CN110755456A - 美洲大蠊提取物与抗真菌药物组成的抗真菌药物组合物 - Google Patents
美洲大蠊提取物与抗真菌药物组成的抗真菌药物组合物 Download PDFInfo
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- CN110755456A CN110755456A CN201911196266.7A CN201911196266A CN110755456A CN 110755456 A CN110755456 A CN 110755456A CN 201911196266 A CN201911196266 A CN 201911196266A CN 110755456 A CN110755456 A CN 110755456A
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- antifungal
- periplaneta americana
- pharmaceutical composition
- extract
- fluconazole
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Abstract
本发明公开了美洲大蠊提取物与抗真菌药物组成的抗真菌药物组合物。本发明提供的药物组合物抗真菌效果明显优于美洲大蠊提取物与氟康唑单用,具有较好的应用前景。本发明为开发利用美洲大蠊药用资源提供了新的思路,也为临床上治疗外阴阴道念珠菌病提供了新的候选药物以及治疗方案,有望减少广大女性患者的痛楚。对于合理、持续地开发利用美洲大蠊这一天然药物资源具有重要的意义。
Description
技术领域
本发明属于医药技术领域,具体涉及美洲大蠊提取物与抗真菌药物组成的抗真菌药物组合物。
背景技术
中医认为,外阴阴道念珠菌病多因湿热生虫、虫蚀阴中所致,属外感湿浊秽毒之邪。其主要病因是脾气之虚、肝气之郁、湿气之浸、热气之逼、带脉之伤所致。此外,尚可因摄生不慎、洗浴用具不洁感染湿毒,直犯阴器,侵于任带二脉,致任脉不固,带脉失约,秽液下流而发。目前临床用于治疗外阴阴道念珠菌病的药物,如唑类抗真菌药、中药洗剂等因大量长期使用,使得真菌产生耐药性,临床治愈率下降。因此运用中医药思维,寻找相应的中药及复方,与化学药联合用药,以此预防和治疗外阴阴道念珠菌病具有很好的发展前景。
美洲大蠊为昆虫纲翅亚纲蜚蠊目蜚蠊科大蠊属昆虫,俗称“蟑螂”,在我国分布广泛,入药始载于《神农本草经》,其功效为散瘀消结、解毒利尿,临床常外用治疗蛇虫咬伤、痈疮肿毒、脚气水肿、气喘、小便淋浊等症。生物学家发现,美洲大蠊进化史漫长,繁殖能力强,生活环境较为复杂,携带50多种致病或非致病菌,但自身却不被感染,说明其具有较强的抗菌性。康复新液是美洲大蠊干燥虫体的乙醇提取物,属于纯天然昆虫提取物,来源丰富、药用价值高、不良反应低、安全性高、使用方便,不易产生耐药性。发明人在研究过程中,意外地发现发明人自提的美洲大蠊提取物与市售的康复新液联合氟康唑对阴道菌群均有抑制或杀灭作用。
发明内容
本发明的目的在于提供一种抗真菌药物组合物,由美洲大蠊提取物与抗真菌药物组成。
抗真菌药物为氟康唑、酮康唑、伏立康唑、伊曲康唑、两性霉素B、卡泊芬净、氟胞嘧啶、特比萘酚和阿莫罗芬。
抗真菌药物为氟康唑。
真菌为白色念珠菌。
真菌是白色念珠菌标准株或白色念珠菌耐药株。
美洲大蠊提取物通过以下方式得到:
