CN100387230C - 由大麻提取物制成的药物组合物 - Google Patents
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- CN100387230C CN100387230C CNB028059956A CN02805995A CN100387230C CN 100387230 C CN100387230 C CN 100387230C CN B028059956 A CNB028059956 A CN B028059956A CN 02805995 A CN02805995 A CN 02805995A CN 100387230 C CN100387230 C CN 100387230C
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
本发明公开了一种适用于癌症姑息治疗并且在神经疾病中作为具有肌肉松弛作用和/或止痛作用的药物的药物组合物。所述组合物含有的四氢大麻酚(THF)和大麻二酚(CBD)是存在于组合物中的大麻素总重量的至少80wt%，优选90wt%。THC/CBD的重量比是75∶25-20∶80，优选3∶1-1∶2，尤其优选2∶1。所述组合物可被用于生产药理活性药物，所述药理活性药物可以被用在癌症姑息治疗和神经疾病的治疗中。
Description
本发明涉及含有大麻化合物的药物组合物，所述大麻化合物选自植物印度大麻(Cannbis sativa)(herba et flos sicc)。具体地，本发明的组合物以下文所述的选择的重量比含有成份四氢大麻酚(THC)和大麻二酚(CBD)。这些组合物在癌症的姑息治疗、治疗痉挛和治疗多发性硬化症患者的疼痛性肌僵直中显示令人惊奇的高药理活性。这些组合物进一步显示优异的止痛作用。
人们基本了解大麻植物印度大麻的这些成份并且已将其用于治疗。如对应通式(a)的Δ9-四氢大麻酚(Δ9-THC)和对应通式(b)的大麻二酚(CBD)。
目前已经发现了一种组合物具有令人惊奇的高药理活性，所述组合物含有的THC和CBD为存在于组合物中的大麻素总重量的至少80wt％，优选至少90wt％；并且THC∶CBD的重量比为75∶25-20∶80，优选3∶1-1∶2，尤其优选2∶1。这里，所述的总重量值对应于存在于组合物中的大麻素，而THC∶CBD的重量比值与从相应的HPLC色谱图的峰面积计算或获得的值相对应。
本发明在权利要求书中加以详细说明。具体地说，本发明涉及适合用于癌症的姑息治疗并且在神经疾病中作为具有肌肉松驰作用和/或止痛作用的药物的药理有效组合物。该组合物的特征在于其含有的四氢大麻酚(THC)和大麻二酚(CBD)是存在于组合物中的大麻素总重量的至少80wt％，优选至少90wt％，并且THC∶CBD的重量比为75∶25-20∶80，优选3∶1-1∶2，尤其优选2∶1。
本发明进一步涉及活性成份THC和CBD在合适的溶剂或者悬浮载体中的药理有效溶液或者悬浮液，这种溶液或者悬浮液的特征在于这种溶液或者悬浮液中的THC和CBD的总重量为溶液或者悬浮液总重量的1-25wt％，优选1.5-6wt％；THC和CBD含量为存在于溶液或者悬浮液中的大麻素总重量的至少80wt％，优选至少90wt％，并且THC∶CBD的重量比为75∶25-20∶80，优选3∶1-1∶2，尤其优选约2∶1。
本发明进一步涉及用于口服给药的单剂量给药形式，例如压缩形式如片剂或者包衣片剂和硬明胶胶囊或者软明胶胶囊，其优选含有本发明的药理活性组合物的软明胶胶囊。
本发明涉及的药理活性组合物为植物提取物形式。
本发明进一步涉及生产本发明组合物的方法。
本发明进一步涉及本发明组合物在生产用于癌症姑息治疗和与MS相关的痉挛治疗的药理活性药物中的应用。
本发明还涉及本发明的组合物对癌症姑息治理中患者的给药方法和在神经疾病如多发性硬化症中作为具有肌肉松驰作用和/或止痛作用的药物。
