CN116036103A - 一种复方氢醌乳剂及其制备方法和应用 - Google Patents
一种复方氢醌乳剂及其制备方法和应用 Download PDFInfo
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- CN116036103A CN116036103A CN202310158191.3A CN202310158191A CN116036103A CN 116036103 A CN116036103 A CN 116036103A CN 202310158191 A CN202310158191 A CN 202310158191A CN 116036103 A CN116036103 A CN 116036103A
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- Prior art keywords
- emulsion
- hydroquinone
- compound
- water
- compound hydroquinone
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 48
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- 239000004480 active ingredient Substances 0.000 claims abstract description 11
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 8
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
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- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 2
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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Abstract
本发明公开了一种复方氢醌乳剂及其制备方法和应用，属于医药技术领域。所述复方氢醌乳剂包括活性成分和药学上可接受的载体，所述活性成分包括以下按乳剂重量百分比计的组分：氢醌或其水溶性衍生物2～4％、克立硼罗0.5～5％、维生素A 0.01～0.05％、维生素B6 1.5～7.5％、积雪草苷0.2～3％。本发明的复方氢醌乳剂氢醌含量高、透皮吸收率高，具有刺激性小、适用范围广、生产厂房不受必须允许含激素原料的厂房限制、生产成本低等优点。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种复方氢醌乳剂及其制备方法和应用。
背景技术
目前，现有复方氢醌乳霜的活性成分一般由以下组分组成：氢醌1-4％(w/w)、外用皮质类固醇0.01-0.05％(w/w)、维甲酸0.01-0.05％(w/w)。在以上复方氢醌乳霜中，由于氢醌不稳定，在制备及储存中易受光照、温度等环境因素的影响而发生氧化降解反应生成杂质，而氧化降解产物会与氢醌形成有色复合物，进而影响氢醌及其产品的纯度、质量、稳定性和性状外观等。水包油型氢醌乳剂存在氧化变色、稳定性较差和头皮吸收率较低的缺陷。为了克服这一缺陷，中国专利CN202011224161.0提出了一种油包水型复方氢醌乳剂，其由油组分、水相组分和复方活性成分组成，其中复方活性成分包括氢醌、维甲酸和氟轻松等组分，但维甲酸对皮肤的刺激性比较高，导致其适用人群大大缩小；另外，如氟轻松等原料药只能依靠进口，导致生产成本大大增加，其对适用年龄或适用范围等也均有限制，使其应用受到限制。
