CN109641069A - 含有缓冲剂的组合物 - Google Patents
含有缓冲剂的组合物 Download PDFInfo
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- CN109641069A CN109641069A CN201780050768.1A CN201780050768A CN109641069A CN 109641069 A CN109641069 A CN 109641069A CN 201780050768 A CN201780050768 A CN 201780050768A CN 109641069 A CN109641069 A CN 109641069A
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- Prior art keywords
- buffer
- sequestration
- acid
- targeting agent
- radioactive metal
- Prior art date
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Abstract
本发明提供一种在利用90Y、153Sm、165Dy、165Er、166Ho或177Lu标记螯合化靶向剂时使用的含有缓冲剂的组合物。在含有螯合化靶向剂的组合物中含有选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂。
Description
技术领域
本发明涉及用于制备放射性金属标记螯合化靶向剂的、含有缓冲剂的组合物。
背景技术
在核医学中使用的放射性医药具有被称为试剂盒的形态和被称为注射液的形态。试剂盒是用于在临床医疗中使放射性金属与螯合化靶向剂反应制备向人给药的注射液的组合物,至少由放射性金属和与其分别收纳的螯合化靶向剂构成。另一方面,注射液是制备成能够在临床医疗中直接给药的方式的组合物。
构成试剂盒的放射性金属通常以pH为1左右的盐酸溶液的形态提供。例如,在构成RI标记抗体疗法制剂Zevalin(注册商标)的试剂盒的111In或90Y中,作为添加物,添加有适量的盐酸。其它大多数的放射性金属以盐酸溶液的形态提供。
螯合化靶向剂是螯合基团和靶向部的连结体,通过形成螯合基团与放射性金属的配位化合物,利用放射性金属标记螯合化靶向剂。例如,Zevalin(注册商标)的替伊莫单抗(Ibritumomab Tiuxetan)是螯合化靶向剂,是作为抗CD20抗体的称为Ibritumomab的靶向部和称为Tiuxetan或MX-DTPA的螯合基团的结合体。接着,利用111In或90Y将其标记后使用。
螯合基团与放射性金属的反应大多情况下在弱酸性至中性的水溶液中进行,为了调节这样的标记反应中的pH,试剂盒中通常还含有缓冲剂。设计为利用该缓冲剂中和溶解有放射性金属的盐酸,并调节为最适于反应的pH。Zevalin(注册商标)中作为缓冲剂含有乙酸钠。
另外,作为使用了乙酸缓冲剂的例子,申请人公开了在乙酸缓冲剂(乙酸铵-HCl)存在下利用67Ga、111In或90Y标记抗钙粘素(Cadherin)抗体而得到的放射性金属标记抗钙粘素抗体(专利文献1)。
乙酸缓冲剂是在这种放射性金属标记中利用最广的缓冲剂,但是其酸解离常数(pKa)为4.76,存在缓冲能力只能达到其前后的pH范围这样的制约。
根据这样的背景,在专利文献2中对利用镓的螯合物配位方法进行了研究,公开了在将乳酸、酒石酸、碳酸、磷酸、抗坏血酸、琥珀酸、马来酸用作缓冲剂时,螯合物与镓完全配位,但在使用柠檬酸时,不发生配位。另外,Octreoscan(注册商标)是用于诊断神经内分泌肿瘤的试剂盒,由111In和喷曲肽(Pentetreotide)构成,作为其他缓冲剂,含有柠檬酸和柠檬酸钠。这样表明在利用放射性金属的螯合物配位中,柠檬酸缓冲剂虽然不适用于镓但却适用于铟,缓冲剂之中对于每种放射性金属混合存在适用和不适用的情况。
