CN101801380A - 血管舒缩症状的治疗 - Google Patents
血管舒缩症状的治疗 Download PDFInfo
- Publication number
- CN101801380A CN101801380A CN200880106932A CN200880106932A CN101801380A CN 101801380 A CN101801380 A CN 101801380A CN 200880106932 A CN200880106932 A CN 200880106932A CN 200880106932 A CN200880106932 A CN 200880106932A CN 101801380 A CN101801380 A CN 101801380A
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- Prior art keywords
- acid
- vasomotor symptoms
- flibanserin
- relevant
- menopause
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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Abstract
本发明涉及一种治疗血管舒缩症状的方法,该方法包括给药治疗有效量的氟班色林。
Description
本发明涉及治疗与绝经有关的血管舒缩症状的方法,该方法包括给药治疗有效量的氟班色林。
发明详述
化合物1-[2-(4-(3-三氟甲基-苯基)哌嗪-1-基)乙基]-2,3-二氢-1H-苯并咪唑-2-酮(氟班色林(flibanserin))以盐酸盐的形式公开于欧洲专利申请EP-A-526434,并具有以下化学结构:
氟班色林对5-HT1A和5-HT2-受体显示亲合力。因此,对于治疗例如抑郁、精神分裂症和焦虑的各种疾病,其是一种具有前景的治疗剂。
经历绝经的妇女常常感受到由卵巢衰竭导致的雌激素丧失而引起的各种症状。绝经定义为妇女月经停止。绝经时间事后才知道,在闭经后十二个月得以确定。大多数妇女在40岁至55岁之间经历绝经。绝经过渡期(menopausal transition)的特征在于:潮热、头痛、盗汗、萎缩性阴道炎、频繁尿道感染、手脚发冷、健忘和注意力分散。绝经过渡期的情绪表现包括焦虑、沮丧、烦躁不安、情绪波动、抑郁和性冲动减少。当女性经历绝经时,因身体变化造成的不良症状繁多至无法详述。
一些症状(如外阴和阴道萎缩)可明确地归因于雌激素不足;然而,潮热很可能是位于下丘脑前部中枢神经系统体温调定点变化的结果。潮热(hotflashes)(又名″血管舒缩潮热(vasomotor flushes)″或″潮热(hot flushes)″)在绝经前和绝经后妇女中很常见。潮热期间,外周血管扩张导致皮肤发红和变暖。进一步的症状如心率加快、盗汗、头痛、眩晕、体重增加、疲劳和失眠可能与潮热有关。潮热可以出现于月经停止之前,并可能是绝经临近的首要体征。在绝经前期期间,约75%的妇女主诉潮热。在此类大多数妇女中,该症状将持续约1年。大约三分之一的绝经后妇女报告,在自然绝经后,该症状持续达5年,20%或更多的妇女潮热持续达15年。手术引起的绝经在第一年期间发生潮热的可能性约为90%,与非手术绝经有关的潮热相比,与手术有关的潮热常常为更急剧且严重,并持续更久。
美国人口普查局(US Bureau of Census)估计当前有49,000,000位美国妇女年龄超过50岁。因此,在美国,当今超过32,000,000位妇女可能已经出现潮热,且达到6,000,000位可能已经报告有严重的症状。
现在,来自严重抑郁症(Major Depressive Disorder)病人研究的实验结果已显示氟班色林可用于治疗血管舒缩症状(vasomotor symptoms)(如潮热(hotflashes)、盗汗(night sweats)、情绪波动(moodswings)和烦躁不安(irritability))。
因此,本发明涉及一种治疗血管舒缩症状的方法,其包括给药治疗有效量的氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式。
在另一方面,本发明涉及一种治疗与绝经过渡期有关的血管舒缩症状的方法,其包括给药治疗有效量的氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式。
