CN104383292B - 铁皮石斛提取物在制备预防和/或治疗高尿酸血症药物中的应用 - Google Patents
铁皮石斛提取物在制备预防和/或治疗高尿酸血症药物中的应用 Download PDFInfo
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- CN104383292B CN104383292B CN201410607277.0A CN201410607277A CN104383292B CN 104383292 B CN104383292 B CN 104383292B CN 201410607277 A CN201410607277 A CN 201410607277A CN 104383292 B CN104383292 B CN 104383292B
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- dendrobium candidum
- extract
- hyperuricemia
- gout
- candidum extract
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Abstract
本发明涉及铁皮石斛提取物在制备预防和/或治疗高尿酸血症,由于高尿酸血症而导致的急性痛风、慢性痛风、痛风关节炎、痛风发作、尿酸性肾石病和痛风性肾病的药物或保健品中的应用。本发明以铁皮石斛提取物作为制备治疗高尿酸血症药物的活性成分,可降低血液中尿酸的浓度,在治疗高尿酸血症上具有显著的效果,且不具毒副作用。
Description
技术领域
本发明涉及铁皮石斛提取物的新用途。
背景技术
近年来,随着人们生活水平的提高,饮食结构发生变化,糖、脂肪、蛋白质的摄入量明显增加,高尿酸血症和痛风的发病率日益增高,己成为一种常见病。
一般认为血尿酸465μmol/L时为高尿酸血症,约5%-l2%高尿酸血症患者会发展成为痛风。临床特点是:痛风性急性关节炎反复发作、痛风石沉积、特征性慢性关节炎和关节畸形,常累及肾脏引起慢性间质性肾炎和肾尿酸结石形成。痛风的急性发作是尿酸钠(monosodium urate crystal,MSU)在关节及关节周围组织以结晶形式沉积引起的急性炎症反应。痛风不仅可以侵犯骨和关节,而且还容易累及肾脏和心血管***。高尿酸血症及原发性痛风与肥胖症、高脂血症、高血压病、糖尿病、动脉粥样硬化等疾病呈显著正相关。因此,高尿酸血症是危害人类健康的一种严重的代谢性疾病。
目前,对血中尿酸的控制是通过两种途径实现的:一是抑制尿酸的生成。黄嘌呤氧化酶是次黄嘌呤转化为黄嘌呤和黄嘌呤转化为尿酸所必需的酶,治疗痛风的一条有效途径是抑制黄嘌呤氧化酶(xanthine oxidase,XO)活性,从而抑制尿酸的形成。抑制尿酸生成的药物如别嘌呤醇,非布索坦。二是促进尿酸的***,促进尿酸***的药物如丙磺舒、苯溴马龙等。但上述药物毒副作用大,例如别嘌呤醇可引发***反应(发生率10-15%)、超敏综合症(27.5%斑丘疹患者死亡)、骨髓抑制等严重毒副作用;丙磺舒、苯溴马隆具有胃肠道反应、肾绞痛及激发痛风急性发作等副作用,在一定程度上限制了这些药物的临床应用。因此,寻找新型的高效低毒的抗痛风和高尿酸血症药物依然是目前药学研究的一个热点。
铁皮石斛为兰科(Orchidaceae)石斛属(Dendrobium)植物。铁皮石斛(Dendrobiumofficinale Kimura et Migo)的干燥茎,又名黑节草。2010年版《中华人民共和国药典》(一部)将其单列,味甘,微寒,归胃、肾经。具有益胃生津,滋阴清热的作用,用于阴伤津亏,口干烦渴,胃阴不足,食少干呕,病后虚热不退,阴虚火旺,骨蒸劳热,目暗不明,筋骨痿软,早在东汉时期《神农本草经》就将其列为上品,具有伤中、除痹、下气、补五脏虚劳羸弱、强阴、久服厚肠胃及轻身延年等功效。现代研究证明,铁皮石斛主要含有多糖、芪类、酚类、木质素等化合物,具有抗衰老,抗肿瘤,降低血糖和提高免疫等作用。根据我们的文献调研,尚未发现铁皮石斛或者铁皮石斛提取物在治疗高尿酸血症或痛风方面的应用和研究。
