CN110179811B - 20(R)-人参皂苷Rg3的制备方法及其在制备热应激致生精损伤药物中的应用 - Google Patents
20(R)-人参皂苷Rg3的制备方法及其在制备热应激致生精损伤药物中的应用 Download PDFInfo
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- CN110179811B CN110179811B CN201910608981.0A CN201910608981A CN110179811B CN 110179811 B CN110179811 B CN 110179811B CN 201910608981 A CN201910608981 A CN 201910608981A CN 110179811 B CN110179811 B CN 110179811B
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Abstract
本发明属于医药领域,具体公开了一种20(R)‑人参皂苷Rg3(ginsenoside R‑Rg3,C42H72O13)在制备治疗或预防热应激致生精损伤的药物中的应用。其中,主要R‑Rg3的获得主要是利用二醇型皂苷Rd经酸水解反应制备含有R‑Rg3的组合物,再经传统制备分离而获得高纯度的目标产物。经体内和体外试验研究表明:20(R)‑人参皂苷Rg3在治疗热应激所致生精损伤效果显著,可有效避免因热应激导致的生育障碍等问题,无毒副作用,是一种安全有效,稳定,制备工艺简单,能够治疗热应激的药物,适合工业化生产,易于推广。本发明为治疗和预防环境热应激所致的生精损伤及其系列问题提供了一种新的药物来源。
Description
技术领域:
本发明属于天然药物活性开发的医药技术领域,涉及一种治疗生精损伤的药物或保健品,具体涉及了一种天然化合物—20(R)人参皂苷Rg3的制备方法及在制备治疗或预防环境热应激所致生精损伤药物及保健品方面的新应用。
背景技术
热应激(heat stress,HS)是指一般生物在高温等不利环境条件下发生的应激反应,随着全球环境变暖和人们生活习惯的改变,近年来,男性的精液质量明显下降,男性不育症的发病率逐步上升。然而,人们多关注环境污染物及感染等因素对男性生殖的影响,而对环境温度升高及生活方式改变对男性生殖发育和功能的影响并未受到充分重视。而精子发生是一个温度依赖性的过程,精原细胞对精子的形成及维持精子数量稳定起着决定性的作用,对温度要求极其敏感,据研究表明,男性睾丸温度比核心体温低2-8℃,这对于阴囊内维持精子的发生是最佳条件,也是睾丸生长必需条件之一,即使人体最适温度(37℃)也会通过引起隐睾等影响破坏哺乳动物睾丸中的精子的发生(参见:Kopalli,S.,et al.,Pectinase-treated protects against chronic intermittent heat stress-inducedtesticular damage by modulating hormonal and spermatogenesis-relatedmolecular expression in rats.J Ginseng Res,2017.41(4),578-588;Gat,I.,et al.,Optimal culture conditions are critical for efficient expansion of humantesticular somatic and germ cells in vitro.Fertil.Steril.,2017.107(3),595-605)。
