CN107427468B - Btk抑制剂的部位特异性给药 - Google Patents
Btk抑制剂的部位特异性给药 Download PDFInfo
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- CN107427468B CN107427468B CN201580076897.9A CN201580076897A CN107427468B CN 107427468 B CN107427468 B CN 107427468B CN 201580076897 A CN201580076897 A CN 201580076897A CN 107427468 B CN107427468 B CN 107427468B
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Abstract
本文公开的是化合物(I)或其药学上可接受的盐的制剂和部位特异性给药方法。化合物(I)是有效的BTK抑制剂,因此可用于治疗疾病如癌症、自身免疫疾病和炎性疾病。
Description
互相参引
本申请要求于2014年12月24日提交的美国临时专利申请第62/096,809号的优先权。其内容以引证的方式纳入本文。
技术领域
本文公开的是化合物(I)或其药学上可接受的盐的制剂和部位特异性给药方法。化合物(I)是有效的BTK抑制剂,因此可用于治疗疾病如癌症、自身免疫疾病和炎性疾病。
背景技术
治疗剂可通过数种不同途径例如口服、局部、静脉内、皮下、吸入等途径给予患者。迄今为止,治疗剂的口服给药是最优选的给药途径,其相比其它给药途径提供多种优势。口服递送的药物易于自己给药,从而导致患者依从性增加并且不需要注射治疗或吸入治疗的专门递送装置或在治疗设备中的递送。其通常是使药物进入机体最安全的途径,因为其不需要复杂的装置或刺穿机体的表面或膜。另外,剂量容易控制,这对于其它给药方式(例如吸入治疗)而言可能是具有挑战性的。
尽管有许多优势,但是通过口服给药获得一致且充分的药物循环水平可能是有挑战性的,这归因于例如水溶性差、在生物液体中溶解速率慢、生理pH下药物稳定性差、穿过生物膜的渗透性差、广泛的系统前代谢、个体之间或胃肠系统特定区域中的系统吸收不充分或不一致等等。另外,一次治疗与另一次治疗的药物吸收可能有所不同,药物吸收取决于许多因素,例如在给药时患者是处于已进食状态还是禁食状态,或者是否该药物与其它药物同时服用。从安全的角度来看,使功效的总剂量需求最小化以及减少吸收的差异性,应当能够产生更少的不希望的副作用。因此,非常需要能够高效并一致地暴露药物的递送口服药物的特定方法。
例如,可逆共价药物分子——即含有具有第二吸电子基团的迈克尔(Michael)受体的药物,当该药物口服给药时可表现出差的生物利用度或延迟的全身性吸收,这可通过低的血浆AUC和/或Cmax值证明,从而导致欠佳的体内功效。这种新一类药物的差的生物利用度可部分归因于这些药物中的可逆共价迈克尔受体部分的反应性。因此,限制可逆共价药物暴露于胃——其中存在低pH和消化酶或代谢酶以及其它硫醇源的组合,可以获得药物的全身性全身性暴露的显著增加。
此外,代谢酶(如半胱氨酸蛋白酶)、粘蛋白、转运蛋白和胃中的含反应性硫醇的分子(例如谷胱甘肽)的表达也可促成含可逆共价迈克尔受体的药物的低口服生物利用度(参见例如Johnson DS等人,Future Med Chem.2010年6月1日;2(6):949-964和PotashmanM.H.等人,J.Med.Chem.,第52卷,第5期,第1231-1246页)。例如,消化酶例如半胱氨酸蛋白酶、胃蛋白酶、转运蛋白和代谢酶如胃粘膜中的CYP酶的组合可导致可逆和不可逆共价迈克尔受体在低pH下的高化学转化和/或代谢转化。因此,通过避免可逆共价药物暴露于胃——其中存在低pH和消化酶或代谢酶以及其他硫醇源的组合,可以获得这些药物的全身性全身性暴露的显著增加。此外,避免暴露于胃可以减少或完全消除这些药物的潜在副作用,如腹泻和吐,通常称为呕吐。
发明内容
化合物(I),一种BTK抑制剂,目前被开发用于治疗自身免疫疾病,其在2013年9月6日提交的申请号为PCT/US2013058614的PCT申请的实施例31中被公开。虽然在低pH下合理的溶解度大于10%(w/v),但在大鼠中口服给药时,化合物(I)具有差的生物利用度,如通过AUC(曲线下面积)所测量的。根据实施例11,当将溶液通过口服管饲法给予大鼠时,AUC在668至1640ng*hr/ml的范围内,且在暴露方面显示出高的差异性。
为了提高生物利用度并降低差异性,申请人评估了化合物(I)的不同部位特异性肠胃给药策略的影响,如通过下文实施例11中所述的AUC所确定的。用于比较的基线是通过上文的口服管饲法给药时所获得的AUC。出人意料地发现,与通过胃部管饲法口服给予化合物(I)相比,通过十二指肠内插管经十二指肠内(ID)给予于上述制剂中的化合物(I)使得AUC增加约2倍(994增加至1780ng*hr/ml)。与口服管饲法相比,绕过小肠起始部通过空肠内(IJ)插管给予化合物(I),观察到AUC增加10至40倍(IJ给药的AUC为14400至26800ng*hr/ml)。此外,IJ给药使得动物间的血浆中暴露的差异性更小,特别当与前述口服管饲法相比时,标准偏差提高3至10倍,且当IJ给药时,代谢更加稳定。对于口服给予的药物来说,这种量级的差异不是典型的。因此,沿肠道再向下释放化合物(I),可以实现所期望的暴露的增加和差异性的降低。
因此,在本公开内容的各个方面中,提供化合物(I)或其药学上可接受的盐的某些部位特异性给药方法和制剂以增加化合物(I)或其药学上可接受的盐的口服生物利用度。
一方面,提供一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自十二指肠、空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的立即释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约150%至约4000%。
在第二方面,提供了一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自十二指肠、空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的立即释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约150%至约4000%,条件是当将所述固体口服剂型给予处于禁食状态的哺乳动物时,在给药之后约1.5至约2小时之内所贡献的AUC占由给予所述固体口服剂型而引起的AUC的不多于10%。
在第三方面,提供了一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的十二指肠内释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约125%至约2000%。
在第三方面的一个实施方案中,化合物(I)和/或其药学上可接受的盐的释放开始于哺乳动物的空肠或回肠。
在第四方面,提供了一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于其药学上可接受的盐在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的十二指肠内释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约125%至约2000%,条件是当将所述固体口服剂型给予处于禁食状态的哺乳动物时,在给药之后约1.5至约2小时之内所贡献的AUC占由给予所述固体口服剂型而引起的AUC的不多于10%。
在第五方面,提供了一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)肠溶衣,其在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐,所述肠部位选自十二指肠、空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂。
在第六方面,提供一种在需要抑制BTK的哺乳动物中抑制BTK的方法,其包括给予需要该BTK抑制的哺乳动物治疗有效量的于第一、第二、第三、第四或第五方面中任何一个方面(或本文中所公开的其实施方案)的固体口服剂型中的化合物(I)和/或其药学上可接受的盐。
在第七方面,提供一种在需要治疗由BTK介导的疾病的哺乳动物中治疗所述疾病的方法,其包括给予需要这种疾病治疗的哺乳动物治疗有效量的于第一、第二、第三、第四或第五方面中任何一个方面(或本文中所公开的其实施方案)的固体口服剂型中的化合物(I)和/或其药学上可接受的盐。
在第七方面的一个实施方案中,需要这种疾病治疗的哺乳动物患有自身免疫疾病,例如血栓性血小板减少性紫癜,结节性多动脉炎,皮肤狼疮,系统性硬化病的皮肤形式(CREST),系统性硬化病,混合性结缔组织病,冷球蛋白血症,原发性胆汁性硬化症,硬化性胆管炎,AI荨麻疹,IgA肾病,炎性肠病(如溃疡性结肠炎),包括狼疮肾炎在内的狼疮,类风湿性关节炎,银屑病关节炎,骨关节炎,斯提耳氏病(Still′s disease),幼年型关节炎,糖尿病,重症肌无力,伴有多血管炎的肉芽肿病,桥本氏甲状腺炎,奥德甲状腺炎(Ord’sthyroiditis),格雷夫斯氏病,合格伦综合征(Sjogren′s syndrome),舍格伦氏干眼症,非-舍格伦氏干眼症,多发性硬化,格-巴二氏综合征(Guillain-Barre syndrome),急性播散性脑脊髓炎,爱迪生氏病,视性眼阵挛-肌阵挛综合征(opsoclonus-myoclonus syndrome),强直性脊柱炎,多发性硬化,抗磷脂抗体综合征,再生障碍性贫血,自身免疫性肝炎,乳糜泻,古德帕斯丘综合征(Goodpasture′s syndrome),特发性血小板减少性紫癜,视神经炎,硬皮病,原发性胆汁性肝硬化,莱特尔氏综合征(Reiter′s syndrome),高安氏动脉炎(Takayasu′s arteritis),颞动脉炎,自身免疫性溶血性贫血,银屑病,普秃,贝切特氏病(Behcet′s disease),慢性疲劳,自主神经失调症,子宫内膜异位,间质性膀胱炎,神经性肌强直,硬皮病,疱病如寻常型天疱疮、类天疱疮,以及外阴痛。在第七方面的另一个实施方案中,所述疾病是类风湿性关节炎或银屑病关节炎。在又一个实施方案中,所述自身免疫疾病是狼疮、寻常型天疱疮、伴有多血管炎的肉芽肿病或类风湿性关节炎。
在第七方面的另一个实施方案中,需要这种疾病治疗的哺乳动物正患有异种免疫病症或疾病,例如移植物抗宿主病、移植、输血、过敏反应、变态反应、I型超敏反应、过敏性结膜炎、过敏性鼻炎和特应性皮炎。
在第七方面的又一实施方案中,需要这种疾病治疗的哺乳动物正患有炎性疾病,例如哮喘、阑尾炎、睑缘炎、细支气管炎、支气管炎、滑囊炎、宫颈炎、胆管炎、胆囊炎、结肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、小肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、肝炎、化脓性汗腺炎、喉炎、乳腺炎、脑膜炎、脊髓炎、心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、局限性肺炎(pneumonitis)、肺炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、鼻窦炎、口腔炎、滑膜炎、肌腱炎、扁桃体炎、葡萄膜炎、阴道炎、血管炎或外阴炎,优选哮喘或葡萄膜炎。
在第七方面的又一实施方案中,需要这种疾病治疗的哺乳动物正患有炎性皮肤病,例如皮炎,接触性皮炎,湿疹,荨麻疹,红斑痤疮以及皮肤、关节或其他组织或器官中的瘢痕性银屑病病变(sacrring psoriatic lesions)。
在第七方面的又一实施方案中,需要这种疾病治疗的哺乳动物正患有癌症。在一个实施方案中,所述癌症是B细胞增殖性疾病,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤(CLL)、慢性淋巴细胞白血病、慢性髓细胞性白血病、B-ALL、费城染色体阳性B-ALL、B细胞幼淋巴细胞白血病、小淋巴细胞淋巴瘤(SLL)、多发性骨髓瘤、B细胞非霍奇金淋巴瘤、淋巴质浆细胞淋巴瘤/瓦尔登斯特伦(Waldenstrom)巨球蛋白血症、脾边缘区淋巴瘤、浆细胞骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘带B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特(burkitt)淋巴瘤/白血病或淋巴瘤样肉芽肿。
在第七方面的又一实施方案中,需要这种疾病治疗的哺乳动物正患有血栓栓塞性疾病,例如心肌梗死、心绞痛、血管成形术后再闭塞、血管成形术后再狭窄、主动脉冠状动脉分流术后再闭塞、主动脉冠状动脉分流术后再狭窄、中风、短暂性缺血、外周动脉闭塞性疾病、肺栓塞或深静脉血栓形成。
在本文中所公开的前述实施方案的任何一个中,本发明的剂型可以与另外的抗炎剂、免疫抑止剂或抗癌剂一起给药。在一个实施方案中,至少一种另外的药剂是阿仑单抗、三氧化二砷、天冬酰胺酶(聚乙二醇化的或非-聚乙二醇化的)、贝伐单抗、西妥昔单抗、铂类化合物如顺铂、克拉屈滨、柔红霉素/多柔比星/伊达比星、伊立替康、氟达拉滨、5-氟尿嘧啶、吉妥珠单抗、甲氨蝶呤、紫杉醇、TaxolTM、多西紫杉醇、替莫唑胺、硫鸟嘌呤;以及包括以下药物的药物种类:激素类(抗雌激素、抗雄激素、或促性腺激素释放激素类似物),干扰素类如α干扰素,氮芥类如白消安或美法仑或氮芥,类视色素类如维甲酸,拓扑异构酶抑制剂如依立替康或拓扑替康,酪氨酸激酶抑制剂如吉非替尼或伊马替尼,奥法木单抗,苯达莫司汀,利妥昔单抗,阿妥珠单抗,IPI-145,GS-1101,BKM-120,GDC-0941,DGDC-0980,GS-9820,CAL-263, delanzomib,U0126,PD98059,PD184352,PD0325901,ARRY-142886,SB239063,SP600125,BAY43-9006,渥曼青霉素,多吉美特罗凯索坦克唑替尼(Crizotinib),或LY294002;或治疗由此类治疗引发的体征或症状的药剂,包括别嘌呤醇、非格司亭、格拉司琼/昂丹司琼/帕洛诺司琼、屈大麻酚。当使用联合疗法时,可同时或依序给予所述药剂。
在第七方面的又一实施方案中,需要这种疾病治疗的哺乳动物正患有血栓性血小板减少性紫癜、结节性多动脉炎、皮肤狼疮、系统性硬化病(CREST)的皮肤形式、系统性硬化病、混合性结缔组织病、冷球蛋白血症、原发性胆汁性硬化症、硬化性胆管炎、AI荨麻疹、IgA肾病、狼疮肾炎、自身免疫性溶血性贫血、伴有多血管炎的肉芽肿病、或天疱疮包括寻常型天疱疮。
附图的简要说明
在下面的图1A中示出了化合物(I)的代表性HPLC追踪,表示化合物(I)的E异构体和Z异构体的分离。在4.215处的峰是化合物(I)的Z异构体,在4.363处的峰是化合物(I)的E异构体。
在下面的图1B中示出了E/Z比为约9/1的无定形形式的化合物(I)的代表性XRPD衍射图。
在下面的图2A中示出了根据实施例2制备的从乙酸乙酯中获得的E/Z比为约9/1的化合物(I)的半H2SO4盐的代表性XRPD衍射图。
在下面的图2B中示出了来自根据实施例2制备的从乙酸乙酯中获得的E/Z比为约9/1的化合物(I)的H2SO4盐的代表性XRPD衍射图。
在下面的图3中示出了根据实施例3制备的从乙酸乙酯中获得的E/Z比为约9/1的无定形形式的化合物(I)的单盐酸盐的代表性XRPD衍射图。
在图4A中示出了根据实施例4制备的从MTBE中获得的E/Z比为约9/1的化合物(I)的单甲磺酸盐的代表性XRPD衍射图。
在图4中示出了根据实施例4制备的从MTBE中获得的E/Z比为约9/1或约1/9的化合物(I)的二-甲磺酸盐的代表性XRPD衍射图。
在图5中示出了根据实施例5制备的从乙酸异丙酯中获得的E/Z比为约9/1的化合物(I)的草酸盐的代表性XRPD衍射图。
在图6中示出了根据实施例6制备的E/Z比为约9/1的化合物(I)的柠檬酸盐的代表性XRPD衍射图。
在图7描绘了由根据实施例12进行的研究所观察到的化合物(I)的E和Z异构体(约9∶1)的混合物在GI肠道——包括胃、十二指肠、回肠、空肠和结肠——的多个区域的渗透性12。
具体实施方案
定义
除非另有说明,否则在本说明书和权利要求书中使用的以下术语是为本申请的目的而定义的,并且它们具有以下含义。在本申请中使用的所有未定义的技术术语和科学术语都具有本发明所属领域的普通技术人员普遍理解的含义。
在本文中使用的不定冠词“一”或“一个”实体是指一个或多个该实体;例如,除非另有说明,否则一个化合物是指一种或多种化合物或至少一种化合物。因此,术语“一”(或一个)、“一种或多种”以及“至少一种”在本文中可以互换使用。
术语“约”在本文中意指大约地、左右、大致地或附近。当术语“约”与数值范围结合使用时,其通过延伸所述数值的上下边界而对该范围进行修饰。通常,本文使用的术语“约”修饰的数值上下浮动5%。
本文使用的化合物(I)是指“(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)异构体、(Z)异构体或(E)和(Z)异构体混合物;(S)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)异构体、(Z)异构体或(E)和(Z)异构体混合物;或2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物的(E)异构体、(Z)异构体或(E)和(Z)异构体混合物”,其具有以下结构:
其中*C是立体化学中心;
或其药学上可接受的盐。