另外,试剂盒有时也采用冻干制剂的形态,但是由于广泛使用的乙酸缓冲剂在冻干过程中升华,因而无法选择乙酸缓冲剂作为缓冲剂。
现有技术文献
专利文献
专利文献1:日本再公表2011-99524号公报
专利文献2:日本特表2012-517974号公报
发明内容
发明所要解决的课题
这样一来,在90Y、153Sm、165Dy、165Er、166Ho或177Lu中,什么样的缓冲剂能够使用、以及能否作为冻干制剂使用尚不明确。
为此,本发明的课题在于提供一种在利用90Y、153Sm、165Dy、165Er、166Ho或177Lu标记螯合化靶向剂时使用的新型的含有缓冲剂的组合物。
另外,本发明的另外的课题在于提供一种在利用90Y、153Sm、165Dy、165Er、166Ho或177Lu标记螯合化靶向剂时使用的新型的含有缓冲剂且经冻干的组合物。
另外,本发明的另外的课题在于提供一种新型的在缓冲剂的存在下利用90Y、153Sm、165Dy、165Er、166Ho或177Lu标记螯合化靶向剂的放射性金属标记螯合化靶向剂的制造方法。
用于解决课题的方法
为此,本发明的发明人在90Y标记反应中使用各种各样的缓冲剂进行了研究,结果发现选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的化合物作为缓冲剂是有用的,从而完成了本发明。
即,本发明提供以下的〔1〕~〔13〕。
〔1〕一种组合物,其含有:
(a)螯合化靶向剂,其为螯合基团和靶向部的连结体;和
(b)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂,
上述组合物用于由选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属与上述螯合化靶向剂形成配位化合物。
〔2〕如〔1〕所述的组合物,其中,放射性金属选自90Y和177Lu。
〔3〕如〔1〕或〔2〕所述的组合物,其中,螯合基团为具有DOTA结构、DTPA结构或NETA结构的螯合基团。
〔4〕如〔1〕~〔3〕中任一项所述的组合物,其中,上述螯合基团选自下列螯合基团。
〔5〕如〔1〕~〔4〕中任一项所述的组合物,其中,靶向部选自低分子化合物、肽、蛋白质、抗体或其片段、以及核酸。
〔6〕如〔1〕~〔5〕中任一项所述的组合物,其中,螯合化靶向剂和上述缓冲剂收纳在同一容器中。
〔7〕如〔1〕~〔6〕中任一项所述的组合物,其中,缓冲剂被冻干。
〔8〕如〔1〕~〔7〕中任一项所述的组合物,其中,还具有选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属,放射性金属和上述螯合化靶向剂以彼此不接触的状态收纳。
〔9〕一种放射性金属标记螯合化靶向剂的制造方法,在选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂的存在下,将选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属与螯合化靶向剂混合,
由放射性金属和螯合化靶向剂形成配位化合物。
〔10〕一种螯合化靶向剂的对象疾病的诊断或治疗药,其通过将(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)上述螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂组合而成。
〔11〕(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂的组合用于制造上述螯合化靶向剂的对象疾病的诊断或治疗药的用途。
〔12〕一种(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂的组合,其用于诊断或治疗上述螯合化靶向剂的对象疾病。。
