CN109069524A - 用于预防、补救或治疗雌性更年期综合征的包含马钱苷或其衍生物作为活性成分的组合物 - Google Patents
用于预防、补救或治疗雌性更年期综合征的包含马钱苷或其衍生物作为活性成分的组合物 Download PDFInfo
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Abstract
本发明涉及用于预防、补救或治疗雌性更年期综合征的组合物，所述组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。根据本发明的马钱苷能够使绝经期小鼠模型的血液中的雌二醇(17β‑雌二醇，E2)浓度提高，并显示出如下作用：例如，子宫中雌激素受体α表达增加；补救子宫收缩和退化；肝和腹部脂肪组织中脂肪细胞的积累和尺寸减少；以及体重减轻。因此，马钱苷能够补救更年期女性中的如下症状：例如，雌激素缺失、体重增加以及肝和腹部脂肪组织中脂肪积累以及脂肪细胞的尺寸增加。因此，期望将根据本发明的马钱苷和含有其作为活性成分的组合物用作药物组合物，以用于预防和补救更年期症状。
Description
技术领域
本发明涉及用于预防、改善或治疗雌性更年期综合征的组合物，该组合物包含马钱苷(Loganin)、其衍生物或其药学上可接受的盐作为活性成分。
背景技术
雌激素是作为雌性象征的一种代表性激素，是一种重要的雌性激素，该激素通过月经、怀孕和绝经来调节女性的寿命。雌激素是众所周知的雌性激素，其主要由卵巢中的卵泡、黄体和胎盘分泌，是雌酮(E1)、雌二醇(E2)和雌三醇(E3)的总称。其中，在雌激素中雌二醇(E2)显示出最强的活性。
女性的性激素主要与生殖活动有关，其分泌受月经周期的调节。这些由促卵泡激素(FSH)控制。当分泌雌激素时，反馈作用减少促卵泡激素分泌并增加黄体生成素(LH)的分泌。体内使用的雌激素转变为适当的结构，以从肝释放然后通过尿液排出。除雌激素外，孕酮还受黄体生成素调节，并与雌激素密切相关，因此雌激素和孕酮的恰当的平衡是重要的。
雌激素影响广泛的组织和器官，范围从脑到肝和骨骼。特别需要雌激素来维持子宫、泌尿系统、乳房、皮肤和血管的弹性和正常状态(图1)。
女性更年期(又称绝经期)是指基于卵巢的功能，由成熟向老年过渡的时期。更年期年龄根据身体状况、营养状况和分娩数而变化，但统计学上为约50岁。由于预期寿命的延长，绝经期往往略有延迟。更年期的发生开始于围绝经期，在此期间雌激素的量开始减少。在绝经期，雌激素和孕酮的产生非常低，月经完全停止。此外，绝经后期在月经完全停止后约12个月开始(图2)。
当更年期开始时，由卵巢分泌的雌性激素因卵巢功能减退和失常而减少，这导致了各种症状，例如，不规律的月经周期、月经时间和月经量；主要在面部和上身的面部潮红症状；出汗和心不停跳；生殖器官萎缩，例如外阴变得干燥和阴道粘液分泌减少；排尿的频率增加以及排尿时疼痛。此外，可能出现例如头晕、耳鸣、高血压、消化紊乱、头痛、睡眠障碍、记忆力丧失、认知损伤、情绪波动和抑郁等症状。此外，在绝经期期间，钙从骨骼中渗出并使骨骼变弱，这可引起背痛或其它与骨骼相关的疼痛，并且骨骼可容易地断裂。因为雌激素参与刺激子宫中的肌肉并使其发育，雌激素受体由于雌激素减少在子宫组织细胞中显著下降。
雌激素受体由雌二醇(17β-雌二醇，E2)激活并具有雌激素受体α和雌激素受体β两类。在子宫中，相比雌激素受体β，雌激素受体α起更重要的作用，并且在更年期期间，雌激素受体α的显著下降导致子宫的收缩和退化。其还由脂肪组织中的脂肪细胞产生新的雌激素以弥补雌激素缺乏。在此过程中，产生了更多的脂肪细胞并可引起腹部肥胖(图3)。
更年期症状的类型和程度根据个体差异差别很大，从轻微到足以日常生活到严重到足以躺在病床上(图4)。已知大约30％的绝经期女性有严重的症状并有待治疗。关于治疗，使用雌性激素治疗，但是有副作用的报道，并且存在骨密度持续降低并且需要治疗骨质疏松的一些情况。另一方面，保健功能食品如白首乌(cynanchi wilfordii radix)复方提取物和石榴浓缩物或对骨骼健康有益的钙、维生素D和异黄酮也用于缓解绝经期症状，但它们的效果有限。因此，需要开发更有效地预防、改善和治疗女性更年期症状的药物制剂或保健功能食品。
