CN111840219A - 一种米诺地尔与西地那非联合的生发酊剂 - Google Patents
一种米诺地尔与西地那非联合的生发酊剂 Download PDFInfo
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Abstract
本发明公开了一种用于治疗脱发的米诺地尔与西地那非联合的生发酊剂,其是以米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠为主要原料制成。其中通过将米诺地尔和西地那非相联合,使其生发效率大大提高,并且通过添加非那雄胺起到局部对抗DHT的作用,并可减少内服非那雄胺对其他雄激素依赖性组织产生的副作用;而水溶性氮酮和维甲酸的添加可极大促进药物渗透性,大大提高药物吸收率;所用的依地酸二钠可提高生发酊剂的抗氧化能力,提高药物的利用率。
Description
技术领域
本发明涉及一种生发酊剂,特别涉及一种用于治疗脱发的高效型米诺地尔与西地那非联合酊剂。
背景技术
脱发是当代年轻人面临的一大问题,并且随时代发展脱发群体不断年轻化,脱发的原因有很多,常见的脱发疾病主要有雄激素脱发(脂溢性脱发)、遗传性脱发、斑秃等,男女皆可发病。米诺地尔(Minoxidil,化学名称为2,4-二氨基-6-哌啶基嘧啶-3-氧化物)是一种血管舒张药,是目前世界上被认为对脱发较为有效的外用化学药。目前的研究认为米诺地尔可以直接刺激毛囊上皮细胞增殖和分化、促进血管形成、增加局部血流量、开放钾离子通道,使毛囊由休止期向生长期转化。已有的临床试验证实米诺地尔对雄激素性脱发、斑秃有较好的疗效,但需长期用药维持疗效,治疗周期较长,效率较低,且药物渗透性差,利用率低,药物挥发快,一般单独使用效果不佳。
西地那非是一种磷酸二酯酶5(PDE5)抑制剂,其可增加细胞内环单磷酸鸟苷(cGMP)的水平,从而引起血管舒张,促进人真皮乳头细胞的增殖,并上调负责毛发生长的血管内皮生长因子和血小板衍生生长因子的mRNA表达,有利于毛发的生长。
目前市面上不少生发产品主要含有米诺地尔,但未有含有西地那非或是两者联合的生发产品。
发明内容
本发明的目的是提供一种安全、高效且可局部抑制DHT、减少非那雄胺副作用的米诺地尔与西地那非联合的生发酊剂。
为实现上述目的,本发明采用如下技术方案:
一种米诺地尔与西地那非联合的生发酊剂,配制1000ml所述生发酊剂需使用米诺地尔20-75g、西地那非10-30g、非那雄胺1-2.5g、乙醇200-350ml、丙二醇500-650ml、水溶性氮酮10-25ml、维甲酸0.1-0.25g、依地酸二钠0.5-1g。
优选地,配制1000ml所述生发酊剂需使用米诺地尔30-70g、西地那非10-18g、非那雄胺1.5-2g、乙醇250-300ml、丙二醇550-600ml、水溶性氮酮15-25ml、维甲酸0.1-0.25g、依地酸二钠0.5-1g。
更优选地,配制1000ml所述生发酊剂需使用米诺地尔40g、西地那非10g、非那雄胺1.5g、乙醇250ml、丙二醇550ml、水溶性氮酮25ml、维甲酸0.1g、依地酸二钠0.5g。
所述米诺地尔与西地那非联合的生发酊剂的一种制备方法包括以下步骤:
1)按配方用量分别称取米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠;
2)将米诺地尔与丙二醇混合搅拌20-30分钟,然后静置10-20分钟,得到上清液A和沉淀A;
3)在步骤2)得到的上清液A中缓慢加入西地那非并混合搅拌10-20分钟,再静置10-20分钟后得到上清液B和沉淀B;
4)将水溶性氮酮和乙醇缓慢加入到步骤3)得到的上清液B中,得到溶液C;
