CN109843280A - 包含齐墩果酸乙酸酯作为有效成分的用于预防、改善或治疗由药剂诱发的肾脏毒性的组合物 - Google Patents
包含齐墩果酸乙酸酯作为有效成分的用于预防、改善或治疗由药剂诱发的肾脏毒性的组合物 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Nutrition Science (AREA)
- Mycology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Inorganic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及包含齐墩果酸乙酸酯(oleanolic acid acetate)作为有效成分的用于预防、改善或治疗由药剂诱发的肾脏毒性的的组合物。具体而言,本发明涉及包含齐墩果酸乙酸酯或其药学上可接受的盐作为有效成分的用于预防或治疗由药剂诱发的肾脏毒性的药学组合物、包含所述有效成分的用于预防或改善由药剂诱发的肾脏毒性的健康功能食品以及包含所述有效成分的抗癌助剂。本发明的齐墩果酸乙酸酯源自天然产物,因而无副作用且无细胞毒性,在预防、改善及治疗由药剂诱发的,尤其,由铂类抗癌药物诱发的肾脏毒性的效果显著,因而可有效利用于对其的药学组合物、健康功能食品及抗癌助剂。
Description
技术领域
本发明涉及用于预防、改善或治疗由药剂诱发的肾脏毒性的包含齐墩果酸乙酸酯(oleanolic acid acetate)作为有效成分的组合物。
具体而言,本发明涉及包含齐墩果酸乙酸酯或其药学上可接受的盐作为有效成分的用于预防或治疗由药剂诱发的肾脏毒性的药学组合物、包含所述有效成分的用于预防或改善由药剂诱发的肾脏毒性的健康功能食品以及包含所述有效成分的抗癌助剂。并且,提供利用齐墩果酸乙酸酯或其药学上可接受的盐的治疗由药剂诱发的肾脏毒性的方法、利用齐墩果酸乙酸酯或其药学上可接受的盐及铂类抗癌药物的治疗癌症的方法以及齐墩果酸乙酸酯或其药学上可接受的盐的多种用途。
背景技术
据估计,全球约有1400万人患上癌症,约有820万人死于癌症。在韩国,癌症自1983年以来一直为处于死亡原因第一位的疾病,在2013年所有死亡人数中的28.3%为癌症相关死亡(韩国国立癌症中心,韩国癌症发病现况,2012年)。
目前,如手术、放射疗法、基因疗法等诸多方法作为用于治疗癌症的方法,但最常用的治疗方法之一为施用抗癌药物的化疗法。作为典型的抗癌药物的顺铂(Cisplatin,cis-diammine-dichloroplatinum II)是铂类抗癌药物之一,并在临床上广泛用于治疗卵巢癌、膀胱癌、肺癌、头颈癌、睾丸癌等的化学药剂。
众所周知,顺铂产生活性氧簇来攻击癌细胞,在癌细胞中诱导脱氧核糖核酸(DNA)链间-链内交联(inter-intrastrand cross-linking)、脱氧核糖核酸(DNA)加合物的形成,使得抑制细胞分裂旺盛的癌细胞的脱氧核糖核酸(DNA)复制,从而表现出抗癌效果(Boulikas T.,Oncology Rep,10:1663-1682,2003),但报道有骨髓抑制、胃肠毒性、神经毒性、肾脏毒性、肝毒性等副作用,其中肾脏毒性被认为是最大问题。已知顺铂集中累积在肾脏,并且与给药剂量成比例地增加,因此导致严重的毒性(Safirstein R.,Am J KidneyDis 8:356-367,1986)。
在临床上给药顺铂的患者的25-35%中诱发肾脏毒性(Merouani A.,Am JNephrol 17:53-58,1997),因此正在研究降低这种毒性的药理学方法。并且,已有实验依据表明由顺铂诱发的肾脏毒性的疾病生理机制可解释为炎症反应的变化,从而正在研究与肾脏毒性调节有关的炎症相关因子(Ramesh G.,J Clin Invest 110:835-842,2002)。不仅如此,由抗癌药物诱发的急性肾衰竭毒性为由肾脏细胞毒素(nephrotoxin)诱发的毒性,在使用抗生素时也表现出毒性。因此,认为由顺铂诱发的肾脏毒性的抑制物质对由抗生素诱发的肾脏毒性也具有效果。
在这种背景下,本发明人为了寻找用于预防或治疗由药剂诱发的,尤其由铂类抗癌药物诱发的肾脏毒性的物质而锐意研究的结果,确认到齐墩果酸乙酸酯在由铂类抗癌药物诱发急性肾衰竭的动物模型中具有抑制肾脏毒性的功效并对其进行推究,从而完成了用于预防、改善及治疗由药剂诱发的肾脏毒性的组合物以及利用其的抗癌助剂的发明。
发明内容
本发明的目的在于,提供包含齐墩果酸乙酸酯的用于预防、改善或治疗肾脏毒性的组合物。
具体而言,本发明的一目的在于,提供包含齐墩果酸乙酸酯或其药学上可接受的盐作为有效成分的用于预防或治疗由药剂诱发的肾脏毒性的药学组合物。
本发明的再一目的在于,提供包含齐墩果酸乙酸酯或其食品学上可接受的盐作为有效成分的用于预防或改善由药剂诱发的肾脏毒性的健康功能食品。
本发明的另一目的在于,提供包含齐墩果酸乙酸酯或其药学上可接受的盐作为有效成分的用于预防或治疗由抗癌药物诱发的肾脏毒性的抗癌助剂。
本发明的还一目的在于,提供向患者给药药学有效量的齐墩果酸乙酸酯或其药学上可接受的盐的来治疗由药剂诱发的肾脏毒性的方法。
本发明的又一目的在于,提供齐墩果酸乙酸酯或其药学上可接受的盐在制备用于治疗由药剂诱发的肾脏毒性的药剂中的用途。
本发明的又一目的在于,提供用于由药剂诱发的肾脏毒性的治疗的包含齐墩果酸乙酸酯或其药学上可接受的盐的组合物。
本发明的又一目的在于,还提供用于治疗由药剂诱发的肾脏毒性的所述齐墩果酸乙酸酯或其药学上可接受的盐的用途。
本发明的又一目的在于,提供向患者给药药学有效量的作为抗癌助剂的齐墩果酸乙酸酯或其药学上可接受的盐以及药学有效量的铂类抗癌药物的治疗癌症的方法。
本发明的又一目的在于,提供齐墩果酸乙酸酯或其药学上可接受的盐在制备抗癌助剂中的用途。
