CN115475176A - 罗汉果皂苷v在治疗溃疡性结肠炎药物中的应用 - Google Patents
罗汉果皂苷v在治疗溃疡性结肠炎药物中的应用 Download PDFInfo
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Abstract
一种罗汉果皂苷V在治疗溃疡性结肠炎药物中的应用,属于医药技术领域。本发明的目的是以罗汉果皂苷V为主要活性成分在制备治疗和/或预防溃疡性结肠炎药物中的应用。本发明可以显著有效的治疗缓解溃疡性结肠炎的相应症状,具体包括改善患有溃疡性结肠炎动物的疾病活动指数,逆转结肠长度缩短,降低结肠组织的病理损伤状况,恢复肠道屏障正常通透性,使结肠组织中细胞因子含量趋于正常值。
Description
技术领域
本发明属于医药技术领域。
背景技术
溃疡性结肠炎(UC)是一种非特异性的慢性的炎症性肠病,其病症累及于直肠和结肠的粘膜和粘膜下层,主要临床症状表现为腹部疼痛、腹泻以及血便脓便等。当前研究还未十分明确UC的发病因素,目前多认为与环境多样性、遗产易感性、免疫异常及炎症侵蚀因素相关。UC持续时间长、病程反复发作且病变范围广泛,多易感于青壮人群,被认为现代难治病症之一。随着人们当代生活作息改变,UC发病率在全球范围逐渐呈递增趋势,且值得注意的是,亚洲地区UC发病率增长尤其显著,印度地区已有大量UC患者出现。
目前来说,治疗UC的主要方法有药物治疗及手术疗法,手术疗法多应用于UC后期且有着高死亡率的风险,药物治疗为常见的治疗UC方法,其主要治疗药物有氨基水杨酸类药物、糖皮质激素类药物、免疫抑制剂类药物、抗菌抗感染类药物以及生物制剂类药物等。然而这些药物疗效不稳定,大多只能治标起缓解作用,不良反应多适应性不足并且一些药物如生物制剂价格昂贵,无法长期用药。因此,寻找一种药效准确安全、不良反应少且价格易于接受,质量可靠的药物有着重要确切的价值。
我国有着资源丰富的中药产物,在天然植物中筛选新型生物活性的化合物或者在已发现的化合物中探究新的生物用途已经成为新药开发的一种重要途径。罗汉果皂苷V是从罗汉果中提取出的一种天然生物活性成分,具有润肺、止咳、抗炎抗氧化及抗肿瘤等多种功能。
发明内容
本发明的目的是以罗汉果皂苷V为主要活性成分在制备治疗和/或预防溃疡性结肠炎药物中的应用。
本发明的罗汉果皂苷V在制备预防或/和治疗溃疡性结肠炎药物中的应用。
本发明包含罗汉果皂苷V的药物组合物在制备预防和/或治疗溃疡性结肠炎药物中的应用。
本发明可以显著有效的治疗缓解溃疡性结肠炎的相应症状,具体包括改善患有溃疡性结肠炎动物的疾病活动指数,逆转结肠长度缩短,降低结肠组织的病理损伤状况,恢复肠道屏障正常通透性,使结肠组织中细胞因子含量趋于正常值。本发明对于溃疡性结肠炎的临床应用治疗具有良好的潜力,并且依据相关急性毒性实验证实,罗汉果皂苷V在较高剂量仍然安全无毒,每日施用的罗汉果皂苷V含量不会有着明显限制,因此可依据临床具体情况,灵活施用剂量。本发明在临床应用上为治疗和/或预防溃疡性结肠炎提供了一种新的可行性药物选择。
附图说明
图1是第0天至第7天每组小鼠的每日体重变化趋势图;
图2是第0天至第7天每组小鼠的DAI评分结果统计图;
图3是在第7日时每组小鼠结肠宏观图;
图4是在第7日时每组小鼠结肠长度的结果统计图;
图5是经过施用不同浓度的罗汉果皂苷V后的小鼠结肠组织病理结构变化图;
图6是经过施用不同浓度的罗汉果皂苷V后的小鼠结肠组织病理学评分结果统计图;
图7是不同浓度的罗汉果皂苷V对小鼠结肠组织中炎症因子TNF-α水平的影响结果图;
图8是不同浓度的罗汉果皂苷V对小鼠结肠组织中炎症因子IL-1β水平的影响结果图;
图9是罗汉果皂苷V对DSS诱导的小鼠结肠炎中肠道通透性的影响结果图。
