CN108003358A - 一种多孔半互穿温敏性复合水凝胶的制备方法 - Google Patents
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Abstract
本发明涉及一种多孔半互穿温敏性复合水凝胶的制备方法,属于生物材料技术领域。本发明以具有独特的纳米纤维三维网状结构和优良的载药特性的高含水量、高结晶度、高纯度以及良好的生物相容性的由微生物发酵合成的天然纤维素为主体网络,将温敏性材料甲基丙烯酸‑N,N‑二甲氨基乙酯的单体引入纳米纤维网络内部进行聚合成第2网络结构形成凝胶时间较短的半互穿复合凝胶,使细菌纤维素材料具有温度响应性,能快速响应外界温度刺激失水,通过水凝胶内部的网络结构及自身降解作用,水凝胶内部药物会平稳的从凝胶内部释放出来,达到长期缓释的效果。
Description
技术领域
本发明涉及一种多孔半互穿温敏性复合水凝胶的制备方法,属于生物材料技术领域。
背景技术
在疾病治疗过程中,药物在临床存巧多种途径进入体内达到治疗效果。但由于药物本身缺点如半衰期较短,自身毒性较大,缺乏选择性以及体内酶、自身代谢等对药物的分解作用等,某些药物如粒细胞集落刺激因子、干扰素、粒细胞-巨细胞集落刺激因子等蛋白类药物以及紫杉醇、阿霉素等小分子药物在进入体能后作用时间较短,毒性作用较大,且真正能够发挥作用的药物只有一小部分,而增加药物浓度或频繁给药往往造成血清中药物浓度的急剧升高,随后迅速下降。这种大范围的变化导致在药物浓度较高时可能引起严重的毒性作用,而当药物浓度下降到一定水平后又达不到治疗效果。这就需要一种新型的给药途径以克服药物产生的这些不利影响。近年来,智能高分子材料作为药物载体被用作延长药物作用时间、减少给药次数的研究越来越多。
随着现代材料学的发展,新的高分子材料不断被合成和发现。在这些高分子材料中,智能高分子材料作为当今世界上快速兴起并迅速发展的新型材料,在药物载体的应用中被不断研究和开发。智能髙分子材料是指可响应外界环境如温度、pH、光、电、磁场、离子等的变化而产生相应改变的一类高分子材料,这些智能髙分子材料的开发被用于工业、农业、药物载体、组织工程等各个领域。在这些智能材料中,研究最为广泛的为温敏性水凝胶和pH敏感性水凝胶。
温敏性水凝胶是一类可以响应周围温度变化而产生相应功能性改变的一类凝胶材料。即存在体积发生变化的临界转变温度,称为低温溶解湿度,当周围温度低于低温溶解温度时,温敏性水凝胶呈现为流动的液态,此时可以对药物进行添加和包埋;当温度逐渐升高并达到或超过低温溶解温度时,凝胶内部疏水作用力增强,凝胶发生相变,水凝胶溶液发生脱水而迅速转变成凝胶状态。通过水凝胶内部的网络结构及自身降解作用,水凝胶内部药物会平稳的从凝胶内部释放出来,达到长期缓释的效果。因为温敏性水凝胶的这一特性,可以在溶液状态时完成注射,随着温度的升高在体内成胶并完成对药物的释放。
在以往的研究过程中,多种药物控释系统在药物释放中表现出良好的性能,使得药物可以在需要部位富集,提高了药物的利用率,减少了给药次数,延长了药物的作用时间,降低了药物对机体其他脏器如肝、肾等的药物代谢负担。但凝胶时间较长、药物惨入困难、蛋白类药物易失活、释放时间短、降解性能差等弊端仍然存在。
