CN116036360B - 一种载药的cs-ca缓释水凝胶伤口敷料的制备方法和应用 - Google Patents
一种载药的cs-ca缓释水凝胶伤口敷料的制备方法和应用 Download PDFInfo
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Abstract
本发明涉及药物缓释载体材料领域,具体公开了一种载药的CS‑CA缓释水凝胶伤口敷料的制备方法和应用。本发明的水凝胶伤口敷料材料是以高分子材料壳聚糖(CS)为原料,以柠檬酸(CA)为交联剂,采用高温交联的方法使CS与CA形成网状结构,从而制成CS‑CA水凝胶伤口敷料。该凝胶材料制备方法简单,且无剧烈反应。以酮康唑环糊精包合物作为模型药物,结果显示本发明的凝胶体系对药物具有缓释效果且有一定的抗菌性能。
Description
技术领域
本发明涉及药物缓释载体材料领域,具体涉及一种载药的CS-CA缓释水凝胶伤口敷料的制备方法和应用。
背景技术
水凝胶是介于液体和固体之间的三维网络或互穿网络,是一种能显著地溶胀于水但在水中并不能溶解的亲水聚合物凝胶。水凝胶具有很好的生物相容性,固定在水凝胶中的生物活性分子能较长的时间保持活性,因此水凝胶在生物、化学、医学等方面都有着广泛的应用。水凝胶载体由于其良好的生物相容性、环境敏感性和控制释放等特性在药物传输技术中占据重要的位置,已经成为近年来缓释、控释制剂研究的热点。采用水凝胶膜剂作为控释载体,将药物包裹在膜剂中,使得药物透过凝胶网络慢慢释放从而得以发挥作用。
壳聚糖(Chitosan,CS)于1859年,由法国人Rouget首先发现,是由自然界广泛存在的几丁质(Chitin)经过脱乙酰作用得到的。壳聚糖没有生物毒性,没有皮肤刺激性,容易粘附在皮肤表面,具有良好的生物相容性及可降解性,并具有止血,抗菌等独特的功效,适合用作伤口修复材料。制备壳聚糖水凝胶的方法主要有化学交联法和物理交联法,通过化学交联的壳聚糖水凝胶与物理交联的水凝胶相比具有较强的机械强度及稳定性。
发明内容
由于伤口的局部血液供应不足,全身性抗生素无效,存在抗生素副作用和细菌耐药性的风险。本发明利用壳聚糖抗菌及交联后缓慢释放药物的特性,通过化学交联将抗生素加载到水凝胶上,从而制备一种具有缓慢释放抗生素的水凝胶伤口敷料。
本发明将CS与CA进行交联,制备一种化学交联的缓释水凝胶伤口敷料。并以酮康唑β-环糊精包合物为模型药物探究水凝胶的释药行为。
本发明是通过以下技术方案实现的:
一种载药的CS-CA缓释水凝胶伤口敷料的制备方法,包括以下步骤:
(1)将柠檬酸和蒸馏水混合配制成柠檬酸水溶液;
(2)向柠檬酸水溶液中加入壳聚糖,搅拌使壳聚糖充分溶解,继续向所得溶液中加入咪唑类抗菌药物的β-环糊精包合物,搅拌使药物均匀分散在体系中;体系中:柠檬酸的浓度为4w/v%,g/mL;壳聚糖的浓度为2w/v%,g/mL;
其中,柠檬酸及壳聚糖的浓度均是指该物质的质量与体系中水的体积之比;
(3)将步骤(2)所得溶液脱泡,流延成膜,并在80-110℃温度下交联2-3h;交联完成后,水洗,固化,得到载药的CS-CA缓释水凝胶伤口敷料。
进一步,步骤(2)中所述咪唑类抗菌药物的β-环糊精包合物的制备方法为:
S1.将咪唑类抗菌药物溶解于无水乙醇中;
S2.将β-环糊精溶解于蒸馏水中;
S3.将β-环糊精水溶液分批缓慢滴入咪唑类抗菌药物乙醇溶液中,每次间隔15-20min,先密封搅拌,后敞开搅拌,至挥发完乙醇;
S4.将S3所得浓缩液静置,抽滤,所得沉淀物依次用无水乙醇和蒸馏水快速洗涤,干燥,得到咪唑类抗菌药物β-环糊精包合物。
步骤S3中,咪唑类抗菌药物与β-环糊精的摩尔比为1:1。
