CN116509878A - 防止卵巢储备功能下降的药物组合物及其应用 - Google Patents
防止卵巢储备功能下降的药物组合物及其应用 Download PDFInfo
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- CN116509878A CN116509878A CN202310714564.0A CN202310714564A CN116509878A CN 116509878 A CN116509878 A CN 116509878A CN 202310714564 A CN202310714564 A CN 202310714564A CN 116509878 A CN116509878 A CN 116509878A
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及用于防止卵巢储备功能下降的药物组合物及其应用。所述药物组合物包含辅酶Q10和隐丹参酮，二者在防止卵巢储备功能下降产生明显的协同增效作用，可以大幅提高预防和治疗卵巢储备功能下降的效果，因此能够大大减少药物用量，从而具有更好的预防治疗效果和安全性。
Description
技术领域
本发明涉及医药领域，具体来说，本发明涉及一种防止卵巢储备功能下降的药物组合物，本发明还涉及所述药物组合物的应用。
背景技术
卵巢储备功能(Ovarian Reservation,OR)是指卵巢皮质区内储存卵子数量和质量的潜能，与女性生育能力密切相关。当卵巢内存留的原始卵泡过早耗尽、卵泡生长障碍及闭锁加速导致卵泡数量减少或卵母细胞质量下降，近而导致生育潜能下降和内分泌功能紊乱时，称之为卵巢储备功能下降(DOR)。DOR临床主要表现为月经稀发、经量减少，甚至闭经、不孕等一系列围绝经期的临床症状，如不尽早干预将逐渐演变成卵巢早衰(prematureovarian failure，POF)，严重影响患者的生殖健康和生活质量。因此，对于DOR患者亟需进行早期干预与预防，保护卵巢功能，提高患者的生活质量和生育功能。
DOR的发生除卵巢功能的生理性衰退外，还与遗传学因素、医源性因素、感染因素、自身免疫性疾病、心理社会因素及不良生活习惯等有关。上述病因可导致基因组DNA突变和表观修饰的改变、端粒缩短和端粒酶活性下降、卵巢微环境的改变(包括卵巢免疫功能的改变、卵巢间质的改变及细胞因子的改变等)、氧化应激损伤、卵泡池的耗竭、卵巢血供受阻等，从而引起DOR；此外，近年来有研究发现，线粒体遗传的异常(包括线粒体数量变化、线粒体DNA片段缺失、突变等)亦可加速卵母细胞的凋亡并导致DOR的发生。
DOR的纳入标准包括：①20岁≤年龄≤40岁；②自然周期双侧卵巢窦卵泡数(AFC)≤5个；③卵泡刺激素(FSH)≥l0mIU/mL或抗苗勒管激素(AMH)≤1.1mIU/mL。排除标准：辅助生殖技术助孕周期数>3、宫腔粘连病史、子宫畸形、子宫内膜异位症、子宫腺肌病、甲状腺和肾上腺功能异常等。
DOR的西医治疗分为非生育期和生育期，非生育期患者主要是补充性激素，改善临床症状，保存患者生育能力；有生育需求的患者则积极试孕或直接应用辅助生殖技术进行助孕治疗，在治疗周期中应用预处理药物如脱氢表雄酮(DHEA)和生长激素(GH)，以及控制性超促排卵(COH)。中医治疗主要是平衡气血阴阳，调理脏腑冲任，补虚泻实。但是，目前中西医治疗DOR的方法各有利弊，西医治疗见效快，但价格昂贵、不良反应和禁忌证较多；中医治疗强调整体观，以补肾为治疗大法，但存在治疗时间长，患者治疗依从性差的缺点。因此，有必要提供更为有效、安全的DOR治疗方法。
发明内容
针对现有技术存在的上述问题，本发明提供了一种用于防止卵巢储备功能下降的药物组合物，其具有改善的防止卵巢储备功能下降的作用。
在本发明的一个方面，本发明提供了一种药物组合物，包含辅酶Q10和隐丹参酮，辅酶Q10和隐丹参酮的重量比为(1-10)：(10-1)。
在一个实施方案中，辅酶Q10和隐丹参酮的重量比为(1-2)：(3-8)。
在一个实施方案中，辅酶Q10和隐丹参酮的重量比为2：4-6，优选为2：5。
在一个实施方案中，所述药物组合物还包含一种或更多种药学上可接受的载体。
进一步，上述药物组合物中，所述其他药学上可接受的载体选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
进一步，上述药物组合物中，作为上述药学上可接受的载体，选自例如水、乳糖、右旋糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、明胶、海藻酸盐、硅酸钙、磷酸钙、纤维素、羟丙基甲基纤维素、羧甲基淀粉钠、糖水、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、十二烷基硫酸钠、甘油、芝麻油、橄榄油、大豆油中的至少一种。
所述药物组合物以单位剂型呈现，所述单位剂型为诸如片剂、丸剂、胶囊剂、散剂、颗粒剂、混悬剂、口服液体剂、气雾剂或液体喷雾剂、滴剂、安瓿、自我注射器装置或栓剂；用于口腔的胃肠外、鼻内、舌下或直肠给药或用于吸入或喷射给药的剂型。优选所述药物剂型为口服制剂，更优选是片剂、丸剂、胶囊剂、颗粒剂、混悬剂、散剂、口服液体剂。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。药学上本发明药物组合物中活性成分的含量应在整个组合物的0.05重量％至90重量％、优选0.1重量％至50重量％范围内。
