CN105476979B - 一种含有荧光增白剂cbs的药物组合物及其应用 - Google Patents
一种含有荧光增白剂cbs的药物组合物及其应用 Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
本发明提供了一种含有荧光增白剂CBS的药物组合物及其应用,所述药物组合物包含荧光增白剂CBS,任选地包含药学上可接受的辅料。本发明通过研究发现了荧光增白剂CBS对真菌,尤其是红色毛癣菌具有显著的抑制作用,并且与抗菌药联用具有协同作用,特别是与盐酸特比萘芬、酮康唑联合应用时可显著缩短治疗时间,降低药物的毒副作用。
Description
技术领域
本发明涉及医药领域,具体地,本发明涉及一种含有荧光增白剂CBS的药物组合物及其在抑制红色毛癣菌中的应用。
背景技术
皮肤癣菌病(dermatophytoses)是由寄生在人体皮肤、毛发和指(趾)甲等角蛋白组织的皮肤癣菌引起的浅部真菌病,老年人、糖尿病患者及免疫力低下的人群更易患皮肤病。红色毛癣菌(Trichophyton rubrum)是引发皮肤癣菌病的主要致病菌,约占60%以上。红色毛癣菌属毛癣菌属,主要感染人的皮肤、指(趾)甲,偶见侵犯毛发,常引起手足癣、体癣、股癣及甲癣等。红色毛癣菌的流行病学特征,成为人类的丝状真菌感染生物学研究的理想模型,但是至今却对其主要致病机制及可用于治疗的药物的作用靶点了解甚少。目前开发出了多种不同的新型抗真菌药物,其中大多数的抗真菌剂都是针对真菌特异性代谢途径--麦角甾醇生物合成途径开发的,但是抗真菌药物存在毒副作用大和致病菌耐药性问题。因此,发现和研究以细胞壁的合成途径为药物靶标的药物及其衍生药物对临床治疗皮肤癣菌引起的浅部真菌病以及克服真菌耐药性有重要的意义。2012年,Kingsbury等人研究发现,二苯乙烯类荧光增白剂对红色毛癣菌及白色念珠菌有抗菌活性,如卡尔科弗卢尔荧光增白剂(Calcofluor White,简称CFW)。
荧光增白剂CBS全称二苯乙烯联苯二磺酸钠,是一种新型荧光增白剂。具有优良的耐氯漂、耐酸碱、耐日晒性能,是轻工、纺织及日化行业的理想添加剂。荧光增白剂CBS广泛用于纺织、洗涤剂和造纸工业中,具有一定的美白效果,全面的毒理学研究表明荧光增白剂CBS对哺乳动物无毒害作用。目前尚没有将荧光增白剂CBS用于抑制真菌的报道。
发明内容
本发明的发明人在研究中发现,荧光增白剂CBS对于真菌具有抑制作用,并且在进一步的研究中发现荧光增白剂与抗真菌药物具有协同作用,与抗真菌药物联用可以起到显著的抑制真菌的效果。本发明的目的之一就是提供一种含有荧光增白剂CBS的用于治疗皮肤癣菌病的药物组合物,并且进一步提供了将荧光增白剂与抗真菌药物联用治疗皮肤癣菌病的药物组合物。
为实现上述目的,本发明提供如下的技术方案:
一种用于治疗皮肤癣菌病的药物组合物,所述药物组合物包含荧光增白剂CBS,任选地包含药学上可接受的辅料。
在根据本发明的一个实施方案中,所述药物组合物中荧光增白剂CBS的浓度为0.02~10mg/ml;优选为2.5mg/ml。
本发明还提供了一种有效成分包含荧光增白剂CBS和抗真菌药物的药物组合物;优选地,所述抗真菌药物选自盐酸特比萘芬和酮康唑中的一种或两种。
在根据本发明的一个实施方案中,所述药物组合物的有效成分为荧光增白剂CBS和酮康唑时,其中,酮康唑的浓度为2μg/ml,荧光增白剂CBS的浓度为2.5mg/ml。
在根据本发明的一个实施方案中,所述药物组合物的有效成分为荧光增白剂CBS和盐酸特比萘芬时,其中,盐酸特比萘芬的浓度为0.0625μg/ml,荧光增白剂CBS的浓度为5mg/ml。
