CN109331050A - 卤蕨水提物在制备治疗急性胃溃疡药物中的应用 - Google Patents
卤蕨水提物在制备治疗急性胃溃疡药物中的应用 Download PDFInfo
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Abstract
本发明涉及卤蕨水提物在制备治疗急性胃溃疡药物中的应用。本应用中所述的卤蕨水提物可显著降低模型大鼠胃溃疡面积和病理学评分,恢复胃粘膜完整性,修复组织病理学变化,减轻胃部炎性反应和黏膜损伤,因此可制备成临床上常见的口服制剂。
Description
技术领域
本发明涉及来自卤蕨科卤蕨属植物的未确定结构的药物,具体涉及治疗消化道或消化系统疾病的药物。
背景技术
胃溃疡(Gastric ulcer)是一种常见的消化性疾病,该病反复发作,极大影响患者的生活质量。出血、穿孔是胃溃疡的首发症状,患者腹部会出现隐痛、胀痛、烧灼样痛。近年来,随着我国社会经济的迅速发展,人们饮食习惯也随之发生相应转变,胃溃疡的发病率逐步呈上升趋势。胃溃疡是世界性范围的疾病,约占全球人口10%的人都曾患过胃溃疡,其中1%的溃疡可转化为胃癌,故本病被世界卫生组织列为癌前状态疾病,对人类危害颇大。急性胃溃疡是胃溃疡的一种,常发生于过量吸烟饮酒、服用非甾体抗炎药物等,临床主要表现为中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻。目前胃溃疡的治疗药物主要有组胺H2受体阻断药、质子泵抑制剂、胃粘膜保护剂等。上述药物虽对胃溃疡具有一定的保护作用,但存在副作用明显、价格昂贵等缺点。中医中药在胃溃疡治疗方面有显著优势,近年中医药治疗胃溃疡取得较多成果。由于众多医疗和科研工作者对胃溃疡的关注,寻找对胃溃疡具有良好治疗作用的中药,探明其作用机制,对于研发新一代安全、高效的抗胃溃疡药物,具有重要的现实意义。
卤蕨(Acrostichum aureurm Linn.)为卤蕨科(Acrostichaceae)植物,遍布于亚洲热带海岸、大西洋的非洲西岸和美洲东岸以及大洋洲沿岸,属于嗜热广布性种类,在我国分布于广东、广西、台湾、福建和海南,为组成红树林的树种之一。红树植物卤蕨在国内外有很好的药用价值,在孟加拉国,其根状茎和叶子的配制剂治疗创伤、溃疡、烫伤,叶子用于止血。在中国大陆,根状茎用于治疗蠕虫传染,在斐济,该植物用于治疗哮喘、便秘、象皮肿、胸疼,在哥斯达黎加,卤蕨的叶子用于润滑剂。
发明内容
本项发明所要解决的技术问题是提供卤蕨的新用途,即在制药中的应用。
上述应用具体是,卤蕨水提物在制备治疗急性胃溃疡药物中的应用。
上述应用中所述的药物由卤蕨水提物和医学上可接受的辅料组成常见口服制剂,如口服液、胶囊、滴丸或颗粒剂。
上述应用中所述卤蕨水提物由以下方法制得:取干燥后的卤蕨地上部分剪成小段,加入10倍量水浸泡后,采用煎煮法提取2次,每次2h,过滤,合并滤液,加热浓缩,冷冻真空干燥成浸膏粉,即得所述的卤蕨水提物。
本发明所述的药物可显著降低模型大鼠胃溃疡面积和病理学评分,恢复胃粘膜完整性,修复组织病理学变化,减轻胃部炎性反应和黏膜损伤,进而实现治疗急性胃溃疡的目的。
附图说明
图1为卤蕨水提物对无水乙醇诱导大鼠胃溃疡影响的显微照片,其中,a为正常组;b为模型组;c为LSZ组(30mg/kg);d为WEAC低剂量组(100mg/kg); e为WEAC中剂量组(200mg/kg);f为WEAC高剂量组(400mg/kg)。
图2为卤蕨水提物对无水乙醇诱导大鼠胃溃疡面积与溃疡抑制率影响的条形图(Mean±SD,n=8);其中,a图为溃疡面积(mm2)的统计结果;b图为溃疡抑制率(%)的统计结果,与正常组(Normal)相比##P<0.01,与模型组(Model) 相比**P<0.01。
图3为卤蕨水提物对无水乙醇诱导急性胃溃疡大鼠胃组织病理学分析 (Mean±SD,n=8)的显微照片和条形图;其中,a为正常组显微照片;b为模型组显微照片;c为LSZ组(30mg/kg)显微照片;d为WEAC低剂量组(100 mg/kg)显微照片;e为WEAC中剂量组(200mg/kg)显微照片;f为WEAC 高剂量组(400mg/kg)显微照片;g为组织学病理损伤评分的条形图,与正常组(Normal)相比##P<0.01,与模型组(Model)相比**P<0.01。
