CN112043717B - 一种治疗肺癌的药物组合物及其制剂 - Google Patents
一种治疗肺癌的药物组合物及其制剂 Download PDFInfo
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- CN112043717B CN112043717B CN202010408016.1A CN202010408016A CN112043717B CN 112043717 B CN112043717 B CN 112043717B CN 202010408016 A CN202010408016 A CN 202010408016A CN 112043717 B CN112043717 B CN 112043717B
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Abstract
本发明提供了一种用于治疗肺癌的药物组合物及其制剂,属于药物领域。所述药物组合物包含表皮生长因子受体酪氨酸激酶抑制剂(EGFR‑TKI)和天麻素。还提供了所述药物组合物的相关制剂及其用途。所述药物组合物显著抑制肺癌裸鼠移植瘤生长并显著改善裸鼠的生存期,效果显著优于同等剂量EGFR‑TKI和天麻素单独用药,这表明药物联用后,具有显著的协同增效作用,临床应用前景良好。
Description
技术领域
本发明涉及一种用于治疗肺癌的药物组合物及其制剂,属于药物领域。
背景技术
肺癌是常见的恶性肿瘤,其患病率和死亡率均居于全球恶性肿瘤之首,这种疾病严重威胁世界人民的健康。根据世界卫生组织(WHO)提出的肺部肿瘤组织学分类法,可以将肺癌分为两大类:小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)。NSCLC在组织学上又进一步分为腺癌、鳞状细胞癌和大细胞癌三种类型,其中NSCLC占肺癌总数的80-90%。肺癌的预后较差,多数肺癌患者确诊时就已经属于晚期,NSCLC的5年生存率通常低于15%。
在过去很长一段时间里,晚期肺癌患者可以选择的化疗药物种类有限,仅为含铂类药物和紫杉醇等,这虽然在一定程度上能够延长患者的总生存期(8-10个月),但是效果不尽如人意。随着分子遗传学技术的发展,近年来表皮生长因子受体(EGFR)靶点成为小分子激酶抑制剂领域的研究热点。针对这一靶点,已经开发出很多高效、低毒的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),例如吉非替尼、厄洛替尼、奥希替尼等,在肺癌治疗上取得了显著的疗效,目前已将其作为EGFR突变型肺癌(特别是NSCLC)患者的一线推荐治疗药物。但是,不幸的是,绝大部分肺癌患者在使用EGFR-TKI一线治疗9-13个月后就会出现耐药,使得药物的疗效下降,这成为阻碍此类药物发展的巨大障碍。
大量的临床用药经验和实验室研究表明,联合用药可以在某种程度上解决抗肿瘤药物耐药的问题,并且联合用药与单药治疗相比具有很多优点,如克服肿瘤耐药、产生协同增效作用和降低毒副作用等。但是,如何从浩如烟海的药物中,选择出能够与EGFR-TKI产生协同增效作用并降低其耐药性的组合,则又成为了药物研发领域的科学家所面临的新挑战。有研究表明,天然产物在调节肿瘤微环境、抑制肿瘤转移、改善肿瘤耐药方面有独特的优势。因此,寻找对EGFR-TKI获得性耐药有效并能够增强其疗效的天然产物,对改善肺癌患者的治疗结局和生存期具有十分重要的临床意义。
天麻是兰科植物天麻Gastrodia elata Bl.的干燥块根,其性辛、温,临床上主要用于治疗头晕目眩,肢体麻木,癫痫抽搐等。近年来天麻在抗肿瘤、调节免疫等方面的作用倍受关注。天麻的化学成分主要有天麻素、天麻醚苷以及天麻多糖等。研究发现,天麻素具有刺激癌症免疫反应的作用。此前,有研究表明天麻素在体外可抑制小鼠胃癌和乳腺癌细胞的增殖(例如参见,季蒙蒙等,“天麻素对胃癌细胞活力和凋亡的影响”,现代生物医学进展,第15卷,第13期,2015年5月,第2421-2424页;李余星等,“天麻素对长春新碱抗肿瘤作用的影响”,时珍国医国药,第27卷,第12期,2006年,第2866-2869页)。但是尚无天麻素单独使用或其与EGFR-TKI联用在治疗肺癌方面的研究。