在根据本发明的一个实施方案中,所述药物组合物的有效成分为荧光增白剂CBS、酮康唑和盐酸特比萘芬时,其中,荧光增白剂CBS的浓度为0.5~5mg/ml,酮康唑的浓度为1.5~6μg/ml,盐酸特比萘芬的浓度为0.05~0.5μg/ml;优选地,所述药物组合物还包含十二烷基磺酸钠和氮酮,所述十二烷基磺酸钠的浓度为2~20mg/ml,所述氮酮的浓度为6~24mg/ml;更优选地,所述药物组合物包含荧光增白剂CBS、酮康唑、盐酸特比萘芬,十二烷基磺酸钠和氮酮时,荧光增白剂CBS的浓度为1.861mg/ml,酮康唑的浓度为1.5μg/ml,盐酸特比萘芬的浓度为0.175μg/ml,十二烷基磺酸钠的浓度为0.0774mg/ml,氮酮的浓度为6mg/ml。
本发明还提供了荧光增白剂CBS在制备用于治疗皮肤癣菌病的药物中的应用。优选地,所述皮肤癣菌病的致病菌为红色毛癣菌。
本发明还提供了荧光增白剂CBS协同抗真菌药物在制备用于治疗皮肤癣菌病的药物中的应用。优选地,所述抗真菌药物选自盐酸特比萘芬和酮康唑中的一种或两种;更优选地,所述皮肤癣菌病的致病菌为红色毛癣菌
由于采用了上述技术方案,本发明具有如下的优点:
本发明在研究中发现,荧光增白剂CBS能够有效的抑制皮肤癣菌病的致病菌,尤其是对红色毛癣菌具有显著的抑制作用。本发明通过优化配方药物治疗的豚鼠治愈的时间较单一用药治疗的豚鼠平均缩短6天左右,也可以初步反应出优化配方药物明显缩短了治疗时间,提高了治愈率。同时,使用荧光增白剂与抗菌药物联用,可在减少抗菌药物用量的同时,显著降低了抗菌药物的毒副作用,有助于提高用药安全。
附图说明
图1为实施例1中红色毛癣菌纸片扩散法实验的结果,其中a为荧光增白剂CBS浓度为5mg/ml时的抑菌效果;b为荧光增白剂CBS浓度为10mg/ml时的抑菌效果。
图2A~C显示单一药物对红色毛癣菌的抑制率;其中,图2A为荧光增白剂对红色毛癣菌的抑制作用;图2B为酮康唑对红色毛癣菌的抑制作用;图2C为盐酸特比萘芬对红色毛癣菌的抑制作用。
图3为荧光增白剂CBS与酮康唑联合用药与两者分别单一用药时的抑菌效果柱形图;其中,a为荧光增白剂单一用药抑制率;b为两者联合用药抑制率;c为酮康唑单一用药抑制率。
图4为荧光增白剂CBS盐酸特比萘芬联合用药与两者分别单一用药时的抑菌效果柱形力;其中,a为荧光增白剂CBS单一用药的抑制率;b为两者联合用药的抑制率;c为盐酸特比萘芬单一用药的抑制率。
图5为豚鼠模型的表观变化;其中,a为剪毛并脱毛后的豚鼠;b为毛发生长10日后的空白对照组豚鼠;c为毛发生长10日的阳性对照组豚鼠;d为联合用药10天后的实验组豚鼠。
图6为对模型豚鼠的皮肤组织进行检测的结果图;其中,a为空白对照组豚鼠;b为用配方药组豚鼠;c为阳性对照组豚鼠;空白对照组HE切片为正常皮肤组织形态,阳性对照组HE切片可见真皮层细胞浸润,细胞间液体增加,使细胞间的间隙增宽,细胞间桥拉长,形成海绵水肿,毛囊部位有菌丝及孢子存在;用配方药组的豚鼠皮肤的HE切片与空白对照组的正常皮肤组织无异,未发现菌丝和孢子的存在。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进一步详细说明。应当理解,此处说描述的具体实施例仅用以解释本发明,并不用于限定本发明。
一、试剂和材料
红色毛癣菌等(重庆大坪医院皮肤科);豚鼠(重庆市中药研究院);二甲基亚砜、SDS、氮酮等(成都市科龙化工试剂厂);荧光增白剂CBS(河北三川化工公司);盐酸特比萘芬(沈阳日曜药业公司);酮康唑(大连美仑生物技术公司);地塞米松注射液(广西安康药业公司);曲安奈德注射液(西安南德药业股份公司)。
实施例1CBS滤纸片扩散法实验检测荧光增白剂CBS的抗菌作用
定性滤纸打孔为直径6mm的圆形纸片,灭菌后部分浸泡于荧光增白剂CBS药液(5mg/ml、10mg/ml),部分浸泡于无菌生理盐水,备用。取菌悬液均匀涂抹于固体平板,人为将平板分为四部分,浸药滤纸片贴于其中3部分,最后一部分作为空白对照贴上。在28℃下培养7d后观察。如图1所示,浸药滤纸片的周围有一定程度的抑菌圈出现。空白对照滤纸长满菌。由此可见,CBS对红色毛癣菌有抑制作用。
实施例2单一用药对红色毛癣菌的抗菌作用
