CN110664796B - 百里香酚异丁酸酯在制备降血脂药物中的应用 - Google Patents
百里香酚异丁酸酯在制备降血脂药物中的应用 Download PDFInfo
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Abstract
本发明公开了百里香酚异丁酸酯在制备降血脂药物中的应用,属于降血脂药物技术领域。本发明提供了一种百里香酚异丁酸酯在制备降血脂药物中的应用,所述百里香酚异丁酸酯为8,9‑环氧‑10‑异丁氧基百里香酚异丁酸酯,具有安全性高、降脂作用好的性能,可应用于预防和辅助治疗肥胖、酒精性脂肪肝、非酒精性脂肪肝、2型糖尿病、代谢综合征、冠心病、动脉粥样硬化疾病的药品、食品或功能食品。
Description
技术领域
本发明涉及百里香酚异丁酸酯在制备降血脂药物中的应用,属于降血脂药物技术领域。
背景技术
高脂血症是由于脂肪转运或代谢异常所致的血浆或血清中一种或者多种脂质高于正常范围内的全身性疾病,具体表现为甘油三酯、总胆固醇、低密度脂蛋白胆固醇异常升高,是一种常见的慢性疾病。现有研究表明,高脂血症可导致脂肪肝、肝硬化、胰腺炎、眼底出血、周围血管疾病、高尿酸血症等疾病。此外,高脂血症还是冠心病、脑卒中、心肌梗死、脑梗死、高血压、糖耐量异常、糖尿病、动脉粥样硬化发生、发展的重要危险因素(McFarlane SI,Jacober S J,Winer N,et al.Control of cardiovascular risk factors inpatients with diabetes and hypertension at urban academic medical centers[J].DIABETES CARE,2002,25(4):718-723.)。因此,防治高脂血症是预防相关慢性疾病的重要环节。
目前,高脂血症的治疗包括药物治疗、手术治疗、基因免疫疗法及保健性产品降血脂治疗等四个方面。高脂血症的药物治疗是目前临床上的主要治疗手段,其疗效确切、适用性广泛,常用的化学药物是他汀类、贝特类、烟酸类、树脂类等,但存在一些副作用(Ballantyne C M,Blazing M A,King T R,et al.Efficacy and safety of ezetimibeco-administered with simvastatin compared with atorvastatin in adults withhypercholesterolemia[J].The American Journal of Cardiology,2004,93(12):1487-1494.),例如他汀类药物会造成括肌痛、肌炎、横纹肌溶解等肌病和肝功能受损,烟酸会造成恶心、呕吐,严重时会诱发溃疡和肝脏损伤,还可能会加重痛风和糖尿病的病情(孙昌华.南极磷虾油主要生物学特性及其降血脂机制研究[D].中国农业大学,2019.)。手术与基因免疫疗法虽然取得了部分疗效,但仍处于探索试验阶段。
过量脂肪在多个组织、脏器异位沉积,诱发氧化应激、炎症反应,损伤细胞形态和功能,是脂代谢异常慢性疾病,如肥胖、酒精性脂肪肝、非酒精性脂肪肝、2型糖尿病、代谢综合征、冠心病、动脉粥样硬化等疾病发生、发展的重要因素。现阶段的生活方式干预及针对疾病症状的对抗治疗,远期疗效不佳,难以逆转疾病的发展,凸显开发新型干预策略及防治药物的重要性。从传统药食两用资源中寻找安全、降脂作用好的组分,是发展脂代谢异常慢性疾病干预策略的重要方向之一。
我们研究首次发现8,9-环氧-10-异丁氧基百里香酚异丁酸酯为药食两用植物小黑药(显脉旋覆花,Inula nervosa wall)的主要功效成分,主要存在于小黑药醇提物中低极性部位。研究表明小黑药具有较高的安全性,以2000、4000、8000mg/kg·BW剂量的掺显脉旋覆花干粉饲料饲喂雌雄大鼠90天,结果发现大鼠生长活动状况正常,血液学、血生化学、脏器系数等指标未见有明显异常,病理组织学检查未发现对大鼠造成的病理性损伤(刘敏,胡嘉想,徐晓静,樊丽惠,秦光和,景箫.显脉旋覆花的大鼠亚慢性毒性研究[J].毒理学杂志,2012,26(02):156-157.)。有研究表明,显脉旋覆花富含酚类和挥发油成分,其中麝香草酚和百里香酚异丁酸酯为挥发油中的主要成分,由其挥发油研制的云威灵油软胶囊用于治疗风湿痹病(李柯,史蕾喆,陈丹,胡薏冰,卢茂芳,李若存,李顺祥.HPLC测定不同药用部位、产地及采收期显脉旋覆花中麝香草酚和异丁酸百里香酯的含量[J].湖南中医药大学学报,2013,33(07):41-44)。但目前尚未有8,9-环氧-10-异丁氧基百里香酚异丁酸酯降血脂活性的报道。我们的研究首次发现8,9-环氧-10-异丁氧基百里香酚异丁酸酯具有降血脂活性。