血管舒缩症状的出现并不仅仅由于自然发生的绝经,而且也可能由于手术(例如子宫切除和双侧卵巢切除)引起的绝经或使用药物(例如使用选择性雌激素受体调节剂、GnRH类似物和芳香化酶抑制剂)引起的绝经,或因放射和化疗剂引起的绝经,因此,本发明涉及一种治疗或预防与医源性引起的绝经(iatrogenic induced menopause)有关的血管舒缩症状的方法,其包括给药治疗有效量的氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式。
在另一个实施方案中,本发明涉及一种治疗潮热、盗汗、情绪波动和烦躁不安的方法,其包括给药治疗有效量的氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式。
本发明的另一方面涉及氟班色林用于治疗与男性自然或医源性性腺机能减退(natural or iatrogenic hypogonadal state in men)有关的中度至重度血管舒缩症状的用途。
本发明另一方面涉及氟班色林用于治疗男性潮热(优选在性腺机能减退的男性中),以及因治疗而丧失雄激素或接受阉割的男性的用途。
本发明的另一个实施方案涉及氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式在制备用于治疗上述任一疾病的药物中的用途。
如上所述,氟班色林可以其游离碱的形式、任选以其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式使用。适宜的酸加成盐包括例如那些与选自下列的酸所形成的酸加成盐:琥珀酸、氢溴酸、乙酸、富马酸、马来酸、甲磺酸、乳酸、磷酸、盐酸、硫酸、酒石酸和柠檬酸。也可使用上述酸加成盐的混合物。在上述酸加成盐中,优选盐酸盐和氢溴酸盐,尤其优选盐酸盐。如果氟班色林以游离碱的形式使用,优选使用WO 03/014079所公开的氟班色林多晶型A的形式。
氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式,可以以固体、液体或者喷雾形式掺入至常规的药物制剂中。组合物可(例如)以适于口服、直肠、肠胃外给药或经鼻吸入的形式存在,优选的形式包括(例如)胶囊、片剂、包衣片剂、安瓿、栓剂和鼻喷雾剂。
活性成分可掺入至药物组合物中常规使用的赋形剂或载体中,例如,滑石、阿拉伯胶、乳糖、明胶、硬脂酸镁、玉米淀粉、水性或非水性溶媒、聚乙烯吡咯烷酮、半合成脂肪酸的甘油酯、苯扎氯铵、磷酸钠、EDTA、聚山梨酯80。该组合物有利地以剂量单位形式配制,每一剂量单位适于提供单一剂量的活性成分。每日的适宜剂量范围介于0.1至400mg之间,优选介于1.0至300mg之间,更有选介于2至200mg之间。每一剂量单位可适宜地包含0.01至100mg,优选0.1至50mg。
适宜的片剂可(例如)通过将活性物质与下述物质混合而获得,已知的赋形剂,例如,惰性稀释剂如碳酸钙、磷酸钙或乳糖,崩解剂如玉米淀粉或藻酸,粘合剂如淀粉或明胶,润滑剂如硬脂酸镁或滑石,和/或用于延迟释放的试剂如羧甲基纤维素、邻苯二甲酸乙酸纤维素或聚乙酸乙烯酯。片剂也可包含若干层。
包衣片剂可相应地通过使用片剂包衣通常使用的物质涂覆类似于片剂制备的片芯而制备,用于包衣的物质如:可力酮或虫胶、阿拉伯胶、滑石、二氧化钛或糖。为了达到延迟释放或防止不兼容性,片芯也可由许多层组成。同样地,该片剂包衣亦可由许多层组成以达到延迟释放,可使用如上所述用于片剂的赋形剂。
本发明的包含活性物质或其组合的糖浆或酏剂可以另外包含增甜剂,如糖精、甜蜜素(cyclamate)、甘油或糖,和风味增强剂,例如,香料如香兰素或香橙提取物。它们也可包含助悬剂或增稠剂,如羧甲基纤维素钠,润湿剂,如脂肪醇与环氧乙烷的缩合产物,或防腐剂,如对羟基苯甲酸酯。
注射用溶液按常规方法制备,例如,添加防腐剂如对羟基苯甲酸酯,或稳定剂如乙二胺四乙酸的碱金属盐,并转移入注射小瓶或安瓿中。
包含一种或多种活性物质或活性物质组合的胶囊可(例如)通过将活性物质与惰性载体如乳糖或山梨糖醇混合,并填充至明胶胶囊中而制备。
适宜的栓剂可(例如)通过将为此目的提供的载体,如中性脂肪或聚乙二醇或其衍生物混合而制备。
下面的实施例用于示例性地说明本发明,而不是对其范围进行限制:
实施例
临床试验
在确诊为严重抑郁症病人的12个II期临床研究中,超过1500名介于18至65岁之间的男性与女性受试者接受介于2mg至100mg之间(1天2次(b.i.d.))的一种或多种剂量的氟班色林。初步分析这些受试者的安全数据显示:相较于安慰剂(1.25%)或选择性5-羟色胺再吸收抑制剂(2.1%),氟班色林基本上没有出现AE(以潮热/面红表示)。(参见表1)。
