CN111317827A - 一种口服结肠靶向番茄红素纳米脂质体及其制备方法 - Google Patents
一种口服结肠靶向番茄红素纳米脂质体及其制备方法 Download PDFInfo
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Abstract
本发明涉及药剂学技术领域,具体涉及一种口服结肠靶向番茄红素纳米脂质体及其制备方法,由脂质体核心和修饰层外壳组成,其中,所述的脂质体核心为采用乙醚注入法制备的带负电荷的载番茄红素脂质体;其中,所述的修饰层外壳由结肠特异性降解材料构成,本发明所得纳米脂质体与常规脂质相比,胃肠道稳定性大幅度提高,具有明显的结肠靶向释放效果,可以明显的增强结肠部分的修复效率,平均均粒径在560nm左右。
Description
技术领域
本发明涉及药剂学技术领域,具体涉及一种口服结肠靶向番茄红素纳米脂质体及其制备方法。
背景技术
结肠是人体重要的消化部位,具有吸收水和电解质等功能。近年来,由于人们生活水平的提高,生活方式及饮食习惯的改变,结肠类疾病(结肠癌、结肠炎等)发病率逐渐增长。伴随着药剂学的不断改进和发展,口服结肠靶向给药系统(Oral colon-specific drugdelivery system,OCDDS)的研究和开发成为研究热点。OCDDS是通过一定的制剂学手段,依据结肠部位特殊的消化环境(pH,代谢酶、蠕动速度)设计的一种可使药物经口服后不在胃肠道上端释放,而到达回盲部后即开始崩解或溶出的结肠疾病靶向治疗制剂。
目前常见的OCDDS剂型有微丸、微球、水凝胶等,但该类载体存在以下缺点:1)粒径较大,与消化液接触面积小,在结肠内的降解速度较慢,包埋物生物利用度低;2)缺乏稳固核心,多呈松散状态,机械性能差,易受胃肠蠕动作用导致结构破坏,包埋物提早释放,结肠定位释药效果难以令人满意。
基于上述现状,发明人欲提供一种结构稳固,粒径较小的结肠靶向制剂,实现药物在结肠部位的高效释放。
脂质体(liposome)是一种具有磷脂双分子层结构的封闭囊泡。具有粒径小,良好的缓释性、细胞亲和性和组织相容性等优点。但脂质体直接口服后,其脂质双分子层结构易被肠道中磷脂酶降解破坏,引起包埋物渗漏或过早释放。
壳聚糖、果胶分别作为天然聚阳、阴离子多糖,具有在结肠菌群糖苷酶作用下特异性降解的特性。
番茄红素是植物中所含的一种天然色素,多存在于茄科植物西红柿的成熟果实中。它是目前在自然界的植物中被发现的最强抗氧化剂之一,其淬灭单线态氧速率常数是维生素E的100倍,可以有效防治因衰老,免疫力下降引起的各种疾病,如炎症、肿瘤等。然而,番茄红素对外界环境极为敏感,易发生降解及异构化,丧失生理活性;水溶性差,直接口服,生物利用度低。为了解决上述问题,有研究者曾采用一些传统剂型(普通脂质体,微胶囊、微球、乳液)对其进行了包埋保护,但这些剂型存在胃肠道稳定性差,靶向性不理想等缺陷。
基于上述研究成果,发明人首先构建带负电的脂质体,并以此为核心,利用聚电解质络合技术在其表面层层自组装构建果胶-壳聚糖聚电解多层修饰脂质体(pectin-chitosan modified liposomes,Pe-Ch-Liposomes)。Pe-Ch-Liposomes融合了脂质体、OCDDS二者的优势,既可赋予结肠靶向聚电解复合物凝胶层稳固核心,增强其缓控释性,又可避免人体消化道各种酶和过酸环境对脂质体和包埋物的不利影响,实现脂质体口服结肠靶向转运活性成分的目的。
发明内容
