CN110662540A - 用于治疗癌症的瑞格菲尼和pd-1/pd-l1(2)抑制剂的组合产品 - Google Patents
用于治疗癌症的瑞格菲尼和pd-1/pd-l1(2)抑制剂的组合产品 Download PDFInfo
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- CN110662540A CN110662540A CN201880036504.5A CN201880036504A CN110662540A CN 110662540 A CN110662540 A CN 110662540A CN 201880036504 A CN201880036504 A CN 201880036504A CN 110662540 A CN110662540 A CN 110662540A
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- regorafenib
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Abstract
本发明涉及用于治疗、预防或管理人类和其它哺乳动物的疾病和病况,包括过度增殖障碍如癌症的包含瑞格菲尼或其水合物、溶剂化物、代谢物或可药用盐或其多晶型物和PD‑1/PD‑L1(2)抑制剂的药物组合物和组合产品。
Description
本发明涉及用于治疗、预防或管理人类和其它哺乳动物的疾病和病况,包括过度增殖障碍如癌症的包含瑞格菲尼(regorafenib)或其水合物、溶剂化物、代谢物或可药用盐或其多晶型物和PD-1/PD-L1(2)抑制剂的药物组合物和组合产品。
瑞格菲尼,其是式(I)化合物4{4-[3-(4-氯-3-三氟甲基苯基)-脲基]-3-氟苯氧基}-吡啶-2-甲酸甲酰胺
是对VEGFR、PDGFR、raf、p38和/或flt-3激酶信号传导分子具有各种活性包括抑制活性的强效抗癌、抗血管生成和抗转移剂,并且其可用于治疗如WO 2005/009961中描述的各种疾病和病况,如过度增殖障碍,如癌症、肿瘤、淋巴瘤、肉瘤和白血病。其目前被批准用于在特定条件下治疗结直肠癌、胃肠道间质瘤和肝癌。在WO 2005/009961中还提到式(I)化合物的盐,如其盐酸盐、甲磺酸盐和苯磺酸盐。在WO 2008/043446中提到式(I)化合物的一水合物。在WO 2011/128261中描述了改进的制造高纯度瑞格菲尼的方法。
最近,PD-1/PD-L1(2)信号传导通路已作为免疫系统活性的重要调节物出现。在癌症中,肿瘤细胞表达PD-L1——PD-1的配体,它们借此避开被宿主免疫系统杀死。最近已开发出抗PD-1及其配体PD-L1和PD-L2的抑制剂,它们干扰这种免疫抑制机制并已通过延长患有各种类型癌症的患者的总生存期表现出惊人的临床效果。这些抑制剂中的一些已被批准用于各种癌症适应症,如黑色素瘤、NSCLC、HNSCC、RCC、膀胱癌和NHL。在其它适应症中和/或为了改进治疗活性而与各种其它抗肿瘤剂结合地,正在进行大量另外的临床试验(Iwai等人, J. Biomedical Sci. (2017) 24:26, 1-11;Sweis和Luke, Pharm. Res. (2017)120, 1-9;Bersanelle和Buti, World Journal of Clinical Oncology, (2017) 8(1),37-53;Park等人, Arch. Pharm. Res. (2016) 39, 1577-1587)。
PD-1抑制剂是生物制剂,主要G亚类免疫球蛋白,其结合到也被称为PD-1的程序性细胞死亡蛋白1上并阻断其活性。已知的PD-1抑制剂是纳武单抗(Opdivo、BMS-936558、MDX1106)、派姆单抗(Keytruda、MK-3475、帕博利珠单抗(lambrolizumab))、pidilizumab(CT-011)、PDR-001、JS001、STI-A1110、AMP-224和AMP-514(MEDI0680)。后两者是PD-L2融合蛋白(Iwai等人, J. Biomedical Sci. (2017) 24:26, 1-11;Menon等人, Cancers(2016) 8, 106, 1-21)。
PD-1(CD279)是作为单体在各种免疫细胞的表面上,主要在活化CD4+和CD8+ T细胞上、在巨噬细胞上和在活化B细胞上表达,但也在自然杀伤(NK)细胞和抗原呈递细胞(APC)上发现的受体蛋白。这种I型膜蛋白的胞外结构域由单个IgV样结构域构成,接着跨膜结构域和胞质区(其含有基于免疫受体酪氨酸的抑制和转换基序(ITIM和ITSM))。在结合到其配体PD-L1或PD-L2上后,征募磷酸酶SHP-2,其将激酶ZAP70(T细胞受体(TCR)信号传导复合物的主要组分)去磷酸化。这关闭TCR信号传导并抑制T细胞的细胞毒活性、它们的干扰素γ生成和增殖。此外,PD-1连接(ligation)上调E3-泛素连接酶CBL-b和c-CBL,它们触发T细胞受体下行调节(down-modulation)。PD-1在人类中通过Pdcd1基因编码并被在TCR活化时活化的转录因子NFATc1、IRF9和FoxO1和被T细胞衰竭信号如转化生长因子ß和eomesodermin转录激活。PD-1的激活诱导表达表明这种受体调节外周组织中的免疫应答的相当后期(效应期、记忆应答和慢性感染)。这不同于CTLA-4(另一免疫检查点蛋白),其在免疫应答的更早启动期更有活性并且CTLA-4抑制剂(例如伊匹单抗)看起来在患者中的耐受性较差(Iwai等人, J. Biomedical Sci. (2017) 24:26, 1-11;Sweis和Luke, Pharm.Res. (2017) 120, 1-9;Park等人, Arch. Pharm. Res. (2016) 39, 1577-1587)。
