CN109394798A - 一种桂东黄菌干提取物的制备方法及其降尿酸应用 - Google Patents
一种桂东黄菌干提取物的制备方法及其降尿酸应用 Download PDFInfo
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Abstract
本发明涉及一种桂东黄菌干提取物的制备方法及其降尿酸应用,包括:(1)将干燥的桂东黄菌干粉碎;(2)在0‑75℃中用乙醇萃取,过滤分离滤渣和滤液,重复一至三次;(3)将步骤(2)所得的滤液合并后蒸馏浓缩至每克桂东黄菌干100mL以内的液体,烘干或冻干后得到桂东黄菌干醇提物;可选地,(4)在0‑100℃中用水作为溶剂萃取醇提后的桂东黄菌干残渣,后过滤分离滤渣和滤液,重复一至三次;(5)将步骤(4)所得的滤液合并后蒸馏浓缩,并冻干得到桂东黄菌干水提取物。本发明桂东黄菌干提取物具有显著的降尿酸作用,能够用于制备缓解痛风病症的药物,为改善目前痛风病药物副作用大的现象提供了新的方向。
Description
技术领域
本发明涉及一种桂东黄菌干提取物的制备方法及其降尿酸应用,属于保健品和中药领域。
背景技术
随着现代生活习惯和饮食结构的改变,高尿酸血症的发病率升高。高尿酸血症是体内尿酸的产生增加,肾尿酸的排泄减少,使得体内尿酸浓度高于血液溶解能力(>360μmol/L)。尿酸以晶体形式在关节中沉积,并导致反复发作导致痛风性关节炎和尿酸性肾结石。这些沉积结晶引起软组织、关节和骨组织反复发炎性剧烈疼痛,严重降低患者生活质量。
高尿酸血症的治疗需要降低体内血尿酸浓度。在肾单位的细胞上的特定转运蛋白(如肾尿酸转运蛋白1)是高尿酸血症的重要靶点。阿片类药物,如丙磺舒,磺吡酮和苯溴马隆均是直接作用于肾小管靶点的药物,通过抑制尿酸盐增加尿酸的肾排泄,通过与一种或多种转运蛋白相互作用而重吸收蛋白质,但是由于过敏反应等不良副作用而使用受限。黄嘌呤氧化酶(XOD)是另一个重要的靶标,主要分布在肝脏和肠道,并在嘌呤代谢途径中将次黄嘌呤和黄嘌呤氧化成尿酸。现抑制XOD的降尿酸药物可分为嘌呤和非嘌呤类。别嘌呤醇是最常用的临床XOD嘌呤类抑制剂,但其因史蒂文斯—约翰逊综合征、肾毒性等毒副作用而备受争议。非布索坦作为非嘌呤XOD抑制剂也会导致心血管并发症,食品和药物管理局(FDA)也要补充该药物的警示性声明。
因此,开发新型的安全有效的降尿酸药物迫在眉睫。
发明内容
针对以上不足,本发明提供一种桂东黄菌干提取物的制备方法及其降尿酸应用。
本发明通过以下方案达到上述目的:
本发明的制备方法,采用无毒无害的提取溶剂,能够在降低成本及避免有机溶剂污染基础上,得到降尿酸效果显著的桂东黄菌干提取物。
在第一方面,提供一种桂东黄菌干提取物的制备方法,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在0-75℃中用乙醇按照乙醇:桂东黄菌干为1:1-20:1的体积重量比萃取,过滤分离滤渣和滤液,重复一至三次;
(3)将步骤(2)所得的滤液合并后蒸馏浓缩至每克桂东黄菌干100mL以内的液体,烘干或冻干后得到桂东黄菌干醇提物;
可选地,
(4)在0-100℃中用水作为溶剂萃取醇提后的桂东黄菌干残渣,后过滤分离滤渣和滤液,重复一至三次;
(5)将步骤(4)所得的滤液合并后蒸馏浓缩至每克桂东黄菌干100mL以内的液体,并冻干得到桂东黄菌干水提取物。
优选的,所述步骤(2)为在60℃用乙醇萃取。
优选的,所述步骤(2)加入乙醇的萃取时间为0.1-3小时。
优选的,所述步骤(2)的乙醇:桂东黄菌干的体积重量比为3:1。
优选的,所述步骤(4)为在85℃用水萃取。
优选的,所述步骤(4)加入水的萃取时间为0.1-3小时。
优选的,所述步骤(4)的加入水的用量为水:桂东黄菌干的体积重量比为20-1:1-20,更优选为3:1。
