CN112336688A - 一种水包油型复方氢醌乳剂及其制备方法和其应用 - Google Patents
一种水包油型复方氢醌乳剂及其制备方法和其应用 Download PDFInfo
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- CN112336688A CN112336688A CN202011224156.XA CN202011224156A CN112336688A CN 112336688 A CN112336688 A CN 112336688A CN 202011224156 A CN202011224156 A CN 202011224156A CN 112336688 A CN112336688 A CN 112336688A
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- Prior art keywords
- hydroquinone
- pharmaceutically acceptable
- emulsion
- oil
- ester
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Abstract
本发明涉及一种水包油型复方氢醌乳剂及其制备方法和其应用。本发明提供一种水包油型复方氢醌乳剂,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1‑4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01‑0.05%(w/w)和类维生素A 0.01‑0.05%(w/w)组成,所述的药学上可接受的载体中含有缓释剂0.5‑1%(w/w)。本发明的复方氢醌乳剂具有祛斑疗效确切,皮肤刺激性低等优点。
Description
技术领域
本发明属于医药技术领域,具体涉及一种水包油型复方氢醌乳剂及其制备方法和其应用。
背景技术
氢醌(又称氢醌)作为酪氨酸酶抑制剂主要通过络合作用抑制酪氨酸酶活性,调控黑色素细胞代谢过程,使表皮内多巴反应阳性黑色素细胞数量显著减少,产生可逆性的皮肤褪色。Oette l于1936年首次提出氢醌具有美白皮肤的作用。自20世纪60年代起,许多国家将氢醌的单方制剂或复方制剂用作化妆品的增白剂和皮肤科用于治疗色素沉着症、祛斑等外用制剂。但须严格控制氢醌的用量。
CN1738587B公开了一种具有优良祛斑效果的复方氢醌乳剂,该乳剂中含有活性组分和非活性组分,其中,活性组分为氟轻松0.01%(0.1mg)、对苯二酚4%(40mg)和维甲酸0.05%(0.5mg),非活性组分为丁基化羟基甲苯、鲸蜡醇、柠檬酸、甘油、硬脂酸甘油酯、硅酸铝镁、甲基葡萄糖甙十环氧乙烷(methyl gluceth10)、对羟基苯甲酸甲酯、PEG-100硬脂酸酯、对羟基苯甲酸丙酯、净化水、焦亚硫酸钠、硬脂酸和十八烷醇。但该乳剂存在皮肤刺激,如红斑、脱屑、皮肤烧灼感、干燥、瘙痒等皮肤不良反应。为此,急需研究降低刺激性、提高皮肤舒适感、适应更多敏感性皮肤的复方氢醌制剂。
发明内容
本发明的目的在于提供一种水包油型复方氢醌乳剂,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)和类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)组成,所述的药学上可接受的载体中含有缓释剂0.5-1%(w/w)。
本发明的优选技术方案中,所述乳剂包括油组分10-40%(w/w)、乳化剂1-5%(w/w)、活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)和类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)组成,所述的药学上可接受的载体中含有缓释剂0.5-1%(w/w)。
本发明的优选技术方案中,所述药学上可接受的盐选自盐酸盐、氢溴酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、富马酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐的任一种或其组合。
本发明的优选技术方案中,所述的药学上可接受的酯包括但不限于丁酸酯、丙酸酯、乙酸酯、甲酸酯、棕榈酸酯、昔萘酸酯、磷酸酯、硫酸酯的任一种或其组合。
本发明的优选技术方案中,所述外用皮质类固醇或其药学上可接受的盐或其酯的含量为0.02-0.04%(w/w)。
本发明的优选技术方案中,所述外用皮质类固醇或其药学上可接受的盐或其酯选自氟轻松、醋酸氟轻松、氟氯舒松、地塞米松双丙酸酯、氯倍他索丙酸酯中的任一种或其组合。
本发明的优选技术方案中,所述类维生素A或其药学上可接受的盐或其酯的含量为0.02-0.04%(w/w)。
本发明的优选技术方案中,所述类维生素A或其药学上可接受的盐或其酯选自维A酸、异维A酸、维生素A乙酸酯、阿达帕林、他扎罗汀的任一种或其组合。
本发明的优选技术方案中,所述乳剂中的氢醌含量为1.5-3.5%(w/w),优选为2-3%(w/w)。
本发明的优选技术方案中,所述氢醌的纯度不低于99.0%,优选不低于99.5%,更优选不低于99.9%。
本发明的优选技术方案中,所述氢醌中对苯醌的含量不高于0.1%,优选不高于0.08%,还优选不高于0.05%,更优选不高于0.03%。
本发明的优选技术方案中,所述氢醌中对苯醌、苯胺、硝基苯的任一含量均不高于0.08%,优选不高于0.05%,还优选不高于0.03%。
本发明的优选技术方案中,所述氢醌中除对苯醌、苯胺、硝基苯之外的有关物质的总含量不高于0.3%,优选不高于0.1%,还优选不高于0.05%。
