CN114025754A - 花青素-阴离子多糖复合物用于预防或治疗甲型流感病毒感染的用途 - Google Patents
花青素-阴离子多糖复合物用于预防或治疗甲型流感病毒感染的用途 Download PDFInfo
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- CN114025754A CN114025754A CN202080046672.XA CN202080046672A CN114025754A CN 114025754 A CN114025754 A CN 114025754A CN 202080046672 A CN202080046672 A CN 202080046672A CN 114025754 A CN114025754 A CN 114025754A
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- influenza
- anthocyanin
- anionic polysaccharide
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Abstract
本发明涉及一种花青素‑阴离子多糖复合物用于预防或治疗甲型流感病毒感染的用途以及,更具体地,涉及一种药物组合物、食品/保健功能性食品/保健辅助食品组合物和准药品组合物,其各自包含花青素‑阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。本发明提供的包含花青素‑阴离子多糖复合物作为活性成分的组合物对甲型流感病毒表现出优异的抗病毒活性,因此在开发用于预防或治疗甲型流感病毒感染引起的疾病的药剂方面具有非常有利的应用。
Description
相关申请的交叉引用
本申请要求于2019年6月25日提交的韩国专利申请号10-2019-0075991的权益,其通过引用以其全文并入本文。
技术领域
本发明涉及一种花青素-阴离子多糖复合物用于预防或治疗甲型流感病毒感染的用途以及,更具体地,涉及一种药物组合物、食品组合物和准药品组合物,其各自包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
背景技术
流感是由正粘病毒科流感病毒引起的急性呼吸道疾病。流感病毒是单链RNA病毒,根据核蛋白(NP)和基质抗原的抗原性分为甲型、乙型和丙型三种类型,并且根据血凝素(HA)的类型分为16个亚型(H1-H16),血凝素(HA)是从病毒包膜中突出的糖蛋白,以及根据神经氨酸酶的类型进一步分为9个亚型(N1-N9)。血凝素是最重要的抗原决定簇,它与宿主细胞表面的唾液酸受体结合以促进病毒侵入宿主。神经氨酸酶通过从宿主细胞去除唾液酸来催化病毒粒子分离,并防止病毒粒子聚集,从而使新产生的病毒易于释放。此外,病毒膜蛋白中少量存在的M2蛋白发挥离子通道作用以控制病毒内部的pH值,从而使病毒RNA暴露于宿主细胞中。
其中,甲型流感是人畜共患传染性病原体,其可感染动物和人,具有强传染性,造成全球大流行,并在人类历史上造成大量伤亡。西班牙流感在1918年至1920年间具有高度传染性并席卷欧洲,造成约4000万人死亡,成为历史上最致命的流感。2009年3月,新型甲型H1N1流感病毒在全球蔓延,造成10,000多人死亡。在韩国,这导致超过860,000例确诊病例和270人死亡。此外,根据国家循证医疗保健合作机构的一项研究,估计每年有2,370人死于季节性流感。
作为针对流感病毒的预防方法的疫苗开发需要具有高安全性水平的设施和获得高产量的技术。此外,由于需要根据病毒蛋白突变进行另外的研究从而开发需要大量时间,并因此需要相当大的成本。除了疫苗开发之外,还已开发抗病毒剂并将其用作抗病毒治疗。常用的抗病毒剂包括金刚烷胺、金刚乙胺、扎那米韦和奥司他韦。金刚烷胺和金刚乙胺通过抑制M2蛋白的活性而具有抗病毒活性,奥司他韦和扎那米韦通过抑制病毒外膜中存在的神经氨酸酶而具有抗病毒活性。然而,最近报道了对这些抗病毒剂具有抗性的流感病毒,并且由于抗病毒剂的生产期和许可问题,它们的使用受到限制。此外,最常用的奥司他韦具有严重呕吐的副作用。扎那米韦虽然具有较高的抗病毒作用,但存在生物利用度低和肾脏排泄快的缺点。
迄今为止开发的大多数抗流感剂均具有副作用。因此,迫切需要开发基于天然产物的甲型流感病毒感染疾病的治疗剂,其对流感的预防和治疗有效但无副作用。
发明内容
因此,本发明人反复深入研究以开发基于天然产物的甲型流感病毒感染疾病治疗剂。结果,本发明人发现通过使用具有优异药理活性的花青素和带负电荷的多糖形成复合物,可以提高花青素的稳定性,从而进一步抑制甲型流感病毒的感染,从而完成本发明。
本发明的目的是提供一种药物组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或治疗甲型流感病毒感染疾病。
