CN109999042B - 包含脱氢表雄酮或其硫酸酯、左卡尼汀、乙酰左卡尼汀或它们的可药用盐的组合物及其应用 - Google Patents
包含脱氢表雄酮或其硫酸酯、左卡尼汀、乙酰左卡尼汀或它们的可药用盐的组合物及其应用 Download PDFInfo
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- A61K31/568—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
- 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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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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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男性少精、弱精、减少精子畸形的药物或膳食补充剂中的用途。该组合物包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)、左卡尼汀或其可药用盐、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，可以更显著地提高精液浓度和精子活力、减少精子畸形。
Description
技术领域
本发明涉及改善男性少精、弱精，增加精子浓度和精子活力的组合物及其应用，特别涉及一种包含脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯(DHEAS)、左卡尼汀或其可药用盐、乙酰左卡尼汀或其可药用盐的组合物及其在改善男性少精和弱精，增加精子浓度和精子活力，减少精子畸形中的应用。
背景技术
近年随着社会的发展，生活压力增大、生活环境的恶化，生活节奏的加快，生活和饮食结构出现了很多不合理的现象，导致育龄夫妇发生不育不孕的现象明显上升趋势，其中男性因素约占不孕症的35％-50％。男性不育主要表现为精液检查时的少精症、弱精症、精子畸形，大部分患者并不能找到明确的病因，因此又称为特发性少精子症、特发性弱精子症、特发性少弱精子症，对这部分患者，目前尚缺乏特效治疗药物，少弱精子症逐渐成为全球性的疑难杂症，严重影响人类的繁衍生息，男性患者的身心健康。
目前对少精弱精的治疗制剂较为单一，大多采用各种中草药，中成药进行调理，具有成分及含量不确定，用药不方便，疗程漫长和效果不显著不确定的缺点。因此临床亟需一种具有更好疗效、且可长期服用的药品或保健品。
本发明人意外发现，左卡尼汀、乙酰左卡尼汀和脱氢表雄酮在治疗男性的少精弱精，精子畸形方面具有意想不到的协同效果，该组合物具有长期服用安全有效的特点，现有技术中，关于左卡尼汀、乙酰左卡尼汀和脱氢表雄酮组合物在治疗少弱精子症方面的应用，目前还未见报道。
专利CN 1330301公开了一种左卡尼汀、乙酰左卡尼汀和丙酰左卡尼汀组合物用于治疗精子减少，精子活力不足和精子畸形的应用，其专利产品Proxeed
(勃锐精增效版)被认为是迄今最好的一种用于治疗男性少精弱精的膳食补充剂，在研究本发明组合物的有益效果时采用该专利产品作为阳性对照品，本发明的试验结果证实了Proxeed
的活性，但出人意料的是，本发明的组合物较Proxeed
具有更优的疗效。
发明内容
现已发现，左卡尼汀或其可药用盐、乙酰左卡尼汀或其可药用盐与脱氢表雄酮或脱氢表雄酮硫酸酯联合用药具有治疗少精、弱精、精子畸形的出人意料的协同作用。
本发明的一个目的是提供一种包含左卡尼汀或其可药用盐、乙酰左卡尼汀或其可药用盐以及脱氢表雄酮或脱氢表雄酮硫酸酯的组合物。
本发明的另一个目的是提供一种包含左卡尼汀或其可药用盐、乙酰左卡尼汀或其可药用盐与脱氢表雄酮或脱氢表雄酮硫酸酯的组合物在制备用于改善男性少精与弱精，增加精子浓度和精子活力，减少精子畸形的膳食补充剂或药物中的应用。
本发明的另一个目的是提供一种包含左卡尼汀或其可药用盐、乙酰左卡尼汀或其可药用盐与脱氢表雄酮或脱氢表雄酮硫酸酯的组合物在改善男性少精与弱精，增加精子浓度和精子活力，减少精子畸形中的应用。
