CN108261561B - 一种可显影透明质酸微球栓塞剂及其制备方法和应用 - Google Patents

一种可显影透明质酸微球栓塞剂及其制备方法和应用 Download PDF

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CN108261561B
CN108261561B CN201810088706.6A CN201810088706A CN108261561B CN 108261561 B CN108261561 B CN 108261561B CN 201810088706 A CN201810088706 A CN 201810088706A CN 108261561 B CN108261561 B CN 108261561B
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朱剑锋
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Hangzhou Singclean Medical Products Co Ltd
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Abstract

本发明提供一种可显影透明质酸微球栓塞剂及其制备方法和应用，该微球栓塞剂由改性后的生物可降解材料透明质酸和水溶性碘化物组成，可在X射线下显影，可用于子宫癌、肺癌、肝癌、肾癌、血管瘤及各种富血管性实质脏器肿瘤的动脉栓塞和局部靶向栓塞的治疗中。它包括以下步骤：水溶性碘化物的透明质酸溶液加到含乳化剂的油相中形成油包水乳液，乳液中加入交联剂后反应获得含碘化物的透明质酸微球，最后经萃取，真空干燥获得可显影透明质酸微球栓塞剂。

Description

一种可显影透明质酸微球栓塞剂及其制备方法和应用
技术领域
本发明涉及一种可显影透明质酸微球栓塞剂及其制备方法。
背景技术
介入栓塞治疗是指药物在X射线透视下通过插入的靶动脉导管输送栓塞药物，阻断肿瘤血供，达到物理栓塞的作用。该方法最用于肝癌的治疗，相比传统的化疗具有明显的优势。
目前临床使用的大部分栓塞剂材料均能够被X射线透过，实际的使用过程中需与不透X射线的显影剂混合，如硫酸钡、钽粉等。但混合注入人体后容易发生栓塞剂和显影剂的分离，增加了造成误栓和异位栓塞的可能性；且这显影剂进入人体血管后很快随着血液经肾脏代谢出体外，在后期术后复查随访时不能用X射线进行观察，而需再次作二次血管造影，增加了对病人身体的损害。
对此，制备具有显影功能的新型血管栓塞剂成了近年来该领域研究的主要方向。目前研究的最多的为聚乙烯醇颗粒栓塞剂，包埋的显影剂有钽粉、碘化油等，但该颗粒大小不均一，形状不规则，容易造成栓塞不彻底。近年来微球型栓塞剂逐渐替代普通颗粒型栓塞剂，微球型栓塞剂能更有效的栓塞远端血管，并在栓塞过程中大大地降低血管中的摩擦系数。
透明质酸最早是从牛眼玻璃体中发现，由葡萄糖醛酸和乙酰氨基葡萄糖双糖相互结合构成的线性高分子多糖，天然的透明质酸在体内存留时间约在3～15天之间，经化学修饰改性后在抗降解性提高的同时也保留了天然透明质酸原本特有的生物相容性，高粘弹性及无任何副作用的性质。通过乳液聚合的方法将透明质酸包埋显影剂，并对透明质酸进行化学改性，制备出表面光滑的、不透X射线的透明质酸微球栓塞剂。
发明内容
本发明的第一个目的在于提供一种可显影透明质酸微球栓塞剂，该栓塞剂球体形态均一、表面光滑、可降解、不透X射线。为此，本发明采用以下技术方案：
一种可显影透明质酸微球栓塞剂，由透明质酸和不透X射线的造影材料组成，不透X射线的造影材料由透明质酸所包埋。
所述的透明质酸指改性后的透明质酸，改性方式可为交联、接枝、酯化和复合，优选为交联改性；
本发明的第二个目的在于提供一种可显影透明质酸微球栓塞剂的制备方法包括以下步骤：
1)配制浓度为0.1～0.3g/mL的透明质酸溶液，溶液中包含了碘化物；
2)将步骤1)的透明质酸溶液加到含乳化剂的液体石蜡中，经剪切机500rpm～2000rpm乳化，形成包埋了碘化物的透明质酸微球的油包水型乳液；
3)在步骤2)所得的乳液中加入0.2～2％体积百分比的交联剂，室温下搅拌4～6h进行交联反应，反应结束后静置去除油相层，依次用酸性溶剂、水溶性有机溶剂洗涤水相层洗涤水相层，最后真空干燥获得含碘化物的透明质酸微球，微球可在X线机下显影。
所述的不透X射线的造影材料为水溶性碘化物，优选为无机碘化物的碘化钠，有机碘化物中毒副作用较小的非离子型碘化物，为N,N'-双(2,3-二羟丙基)-2,4,6-三碘-5-[(2-甲氧基乙酰基)氨基]-N'-甲基苯基-1,3-甲酰胺(碘普罗胺)、N,N'-双(2,3-二羟基丙基)-5-[N-(2,3-二羟基丙基)乙酰氨基]-2,4,6-三碘异酞酰胺(碘海醇)、(S)-N,N'-双[2-羟基-1-(羟甲基)乙基]-5-[N-[(2-羟基-1-氧化丙基)氨基]-2,4,6-三碘-1,3-苯二甲酰胺(碘帕醇)、5,5'-((2-羟基-1,3-丙烷)双(乙酰亚氨))双(N,N'-二(2,3-二羟基丙基)-2,4,6-三碘-1,3-苯二甲酰胺(碘克沙醇)。
所述的透明质酸选用细菌发酵法生产的透明质酸钠，避免了动物提取所带的动物源性风险。为提高微球的收益，透明质酸分子量介于30万～300万道尔顿之间，优选为60万～200万道尔顿之间。
