CN106309546A - 治疗糖尿病肾病的提取物 - Google Patents
治疗糖尿病肾病的提取物 Download PDFInfo
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- CN106309546A CN106309546A CN201510942960.4A CN201510942960A CN106309546A CN 106309546 A CN106309546 A CN 106309546A CN 201510942960 A CN201510942960 A CN 201510942960A CN 106309546 A CN106309546 A CN 106309546A
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- petroleum ether
- herba rosmarini
- rosmarini officinalis
- extraction
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Abstract
本发明涉及迷迭香石油醚提取物用于制备治疗或预防糖尿病肾病的组合物,迷迭香石油醚提取物的组分含有:鼠尾草酸、鼠尾草酚、迷迭香酚、表迷迭香酚、表异迷迭香酚、鼠尾酸甲酯等。
Description
技术领域
本发明涉及一种植物提取物的医药新用途,迷迭香提取物在制备治疗糖尿病肾病药物中的应用,属于天然药物领域。
背景技术
近年来,随着社会进步、生活改善和膳食结构改变,糖尿病的发病率逐年增长,低龄化趋势加剧。糖尿病肾病(Diabetic nephropathy,DN)是糖尿病人的最重要的合并症之一,最终有可能发展成高致死率的终末期肾病(End stage renaldisease,ESRD)。在我国DN是终末期肾病的第二大病因,而在西方国家,DN早已成为终末期肾病发病的首要因素。糖尿病肾病是糖尿病最常见的微血管并发症之一,也是糖尿病患者致死、致残的主要原因。由于其存在复杂的代谢紊乱,一旦发展到终末期肾脏病,往往比其他肾脏疾病的治疗更加棘手,因此及时防治对于延缓糖尿病肾病的意义重大。
近些年随着DN发病率的增高,对其发病机制的研究也取得了较大的进展。一般认为主要由遗传因素、肾脏血流动力学改变、生化代谢紊乱、氧化应激损伤、高血压、细胞生长因子异常增多和血管活性物质代谢异常等多种原因相互影响共同导致DN的发生。
糖尿病病人临床上出现肾脏损害应考虑糖尿病肾病,家族中有肾脏病者、明显高血压、胰岛素抵抗,肾小球率过滤(Glomerular filtration rate,GFR)明显过高或伴严重高血压者为发生糖尿病肾病的高危因素。糖尿病临床表现主要分为5期,分别是肾小球肥大高功能期、无临床症状肾损害期、糖尿病肾病早期、显性蛋白尿肾病期、肾功能衰竭期。
临床糖尿病肾病诊断主要为糖尿病患者持续性蛋白尿>0.5g/24h,早期糖尿病肾病的尿蛋白量为0.15-0.5g/24h,尿白蛋白***率为15-200μg/min。诊断较困难者,应结合其他器官的糖尿病微血管病损情况。必要时科进行肾活检。
目前糖尿病肾病没有良好的针对性药物。患者主要靠控制血糖、血压,调节日常饮食以缓解症状。进入终末期肾衰竭的患者则需要进行透析和器官移植,但此举并不能防止糖尿病肾病再发生。
迷迭香(Rosmarinus officinalis L.)唇形科灌木,原产于地中海地区。中国科学院植物研究所于1981年成功地从西班牙引进了迷迭香,成分主要为鼠尾草酸、鼠尾草酚、迷迭香酚、熊果酸、迷迭香酸等。迷迭香植物为常绿灌木,株直立,主茎高约1米(有时达2米)。叶狭细尖状,长约1厘米,形似弯曲的松针;深绿色,上面光亮,下面白色,叶缘向叶背卷曲,叶片发散松树香味。
迷迭香具有镇静安神、醒脑作用,对消化不良和胃痛均有一定疗效。也可用于治疗失眠、心悸、头痛、消化不良等多种疾病。外用可治疗外伤和关节炎。还具有强壮心脏、促进代谢、促进末梢血管的血液循环等作用。同时还改善语言、视觉、听力方面的障碍,增强注意力,治疗风湿痛,强化肝脏功能,降低血糖,有助于动脉硬化的治疗,帮助***四肢恢复活动能力。近年来,迷迭香在糖尿病治疗上也有所进展,但是迷迭香石油醚提取物在糖尿病肾病方向上却未曾有报道。
发明内容
本发明公开了迷迭香石油醚提取物在制备治疗糖尿病肾病的组合物中的应用。