发明内容
我们在研究中意外发现,铁皮石斛提取物对黄嘌呤氧化酶具有抑制作用,可以降低尿酸,为此,本发明克服现有技术中对于高尿酸血症的治疗都需要采用具有毒副作用的药物的不足,提供一种新的可用于治疗高尿酸血症的天然植物即铁皮石斛提取物在制备治疗高尿酸血症,由于高尿酸血症而导致的急性痛风、慢性痛风、痛风关节炎、痛风发作、尿酸性肾石病和痛风性肾病的药物或保健品中的应用。
一般地,铁皮石斛提取物中总多酚的质量含量为2.7%-70%。本发明中,铁皮石斛提取物中总多酚的质量含量优选在15%以上。更优选地,铁皮石斛提取物中总多酚的质量含量在20%以上。进一步优选地,铁皮石斛提取物中总多酚的质量含量在30%以上,更优选在50%以上。最优选地,铁皮石斛提取物中总多酚的质量含量在60%以上。
根据本发明,铁皮石斛提取物可以为铁皮石斛粗提物或进一步分离纯化铁皮石斛粗提物所得铁皮石斛总多酚富集的提取物。优选地,铁皮石斛提取物为铁皮石斛总多酚富集的提取物,且总多酚的质量含量在50%以上。
本发明同时提供一种植物来源,具有较高安全性,无毒副作用的药物组合物,具体如下:一种预防和/或治疗高尿酸血症,由于高尿酸血症而导致的急性痛风、慢性痛风、痛风关节炎、痛风发作、尿酸性肾石病和痛风性肾病的药物组合物,其包括有活性成分,该活性成分至少包括铁皮石斛提取物,铁皮石斛提取物中总多酚的质量含量在15%以上。
所述铁皮石斛提取物中总多酚的质量含量在30%以上。
所述铁皮石斛提取物中总多酚的质量含量在50%以上。
根据本发明,铁皮石斛提取物中总多酚的含量越高越好。
所述药物组合物中的活性成分可以是仅为铁皮石斛提取物,也可以是铁皮石斛提取物与其他已知活性成分的组合。
根据本发明,铁皮石斛提取物是已知的。铁皮石斛提取物可以是粗提物(初提物)或进一步分离纯化所得总多酚富集的提取物。铁皮石斛提取物可以根据常规手段制备,也可以商购获得。
进一步地,本发明提供了一种铁皮石斛提取物的制备方法,其将铁皮石斛浸于溶剂中提取活性成分即可。
进一步的,将铁皮石斛浸于溶剂中回流提取,过滤,得到铁皮石斛提取液,浓缩所述铁皮石斛提取液,得到铁皮石斛粗提物。
更进一步的,将铁皮石斛浸于溶剂中,浸泡至少3-5h,再在20-80℃下回流提取1h以上,过滤,得到铁皮石斛提取液,浓缩所述铁皮石斛提取液至干,得到铁皮石斛粗提物。
优选的,所述溶剂为乙醇。
进一步地,铁皮石斛提取物的制备方法还包括将铁皮石斛粗取物加水溶解、精制提纯的步骤。优选的,所述精制提纯包括大孔吸附树脂层析、萃取提纯中的一种。
所述大孔吸附树脂层析包括以下步骤:将铁皮石斛粗提物用水溶解,用大孔吸附树脂进行层析,先用10v%-30v%的乙醇溶液洗脱,再用40v%-60v%的乙醇溶液洗脱,得到各个洗脱部位,将各个部位浓缩至干即得铁皮石斛提取物。
本发明的药物组合物还含有常规辅料以将组合物制成临床上应用的各种剂型例如胶囊剂、片剂、丸剂、颗粒剂、膏剂、合剂、混悬剂等。
本发明中所述的“常规辅料”是指药学上可接受的材料、组合物或媒介物,例如液体或固体填充剂、稀释剂、赋形剂(如可可脂和栓蜡)、溶剂或包装材料。药学上可接受的载体是与组合物的其他成分、与施用的模式相容的并且对患者无害。药学上可接受的载体可以是水性或非水性的。常规辅料包括胶质,例如明胶;淀粉,例如玉米淀粉、马铃薯淀粉;糖,例如乳糖、葡萄糖和蔗糖;纤维素材料及其混合物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素。可用作药学上可接受的载体的材料包括但不限于,西黄蓍胶粉、麦芽、滑石粉、油(如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油、大豆油等)、醇类(如丙二醇、乙醇、甘油、山梨糖醇、甘露醇、聚乙二醇等)、酯类(如油酸乙酯、月桂酸乙酯、琼脂)、缓冲剂(如氢氧化镁、氢氧化铝、硼酸和硼酸钠以及磷酸盐缓冲液)、褐藻酸、无热源的水、等渗盐水、林格氏液。