本发明的组合物既含有由合成途径生产的化合物也含有从植物提取物中获得的化合物。可通过如合成途径生产化合物四氢大麻酚(THC)。然而THC的合成和副产物的控制是困难的并且所得产品的纯度不是最优的。本发明所使用的化合物THC和CBD优选从植物印度大麻中提取(干花序和植物，herba et flos sicc)。在每种情况中，总是在排除氧的条件下进行操作。另外采用本领域公知方法如使用低分子醇如甲醇、乙醇、丁醇或者丙醇；乙酸酯如乙酸甲酯或者乙酸乙酯；酮如丙酮；醚如甲醚或者乙醚；或者使用低沸点的脂肪烃或者芳香烃或者氯化烃从植物中提取大麻化合物。例如通常使用约3-10倍重量的所述溶剂或其混合物在回流温度对洁净、干燥和切割植物(花序、叶、茎等)进行处理，优选至少处理约1小时，然后过滤除去残余物。小心地将仍然存在于残余物中的液体挤出并且加入到滤液中。随后除去溶剂，优选在真空条件下，如在约80mbar气压和温度约40-60℃条件下除去溶剂。由这种方法获得的提取物通常为蜂蜜状树脂，然后在温度约110-135℃，优选在约120℃，优选在高压釜内加热这种提取物约40分钟。在这个温度，提取物中作为羧酸存在的化合物被脱羧，并以几乎定量的收率形成化合物THC和CBD。随后将冷却的产品优选溶解在石油醚中，并使用合适流动相如石油醚/乙酸乙酯的混合物在硅胶上进行色谱分离。获得的大麻素组分借助于薄层色谱法可加以检测，随后在疏水硅胶如十八烷基甲硅烷基化的硅胶上进行色谱分离，优选用于色谱法的流动相混合物由甲醇/水和乙酸或者乙醇/水和乙酸组成。这种纯化导致作为第一组分的纯CBD和作为第二组分的纯THC。借助于HPLC确定所得化合物或者活性成份的纯度，通常获得的纯度为存在于该组分中的成份总重量的至少90wt％。
然而，还可能有另外的方法，以本领域公知方式使用约3-10倍重量的不溶于水的即与水形成两相系统的有机溶剂从洁净、干燥和切割的植物部分中提取大麻化合物。在每种情况中，这里也要求在排除氧的条件下进行操作。合适溶剂如水不溶性乙酸酯，优选乙酸甲酯或者乙酸乙酯；水不溶性醚如乙醚或者乙基丙基醚；或者脂肪烃或者芳香烃或者氯代烃。将含有被提取大麻化合物的有机溶剂过滤，然后用2％的氢氧化钠水溶液至少提取两次，所述氢氧化钠水溶液优选含有约20wt％的乙醇。通过处理，特别是含有羧基的大麻化合物进入水/醇相。将合并的水/醇与5％的硫酸溶液混合以使酸值(pH)约2-4，然后使用极低沸点亲油溶剂如低沸点脂肪烃或者芳香烃或者氯代烃；乙酸酯如乙酸甲酯或者乙酸乙酯或者其混合物提取至少两次。低温真空下除去溶剂。然后在疏水硅胶如十八烷基甲硅烷基化的硅胶上对残余物进行色谱分离，优选用于色谱法的流动相混合物由甲醇/水和乙酸或者乙醇/水和乙酸组成。使用UV检测器在280nm进行检测。获得含有天然物质CBD酸和THC酸的含活性成份的组分。借助于HPLC鉴别和确定组分纯度。然后真空除去组分中的提取剂(溶剂)。优选将活性成份或者天然起始物质(即，CBD酸和THC酸)溶解于亲油溶剂或者悬浮载体中。然后在约110-135℃，优选约120℃加热活性成份或者活性成份溶液，优选在高压釜内无氧存在下加热约40分钟。在这个温度，提取物中作为羧酸存在的化合物被脱羧，并以几乎定量的收率形成化合物THC和CBD。使用本领域公知方法如使用薄层色谱法(TLC)确定成份。优选使用高压液相色谱法(HPLC)确定纯度和含量。
合适的亲油溶剂或者悬浮载体的实例为中链和/或短链甘油三酯、中链偏甘油酯、聚氧乙基化脂肪醇、聚氧乙基化脂肪酸、聚氧乙基化脂肪酸甘油三酯或者偏甘油酯、脂肪酸与低分子量醇的酯、山梨聚糖与脂肪酸的偏酯、山梨聚糖与脂肪酸的聚氧乙基化偏酯、糖或者低聚糖与脂肪酸的偏酯、聚乙二醇及其混合物。还可以是所述化合物与脂肪、油和/或蜡或乙二醇的混合物，或所述化合物在卵磷脂和/或油和/或蜡混合物中形成的悬浮液。
上述提取方法通常获得提取物或者提取组分，每种都含有的成份四氢大麻酚(THC)和大麻二酚(CBD)是存在于提取物中的大麻素总重量的至少90wt％。剩余重量部分由存在于大麻植物中的其它化合物组成。
