CN117503816A - 一种治疗溃疡性结肠炎的中药组合物的制备及应用 - Google Patents
一种治疗溃疡性结肠炎的中药组合物的制备及应用 Download PDFInfo
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Abstract
本发明属于中药新用途技术领域,具体公开了一种中药组合物的制备及其在预防和治疗溃疡性结肠炎中的应用。该中药组合物的特征在于:包括青蒿9g,醋艾叶9g,淡豆豉9g。本申请公开的中药组合物甲醇提取物对预防和治疗溃疡性结肠炎具有明显的有益效果,因而在防治溃疡性结肠炎领域具有一定的经济效益和应用推广价值。
Description
技术领域
本发明属于中药组合物技术领域,尤其涉及一种治疗溃疡性结肠炎的中药组合物及其制备方法和应用。
背景技术
溃疡性结肠炎(Ulcerative colitis,UC)是一种慢性非特异性肠道炎症性疾病,最常发生于青壮年期。主要累及直肠和结肠,多呈现反复发作的慢性病程,临床表现为持续或反复发作的腹泻、黏液脓血便伴腹痛、里急后重和不同程度的全身症状。可有皮肤、黏膜、关节、眼、肝、胆等肠外表现。并发症包括中毒性巨结肠、肠穿孔、下消化道大出血、上皮内瘤变以及癌变。病因尚未十分清楚,目前认为主要是环境、遗传、肠道微生态和免疫等多因素相互作用所致,治愈难度大,复发率高。当前我国缺少确切的UC发病率数据,基于区域性的流行病学调查提示我国的UC发病率为0.42~2.22/10万。虽然与西方国家相比发病率仍然较低,然而与20年前相比,呈明显上升趋势。
西医对于UC的治疗目标在于诱导并维持缓解以及黏膜愈合,防治并发症,改善生命质量。主要根据疾病活动严重程度、病变累及范围、治疗反应等选择治疗方案。传统治疗药物主要包括氨基水杨酸制剂、糖皮质激素、免疫抑制剂等。对于传统治疗无效、不能耐受以及糖皮质激素依赖的中重度活动性UC患者,可选择肿瘤坏死因子α(TNF-α)拮抗剂。对传统治疗或TNF-α拮抗剂应答不足、失应答或无法耐受的中重度活动性UC患者,可选择α4β7整合素拮抗剂。
实践发现,中医从辨证治疗的角度,运用中药方剂治疗溃疡性结肠炎可显著提升患者的治疗效果,降低不良反应发生率,明显改善患者的生活质量及远期预后。
在中医古典医籍中,并无溃疡性结肠炎这一病名,根据其临床表现可归属于“痢症”“下痢”“久痢”“便血”“腹痛”“滞下”“泄泻”“肠风”等范畴,病因涉及外感六淫、饮食不慎、情志失调、劳倦内伤等,进而导致脏腑功能失调,气机紊乱,气滞血瘀,肠络受损,湿热内蕴,气血搏结,化为脓血,久病则气损及阳,虚实错杂,反复发作。溃疡性结肠炎病位在大肠,为本虚标实之病,其本在脾,湿热为标,久病及肾,损及肾阳,寒热并见,而致病势缠绵,难治难愈。
基于溃疡性结肠炎的病因病机,寒热错杂型为其临床常见证候类型,主因为饮食生冷或感受寒湿、湿热影响脾胃运化而发病,湿浊不化,下注大肠,凝滞气血,蕴结化热,化腐成脓,伤及肠络,呈现本虚标实、寒热交错的现象,脾虚内生湿邪始终为病发之本,且与寒热之邪并存,治疗应寒热并用,邪正兼顾。
据《本草纲目》青蒿项下记载,蒿豉丹源于《圣济总录》,主治赤白痢下,“5月5日采青蒿、艾叶等分,同豆豉捣作饼,日干,名蒿豉丹。每用1饼,以水1盏半煎服”。该方寒温并用,由青蒿、艾叶、淡豆豉3味药组成,青蒿苦寒清泄,清热解毒,凉血除蒸,艾叶辛香苦燥,温经散寒,祛湿消肿,淡豆豉辛凉微苦,疏散风热,宣散郁热,三药合用具有清热解毒,温经散寒,健脾祛湿的作用,适用于治疗寒热错杂型的溃疡性结肠炎。
发明内容