发明内容
技术问题
本发明提供了用于预防、改善或治疗雌性更年期综合征的组合物，所述组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分，更具体而言，提供了用于预防、改善和治疗雌激素减少、体重增加、肝和腹部脂肪组织中脂肪积累以及脂肪细胞尺寸增加的组合物。
技术手段
本发明提供了用于预防或治疗雌性更年期综合征的药物组合物，所述药物组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。
此外，本发明提供了用于预防或改善雌性更年期综合征的保健食品组合物，所述保健食品组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。
有益效果
本发明涉及用于预防、改善或治疗雌性更年期综合征的组合物，所述组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。本发明的马钱苷提高了绝经期小鼠模型中雌二醇(17β-雌二醇，E2)的血液浓度，提高了子宫中雌激素受体α的表达水平，改善了子宫收缩和退化，并显示出肝和腹部脂肪组织中脂肪细胞积累和尺寸降低以及体重减轻的作用。马钱苷具有改善绝经期女性雌激素减少、体重增加、肝和腹部脂肪组织中脂肪积累和脂肪细胞尺寸增加的作用。因此，本发明的马钱苷和含有其作为活性成分的组合物有望用作药物制剂，以用于预防和改善与更年期综合征相关的症状。
附图说明
图1示出了雌激素对身体的作用。
图2示出了女性一生中雌激素的水平。
图3示出了腹部脂肪组织中的脂肪细胞积累过程，以弥补雌激素缺乏。
图4示出了雌性更年期综合征的类型和症状。
图5示出了马钱苷的化学式。
图6示出了在向更年期小鼠模型(切除卵巢小鼠)给予10mg/kg/天的马钱苷12周并接着从小鼠的血液中分离血清之后，测量雌性激素雌二醇(E2)(图6a)和孕酮(图6b)的结果，表明马钱苷在抑制更年期的雌性激素降低方面显著有效。
图7示出了在向更年期小鼠模型给予10mg/kg/天的马钱苷12周并接着摘除子宫后，通过子宫切片的免疫组织化学对雌激素受体α基因的mRNA表达水平(图7a)和雌激素受体α蛋白表达水平(图7b)进行测量的结果，表明马钱苷在抑制由更年期引起的子宫组织细胞中雌激素受体α表达水平降低方面显著有效。
图8例示了如下照片：所述照片示出了在向更年期小鼠模型给予10mg/kg/天的马钱苷12周后，摘除子宫的小鼠(图8a)、子宫的H&E染色切片(图8b)和子宫的重量(图8c)的结果，表明马钱苷在抑制由更年期引起的子宫收缩和退化方面显著有效。
图9示出了在向更年期小鼠模型给予10mg/kg/天的马钱苷12周后，测量小鼠体重(图9a)以及从小鼠血液中分离的血清中的胰岛素(图9b)和瘦素(图9c)(其为与脂肪代谢有关的激素)的量的结果，表明马钱苷在抑制由更年期引起的体重增加以及与脂肪代谢有关的激素增加方面显著有效。
图10示出了在向更年期小鼠模型给予10mg/kg/天的马钱苷12周并接着摘除肝和腹部脂肪组织后，小鼠的肝(图10a)和腹部脂肪组织(图10b)的H&E染色的结果，表明马钱苷在抑制由更年期引起的肝中的脂肪堆积以及腹部脂肪组织中的脂肪组织细胞尺寸增加方面显著有效。
具体实施方式
因此，本发明人已发现马钱苷的体内功效并完成了本发明，所述马钱苷对于雌激素降低有效，并改善更年期女性中由此产生的体重增加以及肝和腹部脂肪组织中的脂肪积累和脂肪细胞尺寸增加。
本发明提供了用于预防或治疗雌性更年期综合征的药物组合物，所述药物组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。
特别是，雌性更年期综合征可由雌激素分泌的减少引起，并且雌激素分泌的减少可降低子宫组织细胞中雌激素受体α的表达水平并增加血液中的胰岛素和瘦素蛋白。
