CN115518093A - 一种具有降血糖作用的中药提取物及其制备方法与应用 - Google Patents
一种具有降血糖作用的中药提取物及其制备方法与应用 Download PDFInfo
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Abstract
本方案公开了中药化学领域的一种具有降血糖作用的中药提取物,所述提取物由艾纳香药材的叶和/或嫩枝经CO2超临界流体萃取得到,其中含有1,2‑二甲基‑1‑甲酸乙酯‑2‑环戊烯。且所述提取物中的1,2‑二甲基‑1‑甲酸乙酯‑2‑环戊烯含量≥25%。制备所述提取物的主要药材艾纳香价格低廉,易获得,且提取物作用于生命体后明显毒副作用,不会引起水肿及体重增加的现象,无其它继发性症状和疾病发生。所述提取物可单独使用于制备降血糖作用的药物、食品或保健品,其降血糖的功能活性强。
Description
技术领域
本发明属于中药化学领域,特别涉及一种具有降血糖作用的中药提取物及其制备方法与应用。
背景技术
糖尿病是一种临床常见病、多发病。糖尿病患者机体中长期的高血糖状态会导致人体各种组织、器官的慢性损害、功能障碍,严重危害生命健康。并且长期用药对患者家庭及国家医保造成极大负担,因此,开发安全性高、疗效好的降糖药物及保健品具有重要的社会价值及经济价值。
虽然随着医疗技术的不断提高,糖尿病的治疗新药不断上市,但糖尿病的发病率在全世界范围内仍呈现上升趋势,其主要原因在于西药的治疗靶点过于单一,无法根治糖尿病,且具有较多的副作用。当前常用的用于治疗糖尿病的西药包括二甲双胍、磺酰脲类、格列奈类、α-糖苷酶抑制剂、胰岛素增敏剂、GLP-1受体激动剂、DPP-4抑制剂、SGLT-2抑制剂和胰岛素及其类似物等。
二甲双胍除了能有效降糖以外,还可降低体重、血压及血脂,具有心血管保护作用,显着改善长期预后,是超重或肥胖糖尿病患者的首选。但其胃肠道反应多见,长期应用可能会影响维生素B12的吸收。
磺酰脲类(例如格列喹酮(糖适平)、格列齐特(达美康)、格列本脲(优降糖)、格列吡嗪(美吡达)和格列美脲(亚莫利)等)疗效突出、价格便宜,是2型糖尿病一线用药,但其容易发生低血糖及体重增加,个别病人会出现皮肤过敏反应、白细胞减少等。
格列奈类(例如瑞格列奈(诺和龙)和那格列奈(唐力))餐时即服,方便灵活,病人依从性好,对于进餐不规律者或老年患者更适用。但其价格较高,使用不当也会引起低血糖。
α-糖苷酶抑制剂(例如阿卡波糖(拜唐平))降糖效果肯定,主要在肠道局部作用,仅2%吸收入血,肝肾等全身副作用少,不增加体重或能减轻体重,单用本药不引起低血糖,对心血管有保护作用,适合于老年糖尿病人和伴有肾功能损害患者。但由于本类药物阻碍碳水化合物在肠道的分解和吸收,使之滞留时间延长,因而导致细菌酵解产气增加。
胰岛素增敏剂(例如罗格列酮(文迪雅、太罗)和吡格列酮(艾可拓))不刺激胰岛素分泌,而是通过增强组织对胰岛素的敏感性来发挥降糖作用。这类药物适用2型糖尿病、糖耐量减低及有代谢综合征,可与双胍类、磺脲类药物或胰岛素合用可进一步改善血糖控制。单独使用不会引起低血糖。但其增加心衰风险,起效较慢,可导致水钠潴留,引起水肿及体重稍增。
GLP-1受体激动剂(例如艾塞那肽(百泌达)和利拉鲁肽(诺和力))除了能够显着降低血糖,还能减轻体重,降低血压、改善β细胞功能。但其半衰期短,有恶心、呕吐等消化道不良反应。价格昂贵,需注射用药,不推荐该药作为一线用药。
