CN105497087A - 负载三七纳米氧化锌缓释凝胶及其制备方法和应用 - Google Patents
负载三七纳米氧化锌缓释凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了负载三七纳米氧化锌缓释凝胶及其制备方法和应用，以聚丙烯酰胺或聚乙烯醇为凝胶基质材料，结合纳米氧化锌及中药三七制备中西药联用的缓释凝胶；其组分为：三七粉、纳米金属氧化锌、凝胶基质材料、水溶性壳聚糖、保湿剂；其中，纳米氧化锌作为靶向药物的有效载体，将中药三七输送到特定靶组织，同时纳米氧化锌和三七起协同作用，从多种机制治疗干槽症，增强药效的同时减少药物副作用，具有缓释、靶向、生物利用度高等特点。
Description
技术领域
本发明涉及纳米材料与抗菌止血药物协同作用的临床研究，用于治疗口腔疾病，特别用于治疗干槽症。
背景技术
干槽症是下颌阻生智齿拔除后常见的一种手术并发症。多数学者认为创伤和感染是引起该病的主要病因。关于本病的细菌感染，多认为是以链球菌及革兰阴性杆菌为主的需氧菌和厌氧菌混合感染。由于没有治疗干槽症的特效药物，临床上一般由医生自行决定治疗方案。常见的预防干槽症方法及其不足：
(1)应用碘仿、碘伏、甲硝唑等置于拔牙创内，虽然这些药物具有抗菌谱广、稳定性好、甚至促进肉芽组织生长等优点，但异味较深，患者易感到不适而漱口导致血凝块脱落，增加感染及形成干槽症的机会。
(2)常用的止血粉，往往存在着高温高压消毒后变质问题，且多数止血粉溶解性较差，不易被机体吸收，异物反应较大。
(3)明胶海绵具有可被机体吸收的优点，但其主要成分是蛋白质，在口腔内有菌环境中极易腐败，导致感染或干槽症。据文献记载，在下领阻生齿拔除后，应用明胶海绵的干槽症率高达24.1％。另外，明胶海绵粘度较差，易脱落，影响血块丰满性。
(4)进口的氧化纤维素具有止血快，异物反应小等优点，但价格昂贵，不宜广泛使用。
因此寻求异物反应小、止血迅速、易于推广使用的新型干槽症预防治疗药物，是医学上急待解决的问题。
发明内容
本发明所解决的技术问题是提供一种治疗干槽症的负载三七纳米氧化锌缓释凝胶及其制备方法和应用。
本发明的技术方案如下：
一种负载三七纳米氧化锌缓释凝胶的制备方法，以聚丙烯酰胺或聚乙烯醇为凝胶基质材料，结合纳米氧化锌及中药三七制备中西药联用的缓释凝胶；其组分为：三七粉、纳米金属氧化锌、凝胶基质材料、水溶性壳聚糖、保湿剂；重量百分比为：三七粉0.1％～1.0％(W/W)，纳米金属氧化锌0.2％～0.8％(W/W)，凝胶基质材料84％～90％(W/W)，水溶性壳聚糖5％～10％(W/W)，保湿剂2.5％～5％(W/W)。
所述的制备方法，所述保湿剂为甘油、丙二醇中的一种或多种。
所述的制备方法，所述负载三七纳米氧化锌缓释凝胶制备步骤如下：
1)先辐射后冻融的方法制备聚丙烯酰胺(PAM)/水溶性壳聚糖水凝胶；
2)反胶束法制备纳米氧化锌，粒径保持在20～200纳米；
3)先超声后冷冻干燥制备负载三七氧化锌的纳米粒子；
4)溶剂挥发法将负载三七氧化锌的纳米粒子制备水凝胶。
所述的制备方法，聚丙烯酰胺(PAM)/水溶性壳聚糖水凝胶的制备方法如下：将聚丙烯酰胺按照1∶20g/ml的比例浸泡于蒸馏水中，重复三次，于95℃恒温回流3h至聚合物完全溶解；将冷却后的聚丙烯酰胺溶液与所述水溶性壳聚糖和所述保湿剂混合，机械搅拌30min，之后在超声波清洗器中超声15min去泡，将所得溶液倒入塑料培养皿中静置，采用先紫外辐射后冻融法制备水凝胶：辐照在氮气气氛下进行，剂量分别为40和60kGy，剂量率为0.76kGy/h；将辐照得到的水凝胶再进行循环冷冻融化处理1～2次，冷冻温度为20℃，冷冻时间为15h；室温下融化，融化时间为1h。
