CN112739328A - 大麻素的速释配方 - Google Patents
大麻素的速释配方 Download PDFInfo
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- CN112739328A CN112739328A CN201980060903.XA CN201980060903A CN112739328A CN 112739328 A CN112739328 A CN 112739328A CN 201980060903 A CN201980060903 A CN 201980060903A CN 112739328 A CN112739328 A CN 112739328A
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Abstract
速释一种或多种大麻素的组合物,其中所述组合物包含颗粒群。每个颗粒可包含一种或多种大麻素和一种或多种颗粒内赋形剂。或者,每个颗粒可包含一个或多个大麻素和多孔珠粒核。所述组合物可以通过以下方法制备,所述方法包括将一种或多种大麻素与一种或多种颗粒内赋形剂混合,然后例如通过流化床制粒,剪切诱导的湿法制粒或喷雾制粒将所述组合制粒。该组合物也可以通过一种方法来制备,该方法包括将一种或多种大麻素与一组多孔珠核混合。
Description
技术领域
本发明涉及用于口服施用一种或多种大麻素的速释多颗粒药物递送平台。本发明的药物递送系统实现了目标药代动力学特征,并在胃肠道中提供了均匀的药物分布,并为各种治疗适应症提供了精确计算的剂量。为了方便施用和处理,本发明的递送系统可以以胶囊,片剂,散剂,或棒状包装的形式施用。
技术背景
大麻素是大麻和大麻烟的植物属,具有许多药用和精神活性,据报道它们可减轻与严重医疗条件有关的多种症状,同时比大多数目前的处方药提供更安全和更少的严重副作用。例如大麻已被用来对抗与癌症,厌食症,艾滋病,慢性疼痛,肌肉痉挛,青光眼,关节炎,偏头痛和许多其他疾病有关的症状。
大麻素是一类来自大麻植物的多种化学物质,它们作用于大麻素受体,可抑制大脑中神经递质的释放。Δ9-四氢大麻酚(THC)和大麻二酚(CBD)是大麻中发现的两种最突出的大麻素。迄今为止,尽管科学家在大麻中发现了100多种不同的大麻素,但CBD和THC却是迄今为止研究最广泛和了解最多的大麻素。CBD和THC都与人体的内源性大麻素系统相互作用,后者是负责调节多种功能的重要信号系统。
THC是一种源自大麻的精神药物,它作用于人体的大麻素受体上,类似于人体天然产生的化学物质。THC是一种精神活性物质,可激活CB1和CB2受体并影响知觉,情绪,意识,认知和行为。在医学应用中,THC具有止痛和食欲兴奋剂的特性。据报道,THC会产生放松和幸福的状态,诱发睡眠并引起欣快感。这些作用已用于治疗各种健康问题,例如疼痛,炎症,恶心,睡眠呼吸暂停和压力障碍。此外,THC已被证明可抵抗化学疗法,多发性硬化症,青光眼,艾滋病和脊柱损伤的副作用和症状。
当前,只有三种由食品和药物管理局(FDA)批准用于THC的药品: 和和都含有屈大麻酚,这是一种合成的THC,不溶于水,pKA为10.6。可作为剂量强度为2.5mg,5mg和10mg的软明胶胶囊而获得,可作为口服溶液(5mg/ml)而获得。和均适用于治疗与艾滋病患者与体重减轻相关的厌食症,以及治疗对常规止吐疗法没有充分反应的患者的与癌症化学疗法相关的恶心和呕吐。
含有萘比隆,萘比隆是一种化学上类似于THC的合成大麻素。萘比隆为原料,为白色至类白色多晶型结晶粉末。在水性介质中,萘丁酮的溶解度小于0.5mg/L,pH值为1.2至7.0。可以粉末填充的胶囊形式(1mg/胶囊)口服给药,适用于对常规止吐疗法没有充分反应的患者,用于治疗与癌症化学疗法有关的恶心和呕吐。然而,据报道,口服后的效果会持续一段可变且不可预测的时间。例如停止治疗后,使用引起的不良精神病反应会持续48至72小时。
CBD是另一种衍生自大麻的有效化学物质,其被患者广泛吸食大麻叶而被吸入。迄今为止,FDA仅批准了(一种含有植物来源的CBD的口服溶液(100mg/ml))用于治疗两岁及以上的与两种罕见和严重形式的癫痫病(Lennox-gastaut syndrome综合征和Dravet syndrome综合征)相关的癫痫发作。CBD是白色至浅黄色的结晶固体。不溶于水,可溶于有机溶剂。CBD的主要医学应用是对抗严重和慢性疼痛,压力,抑郁,焦虑,癌症,癫痫病,精神分裂症,多发性硬化症,偏头痛,关节炎以及化学疗法的不利影响。
CBD的存在可以平衡THC的激动活性。THC激活大脑中存在的大麻素受体CB1和CB2,这些物质负责THC的精神活性,而CBD通过充当大麻素激动剂的间接拮抗剂来抑制CB1和CB2受体。因此,CBD通过类似THC的大麻素抑制了CB1和CB2受体的激活,从而产生了平衡的效果。
THC和CBD组合使用时,具有抗炎,食欲刺激,止吐,抗惊厥,抗氧化剂,神经保护和抗肿瘤作用。THC和CBD也可用于抵抗癫痫,抑郁,焦虑,精神分裂症,多发性硬化症,偏头痛和关节炎,并减轻癌症,艾滋病和脊柱损伤的症状;所有这些改善了那些使人虚弱的患者的生活质量。
