CN113616683A - 罗布麻黄酮自微乳方法及其应用 - Google Patents
罗布麻黄酮自微乳方法及其应用 Download PDFInfo
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Abstract
本发明涉及药物制剂技术领域,尤其涉及罗布麻黄酮自微乳及其应用。本发明是将罗布麻黄酮与乳化助剂和溶剂共同制成自微乳制剂,其中溶剂为乙醇和/或罗布麻全谱系精油。纳米微乳滴粒径约8~24nm。罗布麻黄酮在水中的溶解度可以提高到20~35mg/mL,罗布麻全谱系精制油提高到1%~10%。相较于已有的水溶性罗布麻黄酮粉末制剂,本发明使罗布麻黄酮的溶解度进一步提高,生物利用度提高2~10倍。本发明制备的自微乳工艺简单,便于操作,且本发明热力学稳定性好,贮存稳定性良好,久置不分层,离心加速试验中,12000rpm离心20min不分层。
Description
技术领域
本发明涉及药物制剂技术领域,尤其涉及罗布麻黄酮自微乳及其应用。
背景技术
黄酮类化合物(flavonoids)是罗布麻提取物种具价值的一类有效成分,它们分子中有一个酮式羰基,第一位上的氧原子具碱性,能与强酸成盐,其羟基衍生物多具黄色,故又称黄碱素或黄酮。药理实验表明罗布麻对预防和治疗高血压、高血脂有较好疗效,对治疗多发性硬化症具有良好的效果。同时具有抗菌、抗失眠等一系列生理活性功能。黄酮还具有抗氧化作用,效果优于抗坏血酸盐或维生素E,是一个潜在的抗氧化剂。因此,黄酮具有极其广阔的生物医药应用前景。
由于生物体复杂的新陈代谢网络,单质化学物质往往难以达到全面调节生理机能的作用,因此往往需要复合性的制剂调节。罗布麻是我国值得重视的多年生草本韧皮纤维植物和药用资源植物。近年来,罗布麻保健织物倍受青睐,其化学成分、药理研究也异常活跃。罗布麻植株中含有富含罗布麻黄酮(>70%)和其他挥发性物质。这些挥发性物质在一定浓度下也能达到类似抗菌、抗炎等效果。相较于罗布麻黄酮纯品,价格实惠的、富含挥发性物质的罗布麻精油在日用和化妆品领域更为受欢迎。但是,无论是纯罗布麻黄酮还是罗布麻精制油,都不容易溶于水,为了提高它们的生物利用度,往往需要制剂或工艺上的改进来增加它们的水溶性来实现最大利用度。
近年来,国内外对罗布麻黄酮的研究主要专注于包括其提取工艺、含量测定与药理活性,但是对罗布麻黄酮或罗布麻全谱系精制油的制剂研究较少,只有水溶性罗布麻黄酮粉末,尚未出现罗布麻黄酮或罗布麻全谱系精制油相关乳剂的研究和应用。
发明内容
有鉴于此,本发明要解决的技术问题在于提供罗布麻黄酮自微乳及其应用,该自微乳平均粒径较小,载药量高,溶解性高,且久置稳定性良好。
本发明提供了一种罗布麻黄酮自微乳,其由罗布麻黄酮、溶剂、水和乳化助剂制成;其中,罗布麻黄酮的质量分数为0.5%~5%;
所述溶剂选自乙醇或罗布麻全谱精油中至少一种;
所述乳化助剂选自甘油、聚丙二醇-13-癸基十四醇聚醚-24或聚乙二醇/聚丙二醇/聚丁二醇-8/5/3中至少一种。
本发明中,所述罗布麻黄酮自微乳由罗布麻黄酮、甘油、乙醇、水、聚丙二醇-13-癸基十四醇聚醚-24和聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;
或由罗布麻黄酮、罗布麻全谱精油、乙醇、水、聚丙二醇-13-癸基十四醇聚醚-24和聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成。
一些实施例中,所述罗布麻黄酮自微乳由0.5质量份罗布麻黄酮、0.64质量份甘油、乙醇、水、5质量份聚丙二醇-13-癸基十四醇聚醚-24和5质量份聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;其中罗布麻黄酮与乙醇的质量-体积比为0.5g:1mL,水的体积不超过乙醇的1/10。
