CN108744014B - 一种具有缓释作用抗菌敷料的制备方法及其产品 - Google Patents
一种具有缓释作用抗菌敷料的制备方法及其产品 Download PDFInfo
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Abstract
本发明提供一种具有缓释作用抗菌敷料的制备方法及其产品,其制备方法包括:(1)将羧甲基壳聚糖、大分子胶原蛋白、含羧基抗生素混合;(2)再将混合液倒入模具中,静置,干燥,得到未交联的海绵状材料;(3)将未交联的海绵状材料浸泡于含EDC/NHS的无水乙醇溶液中,室温交联,得到抗菌敷料。本发明利用抗生素上的羧基与复合型敷料基质上的氨基共价键合形成酰胺键的方式实现抗生素接枝于敷料基质上,并通过聚合物骨架上酰胺键的缓慢断裂实现敷料中抗生素的缓慢释放,从而制得具有较高生物相容性、长期抗菌活性、促进伤口愈合的抗菌敷料。
Description
技术领域
本发明涉及创伤敷料,尤其是一种具有缓释作用抗菌敷料的制备方法及其产品。
背景技术
为了避免伤口感染,创伤敷料应具有良好的抗菌活性。理想的抗菌敷料能够有效杀死伤口感染中的细菌或真菌,阻止细菌生物膜形成,并防止伤口在愈合、伤口检查、外科手术或换药过程中的再感染。然而,目前常用的抗菌敷料制备方法是通过物理混合小分子药物在材料中(例如授权公告号为CN201337582的中国专利公布了一种将环丙沙星通过物理混合的方式加入到壳聚糖胶液中来制备壳聚糖杀菌敷料的方法),其为伤口感染的治疗提供了一种可行的选择。然而,由于该种抗菌敷料上的抗菌药物通常在48小时内就会释放完,导致伤口组织部位短时间内抗菌药物浓度过高,抗菌药物进一步进入体内,对重要器官造成负面影响;并且,由于这些抗菌敷料的抗菌效力维持时间不超过48小时,就需要通过频繁更换敷料来维持对伤口部位的抗菌效力,增加了护理成本和患者痛苦。因此迫切需求开发一种具有长期抗菌活性的创伤敷料。
近年来,采用纳米尺寸抗菌材料制备的具有长期抗菌活性的抗菌敷料也获得了越来越多的关注。例如,采用纳米银、纳米金属氧化物、碳纳米管等制备的复合敷料具有显著的抗菌和抗炎作用,并具备长期的抗菌活性(具体参考文献为:Mosselhy D A, GranbohmH, Hynönen U, et al. Nanosilver-silica composite: Prolonged antibacterialeffects and bacterial interaction mechanisms for wound dressings [J].Nanomaterials, 2017, 7(9);Díezpascual A M, Díezvicente A L. Wound healingbionanocomposites based on castor oil polymeric films reinforced withchitosan-modified zno nanoparticles [J]. Biomacromolecules, 2015, 16(9):2631-2644;Chen Y, Xu P, Wu M, et al. Colloidal rbc-shaped, hydrophilic, andhollow mesoporous carbon nanocapsules for highly efficient biomedicalengineering [J]. Advanced Materials, 2014, 26(25): 4294)。然而,这些纳米材料的毒性不容忽视,研究表明纳米银对脾脏、肝脏和肾脏等多种器官均有明显的损害。纳米金属氧化物可引起器官损伤、渗透调节改变和免疫紊乱。此外,据报道,碳纳米管可以很容易地刺穿细胞,并可诱导促炎细胞因子的释放。因此,制备具有高生物相容性和长期抗菌活性的创伤敷料仍是临床应用的迫切要求。
