CN116808041B - 一种治疗胃癌的药物组合物及其用途 - Google Patents
一种治疗胃癌的药物组合物及其用途 Download PDFInfo
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- CN116808041B CN116808041B CN202310214206.3A CN202310214206A CN116808041B CN 116808041 B CN116808041 B CN 116808041B CN 202310214206 A CN202310214206 A CN 202310214206A CN 116808041 B CN116808041 B CN 116808041B
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- Prior art keywords
- irinotecan
- ligustrazine
- pharmaceutically acceptable
- acceptable salt
- gastric cancer
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- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明涉及一种治疗胃癌的药物组合物及其用途。所述药物组合物包含伊立替康或其药学上可接受的盐和川芎嗪或其药学上可接受的盐。本发明的药物组合物在抑制胃癌细胞增殖、减小肿瘤体积上存在协同增效的作用，并且可以防止胃癌凝血。因此，与单药相比，更加适合在产业上应用。
Description
技术领域
本发明涉及抗肿瘤药物领域，具体来说，本发明涉及一种治疗胃癌的药物组合物及其用途。
背景技术
胃癌是消化系统最常见的恶性肿瘤之一。对于早期胃癌患者，可进行根治性切除术，5年生存率较高；但由于胃癌早期症状不明显和胃镜常规检查普及不足等原因，胃癌患者就诊时很多已到晚期，且大多伴有广泛的侵犯和远处转移，失去了根治性手术的机会，此时单纯手术治疗的总生存率较低。
对于不可手术切除的晚期胃癌患者，通常采用姑息性化疗方法，大部分患者能够通过化疗缓解症状并获得生存益处；常用的胃癌化疗方案主要包括以下4类：(1)氟脲嘧啶及其衍生物：5-氟尿嘧啶(5-Fu)、卡培他滨和替吉奥等；(2)紫杉类：紫杉醇、多西紫杉醇等；(3)铂类：顺铂、奥沙利铂等；(4)拓扑异构酶抑制剂：伊立替康等。然而，单药的化疗存在药物用量高、效果差、副作用严重等问题，因此已针对性开发了大量联合给药方案，例如DCF(多西他赛+顺铂+5-Fu)、TCF(紫杉醇+顺铂+5-Fu)、FOLFIRI(5-Fu+亚叶酸钙+伊立替康)、FOLFOX(5-Fu+奥沙利铂+亚叶酸钙)、XP(卡培他滨+顺铂)、IP(顺铂+伊立替康)、SP(替吉奥+顺铂)、IE(伊立替康+依托泊苷)等，但这些方案并非都能实现协同效果。因此，寻找更多能够协同治疗胃癌的药物组合物仍是迫切需求。
发明内容
为了克服现有治疗胃癌存在的问题和不足，本发明提供了一种复配的治疗胃癌的药物组合物，其药物活性成分之间存在协同增效作用，对胃癌疗效明确，具有用量降低、效果提高的优点。
本发明的技术方案如下：
一种治疗胃癌的药物组合物，其包含伊立替康或其药学上可接受的盐和川芎嗪或其药学上可接受的盐。
伊立替康属于半合成水溶性喜树碱衍生物，伊立替康以及其代谢产物SN38均为DNA拓扑异构酶I抑制剂，其与TopoI及DNA形成的复合物能引起DNA单链断裂，阻止DNA复制及抑制RNA合成，为细胞周期S期特异性。研究表明伊立替康对体外多株肿瘤细胞系(包括鼠白血病、人胃癌、肺癌、乳腺癌等)及体内多种实验肿瘤模型(Co4结肠癌、S-15和Sc-16胃癌、Mx-1乳腺癌等)有广谱抗瘤活性，并且进一步研究表明伊立替康在体外与顺铂、阿糖胞苷、氟尿嘧啶及TopoI抑制剂合用有协同或相加作用。
