CN115093497A - 聚(2-氰基丙烯酸)及其在栓塞微球的应用 - Google Patents
聚(2-氰基丙烯酸)及其在栓塞微球的应用 Download PDFInfo
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- CN115093497A CN115093497A CN202210961226.2A CN202210961226A CN115093497A CN 115093497 A CN115093497 A CN 115093497A CN 202210961226 A CN202210961226 A CN 202210961226A CN 115093497 A CN115093497 A CN 115093497A
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Abstract
本发明涉及聚(2‑氰基丙烯酸)及其在栓塞微球的应用,属于医药化工领域。本发明聚(2‑氰基丙烯酸)分散于水中形成带有负电荷的微球,即得到新型空白栓塞微球,其粒径能在微米级范围内调整,且具有变形功能以通过特定形态的血管,可以紧密栓塞血管避免脱落造成异位栓塞。将空白栓塞微球与荷正电荷的药物相结合,即得到新型载药栓塞微球,其采用电荷反转的原理,用高分子的羧基主动装载荷正电荷的药物,能在病变组织局部直接释放药物,药物很少进行全身流动,从而提高药物对病变组织局部的疗效,减轻药物对全身的毒副作用。
Description
本申请是申请号为201910836249.9、申请日为2019年09月05日、发明名称为“聚(2-氰基丙烯酸)及其制备方法和应用”的分案申请。
技术领域
本发明涉及医药化工领域,具体涉及聚(2-氰基丙烯酸)及其应用。
背景技术
一般认为血管内栓塞应当避免,但某些血管如果能选择性地使之部分栓塞,却能收到良好的治疗效果。近年来,由于医疗技术的发展,人们已可以通过插入的导管向有关动脉注入血管栓塞剂(Vascular Occlusive Agent)来治疗一些疾病,尤其对于一些难以用手术或药物控制的疾病,例如肿瘤或者胃底静脉曲张。这种技术在医疗上称为选择性血管栓塞术。经导管动脉栓塞术在20世纪70年代首先被用于治疗前列腺穿刺活检或经尿道前列腺切除术后的前列腺出血以及前列腺来源的顽固性血尿。在进行血管栓塞术时,必须使用栓塞剂,除使用一些天然的栓塞物质如血凝块外,可用气囊、金属小球、弹簧管等进行机械性堵塞。目前使用的栓塞剂分为固体和液体二大类,一些天然的栓塞剂也列入固体类栓塞剂。
动脉栓塞术也用于治疗肿瘤、肿瘤止血、肿瘤止痛。肿瘤栓塞治疗是近几年来介入性放射学发展的一个方面,即通过导管将栓塞物质注入肿瘤血管内,使肿瘤血管栓塞,肿瘤缺血坏死,体积缩小或消失。主要适应于不能耐受手术或已经失去手术机会而又无其他合适的治疗方法者。对于治疗肿瘤引起的顽固性出血、疼痛以及副癌综合征具有一定意义。特别是癌组织出血,由于肿瘤血管对血管收缩剂反应差,又因癌肿病人常有凝血障碍,不能在出血点形成血凝块。故用输注加压素止血常无效,而栓塞术可赢得时间,以进行其他治疗。目前常用的是动脉栓塞化疗法治疗肿瘤。动脉化疗栓塞术(Transarterialchemoembolization,TACE)是把化疗药物与造影剂(碘油)混合乳化后,经导管进行肝癌动脉灌注,然后用栓塞剂如明胶海绵微粒栓塞肝癌动脉,需要两步完成,医生进行带线操作时间较长。