此外,THC和CBD优于其他目前的处方药,因为它们无习惯形成,安全且耐受性良好。目前,由于阿片类药物的养成习惯,约有200万美国人开始依赖或滥用处方止痛药。此外,阿片类药物与过量用药导致死亡的风险较高。在本领域中需要强壮的非习惯性止痛药以及耐受性良好且安全的止痛药,以防止过量服用引起的死亡。THC和CBD都是非习惯性强效止痛药,可替代阿片类药物治疗严重和慢性疼痛。
此外,医用大麻最普遍的给药方式是吸烟。不幸的是,这种给药方式对肺有不利影响。大麻烟雾比烟草携带更多的焦油和其他微粒物质,并且可能是包括肺癌在内的肺部疾病的原因。吸烟也可能对大麻素的吸收产生负面影响。研究表明,随着参与者滴定THC剂量,吸入时间,保持时间和抽吸间隔时间应归因于受试者间血浆THC浓度的巨大差异,这归因于吸入深度的差异。此外,许多患者可能会发现吸烟无吸引力,而且总体上不健康。
大麻素也已被研究用于通过其他途径递送。欧洲专利号1361864描述了一种以颊喷雾剂形式的大麻素制剂,但是与该递送途径相关的挑战包括对粘膜的刺激。开发用于施用大麻素的其他递送方法包括如美国专利号6,328,992和美国专利公开号2016/0022627中所述的透皮途径。但是,经皮给药的生物活性物质可能导致不稳定的作用,并降低药物对系统的吸收,而长期使用后,使用渗透促进剂改善药物吸收可能对皮肤有毒。其他输送系统包括提供定量剂量的大麻素的推进剂,如美国专利第6,509,005号和第6,713,048号中所述;如美国专利号6,946,150中所述的泵送喷雾剂,美国专利号6,383,513和6,380,175中所讨论的鼻内递送系统;如美国专利第5,891,496号所述,以及通过口服给药组成的口服固体脂质制剂。
因此,对开发其他向患者施用大麻的手段有着极大的兴趣。
本领域仍然需要单独或组合的THC和CBD剂型用于多种临床疾病的治疗。如下所述的多颗粒,速释剂型将允许精确的剂量,均匀的药物递送,靶向的药代动力学,最小化的副作用以及给药的便利性。
发明内容
本发明提供包含一种或多种大麻素的多颗粒固体口服剂型。系统可包括直径范围可为约30μm至约1500μm或约50μm至约1000μm的颗粒(例如任何形状的颗粒,颗粒团块,珠子,或丸粒),并均匀加载。本发明的多颗粒固体口服剂型可以以提供一种或多种大麻素的速释的方式配制。还可以配制本发明的剂型以实现靶向的药代动力学特征并提供在胃肠道中的均匀分布。
所述多颗粒形式可以提供自由流动,精确计量,以及均匀的药物装载,并且可以压制成片剂(常规片剂,口服崩解片剂(ODT),自崩解片剂,可咀嚼片剂),填充入胶囊(常规硬明胶胶囊和易开胶囊喷洒)或装进棒状包装中,以撒在食物或水或其他液体饮料上。
本发明的一个方面涉及用于速释一种或多种大麻素。在本发明的实施方案中,速释组合物可包含颗粒群,其中每个颗粒包含:至少一种活性剂,和一种或多种颗粒内赋形剂。
在一些实施方案中,一种或多种大麻素可包含THC,CBD,或其组合物。
在一些实施方案中,一种或多种颗粒内赋形剂可包含一种或多种稀释剂,粘合剂,填充剂,表面活性剂/乳化剂,崩解剂或其组合。在某些实施方案中,一种或多种颗粒内赋形剂可包含一种或多种纤维素衍生物稀释剂。纤维素衍生物稀释剂的实例可包括乳糖,异麦芽酮糖醇,纤维素,淀粉,环糊精,甘露醇,和山梨糖醇。
在一些实施方案中,每个颗粒可以进一步包含一种或多种表面活性剂/乳化剂。
在本发明的实施方案中,组合物可包含颗粒群,其中每个颗粒包含一种或多种大麻素,以及多孔珠核,例如中孔二氧化硅珠或多孔可生物降解的玻璃珠。所述颗粒可具有约10μm和1000μm的直径。孔体积与粒度的比可以在约0.001至约0.8的范围内。每个颗粒可以进一步包含一种或多种表面活性剂/乳化剂。
本发明的组合物可以以剂型提供,例如片剂(例如ODT,自崩解片剂或可咀嚼片剂),胶囊剂或用于口服给药的棒状包装。在一些实施方案中,剂型可包含一种或多种颗粒外赋形剂,例如一种或多种填充剂,粘合剂,崩解剂,表面活性剂,润滑剂,抗氧化剂和/或调味剂/甜味剂。
本发明的另一方面涉及制备本发明的速释组合物的方法。在本发明的实施方案中,制备包含一种或多种大麻素和一种或多种颗粒内赋形剂的颗粒的组合物的方法可包括将一种或多种大麻素与一种或多种颗粒内赋形剂组合,并将该组合物制粒为产生速释的颗粒。在本发明的实施方案中,制备包含一种或多种大麻素和多孔珠核的颗粒的组合物的方法可以包括将一种或多种大麻素装载到多孔珠核上。
在一些实施方案中,当将一种或多种大麻素与一种或多种颗粒内赋形剂组合和/或加载到多孔珠粒核上时,一种或多种大麻素可处于制粒液体中。造粒液体可以是乳液,悬浮液,水醇混合物或其组合。造粒液体可包含一种或多种大麻素,一种或多种增溶剂以及在一些实施方案中的一种或多种表面活性剂/乳化剂。在一些实施方案中,一种或多种增溶剂可以选自油,甘油酯,醇,水醇溶液或其组合。在某些实施方案中,一种或多种增溶剂可以是油,例如大麻油或芝麻油。在某些实施方案中,一种或多种增溶剂可以是水醇溶液。
在一些实施方案中,该方法可以进一步包括制备包含一种或多种大麻素的制粒液体。造粒液可以通过将一种或多种大麻素与一种或多种增溶剂混合来制备。在某些实施方案中,可通过将一种或多种大麻素与一种或多种增溶剂以及与一种或多种表面活性剂/乳化剂混合来制备制粒液体。
