CN116650571A - 代代花提取物在制备治疗糖尿病肾病药物中的用途 - Google Patents
代代花提取物在制备治疗糖尿病肾病药物中的用途 Download PDFInfo
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A—HUMAN NECESSITIES
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- A61K2236/30—Extraction of the material
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Abstract
本发明公开了一种代代花提取物在制备治疗糖尿病肾病药物中的新用途,本发明还公开了一种代代花提取物的纯化方法,属于制药领域。通过建立糖尿病肾病动物模型,发现代代花提取物能够减少尿蛋白,改善动物的肾功能以及肾脏指数等,从而对延缓糖尿病肾病进程发挥很好的疗效,而且该疗效是通过直接作用于肾脏靶器官且与代代花总生物碱的含量密切相关。因此,代代花提取物可用于制备治疗糖尿病肾病的药物,具有疗效好,安全性高等优点。
Description
技术领域
本发明属于制药领域,涉及代代花提取物的制药新用途,尤其是在制备治疗糖尿病肾病药物中的新用途,本发明还涉及一种代代花提取物的纯化方法。
背景技术
糖尿病肾病属于微血管病变,微血管病变是由微循环的障碍以及微血管基底膜增厚引起的,会发生于许多的组织器官,例如视网膜,肾脏以及心脏和神经等。糖尿病微血管病变主要有糖尿病肾病、糖尿病视网膜病变、糖尿病心肌病,以及糖尿病神经病变等,其中最典型的就是糖尿病肾病。
流行病学调查数据显示,2021年我国成年人糖尿病患者高达1.4亿,占全球第一,而糖尿病肾病已取代原发性肾小球疾病成为我国慢性肾脏病的首要病因。糖尿病患者中有30~40%发生糖尿病肾病,是糖尿病引起的危害性最大的一种慢性并发症,主要涉及肾小球病变,肾小球周边部位出现嗜酸性K-W结节(糖尿病性结节性肾小球硬化症),引起蛋白尿、血清肌酐和血清尿素氮水平上升,最终发展成末期肾病而导致肾衰竭甚至死亡。
迄今为止,糖尿病肾病的发病机制尚未阐明,现有的研究表明其发病机制包括糖脂代谢紊乱、血流动力学改变、遗传缺陷、多元醇通路激活、血管内各种因子的表达、氧化应急、炎症反应、足细胞损伤及肾滤过屏障的受损等参与的一系列非常复杂的、渐进性的病理生理反应。目前尚缺乏针对糖尿病肾病致病机理、能有效阻止病情进展的治疗方法。早期以控糖控脂、改善肾脏循环和抗凝等一般性治疗为主,一旦进入中晚期,根据《糖尿病肾病多学科诊治与管理专家共识》,使用肾素-血管紧张素系统抑制剂、改善肾脏微循环药物以及中草药等延缓糖尿病肾病进展,防治心脑血管并发症等,如ACEI或ARB类药物、前列地尔、硫辛酸等药物。但这些药物均有使用禁忌症和副作用,而且对普通糖尿病患者不能延缓肾病进展,还可能增加心血管风险。因此,寻求不仅能够改善糖尿病肾病病情、延缓病情进展而且又安全无毒副作用的治疗手段具有十分重要的意义。
代代花为芸香科植物代代花(CitrusaurantiumL.var.amaraEngl.)的干燥花蕾,见于许多国家的药食之中,具有强心、利尿、镇静等功能,能降低神经系统的兴奋性和脊髓反射机能亢进,用于心功能不全,主治充血性心力衰竭、心脏性水肿和心房纤维性颤动,与溴化银的合用能加强对癫痫病的治疗作用。代代花的主要化学成分包括挥发油、黄酮类、生物碱,还含有强心苷和非强心苷等成分,同时含有丰富的维生素类、人体必需氨基酸以及香豆素类。目前国内外对代代花的研究报道较少,主要集中在黄酮,挥发油及多糖类。据个别文献报道,代代花中生物碱主要成分为辛弗林和N-甲基酪胺,二者具有抗炎、抗菌、抗肿瘤和提高肠胃动力等药理功效。目前,关于代代花提取物尤其是其总生物碱对改善肾功能治疗糖尿病肾病的相关研究尚未见报道。
发明内容
为了更好地利用代代花这一宝贵中草药资源,本发明提供一种代代花提取物在制备治疗糖尿病肾病药物中的新用途,另外,本发明还对代代花提取物中的治疗糖尿病肾病功效成分进行了有效探索,并在此基础上提供了一种代代花提取物的纯化方法。
