CN106660936A - 用于治疗adhd的方法和达斯曲林(dasotraline)组合物 - Google Patents
用于治疗adhd的方法和达斯曲林(dasotraline)组合物 Download PDFInfo
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- CN106660936A CN106660936A CN201580027069.6A CN201580027069A CN106660936A CN 106660936 A CN106660936 A CN 106660936A CN 201580027069 A CN201580027069 A CN 201580027069A CN 106660936 A CN106660936 A CN 106660936A
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Abstract
本发明披露使用达斯曲林(dasotraline)治疗注意缺陷多动障碍(ADHD)的剂型和治疗方案。本文所述的组合物不呈现滥用可能。
Description
相关申请案的交叉参考
本申请案要求2014年5月13日申请的美国临时申请案61/992,588的优先权。US61/992,588的全部内容以引用的方式并入本文中。
技术领域
本发明涉及使用[(1R,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺](达斯曲林)治疗注意缺陷多动障碍(ADHD)的剂型和治疗方案。
背景技术
注意缺陷多动障碍(ADHD)是影响儿童和青少年的常见病状并且一些人可以持续到成人期。尽管一些专家相信ADHD在8%到10%学龄儿童中发生,但国家心理卫生研究所(National Institute of Mental Health;NIMH)估计3%到5%儿童患有ADHD。大量证据表明约50%儿童可能不会发生ADHD。无论确切数字如何,ADHD都是儿童和成年人中的严重精神健康问题。
ADHD治疗最通常呈刺激剂形式,如哌醋甲酯(例如CONCERTMETAD和)、安非他明(amphetamine)和右旋苯丙胺(dextroamphetamine)以及其前药尽管用刺激剂治疗多动症可能看起来违反常理,但认为刺激剂可活化负责注意力和精神集中状态的大脑回路,由此减轻多动症。对于许多儿童,ADHD药物减轻多动症和冲动性并且改良其精神集中、工作和学习能力。药物还可以改良身体协调。然而,当前指定的所有刺激剂皆呈现较高滥用可能。所有前述药物皆由DEA通过其II期疗程状况的分配来控制,其意指药物“具有较高滥用可能……并且可引起严重的心理和生理依赖性”。
因此,具有可以口服剂型形式、按可有效治疗ADHD但不存在滥用可能倾向的剂量提供的药物将是有利的。
反4-(3,4-二氯苯基)-l,2,3,4-四氢-1-萘胺(其也称为“反式枸橼酸舍曲林”或TNS)和其CNS药理学已描述于美国专利案7,105,699中。
发明内容
现已发现反式4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺的(1R,4S)对映异构体,为方便起见,其在本文中称为“达斯曲林”,在极特定剂量和剂量疗程下,提供ADHD的有效治疗而不具有可辨别的滥用倾向。
在一个方面中,本发明涉及用于治疗ADHD同时最小化药物滥用风险的方法,其包含投与经诊断患有ADHD的患者达斯曲林的口服剂型,其中所述口服剂型在每天投与一次时提供达斯曲林的10ng/mL与18ng/mL之间的24小时时间平均血清浓度(在第3周测量)。
在另一个方面中,本发明涉及治疗ADHD同时最小化药物滥用风险的方法,其包含向经诊断患有ADHD的患者每天一次投与达斯曲林的口服剂型,其中口服剂型含有6mg到8mg达斯曲林。
在另一个方面中,本发明涉及用于治疗ADHD同时最小化药物滥用风险的方法,其包含向经诊断患有ADHD的患者投与达斯曲林的口服剂型,其中口服剂型在单次投药之后18小时提供达斯曲林的1ng/mL与4ng/mL之间的血清浓度。
附图说明
图1是基于ADHD RS-IV总评分,8mg达斯曲林对比安慰剂的从开始到第四周,作为时间函数的最小二乘平均值从基线的变化的图。
图2是基于CGI-S评分,8mg达斯曲林对比安慰剂的从开始到第四周,作为时间函数的最小二乘平均值从基线的变化的图。
