CN111787911B - 包含大麻素的药物组合物 - Google Patents
包含大麻素的药物组合物 Download PDFInfo
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- CN111787911B CN111787911B CN201980015028.3A CN201980015028A CN111787911B CN 111787911 B CN111787911 B CN 111787911B CN 201980015028 A CN201980015028 A CN 201980015028A CN 111787911 B CN111787911 B CN 111787911B
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- formulation
- oil
- poloxamer
- acid
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Abstract
本发明涉及一种新颖的大麻素口服药物剂型,该大麻素口服药物剂型基于如使用脂质制剂分类系统分类的IV型制剂或IV型样制剂。所述制剂被包含在容器中。IV型样意指所述制剂不包含油,例如不包含甘油三酯或混合的甘油酯。
Description
发明领域
本发明涉及包含在容器中的口服药物制剂。该口服药物制剂包含大麻素。
发明背景
大麻素是已知难溶于水(小于1μg/mL)的亲脂性物质。作为实例,大麻二酚(CBD)可溶于乙醇(36mg/mL)和二甲基亚砜DMSO(60mg/mL)。
首先,口服服用的药物物质的生物利用度取决于药学上活性物质穿过肠粘膜从肠环境被吸收的程度。亲脂性药物物质通常从肠环境中被不良地吸收,尤其是因为它们在水中差的溶解度和/或分散性。此外,口服服用的药物物质的生物利用度取决于该物质对所谓的首过效应的易感性。从肠中吸收的物质在被分布在整个身体之前,必须首先经过肝,在肝中所述物质可以被立即代谢。通常假定CBD对首过肝代谢是相当易感的。CBD的口服生物利用度是低的且不可预测的(S.Zhornitsky,S.Potvin,Pharmaceuticals(2012)5,529-552)。此外,CBD是一种不稳定的药物(A.J.Poortman,H.Huizer,Forensic ScienceInternational(1999)101,1-8)。
在WO 2012/033478中,自乳化药物递送系统(SEDDS)已经被用于提供大麻素的改进的施用。
SEDDS(自乳化药物递送系统)通常由填充有液体或凝胶的硬胶囊或软胶囊组成,该液体或凝胶由亲脂性活性药物成分(API)、油(为了溶解API)和表面活性剂组成。在与胃液接触后,SEDDS由于表面活性剂的存在而自发地乳化。然而,许多表面活性剂是基于脂质的,并且与胃肠道(GIT)中的脂肪酶相互作用。这可能导致基于脂质的表面活性剂乳化API以及油载体的能力降低,两者均降低生物利用度。
在WO 2015/184127中,公开了包含大麻素、聚乙二醇和丙二醇的不含醇的制剂。
在WO 2012/033478中,使用了基于I型、II型和III型的SEDDS制剂。
在PCT/GB2017/051943(至今仍未公布)中,公开了包含大麻素的IV型制剂或IV型样制剂。
与本发明的背景相关的其他文件是CN103110582;CN101040855;US2012/183606;Thumma S等人,European Journal of Pharmaceutics and Biopharmaceutics.第70卷,第2期,2008年10月1日,第605-614页;以及Edward Maa等人,Epilepsia,第55卷,第6期,2014年6月1日,第783-786页。
脂质制剂分类系统(LFCS)被引入以帮助确定脂质系统的特性(C.W.Pouton,Eur.J.Pharm.Sci.,11(增刊2)(2000),第S93–S98页)。如LFCS中所分类的,I型制剂是需要消化的油,II型制剂是水不溶性自乳化药物递送系统(SEDDS),III型系统是SEDDS或自微乳化药物递送系统(SMEDDS)或自纳米乳化药物递送系统(SNEDDS),III型系统包含一些水溶性表面活性剂和/或助溶剂(IIIA型)或更大比例的水溶性组分(IIIB型)。类别IV型代表趋向主要包含亲水性赋形剂表面活性剂和助溶剂的制剂的最新趋势。下文是取自US 2015/111939的表格式脂质制剂分类系统概述:
制剂的含量(wt.-%)
脂质制剂分类系统的另外的描述还可以在FABAD J.Pharm.Sci.,第55-64页,2013中找到。
如在上表中可以看出的,IIIB型制剂包含基于总组合物的<20wt%的油。然而,应该注意的是,根据定义,IIIB型制剂包含一定的油,即使仅非常少的量。
对水分、氧气和/或光敏感的药物物质的暴露可以导致严重后果。例如,暴露可能引起产品的软化和解聚,并且可以使活性成分降解,例如通过水解、光解和氧化来降解。最终,如果药物被证明不稳定,则它可能不能通过临床试验。对暴露于环境的药物产品的损害可以通过测量药物产品成分例如活性成分的降解物的量以及成分本身的量来定量。此外,等分试样可以在指定的时间段被获取并分析,以获得在某些条件下储存的药物产品的稳定性概况。
大麻素易于通过暴露于环境而降解,例如通过暴露于光、热、氧气和/或水分而降解。
大麻素四氢大麻酚(THC)在暴露于环境因素时被降解为大麻素大麻酚(CBN)。这种大麻素结合到不同的受体并且对人体具有不同的生理效应,并且因此当大麻素被用作药物活性成分时,大麻素的降解是有害的。
存在提供对包含大麻素的药物制剂的保护,以保持药物产品的物理稳定性和化学稳定性的需求。
存在提供呈现出改进的性质诸如生物利用度、储存稳定性和均匀性的包含大麻素的口服药物制剂的需求。
发明简述
本发明涉及一种新颖的大麻素口服药物剂型,该大麻素口服药物剂型基于如使用脂质制剂分类系统分类的IV型制剂或IV型样制剂。所述制剂被包含在容器中。IV型样意指所述制剂不包含油,例如不包含甘油三酯或混合的甘油酯。当使用IV型样制剂时,其可以包含基于总组合物的超过50wt%的溶剂,如LFCS表中所指定的。
口服药物剂型或制剂包含至少一种大麻素;至少一种泊洛沙姆;以及溶剂,其中溶剂根据式(I)定义
其中R1和R2独立地选自氢、C(O)CH3、OH、C(O)CH3、CH2OH和C(O)OCH2CH3;R3独立地选自CH3、CH2OH、OH、CH2OC(O)CH3和CH2C(O)CH2CH3;并且R4独立地选自氢和C(O)OCH2CH3。口服药物制剂被包含在容器中。
本发明还涉及包含药物制剂的口服药物单位剂型,所述药物制剂包含至少一种大麻素;至少一种泊洛沙姆;以及溶剂,其中溶剂根据式(I)定义