发明内容
本发明的目的是为长期使用EGFR-TKI靶向药治疗肺癌的患者提供一种具有协同增效作用的治疗肺癌的药物组合物,为临床上能够安全、有效、方便、经济地治疗肺癌,并尽可能延缓对EGFR-TKI耐药提供一种新思路。
实现本发明目的的技术方案如下:
本发明的第一个方面提供了一种治疗肺癌的药物组合物,所述药物组合物包含表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)和天麻素,所述EGFR-TKI和天麻素的重量比为1:0.1-1。
在一个实施方式中,所述EGFR-TKI选自吉非替尼、厄洛替尼、埃克替尼、阿法替尼、奥希替尼中的一种或多种。
在另一个实施方式中,EGFR-TKI和天麻素的重量比为1:0.2-0.7。
在又一个实施方式中,所述EGFR-TKI选自奥希替尼,且EGFR-TKI和天麻素的重量比为1:0.5。
本发明的第二个方面提供了一种用于治疗肺癌的药物制剂,所述药物制剂由上述药物组合物和药学上可接受的载体制成。
在一个实施方式中,所述药物制剂为口服制剂。
在另一个实施方式中,所述口服制剂为片剂、胶囊剂、粉剂、颗粒剂或缓释控释制剂。
所述药学上可接受的载体选自稀释剂、润滑剂、粘合剂、崩解剂、稳定剂或溶剂中的一种或多种。
本发明所述稀释剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等;所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆等;所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等;所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等;所述稳定剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等;所述溶剂包括但不限于水、平衡的盐溶液等。
本发明的第三个方面提供了一种上文所述的药物组合物或药物制剂在制备治疗肺癌的药物中的用途。
在一个实施方式中,所述肺癌是小细胞肺癌或非小细胞肺癌。
在另一个实施方式中,所述非小细胞肺癌是腺癌、鳞状细胞癌或大细胞癌。
此外,还可以将上文所述的药物组合物或药物制剂与临床上常用于治疗肺癌的化疗药物联用。
所述化疗药物包括但不限于顺铂、紫杉醇、吉西他滨、长春新碱或培美曲塞中的一种或多种。
并且,在上文所述的医药用途中,对于本发明组合物的给药时间、给药次数和给药频率等等,需要根据病情的具体诊断结果而定,这在本领域技术人员掌握的技术范围之内。例如,将对小鼠或大鼠的治疗方案应用于人体上,所有药物对人的有效剂量可以通过该药物对小鼠或大鼠的有效剂量进行换算,这对于本领域的普通技术人员而言也是容易实现的。
与现有技术相比,本发明具有以下有益效果:
(1)本发明结合我国在天然产物研究方面的优势,筛选出一种在治疗肺癌方面具有协同增效作用的药物组合物,通过将天麻素与EGFR-TKI联合使用,显著增强了EGFR-TKI治疗肺癌的作用,进而使得通过降低EGFR-TKI的用量,增加此类药物的安全性并延缓肿瘤耐药的产生成为可能。
(2)天麻在我国来源广泛,天麻素制备方法简单,且已经有成熟的工业化生产方法,成本较低。因此,通过在价格昂贵的EGFR-TKI中加入天麻素增强其疗效,能够极大地降低我国肺癌患者的用药成本,切实减轻了患者的经济负担。
具体实施方式