表1:
表1中显示:接受安慰剂的718人中有9人(1.25%)、接受帕罗西汀(Paroxetine)的275人中有5人(1.8%)或接受氟西汀(Fluoxetine)的145人中有4人(2.75%)出现面红或潮热。形成鲜明对比的是:接受日剂量50至200mg氟班色林的802患者中仅有1人出现面红。
这些数据显示,氟班色林可用于治疗绝经妇女的血管舒缩症状如潮热。
药物制剂实施例
A) 片剂 每片
盐酸氟班色林 100mg
乳糖 240mg
玉米淀粉 340mg
聚乙烯吡咯烷酮 45mg
硬脂酸镁 15mg
740mg
将精细粉碎的活性物质、乳糖和一些玉米淀粉一起混合。将混合物过筛,然后使用聚乙烯吡咯烷酮于水中的溶液润湿、捏合、湿法制粒并干燥。将颗粒、剩余的玉米淀粉和硬脂酸镁过筛并混合。将混合物压制以制备适宜形状和大小的片剂。
B) 片剂 每片
盐酸氟班色林 80mg
玉米淀粉 190mg
乳糖 55mg
微晶纤维素 35mg
聚乙烯吡咯烷酮 15mg
羧甲基淀粉钠 23mg
硬脂酸镁 2mg
400mg
将精细粉碎的活性物质、一些玉米淀粉、乳糖、微晶纤维素和聚乙烯吡咯烷酮一起混合,将混合物过筛,并与剩余的玉米淀粉和水加工,形成颗粒,将其干燥并过筛。添加羧甲基淀粉钠和硬脂酸镁,并混合,将混合物压制以制备适宜大小的片剂。
C)包衣片剂 每包衣片
盐酸氟班色林 5mg
玉米淀粉 41.5mg
乳糖 30mg
聚乙烯吡咯烷酮 3mg
硬脂酸镁 0.5mg
80mg
将活性物质、玉米淀粉、乳糖和聚乙烯吡咯烷酮均匀混合,并用水润湿。将该润湿的物质通过1毫米网目的筛网,在大约45℃干燥,然后将该颗粒再通过相同的筛网。与硬脂酸镁混合后,在制片机中压制成6毫米直径的凸面片剂片芯。按照已知方式使用基本上由糖和滑石组成的包覆层包衣所制造的片剂片芯。使用蜡抛光制成的片剂。
D) 胶囊 每胶囊
盐酸氟班色林 150mg
玉米淀粉 268.5mg
硬脂酸镁 1.5mg
420mg
将该物质和玉米淀粉混合,并用水润湿。将该润湿物质过筛并干燥。将干燥颗粒过筛并与硬脂酸镁混合。将最终的混合物填充至1号硬明胶胶囊中。
E) 安瓿溶液
盐酸氟班色林 50mg
氯化钠 50mg
注射用水 5ml
将活性物质以其自身pH或任选在pH5.5至6.5溶于水中,并添加氯化钠使其等渗。将所得的溶液过滤,以去除致热原,并在无菌条件下将滤液转移至安瓿,然后将其杀菌并熔融密封。
F) 栓剂
盐酸氟班色林 50mg
固体脂肪 1650mg
1700mg
将硬质脂肪熔化。在40℃,将研磨的活性物质均匀地分散。将其冷却至38℃,并倒入至稍冷的栓剂模型中。
在本发明的一个特别优选的实施方案中,氟班色林以特定的膜包衣片剂的形式给药。这些优选制剂的实例列于下文。如下所列的膜包衣片剂可按照现有技术中已知的方法制造(参考WO 03/097058)。
G)膜包衣片剂
片芯
成分 | mg/片 |
氟班色林 | 25.000 |
乳糖单水合物 | 71.720 |
微晶纤维素 | 23.905 |
HPMC(Methocel E5(甲基纤维素E5)) | 1.250 |
羧甲基纤维素钠 | 2.500 |
硬脂酸镁 | 0.625 |
包衣
成分 | mg/片剂 |
HPMC(Methocel E5) | 1.440 |
聚乙二醇6000 | 0.420 |
二氧化钛 | 0.600 |
滑石 | 0.514 |
氧化铁红 | 0.026 |
膜包衣片剂总重 | 128.000 |
H)膜包衣片剂
片芯
成分 | mg/片剂 |
氟班色林 | 50.000 |
乳糖单水化物 | 143.440 |
微晶纤维素 | 47.810 |
HPMC(例如Pharmacoat 606) | 2.500 |
羧甲基纤维素钠 | 5.000 |
硬脂酸镁 | 1.250 |
包衣
成分 | mg/片剂 |
HPMC(例如Pharmacoat 606) | 2.400 |
聚乙二醇6000 | 0.700 |
二氧化钛 | 1.000 |
滑石 | 0.857 |
成分 | mg/片剂 |
氧化铁红 | 0.043 |
膜包衣片剂总重 | 255.000 |
I)膜包衣片剂
片芯
成分 | mg/片剂 |
氟班色林 | 100.000 |
乳糖单水化物 | 171.080 |
微晶纤维素 | 57.020 |
HPMC(例如Methocel E5) | 3.400 |
羧甲基纤维素钠 | 6.800 |
