CN102160864A - 用替莫唑胺改善癌症治疗 - Google Patents
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Abstract
本申请涉及用替莫唑胺改善癌症治疗。本发明提供一种治疗癌症病人的方法,该方法给予所述病人至少两个周期的给药周期剂量表的替莫唑胺,其中各周期包括5-25天的给药期,在此给药期内每天给予40-150mg/m2/天剂量的替莫唑胺,接着是5-14天的休息期,在此休息期内不给予替莫唑胺。本发明也提供一种给予替莫唑胺的药盒,该药盒具有按照上述周期给药剂量表给予替莫唑胺的打印说明书和至少一个周期的剂量单位形式的替莫唑胺,其中各剂量单位含有5-250mg替莫唑胺和可药用载体。
Description
本申请是申请号为00805865.2、中国申请日为2001年9月29日、国际申请日为2000年3月27日的发明专利申请的分案申请。
技术领域
本发明涉及癌症的治疗,特别是涉及用替莫唑胺治疗癌症。
背景技术
本发明背景
替莫唑胺因其抗肿瘤作用为人们所知道。例如,在一项研究中,有17%晚期黑素瘤病人获得临床反应(Newlands等人Br.J.Cancer 65(2)287-291(1992))。在另一项研究中,有21%晚期黑素瘤病人获得临床反应(Journal of Clinical Oncology,Vol 13,No.4(April),1995,pp 910-913)。用替莫唑胺治疗成人神经胶质瘤也是已知的(Eur.J.Cancer 1993;29A:940)。用替莫唑胺治疗下列成人癌症也已经公开:转移黑素瘤;高级神经胶质瘤,成胶质细胞瘤和其他脑癌;肺癌;乳腺癌;睾丸癌;结肠和直肠癌;癌;肉瘤;淋巴瘤;白血病和蕈样真菌病。在本发明之前,通常采用的替莫唑胺给药方法是以28天为一周期给药,在该周期的前5天每天给药,然后休息23天,在休息期内不给药。Newlands等人Br.J.Cancer 65(2)287-291(1992)。已经进行了临床试验,在该试验中,结合放射性治疗连续给予每日剂量的替莫唑胺6-7周。例如,参见Brock等人,Cancer Research 58,4363-4367(1998)。
发明内容
本发明概述
本发明提供一种治疗癌症病人的方法,它包含给予所述病人至少两个周期的给药周期剂量表的替莫唑胺,其中各周期包含5-25天的给药期,在此给药期内每天给予40-150mg/m2/天剂量的替莫唑胺,接着是5-14天的休息期,在此休息期内不给予替莫唑胺。
本发明另一方面提供给予替莫唑胺的药盒,其中包含按照上述给药周期剂量表给予替莫唑胺的打印说明书和提供至少一个周期剂量单位形式的替莫唑胺,其中各剂量单位包含5-250mg替莫唑胺和可药用载体。
本发明详述
术语“替莫唑胺”是指具有下列结构式的化合物:
替莫唑胺的一个化学名是3,4-二氢-3-甲基-4-氧代咪唑并-[5,1-d]1,2,3,4-四嗪-8-甲酰胺。替莫唑胺的合成是公知的。例如,参见Stevens et al.,J.Med.Chem,1984,27,196-201和Wang etal.,J.Chem.Soc.,Chem.Commun.,1994,pp 1687-1688。
本文所使用的术语“mg/m2/天”是指以mg每平方米病人体表面积表示的日剂量。
本文所使用的术语“病人”是指哺乳动物,优选人。
可用本发明方法治疗的癌症实例包括但不限制于黑素瘤;高级神经胶质瘤,成胶质细胞瘤和其他脑癌;肺癌;乳腺癌;睾丸癌;胃肠道癌包括结肠癌,直肠癌,胰腺癌和胃癌,肝细胞癌;头颈癌;***癌,肾细胞癌;腺癌;肉瘤;淋巴瘤;白血病和蕈样真菌病。本发明可以在癌症发现至晚期的任何阶段治疗这些癌症和其他癌症。本发明包括治疗原发癌及其转移癌。
癌症患者可表现出一种或多种下列迹象或症状:
(a)、存在癌性肿瘤,
(b)、疲劳,
(c)、疼痛,
(d)、由肿瘤负担造成的工作业绩降低状态,和
(e)、与各特定癌有关的公知的症状。
本发明休息期(周期中不给予替莫唑胺的时期)是5-14天,更优选5-10天,最优选1周。本发明给药期是5-25天,更优选1,2,或3周,并且最优选1或3周。只要治愈、减轻或消除所治疗的癌症需要,治疗期可延长。
在本发明给药期的每日剂量为40-150mg/m2/天,更优选40-125mg/m2/天,最优选75-125mg/m2/天。每日剂量可以以单次剂量,或以加起来等于单次剂量的多次剂量形式给予。例如,每日100mg/m2的剂量可以以两次50mg/m2的剂量或以四次25mg/m2的剂量给予。如果遇到有不耐受副的作用或血液学毒性,可以降低所选择的剂量。
