CN112638369A - 固体自乳化药物组合物 - Google Patents
固体自乳化药物组合物 Download PDFInfo
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- CN112638369A CN112638369A CN201980050455.5A CN201980050455A CN112638369A CN 112638369 A CN112638369 A CN 112638369A CN 201980050455 A CN201980050455 A CN 201980050455A CN 112638369 A CN112638369 A CN 112638369A
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Abstract
本公开描述了用于口服固体剂量的包含至少一种***素的固体自乳化组合物和制备所述固体自乳化组合物的方法。本文公开的组合物可以容易地配制成适于施用给需要治疗的受试者的药学上可接受的口服固体剂量制剂,从而提供关于施用预定治疗有效量的至少一种***素的确定性。
Description
技术领域
本公开涉及包含至少一种***素的固体自乳化药物组合物以及制备所述组合物的方法。
背景技术
对本公开的背景的讨论旨在促进对本公开的理解。然而,应当理解,该讨论不是确认或承认所引用的任何材料在本申请的优先权日时是公开的、已知的或公知常识的一部分。
对***和***素用于治疗广泛的医学病症和障碍的用途存在日益增长的兴趣。
目前,药用***可以以几种形式施用,包括含有干燥粉末状***植物材料的胶囊;通过将***提取物注入脂质相(例如黄油、烹调油、食用脂肪)或溶剂相(例如甘油、葡萄糖、醇)中而生产的可食用“食品”产品;含有溶解在中链甘油三酯或载体油中的***素的硬或软壳明胶胶囊;含有不同比例和浓度的***二酚(CBD)和δ-9-四氢***酚(THC)的***提取物的油基液体;口香糖,通过蒸发干燥植物材料而生产的吸入器;通过递送至口腔粘膜的液体喷雾剂或气雾剂;以及作为与脂质纳米球内的维生素、矿物质和其它营养物组合的营养品。
许多上述制剂的缺点包括活性成分的组成变化广泛、稳定性差和生物利用度低。通常,这些缺点是由于***素的物理化学性质引起的,所述***素是亲脂性的,水不溶性的,并且通常作为粘性的,树脂性的焦油样物质存在,其包含各种化学化合物的复杂混合物。
需要用于***和***素,特别是THC和CBD的有效口服递送媒介物,其提供具有可预测的生物利用度的活性成分的一致和稳定剂量。
本文所公开的各种实施方案旨在克服上述缺点中的至少一些。
发明内容
本公开提供了用于口服固体剂量的包含至少一种***素的固体自乳化组合物,制备所述固体自乳化组合物的方法,以及包括含所述固体自乳化组合物的口服固体剂量制剂。
本公开的各种实施方案提供了用于口服固体剂量的固体自乳化组合物,其包含至少一种***素、亲脂性溶剂、乳化剂和吸附剂。应当理解,亲脂性溶剂、乳化剂和吸附剂可以是药学上可接受的物质。
在一个实施方案中,至少一种***素可以选自包含以下各项组成的组:花生四烯酸乙醇胺、2-花生四烯酸甘油、***色烯(cannabichromene,CBC)、***色烯酸(cannabichromenic acid,CBCA)、cannabichormevarin(CBCV)、cannabichromevarinicacid(CBCVA)、***二酚(cannabidiol,CBD)、***二酚酸(cannabidiolic acid,CBDA)、次***二酚(cannabidivarin,CBDV)、次***二酚酸(cannabidivarinic acid,CBDVA)、cannabielsoin(CBE)、***环醇(cannabicyclol,CBL)、cannabinodiol(CBND)、***萜酚(cannabigerol,CBG)、***萜酚酸(cannabigerolic acid,CBGA)、次***萜酚(cannabigerovarin,CBGV)、次***萜酚酸(cannabigerovarinic acid,CBGVA)、***酚(cannabinol,CBN)、***酚酸(cannabinolic acid,CBNA)、***三醇(cannabitriol,CBT)、δ-8-四氢***萜醇(delta-8-tetrahydrocanninol)、δ-8-四氢***酚酸(deleta-8-tetrahydrocannabinolic acid)、δ-9-四氢***酚(delta-9-tetrahydrocannabinol,THC)、δ-9-四氢***酚酸(delta-9-tetrahydrocannabinolic acid,THCA)、δ-9-四氢次***酚(delta-9-tetrahydrocannabivarin,THCV)、δ-9-四氢次***酚酸(delta-9-tetrahydrocannabivarinic acid,THCVA)、11-去甲-9-羧基-δ-9-四氢***酚(11-nor-9-carboxy-delta-9-tetrahydrocannabinol,THCCOOCH)、11-去甲-9-羧基-δ-8-四氢***酚(11-nor-9-carboxy-delta-8-tetrahydrocannabinol)、11-羟基-δ-8-四氢***酚(11-hydroxy-delta-8-tetrahydro-cannabinol)和11-羟基-δ-9-四氢***酚(11-hydroxy-delta-9-tetrahydrocannabinol)、二甲基庚基戊基***二酚(dimethyl heptylpentylcannabidiol,DMHP-CBD)、6,12-二氢-6-羟基***二酚、(3S,4R)-7-羟基-δ6-四氢***酚同系物和衍生物、(+)-4-[4-DMH-2,6-二乙酰氧基-苯基]-2-羧基-6,6-二甲基双环[3.1.1]庚-2-烯和其他4-苯基烯(4-phenylpinene)衍生物和***二酚(-)(CBD)类似物,如(-)CBD-单甲醚、(-)CBD二甲醚;(-)CBD二乙酸酯;(-)3'-乙酰基-CBD单乙酸酯、***酚丙基变体(CBNV)和***隆。
在某些实施方案中,所述***素包括***二酚(CBD)。
在某些实施方案中,所述***素包含δ-9-四氢***酚(THC)。