发明内容
为了解决上述问题,本发明提供了一种百里香酚异丁酸酯在制备降血脂药物中的应用,具有安全性高、降脂作用好的性能,可应用于预防和辅助治疗肥胖、酒精性脂肪肝、非酒精性脂肪肝、2型糖尿病、代谢综合征、冠心病、动脉粥样硬化疾病的药品、食品或功能食品,具有广阔的经济效益和社会效益。
本发明的第一个目的是提供一种百里香酚异丁酸酯在制备降血脂药物中的应用,所述百里香酚异丁酸酯为8,9-环氧-10-异丁氧基百里香酚异丁酸酯,所述8,9-环氧-10-异丁氧基百里香酚异丁酸酯的结构式为:
在本发明的一种实施方式中,所述应用包括可应用于预防和辅助治疗肥胖、酒精性脂肪肝、非酒精性脂肪肝、2型糖尿病、代谢综合征、冠心病、动脉粥样硬化疾病。
在本发明的一种实施方式中,所述应用为调控细胞脂代谢、氧化应激中的应用。
本发明的第二个目的是提供一种降血脂药物组合物,所述药物组合物包含8,9-环氧-10-异丁氧基百里香酚异丁酸酯,所述8,9-环氧-10-异丁氧基百里香酚异丁酸酯的结构式为:
在本发明的一种实施方式中,所述的药物组合物还包括药物载体和/或药用辅料。
在本发明的一种实施方式中,所述的药物组合物的剂型为医学上认可的任意一种剂型。
本发明的第三个目的是提供一种降血脂药物制剂,所述药物制剂包含8,9-环氧-10-异丁氧基百里香酚异丁酸酯,所述8,9-环氧-10-异丁氧基百里香酚异丁酸酯的结构式为:
在本发明的一种实施方式中,所述制剂包括粉剂、注射液、胶囊、片剂、口服液。
本发明的第四个目的是提供一种辅助调节血脂的膳食补充剂或保健品或食品或饲料,所述膳食补充剂或保健品或食品或饲料的配方包含8,9-环氧-10-异丁氧基百里香酚异丁酸酯,其结构式为:
本发明的第五个目的是提供一种血脂调节剂,所述血脂调节剂的配方包含8,9-环氧-10-异丁氧基百里香酚异丁酸酯,其结构式为:
本发明的有益效果:
与现有技术相比,本发明提供了一种具有降脂作用的小黑药百里香酚酯组合物,具有安全性高、降脂作用好的性能,可应用于预防和辅助治疗肥胖、酒精性脂肪肝、非酒精性脂肪肝、2型糖尿病、代谢综合征、冠心病、动脉粥样硬化疾病的药品、食品或功能食品。通过给予20mg/kg 8,9-环氧-10-异丁氧基百里香酚异丁酸酯,血液中的甘油三酯含量降低53.4%,总胆固醇水平降低11.1%,低密度脂蛋白胆固醇降低33.2%,高密度脂蛋白胆固醇升高98.6%;在细胞中给药1-10μM 8,9-环氧-10-异丁氧基百里香酚异丁酸酯可降低肝细胞内的脂质累积含量,其中给予10μM 8,9-环氧-10-异丁氧基百里香酚异丁酸酯降低脂质累积的效果最好,细胞内脂质累积降低36.4%。
附图说明
图1 8,9-环氧-10-异丁氧基百里香酚异丁酸酯的化学结构式。
图2 8,9-环氧-10-异丁氧基百里香酚异丁酸酯的核磁共振氢谱(400MHz)。
图3 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对游离脂肪酸诱导的HepG2细胞内脂质累积量(A)和细胞内活性氧生成量(B)的影响。
具体实施方式
以下对本发明的优选实施例进行说明,应当理解实施例是为了更好地解释本发明,不用于限制本发明。
实施例1:8,9-环氧-10-异丁氧基百里香酚异丁酸酯的制备
按照下述方法制备得到:
(1)制备小黑药醇提物:100g小黑药干燥根茎采用药材粉碎机(黄城HC-2500Y304,武义海纳电器有限公司)粉碎,过100目筛,按1:20质量体积比加入95%乙醇(分析纯,常州恒光化学试剂有限公司),置超声清洗机(东森DS-100S,深圳市品凰科技有限公司)中进行超声提取1小时,离心取上清液进行旋转蒸发仪(上海亚荣RE-52A,上海亚荣生化仪器厂)减压浓缩至干,得9.5g小黑药乙醇提取物。
