CN115364109B - 一种用于肺癌治疗的药物制剂 - Google Patents
一种用于肺癌治疗的药物制剂 Download PDFInfo
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- CN115364109B CN115364109B CN202211150046.2A CN202211150046A CN115364109B CN 115364109 B CN115364109 B CN 115364109B CN 202211150046 A CN202211150046 A CN 202211150046A CN 115364109 B CN115364109 B CN 115364109B
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- lung cancer
- triptolide
- oridonin
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Abstract
本发明提供了一种用于肺癌治疗的药物制剂。所述药物制剂包括特定比例的雷公藤甲素和冬凌草甲素，二者协同增效大大提高了抑制肺癌细胞增殖的能力，具有更佳的药物有效性和安全性，为肺癌特别是非小细胞肺癌的治疗提供新的思路。
Description
技术领域
本发明涉及抗癌药物领域，具体而言，本发明涉及一种用于肺癌治疗的药物制剂。
背景技术
原发性肺癌是我国最常见的恶性肿瘤，也是我国30年来发生率增长最快的恶性肿瘤，在癌症死因中，肺癌从早期的排在胃癌、食管癌、肝癌和宫颈癌之后的第5位，发展到现在的居于癌症死亡原因首位。肺癌的主要危险因素包括：吸烟和被动吸烟、慢性阻塞性肺疾病史、职业暴露、肺癌家族史和遗传易感性等。
从病理和治疗角度，肺癌大致可以分为非小细胞肺癌(non-small cell lungcancer，NSCLC)和小细胞肺癌(small cell lung cancer，SCLC)两大类，其中非小细胞肺癌约占80％～85％，包括腺癌、鳞癌等组织学亚型，其余为小细胞肺癌。肺癌治疗目前主要有化疗、放疗、手术治疗等，其中化疗是治疗非小细胞癌的主要手段，化疗治愈非小细胞肺癌的治缓解率为40％至50％。近年来，靶向治疗成为肺癌的常规临床治疗手段。但是，化疗由于药物毒性，一般伴随着较为严重的副作用，即便是靶向治疗，在临床上也表现出不容忽视的毒副作用，比如：恶心呕吐、腹泻、皮疹、脱发、乏力等。
中药在我国一直有着举足轻重的地位，中药所含化学成分很复杂，通常有糖类、氨基酸、蛋白质、油脂、蜡、酶、色素、维生素、有机酸、鞣质、无机盐、挥发油、生物碱、甙类等。每一种中药都可能含有多种成分，在这些成分中，有一部分具有明显生物活性并起医疗作用的，常称为有效成分。近年来，相关专家学者不断从中药中分离提取出了一系列有效成分，其中很多已证实具有抗肿瘤作用。另外，用中药活性成分增效一线抗癌药物已被证实较为有效。但中药活性成分之间相互增效的研究较少，特别是协同用于治疗肺癌的中药活性成分药物制剂的研究仍然较为落后。因此，有必要开发更多地能够有效防治肺癌的药物制剂，以期提高肺癌的治疗效果。
发明内容
为了克服现有治疗肺癌的药物所存在的问题和不足，本发明提供了一种用于肺癌治疗的药物制剂，其药物活性成分之间存在协同增效作用，对肺癌具有改善的疗效。
为此，本发明提供了一种药物制剂，其包含雷公藤甲素以及和冬凌草甲素，其中雷公藤甲素与冬凌草甲素的摩尔比为1：0.5～5。
雷公藤甲素(Triptolide，TP)是从雷公藤(Tripterygium wilfordii Hook f.)中分离出的活性最高的化学成分之一，具有二萜结构。雷公藤别名黄藤，具有祛除风湿、通络消肿、解毒止痛的功效，用于湿热结节、癌瘤积毒。雷公藤甲素具有抗炎、免疫调节、抗生育等多种药理活性，现代临床广泛应用于类风湿关节炎、各种原发性及继发性肾病、结缔组织病等，近期研究表明其可以在鼻咽癌、乳腺癌、肝癌、胃癌、肺癌、胰腺癌、结肠癌、宫颈癌、卵巢癌等多种恶性肿瘤及其肿瘤细胞株中发挥抗肿瘤作用。
