CN117462553A - 药物组合产品以及组合疗法 - Google Patents
药物组合产品以及组合疗法 Download PDFInfo
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- CN117462553A CN117462553A CN202210872332.3A CN202210872332A CN117462553A CN 117462553 A CN117462553 A CN 117462553A CN 202210872332 A CN202210872332 A CN 202210872332A CN 117462553 A CN117462553 A CN 117462553A
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Abstract
本发明涉及药物组合产品及其组合疗法。具体地,本发明提供了包含第一药物活性成分和第二药物活性成分的药物组合产品。本发明还提供了治疗异常细胞生长(例如癌症)的组合疗法,其包括向有需求的受试者施用根据本发明的药物组合产品。
Description
技术领域
本发明涉及药物组合产品,其包含第一药物活性成分和第二药物活性成分。本发明还涉及治疗异常细胞生长(例如癌症)的组合疗法,其包括向受试者单独或同时施用第一药物活性成分和第二药物活性成分。
背景技术
癌症是当代最严重的威胁人类生命和健康的疾病之一,在世界范围内,每年癌症死亡人数达七百万。目前,癌症的治疗主要采用四种方法:手术治疗、药物治疗、放射治疗及免疫治疗;此外,还有辅助疗法。在当前的各种治疗方法中,靶向药物疗法是最有前景和最有希望治疗癌症的一种疗法,人们一直探索有效的靶向药物疗法。
CN112585129公开了一种新型的杂环化合物,其可以用于抑制细胞中的KRAS G12C突变蛋白。该专利申请还公开了所述杂环化合物与铂基药物(例如顺铂或卡铂)、SHP2抑制剂(例如RMC-4550、RMC-4630、TNO155)和/或MEK抑制剂(例如曲美替尼)组合使用,用于减少肿瘤体积。
WO2010058032公开了一种嘧啶类化合物,其可以作为FAK抑制剂用于预防和/或治疗以过度或异常细胞增殖为特征的疾病。该嘧啶类化合物包括用于临床试验的BI853520/IN10018化合物。
W02021155764公开了BI853520化合物与化疗药物的联用,该化疗药物包括聚乙二醇化脂质体阿霉素(PLD)、紫杉烷或顺铂。
WO2021154929公开了治疗异常细胞生长的联合疗法。该专利申请的结论表明,RAF/MEK抑制剂(例如VS-6766)、FAK抑制剂(例如地法替尼)和KRAS G12C抑制剂(例如AMG-510)的三重组合在小鼠中产生肿瘤消退。
尽管癌症患者有许多治疗选择,但仍需要有效和安全的治疗剂,并且需要可以用于有效的长期癌症治疗的新组合疗法。有效的癌症治疗剂的组合可以更有效地预防和/或治疗异常细胞生长相关疾病(例如癌症)。
发明内容
在一个方面,本发明提供一种包含第一药物活性成分和第二药物活性成分的药物组合产品,其中所述第一药物活性成分是式(I)的化合物或其药学上可接受的盐,
和其中所述第二药物活性成分是式(II)的化合物或其药学上可接受的盐,
在一些实施方案中,所述第一药物活性成分是式(I)的化合物。在一些实施方案中,所述第二药物活性成分是式(II)化合物的药学上可接受的盐。
在一些实施方案中,所述第一药物活性成分是式(I)的化合物的游离碱。在一些实施方案中,所述第二药物活性成分是式(II)化合物的药学上可接受的盐(例如,马来酸盐、苹果酸盐或酒石酸盐)。
在一些实施方案中,所述第一药物活性成分与所述第二药物活性成分的重量比为约50∶1至约1∶50,优选约25∶1至约1∶25,和更优选约15∶1至约1∶15。
在一些实施方案中,所述第一药物活性成分与所述第二药物活性成分可以单独给药,不分先后。在一些实施方案中,所述第一药物活性成分与所述第二药物活性成分可以同时给药。
在一些实施方案中,所述药物组合产品呈药物组合物的形式。在一些实施方案中,其中所述药物组合物还包含一种或多种可药用的赋形剂。