本发明的又一目的在于,提供包含用作抗癌助剂的齐墩果酸乙酸酯或其药学上可接受的盐的组合物。
本发明又一目的在于,提供用作抗癌助剂的齐墩果酸乙酸酯或其药学上可接受的盐的用途。
为了解决所述问题,作为一实例,本发明提供包含作为由以下化学式1表示的化合物的齐墩果酸乙酸酯或其药学上可接受的盐作为有效成分的用于预防或治疗由药剂诱发的肾脏毒性的药学组合物。
化学式1
本发明人首先推究,齐墩果酸乙酸酯具有改善由药剂诱发的肾脏毒性的效果,尤其,具体而言,根据本发明一实施例确认到,齐墩果酸乙酸酯可有效地降低在由作为铂类抗癌药物之一的顺铂诱发急性肾衰竭的动物模型中用作肾功能指标的血尿素氮(BUN)值(图2d)及血液炎症细胞因子(肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6))值(图3a、图3b)、肾脏组织内炎症因子(肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、环氧化酶-2(COX-2)、单核细胞趋化蛋白-1(MCP-1))表达量(图4a、图4b、图4c、图4d)。因此,本发明的齐墩果酸乙酸酯不仅在顺铂中还在已知诱发肾脏毒性的作用机制相似的其他铂类抗癌药物中,例如,卡波铂(carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)以及肾脏毒性诱发机制也相似的抗生素,例如,氨基糖苷类(aminoglycoside)、四环素类(tetracycline)、磺胺类药物(sulfa drug)、庆大霉素(gentamicin)等中也均具有相同的效果。
并且,在本发明一实施例中确认了齐墩果酸乙酸酯的细胞毒性明显比齐墩果酸低,因此适用于动物或人体时无副作用,并且能够以预防、改善及治疗肾脏毒性的用途来多样化利用。
本发明的齐墩果酸乙酸酯可通过市售化合物或公知的方法来获得。根据本发明一实施例,本发明人利用了从赤小豆分离纯化的本发明的齐墩果酸乙酸酯。具体而言,利用己烷分馏赤小豆的乙醇提取物以获得己烷可溶分馏物,利用己烷和乙酸乙酯的混合溶剂并通过硅胶柱色谱分离之后,利用甲醇进行重结晶,使得分离出化学式1的纯的齐墩果酸乙酸酯化合物。
化学式1
本发明的术语中的“由药剂诱发的肾脏毒性”是指因使用以诊断或治疗为目的使用的药剂而使肾脏受损的意思。所给药的药物可使流向肾脏的血液流量减少或抑制肾小球和肾小管的功能,因此可诱发肾脏的损伤,并有可能诱发近端肾小管坏死,更严重时有可能诱发肾衰竭。只要是诱发肾脏毒性的药剂,任何药剂均包括在本发明的范畴之内,例如,铂类抗癌药物,如可例举选自由顺铂、卡波铂(carboplatin)、奥沙利铂(oxaliplatin)及奈达铂(nedaplatin)组成的组中的一种以上,肾脏毒性诱发机制相似的抗生素,例如,可例举选自由氨基糖苷类(aminoglycoside)、四环素类(tetracycline)、磺胺类药物(sulfa drug)及庆大霉素(gentamicin)组成的组中的一种以上。
本发明的包含化学式1的化合物或其药学上可接受的盐的药学组合物还可包含常规用于药学组合物的制备的适当的载体、赋形剂或稀释剂。其中,包含于所述组合物中的所述齐墩果酸乙酸酯、其盐、提取物或分馏物的含量无特别限定,但可以制备成相对于组合物总重量,包含0.0001重量百分比至10重量百分比,优选地,包含0.001重量百分比至1重量百分比。
本发明的术语中的“药学上可接受的盐”是指在阳离子与阴离子借助静电引力来相结合的物质的盐中的在药剂学上可使用的形态的盐,通常,可以为金属盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或酸性氨基酸形成的盐等。例如,作为金属盐,可以为碱金属盐(钠盐、钾盐等)、碱土金属盐(钙盐、镁盐、钡盐等)、铝盐等;作为与有机碱形成的盐,可以为与三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己胺、N,N-二苄乙烯二胺等形成的盐;作为与无机酸形成的盐,可以为与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐;作为与有机酸形成的盐,可以为与甲酸、乙酸、三氟乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、p-甲苯磺酸等形成的盐;作为与碱性氨基酸形成的盐,可以为与精氨酸、赖氨酸、鸟氨酸等形成的盐;作为与酸性氨基酸形成的盐,可以为与天冬氨酸、谷氨酸等形成的盐。
本发明的包含化学式1的化合物或其药学上可接受的盐的组合物可分别根据常规方法来剂型化为如散剂、颗粒剂、纯化、胶囊剂、悬浮剂、乳液、糖浆、气溶胶等口服剂型、外用药、栓剂及无菌注射液的形态来使用。在本发明中,可包含在含有赤小豆提取物及分馏物的组合物中的载体、赋形剂及稀释剂可例举有乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、金合欢橡胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁及矿物油。在进行制剂化的情况下,利用通常使用的填充剂、稀释剂、粘合剂、润湿剂、分裂剂、表面活性剂等稀释剂或赋形剂来调配。用于口服给药的固体制剂中包含片剂、丸剂、散剂、颗粒剂、胶囊剂等,这种固体制剂通过向所述赤小豆提取物及其的分馏物中混合至少一种赋形剂,例如淀粉、碳酸钙、蔗糖或乳糖、明胶等来进行调配。并且,除了简单的赋形剂之外,还使用如硬脂酸镁、滑石粉等的润滑剂。用于口服的液体制剂可包含悬浮剂、内用液剂、乳剂、糖浆剂等,除了作为经常使用的简单稀释剂的水、液体石蜡之外,还可包含多种赋形剂,例如润湿剂、甜味剂、芳香剂、防腐剂等。用于肠胃外给药的制剂中包含灭菌的水溶液、非水溶剂、悬浮剂、乳剂、冻干制剂、栓剂。作为非水溶剂、悬浮剂,可使用如丙二醇(propylene glycol)、聚乙二醇、橄榄油等的植物油,如油酸乙酯等的可注射的酯等。作为栓剂的基质,可使用合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)61、可可油脂、三月桂酸甘油酯、甘油明胶等。
