CN106349318B - 一种五环三萜化合物在制备治疗肥胖症药物中的应用 - Google Patents
一种五环三萜化合物在制备治疗肥胖症药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种五环三萜化合物在制备治疗肥胖症药物及减肥功能性食品中的应用。所述五环三萜化合物包括长梗冬青苷和救必应酸。该类化合物对脂肪酶有较强的抑制作用,相比于合成药物奥利司作用温和,对胃肠道无刺激作用,适于长期服用。
Description
技术领域
本发明涉及一种治疗肥胖症药物,具体是一类治疗肥胖症药物五环三萜化合物。
背景技术
长梗冬青苷(Pedunculoside)和救必应酸(Rotundic acid)属于五环三萜为化合物,具有近似的分子结构,分子式分别为C36H58O10和C30H48O5,分子量分别为650.84和488.71,可提取自中药救必应(冬青科冬青属植物铁冬青Ilex rotunda Thunb.的干燥树皮),含量较高,也可从其他冬青科冬青属植物中得到,铁冬青植物资源在中国岭南地区较为丰富。
长梗冬青苷和救必应酸等五环三萜化合物有着广泛用途。专利文献CN101961340A公开了长梗冬青苷具有治疗心律失常、心肌缺血、脑缺血等疾病的作用;专利文献CN101856357A公开了救必应酸用于预防和治疗缺血性心脑血管疾病,如心绞痛、心肌梗死、脑梗死的用途。专利文献CN105125567A公开了长梗冬青苷具有一定的抗炎效果;专利文献CN102127142A公开了救必应酸及其衍生物具有抗肿瘤活性;专利文献CN101342186A表明长梗冬青苷或救必应酸具有显著的降血脂作用。同时,文献报道长梗冬青苷服用安全,无溶血性,未见相关不良安全事件目前尚无长梗冬青苷、救必应酸或其衍生物具有治疗肥胖症作用的报道。
肥胖是全球增长最快速的健康问题之一,与高血脂、糖尿病、心脏病等一系列疾病密切相关,但市场上多数抗肥胖药物副作用较多。奥利司他是较为常用的治疗肥胖症药物,为强效的全合成胃肠道脂肪酶抑制剂[Henness S,Perry C M.Orlistat:a review of itsuse in the management of obesity.[J].Drugs,2006,66(12):1625-56],其常见不良反应主要为酶抑制作用较强导致的胃肠道紊乱,表现为油性斑点、胃肠排气增多、脂肪泻等,临床发生率约为26%,且与高脂饮食合用时,发生胃肠道反应概率会增加,少见的不良反应有严重的肝损伤、过敏、代谢和内分泌系统异常等。此外,奥利司他的服用也会减少脂溶性维生素包括维生素K的吸收[訾梅,李祥霞.奥利司他的不良反应及安全应用[J].药物不良反应杂志,2007,9(3):182-185.]。目前,更为安全有效的治疗肥胖症药物或减肥功能性食品有待研究开发。
发明内容
本发明公开了一类五环三萜化合物在制备治疗肥胖症药物中的应用,包括长梗冬青苷和救必应酸在制备治疗肥胖症药物中的应用。
所述五环三萜化合物的结构通式为:
式中,R为COOH、COO―β―D―葡萄糖基或其他药学上可接受的基团,COO―β―D―葡萄糖基的结构为:
当式中的R为COOH时,化合物名为救必应酸(Rotundic acid),当式中R为COO―β―D―葡萄糖基时,化合物名为长梗冬青苷(Pedunculoside)。
本发明包括以上述以一种五环三萜为母核的同类化合物为原料的治疗肥胖症的各种药物制剂。药物剂型包括片剂、胶囊剂、颗粒剂、口服液体制剂和注射剂等。
本发明用于治疗肥胖症的制剂中药用辅料包括赋形剂、防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、崩解剂、填充剂、润滑剂等。具体有羟丙纤维素、羧甲淀粉钠、聚维酮K30、十二烷基硫酸钠、滑石粉、预胶化淀粉、微粉硅胶和硬脂酸镁等。
本发明所述的化合物占药物制剂总质量的1%-99%,优选为50%-70%。
本发明所述的化合物对脂肪酶有较强的抑制作用,可以有效抑制高脂饮食诱导的肥胖症大鼠对脂肪的吸收能力,降低体重增加。据此,本发明表明所述的化合物可用于制备治疗肥胖症的药物制剂或减肥功能性食品,其治疗肥胖症效果涉及由高脂饮食等因素引起的肥胖或体重超标疾病,降低糖尿病、高血脂症等代谢综合症,心血管疾病,肌肉骨骼疾病,非酒精性脂肪肝疾病的风险。且无现有其他减肥药物的副作用。
附图说明
图1最后四周各组脂肪排出比统计图。
具体实施方式
下面结合具体的实施例对本发明做进一步的详细说明,但本发明并不局限于此。
实施例1-3中所采用比例均在50%-70%的优选范围内。
实施例1
片剂的制备:将60g长梗冬青苷与20g预胶化淀粉混合均匀,加入粘合剂50%的乙醇,制软材,过20目筛,制成颗粒,得到的湿颗粒置于75℃烘箱中干燥2h,在颗粒中加入适量微粉硅胶和硬脂酸镁,并混合均匀,压片分装。
实施例2