优选的,一种桂东黄菌干提取物的制备方法,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在60℃用乙醇按照乙醇:桂东黄菌干为3:1的体积重量比萃取2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(3)将步骤(2)所得的滤液合并后减压蒸馏浓缩每克桂东黄菌干1-5mL的液体,得到桂东黄菌干醇提物;
可选地,
(4)在85℃用水作为溶剂萃取醇提后的桂东黄菌干残渣2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(5)将步骤(4)所得的滤液合并后减压蒸馏至每克桂东黄菌干1-5mL的液体,并冻干得到桂东黄菌干水提取物。
优选的,一种桂东黄菌干提取物的制备方法,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在60℃用乙醇乙醇:桂东黄菌干为3:1的体积重量比萃取2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(3)将步骤(2)所得的滤液合并后减压蒸馏浓缩每克桂东黄菌干1-5mL的液体,得到桂东黄菌干醇提物;
(4)在85℃用水作为溶剂萃取醇提后的桂东黄菌干残渣2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(5)将步骤(4)所得的滤液合并后减压蒸馏至每克桂东黄菌干1-5mL的液体,并冻干得到桂东黄菌干水提取物。
优选的,所述步骤(2)的萃取为超声提取。
优选的,所述步骤(4)的萃取为超声提取。
优选的,一种桂东黄菌干提取物的制备方法,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在60℃用乙醇乙醇:桂东黄菌干为3:1的体积重量比超声提取2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(3)将步骤(2)所得的滤液合并后减压蒸馏浓缩每克桂东黄菌干1-5mL的液体,得到桂东黄菌干醇提物;
可选地,
(4)在85℃用水作为溶剂超声提取醇提后的桂东黄菌干残渣2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(5)将步骤(4)所得的滤液合并后减压蒸馏至每克桂东黄菌干1-5mL的液体,并冻干得到桂东黄菌干水提取物。
进一步优选的,一种桂东黄菌干提取物的制备方法,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在60℃用乙醇:桂东黄菌干为3:1的体积重量比超声提取2小时,后减压过滤分离滤渣和滤液,重复三次;
(3)将步骤(2)所得的滤液合并后减压蒸馏浓缩每克桂东黄菌干1-5mL的液体,得到桂东黄菌干醇提物;
(4)在85℃用水作为溶剂超声提取醇提后的桂东黄菌干残渣2小时,后减压过滤分离滤渣和滤液,重复三次;
(5)将步骤(4)所得的滤液合并后减压蒸馏至每克桂东黄菌干1-5mL的液体,并冻干得到桂东黄菌干水提取物。
本发明采用绿色无毒的乙醇,并且通过提取参数,例如温度、时间、溶剂体积比例等限定,使得在提取效率、提取速率等方面取得了显著的进步,并且适当的乙醇、水的加入比例,使得在后续阶段不会产生污染,节省成本。
在第二方面,提供一种上述制备方法制备得到的桂东黄菌干提取物,包括桂东黄菌干醇提物和/或桂东黄菌干水提物。
在第三方面,提供一种上述桂东黄菌干提取物在降尿酸方面的应用。
优选的,所述降尿酸包括以黄嘌呤氧化酶(XOD)为靶点的的降尿酸方面。
在第四方面,提供一种上述桂东黄菌干提取物在治疗高尿酸疾病及相关疾病的应用。
