CN115212214A - 一种萘替芬酮康唑乳膏组合物和制备方法 - Google Patents
一种萘替芬酮康唑乳膏组合物和制备方法 Download PDFInfo
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- CN115212214A CN115212214A CN202210773520.0A CN202210773520A CN115212214A CN 115212214 A CN115212214 A CN 115212214A CN 202210773520 A CN202210773520 A CN 202210773520A CN 115212214 A CN115212214 A CN 115212214A
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- water
- ketoconazole
- naftifine
- cream
- oil
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Abstract
本发明公开了一种萘替芬酮康唑乳膏的组合物和制备方法。所述乳膏由盐酸萘替芬和酮康唑活性成分、油性基质、保湿剂、乳化剂、水,以及可选择的防腐剂、抗氧剂和螯合剂等辅料组成。本发明获得的萘替芬酮康唑乳膏具有易于涂抹、不油腻、可增强皮肤润肤度,显著改善手足癣、体股癣、头癣、皮肤念珠菌病等皮肤脱屑和开裂现象,更易于患者接受,稳定性优于市售的萘替芬酮康唑乳膏。
Description
技术领域
本发明属于药物制剂领域,涉及一种萘替芬酮康唑乳膏组合物及其制备方法。
背景技术
萘替芬酮康唑乳膏是一种外用抗真菌药,是由1%盐酸萘替芬和0.25%酮康唑组成的复方制剂,最早是由重庆华邦制药于2005年10月在中国上市的新药,商品名为必亮,其特点是将盐酸萘与替酮康唑芬按照4:1组成复方制剂,活性成分的浓度为1%盐酸萘替芬和0.25%酮康唑,远远低于单一制剂酮康唑乳膏中酮康唑的浓度2%,减少毒副作用,合用后能起到协同抗菌的作用。
盐酸萘替芬和酮康唑均可抑制真菌细胞膜麦角固醇的合成,使膜结构破坏从而抑制真菌细胞的生长,但二者影响麦角固醇合成的机制不同。酮康唑作用域羊毛类固醇的C-14去甲基化酶,抑制羊毛类固醇向14-去甲基羊毛类固醇的转化,从而抑制麦角固醇的合成,对皮肤癣菌和酵母菌等均有抑制和杀菌作用。盐酸萘替芬作用靶位是角鲨烯环氧化酶,抑制角鲨烯转化为角鲨烯环氧化物,最终抑制麦角固醇的生物合成。此外,角鲨癣杀菌力强,而对酵母菌则呈抑菌作用。盐酸萘替芬和酮康唑组成复方制剂,从作用机制的角度起到协同抗菌的作用。
目前市售的萘替芬酮康唑乳膏存在常温下析晶、离心容易分层等缺点,所以需要制备一种稳定性和保湿性更好的萘替芬酮康唑乳膏制剂。
发明内容
本发明的目的是研制一种烯丙胺类药物和唑类药物联合使用,通过不同的作用机制,提供协同作用,抗菌效果与市售的萘替芬酮康唑乳膏(商品名为必亮)相似,具有易于涂抹、不油腻、可增强皮肤润肤度,保湿性和稳定性均优于必亮的萘替芬酮康唑乳膏组合物。
本发明的目的是通过以下技术方案来实现的:
本发明涉及一种含萘替芬和酮康唑的乳膏组合物,所述的乳膏为油包水型乳膏。包括盐酸萘替芬和酮康唑活性成分和外用制剂的辅料,辅料包括油性基质、保湿剂、乳化剂,防腐剂、抗氧剂、pH调节剂、螯合剂和水等。
作为一个实施方案,活性成分和辅料在乳膏组合物总重量的质量百分比分别为:盐酸萘替芬1%、酮康唑0.25%、油相基质15-30%、水包油乳化剂2.5-3.5%、油包水乳化剂0.5%-1.0%、保湿剂3.5-8%、抗氧化剂0.1-0.3%、防腐剂0.15-0.25%、螯合剂0.025-0.075%、适当的pH调节剂、水65-75%,水定重至100。
