CN107325300B - 一种pH敏感水凝胶及其制备和应用 - Google Patents
一种pH敏感水凝胶及其制备和应用 Download PDFInfo
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- CN107325300B CN107325300B CN201710473362.6A CN201710473362A CN107325300B CN 107325300 B CN107325300 B CN 107325300B CN 201710473362 A CN201710473362 A CN 201710473362A CN 107325300 B CN107325300 B CN 107325300B
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Abstract
本发明公开了一种pH敏感水凝胶及其制备和应用。该pH敏感水凝胶由原料A、原料B和成胶液构成;原料A和原料B的质量之和在水凝胶中的质量百分比为10%‑60%,其中原料A为醛基化透明质酸钠,原料B为四臂端氨基修饰的聚乙二醇;主要通过四臂端氨基修饰的聚乙二醇的氨基和醛基化透明质酸钠或者醛基化葡聚糖的醛基形成的亚胺动态键得到pH敏感水凝胶。该pH敏感水凝胶可作为药物载体、栓塞材料或者组织工程材料等应用。所述pH敏感水凝胶的制备方法,包括步骤:将原料A和原料B加成胶液混合均匀,得到pH敏感水凝胶;具有制备过程简便、快速,易于大规模生产的优势。
Description
技术领域
本发明属于生物分子医药技术领域,具体涉及一种pH敏感水凝胶及其制备和应用。
背景技术
水凝胶是由高分子交联的三维网络结构,在生物医药领域如药物释放、组织工程和生物传感等有着广泛的应用。向高分子链上引入生理环境敏感的基团或化学结构,可以构筑刺激响应性水凝胶,即智能水凝胶。智能水凝胶能对环境刺激做出响应,如pH、温度、离子强度、生化信号和磁场等,引起了研究者们越来越广泛的兴趣。在人体内,某些细胞器和病变部位的生理微环境与正常组织的生理微环境会有差别,如溶酶体、内涵体、炎症部位和肿瘤组织的pH值要低于正常组织的生理pH值7.4,肿瘤组织和糖尿病患者的葡萄糖浓度偏高等,因此,构筑生理环境响应性的水凝胶在药物释放和组织工程领域具有十分重要的意义。
目前,制备原位凝胶体系的方法有化学交联和物理交联,化学交联包括自由基聚合和迈克尔加成等,通常需要加入引发剂或生成小分子副产物,物理交联通过物理变化包括pH值、温度和离子强度等变化实现。使用动态共价键构筑的水凝胶(即动态键凝胶)具有较高机械强度和可注射性,且由于敏感基团是化学键,从而极大的拓宽了可选择高分子材料的范围,可构筑具有多重响应性的水凝胶。杨等使用苯甲酰亚胺键可构筑pH/温度双敏感的可注射壳聚糖基质水凝胶,苯甲酰亚胺键具有生理pH响应性,可通过调节pH值触发凝胶的形成与破坏,不需要引发剂,且该反应的小分子产物为水,避免了凝胶过程中杂质的引入。形成的水凝胶具有较好的机械强度,在高分子含量较低(5.0wt%)时其弹性模量可达103-104Pa,该水凝胶可用于抗肿瘤药物的长效可控释放,并取得了较好的肿瘤治疗效果(Dually Responsive Injectable Hydrogel Prepared by In Situ Cross-Linking ofGlycol Chitosan and Benzaldehyde-Capped PEO-PPO-PEO,Biomacromolecules 2010,11,1043-1051)。苯硼酸酯由苯硼酸衍生物和多羟基化合物反应形成,反应不需要引发剂,不产生除水以外的其它副产物,与葡萄糖氧化酶(GOx)、凝集素是构筑葡萄糖响应体系的三大体系。