CN116173177A - 一种持续改善男性性功能的药物组合物及制备方法 - Google Patents
一种持续改善男性性功能的药物组合物及制备方法 Download PDFInfo
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Abstract
本发明涉及药品保健品技术领域，且公开了一种持续改善男性性功能的药物组合物。它是由调节勃起神经通路的功能成分和补肾固本的功效成分构成。创造性的把组合形式的育亨宾与神经酸、植物细胞外泌体，应用到改善男性性功能的产品中。克服现有技术中药治疗性功能障碍存在的物质基础不清、起效慢、周期长、治疗效果不明显及不良反应多的不足，本专利产品天然、安全、有效，既显著性的治疗勃起功能障碍，又具有标本兼治，固本培元的功效，治疗有效率达到90%以上，具有积极的推广价值。
Description
技术领域
本发明属于医药、保健品的技术领域，具体涉及一种持续改善男性性功能的药物组合物及其制备方法、应用。
背景技术
男性性功能障碍，主要包括勃起功能障碍（ED）、遗精、早泄和精子质量下降等症状。
永久的或暂时的勃起功能障碍的病患，有器质性的，但大多数患者是非器质性的。对此类疾病的治疗，现有技术中主要有海绵体内药物注射，口服化学药品，口服中药药品。海绵体内药物注射有效果，但大多数人难以接受。以西地那非及衍生物为代表的口服西药，采用现用现吃的临时给药方式，据资料报道平均有效率达67%，但易引起头疼、失眠、血压升高等副作用，治标不治本。久服激素药物甚至完全丧失性功能。国家对这类原料用于保健食品是有严格限制。以中草药原料为基础组分形成的中药制剂，多数物质基础不清楚，产品有效成分含量低、效果很差，服用时间长，这些中药产品还易对身体产生副作用。另外中药组合物还存在口感风味苦涩、制备方法复杂、原料成本高等问题。在中药原料的优选、药理机制清晰和中药提纯精制技术上，需要改进的潜力很大。如何找到科学有效的天然药物来改善男性性功能功能，提高性生活质量，是当前研究的重要课题。
发明内容
要解决的技术问题。
本发明要解决的技术问题之一在于，针对中药治疗男性性功能障碍现有技术存在的有效成分不清，起效慢，剂量大，服药周期长，治疗效果不明显及不良反应的不足，通过优选天然原料、精准定位药理机制、采用植物细胞外泌体技术、有效单体分离纯化等技术方案，提供一种天然、安全、有效的治疗男性性功能障碍且具有标本兼治，固本健身功效的产品。
本发明要解决的技术问题之二在于，提供治疗男性性功能障碍且具有标本兼治，固本培元健身功效的产品的制备方法及应用。
发明技术方案
一种改善男性性功能的药物组合物，其原料由改善勃起功能的活性成分、补肾固本的活性成分组成。所述的改善勃起功能活性成分包括盐酸育亨宾、顺-15二十四碳烯酸（中文名：神经酸）、牡蛎肽、L-精氨酸、虫草菌丝粉、柠檬酸锌；所述的补肾固本的活性成分，包括肉苁蓉细胞外泌体纳米冻干粉、人参细胞外泌体纳米冻干粉、玛咖细胞外泌体纳米冻干粉、黄精细胞外泌体纳米冻干粉、枸杞子细胞外泌体纳米冻干粉、杜仲雄花细胞外泌体纳米冻干粉。
组合物中还包括占原料重量份一定比例的辅料。
进一步的，所述的改善男性性功能的药物组合物，包括按每日治疗有效量重量份的原料：
盐酸育亨宾（以育亨宾计） 2份-30份；
顺-15二十四碳烯酸 10份-150份；
虫草菌丝粉 15份-100份；
牡蛎肽 15份-40份；
L-精氨酸 125份 -350份；
柠檬酸锌 50份-80份；
肉苁蓉细胞外泌体冻干粉 10份- 100份
人参细胞外泌体冻干粉 10份-40份
玛咖细胞细胞外泌体冻干粉 10份-40份
黄精细胞细胞外泌体冻干粉 15份-40份
枸杞子细胞细胞外泌体冻干粉 30份-60份
杜仲雄花细胞细胞外泌体冻干粉 10份-30份
组合物中还包括占原料重量份一定比例的辅料。
优选的，所述的改善男性性功能的药物组合物，按每日治疗有效量重量份原料：
