CN107715124B - 医用钇-90碳微球及其制备方法 - Google Patents
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Abstract
本发明公开了一种用于肿瘤治疗的医用钇‑90（90Y）碳微球及其制备方法。医用钇‑90系列碳微球是用系列碳微球吸附90YCl3溶液和乙二胺四乙酸二钠盐溶液生成的络合物（90Y‑EDTA）制备成医用钇‑90系列碳微球。本发明的医用系列碳微球对钇‑90核素的吸附或固化效率高于99%，而经进一步净化处理后医用钇‑90系列碳微球的钇‑90的释放率低于0.01%，生物相容性好，可用于体内肿瘤放射治疗。
Description
技术领域
本发明涉及一种肿瘤放射治疗药物及其制备方法，具体涉及一种医用钇-90碳微球及其制备方法。
背景技术
内照射治疗（又称介入放射治疗）是近年来发展起来的一种治疗恶性肿瘤的方法，多种途径应用不同放射性核素的内照射治疗不断被应用到动物试验及临床试验中，取得了很好的疗效。放射性微球介入治疗肿瘤，因具有内放射和血管栓塞的双重效应而使治疗效果相较其它栓塞方式而更为突出，理化性质稳定、高效的新型放射性微球（90Y玻璃微球和90Y树脂微球）在加拿大、美国、日本等国家已经被用于治疗肝癌患者[ZP1 Y, G L, HY Z,YH D. An experimental study and clinical pilot trials on yttriμm-90 glassmicrospheres through the hepatic artery for treatment of primary livercancer. Cancer 1993; 72(11): 3210-5][RS1 S, RJ C, AW M. Selective internalradiation therapy (SIRT) with 90Yttriμm microspheres for extensive colorectalliver metastases. Hepatogastroenterology 2001; 48(38): 333-7]。
钇-90（90Y）是核医学最常用的治疗核素，90Y发射纯β射线，其β射线的最高能量E0=2.26MeV，平均能量E=0.937 MeV，半衰期T1/2=64小时，组织内最大射程R0=10.3mm，平均射程R=2.5mm，很适合作内照射放射源[孙福印，苑淑渝. 90Y-玻璃微球治疗肝癌的吸收剂量及其估算方法.国外医学·放射医学核医学分册，1997,21（2）：71-73] 。已有用于肝癌治疗的钇-90玻璃微球和阳离子树脂微球及用于治疗非霍金氏淋巴瘤的单抗药物Zevalin(90Y-鼠源抗体)，Zevalin(90Y-鼠源抗体)是美国已经上市的抗CD20单克隆抗体药物,但由于它是鼠源抗体治疗药物，使用中将发生HAMA反应,不能反复使用,疗效受到限制。
发明内容
鉴于上述不足之处，本发明的目的在于提供一种工艺简单、核素吸附率高、释放率低的医用钇-90碳微球及其制备方法。
为了达到上述目的，本发明采用了以下技术方案：
本发明是利用系列碳微球为一种载体，将放射性钇-90（90Y）核素与乙二胺四乙酸二钠（EDTA-2Na）通过络合反应生成90Y-EDTA络合物再通过物理吸附在系列碳微球内，其对钇-90核素的吸附效率高于99%，经进一步净化处理后，钇-90的释放率低于0.01%。本发明的医用钇-90系列碳微球适用于肿瘤放射治疗。
本发明碳微球吸附是物理吸附，由于钇-90核素是以90YCl3化合物形式存在，钇-90是正三价态阳离子（90Y3+），在溶液酸度高时，被系列碳微球吸附直接物理吸附的量少（<30mgY/g微球），在溶液pH值大于1时，90Y3+离子容易水解生成沉淀，因此为了提高碳微球吸附钇-90核素的量，必须采取适当措施防止90Y3+离子水解，并在提高碳微球吸附钇-90核素的吸附容量的同时，降低钇-90核素被碳微球吸附后的释放率，具体方法是选择一种络合剂与90Y3+离子生成一种稳定络合物，防止90Y3+离子水解并使该络合物被碳微球牢固吸附，吸附后钇-90核素的释放率极低（<0.01%）。经过筛选试验，本发明发现络合剂EDTA可用于制备钇-90系列碳微球。具体制备方法如下：
一种医用钇-90碳微球，主要是由碳微球和沉淀固化在碳微球内的放射性核素钇-90构成。
进一步的，所述的医用钇-90碳微球是将90YCl3溶液和乙二胺四乙酸（EDTA）溶液生成的络合物90Y-EDTA吸附在碳微球内制备而成的。
一种医用钇-90碳微球的制备方法包括以下步骤：
（1）90Y-EDTA络合物的制备：将90YCl3溶液和乙二胺四乙酸二钠(EDTA-2Na)溶液按1:2-2.5的摩尔比混合生成90Y-EDTA络合物，其溶液的pH值为3.0，Y离子含量为50-60mg/mL；
（2）医用钇-90碳微球的制备：将碳微球与90 Y-EDTA络合物溶液充分混合，在30℃-40℃恒温下震荡50-60分钟，经固液分离除去反应液后用生理盐水反复清洗，即得医用钇-90碳微球。
