CN116474079A - 包含萝卜硫苷的组合物及其用途 - Google Patents
包含萝卜硫苷的组合物及其用途 Download PDFInfo
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- CN116474079A CN116474079A CN202310458458.0A CN202310458458A CN116474079A CN 116474079 A CN116474079 A CN 116474079A CN 202310458458 A CN202310458458 A CN 202310458458A CN 116474079 A CN116474079 A CN 116474079A
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- Prior art keywords
- glucoraphanin
- sulforaphane
- disease
- composition
- broccoli
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Classifications
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Abstract
本发明涉及一种包含萝卜硫苷的组合物,所述组合物包含提供萝卜硫苷的组分1、提供黑芥子酶的组分2及碱性盐化合物,所述组合物具有良好的稳定性,克服了现有技术中存在的萝卜硫苷含量降低、产品变色和味道变苦等问题。本发明还涉及所述组合物的制药用途。
Description
技术领域
本发明属于生物医药领域,具体地涉及一种包含萝卜硫苷的组合物,本发明还涉及所述组合物在制备用于预防和/或治疗可利用萝卜硫素预防和/或治疗的疾病或病症的产品中的用途。
背景技术
根据世界卫生组织2014年度报告,癌症是全球发病和死亡的主要原因,对人民生命健康造成巨大威胁,给社会发展带来了沉重的经济负担。在对抗癌症的漫长过程中,人们于1976年提出了癌症化学预防的概念,是指利用天然的或者合成的化学物质来预防、减缓或逆转癌症发生发展的策略。
萝卜硫素(Sulforaphane,SFN),又称莱菔硫烷,化学名为1-异硫氰酸-4-甲磺酰基丁烷,属于异硫氰酸酯类,是美国约翰·霍普金斯大学的Paul Talalay从西兰花中发现的一种具有预防癌症能力的生物活性物质,是迄今为止蔬菜中发现的最强的抗癌成分。针对萝卜硫素的分子作用机理研究及细胞实验结果进一步显示,萝卜硫素通过调控II相酶活性对I相酶代谢物或外来物进行代谢脱毒等多种途径起到与癌症化学预防相同或相似的作用(Myzak MC,DashwoodRH.CancerLett.,2006,233:208-18.)。已知萝卜硫素是一种Nrf2(NF-E2相关因子2,一种细胞调节抗氧化应激反应的转录因子)诱导剂,主要作用机制是激活Nrf2信号通路,诱导Ⅱ相酶(NQO1、谷胱甘肽巯基转移酶、γ-谷氨酰半胱氨酸合成酶、葡萄糖醛酸基转移酶等)的表达,调控抗氧化剂反应元件等。现有技术公开了萝卜硫素及其前体化合物萝卜硫苷的多种活性和作用,例如作为化学保护剂对胃溃疡、幽门螺杆菌感染的作用(CN1935003A;CN1170472C;CN101208079B)。已知Nrf2是调节许多解毒酶和抗氧化剂酶的表达的转录因子。已知萝卜硫素和萝卜硫苷是针对革兰氏阳性细菌和革兰氏阴性细菌和酵母的抗微生物活性。此外,已经证明它们对帕金森氏病发挥保护作用(在小鼠模型中)并且它们尤其是还具有利尿、抗贫血和通便性质。对莱菔硫烷的作用机制的分子基础的调查表明萝卜硫素和萝卜硫苷通过刺激II相解毒酶间接地充当抗氧化剂。此外,作为莱菔硫烷类化合物的萝卜硫素和萝卜硫苷还证实具有紫外线辐射保护作用,由此避免晒伤、由ROS(活性氧)引起的退化和皮肤癌的发生(Talalay P.;Fahey J.W.;Healy Z.R.;Wehage S.L.;BenedictA.L.;Min C.;Dinkova-Kostova A.T.PNAS,2007,104,17500-17505;CN104284885B)。近年来已证明因子Nrf2在生长因子调控、信号传导和组织修复(具体地,由氧化应激诱导的肝再生)中具有重要作用(Beyer T.;Xu W.;Teupser D.;Keller U.;Bugnon P.;Hildt E.;Thiery J.;YuetWai K.;Werner S.The EMBO Journal,2008,27,212-223)。