在某些实施方案中,所述***素包含比例为1:100至100:1、1:10至10:1、1:3至3:1、1:2至2:1的CBD和THC。
在某些实施方案中,亲脂性溶剂包括植物油、中链甘油三酯或其混合物。植物油的合适实例包括但不限于棉籽油、红花油、向日葵油、花生油、亚麻子油、玉米油、橄榄油、椰子油、大豆油、芝麻油、鼠尾草(Salvia Hispanica L.)籽油、小麦胚芽油、低芥酸菜籽油、蓖麻油、氢化蓖麻油及其任何混合物。可适用于本公开的实施方案的中链甘油三酯的实例包括三己酸甘油酯、三辛酸甘油酯、三癸酸甘油酯、三月桂酸甘油酯及其混合物。
在某些实施方案中,乳化剂包括表面活性剂,特别是非离子表面活性剂,特别是聚乙氧基化非离子表面活性剂。聚乙氧基化非离子表面活性剂的合适实例包括但不限于乙氧基化直链醇、乙氧基化烷基酚、酸乙氧基化脂肪酸、甘油酯、己糖醇和环状脱水己糖醇的酯。在一个特定实施方案中,乳化剂包含聚烃氧基蓖麻油。
在一个实施方案中,吸附剂可以包含惰性颗粒材料。惰性颗粒材料可以具有约3至350微米,特别是约20微米至约60微米范围内的粒度。惰性颗粒材料可以是介孔的,具有在约1.5mL/g至约1.9mL/g范围内的介孔体积。惰性颗粒材料可以具有约150至350m2/g,特别是约260至约320m2/g的表面积。
在某些实施方案中,惰性颗粒材料可以包含无定形二氧化硅。
在一个替代实施方案中,惰性颗粒材料可包含药学上可接受的金属氧化物。药学上可接受的金属氧化物的合适实例包括但不限于氧化锌、二氧化钛、氧化铈和氧化铁。
在一个实施方案中,固体自乳化组合物可以进一步包含抗氧化剂,特别是亲脂性抗氧化剂如dl-α-生育酚。
本公开的各种实施方案提供了一种制备固体自乳化组合物的方法,其包含:
a)提供至少一种***素和乳化剂在亲脂性溶剂中的溶液;
b)将所述溶液与吸附剂混合以产生固体自乳化组合物。
在某些实施方案中,混合步骤包含在连续搅拌下将所述溶液滴加到吸附剂中并将所得到的混合物共混足够时间以获得所述固体自乳化组合物。有利地,固体自乳化组合物可以是自由流动粉末。将溶液加入吸附剂中的速率可以在60-600滴/分钟之间。连续搅拌的速率可以为50至400rpm。混合物可以以100-1000rpm的速率共混5至60分钟。在进一步加工之前可以将混合物保持30分钟至12小时,以使溶液液滴在吸附剂的孔内沉降。
在替代实施方案中,混合步骤包含在连续搅拌下将溶液喷雾到吸附剂上并将所得到的混合物共混足够时间以获得所述固体自乳化组合物。所述固体自乳化组合物可以包含自由流动粉末或结晶粉末。
在一个实施方案中,所述溶液包含稀释因子为约1:1至约1:90的至少一种***素和亲脂性溶剂。
在某些实施方案中,所述溶液包含约3wt%至约40wt%的乳化剂。
在一个实施方案中,所述溶液可以进一步包含抗氧化剂,特别是亲脂性抗氧化剂如dl-α-生育酚。溶液可以包含0.02-1%dl-α-生育酚。
在一些实施方案中,方法还包括将固体自乳化组合物与一种或多种赋形剂共混。
本公开的各种实施方案还提供了包含如上定义的固体自乳化组合物的口服剂量制剂。口服剂量制剂可以是用于口服施用的可接受的药物形式。这种可接受的药物形式的合适实例包括但不限于硬明胶胶囊、软明胶胶囊、羟丙基甲基纤维素(HPMC)胶囊、支链淀粉胶囊、片剂、泡腾片、条、囊片、囊剂、锭剂、悬浮液、栓剂、用于局部吸收的舌下或口腔递送形式、泡腾粉末或用于悬浮液的粉末。
在一个实施方案中,口服剂量制剂可还包含至少一种选自包含以下各项组成的组的药物赋形剂:填充剂、粘合剂、抗结块剂、崩解剂、润滑剂、助流剂、抗氧化剂、着色剂、包衣剂、甜味剂、缓释剂。
在一些实施方案中,CBD可以以约0.5mg至200mg,或约2.5mg至20mg的量存在于口服剂量制剂中。
在一些实施方案中,THC可以以约0.5mg至200mg,或约2.5mg至20mg的量存在于口服剂量制剂中。
在一些实施方案中,亲脂性溶剂可以以约2wt%至约35wt%的量存在于口服剂量制剂中。
在一些实施方案中,乳化剂可以以约1wt%至30wt%的量存在于口服剂量制剂中。
在一些实施方案中,吸附剂可以以约4wt%至约35wt%的量存在于口服剂量制剂中。
在一些实施方案中,抗氧化剂可以以约0.02wt%至约1.0wt%的量存在于口服剂量制剂中。
在一些实施方案中,填充剂和/或粘合剂可以以约10wt%至约60wt%的量存在于口服剂量制剂中。
在一些实施方案中,抗结块剂可以以约5wt%至约45wt%的量存在于口服剂量制剂中。
本公开的一些实施方案涉及如上定义的固体自乳化组合物或口服剂量制剂,其用于制造用于预防、治疗受试者的疾病和/或减轻受试者的疾病的严重程度的药物,其中所述疾病是炎性障碍、神经障碍、精神障碍、恶性肿瘤、免疫障碍、代谢障碍、传染病、胃肠道障碍、心血管障碍、癌症、疼痛中的至少一种。
一些实施方案涉及预防、治疗受试者的疾病和/或减轻受试者的疾病的严重程度的方法,其中所述疾病是炎性障碍、神经障碍、精神障碍、恶性肿瘤、免疫障碍、代谢障碍、传染病、胃肠道障碍、心血管障碍、癌症、疼痛中的至少一种,所述方法包含向有需要的受试者施用有效量的如上定义的固体自乳化组合物或口服剂量制剂。
一些实施方案涉及包含至少一个容器的试剂盒,所述容器包含预定量的如上定义的固体自乳化组合物。
一些实施方案涉及在受试者中提供预定浓度范围内的至少一种***素的血浆浓度的方法,其包含向受试者施用预定量的如上定义的固体自乳化组合物或口服剂量制剂。
一些实施方案涉及用于改善至少一种***素的药代动力学曲线的方法,其包含向需要这种治疗的受试者施用有效量的如上定义的固体自乳化组合物或口服剂量制剂。
具体实施方式
本公开涉及包含至少一种***素的固体自乳化组合物,所述固体自乳化组合物的口服固体剂量制剂和制备所述固体自乳化组合物的方法。
一般术语
在整个说明书中,除非另有特别说明或上下文另有要求,提及单个步骤、物质组成、步骤组或物质组成组应被认为包括一个和多个(即一个或更多个)那些步骤、物质组成、步骤组或物质组成组。因此,如本文所用,单数形式“一个(a)”、“一个(an)”和“该(the)”包括复数方面,除非上下文另外明确指出。例如,提及“一个(a)”包括单个以及两个或更多个;提及“一个(an)”包括单个以及两个或更多个;提及“该(the)”包括单个以及两个或更多个等。
除非另外特别说明,本文所述的本公开的每个实施例在作必要的修正后适用于每个和所有其它实施例。本公开不限于这里描述的具体实施例的范围,其仅用于示例性目的。如本文所述,功能等同的产物、组合物和方法显然在本公开的范围内。