在一些实施方案中,一种或多种大麻素与一种或多种颗粒内赋形剂的组合在将组合物制粒的同时全部或部分地发生。在一些实施方案中,一种或多种大麻素与一种或多种颗粒内赋形剂的组合发生在将组合物制粒之前。
在一些实施方案中,制粒过程可以是流化床制粒过程,湿法制粒过程或喷雾制粒过程。
在一些实施方案中,使用剪切混合器将包含一种或多种大麻素的制粒液体装载到多孔珠粒核上。
在本发明的另一方面,用于速释一种或多种大麻素的组合物的任何实施方案可用于在有此需要的受试者中治疗健康问题的方法,其中健康问题选自疼痛,恶心,睡眠呼吸暂停,压力障碍,炎症,抑郁,焦虑,癫痫,精神分裂症,偏头痛,关节炎,体重减轻,食欲不振及其组合。在一些实施方案中,组合物可以口服施用。在某些实施方案中,在施用之前,可以将组合物撒在固体,半固体食物或营养物上或撒入液体;或水中;或其它类型的液体饮料中。
附图说明
为了更好地理解本发明,请参考以下对本发明实施例的描述以及附图,其中:
图1示出了如实施例1中所述的根据本发明的实施方案的THC颗粒和CBD颗粒的粒度分布。
图2A和2B示出了根据本发明的实施方式的THC颗粒和CBD颗粒的30X(图2A)和75X(图2B)的放大的扫描电子显微镜(SEM)图像,如实施例1中所述。
图3示出了如实施例1中所述的根据本发明的实施方案的THC颗粒和CBD颗粒的溶出曲线。
图4示出了如实施例2中所述的根据本发明的实施方案的THC颗粒和CBD颗粒的粒度分布。
图5A和5B示出了如实施例2中所述的根据本发明的实施方案的THC颗粒和CBD颗粒在30X(图5A)和75X(图5B)的放大倍数下的SEM图像。
图6示出了如实施例3中所述的根据本发明的实施方案的THC颗粒和CBD颗粒的溶解曲线。
图7A示出了根据本发明的实施方式的THC颗粒和CBD颗粒的粒径分布,并且图7B示出了如实施例3中所述的空白多孔珠粒核的粒径分布。
图8A-8F显示了如实施例3中所述的根据本发明实施方案的THC和CBD颗粒以及空白多孔珠核颗粒的SEM图像。图8A-8C显示了190x(图8A),1600x(图8B),和2200x(图8C)放大倍率下的THC和CBD颗粒的SEM图像。图8D-8F显示了220x(图8D),1000x(图8E),和1600x(图8F)放大倍数的空白多孔珠核。
图9示出了如实施例3中所述的根据本发明的实施方案的THC颗粒和CBD颗粒的溶解曲线。
具体实施方式
根据本发明,提供了多颗粒速释剂型,用于施用一种或多种大麻素。一方面,一种或多种大麻素包含THC,CBD或其组合。在一些实施方案中,一种或多种大麻素的量可以为约1%至约90%w/w。在某些实施方案中,THC和CBD的最终组成,单独地或一起,可以在约1%至约90%w/w的范围内。
在本发明的实施方案中,组合物可包含一群颗粒,其中每个颗粒包含一种或多种大麻素和一种或多种颗粒内赋形剂。在本发明的实施方案中,组合物可包含一群颗粒,其中每个颗粒包含一种或多种大麻素和多孔珠核。本发明的组合物可以以剂型提供,例如片剂(例如常规片剂,ODT,自崩解片剂或可咀嚼片剂),胶囊,或棒状包装。
本发明的另一方面涉及制备本发明的组合物的方法。在本发明的实施方案中,包含颗粒的组合物可以通过以下方法制备,所述颗粒各自包含一种或多种大麻素和一种或多种颗粒内赋形剂,所述方法包括将一种或多种大麻素与一种或多种颗粒内赋形剂合并,然后将其造粒。结合产生速释颗粒。在本发明的实施方案中,可以通过包括将一种或多种大麻素装载到多孔珠核上的方法来制备包含各自包含一个或多个大麻素和多孔珠核的颗粒的组合物。
在本发明的另一方面,本发明的各种组合物的实施方案可以用于在有需要的受试者中治疗健康问题的方法,其中该健康问题选自疼痛,恶心,睡眠呼吸暂停,压力障碍,炎症,抑郁,焦虑,癫痫,精神分裂症,偏头痛,关节炎,体重减轻,食欲不振及其组合。在一实施方案中,组合物可以口服施用。在另一个实施方案中,在施用之前,可以将组合物撒在固体,半固体食物或营养物上或撒入液体;或水中;或其它类型的液体饮料中。
本发明的组合物
本发明的组合物包含颗粒,其中每个颗粒包含一种或多种大麻素。一种或多种大麻素可包含THC,CBD或其组合。在某些实施方案中,一种或多种大麻素包含THC和CBD。
在本发明的实施方案中,组合物的每个颗粒可包含一种或多种大麻素和一种或多种颗粒内赋形剂。一种或多种颗粒内赋形剂可包含一种或多种稀释剂,一种或多种粘合剂,一种或多种填充剂,一种或多种表面活性剂/乳化剂,一种或多种崩解剂或它们的组合。稀释剂可以起到不同的作用,例如增加重量和改善含量均匀性,改善内聚性和/或促进流动。稀释剂的实例包括但不限于纤维素衍生物,例如乳糖,蔗糖,异麦芽酮糖醇,纤维素,淀粉,环糊精,甘露醇,微晶纤维素和山梨糖醇。碳酸钙纯或无水磷酸钙;磷酸氢钙;脱水二碱或三碱磷酸钙;碳酸镁;氧化镁;淀粉;氯化钠;及其组合。
粘合剂是赋形剂,其可以充当粘合剂以“粘合在一起”并在某些情况下赋予机械强度。另外,粘合剂也可以为组合物提供体积。粘合剂的实例可包括但不限于糖,例如蔗糖,乳糖和葡萄糖;和玉米糖浆;大豆多糖;明胶;聚维酮(例如 );支链淀粉;纤维素衍生物,例如微晶纤维素,羟丙基甲基纤维素(例如),羟丙基纤维素(例如),乙基纤维素,羟乙基纤维素,羧甲基纤维素钠和甲基纤维素;丙烯酸和甲基丙烯酸共聚物;卡波姆(例如);聚乙烯基聚吡咯烷,聚乙二醇药用釉;海藻酸盐,例如海藻酸和海藻酸钠;树胶,例如阿拉伯树胶;瓜尔豆胶,和金合欢树胶;黄芪胶;糊精和麦芽糊精;乳衍,生物如乳清;淀粉,例如预糊化淀粉和淀粉糊;氢化植物油;硅酸铝镁;及其组合。