〔13〕一种螯合化靶向剂的对象疾病的诊断或治疗方法,组合给予(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)上述螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂。
发明的效果
本发明的组合物由于组合物中所含的缓冲剂能够在螯合化靶向剂的放射性金属标记反应中发挥pH缓冲作用而不妨碍该反应,因此,作为用于制备放射性金属螯合化靶向剂的组合物是有用的。
另外,本发明的组合物由于组合物中所含的缓冲剂在冻干过程中不会升华,因此,作为冻干制剂是有用的。
另外,本发明的制造方法使用能够在螯合化靶向剂的放射性金属标记反应中发挥pH缓冲作用而不妨碍该反应的缓冲剂,因此,作为放射性金属标记螯合化靶向剂的制造方法是有用的。
另外,本发明的组合物作为螯合化靶向剂的对象疾病的诊断或治疗药是有用的。
具体实施方式
以下,详细地说明本发明。
缓冲剂是指具有缓和添加酸或碱时的pH变化的作用、即具有缓冲作用的化合物。例如,作为缓冲剂,可以列举弱酸与其共轭碱、或者弱碱与其共轭酸的混合物。其中,缓冲剂只要能够在溶于介质时形成混合物即可,例如,仅将弱酸溶于水时,由于酸解离而形成平衡,从而形成弱酸与其共轭碱的混合物,因此,在本发明中,缓冲剂也包括试剂为1种的情况。
本发明的缓冲剂为选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上。作为盐,例如可以列举与钠和钾等碱金属的盐、与钙和镁等碱土金属的盐、铵盐。优选的缓冲剂为选自苯甲酸、马来酸、琥珀酸和它们的盐中的1种或2种以上,特别优选的缓冲剂为选自苯甲酸及其盐中的1种或2种以上。
为了调节为目标pH,可以将弱酸与其共轭碱的盐混合,也可以将弱酸或其共轭碱的盐与后述的pH调节剂混合。从缓冲能力的方面考虑,优选具有接近目标反应中的pH的pKa的缓冲剂。在将本发明的组合物制成放射性金属标记螯合化靶向剂时,该溶液的pH优选为2以上8以下,更优选为3以上7以下,特别优选为4以上6以下。
螯合化靶向剂的靶向部是指具有在人体内选择性地进入标的部位或局部存在于标的部位的功能的化合物。大多情况下,在疾病的诊断或治疗中,以该疾病中特征性的分子或环境为标的,选择对它们具有特异性的化合物作为靶向部。靶向部的局部存在的机制没有特别限定,例如,可以列举与抗原结合的抗体或抗体片段、与受体结合的激动剂或拮抗剂、与蛋白质结合的适配体、利用EPR效应的脂质体、胶束、碳纳米管等的高分子、聚集于低氧部位的硝基咪唑化合物等的低分子化合物等。
靶向部可以是合成的也可以是天然的,分子量也没有限定。具体可以列举低分子化合物、可以是线状、环状或其组合的任一种的肽、蛋白质、抗体或抗体片段、生长因子、亲合体(Affibody)、单抗体(Unibody)、纳米抗体(Nanobody)、单糖类、多糖类、维生素、核酸、肽核酸、适配体、脂质体、胶束、碳纳米管等。
靶向部为抗体或其片段时,是指多克隆抗体、单克隆抗体、嵌合抗体、人源化抗体、人型抗体或它们的片段。抗体片段是指Fab片段、F(ab′)2片段。
优选的靶向部为抗CDH3抗体(抗P-钙粘素抗体),特别优选的靶向部为专利文献1所记载的抗CDH3抗体。作为抗CDH3抗体,例如可以列举由细胞株PPMX2016、PPMX2025、PPMX2029、PPAT-052-02、PPAT-052-03、PPAT-052-09、PPAT-052-24、PPAT-052-25、PPAT-052-26、PPAT-052-28、PPAT-052-02c、PPAT-052-03c、PPAT052-09c、PPAT-052-21c、PPAT-052-24c、PPAT-052-25c、PPAT-052-26c、PPAT-052-27c、PPAT-052-28c或PPAT-052-29c产生的抗体。
放射性金属是指金属元素且为放射性核素的核素。
