岩黄连药材经过制备所得到的提取物已被制成岩黄连注射液,临床主要应用于治疗肝硬化、肝癌、肝炎和高胆红素血症等疾病。如:专利申请CN 114767739A公开了岩黄连及岩黄连总碱在制备预防和/或治疗2型糖尿病药物中的应用;专利申请CN 111184774 A公开了岩黄连及其制剂在制备治疗非酒精性脂肪性肝病的药物中的应用;专利申请CN108186740 A公开了岩黄连与其提取物制备治疗肠道紊乱药物或保健品及应用。但是现有技术并未有岩黄连总生物碱具有治疗溃疡性结肠炎作用的相关报道。
发明内容
有鉴于此,本发明的目的在于提供岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用。
为了实现上述发明目的,本发明提供了以下技术方案:
本发明提供了岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用。
优选的,所述岩黄连总生物碱经由如下步骤制备所得:采用pH为1~2的盐酸乙醇溶液浸渍岩黄连后,回流提取,提取液浓缩得浸膏;将浸膏用盐酸溶液溶解除杂后,采用大孔树脂进行吸附,将吸附后的大孔树脂用水冲洗除杂,用乙醇溶液洗脱,收集洗脱液浓缩干燥即得岩黄连总生物碱。
优选的,浸渍岩黄连所用的乙醇溶液的浓度为70%~90%。
优选的,所述岩黄连与盐酸乙醇溶液的料液比为1:30。
优选的,所述盐酸溶液的浓度为0.2%~1%。
优选的,所述大孔树脂为XDA-8、LX-60或LX-8。
优选的,洗脱用的乙醇溶液的浓度为70%~90%。
本发明的有益效果:
本发明首次提出岩黄连总生物碱具有治疗溃疡性结肠炎的作用,通过动物实验证实,采用本发明制备方法制备所得的岩黄连总生物碱对用葡聚糖硫酸钠(DSS)诱导的小鼠溃疡性结肠炎具有较好的治疗效果,可以显著缓解由DSS诱导的溃疡性结肠炎小鼠的体重下降、降低DAI评分、延长结肠长度、减轻结肠组织炎症浸润程度;调节小鼠结肠组织中炎症、氧化应激等生化指标;同时对小鼠肠道菌群也具有一定调节作用。
另外,本发明提供的制备方法与本领域目前已有的岩黄连总生物碱制备方法相比,本发明制备方法更加简单,但是仍可以得到含量达到50%以上的岩黄连总生物碱。
附图说明
图1为岩黄连总生物碱对UC模型小鼠体重的影响;
图2为岩黄连总生物碱对UC模型小鼠疾病活动指数(DAI)的影响;
图3为岩黄连总生物碱对UC模型小鼠结肠长度(Conlon length)的影响,其中左图为拍照记录结肠长度结果,右图为长度统计结果;
图4为岩黄连总生物碱对UC模型小鼠结肠组织炎症浸润程度的影响;
图5为岩黄连总生物碱对UC模型小鼠炎症应激生化指标的影响,其中A-F分别为岩黄连总生物碱对UC模型小鼠结肠组织中TNF-α、IL-1β、IL-6、MMP-9、MIP-1β和IL-10炎症应激生化指标的影响;
图6为岩黄连总生物碱对UC模型小鼠氧化应激生化指标的影响,其中A-C分别为岩黄连总生物碱对UC模型小鼠中SOD、MDA和MPO氧化应激生化指标的影响;
图7为岩黄连总生物碱对UC模型小鼠肠道菌群的影响。
具体实施方式
本发明提供了岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用。本发明对于药物中的其余辅料等没有特殊限定,采用本领域常规药物制剂的辅料即可。
在本发明中,所述岩黄连总生物碱优选的经由如下步骤制备所得:采用pH为1~2的盐酸乙醇溶液浸渍岩黄连后,回流提取,提取液浓缩得浸膏;将浸膏用盐酸溶液溶解除杂后,采用大孔树脂进行吸附,将吸附后的大孔树脂用水冲洗除杂,用乙醇溶液洗脱,收集洗脱液浓缩干燥即得岩黄连总生物碱。