具体实施方式
本发明的首要目的在于克服当前技术的局限性,制备出一种治疗效果明确、无不良反应且原料易得、成本低廉的可治疗溃疡性结肠炎的药物,具体来说是以罗汉果皂苷V为主要活性成分在制备治疗和/或预防溃疡性结肠炎药物中的应用。
本发明公开了罗汉果皂苷V的一种生物医药方面的新用途,即在制备治疗溃疡性结肠炎药物中的应用。
本发明提供一种用于治疗和/或预防溃疡性结肠炎的药物组合物及其应用。
本发明的上述目的将会通过下述技术方法来实现:
罗汉果皂苷V在治疗溃疡性结肠炎药物中的应用。
其能够缓解治疗溃疡性结肠炎的药物可以改善患有溃疡性结肠炎动物的疾病活动指数,逆转结肠长度缩短,降低结肠组织的病理损伤状况,恢复肠道屏障正常通透性,使结肠组织中细胞因子含量趋于正常值。
所述的疾病活动指数包含体重的下降、粪便是否带血以及腹泻情况。
所述的降低结肠组织病理结构损伤包括隐窝结构完整性复原、结肠粘膜上皮组织坏死状态减轻、炎性细胞浸润状态减轻。
所述的使结肠组织中细胞因子含量趋于正常值包括降低TNF-α、IL-1β分泌含量、提高炎症因子IL-2的分泌量。
所述的罗汉果皂苷V结构如所示:
所述的溃疡性结肠炎包括但不仅限制为由葡聚糖硫酸钠引发的溃疡性结肠炎。
所述的罗汉果皂苷V有效浓度在25-100mg/kg。
罗汉果皂苷V在制备用于治疗溃疡性结肠炎的药物组合物中的相关应用。
一种应用在治疗溃疡性结肠炎的药物组合物的特征在于,包含罗汉果皂苷V,和/或罗汉果皂苷V在化学中可被接受的与酸组合形成的盐。
所述的药物组合物还包括了药学中可被承认的辅料。
所述的药物组合物剂型还包括片剂、颗粒剂、胶囊剂、栓剂和口服液等形式。
本发明经过前期了解发现罗汉果皂苷V有着润肺止咳等功效,但目前为止,还未有用罗汉果皂苷V作为唯一活性成分用于制备治疗和/或预防溃疡性结肠炎药物的相关报道。进一步探寻罗汉果皂苷V是否可作用于大肠,有着治疗结肠炎的相关作用。经过试验探证,罗汉果皂苷V可以明显缓解治疗实验性溃疡性结肠炎小鼠的体重减轻、血便、结肠缩短以及结肠组织病理性破坏等。因此,罗汉果皂苷V可用于制备治疗和/或预防溃疡性结肠炎的药物。
若非特殊说明,以下实施案例所使用的材料和试剂都可在市场上购买:
本发明的罗汉果皂苷V可以单独使用也可作为药物组合物的一部分进行使用,药物组合物则包括作为活性药物的罗汉果皂苷V及其可药用载体,即药物组合物包含了0.1%-99.9%重量百分比的罗汉果皂苷V,而可药用载体不可破坏罗汉果皂苷的药物活性,且其有效剂量不可对人体或动物产生毒性。
上所述的可药用载体包括且不限于:水、盐、软磷脂、硬脂酸铝、氧化铝、离子交换材料、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、硅酸镁、饱和脂肪酸、部分甘油酯混合物等被药学所承认的物质。
药物组合物中常用的药物辅料类别有填充剂(淀粉、葡萄糖、乳糖珠粒和无水乳糖等)、崩解剂(交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素等)、润滑剂(如硬脂酸镁)、粘合剂(如微晶纤维素) 以及吸收促进剂、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
本发明的罗汉果皂苷V及相应的药物组合物能够按照本专业领域的常规方法制备,其给药方式可通过肠道或非肠道或局部区域等。肠道给药制剂主要以栓剂存在;其口服制剂包括口服液、颗粒剂、片剂、胶囊、丸剂、散剂、丹剂、膏剂等;非肠道给药制剂主要以注射剂形式存在;局部给药制剂则包括霜剂、贴剂、喷雾剂、软膏剂等;其中推荐优选药物制剂为口服制剂。
本发明的罗汉果皂苷V以及其药物组合物的给药途径主要为口服、舌下、经皮、经肌肉或皮下注射、皮肤粘膜浸润、静脉、尿道等。