在另一个方面,本发明提供一种根据本发明所述的药物组合产品在制备用于治疗异常细胞生长(例如癌症)的药物中的用途。
在一些实施方案中,所述异常细胞生长包括实体瘤、软组织肿瘤、转移或非实体癌。在一些实施方案中,所述异常细胞生长是KRAS G12C突变阳性的局部晚期或转移性实体肿瘤,例如非小细胞肺癌、结直肠癌、胆管癌。
在又一个方面,本发明提供一种治疗异常细胞生长相关疾病的方法,其包括向有需要的受试者施用根据本发明所述的药物组合产品。
在一些实施方案中,所述第一药物活性成分通过口服施用。在一些实施方案中,所述第一药物活性成分每天至少施用一次,例如,所述第一药物活性成分每天施用一次,或,所述第一药物活性成分每天施用两次或多次。在一些实施方案中,所述第一药物活性成分以约1mg至约5000mg的单剂量施用。
在一些实施方案中,所述第二药物活性成分通过口服施用。在一些实施方案中,所述第二药物活性成分每天至少施用一次,例如,所述第二药物活性成分每天施用一次,或,所述第二药物活性成分每天施用两次或多次。在一些实施方案中,所述第二药物活性成分以约1mg至约5000mg的单剂量施用。
在一些实施方案中,所述异常细胞生长相关疾病包括实体瘤、软组织肿瘤、转移或非实体癌。在一些实施方案中,所述施用包括将第一药物活性成分与第二药物活性成分单独给药或同时给药。
令人惊奇地发现,根据本发明的第一药物活性成分和第二药物活性成分可以协同地实现肿瘤总体缓解,并增加临床前模型中的中值存活百分比。
在衍生自患者的肿瘤异种移植中,与单一药物活性成分相比,包含第一药物活性成分和第二药物活性成分的药物组合产品可以产生协同的抗肿瘤活性。试验数据表明,对于KRAS G12C突变阳性的局部晚期或转移性实体肿瘤(例如非小细胞肺癌、结直肠癌、胆管癌等),第一药物活性成分和第二药物活性成分的组合可以实现更大和更持久的应答。重要的是,第一药物活性成分和第二药物活性成分用作单一药物活性成分时仅能降低肿瘤生长速率,而相同剂量在两种药物活性成分组合时可以实现肿瘤体积减小,从而总体缓解肿瘤生长。
附图说明
图1显示了人非小细胞肺癌细胞NCl-H358异种移植模型各给药组的小鼠体重变化;
图2显示了人非小细胞肺癌细胞NCl-H358异种移植模型各给药组的小鼠体重变化率;
图3显示了人非小细胞肺癌细胞NCl-H358异种移植模型各给药组的肿瘤体积变化;
图4显示了人非小细胞肺癌细胞NCl-H358异种移植模型各给药组的肿瘤体积变化率。
具体实施方式
第一药物活性成分
本发明提供了一种包含第一药物活性成分的药物组合产品。在一些实施方案中,所述第一药物活性成分是式(I)的化合物或其药学上可接受的盐,
在一些实施方案中,所述第一药物活性成分是式(I)的化合物。本文所述式(I)的化合物是已知化合物,其所有已知形式和成分,都可以用于本发明所提供的药物组合产品中。例如,式(I)化合物的制备和确认已经描述在PCT国际申请WO2020233592、WO2021121330和WO2021120045中。
在一些实施方案中,所述第一药物活性成分是式(I)化合物的药学上可接受的盐,其包括但不限于盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在一些实施方案中,所述第一药物活性成分可以是无定形、结晶形式及其组合。
在另一些实施方案中,所述第一药物活性成分还可以是与式()化合物药效相同或相似的其他药物活性成分,例如现有技术中已知的ARS-853、ARS-853、ARS-1620、ARS-3248、LY3499446和MRTX849,或其药学上可接受的盐。
第二药物活性成分
本发明提供了一种包含第二药物活性成分的药物组合产品。在一些实施方案中,所述第二药物活性成分是式(II)的化合物或其药学上可接受的盐,
在一些实施方案中,所述第二药物活性成分是式(I1)的化合物。本文所述式(II)的化合物是已知化合物,其所有已知形式和成分,都可以用于本发明所提供的药物组合产品中。例如,式(II)化合物的制备和确认已经描述在WO2010058032中。
在一些实施方案中,所述第二药物活性成分是式(I)化合物的药学上可接受的盐,其包括但不限于盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。在一些实施方案中,所述药学上可接受的盐为马来酸盐、苹果酸盐或酒石酸盐,进一步,优选为酒石酸盐。