本发明的优选技术方案中,所述有关物质选自对苯醌、苯胺、硝基苯、连苯三酚、间苯二酚、邻苯二酚的任一种或组合。
本发明的优选技术方案中,所述有关物质选自对苯醌、苯胺、硝基苯、连苯三酚、间苯二酚、邻苯二酚、偏苯三酚、间苯三酚、苯酚、氢醌硫酸钾的任一种或组合。
本发明的优选技术方案中,所述氢醌为其环糊精包合物,优选包合物中氢醌:环糊精的摩尔比为1∶1-10,优选为1:3-5。
本发明的优选技术方案中,所述环糊精选自α-环糊精、β-环糊精、γ-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精、二羟丙基-β-环糊精、甲基-β-环糊精、葡萄糖环糊精、麦芽糖环糊精、麦芽三糖环糊精、羧甲基环糊精、磺烷基环糊精中的任一种或其组合。
本发明的优选技术方案中,所述缓释剂含量为0.6-0.9%(w/w),优选为0.7-0.8%(w/w)。
本发明的优选技术方案中,所述缓释剂为二聚甘油。
本发明的优选技术方案中,所述乳剂中还包括透皮吸收促进剂。
本发明的优选技术方案中,所述乳剂中的透皮吸收促进剂的含量为1-5%(w/w),优选为1.5-4%(w/w),更优选为2-3%(w/w)。
本发明的优选技术方案中,所述透皮吸收剂选自冰片、薄荷、氮酮中的任一种或其组合。
本发明的优选技术方案中,所述透皮吸收剂选自氮酮和冰片的组合、氮酮和薄荷的组合、氮酮和薄荷及冰片的组合的任一种。
本发明的优选技术方案中,所述氮酮和冰片、氮酮和薄荷的任一组合中,氮酮:冰片或氮酮:薄荷的任一重量比为1:1-6:1,优选为2:1-5:1,更优选为3:1-4:1。
本发明的优选技术方案中,所述氮酮、薄荷与冰片的三者组合中,氮酮:薄荷:冰片的重量比为1:1:1-6:1:1,优选为1.5:1:1-5:1:1,更优选为2:1:1-3:1:1。
本发明的优选技术方案中,所述乳剂中的油组分含量为12-35%(w/w),优选为15-30%(w/w)。
本发明的优选技术方案中,所述油相中的油组分选自硅油、二甲基硅氧烷、硬脂酸、聚二甲基硅氧烷、碳酸二辛酯、乳木果油、辛酸癸酸甘油酯、棕榈酸异丙酯、天然角鯊烷、合成角鯊烷、医用白油10号、霍霍巴油、甜杏仁油、鳄梨油、医用凡士林、医用白油20号、十八醇、地蜡、微晶蜡、蜂蜡、异十六烷、十六醇、二十二硅氧基二甲基硅氧烷、硅蜡、肉豆蒄酸肉豆蒄酯、庚酸硬脂酯中的任一种或其组合。
本发明的优选技术方案中,所述乳剂中的乳化剂含量为1.5-4%(w/w),优选为2-3%(w/w)。
本发明的优选技术方案中,所述乳化剂选自十六烷基醇、十六烷基葡萄糖苷、十八烷基葡萄糖苷、C14-22烷基醇、C12-20烷基葡萄糖苷、花生醇、山嵛醇、花生醇葡糖苷、聚氧乙烯-21硬脂醇醚、聚氧乙烯-2硬脂醇醚、甲基葡萄糖、甲基葡萄糖苷倍半硬脂酸酯、乙氧基化甲基葡萄糖苷倍半硬脂酸酯、单硬脂酸甘油酯、聚乙二醇(100)硬脂酸酯、乙氧烯化脂肪酸酯、聚氧乙烯二十二烷基甲基萄葡糖苷倍半硬脂酸酯中的任一种或其组合。
本发明的优选技术方案中,所述乳化剂选自NIKKOMULESE、SIMULSOL 165、MONTANOV 68、GenioCare SY、NIKKOLmulese 41、ABIL Care 85、MONTANOV 202、MONTANOV82、Synperonce PEF127、MONTANOV 68、MONTANOV L、SENSANOV WR、SKYCORE PE98、Emulsifier HP30、BRIJ 721、BRIJ 72、Arlacel 165、Arlacel 985、Span系列中的任一种或其组合。
本发明的优选技术方案中,所述乳化剂HLB值为8-18,优选为12-16,更优选为14-15。
本发明的优选技术方案中,所述药学上可接受的载体还包括美白保湿剂、增稠剂、防腐剂、酸碱调节剂、抗氧化剂的任一种或其组合。
本发明的优选技术方案中,所述乳剂中的美白保湿剂含量为1-10%(w/w),优选为3-8%(w/w),优选为4-6%(w/w)。
本发明的优选技术方案中,所述美白保湿剂选自透明质酸、甘油、1,3-丁二醇、丙二醇、鲸蜡醇、尿素、氨基酸、羊毛脂、半胱氨酸、半胱氨酸盐酸盐、L-半胱氨酸、L-半胱氨酸盐酸盐、乙酰半胱氨酸中的任一种或其组合。
本发明的优选技术方案中,乳剂中的增稠剂含量为0.1-2%(w/w),优选为0.15-1.5%(w/w),更优选为0.2-1%(w/w)。
本发明的优选技术方案中,所述增稠剂选自硅酸铝镁、聚丙烯酸钠接枝淀粉、汉生胶、聚丙烯酸酯-13、聚异丁烯、聚山梨醇酯-20、羟丙基甲基纤维素、甲基乙烯基醚-马来酸酐与1,9-癸二烯交联共聚物、羟乙基纤维素、聚丙烯酸钠HPMCHY-30T的任一种或其组合。
本发明的优选技术方案中,乳剂中的防腐剂含量为0.1-2%(w/w),优选为0.2-1.5%(w/w),更优选为0.5-1%(w/w)。
本发明的优选技术方案中,所述防腐剂选自苯氧乙醇、尼泊金甲酯丙酯、甲基异噻唑啉酮、羟苯甲酯、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲酸钠、山梨酸钾中的任一种或其组合。
本发明的优选技术方案中,所述乳剂中还含有酸碱调节剂0.5-3%(w/w),优选为1-2.5%,更优选为1.5-2%。
本发明的优选技术方案中,所述酸碱调节剂选自三乙醇胺、氢氧化钠、柠檬酸、柠檬酸钠、枸橼酸、枸橼酸钠、苹果酸、苹果酸钠、醋酸、醋酸钠中的任一种或其组合。
本发明的优选技术方案中,所述乳剂pH 5-9,优选为pH 6-7.5,更优选为pH 6.5-7。
本发明的优选技术方案中,乳剂中的抗氧化剂含量为0.1-4%(w/w),优选为0.5-3(w/w),更优选为1-2%(w/w)。
本发明的优选技术方案中,所述抗氧化剂选自亚硫酸氢钠、叔丁基对甲酚、焦亚硫酸钠、维生素E、抗坏血酸葡糖苷、抗坏血酸乙基醚、抗坏血酸棕榈酸酯、维生素C磷酸酯钠、维生素C磷酸镁、乙二胺四乙酸二钠的任一种或其组合。