以下将结合具体实施案例及附图来进一步对本发明进行说明,但是此实施案例并不会对本发明进行任何形式的限定。若非进行额外特殊说明,否则本发明所采用的试剂、方法以及
设备均为在此技术领域的常规试剂、方法以及设备。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。
除非进行额外定义,本发明中所使用的所有专业与科学用语都是与本专业人员熟悉使用的意义相同;另外,任何与所记载内容相似或均等的方法及材料都是可以应用在本发明方法中,本发明所例举的例子仅作为示范。
实施案例1:罗汉果皂苷V对实验型溃疡性结肠炎的作用
1.实验材料
1.1实验药物
罗汉果皂苷V(Mogroside V,纯度≥98%,CAS号:88901-36-4)购于成都曼思特生物科技有限公司。其纯度符合药用标准,本发明所使用的罗汉果皂苷V纯度≥98%合适。
罗汉果皂苷V结构如式(I)所示:
1.2 实验试剂
葡聚糖硫酸钠(DSS,MW:36000-50000)购于北京酷来搏科技有限公司;4%多聚甲醛溶液、PBS缓冲液、苏木精、伊红均购于武汉赛维尔生物科技有限公司;小鼠ELISA试剂盒:肿瘤坏死因子α(TNF-α)试剂盒、白介素1β(IL-1β)试剂盒均购于美国BioLegend公司
1.3 实验动物
6-8周SPF级雌性C57BL/6J小鼠(20-22g)购置于辽宁长生生物技术股份有限公司,动物许可证号为SCXK(辽)2020-0001。在实验进行期间,动物先在24±2℃相对温度、50±10%相对湿度下,以12小时光照12小时黑暗环境中适应性饲喂7天,小鼠可自由采食和饮水。
1.4 实验仪器
切片机,HNE公司;光学显微镜,日本 Olympus 公司;电子天平;上海精天电子仪器有限公司;酶标仪,美国伯腾仪器有限公司;高速离心机,长沙湘仪离心机仪器有限公司。
2.实验方法
2.1 动物分组及剂量设计
首先分别称量记录每只小鼠体重,通过体重将小鼠随机分为5组:正常(Control)组、模型(DSS)组、罗汉果皂苷V低剂量(MV-L,25mg/kg)组、罗汉果皂苷V中剂量(MV-M,50mg/kg)组、罗汉果皂苷V高剂量(MV-H,100mg/kg)组,确保每组小鼠平均体重保持相近,每组6只小鼠,将组内每只小鼠标记号码(1-6)。
2.2 溃疡性结肠炎模型的建立
通过让C57小鼠自由饮用3%DSS溶液7天以诱导溃疡性结肠炎模型的产生。在自由饮用DSS溶液的同时,对各组小鼠给予相应剂量点的药物进行治疗,对于空白组和模型组,则向其灌胃等量的治疗药物的对应溶剂即生理盐水。持续给药时间为7日,在第8日时,对所有小鼠进行眼眶采血1ml,之后脱臼处死,剖取相应结肠组织保存。
2.3 对疾病活动指数(Disease Activity Index,DAI)的评分
在实验进行中,每天称取记录小鼠的体重变化,观察小鼠的活动精神状态、粪便状况以及是否便血,并依据下列规则进行评分记录:体重下降评分:没有变化,记为0分;下降1-5%,记为1分;下降5-10%,记为2分;下降10-20%,记为3分;下降超过20%,记为4分。粪便性状评分:正常形状,记为0分;粪便松软,记为1分;粪便湿润不定型,记为2分;粪便为半稀便,记为3分;粪便为稀便,记为4分。血便评分:无血便,记为0分;外表无血便但粪便潜血结果为阳性,记为2分;可观察到明显血便,记为4分。
DAI分数为体重下降评分、粪便性状评分和血便评分之和。
2.4 结肠长度测量记录和样本留存
在小鼠脱臼处死后,放置于解剖台上固定,在腹部喷洒适量的75%乙醇润湿毛发,剖开腹腔,分离肠道,获取结肠。之后,将结肠放置于提前准备好的蓝色干净无纺布上,使用直尺测量从肛门端至盲肠结肠交界处的距离长度,记录数据并且拍照留存结肠图片。
