CN112617178B - 一种具有缓释效应的萝卜硫素微胶囊的制备方法 - Google Patents
一种具有缓释效应的萝卜硫素微胶囊的制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有缓释效应的萝卜硫素微胶囊的制备方法,本发明获得的萝卜硫素微胶囊,在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,在25℃下贮藏180天,萝卜硫素降解率小于10%。本发明采用双重包埋方法,通过二次包埋进一步提高了萝卜硫素贮藏稳定性,并显著延缓萝卜硫素消化过程的释放,可实现血浆中萝卜硫素持续保持一定浓度,进而有利于其功能的发挥。此外,本发明采用静电喷雾方法包埋萝卜硫素,在室温下即可以实现其干燥,避免了萝卜硫素在高温干燥下的损失。本发明借助静电喷雾手段,可降低微胶囊粒径60%以上,最终获得的微胶囊经冷冻干燥后平均粒径小于200μm,有利于在食品体系中的应用。
Description
技术领域
本发明具体涉及一种具有缓释效应的萝卜硫素微胶囊的制备方法。
背景技术
萝卜硫素是目前发现的具有极强抗癌活性的植物源化学物质,其前体硫代葡萄糖苷广泛存在于十字花科植物中,其中在西兰花中含量最高。研究指出,每周消费十字花科蔬菜3-5次可显著降低如肺癌、肠癌等30-40%的发病风险。因此,萝卜硫素以其强大的疾病预防作用而具有非常好的开发前景。
萝卜硫素在癌症等疾病发生的启动阶段主要通过调节I、II相酶系统发挥阻遏因子和抑制因子的作用以预防或消除疾病的发生。作为阻遏因子,萝卜硫素通过与致癌代谢中的一些关键性靶位点发生反应来预防癌症的发生。研究表明,萝卜硫素可激活Keap1-Nrf2/ARE通路,调控抗氧化剂反应元件,进而极强地诱导II相酶活性,保护生物机体免受氧化应激、有毒环境暴露等刺激信号的伤害,从而实现疾病预防功效;而作为抑制因子,萝卜硫素直接通过共价结合形成竞争抑制作用来改变I相酶的水平,抑制致癌物-DNA加合物或致癌剂的作用。另外,萝卜硫素对癌症的预防作用还体现在对细胞周期、细胞程序性死亡、细胞抗氧化防御和慢性炎症的表观遗传调节方面。这些作用已在至少12大类癌症细胞、27种不同细胞系被证实(Tortorella SM,Royce SG,Licciardi PV,et al.DietarySulforaphane in Cancer Chemoprevention:The Role of Epigenetic Regulation andHDAC Inhibition.Antioxid Redox Sign.2015;22:1382-1424.)。
研究表明,为了实现对组蛋白脱乙酰酶活性的更好抑制,需要组蛋白脱乙酰酶抑制剂在体循环中持续存在;同时由于萝卜硫素化学预防主要作用机制是增强对致癌物基因毒性的解毒作用,因而需要重复摄入以最大程度诱导如谷胱甘肽转移酶和NOQ1酶活性([Drummond DC,Noble CO,Kirpotin DB,et al.Clinical development of histonedeacetylase inhibitors as anticancer agents.2005;45:495-528.)。