本发明的另一个目的是提供一种食品组合物、保健功能性食品组合物或保健补充食品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或改善甲型流感病毒感染疾病。
本发明的另一个目的是提供一种准药品(quasi-drug)组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防甲型流感病毒感染。
本发明的另一个目的是提供一种用于预防或治疗甲型流感病毒感染疾病的方法,所述方法包括以治疗有效量向哺乳动物施用药物组合物的步骤,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病,所述哺乳动物包括人。
本发明的另一个目的是提供一种药物组合物用于制备用于甲型流感病毒感染疾病的制剂的用途,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
本发明的另一个目的是提供一种药物组合物用于治疗甲型流感病毒感染疾病的用途,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
为实现上述目的,本发明提供了一种药物组合物,包含花青素-阴离子多糖复合物作为活性成分预防或治疗甲型流感病毒感染疾病。
本发明还提供了一种食品组合物、保健功能性食品组合物或保健补充食品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或改善甲型流感病毒感染疾病。
本发明还提供了一种准药品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防甲型流感病毒感染。
本发明还提供了一种用于预防或治疗甲型流感病毒感染疾病的方法,所述方法包括以治疗有效量向哺乳动物施用药物组合物的步骤,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病,所述哺乳动物包括人。
本发明还提供了一种药物组合物用于制备用于甲型流感病毒感染疾病的制剂的用途,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
此外,本发明提供了一种药物组合物用于治疗甲型流感病毒感染疾病的用途,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
具体实施方式
下文详细说明本发明。
一种药物组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或治 疗甲型流感病毒感染疾病
本发明提供了一种药物组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或治疗甲型流感病毒感染疾病。
在本发明中,“花青素”是存在于植物中的水溶性色素糖苷,是指根据细胞液的酸浓度、色素化合物的化学结构以及与各种金属离子的结合状态而呈现颜色(例如紫色、红色和蓝色)的天然植物色素。最近,已知花青素具有多种生理活性,例如,已鉴定抗衰老活性、抗菌活性、诱变抑制活性、降低胆固醇活性、视力改善作用、血管保护功能和抗溃疡功能。
本发明中,所述花青素可以从植物分离和提取,也可以化学合成。该植物可以包括产生花青素的任何植物,例如,可以是黑米、黑豆、黑醋栗(black currant)、苦莓(chokeberry)、黑苦莓、蔓越莓、野樱莓、桑葚、樱桃、覆盆子、蓝莓、黑莓、茄子、巴西莓、野生葡萄或葡萄,优选为野樱莓。
在本发明中,对所述花青素的种类没有特别限制,可以选自由以下项组成的组中的至少一种:芍药素、矢车菊素3-阿拉伯糖苷、矢车菊素-3-(木糖基葡萄糖)-5-半乳糖、矢车菊素-3-木糖苷、矢车菊素3-葡萄糖苷、矢车菊素3-半乳糖苷、矢车菊素-3-(香豆酰基-木糖基葡萄糖)-5-半乳糖、飞燕草素3-葡萄糖苷、飞燕草素3-芸香糖苷、芍药素3-阿拉伯糖苷、芍药素3-半乳糖苷、矮牵牛素3-葡萄糖苷、矢车菊素、飞燕草素、锦葵素、天竺葵素、芍药素、矢车菊素3,5-二葡萄糖苷、矢车菊素3-芸香糖苷、天竺葵素3-葡萄糖苷、芍药素3-葡萄糖苷、锦葵素3-葡萄糖苷和锦葵素3,5-二葡萄糖苷。
在本发明中,对所述阴离子多糖并没有特别限制,只要其具有生物相容性即可,并且可以包括一个或更多个带负电荷的官能团。术语“多糖”是指两个或更多个单糖分子的聚合物,其中单糖可以相同或不同。本发明的多糖可以交联或不交联。
本发明的复合物可以通过使用阴离子多糖本身形成,或通过对不含或含有少量带负电荷的官能团的常规多糖进行化学修饰以赋予带负电荷的官能团形成。带负电荷的官能团可以是,例如,一个或两个或更多个羧基或硫酸基(sulfate group)。