本发明的放射性金属选自90Y、153Sm、165Dy、165Er、166Ho和177Lu。Sm、Dy、Er、Ho、Lu称为镧系元素,与Y同属于稀土元素,彼此的物理性质和化学性质是共通的。均易形成3价的氧化状态,由于镧系收缩,离子半径也接近。因此,Y和镧系元素在配位化学中被同样对待,具有类似的关系(Liu等、Advanced Drug Delivery Reviews 60:1347-1370(2008))。作为本发明的放射性金属,优选90Y或177Lu,特别优选90Y。
螯合基团是指能够与放射性金属结合为螯合物的有机基团。具体可以列举具有1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)结构、二乙三胺五乙酸(DTPA)结构或[2-(4,7-双羧甲基[1,4,7]三氮杂环壬烷-1-基-乙基)羰基甲基氨基)乙酸(NETA)结构作为基本骨架的螯合基团。已知NETA是期待兼备DOTA的高配位稳定性和DTPA的高配位速度这两个特征的性能而考虑的螯合物,且与Y的配位速度也比DOTA快(Chong等、Journal ofMedicinal Chemistry 45:3458-3464(2002))。这些基本骨架中,1个羧基可以用于与靶向部的酰胺键,DOTA结构、DTPA结构、NETA结构通过氨基、羧基和任意的酰胺的羰基与Y或镧系元素配位而形成稳定的配位化合物。另外,这些基本骨架中,亚乙基中的1个可以为亚环己基或亚异丙基。另外,螯合基团经由1个导入羧基或基本骨架的亚乙基或亚甲基的侧链与靶向部连结。作为这样的侧链,只要能够简单地与靶向部连结即可,已知具有酸酐基、溴乙酰胺基、碘乙酰胺基、异硫氰酸根基、异硫氰酸根苄基、N-羟基琥珀酸酰亚胺基或马来酰亚胺基等活性基团的基团(Liu等、Advanced Drug Delivery Reviews 60:1347-1370(2008))。
作为本发明的螯合基团,优选具有DOTA结构、DTPA结构或NETA结构的螯合基团,更优选下式所示的任一螯合基团:
最优选下式所示的任一螯合基团:
螯合化靶向剂是指螯合基团与靶向部经由共价键连结而成的连结体。连结中通常使用上述的具有活性基团的基团。在连结时,在螯合基团与靶向部之间可以任意地夹入称为连接基(linker)或间隔基(spacer)等的基团,例如可以列举专利文献1中的各种类型的连接基。连接基用于控制电荷、亲油性、亲水性以使靶向部的生物体内分布最优化,并且,也有助于体积大的配位化合物不会在空间上阻碍与生物体内的标的的结合。
冻干是指使水在真空环境下从经过冻结的组合物升华而将其除去的技术。本发明的缓冲剂由于不因冻干而升华,因此,在冻干制剂中也能够利用。特别是在对蛋白质进行处理的领域中,通常被用作解决其变性、聚集等的物理不稳定性和脱酰胺化、氧化等的化学不稳定性所引起的问题的方法,能够延长组合物的有效期。因此,在本发明的螯合化靶向剂为蛋白质时,特别优选将其与缓冲剂收纳于同一容器中的冻干制剂。本发明的组合物也可以是经过冻干的状态。即,通过在本发明的组合物中加水并使其冻干,能够将本发明的组合物制成经过冻干的状态。
缓冲剂的有效的含量优选在与含放射性金属的溶液混合时能够将该溶液中所含的酸中和、并且能够维持最佳的反应pH的量。放射性金属根据其半衰期而随时减少,因此,制备注射液时所需要的放射性金属的量从预定向人体给药的时刻起回溯计算。即,在制备注射液时使用的含放射性金属的溶液的量通常不是固定的。因此,缓冲剂的含量优选为能够应对假定最多的含放射性金属的溶液量的量,在制备注射剂时可以使用其全部量,也可以根据含放射性金属的溶液量而变化。这样的缓冲液的量只要能够将反应中的pH调节至所期望的pH的范围内即可,没有特别限定,优选将利用放射性金属标记螯合化靶向剂时的反应液的pH调节至所使用的缓冲剂的pKa值±1.5的范围内的量,更优选调节至所使用的缓冲剂的pKa值±1.0的范围内的量,特别优选调节至所使用的缓冲剂的pKa值±0.5的范围内的量。这样的缓冲剂的含量在利用放射性金属标记螯合化靶向剂时的反应液中为2mmol/L以上1000mmol/L以下的浓度即可,优选为10mmol/L以上500mmol/L以下的浓度,更优选为50mmol/L以上250mmol/L以下的浓度。