作为一个实施案例,所述油相基质选自十六醇、十八醇、轻质液体石蜡、凡士林、硬脂酸等中的一种或者几种,优选十六醇、十八醇、轻质液体石蜡混合物,优选占比16-20%。
作为一个实施案例,所选的乳化剂为水包油型乳化剂和油包水型乳化剂两种组合,选自如吐温60、吐温80、司盘60、司盘80、单双硬脂酸甘油酯、单硬脂酸甘油酯中的两种,其中一种为水包油型乳化剂如吐温60、吐温80,另一种为油包水型乳化剂如司盘60、司盘80、单双硬脂酸甘油酯、单硬脂酸甘油酯,以萘替芬酮康唑乳膏总重的质量百分比计,水包油性乳化剂占比在2.5-3.5%范围内,优选2.7-3.3%,油包水乳化剂占比在0.5-1.0%范围内,优选0.65-0.85%。
作为一个实施方案,所述的保湿剂选自丙二醇、甲基葡萄醇聚醚-10、甲基葡萄醇聚醚-20、AQUAXYLTM的一种或者多种,优选甲基葡萄醇聚醚-20、AQUAXYLTM,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在3.5-8%,优选4-6%。保湿剂丙二醇、甲基葡萄醇聚醚-20、AQUAXYLTM等在乳膏体系中即可以作为活性成分的溶剂,又起到保湿润肤的作用。
作为一个实施方案,所述的抗氧化剂选自焦亚硫酸钠、亚硫酸钠、BHA、BHT的一种,优选焦亚硫酸钠、亚硫酸钠,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在0.1-0.3%,优选0.15-0.25%。
作为一个实施方案,所述的螯合剂选自依地酸二钠、醋酸钙、柠檬酸钾、三乙酯二胺四乙酸二钠的一种,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在0.025-0.075%。
作为一个实施方案,所述的防腐剂选自山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯一种,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在0.15-0.25%。
作为一个实施方案,所述的萘替芬和酮康唑的乳膏组合物通过适量的pH调节剂将乳膏的pH调节到6.5-7.5,所述的pH调节剂为氢氧化钠或盐酸溶液。
作为一个实施方案,活性成分和辅料在乳膏组合物总重量的质量百分比分别为:盐酸萘替芬1%、酮康唑0.25%、油相基质(由十六醇、十八醇和液体石蜡组成)15-30%,水包油乳化剂为吐温2.5-3.5%、油包水乳化剂为司盘0.5%-1.0%、水65-75%、保湿剂(选自丙二醇、甲基葡萄醇聚醚-20或者AQUAXYLTM中的任意一种)占比3.5-8%、抗氧化剂0.1-0.3%、防腐剂0.15-0.25%,螯合剂0.025-0.075%,适当的pH调节剂。
作为一个实施方案,酮康唑在酸性条件下不稳定,且盐酸萘替芬呈酸性,两个活性物质直接混合会导致酮康唑降解并导致性状发生变化,故在乳膏基质中优先加入盐酸萘替芬分散液,调节至pH值至6.5-7.5后加入酮康唑分散液。
本发明还涉及一种萘替芬酮康唑乳膏制备方法,所述方法包含如下步骤:
(1)活性相I配制:取处方量的盐酸萘替芬、部分保湿剂/溶剂,加热溶解,备用。
(2)活性相II配制:取处方量的酮康唑、处方余量的保湿剂/溶剂,加热溶解,备用。
(3)水相的配制:取处方量的水,加入处方量的水、水包油乳化剂、保湿剂、抗氧化剂、螯合剂、防腐剂,加热,搅拌溶解。
(4)油相的配制:取处方量的油包水乳化剂、油相基质,加热,搅拌溶解。
