CN113368099B - 淫羊藿苷元在制备血小板功能异常相关疾病防治药物中的用途 - Google Patents
淫羊藿苷元在制备血小板功能异常相关疾病防治药物中的用途 Download PDFInfo
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Abstract
本发明属于医药领域，涉及淫羊藿苷元的医药用途，具体涉及淫羊藿苷元在制备血小板功能异常相关疾病防治药物中的用途。为寻找一种对血小板功能异常具有治疗作用的特效药物，本发明对淫羊藿苷元对血小板的功能的影响进行了研究，结果表明：淫羊藿苷元可促进血小板的活化和聚集功能，进而不仅对遗传性血小板功能异常导致的疾病具有显著的治疗作用，对阻止引起血小板功能异常的原发性疾病的进展也具有极其深远的临床意义。
Description
技术领域
本发明属于医药领域，涉及淫羊藿苷元的医药用途，具体涉及淫羊藿苷元在制备血小板功能异常相关疾病防治药物中的用途。
背景技术
血小板功能异常(Qualitative plateletdefects)是一组因血小板粘附、聚集、释放、促凝功能及花生四烯酸代谢缺陷而致的出血性疾病。分为先天性及后天获得性两类，小儿多为先天遗传性，共同的特点是血小板数目多无明显减少，而血小板功能异常：如出血时间延长，凝血酶原消耗减低，凝血活酶生成不佳，束臂试验阳性，但凝血时间、凝血酶原时间、凝血酶时间以及部分凝血活酶时间则均正常。其中，先天性血小板缺陷常见于巨血小板综合征，血小板无力症，先天性结缔组织病等；获得性血小板缺陷常见于尿毒症，骨髓异常综合征，药物引起血小板功能障碍，异常蛋白症，肝病，弥漫性血管内凝血等。获得性血小板功能异常临床上相当常见，了解各种疾病中获得性血小板功能异常的特征及其发生机制，寻找一种对血小板功能异常具有治疗作用的特效药物，对预防出血及血栓形成的发生，并阻止原发疾病的进展有指导意义。
淫羊藿为小檗科植物淫羊藿(Epimedium brevicornum Maxim.)、箭叶淫羊藿(Epimedium sagittatumMaxim.)、柔毛淫羊藿(Epimedium pubescens Maxim.)、或朝鲜淫羊藿(Epimedium koreanum Nakai)的干燥茎叶。临床上主要用于肾阳虚，阳痿尿频，不孕；风湿痹痛，肢体麻木拘挛，筋骨痿软，步履艰难；肾阳虚，喘咳短气。淫羊藿苷能增加心脑血管血流量、促进造血功能、免疫功能及骨代谢，具有补肾壮阳、抗衰老、抗肿瘤等功效。
淫羊藿苷元(icaritin,IT)为小檗科淫羊藿属植物淫羊藿中的一种多羟基黄酮类单体成分。药理研究表明：IT抗骨质疏松作用较淫羊藿中其他黄酮苷类化合物强，在体外具有促进成骨细胞活性，抑制破骨细胞活性的作用。近年来作为淫羊藿中重要活性成分的淫羊藿苷和淫羊藿苷元越来越受到医药工作者的关注。如专利CN201310652615.8公开了淫羊藿苷元在制备抗疲劳药物中的应用；专利CN201310373517.0公开了淫羊藿苷元在制备治疗哮喘药物中的用途。
目前还没有文献关于淫羊藿苷元用于血小板功能异常相关疾病治疗方面的报道。
发明内容
本发明的主要目的为提供一种能改变血小板功能异常状态的特效药物，从而实现对因遗传性血小板功能障碍及继发性血小板功能障碍引起的相关疾病的治疗。
本发明的目的是通过如下技术方案实现的：
淫羊藿苷元对血小板活化功能影响研究结果显示：给予淫羊藿苷元3天后，动物外周抗凝血经ADP相同条件激活后，在CD61标记的所有血小板中，CD62p表达明显增加，即经ADP激活的血小板活化率升高，与给药前的基础值比较有显著性差异。提示在本实验条件下，淫羊藿苷元灌胃给药，可明显促进大鼠外周抗凝血中由ADP诱导的血小板活化。