人们普遍认为,桑拿浴可使机体适应类似急性运动所引起的代谢热应激,对机体的免疫功能具有保护作用,在温度适宜(41-43℃)坐浴15-20min,有利于男性健康,这也是目前医学上常用的治疗方法之一;而这些研究没有认识到温度升高对男性生殖的损害作用,有调查结果表明,长期桑拿浴或热水浴的阴囊加热及贴身内衣,电热毯等方式,能显著改变精子参数和线粒体功能,引起精子DNA组装异常,最终损害精子发生,影响男性的生育能力(参见:穆柯瀚,曹博阳,等.短暂轻度阴囊热应激对小鼠睾丸的损害作用.中华疾病控制杂志,2016,20(10),1061-1064+1068;陈小琼,肖国强,等.桑拿浴对人体力竭运动后外周血白细胞计数与分类的影响.体育研究与教育,2013,28(4):123-125;Jurewicz J,RadwanM,Sobala W,et al.Lifestyle and semen quality:role of modifiable riskfactors.Syst Biol Reprod Med,2014,60(1):43-51)。
目前,对于热应激致生精损伤的治疗药物研究较少。近年来,从一些天然药中发现具有良好的抗生精损伤作用,如红参提取物可以抵御环境所带来阴囊热应激的损伤;此外,辣椒素也能够缓解阴囊热应激诱导的生精细胞的氧化损伤和凋亡(参见:Kim,K.J.,etal.,Role of the Red Ginseng in Defense against the Environmental Heat Stressin Sprague Dawley Rats.Molecules,2015.20(11):p.20240-53;Park,S.G.,et al.,Capsaicin attenuates spermatogenic cell death induced by scrotal hyperthermiathrough its antioxidative and anti-apoptotic activities.Andrologia,2017.49(5):e12656)。中药及其天然成分具有服用安全,可靠,无毒副作用,廉价易得,因此,从天然药物中寻找预防和治疗热应激诱导生精细胞损伤具有很好的应用前景。
人参来源于五加科植物人参(Panax ginseng C.A.Meyer),是我国传统特色中草药,被誉为“百草之王”,始载于《神农本草经》。现代药理学证明其具有多重药理活性,包括:抗癌、抗肿瘤,增强肝肾功能,调节神经系统和免疫功能,抗疲劳,抑制衰老等活性。其主要有效成分为人参皂苷类成分。其中人参皂苷Rg3(ginsenoside Rg3)是存在于人参中的一种四环三萜类稀有皂苷,在生晒参中含量很低,经加工后可大量产生(陈爽,等.西洋参发酵前后人参皂苷Rb1、Rg3含量比较研究.人参研究,2017,29(02):28-31;李明晶,等.人参皂苷Rg3的研究进展.中国老年学杂志,2017,37(23):6000-6002.)。
值得注意的是,人参皂苷Rg3天然存在两种构型(S)-Rg3和(R)-Rg3,经大量研究表明,R型药理活性明显强于S型,是目前研究的热点构型,结构如附图1所示。研究亦发现:红参中主要以S构型为主,只存在微量的R构型Rg3,S型Rg3约为R构型的1~3倍(Hee-WonPark,et al.,J Ginseng Res 2013,37,457-467;Jin Yan,et al.,Plant Foods HumNutr,2015,70:141–145;Lee,et al.,J.Ginseng Res.2012,36,102-106);当采用酸水解的时候,R构型为优势构型,转化生成较多,S构型含量远远小于R构型。当采用碱水解的时候,一般很少生成R构型。目前,可通过弱酸水解方法高效制备人参皂苷R构型Rg3已实现了工业化生产,并制成抗癌药物使用,且有新药上市,如亚泰制药生产的“参一胶囊”。同时也有制成抗肿瘤的口服液及注射剂应用于临床。
