CN108888595A - 一种含有羟基酪醇的纳米乳制剂及其冻干剂的制备方法 - Google Patents
一种含有羟基酪醇的纳米乳制剂及其冻干剂的制备方法 Download PDFInfo
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- CN108888595A CN108888595A CN201811060070.0A CN201811060070A CN108888595A CN 108888595 A CN108888595 A CN 108888595A CN 201811060070 A CN201811060070 A CN 201811060070A CN 108888595 A CN108888595 A CN 108888595A
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- hydroxytyrosol
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Classifications
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- Pharmacology & Pharmacy (AREA)
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Abstract
本发明公开了一种含有羟基酪醇的纳米乳制剂及其冻干剂，是由包括以下组分制成的：羟基酪醇、表面活性剂、油相、水相，是通过以下制备方法制得的：(1)称取表面活性剂、羟基酪醇加入到油中作为油相，水浴中搅拌融合；(2)称取纯化水到烧杯中，置于水浴中，在水浴条件下将油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有淡蓝色乳光的澄清透明溶液；(3)将上述纳米乳制剂冷冻干燥去除水分，制备得羟基酪醇纳米乳冻干制剂。通过本发明制备的羟基酪醇纳米乳剂具有稳定性好、黏度低、粒径小更易扩散渗透进入皮肤的优点，冻干制剂，便于储存与运输，可更灵活、方便的添加于化妆品、药品和保健食品中。
Description
技术领域
本发明涉及化妆品和药物制剂领域，具体涉及一种含有羟基酪醇的纳米乳冻干制剂及其制备方法。
背景技术
羟基酪醇化学名为3，4－二羟基苯乙醇，分子量为154.2，是一种天然抗氧化剂，广泛存在于橄榄科橄榄属植物的枝叶及果实中，特别是地中海地区的橄榄树中含量较高，是橄榄油的有效成分。近年来，国内外大量研究证实羟基酪醇具有较强的抗氧化活性，在抗癌、抗血栓、调血脂和抗动脉硬化、抗病原微生物、防治视网膜黄斑变性、保护软骨和抗骨质疏松等多方面具有优良的生物药理学作用。因此，羟基酪醇因其特殊的生物和药理活性，用途十分广泛。在食品工业中，可作为天然的防腐剂，防止食品的氧化变质；在营养保健领域，可作为营养补充剂、抗菌剂，添加到各种食品中；还可以添加到化妆品中，利用其捕捉自由基的能力，减少紫外线对皮肤的损伤作用，延缓皮肤老化。但羟基酪醇由于其结构特点，有两个酚羟基，另外，还有一个醇羟基，是一种具有酚羟基特性也具有醇羟基特性的两性分子，易被氧化，在室温下存放也不稳定，活性易降低，因此其应用受到了限制。迄今，并无解决上述问题的方案。
纳米乳是由水相、油相、表面活性剂和助表面活性剂按适当比例形成粒径为10～100nm，具低黏度、各向同性的热力学和动力学稳定的透明的或半透明体系。纳米乳作为药物载体具有独特优点：①属热力学稳定***，久置不分层，不破乳；②制备工艺简单，过程不需特殊设备，可自发形成，条件易于控制，重现性好的优势利于进行工业化大规模生产；③具有缓释和靶向作用，可减少药物的刺激性及毒副作用；④生物相容性好，可生物降解，用作不稳定药物的载体，提高药物的稳定性。因此纳米乳作为一种药物载体已广泛应用于药物制剂及化妆品领域。