术语“和/或”,例如“X和/或Y”应理解为“X和Y”或“X或Y”,并应被视为对两种含义或其中一种含义提供明确支持。
在整个说明书中,单词“包含(comprise)”或诸如“包含(comprise或comprising)”将被理解为暗示包括所述元件、整体或步骤,或一组元件、整体或步骤,但不排除任何其他元件、整体或步骤,或一组元件、整体或步骤。
除非另外定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。尽管在本发明的实践或测试中可以使用与本文所述的那些类似或等同的方法和材料,但是下面描述了合适的方法和材料。在发生冲突的情况下,以本说明书(包括定义)为准。此外,材料、方法和实施例仅仅是说明性的而不是限制性的。
本文所用的术语“约”是指在给定值或范围的5%内,更优选在1%内。例如,“约3.7%”意指从3.5至3.9%,优选地从3.66至3.74%。当术语“约”与值的范围(例如,“约X%至Y%”)相关联时,术语“约”旨在修饰所述范围的下(X)值和上(Y)值两者。例如,“约20%至40%”相当于“约20%至约40%”。
组合物中的所有重量百分比是相对于整个组合物的重量百分比。
具体术语
如本文所用,术语“自乳化组合物”是指液体或半固体活性成分、油/亲脂性溶剂、表面活性剂和/或助表面活性剂的各向同性混合物,其在用生理流体稀释时形成细乳液/液滴。
关于如本文所用的物质的术语“药学上可接受的”意指适合用于与人和低等动物的组织接触而没有不适当的毒性、刺激、过敏反应等,与合理的益处/风险比相称,并且当所述物质用于药物组合物中时对于预期用途有效的物质。
本文所用的术语“治疗有效量”是指在血流或靶器官中提供期望水平的活性成分以提供预期的生理反应所需的活性成分的量。精确的量将响应于若干因素而变化,所述因素包括但不限于活性成分的类型、活性成分的生物利用度、患者特征(例如年龄、体重、性别)、症状的严重程度、禁忌症等。治疗有效量的活性成分可以以单剂量施用,或通过累积提供治疗效果的量的多剂量施用。‘治疗效果’可以降低疾病、医学病症或一种或多种相关症状的严重程度,和/或可以在疾病或医学病症的部分或完全治愈方面是治疗性的。
固体自乳化组合物
本公开的各种实施方案提供了用于口服固体剂量制剂的固体自乳化组合物,其包含至少一种***素、亲脂性溶剂、乳化剂和吸附剂。
如本文所公开的固体自乳化组合物以可以稳定维持的自由流动粉末的固体形式提供至少一种***素。提供作为自由流动粉末的固体形式的至少一种***素的能力对于其药物用途是有利的,因为***素具有亲脂性/疏水性,这在溶解和生物利用度方面是有问题的。本文所述的组合物在施用给需要治疗的受试者后具有更好的溶解性质并因此具有改善的生物利用度。
本文公开的组合物也是有利的,因为它们可以容易地配制成适于施用给需要治疗的受试者的药学上可接受的口服固体剂量制剂,从而提供关于施用预定治疗有效量的至少一种***素的确定性。
相反,目前可获得的含有一种或多种***素的组合物以液体形式获得,其不稳定并且不便于以预定剂量配制。
目前***素也可以以***植物材料的干燥粉末形式或作为树脂提取物获得。在这些具体形式中,所关注的一种或多种活性成分可以不同的量存在,并且因此难以施用预定的治疗有效剂量。此外,还存在多种***素以及其他***植物成分,例如萜烯、倍半萜烯、胡萝卜素、类黄酮也存在,并且与所关注的活性成分一起共同施用。因此,可以显著改变活性成分的预期治疗效果。
如本文所用的术语“***素”是指一类C21萜酚化合物,其代表在***(Cannabissativa)中发现的一组化合物。该术语包括这样的C21萜酚化合物的合成类似物。
至少一种***素可以选自包含以下各项组成的组:花生四烯酸乙醇胺、2-花生四烯酸甘油、***色烯(cannabichromene,CBC)、***色烯酸(cannabichromenic acid,CBCA)、cannabichormevarin(CBCV)、cannabichromevarinic acid(CBCVA)、***二酚(cannabidiol,CBD)、***二酚酸(cannabidiolic acid,CBDA)、次***二酚(cannabidivarin,CBDV)、次***二酚酸(cannabidivarinic acid,CBDVA)、cannabielsoin(CBE)、***环醇(cannabicyclol,CBL)、cannabinodiol(CBND)、***萜酚(cannabigerol,CBG)、***萜酚酸(cannabigerolic acid,CBGA)、次***萜酚(cannabigerovarin,CBGV)、次***萜酚酸(cannabigerovarinic acid,CBGVA)、***酚(cannabinol,CBN)、***酚酸(cannabinolic acid,CBNA)、***三醇(cannabitriol,CBT)、δ-8-四氢***萜醇(delta-8-tetrahydrocanninol)、δ-8-四氢***酚酸(deleta-8-tetrahydrocannabinolic acid)、δ-9-四氢***酚(delta-9-tetrahydrocannabinol,THC)、δ-9-四氢***酚酸(delta-9-tetrahydrocannabinolic acid,THCA)、δ-9-四氢次***酚(delta-9-tetrahydrocannabivarin,THCV)、δ-9-四氢次***酚酸(delta-9-tetrahydrocannabivarinic acid,THCVA)、11-去甲-9-羧基-δ-9-四氢***酚(11-nor-9-carboxy-delta-9-tetrahydrocannabinol,THCCOOCH)、11-去甲-9-羧基-δ-8-四氢***酚(11-nor-9-carboxy-delta-8-tetrahydrocannabinol)、11-羟基-δ-8-四氢***酚(11-hydroxy-delta-8-tetrahydro-cannabinol)和11-羟基-δ-9-四氢***酚(11-hydroxy-delta-9-tetrahydrocannabinol)、二甲基庚基戊基***二酚(dimethyl heptylpentylcannabidiol,DMHP-CBD)、6,12-二氢-6-羟基***二酚、(3S,4R)-7-羟基-δ6-四氢***酚同系物和衍生物、(+)-4-[4-DMH-2,6-二乙酰氧基-苯基]-2-羧基-6,6-二甲基双环[3.1.1]庚-2-烯和其他4-苯基烯(4-phenylpinene)衍生物和***二酚(-)(CBD)类似物,如(-)CBD-单甲醚、(-)CBD二甲醚;(-)CBD二乙酸酯;(-)3'-乙酰基-CBD单乙酸酯、***酚丙基变体(CBNV)和***隆。