本发明对于岩黄连和盐酸乙醇溶液的具体来源没有特殊限定,其中盐酸的作用是调节乙醇溶液的pH值。在本发明中,所述岩黄连优选的需粉碎成粉末后再进行浸渍,本发明对于粉碎的具体方式以及粒径没有特殊要求,浸渍岩黄连所用的乙醇溶液的浓度优选为70%~90%,更优选为80%,所述浸渍的时间优选为20~40min,更优选为30min,所述岩黄连与盐酸乙醇溶液的料液比优选为1:30。采用pH为1~2的盐酸乙醇溶液浸渍岩黄连后,将岩黄连与盐酸乙醇溶液全部转移至回流提取器中,进行回流提取。本发明对于回流提取的具体温度没有特殊限定,采用本领域常规回流提取温度即可。在本发明中,所述回流提取的次数优选为2~3次,所述回流提取的时间优选为1~2h。回流提取后,收集提取液进行浓缩,本发明对于浓缩的具体方法没有特殊限定,优选为减压浓缩的方式。获得浸膏后,优选的用浓度为0.2%~1%的盐酸溶液溶解浸膏,以进一步除杂,然后过滤,将滤液转移至装有大孔树脂的层析柱中进行动态吸附。在本发明中,所述大孔树脂优选的为XDA-8、LX-60或LX-8。采用水冲洗吸附完毕后的大孔树脂,以除去杂质,所述水的用量优选的为10~40bv(其中bv指填充树脂的那部分柱体积)。在本发明中,采用乙醇溶液对大孔树脂进行洗脱时,所述乙醇溶液的浓度优选为70%~90%,更优选为90%,所述洗脱用的乙醇溶液的量优选为10~40bv。洗脱结束后,收集洗脱液浓缩干燥即得岩黄连总生物碱,本发明对于浓缩干燥的具体条件没有特殊限定,采用本领域常规浓缩干燥方式即可。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
下述实施例中,如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1
取干燥岩黄连药材100g,将其粉碎过筛得粉末,用pH为2的盐酸乙醇溶液(乙醇浓度为80%)浸渍30min(岩黄连与盐酸乙醇溶液的料液比为1:30);将浸渍的药材以及溶液均转移至回流提取器中,回流提取2次,每次回流提取的时间为2h,过滤,合并滤液,减压浓缩得到岩黄连总生物碱的粗提物;将所得到的粗提物用浓度为0.2%的盐酸溶液溶解,过滤;将所得的滤液转移至装有XDA-8大孔树脂的层析柱中进行动态吸附;将吸附完毕后的大孔树脂用40bv水冲洗除杂后,再用浓度为90%的乙醇溶液洗脱40bv,收集乙醇洗脱液,浓缩干燥,得到岩黄连总生物碱制备物。制备物经酸性染料比色法,以脱氢卡维丁为对照品,利用紫外-可见分光光度计检测并计算,制备物中岩黄连总生物碱的含量可达到52.4%,转移率可达到68.5%。
实施例2
取干燥岩黄连药材100g,将其粉碎过筛得粉末,用pH为1的盐酸乙醇溶液(乙醇浓度为90%)浸渍30min(岩黄连与盐酸乙醇溶液的料液比为1:30);将浸渍的药材以及溶液均转移至回流提取器中,回流提取3次,每次回流提取的时间为2h,过滤,合并滤液,减压浓缩得到岩黄连总生物碱的粗提物;将所得到的粗提物用浓度为1%的盐酸溶液溶解,过滤;将所得的滤液转移至装有LX-60大孔树脂的层析柱中进行动态吸附;将吸附完毕后的大孔树脂用40bv水冲洗除杂后,再用浓度为90%的乙醇溶液洗脱40bv,收集乙醇洗脱液,浓缩干燥,得到岩黄连总生物碱制备物。制备物经酸性染料比色法,以脱氢卡维丁为对照品,利用紫外-可见分光光度计检测并计算,制备物中岩黄连总生物碱的含量可达到51.7%,转移率可达到63.5%。
实施例3