其中R1和R2独立地选自氢、C(O)CH3、OH、C(O)CH3、CH2OH和C(O)OCH2CH3;R3独立地选自CH3、CH2OH、OH、CH2OC(O)CH3和CH2C(O)CH2CH3;并且R4独立地选自氢和C(O)OCH2CH3。单位剂型被包含在容器中。
本发明还涉及药物包装,其中所述药物包装包含口服药物制剂(或包含口服药物制剂的至少一种单位剂型),所述口服药物制剂包含至少一种大麻素;至少一种泊洛沙姆;以及溶剂,其中溶剂根据式(I)定义
其中R1和R2独立地选自氢、C(O)CH3、OH、C(O)CH3、CH2OH和C(O)OCH2CH3;R3独立地选自CH3、CH2OH、OH、CH2OC(O)CH3和CH2C(O)CH2CH3;并且R4独立地选自氢和C(O)OCH2CH3。
与基于如通过脂质制剂分类系统分类的I型、II型、IIIA型和IIIB型的其他制剂相比,该制剂提高大麻素的生物利用度。因此,口服药物剂型或制剂不是基于油的,即它大体上不包含油。“大体上无油”或“大体上不含油”意指制剂包含基于总组合物的少于2wt%、优选地少于1wt%的油。这样的制剂被分类为IV型或IV型样。
通过提高生物利用度,可以减少在特定疾病的治疗中的某一时间窗期间所需的大麻素和赋形剂的总量。
根据本发明的制剂在多种条件下,特别是在干燥储存条件下呈现出优异的稳定性。
通过提高稳定性,可以增加制剂适于消耗特别是口服施用的时间长度。
发明详述
大麻素
根据本发明的制剂包含至少一种选自由以下组成的组的大麻素:大麻环萜酚(CBC)、大麻环萜酚酸(CBCV)、大麻二酚(CBD)、大麻二酚酸(CBDA)、次大麻二酚(CBDV)、次大麻二酚酸(CBDVA)、大麻萜酚(CBG)、大麻萜酚丙基变体(CBGV)、大麻环醇(CBL)、大麻酚(CBN)、大麻酚丙基变体(CBNV)、二羟基大麻酚(CBO)、四氢大麻酚(THC)、四氢大麻酚酸(THCA)、四氢次大麻酚(THCV)和四氢次大麻酚酸(THCVA)。该清单不是详尽的,并且仅详细说明了在本申请中被确定用于参考的大麻素。迄今为止,已经确定超过100种不同的大麻素,并且这些大麻素可以被分成如下不同的组:植物大麻素;内源性大麻素;和合成大麻素。优选地,本发明中使用的大麻素是选自由植物大麻素和内源性大麻素组成的组的至少一种。植物大麻素和内源性大麻素可以被合成地产生或从它们的天然来源高度纯化。
根据本发明的制剂还可以包含至少一种选自在Handbook of Cannabis,RogerPertwee,第1章,第3至15页中公开的那些的大麻素。
优选的是,制剂仅包含一种或两种大麻素,该一种或两种大麻素优选地选自由以下组成的组:大麻二酚(CBD)、次大麻二酚(CBDV)、四氢大麻酚(THC)、四氢次大麻酚(THCV)、大麻萜酚(CBG)和大麻二酚酸(CBDA)或其组合。优选的是,制剂包含大麻二酚和/或次大麻二酚。
优选的是,制剂包含四氢大麻酚(THC)(或其类似物,诸如THCV、THCA和THCVA)和大麻二酚(CBD)(或其类似物,诸如CBDV、CBDA和CBDVA)。
优选的是,大麻素以基于总组合物的从约5wt%至80wt%、优选地从约10wt%至50wt%、更优选地从约20wt%至30wt%的量存在。大麻素可以以约30wt%的量存在。
优选地,大麻素被合成地产生或从其天然来源高度纯化(例如,植物来源的重结晶形式,诸如CBD的植物来源的重结晶形式)。当使用高度纯化的来源时,将它纯化,使得大麻素以总提取物的大于95%、更优选地大于98%存在(w/w)。使用合成地产生的或高度纯化的大麻素是有利的,因为这些大麻素包含相对少量的蜡。这有助于防止油性制剂的形成,增加制剂的物理稳定性和在含水环境中的润湿性。
当制剂包含四氢大麻酚(THC)(或其类似物)和大麻二酚(CBD)(或其类似物)时,优选的是THC:CBD的重量比在从100:1至1:100、优选地60:1至1:60的范围内。
当制剂包含四氢大麻酚(THC)(或其类似物)和大麻二酚(CBD)(或其类似物)时,优选的是THC:CBD的重量比在从20:1至1:20、更优选地5:1至1:5的范围内。例如,THC:CBD的比可以是1:1。
口服药物制剂中大麻素的单位剂量可以在从0.001mg至350mg、优选地0.1mg至350mg、更优选地1mg至250mg的范围内。
例如,设想的是当处于片剂或胶囊单位剂型时,存在的大麻素的量可以是0.5mg、2mg、10mg、25mg、50mg、100mg、150mg、200mg、250mg、300mg或350mg。
制剂中存在的大麻素的量可以是基于总组合物的20wt%至30wt%。已经发现,即使当大麻素的含量是相对高的诸如25wt%、30wt%或35wt%时,制剂是稳定的并且在室温和室压力(在本文中被定义为20℃和1个大气压)是固体。不希望受理论所束缚,据信特别是对于高大麻素含量,至少一种泊洛沙姆对制剂的稳定性是至关重要的。
溶剂
根据本发明的制剂包含根据式(I)定义的溶剂
其中R1和R2独立地选自氢、C(O)CH3、OH、C(O)CH3、CH2OH和C(O)OCH2CH3;R3独立地选自CH3、CH2OH、OH、CH2OC(O)CH3和CH2C(O)CH2CH3;并且R4独立地选自氢和C(O)OCH2CH3。
溶剂可以选自由以下组成的组:二乙酸甘油酯(diacetin)、丙二醇、三乙酸甘油酯(triacetin)、单乙酸甘油酯(monoacetin)、二乙酸丙二醇酯、柠檬酸三乙酯及其混合物。
二乙酸甘油酯也被称为二乙酸甘油酯(glycerol diacetate)。
三乙酸甘油酯也被称为1,2,3-三乙酰氧基丙烷、1,2,3-三乙酰基甘油或三乙酸甘油酯(glycerol triacetate)。
单乙酸甘油酯也被称为单乙酸甘油酯(glycerol monoacetate)或乙酸甘油酯(glycerol acetate)。
柠檬酸三乙酯也被称为柠檬酸乙酯。
丙二醇、二乙酸丙二醇酯和柠檬酸三乙酯是优选的溶剂。优选地,溶剂是柠檬酸三乙酯或丙二醇。优选地使用柠檬酸三乙酯。
溶剂可以以基于总组合物的从约10wt%至80wt%、优选地约20wt%至80wt%、更优选地约20wt%至65wt%、甚至更优选地约20wt%至50wt%、最优选地约20wt%至30wt%的量存在。溶剂可以以约25wt%的量存在。
当所使用的溶剂是二乙酸甘油酯时,优选的是该溶剂以基于总组合物的从约20wt%至50wt%的量存在。
当所使用的溶剂是丙二醇时,优选的是该溶剂以基于总组合物的从约20wt%至30wt%的量存在。
当溶剂是三乙酸甘油酯时,优选的是该溶剂以基于总组合物的从约20wt%至50wt%的量存在。
当溶剂是柠檬酸三乙酯时,优选的是该溶剂以基于总组合物的从约20wt%至50wt%、更优选地约20wt%至30wt%的量存在。
当溶剂是二乙酸丙二醇酯时,优选的是该溶剂以基于总组合物的从约20wt%至50wt%的量存在。
当仅存在一种泊洛沙姆时,如下文将描述的,优选的是溶剂以基于总组合物的从约45wt%至55wt%、优选地45wt%至50wt%的量存在。