上述目的是通过以下技术方案实现的:
从糖尿病肾病微血管病变的病理学角度,根据系列试验结果,发现代代花提取物能够减少糖尿病肾病模型的尿蛋白,改善动物模型的肾功能以及肾脏指数等,从而对延缓糖尿病肾病进程发挥很好的疗效,而且该疗效的发挥是通过直接作用于肾脏靶器官且与代代花总生物碱的含量密切相关。
以上试验结果表明,代代花提取物具有改善糖尿病肾病作用,可用于制备治疗糖尿病肾病的药物。
一种代代花提取物的纯化方法,包括以下步骤:
1)将代代花提取物用有机溶剂萃取,收集有机相并挥干,得到初纯化产物;
2)将初纯化产物用乙醇复溶后调pH至酸性,然后上离子交换树脂并用氨水洗脱,收集洗脱液,浓缩,干燥后得到富集总生物碱的代代花提取物。
优选地,所述有机溶剂是乙酸乙酯或正丁醇。
优选地,所述pH为3-5。
优选地,所述离子交换树脂是强酸性阳离子交换树脂。
优选地,所述氨水的体积浓度为2-5%。
优选地,所述洗脱的流速为1-5ml/min。
本发明提供的纯化方法能得到总生物碱含量50%以上的代代花提取物,并且进一步提高了治疗糖尿病肾病的疗效。
在制备这些药物时,可以将代代花提取物按照本领域所熟知的药剂学方法制成适合临床使用的各种制剂,包括片剂、胶囊剂、口服液、注射剂、丸剂等,本发明优选的是口服制剂。另外,还可将代代花提取物作为药食同源物质用于保健食品或功能性食品。
在制备以上所述药物、保健食品或功能性食品时,既可以将代代花提取物单独作为活性成分,也可以与改善糖尿病肾病的其它物质组合后共同作为活性成分,这些添加代代花提取物并将其用于改善糖尿病肾病的制药用途都在本发明的保护范围内。
具体实施方式
下面通过具体实施例对本发明进行详细说明。
实施例1代代花提取物对糖尿病肾病大鼠肾功能的改善作用
申请人通过市售途径购买获得了4个不同厂家、批次的代代花提取物,药效试验前先检测4批次代代花提取物中的活性成分,具体方法如下:
4批代代花提取物的功效成分检测:以芦丁为标准品,采用NaNO2-Al(NO3)3-NaOH比色法测定4种提取物的总黄酮含量;以辛弗林为标准品,采用HPLC法测定4种提取物的总生物碱含量,色谱柱为C18(250*4.6mm,5um),进样体积10ul,流速1ml/min,检测波长275nm,柱温25℃,以乙腈和0.1%磷酸水作为溶剂梯度洗脱,洗脱程序0-25-35-45-50-60min,15-20-20-30-15-15%乙腈。检测结果见表1,总黄酮的含量大小依次为201804<201802<201803<201801,其中201801批次的总黄酮含量最高;总生物碱的含量依次为201801<201802<201804<201803,其中201803批次的总生物碱含量最高。
表1 4种代代花提取物的功效成分含量(%)
201801 | 201802 | 201803 | 201804 | |
总黄酮 | 32.15 | 20.67 | 25.94 | 10.81 |
总生物碱 | 2.93 | 6.27 | 13.61 | 7.86 |
接着,以糖尿病肾病大鼠为模型,观察这4批次代代花提取物对大鼠肾功能(24h尿微量白蛋白、尿白蛋白/肌酐比值、血清肌酐、血清尿素氮)和肾脏指数的影响,具体方法如下:
1.大鼠糖尿病肾病模型的建立以及动物分组与处理
采用大鼠腹腔注射链脲佐菌素(STZ)联合高糖高脂建立糖尿病肾病模型。通过低剂量STZ注射(30mg/kg),避免高剂量STZ所导致的动物死亡,同时也减少了STZ本身的肾毒性所造成的肾脏损害。正常对照组大鼠予腹腔注射等体积柠檬酸缓冲液。
SPF级SD成年雄性大鼠(体重180-230g)适应性喂养1周后,检测其空腹血糖和尿蛋白水平,均为正常值用于实验。用于实验观察的大鼠共72只,自由采食与饮水,其中12只作为正常对照组。STZ造模后连续3周每天尾静脉采血测空腹血糖(FBG),根据文献,连续三次FBG值大于等于16.7mmol/L表明糖尿病模型建立成功。成功构建的糖尿病大鼠模型在STZ处理后4周,将每只大鼠分别放入代谢笼中收集24h尿液,收集尿液前18h禁食,正常饮水,记录总尿量后用全自动生化分析仪测定24h尿微量白蛋白含量,根据文献,24h尿微量白蛋白达到30mg(即排泄率>20μg/min),为大鼠糖尿病肾病模型构建成功。将60只糖尿病肾病大鼠随机分为模型组(12只)和4个给药物(每组12只)。最终每组有8-10只动物纳入统计,试验结果以平均值±标准误表示。
