CN117320711A - 新型n,n-二甲基色胺组合物和方法 - Google Patents
新型n,n-二甲基色胺组合物和方法 Download PDFInfo
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
一种组合物,其包含N,N‑二甲基色胺(DMT)或其药学上可接受的盐,当施用于人类时,所述N,N‑二甲基色胺(DMT)或其药学上可接受的盐能够在介于约20分钟与约60分钟之间的时间表现出治疗有效血液水平的DMT。一种治疗神经疾病或病状的方法,所述方法包括向有需要的受试者经颊施用、舌下施用、皮下施用或鼻内施用有效量的DMT或其药学上可接受的盐,当施用于人类时,所述DMT或其药学上可接受的盐能够表现出治疗有效水平的DMT,持续介于约至约60分钟之间的时间。
Description
相关申请交叉引用
本申请要求于2021年4月26日提交的美国临时专利申请第63/179,679号的优先权和权益,所述美国临时专利申请的全部内容出于所有目的通过引用整体并入本文。
技术领域
本公开涉及新型N,N-二甲基色胺(“DMT”)组合物以及治疗神经疾病和病状的方法。具体地,本公开提供了用于治疗神经疾病和病状的包括N,N-二甲基色胺或其药学上可接受的盐的改进的药物组合物。
背景技术
麦角酸二乙酰胺(“LSD”)、赛洛西宾(psilocybin)和N,N-二甲基色胺是通常被称为“经典致幻剂”或“迷幻剂”的血清素类药剂,并且具有诱导定性改变的意识状态的能力,如欣快、恍惚、超越时空、精神体验或自我边界的消解,而其它作用如镇静、麻醉或过度刺激仅是最小的。在化学上,血清素类迷幻剂是苯基烷基胺或吲哚胺,其中吲哚胺的类别被分为两个子集,麦角灵和色胺。
天然存在的迷幻剂(如包含在南美灌木小灌木丛(Psychotriaviridis)中的N,N-二甲基色胺、包含在超过200个蘑菇物种中的赛洛西宾或包含在美国西南部和墨西哥北部的皮约特仙人掌(Peyote cactus)中的墨斯卡灵(mescaline))几个世纪以来一直被土著文化用于仪式或社会文化背景中以及宗教圣礼的背景中。虽然非特异性的“治愈”潜力归因于在那些环境中使用天然存在的迷幻剂,但是直到1943年发现合成麦角灵麦角酸二乙酰胺(“LSD”)之后,才开始对其在特定疾病中的潜在治疗应用进行更多的科学研究。
随着人们对血清素系统和其在脑功能中的作用的不断了解,研究人员开始对迷幻药物的分子活性进行具体说明。然而,所述活性如何转化为在精神障碍中观察到的治疗效果尚不清楚。提出了两个主要概念:第一个概念被创造为“致幻疗法”,并且所述概念强调以低剂量给予的迷幻剂促进放松心理防御机制松动的能力,所述致幻疗法与心理疗法的组合允许深刻的内省洞察和创伤的恢复及其随后的宣泄。因此,在致幻方法中考虑的基本机制是伴随的心理治疗过程的激活和深化,并且所述基本机制需要多个药物和疗法会话。第二个概念被创造为“迷幻疗法”,并且所述概念强调以相对高的单剂量给予的迷幻剂诱导所谓的“峰值迷幻体验”的能力。峰值体验的主要特征在于丧失对时间和空间的判断以及自我边界的消解,这通常以幸福状态的体验和在宇宙统一中作为整体和和谐存在的感觉为最终结果。因此,在直观感知心理一体化与和谐以及随后的自我改善和增强的生活乐趣和内心平静感的情况下,在迷幻方法中考虑的基本机制是产生独特的压倒性体验。
尽管关于使用迷幻剂治疗精神障碍的科学研究在20世纪60年代蓬勃发展,但这些物质的娱乐用途也在迅速增长,并且不久迷幻剂就被媒体描述为高度危险的滥用药物。意识到对社会秩序的威胁导致1970年的《美国受控物质法案》通过,根据所述法案,LSD和其它迷幻剂被列入最严格的类别附表1,所述附表含有被认为没有医疗用途且很可能被滥用的药物。在接下来的30年里,关于迷幻药物的可能治疗用途进展甚微。
最近,人们重新燃起对迷幻疗法领域的兴趣,并且经典迷幻剂在治疗精神障碍方面显示出临床前和临床前景(Carhart-Harris和Goodwin,迷幻药物的治疗潜力:过去、现在和未来(The Therapeutic Potential of Psychedelic Drugs:Past,Present andFuture),《神经精神药理学(Neuropsychopharmacology)》;42,2105-2113(2017))。具体地,在随机双盲研究中,赛洛西宾在一系列抑郁和焦虑等级量表中表现出显著改进(Griffiths等人,赛洛西宾在患有危及生命的癌症的患者中在抑郁和焦虑方面产生显著且持续的减少:随机双盲试验(Psilocybin produces substantial and sustained decreases indepression and anxiety in patients with life-threatening cancer:arandomizeddouble-blind trial)《精神药理学杂志(Journal of Psychopharmacology)》30(12),1181-1197(2016))。
N,N-二甲基色胺(在下文中称为“DMT”)也被理解为作为迷幻剂具有治疗价值,其中正在进行功效试验以评估静脉内施用于患有重度抑郁症(“MDD”)的受试者的DMT或DMT富马酸盐的效果。然而,尽管DMT的固有性质使其成为有吸引力的可能药物,特别是对于神经疾病和病状,但是目前的治疗组合物和施用方式使治疗复杂化并且可能无法提供最佳的治疗效果。例如,当抽吸或静脉内递送时,DMT具有非常快速的起效和短的作用持续时间,这对于确定具有适当剂量和施用DMT频率的合适施用方案以提供针对神经疾病和病状的有效疗法提出了挑战。这对于神经疾病和病状尤其如此,所述神经疾病和病状将在施用后比通过注射或吸入的单剂量DMT可以实现的更长的时间段内受益于DMT的治疗性血液水平的存在。
因此,非常需要易于施用的DMT药物来治疗神经疾病和病状。在使药物副作用能够得到有效控制的同时使功效最大化的此类药物尤其受到关注,尤其是如果可通过方便的途径施用,包含自我施用。本公开通过提供包括DMT或其药学上可接受的盐的新型组合物解决了此需求,当鼻内、经颊、舌下或通过皮下注射施用时,与通过IV注射或吸入施用的DMT相比,所述组合物具有快速起效,而且还延长DMT的有效作用持续时间。
发明内容
在一个方面,本公开提供了一种药物组合物,其包括DMT或其药学上可接受的盐,其中在施用于受试者后,DMT人类血浆Tmax介于约1分钟至约60分钟之间、或介于约1.5分钟至约45分钟之间、或介于约1.7分钟至约35分钟之间、或介于约2分钟至约30分钟之间、或介于约2分钟至约20分钟之间(例如,介于约5分钟至约15分钟之间,特别为约5分钟、6分钟、7分钟、8分钟、9分钟或10分钟)。优选地,在达到Tmax之后,将DMT的浓度维持在Cmax的约50%或更多,优选地80%或更多,持续介于约10分钟至约30分钟之间(例如,约10分钟、约15分钟、约20分钟、约25分钟、约30分钟)。
