CN108721276A - 一种小白菊内酯和原花青素复方药物组合物及其用途 - Google Patents
一种小白菊内酯和原花青素复方药物组合物及其用途 Download PDFInfo
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Abstract
本发明属于天然药物领域，公开了一种小白菊内酯和原花青素复方药物组合物及其用途。该复方药物组合物的活性成分是由质量比为1:10～1:200小白菊内酯和原花青素组成。两者联合用药具有较强的协同治疗淋巴瘤的用途。
Description
技术领域
本发明属于天然药物领域，特别涉及一种小白菊内酯和原花青素复方药物组合物及其用途。
背景技术
癌症是严重危害人类健康的一大顽症，现已成为仅次于心血管病的第二大杀手。进入21世纪以来，由于现代工业化的快速进程，环境污染等诸多因素导致淋巴细胞系统免疫被破坏而引起淋巴瘤发病率呈逐年上升的趋势，使我们意识到研发出一种能够用于防治淋巴瘤的药物系统显得非常迫切。
小白菊内酯(Parthenolide，PTL)是中药野生甘菊(银胶菊属银胶菊Partheniumhysterophorus)的主要提取成分，它是倍半萜烯内酯的主要成分。小白菊内酯的分子式为C15H20O3(化学结构式见图1)，相对分子质量为248.3，小白菊内酯含有α-亚甲基-γ-内酯环和环氧化物结构，这些结构可以和含有巯基基团的酶和其它功能蛋白反应，干扰细胞的许多关键生物过程，如细胞的信号传导途径，线粒体呼吸，增殖和凋亡等。这些反应可降低酶的活性，改变谷胱甘肽(GSH)的代谢并引起细胞内氧化还原平衡状态的严重失衡。小白菊内酯的环氧亚甲基结构使其具有细胞毒性。PTL主要抗肿瘤作用机制为抑制NF-κB和STAT3的信号通路、氧化应激作用、调节线粒体活性、维持JNK活性、调节DNA甲基化和促进MDM2的泛素化；PTL还具有对癌症干细胞具有选择性杀灭作用(Blood 2005,105,4163-4169.；Blood2007,110,4227-4435.；Drug Discovery Today 2010,15,668-678.)。
原花青素(Oligomeric Proantho Cyanidins，OPC)，是一种有着特殊分子结构的生物类黄酮，是目前国际上公认的清除人体内自由基最有效的天然抗氧化剂。一般为红棕色粉末，气微、味涩，溶于水和大多有机溶剂。最新研究表明蓝莓叶提取物原花青素可阻止丙肝病毒复制。原花青素主要分布在葡萄、银杏、大黄、山楂、小连翘、花旗松、日本罗汉柏、白桦树、野草莓、海岸松、甘薯等植物中，但研究发现葡萄籽提取物中原花青素的含量最高。一般的OPC为葡萄籽提取物或法国海岸松树皮提取物。原花青素(葡萄籽提取物)是一种新型高效抗氧化剂，是目前为止所发现的最强效的自由基清除剂，具有非常强的体内活性。实验证明，OPC的抗自由基氧化能力是维生素E的50倍，维生素C的20倍，并吸收迅速完全，口服20分钟即可达到最高血液浓度，代谢半衰期达7小时之久。大量研究和临床结果表明，OPC具有抗氧化、抗肿瘤、抗衰老、美容、抗炎、保护心血管、视力保护和消除水肿等多种生物学活性，同时广泛试验证明了原花青素是无毒、不致癌、没抗原性、不致胎儿畸形的天然滋补品(Br J Pharmacol.2016 Sep 20.doi:10.1111/bph.13630.；PLoS One.2015；10(11):e0142157.Carcinogenesis.2014；35(10):2314-20.；Clin Cancer Res.2009；15(3):821-31.)。因此，原花青素是一种极具潜力的能够选择性杀死肿瘤的绿色天然产物。
这些为复合OPC和PTL给药治疗恶性肿瘤淋巴瘤提供了全新的机会。将原花青素的优越抗癌疗效与具有良好抗癌活性的天然药物联合协同治疗淋巴瘤等恶性肿瘤，是一个值得关注而又很有潜力的抗肿瘤复合药物方向。组合原花青素和天然药物小白菊内酯用于恶性肿瘤淋巴瘤的预防和治疗作用尚未见相关文献报道几乎没有。
发明内容
为了克服现有技术中存在的缺点和不足，本发明的首要目的在于提供一种小白菊内酯和原花青素复方药物组合物；该复方药物组合物的活性成分是由小白菊内酯和原花青素组成。
本发明的另一目的在于提供一种上述复方药物组合物的用途；药理试验证明该复方药物组合物具有协同抗淋巴瘤作用。