盐酸育亨宾（以育亨宾计） 10份-15份
顺-15二十四碳烯酸 50份-100份
虫草菌丝粉 20份-30份
牡蛎肽 20份-30份
L-精氨酸 250-300份
柠檬酸锌 60份-70份
肉苁蓉细胞外泌体冻干粉 25-50份
人参细胞外泌体冻干粉 20份-30份
玛咖细胞外泌体冻干粉 20份-30份
黄精细胞外泌体冻干粉 20份-30份
枸杞细胞外泌体冻干粉 40份-60份
杜仲雄花细胞外泌体冻干粉 15份-20份
组合物中还包括占原料重量份一定比例的辅料
在一个实施例中，所述的改善男性性功能的药物组合物，按每日治疗有效量重量份的原料：
盐酸育亨宾（以育亨宾计） 12份
顺-15二十四碳烯酸 60份
虫草菌丝粉 25份
牡蛎肽 20份
L-精氨酸 260份
柠檬酸锌 65份
肉苁蓉细胞外泌体冻干粉 30份
人参细胞外泌体冻干粉 25份
玛咖细胞外泌体冻干粉 25份
黄精细胞外泌体冻干粉 25份
枸杞子细胞外泌体冻干粉 45份
杜仲雄花细胞外泌体冻干粉 17份
组合物中还包括占原料重量份一定比例的辅料。
本发明药物组合物中各原料的质量要求：
所述的育亨宾是从西非茜草科育亨宾树皮的提取物，盐酸育亨宾是育亨宾的可药用盐形式，更佳地以育亨宾树皮提取物总重量计，其中含有8w/w％盐酸育亨宾，盐酸育亨宾可商购获得；
所述的顺-15二十四碳烯酸（Cis-15-Tetracosenoic Acid）纯度≥85%，在特殊的使用场景下在有些实施例中，顺-15二十四碳烯酸也可以用含有天然顺-15二十四碳烯酸的元宝枫籽油油脂粉末替代，油脂粉末添加量根据本发明要求的顺-15二十四碳烯酸当量进行换算，顺-15二十四碳烯酸、元宝枫籽油油脂粉末均可商购获得。
所述的植物细胞外泌体纳米冻干粉，是以新鲜肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花的汁液，经现代生物技术制成肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花细胞外泌体纳米冻干粉，也可用肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花的有机溶剂提取物替代，使得生药：提取物重量份至少达到100：1。
所述的药物组合物的其他原料，符合国家药典或相关食品安全标准的要求。
本发明术语“有效量”是指可对人产生功能或活性的且可被人所接受的量。
本发明术语“重量份”或“重量份数”可互换使用，所述的重量份可以是任何一个固定的以毫克、克数或千克数表示的重量。
本发明药物组合物，还包括添加占原料重量份一定比例的辅料，所述的辅料是药学、食品学上可接受的填充剂、润滑剂、分散剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。辅料成分的加入不改变药物组合物在疾病治疗过程中的主导地位，而仅仅发挥对成分已知活性的利用。所述的辅料包括但不限于异麦芽酮糖醇、赤藓糖醇、淀粉、预胶化淀粉、糊精、羧甲基淀粉、食用香精、硬脂酸镁、二氧化硅、氢氧化钠；辅料占原料的比例没有严格的限定，例如但不限于辅料占原料的重量份10%、20%、30%。
本发明所述的药物组合物各原料的药理机制和配方研究
男性性功能减退，是由年龄因素，精神心理性因素,神经因素包括性腺功能减退、代谢性疾病，如糖尿病等、血管性病因，如动脉性阳痿和静脉性阳痿等综合因素所致。从中医角度，自身体质如肾虚、肝郁、血瘀、湿热和前列腺炎等都是性功能减退病因。改善男性性功能，不能单纯刺激勃起功能，而是着眼于固本培元，补肾益精，持续的、长期的增强性腺功能，从根本上改善或逆转性功能减退，重在改善阴阳虚亏，恢复体质健康。
