CN109562080B - 用于治疗癌症和癌症并发症的药物组合物 - Google Patents
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Abstract
本发明涉及一种药物组合物，其特征在于其包含β‑榄香烯、羽扇豆醇和药物活性剂的组合作为活性物质，该药物活性剂选自肉桂醛、2‑羟基肉桂醛、2′‑苯甲酰氧基肉桂醛、β‑谷甾醇、姜黄素、及其混合物。
Description
技术领域
本发明涉及可用作药物的药物组合物，特别是用于治疗癌症，特别是肝细胞癌。
背景技术
长期以来认为肝细胞癌(HCC)的有效姑息治疗是困难的，因为这种类型的肿瘤对常规细胞毒性化学疗法通常具有抗性。此外，由于全身副作用的高风险，通常不能向肝功能受损的肝硬化患者提供具有几种非选择性细胞毒性分子的侵袭性化学疗法。
对肿瘤发生中涉及的分子过程的改进知识已经指引鉴定用于治疗癌症的新靶标。因此，目前在治疗HCC和其他肿瘤中可使用新的所谓“靶向”疗法。它们主要干预信号的转导(要求细胞繁殖的信号)。所谓的酪氨酸激酶途径是迄今为止最为人所知的。该途径可被单克隆抗体(Mab)或酶抑制剂(inib)阻断。这些药物包括VEGF(血管内皮生长因子；VEGF由大多数肿瘤细胞分泌，部分由于缺乏局部氧合作用，促进血管生成)抑制剂、EGFR(表皮生长因子受体)抑制剂、一些具有酪氨酸激酶活性同时靶向血管生成和细胞增殖的受体抑制剂、激酶抑制剂、IGF-IR抑制剂、mTOR抑制剂和MEK-ERK信号通路抑制剂。
然而，在大多数情况下，这些靶向治疗在HCC，特别是晚期HCC的效率和存活方面产生相对适度的结果。更重要的是，针对HCC的靶向治疗的有效性仍然受到抗药性现象的限制。一些癌细胞具有或获得规避药物作用机制的能力，而另一些癌细胞初始敏感但在治疗过程中产生抗性能力。
还应该注意的是，与这些靶向治疗相关的显著副作用可能引起下列不适，从而使患者丧失更好的生活质量：骨髓抑制(定期进行血液检查以检查红细胞、白细胞和血小板)，脱发(其对患者来说可能是心理障碍，因为其是疾病的一个具体而明显的标志)、皮肤病和手足综合征、腹泻、血压升高、蛋白尿、高血糖、高胆固醇血症、过敏反应、细胞因子释放综合征、可以自维持肿瘤的肿瘤裂解综合征等。
此外，一些观察指出慢性炎症与患癌症风险之间存在密切联系。毫无疑问，这种相关性的最好例子之一是患有炎性肠病(特别是溃疡性结肠炎)的人患结肠癌的风险显著增加(20倍)。该情况也适用于胃癌，其在由细菌幽门螺杆菌(Helicobacter pylori)的存在引起的炎症后进展。前列腺癌是由前列腺炎症(前列腺炎)引起的。在HCC中，假设是慢性炎症增加DNA突变并且再生结节中肝细胞的增殖增加使得致癌突变附着的可能性增加。此外，强烈推荐结合皮质类固醇和抗组胺药的输注前和输注后药物治疗，以降低与某些靶向治疗相关的过敏反应的风险。
虽然生物标志物已经被验证用于乳腺癌(HER的拷贝数)、肺癌(EGFR突变)或结肠癌(Kras突变)，但目前在靶向治疗方面没有用于HCC的有效预后生物标志物。
许多研究表明，在癌变过程中，reptin和/或pontine过度表达；它们的核质位置根据癌症的类型而变化，并不一定是预后不良的因素。另一方面，reptin和pontine的过度表达是HCC预后不良的一个因素，而pontine高水平的mRNA与预后不良有关[(Haurie等，2009).Hepatology.2009-12；50(6)：1871-83.doi：10.1002/hep.23215]。
