CN112843104B - 亮叶杜英提取物在制备治疗胃相关疾病药物中的应用 - Google Patents
亮叶杜英提取物在制备治疗胃相关疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了提供亮叶杜英提取物在制备H+‑K+‑ATP酶抑制剂中的应用，以及其在制备预防或治疗胃相关疾病药物中的应用。以及亮叶杜英提取物制备方法。所述的胃相关疾病包括胃粘膜出血、胃溃疡、反流性食管炎。所述的胃粘膜出血包括消炎痛引起的胃粘膜出血、冷应激引起的胃粘膜出血。
Description
技术领域
本发明属于医药技术领域，具体涉及亮叶杜英提取的新用途，即亮叶杜英的提取物在制备预防或治疗胃相关疾病药物中的应用，在制备H+-K+-ATP酶抑制剂中的应用。
背景技术
亮叶杜英(Elaeocarpus nitentifolius)是杜英科杜英属植物，该属约200种分布于东亚，东南亚及西南太平洋和大洋洲。我国产38种，6变种，主要分布于华南及西南地区，是阔叶常绿林的常见的中层乔木。亮叶杜英主要产于广东、广西、越南等地，为暖地、中性偏阴树种，主要用作优美的庭园观赏树种。未见药用记载。
我们在大量筛选工作中发现亮叶杜英的提取物具有很高的胃H+-K+-ATP酶的抑制作用的活性，提取物对消炎痛和冷应激引起的胃粘膜出血有明显的保护作用，至今未见亮叶杜英有治疗胃病研究的报道。
发明内容
本发明解决的技术问题是提供亮叶杜英提取物在制备预防或治疗胃相关疾病药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了亮叶杜英的取物在制备H+-K+-ATP酶抑制剂中的应用。
本发明第一方面还提供了亮叶杜英的取物在制备预防或治疗胃相关疾病药物中的应用。
进一步的，所述的胃相关疾病包括胃粘膜出血、胃溃疡。
进一步的，所述的胃粘膜出血包括消炎痛引起的胃粘膜出血、冷应激引起的胃粘膜出血。
进一步的，所述的亮叶杜英提取物的制备方法，其特征在于：亮叶杜英的提取溶剂使用水、醇类、或水与醇类的混合物，加热回流提取3次。优选的醇类包括甲醇、乙醇、异丙醇、丁醇等。上步结束后，合并滤液，滤去药渣。将滤液合并进一步减压浓缩成膏状。
进一步的，所述的亮叶杜英提取物的制备方法，其特征在于：原药材用水在静态或动态下，室温或加热(或回流)提取，提取溶剂量为原药重量的4-14倍，提取可连续或间歇进行，间歇提取时可重复1-4次，然后滤去药渣，滤液在常压或减压、在动态状态下加热浓缩至药材重量1-5倍的体积后冷却，滤除去不溶物,将滤液合并进一步浓缩成膏状。或者，原药材用醇类(甲醇、乙醇、异丙醇、丁醇等)或含水的醇(40-80％)在静态或动态下，室温或加热(或回流)提取，提取溶剂量为原药重量的4-14倍，提取可连续或间歇进行，间歇提取时可重复1-4次，然后滤去药渣，滤液在常压或减压、在动态状态下加热浓缩至药材重量1-5倍的体积下冷却，然后离心除去不溶物,并加少量水洗不溶物1-3次，将滤液合并进一步浓缩成膏状。
浸膏可经冷冻干燥或真空干燥成干粉，也可把浓缩液体直接喷雾干燥成干粉进行制剂成型。
本发明技术方案的第二方面是提供了一种药物组合物在制备H+-K+-ATP酶抑制剂中的应用，其特征在于，所述的药物组合物包括本发明第一方面所述的亮叶杜英的提取物以及药学上可接受的载体或赋形剂。
本发明第二方面还提供了一种药物组合物在制备预防或治疗胃相关疾病药物中的应用，其特征在于，所述的药物组合物包括权利要求1-7任一项所述的亮叶杜英的提取物以及药学上可接受的载体或赋形剂。
