CN109337098A - 一种酶响应型结肠靶向载药凝胶的制备方法 - Google Patents
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Abstract
本发明提供一种酶响应型结肠靶向载药凝胶的制备方法,该凝胶的有效成分是通过聚乙二醇交联剂合成含偶氮键的壳聚糖水凝胶,采用如下方法制备:首先将含偶氮键奥沙拉嗪钠酸化,进而与聚乙二醇交联,最后在通过酯化反应链接壳聚糖,形成含偶氮键的壳聚糖水凝胶。本发明反应条件温和,交联剂无毒无害,生物相容性较好的酶响应型结肠靶向载药凝胶。壳聚糖与PEG结合,大大增加了壳聚糖的网状结构的稳定,同时利用奥沙拉嗪钠特定的偶氮结构进一步合成具有酶响应、无毒、无害、可促进伤口愈合、组织修复、可生物降解、良好的生物相容性的生物响应水凝胶,在结肠靶向药物传递释放领域具有潜在的应用价值。
Description
技术领域
本发明涉及一种载药凝胶的制备方法,尤其涉及一种酶响应型结肠靶向载药凝胶的制备方法。
背景技术
奥沙拉嗪钠结构中含有2分子5-氨基水杨酸(5-ASA),5-ASA对于结肠炎症具有一定的治疗作用,此药为磺胺含偶氮基的药物前体,2分子5-氨基水杨酸(5-ASA),通过偶氮键相连,得到双水杨酸盐化合物,该药可在结肠细菌产生的偶氮键还原酶的作用下分解,从而发挥药效。偶氮聚合物在这种酶响应的方式的情况下能表现出出色的性能,这关于结肠靶向输送药物中非常关键的一个过程存在着十分关键的引路作用。
壳聚糖是自然界中唯一大量存在的高分子碱性氨基多糖,其分子链上带有大量的活性氨基以及羟基,易于化学修饰;具有来源丰富、无毒、可促进伤口愈合、组织修复、可生物降解以及良好的生物相容性等优点、可用于药物的缓释控释、抗肿瘤药物、生物医用材料等方面的研究。壳聚糖应用十分广泛,可制备成膜,水凝胶,纳米微球,海绵等各种形式;并且可以释放生长因子、多肽、抗生素等促进修复。水凝胶结构类似于机体组织,既不影响生命体的代谢过程,代谢产物又可以通过水凝胶排出,常被用于人体器官/组织替代物。但纯壳聚糖凝胶的机械强度较小,壳聚糖被应用于支架材料时,往往与其它聚合物合用,或者采用化学改性后的壳聚糖衍生物材料。
发明内容
本发明的目的是为了能够较好的起到结肠靶向给药的作用而提供一种酶响应型结肠靶向载药凝胶的制备方法。
本发明的目的是这样实现的:
一种酶响应型结肠靶向载药凝胶的制备方法,包括以下步骤:
(1)奥沙拉嗪钠的酸化:
将奥沙拉嗪钠溶解并将pH调至4以下,反复洗涤沉淀至中性,烘干得到酸化后的奥沙拉秦;
(2)共聚物奥沙拉秦-聚乙二醇的制备:
将奥沙拉秦(OLZ)与聚乙二醇(PEG)进行混合,加入N,N-二甲基甲酰胺(DMF)溶液中,并加入催化剂,得到主链含偶氮键的线型嵌段共聚物奥沙拉秦-聚乙二醇(PEG-OLZ-PEG);
(3)偶氮交联剂的制备:
将聚合物PEG-OLZ-PEG加入DMF溶剂中,并加入催化剂,再加入对甲酰基苯甲酸进行反应,生成偶氮交联剂(CHO-PEG-OLZ-PEG-CHO);
(4)载药凝胶的合成:
配制壳聚糖与偶氮交联剂溶液,加入氟尿嘧啶(5-FU),将混合后的溶液转移到模具中,在室温下发生交联固化反应合成载药凝胶。
本发明还包括这样一些特征:
1.所述催化剂为4-甲氨基吡啶和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;
2.所述步骤(4)中壳聚糖与偶氮交联剂的比例为10~60:1;
3.所述奥沙拉秦与聚乙二醇的比例为1:2;