采用β-环糊精将咪唑类抗菌药物制备成包合物,不仅能够提高药物的溶解性,还能缓慢释放药物。所述咪唑类抗菌药物为酮康唑、益康唑等。
进一步,步骤(2)中,所述壳聚糖分子量为10-100万,优选为100万。
进一步,步骤(3)中,交联反应温度不能降低,否则不发生交联反应。
优选的,步骤(3)中,交联条件为:在80℃温度下交联3h。
进一步,步骤(3)制备所得载药的CS-CA缓释水凝胶伤口敷料中咪唑类抗菌药物的质量与步骤(2)膜材料制备过程体系中蒸馏水的体积之比≥84μg/mL;优选为84μg/mL-210μg/mL。
使用上述载药的CS-CA缓释水凝胶伤口敷料,步骤为:将CS-CA膜贴于患处。
本发明方法具有以下优点:
本发明制备的缓释水凝胶载体材料具有明显的缓释效果,可以使KZ/β-CD缓慢释放,且具有一定抗菌性能。
该水凝胶材料制备条件温和,方法简单,且无剧烈反应。
附图说明
图1是本发明制备CS-CA缓释凝胶伤口敷料的原理图。
图2是实施例1制备的CS-CA缓释凝胶伤口敷料与CS凝胶膜的溶胀曲线图。其中:图a为在pH=6.8PBS缓冲液下的,图b为在pH=1.2盐酸下的。
图3是实施例1制备的2%CS-4%CA缓释凝胶伤口敷料与CS凝胶膜的水蒸气透过率(WVTR)图。
图4是实施例1制备的2%CS-4%CA缓释凝胶伤口敷料、CS与CA的红外光谱(IR)图。
图5是实施例1制备的2%CS-4%CA缓释凝胶伤口敷料与CS凝胶膜的热重分析图。其中:图a为CS和CS-CA凝胶膜的TG曲线,图b为CS和CS-CA凝胶膜的DTG曲线。
图6是实施例1制备的2%CS-4%CA缓释凝胶伤口敷料与CS凝胶膜的X射线衍射(XRD)图。
图7为酮康唑的标准曲线。
图8是实施例2制备的载药的CS-CA缓释凝胶伤口敷料的累计释药率曲线图。
图9是实施例2制备的载药的CS-CA缓释凝胶伤口敷料、载药的CS凝胶膜与未载药CS-CA缓释凝胶伤口敷料的时间-抑菌曲线图。其中:图a为负载不同浓度的KZ/β-CD的CS-CA凝胶膜与菌液共孵育24h的抑菌曲线,图b为负载KZ/β-CD的CS-CA凝胶膜、负载KZ/β-CD的CS凝胶膜和未载药CS-CA凝胶膜与菌液共孵育24h的抑菌曲线。
图10是实施例1制备的2%CS-4%CA缓释凝胶伤口敷料对L929细胞毒性的图。
具体实施方式
下面结合具体的实施例对本发明的技术方案做进一步的详细说明。
以下实施例中壳聚糖(CS)购置于浙江金壳药业股份有限公司,货号为M-PK-1908002,分子量为100万,CAS号为9012-76-4;β-环糊精(β-CD)、酮康唑(KZ)购置于阿拉丁试剂有限公司,货号分别为C104384、K129737,CAS号分别为7585-39-9、65277-42-1;柠檬酸(CA)、冰醋酸、无水乙醇、氢氧化钠、磷酸二氢钠、磷酸二氢钾、十二烷基硫酸钠购置于国药集团化学试剂有限公司,货号分别为10007118、10000218、10009218、10019718、20040718、10017618、30166428,CAS号为5949-29-1、64-19-7、64-17-5、1310-73-2、13472-35-0、7778-77-0、151-21-3;白色念珠菌CMCC(F)98001,由中国典型培养物保藏中心提供;小鼠成纤维细胞L-929,由中国典型培养物保藏中心提供。
以下实施例中,未写明单位的溶液浓度中“%”指质量体积百分比浓度(w/v%,w/v%=g/100mL)。
实施例1:一种CS-CA缓释水凝胶伤口敷料材料的制备