本发明的所述药学组合物的优选剂量根据患者的病症及体重、疾病程度、药物形态、给药途径及时间而不同,可由本发明所属技术领域的普通技术人员来适当选择。但是,为了更有效的预防或治疗,本发明的所述齐墩果酸乙酸酯、其盐、提取物或分馏物每日以0.0001mg/kg至100mg/kg给药,优选地,以0.001mg/kg至100mg/kg给药,可一日一次给药,也可分数次给药。
本发明的药学组合物能够以多种途径向大鼠、小鼠、家畜、人等哺乳动物进行给药。可预期给药的所有方法,可通过例如口服、直肠或静脉、肌肉、皮下、子宫内硬脑膜或脑室内(intracerebroventricular)注射来进行给药。
本发明的术语中的“肿瘤坏死因子-α(TNF-α)”为肿瘤坏死因子(tumor necrosisfactor)的缩写,是指炎症细胞因子的一种。
本发明的术语中的“白细胞介素-6(IL-6)”为白细胞介素-6(interleukin-6)的缩写,是指炎症细胞因子的一种。
本发明的术语中的“环氧化酶-2(COX-2)”为环氧化酶-2(Cyclooxygenase-2)的缩写,是指前列腺素E2(prostaglandin E2,PGE2)合成酶。
本发明的术语中的“单核细胞趋化蛋白-1(MCP-1)”为单核细胞趋化蛋白-1(monocyte chemoattractant protein-1)的缩写,是指炎症趋化因子的一种。
本发明的术语中的“赤小豆(赤小豆)”是指豆科的赤豆(Phaseolus angularisWight)的种子,形态上呈圆柱形,微扁,种皮为红棕色,光滑有光泽,在药理活性方面上,用于治疗利尿、消炎、排脓、解热、全身浮肿、肝硬化、黄疸、脓肿、化脓性疾病、水肿、脚气病、消渴症、痢疾状腹泻等的民间疗法中。出于本发明的目的,所述赤小豆用于表示赤豆(Phaseoli angularis Wight)或红豆(或红饭豆,Phaseolus calcaratus Roxburgh)的种子,但不限定于此。
本发明的术语中的“赤小豆提取物”是指通过提取赤小豆来获得的提取物,出于本发明的目的,赤小豆提取物可以为利用水、碳原子数为1至6的醇(甲醇、乙醇、丁醇等)、它们的混合溶剂等提取赤小豆的粉碎产物而得到的结果产物,但不限定于此,所述结果产物包含提取液、提取液的稀释液或浓缩液、通过干燥提取液获得的干燥产物或它们的粗纯化产物或纯化产物等。
根据本发明一实施例,使用干燥重量的约2倍至20倍的体积,优选地,使用干燥重量的约3倍至5倍的体积的水、如甲醇、乙醇及丁醇等的碳原子数为1(C1)至6(C6)的醇的极性溶剂或它们的混合比约1:0.1至1:10的混合溶剂作为洗脱溶剂,提取温度为20℃至100℃,优选地,为室温,提取时间为约12小时至4天,优选地,为3天,利用热水提取、冷浸提取、回流冷却提取或超声提取等的提取方法来提取赤小豆粉碎产物。优选地,用冷浸提取连续提取1次至5次并真空过滤,利用真空旋转浓缩仪在20℃至100℃温度下,优选地,在室温下减压浓缩该过滤提取物,从而可获得可溶于低级醇或它们的混合溶剂的赤小豆(赤豆及红豆)粗提取物。
本发明的术语中的“分馏物”是指通过包含多种构成成分的混合物分离特定成分或特定组的分馏方法来获得的结果产物。在本发明中,优选地,可以为通过利用n-己烷、乙酸乙酯等的溶剂的溶剂分馏方法来分馏赤小豆的提取物的结果产物,均包含极性溶剂分馏物及非极性溶剂分馏物,具体而言,可使用己烷分馏物、乙酸乙酯分馏物及水分馏物等。
根据本发明一实施例,可将所得的所述赤小豆粗提取物悬浮于蒸馏水中之后,加入悬浮剂的约1倍至100倍体积,优选地,约1倍至5倍体积的如己烷、乙酸乙酯等的非极性溶剂经过1次至10次,优选地,2次至5次提取非极性溶剂可溶性层,并分离获得。并且,还可额外地进行常规分馏工序(Harborne J.B.Phytochemical methods:A guide to moderntechniques of plant analysis,3rd Ed.p6-7,1998)。具体地,将所述赤小豆粗提取物悬浮于水中之后,利用等量的n-己烷及乙酸乙酯溶剂并通过连续提取来获得赤小豆的各个溶剂可溶提取物,更具体地,可将赤小豆粗提取物悬浮于水中之后,混合相同量的n-己烷,然后分馏并获取n-己烷可溶性分馏物及水溶性分馏物,可向该水溶性分馏物中加入乙酸乙酯来获得乙酸乙酯可溶性分馏物及水溶性分馏物。
根据本发明的另一实例,本发明提供包含作为由所述化学式1表示的化合物的齐墩果酸乙酸酯或其食品学上可接受的盐作为有效成分的用于预防或改善由药剂诱发的肾脏毒性的健康功能食品。
本发明的化学式1的化合物源自天然产物,因此其安全性已得以证实,因而可用于食品组合物。相对于食品组合物的总重量,可包含0.01重量百分比至100重量百分比的所述齐墩果酸乙酸酯或其食品学上可接受的盐,更优选地,可包含1重量百分比至80重量百分比。当食品为饮料的情况下,以100mL为基准,能够以1g至30g的比率包含,优选地,能够以3g至20g的比率包含。并且,所述组合物可包含通常用于食品组合物以提高气味、味道、视觉等的成分。例如,可包含维生素A、C、D、E、B1、B2、B6、B12、烟酸(niacin)、生物素(biotin)、叶酸(folate)、泛酸(panthotenic acid)等。并且,可包含锌(Zn)、铁(Fe)、钙(Ca)、铬(Cr)、镁(Mg)、锰(Mn)、铜(Cu)等的矿物质。并且,可包含赖氨酸、色氨酸、半胱氨酸、缬氨酸等的氨基酸。并且,可添加防腐剂(山梨酸钾、苯甲酸钠、水杨酸、乙酸二氢钠等)、消毒剂(漂白粉及高效漂白粉、次氯酸钠等)、抗氧化剂(丁基羟基茴香醚(BHA)、丁基羟基甲苯(BHT)等)、着色剂(焦油色素等)、显色剂(亚硝酸钠、亚硝酸钠等)、漂白剂(亚硫酸钠)、调味剂(MSG谷氨酸钠等)、甜味剂(甘素、甜蜜素、糖精、钠等)、香料(香兰素、内酯类等)、膨胀剂(明矾、D-酒石酸钾等)、增强剂、乳化剂、增稠剂(糊料)、涂层剂、胶基剂、泡沫抑制剂、溶剂、改善剂等的食品添加物(food additives)。所述添加物根据食品的种类来选择并使用适当量。