生产本发明的混合物的方法优选将含有活性成份的两种溶液以合适比率混合在一起以使活性成份THC∶CBD的比为75∶25-80∶20，优选3∶1-1∶2，尤其优选约2∶1。
另外药理活性溶液或者悬浮液中的四氢大麻酚(THC)和大麻二酚(CBD)的总含量优选为溶液或者悬浮液中所有成份重量的1-25wt％，更优选为1-6wt％，尤其优选1.5-6wt％。在片剂或者包衣片剂的生产中，活性成份THC∶CBD的比同上所述，但是其基于片剂或者包衣片剂总重量的浓度可以更高。
在本发明的组合物用于癌症姑息治疗适应症的治疗应用中，作为治疗剂量，THC每天给药的剂量范围为2.5-20mg，平均5mg THC(以THC和CBD的干重计，这一剂量相当于3.75-120mg的本发明的组合物)。在与MS相关痉挛适应症的治疗应用中，作为治疗剂量，THC每天给药的剂量范围为5-30mg，平均10mg THC(这个剂量相当于7.5-120mg的本发明组合物)。
本发明的组合物有两个主要用途，即(i)癌症姑息治疗(没有食欲/体重下降，恶心/呕吐，慢性疼痛和反应性抑郁)和(ii)在神经疾病尤其是多发性硬化症中的肌肉松驰作用和/或止痛作用。
本发明的组合物的药理作用可进一步应用到以下领域：
刺激食欲作用：本发明的组合物的刺激食欲作用还可用于治疗HIV阳性患者的食欲缺乏/恶病质(AIDS萎缩)和用于患者(尤其是那些通气时间过长的患者)术后改为口服营养。
止吐(恶心抑制)作用：本发明的组合物的止吐作用还可用于防止癌症患者因化疗(有治疗意义)而引起的恶心/呕吐(尤其在使用5HT3拮抗剂的治疗中作为辅助止吐药)和HIV感染/AIDS和乙肝的止吐支持治疗。
止痛(疼痛减轻)作用：本发明的组合物的止痛作用还可用于治疗除了由晚期癌症或者神经疾病以外的疾病所引起的慢性疼痛，如用于偏头痛、运动系统障碍和关节和肌肉组织障碍(关节病、关节炎、肌病)、痛经、胃肠道紊乱(如克罗恩氏病)和幻觉痛。尤其强调本发明的组合物用于神经病疼痛，特别是带状疱疹神经痛的止痛作用。
抗抑郁(情绪轻松)作用和抗焦虑(焦虑减轻)作用：本发明的组合物的抗抑郁作用和抗焦虑作用还可用于其它慢性的或者(现在)不能治愈的疾病如AIDS、截瘫或者慢性风湿性关节炎的支持治疗。
本发明组合物的其它药理作用是镇静/催眠作用(失眠)、抗癫痫作用(癫痫)、支气管扩张作用(支气管哮喘)、调节运动神经原过程(神经运动障碍性疾病如肌张力障碍、图雷特综合症)，或者减轻眼内压(青光眼)、抗炎(炎症抑制)作用(克罗恩氏病、溃疡性结肠炎、关节炎、神经性皮肤炎)。
在大多数情况中所述药理作用是源自本发明组合物中的THC内容物，但是通过CBD内容物对THC内容物进行关键性调整、修正并因此增强了其有益效果。由于CBD特别的抗焦虑作用、抗幻觉作用和抗精神病作用，其另外可显著减轻在给药分离的THC时所观察到的副作用，并因此提高本发明的组合物的耐受性。
因为本发明的组合物在麻醉药法案中被列为管制物质并且只能被专门用于临床研究，直到2000年11月其仅能用于两种主要用途(癌症姑息治疗和与多发性硬化症相关的肌肉痉挛)。将于2001年秋季完成多中心、随机、双盲、安慰剂对照研究，以比较本发明的组合物与分离的THC在其对食欲缺乏/恶病质、恶心和反应性抑郁的治疗作用及其在姑息情况下癌症患者中的耐受性，预计将获得阳性结果，尤其是涉及本发明的组合物的作用与THC的作用相比较。
下面的实施例阐述了本发明。
实施例1(单独THC和CBD组分的生产)
a)360g植物印度大麻(Cannabis sativa L.)的干燥和洁净植物材料(flos et herba sicc.，干花序和植物)与3600g乙醇(96％纯度)混合，常压回流提取1小时。冷却后，从植物材料中挤出液体并过滤滤液。
b)在103pa(＝100bar)压力和40℃下减压除去由a)部分得到的溶液中的溶剂，并在高压釜内将所得的树脂状残余物在120℃加热40分钟。冷却后，树脂溶解于石油醚中，过滤除去任何残余物。
