CN114146088A - 用于治疗神经精神类障碍的组合物及方法 - Google Patents
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Abstract
本发明涉及联合治疗的组合物及方法,一时调节内在的功能异常神经过程(dysfunctional neural processes),并可降低包括但并不限定于精神刺激剂使用障碍(PUD:psychostimulant use disorder)及其他物质相关的成瘾性疾病、创伤后应激障碍(PTSD:post‑traumatic stress disorder)及其他创伤及应激相关障碍以及左旋多巴引起的运动障碍(LID:levodopa‑induced dyskinesia)及其他形态的运动障碍的症状和/或征兆的神经精神类障碍。本发明描述给药量形态的具体例。
Description
本申请是原申请的申请日为2016年01月28日,申请号为201680007760.2,发明名称为《用于治疗神经精神类障碍的组合物及方法》的中国专利申请的分案申请。
技术领域
联邦政府资助及权利
本发明通过使用一部分“可卡因禁止:治疗机会之窗”为题目的R01 DA012768;“关于滥用甲基苯丙胺药物开发”为题目的R01 DA14323;“突触传递机制及帕金森氏症”为题目的NS42124;以及“用于精神刺激剂滥用的联合治疗的新型奥坦西隆制剂”为题目的RC2DA028905的根据美国国立卫生研究院(NIH)许可的美国联邦政府的资金来进行。因此,联邦政府可具有对本发明的特定的权利。
优先权主张
本发明主张为了所有目的而其全部作为参照被引用的2015年1月28日申请的美国临时申请号62/108,616号的优先权。
技术领域
本发明涉及联合治疗的组合物及方法,一时调节内在的功能异常神经过程(dysfunctional neural processes),并可降低包括但并不限制于精神刺激剂使用障碍(PUD:psychostimulant use disorder)及其他物质相关的成瘾性疾病(Substance-related and addictive disorders)、创伤后应激障碍(PTSD:post-traumatic stressdisorder)及其他创伤及应激相关障碍(Trauma-and stressor-related disorders)及左旋多巴引起的运动障碍(LID:levodopa-induced dyskinesia)及其他形态的运动障碍(dyskinesia)的症状和/或征兆的神经精神类障碍。
背景技术
在本发明中描述的所有精神障碍,根据在精神障碍诊断统计手册[第5版](theDiagnostic and Statistical Manual of Mental Disorders Version 5,DSM-5),疾病及有关健康问题的国际统计分类[第10版](International Statistical Classificationof Diseases and Related Health Problems version 10,ICD-10)或在两侧均描述的为基准进行描述。同时,对于本技术领域的普通技术人员而言,易于理解在本发明中所描述的内容。
正开发用于治疗神经精神类障碍的多个治疗法,但仍需要对其副作用的解决方案。
看一神经精神类障碍的几个例。
精神刺激剂使用障碍
可可因(COC:cocaine)、甲基苯丙胺(METH:methamphetamine)及相关药物(以下统称为“精神刺激剂”)的误用不仅作为原发性精神疾病(primary psychiatric disorder),例如,作为精神分裂症、双相障碍、C型肝炎、艾滋病(HIV)等多种其他神经精神及疾病中的显著的伴随疾病/风险(comorbid/risk)因子,在全世界范围内不断使法定、社会经济及医疗费用增加(参照文献Whiteford et.al.,2013(Whiteford,HA,Degenhardt,L,Rehm,J,Baxter,AJ,Ferrari,AJ,Erskine,HE,Charlson,FJ,Norman,RE,Flaxman,AD,Johns,N,Burstein,R,Murray,CJL,Vos,T(2013).Global burden of disease attributable tomental and substance use disorders:findings from the Global Burden of DiseaseStudy 2010.The Lancet 382:1575-1586))。
尽管对于精神刺激剂使用障碍的有效的治疗的有关医疗领域中的高的未满足需求,但是到目前为止所进行临床实验的20多种以上的药物中仅出现有限的疗效,对于此适应症任意药物也没有得到美国食品药品监督管理局(FDA)的认证。目前,使用于精神刺激剂使用障碍患者的药物典型地局限制于伴随疾病精神障碍(comorbid psychiatriccondition)的治疗法。另一方面,为了治疗精神刺激剂依赖性,在没有得到美国食品药品监督管理局的认证下使用了各种向精神性药物(“非标签使用(off-label use)”),但是对于其效果没有进行严格的测试。在之前临床试验中被试验的药物中包含单独使用的其他精神刺激剂(例如,右旋苯丙胺,盐酸哌甲酯)、选择性多巴胺(DA)或血清素吸收抑制剂(例如,氟西汀)、完全或部分多巴胺激动剂(“full or partial DA agonist”;例如,阿立哌唑)、多巴胺拮抗剂(例如,利培酮)、γ-氨基丁酸(GABA)激动剂(例如,加巴喷丁)、中枢兴奋剂莫达非尼。额外的对多个药物(例如,安非他酮、n-乙酰半胱氨酸、抗癫痫剂硫加宾及托吡酯等)及其他治疗方式(例如,抗可可因及抗甲基苯丙胺疫苗或经颅磁刺激)急需进行临床评价(参照文献Haile et.al.,2012(Haile,CN,Mahoney,JJ,3rd,Newton,TF,De La Garza,R,2nd(2012).Pharmacotherapeutics directed at deficiencies associated with cocainedependence:focus on dopamine,norepinephrine and glutamate.Pharmacol Ther 134:260-277)),但是这些临床试验中的治疗结果的共同模式是:(1)在小规模临床试验中具有可行性的治疗,在大规模试验中无法证明其疗效(例如,氨己烯酸);(2)仅在特定的下位组的患者中具有疗效(例如,莫达非尼及托吡酯仅对不伴随酒精使用障碍的患者有效、戒酒硫仅对伴随特定基因型的患者、仅注射搭载有有效的抗体的抗可可因疫苗的患者的1/3有效)。因此,对于以减少精神刺激剂的不法使用为目的的、可有效地使用于精神刺激剂使用障碍的药物的未满足需求,仍存在于相关医疗领域内。
与人临床试验或医疗行为中的较好的治疗结果不同,多巴胺激动剂及血清素2(5HT2)、血清素3(5-HT3)或NK-1受体拮抗剂的被选择的组合可恢复精神刺激剂使用障碍的过敏反应(sensitization)及自我管理(self-administration)动物模型中所观察的行动及神经生物学变更。因此,如最近文献Lee et al.,2012(Lee,TH,Szabo,ST,Fowler,JC,Mannelli,P,Mangum,OB,Beyer,WF,Patkar,A,Wetsel,WC(2012).Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit:a novel treatment strategy.Drug and alcohol dependence 124:11-18)中所述的,这种治疗(1)可恢复预成立的可可因或甲基苯丙胺行为过敏性;(2)减少根据进行率及药物引起的恢复模式的自己给药;(3)正常化与神经生物学相关的指标。此调查的重要发现如下,包括:(1)仅在给药激动剂之前或不是一同给药而是在3.5小时之后给药拮抗剂的情况下,可在动物模型中实现一致的治疗效果;(2)单独进行给药的每天多巴胺激动剂或血清素拮抗剂没有效果。
多巴胺激动剂的给药后,进行固定的3.5小时的延迟后,在动物精神刺激剂使用障碍模型中,充分构建有对动物给药血清素2或NK-1受体拮抗剂的联合治疗方法(参照上述文献Lee et al.,2012),但是实际上为了得到与此类似的治疗效果,存在仅能完全要依赖于强制患者按照个别的处方服用2种药物的义务性服用法(dosing regimen)(即,给药激动剂3.5小时后给药拮抗剂)的局限。由于被诊断为原发性或伴随疾病精神疾病的患者们不愿遵守典型地处方的治疗计划或无法遵守,在没有用于保证治疗遵守事项的医疗实务措施的情况下,若适用于以减少精神刺激剂使用障碍及其他精神疾病患者们的不发药物使用为目标的这种治疗,则失败的可能性很高。因此,为了这种,在患者中的联合治疗的成功使用,典型的需要如住院或居住治疗设施等被监控环境。
左旋多巴引起的运动障碍