发明内容
本发明所要解决的技术问题:针对市场中现有水凝胶凝胶时间较长、药物惨入困难、蛋白类药物易失活、释放时间短、降解性能差的问题,提供了一种多孔半互穿温敏性复合水凝胶的制备方法。
为解决上述技术问题,本发明采用的技术方案是:
一种多孔半互穿温敏性复合水凝胶的制备方法,具体制备步骤为:
(1)取葡萄糖、酵母浸膏、琼脂、蛋白胨、去离子水混合均匀,并用柠檬酸调节pH为5.0~6.0,高温灭菌后得发酵培养基;
(2)按接种量5~8%(V/V)将木醋杆菌接种至发酵培养基中,在30~32℃恒温培养箱中培养8~10天,取出凝胶状产物,得细菌纤维素水凝胶膜;
(3)将细菌纤维素水凝胶膜多次浸泡在氢氧化钠溶液中,再用去离子水浸泡洗涤至洗涤液呈中性,得纯化细菌纤维素凝胶;
(4)取甲基丙烯酸-N,N-二甲氨基乙酯、N,N-亚甲基双丙烯酰胺、偶氮二异丁腈,加入二甲基亚砜中搅拌均匀,再加入纯化细菌纤维素凝胶,振荡均匀得混合液;
(5)将混合液注入聚四氟乙烯模具中并加热至60~70℃,反应15~20h后取出凝胶,并用二甲基亚砜洗涤2~3次,再将凝胶浸泡在去离子水中3~5天,每天更换2~3次去离子水,得多孔半互穿温敏性复合水凝胶。
步骤(1)所述葡萄糖、酵母浸膏、琼脂、蛋白胨、去离子水的重量份为20~25份葡萄糖,3~5份酵母浸膏,15~20份琼脂,5~8份蛋白胨,800~1000份去离子水。
步骤(3)所述多次浸泡过程为在70~80℃恒温水浴下,浸泡1~2h后更换氢氧化钠溶液重复浸泡操作3~5次。
步骤(4)所述各物料的重量份为7~14份甲基丙烯酸-N,N-二甲氨基乙酯,0.07g~0.14份N,N-亚甲基双丙烯酰胺,0.13~0.26份偶氮二异丁腈,10~20份二甲基亚砜,5~8份纯化细菌纤维素凝胶。
步骤(4)所述振荡过程为在30~35℃下,以100~120r/min摇床振荡3~5h。
本发明与其他方法相比,有益技术效果是:
本发明以具有独特的纳米纤维三维网状结构和优良的载药特性的高含水量、高结晶度、高纯度以及良好的生物相容性的由微生物发酵合成的天然纤维素为主体网络,将温敏性材料甲基丙烯酸-N,N-二甲氨基乙酯的单体引入纳米纤维网络内部进行聚合成第2网络结构形成凝胶时间较短的半互穿复合凝胶,使细菌纤维素材料具有温度响应性,能快速响应外界温度刺激失水,通过水凝胶内部的网络结构及自身降解作用,水凝胶内部药物会平稳的从凝胶内部释放出来,达到长期缓释的效果。
具体实施方式
取20~25g葡萄糖,3~5g酵母浸膏,15~20g琼脂,5~8g蛋白胨,加入800~1000mL去离子水中,以300~400r/min搅拌20~30min,并用柠檬酸调节pH为5.0~6.0,再置于高压灭菌锅中,在121~125℃下,灭菌处理20~30min,得发酵培养基,按接种量5~8%(V/V)将木醋杆菌接种至100~120mL发酵培养基中,在30~32℃恒温培养箱中培养8~10天,用镊子取出发酵培养基表面生成的凝胶状产物,得细菌纤维素水凝胶膜,将细菌纤维素水凝胶膜浸泡在100~200mL质量分数为0.1%氢氧化钠溶液中,在70~80℃恒温水浴下,浸泡1~2h后更换氢氧化钠溶液重复浸泡操作3~5次,再用去离子水浸泡洗涤至洗涤液呈中性,得纯化细菌纤维素凝胶,取7~14g甲基