CN107735086A - 大麻油的氢化 - Google Patents
大麻油的氢化 Download PDFInfo
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- CN107735086A CN107735086A CN201680035037.5A CN201680035037A CN107735086A CN 107735086 A CN107735086 A CN 107735086A CN 201680035037 A CN201680035037 A CN 201680035037A CN 107735086 A CN107735086 A CN 107735086A
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- hydrogenation
- essential oil
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- cannabis
- oil
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Abstract
本发明涉及大麻植物精油的提取和氢化。本发明包括氢化大麻化合物和组合物、及制备方法和用于使癌症患者中的肿瘤退缩的治疗用途。所述提取物可以包括9‑四氢大麻酚酸和9‑大麻二酚酸,所述氢化的大麻油可以包括氢化的9‑四氢大麻酚酸、氢化的9‑大麻二酚酸、及其混合物和掺合物。
Description
相关申请的交叉引用
本申请要求在35U.S.C.§119(e)下2015年5月7日提交的名称为“大麻油的氢化”的美国临时专利申请系列号62/158,025的优先权,将其通过援引并入本文中。
发明领域
本发明一般涉及大麻植物精油的氢化,所述大麻植物包括大麻植物品种大麻(Cannabis sativa)、印度大麻(C.indica)和莠草大麻(C.ruderalis)。植物精油的氢化提供了六氢大麻素类(hexahydrocannabanoids)富集的来源,所述六氢大麻素类用于治疗多种病症和疾病,比如,但不限于癌症。
背景技术
一般而言,已经证实六氢大麻素类(HHC)是抑制细胞增殖和肿瘤血管生成的抗癌化合物(Eur J Pharmacol.2011 650(1):64-71)。六氢大麻素类似物LYR-8在人结肠直肠肿瘤异种移植物中的抗-肿瘤活性经由抑制Akt和低氧-可诱导的因子-1α的活化介导。已经通过各种方法制备了HHC化合物,所述方法包括在美国专利申请公布2010/0298579A1中描述的方法。该合成制备方法包括用取代的3-酰基-间苯二酚进行香茅醛的关键胺催化环化。
本领域需要改善用于制备包括HHC的氢化大麻油的方法以及氢化大麻油的治疗用途。
发明简述
本发明涉及从大麻油的氢化得到的产物,例如化合物,包括所述产物的组合物,以及制备所述产物的方法。氢化将大麻油中存在的大麻素类以及萜类、黄酮类和甾醇类转化成于氢化大麻油(HCO)混合物中的它们的氢化衍生物。HCO产品中氢化化合物的含量取决于起始大麻油中前体的含量,其会基于所应用的植物种类变化。进一步,形成的氢化化合物可取决于使用的氢化反应条件,并且可以通过改变使用的反应条件和氢化催化剂形成不同的产物化合物。
在一个方面,本发明提供氢化大麻油的方法,包括获得具有精油的大麻植物,所述精油包括9-四氢大麻酚酸(tetrahydrocannabinoic acid)和9-大麻二酚酸中至少一种;从大麻植物提取精油,形成精油提取物;和氢化所述精油提取物,形成氢化的大麻油,其包括9-四氢大麻酚酸和9-大麻二酚酸中的至少一种。
提取和氢化步骤可以包括使用抽提溶剂从大麻植物提取精油,分离精油提取物,包括9-四氢大麻酚酸和9-大麻二酚酸中至少一种,并且在不存在抽提溶剂下氢化该精油提取物。
在另一个方面,本发明提供氢化的大麻油组合物,其包括氢化的酸,选自氢化的9-四氢大麻酚酸、氢化的9-大麻二酚酸及其混合物和掺合物。
在仍然另一个方面,本发明提供用于使癌症患者中肿瘤退缩(regress)的方法,包括制备氢化的大麻油组合物,其包括获得具有精油的大麻植物,所述精油包括9-四氢大麻酚酸和9-大麻二酚酸中至少一种,从大麻植物提取精油,形成精油提取物,和氢化所述精油提取物,形成氢化的大麻油,其包括氢化的9-四氢大麻酚酸和9-大麻二酚酸中至少一种;和向所述癌症患者给药治疗有效量的所述氢化的大麻油组合物。
优选的实施方案的详细说明
本发明涉及新的化合物、组合物及用于提取和氢化大麻植物精油的方法。六氢大麻素类(HHC)可以通过氢化四氢大麻素化合物的混合物制备,所述四氢大麻素类化合物是来自大麻植物精油,本文称为大麻油的主要组分。大麻油可以通过各种常规分离方法从大麻(Cannabis sativa)、印度大麻(C.indica)和莠草大麻(C.ruderalis)植物获得,所述常规分离方法包括蒸汽蒸馏、有机溶剂提取、微波辅助有机溶剂提取、超临界流体提取和低温机械方法(cryo-mechanical methods)。由这些方法得到的粗大麻油、提取物或浓缩物都可以在没有任何纯化下通过下述方法用于制备HHC-富集的大麻油:直接氢化所述油以还原所述油中的四氢大麻素化合物的碳-碳双键,所述四氢大麻素化合物比如Δ-9-四氢大麻酚酸(THCA)和Δ-9-大麻二酚酸(CBDA)。