图3是作为时间函数的达斯曲林的血清浓度(ng/mL)的图。
图4是作为时间函数的达斯曲林的血清浓度(ng/mL)的图。
图5是作为时间函数的达斯曲林的血清浓度(ng/mL)的图。
图6描绘在成瘾性对比时间的测量曲线上,两种剂量的安慰剂、哌醋甲酯和三种剂量达斯曲林的药物成瘾的6种并列比较。在这些曲线上,50%表示中性。
具体实施方式
达斯曲林[(1R,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢萘-1-胺是具有DNRI药理学的新型化合物。达斯曲林充当人类DA输送体(DAT;多巴胺吸收IC503nM)和NE输送体(NET;去甲肾上腺素吸收IC50 4nM)的强效抑制剂,和人类血清素输送体的较弱抑制剂(SERT;血清素吸收IC50 15nM)。
已在一系列临床试验中发现,当根据提供10ng/mL与18ng/mL之间的24小时时间平均血清浓度的疗程投与时,达斯曲林在治疗ADHD方面有效并且不具有可检测的滥用倾向。此外,由于达斯曲林药物动力学的两种独特特征的组合(即不寻常的长血清半衰期,以及多巴胺转运体(DAT)抑制的缓慢起效),可每天一次投与6到8mg达斯曲林,并且无需在每天的任何特定时间给药。
在下文所描述的研究中,在人类患者中的临床试验中证实达斯曲林治疗ADHD的功效和其不具有滥用可能。尽管不希望受当前理论约束,但可通过比较达斯曲林药理学与常规刺激剂并且具体来说,哌醋甲酯的药理学来断定这一临床结果的相干说明。
所提出的哌醋甲酯、安非他明和其它刺激剂的作用机制是释放和增加CNS多巴胺。这一释放在其对多巴胺传送机构的影响之后发生,其产生增加量的突触后多巴胺。哌醋甲酯的确切作用机制与安非他明(amphetamines)和可卡因(cocaine)不同,但所有三种药物的净效果都是突触多巴胺增加。用经(11C)标记的哌醋甲酯和可卡因进行的放射研究发现两种药物的结合都位于相同的大脑区域(纹状体)中。当滥用哌醋甲酯时,认为伏隔核和眶额叶皮质纹状体中Dl多巴胺受体的刺激与欣快症和重复使用有关。
霍夫曼(Hoffman)和莱夫科维茨(Lefkowitz)在其于古德曼(Goodman)和吉尔曼(Gilman)的治疗学的药理学基础(The Pharmacological Basis of Therapeutics),第9版中关于儿茶酚胺、拟交感神经药药物和肾上腺素能受体拮抗剂的章节中提出哌醋甲酯的药理学特性“与安非他明实质上相同于”并且滥用可能的注意事项与安非他明类似,尤其在具有“药物依赖性或酒精中毒病史”的患者中。
当经口投药时,哌醋甲酯由胃肠道快速和完全吸收。峰值浓度在给药之后1到2小时出现。哌醋甲酯的药物动力学半衰期是约2小时。当静脉内投与哌醋甲酯和可卡因时,其药物动力学非常类似,每种药物的大脑吸收百分比和其吸收率是并列的,但可卡因的大脑清除率比哌醋甲酯更快。在基底节和纹状体中,可卡因和哌醋甲酯在多巴胺输送体处的受体结合亲和力类似。值得注意的是,与静脉内哌醋甲酯的“高量”关联性是在基底节中出现峰值浓度之前产生。因此,滥用可能与纹状体中多巴胺含量的快速涌现有关。针对这一背景,达斯曲林不具有滥用可能将符合其药物动力学概况。达斯曲林呈现约10-12小时的时间最大浓度(Tmax)(与哌醋甲酯的1-2小时相比)和47-77小时的血清半衰期(t1/2)。多巴胺缓慢增加是不存在“高量”的结果,并且长T1/2是在每天给药后,血清浓度在约7天时程内逐渐增加到稳定状态的结果。因此,如果经口投与的达斯曲林的剂量是在稳定状态下产生10与18ng/mL之间的血清浓度的剂量,那么其将提供有效疗法而不诱导高量。
下文阐述的临床结果表明含有6-8mg达斯曲林的口服剂型将在大部分患者中提供10-18ng/mL的血清浓度。尽管所属领域的技术人员应理解,药效动力学在任何群体的个别成员之间不同,但6-8mg达斯曲林的口服剂量将通常在约一周时段内产生预期的治疗效果。6-8mg剂量的优势在于其在人类测试个体中从疗法开始起尽可能快地产生治疗学有效血清浓度,同时不呈现药物成瘾反应。