在一个实施例中,包括DMT或其药学上可接受的盐的所述药物组合物经颊施用、舌下施用、皮下施用或鼻内施用。
在一个方面,本公开提供了一种药物组合物,其包括DMT或其药学上可接受的盐,其中在经颊、舌下、皮下或鼻内施用于受试者后,将DMT的血液水平维持在治疗有效的血液水平,优选地维持在处于或高于约250nmol/L的浓度下(或在188.27g/mol下,47.07ng/mL游离碱当量)持续至少约10分钟(例如,约10分钟、约15分钟、约20分钟、约25分钟、约30分钟、约35分钟、约40分钟、约45分钟或约50分钟),并且然后优选地在约20分钟或更短时间(例如,约10分钟、约15分钟或约20分钟)内降低至Cmax的约10%或更少。
在一个方面,本公开提供了一种药物组合物,其包括DMT或其药学上可接受的盐,其中在经颊、舌下、皮下或鼻内施用于受试者后,人类血浆T1/2为约5分钟至约20分钟,例如,约10分钟至约20分钟。
在一个方面,本公开提供了一种药物组合物,其包括DMT或其药学上可接受的盐,其中在以约5mg至约80mg(例如,约50mg)的剂量经颊、舌下、皮下或鼻内施用于受试者后,约100%的药物在约15分钟至约50分钟内,例如约20分钟至约30分钟内从所述组合物中释放。
在前述方面中的任何方面的一个实施例中,所述药物是经粘膜递送的。
在前述方面中的任何方面的一个实施例中,所述药物组合物是鼻内施用的。在特定实施例中,所述药物通过鼻粘膜被吸收。
在前述方面中的任何方面的一个实施例中,所述药物组合物是经颊施用的。在特定实施例中,所述药物通过颊粘膜被吸收。
在前述方面中的任何方面的一个实施例中,所述药物组合物是舌下施用的。在特定实施例中,所述药物通过舌下粘膜被吸收。
在前述方面中的任何方面的一个实施例中,所述药物组合物是皮下施用的。在特定实施例中,所述药物组合物是通过皮下注射施用的。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者经粘膜施用有效量的DMT或其药学上可接受的盐。在此方面的一个实施例中,所述药物通过颊粘膜被吸收。在此方面的一个实施例中,所述药物通过舌下粘膜被吸收。在此方面的一个实施例中,所述药物通过鼻粘膜被吸收。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者皮下施用有效量的DMT或其药学上可接受的盐。在此方面的一个实施例中,所述药物是通过皮下注射施用的。
附图说明
当结合附图时,通过参考以下具体实施方式和权利要求,本公开的各种目的和优点以及更完整的理解是显而易见的且更容易理解的,其中:
图1是在施用包含50毫克(“mg”)DMT富马酸盐的本公开的药物组合物后,人类血清中的DMT浓度随时间推移的变化的表。
图2是在施用包括DMT富马酸盐的本公开的三种不同调配物后,血清中的DMT随时间推移的释放%的表。调配物1、2和/或3可以例如选自颊薄膜以及用于皮下施用的肠胃外注射剂。
图3a示出了在Franz扩散池中测量的DMT渗透穿过猪颊粘膜的三个复制品测量结果的平均值和标准偏差。
图3b示出了在Franz扩散池中测量的三个复制品中的每个复制品的通过猪颊粘膜的DMT渗透性数据。
图4示出了在单次皮下给药5mg/kg或10mg/kg DMT琥珀酸盐后,大鼠体内的DMT的血浆浓度。
图5示出了Franz扩散池的组件。
具体实施方式
药物可以通过粘膜表面吸收,如鼻通道和口腔中的粘膜表面。通过粘膜表面进行的药物递送可能是有效的,因为所述粘膜表面缺少表皮的角质层,角质层是跨皮肤吸收的主要屏障。粘膜表面通常还富含血液供应,这可以快速地全身转运药物,同时避免通过首过肝代谢实现的显著降解。
对于喷涂到嗅觉粘膜上的药物,存在三种吸收途径,包含通过嗅觉神经元、通过支持细胞和周围毛细血管床以及进入脑脊液。通过嗅觉神经元和进入脑脊液实现的吸收有可能对脑产生直接影响,同时使全身浓度最小化。药物通过鼻粘膜的吸收往往很快。
类似于鼻内施用,口腔经粘膜吸收通常是快速的,这是因为粘膜具有丰富的血管供应以及表皮中缺少角质层。这种药物转运通常使血液浓度迅速升高,并且类似地避免肠肝循环和胃酸的直接破坏或肠壁和肝代谢的部分首过效应。
在一个方面,本公开基于DMT或其药学上可接受的盐的某些组合物的发现,所述组合物在施用于有需要的受试者后提供药物的快速起效,特别是当药物通过鼻、经颊或舌下途径经粘膜施用时,而且当皮下施用时。在本公开的特定方面,快速起效之后是有效DMT暴露的时段,所述时段可以超过当静脉内施用同一药物时可实现的有效暴露时段。
在另一个方面,本公开的组合物可以实现DMT在治疗有效水平下的延长的暴露时段,随后快速失效。因此,例如,在施用后,DMT的治疗有效血液水平可以维持至多约15分钟至约60分钟,此后DMT血液水平快速下降。例如,历经约20分钟或更短时间的时段,DMT血液水平的下降可能导致血液中含有约10% Cmax或更低水平的DMT。在一个方面,在施用后约60分钟内100%的DMT被释放。
本公开的组合物所表现出的独特的PK曲线在治疗神经疾病或病状时产生了特定益处。此类组合物优于DMT或其药学上可接受的盐的组合物,其表现出(1)剧烈的起效效应(例如,由非常快速的起效引起)(2)较短的DMT治疗暴露时段和/或(3)较慢的失效。
因此,本公开涉及包括DMT或其药学上可接受的盐的新型药物组合物,以及其用途,特别是用于治疗神经疾病或病状。具体地,在一个方面,本公开提供了包括DMT或其药学上可接受的盐的药物组合物,其在经粘膜(例如,经颊、舌下或鼻内)施用于受试者后表现出快速起效、DMT的延长的治疗暴露时段和快速失效。在第二方面,本公开还提供了包括DMT或其药学上可接受的盐的药物组合物,其在皮下施用于受试者后表现出快速起效、DMT的延长的治疗暴露时段和快速失效。
定义
如本文所使用的,除非另有明确说明,否则以下术语被定义为具有以下含义:
当在数字标识(例如,pH、温度、量或浓度)之前使用时,术语“约”指示可以变化至多(+)或(-)5%的近似值。
除非上下文另有明确说明,否则单数形式“一个(a)”、“一种(an)”和“所述(the)”包含复数指示物。例如,术语“药学上可接受的载体”可以包含多种药学上可接受的载体,包含其混合物。
术语“和/或”旨在意指本发明的两种组分中的任一种或两种组分。
术语“受试者”、“个体”和“患者”在本文中可互换地使用,并且是指人类。
如本文所使用的,术语“装置”是指能够将药物递送到有需要的患者的设备或系统。
当提及治疗时,术语“需要治疗”和术语“有需要”可互换地使用并且是指由护理者(例如,医生、护士、执业护士)做出的患者将受益于治疗的判断。