近年来,出现了一种新型的TACE方法,即采用生物相容性较好的材料制备具有缓释功能的载药微球(Drug-loaded microspheres),或称为药物缓释微球(Drug-elutingbeads,DEB),在单次影像导引下即可同时实现药物与栓塞剂的肝癌动脉递送,简化了操作步骤,缩短了医生介入治疗带线操作的时间。DC-Bead分子结构中,存在大量磺酸基,可以吸引带有荷正电荷的抗癌药物,用于肿瘤的动脉血管栓塞,抑制肿瘤生长,减少肿瘤出血,减轻肿瘤的疼痛。DC-Bead中有磺酸基,生物相容性不好,且容易引起过敏。
发明内容
针对现有技术存在的问题,本发明提供一种新材料聚(2-氰基丙烯酸)的制备方法,以及采用聚(2-氰基丙烯酸)所开发的新型空白栓塞微球,和采用新型空白栓塞微球进一步所开发的新型载药栓塞微球的制备方法及应用。本发明的技术方案如下:
聚(2-氰基丙烯酸)的制备方法,先制备α-氰基丙烯酸酯聚合物,再在碱性条件下选择性水解聚合物中的酯键,纯化后,即得到聚(2-氰基丙烯酸)。
本发明同时请求保护按照所述制备方法制备得到的聚(2-氰基丙烯酸)。
本发明请求保护所述的聚(2-氰基丙烯酸)的应用,为将聚(2-氰基丙烯酸)制备成为空白栓塞微球。
进一步的:所述的空白栓塞微球的制备方法为:将聚(2-氰基丙烯酸)分散于水中形成带有负电荷的微球,即得到空白栓塞微球。
进一步的:空白栓塞微球的粒径能在微米级范围内调整,以适应不同管径血管栓塞靶点的要求,同时根据需要空白栓塞微球具有变形功能,以通过栓塞路径上的血管狭窄,可紧密栓塞血管,能避免脱落造成的异位栓塞。
本发明请求保护所述的聚(2-氰基丙烯酸)的应用,为将聚(2-氰基丙烯酸)制备成为的空白栓塞微球,再制备成为载药栓塞微球。
进一步的:所述的载药栓塞微球的制备方法为:将空白栓塞微球与荷正电荷的药物相结合,即得到载药栓塞微球。
进一步的:载药栓塞微球以反转电荷的原理主动装载(pH≥7.4)和释放(pH≤6.5)药物。
进一步的:载药栓塞微球在血管通透性高、pH值低的病变组织,能直接释放药物进入病变组织局部,药物很少进行全身流动,从而提高药物对病变组织局部的疗效,减轻药物对全身的毒副作用。
本发明同时请求保护聚(2-氰基丙烯酸),化学式为:
-[CH2-C(CN)(COOH)]n-。
更具体优选的制备方法和应用如下:
1.聚(2-氰基丙烯酸)的制备
(1)方法一:
在pH值2.0-4.0的生理盐水或5%以上葡萄糖溶液或5%以上右旋糖酐溶液中,用非离子表面活性剂如聚乙二醇型非离子表面活性剂或吐温类表面活性剂或司盘类表面活性剂或泊洛沙姆等,制备α-氰基丙烯酸酯或其植物油溶液的乳剂。再将pH值调节到7.4以上,加速聚合反应形成α-氰基丙烯酸酯聚合物。再在碱性条件下选择性水解聚合物的酯键并保留氰基,植物油将会皂化,透析除去杂质,即得到聚(2-氰基丙烯酸)。
非离子表面活性剂含量越高,α-氰基丙烯酸酯的用量越少,乳剂粒径越小。聚(2-氰基丙烯酸)的聚合度大小可由α-氰基丙烯酸酯乳剂粒径大小来控制,乳剂粒径越小聚合度越小。
不同分子量范围的聚(2-氰基丙烯酸)可由透析法或凝胶色谱法分离制备。
(2)方法二:
将α-氰基丙烯酸酯溶于无水乙醇或丙酮或乙腈中。在硬塑分散器高速分散条件下,把α-氰基丙烯酸酯的无水乙醇或乙腈或丙酮溶液,缓慢滴入酸性水中,磁力搅拌过夜。高速离心收集α-氰基丙烯酸酯聚合沉淀物。再在碱性条件下选择性水解聚合物的酯键并保留氰基,透析除去杂质,即得到聚(2-氰基丙烯酸)。