(2)提取中低极性部位:取9.0g小黑药乙醇提取物分散于90mL蒸馏水中,按3:1体积比分别加入石油醚、乙酸乙酯(分析纯,常州恒光化学试剂有限公司)进行液液分配萃取,得到中低极性的小黑药石油醚部位0.68g、乙酸乙酯部位1.25g以及水溶性部位6.80g。
(3)提取8,9-环氧-10-异丁氧基百里香酚异丁酸酯:取小黑药乙酸乙酯部位样品(1.25g)与200-300目硅胶(烟台江友硅胶开发有限公司)按质量比1:1拌样后上Rf+Lumen快速色谱仪进行梯度洗脱,洗脱溶剂为100%正己烷→100%乙酸乙酯,洗脱时间为1h,仪器自动收集流分。采用薄层色谱法合并相同的流分,共得到6个流分。对第二个流分(72mg)进行半制备液相色谱仪(沃特斯600型半制备色谱仪)分离,采用80%甲醇等度洗脱,流速为2mL/min,收集保留时间为45min的流分,得到XHY-1 3mg。通过高分辨质谱(瓦里安MAT-212型质谱仪)和核磁共振波谱(400M Hz,Bruker Avance III核磁共振波谱仪)鉴定了XHY-1为8,9-环氧-10-异丁氧基百里香酚异丁酸酯,其结构式和核磁共振氢谱见图1和2。其质谱和核磁数据如下:
C18H24O5,HR-ESI-MS:m/z 321.1696[M+H]+;1H NMR(CDCl3,400MHz,δ,ppm,J/Hz):1.09(3H,d,J=7.6Hz,3′-CH3),1.11(3H,d,J=7.6Hz,4′-CH3),1.32(6H,d,J=7.2Hz,3″,4″-CH3),2.35(3H,s,10-CH3),2.52(1H,sep,J=6.8Hz,H-2′),2.79(1H,d,J=5.3Hz,H-8b),2.85(1H,sep,J=7.2Hz,H-2″),3.03(1H,d,J=5.3Hz,H-8a),4.19(1H,d,J=12.2Hz,H-9b),4.57(1H,d,J=12.2Hz,H-9a),6.87(1H,brs,H-2),7.05(1H,brd,J=7.8Hz,H-6),7.35(1H,d,J=7.8Hz,H-5)。
实施例2:8,9-环氧-10-异丁氧基百里香酚异丁酸酯的调控细胞脂代谢(A)、氧化应激(B)的作用
将摩尔比1:2的油酸钠、棕榈酸钠(Sigma-Aldrich)分别用无脂肪酸牛血清白蛋白(上海翊圣生物科技有限公司)偶联后混合,制得混合游离脂肪酸。将1.2mM混合游离脂肪酸加入到6孔板中预先贴壁生长的人肝癌HepG2细胞(中国科学院典型培养物保藏委员会细胞库)中,在37℃的5%CO2细胞培养箱(Forma,Thermo Scientific)中培养24h,建立游离脂肪酸诱导的脂质累积模型。在建立的细胞模型中,对8,9-环氧-10-异丁氧基百里香酚异丁酸酯(XHY-1)的降低氧化应激作用进行评价,结果见表1和2。实验结果表明,8,9-环氧-10-异丁氧基百里香酚异丁酸酯浓度依赖性地降低细胞内脂质累积、甘油三酯(TG)水平,而对总胆固醇(T-CHO)没有明显影响,细胞内脂质累积量由模型组的640.8%±50.7%显著降低至407.8%±32.9%(正常组为100.57±13.80%),下降比例为36.4%,TG含量由0.148±0.007mmol/g prot显著降低至0.103±0.019mmol/g prot。实验结果表明,8,9-环氧-10-异丁氧基百里香酚异丁酸酯具有良好的降低肝细胞脂质累积、调节氧化应激的效果。
表1 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对游离脂肪酸诱导的HepG2细胞氧化还原稳态的影响
表2 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对游离脂肪酸诱导的HepG2细胞脂代谢的影响
实施例3:8,9-环氧-10-异丁氧基百里香酚异丁酸酯的降体重、降脂作用
