CN106109447A - 一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法及其应用 - Google Patents
一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法及其应用 Download PDFInfo
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Abstract
一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法及其应用，能够可控缓释碱性成纤维细胞生长因子和左氧氟沙星，并达到各自的有效浓度，可在预防感染的同时，促进角膜上皮细胞的生长，复合膜规则的孔洞结构可为角膜上皮细胞的生长提供机械保护支架，并有利于营养物质及细胞代谢产物的流通，复合膜可减少光线的透过率，减少光线对受损角膜的刺激，该复合膜可用于外伤性、或角膜屈光手术等医源性角膜上皮缺损的愈合修复，减少角膜感染，提升患者依从性和诊疗体验。
Description
技术领域
本发明具体涉及药物制剂技术领域，具体涉及一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法及其应用。
背景技术
角膜病是致盲的重要原因之一，角膜上皮损伤导致屏障作用破坏是主要致盲角膜病发生的关键环节，目前治疗角膜上皮缺损主要有局部用药及局部保护。局部用药包括使用含有生长因子或者抗生素的滴眼液及眼用凝胶，由于自然瞬目，泪道的排出，以及角膜屏障作用，导致滴眼液及眼用凝胶的药物生物利用率极低。频繁的给药，使得患者在依从性上难以保证。同时随着给药次数的增多，药物进入全身血流增加，可引起全身的副作用。
局部保护措施主要包括绷带式角膜接触镜以及羊膜移植，但移植羊膜需要手术操作，患者的花费较大，而且对患者的外观及视力造成影响。角膜接触镜，由于透氧性能的限制，连续配戴可能引起角膜水肿，同时角膜接触镜会干扰其他药物的利用率，增加感染的风险。
因此，可以提高眼局部用药生物利用度，同时具有局部保护作用，并负载所需药物的缓释给药系统是一个非常值得研究和探索的领域，具有广阔前景。
左氧氟沙星作为喹诺酮类药物中的一种，是氧氟沙星的左旋光学异构体，具有广谱抗菌作用，对多数的革兰阳性菌和革兰阴性菌有较强的抗菌活性。目前，含有诺氟沙星或氧氟沙星等喹诺酮类药物的滴眼液，已广泛用于治疗眼部的细菌感染。
生长因子在角膜损伤修复中扮演重要角色，可调节角膜上皮和基质的增殖，并可对细胞外基质进行重塑。碱性成纤维细胞生长因子在1987年被首次发现，广泛分布由中胚层及神经外胚层发育而来的组织中，其产生的机制尚不明确，但其在细胞损伤时分泌增加。在眼表组织中，bFGF的分布极为广泛，分布在角膜上皮、基质及内皮，甚至也分布在房水中，对角膜细胞的增殖起着重要作用。
发明内容
针对现有技术的局限，本发明的提供了一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法及其应用，通过放置于角膜表面，缓释出复合膜内药物用于促进角膜上皮生长并预防感染。
本发明采用的技术解决方案是：一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜在角膜上皮损伤修复上的应用。
所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜与Ca2+离子离子交联后用于角膜上皮损伤的修复。
一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法，包括以下步骤：将海藻酸钠溶液与聚乙烯醇溶液按4-0.5∶1质量比混合，同时加入的负载生长因子溶液及左氧氟沙星溶液，搅拌6h后，使其完全混和均匀，随后倒入培养皿中平铺，烘干成膜，待复合膜干燥后，放置4℃条件下保存。
所述的海藻酸钠溶液与聚乙烯醇溶液的质量比为0.5∶1。
所述的烘干成膜的温度为37℃。
所述的培养皿直径为5.6cm。