冬凌草甲素(Oridonin)系从唇形科(Labtea)香茶菜属(Rabdosia)植物例如冬凌草中分离出来的一种有生物活性的天然物质，化学结构为对映贝壳杉烯二萜类有机化合物。冬凌草甲素具有较强的抗炎、抗菌和抗肿瘤活性，通过诱导肿瘤细胞凋亡、阻滞肿瘤细胞增殖周期及降低端粒酶活性等发挥抗肿瘤作用。文献报道对体外培养的Hela细胞、人体食管癌109细胞及肝癌BEL-7402细胞、人肝癌细胞A549等有明显的抑制作用，对多种移植性动物肿瘤如ECA、S180、P388肝癌及AKS等有明显的抑制作用，并且对食管上皮增生有轻度抑制作用，临床上主要用于肝癌、食管癌、胰腺癌等的治疗。冬凌草甲素的结构中与环外亚甲基共轭的环戊酮结构为抗癌活性中心。
本发明发现，雷公藤甲素和冬凌草甲素联用时，与单独使用相比，能够大大提高抑制肺癌细胞的增殖的能力，产生了协同作用。
本发明中，所述药物制剂用于治疗肺癌，尤其是非小细胞肺癌。
本发明中，优选的，所述雷公藤甲素与冬凌草甲素摩尔比为1:0.8～3，进一步优选为1：1～2。尤其优选的，其可以为1：1或者1：2。
本发明所述药物制剂除了包含雷公藤甲素以及冬凌草甲素外，还可以包含其他抗癌活性成分，包括但不限于：顺铂、卡铂、奈达铂、长春瑞滨、吉西他滨、多西他赛、培美曲赛、紫杉醇、依托泊甙、吉非替尼、厄洛替尼。
本发明所述药物制剂除了药物活性成分外，还可以包含药学上可接受的辅料。所述药物制剂中，药物活性成分的含量可控制在0.1～20wt％，其余为药物辅料。所述药物辅料可包括药学上适用的赋形剂，例如填充剂、粘合剂、崩解剂、表面活性剂、润滑剂和助流剂之几种的混合物。所述填充剂例如为淀粉、可压性淀粉、糊精、蔗糖、乳糖、果糖、葡萄糖、木糖醇、甘露醇、微晶纤维素、碳酸钙、碳酸镁、磷酸钙、磷酸氢钙、硫酸钙、氧化镁、氢氧化铝、羧甲基纤维素钙、羧甲基纤维素钠。优选糖醇类、可压性淀粉、磷酸钙、磷酸氢钙、硫酸钙、微晶纤维素。所述粘合剂例如为水、乙醇、羟丙甲纤维素。所述崩解剂例如为交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素。所述表面活性剂例如为吐温-80、泊洛沙姆。所述润滑剂选自例如为硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸锌、滑石粉、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、十二烷基硫酸镁、聚乙二醇、硬脂基富马酸钠。所述助流剂例如为胶体二氧化硅、粉状纤维素、三硅酸镁、滑石粉。
本发明药物制剂与药学上可接受的辅料可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明药物制剂可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
本发明药物制剂的典型给药途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、鼻内、眼内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
本发明药物制剂中的各活性成分可以在同一药物制剂中同时给药，或者以分开的不同制剂的形式联合给药。
因此，本发明还提供一种试剂盒，其由含有雷公藤甲素的治疗剂，以及含有冬凌草甲素的治疗剂配套成，所述含有雷公藤甲素的治疗剂中的雷公藤甲素与所述含有冬凌草甲素的治疗剂中的冬凌草甲素的摩尔比为1：0.5～5。
在一个优选的方案中，所述含有雷公藤甲素的治疗剂中的雷公藤甲素与所述含有冬凌草甲素的治疗剂中的冬凌草甲素为1:0.8～3，进一步优选为1：1～2。尤其优选的，其可以为1：1或者1：2。
在一个优选的方案中，所述试剂盒还可以包括包含其他抗癌活性成分的治疗剂，具体如本文前文所述。
本发明的试剂盒中各治疗剂除了所述药物活性成份外，还可包含如本发明前文所述的药学上可接受的辅料。
本发明还提供本发明的药物制剂在制备药物中的应用，所述药物用于治疗肺癌。
本发明还提供一种治疗肺癌的方法，所述方法包括向有需要的个体提供本发明所述的药物制剂。
本发明中，所述肺癌优选为非小细胞肺癌。
有益效果