特别是，雌性更年期综合征包含热潮红、出汗、失眠、神经过敏、抑郁、头晕、注意力缺乏、短期记忆力损伤、焦虑、记忆力丧失、心悸、肌痛、关节疼痛、皮肤干燥、阴道干燥、阴道萎缩、下尿道萎缩、阴道炎、子宫萎缩、膀胱炎、痢疾、风疹、腹部肥胖、高脂血症、动脉硬化或脂肪肝，但不限于此。
本发明的马钱苷由化学式1表示，分子式为C17H26O10。
化学式1
在本发明中，所述药学上可接受的盐可以是与如下酸产生的酸加成盐：有机酸，所述有机酸选自于由草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸和苯甲酸所组成的组；或无机酸，所述无机酸选自于由盐酸、硫酸、磷酸和氢溴酸所组成的组。
在本发明的组合物为药物组合物的情况中，可将所述药物组合物配制成霜剂、凝胶剂、贴剂、喷雾剂、软膏剂、硬膏剂、洗剂、擦剂、糊剂和巴布剂等。同时，除马钱苷以外，所述药物组合物可包含药学上可接受的载体，上述药学上可接受的载体是常规用于药物制剂的载体，例如乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯橡胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等，但不限于此。此外，所述药物组合物可进一步包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等作为添加剂。
所述药物组合物的给予方法可根据更年期综合征症状的严重程度来确定，通常优选局部给予。所述药物组合物中活性成分的剂量可根据给予途径，疾病的严重程度，患者的年龄、性别和体重而变化，并且可每天给予一次至几次。
此外，本发明提供了用于预防或改善雌性更年期综合征的保健食品组合物，所述保健食品组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。
所述保健食品组合物可以粉剂、颗粒剂、片剂、胶囊剂、糖浆剂、饮料或丸剂的形式提供，并且除活性成分马钱苷以外，所述保健食品组合物可包含其它食品或食品添加剂，并且可根据常规方法适当地使用。可根据其使用目的(例如预防、保健或治疗处理)，恰当地确定要混合的活性成分的量。
可根据所述药物组合物的有效剂量来使用上述保健食品组合物中所含的马钱苷的有效剂量，但是在长期摄入以用于保健和卫生目的或控制健康的情况下，活性成分能够以上述范围及以下的量来使用；并且很明显，由于不存在安全性问题，活性成分能够以上述范围及以上的量来使用。
对保健食品的种类没有特别限制，其实例包括肉类、香肠、面包、巧克力、糖果、点心、糕点、比萨、拉面、其它面条、口香糖、乳制品(包括冰淇淋)、各种汤、饮料、茶、饮品、酒精饮料和维生素复合物等。
实施例
在下文中，将参考以下实施例对本发明进行详细描述。然而，本发明能够以许多不同的形式实施，而不应当限于为了向本发明所属领域的技术人员清楚地说明本发明而在本文中阐述的实施方式。
实施例1更年期动物模型实验概述
在本发明的动物实验中使用的单一测试化合物是马钱苷。马钱苷是环烯醚萜苷，其名称源自马钱科，其化学式为C17H26O10(图5)。马钱苷是一种天然存在的单一化合物，其在马钱子(nux vomica)和山茱萸(Cornus officinalis)中富含。
将10周龄切除卵巢的ddY雌性小鼠(OVX小鼠)用作更年期动物模型，来评价马钱苷的体内功效(8周后卵巢切除，额外饲养2周以恢复状况)。将切开腹部但未进行卵巢切除的小鼠假手术组(正常对照组)用作对照组，并使用OVX小鼠组(其中向切除卵巢的小鼠单独给予生理盐水，阴性对照组)和SrCl2小鼠组(其中以10mg/kg/天的剂量经口注入单一化合物氯化锶(SrCl2)，给予无效化合物的对照组)。10周龄假手术操作的雌性小鼠和切除卵巢的ddY雌性小鼠购自Central Laboratory Animals Co.，并在韩国亚洲大学的实验动物中心的检疫室净化1周后转移到干净的动物养殖区。测量每只小鼠的重量并进行分组分离，使得实验组之间没有统计学上的显著重量差异。为了实验，将马钱苷的测试溶液制备成水溶液，并且为了带入实验室动物中心，通过放射照射专业公司(Soyagreentec Co.,Ltd.)用γ射线照射进行灭菌操作。在测试组中，以10mg/kg/天的剂量经口注入马钱苷12周，并对血液雌激素水平、子宫组织中的雌激素受体α表达水平、子宫尺寸、体重以及肝和腹部脂肪组织的脂肪细胞尺寸进行测量和分析。
