CN1764381A - 用于酪氨酸激酶抑制剂的制剂 - Google Patents
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- CN1764381A CN1764381A CNA2004800078138A CN200480007813A CN1764381A CN 1764381 A CN1764381 A CN 1764381A CN A2004800078138 A CNA2004800078138 A CN A2004800078138A CN 200480007813 A CN200480007813 A CN 200480007813A CN 1764381 A CN1764381 A CN 1764381A
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Abstract
本发明涉及适合于用稀释剂重构的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮,酪氨酸激酶抑制剂的粉末、粉末共混物或者颗粒化制剂。本发明还涉及制得的水悬浮液或分散液制剂,特别是稳定的口服药物制剂,其包括与稀释剂混合的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的颗粒。另外,本发明还涉及制备这些制剂的方法。
Description
发明背景
血管生成的特征在于有过度的血管内皮细胞生长因子(VEGF)活性(如美国专利6,245,759B1所述)。KDR介导VEGF的促有丝***功能,而Flt-1看起来则调节着非促有丝***的功能,如与细胞粘着有关的功能。因此,抑制KDR会调节促有丝***的VEGF活性的水平。事实上,已经证明,肿瘤的生长容易受到VEGF受体拮抗体的抗血管生成的影响。(Kim等人,Nature,362,841-844页,1993)。
实体肿瘤可以通过酪氨酸激酶抑制剂来治疗,原因是这些肿瘤取决于对支撑血管生长来说必需的形成血管时的血管生成。这些实体肿瘤包括组织细胞淋巴瘤,脑、泌尿生殖道、淋巴***、胃、喉和肺癌,包括肺腺癌和小细胞肺癌。另外的实例包括,其中观察到Raf-活化致癌基因(如,K-ras、erb-B)超表达或活化的癌症。这种癌症包括胰腺和***癌。因此,这些酪氨酸激酶的抑制剂可用于预防和治疗依赖于这些酶的增殖疾病。
对KDR或Flt-1的抑制涉及到病理性的血管生成,这些受体可用于治疗其中血管生成属于整个病状一部分的疾病,如,发炎,糖尿病患者视网膜血管化,以及各种形式的癌症,因为大家公知,肿瘤的生长取决于血管生成。(Weidner等,N.Engl.J.Med.,324,1-8页,1991)。
在2001年10月23日授权的美国专利6,306,874中已经一般性地和具体地公开了包含喹啉片断的化合物,如,3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮。
因此,酪氨酸激酶抑制剂可用于治疗癌症。因为幼小或年长的患者可能在吞咽片剂方面有困难,所以可以使用包含酪氨酸激酶抑制剂的口服悬浮液。
发明概述
本发明涉及适合于用稀释剂重构的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮,一种酪氨酸激酶抑制剂的颗粒化制剂。本发明还涉及制得的水悬浮液或分散液制剂,特别是稳定的口服药物制剂,其包括与稀释剂混合的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的颗粒。另外,本发明还涉及制备这些制剂的方法。
附图简述
图1阐明了适合于用稀释剂重构的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮,一种酪氨酸激酶抑制剂的颗粒化制剂的制备方法流程图。
发明详述
在第一实施方案中,本发明涉及一种适合于用稀释剂重构的粉末制剂,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮作为活性成分,和
b)至少一种填料,其中所述填料占粉末制剂重量的约10%-约75%。
在第二实施方案中,本发明涉及一种适合于用稀释剂重构的粉末共混物制剂,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮作为活性成分,和
b)至少一种填料,其中所述填料占共混制剂重量的约10%。