本发明的另一个目的是提供一种包含左卡尼汀或其可药用盐、乙酰左卡尼汀或其可药用盐与脱氢表雄酮或脱氢表雄酮硫酸酯的药物或膳食补充剂组合物的制备方法。
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括左卡尼汀、乙酰左卡尼汀和脱氢表雄酮。
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括左卡尼汀富马酸盐、乙酰左卡尼汀和脱氢表雄酮。
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括左卡尼汀、乙酰左卡尼汀富马酸盐和脱氢表雄酮。
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括左卡尼汀富马酸盐、乙酰左卡尼汀富马酸盐和脱氢表雄酮。
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括左卡尼汀、乙酰左卡尼汀和脱氢表雄酮硫酸酯。
本发明的组合物中，脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯、左卡尼汀或其可药用盐、乙酰左卡尼汀或可药用盐的重量比为1(以脱氢表雄酮计)：10～30(以左卡尼汀计)：5～20(以乙酰左卡尼汀计)。
本发明的组合物中，脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯、左卡尼汀或其可药用盐、乙酰左卡尼汀或可药用盐的重量比为1(以脱氢表雄酮计)：15～25(以左卡尼汀计)：15～25 (以乙酰左卡尼汀计)。
本发明的组合物中脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯、左卡尼汀或其可药用盐、乙酰左卡尼汀或可药用盐的重量比为1(以脱氢表雄酮计)：20(以左卡尼汀计)：10(以乙酰左卡尼汀计)。
在一个实施方案中，本发明的组合物为单位剂型，其含有50mg(以脱氢表雄酮计)脱氢表雄酮(DHEA)或脱氢表雄酮硫酸酯、1g(以左卡尼汀计)左卡尼汀或其可药用盐、0.5g(以乙酰左卡尼汀计)乙酰左卡尼汀或可药用盐。
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使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现有的被认为是迄今最好的一种用于治疗男性少精弱精的膳食补充剂(Proxeed
/勃锐精增效版)表现出更优良和确切的效果。
具体实施方式
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左卡尼汀、乙酰左卡尼汀和脱氢表雄酮干混悬剂的制备(1000袋处方)
| 左卡尼汀 | 1000g |
| 乙酰左卡尼汀 | 500g |
| 脱氢表雄酮 | 50g |
| 蔗糖 | 2000g |
| 三氯蔗糖 | 100g |
| 苯甲酸钠 | 50g |
| 草莓味香料 | 10g |
| 黄原胶 | 50g |
| 胶态二氧化硅 | 20g |
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。
实施例2左卡尼汀富马酸盐、乙酰左卡尼汀和脱氢表雄酮颗粒剂的制备(1000袋处方)
将原料药过80目筛，备用。将蔗糖和阿拉伯树胶于高速多功能粉碎机中粉碎，过60目筛备用，其它各辅料分别过60目筛备用。称取处方量的羟丙基纤维素，加入适量的纯化水使其溶解，搅拌均匀，备用。称取处方量的蔗糖、糊精、西黄蓍胶、阿拉伯胶，左卡尼汀富马酸盐、乙酰左卡尼汀和脱氢表雄酮到湿法制粒机中搅拌均匀，然后加入上述制备的粘合剂，搅拌均匀，制成软材。将上述软材于摇摆颗粒机中(40目筛)制粒。将上述颗粒于60℃流化床中干燥至水分小于2％。将干燥后的颗粒于摇摆颗粒机(24目筛)中整粒。颗粒分装机中进行分装，即得。
实施例3左卡尼汀、乙酰左卡尼汀富马酸盐和脱氢表雄酮口服液的制备(1000支处方)
称取处方量的糖精钠、苯甲酸钠、DL-苹果酸、左卡尼汀、乙酰左卡尼汀富马酸盐和脱氢表雄酮加入到总体积80％的纯化水中搅拌使溶解，补加纯化水至全量。搅拌均匀后过滤，将所得滤液灌装至钠钙玻璃管制口服液瓶、轧盖、105℃下热压灭菌30分钟，即得。