在具体的实例中,所述阴离子多糖可以选自由以下项组成的组:透明质酸、邻硫酸化透明质酸(邻硫酸化HA)、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角质素、肝素、硫酸肝素、海藻酸、岩藻多糖、角叉菜胶、其混合物和其复合物,优选为海藻酸,但并不总是限于此。
阴离子多糖是食品和饮料中经常使用的材料,不仅对人体无害,但在中性溶液中也带有很强的负电荷,使其与带正电荷的花青素有效离子键合形成复合物。
对多糖没有特别限制,但其重均分子量可以在约1,000至1,000,000的范围内,优选在约10,000至300,000的范围内,更优选在20,000至50,000的范围内。
在本发明的阴离子多糖中,可以通过利用多糖的负电荷的种类和数量调节与花青素的离子键合比来控制花青素的包封率。因此,只要是带负电荷的多糖,就可以根据目的使用一种或更多种具有不同分子量的多糖。复合物中花青素与阴离子多糖的重量比可以为1:1至100,优选为1:1至50,更优选为1:1至10,最优选为1:5至10。在上述范围内,由本发明的多糖形成的复合物在提高花青素的稳定性和生理活性方面可以表现出有利的效果。
花青素在低pH值下具有高稳定性,并且已知它具有最高稳定性和最高抗氧化活性,尤其是在pH 3或更低的情况下。此外,由于花青素在pH 3或更低时具有正电荷,因此它可以通过与具有生物相容性的阴离子多糖经由离子键形成复合物而在结构上稳定。由于花青素-阴离子多糖纳米复合物具有优异的氧化稳定性和储存稳定性,当它应用于药品或食品时,可能改善加工条件和储存性能。此外,当使用复合物时,由于稳定性增强,可以增加体内吸收,这可能对药物开发非常有用。
在本发明中,复合物的尺寸可以在10nm至1000μm的范围内,并且花青素可以被多糖包封,但并不总是限于此。根据使用目的或领域,根据本发明的花青素-多糖复合物可以是混悬液或粉末。
在一些情况下,花青素-多糖复合物可以进一步包括生物相容的或生物可降解的载体。在这种情况下,花青素-多糖复合物在载体中或载体的一部分中,并且该载体可以是脂质体、胶束或聚合囊泡。
在本发明的复合物的最优选形式中,阴离子多糖可以是海藻酸,其重均分子量在20,000至50,000范围内,并且该花青素可以是矢车菊素糖苷,优选为矢车菊素-3-半乳糖苷、矢车菊素-3-葡萄糖苷、矢车菊素-3-阿拉伯糖苷和/或矢车菊素-3-木糖苷。
该矢车菊素糖苷可以与阴离子多糖通过离子键结合形成复合物。
本发明中,对花青素-阴离子多糖复合物的制备方法没有特别限制,但其可以通过包括以下步骤的方法制备:
(i)在酸性环境中形成花青素-阴离子多糖复合物;和/或
(ii)回收上述形成的复合物。
在另一个实施方案中,用于制备花青素-多糖复合物的方法可以包括以下步骤:
(iii)在中性或酸性环境中形成花青素-阴离子多糖复合物。
形成花青素-阴离子多糖复合物时,对溶剂没有特别限制,但可食用的溶剂更佳。将多糖和花青素按适当比例制备后,将两种溶液搅拌均匀,在约4℃下待复合物完全形成。
根据剂型在口服制剂的情况下,通过上述(i)的方法形成的复合物可以保持在酸性环境,但当用作注射剂时,优选通过(ii)的方法中和pH值。
使用(i)和(iii)的方法之间的差异取决于形成复合物的多糖具有的官能团类型。例如,(i)和(iii)两种方法均可以用于具有硫酸基的多糖,因为它们的pKa值低,但是对于具有羧基的多糖,适合采用(iii)的方法。虽然(i)的方法可用于具有羧基的多糖,但必须通过(ii)的过程才能与花青素稳定地形成复合物。
在本发明中,对甲型流感病毒的类型没有特别限制,其可以是H1N1、H1N2、H2N2、H3N2、H5N1、H5N6或H7N9,优选为H1N1。更优选地,在本发明中,甲型流感病毒可以是H1N1 A/California/O4/09或A/California/7/2009,并且最优选为H1N1A/California/7/2009。
根据本发明的实施方案,花青素-海藻酸复合物表现出显著抗病毒有效性,即,与花青素或海藻酸单独使用相比,对甲型流感病毒具有协同作用。另一方面,已确证花青素-海藻酸复合物对乙型流感病毒没有任何协同作用。
在本发明中,甲型流感病毒感染疾病可以为流感、感冒、咽喉炎、支气管炎、肺炎、禽流感、猪流感或羊流感,优选为流感、感冒、喉咽炎、支气管炎或肺炎。
同时,在本说明书中,“包含作为活性成分”意指包括足以实现花青素-阴离子多糖复合物的有效性或活性的量。在本发明的一个实施方案中,本发明的组合物中的花青素-阴离子多糖复合物为,例如,0.001mg/kg或更多,优选为0.1mg/kg或更多,更优选为10mg/kg或更多,甚至更优选为100mg/kg或更多,更优选为250mg/kg或更多,并且最优选为0.1g/kg或更多。由于花青素-阴离子多糖复合物是天然产物并且即使过量施用也没有副作用,本领域技术人员可以在适当的范围内选择本发明的组合物中所含的花青素-带负电荷的多糖复合物的量的上限。
除了活性成分之外,本发明的药物组合物还可以使用药学上合适的和生理学上可接受的佐剂进行制备。作为佐剂,可以使用辅料、崩解剂、甜味剂、粘合剂、包衣剂、膨胀剂、润滑剂、助滑改性剂或调味剂。