据报道,CN200710064326.0,公开了人参皂苷Rg1具有生精作用,及其在制备生精产品的用途,并进一步研究其促生精作用的机制,主要是利用Rg1能显著降低睾丸组织内过量的NO,从而保护精子免受NO的破坏并升高血中T的含量,起到生精的作用;CN200710176470.3,公开了人参皂苷Rb1在制备生精产品中的新用途,本发明通过对大鼠注射醋酸棉酚建立大鼠生精障碍模型,以灌胃方式给予不同剂量的人参皂苷Rb1,从而发现Rb1能够明显改善棉酚所致的生精减少,存活率降低,证明Rb1可增加精子数量,提高精子存活率,增强精子的活力作用。上述两个专利仅仅揭示了人参皂苷具有生精作用,通过采用化学药品醋酸棉酚建立生精障碍模型,证明人参皂苷具有生精作用,达到提高生精活力作用,对生精细胞损伤作用机制尚未研究,而且化学性药品在日常生活极为少见,实用性相对较少。
随着全球变暖现象益加重,热应激所引起的一系列问题日益加重,但到目前为止,有关人参皂苷Rg3对阴囊热应激所致生精损伤保护作用尚未报道,本发明创造性的提出并证明了20(R)-Rg3可用于治疗和预防环境热应激所致的生精损伤,与人们生活息息相关,具有很强的实用性。
本发明在通过现代科学技术,开发利用酸处理人参茎叶皂苷方式实现20(R)-人参皂苷Rg3工业化生产的基础上,创造性提出且证明20(R)-人参皂苷Rg3是一种非常有前途和开发价值的生精损伤保护剂,可应用于环境热应激所致的生育障碍等问题,有很好应用前景。且R构型的生精障碍保护活性明显好于S构型。
发明内容
本发明首先提供了20(R)-人参皂苷Rg3(ginsenoside R-Rg3,C42H72O13)在制备治疗和预防环境热应激所致的生精细胞损伤药物或保健食品方面的新应用。
作为本发明的一种实施方案,20(R)-人参皂苷Rg3和20(S)-人参皂苷Rg3在制备用于治疗和预防热应激所致生精损伤药物及保健品中的应用,其中,20(R)-人参皂苷Rg3和20(S)-人参皂苷Rg3的质量比为2:1-3:1。
上述所述药物20(R)-人参皂苷Rg3在制备药物时可与药学上常用载体组合。
本发明所述的人参皂苷Rg3在用于上述用途时,其口服或胃肠外给药,均是安全的,可制成片剂,胶囊剂,散剂,注射剂,软胶囊、丸剂,糖浆剂,颗粒剂和膏剂等。
上述所述的20(R)-人参皂苷Rg3,在制成药物时其含量为1%~98%;优选为30~80%,进一步优选为60%,再进一步优选≥80%。
所述20(R)-人参皂苷Rg3的重量与所述外用制剂的总重量之比为0.01~10:100,优选为0.1~10:100,进一步优选为1~10:100。
上述20(R)-人参皂苷Rg3含量及重量配比是治疗环境热应激所致的生精损伤的有效量优选,也可根据给药途径和制剂的性质、接受者的体重、年龄等一般情况以及所治疗疾病的性质和严重程度进一步优选最佳配比。
上述药物在药学上可接受载体通常是认为可作为药剂的非活性成分,本发明在制备保护生精细胞损伤药物是由有效单体或有效成分与上述固体或液体的赋形剂一起构成的,这里使用的固体或液体的赋形剂在本领域是众所周知的,下面举几个例子,散剂是内服的粉末剂,它的赋形剂有乳糖,淀粉,糊精,碳酸钙,合成或天然硫酸铝,氧化镁,硬脂酸镁,碳酸氢钠,干燥酵母等;溶液剂的赋形剂有水,甘油,1,2-丙二醇,单糖浆,乙醇,乙二醇,聚乙二醇,山梨糖醇等;软膏剂的赋形剂可以使用脂油,含水羊毛脂、凡士林、甘油、蜂蜡、木蜡、液体石蜡等组合成的疏水剂或亲水剂。本发明的药物组合物可以按现有技术中已知的方法如混合、制粒、压片来制备。本发明药物组合物也可以添加包括各种药学使用的任何组分,如香味剂、着色剂、甜味剂等。