此外，已知reptin在前列腺癌、肝细胞癌(HCC)、胃癌、肾癌和乳腺癌中过表达。
还已知pontine在肝细胞癌、肺癌和结肠直肠癌中过表达。
reptin和/或pontine的功能障碍也已在其他癌症中得到证实，例如慢性白血病、间皮瘤和多发性骨髓瘤、高级别淋巴瘤、伯基特淋巴瘤、脑肿瘤(如神经胶质瘤和膀胱肿瘤)。
在癌症的情况下，存活蛋白(survivin)也被称为治疗靶标。大多数实体瘤(乳腺癌、前列腺癌、肺癌、肾癌等)或造血肿瘤(多发性骨髓瘤、白血病等)以异常方式表达。还已知癌性乳腺癌、肺癌和肾癌肿瘤细胞过度表达存活蛋白。
此外，β-榄香烯已知可用作抗癌药物。更重要的是，它具有广泛的抗肿瘤谱，包括对常规使用的抗癌药物具有抗性的肿瘤。还已知其是非细胞毒性的且患者对其具有良好耐受性。它能够通过血脑屏障并具有免疫刺激特性。它的抗炎活性也是众所周知的。还已知β-榄香烯抑制存活蛋白。另外已知其降低或甚至抑制癌细胞对抗癌药物的抗性。
另外已知β-榄香烯还降低癌细胞对某些药物的抗性。例如，它对MDR1、MRP和GST-π具有显著的抑制作用。Chen等，(2006)(Journal of Medicinal Plants Research，第6卷，第46期，第5720-5729页，2012-12-3)已经表明，β-榄香烯不可避免地增加U251/AMD细胞(已经对AMD产生抗性的细胞)中AMD的细胞内积累，并将U251/AMD细胞的IC50从0.915降低到0.051mg/l。
此外，还已知羽扇豆醇(lupeol)(也称为Fagarasterol或Clerodol)是具有抗炎、抗癌特性的药理活性化合物，特别是由于其抗增殖活性，其对细胞周期、细胞凋亡和血管生成的调节，及其对上皮-间质细胞转化的影响。它还刺激癌症患者的免疫系统。应注意，在有效治疗剂量下，羽扇豆醇对正常细胞和组织没有毒性。
在HCC的情况下，已知羽扇豆醇抑制脑源性神经营养因子(BDNF)。羽扇豆醇通过激活Caspase-3和切割PARP[聚(ADP-核糖)聚合酶]在一定的浓度和时间下，抑制HCC的HCCLM3细胞的增殖。但是，Zhang L.等(European Journal of Pharmacology，第762卷，2015-9-5，第55-62页)也发现由羽扇豆醇诱导的这些细胞的死亡与BDNF蛋白表达和GSK-3β(糖原合成酶激酶3β)的ser-9-磷酸化显著降低有关，同时伴随抑制Akt1、PBK(磷脂酰肌醇3-激酶)、β-连环蛋白、c-Myc和细胞周期蛋白D1的mRNA的表达。因此，抑制BDNF的过表达是Akt和PI3k蛋白表达降低以及GSK-3β功能再激活的结果。
更重要的是，在大鼠中连续18天以50mg/kg的剂量口服施用羽扇豆醇既未产生死亡也未产生全身毒性。
还已知肉桂醛类，特别是肉桂醛(CA)、2-羟基肉桂醛(HCA)和2-苯甲酰氧基肉桂醛(BCA)、HCA的一种半合成衍生物，对许多人类癌细胞(如黑素瘤、乳腺癌、肺癌、卵巢癌、结肠癌、前列腺癌、骨髓瘤和白血病)各自具有抗炎、抗增殖、抗血管生成、抗转移活性、抑制TEM(上皮-间质细胞转化)和促凋亡活性。
还已知HCA对HCC有影响。因此，Moon E.Y.(Eun-Yi Moon等，(2005)EuropeanJournal of Pharmacology 530(2006)270-275)研究了HCA对法呢基转移酶(farnesyltransferase)的抑制作用。该酶在模型小鼠中在转基因H-rasl 2V突变后并且在特定启动子(如白蛋白)的控制下发展肝细胞癌，发现与对照组相比，施用HCA/BCA 10周延迟了肝癌的发展。HCA/BCA显著降低肝损伤的频率和程度。HCA/BCA增加脾脏细胞的数量和肝脏中淋巴细胞的浸润。这些数据表明肝癌的延迟发作可能是由HCA/BCA对T细胞的免疫刺激作用引起的。
