WO2016119143A1 - 一种叶黄素微胶囊制剂及其制备方法 - Google Patents
一种叶黄素微胶囊制剂及其制备方法 Download PDFInfo
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- WO2016119143A1 WO2016119143A1 PCT/CN2015/071749 CN2015071749W WO2016119143A1 WO 2016119143 A1 WO2016119143 A1 WO 2016119143A1 CN 2015071749 W CN2015071749 W CN 2015071749W WO 2016119143 A1 WO2016119143 A1 WO 2016119143A1
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- lutein
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Abstract
一种叶黄素微胶囊制剂及其制备方法,所述制剂含有以下成分:叶黄素晶体、水溶性乳化剂、油溶性抗氧化剂、壁材、填充剂、水溶性抗氧化剂和纯净水。其制备方法为,将叶黄素晶体和油溶性抗氧化剂溶解于水溶性乳化剂中,制得油相;将壁材、水溶性抗氧化剂和填充剂加入纯净水中,制得水相;将油相加入到水相中,研磨使乳液微粒粒径小于100nm,造粒。
Description
本发明属于类胡萝卜素微胶囊技术,具体涉及一种叶黄素微胶囊制剂及其制备方法。
叶黄素(Lutein),别名:二羟基-d-胡萝卜素,9-胡萝烯-3-3'-二醇,是一种含氧的类胡萝卜素,除了可用作着色剂外,还具有多种生理功能,比如抗氧化、消除自由基、抗癌、减少心血管疾病的发病率和视觉保护等,尤其是在预防老年性白内障和老年黄斑变性等方面,受到广泛的关注。叶黄素广泛分布于香蕉、猕猴桃、玉米和万寿菊等植物中,食品工业、饲料工业、制药业使用的叶黄素一般是从万寿菊中提取,通常与肉豆蔻酸、月桂酸和棕榈酸这样的脂肪酸以酯化的形式存在,需转化成游离的叶黄素,才可以被人体代谢。
游离的叶黄素也就是叶黄素晶体很不稳定,对光和氧十分敏感,易被氧化分解,且不溶于水,大大限制了其在食品及药物、饲料工业中的应用。
微胶囊技术则是解决上述问题的有效方法,由于叶黄素被包裹于连续的囊材形成的微小的囊中,避免了与环境的直接接触,保持其在贮藏、运输以及使用过程中的稳定性。
有关叶黄素微囊化或类似制剂的报道有:
CN200580031802.8(CN101023140A)涉及一种生产至少一种类胡萝卜素的干粉的方法,将至少一种类胡萝卜素分散于由异麦芽酮糖醇和至少一种保护胶体形成的混合物的水性分子溶液或胶体溶液中,再通过分离水,任选添加溶剂,然后干燥,将已经形成的分散液转化为干粉。该方法所得干粉稳定性较差,无法满足市场要求。
CN200810137559.3(CN101433528A)涉及一种从叶黄素晶体制备稳定水分散体叶黄素微胶囊方法,方法中采用瞬时高温熔融法将叶黄素晶体溶解于食用油中,添加乳化基质进行乳化,经高压均质机将活性化合物均质
得到叶黄素溶液,采用流化床制粒包衣,将包衣载体通过雾滴表面吸附并冷却成型。相关性较大,该制备过程所得到的叶黄素微胶囊的粒径为5~40μm,没有达到纳米级,分散于水中达不到澄清透明的效果,且需要大量的食用油,无法制备高含量的微胶囊,相同含量条件下,壁材所占比例小,稳定性差。
