CN101198331B - 增溶化制剂 - Google Patents
增溶化制剂 Download PDFInfo
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- CN101198331B CN101198331B CN2006800210272A CN200680021027A CN101198331B CN 101198331 B CN101198331 B CN 101198331B CN 2006800210272 A CN2006800210272 A CN 2006800210272A CN 200680021027 A CN200680021027 A CN 200680021027A CN 101198331 B CN101198331 B CN 101198331B
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Abstract
一种lurasidone的溶液型制剂，其含有作为活性成分的N-[4-[4-(1，2-苯并异噻唑-3-基)-1-哌嗪基]-(2R，3R)-2，3-四亚甲基-丁基]-(1’R，2’S，3’R，4’S)-2，3-二环[2，2，1]庚烷二酰亚胺盐酸盐(lurasidone)以及至少一种选自苄醇、N，N-二甲基乙酰胺、乳酸和丙二醇的物质。
Description
技术领域
本发明涉及一种溶液型制剂，其含有N-[4-[4-(1，2-苯并异噻唑-3-基)-1-哌嗪基]-(2R，3R)-2，3-四亚甲基-丁基]-(1’R，2’S，3’R，4’S)-2，3-二环[2，2，1]庚烷二酰亚胺盐酸盐(lurasidone)的游离形式或其可药用酸加成盐作为活性成分。更具体地，本发明涉及溶液型制剂，其中lurasidone的游离形式或其可药用酸加成盐是被增溶的。
背景技术
lurasidone的游离形式和其酸加成盐作为一种治疗药剂已知具有治疗精神病活性并且是有效的，特别对精神分裂症或老年性痴呆等。老年性痴呆广义地分为阿尔茨海默型痴呆和脑血管性痴呆，可以说这两类痴呆在老年性痴呆中占了约80％。随着人口快速老年化，患有痴呆的患者趋于增加，其中在日本65岁或以上的人群中约7％被推测患有痴呆，因此，期望开发对痴呆有效的治疗药剂。lurasidone已知可以口服或胃肠外给药，并且专利文献1公开了以固体剂型如片剂或胶囊、或作为口服制剂的口服液体制剂和作为胃肠外制剂的注射剂或栓剂的给药方法。口服制剂的给药，特别是固体制剂，常常被认为是最常用的并且在许多疾病的治疗中优选使用。但是，精神分裂患者或老年性痴呆患者各自有广泛的症状，因此，有时仅仅通过口服固体制剂来治疗这样的患者并不足够，例如，对急性发作期的精神分裂患者的给药，对拒绝服药的患者或老年患者的给药。
如果难溶的lurasidone的游离形式或其酸加成盐能够被制备成溶液型制剂，它可以在广泛的制剂领域应用，包括胃肠外制剂(如注射剂)，或口服液体制剂，并且可以提供多种方便且有效的治疗更多患者的方法。但是，既然lurasidone或其游离形式在水中溶解度不到几个微克/毫升，迄今很难制备出含有高浓度lurasidone或其游离形式的水溶液型制剂。而且，迄今为止，也不知道增溶lurasidone和其游离形式的方法。在使用溶液型制剂进行如注射的胃肠外给药的情况下，潜在的问题是，由于所使用的有机溶剂的不同而产生例如局部刺激、溶血、神经毒性等，因此，溶液中有机溶剂的剂量或含量受到限制，并且因此需要减少有机溶剂的量。
专利文献1：JP2800953
发明内容
本发明的目的是提供一种溶液型制剂，其中lurasidone的游离形式和其酸加成盐被增溶，其用于精神分裂患者或老年痴呆患者的治疗。
根据本发明研究，本发明人研究发现难溶的lurasidone其水中溶解度低于几个微克/毫升，通过加入至少一种选自苄醇、N，N-二甲基乙酰胺、乳酸和丙二醇的物质，其能够被增溶到约10000到200000倍的高浓度，从而能够制备高稳定性的溶液型制剂。依照下列方法该目的可以实现。
本发明包括如下具体实施方案：
(1).一种溶液型制剂，其含有lurasidone的游离形式N-[4-[4-(1，2-苯并异噻唑-3-基)-1-哌嗪基]-(2R，3R)-2，3-四亚甲基-丁基]-(1’R，2’S，3’R，4’S)-2，3-二环[2，2，1]庚烷二酰亚胺或者其可药用酸加成盐作为活性成分，其中通过加入至少一种选自苄醇、N，N-二甲基乙酰胺、乳酸、无水乙醇和丙二醇的物质使活性成分增溶。
(2).(1)的溶液型制剂，其为胃肠外制剂的形式。
(3).(1)或(2)的任一溶液型制剂，其用于静脉内、肌肉内、皮下或皮内注射。
(4).(1)的溶液型制剂，其为口服液体制剂的形式。
(5).(1)至(4)的任一溶液型制剂，其用于治疗精神分裂或老年痴呆，其含有治疗有效量的用于治疗所述精神病的lurasidone或其可药用酸加成盐。