在第三实施方案中,本发明涉及一种适合于用稀释剂重构的颗粒化制剂,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮作为活性成分,
b)至少一种粘合剂;和
c)至少一种填料,其中所述填料占颗粒化制剂重量的约10%-约75%。
在本发明另外的实施方案中,上述制剂进一步包括一种或多种药学上可接受的赋形剂,其选自粘合剂,崩解剂,润滑剂,调味剂,甜味剂,缓冲剂,稳定剂,和粘度调节剂。
也可以使用水与稀释剂的结合来把粉末、粉末共混物或颗粒化制剂重构形成悬浮液。
在另一个实施方案中,本发明涉及如上第一实施方案中所述颗粒化制剂的制备方法,其包括:
a)通过湿法制粒而制备含3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮与至少一种填料的湿颗粒;
b)将湿颗粒干燥然后碾磨形成磨碎的颗粒;
c)用润滑剂润滑所述磨碎的颗粒形成颗粒化制剂;和
d)把所述颗粒化制剂填充到容器中。
本发明的另一个实施方案是一种用于制备药物悬浮液的试剂盒,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮;
b)稀释剂;和
c)至少一种填料。
本发明的另一个实施方案是3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的药物悬浮液的制备方法,其包括,将包含3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮和至少一种填料的颗粒化制剂与稀释剂混合。
也可以使用水与稀释剂的结合来把颗粒化制剂重构形成悬浮液。
在第四实施方案中,本发明涉及水悬浮液制剂,其包括与稀释剂混合的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的颗粒。
本发明的第五实施方案是一种在小儿或成年患者中治疗癌症的方法,其包括给予需要所述治疗的患者有效量的颗粒化制剂。
本发明的第六实施方案是一种在小儿或成年患者中治疗癌症的方法,其包括给与需要所述治疗的患者有效量的水悬浮液制剂。
3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的制备参见2001年10月23日授权的美国专利6,306,874,并全文在此引入作为参考。另外,3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮也可以用2002年12月26日公开的US 2002-0198252中所述的方法制备。
根据本发明的制剂提供用于重构形成口服悬浮液的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的粉末、粉末共混物或者颗粒。本发明的制剂可以包装成悬浮液的形式,或者制剂的各组分可以独立包装在试剂盒中,交到适当的用户,如医生手中或药房。一旦供给,就可以将各组分重构形成如本发明中所述的悬浮液,并给予需要的人。例如,在临床点,适当的用户将把5mL纯水加入到包含4克3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮颗粒的容器,如PET瓶中,并轻轻地摇振。然后,加入95mL稀糖浆,并摇振容器。在给以患者之前,应当再次摇振悬浮液。
这里使用的粉末共混物是两种或多种粉末的混合物。这里使用的颗粒是指通过粘合剂粘合在一起的颗粒聚结物,其改进了粉末的流动性。
可以用于本发明的稀释剂的实例包括,但是不局限于,Humco′sSimple Syrup,Emerson Cherry Syrup,Paddock′s Ora-SweetSyrup,Paddock′s Ora-Plus Oral Suspending Vehicle,Ora-SweetSFTM Sugar Free Syrup,所述稀释剂的组合,等。另外,稀释剂可以是水和粉末如Acacia Powder、Humco′s Dextrose Powder等的混合物。在本发明的具体实施方案中,利用Humco′s Simple Syrup作为稀释剂。
用于本发明的填料的实例包括但是不局限于,微晶纤维素、乳糖水合物、狄派克(dipac)、甘露糖醇、葡萄糖、蔗糖、磷酸二钙、磷酸三钙等中的一种或多种。在具体实施方案中,填料是微晶纤维素或乳糖水合物。