在被诊断为帕金森氏病和/或其他有关障碍(以下简称为“PD”)的患者的情况下,多巴胺代替治疗通过恢复大脑内中的多巴胺神经传递,来为了缓解PD及其他有关障碍的症状及征兆而使用。多巴胺前体左旋多巴(L-3,4-dihydroxyphenylalanine)为对PD运动征兆和症状缓解最重要的药物之一。然而,由于根据使用此药物的副作用,即引起左旋多巴引起的运动障碍及有关的疗效损失的趋势,在PD患者的长期管理方面仅具有有限的有用性。甚至在“最佳的”左旋多巴治疗法中,帕金森氏病患者的最大90%在5年至10内发展成左旋多巴引起的运动障碍。由此,左旋多巴引起的运动障碍成为PD患者的左旋多巴(与是否使用辅助多巴胺激动剂无关)治疗失败的主要原因之一。
左旋多巴敏化及左旋多巴引起的运动障碍
在各种机制中,左旋多巴敏化(levodopa sensitization)在左旋多巴引起的运动障碍发达及保持中起重要的作用。根据进行性多巴胺神经元的凋亡和/或血清素末端中的“异位(ectopic)”多巴胺合成及释放的多巴胺合成、细胞外多巴胺的释放及净空(clearance)的失调(dysregulation)引起给药左旋多巴后突触多巴胺浓度的过度偏离。这种偏离依次诱导基底核及其他大脑领域的功能异常突触变化。
基于偏离的突触多巴胺水平的推定作用,使以保持一致的左旋多巴水平的方式设计的各种治疗战略与阻断左旋多巴引起的运动障碍(敏感性)发达或通过耐性的诱导的左旋多巴敏感性表达相对应。这种战略包括:
(1)控制或延长释放左旋多巴剂型或“持续型(round-the-clock)”左旋多巴给药治疗的使用;(2)用于减少突触多巴胺浓度偏离的儿茶酚-o-甲基转移酶(catechol-o-methyltransferase)抑制剂的附加;(3)十二指肠内左旋多巴投入;及(4)左旋多巴药贴。不幸的是,这种“持续性的”左旋多巴接近方式未达到原来期待的效果。这种适当以下的疗效(less-than-optimal efficacy)的理由可包括:(1)(与指定的“同等的”给药量相比)减少的最大左旋多巴浓度;(2)药代动力学耐性的发达;以及(3)作为基于直接性的多巴胺激动剂充分被证明的现象的、延长的“持续性的”左旋多巴治疗期间的新型的且明确的神经生物学变化的出现,但并不限制于此。最大12小时/天至14小时/天保持多巴胺激动剂的水平为仍然导致行为敏感性(behavioral sensitization),与此相反,事实上要留意进一步延长的药物浓度的持续(例如,8小时/天以上的投入)也诱导耐性(参照文献Ellinwood et al.,2002(Ellinwood,EH,Davidson,C,Yu,GZ,King,GR,Lee,TH(2002).Effect of dailydosing duration of direct and indirect dopamine receptor agonists:cocainecross-tolerance following chronic regimens.European neuropsychopharmacology:the journal of the European College of Neuropsychopharmacology 12:407-415))。据悉,在延长的时间内的有效治疗范围中的药物浓度的保持,往往导致增加噩梦、睡眠障碍等夜间副作用的发生。通过多种这种考虑事项,来提示包含药物代谢中的个人差异、患者可保持处方的给药治疗的能力和/或增加的左旋多巴引起的运动障碍或其他副作用引起的未遵守治疗的多种因子,在一定的左旋多巴水平的持续时间导致可变性,由此,可限制作为“抗-左旋多巴引起的运动障碍”战略的“持续型”治疗法。
与“持续型”左旋多巴治疗一同提示的另一种“抗-左旋多巴引起的运动障碍”战略包括用于利用作为左旋多巴代替药物的代替或防止左旋多巴引起的运动障碍发达或阻断现有的左旋多巴引起的运动障碍的发达的左旋多巴及“抗左旋多巴引起的运动障碍药物”的联合给药。除此之外,正进行对处于多种开发阶段的多种治疗剂或治疗法多个候选评价。最近,尽管具有与侵入性属性及长期或短期手术或合并症有关的危险,但是深部脑刺激(DBS:deep brain stimulation)还再增加,但是还没有系统性的阐明是否直接变更作为左旋多巴引起的运动障碍的核心的神经生物学变化或者是否具有间接影响,如左旋多巴用量减少、阻断第二次左旋多巴引起的运动障碍表达和/或缓解PD进展速度。
创伤后应激障碍
在美国的情况下,根据伴随疾病症调查(NCS-R:National Comorbidity SurveyReplication),具估计对创伤后应激障碍的成人的12个月(年间)患病率为3.5%。其中,36.6%为重症。从整体上来看,据估计在美国的创伤后应激障碍的终生患病率为8%至9%,与此相关地,发生约80亿美元的费用,女生为男生的2倍。在12个月患病率的情况下,男生为1.8%、女生为5.2%(国立心理健康研究所(National Institute of Mental Health),2010)、青少年(13岁至18岁)的患病率约为4%。由于这样高的患病率,在美国的情况下,每年患病人口的49.9%的任自愿接受治疗,其中,42%接受最低限度的适当治疗。
在韩国的情况下,据国民健康保险(Korean National Health Insurance)的统计,显示总创伤后应激障碍患者的数(外来及住院患者)在2014年为6981名、2013年为6741名及2012年为6950名。按照性别分析总患者的数,男性患者的数高于女性患者的数的1.5倍。在10岁至60岁之间的范围内按照年龄分析,在所有年龄段存在较均匀的患者数
目前,在“创伤后应激障碍防治指南”2013年(防治指南)中,据悉具有“显著的”或“一定程度”的优势的治疗方案中包括心理治疗(例如,“认知(cognitive)”、“暴露(exposure)治疗”及药物治疗。在药物治疗的情况下,抗抑郁药尤其是选择性血清素或血清素/去甲肾上腺素重吸收抑制剂的单独治疗,在对照试验中具有疗效;期中,只有舍曲林及帕罗西汀为了创伤后应激障碍的治疗获得美国食品药品监督管理局认证。同时也检查了多个苯二氮卓、非典型抗精神病药物、抗惊厥药,但是这些药物没有一致的疗效,也不存在于在所述的方针中所推荐的药物目录中。另一方面,据报告与暴露治疗相比,治疗暴露治疗和帕罗西汀的联合治疗没有额外的效果。目前,对额外的治疗法及试验用新药(IND:investigational new drug),作为与单独治疗或现有形态的创伤后应激障碍治疗有关的战略继续进行临床评价。
基于神经精神类障碍的神经
精神刺激剂使用障碍,包括左旋多巴引起的运动障碍及创伤后应激障碍的多种神经精神类障碍被视为不适应功能异常神经回路(maladaptive dysfunctional neuralcircuit)的被强化的形态(“功能异常神经可塑性(dysfunctional neural plasticity)”或“功能异常记忆”(dysfunctional memory))。障碍特异性神经可塑性包括神经机制及处理器、大脑领域、大脑领域连接性、大脑网络及大脑内或不伴随大脑的网络相互作用,但是可变为并不限定于此的多种水平,这被视为是形成特定的障碍的多个征兆及症状的基础(参照文献Headley and Pare,2013(Headley,DB,Pare,D(2013).In sync:gammaoscillations and emotional memory.Front Behav Neurosci 7:170))。因此,这种神经可塑性变化的治疗介质正常化(treatment-mediated normalization)可能会带来成功的治疗结果。
在图1中示出功能异常神经回路的位置机制。
例如,如图1所示,在被诊断为精神刺激剂使用障碍的患者的情况下,稳定且被强化的“精神刺激剂使用障碍神经回路”可借助被暴露于精神刺激剂本身(例如,“使用少量的药物(drug tasting)”)、与使用药物相关的环境信号(例如,吸毒工具(drugparaphernalia))或"“应激”等多种刺激剂来被再活性化(参照文献Childress et al.,1999(Childress,AR,Mozley,PD,Mcelgin,W,Fitzgerald,J,Reivich,M,O'brien,CP(1999).Limbic activation during cue-induced cocaine craving.The Americanjournal of psychiatry 156:11-18);Sinha,2006(Sinha,R,Garcia,M,Paliwal,P,Kreek,MJ,Rounsaville,BJ(2006).Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapseoutcomes.Archives of general psychiatry 63:324-331);上述参照文献Lee et al.,2012等)。在不被干涉的情况下,被再活性化的记忆在戒断中被再加强(reconsolidation)。例如,戒断中的破坏(“crash”)症状对应于此。
