CN116059386A - 一种水溶性叶黄素复合纳米颗粒及其制备方法 - Google Patents
一种水溶性叶黄素复合纳米颗粒及其制备方法 Download PDFInfo
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- CN116059386A CN116059386A CN202310302133.3A CN202310302133A CN116059386A CN 116059386 A CN116059386 A CN 116059386A CN 202310302133 A CN202310302133 A CN 202310302133A CN 116059386 A CN116059386 A CN 116059386A
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Abstract
本发明公开了一种水溶性叶黄素复合纳米颗粒及其制备方法,属于医药中间体及其制备技术领域。本发明的水溶性叶黄素复合纳米颗粒的制备方法先以叶黄素与水溶性高分子聚丙烯酸Steglich酯化反应合成以聚丙烯酸为主链、叶黄素为侧链的接枝共聚物,然后接枝聚合物在水中进行自组装并将未反应的叶黄素负载于其中,形成复合纳米颗粒。提高了叶黄素的水溶性,使其能够直接溶解在水中。未进行酯化反应的叶黄素就地封装在接枝共聚物形成的胶束中,提高了生物可及度和体内利用率。整个过程不经过自由基聚合过程,避免了自由基聚合反应对叶黄素结构的破坏,使得叶黄素的结构得到最大程度的保留。合成简便高效、条件温和、体系简单纯净,所制得产品水溶性好。
Description
技术领域
本发明公开了一种水溶性叶黄素复合纳米颗粒及其制备方法,属于医药中间体及其制备技术领域。
背景技术
叶黄素分子式为C40H56O2,分子量为568.85,有8个立体异构体,3个不对称手性中心,易溶于丙酮,二氯甲烷,四氢呋喃,氯仿,不溶于水。叶黄素作为一种天然类胡萝卜素,主要存在于万寿菊花、蛋黄、玉米和西蓝花等蔬菜中。研究发现叶黄素在人体的视网膜中含量丰富,由于拥有吸收有害蓝光的能力,因此,在预防白内障和老年性黄斑变性等眼部疾病方面具有决定性作用。除了眼部,叶黄素也被发现于其他组织中,其本身具有的抗氧化特性也意味着它可以保护人体内细胞免受自由基的损伤,在对抗组织炎症及防止皮肤受紫外线引起的损伤等方面发挥着重要作用。在工业方面,叶黄素也被用作天然色素和食品添加剂。叶黄素的这些独特生理性能使其在医药保健和功能食品研发中日益受重视,应用前景广阔。
然而,叶黄素不能在人体中合成,饮食摄入为唯一来源。并且,叶黄素两端的羟基容易被氧化光解,性质不稳定,容易受到酸、高温、高湿、空气、光照等一些物理化学因素的影响。使其在暴露于光、氧和热时容易降解,水溶性很差且易被氧化失效。研究表明,尽管许多食物含有高水平的叶黄素,但大部分叶黄素在消化过程中由于以上缺点很难掺入到胶束相中被吸收利用。因此,为扩大叶黄素在食品与医药领域的应用,提高叶黄素的水溶性和生物利用度需要解决的主要问题之一。
