CN112438974A - 淫羊藿苷元在制备预防或治疗溃疡性结肠炎药物中的应用 - Google Patents
淫羊藿苷元在制备预防或治疗溃疡性结肠炎药物中的应用 Download PDFInfo
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- CN112438974A CN112438974A CN202010889217.8A CN202010889217A CN112438974A CN 112438974 A CN112438974 A CN 112438974A CN 202010889217 A CN202010889217 A CN 202010889217A CN 112438974 A CN112438974 A CN 112438974A
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
本发明属于医药领域,具体涉及淫羊藿苷元的用途,即淫羊藿苷元在用于制备预防或治疗溃疡性结肠炎药物的用途。动物试验显示,淫羊藿苷元对于溃疡性结肠炎具有显著的防治作用,可显著降低溃疡性结肠炎小鼠的DAI和TDI。淫羊藿苷元抗溃疡性结肠炎作用疗效确切、副作用低,有广阔的医疗应用前景。
Description
技术领域
本发明属于医药领域,涉及一种淫羊藿苷元的医药用途,具体涉及淫羊藿苷元在制备预防或治疗溃疡性结肠炎药物中的医药用途。
背景技术
淫羊藿为小檗科植物淫羊藿、箭叶淫羊藿、粗毛淫羊藿、巫山淫羊藿或朝鲜淫羊藿的干燥地上部分。淫羊藿含多种黄酮类成分,如淫羊藿苷、淫羊藿次苷、淫羊藿苷元(Icaritin, ICT)等。中医认为其味辛、甘,性温,归肝、肾经,主治功能:补肾阳,强筋骨,祛风湿。淫羊藿苷元属黄酮醇类化合物,少量存在于淫羊藿药材中,其化学结构式如下:
淫羊藿苷元可以从淫羊藿药材中分离得到(孙朋悦,徐颖,文晔等,朝鲜淫羊藿的化学成分,中国植物化学杂志,1998,8(2):122-125),或将淫羊藿苷经酶解分离得到(叶海涌,刘健,楼宜嘉,淫羊藿苷衍生物的制备及其雌激素样作用研究,浙江大学学报,2005, 34(2):131-136)。
有文献报道淫羊藿苷元具有抗Aβ肽致大鼠原代培养神经细胞凋亡的作用(张翔南,王欢欢,王志强等,淫羊藿苷元抗Aβ肽致大鼠原代培养神经细胞凋亡的作用,浙江大学学报, 2007,36(3):224-226)。中国专利CN101836976A公开了淫羊藿苷元具有抗肿瘤血管生成的作用。中国专利CN101428015A公开了淫羊藿苷元具有抗内毒素血症的作用。中国专利 CN101284000A公开了淫羊藿苷元具有防治肥胖症或脂肪肝的作用。中国专利CN1869204A 公开了淫羊藿苷元在诱导干细胞体外定向分化方面的用途。中国专利CN1194701C公开了淫羊藿苷元或去甲基淫羊藿苷元具有在制备雌激素受体调节剂中的应用。
溃疡性结肠炎(ulcerative colitis,UC)又名慢性非特异性溃疡性结肠炎,是以直、结肠的表浅性、非特异性炎症病为主,伴有肠外多器官损害的疾病,目前认为本病与遗传因素有关,以自身免疫机制为根本,感染、神经因素为诱因,病变主要在直肠、乙状结肠。首先是粘膜浅层的弥漫性炎症改变。继之充血、水肿、肥厚和脆性增加,产生小溃疡,进而发展成大溃疡,晚期由于结肠组织增生,肠壁变厚、变窄、肠管变短。其病程漫长,严重影响患者的身体健康和生活质量,且随病程的延长发生大肠癌的几率增加,因此被世界卫生组织列为现代难治病之一。本病在我国较欧美少见,且病程一般较轻,但近年患病率日趋增高,重症也常有报道。
