CN112999197A - 一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒及其制备方法 - Google Patents
一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒及其制备方法 Download PDFInfo
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- CN112999197A CN112999197A CN202110242741.0A CN202110242741A CN112999197A CN 112999197 A CN112999197 A CN 112999197A CN 202110242741 A CN202110242741 A CN 202110242741A CN 112999197 A CN112999197 A CN 112999197A
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Abstract
本发明公开了一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒及其制备方法,所述纳米粒包括以下重量百分比的组分:五环三萜类化合物0~15%、壳聚糖或其衍生物5~20%、单硬脂酸甘油酯20~50%、硬脂酸10~30%、泊洛沙姆5~75%;所述纳米粒是通过五环三萜类化合物和硬脂酸上的羧基与壳聚糖或其衍生物上氨基的静电作用,在单硬脂酸甘油脂和泊洛沙姆的共同作用下,所形成的两亲性结构。与现有技术相比,本发明构建了壳聚糖或其衍生物包覆脂质纳米粒,具备体内脂蛋白的仿生结构。该给药载体对于五环三萜类药物具有一定的载药能力,具有缓释及促进药物吸收的作用,效果显著。
Description
技术领域
本发明涉及一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒及其制备方法,属于固体脂质纳米粒技术领域。
背景技术
五环三萜类化合物如山楂酸、齐墩果酸、熊果酸等(如下结构式所示,a.山楂酸,b.齐墩果酸,c.熊果酸),广泛存在于多种植物中,具有抗炎、抗肿瘤、抗艾滋病、抗氧化、抗II型糖尿病等多种药理活性。
齐墩果酸(Oleanolic acid,OA)具有护肝、降脂、降糖、抗突变、抗肿瘤等作用,20世纪70年代开始该药即用于治疗肝炎,对于对乙酰氨基酚、四氯化碳、镉等造成的肝损伤从刺激肝细胞增殖、抑制细胞色素P450或诱导产生金属硫蛋白等多种机制明显改善;熊果酸(Ursolic Acid,UA)具有抗炎、抗氧化、抗糖尿病、抗溃疡、降低血糖、抗肿瘤等多种生物学效应,并具有显著且快速降低谷丙转氨酶、血清转氨酶、消退黄疽、增进食欲、抗纤维化和恢复肝功能等作用,山楂酸(Maslinic acid,MA)的抗炎、抗肿瘤、降糖、神经保护等机制均较为明确。
五环三萜类化合物应用于肝损伤治疗极具前景,但目前存在的主要问题是该类药物在水中溶解度极低,难以分散在胃肠液中,不能与胃肠道粘膜充分接触,导致口服生物利用度很差,限制其进一步应用。
纳米技术应用于医药领域制成纳米给药系统,常见的有聚合物纳米粒、固体脂质纳米粒、环糊精包合物、脂质体、胶束等,具有靶向性、缓释性等特性,并具有促进细胞内吞、增加跨膜转运等特点,可应用于提高难溶性药物的溶解度和口服生物利用度。迄今为止,已有多个难溶性药物的纳米口服制剂上市,如新山地明(环孢素A)、(利托那韦)和(沙奎那韦)等。
