CN113368084A - 含有大麻二酚，丙泊酚前药和别孕烯醇酮前药化合物的药物组合物及其在医药上的应用 - Google Patents
含有大麻二酚，丙泊酚前药和别孕烯醇酮前药化合物的药物组合物及其在医药上的应用 Download PDFInfo
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Abstract
本发明涉及一种含大麻二酚，还包括丙泊酚前药化合物或别孕烯醇酮前药化合物中的一种或两种的组合物及其在医药上的应用。
Description
技术领域
本发明涉及一种含大麻二酚，还包括丙泊酚前药化合物或别孕烯醇酮前药化合物中的一种或两种的组合物及其在医药上的应用。
背景技术
大麻(Cannabis sativa L.)为桑科大麻属一年生草本植物，起源于中亚和东亚，广泛分布于美国、印度、巴西等地。大麻的药用历史悠久，但成瘾性和精神致幻作用，使其临床应用受到极大限制。大麻含有数百种不同的化学物质，大约有70多种成分被称为大麻素，主要包括大麻二酚(cannabidiol，CBD)、大麻酚(cannabinol，CBN)、四氢大麻酚(Tetrahydrocannabinol，THC)及其同系物等。THC和CBD具有广泛的治疗特征，对神经疾病具有明显的改善作用，另外在抗肿瘤、抗炎、肝脏保护、疼痛、抗焦虑、抗失眠、抗惊厥、抗呕吐、抗痉挛、抗氧化、神经保护的治疗上，也表现出很好应用前景。
丙泊酚(propofol)，化学名称为2,6-二异丙基苯酚，是目前临床上广泛应用的烷基酸类短效静脉全身麻醉药品，在国内外静脉麻醉药物市场处于领先和主导地位。静脉注射后迅速分布于全身，40秒钟内可产生睡眠状态，进入麻醉迅速、平稳。在临床使用上，同其他麻醉药物相比，丙泊酚起效快速，苏醒快速，且药代动力学和药效动力学完全可控、适用症广泛、禁忌症少，普通病人和高危病人均可安全使用。
丙泊酚的酚羟基容易发生氧化反应，产生降解杂质，稳定性差。因异丙基的位阻影响，丙泊酚水溶性很差，目前普遍将丙泊酚配制成脂肪乳剂用于静脉注射麻醉，会产生局部疼痛，较大的油滴有引起栓塞的风险；脂肪乳会加重脂质代谢负荷，易污染导致细菌感染及过敏反应等风险。
根据前药的原理，将丙泊酚的羟基进行前体改造的磷酰胺基团前药化合物，明显改善其溶解度、稳定性，从而明显改善了药物的理化性质、改善药物在体内的吸收、分布、代谢与排泄过程、提高口服生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。这类药物通过口服进入体内后，可按照设计要求以一定的水解速度释放出2,6-二异丙基苯酚衍生物，产生麻醉、镇静和催眠效应，从而克服丙泊酚水溶性差和稳定性差的缺点。
别孕烯醇酮，为一种天然存在的神经甾体和黄体酮的代谢产物，为变构的GABA-A受体调节剂。目前公开的专利和文献中，别孕烯醇酮均采用注射给药方式，无法进行口服给药。
根据前药的原理，本发明的别孕烯醇酮的羟基前体，改善其溶解度、稳定性，以达到改善药物的理化性质、改善药物在体内的吸收、分布、代谢与排泄过程、提高口服生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。这类药物进入体内后，可按照设计要求以一定的水解速度释放出别孕烯醇酮，从而治疗中枢神经系统相关的疾病，包括震颤、抑郁症、产后抑郁症失眠症、心境障碍、惊厥性障碍、记忆障碍、注意障碍、焦虑、双相型障碍、精神分裂、双相型障碍、情感分裂性精神障碍、心境障碍、焦虑障碍、人格障碍、精神病、强迫性障碍、创伤后应激障碍、自闭症谱系障碍、精神抑郁症、社交焦虑障碍、强迫症、疼痛、睡眠障碍、记忆障碍、痴呆、阿尔茨海默病、发作性疾病、创伤性脑损伤、中风、成瘾性障碍、自闭症、亨廷顿舞蹈症、帕金森病、Rett综合征、戒断综合征或耳鸣；从而有利于克服别孕烯醇酮水溶性差和稳定性差的缺点。
目前，人们对丙泊酚前药化合物、别孕烯醇酮前药化合物、大麻二酚都是采用其各自的药效，将丙泊酚前药化合物与大麻二酚，别孕烯醇酮前药化合物与大麻二酚，或者丙泊酚前药化合物，别孕烯醇酮前药化合物与大麻二酚配伍制备成组合物的技术尚未见报道。
发明内容
为了满足临床需要，本发明提供一种含大麻二酚，还包括丙泊酚前药化合物或别孕烯醇酮前药化合物中的一种或两种的组合物，以及其在制备药物的用途。本申请人惊奇地发现，本发明制备的组合物具有意料不到的效果，本发明的组合物具有如下优点：
(1)首次提供丙泊酚前药化合物与大麻二酚，别孕烯醇酮前药化合物与大麻二酚，或者丙泊酚前药化合物，别孕烯醇酮前药化合物与大麻二酚配伍制备成组合物，可以用于制备心血管疾病、神经系统疾病、疼痛等疾病领域用途，其具有协同增效的作用，优于单独用药。
(2)本发明药物组合物，制备工艺简便适应于工业化大生产，有效成分明确，制剂质量较高，稳定性好，安全性更高，可以保证临床用药安全。