5)将步骤2)所得沉淀A、步骤3)所得沉淀B和非那雄胺、维甲酸缓慢加入步骤4)所得溶液C中,40℃加热搅拌5-15分钟,使其充分混匀,再经冷却,得溶液D;
6)将依地酸二钠加入溶液D中搅拌混匀,然后加入无菌蒸馏水定容至1000ml,再经0.22μm微孔滤膜精滤,滤液分装,即得。
所述米诺地尔与西地那非联合的生发酊剂的另一种制备方法包括以下步骤:
1)按配方用量分别称取米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠;
2)将米诺地尔与部分丙二醇混合搅拌10-30分钟,然后静置10-20分钟,得到上清液A和沉淀A;
3)将西地那非与剩余丙二醇混合搅拌10-30分钟,然后静置10-20分钟,得到上清液B和沉淀B;
4)将上述得到的上清液A和上清液B迅速混合,再加入乙醇和水溶性氮酮搅拌均匀,得到溶液C;
5)将非那雄胺、维甲酸、依地酸二钠以及步骤2)所得沉淀A、步骤3)所得沉淀B加入溶液C中,再加入适量无菌蒸馏水,40℃加热搅拌5-15分钟让其充分溶解,经冷却后加无菌蒸馏水定容至1000ml,再用0.22μm微孔滤膜精滤,滤液分装,即得。
所述米诺地尔与西地那非联合的生发酊剂的第三种制备方法包括以下步骤:
1)按配方用量分别称取米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠;
2)将米诺地尔、西地那非与丙二醇混合搅拌10-30分钟,得到溶液A;
3)将乙醇、水溶性氮酮在搅拌条件下依次与溶液A混合后,再继续搅拌10-20分钟,得到溶液B;
4)将适量无菌蒸馏水加入溶液B中,40℃加热搅拌5-15分钟并冷却至室温,得到溶液C;
5)将非那雄胺、维甲酸、依地酸二钠加入溶液C中,搅拌20-30分钟,再加无菌蒸馏水定容至1000ml,用0.22μm微孔滤膜精滤,滤液分装,即得。
由于温度低于10℃时米诺地尔和西地那非容易析出,且当温度低于15℃时水溶性氮酮也容易析出,而当温度高于30℃时容易加速生发酊剂的氧化和细菌滋生,从而影响保质期。因此,所制备的米诺地尔与西地那非联合的生发酊剂于12-28℃的温度范围内避光保存。
本发明在采用米诺地尔为主要原料的基础上,还添加了西地那非。经研究发现,西地那非还可增强真皮乳头细胞的增殖,上调负责毛发生长的血管内皮生长因(VEGF)和血小板衍生生长因子(PDGF)的mRNA表达,从而起到生发作用。
非那雄胺为一种4-氮杂甾体化合物,它是睾酮代谢成为更强的二氢睾丸酮过程中的细胞内酶-II型5a-还原酶的特异性抑制剂,部分患者内服非那雄胺会对其他雄激素依赖性组织产生副作用,如射精障碍,性欲减弱和胸部发育等问题。本发明将米诺地尔、西地那非与非那雄胺联合用药能达到良好协同效果,且其外用可减少内服非那雄胺造成的副作用。
此外,依地酸二钠、水溶性氮酮和维甲酸等辅料的添加可提高所得酊剂的抗氧化性和药物渗透性。
总之,本发明米诺地尔与西地那非联合的生发酊剂中,通过米诺地尔和西地那非相联合,使其生发效率大大提高,解决了单独使用米诺地尔生发速度慢的问题;同时,通过添加非那雄胺起到局部对抗DHT的作用,并可减少内服非那雄胺对其他雄激素依赖性组织引起的副作用;而通过水溶性氮酮和维甲酸的添加极大促进了药物渗透性,大大提高药物吸收率,其中维甲酸还可促进基底层细胞分化和角质层形成减少,可上调对毛囊分化和生长期关键作用的生长因子,溶解角质,减少皮脂腺分泌,促使上皮细胞增殖分化,增加毛发生长率;所用的依地酸二钠可提高生发酊剂的抗氧化能力,提高药物的利用率,因此,该产品具有良好的推广价值及市场前景。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
实施例1