相比24h单次摄入,同等剂量萝卜硫素分成12h两次供给,后者明显能保持血浆更高的萝卜硫素水平,进而对降低组蛋白脱乙酰酶活性作用持续更长时间(Atwell LL,Beaver LM,Shannon J,etal.Epigenetic Regulation by Sulforaphane:Opportunities for Breast andProstate Cancer Chemoprevention.Curr Pharmacol Rep.2015;1:102-111)。与萝卜硫素单次处理相比,萝卜硫素等量多频次处理的肌原细胞显示出对Nrf2调节的mRNA表达显著的剂量依赖性诱导,进而降低辐射引起的肌原细胞损伤。因此,如何保证萝卜硫素的血浆浓度并延长其作用时间就是提高其生物功效的关键。
微载体药物递送系统可解决药物溶解度低、稳定性差和吸收受限等问题,提高生物利用度和稳定性,通过缓释效应维持血药浓度稳定并延长药物作用时间,或发挥靶向作用。然而,目前并没有萝卜硫素微载体缓释递送系统构建的研究。
萝卜硫素还有个突出特点是稳定性差,常温下无法长时间保藏,是制约其产业化开发和应用的主要障碍。
因此,寻找一种可以保证萝卜硫素贮藏稳定性又可以实现其体内缓释代谢的微载体形式,将对以萝卜硫素为主要功效成分的相关保健食品或药品的开发具有积极推动作用。
发明内容
针对上述情况,为克服现有技术的缺陷,本发明提供一种具有缓释效应的萝卜硫素微胶囊的制备方法。
为了实现上述目的,本发明提供以下技术方案:
一种具有缓释效应的萝卜硫素微胶囊的制备方法,包括以下步骤:
(1)配制辅料溶液,所述辅料为明胶或/和玉米醇溶蛋白;
(2)将萝卜硫素添加到步骤(1)得到的辅料溶液中,超声处理,搅拌;
(3)将步骤(2)得到的混合溶液,进行静电喷雾,制得萝卜硫素纳米粒子;
(4)制备海藻酸钠-果胶溶液;
(5)将步骤(3)制备的萝卜硫素粒子加入步骤(4)得到的海藻酸钠-果胶混合溶液中,混匀,获得载有萝卜硫素纳米粒子的悬浮液;
(6)配置质量分数为0.5-1%壳聚糖、质量分数1%-2%的氯化钙混合水溶液作为接收液;
(7)将步骤(5)得到的包含萝卜硫素粒子悬浮液,进行静电喷雾,滴落至步骤(6)制得的接收液中固化形成微球;
(8)将步骤(7)得到的微球从接收液中分离出,经干燥即得萝卜硫素微胶囊。
进一步地,步骤(1)中,所述辅料溶液为质量分数为8-10%的明胶水溶液或/和质量分数为5-8%的玉米醇溶蛋白乙醇溶液。
进一步地,步骤(2)中,萝卜硫素与辅料(即壁材)的质量比为1:2~1:1。这样的质量比使得静电喷雾制得的萝卜硫素纳米粒子包埋率较高。如果萝卜硫素较少,辅料较多,那么就会造成壁材较厚,有效物质(萝卜硫素)较少;如果萝卜硫素比例大时,容易导致壁材包不住萝卜硫素,导致包埋率降低。
进一步地,步骤(3)的静电喷雾条件为:流速为0.15-0.3mL/h,电压为20-25KV,接收距离为8-13cm。所述喷雾条件能够连续稳定喷雾,且喷雾获得的纳米粒子形态较好。
进一步地,步骤(4)的制备过程为:将果胶以0-30%的质量比例与海藻酸钠混合,加水溶解,得到质量分数为1%-1.5%的海藻酸钠-果胶溶液。
进一步地,步骤(5)中,获得的悬浮液中萝卜硫素纳米粒子浓度为10-20mg/mL。这样设置能够保证悬浮液中有足够的纳米粒子,同时纳米粒子均匀分布,不至于沉降。
进一步地,步骤(6)中,配置质量分数为0.5-1%壳聚糖、质量分数1%-2%的氯化钙混合水溶液作为接收液。
进一步地,步骤(7)中,静电喷雾条件为:流速为0.5-0.8mL/h,电压15-20KV,接收距离8-13cm。所述静电喷雾条件能够保证连续喷雾,且获得的微胶囊形态好。
本发明的有益效果是:
(1)本发明获得的萝卜硫素微胶囊,在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放30-45%,2-5小时累计释放60-75%,5-8小时累计释放大于70%。稳定性方面,在25℃下贮藏180天,萝卜硫素降解率小于10%。
(2)与现有技术相比,本发明采用双重包埋方法,以明胶或玉米醇溶蛋白包埋萝卜硫素制备形成纳米粒子为一次包埋,将纳米粒子嵌入到海藻酸钠-果胶-壳聚糖复合微胶囊中形成二次包埋,通过二次包埋进一步提高了萝卜硫素贮藏稳定性,并显著延缓萝卜硫素消化过程的释放,可实现血浆中萝卜硫素持续保持一定浓度,进而有利于其功能的发挥。此外,本发明采用静电喷雾方法包埋萝卜硫素,相比于现在喷雾干燥技术,本发明所采用技术在室温下即可以实现其干燥,避免了萝卜硫素在高温干燥下的损失。相比于以往锐孔-凝固浴法制备海藻酸钠-壳聚糖微胶囊,本发明借助静电喷雾手段,可降低微胶囊粒径60%以上,最终获得的微胶囊经冷冻干燥后平均粒径小于200μm,有利于在食品体系中的应用。
附图说明
图1是实施例1制得的萝卜硫素微胶囊的扫描电镜图,图中,EHT表示加速电压,WD表示工作距离,Mag表示放大倍数,Signal A=SE2表示采用SE2探测器。
具体实施方式
以下结合附图对本发明的技术方案做进一步详细说明,应当指出的是,具体实施方式只是对本发明的详细说明,不应视为对本发明的限定。以下实施例中所用到的试剂、材料、仪器等均能够通过商业途径购得。
实施例1
(1)配制质量分数为8%的明胶水溶液;
(2)按萝卜硫素与明胶的质量比5:8的比例称取萝卜硫素,并加入到上述明胶溶液中,并采用手持高速分散均质机在3000rpm/min转速下混合均匀;
(3)将上述混合溶液,装入注射器,连接针头在常温条件下进行静电喷雾,制得干燥的萝卜硫素粒子,喷雾条件为:流速为0.15mL/h,电压20KV,接收距离10cm;
(4)果胶以5%质量比例与海藻酸钠混合,加水溶解,得到质量分数为1%海藻酸钠-果胶溶液;
(5)将静电喷雾制备的萝卜硫素粒子缓慢加入步骤(4)得到的海藻酸钠-果胶混合溶液中,并采用手持高速分散均质机在1000rpm/min转速下混合均匀,获得载有萝卜硫素粒子的悬浮液,悬浮液中纳米粒子浓度为10mg/mL。
(6)配置质量分数为0.5%壳聚糖和质量分数1%的氯化钙混合水溶液作为固化液,用于接收微球。
(7)将以上包含萝卜硫素-壳聚糖粒子悬浮液,装入注射器,连接针头在常温条件下进行静电喷雾,滴落至接收液中固化形成微球。喷雾条件为:流速为0.5mL/h,电压为15KV,接收距离为10cm。
(8)将以上微球从接收液中分离出,经-40℃真空冷冻干燥即得萝卜硫素缓释微球。
本实施例中制得的微球平均粒径为183±17.5μm,实施例1制得的萝卜硫素微胶囊的扫描电镜图如图1所示(采用的扫描电镜是ZEISS扫描电镜),由图1可得,采用本发明的制备方法制得的萝卜硫素微胶囊分布均匀,而且粒径均匀,大小一致。在25℃下存放180d后萝卜硫素保留率为92.1±1.23%。在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放37.5%,2-5小时累计释放67.2%,5-8小时累计释放75.1%,具有良好的缓释效果。
实施例2
(1)配制质量分数为8%的明胶水溶液;
(2)按萝卜硫素与明胶的质量比1:1的比例称取萝卜硫素,将萝卜硫素加入到上述明胶溶液中,并采用手持高速分散均质机在3000rpm/min转速下混合均匀;