所述药学上可接受的盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。
在一些实施方案中,所述第二药物活性成分可以是无定形、结晶形式及其组合。
在另一些实施方案中,所述第二药物活性成分还可以是与式(II)化合物药效相同或相似的其他药物活性成分,例如现有技术中已知的defactinib、TAE226、GSK2256098、PF-03814735、BI-4464、VS-4718和APG-2449,或其药学上可接受的盐。
药物组合产品
根据本发明的药物组合产品包含第一药物活性成分和第二药物活性成分。
根据本发明的药物组合产品可以包括所述第一和/或第二药物活性成分的所有合适的同位素变体。本发明化合物的同位素变体定义为:其中至少一个原子被原子序数相同但原子量不同于自然界中通常或主要发现的原子量的原子替代的本发明的化合物。可以掺入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,例如分别为2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129|和131I。本发明化合物的某些同位素变体,例如,其中引入一个或多个放射性同位素(例如,3H或14C)的那些变体可用于药物和/或底物组织分布研究。尤其优选氚和碳-14(即,14C)同位素,这是由于它们的容易制备和可检测性。进一步,用同位素诸如氘取代可以提供由更好的代谢稳定性导致的确定的治疗优点,例如增加的体内半衰期或减小的剂量需求,并且因此在一些情况下可以是优选的。通常可以利用本领域技术人员已知的常规方法,例如,利用说明性方法或下文实施例所描述的制备方法,使用合适试剂的合适的同位素变体来制备本发明化合物的同位素变体。
根据本发明的药物组合产品可以包括作为单一立体异构体或呈任何比率的所述立体异构体的任何混合物的所述第一和/或第二药物活性成分的所有可能的立体异构体。可通过任意适合的现有技术方法例如色谱法,特别是例如手性色谱法实现本发明化合物的单一立体异构体例如单一对映体或单一非对映体的分离。
根据本发明的药物组合产品可以包括所述第一和/或第二药物活性成分的所有可能的互变异构体,其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
另外,根据本发明的药物组合产品可以包括所述第一和/或第二药物活性成分的所有可能的结晶形式或多晶型物,其作为单一多晶型物或多于一种多晶型物的任意比例的混合物。
在一些实施方案中,根据本发明的药物组合产品还包含任选的第三药物活性成分,其选自HDAC抑制剂、CDK4/6抑制剂、ALK抑制剂、JAK2抑制剂、Bcl-2抑制剂、Hsp90抑制剂、糖皮质激素、长春花生物碱、抗代谢物、DNA损伤剂、来那度胺、利妥昔单抗、PKC干扰原、Lyn/Fyn抑制剂、Syk抑制剂、PI3K抑制剂、PKCβ抑制剂、IKK抑制剂、20s蛋白酶体、IRF-4、IRAK4抗体、CXCR4抗体、CXCR5抗体、GLS抗体、PLK抗体、CD20抗体、Topo II抑制剂、DNA甲基转移酶抑制剂、Ras/MAPK抑制剂或FGFR1抑制剂;所述HDAC抑制剂,优选帕比司他乳酸、贝利司他、西达本胺、罗米地辛、伏立诺他、倍赛诺他或恩替诺特,所述CDK4/6抑制剂,优选Palbociclib、Blinatumomab、Tiagabine Hydrochloride或Itolizumab,所述Bcl-2抑制剂,优选Venetoclax、安普利森钠、ABT-737或HA14-1,所述Hsp90抑制剂,优选Sebelipase alfa或Retaspimycin Hydrochloride,所述JAK2抑制剂,优选枸橼酸托法替尼、RuxolitinibPhosphate、Lestaurtinib、Momelotinib Dihydrochloride、Peficitinib或Filgotinib,所述PKC干扰原,优选替普瑞酮、Truheal、HO/03/03、Sotrastaurin、恩扎妥林或GF109203X,所述ALK抑制剂,优选Alectinib Hydrochloride、色瑞替尼、克唑替尼、苯达莫司汀、卡莫司汀、洛莫司汀、盐酸氮芥或NVP-TAE684,所述PI3K抑制剂,优选GS-1101、IPI-145、BKM120、BEZ235、GDC-0941、AMG319、CAL-101或A66,所述IKK抑制剂,优选金诺芬、BAY 86-9766或RDEA-119。
