CN1444479A - 含有西兰司琼的药物用于治疗男性非便秘性ibs－病人 - Google Patents
含有西兰司琼的药物用于治疗男性非便秘性ibs－病人 Download PDFInfo
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- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 claims description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
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- A61K31/4164—1,3-Diazoles
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Abstract
本发明涉及西兰司琼的应用，用于治疗非便秘性男性IBS－病人。
Description
本发明涉及西兰司琼(Cilansetron)或其酸加成盐的新的医学应用。
西兰司琼是一种5HT3-受体拮抗剂，它包含在欧洲专利EP 0 297651 B1的范畴内，其化学名为(R)-(-)-4，5，6，8，9，10-六氢化-10-[(2-甲基-1H-咪唑-1-基)甲基]-11H-吡啶并-[3，2，1-jk]-咔唑-11-酮。
由欧洲专利EP 0 601 345 B1已知的其中有西兰司琼应用于制备药物以治疗较大哺乳类动物和人类的与结肠段疼痛敏感性过高和/或结肠区排便异常加速相关的下段肠道功能性障碍。属于功能性障碍的而能通过有如西兰司琼治疗的例如还有“过敏性肠道综合症”(＝IBS，肠道刺激综合症)，尤其当伴有结肠段排便异常过速时。
在国际专利申请，公开号WO 99/17755中描述了5HT3-受体拮抗剂，它很好地适合于治疗女性非便秘性IBS-病人(＝以腹泻为主的IBS-病人群；与便秘为主的IBS-病人群相反)。作为实例在WO 99/17755中提及阿洛司琼(Alosetron)，临床试验表明：其对女性IBS-病人比对男性IBS-病人有明显更好的疗效。在这些临床试验中，用阿洛司琼治疗过的男性受试病人与安慰剂组相比较无法有力地确定症状的好转。在WO 99/17755专利申请主题的一种实施形式中，列举落入其公开的范围的其中有西兰司琼。
如今令人惊异地发现，西兰司琼同样地适合于治疗男性和女性患有非便秘性肠道刺激综合症(＝IBS)的病人。
本发明的主题因此是，西兰司琼或其药理学可耐受的酸加成盐和/或溶剂化物的应用，用于制备治疗和/或预防男性病人的非便秘性肠道刺激综合症(＝IBS)的药物。
IBS指具有下腹部疼痛和/或不适感以及变化的肠道活动性所引发的症状如，腹泻、便秘(Konstipation)或腹泻和便秘交替出现的一组症状群。由于至今还没有明确清楚的生理学或其它器质性检查结果能够解释IBS病因，所以该疾病的临床诊断依据为缺乏或存在通常对于IBS来说被视典型的一系列症状，例如在“罗马标准(RomeCriteria)”中(参见W.G.Thompson等，胃肠道内科学(Gastroent.Int.)
2(1989)92-95；W.G.Thompson等，Gut
45/II(1999)II43-II 47；W.G.Thompson等，柳叶刀(Lancet)
341(1993)1569-1572)所确定的。
按照本发明可以优选以西兰司琼-盐酸盐的形式应用西兰司琼。通常应用西兰司琼-盐酸盐-一水合物。其它药理学可耐受的西兰司琼的酸加成盐类已经在EP 0 297 651 B1中公开。
临床试验数据表明：西兰司琼令人惊异地与治疗女性一样地适合于治疗男性非便秘性IBS-病人。
具有随机(randomized)挑选病例和并列试验组病例进行的12周安慰剂对比性临床双盲试验中，检验了西兰司琼对男女性别非便秘性IBS-病人的作用。本研究范围内所指的非便秘性IBS-病人为，其病征符合“罗马标准”(见上述)，其大便性状和排便频率应符合以下标准：
i)≤25％因便秘而影响IBS-症状。
ii)作为非便秘性，其特性符合“罗马标准”(见上述，病人每周不＜3次肠道运动(＝“bowel movements”)，和/或大便性状表现为硬/成团块状)。
iii)在2周的连续观察期间(＝“run-in period”)，≤4天(前后连续或不连续)没有肠道运动。
iv)在2周的观察期间平均的大便性状≥4(根据“布里斯托(Bristol)-大便分级法”)。
如果病人在回答下腹部疼痛或不适感的问题时≤50％情况下回答“没有：或者以“有限地”来评价在2周的观察期间其下腹部疼痛或不适感＜2次，则这些病人也照样被吸收入该试验中。
西兰司琼的应用剂量为1、2、8和16mg。每周检查病人的IBS-症状(腹痛如腹部疼痛、肠道活动异常)是否“适当减轻”(＝初级疗效参数)。病人每天评判其腹痛如腹部疼痛、大便性状和次数(＝次级疗效参数)。
在目前的双盲试验结果中评估了总共454病例(297女性病例和157男性病例)的数据，并列于下表中。根据本临床双盲试验所依据的标准，在男性IBS-和女性IBS-的二个病例组中，确定了下表说明有关IBS-症状的“适当减轻”的成效比例
表
| 成效比例[％] | 安慰组 | 西兰司琼(mg TID) | |||
