CN113164411A - 大麻素在治疗癫痫中的用途 - Google Patents
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Abstract
本发明涉及大麻二酚(CBD)在治疗由GRIN2A基因的突变引起的癫痫中的用途。所使用的CBD呈大麻属的高度纯化的提取物的形式,使得CBD以总提取物的大于98%(w/w)存在,并且该提取物的其他组分被表征。特别地,大麻素四氢大麻酚(THC)以从0.02%至0.1%(w/w)的量存在。在可选择的实施方案中,CBD可以呈合成形式。在使用中,CBD也可以与一种或更多种其他抗癫痫药物(AED)同时使用。CBD可以被配制用于与一种或更多种AED分开地、依次地或同时地施用,或者可以以单一剂型提供组合。在CBD被配制用于分开地、依次地或同时地施用时,CBD可以作为试剂盒提供,或与使用说明一起提供,以便按指示的方式施用一种或更多种组分。CBD也可以作为唯一的药物使用,即作为单一疗法。
Description
发明领域
本发明涉及大麻二酚(CBD)在治疗由GRIN2A基因的突变引起的癫痫(epilepsy)中的用途。
所使用的CBD呈大麻属的高度纯化的提取物的形式,使得CBD以总提取物的大于98%(w/w)存在,并且该提取物的其他组分被表征。特别地,大麻素四氢大麻酚(THC)以从0.02%至0.1%(w/w)的量存在。在可选择的实施方案中,CBD可以呈合成形式。
在使用中,CBD也可以与一种或更多种其他抗癫痫药物(AED)同时使用。CBD可以被配制用于与一种或更多种AED分开地、依次地或同时地施用,或者可以以单一剂型提供组合。在CBD被配制用于分开地、依次地或同时地施用时,CBD可以作为试剂盒提供,或与使用说明一起提供,以便按指示的方式施用一种或更多种组分。CBD也可以作为唯一的药物使用,即作为单一疗法。
发明背景
全世界人口的约1%患有癫痫(Thurman等人,2011),其中的70%能够利用现有可用的抗癫痫药物(AED)充分控制其症状。然而,该患者组的30%(Eadie等人,2012)使用可用的AED不能获得癫痫发作免除(seizure freedom),并且因此被称为患有难治性癫痫(intractable epilepsy)或“难治性癫痫(treatment-resistant epilepsy)”(TRE)。
难治性癫痫(intractable epilepsy)或难治性癫痫(treatment-resistantepilepsy)在2009年被国际抗癫痫联盟(ILAE)定义为“未能通过两种耐受的且适当选择和使用的AED方案(无论是作为单一疗法还是组合)的足够的试验来实现持续的癫痫发作免除”(Kwan等人,2009)。
在生命的最初几年期间发展癫痫的个体通常难以治疗,并且因此通常被称为难治性。儿童时期经历频繁的癫痫发作的儿童通常留下神经损伤,这可能引起认知、行为和运动的延迟。
儿童癫痫是一种相对常见的儿童和年轻成人的神经紊乱,具有每100,000人中约700人的患病率。这是每单位人口中癫痫成人的数目的两倍。
当儿童或年轻成人表现癫痫发作时,通常进行调查以便调查原因。儿童癫痫可能由许多不同的综合征和基因突变引起,并且因此对这些儿童的诊断可能花费一些时间。
癫痫的主要症状是反复的癫痫发作。为了确定患者罹患的癫痫或癫痫综合征的类型,对患者正在经历的癫痫发作的类型进行调查。进行临床观察和脑电图学(EEG)测试,并且根据下文描述的ILAE分类对癫痫发作的类型进行分类。
由ILAE提出的癫痫发作类型国际分类于1981年被采用,并且修订提案由ILAE于2010年公布并尚未取代1981年的分类。图1改编自2010年的修订术语的提案,并且包括用术语局灶性(focal)替代术语部分性(partial)的所提出的修改。此外,术语“简单部分性癫痫发作(simple partial seizure)”已经被术语“认知/反应未受损的局灶性癫痫发作(focalseizure where awareness/responsiveness is not impaired)”替代,并且术语“复杂部分性癫痫发作(complex partial seizure)”已经被术语“认知/意识受损的局灶性癫痫发作(focal seizure where awareness/consciousness is impaired)”替代。