该固体自乳化组合物可以包含***二酚(cannabidiol,CBD)、δ-9-四氢***酚(delta-9-tetrahydrocannabinol,THC),或CBD和THC的混合物,比例可以从1:100至100:1、1:10至10:1,或1:1变化。
在亲脂性溶剂中提供测定量的至少一种***素。特别地,亲脂性溶剂中的所述至少一种***素以约1:1至约1:90的稀释因子存在。亲脂性溶剂包括植物油、中链甘油三酯或其混合物。可适用于本公开的实施方案的植物油的实例包括棉籽油、红花油、向日葵油、花生油、亚麻子油、玉米油、橄榄油、椰子油、大豆油、芝麻油、鼠尾草(Salvia Hispanica L.)籽油、小麦胚芽油、低芥酸菜籽油、蓖麻油、氢化蓖麻油及其任何混合物。
本文所用的术语“中链甘油三酯(MCT)”是指其脂肪酸具有6-12个碳原子的脂族尾部的甘油三酯。可适用于本公开的实施方案的中链甘油三酯的实例包括三己酸甘油酯、三辛酸甘油酯、三癸酸甘油酯、三月桂酸甘油酯及其混合物。应当理解,术语“中链甘油三酯”还涵盖具有8和10个碳原子的饱和脂肪酸例如辛酸和癸酸的甘油三酯的混合物。
在组合物中包含乳化剂有利于液体自乳化组合物的形成。所述液体自乳化组合物通常通过将至少一种***素溶解在所述亲脂性溶剂中并将所述溶液与所述乳化剂混合或共混来制备。
所述乳化剂可以是表面活性剂,特别是非离子表面活性剂。如本文所用,术语“非离子表面活性剂”是指具有共价键合的含氧亲水性基团的有机化合物,所述含氧亲水性基团键合到疏水性母体结构,并且能够降低两种不可混溶的液体,特别是亲水性液体和疏水性液体之间的表面张力。
特别地,乳化剂可以是聚乙氧基化非离子表面活性剂。适用于本文公开的组合物中的聚乙氧基化非离子表面活性剂的实例包含乙氧基化直链醇、乙氧基化烷基酚、酸乙氧基化脂肪酸、甘油酯、己糖醇和环状脱水己糖醇的酯。特别地,乳化剂可以是聚烃氧基蓖麻油。
乳化剂还促进至少一种***素在分子水平上的亲脂性溶液在吸附剂中的分散,以提供如本文所公开的固体自乳化组合物。本文所用的术语“固体自乳化组合物”是指适用于口服固体剂量制剂的粉末或纳米颗粒形式的液体自乳化组合物的固相。组合物的特征在于它们的流动性,其允许将它们配制成口服固体剂量制剂。
所述固体自乳化组合物可以包含约3wt%至约40wt%的乳化剂。
该吸附剂可以包含惰性颗粒材料。例如,惰性颗粒材料可以包含无定形二氧化硅。本文所用的术语“无定形”是指非晶态。无定形二氧化硅的合适实例包括但不限于以商品名Aeroperl 300Pharma grade,Syloid244FP二氧化硅、Syloid XDP二氧化硅出售的胶态无定形二氧化硅,Supernat范围的二氧化硅或Aerosil范围的胶态二氧化硅。
或者,惰性颗粒材料可以是药学上可接受的金属氧化物。药学上可接受的金属氧化物的合适实例包括但不限于氧化锌、二氧化钛、氧化铈和氧化铁。
在另一个实施方案中,惰性颗粒材料可包含微晶纤维素、硅化微晶纤维素、粉末状纤维素、淀粉、右旋糖、多糖和葡萄糖结合剂(dextrate)。
该惰性颗粒材料可以具有在从约20微米至约60微米的范围内的粒度。可以使用光学显微术、激光衍射粒度分析、动态光散射、成像颗粒分析或本领域技术人员已知的其他技术来测量粒度分布。
惰性颗粒材料可以是介孔的,具有在约1.5mL/g至约1.9mL/g范围内的介孔体积。如本文所用,术语“介孔”是指尺寸范围为约2nm至约100nm的孔。这些孔被分类为“开放的孔”或“封闭的孔”,这些“开放的孔”穿过颗粒的表面连接并且开放到颗粒的表面上,这些“封闭的孔”被密封以防止流体从颗粒的表面进入。颗粒的孔径分布和总孔体积可以使用气体吸附和测比重术或本领域技术人员已知的其他技术来测量。
该惰性颗粒材料可以具有从约260至约320m2/g的表面积。
吸附剂与液体自乳化组合物的重量比可为约1:1.0至约1:2,特别是约1:1.5至约1:1.75,甚至约1:1.588至约1:1.65。
该固体自乳化组合物可以进一步包含抗氧化剂以增加稳定性,特别是亲脂性抗氧化剂如dl-α-生育酚。所述抗氧化剂可以以约0.02wt%至约1.0wt%的量存在于所述组合物中。
本文所述的固体自乳化组合物可以采取自由流动粉末或结晶粉末的形式,并且口服剂量制剂可以方便地配制成用于口服施用的可接受的药物形式。这种可接受的药物形式的合适实例包括但不限于硬明胶胶囊、软明胶胶囊、羟丙基甲基纤维素(HPMC)胶囊、支链淀粉胶囊、片剂、泡腾片、条、囊片、囊剂、锭剂、悬浮液、栓剂、用于局部吸收的舌下或口腔递送形式、泡腾粉末或用于悬浮液的粉末。
通常,口服剂量制剂还可包含至少一种选自包含以下各项组成的组的药物赋形剂:填充剂、粘合剂、抗结块剂、崩解剂、润滑剂、助流剂、防腐剂、抗氧化剂、表面活性剂、泡腾赋形剂、着色剂、包衣剂、甜味剂、缓释剂等,以用于其常规目的,并且以不会不利地影响组合物的性质的典型量包含所述药物赋形剂。
填充剂和粘合剂的合适实例包括但不限于乳糖、甘露醇、木糖醇、微晶纤维素、甲基纤维素、磷酸氢钙(无水和二水合物)、淀粉及其任何组合。
可包括抗结块剂以防止块(结块)的形成并有助于口服固体剂量制剂的流动性能。抗结块剂的合适实例包括但不限于二氧化硅、乳糖、磷酸三钙及其任何组合。
可以将崩解剂加入到口服固体剂量制剂中以帮助它们的解聚集并且当它们与水分接触时引起固体的快速崩解。崩解剂的合适实例包括但不限于玉米淀粉、马铃薯淀粉、羟基乙酸淀粉钠、藻酸钠、羧甲基纤维素钠、甲基纤维素和交联羧甲纤维素钠、交联聚维酮和交联形式的聚乙烯吡咯烷酮及其任何组合。
可将润滑剂和助流剂加入口服固体剂量制剂中以通过减少颗粒间摩擦来增强粉末流动。润滑剂的合适实例包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酰富马酸钠、滑石及其任何组合。
助流剂的合适实例包括但不限于金属硅酸盐、二氧化硅例如胶体无水二氧化硅,高级脂肪酸金属盐、金属氧化物、碱土金属盐、金属氢氧化物及其任何组合。