基于上述中医基础理论及药理实验验证,本发明的目的在于提供一种治疗溃疡性结肠炎的中药组合物,为溃疡性结肠炎患者的康复治疗提供新的选择。
为了实现上述的目的,本发明采用以下技术方案:
技术方案一:一种治疗溃疡性结肠炎的中药组合物,是由以下质量份的原料药制成:
青蒿6~9份、艾叶6~9份、淡豆豉6~27份;
具体地,本发明所提供的中药组合物,由A~C任意一组原料药制成:
A组:青蒿9g、艾叶9g、淡豆豉9g;
B组:青蒿9g、艾叶9g、淡豆豉18g;
C组:青蒿9g、艾叶9g、淡豆豉27g;
优选地,所述中药组合物由以下A组原料药制成:
A组:青蒿9g、艾叶9g、淡豆豉9g;
技术方案二:上述中药组合物通过包括以下两种方法制备得到:水煎煮和甲醇提取。
水煎煮:按配比称取上述原料,加10倍量的蒸馏水煎煮3次,每次提取1h,过滤,合并滤液,60℃旋蒸浓缩,得到水提浸膏。
甲醇提取:按配比称取上述原料,加10倍量的甲醇回流提取3次,每次提取2h,过滤,合并滤液,40℃旋蒸浓缩,得到甲醇提取浸膏。
优选地,所述中药组合物由甲醇提取制得;
技术方案三:在上述技术方案的基础上,该中药组合物中的艾叶原料药可被替换成艾叶的炮制品:醋艾叶和醋艾炭;具体的,本发明所提供的中药组合物,由a~c任意一组原料药制成:
a组:青蒿9g、艾叶9g、淡豆豉9g;
b组:青蒿9g、醋艾叶9g、淡豆豉9g;
c组:青蒿9g、醋艾炭9g、淡豆豉9g;
优选地,所述中药组合物由以下b组原料药制成:
b组:青蒿9g、醋艾叶9g、淡豆豉9g;
技术方案四:一种所述的中药组合物甲醇提取物在制备治疗溃疡性结肠炎的药物中的应用。
技术方案五:一种所述的中药组合物甲醇提取物的特征图谱。
本发明采用优化条件的前处理及高效液相色谱方法,建立了蒿豉丹(醋艾叶)的特征图谱,能够对蒿豉丹(醋艾叶)中的7个化学成分进行分析,从而保证临床用药的安全有效。本发明方法能全面的、准确的评价药物制剂的整体的、内在的质量。
本发明药物组合使用的药材如下,均应符合中国药典对药材质量的要求。
青蒿是菊科植物黄花蒿Artemisia annua L.的干燥地上部分。
艾叶是为菊科植物艾Artemisia argyi Levl.et Vant.的干燥叶。
淡豆豉为豆科植物大豆Glycine max(L.)Merr.的干燥成熟种子(黑豆)的发酵加工品。所用的淡豆豉为实验室自制,经检测,含大豆苷元和染料木素的总量为1.22±0.10‰,符合药典中对于淡豆豉的质量控制规定:干燥品计算含大豆苷元和染料木素的总量不得少于0.040%。
本发明中的醋艾叶和醋艾炭均为艾叶的炮制加工品,醋艾叶制法:取净艾叶,以(100g:15mL)的比例加入米醋拌匀,闷润至透,置锅内,用文火加热,炒干,取出,及时摊晾,凉透。醋艾炭制法:取净艾叶,置热锅内,用武火炒至表面焦黑色、内部焦褐色,喷淋米醋,灭尽火星,炒干,取出,及时摊晾,凉透。艾叶每100千克用米醋15千克。
优选地,所述的中药组合物的剂型为口服剂型。
进一步的,所述的中药组合物可与药学上能够接受的辅料制备而成制剂;所述制剂包括汤剂、颗粒剂、合剂、片剂、胶囊剂、丸剂、粉剂、散剂、糖浆剂、微囊剂、膏剂。
本发明的另一个目的在于提供蒿豉丹在治疗溃疡性结肠炎中的用途。
本发明与现有技术相比具备以下有益效果:本中药复方是在中医基础创新理论指导下由古籍中记载的蒿豉丹发展所得,由青蒿、艾叶、淡豆豉三味药组成,治疗溃疡性结肠炎具有多途径、多靶点的作用优势。本发明经药理研究发现,蒿豉丹甲醇提取物中剂量组(1.7g/kg)能延缓硫酸葡聚糖(Dextran sulphate sodium,DSS)造模引起的小鼠体重下降及稀便血便等情况,显著降低溃疡性结肠炎小鼠疾病活动指数(Disease activity index,DAI)、缓解小鼠结肠缩短,减轻组织炎症反应,对溃疡性结肠炎有防治作用。而进一步的药理实验结果表明蒿豉丹(醋艾叶)的疗效优于蒿豉丹(艾叶)和蒿豉丹(艾叶炭)组。