直接氢化粗大麻油还将氢化大麻油中存在的其它化合物中的不饱和基团,比如萜烯类、萜类、黄酮类、甾醇类及其它不饱和化合物。通过氢化它们的不饱和的官能团对大麻油中这些化合物的化学转化改变了产物本文称为氢化大麻油(HCO)的性质。HCO是富含六氢大麻素类和氢化萜类的大麻油氢化产物。起始大麻油中个体大麻素类和萜烯类的浓度,其在不同种类的大麻植物中不同,决定了HCO产品中氢化化合物的浓度。
因此,通过提取整株植物制备的大麻油可以用于制备氢化大麻油(HCO)的氢化反应中,所述氢化大麻油富含HHC以及氢化萜烯类(terpenes),例如萜类(terpenoids)。
如本文使用的,下述术语具有提供的定义。
如本文使用的术语“四氢大麻酚酸”指具有如式1a和1b描绘的Δ-9-四氢大麻酚酸(THCA)和Δ-9-大麻二酚酸(CBDA)的化学结构的化合物。
如本文使用的术语“四氢大麻酚”指具有如式2a和2b描绘的THC和CBD的化学结构的化合物。
如本文使用的通过氢化大麻素形成的术语“六氢大麻素”(“HHC”)指具有如式3a、3b、3c和3d描绘的HTHCA、HCBDA、HTHC和HCBD的化学结构的化合物。
如本文使用的通过氢化大麻素形成的术语“2-羟甲基-六氢大麻素”(“2-HM-HHC”)指具有如式4a和4b中描绘的2-HMHTHC和2-HMHCBT的化学结构的化合物。
如本文使用的通过氢化CBD选择性地还原异丙烯基形成的术语“部分氢化的大麻二酚”(“PHCBD”)指具有如式5描绘的化学结构的化合物。
如本文使用的术语“大麻油”指从大麻植物分离的提取物。大麻油是通过适用于本发明的各种分离方法从大麻(Cannabis sativa)、印度大麻(C.indica)和莠草大麻(C.ruderalis)植物获得,所述分离方法包括蒸汽蒸馏、有机溶剂提取、微波辅助有机溶剂提取、超临界流体提取和低温机械方法。如此得到的粗大麻油、提取物或浓缩物都可以在没有任何纯化下通过下述方法用于制备HHC-富集的大麻油:直接氢化所述油以还原所述油中的四氢大麻素化合物的碳-碳双键,所述四氢大麻素化合物比如Δ-9-四氢大麻酚酸(THCA)和Δ-9-大麻二酚酸(CBDA)。
内源性大麻素系统(ECS)是在脑、器官、结缔组织、腺体和免疫细胞中遍布人体发现的基于化学的信号传递系统。ECS系统是基于配体结合膜结合的G-蛋白偶联受体,即,CB1和CB2受体起作用的。已知的内源性大麻素是花生四烯酸乙醇胺(anandamide)和2-花生四烯酰基甘油(arachidonoylglycerol)。由大麻产生的植物大麻素类(phytocannabinoids)也结合和活化这些受体。
对于CB1或CB2具有受体亚型选择性的非植物来源的合成衍生物是本领域已知的。
如本文使用的术语“氢化”指分子氢(H2)与有机化合物的化学反应,导致将氢分子加成到有机化合物。有机化合物和有机化合物的混合物的氢化是本领域熟知的。具有碳-碳和碳-氧双键的有机化合物和有机化合物的混合物的氢化通常是本领域已知的。
催化氢化使用提高有机化合物间反应速率的催化剂。使用的氢化催化剂在反应介质比如,固体催化剂上的溶液中是非均相的,或者在反应溶剂中是均相的。在有机化合物和有机化合物的混合物的氢化中使用非均相和均相催化剂也通常是本领域已知的。
如本文使用的术语“催化剂”指影响化学反应速率(而不是反应平衡)且化学上未改变地脱离所述过程的物质。如本文使用的术语“促进剂”指加入以增强催化剂的物理或化学功能的化合物。化学促进剂通常增强催化剂的活性,并且可以在化学处理催化剂组分的任何步骤期间加入到催化剂中。化学促进剂通常增强催化剂试剂的物理或化学功能,还可以加入以阻止不期望的副反应。“金属促进剂”指加入以增强催化剂的物理或化学功能的金属化合物。
许多氢化催化剂是有效的,包括(不限于)包含作为主组分的元素例如铱、钯、铑、镍、钌、铂、铼、其化合物、其组合以及其负载性变体的那些。负载型催化剂是其中通过喷雾、浸泡或物理混合,接着干燥、煅烧且如有必要经由方法比如还原或氧化活化将活性催化剂试剂沉积在载体物质上的一种催化剂。经常用作载体的物质是具有高总表面积(外表面积和内表面积)的多孔固体,其可以提供每单位重量的催化剂高浓度的活性部位。催化剂载体可以增强催化剂试剂的功能;并且因为使用活性金属催化剂更有效,所以负载型催化剂通常是优选的。未负载在催化剂载体物质上的催化剂是非负载型催化剂。本发明的方法中使用的金属催化剂可以用作负载型催化剂或非负载型催化剂。
催化剂载体可以是任何固体、惰性物质,包括但不限于氧化物比如二氧化硅、氧化铝、二氧化钛、碳酸钙、硫酸钡和碳。催化剂载体可以为粉末、颗粒、小球等的形式。在某些实施方案中,本发明的载体物质选自碳、氧化铝、二氧化硅、二氧化硅-氧化铝、二氧化钛、二氧化钛-氧化铝、二氧化钛-二氧化硅、钡、钙、其化合物及其组合。合适的载体包括碳、SiO2、CaCO3、BaSO4和Al2O3。而且,负载的催化金属可以具有相同的负载材料或不同的负载材料。在本发明的一个实施方案中,载体为碳。进一步,载体例如碳,可以具有约100至约200m2/g的表面积。而且,载体例如碳,可以具有至少约200m2/g或至少约300m2/g的表面积。
