CN108606967A - 一种复方酮康唑外用组合物 - Google Patents
一种复方酮康唑外用组合物 Download PDFInfo
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- ketoconazol
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- 229960004125 ketoconazole Drugs 0.000 title claims abstract description 53
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
一种复方酮康唑外用组合物,由作为活性成分的酮康唑和(3‑(4(3H)‑喹唑啉酮))甲基‑1‑(4‑(3‑甲基苄氧基)苯基)‑5‑(2‑吡啶基)‑1,4‑戊二烯‑3‑酮肟醚(I3),和至少一种用于皮肤外用的辅料组成;所述组合物中酮康唑的质量百分比含量为0.3~0.5%,化合物(I3)与酮康唑的质量比为1:1.0~1.5。所述组合物制成凝胶剂,所述辅料选自卡波姆、保湿剂、溶剂、防腐剂、表面活性剂、pH调节剂中的一种或几种,以及余量的水。
Description
技术领域:
本发明提供了一种外用抗真菌组合物,尤其是一种含有酮康唑的外用组合物。
背景技术:
酮康唑(ketoconazole,CAS:65277-42-1)是一种咪唑类广谱抗真菌药,广泛的用于皮肤外用组合物,用于治疗各种皮肤真菌感染。但是由于酮康唑的口服制剂容易造成严重的肝损伤,我国食品药品监督管理局已经于2015年停止了酮康唑口服制剂的生产,并且已经将现有的多种含有酮康唑的外用药,如复方酮康唑发用洗剂、复方酮康唑软膏、酮康他索乳膏调出了OTC药物目录。说明由于具有造成肝损伤的副作用,酮康唑的使用受到了很大的限制,现有的酮康唑外用制剂酮康唑含量为1%~2%。如何在现有技术基础上,提高酮康唑制剂的效果,并通过降低外用制剂中酮康唑用量来避免其造成肝损伤的潜在副作用成为现有技术中亟待解决的问题。
发明内容:
在研究中我们发现中国专利文献CN 106749046 A公开了一系列含喹唑啉酮的1,4-戊二烯-3-酮肟醚类衍生物,并公开了上述化合物可以用于抗植物病毒,该文献中公开了(3-(4(3H)-喹唑啉酮))甲基-1-(4-(3-甲基苄氧基)苯基)-5-(2-吡啶基)-1,4-戊二烯-3-酮肟醚(I3),虽然该文献中指出化合物(I3)对烟草花叶病毒具有一定防治效果,但其效果明显低于对照药物。在进一步实验中我们惊奇的发现,当采用化合物(I3)与酮康唑制成复方后,可以显著提高对人体皮肤真菌病的常见病原的抗菌效果,基于此,本发明提供的技术方案为:
一种复方酮康唑外用组合物,其特征在于所述组合物由作为活性成分的酮康唑和(3-(4(3H)-喹唑啉酮))甲基-1-(4-(3-甲基苄氧基)苯基)-5-(2-吡啶基)-1,4-戊二烯-3-酮肟醚(I3),和至少一种用于皮肤外用的辅料组成;所述组合物中酮康唑的质量百分比含量为0.3~0.5%,化合物(I3)与酮康唑的质量比为1:1.0~1.5。
一种复方酮康唑外用组合物,其特征在于所述化合物(I3)与酮康唑的质量比为1:1.2~1.4。
所述的一种复方酮康唑外用组合物,其特征在于所述组合物优选制成乳膏剂、软膏剂、凝胶剂、混悬剂中的一种。
所述的一种复方酮康唑外用组合物,其特征在于所述组合物制成凝胶剂,所述辅料选自卡波姆、保湿剂、溶剂、防腐剂、表面活性剂、pH调节剂中的一种或几种,以及余量的水。
所述卡波姆选自卡波姆934,卡波姆940,卡波姆941中的一种,所述卡波姆用量为组合物总质量的0.5%~1.5%。
所述溶剂选自乙醇、丙二醇、DMF(N,N-二甲基甲酰胺)、DMSO(二甲亚砜)中的一种或几种,优选乙醇。所述溶剂加入量以能将活性成分溶解的最小量为准。
所述的保湿剂包括但不仅限于丙三醇、丙二醇、山梨醇。优选丙三醇,用量为4%~10%。
所述表面活性剂优选吐温-80,用量为0.5%~1%。
所述的pH调节剂选自氢氧化钠、磷酸/磷酸盐缓冲剂、醋酸/醋酸盐缓冲剂、柠檬酸/柠檬酸盐缓冲剂、硼酸/硼酸盐缓冲剂。
本发明中所述百分比均为占组合物的重量百分比。
在研究中我们意外的发现当化合物(I3)与酮康唑的配比在1:1.0~1.5的范围内,对常见的人体皮肤真菌病的病原可以产生更好的治疗效果,此外对化合物(I3)进行毒性实验和皮肤刺激实验均表明,作为活性成分的化合物(I3)的小鼠急性经口毒性实验LD50在2500~4000mg,属于低毒物质,且无明显的皮肤刺激性和口服的蓄积毒性。基于上述发现本发明提供了一种复方酮康唑外用组合物,动物实验表明,该外用组合物皮肤真菌病的治疗疗效果,高于单独施用酮康唑和化合物(I3),说明特定比例的化合物(3)与酮康唑产生了协同作用,在进一步实验中我们发现,化合物(I3)与酮康唑的配比在1:1.2~1.4时,上述协同效果更为明显。而在本发明提供的配比范围(1:1.0~1.5)之外,得到的组合物的抗真菌效果开始出现明显下降。