(5)油水混合乳化:取水相加入油相,搅拌,均质。加入活性相I,搅拌,调节pH值至6.5-7.5,降温后加入活性相II,搅拌。
(6)灌装得萘替芬酮康唑乳膏。
本发明还涉及一种萘替芬酮康唑乳膏组合物在制备治疗真菌性皮肤病的药物中的应用,真菌性皮肤病如手足癣、体股癣、头癣、皮肤念珠菌病等疾病。
与现有技术相比,本发明具有如下有益效果:
本发明提供了一种萘替芬酮康唑乳膏的组合物和制备方法,所制备得到的乳膏保湿性明显优于萘替芬酮康唑乳膏(商品名为必亮),具有易于涂抹、不油腻、可增强皮肤润肤度的优势,显著改善手足癣、体股癣、头癣、皮肤念珠菌病等皮肤脱屑和开裂现象,更易于患者接受,本发明制备得到的萘替芬酮康唑乳膏稳定性优于市售必亮。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述,本发明的其它特征、目的和优点将会变得更明显:
图1为实施例2的乳膏外观图片;
图2为实施例2的乳膏离心分层图片;
图3为必亮的离心分层图片。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干调整和改进。这些都属于本发明的保护范围。
本发明的萘替芬酮康唑乳膏,为油包水乳膏,包括盐酸萘替芬和酮康唑活性成分和外用制剂的辅料,盐酸萘替芬1%、酮康唑0.25%,辅料包括水包油乳化剂2.5-3.5%、油包水乳化剂0.5%-1.0%,保湿剂3.5-8%、抗氧化剂0.1-0.3%、防腐剂0.15-0.25%,螯合剂0.025-0.075%,油相基质15-30%,适当的pH调节剂,水65-75%,定重至100。
本发明的萘替芬酮康唑乳膏的制备方法包括如下步骤:
(1)活性相I配制:取处方量的盐酸萘替芬、处方量25%的保湿剂,加热至60-70℃溶解,备用。
(2)活性相II配制:取处方量的酮康唑、处方量75%的保湿剂,加热至40-50℃溶解,备用。
(3)水相的配制:75-85℃条件下,加入处方量的水、水包油乳化剂、保湿剂/溶剂、抗氧化剂、螯合剂、防腐剂,搅拌溶解。
(4)油相的配制:75-85℃条件下,取处方量的油包水乳化剂、油相基质,搅拌溶解。
(5)油水混合乳化:在75-85℃条件下,取水相加入油相,搅拌15-30min,均质。
降温至60-65℃,加入活性相I,搅拌30min-1h,用pH调节剂将体系pH值调节至6.5-7.5,降温至45-50℃,加入活性相II,搅拌30min-1h。
(6)降温至30-35℃,灌装得萘替芬酮康唑乳膏。
具体应用示例如下:
实施例1-3
采用油包水型乳化剂和水包油型乳化剂作为乳膏的复合乳化剂、保湿剂丙二醇、甲基葡萄醇聚醚-20、AQUAXYLTM等在乳膏体系中即可以作为活性成分的溶剂,又起到保湿润肤的作用。采用如上处方制备出的乳膏、高速离心不分层、细腻、有关物质和含量均符合制剂要求。
对比例1:
萘替芬酮康唑乳膏具体处方见表2,制备方法同实施例1-3中萘替芬酮康唑乳膏的制备方法。
表2
对比例2
萘替芬酮康唑乳膏具体处方见表3,制备工艺如下:
(1)水相A液的配制
称取处方量的纯化水、氢氧化钠、亚硫酸氢钠、吐温80、羟苯乙酯、依地酸二钠,置油浴85±2℃搅拌使溶解,保温备用,为A液。
(2)油相B液的配制
称取处方量的十六十八醇、肉豆蔻酸异丙酯、司盘60,置油浴85±2℃搅拌使溶解,保温备用,为B液。
(3)药液C的配制
称取处方量的甘油,加热至95±2℃后,投入处方量的盐酸萘替芬粉末,完全溶解后,降温至60±2℃,保温备用,为C液。
(4)药液D的配制
称取处方量的丙二醇,加热至60±2℃后,投入处方量的酮康唑粉末,完全溶解后,保温备用,为D液。
(5)乳膏制备
在快速搅拌(500r/min)下,将A液缓缓加入到B液,至完全乳化后,依次缓缓加入C液和D液,调节pH至7.2~7.4,再搅拌降温至40~45℃,灌装,即得。