在以下研究中,达斯曲林以其盐酸盐形式投与。除以游离碱形式投药以外,达斯曲林还可以配制成除盐酸盐以外的医药学上可接受的盐。术语“医药学上可接受的盐”指其中相对离子是来源于医药学上可接受的无毒性酸和碱的盐。用于本发明的化合物的盐的适合的医药学上可接受的酸包括例如乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸(苯磺酸)、苯甲酸、硼酸、丁酸、樟脑酸、樟脑磺酸、碳酸、柠檬酸、乙二磺酸、乙磺酸、乙二胺四乙酸、甲酸、反丁烯二酸、葡庚糖酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、氢碘酸、羟基萘甲酸、羟乙基磺酸、乳酸、乳糖酸、月桂基磺酸、马来酸、苹果酸、杏仁酸、甲烷磺酸、粘液酸、亚萘基磺酸、硝酸、油酸、双羟萘酸、泛酸、磷酸、特戊酸、聚半乳糖醛酸、水杨酸、硬脂酸、丁二酸、硫酸、鞣酸、酒石酸、特拉克酸(teoclatic)、对甲苯磺酸等。本文中所描述的量是以游离碱形式计算的达斯曲林的量。可根据配制物中使用的达斯曲林的盐形式调节所述量,并且实际上,在下文所描述的临床研究中,使用9mg盐酸盐(等效于8mg自由达斯曲林)。盐酸达斯曲林是优选盐,并且其制备方法和配制物描述于美国公开申请案2013/0116332中。
本发明的适用于经口投药的配制物可以离散单元形式呈递,如胶囊、扁胶剂或片剂,其各自含有6-8mg达斯曲林或6-8mg达斯曲林游离碱的盐等效物(摩尔)。应理解,本发明的配制物可包括口服调配物领域中的其它常规试剂,例如着色剂、崩解剂和调味剂。
如本文中所使用,“治疗(treatment/treating)”或“减轻”或“改善”在本文中可互换地使用。这些术语指获得治疗效益并且根除或改善与ADHD相关联的一种或多种症状使得在患者中观察到改良(尽管患者可能仍患有ADHD)的方法。可由医生、医生的助理、护士或其它保健专业人员向经诊断患有ADHD的患者投与组合物。
在4周治疗周期内,每天一次使用8mg对比安慰剂,评估患有ADHD的成年人中达斯曲林的功效和安全性的2期、随机、双盲、平行群、多中心、门诊研究。研究由3个周期组成,包括筛选、治疗和清除/随访,如下文所述。在成年人提示下使用ADHD分级量表版本IV(ADHDRS-IV)评估功效。使用临床数据储存库系统评估对认知的作用。在整个研究期间,通过收集生理检查、12导联心电图(ECG)、生命体征、不良事件(AE)、血液学、血液化学、尿分析、失眠严重度指数(ISI)和哥伦比亚自杀严重度分级量表(Columbia-Suicide Severity RatingScale;C-SSRS)来监测安全性和耐受性。使用所测量的血浆达斯曲林浓度进行群体药物动力学方法。研究达斯曲林血浆浓度与主要和所选择的次要临床结果测量值之间的关系,以及使用群体药物动力学和药效动力学方法的达斯曲林血浆浓度和3,4-二羟苯基二醇/去甲肾上腺素浓度。
所有个体在基线处(第1天)的ADHD RS-IV评分>26并且CGI-S评分>4。在第1天,经由相互作用反应系统将个体随机分入治疗组(8mg达斯曲林)或安慰剂组,并且在当晚睡觉之前开始服用研究药物。在第1天到第28天,个体在家在每晚大致相同时间自行投与研究药物。在第1天之后,个体在第8、15、22和29天返回诊所。在第1天开始并且在治疗周期期间的每次访问时,完成ADHD RS-IV、温德-蕾赫尔成年人注意缺陷障碍量表(Wender-ReimherrAdult Attention Deficit Disorder Scale;WRAADDS)和临床总体印象严重度(CGI-S)。在基线以及第15天和第29天管理临床数据储存库系统。在第1、8、15、22和29天收集关于达斯曲林、血浆浓度和DHPG/NE血浆含量的抽血。
在4周治疗周期结束(第29天)时,个体进入2周清除期以监测在清除期间的达斯曲林血浆浓度,使用医生戒断检查表(Physician Withdrawal Checklist)评估戒断反映的出现,并且在停用研究药物之后测定治疗效果的持续时间。在第36和43天,个体返回诊所并且完成ADHD RS-IV、WRAADDS和CGI-S。在第43天完成临床数据储存库系统。在第36和43天收集关于达斯曲林血浆浓度和DHPG/NE血浆含量的抽血。
结果以图形方式呈现于图1和2中。图1是基于ADHD RS-IV总评分,8mg达斯曲林对比安慰剂的从开始到第四周,作为时间函数的LS平均值从基数的变化的图。ADHD RS-IV总评分上从安慰剂分离的趋势到第2周开始显而易见;差异在第三周和第四周是统计差异(分别是p<0.05和p<0.025)。
图2是基于CGI-S评分,8mg达斯曲林对比安慰剂的从开始到第四周,作为时间函数的LS平均值从基线的变化的图。差异在第四周是统计差异(p<0.05)。
温德-蕾赫尔ADD总评分并未改良到足以实现统计显著性,但达斯曲林组与安慰剂组相比,注意力困难分量和结构紊乱分量的分项评分在第4周展示统计显著改良。