PD-L1抑制剂是生物制剂,主要G亚类免疫球蛋白,其结合到PD-1的配体上并阻断其活性。已知的PD-L1抑制剂是阿特珠单抗(Tecentriq、MPDL3280A)、度伐单抗(durvalumab)(MEDI4736)、阿维单抗(avelumab)(MSB0010718C)、BMS-936559(MDX1105)和LY3300054。
PD-L1(B7-H1、CD274)是PD-1的配体之一。PD-L1在许多不同的免疫细胞群体(例如T-、B-、NK细胞、DC、单核细胞、巨噬细胞)的细胞表面上、在活化血管内皮细胞,以及上皮细胞包括各种实体如黑色素瘤、肺癌、卵巢癌和结肠癌的肿瘤细胞上广泛表达。通过促炎细胞因子如干扰素γ、I型干扰素和γ链细胞因子(IL-2、-4、-7、-9、-15、-21)增强PD-L1的表达。如上所述,在与PD-1相互作用后抑制T细胞活化并由此抑制免疫应答(Park等人, Arch.Pharm. Res. (2016) 39, 1577-1587;Menon等人, Cancers (2016) 8, 106, 1-21)。
PD-L2(CD273、B7-DC)是被确认为结合到PD-1上的第二配体。其也是膜结合蛋白并且其表达限于免疫细胞的小亚群(DC和巨噬细胞)并在若干肿瘤适应症如肝癌、宫颈癌和食管癌中出现。目前,PD-L2用作融合蛋白,正作为阻断PD-1活性的治疗剂处于研发中,并且PD-L2抑制剂最终也可能作为治疗剂出现。
最初,PD-1/PD-L1抑制剂包含抗体生物制剂。但是,最近的研究已发现其它类型的PD-1/PD-L1(2)抑制剂,如小分子和肽。所述PD-1/PD-L1的小分子抑制剂的实例是BMS-202、BMS-8、BMS-37(Zak等人, Structure. 2017 Aug 1;25(8):1163-1174;Guzik等人, J MedChem. 2017 Jul 13;60(13):5857-5867)、CA-170、CA-137(Tuck D ICI symposium March2017)和咖啡酰奎宁酸化合物(Han等人, Anal Biochem. 2018 Apr 15;547:52-56)。肽抑制剂的实例描述在Maute等人(Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6506-14)中。此外,也已确认影响PD-1转录的小分子抑制剂,如GSKa/ß抑制剂SB415286(Taylor等人, Cancer Res. 2018 Feb 1;78(3):706-717)。
在WO 2015/11993中描述了用于治疗癌症的VEGF抑制剂和PD-1拮抗剂的组合产品。
本发明的目的是通过瑞格菲尼和PD-1/PD-L1(2)抑制剂联合给药改进癌症治疗。
令人惊讶地,瑞格菲尼和PD-1/PD-L1(2)抑制剂的组合产品表现出与单药疗法的总和相比显著的效力改进,特别是显著的抗肿瘤和/或抗转移效力改进。还可改进副作用状况(例如手足综合征、血压升高、疲劳、腹泻和粘膜炎症)。
本发明涉及包含瑞格菲尼或其水合物、溶剂化物、代谢物或其可药用盐或其多晶型物和PD-1/PD-L1(2)抑制剂的组合产品,瑞格菲尼是式(I)化合物
术语“式(I)化合物”或“瑞格菲尼”是指如式(I)中描绘的4-{4-[({[4-氯-3-(三氟甲基)苯基]氨基}羰基)氨基]-3-氟苯氧基}-N-甲基吡啶-2-甲酰胺。
溶剂化物对本发明而言是所述化合物或其盐的某些形式,其中溶剂分子形成固态化学计量配合物并且包括但不限于例如水、乙醇和甲醇。
水合物是溶剂化物的一种具体形式,其中溶剂分子是水。本发明的化合物或其盐的水合物是该化合物或盐与水的化学计量组合物,例如半水合物、一水合物或二水合物。优选的是瑞格菲尼的一水合物。
盐对本发明而言优选是根据本发明的化合物的可药用盐。合适的可药用盐是本领域技术人员公知的并包括无机酸和有机酸,如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸(甲苯磺酸盐)、1-萘磺酸、2-萘磺酸、乙酸、三氟乙酸、苹果酸、酒石酸、柠檬酸、乳酸、草酸、琥珀酸、富马酸、马来酸、苯甲酸、水杨酸、苯乙酸和扁桃酸的盐。此外,可药用盐包括无机碱的盐,如含有碱金属阳离子(例如Li+、Na+或K+)、碱土金属阳离子(例如Mg+2、Ca+2或Ba+2)、铵阳离子的盐,以及有机碱包括脂族和芳族取代铵和季铵阳离子的酸式盐,如由三乙胺、N,N-二乙胺、N,N-二环己基胺、赖氨酸、吡啶、N,N-二甲基氨基吡啶(DMAP)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)的质子化或全烷基化(peralkylation)生成的那些。优选的是瑞格菲尼的盐酸盐、甲磺酸盐或苯磺酸盐。