本领域普通技术人员应理解,当化合物(I)表示为(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈时,其可含有小于约1重量%的相应的(S)对映异构体作为杂质。相应地,当化合物(I)表示为2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基-4-甲基-4-[4-(氧杂环丁-3-基)]哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物时,其意味着所述混合物中(R)或(S)对映异构体的量大于约1重量%。类似的分析适用于当化合物(I)表示为(E)异构体、(Z)异构体、或(E)异构体和(Z)异构体的混合物时。在本说明书中,化合物(I)或其药学上可接受的盐也可称为“药物”、“活性剂”或“治疗活性剂”。
“无定形形式”是指不具有可区分的晶格并且分子的分子排列缺乏晶体的长程有序特征的固体。特别地,无定形表示不显示尖锐的布拉格衍射峰的材料。
术语“纤维素衍生物”或“多糖衍生物”是指其中糖重复单元上的至少部分羟基已经反应形成醚键或酯键的纤维素聚合物或多糖。实例包括但不限于羟烷基纤维素、羟烷基烷基纤维素和羧烷基纤维素酯,例如羟丙基甲基纤维素(羟丙甲纤维素或HPMC)、羟丙基纤维素(HPC)等。
为本公开内容的目的,术语“亲水的”是指对水具有亲和性的材料。
为本公开内容的目的,术语“水可溶的”是指在pH为约1至约8的水性介质中溶解至所需程度的材料,并且没有特别的限制。
为本公开内容的目的,术语“水可溶胀的”是指相对不溶于水但可吸收水的材料。
合适的亲水材料包括水可溶材料或水可溶胀材料。这些材料的实例包括盐、糖和聚合物,例如羟烷基纤维素、羟烷基烷基纤维素和羧基烷基纤维素酯,如羟丙基甲基纤维素(羟丙甲纤维素或HPMC)、羟丙基纤维素(HPC)以及包含一种或多种前述材料的组合物。
可用于本公开内容且本质上亲水的羟丙基甲基纤维素以不同粘度等级出售,例如从Dow Chemical Co.可得的以商标MethocelTM出售的那些。低粘度等级的羟丙基甲基纤维素的实例包括以商标Methocel E5、Methocel E-15 LV、Methocel E50 LV、Methocel K100LV和Methocel F50 LV可得的那些,它们的2重量%的水溶液分别具有5cP、15cP、50cP、100cP和50cP的粘度。具有中等粘度的羟丙基甲基纤维素的实例包括以商标Methocel E4M和Methocel K4M可得的那些,它们的2重量%的水溶液均具有4000cP的粘度。具有高粘度的羟丙基甲基纤维素聚合物的实例包括以商标Methocel K15M和Methocel K100M可得的那些,它们的2重量%的水溶液分别具有15,000cP和100,000cP的粘度。羟丙基甲基纤维素聚合物可以以约0.1重量%至50重量%的量存在于本公开内容的药物组合物中。
可用于本公开内容的羟丙基纤维素聚合物还包括,例如,以商标KlucelTM可得的聚合物,从Nippon Soda Co.可得。低粘度亲水聚合物的实例为以商标Klucel EF、Klucel LF、Klucel JF和Klucel GF可得的羟丙基纤维素聚合物,其2重量%的水溶液具有小于1000cP的粘度。以商标Klucel ME可得到的羟丙基纤维素聚合物——其2重量%的水溶液具有4,000-6,500cP范围的粘度——是中等粘度的亲水聚合物。低粘度亲水聚合物的实例为作为HPC-SL、HPC-L和HPC-M出售的可得的羟丙基纤维素聚合物,其2重量%的水溶液分别具有3-6cP、6-10cP和150-400cP的粘度,而HPC-H具有1,000-4000cP的粘度且其为中等粘度的亲水聚合物的实例。羟丙基纤维素聚合物可以以约0.1重量%至50重量%的量存在。
适用于制备延迟释放剂型的水可溶胀的材料是在暴露于水性液体如胃肠液体时能够膨胀的化合物。包衣和任选地一种或多种药学上可接受的赋形剂中可存在一种或多种水可溶胀化合物。
可用作水可溶胀物质的合适的化合物包括,例如,低取代的羟丙基纤维素,例如L-HPC;交联聚乙烯吡咯烷酮,例如PVP-XL、KollidoneTM CL和PolyplasdoneTM XL;羧甲基纤维素钠;交联的羧甲基纤维素钠,例如Ac-di-solTM和PrimelloseTM;羟乙酸淀粉钠,例如PrimojelTM;羧甲基纤维素钠,例如NymcelTM ZSB10;羧甲基淀粉钠,例如ExplotabTM;离子交换树脂,例如DowexTM或AmberliteTM产品;微晶纤维素,例如AvicelTM产品;淀粉和预胶化淀粉,例如,Starch 1500TM和Sepistab ST200TM;福尔马林-酪蛋白,例如Plas-VitaTM;以及包含一种或多种前述水可溶胀物质的组合物组合物。
在一些实施方案中,亲水性材料包括聚环氧烷、多糖胶和交联的聚丙烯酸。合适的聚环氧烷如未取代的环氧乙烷的线性聚合物包括来自美国The Dow Chemical Company的PolyoxTM产品,其分子量为约100,000-7,000,000。其它有用的聚环氧烷聚合物由环氧丙烷、或环氧乙烷和环氧丙烷的混合物制成。
可以使用天然的和改性(半合成)的多糖胶。实例是葡聚糖、黄原胶、结冷胶、文莱胶和鼠李胶。
可以使用的交联聚丙烯酸包括具有与上文描述的烷基取代的纤维素和聚环氧烷聚合物的性质类似的性质的那些。有用的交联聚丙烯酸包括具有约4,000至约40,000cP的粘度(对于25℃下的1%水溶液而言)的那些。三个具体实例是CARBOPOLTM等级971P、974P和934P(由The Lubrizol Corporation,Cleveland,Ohio,USA出售)。其他实例是称为WATERLOCKTM的聚合物,其是从Grain Processing Corporation,Muscatine,Iowa,USA可得的淀粉/丙烯酸酯/丙烯酰胺共聚物。
这些聚合物的亲水性和水可溶胀性导致口服给药后因水的进入而使底衣尺寸膨胀。活性剂从底衣中的释放速率主要取决于抑水率和活性剂从溶胀的聚合物中溶解和扩散的速率,而所述溶解和扩散速率又与活性剂的溶解度和溶解速率、活性剂粒径和/或剂型中活性剂的浓度有关。
合适的“疏水”材料是水不溶性的中性的或合成的蜡;脂肪醇如月桂醇、肉豆蔻醇、硬脂醇、鲸蜡醇、鲸蜡硬脂醇;脂肪酸及其衍生物,包括脂肪酸酯如单硬脂酸甘油酯、单油酸甘油酯、乙酰化单甘油酯、硬脂精、棕榈精、月桂精、甘油三肉豆蔻酸酯、鲸蜡基酯蜡、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、氢化蓖麻油、棉籽油,脂肪酸甘油酯(甘油单酯、甘油二酯和甘油三酯)、氢化脂肪、烃、普通蜡、硬脂酸、硬脂醇、具有烃骨架的材料,以及包含一种或多种前述材料的组合物。合适的蜡包括但不限于蜂蜡、(N,N′-二硬脂酰乙二胺来自Lonza)、蓖麻蜡、巴西棕榈蜡和蜡样物质。
本文中所用的术语“立即释放剂型”是指液体或固体形式的剂型剂型,其在胃中释放药物并且不具有用于延迟药物与肠粘膜接触的保护性包衣。在“立即释放剂型”中可以包含美观包衣或掩味包衣。
本文中所用的术语“十二指肠内释放剂型”是指在十二指肠内开始释放药物的液体或固体形式的剂型。
本文中所用的“哺乳动物”是指被驯养的动物(例如狗、猫和马)和人。在一个实施方案中,哺乳动物是人。
本文中所用的“药学上可接受的盐”是指酸加成盐,其是药学上可接受的并且具有制备该盐的化合物(在下文中,有时称为“母体化合物”)所具有的期望药理学活性。这样的盐包括使用无机酸如盐酸、氢溴酸、硫酸、磷酸等形成的盐;或与有机酸如甲酸、乙酸、丙酸、己酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、苯磺酸、4-甲苯磺酸等形成的盐。
“药学上可接受的载体或赋形剂”是指可用于制备药物组合物的载体或赋形剂;其通常是安全的,既不是生物学材料的也不是所不期望的材料,包括对于哺乳动物的医药使用而言可接受的载体或赋形剂。
疾病的“治疗”包括:
(1)抑制疾病,即阻止或减少疾病或其临床症状的发展;或
(2)缓解疾病,即引起疾病或其临床症状的消退。
“治疗有效量”是指当向需要治疗或认识到需要治疗疾病的哺乳动物给药时,化合物(I)的量足以达到这种疾病治疗的目的。“治疗有效量”将根据化合物、疾病及其严重程度以及待治疗的哺乳动物的年龄、体重等而变化。
如本文中所用的“基本上纯的”是指这样的化合物(或其盐)如化合物(I)(或其盐),其中至少约70重量%的化合物(或其盐)以给定的固态形式存在。例如,短语“基本上纯的无定形形式的化合物(I)(或其盐)的盐的无定形形式”是指其中大于约70重量%的化合物(或其盐)为无定形形式且其余以结晶形式存在的化合物I(或其盐)的固态形式。在一个实施方案中,所述组合物含有至少约80重量%的无定形形式的化合物(I)(或其盐)。在另一实施方案中,至少约85重量%的化合物(I)(或其盐)为无定形形式。在又一实施方案中,至少约90重量%的化合物(I)(或其盐)为无定形形式。在又一实施方案中,至少约95重量%的化合物(I)(或其盐)为无定形形式。在又一实施方案中,至少约97重量%或约98重量%的化合物(I)(或其盐)为无定形形式。在又一实施方案中,至少约99重量%的化合物(I)为无定形形式。固体混合物中的结晶形式和/或无定形形式的相对量可通过本领域所熟知的方法来确定。例如,X射线衍射提供了一种定量测定固体混合物中结晶形式和/或无定形形式的相对量的方便实用的方法。X射线衍射适用于定量应用,因为混合物中给定化合物的衍射峰的强度与混合物中相应粉末的分数成比例。虽然化合物(I)的所有盐都是无定形的,但是如果任何结晶形式的化合物(I)(或其盐)存在于混合物中,则可以测定未知组合物中的晶体化合物(I)(或其盐)的百分比组成。优选地,在化合物(I)(或其盐)的固体粉末上进行测量。可以将未知组合物的X射线粉末衍射谱图与已知的定量的含有纯结晶形式的化合物(I)(或其盐)(如果有的话)的标准品进行比较,以确定具体结晶形式的百分比。如果组合物中的大部分是无定形形式,则还可将该量与进行分析的固体的总重量进行比较。这通过将未知固体粉末组合物的衍射图谱的峰的相对强度与源自已知的纯样品的X射线衍射图的校准曲线进行比较来完成。所述曲线可基于结晶形式的化合物(I)(或其盐)的纯样品的最强峰的X射线粉末衍射谱图来校准。校准曲线可以以本领域那些技术人员已知的方式建立。例如,可以制备五种或更多种不同量的结晶形式的化合物(I)(或其盐)的人工混合物。在非限制性实例中,这些混合物可含有2%、5%、7%、8%和10%的每种结晶形式的化合物(I)(或其盐)。然后,使用标准X射线衍射技术获得每种人工混合物的X射线衍射图。峰位置的轻微差异(如果有的话)可通过调整待测量的峰的位置来消除。然后对于每种人工混合物,将所选特征峰的强度相对于已知的结晶形式的重量百分比进行绘图。得到的图是校准曲线,使得能够确定未知样品中结晶形式化合物(I)(或其盐)的量。对于化合物(I)(或其盐)的结晶形式和无定形形式的未知混合物,相对于校准混合物中所选特征峰的强度,混合物中该峰的强度可用于确定组合物中给定结晶形式的百分比,其余部分确定为无定形材料。总结晶度可如下确定:%结晶度=(C/A+C-B)×100,其中C是结晶峰的面积,A是无定形晕的面积,B是由空气散射、荧光灯造成的背景噪声。
本文所用的术语“通道”是指包衣或底衣中允许至少水流入剂型的路径。在一个实施方案中,水流入剂型中在剂型内部建立渗透压,并导致药物从剂型中流出。在另一个实施方案中,渗透压导致底衣或包衣破裂,从而从剂型中释放出药物。可在包衣中形成通道或孔的材料是本领域公知的。它们可以是有机的或无机的,并且包括在使用环境中可从包衣中溶解、提取或过滤的材料。
AUC(“曲线下面积”)是用于评估药物分子的生物利用度的参数之一。
它是指血浆中药物浓度相对于时间的图的曲线下面积(即积分)。单剂量的AUC(从零到无穷大)代表随时间的总药物暴露,并且,假设具有线性药代动力学,AUC与来自被机体吸收的单剂量的药物的总量(即,到达血液循环的未改变的药物的总量)成比例。
在一些实施方案中,本文中所述的固体剂型包含肠溶衣,即作为本文所述的利用肠溶衣来实现化合物在胃肠道的肠中的释放的药物组合物的口服剂型。“肠溶包衣的”药物或片剂是指采用在胃中保持完整但一旦到达肠便溶解并释放药物的物质——即“肠溶包衣”——包覆的药物或片剂。本文所用的“肠溶衣”,是例如聚合物材料之类的材料或是将治疗活性剂包入剂型或颗粒的材料。通常,大部分量的或全部的肠溶衣材料是在治疗活性剂从剂型中释放之前溶解,以便实现治疗活性剂在肠中的延迟溶解。例如,Loyd,V.Allen,Remington:The Science and Practice of Pharmacy,第21版,Pharmaceutical Press,2005;和P.J.Tarcha,Polymers for Controlled Drug Delivery,第3章,CRC Press,1991中讨论了肠溶衣。将肠溶衣施用于药物组合物的方法是本领域公知的,包括例如美国专利公开第2006/0045822号。
剂型可以是包含任选与其它赋形剂混合的化合物(I)或其药学上可接受的盐(或其任何实施方案)的颗粒、粉末、丸粒、珠粒或微粒的压制或模制或挤出的片剂(包覆或未包覆肠溶衣),所述其他赋形剂本身包覆或未包覆肠溶衣,条件是至少片剂和/或化合物(I)的颗粒、粉末、丸粒、珠粒或微粒是被包覆的。口服剂型还可以是包含任选与其它赋形剂混合的式(I)化合物或其药学上可接受的盐(或其任何实施方案)的丸粒、珠粒或颗粒的胶囊(包覆或未包覆肠溶衣),所述其他赋形剂本身包覆或未包覆肠溶衣,条件是至少胶囊和/或化合物(I)的颗粒、粉末、丸粒、珠粒或微粒是被包覆的。最初被用作肠溶衣的包衣材料的一些实例是蜂蜡和单硬脂酸甘油酯;蜂蜡、虫胶和纤维素;以及鲸蜡醇、乳香脂和虫胶以及虫胶和硬脂酸(美国专利第2,809,918号);聚乙酸乙烯酯和乙基纤维素(美国专利第3,835,221号)。最近,所用的肠溶衣是聚甲基丙烯酸酯的中性共聚物(Eudragit L30D);(F.W.Goodhart等人,Pharm.Tech.,第64-71页,1984年4月);甲基丙烯酸和甲基丙烯酸甲酯的共聚物(Eudragit S)、或含有硬脂酸金属盐的聚甲基丙烯酸酯的中性共聚物(参见Mehta等人的美国专利第4,728,512号和第4,794,001号)、琥珀酸乙酸纤维素和羟丙基甲基纤维素邻苯二甲酸酯。
任何表现出pH依赖性溶解度特征的阴离子聚合物均可用作本文所述方法和组合物中的肠溶衣,以实现对肠的部位特异性递送。在一个实施方案中,部位特异性递送是递送至空肠和/或回肠。在一些实施方案中,本文所述的聚合物是阴离子羧基聚合物。在其它实施方案中,聚合物及其相容的混合物,以及具有它们的性质的一些物质,包括但不限于:
虫胶:也称为纯化紫胶,它是从昆虫的树脂分泌物中获得的精制产物。这种包衣材料溶于pH>7的介质;
丙烯酸聚合物:丙烯酸聚合物的性能(主要是它们在生物液体中的溶解度)可以根据取代的程度和类型而变化。合适的丙烯酸聚合物的实例包括甲基丙烯酸共聚物和甲基丙烯酸铵共聚物。可以以溶于有机溶剂、水分散体或干粉中中的形式获得Eudragit系列L、S和RS(由Rohm Pharma制造,被称为Evonik)。Eudragit系列RL、NE和RS在胃肠道中不溶解,但是是可渗透的,主要用于结肠靶向。Eudragit系列L、L-30D和S在胃中不溶解,在肠中溶解;
纤维素衍生物:合适的纤维素衍生物的实例是:乙基纤维素;纤维素的部分乙酸酯与邻苯二甲酸酐的反应混合物。所述性能可以基于取代的程度和类型而变化。邻苯二甲酸乙酸纤维素(CAP)在pH>6下溶解。Aquateric(FMC)是一种基于水的体系,是颗粒<1μm的喷雾干燥的CAP假胶乳。Aquateric中的其他组分可包括普朗尼克类、吐温类和乙酰化的单甘油酯类。其他合适的纤维素衍生物包括乙酸纤维素偏苯三酸酯(Eastman);甲基纤维素(Pharmacoat,Methocel);羟丙基甲基纤维素邻苯二甲酸酯(HPMCP);羟丙基甲基琥珀酸纤维素(HPMCS);和乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS,例如AQOAT(Shin Etsu))。所述性能可基于取代的程度和类型而变化。例如,HPMCP,如HP-50、HP-55、HP-55S、HP-55F等级是合适的。所述性能可基于取代的程度和类型而变化。例如,乙酸羟丙基甲基纤维素琥珀酸酯的合适等级包括但不限于AS-LG(LF),其在pH 5下溶解;AS-MG(MF),其在pH 5.5下溶解;和AS-HG(HF),其在较高pH下溶解。这些聚合物是作为适合水分散提的颗粒或细粉末而提供的;
聚乙酸乙烯邻苯二甲酸酯(PVAP):PVAP在pH>5下溶解,其比水蒸气和胃液的可渗透性低得多。上述聚合物及其pH依赖性溶解度的详细描述可在http:// pop.www.capsugel.com/media/library/enteric-coated-hard-gelatin-capsules.pdf上由教授Karl Thoma和Karoline Bechtold发表的题为“Enteric coated hard gelatincapsules”的文章中找到。
在一个实施方案中,肠溶衣由以下制成:丙烯酸、甲基丙烯酸或乙基丙烯酸聚合物或共聚物、乙酸纤维素(及其琥珀酸酯和邻苯二甲酸酯衍生物)、羟丙基甲基纤维素邻苯二甲酸酯、聚乙酸乙烯邻苯二甲酸酯、羟乙基乙基纤维素邻苯二甲酸酯、四氢邻苯二甲酸乙酸纤维素、丙烯酸树脂或虫胶。在另一个实施方案中,所述聚合物选自邻苯二甲酸乙酸纤维素(CAP;pH 6以上溶解)、聚乙酸乙烯邻苯二甲酸酯(PVAP,在pH 5下分解)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP,在pH 5下分解的等级HP50,以及在pH 5.5下分解的等级HP50)、甲基丙烯酸共聚物(在约6和约7之间分解的Eudragit L 100和L12.5;在pH大于5.5下分解的Eudragit L-30和L100-55;在pH大于7下分解的Eudragit S100、S12.5和FS 30D)。
在一些实施方案中,包衣材料可包含且通常确实包含增塑剂和可能的其它包衣赋形剂,例如本领域熟知的着色剂、滑石和/或硬脂酸镁。合适的增塑剂包括柠檬酸三乙酯(Citroflex 2)、三醋精(三乙酸甘油酯)、乙酰柠檬酸三乙酯(Citroflec A2)、Carbowax400(聚乙二醇400)、邻苯二甲酸二乙酯、柠檬酸三丁酯、乙酰化的单甘油酯、甘油、脂肪酸酯、丙二醇和邻苯二甲酸二丁酯。特别地,阴离子羧基丙烯酸聚合物通常会含有10-25重量%的增塑剂,特别是邻苯二甲酸二丁酯、聚乙二醇、柠檬酸三乙酯和三醋精。