DPP-4抑制剂(例如西格列汀(捷诺维)、沙格列汀(安立泽)和维格列汀(佳维乐))增加内源性GLP-1水平,同时改善胰岛α和β细胞功能障碍,具有降糖疗效确切、低血糖风险小、不增加体重、无胃肠道反应,安全性及耐受性高等优点。但DPP-4是一种多效酶,其抑制剂还可能延长生长素释放激素、神经肽Y和P物质等激素的作用,可能产生神经源性炎症、血压升高、促发免疫反应等不良反应。
SGLT-2抑制剂(例如达格列净)极少发生低血糖,并对改善体重和血压有益处。但其可能与鼻咽炎、真菌感染以及泌尿生殖系统感染有关,长期用药的安全性有待于进一步观察。
胰岛素及胰岛素类似物是迄今为止控制血糖最强有力的武器,对肝肾无不良影响,所有不适合用口服降糖药的糖尿病人(如1型糖尿病、孕妇、糖尿病酮症酸中毒、肝肾功能不全患者等等)均可改用胰岛素治疗。早期使用胰岛素还可有助于保护和修复胰岛β细胞功能。但其低血糖风险相对较高,可致体重增加,个别患者注射部位出现皮肤过敏或脂肪萎缩,注射给药给患者带来不便,胰岛素类似物的价格较高。
因此,现有技术中的降血糖西药主要有以下几方面的缺陷:
缺陷一:低血糖风险相对较高。
缺陷二:易引起胃肠道不良反应。
缺陷三:价格昂贵影响药品可及性。
缺陷四:易引起水肿及体重增加。
缺陷五:易引起其它继发性症状和疾病,例如皮肤过敏反应、白细胞减少、心衰、神经源性炎症、血压升高、促发免疫反应、鼻咽炎、真菌感染以及泌尿生殖系统感染。
基于上述原因,需要对降血糖药物进一步研究。中药具有上千年的临床应用历史,在中华民族的繁衍生息过程中发挥的不可磨灭的作用,将中医药用于糖尿病治疗的创新,以解决常见的降血糖药物低血糖风险相对较高、易引起胃肠道不良反应、价格昂贵、易引起水肿及体重增加、易引起其它继发性症状和疾病的问题具有重要社会意义和经济价值。
发明内容
本发明意在提供一种具有降血糖作用的中药提取物,以解决现有技术中常见的降血糖药物低血糖风险相对较高、易引起胃肠道不良反应、价格昂贵、易引起水肿及体重增加、易引起其它继发性症状和疾病的问题。
本方案中的一种具有降血糖作用的中药提取物,所述提取物由艾纳香药材的叶和/或嫩枝经CO2超临界流体萃取得到,其中含有1,2-二甲基-1-甲酸乙酯-2-环戊烯。
且所述提取物中的1,2-二甲基-1-甲酸乙酯-2-环戊烯含量≥25%。
本发明从艾纳香药材中经过CO2超临界流体萃取得到含有1,2-二甲基-1-甲酸乙酯-2-环戊烯的提取物,该提取物可单独使用于制备降血糖作用的药物、食品或保健品,其降血糖的功能活性强,无明显的毒副作用。
所述的提取物与二甲双胍、格列喹酮、格列齐特、格列本脲、格列吡嗪、格列美脲、瑞格列奈、那格列奈、阿卡波糖、罗格列酮、吡格列酮、艾塞那肽、利拉鲁肽、西格列汀、沙格列汀、维格列汀、达格列净、胰岛素和免疫抑制剂中的一种或多种组合后可用于糖尿病患者的治疗。
制备所述提取物的主要药材艾纳香价格低廉,易获得,且提取物作用于生命体后明显毒副作用,不会引起水肿及体重增加的现象,无其它继发性症状和疾病发生。
本发明还提供了一种具有降血糖作用的中药提取物的制备方法,取干燥的艾纳香叶和/或嫩枝,粉粹后装入CO2超临界萃取仪的萃取釜中,设置压力25~35MPa、温度46℃~47℃,用超临界CO2循环萃取80~85min,然后从萃取釜中分离出艾纳香CO2超临界提取物,即得。
通过本方法制备的提取物中,1,2-二甲基-1-甲酸乙酯-2-环戊烯的含量在25%以上。相比其他方法,本方法所制备得到的1,2-二甲基-1-甲酸乙酯-2-环戊烯的含量至少提高5%以上,同时降低了生产成本和提高了提取物的品质。
进一步,所述萃取釜中的压力为30MPa。
进一步,超临界CO2循环萃取的时间为80min。
进一步,所述萃取釜中的压力及温度为:I分压力:7MPa;I分温度:41℃~42℃;II分压力:6MPa;II分温度:44℃~45℃