除了上述施用的活性成分之外,该药物组合物可以优选地通过包括一种或更多种药学上可接受的载体来配制成药物组合物。
药学上可接受的载体为本领域常用的载体,例如乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、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、硬脂酸镁和矿物油,但并不总是限于此。此外,本发明的药物组合物可以另外包括稀释剂或辅料,例如填充剂、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂,以及其他药学上可接受的添加剂。
药物组合物的制剂可以是颗粒剂、粉剂、片剂、包衣片剂、胶囊剂、栓剂、溶液剂、糖浆剂、汁剂、混悬剂、乳剂、滴剂或可注射液。例如,对于片剂或胶囊形式的制剂,活性成分可以与口服的、无毒的、药学上可接受的惰性载体(例如乙醇、甘油、水等)组合。此外,如有需要或必要,合适的粘合剂、润滑剂、崩解剂和显色剂也可包括在混合物中。合适的粘合剂包括淀粉、明胶、天然糖类(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶例如阿拉伯树胶、黄蓍胶(tracacanth)或油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等,但并不总是限于此。崩解剂包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等,但并不总是限于此。
在配制为液体溶液的组合物中,药学上可接受的载体是无菌且生物相容性的,并且可以通过将盐水、无菌水、林格氏溶液、缓冲盐水、白蛋白注射液、葡萄糖溶液、麦芽糊精溶液、甘油、乙醇和一种或更多种这些组分混合而使用。如有必要,可以添加其他常规添加剂,例如抗氧化剂、缓冲剂和抑菌剂。此外,本发明的组合物可以通过与稀释剂、分散剂、表面活性剂、粘合剂和润滑剂混合而配制成不同的形式,包括注射用水溶液、混悬剂和乳液剂,丸剂,胶囊剂,颗粒剂或片剂。
该组合物可以进一步根据成分按照Remington制药科学,Mack出版公司,EastonPA(Remington’s Pharmaceutical Science,Mack Publishing Company,Easton PA)中的方法制备成合适的形式。
本发明的药物组合物可以口服或肠胃外施用,并且在肠胃外施用的情况下,可以通过静脉内注射、皮下注射、肌内注射、腹腔注射、透皮施用等施用,但优选口服施用。
在本发明中,术语“口服施用”是通过口腔注射缓解病理症状的药物的方法。在本发明中,术语“肠胃外施用”是指除了口服施用之外,使用管进行皮下、肌内、静脉内或腹腔施用的方法。
本发明的药物组合物可以向哺乳动物(例如大鼠、小鼠、家畜和人)口服施用。
对于肠胃外施用的制剂,无菌水溶液、液体、非水溶液、混悬剂、乳剂、滴眼剂、眼膏、糖浆剂、栓剂、外用制剂(例如气雾剂)和无菌注射剂可以通过常规方法制备,并且优选可以制备皮肤外用药物组合物,例如乳膏、凝胶、贴剂、喷雾剂、软膏、硬膏、洗剂、搽剂、糊剂或巴布剂(cataplasm),但并不总是限于此。根据临床处方,用于局部施用的组合物可以是无水的或水性的。除了活性化合物之外,非水溶液和混悬剂还可以含有丙二醇、聚乙二醇、植物油(如橄榄油)、注射用酯(如乙醇酸酯)等。除了活性化合物之外,栓剂还可以含有witepsol、聚乙二醇、吐温61、可可脂、月桂脂、甘油明胶等。
本发明的药物组合物的合适剂量取决于以下因素:制剂方法、施用方法、年龄、体重、性别、病理状况、食物、施用时间、施用途径、排泄率和患者的反应敏感性。普通专科医生可以很容易地确定和开具用于期望治疗或预防的有效剂量。根据本发明的优选实施方案,本发明的药物组合物的日剂量为0.001-10g/㎏。
本发明的药物组合物可以由本领域技术人员通过使用药学上可接受的载体和/或辅料以单位剂量或多剂量容器的形式进行配制。制剂可以是油或水溶性介质中的溶液剂、混悬剂或乳液剂,提取物,粉剂,颗粒剂,片剂或胶囊的形式。此时,可以另外包括分散剂或稳定剂。
一种食品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或改 善甲型流感病毒感染疾病
本发明还提供了一种食品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或改善甲型流感病毒感染疾病。
在本发明中,术语“改善”是指通过向受试者施用或摄取本发明的组合物来提高恶病质的不良状态的任何作用。
根据本发明的食品组合物可以以与药物组合物相同的方式配制并用作功能性食品或添加至各种食品中。例如,本发明的组合物可以添加至饮料、酒精饮料、零食、减肥棒、乳制品、肉类、巧克力、比萨、拉面、其他面条、口香糖、冰淇淋、维生素复合物、保健补充品等。
