CN111491632A - 癌症治疗药 - Google Patents
癌症治疗药 Download PDFInfo
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- CN111491632A CN111491632A CN201880082290.5A CN201880082290A CN111491632A CN 111491632 A CN111491632 A CN 111491632A CN 201880082290 A CN201880082290 A CN 201880082290A CN 111491632 A CN111491632 A CN 111491632A
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- Prior art keywords
- cancer
- therapeutic agent
- cyclodextrin
- injection
- acid
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Abstract
O‑(5‑氨基‑2‑苯基苯并
Description
技术领域
本发明涉及癌症治疗药。
背景技术
肿瘤细胞中,为了维持快速的细胞增殖、亢进的细胞内代谢,从外部摄入糖和氨基酸等营养的转运蛋白的表达增加。特别是,LAT1(L型氨基酸转运蛋白1)是在肿瘤细胞中特异性表达的转运蛋白,担负着输送包括也作为信号因子的亮氨酸的必需氨基酸、对肿瘤细胞供给必需的营养这样的重要作用。与此相对,已知LAT2(L型氨基酸转运蛋白2)广泛地在正常细胞中进行表达。因此,对LAT1具有选择性抑制活性的化合物可能成为副作用少的抗癌剂。
另外,在专利文献2中公开了含有JPH203的注射剂。
现有技术文献
专利文献
专利文献1:国际公开第2008/081537号
专利文献2:日本特开2017-155023号公报
发明内容
发明所要解决的问题
本发明的目的在于提供新的癌症治疗药。
用于解决问题的方法
本发明人进行深入研究的结果发现,JPH203对预定的癌症显示出高的治疗效果(肿瘤缩小效果和/或总生存期的延长效果),从而完成了本发明。
即,本发明提供以下的[1]~[6]。
[1]一种癌症治疗药,其是含有JPH203或其药理学上可接受的盐的癌症治疗药,其中,癌症为胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌。
[2]一种癌症治疗用药物组合物,其是含有JPH203或其药理学上可接受的盐和医药品添加物的癌症治疗用药物组合物,其中,癌症为胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌。
[3]一种癌症治疗方法,其是包括将JPH203或其药理学上可接受的盐给药于有此需求的患者的步骤的、治疗癌症的方法,其中,癌症为胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌。
[4]JPH203或其药理学上可接受的盐,其是用于癌症治疗的JPH203或其药理学上可接受的盐,其中,癌症为胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌。
[5]JPH203或其药理学上可接受的盐在制造癌症治疗药中的应用,其中,癌症为胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌。
[6]如上述[1]~[5]所述的癌症治疗药、癌症治疗用药物组合物、癌症治疗方法、化合物或应用,其中,JPH203或其药理学上可接受的盐以一次1mg/m2~60mg/m2来给药。