称取2g CA溶于50mL蒸馏水中,向所得柠檬酸水溶液中加入1g CS,然后置于磁力搅拌器上搅拌至溶解。超声30min后,静置过夜除气泡。通过流延法将25mL上述溶液倒入铺有锡纸的直径85mm培养皿中,真空50℃干燥,揭膜,并裁成所需大小(10mm×40mm),置于80℃的烘箱中交联3h,用少量蒸馏水洗涤凝胶膜上未交联的物质(避免使其充分溶胀),在110℃下再次干燥固化5min,得到2%CS-4%CA缓释水凝胶伤口敷料,干燥器中储存备用。
作为对比,将加入的CA用量改变为2.5g,得到2%CS-5%CA缓释水凝胶伤口敷料。
作为对比,将加入的CA用量改变为3g,得到2%CS-6%CA缓释水凝胶伤口敷料。
图1是本发明制备CS-CA缓释凝胶伤口敷料的原理图。
作为对比,纯CS膜,其制备方法为:取1g CS,加入50mL蒸馏水(含有0.5mL冰醋酸)中,置于磁力搅拌器上搅拌至溶解。超声30min后,静置过夜除气泡。通过流延法将25mL上述溶液倒入铺有锡纸的直径85mm培养皿中,真空50℃干燥,揭膜,并裁成所需大小(10mm×40mm),置于80℃的烘箱中交联3h,用蒸馏水洗涤凝胶膜上未交联的物质,在110℃下再次干燥固化5min,得到纯CS膜,干燥器中储存备用。
实施例2:一种载药的CS-CA缓释水凝胶伤口敷料材料的制备
KZ/β-CD包合物的制备:称取KZ 0.5314g(1mmol),溶解于20mL无水乙醇中,置于50℃恒温磁力加热搅拌器上搅拌溶解。另称取1.1350g(1mmol)β-CD溶于30mL蒸馏水中,在50℃恒温磁力加热搅拌器搅拌至溶解。用胶头滴管将30mLβ-CD溶液分两次滴入KZ溶液中,每次约15mL,两次间隔20min。密封搅拌3h,敞开搅拌2h,挥散乙醇,使溶液浓缩至约30mL。置4℃冰箱中过夜,抽滤,沉淀物依次用25mL无水乙醇和25mL蒸馏水快速洗去未包合的KZ和β-CD后,避光处理,置于40℃烘箱干燥,得到0.8g KZ/β-CD。
KZ/β-CD包合物中KZ的载药量(即包合物中KZ的质量与包合物质量的比)为40.65%,其检测方法为称取KZ/β-CD包合物100mg,置于50mL容量瓶中,用无水乙醇稀释至刻度,超声15min,过滤,吸取滤液2mL于25mL容量瓶中,用无水乙醇稀释至刻度。以无水乙醇为空白,在波长λ=295nm下测定吸光度值。
根据标准曲线计算浓度,再按下式计算出载药量。
称取2gCA溶于50mL蒸馏水中,向所得柠檬酸水溶液中加入1g CS,然后置于磁力搅拌器上搅拌至溶解。称取0.5g KZ/β-CD包合物,加入上述柠檬酸壳聚糖水溶液中,于磁力搅拌器搅拌1h,使药物均匀分散在体系中。超声30min后,静置过夜除气泡。通过流延法将25mL上述溶液倒入铺有锡纸的直径85mm培养皿中,真空50℃干燥,揭膜,并裁成所需大小(10mm×40mm),置于80℃的烘箱中交联3h,用少量蒸馏水洗涤凝胶膜上未交联的物质(避免使其充分溶胀),在110℃下再次干燥固化5min,得到载KZ/β-CD的CS-CA缓释水凝胶伤口敷料。所得载KZ/β-CD的CS-CA缓释水凝胶伤口敷料以KZ计,膜中KZ的质量(μg)与膜制备过程中体系中蒸馏水的体积(mL)之比为3.8μg/mL,即浓度为3.8μg/mL。
作为对比,载药的CS膜(CS+KZ/β-CD),其制备方法为:称取1gCS溶于50mL蒸馏水(含有0.5mL冰醋酸)中,置于磁力搅拌器上搅拌至溶解。称取0.5gKZ/β-CD包合物,加入上述溶液中,于磁力搅拌器搅拌1h,使药物均匀分散在体系中。超声30min后,静置过夜除气泡。通过流延法将25mL上述溶液倒入铺有锡纸的直径85mm培养皿中,真空50℃干燥,揭膜,并裁成所需大小(10mm×40mm),置于80℃的烘箱中交联3h,用蒸馏水洗涤凝胶膜上未交联的物质,在110℃下再次干燥固化5min,得到载KZ/β-CD的CS膜。