随着纳米载体口服给药的研究进一步深入,人们逐渐认识到药物的口服生物利用度更大程度上依赖于载体类型和体内处置过程。具有类似于内源性结构的脂质载体有利于肠道摄取。脂蛋白(Lipoprotein)是普遍存在于血管中进行脂质运输的生物复合体,由亲水性载脂蛋白(Apolipoprotein)与磷脂、胆固醇和甘油三酯等脂质组成。载脂蛋白是一类两亲性的蛋白质,其疏水部分可以与脂质疏水部分结合,脂质亲水部分朝向外部,从而可自组装成纳米复合物。脂蛋白的结构易于装载难溶性药物,且具有良好的稳定性、自组装特性。但天然来源较少,制备工艺复杂,较难获得。
发明内容
发明目的:为解决现有技术中五环三萜类化合物难吸收,载脂蛋白获取困难等技术问题,本发明提供了一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒及其制备方法。
技术方案:为了实现上述目的,本发明采用以下技术方案:
一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒,包括以下重量百分比的组分:五环三萜类化合物0~15%(优选1~15%)、壳聚糖或其衍生物5~20%、单硬脂酸甘油酯20~50%、硬脂酸10~30%、泊洛沙姆5~75%;所述纳米粒是通过五环三萜类化合物和硬脂酸上的羧基与壳聚糖或其衍生物上氨基的静电作用,在单硬脂酸甘油脂和泊洛沙姆的共同作用下,所形成的两亲性结构。
优选,所述五环三萜类化合物选自如山楂酸、齐墩果酸、熊果酸的一种或几种。
优选,所述壳聚糖或其衍生物,其中壳聚糖衍生物包括羧甲基壳聚糖或羟乙基壳聚糖;所述泊洛沙姆选自泊洛沙姆188。
优选,所述纳米粒是将五环三萜类化合物、单硬脂酸甘油酯和硬脂酸所形成的油相,滴加入含泊洛沙姆和壳聚糖或其衍生物的水相中反应,所形成的两亲性结构。
所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒的制备方法,包括以下步骤:
(1)取五环三萜类化合物溶于有机溶剂中,并加入单硬脂酸甘油酯和硬脂酸,完全熔融,为油相溶液;
(2)将壳聚糖或其衍生物溶解成溶液,再加入泊洛沙姆至完全溶解,为水相溶液;
(3)在加热搅拌条件下,将油相溶液滴加入水相溶液中,滴加结束后继续搅拌乳化,然后迅速置于冰浴下超声,过微孔滤膜,即得所述壳聚糖包覆固体脂质纳米粒。
优选,步骤(1)中,有机溶剂选自乙醇;在75-80℃完全熔融。
优选,步骤(3)中,所述油相溶液和水相溶液的体积比为1:2~1:15;所述加热搅拌的温度为75-80℃;滴加结束后在50-80℃下继续搅拌5min-120min进行乳化。
优选,步骤(3)中,所述置于冰浴下超声,超声频率为250-350W,超声时间为10-60min。
本发明以价廉易得且生物相容性好的辅料,借鉴高密度脂蛋白结构制成纳米胶囊(Nano capsule,NP)以实现提高难溶性药物的肠道摄取率,改善其口服生物利用度。
泊洛沙姆188(Poloxamer188)即聚氧乙烯-聚氧丙烯共聚物,聚氧乙烯链相对亲水,聚氧丙烯链相对亲油,是一种无生理活性,无溶血性,毒性小的非离子的表面活性剂,是FDA批准的可注射用的药物辅料。硬脂酸(Stearic acid,SA)是一种内源性的饱和脂肪酸,具有脂肪长链,具有良好的生物相容性,有研究表明脂肪酸可增加药物细胞旁路途径的吸收。单硬脂酸甘油酯(Glyceryl Monostearate,GM)是由C16~C18长链脂肪酸与丙三醇进行酯化反应而制得,是一种非离子型的表面活性剂,生物毒性低,载药范围广等优点。
壳聚糖(Chitosan)是甲壳质脱乙酰基的产物,是自然界唯一大量存在的高分子碱性氨基多糖,具有良好的生物相容性和生物可降解性、低免疫原性和无生物活性等优点,衍生化后的壳聚糖具有水溶性。研究表明人体小肠细胞以及位于肠道中的M细胞对于壳聚糖制成的纳米制剂有较高的吞噬率,使载药壳聚糖纳米凝胶能通过跨细胞途径进入体循环。因此采用壳聚糖及其衍生物进行脂质纳米粒包覆,模拟载脂蛋白,既能稳定脂质纳米粒,亦有利于细胞旁路和跨细胞通道的吸收。