川芎嗪是一种从川芎中分离得到的生物碱，具有抗肿瘤、抗纤维化、抗氧化、抗凝血、抑制血小板聚集等药理作用，其中，抗肿瘤作用倍受研究者关注。大量实验研究表明川芎嗪能够通过诱导肿瘤细胞凋亡和自噬、抑制细胞增殖和迁移、逆转癌细胞的多药耐药、抑制新生血管的形成来阻止癌细胞的生长和繁殖。同时，川芎嗪联合其他抗癌药物如紫杉醇、顺铂、姜黄素等可表现出协同抗癌的作用。此外，大量的临床资料表明肿瘤病人会表现出一定程度的血液高凝，且随着肿瘤恶化进程，血液高凝会加剧；川芎嗪具有抑制纤维蛋白的形成和稳定，改善肿瘤引起的血液高凝如胃癌凝血的作用。
本发明发现，伊立替康与川芎嗪按一定比例制成复方制剂联用，在治疗胃癌时，能够显著抑制胃癌细胞增殖、缩小肿瘤体积，并且产生了协同增效作用。
因此，在一个实施方案中，伊立替康或其药学上可接受的盐与川芎嗪或其药学上可接受的盐的质量比，以伊立替康和川芎嗪计，为1～5:2～10。优选的，其可以为2～3：5～8。尤其优选的，其可以为2：5-8或者3：5-8。具体地，其可以为2:5、2:8、3:5、3:8。
本发明中，伊立替康的药学上可接受的盐，以及川芎嗪的其药学上可接受的盐，是指游离伊立替康或川芎嗪与常规酸形成的酸加成盐，所述酸包括例如：无机酸，例如：盐酸、氢溴酸、硫酸、硝酸、磷酸；有机酸，例如：甲酸、乙酸、己酸、辛酸、癸酸、酒石酸、乳酸、琥珀酸、顺丁烯二酸、反丁烯二酸、硬脂酸、苯磺酸、对甲苯磺酸、萘-2-磺酸、苯甲酸、乙烷磺酸、4-乙酰氨基苯甲酸、肉桂酸、氨基酸、褐藻酸、抗坏血酸、柠檬酸、半乳糖二酸、龙胆酸、乙醇酸、乳糖酸、萘-1,5-二磺酸、烟酸、油酸、草酸、癸二酸、棕榈酸、双羟萘酸、水杨酸等，但不限于此。优选的，伊立替康的药学上可接受的盐，包括盐酸伊立替康；川芎嗪的其药学上可接受的盐，包括盐酸川芎嗪。
本发明的药物组合物中，除了作为药物活性成分的伊立替康与川芎嗪之外，还可包含药物辅料。在制备所述药物组合物时，作为药物活性成分的伊立替康与川芎嗪之间除满足上述的复配比例关系外，在药物组合物中的含量可分别控制在0.1-10wt％。即每100重量份的药物组合物中，可包含伊立替康或其药学上可接受的盐0.1-10份，川芎嗪或其药学上可接受的盐0.1-10份，其余为药物辅料。各药物组分的含量优选可为0.2-5份/100重量份，尤其可为0.2-3份/100重量份。
本发明中，所述药物辅料包括药学上可接受的载体、赋形剂、稀释剂等，即对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体、赋形剂、稀释剂等，其包括但不限于可用于人或家畜动物的任何载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。具体地，其包括：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、羟丙基甲基纤维素、聚乙烯吡咯烷酮、山梨醇、明胶胶浆、阿拉伯胶浆、黄蓍胶浆、微晶纤维素、甲基纤维素、乙基纤维素、羟丙基纤维素、羟乙基纤维素、聚甲基丙烯酸酯、海藻酸、海藻酸钠、聚乙二醇、胶体硅酸镁铝、泊洛沙姆、十二烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠、脂肪酸山梨坦、聚山梨酯类、聚氧乙烯蓖麻油类、辛酸癸酸聚乙二醇甘油酯、月桂酸聚乙二醇甘油酯、硬脂酸聚乙二醇甘油酯、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、硬脂基富马酸钠等等。