瑞格菲尼的代谢物对本发明而言包括4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺1-氧化物、4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-(羟甲基)吡啶-2-甲酰胺、4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]吡啶-2-甲酰胺和4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]吡啶-2-甲酰胺1-氧化物。
优选的是瑞格菲尼和瑞格菲尼的一水合物作为本发明的化合物。
本发明的化合物可通过使用已知化学反应和程序制备。
术语“PD-1/PD-L1(2)抑制剂”是指抗-PD-1抗体,包括但不限于纳武单抗(Opdivo、BMS-936558、MDX1106)、派姆单抗(Keytruda、MK-3475、帕博利珠单抗(lambrolizumab))、pidilizumab(CT-011)、PDR-001、JS001、STI-A1110、AMP-224和AMP-514(MEDI0680),或是指抗-PD-L1抗体,包括但不限于阿特珠单抗(atezolizumab)(Tecentriq、MPDL3280A)、度伐单抗(durvalumab)(MEDI4736)、阿维单抗(avelumab)(MSB0010718C)、BMS-936559(MDX1105)和LY3300054,或是指抗-PD-L2抗体。
优选的是纳武单抗或派姆单抗或pidilizumab作为抗-PD-1抗体。
阿特珠单抗或度伐单抗或阿维单抗也优选作为抗-PD-L1抗体。
术语“PD-1/PD-L1(2)抑制剂”也涉及小分子和肽,包括但不限于BMS-202、BMS-8、BMS-37、咖啡酰奎宁酸化合物和GSKa/ß抑制剂SB415286。
治疗方法:
本发明还涉及使用所述组合产品及其组合物治疗哺乳动物的过度增殖障碍的方法。这种方法包括向需要其的哺乳动物包括人类给予有效治疗障碍的量的所述组合产品。过度增殖障碍包括但不限于实体瘤,如乳腺癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌和它们的远端转移。这些障碍还包括淋巴瘤、肉瘤和白血病。
乳腺癌的实例包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌的实例包括但不限于小细胞肺癌和非小细胞肺癌以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括但不限于脑干和下丘脑胶质瘤、小脑和大脑星形细胞瘤、成神经管细胞瘤、室管膜瘤以及神经外胚层和松果体瘤。
雄性生殖器官肿瘤包括但不限于前列腺癌和睾丸癌。雌性生殖器官肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫肉瘤。
消化道肿瘤包括但不限于肛门癌、结肠癌、结直肠癌、食管癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
优选的是结直肠癌。
也优选的是胃肠道间质瘤(GIST)。
泌尿道肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌和尿道癌。
眼癌包括但不限于眼内黑色素瘤和视网膜母细胞瘤。
肝癌的实例包括但不限于肝细胞癌(具有或不具有纤维板层状变体的肝细胞癌)、胆管癌(肝内胆管癌)和混合型肝细胞胆管癌。
优选的是肝细胞癌。
皮肤癌包括但不限于鳞状细胞癌、卡波济氏肉瘤、恶性黑色素瘤、Merkel细胞皮肤癌和非黑色素瘤皮肤癌。
头颈癌包括但不限于喉癌/下咽癌/鼻咽癌/口咽癌,以及唇癌和口腔癌。
淋巴瘤包括但不限于AIDS相关淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病和中枢神经系统淋巴瘤。
肉瘤包括但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括但不限于急性髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性粒细胞白血病和毛细胞白血病。
这些障碍已在人类中得到充分表征,也以类似的病因学存在于其它哺乳动物中,并且可通过给予本发明的药物组合物来治疗。
基于已知用于评估可用于治疗过度增殖障碍的化合物的标准实验室技术,通过标准毒性试验和通过用于确定哺乳动物中的上述病况的治疗的标准药理学检测和通过这些结果与用于治疗这些病况的已知药剂的结果的比较,可以容易地确定用于治疗各预期适应症的本发明的化合物的有效剂量。在这些病况之一的治疗中要给予的活性成分的量可根据如所用的特定化合物和剂量单位、给药模式、疗程、受治疗患者的年龄和性别、以及治疗病况的性质和程度之类的考量广为变化。