(3)将上述混合溶液,装入注射器,连接针头在常温条件下进行静电喷雾,制得干燥的萝卜硫素粒子,喷雾条件为:流速为0.2mL/h,电压22KV,接收距离10cm;
(4)果胶以20%质量比例与海藻酸钠混合,加水溶解,得到质量分数为1%海藻酸钠-果胶溶液;
(5)将静电喷雾制备的萝卜硫素粒子缓慢加入步骤(4)得到的海藻酸钠-果胶混合溶液中,并采用手持高速分散均质机在1000rpm/min转速下混合均匀,获得载有萝卜硫素粒子的悬浮液,悬浮液中纳米粒子浓度为15mg/mL。
(6)配置质量分数为0.6%壳聚糖和质量分数1.5%的氯化钙混合水溶液作为固化液,用于接收微球。
(7)将以上包含萝卜硫素-壳聚糖粒子悬浮液,装入注射器,连接针头在常温条件下进行静电喷雾,滴落至接收液中固化形成微球。喷雾条件为:流速为0.6mL/h,电压为18KV,接收距离为8cm。
(8)将以上微球从接收液中分离出,经-40℃真空冷冻干燥即得萝卜硫素缓释微球。
本实施例中制得的微球平均粒径为196±14.3μm,在25℃下存放180d后萝卜硫素保留率为90.6±1.54%。在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放39.2%,2-5小时累计释放69.3%,5-8小时累计释放82.1%,具有良好的缓释效果。
实施例3
(1)配制质量分数为10%的明胶水溶液;
(2)按萝卜硫素与明胶的质量比5:10的比例称取萝卜硫素,将萝卜硫素加入到上述明胶溶液中,并采用手持高速分散均质机在3000rpm/min转速下混合均匀;
(3)将上述混合溶液,装入注射器,连接针头在常温条件下进行静电喷雾,制得干燥的萝卜硫素粒子,喷雾条件为:流速为0.3mL/h,电压25KV,接收距离8cm;
(4)果胶以30%质量比例与海藻酸钠混合,加水溶解,得到质量分数为1.5%海藻酸钠-果胶溶液;
(5)将静电喷雾制备的萝卜硫素粒子缓慢加入海藻酸钠-果胶混合溶液中,并采用手持高速分散均质机在1000rpm/min转速下混合均匀,获得载有萝卜硫素粒子的悬浮液,悬浮液中纳米粒子浓度为20mg/mL。
(6)配置质量分数为1%壳聚糖和质量分数2%的氯化钙混合水溶液作为固化液,用于接收微球。
(7)以上包含萝卜硫素-壳聚糖粒子悬浮液,装入注射器,连接针头在常温条件下进行静电喷雾,滴落至接收液中固化形成微球。喷雾条件为:流速为0.8mL/h,电压20KV,接收距离10cm。
(8)将以上微球从接收液中分离出,经-40℃真空冷冻干燥即得萝卜硫素缓释微球。
本实施例中制得的微球平均粒径为175±15.6μm,在25℃下存放180d后萝卜硫素保留率为93.3±0.89%。在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放32.5%,2-5小时累计释放65.4%,5-8小时累计释放73.2%,具有良好的缓释效果。
实施例4
(1)用体积分数为80%乙醇水溶液配制质量分数为5%的玉米醇溶蛋白溶液。
(2)按质量比3%,将萝卜硫素加入到上述玉米醇溶蛋白溶液中,并采用手持高速分散均质机在3000rpm/min转速下混合均匀。
(3)将上述混合溶液,装入注射器,连接针头在常温条件下进行静电喷雾,制得干燥的萝卜硫素粒子,喷雾条件为:流速为0.15mL/h,电压为20KV,接收距离为8cm。
(4)果胶以2%的质量比例与一定量海藻酸钠混合,加水溶解,得到质量分数为1%海藻酸钠-果胶溶液。