CN201110232047.7(CN102258499A)公开了一种叶黄素微囊的制备方法,该方法采用高温熔融法,将叶黄素粉末熔融于药用大豆油中,制得混合芯材溶液,然后,将壁材溶液与混合芯材溶液混合,在高速剪切下形成初乳,再经高压匀质机制备叶黄素乳液,乳液经喷雾干燥后即得叶黄素微囊。该制备方法需要大量的食用油和乳化剂,无法制备高含量的微胶囊,相同含量条件下,壁材所占比例小,稳定性差。
CN200610154617.4(CN101177540B)涉及一种食品级叶黄素水溶性干粉的制备方法,方法中将叶黄素晶体与低沸点、易挥发且对叶黄素晶体溶解度大的有机溶剂混合后,加热溶解,得到油相,与水相混合乳化后进行高压均质,通过常规分离方法去除乳液体系中的有机溶剂,用喷雾干燥法去掉乳液中水分,得干粉。该制备过程使用了有机溶剂溶解叶黄素晶体,尽管采用的是低沸点、易挥发的有机溶剂,但溶剂残留无法避免,另外有机溶剂的使用量较大,回收溶剂也需要一定的能耗。
CN201310392763.0(CN103406079A)将类胡萝卜素晶体悬浮于含有抗氧化剂、保护性胶体和至少一种非离子型乳化剂的水溶液中,在氮气保护下研磨、均质,然后脱水干燥成粉末状颗粒。通过该专利制备的叶黄素微胶囊具有一定的分散性但由于无法使叶黄素晶体溶于乳化剂中,水分散液透明度差,无法满足高端要求。
因此,需要提供一种稳定性高、水溶性好的叶黄素制剂。
发明内容
本发明所要解决的技术问题是克服上述现有技术存在的缺陷,提供一种易于工业化生产的外形为微球的高稳定性叶黄素微胶囊制剂。
本发明提供了一种叶黄素微胶囊制剂,其含有以下成分:叶黄素晶体、油溶性抗氧化剂、水溶性乳化剂、壁材、填充剂、水溶性抗氧化剂和纯净水。
具体的,其含有以下重量份的成分:1份叶黄素晶体、0.1-0.5份油溶性抗氧化剂、0.3-1.0份水溶性乳化剂、3.0-4.0份壁材、4.0-5.0份填充剂、0.2-1.0份水溶性抗氧化剂和8.0-12.5份纯净水。
优选地,其含有以下重量份的成分:1份叶黄素晶体、0.1-0.3份油溶性抗氧化剂、0.5-1.0份水溶性乳化剂、3.5-3.75份壁材、4.5-4.75份填充剂、0.5-0.8份水溶性抗氧化剂和10-11.5份纯净水。
上述制剂中:
所述叶黄素晶体,可以市售购买,其中叶黄素含量80%以上;
所述油溶性抗氧化剂为天然维生素E或迷迭香提取物,所述迷迭香提取物是从迷迭香植物中提取出来的天然抗氧化剂,其有效成分鼠尾草酸含量不低于20%;
所述水溶性乳化剂为HLB值达到13以上的水溶性的乳化剂,优选为聚甘油脂肪酸酯、蔗糖脂肪酸酯或聚氧乙烯失水山梨醇脂肪酸酯中的一种或两种;
所述聚氧乙烯失水山梨醇脂肪酸酯为聚山梨酯-80。
所述壁材为阿拉伯胶或辛烯基琥珀酸淀粉酯中的一种或两种;
所述填充剂为异麦芽糖醇、蔗糖或葡萄糖中的一种或两种;
所述水溶性抗氧化剂为抗坏血酸和茶多酚或抗坏血酸和低聚原花青素的混合物,优选地,所述抗坏血酸和茶多酚的重量比为1:1;抗坏血酸和低聚原花青素的重量比为1:1。
本发明的另一目的是提供上述微胶囊制剂的制备方法,该方法包括以下步骤:
1)将叶黄素晶体熔融于添加了油溶性抗氧化剂和水溶性乳化剂中,制得油相;
2)在50-80℃条件下,将壁材、水溶性抗氧化剂和填充剂加入纯净水中,