本发明药物组合物的给药可通过提供类似用途的药剂的任何可接受给药模式来进行。本发明的药物组合物可通过将伊立替康或其药学上可接受的盐和川芎嗪或其药学上可接受的盐与适宜的药物辅料组合而制备，且可配制成固态、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。
给予本发明药物组合物的典型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。
本发明的药物组合物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。
本发明的药物组合物中，除了伊立替康与川芎嗪之间，还可包含对于癌症的治疗有帮助的其他化合物。优选的，所述其他化合物对于胃癌的治疗有帮助，其可选自：(1)氟脲嘧啶及其衍生物；(2)紫杉类化合物；(3)铂类化合物；(4)其他拓扑异构酶抑制剂。
本发明还提供一种试剂盒，其由含有伊立替康或其药学上可接受的盐的治疗剂，以及含有川芎嗪或其药学上可接受的盐的治疗剂配套成。
所述试剂盒中，所述含有伊立替康或其药学上可接受的盐的治疗剂，以及含有川芎嗪或其药学上可接受的盐的治疗剂，满足本发明前文所述定义。
其中，伊立替康或其药学上可接受的盐与川芎嗪或其药学上可接受的盐的质量比，以伊立替康和川芎嗪计，为1～5:2～10。优选的，其可以为2～3：5～8。尤其优选的，其可以为2：5-8或者3：5-8。具体地，其可以为2:5、2:8、3:5、3:8。
所述试剂盒中还可包含对于癌症的治疗有帮助的其他治疗剂。优选的，所述其他治疗剂对于胃癌的治疗有帮助，其包含选自以下的化合物：(1)氟脲嘧啶及其衍生物；(2)紫杉类化合物；(3)铂类化合物；(4)其他拓扑异构酶抑制剂。
本发明的试剂盒中所述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物辅料。
所述含有伊立替康或其药学上可接受的盐的治疗剂，以及含有川芎嗪或其药学上可接受的盐的治疗剂中，伊立替康或其药学上可接受的盐的含量为0.1-10wt％，即每100重量份含有伊立替康或其药学上可接受的盐的治疗剂可包含伊立替康或其药学上可接受的盐0.1-10份，每100重量份含有川芎嗪或其药学上可接受的盐的治疗剂可包含川芎嗪或其药学上可接受的盐0.1-10份。
本发明还提供本发明的药物组合物在制备药物中的应用，所述药物用于治疗胃癌。
本发明还提供一种胃癌的治疗方法，所述方法包含向有需要的患者给予本发明所述的药物组合物。在所述治疗方法中，所述伊立替康或其药学上可接受的盐，以及和川芎嗪或其药学上可接受的盐，可以同时给药，也可以先后给药。
有益效果
本发明提供了一种治疗胃癌的药物组合物及其用途。试验结果表明，本发明的药物组合物在抑制胃癌细胞增殖、减小肿瘤体积上的效果优于伊立替康单药和川芎嗪单药，并且存在协同增效的作用。因此，本发明的治疗胃癌的药物组合物具有更好的治疗活性，可使用更少的活性药物并因此具备更低的毒副作用。此外，川芎嗪具有抗血凝、抑制血小板聚集等药理作用，因此本发明的药物组合物还能有效防止胃癌凝血。总之，本发明的治疗胃癌的药物组合物是一种效果更为突出的胃癌治疗药物，更适合在产业上应用。
附图说明
图1：裸鼠皮下荷瘤实验结果。
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：裸鼠皮下荷瘤实验
将人胃癌细胞系SGC-7901(来自中国科学院上海生命科学研究院细胞库)在37℃下、5％CO2培养箱内用RPMI1640培养基(含10％FBS)培养至铺满约80％后，利用胰蛋白酶-EDTA消化，用磷酸缓冲液重悬配制成5×107细胞/mL的悬浮液，置于冰上。在4-5周龄免疫缺陷的裸鼠腹背两侧的皮下部位各注射0.1mL细胞悬液。