国内外对溃疡性结肠炎治疗的方案基本一致,临床主要使用柳氮磺胺吡啶水杨酸制剂、强的松或地塞米松等激素制剂、免疫抑制剂硫唑嘌呤等进行治疗,但疗效欠佳,且有较大不良反应。因此,长期以来人们非常重视研究与开发治疗溃疡性结肠炎疾病的药物,其对于减轻患者痛苦,改善患者的生活质量具有十分重要的意义。
迄今为止,未见有关淫羊藿苷元抗溃疡性结肠炎生物活性或应用方面的研究。
发明内容
本发明提供了一种新的预防或治疗溃疡性结肠炎的药物,该药物以淫羊藿苷元为药物活性成分,即本发明涉及淫羊藿苷元在制备预防或治疗溃疡性结肠炎药物中的用途。
上述所述的医药用途中,淫羊藿苷元可以制备成合适的药物剂型口服给药或注射给药,其适用对象可以为人或其他恒温动物。当适用对象为人时,淫羊藿苷元的用量为0.001mg/kg·d~50mg/kg·d,优选为0.01mg/kg·d~10mg/kg·d,更优选为0.1mg/kg·d~5mg/kg·d,进一步优选的,用量为0.5mg/kg·d或1mg/kg·d或0.8mg/kg·d或1.5mg/kg·d。对于本发明预防或治疗溃疡性结肠炎的药物的给药时间和给药次数需要根据病情的具体诊断结果而定,这在本领域技术人员掌握的技术范围之内。例如,将对大鼠或小鼠预防或治疗溃疡性结肠炎的治疗方案应用于人身上,所用药物对人的有效剂量可以通过该药物对大鼠或小鼠的有效剂量进行换算,这对于本领域的普通技术人员来说是显而易见的。
上述所述的医药用途中,根据动物病情以及用药部位可以将淫羊藿苷元制备成合适的药物制剂以方便用药,如淫羊藿苷元可以开发成口服制剂、舌下含服制剂或注射制剂方便患者的使用,其中所述口服制剂可以为片剂、胶囊剂或微乳制剂,优选为片剂;所述舌下含服制剂为含有淫羊藿苷元并适用舌下给药的药物制剂,优选为其舌下片;所述注射制剂可以为其注射液、注射微乳等,优选为注射液。当淫羊藿苷元制备成注射液时,药物可接受的载体可以为注射用水、氯化钠、柠檬酸钠、柠檬酸、甘油、乙醇、丙二醇等。上述所述淫羊藿苷元注射液还可以根据药物的性质加入适宜的附加剂,如渗透压调节剂、pH值调节剂、增溶剂、抑菌剂、乳化剂、助悬剂等,其中所述增溶剂为聚乙二醇400、吐温-80中的任意一种或两种。
上述药物制剂的制备方法均可采用本领域技术人员制备该种剂型常规使用制备方法制得。上述药物制剂中,每一制剂单位中含有淫羊藿苷元的含量为0.001mg~50mg。
与现有技术相比,本发明的优势在于:
1、本发明所述的淫羊藿苷元具有显著的预防或治疗溃疡性结肠炎的作用。本发明实施例10显示本发明的淫羊藿苷元能够显著降低溃疡性结肠炎小鼠的DAI和TDI,淫羊藿苷元治疗溃疡性结肠炎的效果显著优于淫羊藿苷。本发明实施例11显示本发明的淫羊藿苷元能够减小溃疡性结肠炎大鼠的巨检评分,淫羊藿苷元治疗溃疡性结肠炎的效果显著优于淫羊藿苷。
2、本发明所述淫羊藿苷元是从传统中药淫羊藿中提取得到的天然中药单体,其对人体毒副作用低,可以显著提高患者的用药安全性和用药依从性,进而大幅度改善了溃疡性结肠炎患者的治疗效果和生活质量。
具体实施方式
为了使本领域技术人员充分了解本发明,以下通过具体的实施例进一步说明本发明,但本领域技术人员应该知晓,本发明实施例并不以任何方式限制本发明。
实施例1淫羊藿苷元注射液
制备工艺:将处方量的丙二醇和乙醇混合均匀,加入淫羊藿苷元,搅拌溶解,加入处方量的0.9%氯化钠溶液,搅拌均匀,加入0.5%针用活性炭,搅拌,脱炭,即得。