具体实施方式
下面通过具体实施方式进一步详细说明:
正如背景技术部分所描述的,现有技术中常见的降血糖药物低血糖风险相对较高、易引起胃肠道不良反应、价格昂贵、易引起水肿及体重增加、易引起其它继发性症状和疾病的问题。为了解决上述问题,本发明提供了一种具有降血糖作用的中药提取物,该提取物中含1,2-二甲基-1-甲酸乙酯-2-环戊烯不低于25%。
根据本发明的另一方面,提供了一种上述中药提取物在制备用于治疗糖尿病的药物中的用途。
在一些优选的实施方式中,本文提供的中药提取物和医药用途与现有的常规抗糖尿病药物组合使用。糖尿病疗法的实例包括但不限于胰岛素、饮食管理、二甲双胍、磺酰脲、噻唑烷二酮、二肽基肽酶-4抑制剂、SGLT2抑制剂和胰高血糖素样肽-1类似物。因此,在某些实施方式中,还提供了将上述中药提取物与抗糖尿病药物组合使用,以用于在受试者中促进胰岛细胞生长、促进胰岛素产生和/或用于治疗糖尿病。
在一些优选的实施方式中,本文提供的中药提取物和医药用途与现有常规的一种或多种免疫抑制剂组合使用。因此,在某些实施方式中,还提供了与一种或多种免疫抑制剂组合使用的中药提取物,以用于促进胰岛细胞生长、促进胰岛素产生和/或用于治疗受试者的糖尿病。
中药提取物的制备实施例
【实施例1】一种具有降血糖作用的中药提取物的制备
取干燥的艾纳香叶,粉粹,称取500g,装入CO2超临界萃取仪的萃取釜中,设置压力30MPa、温度46℃,用超临界CO2循环萃取80min,然后从萃取釜(I分压力:7MPa;I分温度:41℃;II分压力:6MPa;II分温度:44℃)中分离出艾纳香CO2超临界提取物,得到提取物8.6g,其中1,2-二甲基-1-甲酸乙酯-2-环戊烯含量为34.6%。
【实施例2】一种具有降血糖作用的中药提取物的制备
取干燥的艾纳香嫩枝,粉粹,称取500g,装入CO2超临界萃取仪的萃取釜中,设置压力25MPa、温度47℃,用超临界CO2循环萃取85min,然后从萃取釜(I分压力:7MPa;I分温度:42℃;II分压力:6MPa;II分温度:45℃)中分离出艾纳香CO2超临界提取物,得到提取物5.9g,其中1,2-二甲基-1-甲酸乙酯-2-环戊烯含量为26.9%。
【实施例3】一种具有降血糖作用的中药提取物的制备
取干燥的艾纳香嫩枝,粉粹,称取500g,装入CO2超临界萃取仪的萃取釜中,设置压力35MPa、温度47℃,用超临界CO2循环萃取85min,然后从萃取釜(I分压力:7MPa;I分温度:42℃;II分压力:6MPa;II分温度:45℃)中分离出艾纳香CO2超临界提取物,得到提取物7.3g,其中1,2-二甲基-1-甲酸乙酯-2-环戊烯含量为32.6%。
中药提取物的降血糖活性实验
实施例1至3中的中药提取物的降血糖活性
1、实验目的:观察实施例1-2配伍的中药提取物在动物模型中的降血糖作用。
2、实验材料:
2.1药物与试剂
2.1.1供试品:各中药提取物根据实施例1~2的方法制备。
2.1.2对照药:罗格列酮钠片,葛兰素史克(天津)有限公司。
2.1.3试剂:血糖试纸为三诺生物传感股份有限公司产品。
2.2实验动物:SPF级C57BL/6J雄性小鼠,来源:北京华阜康生物科技股份有限公司。
2.3给药方法:灌胃给药。
2.4试验方法:
取C57BL/6J小鼠,适应性喂养一周后,随机取15只小鼠作为空白组,并测定小鼠体重、空腹血糖值;其余小鼠禁食24小时(自由饮水),腹腔注射四氧嘧啶130mg/kg造模,自由饮食7天后,测定空腹血糖值,血糖值大于10mmol/L的为造模成功小鼠。选取75只成膜小鼠根据血糖值随机分为5组,每组15只。加之空白组,共6组:(1)空白组;(2)模型组;(3)阳性对照品组(5mg/kg/天);(4)中药提取物实施例1组(80mg/kg/天);(5)中药提取物实施例2组(80mg/kg/天);(6)中药提取物实施例3组(80mg/kg/天);每天灌胃给药1次,连续给药20天。测定小鼠空白血糖值、体重,结果如下表:
表1中药提取物对四氧嘧啶致小鼠糖尿病模型血糖的影响
注:模型组与空白组相比较,###P<0.001;阳性对照组或中药提取物组与模型组比较,*P<0.05。
表1数据结果显示,各中药提取物对四氧嘧啶引起的小鼠血糖升高均具有一定的降低作用,但是实施例1~3组对血糖的降低作用较其他提取物效果更好,与模型组比较(*P<0.05)。其中,实施例1组的降血糖效果最佳,效果甚至好于阳性药物组。
表2中药提取物对四氧嘧啶致小鼠糖尿病模型体重的影响
注:模型组与空白组相比较,##P<0.01,#P<0.05;阳性对照组或中药提取物组与模型组比较,*P<0.05。
表2数据结果显示,造模后小鼠体重对比空白组显著下降(##P<0.01,#P<0.05)。与模型组相比较,中药提取物的实施例1~3组给药30天后对体重的缓解较其他提取物效果更好,与模型组比较(*P<0.05)。其中,中药提取物的实施例1组对体重的缓解最佳,效果甚至好于阳性药物组。
以上所述的仅是本发明的实施例,方案中公知的具体结构及特性等常识在此未作过多描述。应当指出,对于本领域的技术人员来说,在不脱离本发明的前提下,还可以作出若干变形和改进,这些也应该视为本发明的保护范围,这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准,说明书中的具体实施方式等记载可以用于解释权利要求的内容。
Claims (9)
1.一种具有降血糖作用的中药提取物,其特征在于:所述提取物中含有1,2-二甲基-1-甲酸乙酯-2-环戊烯。
2.根据权利要求1所述的一种具有降血糖作用的中药提取物,其特征在于:所述提取物中的1,2-二甲基-1-甲酸乙酯-2-环戊烯含量≥25%。
3.根据权利要求1或2所述的一种具有降血糖作用的中药提取物,其特征在于:所述提取物由艾纳香药材的叶和/或嫩枝经CO2超临界流体萃取得到。
4.根据权利要求3所述的一种具有降血糖作用的中药提取物的制备方法,其特征在于:取干燥的艾纳香叶和/或嫩枝,粉粹后装入CO2超临界萃取仪的萃取釜中,设置压力25~35MPa、温度46℃~47℃,用超临界CO2循环萃取80~85min,然后从萃取釜中分离出艾纳香CO2超临界提取物,即得。
5.根据权利要求4所述的一种具有降血糖作用的中药提取物的制备方法,其特征在于:所述萃取釜中的压力为30MPa。
6.根据权利要求5所述的一种具有降血糖作用的中药提取物的制备方法,其特征在于:超临界CO2循环萃取的时间为80min。
7.根据权利要求4~6中任一项所述的一种具有降血糖作用的中药提取物的制备方法,其特征在于:所述萃取釜中的压力及温度为:I分压力:7MPa;I分温度:41℃~42℃;II分压力:6MPa;II分温度:44℃~45℃。
8.根据权利要求1或2所述的一种具有降血糖作用的中药提取物在制备降血糖的药物、食品或保健品。
9.根据权利要求1或2所述的中药提取物与药物的组合在制备用于治疗糖尿病的药物中的应用,其中所述药物选自二甲双胍、格列喹酮、格列齐特、格列本脲、格列吡嗪、格列美脲、瑞格列奈、那格列奈、阿卡波糖、罗格列酮、吡格列酮、艾塞那肽、利拉鲁肽、西格列汀、沙格列汀、维格列汀、达格列净、胰岛素和免疫抑制剂中的一种或多种。
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