使用常规包衣技术来进行包衣,如使用流化床包衣机或Wurster包衣机、或者喷雾包衣法或锅包衣法。包衣厚度必须足以确保口服剂型保持完整,直至到达肠道内的目标递送部位。优化各肠溶衣层的增塑剂的量和所述聚合物的施用量,使得可以调整肠溶衣层的机械特性(即柔性和硬度例如例示为Vickers硬度),以便于如果需要的是片剂,则在将丸粒压制成片剂期间,包覆了肠溶衣层的丸粒的耐酸性不会显著降低。增塑剂的量通常为肠溶衣层聚合物的5重量%以上(在一个实施方案中,增塑剂的量为15-50%,在另一个实施方案中,增塑剂的量为20-50%)。所施用的肠溶衣的最大厚度通常仅受加工条件和期望的溶解特性的限制。
除了增塑剂之外,可以向包衣材料中加入着色剂、表面活性剂、抗粘附剂、消泡剂、润滑剂(例如加洛巴蜡或PEG)和其它添加剂,以促进包衣材料溶解或分散包衣材料,并改善包衣性能和经包覆的产品。为加快肠溶衣的溶解,可以施用肠溶聚合物(例如,EudragitL30D-55)的一半厚度的双包衣,内肠溶衣可具有在10%柠檬酸的存在下最高达pH 6.0的缓冲液;随后是最后一层标准的Eudragit L 30 D-55。与所施用的无缓冲的单层的类似包衣体系相比,施用两层肠溶衣,各为常规肠溶衣厚度的一半,Liu和Basit能够加速肠溶衣溶解(Liu,F.和Basit,A.Journal of Controlled Release.147(2010)242-245.)。例如可通过微丸中药物的降解来衡量肠溶衣的完整性。如USP中所述,首先在胃液中并且单独地在肠液中在溶出试验中测试肠溶衣剂型或丸粒以确定其功能。还可使肠溶衣层中含有添加剂,如分散剂、着色剂、色素聚合物(例如聚丙烯酸乙酯、聚甲基丙烯酸甲酯)、抗粘剂和消泡剂。可以加入其它化合物,以增加膜厚度并减少酸性胃液扩散进入酸敏感材料中。
除非另有说明,否则在本文中公开的制剂包含一种或多种药学上可接受的赋形剂,例如粘合剂、表面活性剂、稀释剂、缓冲剂、抗粘附剂、助流剂、亲水性或疏水性聚合物、阻滞剂、稳定剂、崩解剂或超级崩解剂、分散剂、抗氧化剂、消泡剂、填充剂、香料、着色剂、润滑剂、吸附剂、防腐剂、增塑剂或甜味剂或其混合物,所述赋形剂促使药物分子(或本文中所公开的其实施例)或其药学上可接受的盐,从而加工成药学上可使用的剂型。药学上可接受的赋形剂可存在于包衣中和/或核心里。可使用本领域认为合适的任何熟知的技术和赋形剂,参见例如,Remington:The Science and Practice of Pharmacy,第二十一版(Pharmaceutical Press,2005);Liberman,H.A.、Lachman,L.和Schwartz,J.B.Eds.,Pharmaceutical Dosage Forms,卷1至2,Taylor&Francis 1990;以及R.I.Mahato、Ansel的Pharmaceutical Dosage Forms and Drug Delivery Systems,第二版(Taylor&Francis,2012)。
在一些实施方案中,制剂可包含一或多种pH调节剂或缓冲剂,例如,酸,例如乙酸、硼酸、柠檬酸、乳酸、磷酸和盐酸;碱,例如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠和三羟甲基氨基甲烷;以及缓冲剂,例如柠檬酸盐/葡萄糖、碳酸氢钠、氯化铵等。所述酸、碱和缓冲剂的量足以将组合物的pH维持在可接受范围内。
在一些实施方案中,制剂还可包含一种或多种盐,它们的量足以使组合物的渗透压达到可接受的范围。所述盐包括具有钠、钾或铵阳离子和氯阴离子、柠檬酸根阴离子、抗坏血酸根阴离子、硼酸根阴离子、磷酸根阴离子、碳酸氢根阴离子、硫酸根阴离子、硫代硫酸根阴离子或亚硫酸氢根阴离子的那些盐;合适的盐包含氯化钠、氯化钾、硫代硫酸钠、亚硫酸氢钠和硫酸铵。
在一些实施方案中,制剂还可包含一种或多种消泡剂以减少加工期间的泡沫,所述泡沫可导致水性分散液凝结、成品薄膜中的气泡或通常损害加工工艺。示例性的消泡剂包括硅乳液或倍半油酸山梨聚糖。
在一些实施方案中,制剂还可包含一种或多种抗氧化剂,例如非硫醇抗氧化剂,例如丁羟甲苯(BHT)、抗坏血酸钠、抗坏血酸和生育酚。在某些实施例中,抗氧化剂在需要时增强化学稳定性。
在一些实施方案中,制剂还可包含一种或多种防腐剂以抑制微生物活性。合适的防腐剂包括含汞物质,例如苯汞和硫柳汞;稳定的二氧化氯;和季铵化合物,例如苯扎氯铵、溴化十六烷基三甲铵和西吡氯铵。
在一些实施方案中,制剂还可包含一种或多种粘合剂。粘合剂赋予粘合性并且包括,例如藻酸和其盐;纤维素衍生物,例如羧甲基纤维素、甲基纤维素(例如,)、羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素(例如,)、乙基纤维素(例如,)和微晶纤维素(例如,);微晶葡萄糖;直链淀粉;硅酸镁铝;多聚糖酸;膨润土;明胶;聚乙烯吡咯烷酮/乙酸乙烯酯共聚物;交联聚维酮;聚维酮;淀粉;预胶化淀粉;黄蓍胶、糊精、麦芽糊精、糖(例如,蔗糖(例如))、葡萄糖、葡萄糖、糖蜜、甘露醇、山梨醇、木糖醇(例如,)和乳糖;天然树胶或合成树胶,例如阿拉伯树胶、黄蓍胶、伊丝布尔树皮(isapol husks)的印度树胶粘液、聚乙烯吡咯烷酮(例如,CL、CL、XL-10)、落叶松阿拉伯半乳聚糖、聚乙二醇、聚环氧乙烷、蜡、藻酸钠等。
通常,将约10%至约70%水平的粘合剂用于粉末填充的明胶胶囊制剂中。无论直接压片、湿法制粒、碾压还是使用其它赋形剂(例如其自身可充当温和粘合剂的填料),片剂中的粘合剂使用水平都会变化。虽然本领域中技术制剂人员可确定用于制剂的粘合剂水平,但是在片剂中粘合剂使用水平最高达70%是常规的。
在一些实施方案中,制剂还可包含分散剂和/或黏度调节剂。分散剂和/或黏度调节剂包括通过液体介质或制粒法或共混法控制药物的扩散和均匀性的材料。在一些实施方案中,这些助剂还促进包衣基质或可蚀性基质的有效性。示例性扩散促进剂/分散剂包括例如亲水聚合物;电解质;20、60或80、PEG;聚乙烯吡咯烷酮(PVP;市售名称为);和碳水化合物类分散剂,例如羟丙基纤维素(例如,HPC、HPC-SL和HPC-L)、羟丙基甲基纤维素(例如,HPMC K100、RPMC K4M、HPMC K15M和HPMC K100M)、羧甲基纤维素钠、甲基纤维素、三乙基纤维素、羟乙基-纤维素、羟丙基-纤维素、羟丙基甲基纤维素邻苯二甲酸酯、乙酸羟丙基-甲基纤维素硬脂酸酯(HPMCAS)、非晶质纤维素;硅酸镁铝;三乙醇胺;聚乙烯醇(PVA);乙烯基吡咯烷酮/乙酸乙烯酯共聚物(S630);4-(1,1,3,3-四甲基丁基)-苯酚与环氧乙烷和甲醛的聚合物(也被称作泰洛沙泊);泊洛沙姆(例如,Pluronics F68、F88和F108,其为环氧乙烷与环氧丙烷的嵌段共聚物);和泊洛沙胺(poloxamine)(例如,908,也被称作908,其为通过将环氧丙烷和环氧乙烷依序与乙二胺加成而衍生的四功能嵌段共聚物(新泽西州,帕西帕尼,BASF公司));聚乙烯吡咯烷酮K12、聚乙烯吡咯烷酮K17、聚乙烯吡咯烷酮K25或聚乙烯吡咯烷酮K30;聚乙烯吡咯烷酮/乙酸乙烯酯共聚物(S-630);聚乙二醇(例如,所述聚乙二醇可具有约300至约6000或约3350至约4000或约7000至5400的分子量);羧甲基纤维素钠;甲基纤维素;聚山梨醇酯-80;藻酸钠;树胶(例如,黄芪树胶和阿拉伯树胶);瓜尔胶;黄原胶(包含黄胞胶);糖;纤维素(例如,羧甲基纤维素钠、甲基纤维素、羧甲基纤维素钠);聚山梨醇酯-80;藻酸钠;聚乙氧基化脱水山梨糖醇单月桂酸酯;聚乙氧基化脱水山梨糖醇单月桂酸酯;聚维酮;卡波姆;聚乙烯醇(PVA);藻酸盐;壳聚糖;和其组合。
在一些实施方案中,制剂还可包含一种或多种“稀释剂”,所述稀释剂是指用于在递送前稀释所关注化合物的化学物质。稀释剂还可用于使化合物稳定,因为其可提供更稳定的环境。在本领域中使用溶解于缓冲溶液中的盐(其还可提供pH控制或维持)作为稀释剂,包括但不限于磷酸盐缓冲盐水溶液。在某些实施方案中,稀释剂增加组分的体积以便于压制或建立足够的体积以用于胶囊填充的均匀共混。这种物质包括(例如)乳糖、淀粉、甘露醇、山梨醇、葡萄糖、微晶质纤维素(例如,);磷酸氢钙、二水磷酸二钙;磷酸三钙、磷酸钙;无水乳糖、喷雾干燥的乳糖;预胶化淀粉、可压缩糖(例如,(Amstar));羟丙基甲基纤维素、乙酸羟丙基甲基纤维素硬脂酸酯、蔗糖类稀释剂、糖粉(confectioner’ssugar);碱式硫酸钙一水合物、硫酸钙二水合物;乳酸钙三水合物、葡萄糖结合剂;经水解的谷物固形物、直链淀粉;粉状纤维素、碳酸钙;甘氨酸、高岭土;甘露醇、氯化钠;肌醇、膨润土等。
在一些实施方案中,制剂还可包含表面活性剂,所述表面活性剂为可在亲水/疏水(水/油)界面处累积并且降低所述界面处的表面张力的长链分子。因此,其可使乳液稳定。在一些实施方案中,表面活性剂可包括:(聚氧乙烯山梨酸酯)家族的表面活性剂;(脱水山梨糖醇长链羧酸酯)家族的表面活性剂;(环氧乙烷或环氧丙烷嵌段共聚物)家族表的面活性剂;及(均为聚乙二醇化的甘油酯)家族的表面活性剂;油酸、硬脂酸、月桂酸或其它长链羧酸的脱水山梨糖醇酯;泊洛沙姆(聚乙二醇-聚丙二醇嵌段共聚物或);其它脱水山梨糖醇或蔗糖长链羧酸酯;甘油单酯及甘油二酯;辛酸/癸酸甘油三脂的PEG衍生物及其混合物,或以上各者中之两者或两者以上的混合物。在一些实施方案中,表面活性剂相可包含聚氧乙烯(20)脱水山梨糖醇单油酸酯(Tween)与脱水山梨糖醇单油酸酯(Span)的混合物。
在一些实施方案中,制剂还可包含一种或多种“崩解剂”,所述崩解剂使所述剂型在与胃肠液接触时溶解和分散。“崩解助剂或崩解剂”促进药物的破碎或分解。崩解助剂的实例包括淀粉,例如天然淀粉(例如玉米淀粉或马铃薯淀粉)、预胶化淀粉(例如National1551)或羧基乙酸淀粉钠(例如或);纤维素,例如木产品、甲基晶质纤维(例如,PH101、PH 102、PH105、P100、和)、甲基纤维素、交联羧甲纤维素或交联的纤维素(例如,交联羧甲基纤维素钠)、交联羧甲基纤维素或交联的交联羧甲纤维素;交联的淀粉,例如羧基乙酸淀粉钠;交联的聚合物,例如交联聚维酮、交联聚乙烯吡咯烷酮;藻酸盐,例如藻酸或藻酸的盐(例如藻酸钠);粘土,例如HV(硅酸镁铝);树胶,例如琼脂、瓜尔胶、刺槐豆胶、梧桐胶、果胶或黄蓍胶;羧基乙酸淀粉钠;膨润土;天然海绵;表面活性剂;树脂,例如阳离子交换树脂;柑橘果肉;十二烷基硫酸钠、与淀粉组合的十二烷基硫酸钠等。
在一些实施方案中,制剂还可包含侵蚀促进剂。“侵蚀促进剂”包括控制特定材料在胃肠液中的侵蚀的材料。侵蚀促进剂通常是本领域中普通技术人员已知的。示例性的侵蚀促进剂包括(例如)亲水聚合物、电解质、蛋白质、肽和氨基酸。
在一些实施方案中,制剂还可包含一种或多种填充剂,所述填充剂包括例如以下化合物:乳糖、碳酸钙、磷酸钙、磷酸氢钙、硫酸钙、微晶纤维素、纤维素粉、葡萄糖、葡糖糖结合剂、葡聚糖、淀粉、预胶化淀粉、蔗糖、木糖醇、乳糖醇、甘露醇、山梨醇、氯化钠、聚乙二醇等。
在一些实施方案中,制剂还可包含一种或多种香料和/或“甜味剂”,例如,阿拉伯胶糖浆、安赛蜜K、阿力甜、大茴香、苹果、阿斯巴甜、香蕉、巴伐利亚奶油草莓、黑醋栗多酚、奶油糖果、柠檬酸钙、樟脑、焦糖、樱桃、樱桃奶油巧克力、肉桂、泡泡糖、柑桔、柑桔饮料、柑桔奶油、棉花糖、可可饮料、可乐、冷樱桃、冷柑桔、环己氨基磺酸盐、甜精(cylamate)、葡萄糖、桉树、丁香油酚、果糖、水果饮料、姜、甘草亭酸酯、甘草(欧亚甘草)糖浆、葡萄、葡萄柚、蜂蜜、异麦芽、柠檬、青柠、柠檬奶油、甘草酸一铵、麦芽酚、甘露醇、枫树、蜀葵糖浆、薄荷醇、薄荷乳、混合浆果、新橙皮苷DC、纽甜、橙子、梨、桃、薄荷、薄荷奶油、粉、覆盆子、根汁汽水、朗姆酒、糖精、黄樟素、山梨醇、留兰香、留兰香奶油、草莓、草莓奶油、甜叶菊、三氯蔗糖、蔗糖、糖精钠、糖精、阿斯巴甜、乙酰氨基磺酸钾、甘露醇、踝蛋白、sylitol、三氯蔗糖、山梨醇、瑞士奶油、塔格糖、红橘、索马甜、水果冰淇淋、香草、胡桃、西瓜、野樱桃、冬青油、木糖醇或这些香料成分的任何组合,例如大茴香-薄荷醇、草莓-大茴香、肉桂-橙子、草莓-肉桂、巧克力-薄荷、蜂蜜-柠檬、柠檬-青柠、柠檬-薄荷、薄荷醇-桉、橙子-奶油、香草-薄荷,和其混合物。
在一些实施方案中,制剂还可包含一种或多种润滑剂和助流剂,所述润滑剂和助流剂是防止、减小或抑制材料的粘结或摩擦的化合物。示例性润滑剂包括(例如)硬脂酸;氢氧化钙;滑石;硬脂酰富马酸钠;烃,例如矿物油或氢化植物油例,如氢化大豆油;高级脂肪酸及其碱金属和碱土金属盐,例如,硬脂酸的铝、钙、镁、锌盐,硬脂酸钠,甘油,滑石,蜡,硼酸,苯甲酸钠,乙酸钠,氯化钠,亮氨酸,聚乙二醇(例如PEG4000)或甲氧基聚乙二醇例如油酸钠,苯甲酸钠,山嵛酸甘油酯,聚乙二醇,十二烷基硫酸镁或十二烷基硫酸钠,胶体二氧化硅例如淀粉例如玉米淀粉,硅油,表面活性剂等。
在一些实施方案中,制剂还可包含一种或多种增溶剂,所述增溶剂包括例如以下化合物:三乙酸甘油酯、柠檬酸三乙酯、油酸乙酯、辛酸乙酯、十二烷基硫酸钠、多库酯钠、维生素E TPGS、二甲基乙酰胺、N-甲基吡咯烷酮、N-羟乙基吡咯烷酮、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基环糊精例如乙醇、正丁醇、异丙醇、胆固醇、胆盐、聚乙二醇200-600、四甘醇、卡必醇、丙二醇和二甲基异山梨醇酯等。在一个实施方案中,增溶剂为维生素E TPGS和/或
在一些实施方案中,制剂还可包含一种或多种助悬剂,所述助悬剂包括例如以下化合物:聚乙烯吡咯烷酮(例如,聚乙烯吡咯烷酮K112、聚乙烯吡咯烷酮K17、聚乙烯吡咯烷酮K25或聚乙烯吡咯烷酮K30)、乙烯基吡咯烷酮/乙酸乙烯酯共聚物(S630)、聚乙二醇(例如,聚乙二醇可具有约300至约6000或约3350至约4000或约7000至约5400的分子量)、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙酸羟甲基纤维素硬脂酸酯、聚山梨酯-80、羟乙基纤维素、藻酸钠、树胶(例如,黄蓍胶和阿拉伯树胶)、瓜尔胶、黄原胶(包含黄胞胶)、糖、纤维素(例如,羧甲基纤维素钠、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、羟乙基纤维素)、聚山梨酯-80、藻酸钠、聚乙氧基化脱水山梨糖醇单月桂酸酯、聚乙氧基化脱水山梨糖醇单月桂酸酯、聚维酮等。
在某些实施方案中,制剂还可包含一种或多种表面活性剂,所述表面活性剂包括例如以下化合物:,十二烷基硫酸钠、多库酯钠、吐温60或80、三乙酸甘油酯、维生素E TPGS、脱水山梨糖醇单油酸酯、聚氧乙烯脱水山梨糖醇单油酸酯、聚山梨醇酯、泊洛沙姆、胆盐、单硬脂酸甘油酯、环氧乙烷和环氧丙烯的共聚物例如(BASF)等。一些其它表面活性剂包括聚氧化乙烯脂肪酸甘油酯和植物油,例如,聚氧化乙烯(60)氢化蓖麻油;和聚氧化乙烯烷基醚和烷基苯基醚,例如,辛苯昔醇10、辛苯昔醇40。在一实施方案中,还可包含表面活性剂以增强物理稳定性或用于其它目的。
在某些实施方案中,制剂还可包含一种或多种增粘剂,所述增粘剂包括(例如)甲基纤维素、黄原胶、羧甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、乙酸羟丙基甲基纤维素硬脂酸酯、羟丙基甲基纤维素邻苯二甲酸酯、卡波姆、聚乙烯醇藻酸盐、阿拉伯树胶、壳聚糖和其组合物。
在一些实施方案中,制剂还可包括一种或多种润湿剂,所述润湿剂包括例如以下化合物:油酸、单硬脂酸甘油酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单月桂酸酯、油酸三乙醇胺、聚氧乙烯脱水山梨糖醇单油酸酯、聚氧乙烯脱水山梨糖醇单月桂酸酯、多库酯钠、油酸钠、十二烷基硫酸钠、多库酯钠、三乙酸甘油酯、吐温80、维生素E TPGS、铵盐等。
应理解,用于本文中所描述的固体剂型中的赋形剂之间存在相当大的重叠。因此,上文所列出的添加剂应仅作为示例,其不限制可包含于本文中所描述的固体剂型中的赋形剂类型。本领域普通技术人员可根据所需特定性质容易地确定所述赋形剂的类型和量。
实施方案:
在下面的实施方案1-60中,本公开内容包括:
1.一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自十二指肠、空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的立即释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约150%至约4000%。
2.一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自十二指肠、空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的立即释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约150%至约4000%,条件是当将所述固体口服剂型给予处于禁食状态的哺乳动物时,在给药之后约1.5至约2小时之内所贡献的AUC占由给予所述固体口服剂型而引起的AUC的不多于10%。
3.一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的十二指肠内释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约100%至约2000%。在第三方面的一个实施方案中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为约125%至约2000%。在第三方面的第二实施方案中,化合物(I)和/或其药学上可接受的盐在哺乳动物的空肠或回肠部位开始释放。
4.一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)用于在一个或多个哺乳动物肠部位释放化合物(I)和/或其药学上可接受的盐的手段,所述肠部位选自空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂;
