CN111249251A - 一种恩诺沙星壳聚糖纳米粒 - Google Patents
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Abstract
本发明公开了一种恩诺沙星壳聚糖纳米粒,其由以下方法制备而成:1、将壳聚糖加入到醋酸溶液中,搅拌溶解后溶胀过夜,得到壳聚糖凝胶;2、将三聚磷酸钠溶于去离子水中,得到三聚磷酸钠溶液;3、将恩诺沙星加入壳聚糖凝胶,搅拌均匀,加入NaOH调节pH值至5.0,继续搅拌,接着滴加三聚磷酸钠溶液,滴加完成时产生淡蓝色乳光,再继续搅拌1h,得到恩诺沙星壳聚糖纳米粒混悬液;4、将恩诺沙星壳聚糖纳米粒混悬液进行干燥,得到所述的恩诺沙星壳聚糖纳米粒。该纳米粒制备方法简单,无不良气味,适口性好,对鲶爱德华氏菌有很好的杀灭作用。
Description
技术领域
本发明属于鱼类疾病防治药物技术领域,具体涉及一种恩诺沙星壳聚糖纳米粒。
背景技术
鲶爱德华氏菌主要通过巨噬细胞吞噬,并经血液循环到达鱼体各组织引起发急性感染等疾病。对于已经感染鲶爱德华氏菌并已出现疾病症状的鱼体来说,必须马上进行药物治疗以控制死亡率。有研究表明,鲶爱德华氏菌对多种抗生素敏感,如氨基糖苷类、头孢类及喹诺酮类等。其中,作为兽医专用的第三代喹诺酮类抗菌药的恩诺沙星,对革兰氏阴性菌、阳性菌、支原体、衣原体等都有杀灭作用,毒副作用小,与其它抗菌药无交叉耐药性。
恩诺沙星通过DNA旋转酶抑制剂,干扰DNA超螺旋结构的解旋,阻碍DNA复制,呈现广谱杀菌作用。然而,恩诺沙星味苦,口服适应性较差,对胃肠道的刺激性大,需多次给药才能充分发挥其药效,不但对鱼体造成较大的应激反应,而且还可能造成药物残留等一系列问题。
发明内容
为了解决上述现有技术存在的问题,本发明提供了一种恩诺沙星壳聚糖纳米粒,该纳米粒制备方法简单,无不良气味,适口性好,对鲶爱德华氏菌有很好的杀灭作用。
实现本发明上述目的所采用的技术方案为:
一种恩诺沙星壳聚糖纳米粒,由以下方法制备而成:
1、将壳聚糖加入到醋酸溶液中,搅拌溶解后溶胀过夜,得到壳聚糖凝胶;
2、将三聚磷酸钠溶于去离子水中,得到三聚磷酸钠溶液;
3、将恩诺沙星加入壳聚糖凝胶中,搅拌溶解,加入NaOH调节pH值至5.0-5.5,继续搅拌并滴加三聚磷酸钠溶液,恩诺沙星、壳聚糖、三聚磷酸钠的质量比为:1:4.5-15:3,滴加完成时产生淡蓝色乳光,再继续搅拌1-1.5h,得到恩诺沙星壳聚糖纳米粒混悬液;
1.4、将恩诺沙星壳聚糖纳米粒混悬液进行干燥,得到所述的恩诺沙星壳聚糖纳米粒。
进一步,所述的醋酸溶液的质量百分比浓度为1-5%,壳聚糖与醋酸溶液的质量体积比为1-2mg:1mL。
进一步,三聚磷酸钠溶液的浓度为1.5-2mg/mL。
进一步,将恩诺沙星壳聚糖纳米粒混悬液进行干燥的方法为:将恩诺沙星壳聚糖纳米粒混悬液加入冷冻瓶中,在-70-80℃下预冷冻1.5-2h,然后在-50-60℃下抽真空冷冻干燥。
与现有技术相比,本发明的有益效果和优点在于:
1、本发明将恩诺沙星制成纳米粒过程中加入壳聚糖,以此来掩盖恩诺沙星的不良气味和口味,大幅度提高了适口性。
2、本发明的恩诺沙星壳聚糖纳米粒稳定高,且可以减缓恩诺沙星在体内的释放速度,从而提高恩诺沙星的生物利用度,减少给药次数,更好的发挥其药效。