4.所述载药凝胶具有三维网状结构。
与现有技术相比,本发明的有益效果是:
本发明中壳聚糖与PEG结合,大大增加了壳聚糖的网状结构的稳定,同时利用奥沙拉嗪钠特定的偶氮结构进一步合成具有酶响应、无毒、无害、可促进伤口愈合、组织修复、可生物降解、良好的生物相容性的生物响应水凝胶,对于生物医用凝胶有着较为重要的应用前景。
5-FU是嘧啶类抗代谢肿瘤药物,是治疗结肠癌的首选化疗药物,但是5-FU的普通口服制剂给药后吸收不规则,口服后20分钟血液中药物浓度达到最高值,不能有效运用于结肠处,生物利用度低,并对胃肠道刺激严重。因此本发明选用5-FU作为我们合成的偶氮凝胶载体的药物模型是非常有意义的。
本发明制备的酶响应型结肠靶向载药凝胶具有独特的偶氮酶响应,在结肠靶向载药凝胶领域有着潜在的应用价值。与现有的技术比较具有诸多优点,其制备方法条件温和,室温固化,并采用双催化剂进行催化。其具有的偶氮键可以被肠内特定的酶识别,可以有效地将5-FU运输到结肠患处进行治疗,还能有效地避免5-FU对其他部位所造成的伤害,并且该对人体无毒无害,具有较好的生物相容性。
附图说明
图1是本发明制备的酶响应型结肠靶向载药凝胶的红外光谱图;
图2是本发明制备的酶响应型结肠靶向载药凝胶的扫描电子显微镜(SEM)图;
图3是本发明制备的酶响应型结肠靶向载药凝胶在37℃下,pH为7.4磷酸盐缓冲液液中的平衡溶胀曲线;
图4是本发明制备的酶响应型结肠靶向载药凝胶体外药物释放随时间的变化曲线。;
图5是本发明制备的偶氮交联剂的红外光谱图。
具体实施方式
下面结合附图与具体实施方式对本发明作进一步详细描述。
本发明要解决的技术问题是:为了解决现有技术中存在的不足问题,提供一种新型的酶响应型结肠靶向载药凝胶的制备方法。该凝胶的有效成分是通过聚乙二醇交联剂合成出含偶氮键的壳聚糖水凝胶,该反应条件温和,交联剂无毒无害,且具有酶响应型结肠靶向载药水凝胶。在结肠靶向药物传递释放领域具有潜在的应用价值。
本发明提供的酶响应型结肠靶向载药凝胶,其有效成分是偶氮键交联的壳聚糖衍生物,由酸化奥沙拉嗪钠结合聚乙二醇形成交联剂,进一步与壳聚糖室温下固化形成具有结肠靶向载药水凝胶。
本发明提供的酶响应型结肠靶向载药凝胶制备方法,具体采用以下步骤方法:
(1)奥沙拉嗪钠的酸化:
将奥沙拉嗪钠加入足量的去离子水中磁力搅拌使其完全溶解,并加入足量盐酸,将pH调至4以下后,再多次反复洗涤沉淀至中性,烘干,得到酸化后的奥沙拉嗪;
(2)PEG-OLZ-PEG的制备:
将奥沙拉嗪(OLZ)与聚乙二醇(PEG200-4000)以1:2的比例进行混合,加入以N,N-二甲基甲酰胺(DMF)溶液中,并将4-甲氨基吡啶(DMAP)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)作为反应的催化剂加入到上述溶液中,得到主链含偶氮键的线型嵌段共聚物奥沙拉嗪聚乙二醇聚合物PEG-OLZ-PEG,将得到的聚合物置于真空干燥箱中烘干。
(3)CHO-PEG-OLZ-PEG-CHO的制备:
将聚合物PEG-OLZ-PEG加入DMF溶剂中,并DMAP和EDC作为反应的催化剂,再加入对甲酰基苯甲酸进行反应,再次发生反应生成偶氮交联剂CHO-PEG-OLZ-PEG-CHO,将反应得到的偶氮交联剂CHO-PEG-OLZ-PEG-CHO进行多次抽滤、洗涤处理后,将所得产物置于真空干燥箱中烘干。
(4)CHO-PEG-CHO的制备:
配制DMF有机溶剂,加入PEG,再加入DMAP和EDC作为反应的催化剂,再加入对甲酰基苯甲酸进行反应得到非偶氮交联剂CHO-PEG-CHO。将得到的非偶氮交联剂置于真空干燥箱中烘干。
