CN116437911A - 含有银杏内酯类化合物和大麻二酚的药物组合物及其在医药上的应用 - Google Patents
含有银杏内酯类化合物和大麻二酚的药物组合物及其在医药上的应用 Download PDFInfo
- Publication number
- CN116437911A CN116437911A CN202180076840.4A CN202180076840A CN116437911A CN 116437911 A CN116437911 A CN 116437911A CN 202180076840 A CN202180076840 A CN 202180076840A CN 116437911 A CN116437911 A CN 116437911A
- Authority
- CN
- China
- Prior art keywords
- ginkgolide
- cannabidiol
- pharmaceutical composition
- acid
- bilobalide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
一种含银杏内酯类化合物和大麻二酚的组合物及其在医药上的应用。
Description
本发明涉及一种含有银杏内酯类化合物和大麻二酚的药物组合物，以及其在制备药物的用途。
银杏是我国重要的中药，银杏叶入药始于明代，银杏的医用价值已引起国内外的广泛关注，国内外学者对银杏叶的化学、药理、制剂等进行了广泛的研究，并在此基础上开发了一系列药物。进口注射用银杏叶提取物，商品名为金纳多，主要用于各种脑部、周边等血液循环障碍，主治急慢性脑机能不全及其后遗症、耳部血流及神经障碍、眼部血流及神经障碍、末梢循环障碍等。国产金阁莱(银杏叶提取物注射液)，主要用于活血化瘀，通经活络，用于瘀血阻络所致的缺血性中风病中经络等。银杏内酯为银杏叶经提取加工制成的萜类内酯提取物。银杏内酯也是银杏叶的主要有效成分，包括银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯等。药理和临床研究表明，银杏内酯是血小板活化因子(PAF)受体特异高效的强抑制剂，可以选择性的拮抗由PAF诱导的血小板聚集，可有效的防止血小板聚集和血栓的形成。银杏内酯对中枢神经系统作用主要表现为能降低脑血管阻力，增加脑血流量，促进脑血循环；能阻止脑缺血后引起的损伤，明显改善脑缺血状态，显著抑制缺血引起的脑水肿、电解质紊乱、炎性细胞浸润。银杏内酯对血液循环系统的作用主要表现为可以抑制血小板聚集，降低血液粘度，改善缺血病人的微循环，减少血栓形成。
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，其中大麻二酚(CBD)含量最高。CBD具有广泛的药理活性，近年来，大麻素相关药品被陆续开发，例如；GW Pharmaceuticals的大麻素口腔黏膜喷雾剂(Sative)，用于治疗多发性硬化症痉挛，另一个大麻素口服溶液(Epidiolex)用于治疗儿童发作性癫痫。
目前，人们对银杏内酯和大麻二酚都是采用其各自的药效，将银杏内酯与大麻二酚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，本发明提供一种银杏内酯与大麻二酚的药物组合物，以及其在制 备药物的用途。
本发明涉及一种药物组合物，其特征在于，所述的药物组合物包含以下成分：(1)银杏内酯,(2)大麻二酚，其中，所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯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，其特征在于，所涉及的药物组合物包括(1)银杏内酯,(2)大麻二酚，其中，所述的银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯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，所述的银杏内酯或其立体异构体、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％，优选10-30％。
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％，优选70-90％。
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的银杏内酯或其立体异构体、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，其中所述的银杏内酯或其立体异构体、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，其中大麻二酚和银杏内酯彼此分别、顺序或同时给药；给药剂量分别为：大麻二酚1-300mg/kg，银杏内酯1-100mg/kg；进一步优选，给药剂量分别为：大麻二酚1-200mg/kg，银杏内酯1-50mg/kg；药物给与对象包括人及动物。
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创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁药物的用途。
本申请的一个或多个实施方式提供了本申请的药物组合物，其用作药物。
本申请的一个或多个实施方式提供了本申请的药物组合物，其用于治疗/抑制创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁的方法。
本申请的一个或多个实施方式提供了治疗/抑制创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁的方法，其包括将本申请的组合物施用于有此需要的对象。
发明详述
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。
“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。
图1为在实施例3恐惧记忆测试中由记录数据计算的僵直时间百分比。
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。以下通过实施例具体说明本发明的有益效果。
银杏内酯和大麻二酚药物组合物对创伤后应激障碍的作用
1实验材料
1.1实验动物
6周龄健康雄性Wistar大鼠72只(由中国科学院上海实验动物中心提供)，体重为180～210g。
1.2实验试剂
银杏内酯注射液(成都百裕制药股份有限公司市售的银杏内酯注射剂，其中，银杏内酯A：B：C＝20：30：10，银杏内酯A、B、C总量与白果内酯的重量比为52：48，银杏总内酯含量为5mg/ml)；
大麻二酚(购于Ryss Lab,Inc.，HPLC检测纯度为99.26％，溶于乙醇：聚氧乙烯蓖麻油：生理盐水＝1：1：18的混合溶液，制备成20.0mg/ml大麻二酚溶液)。