3、本发明的恩诺沙星壳聚糖纳米粒具有独特的功能优势:①壳聚糖微球表面富含多糖链,可被特异性细胞或组织所识别,从而激活并引发局部免疫应答反应,增强对特异性细胞(组织)的靶向作用;②壳聚糖具有相对好的粘附性,能够很好的满足粘膜组织给药后对于药物滞留性的要求;③壳聚糖表面的功能基团,可以包裹或吸附的方式负载不同的药物等,以恩诺沙星为药芯,以壳聚糖为壁壳制备的恩诺沙星壳聚糖纳米粒在鱼体的体内、体外评价中表现出较好的药剂学特性。
4、本发明采用离子交联法,利用壳聚糖在稀酸水溶液中形成带正电的阳离子,三聚磷酸钠溶解形成带负电的阴离子,阴阳离子交联并将恩诺沙星药物包裹其中,再经过低温冷冻干燥,得到恩诺沙星壳聚糖纳米粒,其中三聚磷酸钠作为一种聚阴离子电解质,无毒无害的理化性质避免了对细胞的毒性作用,在与壳聚糖制备纳米粒的技术上表现出较好的优越性,此外,冷冻干燥法是将溶液在低温低压条件下,从冻结状态直接升华除去水分完成干燥,使制得的药物保持原有的理化性质和生理活性,而且冷冻干燥后的药物具有疏松多孔的结构,含水量低,还可提高药物稳定性。
附图说明
图1为实施例1制备的恩诺沙星壳聚糖纳米粒的外观图。
图2为实施例1制备的恩诺沙星壳聚糖纳米粒的倒置显微镜扫描图。
图3为实施例1制备的恩诺沙星壳聚糖纳米粒在黄颡鱼体外的药效评价图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1
1、称取30mg壳聚糖,加入到20mL1wt%的醋酸溶液中,搅拌溶解后溶胀过夜,得到壳聚糖凝胶;
2、称取三聚磷酸钠,溶于去离子水中,得到1.5mg/mL的三聚磷酸钠溶液;
3、称取4mg恩诺沙星,加入壳聚糖凝胶中,充分搅拌使之溶解,加入1mol/lNaOH溶液调节pH值至5.0,在室温下继续搅拌,并逐滴加入三聚磷酸钠溶液,待体系中产生淡蓝色乳光时,停止滴加三聚磷酸钠溶液,三聚磷酸钠溶液滴加的体积为8mL,再继续搅拌1h,得到恩诺沙星壳聚糖纳米粒混悬液;
4、将剩余的恩诺沙星壳聚糖纳米粒混悬液加入冷冻瓶中,在-70℃下预冷冻2h,然后在-50℃下抽真空冷冻干燥,得到恩诺沙星壳聚糖纳米粒,其为白色细小薄片,表面疏松多孔,如图1所示。
将所制得的部分恩诺沙星壳聚糖纳米粒混悬液置于4℃冰箱中,30天后没有沉淀析出,由此表明,本实施例制备的恩诺沙星壳聚糖纳米粒的稳定性良好。
将所制得的恩诺沙星壳聚糖纳米粒用倒置显微镜进行扫描,所得的倒置显微镜扫描图如图2所示,从图2中可以看出,所得的恩诺沙星壳聚糖纳米粒为纳米粒。
试验一、本发明的恩诺沙星壳聚糖纳米粒MIC测定试验
试验方法:
取一个96孔板(共8行,每行12个孔),标记为96孔板,在96孔板每个孔中加入100μl BHI液体培养基,然后在第1行的各孔中加入100μl药液(此处指的是指将实施例1制得的恩诺沙星壳聚糖纳米粒分散于PBS缓冲液中配制而成的12.5μg/ml的药液),从第1行各孔中吸取100μl混合液分别加入第2行的各孔中,依次类推至第6行,并从第六行中吸取100μl混合液弃去,得到2、4、8、16、32、64倍稀释的药物,即为实验组。第7行的各孔加入10μl双抗(将青霉素与链霉素混合溶液(100×双抗)进行稀释100倍)作为阳性对照组,第8行的各孔不加药液与双抗作为阴性对照组。在上述实验组、阴性对照与阳性对照液体加入完毕后,并在96孔板各孔加入10μl1×106CFU/ml鲶爱德华氏菌菌液,37℃培养24h后取出观察96孔板中个孔中的浑浊度(即鲶爱德华氏菌在各孔中的生长情况),从而得到MIC值。重复两次试验。