只要是本领域技术人员,这样的缓冲剂的量能够根据制品设计设定所使用的放射性金属的溶液的量,能够根据其量适当设定。
本发明的组合物可以适当混合药理学上可接受的追加的添加物。作为添加物,例如可以进一步含有赋形剂、表面活性剂、pH调节剂、等渗剂、稳定化剂。
作为赋形剂,可以列举:赤藓糖醇、甘露醇、木糖醇和山梨糖醇等糖醇类;白糖、糖粉、乳糖、蔗糖、海藻糖和葡萄糖等糖类;α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精和磺丁基醚-β-环糊精钠等环糊精类;结晶纤维素和微晶纤维素等纤维素类;以及玉米淀粉、马铃薯淀粉和α化淀粉等淀粉类等。
作为表面活性剂,可以列举月桂基硫酸钠、磺基琥珀酸二辛基钠、聚山梨醇酯和聚氧乙烯氢化蓖麻油等。
作为pH调节剂,可以列举盐酸、氢氧化钠等。pH调节剂也可以与缓冲剂一起使用来调节pH。
作为等渗剂,可以列举氯化钠、葡萄糖、甘露醇、甘油等。
作为稳定化剂,可以列举抗坏血酸、苯甲醇、龙胆酸、α-硫代甘油、聚乙烯吡咯烷酮、乙醇等。
这些添加物可以使用任意一种或组合两种以上。配合量没有特别限定,根据各自的目的适当配合以充分表现其效果即可。
本发明的组合物可以将螯合化靶向剂和缓冲剂收纳于同一容器中,也可以收纳于不同的容器中,优选收纳于同一容器中。在收纳于同一容器中的组合物时,能够仅通过使该组合物与放射性金属混合来制备放射性金属标记螯合化靶向剂。在临床医疗中能够尽可能使操作简便,从防止误操作的观点考虑是优选的。在收纳于不同的容器中的组合物时,可以使螯合化靶向剂与缓冲剂混合、接着再与放射性金属混合,也可以使螯合化靶向剂与放射性金属混合、接着再与缓冲剂混合,还可以使缓冲剂与放射性金属混合、接着再与螯合化靶向剂混合,优选使螯合化靶向剂与缓冲剂混合、接着再与放射性金属混合。在先混合螯合化靶向剂和放射性金属时,由于没有调整pH就使两者接触,可能会发生其它的反应。另外,先混合缓冲剂和放射性金属时,介质被调节至中性侧,放射性金属可能会形成氢氧化物而沉淀。
另外,本发明的组合物除了可以为含有螯合化靶向剂和缓冲剂的组合物以外,还可以为进一步含有放射性金属的组合物。这意味着用于制备放射性医药的有效成分所需要的全部材料形成为一套的试剂盒。大多情况下,提供螯合化靶向剂和放射性金属的主体是独立的,但将它们作为一套一起提供,对于使用者来说更为便利。但是,放射性金属与螯合化靶向剂必须以彼此不接触的状态收纳,优选收纳于不同的容器中。
(A)上述放射性金属、(B)螯合化靶向剂和(C)上述缓冲剂的组合(详细而言,由放射性金属与螯合化靶向剂形成的配位化合物和缓冲剂的混合物)作为以上述螯合化靶向剂为对象的诊断药或治疗药是有用的。这里,诊断药和治疗药的对象疾病由靶向部决定。例如在靶向部为抗CDH3抗体时,为咽癌、喉癌、舌癌、肺癌、乳腺癌、食道癌、胃癌,大肠癌、子宫癌、卵巢癌、肝癌、胰腺癌、胆囊癌、肾癌、前列腺癌、恶性黑色素瘤、甲状腺癌等上皮癌;骨肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、脂肪肉瘤、血管瘤、纤维瘤、白血病和恶性淋巴瘤、骨髓瘤等非上皮癌等。
将本发明的组合物用作治疗药时,给药途径通常为非口服给药途径,例如,通过注射剂(皮下注射、静脉注射、肌肉注射、腹腔内注射等)、经皮、经粘膜、经鼻、经肺等给药。作为治疗药的给药量因患者的症状、给药途径、体重、年龄等而异,例如成人的每1次的给药量优选为37~3700MBq。