本发明的食品组合物不仅可以包括花青素-阴离子多糖复合物作为活性成分,还可以包括食品生产过程中常添加的成分,例如蛋白质、碳水化合物、脂肪、营养素、调味料和调味剂。上述碳水化合物可以是以下项中的一种:单糖,例如葡萄糖和果糖;二糖,麦芽糖、蔗糖和寡糖;多糖,例如糊精和环糊精,以及葡萄糖醇,例如木糖醇、山梨糖醇和赤藓糖醇。此外,可以包括天然甜味剂(奇异果甜蛋白、甜菊提取物,例如莱鲍迪苷A、甘草甜素等)和合成甜味剂(糖精、阿斯巴甜等)作为甜味剂。例如,当将本发明的食品组合物制备为饮品或饮料时,除了本发明的花青素-阴离子多糖复合物之外,可以另外包括柠檬酸、高果糖玉米糖浆、糖、葡萄糖、乙酸、苹果酸、果汁和各种植物提取物。
本发明提供一种含有食品组合物的保健功能性食品或保健补充食品,该食品组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或改善甲型流感病毒感染疾病。所述保健功能性食品或保健补充食品是指根据保健功能性食品法,采用对人体有益的原料或成分生产和加工而成的食品。术语“功能性”是指为了获得有益于健康目的的效果例如调节人体结构和功能所需的营养物质或生理效果而摄入。在本发明中,保健功能性食品是通过向食品原料(例如饮料、茶、香料、口香糖、零食等)中添加花青素-阴离子多糖复合物而制成的食品,或通过将花青素阴离子多糖复合物制成胶囊、粉剂、混悬剂等。在摄入上述食品的情况下,可带来特定的健康效果,而且与常规药物不同,没有通过采用食品作为原料而长期服用药物时可能出现的副作用。以这种方式获得的本发明的保健功能性食品或保健补充食品非常有用,因为它可以每天服用。
此类保健功能性食品或保健补充食品中花青素-阴离子多糖复合物的添加量根据目标保健功能性食品的种类而异,而不能统一规定,但可以在不影响食品原味的范围内添加。具体地,复合物的添加量通常为目标食品的0.01至50重量%,并且优选为0.1至20重量%。此外,在保健功能性食品或保健补充食品以丸剂、颗粒剂、片剂或胶囊剂形式的情况下,其添加量通常为0.1至100重量%,并且优选为0.5至80重量%。在本发明的一个实施方案中,本发明的保健功能性食品或保健补充食品可以以丸剂、片剂、胶囊或饮料的形式。
本发明的食品组合物可以包括常规食品添加剂。是否适合作为“食品添加剂”根据食品药品安全部批准的《食品添加剂法典》的通则和通用检测方法,根据相关条款的规范和标准进行判断,除非另有规定。
《食品添加剂法典》中列出的条款包括,例如,化学化合物,例如酮类、甘氨酸、柠檬酸钾、烟酸和肉桂酸;天然添加剂,柿子色素、甘草提取物、结晶纤维素、高粱色素和瓜尔胶;以及混合制剂,例如L-谷氨酸钠制剂、面条用碱添加剂、防腐剂和焦油色素制剂。
此外,为了预防和/或改善甲型流感病毒感染疾病,本发明的食品组合物可以以片剂、胶囊剂、粉剂、颗粒剂、液体剂和丸剂的形式生产和加工。
例如,片剂形式的保健功能性食品可以通过将包含根据本发明的花青素-阴离子多糖复合物作为活性成分的药物组合物、辅料、粘合剂、崩解剂和其他添加剂的混合物以常规方式制粒,然后通过添加润滑剂压缩成型进行制备。可选地,混合物可以直接压缩成型。此外,片剂形式的保健功能性食品可以含有增味剂等,并且必要时可以用合适的包衣剂进行包衣。
在胶囊形式的保健功能性食品中,硬胶囊可以通过用包含根据本发明的花青素-阴离子多糖复合物作为活性成分的药物组合物和辅料的混合物、其颗粒剂或其包衣颗粒剂填充常规硬胶囊进行制备。软胶囊可以通过用根据本发明的食品组合物和添加剂(例如辅料)的混合物填充胶囊基质(例如明胶)进行制备。
丸剂形式的保健功能性食品可以通过使用合适的方法将包含根据本发明的花青素-阴离子多糖复合物作为活性成分的药物组合物、辅料、粘合剂、崩解剂等的混合物成型进行制备。如有必要,丸剂可以用蔗糖或其他合适的包衣剂进行包衣,或可以用淀粉、滑石粉或合适的材料进行包衣。
颗粒形式的保健功能性食品可以通过使用适当的方法将包含根据本发明的花青素-阴离子多糖复合物作为活性成分的药物组合物、辅料、粘合剂、崩解剂等的混合物制粒进行制备,并且如有必要,可以含有调味剂、增味剂等。当使用12号(1680μm)、14号(1410μm)和45号(350μm)筛进行粒度检测时,保健功能性食品颗粒的总量通过12号筛,14号筛上保留保健功能性食品颗粒总量的5.0%或更少,并且保健功能性食品颗粒总量的15.0%或更少通过45号筛。
辅料、粘合剂、崩解剂、润滑剂、增味剂、调味剂等的术语定义在本领域已知的文献中描述并且包括具有相同或相似功能的那些(韩国药典,Moonsung Publishing Co.,韩国药学教育协会,第5版,第33-48页,1989)。
对本文的食品没有特别限定,广义上几乎可以包括所有的保健功能性食品。
一种准药品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防甲 型流感病毒感染