发明内容
本发明的目的之一在于提供一种具有缓释作用抗菌敷料的制备方法,通过该制备方法制得的抗菌敷料产品不仅具有较高的生物相容性,而且同时具备长期抗菌活性和促进伤口愈合的功能。
为实现上述目的,本发明采用如下技术手段:
一种具有缓释作用抗菌敷料的制备方法,包括以下步骤:
(1)将羧甲基壳聚糖、大分子胶原蛋白、含羧基抗生素溶于去离子水中,搅拌均匀,得到混合液,混合液中羧甲基壳聚糖与大分子胶原蛋白的质量比为0.75~2.5: 1,含羧基抗生素的浓度为0.5~1 mmol/L;
(2)再将步骤(1)得到的混合液倒入模具中,静置去泡,冷冻干燥,干燥后得到未交联的海绵状材料;
(3)将步骤(2)得到的未交联的海绵状材料浸泡于含EDC/NHS的无水乙醇溶液中,EDC的用量以EDC的摩尔量相对于混合物中羧基的总摩尔量过量为准,室温条件下交联反应18-24h,弃去多余的交联溶液,清洗3~5次,去除多余的交联剂,再次冷冻干燥后得到复合交联海绵敷料,即抗菌敷料。
所述大分子胶原蛋白采用分子量为80-100 KDa的胶原蛋白。
所述的含羧基抗生素优选盐酸环丙沙星。盐酸环丙沙星作为新一代的氟喹诺酮类合成抗菌药,其抗菌活性高、口服吸收完全、体内分布广泛,且不易产生耐药性,其在体外具良好的抗菌作用。此外,盐酸环丙沙星在271 nm波长紫外光下有吸收峰,方便对药物的检测和缓释性能的测定。
所述的步骤(3)中EDC的用量优选为EDC与羧甲基壳聚糖的质量比为:1.6~2.88:1。此时,交联物的稳定性好。
所述的步骤(3)中EDC与NHS的摩尔比优选为4:1。
所述的步骤(2)中静置去泡后的混合液,进行密封,并对混合液进行预冻使之固化;然后再进行冷冻干燥。在对混合液进行冷冻干燥之前,先将混合液密封、缓慢预冻,可有效避免混合液表面失水过快和冰晶大量产生,导致表面出现裂纹,从而影响产品表面的平整度。
所述的模具优选采用聚氟乙烯材质的模具。此模具与产品之间不易发生粘连,利于脱模,同时由于产品边缘和底部比较平整,提高了出产率;另,在同等条件下,与铁制模具或玻璃模具相比,采用聚氟乙烯材质的模具制作的产品的孔隙较大,对伤口愈合更有利。
本发明的另一目的在于提供一种根据上述具有缓释作用抗菌敷料的制备方法制得的抗菌敷料。
本发明以天然高分子材料——羧甲基壳聚糖和大分子胶原蛋白为基质材料,通过EDC/NHS使羧甲基壳聚糖和大分子胶原蛋白上的羧基与氨基进行共价键合实现两者的交联从而形成复合型敷料基质,同时,通过EDC/NHS使含羧基抗生素上的羧基与该复合型敷料基质上的氨基共价键合形成酰胺键实现抗生素接枝于复合型敷料基质上,制得一种新型抗菌敷料。该新型抗菌敷料具有如下优点:
(1)本发明的经交联后的敷料形成不溶于水却能溶胀吸收大量液体的三维网状聚合结构;其具有良好的吸水率、水蒸气透过率和机械强度;
(2)本发明所制得的抗菌敷料的基质材料——羧甲基壳聚糖和大分子胶原蛋白均为具有良好生物相容性的天然高分子材料,使得本发明所制得的新型抗菌敷料无细胞毒性,生物相容性较好,并且在试验中还发现:本发明所制得的抗菌敷料能有效提高细胞黏附与增殖;
(3)本发明所制得的抗菌敷料通过酰胺键的缓慢断裂,实现了抗生素在复合型敷料基质上的释放,达到了长期抗菌的效果,避免了频繁更换伤口处敷料对伤口愈合造成的不利影响,同时,又防止了抗菌敷料中药物的爆裂释放对身体产生不利影响;