可以向口服固体剂量制剂中加入防腐剂,以通过减少活性成分随时间的降解和变化来延长所述制剂的储存寿命。防腐剂的合适实例包括但不限于亚硫酸盐、苯扎氯铵、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲醇、苯甲酸钠及其任何组合。
抗氧化剂是一类抑制其它分子氧化的防腐剂。抗氧化剂的合适实例包括但不限于基于酚的抗氧化剂,如丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、叔丁基对苯二酚(TBHQ)、4-羟甲基-2,6-二叔丁基酚(HMBP)、2,4,5-三羟基-丁酰苯(THBP)、没食子酸丙酯(PG)、没食子酸三戊酯、没食子酸(GA)、生育酚乙酸酯,还原剂,如L-抗坏血酸(维生素C)、L-抗坏血酸棕榈酸酯、L-抗坏血酸硬脂酸酯、巯基乙酸(TGA)、抗坏血酸棕榈酸酯(ASP),基于亚硫酸盐的抗氧化剂,如亚硫酸钠、偏亚硫酸氢钠、亚硫酸氢钠和硫代甘油以及其它试剂,如乙二胺四乙酸二钠(EDTA)、焦磷酸钠、偏磷酸钠、甲硫氨酸、异抗坏血酸和卵磷脂及其任何组合。
表面活性剂可用于通过促进固体自乳化组合物的润湿来增加其溶解速率。表面活性剂的合适实例包括脂肪酸和烷基磺酸酯、苯扎氯铵、磺基琥珀酸二辛酯钠、聚氧乙烯脱水山梨糖醇脂肪酸酯、天然表面活性剂如牛磺胆酸钠、1-棕榈酰基-2-油酰基-sn-甘油基-3-磷酸胆碱、卵磷脂,以及其它磷脂和单和二甘油酯,以及其任何组合。
泡腾赋形剂可与酸性剂组合以粉末和片剂使用,以引起产生二氧化碳的反应。泡腾赋形剂的合适实例包括碳酸氢钠、碳酸氢钾、碳酸氢镁、碳酸氢铵。泡腾赋形剂可以与酸性剂、典型地弱有机酸如柠檬酸和/或抗坏血酸组合。
口服固体剂量制剂可另外包括无机盐如氯化钠、氯化钾、氯化钙、磷酸钠、磷酸钾、碳酸氢钠和有机盐如柠檬酸钠、柠檬酸钾、乙酸钠等。
在一些实施方案中,如本文所述的口服固体剂量制剂可以包含至多约40wt%的量的所述至少一种***素。在一些实施方案中,包含在所述口服固体剂量制剂中的所述至少一种***素的量可以为至多至少1wt%、5wt%、10wt%、15wt%、20wt%、25wt%、30wt%、35wt%和40wt%,并且进一步在至少0.1-1wt%、1-5wt%、5-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%、30-35wt%、35-40wt%的范围内。
在一些具体的实施方案中,口服固体剂量制剂可以包含约0.5mg至约200mg,或约2.5mg至约20mg的量的CBD。
在一些具体实施方案中,口服固体剂量制剂可以包含约0.5mg至约200mg,或约2.5mg至约20mg的量的THC。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含约2wt%、5wt%、10wt%、15wt%、20wt%、25wt%、30wt%和35wt%,并且进一步在至少2-5wt%、5-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%、30-35wt%的范围内的量的亲脂性溶剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含约1wt%、5wt%、10wt%、15wt%、20wt%、25wt%和30wt%,并且进一步在至少0.1-1wt%、1-5wt%、5-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%的范围内的量的乳化剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含约4wt%、8wt%、10wt%、15wt%、20wt%、25wt%、30wt%、35wt%、40wt%、45wt%、50wt%、55wt%、60wt%、65wt%、70wt%、75wt%和80wt%,并且进一步在至少4-8wt%、8-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%、30-35wt%、35-40wt%、40-45wt%、45-50wt%、50-55wt%、55-60wt%、60-65wt%、65-70wt%、70-75wt%、75-80wt%的范围内的量的吸附剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含约0.01wt%、0.05wt%、0.1wt%、0.2wt%、0.3wt%、0.4wt%、0.5wt%、0.6wt%、0.7wt%、0.8wt%、0.9wt%和1.0wt%的量的抗氧化剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含0wt%、15wt%、20wt%、25wt%、30wt%、35wt%、40wt%、45wt%、50wt%、60wt%,并且进一步在至少5-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%、30-35wt%、35-40wt%、40-45wt%、45-50wt%、50-60wt%的范围内的量的填充剂和/或粘合剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含5wt%、10wt%、15wt%、20wt%、25wt%、30wt%、35wt%、40wt%、45wt%、50wt%,并且进一步至少在5-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%、30-35wt%、35-40wt%、40-45wt%的范围内的量的抗结块剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含1wt%、5wt%、10wt%、15wt%、20wt%、25wt%、30wt%,并且进一步在至少1-5wt%、5-10wt%、10-15wt%、15-20wt%、20-25wt%、25-30wt%的范围内的量的表面活性剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含约0.1wt%、0.2wt%、0.5wt%、1.0wt%、2wt%、3wt%、4wt%、5wt%的量的助流剂和/或润滑剂。
在一些实施方案中,本文所述的口服固体剂量制剂可以包含约0.1wt%、0.2wt%、0.3wt%、0.4wt%、0.5wt%、0.6wt%、0.7wt%、0.8wt%、0.9wt%and 1.0wt%的量的崩解剂。