葡萄糖氧化酶和凝集素为蛋白类化合物,对环境要求比较苛刻,外界环境的变化可能会导致其失活,限制了其应用。而亚胺键由于其设计的多样性和更好的稳定性,在发展葡萄糖响应体系方面具有较大的优势,引起了研究者们更为广泛的关注。有文献报道由苯硼酸和聚(N-异丙基丙烯酰胺)(PNIPAM)组成的凝胶和微凝胶,在葡萄糖存在时能够溶胀并释放出胰岛素,但这些材料只有在高于苯硼酸pKa值(pH 9)和较高的葡萄糖浓度(20g/L)下才具有葡萄糖响应性,限制了其在生理条件下(pH 7.4,葡萄糖浓度1-3g/L)的应用(Synthesis and Volume Phase Transitions of Glucose-Sensitive Microgels,Biomacromolecules 2006,7,3196-3201,Phenylboronic acid-based glucose-responsive polymeric nanoparticles:synthesis and applications in drugdelivery,Polym.Chem.,2014,5,1503-1518)。
发明内容
为了克服现有技术的不足,本发明提供了一种pH敏感水凝胶,主要通过四臂端氨基修饰的聚乙二醇的氨基和醛基化透明质酸钠的醛基形成的亚胺动态键得到pH敏感水凝胶。
本发明还提供了所述pH敏感水凝胶的制备方法,具有操作简单,易于工业化生产的优势。
本发明采取的具体技术方案如下:
一种pH敏感水凝胶,由原料A、原料B和成胶液构成;所述原料A和原料B的质量之和在水凝胶中的质量百分比为10%-60%,其中原料A为醛基化透明质酸钠,原料B为四臂端氨基修饰的聚乙二醇;
所述醛基化透明质酸钠由数均分子量为0.6KDa-700KDa的透明质酸钠经氧化剂开环氧化得到;
所述四臂端氨基修饰的聚乙二醇的结构式如式Ⅰ所示:
式Ⅰ中n为聚合度,式Ⅰ所示四臂端氨基修饰的聚乙二醇的数均分子量为100KDa-1000Kda。
本发明pH敏感水凝胶,所述醛基化透明质酸钠和四臂端氨基修饰的聚乙二醇均为水溶性高分子化合物,醛基化透明质酸钠在水溶液中会带负电荷且被游离的钠离子环绕,四臂端氨基修饰的聚乙二醇四臂结构为水凝胶提供具有亲水性的柔性链段的网状支架,醛基化透明质酸钠的带负电荷的链段也可充当柔性链段,这两种特有的结构在水溶液中能够保证形成的水凝胶具有多孔且致密的结构,同时在这种多孔且致密的结构中分布有钠离子,在正负电荷的作用下进一步形成一种隐形的缓释屏障,得到的水凝胶具有优良的柔软性和弹性,缓释效果可控;四臂端氨基修饰的聚乙二醇的氨基与醛基化透明质酸钠的醛基形成的亚胺动态键对pH具有响应性,能够原位成胶。
考虑原料A和原料B特定的化学结构,为了达到更好的发明效果,优选:
所述原料A和原料B的质量比为(0.1-10):1,能够增强水凝胶的稳定性。
所述原料A和原料B的质量之和在水凝胶中的质量百分比为10%-50%,进一步优选为10%-30%。原料A和原料B的总质量百分浓度为10%-50%时,注射性更加优良;原料A和原料B的总质量百分浓度大于50%且小于等于60%时,凝胶的稳定性更好。原料A和原料B的总质量百分浓度为10%-30%时,不仅注射性优良,而且更适宜在正常生理pH7.4条件下快速凝胶化。本发明可根据水凝胶的应用领域不同,选择合适的原料A和原料B的总质量百分浓度范围。
所述醛基化透明质酸钠的醛基化率在5%-30%。所述醛基化率为醛基化透明质酸钠中被醛基化的结构单元(例如式Ⅱ所示结构单元)的摩尔数量占所有结构单元(例如式Ⅱ和式Ⅲ所示结构单元)总摩尔数量的百分比。
所述成胶液为去离子水或者pH值在6-8的缓冲溶液,为水凝胶提供成胶环境。