搅拌溶解,制得水相;
3)将油相加入到水相中搅拌均匀,然后过胶体磨粗磨,再经过砂磨机进行精磨,使研磨后的乳液微粒粒径达到100nm以下,将乳液用喷雾-淀粉流化床干燥法进行一步造粒,得到粒径为40目-100目的圆球状微胶囊制剂。
优选地,所述方法包括以下步骤:
1)将叶黄素晶体140℃-180℃熔融于添加了油溶性抗氧化剂和水溶性乳化剂中,制得油相;
2)在50-80℃条件下,将壁材、水溶性抗氧化剂和填充剂加入水中,搅拌溶解30-60分钟,制得水相;
3)将油相加入到水相中搅拌均匀,然后过胶体磨粗磨,再经过砂磨机进行精磨,所述砂磨机的研磨介质粒径为0.5-1.0mm,转速为1500-2000rpm,使研磨后的乳液微粒粒径达到100nm以下,将乳液用喷雾-淀粉流化床干燥法进行一步造粒,得到粒径为40目-100目的圆球状微胶囊制剂。
上述方法中:
喷雾-淀粉流化床干燥过程中,使用的粘合剂为水溶性淀粉,喷雾进风温度为110-130℃,淀粉流化床鼓风温度为60-80℃。
本发明提供的叶黄素的微胶囊制剂具有以下优点:
1、本发明提供的叶黄素微胶囊制剂及其制备方法,原料及整个制备过程没有使用有机溶剂,提高了产品的安全性;没有使用食用油而是将叶黄素晶体熔融于水溶性乳化剂中,结合进一步的研磨使微胶囊粒径达到100nm以下从而使产品的水分散液澄清透明;使用淀粉进行一步造粒,得到圆球状微囊,既能够起到二次包埋的效果提高稳定性,又能克服喷雾干燥法所得粉末耐压性差,不适合进行压片(流动性差),不适合用于灌装硬胶囊等缺点。
2、稳定性试验:本发明提供的微胶囊制剂在40℃、RH75%条件下放置6个月后的含量保留率大于97%。
以下实施例用于说明本发明,但不用来限制本发明的范围。
所述迷迭香提取物是从迷迭香植物中提取出来的天然抗氧化剂,其有效成分鼠尾草酸含量不低于20%,购自河南森源本草天然产物有限公司。
实施例1:叶黄素微胶囊制剂
1.将20g叶黄素含量为80%的叶黄素晶体、2g迷迭香提取物(约为叶黄素的0.1倍)加入到20g聚甘油脂肪酸酯(约为叶黄素的1倍)中,升温至165℃保温5min至完全熔融,熔融的容器进行充氮保护,制得油相。
2.将75g阿拉伯胶(约为叶黄素的3.75倍)、95g异麦芽糖醇(约为叶黄素的4.75倍)、5g抗坏血酸和5g茶多酚(合计约为叶黄素的0.5倍)溶于230g纯净水(约为叶黄素的11.5倍)中,75℃下溶解0.5小时,保温待用,制得水相。
3.将165℃的油相缓慢加入到75℃转速≥10000rpm剪切搅拌下的水相中,搅拌0.5小时,冷却至室温待用,得到混合液。
4.将混合液过一遍胶体磨后,再用砂磨机研磨0.5小时,转速为1900rpm,粒径检测结果为95nm。
5.混合液研磨后用喷雾-淀粉流化床干燥造粒,喷雾进风温度为120℃,淀粉流化床鼓风温度为75℃。得到270g叶黄素含量为5%的叶黄素微囊制剂。
实施例2:叶黄素微胶囊制剂
1.将40kg叶黄素含量为80%的叶黄素晶体、4kg迷迭香提取物(约为叶黄素的0.1倍)加入到40kg聚山梨酯-80(约为叶黄素的1倍)中,升温至160℃保温10min至完全熔融,熔融的容器进行充氮保护,制得油相。
2.将150kg阿拉伯胶(约为叶黄素的3.75倍)、190kg蔗糖(约为叶黄素的4.75倍)、10kg抗坏血酸和10kg低聚原花青素(合计约为叶黄素的0.5倍)溶于450kg(约为叶黄素的11.25倍)纯净水中,70℃下溶解45分钟,保温待用,制得水相。