全身癫痫发作(Generalised seizure)(其中癫痫发作发生在双侧分布的网络内并且迅速进入双侧分布的网络)可以被分为六个亚型:强直阵挛性(大发作)癫痫发作;失神性(小发作)癫痫发作;阵挛性癫痫发作;强直性癫痫发作;失张力性癫痫发作和肌阵挛性癫痫发作。
局灶性(部分性)癫痫发作(其中癫痫发作源自仅局限于一个半球的网络内)也被分为几个子类。在这里,癫痫发作根据癫痫发作的一个或更多个特征来表征,包括先兆、运动、自主和认知/反应。在癫痫发作以局部癫痫发作开始并且迅速演变为在双侧网络中分布时,这种癫痫发作被称为双侧惊厥性癫痫发作(Bilateral convulsive seizure),这是替代继发性全身癫痫发作(从局灶性癫痫发作演变且不再保持局部的全身癫痫发作)的所提出的术语。
受试者的认知/反应被改变的局灶性癫痫发作被称为有损害的局灶性癫痫发作,并且受试者的认知或反应未受损的局灶性癫痫发作被称为无损害的局灶性癫痫发作。
癫痫综合征通常表现许多不同类型的癫痫发作,并且识别患者正在罹患的癫痫发作的类型是重要的,因为许多标准AED针对给定的癫痫发作类型/亚型进行靶向治疗或仅对其有效。
每年约有1/200的儿童被诊断为遗传性癫痫。在该群体中,共存的状况或症状也经常发生,包括语言问题、认知问题和头痛。
在2013年,一种基因被确定为许多儿童癫痫病例以及相关的速度和语言问题的原因。这种基因被称为GRIN2A,负责在神经细胞末端发现的一种蛋白质。已知这种基因的突变引起儿童癫痫。
GRIN2A相关的言语障碍和癫痫可以包括构音障碍和言语运用障碍,以及接受性和表达性的语言延迟/退化两者。在受影响较轻的个体中,会话言语的可理解性(intelligibility)的轻微损害出现。具有GRIN2A突变的儿童的癫痫特征包括通常在3岁和6岁之间开始的癫痫发作,伴有语言和/或整体发育退化的局灶性癫痫,以及脑电图学(EEG)示出睡眠中连续的棘波放电(spike-and-wave discharge)或非常活跃的中央颞部放电。
癫痫发作类型包括与口周感觉异常先兆相关的癫痫发作、局灶性癫痫发作或局灶性运动性癫痫发作(通常演变为全身强直阵挛性)和非典型失神性癫痫发作。
与GRIN2A突变相关的癫痫综合征包括:兰道-克勒夫纳综合征(Landau-Kleffnersyndrome)(LKS)、伴有睡眠期间连续棘波的癫痫性脑病(ECSWS)、伴有中央颞部棘波的儿童癫痫(CECTS)、伴有中央颞部棘波的非典型儿童癫痫(ACECTS)、伴有言语运用障碍的常染色体显性罗兰癫痫(autosomal dominant rolandic epilepsy with speech dyspraxia)(ADRESD)和婴儿期开始的癫痫性脑病。
诊断为GRIN2A突变癫痫的儿童通常是难治的,并且因此需要有效的治疗。
在过去的四十年中,有许多关于使用非精神活性大麻素大麻二酚(CBD)来治疗癫痫发作的动物研究。例如,Consroe等人(1982)确定,在施用促惊厥药物或电流之后,CBD能够防止小鼠的癫痫发作。
在过去的四十年中,也使用CBD进行了在癫痫成人中的研究。Cunha等人报告,向8名患有继发性全身癫痫的成人患者施用CBD导致患者中的4名的癫痫发作显著减少(Cunha等人,1980)。
1978年的一项研究向4名成人患者提供了200mg/天的纯CBD,4名患者中的2名癫痫发作消失,而其余患者的癫痫发作频率未改变(Mechoulam和Carlini,1978)。
与上文描述的研究相反,一项开放标签研究报告,200mg/天的纯CBD在控制12名缺乏自理能力的成人患者的癫痫发作方面是无效的(Ames和Cridland,1986)。
按时间顺序,最近的着眼于CBD在癫痫患者中的有效性的研究证明CBD不能控制癫痫发作,基于这一事实,将不期望CBD可以用作抗惊厥剂。
在过去四十年的研究中,已经有超过三十种药物被批准用于治疗癫痫,其中没有一种是大麻素。事实上,似乎对于大麻素存在偏见,这可能是由于这些化合物的预定性质和/或作为已知精神活性剂的THC已经被归为促惊厥剂的事实(Consroe等人,1977)。
专利申请GB 2,487,712描述了CBD与抗癫痫药物一起的使用,并且WO 2015/193667描述了CBD在治疗难治性癫痫中的用途,特别是患有FIRES的患者显示出特别受益于该治疗。