在计算机化认知评估量表中,未观察到达斯曲林对注意力、工作记忆或间歇性记忆的测量值的显著主要作用。治疗突发性不良事件(TEAE)高于安慰剂组中的TEAE的百分比。大部分不良事件评定为轻微或中度;评定为严重的事件的发生率在达斯曲林组中是13.5%并且在安慰剂组中是2.7%。在达斯曲林组中,引起停止(并且在>2名患者中发生)的最常见不良事件是失眠(10.8%)、焦虑(1.8%)和惊恐发作(panic attack)(2.7%)。
图3是作为时间函数的达斯曲林的血清浓度(ng/mL)的图。可以发现,到第四周,血清浓度开始进入15与20ng/mL之间的平稳区。
由第1、2、3和4周的血清浓度的测量结果,可绘制长期投药的预测性血清浓度图。这类图呈现于图4中。图4展示在6mg剂量下获得约12ng/mL的稳态浓度并且在8mg剂量下获得约17ng/mL的稳态浓度。
在更早的研究过程中,观察到8mg达斯曲林的单次剂量产生约3ng/mL的最大血清浓度(Cmax),其是极缓慢地获得(tmax>6小时)并且无任何“迅速增加”。图5是作为时间函数的达斯曲林浓度(ng/mL)的图。
未在药物作用调查表中观察到药物成瘾的证据,其中在所有评估周,平均项目得分保持在0点的5mm内。未通过滥用可能监测计划侦察到药物误用或分流的证据。当停用研究药物时未观察到戒断反映或症状。
由其它研究(未展示),发现在约5-6ng/mL下实现50%DAT位点占有率,即达斯曲林在单次投药后并未实现足以占据50-75%DAT位点的浓度。因此,在单次投药后18小时提供达斯曲林的1ng/mL与4ng/mL之间的血清浓度的剂型将在某些天的每天一次投药之后产生治疗学有效血清浓度(10-18ng/mL),并且其将在不存在DAT占有率突然增加的情况下实现。达斯曲林8mg/d也降低循环DHPG含量,表明去甲肾上腺素输送体的重要抑制。DNRI机制区分达斯曲林与阿托西汀(atomoxetine),阿托西汀是仅抑制去甲肾上腺素输送体的非刺激剂。达斯曲林的缓慢吸收和长消除半衰期与安非他明、哌醋甲酯和阿托西汀的药物动力学相反。
因为相信哌醋甲酯和类似的DAT抑制剂的滥用可能与DAT位点的快速占据相关联,并且6和8mg达斯曲林不产生进入似乎可能引起高比例的DAT位点的快速占据的血清浓度区域的“突然增加”,进行达斯曲林的研究以观察其是否将不存在与刺激剂相关联的滥用倾向。
进行单次剂量、随机、双盲、双假设、安慰剂和活性控制交叉研究(每位个体进行6次治疗访问)。在健康娱乐性刺激剂使用者中比较3种剂量的达斯曲林(8mg、16mg和36mg)与安慰剂以及40mg和80mg哌醋甲酯(阳性对照)的滥用可能。个体参与医学筛选访问(访问1),一个4天住院病人鉴定阶段(访问2)、由六个5天治疗访问组成的治疗阶段(访问3到8)和安全性随访(访问9)。在21天筛选访问内,个体参与和参加鉴定阶段,其中其以随机双盲交叉方式接收60mg哌醋甲酯或符合条件的安慰剂。给药时间间隔约24小时以确保个体可区分和展示阳性对照的正性效果。
年龄是18到55周岁(包含性)的健康雌性和雄性个体(其为具有可卡因经历并且通过哌醋甲酯鉴定阶段的娱乐性中枢神经系统(CNS)刺激剂使用者)随机接受治疗。
在每此治疗访问的第1天进行药物投药,接着进行药效学(PD)、药物动力学(PK)和安全性评估直到给药后72小时。个体以随机、双盲、双假设方式接受以下6种治疗中的每一种(每次治疗访问一种):8mg达斯曲林、16mg达斯曲林、36mg达斯曲林、40mg哌醋甲酯、80mg哌醋甲酯或安慰剂。个体根据6×6威廉广场设计(William square design)随机接受6种治疗序列中的一种。在每此治疗访问(访问3到8)时接收的胶囊是相同的。在每次治疗访问时进行连续药效学和药物动力学评估,进行达斯曲林的药物动力学分析。安全性监测包括生命体征、临床实验室测试和不良事件(AE)的常规评估,以及给药后至少12小时的连续遥测监测。治疗访问隔离(从给药当天开始)至少21天的冲洗间隔。个体在最后一次治疗访问结束后,在约14天内返回安全性随访。