阴茎勃起的基本原理：被称作海绵体的阴茎勃起组织，是一个能够充满血液的组织器官。在休止时刻，阴茎动脉处于肾上腺能紧张的支配下，使得阴茎处于收缩状态，没有血流充满海绵体。当受到适当刺激时，勃起神经抑制了肾上腺能紧张，阴茎动脉扩张，海绵体充血，阴茎变大变硬，内压增高，压紧了阴茎静脉，阻止了血流流出，维持了阴茎硬度。射精后重新释放肾上腺素，动脉血的供应减少，海绵体压力下降，积累的血液由静脉流出，导致阴茎硬度下降重新回到休止状态。本发明药物组合物，是基于上述原理而开展的研究。
本发明药物组合成分药理作用和配伍依据：
盐酸育亨宾：具有α-肾上腺素能突触前受体拮抗剂的性能，也就是说，它能够抑制肾上腺素的效果，因此有助于动脉血对海绵体的灌注，被用来治疗心源性阳痿。有些研究出版物认为，采用育亨宾单剂治疗ED能达到35-45%的改善效果。还观察到在剂量较大时，出现如头晕、焦虑、烦躁，头痛、失眠和动脉血压升高等副作用，故提升育亨的有效率，减少副作用还需要筛选有效的协同药物。
顺-15二十四碳烯酸（简称神经酸）：是神经纤维尤其是髓鞘生物膜的主要构成物质，它通过在体内合成鞘磷脂和鞘糖脂，维持神经元、髓鞘细胞的组成、结构和功能。对突触前后信息反射有重要影响，对受体有极强的神经可塑性。修复肾上腺神经回路，刺激末梢神经的活性具有独特的作用。研究发现，组合使用盐酸育亨宾和神经酸，表现出令人惊讶的性能，通过正交实验、功能实验显示，盐酸育亨宾和神经酸以混合形式使用，具有明显的协同增效作用，对治疗勃起功能障碍产生明显的有益的结果，同时可使育亨宾和神经酸的用量减低，减少了盐酸育亨宾的副作用。
虫草菌丝体：双向调节免疫，使肾上腺素得到镇静，松弛平滑肌有助于勃起。
牡蛎肽：《本草纲目》记载：牡蛎“治虚损，壮阳，补男女气血”。牡蛎肽更利于吸收利用，提高男性血清睾酮水平，增强男性性功能。
精氨酸：能促进血管内皮产生一氧化氮，激活环鸟腺苷信使因子，使动脉和海绵体的平滑肌产生松弛效果，这对于获得勃起功能是必须的。
锌：锌参与促黄体激素、促性腺激素生化反应，对于性机能有重要的调节作用。
故本发明药物组合物中改善勃起功能的活性成分，由盐酸育亨宾、神经酸组合为君药，以虫草菌丝体、牡蛎肽、精氨酸、锌为臣药。配伍科学，功效明显，具有新颖性、创新性。
本发明的药物组合物主诉功能，不仅仅着眼于短暂的改善勃起功能，而是标本兼治，致力于固本强体，从根本改善性功能减退体质。本发明的配方，还提供了一组植物细胞外泌体冻干粉。肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花，均为传统补肾益精的良药。是中药壮阳方剂中使用频率较高的药品。为什么多数产品效果不佳，其中一个主要原因，配伍不当，制作工艺简单，传统的水提取或醇提取，使药物有效成分提取率低，达不到治疗有效量的利用。
外泌体是活细胞释放到细胞液中微小囊泡，几乎所有的人体细胞、植物细胞都能释放外泌体。植物细胞外泌体具有来源植物的药效作用。外泌体通过“内吞-融合-释放”的方式，长距离的在细胞间传递信息，传递药物，对受体细胞产生治疗作用。比传统的植物提取物有巨大优势，比干细胞治疗也有优势。所以有学者认为；外泌体是干细胞技术下一个发展方向。本发明采用生物技术，成功生产出肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花细胞外泌体。实验看，比传统方法生产的中药产品提高了对男性性能治疗作用。肉苁蓉、人参、玛咖植物细胞外泌体冻干粉构成本发明药物组合的佐药，黄精、枸杞子、杜仲雄花植物细胞外泌体冻干粉，成为本发明药物组合的使药。
按中医学君、臣、佐、使组方原则和多项生物技术完成本发明药物组合物技术方案。本发明产品的药用机理，并不是单一的刺激阴茎的活性，而是针对性功能的整个系统进行调动，从中枢交感神经、到副交感神经、再到阴茎的海绵体的彻底性、全面性的唤起和治疗。
本发明药物组合物剂型为经胃肠道吸收剂型，包括但不限于片剂、粉剂、胶囊剂、颗粒剂、口服液。
本发明药物组合物，是在制备改善男性性功能的药物中应用。
本发明药物组合物，是在制备勃起功能障碍、性欲障碍、性感觉障碍、提升血浆睾酮水平，提高精子活力和补肾益精健身的药物中应用。