本发明的一个实施方案，所涉及的药物组合物，包括大麻二酚，其特征在于，还包括(1)丙泊酚前药化合物(I)或(2)别孕烯醇酮前药化合物(II)中的一种或两种以任意比例的组合；其中所述的丙泊酚前药化合物或别孕烯醇酮前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，包括大麻二酚，其特征在于，还包括丙泊酚前药化合物(I)，其中所述的丙泊酚前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，包括大麻二酚，其特征在于，还包括别孕烯醇酮前药化合物(II)，其中所述的别孕烯醇酮前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，包括大麻二酚，其特征在于，还包括(1)丙泊酚前药化合物(I)和(2)别孕烯醇酮前药化合物(II)以任意比例的组合；其中所述的丙泊酚前药化合物或别孕烯醇酮前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的药物组合物进一步包含药用辅料。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-99％。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-75％。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-99％。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为1mg-1500mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2mg-1500mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2.0mg、2.2mg、2.4mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10mg、11mg、12mg、13mg、14mg、14.4mg、15mg、16mg、17mg、18mg、19mg、19.2mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、38.4mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、60mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg或者1400mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为0.1mg-1500mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为0.1mg-1200mg，优选5mg-900mg，优选5mg-600mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为0.25mg、0.5mg、1mg、1.25mg、1.5mg、2.0mg、2.5mg、2.7mg、5mg、6.5mg、7.5mg、8mg、8.4mg、9mg、10mg、10.5mg、10.8mg、11mg、12mg、12.8mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、21.6mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、32.5mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、80mg、90mg、100mg、110mg、120mg、125mg、130mg、135mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg或者1400mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为1mg-1500mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2.5mg-1200mg，优选120mg-1000mg，优选200-900mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2.5mg、2.7mg、5mg、10mg、15mg、20mg、25mg、30mg、32.4mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg或者1400mg。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中：
所述化合物(I)含量为10mg-600mg，优选10mg、14.4mg、19.2mg、25mg、40mg、50mg、60mg、150mg、200mg、300mg、400mg、500mg或者600mg；
其中所述化合物(II)含量为10mg-600mg，优选10mg、14.4mg、19.2mg、25mg、40mg、50mg、60mg、150mg、200mg、300mg、400mg、500mg或者600mg；
其中所述大麻二酚含量为0.25mg、0.5mg、1mg、1.25mg、1.5mg、2.0mg、2.5mg、2.7mg、5mg、6.5mg、7.5mg、8mg、8.4mg、9mg、10mg、10.5mg、10.8mg、11mg、12mg、12.8mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、21.6mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、32.5mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、80mg、90mg、100mg、110mg或者120mg；