在一些实施方案中,根据本发明的药物组合产品还包含一种或多种可药用的赋形剂、稀释剂或载体。
在一些实施方案中,根据本发明的药物组合物产品可以包含单独的第一药物活性成分和单独的第二药物活性成分。例如,根据本发明的药物组合产品可以包含分别配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂的第一药物活性成分和第二药物活性成分。替代地,根据本发明的药物组合物产品可以是包含第一药物活性成分和第二药物活性成分的药物组合物。例如,将第一药物活性成分和第二药物活性成分一起配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
根据本发明的第一和/或第二药物活性成分可以用常规片剂基质诸如乳糖、蔗糖和玉米淀粉与如下组分的组合压片:粘合剂诸如阿拉伯胶、玉米淀粉或明胶,施用后帮助片剂崩解和溶出的崩解剂诸如马铃薯淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍胶、阿拉伯胶,用于改善片剂颗粒流动和防止片剂材料与片剂模具和冲头表面粘附的润滑剂例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌,用于增强片剂的美学品质和使它们更容易被患者接受的染料、着色剂和矫味剂诸如薄荷、冬青油或樱桃香精。用于口服液体剂型中的合适的赋形剂包括磷酸二钙和稀释剂,例如水和醇(例如乙醇、苯甲醇和聚乙烯醇类),其添加或不添加药学上可接受的表面活性剂、助悬剂或乳化剂。各种其它材料可以以包衣的方式存在或者以其它方式改变剂量单位的物理形式。例如,可以用虫胶、糖或二者将片剂、丸剂或胶囊剂进行包衣。可分散的粉剂和颗粒剂适合用于制备水性混悬剂。它们以与分散剂或润湿剂、助悬剂以及一种或多种防腐剂混合的方式提供活性成分。合适的分散或润湿剂和悬浮剂通过上述已提及的那些例示。也可存在额外的赋形剂,例如上述那些甜味剂、矫味剂和着色剂。
根据本发明的药物组合产品还包括商业包装物,该商业包装物包括用于向有需要的患者同时、分开或顺序施用根据本发明的药物活性成分的说明书。
组合疗法
在一些实施方案中,可以通过调节在根据本发明的药物组合产品中的第一药物活性成分和第二药物活性成分的剂量方案以提供最适期望应答,例如,最大治疗应答和/或最小不良作用。
在一些实施方案中,所述第一药物活性成分的单剂量范围可以为1至5000mg。在一些实施方案中,所述第一药物活性成分的给药频次可以为每天5次、每天4次、每天3次、每天2次、每天1次、每2天1次、等。
在一些实施方案中,所述第二药物活性成分的单剂量范围可以为1至5000mg。在一些实施方案中,所述第二药物活性成分的给药频次可以为每天5次、每天4次、每天3次、每天2次、每天1次、每2天1次、等。
在一些实施方案中,根据本发明的药物组合产品中的第一药物活性成分与第二药物活性成分的重量比可以为约50∶1至约1∶50,优选约25∶1至约1∶25,和更优选约15∶1至约1∶15。在一些实施方案中,所述重量比可以为约14∶1至约1∶14、约13∶1至约1∶13、约12∶1至约1∶12、约11∶1至约1∶11、约10∶1至约1∶10、约9∶1至约1∶9、约8∶1至约1∶8、约7∶1至约1∶7、约6∶1至约1∶6、约5∶1至约1∶5、约4∶1至约1∶4、约3∶1至约1∶3、约2∶1至约1∶2或约1∶1,例如,所述重量比约为14∶1、约12∶1、约10∶1、约8∶1、约6∶1、约5∶1、约4∶1、约3∶1、约2∶1、约1∶1、约1∶1.2、约1∶1.5、约1∶2、约1∶2.5、约1∶3、约1∶4、或约1∶5。
所述给药剂量在本领域普通技术人员的水平内,并且药物的单剂量或日剂量可以根据待施用的受试者的发病程度、发病时间、年龄、健康状况和并发症等的各种因素而变化。