本领域技术人员可以使用本领域中已知的任何方式施用本发明的药物组合物,包括但不限于口服、经鼻、胃肠外、局部、经皮或直肠的施用途径。本发明的药物组合物优选适用于口服或局部施用的剂型,例如,片剂、胶囊(包括硬胶囊、软胶囊)、丸剂、溶液、粉末或粒料、悬浮液、贴片等。且本发明的药物可以采用本领域中公知的方法制为相应剂型。
由于以上技术方案的采用,本发明与现有技术相比具有如下优势:
本发明提出了一种预防和/或治疗高尿酸血症及由其引起的急性痛风等病症的新方法,与已有方法相比,本发明方法无毒副作用,安全性好。
具体实施方式
下面结合具体的实施例对本发明做进一步详细的说明,但本发明不限于以下实施例。以下实施例中,在没有特别说明时,“%”均指质量百分比。
实施例1:铁皮石斛粗提物的制备
取2000g铁皮石斛,用20升70%乙醇室温浸泡一天后,回流提取60分钟,滤出提取液之后,向滤渣中再加入16升70%乙醇,回流提取40分钟,过滤。合并两次提取液,真空浓缩至干,得到310g铁皮石斛粗提物,得率为15.5%。标示为DCE-1。
实施例2:铁皮石斛粗提物的制备
取2000g铁皮石斛,用20升50%乙醇室温浸泡一天后,回流提取60分钟,滤出提取液之后,向滤渣中再加入16升50%乙醇,回流提取40分钟,过滤。合并两次提取液,真空浓缩至干,得到500g铁皮石斛粗提物,得率为25%。标示为DCE-2。
实施例3:铁皮石斛总多酚的制备
取200g实施例1中制备的铁皮石斛粗提物DCE-1,加水溶解,用D101(西安蓝晓科技新材料股份有限公司)大孔吸附树脂进行层析。提取物的质量跟树脂质量的比为1:20。依次用水,30%乙醇,60%乙醇和95%乙醇进行洗脱,每个梯度洗脱4-5个柱体积,流速为2-3个柱体积/小时。洗脱结束后,30%乙醇部位,60%乙醇部位和95%乙醇部位分别浓缩至干,其中,30%乙醇部位共60g(标示为DC30),60%乙醇部位共93g(标示为DC60),95%乙醇部位共35g(标示为DC90)。
实施例4:铁皮石斛总多酚的制备
取200g实施例2中制备的铁皮石斛粗提物DCE-2用500ml水进行混悬,依次用石油醚,乙酸乙酯,正丁醇进行萃取。每种溶剂分别萃取3次,每次用500ml溶剂。萃取结束后,各个部位分别进行合并,真空浓缩至干,得到石油醚部位15g(标示为DCPE),乙酸乙酯部位58g(标示为DCEA),正丁醇部位48g(标示为DCBU),水部位72g(标示为DCW)。
实施例5:含有铁皮石斛粗提物或者铁皮石斛总多酚的药物组合物
以重量份计,药物组合物配方如下:
称取配方量的DCE-1、淀粉、和L-HPC混合,过60目筛三次,混合均匀;加入10%的淀粉浆适量制软材,制粒,干燥,整粒后,加入微粉硅胶、硬脂酸镁混合均匀,压片,包薄膜衣,即得。
实施例6:含有铁皮石斛提取物或者铁皮石斛多酚的药物组合物(胶囊)
以重量份计,药物组合物配方如下:
铁皮石斛总多酚部位DC-60 25份;
微晶纤维素 60份;
叔丁基-4-羟基苯甲醚(抗氧剂) 0.04份;
硬脂酸镁 2份;
乳糖加至 200份。
称取处方量的DC60和上述辅料混合,过60目筛三次,混合均匀;装入胶囊即得。
实施例7铁皮石斛提取物和部位总多酚的测定
铁皮石斛粗提物和部位总多酚的测定参考国标GBT 8313-2008茶叶中茶多酚含量的检测方法,用福林酚(Folin-Ciocalteu)试剂检测多酚含量
(1)10%福林酚试剂(现配):将20ml福林酚试剂转移到200ml容量瓶中,用水定容并摇匀。
(2)7.5%Na2CO3溶液(质量浓度):称取37.50g Na2CO3加适量水溶解,转移至500ml容量瓶中,定容至刻度,摇匀。