所述缓冲溶液采用磷酸氢二钠-柠檬酸缓冲液、磷酸二氢钾-氢氧化钠缓冲液、磷酸氢二钠-磷酸二氢钠缓冲液、巴比妥钠-盐酸缓冲液、三(羟甲基)氨基甲烷-盐酸缓冲液(Tris-HCl缓冲液)、硼酸-硼砂缓冲液、甘氨酸-氢氧化钠缓冲液、硼砂-氢氧化钠缓冲液、碳酸钠-碳酸氢钠缓冲液等缓冲溶液中的一种或者多种。
根据其应用领域的要求,所述成胶液均可选用无菌成胶液。
所述pH敏感水凝胶的制备方法,包括步骤:
将原料A和原料B加成胶液混合均匀,得到pH敏感水凝胶。
所述pH敏感水凝胶的形成温度在20℃-38℃。
本发明所用的原料均可采用市售产品或者采用现有制备方法制备得到。例如将透明质酸钠经氧化剂开环氧化,得到醛基化透明质酸钠。可以通过控制开环氧化的反应进程得到不同醛基化率的醛基化透明质酸钠。所述氧化剂可选用高碘酸钠等开环氧化常用的氧化剂。所述透明质酸钠的数均分子量为0.6KDa-700KDa。醛基化透明质酸钠可具体采用如下现有方法制备:称取适量透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应2h-24h,加入适量丙三醇或乙二醇,继续搅拌15min-20min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析多次,将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠。透明质酸钠(sodium hyaluronate,SH)是由式Ⅲ所示的重复结构单元组成的直链多聚糖的钠盐,在开环氧化的过程中,部分式Ⅲ所示的结构单元中的羟基被开环氧化成醛基形成式Ⅱ所示的结构单元,得到由式Ⅱ和式Ⅲ所示的结构单元组成的直链无规共聚物:醛基化透明质酸钠。
所述pH敏感水凝胶,具有pH响应性及可注射性,可作为药物载体、栓塞材料或者组织工程材料等应用。所述pH敏感水凝胶采用特定结构和分子量范围的原料A和原料B,尤其利于作为负载小分子药物例如阿霉素(DOX)的药物载体,药物释放速率可调节。
本发明具有以下有益效果:
(1)本发明水凝胶的原料采用具有良好水溶性的大分子,原料本身安全无毒可生物降解,凝胶的形成过程无需使用有机溶剂,克服了水凝胶体内使用时的安全隐患。原料B为现有高分子化合物,其来源为化学合成,相较于目前水凝胶大量采用的来自于植物和动物体内的高分子化合物,化学合成的原料具有结构可控制,更容易调节水凝胶的强度、降解速度、药物释放速度等优势。
(2)本发明水凝胶主要是特定结构大分子上的氨基和另一特定结构大分子上的醛基反应形成亚胺键,在人体正常生理pH值下比较稳定,弱酸性条件下会逐渐水解形成溶液。由于亚胺键在正常生理条件下较稳定,在弱酸性条件下易发生水解,本发明可以通过调节两种原料物质的比例、透明质酸钠的醛基化比例,控制生成亚胺键的比例,从而智能的控制凝胶的形成时间、凝胶的致密程度、药物的释放以及凝胶的降解速率。
(3)本发明水凝胶有一定的强度和韧性,由于在形成凝胶的过程中生成了亚胺键,具有自修复性,可通过原料的改性程度、分子量和原料的比例调控凝胶性能,进一步提高了凝胶的生物相容性;本发明制备的凝胶具有生物降解性能,能被人体代谢;具有pH响应性及可注射性,可用作药物载体、栓塞材料以及组织工程材料等。
(4)本发明pH敏感水凝胶的制备方法,具有制备过程简便、快速,易于大规模生产的优势。
附图说明
图1为本发明实施例1中pH敏感水凝胶的电镜扫描图;
图2为本发明实施例3中pH敏感水凝胶的流变图;其中G′表示储能模量,G″表示损耗模量;
图3为本发明应用例3中载药pH敏感水凝胶的药物累积释放曲线图。
具体实施方式
下面结合具体实施例对本发明进一步的描述。本具体实施方式并非对其保护范围的限制。
实施例1