填充剂可以增加组合物的体积并且可以使其更易于处理。填充剂的实例可包括但不限于乳糖,右旋糖,蔗糖,纤维素,淀粉,磷酸钙,蔗糖,右旋糖,糊精,麦芽糊精,微晶纤维素(例如PH102或PH200,),超细纤维素,粉末状纤维素,预糊化淀粉(例如),二水合磷酸钙,大豆多糖(例如),明胶,二氧化硅,硫酸钙,碳酸钙,碳酸镁,氧化镁,山梨糖醇,甘露醇,高岭土,聚甲基丙烯酸甲酯(例如),氯化钾,氯化钠,滑石,及其组合。
表面活性剂/乳化剂可以促进自乳化。表面活性剂/乳化剂的实例可包括但不限于脱水山梨糖醇酯,乙氧基化脱水山梨糖醇酯(Sigma Aldrich,美国),乙氧基化线性醇,乙氧基化烷基酚,脂肪酸酯,胺和酰胺衍生物,烷基聚葡糖苷,环氧乙烷/环氧丙烷共聚物,多元醇和乙氧基化多元醇,硫醇(例如硫醇)及其衍生物,泊洛沙姆,聚乙二醇脂肪酸酯,卵磷脂及其混合物。在某些实施方案中,表面活性剂/乳化剂可以选自聚山梨酸酯(Sigma Aldrich,美国)和蓖麻油酸的聚乙二醇酯(RH 40,EL;BASF,德国)。
当暴露于水性环境时,崩解剂可有助于破碎颗粒。崩解剂的实例可以包括但不限于改性的羟乙酸淀粉钠,交联的聚维酮或交聚维酮(例如),羟丙基纤维素,淀粉,藻酸,藻酸钠,羧甲基纤维素钠,交联羧甲基纤维素钠,羧甲基纤维素钠,微晶纤维素,羧淀粉钠,羧甲基淀粉钠,马铃薯淀粉,小麦淀粉,玉米淀粉,大米淀粉,部分预糊化的淀粉,羟丙基淀粉,藻酸盐,碳酸盐及其组合。
在本发明的实施方案中,组合物的每个颗粒可包含一种或多种大麻素和多孔珠核。使用在此处,术语“核”可以指的是用于吸收和释放例如二氧化硅珠粒的液体的载体。在本发明的一些实施方案中,核可包含二氧化硅珠,可生物降解的玻璃珠或由本领域已知适合于口服施用的任何相容性材料制成的任何其他珠(例如多孔陶瓷,多孔碳酸钙颗粒,多孔沸石颗粒等)。
核可以包括一个或多个从核的表面延伸的孔。核心可包含一种或多种大麻素。根据一些实施方案,孔体积与核的粒径之比可以在约0.001至约0.8之间。
根据本发明,选择核以实现自由流动的多颗粒系统。根据一些实施方案,核可包含中孔二氧化硅(例如3150(美国,格雷斯),(美国,格雷斯),US2(日本,富士化学))。二氧化硅珠的粒度,孔体积和比表面积在下表1中给出。
表1.硅珠的物理性质
本发明的组合物可以在一定时间内释放特定百分比的一种或多种大麻素,如通过溶出度测试所确定的。溶解试验可以在下表2中总结的条件下进行。
表2.根据本发明的实施方式的用于溶出度测试的条件。
参数 | 条件 |
装置 | USP II(桨式) |
桨转速 | 100rpm |
介质 | 在蒸溜水(DW)中加入1%聚山梨酯80 |
介质提及 | 500ml |
浴温 | 37℃ |
采样时间点 | 15,30,60,240,360,720分钟 |
在一些实施方案中,本发明的组合物可在约30分钟(0.5小时)或更短的时间内,或约15分钟(0.25小时)或更短的时间内释放一种或多种大麻素的约30%或更多。从溶出度测试开始算起,大约需要10分钟或更短的时间。在一些实施方案中,组合物可以在约60分钟(1小时)或更短,或约30分钟(0.5小时)或更短,或约15分钟(0.25小时)的时间段内释放约50%或更多的一种或多种大麻素。从溶出度测试开始算起,最多不到10个小时,或者大约10分钟或更短。在一些实施方案中,组合物可在约90分钟(1.5小时)或更短,或约60分钟(1小时)或更短或约30分钟(0.5小时)的时间内释放约80%或更多的一种或多种大麻素。从溶出度测试开始算起,大约需要不到15分钟(0.25小时)或更少,或者大约10分钟或更少。
本发明的组合物可包含具有特定尺寸分布的颗粒。例如在一些实施方案中,约80%的颗粒的直径可在约20μm至约2000μm之间,或在直径约30μm至约1000μm之间,或在约40μm至约900μm之间。在一些实施方案中,约80%的颗粒的直径可在约2μm至约500μm之间,或在约4μm至约300μm之间,或在约5μm至约200μm之间。
本发明的组合物可以以剂型提供,例如片剂(例如ODT,自崩解片剂或可咀嚼片剂),胶囊剂,散剂或棒状包装。该形式可以包含一种或多种颗粒外赋形剂,例如一种或多种填充剂,一种或多种粘合剂,一种或多种崩解剂,一种或多种润滑剂,一种或多种抗氧化剂,一种或多种调味剂/甜味剂或其组合。
润滑剂可以减少颗粒之间的摩擦并因此提高跟随性,并且在片剂压制中防止粘附到模具壁上并且在封装中促进粉末填充。润滑剂也可能有助于崩解时间和影响溶出速率。润滑剂的实例可包括但不限于硬脂酸钙,氢化蓖麻油,单硬脂酸甘油酯,山嵛酸甘油酯,硬脂酸镁,矿物油,聚乙二醇,泊洛沙姆407或188或普通,月桂基硫酸钠,苯甲酸钠,硬脂酸,硬脂富马酸钠,二氧化硅,滑石粉及其组合。