聚(2-氰基丙烯酸)的聚合度大小可由α-氰基丙烯酸酯的浓度决定,其浓度越低聚合度越低。
不同分子量范围的聚(2-氰基丙烯酸)可由透析法或凝胶色谱法分离制备。
2.聚(2-氰基丙烯酸)空白栓塞微球的制备
通过控制聚(α-氰基丙烯酸酯)的聚合时间或α-氰基丙烯酸酯浓度,控制其聚合度,可由此控制空白栓塞微球的粒径大小。
聚(2-氰基丙烯酸)富含羧基,空白栓塞微球在碱性条件下,其羧基会带有负电荷,负电荷之间产生排斥力,因此空白栓塞微球具有弹性和变形能力。
(1)方法一:
聚(2-氰基丙烯酸)有一定表面活性作用且易溶于无水乙醇,将其乙醇溶液分散于水中,即得到富含羧基的空白栓塞微球。
(2)方法二:
聚(2-氰基丙烯酸)有一定表面活性作用且易溶于无水乙醇,将其乙醇溶液分散于水中,并用活性聚乙二醇修饰聚(2-氰基丙烯酸)的部分羧基,即得到羧基修饰的空白栓塞微球。
聚合物羧基结合的聚乙二醇可有效防止网状内皮系统对空白栓塞微球的骨架材料聚(2-氰基丙烯酸)的迅速吞噬和破坏,未被修饰的羧基用以主动装载荷正电荷的药物。
羧基修饰的最佳比例与所运载的药物量和药物种类有关,当药物的分子量比较大,亲水性比较差,则被修饰的羧基比例就要高一点,当药物的分子量比较小,亲水性比较强,则被修饰的羧基比例就可以低一点,此外被修饰羧基的比例还与应用的个体差异有关,必须确保网状内皮系统不能迅速的破坏空白栓塞微球,总之具体的羧基修饰比例和活性聚乙二醇的分子量,要根据临床需求具体制定。
3.聚(2-氰基丙烯酸)空白栓塞微球的应用
聚(2-氰基丙烯酸)空白栓塞微球可根据临床需要调整其粒径大小,且具有弹性和变形能力,粒径≥8um时,行栓塞治疗可通过特定的血管狭窄,并与血管壁紧密作用难以脱落,不会产生异位栓塞。
4.聚(2-氰基丙烯酸)载药栓塞微球的制备
将聚(2-氰基丙烯酸)空白栓塞微球与荷正电荷的各种药物相结合,即得到各种载药栓塞微球。
5.聚(2-氰基丙烯酸)载药栓塞微球的应用
根据临床需要,载药栓塞微球能装载不同的一种或多种荷正电荷药物,进行有特定要求的局部栓塞治疗,其在血管通透性高、pH值低的病变组织,能直接释放药物进入病变组织局部,药物很少进行全身流动,从而提高药物对病变组织局部的疗效,减轻药物对全身的毒副作用。
本发明的有益效果如下:
(1)提供了一种新材料富含羧基的聚(2-氰基丙烯酸)的制备方法;
(2)聚(2-氰基丙烯酸)可用于制备新型空白栓塞微球;
(3)新型空白栓塞微球粒径大小可调,且具有变形通过狭窄的能力;
(4)新型空白栓塞微球可用于制备新型载药栓塞微球;
(5)新型载药栓塞微球可提高所运载药物对病变组织局部的疗效;
(6)新型载药栓塞微球可以减轻所运载药物对全身的毒副作用;
(7)国外DC-bead现有技术中(如图1所示),必须使用N-丙烯酰-氨基乙醛-二甲基缩醛、醋酸丁酯,挥发性高,残留量大,不利于生产环境,安全性较低。本发明仅使用α-氰基丙烯酸酯、植物油、葡萄糖、生理盐水、非离子表面活性剂、活性聚乙二醇、无水乙醇、纯水等,无毒性残留,无污染,工艺简单,生产成本低,安全性较高;
(8)国外DC-bead的单位体积所装载抗癌药物的分子数较少。本发明制备的载药栓塞微球,根据化学结构推算,其分子结构中,大约50%的碳原子携带一个羧基负电荷,而DC-bead分子中大约20%碳原子携带一个羧基负电荷。本发明制备的载药栓塞微球的单位质量负电荷总量显著高于DC-bead,装载药物的能力显著提高;