本发明还提供了一种准药品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防甲型流感病毒感染。
即,根据本发明的花青素-阴离子多糖复合物可以添加至用于预防甲型流感病毒感染目的的准药品中。当本发明的组合物用作准药品添加剂时,该组合物可以单独添加或与其他准药品或准药品成分一起使用,并且可以根据常规方法适当使用。活性成分的混合量可以根据使用目的适当确定。
在本发明中,术语“准药品”是指用于治疗、缓解或预防人或动物疾病的纺织品、橡胶制品等中的一种;非对人体作用较弱或不直接作用于人体的装置、机器等;以及用于杀菌、杀虫和类似用途以防止感染的制剂。也指用于诊断、治疗、缓解或预防人或动物疾病的仪器、机器或装置以外的物品;以及用于在药理学上影响人或动物结构和功能的仪器、机器或装置以外的物品。
在本发明中,准药品具体可以是过滤涂层剂、洗手液、消毒清洁剂、沐浴露、湿纸巾、洗洁皂、加湿器填料、面罩或空气清新剂,但并不总限于此。
在本发明中,准药品组合物可以应用于气相过滤器并用作抗病毒过滤器。
在本发明中,术语“气相过滤器”是指用于去除空气中的微生物和灰尘以防止有害物质或污染物(例如微生物和灰尘)从外部流入,并防止过滤器二次污染的过滤器。因此,根据本发明的气相过滤器可用作汽车的气相过滤器、家用电器的气相过滤器、空调的气相过滤器、防毒面具的气相过滤器、空气净化器的气相过滤器、或洁净室的气相过滤器,优选可用作空气净化器的气相过滤器。
作为过滤器基材,可以使用金属、塑料、无纺布、薄膜等。作为空气净化器的气相过滤器,可以优选使用具有高孔隙率的无纺布,但并不总是限于此。
为了生产气相过滤器,首先制备根据本发明的用于预防流感病毒感染的准药品组合物。优选将用于预防流感病毒感染的准药品组合物溶解或稀释于某种溶剂中,以溶液的形式使用,以制备气相过滤器。作为溶剂,可以使用水、乙醇、甲醇、丁醇或正己烷、正庚烷、DMSO或它们的混合溶剂。
过滤器基材涂覆有用于预防流感病毒感染的准药品组合物。作为涂覆方法,可以使用通过将在其外侧具有吸收性构件(例如海绵)的辊浸入组合物中来涂覆过滤器基材,然后将辊在过滤器基材上滚动并干燥以涂覆基材的方法,通过将其直接浸入组合物中并干燥来涂覆过滤器基材的方法,或通过将组合物喷涂到过滤器基材上并使其干燥而涂覆过滤器基材的方法。
除了本发明的组合物之外,过滤器可以进一步包括现有的抗菌物质、除臭剂(例如,黄酮类化合物、植物杀菌素、木醋液、植物提取物、环糊精、金属离子、二氧化钛等)或集尘过滤器。
一种用于预防或治疗甲型流感病毒感染疾病的方法
本发明提供了一种用于预防或治疗甲型流感病毒感染疾病的方法,该方法包括以治疗有效量向哺乳动物(包括人)施用药物组合物的步骤,该药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
在本说明书中,术语“治疗有效量”是对预防或治疗由甲型流感病毒引起的感染疾病有效的量,例如,向待治疗的受试者施用用于预防或治疗甲型流感病毒感染疾病的量的包含花青素-阴离子多糖复合物作为活性成分的药物组合物。治疗有效量包括预防由甲型流感病毒引起的感染疾病发生或复发的量、减轻症状的量、抑制直接或间接病理后果的量、预防转移的量、降低进展速度的量、缓解或暂时改善状态的量,以及包含花青素-阴离子多糖复合物作为改善预后的活性成分的药物组合物用于预防或治疗甲型流感病毒感染疾病的量。即,治疗有效量可以解释为涵盖通过包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病的药物组合物改善或治愈甲型流感病毒感染疾病症状的所有量。
预防或治疗由甲型流感病毒引起的感染疾病的方法不仅包括在症状出现之前控制疾病本身,还可以通过施用包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病的药物组合物以抑制或避免症状。在疾病的管理中,特定活性成分的预防或治疗剂量可以根据疾病的性质和严重程度以及活性成分的施用途径而变化。剂量和施用频率可以根据个体患者的年龄、体重和反应而变化。考虑这些因素,本领域普通技术人员可以容易地选择合适的剂量方案。此外,本发明的预防或治疗方法可以进一步包括将治疗有效量的用于预防或治疗由甲型流感病毒引起的感染疾病的另外的活性剂与包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病的药物组合物一起施用。另外的活性剂可以与包含花色苷-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病的药物组合物表现出协同或叠加作用。
哺乳动物(包括人)包括哺乳动物例如人、猴、牛、马、犬、猫、兔和大鼠。
一种药物组合物用于预防或治疗甲型流感病毒感染疾病的用途