本发明的工作原理为：聚乙烯醇分子和海藻酸钠分子通过氢键可以形成互穿网络聚合物结构，由于氢键的作用力相对较弱，水分子进入时可以将氢键撑断，从而使得复合膜发生水解。海藻酸钠分子由M片段和G片段组成，其中G片段可以和多价阳离子结合，形成蛋盒模型，这种结构可有效提高复合膜的稳定性。因此，制备出的复合膜需与氯化钙溶液交联，从而增强其稳定性。海藻酸钠与钙离子的交联是离子交联中的一种，二价以上的金属阳离子如Cu2+、Pb2+、Cd2+、Zn2+、Ca2+等极易与海藻酸古罗糖醛酸上的羧基发生静电相互作用，但此过程是可逆的，二价离子很容易与周围环境中的阳离子(如Na+，Mg2+)发生交换，而这过程是难以避免的，因此会逆向溶解。尽管Cu2+、Pb2+、Cd2+、Zn2+等离子都可以和海藻酸钠交联，但这些阳离子具有一定的生物毒性，因子限制了他们在医学领域的应用。而Ca2+无毒，交联后的Ca2+与泪液中的Na+及K+可发生置换，从而释放出Ca2+，钙离子可以促进角膜上皮的修复，对角膜具有重要意义，因此我们选用氯化钙作为交联剂。由于钙离子会与周围环境中的阳离子交换，因此SA/PVA复合膜是一种PH敏感性的复合膜，随着周边阳离子的增加，复合膜溶解的速率增加(如图1、图2所示)。
本发明的有益效果是：本发明提供了一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法及其应用，能够可控缓释碱性成纤维细胞生长因子和左氧氟沙星，并达到各自的有效浓度，可在预防感染的同时，促进角膜上皮细胞的生长，复合膜规则的孔洞结构可为角膜上皮细胞的生长提供机械保护支架，并有利于营养物质及细胞代谢产物的流通，复合膜可减少光线的透过率，减少光线对受损角膜的刺激，该复合膜可用于外伤性、或角膜屈光手术等医源性角膜上皮缺损的愈合修复，减少角膜感染，提升患者依从性和诊疗体验。
附图说明
图1为本发明原理流程图。
图2为本发明原理流程图。
图3为紫外可见近红外分光光度仪对载药及空白复合膜的透光率进行测试结果图。
图4为将质量比SA∶PVA＝0.5∶1的复合膜与氯化钙溶液交联后进行透光率检测结果图。
图5为不同质量比复合膜表面扫描电镜图。
图6为不同质量比复合膜断面扫描电镜图。
图7为不同质量比复合膜Ca2+交联后表面扫描电镜图。
图8为不同质量比复合膜Ca2+交联后断面扫描电镜图。
图9为载药复合膜各时间点左氧氟沙星释放浓度曲线图。
图10为载药复合膜各时间点生长因子体外释放曲线图。
具体实施方式
一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法，包括以下步骤：将海藻酸钠溶液与聚乙烯醇溶液按4-0.5∶1质量比混合，同时加入的负载生长因子溶液及左氧氟沙星溶液，搅拌6h后，使其完全混和均匀，随后倒入直径5.6cm的培养皿中平铺，放入37℃烘箱中，烘干成膜，待复合膜干燥后，放置4℃冰箱中保存。
(1)根据所述的方法制备负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜，采用紫外可见近红外分光光度仪对载药及空白复合膜的透光率进行测试。所得结果如图3所示：从透光率结果可以看出，聚乙烯醇的含量越高，复合膜的透光性越强，同时载药复合膜对紫外光有较强的吸收作用。因此当质量比SA∶PVA＝0.5∶1时，复合膜的透光率相对高于其他质量比复合膜的透光率。
(2)将质量比SA∶PVA＝0.5∶1的复合膜与氯化钙溶液交联后进行透光率检测。结果如图4所示：从图中可以看出，载药复合膜的透光率相对较低，这可以减轻光线对角膜上皮缺损的刺激作用。
(3)将不同质量比的复合膜，经表面喷金后，用扫描电镜观察其表面及断面结构。结果如图5、图6所示，其中图中放大倍率均为4000倍，图中A代表质量比SA∶PVA＝4，B代表质量比SA∶PVA＝2，C代表质量比SA∶PVA＝1，D代表质量比SA∶PVA＝0.5。E代表质量比SA∶PVA＝4，F代表质量比SA∶PVA＝2，G代表质量比SA∶PVA＝1，H代表质量比SA∶PVA＝0.5.从电镜结果可以看出质量比不同的SA/PVA复合膜都具有相对光滑的表面，其中SA与PVA质量比＝0.5∶1时复合膜具有最光滑的表面。由此可以看出复合膜中SA与PVA均匀混合。不同质量比的复合膜微观结构均一，未出现明显的分离，同时均有孔洞结构，当质量比SA∶PVA＝0.5时，复合膜结构最为归整，孔洞细致，形似蜂窝状。