术语“治疗(treat)”和“治疗(treatment)”在本文中是指治疗性治疗,包含预防性或防治性措施,其中目的是预防或减缓(减轻)与疾病或病状相关的不期望的生理变化。有益的或期望的临床结果包含但不限于症状的缓解、疾病或病状程度的减轻、疾病或病状的稳定(即,疾病或病状没有恶化的情况)、疾病或病状进展的延迟或减缓、疾病或病状的改善或缓和以及疾病或病状的缓解(无论是部分还是全部)。“治疗”还可以意味着与未接受治疗的情况下的预期生存期相比,生存期延长。需要治疗的人包含已经患有所述疾病或病状的人以及易于患有所述疾病或病状的人或要预防所述疾病或病状的人。当涉及抑郁症时,“治疗”还可以包含减轻抑郁症的至少一种体征或症状。抑郁症的体征或症状的实例包含情绪低落、活动兴趣减弱、体重减轻或增加、食欲降低或增加、失眠或嗜睡、精神运动性激动或迟钝、疲劳或精力丧失、无价值感或过度或不适当的内疚、专注能力减弱或犹豫不决、或自杀意念或行为。
术语“鼻递送”、“鼻内递送”、“鼻施用”或“鼻内施用”是指药物剂型被送至或穿过鼻子(例如,鼻腔)的施用途径。类似地,“鼻递送装置”或“鼻内递送装置”旨在意指将药物施用到鼻腔中的设备。鼻内施用的非限制性实例包含引入呈鼻喷雾剂或滴剂(直接滴注)形式的溶液或悬浮液、或鼻内应用凝胶、乳液或软膏。
术语“经颊递送”或“经颊施用”是指将药物剂型应用于患者面颊与牙龈(即,颊腔)之间的施用途径。
术语“舌下递送”是指将药物剂型应用于患者舌下的施用途径。
术语“皮下递送”是指用短针将药物剂型注射到皮肤与肌肉之间的组织层中的施用途径。
如本文所使用的,术语“药学上可接受的”是指药物组合物中与调配物的其它成分相容并且对其接受者不过分有害的组分。
如本文中参考“DMT或其药学上可接受的盐”所使用的术语“药学上可接受的盐”意指药学上可接受的酸加成盐。通常,酸性试剂可以用于制备DMT的盐,具体地药学上可接受的盐。合适的酸性试剂的实例包含富马酸、盐酸、酒石酸、柠檬酸、氢溴酸、硫酸、磷酸、乙酸、马来酸、乳酸、酒石酸和葡萄糖酸。通常,在本公开的药物组合物中或以其它方式根据本公开及其实施例的各个方面使用的DMT盐的形式是富马酸盐、盐酸盐、酒石酸盐或柠檬酸盐的药学上可接受的盐,例如,富马酸盐。
术语“载体”是指与治疗剂一起施用的稀释剂、佐剂、赋形剂或媒剂,并且包含但不限于作为亲水物质、疏水物质以及具有亲水性质和疏水性质两者的物质(如乳化剂)的此类液体和粉末。
如本文所使用的,术语“有效量”或“治疗有效量”是指在组织、系统或个体中引发研究者、保健提供者或个体所寻求的生物或药物反应的活性剂的量。
如本文所使用的,术语“神经疾病或病状”意指选自以下的疾病或病状:神经精神障碍,如抑郁症(包含重度抑郁症,如抗治疗性抑郁症、重性抑郁障碍和持续性抑郁障碍);紧张性抑郁症;由医学病状引起的抑郁障碍;产后抑郁症;经前焦虑障碍或季节性情感障碍;焦虑;焦虑障碍;社交焦虑障碍;广泛性焦虑障碍(GAD);动机缺乏障碍(avolitiondisorder);双相情感障碍(包含双相I型障碍和双相II型障碍);创伤后应激障碍;身体畸形障碍;情绪或情感异常,包含上述病状;心境恶劣;分裂情感障碍;精神分裂症和其它精神障碍;惊恐障碍;创伤性应激障碍;恐怖性障碍和伴有异常情绪的人格障碍,如边缘型人格障碍、分裂样和分裂型障碍和自杀意念或负面影响人的行为/情绪/专注能力的沉思/非生产性重复性思维;强迫症;成瘾(包含物质使用障碍,如对尼古丁、酒精、可卡因、阿片类药物、安非他命(amphetamine)、甲基苯丙胺(methamphetamine)、海洛因、吗啡、苯环己哌啶、3,4-亚甲二氧基-甲基苯丙胺以及其它成瘾物质的成瘾);成瘾行为(包含进食、赌博、性、色情、视频游戏、工作、锻炼、精神困扰、自残、旅行和购物成瘾);进食障碍(包含神经性厌食症、神经性暴食症和暴食障碍)和疼痛(包含与偏头痛或头痛或慢性疼痛相关的疼痛)。
如本文所使用的,术语“抗治疗性抑郁症”或“TRD”意指对足够治疗没有满意反应的抑郁症。TRD是受各种抑郁亚型、精神共病和共存的医疗疾病影响的复杂现象。尽管TRD发作最常见地与重性抑郁障碍(MDD)相关,但其也见于双相情感障碍的抑郁期中。
如本文所使用的,术语“起效”意指在施用后达到最大血浆浓度的时间(即,Tmax),并且也可以描述为“作用起效”。在本公开的上下文中的“快速起效”意指药物在约20分钟内(例如,在约2至10分钟内)达到Cmax。然而,与通过IV注射施用DMT的情况相比,在施用根据本公开的组合物后起效较不快速,并且因此对患者来说不那么“剧烈”。
如本文所使用的,术语“失效”是指DMT的浓度最后一次达到Cmax±10%与DMT的血浆浓度第一次降低至阈值水平之间的时间,低于所述阈值水平,药物不再具有任何有意义的治疗效果(例如,约250nmol/L或47.07ng/mL)。在本公开的上下文中,“快速失效”意指少于约10分钟。然而,尽管失效快速,但仍然需要足够长的时间,以使药物发挥合理持续的迷幻效果。
药物组合物和递送
适于鼻内施用的包括DMT或其药学上可接受的盐的药物组合物包含组合物,其中活性成分存在于液体载体中。在各个实施例中,组合物可以呈水性或非水性溶液、悬浮液、脂质体分散体、乳液、微乳液或溶胶-凝胶的形式。载体可以含有添加剂,如增溶剂,例如,丙二醇、表面活性剂、吸收促进剂(如卵磷脂(磷脂酰胆碱)或环糊精)、粘膜粘合剂和/或防腐剂(如对羟基苯甲酸酯)。在本领域中熟知的用于制备鼻内调配物的方法可以在例如《雷明顿(Remington)》,2000中找到。另外,用于调配用于鼻内施用的化合物的方法(包含延长活性剂在鼻腔中的存在,与增强溶解度的药剂组合以及增加生物利用度等)是熟知的。
适于经颊施用和舌下施用的包括DMT或其药学上可接受的盐的药物组合物包含速溶片剂、薄片、膜、条剂或贴剂、口腔分散片剂、口服凝胶、药用棒棒糖、喷雾剂、滴剂和保留在颊或舌下粘膜表面的其它调配物。
适于皮下施用的包括DMT或其药学上可接受的盐的药物组合物可以以单位剂型(例如,在单剂量安瓿瓶中)提供,或者以含有若干剂量并且其中可以添加合适的防腐剂的小瓶提供(参见下文)。组合物可以方便地呈溶液、悬浮液或乳液的形式,或者所述组合物可以以干粉的形式存在以便在使用前用水或另一种合适的媒剂复原。除了DMT或其药学上可接受的盐之外,组合物可以包含合适的肠胃外可接受的载体和/或赋形剂。此外,组合物可以包含悬浮剂、增溶剂、稳定剂、pH调节剂和/或分散剂。
本公开的药物组合物可以包含一种或多种赋形剂、稀释剂、粘合剂、润滑剂、助流剂、崩解剂、脱敏剂、乳化剂、粘膜粘合剂、增溶剂、悬浮剂、粘度调节剂、离子张力剂、缓冲剂、载体、表面活性剂或其混合物。本公开的药物组合物还可以包含如渗透促进剂、生物粘附性聚合物和用于提供活性成分的改良释放(如持续释放)的方式的组分。组合物还可以包含一种或多种药学上可接受的调味剂或其它掩味剂。
DMT的体内释放速率和体内清除速率可能受在本领域中熟知的方式的影响。例如,将活性材料掺入到如聚乳酸、聚乙醇酸、水凝胶等聚合物化合物的颗粒制剂中或其上,或者掺入到脂质体、微乳液、胶束、单层或多层囊泡、红细胞血影或原生质球上。本文还理解的是通过水溶性聚合物的共价连接改性的化合物,所述水溶性聚合物如聚乙二醇、聚乙二醇和聚丙二醇的共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、环糊精、葫芦脲、聚乙烯吡咯烷酮或聚脯氨酸。与对应的未改性化合物相比,改性化合物在施用后可以表现出显著更长的血液中的半衰期。