(4)本发明人建立了SD大鼠全层皮肤伤口模型,在SD大鼠全层皮肤伤口感染模型中,将本发明制备的抗菌敷料用于大鼠伤口的修复实验中,发现:本发明的抗菌敷料显示出良好的再上皮化、致密胶原沉积和血管生成的特征。
附图说明
图1为本发明步骤(2)得到的未交联的海绵状材料的表面微观形貌;
图2为本发明所制得的抗菌敷料的表面微观形貌;
图3为本发明步骤(2)得到的未交联的海绵状材料的纵向断面微观形貌;
图4为本发明所制得的抗菌敷料的纵向断面微观形貌;
图5为本发明所制得的抗菌敷料的产品图片。
具体实施方式
现具体阐述本发明的较优实施方式。
实施例
一种具有缓释作用的抗菌敷料的制备方法,包括以下步骤:
(1)将羧甲基壳聚糖、大分子胶原蛋白、含羧基抗生素溶于去离子水中,搅拌均匀,得到混合液,混合液中羧甲基壳聚糖与大分子胶原蛋白的质量比为0.75~2.5: 1,含羧基抗生素的浓度为0.5~1 mmol/L;
(2)再将步骤(1)得到的混合液倒入模具中,静置去泡,冷冻干燥,干燥后得到未交联的海绵状材料;
(3)将步骤(2)得到的未交联的海绵状材料浸泡于含EDC/NHS的无水乙醇溶液中,EDC的用量以EDC的摩尔量相对于混合液中的羧基总摩尔量过量为准,EDC与NHS的摩尔比为4:1,室温条件下交联反应20 h,弃去多余的交联溶液,清洗3~5次,去除多余的交联剂,再次冷冻干燥后得到复合交联海绵敷料,即抗菌敷料。
本申请人根据上述具有缓释作用的抗菌敷料的制备方法进行了4个实施例(即实施例1~实施例4),其中,实施例1~实施例4中羧甲基壳聚糖、大分子胶原蛋白、含羧基的抗生素、EDC、NHS的用量见表1,实施例1-实施例4所制得的抗菌敷料的吸水率、孔隙率、水蒸气透过率、拉伸强度的测试数据见表2。
实施例1-实施例4中所采用的羧甲基壳聚糖的脱乙酰度为91.6%,分子量为20KDa,购自南通绿神生物工程有限公司;大分子胶原蛋白采用分子量为80-100 KDa的胶原蛋白,购自福建海神生物技术有限公司;含羧基的抗生素选用盐酸环丙沙星,购自北京索莱宝科技有限公司;EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)和NHS(N-羟基琥珀酰亚胺)均购自上海源叶生物科技有限公司。
表1
表2
实施例1-实施例4中的吸水率、水蒸气透过率、拉伸强度的测试方法分别如下:
(1)吸水率的测试方法具体为:将干燥样品剪成20 mm × 20 mm的正方形敷料,用天平称量敷料的重量,记为Mo,将样品敷料置于PBS(10 mmol/L,pH = 7.4)溶液中,30 min后快速用滤纸吸去表面的水分,称重记录样品质量为Mw。每个样品平行做五次实验,求其平均值,样品吸水率按照公式(2-1)计算:
其中,Mo为干燥敷料的重量(g);Mw为吸水后敷料的重量(g);X为敷料的吸水率(%);
(2)水蒸气透过率根据美国标准局的ASTM E96-00方法测定,具体步骤如下:首先,将敷料剪成合适大小置于已装有10 mL去离子水的小瓶瓶口(直径13 mm)处,用橡皮筋密封敷料与瓶口之间的间隙,防止水汽逸散,称量其初始重量。其次,将覆盖敷料的样品瓶放入恒温恒湿培养箱(温度为37ºC,相对湿度为79%)中,以只装有10 mL去离子水的样品瓶为空白对照组。24 h后取出,称其重量。水蒸气透过率按照如下公式(2-2)进行计算:
(3)拉伸强度参照医药行业标准YY/T 0471.4-2004的测试方法进行,采用电子拉力试验机测试敷料的拉伸强度,其承载能力为500 N,效率在 ± 1%以内。具体步骤如下:将样品裁剪成长为90 mm,宽为25 mm的长条形样品。用游标卡尺测量其厚度并记录。在恒温恒湿条件(温度为25oC,相对湿度为70%)下进行拉伸,测试时试样的夹持距离为50 mm,拉伸速率为300 mm/min。按照试验方法规定设置程序,进行检测,每个试验测试5组有效数据,取其平均值。敷料的拉伸强度(TS)按照以下公式计算:
拉伸强度计算公式(2-3):
其中,TS是拉伸强度(MPa),Fmax是样品断裂时所承受的最大拉力(N),L是敷料的厚度(mm),W是敷料的宽度(mm)。
从表1和表2可看出:本发明所制得的抗菌敷料的吸水率均在3100%以上,具有良好的吸水性能。这种高的吸水率主要是由于羧甲基壳聚糖的高亲水性和抗菌敷料的多孔网状结构所致。从敷料在伤口上的应用角度出发,其吸水率越大,越有利于快速吸收伤口渗出液,并保持适当的湿润的愈合环境。而本发明的步骤(2)所得到的未交联的海绵状材料在水中很快就降解,无法测其吸水率。同时,本发明所制得抗菌敷料的水蒸气透过率均在2520.65 g/m2•24h~4114.10 g/m2•24h。与对照组(无敷料覆盖)的实验数据(12705.90 g/m2•24h)相比,本发明所制得的抗菌敷料可以降低大约78%的水分蒸发。因此,与空白对照组相比,本发明所制得的抗菌敷料均能有效减少水蒸气的损失,从而促进表皮细胞和成纤维细胞的增殖;并且,本发明所制得抗菌敷料的拉伸强度均在0.14 MPa以上,具有良好的抗拉伸性能。
另外,本发明人还对实施例4制得的抗菌敷料进行了断裂伸长率的测定,其测定方法具体为:将样品裁剪成长为90 mm,宽为25 mm的长条形样品。用游标卡尺测量其厚度并记录。在恒温恒湿条件(温度为25℃,相对湿度为70%)下进行拉伸,测试时试样的夹持距离为50 mm,拉伸速率为300 mm/min。按照试验方法规定设置程序,进行检测,每个试验测试5组有效数据,取其平均值。断裂伸长率计算公式(2-4):
其中,EB是断裂伸长率(%),L0是试样拉伸前夹具间的距离(mm),L1是试样断裂时夹具的长度(mm)。结果为:本申请的实施例4制得的抗菌敷料在断口处的伸长率在10%左右。断裂伸长率表示材料的柔韧性,因此,本发明所制得的抗菌敷料具有良好的柔韧性,可以保护伤口免受外部的碰撞。
本发明还通过在实施例4所制得的抗菌敷料表面培养HSF细胞(人皮肤成纤维细胞,购于北京鼎国生物科技有限公司),并采用活/死染色试剂盒(购自上海贝博生物有限公司)检测细胞活性,荧光显微镜下观察到的发绿色荧光的细胞为活细胞、发红色荧光的细胞为死亡细胞,观察不同时间的HSF细胞的生长情况,来对本申请所制得的抗菌敷料进行细胞毒性测试,结果显示:实施例4所制得的抗菌敷料组(即将HSF细胞接种于实施例4所制得的抗菌敷料表面上)中均可见细胞大部分存活,与直接接种于组织聚苯乙烯培养皿的对照组相比无明显差异;在接种的第一天,只有少量的细胞粘附和增殖在抗菌敷料组和对照组上;在第二天,细胞开始大量迁移增殖;在第三天,随着培养时间的延长,可以看到大量细胞密集生长于抗菌敷料上,细胞已经接近增殖饱和,细胞排列密集,基本铺满整个底面。这些实验现象表明,本发明所制备的抗菌敷料无细胞毒性,生物相容性较好,并能有效地提高细胞黏附与增殖。