图4为卤蕨水提物对吲哚美辛诱导大鼠胃溃疡影响的显微照片,其中,a为正常组,b为模型组,c为LSZ组(30mg/kg),d为WEAC低剂量组(100mg/kg), e为WEAC中剂量组(200mg/kg),f为WEAC高剂量组(400mg/kg)。
图5为卤蕨水提物对吲哚美辛诱导大鼠胃溃疡面积与溃疡抑制率影响的条形图(Mean±SD,n=8);其中,a图为溃疡面积(mm2)的统计结果;b图为溃疡抑制率(%)的的统计结果,与正常组(Normal)相比##P<0.01,与模型组(Model) 相比**P<0.01。
图6卤蕨水提物对吲哚美辛诱导急性胃溃疡大鼠胃组织病理学分析(Mean ±SD,n=8)的显微照片和条形图;其中,a为正常组显微照片,b为模型组显微照片,c为LSZ组(30mg/kg)显微照片,d为WEAC低剂量组(100mg/kg)显微照片,e为WEAC中剂量组(200mg/kg)显微照片,f为WEAC高剂量组(400 mg/kg)显微照片;g为组织学病理损伤评分的条形图,与正常组(Normal)相比##P<0.01,与模型组(Model)相比**P<0.01。
上述附图1-6中,代号LSZ表示兰索拉唑,代号WEAC表示卤蕨水提物。
具体实施方式
一、效果实验例
1.实验材料
1.1试剂
兰索拉唑(lansoprazole,LSZ)购自汕头鮀滨制药厂。吲哚美辛购自 Sigma-Aldrich(上海)贸易有限公司;无水乙醇,购自天津致远化学试剂有限公司;羧甲基纤维素钠(CMC-Na)购自Sigma-Aldrich(美国)贸易有限公司。
1.2试剂及试药的配制
0.5%CMC-Na溶液配制:称取3.0g CMC-Na溶于600mL生理盐水中,混匀即得;100mg/kg、200mg/kg、400mg/kg卤蕨溶液配制:分别对应称取3.0g、 6.0g、12.0g卤蕨水提浸膏粉,溶于300mL CMC-Na溶液中,混匀即得;30mg/kg 兰索拉唑溶液配制:称取0.9g兰索拉唑,溶于300mL CMC-Na溶液中,混匀即得;造模药吲哚美辛(100mg/kg)溶液配制:称取1.2g吲哚美辛,溶于120 mL CMC-Na溶液中,混匀即得。
1.3实验仪器
SHIMADZU分析天平,广州湘仪机电设备有限公司;PL-203电子天平,梅特勒-托利多仪器(上海)有限公司;BX53荧光显微镜,日本Olympus公司; EOS M3微单相机,日本Canon公司。
1.4实验动物
SPF级Wistar大鼠,雄性,180-220g,购于广州中医药大学实验动物中心(合格证编号:SCXK(粤)2013-0034)。实验动物分笼饲养,适应性饲养7天,实验期间自由饮水和进食。饲养环境温度为22±2℃,相对湿度为60%,每天12 小时光照和12小时黑夜循环。
2.实验方法
2.1卤蕨水提浸膏粉的制备
水提法可以将植物体内的大部分有效成分提取出来,故采用水提法对卤蕨的活性成分进行提取。具体工艺如下:取干燥后的卤蕨地上部分6.28kg,剪成小段,加入10倍的水浸泡后,采用煎煮法提取2次,每次时间为2h,过滤即得提取液。合并提取液,加热蒸发去除大量水分后,再经冷冻真空干燥,即可获得水提浸膏粉。
2.2对无水乙醇诱导的大鼠急性胃溃疡模型的影响
实验开始前取SPF级雄性Wistar大鼠,称重,按体重随机分为正常组 (Normal),模型组(Model),兰索拉唑组(LSZ,30mg/kg),卤蕨水提物(WEAC) 低、中、高剂量组(对应剂量为100,200,400mg/kg),每组8只。分组后,标号,再称量各大鼠体重,记录并计算相应给药体积(1mL/100g)。除正常组和模型组给予0.5%CMC-Na溶液,其他组均给予相应的药物治疗,每天灌胃给药 1次,连续给药7天。于末次给药后1小时,每只大鼠灌胃无水乙醇(0.5mL/100g) 造成急性胃黏膜损伤,造模前大鼠需禁食24小时,自由饮水。