移植后12日起，将小鼠随机分为9组，每组各5只。伊立替康组分别给予20mg/kg、30mg/kg的伊立替康，川芎嗪组分别给予50mg/kg、80mg/kg的盐酸伊立替康，药物组合物组分别给予20mg/kg的伊立替康+50mg/kg的川芎嗪，20mg/kg的伊立替康+80mg/kg的川芎嗪，30mg/kg的伊立替康+50mg/kg的川芎嗪，30mg/kg的伊立替康+80mg/kg的川芎嗪，悬浮于生理盐水后灌胃给药，每天一次，连续给药四周；对照组给予等量生理盐水。每两天利用数显卡尺测定了肿瘤长径及短径，按照下列公式计算肿瘤体积、比肿瘤体积。
肿瘤体积(TV)＝肿瘤长径(mm)×肿瘤短径2(mm2)/2
比肿瘤体积(RTV)＝测定日的肿瘤体积/给药首日的肿瘤体积
对测量结果进行统计，以χ±SD形式记录结果，如表1和图1所示：
表1：
| 药物 | n | 4周后RTV |
| 对照 | 5 | 11.02±3.12 |
| 伊立替康20mg/kg | 5 | 6.01±1.33 |
| 伊立替康30mg/kg | 5 | 4.77±1.04 |
| 川芎嗪50mg/kg | 5 | 10.22±2.89 |
| 川芎嗪80mg/kg | 5 | 9.62±2.58 |
| 伊立替康20mg/kg+川芎嗪50mg/kg | 5 | 2.41±0.71 |
| 伊立替康20mg/kg+川芎嗪80mg/kg | 5 | 2.11±0.60 |
| 伊立替康30mg/kg+川芎嗪50mg/kg | 5 | 1.88±0.54 |
| 伊立替康30mg/kg+川芎嗪80mg/kg | 5 | 1.63±0.50 |
从表1和图1可以看出，川芎嗪本身仅有较弱的抗胃癌细胞增殖活性，但其与伊立替康组合后，可显著增强伊立替康的抗胃癌细胞增殖活性；从肿瘤生长曲线以及最终的肿瘤大小来看，本发明的包含伊立替康和川芎嗪的药物组合物与伊立替康单药和川芎嗪单药相比，在减小肿瘤体积方面显著大于单药的加和效果，因此取得了协同增效的作用。
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 (6)
1.一种治疗胃癌的药物组合物，其包含伊立替康或其药学上可接受的盐和川芎嗪或其药学上可接受的盐，其中，伊立替康或其药学上可接受的盐与川芎嗪或其药学上可接受的盐的质量比，以伊立替康和川芎嗪计，为2～3：5～8，伊立替康药学上可接受的盐选自盐酸伊立替康；川芎嗪药学上可接受的盐选自盐酸川芎嗪。
2.根据权利要求1所述的药物组合物，其特征在于，伊立替康或其药学上可接受的盐与川芎嗪或其药学上可接受的盐的质量比，以伊立替康和川芎嗪计，为2：5-8或者3：5-8。
3.根据权利要求1所述的药物组合物，其特征在于，伊立替康或其药学上可接受的盐与川芎嗪或其药学上可接受的盐的质量比，以伊立替康和川芎嗪计，为2:5、2:8、3:5、3:8。
4.根据权利要求1-3任一项所述的药物组合物，其特征在于，所述药物组合物中，除了伊立替康与川芎嗪之外，还包含对于癌症的治疗有帮助的其他化合物。
5.一种试剂盒，其由含有伊立替康或其药学上可接受的盐的治疗剂，以及含有和川芎嗪或其药学上可接受的盐的治疗剂配套成，其中，伊立替康或其药学上可接受的盐与川芎嗪或其药学上可接受的盐的质量比，以伊立替康和川芎嗪计，为2～3：5～8，伊立替康药学上可接受的盐选自盐酸伊立替康；川芎嗪药学上可接受的盐选自盐酸川芎嗪。
6.根据权利要求1-3任一项所述的药物组合物在制备治疗胃癌的药物中的应用。
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| 《川芎嗪及联用化疗药物对胃癌细胞杀伤作用的研究》;张振玉;《中国现代医学杂志》;19990131;第9卷(第1期);68-69 * |
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