替莫唑胺常见的而且可耐受的副作用是恶心和呕吐。这可通过与替莫唑胺一起给予止吐药减轻。在给予替莫唑胺之前大约30分钟,口服给予大约8mg剂量的止吐药昂丹司琼是优选的。如果需要,也可以使用其他止吐药如Hasaldol,苯海拉明和Ativan。
优选地,替莫唑胺以一种与常规药用载体混合的胶囊剂形式口服给予。优选的替莫唑胺胶囊剂为:
*白色不透明物,无防腐剂,拼合式硬明胶胶囊
如果能够获得,可选择替莫唑胺的其他给药形式,如通过I V注射或输注,通过鞘内,通过缓释剂型,糖浆剂,栓剂,透皮吸收,鼻喷雾剂等给予。只要能释放适当的剂量而不破坏替莫唑胺,任何给药形式都将产生作用。
在某些情况下,在实施本发明周期给药方案之前,先口服给予大约100-500mg/m2剂量的大丸药可能是优选的。
本发明药盒可以是任何形式的药盒,它适用于提供至少一个周期的替莫唑胺和按照周期给药剂量表给药的书写说明书。其实例包括但不限制于各种容器(例如瓶子,硬纸盒,水泡包装和安瓿),其中或者有描述周期给药说明书的包装***页,或者周期给药说明书直接印在或者粘贴在容器上。
下列实施例用于说明上述本发明,但该实施例不应该解释为限制本发明范围。
具体实施方式
实施例1
给予患有神经胶质瘤的病人替莫唑胺,以14天为一个周期,连续给予12个周期,各周期包括一周的给药替莫唑胺期,在该给药期内,以100mg/m2/天的速度给予替莫唑胺,接着是一周的休息期,在该休息期内不给予替莫唑胺。
实施例2
给予患有神经胶质瘤的病人替莫唑胺,以28天为一个周期,连续给予6个周期,各周期包括三周的给药期,在该给药期内,以100mg/m2/天的速度给予替莫唑胺,接着是一周的休息期,在该休息期内不给予替莫唑胺。
实施例3
给予患有晚期黑素瘤的病人替莫唑胺,以14天为一个周期,连续给予12个周期,各周期包括一周的给药期,在该给药期内,以100mg/m2/天的速度给予替莫唑胺,接着是一周的休息期,在该休息期内不给予替莫唑胺。
实施例4
给予患有晚期黑素瘤的病人替莫唑胺,以28天为一个周期,连续给予6个周期,各周期包括三周的给药期,在该给药期内,以100mg/m2/天的速度给予替莫唑胺,接着是一周的休息期,在该休息期内不给予替莫唑胺。
尽管结合上述特定实施方案描述了本发明,但本发明的很多替代、修饰和改变形式对本领域普通技术人员都将是显而易见的。所有这些替代、修饰和改变形式都包括在本发明精神实质和范围内。
Claims (19)
1.一种给予替莫唑胺的药盒,它包含:
(a)给予癌症病人至少两个周期给药周期剂量表的替莫唑胺的打印说明书,其中各周期包含5-25天的给药期,在此给药期内每天给予40-150mg/m2/天剂量的替莫唑胺,接着是5-14天的休息期,在此休息期内不给予替莫唑胺;和
(b)提供至少一个周期的剂量单位形式的替莫唑胺,其中各剂量单位包含5-250mg替莫唑胺和可药用载体。
2.权利要求1的药盒,其中所述的休息期为5-10天。
3.权利要求2的药盒,其中所述的每日剂量为75-125mg/m2/天。
4.权利要求1的药盒,其中所述的休息期为一周。
5.权利要求4的药盒,其中所述的每日剂量为75-125mg/m2/天。
6.权利要求4的药盒,其中所述的给药期为一、二或三周。
7.权利要求4的药盒,其中所述的给药期为一周,并且所介绍的每日剂量为75-125mg/m2/天。
8.权利要求4的药盒,其中所述的给药期为三周,并且所介绍的每日剂量为75-125mg/m2/天。
9.替莫唑胺在制备用于治疗癌症的药物中的用途,其包含给予所述病人至少两个周期的给药周期剂量表的替莫唑胺,其中各周期包含5-25天的给药期,在此给药期内每天给予40-150mg/m2/天剂量的替莫唑胺,接着是5-14天的休息期,在此休息期内不给予替莫唑胺。
10.权利要求9的用途,其中休息期为5-10天。
11.权利要求10的用途,其中每日剂量为75-125mg/m2/天。
12.权利要求9的用途,其中休息期为一周。
13.权利要求12的用途,其中每日剂量为75-125mg/m2/天。
14.权利要求9的用途,其中给药期为一、二或三周。
15.权利要求14的用途,其中休息期为一周。
16.权利要求15的用途,其中给药期为一周。
17.权利要求16的用途,其中每日剂量为75-125mg/m2/天。
18.权利要求15的用途,其中给药期为三周。
19.权利要求18的用途,其中每日剂量为75-125mg/m2/天。