(5)壳聚糖凝胶的合成
配制一定比例5~60:1的壳聚糖与偶氮交联剂溶液,加入5-FU,将混合后的溶液转移到事先准备好的模具中,使之在室温下发生交联固化反应形成载药凝胶。
所述的偶氮水凝胶具有三维网状结构,从而有效的载药,并释放;所述的催化剂EDC与催化剂DMAP双催化剂进行活化,从而形成偶氮交联剂;使用奥沙拉嗪钠作为特定的偶氮提供载体;偶氮键可以被肠道内特定的酶识别并分解。
本发明利用壳聚糖以及偶氮键的可降解性制备具有结肠靶向的载药凝胶。此反应在双催化剂下反应,条件温和,室温固化,交联剂无毒无害。本专利制备的水凝胶具有偶氮响应,能够较好的起到结肠靶向给药的作用。
下面结合实施例和附图对本说明做进一步说明,但不限定本发明。
实施例1:
壳聚糖与偶氮交联剂以及非偶氮交联剂比例均为10:1的凝胶制备:
称取比例均为10:1的壳聚糖与偶氮交联剂以及壳聚糖非偶氮交联剂,将壳聚糖与偶氮交联剂、壳聚糖与非偶氮交联剂分别溶于溶剂中,均加入一定量的5-FU,室温搅拌溶解后转移至特定的容器内,室温固化形成壳聚糖水凝胶。
实施例2:
壳聚糖与偶氮交联剂以及非偶氮交联剂比例均为25:1的凝胶制备:
称取比例均为25:1的壳聚糖与偶氮交联剂以及壳聚糖非偶氮交联剂,将壳聚糖与偶氮交联剂、壳聚糖与非偶氮交联剂分别溶于溶剂中,均加入一定量的5-FU,室温搅拌溶解后转移至特定的容器内,室温固化形成壳聚糖水凝胶。
实施例3:
壳聚糖与偶氮交联剂以及非偶氮交联剂比例均40:1的凝胶制备:
称取比例均为40:1的壳聚糖与偶氮交联剂以及壳聚糖非偶氮交联剂,将壳聚糖与偶氮交联剂、壳聚糖与非偶氮交联剂分别溶于溶剂中,均加入一定量的5-FU,室温搅拌溶解后转移至特定的容器内,室温固化形成壳聚糖水凝胶。
实施例4:
壳聚糖与偶氮交联剂以及非偶氮交联剂比例均为60:1的凝胶制备:
称取比例均为60:1的壳聚糖与偶氮交联剂以及壳聚糖非偶氮交联剂,将壳聚糖与偶氮交联剂、壳聚糖与非偶氮交联剂分别溶于溶剂中,均加入一定量的5-FU,室温搅拌溶解后转移至特定的容器内,室
温固化形成壳聚糖水凝胶。
1.酶响应型结肠靶向载药凝胶平衡溶胀性能测试:
溶胀度是指单位质量的干凝胶溶胀后网络吸收水分的质量,一般采用称重法测量。取圆片干凝胶样品,称重(m0)后浸入37℃不同pH值的缓冲溶液中,直到凝胶溶胀达到平衡(溶胀凝胶的重量经三次称量质量不变)。取出溶胀凝胶,用滤纸擦去表面多余的水分,称重(mx)。根据下列方程计算凝胶的平衡溶胀率。
Qx=(mx-m0)/m0
2.酶响应型结肠靶向载药凝胶药物释放性能测试:
将不同比例的含偶氮键的壳聚糖水凝胶和不含偶氮键的壳聚糖水凝胶放到溶液pH值为7.4的磷酸盐缓冲液,pH值为1.2的小鼠胃液以及小鼠结肠液中。将所制得的样品放到37℃的水浴恒温箱中加热,观察其药物释放情况。
药物累积释放率=(T时间药物释放总质量÷实际负载药物质量)×100%。
图1显示了凝胶的红外光谱分析。
图2显示了在壳聚糖与偶氮交联剂比例为10:1情况下的扫描电子显微镜(SEM)图结果,结果显示水凝胶的骨架为孔径相对均一的连续性蜂窝状的三维网络结构,偶氮交联剂的比例越高,壳聚糖水凝胶交联固化的程度越高,形成的蜂窝状三维网络结构就越牢固,壳聚糖水凝胶越不容易被降解,在药物运输方面的效果较好。
图3显示载药凝胶在37℃下,pH值为7.4磷酸盐缓冲液液中的平衡溶胀曲线,不同比例的偶氮键的壳聚糖水凝胶均在0.5h左右其溶胀度达到最大值,在之后的时间里几乎保持不变。在3.5h后曲线有略微下降,可知随着醛基和氨基比例增加,壳聚糖在pH为7.4溶液中溶胀度逐渐降低。