3.将160℃的油相缓慢加入到75℃转速≥10000rpm剪切搅拌下的水相中,搅拌0.5小时,冷却至室温待用,得到混合液。
4.将混合液过一遍胶体磨后,再用砂磨机研磨1小时,转速为2000rpm,粒径检测结果为90nm。
5.混合液研磨后用喷雾-淀粉流化床造粒干燥后得到540kg叶黄素含量为5%的叶黄素微囊制剂。
实施例3:叶黄素微胶囊制剂
1.将27kg叶黄素含量为80%的叶黄素晶体、3kg天然维生素E(约为叶黄素的0.11倍)加入到27kg蔗糖脂肪酸酯(约为叶黄素的1倍)中,升温至170℃保温10min至完全熔融,熔融的容器进行充氮保护,制得油相。
2.将100kg辛烯基琥珀酸淀粉酯(约为叶黄素的3.70倍)、128kg蔗糖(约为叶黄素的4.74倍)、7.5kg抗坏血酸和7kg茶多酚(合计约为叶黄素的0.54倍)溶于300kg纯净水中,70℃下溶解45分钟,保温待用,制得水相。
3.将170℃的油相缓慢加入到75℃转速≥10000rpm剪切搅拌下的水相中,搅拌0.5小时,冷却至室温待用,得到混合液。
4.将混合液过一遍胶体磨后,再用砂磨机研磨1小时,转速为1800rpm,粒径检测结果为100nm。
5.混合液研磨后用喷雾-淀粉流化床造粒干燥后得到360kg叶黄素含量为5%的叶黄素微囊制剂。
实验例:稳定性、水溶性的考察
1、样品:实施例1-3,对比例1-5,其中:
对比例1:按照CN200580031802.8(CN101023140A)的实施例1提供的方法制备;
对比例2:按照CN200810137559.3(CN101433528A)的实施例1提供的方法制备;
对比例3:按照CN201110232047.7(CN102258499A)的实施例1提供的方法制备;
对比例4:按照CN200610154617.4(CN101177540B)的实施例1提供的方法制备;
对比例5:按照CN201310392763.0(CN103406079A)的实施例6提供的方法制备。
2、考察方法:
稳定性:将实施例1-3和对比例1-5制备的叶黄素微胶囊直接放置于药品稳定性试验箱中,条件为40℃、RH75%、避光,测定样品起始含量及放置6个月之后的含量,计算含量保留率。
水溶性:称取叶黄素微囊样品0.1000g于100ml的容量瓶中,加入纯净水溶解(必要时可以超声),定容至刻度。在50ml比色管底部贴一个类似塞氏圆盘的黑白相间的图案,将溶解后的样品倒入比色管中,直到看不清底部图案为止,记下此时比色管液面的高度,如此重复三次求平均值。
3、试验结果:见表1
表1:检测结果
40℃、RH75%条件下放置6个月后含量保留率(%) | 透明度(cm) | |
实施例1 | 98.2 | 13.75 |
实施例2 | 98.0 | 13.80 |
实施例3 | 97.9 | 14.05 |
对比例1 | 78.8 | 8.6 |
对比例2 | 82.4 | 11.2 |
对比例3 | 85.6 | 13.2 |
对比例4 | 95.2 | 13.5 |
对比例5 | 92.5 | 9.2 |
表1结果显示:保留率,实施例1-3放置6个月后保留率97%以上,对比例1-5的保留率最高为92.5%,低于实施例1-3;透明度,实施例1-3为13.7cm以上,对比例最高为13.5cm。