(9)国外DC-bead是酸性较强的磺酸基团,在肿瘤组织附近选择性释放药物的能力弱。本发明制备的载药栓塞微球所携带的羧基酸性较弱,在不同pH值条件下,释放药物速度不一样,在pH值低的肿瘤组织附近,释放药物速度显著加快,具有较强的肿瘤附近选择性释放药物的特点。
附图说明
图1为传统制备DC-Bead的工艺图;
图2为空白栓塞微球(50倍);
图3为载药栓塞微球制备及发挥作用图;
图4为装载阿霉素的载药栓塞微球(50倍);
图5为装载阿霉素的载药栓塞微球粉碎后的内部形态;
图6为ɑ-氰基丙烯酸乙酯聚合物与聚(2-氰基丙烯酸)的傅里叶-红外吸收光谱比较,其中,图6a为聚(α-氰基丙烯酸乙酯),图6b为聚(2-氰基丙烯酸);
图7为聚(2-氰基丙烯酸)的结构示意图;
图8为聚(2-氰基丙烯酸)的紫外吸收光谱;
图9为聚(2-氰基丙烯酸)的核磁共振氢谱;
图10为聚(2-氰基丙烯酸)的质谱,其中,图10a为样品离子流图(样品和空白对照),图10b乙醇质谱图(特征峰m/z31,辅助特征峰m/z45,m/z46);
图11为聚(2-氰基丙烯酸)的凝胶色谱过滤法分子量分布测定,其中,
图11a为不同分子量聚乙二醇凝胶色谱分离后出峰保留时间(RT)与分子量(MW)的关系曲线;图11b为聚(2-氰基丙烯酸)凝胶色谱过滤的分子流出曲线;图11c为凝胶色谱过滤法测定聚(2-氰基丙烯酸)分子量分布。
具体实施方式
下面结合具体实施例对本发明做进一步的说明和解释,若无特殊说明,本发明所用原料及设备均为常用原料和设备。
实施例1---聚(2-氰基丙烯酸)的制备
(1)配方:α-氰基丙烯酸正丁酯
生理盐水、芝麻油、吐温-80、司盘-20、无水乙醇
将α-氰基丙烯酸正丁酯溶于精制无热原的芝麻油中,形成30%的α-氰基丙烯酸正丁酯的油溶液10mL,分散于pH值4.0的0.25%的吐温-80和司盘-20的生理盐水溶液中。再调节pH值至7.8引发α-氰基丙烯酸正丁酯聚合反应,12小时后离心分离沉淀物,用无水乙醇洗涤沉淀物并离心反复5次,将沉淀物分散于50ml无水乙醇中,加入氢氧化钠,选择性水解酯键并保留氰基,减压蒸发除去无水乙醇,再与100mL蒸馏水混合,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚(2-氰基丙烯酸)。
(2)配方:α-氰基丙烯酸辛酯
50%葡萄糖溶液、泊洛沙姆、无水乙醇
将α-氰基丙烯酸辛酯溶于pH值4.0的0.25%泊洛沙姆的50%葡萄糖溶液中,形成α-氰基丙烯酸辛酯乳剂,pH值调至7.4,在搅拌条件下,室温下聚合12小时,离心分离沉淀物,将沉淀物分散于50ml无水乙醇中,加入氢氧化钠,选择性水解酯键并保留氰基,减压蒸发除去无水乙醇,再与100mL蒸馏水混合,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚(2-氰基丙烯酸)。(3)配方:α-氰基丙烯酸异丁酯
10%右旋糖酐溶液、聚乙二醇400单油酸酯、无水乙醇
将α-氰基丙烯酸异丁酯溶于pH值4.0的0.25%聚乙二醇400单油酸酯的10%右旋糖酐溶液中,形成α-氰基丙烯酸异丁酯乳剂,pH值调至7.4,在搅拌条件下,室温下聚合12小时,离心分离沉淀物,再将沉淀物分散于50ml无水乙醇中,加入氢氧化钠,选择性水解酯键并保留氰基,减压蒸发除去无水乙醇,再与100mL蒸馏水混合,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚(2-氰基丙烯酸)。
(4)配方:α-氰基丙烯酸正丁酯
无水乙醇