抗氧化剂可对组合物的稳定性和功效具有积极作用。抗氧化剂的实例可包括但不限于乙酰半胱氨酸,抗坏血酸棕榈酸酯,丁基化羟基茴香醚(BHA),丁基化羟基甲苯(BHT),单硫代甘油,硝酸钾,抗坏血酸钠,甲醛次硫酸氢钠,焦亚硫酸钠,亚硫酸氢钠,维生素E或其衍生物,没食子酸丙酯,乙二胺四乙酸(EDTA)(例如乙二胺四乙酸二钠),二亚乙基三胺五乙酸(DTPA),三甘醇戊酸酯(NT)及其组合。抗氧化剂还可包含氨基酸,例如蛋氨酸,组氨酸,半胱氨酸和带有带电侧链的氨基酸,例如精氨酸,赖氨酸,天冬氨酸和谷氨酸。可以存在任何特定氨基酸(例如蛋氨酸,组氨酸,精氨酸,赖氨酸,异亮氨酸,天冬氨酸,色氨酸,苏氨酸及其组合)的任何立体异构体(例如L-,D-,或其组合)或这些立体异构体的组合,只要该氨基酸以其游离碱形式或其盐形式存在即可。例如可存在L-立体异构体。
香料/甜味剂可以帮助使组合物更可口。调味剂/甜味剂的实例可包括但不限于糖,右旋糖,果糖,阿斯巴甜,甘油,甘露醇,蔗糖,糖精钠,乙酰磺胺酸钾,右旋糖,液体葡萄糖,麦芽糖醇,糖精,糖精钙;糖精钠,甜蜜素钠,山梨糖醇,甜叶菊,糖浆,木糖醇及其组合。
制备本发明组合物的方法
制备本发明的组合物的方法可包括(a)将一种或多种大麻素与一种或多种颗粒内赋形剂混合,并将该混合物制粒以产生速释颗粒;(b)将一种或多种大麻素装载到多孔珠核上。
与一种或多种颗粒内赋形剂结合和/或负载在多孔珠粒核上的一种或多种大麻素可以在制粒液体中。造粒液体可以是乳液,悬浮液,水醇混合物或其组合。在一些实施方案中,制粒液体可包含一种或多种增溶剂。一种或多种增溶剂可以是油,甘油酯,醇,水醇溶液或其组合。油的实例可以包括但不限于芝麻油,大麻油,琉璃苣油,椰子油,棉籽油,大豆油,红花油,向日葵油,蓖麻油,玉米油,橄榄油,棕榈油,花生油,杏仁油,菜籽油,薄荷油,罂粟籽油,低芥酸菜子油,棕榈仁油,氢化大豆油,氢化植物油及其组合。甘油酯的实例可包括但不限于甘油单酯,甘油二酯,甘油三酯及其组合。醇的实例可包括但不限于一元醇,例如乙醇,甲醇或异丙醇。水醇混合物的实例可以包括但不限于以不同比例与水混合的异丙醇或与水混合的乙醇。
在一些实施方案中,制粒液体可进一步包含一种或多种表面活性剂/乳化剂。表面活性剂/乳化剂可以促进自乳化。当形成乳液或悬浮液时,在两相之间产生表面积膨胀。乳液或悬浮液由表面活性剂/乳化剂分子稳定,该分子在内部相滴周围形成薄膜。在乳液或悬浮液的形成中,过量的表面自由能取决于液滴的大小和界面张力。如果使用表面活性剂/乳化剂无法稳定乳液或悬浮液,则两相将分开,从而降低界面张力和自由能。包括自微乳化药物输送系统(“SMDDS”)的自乳化药物输送系统(“SEDDS”)是天然或合成油,固体或液体表面活性剂或一种或多种亲水性溶剂和助溶剂的混合物能够在温和搅拌下形成水包油乳液或悬浮液,然后在水性介质(如胃肠液)中稀释的表面活性剂。
在一些实施方案中,本发明的方法进一步包括制备包含一种或多种大麻素的造粒液体。制粒液体的制备可包括将一种或多种大麻素与一种或多种增溶剂混合直至一种或多种大麻素溶解。在一些实施方案中,制粒液体的制备可包括将其他组分,例如一种或多种表面活性剂/乳化剂,与至少一种或多种大麻素和一种或多种增溶剂混合。内容物的混合可以通过本领域已知的方法进行。例如可以通过简单的混合来混合内容物,或者可以连续地,周期性地或以它们的组合与混合装置混合。混合装置的实例可包括但不限于磁力搅拌器,振动器,桨式混合器,均化器及其任何组合。
在其中颗粒同时包含THC和CBD的实施方案中,THC和CBD可以在相同的制粒液体中,或可以在不同的制粒液体中。
将一种或多种大麻素与一种或多种颗粒内赋形剂结合并制粒
在本发明的实施方案中,可将制粒液体与一种或多种颗粒内赋形剂混合,并且可将所述组合造粒以产生速释颗粒。制粒液的结合可以在制粒之前进行,或者可以在制粒的全部或部分同时进行。
在颗粒包含THC和CBD两者,并且其中THC和CBD在不同的制粒液体中的实施方案中,可以在与一种或多种颗粒内赋形剂组合之前将制粒液体合并在一起。或者,可将制粒液体与一种或多种颗粒内赋形剂同时混合在一起。
在一些实施方案中,可以通过流化床制粒工艺来进行制粒液体与一种或多种颗粒内赋形剂的组合和制粒。可以将一种或多种颗粒内赋形剂装载到流化床制粒机的制粒机碗中并流化。可以将制粒液体添加到制粒机碗中并添加到一种或多种颗粒内赋形剂上。造粒液体的添加可以通过顶部喷雾,底部喷雾,切向喷雾或其等效方法进行。该过程的参数,包括使造粒机钵中的一种或多种赋形剂流态化所需的压力大小,造粒机钵内的进气温度,造粒机钵内的湿度,造粒液的喷雾速率,流化床喷嘴的大小和高度都可以由本领域普通技术人员确定。可以在本发明的这些方法中使用的流化床制粒机的实例可以包括由GlattGMBH,Sainty International Group,GEA Group,Senieer,LB Bohle,Robert BoschPackaging Technology GmbH和SPX FLOW Danmark制造的。