(1)将美洲大蠊磨成粉末,加入美洲大蠊粉末质量体积(g/ml)1~3倍的石油醚,超声15min后浸泡24小时;处理2-3次,过滤后收集沉淀;
(2)称取经石油醚处理过的美洲大蠊粉末,加入质量体积(g/ml)1~3倍的氯仿甲醇溶剂浸泡12小时,过滤,减压浓缩得到美洲大蠊提取物。
步骤(2)中氯仿甲醇溶剂的体积比为1:1。
美洲大蠊提取物为康复新液。
康复新液与抗真菌药物的质量比为1:1。
药物的剂型为片剂、硬胶囊、软胶囊、散剂、丸剂、颗粒剂。
本发明优点:
本发明的优点和积极效果在于,不仅为开发利用美洲大蠊药用资源提供了新的思路,也为临床上治疗外阴阴道念珠菌病提供了新的候选药物以及治疗方案,有望减少广大女性患者的痛楚。对于合理、持续地开发利用美洲大蠊这一天然药物资源具有重要的意义。
附图说明
图1为康复新液与氟康唑对白色念珠菌的时间-杀菌曲线;
图2为联合用药对VVC模型小鼠一般情况的影响
图3为联合用药对VVC模型小鼠体重的影响;与对照组相比,#P<0.05,##P<0.01;与模型组相比,*P<0.05,**P<0.01,***P<0.001;下同;
图4为联合用药对VVC模型小鼠外阴外观的影响;
图5为联合用药对VVC模型小鼠阴道局部炎症的影响;各时间点部分分组内3只小鼠阴道炎症评分相同,故统计学标准差为0;第0d各组炎症评分均为0,第2、12、13、14d对照组炎症评分为0,第14d康复新液、氟康唑组炎症评分为0,第13、14d联合给药组炎症评分为0,故图中不予显示;
图6为联合用药对VVC模型小鼠阴道菌落定植情况的影响;
图7为联合用药对VVC模型小鼠阴道定植菌落数的影响。
具体实施方式
下面对本发明作进一步的说明,但不以任何方式对本发明加以限制,基于本发明所作的任何变换,均属于本发明的保护范围。
一种抗真菌药物组合物,由美洲大蠊提取物与抗真菌药物组成。
抗真菌药物为氟康唑、酮康唑、伏立康唑、伊曲康唑、两性霉素B、卡泊芬净、氟胞嘧啶、特比萘酚和阿莫罗芬。
抗真菌药物为氟康唑。
真菌为白色念珠菌。
真菌是白色念珠菌标准株或白色念珠菌耐药株。
美洲大蠊提取物通过以下方式得到:
(1)将美洲大蠊磨成粉末,加入美洲大蠊粉末质量体积(g/ml)1~3倍的石油醚,超声15min后浸泡24小时;处理2-3次,过滤后收集沉淀;
(2)称取经石油醚处理过的美洲大蠊粉末,加入质量体积(g/ml)1~3倍的氯仿甲醇溶剂浸泡12小时,过滤,减压浓缩得到美洲大蠊提取物。
步骤(2)中氯仿甲醇溶剂的体积比为1:1。
美洲大蠊提取物为康复新液。
康复新液与抗真菌药物的质量比为1:1。
药物的剂型为片剂、硬胶囊、软胶囊、散剂、丸剂、颗粒剂。
实施例1:
美洲大蠊提取物的制备及其体外抗真菌活性测试;
实施例中的美洲大蠊、菌株、所用试剂均为市售。
1. 美洲大蠊提取物的制备
1.1 原料粉末制备
收集美洲大蠊成虫置-80℃灭活后,经75%乙醇清洗风干后置于-80℃冰箱保存备用。称取适量美洲大蠊成虫虫体在液氮中研磨成粉末,置于-80℃冰箱中冷冻,随后在真空冷冻干燥机内冻干成粉末,充分混匀后置于4℃冰箱内保存备用。
1.2 石油醚提取物制备
1.2.1 取美洲大蠊粉末500g,置于锥形瓶中,加入石油醚1000mL,超声15min,浸泡24h。用玻璃棒搅拌后,超声15min,抽滤,得到滤液680mL。滤渣备用。滤液用旋转蒸发仪于40℃下减压蒸干,回收石油醚,得到美洲大蠊石油醚提取物。
1.2.2 向滤渣中再次加入石油醚680mL,于室温下浸泡提取24h,抽滤,得到石油醚滤液480mL,滤液用旋转蒸发仪于40℃下减压浓缩,回收石油醚,滤渣备用。