所述的透明质酸溶液呈碱性，优选为氢氧化钠溶液所配制的。
所述的交联剂选自环氧化物、二乙烯基砜、1,4—丁二醇二缩水甘油醚或甘油二缩水甘油醚，优选为毒副作用较小的1,4—丁二醇二缩水甘油醚。
所述的乳化剂选自斯盘类或斯盘类与吐温类的混合物中的一种或多种。
所述的可显影透明质酸微球在生理盐水或磷酸盐缓冲液中复溶后的粒径范围在80～2000μm之间。
所述的酸性溶剂优选为乙酸，水溶性有机溶剂优选为乙酸乙酯、无水乙醇、丙酮。酸性溶剂作用主要是调节水相层的pH，阻碍交联反应，避免交联度过高影响显影材料包封效率；水溶性有机溶剂作用主要是洗涤残留的油相。
所述可显影透明质酸微球栓塞剂与抗肿瘤药物结合，载药后可作为栓塞剂。进一步地，所述的可显影透明质酸微球栓塞剂可在制备子宫癌、肺癌、肝癌、肾癌、血管瘤及各种富血管性实质脏器肿瘤的动脉栓塞和局部靶向栓塞的治疗药物中应用。
本发明的优点在于可显影透明质酸微球栓塞剂具有透明质酸良好的生物相容性，采用微生物发酵的透明质酸避免了动物源性，临床安全性得到保证；微球球体形态均一、表面光滑可提高临床栓塞效果，可显影功能大大提高栓塞的成功率，减少栓塞材料和显影剂的使用，大大降低毒副作用；同时可显影透明质酸微球栓塞剂在体内可降解，可在制备过程中加入抗肿瘤药物，在栓塞的同时又能起到靶向药物化疗的作用。
附图说明
图1为实施例1制备的产品在X射线下与阳性对照的显影效果；
图2为实施例1制备的产品在扫描电镜下的视野图，微球形态形态均一、表面光滑；
图3为实施例1制备的产品压缩形变前后的对比
具体实施方式
以下给出本发明的实施例，进一步对本发明进行详细说明，但本发明并不限于此。
实施例1，制备含碘海醇的透明质酸微球栓塞剂
称取透明质酸钠固体粉末8.04g，用0.5％氢氧化钠溶液配制浓度为0.1g/mL的透明质酸溶液，其中包含了0.07g/mL的碘海醇，将透明质酸溶液加入到油相中，该油相含液体石蜡200.71g和Span80 3.41g；混合相经剪切机1000rpm乳化分散10分钟，获得油包水型透明质酸微球乳液；乳液中加入1％的1,4—丁二醇二缩水甘油醚，并在室温下搅拌4h进行交联反应，搅拌结束后静置过夜，使微球沉降；倾倒上层油相，加入乙酸调节pH至4.0‐5.0之间，再依次用乙酸乙酯、无水乙醇洗涤以除去残留的有机相，真空干燥获得含碘化物的透明质酸钠微球；最后经筛分、灭菌即得可显影透明质酸微球栓塞剂。
实施例2，制备含碘海醇的透明质酸微球栓塞剂
称取透明质酸钠固体粉末8.02g，用0.5％氢氧化钠溶液配制浓度为0.1g/mL的透明质酸溶液，其中包含了0.07g/mL的碘海醇，将透明质酸溶液加入到油相中，该油相含液体石蜡201.01g和Span80 3.45g；混合相经剪切机1000rpm乳化分散10分钟，获得油包水型透明质酸微球乳液；乳液中加入1％的1,4—丁二醇二缩水甘油醚，并在室温下搅拌4h进行交联反应，搅拌结束后静置过夜，使微球沉降；倾倒上层油相，依次用乙酸乙酯、无水乙醇洗涤以除去残留的有机相，真空干燥获得含碘化物的透明质酸钠微球；最后经筛分、灭菌即得可显影透明质酸微球栓塞剂。
透明质酸微球栓塞剂显影剂含量测定
取上述实施例制备的干燥状态下的微球，溶于生理盐水当中，充分溶胀后测定微球的显影剂含量。碘海醇含量采用紫外分光光度法测定。
实施例1的微球的碘海醇含量为26％；
实施例2的微球的碘海醇含量为18％。
透明质酸微球栓塞剂显影效果测试
取实施例1制备的透明质酸微球栓塞剂与1mL生理盐水混合，另取碘海醇1mL作阳性对照，在X射线机下做显影测试。
对比例1，制备不含显影材料的交联透明质酸微球栓塞剂
称取透明质酸钠固体粉末8.14g，用0.5％氢氧化钠溶液配制浓度为0.1g/mL的透明质酸溶液，将溶液加入到油相中，该油相含液体石蜡200.98g和Span803.42g；混合相经剪切机1000rpm乳化分散10分钟，获得油包水型透明质酸微球乳液；乳液中加入1％的1,4—丁二醇二缩水甘油醚，并在室温下搅拌4h进行交联反应，搅拌结束后静置过夜，使微球沉降；倾倒上层油相，依次用乙酸乙酯、无水乙醇洗涤以除去残留的有机相，真空干燥获得含碘化物的透明质酸钠微球；最后经筛分、灭菌即得可显影透明质酸微球栓塞剂。
测试例1，包埋显影剂后透明质酸微球栓塞剂性能测试
将实施例和对比例制备的样品进行压缩形变性能、溶胀度、透明质酸钠含量测试，考察包埋显影材料后还是否保持原有的特性。压缩形变性能表征微球的弹性，良好的压缩变形能力，可使栓塞微球能够有效的变形通过注射器及微细导管后能恢复到原状；溶胀度表征微球的交联度，可体现为在体内的降解性；透明质酸钠含量为栓塞微球的有效成分，采用咔唑法检测。
性能测试 实施例1 实施例2 对比例1
压缩形变 62.4％ 44.2％ 59.7％
溶胀度 96 68 90
透明质酸钠含量 12.5mg/mL 16.2mg/mL 13.4mg/mL
由实施例1和实施例2的显影剂含量测定结果对比得知，在其余制备方法相同的情况下，按照本发明的方法，交联反应后的微球用酸性溶剂洗涤以降低pH环境可比直接用水溶性有机溶剂洗涤所获得的微球具有更高的显影剂含量，包封效率更好。
由实施例1和对比例1得知，在投料比和工艺参数不变的条件下实施例1增加了包埋显影材料，制备获得的微球栓塞剂在性能测试方面基本无差异。
以上所述仅为本发明的具体实施例，但本发明的结构特征并不局限于此，任何本领域的技术人员在本发明的领域内，所作的变化或修饰皆涵盖在本发明的保护范围之中。