三十五名个体完成研究,基于事后能力计算,其仍引起大于90%能力以侦测安慰剂与哌醋甲酯之间的平均值差。阳性对照物哌醋甲酯的作用符合具有滥用可能的刺激剂药物,因为在大部分药效学终点观察到与安慰剂相比的显著不同,包括药物成瘾视觉模拟评分(Drug Liking Visual Analog Scale)的主要测量值。与这些结果一致,哌醋甲酯与强刺激剂作用相关联,如通过次要刺激剂测量值测量,并且坚定认为哌醋甲酯是刺激剂(例如d-安非他明、甲基苯丙胺或可卡因)并且在药物类似性视觉模拟评分(Drug SimilarityVisual Analog Scale)中坚定认为不是安慰剂。这些结果表明研究有效并且个体和测量值对评估刺激剂药物的滥用相关作用敏感。哌醋甲酯受到全部个体“喜爱”,个体愿意再次服用哌醋甲酯,并且与安慰剂相比,愿意为哌醋甲酯付出更多。另一方面,在大部分药效学终点,达斯曲林的作用与安慰剂的作用并没有明显的差异,并且在所有药效学终点,8mg剂量展示与安慰剂类似的概况。因此,服用治疗性剂量的达斯曲林的患者或最初参与用单一片剂进行的实验的滥用者不应经历滥用相关主观作用。即使在16mg达斯曲林情况下,也存在极少的与安慰剂的统计显著差异。结果以图形方式展示于图6中,其比较两种剂量的安慰剂、哌醋甲酯和三种剂量的达斯曲林的药物成瘾性。
前述研究表明,对于治疗ADHD的功效,达斯曲林的单次6-8mg经口给药(每天一次)提供位于最佳窗口中的达斯曲林血清浓度,同时避免滥用可能。
制备具有以下组成的六和八毫克胶囊(以及安慰剂):
量(毫克/胶囊)
安慰剂 | 6mg | 8mg | |
盐酸达斯曲林 | 0 | 6.75 | 9 |
滑石 | 2.5 | 6 | 7 |
Pearlitol 160C | 146.3 | 136.05 | 132.8 |
羟基乙酸淀粉钠 | 9.6 | 9.6 | 9.6 |
硬脂酸镁 | 1.6 | 1.6 | 1.6 |
总重量(mg) | 160 | 160 | 160 |
以下是本发明的其它方面:
一种用于治疗ADHD同时最小化药物滥用风险的方法,其包含向经诊断患有ADHD的患者投与达斯曲林的口服剂型,其中所述口服剂型含有6mg到8mg达斯曲林。
如第[0042]段所述的方法,其中所述口服剂型含有6、7或8mg达斯曲林。
一种用于治疗ADHD同时最小化药物滥用风险的方法,其包含向经诊断患有ADHD的患者投与达斯曲林的口服剂型,其中所述口服剂型提供在10ng/mL与18ng/mL之间的达斯曲林的24小时时间平均血清浓度。
根据第[0044]段所述的方法,其中所述剂型提供12ng/mL与16ng/mL之间的24小时时间平均血清浓度。
根据第[0044]段所述的方法,其中所述口服剂型含有6、7或8mg达斯曲林。
在用达斯曲林的口服剂型治疗ADHD的方法中,其改良之处包含投与当每天投与一次并且在第3周测量时,可提供10ng/mL与18ng/mL之间的达斯曲林的24小时时间平均血清浓度的口服剂型。
根据第[0047]段所述的方法,其中所述口服剂型提供12ng/mL与16ng/mL之间的达斯曲林的24小时时间平均血清浓度。
根据第[0047]段所述的方法,其中所述口服剂型在单次投药后18小时提供1ng/mL与4ng/mL之间的达斯曲林血清浓度。
一种用于治疗ADHD的方法,其包含通过在一天内向需要这类治疗的个体经口投与呈片剂或胶囊形式的第一剂量来开始治疗,其中所述片剂或胶囊包含6-8mg达斯曲林,并且通过每天一次经口投与包含6-8mg达斯曲林的片剂或胶囊来继续所述治疗。在前述用于治疗ADHD的方法中,可通过在一天内进行一次6、7或8mg经口给药来开始治疗,并且在随后的日子中,剂量可与早先天提供的剂量不同,但仍在6至8mg范围内。举例来说,可以8毫克/天开始并且接着逐渐减少到6毫克/天,或从较低剂量增长到8mg剂量。当然,可在治疗期间内继续进行单次给药。
一种用于治疗ADHD的方法,其包含通过在一天内向需要这类治疗的个体经口投与呈片剂或胶囊形式的第一剂量来开始治疗,其中所述片剂或胶囊包含6-8mg达斯曲林,并且通过每两天一次或每三天一次经口投与包含6-8mg达斯曲林的片剂或胶囊来继续所述治疗。
一种片剂或胶囊,其包含9mg盐酸达斯曲林和一种或多种药物赋形剂。
一种片剂或胶囊,其包含6.75mg盐酸达斯曲林和一种或多种药物赋形剂。
Claims (9)
1.一种用达斯曲林(dasotraline)的口服剂型治疗ADHD的方法,其改良之处包含投与当每天投与一次并且在第3周测量时,可提供10ng/mL与18ng/mL之间的达斯曲林的24小时时间平均血清浓度的口服剂型。
2.根据权利要求1所述的方法,其中所述口服剂型提供12ng/mL与16ng/mL之间的达斯曲林的24小时时间平均血清浓度。
3.一种用于治疗ADHD的方法,其包含通过在一天内向需要这类治疗的个体经口投与呈片剂或胶囊形式的第一剂量来开始治疗,其中所述片剂或胶囊包含6-8mg达斯曲林,并且通过每天一次经口投与包含6-8mg达斯曲林的片剂或胶囊来继续所述治疗。