其中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的十二指肠内释放剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度的约100%至约2000%,条件是当将所述固体口服剂型给予处于禁食状态的哺乳动物时,在给药之后约1.5至约2小时之内所贡献的AUC占由给予所述固体口服剂型而引起的AUC的不多于10%。在第三方面的一个实施方案中,由给予所述固体口服剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为约125%至约2000%。
5.实施方案1-4中任一项的固体口服剂型,其中所述固体口服剂型在十二指肠的末端部位或空肠的近端部位开始释放化合物(I)和/或其药学上可接受的盐。
6.实施方案1-4中任一项的固体口服剂型,其中所述固体剂型在哺乳动物的肠的空肠-回肠部位开始释放化合物(I)和/或其药学上可接受的盐。
7.实施方案1-4中任一项的固体口服剂型,其中所述剂型在哺乳动物的空肠-回肠或结肠部位开始释放和/或吸收化合物(I)和/或其药学上可接受的盐。
8.实施方案1-7中任一项的固体口服剂型,其中在溶出试验中,在约6.4至约7.4的pH下在约20分钟至约2小时内从所述固体口服剂型中释放不少于约80重量%的化合物(I)和/或其药学上可接受的盐。
9.实施方案1、2和5-7中任一项的固体口服剂型,其中由给予所述固体口服剂型而引起的化合物(I)的血浆AUC为由给予所述立即释放剂型而引起的血浆AUC的至少约200%。
10.实施方案1、2和5-7中任一项的固体口服剂型,其中由给予所述固体口服剂型而引起的化合物(I)的血浆AUC为由给予所述立即释放剂型而引起的血浆AUC的至少约500%。
11.一种固体口服剂型,其包括:
(i)化合物(I)和/或其药学上可接受的盐;
(ii)肠溶衣,其在一个或多个哺乳动物的肠部位释放化合物(I)和/或其药学上可接受的盐,所述肠部位选自十二指肠、空肠、回肠和结肠;以及
(iii)药学上可接受的赋形剂。
12.实施方案11的固体口服剂型,其中所述固体剂型在十二指肠的末端部位或空肠的近端部位开始释放化合物(I)和/或其药学上可接受的盐。
13.实施方案11的固体口服剂型,其中所述固体口服剂型在哺乳动物的肠的空肠-回肠部位开始释放化合物(I)和/或其药学上可接受的盐。
14.实施方案11的固体口服剂型,其中所述固体口服剂型在哺乳动物的空肠-回肠或结肠部位开始释放化合物(I)和/或其药学上可接受的盐,并且化合物(I)和/或其药学上可接受的盐的吸收开始于哺乳动物的空肠-回肠或结肠部位。
15.实施方案11-14中任一项的固体口服剂型,其中在盛有pH小于约3的水溶液的溶出容器中,在约1.5小时内,所述固体口服剂型释放小于约10重量%的化合物(I)和/或其药学上可接受的盐;在盛有pH为约4.5至约5.0的水溶液的溶出容器中,在约1.5小时内,释放小于约10重量%的化合物(I)和/或其药学上可接受的盐;并且在盛有pH为约6.4至约7.4的水溶液的溶出容器中,在约20分钟至约2小时内,释放不少于约80重量%的化合物(I)和/或其药学上可接受的盐。在实施方案15的一个从属实施方案中,在盛有pH为约5.0的水溶液的溶出容器中,在约1.5小时内,释放小于约10重量%的化合物(I)和/或其药学上可接受的盐。
16.实施方案15的固体口服剂型,其中在盛有pH为约6.4至约7.4的水溶液的溶出容器中,在约15分钟内,所述固体口服剂型释放小于约25%的化合物(I)和/或其药学上可接受的盐。
17.实施方案15的固体口服剂型,其中在盛有pH为约6.4至约7.4的水溶液的溶出容器中,在约30分钟内,所述固体口服剂型释放小于约80%的化合物(I)和/或其药学上可接受的盐。
18.实施方案15的固体口服剂型,其中在盛有pH为约6.4至约7.4的水性介质的溶出容器中,在约45分钟内,所述固体口服剂型释放小于约80%的化合物(I)和/或其药学上可接受的盐。
19.实施方案15的固体口服剂型,其中在盛有pH为约6.4至约7.4的水溶液的溶出容器中,在约60分钟内,所述固体口服剂型释放小于约80重量%的化合物(I)和/或其药学上可接受的盐。
20.实施方案15的固体口服剂型,其中在盛有pH为约6.4至约7.4的水溶液的溶出容器中,在约120分钟内,所述固体口服剂型释放至少约80%的化合物(I)和/或其药学上可接受的盐。
21.实施方案11至20中任一项的固体口服剂型,其中所述溶出容器盛有pH为约6.4至约7.4的模拟肠液来替代水溶液,并且所述固体口服剂型具有实施方案11至20中的一项所述的溶出度。
22.实施方案1至21中任一项的固体口服剂型,其中所述固体口服剂型包含化合物(I)的药学上可接受的酸式盐。在实施方案22的第一从属实施方案中,所述酸式盐是化合物(I)的磺酸盐或羧酸盐。在实施方案22的第二从属实施方案中,所述酸式盐是化合物(I)的单-或二-甲磺酸盐、单-或二-苯磺酸盐、单-或二-甲苯磺酸盐、乙烷-1,2-二磺酸盐、富马酸盐、草酸盐、酒石酸盐、马来酸盐、柠檬酸盐或丙二酸盐。在实施方案22的第三从属实施方案中,所述酸式盐是化合物(I)的单-或二-甲磺酸盐。在实施方案22的第四从属实施方案中,所述酸式盐是化合物(I)的柠檬酸盐。
23.实施方案1至21中任一项的固体口服剂型,其中所述固体口服剂型包含化合物(I)。
24.实施方案22或23的固体口服剂型,其中化合物(I)是2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)和(S)异构体的混合物的(E)和(Z)混合物。
25.实施方案22或23的固体口服剂型,其中化合物(I)是(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
26.实施方案1至25中任一项的固体口服剂型,其中至少约85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
27.实施方案1至26中任一项的固体口服剂型,其中至少约90重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。E与Z异构体之比可通过本领域公知的方法计算。所述方法之一是HPLC总面积归一化法。
28.实施方案1至27中任一项的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐基本上是纯的无定形形式。在实施方案28的一个从属实施方案中,至少约90重量%的化合物(I)(和/或其药学上可接受的盐)为无定形形式。在实施方案28的第二从属实施方案中,至少约95重量%的化合物(I)(和/或其药学上可接受的盐)为无定形形式。在实施方案28的第三从属实施方案中,至少约97重量%或约98重量%的化合物(I)(和/或其药学上可接受的盐)为无定形形式。在实施方案28的第四从属实施方案中,至少约99重量%的化合物(I)(和/或其药学上可接受的盐)为无定形形式。
29.实施方案1至28中任一项的固体口服剂型,其还包含其他药学上可接受的酸,所述药学上可接受的酸的量足以提高化合物(I)和/或其药学上可接受的盐在约6.4至约7.4的pH下的溶出。在实施方案29的一个从属实施方案中,所述其他酸是有机酸。在实施方案25的第二从属实施方案中,所述其他酸是琥珀酸、柠檬酸、苯甲酸、酒石酸或苹果酸。
30.实施方案29的固体口服剂型,其中在化合物(I)和/或其药学上可接受的盐从所述剂型中释放之前,所述药学上可接受的酸在所述固体口服剂型之内形成酸性水溶液。
31.实施方案1至30中任一项的固体口服剂型,其还包含表面活性剂,所述表面活性剂的浓度高于其在约50mL水性介质中崩解时的临界胶束浓度。
32.实施方案1至30中任一项的固体口服剂型,其还包含表面活性剂,所述表面活性剂的浓度高于其在约20mL水性介质中崩解时的临界胶束浓度。
33.实施方案1至32中任一项的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐的平均粒径为约0.3微米至约100微米。在实施方案33的一个从属实施方案中,化合物(I)和/或其药学上可接受的盐的平均粒径为约1微米至约50微米。在实施方案33的第二从属实施方案中,化合物(I)和/或其药学上可接受的盐的平均粒径小于或等于约15微米。
34.实施方案11-33中任一项的固体口服剂型,其中所述固体口服剂型包覆有肠溶衣,所述肠溶衣任选地包覆有顶衣。在实施方案34的第一从属实施方案中,所述顶衣是立即释放型包衣。
35.实施方案11-33中任一项的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐任选与药学上可接受的赋形剂混合,并且任选地层压在微粒如晶种、丸粒、珠粒等上,然后用肠溶衣包覆,且所述肠溶衣任选用立即释放型顶衣包覆并任选地用例如低分子量羟丙甲纤维素的中间的密封包衣包覆。
36.实施方案1至35中任一项的固体口服剂型,其中肠溶衣为固体剂型重量的约10%至约150%。在实施方案36的第一从属实施方案中,肠溶衣为固体剂型重量的约20%至约100%。在实施方案36的第二从属实施方案中,肠溶衣为固体剂型重量的约30%至约60%。在实施方案36的第三从属实施方案中,肠溶衣的厚度为约5至约500微米。在实施方案36的第四从属实施方案中,肠溶衣的厚度为约8至约150微米。在实施方案36的第五从属实施方案中,肠溶衣的厚度为约50至约100微米。
37.实施方案11至36中任一项的固体口服剂型,其中所述肠溶衣选自聚合的明胶、虫胶、甲基丙烯酸共聚物型CNF、邻苯二甲酸丁酸纤维素、邻苯二甲酸氢纤维素(cellulosehydrogen phthalate)、邻苯二甲酸丙酸纤维素、聚乙酸乙烯邻苯二甲酸酯(PVAP)、邻苯二甲酸乙酸纤维素(CAP)、乙酸纤维素偏苯三酸酯(CAT)、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯、二氧丙基甲基纤维素琥珀酸酯、羧甲基乙基纤维素(CMEC)、乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)以及(甲基)丙烯酸聚合物和共聚物,所述聚合物由一种单体制成,所述共聚物由两种或更多种单体制成,所述单体选自丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸乙酯。
38.实施方案37的固体口服剂型,其中所述肠溶衣为聚(甲基)丙烯酸酯聚合物。
41.实施方案11至36中任一项的固体口服剂型,其中所述肠溶衣包含纤维素衍生物。
42.实施方案41的固体口服剂型,其中所述纤维素衍生物选自甲基纤维素、邻苯二甲酸乙酸纤维素、羟甲基纤维素邻苯二甲酸酯(HPMCP)、羟丙基甲基纤维素琥珀酸酯(HPMCS)和乙酸羟甲基纤维素琥珀酸酯(HPMCAS)。
43.实施方案11至36中任一项的固体口服剂型,其中所述肠溶衣包含聚乙酸乙烯邻苯二甲酸酯(PVAP)聚合物。
44.实施方案34、36至43中任一项的固体口服剂型,其在肠溶衣下面还包含底衣。
45.实施方案44的固体口服剂型,其中所述底衣是水溶性或亲水的可蚀性聚合物。
46.实施方案44的固体口服剂型,其中所述底衣是低分子量聚合物,其选自羟甲基纤维素(HPMC)、羟乙基纤维素、羟甲基纤维素、羟丙基纤维素、微晶纤维素、聚乙烯吡咯烷酮、多糖(或多糖衍生物)、聚乙烯醇、聚乙二醇(PEG)、聚环氧乙烷(PEO)、聚丙二醇(PPG)、PEG-PPG和PEO-PPG嵌段共聚物。
47.实施方案44的固体口服剂型,其中所述底衣包含水不溶性组合物,所述水不溶性组合物包含(i)能够在水不溶性组合物中形成通道的水溶性化合物的颗粒,或(ii)在与水性介质接触时导致所述底衣膨胀的水不溶性亲水颗粒。本文中所用的术语“水不溶性亲水颗粒”包括但不限于:多糖,包括果胶酸钙、藻酸钙、黄原酸钙;含有酸基的多糖的任何金属盐,其中该盐使得多糖不溶于水;微晶淀粉;不溶性淀粉;任何水不溶性多糖(例如纤维素或微晶纤维素);任何共价交联的多糖,其中所述交联使得所述多糖不溶于水。这样的交联剂包括但不限于戊二醛、甲醛、表氯醇、二酰氯、二异氰酸酯、二酸酐和二胺。
48.实施方案43的固体口服剂型,其中所述底衣为水不溶性组合物(如水不溶性聚合物),并且包含水溶性化合物的颗粒,所述水溶性化合物能够在水不溶性组合物中形成通道并允许至少水流入所述固体口服剂型且允许化合物(I)和/或其药学上可接受的盐扩散到肠中。
49.实施方案47的固体口服剂型,其中所述底衣为水不溶性组合物(例如水不溶性聚合物),且包含在与水性介质或胃液介质接触时导致所述底衣膨胀的不溶性亲水颗粒。
50.实施方案47的固体口服剂型,其中所述底衣包含水不溶性组合物,所述水不溶性组合物包含水溶性化合物的颗粒,所述水溶性化合物能够形成不可渗透化合物(I)和/或其药学上可接受的盐的通道,但所述通道允许至少水进入,使得所述底衣膨胀和破裂并导致化合物(I)和/或其药学上可接受的盐作为弹丸释放。为该剂型的本实施方案和其他实施方案的目的,弹丸应理解为在溶出试验中在漏槽条件下在pH为约6.4至约7.4下在不超过约1小时的时间段内释放所含化合物(I)和/或其药学上可接受的盐的至少约80%。
51.实施方案1至50中任一项的固体口服剂型,其中所述固体口服剂型是片剂或胶囊剂。
52.实施方案1至51中任一项的固体口服剂型,其中所述赋形剂独立地选自粘合剂、表面活性剂、稀释剂、缓冲剂、抗粘附剂、助流剂、崩解剂、抗氧化剂、消泡剂、填充剂、香料、色素、润滑剂、吸附剂、防腐剂、增塑剂和甜味剂。
53.实施方案1至52中任一项的固体口服剂型,其中,由给予所述剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的立即释放剂型而引起的通过血浆AUC所测量的平均全身性生物利用度的约200%至4000%。
54.实施方案1至52中任一项的固体口服剂型,其中,由给予所述药学剂型而引起的通过血浆AUC所测量的化合物(I)的平均全身性生物利用度为由给予含有等量化合物(I)和/或其药学上可接受的盐的十二指肠内释放剂型而引起的通过血浆AUC所测量的平均全身性生物利用度的约125%至约2000%。
55.一种在需要抑制BTK的哺乳动物中抑制BTK的方法,其包括给予需要该BTK抑制的哺乳动物治疗有效量的于实施方案1-54中任一项的固体口服剂型中的化合物(I)和/或其药学上可接受的盐。
56.一种在需要治疗由BTK介导的疾病的的哺乳动物中治疗所述疾病的方法,其包括给予需要这种疾病治疗的哺乳动物治疗有效量的于实施方案1-54中任一项的固体口服剂型中的化合物(I)和/或其药学上可接受的盐。
57.实施方案56的方法,其中所述疾病选自本文中列出的自身免疫疾病、癌症和炎性疾病。
本文所公开的剂型可通过以下方法获得:将一种或多种固体赋形剂与化合物(I)或其药学上可接受的盐混合,在加入合适的赋形剂之后任选地研磨所得混合物并加工颗粒的混合物以获得片剂,所述固体赋形剂例如载体、粘合剂、填充剂、助悬剂、香料、甜味剂、崩解剂、分散剂、表面活性剂、润滑剂、着色剂、稀释剂、增溶剂、润湿剂、增塑剂、稳定剂、渗透促进剂、湿润剂、消泡剂、抗氧化剂、防腐剂或其一种或多种的组合。
本文中所公开的药物制剂还包括由明胶制成的胶囊,以及由明胶和增塑剂(例如,甘油或山梨醇)制成的软密封胶囊。胶囊还可由聚合物例如羟丙甲纤维素制成。所述胶囊可包含与填充剂例如乳糖、粘合剂例如淀粉和/或润滑剂例如滑石或硬脂酸镁以及任选的稳定剂混合的活性成分。在软胶囊中,可将活性化合物溶解或悬浮于合适的液体中,所述液体例如脂肪油、液状石蜡、脂质、增溶剂或液体聚乙二醇。另外,还可添加稳定剂。所有用于口服给药的制剂的剂量应适合于这种给药。
这些制剂可由常规药学技术来制造。常规药学技术包括例如以下方法中的一种或多种的组合:(1)干混法,(2)直接压片法,(3)研磨,(4)干法制粒或非水制粒,(5)湿法制粒,(6)熔融法或(7)挤出法。参见例如Lachman等人的The Theory and Practice ofIndustrial Pharmacy,第3版(1986)。其它方法包括例如喷雾干燥法、锅包衣法、熔融制粒法、制粒、流化床喷雾干燥法或包衣法(例如,Wurster包衣法)、切线喷包衣法、顶喷、压片、挤出、挤出/滚圆等。
含有所公开化合物的肠溶包衣的片剂和胶囊剂型可通过本领域中公知的方法制备。举例来说,含有本文公开的化合物的片剂可使用侧通风包衣锅(Freund Hi-Coater)采用含有苯二甲酸二乙酯、异丙醇、滑石和水的包衣溶液进行肠溶包衣。
替代地,可如下制备包含肠溶包衣的丸粒的多单位剂型,所述丸粒包含化合物(I)且可可纳入到片剂或胶囊中。
核心材料:
采用活性剂层压的种核可为水不溶性种核,包括单独的或混合形式的不同氧化物、纤维素、有机聚合物和其它材料;或可为水溶性种核,包括单独的或混合形式的不同无机盐、糖、蔗糖小丸(non-pareils)和其它材料。此外,所述种核可包括晶体、附聚物、压块等形式的活性剂。种核的大小对于本发明不是必要的但是可在大约0.1到2mm之间变化。采用活性剂层压的种核可通过使用(例如)制粒设备或喷雾包衣层压设备的粉末或溶液/悬浮液层压而产生。所述种核可被肠溶衣或底衣包覆。
对种核进行层压之前,活性剂可与合适的赋形剂如粘合剂、表面活性剂、填充剂、崩解剂、碱性添加剂等混合。粘合剂为例如聚合物,例如羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、羧甲基纤维素钠、聚乙烯吡咯烷酮(PVP)或糖、淀粉或其它药学上可接受的具有粘结性的物质。合适的表面活性剂可为药学上可接受的非离子表面活性剂或离子表面活性剂(例如,十二烷基硫酸钠)。
或者,可将任选地与合适的赋形剂混合的活性剂制成核心材料。所述核心材料可利用传统工艺设备通过挤压/滚圆、成球或压制而制备。所制成的核心材料的粒径为约0.1至4mm,且例如0.1至2mm。所制造的核心材料可采用包含活性剂的其他赋形剂进一步层压和/或可用于进一步处理。
活性剂与药用赋形剂混合以获得优选的处理和加工性能以及活性剂在最终制剂中的合适浓度。可使用药用赋形剂,例如填充剂、粘合剂、润滑剂、崩解剂、表面活性剂和其它药学上可接受的添加剂。