其中所述大麻二酚含量为1mg-1500mg，优选5mg、10mg、20mg、30mg、40mg、60mg、150mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg或者1400mg；
所述的化合物(I)、化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其剂型可以是药学可接受的任何剂型，优选为膏剂、溶液、乳剂、喷雾剂、凝胶剂、贴剂、片剂、胶囊剂、软胶囊剂、颗粒剂、混悬剂、滴丸、丸剂、注射液或粉针剂。
本发明的一个实施方案，所涉及的药物组合物，，其中所述的化合物(I)和大麻二酚的在同一种制剂单元中，或者所述的化合物(I)和大麻二酚的分别在不同的规格制剂单元中，所述的化合物(I)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其中所述的化合物(II)和大麻二酚的在同一种制剂单元中，或者所述的化合物(II)和大麻二酚的分别在不同的规格制剂单元中，所述的化合物(I)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其中所述的化合物(I)、化合物(II)和大麻二酚在同一种制剂单元中，或者所述的化合物(I)、化合物(II)和大麻二酚分别在不同的规格制剂单元中，所述的化合物(I)、化合物(II)或大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中化合物(I)或者大麻二酚的彼此分别、顺序或同时给药，所述的化合物(I)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中化合物(II)或者大麻二酚的彼此分别、顺序或同时给药，所述的化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中化合物(I)化合物(II)和大麻二酚的彼此分别、顺序或同时给药，所述的化合物(I)化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的药物组合物在制备面瘫、中风、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、偏头痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、创伤后应激障碍、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、注意缺陷综合征、秽语综合征、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、吸毒成瘾、厌食症、恶病质、晕车、家族性自主神经障碍恶心和呕吐、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、亨廷顿氏病、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、感觉异常、语言失调、神经失调、视力和听力失调、软瘫、麻痹性痴呆、玄晕、记忆力减退及定向力消失、糖尿病性神经病、肥胖、休克、克罗恩病、溃疡性结肠炎、aGVHD、过敏性肠综合征、银屑病关节炎、手骨关节炎、艾滋病毒感染、寻常痤疮、脑部或脊髓感染、脑膜炎、结节性硬化症、炎症性肠病、震颤、急性胰腺炎、减肥多发性骨髓瘤，胶质母细胞瘤、胃肠道恶性肿瘤、脑癌、胶质瘤、乳腺癌、肝癌、肺癌、胰腺癌、黑色素瘤、卵巢癌、胃癌、肾癌、膀胱癌、头颈部鳞状细胞癌、杀菌、抑菌、诱导和维持动物或者人类的麻醉、镇静、器官组织缺氧缺血损伤保护、促进动物或者人类的镇静催眠、治疗和/或预防恶心、呕吐、偏头痛、癫痫、震颤、抑郁症、失眠症、心境障碍、惊厥性障碍、记忆障碍、注意障碍、双相型障碍、精神分裂、双相型障碍、情感分裂性精神障碍、心境障碍、人格障碍、精神病、强迫性障碍、创伤后应激障碍、自闭症谱系障碍、精神抑郁症、社交焦虑障碍、强迫症、疼痛、睡眠障碍、记忆障碍、痴呆、阿尔茨海默病、发作性疾病、创伤性脑损伤、中风、成瘾性障碍、自闭症、亨廷顿舞蹈症、帕金森病、Rett综合征、戒断综合征或耳鸣药物中的用途。
本发明提供了一种制备所述的药物组合物的方法，其包括以下步骤：
(1)按质量重量比称取化合物(I)和大麻二酚；
(2)将原料混合后，加入药学上可接受的辅料制备成药学上常用的药物制剂。
本发明提供了一种制备所述的药物组合物的方法，其包括以下步骤：
(1)按质量重量比称取化合物(II)和大麻二酚；
(2)将原料混合后，加入药学上可接受的辅料制备成药学上常用的药物制剂。
本发明提供了一种制备所述的药物组合物的方法，其包括以下步骤：
(1)按质量重量比称取化合物(I)、化合物(II)和大麻二酚；
(2)将原料混合后，加入药学上可接受的辅料制备成药学上常用的药物制剂。
其中，所述的药学上可接受的辅料包括：淀粉、预胶化淀粉、乳糖、蔗糖、滑石粉、糊精、环糊精、微晶纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、葡萄糖、葡甲胺、硬脂酸镁、右旋糖酐、甘油、乙醇、丙二醇、聚乙二醇、甘露醇、山梨醇、木糖醇、纤维植物油、苯甲酸钠、水杨酸钠、盐酸、枸橼酸、枸橼酸纳、磷酸二氢钠、磷酸氢二钠、明胶、卵磷脂、维生素C中的的一种或多种。