放射性金属标记螯合化靶向剂的制造方法例如可以如下所述进行。将上述放射性金属和螯合化靶向剂在上述缓冲剂的存在下混合时,上述放射性金属和上述螯合化靶向剂形成配位化合物,能够制造放射性金属标记螯合化靶向剂。如上所述,这些成分的混合方法因螯合化靶向剂和缓冲剂的收纳状态而异。即,螯合化靶向剂和缓冲剂可以收纳于同一容器中,也可以收纳于不同的容器中,优选收纳于同一容器中。在收纳于同一容器中的组合物时,能够仅通过使该组合物与放射性金属混合来制备放射性金属标记螯合化靶向剂。在收纳于不同的容器中的组合物时,可以使螯合化靶向剂与缓冲剂混合、接着再与放射性金属混合,也可以使螯合化靶向剂与放射性金属混合、接着再与缓冲剂混合,还可以使缓冲剂与放射性金属混合、接着再与螯合化靶向剂混合,优选使螯合化靶向剂与缓冲剂混合、接着再与放射性金属混合。
实施例
接着,列举实施例进一步详细地说明本发明,但本发明不限定于此。
1.缓冲剂的评价
作为缓冲剂,选择酒石酸、马来酸、琥珀酸、组氨酸、谷氨酸、苯甲酸、柠檬酸、2-吗啉乙磺酸、乳酸,研究螯合化靶向剂的90Y标记反应中的缓冲能力和标记率。作为对照,也同时对乙酸进行研究。
关于缓冲液,将含有各缓冲剂的水溶液和含有其共轭酸或共轭碱的水溶液混合,或者将含有各缓冲剂的水溶液和盐酸或氢氧化钠水溶液混合,调节为pH5.5。
作为螯合化靶向剂,使用专利文献1中记载的作为DOTA-抗CDH3抗体的DOTA-PPAT-052-28c,将其溶于缓冲液中,调整为2.5mg/mL或5mg/mL的抗体缓冲溶液。
90Y标记通过在缓冲剂的存在下将DOTA-PPAT-052-28c和90YCl3溶液(0.04mol/L盐酸:Cisbio公司生产)混合来进行。此外,关于标记率,利用含有对90Y具有螯合能力的DTPA的水溶液将标记反应液稀释,将其一部分在薄层色谱(BIODEX公司生产、Tec-ControlChromatography 150-771)上点样,利用生理盐水展开后,使用放射性测定器(raytest公司生产、RITA)进行确认。在薄层色谱上,用90Y标记过的DOTA-PPAT-052-28c停留在原点,未反应的90Y与DTPA配位而展开至溶剂前端。
酒石酸、马来酸和琥珀酸的评价
将表1中记载的各浓度的抗体缓冲溶液100μL和90YCl3溶液38μL混合,在40℃反应15分钟。反应后,利用薄层色谱算出标记率。另外,将缓冲液1000μL和0.04mol/L盐酸382μL混合,测定pH。
[表1]
缓冲液 | 缓冲剂浓度(mmol/L) | |
比较例1 | 乙酸钠缓冲液 | 125 |
试验例1 | 酒石酸钠缓冲液 | 125 |
试验例2 | 酒石酸钠缓冲液 | 12.5 |
试验例3 | 马来酸钠缓冲液 | 125 |
试验例4 | 马来酸钠缓冲液 | 12.5 |
试验例5 | 琥珀酸钠缓冲液 | 125 |
试验例6 | 琥珀酸钠缓冲液 | 12.5 |
在表2中表示结果。
可知任一缓冲液在125mmol/L的浓度时均能够发挥与乙酸钠缓冲液同等的缓冲能力。但是,对于酒石酸钠缓冲液,即使在适合于标记反应的pH时,标记率也较低。这表明在90Y标记中酒石酸抑制了反应。对于马来酸钠缓冲液和琥珀酸钠缓冲液,得到了与乙酸钠缓冲剂同等的标记率。
[表2]
混合后的pH | 标记率(%) | |
比较例1 | 5.1 | 99.4 |
试验例1 | 4.7 | 1.8 |
试验例2 | 3.2 | 1.0 |
试验例3 | 5.2 | 97.3 |
试验例4 | 2.2 | 0.1 |
试验例5 | 5.3 | 95.6 |
试验例6 | 3.8 | 80.9 |
组氨酸、谷氨酸、苯甲酸和马来酸的评价
将表3中记载的抗体缓冲溶液和90YCl3溶液以50∶41混合,在40℃反应15分钟。反应后,利用薄层色谱算出标记率。关于pH,将表3中记载的抗体缓冲溶液和0.05mol/L盐酸以50∶41混合进行测定。
[表3]
抗体缓冲溶液 | 缓冲剂浓度(mmol/L) | |
比较例2 | 乙酸钠缓冲液 | 250 |
试验例7 | 组氨酸缓冲液 | 200 |
试验例8 | 谷氨酸钠缓冲液 | 250 |