附图说明
图1:造模方法及给药方案。
图2:实施例2中各组小鼠的体重变化百分比图(图A)和疾病活动指数(DAI)图(图B)。
图3:实施例2中各组小鼠的结肠长度图。(*p<0.05和**p<0.01,与空白组比较;#p<0.05和##p<0.01,与模型组比较;+p<0.05和++p<0.01,与蒿豉丹(艾叶)甲醇提取物高剂量组比较。)
图4:实施例2中各组小鼠的结肠形态图。
图5:实施例2中各组小鼠的结肠病理评分图。(*p<0.05和**p<0.01,与空白组比较;#p<0.05和##p<0.01,与模型组比较。)
图6:实施例2中各组小鼠结肠组织HE染色(×10,×40)图(图A)和PAS/AB染色(×10,×40)图(图B)。
图7:实施例3中各组小鼠的体重变化百分比图和疾病活动指数(DAI)图。
图8:实施例3中各组小鼠的结肠长度图。(*p<0.05,**p<0.01和***p<0.001,与空白组比较;#p<0.05,##p<0.01和###p<0.001,与模型组比较。)
图9:实施例3中各组小鼠的结肠形态图和脾形态图。
图10:实施例3中各组小鼠结肠组织HE染色图(图A)和PAS/AB染色(×10,×40)图(图B)。
图11:实施例3中各组小鼠脾脏指数和胸腺指数。(*p<0.05,**p<0.01和***p<0.001,与空白组比较;#p<0.05,##p<0.01和###p<0.001,与模型组比较。)
图12:实施例3中各组小鼠血清中ALB、ALT、AST、HS-CRP、UREA的表达水平(*p<0.05,**p<0.01和***p<0.001,与空白组比较;#p<0.05,##p<0.01和###p<0.001,与模型组比较。)
图13:实施例2中各组小鼠肝组织HE染色图(图A)和肾组织HE染色图(图B)。
图14:对照品化学结构图。(A:东莨菪内酯;B.异绿原酸B;C.异绿原酸A;D.异绿原酸C;E.棕矢车菊素;F.猫眼草酚D;G.异泽兰黄素;H.蔓荆子黄素;I.艾黄素)
图15:蒿豉丹(醋艾叶)甲醇提取物的UPLC特征图谱。(1:东莨菪内酯;3:异绿原酸C;13:棕矢车菊素;14:猫眼草酚D;16:异泽兰黄素;17:蔓荆子黄素;18:艾黄素)
具体实施方式
下面结合实施例对本发明做进一步详细的说明。
虽然以下描述了本发明的优选实施方式,然而应该理解,可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
实施例1:中药组合物原料药配比的组方优化
一种治疗溃疡性结肠炎的中药组合物,是由以下质量份的原料药制成:青蒿6~9份、艾叶6~9份、淡豆豉6~27份;
具体地,本发明所提供的中药组合物,由A~C任意一组原料药制成:
A组:青蒿9g、艾叶9g、淡豆豉9g;
B组:青蒿9g、艾叶9g、淡豆豉18g;
C组:青蒿9g、艾叶9g、淡豆豉27g;
制备方法:按配比称取上述原料,加适量的水,充分混匀,搓成丸状,烘箱40℃烘干。
结果表明蒿豉丹中的三味药以1:1:1可以很好地制成药丸,随着淡豆豉加入得越多,药丸越硬。即该中药组合物以A组:青蒿9g、艾叶9g、淡豆豉9g为最佳。
实施例2:基于药效的中药组合物提取物的制备方法优化
配方:青蒿9g、艾叶9g、淡豆豉9g。
制备方法一:按配比称取上述原料,加10倍量的蒸馏水煎煮3次,每次提取1h,过滤,合并滤液,60℃旋蒸浓缩,得到水提浸膏。