可以用于本发明的粘合剂的实例包括但是不局限于,羟基丙基纤维素EXF(HPC-EXF),其它级别的HPC(如HPC,HPC-SL),羟丙基甲基纤维素(HMPC),淀粉1500,聚乙烯吡咯烷酮(PVP),氢化植物油,等。在本发明的具体实施方案中,使用HPC-EXF。崩解剂的实例包括但不限于croscarmellose钠,聚维酮,交联聚维酮,淀粉1500,淀粉羟基乙酸钠等。在本发明的具体实施方案中,崩解剂是croscarmellose钠。
可以用于本发明的润滑剂的实例包括但是不局限于,硬脂酸镁,硬脂酸,滑石粉,等。可以用于本发明的缓冲剂的实例包括但是不局限于,柠檬酸,苯甲酸,乙酸,抗坏血酸,酒石酸,马来酸,苹果酸,乳酸,琥珀酸,磷酸,富马酸,等。可以用于本发明的稳定剂的实例包括但是不局限于,HPC,HPC-SL,HPMC,甲基纤维素,羟丙基纤维素,乙基纤维素,表面活性剂,等。
可以用于本发明的粘度调节剂的实例包括但是不局限于,HPC,HPMC,黄原胶,聚糊精,蔗糖,明胶等。
如上所述,颗粒是通过粘合剂粘合在一起的颗粒聚结物,其改进了粉末的流动性。颗粒化是用于制备颗粒的方法,其可以是湿法或干法。如本领域所周知,干法制粒法使用碾压,而湿法制粒法则使用液体如溶剂来粒化。在本发明中,颗粒化制剂的颗粒是通过在高剪切造粒机中进行湿法制粒制备的。这些颗粒包括3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的HCl盐、微晶纤维素、填料如乳糖水合物、粘合剂如羟基丙基纤维素EXF(HPC-EXF)以及崩解剂如croscarmellose钠。可以使用水作为粒化溶剂。湿颗粒在流化床干燥器中干燥,然后在Comil中磨碎。磨碎的颗粒用润滑剂如硬脂酸镁润滑,然后填充到容器中。在本发明的具体实施方案中,使用的容器是聚对苯二甲酸乙二醇酯(PET)瓶。
通常,可以使用起粘度增加剂(增稠剂)作用的、具有较大溶胀能力的、较低浓度(0.2-5%)的其它类型纤维素来制备悬浮液。微晶纤维素主要在口服片剂和胶囊制剂中作为稀释剂使用。
优选粒径为20-100μm的微晶纤维素。适当的级别包括Avicel类型pH101,102,103,104,112,113,301和302。这些类型在物理性能如粒径、体积密度、干燥失重、粘度和化学特性如聚合度方面有差异。
除非另外指出,本说明书中提到的百分比或量以重量计。百分比或比例的选择使得总量为100%。
在本发明的制剂中,预先干燥的纤维素用作填料,其同时又起到粘度增加剂的作用,稳定剂在使用期内为重构后的悬浮液提供优良的稳定性。作为制剂中主要填料的纤维素的量可以为约5%-约90%w/w。在本发明具体的实施方案中,所述范围为大约10-约75%w/w。在本发明另外的实施方案中,所述范围为干燥制剂的约10-约70%w/w。活性物质的百分比为约1-约90%。在本发明的具体实施方案中,活性物质的百分比为约1-约70%。在另外的实施方案中,活性物质的百分比为约1-约50%。在本发明中可以存在各种不同量的另外的赋形剂,其量使得本发明制剂中各成分的百分比或比例总计为100%。
可以使用平均粒度为20μm的微晶纤维素(Avicel,Emcocel,Vitacel),或优选使用平均粒度为50μm的微晶纤维素。可以使用具有不同粒径的或呈粒化粉末形式的粉末纤维素(Vivacel,Elcema,SolkaFlok)。本发明的制剂还可以包含本领域可能实质上通用的辅助成分。为了改进味道,可以加入口服制剂容许量的调味剂和甜味剂,优选糖精、糖精钠或芦笋。可以使用的调味剂可以包括常见的香料如草莓、樱桃、野樱、柠檬、香蕉、木莓、橙子、焦糖或其混合物,其与抗生素的结合提供令人愉快的香味和味道。
适当的赋形剂可以包括缓冲剂,如不同的酸以及它们的盐,例如柠檬酸,柠檬酸钠,丁二酸,膨润剂和粘度增加剂如悬浮稳定剂及其它添加剂。
本发明的制剂适合于以指定剂量进行BID或TID给药。它们被指明用于治疗孩子、成年和老年人,以及吞咽有困难的患者。
本发明的制剂可以保存在气密的螺旋帽瓶或塑料容器中,或者保存在在即要使用之前分别用于制备悬浮液或分散液的小袋中。
本发明的制剂可以用通用的制造工序如均化、筛分和磨碎来制造。一部分成分可以预先粒化,或者可以用粒化后的成分来改进粉末流动性,这对于小袋包装来说尤为重要。
实施例
所提供的实施例旨在助于进一步理解本发明。使用的具体物质、物种和条件旨在进一步说明本发明而不限制其合理的范围。
实施例1 5-{[4-叔-(丁氧基羰基)哌嗪-1-基]甲基}-1H-吲哚-1-
羧酸叔丁酯1-4
