CN102670588B - 鞣花酸用于制备抗病毒药物的应用 - Google Patents
鞣花酸用于制备抗病毒药物的应用 Download PDFInfo
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Abstract
本发明公开了一种鞣花酸用于制备抗病毒药物的应用，所述病毒为单纯疱疹病毒和人乳头瘤病毒。本发明还公开了一种以鞣花酸为活性成分的药物组合物。本发明为鞣花酸的应用开辟了一条新的途径。
Description
技术领域
本发明属于生物医药领域，具体地说，是关于一种鞣花酸用于制备抗病毒药物的应用。
背景技术
鞣花酸（Ellagic acid）是存在于众多水果和蔬菜中的天然酚类抗氧化剂。黑莓、覆盆子、草莓、蔓越莓、五倍子、山核桃、石榴、枸杞等植物内鞣花酸含量较高。鞣花酸具有多种生物活性功能，如抗氧化功能、抗癌、抗突变、抗菌、降压、镇静等作用，对人体免疫缺陷病毒、乙肝病毒HBV、小鼠疱疹病毒、鸟的成髓细胞瘤的逆转录病毒有抑制作用。此外，研究发现，鞣花酸还能抑制HPV18的E7蛋白的表达以及诱导HPV16阳性细胞Caski的凋亡（J.Agr Food Chem,1987,35:808-812;Phytochemistry,1988,27:1315-1320;Antibiotixs,1989,42:107-115;BioorgMed Chem Lett,1993,3(2):225-230;Antiviral Research,2006,72(2):100-106;Journal of Virology,2009,83(11):5630-5639;Cancer Lett,1999,136(2):215-21）。
单纯疱疹病毒HSV（Herpes simplex virus）属于疱疹病毒科a病毒亚科，根据抗原性的差别分为1型和2型（HSV-1和HSV-2），可引起口唇性疱疹、疱疹性角膜炎、疱疹性皮肤炎、阴部疱疹、卡波西病等，有时也是脑膜炎、脑炎的病因，HSV-1常引起腰部以上感染，尤其眼及口腔部位的感染，HSV-1也能引起生殖器疱疹（10%），HSV-2是生殖器疱疹的主要病原体（90%），可通过胎盘及产道感染新生儿，导致流产及新生儿死亡，与宫颈癌的发生也有关，危害较大。
人乳头瘤病毒HPV（Human papillomavirus）是一种属于乳多空病毒科的乳头瘤空泡病毒A属，是球形DNA病毒，人是它唯一的宿主，HPV与多种疾病有关，分为许多亚型，按其对组织恶性转化程度不同，可分为高危型、中危型和低危型三类。HPV与其他病原体不同，它并不引起炎症性反应，而是促发宿主细胞的增殖，呈肿瘤性生长，可导致恶性肿瘤的发生，如皮肤癌、舌癌等，上个世纪末，国际上已确认宫颈上皮HPV的慢性感染是宫颈癌的病因，此外HPV常会引起人类的各种疣，如寻常疣、扁平疣、跖疣、甲缘疣及尖锐湿疣等。尖锐湿疣是我国最主要的性病之一，至少有10个类型与其有关，其中又以HPV6、11型最常见，目前的治疗方式很难直接从病毒入手，因此治标不治本。
至今为止，尚未发现鞣花酸具有抑制人的单纯疱疹病毒及直接破坏人乳头瘤病毒6和11型DNA作用的文献。
发明内容
本申请的发明人在长期的研究中发现，鞣花酸对2型单纯疱疹病毒（HSV-2）和人乳头瘤病毒（HPV6/11）均有较强的抑制作用。
因此，本发明的目的在于提供一种鞣花酸用于制备抗病毒药物的应用。
根据本发明，所述病毒为单纯疱疹病毒和人乳头瘤病毒。
根据本发明的优选实施例，所述单纯疱疹病毒为单纯疱疹病毒2型，所述人乳头瘤病毒为人乳头瘤病毒6型和11型。
本发明还提供了一种药物组合物，该药物组合物以鞣花酸为活性成分。
根据本发明，所述药物组合物包括治疗有效量的鞣花酸和一种或多种可药用载体。
本发明为鞣花酸的应用开辟了一条新的途径。
具体实施方式
本发明的问世部分是基于这样一个意外发现：鞣花酸在体外可显著抑制人乳头瘤病毒6和11（HPV6/11）和单纯疱疹病毒2型（HSV-2），因而可以用于制备抗病毒药物。
本发明的上下文中，术语“治疗有效量”是指能够达到治疗效果的提取物的量。本领域的专业人员能够理解“治疗有效量”可以随着给药的方式、载体的使用以及可能和其他治疗剂合用等而有所不同。
根据本发明，鞣花酸可以单独使用或以药物组合物的形式使用。药物组合物以本发明的鞣花酸为活性成分，包括治疗有效量的鞣花酸以及一种或多种可药用载体。“可药用载体”不会破坏本发明的鞣花酸的药学活性，同时其有效用量，即能发挥药物载体作用时的用量对人体无毒。