本发明药物组合物的制备方法包含以下步骤：
S1、按配方分别称量原料和加入的辅料，置入混合机中混合30min，得到混合物；
S2、向混合物中加入35%乙醇制软材，上制粒机制粒，得到湿颗粒；
S3、将湿颗粒置60℃烘箱中干燥，使水分≤5%，得干燥颗粒，然后10-20目整粒；
S4、整粒后物料添加或不添加硬脂酸镁，总混25-35min。
S5、按药典常规制剂规程压片、充填胶囊、粉剂灌装、颗粒包装或按口服液工艺进行灌装。
S6、检验、外包转，入库。
本发明提供植物细胞外泌体纳米冻干粉的制备方法，包含以下步骤：
新鲜植物细胞外泌体冻干粉制备
S1、取一定量的新鲜植物，去除根须、杂质，用生活饮用水冲洗干净，再用纯化水洗三次，最后用超纯水洗三次，每次冲洗时间3-5min；
S2、将洗净的新鲜植物切成块，分别置榨汁机混合粉碎，连续榨三次后，过滤，取汁液，得植物原汁；
S3、将植物原汁分别于4℃下梯度差速离心，第一次离心力1000g，离心10min，得上清液A；然后将上清液A以3000g，离心20min，得上清液B；然后将上清液B以10000g，离心40min，去除杂质，获得上清液C，最后将上清液C于150000g下超高速离心120min，取沉淀，用PBS（磷酸缓冲盐溶液）洗涤三次，即各得植物外泌体提取液(上清液A-C为不同步骤收集的上清液）；
S4、将步骤S3得到的植物外泌体提取液，分别与甘露醇复配，形成均一溶液，并将溶液注入模具中，预冻0 .5-3h，然后转入冻干机中，在0.01-10mbar，-50℃-4℃的条件下冷冻干燥5-10h，即分别得到植物外泌体冻干粉。
在优选的实施方式中，所述的植物细胞外泌体纳米冻干粉为肉苁蓉细胞外泌体冻干粉、人参细胞外泌体冻干粉、玛咖细胞外泌体冻干粉、黄精细胞外泌体冻干粉、枸杞细胞外泌体冻干粉、杜仲雄花细胞外泌体冻干粉。
所述的植物细胞外泌体冻干粉检测，通过纳米颗粒跟踪分析仪（Particle MetrixGmbH），测定植物外泌体粒的粒径分布及密度，根据峰的分布初步判断其纯度，峰数量越少纯度越高；通过每ml外泌体的数量，判断外泌体粒的得率，数量越大得率越大。测得植物外泌体冻干粉粒径分别为50.2-107.7nm，纯度为87.1-95.3%，每ml外泌体数量分别为5.5-5.2E+6。
干品植物细胞外泌体的制备
干品植物提取细胞外泌体，一般制备方法是，分别取肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花干品，去杂洗净，粉碎40目，加3倍重量份的磷酸缓冲盐液，浸泡10H，过滤，将滤液分别于4℃梯度差速离心，第一次离心力1000g，离心10min，得上清液A；然后将上清液A以3000g，离心20min，得上清液B；然后将上清液B以10000g离心40min，去除杂质，获得上清液C，最后将上清液C于150000g下超高速离心120min，取沉淀，用PBS（磷酸缓冲盐）洗涤三次，即各得植物外泌体提取液(上清液A-C为不同步骤收集的上清液），将植物外泌体提取液，分别与甘露醇复配，形成均一溶液，并将溶液注入模具中，预冻0.5-3h，然后转入冻干机中，在0.01-10mbar，-50℃-4℃的条件下冷冻干燥5-10h，即分别得到肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花植物细胞外泌体冻干粉。
相对于新鲜植物，干品植物制备外泌体得率低，工艺复杂。在特殊的使用场景下，在另一实施例中，肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花干品饮片，可用大孔吸附树脂富集与纯化技术，制得纯度较高的提取物，来替代干品植物外泌体冻干粉。这种制备方法：取干品肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花，称量，去杂，分别粉碎20目粗粉，加药材重量8倍量75%的乙醇，升温75℃，加热回流提取3次，每次1.5小时，3次滤液合并，减压回收乙醇，将提取液通过大孔树脂柱，吸附其中的有效成分，再经洗脱回收，除掉杂质，干燥制得分离纯化物，使得生药与分离纯化物至少达到100：1纯度，得到植物提取物。
