CN116077711A - 一种液态金属栓塞剂 - Google Patents
一种液态金属栓塞剂 Download PDFInfo
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Abstract
本发明涉及医用材料,特别涉及一种液态金属栓塞剂。所述液态金属栓塞剂包括液态金属微球。所述液态金属微球由包括如下重量份的液态金属制备得到:铋5‑40份、铟15‑50份、锡5‑20份、锌0.1‑10份、镓2‑40份。本发明提出的新型液态金属栓塞剂,制备方式简便,栓塞效果佳,同时可联合化疗、热疗等肿瘤治疗方式实现高效治疗。另外该栓塞剂还具有CT成像、MRI成像以及热成像等功能。
Description
技术领域
本发明涉及医用材料,特别涉及一种液态金属栓塞剂。
背景技术
栓塞技术通过将栓塞材料引入异常血管内,可实现供血功能异常的血管,临床应用广泛。目前,常用的栓塞剂有固体栓塞剂、液体栓塞剂与微球栓塞剂。固体栓塞剂常采用固体弹簧实现血流堵塞,易对血管壁造成不可逆损伤;液态栓塞剂常采用可相变型液体高分子聚合物类材料,通过与交联剂或特定离子溶液接触,实现相变栓塞;微球类栓塞剂主要利用聚乙烯醇(PVA)等材料,需要一定时间实现材料在体沉积与栓塞。各类栓塞剂各有优缺点,目前,栓塞剂往往需要与显影剂结合使用,实现可视化。
现有液态金属栓塞剂仍有待改进。
发明内容
本发明首先提供一种液态金属微球,其具有更好的热疗效果,可实现栓塞的治疗。
根据本发明实施例,以重量份计所述液态金属微球包括如下成分:铋5-40份、铟15-50份、锡5-20份、锌0.1-10份、镓2-40份。
本发明液态金属微球具有合适的液-固相变温度,当将其制成液态金属栓塞剂后可实现快速血管内栓塞治疗。
根据本发明实施例,以重量份计所述液态金属微球包括如下成分:铋32-35份、铟45-50份、锡16-20份、锌0.2-0.5份、镓4.2-4.5份。
根据本发明实施例,以重量份计所述液态金属微球包括如下成分:铋32.8份、铟46.8份、锡15.8份、锌0.4份、镓4.2份。
根据本发明实施例,所述液态金属微球的总重量为100份。
根据本发明实施例,所述液态金属微球即是以铋、铟、锡、锌和镓制成的。
根据本发明实施例,所述液态金属微球的粒径为5-500μm,可选为10-100μm,在一些实施例为30μm。发明人发现在上述粒径范围内的液态金属微球不仅具有热疗功能,还可方便地进行表面修饰并携带药物。
根据本发明实施例,所述液态金属微球以均匀微球形式存在。
根据本发明实施例,所述液态金属微球的熔点为37-60℃,例如40℃、50℃、60℃等。研究发现,该熔点范围的微球可通过相变更好地实现原位的永久栓塞。
本发明还提供上述液态金属微球的制备方法,包括:
1)提供液态金属材料;
2)将所述液态金属材料加热至熔化,置于温水中超声分散,形成微米级颗粒材料,筛选出所需尺寸的液态金属微球。
上述制备方法中,所述液态金属材料的组成与所述液态金属微球的组成相同。所述液态金属材料可按本领域常规方法制备。在具体制备时,可将单质金属铋、铋铟锡、铋铟锡锌等合金与单质金属镓、镓铟锡、镓铟锡锌等合金制成液态金属材料,再进一步制成液态金属微球。例如可以先将铋、铟、锡、锌制成铋基合金;将镓、铟、锡制成镓基合金;然后再将铋基合金和镓基合金混合,制成液态金属材料,再进一步制成液态金属微球。通过上述混合方式制备的材料具有更低的混合温度,即可降低材料的制备条件。
根据本发明实施例,所述温水的温度高于所述液态金属材料的熔点,例如所述温水的温度为60-90℃。
根据本发明实施例,所述超声可采用脉冲形式分散5分钟以上。
根据本发明实施例,可采用离心、过滤等方式筛选出所需尺寸的液态金属微球。