特别的是,本发明在应用于治疗生精损伤药物及保健食品时可与其他活性成分(例玄参提取物、麦冬提取物、贝母提取物、薄荷提取物、葡萄籽提取物、植物精油、维生素C及其衍生物或维生素E及其衍生物)组合使用,制备有效的复方药物。
本发明进一步提供了一种R-Rg3的制备方法,采用人参皂苷Rd溶于一定溶度的甲酸溶液中进行反应,优选反应条件为:反应温度95℃,0.1%的甲酸反应3h。
本发明相对于现有技术的有益效果在于:
对实现20(R)-人参皂苷Rg3工业化生产的基础上,发掘了新的药用价值,将其应用于制备治疗和预防环境热应激所致的生精损伤的药物和保健食品方面,本发明的20(R)-人参皂苷Rg3药理作用强,用于缓解、预防和治疗热应激所致的生精损伤功效显著,见效快,可长期服用,安全性好,有良好的药用前景。
同时,所述药物可利用富含人参皂苷的提取物进行酸水解而得到,廉价且容易获得,制备工艺简单,可工业化生产,能制成各种剂型,且服用量少,使用方便,有很强实用性。在应用于制备治疗药物或保健品方面时,既可采用单一成分的20(R)-人参皂苷Rg3活性成分制备生精损伤药物在药学上可接受的任何剂型,又可与其他药食同源活性成分共同组分,制备热应激所致生育障碍的复方药物。
附图说明
附图1.人参皂苷(R)-Rg3化学结构示意图;
附图2.红参中R和S构型Rg3的HPLC分析示意图,A图为红参粉,B图为红参浓缩物;
附图3.热应激诱导生精细胞损伤小鼠睾丸及附睾组织H&E染色示意图。
具体实施方式
本发明的具体实施方式及所获得数据可以通过如下实验例予以支撑,但本发明不局限于此。
实验例1:以人参皂苷Rd为底物制备分离R-Rg3
1.1单因素考察实验
1.1.2酸浓度对反应的影响
精确称取人参皂苷Rd粉末20mg溶于1mL浓度分别为0.05%,0.1%,0.2%的甲酸溶液中,在100℃下反应3h。反应后将样品进行离心,得沉淀和上清浓缩,去部分沉淀甲醇定容于10mL容量瓶中,进行HPLC分析,根据峰面积计算沉淀中稀有人参皂苷Rg3含量,结果如表1所示。由结果可以看出,0.05%时Rg3含量较低,且存在Rd水解不完全的情况,而稀有人参皂苷Rg3的生成量在0.1%的时候呈最大值,且副产物Rk1/Rg5的比值较低,而增加酸浓度,会导致Rk1/Rg5的比值进一步增大,反而Rg3的含量明显减少,原因是酸浓度的增加导致了Rg3继续分解,从而影响了Rg3的产生。
表1不同酸浓度对R-Rg3产生的影响
1.1.2反应时间对R-Rg3产生的影响
精确称取人参皂苷Rb1粉末20mg,分别加入到1mL,0.1%的甲酸溶液中,在100℃下分别转化2h,3h,4h。反应后将样品离心,取相同质量的沉淀用甲醇溶解,定容至10mL,进行HPLC分析,根据产物的峰面积,计算沉淀中Rg3的含量,结果如表2所示,Rg3随时间的增加而增加,在3h时达到最大值,尽管在4h时Rg3产生趋于平稳,但Rk1/Rg5比值却高于3h,故选取3h为最佳时间。
表2反应时间对R-Rg3产生的影响
1.1.3.反应温度对R-Rg3产生的影响
精确称取人参皂苷Rd粉末20mg,分别加到1mL,0.1%的甲酸溶液中,分别在85℃,95℃,105℃反应3h。反应后样品经离心后,选取相同质量的沉淀用甲醇溶解,定容于10mL容量瓶中,进行HPLC分析,根据产物的峰面积,计算沉淀中Rg3含量,结果如表3所示,可以看出,人参稀有皂苷Rg3的生成量随温度的升高呈一定的上升趋势,但在95℃和105℃时差异不大,结合操作的成本和节约的实际情况,反应温度在95℃时最为理想。
表3反应温度对R-Rg3产生的影响
1.2结果分析