以下对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。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。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
实施例1:本发明药物组合物在体外对A549肺癌细胞系的抑制作用1.实验用药液的制备:
(1)奥希替尼组药液:取奥希替尼原料药(购自美国西格玛公司),加入DMSO配制成5mg/mL的母液储存备用,使用前用DMEM完全培养基稀释成50μg/mL备用;(2)天麻素组药液:取天麻素原料药(购自昆明制药基团股份有限公司),加入DMSO配制成1mg/mL的母液储存备用,使用前用DMEM完全培养基稀释成25μg/mL备用;(3)奥希替尼+天麻素组:使用上述奥希替尼和天麻素的母液,临用前用DMEM完全培养基制备含50μg/mL奥希替尼和25μg/mL天麻素的溶液备用。
2.实验方法:
取对数生长期的A549人肺癌细胞系(购自美国国家细胞库[ATCC]),以3x 104个细胞/孔接种于96孔培养板中,培养过夜,细胞生长状态良好后,弃去原有的培养基,然后分别加入按照上述方法制备的含药培养基(200μL/孔,每个样品设置5个复孔),在37℃、5%CO2条件下培养3天后,加入0.5mg/mL的MTT溶液,处理4小时后,弃去上清,每孔加入150μL DMSO振荡混匀,置于酶标仪上测量吸光度值,测定波长为570nm。整个实验独立重复3次。
3.检测指标和统计学方法
细胞抑制率=(1-给药组平均吸光度A值)/对照组平均吸光度A值x 100%。结果采用SPSS 13.0统计软件进行分析,数据以平均值±标准差表示。多组间比较采用单因素方差分析,两组间比较采用t检验,P<0.05表示差异有统计学意义。
4.实验结果
如下表1所示,与对照组相比,奥希替尼在体外对A549细胞的活力具有显著的抑制作用(p<0.05),而天麻素对A549的细胞活力似乎没有明显的影响,其对细胞活性的抑制率仅为3.45%±0.21%。相比之下,将奥希替尼与天麻素联合使用后产生了明显的协同增效作用,其对于A549细胞活力的抑制作用已经显著高于奥希替尼单用组(p<0.001)。
表1:本发明药物组合物对A549肺癌细胞活性的影响
注:*p<0.05,**p<0.01,与对照组比较;##p<0.001,与奥希替尼组比较。
实施例2:本发明药物组合物对NSCLC小鼠移植瘤模型的影响
1.实验目的
考察本发明药物组合物对NSCLC小鼠移植瘤模型的影响
2.实验材料
2.1动物:SPF级BALB/c雌性裸小鼠,6-8周龄,体重18-22g,购自山东大学实验动物中心,许可证号:SCXK(鲁)20130009。
2.2仪器:分析天平、电子天平、1mL注射器、灌胃针头、动物笼具、苦味酸等。
2.3主要药品和试剂:人肺癌细胞系A549,购自美国国家细胞库(ATCC);奥希替尼,250mg/片,购自阿斯利康制药有限公司;天麻素(纯度99.5%),购自昆明制药基团股份有限公司。
3.实验方法
3.1移植瘤模型的建立和给药
将BALB/c雌性裸小鼠于室温下饲养,待其适应环境后,向其接种A549细胞,每只裸小鼠注射3-4x 106个细胞。接种一周后,观察裸鼠左侧腋窝皮下,发现裸鼠接种部位有米粒大小的结节生成。继续饲养,待肿瘤直径5mm左右时,剔除肿瘤尺寸和体重差异较大的裸鼠,并将剩余的裸鼠随机分组。
本实验分为以下几组,每组10只荷瘤小鼠:(1)模型组;(2)奥希替尼(20mg/kg)组;(3)天麻素(10mg/kg)组;(4)奥希替尼(20mg/kg)+天麻素(10mg/kg)组;(5)奥希替尼(20mg/kg)+天麻素(30mg/kg)组。
模型组荷瘤小鼠灌胃给予0.9%生理盐水,其余各组按照荷瘤小鼠的体重灌胃给药,每天给药一次,连续给药4周。4周后,每组处死一半小鼠,剥离瘤块。其余小鼠按照之前的给药方案继续给药,计算各组生存期。
3.2评价指标
3.2.1肿瘤重量和抑瘤率:
给药4周后,每组处死一半小鼠,剥离瘤块后,称重。