本发明中,由于壳聚糖分子链上带有大量活性氨基,可与脂质材料硬脂酸分子上的羧基、包载的五环三萜类药物(如齐墩果酸、熊果酸)羧基发生静电作用,形成亲水亲脂两亲性分子,可形成稳定的纳米粒。
综上,本发明借鉴脂蛋白构造,利用五环三萜类化合物和硬脂酸上的羧基与壳聚糖及其衍生物上的伯氨基的静电作用形成两亲性构造类似于载脂蛋白,与单硬脂酸甘油脂、泊洛沙姆188共同组装为仿生纳米胶囊;由于壳聚糖的线性弯曲结构与药物及其他成分的共同作用实现纳米结构的物理稳定性;通过纳米尺度及表面增强的黏附性以促进药物的吸收。
有益效果:与现有技术相比,本发明构建了壳聚糖或其衍生物包覆脂质纳米粒,具备体内脂蛋白的仿生结构。该给药载体对于五环三萜类药物具有一定的载药能力,具有缓释及促进药物吸收的作用,效果显著。
附图说明
图1为载药仿生纳米粒的原子力显微镜下的形态。
图2为各样品的差示扫描量热图。
图3为载药仿生纳米粒的释放曲线。
图4为纳米粒的细胞毒性考察(n=3)。
具体实施方式
下面结合具体实例,进一步阐明本发明。
本发明提供了一种载五环三萜类药物的壳聚糖及其衍生物包覆脂质纳米结构的给药系统,由药物、壳聚糖及其衍生物、单硬脂酸甘油酯、硬脂酸、泊洛沙姆组成,其组成的重量百分比为:五环三萜类药物(0~15%)、壳聚糖及其衍生物(5~20%)、单硬脂酸甘油酯(20~50%)、硬脂酸(10~30%)、泊洛沙姆(5~75%)。
通过以下步骤实现:
1.壳聚糖包覆脂质纳米结构给药载体的构建及表征
将单硬脂酸甘油酯和硬脂酸于75-80℃完全熔融,滴加入等温下含泊洛沙姆的壳聚糖或其衍生物(羧甲基壳聚糖、羟乙基壳聚糖)的水溶液。乳化5-120min后,冰浴下采用超声法超声10-60min后,过0.45μm微孔滤膜,即得壳聚糖包覆脂质纳米粒。
载药纳米粒则是将药物(齐墩果酸或熊果酸)溶于适量的乙醇中,与油相混合后,同法操作。
采用粒径电位测定仪进行纳米粒的粒径和电位测定,采用原子力显微镜进行纳米粒的形态观察。采用差示扫描热分析(DSC)观察各成分晶型变化。
2、载药工艺优化
以齐墩果酸为模型药物,比较了探头超声法,高速搅拌法,超声法等制备方法对纳米粒的粒径、电位、载药量的影响。采用了单因素考察法,比较了乳化时的温度,油水相的比例,壳聚糖浓度,泊洛沙姆浓度,单甘脂硬脂酸的比例对包封率的影响,以包封率为指标进行工艺优化,制成达到一定浓度的载药仿生纳米粒。
3、体外释放实验
采用恒温振荡仪进行释放度评价,采用透析法,置于含0.5%SLS释放介质(pH1.2和pH 6.8)的体外释放行为,评价载药仿生纳米粒的体外释放情况。
4、Caco-2细胞中的生物转运
采用MTT法进行细胞毒性评价,采用Transwell进行生物转运实验。在Caco-2细胞单层膜中加入含齐墩果酸、熊果酸纳米粒的培养基,评价AP→BL和BL→AP的表观渗透系数(Papp)。
实施例1给药载体的构建及表征
精密称取处方量的齐墩果酸或熊果酸溶于适量乙醇中,并加入处方量的单硬脂酸甘油酯和硬脂酸,75-80℃完全熔融,为油相溶液。精密称取适量羟乙基壳聚糖溶解成溶液;再加入泊洛沙姆适量至完全溶解,为水相溶液。将水相加热至75-80℃,于磁力搅拌下逐滴滴加油相。在50-80℃下继续搅拌5min-120min,再迅速置于冰浴下超声,过0.45μm微孔滤膜,即得载药仿生纳米粒。
将载药仿生纳米粒滴加于云母片上,待水分挥干,置于原子力显微镜下观察,如图1所示。纳米粒呈现一定的球形和类球形。
