CN105147649B - 桑橙素的医药用途 - Google Patents
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Abstract
本发明涉及医药保健品学领域，特别是涉及一种桑橙素的医药用途及其产品。本发明的桑橙素可用于制备防治高尿酸血症或痛风的药物。
Description
技术领域
本发明涉及医药食品保健品领域，特别是涉及一种藤黄酮类化合物的用途及其相关产品。
背景技术
痛风(gout)是由于体内嘌呤代谢紊乱或尿酸排泄减少、导致尿酸在体内关节等处沉积而引起的一组临床综合征，持续的血中高尿酸值是引发痛风的必要但不充分条件。据统计，5％-12％的高尿酸血症患者会发展为痛风，但高尿酸血症亦可在较长时间内单独存在而不发展为痛风。
黄嘌呤氧化酶(Xanthine Oxidase，XOD)是体内嘌呤代谢过程中一种重要的酶，能催化黄嘌呤和次黄嘌呤氧化生成尿酸，同时产生过氧化物自由基。如前所述，尿酸浓度过高将导致高尿酸血症，进而可引发痛风，而自由基则涉及到炎症等一系列病理过程。因此，抑制XOD的活性，既可以减少体内尿酸的形成、有效阻止或延缓痛风及其并发症，又可以减少自由基造成的组织伤害。
目前，黄嘌呤氧化酶抑制剂(XOI)别嘌呤醇自上市后沿用至今，是治疗痛风的主要药物。但其常伴有发热、过敏性皮疹、腹痛、腹泻、白细胞及血小板减少以及肝功能损害等严重副反应。因此,研制开发新的黄嘌呤氧化酶抑制剂具有实际意义。
发明内容
本发明的目的旨在提供一种桑橙素的新用途及其相关产品。
具体地说，本发明的第一方面是提供了桑橙素在制备黄嘌呤氧化酶抑制剂中的应用。
在一优选例中，所述的桑橙素是作为唯一的活性成分应用于黄嘌呤氧化酶抑制剂的制备中。
本发明的第二方面是提供了桑橙素在制备预防或治疗高尿酸血症的药物中的应用。
在一优选例中，所述的桑橙素是作为唯一的活性成分应用于预防或治疗高尿酸血症的药物的制备中。
本发明的第三方面是提供了桑橙素在制备预防或治疗痛风的药物中的应用。
在一优选例中，所述的桑橙素是作为唯一的活性成分应用于预防或治疗痛风的药物的制备中。
本发明还提供了一种防治高尿酸血症或痛风的药物组合物，其特征在于，它含有有效量的桑橙素。
本发明各个方面的细节将在随后的章节中得以详尽描述。通过下文以及权利要求的描述，本发明的特点、目的和优势将更为明显。
具体实施方式
本发明的问世是基于这样一个意外发现：藤黄酮类化合物桑橙素可以显著抑制黄嘌呤氧化酶(XOD)的活性。因此，桑橙素有望开发成为一种可预防或者治疗高尿酸血症或痛风的药物。
进而，本发明的第一方面是提供了桑橙素在制备黄嘌呤氧化酶抑制剂中的应用。
较优选地，所述的桑橙素是作为唯一的活性成分应用于黄嘌呤氧化酶抑制剂的制备中。
本发明的第二方面是提供了桑橙素在制备预防或治疗高尿酸血症的药物中的应用。
较优选地，所述的桑橙素是作为唯一的活性成分应用于预防或治疗高尿酸血症的药物的制备中。
本发明的第三方面是提供了桑橙素在制备预防或治疗痛风的药物中的应用。
较优选地，所述的桑橙素是作为唯一的活性成分应用于预防或治疗痛风的药物的制备中。
本发明还提供了一种防治高尿酸血症或痛风的药物组合物，其特征在于，它含有有效量的桑橙素。
如本发明所用，本发明的化合物桑橙素，中文化学名为(3,4-二羟基苯基)(2,4,6-三羟基苯基)甲酮，英文名为Maclurin，分子式C13H10O6，分子量262.22，CAS号：519-34-6，其化学结构如下：
如本领域的普通技术人员所知，本发明的化合物桑橙素可通过商业途径购买获得或通过化学方法合成(J.Agric.Food Chem..EN；9.1994,42,1869-1871)，其亦可用本领域的常规方法从藤黄属植物如山木瓜、假红树Laguncularia racemosa、桑叶Morus alba、桑枝Morus alba等中提取获得。其纯度均符合药用标准。
本发明的桑橙素可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成分的本发明的桑橙素及可药用载体。较佳地，本发明的药物组合物含有0.1～99.9％重量百分比的作为活性成分的本发明的桑橙素。“可药用载体”不会破坏本发明的桑橙素的药学活性，同时其有效用量，即能发挥药物载体作用时的用量对人体无毒。
所述可药用载体包括但不限于：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、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、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂(如微晶纤维素)、填充剂(如淀粉、葡萄糖、无水乳糖和乳糖珠粒)、崩解剂(如交联PVP、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)、润滑剂(如硬脂酸镁)以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
本发明的桑橙素以及其药物组合物可按本领域常规方法制备并可以通过肠道或非肠道或局部途径给药。口服制剂包括胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等；非肠道给药制剂包括注射液等；局部给药制剂包括霜剂、贴剂、软膏剂、喷雾剂等。优选为口服制剂。