作为对比,2%CS-4%CA与KZ和β-CD共混所得的膜材料,具体制备步骤是:称取2gCA溶于50mL蒸馏水中,向所得柠檬酸水溶液中加入1g CS,然后置于磁力搅拌器上搅拌至溶解。称取0.19g KZ和0.41gβ-CD,加入上述溶液中,于磁力搅拌器搅拌1h,使药物均匀分散在体系中。超声30min后,静置过夜除气泡。通过流延法将25mL上述溶液倒入铺有锡纸的直径85mm培养皿中,真空50℃干燥,揭膜,并裁成所需大小(10mm×40mm),置于80℃的烘箱中交联3h,用蒸馏水洗涤凝胶膜上未交联的物质,在110℃下再次干燥固化5min,得到CS-CA+KZ+β-CD的共混膜。
测试例1:
对实施例1制备干燥的CS-CA缓释水凝胶伤口敷料样品分别在pH=6.8、pH=1.2下进行溶胀度曲线测定。
(1)称取一定量干燥的CS-CA缓释水凝胶伤口敷料样品,将样品浸于温度为37℃、pH=6.8的磷酸盐缓冲液(0.01mol/L),模拟体表温度37℃。
实验结果如图2(a)所示,实施例1制备的2%CS-4%CA缓释水凝胶伤口敷料的最终溶胀度可以达到1.6左右,且能一直保持稳定不下降,说明凝胶体系较稳定。
(2)称取一定量干燥的CS-CA缓释水凝胶伤口敷料样品,将样品浸于温度为37℃、pH=1.2的盐酸,模拟体表温度37℃。
实验结果如图2(b)所示,表明CA与CS是交联的,而纯CS膜在酸性条件下网络结构瓦解,即CA与CS交联的膜对酸性条件较纯CS膜更加稳定。
测试例2:
根据美国材料性能测试标准ASTM方法E96-00对实施例1制备干燥的2%CS-4%CA缓释水凝胶伤口敷料样品进行水蒸气的透过性能测试。
首先,在敞口直径为14mm的西林瓶中加入4mL蒸馏水,然后将凝胶膜裁剪成17mm的圆片,覆盖在瓶口(将西林瓶完全盖住即可),并将接缝处用凡士林及封口膜封住,称重。取一个干燥器并加入饱和的硫酸铵溶液,将西林瓶放入干燥器中,盖上盖子后放入37℃恒温干燥箱中24h后再次称重。
实验结果如图3所示,说明CS-CA缓释水凝胶伤口敷料比CS凝胶膜的水蒸气透过性能好,故CS-CA缓释水凝胶伤口敷料能够排出多余的水蒸气,并保持适宜的湿度环境,益于伤口愈合。
测试例3:
用红外光谱仪对实施例1制备的2%CS-4%CA缓释水凝胶伤口敷料样品、原料CA、CS进行分子结构测定。
采用KBr压片的方法对冷冻干燥后的CS-CA缓释水凝胶样品、CS、CA进行红外光谱分析:将干燥的样品和溴化钾以1:99的重量比例在干燥灯下研磨均匀,用压片装置压片,制得透明薄片,将此片固定于红外试样架上,从4000-400cm-1进行波数扫描,得到红外吸收光谱。
实验结果如图4所示,对比CS、CA与CS-CA水凝胶伤口敷料的红外谱图,可以看出,与CS、CA的红外光谱相比,CS-CA水凝胶伤口敷料在3440cm-1处的峰具有更高的强度,且CS-CA在1600cm-1处的吸收峰展宽成两个峰,其中1620cm-1为仲酰胺C=O伸缩振动,1580cm-1为仲酰胺N-H面内弯曲振动。说明CS分子中的氨基与CA分子中的羧基交联形成了酰胺键。
测试例4:
用热重分析仪对实施例1制备的2%CS-4%CA缓释水凝胶伤口敷料样品和CS凝胶膜进行温度-质量变化关系测定。
用冷冻干燥的CS-CA水凝胶伤口敷料样品和CS膜进行热分析,以10℃/min的升温速率,从40℃升温至700℃,由电脑记录试验数据,通过计算得到TGA曲线。
实验结果如图5所示,从图中可以看出CS-CA缓释水凝胶伤口敷料在200℃以下对热的稳定性较强,在200℃到400℃范围内质量下降较快。但当温度继续缓慢升高后,CS-CA缓释凝胶的质量呈缓慢下降态势。
测试例5:
用X射线衍射仪对实施例1制备的2%CS-4%CA缓释水凝胶伤口敷料样品进行冷冻干燥和CS凝胶膜进行晶体结构测定。
采用X射线衍射仪测定各个样品的晶型结构。管压40kv,扫描速度1°/min,衍射角2θ范围为4°-50°。
实验结果如图6所示,从图中可以看出CS-CA在2θ=19.46°处有一个明显的展宽的衍射吸收峰,相比于CS,它在2θ=8.26°、11.29°处的衍射吸收峰消失,以及2θ=22.12°的衍射峰向较低角度的偏移,可能是CA引起的交联反应,破坏了原有分子间及分子内氢键,改变了材料的晶体结构。
测试例6:
对实施例2制备的干燥的载药的CS-CA缓释水凝胶伤口敷料样品进行累积释药率的测定。
取实施例2制备的干燥的载KZ/β-CD的CS-CA缓释水凝胶伤口敷料(以下简称为“载KZ/β-CD的CS-CA凝胶膜”)0.5g于锥形瓶中,加入50mL、pH=6.8的磷酸盐缓冲溶液(0.01mol/L,含0.2%SDS),在37℃,100rpm的恒温振荡下进行试验,在预设时间点量取2mL样品,同时补充2mL现配的磷酸盐缓冲液。于295nm波长下进行紫外检测;根据标准曲线计算KZ含量,从而算出累积释药率,并得累积释药曲线。
酮康唑标准曲线的制备:
通过在波长λ=295nm下测定一系列已知浓度梯度的KZ溶液的吸光度值,结果见表1。
表1
上述数据进行线性拟合,得回归方程为A=4.4895C+0.0054(R2=0.9997)。标准曲线见图7。
实验结果如图8所示,从图中可以看出CS-CA水凝胶对KZ/β-CD有很好的缓释效果,从图中可以看出以KZ/β-CD为模型药物的水凝胶伤口敷料,累计释药时间可以长达31h,体现了水凝胶膜剂的缓释性,且累积释药率达到68%。相比于CS-CA膜而言,CS膜的累计释药率较低,31h时,累计释药率仅有15%,这可能是因为CS在非酸性条件下的亲水性较差,溶胀率低,导致药物难以释放。
CS-CA+KZ+β-CD的共混膜,其累积释药时长达31h,且累积释药率高达70%以上,较载KZ/β-CD的CS-CA凝胶膜累积释药率还高,其原因是使用包合技术将KZ包载在β-CD中比直接加入KZ药物更加有缓释作用。
测试例7:
按实施例2的方法,制备负载不同浓度的KZ/β-CD的CS-CA缓释水凝胶伤口敷料样品,并进行体外抗菌活性的实验。
取负载不同浓度的KZ/β-CD的CS-CA凝胶膜(14μg/mL、56μg/mL、84μg/mL、140μg/mL、210μg/mL各浓度是指:膜中KZ的质量(μg)与膜制备过程中体系中蒸馏水的体积(mL)之比)、负载KZ/β-CD的CS凝胶膜(膜中KZ的质量(μg)与膜制备过程中所加的蒸馏水的体积(mL)之比为84μg/mL)和不载药CS-CA凝胶膜在PBS(pH=6.8,0.01mol/L)中溶胀,分别取2、4、8、12、24h溶胀液备用。在96孔板里分别加入100μL负载不同浓度的KZ/β-CD包合物的CS-CA凝胶膜、负载KZ/β-CD包合物的CS凝胶膜和不载药CS-CA凝胶膜的不同时间段的溶胀液,同时加入100μL OD(600nm)=0.1时的白色念珠菌菌液,接种白色念珠菌的液体培养基作为生长对照组,液体培养基为空白组,置于37℃培养箱中培养24h。其中在制定时间点24h,用酶标仪测定各孔的OD值,所测得的数据绘制成曲线,并按下式计算抑制率。
实验结果如图9所示,从图9a中可以看出释药时间的增加,对白色念珠菌的抑制效果增加,说明所制备的CS-CA凝胶膜具有缓释效果,且随着CS-CA膜内KZ药物浓度的增加,对白色念珠菌的抑制效果增加,说明抑制效果对浓度有一定的依赖性。从图9b可以看出CS-CA+KZ/β-CD和CS+KZ/β-CD对白色念珠菌均有较好的抑制效果,且CS-CA凝胶膜也有接近10%的抑制率,说明CS-CA载体也有一定的抑菌效果。