在第五方面,提供一种上述桂东黄菌干提取物在制备高尿酸疾病及相关疾病的药物、保健品和/或辅助药物方面的应用。
优选的,所述高尿酸及相关疾病包括:高尿酸血症、痛风性病症例如痛风性关节炎、尿酸性肾结石等。
在第六方面,提供一种治疗高尿酸疾病的药物、保健品和/或辅助药物,包括上述桂东黄菌干醇提取和/或桂东黄菌干水提物。
本发明所述的桂东黄菌干又名小美牛肝菌,购自中国湖南桂东,具有极高的药用价值,抗老防癌。
发明人利用本发明制得的桂东黄菌干提取物在小鼠体内进行降尿酸试验,结果表明用桂东黄菌干提取物连续灌胃7天,可将高尿酸小鼠的血液尿酸浓度降低到正常小鼠尿酸水平,并且没有表现出肾功能损伤及副作用。
本发明首次证实了桂东黄菌干提取物的明显的降尿酸效果。
本发明的有益效果在于:
1、本发明所述桂东黄菌干提取物的制备工艺简单,成本低;
2、本发明采用乙醇、水或者乙醇和水的混合溶剂作为溶剂提取桂东黄菌干,生产成本低,不存在有机溶剂污染或残留的问题,安全环保;
3、本发明桂东黄菌干提取物具有显著的降尿酸作用,能够用于制备缓解痛风病症的药物,且无明显的肝肾毒性,为改善目前痛风病药物副作用大的现象提供了新的方向。
附图说明
图1为试验例1的各组小鼠血清尿酸水平。
图2为试验例1的各组小鼠尿液尿酸水平。
图3为试验例1的各组小鼠血清肌酐水平。
图4为试验例1的各组小鼠血清尿素氮水平。
图5为试验例1的各组小鼠血清XOD酶活性。
图6为试验例1的各组小鼠体重增长情况。
具体实施方式
以下结合具体实施例对本发明进行进一步说明,但实施例并不旨在对本发明做任何形式的限定。
实施例1:桂东黄菌干乙醇提取物的制备
取桂东黄菌干子实体100g,使用粉碎机粉碎后加入锥形瓶中,并加入2L乙醇,将混合物在60℃下水浴萃取2小时,后减压过滤分离滤液和滤渣,提取实验重复三次,将所得滤液合并后减压蒸馏浓缩并冻干得到桂东黄菌干乙醇提取物10.21g,产率6.38%。
实施例2:桂东黄菌干提取物的制备
在80℃的水浴中用2L水作为溶剂萃取醇提后的实施例1的桂东黄菌干残渣2小时,后减压过滤分离滤渣和滤液,提取实验重复三次,将所得滤液合并后减压蒸馏浓缩并冻干得到水提取物35.30g,产率22.06%。
试验例1桂东黄菌干提取物降尿酸药理实验
过程如下:
(1)取52只雄性SPF昆明小鼠(20±2g),随机分为6组:正常对照组,高尿酸血症模型组,别嘌呤醇和苯溴马隆对照组及醇提物组(桂东黄菌干醇提物实验组)和水提物组(桂东黄菌干水提物实验组)。除正常对照组腹腔注射和灌胃蒸馏水外,其他组按照300mg/kg/d的剂量腹腔注射氧嗪酸钾盐,同时灌胃500mg/kg/d剂量的次黄嘌呤造模。造模前一个小时禁食不禁水,造模后1小时,用别嘌呤醇(5mg/kg/d)和苯溴马隆(7.8mg/kg/d)灌胃给药予别嘌呤醇和苯溴马隆对照组的小鼠。醇提物组使用实施例1制得的桂东黄菌干醇提取物按100mg/kg/d的剂量进行灌胃给药。水提物实验组使用实施例2制得的桂东黄菌干水提取物按100mg/kg/d的剂量进行灌胃给药。正常对照组和高尿酸血症模型对照组则灌胃相同体积的纯水,连续7天,并在第1,3,5,7天对小鼠称重记录。结果如图6所示。
(2)第7天灌胃给药1小时后,取血和尿液,血液使用离心机在3800r/min速度下离心10min分离得血清,将血清与尿液存于-20℃。
(3)取(2)中所得血清和尿液分别测定血清尿酸水平,尿液尿酸水平,血清尿素和肌酐水平以及尿液尿素水平。结果如图1、图2、图3、图4所示。
(5)通过XOD测定试剂盒对(2)中所得血清进行XOD活性测定。结果如图5所示。