2实验方法
将大鼠随机分为3个大组，每个大组又随机分为3个试验组和1个空白组，每组6只大鼠，所有试验组进行单次延长应激(single prolonged stress,SPS)。3个大组的大鼠分别用于进行3个实施例的实验。
SPS诱发大鼠创伤后应激障碍：用手术胶带绑住大鼠四肢，限制其头部活动，固定在金属板上2h，紧接着强迫游泳20min，随后休养15min，接着暴露于乙醚蒸气中直到被麻醉并失去反应。将所有大鼠关在饲养笼内，每笼2只，在不受干扰的状态下圈养14天，期间连续每天给药。单一给药组腹腔注射大麻二酚(200mg/kg)，组合用药组先后腹腔注射银杏内酯(50mg/kg)和大麻二酚(200mg/kg)，空白组腹腔注射生理盐水。
实施例1：旷场实验
将大鼠置于旷场箱正中格，随后迅速将手撤出并远离旷场箱以免对动物造成干扰，开始录像，记录5min内以下参数：跨格次数、站立次数、运动总距离。每次测试结束后取出大鼠，清理旷场箱内大鼠粪便和尿液，并用蘸有70％酒精抹布擦拭旷场箱内部，避免留下气味对下一只大鼠的行为测试造成影响。
实验结果：给予大鼠银杏内酯和大麻二酚组合物后，大鼠跨格次数、站立次数、运动总距离明显提高，表明本发明组合物可以改善大鼠的焦虑状态。
实施例2：高架十字迷宫实验
高架十字迷宫由两条相对开放臂(30cm×5cm)和两条相对闭合臂(30cm×5cm)及中央区(5cm×5cm)组成，距离地面50cm。将大鼠置于中央区并使其面向一条开放臂，释放 后开始录像并观察记录5min内大鼠的活动数据：开放臂进入次数、开放臂进入时间、闭合臂进入次数、闭合臂进入时间。5min后取出大鼠，清理迷宫内大鼠粪便和尿液，并用蘸有70％酒精抹布擦拭迷宫，避免留下气味对下一只大鼠的行为测试造成影响。如果在实验过程中大鼠跌落，则删除该数据。
由记录的活动数据计算出：进臂总次数＝开放臂进入次数+闭合臂进入次数；开放臂进入次数比(％)＝开放臂进入次数/(开放臂进入次数+闭合臂进入次数)×100％；开放臂进入时间比(％)＝开放臂进入时间/(开放臂进入时间+闭合臂进入时间)×100％。
实验结果：相比于空白组，SPS刺激导致大鼠趋向于逃离到闭合臂中，且在开放臂停留时间短暂，反映出对外界的探索欲望、好奇心理减弱，且焦虑反应、警觉度增强，与创伤后应激障碍表现相似，而给予大鼠银杏内酯和大麻二酚组合物后可以明显改善创伤后应激障碍的症状。
实施例3：恐惧记忆测试
第1天将大鼠置于观察箱中适应5min，随后给予一声提示音(30s,5kHz,75dB)，接着5min内在观察箱底板上随机施加电击(2s,2mA)10次。结束后，清理观察箱内大鼠粪便和尿液，并用蘸有70％酒精抹布擦拭观察箱，避免留下气味对下一只大鼠的行为测试造成影响。第2天将大鼠置于相同的观察箱中，并给予上述施加电击前的提示音，但不施加电击，录像并观察记录大鼠5min内的僵直反应(除呼吸外，无任何其他运动)时间。同样地，实验结束后，清理观察箱。
由记录的数据计算出僵直时间百分比＝(僵直时间/总时间)×100％。
实验结果在表1中表示。
实验结果：僵直时间百分比可以反映大鼠恐惧记忆强弱情况，实验数据证实，SPS刺激引起的僵直反应与创伤后应激障碍相似，可以推断SPS刺激导致类似创伤的恐惧反应。与空白组和大麻二酚组相比，本发明的银杏内酯和大麻二酚组合物更有效减轻了与创伤后应激障碍相关的恐惧记忆行为。
Claims (5)
- 一种药物组合物，其特征在于，包括(1)银杏内酯,(2)大麻二酚，其中，所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯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。
- 根据权利要求1所述的药物组合物，其特征在于，包括(1)银杏内酯,(2)大麻二酚，其中，所述的银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯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。
- 根据权利要求1、2任一项所述的药物组合物，其特征在于，所述的银杏内酯或其立体异构体、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10-30％；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70-90％。
- 如权利要求1-3任一项所述的药物组合物，其特征在于，其中大麻二酚和银杏内酯彼此分别、顺序或同时给药，给药剂量分别为：大麻二酚1-300mg/kg，银杏内酯1-100mg/kg。
- 如权利要求1-4任一项所述的药物组合物，所述的药物组合物在制备创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁药物的用途。
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| CN110636834A (zh) * | 2017-02-15 | 2019-12-31 | 分子浸剂有限公司 | 制剂 |
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| CN111743936A (zh) * | 2020-07-28 | 2020-10-09 | 云南玉麻生物科技有限公司 | 一种改善记忆力及减压的功能性汉麻口香糖及其制备方法 |
| CN112294709A (zh) * | 2020-11-25 | 2021-02-02 | 上海英翰进出口有限责任公司 | 一种具有抗炎、抗氧化功效的免洗凝胶消毒液及其制备方法 |
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| CN110433133A (zh) * | 2019-08-19 | 2019-11-12 | 中国人民解放军军事科学院军事医学研究院 | 治疗创伤后应激障碍的大麻二酚鼻用制剂 |
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- 2021-03-05 WO PCT/CN2021/079279 patent/WO2022183480A1/zh active Application Filing
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| CN104688784A (zh) * | 2013-12-10 | 2015-06-10 | 成都百裕科技制药有限公司 | 银杏内酯在制备降血压的药物中的用途 |
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| CN111743936A (zh) * | 2020-07-28 | 2020-10-09 | 云南玉麻生物科技有限公司 | 一种改善记忆力及减压的功能性汉麻口香糖及其制备方法 |
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