CN107875436B - 一种负载碳酸氢钠粉末的液体栓塞剂组合物及其应用 - Google Patents
一种负载碳酸氢钠粉末的液体栓塞剂组合物及其应用 Download PDFInfo
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- A61L2300/602—Type of release, e.g. controlled, sustained, slow
Abstract
本发明公开一种负载碳酸氢钠粉末液体栓塞剂组合物及其应用。该液体栓塞剂由阴离子改性的聚乙烯‑聚乙烯醇共聚物(EVOH)，溶剂，小苏打粉末和显影剂按一定比例混合组成。EVOH通过化学修饰或者接枝改性的方法在高分子链上引入负离子基团，这些负离子基团可以通过正负电荷相互作用对阳离子化的化疗抗癌药进行吸附负载。溶剂可以是二甲基亚砜(DMSO)，N‑甲基吡咯烷酮(NMP)，乙醇或者是它们的混合物。显影剂是微米级金属钽粉或者是含碘照影剂，或者是它们的混合物。小苏打可以敏化肿瘤细胞的缺血效应，从而提高栓塞疗效。该液体栓塞剂组合物可广泛应用于制备介入栓塞治疗的药物，尤其适用于制备肝癌经动脉化疗栓塞治疗(TACE)的药物。
Description
技术领域
本发明涉及一种的负载碳酸氢钠粉末的液体栓塞剂组合物及其应用。该液体栓塞剂组合物主要用于介入制备治疗肿瘤疾病的药物上。尤其适用于制备肝癌的TACE治疗的药物。
背景技术：
TACE，经动脉化疗栓塞术(Trans Arterial Chemo Embolization)是日本学者Yamada于1997年首次提出。最早应用于肝癌的治疗，现在已经成为超过90％的中期以及中后期的肝癌病人会选择的主流治疗术式。它是指在X射线下，利用微导管经过股动脉，腹主动脉，肝主动脉将栓塞剂靶向性灌注到肿瘤病灶部位。栓塞剂对肿瘤供血动脉进行栓塞阻断，肿瘤组织血供被阻后，使得肿瘤得不到生长必须的营养，达到饿死肿瘤细胞的目的。除此之外，如果栓塞剂具有载药功能，那么，栓塞剂可以在靠近肿瘤病灶附件形成精准靶向释放抗癌药物的疗效。避免了传统全身性化疗药物治疗对于人体正常组织不必要的伤害。从肝癌病理分析，肝组织由肝动脉和门静脉双重供血。正常肝组织的供血：75％由门静脉供血，25％由肝动脉供血。正常肝组织的供血与肝癌肿瘤组织的供血差异极大。肝癌肿瘤组织的供血95％-99％来自于肝动脉。基于这种差异，利用微导管通过肝动脉对肿瘤部位的肝动脉进行靶向给药，定向栓塞。这样可以使肿瘤病灶部位的药物浓度高出全身性化疗1到2个数量级，极大的保护了正常肝组织，实现了杀死肿瘤细胞的目的。当然，因为肝肿瘤大多为多重供血，因此经动脉化疗栓塞治疗只能在一定范围一定区域有效杀死肝癌肿瘤细胞，难以实现根治肝癌的目的。但是，对于中后期的肝癌病人，肿瘤通常都大于3cm或者已经大于5cm，这时，倘若能够有效控制病情的发展，甚至使肿瘤逐步萎缩达到延长病人生命的目的，也不失为一种有价值的治疗手段。
在TACE术式中，最常用的是碘油和微球。对于低端市场的需求，碘油作为一种液体栓塞剂以其价格便宜，使用方便的优势成为了医生的首选。而对于一些高端市场的雪球，载药微球则因其可载药的优势成为TACE术式中发展趋势。碘油，这种液态栓塞剂，最大的缺点就是它不能形成永久栓塞，它会在1个月左右逐渐被身体代谢掉。所以，栓塞的血管得以再通。所以，往往碘油栓塞1-2个月以后，病人需要再次栓塞。然而，碘油作为液体栓塞剂，它的弥散性，渗透性，导管通过性是微球或者其它栓塞材料无法比拟的。它可以超选到非常细小的血管形成栓塞。而微球或者其它固态栓塞剂，最小也就能阻断到50微米血管。微球作为一种新型的栓塞剂。微球按照所用的材料可以分为聚乙烯醇微球、明胶微球、海藻酸钠微球、聚乳酸微球、聚羟乙基纤维素微球、聚甲基丙烯酸酯类微球、聚壳聚糖微球、淀粉微球。微球的通常具有一下优良性能特点：形状规整，尺寸均一，表面光滑，生物安全性兼容性好，粒子相互粘结性差，微球弹性变形性好。