所述的制备方法，纳米氧化锌的制备方法如下：精确配置1mol/L的乙酸锌水溶液待用；然后，称量0.3644g的十六烷基三甲基溴化铵(CTAB)，加入到10ml的环己烷中；随后向溶液中精确滴加5ml的异丙醇(IPA)，持续搅拌至形成均匀的乳白色乳液；保持搅拌的状态，向溶液中缓慢滴加之前配置的乙酸锌水溶液，直到溶液体系瞬间澄清；继续滴加剩余乙酸锌水溶液，该透明状态仍会在一定范围内保持澄清；3000～4000rpm旋转离心得纳米氧化锌颗粒，粒径保持在20～200纳米。
所述的制备方法，负载三七氧化锌的纳米粒子的制备方法如下：按照丙酮/甲醇体积比1∶1配制混合溶剂，将纳米氧化锌粒子超声分散在混合溶剂中，待充分溶解后，加入三七粉超声溶解，于37℃下缓慢滴入含有少量三乙胺的去离子水，通过减压旋转蒸馏除掉丙酮和甲醇；在8000rpm转速下离心10min，用去离子水洗涤3次除去游离的药物，然后冷冻干燥得到负载三七氧化锌纳米粒子；混合溶剂体积(ml)∶纳米氧化锌粒子质量(mg)∶三七粉质量(mg)∶去离子水体积(ml)＝1∶1-2∶1-2∶8-10。
所述的制备方法，负载三七纳米氧化锌的聚丙烯酰胺/水溶性壳聚糖水凝胶制备方法：将三七氧化锌纳米粒子加入二氯甲烷中，三七氧化锌纳米粒子(mg)∶二氯甲烷(ml)＝3∶1-5，超声充分溶解，立即将所得溶液滴加到机械搅拌下的2.5％聚丙烯酰胺/水溶性壳聚糖水凝胶溶液中；滴加完继续搅拌2分钟，然后在250W下冰浴超声10分钟，转到紫外灯下进行辐射；1小时后，关掉紫外灯，继续搅拌2小时，以挥发完二氯甲烷，得载三七氧化锌的纳米粒混悬液；将所得纳米粒混悬液先于1000rpm下低速离心除去未载入的药物沉淀，再20000rpm高速离心30分钟，沉淀用蒸馏水洗涤3次；将所得到的沉淀超声分散在蒸馏水中，加入甘露醇，沉淀(mg)∶蒸馏水(ml)∶甘露醇(ml)＝1∶1-2∶0.5，冷冻干燥48小时得载三七纳米氧化锌凝胶。
用任一所述的制备方法制备的负载三七纳米氧化锌缓释凝胶。
所述的负载三七纳米氧化锌缓释凝胶在制备治疗干槽症药物中的应用。
本发明与现有技术相比具有以下优点：
(1)水凝胶包埋药物后，通过喷剂的方式直接进入牙槽内，在药物扩散出凝胶和凝胶降解双重作用下，可以长效发挥作用，并调节药物从凝胶中的释放过程，又能起到促进分解，还能遮蔽医药品的苦味和气味。(2)凝胶能较长时间地和用药部位紧密接触，有较好的生物黏附性，从而提高生物利用度。组织相容性好.使用方便，减少了给药频率。(3)凝胶三维网状结构高度亲水.可将所载的药物束缚于其中或者间隙中.实现药物控释。(4)发挥表面效应和纳米效应。药物的粒径降低使其穿透生理组织屏障能力和渗透力增强，比表面积增大，药物与介质的有效接触面积增加，提高药物的溶出度和溶出速度。使用较小剂量的纳米化活性物质，就能达到高剂量非纳米化时使用量的效果，可在保证药物作用的前提下，减少给药量，从而减轻或避免毒副作用。
附图说明
图1为本发明中西药联用纳米缓释凝胶的抑菌性能测试；
图2是本发明的中西药联用纳米缓释凝胶的对金黄色葡萄球菌(Staphylococcusaureus)抑菌性能测试对照实验。
具体实施方式
以下结合具体实施例，对本发明进行详细说明。
实施例1：负载三七纳米氧化锌凝胶的制备