其中,本发明步骤(2)得到的未交联的海绵状材料的表面微观形貌如附图1所示、纵向断面微观形貌如图3所示;本发明所制得的交联后的抗菌敷料的表面微观形貌如图2所示、纵向断面微观形貌如附图4所示。从附图2可看出:本发明所制得的抗菌敷料呈均匀多孔网状结构;从附图4可看出:本发明所制得的抗菌敷料具有层状的孔结构,而这种层状的结构主要是由于羧甲基壳聚糖和大分子胶原蛋白中的羧基与氨基之间会形成互穿网络结构。本发明抗菌敷料的这种片层结构可以更好的吸收伤口渗出液,保持合适的水分环境,增加伤口与外界氧气的接触面积,促进伤口愈合。此外,孔与孔之间相互连通,细胞能够在其内部迁移生长,有利于营养物质的输送,为制备适应于不同伤口条件的敷料创造了条件。
本发明还对实施例4制得的抗菌敷料进行了抗菌性能测试,具体为:
(1)培养基配制
液体LB培养基:称取10 g胰蛋白胨,5 g酵母提取物,10 g氯化钠溶解在1000 mL的去离子水中,搅拌至完全溶解,并用1 mol/L NaOH将pH值调试至7.0 ~7.4之间,高压灭菌(120oC,20 min)得到液体LB培养基;
固体LB培养基:将17 g的琼脂粉加入1000 mL的液体培养基中,高压灭菌,待其冷却至50 ~ 60oC时,倒入无菌的玻璃培养皿(直径90 mm),冷却至室温得到3 mm厚的固体LB培养基。
(2)菌种的复苏和菌悬液的配制
取冻存的革兰氏阳性菌(S. aureus,金黄色葡萄球菌)和革兰氏阴性菌(E. coli,大肠杆菌;P. aeruginosa,铜绿假单胞菌)菌种,解冻后在固体LB培养基上进行复苏培养。隔天挑取复苏后生长良好的单菌落,接种于液体LB培养基37oC培养24 h后,分别用生理盐水稀释,通过平板菌落计数法计数,均配成细菌浓度为1 × 108 CFU/mL的实验室菌悬液。
(3)抑菌圈试验
将实施例4制得的抗菌敷料剪成直径10 mm的圆型试样,在超净工作台紫外照射30min 灭菌。在固体LB培养基上滴取100 μL上述菌悬液,用涂布棒均匀涂布贴上待测样品,正置15 min后将培养皿放置于37oC生化培养箱中倒置培养。培养24 h后取出观察培养基上的细菌生长情况并记录抑菌圈直径(D),每组三个平行样;
结果显示:实施例4制得的抗菌敷料对E. coli、S. aureus、P. aeruginosa的抑菌圈直径为27.0 ± 1.4 mm、22.1 ± 1.2 mm、21.3 ± 0.9 mm,而无抗生素负载的、仅由羧甲基壳聚糖-大分子胶原蛋白交联而成的抗菌敷料对E. coli、S. aureus、P. aeruginosa均没有明显的抑菌圈。
为了确定本发明所制得的抗菌敷料能否维持长期的抗菌性能,本申请人还挑选实施例4所制得的抗菌敷料进行了长期抗菌性能测定。具体方法如下:将实施例4所制得的抗菌敷料剪成直径10 mm的圆型试样,沉浸在10 mL的PBS缓冲溶液中,密封后置于37oC、100rpm的恒温摇床中模拟体外释放。在指定的时间点取出样品,无菌水清洗样品,通过抑菌圈方法进行评价,每组设置3个平行样。结果显示:实施例4所制得的抗菌敷料在第11天对E. coli、S. aureus、P. aeruginosa都基本维持了原来的抑菌圈大小,其抑菌圈大小为24.8± 0.1 mm、21.3 ± 0.0 mm和17.6 ± 0.0 mm,证明了本申请所制备的抗菌敷料具有持久抗菌性。
同时,本发明还针对本申请所制得的抗菌敷料进行了体外药物释放研究,具体步骤如下:
1、药物标准曲线方程
盐酸环丙沙星标准曲线:精密称取盐酸环丙沙星0.1 g溶解在PBS溶液中,100 mL容量瓶定容至刻度线,摇匀,配置成100 mg/L 浓度的储备液。将储备液进行一系列稀释,配置成10 mg/L,8 mg/L,6 mg/L,4 mg/L,0.4 mg/L和0.04 mg/L的溶液。取上述溶液各1 mL于石英比色皿中,用紫外分光光度计测量其在271 nm吸光度值,绘制标准曲线;