因此，十分有必要研发一种稳定性好、刺激性小、适用范围广且生产成本低的复方氢醌乳剂及其制备方法和应用。
发明内容
为了克服现有技术的不足，本发明的目的在于提供一种复方氢醌乳剂，该复方氢醌乳剂稳定性高、延长了产品的使用周期，刺激性小、适用范围广，生产成本低，适合于工业化生产。
为解决上述问题，本发明所采用的技术方案如下：
一种复方氢醌乳剂，其包括活性成分和药学上可接受的载体，所述活性成分包括以下按乳剂重量百分比计的组分：氢醌或其水溶性衍生物2～4％、克立硼罗0.5～5％、维生素A 0.01～0.05％、维生素B6 1.5～7.5％、积雪草苷0.2～3％。
在本发明优选的方案中，所述乳剂还包括有乳化剂，所述乳化剂占乳剂的重量百分比为2～10％。
进一步优选地，所述乳化剂为聚氧乙烯(30)二聚羟基硬脂酸酯、鲸蜡基聚乙二醇/聚丙二醇10/1二甲基硅氧烷、双-聚乙二醇/聚丙二醇-14/14二甲基硅氧烷、聚甘油-4双异硬脂酸酯聚羟基硬脂酸癸二酸酯、司盘-20、司盘-80、司盘-60、司盘-85、烷氧基化甘油失水山梨醇脂肪酸酯、聚甘油硬脂酸酯和聚油油酸酯的任一种或其组合。
在本发明优选的方案中，所述氢醌水溶性衍生物包括但不限于氢醌的单酯或双酯、氢醌的单醚或双醚、氢醌的单糖苷或双糖苷，例如氢醌单乙酸酯、氢醌单乳酸酯、4-羟基苯甲醚或熊果苷。本发明的氢醌或氢醌水溶性衍生物为药学上可接受的安全活性成分，纯度不小于99.5％(重量比)，纯度高、毒性低，适合应用到皮肤上。
在本发明优选的方案中，所述乳剂为油包水复方氢醌乳剂。
进一步优选地，所述乳剂为油包水型复方氢醌乳剂。所述乳剂的粒径为200-600nm，优选为200-400nm。所述乳剂的粘度为1000-50000厘泊(cps)，优选为2500-15000厘泊(cps)。
在本发明优选的方案中，所述乳剂中的油相占乳剂的重量百分比为10～30％。
在本发明优选的方案中，所述油相中的油选自液体亲油性润肤剂、天然及合成油脂、蜡状亲油性润肤剂中的任一种或其组合。
进一步优选地，所述液体亲油性润肤剂包括硅油类润肤剂、二甲基硅氧烷、鲸蜡基二甲基硅氧烷、聚二甲基硅氧烷中的任一种或其组合。
进一步优选地，所述天然及合成油脂包括碳酸二辛酯、乳木果油、GTCC、C24、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、C16-C18混合醇、地蜡、微晶蜡、蜂蜡、异十六烷、十六醇中的任一种或其组合。
进一步优选地，所述蜡状亲油性润肤剂包括硬脂基二甲基硅氧烷、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。
在本发明优选的方案中，所述乳剂中的水相中还含有金属盐。
进一步优选地，所述金属盐占乳剂的重量百分比为0.5～5％。
进一步优选地，所述金属盐为氯化钠和/或氯化镁。
在本发明优选的方案中，所述乳剂还包括有透皮吸收剂，所述透皮吸收剂占乳剂的重量百分比不超过7％；所述透皮吸收剂选自冰片、薄荷、氮酮、肉豆蔻酸异丙酯中的任一种或其组合。进一步优选地，所述透皮吸收剂为冰片、薄荷、氮酮组成的复合透皮吸收剂。更优选地，所述复合透皮吸收剂的组成为：氮酮2～7重量份、冰片1～4重量份、薄荷1～4重量份。
在本发明优选的方案中，所述乳剂还包括有抗氧化剂，所述抗氧化剂占乳剂的重量百分比为1～5％；所述抗氧化剂选自烟硫酸氢钠、叔丁基对甲酚、焦亚硫酸钠、维生素E、二乙酸四醋酸二钠中的任一种或其组合。
在本发明优选的方案中，所述乳剂还包括有防腐剂，所述防腐剂占乳剂的重量百分比为1～5％；所述防腐剂选自羟苯甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯中的任一种或其组合。