制备方法二:按配比称取上述原料,加10倍量的甲醇回流提取3次,每次提取2h,过滤,合并滤液,40℃旋蒸浓缩,得到甲醇提取浸膏。
为验证本发明中药组合物的功效,对以上中药组合物的提取方法进行筛选。发明人开展了相关的药效学试验研究,以下药效学实验仅用于说明本发明中药组合物的功效,而不能限制本发明。
1.材料
1.1实验药品制备
按照实施例2的配方组方,再按照《中药药理研究方法学》,使用人与小鼠的药物剂量折算系数计算出各组小鼠的给药剂量,将生药浓缩成蒿豉丹(艾叶)水提浸膏,给药前,按照换算成的高、中、低剂量,以0.5%的CMC-Na充分溶解,保存于4℃冰箱中备用。
按照实施例2的配方组方,再按照《中药药理研究方法学》,使用人与小鼠的药物剂量折算系数计算出各组小鼠的给药剂量,将生药浓缩成蒿豉丹(艾叶)甲醇提浸膏,给药前,按照换算成的中剂量,以0.5%的CMC-Na充分溶解,保存于4℃冰箱中备用。
美沙拉嗪药液的配制:将药物溶解于0.5%的CMC-Na中配制成混悬液,保存于4℃冰箱中备用。
2.5% DSS药液的配制:称取25g DSS粉末充分溶解于1L娃哈哈瓶装水中,保存于4℃冰箱中备用。
2.实验分组和剂量
70只C57BL/6小鼠,6-8周龄,雄性,体重22±2g。适应性饲养7天后,随机分为7组,每组10只。预防给药7天,之后每天给予2.5% DSS的饮用水,连续7天,第8-10天更换为灭菌水,以复制小鼠急性结肠炎模型,在第11天处死小鼠。
1)空白组(Ctrl):正常饮水、进食,参考给药方案采用相同的给药途径基于同等剂量的0.5% CMC-Na溶液;
2)模型组(DSS):根据上述方法造模,参考给药方案采用相同的给药途径基于同等剂量的0.5% CMC-Na溶液;
3)阳性药-美沙拉嗪组(DSS+Mesalazine):根据上述方法造模,每日给予美沙拉嗪0.3g/kg/d;
4)蒿豉丹(艾叶)甲醇提取物高剂量组(DSS+M-HDC-H):根据上述方法造模,每日给予蒿豉丹甲醇提取物3.4g生药/kg/d;
5)蒿豉丹(艾叶)甲醇提取物中剂量组(DSS+M-HDC-M):根据上述方法造模,每日给予蒿豉丹甲醇提取物1.7g生药/kg/d;
6)蒿豉丹(艾叶)甲醇提取物低剂量组(DSS+M-HDC-L):根据上述方法造模,每日给予蒿豉丹甲醇提取物0.85g生药/kg/d;
7)蒿豉丹(艾叶)水提物中剂量组(DSS+A-HDC-M):根据上述方法造模,每日给予蒿豉丹水提物1.7g生药/kg/d;
3.指标与检测方法
3.1小鼠病理指标统计
实验过程中每天观察和记录小鼠的精神、饮食、活动、排便情况以及体重变化情况。对于小鼠的便隐血情况采用便隐血试剂盒进行检测。参照Cooper M等评估标准,每日监测小鼠的体重、大便性状及便血情况,从而反映炎症程度。DAI=(体重下降分值+粪便性状分值+便血情况分值)/3。
表1.小鼠疾病活动指数评分表
*正常大便:成形大便;半稀便:不粘附于肛门的糊状、半成形大便;稀便:可粘附于肛门的稀水样便。
3.2实验动物处理及样本收集
第10天实验结束后,小鼠称体重后,眼眶取血,约0.5~0.8mL/只,常温放置0.5h后10000rpm,离心3min分离血清,-80℃保存。取血后小鼠颈椎脱臼处死,仰卧位固定,沿腹中线切开腹壁,暴露腹腔组织,小心剥离小鼠结肠,避免牵拉造成器质性损伤,测量并拍照记录肛门上方到盲肠顶部的结肠长度和形态。取距离肛门1~2cm处结肠肠段约1cm,4%多聚甲醛溶液固定备用。之后取结肠和盲肠内容物以及部分结肠,-80℃保存。
3.3组织学评价