本发明的目的是针对现有OCDDS制备技术的不足和脂质体胃肠道稳定性差的弱点,提供一种结构稳固,粒径较小的新型口服结肠靶向制剂,以实现药物在结肠部位的高效释放,提高结肠类疾病的治疗效果。本发明是通过以下技术方案来实现的:
一种口服结肠靶向番茄红素纳米脂质体:由脂质体核心和修饰层外壳组成,其中,所述的脂质体核心为采用乙醚注入法制备的带负电荷的载番茄红素脂质体;其中,所述的修饰层外壳由结肠特异性降解材料构成。
作为优选,所述的结肠特异性降解材料为壳聚糖、果胶对脂质体进行先后修饰所形成;所述的壳聚糖分散于醋酸溶液中,所述的果胶分散于磷酸盐缓冲液中。
所述的纳米脂质体配比为:1L口服结肠靶向番茄红素纳米脂质体成品中各组分及其质量体积比为:卵磷脂0.05~12.50g,胆固醇0.03~4.16g,番茄红素10mg~100mg,壳聚糖0.02~12.00g,果胶0.02~8.00g,醋酸0.03~10mL,其余为是浓度为0.01~0.2M/L磷酸盐缓冲溶液。
所述纳米脂质体的制备方法为:
1)按上述质量体积比分别称取卵磷脂和胆固醇,溶解于无水乙醚中,其中卵磷脂与无水乙醚的用量比为1:30~300g/mL;
2)按上述质量体积比称取番茄红素,配制成0.01~2mg/ml番茄红素二氯甲烷溶液;
3)将步骤2)所得溶液与步骤1)所得溶液充分搅拌混匀;
4)将步骤3)所得溶液按体积比1:1~20注入到恒温45℃并处于搅拌状态下的浓度为0.02~0.2M/L的磷酸盐缓冲液中,得乳状液;
5)取步骤4)所得乳状液,真空旋转蒸发除去乙醚后,经超声处理或高压均质处理,得番茄红素常规脂质体;
6)按上述质量体积比配制壳聚糖醋酸溶液,将步骤5)所得番茄红素常规脂质体按照体积比1:0.5~5注入至壳聚糖醋酸溶液中,室温搅拌20min后,经超声处理或高压均质处理,得壳聚糖修饰脂质体;
7)按上述质量体积比配制果胶磷酸盐缓冲溶液,将步骤6)所得壳聚糖修饰脂质体按照体积比1:0.5~5注入至果胶磷酸盐缓冲溶液中,室温搅拌20min后,经超声处理或高压均质处理,得到口服结肠靶向番茄红素纳米脂质体。
所述步骤5)、6)、7)中超声处理是指在100w功率下连续超声20~30min或在200~350w功率下间歇超声5~10min,所述间歇超生为:1s停止超声,1s超声循环。
所述步骤5)、6)、7)中高压处理是指在70~180MPa压力下循环均质处理1~3次。
本发明的有益效果是:
(1)本发明所得纳米脂质体与常规OCDDS相比粒径更小,平均粒径在560nm左右。
(2)本发明所得纳米脂质体具有明显的核壳结构,结构更加稳固,可减少胃肠道消化阶段对制剂结构的破坏。
(3)本发明所得纳米脂质体与常规脂质相比,胃肠道稳定性大幅度提高,具有明显的结肠靶向释放效果。
具体实施方式
实施例1
称取0.5g蛋黄卵磷脂、0.1g胆固醇完全溶解于50mL无水乙醚中,另取20mg番茄红素完全溶解于10mL二氯甲烷中,将上述两种溶液混匀后,缓慢注入到200mL、pH7.0、浓度为0.02M/L的磷酸盐缓冲溶液中,45℃条件下磁力搅拌20min,然后将其转移到到圆底瓶中,真空旋转蒸发除去无水乙醚和二氯甲烷后,在150MPa压力下循环均质处理2次,得番茄红素常规脂质体;将番茄红素常规脂质体溶液注入至200mL、0.25%的壳聚糖醋酸溶液中(醋酸溶液浓度0.2%),搅拌反应20min后,连续超声处理20min,得到壳聚糖修饰脂质体。再将壳聚糖修饰纳米脂质体逐滴边搅拌边加入至600mL、0.35%的果胶磷酸盐溶液中,搅拌20min后,连续超声处理20min,即得到所述口服结肠靶向番茄红素纳米脂质体。
