CN110279733B - 一种中药提取物的组合物在制备促进卵巢颗粒细胞增殖药物中的用途 - Google Patents
一种中药提取物的组合物在制备促进卵巢颗粒细胞增殖药物中的用途 Download PDFInfo
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Abstract
本发明公开了槲寄生和积雪草提取物的组合物在制备促进卵巢颗粒细胞增殖进而调节卵巢功能失调药物中的新用途。本发明根据中医药理论和卵巢功能失调和卵巢颗粒细胞生长不足的发病机制，充分利用中药资源，通过大量药理实验，开发出槲寄生提取物和积雪草提取物联用在治疗卵巢功能失调和促进卵巢颗粒细胞增殖中的新用途，并且本发明通过大量实验筛选出活性最强的槲寄生和积雪草提取物的组合物中两者的重量配比，与槲寄生提取物、积雪草提取物单独使用相比，槲寄生提取物与积雪草提取物配伍对卵巢颗粒细胞增殖的作用更好，调节卵巢功能失调活性更强，二者产生协同增效作用，两者配伍作为活性成分制备的治疗卵巢功能失调和卵巢颗粒细胞增殖促进的产品，具有疗效好、副作用小、使用方便等优点。
Description
技术领域
本发明涉及一种槲寄生提取物和积雪草提取物的组合物，具体涉及槲寄生提取物和积雪草提取物的组合物在制备促进卵巢颗粒细胞增殖调节卵巢功能药物中的新用途。
背景技术
卵巢的生理功能包括排卵和内分泌功能，对女性的生殖功能、身心健康及生活质量具有重要意义。卵巢功能失调可致排卵功能障碍、黄体功能异常及内分泌紊乱等，从而引起多种妇科疾病，如子宫发育不良、不孕症、卵巢早衰、围绝经期综合征等，并可影响到全身其它脏器的生理功能。
卵巢是雌性动物生殖系统的重要生殖器官，具有两方面的重要作用，一是产生成熟卵子，二是分泌类固醇激素。颗粒细胞是卵巢的主要功能细胞，也是卵巢所分泌雌激素，孕激素的重要合成场所。颗粒细胞的增殖和分化可作为卵泡发育的标志。颗粒细胞是成熟卵泡中最大的细胞群、女性体内唯一表达的细胞，卵母细胞的代谢都需要通过颗粒细胞满足。通过间隙连接从周围的颗粒细胞媒介中摄取小分子代谢物如能量底物、核苷酸和氨基酸等。
卵巢功能早衰一定程度上意味着闭锁卵泡增多，生长中的卵泡减少。而卵巢颗粒细胞( GC) 作为卵泡中重要的体细胞，是卵泡发育的重要标志，卵巢颗粒细胞的凋亡在调控卵泡生长、卵细胞成熟和雌激素分泌过程中都起到十分重要的作用。
目前，西医在促卵巢颗粒细胞增殖，调节卵巢功能中主要依靠激素替代、促排卵治疗等手段，收到一定疗效，但却存在许多副作用，而中药有多系统、多环节、多靶点的整体调节作用，且其副作用少，在调节卵巢功能方面具有一定的优势。因此很有必要在中医药理论的指导下开发出一种有效物质明确、疗效确切，副作用小、服用方便的治疗卵巢功能失调和促进卵巢颗粒细胞增殖活性的产品。
槲寄生〔Viscum coloratum（Kom.）Nakai〕，为桑寄生科槲寄生属灌木植物，通常寄生于麻栎树、苹果树、白杨树、松树各树木，植物带叶的茎枝可供药用，具有舒筋活络，活血散瘀。用于筋骨疼痛，肢体拘挛，腰背酸痛，跌打损伤。补肝肾，强筋骨，祛风湿，安胎等功效，槲寄生提取物可改善微循环，其总生物碱还具有抗肿瘤作用。