淫羊藿苷元体外对血小板聚集功能的影响研究结果显示：淫羊藿苷元各浓度均具有促进ADP诱导的血小板聚集活性的作用，并且随着浓度增加促进作用增强，说明淫羊藿苷元对ADP诱导的血小板聚集活性的促进作用呈剂量依赖关系。
淫羊藿苷元在制备血小板功能异常及其导致的相关疾病防治药物中的用途。
所述的血小板功能异常为血小板活化功能或聚集功能异常。
进一步地，所述的血小板功能异常相关疾病为由先天性血小板缺陷或获得性血小板缺陷引起的疾病。所述的由先天性血小板缺陷引起的疾病为遗传性巨血小板综合征、遗传性血小板无力症或先天性结缔组织病。
所述的获得性血小板缺陷引起的疾病由药物或疾病引起。所述的药物为抗菌药物、抗肿瘤药物或肝素中的一种或多种。所述的疾病为尿毒症、糖尿病、肾病综合征、骨髓增生异常综合征、冠心病、肝脏疾病或白血病中的一种或多种。
淫羊藿苷元不仅对遗传性血小板功能异常引起的疾病如：遗传性巨血小板综合征、遗传性血小板无力症、先天性结缔组织病具有显著的治疗作用，而且能改善因药物及疾病引起的血小板功能异常的状态。
上述药物包括但不限于抗菌药物、抗肿瘤药物或肝素；所述的疾病包括但不限于尿毒症、糖尿病、肾病综合征、骨髓增生异常综合征、冠心病、肝脏疾病或白血病。
本发明的另一个目的为提供在进行上述疾病治疗时所用到的药物制剂，其包含淫羊藿苷元和药学可接受的药用辅料。
药物制剂包括但不限于注射剂、粉针剂、胶囊剂、片剂、微乳、滴丸、肠溶软胶囊。给药途径包括胃肠道途径和非胃肠道途径。
本发明使用的“药学可接受的药用辅料”是指不干扰淫羊藿苷元的生理作用，且对包括人类在内的受试者没有毒性的任何物质。
本发明制剂所用的药用辅料为本领域技术人员已知的常用辅料。适合的药用辅料在《药用辅料大全》(第123页，四川科学技术出版社，1993年出版，罗明生和高天惠主编)中已有详细描述。例如：制备微乳制剂常用的药用辅料包括但不限于大豆油、聚氧乙烯-23-月桂基醚、1,2-丙二醇、氢化椰油甘油脂、月桂酰基聚乙二醇-32-甘油酯、聚乙二醇3350、红花油、棉子油、十甘油单硬脂酸酯；制备滴丸制剂常用的药用辅料包括但不限于聚乙二醇6000、聚乙二醇1000；制备胶囊制剂常用的药用辅料包括但不限于乳糖和玉米淀粉；制备软胶囊制剂常用的可药用载体包括但不限于中链脂肪酸甘油酯、聚氧乙烯蓖麻油、1,2-丙二醇等。
本领域技术人员可以根据实际需要选择适合的药用辅料，并通过本领域已知的方法配制本发明的制剂。所述制剂包括但不限于固体、液体、油、乳剂、凝胶、气溶胶、吸入剂、喷雾、胶囊、丸剂、贴剂和栓剂等。
在进行上述疾病的治疗时，淫羊藿苷元的给药剂量为0.01mg/kg-100mg/kg，优选地，给药剂量为0.1mg/kg-10mg/kg。
具体实施例
以下通过具体实施方式进一步描述本发明，本发明不仅仅限于以下实施例。
制剂实施例1淫羊藿苷元注射液
制备工艺：向处方量的PEG-400加入淫羊藿苷元，搅拌溶解，加入0.9％氯化钠溶液至10L，搅拌均匀，加入0.5％针用活性炭，搅拌，脱炭，即得。
制剂实施例2淫羊藿苷元注射液
制备工艺：将处方量的乙醇和吐温-80混合均匀，加入淫羊藿苷元，搅拌溶解，加入注射用水至10L，搅拌均匀，加入0.5％针用活性炭，搅拌，脱炭，即得。
制剂实施例3淫羊藿苷元注射液
淫羊藿苷元 1g
乙醇 3.3L
注射用水 加至10L
制备工艺：将处方量的乙醇加入淫羊藿苷元，搅拌溶解，加入注射用水至10L，搅拌均匀，加入0.5％针用活性炭，搅拌，脱炭，即得。
制剂实施例4淫羊藿苷元粉针剂
制备工艺：称取处方量的注射用淫羊藿苷元原料,加入适量注射用水溶解。然后，加入经过规定量的预先经过除菌除热原处理的混匀，再加注射用水至规定1000ml；将上述药液中加入注射剂用活性炭5g，在60-80℃加热30分钟，用滤膜过滤，收集滤液。将上述滤液按无菌操作法用除菌滤器进行正压除菌滤过，用0.22μM微孔滤膜过滤，滤液进行热原检查和半成品含量检查然后西林瓶分装。在专用冻干箱内，在-40℃以下预冻1.5-3.5小时，真空度下升华在游离水分去处90％以后加温干燥(最高温度不得超过35℃)，冻干结束即可制备得到淫羊藿苷元粉针剂。