本发明提供了一种药物组合物用于制备用于甲型流感病毒感染疾病的制剂的用途,该药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
本发明提供了一种药物组合物用于治疗甲型流感病毒感染疾病的用途,该药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
用于制备甲型流感病毒感染疾病的制剂的本发明的包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病的药物组合物可以与可接受的载体等混合,并且可以进一步包括其他激动剂。
本发明的药物组合物、食品组合物、准药品组合物、预防或治疗方法和用途中提及的那些,只要它们不相互矛盾,则同样适用。
有益效果
本发明提供的包含花青素-阴离子多糖复合物作为活性成分的组合物对甲型流感病毒表现出优异的抗病毒活性,因此发现在开发用于预防或治疗由甲型流感病毒感染引起的疾病的药剂中具有非常有利的应用。
附图说明
图1是显示使用DLS装置测量花青素-海藻酸复合物粒子大小的结果的一组图(ATC:花青素,ATC/Alg复合物:花青素-海藻酸复合物)。
图2是显示使用分光光度计确证花青素-海藻酸复合物粒子形成的结果的一组图(ATC:花青素,ATC/Alg复合物:花青素-海藻酸复合物)。
图3是显示使用分光光度计确证花青素-海藻酸复合物粒子随时间的稳定性的结果的一组图(ATC:花青素,ATC/Alg复合物:花青素-海藻酸复合物)。
图4是显示通过空斑减少测定确证花青素-海藻酸复合物对甲型流感病毒(H1N1)的抑制作用的结果图。
图5是显示通过空斑减少测定确证花青素-海藻酸复合物对乙型流感病毒的抑制作用的结果图。
优选实施方案的描述
下文将通过以下实施例详细描述本发明。
然而,以下实施例仅用于说明本发明,而本发明的内容不限于此。
实施例1:花青素-阴离子多糖纳米复合物的制备
通过将野樱莓的生果粉碎,用多酚吸附树脂吸附汁液,经乙醇水溶液洗脱并将其粉碎后得到花青素。将20mg上述制备的花青素粉末在40℃下溶解于5ml磷酸盐缓冲液(pH3,PB 3)中,并在室温下将200mg海藻酸(阴离子多糖)溶解于10ml去离子水(D.I水)中。通过将花青素溶液加入海藻酸溶液(1:1,V/V)中,然后在室温下搅拌48小时,制备花青素-阴离子多糖纳米复合物。
实施例2:花青素-阴离子多糖纳米复合物的粒径测量
使用动态光散射(DLS)测量装置Zeta sizer Nano Zs(Malvern InstrumentsLtd,UK)测量实施例1中制备的花青素-海藻酸纳米复合物的粒度分布。作为使用DLS测量装置测量花青素-海藻酸纳米复合物粒径的结果,复合物粒径为约360nm。由于海藻酸(-50±1.66mV)与花青素(2.3±1.01mV)形成复合物,海藻酸的负电荷强度降低,复合物的ζ电位为-26.4±1.17mV(图1)。
实施例3:花青素-阴离子多糖纳米复合物形成的确证
将1ml实施例1中制备的复合物放入UV比色皿中,通过分光光度计确证花青素的最大吸收波长带。将溶解于PB 3/D.I水(1:1体积)中的花青素溶液也进行与上述相同的过程,并且溶液颜色和最大吸收波长带的变化确证复合物形成。
结果,观察到花青素-海藻酸复合物由花青素的阳离子度和海藻酸的阴离子度构建的离子键形成,花青素的最大吸光度由于π-π向更长的波长移动。花青素分子之间的相互作用,因此形成复合物的样品呈淡紫色。因此,确证形成花青素-海藻酸复合物(图2)。
实施例4:花青素-阴离子多糖纳米复合物随时间的稳定性确证
使用分光光度计确证花青素的量以确证实施例1中制备的复合物随时间的稳定性。将40ml的花青素-海藻酸复合物以13000rpm离心30分钟,并将沉淀分散于PBS(pH 3或pH7.4)中。此外,花青素通过将其溶解在PBS(pH 3或pH 7.4)中进行制备。使用分光光度计分别在513nm或520nm的每个波段测量分散在PBS(pH 3或pH 7.4)中的复合物和花青素的吸光度,观察花青素吸光度值的变化。
结果确证花青素在低pH环境(pH 3)中具有稳定性。具体地,在低pH值环境(pH3)下76小时后,该复合物含有高于18.7%的花青素并且更加稳定。由于随pH值的增加发生分解,因此在pH 7.4下花青素的最大吸光度在4小时内显著下降,而复合物的吸光度轻微下降。4小时后,确证花青素和复合物以相似的速度下降。作为以百分比表示花青素的最大吸光度的结果,发现在pH 7.4下4小时内花青素所含的花青素比复合物少42.5%。因此,确证该复合物比花青素具有更高的稳定性(图3)。
实施例5:花青素-阴离子多糖纳米复合物对细胞内病毒感染抑制作用的确证