实施例2在绝经期雌性模型中马钱苷改善血液雌激素降低的作用
典型的雌性更年期症状导致雌性激素(即雌激素和孕酮)显著降低。在向雌性更年期小鼠模型给予马钱苷12周后，通过ELISA测量了血液中的雌二醇(17β-雌二醇，E2)和孕酮(其均为雌激素)的量。与未进行卵巢切除的正常假手术小鼠相比时，在切除卵巢的OVX小鼠中雌性激素雌二醇(图6a)和孕酮(图6b)显著降低。给予非有效化合物的比较组SrCl2小鼠与OVX小鼠无差异。然而，在马钱苷给予组中，血液中的雌二醇和孕酮的下降水平被显著抑制(图6a和图6b)。统计学分析也显示了功效的显著性(*：P<0.05vs.OVX阴性对照)。为了确认各小鼠组的应激水平，血液中的皮质醇(其为由肾上腺分泌的应激激素)的量高于小鼠假手术组血液中的皮质醇，然而，OVX小鼠组、SrCl2小鼠组和给予马钱苷的小鼠组之间没有显著差异(图6c)。
实施例3在雌性更年期小鼠模型中马钱苷改善子宫组织雌激素受体α表达降低的作用
由于雌激素减少，典型的雌性更年期症状导致子宫组织细胞中雌激素受体的显著降低。雌激素受体由雌二醇(17β-雌二醇，E2)激活并具有雌激素受体α和雌激素受体β两类。在子宫中，相比雌激素受体β，雌激素受体α起到更为重要的作用，并且在更年期期间，雌激素受体α的显著降低导致子宫的收缩和退化。在向更年期小鼠模型给予马钱苷12周并接着摘除子宫后，通过子宫切片的免疫组织化学对雌激素受体α基因的mRNA表达水平和雌激素受体α蛋白表达水平进行分析。与未进行卵巢切除的正常假手术小鼠相比时，在切除卵巢的OVX小鼠中雌激素受体αmRNA(图7a)的表达水平和蛋白水平(图7b)显著降低。给予非有效化合物的比较组SrCl2小鼠与OVX小鼠没有差异。然而，马钱苷给予组显著抑制雌激素受体α的mRNA表达和雌激素受体α蛋白的减少(图7a和图7b)。统计学分析还显示功效的显著性(*：p<0.05vs.OVX阴性对照)。
实施例4在雌性更年期小鼠模型中马钱苷改善子宫收缩和退化的作用
由于雌激素减少，典型的雌性更年期症状导致子宫收缩和退化。在向雌性更年期小鼠模型给予马钱苷12周并接着摘除子宫后，对子宫的形状、尺寸、厚度和重量进行观察。当与未进行卵巢切除的正常假手术小鼠相比时，在切除卵巢的OVX小鼠中子宫小(图8a)，切片的厚度薄(图8b)，并且子宫重量轻(图8c)。给予非有效化合物的比较组SrCl2小鼠与OVX小鼠无差异。然而，在马钱苷给予组中，在子宫的外形和尺寸、H&E染色的子宫切片的厚度及其重量方面的变化被显著抑制(图8a、图8b和图8c)。统计学分析也显示了功效的显著性(*：p<0.05vs.OVX阴性对照)。
实施例5在雌性更年期小鼠模型中马钱苷改善体重增加的作用
由于雌激素减少，典型的雌性更年期症状导致体重增加。在向雌性更年期小鼠模型给予马钱苷12周后，测量小鼠体重的变化并通过ELISA测量胰岛素和瘦素(代谢激素蛋白)的存在。与未进行卵巢切除的正常假手术小鼠相比时，在切除卵巢的OVX小鼠中体重显著增加(图9a)并且胰岛素(图9b)和瘦素(图9c)增加。给予非有效化合物的比较组SrCl2小鼠与OVX小鼠无差异。然而，在马钱苷给予组中，体重增加受到显著抑制(图9a)，并且脂质代谢相关激素胰岛素和瘦素的增加也受到显著抑制(图9b和图9c)。统计学分析也显示了功效的显著性(*：p<0.05vs.OVX阴性对照)。
实施例6在雌性更年期小鼠模型中马钱苷改善肝中的脂肪积累和腹部脂肪组织中的脂肪细胞尺寸增加的作用
通常，当雌激素在雌性更年期降低时，从脂肪细胞产生新的雌激素来弥补雌激素缺乏。在该过程中，产生更多的脂肪细胞，并可导致腹部肥胖。换句话说，肝中的脂肪积累和腹部脂肪组织中的脂肪细胞尺寸增加由胰岛素和瘦素(其是与脂质代谢相关的激素蛋白)的增加引起。在向雌性更年期小鼠模型给予马钱苷12周后，摘除小鼠的肝和腹部脂肪组织，并进行H&E染色。与未进行卵巢切除的正常假手术小鼠相比时，在切除卵巢的OVX小鼠中，肝中的脂肪积累显著增加(图10a)，并且腹部脂肪组织的脂肪细胞的尺寸明显增加(图10b)。给予非有效化合物的比较组SrCl2小鼠与OVX小鼠无差异。然而，在马钱苷给予组中，马钱苷显著抑制由更年期引起的肝中的脂肪积累和腹部脂肪组织中的脂肪细胞尺寸的增加(图10a和图10b)。
