CN1852738A - 使用伊马替尼和米哚妥林治疗胃肠道基质肿瘤 - Google Patents
使用伊马替尼和米哚妥林治疗胃肠道基质肿瘤 Download PDFInfo
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- CN1852738A CN1852738A CNA2004800270630A CN200480027063A CN1852738A CN 1852738 A CN1852738 A CN 1852738A CN A2004800270630 A CNA2004800270630 A CN A2004800270630A CN 200480027063 A CN200480027063 A CN 200480027063A CN 1852738 A CN1852738 A CN 1852738A
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- Prior art keywords
- imatinib
- midostaurin
- purposes
- treatment
- stromal tumors
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Classifications
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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Abstract
本发明涉及包含伊马替尼或其可药用盐和米哚妥林或其可药用盐的组合在制备用于治疗胃肠道基质肿瘤、例如伊马替尼抗药性胃肠道基质肿瘤的药物中的用途。
Description
胃肠道基质肿瘤的治疗
本发明涉及包括伊马替尼(imatinib)或其可药用盐和蛋白激酶C抑制剂如星孢素衍生物米哚妥林(midostaurin)(也称为PKC412)或其可药用盐的组合治疗，用于制备用来治疗胃肠道基质肿瘤(GIST)的药物组合物；该组合治疗在治疗GIST中的用途，和治疗患有GIST的温血动物、包括人的方法，该方法向所述需要这种治疗的动物施用伊马替尼或其可药用盐和米哚妥林或其可药用盐的有效组合。
胃肠道基质肿瘤(GIST)是最近表征的一族间充质肿瘤，其起源于胃肠道，最常见于胃(占全部GIST的60-70％)，也源于食管、小肠、结肠和直肠。GIST也罕有地发生于胃肠道外侧。过去，这些肿瘤以不同方式被分类为平滑肌瘤、成平滑肌瘤、或平滑肌肉瘤或其他类型肉瘤。然而，现在已经清楚：基于它们独特的分子发病机理和临床特征，GIST代表一组独特的临床病理学疾病。GIST现在能够被明确诊断并且与其它类型间充质肿瘤区分开来，例如，通过证明典型的组织学特征和/或KIT蛋白表达的免疫组织化学证据。
尽管GIST的约20例/百万的估计发病率较小，但其是最常见的胃肠道间充质肿瘤。直到最近，唯一有效的治疗是手术切除。常规细胞毒化学治疗和放射治疗的有限价值已导致晚期GIST成为必然恶化和致命的病症，患者平均存活时间从20个月(转移的GIST)到一年或更短时间(术后复发)。
伊马替尼是选择性抑制特定酪氨酸激酶的小分子，其最近已显示作为晚期GIST患者的有价值的治疗方法。在此处引入作为参考的PCT公开WO 02/34727中已经描述了使用伊马替尼作为单一疗法用于治疗GIST。但是，已有报道伊马替尼的原药抗药性(primary resistance)存在于患者群中，例如一项研究中13.7％的患者。此外，许多患者对使用伊马替尼治疗获得抗药性。更普遍而言，该抗药性在某些损伤中部分与疾病发展相伴随，但在其它损伤中持续控制疾病。因此，这些患者维持伊马替尼治疗但明确需要额外或替代的治疗。
蛋白激酶C是细胞信号转导途径中的关键酶之一，它在控制细胞增殖和分化中具有枢纽作用。PKC是一族丝氨酸苏氨酸激酶。至少已有12种PKC同工型已被鉴别，基于它们的结构和底物要求，它们通常被分成3组。已发现，与正常胸部组织相比，在人类乳房肿瘤活组织切片检查中PKC的表达升高，高PKC表达已被视为人类星状细胞瘤中恶性肿瘤的生物标记物。PKC的同工型之一PKCθ，是T细胞中存活信号的正性调节剂。有趣的是，PKCθ在GIST中被激活，如GIST中PKCθ的组成型磷酸化所显示以及抑制PKCθ活性导致GIST细胞死亡所证明。因而，PKCθ可被视为治疗性干预GIST的潜在目标激酶。具体而言，PKC抑制剂在治疗伊马替尼抗药性GIST中是有益处的。
因此，本发明涉及治疗GIST的方法，其包括对GIST患者施用伊马替尼和蛋白激酶C抑制剂的组合。
