CN112999213A - 蓓萨罗丁在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用 - Google Patents
蓓萨罗丁在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用 Download PDFInfo
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- CN112999213A CN112999213A CN201911318655.2A CN201911318655A CN112999213A CN 112999213 A CN112999213 A CN 112999213A CN 201911318655 A CN201911318655 A CN 201911318655A CN 112999213 A CN112999213 A CN 112999213A
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- adrenocorticotropic hormone
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Abstract
本发明公开了蓓萨罗丁在制备抗垂体促肾上腺皮质激素腺瘤药物制备中的应用，垂体促肾上腺皮质激素腺瘤使病人长期过度分泌促肾上腺皮质激素(ACTH)，刺激肾上腺分泌大量皮质醇，导致病人出现向心性肥胖、骨质疏松、肌肉萎缩、性功能障碍、高血压、失眠等症状，属罕见病。本发明发现，蓓萨罗丁能显著抑制肿瘤生长，并抑制ACTH分泌和其前体POMC的表达。蓓萨罗丁可用于制备抗垂体促肾上腺皮质激素腺瘤药物，减少不良反应，为疾病的治疗和预防提供一种安全、有效、经济的解决办法。
Description
技术领域
本发明涉及蓓萨罗丁在制备药物中的应用，主要涉及蓓萨罗丁在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用，属于医药技术领域。
背景技术
垂体促肾上腺皮质激素腺瘤是垂体前叶发生的良性激素分泌性肿瘤，属罕见病，是库欣病的主要病因。
垂体促肾上腺皮质激素腺瘤使病人垂体前叶长期过度分泌ACTH，刺激肾上腺皮质产生过量皮质醇，临床表现为库欣综合征，病理变化包括但不限于：向心性肥胖、水牛背、毛发增多、皮肤肌肉萎缩、神经系统损伤、高血压、动脉粥样硬化、糖尿病、免疫损伤和性功能障碍。
垂体促肾上腺皮质激素腺瘤存在下丘脑-垂体-肾上腺轴机能紊乱，是一种耗竭性疾病，极少自行缓解，若不及时诊治，病死率高。
垂体促肾上腺皮质激素腺瘤的治疗可分为手术治疗、放射治疗和药物治疗。手术治疗作为目前的主要治疗方式存在微腺瘤清除不彻底、复发率高、有感染风险等不足，因此垂体促肾上腺皮质激素腺瘤的药物治疗是很有必要的。
垂体促肾上腺皮质激素腺瘤的治疗药物可分为作用于垂体的药物、作用于肾上腺的药物和糖皮质激素受体阻断剂。但目前上市的药物少、药物可及性差，已有药物主要通过抑制激素分泌缓解症状，需要长期用药且治标不治本，因此药物治疗仅作为辅助治疗手段，寻找新的安全有效的治疗药物迫在眉睫。
蓓萨罗丁(Bexarotene)化学名4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸，分子式为C24H28O2。纯品为无毒无味，无刺激性、无过敏性的白色固体，易潮解，需避光保存。蓓萨罗丁是一种抗肿瘤药，分别于1999年和2001年被FDA和EMA批准用于皮肤T细胞淋巴瘤的治疗。它是视黄醇X受体(RXR)的激动剂，通过与RXRα结合调控下游基因转录，诱导细胞分化和细胞凋亡，从而抑制肿瘤生长。其化学结构如下：
对蓓萨罗丁制备抗垂体促肾上腺皮质激素腺瘤药物中的作用尚未见报道。
发明内容
本发明解决的技术问题在于提供蓓萨罗丁在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用，从而为垂体促肾上腺皮质激素腺瘤的治疗提供一种不良反应轻微的解决办法。
为此，本发明提供了如下技术方案：
本发明技术方案的第一方面是提供了如式Ⅰ所示的4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸(蓓萨罗丁)及其药学上可接受的盐在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用
所述垂体促肾上腺皮质激素腺瘤为垂体前叶发生的分泌ACTH的良性肿瘤。
所述的垂体促肾上腺皮质激素腺瘤包括但不限于体细胞突变导致的垂体ACTH分泌腺瘤。
本发明技术方案的第二方面是提供一种药物组合物在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用，其特征在于，所述的药物组合物含有如式I所示的4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸(蓓萨罗丁)及其药学上可接受的盐、及药学上可接受的载体，