Claims (7)
1.一种用于预防或治疗雌性更年期综合征的药物组合物，所述药物组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。
2.如权利要求1所述的用于预防或治疗雌性更年期综合征的药物组合物，其中，所述雌性更年期综合征由雌激素分泌的减少引起。
3.如权利要求2所述的用于预防或治疗雌性更年期综合征的药物组合物，其中，所述雌激素分泌的减少降低了子宫组织细胞中雌激素受体α的表达水平，并增加了血液中的胰岛素和瘦素蛋白。
4.如权利要求1-3中任一项所述的用于预防或治疗雌性更年期综合征的药物组合物，其中，所述雌性更年期综合征选自于由如下所组成的组：热潮红、出汗、失眠、神经过敏、抑郁、头晕、注意力缺乏、短期记忆力损伤、焦虑、记忆力丧失、心悸、肌痛、关节疼痛、皮肤干燥、阴道干燥、阴道萎缩、下尿道萎缩、阴道炎、子宫萎缩、膀胱炎、痢疾、风疹、腹部肥胖、高脂血症、动脉硬化和脂肪肝。
5.一种用于预防或改善雌性更年期综合征的保健食品组合物，所述保健食品组合物包含马钱苷、其衍生物或其药学上可接受的盐作为活性成分。
6.如权利要求5所述的用于预防或改善雌性更年期综合征的保健食品组合物，其中，所述雌性更年期综合征选自于由如下所组成的组：热潮红、出汗、失眠、神经过敏、抑郁、头晕、注意力缺乏、短期记忆力损伤、焦虑、记忆力丢失、心悸、肌痛、关节疼痛、皮肤干燥、阴道干燥、阴道萎缩、下尿道萎缩、阴道炎、子宫萎缩、膀胱炎、痢疾、风疹、腹部肥胖、高脂血症、动脉硬化和脂肪肝。
7.如权利要求5所述的用于预防或改善雌性更年期综合征的保健食品组合物，所述保健食品组合物具有选自于由片剂、胶囊剂、粉剂、颗粒剂、液体和丸剂所组成的组的任一种剂型。
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| CN107213156A (zh) * | 2016-06-23 | 2017-09-29 | 中日友好医院 | 马钱苷在制备预防和治疗抑郁症、焦虑症等精神障碍类疾病药物或保健品中的应用 |
| CN107213156B (zh) * | 2016-06-23 | 2020-02-11 | 中日友好医院 | 马钱苷在制备预防和治疗抑郁症、焦虑症等精神障碍类疾病药物中的应用 |
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| US11116781B2 (en) | 2021-09-14 |
| EP3403656A4 (en) | 2019-09-18 |
| RU2697672C1 (ru) | 2019-08-16 |
| KR101698051B1 (ko) | 2017-01-20 |
| JP6818047B2 (ja) | 2021-01-20 |
| BR112018014254A2 (pt) | 2018-12-18 |
| CA3021083A1 (en) | 2017-07-20 |
| EP3403656A1 (en) | 2018-11-21 |
| AU2017206480A1 (en) | 2018-08-30 |
| US20190000869A1 (en) | 2019-01-03 |
| CA3021083C (en) | 2021-06-15 |
| AU2017206480B2 (en) | 2020-01-23 |
| JP2019503399A (ja) | 2019-02-07 |
| EP3403656B1 (en) | 2023-06-28 |
| WO2017123030A1 (ko) | 2017-07-20 |
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