CN107233575A - 可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法 - Google Patents
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Abstract
本发明公开了一种可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,首先对环糊精进行氨基化和醛基化,然后利用醛基化的环糊精与壳聚糖进行反应,得到壳聚糖接枝环糊精,将得到的壳聚糖接枝环糊精分子浸入药液中,搅拌均匀,过滤后冷冻干燥得到载药的壳聚糖接枝环糊精,最后将载药的壳聚糖接枝环糊精加入到壳聚糖溶液中,加入β‑甘油磷酸钠即可到可注射的温敏性壳聚糖载药凝胶。本发明中反应条件温和,操作较为简便,且本发明制备的凝胶可以长期保持凝胶体系中药物浓度的稳定,使药物能够长期有效的进行缓释,从而提高药物的利用率,应用前景较为广泛。
Description
技术领域
本发明属于水凝胶领域和药物缓释领域,具体涉及一种可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法及其应用。
背景技术
壳聚糖(CS)是一种天然存在的碱性多糖,具有良好的生物相容性、可降解性、抗菌性,广泛的应用于医药卫生、生物组织工程领域。2000年,Chenite等人利用壳聚糖溶液和甘油磷酸钠混合后得到了具有温度敏感性的壳聚糖水凝胶,壳聚糖水凝胶具有与关节软骨的细胞外基质类似的三维多孔网状结构,其化学性质稳定,且CS水凝胶呈生理中性,固化温度约为37℃,与人体体温相近。此外,壳聚糖分子中的主要结构单元葡糖胺与关节软骨细胞外基质中的主要成分糖胺多糖的结构相类似,因而,利用壳聚糖水凝胶作为软骨修复材料具有非常好的应用前景。但是,在关节软骨受损伤后一般会伴随着炎症的发生,目前最为有效的处理方法是在水凝胶中复合一些消炎类药物,从而起到消炎的目的,但是药物一般是属于小分子物质,其较容易从凝胶中释放出来,从而造成在水凝胶植入的初期出现爆释的现象,这虽然可以一直前期的炎症,但是炎症一般持续时间较长,因此这种方法起不到长期消炎的目的。
β-环糊精(β-CD)是目前应用较为广泛的载药体系,其分子结构呈“锥筒”状,两端呈开放状态,环糊精内腔疏水,外壁亲水,正由于这种特殊的结构使环糊精可以通过疏水作用、氢键和范德华力等作用,与药物等形成稳定的包合物,达到对药物的缓释效果。目前β-CD缓释体系一般是纳米药物,但是纳米药物用于软骨炎症的修复显然不合适,这是由于在人体运动的过程中软骨随之运动,可能会使β-CD移位,从而达不到预期的治疗效果。因此,本发明结合了CS水凝胶和β-CD载药的优势,制备了可注射壳聚糖接枝环糊精复合载药水凝胶。
发明内容
本发明所要解决的技术问题是针对现有的CS水凝胶容易造成药物爆释的现象和β-CD纳米药物在软骨修复时适用性较差的问题,提供一种可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法及其应用,使药物能够长期有效的进行缓释,从而提高药物的利用率。
为解决上述技术问题,本发明采用以下技术方案:
一种可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,步骤如下:
(1)将硅烷偶联剂溶解到乙醇水溶液中,使硅烷偶联剂充分水解,然后加入β-环糊精(β-CD)粉末,70℃回流反应8-12h后,用丙酮将反应产物析出后,离心,洗涤得到氨基化的β-环糊精(β-CD-NH2);
(2)配制二醛水溶液,然后将氨基化的β-环糊精(β-CD-NH2)加入到二醛水溶液中,在20℃的条件下搅拌反应6-8h后,将溶液离心、洗涤得到醛基化的β-环糊精(β-CD-CHO);
(3)配制壳聚糖溶液A,将醛基化的β-环糊精(β-CD-CHO)加入到壳聚糖溶液中,60℃回流反应6-12h后,得到壳聚糖接枝β-环糊精(CS-β-CD),然后将壳聚糖接枝β-环糊精(CS-β-CD)浸入药液中常温浸泡12-24h后进行冷冻干燥得到载药的壳聚糖接枝β-环糊精(CS-β-CD)粉末;
(4)配制壳聚糖溶液B,然后加入载药的壳聚糖接枝β-环糊精(CS-β-CD)粉末,搅拌均匀后,加入β-甘油磷酸钠溶液,并调节pH值为7.0-7.2,得到可注射的壳聚糖接枝环糊精复合载药水凝胶。
所述步骤(1)中的硅烷偶联剂为氨基硅烷偶联剂,包括但不限于3-氨丙基乙氧基硅烷,乙醇水溶液的体积分数为90%。
所述步骤(1)中的β-环糊精(β-CD)粉末与硅烷偶联剂的摩尔比为1:1-1:2.5。
所述步骤(2)中的二醛为戊二醛或己二醛,二醛水溶液的体积浓度为1%-3%(V/V);所述的氨基化的β-环糊精(β-CD-NH2)在二醛水溶液中的质量体积浓度为0.01g/mL-0.03g/mL。
所述步骤(3)中壳聚糖溶液A的质量体积浓度为0.005g/mL-0.015g/mL。
所述步骤(3)壳聚糖溶液A中的壳聚糖与醛基化的β-环糊精(β-CD-CHO)的质量比为1:0.5-1:1.5。