灌胃无水乙醇1小时后,各大鼠安乐处死,取出全胃,沿胃大弯剪开胃壁,洗净胃内容物,展开胃组织置于两块玻璃板之间固定以供拍照。用ImageJ图形分析软件(1.47v,National Institutes of Health,USA)测算溃疡面积,并计算抑制率。抑制率(%)=(模型组溃疡面积-给药组溃疡面积)/模型组溃疡面积×100%。于相同部位取0.5cm×0.5cm胃组织,固定于4%多聚甲醛溶液,常规制片,苏木精-伊红染色,显微镜(OLYMPUS BX53荧光显微镜)下观察并拍照,由三位病理医师采用盲法独立评分。
参照文献进行胃黏膜炎症及损伤程度的组织学病理评分并计算总分:
a.上皮细胞损伤程度:上皮细胞无损伤—0分;上皮细胞轻微损伤—1分;上皮细胞中度损伤—2分;上皮细胞严重损伤—3分;
b.出血性损伤程度:无出血性损伤—0分;轻微出血性损伤—1分;中度出血性损伤—2分;高度出血性损伤—3分,严重出血性损伤—4分;
c.炎症细胞产生情况:无炎症细胞产生—0分;少量炎症细胞产生—1分;中等水平的炎症细胞产生—2分;
总分为0分(正常)—9分(严重胃溃疡)不等。
2.3对吲哚美辛诱导的大鼠急性胃溃疡模型的影响
实验开始前取SPF级雄性Wistar大鼠,称重,按体重随机分为正常组 (Normal),模型组(Model),兰索拉唑组(LSZ,30mg/kg),卤蕨水提物(WEAC) 低、中、高剂量组(对应剂量为100,200,400mg/kg),每组8只。分组后,标号,再称量各大鼠体重,记录并计算相应给药体积(1mL/100g)。除正常组和模型组给予0.5%CMC-Na溶液,其他组均给予相应的药物治疗,每天灌胃给药 1次,连续给药7天。于末次给药后30分钟,每只大鼠灌胃吲哚美辛(1mL/100g) 造成急性胃黏膜损伤,造模前大鼠需禁食24小时,自由饮水。灌胃吲哚美辛5 小时后,各大鼠安乐处死,取出全胃,沿胃大弯剪开胃壁,洗净胃内容物,展开胃组织置于两块玻璃板之间固定以供拍照。用ImageJ图形分析软件(1.47v, National Institutes ofHealth,USA)测算溃疡面积,并计算抑制率。抑制率(%) =(模型组溃疡面积-给药组溃疡面积)/模型组溃疡面积×100%。于相同部位取 0.5cm×0.5cm胃组织,固定于4%多聚甲醛溶液,常规制片,苏木精-伊红染色,显微镜(OLYMPUS BX53荧光显微镜)下观察并拍照,由三位病理医师采用盲法独立评分。
参照文献进行胃黏膜炎症及损伤程度的组织学病理评分并计算总分:
d.上皮细胞损伤程度:上皮细胞无损伤—0分;上皮细胞轻微损伤—1分;上皮细胞中度损伤—2分;上皮细胞严重损伤—3-4分;
e.出血性损伤程度:无出血性损伤—0分;轻微出血性损伤—1分;中度出血性损伤—2分;高度出血性损伤—3分,严重出血性损伤—4分;
总分为0分(正常)—8分(严重胃溃疡)不等。
2.4统计学处理
各数据以均数±标准差(mean±SD)表示,应用Graphpad 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),方差齐时,组间两两多重比较采用LSD法;方差不齐时,组间两两多重比较采用Dunnett’s T3法,以P<0.05为标准,表示有显著性差异。正常组与模型组的比较,采用独立样本T检验(Student's t test)。与正常组相比,##:P<0.01;与模型组相比,*:P<0.05,**:P<0.01。
3.实验结果
3.1卤蕨水提浸膏粉的制备
取干燥卤蕨地上部分6.28kg,剪段,加入10倍量水浸泡后,采用煎煮法提取2次,每次2h,过滤即得提取液。合并提取液,加热蒸发去除大量水分后,再经冷冻真空干燥,可获得水提浸膏粉210g,收率为3.34%,样品贮存于4℃冰箱备用。
3.2卤蕨水提物对无水乙醇诱导的大鼠急性胃溃疡模型的影响