本发明还提供本发明的化合物用于制备用于治疗上述障碍的药物组合物的用途。
给药
本发明的组合产品可以以任何形式通过任何有效的途径给药,包括例如口服、肠胃外、肠内、静脉、腹膜内、局部(topical)、透皮(例如使用任何标准贴剂)、经眼、经鼻、局部(local)、非口服,如气雾剂、吸入、皮下、肌内、口腔(buccal)、舌下、直肠、阴道、动脉内和鞘内等。它们可独自给药或与任何成分(活性或无活性)组合给药。
优选的是瑞格菲尼的口服给药,例如作为片剂。
PD-1/PD-L1(2)抑制剂优选可静脉给药。
本发明的组合产品可以以已知方式转化成常见制剂,其可以是液体或固体制剂,例如但不限于普通和肠溶包衣片剂、胶囊、丸剂、粉剂、颗粒剂、酏剂、酊剂、溶液剂、混悬剂、糖浆、固体和液体气雾剂和乳剂。
通常,上文提到的本发明的组合产品的使用会起到下列作用:
(1) 与单独给予任一药剂相比在减轻肿瘤生长或甚至消除肿瘤方面产生更好的功效,
(2) 能够给予更少量的所给化疗剂,
(3) 提供患者良好耐受的化疗治疗,有害药理并发症比用单一药剂化疗和某些其它组合疗法观察到的少,
(4) 能够治疗哺乳动物尤其是人类的更广谱的不同癌症类型,
(5) 在治疗患者中提供更高响应率,
(6) 与标准的化疗治疗相比提供治疗患者的更长存活时间,
(7) 提供更长的肿瘤进展时间,和/或
(8) 与其它癌症药剂组合产品产生抑制效应的已知情况相比,得到至少与单独使用的药剂一样好的功效和耐受性结果。
“组合产品”对本发明而言不仅是指含有所有组分的剂型(所谓的固定组合产品)和含有彼此分开的组分的组合产品包(combination packs),还是指同时或相继给药的组分,只要它们用于预防或治疗同一疾病。
所给活性成分的量可根据如所用的特定化合物和剂量单位、给药模式和时间、疗程、受治疗患者的年龄、性别和一般状况、治疗病况的性质和程度、药物代谢和排泄率、潜在药物组合产品和药物-药物相互作用之类的考量广为变化。
本发明的一个特别有意义的方面是包含给予4至400 mg,优选10至200 mg,更优选10至100 mg的量的瑞格菲尼和给予0.005至10 mg/kg,优选1至10 mg/kg患者体重的量的PD-1/PD-L1(2)抑制剂的组合产品。
根据本发明,瑞格菲尼和PD-1/PD-L1(2)抑制剂可相伴给药。
在本发明的进一步方面中,首先给予瑞格菲尼,接着给予PD-1/PD-L1(2)抑制剂。
或者,首先给予PD-1/PD-L1(2)抑制剂,接着给予瑞格菲尼,这是优选给药方式。
根据本发明的药物组合物每天给药一次或多次,优选最多三次,更优选最多两次。优选通过口服途径给予瑞格菲尼和通过静脉途径给予PD-1/PD-L1(2)抑制剂。
但是,在一些情况下可能有利的是偏离规定的量,这取决于体重、个体对活性成分表现出的行为、制剂类型和实施给药的时间或间隔。例如,低于上述最低量在一些情况下可能足够,而在另一些情况下必须超过规定的上限。在给予相对大量的情况下,可能最好将这些分成在一天内的几个单剂量。
该组合产品可包含有效量的式I的化合物和PD-1/PD-L1(2)抑制剂,这实现比单独使用任一化合物时高的疗效。
也可基于它们各自的作用机制和疾病生物学选择该组合产品中的各化合物的相对比率。各化合物的相对比率可广为变化。
也可酌情控制该组合产品的一种或多种药剂的释放以在单一剂型、组合产品包、药盒时或在分开的独立剂型时提供所需治疗活性。
本发明包括由可药用载体和药物有效量的本发明的化合物构成的药物组合物。可药用载体是在与活性成分的有效活性相符的浓度下对患者相对无毒和无害以使可归因于载体的任何副作用不损害活性成分的有益作用的任何载体。化合物的药物有效量是对受治疗的特定病况产生结果或施加影响的量。
对于口服给药,可以将该化合物配制成固体或液体制剂,如固体分散体、胶囊、丸剂、片剂、口含片(troches)、锭剂、熔体、粉剂、溶液剂、混悬剂或乳剂,并可根据本领域已知用于制造药物组合物的方法制备。固体单位剂型可以是胶囊,其可以是普通硬壳或软壳明胶型胶囊,含有例如表面活性剂、润滑剂和惰性填料,如乳糖、蔗糖、磷酸钙和玉米淀粉。
在另一实施方案中,本发明的化合物可以用常规片剂基质如乳糖、蔗糖和玉米淀粉以及粘合剂如阿拉伯树胶、玉米淀粉或明胶、旨在辅助给药后的片剂崩解和溶出的崩解剂,如马铃薯淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍胶、阿拉伯树胶,旨在改进片剂制粒中的流动和防止片剂材料粘附到片剂模具和冲头表面上的润滑剂,例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌,旨在增强片剂的美学品质并使它们更容易被患者接受的染料、着色剂和调味剂,如薄荷、冬青油或樱桃香精来压片。适用于口服液体剂型的赋形剂包括磷酸二钙和稀释剂,如水和醇,例如乙醇、苄醇和聚乙二醇,加入或不加入可药用的表面活性剂、悬浮剂或乳化剂。各种其它材料可作为包衣存在或以其它方式改变剂量单位的物理形式。例如,可以用虫胶和/或糖将片剂、丸剂或胶囊包衣。