测试例8:
对实施例1制备的干燥的2%CS-4%CA缓释水凝胶伤口敷料样品进行细胞毒性的实验。
实验组:取实施例1制备的干燥的CS-CA缓释水凝胶伤口敷料样品在pH=6.8PBS(0.01mol/L)中充分溶胀,打碎并稀释至不同浓度(100μg/mL、150μg/mL、200μg/mL、250μg/mL、300μg/mL、350μg/mL、400μg/mL、450μg/mL)。L929细胞与MEM在96孔培养板中以5000个细胞/孔的浓度培养。当细胞粘附到孔板底部时,用不同浓度的样品溶液(100μL)替换上清液,并在37℃下培养细胞24h。然后用100μL 0.5mg/mL MTT溶液替换培养基,继续培养4小时。丢弃MTT后,将150μL DMSO添加到培养板中,在黑暗中培养10min,并使用酶标仪测量490nm处的吸光度(OD值)。
阴性对照组:L929细胞与MEM在培养板中以5000个细胞/孔的浓度培养。当细胞粘附到孔板底部时,用MEM替换上清液,并在37℃下培养细胞24h。然后用100μL MTT溶液替换培养基,继续培养4小时。丢弃MTT后,将150μL DMSO添加到培养板中,在黑暗中培养10min,并使用酶标仪测量490nm处的吸光度(OD值)。
MEM培养基为空白对照组。
所测得的数据按下式计算细胞存活率。
实验结果如图10所示,CS-CA凝胶膜在浓度为100-450μg/mL内时L929细胞的存活率均高于85%,可以说明所制备的CS-CA凝胶膜是安全无毒的。
Claims (6)
1.一种载药的CS-CA缓释水凝胶伤口敷料的制备方法,其特征在于,包括以下步骤:
(1)将柠檬酸和蒸馏水混合配制成柠檬酸水溶液;
(2)向柠檬酸水溶液中加入壳聚糖,搅拌使壳聚糖充分溶解,继续向所得溶液中加入咪唑类抗菌药物的β-环糊精包合物,搅拌使药物均匀分散在体系中;体系中:柠檬酸的浓度为4w/v%,g/mL;壳聚糖的浓度为2w/v%,g/mL;
(3)将步骤(2)所得溶液脱泡,流延成膜,并在80-110℃温度下交联2-3h;交联完成后,水洗,固化,得到载药的CS-CA缓释水凝胶伤口敷料;
步骤(2)中所述咪唑类抗菌药物的β-环糊精包合物的制备方法为:
S1.将咪唑类抗菌药物溶解于无水乙醇中;
S2.将β-环糊精溶解于蒸馏水中;
S3.将β-环糊精水溶液分批缓慢滴入咪唑类抗菌药物乙醇溶液中,混合液中咪唑类抗菌药物与β-环糊精的摩尔比为1:1,先密封搅拌,后敞开搅拌,至挥发完乙醇;
S4.将S3所得浓缩液静置,抽滤,所得沉淀物依次用无水乙醇和蒸馏水快速洗涤,干燥,得到咪唑类抗菌药物β-环糊精包合物。
2.根据权利要求1所述的制备方法,其特征在于,所述咪唑类抗菌药物为酮康唑或益康唑。
3.根据权利要求1-2任一所述的制备方法,其特征在于,步骤(3)中制备所得载药的CS-CA缓释水凝胶伤口敷料中咪唑类抗菌药物的质量与步骤(2)膜材料制备过程体系中蒸馏水的体积之比为84μg/mL以上。
4.根据权利要求3所述的制备方法,其特征在于,步骤(3)中制备所得载药的CS-CA缓释水凝胶伤口敷料中咪唑类抗菌药物的质量与步骤(2)膜材料制备过程体系中蒸馏水的体积之比为84μg/mL-210μg/mL。
5.根据权利要求1-2任一所述的制备方法,其特征在于,步骤(3)中,交联条件为:在80℃温度下交联3h。
6.根据权利要求1-2任一所述的制备方法,其特征在于,步骤(2)中所述壳聚糖分子量为10-100万。
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