硬脂酸镁 | 1.700 |
包衣
成分 | mg/片剂 |
HPMC(例如Methocel E5) | 3.360 |
聚乙二醇6000 | 0.980 |
二氧化钛 | 1.400 |
滑石 | 1.200 |
氧化铁红 | 0.060 |
膜包衣片剂总重 | 347.000 |
J)膜包衣片剂
片芯
成分 | mg/片剂 |
氟班色林 | 2.000 |
无水磷酸氢钙 | 61.010 |
微晶纤维素 | 61.010 |
HPMC(Methocel E5) | 1.950 |
羧甲基纤维素钠 | 2.600 |
胶体二氧化硅 | 0.650 |
硬脂酸镁 | 0.780 |
包衣
成分 | mg/片剂 |
HPMC(Methocel E5) | 1.440 |
聚乙二醇6000 | 0.420 |
二氧化钛 | 0.600 |
滑石 | 0.514 |
氧化铁红 | 0.026 |
膜包衣片剂总重 | 133.000 |
K)膜包衣片剂
片芯
成分 | mg/片剂 |
氟班色林 | 100.000 |
成分 | mg/片剂 |
无水磷酸氢钙 | 69.750 |
微晶纤维素 | 69.750 |
HPMC(例如Methocel E5) | 2.750 |
羧甲基纤维素钠 | 5.000 |
胶体二氧化硅 | 1.250 |
硬脂酸镁 | 1.500 |
包衣
成分 | mg/片剂 |
HPMC(例如Methocel E5) | 2.400 |
聚乙二醇6000 | 0.700 |
二氧化钛 | 1.043 |
滑石 | 0.857 |
膜包衣片剂总重 | 255.000 |
L)膜包衣片剂
片芯
成分 | mg/片剂 |
氟班色林 | 20.000 |
乳糖单水化物 | 130.000 |
微晶纤维素 | 43.100 |
羟丙基纤维素(例如Klucel LF) | 1.900 |
成分 | mg/片剂 |
淀粉羟乙酸钠 | 4.000 |
硬脂酸镁 | 1.000 |
包衣
成分 | mg/片剂 |
HPMC(例如Methocel E5) | 2.400 |
聚乙二醇6000 | 0.700 |
二氧化钛 | 1.043 |
滑石 | 0.857 |
膜包衣片剂总重 | 205.000 |
Claims (12)
1.一种治疗血管舒缩症状的方法,所述方法包括给药治疗有效量的氟班色林,任选以其游离碱、其药理学上可接受的酸加成盐的形式和/或任选以其水合物和/或溶剂合物的形式。
2.权利要求1的方法,其特征在于所述血管舒缩症状为与绝经有关的血管舒缩症状。
3.权利要求1的方法,其特征在于所述血管舒缩症状为与手术引起的绝经有关的血管舒缩症状。
4.权利要求1的方法,其特征在于所述血管舒缩症状为与医源性引起的绝经有关的血管舒缩症状。
5.权利要求1或4的方法,其特征在于所述血管舒缩症状为与药物、放射或化疗剂使用有关的血管舒缩症状。
6.权利要求1的方法,其特征在于所述血管舒缩症状选自潮热、盗汗、情绪波动和烦躁不安。
7.权利要求1的方法,其特征在于所述血管舒缩症状选自与男性自然或医源性性腺机能减退有关的中度至重度血管舒缩症状。
8.权利要求7的方法,其特征在于所述血管舒缩症状为与药物、放射或化疗剂使用有关的血管舒缩症状。
9.权利要求7或8的方法,其特征在于所述血管舒缩症状为男性潮热。
10.权利要求1至9中任一项的方法,其特征在于所述氟班色林以可药用酸加成盐的形式施用,该酸加成盐选自与由下列酸所形成的酸加成盐:琥珀酸、氢溴酸、乙酸、富马酸、马来酸、甲磺酸、乳酸、磷酸、盐酸、硫酸、酒石酸、柠檬酸,及其混合物。
11.权利要求1至9中任一项的方法,其特征在于所述氟班色林以氟班色林多晶型A的形式施用。
12.权利要求1至9中任一项的方法,其特征在于所述氟班色林以每日0.1-400mg的剂量范围施用。
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KR20140088230A (ko) | 2006-01-27 | 2014-07-09 | 앱탈리스 파마테크, 인코포레이티드 | 약 염기성 약물과 유기산을 포함하는 약물 전달 시스템 |
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US20090176698A1 (en) * | 2006-02-20 | 2009-07-09 | Boehringer Ingelheim International Gmbh | Benzimidazolone Derivatives for the Treatment of Urinary Incontinence |