本发明公开了提取物为深绿色粉末或膏状固体。
本发明公开了迷迭香石油醚提取物的组分是:鼠尾草酸、鼠尾草酚、迷迭香酚、表迷迭香酚、表异迷迭香酚、鼠尾酸甲酯、Salviol、1-Phenanthrenecarboxylic acid、2-Phenanthrenemethanol。
本发明公开了迷迭香石油醚提取物的组分是:迷迭香酚,鼠尾草酚,鼠尾草酸,鼠尾酸甲酯,Salviol。其相对质谱峰面积比值为:2.23∶10.12∶39.64∶2.93∶32.32。(保留时间如表1.所示,质谱图如图1.所示)
本发明公开了用于制备防治糖尿病肾病的组合物,迷迭香石油醚提取物的含量范围是1mg-2g/mg。
本发明公开了的组合物,其制备为:药物、保健品、或功能性食品,赋形剂或载体为制药或食品领域中常用的赋形剂或载体,如稀释剂,崩解剂,润滑剂等。
本发明公开了用于制备防治糖尿病肾病的组合物,迷迭香石油醚提取物的制备方法是:醇提取迷迭香药材,用水溶解醇提取物,用石油醚萃取水溶液,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
本发明公开了用于制备防治糖尿病肾病的组合物,迷迭香石油醚提取物的制备方法是:
迷迭香药材用乙醇提取,合并95%乙醇提取液,回收乙醇,浸膏加水使溶,加入石油醚,石油醚和溶液萃取多次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
迷迭香药材用甲醇提取,合并甲醇提取液,回收甲醇,浸膏加水使溶,加入石油醚,石油醚和溶液按照萃取多次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
迷迭香药材用正丁醇提取,合并正丁醇提取液,回收正丁醇,浸膏加水使溶,加入石油醚,石油醚和溶液萃取多次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
本发明公开了迷迭香石油醚提取物的制备方法是:迷迭香药材用10倍量95%乙醇提取3次,1h/次,合并95%乙醇提取液,回收乙醇,浸膏加水使溶,加入石油醚,石油醚和溶液按照1;1萃取三次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
本发明公开了迷迭香石油醚提取物的制备方法是:迷迭香药材用10倍量甲醇提取3次,1h/次,合并甲醇提取液,回收甲醇,浸膏加水使溶,加入石油醚,石油醚和溶液按照1;1萃取三次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
本发明公开了迷迭香石油醚提取物的制备方法是:迷迭香药材用10倍量正丁醇提取3次,1h/次,合并正丁醇提取液,回收正丁醇,浸膏加水使溶,加入石油醚,石油醚和溶液按照1;1萃取三次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
基于上述发现,本发明现已完成相关实验。为了便于理解,下面将通过附图和具体实施例进行详细描述。需要特别指出的是,具体实施例和附图仅是为了说明,显然本领域的技术人员可以根据本文说明,对本发明进行各种修正或改变,这些修正和改变也将纳入本发明范围之内。
附图说明
图1.迷迭香石油醚提取物HPLC-ESI-Q-TOF-MS总离子流图
图2.C57BL/6组、STZ+Vehicle组、STZ+Irbesartan组和STZ+PFR组对DN小鼠血糖的影响
图3.C57BL/6组、STZ+Vehicle组、STZ+Irbesartan组和STZ+PFR组对DN小鼠尿白蛋白***率的影响
图4.C57BL/6组、STZ+Vehicle组、STZ+Irbesartan组和STZ+PFR组对DN小鼠UAlb/UCr的影响
具体实施方式
实施例1
迷迭香石油醚提取物提取工艺
迷迭香药材10倍量95%乙醇提取3次,1h/次,合并95%乙醇提取液,回收乙醇,浸膏加水使溶,加入石油醚,石油醚和溶液按照1;1萃取三次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
实施例2
迷迭香石油醚提取物成分鉴定
95%乙醇溶解迷迭香石油醚提取物10mg/ml,12,000rpm离心10min,取上清进行液相分析,
采用Agilent 1290 UPLC-6520 QTOF MS,
流动相为(A)0.1%甲酸水溶液和(B)乙腈.
