CN105885063B - 一种含有纳米银的医用温敏水凝胶的制备方法 - Google Patents
一种含有纳米银的医用温敏水凝胶的制备方法 Download PDFInfo
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Abstract
本发明公开了一种含有纳米银的医用温敏水凝胶的制备方法，主要由下列原料制备而成，均为质量份：壳聚糖细粉20，硝酸银0.01。本发明所制产品具有纳米银和壳聚糖的特点和优势，不仅具备纳米银抗菌性，还具备壳聚糖促进细胞生长，减少疤痕生成，壳聚糖作为纳米银的分散剂和保护剂，使纳米银均匀、稳定的分布温敏水凝胶体系中，且含纳米银的温敏水凝胶具有良好的保湿、透气性，且易降解，生物兼容性好，安全低毒。
Description
技术领域
本发明涉及医药材料领域，特别是涉及一种含有纳米银的医用温敏水凝胶的制备方法。
背景技术
壳聚糖具有可降解性、吸附性、成膜性等，并且由于其分子结构含有大量氨基和羟基等基团，易被化学修饰,生成不同结构和功能的壳聚糖衍生物,如抗癌、抑菌、控释、抗凝血活性等生物学功能，已被广泛应用于生物医药领域。其中壳聚糖生物敷料，具有良好的透气性和保湿性，能够防止水分流失，能吸收创面渗出液，具有良好的抑菌性，防止感染，止血，促进伤口愈合。同时其还具有良好的生物相容性、生物降解性和成膜性，不仅满足了伤口敷料所需要具备的条件，而且在伤口修复方面具有优异的特性，可以制成不同临床目的的医用敷料。纳米银是一种新兴的功能材料，由于纳米银的形貌、粒径及稳定性等使纳米银具有优良的性能。其杀菌作用是普通银的数百倍，对多种致病微生物都有很好的抑制和杀灭作用，对致病菌作用时间长，且不会产生耐药性。如今抗生素使用比较广泛，细菌的抗药性很强，人们开始关注不会产生耐药性的材料，壳聚糖与金属离子具有较强的配位能力，得到的复合材料能同时拥有两者的优点。温度敏感型水凝胶是指随着外界温度的变化而产生刺激响应性的智能材料。温敏水凝胶还可控制药物释放，改变传统药物的缺点如药效短、药物浓度不能控制等，还可以感知外界温度，自动释放药物，能很好的控制药物浓度，使病灶部位的药物浓度一直处于有效浓度范围内。
公布号CN 101927030 A（申请号201010253355.3）的中国专利文献公开了一种含纳米银、锌、铋的生物敷料的制备方法，是用固相合成的方法合成壳聚糖和 / 或壳聚糖衍生物纳米银及锌、铋复合物，并溶于溶液中，加入适量甘油、胶原等，采用流延成膜法得到薄膜敷料，或通过冷冻干燥法得到海绵敷料。公布号CN 102492182 A（申请号201110402089.0）的中国专利文献公开了一种含稀土元素的壳聚糖和 / 或其衍生物生物薄膜，制备方法如下：（1）将壳聚糖和/ 或壳聚糖衍生物研磨为细粉；（2）按照壳聚糖和 /或壳聚糖衍生物与稀土化合物的重量比例100：0.5～10（优选100：2～8，更优选100：5），将步骤（1）所得细粉与稀土化合物细粉混匀，充分快速研磨1～ 3小时（优选1.5～2.5小时，更优选2小时），即得壳聚糖和 / 或其衍生物稀土复合物；（3）将步骤（2）所得细粉用蒸馏水或0.5-1.2% 的冰醋酸溶液配制成质量浓度为1-4%的壳聚糖和 / 或其衍生物稀土复合物溶液；（4）将步骤（3）所得溶液、鱼胶溶液与甘油按一定的体积比混匀，抽真空脱气；（5）将（4）所得混合液倒入平放的洁净玻璃板上，流延成薄膜，自然干燥，既得含稀土元素的壳聚糖和/ 或其衍生物生物薄膜。公布号CN 102358787 A（申请号201110311471.0）的中国专利文献公开了一种银、壳聚糖和 / 或其衍生物纳米复合物的固相合成法，制备方法：（1）将壳聚糖和 / 或壳聚糖衍生物研磨为细粉；（2）将硝酸银研磨成细粉；（3）将壳聚糖和 / 或壳聚糖衍生物细粉与硝酸银细粉混匀，充分研磨1～3小时，壳聚糖和 / 或壳聚糖衍生物与硝酸银的重量比例为100：0.0005～0.5；（4）将步骤（3）得到的细粉进一步研磨1～6小时，暴露于光源下24～48小时，即得银粒径为1～100nm的银、壳聚糖和 / 或壳聚糖衍生物纳米复合物。
壳聚糖/甘油磷酸钠凝胶系统的酸碱度与人体相似，通过药物比例的改变，可以使该凝胶系统的相转变温度维持在人体温度37℃左右，因此可利用该系统这样的特性，研制出一种抗炎杀菌的温敏水凝胶。
发明内容