实施例2淫羊藿苷元注射液
制备工艺:向处方量的PEG-400加入淫羊藿苷元,搅拌溶解,加入0.9%氯化钠溶液至 10L,搅拌均匀,加入0.5%针用活性炭,搅拌,脱炭,即得。
实施例3淫羊藿苷元注射液
制备工艺:将处方量的乙醇和吐温-80混合均匀,加入淫羊藿苷元,搅拌溶解,加入注射用水至10L,搅拌均匀,加入0.5%针用活性炭,搅拌,脱炭,即得。
实施例4淫羊藿苷元注射液
淫羊藿苷元 0.01g
乙醇 3.3L
注射用水 加至10L
制备工艺:将处方量的乙醇加入淫羊藿苷元,搅拌溶解,加入注射用水至10L,搅拌均匀,加入0.5%针用活性炭,搅拌,脱炭,即得。
实施例5片剂的制备
制备工艺:将淫羊藿苷元和辅料微晶纤维素、羧甲基淀粉钠混合均匀,加入适量的淀粉浆制软材,然后过16目筛制粒。湿颗粒在60℃干燥,干颗粒过20目筛整粒,筛出干粒中的细粉,与硬脂酸镁混匀,然后再与干颗粒混匀,压片,每片约200mg,即得。
实施例6淫羊藿苷元舌下片
制备工艺:上述组分烘干、粉碎过筛预处理后混匀直接压片制得。
实施例7淫羊藿苷元舌下片
制备工艺:将主药及各辅料成分烘干、粉碎过筛预处理,将主药与乳糖、羧甲基纤维素钠混匀,以纯水作为粘合剂将混匀的物料制备软材,过20目筛制粒并于60℃下干燥制备干颗粒,将硬脂酸镁加入到上述干颗粒总混,压片即得。
实施例8微乳浓缩物
制备工艺:称取处方量中链脂肪酸甘油酯、聚氧乙烯蓖麻油EL-40、1,2-丙二醇、无水乙醇,混合后搅拌均匀,然后加入淫羊藿苷元溶解,也可以超声波处理以加速溶解,得澄清浓缩液,即为淫羊藿苷元微乳浓缩物。上述微乳浓缩物可进一步稀释用于注射或口服。
实施例9微乳浓缩物
制备工艺:称取处方量PEG-2-硬脂酸酯、吐温-20、1-己醇、PEG3350混合后搅拌均匀,然后加入淫羊藿苷元溶解,也可以超声波处理以加速溶解,得澄清浓缩液,即为淫羊藿苷元微乳浓缩物。上述微乳浓缩物可以根据用药需要进行进一步稀释用于患者注射给药或口服给药。
实施例10淫羊藿苷元对小鼠溃疡性结肠炎的作用研究
1.动物造模、分组及给药
1.1 造模
取健康雄性SPF级BALB/c小鼠,8周龄,体质量(20±2)g,参照文献(Chu C C,Hou YC,Pai M H,et al.Pretreatment with alanyl-glutamine suppresses T-helper-cell-associated cytokine expression and reduces inflammatory responses in micewith acute DSS-induced colitis.[J].Journal of Nutritional Biochemistry,2012,23(9):1092-1099)采用DSS诱导法建立 UC模型:小鼠自由饮用5%DSS溶液100mL(5gDSS溶100mL蒸馏水中),连续7d。
1.2 分组
取造模成功的小鼠随机分为5组,每组10只,分别为模型对照组、淫羊藿苷元低剂量组、淫羊藿苷元高剂量组、淫羊藿苷组、柳氮磺胺吡啶组;另取正常小鼠10只,作为正常对照组。
1.3 给药
自造模后第2天起,连续灌胃给药,每日一次,共7d。
各组分别给予下述药物:
淫羊藿苷元低剂量组:5mg/kg淫羊藿苷元;
淫羊藿苷元高剂量组:10mg/kg淫羊藿苷元;
淫羊藿苷组:10mg/kg淫羊藿苷;