积雪草（Centella asiatica (L.) Urban），为伞形科多年生草本，全草入药，清热利湿、消肿解毒，治痧氙腹痛、暑泻、痢疾、湿热黄疸、砂淋、血淋，吐、血、咳血、目赤、喉肿、风疹、疥癣、疔痈肿毒、跌打损伤等。全草主要含三萜酸和三萜皂甙。三萜有积雪草酸、羟基积雪草酸、异羟基积雪草酸及桦皮酸等。三萜皂甙有积雪草甙、羟基积雪草甙、落得打三糖甙及落得打四糖甙，又谓含参枯甙及异参枯甙。另含山柰素和槲皮素及其甙、积雪草碱、内消旋肌醇、积雪草低聚糖、谷甾醇、维生素C、胡萝卜素、绿色挥发油及树脂状物质。现代药理研究发现积雪草总苷具有抗炎、促进创面愈合、防止疤痕过度增生等作用，主要用于治疗各种皮肤损伤，包括外伤疤痕、消化道溃疡、硬皮病等；另外还有抗泌尿系统感染、诱导肿瘤细胞凋亡等作用。
目前尚未有报道将积雪草提取物和槲寄生提取物用于制备提高卵巢颗粒细胞活性产品的应用。也未出现两者联用的相关报道，两者是否可以联用，联用是否协同增效作用，鲜有人对此进行研究。
发明内容
本发明的目的在于研究槲寄生和积雪草提取物联用提高卵巢颗粒细胞增殖活性的作用，提供一种调节卵巢功能保养卵巢抗卵巢衰老调节卵巢功能的中药组合物，及采用该中药组合物制成的制剂产品等，实现两种中药提高卵巢活性作用的互补，产生协同增效的作用，为开发提高卵巢颗粒细胞增殖活性和调节卵巢功能的产品奠定基础。
技术方案：为了实现以上目的，本发明采取的技术方案为：
槲寄生和积雪草提取物的组合物在制备促进卵巢颗粒细胞增殖药物中的用途。
本发明的第一个方面是提供一种促进卵巢颗粒细胞增殖的中药组合物，其组分包括槲寄生提取物和积雪草提取物，两种中药提取物联用协同促进卵巢颗粒细胞增殖的作用。优选地，所述槲寄生提取物和积雪草提取物的组合物中槲寄生提取物和积雪草提取物的重量比为1∶0.5～4。进一步优选地，所述槲寄生提取物和积雪草提取物中两者的重量比为1∶0.5、1∶1、1∶2或1∶4。
本发明的第二个方面是提供一种促进卵巢颗粒细胞增殖的中药组合物的制备方法，其特征在于所述的槲寄生提取物的制备方法是通过水提取得到的水提物干燥后的固体粉末，提取方法可以为煎煮法，回流提取法等。积雪草提取物的制备方法是通过乙醇提取得到的醇提物干燥后的固体粉末，提取方法可以为煎煮法，回流提取法等；优选浓度为75％的乙醇提取得到的醇提物干燥后的固体粉末，提取方法可以为煎煮法，回流提取法等。
本发明的第三个方面是提供一种促进卵巢颗粒细胞增殖的中药组合物的产品制剂，所述产品制剂的活性成分包括本发明第一个方面提供的中药组合物，或者包括采用本发明第二个方面提供的制备方法制得的中药活性成分。本发明中，所述产品制剂可以根据实际需要为片剂、凝胶、乳膏剂、丸剂、液体制剂、胶囊剂、颗粒剂、冲剂、软胶丸、软胶囊、滴丸剂、喷雾剂、微囊、注射剂、软膏剂或透皮控释贴剂等剂型；根据具体剂型的需要，所述药物制剂还可以包括药学上可接受的辅料。
本发明应用的槲寄生提取物和积雪草组合物作为活性成分和其他调节卵巢功能的中药提取物以及常用辅料配制成滋养卵巢制剂上允许的任意一种剂型。所用的辅料可以采用所述剂型常用辅料，复配所用的其他中药提取物（醇提取或水提物），如菟丝子提取物、续断提取物、人参提取物、地黄提取物、 覆盆子提取物、补骨脂提取物、枸杞提取物、当归提取物等。
本发明的第四个方面是提供如本发明的第一个方面提供的中药组合物、采用本发明的第二个方面提供的制备方法制得的中药活性成分、或本发明的第三个方面提供的药物制剂在制备促进卵巢颗粒细胞增殖药物中的应用。