取齐墩果酸、单硬脂酸甘油酯、硬脂酸、泊洛沙姆、羟乙基壳聚糖、物理混合物、冻干后的纳米粒样品进行差示扫描量热分析,升温速度10℃/min,升温范围25~350℃。结果如图2所示。从上至下分别为齐墩果酸、物理混合物、羟乙基壳聚糖、纳米粒、单硬脂酸甘油酯、泊洛沙姆和硬脂酸。物理混合物呈现四个峰起始点分别为44.6℃,57.4℃,66.12℃和320.5℃,分别对应于羟乙基壳聚糖、泊洛沙姆、单甘酯和硬脂酸以及齐墩果酸,而纳米粒仅余一个峰43.7℃。说明制成的纳米粒药物与各种辅料形成了均一的体系,药物可能以分子状态分散在载体中。
实施例2载药工艺优化
以齐墩果酸为模型药物,羟乙基壳聚糖为壳聚糖材料,比较了探头超声法(500W,超声15s,停15s,共10min),高速搅拌法(10000rpm,5min),超声法(300W,30min)等制备方法对纳米粒的粒径、电位、包封率的影响。
表1不同制备方法所得载药胶束(n=3)
制备方法 | 包封率% | 粒径(nm) | 电位(mV) |
探头超声法 | 84.3±3.2 | 217.2±5.4 | 16.3±2.5 |
高速搅拌法 | 88.5±2.8 | 224.6±8.3 | 15.2±2.8 |
超声法 | 93.2±2.6 | 257.2±7.2 | 16.3±2.1 |
结果表明,超声法所得的纳米粒包封率最高,粒径稍偏大,电位更稳定,因此其后均采用超声法制备。
采用了单因素考察法,比较了乳化时的温度(50℃~80℃),乙醇与水的体积比(1:2~1:15),壳聚糖浓度(0.25%~1%),泊洛沙姆浓度(0.1~5%),单硬脂酸甘油酯在脂质材料中所占比例(0~100%)对包封率的影响,以包封率、粒径、电位为指标进行工艺优化,制成具有良好载药效果且稳定的仿生纳米粒。
表2单因素考察工艺优化结果(n=3)
结果表明,乳化时的温度越高,粒径越小,包封率也逐渐增加,但电位有所下降。为制得较高包封率的纳米粒仍选择80℃为乳化温度。乙醇与水的体积比越小,包封率可逐渐增加,但电位有一定的适宜范围,因而选择醇水体积比为1:10进行后续实验。壳聚糖浓度越高,粒径越大,但稳定性并未增加,最适宜的壳聚糖浓度选择0.5%。泊洛沙姆浓度增加,粒径相应增加,但包封率在其浓度为1%时达到最佳。脂质材料若全部为单硬脂酸甘油酯,粒径偏大且不稳定;比例下降,包封率会有所下降,因而选择单硬脂酸甘油酯在脂质中占有70%,另30%为硬脂酸。
根据优化后的80℃为乳化温度,醇水体积比为1:10,0.5%羟乙基壳聚糖溶液,1%泊洛沙姆,单硬脂酸甘油酯70%。即处方中五环三萜类化合物4.8%、羟乙基壳聚糖19.0%、单硬脂酸甘油酯26.7%、硬脂酸11.4%、泊洛沙姆38.1%。制备优化后的仿生纳米粒,重复六次,可得粒径286.9±5.6nm,电位26.9±1.4mV,包封率93.1±1.7%。
采用羧甲基壳聚糖同法操作制备仿生纳米粒,可得粒径为394.6±6.9nm,电位-38.8mV,包封率94.0±1.9%。
采用上述制备的优化后的仿生纳米粒进行如下体外释放行为实验和Caco-2细胞中的生物转运实验。
实施例3体外释放行为
分别取载药仿生纳米粒和原药物,以齐墩果酸计均为5mg,放入到预先处理好的透析袋(截留相对分子质量为7000~14000)中,并将透析袋置于200mL释放介质中(pH 1.2和pH 6.8的缓冲液,均含有0.5%的SLS),于(37±0.5)℃的恒温水浴振荡(100r/min),分别于1、4、8、12、24和48h取样1mL,并补充同温等量释放介质。样品用0.45μm微孔滤膜滤过,HPLC测定药物含量后进行计算,累积释放百分率与时间关系见图3。结果表明纳米粒在透析袋中的药物释放明显减缓,在不同的pH条件下均具有良好的缓释作用。
实施例4 Caco-2细胞中的生物转运