伊马替尼是具有式1的4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-(4-吡啶-3-基)嘧啶-2-基氨基]苯基]-苯甲酰胺，
伊马替尼的制备及其用途、尤其是作为抗肿瘤剂的用途描述于1993年10月6日公开的欧洲专利申请EP-A-0564409的实施例21中，以及在多个其它国家的同族申请和专利中，例如美国专利5,521,184及日本专利2706682，它们全部在此引入作为参考。
可药用盐是可药用酸加成盐，例如与无机酸所成的盐，如盐酸、硫酸或磷酸，或与合适的有机羧酸或磺酸所成的盐，例如脂肪族单或二羧酸，如三氟乙酸、乙酸、丙酸、羟基乙酸、琥珀酸、马来酸、富马酸、羟基马来酸、苹果酸、酒石酸、柠檬酸或草酸，或氨基酸如精氨酸或赖氨酸，芳香族羧酸如苯甲酸、2-苯氧基-苯甲酸、2-乙酰氧基-苯甲酸、水杨酸、4-氨基水杨酸，芳香族-脂肪族羧酸如扁桃酸或肉桂酸，杂芳族羧酸如烟酸或异烟酸，脂肪族磺酸如甲烷-、乙烷-或2-羟乙烷-磺酸，或芳族磺酸，例如苯磺酸、对-甲苯磺酸或萘-2-磺酸。
1999年1月28日公开的PCT专利申请WO99/03854描述了伊马替尼的单甲烷磺酸加成盐及其优选的晶体形式。伊马替尼的单甲烷磺酸盐在很多国家中以商标Glivec或GleevecTM上市。
取决于种类、年龄、个体状况、施用方式和所涉及的临床情况，向约70千克体重的温血动物、特别是智人(Homo sapiens)种患者施用有效剂量的伊马替尼、特别是其单甲烷磺酸盐，例如日口服剂量为约100-1000mg，优选200-600mg，尤其400mg。对于患有不可切除的或转移的恶性GIST成人患者，根据本发明推荐伊马替尼起始口服剂量为每日400-600mg，特别是每日600mg。对于治疗响应评价后响应不充分的患者，可以安全地考虑将伊马替尼剂量递增至每日800或1000mg，只要患者受益于治疗并且不存在限制性毒性，即可对患者进行治疗。
美国专利第5,093,330号描述了蛋白激酶C抑制剂及其施用，其在此引入作为参考。米哚妥林是特别重要的蛋白激酶C抑制剂。
米哚妥林是式N-[(9S，10R，11R，13R)-2，3，10，11，12，13-六氢-10-甲氧基-9-甲基-1-氧代-9，13-环氧-1H，9H-二吲哚并[1，2，3-gh：3′，2′，1′-lm]吡咯并[3，4-j][1，7]苯并二氮杂环壬四烯-11-基]-N-甲基苯甲酰胺的星孢素衍生物或其盐，被称为米哚妥林或PKC412。
在前引用的美国专利第5,093,330号描述了米哚妥林的制备和其作为蛋白激酶C选择性抑制剂的用途及其可药用盐。
米哚妥林可以口服施用，剂量达约300mg/日，例如100-300mg/日。米哚妥林以单一剂量施用或分成每日2剂或3剂施用，优选2剂。米哚妥林特别重要的剂量是200-225mg/日，特别是每日100mg两次(总共200mg/日)。剂量上限由副作用决定，其可通过对被治疗患者的试验来测定。
用于本文的术语“伊马替尼抗药性GIST”或“伊马替尼治疗难治性的胃肠道基质肿瘤”定义了用伊马替尼不再治疗有效或治疗效果降低的胃肠道基质肿瘤。
本发明涉及伊马替尼或其可药用盐和米哚妥林或其可药用盐的组合的用途。本发明涉及伊马替尼或其可药用盐和米哚妥林或其可药用盐的组合在制备用于治疗胃肠道基质肿瘤、例如伊马替尼抗药性胃肠道基质肿瘤的药物中的用途。
这样的组合治疗在本文中被称为“本发明的组合”。本发明的组合尤其是组合的制剂。本文中所用的术语“组合的制剂”尤其定义了“组分包”，其含义是至少两种上文定义的活性成分可独立给药，或使用不同量成分的不同固定组合给药，即同时或在不同的时间点给药。组分包的各组分可例如同时或按时间顺序交错施用，即在不同时间点和相同或不同的时间间隔施用组分包的任意组分。优选地，所选择的时间间隔使得联合使用各组分对所治疗疾病的效果大于仅使用任何一种活性成分获得的效果。在组合制剂中所施用的伊马替尼和米哚妥林的总量比率可以变化，例如以满足所治疗的患者亚群的需要或单一患者的需要，该不同的需要可能由于患者的年龄、性别、体重等所致。
本发明还涉及包装的伊马替尼或包装的米哚妥林，其包括使用两种化合物或其盐一起用于治疗GIST的说明书。
一方面，本发明提供了治疗GIST的方法，包括向有需要的温血动物、特别是人施用对抗GIST联合治疗有效量的本发明的组合。更特别的是，本发明提供了治疗患有GIST患者的方法，其包括向患者施用伊马替尼或其可药用盐和米哚妥林或其可药用盐的有效组合。更特别的是，本发明提供了治疗患有GIST患者的方法，其包括向患者施用伊马替尼或其可药用盐和米哚妥林或其可药用盐的有效组合，其中伊马替尼作为口服药物制剂以每日100至1000mg、优选每日200至800mg、特别是每日400、600或800mg、最特别为每日600mg的剂量施用，米哚妥林作为口服药物制剂以每日100至300mg、特别是每日150至250mg、最特别为每日200mg的剂量施用。最优选地，伊马替尼以其单甲烷磺酸盐施用。