本发明中作为催化剂载体可以使用的市售可获得的碳包括以下述商标销售的那些:Bameby&SutclilTeTM、DarcoTM、NucharTM、ColumbiaJXNTM、ColumbiaLCKTM、CalgonPCBTM、CalgonBPLTM、WestvacoTM、NoritTM and Barnaby Cheny NBTM。市售可获得的碳也可以包括Calsicat C、Sibunit C或Calgon C(以注册商标市售可获得的)。在某些实施方案中,催化金属和载体系统的组合包括碳上镍、Al2O3上镍、CaCO3上镍、BaSO4上镍、SiO2上镍、碳上铂、Al2O3上铂、CaCO3上铂、BaSO4上铂、SiO2上铂、碳上钯、A12O3上钯、CaCO3上钯、BaSO4上钯、SiO2上钯、碳上铱、Al2O3上铱、SiO2上铱、CaCO3上铱、BaSO4上铱、碳上铼、Al2O3上铼、SiO2上铼、CaCO3上铼、BaSO4上铼、碳上铑、Al2O3上铑、SiO2上铑、CaCO3上铑、BaSO4上铑、碳上钌、Al2O3上钌、CaCO3上钌、BaSO4上钌和SiO2上钌。如上所述,有用的催化金属包括组分,例如元素铱、钯、铑、镍、钌、铂和铼;有用的载体物质包括碳、氧化铝、二氧化硅、二氧化硅-氧化铝、二氧化钛、二氧化钛-氧化铝、二氧化钛-二氧化硅、钡和钙,更特别是碳、SiO2、CaCO3、BaSO4和Al2O3。
负载型催化剂可以由上述金属和载体物质的任意组合制成。然而,负载型催化剂也可以由各种金属和/或各种载体物质的组合制成,其选自通过如上述列出的整组中删除任一个或多个成员形成的前述的亚组。因此,在这样的实例中,负载型催化剂不仅可以由一种或多种金属和/或载体物质制成,其选自可以由如上述列出的整组形成的任何规模的亚组,而且也可以在不存在已经从整组删除的成员以形成亚组来制备。而且,通过从上述整组中删除多个成员形成的亚组可以包含任何数量的整组成员,这样为了形成亚组而排除的整组的那些成员不存在于所述亚组中。例如,在某些情况下可能期望在不存在由钯上碳形成的催化剂下实施所述方法。
虽然载体上催化剂的重量百分比不是决定性的,但是应当理解金属的重量百分比越高,则反应越快。在某些实施方案中,负载型催化剂中金属的含量范围为整个负载型催化剂(催化剂重量加载体重量)的约0.1wt%至约20wt%。在其它实施方案中,催化金属的含量范围为整个负载型催化剂重量的约1wt%至约10wt%。更进一步,另一种催化金属的含量范围为整个负载型催化剂重量的约3wt%至约7wt%。任选地,在本发明的方法中,金属促进剂可以与催化金属一起使用。合适的金属促进剂包括∶1)来自周期表第1和2族的那些元素;2)锡、铜、金、银及其组合;和3)较少量的周期表第8族金属的组合。
温度、溶剂、催化剂、压力和混合速率是影响氢化的所有参数。为了在所述方法的反应中获得期望的转化率、反应速率和选择性,可以调节这些参数之间的关系。在本发明的上下文中,在某些实施方案中,温度为约25℃至250℃,或者约50℃至约150℃,或者约50℃至100℃。
在某些实施方案中,氢压力为约0.1至约20MPa、或约0.3至10MPa、或约0.3至4MPa。
反应可以无溶剂(neat)下进行或在溶剂存在下进行。有用的溶剂包括本领域已知用于氢化反应的那些,比如烃类、醚类、醇类及其混合物和掺合物。在某些实施方案中,使用醇类,例如低级链烷醇类,比如甲醇、乙醇、丙醇、丁醇和戊醇。
当根据某些实施方案进行反应时,可以获得在至少70%范围内的选择性,其中至少85%的选择性可能是典型的。选择性是转化物质即,HCO的重量百分比,其中转化物质为参与氢化反应的起始物质部分。
本发明的方法可以分批、连续成批(即,一系列成批反应器)或在通常用于连续过程的任意装置中以连续方式进行。
在US专利2,419,937中,公开了使用多相催化剂(Pt2O,Adams催化剂)将作为纯化合物的THC氢化为HHC。使用的纯化的THC是通过酸催化异构化CDB合成的,所述CDB是在US2,304,669描述的方法中通过沉淀从“红油”大麻提取物分离的。
使用均相催化剂三-三苯基膦氯化铑(Wilkinson催化剂)选择性氢化萜烯L-香芹酮的异丙烯基部分的方法是本领域已知的。
虽然将分离的纯CBD和THC氢化为它们相应的六氢衍生物是已知的,例如如在Tetrahedron 1966,第22卷,第1481至1488页中报道的,但是大麻油或提取物的直接氢化是新的,所述大麻油或提取物包含CBDA、THCA及其它大麻素类、萜类和黄酮类、甾醇类及油或提取物中存在的其它少量化合物的混合物。氢化通过向分子中加入氢,将大麻素、萜类、黄酮类、甾醇类及油或提取物中存在的其他少量化合物中不饱和的基团,此处定义为非芳族碳-碳双键转化成饱和的基团。不饱和的基团的氢化或饱和改变了氢化产品油的性质,比如颜色、香精、味道、气味、稳定性和生物活性方面的改善。
大麻油也包括不饱和化合物比如单萜类香芹酮、柠檬烯、月桂烯、芳樟醇、长叶薄荷酮、1,8-桉树脑、α-蒎烯、α-萜品醇、萜品-4-醇,对-伞花烃、冰片、Δ-3-蒈烯、香叶醇、香茅醛、香茅醇、柠檬醛、环柠檬醛和倍半萜烯β-石竹烯和橙花叔醇。在大麻油的氢化中,分子中的碳-碳双键与氢反应。
另外,在包含碳-碳双键的大麻油中存在甾醇和黄酮类化合物,所述碳-碳双键在大麻油的氢化中将与氢反应。