流动相洗脱程序为:
10%B(0min),
30%B(5min),
50%B(10min),
80%B(15min),
100%B(25-30min).
流速为0.8ml/min.
质谱干燥气体温度350℃,干燥气体流速10L/h,雾化气压35psig,ESI离子源,电喷雾电压3500v,裂解电压120v,skimmer 65v,OCTIRFVgp750v,扫描离子范围100-1100.二级碰撞电压20v;40v;70v。
质谱鉴定结果如下表
能确定本发明公开了迷迭香石油醚提取物的组分是:鼠尾草酸、鼠尾草酚、迷迭香酚、表迷迭香酚、表异迷迭香酚、鼠尾酸甲酯、Salviol、1-Phenanthrenecarboxylic acid、2-Phenanthrenemethanol等化合物。
表1.迷迭香石油醚提取物质谱表征
迷迭香酚,鼠尾草酚,鼠尾草酸,鼠尾酸甲酯,Salviol。其质谱相对峰面积比值为:2.23∶10.12∶39.64∶2.93∶32.32(图谱如图1.所示)。
实施例3
提取物对C57BL/6小鼠实验性糖尿病肾病的治疗作用实验研究
本实验所用英文缩写词如下。
英文缩写词表
英文缩写 英文全称 中文全称
PFR Petroleum ether fraction of rosemary 迷迭香石油醚提取物
DN Diabetic nephropathy 糖尿病肾病
ESRD End-stage renal diseas 终末期肾病
FBG Fasting blood glucose 空腹血糖
STZ Streptozocin 链脲佐菌素
UAER Urinary albumin excretion rate 尿白蛋白***率
UAlb Urinary albumin 尿微量白蛋白
UCr Urinary creatinine 尿肌酐
本发明的实验方法及实验结果如下
2.1实验材料
2.1.1实验动物
C57BL/6小鼠,雄性,体重20±2g,由扬州大学动物医学实验教学中心提供,质量合格证号:SCXK-(苏)2012-0004。
2.1.2药品与试剂
微量白蛋白(m-Alb)测试盒(ELISA方法)南京建成生物研究所
批号:20150526
以下将迷迭香石油醚提取物简称为PFR。
2.1.3实验仪器
2.2实验方法
2.2.1药物配制
饮食配方:正常小鼠饲料。
链脲佐菌素(STZ)溶液的配制:STZ于-20℃以下保存。临用时以柠檬酸2.1g加入双蒸水100mL中配成A液。柠檬酸钠2.94g加入双蒸水100mL中配成B液。A、B液按1∶1.32混合,pH计测定pH值,调节pH=4.2-4.5,即是所需柠檬酸钠缓冲液。临用时将STZ用檬酸钠缓冲液配制成3mg/ml的链脲佐菌素溶液,避光,30min内注射完毕。
药物配制:将PFR用0.5%羧甲基纤维素钠(CMC-Na)配成7.72mg/ml的溶液。Irbesartan用0.5%的CMC-Na配成0.75mg/ml的溶液。
2.2.2实验模型的建立及给药方法
将38只C57BL/6小鼠适应性喂养7d后随机分为正常组(12只)和模型组(26只),每日喂食正常饮食。7d后,给予模型组连续腹腔注射STZ(60mg/kg)5d。2w后,尾尖取血,检测空腹血糖。将空腹血糖值>16mmol/L的小鼠列入糖尿病动物。
将造模成功的糖尿病小鼠按血糖和体重随机分为3组,即:STZ+Vehicle组(10只)、STZ+PFR(154.4mg/kg)组(5只)、STZ+Irbesartan组(9只)。另选12只正常组小鼠作为C57BL/6组。具体的给药方案为:
各组动物每日按照上述方案灌胃给药,连续24w。实验前一周,收集尿液。将小鼠放入代谢笼中24h,不禁食不禁水,收集24h尿液。实验结束前12h禁食不禁水,用血糖仪测空腹血糖。
2.3观察指标及标本采集
2.3.1一般指标的观察
监测实验过程中各组小鼠的一般状态、空腹血糖、体重、摄食及摄水量等变化。