在本发明优选的方案中，所述乳剂还包括有保湿剂，所述保湿剂占乳剂的重量百分比为1～8％；所述保湿剂选自甘油、多元醇、尿素、氨基酸、丙二醇、鲸蜡醇、石蜡油、羊毛脂及其衍生物、脂肪酸酯、硅油、环甲基硅氧烷、聚二甲基硅醇中的任一种或其组合。
在本发明优选的方案中，所述乳剂还包括有pH调节剂，所述pH调节剂占乳剂的重量百分比为1～5％，所述pH调节剂选自乳酸、柠檬酸、磷酸或羟基乙酸中的任一种或其组合。
本发明的目的之二在于提供一种如上所述的复方氢醌乳剂的制备方法，所述乳剂为油包水型乳剂，所述乳剂按照以下步骤制得：
(1)水相制备：量取纯化水、甘油或者透明质酸，将其置于水相罐中，加热至60～90℃完全溶解后，降低到50-60℃，加入氢醌、积雪草苷和金属盐；
(2)油相制备：量取油相成分，将其置于油相罐中，加热熔化后，再加入透皮吸收剂、复合乳化剂、维生素E，降温至50-60℃备用；
(3)均质乳化：将油相真空吸入乳化罐中，搅拌条件下再将水相用真空吸入乳化罐中，初步均质后再转移至高速均质机，形成微乳液，冷却，即得。
在本发明优选的方案中，所述步骤(3)中的搅拌温度为50～60℃、搅拌速度为50～150r/min、搅拌时间为10～30min，初步均质的均质速度为1000～2000r/min。
在本发明优选的方案中，所述步骤(3)的冷却工序中出口处的乳剂温度为45℃。
本发明的目的之三在于提供如上所述的复方氢醌乳剂在制备治疗、预防或改善皮肤疾病的药品或化妆品中的应用。
在本发明优选的方案中，皮肤疾病可以是：色素沉着，包括色素离散和色素沉着；光化性角化病、太阳能角化病、皮肤瑕疵。
在本发明优选的方案中，皮肤疾病为皮肤斑。所述皮肤斑为局部色素沉着所致，优选所述的皮肤斑选自雀斑、黄褐斑、炎症后色素沉着斑的任一种或其组合。
在本发明优选的方案中，所述皮肤疾病可以是通过暴露于UV辐射引起的皮肤疾病，光诱发的或慢性的老化的皮肤，光化色素沉着和角化病，或任何病理相关联的与慢性老化或光化老化的，特别是皮肤皮脂功能的疾病，特别是痤疮样高皮脂溢性皮炎或简单皮脂溢性或脂溢性皮炎；愈合障碍或孕妇妊娠纹，色素沉着障碍，例如色素沉积，黑斑病，色素沉着不足或白癜风。
为了清楚地表述本发明的保护范围，本发明对下述术语做如下界定：
1、除非另有说明，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。
2、术语“乳剂”是指液滴形式的两种不混溶液体的胶体分散体。乳剂如果连续相为水溶液以符号O/W(水包油)，如果连续相为油以W/O(油包水)来表示。
3、油包水乳剂中的“油相”是指各自超过其在水相中溶解限的制剂中所有成分；这些是通常具有蒸馏水中小于1％溶解度的材料。油相是指油包水乳剂的非水部分。
4、油包水乳剂中的“含水相”或“水相”是指存在的水和任何水溶成分，即未超过其在水中的溶解限。
5、HLB值：乳化剂为具有亲水基团和亲油基团的两亲分子，乳化剂分子中亲水基和亲油基之间的大小和力量平衡程度的量，定义为乳化剂的亲水亲油平衡值。
相比现有技术，本发明的有益效果在于：
1、本发明在复方氢醌乳剂中加入克立硼罗，能够有效降低皮肤刺激性，可以使复方氢醌乳剂的适用范围扩大至几个月大的婴儿至成年人，适用范围广；使用积雪草苷，能够有效提高乳剂的温和性，大大改善了复方氢醌霜的使用体验，同时解决氟轻松原料药需要依赖进口的问题，使生产厂房不受必须允许含激素原料的厂房限制，有效降低了生产成本，适合于工业化生产。
2、本发明通过筛选复合乳化剂、以及控制乳化工艺中油相与水相的分布平衡，实现了油包水型氢醌乳剂的制备；由于氢醌易溶解于水，因此在水相中更容易稳定，乳剂通过油相与外界隔离，有效提高了复方氢醌乳剂的稳定性，从而延长了产品的使用周期，降低了生产成本。
附图说明