所述步骤(3)中药液的质量体积浓度为0.05g/mL-0.1g/mL,且壳聚糖接枝β-环糊精与药液中药物的质量比为1:1-1:3,所述药物为抗菌消炎类药物,所述抗菌消炎类药物包括但不限于万古霉素,氨苄青霉素,甲氧西林。
所述步骤(4)中壳聚糖溶液B的质量体积浓度为0.02g/mL-0.04g/mL,壳聚糖溶液B中的壳聚糖与载药的壳聚糖接枝β-环糊精(CS-β-CD)粉末的质量比为1:0.5-1:1。
所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法制得的壳聚糖接枝环糊精复合载药水凝胶应用于药物的缓控释。
与现有技术相比,本发明的有益效果为:本发明解决了现有壳聚糖载药水凝胶容易导致药物爆释的现象。同时,单纯的纳米β-环糊精药物载体用于软骨缺损修复时操作较为困难,且纳米粒子不能够很好的富集在缺损区域,适用性较差;本发明中所有反应条件温和,操作较为简便,且本发明制备的凝胶可以使药物缓慢的释放到软骨缺损区域,且当凝胶中的药物浓度降低时,环糊精中的药物可以释放到凝胶中,可以长期保持凝胶体系中药物浓度的稳定,使药物能够长期有效的进行缓释,从而提高药物的利用率,应用前景较为广泛。
具体实施方式
下面结合具体实施例,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制本发明的范围,该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
本实施例的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,步骤如下:
(1)将0.41mL(0.00176mol) 3-氨丙基乙氧基硅烷偶联剂溶解到100mL 90%(v/v)的乙醇水溶液中,使硅烷偶联剂充分水解,然后将1g β-CD(0.00088mol)粉末加入到溶液中,70℃回流反应8h后,用丙酮将反应产物析出后,离心,洗涤即可得到氨基化的β-环糊精(β-CD-NH2);
(2)然后将1mL戊二醛溶液加入到100mL去离子水中,然后将1gβ-CD-NH2加入到戊二醛溶液中,20℃下搅拌反应6h后,将溶液离心、洗涤即可得到醛基化的β-环糊精(β-CD-CHO);
(3)配制浓度为0.005g/mL的壳聚糖溶液100mL,然后将0.25g β-CD-CHO加入到壳聚糖溶液中,60℃回流反应12h后,即可得到壳聚糖接枝β-CD(CS-β-CD),然后将0.5g CS-β-CD浸入10mL浓度为0.05g/mL的万古霉素药液中浸泡12h后进行冷冻干燥得到载药的CS-β-CD粉末;
(4)配制10mL 浓度为0.02g/mL壳聚糖溶液,然后加入0.1g的载药的CS-β-CD粉末,搅拌均匀后,加入β-甘油磷酸钠溶液,并调节pH值为7.0,即可得到可注射的壳聚糖环糊精复合载药水凝胶。
实施例2
本实施例的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,步骤如下:
(1)将0.205mL(0.00088mol)3-氨丙基乙氧基硅烷偶联剂溶解到100mL 90%(v/v)的乙醇水溶液中,使硅烷偶联剂充分水解,然后将1g β-CD(0.00088mol)粉末加入到溶液中,70℃回流反应10h后,用丙酮将反应产物析出后,离心,洗涤即可得到氨基化的β-CD(β-CD-NH2);
(2)然后将2mL戊二醛溶液加入到100mL去离子水中,然后将1gβ-CD-NH2加入到戊二醛溶液中,20℃下搅拌反应7h后,将溶液离心、洗涤即可得到醛基化的β-CD(β-CD-CHO);
(3)配制浓度为0.01g/mL的壳聚糖稀溶液100mL,然后将1.0g β-CD-CHO加入到壳聚糖溶液中,60℃回流反应6h后,即可得到壳聚糖接枝β-CD(CS-β-CD),然后将0.5g CS-β-CD浸入10mL浓度为0.1g/mL氨苄青霉素药液中浸泡24h后进行冷冻干燥得到载药的CS-β-CD粉末;
(4)配制10mL 浓度为0.03g/mL壳聚糖溶液,然后加入0.3g的载药的CS-β-CD粉末,搅拌均匀后,加入β-甘油磷酸钠溶液,并调节pH值为7.2,即可得到可注射的壳聚糖环糊精复合载药水凝胶。
实施例3
本实施例的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,步骤如下:
(1)将0.513mL(0.0022 mol)3-氨丙基乙氧基硅烷偶联剂溶解到100mL 90%的乙醇水溶液中,使硅烷偶联剂充分水解,然后将1g β-CD(0.00088mol)粉末加入到溶液中,70℃回流反应8h后,用丙酮将反应产物析出后,离心,洗涤即可得到氨基化的β-CD(β-CD-NH2);
(2)然后将3mL戊二醛溶液加入到100mL去离子水中,然后将3gβ-CD-NH2加入到戊二醛溶液中,20℃下搅拌反应7h后,将溶液离心、洗涤即可得到醛基化的β-CD(β-CD-CHO);
(3)配制浓度为0.015g/mL壳聚糖的稀溶液100mL,然后将2.25g β-CD-CHO加入到壳聚糖溶液中,60℃回流反应8h后,即可得到壳聚糖接枝β-CD(CS-β-CD),然后将0.5g CS-β-CD浸入10mL浓度为0.05g/mL甲氧西林药液中浸泡20h后进行冷冻干燥得到载药的CS-β-CD粉末;