1.2.3 再次向滤渣中加入380mL石油醚,浸泡4天,抽滤,得到石油醚滤液350mL,石油醚滤液静置48h后,可见上层为澄清的黄色液体,下层为白色沙粒状沉淀。得到石油醚提取物1’。
1.2.4 收集所有石油醚提取后剩下的滤渣,挥干石油醚,备用。
1.3 氯仿-甲醇(1:1)提取物制备
称取经石油醚反复提取处理过的美洲大蠊药材粉末1g,用氯仿-甲醇(1:1)30mL浸泡12h,然后超声15min,抽滤,滤渣用氯仿-甲醇(1:1)洗涤5次,每次20mL,合并滤液,滤渣备用。向滤液中加入60mL乙酸乙酯,析出沉淀,经过抽滤,沉淀于40℃减压蒸干,回收乙酸乙酯,到氯仿-甲醇(1:1)提取物2’。
1.4 乙酸乙酯提取物制备
向氯仿-甲醇(1:1)提取剩余的滤渣中加入100mL水,超声处理5min,静置,收集上清液。再加入100mL水,超声处理5min,静置,收集上清液。合并上清液,先用乙酸乙酯萃取3次,每次30mL,合并乙酸乙酯提取液,水层备用。乙酸乙酯提取液于40℃减压蒸干,最终产物较少,无法收集。
1.5 正丁醇提取物制备
再向1.4步骤中提取后的水层中加入正丁醇萃取3次,每次30mL,合并正丁醇提取液,40℃减压干燥后,收集待测免疫活性。萃取剩余的水层也减压蒸干收集提取物。得到水层提取物3’和正丁醇提取物4’。
2. 美洲大蠊提取物体外抗菌活性实验
美洲大蠊4份提取物样本(石油醚提取物(样品1’)、氯仿-甲醇(1:1)提取物(样品2’)、正丁醇提取时的水层浓缩物(样品3’)、正丁醇提取物(样品4’)),样品均溶于DMSO中,所有样品贮存浓度均为100mg/mL 4℃密封避光保存。阳性对照药物氟康唑溶于DMSO,贮存浓度为50mg/mL 4℃密封避光保存。样品和对照药物使用前溶解于沙氏液体培养基中,现用现配。
微量稀释法,在96孔培养板上,阳性药物氟康唑稀释成初浓度为1mg/mL,待测样品稀释成初浓度为1mg/mL,阳性药物和待测样品联合用药,两个浓度翻倍,体积减半;将药物5倍梯度稀释,6个浓度梯度,每个浓度梯度3个重复孔。各孔加入不同浓度药液100μL和白色念珠菌菌悬液100μL,标准株和耐药株的浓度均为1×105 CFU/mL,37℃分别培养24h。酶标仪测定625nm下的OD值。实验同时设置培养基空白对照、菌液对照以及氟康唑阳性药物对照。以半数抑制浓度IC50值判断样品的抗菌作用,确定最佳美洲大蠊提取工艺。
3. 验证最优美洲大蠊提取物杀菌抑菌活性实验
微量稀释法,在96孔培养板上,阳性药物氟康唑稀释成初浓度为1mg/mL,最优美洲大蠊提取物稀释成初浓度为1mg/mL,阳性药物和最优美洲大蠊提取物样品联合用药,两个浓度翻倍,体积减半;将药物5倍梯度稀释,6个浓度梯度,每个浓度梯度3个重复孔。各孔加入不同浓度药液100μL和白色念珠菌菌悬液100μL,标准株和耐药株的浓度均为1×105 CFU/mL,37℃分别培养24h。酶标仪测定625nm下的OD值。实验同时设置培养基空白对照、菌液对照以及氟康唑阳性药物对照。以IC50值判断样品的抗菌作用。
4. 最优美洲大蠊提取物逆转白色念珠菌氟康唑耐药性实验
将最优美洲大蠊提取物设定浓度为1mg/mL,使用药物处理耐药株(6-9株),药物与1×105 CFU/mL耐药株于摇床150r/min共孵育24h,9000r离心去除药物,处理后的菌落划板培养在沙氏琼脂培养基,置于恒温恒湿培养箱培养24h形成菌落,此为药物处理1代。连续处理6代后,挑取部分菌落用沙氏液体培养基重悬,调菌液浓度为1×105 CFU/mL,加入氟康唑,进行氟康唑敏感性测试。观察处理后耐药菌株对氟康唑敏感性是否有变化。