具体实施方式:
化合物(I3)的制备,按照中国专利文献CN 106749046A中公开的方法,制备(3-(4(3H)-喹唑啉酮))甲基-1-(4-(3-甲基苄氧基)苯基)-5-(2-吡啶基)-1,4-戊二烯-3-酮肟醚(I3)原料药,含量98%以上。
一、体外抑菌效果实验
1、培养基的制备
马铃薯葡萄糖琼脂培养基(PDA),质量分数为马铃薯20%、葡萄糖2%、琼脂1.8%。每个试管中加入5ml培养基制备成斜面培养基;直径90mm的平皿中加入20ml培养基制备成平板培养基
2、实验方法
2.1菌株的处理
①将阳性菌落使用灭菌接种环转种于平皿PDA培养基活化菌株,丝状型真菌采取一区划线法,置于28℃恒温培养箱,培养7天;念珠菌使用三区划线法,置于35℃恒温培养箱,培养2天。
②挑取无污染的菌落采取三区划线法转种于平皿PDA培养基进行分纯,培养条件同前。
③挑取单独的纯化菌落以“Z”字形转种于斜面SDA试管培养基中,丝状型真菌置于28℃恒温培养箱,培养10天后经玻片小培养鉴定到种;念珠菌置于35℃恒温箱,培养2天后接种于科玛嘉培养基显色鉴定到种。
本实验采用的的菌株分别为属于皮肤癣菌的红色毛癣菌、须癣毛癣菌、石膏小孢子菌和属于念珠菌的白色念珠菌和光滑念珠菌
2.2制作菌悬液
挑取适当菌落团块,溶于1mL加入吐温80的0.9%灭菌生理盐水。用微量振荡器震荡2min,充分震荡洗脱出孢子,使用血细胞计数器调节菌悬液浊度至5×106~10×106CFU/mL。
2.3制作含菌平板
抽取0.5ml菌悬液置于PDA平皿培养基,用灭菌涂布棒使之均匀分布于培养基表面。
2.4打孔加药
以直径6mm的打孔器在涂菌后的培养基上打孔,挑去孔内琼脂,将待测试药物分别挤入1ml无菌注射器中,每孔内加药0.1ml。
将活性成分溶于DMSO后再按下表所示浓度配制成混合溶液后,作为各组的待测试药物
实验组号 | 1 | 2 | 3 | 4 | 5 | 6 |
化合物(I3)% | 0.5 | 0.4 | 0.3 | 0.6 | 1 | 0 |
酮康唑% | 0.5 | 0.6 | 0.7 | 0.4 | 0 | 1 |
2.5培养与结果测量
药敏实验平板置于28℃恒温培养箱,培养10天。使用游标卡尺测量每种药的抑菌环半径,记录各药孔周围抑菌圈半径mm值。每株菌同时做3个平板。
结果如下(单位mm,n=3,means±s)
实验结果表明,化合物(I3)与酮康唑以1:1.0~1.5的比例混合(实验组1/2)后可以显著提高对各种致病真菌的抑制效果,其抑制效果不但高于单用活性成分的实验组5/6,也高于不同比例的实验组3/4,因此选定化合物(I3)与酮康唑以1:1.0~1.5,并基于该比例制备外用组合物。
二制剂实施例
制剂实施例中将复方酮康唑外用组合物制备成为凝胶剂,配方如下
实施例1
酮康唑5g、化合物(I3)5g,
卡波姆940 5g,丙三醇50g 吐温80 6g
尼泊金乙酯1g 氢氧化钠4g 蒸馏水加至1000g
将卡波姆与吐温80及300ml蒸馏水混合,氢氧化钠溶于100ml水后加入上液搅匀,再将酮康唑及化合物(I3)溶于适量乙醇后逐渐加入搅匀,补足余量的水搅匀即得透明凝胶。
实施例2
化合物(I3)3g 酮康唑4.5g
卡波姆934 10g 丙三醇50g 吐温80 5g
氢氧化钠4g 蒸馏水加至1000g
将卡波姆与吐温80及300ml蒸馏水混合,氢氧化钠溶于100ml水后加入上液搅匀,再将酮康唑及化合物(I3)溶于适量乙醇后逐渐加入搅匀,补足余量的水搅匀即得透明凝胶。
实施例3
化合物(I3)4g、酮康唑4.8g
卡波姆940 15g乙醇50g 丙三醇50g 吐温80 10g
尼泊金乙酯1g 氢氧化钠4g 蒸馏水加至1000g
将卡波姆与吐温80及300ml蒸馏水混合,氢氧化钠溶于100ml水后加入上液搅匀,再将酮康唑及化合物(I3)溶于乙醇后逐渐加入搅匀,补足余量的水搅匀即得透明凝胶。
实施例4
化合物(I3)3g、酮康唑4.2g
卡波姆940 10g 乙醇60g 丙三醇50g吐温80 8g
尼泊金乙酯1g氢氧化钠4g 蒸馏水加至1000g
将卡波姆与吐温80 及300ml蒸馏水混合,氢氧化钠溶于100ml水后加入上液搅匀,再将酮康唑及化合物(I3)溶于乙醇后逐渐加入搅匀,补足余量的水搅匀即得透明凝胶。.