根据要求保护的发明的溶剂或溶剂混合物可以是制剂中唯一的溶剂。例如,制剂可以大体上不含水、大体上不含醇和/或大体上不含油。“大体上不含水”、“大体上不含醇”和“大体上不含油”意指制剂包含基于总组合物的少于2wt%、优选地少于1wt%的水、醇和/或油。
制剂优选地大体上不含乙醇。更优选地,制剂大体上不含醇。
在一些实施方案中,制剂用于儿科患者,即18岁以下的患者。在儿科患者中,可能优选的是,制剂大体上不含醇。
制剂可以大体上不含甘油三酯、甘油二酯或甘油单酯或其混合物或者不包含甘油三酯、甘油二酯或甘油单酯或其混合物,该甘油三酯、甘油二酯或甘油单酯或其混合物衍生自甘油和至少一种选自由以下组成的组的脂肪酸:辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、蜡酸、肉豆蔻油酸、棕榈油酸、顺式-6-十六碳烯酸(sapienic acid)、油酸、反油酸、异油酸、亚油酸、反亚油酸(linoelaidic acid)、α-亚麻酸、花生四烯酸、二十碳五烯酸、芥酸和二十二碳六烯酸及其混合物。优选地,制剂可以大体上不含甘油三酯、甘油二酯或甘油单酯或其混合物或者不包含甘油三酯、甘油二酯或甘油单酯或其混合物。
制剂可以大体上不含氢化植物油、坚果油、茴香油、大豆油、氢化大豆油、杏核油、玉米油、橄榄油、花生油、杏仁油、核桃油、腰果油、米糠油、罂粟籽油、棉籽油、芥花油、芝麻油、氢化芝麻油、椰子油、亚麻籽油、肉桂油、丁香油、肉豆蔻油、芫荽油、柠檬油、橙油、红花油、可可脂、棕榈油、棕榈核油、葵花油、菜籽油、蓖麻油、氢化蓖麻油、聚氧乙烯蓖麻油衍生物、琉璃苣油、蜂蜡、羊毛脂、凡士林、矿物油和轻质矿物油。
更优选地,制剂可以不含衍生自甘油和辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、蜡酸、肉豆蔻油酸、棕榈油酸、顺式-6-十六碳烯酸、油酸、反油酸、异油酸、亚油酸、反亚油酸、α-亚麻酸、花生四烯酸、二十碳五烯酸、芥酸和二十二碳六烯酸及其混合物的甘油三酯、甘油二酯或甘油单酯或其混合物,氢化植物油,坚果油,茴香油,大豆油,氢化大豆油,杏核油,玉米油,橄榄油,花生油,杏仁油,核桃油,腰果油,米糠油,罂粟籽油,棉籽油,芥花油,芝麻油,氢化芝麻油,椰子油,亚麻籽油,肉桂油,丁香油,肉豆蔻油,芫荽油,柠檬油,橙油,红花油,可可脂,棕榈油,棕榈核油,葵花油,菜籽油,蓖麻油,氢化蓖麻油,聚氧乙烯蓖麻油衍生物,琉璃苣油,蜂蜡,羊毛脂,凡士林,矿物油和轻质矿物油。
甚至更优选地,制剂可以是不含油的。
泊洛沙姆
根据本发明的制剂包含至少一种泊洛沙姆。
泊洛沙姆根据式(II)定义
其中a是从10至110的整数,并且b是从20至60的整数。
优选的是,当a是12时,b是20。当a是12并且b是20时,这被称为泊洛沙姆124。
还优选的是,当a是80时,b是27。当a是80并且b是27时,这被称为泊洛沙姆188。
制剂可以包含两种泊洛沙姆。当制剂包含两种泊洛沙姆时,优选的是它们是泊洛沙姆124和泊洛沙姆188。
可用于本发明的其他已知的泊洛沙姆是泊洛沙姆237(a=64;并且b=37)、泊洛沙姆338(a=141;并且b=44)和泊洛沙姆407(a=101;并且b=56)。
已知并且可以可用于本发明的另外的泊洛沙姆包括泊洛沙姆108、泊洛沙姆182、泊洛沙姆183、泊洛沙姆212、泊洛沙姆217、泊洛沙姆238、泊洛沙姆288、泊洛沙姆331、泊洛沙姆338和泊洛沙姆335。
存在的泊洛沙姆的总量可以是以基于总组合物的从约25wt%至75wt%的量。优选地,存在的泊洛沙姆的总量可以在基于总组合物的从约25wt%至60wt%或30wt%至60wt%的范围内。更优选地,存在的泊洛沙姆的总量为从约40wt%至约50wt%。存在的泊洛沙姆的总量可以为约45wt%。
当制剂包含泊洛沙姆124和泊洛沙姆188时,泊洛沙姆124的量可以为基于总组合物的5wt%,并且泊洛沙姆188的量可以为基于总组合物的40wt%。
在一些情况下,制剂可以仅包含一种泊洛沙姆,其中泊洛沙姆是泊洛沙姆188。
已经发现,当使用泊洛沙姆407时,优选的是存在泊洛沙姆124。
已经发现,本发明的制剂具有优异的再水合性质。制剂快速地且均匀地再水合。在再水合后,制剂具有优异的释放性质。
已经发现,本发明的制剂具有优异的稳定性。不希望受理论所束缚,据信,制剂中至少一种泊洛沙姆的存在提供优异的稳定性。
容器(药物包装)
根据本发明的药物制剂被包含在容器(也被称为“药物包装”)中。优选地,容器是密封的容器。
容器(药物包装)是可以容纳本发明的制剂的不可摄取的包容装置。容器(药物包装)的实例包括小袋、瓶子、桶、安瓿、泡罩包装等。优选地,容器是瓶子或泡罩包装。最优选地,容器是泡罩包装。
容器优选地保护药物制剂免受水分。优选地,在环境储存条件例如约25℃和60%RH下,持续至少1年、优选地至少2年的时间段,容器中药物制剂的含水量增加少于5%、优选地少于3%、更优选地少于2%。容器中药物制剂的含水量可以根据ICH指南Q1A-Q1F来测量。
有利地,尽管根据本发明的制剂当不被包含在容器中,即作为独立产品时,呈现出良好的储存稳定性,但是储存稳定性可以通过将制剂包含在容器中来进一步改进。例如,在储存期间API降解物(诸如CBE I、CBE II、OH-CBD和RRT 0.96)的增加可以通过将制剂包含在容器中来减少。
容器可以是瓶子,例如塑料瓶、金属瓶或玻璃瓶。优选地,瓶子由高密度聚乙烯(HDPE)、聚对苯二甲酸乙二醇酯(PET)、聚丙烯(PP)或玻璃制成。瓶子包装是本领域技术人员已知的。
最优选地,容器(药物包装)是泡罩包装。泡罩包装是本领域技术人员已知的。“泡罩包装”涵盖若干种类型的用于消费用商品、食品和药物的预成型的包装。术语“泡罩包装”包括推落式(push-through)泡罩包装、剥离-推按式(peel-push)泡罩包装、撕开式(tear-open)泡罩包装、可剥离的泡罩包装和/或防儿童开启的(child resistant)泡罩包装。泡罩包装的基本构造包括成形膜和封盖材料,该成形膜具有多个通常被称为“口袋”或“泡罩”的腔,用于容纳单位剂型,该封盖材料提供泡罩包装被建立于其上的基础部件。封盖材料被布置在成形膜的包括至少一个腔的凹面的面上。使用本领域中已知的合适方法诸如通过热封,将封盖材料粘合、密封或固定至成形膜。成形膜和封盖材料的构造可变。例如,这些部件中的一个或两个可以包括层压的结构,该层压的结构包括多种材料诸如纸、聚合物和金属的层。可选择地,这些部件中的一个或两个可以包括单层。泡罩包装部件的构造决定了其针对环境例如针对水分、氧气和/或光的“屏障”性质。