制剂实施例5淫羊藿苷元胶囊制剂
制备工艺：将淫羊藿苷元100g、乳糖120g和玉米淀粉130g在混合机中混合10-15分钟，加入硬脂酸镁5g混合1-3分钟，装入1000粒胶囊壳即可。
制剂实施例6淫羊藿苷元片剂
制备工艺:将淫羊藿苷元和辅料微晶纤维素、羧甲基淀粉钠混合均匀，加入适量的淀粉浆制软材，然后过16目筛制粒。湿颗粒在60℃干燥，干颗粒过20目筛整粒，筛出干粒中的细粉，与硬脂酸镁混匀，然后再与干颗粒混匀，压片，每片约200mg，即得。
制剂实施例7淫羊藿苷元微乳制剂
制备工艺：称取处方量大豆油、聚氧乙烯-23-月桂基醚、1,2-丙二醇，混合后搅拌均匀，然后加入淫羊藿苷元溶解，也可以超声波处理以加速溶解，得澄清溶液，即为淫羊藿苷元微乳制剂。激光粒度测定仪测定其粒径，平均粒径为15nm。
制剂实施例8淫羊藿苷元微乳制剂
制备工艺：称取处方量氢化椰油甘油脂、月桂酰基聚乙二醇-32-甘油酯、1,2-丙二醇、聚乙二醇3350，混合后搅拌均匀，然后加入淫羊藿苷元溶解，也可以超声波处理以加速溶解，得澄清溶液，即为淫羊藿苷元微乳制剂。激光粒度测定仪测定其粒径，平均粒径为40nm。
制剂实施例9淫羊藿苷元滴丸制剂
淫羊藿苷元 5.0g
聚乙二醇-6000 14.5g
聚乙二醇-1000 5.0g
制成1000粒
制备工艺：称取处方量过100目筛的淫羊藿苷元，加入已在水浴上加热熔融的含处方量的聚乙二醇6000、聚乙二醇1000的混合液中，充分搅拌，使之均匀，装入滴瓶中，于95±2℃的条件下滴制；滴入盛有4-6mL的甲基硅油的玻璃冷凝柱内，成型后取出，用吸水纸吸去黏附的甲基硅油，即得。
制剂实施例10淫羊藿苷元肠溶软胶囊制剂
内容物处方：
胶皮处方：
明胶 10g
甘油 5g
纯化水 10g
肠溶包衣液处方：
制备工艺：称取处方量中链脂肪酸甘油酯、聚氧乙烯蓖麻油、1,2-丙二醇、无水乙醇，混合后搅拌均匀，然后加入淫羊藿苷元溶解，也可以超声波处理以加速溶解，得澄清浓缩液，即为淫羊藿苷元微乳浓缩物。将上述所得的微乳浓缩物加水按照1：10-20的重量比稀释至澄清溶液，即得软胶囊微乳内容物。称取处方量明胶、甘油、纯化水，混合均匀后压制成胶皮，再称取处方量的Eudragit L30D-55、柠檬酸三乙酯、滑石粉、纯化水混合均匀制得肠溶包衣液。将含有淫羊藿苷元的软胶囊微乳内容物用胶皮包裹制成软胶囊，并在软胶囊上包肠衣制得肠溶软胶囊。
药效实施例淫羊藿苷元对血小板活化功能及体外对血小板聚集功能的影响
1.淫羊藿苷元对血小板活化功能影响
1.1实验动物
SD大鼠，SPF级，体重250-300g，雌雄各半，雌鼠无孕。
1.2血小板活化的FCM检测
大鼠眼眶取血0.5mL，3.8％枸橼酸钠抗凝(血液与抗凝剂的比例为9：1)制备抗凝血。每只动物取抗凝血50ul，用于血小板自发活化率测定；另取抗凝血50ul加入50ul终浓度为10μmol的ADP激活。上述2种抗凝血分别加入CD62p PE/Cy7和CD61 PE各1.0～1.5μL双标，以CD61标记所有血小板，CD62p标记活化血小板。取抗凝血50μL加入50μL终浓度为10μmol的ADP激活。IgG2a-PE/Cy7和IgG-PE双标作为同型对照。以上各管4℃避光孵育20min；再加入0.5mL 4％多聚甲醛固定10min。取固定后的血样50μL，加入1mL稀释液稀释后上机分析。在CD61 PE/侧向角光散射(SSC)双参数散点图中划定血小板细胞群，计数5000个血小板，进一步在CD61/CD62p散点图中计数CD61及CD62p阳性表达的细胞数，并以CD62p阳性表达率占CD61表达率的百分比反映血小板的活化率(％)。
1.3淫羊藿苷元对ADP诱导大鼠体内血小板活化的影响