或者,前文所提到的核心材料可通过使用喷雾干燥或喷雾冷凝技术来制备。
肠溶包衣层:
在将肠溶包衣层施用至呈单个丸粒形式的核心材料上之前,可任选地将丸粒用一层或多层包含药用赋形剂的隔离层覆盖,所述药用赋形剂任选地包括碱性化合物,例如pH缓冲化合物。这一层或多层隔离层将核心材料与外层肠溶包衣层隔离开。保护活性剂的核心材料的这种一层或多层隔离层应为水溶性的或在水中迅速崩解。
可通过包衣步骤或层压步骤在合适设备(例如包衣锅、包衣制粒机)或在流化床装置中使用用于包衣工艺的水和/或有机溶剂而将隔离层施加于核心材料上。作为替代方案,可通过使用粉末包衣技术将隔离层施加于核心材料上。用于隔离层的材料为药学上可接受的化合物,例如,糖、聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、肠溶包衣聚合物的水溶性盐及其他,单独地或以混合的形式使用。隔离层中也可包含添加剂,例如,增塑剂、着色剂、色素、填充剂、抗粘着剂和抗静电剂,例如,硬脂酸镁、二氧化钛、滑石和其它添加剂。
当将任选的隔离层施加至核心材料上时,其厚度可变化。隔离层的最大厚度通常仅受加工条件的限制。隔离层可充当扩散屏障并可充当pH缓冲区。任选地施加的隔离层对于本发明不是必要的。但是,隔离层可提高活性物质的化学稳定性和/或新的多单位片剂的物理性质。
或者,可通过施加于核心材料上的肠溶包衣聚合物层与核心材料中的碱反应性化合物之间的反应而原位形成隔离层。因此,所形成的隔离层包括在肠溶包衣层聚合物与碱反应性化合物之间——这是形成盐的位置——形成的水溶性盐。
通过合适的包衣技术将一层或多层肠溶包衣层施加于核心材料上或覆盖有隔离层的核心材料上。肠溶包衣层材料可在水中或合适有机溶剂中分散或溶解。作为肠溶包衣层聚合物,可单独或组合使用下列的一种或多种:例如,甲基丙烯酸共聚物的溶液或分散体、邻苯二甲酸乙酸纤维素、羟丙基甲基纤维素酞酸酯、乙酸羟丙基甲基纤维素琥珀酸酯、聚乙酸乙烯邻苯二甲酸酯、乙酸纤维素偏苯三酸酯、羧甲基乙基纤维素、虫胶或其它合适的肠溶包衣聚合物。
肠溶包衣层含有药学上可接受的增塑剂以获得期望的力学性能,例如,肠溶包衣层的柔性和硬度。此类增塑剂为(例如)但不局限于三乙酸甘油酯、柠檬酸酯、邻苯二甲酸酯、癸二酸二丁酯、鲸蜡酯、聚乙二醇、聚山梨酯或其它增塑剂。
对于每种肠溶包衣层的配方,根据所选肠溶包衣层聚合物、所选增塑剂和所述聚合物的施用量,优化增塑剂的量,使得肠溶包衣的力学性能(即,柔性和硬度,例如,以Vickers硬度为例)得到调整,以使得如果期望制备的是片剂,则覆盖有肠溶包衣层的丸粒的耐酸性在将丸粒压制成片剂期间不会显著降低。增塑剂的量通常高于肠溶包衣层聚合物的5重量%,例如,15至50%且进一步例如20至50%。肠溶包衣层中也可包括添加剂,例如分散剂、着色剂、色素、聚合物(例如,聚(丙烯乙酯,甲基丙烯酸甲酯))、抗粘着剂和消泡剂。可添加其它化合物以增加膜厚度并减少酸性胃液扩散到酸敏感材料中。所施加的肠溶包衣的最大厚度通常仅受加工条件及所需溶出特性的限制。
外包衣层:
覆盖有肠溶包衣层的丸粒可任选地进一步被一层或多层外包衣层覆盖。外包衣层应为水溶性的或在水中迅速地崩解。可通过包衣步骤或层压步骤在合适的设备(例如包衣锅、包衣制粒机)中或在流化床装置中使用用于包衣或层压工艺的水和/或有机溶剂而在肠溶包衣层压的丸粒上施加外包衣层。用于外包衣层的材料选自药学上可接受的化合物,例如,糖、聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠及其它,单独使用或以混合物的形式使用。外包衣层中也可包含添加剂,例如增塑剂、着色剂、色素、填充剂、抗粘着剂或抗静电剂,例如硬脂酸镁、二氧化钛、滑石及其它添加剂。外包衣层可以进一步防止肠溶包衣层压的丸粒的潜在的团聚,其也可在压实过程期间保护肠溶包衣层避免破裂并且促进压片过程。所施加的外包衣层的最大厚度通常受加工条件及所需溶出特性的限制。外包衣层还可以用作片剂薄膜包衣层。
软明胶胶囊的肠溶包衣可含有乳液、油、微乳剂、自乳化体系、脂质、甘油三酯、聚乙二醇、表面活性剂、其它增溶剂等及其组合,以增加活性剂的溶解度。通过残余水及增塑剂来维持软胶胶囊的柔性。此外,对于明胶胶囊,可将明胶溶于水中,这使得喷雾必须在相对较低的相对湿度下以一定的速率完成,例如可以在流化床或Wurster中完成。另外,应在不除去导致胶囊壳破裂的残余水或增塑剂的情况下完成干燥。用于软胶胶囊的肠溶包衣的优化的市售共混物为例如Instamodel EPD(肠聚合物分散体),可从Ideal Cures,Pvt.Ltd.(印度,孟买)购得。实验室规模的肠溶包衣的胶囊可通过以下步骤制备:a)在烧瓶中旋转胶囊,或在最低可能温度下将胶囊浸入轻微加热的含有增塑剂的肠溶包衣材料的溶液中,或b)在实验室规模的喷雾器/流化床中,随后进行干燥。
对于水性活性剂,尤其期望将药物纳入乳液的水相中。这类“油包水”乳液为药物提供合适的生物物理环境,且可提供可保护药物免受pH或可降解药物的酶的不良影响的油水界面。此外,这类油包水制剂可提供脂质层,所述脂质层可有利地与身体细胞中的脂质相互作用,并且可增加分配于细胞的细胞膜上的制剂。这样的分配可促进所述制剂中的药物吸收进入循环中,因此可提高药物的生物利用度。水相可任选地包含悬浮在水中的活性剂和缓冲剂。
在一些实施方案中,油包水乳液含有由长链羧酸或其酯或其醇组成的油相、表面活性剂或表面活化剂、及主要含有水及活性剂的水相。
长链羧酸为具有至多达三个不饱和键的C8至C22范围内的那些羧酸(也可为支链的)。饱和直链酸的实例为正十二烷酸、正十四烷酸、正十六烷酸、己酸、辛酸、癸酸、月桂酸、豆蔻酸、棕榈酸、硬脂酸、花生酸、山嵛酸、褐煤酸及蜂花酸。还有用的是不饱和单烯键的直链一元羧酸。它们的实例为油酸、鳕油酸及芥酸。还有用的是不饱和(多烯键的)直链一元羧酸。它们的实例为亚油酸、蓖麻油酸、亚麻酸、花生四烯酸及山嵛萘炔酸。有用的支链酸包括例如二乙酰基酒石酸。
长链羧酸酯的实例包括但不限于选自以下群组的那些:单硬脂酸甘油酯;单棕榈酸甘油酯;单硬脂酸甘油酯与单棕榈酸甘油酯的混合物;单亚油酸甘油酯;单油酸甘油酯;单棕酸甘油酯、单硬脂酸甘油酯、单油酸甘油酯及单亚油酸甘油酯的混合物;单亚麻酸甘油酯;单鳕油酸甘油酯;单棕榈酸甘油酯、单硬脂酸甘油酯、单油酸甘油酯、单亚油酸甘油酯、单亚麻酸甘油酯及单鳕油酸甘油酯的混合物;乙酰化甘油酯,例如蒸馏的乙酰化甘油单酯;丙二醇单酯、蒸馏的甘油单酯、硬脂酰乳酸钠及二氧化硅的混合物;d-α生育酚聚乙二醇1000琥珀酸酯;甘油单酯及甘油二酯的混合物,例如Atmul;硬脂酰乳酸钙;乙氧基化的甘油单酯及甘油二酯;乳酸化的甘油单酯及甘油二酯;甘油及丙二醇的乳酸羧酸酯;长链羧酸的乳酸酯;长链羧酸的聚甘油酯、长链羧酸的丙二醇单酯及丙二醇二酯;硬脂酰乳酸钠;失水山梨糖醇单硬脂酸酯;失水山梨糖醇单油酸酯;长链羧酸的其它山梨糖醇酯;琥珀酸单甘油酯;硬脂酰单甘油基柠檬酸酯;硬脂醇庚酸酯;蜡的鲸蜡酯;硬脂醇辛酸酯;C8-C30胆固醇/羊毛甾醇酯;及蔗糖长链羧酸酯。自乳化长链羧酸酯的实例包括选自以下群组的那些:硬脂酸酯、棕榈酸酯、蓖麻醇酸酯、油酸酯、山嵛酸酯、蓖麻醇酸酯、豆蔻酸酯、月桂酸酯、辛酸酯及己酸酯。在一些实施方案中,油相可包括两种或更多种长链羧酸或其酯或其醇的组合。在一些实施方案中,油相可包括辛酸/癸酸甘油三酯与辛酸的C8/C10甘油单酯/甘油二酯的混合物。
可使用的醇的实例为由上文例示的羧酸的羟基形式以及硬脂醇。
表面活化剂或表面活性剂为可在亲水/疏水(水/油)界面处累积并且降低所述界面处的表面张力的长链分子。因此,其可使乳液稳定。在本发明的一些实施方案中,表面活性剂可包括:(聚氧乙烯山梨酸酯)家族的表面活性剂;(山梨聚糖长链羧酸酯)家族的表面活性剂;(环氧乙烷或环氧丙烷嵌段共聚物)家族的表面活性剂;及(聚乙二醇化的甘油酯)家族的表面活性剂;油酸、硬脂酸、月桂酸或其它长链羧酸的脱水山梨糖醇酯;泊洛沙姆(聚乙二醇-聚丙二醇嵌段共聚物或);其它山梨聚糖或蔗糖长链羧酸酯;甘油单酯及甘油二酯;辛酸/癸酸甘油三酯的PEG衍生物及其混合物,或以上中两者或两者以上的混合物。在一些实施方案中,表面活性剂相可包括聚氧乙烯(20)脱水山梨糖醇酐单油酸酯(Tween)与脱水山梨糖醇酐单油酸酯(Span)的混合物。水相可任选地包括悬浮于水中的活性剂及缓冲剂。
在一些实施方案中,这类乳液为粗乳液、微乳液及液晶乳液。在其它实施方案中,这类乳液可任选地包含渗透增强剂。在其它实施方案中,可使用含有胶囊包封的微乳液、粗乳液或液晶乳液的喷雾干燥分散体或微粒或纳米粒。
在一些实施方案中,本文中所描述的固体剂型为非肠道延时释放剂型。本文中所使用的术语“非肠道延时释放”是指这种递送,其使得可在肠道中的一些通常可预测的位置完成药物释放,如果不进行延迟释放修饰,则在到达所述位置的更远端位置处时已经完成了释放。在一些实施方案中,用于延迟释放的方法为包衣,其变得可渗透、溶解、破裂和/或在所设计的持续时间之后不再完整。
延时释放剂型中的包衣可具有固定的溶蚀时间,在所述固定的溶蚀时间后释放药物(合适的包衣包括聚合物包衣,例如HPMC等),或具有由以下组成的核心:超级崩解剂或渗透剂,例如盐、亲水聚合物(典型地聚环氧乙烷或烷基纤维素)、糖等,其透过膜或气体发生剂(例如柠檬酸和碳酸氢钠)吸取水。在膨胀压力在期望的延迟时间内超过某一阈值后,薄膜破裂。或者,可通过在期望的延迟时间内滤出含有药物的水性可提取物而使膜变成多孔的。延时剂型例如在禁食状态下给药,以避免进食状态下胃排空的变化。
在剂型中,肠溶衣或底衣都可用于延迟药物在目标区域中的释放。在其中肠溶衣提供在十二指肠、空肠、回肠或结肠、优选空肠或回肠中释放药物的剂型中,所述肠溶衣溶解的更加缓慢,从而该剂型可沿着肠进一步向下运送至预期的药物释放区域。可使用数种方法制成可用于使药物在小肠中靶向释放的肠溶衣的实例。一种方法是将不同种类的Eudragit与小比例的在较高pH下溶解的Eudragit结合,例如可将在pH 5.5下溶解的Eudragit与小比例的在pH 6或pH 7下溶解的Eudragit共混(97∶3至5∶1重量/重量)。或者,可在包衣中含有少量的酸,如柠檬酸或富马酸,以降低pH。另一方法是向肠溶衣中加入少许可溶解的聚合物,以延缓溶解。此外,可利用增塑剂、造孔剂的水平或包衣的厚度来改变肠溶衣的溶解速率。
当底衣提供延迟时,肠溶衣被设计成溶蚀得更快,例如,在10至30分钟内溶蚀。在十二指肠中溶解的肠溶衣的实例是1)在pH 5.5以上的pH下溶解的Eudragit L30-D-55和L100-55,和2)在pH 6下溶解的Eudragit L100和L12,5。然后,底衣如侵蚀性包衣、渗透泵或突发的渗透泵导致在目标区域中释放药物。底衣具有固定的溶蚀时间,在所述固定的溶蚀时间后释放药物(合适的包衣包括聚合物包衣如HPMC等),或者具有由以下组成的核心:超级崩解剂或渗透剂,如盐、亲水聚合物(典型地聚环氧乙烷或烷基纤维素)、糖等,其透过膜或气体发生剂(如柠檬酸和碳酸氢钠)吸取水。膨胀压力在期望的延迟时间内超过某一阈值之后,膜可能破裂。或者,通过在所需延迟时间内滤出水性可提取物,膜将变成多孔的。
给药
总体而言,本公开内容的化合物将以治疗有效的量给药。在本文中公开的化合物的治疗有效量可在300至约1克的范围内。本公开内容的化合物,即:化合物(I)的磺酸盐、化合物(I)的羧酸盐或化合物(I)的药学上可接受的盐的无定形形式以及上文所公开的其任何实施方案,其实际给药量将取决于多种因素,例如待治疗的疾病的严重性、哺乳动物的年龄和相对健康情况、所使用的化合物和/或其药学上可接受的盐的效力、给药途径和形式以及其它因素。
在本公开内容的化合物或其他药物具有效力的疾病或病症治疗中,本公开内容的化合物可与一种或多种其他药物组合使用,其中药物组合到一起比单独使用药物更安全或更有效。因此所述其他药物可通过一种途径以常规量与本公开内容的化合物同时或依序使用而给予。当本公开内容的化合物与一种或多种其它药物同时使用时,含有所述其它药物及本公开内容的化合物的单位剂型中的药物组合物是优选的。然而,组合疗法还可包括其中本公开内容的化合物与一种或多种其它药物以不同的重叠时间表给药的疗法。还可预期,当与一种或多种活性成分组合使用时,本公开内容的化合物及其它活性成分的剂量可以比各自单独使用时的剂量更少。
因此,除本公开内容的化合物之外,本公开内容的药物组合物还包括含有一种或多种其它活性成分的那些药物组合物。
上述组合不仅包括本公开内容的化合物与一种其它活性化合物的组合,还包括与两种或两种以上其它活性化合物的组合。同样地,本公开内容的化合物可与用于预防、治疗、控制、改善疾病或病况或降低疾病或病况的风险——本公开内容的化合物对所述疾病或病况而言是有用的——的其它药物组合使用。因此,所述其他药物可由本领域那些技术人员通过一种途径以常规量与本公开内容的化合物同时或依序使用而给药。当本公开内容的化合物与一种或多种其它药物同时使用时,除本公开内容的化合物外还含有所述其它药物的药物组合物是优选的。因此,除本公开内容的化合物之外,本发明的药物组合物还包括也含有一种或多种其它活性成分的那些药物组合物。本公开内容的化合物与第二活性成分的重量比可为多变的且将取决于每一成分的有效剂量。一般来说,将使用每一种成分的有效剂量。
在哺乳动物患有自身免疫疾病、炎性疾病或过敏性疾病或处于患有自身免疫疾病、炎性疾病或过敏性疾病的风险中的情况下,本公开内容的化合物可与以下治疗剂中的一种或多种以任意组合的方式一起使用:免疫抑制剂(例如,他克莫司、-45-iethylstilb、雷帕霉素、甲氨喋呤、环磷酰胺、咪唑硫嘌呤、巯基嘌呤、霉酚酸酯或FTY720);糖皮质激素(例如,强的松、乙酸可的松、强的松龙、甲基强的松龙、地塞米松、倍他米松、去炎松、倍氯米松、乙酸氟可的松、乙酸脱氧皮质酮、醛固酮);非甾体抗炎药(例如,水杨酸盐、芳基链烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、昔布类或磺苯胺);Cox-2-特异性抑制剂(例如,伐地考昔、塞来考昔或罗非考昔);来氟米特;硫代葡萄糖金;硫代苹果酸金;aurofin;柳氮磺胺吡啶;羟化氯喹;米诺环素;TNF-α结合蛋白(例如,英利昔单抗、依那西普或阿达木单抗);阿巴西普;阿那白滞素;干扰素-β;干扰素-γ;白介素-2;变态反应疫苗;抗组胺剂;抗白三烯;β-激动剂;茶碱和抗胆碱能药。
在哺乳动物患有B细胞增殖性病症(例如,浆细胞性骨髓瘤)或处于患有B细胞增殖性病症(例如,浆细胞性骨髓瘤)的风险中时,可以采用与一种或多种其它抗癌剂任意组合的本文所公开的化合物来治疗所述哺乳动物。在一些实施方案中,一种或多种抗癌剂为促凋亡剂。抗癌剂的实例包括但不限于以下中的任一者:棉酚、根纳三思(genasense)、多酚E、Chlorofusin、全反式视黄酸(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2′-脱氧胞苷、全反式视黄酸、多柔比星、长春新碱、依托泊苷、吉西他滨、伊马替尼(GleevecTM)、格尔德霉素、17-N-烯丙基氨基-17-脱甲氧基格尔德霉素(17-AAG)、黄酮吡醇(flavopiridol)、LY294002、硼替佐米、曲妥单抗、BAY 11-7082、PKC412或PD184352、TaxolTM(还被称作“紫杉醇”,其为通过增强及稳定微管形成起作用的著名抗癌药物),及多西紫杉醇例如TaxotereTM。具有基本紫杉烷骨架作为共有结构特征的化合物已经显示出具有通过稳定微管而抑制G2-M期细胞的能力,且可用于与本文中所描述的化合物组合以治疗癌症。
与本文所公开的化合物结合使用的抗癌剂的其他实例包含丝裂原活化蛋白激酶信号的抑制剂,例如,U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素或LY294002);Syk抑制剂;mTOR抑制剂;及抗体(例如,美罗华(rituxan))。
可与本文所公开的化合物组合使用的其它抗癌剂包括:阿霉素;更生霉素;博来霉素;长春花碱;顺铂;阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;二霉素;乙酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;氨茴霉素;天门冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;双奈法德二甲磺酸盐;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素C;二甲睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗里霉素;克拉屈滨;甲磺酸克立那托;环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;甲磺酸地扎胍宁;地吖醌;阿霉素;盐酸阿霉素;屈洛昔芬;枸橼酸屈洛昔芬;屈他雄丙酸酯;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺;盐酸法屈唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;II型介白素(包含重组白介素II或rIL2);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸伊立替康;乙酸兰瑞肽;来曲唑;乙酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索丙考;美登素;盐酸氮芥;乙酸甲地孕酮;乙酸美仑孕酮;苯丙氨酸氮芥;美诺立尔;巯基嘌呤;甲氨喋呤;甲氨喋呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托克星;丝裂红素;米托洁林;丝裂马菌素;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺加霉素;奥马铂;奥昔舒仑;培门冬酶;佩里霉素;奈莫司汀;硫酸匹来霉素;培磷酰胺;溴丙哌嗪;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;甲基丝裂霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;洛太米特;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;稀疏霉素;盐酸螺旋锗;螺莫司汀;螺铂;链黑菌素;链脲霉素;磺氯苯脲;他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫代鸟嘌呤;噻替派;噻唑呋林;替拉扎明;柠檬酸托瑞米芬;乙酸曲托龙;曲西立滨磷酸酯;三甲曲沙;葡醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸环氧长春碱;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春氮芥;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。