使用硅胶色谱法(0.035-0.070mm，色谱法使用的流动相混合物为含有1wt％乙酸乙酯的石油醚)获得通过TLC[硅胶60F254(HPTLC预处理板)，正己烷/乙醚为8∶2；检测：125mg坚牢蓝B盐于30ml的1N氢氧化钠溶液中，加入蒸馏水至300ml，在日光下进行评价]而检测的大麻素组分。在十八烷基甲硅烷基化硅胶(LiChrospher 100RP18，7μm)上使用含70wt％乙醇和1wt％冰醋酸的水作为洗脱液通过制备HPLC分离THC和CBD组份。在280nm进行检测。蒸发洗脱液获得THC组分和CBD组分。用HPLC确定组分纯度。这些测量表明两个组分(THC和CBD)的纯度均为所获得的干物质重量的至少90wt％。
实施例2(给药形式的生产)
将实施例1的b)部分所获得的成份以2.5mg THC和1.25mg CBD(各以干物质计算)的比值进行混合。将混合物溶解于中链偏甘油酯(Imwitor 742，Hüls AG生产；化学组成：C8-C12脂肪酸单甘油酯和C8-C12脂肪酸二甘油酯)，因此获得其浓度为每克溶液含10mg的THC。使用本领域公知的软明胶胶囊填充设备将溶液填充到软明胶胶囊中，得到每粒胶囊含有2.5mg的THC和1.25mg的CBD的软明胶胶囊。
Claims (19)
1.一种适用于癌症姑息治疗并且在神经疾病中作为具有肌肉松驰作用和/或止痛作用的药物的药理活性组合物，该组合物的特征在于其包含的四氢大麻酚和大麻二酚为存在于组合物中的大麻素总重量的至少80wt％，并且四氢大麻酚∶大麻二酚的重量比为3∶1-1∶2。
2.权利要求1的组合物，特征在于其包含的四氢大麻酚和大麻二酚为存在于组合物中的大麻素总重量的至少90wt％。
3.权利要求1的组合物，特征在于四氢大麻酚∶大麻二酚的重量比为2∶1。
4.如权利要求1所述的组合物，其特征在于化合物四氢大麻酚或大麻二酚中的至少一种通过合成途径生产。
5.如权利要求1所述的组合物，其特征在于从植物提取物中获得化合物四氢大麻酚和大麻二酚。
6.根据权利要求1-5中任一项所述的组合物，其特征在于从植物印度大麻中获得作为植物提取物的化合物四氢大麻酚和大麻二酚。
7.根据权利要求1-5中任一项所述的组合物，其特征在于将化合物四氢大麻酚和大麻二酚溶解于亲油溶剂或者悬浮载体中。
8.如权利要求7所述的组合物，其特征在于亲油溶剂或者亲油悬浮载体为中链和/或短链甘油三酯、中链偏甘油酯、聚氧乙基化脂肪醇、聚氧乙基化脂肪酸、聚氧乙基化脂肪酸甘油三酯或者偏甘油酯、脂肪酸与低分子量醇的酯、山梨聚糖与脂肪酸的偏酯、山梨聚糖与脂肪酸的聚氧乙基化偏酯、糖或者低聚糖与脂肪酸的偏酯、聚乙二醇及其混合物；或者是这些化合物与脂肪、油和/或蜡或乙二醇的混合物，或这些化合物在卵磷脂和/或油和/或蜡混合物中形成的悬浮液。
9.一种生产权利要求1-8中任一项所述的组合物的方法，其特征在于将含有活性成份的两种溶液以一种方式混合从而使得活性成份四氢大麻酚∶大麻二酚的重量比为3∶1-1∶2。
10.权利要求9的方法，特征在于活性成份四氢大麻酚∶大麻二酚的重量比为2∶1。
11.一种含有权利要求1-8中任一项所述的组合物的药理活性溶液或者悬浮液，其特征在于四氢大麻酚和大麻二酚的总含量为所有成份重量的1-25wt％。
12.权利要求11的药理活性溶液或者悬浮液，其特征在于四氢大麻酚和大麻二酚的总含量为所有成份重量的1.5-6wt％。
13.一种用于口服给药的单剂量给药形式，其中含有权利要求1-8中任一项所述的组合物，所述给药形式采用压缩形式，或者采用硬明胶胶囊或者软明胶胶囊形式。
14.权利要求13的单剂量给药形式，其中所述给药形式采用压缩形式，特征在于其为片剂或包衣片剂。
15.如权利要求13或14所述的给药形式，其特征在于其含有的权利要求1-8所述的组合物的数量为3.75-35.5mg，以四氢大麻酚和大麻二酚的总干重计算。
16.如权利要求15所述的给药形式，其特征在于组合物的数量7.5-25mg。