结合上述数据分析可知,二醇型人参皂苷Rd能完全转化为稀有皂苷Rg3、Rk1、Rg5等成分,上述单因素反应温度(A),酸浓度(B),反应时间(C)是影响稀有皂苷Rg3生成率的关键因素,通过不同因素对人参皂苷Rg3影响程度的不同,进一步确定最佳工艺条件,从人参皂苷Rg3转化率变化程度来看,综合各个因素对Rg3生成率影响的顺序大致应为:酸浓度>反应温度>反应时间,从而选取最佳人参皂苷Rd高效水解成稀有人参皂苷Rg3反应条件为95℃,0.1%的甲酸反应3h(具体数据略)。
对于上述获得转化物采用传统的硅胶柱层析进行分离获得纯度大于98%的R构型Rg3用于后续分析。
实验例2:R和S构型人参皂苷Rg3对小鼠睾丸间质细胞TM3的保护作用
实验方法参照文献(赵剑,等.过氧化氢诱导TM3细胞氧化应激模型建立,中国公共卫生,2015,31,312-314)具体实验方案略。
如表4所示,实验结果表明:两种构型Rg3按三个剂量分别作用TM3细胞24h,过氧化氢造模剂量为600μM,结果发现:同等剂量下,R构型保护效果明显好于S构型,尤其是高剂量组6μM作用更明显。
根据文献报道及本发明的测试结果(Hee-Won Park,et al.,J Ginseng Res2013,37,457-467;Jin Yan,et al.,Plant Foods Hum Nutr,2015,70:141–145;Lee,etal.,J.Ginseng Res.2012,36,102-106),红参中S构型与R构型Rg3比例约为2:1~3:1之间,如附图2(注:A图为红参粉,B图为红参浓缩物,21号色谱峰为S-Rg3,22号色谱峰为R-Rg3)。
本发明选取二者组合进行体外实验,研究结果表明:单独R构型Rg3给药明显优于二者组合,例如单独的4μM-R-Rg3细胞存活率为75.12±2.11,而R:S比例为2:1和3:1(同等给药剂量和为4μM)的给药组细胞存活率分别为67.21±1.33和71.42±2.21;同样,S:R比例为2:1和3:1(同等给药剂量和为4μM)的给药组细胞存活率分别为61.55±1.72和59.61±1.51。
与红参提取物比较实验结果表明:同等剂量下,红参提取物未显示出保护作用,而单独R构型Rg3活性明显优于红参提取物。
表4.人参皂苷Rg3对H2O2致TM3细胞损伤的保护作用
注:与空白组比(**P<0.01,***P<0.001),与模型组比(#P<0.05,##P<0.01)
实验例3:20(R)-人参皂苷Rg3对阴囊热应激诱导的生精细胞损伤的保护作用
3.1材料和方法
3.1.1材料、试剂及仪器
20(R)-人参皂苷Rg3(以下简称Rg3),纯度>98.5%(HPLC);戊巴比妥钠(C11H17N2NaO3),纯度>99%。
丙二醛(MDA)、还原型谷胱甘肽(GSH)和超氧化物歧化酶(SOD)试剂盒等均购自南京建成生物工程研究所;睾酮(Testosterone)试剂盒均购自美国R&D公司。BP211D电子天平,德国Sartorius公司;DK-98-1型电热恒温水浴锅,天津泰斯特仪器有限公司;HC-2517高速离心机,安徽中科中佳公司;Epoch超微量微孔板分光光度计,美国伯腾仪器有限公司;FSH-2A可调高速匀浆机,金坛市华城海龙实验仪器厂。
3.1.2实验动物:
雄性ICR小鼠32只,体重(25±2g)购于长春市亿斯实验动物技术有限责任公司。所有小鼠允许自由进食水和维持饲料,25±2℃的温度,50±10%的相对湿度下昼夜交替循环。所有实验都按照我国科技委员会实验动物管理条例要求进行。
3.1.3动物分组与给药:
给药组按剂量每天灌胃给药一次,连续14天,正常对照组和模型组灌胃等体积纯净水。第七天给药后6h后,利用水浴锅对小鼠进行热应激,每只小鼠腹腔注射65mg/kg戊巴比妥钠麻醉,身体1/3以下43℃水浴18min,应激后放在热垫上恢复体温,第15天依次对各组小鼠进行眼球取血,3000r/min离心10min分离血清,4℃保存备用;迅速解剖取睾丸及附睾。经4℃生理盐水冲洗,滤纸吸干,称重,取左边睾丸和附睾于10%的甲醛溶液中固定,待切片,右边睾丸和附睾于-80℃低温冰箱中保存。