一、聚丙烯酰胺/水溶性壳聚糖水凝胶的制备
将聚丙烯酰胺1g浸泡于20ml蒸馏水中，重复三次，于95℃恒温回流3h至聚合物完全溶解将冷却后的聚丙烯酰胺与0.125g水溶性壳聚糖和5ml甘油混合，机械搅拌30min，之后在超声波清洗器中超声15min去泡，将所得溶液倒入塑料培养皿中静置(厚度约为3mm)，此时溶液中水溶性壳聚糖和甘油的含量分别为2wt％和1wt％，聚丙烯酰胺的含量为9wt％。采用先紫外辐射后冻融法制备水凝胶。辐照在氮气气氛下进行，剂量分别为40和60kGy，剂量率为0.76kGyh；将辐照得到的水凝胶再进行循环冷冻融化处理1～2次，冷冻温度为20℃，冷冻时间为15h；室温下融化，融化时间为1h。凝胶放入冰箱冷藏备用。
二、纳米氧化锌的制备
十六烷基三甲基溴化铵(CTAB)0.3644g、环己烷10ml置于反应瓶中，精确滴加异丙醇(IPA)5ml，室温搅拌至形成均匀的乳白色乳液；保持搅拌的状态，向溶液中缓慢滴加1mol/L的乙酸锌水溶液，直到溶液体系瞬间澄清。3000～4000rpm旋转离心得纳米氧化锌粒子，粒径保持在20～200纳米。
三、负载三七氧化锌纳米粒子的制备
将20mg纳米氧化锌粒子超声分散在24mL丙酮/甲醇(体积比1∶1)混合溶剂中，加入24mg三七超细粉超声溶解，于37℃下缓慢滴入200mL含有少量三乙胺的去离子水，通过减压旋转蒸馏除掉丙酮和甲醇。在8000pm转速下离心10min，用去离子水洗涤3次除去游离的药物，然后冷冻干燥得到负载三七氧化锌纳米粒子。
四、负载三七纳米氧化锌凝胶的制备
将30mg三七氧化锌纳米粒子加入10ml二氯甲烷中超声溶解，立即将上述超声溶解后的溶液滴加于机械搅拌下的2.5％的聚丙烯酰胺水溶性壳聚糖水凝胶中。滴加完继续搅拌2分钟，然后在250W超声下冰浴10分钟，转到紫外灯下进行辐射1小时后，继续搅拌2小时，以挥干二氯甲烷，得载三七氧化锌的纳米粒子混悬液。将所得纳米粒混悬液先于1000rpm下低速离心除去未载入的药物沉淀，再20000rpm高速离心30分钟，沉淀用蒸馏水洗涤3次。将所得到的沉淀超声分散在10ml蒸馏水中，加入3ml甘露醇，冷冻干燥48小时得负载三七纳米氧化锌凝胶。
抑菌性能测试：将四种不同的菌接种到琼脂平板上，用直径为4mm的打孔器在每个营养琼脂平板上均匀打出4个孔。用微量移液器加入25μl配置好的不同纳米氧化锌含量的凝胶(米诺环素浓度为5μg/mL)。静置，倒置培养皿于37℃培养24h后，用游标卡尺测量抑菌直径。抑菌圈直径/mm＝总抑菌直径-孔直径(4mm)。
如图1所示，本发明的中西药联用纳米缓释凝胶的抑菌性能测试结果，抑菌圈直径大于7mm视为有抑菌活性。由结果能看出凝胶的抑菌能力随纳米氧化锌含量增加逐步增大，当纳米氧化锌含量大于0.6％时抑菌能力较为稳定。
图2是本发明的中西药联用纳米缓释凝胶的对金黄色葡萄球菌(Staphylococcusaureus)抑菌性能测试对照实验。从实验结果可以看出加入氧化锌以后，凝胶的抑菌效果成倍增加，优于三七单独使用的效果(凝胶中三七含量均为0.1％，纳米氧化锌含量为0.6％)。
表1是本发明的中西药联用纳米缓释凝胶的临床疗效：治疗组外用中西药联用纳米缓释凝胶(含氧化锌纳米粒质量分数为0.6％，三七含量为0.1％)，30mg/次；对照组碘仿纱条50mg/次；空白组外用空白卡波姆胶，30mg/次，均为日一次。连续治疗7天，观察到新鲜肉芽组织产生即为有效。
表1中西药联用纳米缓释凝胶的临床对照实验