本发明的术语中的“食品学上可接受的盐”是指阳离子与阴离子借助静电引力相结合的物质的盐中的在食品学上可使用的形态的盐,对其种类的具体例包括所述的“药学上可接受的盐”的例示。
在本发明中,术语“健康食品(health food)”是指比一般食品更具有积极的健康维持或增强的效果的食品,健康补充食品(health supplement food)以健康补助为目的的食品。根据情况,功能性食品、健康食品、健康补充食品的术语共用。所述食品能够以片剂、胶囊、粉末、颗粒、液态、丸等的多种形态制备以获得有用的效果。
在本发明中,术语“功能食品(functional food)”为与特殊保健用食品(food forspecial health use,FoSHU)相同的术语,并且是指医学、医疗上效果高的食品,以加工成除了供给营养之外还有效呈现出生物调节功能。
作为这种健康功能食品的具体例,可利用所述组合物制备出以衬托农产品、畜产品或水产品的特性的方式进行变形并具有良好的储存性能的加工食品。包含所述组合物的健康功能性食品不特别限定于此,但优选地,可使用以人造奶油、脂肪连续性(fatcontinuous)或水连续性(water continuous)或双连续性(bicontinuous)涂抹物、脂肪减少涂抹物、巧克力或巧克力涂层或巧克力填充物(fillings)或烘焙产品填充物等的点心类、冰淇淋、冰淇淋涂层、含有冰淇淋的产品、调味汁、蛋黄酱、奶酪、奶油替代品、干汤、饮品、谷物条、酱汁、快餐条、乳制品、临床营养食品、儿童用食品等的形态制备而成的产品。
根据本发明的另一实例,提供包含作为由所述化学式1表示的化合物的齐墩果酸乙酸酯或其药学上可接受的盐作为有效成分的用于预防或治疗由抗癌药物诱发的肾脏毒性的抗癌助剂。
所述抗癌助剂可与顺铂、卡波铂、奥沙利铂、奈达铂、阿霉素、紫杉酚、它莫西芬、盐酸贝洛替康、氟尿嘧啶、格列卫、依托泊苷、唑来膦酸、长春新碱(oncovin)等的现有抗癌药物进行组合给药,从而可降低肾脏毒性并增强抗癌功效。
根据本发明一实施例,确认到在暴露于顺铂的小鼠的情况下,体重和肾脏器官减少,诱发肾脏毒性,导致死亡率为100%,但在顺铂与齐墩果酸乙酸酯组合给药的组中,死亡率减少为44%(图2a、2b、2c)。并且,血液中的血尿素氮(BUN)值为表示作为蛋白质分解的代谢产物的血液中尿素氮的含量的血液生化指标,在给药顺铂的组中,血尿素氮(BUN)值因肾脏毒性而大大增加,但在顺铂和齐墩果酸乙酸酯组合给药的组中表现出减少情况,因此可确认到齐墩果酸乙酸酯使因顺铂而增加的血尿素氮(BUN)降低(图2d)。
在另一实施例中,在给药顺铂的组中,在血液内及肾脏组织内作为炎症细胞因子的肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)大大增加,在肾脏组织内环氧化酶-2(COX-2)及单核细胞趋化蛋白-1(MCP-1)大大增加,但在顺铂和齐墩果酸乙酸酯组合给药的组中这些表现出均降低的情况,因此可确认到齐墩果酸乙酸酯可有效抑制因顺铂而诱发的炎症反应(图3a、3b及图4a、4b、4c、4d)。
本发明还提供向患者给药药学有效量的所述齐墩果酸乙酸酯或其药学上可接受的盐的治疗由药剂诱发的肾脏毒性的方法。所述肾脏毒性的治疗是指在肾脏中所发生的如损伤的减少、改善等的治疗作用。本发明中所使用的所谓“有效量”的术语表示表现出对由药剂诱发的肾脏毒性有效的治疗作用效果的齐墩果酸乙酸酯或其药学上可接受的盐的量。
本发明还提供所述齐墩果酸乙酸酯或其药学上可接受的盐在制备用于治疗由药剂诱发的肾脏毒性的药剂中的用途。
本发明还提供用于由药剂诱发的肾脏毒性的治疗的包含所述齐墩果酸乙酸酯或其药学上可接受的盐的组合物。
本发明还提供所述齐墩果酸乙酸酯或其药学上可接受的盐在治疗由药剂诱发的肾脏毒性中的用途。
本发明还提供向患者给药药学有效量的作为所述抗癌助剂的齐墩果酸乙酸酯或其药学上可接受的盐以及药学有效量的铂类抗癌药物的治疗癌症的方法。作为抗癌助剂,齐墩果酸乙酸酯或其药学上可接受的盐降低并改善由抗癌药物诱发的肾脏毒性,从而实现癌症的有效治疗。
本发明还提供所述齐墩果酸乙酸酯或其药学上可接受的盐在抗癌助剂的制备中的用途。
本发明还提供包含用作抗癌助剂的所述齐墩果酸乙酸酯或其药学上可接受的盐的组合物。
本发明还提供用作抗癌助剂的所述齐墩果酸乙酸酯或其药学上可接受的盐的用途。
本发明的用途、组合物、治疗方法中所提及的事项在不相互矛盾的前提下相同适用。
本发明的齐墩果酸乙酸酯源自天然产物,因此无副作用且无细胞毒性,在预防、改善及治疗由药剂诱发的,尤其是由铂类抗癌药物诱发的肾脏毒性的效果显著,因而可有效利用于对其的药学组合物、健康功能食品及抗癌助剂。
更具体地,本发明的齐墩果酸乙酸酯在由铂类抗癌药物诱发急性肾衰竭的动物模型中明显妨碍用作肾功能指标的血尿素氮(BUN)值及血液炎症细胞因子值、肾脏组织内炎症因子表达量,并抑制肾脏毒性的功效突出,因此具有有效预防、改善及治疗肾脏毒性的效果。
附图说明
图1为示出在作为人胚肾脏细胞(Human embryonic kidney cell)的HEK-293T细胞(图1a)、腹膜巨噬细胞(图1b)、脾细胞(图1c)中通过细胞存活率分析(MTT assay)来进行齐墩果酸或齐墩果酸乙酸酯的细胞毒性比较评价的图形(*:p<0.05与对照组之间的显著性)。