| 1 | 2 | 8 | 16 | ||
| 男性病人 | 30.0 | 51.3 | 63.0 | 56.3 | 58.6 |
| 女性病人 | 41.8 | 69.6 | 60.3 | 56.9 | 61.4 |
“初级疗效参数”相当于每周对病人提问的成效比例(＝responder rate)，提问是在上周是否感到其IBS-症状(下腹部疼痛/不适感；结肠活动异常)“适当减轻”。如果一个男性病人或女性病人接受了至少4周的治疗，对于向其提出的是否出现IBS-症状的“适当减轻”的问题，在其治疗期间的至少一半回答为“是”的，则被看作为“有成效者(responder)”。
本双盲试验结束后，对总共471病例(308女性，163男性)数据进行了评估。最终的成效比例测定安慰组为40％、1mg剂量(每日3次(TID))西兰司琼组为62％、2mg剂量(TID)西兰司琼组为53％、8mg剂量(TID)西兰司琼组为55％、和16mg剂量(TID)西兰司琼组为63％。成效比例在男性病例组和在女性病例组非常接近。所观察到的最大差别是在1mg剂量(TID)西兰司琼时。
由以上说明的数据可见，两种性别的非便秘性IBS-病人都对所有试验剂量下的西兰司琼治疗有反应。
特别令人惊异地是，由上述试验结果所证实的西兰司琼在治疗非便秘性(＝腹泻为主)男性IBS-病人时的疗效，因为专业人员从WO99/17755的内容中所得出的结论是，西兰司琼，同样地还有阿洛司琼，优选只适合于治疗非便秘性女性IBS-病人。
已知的5HT3-受体-拮抗剂在用于治疗IBS-时通常每天2次给药(＝“BID-剂量”)。然而用于治疗二种性别的IBS-病人证实更有利的是每天3次5HT3-受体-拮抗剂，例如对二种性别的IBS-病人分别以1mg至16mg的剂量给药(＝“TID-剂量”)。特别优选的是，将每天3次5HT3-拮抗剂的用药分配在白天，尤其是分配在主餐(早、中和晚)之后。更有利地以每日3次的剂量给药的5HT3-受体-拮抗剂例如包括：阿洛司琼、Azasetron、多拉司琼(Dolasetron)、格拉司琼(Granisetron)、吲地司琼(Indisetron)、伊地司琼(Itasetron)、来立司琼(Lerisetron)、昂丹司琼(Ondansetron)、雷莫司琼(Ramosetron)、托烷司琼(Tropisetron)和(R)-Zacoprid。正证实特别有利于治疗二种性别的IBS-病人的是，给病人每天3次用药西兰司琼或其药理学可耐受的酸加成盐和/或其溶剂化物，例如剂量分别为1mg至16mg范围之间用药。
作为治疗药物，西兰司琼或其药理学可耐受的酸加成盐，按照本发明可以与通常的制药学佐剂和/或载体物质一起，包含在固态或液态的制药学制剂形式中。例如固态制剂为口服用药制剂如片剂、糖衣丸剂、胶囊、粉剂或粒剂、或者还可以是栓剂。这些制剂除可以含有制药学通常的佐剂例如润滑剂或片剂崩解剂外，还可以含有制药学常见的无机和/或有机载体物质，如滑石、乳糖或淀粉。液态制剂如西兰司琼的悬浮液或乳剂可以含有常用的稀释剂如水、油和/或悬浮剂如聚乙二醇和类似物质。还可以附加添入其它佐剂，例如贮藏剂、矫味剂和类似物质。
西兰司琼或其药理学耐受的酸加成盐可以与制药学佐剂和/或载体物质一起按照已知的方式混合和成型。制备固态药物制剂时，可以例如将西兰司琼或其酸加成盐与佐剂和/或载体物质按照常用的方式混合，并以湿式或干式制粒。粒剂或粉剂可以直接充填胶囊，或者按照常用的方式压制成片剂核。这些可以在需要的时候按照通常的方式制成糖衣丸剂。
以下实施例应该说明含有西兰司琼-盐酸盐的药物制剂的制备。
实施例1：片剂
成分：
西兰司琼-盐酸盐-一水合物 4份
玉米淀粉 30份
乳糖 70份
科利当(Kollidon)25R 5份
硬脂酸镁 2份
滑石粉 3份
总计 114份
制备规程：
将活性物质与玉米淀粉和细粉状的乳糖一起在混合器中混合。将所形成混合物与20％聚乙烯吡咯烷酮(BASF公司的Kollidon 25R)一起在去矿物质的水中浸润。必要时，进一步添加去矿物质的水。将湿润的粒剂通过2mm筛，在40℃温度下在木条架上干燥并随后通过1mm筛(Frewitt-机)。在将粒剂与硬脂酸镁和滑石粉混合后，将其压制成重量为114mg的片剂，使每片剂中含有4mg活性物质。
同样地还可以应用例如由EP 0 895 782 A2已知的西兰司琼的药物配剂。
Claims (8)
1.西兰司琼或其药理学耐受的酸加成盐和/或溶剂化物的应用，用于制备治疗和/或预防非便秘性男性肠道刺激综合症病人的药物。
2.按照权利要求1的西兰司琼-盐酸盐的应用。
3.按照权利要求1的西兰司琼-盐酸盐-一水合物的应用。
4.至少一种5HT3-受体拮抗剂的应用，用于制备药物制剂，以通过每天3次给用药物制剂治疗二种性别的患有肠道刺激综合症的病人。
5.按照权利要求4的应用，其中至少一种5HT3-受体拮抗剂以1mg至16mg的剂量应用。
6.按照权利要求4的应用，其中每天3次给药分别在早、中、晚主餐后。
7.按照权利要求4的应用，其中应用阿洛司琼、Azasetron、多拉司琼、格拉司琼、吲地司琼、伊地司琼、来立司琼、昂丹司琼、雷莫司琼、托烷司琼和/或(R)-Zacoprid作为5HT3-受体拮抗剂。
8.按照权利要求4的应用，其中应用西兰司琼或其药理学可耐受的酸加成盐和/或溶剂化物作为5HT3-受体拮抗剂。