本发明的优选技术方案中,所述乳剂粒径不大于300nm,优选为150-250nm,更优选为80-100nm。
本发明的优选技术方案中,所述乳剂中的氢醌含量为1-4%(w/w)、氟轻松或醋酸氟轻松含量为0.01-0.05%(w/w)和维A酸含量为0.01-0.05%(w/w),所述的药学上可接受的载体中含有0.5-1%(w/w)的二聚甘油。
本发明的优选技术方案中,所述乳剂中的氢醌含量为1.5-3.5%(w/w)、氟轻松或醋酸氟轻松含量为0.02-0.04%(w/w)和维A酸含量为0.02-0.04%(w/w),所述的药学可接受的载体中含有0.6-0.8%(w/w)的二聚甘油。
本发明的目的在于提供一种水包油型复方氢醌乳剂,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)、类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)和刺激缓解剂0.5-1%(w/w)组成。
本发明的优选技术方案中,所述乳剂包括油组分10-40%(w/w)、乳化剂1-5%(w/w)、活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)、类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)和刺激缓解剂0.5-1%(w/w)组成。
本发明的优选技术方案中,所述药学上可接受的盐选自盐酸盐、氢溴酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、富马酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐的任一种或其组合。
本发明的优选技术方案中,所述的药学上可接受的酯包括但不限于丁酸酯、丙酸酯、乙酸酯、甲酸酯、棕榈酸酯、昔萘酸酯、磷酸酯、硫酸酯的任一种或其组合。
本发明的优选技术方案中,所述的药学可接受的载体中含有缓释剂0.5-1%(w/w),优选为0.6-0.9%(w/w),更优选为0.7-0.8%(w/w)。
本发明的优选技术方案中,所述缓释剂为二聚甘油。
本发明的优选技术方案中,所述外用皮质类固醇或其药学上可接受的盐或其酯的含量为0.02-0.04%(w/w)。
本发明的优选技术方案中,所述外用皮质类固醇或其药学上可接受的盐或其酯选自氟轻松、醋酸氟轻松、氟氯舒松、地塞米松双丙酸酯、氯倍他索丙酸酯中的任一种或其组合。
本发明的优选技术方案中,所述类维生素A或其药学上可接受的盐或其酯的含量为0.02-0.04%(w/w)。
本发明的优选技术方案中,所述类维生素A或其药学上可接受的盐或其酯选自维A酸、异维A酸、维生素A乙酸酯、阿达帕林、他扎罗汀的任一种或其组合。
本发明的优选技术方案中,所述刺激缓解剂含量为0.6-0.9%(w/w),优选为0.7-0.8%(w/w)。
本发明的优选技术方案中,所述刺激缓解剂选自维生素B6、积雪草苷的任一种或其组合。
本发明的优选技术方案中,所述乳剂中的氢醌含量为1.5-3.5%(w/w),优选为2-3%(w/w)。
本发明的优选技术方案中,所述氢醌的纯度不低于99.0%,优选不低于99.5%,更优选不低于99.9%。
本发明的优选技术方案中,所述氢醌中对苯醌的含量不高于0.1%,优选不高于0.08%,还优选不高于0.05%,更优选不高于0.03%。
本发明的优选技术方案中,所述氢醌中对苯醌、苯胺、硝基苯的任一含量均不高于0.08%,优选不高于0.05%,还优选不高于0.03%。
本发明的优选技术方案中,所述氢醌中除对苯醌、苯胺、硝基苯之外的有关物质的总含量不高于0.3%,优选不高于0.1%,还优选不高于0.05%。
本发明的优选技术方案中,所述有关物质选自对苯醌、苯胺、硝基苯、连苯三酚、间苯二酚、邻苯二酚的任一种或组合。
本发明的优选技术方案中,所述有关物质选自对苯醌、苯胺、硝基苯、连苯三酚、间苯二酚、邻苯二酚、偏苯三酚、间苯三酚、苯酚、氢醌硫酸钾的任一种或组合。
本发明的优选技术方案中,所述氢醌为其环糊精包合物,优选包合物中氢醌:环糊精的摩尔比为1∶1-10,优选为1:3-5。
本发明的优选技术方案中,所述环糊精选自α-环糊精、β-环糊精、γ-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精、二羟丙基-β-环糊精、甲基-β-环糊精、葡萄糖环糊精、麦芽糖环糊精、麦芽三糖环糊精、羧甲基环糊精、磺烷基环糊精中的任一种或其组合。
本发明的优选技术方案中,所述乳剂中的油组分含量为12-35%(w/w),优选为15-30%(w/w)。
本发明的优选技术方案中,所述油相中的油组分选自硅油、二甲基硅氧烷、硬脂酸、聚二甲基硅氧烷、碳酸二辛酯、乳木果油、辛酸癸酸甘油酯、棕榈酸异丙酯、天然角鯊烷、合成角鯊烷、医用白油10号、霍霍巴油、甜杏仁油、鳄梨油、医用凡士林、医用白油20号、十八醇、地蜡、微晶蜡、蜂蜡、异十六烷、十六醇、二十二硅氧基二甲基硅氧烷、硅蜡、肉豆蒄酸肉豆蒄酯、庚酸硬脂酯中的任一种或其组合。
本发明的优选技术方案中,乳剂中的乳化剂含量为1.5-4%(w/w),优选为2-3%(w/w)。
本发明的优选技术方案中,所述乳化剂选自十六烷基醇、十六烷基葡萄糖苷、十八烷基葡萄糖苷、C14-22烷基醇、C12-20烷基葡萄糖苷、花生醇、山嵛醇、花生醇葡糖苷、聚氧乙烯-21硬脂醇醚、聚氧乙烯-2硬脂醇醚、甲基葡萄糖、甲基葡萄糖苷倍半硬脂酸酯、乙氧基化甲基葡萄糖苷倍半硬脂酸酯、单硬脂酸甘油酯、聚乙二醇(100)硬脂酸酯、乙氧烯化脂肪酸酯、聚氧乙烯二十二烷基甲基萄葡糖苷倍半硬脂酸酯中的任一种或其组合。
