CN110101707B - 一种用于改善卵巢储备功能减退和预防卵巢早衰的组合物及其应用 - Google Patents
一种用于改善卵巢储备功能减退和预防卵巢早衰的组合物及其应用 Download PDFInfo
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- CN110101707B CN110101707B CN201910409552.0A CN201910409552A CN110101707B CN 110101707 B CN110101707 B CN 110101707B CN 201910409552 A CN201910409552 A CN 201910409552A CN 110101707 B CN110101707 B CN 110101707B
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- levocarnitine
- dehydroepiandrosterone
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- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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Abstract
本发明描述了一种协同组合物及其在制备用于改善女性卵巢储备功能减退(DOR)和预防卵巢早衰的药物或膳食补充剂中的应用。该组合物包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)和左卡尼汀或乙酰左卡尼汀或其可药用盐,相比于现有技术更加安全有效,比单独施用脱氢表雄酮或脱氢表雄酮硫酸酯表现出更优良的效果。
Description
技术领域
本发明涉及改善女性卵巢储备功能减退和预防卵巢早衰的组合物及其应用,特别涉及一种包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)和左卡尼汀或乙酰左卡尼汀或其可药用盐的组合物及其在改善女性卵巢储备功能减退和预防卵巢早衰中的应用。
背景技术
现代女性意愿生育年龄日益延迟以及人们生活环境和社会压力的因素,女性不孕现象也随之日趋严峻。研究表明,女性随着年龄的增长,其卵巢储备功能日益减退,极易发展成卵巢早衰,这进而导致其生育力降低。美国妇产科医师学会临床实践指南指出:年龄大于35岁的妇女是卵巢储备功能减退(DOR)的高危人群。卵巢储备功能是指卵巢内存留卵泡的数量和质量,反映女性的生育能力。卵巢内存留的可募集卵泡数量减少,卵母细胞质量下降导致生育能力降低或过早绝经的倾向成为卵巢储备功能减退(DOR)。女性卵巢功能减退的结局是女性的不孕率和流产率均增加,有调查显示,女性不孕的现象有25%的可以归咎于其卵巢功能的减退。女性卵巢早衰的前期是卵巢储备功能下降,随着病程的进展,最终发生较早的生育力丧失和低雌激素水平,这严重威胁女性的生殖健康,增加女性患骨质疏松和冠心病的风险。因此女性卵巢储备功能低下的早期治疗显得尤其迫切和重要。
辅助生殖技术(ART)使广大不孕不育夫妇的圆子梦成为可能,但是其该技术现在仍面临诸多问题,DOR患者卵巢功能下降导致受孕的成功率不高。如何改善DOR患者的卵巢储备功能、提高胚胎质量,增加可利用的卵子数,是辅助生殖技术(ART)领域的难题。近年来,脱氢表雄酮(DHEA)在DOR患者治疗中的应用引起广泛关注。
Casson PR,Lindsay MS,Pisarska MD,et al.Dehydroepiandrosteronesupplementation augments ovarian stimulation in poor responders:acase series[J].Hum Reprod,2000,15(10):2129-2132.报道5名年龄<41岁的不吸烟的卵巢低反应(POR)的不孕患者预先服用DHEA 2个月后再行卵泡生成激素(FSH)对卵巢的刺激,结果显示与单用FSH刺激卵巢的患者相比,前者血清基础睾酮(T)及硫酸脱氢表雄酮(DHEAS)、人绒毛膜促性腺激素(HCG)、雌二醇(E2)峰值均增加,患者的卵巢反应性增加。