左旋多巴引起的运动障碍为“功能异常神经可塑性变化”的另一种再加强形态,它通过基于左旋多巴的治疗性给药的反复再活性化和左旋多巴的治疗效果借助药代动力学(PK:pharmacokinetic)和/或药效学(PD:pharmacodynamic)上减少的期间后续进行的再加强来进行保持。
与功能异常精神刺激剂使用障碍或左旋多巴引起的运动障碍神经回路类似,可将概念化成创伤后应激障碍患者的功能异常“创伤后应激障碍神经回路”通过反复的再活性化及再加强循环来保持的。例如,在患者被暴露于之前成为原因的创伤性应激事件(traumatic stressful event;例如,杀死朋友的引爆炸弹爆炸的噪音、大车事故后坐车等)的情况下,功能异常神经回路可被再活性化。这种再活性化会导致创伤后应激障碍征兆和症状的重新出现,在被再活性化的创伤后应激障碍回路稳定而被再加强为易于被再活性化的状态下才能镇定下来。基于再加强,创伤后应激障碍症状及征兆被恶化可成为因受刺激而重新出现的状态。
发明内容
技术问题
本发明的目的在于,提供联合治疗的组合物及方法,一时调节内在的功能异常神经过程,并可降低包括精神刺激剂使用障碍及其他物质相关的成瘾性疾病、创伤后应激障碍及其他创伤及应激相关障碍及左旋多巴引起的运动障碍及其他形态的运动障碍的症状和/或征兆的神经精神类障碍,但并不限制于此。
解决问题的方案
基于上述概念化,根据本发明,其特征在于提供如下的联合治疗的组合物及方法,在组合方法中所使用的激动剂以治疗学上使稳定的功能异常神经回路再活性化为其的“被再活性化的不稳定的”状态,由此给予它一时不稳定的状态的方法,由此,给药激动剂之后,在适当的施加内给的拮抗剂会阻断再加强及后续的回路再稳定化,因此,依次再活性化不适应记忆,且通过阻断其的再加强来使神经精神类障碍的症状和/或征兆逐渐减少至无症状(subclinical)水平,从而一时调节内在的功能异常神经处理器,并可降低包括但并不限定于此的精神刺激剂使用障碍及其他物质相关的成瘾性疾病、创伤后应激障碍及其他创伤及应激相关障碍及左旋多巴引起的运动障碍及其他形态的运动障碍的神经精神类障碍的症状和/或征兆。
发明的效果
根据本发明,提供联合治疗的组合物及方法,一时调节内在的功能异常神经处理器,并可降低包括精神刺激剂使用障碍及其他物质相关的成瘾性疾病、创伤后应激障碍及其他创伤及与应急有关的障碍及左旋多巴引起的运动障碍及其他形态的运动障碍,但并不限制于此的神经精神类障碍的症状和/或征兆,并且治疗包括:(1)包括但并不限制于此烟草使用障碍、酒精使用障碍及大麻使用障碍的其他物质相关障碍;(2)包括但并不限制于此习惯性赌博及网络成瘾的行动成瘾障碍;(3)包括但并不限制于反应性依恋障碍(reactiveattachment disorder)、急性应激障碍及适应障碍的其他创伤及应激相关障碍(traumaand stressor-related disorder);(4)包括但并不限制于广泛性焦虑症(generalizedanxiety disorder)、恐慌症、广场恐怖症、物质/药物诱发的焦虑症的焦虑症;(5)包括但并不限制于强迫症、躯体变形障碍(body dysmorphic disorder)、囤积障碍(hoardingdisorder)、拔毛癖(trichotillomania)及抓痕障碍(excoriation disorder)的强迫症;以及(6)包括但并不限制于神经性厌食症、贪食症及暴食症的进食障碍,但并不限制于此的其他神经精神类障碍有效。
附图说明
图1为示出功能异常神经回路的保持的机制的图。
图2为示出本发明的联合治疗的机制的图。
图3为示出多巴胺激动剂培高利特及血清素2A/2C(5-HT2A/2C)拮抗剂酮色林的组合在作为左旋多巴引起的运动障碍的动物模型的大鼠中显著降低左旋多巴引起的异常不自主运动(LIAIM)的曲线图。
具体实施方式
下述式说明组合物及方法的原理的例示性具体例。具体例用于说明发明的实施方式而提供,但本发明并不限定于任意具体例。发明的范围包括多个多种代替技术方案、多个变更及等同替代物,但仅限制于发明要求保护范围中
在本技术领域中,对技术人员而言,可易于理解通过实施多个目的来很好的适用本发明,以使实施多个目的且获得所提及的多个目标及多个优点的同时获得多个其固有的。其中,所描述的本详细的说明作为目前优选具体例的代表来提供,是例示性的,而并不没有意图要限制本发明的范围。对本发明所属技术领域中的技术人员而言,此范围内中的多个变化及其他多个用途可在发明要求保护范围下进行。
多个具体地详细说明为了完全理解本发明,如下述进行规定。然而,本发明也可以在没有这种特定详细说明的一部分或全部下,根据发明要求保护范围实施。为了明确性,对于与本发明相关的技术领域中公知的技术性资料不进行详细说明,以使不造成不必要的混淆发明。
在本发明内所描述的所有障碍,根据在精神障碍诊断统计手册[第5版]、疾病及有关健康问题的国际统计分类[第10版]或在两侧均描述的为基准进行描述。并且,第一次诊断(名)或第二次诊断(名)或副作用或伴随疾病状态可属于在本发明中所技术的目标适应症中。
如在背景技术中所说明的,将包括精神刺激剂使用障碍、左旋多巴引起的运动障碍及创伤后应激障碍,但并不限定于此的多种神经精神类障碍可概念化为功能异常不适应突触可塑性的稳定的、被强化的形态,它可通过反复的再活性化/再加强循环来进行保持。虽然可将多个药理学方案使用在现在的多种神经精神类障碍,但是多个这种治疗的大部分是原发性和/或伴随疾病障碍的征兆及症状缓解的程度,是“临时权益之计”为主。可视为可对内在的功能异常神经回路进行正常化(“改变疾病(disease modification)”)的更为有效的药理学治疗的高的未满足需求仍存在。
图2为示出本发明的联合治疗的概念模型图。
在如图2所示的新的组合的治疗中,第一组分(组分1)用作在稳定的状态下被再活性化的状态的单一实施例中再活性化功能障碍神经回路的方法,一时形成功能障碍神经回路的不稳定状态。在相同实施例中,与第一组分一同以任意具体例或单一的组合物、剂型或给药形态提供的第二组分(组分2)阻断再加强及之后进行的稳定状态中的再稳定化过程。因此,起使在联合治疗方面最优化的同时具有患者便利性的这种组合物或剂型将障碍的症状及征兆渐进降低为无症状(准临床)水平、反复再活性化记忆以使正常的神经功能恢复(例如,成功的治疗)、阻断再加强的作用。在本发明中所描述的组合物、方法及多个实施例以单一给药形态使这些联合治疗的有效临床适用可行。
包含2个活性的组分,其中所描述的联合治疗具体例中可使用于神经精神类障碍的治疗中。作为联合治疗具体例可治疗的障碍包括精神刺激剂使用障碍、左旋多巴引起的运动障碍及创伤后应激障碍。其他障碍包括:(1)其他物质相关障碍包括但并不限制于烟草使用障碍、酒精使用障碍及大麻使用障碍;(2)行动成瘾障碍包括但并不限制于习惯性赌博及网络成瘾;(3)其他创伤及应激相关障碍(trauma and stressor-related disorder)包括但并不限制于反应性依恋障碍、急性应激障碍及适应障碍;(4)焦虑症包括但并不限制于广泛性焦虑症、恐慌症、广场恐怖症、物质/药物诱发的焦虑症;(5)强迫症包括但并不限制于强迫症、躯体变形障碍、囤积障碍、拔毛癖及抓痕障碍;以及(6)进食障碍包括但并不限制于神经性厌食症、贪食症及暴食症,但并不限制于此。
虽然其他症状、征兆、特定的大脑回路及其他诊断基准区分这些障碍,但是它分享被强化的功能异常神经可塑性的形态的共同属性。它还分享这些各个功能异常神经回路的形成、强化和/或保持中的多巴胺、谷氨酸、源性神经营养因子(BDNF:brain-derivedneurotrophic factor)、多巴胺受体亚型(dopamine receptor subtype),α-氨基-3-羟基-5-甲基-4-异恶唑丙酸盐(AMPA:α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate)、N-甲基-D-天冬氨酸(NMDA:N-methyl-D-aspartate)及代谢型谷氨酸5(mGluR5:metabotropic glutamate 5)谷氨酸受体及多种蛋白激酶及假激酶等一种以上的相同的神经传递物质、受体、分子、信号途径。因此,这些障碍可适应于其中所描述的基于联合治疗的治疗性介入。
联合治疗可以以可与在本技术领域中所理解实施的临床适用相兼容的任意具体例、给药形态(dosage form)、方法或途径进行实施。组分1是不适应功能异常神经回路从稳定状态变为被再活性化的状态,由此,提供基于以使不适应功能异常神经回路的不稳定的方法。与组分1一同包括在任意具体例或单一的组合物、剂型或给药形态内的组分2,阻断再加强及后续的稳定的状态的再稳定化。因此,这种任意具体例或单一的组合物、剂型或给药形态使联合治疗最优化,并以患者便利性高的形态及方法来允许上述多个组分向体内传递,进而,可使目标的障碍的征兆及症状降低为无症状的水平。其中,描述的组合物、剂型、方法及例示性的多个具体例可有效的使用作为给药形态的联合治疗。