此外，已知β-谷甾醇具有抗炎、解热、抗肿瘤和免疫调节性质。
[需要解决的技术问题]
本发明的一个目的是提供一种新的药物组合物，其可用作药物，更具体地用于治疗癌症。
本发明的另一个目的是提供一种新的药物组合物，其可用作药物，更具体地用于治疗癌症，克服上述现有技术的组合物的所有或部分缺陷。
本发明的另一个目的是提供一种特别有利于治疗HCC的药物组合物。
本发明的另一个目的是提供一种药物组合物，该药物组合物可用作药物，特别是用于治疗HCC、肝细胞功能不全，并且特别是肝硬化。
本发明的另一个目的是提供用于治疗乳腺癌和/或前列腺癌的药物组合物。
本发明的另一个目的是提供一种药物组合物，特别是如上所述，其具有降低的毒性和/或患者的良好耐受性。
本发明的另一个目的是提供一种药物组合物，该药物组合物可以降低或抑制耐药性，特别是对抗癌剂的耐药性。
本发明的另一个目的是提供一种药物组合物，其特异性地作用于过表达选自reptin、pontine和存活蛋白中的至少一种蛋白质的癌细胞，并且特别是作用于过表达reptin和pontine以及可能过表达存活蛋白的癌细胞。
本发明的另一个目的是提供一种药物组合物，其抑制基质细胞在癌细胞过表达选自reptin、pontine和存活蛋白中的至少一种蛋白质中的作用。
本发明的另一个目的是提供一种药物组合物，该组合物能够抑制癌细胞对CXCR4受体的过表达并阻止新血管化的形成，从而减少对生长肿瘤的血液供应。
本发明的另一个目的是提供一种药物组合物，其能够抑制肿瘤基质的形成和转移过程，从而降低肿瘤复发的风险。
本发明的另一个目的是提供一种药物组合物，该组合物能够抑制炎症、肠粘膜的改变、细菌或病毒或真菌从肠腔向血流的转运、以及全身免疫过度活化，以诱导强烈的免疫反应，特别是在与消化道相关的淋巴组织中。
发明内容
为了解决上述技术问题中的至少一个，本发明提供一种药物组合物，其通常包含β-榄香烯、羽扇豆醇和药物活性剂的组合作为活性物质，该药物活性剂选自肉桂醛、2-羟基肉桂醛、2′-苯甲酰氧基肉桂醛、β-谷甾醇、姜黄素、及其混合物。
事实上，申请人发现这种药物组合物在癌症治疗中具有活性，特别是在HCC、乳腺癌和前列腺癌的情况下。
申请人还证明了至少两种成分的协同效应，其提供了本发明组合物对癌症现象中涉及的至少一种机制的增强作用，上述癌症现象即选自肿瘤基质的形成、细胞生长、凋亡、血管生成、转移过程、参与炎症的细胞信号通路的活化、脂质和碳水化合物代谢、以及细菌、病毒和真菌感染的机制。
申请人还证明，根据本发明的组合物对过表达reptin和/或pontine的细胞具有作用，该过表达是大多数癌症(包括HCC和乳腺癌和前列腺癌)的癌细胞的情况。
申请人还证明，根据本发明的组合物抑制某些轴，特别是CXCR4/CXCL12，其在增殖、肿瘤生长、转移和免疫抑制微环境的形成中起根本作用。
具体实施方式
根据本发明的药物组合物可以用作药物，特别是用于癌症的治疗性治疗。根据本发明的一个具体实施方案，本发明的组合物还可包含β-谷甾醇和肉桂醛的混合物或β-谷甾醇和2-羟基肉桂醛的混合物或β-谷甾醇和2′-苯甲酰氧基肉桂醛的混合物或肉桂醛类，特别是肉桂醛与一种或多种其合成衍生物和/或代谢物的混合物。
优选地，它不包括2-羟基肉桂醛、2′-苯甲酰氧基肉桂醛和β-谷甾醇的混合物。