H&E染色样本留存:先使用提前4℃预冷的生理盐水缓慢仔细冲洗肠道内容物,再用滤纸吸净结肠上残留水分,取结肠远端处约1cm长度的结肠样本保存于4%多聚甲醛中以用于后面的H&E染色实验。
血清样本收集:将收集好的血液在4℃冰箱放置过夜,之后在离心机中以3000 rpm离心15分钟,吸取上层血清存储在﹣80℃冰箱以用作后续肠通透性检测。
结肠样本收集:收集结肠样本与1.5mL的EP管中,储存于-80℃冰箱中,用于后续相应ELISA实验的进行。
2.5 结肠组织病理学观察和评分记录
将放于4%多聚甲醛的结肠样本取出,进行系列脱水、石蜡包埋以及切片(5μm)操作,使用苏木精和伊红染色剂进行染色,之后在显微镜下进行结肠病理切片观察并记录评分,其评分细则如下:
(1)炎症程度评分:无炎症现象,记为0分;浅表炎症现象,记为1分;有轻微溃疡表现,记为2分;有大量溃疡现象,记为3分;有严重溃疡现象,记为4分。
(2)隐窝损伤程度评分:隐窝形态正常,记为0分;有少量隐窝发生形变,记为1分;有中等隐窝发生形变,记为2分;有大量隐窝发生形变,记为3分。
(3)炎症浸润程度评分:没有炎症浸润现象,记为0分;10%视野以下观察有炎症浸润现象,记为1分;10%-25%视野观察炎症浸润现象,记为2分;25%-50%视野观察炎症浸润现象,记为3分;超过50%视野观察有炎症浸润现象,记为4分。
(4)炎症程度评分:没有炎症现象,记为0分;炎症局限于粘膜层,记为1分;炎症局限于粘膜下层,记为2分;粘膜深入固有层,记为3分。
统计总分为炎症程度评分、隐窝损伤程度评分、炎症浸润程度评分和炎症程度评分相加之和。
2.6 炎性因子含量检测
取出放在-80℃冰箱的结肠组织,准确称取结肠组织重量,按照1:9(w:v)比例加入提前预冷的生理盐水,加入研磨珠研磨,之后以12000rpm 4°条件离心10min,吸取上清液,按照ELISA相应说明书测量炎性因子TNF-α、IL-1β的含量。
2.7 小鼠肠通透性检测
使用不可吸收的FITC-dextran(MW:4000)测定小鼠肠通透性,先将小鼠空腹8小时,之后配置50mg/ml剂量,向每只小鼠给予100ul FITC-dextran,在4小时后进行眼眶取血,离心取血清。准备好标准品,以PBS稀释血清,每孔100ul溶液置于酶标仪测量吸光度(激发波长:480nm,测量波长:520nm),绘制标准曲线,依据标准曲线转换样品浓度。
2.8 数据统计方法
各数据以均数±标准差(mean±SD)表示,应用Graph Pad Prism 7软件制图,SPSS20.0软件进行统计学分析。各组间差异比较,采用单因素方差分析(One-Way ANOVA),组间两两多重比较采用LSD法,P<0.05表示差异有统计学意义。
3.实验结果
3.1 罗汉果皂苷V对DSS诱导的小鼠结肠炎影响
经过实验探究发现,在实验周期中,Control组小鼠摄食饮水及精神状态正常,皮肤毛发柔顺有光泽,其体重稳定。而给予DSS造模的模型组,小鼠精神表现沉郁、蜷缩且不爱走动,被毛光泽凌乱、毛发稀疏,其体重方面前4天保持大体稳定,但从5天后体重就呈大幅下降状态。罗汉果皂苷V各浓度组都可改善小鼠体重造模后的下降状态,且精神状态也会更好。观察各组间的小鼠粪便状况,发现正常小鼠粪便正常,无稀便血便;模型小鼠在第五天后出现明显血便,而罗汉果皂苷V各浓度组可缓解小鼠稀便、血便现象,且呈现剂量依赖关系。
综合上述状态观察记录,统计各组小鼠的DAI评分。如图2所展示,Control组小鼠DAI评分稳态,没有增长;模型组小鼠从第3天开始就呈现上升趋势,在第5天后呈现显著上升状态;与模型组小鼠相对比,罗汉果皂苷V各浓度组DAI评分均有下降,且下降趋势与浓度呈现依赖关系。因此,罗汉果皂苷V的施用可以显著改善小鼠的结肠炎外在表现,说明罗汉果皂苷V有着一定的治疗环境结肠炎作用。