2、体外药物释放测试
将实施例4制得的抗菌敷料剪成30 mm × 30 mm的正方形,沉浸在100 mL的PBS缓冲溶液中,密封后置于37oC、100 rpm 的恒温摇床中模拟体外释放。在指定的时间点取出1mL释放液,同时补加1 mL同温度的新鲜的PBS溶液。采用直接紫外光谱法测定PBS溶液中盐酸环丙沙星的含量,计算药物(盐酸环丙沙星)累计释放量,每组设置3个平行样;
3、试验结果
(1)盐酸环丙沙星在271 nm波长下有紫外吸收。据此,通过配制梯度浓度的盐酸环丙沙星PBS溶液,测定271 nm波长下的吸光值,得到其标准曲线。其标准曲线方程为:y=100x-0.003,式中:x为盐酸环丙沙星浓度(mg/L);y为271 nm波长下测定的为吸光值,R²=0.9998,线性关系较高;
(2)本发明测定了24小时内PBS溶液的OD210值,并通过标准曲线方程计算药物的累计释放浓度,并进一步计算出24小时内的药物释放率(如表3所示)和11天内的药物释放率(如表4所示);
表3
表4
由表3可以看出:本发明所制得的抗菌敷料在最初的12 h内释放出65.19 ±8.74%的盐酸环丙沙星。早期的累计药物释放的增加是由于抗菌敷料表面的抗生素的释放以及抗菌敷料表面的物理结合抗生素的释放。由表4可看出:近10%的盐酸环丙沙星在11天后仍未释放。抗生素的持续释放是由于抗生素与聚合物之间酰胺键的缓慢断裂造成的。
本发明还建立了SD大鼠全层皮肤伤口模型,并在伤口处感染大肠杆菌和金黄色葡萄球菌,将实施例4制得的抗菌敷料用于大鼠伤口的修复实验中,宏观评价了伤口愈合情况和愈合率,并对其进行组织学和免疫组化染色,结果显示:
(1)在伤口愈合速率上,敷料组(伤口处覆盖实施例4制得的抗菌敷料)伤口面积百分比显著低于纱布组(伤口处覆盖普通纱布),与商业抗菌敷料Aquacel Ag组(伤口处覆盖商业抗菌敷料Aquacel Ag)相当;
(2)在组织学观察中,与纱布组相比,敷料组伤口第3天开始上皮化,淋巴细胞和红细胞数目明显较少,且在第6天上皮化基本完成。敷料组在第6天胶原沉积为48.43 ±5.91%,胶原的合成和沉积明显高于商业Aquacel Ag组(33.63 ± 7.98%)和纱布组(26.73± 7.46%)。同时,敷料组在第6天血管密度是137.7 ± 57.3/mm2,血管密度显著高于纱布组(83.4 ± 36.8/mm2),略优于商业Aquacel Ag组(128.1 ± 54.6/mm2)。由此可知,敷料组显示出良好的再上皮化、致密胶原沉积和血管生成等特征。
上述菌种和SD大鼠的来源见下表5:
表5
本发明的含羧基抗生素并不限于实施例1~实施例4的盐酸环丙沙星,其也可以为青霉素、头孢拉定、诺氟沙星、氧氟沙星、左氧氟沙星等,所有含有羧基的抗生素均可利用其上的羧基与羧甲基壳聚糖和大分子胶原蛋白上的氨基发生交联发生形成酰胺键来制作相应的抗菌敷料。
本发明的EDC的用量也并不限于实施例1-实施例3中的具体用量(实施例1~实施例4中EDC与羧甲基壳聚糖的质量比分别为:2.88:1、2.4:1、1.6:1、2.4:1),EDC是一种化学性质极为活泼的交联剂,它具有通过活化羧基,促进羧基与氨基共价形成酰胺键的作用,而其自身并不参与反应,因此,交联完成后不会引入多余的化学基团,因此,EDC的用量并不是固定不变的,通常来说,只要EDC的摩尔量相对于混合物的羧基的总摩尔量过量,就可以达到催化混合物(羧甲基壳聚糖、大分子胶原蛋白、含羧基抗生素)上羧基与氨基共价形成酰胺键的目的。