17.如权利要求1-8中任一项所述的组合物在生产用于癌症姑息治疗和神经疾病治疗的药理活性药物中的应用。
18.如权利要求1-8中任一项所述的组合物在生产用于治疗多发性硬化症，和与多发性硬化症相关痉挛的具有痉挛减轻作用的药理活性药物中的应用。
19.如权利要求1-8中任一项所述的组合物在生产具有疼痛减轻作用的药理活性药物中的应用。
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| EP (1) | EP1368048B1 (zh) |
| JP (1) | JP2004529892A (zh) |
| CN (1) | CN100387230C (zh) |
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| AU (1) | AU2002229456B2 (zh) |
| CA (1) | CA2440070A1 (zh) |
| CH (1) | CH695661A5 (zh) |
| DE (1) | DE50211204D1 (zh) |
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| RU (1) | RU2003129517A (zh) |
| WO (1) | WO2002069993A1 (zh) |
| ZA (1) | ZA200306794B (zh) |
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- 2003-08-29 ZA ZA200306794A patent/ZA200306794B/en unknown
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11084770B2 (en) | 2016-12-07 | 2021-08-10 | Treehouse Biotech, Inc. | Cannabis extracts |
| US11202771B2 (en) | 2018-01-31 | 2021-12-21 | Treehouse Biotech, Inc. | Hemp powder |
| US11040932B2 (en) | 2018-10-10 | 2021-06-22 | Treehouse Biotech, Inc. | Synthesis of cannabigerol |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1547479A (zh) | 2004-11-17 |
| ATE378058T1 (de) | 2007-11-15 |
| JP2004529892A (ja) | 2004-09-30 |
| US20040138293A1 (en) | 2004-07-15 |
| EP1368048B1 (de) | 2007-11-14 |
| WO2002069993A8 (de) | 2003-11-06 |
| WO2002069993A1 (de) | 2002-09-12 |
| AU2002229456B2 (en) | 2007-06-21 |
| DE50211204D1 (de) | 2007-12-27 |
| ZA200306794B (en) | 2004-09-14 |
| CA2440070A1 (en) | 2002-09-12 |
| RU2003129517A (ru) | 2005-03-10 |
| CH695661A5 (de) | 2006-07-31 |
| EP1368048A1 (de) | 2003-12-10 |
| NZ527879A (en) | 2006-04-28 |
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