CN114748680B - 一种明胶-海藻酸盐复合可载药栓塞微球及其应用 - Google Patents
一种明胶-海藻酸盐复合可载药栓塞微球及其应用 Download PDFInfo
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Abstract
本发明公开了一种可载药栓塞微球，以海藻酸钠和明胶作为水相材料与含乳化剂的油相制成微乳后，经醛类交联剂和离子型交联剂交联而成。本发明所述可载药栓塞微球可通过电离作用负载化疗药物，载药性能可控，与现有栓塞微球相比载药量大大提高，并且可以实现化疗药物的缓释，不仅能阻断肿瘤生长所需要的营养来源血供，还可以提高病灶部位的局部药物浓度，同时降低其它脏器中的药物浓度，减少毒副作用,实现栓塞治疗与化疗的协同治疗效果，极具商业化的前景。
Description
技术领域
本发明属于医用生物高分子材料技术领域，具体涉及一种明胶-海藻酸盐复合可载药栓塞微球及其应用。
背景技术
经导管动脉化学栓塞术(Transcatheter Arterial Chemoembolization，简称TACE)是指在医学影像设备的辅助下，通过导丝将微导管***到肿瘤供血靶动脉后，注入适量的栓塞材料，使靶动脉血管闭塞，阻断肿瘤组织的血供，导致肿瘤缺血、缺氧，达到抑制肿瘤细胞生长、促使肿瘤细胞坏死、凋亡的目的。TACE疗法在近年来迅速发展成为一种重要的肿瘤治疗手段，在肝癌、肾癌、子宫肌瘤等血管富集性实体瘤的治疗中具有创伤小、选择性高、病人耐受性好和可靶向控制给药等优势。在该***细胞的介入治疗中，栓塞材料发挥着重要的作用。
第一代固体栓塞产品为形状不规则的明胶海绵和聚乙烯醇(PVA)颗粒，但由于其形状不规则，临床使用存在容易聚集，推注困难，对血管的栓塞不够彻底等缺点；第二代为形状规则的球形空白微球，如聚乙烯醇微球、明胶微球、海藻酸钠微球等，临床使用推注容易，栓塞效果好于第一代的产品；第三代栓塞材料为可载药栓塞微球，除了具有二代产品的形状规则、粒径均匀的特点外，此类微球还具有良好的弹性，可通过更细的导管进行推注。并且，针对大部分的一线抗癌药物都是带有正电荷的药物，现有的可载药微球会通过加入阴离子官能团修饰微球的化学结构，从而实现通过电荷作用负载抗癌药物和栓塞后药物释放的目的。目前市场上最主要的几种药物洗脱微球CalliSpheres、HepaSphere和DC Bead，每1毫升微球能负载的表柔比星的最高载药量在25～40mg之间。不过，此类微球均不可降解，药物只有大概30～40％释放，生物利用度低。
发明内容
本发明针对现有技术不足，提供了一种载药效率高并且具有理想的药物缓释性能的可载药水凝胶微球，所述微球还具有优异的力学性能和良好的生物相容性。本发明具体技术方案如下：
一种可载药栓塞微球，以海藻酸钠和明胶作为水相材料与含乳化剂的油相制成微乳后，经醛类交联剂和离子型交联剂交联而成。
优选的，所述醛类交联剂选自甲醛、戊二醛、双醛淀粉、葡聚糖醛的一种或几种；离子型交联剂包括二价和/或三价的金属离子和阴离子，二价或三价金属离子选自Ca2+、Sr2+、Ba2+、Zn2+、Cd2+、Gd2+、Fe2+、Cu2+、Pb2+、Fe3+、Al3+中的一种或几种，阴离子选自Cl-、Br-、NO3 -、HCO3 -、ClO-、ClO3 -、ClO4 -中的一种或几种。
优选的，所述海藻酸钠和明胶的质量比为1：1～50，进一步优选所述海藻酸钠、明胶、醛类交联剂、离子型交联剂的质量比为1：1～50：1～10：1～10。
优选的，油相中的乳化剂浓度为0.1～5％，更优选为0.5～2％。
优选水相与油相的体积比为1∶2～1∶20，更优选为1∶5～1∶10。
优选的，所述乳化剂选自司盘，吐温中的一种或多种；所述油相选自大豆油、芝麻油、液态石蜡，硅油，或者与水不互溶的有机溶剂中的一种或者多种。
本发明所述的微球，具体可采用如下方法制备：
(1)将海藻酸钠和明胶溶于水中制得水相溶液，海藻酸钠的质量体积百分浓度为0.1％-20％(g/ml)，明胶的质量体积百分浓度为0.1％-50％(g/ml)；