本文公开的组合物也是有利的,因为它们可以容易地配制成适于施用给需要治疗焦虑或恶心的非人动物的兽医学上可接受的口服固体剂量制剂,从而提供关于施用预定治疗有效量的至少一种***素的确定性。合适的非人动物包括但不限于伴侣动物例如猫和狗,实验室动物例如猿、猴、兔和啮齿动物,家畜例如牛、绵羊、山羊、猪或鹿,和动物园动物。
所述兽医学上可接受的口服固体剂量制剂包含如本文所述的固体自乳化组合物和生理学上可接受的载体。本文所用的术语“生理学上可接受的赋形剂”包括适于口服固体剂量和非人哺乳动物的稀释剂、粘合剂、干燥剂、崩解剂、着色剂、调味剂、稳定剂、润滑剂/助流剂、增塑剂和防腐剂中的一种或多种。赋形剂基于最终口服固体剂量制剂的所需物理方面来选择并且可以以与上述相同的量存在。
合适的崩解剂可包括交联羧甲纤维素钠、羟基乙酸淀粉钠、交联聚维酮、低取代羟丙基纤维素中的一种或多种,以及其混合物。
合适的粘合剂可以包括甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、明胶、***树胶、乙基纤维素、聚乙烯醇、支链淀粉、预胶化淀粉、琼脂、黄蓍胶、藻酸钠及其混合物中的一种或多种。
合适的稀释剂可包括纤维素粉末、葡萄糖结合剂、糊精、右旋糖赋形剂、果糖、高岭土、乳糖醇、乳糖、甘露醇、山梨醇、淀粉、预凝胶化淀粉、蔗糖、可压缩糖、糖果及其混合物中的一种或多种。
合适的润滑剂和/或助流剂可以包括胶体无水二氧化硅、硬脂酸镁、硬脂酸、硬脂酸镁、硬脂酸钙、滑石、氢化蓖麻油、脂肪酸的蔗糖酯、微晶蜡、黄蜂蜡、白蜂蜡及其混合物中的一种或多种。
如本文所用的术语“调味剂”是指可以加入到兽医学上可接受的口服固体剂量制剂中以改善非人动物受试者的适口性并且可以采取蛋白质、脂肪、碳水化合物、酵母或其混合物的形式的成分或化合物。合适的调味剂包括但不限于人造或天然牛肉调味剂、人造或天然鸡肉调味剂、猪肝提取物、人造肉调味剂、蜂蜜、酵母、麦芽等。调味剂可以基于固体口服剂量制剂的总重量以10-40wt%,特别是20-30wt%或20-25wt%的量存在于兽医学上可接受的口服固体剂量制剂中。
一种固体自乳化组合物的制备方法
本公开提供了用于制备如上所述的固体自乳化组合物和口服固体剂量制剂的方法。
在一些实施方案中,一种制备固体自乳化组合物的方法,其包含:
a)提供至少一种***素和乳化剂在亲脂性溶剂中的溶液;
b)将所述溶液与吸附剂混合以产生固体自乳化组合物。
应当理解,亲脂性溶剂包含预定量的至少一种***素。所述***素的预定量可以通过本领域技术人员熟知的分析技术测定亲脂性溶液来确定,例如高压液相色谱法(HPLC)、气相色谱法(GC)、气相色谱-质谱法、液相色谱-NMR光谱法等。
该混合步骤可以包含在连续搅拌下将所述溶液滴加到所述吸附剂中并且将所得到的混合物共混足够时间以获得所述固体自乳化组合物,其中所述组合物是一种自由流动粉末或结晶粉末。所述溶液可以用具有0.3mm至2mm的孔尺寸的常规滴管滴加到吸附剂中。
吸附剂可以用叶轮或高剪切共混机搅拌。将溶液加入吸附剂中的速率可以在60-360滴/分钟之间。连续搅拌的速率可以为50至400rpm。该混合物可以以100-1000rpm的速率共混5-60分钟。在加工之前可以将混合物保持30分钟至12小时,以使溶液液滴在吸附剂的孔内沉降。
或者,混合步骤可包含在连续搅拌下将所述溶液喷雾到所述吸附剂上并且将所得到的混合物共混足够时间以获得所述固体自乳化组合物,其中所述组合物是一种自由流动粉末或结晶粉末。
然后可将所得固体自乳化组合物通过分级筛筛分,通常为200微米至1000微米,特别是425微米。可以在以100rpm至500rpm的切碎机速度操作达15分钟的常规共混机中将上述一种或多种赋形剂与固体自乳化组合物共混。
在一些实施方案中,所述方法还包含将所述固体自乳化组合物与一种或多种如上所述的赋形剂共混。
试剂盒
作为口服固体剂量制剂的替代,固体自乳化组合物可以方便地以试剂盒的形式提供,其包含至少一个包含预定量的固体自乳化组合物的容器。该容器可以具有多个隔室,这些隔室被配置成用于容纳多个预定量的所述组合物。所述组合物的预定量可以相同或不同,从而有助于不同剂量的施用或以不同间隔施用相同剂量。此外,容器的多个隔室中的至少一个可以另外地或可选地包含营养物或治疗剂。此外,该多个隔室中的至少一个可以另外地或可替代地含有调味的粉末或调味的液体介质以改善该固体自乳化组合物的风味,由此帮助施用该固体自乳化组合物。
该试剂盒可以用于实现受控的治疗效果,由此该剂量可以针对受试者的需要或症状定制,并且由此施用治疗有效量的至少一种***素,任选地与营养物或治疗剂组合。
所述营养物可以是维生素、维生素补充剂如ω脂肪酸、ω-3-脂肪酸或矿物质。
治疗剂可以是针对其临床效果和适用于治疗人类疾病、病症或障碍而选择的药物或药物组合。这些药物可选自镇痛药、抗酸药、抗焦虑药、抗心律失常药、抗菌剂、抗生素、抗微生物药、抗凝剂和溶栓剂、抗惊厥剂、抗抑郁药、抗腹泻剂、止吐剂、抗癫痫药、抗真菌剂、抗组胺药、抗高血压药、抗炎药、抗肿瘤药、抗精神病药、退热剂、抗痉挛剂、抗病毒剂、巴比妥酸盐、β-阻断剂、支气管扩张剂、感冒药、降胆固醇药、皮质类固醇、咳嗽抑制剂、细胞毒素、减充血剂、利尿剂、祛痰剂、激素、降血糖剂、免疫抑制剂、轻泻剂、肌肉松弛剂、镇静剂、性激素、睡眠药、溶瘤剂和镇定剂。
临床应用
应当理解,本文所述的固体自乳化组合物或口服固体剂量制剂可以治疗性地使用,换言之,用于预防、治疗广泛范围的人类疾病、病症和障碍和/或减轻其严重性,所述疾病、病症和障碍包括炎性、神经、精神障碍、恶性肿瘤和进一步的免疫、代谢障碍、营养缺乏、传染病和胃肠道障碍类型、心血管障碍和各种类型的疼痛(包括慢性和神经性疼痛)。
鉴于目前关于***素在患者中的临床应用的理解,本文所述的固体自乳化组合物或口服固体剂量制剂可以适用于,尽管不仅适用于,抑郁症、睡眠障碍、进食障碍、癌症、多发性硬化、移植物抗宿主病(GVHD)、帕金森病、癫痫、孤独症、结核病、溃疡性结肠炎、克罗恩病、炎性肠病(IBD)、肠易激综合征(IBS)、食欲刺激剂、食欲抑制剂、肥胖症、恶心、神经性疼痛、焦虑、阿尔茨海默病、肌萎缩性侧索硬化(ALS)、胃肠障碍、高血压、失禁、瘙痒、关节炎、关节病、风湿性炎症、失眠、真菌病、局部和/或慢性疼痛、炎症、注意力缺乏和活动过强障碍(ADDH)、呕吐、特应性皮炎、纤维肌痛、自身免疫缺陷综合征(AIDS)、情绪障碍、***功能障碍、癌症、早泄、骨生长、难治性癫痫,特别是难治性儿童癫痫中的至少一种。