一些实施例中,所述罗布麻黄酮自微乳由0.4质量份罗布麻黄酮、0.8质量份甘油、乙醇、水、4.5质量份聚丙二醇-13-癸基十四醇聚醚-24和4.5质量份聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;其中罗布麻黄酮与乙醇的质量-体积比为0.4g:1mL,水的体积不超过乙醇的1/10。
一些实施例中,所述罗布麻黄酮自微乳由0.4质量份罗布麻黄酮、0.5质量份甘油、乙醇、水、4.5质量份聚丙二醇-13-癸基十四醇聚醚-24和4.5质量份聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;其中罗布麻黄酮与乙醇的质量-体积比为0.4g:1mL,水的体积不超过乙醇的1/10。
一些实施例中,所述罗布麻黄酮自微乳由1.25质量份罗布麻黄酮、1.25质量份罗布麻全谱系精油、乙醇、水、4质量份聚丙二醇-13-癸基十四醇聚醚-24和5质量份聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;其中罗布麻黄酮与乙醇的质量-体积比为1.25g:2.5mL,水的体积不超过乙醇的1/25。
一些实施例中,所述罗布麻黄酮自微乳由1.65质量份罗布麻黄酮、1.65质量份罗布麻全谱系精油、乙醇、水、5质量份聚丙二醇-13-癸基十四醇聚醚-24和5质量份聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;其中罗布麻黄酮与乙醇的质量-体积比为1.65g:1.7mL,水的体积不超过乙醇的1/17。
一些实施例中,所述罗布麻黄酮自微乳由2.3质量份罗布麻黄酮、2.3质量份罗布麻全谱系精油、乙醇、水、5质量份聚丙二醇-13-癸基十四醇聚醚-24和5质量份聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;其中罗布麻黄酮与乙醇的质量-体积比为2.3g:0.4mL,水的体积不超过乙醇的1/4。
本发明还提供了罗布麻黄酮自微乳的制备方法,其包括:
步骤1:将罗布麻黄酮溶解于溶剂,制成质量分数为12.5%~50%的黄酮溶液;
步骤2:将所述黄酮溶液与乳化助剂混合后进行搅拌;
步骤3:加入水继续搅拌获得罗布麻自微乳。
本发明中,所述乳化助剂与所述黄酮溶液的质量-体积比为(8.5g~10.64g):(1mL~3.75mL)。
步骤2中所述搅拌的条件为60~65℃,700~900rpm,搅拌2min。
步骤3中所述搅拌包括为60~65℃,700~900rpm,搅拌2min;然后自然降温并于400~500rpm继续搅拌2min。
步骤3中所述加入水的体积至水的体积分数小于10%。
本发明所述制备方法制得的罗布麻黄酮自微乳。
本发明提供的自微乳,在实际应用时,可根据需要,稀释成不同浓度的罗布麻黄酮或罗布麻全谱系精制油纳米微乳液外用。刚开始稀释时体系劲稠,继续滴加超纯水并不断的搅拌,会出现透明凝胶状液体。在低温放置几分钟后,体系变得均一透亮,即是水包油型纳米微乳液。罗布麻黄酮或全谱系精制油纳米微乳液呈澄清透亮、淡黄色。
本发明所述罗布麻黄酮自微乳或本发明所述制备方法制得的罗布麻黄酮自微乳在制备食品、药品和/或化妆品中的应用。
含有本发明所述罗布麻黄酮自微乳或本发明所述制备方法制得的罗布麻黄酮自微乳的食品、药品和/或化妆品。
本发明是将罗布麻黄酮与乳化助剂和溶剂共同制成自微乳制剂,其中溶剂为乙醇和/或罗布麻全谱系精油。纳米微乳滴粒径约8~24nm。罗布麻黄酮在水中的溶解度可以提高到20~35mg/mL,罗布麻全谱系精制油提高到1~10%。相较于已有的水溶性罗布麻黄酮粉末制剂,本发明使罗布麻黄酮的溶解度进一步提高,生物利用度提高2~10倍。本发明制备的自微乳工艺简单,便于操作,且本发明热力学稳定性好,贮存稳定性良好,久置不分层,离心加速试验中,12000rpm离心20min不分层。