最近发表的一篇论文表明,富含大麻二酚的大麻属可能在治疗癫痫中有效。Porter和Jacobson(2013)报告了经由Facebook群组进行的一项家长调查,该家长调查探讨了在患有难治性癫痫的儿童中使用富含CBD的大麻属。发现的是,19名被调查的家长中有16名报告他们孩子的癫痫有所改善。该论文所调查的儿童全都在服用据称含有高浓度的CBD的大麻属,尽管在许多情况下并不知道存在的CBD和包括THC在内的其他成分的量。事实上,虽然CBD水平在从0.5mg/kg/天至28.6mg/kg/天的范围内(在那些测试的提取物中),但报告THC水平高达0.8mg/kg/天。
Press等人的论文(2015)描述了对被提供口服大麻属提取物的75名儿童和青少年的综述(review)。伦诺克斯-加斯托综合征(Lennox-Gastaut syndrome)患者的应答率(responder rate)非常高,为88.9%,而其他儿童癫痫综合征(诸如多泽综合征(Doosesyndrome)和德拉韦综合征(Dravet syndrome))的应答率低得多,或者根本没有显示改善。
向患有TRE的儿童以0.8mg/kg/天的潜在精神活性剂量(psychoactive dose)提供含有THC(其已经被描述为促惊厥剂(Consroe等人,1977))的大麻属提取物是一个令人关切的问题,并且因此需要确定CBD实际是否有效。
更近地在2016年3月,GW Pharmaceuticals宣布了CBD在治疗德拉韦综合征中的第3阶段研究的积极结果。
迄今为止,还没有在患有与GRIN2A突变相关的癫痫的儿童和年轻成人中的CBD的试验或研究。
申请人已经表明,施用特定的CBD组合物对患有GRIN2A突变相关的难治性癫痫的儿童的治疗具有显著影响。
所使用的CBD呈大麻属的高度纯化的提取物的形式,使得CBD以总提取物的大于98%(w/w)存在,并且该提取物的其他组分被表征。特别地,大麻素四氢大麻酚(THC)以从0.02%至0.1%(w/w)的量存在。
本公开内容的简述
根据本发明的第一方面,提供了用于治疗与GRIN2A突变相关的癫痫的大麻二酚(CBD)。
在另外的实施方案中,CBD用于治疗与GRIN2A突变相关的癫痫的非癫痫发作症状。
优选地,癫痫是难治性癫痫(TRE)。
在另外的实施方案中,CBD用于与一种或更多种伴随的抗癫痫药物(AED)组合使用。
在另外的实施方案中,CBD作为大麻属的高度纯化的提取物存在,该提取物包含至少98%(w/w)的CBD。优选地,提取物包含高达0.1%的THC。更优选地,提取物包含0.02%和0.1%之间(w/w)的THC。更优选地,提取物还包含高达1.0%(w/w)的CBDV。
在可选择的实施方案中,CBD作为合成化合物存在。
优选地,CBD的剂量大于5mg/kg/天。因此,对于15kg的患者,将提供每天大于75mg的CBD的剂量。大于5mg/kg/天的剂量,诸如大于10mg/kg/天、大于15mg/kg/天、大于20mg/kg/天和大于25mg/kg/天的剂量也被认为是有效的。
优选地,CBD的剂量在5mg/kg/天和50mg/kg/天之间。
根据本发明的第二方面,提供了一种治疗与GRIN2A突变相关的癫痫的方法,包括向受试者施用大麻二酚(CBD)。
优选地,受试者是人类,更优选地儿童或年轻成人。
附图简述
参考附图,在下文中进一步描述本发明的实施方案,在附图中:
图1示出了治疗之前患者的EEG;以及
图2示出了治疗之后患者的EEG。
定义
用于描述本发明的一些术语的定义在下文详细描述:
本申请中描述的大麻素连同其标准缩写在下文列出。
大麻素及其缩写
上表并非详尽的,并且仅详细描述了本申请中鉴定的大麻素,以供参考。迄今为止,已经鉴定出超过60种不同的大麻素,并且这些大麻素可以被分为如下不同的组:植物大麻素;内源性大麻素和合成大麻素(其可以是新颖的大麻素或合成产生的植物大麻素或内源性大麻素)。
“植物大麻素”是源于自然界的大麻素,并且可以在大麻属植物中发现。植物大麻素可以从植物中分离以产生高度纯化的提取物,或者可以合成重现。
“高度纯化的大麻素提取物”被定义为这样的大麻素:已经从大麻属植物中提取,并且被纯化到与大麻素共同提取的其他大麻素和非大麻素组分已经被大体上除去的程度,使得高度纯化的大麻素是大于或等于98%(w/w)纯的。
“合成大麻素”是具有大麻素或大麻素样结构并且使用化学手段制造而不是通过植物制造的化合物。