(3)没食子酸标准储备溶液(1000g/ml):称取0.100g没食子酸,于100ml容量瓶中溶解并定容至刻度,摇匀。
(4)没食子酸工作液:用移液管分别移取1.0,2.0,3.0,4.0,5.0ml的没食子酸标准储备液于100ml容量瓶中,分别用水定容至刻度,摇匀,浓度分别为10,20,30,40,50g/ml。
(5)没食子酸标准曲线:用移液管分别移取没食子酸工作液1.0ml于刻度管内,在每个试管内分别加入5.0ml福林酚试剂,摇匀。反应3-8分钟内,加入4.0ml Na2CO3溶液,加水定容至刻度,摇匀。室温下放置60min,用10mm比色皿,在765nm波长条件下用分光光度计测定吸光度,根据没食子酸工作液浓度和相对应吸光度,制作标准曲线。
(6)取铁皮石斛提取物和各个部位,配成0.2mg/ml溶液。取样品溶液1mL,按照上述的制作方法,测定其吸光度,每个样品做三个平行试验,取平均值,计算样品中的多酚含量。结果见表1。
表1铁皮石斛粗提物和各个部位总多酚含量
根据结果,铁皮石斛提取物经过两种不同富集工艺之后,总多酚含量均有非常大的提高,其中萃取工艺中乙酸乙酯部位,树脂工艺中60%乙醇洗脱部位总多酚含量最高。
实施例8铁皮石斛粗提物和部位总多酚对高尿酸血症小鼠的影响
本发明通过动物实验验证铁皮石斛提取物和部位对高尿酸血症小鼠的影响
健康雄性KM小鼠120只,体重为15-18g,由上海灵畅生物科技有限公司提供;
按每笼5只进行分笼处理后,在苏州凯祥生物科技有限公司的屏障***内适应性饲养4天,从120只小鼠中选取体重集中的110只小鼠按体重随机平均分为11组,每组10只,分别为空白对照组,高尿酸血症模型组,阳性对照组,受试样品组共8组,代号分别为DCE-1,DCE-2,DCEA,DCBU,DCW,DC30,DC60,DC95。
高尿酸血症的造模
适应期过后随即对小鼠进行灌胃给药,每天上午灌胃1次,其中受试样品组,样品用纯水进行混悬,按照30mg/kg进行灌胃;阳性对照非布索坦用纯水进行混悬,按照1mg/kg进行灌胃;空白对照组和高尿酸血症模型组均用纯水灌胃进行对照,连续灌胃7天;
在第7天上午灌胃0.5小时后对小鼠进行腹腔注射造模,其中空白对照组腹腔注射0.5%羧甲基纤维素钠(CMC-Na)溶液;高尿酸血症模型组、阳性对照组和受试样品组注射氧嗪酸钾(OA),用CMC-Na溶液进行溶解,注射量均为300mg/kg体重;
腹腔注射1.5小时后摘除小鼠的眼球进行采血,采血容量不低于0.5mL,血样采集后于室温放置约1小时,待血液完全凝固后于3500rpm/4℃条件下离心10分钟,取血清在同等条件下复离5分钟,而后取0.2mL血清使用生化分析仪检测UA值;
用Excel和SPSS对数据进行统计分析,计算平均数和SD,经单因素方差分析后比较各实验组的组间差异,与空白对照组相比,高尿酸血症模型组、阳性对照组和受试化合物组小鼠的血清尿酸水平显著提高,有显著性差异,表明造模成功。
实验结果
本次实验中模型组血尿酸与控制组相比显著升高(P<0.01),阳性对照非布索坦1mg/kg组亦显示出了预期的降尿酸作用,表明此次造模成功,实验结果真实可信。
表2:铁皮石斛提取物对高尿酸血症模型小鼠血清尿酸含量的影响
组别 | 剂量(mg/kg) | 尿酸(μmol/L) |
正常组 | 0.5%CMC-Na | 106.9 |
模型组 | 0.5%CMC-Na | 179.1 |
阳性对照组 | 1 | 75.6** |
DCE-1 | 30 | 132.9* |
DCE-2 | 30 | 129.6* |
DCEA | 30 | 80.4** |
DCBU | 30 | 88.7** |
DCW | 30 | 171.5 |
DC30 | 30 | 133.7* |
DC60 | 30 | 79.9** |
DC95 | 30 | 165.5 |
*:与模型组比,P<0.05;**:表示与模型组比,P<0.01(t-test检验)