实施例2
称取0.31g卵磷脂、0.03g胆固醇完全溶解于40mL无水乙醚中,另取10mg番茄红素完全溶解于5mL二氯甲烷中,将上述两种溶液混匀后,缓慢注入到300ml pH6.8、浓度为0.02M的磷酸盐缓冲溶液中,45℃条件下磁力搅拌20min,然后将其转移到圆底瓶中,真空旋转蒸发除去无水乙醚和二氯甲烷后,250w功率下间歇超声5min得番茄红素常规脂质体;将番茄红素常规脂质体溶液逐滴加入至300mL、0.3%的壳聚糖醋酸溶液中(醋酸溶液浓度0.1%),搅拌反应20min后,连续超声处理20min,得到壳聚糖修饰脂质体。再将壳聚糖修饰脂质体逐滴边搅拌边加入至400mL、0.4%的果胶磷酸盐溶液(磷酸盐溶液pH6.8、浓度为0.02M)中,搅拌20min后,在70MPa压力下循环均质处理1次,即得到所述口服结肠靶向番茄红素纳米脂质体。
实施例3
称取10g卵磷脂、4.16g胆固醇完全溶解于300mL无水乙醚中,另取100mg番茄红素完全溶解于50mL二氯甲烷中,将上述两种溶液混匀后,缓慢注入到350mLpH6.8、浓度为0.2M的磷酸盐缓冲溶液中,45℃条件下磁力搅拌20min,然后将其转移到圆底瓶中,真空旋转蒸发除去无水乙醚和二氯甲烷后,在150MPa压力下循环均质处理3次,得番茄红素常规脂质体;将番茄红素常规脂质体溶液逐滴加入至300mL、4%的壳聚糖醋酸溶液中(醋酸溶液浓度0.1%),搅拌反应20min后,连续超声处理20min,得到壳聚糖修饰脂质体。再将壳聚糖修饰脂质体逐滴边搅拌边加入至350mL、2.2%的果胶磷酸盐溶液(磷酸盐溶液pH6.8、浓度为0.2M)中,搅拌20min后,在100MPa压力下循环均质处理1次,即得到所述口服结肠靶向番茄红素纳米脂质体。
实施例4
称取0.05g蛋黄卵磷脂、0.0.03g胆固醇完全溶解于15mL无水乙醚中,另取10mg番茄红素完全溶解于5mL二氯甲烷中,将上述两种溶液混匀后,缓慢注入到400mL、pH7.0、浓度为0.02M/L的磷酸盐缓冲溶液中,45℃条件下磁力搅拌20min,然后将其转移到到圆底瓶中,真空旋转蒸发除去无水乙醚和二氯甲烷后,在150MPa压力下循环均质处理2次,得番茄红素常规脂质体;将番茄红素常规脂质体溶液注入至200mL、0.01%的壳聚糖醋酸溶液中(醋酸溶液浓度0.2%),搅拌反应20min后,连续超声处理20min,得到壳聚糖修饰脂质体。再将壳聚糖修饰纳米脂质体逐滴边搅拌边加入至400mL、0.005%的果胶磷酸盐溶液中,搅拌20min后,200w功率下间歇超声2min,即得到所述口服结肠靶向番茄红素纳米脂质体。
对比例1
本对比例的实施方式为:称取0.31g卵磷脂、0.03g胆固醇完全溶解于40mL无水乙醚中,另取10mg番茄红素完全溶解于5mL二氯甲烷中,将上述两种溶液混匀后,缓慢注入到300ml pH6.8、浓度为0.02M的磷酸盐缓冲溶液中,45℃条件下磁力搅拌20min,然后将其转移到圆底瓶中,真空旋转蒸发除去无水乙醚和二氯甲烷后,250w功率下间歇超声5min得番茄红素常规脂质体。
将实施例1-4所制得的脂质体进行测试,用激光粒度分布测定仪测定脂质体粒径。结果见表1
表1