取干燥岩黄连药材100g,将其粉碎过筛得粉末,用pH为1的盐酸乙醇溶液(乙醇浓度为70%)浸渍20min(岩黄连与盐酸乙醇溶液的料液比为1:30);将浸渍的药材以及溶液均转移至回流提取器中,回流提取2次,每次回流提取的时间为2h,过滤,合并滤液,减压浓缩得到岩黄连总生物碱的粗提物;将所得到的粗提物用浓度为0.5%的盐酸溶液溶解,过滤;将所得的滤液转移至装有LX-8大孔树脂的层析柱中进行动态吸附;将吸附完毕后的大孔树脂用40bv水冲洗除杂后,再用浓度为90%的乙醇溶液洗脱40bv,收集乙醇洗脱液,浓缩干燥,得到岩黄连总生物碱制备物。制备物经酸性染料比色法,以脱氢卡维丁为对照品,利用紫外-可见分光光度计检测并计算,制备物中岩黄连总生物碱的含量可达到51.6%,转移率可达到62.8%。
实施例4
验证实施例1制备得到的岩黄连总生物碱,是否对用葡聚糖硫酸钠(DSS)诱导的溃疡性结肠炎模型小鼠具有明显的治疗效果。
溃疡性结肠炎小鼠造模及试验设计
溃疡性结肠炎小鼠造模:采用国际通用的溃疡性结肠炎造模方法,C57BL/6小鼠适应性饲养一周后,自由饮用灭菌水配制的3%DSS溶液7天,以诱导溃疡性结肠炎小鼠模型,然后以小鼠体重变化、粪便形态和便血程度、结肠长度、结肠组织病理变化等为指标,验证溃疡性结肠炎小鼠模型是否建立成功。
试验设计:60只体重18-22g SPF级健康雄性C57BL/6小鼠适应性喂养7天,随机分为5组:空白组(Control)、模型组(DSS)、岩黄连总生物碱高剂量组(DSS+YHLH)、岩黄连总生物碱中剂量组(DSS+YHLM)、岩黄连总生物碱低剂量组(DSS+YHLL);空白组自由饮用灭菌水,其余各组每日自由饮用含3%DSS的灭菌水,其他条件相同,造模日即为给药日;空白组与模型组按0.1mL/10g体重灌胃给予载体溶剂,高剂量组、中剂量组、低剂量组按0.1mL/10g体重灌胃给予200mg/kg/d、100mg/kg/d、50mg/kg/d的岩黄连总生物碱,每天给药一次,连续给药7天,最后一次给药后,禁食12h,不禁水。
实验7天中每天观察记录小鼠体重变化、粪便形态和便血程度。岩黄连总生物碱对UC模型小鼠体重的影响如图1所示。从第5天,除空白组外,其他各组均出现了明显的体重减轻,模型组小鼠体重减轻最为明显,岩黄连总生物碱各给药组体重减轻有所缓解,由此可得,本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物可以显著缓解溃疡性结肠炎引起的体重减轻。
岩黄连总生物碱对UC模型小鼠疾病活动指数(DAI)的影响如图2所示。其中评定UC模型小鼠的DAI评分表如表1所示。小鼠DAI评分由体质量下降分数、粪便性状分数和便血情况分数组成,计算公式:DAI=(体质量下降分数+粪便性状分数+便血情况分数)/3。
表1溃疡性结肠炎的疾病活动指数(DAI)评分表
(+)表示为“程度轻”,(++)表示为“程度重”
由图2可以看出,随着给药天数的增加,相较于模型组,岩黄连总生物碱各给药组可以显著降低DAI评分,表明本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物显著降低了UC小鼠的DAI评分。
给药7日后处死小鼠,收集并处理小鼠的血液和结肠组织,并拍照记录结肠长度;苏木精-伊红染色(H&E染色)观察结肠组织病理变化;采用ELISA法测定结肠组织炎症、氧化应激等生化指标,根据各试剂盒说明书分别测定肿瘤坏死因子(TNF-α)、白细胞介素-6(IL-6)和白细胞介素-1β(IL-1β)、白细胞介素-10(IL-10)、巨噬细胞炎性蛋白1β(MIP-1β)、基质金属蛋白酶9(MMP-9)和髓过氧化物酶(MPO)、丙二醛(MDA)、超氧化物歧化酶(SOD)的含量(其中TNF-α、IL-6、IL-1β、MMP-9、MIP-1β为促炎因子指标,IL-10为抗炎因子指标);同时收集各组小鼠粪便,对其肠道菌群进行分析。结果如图3~7所示。
由图3可以看出,相较于空白组,模型组小鼠结肠长度显著缩短,而岩黄连总生物碱给药组均得到一定的缓解,表明本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物显著延长了UC小鼠的结肠长度。