所述99YCl3溶液的制备方法为：将Y2O3密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经89Y(n,r)90Y反应生成90Y2O3，比放射性活度大于370G Bq(10Ci)/gY，再用HCl溶液溶解制备而成，90YCl3溶液的核纯度90Y不低于99.9%，放射化学纯度不低于95%，每毫升的放射性活度浓度不低于14.8GBq(400mCi)/mL，使用时再根据使用要求稀释成所需浓度。
所述EDTA-2Na溶液是将EDTA-2Na用纯化水溶解制备而成的，其浓度为 0.1-0.3mol/L，pH值为4.3-4.4。
所述医用钇-90碳微球的制备方法还包括碳微球的纯化处理，具体为：将碳微球用乙酸乙酯、丙酮或乙醇浸泡去脂，用氢氧化钠溶液浸泡去碱溶杂质，用纯化水反复清洗至弱碱性，再用硝酸浸泡去酸溶杂质，用纯化水清洗至pH值为1-2后备用。
所述碳微球是指用富含碳有机材料制备的微球经高温碳化，再经脱脂、碱洗、酸洗等去掉各种杂质，制备成对人体无毒害、生物相容性好的球形微粒。
所述碳微球的直径为20-30μm。
所述碳微球的直径为30-100μm。
所述碳微球的直径为大于100μm，可用于体内植入治疗肿瘤。
所述碳微球的直径为10-100nm。
所述碳微球的直径为100-150nm。
所述医用钇-90碳微球中碳微球对90Y核素的吸附率高于99%。
所述医用钇-90碳微球中90Y核素释放率低于0.01%。
一种用作体内肿瘤放射治疗的制剂，由医用钇-90碳微球制备得到。
用作体内肿瘤放射治疗的制剂中的钇-90的放射性活度为1.85GBq-7.40GBq(50mCi-600 mCi)，治疗肿瘤的碳微球粒径大小根据用途而定：粒径为20μm-30μm的医用钇-90碳微球主要用于动脉灌注栓塞放疗肝癌，粒径为30μm-100μm的医用钇-90碳微球可用于肺癌、肾癌、舌癌、乳腺癌、子宫颈癌等富含血管的肿瘤，也可用于直接分散注射到其它肿瘤内；粒径100μm以上的钇-90碳微球可用于肿瘤的放射性植入治疗；粒径为100nm-150nm的医用钇-90碳微球主要用于淋巴癌的治疗，粒径为10nm-100nm的医用钇-90碳微球具有趋肿瘤的性质，可用于肿瘤靶向治疗。
所述的医用钇-90碳微球在治疗患有医学病症的哺乳动物的药物中的用途，其中所述的医用钇-90碳微球是用介入导管、注射器或体内植入方式给予的。
本发明的有益效果在于：
1.本发明的医用钇-90碳微球是通过用碳微球吸附90Y-EDTA络合物经净化处理而成的。所制备的医用碳微球对钇-90核素的吸附效率高于99%，钇-90的释放率低于0.01%，并且生物相容性好，可用于体内肿瘤放射治疗。不同粒径的碳微球可用于栓塞放疗肝癌等含血管丰富的肿瘤，或通过分散注射放射治疗其它肿瘤，或可用于淋巴癌治疗和淋巴转移癌治疗，含有某些趋肿瘤官能团的医用钇-90碳微球也可用于其它肿瘤治疗。
2.方法简便，引入杂质少，产品纯度高。
3.钇-90利用率高，产生放射性废物少，有利于环境保护。
4.钇-90释放率低，安全性好。
5.医用钇-90碳微球的放射性活度可根据个体需要及时调整，可随时满足个体化的精准治疗要求。
6.钇-90容易从多渠道获得，医用钇-90碳微球的正常生产不受原材料供货影响，能满足常年的生产供货要求。
7.医用钇-90碳微球的生产成本低，疗效好，便于推广应用。
具体实施方式
实施例
（1）碳微球纯化处理：用乙酸乙酯、丙酮或乙醇等有机溶剂浸泡去脂；用稀氢氧化钠溶液（0.1-0.5mol/L）浸泡去碱溶杂质，再反复清洗至弱碱性（pH值为8-10）；再用稀硝酸（0.1mol/L-0.5mol/L）浸泡去酸溶杂质，清洗至pH值为1-2。
（2）将市售优级纯25g Y2O3密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经89Y(n,r)90Y反应生成90Y2O3，比放射性活度大于370G Bq(10Ci)/gY，90Y的核纯度不低于99.9%，再用300mL的HCl溶液[该处盐酸用36-38%的HCl溶液与水按1:1（mL/mL）的比例稀释而成]加微热溶解，冷却至室温后移至500mL容量瓶并用蒸馏水稀释至刻度，制备成90YCl3溶液，90YCl3溶液的放射化学纯度不低于95%。90YCl3溶液的放射性活度浓度不低于18.5GBq(500mCi)/mL，使用时再根据使用要求稀释成所需放射性浓度。
（3）用纯化水溶解市售分析纯EDTA-2Na制备成EDTA-2Na盐溶液，其浓度为 0.2-0.25mol/L，pH值为4.0，用于制备90Y-EDTA络合物。
（4）将90YCl3溶液和EDTA-2Na溶液按1:2.5的摩尔含量比混合生成90Y-EDTA络合物，其溶液的pH值为3.0，Y离子含量为50mg/mL。
