CN1929841A - (+)－赤型－甲氟喹的药物组合物及其用途 - Google Patents

(+)－赤型－甲氟喹的药物组合物及其用途 Download PDF

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CN1929841A
CN1929841A CNA200580008298XA CN200580008298A CN1929841A CN 1929841 A CN1929841 A CN 1929841A CN A200580008298X A CNA200580008298X A CN A200580008298XA CN 200580008298 A CN200580008298 A CN 200580008298A CN 1929841 A CN1929841 A CN 1929841A
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erythro
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H·F·贝克
R·M·班尼斯特
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Sosei R&D Ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract

一种含1－60mg(+)－赤型－甲氟喹的单位剂量形式的药物组合物。其用于每日给药。

Description

(+)-赤型-甲氟喹的药物组合物及其用途
发明领域
本发明涉及(+)-赤型-甲氟喹的组合物及其治疗炎性疾病的用途。
发明背景
甲氟喹外消旋体(拉力灵)是一种已知的抗疟疾药。通常将其配制为含250mg活性成分的片剂，每周服用一次。拉力灵具有众所周知的副作用。
Bates等人，Int.Arch.Allergy Appl.Immunol.(1998)86：446-452，公开了外消旋甲氟喹可刺激人嗜中性白细胞脱粒。虽然数据表明甲氟喹是促炎性的，但仍说明(没有证据)甲氟喹可用作抗炎剂。在长期治疗中，任何这种使用都会被拉力灵已知的副作用损害，特别是在心脏病患者中。
WO02/19994首次公开了(+)-赤型-甲氟喹的单一对映异构体可用于治疗慢性病，特别是慢性炎性疾病，如骨关节炎和类风湿性关节炎。该出版物报道了该特定对映异构体的副作用已经大大降低。
炎性疾病已经用抗-TNF抗体治疗。已知许多患者(多达40％)对该治疗不应。
发明概述
本发明至少部分基于对存在使用(+)-赤型-甲氟喹可用于治疗例如疟疾和炎性疾病的治疗手段的了解。因此，新的药物组合物是含1-60mg(+)-赤型-甲氟喹、基本上没有相反对映异构体的单位剂量形式。该剂量形式用于每日服用。
(+)-赤型-甲氟喹与抗-TNF抗体联合使用可能特别有效。这种抗体可补充(+)-赤型-甲氟喹广泛、适度的IL-1拮抗剂活性，联合给药可帮助克服与对抗-TNF治疗不应的患者(如上所述)有关的问题。因此，这种联合疗法构成本发明的又一方面。
使用(+)-赤型-甲氟喹的另一特征在于可降低免疫抑制剂如氨甲蝶呤的副作用，同时仍然保留功效。因此，与这种药剂联合或共同给药是本发明的又一方面。
优选实施方案的描述
尽管事实上甲氟喹具有较长的半衰期，但本发明建议的每日剂量仍然使活性物质浓度的峰值和谷值降低。如果药物水平在所治疗患者的系统中相对均一，则可增加成功治疗的机会。
应当给予的药剂的用量可由本领域技术人员在考虑患者类型、所治疗疾病的性质、和给药途径等通常因素的情况下很容易地确定。对映异构体的量可高于或等于外消旋体的量，或可根据其它药物的共同给药而改变。
活性成分的剂量可低于和拉力灵给药有关的剂量。本发明的每日剂量可至少为5mg，且常常只是15、20或40mg。妇女优选相对较低的剂量。
用于本发明时，可通过本领域已知的方法，包括已建议的用于外消旋体的方法，将活性物质与载体、赋形剂或稀释剂一起配制，并给药。适宜的组合物将取决于预期的给药途径，其可以是，例如，口服、局部、鼻、直肠、舌下、口腔或透皮。可使用持续、延迟、定时或即时释放组合物。
该制剂优选单位剂量，用于每日给药。它可以是，例如，胶囊、安瓿或，优选，通常含填充剂、压制助剂、崩解剂、湿润剂和润滑剂的片剂。
可治疗的疾病包括涉及软骨破坏的疾病、炎性疾病和由IL-2和IL-6介导的疾病，例如类风湿性关节炎、哮喘、牛皮癣、牛皮癣性关节炎、克罗恩氏病、应激性肠综合征和系统性红斑狼疮。其它相关疾病是溃疡性结肠炎、COPD和哮喘。患者可能易发生CNS副作用和/或可能要经历与另一种药物，例如TNF抗体或免疫抑制剂如氨甲蝶呤的共同治疗。
(+)-赤型-甲氟喹的使用可提供所需的治疗效果，而没有组织破坏，且能够以相对较高的剂量安全给药。所需的甲氟喹对映异构体相对于任何其它对映异构体可至少50％、70％、90％、95％或99％过量。该活性物质可以任何活性形式使用，例如，盐或非盐。
下列研究提供本发明所依据的证据。
组合
制备(+)-赤型-甲氟喹的200mg片剂，分别含(A)4.5mg、(B)9mg和(C)18mg该药剂(4.92mg、9.86mg和19.71mg其HCl盐)。各制剂还含有76mg微晶纤维素、7mg聚维酮、10mg聚乙烯聚吡咯烷酮、2mg十二烷基硫酸钠、2mg硬脂酸镁和乳糖(在A、B和C中分别为98.07mg、93.14mg和87.29mg)。
该制剂用于氨甲蝶呤治疗的背景。观察到下列出现率的不利事件：
安慰剂-36.8％
A-    5.9％
B-    22.2％
C-    16.7％
因此，(+)-赤型-甲氟喹和氨甲蝾呤的组合较之单独的氨甲蝶呤具有更少的不利事件。
功效
相对于制剂B(9mg(+)-赤型-甲氟喹)，记录各受治疗者的DAS28得分 (http：//www.das-score.nl/www.das-score.nl/DAS CRP.html)。结果在图1，即各DAS得分相对于Visit的曲线图中表示。观察到所有患者的DAS得分均降低；在研究过程(1个月)中，平均降低0.71个单位。
CNS益处
当在旅行者研究中测试时，外消旋甲氟喹在情绪状态分布调查问卷(the Profile of Mood States Questionnaire)上显示增加了总心境障碍(TMD)7.5个单位的增加(van Riemskijk等人，Clin，Pharmacol.Ther.2002：72 294-301)。在临床研究中，进行氨甲蝶呤背景治疗的患者每日接受安慰剂，或者制剂A、B或C长达1个月，后者的TMD得分降低(即，患者的心境改善)。其在图2，即TMD(平均得分)相对于时间(天数)的曲线图中表示；◆代表安慰剂，▲代表A，■代表B且★代表C。
PK分布
制剂C的每日给药产生203ng/ml的最小血浆浓度和263ng/ml的最大血浆浓度，差值为60ng/ml。36mg的每日剂量等同于通常的外消旋甲氟喹剂量。预期具有约120ng/ml的最小与最大血浆浓度差值，其明显不同于每周给予约500ng/ml外消旋甲氟喹所见到的血浆浓度的变化。