一种类型的成形膜是聚氯乙烯(PVC)成形膜。由于PVC的低成本和容易成形性,PVC在制药工业中通常被用作泡罩成形材料。PVC作为成形材料为泡罩包装中的药物产品提供针对氧气进入的良好保护,但提供有限的防潮保护(moisture protection)。PVC成形膜可以是透明的或不透明的。PVC成形膜为药物产品提供可接受的保护,但为对水分敏感的药物产品仅提供有限的保护。
另一种类别的成形膜是包含铝的成形膜。当铝被用作成形材料时,它为水分和氧气进入提供大体上完全的屏障。令人惊讶的是,本发明人已经发现这些特性将导致根据本发明的制剂的延长的保质期。不希望受理论所束缚,屏障保护差异背后的原因是由于两种材料的不同化学组成。通过铝的渗透因为分子之间的小的空隙而被阻碍。
泡罩包装可以包括腔成形膜和封盖材料。成形膜可以包含至少一个腔。
成形膜和封盖材料可以由不同的材料制成,或者可以由相同的材料制成。成形膜可以具有层压的结构,或者可以由单层的材料制成。封盖材料可以具有层压的结构,或者可以由单层的材料制成。
成形膜可以包含聚合物、纸、铝或其组合。聚合物优选地选自由以下组成的组:聚乙烯(PE)、聚氯乙烯(PVC)、聚三氟氯乙烯(PCTFE)、聚偏二氯乙烯(PVDC)、高密度聚乙烯(HDPE)、聚苯乙烯(PS)、聚丙烯(PP)、聚对苯二甲酸乙二醇酯(PET)、聚碳酸酯或其组合。
成形膜可以包含PVC、铝或其组合。
优选地,成形膜由包含PVC和PVDC、更优选地PVC、PVDC和PE的层压的材料制成。当成形膜由层压的材料制成时,优选的是封盖材料包含铝。
优选地,成形膜包含铝。当成形膜包含铝时,优选的是封盖材料包含铝。
封盖材料可以包含聚合物、纸、铝或其组合。聚合物可以选自由以下组成的组:聚乙烯(PE)、聚氯乙烯(PVC)、聚三氟氯乙烯(PCTFE)、聚偏二氯乙烯(PVDC)、高密度聚乙烯(HDPE)、聚苯乙烯(PS)、聚丙烯(PP)、聚对苯二甲酸乙二醇酯(PET)、聚碳酸酯或其组合。优选地,封盖材料包含铝。
优选地,成形膜和封盖材料两者均包含铝。
优选地,泡罩包装是冷成形箔泡罩包装(cold-form foil blister pack)(也被称为“alu-alu”泡罩包装或“铝/铝”泡罩包装或“Al/Al”泡罩包装)。
有利地,当容器是泡罩包装时,本发明的制剂,例如呈单位剂型的本发明的制剂,可以单独地被去除,并且因此不污染被另外包含在密封的腔中的其他形式。此外,施用形式彼此分离,防止相互的相互作用,诸如磨损或粘附。
有利地,当成形膜和封盖材料两者均包含铝时,相对于作为独立产品的制剂,根据本发明的制剂的储存稳定性被改进,并且甚至比当制剂被储存在另一种类型的容器例如在成形膜和封盖材料两者中均不包含铝的容器中时更好。不希望受理论所束缚,本发明人相信这是因为对水分和氧气的渗透性被显著降低。
容器可以包含干燥剂,例如小袋或罐中的干燥剂。
干燥剂是从空气去除水分的任何干燥剂。干燥剂的实例包括活性炭、氯化钙、金属氧化物诸如碱土金属氧化物(诸如氧化钙)、碱土金属氢氧化物(诸如氢氧化钙)、碱土金属的硫酸盐(诸如硫酸镁、硫酸钙)、二氧化硅(硅胶)、氧化铝和二氧化硅的键合的产物(硅铝(silica alumina))、氧化铝(活性氧化铝)、天然沸石或合成沸石(分子筛3A、4A、SA、13X)、水铝英石、粘土、粘土和活性炭的混合物、硅胶和活性炭的混合物、硅胶和粘土的混合物、硅铝和活性炭的混合物、合成沸石和活性炭的混合物、水铝英石和活性炭的混合物(诸如添加有活性炭的水铝英石,或与活性炭捏合的水铝英石)、包含硅胶的浆料(诸如混合在纸纤维之间的超细硅胶,包装在纸管中的硅胶)、包含氯化钙的浆料(诸如用液体氯化钙浸渍、干燥并涂覆有膜的纸材料)和包含水铝英石的浆料(诸如用水铝英石液体浸渍、干燥并涂覆膜的浆料,包装在纸管中的水铝英石)。
优选地,干燥剂选自由以下组成的组:硅胶、粘土干燥剂、硫酸钙、氯化钙、氧化钙、沸石、活性氧化铝、活性炭、氧化铝、铝土矿、无水硫酸钙、活性膨润土粘土、吸水性粘土、分子筛及其组合。更优选地,干燥剂选自由以下组成的组:硅胶、粘土干燥剂、硫酸钙、氯化钙、氧化钙、沸石、活性氧化铝、活性炭及其组合。
当容器是瓶子时,容器优选地包含干燥剂。
容器可以包含脱氧剂(oxygen absorber)。
脱氧剂从空气吸收并去除氧气。脱氧剂的实例包括基于金属的物质,该基于金属的物质通过与氧气经由化学键合进行反应(通常形成金属氧化物组分)来去除氧气。基于金属的物质包括元素铁以及氧化铁、氢氧化铁、碳化铁及类似物。用作脱氧剂的其他金属包括镍、锡、铜和锌。脱氧剂的另外的材料包括低分子量有机化合物诸如抗坏血酸、抗坏血酸钠、儿茶酚和苯酚;以及并入树脂和催化剂的聚合物材料。
抗氧化剂
制剂还可以包含抗氧化剂,优选地以基于总组合物的从约0.001wt%至5wt%、更优选地约0.001wt%至2.5wt%的量。
抗氧化剂可以选自由以下组成的组:丁基化羟基甲苯、丁基化羟基茴香醚、α-生育酚(维生素E)、抗坏血酸棕榈酸酯、抗坏血酸、抗坏血酸钠、乙二胺四乙酸、半胱氨酸盐酸盐、柠檬酸、柠檬酸钠、硫酸氢钠、焦亚硫酸钠、卵磷脂、没食子酸丙酯、硫酸钠、硫代甘油(monothioglycerol)及其混合物。
抗氧化剂的优选的组是α-生育酚(维生素E)、硫代甘油、抗坏血酸、柠檬酸及其混合物。优选的抗氧化剂是α-生育酚(维生素E)。
有利地,当制剂包含抗氧化剂时,制剂的稳定性仍可以进一步被改进。
另外的剂
制剂可以另外地包含调味剂,诸如薄荷。
制剂可以另外地包含甜味剂,诸如蔗糖。
形式
根据本发明的制剂可以呈选自由以下组成的组的口服剂型:粘膜粘附凝胶、片剂、粉末、液体凝胶胶囊、固体胶囊、口服溶液、颗粒剂或挤出物。口服剂型的优选的组是由凝胶胶囊和固体胶囊组成的组。
口服剂型优选地包含改性释放剂。
改性释放剂可以选自由以下组成的组:聚甲基丙烯酸酯衍生物、羟丙甲纤维素衍生物、聚乙酸乙烯酯衍生物、聚乙烯醚衍生物、纤维素衍生物、虫胶、结冷胶(gellan gum)、玉米醇溶蛋白、海藻酸和蜡。
改性释放剂可以选自由以下组成的组:聚甲基丙烯酸酯衍生物(诸如甲基丙烯酸和甲基丙烯酸酯的共聚物、甲基丙烯酸和甲基丙烯酸甲酯的共聚物或甲基丙烯酸和丙烯酸乙酯的共聚物);羟丙甲纤维素衍生物(诸如乙酸羟丙基甲基纤维素琥珀酸酯(HPMC-AS)和羟丙基甲基纤维素邻苯二甲酸酯(HPMCP));聚乙酸乙烯酯衍生物(诸如聚乙酸乙烯邻苯二甲酸酯(PVAP));聚乙烯醚衍生物(诸如甲基乙烯基醚和马来酸酐的共聚物);纤维素衍生物(诸如乙酸邻苯二甲酸纤维素(CAP)、乙酸对苯二甲酸纤维素、乙酸间苯二甲酸纤维素、乙酸丁酸纤维素(CAB)、乙酸偏苯三酸纤维素(CAT)、乙酸琥珀酸纤维素(CAS)、乙基纤维素、甲基纤维素);虫胶、结冷胶、玉米醇溶蛋白、海藻酸、蜡及其混合物。
改性释放剂可以选自由以下组成的组:甲基丙烯酸和甲基丙烯酸酯的共聚物、甲基丙烯酸和甲基丙烯酸甲酯的共聚物、甲基丙烯酸和丙烯酸乙酯的共聚物、乙酸羟丙基甲基纤维素琥珀酸酯(HPMC-AS)、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、聚乙酸乙烯邻苯二甲酸酯(PVAP)、甲基乙烯基醚和马来酸酐的共聚物、乙酸邻苯二甲酸纤维素(CAP)、乙酸丁酸纤维素(CAB)、乙酸偏苯三酸纤维素(CAT)、乙酸琥珀酸纤维素(CAS)、乙基纤维素、甲基纤维素、虫胶、结冷胶、玉米醇溶蛋白、海藻酸和蜡。
