CN114557957A - 一种可注射型原位交联疏水药物缓释水凝胶的制备方法 - Google Patents
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Abstract
本发明公开了一种可注射型原位交联疏水药物缓释水凝胶的制备方法：(1)使用有机溶剂配制疏水药物溶液，再将疏水药物溶液缓慢滴入持续搅拌的纯水中，制备得到疏水药物分散颗粒；(2)将疏水药物分散颗粒与多巴胺溶液进行搅拌混合，制备得到包裹药物的聚多巴胺纳米微球；(3)将包裹药物的聚多巴胺纳米微球用去离子水配成悬液，与巯基官能化透明质酸混合制备得到水凝胶。制备得到的水凝胶为一种微创的疏水性药物的体内递送体系，结合透明质酸、多巴胺良好的生物相容性，并兼具交联型体系原位快速交联、降解速度慢等优势达到药物长期原位缓释的效果。
Description
技术领域
本文涉及医学领域，具体涉及一种可注射型原位交联疏水药物缓释水凝胶的制备方法。
背景技术
多数临床治疗常用非甾体类解热镇痛药物(双氯芬酸等)、激素类药物(地塞米松等)，以及有机小分子药物(Kartogenin，Resveratrol等)等疏水性药物分子具有较低的水溶性，因此在应用时往往面临药物递送效率低、需反复注射、无法大剂量使用等问题。针对需长期治疗的疾病，如风湿、骨关节炎、较严重软组织损伤等该问题尤为突出，因此可直接作用于患处，长期缓释的给药体系将极大的弥补该类药物的使用缺陷，将为治疗此类疾病带来福音。
透明质酸(Hyaluronic Acid，HA)是一种由D-葡萄糖醛酸和D-N-乙酰葡糖胺组成的不含硫的天然直链蛋白多糖，广泛存在于多种人体组织中(包括结缔、上皮及神经组织)。HA在多种生物过程均中发挥重要作用，如细胞内信号传导、细胞分化和增殖、血管生成及炎症反应等。由于其高度亲水和聚阴离子的特性，HA可以吸收大量的水分子，形成一个高度含水网络。由于其具有极好的生物相容性、生物可降解性和低免疫原性，HA及其衍生物被广泛地应用于临床医学、组织工程和再生医学。
近年来，以HA为主体的水凝胶支架结构已广泛应用于皮肤伤口护理、骨和软骨缺损修复、生物分子和细胞输送等领域。交联型HA水凝胶网络较非交联型HA分子具有更强的抗酶降解效果，使水凝胶得以在体内得以存续较长时间。但水凝胶作为水溶性体系，在负载疏水性药物分子时需结合有效的药物包被或改造技术，其中使用高分子等载体包裹药物分子可有效的保护药物，增加了药物在体内的稳定性。
多巴胺是神经递质的一种，具有良好的生物相容性，其分子结构中的儿茶酚基与氨基可经氧化反应发生自聚合，形成聚多巴胺微球，或附着于有机或无机材料表面形成薄膜。多巴胺的自聚合可通过溶液氧化的方式，即在pH>7.5的碱性溶液中进行，反应条件简单、成分低廉，易于放大制备，目前已被广泛应用。聚多巴胺微球可在体内经氧化酶产生的过氧化氢作用下降解，从而缓慢释放包裹内容物。同时，聚多巴胺中的双键可结合巯基，通过迈克尔加成反应快速交联。因此，可利用多巴胺自聚合包裹疏水性药物，结合巯基官能化透明质酸形成水凝胶体系，实现该类药物的体内原位递送及缓释。
发明内容
本发明的目的在于提供一种可注射型原位交联疏水药物缓释水凝胶的制备方法，制备得到的水凝胶为一种微创的疏水性药物的体内递送体系，结合透明质酸、多巴胺良好的生物相容性，并兼具交联型体系原位快速交联、降解速度慢等优势达到药物长期原位缓释的效果。
本发明的目的通过下述技术方案得以实现：
一种可注射型原位交联疏水药物缓释水凝胶的制备方法，所述制备方法包括：
(1)使用有机溶剂配制疏水药物溶液，再将疏水药物溶液缓慢滴入持续搅拌的纯水中，制备得到疏水药物分散颗粒；
(2)将疏水药物分散颗粒与多巴胺溶液进行搅拌混合，制备得到包裹药物的聚多巴胺纳米微球；
(3)将包裹药物的聚多巴胺纳米微球用去离子水配成悬液，与巯基官能化透明质酸混合制备得到水凝胶。
本发明利用多巴胺自聚合反应包裹疏水药物颗粒，聚多巴胺的双键与巯基官能化透明质酸混合后发生迈克尔加成反应原位交联形成凝胶，由此获得可缓慢释放疏水药物的透明质酸可注射型水凝胶。
优选的，在步骤(1)中，所述疏水性药物为非甾体类解热镇痛药物、激素类药物或有机小分子药物。
优选的，在步骤(1)中，所述有机溶剂选用无水乙醇或丙酮。疏水药物使用易于挥发的有机试剂作为溶剂更利于颗粒分散，因此，选用无水乙醇或丙酮制备疏水药物溶液。
优选的，在步骤(1)中，保持100-1000rpm的搅拌速度并持续4-12小时。
优选的，在步骤(2)中，所述多巴胺溶液的浓度为2-20mg/mL。
优选的，在步骤(3)中，所述巯基官能化透明质酸的分子量为10-2000kDa。
优选的，在步骤(3)中，所述包裹药物的多巴胺纳米微球水溶液与巯基官能化透明质酸的混合体积为1：0.1至0.1：1。
优选的，在步骤(3)中，所述包裹药物的多巴胺纳米微球配成的悬液浓度为1％(w/v)，巯基官能化透明质酸的溶度为2-4％(w/v)，成胶温度为37℃，成胶时间为10-30min。
