CN100347225C - 一种生物可降解的反向温度敏感材料的制备方法 - Google Patents
一种生物可降解的反向温度敏感材料的制备方法 Download PDFInfo
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Abstract
一种生物可降解的反向温度敏感材料的制备方法,涉及一种在药物传输***、细胞包埋、生物组织工程、医疗器械领域使用的材料的制备。本发明以多聚糖类生物可降解材料诸如明胶、黄原胶、壳聚糖或木聚糖为主要骨架材料,导入网络贯穿助剂聚烯醇,形成双交联或者杂化凝胶网络结构。制备方法如下:多聚糖与聚烯醇的水溶液经交联剂交联,再与多羟基磷酸盐冰浴共溶,反应后用饱和磷酸氢二钠溶液调节pH至6.8~7.4,得到可注射的生物可降解的溶胶-凝胶转变体系。本材料在37℃迅速形成凝胶,具有温度敏感性;聚烯醇的加入增强了疏水相互作用,提高了凝胶的强度,同时可减缓药物分子在凝胶网络中的扩散速度。
Description
技术领域
本发明涉及一种生物可降解的、具有反向温度敏感性的材料及其制备方法,该材料将在药物传输***、细胞包埋、生物组织工程、医疗器械领域具有良好的应用前景。
背景技术
新型材料的开发成功对于迅速发展的医药技术具有非常重要的意义。特别是生物高分子材料在给药技术领域、组织工程领域有着非常广泛的应用。传统应用的材料,如硅橡胶,不具有生物相容性和生物降解性,因而会具有某些毒性和刺激性;同时在作为给药材料的载体,特别是应用于诸如埋植给药***中时,无可避免的要使用手术进行植入,这是这类体系存在的最大的缺点。目前,大多数研究采用合成型温敏型生物可降解材料作为新一代的替代品,如PLA-PEO-PLA共聚物等:这类共聚物的溶液在45℃时为溶液状态,在体温37℃凝固,形成凝胶,属于正向温度敏感材料。但是这类材料因其注射温度高和高聚物浓度高而可能影响其临床应用前景。目前国外报道的一些室温下为液体、体温下为固体的温度敏感性材料在稳定性、凝胶强度、生物相容性或生物可降解性方面存在着一些问题,例如文献“Yong Qiu,KinamPark,Environment-sensitive hydrogels for drug delivery,Advanced Drug DeliveryReviews 53(2001)321-339”。
发明内容
本发明的目的在于提供一种生物可降解的反向温度敏感材料的制备方法,从而开发一种凝胶性质稳定、凝胶强度较大,可在药物传输***、细胞包埋、生物组织修复、医疗器械等领域使用的生物可降解的具有反向温度敏感性的材料。
本发明的技术方案如下:一种生物可降解的反向温度敏感材料的制备方法,其特征在于该方法按如下步骤进行:
1)将除杂得到的多聚糖粉末溶解于弱酸或水中,制成质量/体积浓度0.5%~4%的溶液,过滤除杂备用;
2)在所述溶液中加入网络贯穿助剂聚烯醇,于70~80℃加热至完全溶解,聚烯醇与多聚糖的质量比为10∶1~1∶10,控制体系的最终质量/体积浓度为1.0~8.0%,冷却至室温,消泡;
3)边搅拌边滴加交联剂,交联剂在体系中的最终浓度为0.1~1000μM;所述交联剂采用表氯醇、戊二醛或多聚磷酸钠;
4)交联反应结束后,转入冰水浴,加入含有多羟基磷酸基团的盐的饱和水溶液,使多羟基磷酸盐的最终质量/体积浓度为0.5~15%,搅拌至少30分钟;
5)缓慢滴加饱和磷酸氢二钠水溶液,调节pH至6.8~7.4,得到可注射的生物可降解的溶胶-凝胶转变体系。