称取适量数均分子量15KDa的透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应2h,加入适量乙二醇,继续搅拌15min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析72h,每四小时更换一次水。将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠,醛基化率5%。
将5g醛基化透明质酸钠(醛基化率5%)和1g数均分子量600KDa的四臂端氨基修饰的聚乙二醇(Laysan)加14g无菌去离子水,37℃迅速震荡混合均匀,22秒后得到20g呈透明、均匀状态的pH敏感水凝胶。
该pH敏感水凝胶的电镜扫描图见图1,显示水凝胶具有多孔且致密的结构,孔径在0.05mm-0.3mm,同时在正负电荷的相互作用下水凝胶的网孔孔径分布范围小,更加致密均匀。
实施例2
称取适量数均分子量300KDa的透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应2h,加入适量乙二醇,继续搅拌15min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析72h,每四小时更换一次水。将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠,醛基化率5%。
将10g醛基化透明质酸钠(醛基化率5%)和1g数均分子量1000KDa的四臂端氨基修饰的聚乙二醇(Laysan)加44g磷酸氢二钠-柠檬酸缓冲液(pH=6.5),37℃迅速震荡混合均匀,25秒后得到55g呈透明、均匀状态的pH敏感水凝胶。
pH敏感水凝胶的电镜扫描图显示水凝胶具有多孔且致密的结构,孔径在0.1mm-0.2mm,在正负电荷的相互作用下水凝胶的网孔孔径分布范围小,更加致密均匀。
实施例3
称取适量数均分子量700KDa的透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应2h,加入适量乙二醇,继续搅拌15min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析72h,每四小时更换一次水。将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠,醛基化率5%。
将0.1g醛基化透明质酸钠(醛基化率5%)和1g数均分子量800KDa的四臂端氨基修饰的聚乙二醇(Laysan)加9.9g磷酸氢二钠-磷酸二氢钠缓冲液(pH=7.4),37℃迅速震荡混合均匀,30秒后得到11g呈透明、均匀状态的pH敏感水凝胶。
pH敏感水凝胶的电镜扫描图显示水凝胶具有多孔且致密的结构,孔径在0.1mm-0.15mm,在正负电荷的相互作用下水凝胶的网孔孔径分布范围小,更加致密均匀。
实施例4
称取适量数均分子量0.6KDa的透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应10h,加入适量乙二醇,继续搅拌15min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析72h,每四小时更换一次水。将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠,醛基化率10%。
将7g醛基化透明质酸钠(醛基化率10%)和1g数均分子量100KDa的四臂端氨基修饰的聚乙二醇(Laysan)加12g巴比妥钠-盐酸缓冲液(pH=6),38℃迅速震荡混合均匀,20秒后得到20g呈透明、均匀状态的pH敏感水凝胶。
pH敏感水凝胶的电镜扫描图显示水凝胶具有多孔且致密的结构,孔径在0.05mm-0.15mm,在正负电荷的相互作用下水凝胶的网孔孔径分布范围小,更加致密均匀。
实施例5