柳氮磺胺吡啶组:300mg/kg柳氮磺胺吡啶;
以上药物均0.5%羧甲基纤维素钠混悬。
正常对照组:等体积的羧甲基纤维素钠;
模型对照组:等体积的羧甲基纤维素钠。
2.实验方法及数据处理
2.1 一般情况观察
造模之日起,每天观察并记录小鼠的精神活动状态、摄食量和饮水量等一般情况,每天定时称量体质量,观察粪便性状并行隐血试验,参照文献(Maslowski KM,Mackay CR.Diet,gut microbiota and immune responses.Nat Immunol.2011;12(1):5-9)进行疾病活动度指数(disease activity index,DAI),DAI=(体质量减轻率分数+大便性状分数+隐血程度分数) /3。
2.2 结肠组织病理学检测
药物治疗结束后,全部小鼠以颈部脱臼法处死,严格无菌条件下取出结肠组织,修整大小为1.0cm×1.0cm×0.2cm,4%多聚甲醛固定4天,石蜡包埋,4μm厚连续切片,HE染色后光镜下观察组织病理学变化,并参照文献(Andújar I,Ma C R,Giner R M,etal.Inhibition of Ulcerative Colitis in Mice after Oral Administration of aPolyphenol-Enriched Cocoa Extract Is Mediated by the Inhibition of STAT1 andSTAT3 Phosphorylation in Colon Cells[J].J Agric Food Chem,2011,59(12):6474-6483)进行组织损伤指数(tissue damage index,TDI)评分:正常结肠黏膜为0分,隐窝腺体丢失1/3为1分,隐窝腺体丢失2/3为2分,隐窝腺体全部丢失,黏膜上皮完整伴有轻度炎细胞浸润为3分,黏膜上皮糜烂、破坏、伴有明显炎细胞浸润为4分。每个样本于200倍镜下随机选取10个视野观察,记录并评分统计。
2.3 数据统计与分析
3.结果与讨论
3.1 小鼠一般情况和疾病活动度变化
造模成功后,模型对照组和各给药治疗组小鼠均出现不同程度的精神呆滞、行动缓慢、进食少,伴有大便稀溏、便血、体质量下降,而空白对照组小鼠的精神、活动、饮食、大便、体质量等一般情况均正常。
试验结果见表1。
与模型对照组比较,淫羊藿苷元低、高剂量组的DAI明显降低(P<0.01);淫羊藿苷组、柳氮磺胺吡啶组的DAI有降低(P<0.05)。
与淫羊藿苷组比较,淫羊藿苷元组DAI明显降低(P<0.01)。
与模型对照组比较,淫羊藿苷元低、高剂量组的TDI明显降低(P<0.01);淫羊藿苷组、柳氮磺胺吡啶组的TDI有降低(P<0.05)。
与淫羊藿苷组比较,淫羊藿苷元组TDI明显降低(P<0.01)。
表1各组小鼠治疗后DAI和TDI评分比较
与正常对照组相比,¥P<0.05,¥¥P<0.01;
与模型对照组相比,#P<0.05,##P<0.01;
与淫羊藿苷组相比,&P<0.05,&&P<0.01。
3.2 小鼠结肠组织病理改变
镜下可见,空白对照组结肠组织结构正常,黏膜上皮未见病变;模型对照组结肠可见黏膜下隐窝腺体全部丢失,炎性细胞浸润黏膜至上皮结构破坏;淫羊藿苷元低、高剂量组中,以淫羊藿苷元高剂量组小鼠结肠组织结构与正常对照组最为接近,淫羊藿苷元低剂量组可见隐窝腺体大片丢失,黏膜下炎细胞浸润,部分黏膜上皮可见水肿。
淫羊藿苷元具有预防和/或治疗溃疡性结肠炎疾病的功效。
