CN105860103A - 一种新型纳米水凝胶的制备方法及其应用 - Google Patents
一种新型纳米水凝胶的制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及一种纳米水凝胶及其制备方法,该纳米水凝胶包括反应基质1‑5份、糖类化合物1‑5份、醇类化合物3‑20份、氧化剂0.1‑0.5份、碱溶液1‑5份、致孔剂1‑5份、催化剂0.2‑1份醚化剂10‑20份及反应介质10‑20份,本发明制备得到的纳米水凝胶具有生物相容性高、体系稳定、可以提高药效的纳米水凝胶载体,具有极高载药率和生物抗菌性。
Description
技术领域
本发明涉及高分子化学、生物化学、药物制剂等技术领域,提供了一种新型纳米水凝胶材料及其制备方法和用途。
背景技术
在21世纪,心血管疾病、肿瘤与糖尿病成为危害人类健康的三大疾病,目前,临床中使用的常规药物制剂,如溶液、悬液或乳液等,存在生物利用度低,稳定性差,靶向性弱等局限性,并具有一定的毒副作用,已逐渐不能满足临床用药的需求,纳米技术的发展有望在这一方面取得突破。
与传统的药物制剂相比,纳米药物载体具备特定的优势,表现在:1)纳米药物载体可经血液循环进入毛细血管,还可透过内皮细胞间隙,进入病灶,被细胞以胞饮的方式吸收,实现靶向用药,提高了药物的生物利用率。2)纳米载体粒径较小,拥有较高的比表面,可以包埋疏水性药物,提高其溶解性,减少常规用药中助溶剂的副作用。3)纳米药物载体经靶向基团修饰后可实现靶向药物给药,可减少用药剂量,降低其副作用。4)纳米载体可延长药物的消除半衰期,提高有效血药浓度时间,提高药效,降低用药频率,减少其毒副作用。5)纳米载体可透过机体屏障对药物作用的限制,使药物到达病灶,提高药效。
然而,目前纳米药物载体的应用还不成熟,纳米材料的生物安全性还需要进一步的论证、研究。与单纯的药物相比,纳米药物载体可实现靶向药物治疗。在特定的导向机制作用下,纳米药物载体输送药物到特定靶点,发挥治疗作用,可达到药剂用量少、毒副作用低、药效持续、生物利用度高、长时间保持靶目标的有效药物浓度的效果。
纳米药物载体具有生物相容性、缓释控释、靶向给药、提高药效等特点,已成为药剂学研究的热点。除了靶向药物给药系统外,纳米药物载体还可以实现肿瘤的早期诊断,降低肿瘤细胞的转移,逆转肿瘤细胞的多药耐药性,根据个性特征进行个性化治疗等,在疾病治疗领域凸显广阔的应用前景。
发明内容
本发明目的在于提供一种生物相容性高、体系稳定、可以提高药效的纳米水凝胶载体。
为了实现上述目的,本发明所采取的技术方案为:
一种纳米水凝胶,其特征在于,由按重量份计的下述组分组成:
所述反应基质为海藻酸钠、海藻酸中的一种或两种组合物。
所述糖类化合物为壳聚糖、β-环糊精、葡萄糖、蔗糖、麦芽糖、乳糖、淀粉、纤维素中的一种或两种以上组合物,其中壳聚糖具有良好的生物相容性、生物粘附性,可作为一种粘合剂使用,与海藻酸钠配合使用效果最佳,形成复合的对人体无毒无害、生物相容性较好的纳米水凝胶。
所述的醇类化合物为无水乙醇、乙二醇一种;乙二醇能与高碘酸钠反应,乙二醇碳链断裂生成醛,反应比为1:1,可将未反应的氧化剂去除;无水乙醇将沉淀析出,多次洗涤产物。
所述的氧化剂为高碘酸钠、高锰酸钾中的一种;该氧化剂可与乙二醇按1:1反应,生成醛基,未反应完全的氧化剂与乙二醇反应而去除。