在一些实施方案中,可以通过湿法制粒工艺将一种或多种制粒液体与一种或多种颗粒内赋形剂的组合和制粒。在某些实施方案中,湿法制粒过程可以用高剪切制粒机进行。可以将一种或多种颗粒内赋形剂装入高剪切造粒机的碗中,并以约25rpm至约1000rpm,或约100rpm至约500rpm的速度混合。可以将制粒液体添加到制粒机钵中并添加到一种或多种颗粒内赋形剂中,并且在高剪切力下以约500rpm至约5000rpm,或约1000rpm至约3000rpm的速度混合制粒液体和一种或多种赋形剂的组合。该方法的参数,例如制粒液体的添加速率,都可以由本领域普通技术人员确定。在一些实施方案中,高剪切造粒机可以是立式高剪切造粒机。立式高剪切造粒机可以是顶部驱动的或底部驱动的。在其他实施方案中,高剪切造粒机可以是卧式高剪切造粒机。可以在本发明的这些方法中使用的高剪切造粒机的实例可以包括由Glatt GMBH,SERVOLiFT LLC,Sainty International Group,GEA Group,Senieer,LB Bohle和Robert Bosch Packaging Technology GmbH制造的。
在某些实施方案中,可以用Glatt CPSTM技术(Complex Perfect SpheresTechnology)进行湿法制粒。CPSTM是Glatt GMBH的一项专利技术,其中球形颗粒分两个阶段制造(i)粉末成核,其中溶剂充当粘合剂,在活性成分和填充剂(例如微晶纤维素)的颗粒之间形成桥连,导致团聚;和(ii)由于改性转子盘的同时纺丝而产生的离心力使颗粒球形化,从而产生光滑的球形颗粒/小丸。CPS技术在美国专利号6,354,728和PCT公开号WO04052607中公开,其通过引用并入本文。可以将一种或多种颗粒内赋形剂加载到碗中,并且可以将制粒液体添加到碗中并添加到一种或多种赋形剂上。
在某些实施方案中,可以通过挤出滚圆法进行湿法制粒工艺。可以将一种或多种颗粒内赋形剂加载到碗中,并且可以将制粒液体添加到碗中并添加到一种或多种颗粒内赋形剂上。可以将造粒液体和一种或多种赋形剂的组合进行混合,例如使用行星式混合器,如上所述的高剪切混合器或sigma叶片混合器(sigma blade mixer)。然后可以对组合混合物进行挤出,其中向组合混合物施加压力,直到它通过一个或多个孔口流出以产生挤出物。可以使用螺杆挤出机进行挤出,该螺杆挤出机使用螺杆产生必要的压力以迫使组合混合物流过一个或多个孔;筛子挤出机,其使用旋转或摆动臂将组合混合物压过筛子;篮式挤出机,它使用旋转或摆动臂将组合混合物压过筛子,该筛子是垂直圆柱壁的一部分;辊式挤出机,其中组合混合物在辊和多孔板或环之间送入;ram挤出机,其中组合混合物被位于圆柱体或通道内的活塞压缩并迫使通过一个或多个孔口;或本领域已知的其他类型的挤出机。然后可以将挤出的组合混合物进行滚圆化处理,其中将混合物破碎成均匀的长度,然后逐渐转变为球形。挤出滚圆法的参数可以由本领域普通技术人员之一确定。可以在本发明的这些方法中使用的挤出滚圆设备的示例可以包括由Glatt GMBH,Sainty InternationalGroup,GEA Group,LB Bohle和Robert Bosch Packaging Technology GmbH制造的设备。
在某些实施方案中,可以使用本领域已知的方法,用连接混合机,辊式压实机或“V”型混合机进行湿法制粒。
在湿法制粒之后,可以使用本领域已知的方法例如使用流化床处理器将颗粒干燥。
在一些实施方案中,可通过喷雾制粒方法将制粒液体与一种或多种颗粒内赋形剂的组合和制粒。将包含一种或多种如上所述的表面活性剂的制粒液体与一种或多种颗粒内赋形剂充分混合,得到分散体。该分散体可包含约5%至约90%的固体含量。然后将分散体喷雾到流化床或喷射床上以产生颗粒。该过程的参数可以由本领域普通技术人员确定。可以在本发明的这些方法中使用的喷雾制粒机的实例可以包括由Glatt GMBH,GEA Group,LBBohle,Robert Bosch Packaging Technology GmbH和Allgaier Werke GmbH制造的那些。
将一种或多种大麻素装载到多孔珠核上
在本发明的实施方案中,可以将包含一种或多种大麻素的制粒液体装载到多孔珠核上。可通过将粒化液体与核混合,将粒化液体装载到多孔珠粒核上。在某些实施方案中,可使用高剪切制粒机将制粒液体与多孔珠核混合。在一些实施方案中,可以进行混合直到产生自由流动的粉末混合物。此后,形成根据本发明的组合物。
准备剂型
根据本发明的实施方案,可以根据本领域已知的方法对包括通过上述方法制备的一种或多种大麻素的颗粒进行分级,研磨和筛选。可以将颗粒与如上所述的颗粒外赋形剂混合,并且可以使用常规方法将所得的混合物加工成剂型,例如片剂,胶囊剂或棒状包装。
本发明的组合物的应用方法
本发明的一个方面涉及在有需要的受试者中治疗健康问题的方法,其中所述方法包括施用本发明的速释组合物。
本发明还涉及本发明的速释组合物在需要治疗的受试者中治疗健康问题的用途。所述用途可包括将所述组合物施用于受试者。
本发明涉及本发明的速释组合物在制备用于治疗需要治疗的受试者健康问题的药物中的用途。
本发明进一步涉及本发明的速释组合物,其用于治疗有此需要的受试者的健康问题。所述用途可包括将所述组合物施用于受试者。
健康问题可以选自疼痛,恶心,睡眠呼吸暂停,压力障碍,炎症,抑郁,焦虑,癫痫,精神分裂症,偏头痛,关节炎,体重减轻,食欲不振及其组合。
在一些实施方案中,可以口服施用组合物。
在一些实施方案中,在施用之前,可以将组合物撒在固体,半固体或液体的食物或营养物上;水中或放入其他类型的液体饮料中。
示例
例子1