实施例4左卡尼汀富马酸盐、乙酰左卡尼汀富马酸盐和脱氢表雄酮胶囊的制备(1000粒处方)
称取500g95％的乙醇，加入纯化水至950g，配成50％的乙醇溶液，加入50g聚维酮k30 搅拌使溶解，即得5％PVP50％乙醇溶液，备用。将原辅料分别过80目筛备用。称取处方量的左卡尼汀富马酸盐、乙酰左卡尼汀富马酸盐和脱氢表雄酮、微晶纤维素、交聚维酮、十二烷基硫酸钠充分混合均匀。用上述5％PVP50％的乙醇溶液制软材，过16目筛制粒，55℃～60℃烘干。将烘干后的颗粒16目筛整粒，加入处方量的二氧化硅，混合均匀。确定粒重后灌装入胶囊，即得。
实施例5左卡尼汀、乙酰左卡尼汀和脱氢表雄酮硫酸酯分散片的制备(1000片处方)
称取处方量的乙醇，加入处方量的聚维酮K30，搅拌使溶解，配成3％聚维酮K30乙醇溶液，备用。将原、辅料过60目筛，备用。将主药与内加量的交联聚维酮、乳糖、甘露醇、阿司帕坦、桔子粉末香精混合均匀。用3％聚维酮K30乙醇溶液制软材，20目筛制颗粒，湿颗粒于45℃烘干，过40目筛整粒。加入剩余量的交联聚乙烯吡咯烷酮、微晶纤维素、硬脂酸镁与干颗粒混匀。确定片重，用8mm冲头压片，即得。
实施例6本发明组合物对小鼠精子畸形的影响
动物分组：选择健康清洁级雄性昆明种小鼠，体重18-22g，常规适应性喂养2天后，随机分为2组(空白组、阳性对照组、实施例1组合物组)。
空白组溶液：等体积的纯化水。
阳性对照组溶液：取专利CN03805093的专利产品Proxeed
内容物适量溶于纯化水中，配制成含左卡尼汀3.5mg/ml，乙酰左卡尼汀1.75mg/ml，丙酰左卡尼汀0.875mg/ml的溶液。
实施例1组合物：取本发明的实施例1组合物内容物适量溶于纯化水中，配制成含左卡尼汀3.5mg/ml，乙酰左卡尼汀1.75mg/ml，脱氢表雄酮0.175mg/ml的溶液。
给药剂量的确定：根据本发明组合物给人推荐剂量(2g左卡尼汀/1g乙酰左卡尼汀/0.1g脱氢表雄酮)的小鼠等效剂量作为的灌胃剂量。
实验方法：每天灌胃给药1次，连续给药12周天。于灌胃灌胃给药12周颈椎脱臼处死小鼠，取附睾尾剪碎，置生理盐水中于37℃游离，过滤，涂片，甲醇固定，最后用曙红染色制片。每只小鼠观察5000个精子中的异常精子数。
表1各组小鼠精子畸形率比较
*P<0.05，**P<0.01vs空白组；#P<0.05vs阳性对照组
由结果可知，阳性对照组和实施例1组合物组均显著降低小鼠基础精子畸形率，且本发明实施例1组合物组要优于阳性对照组，表明本发明具有更优异的改善精子质量的作用。
实施例7本发明组合物对实验性少精、弱精症大鼠精子影响
药物的配制：
空白组溶液：等体积的纯化水。
阳性对照组溶液：取专利CN03805093的专利产品Proxeed
内容物适量溶于纯化水中，配制成含左卡尼汀0.7mg/ml，乙酰左卡尼汀0.35mg/ml，丙酰左卡尼汀0.175mg/ml的溶液。
实施例2组合物：取本发明的实施例2组合物内容物适量溶于纯化水中，配制成含左卡尼汀0.7mg/ml，乙酰左卡尼汀0.35mg/ml，脱氢表雄酮0.035mg/ml的溶液。
按照文献《童建军，孙烨等，雷公藤多甙对雄性大鼠抗生育作用的研究，中国药学杂志， 1991,26(2)：85～87.》中的方法建立少精弱精症动物模型：
实验方法：取40只12周雄性SD大鼠，随机分为4组，每组10只。分别为：
正常对照组：大鼠每日灌胃给予等体积的纯化水，共给药6周，普通饲养60天后处死后取材测定精子活率得分(SSA)、精子密度(SC)、血清睾酮(CA)和睾丸体重比(RWT-B)。
模型组：大鼠每日灌胃给予雷公藤多甙片10mg/kg，共给药6周，普通饲养60天处死后取材测定精子活率得分(SSA)、精子密度(SC)、血清睾酮(CA)和睾丸体重比(RWT-B)，根据与正常对照组的比较评价建模的情况。
阳性对照组：大鼠每日灌胃给予雷公藤多甙片10mg/kg，共给药6周，之后每天灌胃给予阳性对照药，灌服12周取材，测定精子活率得分(SSA)、精子密度(SC)、血清睾酮(CA)和睾丸体重比(RWT-B)，从而评价阳性对照药对实验性少精、弱精症大鼠的治疗效果。