2.3.2尿蛋白的测定
实验前一周收集各组小鼠24h尿样,留尿期间不禁食,不禁水,将小鼠放入洗净的代谢笼内,记录尿量后取2ml,5000rpm离心1min,去除沉渣,分装于EP管中,-80℃冰箱保存。用ELISA试剂盒检测尿白蛋白浓度。
2.3.3尿肌酐的测定
实验前一周收集各组小鼠24h尿样,用试剂盒检测尿中肌酐浓度。
2.4统计方法
实验数据,计量资料进行组间t检验,P<0.05为具有显著性统计学意义。(*P<0.05,**P<0.01,***P<0.001)
2.5实验结果
2.5.1一般状态观察
模型组小鼠腹腔注射STZ 14d后,一般状态表现为:活动减少;多饮,平均饮水量是C57BL/6组的三倍;多尿,垫料明显潮湿,每日需更换1-2次,体重逐渐下降,精神萎靡,毛色灰暗,粗糙。与STZ+Vehicle组比较,STZ+PFR组,STZ+Irbesartan组小鼠的饮水量、尿量增多,体重下降及精神状态等均有所改善。
2.5.2 PFR对的影响
与C57BL/6组比较,24周后,STZ+Vehicle组小鼠血糖值均显著升高(P<0.001)。与STZ+Vehicle组比较,STZ+PFR组血糖值均显著降低(P<0.05),STZ+Irbesartanl组血糖值无统计学意义(P>0.05)。实验结果见图2.。
表2.实验C56BL/6小鼠空腹血糖(mM)
2.5.3 PFR对DN小鼠尿白蛋白***率的影响
与C57BL/6组比较STZ+Vehicle组尿白蛋白***率(UAER)均显著升高(P<0.001)。与STZ+Vehicle组比较,STZ+PFR组UAER显著降低(P<0.01)。STZ+Irbesartanl组UAER无统计学意义(P>0.05)实验结果见图3.。
表3.实验C56BL/6小鼠尿白蛋白***率(μg/24h)
2.5.4 PFR对DN小鼠尿微量白蛋白与肌酐比值的影响
与C57BL/6组比较,STZ+Vehicle组尿微量白蛋白与肌酐比值(UAlb/UCr)均显著升高(P<0.001)。与STZ+Vehicle组比较,STZ+PFR组UAlb/UCr值显著降低(P<0.01)。STZ+Irbesartanl组UAlb/UCr值无统计学意义(P>0.05)实验结果见图4.。
表4.实验C56BL/6小鼠尿微量白蛋白与肌酐比值(μg/mg)
实施例4
迷迭香石油醚提取物的制剂
迷迭香石油醚提取物的片剂:迷迭香石油醚提取物10mg,淀粉88g,硬脂酸镁3g
制备工艺:取实施例1的迷迭香石油醚提取物过100目筛,加淀粉、硬脂酸镁混合均匀,制成颗粒,干燥,压片,即得。
迷迭香石油醚提取物的胶囊
迷迭香石油醚提取物10mg,淀粉88g,硬脂酸镁3g
制备工艺:取实施例1的迷迭香石油醚提取物过100目筛,加淀粉、硬脂酸镁混合均匀,制成颗粒,干燥,装胶囊,即得。
迷迭香石油醚提取物的软胶囊
迷迭香石油醚提取物10mg,大豆卵磷脂100g
制备工艺:取实施例1的迷迭香石油醚提取物,加大豆软磷脂,胶体磨混匀,抽真空,压制,即得软胶囊。
迷迭香石油醚提取物的冻干粉:
迷迭香石油醚提取物2.0g,亚硫酸钠4.0g,乙醇50ml,加水定容至1000mL;
制备工艺:取实施例1的迷迷迭香石油醚提取物分散在乙醇中,亚硫酸钠溶于水中,在超声或搅拌条件下将拿硫酸钠溶液逐渐加入,使成澄清透明溶液;补加水定容至足量;经0.22μM微孔滤膜过滤,冷冻干燥得到。
取迷迭香提取物10克,加入1000ml丙二醇和1000ml注射用水,搅拌溶解,过滤,灭菌,罐装,每支2ml,得迷迭香提取物注射液。
实施例5
迷迭香石油醚提取物的食品制剂
干酵母5g、温水90ml、水少许、面粉150g、迷迭香石油醚提取物5mg,植物油10g、低钠盐少许
饼干做法:把酵母撒在温水里搅拌倒溶化,加入实施例1的迷迭香石油醚提取物。加入面粉搅拌,再加入植物油,揉成光滑的面团;面团制成0.2cm厚的薄片;压出造型,刺洞,表面撒上水,撒上一点低钠盐,室温发酵10分钟;烤箱预热120度,放在上层,烤约10分钟,得含迷迭香石油醚提取物的食品。