施用如本文所述的固体自乳化组合物或口服剂量制剂的剂量或频率将容易由本领域技术人员确定,并且取决于年龄、体重、一般身体状况或对待治疗的受试者特异的其他临床症状。
与目前可获得的***素的口服剂量制剂相比,本文所述的固体自乳化组合物或口服剂量制剂中的所述至少一种***素的生物利用度得到改善,从而导致所述至少一种***素的药代动力学曲线改善。如本文所用的术语“改善的药代动力学曲线”是指与一种或更多种***素的常规口服剂量制剂相比,以下标准中的一个或更多个:1)高平均Cmax;2)具有降低的变化的药代动力学参数;和/或3)降低的有效剂量。
本领域技术人员将理解,在不偏离本公开的广泛的一般范围的情况下,可以对上述实施方案进行许多变化和/或修改。因此,本实施方案在所有方面都被认为是说明性的而非限制性的。
实施例
以下实施例仅应理解为示例性的。因此,不应将它们解释为以任何方式限制本发明。
根据以下程序制备如下表中所述的包括活性成分和赋形剂的量的口服固体剂量制剂。
将所需量的含有CBD、THC或CBD:THC的混合物的***素树脂放入不锈钢或玻璃容器中。将大约一半所需量的中链甘油三酯(MCT)与树脂一起转移到容器中,并将合适尺寸的磁力搅拌棒或共混机放置到容器中。以避免形成涡流的速度缓慢搅拌混合物,直到树脂溶解。然后向容器中加入维生素E,接着加入剩余的MCT,并将混合物共混直至均匀。
所需量的聚烃氧基蓖麻油(例如Kolliphor EL”)加入到***素的亲脂性溶液中并以避免涡流的速度共混10-30分钟。
将所需量的胶体无水二氧化硅转移到共混机中,并将预定量的***素的亲脂性溶液以约60-600滴/分钟的速率滴加到二氧化硅中,其在叶轮速度为50-400rpm的连续搅拌下进行。
加入亲脂性溶液后,将混合物以100-1000rpm的叶轮速度混合约10分钟。可通过使固体自乳化组合物通过425微米孔径的筛来除去任何块。
在加入赋形剂之前,将各干粉赋形剂通过425微米孔径筛过筛。将预筛分的微晶纤维素和磷酸三钙转移到共混机中并铺展在固体自乳化组合物床上。
然后将叶轮速度设定为200-500rpm,并将混合物共混大约15-30分钟,直到获得均匀的共混物。然后将预筛分的硬脂酸镁转移到共混机中,将叶轮速度设定为200至500rpm,并将混合物共混120至300秒。
然后将最终的母料共混物排放到合适的中型散装容器中用于运输和/或储存。
最终的主共混物可以在封装机器中加工以填充硬壳羟丙基甲基纤维素胶囊。然后可以将填充的硬壳羟丙基甲基纤维素胶囊包装在泡罩包装中并且进一步包装在批准尺寸的“可上架”纸箱中。
口服固体剂量制剂1
口服固体剂量制剂2
口服固体剂量制剂3
固体口服剂量制剂4
口服固体剂量制剂5
Claims (47)
1.一种用于口服固体剂量的固体自乳化组合物,其包含至少一种***素、亲脂性溶剂、乳化剂和吸附剂。
2.根据权利要求1的组合物,其中所述至少一种***素选自包含以下各项组成的组:花生四烯酸乙醇胺、2-花生四烯酸甘油、***色烯(cannabichromene,CBC)、***色烯酸(cannabichromenic acid,CBCA)、cannabichormevarin(CBCV)、cannabichromevarinicacid(CBCVA)、***二酚(cannabidiol,CBD)、***二酚酸(cannabidiolic acid,CBDA)、次***二酚(cannabidivarin,CBDV)、次***二酚酸(cannabidivarinic acid,CBDVA)、cannabielsoin(CBE)、***环醇(cannabicyclol,CBL)、cannabinodiol(CBND)、***萜酚(cannabigerol,CBG)、***萜酚酸(cannabigerolic acid,CBGA)、次***萜酚(cannabigerovarin,CBGV)、次***萜酚酸(cannabigerovarinic acid,CBGVA)、***酚(cannabinol,CBN)、***酚酸(cannabinolic acid,CBNA)、***三醇(cannabitriol,CBT)、δ-8-四氢***萜醇(delta-8-tetrahydrocanninol)、δ-8-四氢***酚酸(deleta-8-tetrahydrocannabinolic acid)、δ-9-四氢***酚(delta-9-tetrahydrocannabinol,THC)、δ-9-四氢***酚酸(delta-9-tetrahydrocannabinolic acid,THCA)、δ-9-四氢次***酚(delta-9-tetrahydrocannabivarin,THCV)、δ-9-四氢次***酚酸(delta-9-tetrahydrocannabivarinic acid,THCVA)、11-去甲-9-羧基-δ-9-四氢***酚(11-nor-9-carboxy-delta-9-tetrahydrocannabinol,THCCOOCH)、11-去甲-9-羧基-δ-8-四氢***酚(11-nor-9-carboxy-delta-8-tetrahydrocannabinol)、11-羟基-δ-8-四氢***酚(11-hydroxy-delta-8-tetrahydro-cannabinol)和11-羟基-δ-9-四氢***酚(11-hydroxy-delta-9-tetrahydrocannabinol)、二甲基庚基戊基***二酚(dimethyl heptylpentylcannabidiol,DMHP-CBD)、6,12-二氢-6-羟基***二酚、(3S,4R)-7-羟基-δ6-四氢***酚同系物和衍生物、(+)-4-[4-DMH-2,6-二乙酰氧基-苯基]-2-羧基-6,6-二甲基双环[3.1.1]庚-2-烯和其他4-苯基烯(4-phenylpinene)衍生物和***二酚(-)(CBD)类似物,如(-)CBD-单甲醚、(-)CBD二甲醚;(-)CBD二乙酸酯;(-)3'-乙酰基-CBD单乙酸酯、***酚丙基变体(CBNV)和***隆。
3.根据权利要求2所述的组合物,其中所述***素包含***二酚(CBD)。
4.根据权利要求2所述的组合物,其中所述***素包含δ-9-四氢***酚(THC)。
5.根据权利要求2所述的组合物,其中所述***素包含比例为1:100至100:1的CBD和THC。
6.根据前述权利要求中任一项所述的组合物,其中所述亲脂性溶剂包含植物油、中链甘油三酯或其混合物。