脱氢表雄酮(DHEA)及其硫酸盐(DHEAS)为由肾上腺素与性腺(睾丸、卵巢)分泌的一种类固醇激素,DHEAS是人体血浆中含量最多的皮质类固醇激素,是人体性激素的前体。人体衰老后体内DHEA及DHEAS水平显著降低,同时伴随心血管疾病,肿瘤发病率上升,免疫功能下降。有大量资料显示,人体衰老后补充生理剂量的DHEA,能达到延缓衰老的进程,降低一些相关疾病发病率的作用,在美国已有大量的作为膳食补充剂的DHEA制剂。
自从发现DHEA的这些功效以来,国内外也有大量的研究关于DOR患者应用后DHEA后的报道。有研究报道对于辅助生殖技术治疗中卵巢功能减退的妇女通过脱氢表雄酮(DHEA)补充的预治疗可增加获卵数,改善胚胎质量,提高妊娠率和活产率。但也研究持反对意见的学者认为目前所进行的研究报道试验设计不合理,试验证据尚不充分,DHEA对DOR患者行ART的最终疗效还不明确。
本发明意外的发现,DHEA在与左卡尼汀二者具有协同功效,在联合合应用后,其较单独施用DHEA可以更显著地增强卵巢储备功能,预防卵巢早衰和促进卵巢反应性的功效。目前的临床实践中单独采用DHEA治疗女性的卵巢储备功能低下,尚无DHEA联合左卡尼汀用于治疗卵巢储备下降具有功效更强,疗效更确切的公开报道,因此,本发明为对现有技术的一个重大改进突破。
发明内容
本发明的一个目的是提供一种组合物,包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)和左卡尼汀或乙酰左卡尼汀或其可药用盐。
本发明的另一个目的是提供一种包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)和左卡尼汀或乙酰左卡尼汀或其可药用盐的组合物在制备用于改善女性卵巢储备功能减退和预防卵巢早衰的药物中的应用。
本发明的另一个目的是提供一种包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)和左卡尼汀或乙酰左卡尼汀或其可药用盐的组合物在制备用于改善女性卵巢储备功能减退和预防卵巢早衰的膳食补充剂中的应用。
本发明的另一个目的是提供一种包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)和左卡尼汀或乙酰左卡尼汀或其可药用盐的组合物的制备方法,包括将:
i)脱氢表雄酮或脱氢表雄酮硫酸酯;和
ii)左卡尼汀或其可药用盐,或乙酰左卡尼汀或其可药用盐;
按比例混合,再添加适当的赋形剂,混合均匀后压制成片剂或制成颗粒剂、硬胶囊剂、软胶囊剂或干混悬剂。
在本发明的一个实施例方案中,所述的药物组合物或膳食补充剂组合物包含脱氢表雄酮和左卡尼汀。
在本发明的一个实施例方案中,所述的药物组合物或膳食补充剂组合物包含脱氢表雄酮和乙酰左卡尼汀。
在本发明的一个实施例方案中,所述的药物组合物或膳食补充剂组合物包含脱氢表雄酮硫酸酯和左卡尼汀。
在本发明的一个实施例方案中,所述的药物组合物或膳食补充剂组合物包含脱氢表雄酮和左卡尼汀富马酸盐。
在本发明的一个实施例方案中,所述的药物组合物或膳食补充剂组合物包含脱氢表雄酮硫酸酯和乙酰左卡尼汀。
本发明所述的药物或膳食补充剂组合物,每个制剂单位包含10mg~75mg(以脱氢表雄酮计),优选15~60mg(以脱氢表雄酮计),更优选25mg(以脱氢表雄酮计)的脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS),0.1-2g(以左卡尼汀计),优选0.15-1g(以左卡尼汀计),更优选200mg(以左卡尼汀计)的左卡尼汀或乙酰左卡尼汀或其可药用盐。
本发明所述的药物或膳食补充剂组合物,其剂型可以为片剂、硬胶囊剂、颗粒剂、丸剂、微丸剂、软胶囊剂、滴丸剂、干混悬剂、冲剂,优选硬胶囊剂,软胶囊剂,片剂,颗粒剂,干混悬剂。
本发明的所述的药物或膳食补充剂组合物中可以添加本领域常用的任何赋形剂制备成合适的剂型。所述的赋形剂包括但不限于填充剂、崩解剂、润滑剂、润湿剂、增溶剂、助溶剂、着色剂、黏合剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、增塑剂、表面活性剂等。