应当理解的是，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，而所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (9)
1.一种负载三七纳米氧化锌缓释凝胶的制备方法，其特征在于：以聚丙烯酰胺或聚乙烯醇为凝胶基质材料，结合纳米氧化锌及中药三七制备中西药联用的缓释凝胶；其组分为：三七粉、纳米金属氧化锌、凝胶基质材料、水溶性壳聚糖、保湿剂；重量百分比为：三七粉0.1％～1.0％(W/W)，纳米金属氧化锌0.2％～0.8％(W/W)，凝胶基质材料84％～90％(W/W)，水溶性壳聚糖5％～10％(W/W)，保湿剂2.5％～5％(W/W)。
2.根据权利要求1所述的制备方法，其特征在于：所述保湿剂为甘油、丙二醇中的一种或多种。
3.根据权利要求1所述的制备方法，其特征在于：所述负载三七纳米氧化锌缓释凝胶制备步骤如下：
1)先辐射后冻融的方法制备聚丙烯酰胺(PAM)/水溶性壳聚糖水凝胶；
2)反胶束法制备纳米氧化锌，粒径保持在20～200纳米；
3)先超声后冷冻干燥制备负载三七氧化锌的纳米粒子；
4)溶剂挥发法将负载三七氧化锌的纳米粒子制备水凝胶。
4.根据权利要求3所述的制备方法，其特征在于：聚丙烯酰胺(PAM)/水溶性壳聚糖水凝胶的制备方法如下：将聚丙烯酰胺按照1∶20g/ml的比例浸泡于蒸馏水中，重复三次，于95℃恒温回流3h至聚合物完全溶解；将冷却后的聚丙烯酰胺溶液与所述水溶性壳聚糖和所述保湿剂混合，机械搅拌30min，之后在超声波清洗器中超声15min去泡，将所得溶液倒入塑料培养皿中静置，采用先紫外辐射后冻融法制备水凝胶：辐照在氮气气氛下进行，剂量分别为40和60kGy，剂量率为0.76kGy/h；将辐照得到的水凝胶再进行循环冷冻融化处理1～2次，冷冻温度为20℃，冷冻时间为15h；室温下融化，融化时间为1h。
5.根据权利要求3所述的制备方法，其特征在于：纳米氧化锌的制备方法如下：精确配置1mol/L的乙酸锌水溶液待用；然后，称量0.3644g的十六烷基三甲基溴化铵(CTAB)，加入到10ml的环己烷中；随后向溶液中精确滴加5ml的异丙醇(IPA)，持续搅拌至形成均匀的乳白色乳液；保持搅拌的状态，向溶液中缓慢滴加之前配置的乙酸锌水溶液，直到溶液体系瞬间澄清；继续滴加剩余乙酸锌水溶液，该透明状态仍会在一定范围内保持澄清；3000～4000rpm旋转离心得纳米氧化锌颗粒，粒径保持在20～200纳米。
6.根据权利要求3所述的制备方法，其特征在于：负载三七氧化锌的纳米粒子的制备方法如下：按照丙酮/甲醇体积比1∶1配制混合溶剂，将纳米氧化锌粒子超声分散在混合溶剂中，待充分溶解后，加入三七粉超声溶解，于37℃下缓慢滴入含有少量三乙胺的去离子水，通过减压旋转蒸馏除掉丙酮和甲醇；在8000rpm转速下离心10min，用去离子水洗涤3次除去游离的药物，然后冷冻干燥得到负载三七氧化锌纳米粒子；混合溶剂体积(ml)∶纳米氧化锌粒子质量(mg)∶三七粉质量(mg)∶去离子水体积(ml)＝1∶1-2∶1-2∶8-10。