根据本发明的药物组合产品可以,单独地或组合地,通过口服施用,替代地,根据本发明的药物组合产品可以,单独地或组合地,肠胃外施用,即皮下、静脉内、眼内、滑膜内、肌内或腹膜间,作为优选在生理学上可接受的稀释剂与药物载体中的化合物的可注射剂量施用,所述药物载体可以是无菌液体或液体的混合物,诸如水、盐水、右旋糖水溶液和相关糖溶液,醇诸如乙醇、异丙醇或十六醇,二醇类诸如丙二醇或聚乙二醇,甘油缩酮类诸如2,2-二甲基-1,1-二氧杂环戊烷-4-甲醇,醚类诸如聚(乙二醇)400、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯或乙酰化脂肪酸甘油酯,加入或不加入药学上可接受的表面活性剂诸如皂或洗涤剂,助悬剂诸如果胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂和其它药物助剂。
在每日一次给予式(I)所示化合物和式(II)所示化合物的情况下,这可以通过给予含有式(I)所示化合物和式(11)所示化合物的组合的固定剂量组合来完成。
如果需要口服剂型可以在包装或分配器装置中呈现,例如FDA认可的试剂盒,其可含有有活性成分的一种或多种单位剂型。例如,包装可以包括金属或塑料箔,例如泡罩包装。包装或分配器装置可以伴随着给药指令。
治疗用途
本发明提供了治疗异常细胞生长的组合疗法,其包括向有需求的受试者施用根据本发明的药物组合产品。
在一些实施方案中,本发明的药物组合物产品包含治疗有效量的第一药物活性成分和治疗有效量的第二药物活性成分;在一些实施方案中,本发明的药物组合物产品可以包含治疗有效量的单独的第一药物活性成分和治疗有效量的单独的第二药物活性成分。
在一些实施方案中,所述异常细胞生长,例如癌症,非限制性的包括实体瘤、软组织肿瘤、转移或非实体癌。在一些实施方案中,癌症是实体瘤。在一些实施方案中,实体瘤是器官(例如肺、乳腺、淋巴、胃肠道(例如结肠)和泌尿生殖器(例如肾、泌尿道上皮或睾丸的肿瘤)、咽、前列腺和卵巢)的恶性肿瘤(例如肉瘤、腺癌和癌)。在一些实施方案中,所述癌症为间皮瘤;神经纤维瘤病;例如,2型神经纤维瘤病、1型神经纤维瘤病;肾癌;肺癌、非小细胞肺癌;肝癌;甲状腺癌;卵巢癌;乳腺癌;神经系统肿瘤;神经鞘瘤;脑膜瘤;神经鞘瘤病(schwannomatosis);听神经瘤;腺样囊性癌;室管膜瘤;或室管膜肿瘤。在一些实施方案中,所述癌症为间皮瘤(例如,恶性胸膜间皮瘤,例如,手术可切除的恶性胸膜间皮瘤)、乳腺癌(例如,三阴性乳腺癌)、卵巢癌(例如,晚期卵巢癌)、肺癌(例如,非小细胞肺癌(NSCLC),例如,KRAS突变的NSCLC))或非血液恶性肿瘤。在一些实施方案中,所述癌症为非小细胞肺癌(NSCLC),例如,KRAS突变的NSCLC)。在一些实施方案中,所述癌症为黑素瘤(例如,N-Ras突变的局部晚期或转移恶性的皮肤黑素瘤)、结肠直肠癌(例如,转移性结肠直肠癌)、白血病(例如,急性骨髓性白血病)、腺癌(例如,胰腺腺癌)或实体瘤(例如,局部晚期的实体瘤、转移性实体瘤、肝细胞癌)。
所述癌症可包括特征为包含癌症干细胞、癌症相关间充质细胞或肿瘤起始癌细胞的癌症。癌症可包括已被表征为富含癌症干细胞、癌症相关间充质细胞或肿瘤起始癌细胞的癌症(例如,富含经历上皮-间充质转化的细胞的肿瘤或转移性肿瘤)。
肿瘤可以是原发性肿瘤,即位于肿瘤生长起始的解剖部位。该癌症也可以是转移性的,即至少出现除肿瘤生长起始的解剖部位之外的第二解剖部位。这种癌症可能是一种复发性癌症,即在治疗后以及在一段时间内无法检测到癌症后复发的癌症。复发癌可以在解剖学上定位于原发肿瘤的局部,例如,在解剖学上靠近原发肿瘤;在原发肿瘤区域,例如位于原发肿瘤附近的淋巴结;或远离原始肿瘤,例如,在解剖学上远离原始肿瘤的区域。
癌症还可包括肺腺癌、结直肠癌(CRC)、子宫内膜样癌、膀胱尿路上皮癌、乳腺浸润性小叶癌、宫颈鳞状细胞癌、皮肤黑色素瘤、宫颈腺癌、肝细胞癌、胰腺癌、双相型胸膜间皮瘤、肾透明细胞癌、肾透明细胞癌、胃腺癌、管状胃腺癌、子宫癌肉瘤或子宫恶性混合苗勒管瘤、或其他癌症。