(2)将步骤(1)制备的水相溶液加到50～60℃含乳化剂的油相中，搅拌后(30min)，将温度降到2～8℃，持续搅拌(60min)；
(3)将步骤(2)的料液进行固液分离，并洗涤微球表面残留的油相；
(4)将步骤(3)得到的微球加到醛类交联剂的水溶液中搅拌分散均匀，于2-8℃下反应(0.1～24小时)，然后用蒸馏水洗涤微球；
(5)将步骤(4)得到的微球加到离子型交联剂的水溶液中搅拌分散均匀，于常温下反应(0.1～24小时)，然后用蒸馏水洗涤得到微球。
上述方法制得的微球还可以进一步冷冻干燥保存，或者在生理盐水或缓冲液中保存。
本发明还公开了上述微球在制备抗肿瘤药物载体中的应用。
本发明还公开了一种载药栓塞微球，其特征在于采用上所述微球与带正电荷药物混合，通过电离作用负载药物。
优选的，所述带正电荷药物选自盐酸阿霉素、表阿霉素、伊利替康、表柔比星、叱柔比星、吉西他滨、博来霉素、长春瑞滨、奥沙利铂中的一种或几种。
所述载药栓塞微球可以用于预防和***，例如肝癌、结直肠癌肝转移、肾癌、子宫肌瘤、血管瘤、乳腺恶性肿瘤等肿瘤。
微球为球形，粒径范围为10～2000μm，可筛分为10～100μm，100～300μm，300～500μm或500～700μm等粒径范围。
本发明所述的微球具有优异的力学性能，弹性模量为20-200kPa，优选为50-200kPa；降解时间为1～360天，优选为30～90天。
本发明优点：
(1)本发明所述微球内部天然具有带负电荷的结构，对带有正电荷基团的药物具有极强的亲和力，载药量高，有弹性，结构稳定。药物能够极为稳定地包裹在微球内，在植入人体后，可长期稳定的释放，既避免了此类抗肿瘤药物对正常组织的伤害，又提升了药物的治疗效果。
(2)本发明所述微球力学性能可控，可满足各种规格导管注射的要求。同时其药物负载量也可控，最大载药量高于市面上已有的可载药栓塞微球产品。本发明的载药微球所有药物会随着微球降解而全部释放，药物释放量大，大大的提高了药物的生物利用度。
附图说明
图1实施例1实验组5微球光镜图。
图2实施例1实验组5微球载药后的光镜图。
图3实施例1实验组3，4，5微球的载药曲线。
图4实施例1实验组5，11，12，14载药微球的药物释放曲线。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是示例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例1海藻酸盐-明胶微球的制备
水相：参照表1制备水相溶液10ml(加热至60℃溶解)。
油相：液体石蜡，2％Span80，50ml(加热至60℃)。
操作步骤：将油相加入烧杯，水浴60℃搅拌；加入水相，搅拌1分钟实现乳化；乳化后，转移至冰浴中降温继续搅拌1小时。用筛网过滤，用正己烷洗涤，最后用乙醇洗涤，收集。转移至10ml的20％的交联剂1溶液(pH8，4℃)中搅拌24hr进行交联。用水洗涤后，再将微球转移至50ml的5％交联剂2水溶液中搅拌3小时进行进一步交联。将水凝胶微球混悬液进行湿法筛分。光镜下观察微球形态。各实验组都能得到形状规则的圆球形的水凝胶微球。图1为实验组5微球光镜图。可看出，不同颗粒大小的微球被筛分出来，表面光滑，粒径较均一。
将筛分为～2000μm大小的水凝胶微球装入固定容器中平铺成固定高度，通过质构仪测量其在形变30％时对应的弹性模量。将表1各组的0.25ml的微球转移至西林瓶中，分别加入1ml 30mg/ml的表柔比星水溶液，浸泡过程中在0.5hr，1hr，2h，5hr，18hr取上清测量药物浓度，用以计算载药量。各实验组的复合水凝胶微球的弹性模量和最大载药量结果如表1所示。各组载药后微球仍然保持表面光滑，粒径较均一。图2为实验组5微球载药后的光镜图。
表1
结果表明：(1)单一成分的水相材料制成的微球载药量不理想；(2)交联剂1可显著提高微球的力学性能，交联剂2有利于提高微球的载药量；(3)海藻酸钠和明胶的组合相对于其它成分组合(实验组9和10)具有更为理想的载药量。其中第5组(2％海藻酸钠与10％明胶，20％戊二醛与5％氯化钙作交联剂)在形变30％时对应的弹性模量优于其他组，且最大载药量也明显优于其他组。