所述的碱溶液为质量分数为20%的氢氧化钠溶液;壳聚糖含有较强的氢键,致密的晶型结构,使反应物难已渗透其中参与反应,须对壳聚糖进行预溶胀处理(碱化处理)生成的碱化壳聚糖具有很强的化学反应能力,壳聚糖经过碱的膨化作用发生预溶胀,有利于反应试剂向壳聚糖内的扩散,使环氧丙烷能与碱化壳聚糖充分发生反应。
所述的致孔剂为氯化钠;在氯化钠存在的条件下,由于小分子电解质的屏蔽作用使聚电解质海藻酸钠分子链发生coil-to-glouble转变,形成聚电解质微粒。当单体和交联剂在聚电解质微粒周围聚合物形成聚合物网络后,除去聚电解质微粒即形成多孔结构的纳米水凝胶。
所述的催化剂为四甲基氢氧化铵;该催化剂能提高产物的取代度。壳聚糖与环氧丙烷的反应是非均相反应,适当加入相转移催化剂,可在一定程度上增加环氧丙烷与壳聚糖的接触机会,提高环氧丙烷的利用率,有利于反应的进行。
所述的醚化剂为环氧丙烷;该醚化剂可与碱化处理的反应物发生反应,生成羟丙基化合物,改善分子的空间结构,削弱壳聚糖分子间和分子内的氢键作用,制备水溶性壳聚糖衍生物羟丙基壳聚糖。
所述的反应介质为异丙醇;该反应介质对壳聚糖具有一定的溶胀作用,碱化时可确保碱液能够均匀地渗透分散,能将碱化过程中放出的热量传递出来,减少了碱化壳聚糖的水解逆反应。同时,异丙醇的存在,还可提高反应活性和反应的均匀性,从而得到取代度较高、更加均匀的碱化壳聚糖。
本发明所述的纳米水凝胶的制备方法,包括以下步骤:
(1)将反应基质溶于80份蒸馏水中加入氧化剂,在40℃避光反应6h,加入醇类化合物和致孔剂,搅拌15min终止反应,将沉淀析出、洗涤、抽滤,45℃真空干燥,所得固体粉末在蒸馏水中透析,期间不停换水,取透析液加入到AgNO3溶液中,确保无沉淀产生,然后将透析液冷冻干燥;
(2)室温下将糖类化合物中加入碱溶液中搅拌均匀,进行碱化处理,加入反应介质、催化剂、醚化剂,常温下反应1h后,45℃下恒温反应6h,将溶液静置,滤去上层清夜,加入20份的蒸馏水搅拌溶解,在55℃下于旋转蒸发仪中旋蒸20min,取出待用;
(3)将步骤(1)和(2)得到的产物分别溶于蒸馏水,配成质量分数为6%的溶液,取8份步骤(1)配成的溶液,按质量比4:5的加入量向其中加入步骤(2)配成的溶液,经充分搅拌后静置得到纳米水凝胶。
综上所述,上述制备方法得到的水凝胶具有亲水性、无毒无害、生物相容性良好、体系稳定、新型的具有医用潜力的纳米水凝胶。该材料具有很强的抗菌性且载药率高,可长时间保持靶目标的有效药物浓度的效果。且整个制备过程绿色无污染、可操作性强,加入纤维素后使得凝胶的亲水性增强,产率较高。
具体实施方式
以下结合具体实施例,对本发明做进一步说明。应理解,以下实施例仅用于说明本发明,而非用于限定本发明的范围。
实施例1
一种纳米水凝胶,由按重量份计的下述组分组成:
(1)将3份海藻酸溶于80份蒸馏水中加入0.2份高碘酸钠,在40℃避光反应6h,加入10份乙二醇和3份NaCl搅拌15min终止反应,用10份无水乙醇将沉淀析出、洗涤、抽滤,45℃真空干燥,所得固体粉末在蒸馏水中透析,期间不停换水,取透析液加入到AgNO3溶液中,确保无沉淀产生,然后将透析液冷冻干燥;
(2)室温下将3份蔗糖和3份纤维素中加入4份质量分数为20%的氢氧化钠溶液中搅拌均匀,进行碱化处理,加入15份异丙醇、0.8份四甲基氢氧化铵、16份环氧丙烷,常温下反应1h后,45℃下恒温反应6h,将溶液静置,滤去上层清夜,加入20份蒸馏水搅拌溶解,在55℃下于旋转蒸发仪中旋蒸20min,取出待用;
(3)将步骤(1)和(2)得到的产物分别溶于蒸馏水,配成质量分数为6%的溶液,取8份步骤(1)配成的溶液,按质量比4:5加入量向其中加入步骤(2)配成的溶液,经充分搅拌后静置得到纳米水凝胶。