其他癌症包括但不限于葡萄膜黑色素瘤、脑、腹部、食道、胃肠道、胶质瘤、肝、舌、神经母细胞瘤、骨肉瘤、卵巢、视网膜母细胞瘤、Wilms瘤、多发性骨髓瘤、皮肤、淋巴瘤、血液和骨髓癌(如晚期血液系统恶性肿瘤、白血病,如急性髓系白血病(如原发性或继发性)),急性淋巴细胞白血病、急性淋巴细胞白血病、T细胞白血病、血液系统恶性肿瘤、晚期骨髓增生性疾病、骨髓增生异常综合征、复发或难治性多发性骨髓瘤、晚期骨髓增生性疾病)、视网膜、膀胱、宫颈、肾脏、子宫内膜、脑膜瘤、淋巴瘤、皮肤、子宫、肺、非小细胞肺、鼻咽癌、神经母细胞瘤、实体瘤、血液系统恶性肿瘤、鳞状细胞癌、睾丸、甲状腺、间皮瘤、脑外阴、肉瘤、肠、口腔、内分泌、唾液、精母细胞精原细胞瘤、散发性髓样甲状腺癌、非增殖性睾丸细胞、与恶性肥大细胞相关的癌症、非霍奇金淋巴瘤和弥漫性大B细胞淋巴瘤。
定义
如本文所用,修饰与本发明有关的量的术语″约″是指可能发生的数值数量变化,例如通过常规测试和处理;通过此类测试和处理中的无意错误;通过本发明所用成分的制造、来源或纯度上的差异等。如本文所使用的,″约″特定值还包括该特定值,例如,约10%包括10%。不论是否被术语″约″修饰,权利要求均包括所列举数量的等同形式。在一个实施方案中,术语″约″是指在所报告的数值的20%以内、10%以内或5%以内。
如本文所用,术语″治疗″是指消除、减轻或缓解疾病或病症和/或与之相关的症状。尽管没有排除,但是治疗疾病或病症并不需要完全消除所述疾病、病症或与其相关的症状。如本文所用,术语″治疗″可以包括″预防性治疗″,其是指,对没有患病,但有风险或易于再发展疾病或病症或者复发疾病或病症的受试者而言,降低疾病或病症的再发展或先前控制的复发的可能性。术语″治疗″和同义词理解为向需要这种治疗的受试者施用治疗有效量的根据本发明的药物组合物。
如本文所用,术语“治疗有效量”是指在研究人员、兽医、医学博士或其他临床医生正在寻求的组织系统、动物或人类中引发生物或药物反应的活性化合物或药剂的量,该反应包括所治疗的疾病或病症的症状的减轻或逆转。本文中,术语“治疗有效量”可以基于单个药物活性成分,也可以基于两个药物活性成分的组合。
实施例
化合物原料来源及储藏
下列实施例中未注明具体条件的实验方法均可以按照这类反应的常规条件进行或者按照制造厂商所建议的条件进行。
如果没有特别说明,以下实施例中所使用的实验材料和试剂均可从市售渠道获得。
第一药物活性成分(API)是式(I)的化合物,其按照专利申请WO2020233592、WO2021121330或WO2021120045中公开的方法制备,纯度为大于99%,在室温下避光保存。
第二药物活性成分(API)是式(II)化合物的酒石酸盐,式(II)化合物按照专利申请WO2010058032中公开的方法制备,式(II)化合物的酒石酸盐按照由碱性化合物制备酸加成盐的常规操作制得,所述式(II)化合物的酒石酸盐的纯度为大于97%,在4℃下避光保存。
实验动物
种属: 小鼠
品系: 雌性BALB/c裸小鼠
年龄: 6-8周龄
性别: 雌性
体重: 17-24克
数量: 32只
实施例1
1、动物饲养
动物到达后在实验环境饲养3-7天后方开始实验。动物在SPF级动物房以独立送风系统(IVC)笼具饲养(每笼5只)。每笼动物信息卡注明笼内动物数目,性别,品系,接收日期,给药方案,实验编号,组别以及实验开始日期。所有笼具、垫料及饮水在使用前均灭菌。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下:
温度:20-26摄氏度。
湿度:32-70%。
笼具:以聚碳酸酯制成,体积300mmx180mmx150mm。垫料为玉米芯,每周更换两次。
食物:实验动物在整个实验阶段中可自由进食(照射灭菌,干颗粒状食物)。
饮水:实验动物可自由饮用灭菌水。
2、动物分组和给药
将小鼠分成4组,每组8只,分别按照表a中的给药方法进行给药。
表a:体内药效试验动物分组以及给药方案
3、空白溶液和化合物溶液配置
按表1所述的方法和配方配置空白对照组,并将第一API和第二APl分别按照下述方法和配方,配置成溶液。
表1:空白溶液和化合物溶液配置及贮存条件
4、细胞培养
人非小细胞肺癌细胞NCl-H358(CRL-5807TM)体外单层培养,培养条件为基础培养基RPMI-1640中加入10%胎牛血清,100单位每毫升青霉素和100微克每毫升链霉素,37摄氏度5%CO2细胞培养箱中培养。一周两次用胰蛋白消化酶进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数,接种。