准确称取适量盐酸特比奈芬,加入二甲基亚砜充分溶解,然后用沙士葡萄糖液体培养基配制成0.5、0.25、0.125、0.0625μg/ml等10个梯度浓度备用;同理准确称取适量酮康唑配制成16、8、4、2μg/ml等10个浓度梯度备用;准确称取适量荧光增白剂CBS,加入沙士葡萄糖液体培养基配制成10、5、2.5、1.25mg/mL等10个浓度梯度备用。用移液枪吸取100μL的样品溶液及阳性对照溶液(沙士葡萄糖液体培养基),菌悬液100μL,依次加入96孔板,以及空白对照(沙士葡萄糖液体培养基)200μL。恒温培养93h后,加入20μL的MTT,继续孵育3h,每孔吸出100μL上清液,再加入100μL二甲亚砜,酶标仪530nm检测吸光度值并记录。用下列公式计算抑制率:抑制率=(1-测定孔OD值/阳性对照孔OD值)×100%,即得到抑制率。如图2A~C所示,单一用药时,荧光增白剂CBS在浓度2.5mg/ml时对红色毛癣菌的抑制作用最强;酮康唑浓度为4μg/ml时对红色毛癣菌的抑制作用最强;盐酸特比萘芬为0.25μg/ml时对红色毛癣菌的抑制作用最强。
实施例3联合用药对红色毛癣菌的抑制作用
1)酮康唑联合荧光增白剂CBS
酮康唑和荧光增白剂CBS(浓度与单一用药相同,剂量减半)联合使用后,经总体方差分析p<0.05,差异有统计学意义;进一步进行主体间效应检验,证实酮康唑与荧光增白剂CBS间存在协同作用,进行多次比较后,得出酮康唑为2μg/ml,荧光增白剂CBS为2.5mg/ml时,对红色毛癣菌的抑制作用最强。与单一用药时相比,如图3所示,荧光增白剂CBS联合酮康唑用药,比同浓度下的单一药物抑制率高,抑制作用强。
2)盐酸特比萘芬联合荧光增白剂CBS
步骤同上,盐酸特比萘芬和荧光增白剂CBS联合使用后,证实两者间具有协同作用,并且当盐酸特比萘芬为0.0625μg/ml,荧光增白剂CBS为5mg/ml时,对红色毛癣菌的抑制作用最强。与单一用药时相比,如图4所示。
实施例4均匀设计优化协同药物配比
1.通过SPSS软件进行因素水平分析,得到实验方案表(表1),根据实验方案,配制相应浓度下的药品,然后通过MTT法测定吸光度值,然后通过公式计算抑制率。
表1实验方案表
(1-荧光增白剂CBS;2-酮康唑;3-盐酸特比萘芬;4-十二烷基磺酸钠;5-氮酮)
由实验结果可以看出,当荧光增白剂CBS浓度为4.5mg/ml,酮康唑浓度为3.5μg/ml,盐酸特比萘芬浓度为0.15μg/ml,SDS浓度为2mg/ml,氮酮浓度为12mg/ml时对红色毛癣菌的抑菌作用最强,最大抑菌率为66.14%。
2.通过SPSS软件逐步递进回归法对实验数据进行分析,采用Excel2007分析后得到了红色毛癣菌抑制率、荧光增白剂CBS浓度、盐酸特比萘芬浓度、酮康唑浓度、SDS浓度、氮酮浓度的数学模型。
公式如下:
Y=2.436A+0.033A2E+0.802A2-0.4A2D+0.137A2B-0.124AD-11.112C2B-22.664D2B-75.654C2-138.76C3-19.475C-2.043CD-4.087C2D-3.741C2E+72.614
式中:
Y----红色毛癣菌抑制率 A----荧光增白剂CBS浓度
B----酮康唑浓度 C----特比萘芬浓度
D----SDS浓度 E----氮酮浓度
其中:
显著性水平 α=0.1 剩余标准差 s=8.12×10-2
复相关系数 R=0.9978 决定系数 R2=0.9956
对回归方程求偏导得到理论的最优组合,结果为荧光增白剂CBS为1.861mg/ml,酮康唑浓度为1.5μg/ml,盐酸特比萘芬浓度为0.175μg/ml,SDS浓度为0.0774mg/ml,氮酮浓度为6mg/ml,可得的对红色毛癣菌的抑制率为75.34%。
2)验证实验结果
表2验证实验结果表
如表2所示,经验证,红色毛癣菌的抑制率均大于理论最优组合,证明数学建模成功,得到的回归方程正确。
实施例5构建豚鼠模型及药效评价
首先配置终浓度为0.525μg/mL盐酸特比奈芬药液,4.5μg/mL和4μg/ml的酮康唑药液,5.58mg/ml的荧光增白剂CBS,120mg/mL的氮酮,8%硫化钠溶液,10%氢氧化钾溶液。然后选取24只普通健康豚鼠雌雄各半,重量约300g,体重、性别随机分为4组,每组6只。