取决于所使用的递送装置,实现了介于约25%与约100%的药物产品(即,DMT)之间的递送。然而,应当理解,由于药物递送装置的性质,本领域的普通技术人员将认识到,不是所有的药物都可以被递送,因为这是所使用的递送装置的功能。因此,为了清楚起见,应当理解,所递送的约25%至约100%的药物产品取决于所选择的药物递送方法和/或装置。因此,所递送的100%的药物产品可能不是所有药物产品,但其将是所选择的装置能够递送的所有药物产品。
鼻内组合物
相对于口服剂型(如片剂或胶囊),鼻内递送提供了快速吸收、更快的治疗作用起效和避免肠壁或肝脏首过代谢。对于吞咽片剂、胶囊或其它固体有困难的患者或患有肠衰竭的患者,鼻内递送途径可以是优选的。
用于鼻施用的本公开的组合物包含DMT或其药学上可接受的盐,并且任选地还可以包括其它成分,包含但不限于载体和赋形剂,如在鼻施用后促进活性成分的鼻吸收的吸收促进剂和在鼻施用后改善药物的脑渗透的药剂。其它任选的赋形剂包含稀释剂、粘合剂、润滑剂、助流剂、崩解剂、脱敏剂、乳化剂、粘膜粘合剂、增溶剂、悬浮剂、粘度调节剂、离子张力剂、缓冲剂、载体、调味剂和其混合物。在一个实施例中,活性成分的粒径小于或等于约60微米,这可以帮助确保颗粒与其它成分的任何共混物的均匀性,或者在液体媒剂中提供足够的分散体。
所吸收的药物的量取决于许多因素。这些因素包含药物浓度、药物递送媒剂、粘膜接触时间、粘膜组织的静脉引流、药物在吸收位点的pH下离子化的程度、药物分子的大小和其相对脂溶性。考虑到这些因素,本领域的技术人员可以容易地制备适当的鼻内组合物,其递送适当量的活性剂。
活性成分穿过正常粘膜表面(如鼻粘膜或颊粘膜)的转运可以通过任选地将所述活性成分与吸收促进剂组合来增强。这些吸收促进剂的实例包含但不限于阳离子聚合物、表面活性剂、螯合剂、粘液溶解剂、环糊精、聚合物水凝胶、其组合以及本领域技术人员已知的任何其它类似的吸收促进剂。代表性吸收促进赋形剂包含磷脂,如磷脂酰甘油或磷脂酰胆碱;溶血磷脂酰衍生物,如溶血磷脂酰乙醇胺、溶血磷脂酰胆碱、溶血磷脂酰甘油、溶血磷脂酰丝氨酸或溶血磷脂酸;多元醇,如甘油或丙二醇;其脂肪酸酯,如甘油酯、氨基酸及其酯;以及环糊精。还可以使用胶凝赋形剂或增粘赋形剂。
活性成分穿过正常粘膜表面的转运还可以通过增加调配物粘附至粘膜表面的时间来增强。粘膜粘附性/生物粘附性聚合物(例如,形成水凝胶的粘膜粘附性/生物粘附性聚合物)表现出粘膜粘附性和受控的药物释放性质,并且可以包含在本文所述的鼻内或经颊组合物中。能够与鼻粘膜结合的代表性生物粘附性或水凝胶形成聚合物是本领域技术人员熟知的,并且包含聚卡波非(polycarbophil)、聚赖氨酸、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、羟乙基纤维素、果胶、卡波普934P、聚氧化乙烯600K、一种或多种泊洛沙姆(如普朗尼克F127和/或普朗尼克F-68)、聚异丁烯(PIB)、聚异戊二烯(PIP)、聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)、黄原胶、瓜尔胶和刺槐豆胶。其它鼻递送组合物是基于壳聚糖的,并且适于增加活性成分在粘膜表面上的停留时间,这使得其生物利用度得以增加。与粘膜的富含半胱氨酸的亚结构域形成共价键的硫醇化聚合物赋形剂还可以提供粘膜粘附,这延长了活性成分与膜之间的接触时间。
鼻内组合物还可以包含一种或多种防腐剂。代表性防腐剂包含季铵盐,如劳拉氯铵(lauralkonium chloride)、苯扎氯铵、苯度氯铵(benzododeciniumchloride)、氯化十六烷吡啶(cetyl pyridium chloride)、溴化十六烷基三甲铵、溴化度米芬(domiphenbromide);醇类,如苯甲醇、氯丁醇、邻甲酚、苯基乙醇;有机酸或其盐,如苯甲酸、苯甲酸钠、山梨酸钾、对羟基苯甲酸酯;或络合形成剂,如EDTA。
载体和赋形剂包含离子交换微球,所述离子交换微球携带合适的阴离子基团,如羧酸残基、羧甲基、磺丙基和甲基磺酸酯基。也可以使用离子交换树脂,如阳离子交换剂。壳聚糖,其是部分脱乙酰化甲壳质或聚-N-乙酰基-D-葡糖胺或其药学上可接受的盐,如盐酸盐、乳酸盐、谷氨酸盐、马来酸盐、乙酸盐、甲酸盐、丙酸盐、苹果酸盐、丙二酸盐、己二酸盐或琥珀酸盐。用作非离子交换微球的合适的其它成分包含淀粉、明胶、胶原和白蛋白。
组合物还可以包含选自由以下组成的组的适当的酸:盐酸、乳酸、谷氨酸、马来酸、乙酸、甲酸、丙酸、苹果酸、丙二酸、己二酸和琥珀酸。其它成分(如稀释剂)是纤维素、微晶纤维素、羟丙基纤维素、淀粉、羟丙基甲基纤维素等。可以添加调节组合物张力的赋形剂,如氯化钠、葡萄糖、右旋糖、甘露醇、山梨醇、乳糖等。也可以向鼻内组合物中添加酸性或碱性缓冲剂来控制pH值。
除了使用增加活性剂通过粘膜的转运的吸收增强剂和延长活性剂沿着粘膜的接触时间的生物粘附性材料之外,可以通过使用控释调配物来控制活性剂的施用。存在许多本领域的技术人员已知的颗粒药物递送媒剂,其可以包含活性成分并且以受控方式递送所述活性成分。实例包含颗粒聚合物药物递送媒剂(例如,生物可降解聚合物)和由非聚合物组分形成的颗粒。这些颗粒药物递送媒剂可以呈粉末、微粒、纳米颗粒、微胶囊、脂质体等形式。通常,如果活性剂呈颗粒形式而没有添加组分,则所述活性剂的释放速率取决于活性剂自身的释放。通常,通过以微粉化形式呈递药物来增强吸收速率,其中颗粒直径小于20微米。相比之下,如果活性剂以颗粒形式作为活性剂和聚合物的共混物,则活性剂的释放至少部分地通过去除聚合物来控制,通常通过溶解、生物降解或从聚合物基质中扩散来控制。
鼻内递送
鼻内递送装置在本领域中是已知的。因此,可以使用适于将药物递送至鼻粘膜的任何装置。可用于施用液体组合物的装置的非限制性实例包含蒸气装置(例如,蒸气吸入器)、滴装置(例如,导管、单剂量滴管、多剂量滴管和单位剂量移液管)、机械喷雾泵装置(例如,挤压瓶、多剂量计量喷雾泵和单/双剂量喷雾泵)、双向喷雾泵(例如,呼吸致动的鼻递送装置)、气体驱动的喷雾系统/雾化器(例如,单剂量或多剂量HFA或氮推进剂驱动的计量吸入器,包含传统和周向速度吸入器)以及电动喷雾器/雾化器(例如,脉动膜喷雾器、振动机械喷雾器和手持机械喷雾器)。可用于施用粉末组合物(例如,冻干的或以其它方式干燥的合并的组合物)的装置的非限制性实例包含机械粉末喷雾器(例如,手动致动的基于胶囊的粉末喷雾装置和手动致动的粉末喷雾装置、手动致动的凝胶递送装置)、呼吸致动的吸入器(例如,单剂量或多剂量鼻吸入器和基于胶囊的单剂量或多剂量鼻吸入器)和吹入器(例如,呼吸致动的鼻递送装置)。