3.1.4血清中生化指标的测定:
采集小鼠血液分离血清,按照试剂盒方法测定睾酮(Testosterone)。
3.1.5睾丸中氧化指标的测定:
取左边睾丸称重,加入9倍体积的冰生理盐水,用组织匀浆机制得10%的睾丸组织匀浆,离心取上清液。按照试剂盒方法点板,在450nm处测定OD值,根据公式计算睾丸中MDA的含量、GSH的活性和SOD的水平。
3.1.6睾丸及附睾组织病理学观察
取左边睾丸及附睾组织置于10%的中性甲醛溶液中固定,低浓度到高浓度酒精脱水,二甲苯中透明,常规石蜡包埋,切片,脱蜡后用H&E染色,于光学显微镜下观察睾丸及附睾组织病理学变化。
3.1.7数据处理
3.2结果:
3.2.1人参皂苷R-Rg3对阴囊热应激导致生精细胞损伤小鼠睾丸及附睾指数的影响
从实验的结果可以看出,经阴囊热应激(heat stress,HS)之后,与对照组相比,HS组小鼠睾丸明显缩小,经R-Rg3给药后,小鼠睾丸及附睾得到明显改善,但小鼠的体重无明显变化,睾丸和附睾指数显著降低(P<0.001),而Rg3组(5mg/kg和10mg/kg)与HS组相比则显著升高(P<0.001)。此外,各组之间的其他脏器指数没有明显变化,结果如表5所示。
表5.人参皂苷R-Rg3对热应激诱导的生精细胞损伤小鼠睾丸及附睾指数的影响
注:与空白组比(***P<0.001),与模型组比(#P<0.05,##P<0.01,###P<0.001)。
3.2.2人参皂苷R-Rg3对HS导致生精细胞损伤小鼠睾酮的影响
睾酮是由男性的睾丸分泌的一类激素,它是主要的男性性激素及同化激素,对健康及有着重要的影响。热应激使血清中睾酮的浓度明显降低(P<0.05)。给予R-Rg3治疗后睾酮与模型组比升高,恢复了睾酮的水平,并成一定的剂量依赖性。结果如表6.
表6.人参皂苷Rg3对HS导致生精细胞损伤小鼠睾酮的影响
注:与空白组比(*P<0.05),与模型组比(#P<0.05,##P<0.01)。
3.2.3人参皂苷R-Rg3对HS导致生精细胞损伤小鼠睾丸组织过氧化影响
与空白组相比,模型组小鼠氧化组织匀浆中MDA含量明显的上升,GSH和SOD水平显著下降(P<0.05),使小鼠体内脂质过氧化产物累积,抗氧化代谢水平降低;与模型组相比,人参皂苷R-Rg3给药组MDA含量明显的下降(P<0.01),GSH和SOD水平均显著升高(P<0.001),表明人参皂苷Rg3可以在一定程度上缓解热应激引起的脂质过氧化,调节体内抗氧化代谢水平,结果如表7所示。
表7.人参皂苷R-Rg3对HS导致生精细胞损伤小鼠睾丸组织过氧化影响
注:与空白组比(**P<0.01,***P<0.001),与模型组比(#P<0.05,##P<0.01)
3.2.4人参皂苷R-Rg3对睾丸及附睾组织病理学的影响
通过对睾丸及附睾组织病理学的观察,对照小鼠睾丸组织中生精细胞排列整齐,显示出正常的细胞形态,HS模型组睾丸显示出严重的生精细胞坏死,细胞核发生皱缩,部分生精小管因生殖细胞层脱落而萎陷或萎缩。然而,Rg3给药组小鼠的睾丸切片显示睾丸组织几乎恢复正常结构,保存良好的生精细胞形态并含有大量精母细胞、精子细胞。由H&E染色可知,HS模型组睾丸损伤坏死比较严重,而Rg3低、高剂量组对缓解睾丸损伤有一定的保护作用。如附图3所示。
3.3结论
人参皂苷R-Rg3在5和10mg/kg剂量范围内,可以显著改善热应激诱导的小鼠生精细胞损伤,主要通过改善急性氧化应激水平及降低炎症因子等,是一种很有前景的生精细胞损伤保护剂,可应用于制备治疗和预防环境热应激所致的生育障碍的药物和保健食品方面,进一步扩大20(R)-人参皂苷Rg3应用范围,为临床治疗热应激药物提供新的药物来源。