并且载药微球因为微球表面有一些负电荷的化学基团，因此可以靠电荷相互作用吸附带正电荷的抗癌化疗药物。因此，微球在生理盐水中的悬浮稳定性和在微导管内的输送性都非常好，且可以对肝癌肿瘤组织定点靶向缓释化疗药物。载药微球作为栓塞剂的治疗效果更加安全有效，是目前最常用的栓塞剂。按照在人体内栓塞时间的长短，栓塞微球可分为可降解性微球和不可降解性微球。其中不可降解性微球栓塞动脉后能够持久停留，具有强大的栓塞作用，起着真正的永久性栓塞作用。国外已有较多成熟并投入使用的不可降解性栓塞微球，例如EmboSphere微球，HepaShpere微球，BeadBlock微球，DC Bead微球，LC Bead微球，SAP微球，Embozene微球，Tandem微球等等。这些微球可以长时间在血管中栓塞，不被人体降解，因此会永远留在病人体内，形成永久栓塞；而且现今大多数微球的显影与给药是单独进行的，也就是说在分别将微球和造影剂注射病人体内后，可能造成微球和造影剂的分离脱节，从而不能准确地观察到微球的具体位置。简单讲，迄今仍然还没有一种微球自带显影性能。此外，进口微球价格昂贵，病人难以承受。
浙江大学肿瘤研究所教授胡汛和研究团队一起发现了“饿死”癌细胞的新疗法，并发表在国际生物和医学领域权威杂志elife上，得到了国际著名肿瘤学者的肯定。“饿死”癌细胞也需要‘吃’东西才能生存，剥夺它的食物，“饿死”癌细胞就会死亡。该研究团队认为肿瘤中有大量的乳酸，乳酸解离成乳酸阴离子和氢离子，成为癌细胞的两位“帮手”，让其自身能够根据“食物”的多少决定“消耗”多少。因此，若想有效“饿死”癌细胞，不仅要剥夺葡萄糖，还需同时破坏乳酸阴离子和氢离子的协同作用。在葡萄糖饥饿或缺乏的前提下，只要去除这两个因子中的任何一个，癌细胞就会快速死亡。研究团队临床研究结果显示：用cTACE(传统碘油栓塞的TACE)治疗了37例病人，18例有效；用TILA-TACE(小苏打结合传统TACE手术)治疗了40例病人，40例有效。而且，在这个临床研究中用TILA-TACE治疗的肝癌都是难治型肝癌。而国际上综合报道，cTACE治疗的平均客观有效率仅为35％。
发明内容
本发明的目的在于克服上述技术的不足，提供一种负载碳酸氢钠粉末的药液体栓塞剂组合物及其应用。含有聚乙烯-聚乙烯醇重复单元的共聚物的Onyx胶是一种新型的液态栓塞剂,允许长时间注射,具有更好的弥散性和更高的栓塞率,自显影性，且具有非粘附的特点。Onyx胶在脑动静脉畸形(AVM)的栓塞中普遍被使用。Onyx胶组成非常简单，它由聚乙烯醇聚乙烯共聚物(EVOH)，二甲基亚砜(DMSO)溶剂和微米级钽粉组成。因此本发明是基于原Onyx胶进行优化改进。将Onyx胶中的聚乙烯-聚乙烯醇重复单元的共聚物(EVOH聚合物)做化学改性修饰。通过对EVOH聚合物的高分子链的化学修饰，使高分子链化学键合上一些阴离子基团。这些阴离子基团可以对带正电荷的阳离子化的抗癌药物进行吸附负载。同时保留原微米级金属钽粉使该液体栓塞剂具有显影性。而原DMSO溶剂将被N-甲基吡咯烷酮所取代。或者是DMSO和N-甲基吡咯烷酮的混合溶剂。通过替换溶剂，可以减少DMSO的血管毒性，以及它对于肝功能的代谢压力。通常来讲，外周血管栓塞所用栓塞剂的量是颅内血管栓塞的两倍甚至更多。所以DMSO不适合于外周血管的栓塞。并且在此基础上该液体栓塞剂的组合物中可以兼容微米-纳米级的小苏打粉末。
本发明提供的一种负载碳酸氢钠粉末的液体栓塞剂组合物，由水不溶解的聚合物、该聚合物的溶剂、显影剂以及微米级的碳酸氢钠粉末四个成分组成，该组合物的栓塞主剂为水不溶解的聚合物，所述聚合物中含聚乙烯-聚乙烯醇重复单元的共聚物，并且需对聚乙烯-聚乙烯醇重复单元做阴离子化的化学修饰改性。
所述的液体栓塞剂组合物，其中，聚乙烯-聚乙烯醇重复单元在共聚物中所占比例为摩尔比例为70％-30％。
所述的液体栓塞剂组合物，其中，对聚乙烯-聚乙烯醇重复单元的共聚物中聚乙烯醇部分进行阴离子化学修饰的摩尔比例为40％-10％。