发明内容
针对上述现有技术，本发明提供一种羟基酪醇的纳米乳，其稳定性好、黏度低、粒径小更易扩散渗透进入皮肤，可直接使用，解决了羟基酪醇在室温下稳定性差、颜色发生变化、易降解的问题。
本发明又一目的在于提供一种羟基酪醇纳米乳冻干制剂，便于储存与运输，可更灵活、方便的添加于化妆品与保健食品中。
本发明是通过以下技术方案实现的：
一种含有羟基酪醇的纳米乳，是由包括以下重量百分比的组分制成：
一种含有羟基酪醇的纳米乳制剂及其冻干剂是通过以下制备方法制得的：
(1)称取表面活性剂、羟基酪醇加入到油中作为油相，水浴中搅拌融合；
(2)称取纯化水到烧杯中，置于水浴中；
(3)在水浴条件下将油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有淡蓝色乳光的澄清透明溶液，记录体系由浑浊变澄清时临界水量，此时产生的即是o/w型羟基酪醇纳米乳；
(4)向上述纳米乳制剂中加入0.5％～10％(单位mg/ml)的冻干保护剂；
(5)冷冻干燥去除水分，制备干燥的羟基酪醇纳米乳冻干制剂。
所述步骤(1)中表面活性剂为15-羟基硬脂酸聚乙二醇酯、月桂醇聚醚硫酸酯钠、蓖麻油聚氧乙烯醚、氢化蓖麻油聚氧乙烯醚、聚氧乙烯脱水山梨醇单油酸酯(吐温-80)、山梨糖醇酐单油酸酯中的任一种或几种混合物。
所述的表面活性剂中还可以加入助表面活性剂。
所述的助表面活性剂是乙醇、丙二醇，聚乙二醇类中一种或几种。
所述的步骤(1)中油相为辛酸/癸酸甘油三酯、棕榈酸异丙酯、大豆油、乳木果油、肉豆蔻酸异丙酯、液体石蜡、甜杏仁油、山茶籽油、维生素E中一种或两种以上。
所述的步骤(1)中所使用的水浴温度优选为65-85℃
所述的步骤(2)中，所使用的水浴温度优选为65-85℃
所述的步骤(3)中所使用的水浴温度优选为65-85℃
所述的步骤(4)中冻干保护剂选自：甘露醇、山梨醇、蔗糖、葡萄糖、乳糖、果糖、海藻糖中的任一种，或它们的混合物。
相对于现有技术中的方案，本发明的优点在于：
(1)本发明运用纳米技术制备羟基酪醇纳米乳与脂质体等其它靶向性药物传递***相比，纳米乳载体更加稳定，可增强羟基酪醇的稳定性，解决其稳定性差的缺点。
(2)本发明羟基酪醇纳米乳外观为淡蓝色澄清透明，黏度低、粒径小、经皮渗透吸收作用更快。本发明中制备纳米乳应用的基质也可作为渗透促进剂，例如肉豆蔻酸异丙酯常作为纳米乳中的油相，但同时它也是一种透皮吸收促渗剂，能大大促进制剂的透皮效率，更易发挥羟基酪醇的药理作用，提高使用效果。
(3)本发明的制备方法得到羟基酪醇纳米乳冻干剂，所述方法设备工艺简单可控，重复性好，可实现工业化生产，可方便应用于化妆品、保健品、医药等领域。
具体实施方式
以下通过试验例来进一步阐述本发明所述羟基酪醇纳米乳的生物功效。
1、受试者筛选：
通过选取30名23-27岁女性志愿者，室内工作者，受试者无严重***性疾病、无免疫缺陷或自身免疫性疾病；无活动性过敏性疾病；对护肤类化妆品无过敏史；1个月内未曾全身使用激素类药物及免疫抑制剂，非妊娠或哺乳期；皮肤颜色在Ⅱ～Ⅳ之间。
2、实验方法
以实施例1制备的纳米乳为原料，加入霜的基质配方中，添加量3.0wt％，利用皮肤黑色素和血红素测试仪测定皮肤黑色素含量，计算出黑色素变化值来表征美白效果。选择受试者左、右手臂曲臂内侧为受试区，进行随机标记，并设定空白区(不使用任何样品)，受试区涂抹样品I，II和III，每日早晚各涂抹1次(用量为2mg/cm2)，使用周期为4周，每周同一时间受试者将涂抹部位洗净，在特定的测试环境中静坐15min，由测试者使用皮肤黑色素和血红素测试仪测定涂抹部位数值。
3、测试仪器及指标
测试仪器：Mexameter MX 18皮肤黑色素和血红素测试仪、MPA9多功能皮肤测试仪及色度测试探头，德国CK公司。
基质膏霜：实验室自制。
记录总结数据，可得到皮肤黑色素变化规律。仪器测试值T越大，代表黑色素含量越高，△T＝使用产品后黑色素测定值-使用前黑色素测定值，取平均值，实验数据见表1.