取近盲肠处结肠组织,用生理盐水冲洗肠腔,用4%多聚甲醛固定24h,结肠标本经70%乙醇处理后,石蜡包埋块体切片5μm厚,苏木素-伊红(H&E)染色。显微镜下观察组织炎症程度,病变深度,炎性细胞浸润和上皮破坏情况。结肠病理评分按照Melgar S等建立的方法进行。对结肠组织进行杯状细胞(PAS/AB染色)。
表2.结肠病理评分标准
计分 | 炎症 | 肉芽组织 | 病变深度 | 隐窝破坏 |
0 | 无 | 无 | 无 | 无 |
1 | 轻度 | 有 | 黏膜下层 | 基底1/3隐窝破坏 |
2 | 重度 | 肌层 | 基底2/3隐窝破坏 | |
3 | 浆膜层 | 仅有完整表面上皮 | ||
4 | 全部上皮破坏 |
3.4统计学分析
获得数据后使用GraphPad Prism 8.4.3对数据进行统计分析。采用平均值±标准误表示。多组间差异比较采用单因素方差分析。P<0.01或P<0.05为差异有统计学意义。
4.结果
结果见图2~图6。本研究以临床抗炎药物美沙拉嗪作为阳性对照,系统地对比了蒿豉丹的醇提物和水提物对DSS诱导的溃疡性结肠炎小鼠体重、疾病活动指数和结肠长度的影响。结果显示:从DSS造模第4天开始小鼠出现稀便和血便的情况,随后在第6天到第10天小鼠的体重显著下降,腹泻和便血情况加剧。蒿豉丹(艾叶)水提物中剂量组与DSS组相比能够明显抑制体重的降低,改善大便性状、结肠出血等病例症状,缓解小鼠结肠缩短。结肠病理结果表明空白对照组结肠组织结构完整,上皮细胞排列整齐,无损伤。而DSS组小鼠结肠组织出现大面积炎性细胞浸润,杯状细胞缺失,大肠腺消失,浆膜层水肿等为主要特征。而蒿豉丹(艾叶)甲醇提取物中剂量组能够明显改善肠炎小鼠肠上皮结构,减轻炎性细胞浸润。
实施例3:基于药效的中药组合物中艾叶生品及其炮制品的筛选
在上述技术方案的基础上,该中药组合物中的艾叶原料药被替换成艾叶的炮制品:醋艾叶和醋艾炭;具体的,本发明所提供的中药组合物,由a~c任意一组原料药制成:
a组:青蒿9g、艾叶9g、淡豆豉9g;
b组:青蒿9g、醋艾叶9g、淡豆豉9g;
c组:青蒿9g、醋艾炭9g、淡豆豉9g;
制备方法:按配比称取上述原料,加10倍量的甲醇回流提取3次,每次提取2h,过滤,合并滤液,40℃旋蒸浓缩,得到甲醇提浸膏。
为验证本发明中药组合物的功效,并对实施例3中的中药组合物中艾叶的生品和各炮制品进行筛选。发明人开展了相关的药效学试验研究,以下药效学实验仅用于说明本发明中药组合物的功效,而不能限制本发明。
1.实验药品制备
按照实施例3的配方组方,再按照《中药药理研究方法学》,使用人与小鼠的药物剂量折算系数计算出各组小鼠的给药剂量,将各组生药浓缩成甲醇提浸膏,给药前,以0.5%的CMC-Na充分溶解,保存于4℃冰箱中备用。
2.实验分组和剂量
100只C57BL/6小鼠,6-8周龄,雄性,体重22±2g。适应性饲养7天后,随机分为10组,每组10只。预防给药7天,之后每天给予2.5% DSS的饮用水,连续7天,第8-10天更换为灭菌水,以复制小鼠急性结肠炎模型,在第11天处死小鼠。
1)空白组(Ctrl):正常饮水、进食,参考给药方案采用相同的给药途径基于同等剂量的0.5% CMC-Na溶液;
2)模型组(DSS):根据上述方法造模,参考给药方案采用相同的给药途径基于同等剂量的0.5% CMC-Na溶液;
3)阳性药-美沙拉嗪组(DSS+Mesalazine):根据上述方法造模,每日给予美沙拉嗪0.3g/kg/d;
4)阳性药-枫蓼肠宁康组(DSS+FLC):根据上述方法造模,每日给予枫蓼肠宁康1.125g/kg/d;