可分散粉剂和颗粒剂适于制备水性混悬剂。它们提供与分散或湿润剂、悬浮剂和一种或多种防腐剂混合的活性成分。合适的分散或湿润剂和悬浮剂以上文已提到的那些为例。也可存在另外的赋形剂,例如上述那些甜味剂、调味剂和着色剂。
本发明的药物组合物也可以是水包油乳剂形式。油相可以是植物油如液体石蜡或植物油的混合物。合适的乳化剂可以是(1) 天然存在的树胶,如阿拉伯树胶和黄蓍胶,(2)天然存在的磷脂,如大豆和卵磷脂,(3) 由脂肪酸和己糖醇酐衍生的酯或偏酯,例如失水山梨糖醇单油酸酯,(4) 所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯失水山梨糖醇单油酸酯。乳剂也可含有甜味剂和调味剂。
可以通过将活性成分悬浮在植物油例如花生油、橄榄油、芝麻油或椰子油或矿物油如液体石蜡中来配制油性混悬剂。油性混悬剂可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。混悬剂也可含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯;一种或多种着色剂;一种或多种调味剂;和一种或多种甜味剂,如蔗糖或糖精。
可以用甜味剂例如甘油、丙二醇、山梨糖醇或蔗糖配制糖浆剂和酏剂。此类制剂也可含有缓和剂(demulcent)和防腐剂,如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯,以及调味剂和着色剂。
本发明的化合物也可肠胃外,即皮下、静脉、眼内、滑膜内、肌内或腹膜内给药,作为该化合物在生理可接受的稀释剂和药物载体中的可注射剂型,所述药物载体可以是无菌液体或液体混合物,如水、盐水、右旋糖水溶液和相关糖溶液,醇,如乙醇、异丙醇或十六醇,二醇,如丙二醇或聚乙二醇,甘油缩酮,如2,2-二甲基-1,1-二氧杂环戊烷-4-甲醇,醚,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;加入或不加入可药用表面活性剂,如皂或洗涤剂,悬浮剂,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。
可用于本发明的肠胃外制剂的示例性油是石油、动物、植物或合成来源的那些,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、矿脂和矿物油。合适的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。合适的脂肪酸酯是例如油酸乙酯和肉豆蔻酸异丙酯。合适的皂包括脂肪酸的碱金属盐、铵盐和三乙醇胺盐,且合适的洗涤剂包括阳离子洗涤剂,例如二甲基二烷基卤化铵、烷基卤化吡啶鎓和烷基胺乙酸盐;阴离子洗涤剂,例如烷基、芳基和烯烃的磺酸盐,烷基、烯烃、醚和甘油单酯的硫酸盐,和磺基琥珀酸盐;非离子洗涤剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺,和聚(氧乙烯-氧丙烯)或环氧乙烷或环氧丙烷共聚物;和两性洗涤剂,例如β-氨基丙酸烷基酯和2-烷基咪唑啉季铵盐,以及混合物。
本发明的肠胃外组合物通常含有大约0.5重量%至大约25重量%的溶解的活性成分。也可有利地使用防腐剂和缓冲剂。为了最大限度减轻或消除注射部位的刺激,此类组合物可含有具有大约12至大约17的亲水-亲油平衡值(HLB)的非离子表面活性剂。此类制剂中的表面活性剂的量为大约5重量%至大约15重量%。表面活性剂可以是具有上述HLB的单一组分,或可以是具有所需HLB的两种或更多种组分的混合物。
用于肠胃外制剂的示例性表面活性剂是聚乙烯失水山梨糖醇脂肪酸酯类,例如失水山梨糖醇单油酸酯,和环氧乙烷与通过环氧丙烷与丙二醇的缩合形成的疏水基质的高分子量加合物。
该药物组合物可以是无菌可注射水性混悬剂形式。此类混悬剂可根据已知方法使用下列物质配制:合适的分散或湿润剂和悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散或湿润剂,其可以是天然存在的磷脂,如卵磷脂,环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,环氧乙烷与长链脂族醇的缩合产物,例如十七亚乙基氧基鲸蜡醇,环氧乙烷与由脂肪酸和己糖醇衍生的偏酯的缩合产物,如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物,例如聚氧乙烯失水山梨糖醇单油酸酯。
该无菌可注射制剂也可以是在无毒的肠胃外可接受稀释剂或溶剂中的无菌可注射溶液剂或混悬剂。可用的稀释剂和溶剂是例如水、林格氏液、等渗氯化钠溶液和等渗葡萄糖溶液。此外,传统上使用无菌不挥发油作为溶剂或悬浮介质。为此,可以使用任何温和的不挥发油,包括合成甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于制备注射剂。
本发明的组合物也可以以栓剂形式给药以用于药物的直肠给药。这些组合物可通过将药物与在常温下为固体但在直肠温度下为液体并因此在直肠中熔化以释放药物的合适的无刺激赋形剂混合来制备。此类物质是例如可可脂和聚乙二醇。
用于肠胃外给药的控释制剂包括本领域中已知的脂质体、聚合微球和聚合凝胶制剂。