相对于现有技术，本发明的有益效果在于：
1、本发明提供的以天然原料制备的改善男性性功能产品，相对于现有中药制剂技术具有提取富集技术先进、有效成分利用率高，成本低廉，不伤身体，标本兼治、安全有效的优点，具有新颖性、创造性；
2、首次把盐酸育亨宾和顺-15二十四碳烯酸以组合形式配伍，应用本发明药物组合物中，提升了治疗男性性功能的效果，有效避免了育亨宾的毒副作用，安全性良好，减少原料用量，具有突出优点和创造性；
3、首次把改善男性性功能植物细胞外泌体，以纳米冻干粉的形式应用本发明药物组合物中，相对于现有中药制剂技术，本植物外泌体的囊泡粒径在50.2-107.7nmnm，纯度为87.1-95.3%，具有来源植物的药效，又携带DNA、miRNA、蛋白、磷脂等多种生物活性分子，介导细胞信号传递。参与组织修复，产品经实验，治疗效果稳定。是中药治疗男性性功能产品的实质性进步；
4、本发明药物组合物，把有效刺激一次性勃起功能和持续性、整体性改善性功能减退体质，统一于一个治疗技术方案之中。达到标本兼治，固本培元健身的目标。具有实用性和推广应用价值。
具体实施方式
结合本发明实施例，对本发明的技术方案进行清楚、完整地描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员，在没有做出创造性劳动前提下，所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：本发明药物组合物配方与制备方法
处方：
盐酸育亨宾（以育亨宾计）2份-30份；顺-15二十四碳烯酸 10份-150份；虫草菌丝粉15份-100份；牡蛎肽15份-40份；L-精氨酸125份-350份；柠檬酸锌50份-80份；肉苁蓉细胞外泌体冻干粉10份-100份；人参细胞外泌体冻干粉10份-40份；玛咖细胞细胞外泌体冻干粉10份-40份；黄精细胞细胞外泌体冻干粉15份-40份；枸杞子细胞细胞外泌体冻干粉30份-60份；杜仲雄花细胞细胞外泌体冻干粉10份-30份，添加异麦芽酮糖醇、玉米淀粉、硬脂酸镁，二氧化硅，预胶化淀粉中一种或几种适量辅料。
制法：
S1、按配方分别称量原料和辅料，置入混合机中混合30min，得到混合物；
S2、向混合物中加入35%乙醇制软材，上制粒机制粒，得到湿颗粒；
S3、将湿颗粒置60℃烘箱中干燥，使水分≤5%，得干燥颗粒，然后10-20目整粒；
S4、整粒后物料添加或不添加硬脂酸镁，总混25-35min；
S5、压片、充填胶囊、粉剂、颗粒包装或按口服液工艺进行灌装；
S6、检验、外包转，入库。
实施例2：本发明药物组合物的植物细胞外泌体纳米冻干粉的制备方法
S1、取一定量的新鲜肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花，去除杂质，用生活饮用水冲洗干净，再用纯化水洗三次，最后用超纯水洗三次，每次冲洗时间3-5min；
S2、将洗净的新鲜植物切成块，分别置榨汁机混合粉碎，连续榨三次后，过滤，取汁液，得植物原汁；
S3、将植物原汁分别于4℃下梯度差速离心，第一次离心力1000g，离心10min，得上清液A；然后将上清液A以离心力3000g，离心20min，得上清液B；然后将上清液B以离心力10000g，离心40min，去除杂质，获得上清液C，最后将上清液C于离心力150000g下超高速离心120min，取沉淀，用PBS（磷酸缓冲盐溶液）洗涤三次，即各得植物外泌体提取液(上清液A-C为不同步骤收集的上清液）；