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US28134899A | 1999-03-30 | 1999-03-30 | |
US09/281348 | 1999-03-30 |
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CN2011100359769A Pending CN102160864A (zh) | 1999-03-30 | 2000-03-27 | 用替莫唑胺改善癌症治疗 |
CN00805865A Pending CN1345240A (zh) | 1999-03-30 | 2000-03-27 | 用替莫唑胺改善癌症治疗 |
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CN00805865A Pending CN1345240A (zh) | 1999-03-30 | 2000-03-27 | 用替莫唑胺改善癌症治疗 |
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EP (1) | EP1165071B1 (zh) |
JP (2) | JP2002540148A (zh) |
CN (2) | CN102160864A (zh) |
AR (1) | AR023185A1 (zh) |
AT (1) | ATE310515T1 (zh) |
AU (1) | AU780892B2 (zh) |
BR (1) | BR0009380A (zh) |
CA (1) | CA2368614C (zh) |
DE (1) | DE60024243T2 (zh) |
DK (1) | DK1165071T3 (zh) |
ES (1) | ES2251987T3 (zh) |
HK (1) | HK1044111B (zh) |
HU (1) | HUP0200805A3 (zh) |
NO (1) | NO330651B1 (zh) |
NZ (1) | NZ536302A (zh) |
TW (1) | TWI276434B (zh) |
WO (1) | WO2000057867A2 (zh) |
ZA (1) | ZA200107736B (zh) |
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CN100366249C (zh) * | 2002-09-29 | 2008-02-06 | 天津帝士力投资控股集团有限公司 | 一种替莫唑胺控释给药*** |
CN1742723A (zh) * | 2004-09-02 | 2006-03-08 | 天津倍方科技发展有限公司 | 含有替莫唑胺-8-羧酸酯的药物组合物以及该类化合物用于制备抗肿瘤药物的用途 |
CN1299772C (zh) * | 2004-10-14 | 2007-02-14 | 孔庆忠 | 一种抗癌药物组合物 |
US20060100188A1 (en) * | 2004-11-09 | 2006-05-11 | Chen Zong | Treatment methods |
US20070265324A1 (en) * | 2006-01-17 | 2007-11-15 | Wolfgang Wernet | Combination Therapy with Parp Inhibitors |
SG10201500028RA (en) * | 2006-04-05 | 2015-02-27 | Opko Health Inc | Pharmaceutical formulations: salts of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and treatment methods using the same |
AR061618A1 (es) * | 2006-06-26 | 2008-09-10 | Schering Corp | Formas de dosificacion unitaria de temozolomida |
WO2008022535A1 (fr) * | 2006-08-09 | 2008-02-28 | Tian Jin Tasly Group Co., Ltd. | Composition pharmaceutique pour traiter le gliome du cerveau, son procédé et sa préparation pharmaceutique |