实施例2
一种纳米水凝胶,由按重量份计的下述组分组成:
(1)将3份海藻酸钠溶于80份蒸馏水中加入0.4份高锰酸钾,在40℃避光反应6h,加入6份乙二醇和2份NaCl搅拌15min终止反应,用12份无水乙醇将沉淀析出、洗涤、抽滤,45℃真空干燥,所得固体粉末在蒸馏水中透析,期间不停换水,取透析液加入到AgNO3溶液中,确保无沉淀产生,然后将透析液冷冻干燥;
(2)室温下将5份β-环糊精和5份纤维素中加入3份质量分数为20%的氢氧化钠溶液中搅拌均匀,进行碱化处理,加入18份异丙醇、0.6份四甲基氢氧化铵、10份环氧丙烷,常温下反应1h后,45℃下恒温反应6h,将溶液静置,滤去上层清夜,加入20份蒸馏水搅拌溶解,在55℃下于旋转蒸发仪中旋蒸20min,取出待用;
(3)将步骤(1)和(2)得到的产物分别溶于蒸馏水,配成质量分数为6%的溶液,取8份步骤(1)配成的溶液,按质量比4:5加入量向其中加入步骤(2)配成的溶液,经充分搅拌后静置得到纳米水凝胶。
实施例3
一种纳米水凝胶,由按重量份计的下述组分组成:
(1)将1份海藻酸溶于80份蒸馏水中加入0.3份高锰酸钾,在40℃避光反应6h,加入3份乙二醇和1份NaCl搅拌15min终止反应,用15份无水乙醇将沉淀析出、洗涤、抽滤,45℃真空干燥,所得固体粉末在蒸馏水中透析,期间不停换水,取透析液加入到AgNO3溶液中,确保无沉淀产生,然后将透析液冷冻干燥;
(2)室温下将2份壳聚糖和2份β-环糊精中加入4份质量分数为20%的氢氧化钠溶液搅拌均匀,进行碱化处理,加入12份异丙醇、0.6份四甲基氢氧化铵、20份环氧丙烷,常温下反应1h后45℃下恒温反应6h,将溶液静置,滤去上层清夜,加入20份蒸馏水搅拌溶解,在55℃下于旋转蒸发仪中旋蒸20min,取出待用;
(3)将步骤(1)和(2)得到的产物分别溶于蒸馏水,配成质量分数为6%的溶液,取8份步骤(1)配成的溶液,按质量比4:5加入量向其中加入步骤(2)配成的溶液,经充分搅拌后静置得到纳米水凝胶。
实施例4
一种纳米水凝胶,由按重量份计的下述组分组成:
(1)将2份海藻酸钠溶于80份蒸馏水中加入0.1份高碘酸钠,在40℃避光反应6h,加入10份乙二醇和4份NaCl搅拌15min终止反应,用13份无水乙醇将沉淀析出、洗涤、抽滤,45℃真空干燥,所得固体粉末在蒸馏水中透析,期间不停换水,取透析液加入到AgNO3溶液中,确保无沉淀产生,然后将透析液冷冻干燥;
(2)室温下将2份壳聚糖和4份纤维素加入2份质量分数为20%的氢氧化钠溶液搅拌均匀,进行碱化处理,加入18份异丙醇、0.6份四甲基氢氧化铵、10份环氧丙烷,常温下反应1h后45℃下恒温反应6h,将溶液静置,滤去上层清夜,加入20份的蒸馏水搅拌溶解,在55℃下于旋转蒸发仪中旋蒸20min,取出待用;
(3)将步骤(1)和(2)得到的产物分别溶于蒸馏水,配成质量分数为6%的溶液,取8份步骤(1)配成的溶液,按质量比4:5加入量向其中加入步骤(2)配成的溶液,经充分搅拌后静置得到纳米水凝胶。
试验例
普通纳米水凝胶与本发明制备的纳米水凝胶按下列标准测试:载药率、抗菌性。
载药率测试:
取实施例4制得的纳米水凝胶10mg,加入9mg阿奇霉素,配成20mL的磷酸盐缓冲溶液,常温下搅拌24h,产物经离心、冷冻干燥制成负载有阿奇霉素的纳米水凝胶药物载体,载药率的比重为78.6%。
抗菌性测试:
实验设计量于步骤(2)溶液中加入不同浓度的磺胺嘧啶银,再加入8mL的步骤(1)溶液,根据磺胺嘧啶银的加入量(分别为0.01,0.02,0.03,0.04,0.05g),将水凝胶分别标记为ASPS-Ag1、ASPS-Ag2、ASPS-Ag3、ASPS-Ag4、ASPS-Ag5,按上述方法制得上述磺胺嘧啶银水凝胶。采用抑菌圈法测定水凝胶的抑菌性能。
以采样器制得水凝胶圆柱形样品,在紫外灯下光照灭菌1h;采用肉汤培养基作为细菌培养基,成分(质量分数/%)为:牛肉膏0.8%,蛋白胨1%,NaCl 0.5%,琼脂2.5%,蒸馏水余量,以0.1mol/L NaOH溶液调节pH值至7.2;经高温高压灭菌倾注至培养皿中,待其自然冷却制得平板;大肠杆菌或金黄葡萄球菌加入到PBS溶液中配制成菌悬液,浓度为15~30cfu·mL-1,均匀涂布于平板上;将预处理过的水凝胶样品置于平板中心,于37℃培养箱中培养24h,测量样品的抑菌圈大小。抑菌圈变化率按下式计算:R=×100%,
式中:D(mm)为抑菌圈外围直径;d(mm)为水凝胶样品直径。
表1加入磺胺嘧啶银前后的水凝胶(黄金葡萄球菌悬菌液)抑菌圈变化率
表2加入磺胺嘧啶银前后的水凝胶(大肠杆菌悬菌液)抑菌圈变化率
结果表明:引入磺胺嘧啶银作为抗菌剂,以金黄葡萄球菌和大肠杆菌为实验菌种进行抗菌测试,结果表明引入磺胺嘧啶银后,水凝胶具有良好的抑菌性能;且随步骤(1)加入量的增大水凝胶内部空间结构越来越密实。
与空白水凝胶相比,抗菌剂的引入对水凝胶的内部三维网络结构无明显影响,但引入磺胺嘧啶银后水凝胶骨架表面出现少许颗粒沉积,加入不用浓度的磺胺嘧啶银的水凝胶抑菌圈变化率较空白水凝胶的抑菌圈变化率有了明显提高,抑菌效果良好。
Claims (8)
1.一种纳米水凝胶,其特征在于,由按重量份计的下述组分组成:
。
2.如权利要求1所述的纳米水凝胶,其特征在于,所述反应基质为海藻酸钠、海藻酸中的一种或两种组合物。
3.如权利要求1所述的纳米水凝胶,其特征在于,所述糖类化合物为壳聚糖、β-环糊精、葡萄糖、蔗糖、麦芽糖、乳糖、淀粉、纤维素中的一种或两种以上组合物。
4.如权利要求1所述的纳米水凝胶,其特征在于,所述的醇类化合物为无水乙醇、乙二醇中的一种。
5.如权利要求1所述的纳米水凝胶,其特征在于,所述的氧化剂为高碘酸钠、高锰酸钾中的一种。
6.如权利要求1所述的纳米水凝胶,其特征在于,所述的碱溶液为质量分数为20%的氢氧化钠溶液。
7.如权利要求1所述的纳米水凝胶,其特征在于,所述的致孔剂为氯化钠;所述催化剂为四甲基氢氧化铵;所述醚化剂为环氧丙烷;所述的反应介质为异丙醇。
8.权利要求1所述的纳米水凝胶的制备方法,其特征在于,包括以下步骤:
(1)将反应基质溶于80份蒸馏水中加入氧化剂,在40℃避光反应6h,加入醇类化合物和致孔剂,搅拌15min终止反应,将沉淀析出、洗涤、抽滤,45℃真空干燥,所得固体粉末在蒸馏水中透析,期间不停换水,取透析液加入到AgNO3溶液中,确保无沉淀产生,然后将透析液冷冻干燥;
(2)室温下将糖类化合物中加入碱溶液中搅拌均匀,进行碱化处理,加入反应 介质、催化剂、醚化剂,常温下反应1h后,45℃下恒温反应6h,将溶液静置,滤去上层清夜,加入20份的蒸馏水搅拌溶解,在55℃下于旋转蒸发仪中旋蒸20min,取出待用;
(3)将步骤(1)和(2)得到的产物分别溶于蒸馏水,配成质量分数为6%的溶液,取8份步骤(1)配成的溶液,按质量比4:5的加入量向其中加入步骤(2)配成的溶液,经充分搅拌后静置得到纳米水凝胶。
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