实施例2组合物组：大鼠每日灌胃给予雷公藤多甙片20mg/kg/d，共给药6周，之后每天灌胃给予本发明实施例2组合物，灌服12周取材，测定精子活率得分(SSA)、精子密度(SC)、血清睾酮(CA)和睾丸体重比(RWT-B)，从而评价本发明组合物对实验性少精、弱精症大鼠的治疗效果。试验结果见下表：
表2试验药物对大鼠少精弱精症的影响(
n＝10)
由结果可知，与正常对照组相比，模型组各项指标均显著低于正常对照组(p<0.01),说明建模成功。与少精弱精的模型组相比，本发明所述的组合物可以显著提高各组大鼠的精子活率得分、精子密度、血清睾酮及睾丸体重比等(p<0.01)，也优于阳性对照组，提示本发明所述组合物可以明显改善实验大鼠少精、弱精的症状。
Claims (7)
1.一种组合物在制备用于改善男性少精或弱精以及减少精子畸形的药物中的用途，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；
iii)乙酰左卡尼汀或其可药用盐；和
iv)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，其中所述组合物中的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、和iii)乙酰左卡尼汀或其可药用盐的重量比为1：10～30：10～30，其中所述脱氢表雄酮或脱氢表雄酮硫酸酯以脱氢表雄酮计，所述左卡尼汀或其可药用盐以左卡尼汀计，所述乙酰左卡尼汀或其可药用盐以乙酰左卡尼汀计。
3.根据权利要求1所述的用途，其中所述组合物中的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、和iii)乙酰左卡尼汀或可药用盐的重量比为1：15～25：15～25，其中所述脱氢表雄酮或脱氢表雄酮硫酸酯以脱氢表雄酮计，所述左卡尼汀或其可药用盐以左卡尼汀计，所述乙酰左卡尼汀或其可药用盐以乙酰左卡尼汀计。
4.根据权利要求1所述的用途，其中所述组合物中的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、和iii)乙酰左卡尼汀或可药用盐的重量比为1：20：10，其中所述脱氢表雄酮或脱氢表雄酮硫酸酯以脱氢表雄酮计，所述左卡尼汀或其可药用盐以左卡尼汀计，所述乙酰左卡尼汀或其可药用盐以乙酰左卡尼汀计。
5.根据权利要求1所述的用途，其中所述组合物为单位剂型，其包含：
i)以脱氢表雄酮计50mg的脱氢表雄酮或脱氢表雄酮硫酸酯；
ii)以左卡尼汀计1g的左卡尼汀或其可药用盐；和
iii)以乙酰左卡尼汀计0.5g的乙酰左卡尼汀或其可药用盐。
6.根据权利要求1所述的用途，其中所述组合物的剂型为口服溶液剂、硬胶囊剂、软胶囊剂、片剂、颗粒剂或干混悬剂。
7.根据权利要求6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；
ii)左卡尼汀或其可药用盐；和
iii)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口服溶液剂、颗粒剂、硬胶囊剂、软胶囊剂或干混悬剂。
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| Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term daily oral administration to healthy young men;Acacio, BD; Stanczyk, FZ; Mullin, P; 等;《FERTILITY AND STERILITY》;20040331;第81卷(第3期);第595-604页 * |
| Spermatogenesis in immature hypophysectomized rats injected with androgens;Cutuly, E; Cutuly, EC; McCullagh, DR;《PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE》;19380630;第38卷(第5期);第818-823页 * |
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