为此,现有技术开发出了提高叶黄素水溶性的技术方案。在提高叶黄素的水溶性、化学稳定性及生物利用度方面,国内外科研工作者们主要采取物理封装和化学修饰改性两种方法。物理封装改性通常是指将活性材料嵌入或包覆在壁材中的过程,这种方法通过在叶黄素与外部环境之间建立屏障来提高叶黄素的稳定性。若将物理封装按封装物的类型进行区分,则主要包括:脂质体体系、乳液体系和嵌段共聚物胶束体系。这种方法存在的问题是,需要外加大量乳化剂,或者嵌段共聚物胶束的制备复杂,载药量低。中国专利CN102475696 A公开了一种水溶性叶黄素及其制备工艺,其处方组成及重量比为叶黄素粉末:乳化剂:附加剂=1:2~20:0~5。采用无溶剂减压熔融方法制备水溶性叶黄素粉末中叶黄素的溶出率可达98%,且水溶性良好,稳定性高,分散性好。中国专利CN 103860476 B公开了水溶性粉末及其制备方法,主要将叶黄素、水溶性载体、表面活性剂和附加剂按重量比为1:5~20:1~5:0~3于20~60℃条件下溶解于有机溶剂中,完全溶解后进行喷雾干燥。所制得的叶黄素水溶性粉末水溶性高,稳定性强,颜色均匀持久,流动性佳,在水中的溶解度达95%以上。中国专利CN 104434814 A公开了一种水溶性叶黄素颗粒及其制备工艺和应用,将叶黄素与水溶性高分子辅料的混合粉末采用CO2超临界流体重结晶得到水溶性叶黄素颗粒。中国专利CN 107137383 A公开了一种低温熔融挤出制备水溶性叶黄素的方法与产品,主要通过叶黄素与非离子高分子表面活性剂混合后再经过热熔挤出机在一定条件下挤出。
叶黄素的化学修饰改性主要利用两端的羟基进行化学反应改性,对水溶性的改进效果有限。如中国专利CN 106543323 B公开了一种聚类胡萝卜素丙烯酸酯蓝光吸收剂及其制备方法,以聚叶黄素丙烯酸酯是将类胡萝卜素制备得类胡萝卜素丙烯酸酯,然后将类胡萝卜素丙烯酸酯聚合,得到聚丙烯酸类胡萝卜素酯固体。提出先合成含叶黄素的丙烯酸酯类单体,然后进行自由基聚合得到接枝共聚物,这种方法的缺陷在于,在自由基聚合过程中,叶黄素作为自由基的捕捉剂,其结构中的碳碳双键与自由基迅速反应,结构被完全破坏,并且,得到的接枝共聚物不含亲水性基团,在水中完全不溶解。
上述方案虽然提高了叶黄素的水溶性,但也存在一定的技术问题:乳化剂、表面活性剂、稳定剂使用较多,有些存在有害溶剂残留,为最终产品带来了潜在风险;而且所制备的水溶性叶黄素实际上是将叶黄素进行物理上的均匀分散,形成纳米颗粒;所得叶黄素水溶性提高有限。
因此,一种所制备的叶黄素水溶性好、性质稳定,反应条件温和、适用于工业化、由天然叶黄素生产新型水溶性叶黄素复合纳米颗粒的制备方法急需研究开发出来。
发明内容
本发明的目的在于针对现有技术的叶黄素水溶性有待提高、性质不稳定的问题,提供了提供一种反应条件温和、适用于工业化、由天然叶黄素生产新型水溶性叶黄素复合纳米颗粒的制备方法,使其在食品及医药领域得到大规模应用。
为达到发明目的本发明采用的技术方案是:预先将聚丙烯酸回流除去可能残留的氧化性引发剂,经过冷冻干燥后,将聚丙烯酸溶解于无水四氢呋喃中。然后利用Steglich酯化法,在温和的条件下合成叶黄素接枝共聚物。最后,利用减压蒸馏除去溶剂,向其中加入去离子水完成两亲性叶黄素接枝共聚物的自组装及对未反应叶黄素的物理负载,制备得到水溶性叶黄素复合纳米颗粒。
本发明的具体步骤为:
S1:将聚丙烯酸溶于水中,配制成质量浓度为30%的水溶液,回流一段时间,除去存在的氧化性引发剂。
S2:将步骤S1中回流制得的聚丙烯酸溶液进行冷冻干燥24h,而后溶解于一定量的无水四氢呋喃溶液中,备用。
S3:向步骤S2制备的溶液中加入一定量的叶黄素、二环己基碳二亚胺和4-二甲氨基吡啶后,在一定温度下避光搅拌反应一定的时间,备用。
S4:通过45℃减压蒸馏1h将步骤S3中反应后的溶剂蒸发,向其中加入与步骤S2制备的溶液同体积的去离子水完成两亲性共聚物的自组装,经过冷冻干燥24h制备得到水溶性叶黄素复合纳米颗粒。
优选的,所述步骤S1中的回流时间为6~24小时。