向50L圆底烧瓶中加入甲苯(8升),5-氰基吲哚1-1(2公斤,1当量),以及4-(二甲氨基)吡啶(DMAP)(17克,0.01当量)。然后慢慢加入呈甲苯(2L)溶液形式的Boc2O(3.15公斤,1.03当量),温度保持在约20-约30℃。然后加入四氢呋喃(THF)(8升)作为冲洗液。30分钟后,用如下所述的HPLC法对混合物进行化验,然后冷却到约15℃-约18℃的温度。在3小时内加入二异丁基铝氢化物(DiBAL)(21.5升;1.5M的甲苯溶液;2.3当量),保持温度在约15℃-约18℃。溶液在室温下放置1小时到整夜的时间,然后用HPLC进行化验。可以加入另外的DiBAL(约1L)以使Boc-氰基吲哚的分析低于1mol%。
把DiBAL反应混合物加料到NaHSO4(20公斤)水(60L)溶液的一半中,同时将温度保持在约35℃-约45℃。加料速率通过把温度保持在约35℃-约45℃的能力来决定,并控制逸出气体的量。
在约35℃-约45℃切出水相,其余的硫酸氢盐溶液加料到有机相中。在35℃-约45℃下15分钟后,切出水相,有机相用水(8升)和盐水(8升)洗涤,之后转移到包含有约5-约10公斤Na2SO4的筒中,以除去第二水相。少量的红色油,残余的过还原副产物,出现在水切出馏分的表面上,并与水一起切除。
将100升抽提器用水洗涤,并通过THF boil-out试验进行干燥,然后通过10微米的管道过滤器再装填有机相,随后用甲苯冲冼(4升)。加入Boc-哌嗪1-3(2.61公斤,1当量),然后分步加入三乙酰氧基硼氢化物(3.86公斤,1.3当量),同时使温度保持在约23℃-约27℃。这一加料过程中等放热。将混合物放置1.5小时,分析然后加入2.5v/v%乙酸水(20升)溶液猝灭。猝灭后的总体积为约80升。
有机相用水(20升)洗涤,切除水相,通过在50升圆底烧瓶中进行真空批料浓缩将有机相溶剂转换为MeOH,至目标体积为25升。批料升温到约30℃-约35℃的温度下,并种晶。形成充分的种床之后,在1小时内加入60/40的水/甲醇(20升),把批料急冷到约5℃并放置1小时。通过过滤分离产物,洗涤(3升,70∶30的MeOH∶水),并通过压缩氮气吹洗干燥。得到约5公斤(85%)的5-{[4-叔-(丁氧基羰基)哌嗪-1-基]甲基}-1H-吲哚-1-羧酸叔丁酯1-4,白色固体。
实施例2:中间体硼酸2-1的制备
将1-4(2780克;6.69摩尔)、11.1升甲苯和2.8升THF(四氢呋喃)的混合物冷却到-78℃。然后慢慢地加入5.4升(10.7摩尔)2M的LDA(二异丙基酰胺锂),使得温度低于约-70℃。然后将反应混合物放置2小时。
慢慢地加入4.6升(19.9摩尔)三异丙基硼酸酯,同时将温度保持在约-70℃以下。当1-4的剩余量为2%或以下时,反应结束。如果需要,可以加入另外的LDA驱动反应完成。30分钟后,用冰浴把反应升温到约0℃。之后,用12升2N的HCl(24.1摩尔)将反应猝灭,把pH值调节到约7。除去冰浴,两相溶液搅拌约30分钟以保证所有物质均在溶液中。然后分离各层,有机层不经纯化用于下一个反应。
实施例3:喹吲哚中间体3-2的制备
在50升圆底烧瓶中,混合3-溴喹啉-2-酮(1公斤,4.46摩尔),乙酸钯(50.1克,0.223摩尔),PPh3(117克,0.446摩尔),二环己胺(2.7升,13.4摩尔)和二甲基乙酰胺(DMAC)(10升)。将溶液脱气两次,并且每次都用氮气吹扫。把反应混合物加热到60℃。在60℃下,在2小时内加入溶液形式(该溶液没有脱气)的硼酸(如实施例2所述制备)(3.073公斤,6.69摩尔)。然后将反应放置过夜。
通过HPLC对反应进行分析。当喹啉酮或硼酸消失后,反应结束。希望的产物与不希望的产物之比将为3.5∶1或更好。
将Darco KB(125克;理论产率的5重量%)加入到反应混合物中。把反应混合物在60℃下加热30分钟,然后冷却到室温。
把硅藻土(125克;理论产率的5重量%)加入到反应混合物中。将反应过滤,烧瓶用1-2升甲苯冲洗。滤饼用1-2升甲苯洗涤。
把滤液转移到100升圆筒形抽提器中并升温到55℃,慢慢地加入水(10升),以便保持温度。
混合物搅拌30分钟,然后分层。
把有机层转移到50升圆底烧瓶中并浓缩到体积为12升或以下。向所得混合物中加入EtOAc(12升)。搅拌至少两小时或过夜。
所得固体经过过滤,滤饼用1∶1的EtOAc/甲苯混合物(1.3升)洗涤。然后将固体干燥。
实施例4:3-2的脱保护
在50升烧瓶中,将如实施例3所述制备的喹吲哚3-2(1.85公斤)在无水乙醇(28升)中的浆液用浓HCl水溶液进行处理。将溶液加热到65℃,加热8小时或以上,然后冷却到室温。通过过滤收集二HCl盐形式的仲胺,用5升乙醇洗涤。