4.根据权利要求3所述的方法,其中所述口服剂型含有6、7或8mg达斯曲林。
5.根据权利要求3所述的方法,其中所述口服剂型含有8mg达斯曲林。
6.根据权利要求3所述的方法,其中所述口服剂型含有6mg达斯曲林。
7.根据权利要求6所述的方法,其中所述口服剂型含有8mg呈盐酸盐形式的达斯曲林。
8.根据权利要求3所述的方法,其中所述剂型由9mg盐酸达斯曲林和多种药学上可接受的赋形剂组成。
9.根据权利要求3所述的方法,其中所述剂型由6.75mg盐酸达斯曲林和多种药学上可接受的赋形剂组成。
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US (1) | US20170266133A1 (zh) |
EP (1) | EP3142999A4 (zh) |
JP (1) | JP2017515858A (zh) |
KR (1) | KR20170003677A (zh) |
CN (1) | CN106660936A (zh) |
AU (1) | AU2015259337A1 (zh) |
CA (1) | CA2948829A1 (zh) |
IL (1) | IL248846A0 (zh) |
MX (1) | MX2016014780A (zh) |
WO (1) | WO2015175514A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20200405867A1 (en) * | 2018-01-19 | 2020-12-31 | Sunovion Pharmaceuticals Inc. | Oral dosage forms |
WO2020092496A1 (en) * | 2018-10-31 | 2020-05-07 | Sunovion Pharmaceuticals Inc. | Methods of treating central nervous system disorders |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4556676A (en) * | 1979-11-01 | 1985-12-03 | Pfizer Inc. | Antidepressant derivatives of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
US4981870A (en) * | 1989-03-07 | 1991-01-01 | Pfizer Inc. | Use of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives in the treatment of psychosis, inflammation and as immunosuppressants |
CN1688538A (zh) * | 2002-09-16 | 2005-10-26 | 塞普拉科公司 | 用反式4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺及其甲酰胺治疗cns病症 |
CN102740842A (zh) * | 2009-12-04 | 2012-10-17 | 桑诺维恩药品公司 | 反式降舍曲林的制剂、盐和多晶型物及其应用 |
WO2012158492A2 (en) * | 2011-05-13 | 2012-11-22 | Dainippon Sumitomo Pharma Co., Ltd. | Treatment and management of cns disorders |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1542961T3 (da) * | 2002-09-16 | 2013-11-04 | Sepracor Inc | Trans-4-(3,4-dichlorphenyl)-1,2,3,4-tetrahydro-1-napthalenamin til anvendelse til behandling af cns-forstyrrelser |
-
2015