由图4可以看出,空白组小鼠的结肠组织具有完整的黏膜和正常的绒毛,且没有炎性细胞浸润或黏膜侵蚀;与空白组相比,模型组小鼠结肠组织形态发生明显的改变,大量的炎性细胞浸润,杯状细胞以及隐窝数量显著减少,结肠黏膜下区水肿,细胞间隙不完整,结肠黏膜屏障受损严重;而岩黄连总生物碱高剂量组治疗后,UC小鼠的结肠组织形态明显改善,炎性细胞浸润明显减少,肠道黏膜屏障相对完整。由此可得,本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物显著减轻了溃疡性结肠炎引起的结肠组织炎症浸润程度。
由图5可以看出,相对于模型组,岩黄连总生物碱各给药组可以显著抑制促炎因子TNF-α、IL-6、IL-1β、MMP-9和MIP-1β的释放,并且呈现出剂量依赖性,其中岩黄连总生物碱高剂量组抑制效果最好;相对于模型组,岩黄连总生物碱各给药组可以显著促进抗炎因子IL-10的释放,并且呈现出剂量依赖性,其中岩黄连总生物碱高剂量组促进效果最好。可见,采用本发明制备方法制备所得的岩黄连总生物碱通过抑制促炎因子和促进抗炎因子的释放,从而发挥药物作用,本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物可以显著缓解溃疡性结肠炎引起的炎症应激生化指标失衡。
由图6可以看出,通过与空白组、模型组对比,岩黄连总生物碱各给药组可以促进SOD和抑制MDA、MPO的释放,从而发挥作用。表明本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物可以显著缓解溃疡性结肠炎引起的氧化应激生化指标失衡。
由图7可以看出,岩黄连总生物碱制备物通过调节小鼠肠道有害和有益菌群的比例而发挥治疗作用,表明本发明治疗溃疡性结肠炎的岩黄连总生物碱制备物可以显著调节溃疡性结肠炎引起的肠道菌群失衡。
综上可以看出,采用本发明制备方法制备所得的岩黄连总生物碱可以显著缓解DSS诱导的溃疡性结肠炎小鼠的体重下降、降低DAI评分、延长结肠长度、减轻结肠组织炎症浸润程度;调节小鼠结肠组织中炎症、氧化应激等生化指标;调节小鼠肠道菌群。
另外,采用实施例4所述的试验方法分别验证实施例2和3制备得到的岩黄连总生物碱是否具有治疗溃疡性结肠炎作用时,所得到的结果与实施例1的结果一致,均表明采用本发明制备方法制备所得的岩黄连总生物碱可以显著缓解DSS诱导的溃疡性结肠炎小鼠的体重下降、降低DAI评分、延长结肠长度、减轻结肠组织炎症浸润程度;调节小鼠结肠组织中炎症、氧化应激等生化指标;调节小鼠肠道菌群。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.岩黄连总生物碱在制备治疗溃疡性结肠炎药物中的应用,其特征在于,所述岩黄连总生物碱经由如下步骤制备所得:采用pH为1~2的盐酸乙醇溶液浸渍岩黄连后,回流提取,提取液浓缩得浸膏;将浸膏用盐酸溶液溶解除杂后,采用大孔树脂进行吸附,将吸附后的大孔树脂用水冲洗除杂,用乙醇溶液洗脱,收集洗脱液浓缩干燥即得岩黄连总生物碱;
浸渍岩黄连所用的乙醇溶液的浓度为70%~90%;
洗脱用的乙醇溶液的浓度为70%~90%。
2.根据权利要求1所述的应用,其特征在于,所述岩黄连与盐酸乙醇溶液的料液比为1:30。
3.根据权利要求1所述的应用,其特征在于,所述盐酸溶液的浓度为0.2%~1%。
4.根据权利要求1所述的应用,其特征在于,所述大孔树脂为XDA-8、LX-60或LX-8。
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