(8)统计分析使用专业数据处理程序SPSS(Release 11.5,SPSS Inc.,2001)进行。所有数据表示为平均值±标准误差(S.D.),并通过单因素方差分析(ANOVA)进行分析,并通过双尾Student's t检验比较组平均值。差异有统计学意义(P<0.05或P<0.01)的用以下符号表示:与正常组对照有差异:*P<0.05,**P<0.01;与PO和HX诱导的高尿酸血症模型组对照有差异,#P<0.05,##P<0.01;与别嘌呤醇组对照有差异,△P<0.05,△△P<0.01。
血尿酸是评价降尿酸效果的直接指标,结果如图1所示。氧嗪酸钾和次黄嘌呤联合给药导致高尿酸血症模型组血清尿酸水平升高,与正常小鼠(121μmol/L)相比,高尿酸血症小鼠显着升高至439μmol/L(P<0.01),说明造模成功。别嘌呤醇(251mol/L,P<0.01)和苯溴马隆(1376μmol/L,P<0.01)对照组的血尿酸水平下降也证实了高尿酸血症造模的成功。重要的是,桂东黄菌干醇提物给药组中,高尿酸血小鼠的血尿酸174μmol/L(P<0.01)。桂东黄菌干水提物给药组中,高尿酸血症小鼠的血清尿酸水平降低至131μmol/L(P<0.01)。桂东黄菌干醇提物和水提物都在这个模型中表现出显著的降血尿酸作用。
由于尿酸通过肾脏排泄,与血尿酸水平直接相关,本例为阐明用桂东黄菌干醇提物和水提物治疗的血尿酸水平降低可能是由于肾尿酸排泄的增强,测定它们对尿尿酸水平的影响,结果如图2所示。与正常组(568μmol/L)相比,在模型组(2639μmol/L)中观察到尿尿酸水平的升高,通过别嘌呤醇给药(2672μmol/L)未明显改变尿尿酸水平。通过苯溴马隆给药使尿尿酸水平轻微上升至2922μmol/L,桂东黄菌干的醇提物和水提物组的尿尿酸水平分别为2349μmol/L和1975μmol/L,与模型组相比均没有起到升高尿尿酸含量的作用。
为研究桂东黄菌干对肾功能的影响,我们还测定高尿酸血症小鼠肾功能参数。肌酐,是含氮有机代谢物的代谢终产物,由肾小球滤过,随尿液排出。但肾功能受损失,肌酐含量上升。因此肌酐值成为评价肾功能的主要指标之一。如图3所示,氧嗪酸钾和次黄嘌呤的给药能使正常小鼠的血清肌酸酐水平(51.82mmol/L)升高至60.30mmol/L。与高尿酸血症模型组相比,桂东黄菌干醇提物和水提物能使小鼠血清肌酐水平下降至54.15mmol/L和51.80mmol/L,显示其对肾脏器官的恢复有一定效果。
尿素氮(BUN)是肾功能主要指标之一。尿素氮是人体蛋白质代谢的主要终末产物,主要由肾小球(肾脏的重要组成部分)滤过排出体外。在肾功能损害早期,血尿素氮可在正常范围。当肾小球滤过率下降到正常的50%以下时,血尿素氮的浓度才迅速升高。因此,血尿素氮水平反映了肾功能的状况:血尿素氮的水平越高,肾功能的损伤程度越严重。结果如图4所示,高尿酸模型组(2.61mmol/L)比正常小鼠2.48mmol/L的BUN水平略高。别嘌呤醇组的BUN(5.88mmol/L,P<0.01)比模型组更高,表明别嘌呤醇使高尿酸血症小鼠的肾功能受损。与别嘌呤醇组相比,用桂东黄菌干醇提物和水提物给药,血清BUN参数分别为3.05和2.56mmol/L,显著低于别嘌醇的对照且差异有统计学意义(P<0.01)。
XOD(Xanthione oxidase,黄嘌呤氧化酶)直接调控人体内尿酸水平的高低。非嘌呤类前体物质在体内经过系列生化转化生成嘌呤类核苷酸,继续分解生成次黄嘌呤和黄嘌呤,最终经过XOD的连续氧化而生成尿酸。其主要分布在肝脏和小肠,高尿血酸症状态下XOD活性增强。血清XOD活性结果如图5所示,模型组的血清XOD活性(12.22U/L)比正常组(10.16U/L,P<0.01)更高。别嘌呤醇对照组显着抑制高尿酸血症小鼠血清XOD活性至9.83U/L(P<0.01)。桂东黄菌干醇提物和水提物的XOD活性分别为12.59和13.04U/L,血清XOD活力未降低。这些结果可能表明,桂东黄菌干提取物的降尿酸作用可能不是通过对XOD活性的抑制作用。