总之,基于上述机制,已发现和证实作为异硫氰酸酯的萝卜硫素具有多种与其II相酶调节作用和Nrf2激活作用相关的活性和功能。随着研究的不断深入,人们发现萝卜硫素除了癌症化学预防领域的作用外,还对包括糖尿病、心血管疾病、幽门螺旋杆菌感染、自闭症、精神分裂症、抑郁症、阿尔茨海默病(Alzheimer disease,AD)等在内的多种疾病也具有预防和/或治疗的作用,并在动物试验与临床试验中得到了验证。例如,萝卜硫素可以减少2型糖尿病患者的肝糖产生量,改善血糖控制(AxelssonAS,Tubbs E,Mecham B,etal.Sci TranslMed.,2017,9(394));能够减轻小鼠血管炎症,阻止TNF-α诱导的单核细胞对原代上皮细胞的黏附(Nallasamy P,Si H,Babu PV,et al.JNutrBiochem.,2014,25(8):824-33.);抑制幽门螺旋杆菌在小鼠和人类的胃部定殖,减轻感染引发的胃部炎症(YanakaA,Fahey JW,Fukumoto A,et al.Cancer Prev Res(Phila).,2009,2(4):353-60.);临床试验中能逆转自闭症相关的异常症状,包括氧化应激、低抗氧化能力、受抑制的谷胱甘肽合成、减弱的线粒体功能与氧化磷酸化作用、增强的脂质过氧化和神经炎症(Singh K,Connors SL,Macklin EA,et al.ProcNatlAcadSci USA,2014,111(43):15550-5.);能够改善精神分裂症患者的认知功能(Shiina A,Kanahara N,Sasaki T,et al.ClinPsychopharmacol Neurosci.,2015,13(1):62-7.);饮食摄入富含萝卜硫素的西兰花芽苗对抑郁症有预防作用(Zhang JC,Yao W,Dong C,et al.JNutrBiochem.,2017,39:134-144.);给予萝卜硫素可改善β-淀粉样蛋白(amyloidβ-protein,Aβ)诱导的急性AD小鼠模型在Y迷宫和被动回避行为测试中的认知功能(Kim HV,Kim HY,Ehrlich HY,etal.Amyloid.,2013,20(1):7-12.)。此外,韩丽等报道了萝卜硫素通过Nrf2途径对于减轻肺纤维化的作用(韩丽,江涛,《中国新药与临床杂志》,2016第12期)。已经知道,十字花科植物是萝卜硫素及其前体化合物萝卜硫苷的主要来源。西兰花是提供萝卜硫素及其前体化合物萝卜硫苷来源的优选的十字花科植物。西兰花又名绿花菜、青花菜等,为十字花科芸苔属植物。已知在西兰花种子和芽苗(嫩芽)中前体萝卜硫苷含量相对更高。即便如此,要想通过食用西兰花来摄入有效量的萝卜硫素仍是不现实的。因此,有必要通过对西兰花进行提取,通过其提取物实现其有效的生物效能。
另一方面,西兰花中含的是没有生物活性的萝卜硫素前体,即萝卜硫苷,需要植物中所含的黑芥子酶分解萝卜硫苷,才能使其转化成有活性的萝卜硫素。黑芥子酶主要存在于十字花科植物中。在一定的条件下,黑芥子酶可以将硫代葡萄糖苷分解,生成包括有生物活性的异硫代氰酸盐在内的产物。但是,我们发现,即使用黑芥子酶将西兰花中的萝卜硫素前体萝卜硫苷预先转化为萝卜硫素,但产品中的萝卜硫素对氧气、对热都不稳定,因此也很难保存和使用。
本发明人发现,如果将黑芥子酶和萝卜硫苷原料分别制成固体形式以预混合物的形式提供,则可以避免保存过程中酶对萝卜硫苷的分解,而在加水服用或口服后可以在溶液环境中实现酶的分解作用,并实现对萝卜硫素的有效吸收。
然而,在研究过程中,意外的是,即使固体形式存在的黑芥子酶和萝卜硫苷原料(包括以西兰花和/或其提取物形式存在的原料)的混合物,在储存和放置过程中仍存在稳定性问题,表现在萝卜硫苷含量降低,并且还导致产品外观变色、味道变苦等影响产品质量的问题。