可与本文所公开的化合物和/或其药学上可接受盐组合使用的其它抗癌剂包括:20-表-1,25二羟维生维D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;酰基富烯;腺环戊醇;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;amidox;氨磷汀;氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯;抗背侧形态发生蛋白-1(anti-dorsalizing morphogenetic protein-1);抗雄激素;前列腺癌;抗雌激素;抗瘤酮;反义寡核苷酸;甘氨酸阿非科林;细胞凋亡基因调节剂;细胞凋亡调节剂;脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;奥沙那宁(asulacrine);阿他美坦;阿莫司汀;阿新那汀1(axinastatin 1);阿新那汀2(axinastatin2);阿新那汀3(axinastatin 3);阿扎司琼;阿扎霉素;重氮酪氨酸;浆果赤霉素III衍生物;balanol;巴马司他;BCR/ABL拮抗剂;benzochlorins;苯甲酰基星状孢子素;β内酰胺衍生物;β-阿勒欣(β-alethine);倍他克拉霉素B(betaclamycin B);桦木酸;bFGF抑制剂;比卡鲁胺;比生群;双吖啶基精素(bisaziridinylspermine);双奈法德;bistratene A;比折来新;breflate;溴匹立明;布度钛;丁硫氨酸硫酸亚胺;卡泊三醇;钙磷酸蛋白C(calphostinC);喜树碱衍生物;金丝雀痘IL-2;卡培他滨;甲酰胺-氨基-三唑;羧胺三唑;CaRest M3;CARN 700;软骨源性抑制剂(cartilage derived inhibitor);卡折来新;酪蛋白激酶抑制剂(ICOS);栗精胺;天蚕抗菌肽B;西曲瑞克;二氢卟酚(chlorlns);氯喹喔啉磺胺(chloroquinoxaline sulfonamide);西卡前列素;顺式卟啉;克拉屈滨;氯米芬类似物;克霉唑;碰撞霉素A(collismycin A);碰撞霉素B(collismycin B);考布他汀A4;考布他汀类似物;conagenin;crambescidin 816;克立那托;自念珠藻环肽8(cryptophycin 8);自念珠藻环肽A衍生物;curacin A;环戍蒽醌(cyclopentanthraquinones);cycloplatam;cypemycin;阿糖胞苷烷磷酯;细胞溶解因子;磷酸己烷雌酚;达昔单抗;地西他滨;脱氢膜海鞘素B(dehydrodidemnin B);地洛瑞林;地塞米松;右异环磷酰胺(dexifosfamide);右雷佐生;右维拉帕米;地吖醌;膜海鞘素B;didox;二乙基去甲精胺;二氢-5-氮杂胞苷;9-二氧霉素;二苯基螺莫司汀;二十二烷醇;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;多卡米星SA(duocarmycin SA);依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;磷酸依托泊苷;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;fmasteride;黄酮吡醇;氟卓斯汀;fluasterone;氟达拉滨;fluorodaunorunicin盐酸盐;福酚美克;福美司坦;福司曲星;福莫司汀;德卟啉钆(gadolinium texaphyrin);硝酸镓;加洛他滨;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;调蛋白;六亚甲基二乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;咪唑并吖啶酮;咪喹莫特;免疫刺激肽;胰岛素类生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素;碘苄胍;碘阿霉素;4-甘薯苦醇;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;片螺素-N三乙酸盐(lamellarin-N triacetate);兰瑞肽;leinamycin;来格司亭;香菇多糖硫酸酯;leptolstatin;来曲唑;白血病抑制因子;白细胞α干扰素;亮丙瑞林+雌激素+黄体酮;亮丙瑞林;左旋咪唑;利阿唑;线性多胺类似物;亲脂性二糖肽;亲脂性铂化合物;lissoclinamide 7;洛铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;得克萨菲啉镥(lutetium texaphyrin);lysofylline;溶解肽;美坦辛;制甘糖酶素A(mannostatin A);马立马司他;马索罗酚;乳腺丝氨酸蛋白酶抑制物;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;美巴龙(merbarone);美替瑞林;甲硫氨酸酶;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;丝裂毒素成纤维细胞生长因子-皂草素(mitotoxin fibroblast growth factor-saporin);米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体;人绒毛膜促性腺激素;单磷酰脂质A+-48-iethylstilb细胞壁sk;莫哌达醇;多药耐药性基因抑制剂;基于多肿瘤抑制基因1的治疗;氮芥抗癌剂;印度洋海绵B(mycaperoxide B);分枝杆菌细胞壁提取物;myriaporone;N-乙酰基地那林;N-取代的苯甲酰胺;那法瑞林;nagrestip;纳洛酮+喷他佐辛;napavin;naphterpin;那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;nisamycin;一氧化氮调节剂;硝基氧抗氧化剂;nitrullyn;O6-苄基鸟嘌呤;奥曲肽;okicenone;寡核苷酸;奥那司酮;昂丹司琼;昂丹司琼;oracin;口服细胞因子诱导剂;奥马铂;奥沙特隆;奥沙利铂;oxaunomycin;帕劳胺(palauamine);棕榈酰根霉素;帕米膦酸;人参三醇;帕诺米芬;副细菌素(parabactin);帕折普汀;培门冬酶;培得星;戊聚硫钠;喷司他丁;pentrozole;全氟溴烷;培磷酰胺;紫苏醇;苯连氮霉素(phenazinomycin);乙酸苯酯;磷酸酶抑制剂;毕西巴尼;盐酸毛果芸香碱;吡柔比星;吡曲克辛;placetin A;placetin B;纤溶酶原激活物抑制剂;铂络合物;铂化合物;铂-三胺络合物;卟吩姆钠;泊非霉素;强的松;丙基二-吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;蛋白激酶C抑制剂;微藻(microalgal);蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素;吡唑啉吖啶;吡醇羟乙酯化血红蛋白聚氧化乙烯缀合物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法尼基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基瑞替普汀;依替膦酸铼Re186(rhenium Re 186etidronate);根霉素;核酶;R.sub.11维甲酰胺(R.sub.11 retinamide);罗谷亚胺;罗希吐碱(rohitukine);罗莫肽;罗喹美克;rubiginone B1;ruboxyl;沙芬戈;saintopin;SarCNU;肌植醇A;沙格司亭;Sdi 1模拟物;司莫司汀;衰老衍生的1(senescence derived 1);有义寡核苷酸;信号转导调节剂;信号转导调节剂;单链抗原结合蛋白;sizofuran;索布佐生;硼卡钠;苯基乙酸钠;solverol;生长调节素结合蛋白;索纳明;膦门冬酸;螺旋霉素D(spicamycin D);螺莫司汀;斯耐潘定(splenopentin);海绵素1(spongistatin 1);角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素抑制剂;sulfinosine;超活性血管活性肠肽拮抗剂;suradista;苏拉明;苦马豆素;合成的葡糖氨基聚糖;他莫司汀;他莫西芬甲硫碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;tellurapyrylium;端粒酶抑制剂;替莫泊芬;替莫唑胺;替尼泊苷;四氯癸烷氧化物;tetrazomine;菌体胚素;噻可拉林;血小板生成素;血小板生成素模拟物;胸腺法新;促胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;乙基本紫红素锡(tin ethyl etiopurpurin);替拉扎明;环戊二烯钛二氯化物(titanocene bichloride);topsentin;托瑞米芬;全能干细胞因子;翻译抑制剂;维A酸;三乙酰基尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂;UBC抑制剂;乌苯美司;泌尿生殖窦-衍生的生长抑制因子;尿激酶受体拮抗剂;伐普肽;variolin B;载体系统;红细胞基因治疗;维拉雷琐;藜芦明;verdins;维替泊芬;长春瑞滨;vinxaltine;vitaxin;伏氯唑;扎诺特隆;折尼铂;亚苄维C(2H)(zilascorb);及净司他丁斯酯。
还可与本文所公开的化合物组合使用的其它抗癌剂包括烷化剂;抗代谢物;天然产物;或激素,例如氮芥类(例如,氮芥、环磷酰胺、苯丁酸氮芥等);烷基磺酸盐(例如,白消安);亚硝基脲(例如,卡莫司汀、环己亚硝脲等);或三氮烯(达卡巴嗪等)。抗代谢物的实例包含但不限于叶酸类似物(例如,甲氨喋呤)、或嘧啶类似物(例如,阿糖胞苷)、嘌呤类似物(例如,巯嘌呤、硫鸟嘌呤、喷司他丁)。
与本文所公开的化合物组合使用的天然产物的实例包含但不限于长春花生物碱类(例如,-50-iethylstilb、长春新碱)、表鬼臼毒素(例如,依托泊苷)、抗生素(例如,柔红霉素、多柔比星、博来霉素)、酶(例如,左旋天冬酰胺酶),或生物应答调节剂(例如,干扰素α)。
可与本文所公开的化合物组合使用的烷化剂的实例包括但不限于:氮芥类(例如,氮芥、环磷酰胺、苯丁酸氮芥、美法仑等)、乙烯亚胺及甲基蜜胺(例如,六甲蜜胺、噻替派)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、环己亚硝脲、司莫司汀、链脲霉素等),或三氮烯(达卡巴嗪等)。抗代谢物的实例包括但不限于:叶酸类似物(例如,甲氨喋呤)、或嘧啶类似物(例如,氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(例如,巯嘌呤、硫鸟嘌呤、喷司他丁)。
与本文所公开的化合物组合使用的激素及拮抗剂的实例包括但不限于:肾上腺皮质类固醇类(例如,强的松)、孕激素(例如,己酸羟孕酮、醋酸甲地孕酮、醋酸甲羟孕酮)、雌激素(例如,己烯雌酚、乙炔雌二醇)、抗雌激素(例如,它莫西芬)、雄激素(例如,丙酸睾酮、氟甲睾酮)、抗雄激素(例如,氟他胺)、促性腺激素释放激素类似物(例如,亮丙瑞林)。可用于本文所描述的治疗或预防癌症的方法和组合物的其它试剂包括铂配位络合物(例如,顺铂、卡铂)、蒽二酮(例如,米托蒽醌)、取代的脲(例如,羟基脲)、甲肼衍生物(例如,丙卡巴肼)、肾上腺皮质遏抑剂(例如,米托坦、氨鲁米特)。
通过稳定微管而将细胞阻滞在G2-M阶段的且可与本公开内容的化合物组合使用的抗癌剂的实例包括但不限于以下上市的药物及开发中的药物:厄布洛唑(也称为R-55104);多拉司他汀10(也称为DLS-10和NSC-376128);羟乙基磺酸米伏布林(也称为CI-980);长春新碱;NSC-639829;圆皮海绵内酯(Discodermolide)(也称为NVP-XX-A-296);ABT-751(Abbott,也称为E-7010);阿托海汀(Altorhyrtins)(例如阿托海汀A和阿托海汀C);海绵抑制素(Spongistatins)(例如海绵抑制素1、海绵抑制素2、海绵抑制素3、海绵抑制素4、海绵抑制素5、海绵抑制素6、海绵抑制素7、海绵抑制素8和海绵抑制素9);盐酸西马多丁(也称为LU-103793和NSC-D-669356);埃博霉素类(例如埃博霉素A、埃博霉素B、埃博霉素C(也称为脱氧埃博霉素A或dEpoA)、埃博霉素D(也称为KOS-862、dEpoB和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素B N-氧化物、埃博霉素A N-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(也称为BMS-310705)、21-羟基埃博霉素D(也称为脱氧埃博霉素F和dEpoF)、26-氟代埃博霉素);阿里他汀PE(Auristatin)(也称为NSC-654663);索利多丁(也称为TZT-1027);LS-4559-P(法玛西亚(Pharmacia),也称为LS-4577);LS-4578(法玛西亚,也称为LS-477-P);LS-4477(法玛西亚);LS-4559(法玛西亚);RPR-112378(安内特(Aventis));硫酸长春新碱;DZ-3358(Daiichi);FR-182877(藤泽(Fujisawa);也称为WS-9885B);GS-164(武田制药(Takeda));GS-198(武田制药);KAR-2(匈牙利科学院(HungarianAcademy of Sciences));BSF-223651(BASF,也称为ILX-651和LU-223651);SAH-49960(Lilly/Novartis);SDZ-268970(Lilly/Novartis);AM-97(Armad/Kyowa Hakko);AM-132(Armad);AM-138(Armad/Kyowa Hakko);IDN-5005(Indena);Cryptophycin 52(也称为LY-355703);AC-7739(味之素(Ajinomoto),也称为AVE-8063A和CS-39.HCI);AC-7700(味之素,也称为AVE-8062、AVE-8062A、CS-39-L-Ser.HCI和RPR-258062A);Vitilevuamide;Tubulysin A;Canadensol;矢车菊黄素(也称为NSC-106969);T-138067(Tularik,也称为T-67、TL-138067和TI-138067);COBRA-1(休斯研究院(Parker Hughes Institute),也称为DDE-261和WHI-261)、H10(堪萨斯州立大学(Kansas StateUniversity));H16(堪萨斯州立大学);Oncocidin A1(也称为BTO-956和DIME);DDE-313(休斯研究院);Fijianolide B;Laulimalide;SPA-2(休斯研究院);SPA-1(休斯研究院,也称为SPIKET-P);3-IAABU(细胞骨架/西奈山医学院(Cytoskeleton/Mt.Sinai School of Medicine),也称为MF-569);那可丁(也称为NSC-5366);Nascapine;D-24851(Asta Medica);A-105972(雅培(Abbott));Hemiasterlin;3-BAABU(细胞骨架/西奈山医学院,也称为MF-191);TMPN(亚利桑那州立大学(Arizona State University));乙酸丙酮二茂钒(Vanadocene acetylacetonate);T-138026(Tularik);Monsatrol、lnanocine(也称为NSC-698666);3-1AABE(细胞骨架/西奈山医学院);A-204197(雅培);T-607(Tuiarik,也称为T-900607);RPR-115781(安内特);软珊瑚醇(Eleutherobins)(例如去甲软珊瑚醇(Desmethyleleutherobin)、去乙酰软珊瑚醇(Desaetyleleutherobin)、异软珊瑚醇A(Isoeleutherobin A)和Z-软珊瑚醇);Caribaeoside;Caribaeolin;软海绵素B;D-64131(Asta Medica);D-68144(Asta Medica);含氯环肽A(Diazonamide A);A-293620(雅培);NPI-2350(Nereus);箭根薯酮内酯A(Taccalonolide A);TUB-245(安内特);A-259754(雅培);Diozostatin;(-)-Phenylahistin(也称为NSCL-96F037);D-68838(Asta Medica);D-68836(Asta Medica);肌基质蛋白(Myoseverin)B;D-43411(Zentaris,也称为D-81862);A-289099(雅培);A-318315(雅培);HTl-286(也称为SPA-110,三氟乙酸盐)(惠氏公司(Wyeth));D-82317(Zentaris);D-82318(Zentaris);SC-12983(NCI);瑞伐斯他汀磷酸钠(Resverastatin phosphatesodium);BPR-OY-007(国家卫生研究院(National Health Research Institutes))和SSR-250411(赛诺菲(Sanofi))。