根据本发明实施例,所述液态金属微球的制备方法具体包括:首先,配置铋基金属或合金,将铋、铟、锡、锌等金属按比例称重,高温融化搅拌均匀,2-6小时后置于室温备用。将镓、铟、锡、锌等金属按比例称重,高温融化搅拌均匀,2-6小时后置于室温备用。将上述铋基与镓基金属按比例混合后,于高温融化搅拌均匀备用,得到具有合适熔化、凝固特性的混合材料。取适量液态金属溶液于温水中超声,将材料分散成微米级颗粒材料,后可通过过滤筛选等方式选出合适尺寸的微球。
本发明还提供上述液态金属微球的另一种制备方法,包括:
1)提供液态金属材料;
2)将所述液态金属材料加热至熔化,填充于塑型模具中,通过模具洗脱的方式,制备出所需尺寸的液态金属微球。
本发明还提供上述液态金属微球的另一种制备方法,包括:
1)提供液态金属材料;
2)将所述液态金属材料通过微流体注射方法,制备出所需尺寸的液态金属微球。
本发明通过调控注射泵速度,可实现快速大量液态金属微球的制备。
以上利用模具法与微流体注射法等需要外接加温设备以实现流体法制备,将材料注入模板中,再洗脱、去除模板;微流体注射法需要结合高温注射装置。
选用塑型模具或微流体注射法可实现均匀化液态金属微球的制备。
本发明上述液态金属微球的制备方法相对于传统方法更为简便。
本发明液态金属微球可利用介入导管协同递送于肿瘤部位。另,对于尺寸较大的微球,可通过加热融化以减小导管尺寸或注射器针头尺寸,将微球通过介入导管递送或直接注射器注入的方式完成栓塞。
值得注意的是,对于尺寸较大的液态金属微球,通过介入导管递送可同时于导管内部集成加热装置,实现微球的熔化和变形挤出。对于注射器介导的微球递送,外部可结合配合栓塞剂使用的特殊注射装置联合使用。
如上所述,基于本发明液态金属微球具有更佳的热疗效果以及进一步增加了载药量,可以将其用于制备液态金属栓塞剂。
本发明还提供上述液态金属微球在制备液态金属栓塞剂上的应用。
本发明还提供一种液态金属栓塞剂,包括上述液态金属微球。
根据本发明实施例,所述液态金属栓塞剂还包括高分子材料(高分子聚合物)。可选地,所述高分子材料覆于所述液态金属微球的表面。
具体地,所述高分子材料包括壳聚糖、透明质酸、胶原、聚乙二醇、聚丙烯酸、聚乙烯醇等。研究发现,在所述液态金属微球表面通过带有巯基、羟基、羧基、氨基等基团的高分子材料修饰,可以提高所述液态金属微球的稳定性。
通常,所述液态金属栓塞剂中,上述液态金属微球与高分子材料的质量比为1:(1-100)。
所述液态金属栓塞剂的制备方法,包括将液态金属微球和高分子材料置于热水中进行超声的步骤。通常,将所述液态金属微球、高分子材料置于热水中后在超声条件下混合,即可制备出液态金属栓塞剂。例如超声条件为使用脉冲超声仪,超声时间在5-30分钟左右。这种方法可同时实现液态金属微球的制备和高分子材料在液态金属微球的表面修饰,从而一步法制备出液态金属栓塞剂。
在一些实施例,高分子聚合物等可添加在超声溶液中实现微球的制备和表面修饰;通过模板法、微流体注射法等可将高分子聚合物与液态金属微球于超声下实现有序包裹。
在一些实施例,可将高分子材料加入液态金属微球溶液中,于超声下通过物理吸附等方式实现药物加载。
根据本发明实施例,所述液态金属栓塞剂还包括化疗药物。通常,所述液态金属栓塞剂中,上述液态金属微球与化疗药物的质量比为1:(0.1-5)。所述化疗药物为临床上常用的抗肿瘤治疗药物,包括但不限于各类小分子抗癌药(抗肿瘤药物)、免疫制剂(免疫类治疗药物)等,例如阿霉素、紫杉醇、吉他西滨、索拉非尼、阿帕替尼、PD-1、PDL-1等。
所述液态金属栓塞剂的制备方法包括将所述液态金属微球、化疗药物,或者还包括高分子材料置于热水中进行超声的步骤。通常,将所述液态金属微球、化疗药物或者还包括高分子材料在超声条件下混合,即可制备出液态金属栓塞剂。例如超声条件为脉冲超声仪,超声时间在10-60分钟左右。