结果表明:本发明人提供的叶黄素微囊稳定性由于对比专利,水分散液透明度也属于上游水平,可以满足实际生产需要。
本发明提供了一种易于工业化生产的外形为微球的高稳定性叶黄素微胶囊制剂,该制剂及其制备方法没有使用有机溶剂,提高了产品的安全性;没有使用食用油而是将叶黄素晶体熔融于水溶性乳化剂中,结合进一步的
研磨使微胶囊粒径达到100nm以下从而使产品的水分散液澄清透明;使用淀粉进行一步造粒,得到圆球状微囊,既能够起到二次包埋的效果提高稳定性,又能克服喷雾干燥法所得粉末耐压性差,不适合进行压片(流动性差),不适合用于灌装硬胶囊等缺点。
Claims (10)
- 一种叶黄素微胶囊制剂,其含有以下成分:叶黄素晶体、油溶性抗氧化剂、水溶性乳化剂、壁材、填充剂、水溶性抗氧化剂和纯净水。
- 根据权利要求1所述的制剂,其特征在于,其含有以下重量份的成分:1份叶黄素晶体、0.1-0.5份油溶性抗氧化剂、0.3-1.0份水溶性乳化剂、3.0-4.0份壁材、4.0-5.0份填充剂、0.2-1.0份水溶性抗氧化剂和8.0-12.5份纯净水。
- 根据权利要求2所述的制剂,其特征在于,其含有以下重量份的成分:1份叶黄素晶体、0.1-0.3份油溶性抗氧化剂、0.5-1.0份水溶性乳化剂、3.5-3.75份壁材、4.5-4.75份填充剂、0.5-0.8份水溶性抗氧化剂和10-11.5份纯净水。
- 根据权利要求1-3任一项所述的制剂,其特征在于,所述油溶性抗氧化剂为天然维生素E或迷迭香提取物。
- 根据权利要求1-3任一项所述的制剂,其特征在于,所述水溶性乳化剂的HLB值达到13以上,优选为聚甘油脂肪酸酯、蔗糖脂肪酸酯、聚山梨酯-80或聚氧乙烯失水山梨醇脂肪酸酯中的一种或两种。
- 根据权利要求1-3任一项所述的制剂,其特征在于,所述壁材为阿拉伯胶或辛烯基琥珀酸淀粉酯中的一种或两种。
- 根据权利要求1-3任一项所述的制剂,其特征在于,所述填充剂为异麦芽糖醇、蔗糖或葡萄糖中的一种或两种。
- 根据权利要求1-3任一项所述的制剂,其特征在于,所述水溶性抗氧化剂为抗坏血酸和茶多酚或抗坏血酸和低聚原花青素的混合物。
- 一种制备权利要求1-8任一项所述制剂的制备方法,其特征在于,该方法包括以下步骤:1)将叶黄素晶体熔融于添加了油溶性抗氧化剂和水溶性乳化剂中,制得油相;2)在50-80℃条件下,将壁材、水溶性抗氧化剂和填充剂加入纯净水中,搅拌溶解,制得水相;3)将油相加入到水相中搅拌混合,然后过胶体磨粗磨,再经过砂磨机进行精磨,使研磨后的乳液微粒粒径达到100nm以下,将乳液用喷雾-淀粉流化 床干燥法进行一步造粒,得到粒径为40目-100目的圆球状微胶囊制剂。
- 根据权利要求9所述的方法,其特征在于,,所述方法包括以下步骤:1)将叶黄素晶体140℃-180℃熔融于添加了油溶性抗氧化剂和水溶性乳化剂中,制得油相;2)在50-80℃条件下,将壁材、水溶性抗氧化剂和填充剂加入水中,搅拌溶解30-60分钟,制得水相;3)将油相加入到水相中搅拌均匀,然后过胶体磨粗磨,再经过砂磨机进行精磨,所述砂磨机的研磨介质粒径为0.5-1.0mm,转速为1500-2000rpm,使研磨后的乳液微粒粒径达到100nm以下,将乳液用喷雾-淀粉流化床干燥法进行一步造粒,得到粒径为40目-100目的圆球状微胶囊制剂。
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