CN113304140A - Caraphenol A在制备黄嘌呤氧化酶抑制药物中的应用 - Google Patents
Caraphenol A在制备黄嘌呤氧化酶抑制药物中的应用 Download PDFInfo
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Abstract
本发明属于中药材有效成分应用的技术领域，具体涉及Caraphenol A在制备黄嘌呤氧化酶抑制药物中的应用，所述Caraphenol A为二苯乙烯三聚体，其分子式为C42H28O9，所述的CaraphenolA能够制备成适于临床使用的药物剂型，包括注射剂、颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂，具有显著抑制黄嘌呤氧化酶活性的作用。
Description
技术领域
本发明属于中药材有效成分应用的技术领域，具体涉及Caraphenol A在制备黄嘌呤氧化酶(Xanthine Oxidase,简称XO)抑制药物中的应用。
背景技术
痛风是一种由持续的高尿酸血症引起的尿酸盐晶体沉积在关节处而引发的炎性关节炎。通常高尿酸血症被认为是痛风的标志，据统计大约有5％-12％的高尿酸血症最终会发展成为痛风。当血尿酸水平超过其在血液或者组织中的饱和度时，就会在关节等部位形成晶体，局部炎症和组织破坏；高尿酸血症典型的的特征是体内尿酸水平的升高，控制尿酸水平的升高是治疗高尿酸血症和痛风的重要方式。通常临床治疗痛风目标是将患者的血清尿酸(SUA)水平降低至360mmol/L以下，对于伴有合并症的痛风患者则需控制在300mmol/L以下，才能有效控制痛风发作。
人体内嘌呤类物质最终代谢的产物为尿酸，XO是催化人体内黄嘌呤和次黄嘌呤生成尿酸的关键酶。黄嘌呤氧化酶抑制剂是降低痛风患者体内血尿酸水平的主要治疗手段；同时，由于XO抑制剂比促尿酸排泄药物和抗炎药物通常具有更小的副作用，黄嘌呤氧化酶抑制剂在痛风的治疗中意义重大。降尿酸药物别嘌呤醇自1963年用于临床以来，一直作为一线抗痛风药，但是由于其一直存在过敏、肝肾损伤以及骨髓抑制等不良反应，其副作用的总发生率为5-20％，大大限制了其临床使用；2009年XO选择性抑制剂非布司他通过美国FDA审核获批上市，其抑制XO活性进一步提升，效果优于别嘌呤醇，但是其仍旧出现了胃疼、腹泻、肝损伤和肌肉疼痛等不良反应。
因此，黄嘌呤氧化酶抑制剂的进一步研发，寻找更有效更合理的抗痛风药物，也是当前药物工作者的重要任务。
发明内容
本发明针对现有技术的不足，提出了Caraphenol A在制备黄嘌呤氧化酶抑制药物中的应用。
具体是通过以下技术方案来实现的：
Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，黄嘌呤氧化酶抑制药物由以Caraphenol A为活性成分和其他药物赋形剂或载体制成。
所述Caraphenol A为二苯乙烯三聚体，其分子式为C42H28O9，化学名为(2S,2aS,7R,7aR)-2,7,12-Tris(4-hydroxyphenyl)-2,2a,7,7a-tetrahydrobis[1]benzofuro[3',4':4,5,6；3”,4”:7,8,9]cyclonona[1,2,3-cd][1]benzofuran-4,9,14-triol。
所述Caraphenol A的结构式如下：
所述Caraphenol A是从天然药物(如金雀花根)中直接提取或者通过化学合成制得。
所述黄嘌呤氧化酶抑制表现为通过抑制黄嘌呤氧化酶的活性，减少体内尿酸的生成，进行高尿酸血症、痛风、糖尿病肾病、心血管疾病等与黄嘌呤氧化酶活性相关的疾病的防治。
所述黄嘌呤氧化酶抑制药物为口服剂或注射剂。
进一步优选，所述口服剂为颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂中任意一种或多种。
有益效果：
本发明的Caraphenol A是从具有多年临床应用历史、安全有效的金雀花根药材中分离得到的一种单体化合物，系纯天然成分，是中药金雀花根抗痛风作用的有效成分，未见相关毒副作用报道，经药效验证在低浓度条件下，其仍具有显著的黄嘌呤氧化酶活性抑制作用，其IC50(23.6mol/L)明显优于临床用药别嘌呤醇(IC50:71.7mol/L)
本发明以Caraphenol A为活性成分搭配其他药物赋形剂或载体制成药物制剂，不仅能够治疗痛风，还避免了胃疼、腹泻、肝损伤和肌肉疼痛等不良反应的出现。
本发明的Caraphenol A具有良好的相容性，能够与多种辅料相适应，适应注射剂、颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂等多种剂型的制备工艺，极大拓宽了用药途径。
附图说明
图1为Caraphenol A不同浓度对黄嘌呤氧化酶的抑制作用。
具体实施方式
下面对本发明的具体实施方式作进一步详细的说明，但本发明并不局限于这些实施方式，任何在本实施例基本精神上的改进或代替，仍属于本发明权利要求所要求保护的范围。
实施例1
Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，所述黄嘌呤氧化酶抑制表现为通过抑制黄嘌呤氧化酶的活性，减少体内尿酸的生成，进行高尿酸血症、痛风、糖尿病肾病、心血管疾病等与黄嘌呤氧化酶活性相关的疾病的防治；
所述黄嘌呤氧化酶抑制药物由以Caraphenol A为活性成分和其他药物赋形剂或载体制成；