从表2可以看出,给予受试样品后,与模型组相比铁皮石斛粗提物具有一定的降低尿酸效果。比较两种不同提取物的效果,不同溶剂提取物没有显著性差异。经过两种不同的总多酚富集工艺之后,DCEA和DC60两个部位具有显著降低尿酸的效果,跟其它部位相比,效果更加明显。
实验例9:受试样品体外对黄嘌呤氧化酶的影响
溶液配制
磷酸盐缓冲溶液:称取19.48g的K2HPO4·3H2O和1.99g的KH2PO4溶于500mL蒸馏水中,配成浓度为0.2mmol/L的磷酸盐缓冲溶液(pH=7.5);
黄嘌呤底物溶液:称取黄嘌呤15.2mg,溶解于250mL蒸馏水中,配成浓度为0.4mmol/L的黄嘌呤底物溶液;
黄嘌呤氧化酶溶液:取黄嘌呤氧化酶5U,用上述磷酸盐缓冲溶液稀释至160mL,配成浓度为80U/L的黄嘌呤氧化酶溶液,4℃保存;
样品和阳性对照溶液:精密称取样品、别嘌呤醇(作为阳性对照),分别用二甲亚砜溶解、蒸馏水稀释,配成浓度为0.05mg/mL的溶液进行测试(其中二甲亚砜的最终浓度小于1%)。
抑制作用测试
样品组测试:在2mL离心管中依次加入黄嘌呤底物溶液200μL、样品溶液100μL和黄嘌呤氧化酶溶液200μL,涡旋震荡5秒后置于25℃水浴锅中反应5分钟,反应完毕后加入1.5mL无水乙醇,涡旋震荡5秒终止反应。反应液经3500rpm离心5分钟,吸取200μL到1.5mL离心管中,用生化分析仪分别检测每个样品的UA值,每个样品平行操作三次取平均值。
空白对照组测试:在2mL离心管中依次加入黄嘌呤底物溶液200μL、磷酸盐缓冲溶液100μL和黄嘌呤氧化酶溶液200μL,同法检测空白对照组的UA值,平行操作三次取平均值。
阳性对照组测试:在2mL离心管中依次加入黄嘌呤底物溶液200μL、阳性对照溶液100μL和黄嘌呤氧化酶溶液200μL,同法检测阳性对照组的UA值,平行操作三次取平均值。
测试结果
根据黄嘌呤氧化酶抑制率=[(空白对照组UA值-样品组UA值)/空白对照组UA值]*100,计算抑制率,结果参见表3。
表3:铁皮石斛粗提物和各个部位抑制黄嘌呤氧化酶的活性
组别 | 浓度 | UA(μmol/L) | 抑制率% |
空白对照 | ‐ | 134.9 | - |
别嘌醇 | 0.01mg/mL | 70.49 | 47.7% |
DCE‐1 | 0.05mg/ml | 62.45 | 53.7% |
DCE‐2 | 0.05mg/ml | 77.66 | 42.4% |
DCEA | 0.05mg/ml | 33.86 | 74.9% |
DCBU | 0.05mg/ml | 46.50 | 65.5% |
DCW | 0.05mg/ml | 89.66 | 33.5% |
DC30 | 0.05mg/ml | 69.33 | 48.6% |
DC60 | 0.05mg/ml | 20.57 | 84.7% |
DC95 | 0.05mg/ml | 97.65 | 27.6% |
从表3可以看出,铁皮石斛粗提物和各个部位对黄嘌呤氧化酶都有不同程度的抑制作用。其中总多酚含量最高的部位抑制作用更强,这一结果跟动物实验比较吻合,说明总多酚可能是其真正活性部位。
以上对本发明做了详尽的描述,其目的在于让熟悉此领域技术的人士能够了解本发明的内容并加以实施,并不能以此限制本发明的保护范围,凡根据本发明的精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围内。
Claims (2)
1.铁皮石斛提取物在制备预防和/或治疗高尿酸血症,或由于高尿酸血症而导致的急性痛风、慢性痛风、痛风关节炎、痛风发作、尿酸性肾石病或痛风性肾病的药物或保健品中的应用;所述的铁皮石斛提取物中总多酚的质量含量在50%以上。
2.如权利要求1所述的应用,其特征在于:所述的铁皮石斛提取物为进一步分离纯化铁皮石斛粗提物所得铁皮石斛总多酚富集的提取物。
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