5. 结果
5.1 美洲大蠊提取物的提取工艺研究
对美洲大蠊提取物的提取工艺研究,检测美洲大蠊提取物体外抗菌抑菌活性,发现四种样品对白色念珠菌标准株和耐药株抑菌效果不佳,但是氯仿-甲醇(1:1)提取物(样品2’)、正丁醇提取时的水层浓缩物(样品3’)、正丁醇提取物(样品4’)与氟康唑联用对白色念珠菌耐药株有联合抗菌的效果,样品2’、3’、4’的联合指数CI值分别为0.32、0.33、0.40,0.3<CI<0.7,具有协同作用。并确定氯仿-甲醇(1:1)提取物为杀菌和抑菌效果较好的提取和萃取方式,作为美洲大蠊最佳提取工艺。
表1 美洲大蠊提取物体外抗真菌活性测定结果
注:数据以三次重复实验的平均数表示
5.2 验证最优美洲大蠊提取物杀菌抑菌活性
进一步验证最优美洲大蠊提取物杀菌抑菌活性,发现其对白色念珠菌标准株没有抑菌作用,但是对23#耐药株有一定的抑菌作用;最优美洲大蠊提取物与氟康唑联用对白色念珠菌标准株和耐药株有联合抗菌的效果。
表2 最优美洲大蠊提取物抗真菌活性测定结果
注:数据以三次重复实验的平均数表示
5.3 最优美洲大蠊提取物逆转白色念珠菌氟康唑耐药性研究
研究最优美洲大蠊提取物是否具备逆转白色念珠菌氟康唑耐药性的功能,发现氟康唑对最优美洲大蠊提取物处理过的耐药白色念珠菌IC50大于1000μg/mL,证明最优美洲大蠊提取物并不具备逆转白色念珠菌氟康唑耐药性的作用。
表3 氟康唑对最优美洲大蠊提取物处理后耐药株抗真菌活性测定结果
注:数据以三次重复实验的平均数表示
实施例2:
康复新液联合氟康唑体外抗白色念珠菌活性的实验;
实施例中的康复新液、菌株、所用试剂均为市售。
1. 微量稀释法测定康复新液联合氟康唑抗菌活性
微量稀释法,在96孔培养板上,阳性药物氟康唑储存浓度浓度为50 mg/mL,稀释成初浓度为1mg/mL,康复新液以原液用药,实验时用沙氏液体培养基稀释,阳性药物和康复新液联合用药,氟康唑与康复新液的重量比为(1:1);将药物5倍梯度稀释,6个浓度梯度,每个浓度梯度3个重复孔。各孔加入不同浓度药液100μL和白色念珠菌菌悬液100μL,标准株和耐药株的浓度均为1×105 CFU/mL,37℃分别培养24h。酶标仪测定625nm下的OD值。实验同时设置培养基空白对照、菌液对照以及氟康唑阳性药物对照。以IC80值判断康复新液的抗菌作用。
2. 时间-杀菌曲线测定康复新液联合氟康唑抗菌作用
实验以白色念珠菌ATCC10231、临床耐药株23#为研究对象,调整菌浓度为1×105 CFU/mL,分别与康复新液(原液50%)、氟康唑(200μg/mL)、两药联合在YEPD培养基中共同培养,恒温摇床150r/min孵育,分别取2、4、8、12、24、36、48、72 h时间点的菌液,酶标仪测定625nm下的OD值,检测菌株在YEPD培养基中的时间-生长曲线,判断不同药物单独用药与联合用药对菌株生长情况的影响,同时观察各组随时间变化的动态生长情况。
3. 结果
3.1微量稀释法测定康复新液联合氟康唑抗菌活性
实验结果显示,康复新液对白色念珠菌标准株有一定的抑制效果,80%抑制浓度大约为康复新液原液44.55%稀释浓度;康复新液对临床耐药株的抑制效果较好,80%抑制浓度大约为康复新液原液36.56%稀释浓度。康复新液与氟康唑联合用药对标准株和耐药株的抑菌效果明显,抑菌作用明显增强,两药联合对标准株和耐药株的FICI指数分别为0.3608、0.0044,表明两药具有协同抗菌作用。此结果表明:康复新液与本项目自提最优美洲大蠊提取物(氯仿-甲醇(1:1)提取物)相比,抗菌抑菌效果好,且联合氟康唑,协同抗菌抑菌效果更好。