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| DE10036645 | 2000-07-26 | ||
| DE10036645.7 | 2000-07-26 | ||
| DE10123447.3 | 2001-05-14 | ||
| DE10123447A DE10123447A1 (de) | 2000-07-26 | 2001-05-14 | Cilansetron enthaltende Arzneimittel zur Behandlung nicht-obstipativer männlicher IBS-Patienten |
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| JP (1) | JP2004504343A (zh) |
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| MX (1) | MXPA02012917A (zh) |
| NO (1) | NO20030373D0 (zh) |
| PL (1) | PL363517A1 (zh) |
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| GB0216027D0 (en) | 2002-07-10 | 2002-08-21 | Arachnova Therapeutics Ltd | New therapeutic use |
| WO2005073220A1 (ja) * | 2004-01-30 | 2005-08-11 | Yamanouchi Pharmaceutical Co., Ltd. | 下痢型過敏性腸症候群治療剤 |
| RU2314808C2 (ru) * | 2004-01-30 | 2008-01-20 | Астеллас Фарма Инк. | Средство для лечения синдрома раздраженного кишечника с преобладанием диареи |
| JP4632204B2 (ja) * | 2005-09-21 | 2011-02-16 | アステラス製薬株式会社 | 下痢型過敏性腸症候群治療剤 |
| US7662831B2 (en) | 2006-07-27 | 2010-02-16 | Wyeth Llc | Tetracyclic indoles as potassium channel modulators |
| US7601856B2 (en) | 2006-07-27 | 2009-10-13 | Wyeth | Benzofurans as potassium ion channel modulators |
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| GB9930077D0 (en) * | 1999-12-20 | 2000-02-09 | Glaxo Group Ltd | Medicaments |
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- 2001-07-18 JP JP2002513449A patent/JP2004504343A/ja active Pending
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| Publication number | Publication date |
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| HUP0301479A2 (hu) | 2003-09-29 |
| CZ2003158A3 (cs) | 2003-08-13 |
| MXPA02012917A (es) | 2003-05-14 |
| AR028970A1 (es) | 2003-05-28 |
| JP2004504343A (ja) | 2004-02-12 |
| PL363517A1 (en) | 2004-11-29 |
| SK1272003A3 (en) | 2003-07-01 |
| EP1307195A2 (de) | 2003-05-07 |
| BR0112690A (pt) | 2003-06-24 |
| IL153972A0 (en) | 2003-07-31 |
| AU2001276409A1 (en) | 2002-02-05 |
| RU2003104798A (ru) | 2004-06-27 |
| NO20030373L (no) | 2003-01-24 |
| CA2417677A1 (en) | 2003-01-27 |
| WO2002007713A3 (de) | 2002-11-14 |
| WO2002007713A2 (de) | 2002-01-31 |
| NO20030373D0 (no) | 2003-01-24 |
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