根据本发明实施例,所述液态金属栓塞剂同时包括高分子材料和化疗药物。在一些实施例,所述液态金属栓塞剂中,所述液态金属微球、高分子材料、化疗药物的质量比为1:(1-100):(0.1-5)。
当所述液态金属栓塞剂包括高分子材料和/或化疗药物时,可在制备所述液态金属微球的过程中即将所述液态金属材料加热至熔化后,加入高分子材料,按上述方法继续进行制备。也可将所述液态金属微球、高分子材料、化疗药物在超声条件下混合,即可制备出液态金属栓塞剂。例如超声条件为脉冲超声仪,超声时间在10-60分钟左右。
通过模板法、微流体注射法等可将高分子聚合物与液态金属微球于超声下实现有序包裹。
根据本发明实施例,所述液态金属栓塞剂中,高分子材料和/或化疗药物包括在所述液态金属微球之外。
根据本发明实施例,所述液态金属栓塞剂中还包括具有磁性或放射性的材料,如金属铁、钴、镍、氧化铁、四氧化三铁及其合金的一种或多种。
根据本发明实施例,所述液态金属栓塞剂可作为多模态造影剂,实现如X射线、CT和核磁等成像功能。
根据本发明实施例,所述液态金属的相变栓塞剂可通过特殊的加热装置利用注射、介入导管等介质递送于需堵塞的血管中。在材料进入血管后可于几秒内快速相变,实现适形化栓塞与微血管堵塞。另外,同时匹配电磁加热装置可实现同步的栓塞、化疗与热疗。
本发明的有益效果至少包括:
本发明提出的液态金属栓塞剂,制备方式简便,栓塞效果佳,同时可联合化疗、热疗等肿瘤治疗方式实现高效治疗。另外,该栓塞剂还具有CT成像、MRI成像以及热成像等功能。
附图说明
图1为本发明实施例液态金属栓塞剂的结构示意图。其中,1-液态金属微球,2-高分子材料,3-化疗药物。
图2为本发明实施例用液态金属栓塞剂进行治疗的示意图。其中,1-液态金属微球,2-血管,3-注射装置/介入导管。
图3为本发明实施例基于液态金属栓塞剂的栓塞与热疗的联合治疗的示意图。其中,1-液态金属栓塞剂,2-外部交变电磁场设备。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
以下实施例中,所用仪器等未注明生产厂商者,均为可通过正规渠道商购买得到的常规产品。所述方法如无特别说明均为常规方法,所用原材料如无特别说明均能从公开商业途径而得。
实施例1
本实施例提供一种液态金属微球,由如下成分组成:铋32.8wt%、铟46.8wt%、锡15.8wt%、锌0.4wt%、镓4.2wt%;所述液态金属微球的粒径为30μm。
制备方法如下:
将铋、铟、锡、锌进行称量,按照质量分数分别为35%、48.6%、16%和0.4%的比例取出相应质量的金属材料在真空熔化炉中熔化搅拌均匀,冷却至室温,制备得到铋基合金备用。将镓、铟、锡进行称量,按照质量分数分别为67%、20.5%和12.5%的比例取出相应质量的金属材料在放入烧杯中,加热至160℃至完全融化,用玻璃棒搅拌均匀,冷却至室温,制备得到镓基合金备用。以上铋基合金和镓基合金以15:1的质量比在100℃下混合得到液态金属材料,熔点为45℃左右。
将所述液态金属材料通过超声分散的方式制备出尺寸较为均匀的30μm液态金属微球。
实施例2
本实施例提供一种液态金属栓塞剂,包括实施例1制备的液态金属微球、壳聚糖和阿霉素,三者质量比为1:10:0.5。
制备方法:将按上述质量比的液态金属微球、壳聚糖和阿霉素置于热水中,超声破碎处理15min,制成液态金属栓塞剂。
本实施例液态金属栓塞剂的结构示意图参见图1。其中,1-液态金属微球,2-高分子材料,3-化疗药物。
本实施例实现了载药微球(液态金属栓塞剂)的制备。将载药微球通过介入导管递送的方式可堵塞肝肿瘤血管。
实施例3