图4显示凝胶体外药物释放随时间的变化曲线,随着着醛基和氨基比例增加,5-FU的最终药物释放量逐渐降低;且含偶氮键的壳聚糖凝胶药物释放速度明显高于不含偶氮键的壳聚糖载药凝胶,证明含偶氮键的凝胶具有明显的结肠酶响应性。剂CHO-PEG-OLZ-PEG-CHO进行多次抽滤、洗涤处理后,将所得产物置于真空干燥箱中烘干。
综上所述:本发明涉及一种用作酶响应型结肠靶向载药凝胶的制备方法,该凝胶的有效成分是通过聚乙二醇交联剂合成含偶氮键的壳聚糖水凝胶,采用如下方法制备:首先将含偶氮键奥沙拉嗪钠酸化,进而与聚乙二醇交联,最后在通过酯化反应链接壳聚糖,形成含偶氮键的壳聚糖水凝胶。该反应条件温和,交联剂无毒无害,生物相容性较好的酶响应型结肠靶向载药凝胶。在结肠靶向药物传递释放领域具有潜在的应用价值。
Claims (9)
1.一种酶响应型结肠靶向载药凝胶的制备方法,其特征是,包括以下步骤:
(1)奥沙拉嗪钠的酸化:
将奥沙拉嗪钠溶解并将pH调至4以下,反复洗涤沉淀至中性,烘干得到酸化后的奥沙拉秦;
(2)共聚物奥沙拉秦-聚乙二醇的制备:
将奥沙拉秦(OLZ)与聚乙二醇(PEG)进行混合,加入N,N-二甲基甲酰胺(DMF)溶液中,并加入催化剂,得到主链含偶氮键的线型嵌段共聚物奥沙拉秦-聚乙二醇(PEG-OLZ-PEG);
(3)偶氮交联剂的制备:
将聚合物PEG-OLZ-PEG加入DMF溶剂中,并加入催化剂,再加入对甲酰基苯甲酸进行反应,生成偶氮交联剂(CHO-PEG-OLZ-PEG-CHO);
(4)载药凝胶的合成:
配制壳聚糖与偶氮交联剂溶液,加入氟尿嘧啶(5-FU),将混合后的溶液转移到模具中,在室温下发生交联固化反应合成载药凝胶。
2.根据权利要求1所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述催化剂为4-甲氨基吡啶和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
3.根据权利要求1或2所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述步骤(4)中壳聚糖与偶氮交联剂的比例为10~60:1。
4.根据权利要求1或2所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述奥沙拉秦与聚乙二醇的比例为1:2。
5.根据权利要求3所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述奥沙拉秦与聚乙二醇的比例为1:2。
6.根据权利要求1或2所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述载药凝胶具有三维网状结构。
7.根据权利要求3所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述载药凝胶具有三维网状结构。
8.根据权利要求4所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述载药凝胶具有三维网状结构。
9.根据权利要求5所述的酶响应型结肠靶向载药凝胶的制备方法,其特征是,所述载药凝胶具有三维网状结构。
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