给药组给予相应4种代代花提取物200mg/kg·BW,模型组及正常对照组给予等体积的生理盐水,灌胃体积为1ml/100g体重,每天灌胃一次,连续灌胃8周。最后一次给药后大鼠禁食12h,处死前测血糖、收集晨尿送检,测定24h尿微量白蛋白(mAlb)及24h尿白蛋白/肌酐比值(UACR),三氯乙醛麻醉后腹主动脉采血,取组织,-20℃保存待后续检测血清肌酐(Scr)、血清尿素氮(BUN)及肾脏指数(结果见表2-3)。
2.实验结果
(1)代代花提取物对糖尿病肾病大鼠空腹血糖、24h尿微量白蛋白及24h尿白蛋白/肌酐比值的影响
从表2中可以看出,糖尿病肾病大鼠的空腹血糖(FBG)明显高于正常组(P<0.01),经过8周的给药,4组代代花提取物给药组的大鼠FBG并没有明显降低,表明代代花提取物不能降低糖尿病大鼠的血糖浓度。模型组大鼠的24h尿微量白蛋白(mAlb)及尿白蛋白/肌酐比值(UACR)明显高于正常组,具有统计学差异(P<0.01)。与模型组相比,除201801组外,其他3种提取物均能显著降低mAlb(P<0.05),其中201803组具有极显著差异(P<0.01);同时,4种提取物均能一定程度上降低糖尿病肾病大鼠的UACR值,但只有201803组具有显著差异(P<0.01)。
表2 4种代代花提取物对糖尿病肾病大鼠FBG、mAlb和UACR的影响
注:与正常组比较,**P<0.01;与模型组比较,#P<0.05,##P<0.01。
(2)代代花提取物对糖尿病肾病大鼠血清肌酐、血清尿素氮及肾脏指数的影响
从表3中可以看出,与正常组相比,糖尿病肾病模型组血清肌酐(Scr)显著升高(P<0.01)。与模型组相比,各提取物均能一定程度降低Scr,但只有201803组具有显著差异(P<0.05)。糖尿病肾病模型组(BUN)和肾脏指数显著高于正常组(P<0.05或P<0.01)。各提取物均能降低BUN和肾脏指数,其中201803组具有显著差异(P<0.05)。结果表明代代花提取物能改善肾功能及肾脏指数,且疗效与总生物碱含量二者之间存在量效关系。
表3 4种代代花提取物对糖尿病肾病大鼠肾功能及肾脏指数的影响
注:与正常组比较,*P<0.05,**P<0.01;与模型组比较,#P<0.05。
3.结果分析
1)代代花提取物对糖尿病肾病大鼠模型具有改善作用,对24h尿微量白蛋白、24h尿白蛋白/肌酐比值、血清肌酐、血清尿素氮及肾脏指数均能产生一定影响,但对糖尿病肾病大鼠的空腹血糖没有产生明显作用,表明代代花提取物是直接作用于肾脏靶器官而改善糖尿病肾病。
2)4批提取物的总生物碱含量大小依次是201801<201802<201804<201803,mAlb值恰好也是201801>201802>201804>201803,二者存在明显的量效关系,UACR值以及肾功能、肾脏指数也都存在一定的量效关系,而总黄酮含量与疗效之间则不存在这种关系,由此推断总生物碱是代代花提取物中的关键活性成分,在糖尿病肾病的治疗方面发挥至关重要的作用,提示我们后期可通过纯化代代花总生物碱进一步提高药物疗效。
实施例2代代花总生物碱的纯化及其功效验证
在前期药效学实验的基础上,我们受到启发,即代代花提取物中的总生物碱可能是其发挥糖尿病肾病治疗作用的关键活性成分,为此,我们在本实施例中,以总生物碱含量较高的201803批提取物为原料,对其进行了纯化工艺研究,具体方法如下:
1.提取物的初步纯化
使用本领域所熟知的液相萃取法,去除提取物中的部分难溶性杂质,萃取过程中,我们考察了四种有机溶剂,即80%乙醇、氯仿、乙酸乙酯和正丁醇,有机相干燥后检测总黄酮和总生物碱含量,结果见表4。
表4 4种萃取剂对代代花提取物成分含量的影响(%)
含量% | 乙醇相 | 氯仿相 | 乙酸乙酯相 | 正丁醇相 |