植物大麻素可以以中性形式(脱羧形式)或羧酸形式获得,这取决于用于提取大麻素的方法。例如,已知的是,加热羧酸形式将使大多数羧酸形式脱羧成中性形式。
“难治性癫痫(treatment-resistant epilepsy)”(TRE)、“难治性癫痫(refractory epilepsy)”或“难治性癫痫(intractable epilepsy)”根据2009年ILAE指南被定义为一种或更多种AED的试验未充分控制的癫痫。
“儿童癫痫”指的是可以在儿童时期发生以引起癫痫的许多不同的综合征和基因突变。其中一些的实例如下:德拉韦综合征;肌阵挛失神性癫痫;伦诺克斯-加斯托综合征;不明原因的全身癫痫;CDKL5突变;艾卡尔迪综合征(Aicardi syndrome);双侧多小脑回畸形;Dup15q;SNAP25;和与发热感染相关的癫痫综合征(FIRES);良性罗兰癫痫(benignrolandic epilepsy);青少年肌阵挛性癫痫;斯德奇-韦伯综合征(Sturge WeberSyndrome)(SWS);婴儿痉挛(韦斯特综合征(West syndrome));和兰道-克勒夫纳综合征。上文列表并非详尽的,因为存在许多不同的儿童癫痫。
“局灶性癫痫发作”被定义为源自仅局限于一个半球的网络内的癫痫发作。癫痫发作期间发生什么取决于癫痫发作发生在脑中的什么位置,以及脑的那个部分通常做什么。
“认知/意识受损的局灶性癫痫发作”已经替代了术语“复杂部分性癫痫发作”。这些癫痫发作通常始于脑的颞叶或额叶的小区域,并且涉及同一半球内影响警觉和认知的其他脑区域。大多数受试者在意识受损的局灶性癫痫发作期间经历自动行为(automatism)。
“癫痫发作频率下降百分比”被定义为第14周的癫痫发作次数减去基线的癫痫发作次数,除以基线的癫痫发作次数,乘以100。在对现有AED应答差的患者中,任何反应的改善,特别是改善没有副作用(诸如对中枢神经系统的运动副作用)的情况是高度合意的。
详述
高度纯化的CBD提取物的制备
以下描述了植物来源的高度纯化的(>98%w/w)大麻二酚提取物的产生,该提取物具有已知且恒定的组成,在以下实施例中使用。
总之,所使用的药物物质是大麻(Cannabis sativa L.)的高CBD含量化学型的液体二氧化碳提取物,其已经通过溶剂结晶方法进一步纯化以产生CBD。结晶过程特定地除去其他大麻素和植物组分,以产生大于98%的CBD。虽然CBD是高度纯化的,因为它是从大麻属植物中产生的,而不是合成产生的,但还存在少量的与CBD共同产生和共同提取的其他大麻素。这些大麻素及其在药物中存在的量的详细说明如下:
大麻素 | 浓度 |
CBDV | 0.2%–0.8%(w/w) |
CBD-C4 | 0.3%–0.4%(w/w) |
CBD-C1 | 0.1%–0.15%(w/w) |
Δ<sup>9</sup>THC | 0.02%–0.1%(w/w) |
药物产品的产生
药物产品作为口服溶液呈现。口服溶液表现形式(oral solution presentation)含有25mg/ml或100mg/ml的CBD,以及赋形剂芝麻油、乙醇、三氯蔗糖和调味剂。两种产品强度可用于允许在宽的剂量范围内进行剂量调整。
25mg/ml溶液适用于较低剂量,并且100mg/ml溶液适用于较高剂量。
药物产品配方如下文描述:
组分 | 定性组成 | 功能 | 质量标准参考 |
大麻二酚(CBD) | 25mg/ml或100mg/ml | 活性剂 | 内部 |
无水乙醇 | 79.0mg/ml* | 赋形剂 | Ph.Eur. |
三氯蔗糖 | 0.5mg/ml | 甜味剂 | 内部 |
草莓调味剂 | 0.2mg/ml | 调味剂 | 内部 |
芝麻油 | q.s至1.0ml | 赋形剂 | Ph.Eur. |
药物物质CBD不溶于水。选择芝麻油作为赋形剂以溶解药物物质。
需要甜味剂和水果调味剂来改善芝麻油溶液的适口性(palatability)。
需要乙醇来溶解甜味剂和调味剂。
组成可以是大体上等同的,这意味着功能性成分可以从上文指定的定性组成改变高达10%的量。
下文实施例1描述了包含大麻二酚(CBD)的高度纯化的大麻属提取物的用途。大麻二酚是所选择的化学变型中最丰富的非精神活性大麻素。先前在动物中的研究证明,CBD在多种物种和模型中具有抗惊厥效力。