本发明的优选技术方案中,所述乳化剂选自SIMULSOL 165、MONTANOV 68、GenioCare SY、NIKKOMULESE 41、NIKKOLmulese 41、ABIL Care 85、MONTANOV 202、MONTANOV 82、Synperonce PE F127、MONTANOV 68、MONTANOV L、SENSANOV WR、SKYCOREPE98、Emulsifier HP30、BRIJ 721、BRIJ 72、Arlacel 165、Arlacel 985、Span系列中的任一种或其组合。
本发明的优选技术方案中,所述乳化剂HLB值为8-18,优选为12-16,更优选为14-15。
本发明的优选技术方案中,所述乳剂中还包括透皮吸收剂、美白保湿剂、增稠剂、防腐剂、酸碱调节剂、抗氧化剂的任一种或其组合。
本发明的优选技术方案中,所述乳剂中的透皮吸收促进剂含量为1-5%(w/w),优选为1.5-4%(w/w),更优选为2-3%(w/w)。
本发明的优选技术方案中,所述透皮吸收剂选自冰片、薄荷、氮酮中的任一种或其组合。
本发明的优选技术方案中,所述透皮吸收剂选自氮酮和冰片的组合、氮酮和薄荷的组合、氮酮和薄荷及冰片的组合的任一种。
本发明的优选技术方案中,所述氮酮和冰片、氮酮和薄荷的任一组合中,氮酮:冰片或氮酮:薄荷的任一重量比为1:1-6:1,优选为2:1-5:1,更优选为3:1-4:1。
本发明的优选技术方案中,所述氮酮、薄荷与冰片的三者组合中,氮酮:薄荷:冰片的重量比为1:1:1-6:1:1,优选为1.5:1:1-5:1:1,更优选为2:1:1-3:1:1。
本发明的优选技术方案中,所述药学上可接受载体还包括美白保湿剂、增稠剂、防腐剂、酸碱调节剂、抗氧化剂的任一种或其组合。
本发明的优选技术方案中,乳剂中的美白保湿剂含量为1-10%(w/w),优选为3-8%(w/w),优选为4-6%(w/w)。
本发明的优选技术方案中,所述美白保湿剂选自透明质酸、甘油、1,3-丁二醇、丙二醇、鲸蜡醇、尿素、氨基酸、羊毛脂、半胱氨酸、半胱氨酸盐酸盐、L-半胱氨酸、L-半胱氨酸盐酸盐、乙酰半胱氨酸中的任一种或其组合。
本发明的优选技术方案中,乳剂中的增稠剂含量为0.1-2%(w/w),优选为0.15-1.5%(w/w),更优选为0.2-1%(w/w)。
本发明的优选技术方案中,所述增稠剂选自硅酸铝镁、聚丙烯酸钠接枝淀粉、汉生胶、聚丙烯酸酯-13、聚异丁烯、聚山梨醇酯-20、羟丙基甲基纤维素、甲基乙烯基醚-马来酸酐与1,9-癸二烯交联共聚物、羟乙基纤维素、聚丙烯酸钠、HPMCHY-30T的任一种或其组合。
本发明的优选技术方案中,乳剂中的防腐剂含量为0.1-2%(w/w),优选为0.2-1.5%(w/w),更优选为0.5-1%(w/w)。
本发明的优选技术方案中,所述防腐剂选自苯氧乙醇、尼泊金甲酯丙酯、甲基异噻唑啉酮、羟苯甲酯、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲酸钠、山梨酸钾中的任一种或其组合。
本发明的优选技术方案中,所述乳剂中还含有酸碱调节剂0.5-3%(w/w),优选为1-2.5%,更优选为1.5-2%。
本发明的优选技术方案中,所述酸碱调节剂选自三乙醇胺、氢氧化钠、柠檬酸、柠檬酸钠、枸橼酸、枸橼酸钠、苹果酸、苹果酸钠、醋酸、醋酸钠中的任一种或其组合。
本发明的优选技术方案中,所述乳剂pH 5-9,优选为pH 6-7.5,更优选为pH 6.5-7。
本发明的优选技术方案中,乳剂中的抗氧化剂含量为0.1-4%(w/w),优选为0.5-3(w/w),更优选为1-2%(w/w)。
本发明的优选技术方案中,所述抗氧化剂选自亚硫酸氢钠、叔丁基对甲酚、焦亚硫酸钠、维生素E、抗坏血酸葡糖苷、抗坏血酸乙基醚、抗坏血酸棕榈酸酯、维生素C磷酸酯钠、维生素C磷酸镁、乙二胺四乙酸二钠的任一种或其组合。
本发明的优选技术方案中,所述乳剂粒径不大于300nm,优选为150-250nm,更优选为80-100nm。
本发明的优选技术方案中,所述乳剂中含有1-4%(w/w)的氢醌、0.01-0.05%(w/w)的氟轻松或醋酸氟轻松的任一种或其组合、0.01-0.05%(w/w)的维A酸和0.5-1%(w/w)的维生素B6。
本发明的优选技术方案中,所述乳剂中的氢醌含量为1.5-3.5%(w/w)、氟轻松或醋酸氟轻松的任一种或其组合的含量为0.02-0.04%(w/w)、维A酸含量为0.02-0.04%(w/w)和维生素B6的含量为0.6-0.8%(w/w)。
本发明的另一目的在于提供一种水包油型复方氢醌乳剂的制备方法,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)和类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)组成,所述的药学可接受的载体中含有缓释剂0.5-1%(w/w),所述复方乳剂的制备方法包括下述步骤:
1)水相制备;
2)油相制备;
3)将步骤2)制得的油相加入到步骤1)制得的水相中,进行初次均质乳化;
4)将步骤3)制得的初次均质乳化液冷却降温后,加入活性组分后,进行二次均质乳化,制得水包油乳剂。
本发明的优选技术方案中,所述活性组分中添加刺激缓解剂。
本发明的优选技术方案中,所述活性组分中添加透皮吸收促进剂。
本发明的优选技术方案中,所述水相制备中,量取所需量的水和甘油或二聚甘油的任一种或其组合,将其置于水相罐中,加热至60-90℃溶解后,维持温度备用。
本发明的优选技术方案中,所述水相制备中,在60-90℃保温条件下,加入美白保湿剂、增稠剂、乳化剂、抗氧化剂、防腐剂、pH调节剂中的任一种或其组合,搅拌至完全溶解。
本发明的优选技术方案中,所述水相制备中,加热温度为65-85℃,优选为70-80℃。
本发明的优选技术方案中,所述油相制备中,将所需量的油组分置于油相罐中,加热至60-90℃熔化后,加入余量乳化剂、防腐剂,保温备用。
本发明的优选技术方案中,所述油相制备中,加热温度为65-85℃,优选为70-80℃。