5、肿瘤细胞接种
将含有1×107个NCl-H358细胞的100μL PBS皮下接种于每只小鼠的右前肢肩胛皮下,在细胞接种后第28天,开始分组给药,每组平均肿瘤体积为246.38mm3。
6、实验动物日常观察
每天监测动物的健康状况及死亡情况,例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动,摄食摄水量(仅目测),体重变化(每周测量两次体重),外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
7、肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。
每周两次用游标卡尺测量肿瘤直径。
肿瘤体积的计算公式为:V=0.5a×b2,a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(%)评价。TGI(%),反映肿瘤生长抑制率。
TGI(%)的计算:TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%。
TGI值具有以下含义:
a)TGI>100%,表明肿瘤总体缓解;
b)TGI=100%,表明肿瘤生长停滞;
c)100%>TGI,表明肿瘤生长速度降低。
8、实验结果
8.1体重
不同组荷瘤鼠体重变化以及变化率情况如图1和图2所示。图中,相对体重变化为基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比。误差线代表标准误(SEM)。
8.2肿瘤生长体积
不同组动物在各个时间段的肿瘤生长体积如表2所示。
表1.各组不同时间段肿瘤体积
8.3肿瘤生长抑制率
在给药期间动物可以耐受受试药物,因此以最后一天(第二十八天)的数据计算肿瘤生长抑制率(TGI%)和p值。
表2:肿瘤大小抑制评价
备注:
a.平均值±标准差
b.p值根据不同组中各老鼠的相对肿瘤体积计算,运用One-way ANOVA方法通过对比对照组和各给药组得出P值,P<0.01统计学分析代表各组与对照组存在显著差异,P>0.05统计学分析代表各组于对照组之间不存在显著差异。
c.P值运用One-way ANOVA方法通过对比第一API和第二API联合剂量组与单药组得出的P值。P<0.01统计学分析代表各组与对照组存在显著差异。
QD为每天一次。
8.4肿瘤重量
不同组动物肿瘤重量如表4所示。
表3:肿瘤重量抑制评价
备注:
a.平均值±标准差
b.P值运用T-test方法通过对比对照组和各给药组得出,P<0.01统计学分析代表各组与对照组存在显著差异。
c.P值运用T-test方法通过对比(第一API+第二API)联合用药组和两个单药组得出,P<0.01统计学分析代表各单药组与联合用药组存在显著差异。
QD为每天一次。
在本实施例中,评价了受试药物的第一API和第二API的单药以及联合用药在人非小细胞肺癌细胞NCI-H358皮下异种移植型中的药效。给药后,各组在不同时间点动物体重变化情况如图1和图2所示。
给药后,各组在不同时间点肿瘤体积和重量变化如表2、表3、表4以及图3、图4所示。给药后第二十七天空白组肿瘤体积达到1255.3立方毫米。在单药治疗组中,第一API和第二API的肿瘤生长抑制率TGI(%)分别为84.95%和60.05%。相比之下,第一API化合物和第二API化合物的联合用药组的肿瘤生长抑制率TGI(%)达到118.85%。TGI数值表明,第一API化合物和第二API化合物的联合用药组的药效显著优于各单药剂量组(p<0.01),实现了肿瘤总体缓解作用。
应当理解,上述说明可以阐述本发明的一个或多个、但不是全部的示例性实施方案,本发明的范围不应受到任何上述示例性实施方案的限制。
如果本发明的各方面被描述为″包括″或″包含”特征,则还可以想到″由...组成″或″基本上由...组成″的实施方案。
本文描述的所有各种方面、实施方案、选项和数值范围可以以任何和所有变型进行组合。