图1为本发明实施例1所制得的复方氢醌乳剂未经高压均质的显微图片；
图2为本发明实施例1所制得的复方氢醌乳剂经高压均质后的显微图片；
图3为本发明对比例1～2和实施例1～2的皮肤刺激性动物实验图片；
图4为本发明对比例1所制得的乳剂加速离心前后的对比图；
图5为本发明实施例1所制得的乳剂加速离心前后的对比图；
图6为本发明实施例2所制得的乳剂加速离心前后的对比图。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步详细说明。
实施例1
本实施例的复方氢醌乳剂的由油相和水相组成，其中油相组分组成如下：
辛酸癸酸甘油酯25g、液体石蜡65g、十六醇40g、十八醇30g、微晶蜡20g、二甲基硅油25g、乳化剂Arlacel P135(聚氧乙烯(30)、二聚羟基硬脂酸酯)30g、尼泊金丙酯0.2g、维生素B6 5g、克立硼罗2g；
水相组分组成如下：
1,3-丁二醇50g、甘油40g、透明质酸0.5g、焦亚硫酸钠2g、尼泊金甲酯1.8g、氯化钠8g、去离子水585.5g、氢醌40g、积雪草苷30g。
本实施例的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、1,3-丁二醇、甘油、透明质酸倒入水相锅，夹层中通入蒸汽，加热至70±5℃，然后向水相锅中加入水相组分，以40rp/min的转速搅拌至完全溶解后，最后向水相锅中加入焦亚硫酸钠、尼泊金甲酯、氯化钠、氢醌、积雪草苷、以40rp/min的转速搅拌至完全溶解，降低到50-60℃备用。
(2)油相制备：将油相组分加入油相锅中并通入蒸汽加热熔化，降低到50-60℃加入克立硼罗搅拌均匀备用。
(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，先将步骤(2)制得的油相吸入乳化罐后，再将步骤(1)制得的水相在搅拌下缓缓吸入乳化罐中，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45℃时，加入活性组分，在45±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，得到所述复方氢醌乳剂。
制得所述复方氢醌乳剂，还可经高压均质経高压均质
图1为本发明实施例1所制得的复方氢醌乳剂未经高压均质的显微图片；
图2为本发明实施例1所制得的复方氢醌乳剂经高压均质后的显微图片。
由图1与图2的对比可知，本发明的复方氢醌乳剂经过高压均质后，能够使乳剂中的乳液粒径进一步降低，从而有效提高乳剂的透皮吸收性。
实施例2
本实施例的复方氢醌乳剂的由油相和水相组成，其中油相组分组成如下：
辛酸癸酸甘油酯25g、液体石蜡65g、十六醇40g、十八醇30g、微晶蜡20g、二甲基硅油25g、Arlacel 780(烷氧基化甘油失水山梨醇脂肪酸酯)30g、尼泊金丙酯0.2g、维生素B65g、克立硼罗3g；
水相组分组成如下：
1,3-丁二醇50g、甘油40g、透明质酸0.5g、焦亚硫酸钠2g、尼泊金甲酯1.8g、氯化钠5g、去离子水584.5g、氢醌40g、积雪草苷30g。
本实施例的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、1,3-丁二醇、甘油、透明质酸倒入水相锅，夹层中通入蒸汽，加热至70±5℃，然后向水相锅中加入水相组分，以40rp/min的转速搅拌至完全溶解后，最后向水相锅中加入焦亚硫酸钠、氯化钠、尼泊金甲酯，以40rp/min的转速搅拌至完全溶解，降低到50-60℃备用。