本发明的目的通过下述技术方案实现：
一种小白菊内酯和原花青素复方药物组合物，该复方药物组合物的活性成分是由小白菊内酯和原花青素组成。
优选的，所述小白菊内酯和原花青素的质量比为1:10～1:200。
更加优选的，所述小白菊内酯和原花青素的质量比为1:100～1:200。
更加优选的，所述小白菊内酯和原花青素的质量比为1:200。
该复方药物组合物还含有药物上可接受的载体。
所述复方药物组合物按照常规制备工艺制备得到。
上述的小白菊内酯和原花青素复方药物组合物在制备抗淋巴瘤药物中的用途。
上述药物可用于包括人在内的哺乳动物的淋巴瘤的治疗。
本发明与现有技术相比具有如下突出的优点及有益效果：
本发明人在对小白菊内酯和原花青素配伍药理活性的研究中发现，将原花青素(OPC)和小白菊内酯(PTL)组合给药，特别是当两者质量比为1:10-1:200配伍时具有很好抗癌细胞的协同作用；发明人分别对Daudi，Raji和BC-3为模型进行体外MTT筛选，发现其具有很强的抗增殖活性并呈良好的时效与量效关系，结合经典联合给药分析原理(Median-effect Principle)和统计分析，结果表明其具有协同作用，尤其是在fa＜0.5时可明显产生协同效应抑制三种癌细胞增殖，这说明小白菊内酯和OPC组合物可在低剂量配伍时产生OPC或PTL单药高剂量的生物学效应，从而可以大大降低药物的毒副作用产生，具有良好的临床用药开发前景；同时，等效应剂量评价表明，复合药物对正常肝细胞L-O2的毒性尚未增加。
附图说明
图1为OPC和PTL及优化配伍组合作用PBMC细胞72小时的安全性评价(细胞凋亡率)。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1：采用Daudi细胞、Raji细胞和BC-3细胞筛选优化原花青素(OPC)和小白菊内酯(PTL)复方药物组合物
取对数生长期的细胞，分别接种3×104个细胞/孔于96孔板上，待生长6小时后，离心弃上清，然后按以下分组给药：肿瘤细胞设不加药组和加药组，其中加药组设OPC和PTL单药组、OPC和PTL联合用药不同质量比例组，每组设4-6个复孔，培养24小时，弃上清，加入100μl含0.5mg/ml的MTT(四氮唑盐)无血清培养液培养4小时，加入100μl DMSO(二甲亚砜)，放置于微型振荡仪上振荡10min，再置于酶标仪上570nm处检测OD值。结果按照以下抑制率公式计算每种情况下肿瘤细胞生长的抑制率，具体结果见表1。
抑制率＝(1-加药组OD值/对照组OD值)
表1为PTL和OPC单独和联合给药作用细胞72小时后不同浓度的IC50抑制率。
当PTL和OPC按质量比1:10和1:200配伍组合时的抑制情况。从其中我们可以获得随着配伍浓度的增加，其抑制率呈浓度依赖性。其中我们发现随着配伍浓度的增加，其抑制率呈浓度依赖性。
表1 PTL和OPC单药作用72小时IC50(μg/mL)
实施例2：OPC和PTL联合给药效应分析
以Median-effect Principle(中效原理或Chou-Talalay联合指数法)为评价基础，应用CombiDrug统计软件绘制剂量-效应曲线及不同效应下的合用指数曲线(fa-C曲线)，从两药合用的效应与合用指数的关系定量评价两药之间是协同、拮抗或相加关系。具体步骤如下：
药物作用效应即抑制率(fa)＝1-(试验组平均OD570值/肿瘤细胞空白对照组平均OD570)根据中效方程式fa/fu＝(D/Dm)m，两边取对数logfa/fu＝mlogD–mlogDm，设a＝-mlogDm，b＝m，x＝logD，y＝logfa/fu,代入中效方程式得y＝bx–a；其中fa为药物作用效应，fu＝1–fa，D为药物浓度，m为斜率，Dm为中效浓度，即50％效应时的药物浓度。依上述公式，计算出两种抗癌药单用及合用时各自的中效浓度Dm(logDm＝-a/m)，再计算出单用及两药合用时在各种效应时所需药物浓度〔D＝Dm(fa/f u)1/m〕，可计算出两药合用时在各种效应时的合用指数〔CI＝D1/DX1+D2/DX2+α(D1D2)/(DX1DX2)，D1、D2为两药合用时产生X效应时两药各自所需浓度，DX1、DX2为两药单独使用时产生X效应时两药各自浓度〕。α＝0为两种相互排斥性药物，α＝1为两种相互非排斥性药物。因OPC与小白菊内酯作用机制不同，故本实验中取α＝0。当CI<1，两药合用效应为协同；CI＝1，两药合用效应相加；CI>1，两药合用效应拮抗。