实验结果(图1与图2)表明,在正常组中几乎没有观察到肉眼可见的损伤。与正常组相比,灌胃无水乙醇可显着增加溃疡面积,平均为212.69±23.46mm2,表明乙醇诱导的胃溃疡模型成功建立。在兰索拉唑的作用下,溃疡面积显著减少,平均为30.96±3.94mm2(抑制率为83.09%)。用不同剂量的卤蕨水提物(100, 200和400mg/kg)给药后,溃疡面积显着降低,呈现剂量依赖性关系。此外,剂量为400mg/kg的卤蕨组溃疡面积最小(26.57±3.45mm2),抑制率最高 (87.74%)。
组织学观察(图3)显示,大鼠正常胃黏膜结构完整,黏膜内腺体排列紧密规则,上皮未见脱落,腺体未见损伤,固有层未见出血及炎细胞浸润;模型组胃粘膜损伤较深且面积较大,出现炎性浸润,大量上皮细胞变性,脱落、糜烂,腺体结构紊乱,有的缺失,固有层见高度出血(总评分为8.25±0.96);兰索拉唑组胃黏膜完整,上皮未见脱落,腺体轻微损伤,固有层未见出血及炎细胞浸润(总评分为1.63±0.48);卤蕨给药组对上述病理损伤具有改善作用,其中卤蕨高剂量组(400mg/kg)作用较明显,胃黏膜保持完整,上皮未见脱落,腺体未见损伤,固有层少见出血及炎细胞浸润(总评分为1.5±0.41),其他剂量均有不同程度的保护作用。
3.3卤蕨水提物对吲哚美辛诱导的大鼠急性胃溃疡模型的影响
实验结果(图4与图5)表明,在正常组中几乎没有观察到肉眼可见的损伤。与正常组相比,灌胃吲哚美辛可显着增加溃疡面积,表明吲哚美辛诱导的胃溃疡模型成功建立。在兰索拉唑的作用下,溃疡面积显著减少,平均为5.83±1.56 mm2(抑制率为89.86%)。用不同剂量的卤蕨水提物(100,200和400mg/kg) 给药后,溃疡面积显着降低,呈现剂量依赖性关系。此外,剂量为400mg/kg的卤蕨组溃疡面积为5.82±1.55mm2,抑制率为89.81%。剂量为200和100mg/kg 的卤蕨组中,溃疡面积分别为21.85±2.23(抑制为61.78%)和37.31±4.21mm2 (抑制率为34.97%)。
组织学观察(图6)显示,大鼠正常胃黏膜结构完整,黏膜内腺体排列紧密规则,上皮未见脱落,腺体未见损伤,固有层未见出血;模型组胃粘膜损伤较深且面积较大,大量上皮细胞变性,脱落、糜烂,腺体结构紊乱,有的缺失,固有层见中度出血(总评分为7.63±0.48);兰索拉唑组胃黏膜完整,上皮少量脱落,腺体未见损伤,固有层未见出血及炎细胞浸润(总评分分为1.38±0.48);卤蕨给药组对上述病理损伤具有改善作用,其中卤蕨高剂量组(400mg/kg)作用较明显,胃黏膜保持完整,上皮少量脱落,腺体未见损伤,固有层未见出血 (总评分为1.38±0.25),其他剂量均有不同程度的保护作用,中剂量组和低剂量组的总评分分别为4.00±0.41和5.55±0.71。
二、药物的制备例
下述制备例1-13中所用卤蕨水提浸膏粉均采用下述方法制得:
取干燥后的卤蕨地上部分剪成小段,加入10倍量水浸泡后,采用煎煮法提取2次,每次2h,过滤,合并滤液,加热浓缩,冷冻真空干燥,即得卤蕨水提浸膏粉。
例1(口服液)
称取100g卤蕨水提浸膏粉,加入增溶剂吐温80,和一定比例的乙醇,充分搅匀;然后加入甜菊甙、山梨酸钾等适宜附加剂(如矫味剂、抑菌剂、抗氧化剂、着色剂),溶解均匀,滤过澄清,将内容物装入口服液玻璃瓶中,灭菌。规格为每瓶含卤蕨400mg的口服液,每瓶净含量10mL。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例2(口服液)
称取100g卤蕨水提浸膏粉,加入增溶剂吐温80,和一定比例的乙醇,充分搅匀;然后加入甜菊甙、苯甲酸等适宜附加剂(如矫味剂、抑菌剂、抗氧化剂、着色剂),溶解均匀,滤过澄清,将内容物装入口服液玻璃瓶中,灭菌。规格为每瓶含卤蕨400mg的口服液,每瓶净含量10mL。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例3(口服液)
称取100g卤蕨水提浸膏粉,加入增溶剂吐温80,和一定比例的乙醇,充分搅匀;然后加入木糖醇、山梨酸钾等适宜附加剂(如矫味剂、抑菌剂、抗氧化剂、着色剂),溶解均匀,滤过澄清,将内容物装入口服液玻璃瓶中,灭菌。规格为每瓶含卤蕨400mg的口服液,每瓶净含量10mL。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例4(胶囊剂)
