盐酸阿莫罗芬乳膏的研制及质量研究

发布时间：2018-04-15 15:39

本文选题：盐酸阿莫罗芬 + 真菌　；参考：《湖北中医药大学》2014年硕士论文

【摘要】：在日常生活中，皮肤真菌病很常见，它容易感染、传染性也比较大、并且经常复发，严重影响着病人的生活质量，目前临床上主要使用局部外用抗真菌药来治疗皮肤真菌病。阿莫罗芬作为抗真菌药物中的新类型，其抗菌作用比较强，很多常见致病菌都对它比较敏感，如皮肤癣菌、酵母菌、暗色孢科真菌、双相型真菌和一些条件致病真菌等。盐酸阿莫罗芬局部外用时可被甲蛋白吸收,对14位还原酶和7~8位异构酶具有双重抑制作用,并且能够有效杀灭和抑制灰指甲的常见致病菌(皮肤癣菌、酵母菌和霉菌)，具有极高的体外药理活性。本课题以盐酸阿莫罗芬为模型药物，剂型为乳膏剂，其规格为0.25%，并对其进行了以下四方面的研究：在处方工艺研究部分，根据防治疾病的需要，皮肤病一般选择软膏剂为最佳剂型，而乳剂型基质的软膏更易涂布，吸收也较好，对皮肤也有保护作用。我们在处方中加入了防腐剂、pH调节剂等功能性辅料，对乳化剂和油相的用量进行了处方筛选来确定最优处方。在初步确定处方之后，，以性状、pH值、分层现象等作为初步评价指标，并对制备的乳膏样品进行留样，根据留样结果再来设计处方，最后挑选出的处方既满足性状、pH值（6.0～7.5）、分层现象等评价指标，又能通过稳定性试验，作为最优处方。在质量标准研究部分，据药物剂型的特点和制剂的标准，对各项指标进行质量监控。为保证药物临床应用的安全性，我们对杂质进行了限量考察，对防腐剂苯氧乙醇进行了定量考察。用高效液相色谱法进行有关物质检测和主药含量测定，防腐剂的测定采用的是气相色谱法。对小试三批的样品进行测定，防腐剂的平均含量为0.498，主药平均含量为99.67%，有关物质均未检出。为保证制剂的有效性及临床应用安全性，我们对盐酸阿莫罗芬乳膏进行稳定性试验，其考察项目主要有影响因素试验、加速试验和长期稳定性试验和开包装稳定性试验。在影响因素试验中，高温情况下降解出了杂质Ro16-8652，5天为0.159%、10天为0.183%。稳定性试验结果给药物制剂的储藏条件提供了理论依据，该制剂应该密封置于凉暗处。最后，我们对所研制的盐酸阿莫罗芬乳膏的体外透皮吸收试验进行了方法学验证，测定其体外透皮量，并与市售乳膏进行了比对，透皮速率分别为2.2401g·(cm2)-1·h-1和2.3359　g·(cm2)-1·h-1，实验结果表明自制乳膏与市售乳膏的单位面积累积透皮量相近，它们的疗效相当，自制乳膏能够达到临床可替代性。
[Abstract]:In daily life, dermatomycosis is very common, it is easy to be infected, infectious and recurrent frequently, which seriously affects the quality of life of patients. At present, topical antifungal drugs are mainly used in the treatment of dermatomycosis.As a new type of antifungal drugs, amoxifene has strong antimicrobial activity, and many common pathogenic bacteria are sensitive to it, such as dermatophytes, yeasts, cytosporaceae, biphasic fungi and some conditional pathogenic fungi.Amoxifene hydrochloride can be absorbed by nail protein when it is used locally, it has double inhibitory effect on 14 reductase and 78 isomerase, and can effectively kill and suppress common pathogenic bacteria (dermatophytes, dermatophytes).Yeasts and molds have very high pharmacological activity in vitro.In this paper, amoxifen hydrochloride was used as the model drug, and the dosage form was used as cream, its specification was 0.25, and the following four aspects were studied.In the research part of prescription technology, according to the need of preventing and treating diseases, the cream of skin disease is generally chosen as the best dosage form, while the cream of emulsion type matrix is easier to coat, absorb better, and also has protective effect on skin.Functional excipients such as preservative and pH regulator were added to the prescription and the dosage of emulsifier and oil phase was selected to determine the optimal formulation.After the prescription was preliminarily determined, the pH value and stratification were taken as the initial evaluation indexes, and the samples of the prepared cream were retained, and the prescription was designed according to the retention results.The selected prescription can not only meet the evaluation indexes of pH value 6.0 and 7.5, stratification, but also can be used as the best prescription through the stability test.In the part of quality standard research, according to the characteristics of drug dosage form and the standard of preparation, the quality control of each index is carried out.In order to ensure the safety of drug clinical application, the impurity was limited and the preservative phenoxyethanol was quantitatively investigated.High performance liquid chromatography (HPLC) was used for the determination of related substances and main drug content, and gas chromatography was used for the determination of preservatives.The results showed that the average content of preservative was 0.498, the average content of main drug was 99.677.All the related substances were not detected.In order to ensure the efficacy of the preparation and the safety of clinical application, the stability test of amoxifene hydrochloride cream was carried out. The main items of the study were factor test, accelerated test, long-term stability test and open package stability test.In the experiment of influencing factors, the impurity Ro16-8652O5 days was 0.159% and 0.183% in 10 days.The stability test results provide a theoretical basis for the storage conditions of the drug preparation, which should be sealed in a cool dark place.Finally, the method of in vitro transdermal absorption test of amoxifene hydrochloride cream was verified, and the amount of in vitro transdermal absorption was determined and compared with that of commercial cream.The transdermal rate was 2.2401g / cm ~ (2) ~ (-1) h ~ (-1) and 2.3359 g / cm ~ (-2) 路h ~ (-1), respectively. The experimental results showed that the cumulative transdermal amount per unit area of self-made cream was similar to that of marketable cream, and the efficacy of self-made cream was similar, and the self-made cream could be substituted clinically.
【学位授予单位】：湖北中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R944

【参考文献】