试验例9 | 苯甲酸钠缓冲液 | 250 |
试验例10 | 马来酸钠缓冲液 | 200 |
在表4中表示结果。
可知对于谷氨酸钠缓冲液、苯甲酸钠缓冲液、马来酸缓冲液,能够发挥与乙酸钠缓冲液同等的缓冲能力。但是,对于谷氨酸钠缓冲液,即使在适合于标记反应的pH时,标记率也较低。这表明在90Y标记中谷氨酸抑制了反应。对于苯甲酸钠缓冲液和马来酸钠缓冲液,得到了与乙酸钠缓冲剂同等的标记率。
并且可知对于组氨酸缓冲液,以试验例7的浓度时未能得到令人满意的缓冲能力。
[表4]
混合后的pH | 标记率(%) | |
比较例2 | 4.9 | 99.5 |
试验例7 | 1.9 | 0.1 |
试验例8 | 4.8 | 22.2 |
试验例9 | 4.6 | 98.8 |
试验例10 | 5.1 | 97.1 |
柠檬酸、2-吗啉乙磺酸和乳酸的评价
将表5中记载的抗体缓冲溶液和90YCl3溶液以50∶41混合,在40℃反应20分钟。反应后,利用薄层色谱算出标记率。关于pH,将表5中记载的抗体缓冲溶液和0.05mol/L盐酸以50∶41混合进行测定。
[表5]
抗体缓冲溶液 | 缓冲剂浓度(mmol/L) | |
比较例3 | 乙酸钠缓冲液 | 250 |
试验例11 | 柠檬酸钠缓冲液 | 250 |
试验例12 | 2-吗啉乙磺酸缓冲液 | 250 |
试验例13 | 乳酸缓冲液 | 250 |
在表6中表示结果。
可知任一缓冲液均能够发挥与乙酸钠缓冲液同等的缓冲能力。但是,对于柠檬酸钠缓冲液和乳酸缓冲液,即使在适合于标记反应的pH时,标记率也较低。这表明在90Y标记中柠檬酸和乳酸抑制了反应。对于2-吗啉乙磺酸缓冲液,得到了与乙酸钠缓冲剂同等的标记率。
[表6]
混合后的pH | 标记率(%) | |
比较例3 | - | 99.3 |
试验例11 | 5.5 | 0.2 |
试验例12 | 4.3 | 99.4 |
试验例13 | 4.3 | 4.3 |
2.冻干制剂的制备和90Y标记
在表现与乙酸缓冲剂同等的缓冲能力和标记率的缓冲剂之中,选择苯甲酸制备冻干制剂。接着,使用其进行90Y标记。
在表7所示的条件下,将含有5mg/mL的DOTA-PPAT-052-28c和100mg/mL的海藻糖的250mmol/L苯甲酸钠缓冲液1.4mL冻干,得到白色饼状的冻干制剂。
接着,使用该冻干制剂进行90Y标记。在生成的饼中添加1.4mL的注射用水(试验例14)。另外,作为对照,使用含有5mg/mL的DOTA-PPAT-052-28c的250mmol/L乙酸钠缓冲液(比较例4)。将这些抗体溶液和90YCl3溶液分别以50∶41混合,在40℃反应15分钟。反应后,利用薄层色谱算出标记率。
[表7]
温度(℃) | 时间(小时:分钟) | |
分组(Segment)1 | -40 | 16:00 |
分组2 | -35 | 0:40 |
分组3 | -25 | 0:40 |
分组4 | -10 | 10:20 |
分组5 | 0 | 2:20 |
分组6 | 10 | 2:20 |
分组7 | 20 | 5:20 |
在表8中表示结果。
即使实施冻干,250mmol/L苯甲酸钠缓冲液也能够得到与乙酸钠缓冲液同等的标记率。这表明苯甲酸缓冲剂即使经过冻干工序也不会升华,能够在使用时维持令人满意的缓冲能力,适于作为冻干制剂的缓冲剂。
[表8]
标记率(%) | |
比较例4 | 98.5 |
试验例14 | 99.2 |
产业上的可利用性
本发明的组合物中,组合物所含的缓冲剂能够发挥pH缓冲作用而不会抑制放射性金属与螯合化靶向剂的反应,因此,在放射性金属标记螯合化靶向剂的制造中有用。
Claims (13)
1.一种组合物,其特征在于,含有:
(a)螯合化靶向剂,其为螯合基团和靶向部的连结体;和
(b)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂,