大麻油的氢化中的不同反应条件(催化剂、溶剂、温度、压力)决定了该反应中形成的化合物,且因此决定了HCO产品的分子构成。
大麻油可以使用本领域已知的各种常规提取技术和装置从大麻植物获得。例如,大麻油是通过适用于本发明的各种分离方法从大麻、印度大麻和莠草大麻植物获得的,所述分离方法包括蒸汽蒸馏、有机溶剂提取、微波辅助有机溶剂提取、超临界流体提取和低温机械方法。在存在或不存在溶剂下包括粗大麻油的大麻提取物适于直接用于本发明中,而无需分离大麻油、提取物或浓缩物。如此得到的大麻提取物可以不经任何纯化使用。在某些实施方案中,进行大麻提取物的直接氢化。
可以通过称为冬化处理(winterization)的冷却方法使提取物脱脂纯化包含粗大麻油和挥发性溶剂的大麻提取物,所述冬化处理使脂质级分从提取物中沉淀出。如此得到的纯化的、脱脂的大麻提取物适用于本发明。脱脂的大麻提取物的直接氢化是优选的。
氢化反应可以在单个反应器中分批进行,在一系列反应器中以连续成批进行,在一个或多个反应器中的反应区中进行,或者在通常用于连续过程的任意装置中以连续方式进行。
在某些实施方案中,提取和氢化过程可以如下进行。收割大麻植物。已知在大麻植物的收割和随后老化时开始精油的脱羧基化。在室温下,脱羧基最少。然而,提高温度,例如通过加热,会加速该脱羧基化过程。伴随最少的脱羧基,大麻植物和包含在其中的精油都富含分别如式1a和1b所示的THCA和/或CBDA。使用常规提取方法,比如在不存在加热或在低温下的溶剂提取来提取精油,得到富含THCA和/或CBDA的大麻油提取物。为了在从其中得到的精油和提取物中保持显著浓度或水平的THCA和CBDA,例如,酸,可以将大麻植物在收割之后冷冻。因此,提取大麻植物的精油可以得到THCA-富集的提取物或CBDA-富集的提取物或THCA-和CBDA-富集的提取物。使用本领域已知的常规氢化技术和装置氢化所述精油提取物。如前所述,氢化通常指用氢处理化合物或组合物,例如一般在催化剂比如但不限于镍、钯或铂的存在下,分子氢(例如H2)之间的化学反应。氢化引起化合物例如烃中的双键还原。当除去任何溶剂时,得到富含分别如式3a和3b所示HTHCA和/或HCBDA的氢化精油。
在某些实施方案中,氢化是对分离的大麻提取物进行的,例如已经与抽提溶剂分离且不含抽提溶剂的大麻提取物。在其它实施方案中,氢化是对包括存在抽提溶剂的大麻提取物进行的,所述抽提溶剂为比如饱和烃,包括但不限于丁烷、丙烷及其混合物和掺合物。
在氢化反应之后,可以通过本领域技术人员熟知的分离方法比如倾析或过滤,从反应混合物回收氢化大麻油。例如通过柱色谱,可以从氢化大麻油分离和纯化HHC。
除了THCA和/或CBDA分别被氢化为HTHCA和/或HCBDA之外,大麻植物精油的其它组分都可以被氢化。例如,预期THCA-和/或CBDA-富集的油和提取物还将包含分别如式2a和2b所示的THC和CBD,因为由于大麻植物的收割以及任何随后的老化的结果发生一些水平或程度的脱羧基化。不过,精油和提取物中THCA和/或CBDA的浓度或水平应当大于THC和/或CBD的浓度或水平。因此,HCO也可以包括分别如式3c和3d所示的HTHC和/或HCBD(例如,以比THCA和/或CBDA更少的量存在)。而且,如前所述,在氢化精油的过程中,萜类、黄酮类、甾醇类及所述油和提取物中存在的其它少量化合物也被氢化,因此,存在于HCO中(例如,以比THCA和/或CBDA更少的量存在)。
大麻素和大麻素衍生物用于治疗许多疾病,本领域熟知其中一些是内源性大麻素系统介导的。大麻素受体亚型CB1和CB2以及调节那些受体的合成拮抗剂和激动剂也是本领域熟知的。可以施用治疗应用以治疗多种病症和疾病,比如癌症、癫痫、创伤后应激障碍、糖尿病、克隆病、痛风、疼痛缓解、青光眼、阿片依赖、酒精滥用、失眠、银屑病、带状疱疹、厌食、哮喘、纤维肌痛、类风湿性关节炎、偏头痛、Dravet综合征、多发性硬化症、自闭症和月经痛。
过度腹部肥胖与其它危险因素一起导致代谢综合征,其可以导致心脏病、2型糖尿病和死亡。内源性大麻素系统(ECS)是由中性脂质组成,其经由G-蛋白偶联的大麻素受体CB1和CB2发信号。在腹部肥胖中,中枢和外周组织中的ECS通常上调,并且ECS阻断导致正向代谢变化。
CB1受体参与保持内环境稳定,并且潜在地是设计针对代谢综合征的疗法的临床相关靶标,值得开发和临床试验可以通过血脑屏障的CB1-中性拮抗剂或外周限制性反向激动剂/中性拮抗剂。选择性CB1拮抗剂用于体重减轻和戒烟。
选择性CB1激动剂可用于将受体的作用与CB2受体分开,因为大多数的大麻素和内源性大麻素结合两种受体亚型。
如可以通过上述竞争性结合测定证实的,本发明的化合物用于调节CB2受体功能。凭借该事实,这些化合物在治疗CB2受体功能介导的或将受益于CB2受体功能调节的疾病状态和病症中具有治疗用途。
因为本发明的化合物调节CB2受体功能,它们具有非常有用的抗炎和免疫抑制活性,它们可作为药物,特别是以如下所述药物组合物形式,用于患者中治疗疾病-状态和病症。
如之前所述,其为CB2激动剂的那些化合物也可以用于治疗疼痛。
根据本发明的激动剂、拮抗剂和反向激动剂化合物可以作为药物组合物例如药物用于患者中,用于治疗下述伴有炎性过程的疾病状态、病症或适应症∶