使用计量喷雾剂进行鼻内递送也可以通过将活性成分包含在合适介质中的溶液或分散体中来实现,所述介质可以作为喷雾剂施用。这种类型的代表性装置公开于以下专利、专利申请和出版物中:WO03/026559、WO02/011800、WO00/51672、WO02/068029、WO02/068030、WO02/068031、WO02/068032、WO03/000310、WO03/020350、WO03/082393、WO03/084591、WO03/090812、WO 00/41755,以及药学文献(参见,Bell,A.药物递送装置基础和应用中的鼻内递送装置(Intranasal Delivery Devices,in Drug Delivery DevicesFundamentals and Applications),TyIe P.(编辑),纽约的德克出版社(Dekker,NewYork),1988),《雷明顿药物科学(Remington's Pharmaceutical Sciences)》,麦克出版公司(Mack Publishing Co.),1975中,所有所述文献均通过引用并入本文。
除了前述内容之外,如在本领域中已知的,化合物还可以以冲洗和灌洗的形式鼻内施用。鼻冲洗涉及定期用包含药物的溶液冲洗鼻腔。通常通过以下方式使用鼻灌洗器:用包含药物的溶液填充鼻灌洗器,将来自灌洗器的喷嘴插入到一个鼻孔中,张开嘴进行呼吸,并且使溶液流入一个鼻孔,冲洗隔膜周围,并从另一个鼻孔排出。
在本文中特别令人感兴趣的是将药物递送至鼻腔的上部部分的装置,如筛状装置。还令人感兴趣的是沿着三叉神经通路进行的药物递送。
经颊和舌下组合物及递送
相对于口服剂型(如片剂或胶囊),类似于鼻内递送,口服经粘膜递送可以提供快速吸收、更快的治疗作用起效和避免肝脏或肠壁首过代谢。对于吞咽片剂、胶囊或其它固体有困难的患者或患有肠衰竭的患者,经颊或舌下递送途径是优选的。
用于经颊或舌下施用的组合物包含DMT或其药学上可接受的盐以及至少一种赋形剂以形成固体剂型。固体剂型在口腔中或在舌下以最少的液体暴露并且在体温下崩解,并且理想地通过与组织的直接粘附或在经颊施用的情况下将剂型截留在牙龈与内颊之间而粘附至口腔的体组织或舌下的组织。在具有或不具有流体、唾液流体、机械侵蚀或其组合的帮助下,固体剂型在体温下崩解或熔化。可替代地,剂型可以以溶液喷雾剂或干粉的形式喷雾到口腔中或舌下。通常,组合物可以是朝向衬有患者的口腔的体组织或舌下的粘附剂。
剂型可以是但不限于片剂、生物粘附性贴剂或膜、海绵、锭剂、硬糖、薄片、棒棒糖、喷雾剂、口香糖、丸剂、团粒、球体、其组合以及本领域的技术人员已知的其它形式。
颊膜或舌下膜表示用于施用本公开的药物组合物的特别方便的媒剂。在一个方面,膜的实例包含在粘膜粘附性聚合物中包括DMT或其药学上可接受的盐的组合物。合适的粘膜粘附性聚合物包含一种或多种选自以下的聚合物:纤维素衍生物、聚丙烯酸、聚丙烯酸酯、聚环氧乙烷、聚乙烯吡咯烷酮、聚乙烯醇、黄蓍胶、藻酸盐、胶(包含刺梧桐胶、瓜尔胶、黄原胶)、可溶性淀粉、明胶、凝集素、果胶和壳聚糖。在一些实施例中,粘膜粘附性聚合物包括一种或多种选自亲水聚合物、多糖及其衍生物和水凝胶的聚合物。在一些实施例中,粘膜粘附性聚合物包括一种或多种选自以下的聚合物:聚丙烯酸、聚丙烯酸酯、纤维素(例如,羧基纤维素(例如,羧甲基纤维素钠))、羟烷基纤维素(例如,羟丙基纤维素、羟乙基纤维素和羟乙基乙基纤维素)、聚乙烯吡咯烷酮和聚乙烯醇。在一些实施例中,粘膜粘附性聚合物包括一种或多种选自以下的聚合物:卡波普(聚丙烯酸)、羧甲基纤维素、羧乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素和胶。在一些实施例中,粘膜粘附性聚合物是水溶胀性的。通常,粘膜粘附性聚合物以膜组合物的约15重量%至约60重量%的量存在。
膜组合物可以进一步包含渗透促进剂和/或抗氧化剂。例如,在一些实施例中,膜组合物包括渗透促进剂,例如,包括一种或多种选自以下的渗透促进剂:二甲基亚砜(DMSO)、油醇、油酸、油酸油酯、乙酰丙酸、丙二醇、二丙二醇、乙醇和表面活性剂。在一些实施例中,渗透促进剂以膜组合物的约5重量%至约30重量%的量存在。在一些实施例中,膜组合物包括抗氧化剂,例如,生育酚乙酸酯、α-生育酚、L-谷胱甘肽、L-半胱氨酸、抗坏血酸、抗坏血酸棕榈酸酯、没食子酸丙酯、丁基化羟基甲苯(BHT)、丁基化羟基茴香醚(BHA)、tocobiol和乙二胺四乙酸(EDTA)。
在一些实施例中,膜组合物可以形成双层或多层膜组合物。通常,这种双层或多层膜可以提供两相释放曲线,这在某些情况下可以是有利的。在一些实施例中,快速释放膜层包括水溶性聚合物。在一些实施例中,快速释放膜中的水溶性聚合物包括一种或多种选自以下的聚合物:羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、聚维酮、共聚维酮、聚乙烯醇(PVA)、低分子量聚环氧乙烷和基于淀粉的聚合物。在一些实施例中,快速释放膜还可以任选地包含渗透促进剂,例如,一种或多种选自以下的渗透促进剂:二甲基亚砜(DMSO)、油醇、油酸、油酸油酯、乙酰丙酸、丙二醇、二丙二醇、乙醇和表面活性剂。在一些实施例中,快速释放膜还可以任选地包含抗氧化剂,如生育酚乙酸酯。
存在适于经颊或舌下递送活性成分的许多组合物和递送媒剂。除了DMT或其药学上可接受的盐之外,剂型的其它组分包含但不限于淀粉、甘露醇、木糖醇、糖精、三氯蔗糖、l-薄荷醇、柠檬酸、l-谷胱甘肽、高岭土、硫酸钙、无机盐(如氯化钠)、粉末状纤维素衍生物、磷酸氢钙和磷酸三钙、硫酸钙、碳酸镁、氧化镁、泊洛沙姆(如聚环氧乙烷)、羟丙基甲基纤维素、阴离子赋形剂、阳离子赋形剂、两性离子赋形剂,参考US6,436,950,所述文献关于此类赋形剂、聚合物水凝胶、粉末微球粘膜粘附性组合物、硫醇化聚合赋形剂、聚阳离子材料、壳聚糖、交联淀粉、脂肪、碳水化合物、多元醇、缓冲剂、磷酸盐缓冲剂、乙酸盐缓冲剂、甲基纤维素、氯化钠、水、乳酸、苯扎氯铵、软化水、纤维素、微晶纤维素、羟丙基纤维素、氢化植物油、调味剂、磷脂、木糖醇、可可、其组合以及本领域的技术人员已知的其它类似赋形剂通过引用并入本文。也可以存在增塑剂。代表性增塑剂包含聚乙二醇、丙二醇、蓖麻油、植物油等。
也可以存在粘合剂。合适的粘合剂包含如纤维素等物质,包含但不限于纤维素、甲基纤维素、乙基纤维素、羟丙基纤维素和羟甲基纤维素、聚丙烯吡咯烷酮、聚乙烯吡咯烷酮、明胶、聚乙二醇、淀粉、天然胶(如阿拉伯胶、藻酸盐、瓜尔胶和阿拉伯胶)以及合成胶和蜡。
皮下组合物和递送
对于皮下施用,可以使用水性悬浮液、等渗盐溶液和无菌可注射溶液,任选地含有可以包含分散剂和/或润湿剂(如丙二醇或丁二醇)的药学上可接受的赋形剂。另外,DMT或其药学上可接受的盐的悬浮液可以制备成适当的油性注射悬浮液。合适的亲脂溶剂或媒剂包含脂肪油(如芝麻油)或合成脂肪酸酯(如油酸乙酯或甘油三酯)或脂质体。水性注射悬浮液可能含有增加悬浮液粘度的物质,如羧甲基纤维素钠、山梨醇或葡聚糖。任选地,悬浮液还可以含有合适的稳定剂或增加化合物的溶解度的药剂,以允许制备高浓度溶液。可替代地,DMT或其药学上可接受的盐可以呈粉末形式,以便在使用前与合适的媒剂(例如,无菌无热原水)一起构建。溶液或悬浮液可以使用熟知的装置和技术通过注射皮下施用于受试者。可以方便地使用任何适当的注射器,包含可以允许自我施用的自动注射器。