总黄酮 | 27.67 | 26.44 | 29.07 | 28.52 |
总生物碱 | 12.43 | 10.18 | 21.56 | 17.64 |
结果表明,乙醇和氯仿萃取的有机相中总生物碱的含量出现下降,含量低于原料提取物的13.61%,表明二者不适合用于代代花总生物碱的富集;乙酸乙酯和正丁醇有机相中的总生物碱含量提高,且乙酸乙酯相的含量更高,但其中仍含有较高的总黄酮,故拟采用离子交换树脂的方法进一步对其纯化。
2.离子交换树脂纯化
采用强酸性阳离子交换树脂对上述步骤1中的乙酸乙酯相进行纯化,具体方法如下:
方法(1):将乙酸乙酯有机相挥干,用乙醇复溶后调pH=3上强酸性阳离子交换树脂(树脂型号为001ⅹ8型),上样量3倍柱体积,吸附平衡后先用水洗脱5倍柱体积,然后用2%氨水洗脱4倍柱体积,洗脱流速1ml/min,收集2%氨水洗脱液,浓缩,干燥,检测总黄酮和总生物碱含量,结果见表5。
方法(2):将乙酸乙酯有机相挥干,用乙醇复溶后调pH=4上强酸性阳离子交换树脂,上样量2.5倍柱体积,吸附平衡后先用水洗脱5倍柱体积,然后用3%氨水洗脱3倍柱体积,洗脱流速2ml/min,收集3%氨水洗脱液,浓缩,干燥,检测总黄酮和总生物碱含量,结果见表5。
方法(3):将乙酸乙酯有机相挥干,用乙醇复溶后调pH=5上强酸性阳离子交换树脂,上样量2倍柱体积,吸附平衡后先用水洗脱5倍柱体积,然后用5%氨水洗脱2倍柱体积,洗脱流速3ml/min,收集5%氨水洗脱液,浓缩,干燥,检测总黄酮和总生物碱含量,结果见表5。
表5纯化方法对代代花提取物成分含量的影响(%)
含量% | 方法(1) | 方法(2) | 方法(3) |
总黄酮 | 10.81 | 7.17 | 8.05 |
总生物碱 | 50.56 | 61.34 | 53.01 |
结果表明,经阳离子交换树脂纯化,总生物碱得到进一步富集,含量可提高到50%以上,同时总黄酮含量显著下降。在此基础上,我们以方法(2)制备的生物碱提取物为原料进行药效考察,检测其对糖尿病肾病大鼠24h尿微量白蛋白(24h-mAlb)、24h尿白蛋白/肌酐比值(UACR)的影响,实验方法参见实施例1,每组8-10只动物纳入统计,结果见表6。
表6代代花总生物碱提取物对糖尿病肾病大鼠mAlb和UACR的影响
注:与正常组比较,**P<0.01;与模型组比较,#P<0.05,##P<0.01。
结果表明,与模型组相比,代代花总生物碱提取物能显著降低糖尿病肾病大鼠模型的24h尿微量白蛋白和尿白蛋白/肌酐比值,进而改善各项肾功能指标,其疗效相比原料提取物大幅提高,且高剂量组效果最佳,具有明显的剂量依耐性。
Claims (10)
1.代代花提取物在制备治疗糖尿病肾病药物中的用途。
2.如权利要求1所述的用途,其特征在于:代代花提取物能减少糖尿病肾病患者的尿蛋白以及改善肾功能和肾脏指数,从而延缓糖尿病肾病进程,其疗效是通过直接作用于肾脏靶器官且与代代花总生物碱的含量密切相关。
3.如权利要求1所述的用途,其特征在于:所述代代花提取物是代代花的总生物碱提取物。
4.如权利要求3所述的用途,其特征在于:所述总生物碱提取物中含有50%以上含量的总生物碱。
5.一种代代花提取物的纯化方法,其特征在于包括以下步骤:
1)将代代花提取物用有机溶剂萃取,收集有机相并挥干,得到初纯化产物;
2)将初纯化产物用乙醇复溶后调pH至酸性,然后上离子交换树脂并用氨水洗脱,收集洗脱液,浓缩,干燥后得到富集总生物碱的代代花提取物。
6.如权利要求5所述代代花提取物的纯化方法,其特征在于:所述有机溶剂是乙酸乙酯或正丁醇。
7.如权利要求5所述代代花提取物的纯化方法,其特征在于:所述pH为3-5。
8.如权利要求5所述代代花提取物的纯化方法,其特征在于:所述离子交换树脂是强酸性阳离子交换树脂。
9.如权利要求5所述代代花提取物的纯化方法,其特征在于:所述氨水的体积浓度为2-5%。
10.如权利要求5所述代代花提取物的纯化方法,其特征在于:所述洗脱的流速为1-5ml/min。
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