表4 康复新液抗白色念珠菌体外活性测定结果
注:数据以三次重复实验的平均数表示
FICI<0.5:两种药为协同作用;0.5<FICI<1:两种药为相加作用;1<FICI<2:两种药为无关作用;2<FICI:两种药为拮抗作用。
3.2 时间-杀菌曲线测定康复新液联合氟康唑抗菌作用
实验结果显示,单用康复新液对ATCC10231有轻度的抗菌作用,单用氟康唑对ATCC10231有较好的抗菌作用,两药联合抗菌效果更好;单用康复新液对耐药株23#有轻度的抗菌作用,单用氟康唑对耐药株23#无抗菌作用,两药联合抗菌效果显著。
实施例3:
康复新液联合氟康唑体内抗白色念珠菌感染的实验
实施例中的康复新液、菌株、所用试剂均为市售
1. 动物分组
150只SPF级雌性Balb/c小鼠(4~6周龄,体重20±2g,动物合格证号:SCXK(滇)K2015-0002)适应性喂养1周后,按随机数表法分为5组,每组30只,分别为对照组、真菌感染模型组、康复新液治疗组、氟康唑治疗组、联合给药治疗组。实验周期为14天,各组小鼠均给予正常饮食,饲养于24±2℃,明暗12h交替的洁净动物室内,实验前每只小鼠用无菌PBS阴道灌洗并将灌洗液进行培养,选择灌洗液培养皿中无白色念珠菌生长的小鼠用于正式实验。
2. 外阴阴道念珠菌病模型建立及给药
参考夏德超等(中国麻风皮肤病杂志, 2006, 22(6), 441-443.)和孔小锋等(中西医结合研究, 2009, 1(5), 236-240.)模型复制方法并进行适度改良后建立外阴阴道念珠菌病(VVC)小鼠模型。
2.1 预处理
接种前4d开始每鼠分别皮下注射苯甲酸雌二醇E2(1mg/mL)0.025mL,1次/d,连续注射4d,造成小鼠假发情,阴道扩张,之后每2d注射1次,直至实验结束;接种前3d开始每鼠腹腔注射环磷酰胺(100mg/kg)10mL/kg,1次/d,连续注射3d,造成小鼠自身免疫缺陷,之后每3d注射1次(75mg/kg)10mL/kg,直至实验结束。
2.2 真菌接种
阴道接种前用无菌PBS将白色念珠菌标准株密度调为2.5×107CFU/mL,用微量加样器吸取菌悬液20μL,注入模型组和治疗组小鼠的阴道内,原位停留1~2 min,防止菌液溢出;空白对照组阴道内注入20μL无菌PBS。接种后的第2天、第4天和第7天,每组取3只小鼠用无菌PBS阴道灌洗,将灌洗液进行培养,评价VVC动物模型建立是否成功。
2.3 给药
模型成功建立24h后,康复新液治疗组阴道灌洗给予相应药液100μL/只(5mL/kg),氟康唑治疗组阴道灌洗给药100μL/只(10mg/kg),联合给药组阴道灌洗两种治疗药物(氟康唑与康复新液重量比1:1)100μL/只,对照组、模型组阴道灌洗无菌PBS 100μL/只,连续给药7d,每天按照检测指标评价抗菌活性。
3. 指标检测
3.1 小鼠一般情况观察
实验期间每个灌洗日进行全身情况观察,记录小鼠体表状态。
3.2 小鼠体重记录
实验期间每个灌洗日记录小鼠体重,实验结束后整理小鼠体重变化。
3.3 小鼠外阴局部情况观察
实验期间每个灌洗日做阴道局部症状评分。评分标准为:0分:外阴阴道无红肿及分泌物增多;1分:外阴阴道轻微红肿,无分泌物增多;2分:外阴阴道明显红肿伴分泌物增多;3分:外阴阴道明显红肿,出现溃疡,并伴分泌物增多;4分:死亡。
3.4 小鼠阴道灌洗液菌落培养计数