进一步，所述蓓萨罗丁可与药学上可接受的辅料按常规制剂方法制成各种剂型的抗垂体促肾上腺皮质激素腺瘤药物。
进一步，所述蓓萨罗丁可与保健品包括保健食品和功能食品可接受的辅料按常规制剂方法制成各种抗垂体促肾上腺皮质激素腺瘤的保健品。
本发明因此还涉及以本发明化合物作为活性成分的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过发明所述蓓萨罗丁与一种或多种药学上可接受的固体或液体赋形剂和/或辅料组合，制成与人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-99％。
进一步，本发明还涉及以本发明化合物作为活性成分的保健品组合物。该组合物可根据本领域公知的方法制备。可通过发明所述蓓萨罗丁与一种或多种保健品和食品上可接受的固体或液体赋形剂和/或辅料组合，制成与人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-99％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可以为胃肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
所述的药物组合剂型包括口服制剂，注射给药剂型，皮肤黏膜途径给药剂型。
进一步的，所述的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂，所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注，所述的皮肤黏膜给药剂型包括鼻腔喷剂、鼻腔滴剂。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羧丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、酷酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-400mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
有益技术效果：
本发明采用小鼠垂体瘤细胞(ACTH分泌型，AtT-20细胞)对蓓萨罗丁抑制垂体瘤细胞生长作用进行了考察，结果显示，蓓萨罗丁可显著抑制AtT-20细胞生长。本发明采用小鼠皮下移植瘤模型，对蓓萨罗丁抗垂体促肾上腺皮质激素腺瘤和降低血ACTH水平作用进行了考察，结果显示，通过口服给药蓓萨罗丁可显著抑制肿瘤生长，可显著降低小鼠血浆ACTH水平，可显著降低肿瘤组织阿片促黑色素皮质激素原(POMC)mRNA表达水平，所以为垂体促肾上腺皮质激素腺瘤预防与治疗提供了一种安全、有效、经济的解决办法。
附图说明
图1.蓓萨罗丁对小鼠垂体瘤细胞(ACTH分泌型，AtT-20细胞)增殖情况影响。
图2.各组皮下移植瘤模型小鼠平均肿瘤体积变化趋势图。n＝8。
图3.给药终点各组皮下移植瘤模型小鼠肿瘤对比图。
图4.蓓萨罗丁对皮下移植瘤模型小鼠血浆促肾上腺皮质激素(ACTH)水平影响。
具体实施方式
为使本发明的目的、技术方案、优点更加清楚，下面将结合附图对本发明作进一步的详细描述。
实验例1.蓓萨罗丁对小鼠垂体瘤细胞(ACTH分泌型，AtT-20细胞)增殖情况影响。
实验材料：AtT-20细胞购自美国模式培养物研究所(American Type CultureCollection)。蓓萨罗丁购自Selleck(中国，上海蓝木化工有限公司)。二甲基亚砜(DMSO)购自默克生命科学技术(南通)有限公司。DMEM、胎牛血清(FBS)和马血清(HS)购自赛默飞世尔科技(中国)有限公司。青链霉素混合液购自北京索莱宝科技有限公司。CCK-8剂盒购自江苏凯基生物技术股份有限公司。
溶液配制：将蓓萨罗丁溶于DMSO配成浓度为100mM的母液。
AtT-20细胞接种于96孔板，0.5％FBS饥饿细胞12h后加FBS至终浓度10％，同时按终浓度0、10、20、40、60、80、100uM剂量加入蓓萨罗丁，培养箱中孵育48h后加入CCK-8测细胞增值率。
结果：蓓萨罗丁能够剂量依赖地抑制AtT-20细胞增殖。
表1.蓓萨罗丁对AtT-20细胞增值抑制率
与对照组比较，给药剂量60uM、80uM、100uM，P<0.01。
实验例2.蓓萨罗丁对皮下移植瘤模型小鼠肿瘤生长影响。
实验材料：BAL/BC小鼠购自北京维通利华实验动物技术有限公司。AtT-20细胞购自美国模式培养物研究所(American Type Culture Collection)。蓓萨罗丁、替莫唑胺和吉非替尼购自Selleck(中国，上海蓝木化工有限公司)。羧甲基纤维素钠(CMC-Na)购自国药集团化学试剂有限公司。