对于成人患者，本发明化合物能够以口服或非口服的方式将作为1次的给予量的0.001～500mg、1天1次或分为数次来给予。应予说明，该给予量可根据治疗对象的疾病的种类、患者的年龄、体重、症状等适当增减。
本发明另一方面提供了所述药物组合物在制备药物中的应用，所述药物用于：1)预防和/或治疗防止卵巢储备功能下降；或者2)提高卵巢功能。
有益效果
本发明提供了一种用于防止卵巢储备功能下降的药物组合物，所述药物组合物包含辅酶Q10和隐丹参酮。辅酶Q10和隐丹参酮均能在一定程度上提高卵巢功能，本发明发现辅酶Q10和隐丹参酮在防止卵巢储备下降、提高卵巢功能上具有协同增效作用，可以大幅提高预防和治疗卵巢储备功能下降的效果，因此能够大大减少药物用量，从而具有更好的预防治疗效果和安全性。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
下面实施例中的实验方法，如无特殊说明，均为常规方法。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。
实施例1：本发明药物组合物对DOR的效果
1实验方法
取SPF雌性SD大鼠(年龄12周；无出生；体重200±15g)适应性喂养一周后，通过大鼠阴道脱落细胞美兰染色涂片于显微镜下观察大鼠的动情周期，取动情周期正常的大鼠进行实验。除正常对照组外，其余大鼠采用一次性腹腔注射环磷酰胺75mg/kg制备DOR大鼠模型，造模第二天开始于每天上午8点，行大鼠阴道脱落细胞美兰染色涂片，若涂片显示周期延长、紊乱提示造模成功。实验中共有38只大鼠造模成功，从中随机选取32只并进行随机分组，按照下列方案每天灌胃给药，连续给药28d。
表1：动物分组及给药信息表(n＝8)
| 分组 | 每日给药方案 |
| 正常组 | 灌胃生理盐水 |
| 模型组 | 灌胃生理盐水 |
| 辅酶Q10组 | 20mg·kg-1·d-1 |
| 隐丹参酮组 | 50mg·kg-1·d-1 |
| 辅酶Q10+隐丹参酮组 | 辅酶Q1020mg·kg-1·d-1+隐丹参酮50mg·kg-1·d-1 |
2结果采集
第28天给药结束后，乙醚吸入麻醉大鼠，心脏取血，收集血清。用ELISA法检测各组大鼠血清AMH(抗穆勒氏激素)、E2(雌二醇)、FSH(卵泡刺激素)和LH(黄体生成激素)的水平，根据试剂盒(武汉华美公司)说明书进行操作。AMH、E2、FSH、LH水平是反映卵巢储备功能力的指标，AMH、E2水平降低，FSH、LH水平升高与卵巢储备功能降低息息相关。用全波长酶标仪于波长450nm处检测光密度(OD)值，绘制标准化曲线，计算AMH、E2、FSH、LH浓度。称重后处死大鼠，分离大鼠的卵巢、子宫并称重，计算单侧卵巢指数(单侧卵巢重量mg/大鼠体重g)、子宫指数(子宫重量mg/大鼠体重g)。统计学分析采用SPSS26.0软件行统计学分析，数据用均值±标准差表示，同一列数值上不同字母表示存在显著性差异(P<0.05)。结果示于以下表2和表3中：
表2：各组大鼠体重、卵巢指数、子宫指数的比较(n＝8)
表3：各组大鼠血清抗苗勒氏管激素和性激素水平的比较(n＝8)
表2和表3的结果显示，模型组大鼠的体重、卵巢指数显著降低，E2和AMH水平降低，FSH和LH水平增加，差异均有统计学意义，表明建模成功。所述用量的辅酶Q10和隐丹参酮在防止DOR上效果一般，而辅酶Q10和隐丹参酮的组合相比于辅酶Q10和隐丹参酮单独使用，能够更为显著地缓解体重、卵巢指数降低的情况，并且可以显著改善AMH和E2水平降低、FSH和LH水平增加的情况，差异均有统计学意义。这表明辅酶Q10和隐丹参酮在防止DOR上具有协同增效的作用。
实施例2：片剂组合物
制备方法：
第一步辅酶Q10和隐丹参酮过100目筛，其他辅料过80目筛；
第二步称取处方量的辅酶Q10，与处方量的十二烷基硫酸钠、羧甲基淀粉钠混合均匀，用45％乙醇湿润制软材；
第三步加入处方量的乳糖、羟丙基甲基纤维素，混匀，用45％乙醇湿润制软材，整粒；过40目筛；
第四步加入处方量的硬脂酸镁，压片。每片含有20mg的辅酶Q10，50mg的隐丹参酮。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (8)
1.一种药物组合物，包含辅酶Q10和隐丹参酮，辅酶Q10和隐丹参酮的重量比为(1-10)：(10-1)。
2.根据权利要求1所述的药物组合物，其特征在于，辅酶Q10和隐丹参酮的重量比为(1-2)：(3-8)。
3.根据权利要求1所述的药物组合物，其特征在于，辅酶Q10和隐丹参酮的重量比为2：4-6。
4.根据权利要求1所述的药物组合物，其特征在于，辅酶Q10和隐丹参酮的重量比为2：5。
5.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包含一种或更多种药学上可接受的载体。
6.根据权利要求1所述的药物组合物，其特征在于，所述药学上可接受的载体选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
7.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物包括片剂、丸剂、胶囊剂、散剂、颗粒剂、混悬剂、口服液体剂、气雾剂或液体喷雾剂、滴剂、安瓿、自我注射器装置或栓剂。
8.根据权利要求1-7任一项所述的药物组合物在制备药物中的应用，所述药物用于：1)预防和/或治疗防止卵巢储备功能下降；或者2)提高卵巢功能。
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