(4)将不同质量比的复合膜交联后，用扫描电镜观察其表面及断面结构。结果如图7、图8所示，其中图中放大倍率均为4000倍，其中I代表质量比SA∶PVA＝4，J代表质量比SA∶PVA＝2，K代表质量比SA∶PVA＝1，L代表质量比SA∶PVA＝0.5，M代表质量比SA∶PVA＝4，N代表质量比SA∶PVA＝2，0代表质量比SA∶PVA＝1，P代表质量比SA∶PVA＝0.5。从电镜结果可以看出，交联后复合膜结构变得更加致密，并未出现明显的断裂现象。横断面电镜结果可以看出，当质量比SA∶PVA＝1时复合膜开始出现较大的孔洞，当质量比SA∶PVA＝0.5时，复合膜的孔洞最大，并分布均匀，这种结构有利于营养物质的流通以及细胞代谢产物的排出。
(5)将载药复合膜各取3片，直径10mm，与氯化钙溶液交联后置于5mlFP管中，加入4ml去离子水，放入37℃摇床中模拟体内环境，摇床以每分钟100圈的速度运行。每个样本于0.5h，1h，2h，3h，6h，12h，24h，36h，48h及72h取样，完全取出FP管中去离子，同时置换入新鲜的去离子水4mL，收集的样品4℃冰箱保存。一部分溶液使用紫外分光光度法侧定左氧氟沙星浓度，另一部分，使用双抗体夹心ABC-ELISA法测定bFGF含量。
体外释放结果：
载药复合膜各时间点左氧氟沙星释放浓度
绘制左氧氟沙星释放曲线，如图9所示，图中数据点表示平均数±标准差，n＝3。
bFGF的体外释放结果：
绘制bFGF体外释放曲线，如图10所示，图中各数据点表示平均值±标准差，n＝3。
由载药SA/PVA复合膜的左氧氟沙星的释放中可以发现，各复合膜具有相似的释放规律，在前3个小时有突释现象，随着时间的推移逐渐变得平缓，在72小时仍有药物的释放。72小时后，左氧氟沙星的浓度依然在0.05ug/mL以上。采用单因素方差分析统计，P>0.5，均无统计学意义。
而复合膜的bFGF的释放无明显突释现象，并可缓慢释放72h。随着时间的推移，bFGF的浓度未见明显减少，原因考虑为bFGF是大分子物质，相对不易从复合膜的孔隙中流出，而随着SA遇水溶解，孔隙结构的破坏，bFGF随之释放。经过72小时的释放，bFGF的浓度保持在5pg/mL以上。采用单因素方差分析统计，P>0.5，均无统计学意义。
综上所述，SA/PVA复合膜是左氧氟沙星和bFGF理想的缓释载体，复合膜不同的质量比对其缓释效果无明显影响。但质量比SA∶PVA＝0.5时，复合膜结构最为规整，孔洞直径最大，孔壁较薄，形似蜂窝状。同时载药复合膜的透光率相对较低，可有效减轻光线对角膜上皮缺损的刺激。
以上所述仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.一种负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法，其特征在于，包括以下步骤：将海藻酸钠溶液与聚乙烯醇溶液按4-0.5∶1质量比混合，同时加入的负载生长因子溶液及左氧氟沙星溶液，搅拌6h后，使其完全混和均匀，随后倒入培养皿中平铺，烘干成膜，待复合膜干燥后，放置4℃条件下保存。
2.根据权利要求1所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法，其特征在于，所述的海藻酸钠溶液与聚乙烯醇溶液的质量比为0.5∶1。
3.根据权利要求1所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法，其特征在于，所述的烘干成膜的温度为37℃。
4.根据权利要求1所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜的制备方法，其特征在于，所述的培养皿直径为5.6cm。
5.一种权利要求1所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜在角膜上皮损伤修复上的应用。
6.根据权利要求5所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜在角膜上皮损伤修复上的应用，其特征在于，所述的负载生长因子和左氧氟沙星的海藻酸钠/聚乙烯醇复合膜与Ca2+离子离子交联后用于角膜上皮损伤的修复。
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