前面对特定实施方案的描述将如此充分地揭示本发明的一般性质,从而使得在不脱离本发明的一般概念的情况下,其他人可以通过应用本领域技术知识容易地修改和/或适应诸如这些特定实施方案的各种应用,而无需过度实验。因此,基于本文提出的教导和指导,这样的适应和修改也包含在所公开的实施方案的等同形式的含义和范围内。应当理解,本文中的措词或术语是出于描述而非限制的目的,因此本说明书的术语或措辞将由技术人员根据教导和指导来解释。
Claims (10)
1.一种包含第一药物活性成分和第二药物活性成分的药物组合产品,其中所述第一药物活性成分是式(I)的化合物或其药学上可接受的盐,
和其中所述第二药物活性成分是式(II)的化合物或其药学上可接受的盐,
2.根据权利要求1所述的药物组合产品,其中所述第一药物活性成分是式(I)的化合物,和其中所述第二药物活性成分是式(II)化合物的药学上可接受的盐。
3.根据前述权利要求中任一项所述的药物组合产品,其中所述第一药物活性成分与所述第二药物活性成分的重量比为约50∶1至约1∶50,优选约25∶1至约1∶25,和更优选约15∶1至约1∶15。
4.根据前述权利要求中任一项所述的药物组合产品,其中所述第一药物活性成分与所述第二药物活性成分单独给药或同时给药。
5.根据前述权利要求中任一项所述的药物组合产品,其中所述药物组合产品呈药物组合物的形式,其中所述药物组合物还包含一种或多种可药用的赋形剂。
6.一种根据前述权利要求中任一项所述的药物组合产品在制备用于治疗异常细胞生长(例如癌症)的药物中的用途。
7.根据前述权利要求所述的用途,其中所述异常细胞生长包括实体瘤、软组织肿瘤、转移或非实体癌。
8.一种治疗异常细胞生长相关疾病的方法,其包括向有需要的受试者施用治疗有效量的根据权利要求1至5中任一项所述的药物组合产品。
9.根据权利要求8所述的方法,其中所述第一药物活性成分通过口服施用;优选地,其中所述第一药物活性成分每天至少施用一次,例如,所述第一药物活性成分每天施用一次,或,所述第一药物活性成分每天施用两次或多次;优选地,其中所述第一药物活性成分以约1mg至约5000mg的单剂量施用;
和/或
其中所述第二药物活性成分通过口服施用;优选地,其中所述第二药物活性成分每天至少施用一次,例如,所述第二药物活性成分每天施用一次,或,所述第二药物活性成分每天施用两次或多次;优选地,其中所述第二药物活性成分以约1mg至约5000mg的单剂量施用。
10.根据权利要求8所述的方法,其中所述异常细胞生长相关疾病包括实体瘤、软组织肿瘤、转移或非实体癌,其中所述施用包括将第一药物活性成分与第二药物活性成分单独给药或同时给药。
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TWI491605B (zh) * | 2008-11-24 | 2015-07-11 | Boehringer Ingelheim Int | 新穎化合物 |
AR101982A1 (es) * | 2014-09-18 | 2017-01-25 | Araxes Pharma Llc | Terapias combinadas para el tratamiento del cáncer y composiciones |
CN112585129B (zh) * | 2019-05-21 | 2022-03-01 | 益方生物科技(上海)股份有限公司 | 杂环化合物,其制备方法和用途 |
WO2021120045A1 (en) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
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2022
- 2022-07-20 CN CN202210872332.3A patent/CN117462553A/zh active Pending
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2023
- 2023-07-20 WO PCT/CN2023/108288 patent/WO2024017316A1/zh unknown
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