制成注射剂时，可采用现有制药领域中的常规方法生产，可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水，也可用0.9％氯化钠溶液或其他适宜的水溶液；常用的非水性溶剂为植物油，主要为供注射用大豆油，其他还有乙醇、丙二醇、聚乙二醇等的水溶液。配制注射剂时，可根据药物的性质加入适宜的附加剂，如渗透压调节剂、pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。常用的渗透压调节剂包括氯化钠、葡萄糖、氯化钾、氯化镁、氯化钙、山梨醇等，优选氯化钠或葡萄糖；常用的pH值调节剂包括醋酸-醋酸钠、乳酸、枸橼酸-枸橼酸钠、碳酸氢钠-碳酸钠等；常用的增溶剂包括聚山梨酯80、丙二醇、卵磷脂、聚氧乙烯蓖麻油等；常用的填充剂包括乳糖、甘露醇、山梨醇、右旋糖酐等；常用的抗氧剂有亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠等；常用抑菌剂为苯酚、甲酚、三氯叔丁醇等。注射剂常用容器有玻璃安瓿、玻璃瓶、塑料安瓿、塑料瓶等。
用于口服时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。片剂系指药物与适宜的辅料混匀压制而成的圆片状或异形片状的固体制剂，以口服普通片为主，另有含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、缓释片、控释片与肠溶片等。胶囊剂系指药物或加有辅料充填于空心胶囊或密封于软质囊材中的固体制剂，依据其溶解与释放特性，可分为硬胶囊(通称为胶囊)、软胶囊(胶丸)、缓释胶囊、控释胶囊和肠溶胶囊等。丸剂系指药物与适宜的辅料均匀混合，以适当方法制成的球状或类球状固体制剂，包括滴丸、糖丸、小丸等。颗粒剂系指药物与适宜的辅料制成具有一定粒度的干燥颗粒状制剂，可分为可溶颗粒(通称为颗粒)、混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒和控释颗粒等。口服溶液剂系指药物溶解于适宜溶剂中制成供口服的澄清液体制剂。口服混悬剂系指难溶性固体药物，分散在液体介质中，制成供口服的混悬液体制剂，也包括干混悬剂或浓混悬液。糖浆剂系指含有药物的浓蔗糖水溶液。
制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。常用填充剂包括淀粉、糖粉、磷酸钙、硫酸钙二水物、糊精、微晶纤维素、乳糖、预胶化淀粉、甘露醇等；常用粘合剂包括羧甲基纤维素钠、PVP-K30、羟丙基纤维素、淀粉浆、甲基纤维素、乙基纤维素、羟丙甲纤维素、胶化淀粉等；常用崩解剂包括干淀粉、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等；常用润滑剂包括硬脂酸镁、滑石粉、十二烷基硫酸钠、微粉硅胶等。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“共晶”是指活性药物成分和共晶形成物在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与或溶剂化物形成的多元共晶。所述“共晶形成物”的非限定性实例包括丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、门冬氨酸、谷氨酸、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶和N-乙基哌啶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (26)
1.一种药物组合物，包括大麻二酚，其特征在于，还包括(1)丙泊酚前药化合物(I)或(2)别孕烯醇酮前药化合物(II)中的一种或两种以任意比例的组合；其中所述的丙泊酚前药化合物或别孕烯醇酮前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
2.根据权利要求1所述的药物组合物，包括大麻二酚，其特征在于，还包括丙泊酚前药化合物(I)，其中所述的丙泊酚前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
3.根据权利要求1所述的药物组合物，包括大麻二酚，其特征在于，还包括别孕烯醇酮前药化合物(II)，其中所述的别孕烯醇酮前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
4.根据权利要求1所述的药物组合物，包括大麻二酚，其特征在于，还包括(1)丙泊酚前药化合物(I)和(2)别孕烯醇酮前药化合物(II)以任意比例的组合；其中所述的丙泊酚前药化合物或别孕烯醇酮前药化合物包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
5.根据权利要求1-4任一项所述的药物组合物，其特征在于，所述的药物组合物进一步包含药用辅料。
6.根据权利要求1、2、4或5任一项所述的药物组合物，其特征在于，所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-99％。