在哺乳动物正患有血栓栓塞性疾病(例如,中风)或处于患有血栓栓塞性疾病(例如,中风)的风险中的情况下,可以用本文公开的化合物与一种或多种其它抗血栓栓塞剂任意组合来治疗该哺乳动物。抗血栓栓塞剂的实例包括但不限于以下任一者:血栓溶解剂(例如,阿替普酶、阿尼普酶、链激酶、尿激酶或组织型纤溶酶原激活物);肝素;亭扎肝素;华法林;达比加群(例如,达比加群酯);Xa因子抑制剂(例如,磺达肝素、draparinux、利伐沙班、DX-9065a、奥米沙班、LY517717或YM150);噻氯匹定;氯吡格雷;CS-747(普拉格雷、LY640315);希美加群或BIBR1048。
实施例
以下实施例说明了在本发明范围内的组合物的制备。提供这些组合物是为了使本领域那些技术人员能够更清楚地理解并实践本发明。不应将它们理解成是对本发明的范围的限制,而仅作为其说明和代表。
实施例
分析方法
1H-NMR实验在Bruker AV400(1H频率:400MHz)上进行。每个样品的1H-NMR实验在DMSO-d6或CDCl3中进行,并且将每个样品制备为约5mg/mL浓度。
离子色谱法在配备有带AG11-HC保护柱的Dionex Ionpac AS11-HC 4×250mm柱的Dioned ICS-3000离子色谱仪上在30℃下以1.5ml/min实施。洗脱液为5mM NaOH。使用电导率检测器检测离子。
XRPD分析在Siemens D5000衍射仪上使用Cu K-α辐射源在3至30°2-θ之间扫描样品(当分析输入的材料时,在3至30°2-θ之间)进行。将样品轻轻按压到插入XRPD试样架内的玻璃盘上。然后将样品装载到以反射模式运行的衍射仪内,并进行分析。
实施例1
(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈中E异构体和Z异构体比例的测定
高效液相色谱法(HPLC)在配备有柱加热器、梯度洗脱能力、自动进样器和UV检测器的Agilent 1100上实施。所述柱为在40℃下的Zorbax SB-Phenyl,洗脱液为含0.1%甲磺酸的水/甲醇梯度和在225nm处的UV检测。总运行时间为8分钟。使用以下梯度(A是水,B是甲醇):
盐形成
实施例2
E/Z比为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的半硫酸盐和硫酸盐的制备
半硫酸盐:
在环境温度下,向(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)(4.2g)于EtOAc(60mL,15体积)中的溶液中加入硫酸(0.31g,0.17mL,0.5当量)于EtOAc(20mL,5体积)中的溶液。将悬浮液在环境温度下搅拌~2小时,然后在40℃下搅拌4小时,然后在环境温度下搅拌至少1小时。在环境温度下在真空下过滤并干燥后,获得1.5g白色粉末。在环境温度下半硫酸盐在水中的溶解度为>100mg/mL。
硫酸盐
在环境温度下,向(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)(810mg)于EtOAc(8mL,10体积)中的溶液中加入硫酸(0.06mL,1.0当量)于EtOAc(2.5mL,5体积)中的溶液。将得到的悬浮液在40℃下搅拌2小时,然后冷却至环境温度保持至少1小时。过滤之后,通过在氩下抽吸1小时而将固体干燥,获得白色粉末(0.68g),收率69%。
盐形式 | 溶剂 | XRD |
H<sub>2</sub>SO<sub>4</sub> | EtOAc | 无定形 |
0.5H<sub>2</sub>SO<sub>4</sub> | EtOAc | 无定形 |
实施例3
E/Z比为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈盐酸盐的制备
在环境温度下,向(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)(100mg,0.15mmol)于CH2Cl2(1ml)中的溶液中加入2当量HCl(0.3mmol,0.15ml于1∶1的二噁烷∶CH2CI2中的2M HCl)。将所得均一溶液在环境温度下搅拌1小时,并逐滴加入15体积的乙酸乙酯(相对于CH2CI2),导致形成白色固体。将混合物在环境温度下熟化1h,并在2-8℃下放置19小时。经过滤以及用乙酸乙酯洗涤滤饼并干燥,获得白色固体。XRPD分析表明形成了无定形固体。1H-NMR和IC分析均表明形成了盐。IC表明形成了单HCl盐。
盐形式 | 溶剂 | 抗溶剂 | XRPD |
HCl | CH<sub>2</sub>Cl<sub>2</sub> | EtOAc | 无定形 |
实施例4
用于制备E/Z比为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的单-和二-甲磺酸盐的一般步骤
在环境温度下,向(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)(100mg,0.15mmol)于CH2Cl2(1ml)中的溶液中加入1当量甲磺酸(0.15mmol,0.2ml于CH2Cl2中的74mg/ml溶液)或2当量甲磺酸(0.3mmol,0.4ml于CH2Cl2中的74mg/ml溶液)。将所得均一溶液在环境温度下搅拌1小时,并逐滴加入10体积的抗溶剂(乙酸乙酯、甲基叔丁基醚(MTBE)或环己烷)(10ml,相对于CH2Cl2),导致形成白色固体。将混合物在环境温度下熟化1h,并在2-8℃下放置19小时。经过滤以及用抗溶剂洗涤滤饼并干燥后,获得白色固体。XRPD分析表明形成无定形固体。1H-NMR和IC分析均表明除了抗衡离子的比例之外还形成了盐。
或者,可将(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)溶解在4体积的乙酸异丙酯中,并在0℃下添加至2当量的甲磺酸于6体积乙酸异丙酯中的溶液中,以生成二甲磺酸盐。
1.理论上的甲磺酸盐含量,甲磺酸盐=12.6%,二甲磺酸盐=22.4%,ND=未测定
实施例5
用于制备E/Z比为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的羧酸盐的一般步骤
将约20mg(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)溶解在最小量的分配的溶剂体系中。然后将这些与适当当量数的在分配的溶剂中溶解或浆化的抗衡离子混合。
如果上文的化合物在所选的溶剂中不可溶,则使用加入300μL后的样品的浆体。
如果酸在所选的溶剂中不可溶,则使用加入300μL后的酸的浆料。
如果酸是液体,则将酸加入到溶解/浆化的化合物(I)中,所述溶解/浆化的化合物(I)来自于分配的溶剂中的储备溶液。
使从上述化合物的混合物中产生的悬浮液/沉淀物在环境温度(约22℃)和40℃之间以4小时循环进行温度循环,进行约48小时(每4小时周期后冷却/加热速率为约1℃/min)。目视检查混合物,将任何存在的固体分离出来,并在环境条件下干燥,然后进行分析。当不存在固体时,允许样品在环境温度下蒸发。在上述处理之后,在环境条件(约22℃)下将制备无定形材料的样品重新溶解,然后使用抗溶剂(叔丁基甲基醚)添加法进行沉淀,即:将所选的抗溶剂加入每种溶液中,直到目视观察不到进一步沉淀或直到无法加入更多的抗溶剂。在该制备中使用的溶剂是乙腈、丙酮、乙酸异丙酯、THF和MTBE。所使用的酸是草酸、L-天冬氨酸、马来酸、丙二酸、L-酒石酸和富马酸。
实施例6
用于制备E/Z比为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的半柠檬酸盐的一般步骤
向(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(E/Z比为约9/1)(5g,7.5mmol)于乙醇(50ml)中的溶液中加入溶解于2ml水中的柠檬酸(720.5mg,3.76mmol)。将混合物在环境温度下搅拌15min,再加入0.5ml水,并将混合物搅拌1小时,真空浓缩至胶质。加入乙醇并将混合物浓缩。将该过程再重复两次,然后向混合物中加入CH2Cl2。经浓缩,获得白色固体,将所述白色固体在减压下在40℃下滚筒干燥4小时,然后在真空烘箱中干燥19小时,获得5.4g固体。XRD分析表明形成无定形固体。
实施例7
用于回肠-空肠递送的渗透压激活的剂型
使用以下成分用于制备化合物(I)的回肠-空肠剂型:
测量用于每个核心层的共混物的大小并进行干混,最后添加润滑剂并进行额外的混合。将2种共混物通过常规压片技术在旋转双层压片机上压片。也可任选地向未包衣的核心施用羟丙甲纤维素溶液的预包衣。将用于片剂的共混物在压片机中层压,并以单次压缩压制成片剂。
使用螺旋桨式混合器将半透膜的成分加入到二氯甲烷∶甲醇(4∶1重量/重量)溶液中。将未包衣的片剂喷雾包衣并干燥。
然后将这些包衣的片剂采用水溶液进行不同程度的肠溶包衣,直到片剂在酸性介质中抵抗释放达2小时,通常重量增加量为6%至15%,包衣厚度为约50至约150微米。
实施例8
用于回肠-空肠递送的肠溶包衣片剂
首先为每种包衣的片剂测量200mg化合物(I),然后将其与7mg交联羧甲基纤维素钠和143mg微晶纤维素(PH 101)在V-混合器中干混20至30分钟。随后,加入5mg硬脂酰富马酸钠作为润滑剂并共混4至5分钟。将该共混物在旋转压片机上使用5/16”标准凹形冲头进行压片。由250gL-30 D-55、7.5g柠檬酸三乙酯、37.5g滑石和205g去离子水制备包衣混合物。将片剂核心放置在40℃下在15rpm下旋转的带孔盘的包衣锅(perforated pan coater)中。将该混合物喷雾,其中进气温度为44至48℃,排气温度为29至32℃,产品温度为26℃,在30至32rpm下旋转,喷雾压力为20psi,以及气流为30-32CFM。采用60℃的进气温度在15rpm下旋转固化30分钟之后,关闭加热,然后将片剂在旋转的同时冷却至环境温度。包衣后,重量增加量为约5%至约15%,通常为约10%。在pH 6.8下肠溶衣的溶出时间目标为在1小时内大于80%。
实施例9
肠溶包衣的颗粒
纳入粒径范围为300至500微米的肠溶包衣的颗粒,以将其包封在胶囊(明胶胶囊或羟丙甲纤维素胶囊)、小药囊或棒包装(stickpacks)、或口服悬浮液中。测量化合物(I)和低粘度羟丙甲纤维素(约2%)并在V型混合器中混合,然后加入到流化床造粒机中。通过向粉末上喷雾聚乙烯吡咯烷酮的稀水性溶液而形成颗粒,然后在45℃下在流化床中干燥所述颗粒。然后在流化床中,将这些干燥的颗粒用Clear于水中的溶液包衣,以提供密封包衣,并干燥。将作为30%聚合物、0.7%月桂基磺酸钠和2.3%20的水分散体的L-30 D-55与增塑剂柠檬酸三乙酯和单硬脂酸甘油酯组合,并在流化床中将它们包覆在粉末上。干燥之后,最终的肠溶包衣颗粒的组成为约81.8%活性成分、约1.5%羟丙甲纤维素、约0.5%Opadry Clear、约14.5%甲基丙烯酸共聚物、1.45%柠檬酸三乙酯和0.25%单硬脂酸甘油酯。将经干燥颗粒填充到0号羟丙甲纤维素胶囊中。在pH 2下,胶囊崩解,颗粒从胶囊中释放,但在2小时时释放不到2%的药物至溶液中。
实施例10
肠溶包衣珠粒中的药物
将1kg药物和0.1kg滑石在V型混合器中共混15分钟。然后研磨并筛分以得到细粉。采用于水中的10%(w/v)PVP制备粘合剂溶液。然后向包衣锅中装入1kg惰性糖球(20至50目)。然后采用粘合剂溶液喷洒糖球,并将药物共混物施用于所述球上,直至耗尽所有药物。然后将载药的珠粒在流化床干燥器中干燥。
向流化床包衣机中装入1kg上述载药珠粒。然后采用1kg实施例1的包衣溶液包覆所述珠粒,然后干燥。在包衣工艺期间可使用滑石来降低粘性。
实施例11
E/Z异构体比例为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈在大鼠中的回肠-空肠给药
将化合物(I)以10mg/mL的柠檬酸水溶液的形式以20mg/kg的剂量给予Wister-Hans大鼠。将化合物(I)的游离碱溶于柠檬酸水溶液(含有0.5当量的无水柠檬酸)中。该实验重复3次,每次采用2个独立的组,且每次研究中包括一个口服(PO)管饲组。在插管的大鼠中进行空肠(IJ)和十二指肠内(ID)给药。在第一次研究中,与PO组相比,IJ给药组使AUC增加了约40倍,在PO组中存在的主要代谢物在IJ组中减少了20倍。
实施例12
在尤斯室(Ussing Chambers)中穿过大鼠不同肠区域的体外渗透
试剂:制备由1.26M NaCl(Promega,Madison,WI)、25mM KCl、250mM NaHCO3、12mMNaH2PO4、12mM MgCl2、25mM CaCl2和18g/L D-葡萄糖(均来自Sigma Aldrich,St.Louis,MO)组成的10X Krebs-Ringer缓冲液(KRB),并将其单独储存以防止结晶。使用前稀释至1X工作浓度,并调节pH:采用卡波金(carbogen)灌注20分钟而调节至pH 7.4(充了氧的KRB)或采用1M HCl(Alfar Aesar,Ward Hill,MA)调节至pH 3.5、6.5或7.4。0.1%苯酚红、安替比林和阿替洛尔购自Sigma Aldrich,St.Louis,MO。
肠道组织的采集和制备:实验前,使4至9月龄的成年雌性未配种Sprague-Drawley大鼠(Harlan Laboratories,Livermore,CA)在室内适应至少3天。应避免使用青春期动物和老年动物,以防止胃肠形态和功能方面的年龄-相关的差异。按照IACUC批准的饲养方案饲养动物,包括12小时光照和12小时黑暗的循环,允许自由进食标准食物和水。组织采集应一次在一只动物上实施,以保持组织活力。一次一只,在缓慢充满了10%(v/v)/min二氧化碳的密封气室中,将大鼠麻醉约3-5分钟或直到完全镇静——这由对掐捏脚尖缺乏反应和缺乏浅呼吸来证明——以使鼻粘膜的痛苦最小化。然后,通过颈椎脱位使大鼠迅速安乐死。
使用改进的文献方案(DI Kosik-Bogacka等人,(2011)“The effect of L-ascorbic acid and/or tocopherol supplementation on electrophysiologicalparameters of the colon of rats chronically exposed to lead”Med.Sci.Monit.2011 17(1):BR16-26)。实施中线切口以暴露腹腔。将从胃到升结肠这段胃肠组织以一片一片的形式切割下来,并置于盛满了pH7.4的冰冷的充氧的KRB的预冷解剖盘中。将组织快速移入新鲜的盛满了pH7.4的冰冷KRB的解剖盘中,并用卡波金气体(95%O2、5%CO2)(CryoSpec,South San Francisco,CA)连续鼓泡。然后根据图表用解剖刀分离肠的不同区段。胃占约1.5英寸,十二指肠约2英寸,空肠约8-10英寸,回肠约1英寸以及升结肠约1英寸。
然后将每个管状区段沿着肠系膜边界纵向切割,露出管腔表面。将肠内容物仔细地轻轻地冲洗掉,小心不要扰乱管腔的表面。将每个区段进一步切割成测量为约8mm×10mm的更小的片段,轻轻拉伸并安装在有效表面积为0.49cm2的一半垂直扩散尤斯室(Navicyte,Harvard Apparatus Inc.,Holliston,MA)的针上。在与所述室的第二半结合之前,目视检查已安装的区段的撕扯情况。立即用5ml生理pH匹配的KRB填满所述室(粘膜室:胃pH 3.5,十二指肠pH 6.5,空肠pH 6.5,回肠pH 7.4,结肠pH 6.5;绒膜室:所有部分均为pH 7.4)。将各个完整的尤斯室组件串联安装在保持在37℃下的热循环加热块上,并连接至以3-5个气泡/秒的速率连续喷射卡波金气体的气体歧管。将酚红(10μL,0.1%)加入到每个粘膜室中以检查pH平衡和组织中微观撕裂的证据。
实验方案:首先将E/Z比为约9/1的(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈(实验样品和对照样品)制成于100%DMSO中的10mM储备液。实验大纲根据(S.Haslam等人,“Intestinal Ciprofloxacin Efflux:The Role of Breast Cancer ResistanceProtein(ABCG2)”Drug Met.Disp.2011 39(12):2321-28)进行。简而言之,然后除去相同体积的KRB,并用所述体积的每种化合物代替,以获得100μM的起始浓度。在每个实验中都包含安替比林和阿替洛尔作为内参对照品,这样每个实验中最多总共5种化合物(包括参照对照品)。在t=0和t=150分钟时,从粘膜室取出样品(100μL),同时在t=30、60、90和150分钟时,从绒膜室取出100μl样品。将样品置于96孔板中,在-80℃下冷冻以用于RapidFire-LC-MS/MS分析。表观渗透性Papp表示为Papp=(dQ/dt)(1/(A.C0)),其中dQ/dt是从粘膜室到绒膜室的转运速率,A为组织的有效表面积,C0为初始粘膜浓度(A.Sjoberg等人,“Comprehensive study on regional human intestinal permeability and predictionof fraction absorbed of drugs using the Ussing chamber technique”Eur.JPharm.Sci.201348:166-180)。