1)称取米诺地尔固体70g,将其与600ml丙二醇混合搅拌25分钟,使米诺地尔均匀分散在丙二醇中,然后静置15分钟,使不溶的米诺地尔充分沉淀,上清液倾倒出来记为溶液A;
2)称取西地那非固体10g,缓慢加入溶液A中,并且迅速搅拌15分钟,让其充分溶解,再静置10分钟,使不溶的西地那非充分沉淀,上清液倾倒出来记为溶液B;
3)量取300ml乙醇和10ml水溶性氮酮,将其分别缓慢加入溶液B中,边加边搅拌,得到溶液C;
4)分别称取非那雄胺固体2.5g和维甲酸固体0.2g,将其与步骤1)中未溶解的米诺地尔沉淀和步骤2)中未溶解的西地那非沉淀混合后,一起缓慢加入溶液C中,在40℃水浴下搅拌10分钟,再静置10分钟使其冷却至室温,得到溶液D;
5)称取0.5g依地酸二钠,将其加入溶液D中,充分搅拌均匀,然后加入无菌蒸馏水定容至1000ml,用φ0.22μm微孔滤膜精滤,滤液分装,即得生发酊剂,将得到的生发酊剂于室温25℃的环境中用黑色塑料瓶避光保存。
实施例2
1)称取米诺地尔固体25g,将其与250ml丙二醇混合搅拌20分钟,使米诺地尔均匀分散在丙二醇中,然后静置15分钟,使不溶的米诺地尔充分沉淀,上清液倾倒出来记为溶液A;
2)称取西地那非固体25g,将其与250ml丙二醇混合搅拌20分钟,让其充分溶解,然后静置15分钟,使不溶的西地那非充分沉淀,上清液倾倒出来记为溶液B;
3)将上述得到的溶液A和溶液B迅速混合,再加入250ml乙醇和15ml水溶性氮酮搅拌均匀得到溶液C;
4)将2.5g非那雄胺,0.25g维甲酸,0.5g依地酸二钠,以及步骤1)中未溶解的米诺地尔沉淀和步骤2)中未溶解的西地那非沉淀加入溶液C中,再加入适量无菌蒸馏水,在40℃水浴下搅拌10分钟让其充分溶解,然后静置20分钟,再冷却至室温,最后加无菌蒸馏水定容至1000ml,用φ0.22μm微孔滤膜精滤,滤液分装,即得生发酊剂,将得到的生发酊剂于室温25℃的环境中用黑色塑料瓶避光保存。
实施例3
1)称取米诺地尔固体40g,西地那非固体10g,将其与550ml丙二醇混合搅拌5分钟,让固体大体溶解均匀,得到溶液A;
2)量取250ml乙醇,25ml水溶性氮酮,在搅拌条件下依次与溶液A混合,混合后再继续搅拌15分钟,得到溶液B;
3)将适量无菌蒸馏水加入溶液B中,在40℃水浴下搅拌10分钟使其充分溶解,然后静置20分钟,冷却至室温,得到溶液C;
4)将1.5g非那雄胺,0.1g维甲酸,0.5g依地酸二钠加入溶液C中,搅拌30分钟,再加无菌蒸馏水定容至1000ml,混合均匀后用φ0.22μm微孔滤膜精滤,滤液分装,即得生发酊剂,将得到的生发酊剂于室温25℃的环境中用黑色塑料瓶避光保存。
功效试验
选取60名雄性激素脱发患者,随机分成治疗组和对照组A、B各20名,治疗组使用实施例3所制备的生发酊剂,使用方法为早晚各一次,每次1ml左右,于头皮出涂抹,并按摩2分钟直到充分吸收,连续使用5个月;对照组A使用市售5%的米诺地尔酊剂(配方原料为米诺地尔、乙醇、丙二醇、水),对照组B使用配制的1%的西地那非酊剂(配方原料为西地那非、乙醇、丙二醇、水),使用方法和疗程同治疗组。使用过程中以每天早晨洗头留在盆内的头发量计算脱发数量;5个月后,通过毛发镜仪器放大70倍,分别采集患者左侧、右侧和头顶固定靶区非偏振光源照片,计算每平方厘米面积的毛发数量。结果见表1、2。
表1 治疗过程脱发数量对比
表2 治疗前后不同部位毛发密度对比
结果显示,治疗组患者治疗期间,脱发数量明显少于对照组,治疗组5个月平均每人每天脱发数量为46.55根,对照组平均每人每天脱发数量分别为58.42根和57.50根;五个月后治疗组和对照组患者的脱发处均有新的毛发长出,但治疗组的毛发生长速度和密度均高于对照组,且并未出现口服非那雄胺常出现的副作用(如射精障碍,性欲不振,胸部疼痛,胸部发育等现象)。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (6)