给药
施用于如本文所定义的患有神经疾病或病状的患者的DMT或其药学上可接受的盐的剂量通常为约0.1mg/kg至约1mg/kg。典型的人类剂量(对于体重50至80kg的成人而言)将相当于约5mg至约80mg的剂量。在一个实施例中,剂量为约10mg至约60mg,如约20mg至60mg、约30mg至60mg、约40mg至60mg或其间的任何具体量,包含10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg和60mg。在本公开中,当阐述范围(如“约20mg至60mg”)时,本发明人设想了所述范围内的所有离散值,但出于简洁的目的,所述离散值中的一些离散值被具体提及,并非所有离散值被具体提及。
在特定实施例中,DMT或其药学上可接受的盐可以历经24小时时段以一个或多个剂量(例如,1个、2个、3个、4个或5个剂量)施用于患者。然而,历经24小时时段施用于受试者的总剂量不应超过约100mg。
用途
在一个方面,如本文进一步描述的,本公开提供了一种用于治疗神经疾病或病状的药物组合物。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者经粘膜施用有效量的DMT或其药学上可接受的盐。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者鼻内施用有效量的DMT或其药学上可接受的盐。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者经颊施用有效量的DMT或其药学上可接受的盐。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者舌下施用有效量的DMT或其药学上可接受的盐。
在一个方面,本公开提供了一种治疗神经疾病或病状的方法,所述方法包括向受试者皮下施用有效量的DMT或其药学上可接受的盐。
在上述方面中的任一方面中,神经疾病或病状可以是例如神经精神障碍。
可以用DMT或其药学上可接受的盐治疗的神经精神障碍的实例包含抑郁症(例如,TRD)、焦虑、双相情感障碍、创伤后应激障碍、情绪或情感异常(包含上述病状)、心境恶劣、分裂情感障碍、精神分裂症和其它精神障碍、惊恐障碍、创伤性应激障碍、恐怖性障碍、进食障碍和伴有异常情绪的人格障碍,如边缘型人格障碍、分裂样和分裂型障碍和自杀意念或负面影响人的行为/情绪/专注能力的沉思/非生产性重复性思维。
在上述方面中的任一方面中,神经疾病或病状可以是例如成瘾。
可以用DMT或其药学上可接受的盐治疗的成瘾的实例包含物质使用障碍,如对尼古丁、酒精、可卡因、阿片类药物、安非他明、甲基苯丙胺、海洛因、吗啡、苯环己哌啶、3,4-亚甲二氧基-甲基苯丙胺以及其它成瘾物质的成瘾。
在上述方面中的任一方面中,神经疾病或病状可以是例如成瘾行为。
可以用DMT或其药学上可接受的盐治疗的成瘾行为的实例包含对进食、赌博、性、色情、视频游戏、工作、锻炼、精神困扰、自残、旅行和购物的成瘾以及物质使用障碍(SUD)。
在特定实施例中,本公开提供了一种治疗抑郁症(包含重度抑郁症,如抗治疗性抑郁症、重性抑郁障碍和持续性抑郁障碍、紧张性抑郁症、由医学病状引起的抑郁障碍或产后抑郁症)的方法,所述方法包括向受试者经粘膜(例如,经颊、舌下或鼻内)施用有效量的DMT或其药学上可接受的盐。
在特定实施例中,本公开提供了一种治疗抑郁症(包含重度抑郁症,如抗治疗性抑郁症、重性抑郁障碍和持续性抑郁障碍、紧张性抑郁症、由医学病状引起的抑郁障碍或产后抑郁症)的方法,所述方法包括向受试者皮下施用有效量的DMT或其药学上可接受的盐。
组合疗法
本文所述的方法包含施用DMT或其药学上可接受的盐作为唯一的活性成分。然而,用于治疗神经疾病或病状的方法也涵盖在本公开的范围内,所述方法包括施用DMT或其药学上可接受的盐与一种或多种另外的药剂的组合。
在一个方面,这些另外的药剂是适用于被治疗的疾病或病症的治疗剂,如本领域中已知的。在一些实施例中,可以将DMT或其药学上可接受的盐与一种或多种抗抑郁药或抗焦虑药(如SSRI、三环抗抑郁药(TCA)、单胺氧化酶抑制剂(MAOI)或血清素去甲肾上腺素再摄取抑制剂(SNRI))的组合施用于受试者。
在一些实施例中,本公开提供了一种减轻接受DMT或其药学上可接受的盐的治疗的受试者的焦虑的方法,所述方法包括向受试者施用:i)DMT或其药学上可接受的盐,以及ii)一种或多种苯并二氮杂卓。
在一些实施例中,所述一种或多种苯并二氮杂卓与DMT或其药学上可接受的盐同时或大约同时施用于受试者。在一些实施例中,在施用DMT或其药学上可接受的盐之前,如在施用赛洛西宾或其前体或衍生物之前约10分钟、约15分钟、约20分钟、约30分钟、约45分钟、约60分钟、约75分钟、约90分钟、约105分钟、约120分钟、约150分钟或约180分钟,向受试者施用所述一种或多种苯并二氮杂卓。在一些实施例中,在DMT或其药学上可接受的盐之后,如在施用赛洛西宾或其前体或衍生物之后约10分钟、约15分钟、约20分钟、约30分钟、约45分钟、约60分钟、约75分钟、约90分钟、约105分钟、约120分钟、约150分钟或约180分钟,向受试者施用所述一种或多种苯并二氮杂卓。
在一些实施例中,苯并二氮杂卓选自由以下组成的组:阿地唑仑(adinazolam)、阿普唑仑(alprazolam)、苯他西泮(bentazepam)、溴他西尼(bretazenil)、溴西泮(bromazepam)、宁神定(bromazolam)、溴替唑仑(brotizolam)、卡马西泮(camazepam)、利眠宁(chlordiazepoxide)、西那西泮(cinazepam)、西诺西泮(cinolazepam)、氯巴占(clobazam)、氯硝安定(clonazepam)、氯硝西泮(clonazolam)、氯拉卓酸(clorazepate)、氯噻西泮(clotiazepam)、氯噁唑仑(cloxazolam)、地洛西泮(delorazepam)、去氯依替唑仑(deschloroetizolam)、安定(diazepam)、二氯西泮(diclazepam)、艾司唑仑(estazolam)、乙卡氟特(ethyl carfluzepate)、氯氟卓乙酯(ethyl