优选的,所述步骤S2中的无水四氢呋喃与聚丙烯酸的质量比为10: 1~100: 1。
优选的,所述步骤S3中的混合溶液中,叶黄素与聚丙烯酸的质量比为1:4~1:1,叶黄素以纯品计。
优选的,所述步骤S3中的叶黄素与二环己基碳二亚胺、4-二甲氨基吡啶的三项质量比为284:103~412:6.1,叶黄素以纯品计。
优选的,所述步骤S3中的搅拌反应的温度为25~45℃。
优选的,所述步骤S3中的搅拌反应的时间为4~12小时。
本发明的另一目的在于上述方法制备的水溶性好且性质稳定的叶黄素水溶性粉末;将其辅以药学上或功能食品上可接受的辅料,可制成片剂、胶囊剂、散剂、膏剂或溶液剂等。
与现有技术相比,本发明的有益效果是:
1、本发明的水溶性叶黄素复合纳米颗粒制备方法,采用叶黄素与水溶性高分子聚丙烯酸的Steglich酯化反应合成以聚丙烯酸为主链、叶黄素为侧链的接枝共聚物,二者以共价键结合,提高了叶黄素的水溶性,使其能够直接溶解在水中。
2、本发明的水溶性叶黄素复合纳米颗粒制备方法,反应过程中未进行酯化反应的叶黄素就地封装在接枝共聚物形成的胶束中,因为接枝共聚物的侧链为叶黄素,与未反应的叶黄素有最大的相容性,提高了载药量。而且,得到的接枝共聚物因为是部分酯化,含有很多亲水性基团,可以完全胶束化溶解在水中,大大提高了生物可及度和体内利用率。
3、本发明的水溶性叶黄素复合纳米颗粒制备方法,不经过自由基聚合过程,避免了自由基聚合反应对叶黄素结构的破坏,使得叶黄素的结构得到最大程度的保留。整个过程简便高效、条件温和、体系简单纯净。
附图说明
本发明的其它特征和优点将通过下面的参考附图进行的描述而得以显现,其中:
图1为实施例2样品的紫外光谱图;
图2为实施例2样品的透射电镜及粒径分布图;
图3为实施例2样品的饱和溶解度及生物可及度对比图;
图4为实施例2样品的在小鼠模型中的药代动力学实验结果。
其中,图1中a为叶黄素,b为叶黄素复合纳米颗粒;图2中a和b为叶黄素复合纳米颗粒,d和e为纯叶黄素接枝共聚物,c为叶黄素复合纳米颗粒,f为纯叶黄素接枝共聚物;图3中a为叶黄素,b为叶黄素复合纳米颗粒,c为市售水溶性叶黄素微粉;图4中a为在小鼠血浆中,b为在肝脏中,c为在肠系膜组织中,d为在眼球中。
具体实施方式
下面结合实施例对本发明做进一步的描述,以下实施例用于说明本发明,但不能用来限制本发明的保护范围。实施例中的条件可以根据具体条件做进一步的调整,在本发明的构思前提下对本发明的方法简单改进都属于本发明要求保护的范围。
本发明实施例中,叶黄素(85%)和水溶性叶黄素微粉(5%)来自山东天音生物科技有限公司。
实施例1
取50份聚丙烯酸(Mw5000)溶于水中,配制成质量浓度为30%的水溶液,回流6小时;回流完毕后将聚丙烯酸溶液进行冷冻干燥24h,而后溶解于500份的无水四氢呋喃中;按顺序向其中加入14.71份叶黄素,4.5份二环己基碳二亚胺和0.268份4-二甲氨基吡啶后在25℃下避光搅拌反应4小时;反应完毕后,在45℃温度下减压蒸馏1h除去其中的溶剂,向其中加入去离子水进行两亲性共聚物的自组装,经过24h冷冻干燥制备得到水溶性叶黄素复合纳米颗粒,所述份数均为质量份。
实施例2
取100份聚丙烯酸(Mw5000)溶于水中,配制成质量浓度为30%的水溶液,回流12小时;回流完毕后将聚丙烯酸溶液进行冷冻干燥24h,而后溶解于5000份的无水四氢呋喃中;按顺序向其中加入58.82份叶黄素,36.3份二环己基碳二亚胺和1.074份4-二甲氨基吡啶后在35℃下避光搅拌反应8小时;反应完毕后,在45℃温度下减压蒸馏1h除去其中的溶剂,向其中加入去离子水进行两亲性共聚物的自组装,经过24h冷冻干燥制备得到水溶性叶黄素复合纳米颗粒,所述份数均为质量份。