试验结果:
测得实施例所制得的恩诺沙星壳聚糖纳米粒的MIC为0.391μg/ml。
试验二、本发明的恩诺沙星壳聚糖纳米粒的黄颡鱼体外药效评价试验
试验方法:
将分离得到的黄颡鱼头肾巨噬细胞培养2-3h,换液备用。将冻存的鲶爱德华氏菌菌种接入BHI液体培养基中,在28℃下进行复苏培养,长出菌落后再转接于新的BHI固体培养基中,直至长出新菌落以备用。以MOI=1:10(1细胞:10细菌)对黄颡鱼头肾巨噬细胞进行感染,感染半小时后,用无菌PBS缓冲液洗去未感染的鲶爱德华氏菌。实验组加入新的BHI液体培养基,接着加入恩诺沙星壳聚糖纳米粒乳液(将恩诺沙星壳聚糖纳米粒加入无菌PBS缓冲液分散均匀所制得),此时恩诺沙星壳聚糖纳米粒的浓度为2μg/mL,对照组加入新的BHI液体培养基,将实验组和对照组的黄颡鱼头肾巨噬细胞继续培养0.5h、1.0h、1.5h、2h、2.5h、3h后,收取相应时间点的黄颡鱼头肾巨噬细胞,并用无菌水裂解黄颡鱼头肾巨噬细胞,释放出胞内的鲶爱德华氏菌,将收集到的菌液按不同的浓度梯度稀释后涂平板,每组涂3个板,重复3次试验。
试验结果:
如图3所示,实验组在恩诺沙星壳聚糖纳米粒的作用下,黄颡鱼头肾巨噬细胞内的鲶爱德华氏菌数量呈现先升高后下降的趋势,并在孵育1.5h时,胞内菌数量最多;同样,只经鲶爱德华氏菌感染,未进行药物处理的对照组,其胞内菌也呈现先增高后下降的趋势,并在1.0h时,胞内菌数量达到最大;与实验组相比,对照组的每个取样点的胞内菌数量都极显著高于实验组(p<0.001)。
作为鱼类中非特异性免疫系统中的吞噬细胞,广泛分布于鱼体中,但以头肾中居多。头肾中的巨噬细胞具有较强的吞噬能力,可将所制成的恩诺沙星壳聚糖纳米粒吞入胞内进而发挥药效,而恩诺沙星壳聚糖纳米粒中的壳聚糖可与巨噬细胞表面的受体发生特异性结合,从而通过巨噬细胞的内吞作用将恩诺沙星壳聚糖纳米粒摄入其中。恩诺沙星壳聚糖纳米粒通过主动与被动运输作用进入黄颡鱼的头肾巨噬细胞,在胞内经过各种酶作用使得纳米粒中的壳聚糖发挥其抑菌作用,恩诺沙星发挥其杀菌作用从而抑制胞内菌的生长。
Claims (4)
1.一种恩诺沙星壳聚糖纳米粒,其特征在于由以下方法制备而成:
1.1、将壳聚糖加入到醋酸溶液中,搅拌溶解后溶胀过夜,得到壳聚糖凝胶;
1.2、将三聚磷酸钠溶于去离子水中,得到三聚磷酸钠溶液;
1.3、将恩诺沙星加入壳聚糖凝胶中,搅拌溶解,加入NaOH调节pH值至5.0-5.5,继续搅拌并滴加三聚磷酸钠溶液,恩诺沙星、壳聚糖、三聚磷酸钠的质量比为:1:4.5-15:3,滴加完成时产生淡蓝色乳光,再继续搅拌1-1.5h,得到恩诺沙星壳聚糖纳米粒混悬液;
1.4、将恩诺沙星壳聚糖纳米粒混悬液进行干燥,得到所述的恩诺沙星壳聚糖纳米粒。
2.根据权利要求1所述的恩诺沙星壳聚糖纳米粒,其特征在于:所述的醋酸溶液的质量百分比浓度为1-5%,壳聚糖与醋酸溶液的质量体积比为1-2mg:1mL。
3.根据权利要求1所述的恩诺沙星壳聚糖纳米粒,其特征在于:三聚磷酸钠溶液的浓度为1.5-2mg/mL。
4.根据权利要求1所述的恩诺沙星壳聚糖纳米粒,其特征在于将恩诺沙星壳聚糖纳米粒混悬液进行干燥的方法为:将恩诺沙星壳聚糖纳米粒混悬液加入冷冻瓶中,在-70-80℃下预冷冻1.5-2h,然后在-50-60℃下抽真空冷冻干燥。
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