采用MTT法进行细胞毒性试验,结果如图4所示,按OA浓度0.01~1000μg/mL(空白载体浓度则以相当浓度计)。浓度1mg/mL会导致细胞凋亡,浓度降至100μg/mL及以下后,细胞增殖情况与对照组趋于接近,说明纳米粒具有较低的细胞毒性。
Caco-2细胞株接种于Transwell板上,至TEER值>450Ω/cm2。配置含药(以药物浓度为10μg/mL计)纳米粒,加入Tranwell转运孔中,测定两侧的药物含量,评价AP→BL和BL→AP的表观渗透系数(Papp)。评价不同浓度的载药纳米粒在Caco-2细胞模型上的转运效果,结果见表3。
表3齐墩果酸、熊果酸仿生纳米粒在Caco-2细胞模型上的转运
结果表明采用羟乙基壳聚糖包覆脂质纳米粒后具有明显的促进齐墩果酸、熊果酸等五环三萜类化合物渗透的作用。
Claims (8)
1.一种促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒,其特征在于,包括以下重量百分比的组分:五环三萜类化合物0~15%、壳聚糖或其衍生物5~20%、单硬脂酸甘油酯20~50%、硬脂酸10~30%、泊洛沙姆5~75%;所述纳米粒是通过五环三萜类化合物和硬脂酸上的羧基与壳聚糖或其衍生物上氨基的静电作用,在单硬脂酸甘油脂和泊洛沙姆的共同作用下,所形成的两亲性结构。
2.根据权利要求1所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒,其特征在于,所述五环三萜类化合物选自如山楂酸、齐墩果酸、熊果酸的一种或几种。
3.根据权利要求1所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒,其特征在于,所述壳聚糖或其衍生物,其中壳聚糖衍生物包括羧甲基壳聚糖或羟乙基壳聚糖;所述泊洛沙姆选自泊洛沙姆188。
4.根据权利要求1所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒,其特征在于,所述纳米粒是将五环三萜类化合物、单硬脂酸甘油酯和硬脂酸所形成的油相,滴加入含泊洛沙姆和壳聚糖或其衍生物的水相中反应,所形成的两亲性结构。
5.权利要求1-4任一项所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒的制备方法,其特征在于,包括以下步骤:
(1)取五环三萜类化合物溶于有机溶剂中,并加入单硬脂酸甘油酯和硬脂酸,完全熔融,为油相溶液;
(2)将壳聚糖或其衍生物溶解成溶液,再加入泊洛沙姆至完全溶解,为水相溶液;
(3)在加热搅拌条件下,将油相溶液滴加入水相溶液中,滴加结束后继续搅拌乳化,然后迅速置于冰浴下超声,过微孔滤膜,即得所述壳聚糖包覆固体脂质纳米粒。
6.根据权利要求5所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒的制备方法,其特征在于,步骤(1)中,有机溶剂选自乙醇;在75-80℃完全熔融。
7.根据权利要求5所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒的制备方法,其特征在于,步骤(3)中,所述油相溶液和水相溶液的体积比为1:2~1:15;所述加热搅拌的温度为75-80℃;滴加结束后在50-80℃下继续搅拌5min-120min进行乳化。
8.根据权利要求5所述的促五环三萜类药物吸收的壳聚糖包覆固体脂质纳米粒的制备方法,其特征在于,步骤(3)中,所述置于冰浴下超声,超声频率为250-350W,超声时间为10-60min。
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