举例来说，相对于活性物质的总重量，其可以包含基本上等于或大于15％且基本上等于或小于55％、特别是基本上等于或大于30％且基本上等于或小于50％的羽扇豆醇的重量百分比；基本上等于或大于10％且基本上等于或小于55％、特别是基本上等于或大于20％且基本上等于或小于40％的β-榄香烯的重量百分比；基本上等于或大于10％且基本上等于或小于45％、特别是基本上等于或大于20％且基本上等于或小于40％的肉桂醛的重量百分比；基本上等于或大于10％且基本上等于或小于45％、特别是基本上等于或大于20％且基本上等于或小于40％的2-羟基肉桂醛的重量百分比；基本上等于或大于10％且基本上等于或小于45％、特别是基本上等于或大于20％且基本上等于或小于40％的2’-苯甲酰氧基肉桂醛的重量百分比；当组合物含有β-谷甾醇时，该组分的重量百分比基本上等于或大于10％且基本上等于或小于45％、特别是基本上等于或大于20％且基本上等于或低于40％。
当组合物包含肉桂醛及其衍生物之一时，它们相对于活性物质总重量的重量百分比具体地等于并且特别基本上等于20％。
根据本发明的组合物还包含至少一种药学上可接受的赋形剂。该赋形剂可以是固体或液体。它可以选自，例如，纯净水、乙醇、丙二醇、甘油、植物油、动物油、碳氢化合物、硅氧烷、糖类(如葡萄糖或果糖)、小麦淀粉、玉米淀粉、马铃薯淀粉、黄原胶、阿拉伯树胶、黄蓍胶、刺梧桐树胶、瓜尔豆胶或“瓜尔豆盐(guaranates)”、果胶、藻酸盐、角叉菜酸盐、琼脂或琼胶、明胶、纤维素及其衍生物。
本发明的组合物可以通过任何合适的途径给药，例如通过口服，直肠，局部(例如外用局部(topical))，腹膜内，全身，静脉内，肌肉内，皮下或粘膜途径，特别是舌下或使用贴剂，或包封在脂质体、微粒、微胶囊中或固定在脂质体、微粒、微胶囊上或与纳米颗粒等组合。适用于口服给药的赋形剂的一些值得注意的非限制性实例包括滑石、乳糖、淀粉及其衍生物、纤维素及其衍生物、聚乙二醇、丙烯酸聚合物、明胶、硬脂酸镁、动物或植物或合成脂肪、石蜡衍生物、乙二醇、稳定剂、防腐剂、抗氧化剂、润湿剂、抗结块剂、分散剂、乳化剂、味道改良剂、渗透剂和增溶剂。药物和药物组合物的配制和给药技术在相关领域中是众所周知的。特别地，本领域技术人员可以特别参考《Remington′s Pharmaceutical Sciences》一书的最新版本。
根据本发明，组合物可以有利地通过静脉内注射口服给药。
有利地，根据本发明的组合物适于以基本上等于或大于40mg/kg/24h并且基本上等于或小于200mg/kg/24h的剂量通过口服或静脉一次或多次向具有此需要的哺乳动物给药。
举例来说，本发明的组合物可用于治疗选自肝细胞癌、结肠癌、直肠癌、胃癌、口腔癌(特别是舌癌)、前列腺癌、转移性前列腺癌的癌症、肾癌、乳腺癌、化疗耐药性乳腺癌、膀胱癌、慢性或急性白血病、多发性骨髓瘤、淋巴瘤、脑肿瘤、肺癌(特别是肺腺癌)、子宫癌、卵巢癌、骨肿瘤、胰腺癌、胆囊癌症和肝癌。
根据本发明的组合物可有利地用于患有慢性炎性疾病的患者，特别是炎性肠病，更特别是溃疡性结肠炎；携带能够引起炎症的病原体的患者，特别是幽门螺杆菌；糖尿病、血脂异常或骨关节疾病患者；肝细胞功能不全患者；患有细菌、真菌或病毒感染的患者，特别是患有乙型肝炎病毒和/或丙型肝炎病毒和/或人类免疫缺陷病毒(HIV)的患者。
在HCC的情况下，申请人已经证明，根据本发明的组合物至少在体外产生了良好的结果，并且对患者的肝细胞没有表现出毒性。