为了确证实施例1中制备的花青素-海藻酸复合物的抗病毒作用,进行流感病毒的空斑减少测定。首先,制备装有单层MDCK细胞的12孔细胞培养皿。将制备的花青素-海藻酸复合物与甲型流感病毒(A/California/07/2009,H1N1)浓缩混合后,各取0.1mL置于装有MDCK细胞的12孔细胞培养皿中,并使细胞感染病毒1小时30分钟。作为对比组,形成复合物的海藻酸和花青素也以相同的浓度以与上述相同的方式进行。1小时30分钟后,每孔加入1.5mL含无血清DMEM的1%琼脂糖凝胶并硬化。将细胞在37℃,5%CO2培养箱中培养72小时后,将细胞固定液(甲醇:醋酸=3:1)和结晶紫溶液(1:1)混合,各取2mL置于固体凝胶上染色24小时。取出并清洗孔中的凝胶后,计算未染色部分的空斑数。对乙型流感病毒进行相同的方法。使用奥司他韦作为阳性对照。
空斑数量减少表示具有感染性的病毒数量减少。
如图4所示,花青素从1μg/ml或更高的浓度对甲型流感病毒显示出显著抗病毒作用,而海藻酸是维持花青素稳定性的物质,没有显示出抗病毒作用。在花青素-海藻酸复合物处理组的情况下,确证即使在各单药施用组几乎未显示出作用的浓度组合(海藻酸0.5μg/ml+花青素0.1μg/ml)下也可显著抑制甲型流感病毒。由以上结果确证,花青素-海藻酸复合物对甲型流感病毒的抗病毒作用具有协同作用。特别是花青素-海藻酸复合物对甲型流感病毒的抗病毒作用即使在较低浓度下也明显优于用作阳性对照的奥司他韦。
如图5所示,与甲型流感病毒不同,海藻酸在一定浓度或更高浓度下对乙型流感病毒显示出抗病毒作用,花青素在1μg/ml或更高浓度下也显示出约50%的抗病毒作用。在花青素-海藻酸复合物处理组的情况下,未出现海藻酸与花青素联合使用的协同作用,而花色苷-海藻酸复合物处理仅表现出与花青素单独处理相似的抗病毒作用。
工业适用性
本发明提供的包含花青素-阴离子多糖复合物作为活性成分的组合物对甲型流感病毒表现出优异的抗病毒活性,因此发现在开发用于预防或治疗由甲型流感病毒感染引起的疾病的药剂中具有非常有利的应用。
Claims (14)
1.一种药物组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或治疗甲型流感病毒感染疾病。
2.根据权利要求1所述的药物组合物,其中所述阴离子多糖含有硫酸基或羧基。
3.根据权利要求1所述的药物组合物,其中所述阴离子多糖为选自由以下项组成的组中的至少一种:海藻酸、透明质酸、邻硫酸化透明质酸(邻硫酸化HA)、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素、岩藻多糖、角叉菜胶、其混合物和其复合物。
4.根据权利要求1所述的药物组合物,其中所述花青素为选自由以下项组成的组中的至少一种:芍药素、矢车菊素3-阿拉伯糖苷、矢车菊素-3-(木糖基葡萄糖)-5-半乳糖、矢车菊素-3-木糖苷、矢车菊素3-葡萄糖苷、矢车菊素3-半乳糖苷、矢车菊素-3-(香豆酰基-木糖基葡萄糖)-5-半乳糖、飞燕草素3-葡萄糖苷、飞燕草素3-芸香糖苷、芍药素3-阿拉伯糖苷、芍药素3-半乳糖苷、矮牵牛素3-葡萄糖苷、矢车菊素、飞燕草素、锦葵素、天竺葵素、芍药素、矢车菊素3,5-二葡萄糖苷、矢车菊素3-芸香糖苷、天竺葵素3-葡萄糖苷、芍药素3-葡萄糖苷、锦葵素3-葡萄糖苷和锦葵素3,5-二葡萄糖苷。
5.根据权利要求1所述的药物组合物,其中所述花青素-阴离子多糖复合物通过包括以下步骤的方法制备:
(a)在酸性环境中形成花青素-阴离子多糖复合物;和
(b)回收上述形成的复合物。
6.根据权利要求1所述的药物组合物,其中所述甲型流感病毒为H1N1亚型。
7.根据权利要求1所述的药物组合物,其中所述甲型流感病毒感染疾病为流感、感冒、咽喉炎、支气管炎、肺炎、禽流感、猪流感或羊流感。
8.根据权利要求1所述的药物组合物,其中所述复合物中花青素与阴离子多糖的重量比为1:1至100。
9.一种食品组合物、保健功能性食品组合物或保健补充食品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防或改善甲型流感病毒感染疾病。
10.一种准药品组合物,包含花青素-阴离子多糖复合物作为活性成分,以用于预防甲型流感病毒感染。
11.根据权利要求10所述的准药品组合物,其中所述准药品为气相过滤器、过滤涂层剂、洗手液、消毒清洁剂、沐浴露、湿纸巾、洗洁皂、加湿器填料、面罩或空气清新剂。
12.一种用于预防或治疗甲型流感病毒感染疾病的方法,所述方法包括以治疗有效量向哺乳动物施用药物组合物的步骤,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病,所述哺乳动物包括人。
13.一种药物组合物用于制备用于甲型流感病毒感染疾病的制剂的用途,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
14.一种药物组合物用于治疗甲型流感病毒感染疾病的用途,所述药物组合物包含花青素-阴离子多糖复合物作为活性成分以用于预防或治疗甲型流感病毒感染疾病。
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