丙烯酸-N,N-二甲氨基乙酯,0.07g~0.14gN,N-亚甲基双丙烯酰胺,0.13~0.26g偶氮二异丁腈,加入10~20g二甲基亚砜中,以300~400r/min搅拌20~30min,再加入5~8g纯化细菌纤维素凝胶,在30~35℃下,100~120r/min摇床振荡3~5h,得混合液,将混合液注入聚四氟乙烯模具中并加热至60~70℃,反应15~20h后取出凝胶,并用二甲基亚砜洗涤2~3次,再将凝胶浸泡在去离子水中3~5天,每天更换2~3次去离子水,得多孔半互穿温敏性复合水凝胶。
实例1
取20g葡萄糖,3g酵母浸膏,15g琼脂,5g蛋白胨,加入800mL去离子水中,以300r/min搅拌20min,并用柠檬酸调节pH为5.0,再置于高压灭菌锅中,在121℃下,灭菌处理20min,得发酵培养基,按接种量5%(V/V)将木醋杆菌接种至100mL发酵培养基中,在30℃恒温培养箱中培养8天,用镊子取出发酵培养基表面生成的凝胶状产物,得细菌纤维素水凝胶膜,将细菌纤维素水凝胶膜浸泡在100mL质量分数为0.1%氢氧化钠溶液中,在70℃恒温水浴下,浸泡1h后更换氢氧化钠溶液重复浸泡操作3次,再用去离子水浸泡洗涤至洗涤液呈中性,得纯化细菌纤维素凝胶,取7g甲基丙烯酸-N,N-二甲氨基乙酯,0.07ggN,N-亚甲基双丙烯酰胺,0.13g偶氮二异丁腈,加入10g二甲基亚砜中,以300r/min搅拌20min,再加入5g纯化细菌纤维素凝胶,在30℃下,100r/min摇床振荡3h,得混合液,将混合液注入聚四氟乙烯模具中并加热至60℃,反应15h后取出凝胶,并用二甲基亚砜洗涤2次,再将凝胶浸泡在去离子水中3天,每天更换2次去离子水,得多孔半互穿温敏性复合水凝胶。
实例2
取22g葡萄糖,4g酵母浸膏,17g琼脂,6g蛋白胨,加入900mL去离子水中,以350r/min搅拌25min,并用柠檬酸调节pH为5.5,再置于高压灭菌锅中,在123℃下,灭菌处理25min,得发酵培养基,按接种量6%(V/V)将木醋杆菌接种至110mL发酵培养基中,在31℃恒温培养箱中培养9天,用镊子取出发酵培养基表面生成的凝胶状产物,得细菌纤维素水凝胶膜,将细菌纤维素水凝胶膜浸泡在150mL质量分数为0.1%氢氧化钠溶液中,在75℃恒温水浴下,浸泡1h后更换氢氧化钠溶液重复浸泡操作4次,再用去离子水浸泡洗涤至洗涤液呈中性,得纯化细菌纤维素凝胶,取11g甲基丙烯酸-N,N-二甲氨基乙酯,0.12gN,N-亚甲基双丙烯酰胺,0.19g偶氮二异丁腈,加入15g二甲基亚砜中,以350r/min搅拌25min,再加入7g纯化细菌纤维素凝胶,在33℃下,110r/min摇床振荡4h,得混合液,将混合液注入聚四氟乙烯模具中并加热至65℃,反应17h后取出凝胶,并用二甲基亚砜洗涤2次,再将凝胶浸泡在去离子水中4天,每天更换2次去离子水,得多孔半互穿温敏性复合水凝胶。
实例3