针对现有技术的不足，本发明的目的是提供一种方法简单、产品安全的含有纳米银的医用温敏水凝胶的制备方法。
本发明的技术方案是:
一种含有纳米银的医用温敏水凝胶，主要由下列原料制备而成，均为质量份：壳聚糖细粉20，硝酸银0.01；步骤如下：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨1.5-2.5小时，出料，紫外灯下照射3-5小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至4-10℃制得样品溶液，在搅拌状态下，再滴加56%的β-甘油磷酸钠水溶液，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节至pH为6.80-7.00；
（3）将步骤（2）所得产物放入恒温水浴锅内加热，取出，即得水凝胶。
所述的制备方法，步骤（1）研磨转速为3000-5000转/分钟（优选的，转速为3500-4500转/分钟；更加优选的，转速为4000转/分钟）。
所述的制备方法，步骤（1）研磨1.8-2.2小时（优选的，研磨2小时）。
所述的制备方法，步骤（1）紫外灯下照射3.5-4.5小时（优选的，紫外灯下照射4小时）。
所述的制备方法，其特征在于，步骤（2）冰浴至5-9℃（优选的，冰浴至7℃）。
所述的制备方法，步骤（2）样品溶液的浓度为1%-3%（优选的，样品溶液的浓度为1.5-2.5%；更加优选的，样品溶液的浓度为2%）。
所述的制备方法，步骤（2）56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:8-12（优选的，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:9-11；更加优选的，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:10）。
所述的制备方法，步骤（2）调节pH为6.88-6.92（优选的，调节pH为6.90）。
所述的制备方法，步骤（2）搅拌状态下的转速为1000-1500转/分钟（优选的，转速为1100-1400转/分钟；更加优选的，转速为1300转/分钟）。
所述的制备方法，步骤（3）恒温水浴锅的温度为35-39℃（优选的，温度为36-38℃；更加优选的，温度为37℃）。
所述的制备方法，步骤（3）加热2-6分钟（优选的，加热3-5分钟；更加优选的，加热4分钟）。
本发明提供的一种含有纳米银的医用温敏水凝胶制备简单，保湿性好。除此之外，本发明的优良效果还表现在：
1、本发明所制产品具有纳米银和壳聚糖的特点和优势，不仅具备纳米银抗菌性，还具备壳聚糖促进细胞生长，减少疤痕生成的作用；
2、壳聚糖作为纳米银的分散剂和保护剂，使纳米银均匀、稳定的分布温敏水凝胶体系中；
3、含纳米银温敏水凝胶具有良好的保湿、透气性，且易降解，生物兼容性好，安全低毒。
具体实施方式
下面结合实施例和实验例详细说明本发明的技术方案，但保护范围不限于此。
实施例1 一种含有纳米银的医用温敏水凝胶，主要由下列原料制备而成（每份100g）：壳聚糖细粉20份，硝酸银0.01份。
一种含有纳米银的医用温敏水凝胶的制备方法是：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨1.5小时，转速为3000转/分钟，出料，紫外灯下照射3小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至4℃制得浓度为1%的样品溶液，在转速为1000转/分钟的搅拌状态下，再滴加56%的β-甘油磷酸钠水溶液，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:8，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节至pH为6.80；
（3）将步骤（2）所得产物放入35℃的恒温水浴锅内加热2分钟，取出，即得水凝胶。
实施例2 一种含有纳米银的医用温敏水凝胶，主要由下列原料制备而成（每份200g）：壳聚糖细粉20份，硝酸银0.01份。