本发明的优选技术方案中,所述初次均质乳化步骤为:在搅拌、60-100℃条件下,将水相真空吸入乳化罐中后,再将油相真空吸入乳化罐中,在真空度不低于-80KPa条件下,均质乳化10-60分钟。
本发明的优选技术方案中,所述初次均质温度为65℃-95℃,优选为70-90℃,更优选为75-85℃。
本发明的优选技术方案中,所述二次均质乳化步骤为:将初次均质乳化液降温至30-60℃,加入活性成分,均质温度为30-70℃,均质乳化10-60分钟,冷却至室温,制得乳剂。
本发明的优选技术方案中,所述二次均质温度为35-65℃,优选为40-60℃。
本发明的优选技术方案中,所述的均质乳化选自超声均质乳化、高压均质乳化的任一种或其组合。
本发明的优选技术方案中,所述均质乳化时间为15-50分钟,优选为20-30分钟。
本发明的优选技术方案中,所述均质乳化压力在600-1500bar,优选为700-1200bar,更优选为800-1000bar。
本发明的优选技术方案中,所述均质乳化级数为1-6级,优选为2-5级,更优选为3-4级。
本发明的另一目的在于提供复方氢醌乳剂用于制备祛斑、增白、保湿的药物或化妆品中的应用。
本发明的另一目的在于提供复方氢醌乳剂用于制备防治皮肤病症、祛除色斑、祛除色素沉着症的制品中的应用。
本发明优选的技术方案中,所述色斑选自黄褐斑、雀斑、老年斑、肝斑、黑眼圈、严重痘印色素、炎症后色素沉着斑、局部色素沉着所致色斑、黑斑的任一种或其并发症。
为了清楚地表述本发明,本发明对下述术语界定如下:
本发明所述的“无氧条件”为隔绝氧气或隔绝其它氧化剂的反应条件,所述的“无氧条件”选自采用惰性气体保护或者加入还原剂的任一种或其组合。
本发明所述的“复合功效组分”包括活性组分或其与刺激缓解剂、缓释剂、透皮吸收促进剂中的任一种或其组合的组合。
除非另有说明,本发明所述的活性组分或药学上可接受载体的含量或占比均为其在乳剂中的含量或占比。
除非另有说明,本发明中的“份”是指重量份,“%”是指重量百分比。本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
与现有技术相比,本发明取得了下述有益效果:
1、本发明复方氢醌乳剂中增加缓释剂,减缓制剂中活性成分的刺激作用并增加活性成份的利用率;二是增加透皮促进剂,促进活性成分的透皮吸收与利用;三是增加刺激缓解剂,显著减轻皮肤刺激等不良反应。本发明的乳剂显著降低了上市乳剂的刺激性并提高了药物疗效、有效性和安全性,保障患者用药安全。
2、本发明复方氢醌乳剂中所采用的氢醌未检出对苯醌、苯胺、硝基苯等基因毒性物质,具有优良的安全性,保障患者用药安全。
3、本发明的制备方法具有操作简便、显著降低生产成本,适合于大规模工业化生产等优点。
附图说明
图1实施例1制得氢醌在0.1%冰乙酸水溶液-乙腈(97:3)条件下氢醌中有关物质的分离与检测结果;
图2实施例2制得氢醌在0.1%冰乙酸水溶液-乙腈(97:3)条件下氢醌中有关物质的分离与检测结果;
图3实施例3制得氢醌在0.1%冰乙酸水溶液-乙腈(97:3)条件下氢醌中有关物质的分离与检测结果。
图4a实施例4制得氢醌精制品在pH3.85磷酸二氢钾缓冲液-乙腈(75:25)条件下氢醌中有关物质的分离与检测结果;
图4b硝基苯在pH3.85磷酸二氢钾缓冲液-乙腈(75:25)条件下的定位检测结果;
图5实施例4制得氢醌在pH3.0磷酸二氢钾缓冲液-乙腈(95:5)条件下氢醌中有关物质的分离与检测结果;
图6实施例5制得氢醌在pH3.0磷酸二氢钾缓冲液-乙腈(95:5)条件下氢醌中有关物质的分离与检测结果;
图7实施例6制得氢醌在pH3.0磷酸二氢钾缓冲液-乙腈(95:5)条件下氢醌中有关物质的分离与检测结果;
图8 UVB和UVA连续照射4周实验动物皮肤的外观;
图9本发明的复方氢醌乳剂动物皮肤刺激性研究结果;
图10本发明的复方氢醌乳剂用于防治黑斑病的研究结果。
具体实施方式
以下参照实施例说明本发明,但本发明不局限于实施例。
实施例1本发明氢醌的制备
氢醌的制备方法,包括下述步骤:
1)将MnO2 280g、98%硫酸430g、水2.0L加入反应瓶内,在5-10℃条件下,缓慢滴加苯胺100g,搅拌,逐渐升温至25℃左右,至反应完全。将反应液在60-90℃蒸汽蒸馏,将收集的对苯醌冷凝液导入另一反应瓶;
2)在遮光、氮气保护条件下,在收集的对苯醌冷凝液中加入铁粉42g,在90-100℃条件下,搅拌反应3-4小时,至反应完全,过滤,收集的滤液减压浓缩至浓缩液中氢醌含量为35%;
3)在浓缩液中加入焦亚硫酸钠550mg、活性炭2.2g、锌粉330mg,加热至95℃,热过滤,收集滤液,降温至5℃,搅拌析晶,离心,收集湿品,60℃真空干燥,制得氢醌100.86g。
实施例2本发明氢醌的制备
氢醌的制备方法,包括下述步骤:
1)将MnO2 350g、98%硫酸500g、水2.0L加入反应瓶内,在5℃-8℃条件下,缓慢滴加苯胺100g,搅拌,逐渐升温至25℃左右,至反应完全。将反应液60-90℃条件下蒸汽蒸馏,将收集的对苯醌冷凝液导入另一反应瓶;
2)在遮光、氮气保护条件下,在收集的对苯醌冷凝液中加入铁粉60g,在90-100℃条件下,搅拌反应2-3小时,至反应完全,过滤,收集滤液减压浓缩至浓缩液中氢醌含量为25%;
3)在浓缩液中加入焦亚硫酸钠750mg、活性炭3.1g、铁粉500mg,加热至90℃,过滤,将滤液降温至8℃,搅拌析晶,离心,收集湿品,65℃真空干燥,制得氢醌96.20g。
实施例3本发明氢醌的制备
氢醌的制备方法,包括下述步骤:
1)将MnO2 250g、98%硫酸370g、水2.5L加入反应瓶内,在6-10℃条件下,缓慢滴加苯胺100g,搅拌,逐渐升温至25℃左右,至反应完全。将反应液在70-95℃蒸汽蒸馏,将收集的对苯醌冷凝液导入另一反应瓶;