有益技术效果：亮叶杜英的提取物在制备治疗胃溃疡药物中的应用为首次发现，在国内未见报道。
具体实施方式
原药材经中国医学科学院药物研究所标本室鉴定为亮叶杜英。
实施例1亮叶杜英提取物的制备(水提浸膏)
亮叶杜英枝叶1公斤，用蒸馏水热回流提取三次，每次一小时，提取液减压浓缩后得水提取物70g。
实施例2亮叶杜英提取物的制备(醇提浸膏实例)
亮叶杜英叶2.2公斤，加6倍量90％乙醇，浸泡过夜或4小时，缓慢加热至沸腾，回流1小时，过滤；全过程重复二次，合并滤液，减压浓缩，温度60—70℃，压力85-98KPa，浓缩至完全无乙醇时加入与药材相同重量的水继续加热至沸腾，冷却后离心除去不溶物,并加少量水洗不溶物三次，将滤液合并，在温度60-70C下减压浓缩,然后减压干燥(温度70—80℃，压力85—98Kpa)得提取物147g。
药理实验：
药理实验所用样品均为实施例2亮叶杜英提取物的制备(醇提浸膏实例)所得样品。
实验例1.亮叶杜英提取物对H+-K+-ATP酶活性影响
方法：取96孔板，空白和对照加溶酶、亮叶杜英的提取物1.0mg/ml和0.25mg/ml、雷贝拉唑钠10-3mol/L和10-4mol/L，体积均为20ul。加用反应液稀释20倍的猪H+-K+-ATP酶160ul，在37℃温孵20分钟，加20mg/ml ATP 20ul，空白不加ATP。37℃反应30分钟。加10％TCA 50ul终止反应。空白加20mg/ml ATP20ul。取50μl置于96孔酶标板内，加定磷液200ul进行显色反应，在660nm比色。计算抑制率，抑制率＝(对照－样品)/(对照－空白)×100％。
结果：亮叶杜英的提取物对猪胃H+-K+-ATP酶活性具有较强的抑制作用，100ug/ml和20ug/ml抑制率分别为58％和26％。雷贝拉唑钠10-4mol/L和10-5mol/L抑制率分别为72％和57％。
实验例2.亮叶杜英提取物对大鼠消炎痛型胃溃疡模型的影响
方法:取雄性wistar大鼠，禁食48小时。随机分为对照组，雷贝拉唑钠组和亮叶杜英的提取物组，每组5只。灌胃给药10ml/kg。对照组给溶媒，雷贝拉唑钠灌给10mg/kg，亮叶杜英的提取物给500mg/kg。0.5小时后腹腔注射消炎痛35mg/kg,6.0小时后脱颈椎处死大鼠,取出胃注入10ml水，置3％的甲醛溶液中固定，计粘膜部出血点数。用t-程序进行显著性测验。
结果:预先灌胃给与亮叶杜英的提取物后，可明显减少由消炎痛引起的胃粘膜出血点，亮叶杜英的提取物对消炎痛引起的胃粘膜出血有明显的保护作用。与对照比均有显著性差异，抑制率为76％。雷贝拉唑钠在所用剂量下抑制率为18％。
实验例3.亮叶杜英提取物对大鼠水应拘束溃疡模型的影响
方法：取雄性wistar大鼠，禁食48小时。随机分为对照组，雷贝拉唑钠组和亮叶杜英的提取物组，每组5只。灌胃给药10ml/kg。对照组灌胃给与溶媒，雷贝拉唑钠灌胃给与20mg/kg，灌胃给与亮叶杜英的提取物500mg/kg。0.5小时后将大鼠置于特制应激笼内，并放在16℃水浴中，水面达大鼠剑突处。6小时后处死动物。取出胃注入10ml水，置3％的甲醛溶液中固定后，剪开胃，计粘膜部溃疡数。
结果：预先灌胃给与亮叶杜英的提取物后，可明显减少由冷应激引起的胃粘膜出血点，亮叶杜英的提取物对冷应激引起的胃粘膜出血有较好的保护作用。抑制率为50％。雷贝拉唑钠在所用剂量下抑制率为97％。
制剂的制备
用实施例1和2制备的浸膏或浸膏粉，加入相关的辅料，制成冲剂、散剂、胶囊剂、片剂、口服液等剂型。