1.组分1可选自小分子(small molecule)、其他形态的分子及其多种变形(例如,制剂、前体药物等)。其他形态的多个分子中包含小干扰核糖核酸(siRNA)、微小核糖核酸、反义寡核苷酸、适配体、肽、蛋白质(例如,抗体)、自然发生(naturally-occurring)有机活无机分子、化学元素(例如,锂)及更大于或小于小分子的任意多个合成化合物,但并不限制于此,优选地,通过任意安全的、可收容且有效的给药途径来进行传递,从而可包含在用于实现功能异常神经回路从稳定的状态转移为再活性化及不稳定状态的功能异常神经回路再活性化的单一的联合治疗给药形态内。
2.在一种联合治疗具体例中,组分1为伴随或不伴随去甲肾上腺素(NE:norepinephrine)和/或血清素(5-HT)作用疗效(agonistic efficacy)的、药理学上有效的间接或直接多巴胺激动剂或其药剂学上可接受的盐。若在选择直接多巴胺激动剂的情况下,此激动剂可能对D1-型或D2-型多巴胺受体显示或不显示偏好度。重要的是,除非另有说明,术语“D1”及“D1-型”可互换使用,用作在多个D1及D5受体中的任一种或两种。类似地,“D2”及“D2-型”可互换使用,用作多个D2、D3及D4多巴胺受体各个及其中的任一种。在选择的组分1的立体异构体存在的情况下,可使用任意立体异构体单独或各个的最优化的比率的组合。组分1还可以是如上述1中所述的任意物质及其多种变形,并预期为(1)包括如基于本技术领域技术人员所熟知的任意分析方法来评价的、而且基于药效(pharmacophore)“连接(docking)”、虚拟计算筛选(virtual computational screening)及其他试管内(invitro)/在硅之中(in silico)分析法,但并不限制于此的公知的生理化学特性;和/或(2)基于试管内和/或省体内药学曲线图的功能性多巴胺激动剂。
2.1.在作为组分1选择间接多巴胺激动剂的情况下(例如,多巴胺前体、多巴胺释放剂或多巴胺重吸收阻断剂),与间接多巴胺激动剂(例如,选择性多巴胺重吸收阻断剂)而不是药理学上有效的去甲肾上腺素和/或血清素激动剂相比,更偏好于药理学上有效的去甲肾上腺素和/或血清素激动剂(例如,d-安非他明、盐酸哌甲酯、选择性多巴胺去甲肾上腺素重吸收抑制剂)。
2.2.在作为组分1选择直接多巴胺激动剂的情况下,与D1-选择性或D2-选择性受体激动剂相比,偏好于D1-型及D2-型多巴胺受体激动剂。
2.3.在作为组分1选择直接多巴胺激动剂的情况下,并且,与不伴随去甲肾上腺素和/或血清素疗效的相比,偏好于作为药理学上有效的去甲肾上腺素和/或血清素激动剂作用的激动剂。
2.4.与示出即时性或延迟性或脉动性或延长/持续性释放曲线的任意其他组合/排列相比,偏好于本技术领域技术人员所熟知的试管内和/或活体内试验(例如,试管内溶解试验、活体内药代动力学参数的评价)中示出即时的且脉动性的释放曲线的激动剂及其药剂学上可接受的盐及任意变形形态。在一优选的试管内激动剂释放曲线为在胃或肠试管内溶解试验条件下,在2小时以内溶解90%以上,更优选的曲线图为在相同的试验条件下,1小时以内溶解80%以上。
2.5.激动剂及其药剂学上可接受的盐及变形形态(包含任一种及所有活性代谢产物)在人体内可具有20小时下回以下的消除半衰期(terminal elimination half life;t1/2)。合适的消除半衰期(t1/2)为10小时,更优选的消除半衰期为(t1/2)5小时以下。
3.组分2可选自小分子、其他形态的分子及其多种变形(例如,制剂、前体药物等)。其他形态的多个分子种包含小干扰核糖核酸、微小核糖核酸、反义寡核苷酸、适配体、肽、蛋白质(例如,抗体),天然有机或无机分子、化学元素(例如,锂)及更大于或小于小分子的任意多个合成化合物,但并不限制于此,优选地,通过任意安全的、可收容且有效的给药途径来进行传递,从而可包含在用于实现功能异常神经回路从稳定的状态转移为再活性化及不稳定状态的功能异常神经回路再活性化的单一的联合治疗给药形态内。
4.在一具体例中,组分2包含血清素2及NK-1受体亚型(subtype)、单核苷酸多形体及在任重表达的各个受体的其他转录、翻译及翻译后变形,是血清素2受体的选择性或非选择性受体拮抗剂或反向激动剂(inverse-agonist)、受体的选择性或非选择性受体拮抗剂或反向激动剂、NK-1受体的选择性或非选择性拮抗剂或反向激动剂。作为此具体例,可包含酮色林及其化学同构体(例如,米安色林);米氮平及其化学同构体(例如,司普替林);奥坦西隆,格拉司琼,多拉司琼,帕洛诺司琼及托烷司琼,但并不限制于此。
在被选择的组分2的立体异构体存在的情况下,可使用任意立体异构体单独或各个最优化的比率的组合。
组分2还可以是在上述3中所述的任意物质及其多种变形,并预期为(1)包括如基于本技术领域技术人员所熟知的任意分析方法来评价的、而且基于药效“连接”、虚拟计算筛选及其他试管内/在硅之中分析法,但并不限制于此的公知的生理化学特性;和/或(2)基于试管内和/或活体內药理学曲线图的血清素2和/或NK-1激动剂中的功能性拮抗剂。
4.1.在作为组分2选择血清素2拮抗剂或反向激动剂的情况下,与偏好其他血清素2亚型的其他血清素2拮抗剂或反向激动剂相比,偏好于单独偏好血清素2A亚型、血清素2C亚型或偏好所有血清素2A亚型及血清素2C亚型的拮抗剂或反向激动剂。
4.2.在作为组分2选择药理学上有效的拮抗剂或反向激动剂的情况下,拮抗剂或激动剂可示出或为示出在α7(α7)烟碱性受体(nicotinic receptor)中作为拮抗剂、反向激动剂或完全或部分激动剂的所期待的生理化学性、试管内及活体内药理学特性和/或曲线图。与作为拮抗剂本身或药理学上有效的α7烟碱性拮抗剂、反向激动剂或完全或部分激动剂所期待的相比,更偏好于选择性拮抗剂。
4.3.在作为组分2选择药理学上有效的NK-1拮抗剂或反向激动剂的情况下,与NK-2和/或NK-3受体亚型相比,拮抗剂或反向激动剂可对NK-1受体亚型使选择性的或是非选择性的。然而,与选择性NK-1拮抗剂相比,偏好于非选择性NK-1拮抗剂。
4.4.与示出即时性或延迟性或脉动性或延长/持续性释放曲线的任意其他组合/排列相比,偏好于本技术领域技术人员所熟知的试管内和/或活体内试验(例如,试管内溶解试验、活体内药代动力学参数的确定)中示出延迟的且脉动性的释放曲线的拮抗剂及其药剂学上可接受的盐及任意变形形态。在一优选的试管内激动剂释放曲线为在胃或肠试管内溶解试验条件下,在3小时以上溶解10%以下至在7小时以下溶解80%以上。
4.5.拮抗剂及其药剂学上可接受的盐及变形形态(包含任一种及所有活性代谢产物)在人体内可具有20小时以下的消除半衰期(t1/2)。合适的消除半衰期(t1/2)为16小时以下,更合适的消除半衰期(t1/2)为14小时以下,更优选的消除半衰期(t1/2)的范围为3小时至13小时。
5.将给药活体内的最大药物浓度规定为“Cmax”,并将到达Cmax的时间规定为“Tmax”。组分1的药理学活性形态的Tmax和组分2的药理学活性形态的Tmax见得差异,在决定联合治疗的疗效中起至关重要的作用。对于其中所述的所有治疗上的指标,在人中组分1和组分2的药理学上为活性形态的血浆或血清浓度间的Tmax分离可以自1小时至12小时的范围中。适当的范围为1小时至8小时,更适当的分离为2小时至8小时。更优选的为2小时至7小时。
6.组分1和/或组分2的Tmax可通过(1)包括胃肠管、血液、肝或其他器官中执行活性化的,但并不限制于此的药理学上非活性化的前体药物的使用;或者(2)包括基于药理学上有效的母形状(parent form)的剂型的变形,但并不限制于此的多种方法来进行变更。可通过使用包括基于pH、基于渗透压、基于脂质体变形方法,但并不限制于此的多种基于剂型变更,来在任重的活体内实现药代动力学曲线图中目标的。
7.用于联合治疗的组合物可以以包括片剂、胶囊、溶液、凝胶、悬浮液、膜、药贴及栓剂,但并不限制于此的任意形态来实现。上述概要形态可以是药剂学组合物,其作为活性成分包含上述组分1及组分2,进一步地,还可包含用于剂型化的赋形剂、载体等药剂学上可接受的添加剂,上述添加剂为药学上可接受的,可使用任意有助于成型等剂型化、有助于摄取的。例如,在作为粉末或颗粒、溶液或水性或非水性液体中悬浮液、油包水乳液或油包水液体乳液中包含一定量的活性。可以以任意药学方法制备各剂型,但是所有方法包括使由一种以上必须成分构成的载体和活性成分缔合的步骤。通常地,通过均匀且细细的混合液体载体或细碎的固体载体或两种与活性成分来制备组合物后,在必要的情况下,以为目的的外形形成生成物。例如,根据情况,可利用一种以上的附加成分借助压缩或成型来制备片剂。被压缩的片剂在适当的机械中,根据情况在如与赋形剂,作为非限制性例的粘结剂、润滑剂、惰性稀释剂和/或表面活性剂或分散剂混合而成的粉末或颗粒等的自由流动形态下,通过压缩活性成分来制备而成。成型的片剂在适当的机械中,通过利用惰性液体稀释剂对湿润的粉末状合物混合物进行成型来制备而成。
本发明由于水促进一些化合物的分解,因此还包括包含无水药学组合物及活性成分的剂型。例如,为了随时测定制备物的特征如寿命或稳定性,因此在药学领域中作为刺激长期保管的方法可添加水。本发明的无水药学组合物及剂型可通过利用无水或水分含有成分低的或低的水分或低的适度状态来制备而成。对于包含乳糖的本发明的药学组合物及剂型,在预期进行制备、包装和/或保管期间与水分和/或适度有实际上的接触的情况下,可制备无水物。制备无水药学组合物并可以以保持其无水性质的方式保管。因此,无水组合物可利用防止暴露于水的公知的材料来包装,以使包含在适当的规定试剂盒的方式。作为适当的包装的例包括作为非限制性例的密封铝箔、塑料等、单位容量容器、发泡剂膜及剥离膜。
