CN113827608A - 一种含有嘌呤核苷的高效型米诺地尔生发酊剂及其制备方法 - Google Patents
一种含有嘌呤核苷的高效型米诺地尔生发酊剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含有嘌呤核苷的高效型米诺地尔生发酊剂及其制备方法,而嘌呤核苷主要指腺嘌呤核苷(腺苷)。本发明含有嘌呤核苷的高效型米诺地尔生发酊剂由以下原料制得:米诺地尔、腺苷、西地那非、非那雄胺、乙醇、丙二醇、无菌蒸馏水、水溶性氮酮、维甲酸、醋酸氟轻松、壬二酸、咖啡因和乙二胺四乙酸二钠。本发明所述生发酊剂安全、高效,生发周期短,作用效果佳。
Description
技术领域
本发明涉及一种生发酊剂,特别是涉及一种用于治疗脱发的含有嘌呤核苷的高效型米诺地尔生发酊剂制备方法。
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,目前世界上被认为对脱发较为有效的外用化学药。米诺地尔可通过多种途径生发,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。已有充分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,并且在一年的治疗后整体头发密度虽然会增加,但是依然有不少毛发较为细软,其增粗增厚效果不足,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。
现有米诺地尔酊剂产品主要存在的问题是需长期用药,治疗周期长,效率低下,且药物渗透性不足,利用率低,一大部分患者容易发生皮炎,治疗容易达到瓶颈,一般容易增加毛发密度,但是在头发增粗增厚上效果较差,单独使用效果不佳,需要和内服非那雄胺联合用药才能达到较好效果,而非那雄胺为一种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、心情抑郁和胸部发育等问题。
发明内容
本发明要解决的技术问题是提供一种安全、高效且可局部抑制DHT,减少内服非那雄胺对其他雄激素依赖性组织的副作用,并含有嘌呤核苷的高效型米诺地尔生发酊剂及其制备方法。
本发明一种含有嘌呤核苷的高效型米诺地尔生发酊剂制备方法,配制1000ml含有嘌呤核苷的高效型米诺地尔生发酊剂需要下列原料:米诺地尔20-75g、腺苷5-15g、西地那非10-30g、非那雄胺0.5-2.5g、醋酸氟轻松0.1-0.5g、壬二酸5-20g、咖啡因0.01-0.03g、75%乙醇溶液200-400ml、丙二醇400-650ml、水溶性氮酮10-25ml、维甲酸0.1-0.25g和乙二胺四乙酸二钠0.5-1g,其中75%乙醇溶液指的是体积浓度。
优选的,配制1000ml生发酊剂需要下列原料:米诺地尔30-70g、腺苷6-12g、西地那非10-18g、非那雄胺1.5-2g、醋酸氟轻松0.1-0.3g、壬二酸10-18g、咖啡因0.01-0.02g、75%乙醇溶液250-300ml、丙二醇550-600ml、水溶性氮酮15-20ml、维甲酸0.1-0.25g和乙二胺四乙酸二钠0.5-1g,更优选,配制1000ml含有嘌呤核苷的高效型米诺地尔生发酊剂需要下列原料:米诺地尔50g、腺苷8g、西地那非10g、非那雄胺2g、醋酸氟轻松0.1g、壬二酸15g、咖啡因0.01g、75%乙醇溶液300ml、丙二醇500ml、水溶性氮酮15ml、维甲酸0.2g和乙二胺四乙酸二钠0.5g。
本发明所述一种含有嘌呤核苷的高效型米诺地尔生发酊剂的第一种制备方法,包括以下步骤:
(1)按配比分别称量各原料,将腺苷与50-200ml无菌蒸馏水混合,在水浴30℃-60℃封口条件下通过磁力搅拌10-20分钟,得到液体A;