实施例3
取250份聚丙烯酸(Mw5000)溶于水中,配制成质量浓度为30%的水溶液,回流24小时;回流完毕后将聚丙烯酸溶液进行冷冻干燥24h,而后溶解于25000份的无水四氢呋喃中;按顺序向其中加入294.12份叶黄素,363.1份二环己基碳二亚胺和5.372份4-二甲氨基吡啶后在45℃下避光搅拌反应12小时;反应完毕后,在45℃温度下减压蒸馏1h除去其中的溶剂,向其中加入去离子水进行两亲性共聚物的自组装,经过24h冷冻干燥制备得到水溶性叶黄素复合纳米颗粒,所述份数均为质量份。
将实施例2制备的水溶性叶黄素复合纳米颗粒进行表征测试:
1. 采用紫外-可见光谱仪,以乙醇为参比,记录了叶黄素及叶黄素复合纳米颗粒的吸收光谱。
2. 采用透射电子显微镜,在200 KV的加速电压下,分别对叶黄素复合纳米颗粒和纯叶黄素接枝共聚物的自组装形态进行观测。制样方法为:取样品的自组装水溶液滴于覆有镀碳膜的铜网上,在自然风干3 h后再进行10 h的真空干燥。
3. 对等叶黄素含量的叶黄素单体、叶黄素复合纳米颗粒和市售水溶性叶黄素微粉进行饱和溶解度的测定。将室温下的去离子水添加到30 mg样品中,最终体积定容为5mL,在黑暗中密封搅拌24 h。然后10000 rpm离心5 min,悬浮液通过孔径为0.45 μm的过滤膜进行过滤,收集滤液进行冷冻干燥。通过测量吸光度确定滤液中叶黄素的含量。
4. 通过构建体外模拟胃和小肠对叶黄素(等叶黄素含量的叶黄素单体、叶黄素复合纳米颗粒和市售水溶性叶黄素微粉)的消化过程,而后对从模拟消化结束的混合液中提取的叶黄素进行含量测定,以此来计算生物可及度。提前将人工胃液储备液(2 g NaCl、7mL浓HCl(37% w/w)定容于1 L蒸馏水水中)配制好,消化实验前将质量分数为0.32%的胃蛋白酶加入人工胃液储备液中,于37℃水浴锅中搅拌,配成胃蛋白酶工作液。取胃蛋白酶工作液与叶黄素制品混合,使用NaOH溶液调节pH值并保持在2.5,置于37℃恒温水浴锅中,在氩气保护下避光搅拌消化。
使用NaOH溶液将胃消化阶段后消化液的pH滴定至7.0,加入小肠盐溶液(0.25MCaCl2和3.0M NaCl,溶于50mM KH2PO4缓冲液)和胆盐溶液(54 mg/mL猪胆盐,溶于50mMKH2PO4缓冲液)。待消化液充分混合,再加入胰酶工作液(24 mg/mL胰酶,溶于50mM KH2PO4缓冲液)进行小肠阶段的模拟消化。消化期间将pH恒定在7.0,置于37℃恒温水浴锅中,在氩气保护下避光搅拌消化。
将消化后的消化液在4℃下离心,然后将上清液转移到分液漏斗中,加入正己烷进行萃取。多次萃取后,将有机相合并后进行减压蒸馏,蒸馏底物用乙醇溶解并转移至容量瓶中定容。通过测量吸光度确定体外消化的叶黄素量。
5. 雄性昆明小鼠(8周龄,体重20-22 g)购自山东省实验动物中心(中国济南),许可号SCXK 2020-0005。所有动物程序均按照山东理工大学实验动物护理和使用指南进行,并经山东理工大学动物伦理委员会许可。小鼠被饲养在28±2℃,光/暗循环周期为12 h的条件下。
将小鼠随机分为空白对照组(n=3)、叶黄素组(每个时间点3只)、叶黄素复合纳米颗粒组(每个时间点3只)。各组均采用普通饲料适应性喂养1周,期间可自由取食颗粒饲料和饮用水。禁食12 h后,将叶黄素按体重加入面粉浆中灌胃,空白对照组仅灌胃面粉浆。分别于灌胃后0.5、1、1.5、2、4、8、12、24小时测定叶黄素的生物利用度。