图2为示出顺铂诱发肾脏毒性的动物实验时,将齐墩果酸乙酸酯以50mg/Kg的浓度给药之后的体重(图2a)、肾脏组织重量(图2b)、死亡率(图2c)、血液中血尿素氮(BUN)值变化(图2d)的图形(*:p<0.05与对照组之间的显著性,#:p<0.05与仅处理顺铂的组之间的显著性)。
图3为示出顺铂诱发肾脏毒性的动物实验时,将齐墩果酸乙酸酯以50mg/kg浓度给药之后的血液炎症细胞因子的肿瘤坏死因子-α(TNF-α)(图3a)、白细胞介素-6(IL-6)(图3b)的数值变化的图形(*:p<0.05与对照组之间的显著性,#:p<0.05与仅处理顺铂的组之间的显著性)。
图4为示出顺铂诱发肾脏毒性的动物实验时,将齐墩果酸乙酸酯以50mg/kg浓度给药之后的肾脏组织内炎症因子的肿瘤坏死因子-α(TNF-α)(图4a)、白细胞介素-6(IL-6)(图4b)、环氧化酶-2(COX-2)(图4c)、单核细胞趋化蛋白-1(MCP-1)(图4d)的表达量的图形(*:p<0.05与对照组之间的显著性,#:p<0.05与仅处理顺铂的组之间的显著性)。
具体实施方式
以下,通过实施例进一步详细说明本发明。但是,这些实施例仅用于示例性地说明本发明,本发明的范围并不限定于这些实施例。
实施例1:赤小豆乙醇提取物的制备及化学式1的化合物的分离纯化
实施例1-1:赤小豆提取物的制备
用水将赤小豆(赤豆或红豆)清洗干净,在阴凉处干燥之后,用美国皇庭牌(WARING)捣碎机使之粉末化。将粉末状的赤小豆20kg放入100L的甲醇中,在室温下冷浸提取3天之后,用滤纸(沃特曼公司(Whatman),美国生产)真空过滤,然后过滤提取物在室温下用真空旋转浓缩仪除去甲醇溶剂之后制备了的赤小豆提取物作为提取的残余物。
实施例1-2:分馏物的制备
为了从制备的所述赤小豆提取物中分离活性分馏物,使赤小豆提取物悬浮于1L水中并加入相同量的n-己烷进行混合、分馏,将该工序重复4次以获得了水溶性分馏物1L和n-己烷可溶性分馏物4L。接着,减压浓缩所述n-己烷可溶性分馏物并获得了n-己烷可溶性提取物50g。
并且,向所述水溶性分馏物1L中加入相同量的乙酸乙酯进行混合、分馏,将该工序重复3次以再次获得了水溶性分馏物1L和乙酸乙酯可溶性分馏物3L。
减压浓缩获得的所述乙酸乙酯可溶性分馏物,并获得乙酸乙酯可溶性提取物35g,减压浓缩剩余的水溶性分馏物以获得了35g,并将其用作水分馏物。
实施例1-3:赤小豆提取物及分馏物的高效液相色谱仪(HPLC)分析
以将所述实施例1-1及1-2中获得的各个赤小豆提取物及分馏物为对象进行了高效液相色谱仪(HPLC)分析。
在此情况下,高效液相色谱仪(HPLC)使用了美国安捷伦科技有限公司出品的1200系列(Agilent Technologies 1200series),分析柱使用了日本维美希(YMC)公司出品的J'sphere ODS-H80(YMC,4μm,4.6mm I.D.x 150mm)色谱柱。在此情况下,分析溶剂在210nm下随着以1mL/min流淌5%~90%的CH3CN进行了分析,试样注入了10μL(表1)。
表1
分别在5.5、24.5、35.5、35.5分钟处观察到儿茶酚-7-吡喃葡萄糖苷(catechin-7-glucopyranoside,catechin-7-glu)、芸香苷(rutin)、齐墩果酸乙酸酯(oleanolic acidacetate,OAA)及豆甾醇(stigmasterol)的峰值,并可确认到赤豆及红豆的高效液相色谱仪(HPLC)色谱图显示相似的模式。
实施例1-4:有效成分的纯化
利用由己烷:乙酸乙酯(100:1→1:1)构成的分步浓度梯度(step gradient)溶剂系统,将在所述实施例1-2获得的n-己烷分馏物80g适用于硅胶柱色谱法(silica gelcolumn chromatography)并获得了5个活性分馏(Fr.1-5)。在所述活性分馏中,向第3及第4分馏中加入甲醇进行重结晶工序,从而纯化了呈白色粉末状的两种化合物。
将所纯化的所述两种化合物适用于仪器分析(1H-,13C-NMR,MS)及文献值(Voutquenne L.et al.Phytochemistry 2003,64,781-789;Kongduang D.etal.Tetrahedron letters 2008,49,4067-4072)可确认分别为齐墩果酸乙酸酯(oleanolicacid acetate,化学式1)。
化学式1:齐墩果酸乙酸酯
4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydr opicene-4a-carboxylic acid acetate(4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS-10-羟基-2,2,6a,6b,9,9,12a-七甲基-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-四癸羟噻嗪-4a-羧酸乙酸酯)
实施例2:齐墩果酸及齐墩果酸乙酸酯的细胞毒性的比较评价
为了比较齐墩果酸及齐墩果酸乙酸酯的细胞毒性,利用人肾脏细胞株和小鼠腹膜巨噬细胞、脾原代(primary)细胞进行了确认。
实施例2-1:细胞株培养及原代细胞(Primary cell)的分离
在添加有热灭活的10%胎牛血清(FBS)的吉布科(Gibco)公司(美国)的达尔伯克改良伊格尔培养基(Dulbecco’s modified eagle medium,Cat No.12800-017)中培养了作为人胚肾脏细胞(Human embryonic kidney cell)的HEK-293T细胞。