实验组3、4、5的载药曲线如图3所示。结果显示实验组5微球的载药速度最快，2个小时后载药量趋于平缓，最大载药量为100.3mg每1ml微球，远高于市场上的产品的最高载药量40mg/ml微球。
实施例2以明胶、海藻酸钠为水相材料，以醛类、离子型交联剂交联，考察各组分比例对力学性能和载药的影响。
水相：参照表2制备水相溶液10ml(加热至60℃溶解)。
油相：液体石蜡，2％Span80，50ml(加热至60℃)。
操作步骤：将油相加入烧杯，水浴60℃搅拌；加入水相，搅拌1分钟实现乳化；乳化后，转移至冰浴中降温继续搅拌1小时。用筛网过滤，用正己烷洗涤，最后用乙醇洗涤，收集。转移至10ml的20％的交联剂1溶液(pH8，4℃)中搅拌24hr进行交联。用水洗涤后，再将微球转移至50ml的5％交联剂2水溶液中搅拌3小时进行进一步交联。将水凝胶微球混悬液进行湿法筛分。
将筛分为～2000μm大小的水凝胶微球装入固定容器中平铺成固定高度，通过质构仪测量其在形变30％时对应的弹性模量。
各实验组的复合水凝胶微球的弹性模量见表2中。将各组的0.25ml的微球转移至西林瓶中，分别加入1ml 30mg/ml的表柔比星水溶液，测量最大载药量，结果如表2所示。
表2
结果表明海藻酸钠和明胶质量比为1：1时具有较好的载药量，在此基础上随着明胶比例的增加，力学性能和载药量都有明显的增加。而若海藻酸钠的比例高于明胶，载药量会有明显下降。其中第5组(2％海藻酸钠与10％明胶，20％戊二醛与5％氯化钙作交联剂)在形变30％时对应的弹性模量优于其他组且载药量最高。水相中明胶浓度高的实验组5，11，12制备出来的微球的力学性能和最大载药量明显优于其他实验组。
实施例3考察本发明所述载药微球的药物释放行为
将实施例2中载药后的实验组5，11，12，14的0.25ml微球转移至含有40ml生理盐水的离心管并置放于37℃水浴摇床中进行药物释放实验，在固定时间点0.5hr，1hr，2hr，5hr，24hr，48hr及72hr测量浸提液中的药物含量，从而计算药物的累积释放曲线。结果如图4所示。结果表明，各实验组的药物释放均能在3天内达到平台期，累计释放药物量均超过30％。实验组5的微球3天内累计释放率达到38％，相当于每1mL的载药微球在3天内最大能释放38mg的表柔比星，远高于市面上的可载药微球产品(每1mL微球最多释放～16mg表柔比星)。
Claims (3)
1.一种载表柔比星的栓塞微球，其特征在于以海藻酸钠和明胶作为水相材料与含乳化剂的油相制成微乳后，经醛类交联剂和离子型交联剂交联而成，采用如下方法制备：
(1)将海藻酸钠和明胶溶于水中制得水相溶液，海藻酸钠质量体积百分浓度为2％，明胶的质量体积百分浓度为10％；
(2)将步骤(1)制备的水相溶液加到50～60℃含乳化剂的油相中，搅拌后，将温度降到2～8℃，持续搅拌，油相中的乳化剂质量体积百分浓度为0.5～2％，水相与油相的体积比为1∶5～1∶10；
(3)将步骤(2)的料液进行固液分离，并洗涤微球表面残留的油相；
(4)将步骤(3)得到的微球加到质量体积百分浓度为20％戊二醛的水溶液中搅拌分散均匀，于2-8℃下反应，然后用蒸馏水洗涤微球；
(5)将步骤(4)得到的微球加到质量体积百分浓度为5％离子型交联剂的水溶液中搅拌分散均匀，于常温下反应，然后用蒸馏水洗涤得到微球，所述离子型交联剂为Ca2+和阴离子，所述阴离子选自Cl-、Br-、NO3 -、HCO3 -、ClO-、ClO3 -、ClO4 -中的一种或几种；所述海藻酸钠、明胶、醛类交联剂、离子型交联剂的质量比为1：1～50：1～10：1～10；
(6)将步骤(5)制备得到的微球加入表柔比星水溶液，通过电离作用负载表柔比星。
2.根据权利要求1所述的微球，其特征在于所述乳化剂选自司盘，吐温中的一种或多种；所述油相选自大豆油、芝麻油、液态石蜡或硅油中的一种或者多种。
3.权利要求1或2所述微球在制备抗肿瘤药物载体中的应用。
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