发明效果
JPH203或其药理学上可接受的盐对胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌显示出高的治疗效果。
附图说明
图1是表示JPH203的I期临床试验结果的瀑布图(Waterfall plot)的图。
图2是表示JPH203的I期临床试验结果的Swimmer plot的图。
具体实施方式
JPH203或其药理学上可接受的盐可以通过专利文献1中记载的方法来制造。
药理学上可接受的盐只要是在医药上、药理学上(制药上)或生理学上可接受的盐则没有特别限制。作为这样的盐,具体可以列举与无机酸的盐、与有机酸的盐、与无机碱的盐、与有机碱的盐、与酸性或碱性氨基酸的盐等。
作为与无机酸的盐的优选例,可以列举例如与盐酸、氢溴酸、硫酸、硝酸、磷酸等的盐。作为与有机酸的盐的优选例,可以列举例如与乙酸、琥珀酸、富马酸、马来酸、酒石酸、柠檬酸、乳酸、硬脂酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸等的盐。
作为与无机碱的盐的优选例,可以列举例如钠盐、钾盐等碱金属盐、钙盐、镁盐等碱土金属盐、铝盐、铵盐等。作为与有机碱的盐的优选例,可以列举例如与二乙胺、二乙醇胺、葡甲胺、N,N-二苄基乙二胺等的盐。
作为与酸性氨基酸的盐的优选例,可以列举例如与天冬氨酸、谷氨酸等的盐。作为与碱性氨基酸的盐的优选例,可以列举例如与精氨酸、赖氨酸、鸟氨酸等的盐。
药理学上可接受的优选盐为与无机酸的盐、特别是盐酸盐。
本发明的癌症治疗药含有JPH203或其药理学上可接受的盐。另外,可以根据需要含有医药品添加物。癌症治疗药可以以片剂、颗粒剂、细粒剂、粉剂、胶囊剂等固体制剂或液剂、冻胶剂、糖浆剂等的形态进行口服给药。另外,癌症治疗药可以以注射剂、栓剂、软膏剂等的形态进行非口服给药。
癌症治疗药的优选形态为注射剂。在此,“注射剂”不限于最终形态下的注射液,在还包含可以在临用时使用溶解液制备最终注射液的注射液前体(例如,液态注射剂(浓稠或浓缩注射剂)或固态注射剂(冻干注射剂等))的含义下使用。注射剂优选含有作为医药品添加物的pH调节剂和环糊精类。通过含有这些医药品添加物,能够制成减少了不溶性微粒数的注射剂,另外,能够制成改善了再溶解性的冻干制剂(专利文献2)。
pH调节剂只要是在医药上、药理学上(制药上)或生理学上可接受的pH调节剂则没有特别限制。作为这样的pH调节剂,可以列举例如碳酸钠、碳酸钾、乙醇钠、丁醇钾、氢氧化钠、氢氧化钾这样的碱金属氢氧化物、氢化钠、氢化钾这样的碱金属氢化物、碱金属或碱土金属的碳酸盐、碱金属醇盐等。
pH调节剂可以单独使用一种,另外,也可以将两种以上任意组合来使用。作为配合于注射剂中的pH调节剂,优选氢氧化钠和碳酸钠,更优选氢氧化钠。
注射剂可以使用pH调节剂而适宜地调节至适当的pH。从即使在使用非强酸性的水溶液时也可减少所形成的不溶性微粒数的观点和改善在非强酸性的水溶液中的再溶解性的观点考虑,注射剂的pH优选为3~6,更优选为3~5,进一步优选为3~4.5,特别优选为3.5~4.5。
环糊精类只要是在医药上、药理学上(制药上)或生理学上可接受的环糊精类则没有特别限制。作为这样的环糊精类,可以列举例如未修饰环糊精、修饰环糊精等。作为未修饰环糊精,可以列举例如α-环糊精、β-环糊精、γ-环糊精等。另外,作为修饰环糊精,可以列举例如烷基化环糊精(例如,二甲基-α-环糊精、二甲基-β-环糊精、二甲基-γ-环糊精等)、羟烷基化环糊精(例如,羟丙基-α-环糊精、羟丙基-β-环糊精、羟丙基-γ-环糊精等)、磺烷基醚环糊精(例如,磺丁基醚-α-环糊精、磺丁基醚-β-环糊精、磺丁基醚-γ-环糊精)、支链环糊精(例如,麦芽糖基-α-环糊精、麦芽糖基-β-环糊精、麦芽糖基-γ-环糊精等)等。