在灌胃后预定时间通过CO2快速麻醉处死小鼠。通过心脏穿刺将血液收集到涂有肝素的试管中,并在4℃下离心,收集血浆。采集肝脏、肠系膜脂肪组织和眼球,用冷的生理盐水冲洗后,立即在液氮中冷冻并储存。
将体积比为2:1的二氯甲烷:甲醇混合溶液添加到血浆中并涡旋混合1min。将正己烷添加到混合物中,充分混合,并离心,收集所得上层正己烷/二氯甲烷层。用二氯甲烷和正己烷对底层重复萃取两次。将上层提取物合并,然后在氮气下吹干,用于分析。
用生理盐水分别对肝脏、肠系膜和眼球进行匀浆。将匀浆液用于叶黄素的提取。提取物分别用10 mol/L氢氧化钾在60℃下皂化45 min以分离叶黄素。根据对血浆所述的程序,对组织中的叶黄素进行提取。所有的匀浆、皂化和提取程序均在4℃的昏暗黄光下进行,以尽量减少对叶黄素的光致异构化和氧化。通过测量吸光度确定叶黄素量。
结果详见说明书附图1-4。
结果对比分析
附图1说明复合粒子的合成过程中,叶黄素的结构没有被破坏;附图2表明,合成的复合粒子在水中自组装成均匀分散的球形纳米颗粒,粒径为100nm左右,分离以后的纯接枝共聚物粒径减小,为40nm左右,说明未反应的叶黄素被包覆在聚丙烯酸接枝叶黄素共聚物纳米胶束中;附图3表明,合成的复合粒子的饱和溶解度和生物可及度比叶黄素分别提高78~90倍和3~5倍,比市售水溶性叶黄素微粉分别提高25~30倍和7~8倍;附图4表明,与叶黄素相比,合成的复合粒子在血浆中生物利用度提高了6~8倍,并且还促进了叶黄素在肝脏、肠系膜组织和眼球中的积累。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (7)
1.一种水溶性叶黄素复合纳米颗粒的制备方法,其特征在于包括如下步骤:
S1:将聚丙烯酸溶于水中,配制成质量浓度为30%的水溶液,回流一段时间,除去存在的氧化性引发剂;
S2:将步骤S1中回流制得的聚丙烯酸溶液进行冷冻干燥24h,而后溶解于一定量的无水四氢呋喃溶液中,备用;
S3:向步骤S2制备的溶液中加入一定量的叶黄素、二环己基碳二亚胺和4-二甲氨基吡啶后,在一定温度下避光搅拌反应一定的时间,备用;
S4:通过45℃减压蒸馏1h将步骤S3中反应后的溶剂蒸发,向其中加入与步骤S2制备的溶液同体积的去离子水完成两亲性共聚物的自组装,经过冷冻干燥24h制备得到水溶性叶黄素复合纳米颗粒。
2.一种如权利要求1所述的水溶性叶黄素复合纳米颗粒的制备方法,其特征在于:步骤S1中所述的回流时间为6~24小时。
3. 一种如权利要求1所述的水溶性叶黄素复合纳米颗粒的制备方法,其特征在于:步骤S2中所述的无水四氢呋喃与聚丙烯酸的质量比为10: 1~100: 1。
4.一种如权利要求1~3任意一项所述的水溶性叶黄素复合纳米颗粒的制备方法,其特征在于:步骤S3中所述的混合溶液中,叶黄素与聚丙烯酸的质量比为1:4~1:1,叶黄素以纯品计。
5.一种如权利要求1~3任意一项所述的水溶性叶黄素复合纳米颗粒的制备方法,其特征在于:步骤S3中所述的叶黄素与二环己基碳二亚胺、4-二甲氨基吡啶的三项质量比为284:103~412:6.1,叶黄素以纯品计。
6.一种如权利要求1~3任意一项所述的水溶性叶黄素复合纳米颗粒的制备方法,其特征在于:步骤S3中所述的搅拌反应的温度为25~45℃,搅拌反应的时间为4~12小时。
7.一种如权利要求1~6任一项所述方法制得的水溶性叶黄素复合纳米颗粒,其特征在于将其辅以药学上或功能食品上可接受的辅料,可制成片剂、胶囊剂、散剂、膏剂或溶液剂。
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