(i)肺病∶例如哮喘、支气管炎、过敏性鼻炎、肺气肿、成人呼吸窘迫综合征(ARDS)、鸽病(pigeon fancier's disease)、农民肺、慢性阻塞性肺病(COPD)、哮喘包括变应性哮喘(特应性或非特应性)以及运动诱发的支气管收缩、职业性哮喘、病毒或细菌性哮喘加剧、其它非变应性哮喘和“喘鸣-婴儿综合征(wheezy-infant syndrome)”、肺尘埃沉着病包括铝尘肺、煤尘肺、石棉肺、石末肺、驼鸟毛尘肺、铁尘肺、硅肺、烟草尘肺病和棉尘肺;
(ii)风湿性疾病或自身免疫疾病或肌骨胳疾病∶所有形式的风湿性疾病,特别是类风湿性关节炎、急性风湿热和风湿性多肌痛;反应性关节炎;风湿性软组织疾病;其它病因的炎症软组织疾病;退化性关节疾病(关节病)的关节炎症状;腱炎、滑囊炎、骨关节炎、创伤性关节炎;任何病因的胶原病,例如系统性红斑狼疮、硬皮病、多发性肌炎、皮肌炎、干燥综合征( syndrome)、斯蒂尔病(Still disease)、费尔蒂综合征(Feltysyndrome);和骨质疏松症及其它骨吸收疾病;
(iii)变应性疾病∶各种形式的变态反应,例如血管神经性水肿、枯草热、昆虫咬伤,药物、血液衍生物、造影剂等的变态反应,变应性休克(过敏症)、荨麻疹、血管神经性水肿和接触性皮炎;
(iv)血管疾病∶结节性全动脉炎、结节性多动脉炎、结节性动脉周围炎、颞动脉炎(arteritis temporalis)、韦格纳肉芽肿病(Wegner granulomatosis)、巨细胞关节炎、动脉粥样硬化、再灌注损伤和结节性红斑;
(v)皮肤病∶例如皮炎、银屑病;晒伤、烧伤、湿疹;
(vi)肾脏病∶例如肾病综合征;和所有类型的肾炎,例如肾小球肾炎;和胰腺炎(pancreatits);
(vii)肝脏疾病∶例如,急性肝细胞裂解;各种病因的急性肝炎,例如病毒、毒物、药物诱发的;和慢性侵袭性和/或慢性间歇性肝炎;
(viii)胃肠疾病:例如炎性肠病、肠易激综合征、局限性肠炎(克隆病)、溃疡性结肠炎;胃炎;口疮性溃疡、乳糜泻、节段性回肠炎、胃食管反流疾病;
(ix)神经保护∶例如治疗中风;心脏停搏;肺循环(pulmonary bypass);外伤性脑损伤;脊髓损伤等之后的神经变性;
(x)眼病∶过敏角膜炎、葡萄膜炎或虹膜炎;结膜炎;睑缘炎;视神经炎(neuritisnervi optici);脉络膜炎;青光眼和交感性眼炎;
(xi)耳、鼻和咽喉(ENT)区域的疾病:例如,耳鸣、过敏性鼻炎或枯草热;外耳炎;接触性皮炎引起的感染等;和中耳炎;
(xii)神经性疾病:例如脑水肿,特别是肿瘤相关的脑水肿;多发性硬化症;急性脑脊髓炎;脑膜炎;急性脊髓损伤;创伤;痴呆,特别是退行性痴呆(包括老年痴呆、阿尔茨海默病;帕金森病和克-雅病(Creutzfeldt-Jacob disease);亨廷顿氏舞蹈病、皮克氏病;运动神经元病)、血管性痴呆(包括多发性梗塞痴呆症)以及与颅内占位性病变有关的痴呆;感染和相关病症(包括HIV感染);格林-巴利综合征(Guillain-Barre syndrome);重症肌无力、中风;和各种形式的发作,例如点头状痉挛;
(xiii)血液疾病;获得性溶血性贫血;再生障碍性贫血,和特发性血小板减少症;
(xiv)肿瘤疾病;急性淋巴性白血病;霍奇金病、恶性淋巴瘤;淋巴肉芽肿病;淋巴肉瘤;实体恶性肿瘤;和广泛性转移瘤;
(xv)内分泌疾病∶内分泌眼病;内分泌眼眶病(endocrine orbitopathia);甲状腺毒性危象;亚急性甲状腺炎(Thyroiditis de Quervain);桥本甲状腺炎;Morbus Basedow;肉芽肿性甲状腺炎;淋巴瘤性甲状腺肿;格雷夫斯病;和I型糖尿病(胰岛素依赖性糖尿病);
(xvi)器官和组织移植和移植物抗宿主疾病;
(xvii)严重休克状态,例如过敏性休克、变应性休克和全身炎性反应综合征(SIRS);
(xviii)急性疼痛,比如牙痛、手术疼痛、术后痛、外伤性疼痛、肌肉疼痛、烧伤皮肤疼痛、晒伤、三叉神经痛、晒伤;胃肠道或子宫和结肠的痉挛;
(xix)内脏痛,比如与下述有关的疼痛:慢性骨盆痛、胰腺炎、消化性溃疡、间质性膀胱炎、肾绞痛、心绞痛、痛经、月经、妇科疼痛、肠易激综合征(IBS)、非溃疡性消化不良、非心源性胸痛和心肌缺血;
(xx)神经性疼痛,比如腰痛(low back pain)、非疱疹性神经痛、疱疹后神经痛、糖尿病神经病变、神经损伤、获得性免疫缺陷综合症(AIDS)相关的神经性疼痛、头部创伤、疼痛外伤性的单神经病、毒素和化疗诱发的疼痛、假肢痛、疼痛性多神经病、丘脑性疼痛综合征、中风后疼痛、中枢神经系统损伤、手术后疼痛、残端痛、反复性运动痛、乳房切除术后综合征诱发的疼痛、多发性硬化症、根性撕脱伤、胸廓切开术后综合征、神经性疼痛相关的痛觉过敏和异常性疼痛;
(xxi)由下述病症诱发的或与其相关的炎症/伤害性疼痛:比如骨关节炎、类风湿性关节炎、风湿性疾病、腱鞘炎、痛风、外阴痛、筋膜疼痛(肌肉损伤、纤维肌痛)、腱炎、骨关节炎、幼年关节炎、脊椎炎、痛风性关节炎、银屑病关节炎、肌骨骼痛、纤维肌痛、扭伤拉伤、交感神经维持性疼痛、肌炎、与偏头痛有关的疼痛、牙痛、流行性感冒及其它病毒感染比如普通感冒、风湿热、全身性狼疮和红斑性症;
(xxii)由下述疾病诱发的或与其有关的癌症疼痛:比如淋巴细胞性白血病;霍奇金病、恶性淋巴瘤;淋巴肉芽肿病;淋巴肉瘤;实体恶性肿瘤;广泛性转移瘤;
