CN108721275B - 一种腺花素和穿心莲内酯复方药物组合物及其用途 - Google Patents
一种腺花素和穿心莲内酯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，公开了一种腺花素和穿心莲内酯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摩尔比为1:1～1:20的腺花素和穿心莲内酯组成。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，特别涉及一种腺花素和穿心莲内酯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，所以寻找安全、有效、低毒的抗肿瘤药物和研究其作用机理，具有重要意义。
腺花素(Adenanthin，ADE)，我国云南一种称为腺花香茶菜植物中，提取到一种小分子二萜类化合物，腺花素是一种植物中天然存在的化合物，具有较高的安全性。最近研究发现，ADE可诱导白血病APL分化和杀死肝癌细胞(Nat Chem Biol.2012Apr 8；8(5):486-93.Cell Death Dis.2014Sep 4；5:e1400.)，具有开发成新型肿瘤药物的潜力。
穿心莲内酯(andrographolide,ADH)，系自爵床科植物穿心莲Andrographispaniculata(Burm.f)Nees中提取得到的二萜内酯类化合物,是中药穿心莲的主要有效成分之一。分子式C20H30O5，天然植物穿心莲的主要有效成份，具有祛热解毒，消炎止痛之功效，对细菌性与病毒性上呼吸道感染及痢疾有特殊疗效，被誉为天然抗生素药物。现代研究表明,穿心莲内酯具有消炎抗菌、抗病毒感染、抗心血管疾病、抗肿瘤、免疫刺激、保肝利胆及抗生育等多种功能。近年来，大量研究表明穿心莲内酯在体内、体外均有抑制多种肿瘤增殖和诱导分化的作用(Cell Cycle.2016；15(6):819-26.；J Control Release.2016.pii:S0168-3659(16)31082-3.；Biochem Pharmacol.2016；121:8-17.；Biochem Pharmacol.2014；91(1):40-50.Oncotarget.2017.doi:10.18632/oncotarget.15393.)。
ADE及其与ADH组合协同对淋巴瘤的作用尚未见报道。这些为复合ADH和ADE给药治疗恶性肿瘤淋巴瘤提供了全新的机会。
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腺花素和穿心莲内酯复方药物组合物；该复方药物组合物的活性成分是由腺花素和穿心莲内酯组成。
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：
一种腺花素和穿心莲内酯复方药物组合物，该复方药物组合物的活性成分是由腺花素和穿心莲内酯组成。
优选的，所述腺花素和穿心莲内酯的摩尔比为1:1～1:20。
更加优选的，所述腺花素和穿心莲内酯的摩尔比为1:1～1:10。
更加优选的，所述腺花素和穿心莲内酯的摩尔比为1:5或1:10。
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。
上述的腺花素和穿心莲内酯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：
本发明人在对腺花素(ADE)和穿心莲内酯(ADH)配伍药理活性的研究中发现，将ADE和ADH组合给药，特别是当两者摩尔比为1:1-1:10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ADH和ADE组合物可在低剂量配伍时产生ADH或ADE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ADH和ADE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细胞筛选优化腺花素(ADE)和穿心莲内酯(ADH)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ADH和ADE单药组、ADH和ADE联合用药不同摩尔比例组，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ADH和ADE单独和联合给药作用细胞72小时后不同浓度的IC50抑制率。
ADE和ADH按摩尔比1:1和1:20配伍组合时的抑制情况见表1，当摩尔比为1:5，1:10和1：20时，ADE配伍的浓度相应调整增加。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 ADH和ADE单药作用72小时IC50(μM)
实施例2：ADE和ADH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ADH与ADE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，ADE和ADH配伍具有协同效应；尤其是当两者摩尔比为1-1:10配伍时具有良好的协同效应，当两者摩尔比为1:5或1:10时协同效应最强。
表2 ADH和ADE不同配伍组合作用72小时的联合指数CI比较
实施例3：ADE和ADH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ADH和ADE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(ADE 10μM，ADH 50μM，ADE/ADH＝1/5(10μM/50μM))，加药及对照进行流式检测细胞凋亡率。D1-D6为志愿者1-6号的血液样本。
实施例4：腺花素(ADE)和穿心莲内酯(ADH)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ADE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。将穿心莲内酯与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 (5)
1.一种腺花素和穿心莲内酯复方药物组合物，其特征在于：该复方药物组合物的活性成分是由腺花素和穿心莲内酯组成；所述腺花素和穿心莲内酯的摩尔比为1:1~1:20。
2.根据权利要求1所述的一种腺花素和穿心莲内酯复方药物组合物，其特征在于：所述腺花素和穿心莲内酯的摩尔比为1:1~1:10。
3.根据权利要求1所述的一种腺花素和穿心莲内酯复方药物组合物，其特征在于：所述腺花素和穿心莲内酯的摩尔比为1:5或1:10。
4.根据权利要求1所述的一种腺花素和穿心莲内酯复方药物组合物，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。
5.根据权利要求1~4任一项所述的腺花素和穿心莲内酯复方药物组合物在制备抗淋巴瘤药物中的用途。
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