表1志愿者黑色素变化值△T
| 样品编号 | 0 | 1周 | 2周 | 3周 | 4周 |
| I | 0 | -13.98 | -15.97 | -18.59 | -23.91 |
| II | 0 | -14.86 | -16.92 | -17.03 | -17.21 |
| III | 0 | -5.28 | -6.35 | -6.87 | -6.92 |
I：基质膏霜添加3.0wt％实施例2制备的纳米乳的美白霜
II：与I相同基质膏霜，添加未包埋的，仅溶解于混合溶剂中的羟基酪醇，换算成与I相同的羟基酪醇浓度；
III：与I相同基质膏霜，未添加羟基酪醇及其纳米乳的空白样品；
从表1可以看到，a使用样品I和II 4周后使用部位的黑色素降低量明显比样品III更显著，说明该化妆品具有良好的美白效果，其美白功效显著大于配方基质；b样品II的降低量在1-2周内效果比较好，但是持续时间短，3-4周的作用效果明显差于样品I，说明羟基酪醇纳米乳可以表现出优于羟基酪醇的美白功效，持续作用时间更长，效果更持久。
下面结合具体实施例对本发明的产品和制备方法作详细的阐述，但不限于这些具体记载的实施例。
实施例1：
精密称取15-羟基硬脂酸聚乙二醇酯2.0g、辛酸癸酸甘油三酯1.0g、羟基酪醇0.72g放入烧杯中置于水浴70℃，作为油相；精密量取46.28g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例2：
精密称取15-羟基硬脂酸聚乙二醇酯2.0g、辛酸癸酸甘油三酯1.0g、羟基酪醇1.15g放入烧杯中置于水浴70℃，作为油相；精密量取45.85g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例3：
精密称取15-羟基硬脂酸聚乙二醇酯2.0g、辛酸癸酸甘油三酯1.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取45.5g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例4：
精密称取15-羟基硬脂酸聚乙二醇酯2.0g、辛酸癸酸甘油三酯2.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取44.5g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例5：
精密称取15-羟基硬脂酸聚乙二醇酯1.8g、聚乙二醇4001.0g、辛酸癸酸甘油三酯1.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取45g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例6：
精密称取15-羟基硬脂酸聚乙二醇酯1.5g、聚乙二醇4001.0g、辛酸癸酸甘油三酯0.5g、肉豆蔻酸异丙酯0.5g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取45g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例7：
精密称取15-羟基硬脂酸聚乙二醇酯1.5g、聚乙二醇4001.0g、肉豆蔻酸异丙酯1.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取45g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例8：
精密称取15-羟基硬脂酸聚乙二醇酯1.5g、聚乙二醇4001.0g、辛酸癸酸甘油三酯0.5g、乳木果油1.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取44.5g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例9：
精密称取吐温-803.0g、辛酸癸酸甘油三酯1.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取44.5g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
实施例10：
精密称取蓖麻油聚氧乙烯醚3.0g、聚乙二醇4001.0g、辛酸癸酸甘油三酯1.0g、羟基酪醇1.5g放入烧杯中置于水浴70℃，作为油相；精密量取44.5g纯化水中置于水浴70℃搅拌融合，作为水相；在70℃水浴条件下，将含有羟基酪醇的油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有蓝色乳光的澄清透明溶液，既得o/w型羟基酪醇纳米乳。
以上制备的纳米乳每2ml加入1.0g(2％)甘露醇后装入西林瓶中，置冷冻干燥机中-40℃、预冻4h，升华干燥24h，解析干燥6h，冻干得白色疏松状羟基酪醇纳米乳冻干制剂，该冻干制剂加入2ml纯化水经振摇可于1min内完全复溶。
Claims (9)
1.一种含有羟基酪醇的纳米乳，其特征在于，包括以下重量百分比的组分制成：
一种含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于，是通过以下制备方法制得的：
(1)称取表面活性剂、羟基酪醇加入到油中作为油相，水浴中搅拌融合；
(2)称取纯化水到烧杯中，置于水浴中；
(3)在水浴条件下将油相缓慢滴加到水相中并充分搅拌完全乳化，直至形成黏度与水溶液相似的带有淡蓝色乳光的澄清透明溶液，记录体系由浑浊变澄清时临界水量，此时产生的即是o/w型羟基酪醇纳米乳；
(4)向上述纳米乳制剂中加入0.5％～10％(单位mg/ml)的冻干保护剂；
(5)冷冻干燥去除水分，制备干燥的羟基酪醇纳米乳冻干制剂。
2.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于：所述步骤(1)中，表面活性剂为15-羟基硬脂酸聚乙二醇酯、月桂醇聚醚硫酸酯钠、蓖麻油聚氧乙烯醚、氢化蓖麻油聚氧乙烯醚、聚氧乙烯脱水山梨醇单油酸酯(吐温-80)、山梨糖醇酐单油酸酯中的任一种或几种混合物。
3.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于：所述步骤(1)中，表面活性剂中还可以加入助表面活性剂；所述的助表面活性剂是乙醇、丙二醇，聚乙二醇类中一种或几种。
4.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于：所述步骤(1)中，油相为辛酸/癸酸甘油三酯、棕榈酸异丙酯、大豆油、乳木果油、肉豆蔻酸异丙酯、液体石蜡、甜杏仁油、山茶籽油、维生素E中一种或两种以上。
5.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于：所述步骤(1)中，所使用的水浴温度优选为65-85℃。
6.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于：所述步骤(2)中，所使用的水浴温度优选为65-85℃。
7.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂，其特征在于：所述的步骤(3)中所使用的水浴温度优选为65-85℃。
8.根据权利要求1所述的含有羟基酪醇的纳米乳制剂及其冻干剂的制备方法，其特征在于：所述的步骤(4)中冻干保护剂选自：甘露醇、山梨醇、蔗糖、葡萄糖、乳糖、果糖、海藻糖中的任一种，或它们的混合物。
9.根据权利要求1-7任一项所述的含有羟基酪醇的纳米乳制剂及其冻干剂的制备方法所制备得到的纳米乳制剂及其冻干。
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