本发明的药物组合物也可以是固体分散体形式。固体分散体可以是固溶体、玻璃溶液、玻璃混悬液、在结晶载体中的无定形沉淀物、共晶或monotecic化合物或配合物形式和它们的组合。
本发明的一个特别有意义的方面是包含固体分散体的药物组合物,其中基质包含可药用聚合物,如聚乙烯吡咯烷酮、乙烯吡咯烷酮/乙酸乙烯酯共聚物、聚烷撑二醇(即聚乙二醇)、羟烷基纤维素(即羟丙基纤维素)、羟烷基甲基纤维素(即羟丙基甲基纤维素)、羧甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚甲基丙烯酸酯、聚乙烯醇、聚乙酸乙烯酯、乙烯醇/乙酸乙烯酯共聚物、聚乙二醇化甘油酯(polyglycolized glycerides)、黄原胶、角叉菜胶、壳聚糖、几丁质、聚糊精、糊精、淀粉和蛋白质。
本发明的另一方面是包含固体分散体的药物组合物,其中基质包含糖和/或糖醇和/或环糊精,例如蔗糖、乳糖、果糖、麦芽糖、棉子糖、山梨糖醇、乳糖醇、甘露醇、麦芽糖醇、赤藓糖醇、肌醇、海藻糖、异麦芽酮糖醇(isomalt)、菊粉、麦芽糖糊精、β-环糊精、羟丙基-β-环糊精或磺丁基醚环糊精。
可用于形成固体分散体的基质的另外合适的载体包括但不限于醇、有机酸、有机碱、氨基酸、磷脂、蜡、盐、脂肪酸酯、聚氧乙烯失水山梨糖醇脂肪酸酯和脲。
瑞格菲尼在基质中的固体分散体可含有某些另外的可药用成分,如表面活性剂、填料、崩解剂、再结晶抑制剂、增塑剂、消泡剂、抗氧化剂、防粘剂、pH调节剂、助流剂和润滑剂。
本发明的固体分散体根据本领域已知用于制造固体分散体的方法制备,如熔合/熔融(fusion/melt)技术、热熔挤出、溶剂蒸发(即冻干、喷雾干燥或颗粒粉末成层(layering))、共沉淀、超临界流体技术和静电纺丝法。
本发明的组合物也可视必要或需要含有通常被称为载体或稀释剂的其它常规可药用混配成分。可以使用将此类组合物制备成适当剂型的常规程序。
可酌情用于配制该组合物以用于其预期给药途径的常用药物成分包括:
酸化剂(实例包括但不限于乙酸、柠檬酸、富马酸、盐酸、硝酸);
碱化剂(实例包括但不限于氨溶液、碳酸铵、二乙醇胺、单乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺(triethanolamine)、三乙醇胺(trolamine));
吸附剂(实例包括但不限于粉状纤维素和活性炭);
气雾剂抛射剂(实例包括但不限于二氧化碳、CCl2F2、F2ClC-CClF2和CClF3);
空气置换剂(实例包括但不限于氮气和氩气);
抗真菌防腐剂(实例包括但不限于苯甲酸、对羟基苯甲酸丁酯、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸钠);
抗微生物防腐剂(实例包括但不限于苯扎氯铵、苄索氯铵、苄醇、西吡氯铵、氯丁醇、酚、苯乙醇、硝酸苯汞和硫柳汞);
抗氧化剂(实例包括但不限于抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、次磷酸、单硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛次硫酸氢钠、焦亚硫酸钠);
粘合物质(实例包括但不限于嵌段聚合物、天然和合成橡胶、聚丙烯酸酯、聚氨酯、硅酮、聚硅氧烷和苯乙烯-丁二烯共聚物);
缓冲剂(实例包括但不限于偏磷酸钾、磷酸氢二钾、乙酸钠、无水柠檬酸钠和二水合柠檬酸钠);
载体(实例包括但不限于阿拉伯胶糖浆、芳香糖浆、芳香酏剂、樱桃糖浆、可可糖浆、柑桔糖浆、糖浆、玉米油、矿物油、花生油、芝麻油、抑菌氯化钠注射液和抑菌注射用水);
螯合剂(实例包括但不限于依地酸二钠和依地酸);
着色剂(实例包括但不限于FD&C Red No. 3、FD&C Red No. 20、FD&C Yellow No. 6、FD&C Blue No. 2、D&C Green No. 5、D&C Orange No. 5、D&C Red No. 8、焦糖和氧化铁红);
澄清剂(实例包括但不限于膨润土);
乳化剂(实例包括但不限于阿拉伯树胶、聚西托醇(cetomacrogol)、鲸蜡醇、单硬脂酸甘油酯、卵磷脂、失水山梨糖醇单油酸酯、聚氧乙烯50单硬脂酸酯);
包囊剂(实例包括但不限于明胶和邻苯二甲酸乙酸纤维素);
香料(实例包括但不限于茴香油、肉桂油、可可、薄荷醇、橙油、薄荷油和香草醛);
保湿剂(实例包括但不限于甘油、丙二醇和山梨糖醇);
研磨剂(实例包括但不限于矿物油和甘油);
油(实例包括但不限于花生油(arachis oil)、矿物油、橄榄油、花生油(peanut oil)、芝麻油和植物油);
软膏基质(实例包括但不限于羊毛脂、亲水软膏、聚乙二醇软膏、矿脂、亲水矿脂、白色软膏、黄色软膏和玫瑰水软膏);
渗透促进剂(透皮递送)(实例包括但不限于单羟基或多羟基醇、一价或多价醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酯、饱和或不饱和二羧酸、精油、磷脂酰衍生物、脑磷脂、萜烯、酰胺、醚、酮和脲);
增塑剂(实例包括但不限于邻苯二甲酸二乙酯和甘油);