所述的液体栓塞剂组合物，其中，对聚乙烯-聚乙烯醇重复单元的共聚物中聚乙烯醇部分进行磺化改性，磷酸根离子改性，硝酸根离子改性，目的均是让聚乙烯-聚乙烯醇重复单元的聚合物化学接枝上阴离子基团。
所述的液体栓塞剂组合物，其中，所述溶剂是N-甲基吡咯烷酮，或者是N-甲基吡咯烷酮和DMSO的混合溶剂，或者是N-甲基吡咯烷酮、DMSO和无水乙醇的混合溶剂，或者是N-甲基吡咯烷酮和无水乙醇的混合溶剂。
所述的液体栓塞剂组合物，其中，聚乙烯-聚乙烯醇重复单元的共聚物在N-甲基吡咯烷酮溶剂中为液体，在进入人体血管中转变为固体。
所述的液体栓塞剂组合物，其中，所述显影剂是微米化的金属钽粉，或者是微米化的铂金粉末，或者是微米化的铂钨合金粉末。
所述的液体栓塞剂组合物，其中，该组合物和阳离子化的抗癌药物形成离子相互作用，提高其对于阳离子化的抗癌药物的负载和缓释效果，阳离子化的抗癌药是阿霉素，或者伊立替康。
所述的液体栓塞剂组合物，其中，所述碳酸氢钠粉末的粉末粒径分布范围为200纳米-20微米。
如，5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，常用的磺化剂是浓硫酸、氯磺酸、三氧化硫、硫酰氯等，有时可用硫酸银作催化剂，加速反应的进行。加热搅拌反应2-3个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、钽(Ta)粉显影剂以及微米级碳酸氢钠(也称小苏打)粉末，按比例混合，搅拌溶解，得到本发明所述负载碳酸氢钠粉末的液体栓塞剂组合物。
本发明还提供了上述液体栓塞剂组合物在制备治疗肿瘤的药物上的应用。
该负载碳酸氢钠粉末的液体栓塞剂组合物将具备以下特点：
①本发明的液体栓塞剂组合物作为一种非黏附性液体栓塞材料，具有自显影性容易判断栓塞起点和终点，使栓塞部位更精准，容易通过输送微导管，并可兼容各种市售的微导管；
②本发明液体栓塞剂组合物中的主体聚合物具有磺酸根基团，因此它与阳离子化的抗癌药物离子相互作用，最终表现为对阳离子药物的负载以及缓释的作用；
③本发明的液体栓塞剂组合物黏度低、生物相容性好、无细胞毒性、可控性好，栓塞后不会引起化学或免疫作用，应用安全；
④N-甲基吡咯烷酮作为本发明药液体栓塞剂组合物的溶剂是安全的，不会引起血管内外破坏等不良反应；
⑤本发明的液体栓塞剂组合物栓塞渗透性、弥散性好，栓塞效果稳定可靠；
⑥本发明的液体栓塞剂组合物与碳酸氢钠粉末可以有效兼容，且能在血管内被聚合物包埋沉淀，并且随着时间小苏打能够逐渐溶解释放进入到血管，进而进入肿瘤细胞中。
动物实验证明：本发明的液体栓塞剂组合物适用于制备供良恶性实质脏器肿瘤和出血病变的栓塞治疗的药物。本发明的液体栓塞剂组合物可直接注入动脉瘤瘤腔内，完全适应不同形状和大小的动脉瘤腔，使瘤壁与栓塞材料之间不留任何空隙，从而达到永久性栓塞的目的。本发明所述液体栓塞剂组合物，在常态下为液体，在接触人体血液后为固体，可以应用于制备治疗各种血管性肿瘤的药物。
具体实施例方式
以下结合具体实施例的具体实施方式
对本发明的上述内容作进一步的详细说明
实施例1 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用的磺化剂是浓硫酸5g，加少许约0.01g硫酸银作催化剂，加速反应的进行。70度加热搅拌反应3个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂、微米级小苏打粉末按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW01。