2)在遮光,氮气保护条件下,在收集的对苯醌冷凝液中加入铁粉31g,在90-100℃条件下搅拌反应2-3小时,至反应完全,过滤,收集滤液减压浓缩至浓缩液中氢醌含量为30%;
3)在浓缩液中加入焦亚硫酸钠550mg、活性炭2.20g、锌粉350mg,加热至90℃,过滤,将滤液降温至10℃,搅拌析晶,离心,收集湿品,65℃真空干燥,制得氢醌98.43g。
实施例4本发明氢醌的纯化
氢醌的纯化方法,包括下述步骤:
将25g待精制的氢醌溶解于100ml 95℃水中,再加入焦亚硫酸钠140mg、活性炭600mg、锌粉100mg,搅拌40min,趁热过滤,收集滤液,降温至8℃,静置析晶11h,过滤,用水洗涤收集结晶后,将其置于70℃真空干燥,将制得的22.8g氢醌用棕色玻璃瓶内包并用黑色袋外包,瓶内充氮。
实施例5本发明氢醌的纯化
氢醌的纯化方法,包括下述步骤:
将40g待精制的氢醌溶解于120ml 92℃水中,再加入焦亚硫酸钠100mg、活性炭400mg、铁粉60mg,搅拌35min,趁热过滤,收集滤液,氮气保护,降温至5℃,静置析晶12h,过滤,用水洗涤收集结晶后,将其置于65℃真空干燥,将制得的36.8g氢醌用棕色玻璃瓶内包并用黑色袋外包,瓶内充氮。
实施例6本发明氢醌的纯化
氢醌的纯化方法,包括下述步骤:
将50g待精制的氢醌溶解于140ml 100℃水中,再加入锌粉175mg后,搅拌30min,再加入活性炭1.10g和焦亚硫酸钠275mg,搅拌10min,趁热过滤,收集滤液,氮气保护,降温至10℃,静置析晶12h,趁热过滤,用水洗涤收集结晶后,将其置于65℃真空干燥,将制得的45g氢醌用棕色玻璃瓶内包并用黑色袋外包,瓶内充氮。
实施例7-9本发明氢醌纯度检测
1、色谱条件
因素 | 色谱参数 |
色谱柱 | GL-science,WondaSil C18 Superb 4.6×250mm 5μm |
流动相 | 0.1%冰乙酸水溶液-乙腈(97:3) |
洗脱梯度 | 等度洗脱 |
流速 | 1.0ml/min |
检测波长 | 220nm |
柱温 | 30℃ |
进样体积 | 10μl |
稀释溶剂 | 0.1%冰乙酸水溶液-乙腈(97:3) |
2、溶液的配制
检测样品:实施例1-3制得氢醌。
空白溶剂:0.1%冰乙酸水溶液-乙腈(97:3)。
杂质定位溶液:精密称定对苯醌适量,加水溶解并稀释制成每1ml约含10μg的溶液,摇匀,即得。
供试品溶液:精密称取氢醌适量,加稀释溶剂溶解并稀释制成每1ml约含1mg的溶液,摇匀,即得。
对照溶液:精密量取供试品溶液1ml,将其置于100ml量瓶中,用水稀释至刻度,摇匀,即得。
取上述空白溶剂、杂质定位溶液、供试品溶液和对照品溶液各10μl,将其注入液相色谱仪中,记录色谱图,测试产品含量。结果见图1-3。
实施例1-3制得氢醌的纯度分别为99.95%、99.93%、99.96%。
实施例10本发明氢醌纯度检测
1、色谱条件
因素 | 色谱参数 |
色谱柱 | GL-science,WondaSil C18 Superb 4.6*250mm 5μm |
流动相 | pH3.85磷酸二氢钾缓冲液-乙腈(75:25) |
洗脱梯度 | 等度洗脱 |
流速 | 1.0ml/min |
检测波长 | 220nm |
柱温 | 30℃ |
进样体积 | 10μl |
稀释溶剂 | pH3.85磷酸二氢钾缓冲液-乙腈(75:25) |
2、溶液的配制
检测样品:实施例4制得的氢醌精制品。
空白溶剂:pH3.85磷酸二氢钾缓冲液-乙腈(75:25)。
供试品溶液:精密称取氢醌精制品适量,加稀释溶剂溶解并稀释制成每1ml约含1mg的溶液,摇匀,即得。
对照溶液:精密量取供试品溶液1ml,将其置于100ml量瓶中,用水稀释至刻度,摇匀,即得。
硝基苯定位溶液:精密称取硝基苯适量,加稀释溶剂溶解并稀释制成每1ml约含1mg的溶液,摇匀,即得。
取上述空白溶剂、供试品溶液和对照溶液,硝基苯定位溶液各10μl,将其注入液相色谱仪中,记录色谱图,结果见图4a-4b。
实施例4氢醌纯度为100%。
实施例11-13本发明氢醌纯度检测
1、色谱条件
因素 | 色谱参数 |
色谱柱 | GL-science,WondaSil C18 Superb 4.6*250mm 5μm |
流动相 | pH3.0磷酸二氢钾缓冲液-乙腈(95:5) |
洗脱梯度 | 等度洗脱 |
流速 | 1.0ml/min |
检测波长 | 220nm |
柱温 | 30℃ |
进样体积 | 10μl |
稀释溶剂 | pH3.0磷酸二氢钾缓冲液-乙腈(95:5) |
2、溶液的配制
检测样品:实施例4-6制得的氢醌。
空白溶剂:pH3.0磷酸二氢钾缓冲液-乙腈(95:5)。
杂质定位溶液:精密称定对苯醌适量,加水溶解并稀释制成每1ml约含10μg的溶液,摇匀,即得。
供试品溶液:精密称取氢醌精制品适量,加稀释溶剂溶解并稀释制成每1ml约含1mg的溶液,摇匀,即得。
对照溶液:精密量取供试品溶液1ml,将其置于100ml量瓶中,用水稀释至刻度,摇匀,即得。
取上述空白溶剂、供试品溶液和对照品溶液各10μl,将其注入液相色谱仪中,记录色谱图,测试产品含量,结果见图5-7。
实施例4-6制得氢醌的纯度分别为100%、100%、100%。
实施例14复方氢醌乳剂的制备
复方氢醌乳剂的组成:
油相组分
水相组分
复合功效组分
复方氢醌乳剂的制备方法,包括下述步骤:
(1)水相制备:将纯化水、甘油倒入水相锅,夹层中通入蒸汽,加热至70±5℃,再向水相锅中加入水相组分,40rp/min搅拌至完全溶解后,维持70±5℃备用。
(2)油相制备:将十六醇、十八醇、硬质酸、Arlacel 165加入油相锅中,通入蒸汽加热熔化,至70±5℃时,加入尼泊金丙酯,维持70±5℃备用。