1、冲剂
包括可溶性颗粒剂及块状剂，用方法一、方法二得到的干粉和适量赋型剂(可选用糊精、淀粉、微晶纤维素、纤维素、海藻酸、海藻酸钠、羧甲基淀粉、低取代羟丙基纤维素等)混合均匀后，压干成颗粒，经整粒分装于防湿包装材料中(如：厚塑料、铝箔等)。也可用浸膏加上述赋型剂后湿法制粒，干燥后压成块剂。
2、胶囊剂
用方法一、方法二得到的干粉或浸膏加入适量辅料(可选用碳酸钙、甘露醇、碳酸镁、氧化镁、微粉硅胶等)，适量润滑剂(可选用滑石粉、硬脂酸镁、乙二醇酯、聚硅酮类等)，适量粘合剂、(可选用矿物油、食油等)，混合成干粉或制成颗粒，填充入胶囊。也可用适量赋型剂(聚乙二醇、油类等)制成软材用泵压法进囊，分装入密封铝塑包装中。
3、片剂
包括普通片、薄膜衣片等。用方法一、方法二得到的干粉或浸膏加入适量稀释剂(可选用糊精、淀粉、微晶纤维素、甘露醇等)，适量黏合剂(可选用水、乙醇、淀粉浆、纤维素类等)，适量崩解剂(可选用淀粉、海藻酸、海藻酸钠、羧甲基淀粉、低取代羟丙基纤维素等)，适量润滑剂(可选用滑石粉、硬脂酸镁、聚乙二醇等)，按常规湿法制粒，干燥后整粒或干法制粒整粒后压片。如是包薄膜衣片，可用成膜材料(选用纤维素类、聚乙醇类等)按常规包衣，分装入密闭瓶或铝塑板中。
4、口服液
按常规可溶性口服液工艺配制，用方法一、方法二得到的干粉或浸膏可溶于水或乙醇中，加适量稳定剂(可选用乙二胺四醋酸二钠、焦亚硫酸钠、硫代硫酸钠、VC衍生物等)或适量防腐剂(可选用苯甲酸、对羟基苯甲酸酯类、山梨酸等)，分装于密闭瓶中。
5、散剂
以上各剂型可加入适量甜味剂，如D-木糖、木糖醇、麦芽糖醇、甜叶菊素、天冬甜母等。
Claims (5)
1.亮叶杜英提取物在制备H+-K+-ATP酶抑制剂中的应用，其特征在于，所述亮叶杜英提取物的制备方法为：亮叶杜英，加6倍量90％乙醇，浸泡过夜或4小时，缓慢加热至沸腾，回流1小时，过滤；全过程重复二次，合并滤液，在温度60—70℃、压力85-98KPa下减压浓缩，浓缩至完全无乙醇时加入与药材相同重量的水继续加热至沸腾，冷却后离心除去不溶物,并加少量水洗不溶物三次，将滤液合并，在温度60-70℃下减压浓缩,然后在温度70—80℃、压力85—98Kpa下减压干燥，得提取物。
2.亮叶杜英提取物在制备预防或治疗胃粘膜出血、胃溃疡或反流性食管炎疾病药物中的应用，其特征在于，所述亮叶杜英提取物的制备方法为：亮叶杜英，加6倍量90％乙醇，浸泡过夜或4小时，缓慢加热至沸腾，回流1小时，过滤；全过程重复二次，合并滤液，在温度60—70℃、压力85-98KPa下减压浓缩，浓缩至完全无乙醇时加入与药材相同重量的水继续加热至沸腾，冷却后离心除去不溶物,并加少量水洗不溶物三次，将滤液合并，在温度60-70℃下减压浓缩,然后在温度70—80℃、压力85—98Kpa下减压干燥，得提取物。
3.根据权利要求2的应用，其特征在于，所述的胃粘膜出血为消炎痛引起的胃粘膜出血、冷应激引起的胃粘膜出血。
4.一种药物组合物在制备H+-K+-ATP酶抑制剂中的应用，其特征在于，所述的药物组合物包括权利要求1-2任一项所述的亮叶杜英的提取物以及药学上可接受的载体或赋形剂。
5.一种药物组合物在制备预防或治疗胃粘膜出血、胃溃疡或反流性食管炎疾病药物中的应用，其特征在于，所述的药物组合物包括权利要求1-2任一项所述的亮叶杜英的提取物以及药学上可接受的载体或赋形剂。
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