进行了研究以制备和评估根据本发明的实施方案的组合物,其中该组合物既包含包含THC的颗粒又包含包含CBD的颗粒,如下表3所示。使用根据本发明的实施方式的顶部喷雾流化床造粒方法来制备颗粒。
表3.示例1的成分。
使用动态光散射技术(Malvern设备,美国)获得图1所示的组合物的粒度分布。如图所示,超过70%的颗粒的直径在约100μm至约700μm之间。
使用电子扫描显微镜成像技术获得的颗粒的SEM图像显示在图2A和2B中。
使用纯水USP作为溶解介质,溶解体积为900ml的溶解试验。使用USP II型桨叶设备以75rpm的桨叶速度混合溶解介质。浴温为37℃,并且使用10μm的多孔过滤器取样等分试样。
THC颗粒和CBD颗粒的最终溶出曲线如图3所示。THC颗粒和CBD颗粒的溶出均显示出速释的溶出曲线。
例子2
进行了研究以制备和评估根据本发明的实施方案的组合物,其中该组合物既包含包含THC的颗粒又包含包含CBD的颗粒,如下表4所示。根据本发明的实施方案,使用具有CPS技术的高剪切造粒工艺来制备颗粒。
表4.示例2的成分。
使用动态光散射技术(Malvern设备,美国)获得图4所示的组合物的粒度分布。如图所示,超过70%的颗粒的直径在约80μm至约700μm之间。
使用电子扫描显微镜成像技术获得的颗粒的SEM图像显示在图5A和5B中。
使用在作为溶解介质的蒸馏水中的1%聚山梨酯80,溶解量为500ml进行溶解试验。使用USP II型桨叶设备以100rpm的桨叶速度混合溶解介质。浴温为37℃。
图6显示了THC颗粒和CBD颗粒的所得溶出曲线。THC颗粒和CBD颗粒的溶出均表现出速释的溶出曲线。
例子3
进行了研究以制备和评估根据本发明的实施方案的组合物,其中该组合物既包含包含THC的颗粒又包含包含CBD的颗粒,如下表5所示。根据本发明的实施方案,通过将THC和CBD加载到多孔珠粒核上来制备颗粒。
表5.实施例3的成分。
使用动态光散射技术(Malvern设备,美国)获得了该组合物以及空白多孔珠核的颗粒尺寸分布。如图7A和7B所示,组合物的超过70%的颗粒的直径在约20μm至约200μm之间(图7A),而空白多孔珠粒核的超过70%的颗粒在约2μm至约直径约100μm之间(图7B)。
使用电子扫描显微镜成像技术获得的颗粒的SEM图像显示在图8A-8F中。
使用在蒸馏水中的1%聚山梨酯80作为溶解介质,溶解量为500ml进行溶解试验。使用USP II型桨叶设备以100rpm的桨叶速度混合溶解介质。浴温为37℃。
图9示出了THC颗粒和CBD颗粒的所得溶出曲线。THC颗粒的溶出曲线与CBD颗粒的溶出曲线几乎相同,并且两种颗粒在不到20分钟内均实现了80%的释放。
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尽管这里已经公开了本发明的特定实施例,但是本领域普通技术人员将理解,可以在不脱离本发明的精神的情况下对特定实施例进行改变。因此,本发明的范围不限于特定实施例。此外,意图是所附权利要求覆盖本发明范围内的任何和所有这样的应用,修改和实施例。
Claims (50)
1.一种用于速释一种或多种大麻素的组合物,该组合物包含颗粒群,其中每个颗粒包含:
(a)一种或多种大麻素;
(b)一种或多种颗粒内赋形剂;
其中组合物在约30分钟或更短的时间内释放至少约30%的一种或多种大麻素。
2.根据权利要求1的组合物,其中所述一种或多种大麻素包括Δ9-四氢大麻酚(THC),大麻二酚(CBD),或其组合。
3.根据权利要求1或2的组合物,其中所述一种或多种大麻素包含THC和CBD的组合。
4.根据权利要求1-3中任一项的组合物,其中所述一种或多种颗粒内赋形剂可包含一种或多种稀释剂,一种或多种粘合剂,一种或多种填充剂,一种或多种表面活性剂/乳化剂,一种或多种崩解剂,或其组合。
5.根据权利要求1-4中任一项的组合物,其中所述一种或多种颗粒内赋形剂能够包含一种或多种纤维素衍生物。
6.根据权利要求5的组合物,其中一种或多种纤维素衍生物能够选自乳糖,异麦芽酮糖,纤维素,淀粉,环糊精,甘露醇,山梨糖醇,及其组合。
7.根据权利要求1-6中任一项的组合物,其中所述组合物在约30分钟或更短的时间内释放约30%的一种或多种大麻素。
8.根据权利要求1-7中任一项的组合物,其中所述组合物在约60分钟或更短的时间内释放约50%的一种或多种大麻素。
9.根据权利要求1-8中任一项的组合物,其中所述组合物在约90分钟或更短的时间内释放约80%的一种或多种大麻素。
10.根据权利要求1-9中任一项的组合物,其中所述组合物中约80%的颗粒的直径为约20μm至约2000μm。
11.根据权利要求1-10中任一项的组合物,其中所述组合物中约80%的颗粒的直径为约30μm至约1000μm。
12.根据一种用于速释一种或多种大麻素的组合物,该组合物包含颗粒群,其中每个颗粒包含:
(a)一种或多种大麻素;
(b)多孔磁珠核;
其中组合物在约30分钟或更短的时间内释放至少约30%的一种或多种大麻素。
13.根据权利要求12的组合物,其中所述一种或多种大麻素包含Δ9-四氢大麻酚(THC),大麻二酚(CBD),或其组合。
14.根据权利要求12或13的组合物,其中所述一种或多种大麻素包含THC和CBD的组合。