7.根据权利要求1、3-5任一项所述的药物组合物，其特征在于，所述的化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-75％。
8.根据权利要求1-7任一项所述的药物组合物，其特征在于，所述的大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-99％。
9.根据权利要求1、2、4或5任一项所述的药物组合物，其特征在于，其中所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为1mg-1500mg。
10.根据权利要求9所述的药物组合物，其特征在于，其中所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2mg-1500mg。
11.根据权利要求9-10任一项所述的药物组合物，其特征在于，其中所述的化合物(I)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2.0mg、2.2mg、2.4mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10mg、11mg、12mg、13mg、14mg、14.4mg、15mg、16mg、17mg、18mg、19mg、19.2mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、38.4mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、60mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg或者1400mg。
12.根据权利要求1、3-5任一项所述的药物组合物，其特征在于，其中所述的化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为0.1mg-1500mg。
13.根据权利要求12所述的药物组合物，其特征在于，其中所述化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为0.1mg-1200mg，优选5mg-900mg，优选5mg-600mg。
14.根据权利要求12-13任一项所述的药物组合物，其特征在于，其中所述化合物(II)或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为0.25mg、0.5mg、1mg、1.25mg、1.5mg、2.0mg、2.5mg、2.7mg、5mg、6.5mg、7.5mg、8mg、8.4mg、9mg、10mg、10.5mg、10.8mg、11mg、12mg、12.8mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、21.6mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、32.5mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、80mg、90mg、100mg、110mg、120mg、125mg、130mg、135mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg或者1400mg。
15.根据权利要求1-7任一项所述的药物组合物，其特征在于，其中所述的大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为1mg-1500mg。
16.根据权利要求15所述的药物组合物，其特征在于，其中所述大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2.5mg-1200mg，优选120mg-1000mg，优选200-900mg。
17.根据权利要求15-16任一项所述的药物组合物，其特征在于，其中所述大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为2.5mg、2.7mg、5mg、10mg、15mg、20mg、25mg、30mg、32.4mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg或者1400mg。
18.根据权利要求1-16任一项所述的药物组合物，其特征在于，其中：
所述化合物(I)含量为10mg-600mg，优选10mg、14.4mg、19.2mg、25mg、40mg、50mg、60mg、150mg、200mg、300mg、400mg、500mg或者600mg；
其中所述化合物(II)含量为10mg-600mg，优选10mg、14.4mg、19.2mg、25mg、40mg、50mg、60mg、150mg、200mg、300mg、400mg、500mg或者600mg；
其中所述大麻二酚含量为0.25mg、0.5mg、1mg、1.25mg、1.5mg、2.0mg、2.5mg、2.7mg、5mg、6.5mg、7.5mg、8mg、8.4mg、9mg、10mg、10.5mg、10.8mg、11mg、12mg、12.8mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、21.6mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、32.5mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、80mg、90mg、100mg、110mg或者120mg；