每个灌洗日取灌洗液镜检及菌落培养计数:每个灌洗日小鼠阴道用100μL无菌PBS灌洗,灌洗液置于洁净无菌的EP管中,取10μL灌洗液镜下观察菌丝生成情况;灌洗液用无菌PBS稀释10倍,取10μL接种于YEPD琼脂培养基,37℃培养24h后,进行菌落观察并计数(Colony-Forming Units,CFU,即菌落形成单位,以CFU/mL为单位计数)
4. 结果
4.1 康复新液联合氟康唑对VVC模型小鼠一般情况的影响
实验结果表明,与对照组相比,真菌感染模型组小鼠行动呆滞、体表毛发均有脱毛呛毛现象;与真菌感染模型组相比,联合用药、康复新液、氟康唑治疗组小鼠行动敏捷、毛发光滑、无脱毛呛毛现象。
4.2康复新液联合氟康唑对VVC模型小鼠体重的影响
实验结果表明,与对照组相比,真菌感染模型组小鼠体重整体呈下降趋势,造模第13、14 d体重明显下降( P<0.05);与真菌感染模型组相比,康复新液、氟康唑治疗组小鼠给药第5、6、7 d体重明显上升(P<0.01),联合给药治疗组小鼠给药第5、6、7 d体重显著上升(P<0.001)。
4.3康复新液联合氟康唑对VVC模型小鼠外阴外观及阴道局部炎症的影响
实验结果表明,与对照组相比,真菌感染模型组小鼠接种白色念珠菌后第2d开始外阴红肿明显、分泌物明显增多,且在接种后第2、4、7~14 d阴道炎症评分显著上升(P<0.01);与真菌感染模型组相比,联合用药、康复新液、氟康唑治疗组小鼠给药第3~7d外阴红肿缓解、分泌物减少、阴道局部炎症评分下降(P<0.01)。
4.4 康复新液联合氟康唑对VVC模型小鼠阴道菌落的影响
实验结果表明,与对照组相比,真菌感染模型组小鼠阴道白色念珠菌定植菌落数显著增多(P<0.01);康复新液、氟康唑治疗组与真菌感染模型组相比,小鼠阴道内白色念珠菌定植明显减少,灌洗液培养菌落数明显减少(P<0.01),且联合用药效果更显著,阴道灌洗液培养菌落数显著减少(P<0.001)。
Claims (10)
1.一种抗真菌药物组合物,其特征在于由美洲大蠊提取物与抗真菌药物组成。
2.如权利要求1所述的抗真菌药物组合物,其特征在于所述抗真菌药物为氟康唑、酮康唑、伏立康唑、伊曲康唑、两性霉素B、卡泊芬净、氟胞嘧啶、特比萘酚和阿莫罗芬。
3.如权利要求1所述的抗真菌药物组合物,其特征在于所述制备抗真菌药物为氟康唑。
4.如权利要求1所述的抗真菌药物组合物,其特征在于所述真菌为白色念珠菌。
5.如权利要求1所述的抗真菌药物组合物,其特征在于所述真菌是白色念珠菌标准株或白色念珠菌耐药株。
6.根据权利要求1所述的抗真菌药物组合物,其特征在于所述的美洲大蠊提取物通过以下方式得到:
(1)将美洲大蠊磨成粉末,加入美洲大蠊粉末质量体积(g/ml)1~3倍的石油醚,超声15min后浸泡24小时;处理2-3次,过滤后收集沉淀;
(2)称取经石油醚处理过的美洲大蠊粉末,加入质量体积(g/ml)1~3倍的氯仿甲醇溶剂浸泡12小时,过滤,减压浓缩得到美洲大蠊提取物。
7.根据权利要求6所述的抗真菌药物组合物,其特征在于所述的步骤(2)中氯仿甲醇溶剂的体积比为1:1。
8.根据权利要求1所述的抗真菌药物组合物,其特征在于所述的美洲大蠊提取物为康复新液。
9.如权利要求7所述的抗真菌药物组合物,其特征在于康复新液与抗真菌药物的质量比为1:1。
10.根据权利要求1所述的抗真菌药物组合物,其特征在于所述药物的剂型为片剂、硬胶囊、软胶囊、散剂、丸剂、颗粒剂。
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