有益效果：本发明提供的槲寄生和积雪草提取物的组合物在制备促进卵巢颗粒细胞增殖的制剂产品中的应用具有以下优点：
本发明根据卵巢功能失调和卵巢颗粒细胞生长不足的发病机制，充分利用中药资源，通过大量药理实验，开发出槲寄生提取物和积雪草提取物药对在治疗卵巢功能失调和促进卵巢颗粒细胞增殖中的新的用途，并且本发明通过大量实验筛选出活性较强的槲寄生提取物和积雪草提取物组合物中两者的重量配比，与槲寄生提取物、积雪草提取物单独使用相比，槲寄生提取物与积雪草提取物配伍对卵巢颗粒细胞增殖的作用更好，调节卵巢功能失调活性更强，二者产生协同增效作用，两者配伍作为活性成分制备的治疗卵巢功能失调和卵巢颗粒细胞增殖促进的制剂产品，具有疗效好、副作用小、服用方便等优点。
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施方式，进一步阐述本发明。
具体实施方式
以下通过具体实施方式对本发明效果做进一步说明：
实施例1～7：制备中药组合物
取干燥的槲寄生药材粉碎过筛，加入8-10倍量的水浸泡，再热回流提取2个小时，得到的提取液减压浓缩得到的固体干燥后即得槲寄生提取物固体粉末。
取干燥的积雪草药材粉碎过筛，加入8-10倍量的75%乙醇浸泡，再热回流提取2个小时，得到的提取液减压浓缩得到的固体干燥后即得积雪草提取物固体粉末。
中药组合物组样品配制：实施例1～7中槲寄生提取物与积雪草提取物的重量比为1∶0、0∶1、1∶0.25、1∶0.5、1∶1、1∶2和1∶4。
实施例8：槲寄生提取物和积雪草提取物联用促进卵巢颗粒细胞增殖协同增效作用的研究
1 材料
1.1 实验材料
22-27日龄雌性大鼠，实验动物饲养室室温（22±2）℃ ，湿度55%～65% ，光照昼夜交替，通风良好。CO2培养箱，0.22μm微孔滤膜，细胞培养板，净化工作台，酶联免疫检测仪，电子天平，倒置生物显微镜，电热恒温水槽，全自动离心机。
孕马血清促性腺激素( PMSG)，DMEM为美国GIBCO公司产品,小牛血清（DBCS）为JRHbiosciences公司产品；二甲亚砜: 南京化学试剂有限公司；MTT: 噻唑蓝(MTT)由Ultrapuregrade,Amresco分装,临用前用磷酸盐缓冲液(PBS)配制成50mg/LMTT溶液,于4℃冰箱保存；青霉素；链霉素；DMEM-F12培养液。
1.2 实验样品
样品组1-7为实施例1-7。
2 实验方法与步骤
2.1 卵巢颗粒细胞的分离与原代培养
取22-27日龄雌性大鼠（提前48h皮下注射PMSG, 66U/只），常规饲养48 h后颈椎脱臼法处死，无菌摘取大鼠的双侧卵巢，将卵巢破碎使颗粒细胞释放，用2mL含青霉素和链霉素的DMEM-F12培养液中稀释，并轻轻吹打，使其分散成单个细胞。离心过滤收集颗粒细胞。
2.2 卵巢颗粒细胞增殖功能分析
将一定浓度细胞悬液接种于24孔板，每孔80μl，每孔再加120μl培养液调整细胞密度至200μl/孔，每组设6个平行孔。将其置于5% CO2培养箱中培养24h。取CO2培养箱内培养了24 h的颗粒细胞悬液，每孔先后加入造模浓度氯化镉和样品（2 mg·mL-1），平行设定正常对照组（生理盐水）和模型组（氯化镉和生理盐水）。常规培养20 h后于每孔中加入MTT溶液（5mg·mL-1）20 µL继续培养4 h，每孔加入80 µL的三联液，过夜培养，选择570 nm波长，在酶联免疫检测仪上测定各孔吸光度，记录实验结果。采用 SPSS16. 0 统计软件处理数据，组间比较采用 t 检验。P < 0. 05 有统计学意义。