一种含有纳米银的医用温敏水凝胶的制备方法是：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨2.5小时，转速为5000转/分钟，出料，紫外灯下照射5小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至10℃制得浓度为3%的样品溶液，在转速为1500转/分钟的搅拌状态下，再滴加56%的β-甘油磷酸钠水溶液，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:12，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节至pH为7.00；
（3）将步骤（2）所得产物放入39℃的恒温水浴锅内加热6分钟，取出，即得水凝胶。
实施例3 一种含有纳米银的医用温敏水凝胶，主要由下列原料制备而成（每份500g）：壳聚糖细粉20份，硝酸银0.01份。
一种含有纳米银的医用温敏水凝胶的制备方法是：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨1.8小时，转速为3500转/分钟，出料，紫外灯下照射3.5小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至5℃制得浓度为1.5%的样品溶液，在转速为1100转/分钟的搅拌状态下，再滴加56%的β-甘油磷酸钠水溶液，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:9，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节至pH为6.88；
（3）将步骤（2）所得产物放入36℃的恒温水浴锅内加热3分钟，取出，即得水凝胶。
实施例4 一种含有纳米银的医用温敏水凝胶，主要由下列原料制备而成（每份1kg）：
壳聚糖细粉20份，硝酸银0.01份。
一种含有纳米银的医用温敏水凝胶的制备方法是：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨2.2小时，转速为4500转/分钟，出料，紫外灯下照射4.5小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至9℃制得浓度为2.5%的样品溶液，在转速为1400转/分钟的搅拌状态下，再滴加56%的β-甘油磷酸钠水溶液，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:8，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节至pH为6.92；
（3）将步骤（2）所得产物放入38℃的恒温水浴锅内加热5分钟，取出，即得水凝胶。
实施例5 一种含有纳米银的医用温敏水凝胶，主要由下列原料制备而成（每份5kg）：
壳聚糖细粉20份，硝酸银0.01份。
一种含有纳米银的医用温敏水凝胶的制备方法是：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨2小时，转速为4000转/分钟，出料，紫外灯下照射4小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至7℃制得浓度为2%的样品溶液，在转速为1300转/分钟的搅拌状态下，再滴加56%的β-甘油磷酸钠水溶液，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:10，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节至pH为6.90；
（3）将步骤（2）所得产物放入37℃的恒温水浴锅内加热4分钟，取出，即得水凝胶。
试验例本发明所得一种含有纳米银的医用温敏水凝胶的初始凝胶化时间和抑菌活性的测定：
1、初始凝胶化时间的测定
将实施例1-5中步骤（2）所制产品分别转移至离心管内，放入37℃恒温水浴锅内，开始计时，每隔20s倾斜或倒转离心管，倒置30s后，溶液不再流动则判定形成凝胶，将该时间作为初始凝胶时间，分别测定记录各实施例初始凝胶化时间。
2、抑菌活性测定
试验菌株：①细菌：革兰氏染色阳性菌（G+）：金黄色葡萄球菌标准菌株ATCC25923（聊城市人民医院提供）。革兰氏染色阴性菌（G－）：大肠杆菌临床菌株、阴沟肠杆菌临床菌株、肺炎链球菌临床菌株、铜绿假单胞菌临床菌株（均由聊城市中医医院提供）、流感嗜血杆菌临床菌株（均由聊城市人民医院提供）；②真菌：白色念珠菌、光滑念珠菌（均由聊城市中医医院提供）。