取卤蕨水提浸膏粉1000g,加入乳糖754g、淀粉964g混合均匀,用7%的淀粉浆270g作为粘合剂,湿法制粒,烘干,加入硬脂酸镁12g混匀,填充至1 号胶囊制成10000粒,每粒胶囊内含卤蕨100mg,每粒净重0.3g。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例5(胶囊剂)
取卤蕨水提浸膏粉800g,加入乳糖980g、淀粉1254g混合均匀,用7%的淀粉浆350g作为粘合剂,湿法制粒,烘干,加入硬脂酸镁16g混匀,填充至1 号胶囊制成10000粒,每粒胶囊内含卤蕨80mg,每粒片净重0.3g。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例6(滴丸)
取卤蕨水提浸膏粉300g,加入适量泊洛沙姆作为基质,适量液体石蜡为冷却剂;滴制法制成含有每丸含卤蕨6mg的滴丸,每丸净重30mg。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例7(滴丸)
取卤蕨水提浸膏粉300g,加入适量聚氧乙烯单硬脂酸酯作为基质,适量液体石蜡为冷却剂;滴制法制成含有每丸含卤蕨6mg的滴丸,每丸净重30mg。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例8(滴丸)
取卤蕨水提浸膏粉300g,加入适量PEG4000作为基质,适量二甲基硅油为冷却剂;滴制法制成含有每丸含卤蕨6mg的滴丸,每丸净重30mg。口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例9(颗粒剂)
称取1000g卤蕨水提浸膏粉加入到适量β-环糊精中制成包合物,加入适量淀粉、微晶纤维素、淀粉浆,混合均匀,逐渐加入乙醇和水,制成颗粒,进行分装。规格为每包含卤蕨400mg的颗粒剂,每包净重7g。开水冲服,口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例10(颗粒剂)
称取1000g卤蕨水提浸膏粉加入到适量β-环糊精中制成包合物,加入适量蔗糖粉、交联羧甲基纤维素钠、淀粉浆,混合均匀,逐渐加入乙醇和水,制成颗粒,进行分装。规格为每包含卤蕨400mg的颗粒剂,每包净重7g。开水冲服,口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例11(颗粒剂)
称取1000g卤蕨水提浸膏粉加入到适量β-环糊精中制成包合物,加入适量糊精、交联羧甲基纤维素钠、淀粉浆,混合均匀,逐渐加入乙醇和水,制成颗粒,进行分装。规格为每包含卤蕨400mg的颗粒剂,每包净重7g。开水冲服,口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
例13(颗粒剂)
称取1000g卤蕨水提浸膏粉加入到适量β-环糊精中制成包合物,加入适量乳糖、交联羧甲基纤维素钠、淀粉浆,混合均匀,逐渐加入乙醇和水,制成颗粒,进行分装。规格为每包含卤蕨400mg的颗粒剂,每包净重7g。开水冲服,口服,用于治疗急性胃溃疡。症见:中上腹不适、疼痛,剧烈的腹部绞痛,厌食、恶心、呕吐,腹泻等。
Claims (3)
1.卤蕨水提物在制备治疗急性胃溃疡药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述的卤蕨水提物由以下方法制得:取干燥后的卤蕨地上部分剪成小段,加入10倍量水浸泡后,采用煎煮法提取2次,每次2h,过滤,合并滤液,加热浓缩,冷冻真空干燥成浸膏粉,即得所述的卤蕨水提物。
3.根据权利要求1或2所述的应用,其特征在于,所述的药物为口服液、胶囊、滴丸或颗粒剂。
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