下面通过具体实施方式来进一步描述本发明所述配方的有益效果,这些实施例包括了本发明的20(R)-人参皂苷Rg3在治疗药物时生产胶囊、片剂、滴丸剂的示例,并结合具体药理学实验,进一步说明20(R)-人参皂苷Rg3对环境热应激致生精损伤有明显保护作用。
实施例4:R-Rg3片剂
按照如下配比制备Rg3片剂
人参皂苷R-Rg3(纯度为98%)200g,淀粉1000g,滑石粉1%(12g),硬脂酸镁1%(12g),
将人参皂苷R-Rg3和淀粉混合均匀后,过120目筛整粒,制成颗粒,加入滑石粉和硬脂酸镁混合均匀后压制成10000片,每片含人参皂苷Rg3约200mg。口服,每次3片,每日三次,饭后服用。
实施例5:R-Rg3胶囊剂
按照如下配比准备原料
人参皂苷R-Rg3(纯度为98%)200g,淀粉1000g,将人参皂苷R-Rg3和淀粉充分混匀后,过120目筛整粒,装胶囊,制成1000粒胶囊,每粒重0.25g,每粒含人参皂苷Rg3 200mg。口服,每次3粒,每日三次,饭后服用。
实施例6:R-Rg3滴丸剂
按照如下操作及配比准备原料
聚乙二醇4000 300g,在水浴上熔化,加入人参皂苷R-Rg3原料200g,搅拌均匀,倾入保温管中,调节恒温装置,使药液在80-90℃下滴入冷却过的液体石蜡中(温度±4℃),滴完后,将药丸倾入滤纸上吸干石蜡油,再加入0.2%滑石粉(1g),混匀,得人参皂苷Rg3滴丸1000粒。口服,一次3粒,每日三次,饭后服用。
实施例7:与其他活性成分组合制成R-Rg3片剂
按照如下配比制备Rg3片剂
人参皂苷R-Rg3 30g,玄参提取物20g,麦冬提取物40g,淀粉1000g,滑石粉1%(14.5g),硬脂酸镁1%(14.5g),将以上物质与淀粉混合均匀后,过120目筛整粒,制成颗粒,加入滑石粉和硬脂酸镁均匀后压制成1000片,每片重0.4g,口服,每次5片,每日三次。饭后服用。
实施例8:与其他活性成分组合制成R-Rg3胶囊剂
按照如下配比准备原料
人参皂苷R-Rg3 30g,贝母提取物30g,维生素C 600g,淀粉1000g,将上述物质与淀粉混合均匀后,过120目筛整粒,制成胶囊,每粒重0.4g,口服,每次5粒,每日三次,饭后服用。
上述实施例仅是通过上述方法对本发明临床应用进行简要示例,并结合药理学试验对20(R)-人参皂苷Rg3在制备治疗和预防生精细胞损伤药物的应用进行了详细说明,但本发明并不限于上述实施方式。在不偏离本发明的配方思路、用途范围下可以对本发明技术方案的细节和形式进行修改或替换,可在各种方式中实施本发明,但这些修改和替换均应在本发明的保护范围内,在此不再一一叙述。
Claims (4)
1.20(R)-人参皂苷Rg3(简称“R-Rg3”)在制备用于治疗和预防热应激所致生精损伤药物中的应用。
2.R-Rg3和20(S)-人参皂苷Rg3(简称“S-Rg3”)在制备用于治疗和预防热应激所致生精损伤药物中的应用,其中,R-Rg3和S-Rg3的质量比为2:1或3:1。
3.根据权利要求1或2所述的应用,其特征在于:所述R-Rg3由二醇型皂苷Rd采用酸水解而生成,即采用人参皂苷Rd溶于0.1%的甲酸溶液中进行反应,反应条件为:反应温度95℃,反应时间3h,进而采用制备分离手段而获得纯度大于98%的R-Rg3。
4.根据权利要求1或2所述的应用,其特征在于:将药物制成用于治疗或预防生育障碍的制药中可接受的剂型,选自片剂、胶囊剂、散剂、注射剂、丸剂、颗粒剂、糖浆剂、膏剂的形式。
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