试验方法：①对6种细菌的抑菌作用
将保存的各菌种分别进行活化培养，长出单菌落后，用接种环挑取少许菌体于装有9ml无菌生理盐水的试管内，振荡均匀，分别制备107 cfu/ml的悬浮液。在无菌条件下，在90mm的培养皿中加适量的培养基，凝固后加100微升菌液，涂布均匀，静置20-30min。将制备的样品，即壳聚糖温敏水凝胶、0.01%含纳米银的温敏水凝胶、0.025%含纳米银的温敏水凝胶、本发明所制产品（实施例5），分别做成直径为0.4cm的圆形，放置在同一固体培养基上，重复6次，在37℃的恒温培养箱中培养24h。观察样品与培养基的接触面有无细菌生长，并测量抑菌圈的大小，采用SPSS v11.5软件统计分析，数据以均数±标准差（x±S）表示。
②对2种真菌的抑菌作用
将保存的各菌种分别进行活化培养，分别制备浓度为1×106cfu/ml的菌液,其它操作同上，37℃的恒温培养箱中培养48h，观察样品与培养基的接触面有无细菌生长，测量抑菌圈的大小。采用SPSS软件统计分析，计量资料以均数±标准差（±S）表示。
试验结果：由表1可知，实施例5的初始凝胶化时间最短，说明壳聚糖交联的速度最快。同时由表2可知，四种样品对试验用细菌和真菌均有一定的接触抑菌作用且对细菌的抑制作用优于对真菌的抑制作用，其中本发明所制产品对真菌和细菌的抑菌作用均优于其他三个样品的，可见随着纳米银含量的增加，水凝胶的抑菌作用越好，因此，本发明所制产品具有较好的抑菌效果。
表1 不同实施例的初始凝胶化时间
表2 各样品对细菌和真菌的接触抑菌抑菌圈直径（±SD，单位：cm）
注：A：壳聚糖温敏水凝胶；B：0.01%含纳米银的温敏水凝胶；C：0.025%含纳米银的温敏水凝胶；D：本发明所制产品（实施例5）。
应当指出的是，具体实施方式只是本发明比较有代表性的例子，显然本发明的技术方案不限于上述实施例，还可以有很多变形。本领域的普通技术人员，以本发明所明确公开的或根据文件的书面描述毫无异议的得到的，均应认为是本专利所要保护的范围。
Claims (11)
1.一种含有纳米银的医用温敏水凝胶的制备方法，其特征在于，主要由下列原料制备而成，均为质量份：壳聚糖细粉20，硝酸银0.01；步骤如下：
（1）取壳聚糖细粉和硝酸银，置于研磨机内，高速研磨1.8-2.2小时，研磨转速为3000-5000转/分钟，出料，紫外灯下照射3.5-4.5小时，制得壳聚糖纳米银混合物；
（2）将步骤（1）所制混合物溶于0.1mol/L的醋酸水溶液中，搅拌至完全溶解后冰浴至5-9℃，制得样品溶液，样品溶液的浓度为1%-2%，在搅拌状态下，转速为1000-1500转/分钟，再滴加56%的β-甘油磷酸钠水溶液，56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:8-12，滴加完成后，再滴加饱和的磷酸氢二钠溶液，调节pH为6.88-6.92；
（3）将步骤（2）所得产物放入恒温水浴锅内加热，温度为35-39℃，初始凝胶化后恒温至形成凝胶，取出，即得水凝胶。
2.如权利要求1所述的制备方法，其特征在于，步骤（1）研磨转速为3500-4500转/分钟。
3.如权利要求1所述的制备方法，其特征在于，步骤（1）研磨转速为4000转/分钟。
4.如权利要求1所述的制备方法，其特征在于，步骤（1）研磨2小时。
5.如权利要求1所述的制备方法，其特征在于，步骤（1）紫外灯下照射4小时。
6.如权利要求1所述的制备方法，其特征在于，步骤（2）冰浴至7℃。
7.如权利要求1所述的制备方法，其特征在于，步骤（2）56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:9-11。
8.如权利要求1所述的制备方法，其特征在于，步骤（2）56%β-甘油磷酸钠水溶液与样品溶液的体积比为1:10。
9.如权利要求1所述的制备方法，其特征在于，步骤（2）调节pH为6.90。
10.如权利要求1所述的制备方法，其特征在于，步骤（2）搅拌状态下，转速为1100-1400转/分钟。
11.如权利要求1所述的制备方法，其特征在于，步骤（3）恒温水浴锅的温度为37℃。
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