改性释放剂可以是耐酸剂。
改性释放剂可以是肠溶剂。
口服剂型的优选的组是由凝胶胶囊和固体胶囊组成的组。当口服药物组合物呈胶囊的剂型时,药物制剂被包含在胶囊中,并且胶囊包含改性释放剂(作为胶囊材料的一部分,或胶囊包括包含改性释放剂的包衣)。
胶囊可以包含改性释放剂作为胶囊材料的一部分,例如由包含改性释放剂的材料制成的胶囊。
胶囊可以涂覆有包含改性释放剂的包衣,例如不由包含改性释放剂的材料制成但是涂覆有包含改性释放剂的包衣的胶囊。
口服剂型可以是包含改性释放剂的胶囊,例如由包含改性释放剂的材料制成并且涂覆有包含改性释放剂的包衣的胶囊。
口服剂型可以是耐酸剂型。
口服剂型可以是肠溶剂型,诸如肠溶胶囊。
根据本发明的药物制剂可以被填充到具有改性释放包衣的胶囊中,其中该包衣包含至少一种改性释放剂。
根据本发明的药物制剂可以被填充到改性释放胶囊中,该改性释放胶囊包含至少一种改性释放剂作为胶囊材料的一部分。
优选地,改性释放胶囊包含改性羟丙基甲基纤维素(HPMC)(也被称为“羟丙基甲基纤维素衍生物”和“羟丙甲纤维素衍生物”)。例如,改性释放胶囊可以是包含乙酸羟丙基甲基纤维素琥珀酸酯(HPMC-AS)的胶囊。
优选地,改性释放胶囊包括包含乙酸邻苯二甲酸纤维素(CAP)的包衣。
优选的制剂
优选的是,根据本发明的IV型口服制剂在室温和室压力是固体,即优选地制剂在20℃和1个大气压是固体。这样的制剂在制造期间通常是流体,在室温是固体,并且在37℃再次变成流体。为了本发明的目的,凝胶被认为是固体。
制剂可以包含基于药物制剂的约20wt%至65wt%的溶剂和约25wt%至75wt%的泊洛沙姆。
制剂可以包含基于药物制剂的约20wt%至50wt%的溶剂和两种泊洛沙姆,其中泊洛沙姆的总量为基于药物制剂的约25wt%至60wt%。
制剂可以包含基于药物制剂的约20wt%至30wt%的溶剂和两种泊洛沙姆,其中泊洛沙姆的总量为基于药物制剂的约30wt%至60wt%。
优选地,制剂包含基于药物制剂的约20wt%至30wt%的大麻素、约20wt%至30wt%的溶剂和两种泊洛沙姆,其中泊洛沙姆的总量为基于药物制剂的约30wt%至60wt%。
优选地,制剂包含:至少一种大麻素,其中大麻素是CBD;至少两种泊洛沙姆,其中泊洛沙姆是泊洛沙姆124和泊洛沙姆188;以及溶剂,其中溶剂是柠檬酸三乙酯。更优选地,制剂包含:基于药物制剂的约20wt%至30wt%的CBD;约20wt%至30wt%的柠檬酸三乙酯;以及两种泊洛沙姆,其中泊洛沙姆是泊洛沙姆124和泊洛沙姆188,其中泊洛沙姆的总量为基于药物制剂的约30wt%至60wt%。
在高度优选的制剂中,制剂包含:基于药物制剂的约20wt%至30wt%的CBD;约20wt%至30wt%的柠檬酸三乙酯;抗氧化剂,其中抗氧化剂是α-生育酚;以及两种泊洛沙姆,其中泊洛沙姆是泊洛沙姆124和泊洛沙姆188,其中泊洛沙姆的总量为基于药物制剂的约40wt%至50wt%。在该优选的制剂中,制剂呈口服剂型的形式,其中口服剂型是胶囊;并且胶囊包含改性释放剂。在该优选的制剂中,口服剂型被包含在泡罩包装中。
优选地,制剂由至少一种大麻素;至少一种泊洛沙姆;溶剂;以及任选地抗氧化剂组成,其中溶剂根据式(I)定义
其中R1和R2独立地选自氢、C(O)CH3、OH、C(O)CH3、CH2OH和C(O)OCH2CH3;R3独立地选自CH3、CH2OH、OH、CH2OC(O)CH3和CH2C(O)CH2CH3;并且R4独立地选自氢和C(O)OCH2CH3。
以下代表根据本发明的能够在体温形成凝胶的优选的制剂。
优选的口服药物制剂(在室温为固体凝胶)包含:
25wt%的大麻二酚;
34wt%的泊洛沙姆124;
15wt%的泊洛沙姆188;以及
26wt%的丙二醇。
另外的优选的口服药物制剂(在室温为凝胶)包含:
25wt%的大麻二酚;
34wt%的泊洛沙姆124;
15wt%的泊洛沙姆188;以及
26wt%的二乙酸甘油酯。
另外的优选的口服药物制剂(在室温为半固体凝胶)包含:
25wt%的大麻二酚;
25wt%的泊洛沙姆124;
25wt%的泊洛沙姆407;以及
25wt%的丙二醇。
另外的优选的口服药物制剂(在室温为固体)包含:
25wt%的大麻二酚;
35wt%的泊洛沙姆124;
20wt%的泊洛沙姆188;以及
20wt%的丙二醇。
另外的优选的口服药物制剂(在室温为凝胶)包含:
35wt%的大麻二酚;
28wt%的泊洛沙姆124;
16wt%的泊洛沙姆188;以及
22wt%的丙二醇。
另外的优选的口服药物制剂(在室温为固体)包含:
12.5wt%的大麻二酚;
38wt%的泊洛沙姆124;
19wt%的泊洛沙姆188;以及
30wt%的丙二醇。
另外的优选的口服药物制剂(在室温为凝胶)包含:
25wt%的大麻二酚;
27wt%的泊洛沙姆188;以及
48wt%的二乙酸甘油酯。
另外的优选的口服药物制剂(在室温为凝胶)包含:
30wt%的大麻二酚;
27wt%的泊洛沙姆188;以及
43wt%的二乙酸甘油酯。
另外的优选的口服药物制剂(在室温为凝胶)包含:
25wt%的大麻二酚;
27wt%的泊洛沙姆188;以及
48wt%的三乙酸甘油酯。
另外的优选的口服药物制剂(在室温为半固体凝胶)包含:
25wt%的大麻二酚;
27wt%的泊洛沙姆188;以及
48wt%的丙二醇。
另外的优选的口服药物制剂(在室温为固体)包含:
25wt%的大麻二酚;
35wt%的泊洛沙姆124;
20wt%的泊洛沙姆188;以及
20wt%的柠檬酸三乙酯。
另外的优选的口服药物制剂(在室温为凝胶)包含:
25wt%的大麻二酚;
27wt%的泊洛沙姆188;以及
48wt%的柠檬酸三乙酯。
另外的优选的口服药物制剂(在室温为凝胶)包含:
25wt%的次大麻二酚;
27wt%的泊洛沙姆188;以及
48wt%的柠檬酸三乙酯。
另外的优选的口服药物制剂(在室温为固体)包含:
25wt%的次大麻二酚;
35wt%的泊洛沙姆124;
20wt%的泊洛沙姆188;以及
20wt%的丙二醇。
另外的优选的口服药物制剂(在室温为固体)包含:
20wt%的次大麻二酚;
35wt%的泊洛沙姆124;
25wt%的泊洛沙姆188;以及
20wt%的三乙酸甘油酯。
另外的优选的口服药物制剂(在室温为固体)包含:
25wt%的次大麻二酚;
35wt%的泊洛沙姆124;
20wt%的泊洛沙姆188;以及
20wt%的柠檬酸三乙酯。
治疗
制剂用于在疗法中使用,优选地用于在儿科癫痫中使用。
制剂还可以用于治疗选自由以下组成的组的疾病或紊乱:Dravet综合征、LennoxGastaut综合征、肌阵挛性发作、青少年肌阵挛性癫痫、难治性癫痫、精神分裂症、青少年痉挛、韦斯特综合征、婴儿痉挛、难治性婴儿痉挛、结节性硬化症复合体、脑肿瘤、神经性疼痛、大麻使用障碍、创伤后应激障碍、焦虑、早期精神病、阿尔茨海默病和孤独症。