抑瘤率(%)=(模型组平均肿瘤重量-给药组平均肿瘤重量)/模型组平均肿瘤重量x 100%
3.2.2生存期:在评价生存期时,出于动物福利方面的考虑,将处于濒死状态的荷瘤动物安乐死。
3.3统计学方法
结果采用SPSS 13.0统计软件进行分析,数据以平均值±标准差表示。多组间比较采用单因素方差分析,两组间比较采用t检验,P<0.05表示差异有统计学意义。
4.实验结果
4.1本发明药物组合物对荷瘤小鼠肿瘤的抑制作用
在实验中,裸小鼠接种A549细胞后,经2-3天潜伏期后,肿瘤迅速生长。如下表2所示,结果表明,奥希替尼(20mg/kg)单独使用可有效抑制肿瘤生长(p<0.05)。天麻素单独给药4周后,几乎未显示出对肿瘤的抑制作用。奥西替尼(20mg/kg)+天麻素(30mg/kg)组在给药4周后,对肿瘤重量的影响和抑瘤作用与奥希替尼(20mg/kg)单独给药时几乎相同,可见将奥希替尼与较高剂量的天麻素以上述方式联用,并不会对其抗肿瘤作用产生实质性的影响。但是,令人吃惊的是,奥希替尼(20mg/kg)+天麻素(10mg/kg)组在给药4周后,极其显著地降低了裸小鼠的肿瘤重量(p<0.01),其抑瘤率达到了45.7%。上述结果表明,将奥希替尼与天麻素按照一定比例联用时,其抑瘤作用显著优于奥希替尼和天麻素单独使用的效果,说明两者联合用药发挥了协同抗肿瘤作用。
表2:给药后4周本发明药物组合物对荷瘤小鼠肿瘤的抑制作用
注:*p<0.05,**p<0.01,与模型组比较。
4.2本发明药物组合物对荷瘤小鼠生存期的影响
如下表3所示,结果表明,奥希替尼(20mg/kg)单独使用可有效延长荷瘤小鼠的生存期(p<0.05)。天麻素单独使用与模型组相比对荷瘤小鼠的生存期无改善作用。奥西替尼(20mg/kg)+天麻素(30mg/kg)在给药后,对荷瘤小鼠生存期的改善作用与奥希替尼(20mg/kg)单独给药时几乎相同,可见将奥希替尼与较高剂量的天麻素以上述方式联用,并不会对荷瘤小鼠的生存期产生实质性的改善作用。但是,令人吃惊的是,奥希替尼(20mg/kg)+天麻素(10mg/kg)组在给药后,极其显著地延长了荷瘤小鼠的生存期(p<0.01)。上述结果表明,将奥希替尼与天麻素按照一定比例联用时,其对荷瘤小鼠生存期的改善作用显著优于奥希替尼和天麻素单独使用的效果,说明两者联合用药发挥了协同抗肿瘤作用。
本发明药物组合物对A549移植瘤裸小鼠的肿瘤抑制作用与其对实验动物生存期的影响显示出较为一致的趋势。
表3:本发明药物组合物对荷瘤小鼠生存期的影响
注:*p<0.05,**p<0.01,与模型组比较。
5.实验结论
上述实验结果表明,将奥希替尼与天麻素按照一定比例联用时,其对A549荷瘤小鼠的肿瘤抑制作用和生存期改善作用均显著优于奥希替尼和天麻素单独使用的效果,说明本发明的药物组合物产生了协同增效的治疗肺癌的作用。
此外,在上述动物实验中,未观察到本发明药物组合物存在明显的不良反应,实验动物对其具有良好的耐受性。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (5)
1.一种治疗肺癌的药物组合物,其特征在于,所述药物组合物包含表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)和天麻素,其中所述EGFR-TKI选自奥希替尼,且EGFR-TKI和天麻素的重量比为1:0.5。
2.一种用于治疗肺癌的药物制剂,其特征在于,所述药物制剂由权利要求1中所述的药物组合物和药学上可接受的载体制成,所述药物制剂为口服制剂。
3.权利要求1所述的药物组合物或权利要求2所述的药物制剂在制备治疗肺癌的药物中的用途。
4.如权利要求3所述的用途,其特征在于,所述肺癌为小细胞肺癌或非小细胞肺癌。
5.如权利要求4所述的用途,其特征在于,所述非小细胞肺癌为腺癌、鳞状细胞癌或大细胞癌。
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