15.根据权利要求12-14中任一项的组合物,其中所述多孔磁珠包括二氧化硅珠或多孔可生物降解的玻璃珠。
16.根据权利要求12-15中任一项的组合物,其中所述组合物在约15分钟或更短的时间内释放约30%的一种或多种大麻素。
17.根据权利要求12-16中任一项的组合物,其中所述组合物在约30分钟或更短的时间内释放约50%的一种或多种大麻素。
18.根据权利要求12-17中任一项的组合物,其中所述组合物在约60分钟或更短的时间内释放约80%的一种或多种大麻素。
19.根据权利要求12-18中任一项的组合物,其中所述组合物中约80%的颗粒的直径为约2μm至约500μm。
20.根据权利要求12-19中任一项的组合物,其中所述组合物中约80%的颗粒的直径为约4μm至约300μm。
21.一种制备包含用于速释一种或多种大麻素的颗粒群的组合物的方法,该方法包括
(a)将一种或多种大麻素与一种或多种颗粒内赋形剂组合,和
(b)将组合物造粒以产生颗粒群。
22.根据权利要求21所述的方法,其中所述一种或多种大麻素包括Δ9-四氢大麻酚(THC),大麻二酚(CBD),或其组合。
23.根据权利要求21或22的方法,其中与一种或多种颗粒内赋形剂组合的一种或多种大麻素在制粒液体中。
24.根据权利要求23所述的方法,其中所述造粒液是乳液,悬浮液,水醇混合物,或其组合。
25.根据权利要求23或24所述的方法,其中所述包含增溶剂的造粒液体选自油,甘油酯,醇,水醇溶液,及其组合。
26.根据权利要求25的方法,其中所述油选自芝麻油,大麻油,琉璃苣油,椰子油,棉籽油,大豆油,红花油,向日葵油,蓖麻油,玉米油,橄榄油,棕榈油,花生油,杏仁油,菜籽油,薄荷油,罂粟籽油,低芥酸菜子油,棕榈仁油,氢化大豆油,氢化植物油,及其组合。
27.根据权利要求25所述的方法,其中所述甘油酯选自甘油单酸酯,甘油二酸酯,甘油三酸酯,及其组合。
28.根据权利要求25所述的方法,其中所述醇包括一元醇。
29.根据权利要求23-28中任一项所述的方法,其中所述造粒液体包括表面活性剂。
30.根据权利要求21-29中任一项所述的方法,其中所述一种或多种颗粒内赋形剂能够包含一种或多种稀释剂,一种或多种粘合剂,一种或多种填充剂,一种或多种表面活性剂/乳化剂,一种或多种崩解剂,或其组合。
31.根据权利要求21-29中任一项所述的方法,其中所述一种或多种颗粒内赋形剂能够包含一种或多种纤维素衍生物。
32.根据权利要求31所述的方法,其中所述一种或多种纤维素衍生物能够选自乳糖,异麦芽酮糖,纤维素,淀粉,环糊精,甘露醇,山梨糖醇,及其组合。
33.根据权利要求23-32中任一项所述的方法,还包括制备所述造粒液体。
34.根据权利要求33的方法,其中制粒液体包括将一种或多种大麻素与增溶剂混合。
35.根据权利要求21-34中任一项所述的方法,其中在将所述组合物制粒之前进行所述一种或多种大麻素与所述一种或多种颗粒内赋形剂的组合。
36.根据权利要求21-34中任一项所述的方法,其中将所述一种或多种大麻素与所述一种或多种颗粒内赋形剂的组合与所述组合的造粒同时进行。
37.根据权利要求21-36中任一项的方法,其中所述组合的造粒包括流化床造粒过程,剪切诱导的湿法造粒过程或喷雾造粒过程。
38.一种制备包含用于速释一种或多种大麻素的颗粒群的组合物的方法,该方法包括将一种或多种大麻素与一组多孔珠核混合以产生颗粒群。
39.根据权利要求38所述的方法,其中所述一种或多种大麻素包括Δ9-四氢大麻酚(THC),大麻二酚(CBD),或其组合。
40.根据权利要求38或39所述的方法,其中与所述多孔珠核的群混合的所述一种或多种大麻素在制粒液体中。
41.根据权利要求40所述的方法,其中所述造粒液体是乳液,悬浮液,水醇混合物,或其组合。
42.根据权利要求40或41所述的方法,其中所述包含增溶剂的造粒液体选自油,甘油酯,醇,水醇溶液,及其组合。
43.根据权利要求42所述的方法,其中所述油选自芝麻油,大麻油,琉璃苣油,椰棉子油,籽油,大豆油,红花油,葵花籽油,蓖麻油,玉米油,橄榄油,棕榈油,花生油,杏仁油,菜籽油,薄荷油,罂粟籽油,低芥酸菜子油,棕榈仁油,氢化大豆油,氢化植物油,及其组合。
44.根据权利要求42所述的方法,其中所述甘油酯选自甘油单酸酯,甘油二酸酯,甘油三酸酯,及其组合。
45.根据权利要求42所述的方法,其中所述醇包括一元醇。
46.根据权利要求38-45中任一项所述的方法,其中使用剪切混合器将所述一种或多种大麻素与所述多孔珠核的群体混合。
47.根据权利要求38-46中任一项所述的方法,其中所述多孔珠核包括二氧化硅珠或多孔可生物降解的玻璃珠。
48.一种治疗有此需要的受试者的健康问题的方法,包括施用权利要求1-20中任一项的组合物,其中所述健康问题选自疼痛,恶心,睡眠呼吸暂停,压力障碍,炎症,抑郁症,焦虑症,癫痫症,精神分裂症,偏头痛,关节炎,体重减轻,食欲不振,及其组合。
49.根据权利要求48所述的方法,其中所述组合物经口服施用。
50.根据权利要求48或49所述的方法,其中在施用之前,将所述组合物撒在固体,半固体或液体的食物或营养物上;将其撒入水;或其他类型的液体饮料中。
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