KR101438036B1 (ko) * | 2006-09-29 | 2014-09-04 | 씨아이피엘에이 엘티디. | 테모졸로미드 및 유사체의 개선된 제조방법 |
WO2012075210A2 (en) * | 2010-12-01 | 2012-06-07 | Niiki Pharma Inc. | Method for treating refractory cancer |
CN102526038B (zh) * | 2011-01-12 | 2013-09-11 | 北京人福军威医药技术开发有限公司 | 替莫唑胺的脑靶向药物组合物及其应用 |
CN107397735B (zh) * | 2017-07-28 | 2020-07-10 | 东曜药业有限公司 | 一种替莫唑胺药物组合物及其制备方法和应用 |
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ATE229343T1 (de) * | 1995-10-04 | 2002-12-15 | Schering Corp | Kombination von temozolomide und alpha-interferon zur behandlung von fortgeschrittenem krebs |
CA2184545A1 (en) * | 1996-07-31 | 1998-02-01 | Pascale Reidenberg | Cancer treatment with temozolomide |
CA2184546A1 (en) * | 1996-07-31 | 1998-02-01 | Margaret H. Dugan | Method for treating pediatric high grade astrocytoma including brain stem glioma |
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ZA200107736B (en) | 2003-02-26 |
CA2368614A1 (en) | 2000-10-05 |
NO330651B1 (no) | 2011-05-30 |
ATE310515T1 (de) | 2005-12-15 |
BR0009380A (pt) | 2001-12-26 |
DE60024243T2 (de) | 2006-08-17 |
HUP0200805A3 (en) | 2004-07-28 |
AU3924400A (en) | 2000-10-16 |
CN1345240A (zh) | 2002-04-17 |
ES2251987T3 (es) | 2006-05-16 |
NO20014725L (no) | 2001-11-13 |
AR023185A1 (es) | 2002-09-04 |
AU780892B2 (en) | 2005-04-21 |
EP1165071A2 (en) | 2002-01-02 |
HUP0200805A2 (hu) | 2002-07-29 |
NO20014725D0 (no) | 2001-09-28 |
WO2000057867A3 (en) | 2001-04-19 |
JP2007169297A (ja) | 2007-07-05 |
HK1044111B (zh) | 2006-02-24 |
WO2000057867A2 (en) | 2000-10-05 |
EP1165071B1 (en) | 2005-11-23 |
CA2368614C (en) | 2008-07-22 |
DE60024243D1 (de) | 2005-12-29 |
JP2002540148A (ja) | 2002-11-26 |
TWI276434B (en) | 2007-03-21 |
DK1165071T3 (da) | 2006-02-20 |
HK1044111A1 (en) | 2002-10-11 |
NZ536302A (en) | 2006-05-26 |
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