S4、将步骤S3得到的植物外泌体提取液，分别与甘露醇复配，形成均一溶液，并将溶液注入模具中，预冻0.5-3h，然后转入冻干机中，在0.01-10mbar，-50℃-4℃的条件下冷冻干燥5-10h，即分别得到肉苁蓉细胞外泌体冻干粉、人参细胞外泌体冻干粉、玛咖细胞外泌体冻干粉、黄精细胞外泌体冻干粉、枸杞细胞外泌体冻干粉、杜仲雄花细胞外泌体冻干粉。
实施例3
本发明药物组合物的干品肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花大孔吸附树脂富集与纯化提取物的制备方法：
取干品肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花，称量、去杂，分别粉碎20目粗粉，加药材重量8倍量75%的乙醇，升温75℃，加热回流提取3次，每次1.5小时，3次滤液合并，减压回收乙醇，将提取液通过大孔树脂柱,吸附有效成分，再经洗脱回收，除掉杂质，干燥制得分离纯化物。使得生药与分离纯化物至少达到100：1纯度，得植物提取物。
实施例4-7
制备本发明改善男性性功能的药物组合物实施例4-7，以下述配方制备得到组合物4-7：
实施例4-7配方
制法：
S1、按实施例2制得植物细胞外泌体纳米冻干粉或实施例3制得提取物；
S2、按配方分别称量原料和加入的辅料，置入混合机中混合30min，得到混合物；
S3、向混合物中加入35%乙醇制软材，上制粒机制粒，得到湿颗粒；
S4、将湿颗粒置60℃烘箱中干燥，使水分≤5%，得干燥颗粒，然后10-20目整粒；
S5、整粒后物料添加或不添加硬脂酸镁，总混25-35min；
S6、按药典常规的制剂规程压片、充填胶囊、粉剂灌装、颗粒包装或按口服液工艺进行灌装；
S7、检验、外包转，入库。
以下通过试验例，具体说明本发明的有益效果。实验用药剂采用实施例5所制备的药物。
试验例1：安全性验证
1、急性毒性试验
小鼠连续一次灌胃给予受试制剂45g(生药)/kg，在试验期内未见动物死亡，可确定其小鼠一次给药的最大耐受量为45g(生药)/kg，相当于临床提供人日用量的112.5倍(本专利产品人的口服量为0.4g/kg/日)。根据急性毒性剂量分级标准，属无毒级；
大鼠一次灌胃给予受试制剂40g/kg，试验期内无动物死亡，其最大耐受量为40g/kg，相当于临床提供人日用量的100倍。
、长期毒性试验
以22g(生药)/kg剂量给大鼠连续灌胃给药15周，与对照组蒸馏水比较，未见动物出现一般临床症状、体重增长、血液学、血液生化学检查的各项指标、有关脏器系统和病理组织的毒性改变。停药4周后，留存动物上述相同项目检查，未见该受试药的迟缓性毒性。说明本发明组合物经口服连续给药无明显毒副作用。
试验例2：药效学动物实验
各试验药物中，剂量均为以相当于对应提取原料的生药量 g/kg 计算。
3.1 实验材料
苯甲酸雌二醇、黄体酮注射液、枸橼酸西地那非、本发明组合物、昆明种小鼠及 SD大鼠。
3.2 实验方法及结果
3.2.1 动物饲养及分组
将大鼠雌雄分笼饲养，雄鼠每笼3只，雌鼠每笼5只。将雄性大鼠进行适应性饲养，使其适应环境，喂养时间为1周。称重后随机分组，分为以下5组，即：空白对照组、阳性药物对照组、本发明组合物高剂量组、中剂量组、低剂量组，每组12只。
整个实验过程中使大鼠能自由摄食和饮水，温度控制在18-22℃，相对湿度维持的范围为60-70%。空间内制造12小时光照，12小时黑暗环境。
3.2.2 雌鼠准备
在进行交配实验之前，每晚进行适应性训练，即把雌鼠放置于交配实验用的玻璃观察箱中，使其尽快适应环境。正式实验开始前48小时肌注苯甲酸雌二醇，剂量为200μg/kg；与雄鼠合笼前4小时，注射黄体酮注射液，剂量为2mg/kg，促其发情。
3.2.3 雄鼠给药方法
空白对照组：每日灌胃给予蒸馏水，剂量为2ml/d；
阳性药物对照组：交配实验前灌胃给予枸橼酸西地那非，剂量为10mg/kg；
本发明组合物高剂量组：每日灌胃给予本发明组合物6g/kg；