(5)将静电喷雾制备的萝卜硫素粒子缓慢加入海藻酸钠-果胶混合溶液中,并采用手持高速分散均质机在1000rpm/min转速下混合均匀,获得载有萝卜硫素粒子的悬浮液,悬浮液中纳米粒子浓度为10mg/mL。
(6)配置质量分数为0.5%壳聚糖和2%的氯化钙混合水溶液作为固化液,用于接收微球。
(7)将步骤(5)得到的包含萝卜硫素粒子悬浮液,装入注射器,连接针头进行静电喷雾,滴落至接收液中固化形成微球。喷雾条件为:流速为0.5mL/h,电压15KV,接收距离10cm。
(8)将步骤(7)得到的微球从接收液中分离出,经-40℃真空冷冻干燥即得萝卜硫素缓释微球。
本实施例中制得的微球平均粒径为183±17.3μm,在25℃下存放180d后萝卜硫素保留率为92.5±1.15%。在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放43.6%,2-5小时累计释放71.2%,5-8小时累计释放85.6%,具有良好的缓释效果。
实施例5
(1)用体积分数为80%乙醇水溶液配制质量分数为8%的玉米醇溶蛋白溶液。
(2)按质量比6%,将萝卜硫素加入到上述玉米醇溶蛋白溶液中,并采用手持高速分散均质机在3000rpm/min转速下混合均匀。
(3)将上述混合溶液,装入注射器,连接针头在常温条件下进行静电喷雾,制得干燥的萝卜硫素粒子,喷雾条件为:流速为0.3mL/h,电压为25KV,接收距离为8cm。
(4)果胶以30%的质量比例与一定量海藻酸钠混合,加水溶解,得到质量分数为1.5%海藻酸钠-果胶溶液。
(5)将静电喷雾制备的萝卜硫素粒子缓慢加入海藻酸钠-果胶混合溶液中,并采用手持高速分散均质机在1000rpm/min转速下混合均匀,获得载有萝卜硫素粒子的悬浮液,悬浮液中纳米粒子浓度为20mg/mL。
(6)配置质量分数为1%壳聚糖和1%的氯化钙混合水溶液作为固化液,用于接收微球。
(7)将步骤(5)得到的包含萝卜硫素粒子悬浮液,装入注射器,连接针头进行静电喷雾,滴落至接收液中固化形成微球。喷雾条件为:流速为0.8mL/h,电压20KV,接收距离13cm。
(8)将步骤(7)得到的微球从接收液中分离出,经-40℃真空冷冻干燥即得萝卜硫素缓释微球。
本实施例中制得的微球平均粒径为182±14.2μm,在25℃下存放180d后萝卜硫素保留率为90.4±1.32%。在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放41.2%,2-5小时累计释放65.6%,5-8小时累计释放79.3%,具有良好的缓释效果。
实施例6
(1)用体积分数为80%乙醇水溶液配制质量分数为6%的玉米醇溶蛋白溶液。
(2)按质量比5%,将萝卜硫素加入到上述玉米醇溶蛋白溶液中,并采用手持高速分散均质机在3000rpm/min转速下混合均匀。
(3)将上述混合溶液,装入注射器,连接针头在常温条件下进行静电喷雾,制得干燥的萝卜硫素粒子,喷雾条件为:流速为0.2mL/h,电压为22KV,接收距离为10cm。
(4)果胶以20%的质量比例与一定量海藻酸钠混合,加水溶解,得到质量分数为1.2%海藻酸钠-果胶溶液。
(5)将静电喷雾制备的萝卜硫素粒子缓慢加入海藻酸钠-果胶混合溶液中,并采用手持高速分散均质机在1000rpm/min转速下混合均匀,获得载有萝卜硫素粒子的悬浮液,悬浮液中纳米粒子浓度为15mg/mL。