上述化合物的结果示于图7中。与胃或十二指肠相比,胃肠道远端区域通常具有增加的渗透性,特别地,从统计学上看,在空肠、回肠和结肠区域中上述化合物的渗透性增加。
实施例13
溶出试验
根据美国药典第711节(http://www.pharmacopeia.cn/v29240/usp29 nf24s0_c711h.html),使用配有沉降篮替代物2A的装置2(桨速为75r pm)进行溶出试验。在37℃(±0.5℃)下测试含有900mL酸(pH 2或3)和pH 6.8的两种浴。为了研究向回肠的递送,也可实施在pH 7.4下的溶出。如果溶出试验在pH 6以上的范围内进行,则必须向介质中加入添加剂(如表面活性剂或环糊精),以溶解化合物(I)并确保沉降状态。
Claims (46)
1.一种固体口服剂型,其为片剂或胶囊,包括:
(A)核心材料,其包含(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)异构体、(Z)异构体或(E)和(Z)异构体混合物;(S)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)异构体、(Z)异构体或(E)和(Z)异构体混合物;或2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)异构体和(S)异构体的混合物的(E)异构体、(Z)异构体或(E)和(Z)异构体混合物(化合物(I)),其具有以下结构:
其中*C是立体化学中心;
和/或其药学上可接受的盐;
(B)肠溶衣;
(C)在肠溶衣下面的底衣,其中所述底衣:
(1)是水溶性或亲水的可蚀性聚合物,所述聚合物是低分子量聚合物,其选自微晶纤维素、聚乙烯吡咯烷酮、多糖、多糖衍生物、聚乙烯醇、聚乙二醇(PEG)、聚丙二醇(PPG)、PEG-PPG嵌段共聚物;或
(2)包含水不溶性组合物,所述水不溶性组合物包含(i)能够在水不溶性组合物中形成通道的水溶性化合物的颗粒,或(ii)在与水性介质接触时导致所述底衣膨胀的水不溶性亲水颗粒;以及
(D)药学上可接受的赋形剂;
其中所述固体口服剂型在给药后在哺乳动物的肠的空肠-回肠部位开始释放化合物(I)和/或其药学上可接受的盐;并且
其中在盛有pH为6.4至7.4的水溶液的溶出容器中,在120分钟内,所述固体口服剂型能够释放至少80%的化合物(I)和/或其药学上可接受的盐。
2.权利要求1所述的固体口服剂型,其中所述多糖衍生物为羟甲基纤维素、羟丙基甲基纤维素(HPMC)、羟乙基纤维素或羟丙基纤维素。
3.权利要求1所述的固体口服剂型,其中在盛有pH小于3或pH为4.5至5.0的水溶液的溶出容器中,在1.5小时内,所述固体口服剂型能够释放小于10重量%的化合物(I)和/或其药学上可接受的盐;并且在盛有pH为6.4至7.4的水溶液的溶出容器中,在20分钟至2小时内,所述固体口服剂型能够释放不少于80重量%的化合物(I)和/或其药学上可接受的盐。
4.权利要求1所述的固体口服剂型,其中所述底衣(C)包含水不溶性组合物,所述水不溶性组合物包含水溶性化合物的颗粒。
5.权利要求3所述的固体口服剂型,其中所述底衣(C)包含水不溶性组合物,所述水不溶性组合物包含水溶性化合物的颗粒。
6.权利要求1所述的固体口服剂型,其中所述底衣(C)包含水不溶性组合物,所述水不溶性组合物包含在与水性介质接触时导致所述底衣膨胀的水不溶性亲水颗粒。
7.权利要求3所述的固体口服剂型,其中所述底衣(C)包含水不溶性组合物,所述水不溶性组合物包含在与水性介质接触时导致所述底衣膨胀的水不溶性亲水颗粒。
8.权利要求1所述的固体口服剂型,其中所述底衣(C)为包含水溶性化合物的颗粒的水不溶性组合物,所述水溶性化合物能够在水不溶性组合物中形成通道从而导致水流入所述固体口服剂型中以及化合物(I)和/或其药学上可接受的盐扩散到肠中。
9.权利要求3所述的固体口服剂型,其中所述底衣(C)为包含水溶性化合物的颗粒的水不溶性组合物,所述水溶性化合物能够在水不溶性组合物中形成通道从而导致水流入所述固体口服剂型中以及化合物(I)和/或其药学上可接受的盐扩散到肠中。
10.权利要求1所述的固体口服剂型,其中所述底衣(C)为包含水溶性化合物的颗粒的水不溶性组合物,所述水溶性化合物能够形成不可渗透化合物(I)和/或其药学上可接受的盐的通道,但所述通道允许水进入,使得所述底衣膨胀和破裂并导致化合物(I)和/或其药学上可接受的盐的释放。
11.权利要求3所述的固体口服剂型,其中所述底衣(C)为包含水溶性化合物的颗粒的水不溶性组合物,所述水溶性化合物能够形成不可渗透化合物(I)和/或其药学上可接受的盐的通道,但所述通道允许水进入,使得所述底衣膨胀和破裂并导致化合物(I)和/或其药学上可接受的盐的释放。
12.权利要求1-11中任一项所述的固体口服剂型,其中:
(a)所述水溶液为pH为6.4至7.4的模拟肠液;和/或
(b)所述固体口服剂型包括化合物(I)的药学上可接受的盐;和/或
(c)所述核心材料(A)还包含药学上可接受的酸,其中在化合物(I)和/或其药学上可接受的盐从所述固体口服剂型中释放之前,所述药学上可接受的酸的量在所述固体口服剂型内形成酸性水溶液;和/或
(d)所述核心材料(A)还包含表面活性剂,所述表面活性剂的浓度高于其在50mL水性介质中崩解时的临界胶束浓度;和/或
(e)化合物(I)和/或其药学上可接受的盐的平均粒径为0.3微米至100微米。
13.权利要求1-11中任一项所述的固体口服剂型,其中所述肠溶衣(B):
(a)为所述固体口服 剂型的重量的30%至60%;和/或
(b)厚度为5至500微米;和/或
(c)选自聚合的明胶、虫胶、甲基丙烯酸共聚物型CNF、邻苯二甲酸丁酸纤维素、邻苯二甲酸氢纤维素、邻苯二甲酸丙酸纤维素、聚乙酸乙烯邻苯二甲酸酯(PVAP)、邻苯二甲酸乙酸纤维素(CAP)、乙酸纤维素偏苯三酸醋(CAT)、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯、二氧丙基甲基纤维素琥珀酸酯、羧甲基乙基纤维素(CMEC)、乙酸羟丙基甲基纤维素酯琥珀酸酯(HPMCAS)以及(甲基)丙烯酸聚合物和共聚物,其中所述聚合物由一种单体制成,所述共聚物由两种或更多种单体制成,其中所述单体选自丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸乙酯;和/或
(d)包含纤维素衍生物;和/或
(e)包含聚乙酸乙烯邻苯二甲酸酯(PVAP)聚合物。
14.权利要求12所述的固体口服剂型,其中所述肠溶衣(B):
(a)为所述固体口服 剂型的重量的30%至60%;和/或
(b)厚度为5至500微米;和/或
(c)选自聚合的明胶、虫胶、甲基丙烯酸共聚物型CNF、邻苯二甲酸丁酸纤维素、邻苯二甲酸氢纤维素、邻苯二甲酸丙酸纤维素、聚乙酸乙烯邻苯二甲酸酯(PVAP)、邻苯二甲酸乙酸纤维素(CAP)、乙酸纤维素偏苯三酸醋(CAT)、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸酯、二氧丙基甲基纤维素琥珀酸酯、羧甲基乙基纤维素(CMEC)、乙酸羟丙基甲基纤维素酯琥珀酸酯(HPMCAS)以及(甲基)丙烯酸聚合物和共聚物,其中所述聚合物由一种单体制成,所述共聚物由两种或更多种单体制成,其中所述单体选自丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸乙酯;和/或
(d)包含纤维素衍生物;和/或
(e)包含聚乙酸乙烯邻苯二甲酸酯(PVAP)聚合物。
15.权利要求13所述的固体口服剂型,其中在(c)中,所述肠溶衣包含聚(甲基)丙烯酸聚合物。
16.权利要求14所述的固体口服剂型,其中在(c)中,所述肠溶衣包含聚(甲基)丙烯酸聚合物。
17.权利要求13所述的固体口服剂型,其中所述纤维素衍生物选自甲基纤维素、邻苯二甲酸乙酸纤维素、羟甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、羟丙基甲基纤维素琥珀酸酯(HPMCS)、乙酸羟甲基纤维素琥珀酸酯和乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)。
18.权利要求14所述的固体口服剂型,其中所述纤维素衍生物选自甲基纤维素、邻苯二甲酸乙酸纤维素、羟甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、羟丙基甲基纤维素琥珀酸酯(HPMCS)、乙酸羟甲基纤维素琥珀酸酯和乙酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)。
19.权利要求1-11和14-18中任一项所述的固体口服剂型,其中所述药学上可接受的赋形剂(D)独立地选自粘合剂、表面活性剂、稀释剂、缓冲剂、抗粘附剂、助流剂、崩解剂、抗氧化剂、消泡剂、香料、色素、润滑剂、吸附剂、防腐剂、增塑剂和甜味剂。
20.权利要求12所述的固体口服剂型,其中所述药学上可接受的赋形剂(D)独立地选自粘合剂、表面活性剂、稀释剂、缓冲剂、抗粘附剂、助流剂、崩解剂、抗氧化剂、消泡剂、香料、色素、润滑剂、吸附剂、防腐剂、增塑剂和甜味剂。
21.权利要求13所述的固体口服剂型,其中所述药学上可接受的赋形剂(D)独立地选自粘合剂、表面活性剂、稀释剂、缓冲剂、抗粘附剂、助流剂、崩解剂、抗氧化剂、消泡剂、香料、色素、润滑剂、吸附剂、防腐剂、增塑剂和甜味剂。
22.权利要求1-11、14-18和20-21中任一项所述的固体口服剂型,其中化合物(I)是2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)和(S)异构体混合物的(E)和(Z)混合物。
23.权利要求12所述的固体口服剂型,其中化合物(I)是2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)和(S)异构体混合物的(E)和(Z)混合物。
24.权利要求13所述的固体口服剂型,其中化合物(I)是2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)和(S)异构体混合物的(E)和(Z)混合物。
25.权利要求19所述的固体口服剂型,其中化合物(I)是2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(R)和(S)异构体混合物的(E)和(Z)混合物。
26.权利要求1-11、14-18和20-21中任一项所述的固体口服剂型,其中化合物(I)是(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
27.权利要求12所述的固体口服剂型,其中化合物(I)是(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
28.权利要求13所述的固体口服剂型,其中化合物(I)是(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
29.权利要求19所述的固体口服剂型,其中化合物(I)是(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈的(E)和(Z)混合物。
30.权利要求1-11、14-18、20-21、23-25和27-29中任一项所述的固体口服剂型,其中至少85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
31.权利要求12所述的固体口服剂型,其中至少85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
32.权利要求13所述的固体口服剂型,其中至少85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
33.权利要求19所述的固体口服剂型,其中至少85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
34.权利要求22所述的固体口服剂型,其中至少85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
35.权利要求26所述的固体口服剂型,其中至少85重量%的化合物(I)和/或其药学上可接受的盐是(E)异构体。
36.权利要求1-11、14-18、20-21、23-25、27-29和31-35中任一项所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
37.权利要求12所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
38.权利要求13所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
39.权利要求19所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
40.权利要求22所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
41.权利要求26所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
42.权利要求30所述的固体口服剂型,其中化合物(I)和/或其药学上可接受的盐是基本上纯的无定形形式。
43.权利要求1-42中任一项所述的固体口服剂型用于制备在经认定需要的患者中治疗通过抑制BTK可治疗的疾病的药物的用途,其中给予所述患者治疗有效量的化合物(I)和/或其药学上可接受的盐。
44.权利要求43所述的用途,其中所述疾病选自自身免疫疾病、癌症和炎性疾病。
45.权利要求44所述的用途,其中所述疾病为白血病或淋巴瘤。
46.权利要求44所述的用途,其中所述疾病选自慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、多发性骨髓瘤、套细胞淋巴瘤和B细胞非霍奇金淋巴瘤。
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DK3181567T3 (da) | 2012-09-10 | 2019-06-11 | Principia Biopharma Inc | Pyrazolopyrimidinforbindelser som kinasehæmmere |
CN112353806A (zh) | 2014-02-21 | 2021-02-12 | 普林斯匹亚生物制药公司 | Btk抑制剂的盐和固体形式 |
PT3233103T (pt) | 2014-12-18 | 2021-01-18 | Principia Biopharma Inc | Tratamento de pênfigo |
TW201718572A (zh) | 2015-06-24 | 2017-06-01 | 普林斯匹亞生物製藥公司 | 酪胺酸激酶抑制劑 |
CA3028169A1 (en) | 2016-06-29 | 2018-01-04 | Principia Biopharma Inc. | Modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile |
EP3827008A1 (en) | 2018-07-25 | 2021-06-02 | Novartis AG | Nlrp3 inflammasome inhibitors |
AR119731A1 (es) | 2019-05-17 | 2022-01-05 | Novartis Ag | Inhibidores del inflamasoma nlrp3 |
US20210106583A1 (en) | 2019-10-09 | 2021-04-15 | Principia Biopharma Inc. | Methods of treating pemphigus by administering (r)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile |
CN115209899A (zh) | 2019-10-14 | 2022-10-18 | 普林斯匹亚生物制药公司 | 通过施用(R)-2-[3-[4-氨基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧杂环丁-3-基)哌嗪-1-基]戊-2-烯腈治疗免疫性血小板减少症的方法 |
CR20230125A (es) | 2020-08-14 | 2023-05-11 | Novartis Ag | Derivados de espiropiperidinilo sustituidos con heteroarilo y usos farmacéuticos de los mismos |
BR112023018570A2 (pt) | 2021-04-16 | 2023-11-28 | Principia Biopharma Inc | Métodos para o tratamento de trombocitopenia imune induzida por fármacos e vacinas através da administração de compostos específicos |
US20240067627A1 (en) | 2022-08-03 | 2024-02-29 | Novartis Ag | Nlrp3 inflammasome inhibitors |
WO2024097667A1 (en) | 2022-10-31 | 2024-05-10 | Principia Biopharma Inc. | Methods for treating immune thrombocytopenia by administering (r)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile |
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