loflazepate)、依替唑仑(etizolam)、氟阿普唑仑(flualprazolam)、氟溴西泮(flubromazepam)、氟溴唑仑(flubromazolam)、氟氯唑仑(fluclotizolam)、氟硝西泮(flunitrazepam)、氟硝唑仑(flunitrazolam)、氟安定(flurazepam)、氟他唑仑(flutazolam)、氟托西泮(flutoprazepam)、哈拉西泮(halazepam)、凯他唑仑(ketazolam)、氯普唑仑(loprazolam)、劳拉西泮(lorazepam)、氯甲西泮(lormetazepam)、甲氯西泮(meclonazepam)、美达西泮(medazepam)、美替唑仑(metizolam)、美沙唑仑(mexazolam)、咪达唑仑(midazolam)、奈福泮(nifoxipam)、硝甲西泮(nimetazepam)、尼特西泮(nitemazepam)、硝西泮(nitrazepam)、硝唑仑(nitrazolam)、去甲西泮(nordiazepam)、诺氟西泮(norflurazepam)、奥沙西泮(oxazepam)、芬纳西泮(phenazepam)、匹那西泮(pinazepam)、普拉西泮(prazepam)、普瑞西泮(premazepam)、吡唑仑(pyrazolam)、夸西泮(quazepam)、利马扎封(rilmazafone)、羟基安定(temazepam)、四氢西泮(tetrazepam)和三唑仑(triazolam)。
在某些实施例中,向患者施用如本文所述的DMT或其药学上可接受的盐连同一种或多种5-HT2A特异性拮抗剂和/或反向激动剂。在一些实施例中,向患者同时施用DMT或其药学上可接受的盐以及所述一种或多种5-HT2A特异性拮抗剂和/或反向激动剂。在其它实施例中,在DMT或其药学上可接受的盐施用之前,如但不限于在DMT或其药学上可接受的盐施用之前约10分钟、约15分钟、约20分钟、约30分钟、约45分钟、约60分钟、约75分钟、约90分钟、约105分钟、约120分钟、约150分钟或约180分钟,向患者施用一种或多种5-HT2A特异性拮抗剂和/或反向激动剂。在一些实施例中,在DMT或其药学上可接受的盐施用之后,如但不限于在DMT或其药学上可接受的盐施用之后约10分钟、约15分钟、约20分钟、约30分钟、约45分钟、约60分钟、约75分钟、约90分钟、约105分钟、约120分钟、约150分钟或约180分钟,向患者施用一种或多种5-HT2A特异性拮抗剂和/或反向激动剂。
合适的5-HT2A拮抗剂包含但不限于曲唑酮(trazodone)、米氮平(mirtazapine)、甲麦角林(metergoline)、酮色林(ketanserin)、利坦色林(ritanserin)、奈法唑酮(nefazodone)、氯氮平(clozapine)、奥氮平(olanzapine)、奎硫平(quetiapine)、利培酮(risperidone)、阿塞那平(asenapine)、MDL-100907、赛庚啶(cyproheptadine)、苯噻啶(pizotifen)、LY-367,265、2-烷基-4-芳基-四氢-嘧啶并-氮杂卓、9-氨甲基-9,10-二氢蒽(AMDA)、氟哌啶醇(haloperidol)、氯丙嗪(chlorpromazine)、羟嗪(hydroxyzine)(安泰乐(atarax))、5-MeO-NBpBrT、尼普拉嗪(niaprazine)、阿坦色林(altanserin)、阿立哌唑(aripiprazole)、依托哌酮(etoperidone)、司托哌隆(setoperone)、氯普噻吨(chlorprothixene)、辛那色林(cinaserin)、阿达色林(adatanserin)、美地沙明(medifoxamine)、萝芙素(rauwolscine)、酚苄明(phenoxybenzamine)、普凡色林(pruvanserin)、德伦环烷(deramciclane)、奈洛坦色林(nelotanserin)、鲁巴唑酮(lubazodone)、美吡哌唑(mepiprazole)、托西米定(xylamidine)、R-(+)-α-(2,3-二甲氧基苯基)-1-[2-(4-氟苯乙基)]-4-哌啶甲醇(M100907)、米安色林(mianserin)、AT 1015、DV7028、依利色林(eplivanserin)、4F 4PP、法纳色林(fanaserin)、α-苯基-1-(2-苯基乙基)-4-哌啶甲醇(MDL 1 1,939)、美哌隆(melperone)、美舒麦角(mesulergine)、帕潘立酮(paliperidone)、1-[2-(3,4-二氢-1/-/-2-苯并吡喃-1-基)乙基]-4-(4-氟苯基)哌嗪二盐酸盐(PNU 96415E)、(2R,4R)-5-[2-[2-[2-(3-甲氧基苯基)乙基]苯氧基]乙基]-1-甲基-3-吡咯烷醇(R-96544)、沙波格来(sarpogrelate)、螺哌隆(spiperone)、齐拉西酮(ziprasidone)、佐替平(zotepine)和7-[[4-[2-(4-氟苯基)乙基]-1-哌嗪基]羰基]-1-吲哚-3-甲腈(EMD 281014)。
合适的5-HT2A反向激动剂包含但不限于AC-90179、奈洛坦色林(APD-125)、依利色林、匹莫范色林(pimavanserin)(ACP-103)和窝利色林(volinaserin)。
在一些实施例中,本公开提供了一种减少与接受DMT或其药学上可接受的盐的治疗的患者的创伤性迷幻体验相关的负面副作用的方法。在一方面,所述方法包括向患者施用:i)DMT或其药学上可接受的盐,以及ii)一种或多种5-HT2A特异性拮抗剂和/或反向激动剂。在另一方面,所述方法包括向患者施用:i)DMT或其药学上可接受的盐,以及ii)一种或多种大麻素或大麻素衍生物。
在一些实施例中,大麻素选自由以下组成的组:THC(四氢大麻酚)、THCA(四氢大麻酚酸);CBD(大麻二酚);CBDA(大麻二酚酸);CBN(大麻酚);CBG(大麻萜酚);CBC(大麻色原烯(cannabichromene));CBL(大麻环酚(cannabicyclol));CBV(次大麻酚(cannabivarin));THCV(四氢次大麻酚(tetrahydrocannabivarin));CBDV(次大麻二酚);CBCV(次大麻环萜酚(cannabichromevarin));CBGV(次大麻萜酚(cannabigerovarin));CBGM(大麻萜酚单甲醚);CBE(大麻艾尔松(cannabielsoin));以及CBT(大麻二吡喃环烷(cannabicitran))。在特定实施例中,大麻素是CBD(大麻二酚)。
可以调整剂量方案以提供最佳期望反应。可以使用本领域的技术人员已知的常规方法滴定治疗剂量,以优化安全性和功效。
在本公开的另外的方面,当治疗神经精神疾病或病症,如抑郁症(例如,TRD)、焦虑或成瘾时,本公开的组合物可以与心理疗法、谈话疗法、认知行为疗法、暴露疗法,生物反馈疗法(例如,EEG辅助疗法和虚拟现实辅助疗法)、系统性脱敏、正念、辩证行为疗法、人际关系疗法、眼动脱敏和再处理、社交节律疗法、接受和承诺疗法、家庭聚焦疗法、心理动力学疗法、光疗法、计算机疗法(包含数字认知行为疗法)、认知矫正、锻炼或其它类型的疗法(如经颅磁刺激(TMS))联合施用。在一个实施例中,可以施用本公开的组合物以与数字认知行为疗法联合治疗抑郁症,例如,使用数字程序在一个实施例中,本公开的组合物可以与使用跨诊断方法的疗法联合施用(例如,用于治疗抑郁症或焦虑)(参见《咨询心理学与临床心理学杂志(J Consult Clin Psychol.)》2020年3月;88(3):179-195)。