2.3 卵巢颗粒细胞雌孕激素分泌能力分析
样品与对照组处理同方法2.2，过夜培养后，采用放射免疫法（检测细胞悬液上清中雌二醇（E2）和孕酮（P）的含量。
3 实验结果与分析
样品对卵巢颗粒细胞的增殖作用
表1提取物对离体卵巢颗粒细胞的增殖作用（n=6）
| 组别 | 组别 | 标本数 | OD 值 |
| 正常组 | 正常组 | 6 | 0.381±0.026* |
| 模型组 | 模型组 | 6 | 0.345±0.009 |
| 样品组1 | 槲寄生提取物 | 6 | 0.417±0.045** |
| 样品组2 | 积雪草提取物 | 6 | 0.538±0.016** |
| 样品组3 | 槲:积(1:0.25) | 6 | 0.519±0.045** |
| 样品组4 | 槲:积(1:0.5) | 6 | 0.576±0.012** |
| 样品组5 | 槲:积(1:1) | 6 | 0.579±0.022** |
| 样品组6 | 槲:积(1:2) | 6 | 0.626±0.048** |
| 样品组7 | 槲:积(1:4) | 6 | 0.587±0.025** |
*P<0.05，**P<0.01 vs 模型组.
对卵巢颗粒细胞而言，7个样品均具有增殖作用，对于模型组而言均有极显著性差异（p<0.01）。说明槲寄生提取物和积雪草提取物及其组合物均具有促进卵巢颗粒细胞增殖的活性。样品4-7的结果相对于样品1-2，具有更加明显的促进卵巢颗粒细胞增殖作用（P<0.05，具有显著性差异），说明槲寄生提取物：积雪草提取物比例1:0.5、1:1、1:2、1:4比单用槲寄生提取物和积雪草提取物对卵巢颗粒细胞的增殖作用更好，故槲寄生水提物：积雪草醇提物（1:0.5、1:1、1:2、1:4）配伍表现出明显的协同增效作用。
实施例9：槲寄生提取物和积雪草提取物的组合物乳膏
槲寄生提取物1g，积雪草提取物1g，硬脂酸100g，十六醇20g，单硬脂酸甘油酯10g，液体石腊10g，羟苯甲酯0.8g，羟苯丁酯0.2g，甘油140g，氢氧化钾5g，乙醇10g，蒸馏水加至1000g。
实施例10：槲寄生提取物和积雪草提取物的组合物凝胶
槲寄生提取物1g，积雪草提取物1g，PEG400 450g，己二醇80g，吐温8020g，卡波姆30g，乙醇胺6ml，苯甲醇10g，蒸馏水加至1000g。
实施例11：槲寄生提取物和积雪草提取物的组合物胶囊
槲寄生提取物100g，积雪草提取物1g，淀粉80g，羧甲基淀粉钠24g，糊精17g，70％乙醇适量，制成1000粒。
实施例12：槲寄生提取物和积雪草提取物的组合物片
槲寄生提取物1000g，积雪草提取物500g，乳糖55g，可压性淀粉15g，羟丙纤维素10g，硬脂酸镁5g，70％乙醇适量，制成1000片(每片含槲寄生提取物1000mg，积雪草提取物500mg)。
实施例13：槲寄生提取物和积雪草提取物的组合物颗粒剂
槲寄生提取物5g，积雪草提取物10g，乳糖粉800g，硬脂酸镁194g，70％乙醇适量，制成1000克颗粒(每g颗粒制中含积雪草提取物10mg，槲寄生提取物5mg)。