7.根据前述权利要求中任一项所述的组合物,其中所述乳化剂包含表面活性剂。
8.根据权利要求7所述的组合物,其中所述乳化剂包含非离子表面活性剂。
9.根据权利要求8所述的组合物,其中所述乳化剂包含聚乙氧基化非离子表面活性剂。
10.根据前述权利要求中任一项所述的组合物,其中所述吸附剂包含惰性颗粒材料。
11.根据权利要求10所述的组合物,其中所述惰性颗粒材料具有在约3微米至约350微米范围内的粒度。
12.根据权利要求11所述的组合物,其中所述惰性颗粒材料具有在约20微米至约60微米范围内的粒度。
13.根据权利要求10至12中任一项所述的组合物,其中所述惰性颗粒材料是中孔的,其中孔体积在约1.5mL/g至约1.9mL/g的范围内。
14.根据权利要求10至13中任一项所述的组合物,其中所述惰性颗粒材料具有约150至约350m2/g的表面积。
15.根据权利要求10至14中任一项所述的组合物,其中所述惰性颗粒材料具有约260至约320m2/g的表面积。
16.根据权利要求10至15中任一项所述的组合物,其中所述惰性颗粒材料包含无定形二氧化硅。
17.根据权利要求10至15中任一项所述的组合物,其中所述惰性颗粒材料包含药学上可接受的金属氧化物。
18.根据权利要求10至15中任一项所述的组合物,其中所述惰性颗粒材料包含微晶纤维素、硅化微晶纤维素、粉末状纤维素、淀粉、右旋糖、多糖和葡萄糖结合剂(dextrate)。
19.根据前述权利要求中任一项所述的组合物,进一步包含亲脂性抗氧化剂。
20.一种制备固体自乳化组合物的方法,其包含:
a)提供至少一种***素和乳化剂在亲脂性溶剂中的溶液;
b)将所述溶液与吸附剂混合以产生固体自乳化组合物。
21.根据权利要求20所述的方法,其中所述混合步骤包含在连续搅拌下将所述溶液滴加到所述吸附剂中并且将所得到的混合物共混足够时间以获得所述固体自乳化组合物,其中所述组合物是一种自由流动粉末。
22.根据权利要求21所述的方法,其中将所述溶液加入到所述吸附剂中的速率在60-600滴/分钟之间。
23.根据权利要求21或22所述的方法,其中所述连续搅拌的速率是从约50rpm至约400rpm。
24.根据权利要求20至23中任一项所述的方法,其中将所得到的混合物以100-1000rpm的速率共混5-60分钟。
25.根据权利要求20所述的方法,其中所述混合步骤包含在连续搅拌下将所述溶液喷雾到所述吸附剂上并且将所得到的混合物共混足够时间以获得所述固体自乳化组合物,其中所述组合物是一种自由流动粉末。
26.根据权利要求20至25中任一项所述的方法,进一步包含将所述固体自乳化组合物与一种或多种赋形剂共混。
27.根据权利要求20至26中任一项所述的方法,其中所述溶液包含以约1.1至约1:90的稀释因子存在于所述亲脂性溶剂中的所述至少一种***素。
28.根据权利要求20至27中任一项所述的方法,其中所述溶液包含约3wt%至约40wt%的乳化剂。
29.根据权利要求20至28中任一项所述的方法,其中所述溶液进一步包含亲脂性抗氧化剂。
30.根据权利要求29所述的方法,其中所述溶液包含0.02-1%dl-α-生育酚。
31.一种口服剂量制剂,其包含如权利要求1至19中任一项所定义的固体自乳化组合物。
32.根据权利要求31所述的口服剂量制剂,其中所述口服剂量制剂还包含至少一种选自包含以下各项组成的组的药物赋形剂:填充剂、粘合剂、抗结块剂、崩解剂、润滑剂、助流剂、抗氧化剂、调味剂、着色剂、包衣剂、甜味剂、缓释剂。
33.根据权利要求31或32所述的口服剂量制剂,其中CBD以约0.5mg至50mg的量存在于所述口服剂量制剂中。
34.根据权利要求33所述的口服剂量制剂,其中CBD以约2.5mg至20mg的量存在于所述口服剂量制剂中。
35.根据权利要求31至34中任一项所述的口服剂量制剂,其中THC以约0.5mg至50mg的量存在于所述口服剂量制剂中。
36.根据权利要求35所述的口服剂量制剂,其中THC以约2.5mg至20mg的量存在于所述口服剂量制剂中。
37.根据权利要求31至36中任一项所述的口服剂量制剂,其中所述亲脂性溶剂以从约2wt%至约35wt%的量存在于所述口服剂量制剂中。
38.根据权利要求31至37中任一项所述的口服剂量制剂,其中所述乳化剂以约1wt%至30wt%的量存在于所述口服剂量制剂中。
39.根据权利要求31至38中任一项所述的口服剂量制剂,其中所述吸附剂以从约4wt%至约80wt%的量存在于所述口服剂量制剂中。
40.根据权利要求32至39中任一项所述的口服剂量制剂,其中所述抗氧化剂以从约0.02wt%至约1.0wt%的量存在于所述口服剂量制剂中。
41.根据权利要求32至40中任一项所述的口服剂量制剂,其中所述填充剂和/或粘合剂以从约10wt%至约60wt%的量存在于所述口服剂量制剂中。
42.根据权利要求32至41中任一项所述的口服剂量制剂,其中所述抗结块剂以约5wt%至约45wt%的量存在于所述口服剂量制剂中。
43.根据权利要求1至19中任一项所述的固体自乳化组合物或根据权利要求31至42中任一项所述的口服剂量制剂在制造用于预防、治疗受试者的疾病和/或减轻受试者的疾病的严重程度的药物中的用途,其中所述疾病是炎性障碍、神经障碍、精神障碍、恶性肿瘤、免疫障碍、代谢障碍、传染病、胃肠道障碍、心血管障碍、癌症、疼痛中的至少一种。
44.一种预防、治疗受试者的疾病和/或减轻受试者的疾病的严重程度的方法,其中所述疾病是炎性障碍、神经障碍、精神障碍、恶性肿瘤、免疫障碍、代谢障碍、营养缺乏、传染病、胃肠道障碍、心血管障碍、癌症、疼痛中的至少一种,所述方法包含向有需要的受试者施用有效量的根据权利要求1至19中任一项所述的固体自乳化组合物或根据权利要求31至42中任一项所述的口服剂量制剂。
45.一种试剂盒,所述试剂盒包含至少一个容器,所述容器包含预定量的根据权利要求1至19中任一项所述的固体自乳化组合物。
46.一种在受试者中提供预定浓度范围的至少一种***素的血浆浓度的方法,所述方法包括向所述受试者施用预定量的根据权利要求1至19中任一项所述的固体自乳化组合物或根据权利要求31至42中任一项所述的口服剂量制剂。
47.一种用于改善至少一种***素的药代动力学曲线的方法,所述方法包含向需要这种治疗的受试者施用有效量的根据权利要求1至19中任一项所述的固体自乳化组合物或根据权利要求31至42中任一项所述的口服剂量制剂。
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