实施例5:中间体4-1的甲基磺酰化
将中间体4-1(1.2公斤,2.78摩尔)、THF(24升)和二异丙胺(1.17升,8.35摩尔)加入到50升圆底烧瓶中,把浆液加热到55℃。在3小时内加入甲磺酰氯,将浓的黄色浆液搅拌4小时或过夜。把混合物冷却到室温,然后在1.5小时内加入水(15.6升)。向最后的5升水中加入600毫升浓氢氧化铵,以将浆液的pH值调节到>7(总体积43升)。将浆液放置1小时,然后过滤,用3.6升滤饼洗涤液(60∶40的THF∶水)洗涤。最终产物在70℃和40托下干燥若干天,得到化合物A,黄色固体。
或者,可以用总计24升水猝灭反应。
实施例6:3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-
基]-1H-喹啉-2-酮(化合物A)的颗粒化制剂的制备
制备两种活性制剂:10-毫克/毫升和1-毫克/毫升。对于10-/毫升的制剂来说,把4克含有1克药物的颗粒装到PET瓶中。对于1-/毫升的制剂来说,把400毫克含有100毫克药物的颗粒装到PET瓶中。在临床点,把包含95毫升Humco Simple Syrup和5毫升水的100毫升Humcosimple syrup溶液加入到瓶中,以使浓度分别为10毫克/毫升和1毫克/毫升。制剂的组成示于表1。制造工艺的流程图示于图1。根据所述方法,测定包含4克颗粒/瓶批料的稳定性。
表1:3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮颗粒化制剂的组成
单元浓度 | ||
成分 | 1克 | 100毫克 |
毫克/瓶 | 毫克/瓶 | |
核心片剂 | ||
化合物A的HCl盐* | 1080.0 | 108.0 |
(以游离碱计) | (1000.0) | (100.0) |
微晶纤维素NF(Avicel PH101) | 800.0 | 80.0 |
乳糖水合物NF | 1860.0 | 186.0 |
羟丙基纤维素(lucel-EXF)NF | 120.0 | 12.0 |
Croscarmellose钠NF(Ac-Di-Sol) | 120.0 | 12.0 |
硬脂酸镁NF(Non-Bovine) | 20.0 | 2.0 |
纯水**USP | -- | -- |
瓶中颗粒的总重量 | 4000 | 400 |
*1毫克游离碱=1.08毫克HCl盐
**在加工过程中脱除
Claims (26)
1.一种适合于用稀释剂重构的粉末制剂,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮作为活性成分,和
b)至少一种填料,其中所述填料占粉末制剂重量的约10%-约75%。
2.权利要求1的粉末制剂,其中填料选自微晶纤维素,乳糖水合物,狄派克,甘露糖醇,和其组合。
3.权利要求2的粉末制剂,其中填料是微晶纤维素,乳糖水合物或其组合。
4.一种适合于用稀释剂重构的粉末共混物制剂,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮作为活性成分,和
b)至少一种填料,其中所述填料占共混制剂重量的约10%。
5.权利要求4的粉末共混物制剂,其中填料选自微晶纤维素,乳糖水合物,狄派克,甘露糖醇,和其组合。
6.权利要求5的粉末共混物制剂,其中填料是微晶纤维素,乳糖水合物或其组合。
7.一种适合于用稀释剂重构的颗粒化制剂,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮作为活性成分;
b)至少一种粘合剂;和
c)至少一种填料,其中所述填料占颗粒化制剂重量的约10%-约75%。
8.权利要求7的颗粒化制剂,其中填料选自微晶纤维素,乳糖水合物,狄派克,甘露糖醇,和其组合。
9.权利要求8的颗粒化制剂,其中填料是微晶纤维素,乳糖水合物或其组合。
10.权利要求7的颗粒化制剂,其中水与稀释剂结合用于重构颗粒化制剂。
11.权利要求7的颗粒化制剂,其中所述颗粒化制剂进一步包括一种或多种药学上可接受的赋形剂,其选自粘合剂,崩解剂,润滑剂,调味剂,甜味剂,缓冲剂,稳定剂,和粘度调节剂。
12.一种制备权利要求7的颗粒化制剂的方法,其包括:
a)通过湿法制粒而制备含3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮与至少一种填料的湿颗粒;
b)将湿颗粒干燥然后碾磨形成磨碎的颗粒;
c)用润滑剂润滑所述磨碎的颗粒形成颗粒化制剂;和