所述可药用载体包括但不限于：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂（如微晶纤维素）、填充剂（如淀粉、葡萄糖、无水乳糖和乳糖珠粒）、崩解剂（如交联PVP、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素）、润滑剂（如硬脂酸镁）以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
以下结合具体实施例对本发明作进一步说明，但并不意味着本发明仅限于此。
以下实施例中所使用的鞣花酸为市售产品。
实施例1、鞣花酸对HSV-2病毒的抑制作用
实验材料：
细胞：非洲绿猴肾细胞（Vero），购自中科院细胞库。
病毒：单纯疱疹病毒HSV-2型Sm333标准毒株，由北京中国医学科学院医药生物技术研究所提供。
受试药物：鞣花酸，溶解于DMSO中，制备得60mg/mL母液。
阳性对照：阿昔洛韦（ACV，购自湖北科益药业股份有限公司）。
实验方法：
Vero细胞按常规方法培养于含10%FBS的DMEM培养基中，次日，以1×105/孔接种于96孔板，单层培养24小时后，吸弃上清液、洗涤，加入10TCID50的病毒液，吸附2小时后，吸去病毒，加入不同浓度的药液，培养72小时后观察CPE（病变），设细胞对照组、病毒对照组、阳性对照组、实验药物组，同时观察CPE，抑制病变超过50%的，计算IC50。
实验结果如以下表1所示：
表1、鞣花酸对HSV-2的抑制作用
以上表1的实验结果表明，在Vero细胞中，鞣花酸对HSV-2病毒具有明显抑制作用，且鞣花酸对HSV-2的抑制呈剂量依赖关系。
实施例2、鞣花酸对HPV6、11型病毒的抑制作用
实验材料：
HPV6/11型病毒来源：HPV6、11型病毒取自未经治疗的尖锐湿疣病人的疣体，经生理盐水清洗后在无菌条件下研磨成组织匀浆备用。
受试药物：鞣花酸，溶解于DMSO中，制备得60mg/mL母液。
主要仪器：ABI 7500荧光定量PCR仪。
HPV6/11型FQ-PCR诊断试剂盒：中山大学达安基因股份有限公司。
实验方法：
取尖锐湿疣组织匀浆液100uL，加入受试药物10uL，对照管则加入生理盐水10uL，每次实验同时设阴性及阳性对照管，37℃孵育24小时。
按试剂盒方法提取DNA，取2uL加入反应管中，放入ABI 7500荧光定量PCR仪进行反应，定量结果由电脑软件自动分析，计算其初始拷贝数。
实验结果如以下表2和表3所示：
表2、鞣花酸对HPV6/11抑制的剂量依赖效应
由表2的结果可见，尖锐湿疣组织匀浆液在加入50ug/mL的鞣花酸20小时后，HPV6/11已检测不出，而空白对照管具有很高浓度的HPV病毒量，说明鞣花酸具有快速有效地杀灭尖锐湿疣病毒的作用，且鞣花酸对HPV6/11的杀灭作用呈剂量依赖关系，而且鞣花酸对HPV病毒的杀灭作用可能是通过破坏HPV6/11的DNA而起效。
表3、鞣花酸对HPV6/11抑制的时间依赖效应
以上结果表明，鞣花酸在50ug/mL的浓度下，0.5小时即可完全杀灭HPV6/11，显示其破坏HPV6/11病毒DNA的速度相当快。
实施例3、片剂的制备
片剂组成：
将鞣花酸、HPMCLVIOO、乳糖混匀，以75%乙醇制软材，24目筛制粒，50℃干燥3小时，18目筛整粒，加入硬脂酸镁混匀压片，制成1000片，每片0.1g。
实施例4、胶囊剂的制备
胶囊组成：
将鞣花酸、淀粉、硬脂酸镁混匀，装胶囊，共1000粒，每粒0.1g。
实施例5、注射剂的制备
注射液组成：
鞣花酸，加入10%碳酸钠调PH值至7.0~7.5，冷藏过滤，加入吐温80和尼泊金乙酯，加注射用水至1000mL，滤过，分装，灌封，100℃流通蒸汽灭菌，30min即得。
本发明的鞣花酸可以单独使用或以药物组合物的形式使用。药物组合物以本发明的鞣花酸为活性成分，包括治疗有效量的鞣花酸以及一种或多种可药用载体。这对于本领域的技术人员来说是显而易见的。
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明精神之前提下，本领域专业人员可对其进行等同改变和修饰，所述改变和修饰同样落入本申请所附权利要求的覆盖范围。
Claims (2)
1.鞣花酸作为唯一活性成分用于制备抗病毒药物的应用，其特征在于，所述病毒为单纯疱疹病毒2型和人乳头瘤病毒。
2.如权利要求1所述的应用，其特征在于，所述人乳头瘤病毒为人乳头瘤病毒6型和11型。
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