本发明组合物的作用方式尚不完全清楚。它很可能同时作用于不同的癌症机制。因此，本发明的组合物作为阻断骨髓干细胞向肿瘤微环境的聚集的药剂和/或作为肿瘤基质形成的抑制剂和/或作为针对选自由reptin、pontin和生存蛋白组成的组、优选由reptin和pontin组成的组中的至少一种的过表达的抑制剂，可用于癌症的所述治疗，和/或作为抗炎剂和/或作为引起癌细胞凋亡的药剂和/或作为用于抑制血管生成的药剂和/或作为抗转移剂，可用于癌症的治疗性治疗。
这种机制将包括细胞膜脂质成分的解构和重组，从而抑制代谢疾病的细胞信号传导途径，炎性细胞因子、趋化因子的分泌，细胞增殖，血管生成，转移以及细菌、病毒或真菌感染。
本发明还涉及一种药物制剂，其包含根据本发明的组合物，以及另外的作为混合物或单独包装的至少一种抗癌剂，同时、依次或在一定时间间隔内用于治疗癌症。
举例来说，抗癌剂可选自VEGF抑制剂、EGFR受体抑制剂、具有同时靶向血管生成和细胞增殖的酪氨酸激酶活性的数种受体的抑制剂、激酶抑制剂、IGF-IR受体抑制剂、mTOR抑制剂、MEK-ERK途径抑制剂、紫杉醇、As4S4、他莫昔芬、姜黄素、长春新碱、阿霉素、阿克拉霉素、奥沙利铂、亚叶酸钙、5-氟尿嘧啶、卡培他滨、顺铂、川芎嗪、甲氨蝶呤、柔红霉素、某些优选靶向癌细胞的基因修饰病毒，及其混合物，特别是这些抗癌剂中的两种的混合物，可用于近距离放射治疗的放射性试剂和/或可注射或可摄入的放射性代谢物。
本发明还涉及一种药物制剂，其包含β-榄香烯、羽扇豆醇和/或β-谷甾醇、肉桂醛和/或2-羟基肉桂醛和/或2′-苯甲酰氧基肉桂醛和任选的姜黄素的组合。
本发明还涉及膳食补充剂，其组合包含β-榄香烯、羽扇豆醇和/或β-谷甾醇和选自肉桂醛、2-羟基肉桂醛、2′-苯甲酰氧基肉桂醛及其混合物的药物活性剂、和任选的姜黄素的组合。
[定义]
术语“治疗性治疗”是指治愈性治疗和预防性治疗；在本发明的含义内，治疗性治疗使得可以通过发挥药理学、免疫学或代谢作用来至少部分地恢复、至少部分地校正或至少部分地改变生理功能。
术语“患者”是指动物或人类哺乳动物。根据本发明的组合物还可以用于兽医学中。
出于本发明的目的，“抗癌剂”是至少在体外对癌细胞表现出作用的要素，而与其作用机理无关。出于本发明的目的，术语“作用”应理解为意指癌细胞的至少部分破坏或修饰，其特别地使得限制癌细胞的增殖和/或增殖成为可能。
术语“患有糖尿病的患者”是指患有1型糖尿病的患者、患有2型糖尿病的患者、患有妊娠糖尿病的患者、患有尿崩症的患者和患有肾性糖尿病的患者。
术语“血脂异常”是指根据现行标准确定的高脂血症和低脂血症。
术语“患有骨关节疾病的患者”是指具有选自炎性体征、瘘管和通过引流或血培养检测到的已证实细菌存在中的至少两种体征的患者。
术语“肝细胞功能不全患者”是指患有肝炎的患者，无论其原因(病毒性、毒物性，药物性或缺血性)和肝硬化患者。
术语“病毒感染”是指生物实体，无论是乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人类免疫缺陷病毒(HIV)、疱疹病毒(HSV，单纯疱疹病毒)、或巨细胞病毒(CMV)，其需要宿主(通常是细胞)、用于繁殖的成分。
为了本发明的目的，“膳食补充剂”是一种食品，其目的是补充正常饮食并且构成营养素或其他单独或组合的具有营养或生理作用的物质的浓缩来源。
关于所引用的抗癌剂，除非另有说明，所用术语包括所考虑的化合物的组成异构体、构象立体异构体、对映异构体和非对映异构体。
关于根据本发明的组合物中的肉桂醛，除非另有说明，否则该术语包括肉桂醛衍生物、形成二聚体(在这种情况下为HCA-HCA、BCA-BCA、CA-CA)。
实施例
以下组合物的百分比是相对于活性物质总重量的重量百分比。
组合物1a：β-榄香烯(30％)，羽扇豆醇(30％)和2-羟基肉桂醛(40％)。