5)蒿豉丹(艾叶)甲醇提取物高剂量组(DSS+H-HCD):根据上述方法造模,每日给予蒿豉丹甲醇提取物3.4g生药/kg/d;
6)蒿豉丹(艾叶)甲醇提取物低剂量组(DSS+L-HCD):根据上述方法造模,每日给予蒿豉丹甲醇提取物1.7g生药/kg/d;
7)蒿豉丹(醋艾叶)甲醇提取物高剂量组(DSS+H-cHCD):根据上述方法造模,每日给予蒿豉丹甲醇提取物3.4g生药/kg/d;
8)蒿豉丹(醋艾叶)甲醇提取物低剂量组(DSS+L-cHCD):根据上述方法造模,每日给予蒿豉丹甲醇提取物1.7g生药/kg/d;
9)蒿豉丹(醋艾炭)甲醇提取物高剂量组(DSS+H-ctHCD):根据上述方法造模,每日给予蒿豉丹甲醇提取物3.0g生药/kg/d;
10)蒿豉丹(醋艾炭)甲醇提取物低剂量组(DSS+L-ctHCD):根据上述方法造模,每日给予蒿豉丹甲醇提取物1.5g生药/kg/d;
3.指标与检测方法
3.1小鼠病理指标统计
同实施例2部分
3.2实验动物处理及样本收集
同实施例2部分
3.3组织学评价
同实施例2部分
3.4脾脏指数和胸腺指数
取脾、胸腺,用分析天平称质量,按下列公式计算脾脏指数及胸腺指数。
脏器指数=脏器质量(mg)/体质量(g)×10
3.5小鼠血清中生化指标的检测
取小鼠血清,用全自动生化仪检测小鼠血清中的ALB、ALT、AST、HS-CRP、UREA的含量。
3.6肝脏和肾脏的HE切片
取小鼠的肝脏和肾脏用4%多聚甲醛缓冲液固定,按常规组织处理方法进行处理,处理后组织石蜡包埋。制备5μm厚的皮肤组织切片,然后按标准方法用苏木精和伊红(HE)染色,并在光学显微镜下进行观察。
3.7统计学分析
同实施例2部分
4.结果
结果见图7~图13。在上一步实验的基础上,对蒿豉丹中艾叶的生品及炮制品基于药效进行筛选,以美沙拉嗪和枫蓼肠宁康为阳性药。DSS组小鼠在第5天体重开始下降并出现明显便血、稀便等结肠炎特征,第6-9天小鼠体重呈断崖式下降。其他各给药组小鼠体重下降均有所缓解,稀便血便情况有所改善,其中以DSS+H-cHCD组最为明显。实验期间,正常组小鼠DAI评分变化较小,粪便呈颗粒状,无便血情况。随造模时间延长,模型组小鼠DAI评分逐渐增加,部分小鼠背毛耸立、凌乱,弓背颤抖,精神极度沉郁、反应迟钝,出现稀便或水样便,甚至出现便血。第9和10天(即DSS停用后2天)时,稀便和便血程度稍减弱,DAI评分增长缓慢。各给药组小鼠第6天起,与模型组比较,DAI分数增长明显减缓。
从结肠大体形态图可以看出:正常组小鼠结肠内可见颗粒状粪便,并且结肠没有充血水肿。而其他组小鼠的结肠内可见松软甚至水样便,结肠外观上出现不同程度的水肿,提示造模成功。结肠长度测量结果显示:DSS组小鼠结肠明显缩短。与模型组相比,各给药组小鼠结肠长度增加,具有显著性差异(P<0.001)。与阳性药美沙拉嗪相比,其他各给药组的结肠长度没有明显差异,提示作用效果相似(P>0.05)。
根据HE染色结果(图10-A)可以看出,正常组小鼠结肠组织可观察到完整结肠结构和黏膜上皮,结肠各层结构清晰;模型组结肠出现严重的黏膜损伤与水肿,杯状细胞和隐窝缺失,炎症细胞大量浸润;与模型组比较,各给药组结肠组织症状均存在不同程度上的缓解,黏膜上皮损伤恢复,结肠组织相对完整,炎症细胞浸润减少。为了进一步研究蒿豉丹对DSS诱导结肠炎小鼠肠屏障完整性的影响,采用PAS/AB染色法检测小鼠肠上皮杯状细胞及黏液层情况。结果显示,与空白对照组相比,DSS诱导后小鼠结肠黏液层变薄,杯状细胞明显减少。蒿豉丹的治疗可以恢复黏液层厚度,增加杯状细胞数量,DSS+H-cHCD组明显优于其他给药组。