所述组合物用于由选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属与所述螯合化靶向剂形成配位化合物。
2.如权利要求1所述的组合物,其特征在于:
所述放射性金属选自90Y和177Lu。
3.如权利要求1或2所述的组合物,其特征在于:
所述螯合基团为具有DOTA结构、DTPA结构或NETA结构的螯合基团。
4.如权利要求1~3中任一项所述的组合物,其特征在于:
所述螯合基团选自下列螯合基团:
5.如权利要求1~4中任一项所述的组合物,其特征在于:
所述靶向部选自低分子化合物、肽、蛋白质、抗体或其片段、以及核酸。
6.如权利要求1~5中任一项所述的组合物,其特征在于:
所述螯合化靶向剂和所述缓冲剂收纳在同一容器中。
7.如权利要求1~6中任一项所述的组合物,其特征在于:
所述缓冲剂被冻干。
8.如权利要求1~7中任一项所述的组合物,其特征在于:
还具有选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属,所述放射性金属和所述螯合化靶向剂以彼此不接触的状态收纳。
9.一种放射性金属标记螯合化靶向剂的制造方法,其特征在于:
在选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂的存在下,将选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属与螯合化靶向剂混合,
由所述放射性金属和所述螯合化靶向剂形成配位化合物。
10.一种螯合化靶向剂的对象疾病的诊断或治疗药,其特征在于:
其通过将(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)所述螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂组合而成。
11.(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂的组合用于制造所述螯合化靶向剂的对象疾病的诊断或治疗药的用途。
12.一种(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂的组合,其用于诊断或治疗所述螯合化靶向剂的对象疾病。
13.一种螯合化靶向剂的对象疾病的诊断或治疗方法,其特征在于:
组合给予(A)选自90Y、153Sm、165Dy、165Er、166Ho和177Lu中的放射性金属、(B)所述螯合化靶向剂和(C)选自苯甲酸、马来酸、富马酸、琥珀酸和它们的盐中的1种或2种以上的缓冲剂。
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EP3501554A1 (en) | 2019-06-26 |
EP3501554A4 (en) | 2020-04-15 |
CA3031198A1 (en) | 2018-02-22 |
BR112019003370A2 (pt) | 2019-05-21 |
WO2018034354A1 (ja) | 2018-02-22 |
US11951168B2 (en) | 2024-04-09 |
AU2017311925B2 (en) | 2023-02-16 |
KR20190039695A (ko) | 2019-04-15 |
JPWO2018034354A1 (ja) | 2019-06-20 |
RU2019105539A (ru) | 2020-09-21 |
RU2757768C2 (ru) | 2021-10-21 |
AU2017311925A1 (en) | 2019-02-14 |
RU2019105539A3 (zh) | 2020-12-18 |
JP7104274B2 (ja) | 2022-07-21 |
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