各组小鼠体重变化如图6所示,与正常组小鼠相比,本研究中使用的苯溴马隆、别嘌呤醇、桂东黄菌干醇提物和水提物均对体重造成了一定影响(P<0.01)。
上述结果说明,本发明桂东黄菌干的醇提物和水提物使高尿酸血症小鼠的血清尿酸水平显著降低,接近正常组水平。醇提物和水提物均未显示对XOD活性的抑制作用。另外,桂东黄菌干提取物对肝、肾无毒性,可以用于制备降尿酸、改善痛风的药物、保健品或辅助药剂中。
以上所述,仅为本发明的较佳的具体实施例,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其构思加以等同替换或改变,都应涵盖在本发明的保护范围内。
Claims (10)
1.一种桂东黄菌干提取物的制备方法,其特征在于,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在0-75℃中用乙醇按照乙醇:桂东黄菌干为1:1-20:1的体积重量比萃取,过滤分离滤渣和滤液,重复一至三次;
(3)将步骤(2)所得的滤液合并后蒸馏浓缩至每克桂东黄菌干100mL以内的液体,烘干或冻干后得到桂东黄菌干醇提物;
可选地,
(4)在0-100℃中用水作为溶剂萃取醇提后的桂东黄菌干残渣,后过滤分离滤渣和滤液,重复一至三次;
(5)将步骤(4)所得的滤液合并后蒸馏浓缩至每克桂东黄菌干100mL以内的液体,并冻干得到桂东黄菌干水提取物。
2.根据权利要求1所述的一种桂东黄菌干提取物的制备方法,其特征在于,所述步骤(2)为在60℃用乙醇萃取;所述步骤(2)加入乙醇的萃取时间为0.1-3小时。
3.根据权利要求1所述的一种桂东黄菌干提取物的制备方法,其特征在于,所述步骤(4)为在85℃用水萃取;所述步骤(4)加入水的萃取时间为0.1-3小时。
4.根据权利要求1所述的一种桂东黄菌干提取物的制备方法,其特征在于,所述步骤(2)的乙醇:桂东黄菌干的体积重量比为3:1;所述步骤(4)的加入水的用量为水:桂东黄菌干的体积重量比为20-1:1-20,更优选为3:1。
5.根据权利要求1至4中任一所述的一种桂东黄菌干提取物的制备方法,其特征在于,包括:
(1)将干燥的桂东黄菌干粉碎;
(2)在60℃用乙醇乙醇:桂东黄菌干为3:1的体积重量比萃取2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(3)将步骤(2)所得的滤液合并后减压蒸馏浓缩每克桂东黄菌干1-5mL的液体,得到桂东黄菌干醇提物;
可选地,
(4)在85℃用水作为溶剂萃取醇提后的桂东黄菌干残渣2小时,后减压过滤分离滤渣和滤液,重复一至三次;
(5)将步骤(4)所得的滤液合并后减压蒸馏至每克桂东黄菌干1-5mL的液体,并冻干得到桂东黄菌干水提取物。
6.根据权利要求5所述的一种桂东黄菌干提取物的制备方法,其特征在于,所述步骤(2)的萃取为超声提取;所述步骤(4)的萃取为超声提取。
7.一种权利要求1至6中任一所述的制备方法制备得到的桂东黄菌干提取物,包括桂东黄菌干醇提物和/或桂东黄菌干水提物。
8.一种权利要求7所述的桂东黄菌干提取物在降尿酸方面的应用,优选的,所述降尿酸包括以黄嘌呤氧化酶(XOD)为靶点的的降尿酸方面。
9.一种权利要求7所述的桂东黄菌干提取物在制备高尿酸疾病及相关疾病的药物、保健品和/或辅助药物方面的应用,优选的,所述高尿酸及相关疾病包括:高尿酸血症、痛风性病症例如痛风性关节炎、尿酸性肾结石等。
10.一种治疗高尿酸疾病的药物、保健品和/或辅助药物,包括权利要求7所述的桂东黄菌干醇提取和/或桂东黄菌干水提物。
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