表3
实施例4
对实施例1-3以及对比例1-2和市售的萘替芬酮康唑乳膏(商品名:必亮)进行了黏度、离心、性状、pH、含量、有关物质和含量均匀度等检测,结果如下表4。
表4
质量指标对比结果表明,本专利处方和制备工艺制备的萘替芬酮康唑乳膏在室温条件下,10000rpm离心15分钟,萘替芬酮康唑乳膏不分层,而市售萘替芬酮康唑乳膏(商品名:必亮)有分层现象,其他质量指标均与必亮相似。而对比例1,因黏度太低,呈流动状态,使用时无法涂抹而流淌。对比例2因黏度略大,涂抹性相对较差。
实施例5
对实施例1-3和萘替芬酮康唑乳膏(商品名:必亮)进行了长期稳定性考察,放置于温度为30±2℃、湿度为RH60%±5%的条件下,分别于3月、6月取样检测性状、黏度、pH值、含量、有关物质,具体检测结果见下表5。
表5
稳定性对比结果表明,本专利处方和制备工艺制备的萘替芬酮康唑乳膏,在长期6个月内,黏度基本保持稳定,杂质基本未有明显增加,而萘替芬酮康唑乳膏(必亮)有一定的黏度降低,且有关物质略有增加。表明按照本专利处方和制备工艺制备的萘替芬酮康唑乳膏,外观细腻,具有良好的稳定性。
实施例6体外保湿性能评价
吸湿率测定:称取待测样品于称量瓶中,在25℃、RH92.5%(饱和硝酸钾溶液)的环境中,每间隔一段时间取出称量。根据实验前后待测样品的质量差,计算吸湿率。
保湿率测定:称取待测样品于称量瓶中,将其放置在装有干微粉硅胶的干燥器中,每间隔一段时间取出称量。根据实验前后待测样品的质量差,计算保湿率。取实施例1-3和必亮进行吸湿率和保湿率测定,具体结果分别见表6和表7:
表6
表7
按照本专利处方和工艺制备的乳膏,其吸湿率均高于市售萘替芬酮康唑乳膏必亮,保湿率均小于必亮,说明按照本专利处方和工艺制备的乳膏的保湿性明显优于必亮,可显著改善手足癣、体股癣、头癣、皮肤念珠菌病等皮肤脱屑和开裂现象,更易于患者接受。
实施例7体外透皮试验数据对比
体外透皮实验
方法:Franz扩散池法
仪器:SYSTEM 918-12干加热自动透皮系统,厂家Logan Instruments Corp.(禄亘仪器设备有限公司)
皮肤:实验用猪皮,厚度0.8-1mm,接触直径15mm
接收液:生理盐水
接受液温度:32±0.5℃
转速:600rpm
样品:分别精密称取各处方乳膏样品约300mg,均匀涂布在实验用猪皮上,每个处方重复涂布3个样品,同时将未涂抹乳膏的猪皮最为空白猪皮。
扩散池体积:12ml
试验时间:24小时。
药物滞留量的测定
透皮实验结束后,取下猪皮,清除残留药物制剂,用生理盐水冲洗干净,滤纸吸干,取约0.1g,精密称定,加水2.0ml,匀浆,取1ml过滤进液相测定猪皮中的萘替芬和酮康唑,计算各制剂皮肤滞留量,结果见表8,表格中KCZ代表酮康唑,NTF代表萘替芬。
表8
从表中可以看到,实施案例1-3制备的萘替芬酮康唑乳膏的皮肤滞留量与市售商品必亮(含1%盐酸萘替芬和0.25%酮康唑)相似,说明按照本专利处方和工艺制备的萘替芬酮康唑乳膏具有与必亮相似的临床效果。而对比例2,盐酸萘替芬和酮康唑的皮肤滞留量远远高于市售必亮,同时接受介质中的浓度将变大,大大增加了临床使用的安全性风险。本专利制备的乳膏更易于涂抹、不油腻、可增强皮肤润肤度,显著改善手足癣、体股癣、头癣、皮肤念珠菌病等皮肤脱屑和开裂现象,更易于患者接受。
以上对本发明的具体实施例进行了描述。需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。
Claims (10)
1.一种萘替芬酮康唑乳膏组合物,其特征在于所述的乳膏由盐酸萘替芬和酮康唑活性成分和外用制剂辅料组成,所述外用制剂辅料由油性基质、保湿剂、乳化剂、pH调节剂、水、防腐剂、抗氧剂和螯合剂组成。