(6).(1)至(5)的任一溶液型制剂，其含有浓度为1-100mg/mL的活性成分。
(7).(2)或(3)的任一溶液型制剂，其含有浓度为1-20mg/mL的活性成分。
(8).(1)至(5)的任一溶液型制剂，其含有lurasidone和5-25％(W/W)的无水乙醇。
(9).(1)至(5)的任一溶液型制剂，其含有lurasidone和2-15％(W/W)的苄醇。
增溶为高浓度的lurasidone和其酸加成盐可以制备广泛的制剂例如注射剂、外用制剂或口服液体制剂，并且能提供多种方便有效的治疗更多患者的方法。
具体实施方式
lurasidone的游离形式N-[4-[4-(1，2-苯并异噻唑-3-基)-1-哌嗪基]-(2R，3R)-2，3-四亚甲基-丁基]-(1’R，2’S，3’R，4’S)-2，3-二环[2，2，1]庚烷二酰亚胺以及其酸加成盐，它们是有效的向精神药物，尤其作为用于精神分裂的治疗药剂，并且能够以口服或胃肠外给药制剂的形式进行给药。(参见JP2800953)
lurasidone的游离形式的酸加成盐包括可药用无机酸或有机酸的加成盐。该无机酸包括，例如盐酸、氢溴酸、氢碘酸、硫酸等等，该有机酸包括，例如磷酸、乙酸、草酸、柠檬酸、苹果酸、酒石酸、马来酸、富马酸等等。优选的盐是盐酸盐。
口服给药的剂量是每天5-200mg，优选40-120mg。可以一天内分几次给药，但优选一天一次。对于胃肠外给药特别是静脉内注射、肌肉内注射、皮下注射或皮内注射途径，每天剂量范围在0.1-40mg，优选0.2-20mg，更优选0.4-10mg。可以一天内分几次给药，但优选一天一次。
本发明的溶液型制剂指水性或油性药物组合物，其中活性成分和一种添加剂以溶解状态存在，优选水性制剂。优选的添加剂包括苄醇、N，N-二甲基乙酰胺、乳酸、无水乙醇或丙二醇。所述水性制剂可以通过将lurasidone的游离形式或其酸加成盐和添加剂与水进行混合进行制备。所述油性溶剂能够通过将lurasidone的游离形式或其酸加成盐和添加剂混合制备，并且如果需要可加入可药用的油。除了上述添加剂外的其他添加剂也可任选地加入。所述可药用油包括芝麻油、蓖麻油、花生油、山茶油、豆油、橄榄油、薄荷油等等。
本发明的溶液型制剂可为胃肠外制剂如注射剂或外用制剂，以及口服给药用的液体制剂。
本发明的溶液型制剂含有作为活性成分的lurasidone，其浓度为0.2-160mg/mL，优选1-100mg/mL。更特别地，胃肠外制剂如注射剂包含浓度优选为0.2-40mg/mL的活性组分，更优选0.5-30mg/mL，进一步优选1-20mg/mL，并且口服给药用的液体制剂包含其浓度优选2-160mg/mL，更优选4-100mg/mL，进一步优选10mg/mL-80mg/mL。
本发明的溶液型制剂可含有无水乙醇，基于制剂重量，其量为2.5-40％(W/W)，优选5-25％(W/W)。
本发明的溶液型制剂可含有苄醇，基于制剂重量，其量为1-25％(W/W)，优选2-15％(W/W)。
本发明的溶液型制剂需要设计具有长寿命和高稳定性潜力的制剂，并且特别地，优选的制剂包括在60℃放置4周后其总UK峰在1.5％或更少，特别地1.0％或更少的处方。
本发明的溶液型制剂可任选与其他添加剂如增溶剂、缓冲剂、保存剂、抗氧化剂、稳定剂、等张化剂、甜味剂、增甜剂、调味剂、有机酸、无机酸、氨基酸等。
该添加剂不是特定的但是包括药学上常规使用的。缓冲剂可包括，例如乙酸、磷酸、硼酸或其盐等。保存剂包括，例如苯甲酸、苯甲酸钠、亚硫酸钠、水杨酸、水杨酸钠、二丁基羟基甲苯、山梨酸、山梨酸钾、脱氢乙酸钠、对羟基苯甲酸异丁酯、对羟基苯甲酸异丙酯、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯等。抗氧剂包括，例如亚硝酸钠、抗坏血酸、亚硫酸氢钠、乙二胺四乙酸钠、异抗坏血酸、半胱氨酸盐酸盐、生育酚、大豆卵磷脂、巯基乙酸钠、硫代苹果酸钠、生育酚、焦亚硫酸钠、丁基羟基茴香醚、没食子酸丙酯等。等张化剂包括，例如氯化钠、甘露醇、山梨醇、木糖醇、果糖、乳糖、葡萄糖、硫酸钠、柠檬酸、柠檬酸钠、甘油、硼酸、磷酸、磷酸氢钠、磷酸二氢钠、氢氧化钠、碳酸氢钠、溴化钙、溴化钠等。有机酸包括，例如乙酸等。无机酸包括，例如磷酸、硫酸等。氨基酸包括，例如乳酸、酒石酸、甘氨酸等。
本发明可以通过下述实施例和对比试验更详细地说明，但是不受其必然的限制。
实施例
实施例1
通过使用表1所列的添加剂研究了lurasidone或其游离形式的溶解度(单位：mg/mL)。固体型添加剂在其浓度为10％水溶液中进行研究，液体型添加剂在其浓度为100％溶液中进行研究。特别地，将lurasidone或其游离形式加入到固体型添加剂的10％水溶液中或加入到液体型添加剂的100％溶液中，以使其浓度为10mg/mL，并且混合物通过如搅拌、加热或超声的操作以促进溶解。在该操作30分钟后通过视觉确认混合物是否完全溶解。如果在10mg/mL浓度下混合物完全溶解，则再加入一定量的lurasidone或其游离形式以供评估。