(6)配置质量分数为0.6%壳聚糖和1.5%的氯化钙混合水溶液作为固化液,用于接收微球。
(7)将步骤(5)得到的包含萝卜硫素粒子悬浮液,装入注射器,连接针头进行静电喷雾,滴落至接收液中固化形成微球。喷雾条件为:流速为0.6mL/h,电压16KV,接收距离8cm。
(8)将步骤(7)得到的微球从接收液中分离出,经-40℃真空冷冻干燥即得萝卜硫素缓释微球。
本实施例中制得的微球平均粒径为191±16.5μm,在25℃下存放180d后萝卜硫素保留率为91.2±1.41%。在体外模拟胃肠释放条件下,萝卜硫素可实现缓慢释放,前2小时累计释放36.5%,2-5小时累计释放68.2%,5-8小时累计释放80.1%,具有良好的缓释效果。
表1实施例1-6制得的萝卜硫素微胶囊的平均粒径、保留率和释放率
保留率:萝卜硫素微胶囊在25℃下存放180天后测得的萝卜硫素含量与初始萝卜硫素含量的比值,反映了萝卜硫素的稳定性。
释放率:指的是萝卜硫素微胶囊或者游离样品(萝卜硫素)在模拟消化胃肠液中的释放情况,即在模拟胃肠液中不同时间测得的萝卜硫素量与初始微胶囊中萝卜硫素量的比值;其中0-2h是在模拟胃液中进行,2-8h为在模拟肠液中进行。此表中的释放率为累积释放率。游离样品即萝卜硫素,通过商业途径购买获得。
显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
Claims (5)
1.一种具有缓释效应的萝卜硫素微胶囊的制备方法,其特征是,包括以下步骤:
(1)配制辅料溶液,所述辅料为明胶或/和玉米醇溶蛋白;
(2)将萝卜硫素添加到步骤(1)得到的辅料溶液中,超声处理,搅拌;
(3)将步骤(2)得到的混合溶液,进行静电喷雾,制得萝卜硫素纳米粒子;
(4)制备海藻酸钠-果胶溶液;
(5)将步骤(3)制备的萝卜硫素粒子加入步骤(4)得到的海藻酸钠-果胶混合溶液中,混匀,获得载有萝卜硫素纳米粒子的悬浮液;
(6)配制 壳聚糖与氯化钙混合水溶液作为接收液;
(7)将步骤(5)得到的包含萝卜硫素粒子悬浮液,进行静电喷雾,滴落至步骤(6)制得的接收液中固化形成微球;
(8)将步骤(7)得到的微球从接收液中分离出,经干燥即得萝卜硫素缓释微胶囊;
步骤(1)中,所述辅料溶液为质量分数为8-10%的明胶水溶液或/和质量分数为5-8%的玉米醇溶蛋白乙醇溶液;
步骤(2)中,萝卜硫素与辅料的质量比为1:2~1:1;
步骤(3)的静电喷雾条件为:流速为0.15-0.3mL/h,电压为20-25KV,接收距离为8-13cm。
2.根据权利要求1所述的一种具有缓释效应的萝卜硫素微胶囊的制备方法,其特征是,步骤(4)的制备过程为:将果胶以0-30%的质量比例与海藻酸钠混合,加水溶解,得到质量分数为1%-1.5%的海藻酸钠-果胶溶液。
3.根据权利要求1所述的一种具有缓释效应的萝卜硫素微胶囊的制备方法,其特征是,步骤(5)中,获得的悬浮液中萝卜硫素纳米粒子浓度为10-20mg/mL。
4.根据权利要求1所述的一种具有缓释效应的萝卜硫素微胶囊的制备方法,其特征是,步骤(7)中,静电喷雾条件为:流速为0.5-0.8mL/h,电压15-20KV,接收距离8-13cm。
5.根据权利要求1所述的一种具有缓释效应的萝卜硫素微胶囊的制备方法,其特征是,步骤(6)中,配制 质量分数为0.5-1%壳聚糖、质量分数1%-2%的氯化钙混合水溶液作为接收液。
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