3.2 罗汉果皂苷V对结肠炎小鼠的结肠长度影响
如图3和图4展示,与Control组小鼠相比,模型组小鼠结肠长度显著缩短(P<0.01);而与模型组小鼠相比,罗汉果皂苷V各浓度组逆转了结肠缩短的现象,且呈现一定的剂量依赖现象。因此可看出,罗汉果皂苷V可以逆转结肠炎小鼠的结肠长度缩短状况。
3.3 罗汉果皂苷V对结肠炎小鼠结肠组织损伤情况的影响
如图5和图6所示,Control组小鼠结肠组织结构完整清晰,粘膜层中杯状细胞排列规整且隐窝结构完好,粘膜下层无水肿、无炎性浸润现象,组织病理学评分低。而与Control组相比,模型组小鼠结肠组织可见其结构明显缺损紊乱,上皮细胞受损,杯状细胞数量减少,隐窝缺失,粘膜下层水肿现象严重发生,炎性细胞浸润显著,其病理组织学评分高。与模型组小鼠相比,罗汉果皂苷V各浓度的施用可以恢复上皮组织结构缺失状态,增加杯状细胞数,逆转隐窝结构改变,降低粘膜下层组织水肿状态以及阻止炎症细胞浸润,且这些现象呈一定的剂量依赖关系。
3.4 罗汉果皂苷V对结肠炎小鼠结肠组织内炎症因子的影响
如图7和图8所示,与Control组小鼠相比,模型组小鼠结肠组织炎症因子(TNF-α、IL-1β)含量显著上升;与模型组相比,罗汉果皂苷V可呈剂量依赖趋势的降低炎症因子的含量,这说明罗汉果皂苷V可通过炎症因子来调节小鼠结肠炎的症状。
图1至图4为罗汉果皂苷V显著改善缓解由DSS诱导的小鼠溃疡性结肠炎的症状(n=6)结果图:其中图1是第0天至第7天每组小鼠的每日体重变化趋势图;图2是第0天至第7天每组小鼠的DAI评分结果统计图;图3是在第7日时每组小鼠结肠宏观图;图4是在第7日时每组小鼠结肠长度的结果统计图。其中,#代表与Control组相比P<0.05,##代表与Control组相比P<0.01;*代表与DSS组相比P<0.05,**代表与DSS组相比P<0.01。
图5和图6为罗汉果皂苷V对DSS诱导的小鼠结肠炎中结肠组织损伤的影响结果图(n=6);图5是经过施用不同浓度的罗汉果皂苷V后的小鼠结肠组织病理结构变化图;图6是经过施用不同浓度的罗汉果皂苷V后的小鼠结肠组织病理学评分结果统计图。其中,#代表与Control组相比P<0 .05,##代表与Control组相比P<0 .01;*代表与DSS组相比P<0.05,**代表与DSS组相比P<0.01。
图7和图8为罗汉果皂苷V对DSS诱导的小鼠结肠炎中炎症因子含量影响结果图(n=6);图7是不同浓度的罗汉果皂苷V对小鼠结肠组织中炎症因子TNF-α水平的影响结果图;图8是不同浓度的罗汉果皂苷V对小鼠结肠组织中炎症因子IL-1β水平的影响结果图;其中,其中,#代表与Control组相比P<0.05,##代表与Control组相比P<0.01;*代表与DSS组相比P<0.05,**代表与DSS组相比P<0.01。
图9为罗汉果皂苷V对DSS诱导的小鼠结肠炎中肠道通透性的影响结果图(n=6);其中,#代表与Control组相比P<0.05,##代表与Control组相比P<0.01;*代表与DSS组相比P<0.05,**代表与DSS组相比P<0.01。
Claims (2)
1.一种罗汉果皂苷V在治疗溃疡性结肠炎药物中的应用,其特征在于:罗汉果皂苷V在制备预防或/和治疗溃疡性结肠炎药物中的应用。
2.根据权利要求1所述的罗汉果皂苷V在治疗溃疡性结肠炎药物中的应用,其特征在于:包含罗汉果皂苷V的药物组合物在制备预防和/或治疗溃疡性结肠炎药物中的应用。
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