活性成分可根据常规的药学化合法与药学载体结合配合成混合物。载体可根据对于给药适当的制备形态取各种各样的形态。在制备用于口服剂型的组合物中,任意通常的药学介质为口服液体制备物(例如,悬浮液、溶液及酏剂)或烟雾剂的情况下,可使用例如,水、乙二醇、油、乙醇、风味剂、保存剂、着色剂等的载体;或者在不利用乳糖的一些具体例中,在口服固体制备物的情况下可使用例如,淀粉、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘结剂及崩解剂等的载体。例如,适当的载体可包含具有固体口服制备物的粉末、胶囊及片剂。如果有必要,则片剂可根据标准水性或非水性发来进行涂覆。
在使用于药学组合物及剂型的适当的粘结剂中,作为非限制性例包括玉米淀粉、马铃薯淀粉、或其他淀粉、明胶、天然合成胶,例如,阿拉伯胶,海藻酸钠,果胶酸,其他果胶酸盐,粉末状黄芪,瓜尔豆胶,纤维素及其衍生物(例如,乙基纤维素、纤维素乙酸盐、羧甲基纤维素钙、羧甲基纤维素钠),聚乙烯吡咯烷酮,甲基纤维素,糊化淀粉,羟丙基甲基纤维素,微晶纤维素及其混合物。
在本发明中公开的药学组合物及剂型中使用适当的填充剂的例包括作为非限制性例的滑石、碳酸钙(例如,颗粒或粉末)、微晶纤维素、粉末状纤维素,葡萄糖,高岭土,甘露醇,硅酸,山梨糖醇,淀粉,糊化淀粉及其混合物。
崩解剂为了提供在暴露于水性环境的情况下崩解的片剂,可使用本发明的组合物。很多的崩解剂可生产在病中可崩解的片剂。若太少,由于崩解不充分,因此活性(多个)成分的释放速度及程度会发生变化。因此,可使用不多不少的充足量的崩解剂来使不利于(多个)成分的释放,来形成在本发明中公开的化合物剂型。所使用的崩解剂量可根据制备物类型及给药方式而不同,可被技术人员容易识别。将约0.5重量百分比至15重量百分比的崩解剂或约1重量百分比至5重量百分比的崩解剂使用于药学组合物。可使用于形成本发明的药学组合物及剂型的崩解剂包括,作为非限制性例的琼脂-琼脂、果胶酸、碳酸钙、微晶纤维素、羧甲基纤维素钠、交聚维酮、聚丙烯酸钾、羟基乙酸淀粉钠、马铃薯或木薯淀粉、其他淀粉、糊化淀粉、其他淀粉、粘土、其他海藻酸盐、其他纤维素、胶或其混合物。
使用于形成本发明的药学组合物及剂型的润滑剂作为非限制性例包括硬脂酸钙、硬脂酸镁、矿物油、白色矿物油、甘油、山梨糖醇、甘露醇、聚乙二醇、其他乙二醇、硬脂酸、月桂基硫酸钠、滑石、氢化植物油(例如,花生油、棉子油、葵花籽油、芝麻油、橄榄油、玉米油及豆油)、硬脂酸锌、油酸乙酯、月桂酸乙酯、琼脂或其混合物。
额外的润滑剂包括,例如,甲状腺硅胶、合成二氧化硅的凝固的烟雾剂或其混合物。润滑剂可根据情况添加约小于1重量百分比的药学组合物的量。
在水性悬浮液和/或酏剂适合于口服给药的情况下,其必须成分可与各种甜味剂或风味剂、着色物质或染料及在优选的情况下,与稀释剂如水、乙醇、丙二醇、甘油及其各种组合物一同与乳化剂和/或悬浮剂配合。
片剂为了在胃肠管中延迟分解及吸收可以以公知的方法进行涂覆或不进行涂覆,因此提供长期的持续作用。例如,可使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。用于口服使用的剂型还可以以硬胶囊的形式存在,其中活性成分与惰性固体稀释剂,例如,碳酸钙、磷酸钙或高岭土进行混合,或者作为软胶囊,与活性成分水或油介质,例如,花生油、液体石蜡或橄榄油进行混合。为了治疗剂的快速释放可崩解片剂。
使用于形成本发明的药学组合物及剂型的表面活性剂作为非限制性例包含亲水性表面活性剂,亲油性表面活性剂及其混合物。即,可使用亲水性表面活性剂混合物、亲油性表面活性剂的混合物或一种以上亲水性表面活性剂及一种以上的亲油性表面活性剂的混合物。
适当的亲水性表面活性剂通常可具有10以上的亲水疏水平衡值(HLB),但是适当的亲油性表面活性剂可通常可具有约10以下的亲水疏水平衡值。用于对非离子性两亲性化合物的相对亲水性及疏水性进行特性化的实证变数为亲水性-亲油性的平衡(“亲水疏水平衡值”)。亲水疏水平衡值越低的表面活性剂为更为亲水性或疏水性,油中溶解度更高,与此相反,亲水疏水平衡值更高的表面活性剂为亲水性,在水溶液中具有更高的溶解度。亲水性表面活性剂可考虑通常亲水疏水平衡值约大于10的大化合物、通常不适用亲水疏水平衡值规模的阴离子性、阳离子性或两性离子性化合物。类似的,亲油性(即,疏水性)表面活性剂为具有约10以下的亲水疏水平衡值的化合物。
但是,表面活性剂的亲水疏水平衡值只是在制备工业、药学及美容乳液中通常使用的大概的方针。
亲水性表面活性剂可以是离子性或非离子性。适当的离子性表面活性剂作为非限制性例可包括:烷基铵盐;易熔酸盐;氨基酸的脂肪酸衍生物、寡肽及多肽;氨基酸的甘油酯衍生物、寡肽及多肽;卵磷脂及硬化卵磷脂;溶血卵磷脂及硬化溶血卵磷脂;磷脂及其衍生物;溶血磷脂及其衍生物;肉碱脂肪酸酯盐;烷基硫酸盐;脂肪酸盐;多库酯钠;酰基酰乳酸;单甘酯及乙酰化单甘油二酯及二乙酰化酒石酸酯;琥珀酰单甘油酯及甘油二酯;单甘酯及甘油二酯的柠檬酸酯;及其混合物。
在所述的组中,优选的离子性表面活性剂的例包括:卵磷脂,溶血卵磷脂、磷脂、溶血磷脂及其衍生物;肉碱脂肪酸酯盐;烷基硫酸盐;脂肪酸盐;多库酯钠;酰基酰乳酸;单甘酯及甘油二酯的单乙酰化及二乙酰化酒石酸酯;琥珀酰单甘油酯及甘油二酯;单甘酯及甘油二酯得到柠檬酸酯;以及其混合物。
离子性表面活性剂可以是卵磷脂、溶血卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酸、磷脂酰丝氨酸、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、溶血磷脂酰甘油、溶血磷脂酸、溶血磷脂酰丝氨酸、聚乙二醇-磷脂酰乙醇胺、聚乙烯吡咯烷酮-磷脂酰乙醇胺、脂肪酸的乳酸酯、硬脂酰-2-乳酸、硬脂酰乳酸、羰基琥珀酸单甘油酯、单甘酯/甘油二酯的单乙酰化的酒石酸酯/二乙酰化的酒石酸酯、单甘酯/甘油二酯的柠檬酸酯、胆汁酸酯、己酸酯、辛酸酯、癸酸酯、月桂酸酯、荳蔻酸、棕榈酸酯、油酸、赖氨酸油酸酯、苯甲酸亚油酸、亚麻酸酯、硬脂酸酯、十二烷基硫酸盐、三乙酰硫酸盐、多库酯、月桂酰肉碱、棕榈酰肉碱、肉豆蔻酰基肉碱及其盐及混合物的离子化形态。
亲水性非离子性表面活性剂作为非限制性例可包含:烷基糖苷;烷基麦芽糖苷;烷基葡萄糖苷;十二烷基聚乙二醇甘油酯;聚氧化烯烷基醚,例如,聚乙二醇烷基醚;聚氧化烯烷基苯酚,例如,聚乙二醇烷基苯酚;聚氧化烯烷基苯酚脂肪酸酯,例如,聚乙二醇脂肪酸单酯及聚乙二醇脂肪酸酯;聚乙二醇甘油脂肪酸酯;聚甘油脂肪酸酯;聚氧化烯脱水山梨醇脂肪酸酯,例如,聚乙二醇脱水山梨醇脂肪酸酯;由多元醇和甘油酯、植物油、氢化植物油、脂肪酸及甾醇组成的组中的一种以上的组成员的亲水性酯交换生成物;聚氧乙烯甾醇、衍生物及其类似体;聚氧乙基化的维生素及其衍生物;聚氧乙烯-聚氧丙烯嵌段共聚物;以及其混合物;由聚乙二醇脱水山梨醇脂肪酸酯及多元醇和甘油三酯、植物油及氢化植物油组成的组中的一种以上的组成员的亲水性酯交换生成物。多元醇可以是甘油、乙二醇、聚乙二醇、山梨糖醇、丙二醇、季戊四醇或多糖类。
其他亲水性-非离子性表面活性剂作为非限制性例包含聚乙二醇-10月桂酸、聚乙二醇-12月桂酸、聚乙二醇-20月桂酸、聚乙二醇-32月桂酸、聚乙二醇-32二月桂酸、聚乙二醇-12油酸、聚乙二醇-15油酸、聚乙二醇-20油酸、聚乙二醇-20二油酸、聚乙二醇-32油酸、聚乙二醇-200油酸、聚乙二醇-400油酸、聚乙二醇-15硬脂酸、聚乙二醇-32二硬脂酸、聚乙二醇-40硬脂酸、聚乙二醇-100硬脂酸、聚乙二醇-20二月桂酸、聚乙二醇-25三油酸甘油酯、聚乙二醇-32二油酸、聚乙二醇-20月桂酸甘油酯、聚乙二醇-30月桂酸甘油酯、聚乙二醇-20硬脂酸甘油酯、聚乙二醇-20油酸甘油酯、聚乙二醇-30油酸甘油酯、聚乙二醇-30月桂酸甘油酯、聚乙二醇-40月桂酸甘油酯、聚乙二醇-40棕榈仁油、聚乙二醇-50硬化蓖麻油、聚乙二醇-40蓖麻油、聚乙二醇-35蓖麻油、聚乙二醇-60蓖麻油、聚乙二醇-40硬化蓖麻油、聚乙二醇-60硬化蓖麻油、聚乙二醇-60玉米油、聚乙二醇-6癸酸甘油酯/辛酸甘油酯、聚乙二醇-8癸酸甘油酯/辛酸甘油酯、聚甘油-10月桂酸、聚乙二醇-30胆固醇、聚乙二醇-25植物甾醇、聚乙二醇-30豆甾醇、聚乙二醇-20油酸酯、聚乙二醇-40去水山梨糖醇单油酸酯、聚乙二醇-80去水山梨糖醇月桂酸酯、聚山梨醇酯20、聚山梨醇酯80、聚氧化乙烯-9月桂基醚、聚氧化乙烯-23月桂基醚、聚氧化乙烯-10油醚、聚氧化乙烯-20油醚、聚氧化乙烯-20硬脂酰醚、生育酚聚乙二醇-100琥珀酸盐、聚乙二醇-24胆固醇,聚甘油-lO油酸、吐温40(Tween 40)、吐温60,蔗糖单硬脂酸酯、蔗糖单月桂酸酯、蔗糖单棕榈酸酯、聚乙二醇10-100壬基酚系列、聚乙二醇15-100辛基酚系列系列及泊洛沙姆。