本发明涉及伊马替尼或其可药用盐和米哚妥林或其可药用盐的组合在制备用于治疗胃肠道基质肿瘤、例如伊马替尼-抗药性胃肠道基质肿瘤的药物中的用途，其中伊马替尼和米哚妥林独立给药。在本发明的一个实施方案中，伊马替尼和米哚妥林各自口服施用。
药物组合物
伊马替尼药物制剂
按下列组成制备含有相当于100mg伊马替尼(游离碱)的119.5mg伊马替尼甲磺酸盐作为活性物质的胶囊。
组合物1
伊马替尼甲磺酸盐 119.5mg
纤维素MK GR 92mg
交联聚维酮XL 15mg
Aerosil 200 2mg
硬脂酸镁 1.5mg
230mg
通过混合各成分并将混合物填充入1号硬明胶胶囊中制备胶囊。
米哚妥林药物制剂
组合物A
将Gelucire 44/14(82份)加热至60℃熔化。将粉末状米哚妥林(18份)加入到熔化的物料中。将所得混合物均化，将获得的分散物装入至不同尺寸的硬明胶胶囊中，因此一些胶囊含有25mg剂量、其它胶囊含有75mg剂量的米哚妥林。所得胶囊适于口服施用。
组合物B
将Gelucire 44/14(86份)加热至60℃熔化。将粉末状米哚妥林(14份)加入到熔化的物料中。将混合物均化，将获得的分散物装入至不同尺寸的硬明胶胶囊中，因此一些胶囊含有25mg剂量、其它胶囊含有75mg剂量的米哚妥林。所得胶囊适于口服施用。
从Gattefossé商购可得的Gelucire 44/14是C8-C18饱和脂肪酸与甘油的酯和分子量约为1500的聚乙二醇的混合物，脂肪酸组成规格为以重量计4-10％辛酸、3-9％癸酸、40-50％月桂酸、14-24％肉豆蔻酸、4-14％棕榈酸及5-15％硬脂酸。
Gelucire配方的优选实例的组成为：
Gelucire(44/14)：47g
米哚妥林：3.0g填充至60ml Twist off烧瓶中。
软凝胶实施例将含有下列微乳：
玉米油(cornoil)甘油酯 85.0mg
聚乙二醇400 128.25mg
Cremophor RH 40 213.75mg
米哚妥林 25.0mg
DL α生育酚 0.5mg
无水乙醇 33.9mg
总计 486.4mg
治疗实施例
使用单一日剂量为600mg伊马替尼碱的伊马替尼甲磺酸盐和每日两次100mg剂量的米哚妥林(4胶囊b.i.d.)治疗患有伊马替尼治疗难治性的、不可切除或转移的胃肠道基质肿瘤的成年患者。伊马替尼早晨剂量应当在服用米哚妥林前半小时服用。两种药物均与食物和一大杯水一起服用，以最小化胃肠道刺激的危险。在发生严重副反应的情况下，将米哚妥林的剂量减至100mg/日(50mg b.i.d.)。
六名患者中有两名在治疗期间疾病稳定。
Claims (15)
1.包含伊马替尼或其可药用盐和米哚妥林或其可药用盐的组合在制备用于治疗胃肠道基质肿瘤的药物中的用途。
2.根据权利要求1的用途，其中伊马替尼以100-1000mg剂量施用。
3.根据权利要求2的用途，其中所施用伊马替尼的剂量是每日200-800mg。
4.根据权利要求3的用途，其中每日施用的伊马替尼剂量是400、600或800mg。
5.根据权利要求1的用途，其中米哚妥林以每日100-300mg剂量施用。
6.根据权利要求5的用途，其中剂量是每日150-250mg。
7.根据权利要求6的用途，其中剂量是每日200mg。
8.根据上述权利要求任意一项的用途，其中伊马替尼和米哚妥林各自口服施用。
9.根据上述权利要求任意一项的用途，其中伊马替尼作为其单甲磺酸盐施用。
10.根据上述权利要求任意一项的用途，其中伊马替尼和米哚妥林独立地给药。
11.根据上述权利要求任意一项的用途，其中胃肠道基质肿瘤是伊马替尼抗药性胃肠道基质肿瘤。
12.本发明的组合在制备用于治疗胃肠道基质肿瘤的药物中的用途。
13.权利要求12中的用途，其中胃肠道基质肿瘤是伊马替尼的治疗难治性的。
14.商用包装，包含包装的伊马替尼或包装的米哚妥林以及使用伊马替尼和米哚妥林或其盐一起用于治疗胃肠道基质肿瘤的说明书。
15.治疗患有胃肠道基质肿瘤患者的方法，其包括向患者施用伊马替尼或其可药用盐和米哚妥林或其可药用盐的有效组合。
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| CO4940418A1 (es) * | 1997-07-18 | 2000-07-24 | Novartis Ag | Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso |
| ITMI992711A1 (it) * | 1999-12-27 | 2001-06-27 | Novartis Ag | Composti organici |
| SK287335B6 (sk) * | 2000-10-27 | 2010-07-07 | Novartis Ag | Použitie 4-{(4-metylpiperazin-1-ylmetyl)-N-[4-metyl-3-(4-pyrid-3- yl)pyrimidin-2-ylamino]fenyl}-benzamidu na prípravu farmaceutických kompozícií na liečenie gastrointestinálnych strómových tumorov |
| US20050209244A1 (en) * | 2002-02-28 | 2005-09-22 | Prescott Margaret F | N{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine coated stents |
| JP4429732B2 (ja) * | 2002-04-10 | 2010-03-10 | バージニア コモンウェルス ユニバーシティー | 癌の処置におけるグリベック（ｓｔｉ５７１）とサイクリン依存性キナーゼインヒビター、とりわけフラボピリドールとの組合せ剤 |
-
2004
- 2004-09-17 WO PCT/EP2004/010467 patent/WO2005027971A1/en active Application Filing
- 2004-09-17 AU AU2004273605A patent/AU2004273605B2/en not_active Ceased
- 2004-09-17 MX MXPA06003056A patent/MXPA06003056A/es not_active Application Discontinuation
- 2004-09-17 EP EP04765359A patent/EP1667719B1/en not_active Not-in-force
- 2004-09-17 BR BRPI0414527-5A patent/BRPI0414527A/pt not_active IP Right Cessation
- 2004-09-17 AT AT04765359T patent/ATE489109T1/de not_active IP Right Cessation
- 2004-09-17 CA CA002538523A patent/CA2538523A1/en not_active Abandoned
- 2004-09-17 CN CNB2004800270630A patent/CN100467064C/zh not_active Expired - Fee Related
- 2004-09-17 JP JP2006526596A patent/JP2007505859A/ja active Pending
- 2004-09-17 DE DE602004030265T patent/DE602004030265D1/de active Active
- 2004-09-17 US US10/572,259 patent/US20080096864A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CN100467064C (zh) | 2009-03-11 |
| AU2004273605A1 (en) | 2005-03-31 |
| CA2538523A1 (en) | 2005-03-31 |
| MXPA06003056A (es) | 2006-05-31 |
| BRPI0414527A (pt) | 2006-11-07 |
| ATE489109T1 (de) | 2010-12-15 |
| DE602004030265D1 (de) | 2011-01-05 |
| WO2005027971A1 (en) | 2005-03-31 |
| JP2007505859A (ja) | 2007-03-15 |
| EP1667719B1 (en) | 2010-11-24 |
| EP1667719A1 (en) | 2006-06-14 |
| US20080096864A1 (en) | 2008-04-24 |
| AU2004273605B2 (en) | 2008-07-31 |
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