(4)配制10mL 浓度为0.04g/mL壳聚糖溶液,然后加入0.2g的载药的CS-β-CD粉末,搅拌均匀后,加入β-甘油磷酸钠溶液,并调节pH值为7.0,即可得到可注射的壳聚糖环糊精复合载药水凝胶。
实施例4
本实施例的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,步骤如下:
(1)将0.315mL(0.00132mol)3-氨丙基乙氧基硅烷偶联剂溶解到100mL 90%(v/v)的乙醇水溶液中,使硅烷偶联剂充分水解,然后将1g β-CD(0.00088mol)粉末加入到溶液中,70℃回流反应12h后,用丙酮将反应产物析出后,离心,洗涤即可得到氨基化的β-CD(β-CD-NH2);
(2)然后将2mL戊二醛溶液加入到100mL去离子水中,然后将3gβ-CD-NH2加入到戊二醛溶液中,20℃下搅拌反应8h后,将溶液离心、洗涤即可得到醛基化的β-CD(β-CD-CHO);
(3)配制浓度为0.01g/mL壳聚糖的稀溶液100mL,然后将1.5g β-CD-CHO加入到壳聚糖溶液中,60℃回流反应6h后,即可得到壳聚糖接枝β-CD(CS-β-CD),然后将0.25g CS-β-CD浸入10mL浓度为0.075g/mL的万古霉素药液中浸泡18h后进行冷冻干燥得到载药的CS-β-CD粉末;
(4)配制10mL 浓度为0.02g/mL壳聚糖溶液,然后加入0.2g的载药的CS-β-CD粉末,搅拌均匀后,加入β-甘油磷酸钠溶液,并调节pH值为7.2,即可得到可注射的壳聚糖环糊精复合载药水凝胶。
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (9)
1.一种可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于步骤如下:
(1)将硅烷偶联剂溶解到乙醇水溶液中,使硅烷偶联剂充分水解,然后加入β-环糊精粉末,70℃回流反应8-12h后,用丙酮将反应产物析出后,离心,洗涤得到氨基化的β-环糊精;
(2)配制二醛水溶液,然后将氨基化的β-环糊精加入到二醛水溶液中,在20℃的条件下搅拌反应6-8h后,将溶液离心、洗涤得到醛基化的β-环糊精;
(3)配制壳聚糖溶液A,将醛基化的β-环糊精加入到壳聚糖溶液中,60℃回流反应6-12h后,得到壳聚糖接枝β-环糊精,然后将壳聚糖接枝β-环糊精浸入药液中常温浸泡12-24h后进行冷冻干燥得到载药的壳聚糖接枝β-环糊精粉末;
(4)配制壳聚糖溶液B,然后加入载药的壳聚糖接枝β-环糊精粉末,搅拌均匀后,加入β-甘油磷酸钠溶液,并调节pH值为7.0-7.2,得到可注射的壳聚糖接枝环糊精复合载药水凝胶。
2.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(1)中的硅烷偶联剂为氨基硅烷偶联剂,包括但不限于3-氨丙基乙氧基硅烷,乙醇水溶液的体积分数为90%。
3.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(1)中的β-环糊精粉末与硅烷偶联剂的摩尔比为1:1-1:2.5。
4.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(2)中的二醛为戊二醛或己二醛,二醛水溶液的体积浓度为1%-3%;所述的氨基化的β-环糊精在二醛水溶液中的质量体积浓度为0.01g/mL-0.03g/mL。
5.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(3)中壳聚糖溶液A的质量体积浓度为0.005g/mL-0.015g/mL。
6.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(3)壳聚糖溶液A中的壳聚糖与醛基化的β-环糊精的质量比为1:0.5-1:1.5。
7.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(3)中药液的质量体积浓度为0.05g/mL-0.1g/mL,且壳聚糖接枝β-环糊精与药液中药物的质量比为1:1-1:3,所述药物为抗菌消炎类药物,所述抗菌消炎类药物包括但不限于万古霉素,氨苄青霉素,甲氧西林。
8.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法,其特征在于:所述步骤(4)中壳聚糖溶液B的质量体积浓度为0.02g/mL-0.04g/mL,壳聚糖溶液B中的壳聚糖与载药的壳聚糖接枝β-环糊精粉末的质量比为1:0.5-1:1。
9.根据权利要求1所述的可注射壳聚糖接枝环糊精复合载药水凝胶的制备方法制得的壳聚糖接枝环糊精复合载药水凝胶应用于药物的缓控释。
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Application publication date: 20171010 |