组合物1b：β-榄香烯(30％)，羽扇豆醇(30％)和2′-苯甲酰氧基肉桂醛(40％)。
组合物2：β-榄香烯(30％)，羽扇豆醇(30％)，2-羟基肉桂醛(20％)和2′-苯甲酰氧基肉桂醛(20％)。
组合物3a：β-榄香烯(50％)，羽扇豆醇(30％)和2-羟基肉桂醛(20％)。
组合物3b：β-榄香烯(50％)，羽扇豆醇(30％)和2′-苯甲酰氧基肉桂醛(20％)。
组合物4a：β-榄香烯(15％)，羽扇豆醇(50％)，β-谷甾醇(25％)和2-羟基肉桂醛(10％)。
组合物4b：β-榄香烯(15％)，羽扇豆醇(50％)，β-谷甾醇(25％)和2′-苯甲酰氧基肉桂醛(10％)。
组合物5a：β-榄香烯(20％)，羽扇豆醇(20％)，β-谷甾醇(40％)和2-羟基肉桂醛(20％)。
组合物5b：β-榄香烯(20％)，羽扇豆醇(20％)，β-谷甾醇(40％)和2′-苯甲酰氧基肉桂醛(20％)。
组合物6a：β-榄香烯(25％)，羽扇豆醇(35％，β-谷甾醇(15％)和2-羟基肉桂醛(25％)。
组合物6b：β-榄香烯(25％)，羽扇豆醇(35％)，β-谷甾醇(15％)和2′-苯甲酰氧基肉桂醛(25％)。
组合物7a：β-榄香烯(40％)，羽扇豆醇(20％)，β-谷甾醇(20％)和2-羟基肉桂醛(20％)。
组合物7b：β-榄香烯(40％)，羽扇豆醇(20％)，β-谷甾醇(20％)和2′-苯甲酰氧基肉桂醛(20％)。
[实验结果]
研究了不同的人Hep3B(肝细胞癌)、MCF-7(乳腺癌)、DU-145(前列腺癌)细胞系。选择它们是基于它们过表达reptin、pontin和存活蛋白中的至少一种蛋白质的能力。还研究了基质细胞以确定根据本发明的组合物在肿瘤微环境中的影响。将这些细胞维持在DMEM中，并在标准生长条件下(5％CO2，37℃，湿润气氛)补充10％胎牛血清(FBS)和含有青霉素、链霉素和两性霉素B的1％抗生素-抗真菌溶液(MSP)。将上述组合物溶解并稀释在DMSO中。
将上述细胞用增加溶液(increasing solution)在完全细胞培养基中处理72小时。如前所述制备所有治疗和对照方案。
在单一疗法中，与暴露72小时后的β-榄香烯相比，观察到羽扇豆醇和2-羟基肉桂醛对包括Hep3B、DU-145和MCF-7在内的三种细胞系系具有更显著的抗增殖作用。
已经研究了组合分子的溶液，包括羽扇豆醇-β-榄香烯、2-羟基肉桂醛-β-榄香烯和2-羟基肉桂醛-羽扇豆醇。暴露72小时后，与其他组合相比，在Hep3B、DU145和MCF-7细胞系上观察到较高的2-羟基肉桂醛-羽扇豆醇组合的累加和协同效应。
羽扇豆醇、β-榄香烯和2-羟基肉桂醛的同时组合增强并协同每种分子在单一疗法中对Hep3B和DU145细胞系的抗增殖作用。然而，该组合的抗增殖作用对MCF-7细胞系的影响较小。
在处理48小时后，使用膜联蛋白V/碘化丙啶测定该组合对诱导Hep3B细胞凋亡的影响。在Hep3B细胞中观察到膜联蛋白-V染色增加，而在未处理的对照细胞中仅观察到最低限度的染色。
在癌细胞和基质细胞的共培养中，用任何制备的溶液处理汇合(50％汇合)细胞导致与癌细胞死亡相关的粘附性降低，抑制基质细胞产生肿瘤微环境中发现的且参与转移过程和化学抗性的可溶性因子。
这些结果总体上表明该药物组合物抑制肿瘤基质形成并因此抑制转移性传播和化学抗性。它可以合理地用于治疗肝细胞癌、乳腺癌和前列腺癌——即使是在晚期阶段。
Claims (3)
1.一种在制备治疗前列腺癌和肝癌的药物组合物的应用，其特征在于，所述药物组合物的活性物质为β-榄香烯、羽扇豆醇、2-羟基肉桂醛的混合物。