因此,现有技术中仍需要克服包含萝卜硫苷和黑芥子酶之组合物的稳定性问题,提供一种稳定的、质量令人满意的包含萝卜硫苷和黑芥子酶的组合物。
发明内容
本发明人在研究中出乎意料地发现:如果向包含萝卜硫苷和黑芥子酶的组合物中添加碱性盐化合物,可以很好地改善组合物的稳定性,同时保持外观和味道的稳定。
基于此发现,在本发明的第一个方面,提供了一种组合物,包含以下组分:(1)提供萝卜硫苷的组分1;
(2)提供黑芥子酶的组分2;和
(3)碱性盐化合物。
在本发明中,所述提供萝卜硫苷的组分1可以是能够提供萝卜硫苷化合物来源的任何物质或原料。优选地,所述提供萝卜硫苷的组分1选自十字花科植物、其提取物及其混合物。所述十字花科植物优选选自西兰花(broccoli)、花椰菜(cauliflower)、红甘蓝(redcabbage)、球芽甘蓝(Brussels sprouts)或卷心菜,特别优选西兰花。所述十字花科植物可以是植物的全部或一部分,例如全植株、其地上部分、花球、芽苗、种子或其组合。所述提供萝卜硫苷的组分1还可以是十字花科植物的提取物,例如溶剂提取物,优选水提取物、醇提取物、水醇提取物。除了十字花科植物的植物组织、提取物及其混合物以外,本发明的提供萝卜硫苷的组分1还可以包括化学合成、半化学合成、酶法合成的萝卜硫苷。
在本发明中,所述提供黑芥子酶的组分2可以是能够提供黑芥子酶来源的任何物质或原料。优选地,所述提供黑芥子酶的组分2选自十字花科植物、其提取物及其混合物。优选地,所述提供黑芥子酶的组分2选自辣根、萝卜和甘蓝。在一些优选的实施方案中,所述提供黑芥子酶的组分2选自辣根、萝卜和甘蓝的提取物;在另一些优选的实施方案中,所述提供黑芥子酶的组分2选自辣根、萝卜和甘蓝的汁液或浆液,或者所述汁液或浆液经干燥得到的粉末。
在本发明中,所述西兰花意指西兰花植物的全部或其一部分。优选地,所述西兰花选自通常意义的可食用部分;更优选地,所述西兰花选自西兰花花球、西兰花种子和西兰花芽苗,以及其组合。
在本发明中,所述西兰花提取物意指所述西兰花植物的全部或其一部分的提取物,包括但不限于所述西兰花、西兰花花球、西兰花种子和/或西兰花芽苗的提取物。在另一方面,所述提取物为利用溶剂进行提取得到的提取物,所述提取物优选为水提取物、醇提取物或水醇提取物,特别优选为水提取物。
在本发明中,所述提供萝卜硫苷的组分1优选选自西兰花花球、西兰花种子、西兰花芽苗、西兰花提取物及其混合物。
在本发明中,所述碱性盐化合物可以是碱性的无机酸盐或有机酸盐,优选选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸钠、柠檬酸钠、焦磷酸钾、柠檬酸钾及其混合物。优选地,所述碱性盐化合物意指使本发明组合物与水混合后溶液呈碱性(优选具有大于7.8、8.0、8.2或8.6的pH值)的盐类化合物。
在本发明中,所述组分1、组分2和碱性盐化合物的质量比为10-80:1-80:0.1-1;优选10-50:1-50:0.1-0.5,更优选为10-30:1-20:0.1-0.5。优选地,所述组分1、组分2和碱性盐化合物的质量比为使得萝卜硫苷、黑芥子酶和碱性盐化合物的质量比为1-4:1-10:0.1-0.3的各组分质量比。
在一些优选的实施方案中,本发明的组合物还包含抗坏血酸。
本发明的组合物优选为固体形式,例如,可以为粉末、颗粒、胶囊或片剂的制剂形式。更优选地,在本发明的组合物中,所述组分1、组分2和碱性盐化合物均以固体形式存在。例如,所述组分1可以是提取物、芽苗或种子的粉末(包括冻干粉)形式。
在一些优选的实施方案中,本发明的组分1选自西兰花种子提取物、西兰花芽苗粉、西兰花花球冻干粉及其混合物。
在另一方面,本发明提供了本发明所述的组合物在制备用于预防和/或治疗可利用萝卜硫素预防和/或治疗的疾病或病症的产品中的用途。所述产品可以是药品或食品。优选地,所述产品是药品。在一些优选的实施方案中,所述利用萝卜硫素预防和/或治疗相关的疾病或病症选自癌症、糖尿病、心血管疾病、幽门螺旋杆菌感染、自闭症、精神分裂症、抑郁症、阿尔茨海默病(Alzheimer disease,AD)和肺纤维化。
在又一方面,本发明提供了一种将萝卜硫苷体外转化为萝卜硫素的方法,包括以下步骤:
1)提供如本发明所述的组合物,
2)将所述组合物与水或含水溶液混合。
在另一方面,本发明还提供了一种向有此需要的对象补充萝卜硫素的方法,包括向所述对象施用如本发明所述的组合物。
本发明人发现,通过向组合物中添加碱性盐化合物,可以避免产品中萝卜硫苷含量的降低,并有效改善组合物的稳定性,同时保持外观和味道的稳定。
具体实施方式
实施例1:
(1)本发明组合物1的制备:将720g西兰花种子水提物(含萝卜硫苷13.0%,来自美国Brassica Protection Products LLC,下同)与296g辣根粉和10g碳酸钠混合均匀,得到1.03kg组合物1,其中萝卜硫苷占9.09%。将上述组合物1按每袋5g的重量分装进小袋包装中,得到对应的粉剂产品。
(2)对照组合物1的制备:将720g西兰花种子水提物(含萝卜硫苷13.0%)与296g辣根粉混合均匀,得到1.02kg对照组合物1,其中萝卜硫苷占9.18%。将上述对照组合物1按每袋5g的重量分装进小袋包装中,得到对应的粉剂产品。
(3)加速实验:将上述两种粉剂产品在加速实验箱中于37摄氏度和75%相对湿度下放置3个月后取出打开,观察外观变化并按以下方法检测萝卜硫素生成率。
分别取1.03g组合物1与1.02g对照组合物1(均含有萝卜硫苷93.6mg),加入到30mL水中于37℃保温模拟冲泡条件,分别于5min、8min和30min时取样通过HPLC测定其中萝卜硫素含量,计算萝卜硫素生成率。
萝卜硫素的HPLC测定方法:取样品溶液,过0.45μm滤膜,进行HPLC分析。HPLC条件:色谱柱:华普公司Unitary C18(4.6mm×250mm,5μm);柱温:30℃;流动相:70%水-30%乙腈;流速:0.8mL/min;进样量:10μL;紫外检测波长:245nm。
实验结果见下表1。
表1.组合物1和对照组合物1粉剂产品的萝卜硫素生成率比较
从实验结果可见,相比于不含碱性盐的对照组合物1而言,含碱性盐的本发明组合物1在加速实验后外观、味道无明显变化,萝卜硫素生成率保持较好。加速实验前后萝卜硫素生成率基本不变,这表明了水解后组合物中萝卜硫苷含量相对于水解前几乎没有变化。
实施例2:
(1)本发明片剂1的制备:将200g西兰花芽苗水提物(含萝卜硫苷13.0%)与200g辣根粉、4g维生素C、10g磷酸钠及其596g其他压片辅料(具体组成为淀粉、麦芽糊精、羟丙甲基纤维素,比例(w/w)为5:80:2,下同)混合均匀,按0.6g/片的片重压片,包薄膜衣,得到约1.02kg本发明片剂1,其中萝卜硫苷占2.57%。将上述本发明片剂1按每瓶60片分装进瓶中并加干燥剂后密封瓶口,得到对应的片剂产品。
(2)对照片剂1的制备:将200g西兰花芽苗水提物(含萝卜硫苷13.0%)与200g辣根粉、4g维生素C及其596g其他压片辅料混合均匀,按0.6g/片的片重压片,包薄膜衣,得到约1.01kg对照片剂1,其中萝卜硫苷占2.6%。将上述本发明片剂1按每瓶60片分装进瓶中并加干燥剂后密封瓶口,得到对应的片剂产品。
(3)加速实验:将上述两种片剂产品在加速实验箱中于37摄氏度和75%相对湿度下放置3个月后取出打开,观察外观变化并按以下方法检测其萝卜硫素生成率。
各片剂预先取出30g磨碎后,分别取1.02g本发明片剂1粉末与1.01g对照片剂1粉末(均含有萝卜硫苷26mg),加入到30mL餐后人工胃液模拟液(按2015版《中国药典》二部附录方法配制人工胃液,调节pH为3.5)中,于37℃保温,分别于30min和60min时取样通过HPLC测定其中萝卜硫素含量,计算萝卜硫素生成率。萝卜硫素的HPLC测定方法同实施例1。
实验结果见下表2。
表2.本发明片剂1和对照片剂1的萝卜硫素生成率比较
从实验结果可见,相比于不含碱性盐的对照片剂1而言,含碱性盐的本发明片剂1在加速实验后外观、味道无明显变化,萝卜硫素生成率亦保持较好,加速实验后萝卜硫素生成率明显高于对照片剂。
实施例3:
(1)本发明片剂2的制备:将200g西兰花种子水提物(含萝卜硫苷13.0%)、50g西兰花芽苗粉(含萝卜硫苷4.5%)、50g西兰花花球冻干粉与250g辣根粉、4g维生素C钙、10g柠檬酸钠及596g其他压片辅料混合均匀,按0.6g/片的片重压片,得到约1.16kg本发明片剂2,其中萝卜硫苷占2.80%。将上述片剂按每瓶60片分装进瓶中并加干燥剂后密封瓶口,得到对应的片剂产品。