d)把所述颗粒化制剂填充到容器中。
13.一种用于制备药物悬浮液的试剂盒,其包括:
a)3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的颗粒;
b)稀释剂;和
c)至少一种填料。
14.权利要求13的试剂盒,其中稀释剂选自Humco′s SimpleSyrup,Emerson Cherry Syrup,Paddock′s Ora-SweetSyrup,Paddock′s Ora-PlusOral Suspending Vehicle,Ora-Sweet SFTMSugar Free Syrup,和其组合。
15.权利要求14的试剂盒,其中稀释剂是Humco′s Simple Syrup。
16.权利要求13的试剂盒,其中填料选自微晶纤维素,乳糖水合物或其组合。
17.一种水悬浮液制剂,其包括与稀释剂混合的3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮、至少一种粘合剂和至少一种填料的颗粒。
18.权利要求17的水悬浮液制剂,其中稀释剂选自Humco′s SimpleSyrup,Emerson Cherry Syrup,Paddock′s Ora-SweetSyrup,Paddock′s Ora-PlusOral Suspending Vehicle,Ora-Sweet SFTMSugar Free Syrup,和其组合。
19.权利要求18的粉末制剂,其中稀释剂是Humco′s SimpleSyrup。
20.权利要求17的水悬浮液制剂,其包括与Humco Simple Syrup和水的溶液混合的含有3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的HCl盐、微晶纤维素、乳糖水合物、羟基丙基纤维素EXF和croscarmellose钠的颗粒。
21.制备3-[5-(4-甲基磺酰基-哌嗪-1-基甲基)-1H-吲哚-2-基]-1H-喹啉-2-酮的药物悬浮液的方法,其包括将权利要求7的颗粒化制剂与稀释剂混合。
22.权利要求21的方法,其中稀释剂选自Humco′s Simple Syrup,Emerson Cherry Syrup,Paddock′s Ora-SweetSyrup,Paddock′sOra-PlusOral Suspending Vehicle,Ora-Sweet SFTM Sugar FreeSyrup,和其组合。
23.权利要求22的方法,其中稀释剂是Humco′s Simple Syrup。
24.权利要求21的方法,其中颗粒化制剂与Humco′s Simple Syrup和水的溶液混合。
25.一种在小儿或成年患者中治疗癌症的方法,其包括给予需要所述治疗的患者有效量的权利要求7的制剂。
26.一种在小儿或成年患者中治疗癌症的方法,其包括给予需要所述治疗的患者有效量的权利要求17的制剂。
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CN1764381A true CN1764381A (zh) | 2006-04-26 |
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CNA2004800078138A Pending CN1764381A (zh) | 2003-03-27 | 2004-03-23 | 用于酪氨酸激酶抑制剂的制剂 |
Country Status (7)
Country | Link |
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US (1) | US20060093666A1 (zh) |
EP (1) | EP1610614A2 (zh) |
JP (1) | JP2006521360A (zh) |
CN (1) | CN1764381A (zh) |
AU (1) | AU2004225949B2 (zh) |
CA (1) | CA2519106A1 (zh) |
WO (1) | WO2004087651A2 (zh) |
Families Citing this family (5)
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US7928111B2 (en) * | 2007-06-08 | 2011-04-19 | Senomyx, Inc. | Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors |
ES2647947T3 (es) | 2008-07-31 | 2017-12-27 | Senomyx, Inc. | Procesos y productos intermedios para la preparación de potenciadores del sabor dulce |
AU2010232729A1 (en) | 2009-03-31 | 2011-10-20 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
WO2015031228A1 (en) | 2013-08-30 | 2015-03-05 | Merck Sharp & Dohme Corp. | Oral pharmaceutical formulation of omarigliptin |
MX2021001193A (es) | 2018-08-07 | 2021-04-28 | Firmenich Incorporated | 2,2-dioxidos de 4-amino-1h-benzo[c][1,2,6]tiadiazina 5-sustituidos y formulaciones y usos de los mismos. |
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IL115256A0 (en) * | 1994-11-14 | 1995-12-31 | Warner Lambert Co | 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use |
US6245759B1 (en) * | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
EP1226136B1 (en) * | 1999-10-19 | 2004-12-29 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
-
2004
- 2004-03-23 AU AU2004225949A patent/AU2004225949B2/en not_active Ceased
- 2004-03-23 CA CA002519106A patent/CA2519106A1/en not_active Abandoned
- 2004-03-23 JP JP2006507476A patent/JP2006521360A/ja not_active Withdrawn
- 2004-03-23 EP EP04758216A patent/EP1610614A2/en not_active Withdrawn
- 2004-03-23 WO PCT/US2004/008828 patent/WO2004087651A2/en not_active Application Discontinuation
- 2004-03-23 US US10/544,213 patent/US20060093666A1/en not_active Abandoned
- 2004-03-23 CN CNA2004800078138A patent/CN1764381A/zh active Pending
Also Published As
Publication number | Publication date |
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EP1610614A2 (en) | 2006-01-04 |
AU2004225949A1 (en) | 2004-10-14 |
JP2006521360A (ja) | 2006-09-21 |
AU2004225949B2 (en) | 2006-11-02 |
US20060093666A1 (en) | 2006-05-04 |
CA2519106A1 (en) | 2004-10-14 |
WO2004087651A2 (en) | 2004-10-14 |
WO2004087651A3 (en) | 2004-12-16 |
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