(2)将米诺地尔加入75%乙醇溶液中通过磁力搅拌15-25分钟,静置10-20分钟,得到上清液B和米诺地尔沉淀;
(3)将西地那非与上清液B混合,搅拌10-20分钟,静置10-20分钟,得到上清液C和西地那非沉淀;
(4)将壬二酸与上清液C混合,搅拌5-10分钟,得到液体D;
(5)将水溶性氮酮和丙二醇加入液体D中得到液体E;
(6)将液体A和液体E混合搅拌均匀后得到液体F,再将米诺地尔沉淀、西地那非沉淀、非那雄胺、维甲酸、醋酸氟轻松、咖啡因和乙二胺四乙酸二钠加入液体F中,并用无菌蒸馏水定容至1000ml,在50℃水浴下封口磁力搅拌5-15分钟,充分混均;
(7)用φ0.22μm微孔滤膜精滤,滤液分装,入库,即得。
本发明所述一种含有嘌呤核苷的高效型米诺地尔生发酊剂的第二种制备方法,包括以下步骤:
(1)按配比分别称量各原料,将一半的丙二醇与米诺地尔混合,搅拌10-30分钟,使米诺地尔均匀分散在丙二醇中,静置5-15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)将另一半的丙二醇与西地那非固体混合,搅拌10-30分钟,让其充分溶解,静置5-15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)将腺苷固体缓慢加入50-200ml无菌蒸馏水中,通过磁力搅拌在水浴30℃-60℃封口条件下搅拌10-20分钟,使腺苷均匀分散溶解在无菌蒸馏水中,得溶液C;
(4)将上述得到的三种上清液A、B、C和体积浓度75%乙醇迅速混合后加入水溶性氮酮搅拌均匀得到溶液D;
(5)将非那雄胺,维甲酸,乙二胺四乙酸二钠,壬二酸,醋酸氟轻松、咖啡因以及未溶解的米诺地尔沉淀和西地那非沉淀加入溶液D中,再用无菌蒸馏水定容至1000ml,在水浴50℃下磁力搅拌20-50分钟,让其充分溶解,用φ0.22μm微孔滤膜精滤,滤液分装,即得,得到的生发酊剂。
本发明所述一种含有嘌呤核苷的高效型米诺地尔生发酊剂的第三种制备方法,包括以下步骤:
(1)按配比分别称量各原料,先将腺苷加入到50-200ml无菌蒸馏水中,在水浴30-60℃下封口磁力搅拌10-20分钟得到溶液A;将壬二酸、非那雄胺、醋酸氟轻松、咖啡因和维甲酸加入体积浓度为75%乙醇溶液中,在封口磁力搅拌5-20分钟后,再静置5-15分钟,使不溶的固体充分沉淀,得到上清溶液B和沉淀1;
(2)将丙二醇与米诺地尔和西地那非固体混合,磁力搅拌5-20分钟,让其充分溶解均匀,静置5-15分钟,得到上清溶液C以及沉淀2;
(3)将A和C溶液缓慢加入B溶液,边加边搅拌,使之充分混合一起,得到溶液D;
(4)将水溶性氮酮加入D溶液,边加边搅拌,得到溶液E;
(5)将乙二胺四乙酸二钠、沉淀1和沉淀2加入溶液E后,再将无菌蒸馏水加入溶液E中定容至1000ml,在50℃水浴下磁力搅拌10-30分钟,使其充分溶解,静置5-15分钟,冷却至室温,得到溶液F;
(6)混合均匀后用φ0.22μm微孔滤膜精滤,滤液分装,即得到的生发酊剂。
将上述方法得到的含有嘌呤核苷的高效型米诺地尔生发酊剂保存在12-28℃的温度范围,避光保存,当温度低于10℃时腺苷、米诺地尔和西地那非等容易析出,温度也不宜过高,当温度高于30℃容易加速生发酊的氧化和细菌滋生,从而影响保质期。
本发明使用的水溶性氮酮即月桂氮酮,促进药物渗透作用,市场有售。
目前市面上不少生发产品主要含有米诺地尔,但未见含有腺苷或两者联合应用的高效型生发酊,其中米诺地尔酊剂里成分的基础物质一般为丙二醇、乙醇和水,而这三种基础物质对腺苷和西地那非同样适用,可以很好的溶解,并且可以起到透皮保湿作用。