在本发明的实施方式中,施用所述的药物或膳食补充剂组合物相比于单独施用脱氢表雄酮或脱氢表雄酮硫酸酯表现出更优良的效果。
具体实施例
以下结合实施例为对本发明作进一步的说明,而并非对本发明的限制。
实施例1脱氢表雄酮和左卡尼汀组合物硬胶囊的制备(10000粒处方)
称取处方量的原料,过80目筛备用,辅料过60目筛备用。配制80%乙醇溶液,备用。将脱氢表雄酮、左卡尼汀、氧化镁、淀粉、羧甲淀粉钠以及十二烷基硫酸钠充分混合均匀。将混粉用上述80%乙醇溶液制软材,过16目筛制粒。将制好的湿颗粒在50℃~60℃下干燥。将干颗粒用16目筛整粒。将处方量的硬脂酸镁加入到已整粒的颗粒中,混合均匀。填装胶囊,每粒内容物含脱氢表雄酮25mg,左卡尼汀200mg。
实施例2脱氢表雄酮和乙酰左卡尼汀软胶囊的制备(10000粒处方)
称取处方量脱氢表雄酮、乙酰左卡尼汀加入到玉米油中搅拌均匀。取规定量的琥珀酰明胶、明胶、甘油、D-山梨醇分散于适量纯化水中,60℃搅拌使溶解,通过使用软胶囊成型机冲裁法制备成软胶囊,每粒内容物含脱氢表雄酮20mg,乙酰左卡尼汀(以左卡尼汀计)150mg。
实施例3脱氢表雄酮硫酸酯和左卡尼汀片剂的制备(10000片处方)
称取处方量的原辅料,原料过80目筛,微晶纤维素、交联羧甲基纤维素钠过60目筛备用。将脱氢表雄酮硫酸酯、左卡尼汀、交联羧甲基纤维素钠、微晶纤维素加入到槽型混合机中,混合20min。将前述原辅料充分混合均匀后,加纯化水,混合10min,过16目筛制粒,将制好的湿颗粒置于40~50℃烘干。将干颗粒用16目筛整粒。将处方量的硬脂酸镁、二氧化硅加入到已整粒的颗粒中,混合均匀。调节压片机进行压片,每片含脱氢表雄酮硫酸酯(以脱氢表雄酮计)30mg,左卡尼汀200mg。
实施例4脱氢表雄酮和左卡尼汀富马酸盐颗粒剂的制备(10000袋处方)
将脱氢表雄酮、左卡尼汀富马酸盐、枸橼酸、乳糖过60目筛备用。将聚维酮k30、枸橼酸、乳糖、脱氢表雄酮、左卡尼汀富马酸盐混合均匀,用无水乙醇制软材,过14目筛湿法制粒,湿颗粒于60-65℃干燥。混合、筛分干颗粒,筛除60目筛以下细颗粒,收集10目与60目间中间体颗粒,10目以上颗粒用10目筛整粒后再筛分,合并10目与60目间中间体颗粒,包装,得成品。每袋含脱氢表雄酮30mg,左卡尼汀富马酸盐(以左卡尼汀计)200mg。
实施例5脱氢表雄酮硫酸酯和乙酰左卡尼汀干混悬剂的制备(10000袋处方)
取原辅料,粉碎,分别过200目筛,采用适当的方法干燥,备用;按处方量称取原辅料,采用物理混合法直接混合均匀,过程尽可能迅速,尽量减少水分的进入;将混合均匀后的粉末均匀装入镀铝膜袋中,即得。每袋含脱氢表雄酮硫酸酯(以脱氢表雄酮计)25mg,乙酰左卡尼汀(以左卡尼汀计)300mg。
实施例6 DHEA,DHEA+左卡尼汀对离体大鼠卵巢颗粒细胞增殖活性的影响
卵巢颗粒细胞的增殖活性能反映出卵巢的储备功能,因此本实施例中通过考察离体大鼠卵巢颗粒细胞的增殖活性来考察DHEA,DHEA+左卡尼汀对大鼠卵巢储备功能的影响。
样品溶液的制备:
DHEA(样品1):取适量DHEA溶于少量DMSO,再用生理盐水稀释制成1ml含50mg的溶液。
DHEA+左卡尼汀溶液(样品2):取本发明实施例2中的软胶囊内容物适量溶于少量DMSO,再用生理盐水稀释制成每1ml分别含DHEA 25mg和乙酰左卡尼汀(以左卡尼汀计)187.5mg的溶液。
动物实验:25日龄雌性SD大鼠脱颈处死后无菌摘取大鼠双侧卵巢,破碎使颗粒细胞释放,在高糖DMEM培养液中稀释使分散,1500rpm离心3min,过滤收集颗粒细胞。重悬细胞,将颗粒细胞悬液接种于24孔细胞培养板,每孔50μl,再加150μl高糖DMEM培养液调整细胞浓度至200μl/孔,每组设8个平行孔。将细胞培养板置于37℃,5%CO2培养箱中培养24小时后,每组每孔分别加入生理盐水,样品1溶液及样品2溶液,平行设定对照组(生理盐水组)、样品1组(样品1溶液)和样品2组(样品2溶液),培养20小时后每孔中加入5mg/ml MTT溶液20μl,继续培养4小时,弃上清,每孔中加入120μl DMSO,放置20min,在酶联免疫检测仪上570nm波长下测定各孔吸光度值(A),取平均值,结果见表1。
*p<0.05,**p<0.01vs对照组,Δp<0.05vs样品1组,