为了分离小鼠腹膜巨噬细胞,给5-6周龄的美国癌症研究所(ICR)雄性小鼠(奥莱特生物(Orient bio)首尔,韩国)腹膜给药3mL的3%巯基乙酸培养基(thioglycollatemedium),3天后将6~7ml的磷酸缓冲盐溶液(PBS)向腹膜给药并按摩腹膜之后,采取腹膜液。将所收集的腹膜液进行离心分离之后,悬浮于RPMI(10%胎牛血清(FBS)、1%抗生素(antibiotics))中,移至培养板之后,在37℃温度下稳定2小时。
为了分离小鼠脾细胞,用CO2使5-6周龄的美国癌症研究所(ICR)雄性小鼠(奥莱特生物(Orient bio),首尔,韩国)致死之后,无菌摘除脾脏(spleen)。利用过滤器研磨脾脏以分离单个脾脏细胞之后,利用离心分离使之离心,利用人外周血淋巴细胞分离液(Ficoll)溶解红细胞。将已除去红细胞的细胞用洛斯维·帕克纪念研究所(RPMI)(10%胎牛血清(FBS),1%抗生素(antibiotics))培养基在37℃温度下稳定2小时。
实施例2-2:细胞毒性评价
已结束培养的细胞的生存率利用MTT还原法来进行了测定。MTT溶液可通过存活的细胞中线粒体的脱氢酶(dehydrogenases)形成甲臜(formazan)来确认细胞是否存活。为了细胞毒性的确认,在37℃温度下96孔板培养板中以5×104细胞/孔培养细胞(cell)之后,按照浓度处理齐墩果酸及齐墩果酸乙酸酯并培养了24小时。24小时后,在各个孔中添加20μL的MTT溶液再培养2小时之后,除去培养液,添加100μL的二甲亚砜(dimethylsulfoxide)之后,在570nm测定了吸光度。
实施例2-3:细胞毒性的比较分析
为了齐墩果酸及齐墩果酸乙酸酯的细胞毒性的比较评价,利用人肾脏细胞株及腹膜巨噬细胞、脾细胞来确认了细胞存活率分析(MTT assay)。其结果,在人肾脏细胞株中,齐墩果酸乙酸酯的细胞毒性浓度依赖性地小于齐墩果酸,在最大浓度1000μg/ml中的细胞存活率显示为齐墩果酸为27%,齐墩果酸乙酸酯为43%,因此确认到齐墩果酸乙酸酯诱发较少的细胞毒性(图1a)。
在从小鼠腹膜采取的腹膜巨噬细胞中,齐墩果酸浓度依赖性地表现出细胞毒性,反之,齐墩果酸乙酸酯在最大浓度1000μg/ml中也表现出81%的细胞存活率,这几乎无细胞毒性。并且,确认了齐墩果酸乙酸酯在1000μg/ml中的81%的细胞存活率为41%的齐墩果酸的细胞存活率的两倍左右(图1b)。
在摘除小鼠脾脏并进行分离的脾细胞中,所有浓度(100μg/ml、300μg/ml、600μg/ml)下,齐墩果酸乙酸酯的细胞存活率高于齐墩果酸,因此确认了诱发较少的细胞毒性(图1c)。
实施例3:利用顺铂诱发的肾脏毒性的动物模型的齐墩果酸乙酸酯的肾脏毒性抑制效果
为了确认齐墩果酸乙酸酯的顺铂诱发的肾脏毒性的抑制效果进行了动物实验。
实施例3-1:利用顺铂诱发肾脏毒性
购入体重为20-25g的8周龄C57BL/6雄性小鼠(奥莱特生物(Orient bio),首尔,韩国)随机分为生理盐水给药组(Control,CON)、齐墩果酸乙酸酯给药组(OAA)、顺铂单独给药组(CP)、顺铂及齐墩果酸乙酸酯组合给药组(CP+OAA)。为了试验,将这些小鼠饲养在恒定温度(23±3℃)、湿度(55±15%)及照射量(7:00点至19:00点)条件下进行。购买后,在无特定病原体(SPF)级动物饲养室中稳定小鼠1周之后,用于实验。顺铂(美国西格玛公司(Sigma)出品,圣路易斯(St.Louis),密苏里州(MO),美国(USA))在生理盐水中以2mg/ml浓度溶解之后,以20mg/kg的剂量腹膜给药,齐墩果酸乙酸酯溶于蒸馏水中并以50mg/ml的剂量在顺铂给药1小时之前、给药1天后、3天后、5天后进行了口服给药。所有组的小鼠在顺铂给药5天后将小鼠致死。
实施例3-2:体重、肾脏器官重量、死亡率的监测及血尿素氮(BUN)的分析
小鼠死亡后,测量体重,分离了肾脏,从心脏采血,并测定了作为与肾脏毒性有关的生化指标的血尿素氮(blood urea nitrogen,BUN)。所采取的小鼠血液利用离心分离仪在4℃温度、3000rpm下离心分离15分钟以仅将血清分离之后,利用自动分析装置(automatic analyzer)(富士全自动干式生化分析仪(Fuji Dry-Chem)NX500i,东京(Tokyo),日本(Japan))测定了血尿素氮(BUN)。
如图2a及图2b中所示,在暴露于顺铂的小鼠的情况下,体重和肾脏器官减小,因此确认了诱发肾脏毒性,如图2c观察,确认了顺铂给药组的死亡率为100%,但顺铂及齐墩果酸乙酸酯组合给药组中的死亡率减少为44%。各个组中死亡的小鼠数量除以小鼠总数量来以百分比表示了死亡率。
如图2d所示,血尿素氮(BUN)值为表示作为蛋白质分解的代谢产物的血液中尿素氮的含量的血液生化指标,血液中的血尿素氮(BUN)的提高通常意味着肾脏疾病的存在。因此,确认了在给药顺铂的组中因肾脏毒性而使血尿素氮(BUN)值大大增加,但顺铂及齐墩果酸乙酸酯组合给药的组中使所增加的血尿素氮(BUN)降低。
实施例3-3:血液内炎症细胞因子(TNF-α)、白细胞介素-6(IL-6))的测定
为了测定血液内炎症细胞因子(肿瘤坏死因子-α(TNF-α))、白细胞介素-6(IL-6)),从血液中分离血清之后来使用,利用小鼠酶联免疫吸附测定(ELISA)试剂盒(研发系统公司(R&D system)出品,明尼阿波利斯市(Minneapolis),明尼苏达州(MN),美国(USA))分析了肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)。酶联免疫吸附测定(ELISA)显色程度在450nm波长下利用VarioskanTMLUX多功能微孔板读数仪(赛默飞(Thermofisher)公司,桑尼维尔(Sunnyvale),加利福尼亚州(CA),美国(USA))进行了测定。