Claims (15)

1.一种含1-60mg(+)-赤型-甲氟喹、基本上没有相反对映异构体的单位剂量形式的药物组合物。
2.根据权利要求1所述的组合物，其中该单位剂量是含载体和/或赋形剂的片剂。
3.根据权利要求1或权利要求2所述的组合物，其中该单位剂量含至多40mg的(+)-赤型-甲氟喹。
4.根据权利要求3所述的组合物，其中该单位剂量含至多20mg的(+)-赤型-甲氟喹。
5.根据权利要求3所述的组合物，其中该单位剂量含至多15mg的(+)-赤型-甲氟喹。
6.根据前述任一权利要求所述的组合物，其中该单位剂量含至少5mg的(+)-赤型-甲氟喹。
7.(+)-赤型-甲氟喹用于制备前述任一权利要求所述的治疗炎性疾病的组合物的用途。
8.根据权利要求7所述的用途，其中该疾病为骨关节炎。
9.根据权利要求7所述的用途，其中该疾病为类风湿性关节炎。
10.根据权利要求7-9任何一项所述的用途，其中该疾病也可用抗-TNF抗体治疗。
11.根据权利要求7-10任何一项所述的用途，其中受治疗者还接受免疫抑制剂。
12.根据权利要求11所述的用途，其中免疫抑制剂为氨甲蝶呤。
13.一种含(+)-赤型-甲氟喹和抗-TNF抗体的产品，其以联合制剂的形式同时、分开或顺序用于治疗炎性疾病。
14.一种含(+)-赤型-甲氟喹和免疫抑制剂的产品，其以联合制剂的形式同时、分开或顺序用于治疗炎性疾病且其中还需要免疫抑制。
15.根据权利要求14所述的产品，其中免疫抑制剂为氨甲蝶呤。
CNA200580008298XA 2004-03-17 2005-03-17 (+)－赤型－甲氟喹的药物组合物及其用途 Pending CN1929841A (zh)

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EP (1) EP1773340A2 (zh)
JP (1) JP2007529488A (zh)
KR (1) KR20070030182A (zh)
CN (1) CN1929841A (zh)
AU (1) AU2005224154A1 (zh)
BR (1) BRPI0508855A (zh)
CA (1) CA2558096A1 (zh)
GB (1) GB0406014D0 (zh)
IL (1) IL177751A0 (zh)
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WO2006108666A1 (en) * 2005-04-13 2006-10-19 Proteosys Ag Mefloquine, nelfinavir and saquinavir as novel agents for neurodegenerative and (neuro-) inflammatory diseases
CN114796216A (zh) * 2022-01-04 2022-07-29 南京医科大学 甲氟喹在防治全身代谢性炎症疾病中的应用

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AU730818B2 (en) * 1997-03-07 2001-03-15 Vernalis Research Limited Use of (+)mefloquine for the treatment of malaria
GB0021776D0 (en) * 2000-09-05 2000-10-18 Arakis Ltd The treatment of inflammatory disorders
GB0201025D0 (en) * 2002-01-17 2002-03-06 Arakis Ltd The treatment of degenerative diseases
US20040009172A1 (en) * 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
US7084157B2 (en) * 2002-05-17 2006-08-01 Rajeev Raut Ophthalmic pharmaceutical compositions and methods for treating ocular inflammation
GB0329236D0 (en) * 2003-12-17 2004-01-21 Arakis Ltd Crystalline forms of (+)- and (-)- erthro-mefloquine hydrochloride

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GB0406014D0 (en) 2004-04-21
WO2005089762A3 (en) 2005-11-03
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BRPI0508855A (pt) 2007-08-28
JP2007529488A (ja) 2007-10-25
KR20070030182A (ko) 2007-03-15
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