研究结果是，只有在使用了苄醇、N，N-二甲基乙酰胺、乳酸或丙二醇的情况下，lurasidone或其游离形态的溶解度才能显著增加。
表1
实施例2
包含浓度为30mg/mL的lurasidone和其盐酸盐的溶液按表2的处方制备后在温热条件(60℃和40℃)下保存。一个月贮存期后，主要药剂剩余比例通过反相HPLC进行测定。作为研究结果，lurasidone和其游离形式在使用了苄醇、丙二醇、N，N-二甲基乙酰胺和乳酸的水溶液中被确认是稳定的，上述添加剂在实施例1中作为增溶剂显示出非常好的效果。换言之，本发明能够提供一种具有高稳定性的溶液型制剂，其中lurasidone和其游离形式在高浓度下增溶。HPLC条件：
色谱柱：YMC-Pack AM-312(5μm，6.0mm
×150mm，YMC有限公司制造)
检测器：紫外吸光光度计(检测波长：230nm)
柱温：大约25℃恒温
流动相：
溶液A：0.025％三氟乙酸水溶液/乙腈混合溶液(4∶1)
溶液B：0.025％三氟乙酸的乙腈溶液
流速：1.0mL/min
梯度条件：
表2
BA：苄醇
PG：丙二醇
DMA：N，N-二甲基乙酰胺
LA：乳酸
水：纯净水(MILLI-Q water(MILLIPORE制造的MILLI-Q SP REAGENT WATERSYSTEM))
实施例3
丙二醇处方
通过使用表3所列添加剂研究了lurasidone的溶解性。各混合物通过如搅拌，加热(约70℃)或超声波的操作促进其溶解，该操作30分钟后通过视觉观测确认各混合物是否完全溶解。如果混合物完全溶解则溶解性被评价为○，如果没有完全溶解或在降温至室温时沉淀则被评价为×。
作为研究结果，当使用丙二醇和注射用水时，在其中有浓度在5-33％(W/W)范围的无水乙醇的条件下，可以发现是被溶解的处方。
表3
注射用水：日本药典中的注射用水，Otsuka蒸馏水(Otsuka Pharmaceutical有限公司制造)
实施例4
添加苄醇的处方
通过使用表4所列添加剂研究了lurasidone的溶解性。各混合物通过例如搅拌，加热(约70℃)或超声波的操作促进溶解，并且在完成该操作30分钟后通过视觉观测确认各混合物是否完全溶解。如果混合物完全溶解则被评价为○，如果没有完全溶解或者在降至室温时沉淀则被评价为×。
作为研究结果，当使用丙二醇和注射用水时，在其中有浓度在1-25％(W/W)范围的无水乙醇的条件下，可以发现是被溶解的处方。
表4
实施例5
添加无水乙醇的处方的稳定性试验
对一些处方进行了稳定性试验(无水乙醇：15，25，33％)，这些处方在前面的加有无水乙醇处方的研究中能够被增溶。
HPLC条件：
色谱柱：YMC-Pack Pro C18(5μm，6.0mm×150mm，YMC有限公司制造)
检测器：紫外吸光光度计(检测波长：230nm)
柱温：大约25℃恒温
流动相：
溶液A：5mmol/L磷酸盐缓冲液(pH 7.0)/乙腈混合溶液(4∶1)
溶液B：乙腈
流速：1.1mL/min
梯度条件：
作为分析结果，表5中样品IM080至IM094是稳定的，其中总UK峰是1.5％或更少。特别是，样品IM080和IM087被认为是高稳定性的，其中UK峰为1.0％或更少。
表5
实施例6
添加苄醇的处方的稳定性试验
对前述添加苄醇的处方研究中被增溶的一些制剂(苄醇：5，15，25％)进行稳定性试验。
HPLC条件：
色谱柱：YMC-Pack Pro C18(5μm，6.0mm
×150mm，YMC有限公司制造)
检测器：紫外吸光光度计(检测波长：230nm)
柱温：大约25℃恒温
流动相：
溶液A：5mmol/L磷酸盐缓冲液(pH7.0)/乙腈混合溶液(4∶1)
溶液B：乙腈
流速：1.1mL/mm
梯度条件：
作为分析结果，表6中的样品IM144、IM145、IM109至IM111、IM117和IM118是稳定的，其中总UK峰为1.5％或更少。特别地，样品IM144、IM109、IM110、IM111和IM117确认为具很高稳定性，其中总UK峰为1.0％或更少。
表6
实施例7
添加苄醇和乙酸的处方
对下述在添加苄醇和乙酸的处方中溶解的处方进行稳定性试验。另外，通过乳酸的加入可减少苄醇的量(W/W)。
HPLC条件：
色谱柱：YMC-Pack Pro C18(5μm，6.0mm
×150mm，YMC有限公司制造)
检测器：紫外吸光光度计(检测波长：230nm)
柱温：大约25℃恒温
流动相：
溶液A：5mmol/L磷酸盐缓冲液(pH7.0)/乙腈混合溶液(4∶1)
溶液B：乙腈
流速：1.1mL/min
梯度条件：
表7
实施例8
添加N，N-二甲基乙酰胺和酸的处方
对下述在添加N，N-二甲基乙酰胺和酸的处方中溶解的处方进行稳定性试验，并且确认任一种制剂均显示出高稳定性。
HPLC条件：
色谱柱：YMC-Pack Pro C18(5μm，6.0mm
×150mm，YMC有限公司制造)
检测器：紫外吸光光度计(检测波长：230nm)
柱温：大约25℃恒温