40只初始体重30g的4周龄ICR雄性小鼠(上海斯莱克实验动物有限公司)适应性饲喂1周后,随机分为4组,每组10只,分别为正常组CON,高脂组HFD,高脂8,9-环氧-10-异丁氧基百里香酚异丁酸酯干预组HFD+XHY-1。CON组给予正常日粮,并每日灌胃0.2mL生理盐水;HFD给予高脂日粮(江苏省协同医药生物工程有限责任公司),并每日灌胃0.2mL生理盐水;HFD+XHY-1给予高脂日粮(江苏省协同医药生物工程有限责任公司),并每日按20mg/kg体重灌胃8,9-环氧-10-异丁氧基百里香酚异丁酸酯。从第5周开始,HFD组小鼠平均体重超过CON组平均体重130%,表明高脂日粮诱导小鼠肥胖造模成功。于第6周处死各组小鼠,处死前将小鼠称重(表3),取肝脏测定肝重和肝脏内氧化应激水平(表4、5),取血浆测定小鼠血脂(表6)。实验结果表明,给予20mg/kg 8,9-环氧-10-异丁氧基百里香酚异丁酸酯能有效降低肥胖小鼠体重和肝重,在第6周时体重由48.91±0.38g显著降低至43.05±0.26g,肝重由2.19±0.08g显著降低至1.97±0.05g。8,9-环氧-10-异丁氧基百里香酚异丁酸酯能显著改善甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)水平,但对胆固醇(TC)水平无明显影响,甘油三酯水平由4.83±0.74mmol/mg prot显著降低至2.25±0.14mmol/mg prot,下降比例为53.4%,总胆固醇由7.67±0.90mmol/mg prot降低至6.82±0.45mmol/mg pro,下降比例为11.1%,低密度脂蛋白胆固醇由1.84±0.37mmol/mg prot显著降低至1.23±0.30mmol/mg prot,下降比例为33.2%,高密度脂蛋白胆固醇由1.43±0.18mmol/mg prot显著升高至2.84±0.28mmol/mg prot,升高比例为98.6%。8,9-环氧-10-异丁氧基百里香酚异丁酸酯能显著降低肝脏脂质氧化终产物丙二醛(MDA)水平,升高总抗氧化能力(T-AOC)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-px)、过氧化氢酶(CAT)、GSH/GSSG的水平,丙二醛(MDA)水平由12.59±1.41nmol/mg prot显著降低至7.24±0.88nmol/mg prot,总抗氧化能力由6.36±0.27U/mg prot显著升高至7.74±0.59U/mgprot,超氧化物歧化酶由0.50±0.03U/mg prot显著升高至0.60±0.03U/mg prot,过氧化氢酶由17.19±1.54U/mg prot显著升高至19.57±1.05U/mg prot,谷胱甘肽过氧化物酶由443.55±65.76U/mg prot显著升高至628.24±39.60U/mg prot,GSH/GSSG由1.53±0.40显著升高至3.64±0.21。实验表明,8,9-环氧-10-异丁氧基百里香酚异丁酸酯能有效控制高脂饮食小鼠体重和肝重,并改善高脂血症,减缓肝脏氧化应激。
表3 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对高脂饮食小鼠体重的影响
表4 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对高脂饮食小鼠肝脏重量的影响
表5 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对高脂饮食小鼠氧化还原稳态的影响
表6 8,9-环氧-10-异丁氧基百里香酚异丁酸酯对高脂饮食小鼠脂代谢的影响
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (6)
2.根据权利要求1所述的应用,其特征在于,所述应用为预防和辅助治疗肥胖、非酒精性脂肪肝疾病方面的应用。
3.根据权利要求1或2所述的应用,其特征在于,所述应用为调控细胞脂代谢、氧化应激中的应用。
4.根据权利要求1所述的应用,其特征在于,所述的药物还包括药物载体和/或药用辅料。
5.根据权利要求1所述的应用,其特征在于,所述的药物的剂型为医学上认可的任意一种剂型。
6.根据权利要求1所述的应用,其特征在于,所述的药物的制剂包括粉剂、注射液、胶囊、片剂、口服液。
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