适当的亲油性表面活性剂的例包含:脂肪酸乙醇;甘油脂肪酸酯;乙酰化甘油脂肪酸酯;低级醇脂肪酸酯;丙二醇脂肪酸酯;山梨糖醇酐脂肪酸酯;聚乙二醇脱水山梨醇脂肪酸酯;甾醇及甾醇衍生物;聚氧乙基化甾醇及甾醇衍生物;聚乙二醇烷基醚;糖类酯;糖类醚;单甘酯及甘油二酯的的乳酸衍生物;由多元醇和甘油酯、植物油、氢化植物油、脂肪酸及甾醇组成的组中的一种以上的组成员的疏水性酯交换生成物水;油溶性维生素/维生素衍生物;以及其混合物。在上述组中,优选的亲油性表面活性剂包含甘油脂肪酸酯、丙二醇脂肪酸酯及其混合物或由多元醇和植物油、氢化植物油及甘油三酯组成的组中的一种以上的组成员的疏水性酯交换生成物。
在一具体例中,组合物可包含使活性成分等的溶解性突出并使沉淀最小化的增溶剂。这可能对用于非口服用途的组合物,例如,对注射用组合物尤其重要。可通过添加增溶剂来增加亲水性药物和/或其他成分,例如,表面活性剂的溶解度,或者可保持作为稳定的或均匀的溶液或分散夜的组合物。适当的增溶剂作为非限制性例包含:乙醇及多元醇,例如,乙醇、异丙醇、丁醇、苄醇、乙二醇、丙二醇、丁二醇及其异构体、甘油、季戊四醇、山梨糖醇、甘露醇、卡必醇、二甲基异山梨醇、聚乙二醇、聚丙二醇、聚乙烯醇、羟丙基甲基纤维素及其他纤维素衍生物、环式糊精及环式糊精衍生物;平均分子量约为200至6000的聚乙二醇的醚,例如,四氢糠醇聚乙二醇醚(四甘醇)或甲氧基聚乙二醇;含胺及其他氮化合物,例如,2-吡咯烷酮、2-哌啶酮、ε-己内酰胺、N-烷基吡咯烷酮、N-羟基烷基吡咯烷酮、N-烷基哌啶酮、N-烷基己内酰胺、二甲基乙酰胺及聚乙烯吡咯烷酮;酯,例如,丙酸乙酯、柠檬酸三丁酯、乙酰柠檬酸三丁酯、乙酰柠檬酸三丁酯、柠檬酸三乙酯、油酸乙酯、辛酸乙酯、丁酸乙酯、乙酸甘油酯、丙二醇单甲基乙酸酯、丙二醇二乙酸酯、ε-己内酯及其异构体、δ-戊内酯及其异构体、β-丁内酯及其异构体;以及本领域公知的其他增溶剂,例如,二甲基乙酰胺、二甲基异山梨醇、N-甲基吡咯烷酮、单辛精、二乙二醇单乙醚醚及水。
可使用增溶剂的混合物。作为非限制性例包含乙酸甘油酯、柠檬酸三乙酯、油酸乙酯、辛酸乙酯、二甲基乙酰胺、N-甲基吡咯烷酮、N-羟基乙基吡咯烷酮、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟基丙基环式糊精、乙醇、聚乙二醇200-100、四甘醇、卡必醇、丙二醇及二甲基异山梨醇。尤其,优选地增溶剂包含山梨糖醇、甘油、乙酸甘油酯、乙醇、聚乙二醇-400、四甘醇及丙二醇。
对于可被包含的增溶剂的量没有特别的限制。一定量的增溶剂可限定为本领域技术人员易于进行测定的生物学上可接受的量。在一些环境下,包含小于生物学上可接受的量的增溶剂的量,例如,可有利于使药物的浓度最大化,过量的增溶剂是利用通常的技法,例如,蒸馏或蒸发来在提供给患者之前去除。因此,在存在的情况下,增溶剂以加上药物及其他赋形剂重量为基准可以是10重量百分比、25重量百分比、50重量百分比、100重量百分比最大约为200重量百分比的重量百分比。如果有必要,还可使用极少量的增溶剂,例如,5%、2%、1%以下。通常,增溶剂可以以约为1%至100%的量存在,更进一步地,约为5重量百分比至25重量百分比。
组合物还可包含一种以上的药学上可接受的添加剂及赋形剂。上述添加剂及赋形剂作为非限制性例包括降粘剂、消泡剂、缓冲剂、聚合物、抗氧化剂、保存剂、螯合剂、粘度调节剂、张紧剂、风味剂、着色剂、添味剂、遮光剂、悬浮剂、粘结剂、填充剂、增塑剂、润滑剂及其混合物。
并且,为了使处理方便、为了提高稳定性或因其他理由可向组合物引进酸或碱基。药剂学上可接受的盐的例包含氨基酸、氨基酸酯、氢氧化铵、氢氧化钾、氢氧化钠、碳酸氢钠、氢氧化铝、碳酸钙、氢氧化镁、硅酸铝镁、合成硅酸铝、合成水铝钙石、氢氧化镁铝、二异丙基乙胺、乙醇胺、乙二胺、三乙醇胺、三乙胺、三异丙醇胺、三甲胺、三(羟甲基)氨基甲烷(TRIS)等。并且,适当的是药学上可接受的酸包含作为盐碱基,例如,醋酸、丙烯酸、己二酸、果胶酸、烷基磺酸、氨基酸、抗坏血酸、苯甲酸、硼酸、丁酸、羧酸、柠檬酸、脂肪酸、蚁酸、富马酸、葡萄糖酸、氢醌磺酸、异抗坏血酸、乳酸、马来酸、草酸、对溴苯基磺酸、丙酸、对甲苯磺酸、水杨酸、硬脂酸、琥珀酸、丹宁酸、酒石酸、巯基乙酸、甲苯磺酸、尿酸等。还可使用聚丙酸的盐,例如,磷酸钠、磷酸氢二钠及磷酸二氢钠。碱基为盐的情况下,阳离子为任意通常的药学上可接受的阳离子,例如,可以是氨、碱金属、碱土金属等。作为非限制性例可包含钠、钾、锂、镁、钙及氨。
适当的酸为药学上可接受的有机酸或无机酸。适当的无机酸的例包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸等。适当的有机酸的例包括醋酸、丙烯酸、己二酸、果胶酸、烷基磺酸、氨基酸、抗坏血酸、苯甲酸、硼酸、丁酸、羧酸、柠檬酸、脂肪酸、蚁酸、富马酸、葡萄糖酸、氢醌磺酸、异抗坏血酸、乳酸、马来酸、甲磺酸、草酸、对溴苯基磺酸、丙酸、对甲苯磺酸、水杨酸、硬脂酸、琥珀酸、丹宁酸、酒石酸、巯基乙酸、甲苯磺酸、尿酸等。
在注射用药学组合物的一些具体例中,本发明提供包含减少或去除作为活性成分的组分1及组分2,尤其是组分1的副作用的制剂的注射用药学组合物。在一些具体例中,本发明提供包含减少或去除组分1的副作用的制剂及注射包含中适当的药学赋形剂的组合物的注射用药学组合物。组合物内制剂的成分及量如与本发明所述的一样。
为了将本发明的新型组合物以注射的方式给药,可引入的形态包括水性或油性悬浮液、乳液、芝麻油、玉米油、棉子油、花生油及酏剂、甘露醇、葡萄糖,灭菌水溶液及类似药学介质。
食盐水中水溶液还为了注射通常被使用。还可使用乙醇、甘油、丙二醇、液体聚乙二醇等(及其适当的混合物)、环式糊精衍生物及植物油。适当的流动性例如,可借助涂覆来进行保持,例如,借助卵磷脂的使用、分散液的情况下借助所需的粒度的保持、借助表面活性剂来保持。微生物作用的防止可借助各种抗菌剂及抗真菌剂来防范,例如,防腐剂、氯丁醇、苯酚、山梨酸、硫柳汞等。
照要求量将活性成分引入具有如上所需求的列举的各种其他成分的适当的溶剂中按后,利用过滤的灭菌制备灭菌的可注射液。通常地,分散液通过向包含碱基性分散液介质及如上所需求的列举的其他成分的灭菌介质引入各种灭菌的活性成分来制备。在用于制备灭菌可注射液的灭菌粉末的情况下,优选地制备方法为从活性成分的粉末和其预先灭菌过滤的溶液形成任意额外所目的的成分的真空干燥机冷冻干燥法。
本发明的组合物在对身体局部或局部给药适当的固体、半固体或液体形态,例如,凝胶、水溶性凝胶、霜、乳液、悬浮液、发泡体、粉末、浆料、软膏、溶液、油、焊膏、栓剂、喷雾剂、乳液、食盐水溶液、二甲基亚砜(DMSO)类溶液中,可利用制备物来进行剂型。通常地,密度高的载体可提供长时间暴露于活性成分的部分。对照性地,溶液制备物还可在选择的部分提供活性成分的即时暴露。
药学组合物还可包含适当的固体或凝胶状载体或赋形剂,这是使穿过皮肤的角质层的渗透屏障的治疗性分子的渗透率增加或可促进上述分子的传递的化合物。在局部剂型领域中存在养成的公知的多个渗透提高性分子。作为上述载体及赋形剂的非限制性例包括湿润剂(例如,尿素)、乙二醇(例如,丙二醇)、乙醇(例如,乙醇)、脂肪酸(例如,油酸)、表面活性剂(例如,豆蔻酸异丙酯及月桂基硫酸钠)、吡咯烷酮、单月桂酸甘油酯、亚砜、萜烯(例如,薄荷醇)、胺、胺、烷烃、烷醇、水、碳酸钙、磷酸钙、各种糖类、淀粉,纤维素衍生物、明胶及聚合物,例如,聚乙二醇。
在本发明的方法中使用的另一种剂型使用经皮传递方法(例如,补丁或微型泵)。上述经皮方法可适用于连续或非连续注入控制的量的活性成分。因此,在一些具体例中,本发明提供引入激动剂和/或拮抗剂的经皮方法。
用于传递药学制剂的经皮方法的制造及用途是本领域中公知的。例如,参照美国专利号第5023252号同第4992445号及同第5001139好。上述方法可通过药学制剂的连续传递、搏动性传递或要求时即使传递来制备而成。
吸收用药学组合物、用于吸收或灌入的组合物在药学上可接受的水性或有机溶剂或其混合物及药学上可接受的粉末中,包含溶液及悬浮液。液体或固体组合物可包含所述的适当的药学上可接受的赋形剂。优选地,组合物为了局部或全身效果借助口服或鼻内呼吸途径来进行给药。优选地,药学上可接受的溶剂中组合物可通过使用惰性气体来被烟雾。烟雾溶液可直接从烟雾装置被吸收或附着于面罩篷或间歇正压呼吸器。溶液、悬浮液或粉末组合物以适当的方法可通过切割剂型的方法,优选地口服或鼻内进行给药。
其他药学组合物且本发明所述的组合物可由对舌下、口腔、直肠内、骨髓内、眼睛内、鼻内、硬膜外或脊髓内进行给药适当的药学上可接受的一种以上的赋形剂制备而成。上述药学组合物的制备时本领域中公知的。例如,参照文献[Anderson,Philip O.;Knoben,James E.;Troutman,William G,eds.,Handbook of Clinical Drug Data,TenthEdition,McGraw-Hill,2002;Pratt andTaylor,eds.,Principles of Drug Action,ThirdEdition,Churchill Livingston,New York,1990;Katzung,ed.,Basic and ClinicalPharmacology,Ninth Edition,McGraw Hill,20037ybg;Goodman and Gilman,eds.,ThePharmacological Basis of Therapeutics,Tenth Edition,McGraw Hill,2001;Remingtons PharmaceuticalSciences,20th Ed.,Lippincott Williams&Wilkins.,2000;Martindale,The Extra Pharmacopoeia,Thirty-Second Edition(The PharmaceuticalPress,London,1999)];其所有文献的内容作为参考并入本发明。