如已经陈述的,大麻二酚对于在本发明中使用是优选的。大麻二酚可以用于治疗失张力性发作、失神性发作或部分性发作,特别是单纯性发作或复杂性发作。大麻二酚在减少患有包括以下的病因的患者的发作方面是特别有效的:Lennox-Gastaut综合征;结节性硬化症复合体;Dravet综合征;Doose综合征;CDKL5;Dup15q;Jeavons综合征;肌阵挛性失神性癫痫;神经元蜡样质脂褐质沉积症(NCL)和脑异常。
此外,包含CBDV和/或CBDA的制剂可以用于治疗孤独症谱系障碍,特别是雷特综合征、脆性X综合征、快乐木偶综合征、ADHD和多动障碍诸如图雷特综合征和肌张力障碍。因此,包含CBDV和/或CBDA的制剂可以在治疗这样的紊乱的方法中是有用的。
本发明的制剂可以在治疗患有紊乱的患者的方法中是有用的,所述紊乱选自由以下组成的组:Dravet综合征、Lennox Gastaut综合征、肌阵挛性发作、青少年肌阵挛性癫痫、难治性癫痫、精神分裂症、青少年痉挛、韦斯特综合征、婴儿痉挛、难治性婴儿痉挛、结节性硬化症复合体、脑肿瘤、神经性疼痛、大麻使用障碍、创伤后应激障碍、焦虑、早期精神病、阿尔茨海默病和孤独症。
当在制剂中使用大麻二酚时,制剂可以在治疗患者的失张力性发作、失神性发作或部分性发作,特别是单纯性发作或复杂性发作的方法中是有用的。该制剂在减少患有包括以下的病因的患者的发作的方法中是特别有效的:Lennox-Gastaut综合征;结节性硬化症复合体;Dravet综合征;Doose综合征;CDKL5;Dup15q;Jeavons综合征;肌阵挛性失神性癫痫;神经元蜡样质脂褐质沉积症(NCL)和脑异常。
治疗方法包括向患者施用治疗有效量的制剂或根据本发明的制剂中的大麻素。
定义
“大麻素”是一组化合物,包括内源性大麻素、植物大麻素以及既不是内源性大麻素也不是植物大麻素的在下文中称为“合成大麻素”的大麻素。
“内源性大麻素”是作为CB1受体和CB2受体的高亲和力配体的内源性大麻素。
“植物大麻素”是源于自然界并且可以在大麻属植物中找到的大麻素。植物大麻素可以存在于包括植物药物物质(botanical drug substance)的提取物中、被分离或合成地再产生。
“合成大麻素”是能够与大麻素受体(CB1和/或CB2)相互作用但并非内源性地存在或在大麻属植物中没有找到的那些化合物。实例包括WIN55212和利莫那班(rimonabant)。
“分离的植物大麻素”是已经从大麻属植物中提取并纯化至使得所有另外的组分诸如次级且次要(secondary and minor)大麻素级分以及非大麻素级分已经被去除的程度的植物大麻素。
“合成大麻素”是已经通过化学合成产生的大麻素。该术语包括将分离的植物大麻素改性,通过例如形成其药学上可接受的盐来改性。
“大体上纯的”大麻素被定义为以大于95%(w/w)纯度存在的大麻素、更优选地以大于96%(w/w)至97%(w/w)直至98%(w/w)至99%(w/w)纯度及更大的纯度存在的大麻素。
“高度纯化的”大麻素被定义为这样的大麻素,该大麻素已经从大麻属植物中提取并且纯化到与大麻素共提取的其他大麻素和非大麻素组分已经被大体上去除的程度,使得高度纯化的大麻素大于或等于95%(w/w)的纯度。
“植物药物物质”或“BDS”在2000年8月美国卫生与公众服务部食品与药物管理局药物评价与研究中心(US Department of Health and Human Services,Food and DrugAdministration Centre for Drug Evaluation and Research)的工业植物药物产品指南(Guidance for Industry Botanical Drug Products)草案指南中被定义为:“源自一种或更多种植物、海藻或微小真菌(microscopic fungi)的药物。该药物通过以下工艺中的一种或更多种由植物原材料制备:磨碎、煎煮、压榨(expression)、水提取、乙醇提取或其他类似工艺”。
植物药物物质不包括源自天然来源的高度纯化的或化学改性的物质。因此,在大麻属的情况下,源自大麻属植物的BDS不包括高度纯化的药典级大麻素。
“油”通常被定义为疏水性和亲脂性两者的单一化合物或化合物的混合物。示例性的油包括甘油三酯、甘油二酯、甘油单酯、脂肪酸和脂肪酸酯。甘油三酯、甘油二酯和甘油单酯是衍生自甘油和三当量、两当量或一当量脂肪酸的酯。对于每个酯键,甘油二酯和甘油三酯可以具有相同的脂肪酸或它们可以具有不同的脂肪酸。示例性的脂肪酸包括具有饱和的或不饱和的、直链的或支链的碳链的羧酸,诸如辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、蜡酸、肉豆蔻油酸、棕榈油酸、顺式-6-十六碳烯酸、油酸、反油酸、异油酸、亚油酸、反亚油酸、α-亚麻酸、花生四烯酸、二十碳五烯酸、芥酸和二十二碳六烯酸。油的示例性混合物包括植物和动物的脂肪和蜡,诸如植物油、氢化植物油、坚果油、茴香油、大豆油、氢化大豆油、杏核油、玉米油、橄榄油、花生油、杏仁油、核桃油、腰果油、米糠油、罂粟籽油、棉籽油、芥花油、芝麻油、氢化芝麻油、椰子油、亚麻籽油、肉桂油、丁香油、肉豆蔻油、芫荽油、柠檬油、橙油、红花油、可可脂、棕榈油、棕榈核油、葵花油、菜籽油、蓖麻油、氢化蓖麻油、聚氧乙烯蓖麻油衍生物、琉璃苣油、蜂蜡、羊毛脂、凡士林、矿物油和轻质矿物油。为了本发明的目的,大麻素不被认为是油。
“醇”具有在本领域内的其标准含义。醇包括乙醇、丙醇等。
“室温和室压力”在本文中被定义为20℃和1个大气压。
如本文所使用的“改性释放”指的是将口服剂型改性以在口服剂型的口服施用之后延迟释放药物,或释放药物持续延长的时间段,或释放药物至特定靶的过程和结果。为了本发明的目的,羟丙基甲基纤维素(HPMC)不被认为是改性释放剂。
如本文所使用的“耐酸的(Acid-resistant)”或“耐酸性(acid resistance)”意指口服剂型在具有小于5、优选地小于4、更优选地小于3、甚至更优选地小于2的pH的溶液中实质上不溶解(或崩解);但在具有超过5的pH的溶液中溶解。例如,口服剂型可以在胃酸中不溶解。
术语“肠溶”意指口服剂型在胃酸(处于进食状态或禁食状态)中或在胃中实质上不溶解(或崩解),但在肠(小肠、大肠)中溶解。例如,口服剂型可以在空肠或结肠等中实质上溶解。
实施例
1.实施例中使用的分析程序、大麻素和赋形剂
1.1.再水合(RH)程序
包含至少一种大麻素、至少一种溶剂和至少一种泊洛沙姆的IV型口服药物制剂(OPF)在第3类(Class-3)玻璃无色透明小瓶中通过在室温(RH-RT)添加20mL注射用水或通过在37℃(RH-37)添加20mL注射用水来再水合。将小瓶涡旋持续10秒。
1.2.测试OPF的外观