本发明的显著优点如下:
本发明生发酊组分中,米诺地尔可开启钾离子通道,松弛头皮血管,增加毛囊的血液供应,本发明在米诺地尔基础上增加了腺苷,其为嘌呤核苷的一种,而腺苷介导的信号转导途径可使米诺地尔发挥更加有效的作用,其还可上调真皮乳头细胞中的成纤维细胞生长因子(FGF-7) /角质形成细胞生长因子(KGF)的表达,可以刺激毛乳头细胞的恢复,这对毛发生长会产生积极作用,不仅在治疗脱发中可以增加头发密度,并且可以使细软头发重新恢复粗壮;组分中含有西地那非,其为一种磷酸二酯酶5(PDE5)抑制剂,其会增加细胞内环鸟苷单磷酸(cGMP)的水平,从而引起血管舒张,促进人真皮乳头细胞增殖,并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,从而起到高效生发作用;除了含有西地那非外还含有咖啡因,咖啡因也是一种更为高效的磷酸二酯酶抑制剂,会增加细胞中环磷酸腺苷(cAMP)的水平,可逆转睾酮对角质形成细胞增殖的抑制作用,从而加速细胞代谢并刺激毛发基质角质促进形成细胞增殖——这种机制可能抵消睾酮/二氢睾酮诱导的毛囊小型化,增强毛干伸长率、延长生长期持续时间。此外,咖啡因对于女性毛囊也有更好的渗透效果,不仅可抵消了毛囊中睾酮诱导的转化生长因子-β2 表达(这是一种主要的拮抗性毛发生长调节因子),而且还可导致毛囊中胰岛素样生长因子-1(一种毛发生长的促进剂)的表达增加。同时组分中通过添加非那雄胺外用起到局部对抗DHT作用,减少内服非那雄胺对其他雄激素依赖性组织的副作用;组分中的醋酸氟轻松、壬二酸可以减少自身头皮油脂分泌以及米诺地尔和丙二醇导致的皮炎和狂脱,不仅可以整体提高患者的药物使用体验感而且可以加速毛发的恢复生长;组分中通过水溶性氮酮和维甲酸极大促进了药物渗透性,尤其是维甲酸可以促进细胞分化,对皮肤形成刺激,达到类似使用微针造成局部皮损的效果(微针的侵入式治疗后在自身恢复能力下,可以促进多种表皮生长因子的分泌,可活化毛球部位干细胞,有利于受损毛乳头细胞的恢复,而毛乳头细胞是真正决定毛发密度和毛发厚度的关键因素);所用的乙二胺四乙酸二钠,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。
附图说明
图1为实施例3用药5个月前后对比图,左用药前,右用药后;
图2为市售5%米诺地尔用药5个月后对比图,左用药前,右用药后;
图3为实施例3无腺苷成分生发酊用药5个月后对比图,左用药前,右用药后。
具体实施方式
以下结合实施例和试验数据,对本发明上述的和另外的技术优点做更详细的的说明
实施例1
用电子天平称取腺苷9克。将200ml无菌蒸馏水与腺苷混合,在水浴50℃封口条件下通过磁力搅拌15分钟,使腺苷均匀分散溶解无菌蒸馏水中,得溶液A。
用电子天平称取米诺地尔固体70克。将米诺地尔固体缓慢加入300ml体积浓度为75%乙醇溶液中,并且迅速通过磁力搅拌20分钟,让其充分溶解,静置10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B。
用电子天平称取西地那非固体10克。将西地那非固体缓慢加入溶液B中,并且迅速通过磁力搅拌10分钟,让其充分溶解,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C。
用电子天平称取壬二酸固体15克。将壬二酸固体缓慢加入溶液C中,并迅速通过磁力搅拌10分钟,使其充分溶解,记为溶液D。
用量筒量取450ml丙二醇和10ml水溶性氮酮,分别缓慢加入溶液D中,边加边通过磁力搅拌,得到溶液E。