(2)对照片剂2的制备:将200g西兰花种子水提物(含萝卜硫苷13.0%)、50g西兰花芽苗粉(含萝卜硫苷4.5%)、50g西兰花花球冻干粉与250g辣根粉、4g维生素C钙及596g其他压片辅料混合均匀,按0.6g/片的片重压片,得到约1.15kg对照片剂2,其中萝卜硫苷占2.83%。将上述片剂按每瓶60片分装进瓶中并加干燥剂后密封瓶口,得到对应的片剂产品。
(3)加速实验:将上述两种片剂产品在加速实验箱中于37摄氏度和75%的相对湿度下放置3个月后取出打开,观察外观变化并按以下方法检测其萝卜硫素生成率。
各片剂预先取出100g磨碎后,分别取1.16g本发明片剂2粉末与1.15g对照片剂2粉末(均含有萝卜硫苷28mg),加入到30mL餐后人工胃液模拟液(按2015版《中国药典》二部附录方法配制人工胃液,调节pH为3.5)中,于37℃保温,分别于30min和60min时取样通过HPLC测定其中萝卜硫素含量,计算萝卜硫素生成率。萝卜硫素的HPLC测定方法同实施例1。
实验结果见下表3。
表3.本发明片剂2和对照片剂2的萝卜硫素生成率比较
从实验结果可见,相比于不含碱性盐的对照片剂2而言,含碱性盐的本发明片剂2在加速实验后外观、味道无明显变化,萝卜硫素生成率亦保持较好,加速实验后萝卜硫素生成率明显高于对照片剂。
应理解,虽然通过优选实施方案具体地公开了本发明,但是本领域技术人员可以采用本文所公开的内容所体现的本发明的任选特征、修改、改进和变化,认为这些修改、改进和变化在本发明的范围内。本文所提供的作为示例性优选实例方案的材料、方法和实施例是示例性的,并且不旨在限制本发明的范围。
Claims (10)
1.一种固体形式组合物,包含以下组分:
1)提供萝卜硫苷的组分1;
2)提供黑芥子酶的组分2;和
3)碱性盐化合物。
2.如权利要求1所述的固体形式组合物,其还包含抗坏血酸。
3.如权利要求1或2所述的固体形式组合物,其中所述组分1选自十字花科植物、其提取物及其混合物;优选地,所述十字花科植物为西兰花;更优选地,所述十字花科植物选自花球、种子、芽苗及其混合物。
4.如权利要求1至3中任一项所述的固体形式组合物,其中所述碱性盐化合物选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、焦磷酸钠、柠檬酸钠、焦磷酸钾、柠檬酸钾及其混合物;优选地,所述组分1、组分2和碱性盐化合物的质量比为10-80:1-80:0.1-1。
5.如权利要求1至4中任一项所述的组合物,其为粉末、颗粒、胶囊或片剂的制剂形式;和/或所述组分1选自西兰花种子提取物、西兰花芽苗粉、西兰花花球冻干粉及其混合物;和/或所述组分2选自辣根、萝卜、甘蓝;其汁液或浆液;以及其提取物。
6.如权利要求1至5中任一项所述的组合物在制备用于预防和/或治疗可利用萝卜硫素预防和/或治疗的疾病或病症的产品中的用途;优选地,所述可利用萝卜硫素预防和/或治疗的疾病或病症选自癌症、糖尿病、心血管疾病、幽门螺旋杆菌感染、自闭症、精神分裂症、抑郁症、阿尔茨海默病和肺纤维化。
7.一种将萝卜硫苷体外转化为萝卜硫素的方法,包括以下步骤:
1)提供如权利要求1至5中任一项所述的组合物,
2)将所述组合物与水或含水溶液混合。
8.一种向有此需要的对象补充萝卜硫素的方法,包括向所述对象施用如权利要求1至5中任一项所述的组合物。
9.包含萝卜硫苷与黑芥子酶的组合物在制备用于预防和/或治疗可利用萝卜硫素预防和/或治疗的疾病或病症的产品中的用途;优选地,所述可利用萝卜硫素预防和/或治疗的疾病或病症选自癌症、糖尿病、心血管疾病、幽门螺旋杆菌感染、自闭症、精神分裂症、抑郁症、阿尔茨海默病和肺纤维化。
10.包含萝卜硫苷的固体形式组合物在制备用于预防和/或治疗可利用萝卜硫素预防和/或治疗的疾病或病症的产品中的用途;优选地,所述可利用萝卜硫素预防和/或治疗的疾病或病症选自癌症、糖尿病、心血管疾病、幽门螺旋杆菌感染、自闭症、精神分裂症、抑郁症、阿尔茨海默病和肺纤维。
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