本发明的EDC与NHS的摩尔比也不限于实施例1-实施例4中的4:1,其也可以是1:1、2:1、大于4:1等EDC/NHS交联反应中常用的比例值。
所述的步骤(2)中静置去泡后的混合液,进行密封,并对混合液进行预冻使之固化;然后再进行冷冻干燥(通常来说,静置去泡的温度≥预冻的温度>冷冻干燥的温度,例如:静置去泡的温度为4℃,预冻的温度为4℃或-20℃,冷冻干燥的温度为-50℃左右,但,静置去泡的温度、预冻的温度、冷冻干燥的温度均不限于此)。在对混合液进行冷冻干燥之前,先将混合液密封、预冻,可有效避免混合液表面失水过快和大量冰晶产生,导致表面出现裂纹,从而影响产品表面的平整度。
所述的模具优选采用聚氟乙烯材质的模具。此模具与产品之间不易发生粘连,利于脱模,同时由于产品边缘和底部比较平整,提高了出产率;另,在同等条件下,与铁制模具或玻璃模具相比,采用聚氟乙烯材质的模具制作的产品的孔隙较大,对伤口愈合更有利。
本发明的另一目的在于提供一种根据上述具有缓释作用抗菌敷料的制备方法制得的抗菌敷料,如图5所示。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (9)
1.一种具有缓释作用抗菌敷料的制备方法,其特征在于:包括以下步骤:
(1)将羧甲基壳聚糖、大分子胶原蛋白、含羧基抗生素溶于去离子水中,搅拌均匀,得到混合液,混合液中羧甲基壳聚糖与大分子胶原蛋白的质量比为0.75~2.5: 1,含羧基抗生素的浓度为0.5~1 mmol/L;
(2)再将步骤(1)得到的混合液倒入模具中,静置去泡,冷冻干燥,干燥后得到未交联的海绵状材料;
(3)将步骤(2)得到的未交联的海绵状材料浸泡于含EDC/NHS的无水乙醇溶液中,室温条件下交联反应18-24h,弃去多余的交联溶液,清洗3~5次,去除多余的交联剂,再次冷冻干燥后得到复合交联海绵敷料,即抗菌敷料。
2.根据权利要求1所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:所述大分子胶原蛋白采用分子量为80-100 KDa的胶原蛋白。
3.根据权利要求1所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:所述的含羧基抗生素采用盐酸环丙沙星。
4.根据权利要求1所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:步骤(3)中所述的EDC的用量以EDC的摩尔量相对于混合物中羧基的总摩尔量过量为准。
5.根据权利要求4所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:步骤(3)中EDC的用量为:EDC与羧甲基壳聚糖的质量比为1.6~2.88:1。
6.根据权利要求1所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:步骤(3)中EDC与NHS的摩尔比为4:1。
7.根据权利要求1所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:所述的步骤(2)中静置去泡后的混合液,进行密封,并对混合液进行预冻使之固化;然后再进行冷冻干燥。
8.根据权利要求1所述的一种具有缓释作用抗菌敷料的制备方法,其特征在于:所述的模具采用聚氟乙烯材质的模具。
9.一种根据权利要求1~8中任意一项所述的具有缓释作用抗菌敷料的制备方法制得的抗菌敷料。
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