本发明所述的多聚糖优选为明胶、黄原胶、壳聚糖或木聚糖。所述聚烯醇优选为聚乙烯醇或聚丙烯醇。所述多羟基磷酸基团采用甘油磷酸基团、葡萄糖磷酸基团或果糖磷酸基团。
本发明与现有技术相比具有以下优点及突出性效果:本发明制备工艺简单,是一种基于多聚糖物质形成的水凝胶,但是常见方法制备的这类水凝胶的水含量较高,从而导致凝胶的强度较低。本发明在水凝胶体系中导入网络贯穿助剂(聚烯醇),可形成双交联或者杂化凝胶网络结构。该网络结构通常由共价键、静电相互作用、疏水相互作用维系。网络贯穿助剂的加入可以提高凝胶的强度,增加疏水相互作用,同时可减缓药物分子在凝胶网络中的扩散速度。本发明可作为一种温度敏感型给药制剂,在常温状态下为溶液状态,作为给药制剂时,可制成冻干粉针剂。应用中,可在皮下注射几分钟后可形成凝胶,溶液在体温状态下凝固快,无须通过手术植入和取出。与单纯的多聚糖和多羟基磷酸盐体系相比,对药物分子具有很好的控制释放能力,具有良好的临床应用潜力。
附图说明
图1为利用Brookfield转子粘度计,固定剪切率为1rpm,测定体温条件下四种实施例的粘度随时间的变化曲线。
图2为四种实施例的剪切模量G。
图3为溶菌酶在四种实施例中的释放曲线。
具体实施方式
本发明以多聚糖诸如明胶、黄原胶、壳聚糖或木聚糖生物可降解材料为主要骨架材料,先将其溶于水或弱酸中,制成质量/体积浓度为0.5%~4%的溶液,再与网络贯穿IPN助剂(聚烯醇)共溶,聚烯醇与多聚糖的质量比为10∶1~1∶10,控制体系的最终质量/体积浓度为1.0~8.0%,反应至少30min,一般为30~60min,经与表氯醇、戊二醛或多聚磷酸钠交联剂交联,交联时间一般为1~10min,再与多羟基磷酸盐冰浴共溶,调节pH至6.8~7.4,即制得可注射的生物可降解的溶胶-凝胶转变体系。其特点在于在常温(室温)下为液体,可于人体生理环境下(37℃左右,pH=6.8~7.4)在短时间内形成凝胶。
下面通过几个具体的实施例描述对本发明做进一步的说明。
实施例1:
将除杂得到的明胶粉末溶解于水中,制成质量/体积浓度4%的溶液,过滤除杂备用;在溶液中加入网络贯穿助剂聚丙烯醇,明胶与聚丙烯醇的质量比为1∶1,于70~80℃加热至完全溶解,控制体系的最终质量/体积浓度为8.0%,冷却至室温,消泡;边搅拌边滴加表氯醇浓度至最终浓度为100μM;交联反应结束后,转入冰水浴,加入含有葡萄糖磷酸钠的饱和水溶液,使葡萄糖磷酸钠最终质量/体积浓度为10%,30~60分钟;缓慢滴加饱和磷酸氢二钠水溶液,调节pH至7.4,分装,做3组平行实验。
实施例2:
将除杂得到的壳聚糖粉末溶解于醋酸溶液中,制成质量/体积浓度0.9%的溶液,过滤除杂备用;在溶液中加入网络贯穿助剂聚乙烯醇,壳聚糖与聚乙烯醇的质量比为10∶1,于70~80℃加热至完全溶解,控制体系的最终质量/体积浓度为1.0%,冷却至室温,消泡;边搅拌边滴加戊二醛浓度至最终浓度为0.1μM;交联反应结束后,转入冰水浴,加入含有甘油磷酸钠的饱和水溶液至甘油磷酸钠的质量终质量/体积浓度为15%,30~60分钟;缓慢滴加饱和磷酸氢二钠水溶液,调节pH至7.2,分装,做3组平行实验。
实施例3:
将除杂得到的黄原胶粉末溶解于水中,制成质量/体积浓度0.2%的溶液,过滤除杂备用;在溶液中加入网络贯穿助剂聚丙烯醇,黄原胶与聚丙烯醇的质量比为1∶10,于70~80℃加热至完全溶解,控制体系的最终质量/体积浓度为2.0%,冷却至室温,消泡;边搅拌边滴加多聚磷酸钠至最终浓度为1000μM;交联反应结束后,转入冰水浴,加入含有果糖磷酸钾的饱和水溶液至果糖磷酸钾的质量/体积浓度为0.5%,30~60分钟;缓慢滴加饱和磷酸氢二钠水溶液,调节pH至7.4,分装,做3组平行实验。
实施例4:
将除杂得到的木聚糖粉末溶解于水中,制成质量/体积浓度0.5%的溶液,过滤除杂备用;在溶液中加入网络贯穿助剂聚乙烯醇,木聚糖与聚乙烯醇的质量比为1∶5,于70~80℃加热至完全溶解,控制体系的最终质量/体积浓度为3.0%,冷却至室温,消泡;边搅拌边滴加戊二醛至最终浓度为100μM;交联反应结束后,转入冰水浴,加入含有甘油磷酸钠的饱和水溶液至甘油磷酸钠的质量终浓度为质量/体积浓度10%,30~60分钟;缓慢滴加饱和磷酸氢二钠水溶液,调节pH至6.8,分装,做3组平行实验。
水凝胶性质评价如下:
A:测定上述四处方在体温下,某剪切率为1rpm下粘度值随时间变化,描绘粘度变化曲线,见附图1。该材料具有温度敏感特性,一般在10分钟内形成凝胶,温度稍高,凝固更快。
B:凝胶的强度可以用凝胶的剪切模量G表征。可以用简单方法测定。将直径A0及高度L0均为1cm的圆柱形样条,再其上面施加一定压力F,30s弛豫后读出试样被压缩到的高度L1。应力-应变关系可由方程表征:
F/A0=-G(λ-λ-2);λ=L1/L0为形变比(λ=1.0~0.7)
根据此式可以计算凝胶的剪切模量。不同交联度的水凝胶的剪切模量G见附图2。
C:大分子药物溶菌酶在本材料中的释放:
处方:
溶菌酶 24mg
实施例1~4溶胶用量 12mL
分装,做4组平行实验。
释放条件:水浴振荡仪,溶出介质:PBS缓冲溶液(pH=7.4,0.2M);温度:37℃:转速:80rpm。定期取样测定释放液中溶菌酶的活性,其释放曲线见附图3。本发明较单纯的多聚糖、多羟基磷酸盐水凝胶体系有较好的控制药物释放的能力。
上述实施例中的凝固特性、凝胶强度和药物释放的性质见说明书附图。
Claims (4)
1.一种生物可降解的反向温度敏感材料的制备方法,其特征在于该方法按如下步骤进行:
1)将除杂得到的多聚糖粉末溶解于弱酸或水中,制成质量/体积浓度0.5%~4%的溶液,过滤除杂备用;
2)在所述溶液中加入网络贯穿助剂聚烯醇,于70~80℃加热至完全溶解,聚烯醇与多聚糖的质量比为10∶1~1∶10,控制体系的最终质量/体积浓度为1.0~8.0%,冷却至室温,消泡;
3)边搅拌边滴加交联剂,交联剂在体系中的最终浓度为0.1~1000μM;所述交联剂采用表氯醇、戊二醛或多聚磷酸钠;
4)交联反应结束后,转入冰水浴,加入含有多羟基磷酸基团的盐的饱和水溶液,使多羟基磷酸盐的最终质量/体积浓度为0.5~15%,搅拌至少30分钟;
5)缓慢滴加饱和磷酸氢二钠水溶液,调节pH至6.8~7.4,得到可注射的生物可降解的溶胶-凝胶转变体系。
2.根据权利要求1所述生物可降解的具有反向温度敏感性材料的制备方法,其特征在于:所述的多聚糖为明胶、黄原胶、壳聚糖或木聚糖。
3.根据权利要求1所述生物可降解的具有反向温度敏感性材料的制备方法,其特征在于:所述聚烯醇为聚乙烯醇或聚丙烯醇。
4.根据权利要求1所述生物可降解的具有反向温度敏感性材料的制备方法,其特征在于:所述多羟基磷酸基团为甘油磷酸基团、葡萄糖磷酸基团或果糖磷酸基团。
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