1.一种米诺地尔与西地那非联合的生发酊剂,其特征在于:配制1000ml所述生发酊剂需使用米诺地尔20-75g、西地那非10-30g、非那雄胺1-2.5g、乙醇200-350ml、丙二醇500-650ml、水溶性氮酮10-25ml、维甲酸0.1-0.25g、依地酸二钠0.5-1g。
2.根据权利要求1所述的米诺地尔与西地那非联合的生发酊剂,其特征在于:配制1000ml所述生发酊剂需使用米诺地尔30-70g、西地那非10-18g、非那雄胺1.5-2g、乙醇250-300ml、丙二醇550-600ml、水溶性氮酮15-25ml、维甲酸0.1-0.25g、依地酸二钠0.5-1g。
3.根据权利要求1所述的米诺地尔与西地那非联合的生发酊剂,其特征在于:配制1000ml所述生发酊剂需使用米诺地尔40g、西地那非10g、非那雄胺1.5g、乙醇250ml、丙二醇550ml、水溶性氮酮25ml、维甲酸0.1g、依地酸二钠0.5g。
4.权利要求1-3任一所述的米诺地尔与西地那非联合的生发酊剂,其特征在于:其制备方法包括以下步骤:
1)按配方用量分别称取米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠;
2)将米诺地尔与丙二醇混合搅拌20-30分钟,然后静置10-20分钟,得到上清液A和沉淀A;
3)在步骤2)得到的上清液A中缓慢加入西地那非并混合搅拌10-20分钟,再静置10-20分钟后得到上清液B和沉淀B;
4)将水溶性氮酮和乙醇缓慢加入到步骤3)得到的上清液B中,得到溶液C;
5)将步骤2)所得沉淀A、步骤3)所得沉淀B和非那雄胺、维甲酸缓慢加入步骤4)所得溶液C中,40℃加热搅拌5-15分钟,使其充分混匀,再经冷却,得溶液D;
6)将依地酸二钠加入溶液D中搅拌混匀,然后加入无菌蒸馏水定容至1000ml,再经0.22μm微孔滤膜精滤,滤液分装,即得。
5.权利要求1-3任一所述的米诺地尔与西地那非联合的生发酊剂,其特征在于:其制备方法包括以下步骤:
1)按配方用量分别称取米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠;
2)将米诺地尔与部分丙二醇混合搅拌10-30分钟,然后静置10-20分钟,得到上清液A和沉淀A;
3)将西地那非与剩余丙二醇混合搅拌10-30分钟,然后静置10-20分钟,得到上清液B和沉淀B;
4)将上述得到的上清液A和上清液B迅速混合,再加入乙醇和水溶性氮酮搅拌均匀,得到溶液C;
5)将非那雄胺、维甲酸、依地酸二钠以及步骤2)所得沉淀A、步骤3)所得沉淀B加入溶液C中,再加入适量无菌蒸馏水,40℃加热搅拌5-15分钟让其充分溶解,经冷却后加无菌蒸馏水定容至1000ml,再用0.22μm微孔滤膜精滤,滤液分装,即得。
6.权利要求1-3任一所述的米诺地尔与西地那非联合的生发酊剂,其特征在于:其制备方法包括以下步骤:
1)按配方用量分别称取米诺地尔、西地那非、非那雄胺、乙醇、丙二醇、水溶性氮酮、维甲酸和依地酸二钠;
2)将米诺地尔、西地那非与丙二醇混合搅拌10-30分钟,得到溶液A;
3)将乙醇、水溶性氮酮在搅拌条件下依次与溶液A混合后,再继续搅拌10-20分钟,得到溶液B;
4)将适量无菌蒸馏水加入溶液B中,40℃加热搅拌5-15分钟并冷却至室温,得到溶液C;
5)将非那雄胺、维甲酸、依地酸二钠加入溶液C中,搅拌20-30分钟,再加无菌蒸馏水定容至1000ml,用0.22μm微孔滤膜精滤,滤液分装,即得。
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