本发明组合物中剂量组：每日灌胃给予本发明组合物4g/kg；
本发明组合物低剂量组：每日灌胃给予本发明组合物2g/kg；
3.3 本发明组合物对实验动物性行为的影响
先放置1只雄鼠在玻璃观察箱中，待其适应环境后放置2只发情雌鼠，观察 30min，在观察期内观测并记录各组大鼠的扑捉次数及其潜伏期、乘骑次数及其潜伏期、阴茎勃起次数。结果记录如表 1：
表 1 本发明组合物对大鼠性行为的影响
与空白对照组相比：**p ＜ 0.01 ；与空白对照组相比：*p ＜ 0.05 ；
由表1可以看出，阳性对照组及本发明组合物高、中剂量组都能显著增加实验动物扑捉次数并缩短扑捉潜伏期；阳性对照组及本发明组合物高、中剂量组都能显著增加大鼠骑乘次数和缩短骑乘潜伏期。
实验结果显示本发明组合物能有效提升实验动物性欲，增强实验动物性能力，使扑捉次数和骑乘次数增加，扑捉潜伏期及骑乘潜伏期明显缩短。
本发明组合物对肾阳虚小鼠生育能力的影响
取 60 只雄性小鼠，随机分为 6 组，每组 10 只。除空白对照组外，其余均用氢化可的松 0.5ml/kg ip 连续 9 日造模，在造模同时开始灌胃，连续 12 天。末次给药后1h经眼眶采血，测试血浆睾酮含量、睾丸、附睾重量、附睾精子含量、精子活动能力等指标。试验结果见表 2。
表2 本发明组合物对肾阳虚小鼠生育能力的影响
注：与空白对照组相比 **p ＜ 0.01 ；与模型组相比 ##p ＜ 0.01 ；与阳性对照组相比△△ p ＜ 0.01，阳性药物组与本发明组合物各剂量组血浆睾酮水平均显著高于模型组，且本发明组合物对提升血浆睾酮水平明显高于阳性药物组，本发明组合物中剂量组效果相当。
试验例 3药效学人体实验
临床资料
1、临床资料
1.1 诊断标准参照卫生部阳痿的中医诊断标准，排除有严重心脑血管病、肝硬化、严重变态反应疾病人群。
1.2 一般资料，观察病例100例，男性，已婚，夫妻同居，年龄27-70岁，平均年龄48岁，按国际勃起功能指数评分表评定，重度ED35例，中度ED45例，轻度ED 20例，随机分成两组50例，两组病情轻重程度，无显著差异，具有可比性。
2、治疗方法
治疗组：口服本发明组合物实施例5片剂，每次1片，每次2-3片，40天为观察期；
观察组：口服金贵肾气丸，每次6克，每次3次。
3、实验结果
按<治疗男性ED的疗效评价>标准，观察90天性生活情况，评分评定疗效：
恢复正常：能理想的勃起病完成性交者：
显效：治疗前后评分递增50%；
有效：治疗前后评分递增25%；
无效：治疗前后评分无改善。
实验结果如表3：
表3 本发明组合物对肾虚阳痿人体治疗结果
| 组别 | 例数 | 恢复正常 | 显效 | 有效 | 无效 | 总有效率 |
| 治疗组 | 50 | 17 | 22 | 7 | 4 | 92% |
| 对照组组 | 50 | 11 | 12 | 14 | 13 | 74% |
两组总有效率比较差异有显著性意义（P<0.05），治疗组优于对照组。
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下，可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。
Claims (9)
1.一种改善男性性功能的药物组合物，由改善勃起功能的活性成分、补肾固本的活性成分组成的，其特征在于：它包括按每日治疗有效量的重量份的原料是：
盐酸育亨宾（以育亨宾计） 2份-30份；
顺-15二十四碳烯酸 10份-150份；
虫草菌丝粉 15份-100份；
牡蛎肽 15份-40份；
L-精氨酸 125份-350份；
柠檬酸锌 50份-80份；
肉苁蓉细胞外泌体冻干粉 10份- 100份
人参细胞外泌体冻干粉 10份--40份
玛咖细胞外泌体冻干粉 10份--40份
黄精细胞外泌体冻干粉 15份-40份
枸杞子细胞外泌体冻干粉 30份-60份