1)第1组空白对照只用地塞米松处理,将豚鼠除毛磨皮后出现血痂,逐渐生长出正常的毛发,在处死前毛发已经生长到和除毛前无异。
2)第2组阳性对照用地塞米松处理,然后豚鼠除毛磨皮接菌后持续出现血痂,接种前两天结痂处血色鲜红,逐渐变为暗红色,接种后4天出现掉白色皮屑的现象并伴有脱毛的现象,直至处死前血痂均未褪去。
3)第3组单独使用酮康唑组除毛磨皮后出现血痂,第4日后开始用药,结痂皮损逐渐褪去,并开始生长出正常的毛发,皮损消失的时间分别为13d、15d、13d、14d、14d、13d,颜色呈暗红色。
4)第4组联合用药组除毛磨皮后出现血痂,第4日后开始用药,结痂皮损逐渐褪去,并开始生长出正常的毛发,皮损消失的时间分别为8d、8d、9d、7d、8d、9d,颜色呈暗红色。
用药处理后得到豚鼠表观变化图,如图5所示。
将各组模型豚鼠的皮肤组织进行HE切片检测,如图6所示,第一组空白对照组HE切片为正常皮肤组织形态,第二组阳性对照组HE切片可见真皮层细胞浸润,细胞间液体增加,使细胞间的间隙增宽,细胞间桥拉长,形成海绵水肿,毛囊部位有菌丝及孢子存在;第三组和第四组用配方药组的豚鼠皮肤的HE切片与空白对照组的正常皮肤组织无异,未发现菌丝和孢子的存在。
对建模成功的豚鼠进行单一和优化配比方案药物治疗,通过比较治疗的时间长短证明优化配比方案的药物能通过较短的时间对红色毛癣菌感染的豚鼠进行治疗,并且直至将动物处死前治疗组豚鼠都生长健康,也基本反映出荧光增白剂CBS对活体动物的治疗有一定的安全性。
尽管本发明已进行了一定程度的描述,明显地,在不脱离本发明的精神和范围的条件下,可进行各个条件的适当变化。可以理解,本发明不限于所述实施方案,而归于权利要求的范围,其包括所述每个因素的等同替换。
Claims (8)
1.一种用于治疗皮肤癣菌病的药物组合物,其特征在于,所述药物组合物包含荧光增白剂CBS和抗真菌药物,抗真菌药物为盐酸特比萘芬和酮康唑中的一种或两种,荧光增白剂CBS的浓度为0.5-10mg/ml,盐酸特比萘芬的浓度为0.05-0.5μg/ml,酮康唑的浓度为1.5-6μg/ml,任选地包含药学上可接受的辅料。
2.如权利要求1所述的药物组合物,其特征在于,所述药物组合物的有效成分为荧光增白剂CBS和酮康唑时,其中,酮康唑的浓度为2μg/ml,荧光增白剂CBS的浓度为2.5 mg/ml。
3.如权利要求1所述的药物组合物,其特征在于,所述药物组合物的有效成分为荧光增白剂CBS和盐酸特比萘芬时,其中,盐酸特比萘芬的浓度为0.0625μg/ml,荧光增白剂CBS的浓度为5 mg/ml。
4.如权利要求1所述的药物组合物,其特征在于,所述药物组合物的有效成分为荧光增白剂CBS、酮康唑和盐酸特比萘芬时,其中,荧光增白剂CBS的浓度为0.5~5 mg/ml,酮康唑的浓度为1.5~6μg/ml,盐酸特比萘芬的浓度为0.05~0.5μg/ml。
5.如权利要求4所述的药物组合物,其特征在于,所述药物组合物还包含十二烷基磺酸钠和氮酮,所述十二烷基磺酸钠的浓度为2~20mg/ml,所述氮酮的浓度为6~24mg/ml。
6.如权利要求1所述的药物组合物,其特征在于,所述药物组合物还包含十二烷基磺酸钠和氮酮,当药物组合物的有效成分为荧光增白剂CBS、酮康唑、盐酸特比萘芬,十二烷基磺酸钠和氮酮时,荧光增白剂CBS的浓度为1.861mg/ml,酮康唑的浓度为1.5μg/ml,盐酸特比萘芬的浓度为0.175μg/ml,十二烷基磺酸钠的浓度为0.0774mg/ml,氮酮的浓度为6 mg/ml。
7.权利要求1所述药物组合物在制备用于治疗皮肤癣菌病的药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述皮肤癣菌病的致病菌为红色毛癣菌。
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