实施例2 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用的磺化剂是浓硫酸2.5g，加少许约0.01g硫酸银作催化剂，加速反应的进行。70度加热搅拌反应3个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mLN-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂、微米级小苏打粉末按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW02。(磺化量较HW01减半)
实施例3 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用的磺化剂是氯磺酸5g，加少许约0.01g硫酸银作催化剂，加速反应的进行。70度加热搅拌反应2个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂、微米级小苏打粉末按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW03。
实施例4 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用的磺化剂是氯磺酸2.5g，加少许约0.01g硫酸银作催化剂，加速反应的进行。70度加热搅拌反应2个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mLN-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂、微米级小苏打粉末按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW04。
实施例5 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用多聚磷酸5g为酸化剂，加少许约0.1g尿素作为催化剂，加速反应的进行。70度加热搅拌反应6个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磷酸化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂、微米级小苏打粉末按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW05。
实施例6 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用浓硝酸5g为酸化剂，加少许约0.01g硝酸银作为催化剂，加速反应的进行。70度加热搅拌反应4个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磷酸化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂、微米级小苏打粉末按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW06。
实施例7 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用的磺化剂是浓硫酸5g，加少许约0.01g硫酸银作催化剂，加速反应的进行。70度加热搅拌反应3个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW07。
实施例8 5g EVOH聚合物用30mL N-甲基吡咯烷酮加热搅拌溶解，用的磺化剂是浓硫酸5g，加少许约0.01g硫酸银作催化剂，加速反应的进行。70度加热搅拌反应3个小时后，室温冷却。将冷却后的共聚物倒入200mL-300mL甲醇，使其沉淀析出，取沉淀加入25mL N-甲基吡咯烷酮使之再溶解，加入200mL-300mL甲醇使之再次析出，如此反复几次，最后将沉淀物干燥。或者采用真空干燥。将最后得到的磺化改性EVOH共聚物、N-甲基吡咯烷酮、Ta粉显影剂按一定比例混合，搅拌溶解，得到本发明所述的液体栓塞剂HW08。
选用以上得到的8个配方：6个为含小苏打配方，2个为不含小苏打配方：：