本发明提供的可注射型原位交联疏水药物缓释水凝胶体系包含由多巴胺附着在疏水药物分散颗粒表面自聚合形成的纳米微球，纳米微球上聚多巴胺的双键与巯基官能化透明质酸上的巯基反应成胶，双键与巯基的反应活性受官能团浓度和pH值的影响，成胶时间可以通过控制pH值的方法进行控制，达到可注射的要求。本发明提供的制备方法得到的载药水凝胶可经注射于治疗部位原位交联构成交联网络，可作为疏水药物的缓释载体应用于组织工程及临床治疗。
附图说明
图1为聚多巴胺与巯基反应机理图。
图2为聚多巴胺疏水药物微球粒径分布图。
图3为KGN聚多巴胺微球的包封率。
图4为含KGN的聚多巴胺微球与巯基化透明质酸水凝胶的成胶过程及力学强度。
图5为含KGN的聚多巴胺微球与巯基化透明质酸水凝胶体外缓释曲线。
具体实施方法
下面结合具体实例进一步说明本发明的技术方案，但这些实例并不用来限制本发明。
称取5mg Kartogenin(KGN)加入无水乙醇充分溶解配制成50mM KGN溶液。取100μLKGN溶液，缓慢滴入900rpm搅拌的5ml去离子水中，避光室温持续搅拌12小时。使用pH为8.5的磷酸盐缓冲溶液配制10mg/mL的多巴胺溶液，避光搅拌至完全溶解。
将5mL多巴胺溶液缓慢加入疏水药物颗粒的悬浮液中，900rpm搅拌的5ml去离子水中，室温下避光持续搅拌12小时。12小时后收集反应液，经0.22μm滤膜过滤后使用13000rpm离心20分钟收集包裹KGN的聚多巴胺微球。
将收集的微球用去离子水重悬清洗后再次离心，并使用1mL去离子水再次重悬。
将重悬的KGN多巴胺微球悬液进行冻干，得到黑色粉末状产物。
可缓慢释放疏水药物的透明质酸可注射型水凝胶的制备：
将KGN多巴胺微球用去离子水成配制1％(w/v)的悬液，将巯基官能化透明质酸用磷酸盐缓冲液配制成4％(w/v)的溶液，按照1:1的体积比混合得到凝胶。
其中，图1为聚多巴胺与巯基反应机理图，多巴胺儿茶酚基自聚合后其结构中的双键与巯基通过迈克尔加成反应聚合。
图2为本实施例中聚多巴胺疏水药物微球粒径分布图，经动态光散射仪检测药物颗粒粒径均值约为150nm，粒径分布范围较窄，微球大小较为均一。
图3为本实施例中KGN聚多巴胺微球的包封率，检测结果证实在操作过程中有接近80％的KGN被成功包裹在KGN聚多巴胺微球中。
图4为含本实施例中KGN的聚多巴胺微球与巯基化透明质酸水凝胶的成胶过程及力学强度，流变仪检测数据呈现聚多巴胺微球与巯基透明质酸混合后即时开始交联反应，水凝胶交联20分钟后强度可达2600Pa。
图5为本实施例中含KGN的聚多巴胺微球与巯基化透明质酸水凝胶体外缓释曲线，水凝胶在37度磷酸盐溶液中历时30天缓慢释放KGN。
以上所述的具体实施方式对本发明的技术方案和有益效果进行了详细说明，应理解的是以上所述仅为本发明的最优选实施例，并不用于限制本发明，凡在本发明的原则范围内所做的任何修改、补充和等同替换等，均应包含在本发明的保护范围之内。
Claims (8)
1.一种可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，所述制备方法包括：
(1)使用有机溶剂配制疏水药物溶液，再将疏水药物溶液缓慢滴入持续搅拌的纯水中，制备得到疏水药物分散颗粒；
(2)将疏水药物分散颗粒与多巴胺溶液进行搅拌混合，制备得到包裹药物的聚多巴胺纳米微球；
(3)将包裹药物的聚多巴胺纳米微球用去离子水配成悬液，与巯基官能化透明质酸混合制备得到水凝胶。
2.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(1)中，所述疏水性药物为非甾体类解热镇痛药物、激素类药物或有机小分子药物。
3.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(1)中，所述有机溶剂选用无水乙醇或丙酮。
4.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(1)中，保持100-1000rpm的搅拌速度并持续4-12小时。
5.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(2)中，所述多巴胺溶液的浓度为2-20mg/mL。
6.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(3)中，所述巯基官能化透明质酸的分子量为10-2000kDa。
7.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(3)中，所述包裹药物的聚多巴胺纳米微球水溶液与巯基官能化透明质酸的混合体积为1：0.1至0.1：1。
8.根据权利要求1所述的可注射型原位交联疏水药物缓释水凝胶的制备方法，其特征在于，在步骤(3)中，所述包裹药物的聚多巴胺纳米微球配成的悬液浓度为1％(w/v)，巯基官能化透明质酸的溶度为2-4％(w/v)，成胶温度为37℃，成胶时间为10-30min。
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