将液体A和液体E混合搅拌均匀后得到液体F,再用电子天平分别称取非那雄胺固体2.5克、维甲酸固体0.2克、醋酸氟轻松固体0.1克、咖啡因固体0.01克、乙二胺四乙酸二钠固体0.5克。将非那雄胺固体、维甲酸固体、醋酸氟轻松固体、咖啡因固体、乙二胺四乙酸二钠固体与未溶解的米诺地尔固体和西地那非固体混合,一起缓慢加入溶液F中,并用无菌蒸馏水定容至1000ml,在50℃水浴下搅拌15分钟,静置10分钟冷却至室温,得到溶液G。
最后用φ0.22μm微孔滤膜精滤,滤液分装,即得,得到的生发酊剂,米诺地尔浓度为7%,腺苷浓度为0.9%,西地那非浓度为1%。将得到的生发酊剂保存在室温25℃的环境中,用黑色塑料瓶避光保存。
实施例2
用电子天平称取米诺地尔固体25克。将200ml丙二醇与米诺地尔混合,搅拌20分钟,使米诺地尔均匀分散在丙二醇中,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。
用电子天平称取西地那非固体25克。将200ml丙二醇与西地那非固体混合,搅拌20分钟,让其充分溶解,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。
用电子天平称取腺苷8克。将腺苷固体缓慢加入200ml无菌蒸馏水中,通过磁力搅拌在水浴50℃封口条件下搅拌15分钟,使腺苷均匀分散溶解在无菌蒸馏水中,得溶液C。
将上述得到的三种上清液A、B、C和350ml体积浓度为75%乙醇溶液迅速混合后加入15ml水溶性氮酮搅拌均匀得到溶液D。
将2.5g非那雄胺,0.25g维甲酸,0.5g乙二胺四乙酸二钠,20g壬二酸,0.2g醋酸氟轻松、0.02g咖啡因以及未溶解的米诺地尔沉淀和西地那非沉淀加入溶液D中,再用无菌蒸馏水定容至1000ml,在水浴50℃下磁力搅拌30分钟,让其充分溶解,用φ0.22μm微孔滤膜精滤,滤液分装,即得,得到的生发酊剂,米诺地尔浓度为2.5%,腺苷为0.8%,西地那非浓度为2.5%。将得到的生发酊剂保存在室温25℃的环境中,用黑色塑料瓶避光保存。
实施例3
用电子天平称取8g腺苷,2 g非那雄胺,0.2g维甲酸,0.01g咖啡因,0.1g醋酸氟轻松和15g壬二酸,先将腺苷加入到100ml无菌蒸馏水中,在水浴50℃下封口磁力搅拌15分钟得到A溶液;将壬二酸、非那雄胺、醋酸氟轻松、咖啡因和维甲酸加入300ml体积浓度75%的乙醇溶液中,在封口磁力搅拌10分钟后,再静置10分钟,使不溶的固体充分沉淀,得到上清溶液B和沉淀1。
用电子天平称取50g米诺地尔固体,10g西地那非固体,将500ml丙二醇与米诺地尔和西地那非固体混合,磁力搅拌15分钟,让其充分溶解均匀,静置10分钟,得到上清溶液C以及沉淀2。
将A和C溶液缓慢加入B溶液,边加边搅拌,使之充分混合一起,得到溶液D。
用量筒量取15ml水溶性氮酮,将氮酮加入D溶液,边加边搅拌,得到溶液E。
用电子天平称取0.5g乙二胺四乙酸二钠,将乙二胺四乙酸二钠、沉淀1和沉淀2加入溶液E后,再将无菌蒸馏水加入溶液E中定容至1000ml,在50℃水浴下磁力搅拌15分钟,使其充分溶解,静置10分钟,冷却至室温,得到溶液F。
混合均匀后用φ0.22μm微孔滤膜精滤,滤液分装,即得到的生发酊剂,米诺地尔浓度为5%,腺苷浓度为0.8%,西地那非浓度为1%。将得到的生发酊剂保存在室温25℃的环境中,用黑色塑料瓶避光保存。
试验例