| 兔子编号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 栓塞剂 | HW07 | HW01 | HW02 | HW03 | HW04 | HW05 | HW08 | HW06 |
以上配方术前均与150mg阳离子化的阿霉素进行充分混合。
选用肝癌诱导化的新西兰兔子8只，体重2.5-3.5kg，雌雄不限。术前1禁食，术前30min肌注阿托品1mg，应用盐酸氯胺酮结合咪唑安定将家猪全麻至满意状态。之后分离出股部隐动脉切开，置入5F导管鞘，应用5F造影导管行颈总动脉插管，注射对比剂行颈总动脉造影。之后在roadmap指引下经导引导管将微导管超选送入肝动脉，微导管头端放置在肝动脉的远端，行微导管造影。经微导管用1-2mL注射器在透视监视下注入本发明产品。按预定分组时间随访观察，随访观察时间分别为栓塞后即刻、1周、4周、8周、12周、M周，随访观察内容为动物生存情况(饮食、神经系统)、复查造影，观察有无血管再通现象；最后处死动物，完整取出肝脏进行组织学病理学检查，观察肝脏血管内及其周围的变化，组织学病理学检查。实验中对8只兔子进行了成功栓塞，栓塞及随访观察过程中没有遇到技术性困难，栓塞过程没有发生堵管现象，拔管顺利。并且再次证实共聚物对不同类型微导管兼容性好。栓塞后随访观察实验动物均存活良好，饮食及神经、运动状况均没有异常，也无畸形发生。动物处死后解剖，那些采用了阴离子改性可载药的栓塞剂肝脏癌变组织均有不同程度的缩小。采用无小苏打配方液体栓塞剂的兔子(1#，7#)和采用有小苏打配方液体栓塞剂的兔子(2#，3#，4#，5#，6#，8#)表现出明显的差异。说明了，小苏打的释放确实对于肿瘤治疗起到了非常积极的效果。临床实验证明本发明产品对于良恶性肿瘤介入栓塞疗效确切，使用安全可靠。
Claims (10)
1.一种负载碳酸氢钠粉末的液体栓塞剂组合物，由水不溶解的聚合物、该聚合物的溶剂、显影剂以及微米级的碳酸氢钠粉末四个成分组成，该组合物的栓塞主剂为水不溶解的聚合物，其特征在于，所述聚合物中含聚乙烯-聚乙烯醇重复单元的共聚物，并且需对聚乙烯-聚乙烯醇重复单元做阴离子化的化学修饰改性。
2.根据权利要求1所述的液体栓塞剂组合物，其特征在于，聚乙烯-聚乙烯醇重复单元在共聚物中所占比例为摩尔比例为70％-30％。
3.根据权利要求1所述的液体栓塞剂组合物，其特征在于，对聚乙烯-聚乙烯醇重复单元的共聚物中聚乙烯醇部分进行阴离子化学修饰的摩尔比例为40％-10％。
4.根据权利要求3所述的液体栓塞剂组合物，其特征在于，对聚乙烯-聚乙烯醇重复单元的共聚物中聚乙烯醇部分进行磺化改性，磷酸根离子改性，硝酸根离子改性，目的均是让聚乙烯-聚乙烯醇重复单元的聚合物化学接枝上阴离子基团。
5.根据权利要求1所述的液体栓塞剂组合物，其特征在于，所述溶剂是N-甲基吡咯烷酮，或者是N-甲基吡咯烷酮和DMSO的混合溶剂，或者是N-甲基吡咯烷酮、DMSO和无水乙醇的混合溶剂，或者是N-甲基吡咯烷酮和无水乙醇的混合溶剂。
6.根据权利要求5所述的液体栓塞剂组合物，其特征在于，聚乙烯-聚乙烯醇重复单元的共聚物在N-甲基吡咯烷酮溶剂中为液体，在进入人体血管中转变为固体。
7.根据权利要求1所述的液体栓塞剂组合物，其特征在于，所述显影剂是微米化的金属钽粉，或者是微米化的铂金粉末，或者是微米化的铂钨合金粉末。
8.根据权利要求1所述的液体栓塞剂组合物，其特征在于，该组合物和阳离子化的抗癌药物形成离子相互作用，提高其对于阳离子化的抗癌药物的负载和缓释效果，阳离子化的抗癌药是阿霉素，或者伊立替康。
9.根据权利要求1所述的液体栓塞剂组合物，其特征在于，所述碳酸氢钠粉末的粉末粒径分布范围为200纳米-20微米。
10.权利要求1所述的液体栓塞剂组合物在制备治疗肿瘤的药物上的应用。
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