建模分组：16-18g雌性小鼠脱毛后腋下接种AtT-20细胞，5天后肿瘤生长至直径3-5mm，随机分为模型组(1％CMC-Na)，替莫唑胺组(20mg·kg-1，阳性对照)，吉非替尼组(75mg·kg-1，阴性对照)和蓓萨罗丁组(50mg·kg-1)，每组8只，以未接种肿瘤的正常小鼠作正常对照。
将1％羧甲基纤维素钠溶解，煮沸，冷却后作为溶媒，将蓓萨罗丁和吉非替尼溶解配置成混悬液。将替莫唑胺溶于生理盐水，配制成稳定溶液。按剂量每天给药，持续21天。每3天测量肿瘤长轴直径a和短轴直径b，并根据公式肿瘤体积TV＝3.1416/6*a*b*b mm3计算肿瘤体积。
表2.蓓萨罗丁对小鼠肿瘤生长速度影响。n＝8。
结果：模型动物口服蓓萨罗丁(50mg/kg)能够抑制ACTH垂体瘤生长。
实验例3.蓓萨罗丁对皮下移植瘤模型小鼠血浆促肾上腺皮质激素(ACTH)水平影响。
实验材料：BAL/BC小鼠购自北京维通利华实验动物技术有限公司。AtT-20细胞购自美国模式培养物研究所(American Type Culture Collection)。蓓萨罗丁、替莫唑胺和吉非替尼购自Selleck(中国，上海蓝木化工有限公司)。羧甲基纤维素钠(CMC-Na)购自国药集团化学试剂有限公司。小鼠ACTH Elisa试剂盒购于武汉华美生物工程有限公司。
实验分组：相关实验分组及给药处理同实验例2。
给药终点摘眼球取血，立即低温离心取上清，用小鼠ACTH Elisa试剂盒进行检测，步骤如下：
将试剂盒从4度移至室温下平衡20分钟，并配置标准品和生物素标记抗体溶液。酶标板每孔加入100ul标准品或样品，封板膜封好置于37度摇床，轻摇孵育2小时。移去液体，每孔加入生物素标记抗体100ul，封板后37度孵育1小时。洗板3次，每次加200ul洗涤液并静置2分钟。加100ul二抗，封板后37度孵育1小时。洗板3次，每次加200ul洗涤液并静置2分钟。每孔加90ul显色液，避光孵育15分钟，变蓝后加入50ul终止液，蓝色变为黄色，立即用酶标仪检测450nm波长处吸光度。根据标准曲线计算各孔样品中ACTH浓度，各组结果取平均值，并与正常对照组取比值。
表3.蓓萨罗丁对皮下移植瘤模型小鼠血浆促肾上腺皮质激素(ACTH)水平影响。
与模型组相比，蓓萨罗丁组P<0.05。
结果：模型动物口服蓓萨罗丁(50mg/kg)能减少ACTH分泌，显著降低血浆ACTH水平。
综上所述，本发明采用皮下移植瘤小鼠模型对蓓萨罗丁抗垂体促肾上腺皮质激素腺瘤，包括降低血ACTH水平作用进行了考察，结果显示，通过灌胃给药蓓萨罗丁可显著降低小鼠血浆ACTH水平，并在体内、外水平均可抑制垂体腺瘤细胞增殖。因此，蓓萨罗丁有抗垂体促肾上腺皮质激素腺瘤作用。以蓓萨罗丁为活性物质，单独使用或/与其他具有药理学活性的化合物和/或提取物组成复方使用，按照药学领域的常规制剂方法制成各种剂型的抗垂体促肾上腺皮质激素腺瘤药物，或与其他抗肿瘤药物和/或激素分泌抑制剂等制成复方制剂，用于在保持疗效的情况下减少药物作用中的不良反应，可为垂体促肾上腺皮质激素腺瘤的治疗预防与治疗提供了一种安全、有效、经济的解决办法。
最后说明的是，以上实施例仅用于说明本发明的技术方案而非限制，尽管通过参照本非发明的优选实施例已对本发明进行了描述，但本领域普通技术人员应当理解，可以在实行上和细节上对其做出各种各样的改变，而不偏离所附权利要求说明书所限定的本发明的精神和范围。
Claims (6)
1.如式Ⅰ所示的4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸及其药学上可接受的盐在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用，
2.根据权利要求1的应用，其特征在于，所述垂体促肾上腺皮质激素腺瘤为垂体前叶发生的分泌ACTH的良性肿瘤。
3.根据权利要求1的应用，其特征在于，所述的垂体促肾上腺皮质激素腺瘤包括体细胞突变导致的垂体ACTH分泌腺瘤。
4.一种药物组合物在制备抗垂体促肾上腺皮质激素腺瘤药物中的应用，其特征在于，所述的药物组合物含有如式I所示的4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸及其药学上可接受的盐、及药学上可接受的载体，
5.根据权利要求3的应用，其特征在于，所述的药物组合物选自口服制剂、注射给药剂型、皮肤黏膜途径给药剂型。
6.根据权利要求4的应用，其特征在于，所述的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂，所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注，所述的皮肤黏膜给药剂型包括鼻腔喷剂、鼻腔滴剂。
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