环糊精类可以单独使用一种,另外,也可以将两种以上任意组合来使用。从即使在使注射剂溶解于非强酸性的水溶液中时也能够减少所形成的不溶性微粒数的观点和改善冻干制剂在非强酸性的水溶液中的再溶解性的观点考虑,环糊精类优选羟丙基-β-环糊精或磺丁基醚-β-环糊精,更优选磺丁基醚-β-环糊精。
作为注射剂中的环糊精类的含量,例如,以注射剂的总量为基准,环糊精类的总含量优选为5~50重量%,更优选为10~40重量%,进一步优选为10~30重量%。
关于注射剂中环糊精类相对于JPH203或其药理学上可接受的盐的含量的含有比率,例如,相对于JPH203或其药理学上可接受的盐的含量1质量份,环糊精类的总含量优选为0.01~500质量份,更优选为0.1~100质量份,进一步优选为1~50质量份。
注射剂可以含有缓冲剂、助悬剂、助溶剂、稳定剂、等渗剂、保存剂等。
作为缓冲剂,可以列举例如硼酸缓冲剂、磷酸缓冲剂、碳酸缓冲剂、柠檬酸缓冲剂、乙酸缓冲剂、Tris缓冲剂、天冬氨酸、天冬氨酸盐、ε-氨基己酸等。
作为助悬剂,可以列举例如甲基纤维素、聚山梨醇酯80、羟乙基纤维素、阿拉伯胶、黄芪胶粉末、羧甲基纤维素钠、聚氧乙烯山梨醇酐单月桂酸酯等。
作为助溶剂,可以列举例如聚氧乙烯氢化蓖麻油、聚山梨醇酯80、烟酰胺、聚氧乙烯山梨醇酐单月桂酸酯、聚乙二醇(Macrogol)、甘油脂肪酸酯等。
作为稳定剂,可以列举例如亚硫酸钠、偏亚硫酸钠等。
作为等渗剂,可以列举例如葡萄糖、甘露糖醇、山梨糖醇等。
作为保存剂,可以列举例如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、山梨酸、苯酚、甲酚、氯甲酚等。
注射剂可以是冻干制剂。冻干制剂可以在临用时溶解于例如注射用蒸馏水、输液[电解质液(生理盐水、林格液等)、营养输液、蛋白氨基酸注射液、维生素注射液等]、组合有电解液、营养输液(糖液等)的代用血液、乳化了脂肪的脂肪乳剂等中的一种或上述两种以上的溶剂中制成临用时溶解型注射剂来使用。
作为使冻干制剂溶解于水中时的pH,优选为3~6,更优选为3~5,进一步优选为3~4.5,特别优选为3.5~4.5。上述pH从改善冻干制剂在非强酸性的水溶液中的再溶解性的观点考虑是优选的。
冻干制剂可以通过公知的冻干制剂的制造方法来制作,只要是在医药上、药理学上(制药上)或生理学上可接受的范围内则没有特别限定。作为冻干的方法,可以列举例如如下方法等:在-25℃以下的温度下冷冻后,在干燥箱内将真空度保持于约20Pa以下的同时,升温至搁板温度达到25~40度为止并使其干燥。
注射剂可以是静脉、皮下、肌肉内注射剂、静脉滴注剂。
JPH203或其药理学上可接受的盐的给药量可以根据症状的程度、患者的年龄、性别、体重、敏感性差异、给药时期、给药间隔等而适当选择,从有效性和安全性的观点考虑,优选一次1mg/m2~60mg/m2(体表面积),更优选一次10mg/m2~40mg/m2(体表面积)。
癌症治疗药可治疗的癌症为胆道癌、大肠癌、食管癌、乳腺癌或胰腺癌。JPH203或其药理学上可接受的盐对胆道癌和大肠癌显示出肿瘤缩小效果和总生存期的延长效果,因此,可以期待对胆道癌和大肠癌特别高的治疗效果。JPH203或其药理学上可接受的盐对食管癌和乳腺癌显示出肿瘤缩小效果。JPH203或其药理学上可接受的盐对胰腺癌显示出总生存期的延长效果。
实施例
含有JPH203的注射剂
注射剂为冻干制剂,在1小瓶中含有50mg的JPH203和1200mg的磺丁基醚-β-环糊精。
以患有实体癌的患者作为对象的JPH203的I期临床试验
本临床试验以患有实体癌的患者作为对象。本临床试验的目的在于对JPH203的安全性(剂量限制性毒性:DLT)和有效性进行评价。