血清中生化指标的检测结果显示:与正常组相比较,模型组小鼠血清中ALB(白蛋白)水平明显下降,ALT(丙氨酸转氨酶)和AST(天冬氨酸转氨酶)水平显著上升,提示DSS造模可以造成小鼠的肝损伤。各给药组小鼠的ALT(丙氨酸转氨酶)和AST(天冬氨酸转氨酶)水平与模型组相比,存在显著性的差异,表明可以缓解DSS造成的肝损伤,进一步提示各给药组对小鼠的肝脏没有毒性反应。与正常组相比较,模型组小鼠血清中UREA(尿素)水平显著升高,提示DSS造模可以造成小鼠的肾损伤。而各给药组UREA水平趋近于正常组,提示各给药组对小鼠的肾脏没有毒性反应,并且可以缓解DSS造成的肾损伤。而HE染色结果表明,各组小鼠的肝脏结构清晰,以中央静脉为中心,肝细胞索和肝血窦向周围呈放射状排列,胞浆丰富。肾脏中肾小体结构完整,肾小球位于小体中央且结构完整,未见明显的病变。
综上,蒿豉丹能够有效改善DSS诱导小鼠结肠炎症状,其中以DSS+H-cHCD组最优。
实施例4:对蒿豉丹(醋艾叶)中总黄酮和总皂苷的含量进行测定。
S1:总黄酮的含量测定
以芦丁(500ng/mL)为对照品贮备液,分别吸取0、100、200、400、500、600、800、1000μL,加甲醇补充至1mL,得到浓度为0、50、100、200、250、300、400、500ng/mL的系列标准品溶液。取200μL于5mL试管中,加5%亚硝酸钠溶液0.1mL,摇匀,静置6min,加10%硝酸铝试液0.1mL,摇匀,静置6min,加4%氢氧化钠试液1mL,摇匀,静置15min,摇匀,离心3min(4000r/min),以相应试剂为空白,500nm波长处测定吸光度,以芦丁质量浓度为横坐标,吸光度为纵坐标,绘制标准曲线。得到标准曲线:Y=0.0014X+0.0417(R2=0.9992)。取蒿豉丹(醋艾叶)甲醇提取物用适量甲醇稀释后,同法操作,测定总黄酮含量为14.98±0.34%。
S2:总皂苷的含量测定
以齐墩果酸(500ng/mL)为对照品贮备液,分别吸取0、100、200、300、400、500、700、700μL,加甲醇补充至1mL,得到浓度为0、50、100、150、200、250、300、350ng/mL的系列标准品溶液。取200μL于5mL试管中,将所有试管置于60℃水浴中挥干溶剂。在通风橱中,向试管中加5%香草醛-冰醋酸溶液0.1mL,高氯酸0.4mL,60℃水浴温浸15min,迅速取出,冰水浴终止反应,加入1mL冰醋酸稀释,538nm波长处用酶标仪测定吸光度,以齐墩果酸的质量浓度为横坐标,吸光度为纵坐标,绘制标准曲线。得到标准曲线:Y=0.0023X+0.0543(R2=0.9992)。取蒿豉丹(醋艾叶)甲醇提取物用适量甲醇稀释后,同法操作,测定总皂苷的含量为20.52±0.20%。
实施例5:基于超高效液相色谱的蒿豉丹(醋艾叶)甲醇提取物的特征图谱的构建
1.对照品溶液的制备
分别精密称取东莨菪内酯、异绿原酸B、异绿原酸A、异绿原酸C、棕矢车菊素、异泽兰黄素、蔓荆子黄素、猫眼草酚D和艾黄素的对照品适量,配制成浓度为363μm/mL、325μm/mL、960μm/mL、1575μm/mL、201μm/mL、920μm/mL、1465μm/mL、930μm/mL、249μm/mL的对照品储备液。化学结构见图14。
2.供试品溶液的制备
称取蒿豉丹(醋艾叶)提取物适量于50mL具塞锥形瓶中,精密加入甲醇40mL,密塞,超声处理60min,用甲醇定容,摇匀。10000rpm离心3min,吸取上清液,过0.22μm微孔滤膜,即得。
3.色谱条件
检测器:UPLC-1290超高效液相色谱仪(Agilent Technologies);