目视检查OPF的粘度、均匀性和透明度。
1.3.再水合的OPF的外观
在再水合之后,目视检查制剂的均匀性以及颗粒和/或未再水合的OPF的存在。泡沫的存在是使用足够的泊洛沙姆以使大麻素再水合的指示。
1.4.再水合流体中大麻素的释放
再水合流体中大麻素的释放被测试如下:
再水合的OPF被递交用于HPLC分析。设备:具有可变波长UV检测器或二极管阵列检测器的HPLC系统。柱:Ace C18-AR 150×4.6mm,3μm。前置柱:Ace C18-AR GuardCartridge。流动相:乙腈:0.25%乙酸(62%:38%)。柱温:38℃。流量:1.0ml min-1。检测:220nm。注射体积:10μl。运行时间25分钟。样品制备:一式三份地以约0.15mg/ml的浓度准确地制备测试样品。样品可以以较高的浓度制备,以确保相关物质或降解物的准确定量。0.1mL再水合的OPF用10mL乙醇稀释;将10μL注射到HPLC系统中。
1.5.大麻素
CBD:包含蜡的合成的、植物来源的CBD和植物来源的重结晶CBD(CBD-r)。植物来源的CBDV和合成的CBDV。
1.6.赋形剂
Lutrol L44(BASF,泊洛沙姆124:P124)、Lutrol F68(BASF,泊洛沙姆188:P188)、Lutrol F87(BASF,泊洛沙姆237:P237)、Lutrol F108(BASF,泊洛沙姆338:P338)、LutrolF127(BASF,泊洛沙姆407,P407)、甘油(Sigma:gly)、二乙酸甘油酯(Sigma:di)、三乙酸甘油酯(Sigma:tri)、丙二醇(Sigma:PG)、乙醇(Fischer)、二乙酸丙二醇酯(Sigma:PGDA)、柠檬酸三乙酯(Sigma:TEC)。
1.7.熔化程序
除非另外陈述,否则所有制剂使用以下方法来产生。将赋形剂和大麻素称重到容器中,并且加热直到熔化。在冷却后,将凝胶按重量填充到胶囊或小瓶中。凝胶的粘度是温度的函数,这使得能够灵活地填充到HPMC胶囊、明胶胶囊和软明胶胶囊中。
可选择地,可以制造基于凝胶的制剂,其中赋形剂和大麻素可以被溶解到有机溶剂诸如乙醇、甲醇、丙醇中,并且在蒸发掉有机溶剂以将凝胶留在小瓶中的工艺步骤的情况下被填充到玻璃小瓶中。
2.稳定性
测量作为独立产品的制剂的稳定性以及根据本发明储存在容器中的制剂的稳定性。稳定性研究表明,独立产品具有良好的储存稳定性,但是当产品被储存在容器中时,稳定性被改进,并且当容器是具有均包含铝的成形膜和封盖材料的泡罩包装(Alu/Alu泡罩包装)时,稳定性被进一步改进。
3.独立稳定性
OPF的稳定性根据ICH指南Q1A-Q1F评价。将样品在25℃±2℃/60%RH±5%、30℃±2℃/65%RH±5%RH和40℃±2℃/75%RH±5%储存。OPF的稳定性通过上文描述的化学分析和外观来评估。化学分析通过上文描述的指示稳定性的HPLC方法进行。除了在6个月时进行6次重复实验之外,每个时间点的重复实验数目为3次。样品制备:0.1mL再水合的OPF用10mL乙醇稀释;将10μL注射到HPLC系统中。
制备以下制剂用于独立稳定性研究。
IV型制剂(150mg/胶囊):30%w/w CBD;5%w/w P124;40%w/w P188;以及25%w/w柠檬酸三乙酯。
稳定性测试的目的是提供关于药物产品的质量在各种环境因素诸如温度和湿度的影响下如何随时间变化的证据。为了说明根据本发明的IV型制剂呈现出优异的稳定性,OPF的稳定性根据ICH指南Q1A-Q1F评价。
稳定性研究的结果在下文表1-表3中表示。表1呈现了在25℃±2℃/60%RH±5%储存的样品的数据。表2呈现了在30℃±2℃/65%RH±5%RH储存的样品的数据。表3呈现了在40℃±2℃/75%RH±5%储存的样品的数据。
表1
表2
表3
如表1-表3中示出的,根据本发明的IV型制剂呈现出优异的稳定性,即使在严苛的条件诸如40℃±2℃/75%RH±5%下。即使在40℃±2℃/75%RH±5%的储存条件下,在6个月之后回收98%的初始CBD含量。
总之,已经示出根据本发明的IV型制剂呈现出优异的稳定性。
4.容器中的稳定性
稳定性测试的目的是提供关于药物产品的质量在各种环境因素诸如温度和湿度的影响下如何随时间变化的证据。为了说明根据本发明包含在容器中的制剂呈现出优异的稳定性,测试稳定性。
在研究中评估了三个样品集。制备以下制剂用于容器中的稳定性研究。
样品1(150mg/胶囊):30%w/w CBD;5%w/w P124;40%w/w P188;以及25%w/w柠檬酸三乙酯。胶囊被包含在PVC泡罩包装中。
样品2(150mg/胶囊):30%w/w CBD;5%w/w P124;39.9%w/w P188;25%w/w柠檬酸三乙酯和0.1%w/wα-生育酚。胶囊被包含在PVC泡罩包装中。
样品3(150mg/胶囊):30%w/w CBD;5%w/w P124;39.9%w/w P188;25%w/w柠檬酸三乙酯和0.1%w/wα-生育酚。胶囊被包含在alu-alu泡罩包装中。
稳定性根据ICH指南Q1A-Q1F来评估。样品在40℃±2℃/75%RH±5%储存,这是加速研究的条件并且是高要求的。OPF的稳定性通过上文描述的化学分析和外观来评估。化学分析通过上文描述的指示稳定性的HPLC方法进行。每个时间点的重复实验数目为3次。样品制备:0.1mL再水合的OPF用10mL乙醇稀释;将10μL注射到HPLC系统中。
在0周、3周、9周、12周和24周获取的等分试样中测量CBE I、CBE II、OH-CBD和RRT0.96的量。
研究的结果在下文的表4中呈现。
在40℃±2℃/75%RH±5%储存持续24周之后,还测量根据本发明包含在容器中的制剂的重量。胶囊重量的增加指示水分进入。结果在下文的表5中呈现,并且表示为在24周时胶囊重量相对于在0周时胶囊重量的百分比增加。
表5
样品1 | 样品2 | 样品3 | |
胶囊重量的增加/% | 2.90 | 3.14 | 0.07 |
5.生物利用度
为了说明根据本发明的IV型制剂相对于I型制剂和III型制剂呈现出改进的生物利用度,进行比较并且测量每种制剂的生物利用度。生物利用度研究的结果在下文的表6中表示。
研究的结果也在图1中被描绘。如可以看出的,与具有相同CBD浓度的I型制剂和III型制剂相比,根据本发明的IV型制剂呈现出改进的生物利用度。如表6中示出的,受试者50的结果似乎是异常现象(anomaly),因为它超出改进的生物利用度的一般趋势。这在图1中清楚地示出,尽管包含异常现象。
总之,已经示出,如通过脂质制剂分类系统分类的IV型制剂呈现出CBD的改进的生物利用度。
5.1.用于测量生物利用度的PK研究的细节