所述Caraphenol A为二苯乙烯三聚体，其分子式为C42H28O9，化学名为(2S,2aS,7R,7aR)-2,7,12-Tris(4-hydroxyphenyl)-2,2a,7,7a-tetrahydrobis[1]benzofuro[3',4':4,5,6；3”,4”:7,8,9]cyclonona[1,2,3-cd][1]benzofuran-4,9,14-triol；
所述Caraphenol A的结构式如下：
所述Caraphenol A是从植物花根中直接提取而得；
所述黄嘌呤氧化酶抑制药物的药物剂型为口服剂或注射剂，具体包括但不限于如下剂型：注射剂、颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂。
实施例1XO抑制活性测试：
在25℃下，采用96孔板，反应总体积为200μL，首先加入50μL的酶溶液(反应终浓度为0.05U/mL)，50μL的样品溶液，25℃温育15min后，加入50μL黄嘌呤底物溶液(终浓度为150μmol/L)启动反应。于25℃温育20min后，加入1mol/L的盐酸溶液50μL终止反应。于290nm下检测吸光度值。取该值与温育0min时OD值的差值作为最终检测结果；同法检测空白样品(即不含受试药物，以含5％DMSO的PBS替代样品溶液，以测定酶的最大反应活性)的OD值，并按下式计算各提取物的抑制率：抑制率(％)＝(1-试验样品平均OD值/空白样品平均OD值)×100％。采用Graphpad prism6.0软件进行数据分析。计算半数黄嘌呤氧化酶被抑制时的药物浓度，即IC50。采用别嘌呤醇作为阳性药；活性结果见表1；
其中，酶溶液的制备：称取XO适量，用水1mL溶解，得浓度为100U/mL的XO贮备液；将上述贮备液以每管50μL分装至10mL EPP管中，于-80℃冰箱中保存。取上述贮备液适量，用PBS稀释，制得浓度为0.2U/mL的XO溶液。溶液配制完毕后，立即置于0℃冰箱中保存。
样品溶液的制备：精密称取Caraphenol A适量，用DMSO溶解，再用PBS稀释，制得质量浓度为1000μg/mL的样品母液。采用二倍稀释法，以含DMSO的PBS为溶剂将上述母液逐级稀释，制得质量浓度分别均为1000、500、250、125、62.5、31.3、15.6μg/mL的样品溶液，DMSO含量为1％。
别嘌呤醇对照溶液的制备：精密称取别嘌醇适量，用DMSO溶解，加PBS适量稀释，制得质量浓度为500μg/mL的别嘌醇母液，待用。采用二倍稀释法，以含DMSO的PBS为溶剂将上述母液逐级稀释，制得质量浓度分别为500、250、125、62.5、31.3、15.63、7.82、3.91μg/mL的对照溶液，DMSO含量为1％。
黄嘌呤底物溶液的制备：称取黄嘌呤适量，加入PBS，室温下用NaOH、HCl溶液调节pH至7.5，超声使溶解，制得浓度分别为1200、1000、800、600、400μmol/L的黄嘌呤底物溶液。
表1 Caraphenol A在不同浓度下对XO的抑制率及半数抑制浓度(IC50)
由表1可知：相较于阳性药别嘌呤醇的IC50(71.7μmol/L)以及低浓度下的较低抑制率(12.5和6.25μmol/L时分别为8.3％和4.2％)，本发明申请保护的Caraphenol A的IC50为23.6μmol/L，在低浓度下仍然具有较高的抑制率(12.5和6.25μmol/L时分别为42.1％和20.1％)，其对黄嘌呤氧化酶的抑制效果突出，明显优于别嘌呤醇。
Claims (6)
1.Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，其特征在于，所述黄嘌呤氧化酶抑制药物由以Caraphenol A为活性成分和其他药物赋形剂或载体制成。
2.如权利要求1所述Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，其特征在于，所述Caraphenol A为二苯乙烯三聚体，其分子式为C42H28O9，化学名为(2S,2aS,7R,7aR)-2,7,12-Tris(4-hydroxyphenyl)-2,2a,7,7a-tetrahydrobis[1]benzofuro[3',4':4,5,6；3”,4”:7,8,9]cyclonona[1,2,3-cd][1]benzofuran-4,9,14-triol。
3.如权利要求1或2所述Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，其特征在于，所述Caraphenol A的结构式如下：
4.如权利要求1-3任一项所述Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，其特征在于，所述黄嘌呤氧化酶抑制表现为通过抑制黄嘌呤氧化酶的活性，减少体内尿酸的生成，进行高尿酸血症、痛风、糖尿病肾病、心血管疾病等与黄嘌呤氧化酶活性相关的疾病的防治。
5.如权利要求1所述Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，其特征在于，所述黄嘌呤氧化酶抑制药物为口服剂或注射剂。
6.如权利要求1所述Caraphenol A在制备黄嘌呤氧化酶抑制药物方面的应用，其特征在于，所述口服剂为颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂中任意一种或多种。
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