取大鼠24只，分成3组，每组8只，分别灌胃给予3、6、18mg/kg的淫羊藿苷元，每日给药1次，连续给药3天，给药前和末次给药后20min分别眼眶取血1.0mL，其中0.5mL用于测定血常规，0.5mL用于制备抗凝血，按上述血小板活化的FCM检测方法处理后上机分析，检测给药前经ADP激活的血小板活化率(基础值)以及给药后经ADP激活的血小板活化率，并对二者进行比较。同时在给药前取大鼠抗凝血50ul，不加ADP，同法检测，测定动物抗凝血的自发活化率。每次取血前动物禁食16-24h。
1.4检测项目及试验结果
(1)对ADP诱导大鼠体内血小板活化的影响
给药前动物外周抗凝血经ADP激活后，与自发活化率相比，在CD61标记的所有血小板中，活化血小板的比例明显升高，即CD62p表达明显增加，表明ADP可诱导血小板活化率升高。给予淫羊藿苷元3天后，动物外周抗凝血经ADP相同条件激活后，在CD61标记的所有血小板中，CD62p表达明显增加，即经ADP激活的血小板活化率升高，与给药前的基础值比较有显著性差异。提示在本实验条件下，淫羊藿苷元灌胃给药，可明显促进大鼠外周抗凝血中由ADP诱导的血小板活化。具体结果如表1所示。
表1体内给药前后经ADP激活后血小板活化率的比较
要不要来个对比之类的(下同)
(2)血常规
血常规检测结果如下表所示，从表中可以看出，淫羊藿苷元各剂量组的血常规数值和给药前相比无显著性差异，特别是血小板的数量无显著性差异，此结果说明淫羊藿苷元在增加血小板活性的同时并不影响血小板数量。
表2淫羊藿苷元对ADP诱导大鼠血常规的影响
2.淫羊藿苷元体外对血小板聚集功能的影响
2.1体外促血小板聚集活性实验方法
家兔用普鲁卡因局部麻醉后，手术分离颈总动脉取血，用质量分数为3.8％枸橼酸钠抗凝，以800r/min离心10min，制备富血小板血浆(PRP)，剩余部分再以300r/min离心10min，制备贫血小板血浆(PPP)，进行血小板聚集实验。测定管中加入PRP265ul、淫羊藿苷元30ul(使终浓度分别为0.1mmol/L、0.5mmol/L和5mmol/L)，温孵5min，以5ul二磷酸腺苷(ADP)(终浓度25umol/L)为诱导剂，观察记录5min内最大聚集率。用质量分数为1％的二甲基亚砜(DMSO)作对照，观察各浓度淫羊藿苷元对二磷酸腺苷(ADP)诱导的血小板聚集的促进作用。
2.2实验结果
不同浓度的淫羊藿苷元体外对ADP诱导的血小板聚集作用的促进作用见表3，从表中可以看出，淫羊藿苷元各浓度均具有促进ADP诱导的血小板聚集活性的作用，并且随着浓度增加促进作用增强，说明淫羊藿苷元对ADP诱导的血小板聚集活性的促进作用呈剂量依赖关系。
表3淫羊藿苷元体外促进ADP诱导的血小板聚集活性
| 组别 | 浓度 | 聚集促进率(％) |
| 淫羊藿苷元低剂量组 | 0.1mmol/L | 23.3±4.5 |
| 淫羊藿苷元中剂量组 | 0.5mmol/L | 38.9±8.7 |
| 淫羊藿苷元高剂量组 | 5mmol/L | 52.2±9.0 |
Claims (5)
1.淫羊藿苷元作为唯一活性成分在制备防治血小板无力症药物中的用途。
2.如权利要求1所述的用途，其特征在于，包含淫羊藿苷元的药物制剂为注射剂、胶囊剂、片剂、微乳或滴丸。
3.如权利要求1所述的用途，其特征在于，包含淫羊藿苷元的药物制剂为粉针剂或肠溶软胶囊。
4.如权利要求1至3所述的任一用途，其特征在于，所述的药物在血小板功能异常相关疾病防治时的给药剂量为0.01mg/kg-100mg/kg。
5.如权利要4所述的用途，其特征在于，所述的药物在血小板功能异常相关疾病防治时的给药剂量为0.1mg/kg-10mg/kg。
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