(2)油相制备：将油相组分加入油相锅中并通入蒸汽加热熔化，降低到50-60℃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，先将步骤(2)制得的油相吸入乳化罐后，再将步骤(1)制得的水相在搅拌下缓缓吸入乳化罐中，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45℃时，加入活性组分，在45±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，得到所述复方氢醌乳剂。
对比例1
本对比例按照《福建省医院制剂规范》中所记载的氢醌乳膏的组成及制备方法制备氢醌乳剂。具体组成如下：
氢醌40g，十二烷基硫酸钠9g，十六醇81g，液体石蜡60g，白凡士林150g，NaHSO33g，叔丁基对甲酚1g，甘油50g，蒸馏水1000g。
其制备方法包括油相的制备、水相的制备和乳化：
①油相的制备方法：取十六醇、液体石蜡和凡士林，加热熔化，待温度到约70℃时，依次加入叔丁基对甲酚、氢醌，溶解；
②水相的制备方法为：取甘油与适量蒸馏水混合，加热至约70℃时，加入亚硫酸氢钠、十二烷基硫酸钠，溶解；
③乳化：在搅拌条件下，将油相缓慢加入水相中至全量，乳化，搅拌至凝，即得。
对比例2
以专利CN1738587B所公开的一种具有优良祛斑效果的复方氢醌乳剂作为对比例2，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0.04％、鲸蜡醇4％、柠檬酸0.05％、甘油4％、硬脂酸甘油酯3％、硅酸铝镁3％、甲基葡萄糖甙十环氧乙烷(methyl gluceth10)5％、对羟基苯甲酸甲酯、PEG-100硬脂酸酯3.5％、对羟基苯甲酸丙酯0.02％、净化水68.95％、焦亚硫酸钠0.2％、硬脂酸3％和十八烷醇4％。
本对比例的试验用样品为美国高德美公司CN1738587B专利的市售产品。
一、乳剂粒径的测定
采用德国NANOPHOX(NX0158)粒径分布测量仪测定实施例1～2以及对比例1～2所制得的复方氢醌乳剂，结果如图3和表1所示。
表1实施例1～2以及对比例1～2所制得的乳剂粒径
| 乳剂 | 粒径(nm) |
| 对比例1 | 800-2000 |
| 对比例2 | 500-1500 |
| 实施例1 | 30-300 |
| 实施例2 | 50-400 |
表1的结果表明，本发明实施例1及实施例2粒径平均值分别为165nm、225nm，而对比例1及对比例2的粒径平均值分别为1400nm、1000nm，说明本发明所制得的乳剂粒径比对比例1及对比例2约缩小1/7至1/5，粒径的缩小有利于活性成分的透皮吸收，提高了药物的生物利用率，药物使用量减少可降低对皮肤的刺激性。
二、皮肤刺激性动物实验
对实施例1～2和对比例1～2的乳剂进行皮肤刺激性动物实验评价，具体步骤如下：将白色豚鼠分成5组，每组20只，剃净豚鼠背部的毛，皮肤每日给药3次，均匀涂抹紫外光照射部位，紫外光每次照射剂量为：UVA5.67/cm2、UVB和UVA连续照射2周。实验动物皮肤的外观见图3，出现红斑的动物比例见表2。
表2实施例1～2以及对比例1～2所制得的乳剂的皮肤刺激性动物实验结果
| 乳剂 | 出现红斑的动物比例％ |
| 对比例1 | 100％ |
| 对比例2 | 80％ |
| 实施例1 | 0％ |
| 实施例2 | 0％ |
由图3和表2结果可知，与对比例1～2相比，使用本发明实施例1-2所制得的乳剂的豚鼠皮肤均无由刺激引起的红斑，说明实施例1-2所制得的乳剂对皮肤的刺激性非常低，而对比例1-2均有较严重的不同程度的由刺激产生的红斑。
三、乳剂耐热稳定性测试
在热负荷下的测试(加热测试)实施例1～2以及对比例1～2所制得的乳剂耐热稳定性，具体操作如下：取1克的乳剂置于玻璃样品管中，然后密封，置于60℃的恒温罐中，随着时间的推移观察乳剂的外观以检查油相与水相是否分离，结果见表3。
表3实施例1～2以及对比例1～2所制得的乳剂的耐热实验结果