8.联合治疗给药形态可通过任意途径及方法来进行给药,包括但并不限定于口服、静脉内、鼻内(intranasal)、吸收(例如,给药量-剂量肺内)、舌下、经皮、皮下、大脑内途径。
9.由联合治疗可治疗的神经精神类障碍中包括精神刺激剂使用障碍、左旋多巴引起的运动障碍及创伤后应激障碍。加上精神刺激剂使用障碍、左旋多巴引起的运动障碍及创伤后应激障碍,适应症(indications)包括(1)包括但并不限制于烟草使用障碍、酒精使用障碍及大麻使用障碍的其他物质相关障碍;(2)包括但并不限制于习惯性赌博及网络成瘾的行动成瘾障碍;(3)包括但并不限制于反应性依恋障碍,急性应激障碍及适应障碍的其他创伤及应激相关障碍;(4)包括但并不限制于广泛性焦虑症、恐慌症、广场恐怖症、物质/药物诱发的焦虑症的焦虑症;(5)包括但并不限制于强迫症、躯体变形障碍、囤积障碍、拔毛癖及抓痕障碍的强迫症;以及(6)包括但并不限制于神经性厌食症、贪食症及暴食症的进食障碍,但并不限定于此。
10.组合给药形态可通过同时使用其他治疗法及给药形态,与单独使用组成的组合给药形态相比,实现具有附加的或上升作用的效果。与联合治疗一同使用的治疗法或给药形态的例包括认知行为治疗(cognitive behavioral therapy)、消退疗法(extinctiontherapy)及暴露疗法(exposure therapy)等行为疗法(behavioral therapy)及使用抗癫痫剂(anti-epileptics)、抗精神病药(antipsychotics)、抗抑郁药(antidepressants)及克他命(ketamine)的药物疗法,但并不限定于此。
11.这种障碍的很多症状及征兆作为伴随疾病障碍、二次症状/征兆和/或这种障碍的治疗的副作用,在具有其他原发性神经精神病诊断的患者中往往被观测的程度为止,联合治疗可用作上升作用的、附加的、改良的和/或预防性的辅助治疗。
12.在一优选组合给药形态中,组分1为盐酸哌甲酯的任意无修改或任意其他立即-释放剂型,组分2为奥坦西隆的任意延迟的、脉动性-释放剂型。可使用盐酸哌甲酯和奥坦西隆给药量的任意组合/排列。对给药形态中的盐酸哌甲酯的优选给药量为未变形的盐酸哌甲酯盐酸盐的0.1mg至80mg的等同替代物,对奥坦西隆剂型的优选给药量分为为未变形的奥坦西隆盐酸盐的0.1mg至32mg的等同替代物。对给药形态中的盐酸哌甲酯的进一步优选的给药量为未变形的盐酸哌甲酯盐酸盐的1mg至80mg的等同替代物,对奥坦西隆剂型的进一步优选的给药量范围为未变形的奥坦西隆盐酸盐的1mg至16mg的等同替代物。对给药形态中的盐酸哌甲酯的更优选的给药量范围为未变形的盐酸哌甲酯盐酸盐的5mg至60mg的等同替代物,对奥坦西隆剂型的更优选的给药量范围为未变形的奥坦西隆盐酸盐的4mg至16mg的等同替代物。优选地等同代替物的给药量分为以内中的盐酸哌甲酯及奥坦西隆的任意固定-给药量排列可在单一的给药形态内实现。
13.在存在选择的组分1的立体异构体的情况下,任意立体异构体单独或各个的最优化的比率的组合可使用在联合治疗具体例中。在用于治疗左旋多巴引起的运动障碍的给药形态中,与其他相比,作为组分2的抗抑郁药米氮平(mirtazapine)(例如,)的S(+)立体异构体的艾司米氮平(esmirtazapine)为立体异构体的优选的用途的一个例
13.1.米氮平为4环的、哌嗪-氮杂化合物(tetracyclic,piperazino-azepinecompound)(1,2,3,4,10,14b-六氢-2-甲基吡嗪[2,1-a]吡啶[2,3-c]苯并氮杂(1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine);C17H19N3;分子量:265.36),所谓的去甲肾上腺素活性化/特异性血清素操作性的抗抑郁药。经常,可获取的米氮平制剂(例如,)被视为S(+)及R(-)对映体的50:50外消旋混合物。
13.2.此药物对于与肾上腺素作用性α2及组织胺H1受体相同,对血清素2A及血清素2C受体具有高的亲和性。而且,虽然此药物对于血清素1A受体具有最低的亲和性,但是此药物还可通过α2肾上腺素作用性自己-及异种受体的阻断及后续的血清素释放中的间接性的增加,来强化血清素1A-依赖性神经传递。由于此药物是血清素2及受体拮抗剂,因此首先提高血清素1A-介质血清素作用性传递(功能性血清素1A激动剂)。
13.3.与R(-)对映体相比,艾司米氮平优点如下:(1)对血清素2A及血清素2C(及α2肾上腺素作用性)受体示出更高的亲和性;(2)通过肠壁中的“对映体选择性(enantioselective)”输送过程吸收的更快(但不能太过度);(3)进一步蓄积在大脑内。这种发现暗示相对更低的口服给药量的组分2对左旋多巴引起的运动障碍的联合治疗中更有效。而且,与R(-)对映体相比,艾司米氮平具有更短的消除半衰期(terminal eliminationhalf-life(t1/2),约为50%)。因此,与外消旋米氮平(例如,)或R(-)对映体相比,艾司米氮平与白天发困等有害的副作用发生更低有关。
13.4.艾司米氮平主要由示出临床上显著的遗传多态现象的CYP2D6代谢而成。因此,与过度的代谢者相比,其扫除在更低的代谢者中低于2倍。因此,任意给药量的艾司米氮平实现在单一的联合治疗给药形态内,另一方面,在开始联合治疗之前,可允许选择在各个患者中的CYP2D6表现型的决定对各个患者的药物遗传学上优选的艾司米氮平给药量(“个体化的药物”)。
用于实施发明的方式
实施例1:[盐酸哌甲酯(MPh-IR)+(Ond-PR2)]:临床2A期稳定性/疗效概念验证
奥坦西隆作为活性药学成分(API),是从奥坦西隆制备的水珠剂型。盐酸哌甲酯为盐酸哌甲酯的立即-释放一般剂型。[盐酸哌甲酯+奥坦西隆]是作为组分1及2分别由盐酸哌甲酯及奥坦西隆组成的单一的胶囊化的给药形态。试管内溶解试验及普通的健康的自愿者中的药动学(PK)及稳定性评价(临床1期),接着本发明人进行了概念验证的、随机的、双盲的、微弱控制临床1A期稳定性/疗效临床试验。通过居住程序常住的同时,搜索满足对第一次精神刺激剂滥用的DSM-4基准的患者共48人,将随机分类合适的30人的对象体的[盐酸哌甲酯+奥坦西隆]或微弱处理组的两组。
以每天一次给药包含[盐酸哌甲酯+奥坦西隆]或葡萄糖(微弱)中一种的单一胶囊为14天。对象体在第一次试验给药1天至7天之前(处理-之前)及重新最后给药后3天至7天之间再进行单一的基于功能性磁共振成像(fMRI)的评价(即,在进行完全的药效清洗之后进行处理-之后评价)。在定居的静息-态(resting-state)、信号-反应性(cue-reactivity)及任务执行/非执行模式(Go/noGo task paradigm)下,为了组群比较(group comparison)结果,测定行为评定量表(behavioral rating scale)及血氧水平依赖法(BOLD:blood-oxygenation-level-dependent)功能影像化结果。
28人的对象体完成了2周的药物处理及药物处理-之前及处理-之后功能性磁共振成像评价。
[盐酸哌甲酯+奥坦西隆]药动学分析
在1天及14天中,(1)通过定量化血清盐酸哌甲酯及奥坦西隆浓度来测定2个组分(即,盐酸哌甲酯及奥坦西隆)的药动学参数;(2)每天1次给药14天后,为了确定这些参数是否有变化,收集了[盐酸哌甲酯+Ond-PR2]胶囊的单一口服给药后的24小时血液药动学样品。以平均、标准偏差及变异系数概括了对于在每个时点中的血液盐酸哌甲酯及奥坦西隆浓度的技术统计。药动学参数预测及统计学分析利用SAS 9.3及BABE Solution来进行。
表1为示出处理第1天及最后1天(分别为第1天及第14天)中的[盐酸哌甲酯+奥坦西隆]组合胶囊的单一的口服给药后盐酸哌甲酯及奥坦西隆的药动学参数。在第1天及第14天之间未观察到对盐酸哌甲酯或奥坦西隆中的任一种的Cmax、Cmin、Tmax、t1/2、AUC(0-24)、AUC(0-无限)及Kel参数显著变化。
[表1]
精神刺激剂使用障碍患者中的[盐酸哌甲酯+奥坦西隆]的疗效
所有治疗-之前及治疗-之后的行为等级及功能性磁共振成像数据,首先以事后-事前差异分数进行变化。对其结果的微弱及[盐酸哌甲酯+奥坦西隆]组的[事后-事前]分数,通过使用作为共变量的各个对象体的戒断持续时间(3.0个月至12个月)的共变数的一元协方差分析(one-way analyses of covariance)(ANCOVA))来进行比较(p≤0.05)。提供的数据为选择且提供的多个实施例。