2.如权利要求1所述的萘替芬酮康唑乳膏组合物,其特征在于所述保湿剂选自丙二醇、甲基葡萄醇聚醚-10、甲基葡萄醇聚醚-20、AQUAXYLTM的一种或者多种,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在3.5-8%。
3.如权利要求1所述的萘替芬酮康唑乳膏组合物,其特征在于所述乳化剂为水包油型乳化剂和油包水型乳化剂两种组合,所述水包油型乳化剂选自吐温60、吐温80中的任意一种,所述油包水型乳化剂选自司盘60、司盘80、单双硬脂酸甘油酯、单硬脂酸甘油酯中的任意一种,以萘替芬酮康唑乳膏总重的质量百分比计,所述水包油性乳化剂占比在2.5-3.5%,所述油包水乳化剂占比在0.5-1.0%。
4.如权利要求1所述的萘替芬酮康唑乳膏组合物,其特征在于所述油相基质选自十六醇、十八醇、轻质液体石蜡、凡士林、硬脂酸等中的一种或者几种,以萘替芬酮康唑乳膏总重的质量百分比计,所述油相基质占比为16-20%。
5.如权利要求1所述的萘替芬酮康唑乳膏组合物,其特征在于所述抗氧化剂选自焦亚硫酸钠、亚硫酸钠、BHA、BHT的一种,以萘替芬酮康唑乳膏总重的质量百分比计,所述抗氧化剂占比为0.1-0.3%。
6.如权利要求1所述的萘替芬酮康唑乳膏组合物,其特征在于所述的螯合剂选自依地酸二钠、醋酸钙、柠檬酸钾、三乙酯二胺四乙酸二钠的一种,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在0.025-0.075%;所述的防腐剂选自山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯一种,以萘替芬酮康唑乳膏总重的质量百分比计,其占比为在0.15-0.25%。
7.如权利要求1所述的萘替芬酮康唑乳膏组合物,其特征在于所述的活性成分和外用制剂的辅料在乳膏组合物中的质量百分比分别为:盐酸萘替芬1%、酮康唑0.25%、油相基质15-30%、水包油乳化剂2.5-3.5%、油包水乳化剂0.5%-1.0%、水65-75%、保湿剂3.5-8%、抗氧化剂0.1-0.3%、防腐剂0.15-0.25%、螯合剂0.025-0.075%、pH调节剂适量。
8.如权利要求7所述的萘替芬酮康唑乳膏组合物,其特征在于所述活性成分和辅料在乳膏组合物中质量百分比分别为:盐酸萘替芬1%,酮康唑0.25%,由十六醇、十八醇和液体石蜡组成的油相基质15-30%,水包油乳化剂为吐温2.5-3.5%,油包水乳化剂为司盘0.5%-1.0%,选自丙二醇、甲基葡萄醇聚醚-20或者AQUAXYLTM中的任意一种的保湿剂3.5-8%,抗氧化剂0.1-0.3%,防腐剂0.15-0.25%,螯合剂0.025-0.075%,pH调节剂适量,水定重至100。
9.如权利要求1所述的萘替芬酮康唑乳膏组合物制备方法,其特征在于包含如下步骤:
(1)活性相I配制:取处方量的盐酸萘替芬、部分保湿剂,加热溶解,备用。
(2)活性相II配制:取处方量的酮康唑、处方余量的保湿剂,加热溶解,备用。
(3)水相的配制:取处方量的水,加入处方量的水、水包油乳化剂、保湿剂、抗氧化剂、螯合剂、防腐剂,加热,搅拌溶解。
(4)油相的配制:取处方量的油包水乳化剂、油相基质,加热,搅拌溶解。
(5)油水混合乳化:取水相加入油相,搅拌,均质。加入活性相I,搅拌,调节pH值至6.5-7.5,降温后加入活性相II,搅拌。
(6)灌装得萘替芬酮康唑乳膏。
10.如权利要求1-8任一项所述乳膏组合物在制备治疗真菌性皮肤病药物中的应用。
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