CN115475140A - 一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法 - Google Patents
一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法 Download PDFInfo
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Abstract
本发明公开了一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，配方如下：吴茱萸碱衍生物（主药）、白凡士林、液状石蜡、PEG‑400、硬脂酸、单硬脂酸甘油酯、三乙醇胺、十二烷基硫酸钠、氮酮、二丁基羟基甲苯、保湿剂、防腐剂、香精，余量为纯化水。本发明在制备过程中低速搅拌即可制备得到细腻均匀，涂布性能好的白色乳膏，且具有耐寒耐热与抗离心稳定性，便于工业化生产。本发明制得的新型吴茱萸碱衍生物乳膏主要用于皮肤浅部真菌感染，如手癣、足癣、体癣、股癣、湿疹等。
Description
技术领域
本发明属于化学制药技术领域，具体涉及一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，是一种用于治疗浅部真菌感染的外用药。
背景技术
浅部真菌感染是指皮肤和肢体外层的真菌感染，主要包括足癣、体癣、股癣、甲癣、头癣等，具有传染性和反复发作等特点，影响了全球约20-25%的人口，成为严重困扰各国人民健康的公共卫生问题。据最新统计，我国足癣发病率在各个年龄段发病率最高，而头癣的发病率以儿童最高，甲癣则主要集中在青少年和成人中。浅部真菌主要病原体是丝状真菌，包括毛癣菌属、表皮癣属、犬小孢子属、白念珠菌属等，其中约60%的皮肤癣菌感染由红色毛癣菌引起。近年来由于广谱抗生素、免疫抑制剂和抗恶性肿瘤药物的广泛应用，临床真菌感染发病率逐年上升。目前临床使用的抗浅部真菌药物主要为氮唑类与丙烯胺类，结构骨架相对单一，易产生耐药性与交差耐药性，使病情容易复发。而新药研究也主要集中在对氮唑类结构进行修饰改造。因此，寻找与开发具有新型骨架结构、抗真菌活性强、抗菌谱广、且抗耐药性好的新药，将具有极其重要的意义。
新型吴茱萸碱衍生物为本课题组前期通过对吴茱萸碱的结构修饰改造获得，其制备方法和在治疗浅部真菌感染中的应用已申请专利保护（一种吴茱萸碱衍生物在制备治疗浅部真菌感染药物中的应用，CN 202111134080.6）。本研究团队组在长期对中药的研究过程中，发现吴茱萸（始载于《神农本草经》）自古以来就被用来治疗湿寒脚气。《中药大辞典》：吴茱萸煎剂（100％）对霍乱弧菌有较强抑制效力（琼脂挖沟平板法）。10％水浸剂在试管内对絮状表皮癣菌有抑制作用；1:3水浸剂对奥杜盎氏小芽胞癣菌等11种皮肤真菌有不同程度抑制。吴茱萸的主要的活性成分为吴茱萸碱，但其抗真菌活性较弱。本研究团队前期通过对吴茱萸碱结构修饰改造及全面的体内外生物活性筛选，得到具有显著抗真菌活性化合物。该化合物结构完全不同于已上市抗真菌药物，其结构新颖、抗真菌活性强、抗菌谱广，尤其对红色毛癣菌、须癣毛癣菌、白色念珠菌的杀菌效果均明显优于市场上广泛使用的酮康唑。机制上主要通过抑制真菌生物膜与菌丝的形成，破坏真菌细胞壁、细胞膜结构，降低细胞表面疏水性，进而发挥抗真菌活性。
市场最常见的抗浅部真菌制剂为乳膏剂。乳膏剂为经皮给药制剂，一般起局部治疗效果，具有局部作用时间长，毒副作用小，使用方便等优点，因此，根据临床用药需要，拟将新型的吴茱萸碱衍生物开发为乳膏制剂，以便抗浅部真菌临床应用。基于原料药理化性质特点（稳定性较好，属于难溶性药物）和市售酮康唑乳膏的含药量（2%），因此将新型的吴茱萸碱衍生物制备成含药量2%的O/W乳膏剂型。
发明内容
本发明的目的在于提供一种治疗浅部真菌感染的新型吴茱萸碱衍生物抗浅部真菌乳膏的制备方法。
本发明采用以下技术方案：