(xxiii)头痛,比如丛集性头痛、有无先兆的偏头痛、紧张性头痛、不同原因的头痛、头痛病症包括预防应用和急性应用;和
(xxiv)多种其它疾病状态或病症,包括:经皮穿刺冠状动脉成形术后的再狭窄、急性和慢性疼痛、动脉粥样硬化、再灌注损伤、充血性心力衰竭、心肌梗死、热损伤、创伤继发性多种器官损伤、坏死性小肠结肠炎和与血液透析有关的综合征、白细胞去除、和粒细胞输注、结节病、牙龈炎、发热。与bums有关的创伤导致的水肿、扭伤或骨折、脑水肿和血管性水肿、糖尿病比如糖尿病血管病变、糖尿病神经病变、糖尿病视网膜病、毛细血管后阻力(postcapillary resistance)或与胰岛炎有关的糖尿病症状(例如,高血糖症、多尿、蛋白尿和亚硝酸盐和激肽释放酶尿排泄增加)。
其它适应症包括∶癫痫、败血症性休克例如如抗低血容试剂和/或抗低血压试剂、癌症、败血症、骨质疏松症、良性前列腺肥大和高反应性膀胱(hyperactive bladder)、搔痒症、白癫风、一般胃肠病症、呼吸、泌尿生殖、胃肠或血管区域的内脏活动障碍、创伤、烧伤、组织损伤和术后发热、与瘙痒相关的综合征。
除了用于人类治疗之外,这些化合物也用于陪伴动物、野外动物和家畜包括哺乳动物、啮齿类动物等的兽医治疗。
对于上述疾病和病症的治疗,治疗有效剂量的范围通常应当在约0.01mg至约100mg/kg体重/剂量本发明的化合物之间;在某些实施方案中,治疗有效剂量的范围为约0.1mg至约20mg/kg的体重/剂量。例如,对于向70kg的人给药,剂量范围应当为约0.7mg至约7000mg/剂量本发明的化合物,或者约7.0mg至约1400mg/剂量。为了确定最佳剂量水平和模式,可能需要一些常规剂量优化程度。活性成分可以每日给药1次至6次。
HCO可以通过蒸发、吸烟或使用载体食物、可食用或药物组合物给予。当用作药物时,HCO组合物通常可以使用药物领域熟知的方法制备且包含本发明的HCO产品。HCO产品也可以单独或与助剂组合给药,所述助剂增强本发明化合物稳定性、在某些实施方案中促进给药包含它们的药物组合物、提供增加的溶出或分散、增加的抑制活性、提供辅助治疗等。根据本发明的化合物可以单独使用或者与根据本发明的其它活性物质一起使用,任选地也与其它药理学活性物质一起给药。一般而言,本发明的HCO产品以治疗或药学有效量给药,但是可以以较低量给药用于诊断或其它目的。
给药纯形式或合适的药物组合物中的HCO的方法可以使用药物组合物的任何可接受给药方式进行。因此,给药可以为例如口服、口腔(例如,舌下给药)、经鼻、肠胃外、局部、透皮、阴道、或直肠给药,以固体、半固体、冻干粉末或液体剂型的形式,比如例如片剂、栓剂、丸剂、软弹性胶囊和硬明胶胶囊、粉剂、溶液、混悬液或气雾剂等,优选地以适于单次给药精确剂量的单位剂型。药物组合物通常应当包括常规药物载体或赋形剂和作为活性剂的本发明的化合物,另外可以包括其它医学试剂、药物试剂、载体、助剂、稀释剂、媒介物或其组合。这种可药用赋形剂、载体、或添加剂以及用于各种给药方式的药物组合物的制备方法是本领域技术人员熟知的。
适于口腔(舌下)给药的药物组合物包括锭剂(lozenges)和软锭剂(pastilles),所述锭剂包括含有在矫味基质一般是蔗糖和阿拉伯胶或西黄蓍胶中的本发明的化合物,所述软锭剂含有在惰性基质比如明胶和甘油或蔗糖和阿拉伯胶中的所述化合物。
适于肠胃外给药的药物组合物包含本发明化合物的无菌水性制备物。在某些实施方案中,这些制备物是静脉内给药的,但是给药也可以通过皮下、肌内或皮内注射实施。可注射药物制剂通常是基于可注射的无菌盐水、磷酸盐缓冲盐水、含油脂混悬液或本领域已知的其它可注射载体,并且通常使其无菌且与血液等渗。因此,可注射药物制剂可以提供作为在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,所述稀释剂或溶剂包括1,3-丁二醇、水、林格溶液、等渗氯化钠溶液、不挥发油比如合成甘油单酯或甘油二酯,脂肪酸比如油酸等。根据已知技术,使用合适的分散剂或固化剂和悬浮剂配制这样的可注射药物制剂。可注射组合物通常应当包含0.1至5%w/w的本发明的HCO产品。
用于口服给药所述化合物的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。对于这样的口服给药,包含本发明的化合物的可药用组合物是通过结合任意通常使用的赋形剂形成的,所述赋形剂为比如例如药物级的甘露醇、乳糖、淀粉、预胶化淀粉、硬脂酸镁、糖精钠、滑石、纤维素醚衍生物、葡萄糖、明胶、蔗糖、柠檬酸酯、没食子酸丙酯等。这样的固体药物制剂可以包括如本领域熟知的剂型,以通过任何数量的机制向胃肠道提供药物的延长或缓释递送,所述机制包括但不限于基于小肠pH变化剂型的pH敏感性释放、片剂或胶囊的缓慢溶蚀、基于剂型的物理性质在胃中滞留、剂型向肠道粘膜衬里的生物粘附、或者活性药物从剂型中的酶解释放。
用于口服给药所述化合物的液体剂型包括乳剂、微乳剂、溶液、混悬液、糖浆和酏剂,任选地包含在载体比如例如水、盐水、水性葡萄糖、甘油、乙醇等中的药用助剂。这些组合物也可以包含另外的助剂,比如润湿剂、乳化剂、悬浮剂、甜味剂、调味剂和芳香剂。