出于所有目的,本文中引用的所有参考文献、文章、出版物、专利、专利出版物和专利申请均通过引用整体并入本文。然而,对本文中的任何参考文献、文章、出版物、专利、专利出版物和专利申请的提及不被视为并且不应当被视为对其构成有效的现有技术或形成世界上任何国家的公知常识的一部分的承认或任何形式的暗示。
实例1:通过猪粘膜的DMT经颊施用
DMT颊膜组合物:
方法:
使用Franz扩散池评估DMT颊膜的渗透性(参见图5)。
·将特定大小的颊膜置于供体隔室中。
·将pH为7的M磷酸盐缓冲溶液添加到受体室中。
·两个隔室被猪颊粘膜分开。
·在整个研究期间,通过循环水浴将受体培养基的温度保持在37±1℃并持续搅拌。
·以历经4小时的各预定时间间隔取出0.5mL样品并用等体积的培养基替换。
·通过HPLC分析所取出样品中的药物浓度。
结果:(参见图3a和3b)。
·在pH为7的0.01M磷酸盐缓冲溶液中,评估DMT从颊膜穿过猪颊粘膜的渗透性。
·提供了在不同时间点渗透穿过颊粘膜的DMT的累积量%。
·基于DMT渗透率曲线,观察到DMT渗透的线性增加。
·发现历经4小时,最终颊膜调配物的累积DMT渗透为约20%。
实例2:皮下施用的DMT琥珀酸盐的研究
表1:向大鼠(雄性和雌性组合)单次SC注射5mg/kg和10mg/kg DMT琥珀酸盐后第1
天的DMT血浆浓度参数。
/>
时间(小时) | 5mg/kg | 10mg/kg |
0.5 | 228 | 836 |
1 | 202 | 1260 |
2 | 27.1 | 1170 |
4 | 0 | 149 |
8 | 0 | 0.707 |
12 | 0 | 0 |
24 | 0 | 0 |
也在图4中阐述了结果。
Claims (36)
1.一种组合物,其包括N,N-二甲基色胺(DMT)或其药学上可接受的盐,当施用于人类时,所述N,N-DMT或其药学上可接受的盐能够表现出治疗有效血液水平的DMT(例如,浓度处于或高于约250nmol/L),持续介于约20分钟与约60分钟之间的时间。
2.根据权利要求1所述的组合物,其表现出治疗有效水平的DMT,持续介于约20分钟与约45分钟之间的时间。
3.根据权利要求1所述的组合物,其表现出治疗有效水平的DMT,持续介于约30分钟与约45分钟之间的时间。
4.根据权利要求1所述的组合物,其表现出治疗有效水平的DMT,持续约45分钟。
5.根据权利要求1至4中任一项所述的组合物,其中Tmax小于或等于60分钟。
6.根据权利要求1至4中任一项所述的组合物,其中Tmax介于5分钟与60分钟之间。
7.根据权利要求1至4中任一项所述的组合物,其中Tmax介于8分钟与24分钟之间。
8.根据权利要求1至4中任一项所述的组合物,其中Tmax介于10分钟与20分钟之间。
9.根据权利要求1至8中任一项所述的组合物,其中在达到Tmax之后,将DMT的浓度维持在Cmax的约50%或更多,持续约5分钟至约60分钟。
10.根据权利要求1至8中任一项所述的组合物,其中在达到Tmax之后,将DMT的浓度维持在Cmax的约80%或更多,持续约5分钟至约45分钟。
11.根据权利要求10所述的组合物,其中将DMT的浓度维持在Cmax的约80%或更多,持续约10分钟至约30分钟。
12.根据权利要求1至11中任一项所述的组合物,其中DMT的浓度在约20分钟或更短时间内降低至Cmax的约10%或更少。
13.根据权利要求1至12中任一项所述的组合物,其能够将DMT的血液水平维持在至少约250nmol/L的浓度,持续至少约20分钟。
14.根据权利要求1至12中任一项所述的组合物,其能够将DMT的血液水平维持在至少约250nmol/L的浓度,持续约20分钟至约45分钟。
15.根据权利要求1至14中任一项所述的组合物,其呈适于经颊施用、舌下施用、皮下施用或鼻内施用的形式。
16.根据权利要求15所述的组合物,其能够在施用于受试者后约20分钟内从所述组合物中释放100%的所述DMT。
17.根据权利要求15所述的组合物,其能够在施用于受试者后约20分钟至约30分钟内从所述组合物中释放100%的所述DMT。
18.根据权利要求15所述的组合物,其适于鼻内施用。
19.根据权利要求15所述的组合物,其适于经颊施用。
20.根据权利要求15所述的组合物,其适于舌下施用。
21.根据权利要求15所述的组合物,其适于皮下施用。
22.根据权利要求1至21中任一项所述的组合物,其包括约0.1mg/kg至约1mg/kg的DMT或游离碱当量的所述其药学上可接受的盐。
23.根据权利要求19所述的组合物,其中所述组合物呈快速溶解性片剂、薄片、膜、条剂或贴剂或分散片剂、口服凝胶、药用棒棒糖、喷雾剂或滴剂的形式。
24.根据权利要求23所述的组合物,其呈膜的形式。
25.根据权利要求1至24中任一项所述的组合物,其中所述活性剂是DMT。
26.根据权利要求25所述的组合物,其中所述组合物适于经颊施用。
27.根据权利要求1至24中任一项所述的组合物,其中所述活性剂是DMT的琥珀酸盐。
28.根据权利要求27所述的组合物,其中所述组合物适于皮下施用。
29.根据权利要求1至28中任一项所述的组合物,其与一种或多种另外的治疗剂组合。
30.根据权利要求29所述的组合物,其中所述一种或多种另外的治疗剂包含抗抑郁药或抗焦虑药。
31.一种治疗神经疾病或病状的方法,所述方法包括向有需要的受试者经颊施用、舌下施用、皮下施用或鼻内施用有效量的N,N-二甲基色胺(DMT)或其药学上可接受的盐,当施用于人类时,所述N,N-DMT或其药学上可接受的盐能够表现出治疗有效水平的DMT,持续介于约至约60分钟之间的时间。
32.根据权利要求31所述的治疗方法,其中所述神经疾病或病状是神经精神障碍、经前焦虑障碍或季节性情感障碍、焦虑、焦虑障碍、社交焦虑障碍、广泛性焦虑障碍(GAD)、动机缺乏障碍(avolition disorder)、双相情感障碍、创伤后应激障碍、身体畸形障碍、情绪或情感异常、心境恶劣、分裂情感障碍、精神分裂症、惊恐障碍、创伤性应激障碍、恐怖性障碍以及伴有异常情绪、成瘾、成瘾行为的人格障碍、进食障碍或疼痛。
33.根据权利要求31所述的治疗方法,其包括将DMT或其药学上可接受的盐与一种或多种另外的治疗剂共同施用。
34.根据权利要求33所述的治疗方法,其中所述一种或多种另外的治疗剂包含抗抑郁药或抗焦虑药。
35.根据权利要求23所述的方法,其包括向患者经颊施用DMT游离碱。
36.根据权利要求21所述的方法,其包括向患者皮下施用DMT的琥珀酸盐。
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