溶剂(实例包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯净水、注射用水、无菌注射用水和无菌冲洗用水);
硬化剂(实例包括但不限于鲸蜡醇、鲸蜡酯蜡、微晶蜡、石蜡、硬脂醇、白蜡和黄蜡);
栓剂基质(实例包括但不限于可可脂和聚乙二醇(混合物));
表面活性剂(实例包括但不限于苯扎氯铵、壬苯醇醚10、辛苯昔醇9(oxtoxynol 9)、聚山梨酯80、十二烷基硫酸钠和失水山梨糖醇单棕榈酸酯);
悬浮剂(实例包括但不限于琼脂、膨润土、卡波姆、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄蓍胶和硅酸镁铝(veegum));
甜味剂(实例包括但不限于阿斯巴甜、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨糖醇和蔗糖);
片剂抗粘附剂(实例包括但不限于硬脂酸镁和滑石);
片剂粘合剂(实例包括但不限于阿拉伯树胶、藻酸、羧甲基纤维素钠、可压缩糖、乙基纤维素、明胶、液体葡萄糖、甲基纤维素、非交联聚乙烯吡咯烷酮和预胶化淀粉);
片剂和胶囊剂稀释剂(实例包括但不限于磷酸氢钙、高岭土、乳糖、甘露醇、微晶纤维素、粉状纤维素、沉淀碳酸钙、碳酸钠、磷酸钠、山梨糖醇和淀粉);
片剂包衣剂(实例包括但不限于液体葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、邻苯二甲酸乙酸纤维素和虫胶);
直接压片赋形剂(实例包括但不限于磷酸氢钙);
片剂崩解剂(实例包括但不限于藻酸、羧甲基纤维素钙、微晶纤维素、波拉克林钾(polacrillin potassium)、交联聚乙烯吡咯烷酮、藻酸钠、羟乙酸淀粉钠和淀粉);
片剂助流剂(实例包括但不限于胶体二氧化硅、玉米淀粉和滑石);
片剂润滑剂(实例包括但不限于硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
片剂/胶囊剂遮光剂(opaquants)(实例包括但不限于二氧化钛);
片剂抛光剂(实例包括但不限于巴西棕榈蜡和白蜡);
增稠剂(实例包括但不限于蜂蜡、鲸蜡醇和石蜡);
张度剂(实例包括但不限于右旋糖和氯化钠);
增粘剂(实例包括但不限于藻酸、膨润土、卡波姆、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮、藻酸钠和黄蓍胶);和
润湿剂(实例包括但不限于十七亚乙基氧基鲸蜡醇、卵磷脂、山梨糖醇单油酸酯、聚氧乙烯山梨糖醇单油酸酯和聚氧乙烯硬脂酸酯)。
相信本领域技术人员利用上述信息可在最大程度上利用本发明。
实施例:
实施例1:
在同系小鼠MC38 CRC模型中研究瑞格菲尼和抗小鼠PD-1抗体(RMP1-14,Peng等人,Cancer Res., (2012) 72(20), 5209-5218)的组合活性。
方法:
使MC38同系肿瘤在小鼠中皮下生长并用瑞格菲尼和/或抗小鼠PD-1抗体(RMP1-14)根据下列方案处理:
a) 仅瑞格菲尼,剂量为每天3 mg/kg,每天一次持续15天,作为PluronicF68 / PEG400/ 丙二醇(15/42,5/42,5+20% aqua) po (口服)制剂,和10 mg/kg的非结合rIgG2a同种型对照(克隆2A3),每三天给药一次,共五次,在PBS(磷酸盐缓冲盐水)中,作为ip (腹膜内)制剂,
b) 仅抗小鼠PD-1抗体(RMP1-14),以10 mg/kg给药,每三天一次,共五次,作为PBS ip制剂,和PluronicF68 / PEG400 / 丙二醇(15/42,5/42,5+20%aqua)媒介物,每天一次持续15天,作为po制剂,
c) 相伴地,瑞格菲尼,剂量为每天3 mg/kg,每天一次持续4天,作为PluronicF68 /PEG400 / 丙二醇(15/42,5/42,5+20% aqua) po制剂,和抗小鼠PD-1抗体(RMP1-14),以10mg/kg给药,每三天一次,共五次,作为PBS ip制剂,
d) 相继地,首先瑞格菲尼,剂量为每天3 mg/kg,每天一次持续4天,作为PluronicF68/ PEG400 / 丙二醇(15/42,5/42,5+20% aqua) po制剂,在随机化后第5天接着抗小鼠PD-1抗体(RMP1-14),以10 mg/kg给药,每三天一次,共四次,作为PBS ip制剂,
e) 相继地,首先抗小鼠PD-1抗体(RMP1-14),以10 mg/kg给药,每三天一次,共两次,作为PBS ip制剂,在随机化后第5天接着瑞格菲尼,剂量为每天3 mg/kg,每天一次持续10天,作为PluronicF68 / PEG400 / 丙二醇(15/42,5/42,5) po制剂。
用瑞格菲尼媒介物(PluronicF68 / PEG400 / 丙二醇(15/42,5/42,5+20%aqua))和非结合同种型对照抗体(大鼠IgG2a、克隆2A3)相伴处理对照动物。通过卡尺测量监测肿瘤生长并使用公式a x b计算肿瘤面积,其中a和b分别是肿瘤的长径和短径。在研究完成后测量肿瘤重量。使用媒介物处理动物作为参考计算肿瘤 vs 对照(T/C)。