将α-氰基丙烯酸正丁酯溶于无水乙醇制成50%乙醇溶液,聚合1周,再加氢氧化钠选择性水解酯键并保留氰基,减压蒸发除去无水乙醇,再与100mL蒸馏水混合,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚(2-氰基丙烯酸)。
(5)配方:α-氰基丙烯酸甲酯
丙酮、无水乙醇
将α-氰基丙烯酸甲酯溶于无水乙醇制成50%丙酮溶液,聚合2周,再减压除去丙酮,分散于无水乙醇中,再加氢氧化钠选择性水解酯键并保留氰基,减压蒸发除去无水乙醇,与100mL蒸馏水混合,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚(2-氰基丙烯酸)。
(6)配方:α-氰基丙烯酸乙酯
乙腈、无水乙醇
将α-氰基丙烯酸乙酯溶于乙腈制成50%乙腈溶液,聚合2周,再减压除去乙腈,分散于无水乙醇中,再加氢氧化钠选择性水解酯键并保留氰基,减压蒸发除去无水乙醇,与100mL蒸馏水混合,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚(2-氰基丙烯酸)。
实施例2---聚(2-氰基丙烯酸)空白栓塞微球的制备
(1)配方:聚(2-氰基丙烯酸)
无水乙醇、水
取0.5g聚(2-氰基丙烯酸)制成5mL无水乙醇溶液。置旋转蒸发器中,挥发乙醇至器壁上形成薄膜,与50mL蒸馏水混合,水合12小时,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到空白栓塞微球。
(2)配方:聚(2-氰基丙烯酸)
氨基聚乙二醇2000、水
用氨基聚乙二醇2000修饰羧基,活性聚乙二醇修饰的催化剂:EDC·HCL:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;NHS:N-羟基丁二酰亚胺。聚乙二醇修饰之后,8000rpm离心20分钟,弃去上清液,震摇水洗,再离心,反复5次,即得到聚乙二醇修饰的空白栓塞微球。
实施例3---聚(2-氰基丙烯酸)载药栓塞微球的制备
(1)配方:空白栓塞微球
阿霉素
取空白栓塞微球1mL,与等体积pH值7.4的2mg/mL阿霉素1/15M等渗磷酸盐缓冲液混合,震摇15分钟,倾去剩余阿霉素溶液,再用pH值7.4的1/15M等渗磷酸盐缓冲液冲洗,即得到可供肿瘤动脉血管栓塞的阿霉素载药栓塞微球。
(2)配方:空白栓塞微球
庆大霉素
取空白栓塞微球1mL,与等体积pH值7.4的10mg/mL庆大霉素1/15M等渗磷酸盐缓冲液,震摇5分钟,倾去剩余庆大霉素溶液,再用pH值7.4的1/15M等渗磷酸盐缓冲液冲洗,即得到有抗炎治疗需求的庆大霉素载药栓塞微球。
聚(2-氰基丙烯酸)栓塞微球的功效
1.新型空白栓塞微球
用光学显微镜,扫描电子显微镜对新型空白栓塞微球的粒径大小,表面形态特征进行观察与测定(如图2所示)。在不同贮存温度条件下,检测新型空白栓塞微球长期贮存过程中的粒径变化。新型空白栓塞微球可用于动脉性出血的栓塞治疗,如外伤性盆腔和内脏出血,泌尿系统出血,消化道出血,严重鼻和颌面部出血、大咯血、术后内脏出血。也可用于静脉性出血的栓塞治疗,如消化道静脉曲张。
2.新型载药栓塞微球