附图说明
图1为实施例3制得罗布麻黄酮微乳液的粒径分布图;
图2为实施例3制得罗布麻黄酮微乳液的显微图;
图3为实施例6制得罗布麻黄酮微乳液的粒径分布图;
图4为实施例3制得罗布麻黄酮微乳液的显微图。
具体实施方式
本发明提供了罗布麻黄酮自微乳及其应用,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
本发明采用的试材皆为普通市售品,皆可于市场购得。
其中,所述罗布麻全谱精油的制备方法如下:
1.在罗布麻盛花期,首先捋花序,然后收获全株。鲜花序直接进入精油提取阶段。收获的其他材料晾晒,至50%以上叶片出现干卷现象时,拍打或碾压至叶片脱落,实现叶片与茎秆的分离。收集叶片进入精油提取阶段。
2.提取方法为:鲜花或干叶分别用去离子水搅拌浸泡1~1.5小时制成原料样品,固液质量比为1:6~8。将原料样品加入蒸馏装置中,95~100℃加热蒸馏3.5~4小时得到馏出液。当馏出液澄清透明,不含有油珠状的有机物时,停止蒸馏,收集获得精油。
3.花和叶分别提取精油后,按照1:5~7的比例混合,获得全谱系精油。
所述罗布麻黄酮的制备方法包括:
将适量罗布麻干燥叶片粉碎并过细筛,于80%乙醇超声提取三次,合并提取液并过滤,滤液减压浓缩至干,采用无水乙醇超声溶解后过滤,滤液减压浓缩至最小体积,微孔滤膜过滤后进制备液相(Waters2555),制备色谱柱为GLP-ID100mm×450mm,制备条件:乙腈梯度为10%~90%乙腈,0~60min,收集谱带Ⅰ为270nm和谱带Ⅱ为350nm具有黄酮特征的馏分,收集总黄酮,减压浓缩得到罗布麻总黄酮粉末。分析液相(Waters Acouity)色谱柱为纳微、3μm、4.6×150mm;分析条件:全波长扫描;乙腈梯度:乙腈:0.2%醋酸水,0~60min,10%~90%乙腈。
下面结合实施例,进一步阐述本发明:
实施例1:
一种制备罗布麻黄酮自微乳的方法,包括以下步骤:
(1)称量取各药物组分0.5g罗布麻黄酮、5g PPG-13-癸基十四醇聚醚-24、5g PEG/PPG/聚丁二醇-8/5/3备用;
(2)将(1)中的罗布麻黄酮固体粉末溶解于1mL乙醇中,制成50%罗布麻黄酮乙醇溶液;
(3)向(2)中加入0.64g甘油、5g PPG-13-癸基十四醇聚醚-24与5g PEG/PPG/聚丁二醇-8/5/3于65℃,700~900rpm条件下,搅拌均匀至溶液出现少量气泡,得到澄清透明的罗布麻黄酮油状自微乳;
(4)向(3)中缓慢滴加微量体积(<100μL)的超纯水于65℃,700~900rpm条件下,搅拌均匀;
(5)将上述(4)在自然降温条件下,以400~500rpm搅拌至澄清透亮,得到纯罗布麻黄酮的微乳浓缩液,外观为澄清透亮的无色油状液体。
实施例2:
一种制备罗布麻黄酮自微乳的方法,包括以下步骤:
(1)称量取各药物组分0.4g罗布麻黄酮、4.5g PPG-13-癸基十四醇聚醚-24、4.5gPEG/PPG/聚丁二醇-8/5/3备用;
(2)将(1)中的罗布麻黄酮固体粉末溶解于1mL乙醇中,制成40%罗布麻黄酮乙醇溶液;
(3)向(2)中加入0.8g甘油、4.5g PPG-13-癸基十四醇聚醚-24与4.5g PEG/PPG/聚丁二醇-8/5/3于65℃,700~900rpm条件下,搅拌均匀至溶液出现少量气泡,得到澄清透明的罗布麻黄酮油状自微乳;
(4)向(3)中缓慢滴加微量体积(<100μL)的超纯水于65℃,700~900rpm条件下,搅拌均匀;
(5)将上述(4)在自然降温条件下,以400~500rpm搅拌至澄清透亮,得到纯罗布麻黄酮的微乳浓缩液,外观为澄清透亮的无色油状液体。
实施例3:
一种制备罗布麻黄酮自微乳的方法,包括以下步骤:
(1)称量取各药物组分0.4g罗布麻黄酮、4.0g PPG-13-癸基十四醇聚醚-24、4.0gPEG/PPG/聚丁二醇-8/5/3备用;
(2)将(1)中的罗布麻黄酮固体粉末溶解于1mL乙醇中,制成40%罗布麻黄酮乙醇溶液;
(3)向(2)中加入0.5g甘油、4.0g PPG-13-癸基十四醇聚醚-24与4.0g PEG/PPG/聚丁二醇-8/5/3于65℃,700~900rpm条件下,搅拌均匀至溶液出现少量气泡,得到澄清透明的罗布麻黄酮油状自微乳;
(4)向(3)中缓慢滴加微量体积(<100μL)的超纯水于65℃,700~900rpm条件下,搅拌均匀;
(5)将上述(4)在自然降温条件下,以400~500rpm搅拌至澄清透亮,得到纯罗布麻黄酮的微乳浓缩液,外观为澄清透亮的无色油状液体。
实施例4:
一种制备罗布麻全谱系精制油自微乳的方法,包括以下步骤:
(1)称取各药物组分2.5g罗布麻全谱系精制油(1.25质量份罗布麻黄酮+1.25质量份罗布麻全谱系精油)、5g PPG-13-癸基十四醇聚醚-24、5g PEG/PPG/聚丁二醇-8/5/3备用;
(2)将(1)用乙醇助溶,制成25%的罗布麻全谱系精制油(12.5%黄酮);
(3)向(2)中加入5g PPG-13-癸基十四醇聚醚-24与5g PEG/PPG/聚丁二醇-8/5/3于60℃,700~900rpm搅拌均匀至溶剂冒出微量气泡;
(4)向(3)中缓慢滴加微量体积(<100μL)的超纯水于60℃,700~900rpm条件下,搅拌至均匀;
(5)将上述(4)在自然降温条件下,以400~500rpm搅拌至澄清透亮,得到罗布麻全谱系精制油的微乳浓缩液,外观为澄清透亮的淡黄色油状液体。
实施例5:
一种制备罗布麻全谱系精制油自微乳的方法,包括以下步骤:
(1)称取各药物组分3.3g罗布麻全谱系精制油(1.65质量份罗布麻黄酮+1.65质量份罗布麻全谱系精油)、5g PPG-13-癸基十四醇聚醚-24、5g PEG/PPG/聚丁二醇-8/5/3备用;
(2)将(1)用乙醇助溶,制成66%的罗布麻全谱系精制油(33%黄酮);
(3)向(2)中加入5g PPG-13-癸基十四醇聚醚-24与5g PEG/PPG/聚丁二醇-8/5/3于60℃,700~900rpm搅拌均匀至溶剂冒出微量气泡;
(4)向(3)中缓慢滴加微量体积(<100μL)的超纯水于60℃,700~900rpm条件下,搅拌至均匀;
(5)将上述(4)在自然降温条件下,以400~500rpm搅拌至澄清透亮,得到罗布麻全谱系精制油的微乳浓缩液,外观为澄清透亮的淡黄色油状液体。
实施例6:
一种制备罗布麻全谱系精制油自微乳的方法,包括以下步骤:
(1)称取各药物组分4.6g罗布麻全谱系精制油(2.3质量份罗布麻黄酮+2.3质量份罗布麻全谱系精油、4g PPG-13-癸基十四醇聚醚-24、5g PEG/PPG/聚丁二醇-8/5/3备用;
(2)将(1)用乙醇助溶,制成92%的罗布麻全谱系精制油(46%黄酮);
(3)向(2)中加入4g PPG-13-癸基十四醇聚醚-24与5g PEG/PPG/聚丁二醇-8/5/3于60℃,700~900rpm搅拌均匀至溶剂冒出微量气泡;
(4)向(3)中缓慢滴加微量体积(<100μL)的超纯水于60℃,700~900rpm条件下,搅拌至均匀;
(5)将上述(4)在自然降温条件下,以400~500rpm搅拌至澄清透亮,得到罗布麻全谱系精制油的微乳浓缩液,外观为澄清透亮的淡黄色油状液体。
效果检测
1、外观、粒径,以及溶解度(载药量)检测:
实施例1~3中,实施例3为最佳工艺,纯罗布麻黄酮的载药量(在溶剂中的总溶解度)最高,达到35.6mg/ml,显著性的优于实施例1或实施例2的载药量。无论高倍或者低倍稀释,微乳液外观均呈无色透明,久置稳定。且稀释之后所得纳米乳的粒径相对较小,见图1及图2,可以看出纳米微乳平均粒径在24nm左右,高于实施例1(微乳平均粒径15nm)和实施例2(微乳平均粒径18nm)。三个实施例中制备的自微乳外观无明显变化,久置均很稳定。
实施例4~6中,实施例6为最佳工艺,罗布麻全谱系精制油的载药量(在溶剂中的总溶解度)最高,达10%,显著性的优于实施例1或实施例2的载药量。无论高倍或者低倍稀释,微乳液外观均呈淡黄色透明状,久置稳定。且稀释之后所得纳米乳的粒径相对较小,见图3及图4,可以看出纳米微乳平均粒径在8nm左右。三个实施例中制备的自微乳外观无明显变化,久置均很稳定。
2、稳定性
本发明实施例1~6制备的自微乳工艺简单,便于操作,且本发明热力学稳定性好,贮存稳定性良好,将实施例1~6自微乳液置于28℃培养箱中,放置1-2个月的时间,自微乳液久置皆不分层,皆无颗粒聚集现象出现;
离心加速试验检测发现,12000rpm离心20min条件下,实施例1~6的自微乳皆无分层现象出现,稳定性好。
3、溶解度或生物利用度。实施例1~3的自微乳可以将罗布麻黄酮粉末在水(总溶剂)中的溶解度可以提高到20~35mg/mL;实施例4~6的自微乳可以将罗布麻全谱系精制油在水(总溶剂)中的溶解度提高到1%~10%。实施例1~6的自微乳相较于已有的水溶性罗布麻黄酮粉末制剂,本发明使罗布麻黄酮的溶解度进一步提高,生物利用度提高2~10倍。其中,实施例3的自微乳的生物利用度最高,为现有技术中罗布麻黄酮粉末制剂的10倍。
以上仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.罗布麻黄酮自微乳,其特征在于,由罗布麻黄酮、溶剂、水和乳化助剂制成;其中,罗布麻黄酮的质量分数为0.5%~5%;
所述溶剂选自乙醇或罗布麻全谱精油中至少一种;
所述乳化助剂选自甘油、聚丙二醇-13-癸基十四醇聚醚-24或聚乙二醇/聚丙二醇/聚丁二醇-8/5/3中至少一种。
2.根据权利要求1所述的罗布麻黄酮自微乳,其特征在于,
由罗布麻黄酮、甘油、乙醇、水、聚丙二醇-13-癸基十四醇聚醚-24和聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成;
或由罗布麻黄酮、罗布麻全谱精油、乙醇、水、聚丙二醇-13-癸基十四醇聚醚-24和聚乙二醇/聚丙二醇/聚丁二醇-8/5/3制成。
3.权利要求1或2所述的罗布麻黄酮自微乳的制备方法,其特征在于,包括:
步骤1:将罗布麻黄酮溶解于溶剂,制成质量分数为12.5%~50%的黄酮溶液;
步骤2:将所述黄酮溶液与乳化助剂混合后进行搅拌;
步骤3:加入水继续搅拌获得罗布麻自微乳。
4.根据权利要求3所述的制备方法,其特征在于,所述乳化助剂与所述黄酮溶液的质量-体积比为(8.5g~10.64g):(1mL~3.75mL)。
5.根据权利要求3所述的制备方法,其特征在于,步骤2中所述搅拌的条件为60~65℃,700~900rpm,搅拌2min。
6.根据权利要求3所述的制备方法,其特征在于,步骤3中所述搅拌包括为60~65℃,700~900rpm,搅拌2min;然后自然降温并于400~500rpm继续搅拌2min。
7.根据权利要求3所述的制备方法,其特征在于,步骤3中所述加入水的体积至水的体积分数小于10%。
8.权利要求3~7任一项所述制备方法制得的罗布麻黄酮自微乳。
9.权利要求1或2所述的罗布麻黄酮自微乳或权利要求3~7任一项所述制备方法制得的罗布麻黄酮自微乳在制备食品、药品和/或化妆品中的应用。
10.含有权利要求1或2所述的罗布麻黄酮自微乳或权利要求3~7任一项所述制备方法制得的罗布麻黄酮自微乳的食品、药品和/或化妆品。
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