实验结果显示样品1和样品2在增强卵巢颗粒细胞增殖活性上与对照组相比有显著性提高,而本发明实施例2提供的组合物(样品2组)较DHEA组(样品1组)在增强卵巢颗粒细胞增殖活性上有显著性提高(p<0.05)。进一步显示出DHEA和左卡尼汀在增强卵巢颗粒细胞增殖活性上良好的协同增效的作用。
实施例7本发明组合物对患卵巢早衰的小鼠的影响
临床早衰小鼠动物模型的建立:
6~8周龄SPF级雌性小鼠50只,适应性饲养1周后,随机分为5组,即正常对照组、模型组、戊酸雌二醇组(0.015mg/),DHEA组和本发明实施例1制备的组合物组。除正常对照组小鼠外,其余各组小鼠颈背部皮下注射等量等时的生理盐水6周,其他各组小鼠颈背部皮下注射D-半乳糖200mg/kg/天,共6周,建立卵巢早衰小鼠模型。
模型建立好后第二天,各组小鼠分别灌胃给予相应药物,每日1次,共28日。正常对照组和模型组等体积蒸馏水(10ml/kg),末次给药后1h,各组小鼠眼眶后静脉丛取血,离心,测定血清雌二醇水平。同时取部分卵巢固定,常规取材,石蜡包埋,制片,染色,封片,在光学显微镜下检视,计数卵巢中各种卵泡和黄体数量。
严格按照E2检测试剂盒说明书的方法采用ELISA法测定各血样中血清E2,结果见表2:
◆◆p<0.01vs正常对照组,*p<0.05,**p<0.01vs模型组,Δp<0.05vs DHEA组
试验结果表明,模型组小鼠E2水平较正常对照组有显著性降低(p<0.01),戊酸雌二醇组、DHEA组和本发明实施例1提供的组合物组小鼠血清E2水平较模型组相比显著性增高(p<0.05,p<0.01),本发明实施例1组合物组小鼠血清E2水平较DHEA组相比显著性增高(p<0.05),显示出更强的提高卵巢早衰小鼠血清E2水平的作用,进一步显示出DHEA和左卡尼汀在预防卵巢早衰中良好的协同增效的作用。
各试验组药物对卵巢早衰小鼠卵巢组织病理的影响,实验结果见表3:
表3各试验组药物对卵巢早衰小鼠卵巢组织病理的影响
◆p<0.05,◆◆p<0.01vs正常对照组,*p<0.05vs模型组,Δp<0.05vs DHEA组
由试验结果可知,模型组小鼠发育中卵泡数、成熟卵泡数和黄体数较正常对照组有显著性下降(p<0.01);各给药组小鼠发育中卵泡数、成熟卵泡数和黄体数较模型组有显著性升高(p<0.05,p<0.01),另外试验结果也显示本发明实施例1提供的组合物较DHEA组小鼠发育中卵泡数、成熟卵泡数和黄体数显著增加(p<0.05),说明明前者具有更好的促进卵巢卵泡发育成熟的作用,也表明DHEA和左卡尼汀联用后在预防卵巢早衰中具有良好的协同增效的作用。
Claims (6)
1.一种组合物在制备用于改善女性卵巢储备功能减退和预防卵巢早衰的药物中的用途,其中所述组合物包含:
i)脱氢表雄酮或脱氢表雄酮硫酸酯;
ii)左卡尼汀或其可药用盐,或乙酰左卡尼汀或其可药用盐;和
iii)一种或多种药学上可接受的赋形剂。
2.根据权利要求1所述的用途,其中所述组合物包含:
i)以脱氢表雄酮计10mg~75mg的脱氢表雄酮或脱氢表雄酮硫酸酯;
ii)以左卡尼汀计0.1g-2g的左卡尼汀或其可药用盐,或乙酰左卡尼汀或其可药用盐;和
iii)一种或多种药学上可接受的赋形剂。
3.根据权利要求1所述的用途,其中所述组合物包含:
i)以脱氢表雄酮计15mg~60mg的脱氢表雄酮或脱氢表雄酮硫酸酯;
ii)以左卡尼汀计0.15g-1g的左卡尼汀或其可药用盐,或乙酰左卡尼汀或其可药用盐;和
iii)一种或多种药学上可接受的赋形剂。
4.根据权利要求1所述的用途,其中所述组合物包含:
i)以脱氢表雄酮计25mg的脱氢表雄酮或脱氢表雄酮硫酸酯;
ii)以左卡尼汀计200mg的左卡尼汀或其可药用盐,或乙酰左卡尼汀或其可药用盐;和
iii)一种或多种药学上可接受的赋形剂。
5.根据权利要求1-4中任一项所述的用途,其中所述组合物制备成的剂型为硬胶囊剂、软胶囊剂、片剂、颗粒剂或干混悬剂。
6.根据权利要求5所述的用途,其中所述组合物的制备方法包括将
i)脱氢表雄酮或脱氢表雄酮硫酸酯;和
ii)左卡尼汀或其可药用盐,或乙酰左卡尼汀或其可药用盐;
按比例混合,再添加适当的赋形剂,混合均匀后压制成片剂或制成颗粒剂、硬胶囊剂、软胶囊剂或干混悬剂。
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