对比例1
按照实施例1的配方,将活性成分改为酮康唑10g。
对比例2
按照实施例1的配方,将活性成分改为化合物(I3)10g。
药理实施例1真菌抑菌效果对比实验
1、材料
实验动物为Hartley豚鼠,体重300±20g,雌雄各半,
2、菌悬液的制备
将须癣毛癣菌菌株在PDA固体培养基上连续传代培养2次(28℃),以保证其活力。于第二次培养5d后,挑其菌落与0.9%生理盐水中,制成终浓度为1×108CFU/mL的菌悬液。
3、造模
豚鼠背部剃刀剃毛,用日本脱毛蜡脱毛,形成沿脊柱对称的两个4.0cm×4.0cm的无毛区。对无毛区进行真菌直接镜检及培养,结果均为阴性确认为阴性后用砂纸在豚鼠背上轻轻均匀地摩擦,并将菌悬液200μL均匀涂布于背部无毛区。涂菌1次后,连续观察10天。
4、分组及给药
取造模成功的实验动物随机分组,每组5只,每只动物的两个无毛区,给予同一种药物,连续给药14d,并记录给药前和给药14d后的评分,
评分标准
4分:红、肿、皮肤增厚,皮屑致密布满整个皮损部位。
3分:红、肿,皮损部位皮屑间有点状正常皮肤,累计小于25%。
2分:微红、不肿,皮损部位皮屑间有线状正常皮肤,累计小于50%。
1分:不红、不肿,皮损部位有少许皮屑间,75%以上皮肤正常。
0分:不红、不肿,基本正常。
分组给药与实验结果见下表
实验结果表明,实验1~4组采用本发明实施例提供的组合物,其对真菌感染模型动物的治疗效果既明显优于对照组,也优于采用单一活性成分的实验5/6组,说明本发明提供的组合物通过优选两种活性成分的比例,提高了对于皮肤真菌感染的治疗效果,特别是实验2/3组,其效果也明显优于实验1/4组,说明特别优选的化合物(I3)与酮康唑比例(1:1.2~1.4)能够表现出更好的抗皮肤真菌感染效果。
Claims (5)
1.一种复方酮康唑外用组合物,其特征在于所述组合物由作为活性成分的酮康唑和(3-(4(3H)-喹唑啉酮))甲基-1-(4-(3-甲基苄氧基)苯基)-5-(2-吡啶基)-1,4-戊二烯-3-酮肟醚(I3),和至少一种用于皮肤外用的辅料组成;所述组合物中酮康唑的质量百分比含量为0.3~0.5%,化合物(I3)与酮康唑的质量比为1:1.0~1.5。
2.如权利要求1所述的一种复方酮康唑外用组合物,其特征在于所述化合物(I3)与酮康唑的质量比为1:1.2~1.4。
3.如权利要求1或2所述的一种复方酮康唑外用组合物,其特征在于所述组合物制成乳膏剂、软膏剂、凝胶剂、混悬剂中的一种。
4.如权利要求3所述的一种复方酮康唑外用组合物,其特征在于所述组合物制成凝胶剂,所述辅料选自卡波姆、保湿剂、溶剂、防腐剂、表面活性剂、pH调节剂中的一种或几种,以及余量的水。
5.如权利要求4所述的一种复方酮康唑外用组合物,其特征在于所述卡波姆选自卡波姆934,卡波姆940,卡波姆941中的一种,所述卡波姆用量为组合物总质量的0.5%~1.5%;所述溶剂选优选乙醇,所述溶剂加入量以能将活性成分溶解的最小量为准;所述的保湿剂优选丙三醇,用量为4%~10%;所述表面活性剂优选吐温-80,用量为0.5%~1%;所述的pH调节剂选自氢氧化钠、磷酸/磷酸盐缓冲剂、醋酸/醋酸盐缓冲剂、柠檬酸/柠檬酸盐缓冲剂、硼酸/硼酸盐缓冲剂。
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