色谱柱:色谱柱:Waters ACQUITY UPLC BEH C18 Column(2.1mm×100mm,1.7μm);
检测波长:350nm;
流速:0.3mL/min,
进样量3μL,柱温30℃。
0.1%甲酸水溶液(A)-乙腈(B)梯度洗脱,
洗脱程序见表3。
表3蒿豉丹(醋艾叶)UPLC洗脱程序
4.线性关系考察
分别精密量取东莨菪内酯,异绿原酸C,棕矢车菊素,猫眼草酚D,异泽兰黄素,蔓荆子黄素,艾黄素标准储备液720μL,229μL,3053μL,324μL,240μL,322μL,248μL,434μL于同一离心管中并用甲醇补齐5mL,混匀,作为混合标准母液,以二倍稀释法制备系列标准溶液,按上述条件精密吸取3μL进行检测。以峰面积为纵坐标,各成分浓度为横坐标,绘制标准曲线。
回归方程、相关系数以及线性范围如表4所示,结果表明各成分在所测浓度范围内具有良好的线性。
表4蒿豉丹(醋艾叶)中7种成分标准曲线
成分 | 回归方程 | R2 | 线性范围(μg/mL) |
东莨菪内酯 | Y=42.8620X+6.0710 | 1 | 0.82~52.26 |
异绿原酸C | Y=3.1453X-2.4094 | 0.9997 | 1.13~72.17 |
棕矢车菊素 | Y=45.2093X-0.1473 | 1 | 0.20~13.01 |
猫眼草酚D | Y=28.1899X+2.2424 | 1 | 0.70~44.57 |
异泽兰黄素 | Y=39.0098X+0.9071 | 1 | 0.74~47.45 |
蔓荆子黄素 | Y=30.5417X+4.4494 | 1 | 1.14~72.77 |
艾黄素 | Y=24.4879X+4.4793 | 0.9993 | 0.34~21.62 |
5.特征图谱的建立与含量测定结果
取供试品溶液按照上述方法进行检测,得到UPLC特征图谱。与对照品溶液的特征图谱进行比较,对照品可指认其中的7个峰(1:东莨菪内酯;3:异绿原酸C;13:棕矢车菊素;14:猫眼草酚D;16:异泽兰黄素;17:蔓荆子黄素;18:艾黄素),见图15。
3批样品的含量测定结果见表5.
表5蒿豉丹(醋艾叶)中7种指标成分的含量测定结果(mg/g)
以上实施例对本发明的产品及方法进行了详细介绍,本文中应用了具体例对本发明的主要步骤及实施方式进行了阐述,上述实施例只是帮助理解本发明的方法及核心原理。对于本领域的技术人员,依据本发明的核心原理,在具体实施中会对各条件和参数根据需要而变动,综上所述,本说明书不应理解为对本发明的限制。
Claims (4)
1.一种治疗溃疡性结肠炎的中药组合物的制备及应用,所述中药组合物,由以下质量份数的原料药制成:青蒿9g、醋艾叶9g、淡豆豉9g;
所述中药组合物甲醇提取物通过如下方法制备得到:分别称取青蒿、醋艾叶和淡豆豉,混合,加10倍量的甲醇,加热回流提取2h,共3次,过滤,合并滤液,40℃旋蒸浓缩,即得。
2.如权利要求1所述的中药组合物甲醇提取物的特征图谱,其特征在于:共确定了19个特征峰,与对照品溶液图谱进行比较,可指认其中的7个峰(1:东莨菪内酯;3:异绿原酸C;13:棕矢车菊素;14:猫眼草酚D;16:异泽兰黄素;17:蔓荆子黄素;18:艾黄素)。
3.如权利要求1所述的中药组合物甲醇提取物在治疗溃疡性结肠炎的药物中的应用。
4.如权利要求3所述的应用,其特征在于,将中药组合物的甲醇提取物和药学上可接受的载体制备成颗粒剂、片剂、胶囊剂或口服液制剂。
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