如图3a及图3b所示,作为血液内炎症细胞因子的肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)在顺铂给药组中大大增加,但在顺铂及齐墩果酸乙酸酯组合给药组中使所增加的肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)降低表示抑制对肾脏毒性的血液内炎症反应的效果。
实施例3-4:肾脏组织内炎症因子(肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、环氧化酶-2(COX-2)、单核细胞趋化蛋白-1(MCP-1))的表达量分析
小鼠死亡后,分离肾脏,添加Trizol试剂(英杰(Invitrogen)生命技术有限公司,卡尔斯巴德(Carlsbad),加利福尼亚州(CA),美国(USA))并使之均匀。在这里,添加氯仿并提取核糖核酸(RNA),添加异丙醇之后沉淀。核糖核酸(RNA)沉淀物用75%乙醇清洗之后,核糖核酸(RNA)的浓度和纯度利用2100生物芯片分析系统(2100Bioanalyzer system,安捷伦科技有限公司(Agilent Technologies),圣克拉拉(Santa Clara),加利福尼亚州(CA),美国(USA))进行了测定,利用Taqman逆转录试剂盒(Taqman reverse transcriptionreagents kit,应用生物系统公司(Applied Biosystems),福斯特城(Foster City),加利福尼亚州(CA),美国(USA))合成了cDNA。炎症因子的表达程度利用SYBR Green聚合酶链式反应(PCR)主混合试剂盒(SYBR Green PCR master mix kit,应用生物系统公司(AppliedBiosystems),福斯特城(Foster City),加利福尼亚州(CA),美国(USA))通过实时定量荧光聚合酶链式反应(Real-time PCR)测定。
为了确认作为炎症细胞因子的肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)、作为参与炎症反应的血管通透性增加的前列腺素E2(PGE2)合成酶的环氧化酶-2(COX-2)、作为炎症趋化因子的单核细胞趋化蛋白-1(MCP-1)的表达量,进行各个基因的实时定量荧光聚合酶链式反应(Real-time PCR)并在图4a、图4d中以图形的方式示出。如图4a、图4d中所观察,顺铂给药组中肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、环氧化酶-2(COX-2)、单核细胞趋化蛋白-1(MCP-1)信使核糖核酸(mRNA)表达量大大增加,但顺铂及齐墩果酸乙酸酯组合给药组中使所增加的信使核糖核酸(mRNA)表达量降低表示抑制对肾脏毒性的炎症反应的效果。
总结以上各个结果,可确认到齐墩果酸乙酸酯抑制由顺铂诱发的肾脏毒性,并且有效抑制各个炎症因子的表达及分泌。进而,可确认齐墩果酸乙酸酯的细胞毒性显著低于齐墩果酸且抑制肾脏毒性的效果优异,因此当适用于动物或人体时,无副作用,并且可多样化利用于对肾脏毒性的预防、改善及治疗效果优秀的药学组合物、健康功能食品、抗癌药物等。
制剂例1:散剂的制备
混合齐墩果酸乙酸酯、包含其的赤小豆提取物或所述提取物的分馏物0.1g、乳糖1.5g及滑石粉0.5g之后填充于密封包装以制备了散剂。
制剂例2:片剂的制备
混合齐墩果酸乙酸酯、包含其的赤小豆提取物或所述提取物的分馏物0.1g、乳糖7.9g、结晶纤维素1.5g及硬脂酸镁0.5g之后,通过直接压片法(direct tableting method)来制备了包含50mg有效成分的500mg的片剂。
制剂例3:粉剂的制备
均匀混合齐墩果酸乙酸酯、包含其的赤小豆提取物或所述提取物的分馏物0.1g、玉米淀粉5g及羧基纤维素4.9g以制备粉末,并向硬胶囊中放入所述粉末500mg以制备了胶囊剂。
制剂例4:注射剂的制备
根据常规的注射剂的制备方法,制备了包含齐墩果酸乙酸酯、包含其的赤小豆提取物或所述提取物的分馏物0.1g及适量的注射用灭菌蒸馏水以及pH调节剂的2mL容量的注射用安瓿。
制剂例5:液剂的制备
根据常规的液剂的制备方法,向纯净水中加入齐墩果酸乙酸酯、包含其的赤小豆提取物或所述提取物的分馏物0.1g、异构糖10g及甘露醇5g,溶解之后加入适量柠檬香味,然后混合所述的成分,加入纯净水调节至总量为100mL之后填充至棕色瓶之后灭菌以制备了液剂。
Claims (18)
1.一种用于预防或治疗由药剂诱发的肾脏毒性的药学组合物,其特征在于,包含由以下化学式1表示的化合物或其药学上可接受的盐作为有效成分,
化学式1:
2.根据权利要求1所述的药学组合物,其特征在于,诱发所述肾脏毒性的药剂为选自由顺铂、卡波铂、奥沙利铂及奈达铂组成的组中的一种以上的铂类抗癌药物或抗生素。
3.根据权利要求1所述的药学组合物,其特征在于,所述药学组合物还包含药学上可接受的载体、赋形剂或稀释剂。
4.根据权利要求1所述的药学组合物,其特征在于,所述药学组合物具有肾脏组织内的炎症因子表达抑制活性。
5.根据权利要求4所述的药学组合物,其特征在于,所述炎症因子为选自由肿瘤坏死因子-α、白细胞介素-6、环氧化酶-2及单核细胞趋化蛋白-1组成的组中的一种以上。
6.一种用于预防或改善由药剂诱发的肾脏毒性的健康功能食品,其特征在于,包含由以下化学式1表示的化合物或其食品学上可接受的盐作为有效成分,
化学式1:
7.根据权利要求6所述的健康功能食品,其特征在于,诱发所述肾脏毒性的药剂为选自由顺铂、卡波铂、奥沙利铂及奈达铂组成的组中的一种以上的铂类抗癌药物或抗生素。
8.一种用于预防或治疗由抗癌药物诱发的肾脏毒性的抗癌助剂,其特征在于,包含由以下化学式1表示的化合物或其药学上可接受的盐作为有效成分,