US20090247546A1 (en) * | 2006-02-28 | 2009-10-01 | Boehringer Ingelheim International Gmbh | Treatment of Prevention of Valvular Heart Disease with Flibanserin |
NZ573382A (en) * | 2006-05-09 | 2012-02-24 | Boehringer Ingelheim Int | Use of flibanserin for the treatment of post-menopausal sexual desire disorders |
WO2008000760A1 (en) * | 2006-06-30 | 2008-01-03 | Boehringer Ingelheim International Gmbh | Flibanserin for the treatment of urinary incontinence and related diseases |
EP2043648A1 (en) | 2006-07-14 | 2009-04-08 | Boehringer Ingelheim International GmbH | Use of flibanserin for the treatment of sexual disorders in females |
JP2009543767A (ja) * | 2006-07-14 | 2009-12-10 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | フリバンセリンとカフェインとを含む組成物、その調製方法及び薬剤としての使用 |
CL2007002214A1 (es) * | 2006-08-14 | 2008-03-07 | Boehringer Ingelheim Int | Composicion farmaceutica en la forma de comprimido, donde al menos la longitud del comprimido en el estado anterior de la aplicacion es al menos 7/12 del diametro pilorico del paciente y despues de ingerirlo en estado alimentado, la longitud del comp |
EP2054041A2 (en) | 2006-08-14 | 2009-05-06 | Boehringer Ingelheim International GmbH | Formulations of flibanserin and method for manufacturing the same |
AR062321A1 (es) | 2006-08-25 | 2008-10-29 | Boehringer Ingelheim Int | Sistema de liberacion controlada y metodo para fabricarlo |
EP2097389B1 (en) | 2006-12-20 | 2011-09-14 | Boehringer Ingelheim International GmbH | Sulfated benzimidazolone derivatives having mixed serotonine receptor affinity |
JP2010522714A (ja) | 2007-03-28 | 2010-07-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規な医薬組成物 |
CL2008002693A1 (es) * | 2007-09-12 | 2009-10-16 | Boehringer Ingelheim Int | Uso de flibanserina para el tratamiento de sintomas vasomotores seleccionados de sofocos, sudores nocturnos, cambios de estado de animo e irritabilidad |