本发明的桑橙素以及其药物组合物的给药途径可以为口服、舌下、经皮、经肌肉或皮下、皮肤粘膜、静脉、尿道、阴道等。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。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。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
实施例1化合物桑橙素的分离
实验材料
山木瓜枝于2010年在中国云南省采集，药材标本(编号：20100801)现存于中药创新药物研发上海高校工程研究中心。石油醚、乙醇等试剂均为分析级试剂，购买于中国国药集团化学试剂有限公司；硅胶粉购买于中国青岛海洋化工厂分厂；TLC薄层层析硅胶板购买于烟台江友硅胶开发有限公司；Sephadex LH-20(GE Healthcare Bio-Sciences AB,Sweden)。
Bruker AV-400核磁测谱仪(TMS标准物质)；安捷伦1100系列MSD离子阱质谱仪、安捷伦6210ESI-TOF和安捷伦6520ESI-Q-TOF。高效液相色谱仪(Waters，2695型)。
分离流程
1.取干燥的山木瓜枝条的粉末(4Kg)先用石油醚浸泡提取之后得到的药渣再用80％的乙醇提取，得到的提取液回收溶剂后，以水混悬，继续用乙酸乙酯进行萃取。乙酸乙酯部位用MCI树脂经30％乙醇提取，得到30％乙醇提取部位(10g)；
2.取30％乙醇提取部位用硅胶柱色谱(200目-300目)进行梯度分离(洗脱液：二氯甲烷与甲醇)洗脱液的比例由TLC检测30％乙醇提取部位的Rf值控制，开始Rf＝0.2-0.3；
3.每份收集液为100mL，TLC检测，收集液浓缩，得提取物的分离部位(a)。分离部位(a)再次经sephadex LH-20柱色谱(洗脱液：甲醇)进行两次重复分离，得到的分离部位(b)；
4.分离部位(b)再经制备薄层分离制备，展开剂为甲醇︰二氯甲烷(14:1)，用外检测器下监测分离。得到的目标硅胶色带经丙酮溶剂洗脱；
5.TLC及HPLC检测，洗脱液浓缩干燥得纯化合物Maclurin(4.86mg)。
核磁数据
NMR：1H NMR(MeOD)1δ7.12(d,1H，J＝2.0Hz),7.06(dd,1H，2.0Hz,J＝8.3,),6.68(d,1H，J＝8.3Hz),5.79(s,2H)。
质谱数据
质谱:(ESI)261(M+H)+。
二、验证化合物桑橙素的抗痛风活性
实验材料
黄嘌呤氧化酶(东方酵母公司，批号：27093203)；别嘌呤醇(Oriental Yeast Co.,Ltd.)；黄嘌呤(Tokyo Chemical Industry Co.,Ltd.批号：TGG4402)；DMSO购买于Sigma公司；其它化学试剂：盐酸、磷酸盐缓冲盐水(PBS)等购买于国药控股化学试剂有限公司。酶标仪(Synergy HT,BioTek Instruments,Gene Company Limited)。
实验方法
1.根据上述实施实例的分离的方法制备化合物Maclurin。将其溶解于DMSO溶液配制成100μM溶液；配制10mM PBS(pH7.4)溶液，并以PBS溶液分别配制0.111mM黄嘌呤和0.1U/ml的黄嘌呤氧化酶溶液。
2.在96孔板中加入890μl黄嘌呤PBS溶液和10μl浓度为100μM的Maclurin溶液(空白对照为加入10μl的PBS溶液)，混匀，于37℃预孵育15分钟。加入100μL的0.1U/mL黄嘌呤氧化酶溶液，混匀，再次置于水浴中(37℃)孵育3分钟后，加入100μL1N的HCl溶液中止反应。最终通过分光光度计在295nm处有氧条件下测其吸光度；以别嘌呤醇为黄嘌呤氧化酶抑制剂的阳性对照；
3.通过计算公式计算样品对XOD的抑制率：
公式：抑制率＝(1-B/A)*100％
其中，A为加入空白样品组的酶促反应的吸光度值，B为体系中加入氧化酶抑制剂的吸光度值。
4.测得化合物的抑制黄嘌呤氧化酶的抑制率数据：
化合物抗痛风活性表
实验数据显示，从山木瓜枝的乙酸乙酯部位中提取得到的化合物Maclurin具有良好的抑制XOD活性，在100μM浓度下黄嘌呤氧化酶抑制活性大于50％，IC50为28.9μM。有很好的药用前景。
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明精神之前提下，本领域专业人员可对其进行等同改变和修饰，所述改变和修饰同样落入本申请所附权利要求的覆盖范围。
Claims (4)
1.桑橙素在制备预防或治疗高尿酸血症的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述的桑橙素是作为唯一的活性成分应用于预防或治疗高尿酸血症的药物的制备中。
3.桑橙素在制备预防或治疗痛风的药物中的应用。
4.如权利要求1所述的应用，其特征在于，所述的桑橙素是作为唯一的活性成分应用于预防或治疗痛风的药物的制备中。
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