化学式1:
9.根据权利要求8所述的抗癌助剂,其特征在于,所述抗癌助剂与选自由顺铂、卡波铂、奥沙利铂及奈达铂组成的组中的一种以上的铂类抗癌药物组合给药。
10.根据权利要求8所述的抗癌助剂,其特征在于,所述抗癌助剂具有肾脏组织内的炎症因子表达抑制活性。
11.根据权利要求10所述的抗癌助剂,其特征在于,所述炎症因子为选自由肿瘤坏死因子-α、白细胞介素-6、环氧化酶-2及单核细胞趋化蛋白-1组成的组中的一种以上。
12.一种治疗由药剂诱发的肾脏毒性的方法,其特征在于,向患者给药药学有效量的由以下化学式1表示的化合物或其药学上可接受的盐,
化学式1:
13.一种由以下化学式1表示的齐墩果酸乙酸酯或其药学上可接受的盐在制备用于治疗由药剂诱发的肾脏毒性的药剂中的用途,
化学式1:
14.一种用于由药剂诱发的肾脏毒性的治疗的包含由以下化学式1表示的齐墩果酸乙酸酯或其药学上可接受的盐的组合物,
化学式1:
15.一种治疗癌症的方法,其特征在于,向患者给药药学有效量的作为抗癌助剂的由以下化学式1表示的齐墩果酸乙酸酯或其药学上可接受的盐以及药学有效量的铂类抗癌药物,
化学式1:
16.根据权利要求15所述的治疗癌症的方法,其特征在于,所述铂类抗癌药物为选自由顺铂、卡波铂、奥沙利铂及奈达铂组成的组中的一种以上的铂类抗癌药物。
17.一种由以下化学式1表示的齐墩果酸乙酸酯或其药学上可接受的盐在制备抗癌助剂中的用途,
化学式1:
18.一种包含用作抗癌助剂的由以下化学式1表示的齐墩果酸乙酸酯或其药学上可接受的盐的组合物,
化学式1:
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KR20030082763A (ko) * | 2002-04-18 | 2003-10-23 | 에스케이케미칼주식회사 | 관절조직 보호 작용을 갖는 생약조성물 |
KR20070026898A (ko) * | 2005-06-10 | 2007-03-09 | 안동대학교 산학협력단 | 2-알파-하이드록시-올레아놀산을 함유하는 트롬빈 저해혈전증 예방 및 치료용 조성물 |
CN103648502A (zh) * | 2011-04-29 | 2014-03-19 | 韩国生命工学研究院 | 包含齐墩果酸乙酸酯作为有效成分的预防或者治疗tlr及il-6介导疾病的药物组合物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR930021201A (ko) | 1992-04-29 | 1993-11-22 | 김규원 | 올레아놀산을 주성분으로 하는 항암제 |
JP5466842B2 (ja) | 2008-10-29 | 2014-04-09 | ポーラ化成工業株式会社 | グルタチオン産生促進組成物 |
KR101737277B1 (ko) * | 2016-10-04 | 2017-05-18 | 한국생명공학연구원 | 올레아놀린산 아세테이트를 유효성분으로 포함하는 약제에 의해 유발되는 신장독성의 예방, 개선 또는 치료용 조성물 |
-
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-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20030082763A (ko) * | 2002-04-18 | 2003-10-23 | 에스케이케미칼주식회사 | 관절조직 보호 작용을 갖는 생약조성물 |
KR20070026898A (ko) * | 2005-06-10 | 2007-03-09 | 안동대학교 산학협력단 | 2-알파-하이드록시-올레아놀산을 함유하는 트롬빈 저해혈전증 예방 및 치료용 조성물 |
CN103648502A (zh) * | 2011-04-29 | 2014-03-19 | 韩国生命工学研究院 | 包含齐墩果酸乙酸酯作为有效成分的预防或者治疗tlr及il-6介导疾病的药物组合物 |
Non-Patent Citations (2)
Title |
---|
KI HYUN YOO等: "3-O-Acetyloleanolic Acid Induces Apoptosis in Human Colon Carcinoma Hct-116 Cells", 《PHYTOTHER.RES.》 * |
PRAGNESH J. MANIYA等: "NEPHROPROTECTION BY OLEANOLIC AND URSOLIC ACID AGAINST CISPLATIN IS COMPARABLE TO AMIFOSTINE", 《WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES》 * |
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EP3524239A1 (en) | 2019-08-14 |
US20200046728A1 (en) | 2020-02-13 |
JP2019533657A (ja) | 2019-11-21 |
JP2021054838A (ja) | 2021-04-08 |
EP3524239A4 (en) | 2020-06-03 |
KR101737277B1 (ko) | 2017-05-18 |
JP6861806B2 (ja) | 2021-04-21 |
US11464787B2 (en) | 2022-10-11 |
WO2018066954A1 (ko) | 2018-04-12 |
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