(3)均质乳化:开启乳化锅电源开关,开启真空泵,当真空度为-80KPa时,停止抽真空,开启搅拌为40rp/min,先将水相抽入乳化锅,再将油相在搅拌下缓缓加入乳化锅至全量,在70±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟。
(4)均质乳化完成后,开启冷却水阀门,且冷却水压不宜过大,当温度降至55℃时,加入氢醌、氟轻松、维A酸、维生素B6,在55±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟,将搅拌速度调为30rp/min,冷却约1小时,将搅拌速度下调至5rp/min,至膏体温度冷却至室温。
实施例15复方氢醌乳剂的制备
复方氢醌乳剂的组成:
油相组分
水相组分
复合功效组分
复方氢醌乳剂的制备方法,包括下述步骤:
(1)水相制备:将纯化水和甘油倒入水相锅,夹层中通入蒸汽,加热至70±5℃,再向水相锅中加入1.3-丁二醇、柠檬酸、叔丁基对甲酚、尼泊金甲酯、硅酸铝镁,40rp/min搅拌至完全溶解,维持70±5℃备用。
(2)油相制备:将十六醇、十八醇、硬脂酸、MONTANOV 68、SIMULSOL 165加入油相锅中,通入蒸汽加热熔化,至70±5℃时,加入尼泊金丙酯,维持70±5℃备用。
(3)均质乳化:开启乳化锅电源开关,开启真空泵,当真空度为-80KPa时,停止抽真空,开启搅拌为40rp/min,先将水相抽入乳化锅,再将油相在搅拌下缓缓加入乳化锅至全量,在70±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟。
(4)均质乳化完成后,开启冷却水阀门,且冷却水压不宜过大,当温度降至55℃时,加入氢醌、维A酸、二聚甘油、地塞米松二丙酸酯、维生素B6,在55±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟,将搅拌速度调为30rp/min,冷却约1小时,将搅拌速度下调至5rp/min,至膏体温度冷却至室温。
实施例16复方氢醌乳剂的制备
复方氢醌乳剂的组成:
油相组分
水相组分
复合功效组分
复方氢醌乳剂的制备方法,包括下述步骤:
(1)水相制备:将纯化水、甘油倒入水相锅,夹层中通入蒸汽,加热至70±5℃,再向水相锅中加入1.3丁二醇、柠檬酸、叔丁基对甲酚、尼泊金甲酯、HPMCHY-30T,40rp/min搅拌至完全溶解,维持70±5℃备用。
(2)油相制备:将十六醇、十八醇、硬脂酸、加入油相锅中,通入蒸汽加热熔化,至70±5℃时,加入NIKKOMULESE 41、尼泊金丙酯,维持70±5℃备用。
(3)均质乳化:开启乳化锅电源开关,开启真空泵,当真空度为-80KPa时,停止抽真空,开启搅拌为40rp/min,先将水相抽入乳化锅,再将油相在搅拌下缓缓加入乳化锅至全量,在70±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟。
(4)均质乳化完成后,开启冷却水阀门,且冷却水压不宜过大,当温度降至55℃时,加入氢醌、二聚甘油、维A酸、地塞米松二丙酸酯、维生素B6、维生素A乙酸酯、积雪草苷、维生素C磷酸镁,在55±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟,将搅拌速度调为30rp/min,冷却约1小时,将搅拌速度下调至5rp/min,至膏体温度冷却至室温。
实施例17复方氢醌乳剂的制备
复方氢醌乳剂的组成:
油相组分
水相组分
复合功效组分
复方氢醌乳剂的制备方法,包括下述步骤:
(1)水相制备:将纯化水、甘油倒入水相锅,夹层中通入蒸汽,加热至70±5℃,再向水相锅中加入水相组分,40rp/min搅拌至完全溶解后,维持70±5℃备用。
(2)油相制备:将十六醇、十八醇、硬质酸加入油相锅中,通入蒸汽加热熔化,至70±5℃时,加入尼泊金丙酯、Arlacel 165,维持70±5℃备用。
(3)均质乳化:开启乳化锅电源开关,开启真空泵,当真空度为-80KPa时,停止抽真空,开启搅拌为40rp/min,先将水相抽入乳化锅,再将油相在搅拌下缓缓加入乳化锅至全量,在70±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟。
(4)均质乳化完成后,开启冷却水阀门,且冷却水压不宜过大,当温度降至55℃时,加入氢醌、醋酸氟轻松、维A酸、二聚甘油,在55±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟,将搅拌速度调为30rp/min,冷却约1小时,将搅拌速度下调至5rp/min,至膏体温度冷却至室温。
实施例18复方氢醌乳剂的制备
复方氢醌乳剂的组成:
油相组分
水相组分
复合功效组分
复方氢醌乳剂的制备方法,包括下述步骤:
(1)水相制备:将纯化水、甘油倒入水相锅,夹层中通入蒸汽,加热至70±5℃,再向水相锅中加入水相组分,40rp/min搅拌至完全溶解后,维持70±5℃备用。
(2)油相制备:将十六醇、十八醇、硬质酸加入油相锅中,通入蒸汽加热熔化,至70±5℃时,加入尼泊金丙酯、Arlacel 165,维持70±5℃备用。
(3)均质乳化:开启乳化锅电源开关,开启真空泵,当真空度为-80KPa时,停止抽真空,开启搅拌为40rp/min,先将水相抽入乳化锅,再将油相在搅拌下缓缓加入乳化锅至全量,在70±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟。
(4)均质乳化完成后,开启冷却水阀门,且冷却水压不宜过大,当温度降至55℃时,加入氢醌、氟轻松、维A酸、二聚甘油、氮酮、薄荷、冰片,在55±5℃和真空度为-80KPa条件下,启动乳化机均质器,均质乳化20分钟,将搅拌速度调为30rp/min,冷却约1小时,将搅拌速度下调至5rp/min,至膏体温度冷却至室温。
对比例1复方氢醌乳剂的制备
Arlacel 165[硬脂酸甘油酯和PEG-100硬脂酸酯甘油单硬脂酸酯]