其中所述大麻二酚含量为1mg-1500mg，优选5mg、10mg、20mg、30mg、40mg、60mg、150mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg或者1400mg；
所述的化合物(I)、化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
19.根据权利要求1-18任一项所述的药物组合物，其特征在于，其剂型可以是药学可接受的任何剂型，优选为膏剂、溶液、乳剂、喷雾剂、凝胶剂、贴剂、片剂、胶囊剂、软胶囊剂、颗粒剂、混悬剂、滴丸、丸剂、注射液或粉针剂。
20.根据权利要求1、2、4、5、6、9～11、15～19中任一项所述的药物组合物，其中所述的化合物(I)和大麻二酚的在同一种制剂单元中，或者所述的化合物(I)和大麻二酚的分别在不同的规格制剂单元中，所述的化合物(I)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
21.根据权利要求1、3-5、7～8、12～19任一项所述的药物组合物，其中所述的化合物(II)和大麻二酚的在同一种制剂单元中，或者所述的化合物(II)和大麻二酚的分别在不同的规格制剂单元中，所述的化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
22.根据权利要求1、4、5、8、15～19任一项所述的药物组合物，其中所述的化合物(I)、化合物(II)和大麻二酚在同一种制剂单元中，或者所述的化合物(I)、化合物(II)和大麻二酚分别在不同的规格制剂单元中，所述的化合物(I)、化合物(II)或大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
23.根据权利要求1、2、4、5、6、9～11、15～19任一项所述的的药物组合物，其特征在于，其中化合物(I)或者大麻二酚的彼此分别、顺序或同时给药，所述的化合物(I)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
24.根据权利要求1、3-5、7～8、12～19任一项所述的的药物组合物，其特征在于，其中化合物(II)或者大麻二酚的彼此分别、顺序或同时给药，所述的化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
25.根据权利要求1、4、5、8、15～19任一项所述的的药物组合物，其特征在于，其中化合物(I)化合物(II)和大麻二酚的彼此分别、顺序或同时给药，所述的化合物(I)化合物(II)或者大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。
26.根据权利要求1-20任一项所述的药物组合物，所述的药物组合物在制备面瘫、中风、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、偏头痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、创伤后应激障碍、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、注意缺陷综合征、秽语综合征、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、吸毒成瘾、厌食症、恶病质、晕车、家族性自主神经障碍恶心和呕吐、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、亨廷顿氏病、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、感觉异常、语言失调、神经失调、视力和听力失调、软瘫、麻痹性痴呆、玄晕、记忆力减退及定向力消失、糖尿病性神经病、肥胖、休克、克罗恩病、溃疡性结肠炎、aGVHD、过敏性肠综合征、银屑病关节炎、手骨关节炎、艾滋病毒感染、寻常痤疮、脑部或脊髓感染、脑膜炎、结节性硬化症、炎症性肠病、震颤、急性胰腺炎、减肥多发性骨髓瘤，胶质母细胞瘤、胃肠道恶性肿瘤、脑癌、胶质瘤、乳腺癌、肝癌、肺癌、胰腺癌、黑色素瘤、卵巢癌、胃癌、肾癌、膀胱癌、头颈部鳞状细胞癌、杀菌、抑菌、诱导和维持动物或者人类的麻醉、镇静、器官组织缺氧缺血损伤保护、促进动物或者人类的镇静催眠、治疗和/或预防恶心、呕吐、偏头痛、癫痫、震颤、抑郁症、失眠症、心境障碍、惊厥性障碍、记忆障碍、注意障碍、双相型障碍、精神分裂、双相型障碍、情感分裂性精神障碍、心境障碍、人格障碍、精神病、强迫性障碍、创伤后应激障碍、自闭症谱系障碍、精神抑郁症、社交焦虑障碍、强迫症、疼痛、睡眠障碍、记忆障碍、痴呆、阿尔茨海默病、发作性疾病、创伤性脑损伤、中风、成瘾性障碍、自闭症、亨廷顿舞蹈症、帕金森病、Rett综合征、戒断综合征或耳鸣药物中的用途。
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