取实验室用10只小白鼠,DSS造模小鼠溃疡性结肠炎,记录溃疡面积,分为两组,第一组口服实施例1所制备的脂质体编号为1、2、3、4、5号,第二组编号为:A、B、C、D、E号,第二组口服对比例1所制备的脂质体。在服用7天后取血,处死小鼠,分离结肠,沿肠系膜缘剪开肠腔,生理盐水冲洗,留取病变明显的结肠标本,常规制片,HE染色,镜下行组织学检查,记录结肠恢复效果,结果见表2。
表2
编号 | |
1 | 溃烂部分全部恢复健康状态 |
2 | 溃烂部分全部恢复健康状态 |
3 | 溃烂部分全部恢复健康状态 |
4 | 溃烂部分全部恢复健康状态 |
5 | 溃烂部分全部恢复健康状态 |
A | 溃烂部分三分之一部分恢复健康 |
B | 溃烂部分二分之一部分恢复健康 |
C | 溃烂部分三分之二部分恢复健康 |
D | 溃烂部分二分之一部分恢复健康 |
E | 溃烂部分二分之一部分恢复健康 |
本发明所得纳米脂质体与常规脂质相比,胃肠道稳定性大幅度提高,具有明显的结肠靶向释放效果,可以明显的增强结肠部分的修复效率。
Claims (6)
1.一种口服结肠靶向番茄红素纳米脂质体,其特征在于:由脂质体核心和修饰层外壳组成,其中,所述的脂质体核心为采用乙醚注入法制备的带负电荷的载番茄红素脂质体;其中,所述的修饰层外壳由结肠特异性降解材料构成。
2.根据权利要求1所述的一种口服结肠靶向番茄红素纳米脂质体,其特征在于:所述的结肠特异性降解材料为壳聚糖、果胶对脂质体进行先后修饰所形成;所述的壳聚糖分散于醋酸溶液中,所述的果胶分散于磷酸盐缓冲液中。
3.根据权利要求1所述的一种口服结肠靶向番茄红素纳米脂质体,其特征在于:1L口服结肠靶向番茄红素纳米脂质体成品中各组分及其质量体积比为:卵磷脂0.05~12.50g,胆固醇0.03~4.16g,番茄红素10mg~100mg,壳聚糖0.02~12.00g,果胶0.02~8.00g,醋酸0.03~10mL,其余为是浓度为0.01~0.2M/L磷酸盐缓冲溶液。
4.根据权利要求1-3中的任意一项所述的一种口服结肠靶向番茄红素纳米脂质体,其特征在于,制备方法为:
1)按上述质量体积比分别称取卵磷脂和胆固醇,溶解于无水乙醚中,其中卵磷脂与无水乙醚的用量比为1:30~300g/mL;
2)按上述质量体积比称取番茄红素,配制成0.01~2mg/ml番茄红素二氯甲烷溶液;
3)将步骤2)所得溶液与步骤1)所得溶液充分搅拌混匀;
4)将步骤3)所得溶液按体积比1:1~20注入到恒温45℃并处于搅拌状态下的浓度为0.02~0.2M/L的磷酸盐缓冲液中,得乳状液;
5)取步骤4)所得乳状液,真空旋转蒸发除去乙醚后,经超声处理或高压均质处理,得番茄红素常规脂质体;
6)按上述质量体积比配制壳聚糖醋酸溶液,将步骤5)所得番茄红素常规脂质体按照体积比1:0.5~5注入至壳聚糖醋酸溶液中,室温搅拌20min后,经超声处理或高压均质处理,得壳聚糖修饰脂质体;
7)按上述质量体积比配制果胶磷酸盐缓冲溶液,将步骤6)所得壳聚糖修饰脂质体按照体积比1:0.5~5注入至果胶磷酸盐缓冲溶液中,室温搅拌20min后,经超声处理或高压均质处理,得到口服结肠靶向番茄红素纳米脂质体。
5.根据权利要求4所述的制备方法,其特征在于:所述步骤5)、6)、7)中超声处理是指在100w功率下连续超声20~30min或在200~350w功率下间歇超声5~10min,所述间歇超生为:1s停止超声,1s超声循环。
6.根据权利要求4所述的制备方法,其特征在于:所述步骤5)、6)、7)中高压处理是指在70~180MPa压力下循环均质处理1~3次。
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