Claims (3)

1.一种可显影透明质酸微球栓塞剂，其特征在于：可显影透明质酸微球栓塞剂由透明质酸和不透X射线的造影材料组成；
所述的透明质酸指改性后的透明质酸；所述的不透X射线的造影材料为水溶性碘化物；所述可显影透明质酸微球栓塞剂的制备方法包括以下步骤：
1）配制浓度为0.1~0.3g/mL的透明质酸溶液，溶液中包含了碘化物；
2）将步骤1）的透明质酸溶液加到含乳化剂的液体石蜡中，经剪切机500rpm~2000rpm乳化，形成包埋了碘化物的透明质酸微球的油包水型乳液；
3）在步骤2）所得的乳液中加入0.2~2%体积百分比的交联剂，室温下搅拌4~6h进行交联反应，反应结束后静置去除油相层，依次用酸性溶剂、水溶性有机溶剂洗涤水相层，最后真空干燥获得含碘化物的透明质酸钠微球，微球可在X线机下显影。
2.根据权利要求1所述的一种可显影透明质酸微球栓塞剂，其特征在于所述的透明质酸选用细菌发酵法生产的透明质酸钠，分子量介于30万~300万道尔顿之间；所述的交联剂选自环氧化物、二乙烯基砜、1,4—丁二醇二缩水甘油醚或甘油二缩水甘油醚；所述的乳化剂选自司盘类或司盘类与吐温类的混合物。
3.根据权利要求1所述的一种可显影透明质酸微球栓塞剂在制备子宫癌、肺癌、肝癌、肾癌、血管瘤及各种富血管性实质脏器肿瘤的动脉栓塞和局部靶向栓塞的治疗药物中的应用。
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