| 考察时间 | 对比例1 | 对比例2 | 实施例1 | 实施例2 |
| 0小时 | 未分离 | 未分离 | 未分离 | 未分离 |
| 10天 | 未分离 | 未分离 | 未分离 | 未分离 |
| 20天 | 分离 | 未分离 | 未分离 | 未分离 |
| 30天 | 分离 | 未分离 | 未分离 | 未分离 |
由表3可知，本发明实施例1-2均具有较好的耐热稳定性，对比例1耐热性最差，不符合产品要求。
四、加速稳定性试验
将对比例1、实施例1、实施例2所制得的乳剂同时放置于-18℃的恒温室48小时后，取出样品置于常温下恢复至室温，然后再放置于50℃的恒温箱48小时，取出样品放置常温下恢复至室温，对样品进行离心分离实验，以2500r/min离心30min，观察产品分层情况，结果如图4～图6所示。
由图4可知，对比例1的乳剂经过加速和离心后明显破乳分层，说明对比例1的乳剂稳定性不足。由图5和图6可知，实施例1和实施例2的乳剂样品在加速离心前后均未出现分层，说明实施例1和实施例2的乳剂样品均具有优异的稳定性。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (10)
1.一种复方氢醌乳剂，其特征在于：所述乳剂包括活性成分和药学上可接受的载体，所述活性成分包括以下按乳剂重量百分比计的组分：氢醌或其水溶性衍生物2～4％、克立硼罗0.5～5％、维生素A0.01～0.05％、维生素B6 1.5～7.5％、积雪草苷0.2～3％。
2.根据权利要求1所述的复方氢醌乳剂，其特征在于：所述乳剂还包括有乳化剂，所述乳化剂占乳剂的重量百分比为2～10％。
3.根据权利要求2所述的复方氢醌乳剂，其特征在于：所述乳化剂为聚氧乙烯(30)二聚羟基硬脂酸酯、鲸蜡基聚乙二醇/聚丙二醇10/1二甲基硅氧烷、双-聚乙二醇/聚丙二醇-14/14二甲基硅氧烷、聚甘油-4双异硬脂酸酯聚羟基硬脂酸癸二酸酯、司盘-20、司盘-80、司盘-60、司盘-85、烷氧基化甘油失水山梨醇脂肪酸酯、聚甘油硬脂酸酯和聚油油酸酯的任一种或其组合。
4.根据权利要求1～3中任一项所述的复方氢醌乳剂，其特征在于：所述乳剂为油包水型复方氢醌乳剂。
5.根据权利要求4所述的复方氢醌乳剂，其特征在于：所述乳剂中的油相占乳剂的重量百分比为10～30％。
6.根据权利要求4所述的复方氢醌乳剂，其特征在于：所述乳剂的水相中含有金属盐，所述金属盐占乳剂的重量百分比为0.5～5％；所述金属盐为氯化钠和/或氯化镁。
7.根据权利要求1所述的复方氢醌乳剂，其特征在于：所述乳剂还包括有以下按乳剂重量百分比计的组分：透皮吸收剂1～7％、抗氧化剂1～5％、防腐剂1～5％、保湿剂1～8％、pH调节剂1～5％。
8.一种如权利要求1～7中任一项所述的复方氢醌乳剂的制备方法，其特征在于：所述乳剂为油包水型乳剂，所述乳剂按照以下步骤制得：
(1)水相制备：量取纯化水、甘油或者透明质酸，将其置于水相罐中，加热至60～90℃完全溶解后，降低到50-60℃，加入氢醌、积雪草苷和金属无机盐；
(2)油相制备：量取油相成分，将其置于油相罐中，加热熔化后，再加入透皮吸收剂、复合乳化剂、维生素E，降温至50-60℃备用；
(3)均质乳化：将油相真空吸入乳化罐中，搅拌条件下再将水相用真空吸入乳化罐中，初步均质后再转移至高速均质机，形成微乳液，冷却，即得。
9.根据权利要求8所述的复方氢醌乳剂的制备方法，其特征在于：所述步骤(3)中的搅拌温度为50～60℃、搅拌速度为50～150r/min、搅拌时间为10～30min，初步均质的均质速度为1000～2000r/min。
10.一种如权利要求1所述的复方氢醌乳剂在制备治疗、预防或改善皮肤疾病的药品或化妆品中的应用。
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