实施例6
迷迭香石油醚提取物提取工艺
迷迭香药材10倍量甲醇提取3次,1h/次,合并甲醇提取液,回收甲醇,浸膏加水使溶,加入石油醚,石油醚和水溶液按照1;1萃取三次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
实施例7
迷迭香石油醚提取物提取工艺
迷迭香药材10倍量正丁醇提取3次,1h/次,合并正丁醇提取液,回收正丁醇,浸膏加水使溶,加入石油醚,石油醚和水溶液按照1;1萃取三次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
Claims (8)
1.迷迭香石油醚提取物用于制备治疗或预防糖尿病肾病的组合物。
2.根据权利要求1中的组合物,其特征为:迷迭香石油醚提取物的组分是:鼠尾草酸、鼠尾草酚、迷迭香酚、表迷迭香酚、表异迷迭香酚、鼠尾酸甲酯、Salviol、1-Phenanthrenecarboxylic acid、2-Phenanthrenemethanol。
3.根据权利要求1中的组合物,其特征为:迷迭香石油醚提取物的组分是:迷迭香酚,鼠尾草酚,鼠尾草酸,鼠尾酸甲酯,Salviol。其相对质谱峰面积比值为:2.23∶10.12∶39.64∶2.93∶32.32。
4.根据权利要求1中的组合物,其特征为:
用于制备防治糖尿病肾病的组合物,迷迭香石油醚提取物的含量范围是1mg-2g/kg。
5.根据权利要求1中的组合物,其特征为:药物、保健品、或功能性食品,赋形剂或载体为制药或食品领域中常用的赋形剂或载体,如稀释剂,崩解剂,润滑剂等。
6.根据权利要求1中的组合物,其特征为:
迷迭香石油醚提取物的制备方法是:醇提取迷迭香药材,用水溶解醇提取物,用石油醚萃取水溶液,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
7.根据权利要求1中的组合物,其特征为:
迷迭香石油醚提取物的制备方法是:
迷迭香药材用乙醇提取,合并95%乙醇提取液,回收乙醇,浸膏加水使溶,加入石油醚,石油醚和溶液萃取多次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
迷迭香药材用甲醇提取,合并甲醇提取液,回收甲醇,浸膏加水使溶,加入石油醚,石油醚和溶液按照萃取多次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
迷迭香药材用正丁醇提取,合并正丁醇提取液,回收正丁醇,浸膏加水使溶,加入石油醚,石油醚和溶液萃取多次,合并石油醚层,回收石油醚得迷迭香石油醚提取物。
8.根据权利要求1中的组合物,其特征为:用于治疗糖尿病肾病,诊断糖尿病肾病的标志是糖尿病患者尿白蛋白***率持续升高20~200μg/min,或尿微量白蛋白与尿肌酐比值为30~300μg/mg。
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CN112618586A (zh) * | 2020-12-29 | 2021-04-09 | 温州医科大学 | 菜头肾总酚酸提取物的应用 |
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CN112618586A (zh) * | 2020-12-29 | 2021-04-09 | 温州医科大学 | 菜头肾总酚酸提取物的应用 |
CN112618586B (zh) * | 2020-12-29 | 2021-12-28 | 温州医科大学 | 菜头肾总酚酸提取物的应用 |
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