- 2015-05-12 CA CA2948829A patent/CA2948829A1/en not_active Abandoned
- 2015-05-12 AU AU2015259337A patent/AU2015259337A1/en not_active Abandoned
- 2015-05-12 CN CN201580027069.6A patent/CN106660936A/zh active Pending
- 2015-05-12 WO PCT/US2015/030342 patent/WO2015175514A1/en active Application Filing
- 2015-05-12 JP JP2016567685A patent/JP2017515858A/ja active Pending
- 2015-05-12 KR KR1020167034704A patent/KR20170003677A/ko unknown
- 2015-05-12 US US15/310,344 patent/US20170266133A1/en not_active Abandoned
- 2015-05-12 MX MX2016014780A patent/MX2016014780A/es unknown
- 2015-05-12 EP EP15792097.6A patent/EP3142999A4/en not_active Withdrawn
-
2016
- 2016-11-09 IL IL248846A patent/IL248846A0/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4556676A (en) * | 1979-11-01 | 1985-12-03 | Pfizer Inc. | Antidepressant derivatives of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
US4981870A (en) * | 1989-03-07 | 1991-01-01 | Pfizer Inc. | Use of 4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives in the treatment of psychosis, inflammation and as immunosuppressants |
CN1688538A (zh) * | 2002-09-16 | 2005-10-26 | 塞普拉科公司 | 用反式4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘胺及其甲酰胺治疗cns病症 |
CN102740842A (zh) * | 2009-12-04 | 2012-10-17 | 桑诺维恩药品公司 | 反式降舍曲林的制剂、盐和多晶型物及其应用 |
WO2012158492A2 (en) * | 2011-05-13 | 2012-11-22 | Dainippon Sumitomo Pharma Co., Ltd. | Treatment and management of cns disorders |
Also Published As
Publication number | Publication date |
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KR20170003677A (ko) | 2017-01-09 |
JP2017515858A (ja) | 2017-06-15 |
MX2016014780A (es) | 2017-07-25 |
CA2948829A1 (en) | 2015-11-19 |
IL248846A0 (en) | 2017-01-31 |
EP3142999A1 (en) | 2017-03-22 |
US20170266133A1 (en) | 2017-09-21 |
WO2015175514A1 (en) | 2015-11-19 |
EP3142999A4 (en) | 2017-12-27 |
AU2015259337A1 (en) | 2016-12-08 |
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