流动相：
溶液A：5mmol/L磷酸盐缓冲液(pH7.0)/乙腈混合溶液(4∶1)
溶液B：乙腈
流速：1.1mL/min
梯度条件：
表8
产业实用性
本发明通过高浓度地增溶lurasidone和其游离形式提供了包括胃肠外给药制剂如注射剂和外用制剂以及口服液体制剂的广泛的制剂，并且因此为更多不同症状的患者提供了有效治疗。
Claims (15)
1.一种水性溶液型制剂，其含有lurasidone的游离形式N-[4-[4-(1，2-苯并异噻唑-3-基)-1-哌嗪基]-(2R，3R)-2，3-四亚甲基-丁基]-(1’R，2’S，3’R，4’S)-2，3-二环[2，2，1]庚烷二酰亚胺或其可药用酸加成盐作为活性成分，其中通过加入下述添加剂(i)或(ii)而使活性成分增溶，
(i)丙二醇、水和2.5-40％(W/W)的无水乙醇，或者
(ii)丙二醇、水和1-25％(W/W)的苄醇。
2.如权利要求1所述的水性溶液型制剂，其为胃肠外制剂的形式。
3.如权利要求1或2任一项所述的水性溶液型制剂，其用于静脉内、肌肉内、皮下或皮内注射。
4.如权利要求1所述的水性溶液型制剂，其为口服液态制剂的形式。
5.如权利要求1所述的水性溶液型制剂，其用于治疗精神分裂或老年痴呆，其含有治疗有效量的用于治疗所述精神病的游离形式的lurasidone或其可药用酸加成盐。
6.如权利要求1所述的水性溶液型制剂，其含有浓度为1-100mg/mL的活性成分。
7.如权利要求6所述的水性溶液型制剂，其含有浓度为1-20mg/mL的活性成分。
8.如权利要求7所述的水性溶液型制剂，其加入下述添加剂(i)丙二醇、水和5-33％(W/W)的无水乙醇。
9.如权利要求8所述的水性溶液型制剂，其加入下述添加剂(i)丙二醇、水和5-25％(W/W)的无水乙醇。
10.如权利要求7所述的水性溶液型制剂，其加入下述添加剂(ii)丙二醇、水和1-25％(W/W)的苄醇。
11.如权利要求8所述的水性溶液型制剂，其加入下述添加剂(ii)丙二醇、水和2-15％(W/W)的苄醇。
12.如权利要求7所述的水性溶液型制剂，其中所述制剂选自下表，
13.如权利要求7所述的水性溶液型制剂，其中所述制剂选自下表，
14.如权利要求1所述的水性溶液型制剂，其中制剂是在60℃放置4周后总UK峰在1.5％或更少的处方。
15.如权利要求14所述的水性溶液型制剂，其总UK峰在1.0％或更少。
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| JP2005172725 | 2005-06-13 | ||
| JP172725/2005 | 2005-06-13 | ||
| PCT/JP2006/311739 WO2006134864A1 (ja) | 2005-06-13 | 2006-06-12 | 可溶化型製剤 |
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| CN101198331B true CN101198331B (zh) | 2012-05-02 |
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| EP (1) | EP1891956B1 (zh) |
| JP (1) | JP4866349B2 (zh) |
| KR (1) | KR101328857B1 (zh) |
| CN (1) | CN101198331B (zh) |
| ES (1) | ES2390353T3 (zh) |
| WO (1) | WO2006134864A1 (zh) |
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| AU2010266040B2 (en) | 2009-06-25 | 2015-01-15 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds |
| ES2647361T3 (es) | 2010-01-07 | 2017-12-21 | Alkermes Pharma Ireland Limited | Profármacos de sales de amonio cuaternario |
| US20110166156A1 (en) * | 2010-01-07 | 2011-07-07 | Alkermes, Inc. | Prodrugs for the Treatment of Schizophrenia and Bipolar Disease |
| WO2011116286A2 (en) | 2010-03-18 | 2011-09-22 | Innopharma, Llc | Stable bortezomib formulations |