（5）将1g医用系列碳微球与1mL90YCl3溶液5mLEDTA-2Na盐溶液充分混合，在50℃恒温下震荡60分钟，生成90Y-EDTA络合物并被碳微球吸附，经固液分离（离心或过滤）除去反应液后用生理盐水5mL反复清洗，即得医用钇-90系列碳微球。本发明制备的医用钇-90碳微球对钇-90的吸附高于99%，而90Y的释放率低于0.01%，钇-90碳微球浸泡液的EDTA浓度低于3ug/mL，满足人体内用药所需纯度要求和安全性要求。
Claims (16)
1.一种医用钇-90碳微球，其特征在于：该医用钇-90碳微球主要是由碳微球和沉淀固化在碳微球内的放射性核素钇-90构成，具体为：将90YCl3溶液和EDTA-2Na溶液按1:2-2.5的摩尔比混合生成90Y-EDTA络合物，其溶液的pH值为3.0，Y离子含量为50-60mg/mL；将碳微球与90Y-EDTA络合物溶液充分混合，在30℃-40℃恒温下震荡50-60分钟，经固液分离除去反应液后用生理盐水反复清洗，即得医用钇-90碳微球。
2.根据权利要求1所述的医用钇-90碳微球，其特征在于：所述99YCl3溶液的制备方法为：
将Y2O3密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经89Y(n,r)90Y反应生成90Y2O3，比放射性活度大于370G Bq(10Ci)/gY，再用HCl溶液溶解制备而成，90YCl3溶液的核纯度90Y不低于99.9%，放化化学纯度不低于95%，每毫升的放射性活度浓度不低于14.8GBq(400mCi)/mL，使用时再根据使用要求稀释成所需浓度。
3.根据权利要求1所述的医用钇-90碳微球，其特征在于：所述EDTA-2Na溶液是将EDTA-2Na用纯化水溶解制备而成的，其浓度为 0.1-0.3 mol/L，pH值为4.3-4.4。
4.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述医用钇-90碳微球的制备方法还包括碳微球的纯化处理，具体为：将碳微球用乙酸乙酯、丙酮或乙醇浸泡去脂，用氢氧化钠溶液浸泡去碱溶杂质，用纯化水反复清洗至弱碱性，再用硝酸浸泡去酸溶杂质，用纯化水清洗至pH值为1-2后备用。
5.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述碳微球是指用富含碳有机材料制备的微球经高温碳化，再经脱脂、碱洗、酸洗去掉各种杂质，制备成球形微粒。
6.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述碳微球的直径为20-30μm。
7.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述碳微球的直径为30-100μm。
8.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述碳微球的直径大于100μm。
9.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述碳微球的直径为10-100nm。
10.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述碳微球的直径为100-150nm。
11.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述医用钇-90碳微球中碳微球对90Y核素的吸附率高于99%。
12.根据权利要求1-3任意一项所述的医用钇-90碳微球，其特征在于：所述医用钇-90碳微球中90Y核素释放率低于0.01%。
13.一种用作体内肿瘤放射治疗的制剂，由权利要求1-3任意一项所述医用钇-90碳微球制备得到。
14.根据权利要求13所述的用作体内肿瘤放射治疗的制剂，其特征在于：用于肿瘤治疗的制剂中的钇-90的放射性活度为1.85GBq-7.40GBq(50mCi-600mCi)。
15.权利要求1-3任意一项所述的医用钇-90碳微球在制备治疗患有医学病症的哺乳动物的药物中的用途。
16.如权利要求15所述的用途，其中所述的医用钇-90碳微球是用介入导管、注射器或体内植入方式给予的。
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| CN102671220A (zh) * | 2011-03-11 | 2012-09-19 | 成都云克药业有限责任公司 | 一种放射性阴离子树脂微球及其制备方法 |
| CN104401969A (zh) * | 2015-01-08 | 2015-03-11 | 北京化工大学 | 一种常压干燥制备石墨烯微球的方法 |
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| CN101757644A (zh) * | 2008-12-23 | 2010-06-30 | 李树义 | 放射性微珠的结构和制备方法 |
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