本实施例提供一种液态金属栓塞剂,包括实施例1制备的液态金属微球、壳聚糖和阿霉素,三者质量比为1:50:2。
制备方法:将按上述质量比的液态金属微球、壳聚糖和阿霉素置于热水中超声破碎处理15min,制成液态金属栓塞剂。
本实施例液态金属栓塞剂的结构示意图参见图1。
如图2所示,分别将实施例2和3液态金属栓塞剂用于栓塞治疗。其中,1-液态金属微球,2-血管,3-注射装置/介入导管。
如图3所示,分别将实施例2和3液态金属栓塞剂进行栓塞与热疗的联合治疗。其中,1-液态金属栓塞剂,2-外部交变电磁场设备。在栓塞治疗后,在栓塞部位施加交变磁场,由于金属的涡流效应,栓塞剂产生大量热,从而对肿瘤造成热损伤,实现栓塞和热疗的联合治疗。栓塞材料温度的提高还有助于化学药物的释放作用,实现栓塞、化疗、热疗的联合治疗。
虽然,上文中已经用一般性说明、具体实施方式及试验,对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (10)
1.一种液态金属微球,其特征在于,以重量份计所述液态金属微球包括如下成分:铋5-40份、铟15-50份、锡5-20份、锌0.1-10份、镓2-40份。
2.根据权利要求1所述液态金属微球,其特征在于,以重量份计所述液态金属微球包括如下成分:铋32-35份、铟45-50份、锡16-20份、锌0.2-0.5份、镓4.2-4.5份;可选地,以重量份计所述液态金属微球包括如下成分:铋32.8份、铟46.8份、锡15.8份、锌0.4份、镓4.2份。
3.根据权利要求1或2所述液态金属微球,其特征在于,所述液态金属微球的粒径为5-500μm;可选为10-100μm;和/或,
所述液态金属微球的熔点为37-60℃。
4.权利要求1-3任一项所述液态金属微球的制备方法,其特征在于,选自以下任一种:
所述液态金属微球的制备方法包括:
1)提供液态金属材料;
2)将所述液态金属材料加热至熔化,置于温水中超声分散,形成微米级颗粒材料,筛选出所需尺寸的液态金属微球;或者,
所述液态金属微球的制备方法包括:
1)提供液态金属材料;
2)将所述液态金属材料加热至熔化,填充于塑型模具中,通过模具洗脱的方式,制备出所需尺寸的液态金属微球;或者,
所述液态金属微球的制备方法包括:
1)提供液态金属材料;
2)将所述液态金属材料通过微流体注射方法,制备出所需尺寸的液态金属微球。
5.一种液态金属栓塞剂,其特征在于,包括权利要求1-3任一项所述液态金属微球。
6.根据权利要求5所述液态金属栓塞剂,其特征在于,所述液态金属栓塞剂中还包括高分子材料;可选地,所述高分子材料覆于所述液态金属微球的表面;可选地,所述高分子材料为壳聚糖、透明质酸、胶原、聚乙二醇、聚丙烯酸或聚乙烯醇中的一种或几种;可选地,所述液态金属栓塞剂中,所述液态金属微球与高分子材料的质量比为1:(1-100)。
7.根据权利要求5或6所述液态金属栓塞剂,其特征在于,所述液态金属栓塞剂中还包括化疗药物;
可选地,所述液态金属栓塞剂中液态金属微球与化疗药物的质量比为1:(0.1-5);可选地,所述化疗药物包括但不限于各类小分子抗癌药、免疫制剂。
8.根据权利要求5-7任一项所述液态金属栓塞剂,其特征在于,所述液态金属栓塞剂中还包括具有磁性或放射性的材料,可选为金属铁、钴、镍、氧化铁、四氧化三铁及其合金的一种或多种。
9.权利要求6所述液态金属栓塞剂的制备方法,其特征在于,包括将所述液态金属微球和高分子材料置于热水中进行超声的步骤。
10.权利要求7所述液态金属栓塞剂的制备方法,包括所述液态金属微球、化疗药物,或者还包括高分子材料置于热水中进行超声的步骤。
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