| US8263578B2 (en) | 2010-03-18 | 2012-09-11 | Innopharma, Inc. | Stable bortezomib formulations |
| WO2012053654A1 (en) * | 2010-10-18 | 2012-04-26 | Dainippon Sumitomo Pharma Co., Ltd. | Sustained-release formulation for injection |
| US8258139B2 (en) * | 2010-11-08 | 2012-09-04 | Dainippon Sumitomo Pharma Co., Ltd. | Method of treatment for mental disorders |
| JP5913335B2 (ja) * | 2011-02-02 | 2016-04-27 | 大日本住友製薬株式会社 | 新規外用製剤 |
| WO2012107890A2 (en) * | 2011-02-10 | 2012-08-16 | Ranbaxy Laboratories Limited | Crystalline forms of lurasidone hydrochloride |
| LT2685979T (lt) | 2011-03-18 | 2016-12-12 | Alkermes Pharma Ireland Limited | Injekcinės farmacinės kompozicijos, apimančios vandenyje netirpų antipsichotiką, sorbitano lauratą ir polisorbatą 20 |
| WO2012156981A1 (en) * | 2011-05-13 | 2012-11-22 | Cadila Healthcare Limited | Pharmaceutical compositions of lurasidone |
| CN102793701B (zh) * | 2011-05-25 | 2014-12-17 | 上海医药工业研究院 | 卢拉西酮组合物 |
| AR088372A1 (es) * | 2011-10-19 | 2014-05-28 | Otsuka Pharma Co Ltd | Solucion para administracion oral |
| CN103130795A (zh) * | 2011-12-02 | 2013-06-05 | 苏州二叶制药有限公司 | 卢拉西酮盐酸盐的晶体a及其用途 |
| ES2715562T3 (es) | 2011-12-15 | 2019-06-04 | Alkermes Pharma Ireland Ltd | Profármacos de compuestos de amina secundaria |
| NZ630643A (en) | 2012-03-19 | 2017-08-25 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising fatty acid esters |
| NZ630703A (en) | 2012-03-19 | 2017-02-24 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising glycerol esters |
| EP2827866B1 (en) | 2012-03-19 | 2023-05-03 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising benzyl alcohol |
| CN102688189B (zh) * | 2012-06-21 | 2014-10-29 | 北京鑫开元医药科技有限公司 | 一种鲁拉西酮药物组合物和制法 |
| WO2014080285A2 (en) | 2012-09-19 | 2014-05-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
| CN106132415A (zh) | 2014-03-20 | 2016-11-16 | 奥克梅斯制药爱尔兰有限公司 | 具有增加的注射速度的阿立哌唑制剂 |
| ES2826603T3 (es) | 2014-06-16 | 2021-05-18 | Johnson Matthey Plc | Procesos para la preparación de compuestos de arilpiperazina alquilada y arilpiperidina alquilada que incluyen productos intermedios novedosos |