一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，每制备100 g乳膏配方如下：吴茱萸碱衍生物（主药）2 g、白凡士林5-10 g、液状石蜡5-10 g、PEG-400 5-10 g、硬脂酸10-15 g、单硬脂酸甘油酯5-10g 、三乙醇胺0.5-2 g、十二烷基硫酸钠 0.05-0.2 g、氮酮3-5g、二丁基羟基甲苯0.01-0.02 g、保湿剂10-15 g、防腐剂0.1-0.2 g、香精0.1-0.2 g，余量为纯化水。
制备时采用如下步骤：
1）制备吴茱萸碱衍生物药物混悬液：向预先研磨后过200目筛的吴茱萸碱衍生物药物中加入配方量PEG-400，室温搅拌或超声混合均匀，备用；
2）制备油相：向上述吴茱萸碱衍生物药物混悬液中按配方量投入白凡士林、液状石蜡、硬脂酸、单硬脂酸甘油酯、二丁基羟基甲苯，于75~85℃搅拌4~6 min，备用；
3）制备水相：将上述配方量三乙醇胺、十二烷基硫酸钠、保湿剂、防腐剂、氮酮、纯化水混合，于75~85℃搅拌4~6 min ，备用；
4）制备乳膏：将上述水相缓慢加入油相中，搅拌15~25 min后，取出搅拌降温至40~50℃时加入香精，继续搅拌冷却至室温后封装即得。
其中，所述保湿剂为甘油、丙二醇中的一种或两种。所述防腐剂为羟苯甲酯、羟苯乙酯中的一种或两种。所述香精为丁香油、迷迭香油中的一种。
本发明在制备过程中低速搅拌即可制备得到细腻均匀，涂布性能好的白色乳膏，且具有耐寒耐热与抗离心稳定性，便于工业化生产。本发明制得的新型吴茱萸碱衍生物乳膏主要用于皮肤浅部真菌感染，如手癣、足癣、体癣、股癣、湿疹等。
附图说明
图1为吴茱萸碱衍生物抗浅部真菌乳膏的外观图片；
图2为吴茱萸碱衍生物抗浅部真菌乳膏苏丹IV染色的光学显微照片；
图3为吴茱萸碱衍生物抗浅部真菌乳膏直接涂片制片的光学显微照片。
具体实施方式
下面通过具体实施例对本发明的技术作进一步说明，但实施例不能理解为是对技术方案的限制。
实施例1
一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，每制备100g乳膏配方为：吴茱萸碱衍生物（主药）2 g、白凡士林5 g、液状石蜡5g、PEG-400 10g、硬脂酸15 g、单硬脂酸甘油酯5g 、三乙醇胺1 g、十二烷基硫酸钠0.1g、丙二醇10 g、氮酮5 g、二丁基羟甲苯0.01 g、羟苯乙酯0.2 g、丁香油0.1 g，余量为纯化水；
制备时采用如下步骤：
1）制备新型吴茱萸碱衍生物药物混悬液：向预先研磨后过200目筛的新型吴茱萸碱衍生物中加入配方量PEG-400，搅拌5 min，备用；
2）制备油相：向上述新型吴茱萸碱衍生物混悬液中按配方量投入白凡士林、液状石蜡、硬脂酸、单硬脂酸甘油酯、二丁基羟基甲苯,于80℃搅拌5 min，备用；
3）制备水相：将上述配方量三乙醇胺、十二烷基硫酸钠、丙二醇、羟苯乙酯、氮酮、纯化水于80℃搅拌5 min，备用；
4）制备乳膏：将上述水相缓慢加入油相中，搅拌20 min，取出搅拌降温至45℃，然后加入丁香油，继续搅拌至室温，封装即得。
图2为吴茱萸碱衍生物抗浅部真菌乳膏苏丹IV染色的光学显微照片；图3为吴茱萸碱衍生物抗浅部真菌乳膏直接涂片制片的光学显微照片。
实施例2
一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，每制备100g乳膏配方为：吴茱萸碱衍生物（主药）2g、白凡士林10 g、液状石蜡10 g、PEG-400 5 g、硬脂酸10 g、单硬脂酸甘油酯5g 、三乙醇胺2 g、十二烷基硫酸钠0.05 g、丙三醇5g、丙二醇10g、氮酮3 g、二丁基羟甲苯0.02 g、羟苯甲酯0.1 g、羟苯乙酯0.1 g、迷迭香精0.2 g，余量为纯化水。
制备方法同实施例1。
实施例3
一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，每制备100g乳膏配方为：吴茱萸碱衍生物（主药）2 g、白凡士林5 g、液状石蜡5 g、PEG-400 5 g、硬脂酸10 g、单硬脂酸甘油酯10g 、三乙醇胺0.5 g、十二烷基硫酸钠 0.2 g、丙三醇5 g、丙二醇5 g、氮酮3 g、二丁基羟甲苯0.02 g、羟苯甲酯0.1 g、羟苯乙酯0.1 g、迷迭香精0.2 g，余量为纯化水。