比格犬(由Charles River UK提供)接受15mg/kg的目标水平的口服胶囊剂量。所使用的胶囊是‘0’号明胶胶囊,并且在施用每个胶囊之后,动物接受100mL水冲洗(waterflush)。在每个取样时间获取的血液体积为2mL,并且主要从颈静脉采集。在很少的情况下,采集头静脉样品。取样时间为:给药后0.5h、1h、1.5h、2h、2.5h、3h、4h、5h、6h、8h、12h和24h。对犬血浆中的CBD、6-OH CBD、THC和11OH THC的测定通过用具有串联质谱检测的反相液相色谱法进行蛋白沉淀来进行。CBD的LLOQ为1ng/ml,并且所有代谢物具有0.5ng/ml的LLOQ。
人体等效剂量(human equivalent dose)(HED)可以使用以下式估算:
犬的Km为20,并且人类的Km为37。
因此,对于人类而言,犬中的15mg/kg剂量相当于约8.1mg/kg的人类剂量。
5.2.用于测量生物利用度的制剂
将二乙酸甘油酯按重量称重到小瓶中,随后将P124直接称重到顶部上。将P188称重,并且添加至包含二乙酸甘油酯和P124的容器。最后,称重期望量的CBD,并且添加至容器,并且在涡旋下加热(100℃)直到熔化,以确保均匀的凝胶。在冷却后(30℃-40℃),将凝胶按重量填充到胶囊或小瓶中。凝胶的粘度是温度的函数,这使得能够灵活地填充到HPMC胶囊、明胶胶囊和软明胶胶囊中。在室温,低CBD剂量的凝胶是固体,而较高负载量的CBD制剂仍然是凝胶。
制备以下制剂用于PK研究。
IV型凝胶(125mg/g):12.5%w/w CBD;38%w/w P124;19%w/w P188;以及30%w/w二乙酸甘油酯。释放=99.3%。外观=固体凝胶。
IV型凝胶(250mg/g):25%w/w CBD;34%w/w P124;15%w/w P188;以及26%w/w二乙酸甘油酯。释放=97.4%。外观=透明凝胶。
在两种凝胶制剂中,所使用的CBD是高度纯化的形式。
III(i)型SEDDS(250mg/g):CBD用15wt%的油、45wt%的水溶性表面活性剂和40wt%的亲水性助溶剂来配制。
III(ii)型SEDDS(250mg/g):CBD用31wt%的油、45wt%的水溶性表面活性剂和24wt%的亲水性助溶剂来配制。
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Claims (24)
1.一种口服药物制剂,由如下组成:
在基于总组合物的10wt%至50wt%的量的大麻二酚(CBD);
泊洛沙姆124和泊洛沙姆188,其中泊洛沙姆的总量以基于总组合物的30 wt%至60 wt%的量存在;以及
在基于总组合物的20wt%至50wt%的量的溶剂,其中所述溶剂选自由以下组成的组:二乙酸甘油酯、柠檬酸三乙酯及其混合物;
其中所述口服药物制剂:
i. 在20℃和1个大气压处为固体或凝胶;以及
ii. 被包含在容器中。
2.根据权利要求1所述的制剂,其中所述容器是泡罩包装。
3.根据权利要求2所述的制剂,其中所述泡罩包装包括包含铝的腔成形膜和包含铝的封盖材料。
4.根据权利要求1-3中任一项所述的制剂,其中所述溶剂是柠檬酸三乙酯。
5.根据权利要求1-3中任一项所述的制剂,其中所述CBD是合成的或从它的天然来源高度纯化的。
6. 根据权利要求1-3中任一项所述的制剂,其中所述CBD以基于总组合物的从10 wt%至30 wt%的量存在。
7.根据权利要求1-3中任一项所述的制剂,还包含抗氧化剂。
8. 根据权利要求7所述的制剂,以基于总组合物的从0.001 wt%至5 wt%的量包含抗氧化剂。
9.根据权利要求8所述的制剂,其中所述抗氧化剂选自由以下组成的组:丁基化羟基甲苯、丁基化羟基茴香醚、α-生育酚(维生素E)、抗坏血酸棕榈酸酯、抗坏血酸、抗坏血酸钠、乙二胺四乙酸、半胱氨酸盐酸盐、柠檬酸、柠檬酸钠、硫酸氢钠、焦亚硫酸钠、卵磷脂、没食子酸丙酯、硫酸钠、硫代甘油及其混合物。
10.根据权利要求9所述的制剂,其中所述抗氧化剂选自由以下组成的组:α-生育酚(维生素E)、硫代甘油、抗坏血酸、柠檬酸及其混合物。
11.根据权利要求1-3中任一项所述的制剂,其中所述容器包含干燥剂。
12.根据权利要求11所述的制剂,其中所述干燥剂选自由以下组成的组:硅胶、粘土干燥剂、硫酸钙、氯化钙、氧化钙、沸石、活性炭、氧化铝、铝土矿、膨润土、分子筛及其组合。
13.根据权利要求1-3中任一项所述的制剂,其中所述制剂是选自凝胶胶囊和固体胶囊的口服剂型。
14.根据权利要求13所述的制剂,其中所述口服剂型包含改性释放剂。
15.根据权利要求1-3中任一项所述的制剂,用于在疗法中使用。
16.根据权利要求15所述的制剂,其中治疗的受试者在18岁以下。
17.根据权利要求1-3中任一项所述的制剂,用于在治疗疾病或紊乱中使用,所述疾病或紊乱选自由以下组成的组:Dravet综合征、肌阵挛性发作、青少年肌阵挛性癫痫、难治性癫痫、精神分裂症、青少年痉挛、结节性硬化症复合体、脑肿瘤、神经性疼痛、大麻使用障碍、创伤后应激障碍、焦虑、早期精神病、阿尔茨海默病和孤独症。
18. 根据权利要求1-3中任一项所述的制剂,用于在治疗疾病或紊乱中使用,所述疾病或紊乱选自由以下组成的组:Lennox Gastaut综合征、韦斯特综合征和婴儿痉挛。
19.根据权利要求18所述的制剂,其中所述婴儿痉挛是难治性婴儿痉挛。
20.根据权利要求1-3中任一项所述的制剂,用于在治疗失张力性发作、失神性发作或部分性发作中使用。
21.根据权利要求1-14中任一项所述的制剂在制造用于治疗疾病或紊乱的药物中的用途,所述疾病或紊乱选自由以下组成的组:Dravet综合征、肌阵挛性发作、青少年肌阵挛性癫痫、难治性癫痫、精神分裂症、青少年痉挛、结节性硬化症复合体、脑肿瘤、神经性疼痛、大麻使用障碍、创伤后应激障碍、焦虑、早期精神病、阿尔茨海默病和孤独症。
22. 根据权利要求1-14中任一项所述的制剂在制造用于治疗疾病或紊乱的药物中的用途,所述疾病或紊乱选自由以下组成的组:Lennox Gastaut综合征、韦斯特综合征和婴儿痉挛。
23.根据权利要求22所述的用途,其中所述婴儿痉挛是难治性婴儿痉挛。
24.根据权利要求1-14中任一项所述的制剂在制备用于治疗失张力性发作、失神性发作或部分性发作的药物中的用途。
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CA3087122A1 (en) | 2019-07-11 |
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KR20200106048A (ko) | 2020-09-10 |
EP3735229A1 (en) | 2020-11-11 |
IL275702A (en) | 2020-08-31 |
IL275702B1 (en) | 2024-02-01 |
BR112020013433A2 (pt) | 2020-12-01 |
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