取25g葡萄糖,5g酵母浸膏,20g琼脂,8g蛋白胨,加入1000mL去离子水中,以400r/min搅拌30min,并用柠檬酸调节pH为6.0,再置于高压灭菌锅中,在125℃下,灭菌处理30min,得发酵培养基,按接种量8%(V/V)将木醋杆菌接种至120mL发酵培养基中,在32℃恒温培养箱中培养10天,用镊子取出发酵培养基表面生成的凝胶状产物,得细菌纤维素水凝胶膜,将细菌纤维素水凝胶膜浸泡在200mL质量分数为0.1%氢氧化钠溶液中,在80℃恒温水浴下,浸泡2h后更换氢氧化钠溶液重复浸泡操作5次,再用去离子水浸泡洗涤至洗涤液呈中性,得纯化细菌纤维素凝胶,取14g甲基丙烯酸-N,N-二甲氨基乙酯,0.14gN,N-亚甲基双丙烯酰胺,0.26g偶氮二异丁腈,加入20g二甲基亚砜中,以400r/min搅拌30min,再加入8g纯化细菌纤维素凝胶,在35℃下,120r/min摇床振荡5h,得混合液,将混合液注入聚四氟乙烯模具中并加热至70℃,反应20h后取出凝胶,并用二甲基亚砜洗涤3次,再将凝胶浸泡在去离子水中5天,每天更换3次去离子水,得多孔半互穿温敏性复合水凝胶。
将本发明制备的多孔半互穿温敏性复合水凝胶及广东揭阳某公司生产的温敏水凝胶材料进行检测,具体检测结果如下表表1:
表1多孔半互穿温敏性复合水凝胶性能表征
由表1可知本发明制备的多孔半互穿温敏性复合水凝胶,凝胶时间短,剩余干重比和剩余湿重比低,具有较好的自降解性能,缓释时间长。
Claims (5)
1.一种多孔半互穿温敏性复合水凝胶的制备方法,其特征在于具体制备步骤为:
(1)取葡萄糖、酵母浸膏、琼脂、蛋白胨、去离子水混合均匀,并用柠檬酸调节pH为5.0~6.0,高温灭菌后得发酵培养基;
(2)按接种量5~8%(V/V)将木醋杆菌接种至发酵培养基中,在30~32℃恒温培养箱中培养8~10天,取出凝胶状产物,得细菌纤维素水凝胶膜;
(3)将细菌纤维素水凝胶膜多次浸泡在氢氧化钠溶液中,再用去离子水浸泡洗涤至洗涤液呈中性,得纯化细菌纤维素凝胶;
(4)取甲基丙烯酸-N,N-二甲氨基乙酯、N,N-亚甲基双丙烯酰胺、偶氮二异丁腈,加入二甲基亚砜中搅拌均匀,再加入纯化细菌纤维素凝胶,振荡均匀得混合液;
(5)将混合液注入聚四氟乙烯模具中并加热至60~70℃,反应15~20h后取出凝胶,并用二甲基亚砜洗涤2~3次,再将凝胶浸泡在去离子水中3~5天,每天更换2~3次去离子水,得多孔半互穿温敏性复合水凝胶。
2.如权利要求1所述的一种多孔半互穿温敏性复合水凝胶的制备方法,其特征在于,步骤(1)所述葡萄糖、酵母浸膏、琼脂、蛋白胨、去离子水的重量份为20~25份葡萄糖,3~5份酵母浸膏,15~20份琼脂,5~8份蛋白胨,800~1000份去离子水。
3.如权利要求1所述的一种多孔半互穿温敏性复合水凝胶的制备方法,其特征在于,步骤(3)所述多次浸泡过程为在70~80℃恒温水浴下,浸泡1~2h后更换氢氧化钠溶液重复浸泡操作3~5次。
4.如权利要求1所述的一种多孔半互穿温敏性复合水凝胶的制备方法,其特征在于,步骤(4)所述各物料的重量份为7~14份甲基丙烯酸-N,N-二甲氨基乙酯,0.07g~0.14份N,N-亚甲基双丙烯酰胺,0.13~0.26份偶氮二异丁腈,10~20份二甲基亚砜,5~8份纯化细菌纤维素凝胶。
5.如权利要求1所述的一种多孔半互穿温敏性复合水凝胶的制备方法,其特征在于,步骤(4)所述振荡过程为在30~35℃下,以100~120r/min摇床振荡3~5h。
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