患者的主要选择基准和排除基准如下所述。
选择基准
·已确认患有实体癌、标准的治疗处于无效或不耐受的状态的晚期的患者
·可以利用用于LAT1抗体染色的活检或现有组织的患者
·能够期待从登记日起生存90天以上的患者
排除基准
·患有重度或临床上有问题的既往症、合并症的患者
·在试验药物给药前4周以内接受过化学疗法、放射线疗法、免疫疗法、其他以肿瘤缩小效果为目的的疗法的患者
参加本临床试验的患者的背景如下所述。
[表1]
给药方案如下所述。
1)单次给药
在第1天单次给药规定的给药量。给药量为12mg/m2(4例)、25mg/m2(3例)、40mg/m2(3例)、60mg/m2(6例)或85mg/m2(1例)。12mg/m2给药组中1例病情恶化,因此仅单次给药就中止。
2)周期1
在单次给药的给药起8天以后开始周期1,1天1次,连续给药7天。在周期1的给药开始日起第28~31天进行CT等检查。
3)周期2以后
在上一周期的检查日起28天以内开始下一周期,1天1次,连续给药7天。在给药开始日起第28~31天进行检查。
将在从单次给药起至周期1的结束时检查(周期1开始起第28天)为止的期间内发生、由试验责任(分担)医师判定为无法否定与试验药物的关联性(“有关联”、“或许有关联”、“无法说有无关联”、“或许无关联”)的下述症状作为DLT。但是,DLT的最终决定由试验责任医师和试验委托人协商来进行。需要说明的是,根据需要,在DLT的判定时,向效果安全性评价委员会征求意见。
1)在3级以上、由试验责任(分担)医师判断为难以进行试验药物的持续给药的非血液毒性(其中,不包括3级的痤疮样皮疹、斑丘疹状皮疹、荨麻疹和通过对症疗法在发生后7天以内恢复到1级的恶心、呕吐、食欲不振、痢疾、便秘、疲劳)
2)4级以上的血液毒性或需要输血的3级以上的血小板减少
3)发热性中性粒细胞减少症
有效性和安全性的结果的概要如下所述。
[表2]
给药量 | 有效例 | DLT |
12mg/m<sup>2</sup> | 2/3 | 无 |
25mg/m<sup>2</sup> | 1/3 | 无 |
40mg/m<sup>2</sup> | 1/3 | 无 |
60mg/m<sup>2</sup> | 1/6 | 有 |
85mg/m<sup>2</sup> | 0/1 | 有 |
DLT
60mg/m2给药组和85mg/m2给药组中,确认到3级的AST/ALT升高。
有效性
肿瘤的大小减少了30%以上的例(部分奏效:PR)在12mg/m2给药组中有1例,肿瘤的大小无变化的例(稳定:SD)在12mg/m2给药组、25mg/m2给药组、40mg/m2给药组和60mg/m2给药组中各有1例。另外,淋巴结转移病变中显著的缩小效果在7例中有3例(缩小55%、69.4%、80%)。
图1中示出表示每个受试者的肿瘤缩小比例的瀑布图,图2中示出表示每个受试者的生存月数的Swimmer plot。由图1可明确,JPH203对胆道癌、大肠癌、食管癌和乳腺癌显示出肿瘤缩小效果。另外,由图2可明确,JPH203对胆道癌、大肠癌和胰腺癌显示出生存期的延长效果。需要说明的是,PD(恶化)是指与基线以后测定的最小直径和相比、靶病变的直径和增加20%以上并且直径和的绝对值增加5mm以上的情况。
Claims (7)
2.如权利要求1所述的癌症治疗药,其中,癌症为胆道癌。
3.如权利要求1所述的癌症治疗药,其中,癌症为大肠癌。
4.如权利要求1所述的癌症治疗药,其中,癌症为食管癌。
5.如权利要求1所述的癌症治疗药,其中,癌症为乳腺癌。
6.如权利要求1所述的癌症治疗药,其中,癌症为胰腺癌。
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