| CN104606133A (zh) * | 2015-01-07 | 2015-05-13 | 万特制药(海南)有限公司 | 鲁拉西酮口服混悬液及其制备方法 |
| WO2017119928A1 (en) | 2016-01-08 | 2017-07-13 | Abon Pharmaceuticals, Llc | Long acting injectable formulations |
| WO2018015915A1 (en) | 2016-07-22 | 2018-01-25 | Cadila Healthcare Limited | A parenteral controlled release composition of an atypical antipsychotic agent |
| CA3034995A1 (en) * | 2016-08-31 | 2018-03-08 | Sumitomo Dainippon Pharma Co., Ltd. | Aqueous suspension preparation |
| JPWO2019167977A1 (ja) | 2018-02-28 | 2021-02-04 | 大日本住友製薬株式会社 | 水性懸濁型医薬製剤 |
| CN111989101A (zh) | 2018-02-28 | 2020-11-24 | 大日本住友制药株式会社 | 具有受控溶出的水性悬浮液型药物制剂 |
| CN112423754A (zh) | 2018-03-05 | 2021-02-26 | 奥克梅斯制药爱尔兰有限公司 | 阿立哌唑的给药策略 |
| WO2019213286A1 (en) * | 2018-05-02 | 2019-11-07 | LifeMax Laboratories, Inc. | Extended release suspension formulation of lurasidone |
| AU2022226584A1 (en) | 2021-02-24 | 2023-08-17 | Oakwood Laboratories, Llc | Microsphere formulations comprising lurasidone and methods for making and using the same |
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- 2006-06-12 KR KR1020077028359A patent/KR101328857B1/ko active Active
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| JP2003176228A (ja) * | 2001-12-11 | 2003-06-24 | Rohto Pharmaceut Co Ltd | 液 剤 |
| WO2004113333A1 (ja) * | 2003-06-23 | 2004-12-29 | Dainippon Sumitomo Pharma Co., Ltd. | 老人性痴呆症治療剤 |
| WO2005009999A1 (ja) * | 2003-07-29 | 2005-02-03 | Dainippon Sumitomo Pharma Co., Ltd. | イミド化合物の製造方法 |
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| Publication number | Publication date |
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| EP1891956A4 (en) | 2010-12-01 |
| US8283352B2 (en) | 2012-10-09 |
| WO2006134864A1 (ja) | 2006-12-21 |
| EP1891956A1 (en) | 2008-02-27 |
| JP4866349B2 (ja) | 2012-02-01 |
| HK1109088A1 (zh) | 2008-05-30 |
| EP1891956B1 (en) | 2012-08-29 |
| ES2390353T3 (es) | 2012-11-12 |
| JPWO2006134864A1 (ja) | 2009-01-08 |
| CN101198331A (zh) | 2008-06-11 |
| KR101328857B1 (ko) | 2013-11-13 |
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| US20090286805A1 (en) | 2009-11-19 |
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