实施例11淫羊藿苷元对醋酸致大鼠溃疡性结肠炎的抑制作用
1、方法
1.1试验方法:健康雄性SD大鼠60只,体重(200±20)g。
随机分为正常对照组、模型对照组、淫羊藿苷元低剂量组、淫羊藿苷元高剂量组、淫羊藿苷低剂量组、淫羊藿苷高剂量组。
淫羊藿苷元低剂量组腹腔注射给予淫羊藿苷元5mg/kg,淫羊藿苷元高剂量组腹腔注射给予淫羊藿苷元10mg/kg,淫羊藿苷低剂量组腹腔注射给予淫羊藿苷5mg/kg,淫羊藿苷高剂量组腹腔注射给予淫羊藿苷10mg/kg;正常对照组以及模型对照组给予等体积0.5%CMC,每天一次,给药10d。
溃疡性结肠炎造模方法为:大鼠禁食不禁水48h,戊巴比妥钠30mg/kg腹腔注射麻醉后将导尿管经肛门插入8cm,注入1mL10%醋酸生理盐水溶液(正常对照组用生理盐水代替醋酸溶液),头部朝下肛门朝上手托20s后再注入2mL生理盐水冲洗1次。继续给药7d。
末次给药后禁食12h,断颈处死,迅速剖腹取出肛门至盲肠末端的整个结肠和直肠段,沿肠系膜缘剪开肠腔,用生理盐水将肠内容物冲洗干净,滤纸拭干,然后将整个肠段平铺于铝板上,肉眼观察评分,评分标准见表2。
表2结肠损伤巨检评分标准
2.结果
表3淫羊藿苷元对醋酸致大鼠溃疡性结肠炎的影响
与模型对照组相比,*p<0.05,**p<0.01;
与淫羊藿苷组相比,&p<0.05;&&p<0.01。
(1)醋酸造模后结肠巨检显示结肠肠壁粘连、增厚,内表面溃疡。各治疗组与模型对照组相比,具有显著性差异(p<0.05)。表明淫羊藿苷组及淫羊藿苷元高、低剂量组对醋酸所致溃疡性结肠炎有显著的治疗作用。
(2)与淫羊藿苷组相比,淫羊藿苷元高、低剂量组巨检评分明显减小,淫羊藿苷元各剂量组在抑制溃疡性结肠炎方面与淫羊藿苷组相比,具有极显著性差异。
综上所述,淫羊藿苷元具有预防和/或治疗溃疡性结肠炎疾病的功效。
Claims (10)
1.淫羊藿苷元在制备预防或治疗溃疡性结肠炎药物中的用途。
2.如权利要求1所述的用途,其特征在于所述淫羊藿苷元的给药剂量为0.001mg/kg·d~50mg/kg·d。
3.如权利要求2所述的用途,其特征在于所述淫羊藿苷元的给药剂量为0.01mg/kg·d~10mg/kg·d。
4.如权利要求3所述的用途,其特征在于所述淫羊藿苷元的给药剂量为0.1mg/kg·d~5mg/kg·d。
5.如权利要求4所述的用途,其特征在于所述淫羊藿苷元的给药剂量为0.5mg/kg·d或1mg/kg·d。
6.如权利要求4所述的用途,其特征在于所述淫羊藿苷元的给药剂量为0.8mg/kg·d或1.5mg/kg·d。
7.如权利要求1-6任一项所述的用途,其特征在于所述淫羊藿苷元可制备成口服制剂、舌下含服制剂或注射制剂中的一种或多种。
8.如权利要求7所述的用途,其特征在于所述口服制剂为其片剂、胶囊剂或微乳制剂中的一种或多种。
9.如权利要求7所述的用途,其特征在于所述注射制剂为其注射液或注射微乳中的一种或多种。
10.如权利要求7所述的用途,其特征在于每一制剂单位中淫羊藿苷元的含量为0.001mg~50mg。
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吴晶晶: ""天然类黄酮淫羊藿通过调节巨噬细胞功能对溃疡性结肠炎的治疗作用及机制研究"", 《中国优秀硕士论文数据库》, pages 5 * |
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