7.根据权利要求3所述的制备方法，其特征在于：负载三七纳米氧化锌的聚丙烯酰胺/水溶性壳聚糖水凝胶制备方法：将三七氧化锌纳米粒子加入二氯甲烷中，三七氧化锌纳米粒子(mg)∶二氯甲烷(ml)＝3∶1-5，超声充分溶解，立即将所得溶液滴加到机械搅拌下的2.5％聚丙烯酰胺/水溶性壳聚糖水凝胶溶液中；滴加完继续搅拌2分钟，然后在250W下冰浴超声10分钟，转到紫外灯下进行辐射；1小时后，关掉紫外灯，继续搅拌2小时，以挥发完二氯甲烷，得载三七氧化锌的纳米粒混悬液；将所得纳米粒混悬液先于1000rpm下低速离心除去未载入的药物沉淀，再20000rpm高速离心30分钟，沉淀用蒸馏水洗涤3次；将所得到的沉淀超声分散在蒸馏水中，加入甘露醇，沉淀(mg)∶蒸馏水(ml)∶甘露醇(ml)＝1∶1-2∶0.5，冷冻干燥48小时得载三七纳米氧化锌凝胶。
8.用权利要求1-7任一所述制备方法制备的负载三七纳米氧化锌缓释凝胶。
9.权利要求8所述的负载三七纳米氧化锌缓释凝胶在制备治疗干槽症药物中的应用。
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| CN110354071A (zh) * | 2019-07-26 | 2019-10-22 | 西南交通大学 | 一种包载十八味党参丸的水凝胶及其制备方法 |
| CN111658816A (zh) * | 2020-05-07 | 2020-09-15 | 广州贝奥吉因生物科技股份有限公司 | 一种载药金属纳米颗粒/壳聚糖控释水凝胶及其制备方法与应用 |
| CN114573015A (zh) * | 2022-03-18 | 2022-06-03 | 上海健康医学院 | 一种纳米氧化锌复合抗菌剂分散液及其制备方法 |
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| CN104874009A (zh) * | 2015-05-22 | 2015-09-02 | 苏州市贝克生物科技有限公司 | 一种医用抗菌凝胶材料的制备方法 |
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| CN104874009A (zh) * | 2015-05-22 | 2015-09-02 | 苏州市贝克生物科技有限公司 | 一种医用抗菌凝胶材料的制备方法 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176940A (zh) * | 2016-08-22 | 2016-12-07 | 新乡医学院 | 一种中药肠溶性胶囊及其制备工艺 |
| WO2018095067A1 (zh) * | 2016-11-23 | 2018-05-31 | 佛山科学技术学院 | 吡非尼酮pva水凝胶的制备方法及吡非尼酮pva水凝胶 |
| CN110354071A (zh) * | 2019-07-26 | 2019-10-22 | 西南交通大学 | 一种包载十八味党参丸的水凝胶及其制备方法 |
| CN111658816A (zh) * | 2020-05-07 | 2020-09-15 | 广州贝奥吉因生物科技股份有限公司 | 一种载药金属纳米颗粒/壳聚糖控释水凝胶及其制备方法与应用 |
| CN114573015A (zh) * | 2022-03-18 | 2022-06-03 | 上海健康医学院 | 一种纳米氧化锌复合抗菌剂分散液及其制备方法 |
| CN114573015B (zh) * | 2022-03-18 | 2023-10-27 | 上海健康医学院 | 一种纳米氧化锌复合抗菌剂分散液及其制备方法 |
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