化合物的局部剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉剂、溶液、喷雾剂、吸入剂、眼用软膏、滴眼剂或滴耳剂、浸渍敷料和气雾剂,并且可以包含合适的常规添加剂比如防腐剂、促进药物渗透的溶剂和软膏剂和乳膏剂中的软化剂。局部施用可以是每日一次或多于一次,取决于通常的医学考虑事项。而且,在一些实施方案中,用于本发明的化合物可以经由局部使用合适的鼻内媒介物以鼻内形式给药。剂型也可以包含相容的常规载体,比如乳膏或软膏基质和用于洗剂的乙醇或油醇。这样的载体可以占制剂的约1%至至多约98%,更通常地它们占制剂的至多约80%。
透皮给药也是可能的。适于透皮给药的药物组合物可以作为适合与接受者的表皮密切接触持续延长时间段的离散的贴剂存在。为了以透皮递送系统形式给药,在整个剂量方案中,剂量给药当然应当是连续性的,而不是周期性的。这样的贴剂合适地包含在任选缓冲的、水溶液中、溶解和/或分散在粘合剂中、或分散在聚合物中的本发明的化合物。HCO产品的合适的浓度为约1%至35%,或约3%至15%。
对于吸入给药,本发明的HCO产品方便地从不需要推进气体的泵喷雾装置或压力包装或使用合适的推进剂的喷雾器以气雾喷雾剂的形式递送,所述推进剂为例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、四氟乙烷、七氟丙烷、二氧化碳或其它合适的气体。在任何情况下,气雾喷雾剂剂量单位可以通过提供阀来确定,以递送计量的量,以致得到的计量剂量吸入器(MDI)用于以可再现和受控方式给药本发明的化合物。这样的吸入器、喷雾器或雾化器装置是现有技术已知的,例如公开在PCT国际公开号WO 97/12687(特别是其图6,其为市售喷雾器的基础);WO 94/07607;WO 97/12683;和WO 97/20590。
直肠给药可以利用单位剂量栓剂进行,其中将化合物与低熔点水溶性或不溶性固体比如脂肪、可可脂、甘油胶、氢化植物油、各种分子量的聚乙二醇混合物、或聚乙二醇的脂肪酸酯等混合。活性化合物通常为少量组分,通常为约0.05至10%重量,其余为基础组分。
在所有上述药物组合物中,用可接受的载体或赋形剂配制本发明的化合物。当然,所使用的载体或赋形剂必须在与组合物的其它组分相容的意义上是可接受的,并且必须对于患者无害。载体或赋形剂可以为固体或液体或两者,并且优选地与本发明的化合物一起配制成单位剂量组合物,例如片剂,其可以包含0.05%至95%重量的活性化合物。这样的载体或赋形剂包括惰性填充剂或稀释剂、粘合剂、润滑剂、崩解剂、溶液阻滞剂、再吸收促进剂、吸收剂和着色剂。合适的粘合剂包括淀粉、明胶、天然糖比如葡萄糖或β-乳糖、玉米甜味剂、天然树胶和合成树胶比如阿拉伯胶、西黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
可药用载体和赋形剂涵盖所有前述添加剂等。
实施例
在下述实施例中进一步定义本发明。这些实施例仅仅作为示例给出。根据上述讨论和这些实施例,技术人员可以确定本发明的基本特征,并且在没有背离其精神和范围下,可以进行本发明的各种变化和修饰以使其适用各种用途和条件。
使用下述缩写:GC为气相色谱;GC-MS为气相色谱-质谱;FID为火焰离子化检测器;NMR为核磁共振;℃为摄氏度;MPa为兆帕;kPa为千帕;Pa为帕;rpm为转/分;mL为毫升;CMO为大麻油;wt%为重量百分比;TOS为运行时间(time on stream);NPL为四氢大麻素类;HHC为六氢大麻素类;h为小时;conc.为浓度;conv.为转化率;temp.为温度;℃为摄氏度;kg为千克;XRF为X射线荧光光谱;ppm为百万分率。
实施例1
得到富含THCA的预提取的大麻提取物(374mg)。在100mL圆底烧瓶中,用10%Pd/C(36mg,Aldrich)处理在无水乙醇(20mL)中的大麻提取物,并在室温下于氮气下搅拌。将氢气吹扫到容器中,并鼓泡通过所述混合物。在氢气球下搅拌该混合物过夜。使该混合物穿过硅藻土床过滤。薄层色谱显示稍少的极斑(在硅胶板上30%乙酸乙酯/己烷)。通过旋转蒸发除去溶剂,得到呈澄清油状物的HTHCA产物(330mg),用NMR和MS表征。产物的13C NMR光谱显示分别在124和132ppm烯碳消失。由高分辨率质谱确认分子量,其中观察到M+H为361.2375。
实施例2
得到富含CBDA的预提取的大麻提取物(100mg)。在50mL圆底烧瓶中,用10%Pd/C(10mg,Aldrich)处理在无水乙醇(10mL)中的大麻提取物,并在室温下于氮气下搅拌。将氢气吹扫到容器中,并鼓泡通过所述混合物。在氢气球下搅拌该混合物过夜。使该混合物穿过硅藻土床过滤。薄层色谱显示稍少的极斑(在硅胶板上30%乙酸乙酯/己烷)。通过旋转蒸发除去溶剂,得到呈浅色油状物的HCBDA产物(86mg),用NMR和MS表征。产物的NMR光谱显示所有烯碳消失。由质谱确认分子量,其中观察到呈铵盐的单氢化和二氢化的加合物位于377和375(起始物质显示铵盐位于373m/e)。
实施例3
通过将U87(人成胶质细胞瘤)3×106细胞(50%基质胶)植入三只雌性无胸腺小鼠中评价氢化和非氢化的大麻油对于肿瘤生长和血管生成的影响。每只小鼠,在植入部位皮下植入两个植入物。植入日期为2016年2月1日,给予治疗日期为2016年2月3日。下述组每一种中有三只小鼠,处理包括对三只小鼠中每只进食10mg/kg体重的对应于下述组每一种的处理:
1.未处理的媒介物
2.THCA
3.CBDA
4.HCBDA
5.HTHCA
结束日期为2016年2月11日。在该日,切除肿瘤并称重。结果显示在表1中,并图解在下图中。
表1
表1显示对于未处理的“媒介物”组,三只小鼠切除肿瘤的平均重量为73.8mg,即切除的肿瘤的总重量/六个肿瘤(即,三只小鼠每只中两个肿瘤)。假定“未处理的媒介物”的切除的肿瘤重量基本上等于其开始肿瘤重量。因此,结果表明每一种THCA、CBDA、HCBDA和HTHCA处理均对于减少肿瘤有效。
在处理一周之后,大麻素对于成胶质细胞瘤(U87)肿瘤重量的影响
Claims (15)
1.一种氢化大麻油的方法,包括:
获得具有精油的大麻植物,所述精油包括9-四氢大麻酚酸和9-大麻二酚酸中的至少一种;
从所述大麻植物提取精油,形成精油提取物;和
氢化所述精油提取物以形成氢化的大麻油,其包括氢化的9-四氢大麻酚酸和9-大麻二酚酸中的至少一种。
2.权利要求1的方法,其中所述提取和氢化步骤包括使用抽提溶剂从大麻植物提取精油,分离精油提取物,其包括9-四氢大麻酚酸和9-大麻二酚酸中的至少一种,并在不存在抽提溶剂下氢化所述精油提取物。
3.权利要求1的方法,其中所述精油包括9-四氢大麻酚和9-大麻二醇中的至少一种。
4.权利要求1的方法,其中所述精油包括萜类、黄酮类、甾醇类及其混合物和掺合物。
5.权利要求1的方法,其中所述提取步骤包括用抽提溶剂接触精油。
6.权利要求5的方法,其中所述抽提溶剂包括有机挥发性溶剂。
7.权利要求5的方法,其中所述精油提取物包括约2%至约80%重量的精油。
8.权利要求1的方法,其中所述氢化步骤包括用催化剂和溶剂中的至少一种接触精油提取物。
9.权利要求1的方法,其中所述氢化步骤是在约-10℃至约100℃的温度下进行的。
10.权利要求6的方法,其中除去溶剂是通过真空蒸馏进行的。
11.权利要求1的方法,其中所述精油提取物包括约2%至约80%重量的大麻油。
12.氢化的大麻油组合物,包括氢化酸,其选自氢化的9-四氢大麻酚酸、氢化的9-大麻二酚酸及其混合物和掺合物。
13.使癌症患者中的肿瘤退缩的方法,包括:
制备氢化的大麻油组合物,包括:
获得具有精油的大麻植物,所述精油包括9-四氢大麻酚酸和9-大麻二酚酸中的至少一种;
从所述大麻植物提取精油,形成精油提取物;
氢化所述精油提取物,形成氢化的大麻油,其包括氢化的9-四氢大麻酚酸和9-大麻二酚酸中的至少一种;和
向所述癌症患者给药治疗有效量的所述氢化的大麻油组合物。
14.权利要求13的方法,其中所述组合物包括载体。
15.权利要求13的方法,其中给药所述组合物选自口服、口腔、经鼻、肠胃外、局部、透皮、阴道或直肠。
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RU2017142561A (ru) | 2019-06-10 |
US20170266245A1 (en) | 2017-09-21 |
EP3291807A1 (en) | 2018-03-14 |
HK1251460A1 (zh) | 2019-02-01 |
US10071127B2 (en) | 2018-09-11 |
LT3291807T (lt) | 2020-01-27 |
ES2764159T3 (es) | 2020-06-02 |
MX2017014195A (es) | 2018-08-15 |
AU2016258208B2 (en) | 2021-05-27 |
AU2016258208A1 (en) | 2017-11-30 |
ZA201707529B (en) | 2018-11-28 |
SI3291807T1 (sl) | 2020-02-28 |
IL255478A (en) | 2018-01-31 |
IL255478B (en) | 2020-11-30 |
WO2016179581A1 (en) | 2016-11-10 |
HUE049872T2 (hu) | 2020-11-30 |
EP3291807A4 (en) | 2018-05-16 |
US20160324909A1 (en) | 2016-11-10 |
KR20180002839A (ko) | 2018-01-08 |
RS59828B1 (sr) | 2020-02-28 |
CA2985065A1 (en) | 2016-11-10 |
JP2018515608A (ja) | 2018-06-14 |
RU2017142561A3 (zh) | 2019-11-14 |
HRP20192244T1 (hr) | 2020-03-20 |
US20190030102A1 (en) | 2019-01-31 |
EP3291807B1 (en) | 2019-09-25 |
DK3291807T3 (da) | 2020-01-13 |
US9694040B2 (en) | 2017-07-04 |
PT3291807T (pt) | 2020-01-10 |
CY1122609T1 (el) | 2021-03-12 |
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