脂肪酶抑制率测定实验:取100μl猪胰脂肪酶(PL)溶液(5mg/mL)加入20μL不同浓度的待测样品溶液,用pH=7.4的Tris-HCl缓冲液定容至900μl,混匀,于37℃孵育5min,然后加入100μLp-硝基苯基丁酸酯(p-NPB)溶液(10mol/L),充分震荡,迅速转移200μL至96孔酶标板中,用酶标仪测定其在410nm的吸光度数,每1分钟读取一次,至少测定5次(1至15分钟)。每组每个浓度的测定相同操作重复3次,吸光度取平均值。以时间为横坐标,以实验组中吸光度减去相应空白组吸光度的差值为纵坐标作图,计算吸光度差值随时间的变化率K,根据以下公式计算抑制率:
胰脂肪酶抑制率(%)=(K正常组-K实验组)/K正常组×100%
计算得到胰脂肪酶抑制率后,以待测样品最终浓度为横坐标,胰脂肪酶抑制率为纵坐标作图,计算胰脂肪酶抑制率为50%时对应的待测样品的浓度,即抑制剂的半抑制浓度(IC50)。
反应体系中以不加胰脂肪酶溶液为空白对照,不加待测样品溶液为正常对照,长梗冬青苷实验组加入长梗冬青苷溶液最终浓度为2.02、25.32、50.64、71.76、101.28μg/mL,救必应酸实验组加入救必应酸溶液最终浓度为1.95、24.35、48.70、78.20、97.4μg/mL,阳性药物实验组加入奥利司他(orlistat)溶液最终浓度为0.01138、0.1138、0.2276、0.5690、1.138μg/mL。实验结果表明,不同浓度的长梗冬青苷和救必应酸均对胰脂肪酶具有明显的抑制作用,长梗冬青苷的胰脂肪酶半抑制浓度(IC50)为80.83μg/mL,救必应酸的胰脂肪酶半抑制浓度(IC50)为101.28μg/mL,奥利司他的胰脂肪酶半抑制浓度(IC50)为0.53μg/mL。长梗冬青苷和救必应酸是常用中药救必应的主要有效成分,安全可靠,通过文献对比,其抑制脂肪酶能力在天然产物中较强,但相比于合成药物奥利司他较温和,推测其可能在发挥抗肥胖作用的同时,对胃肠道的不良影响较合成药物小,适于长期服用。
实施例3
以一种五环三萜为母核的同类化合物对高脂饮食诱导的大鼠肥胖症的影响:清洁级的Wistar大鼠54只,3至4月龄,体重180g~200g,雄性,购于广东省实验动物中心。基本营养饲料脂肪能量含量为10%,高脂营养饲料脂肪能量含量为45%。以基本营养饲料适应性喂养一周后,小鼠随机分为9组(n=6),分组情况如下:
组1:以基本营养饲料喂养12周,作为正常组。
组2:以高脂营养饲料喂养12周,其中最后4周每日给予等容量0.5%羟甲基纤维素钠溶液灌胃,作为空白对照组。
组3:以高脂营养饲料喂养12周,其中最后4周每日给予10mg·kg-1奥利司他(orlistat)溶液灌胃,作为阳性药物对照组。
组4:以高脂营养饲料喂养12周,其中最后4周每日给予10mg·kg-1长梗冬青苷溶液灌胃,作为长梗冬青苷低剂量组。
组5:以高脂营养饲料喂养12周,其中最后4周每日给予20mg·kg-1长梗冬青苷溶液灌胃,作为长梗冬青苷中剂量组。
组6:以高脂营养饲料喂养12周,其中最后4周每日给予40mg·kg-1长梗冬青苷溶液灌胃,作为长梗冬青苷高剂量组。
组7:以高脂营养饲料喂养12周,其中最后4周每日给予10mg·kg-1救必应酸溶液灌胃,作为救必应酸低剂量组。
组8:以高脂营养饲料喂养12周,其中最后4周每日给予20mg·kg-1救必应酸溶液灌胃,作为救必应酸中剂量组。
组9:以高脂营养饲料喂养12周,其中最后4周每日给予40mg·kg-1救必应酸溶液灌胃,作为救必应酸高剂量组。
高脂饮食诱导的大鼠肥胖症模型,周期为12周。每周对每组大鼠称重,计算大鼠平均体重;测量最后4周每组大鼠摄入食物中的脂肪的质量和排出粪便的脂肪的质量,计算脂肪排出比例。
计算公式为:
大鼠平均体重=该组大鼠体重之和/该组大鼠个体数
脂肪排出比=排出粪便的脂肪的质量/摄入食物中的脂肪的质量×100%
结果表明不同剂量给药的长梗冬青苷与救必应酸均对高脂饮食诱导的肥胖症大鼠的脂肪排出比有显著提高作用,抑制了脂肪的肠道吸收(见图1)。
同时,不同剂量给药的长梗冬青苷与救必应酸对高脂饮食诱导的肥胖症大鼠的体重增加有显著的降低作用,表明长梗冬青苷与救必应酸的实际抗肥胖药效较强,有广阔的应用前景。最后四周平均体重情况见下表:
表1 最后4周各实验组大鼠平均体重(g)
结论:长梗冬青苷与救必应酸对脂肪吸收强度有显著的抑制作用,对肥胖症大鼠体重增加有明显的降低作用。
长梗冬青苷与救必应酸对高脂饮食诱导的肥胖、体重超标疾病有明显的治疗和预防作用,能降低糖尿病、高血脂症等代谢综合症,心血管疾病,肌肉骨骼疾病,非酒精性脂肪肝疾病的风险。
Claims (2)
1.长梗冬青苷在制备治疗由高脂饮食引起的肥胖症药物或减肥功能性食品中的应用。
2.长梗冬青苷在制备抑制胰脂肪酶作用药物中的应用。
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