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,于头皮处涂抹,并按摩5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使用配制的不含腺苷的实施例3所制备的生发酊剂(配方原料为米诺地尔、西地那非、非那雄胺、乙二胺四乙酸二钠、壬二酸、醋酸氟轻松、咖啡因、维甲酸、水溶性氮酮、75%乙醇溶液、丙二醇,制得的生发酊剂中各物质浓度与实施例3同,其余为水),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,采集患者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 治疗前后毛发密度及直径对比
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个月内平均每人每天脱发数量为43.55根,对照组平均每人每天脱发数量分别为58.95根和47.60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、密度和直径均高于对照组,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 (5)
1.一种含有嘌呤核苷的高效型米诺地尔生发酊剂,其特征在于:配制1000ml含有嘌呤核苷的高效型米诺地尔生发酊剂需要下列原料:米诺地尔20-75g、腺苷5-15g、西地那非10-30g、非那雄胺0.5-2.5g、醋酸氟轻松0.1-0.5g、壬二酸5-20g、咖啡因0.01-0.03g、75%乙醇溶液200-400ml、丙二醇400-650ml、水溶性氮酮10-25ml、维甲酸0.1-0.25g和乙二胺四乙酸二钠0.5-1g。
2.根据权利要求1所述的一种含有嘌呤核苷的高效型米诺地尔生发酊剂,其特征在于:配制1000ml含有嘌呤核苷的高效型米诺地尔生发酊剂需要下列原料:米诺地尔30-70g、腺苷6-12g、西地那非10-18g、非那雄胺1.5-2g、醋酸氟轻松0.1-0.3g、壬二酸10-18g、咖啡因0.01-0.02g、75%乙醇溶液250-300ml、丙二醇550-600ml、水溶性氮酮15-20ml、维甲酸0.1-0.25g和乙二胺四乙酸二钠0.5-1g。
3.根据权利要求1所述的一种含有嘌呤核苷的高效型米诺地尔生发酊剂,其特征在于:配制1000ml含有嘌呤核苷的高效型米诺地尔生发酊剂需要下列原料:米诺地尔50g、腺苷8g、西地那非10g、非那雄胺2g、醋酸氟轻松0.1g、壬二酸15g、咖啡因0.01g、75%乙醇溶液300ml、丙二醇500ml、水溶性氮酮15ml、维甲酸0.2g和乙二胺四乙酸二钠0.5g。
4.根据权利要求1-3任一所述的一种含有嘌呤核苷的高效型米诺地尔生发酊剂的制备方法,其特征在于:包括以下步骤:
(1)按配比分别称量各原料,将腺苷与50-200ml无菌蒸馏水混合,在水浴30℃-60℃封口条件下通过磁力搅拌10-20分钟,得到液体A;
(2)将米诺地尔加入75%乙醇溶液中通过磁力搅拌15-25分钟,静置10-20分钟,得到上清液B和米诺地尔沉淀;
(3)将西地那非与上清液B混合,搅拌10-20分钟,静置10-20分钟,得到上清液C和西地那非沉淀;
(4)将壬二酸与上清液C混合,搅拌5-10分钟,得到液体D;
(5)将水溶性氮酮和丙二醇加入液体D中得到液体E;
(6)将液体A和液体E混合搅拌均匀后得到液体F,再将米诺地尔沉淀、西地那非沉淀、非那雄胺、维甲酸、醋酸氟轻松、咖啡因和乙二胺四乙酸二钠加入液体F中,并加入用无菌蒸馏水定容至1000ml,在50℃水浴下封口磁力搅拌5-15分钟,充分混均;
(7)用φ0.22μm微孔滤膜精滤,滤液分装,入库,即得。
5.根据权利要求4所述的制备方法,其特征在于:将含有嘌呤核苷的高效型米诺地尔生发酊剂保存在12-28℃的温度范围内,避光保存。
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