实施例1描述了患有GRIN2A突变的儿童的病例研究,作为患有难治性癫痫的儿童的扩大准入治疗项目(expanded access treatment program)的一部分,该儿童被提供高度纯化的大麻二酚。
实施例1:大麻二酚在减少患有与GRIAN2A突变相关的癫痫的儿童和年轻成人的癫痫发作和其他症状中的效力
材料和方法
14岁的儿童被纳入CBD的扩大准入同情使用项目(expanded accesscompassionate use program)。该受试者用从大麻属植物中获得的大麻二酚(CBD)的高度纯化的提取物进行治疗。每次访问时记录癫痫发作的频率,以及报告的生活质量变化,包括情绪、行为和认知功能。
患者在4岁时首次表现癫痫发作。他经历了癫痫持续状态,伴有肌阵挛性抖动和非典型失神性癫痫发作,持续30秒至15分钟之间。
患者已经尝试并且失败了10种不同的抗癫痫药物、生酮饮食(ketogenic diet)、维生素B6和迷走神经刺激,然而他的癫痫发作仍然是难治的。
患者具有最初的典型发育,然而,在4岁之后癫痫开始发作时,这种发育显著衰退。
2014年9月开始以5mg/kg/天的剂量使用已知且恒定组成的在芝麻油中的高度纯化的CBD提取物(大于98%CBD w/w)进行治疗,此外还开始其基线抗癫痫药物(AED)方案,并且已经进行持续4年。
日剂量以2mg/kg至5mg/kg增量逐渐增加,直至25mg/kg/天的最大剂量。
以2周-4周的规律间隔看望患者。在基线时和每4周的CBD疗法之后进行血液学、肝功能、肾功能和伴随的AED水平的实验室测试。
结果
图1示出了基线时记录的EEG。存在泛发性2Hz-2.5Hz慢棘波、左额颞叶放电和睡眠癫痫电持续状态(electrical status epilepticus)。
图2示出了用CBD治疗之后的重复EEG。EEG示出9Hzα活动的后向主导节律,与睁眼和闭眼的反应性,左额头部区稀少的癫痫样放电,以及没有先前记录的睡眠期间癫痫电持续状态。
自从治疗开始以来,患者已经没有癫痫发作持续4年。
除了氯巴占和VNS,所有的AED都已经停止。
除了癫痫发作的改善之外,患者的认知功能也已经显著改善。患者现在能够上正规学校,并且参加体育活动,这是他们在治疗之前不能做到的。
结论
这些数据指示CBD在治疗与GRIN2A突变相关的癫痫中是有效的。
令人惊讶的是,在这名非常难治的患者中,已经完全解决癫痫发作,伴随着认知的改善。
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Claims (11)
1.大麻二酚(CBD),用于在治疗与GRIN2A突变相关的癫痫中使用。
2.根据权利要求1所述的用于使用的大麻二酚(CBD),用于治疗与GRIN2A突变相关的癫痫的非癫痫发作症状。
3.根据前述权利要求中任一项所述的用于使用的CBD,其中所述癫痫是难治性癫痫(TRE)。
4.根据前述权利要求中任一项所述的用于使用的CBD,其中所述CBD用于与一种或更多种伴随的抗癫痫药物(AED)组合使用。
5.根据前述权利要求中任一项所述的用于使用的CBD,其中所述CBD作为大麻属的高度纯化的提取物存在,所述提取物包含至少98%(w/w)的CBD。
6.根据权利要求5所述的用于使用的CBD,其中所述提取物包含高达0.1%(w/w)的THC。
7.根据权利要求6所述的用于使用的CBD,其中所述THC以0.02%和0.1%(w/w)之间的浓度存在。
8.根据权利要求5或6所述的用于使用的CBD,其中所述提取物还包含高达1%(w/w)的CBDV。
9.根据权利要求1至4中任一项所述的用于使用的CBD,其中所述CBD作为合成化合物存在。
10.根据前述权利要求中任一项所述的用于使用的CBD,其中CBD的剂量在5mg/kg/天和50mg/kg/天之间。
11.一种治疗与GRIN2A突变相关的癫痫的方法,包括向受试者施用大麻二酚(CBD)。
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GB202002754D0 (en) | 2020-02-27 | 2020-04-15 | Gw Res Ltd | Methods of treating tuberous sclerosis complex with cannabidiol and everolimus |
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