结果:
瑞格菲尼和抗小鼠PD-1抗体相对于对照均抑制MC38肿瘤生长,并且通过相伴处理或在抗PD1后给予瑞格菲尼时显著增强这一效应。
表1:
处理 | T/C (面积) | T/C (重量) |
媒介物/同种型 | 1.00 | 1.00 |
瑞格菲尼(3 mg/kg),根据方案a) | 0.68 | 0.64 |
PD-1 (10 mg/kg),根据方案b) | 0.61 | 0.56 |
首先瑞格菲尼(3 mg/kg),接着PD-1 (10 mg/kg),根据方案d) | 0.64 | 0.71 |
瑞格菲尼(3 mg/kg)和PD-1 (10 mg/kg)相伴,根据方案c) | 0.53 | 0.39 |
首先PD-1 (10 mg/kg),接着瑞格菲尼(3 mg/kg),根据方案e) | 0.48 | 0.41 |
图1: 瑞格菲尼和抗PD-1独自和组合在同系小鼠MC38 CRC模型中的抗肿瘤活性: v+i=媒介物 + 同种型,a) = 方案a),b) = 方案b),c) = 方案c),d) = 方案d),e) = 方案e)。
实施例2:
在同系小鼠CT26 CRC模型中研究瑞格菲尼和抗小鼠PD-1抗体(RMP1-14,Peng等人,Cancer Res., (2012) 72(20), 5209-5218)的组合活性。
使CT26同系肿瘤在小鼠中原位生长(Abou-Elkacem等人, Mol Cancer Ther.2013 Jul;12(7):1322-31)并用瑞格菲尼和/或抗小鼠PD-1抗体(RMP1-14)根据下列方案处理:
a) 仅瑞格菲尼,剂量为每天30 mg/kg,每天一次持续10天,作为PluronicF68 /PEG400 / 丙二醇/水(12/34/34/20) po (口服)制剂,使用仅制剂媒介物作为对照或与每三天一次在PBS中以20 mg/kg的剂量腹膜内(i.p.)给药的非特异性对照抗体结合;
b) 仅抗小鼠PD-1抗体(RMP1-14),以20 mg/kg给药,每三天一次,共四次,作为PBSi.p.制剂,并使用非特异性抗体作为对照;
c) 联合地,瑞格菲尼,剂量为每天20 mg/kg,每天一次持续10天,作为PluronicF68 /PEG400 / 丙二醇/水(/12/34/34/20) p.o.制剂,和抗小鼠PD-1抗体(RMP1-14),以20 mg/kg给药,每三天一次,共四次,作为PBS i.p.制剂。
在停止处理后,观察一些小鼠另外11天以研究肿瘤的再生长(数据未显示)和肝转移的出现(表2)。在处理结束时或在观察期结束时处死小鼠并就肝表面上的转移宏观筛选肝脏。然后将存在肝转移的小鼠数量与各自的研究组中的小鼠总数相关联。
表2: 瑞格菲尼和抗PD1的组合产品比单一药剂更有效地防止肝转移
在表2中用“+”指示使用哪种试验系统。在用瑞格菲尼处理14天后,6只动物中的0只和在PD-1组中6只动物中的4只表现出转移。而在处理25天后,瑞格菲尼和对照抗体的组合产品在8只动物中的8只中表现出转移,但在用瑞格菲尼和PD-1的组合产品处理的组中,令人惊讶地没有一只动物表现出转移。
Claims (11)
1.药物组合产品,其包含瑞格菲尼或其水合物、溶剂化物、代谢物或可药用盐或其多晶型物和PD-1/PD-L1(2)抑制剂。
2.权利要求1的组合产品,其中所述PD-1/PD-L1(2)抑制剂是抗-PD-1抗体或抗-PD-L1抗体或抗-PD-L2抗体。
3.权利要求2的组合产品,其中所述PD-1/PD-L1(2)抑制剂是选自纳武单抗(Opdivo、BMS-936558、MDX1106)、派姆单抗(Keytruda、MK-3475、帕博利珠单抗)、pidilizumab(CT-011)、PDR-001、JS001、STI-A1110、AMP-224和AMP-514(MEDI0680)的抗-PD-1抗体。
4.权利要求2的组合产品,其中所述PD-1/PD-L1(2)抑制剂是选自阿特珠单抗(Tecentriq、MPDL3280A)、度伐单抗(MEDI4736)、阿维单抗(MSB0010718C)、BMS-936559(MDX1105)和LY3300054的抗-PD-L1抗体。
5.权利要求2的组合产品,其中所述PD-1/PD-L1(2)抑制剂是抗-PD-L2抗体。
6.权利要求1-5任一项的组合产品,其是含有彼此分开的组分的组合产品包。
7.权利要求1-6任一项的组合产品,其中所述组分在分开的剂型中同时或相继给药以用于治疗同一疾病。
8.权利要求1-7任一项的组合产品,其用作治疗过度增殖障碍的药物。
9.权利要求8的组合产品,其中所述过度增殖障碍选自乳腺癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌和它们的远端转移。
10.权利要求8的组合产品,其中所述过度增殖障碍选自肝细胞癌、结直肠癌和胃肠道间质瘤(GIST)。
11.治疗需要其的对象的过度增殖障碍的方法,其包括给予有效量的瑞格菲尼或其水合物、溶剂化物、代谢物或可药用盐或其多晶型物和PD-1/PD-L1(2)抑制剂。
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