实施例14：槲寄生提取物和积雪草提取物的组合物软胶囊
槲寄生提取物25g，积雪草提取物50g，大豆油10g，明胶5g，甘油5g，蒸馏水7g，制成1000粒(每粒含槲寄生提取物25mg，积雪草提取物50 mg)。
实施例15：槲寄生提取物和积雪草提取物与其他中药配制成乳膏
槲寄生水提取物1g，积雪草醇提取物1g，菟丝子醇提取物3g，续断水提取物2g，人参水提取物2g，醋酸氯已定0.5g，硬脂酸100g，十六醇20g，单硬脂酸甘油酯10g，液体石腊10g，羟苯甲酯0.8g，羟苯丁酯0.2g，甘油140g，氢氧化钾5g，乙醇10g，蒸馏水加至1000g。实施例16：槲寄生提取物和积雪草提取物与其他中药配制成凝胶
槲寄生水提取物1g，积雪草醇提取物1g，菟丝子醇提取物3g，续断水提取物2g，人参水提取物2g，醋酸氯已定0.5g，PEG400 450g，己二醇80g，吐温8020g，卡波姆30g，乙醇胺6ml，苯甲醇10g，蒸馏水加至1000g。
实施例17：槲寄生提取物和积雪草提取物与其他中药配制成乳膏
槲寄生水提取物1g，积雪草醇提取物1g，地黄醇提取物3g，人参水提取物2g，硬脂酸100g，十六醇20g，单硬脂酸甘油酯10g，液体石腊10g，羟苯甲酯0.8g，羟苯丁酯0.2g，甘油140g，氢氧化钾5g，乙醇10g，蒸馏水加至1000g。
实施例18：槲寄生提取物和积雪草提取物与其他中药配制成凝胶
槲寄生水提取物1g，积雪草醇提取物1g，地黄醇提取物3g，人参水提取物2g，醋酸氯已定0.05g，PEG400 450g，己二醇80g，吐温8020g，卡波姆30g，乙醇胺6ml，苯甲醇10g，蒸馏水加至1000g。
实施例19：槲寄生提取物和积雪草提取物与其他中药配制成乳膏
槲寄生水提取物1g，积雪草醇提取物1g，菟丝子醇提取物3g，覆盆子水提取物3g，补骨脂水提取物2g，醋酸氯已定0.5g，硬脂酸100g，十六醇20g，单硬脂酸甘油酯10g，液体石腊10g，羟苯甲酯0.8g，羟苯丁酯0.2g，甘油140g，氢氧化钾5g，乙醇10g，蒸馏水加至1000g。
实施例20：槲寄生提取物和积雪草提取物与其他中药配制成凝胶
槲寄生水提取物1g，积雪草醇提取物1g，菟丝子醇提取物3g，覆盆子水提取物3g，补骨脂水提取物2g，醋酸氯已定0.5g，PEG400 450g，己二醇80g，吐温8020g，卡波姆30g，乙醇胺6ml，苯甲醇10g，蒸馏水加至1000g。
以上对本发明的具体实施例进行了详细描述，但其只是作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
Claims (3)
1.一种中药提取物的组合物在制备促进卵巢颗粒细胞增殖药物中的用途，其特征在于，其组分由槲寄生水提取物和积雪草75％乙醇提取物制成，所述槲寄生水提取物和积雪草75％乙醇提取物的质量比为1∶0.5、1∶1、1∶2或1∶4。
2.根据权利要求1所述的用途，其特征在于所述的药物剂型为权利要求1中任意一项所述的组合物作为活性成分和常用辅料配制成药用制剂允许的任意一种剂型。
3.根据权利要求2所述的用途，其特征在于所述的剂型为片剂、凝胶、乳膏剂、丸剂、胶囊剂、颗粒剂。
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