对精神刺激剂-有关视觉信号的暴露之后的自报渴望分数。在对于[盐酸哌甲酯+奥坦西隆]的临床2A步骤中,对象患者们在神经成像扫描仪(neuroimaging scanner)内进行信号-反应性期间提供渴望等级分数。本发明人对各治疗组进行渴望等级中的变化(治疗之前-治疗之后)评价。一元协方差分析(共变量为禁欲期间)表示14天的[盐酸哌甲酯+奥坦西隆]治疗使神经成像扫描仪中自报渴望等级显著下降(表2)。
[表2]
在上述表2中,prob.>|t|在实际差异为0的情况下,指可获取平均偏差的预测的值(例如,对可可因信号反应性为-1.63)的可能性。对于可可因渴望分数,联合治疗及微弱治疗组具有相同的平均分数(即,没有偏差)具有约为3.3%的可能性。95%置信区(95%CI(Confidence Inverval))指以95%置信联合治疗及微弱治疗的患者组间的平均(truepopulation mean)在低数和高数之间(例如,对于可可因渴望分数为-3.12至-0.14)。不包括0的置信区,在治疗间以95%的置信具有显著的偏差。与此相反,平均偏差数(例如,对于可可因渴望分数为-1.63)为在本发明人的1次实验(即,n=24)中治疗和微弱治疗患者间的简单的平均偏差。
Shiffman-Jarvik分量表评分(Shiffman-Jarvik Subscale Scores)。精神刺激剂使用障碍患者的大部分还作为伴随疾病诊断,与是否被诊断烟草使用障碍无关的使用烟草产品。Shiffman-Jarvik戒断等级(SJWS:Shiffman-Jarvik Withdrawal Scale)为使用于评价尼古丁戒断症状的心理学试验的一种(参照文献Shiffman and Jarvik,1976)。在治疗之前及治疗之后神经成像测定评价期间,对精神刺激剂使用障碍患者进行Shiffman-Jarvik戒断等级的短文版(short version)(McClernon et al.,2005)。一元协方差分析(共变量为禁欲期间)表示14天的[盐酸哌甲酯+奥坦西隆]治疗对被诊断为精神刺激剂使用障碍的患者中SJS渴望及消极感情分量的分数显著降低(表2)。
实施例2.基于培高利特/酮色林治疗的左旋多巴引起异常的非自主运动(LIAIM:levodopa-induced abnormal involuntary movement)的逆转
在本发明中提示的激动剂/拮抗剂联合治疗使左旋多巴引起的运动障碍有效逆转,并为了证明左旋多巴疗效可恢复,对多巴胺激动剂培高利特及血清素2A/2C拮抗剂酮色林组合进行左旋多巴引起的运动障碍的动物模型实验。在此实验中确认,基于联合治疗的左旋多巴引起的运动障碍的动物模型大鼠中,左旋多巴引起异常的非自主运动(LIAIM)显著降低(图3)。
在本实验中所使用的动物模型的制备如下。首先,在大鼠的右侧前脑束(rightmedial forebrain bundle)内注射1次多巴胺神经毒素6-羟基多巴胺(6-OHDA:6-hydroxydopamine),来诱发黑质纹状体多巴胺途径(nigrostriatal DA pathway)的单侧病变。之后,6-羟基多巴胺处理3周后,对该大鼠以每天2次给药左旋多巴甲基酯(6.5mg/kg腹腔内苄丝肼之前为25mg/kg)14天,来诱发左旋多巴引起异常的非自主运动。此时,进行实验动物的左旋多巴引起异常的非自主运动水平评价的情况下,使用标准左旋多巴引起异常的非自主运动等级尺度,以每周2次给药左旋多巴来以每3小时层左旋多巴引起异常的非自主运动分数并进行评价。构建左旋多巴引起异常的非自主运动后,左旋多巴引起异常的非自主运动值大于25,而示出重症度的左旋多巴引起异常的非自主运动分数时,筛选观察到被结合的四肢(limb)和体轴的动物后,以此动物为对象在2周内以(1)给药培高利特(0.1mg/㎏)3.5小时后给药血清素2A/2C拮抗剂酮色林(1mg/㎏)[L_PK组];(2)培高利特+盐水3.5小时后[L_PS组];以及(3)二甲基亚砜(盐水中1%)+盐水3.5小时后给药[L_SS组]的3中给药疗法中的一种来进行给药。此时,所有药物给药由皮下注射进行。
最终,L_PK、L_PS或L-SS给药2天后,对所有动物给药25mg/kg左旋多巴后,从新测定左旋多巴引起异常的非自主运动分数。对由反向治疗之后及反向治疗之前分数间的比率表示的总左旋多巴引起异常的非自主运动分数具有显著的反向治疗效果(F(2,23)=8.841,p<0.001,一元协方差分析;图2,左侧面板);事后Newman Keul试验(post-hocNewman-Keul's test)表示,与L_SS或L_P/S治疗相比,组合的培高利特/酮色林治疗(L_P/K)显著降低左旋多巴引起异常的非自主运动(p<0.05)。在后者的两组之间没有观测到差一点。右侧面板表示前时间经过,这表示L-P/K与减少的最大左旋多巴引起异常的非自主运动分数相同,更快地结束左旋多巴引起异常的非自主运动。
产业上的可利用性
本发明可利用在如用于治疗神经精神类障碍的组合物的制备等的制药产业及其有关的产业中。
Claims (4)
1.一种用于治疗神经精神类障碍的组合物,其特征在于,所述组合物包含:
a)组分1,包含哌甲酯或其药学上可接受的盐的成分;以及
b)组分2,包含奥坦西隆或其药学上可接受的盐的成分,
组分1,在胃或肠试管内溶解试验条件下,在2小时以内溶解90%以上,或在1小时以内溶解80%以上,
组分2,在胃或肠试管内溶解试验条件下,在3小时以上溶解10%以下,且在7小时以下溶解80%以上,
组分1的药理学活性形态具有Tmax1,组分2的药理学活性形态具有Tmax2,Tmax2大于Tmax1,在人体中Tmax2和Tmax1差异范围为2至7小时,
所述组合物为单一固定组合剂型,包含所述组分1、所述组分2和药学上可接受的赋形剂、载体或其他药学上可接受的添加剂,
所述神经精神类障碍选自由精神刺激剂使用障碍、烟草使用障碍、酒精使用障碍及大麻使用障碍中的一种或多种。
2.根据权利要求1所述的组合物,其特征在于,所述组分1的药理学活性形态具有5小时以下的消除半衰期。
3.根据权利要求1所述的组合物,其特征在于,上述组分2的药理学活性形态具有3至13小时的消除半衰期。
4.根据权利要求1所述的组合物,其特征在于,固定组合剂型包含对应于5mg至80mg盐酸哌甲酯的剂量的哌甲酯剂及对应于4mg至16mg奥坦西隆盐酸盐的剂量的奥坦西隆剂。
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2016
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- 2016-01-28 KR KR1020167021256A patent/KR20160103548A/ko not_active Application Discontinuation
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WO2016122218A3 (ko) | 2016-10-13 |
EP3251699A2 (en) | 2017-12-06 |
KR20210095734A (ko) | 2021-08-02 |
JP2021193118A (ja) | 2021-12-23 |
JP7288016B2 (ja) | 2023-06-06 |
KR20220071297A (ko) | 2022-05-31 |
EP3251699A4 (en) | 2018-08-01 |
KR20180015302A (ko) | 2018-02-12 |
US20230293443A1 (en) | 2023-09-21 |
JP2023109947A (ja) | 2023-08-08 |
US20200197383A1 (en) | 2020-06-25 |
DK3251699T3 (da) | 2024-05-21 |
KR101994596B1 (ko) | 2019-06-28 |
KR20160103548A (ko) | 2016-09-01 |
WO2016122218A2 (ko) | 2016-08-04 |
EP3251699B1 (en) | 2024-04-17 |
JP6943994B2 (ja) | 2021-10-06 |
KR20200032759A (ko) | 2020-03-26 |
JP2018503677A (ja) | 2018-02-08 |
JP2020075938A (ja) | 2020-05-21 |
KR20190077590A (ko) | 2019-07-03 |
US20170326127A1 (en) | 2017-11-16 |
CN107206093A (zh) | 2017-09-26 |
JP6655090B2 (ja) | 2020-02-26 |
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