本发明提供了一种用于肺癌治疗的药物制剂。其具有以下有益效果：雷公藤甲素和冬凌草甲素均为中药提取物，来源丰富、易得，已经有成熟的工业化生产方法。二者联合使用产生协同效果，抑制肺癌细胞增殖的能力大大提高，因此能够降低单药用量，进而提高药物的有效性和安全性，为肺癌特别是非小细胞肺癌的治疗提供新的思路。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
下面实施例中的实验方法，如无特殊说明，均为常规方法。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。
实施例1：抗肺癌活性测试
本发明药物的抗肺癌活性按照MTT法进行，测定对于人肺癌细胞A-549的抑制活性，具体过程如下：
试剂：试剂胎牛血清(FBS)和RPMI 1640培养基为GIBCO公司产品，MTT为Sigma公司产品；人肺癌细胞A549来源于中科院上海细胞生物研究所细胞库。
取A549细胞，将其接种于含10％胎牛血清、100kU/L青霉素、100mg/L链霉素的RPMI1640培养基中，每隔2天更换一次培养基以培养细胞，待细胞长满培养皿底壁后倾去培养基，用无菌37℃的pH约7.2的磷酸缓冲液冲洗，再添加0.25％胰蛋白酶，37℃酶解使细胞脱壁，取1/3的细胞用于传代，实验前共传代4次。
将酶解后单个悬浮的细胞用相应的完全培养基调细胞浓度为1×104个/ml，再接种于96孔板中。每孔接种50μl(5×103/孔)，每块板上留3孔加入50μL不含细胞的培养基作为空白对照。接种后，将该96孔板置于37℃、5％CO2培养箱中培养24小时，然后加入溶解于不同浓度的测试药物DMSO溶液，每孔50μL。继续在相同条件下培养48h。每个浓度设3个平行样。另设相同量的DMSO作为无药对照。
在实验终止前4小时，加入每孔10μL MTT的PBS溶液(5mg/ml)，并继续在37℃、5％CO2的条件下孵育至实验结束。然后每孔加入100μL DMSO以终止反应，然后在酶标仪(Bio-RAD 680)上以655nm作为参考波长，在595nm下读出OD值。
细胞抑制率计算方法：
细胞抑制率(％)＝(1-加药OD值/正常OD值)×100％
协同作用计算方法(金正均q值法)：
q＝PAB/(PA+PB-PAPB)
式中PA、PB和PAB分别为A药组、B药组和两药联用组治疗率，本文中即对于肺癌细胞的抑制率。q<1说明两药合用后产生拮抗作用；q>1说明两药合用后产生协同作用，q＝1说明两药合用后产生相加作用。
结果如下表1-3所示：
表1雷公藤甲素对A549的抑制活性
| 浓度(nmol/L) | 50 | 100 | 200 | 300 |
| 细胞抑制率(％) | 17.9 | 34.7 | 62.4 | 84.5 |
表2冬凌草甲素对A549的抑制活性
| 浓度(nmol/L) | 50 | 100 | 200 | 400 | 800 | 1600 |
| 细胞抑制率(％) | 0.5 | 0.7 | 2.6 | 5.3 | 8.4 | 12.6 |
表3药物制剂对A549的抑制活性
上述结果表明，雷公藤甲素与冬凌草甲素存在协同作用，二者联合使用时抑制肺癌细胞增殖的能力大大增加；其中，当雷公藤甲素的浓度为50nmol、冬凌草甲素的浓度为100nmol时，协同作用最强。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (7)
1.一种用于治疗肺癌的药物制剂，其活性成分为雷公藤甲素和冬凌草甲素，其中雷公藤甲素与冬凌草甲素的摩尔比为1：1～2。
2.根据权利要求1所述的药物制剂，其特征在于，所述肺癌为非小细胞肺癌。
3.根据权利要求1或2所述的药物制剂，其特征在于，所述雷公藤甲素与冬凌草甲素摩尔比为1：1或者1：2。
4.根据权利要求1所述的药物制剂，其特征在于，所述药物制剂还包含药学上可接受的辅料。
5.一种用于治疗肺癌的试剂盒，其由活性成分为雷公藤甲素的治疗剂，以及活性成分为冬凌草甲素的治疗剂配套成，所述活性成分为雷公藤甲素的治疗剂中的雷公藤甲素与所述活性成分为冬凌草甲素的治疗剂中的冬凌草甲素的摩尔比为1：1～2。
6.根据权利要求1-4任一项所述的药物制剂在制备药物中的应用，所述药物用于治疗肺癌。
7.根据权利要求6所述的应用，其特征在于，所述肺癌为非小细胞肺癌。
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