杜仲雄花细胞外泌体冻干粉 10份-30份
组合物中还包括占原料重量份10%—30%的辅料。
2.权利要求1所述的药物组合物的原料特性，其特征在于：所述的育亨宾是西非茜草科育亨宾树皮的提取物及可药用盐，盐酸育亨宾纯度≥8w/w％；所述的顺-15二十四碳烯酸纯度≥85%，在特殊使用场景下，顺-15二十四碳烯酸也可以通过当量换算，由元宝枫籽油油脂粉末替代；所述的植物细胞外泌体纳米冻干粉，粒径在40-150nm，纯度≥85%，干品植物细胞外泌体也可用至少100：1的提取物代替；所述的药物组合物的各原料，符合国家药典或相关食品安全标准的要求。
3.权利要求1所述的药物组合物所添加的辅料，其特征在于：所述的辅料是药学、食品学上可接受的填充剂、润滑剂、分散剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂，它包括但不限于异麦芽酮糖醇、赤藓糖醇、淀粉，预胶化淀粉、糊精、羧甲基淀粉、食用香精、硬脂酸镁、二氧化硅、氢氧化钠。
4.权利要求1所述的药物组合物的剂型，其特征在于：它是经胃肠道吸收剂型，包括但不限于片剂、粉剂、胶囊剂、颗粒剂、口服液。
5.权利要求1所述的药物组合物的制备方法，其特征是：它包含以下步骤：S1、按配方分别称量原料和辅料，置入混合机中混合30min，得到混合物；S2、向混合物中加入35%乙醇制成软材，上制粒机制粒，得到湿颗粒；S3、将湿颗粒置60℃烘箱中干燥，使水分≤5%，整粒机10-20目整粒；S4、整粒后物料添加或不添加硬脂酸镁，总混25-35min；S5、按药典制剂规程进行压片、充填胶囊、粉剂灌装、颗粒包装或按口服液工艺灌装；S6、检验、外包转，入库。
6.权利要求1所述的植物细胞外泌体纳米冻干粉的制备方法，其特征在于：它包含以下步骤：S1、分别取一定量的新鲜肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花植物，去除根须、杂质，用生活饮用水冲洗干净，再用纯化水洗三次，最后用超纯水洗三次，每次冲洗时间3-5min；S2、将洗净的新鲜植物切成块，分别置榨汁机混合粉碎，连续榨三次后，过滤，取汁液，得植物原汁；S3、将植物原汁分别于4℃下梯度差速离心，第一次离心力1000g，离心10min，得上清液A；然后将上清液A以离心力3000g，离心20min，得上清液B；然后将上清液B以离心力10000g，离心40min，去除杂质，获得上清液C，最后将上清液C于离心力150000g，超高速离心120min，取沉淀，用磷酸缓冲盐溶液洗涤三次，即得各植物外泌体提取液，S4、将步骤S3得到的植物外泌体提取液，分别与甘露醇复配，形成均一溶液，并将溶液注入模具中，预冻0.5-3h，然后转入冻干机中，在0.01-10mbar，-50℃-4℃的条件下冷冻干燥5-10h，即分别得到肉苁蓉细胞外泌体冻干粉、人参细胞外泌体冻干粉、玛咖细胞外泌体冻干粉、黄精细胞外泌体冻干粉、枸杞细胞外泌体冻干粉、杜仲雄花细胞外泌体冻干粉。
7.权利要求1、2所述的干品植物提取物的制备方法，其特征是：它包含以下步骤：取干品肉苁蓉、人参、玛咖、黄精、枸杞子、杜仲雄花，称量，去杂，分别粉碎20目粗粉，加药材重量8倍量75%的乙醇，升温75℃，加热回流提取3次，每次1.5小时，3次滤液合并，减压回收乙醇，将提取液通过大孔树脂柱吸附有效成分，再经洗脱回收，除掉杂质，干燥制得分离纯化物，使得生药与分离纯化物至少达到100：1纯度的提取物。
8.权利要求1-7所述的本发明药物组合物的用途，其特征在于：它是在制备改善男性性功能障碍的药物中应用。
9.权利要求1-8所述的本发明药物组合物的用途，其特征在于：它是在制备勃起功能障碍、性欲障碍、性感觉障碍、提升血浆睾酮水平，提高精子活力和补肾益精健身的药物中应用。
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