用紫外-可见分光光度计测定新型载药栓塞微球的载药量,药物自动装载速度及药物释放速度。采取肿瘤组织块包埋法,建立兔VX2肝癌模型,评价了肝动脉使用阿霉素载药栓塞微球的有效性(如图3所示)。在瘤块包埋种植两周后,采取开腹式肝动脉插管注射阿霉素载药栓塞微球(如图4所示)。用高效液相色谱法测定实验兔外周静脉血阿霉素浓度。采用疫荧光染色技术,观察瘤体内阿霉素的分布和肿瘤微血管密度。结果表明这种新型载药栓塞微球大小可以有效栓塞肿瘤动脉血管,抗肿瘤疗效显著,肿瘤血管密度显著降低。动物实验表明此种新型载药栓塞微球还能用于肾癌、肾上腺癌、盆腔内各种富含血管的肿瘤、颌面部恶性肿瘤、四肢、脊柱骨盆恶性肿瘤的治疗。新型栓塞载药微球也可装载荷正电荷的一切药物,用于有特定需求的血管栓塞治疗,可以提高药物对病变组织局部的疗效,减轻药物对全身的毒副作用(如图5所示)。
聚(2-氰基丙烯酸)结构分析
如图6a所示,α-氰基丙烯酸乙酯在无水乙醇中的聚合物中C=C双键(波数1650-1450cm-1)消失,无羧基(波数,1720-1680cm-1),但是仍然含有丙烯酸乙酯的酯键(波数为1750-1730cm-1),氰基(2260-2210cm-1)存在。
如图6b所示,聚(α-氰基丙烯酸乙酯)在无水乙醇中与氢氧化钠反应,酯键消失,氰基(波数,2260-2210cm-1)仍然存在,产生大量羧基(波数,3300-2500cm-1)。因此,所得产物应该是聚(2-氰基丙烯酸)。
称取聚(2-氰基丙烯酸)约5mg,溶于氘代水中,采用核磁共振波谱仪(400MHz)测定聚(2-氰基丙烯酸)的核磁共振氢谱,记录其化学位移值(ppm)。α-氰基丙烯酸乙酯采用本发明方法在无水乙醇中形成聚合物,加氢氧化钠水解去掉酯键并保留氰基,所得产物据推测是聚(2-氰基丙烯酸),其核磁共振波谱如图9所示。
如图10所示,聚合物酯化物0.1052g:乙醇含量49.12μL,根据以上数据,推测聚合物单体含有一个羧基。
如图11可知,聚(2-氰基丙烯酸)分子量数均分子量1742,重均分子量2372,聚(2-氰基丙烯酸)分子量2372。
上述实施例只是用于对本发明的举例和说明,而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是,本发明不局限于上述实施例,根据本发明的教导还可以做出更多种的变型和修改,这些变型和修改均落在本发明所要求保护的范围内。
Claims (10)
1.聚(2-氰基丙烯酸),其特征在于,化学式为:-[CH2-C(CN)(COOH)]n-。
2.如权利要求1所述的聚(2-氰基丙烯酸)的应用,其特征在于,将聚(2-氰基丙烯酸)制备成空白栓塞微球。
3.根据权利要求2所述的应用,其特征在于,空白栓塞微球的粒径≥1um,且可以变形。
4.根据权利要求2所述的应用,其特征在于,空白栓塞微球的粒径能在微米级范围内调整,以适应不同管径血管栓塞靶点的要求。
5.根据权利要求2所述的应用,其特征在于,所述的空白栓塞微球的制备方法为:将聚(2-氰基丙烯酸)分散于水中形成带有负电荷的微球,即得到空白栓塞微球。
6.根据权利要求2所述的应用,其特征在于,将空白栓塞微球制备成载药栓塞微球。
7.根据权利要求6所述的应用,其特征在于,所述的载药栓塞微球的制备方法为:将空白栓塞微球与荷正电荷的药物相结合,即得到载药栓塞微球。
8.根据权利要求6所述的应用,其特征在于,载药栓塞微球以反转电荷的原理主动装载和释放药物。
9.根据权利要求8所述的应用,其特征在于,载药栓塞微球在pH≥7.4主动装载药物;在pH≤6.5主动释放药物。
10.根据权利要求6所述的应用,其特征在于,载药栓塞微球在血管通透性高、pH值低的病变组织,能直接释放药物进入病变组织局部。
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