经过软件分析，本发明的复方药物组合物具有良好的协同作用，具体效应见表2，根据Median-effect Principle评价效应的原则，即CI指数<0.1时具有很强的协同作用(Very strong synergism)；CI指数为0.1–0.3时为强协同效应(Strong synergism)；CI指数为0.3–0.7具有协同效应(Synergism)；CI指数为0.7–0.85具有中度协同效应(Moderatesynergism)；CI指数为0.85–0.90区间时具有弱协同效应(Slight synergism)；CI指数为0.90–1.10区间时具有近叠加效应(Nearly additive)；CI指数>1.10及以上时具有拮抗效应。
表2可见，OPC和PTL配伍具有协同效应；尤其是当两者质量比为1-100:200配伍时具有良好的协同效应，当两者质量比为1:200时协同效应最强。
表2 PTL和OPC不同配伍组合作用72小时的联合指数CI比较
实施例3：OPC和PTL对外周血单核淋巴细胞的安全性
将健康志愿者单核淋巴细胞PBMC进行分离和加药培养后评价OPC和小白菊内酯对PBMC细胞的安全性(图1)：①抽取健康志愿者的新鲜血液到肝素抗凝管中(无菌)；然后用等体积量PBS(或无血清的D-Hank缓冲液)重悬细胞(无菌)；②将悬浮细胞加入预先铺好的人淋巴细胞分离液(预热37℃)，淋巴分离液与细胞悬液的体积比不低于1：1；③500×g(或2000rpm)水平离心机离心20-30min，室温(20-30℃)慢速；④丢弃上层血浆，把中间白色雾层小心吸出加入到5ml(或1-2倍体积)的PBS(或无血清细胞培养缓冲液)中，200×g或1000rpm离心10min，室温(20-30℃)，慢速，弃上清，所得沉淀即为外周血单核淋巴细胞(PBMC)；⑤再按上述操作洗涤2次，每次500×g水平离心10min，室温(20-30℃)慢速，收集细胞沉淀；⑥采用活细胞拒染法(如台盼蓝)等检测细胞活力；⑦按加药设计方案放入细胞培养箱孵育72小时(OPC 2000μg/mL，PTL 10μg/mL，PTL/OPC＝1/200(10μg/mL/2000μg/mL))，加药及对照进行流式检测细胞凋亡率。D1-D8为志愿者1-8号的血液样本。
实施例4：原花青素(OPC)和小白菊内酯(PTL)复方药物组合物按照以下处方制成片剂：
处方如下：
制备工艺如下：
将药物和辅料分别过80目筛，将小白菊内酯与48克微晶纤维素和12克羧甲基淀粉钠充分混合，10％淀粉浆制软材，18目筛制粒，60℃下干燥，得颗粒1。将原花青素与24克微晶纤维素、15克淀粉和8克羧甲基淀粉钠充分混合，10％淀粉浆制软材，18目筛制粒，60℃下干燥，得颗粒2。按等量递增原则，将颗粒1和颗粒2充分混合，16目筛整粒，加入硬脂酸镁，混匀，压片，片重500mg。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (6)
1.一种小白菊内酯和原花青素复方药物组合物，其特征在于：该复方药物组合物的活性成分是由小白菊内酯和原花青素组成。
2.根据权利要求1所述的一种小白菊内酯和原花青素复方药物组合物，其特征在于：所述小白菊内酯和原花青素的质量比为1:10～1:200。
3.根据权利要求1所述的一种小白菊内酯和原花青素复方药物组合物，其特征在于：所述小白菊内酯和原花青素的质量比为1:100～1:200。
4.根据权利要求1所述的一种小白菊内酯和原花青素复方药物组合物，其特征在于：所述小白菊内酯和原花青素的质量比为1:200。
5.根据权利要求1所述的一种小白菊内酯和原花青素复方药物组合物，其特征在于：该复方药物组合物还含有药物上可接受的载体。
6.根据权利要求1～5任一项所述的小白菊内酯和原花青素复方药物组合物在制备抗淋巴瘤药物中的用途。
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| 李蒲: "小白菊内酯对人淋巴瘤Raji细胞增殖的影响及机制探讨", 《世界最新医学信息文摘》 * |
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