称取适量数均分子量100KDa的透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应15h,加入适量丙三醇,继续搅拌15min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析72h,每四小时更换一次水。将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠,醛基化率20%。
将3g醛基化透明质酸钠(醛基化率20%)和1g数均分子量300KDa的四臂端氨基修饰的聚乙二醇(Laysan)加4g Tris-HCl缓冲液(pH=6.4),20℃迅速震荡混合均匀,15秒后得到8g呈透明、均匀状态的pH敏感水凝胶。
pH敏感水凝胶的电镜扫描图显示水凝胶具有多孔且致密的结构,孔径在0.1mm-0.2mm,在正负电荷的相互作用下水凝胶的网孔孔径分布范围小,更加致密均匀。
实施例6
称取适量数均分子量500KDa的透明质酸钠溶于水中,加入过量的高碘酸钠,室温下避光搅拌反应24h,加入适量丙三醇,继续搅拌15min后,将反应混合物转移到到截留分子量为0.6kDa的透析袋中,在去离子水中透析72h,每四小时更换一次水。将透析后的样品冷冻干燥,得到白色粉末状的产物,即醛基化透明质酸钠,醛基化率30%。
将5g醛基化透明质酸钠(醛基化率30%)和1g数均分子量500KDa的四臂端氨基修饰的聚乙二醇(Laysan)加4g硼酸-硼砂缓冲液(pH=8),37℃迅速震荡混合均匀,10秒后得到10g呈透明、均匀状态的pH敏感水凝胶。
pH敏感水凝胶的电镜扫描图显示水凝胶具有多孔且致密的结构,孔径在0.1mm-0.3mm,在正负电荷的相互作用下水凝胶的网孔孔径分布范围小,更加致密均匀。
以阿霉素作为模型药物探索了本发明水凝胶控制药物释放的性质:
应用例1
将阿霉素600mg、5g实施例1中的醛基化透明质酸钠(醛基化率5%)和1g数均分子量600KDa的四臂端氨基修饰的聚乙二醇加13.4g无菌去离子水,37℃迅速震荡混合均匀,22秒后得到20g呈透明、均匀状态的pH敏感载药水凝胶,包封率90%,载药量2.70%。
应用例2
将阿霉素600mg、10g实施例2中的醛基化透明质酸钠(醛基化率5%)和1g数均分子量1000KDa的四臂端氨基修饰的聚乙二醇加43.4g磷酸氢二钠-柠檬酸缓冲液(pH=6.5),37℃迅速震荡混合均匀,25秒后得到55g呈透明、均匀状态的pH敏感载药水凝胶,包封率92%,载药量1.00%。
应用例3
将阿霉素600mg、0.1g实施例3中的醛基化透明质酸钠(醛基化率5%)和1g数均分子量800KDa的四臂端氨基修饰的聚乙二醇加9.3g磷酸氢二钠-磷酸二氢钠缓冲液(pH=7.4),37℃迅速震荡混合均匀,30秒后得到11g呈透明、均匀状态的pH敏感载药水凝胶,包封率88%,载药量4.80%。
本发明水凝胶,随着聚合物浓度的增加成胶时间缩短,水凝胶的成胶时间可以方便的控制在10s-30s。本发明水凝胶成胶时间较短,可以在原位注射时避免各原料和溶液混合后凝胶分子浓度瞬间被体液等稀释而影响水凝胶的形成,具有可注射性。
本发明pH敏感水凝胶在pH=7.4的正常生理环境中稳定存在,至少一周以水凝胶的状态存在,在弱酸性条件下会逐渐水解直至最终变成溶液,降解代谢,例如在pH=6.8的环境中水凝胶一般会在4-5天完全水解成溶液,在pH=6.5的环境中水凝胶一般会在2-3天完全水解成溶液。
将实施例1-6中的pH敏感水凝胶采用RS 6000流变仪(Thermo-Fisher)在37℃的测试平台上进行流变分析测试,以实施例3中水凝胶的流变图(如图2所示)为例,流变结果显示:随着时间的增加储能模量G′与损耗模量G″逐渐增强,相同时间条件储能模量G′明显大于损耗模量G″,表明本发明水凝胶为弹性网孔结构。