制备方法同实施例1。
本发明吴茱萸碱衍生物乳膏按以下质量标准进行检验：
1）性状
本品为水包油型白色乳膏，如图1。
2）鉴别：
HPLC主峰保留时间：在吴茱萸碱衍生物含量测定项下记的色谱图中，供试品溶液主峰的保留时间与对照品溶液主峰的保留时间一致。
3）检查
粒度检查：按《中国药典》2020年版（四部）通则0982第一法（显微镜法），取乳膏适量涂于载玻片上，覆上盖玻片，轻压使均匀，避免产生气泡，不得检出大于180 μm的粒子。
pH 检查：取本品约1g，加新煮沸放冷的纯净水9g，在40 ℃水浴5分钟，搅拌使溶解，放冷，用pH计检测，pH值为7.5-8.0。
4）吴茱萸碱衍生物含量测定方法（照2020年版《中国药典》高效液相色谱法(通则0512)测定）
色谱条件与系统适用性试验：色谱柱：Agilent 5HC-C18(2)柱（250 x 4.6 mm，5 μm）；流动相：甲醇-水（90:10）；流速：1 mL/min；柱温：35℃；检测波长：λ 274 nm；进样量：10μL；检测时间：12 min；理论板数按吴茱萸碱衍生物峰计算不低于5000。
测定法：取本品约50 mg，加无水乙醇适量，超声10min，放冷至室温，用无水乙醇定容至10ml，从中取1mL，加甲醇稀释定容至10 ml摇匀，0.45μm微孔滤膜滤过，滤过，取续滤液备用。精密量取续滤液10μl，注入液相色谱仪，记录色谱图；另取吴茱萸碱衍生物对照品适量，精密称定，加甲醇溶解并定量稀释制成每1ml中约含吴茱萸碱衍生物20μg的溶液，摇匀，同法测定，按外标法以峰面积计算，即得。实施例1-3吴茱萸碱衍生物含量为2%左右。
Claims (4)
1.一种吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，其特征在于：每制备100g乳膏配方为：吴茱萸碱衍生物2 g、白凡士林5-10 g、液状石蜡5-10 g、PEG-400 5-10 g、硬脂酸10-15 g、单硬脂酸甘油酯5-10g 、三乙醇胺0.5-2 g、十二烷基硫酸钠 0.05-0.2 g、氮酮3-5g，二丁基羟基甲苯0.01-0.02 g、保湿剂10-15 g、防腐剂0.1-0.2 g、香精0.1-0.2 g，余量为纯化水；
制备时采用如下步骤：
1）制备吴茱萸碱衍生物药物混悬液：向预先研磨后过200目筛的吴茱萸碱衍生物药物中加入配方量PEG-400，室温搅拌或超声混合均匀，备用；
2）制备油相：向上述吴茱萸碱衍生物药物混悬液中按配方量投入白凡士林、液状石蜡、硬脂酸、单硬脂酸甘油酯、二丁基羟基甲苯，于75~85℃搅拌4~6 min，备用；
3）制备水相：将上述配方量三乙醇胺、十二烷基硫酸钠、保湿剂、防腐剂、氮酮、纯化水混合，于75~85℃搅拌4~6 min ，备用；
4）制备乳膏：将上述水相缓慢加入油相中，搅拌15~25 min后，取出搅拌降温至40~50℃时加入香精，继续搅拌冷却至室温后封装即得。
2.如权利要求1所述的吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，其特征在于：所述保湿剂为甘油、丙二醇中的一种或两种。
3.如权利要求1所述的吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，其特征在于：所述防腐剂为羟苯甲酯、羟苯乙酯中的一种或两种。
4.如权利要求1所述的吴茱萸碱衍生物抗浅部真菌乳膏的制备方法，其特征在于：所述香精为丁香油、迷迭香油中的一种。
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| CN108125969A (zh) * | 2017-11-10 | 2018-06-08 | 牛云飞 | 一种治疗皮肤真菌感染的软膏及其制备方法 |
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