2.根据权利要求1所述的在制备治疗前列腺癌和肝癌的药物组合物的应用，其特征在于，相对于所述活性物质的总重量，所述药物组合物包含大于或等于15％且小于或等于55％的重量百分比的羽扇豆醇、大于或等于10％且小于或等于55％的重量百分比的β-榄香烯、大于或等于10％且小于或等于45％的重量百分比的2-羟基肉桂醛。
3.根据权利要求1或2所述的在制备治疗前列腺癌和肝癌的药物组合物的应用，其特征在于，相对于所述活性物质的总重量，所述药物组合物包含大于或等于30％且小于或等于50％的重量百分比的羽扇豆醇、大于或等于20％且小于或等于40％的重量百分比的β-榄香烯的、大于或等于20％且小于或等于40％的重量百分比的2-羟基肉桂醛。
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| FR1670666A FR3058059B1 (fr) | 2016-10-31 | 2016-11-08 | Composition pharmaceutique comprenant le beta-elemene, le lupeol et le 2-hydroxycinnamaldehyde et/ou le 2'-benzoyloxycinnalmaldehyde et/ou le beta-sitosterol et/ou la curcumine. |
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| FR3100128B1 (fr) * | 2019-08-30 | 2022-02-18 | Nitcheu Guy Faustin Monkam | Composition pharmaceutique destinée à inhiber l’infectiosité du VIH, à traiter le syndrome d’immunodéficience acquise (SIDA) et ses complications |
| WO2021110073A1 (zh) * | 2019-12-03 | 2021-06-10 | 成都康弘药业集团股份有限公司 | 含有榄香烯的药物组合物及其制备方法和用途 |
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| KR20190077449A (ko) | 2019-07-03 |
| FR3058059A1 (fr) | 2018-05-04 |
| WO2018078539A1 (fr) | 2018-05-03 |
| FR3058059B1 (fr) | 2020-07-10 |
| FR3058058A1 (fr) | 2018-05-04 |
| CN109562080A (zh) | 2019-04-02 |
| ZA201902910B (en) | 2020-06-24 |
| US20240197755A1 (en) | 2024-06-20 |
| MA44413A (fr) | 2021-03-17 |
| IL266623A (en) | 2019-07-31 |
| CA3043456A1 (en) | 2018-05-03 |
| EP3429568A1 (fr) | 2019-01-23 |
| MX2019003685A (es) | 2019-09-26 |
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