17.5g
复方氢醌乳剂的制备方法,包括下述步骤:
1、将344.8千克的水、15.0千克硅酸铝镁和0.2千克丁基化羟基甲苯合并,并在75-80℃下混合形成水相。可以以固定的速率搅拌进行混合,制得水相悬浮液。
2、将20.0千克的鲸蜡醇、15.0千克的硬脂酸、20.0千克的十八烷醇、25.0千克的甲基葡萄糖甙十环氧乙烷(methylgluceth-10)、0.9千克的对羟基苯甲酸甲酯、0.1千克的对羟基苯甲酸丙酯和20.0千克的甘油在大约75-80℃下以中速混合在一起,形成非水相。在一个混合器中以中速混合。得到的非水相是悬浮液。第二步可以在第一步之前、之后或同时进行。
3、将非水相加入到水相中,并将合并的两相混合物冷却至68℃至72℃的温度范围内,或冷却至约70℃,而后加入约17.5kg的165、0.25kg维甲酸和0.050kg氟轻松,并在冷却过程中搅拌。将混合物达到60℃时,在混合与冷却下加入0.25kg柠檬酸。
当温度达到55℃时,在混合与冷却下加入20.0kg氢醌。当温度达到约50℃时,在继续冷却下将混合物用均化器均化。当混合物达到45℃时,在搅拌和冷却下加入1.0kg的焦亚硫酸钠。加入氢醌后约30分钟,加入焦亚硫酸钠。以固定的速率在侧刮搅拌器中进行混合。得到的物质的组合物是乳状液,即乳膏剂。
试验例1本发明的复方氢醌乳剂的皮肤刺激性动物实验评价
将白色豚鼠分成6组,每组30只,见表1。剃净豚鼠背部的毛,皮肤每日给药,均匀涂抹紫外光照射部位,紫外光每次照射剂量为:UVA5.67/cm2、UVB0.0841/cm2,连续UV照射4周(累积照射量UVA111.1J/cm2、UVB61.65j/cm2),UVB和UVA连续照射4周实验动物皮肤的外观见图8,出现红斑的动物比例见图9。
试验例2本发明的复方氢醌乳剂防治黑斑病作用研究
选择60例年龄21-75岁之间的黑斑病志愿者患者进行两个有效性和安全性研究,这些患者患有皮肤phototypes I-IV和中度至严重的面部黑斑病。
接受试验患者的面部耳脱用温和无皂的清洁剂洗涤后,每晚使用研究药物,连续使用8周。且要求患者在色素沉着过多的病灶处敷用所研究的药物薄层,以确保覆盖全部病灶,包括扩展至正常色素皮肤的外缘皮肤。给患者提供一种温和的增湿剂,以备需要时使用,且每日使用具有SPF 30的防晒霜。另要求患者避免日光暴晒到面部,穿上防护衣。
观察并评估患者的黑斑病初期及其治疗1周、2周、4周和8周的严重程度。统计分析治疗成功的患者的比例评价本发明复方乳剂的疗效。其中,治疗成功指患者在八周治疗时间结束时消除了黑斑病,试验结果见图10。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (10)
1.一种水包油型复方氢醌乳剂,其特征在于,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)和类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)组成,所述的药学上可接受的载体中含有缓释剂0.5-1%(w/w)。
2.根据权利要求1所述的乳剂,其特征在于,所述乳剂包括油组分10-40%(w/w)、乳化剂1-5%(w/w)、活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)和类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)组成,所述的药学上可接受的载体中含有缓释剂0.5-1%(w/w)。
3.一种水包油型复方氢醌乳剂,其特征在于,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)、类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)和刺激缓解剂0.5-1%(w/w)组成。
4.根据权利要求3所述的乳剂,其特征在于,所述乳剂包括油组分10-40%(w/w)、乳化剂1-5%(w/w)、活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)、类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)和刺激缓解剂0.5-1%(w/w)组成。
5.根据权利要求3-4任一项所述的乳剂,其特征在于,所述的药学可接受的载体中含有缓释剂0.5-1%(w/w),优选为0.6-0.9%(w/w),更优选为0.7-0.8%(w/w)。
6.根据权利要求3-5任一项所述的乳剂,其特征在于,所述刺激缓解剂含量为0.6-0.9%(w/w),优选为0.7-0.8%(w/w)。
7.根据权利要求3-6任一项所述的乳剂,其特征在于,所述刺激缓解剂选自维生素B6、积雪草苷的任一种或其组合。
8.一种水包油型复方氢醌乳剂的制备方法,其特征在于,所述乳剂中含有活性组分和药学上可接受的载体,其中,所述的活性组分由氢醌1-4%(w/w)、外用皮质类固醇或其药学上可接受的盐或其酯0.01-0.05%(w/w)和类维生素A或其药学上可接受的盐或其酯0.01-0.05%(w/w)组成,所述的药学可接受的载体中含有缓释剂0.5-1%(w/w),所述复方乳剂的制备方法包括下述步骤:
1)水相制备;
2)油相制备;
3)将步骤2)制得的油相加入到步骤1)制得的水相中,进行初次均质乳化;
4)将步骤3)制得的初次均质乳化液冷却降温后,加入活性组分后,进行二次均质乳化,制得水包油乳剂。
9.根据权利要求8所述的制备方法,其特征在于,所述活性组分中添加刺激缓解剂。
10.复方氢醌乳剂用于制备防治皮肤病症、祛除色斑、祛除色素沉着症的制品中的应用。
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