应用例1-3中水凝胶负载药物后,水凝胶的成胶时间没有变化,表明本发明水凝胶负载药物前后均可以快速形成凝胶状,均具有良好的可注射性。
将应用例1-3中的所得载药水凝胶置于10ml的pH=7.4的磷酸盐缓冲溶液(PBS溶液)或者pH=6.5的PBS溶液中,37℃,40rpm恒温振荡器中进行体外药物释放,分别于多个时间点(T)取1ml上清液,每次取上清液后及时补入1ml的新鲜PBS溶液,采用HPLC法检测各时段上清液(样品)中阿霉素含量,计算药物累积释放率(%)。
HPLC检测条件:用0.5mL流动相再次溶解,用反相高效液相色谱(RP-HPLC,Agilent1200,Agilent Technologies Inc.,USA)检测其浓度。将20μL样品注射到ZORBAX EclipsePlus C18色谱柱(150mm×4.6mm),5.0μm,Agilent Corp.,USA)中,以1mL/min的淋洗速度洗脱,流动相组成为乙腈/水/甲醇(48/41/11,v/v/v),紫外检测波长为227nm。释放液中DOX的含量用紫外-可见分光光度计检测,检测波长为485nm。释放结果以三次重复测试的平均值绘图。
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%。
从药物释放曲线中发现,本发明水凝胶中的阿霉素能够缓释,并且其能够有效缓释长达12小时,由于凝胶的pH响应性,pH弱酸性条件下(pH6.5)释放的速度大于pH7.4条件下的释放速度,表明此凝胶释放体系在作为化疗药物缓释载体中有应用价值。另外由于本发明水凝胶具有pH敏感的降解性,在植入体内的材料,如栓塞材料或者组织工程材料等领域有应用价值。
Claims (9)
1.一种pH敏感水凝胶,其特征在于,由原料A、原料B和成胶液构成;所述原料A和原料B的质量之和在水凝胶中的质量百分比为10%-60%,其中原料A为醛基化透明质酸钠,原料B为四臂端氨基修饰的聚乙二醇;
所述醛基化透明质酸钠由数均分子量为0.6KDa-700KDa的透明质酸钠经氧化剂开环氧化得到;
所述四臂端氨基修饰的聚乙二醇的结构式如式Ⅰ所示:
式Ⅰ中n为聚合度,式Ⅰ所示四臂端氨基修饰的聚乙二醇的数均分子量为100KDa-1000KDa;
所述成胶液为去离子水或者pH值在6-8的缓冲溶液;
所述原料A和原料B的质量比为(0.1-10):1。
2.根据权利要求1所述的pH敏感水凝胶,其特征在于,所述原料A和原料B的质量之和在水凝胶中的质量百分比为10%-50%。
3.根据权利要求1所述的pH敏感水凝胶,其特征在于,所述原料A和原料B的质量之和在水凝胶中的质量百分比为10%-30%。
4.根据权利要求1所述的pH敏感水凝胶,其特征在于,所述缓冲溶液采用磷酸氢二钠-柠檬酸缓冲液、磷酸二氢钾-氢氧化钠缓冲液、磷酸氢二钠-磷酸二氢钠缓冲液、巴比妥钠-盐酸缓冲液、三(羟甲基)氨基甲烷-盐酸缓冲液、硼酸-硼砂缓冲液、甘氨酸-氢氧化钠缓冲液、硼砂-氢氧化钠缓冲液、碳酸钠-碳酸氢钠缓冲液中的一种或者多种。
5.根据权利要求1所述的pH敏感水凝胶,其特征在于,所述醛基化透明质酸钠的醛基化率在5%-30%。
6.根据权利要求1-5任一项所述的pH敏感水凝胶的制备方法,其特征在于,包括步骤:将原料A和原料B加成胶液混合均匀,得到pH敏感水凝胶。
7.根据权利要求6所述的pH敏感水凝胶的制备方法,其特征在于,所述pH敏感水凝胶的形成温度在20℃-38℃。
8.根据权利要求1-5任一项所述的pH敏感水凝胶在作为药物载体、栓塞材料或者组织工程材料中的应用。
9.根据权利要求8所述的应用,其特征在于,所述的药物载体为用于负载小分子药物的药物载体。
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