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2008
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- 2008-09-11 EP EP08803978.9A patent/EP2200614B1/en active Active
- 2008-09-11 CN CN2008801069327A patent/CN101801380B/zh not_active Expired - Fee Related
- 2008-09-11 JP JP2010524478A patent/JP2010539130A/ja active Pending
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2010
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- 2010-04-08 MA MA32746A patent/MA31757B1/fr unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108349908A (zh) * | 2016-02-02 | 2018-07-31 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的苯并咪唑酮化合物及包含该化合物的组合物 |
CN108349908B (zh) * | 2016-02-02 | 2021-07-20 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的苯并咪唑酮化合物及包含该化合物的组合物 |
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MA31757B1 (fr) | 2010-10-01 |
PE20091188A1 (es) | 2009-08-31 |
JP2010539130A (ja) | 2010-12-16 |
US9949969B2 (en) | 2018-04-24 |
UY31335A1 (es) | 2009-04-30 |
US20190091219A1 (en) | 2019-03-28 |
US10596170B2 (en) | 2020-03-24 |
US20110136825A1 (en) | 2011-06-09 |
US20150250783A1 (en) | 2015-09-10 |
EP2200614B1 (en) | 2013-11-27 |
US20180071283A1 (en) | 2018-03-15 |
US20200253962A1 (en) | 2020-08-13 |
TN2010000108A1 (fr) | 2011-09-26 |
ZA201000384B (en) | 2010-09-29 |
ES2444707T3 (es) | 2014-02-26 |
CA2699414C (en) | 2016-04-05 |
CO6260073A2 (es) | 2011-03-22 |
AR068416A1 (es) | 2009-11-18 |
MX2010002032A (es) | 2010-03-15 |
US10166230B2 (en) | 2019-01-01 |
BRPI0816791A2 (pt) | 2019-09-24 |
CA2699414A1 (en) | 2009-03-19 |
WO2009034111A1 (en) | 2009-03-19 |
EP2200614A1 (en) | 2010-06-30 |
AU2008297104A1 (en) | 2009-03-19 |
CN101801380B (zh) | 2013-05-08 |
US20140005203A1 (en) | 2014-01-02 |
KR20100059848A (ko) | 2010-06-04 |
CL2008002693A1 (es) | 2009-10-16 |
NZ584183A (en) | 2012-05-25 |
TW200927118A (en) | 2009-07-01 |
EA201000433A1 (ru) | 2010-10-29 |
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