难溶性药物体外溶出评价及溶出度方法的建立

发布时间：2018-12-21 15:35

【摘要】：溶出度是指在规定条件下药物活性成分从片剂、胶囊剂或颗粒剂等固体口服制剂中溶出的速率和程度。当前,溶出度的应用日趋广泛,它可以用于处方、制剂工艺和剂型的评价和筛选,固体制剂的质量评价,根据溶出度结果并结合体内外相关性,预测药物的体内生物利用度等,由此可见,溶出度试验现已成为药品质量控制的重要项目之一。然而,现行药品特别是难溶性药物的质量标准中的溶出度方法,其溶出度结果与体内生物利用度是否相关尚存争议,例如为了使药物能够完全溶出,采用过于剧烈的溶出条件,与胃肠道生理环境严重不符。由此可能导致不同企业的同种药物的临床疗效差异较大。因此,探索建立既能反映药物内在质量又能体现其体内生物活性的溶出度方法,对严格控制药品质量,确保药品临床使用的有效性和安全性至关重要。本课题通过考察不同类型的难溶性药物替米沙坦(弱酸性)、卡马西平(中性)和卡维地洛(弱碱性)的溶解度和表观油水分配系数等理化性质,对三种药物的溶出条件从溶出介质、溶出体积和转速等方面进行优化,建立更接近胃肠道内环境的溶出条件,并对不同企业生产的样品分别进行溶出行为考察的同时,与日本橙皮书中的溶出曲线做比对分析。实验表明,优化后的溶出度方法有较好的区分力,能更客观地评价药品的质量,且溶出条件与生理环境相似度高,具有良好的体内外相关性。此外,本课题利用激光共聚焦显微拉曼光谱仪对三种药物的不同企业样品进行拉曼图谱测定,结果表明,卡马西平片和卡维地洛片不同样品问的溶出差异与晶型无关,替米沙坦片存在三种拉曼图谱,相应的溶出情况也不同,主要是由不同的处方或生产工艺造成的。本课题对不同类型难溶性药物的溶出条件进行研究,并根据优选条件比较分析不同工艺和处方制剂的溶出曲线,为研究和建立合理的溶出度方法提供策略和指导,并为进一步研究溶出度的体内外相关性提供有意义的参考。
[Abstract]:Dissolution rate is the rate and extent of dissolution of active components from tablets, capsules or granules. At present, dissolution has been used more and more widely. It can be used in the evaluation and screening of prescriptions, preparation processes and dosage forms, the quality evaluation of solid preparations, and the prediction of bioavailability of drugs in vivo and in vivo according to the dissolution results and the correlation in vivo and in vitro. Thus, dissolution test has become one of the important items of drug quality control. However, whether the dissolution method in the current quality standards for drugs, especially insoluble drugs, is relevant to bioavailability in vivo, for example, in order to allow the drug to be completely dissolved, is subject to excessive dissolution conditions, It is seriously incompatible with the physiological environment of the gastrointestinal tract. This may lead to greater differences in the clinical efficacy of the same drug in different enterprises. Therefore, it is very important to establish a dissolution method which can reflect both the intrinsic quality and the biological activity of drugs, which is very important to strictly control the quality of drugs and ensure the effectiveness and safety of clinical use of drugs. The physical and chemical properties of different insoluble drugs, such as telmisartan (weak acid), carbamazepine (neutral) and carvedilol (weak alkalinity), were investigated. The dissolution conditions of the three drugs were optimized from the aspects of dissolution medium, volume and speed of dissolution, so as to establish the dissolution conditions closer to the environment in the gastrointestinal tract. At the same time, the samples produced by different enterprises were investigated respectively. Compare and analyze the dissolution curve in Japanese orange peel book. The experimental results show that the optimized dissolution method has better discriminating power and can objectively evaluate the quality of drugs, and the dissolution conditions have high similarity with the physiological environment and have good in vitro and in vivo correlation. In addition, the Raman spectra of different samples of three drugs were determined by laser confocal microscopy Raman spectrometer. The results showed that the dissolution of carbamazepine tablets and carvedilol tablets was not related to the crystal type. There are three kinds of Raman patterns in telmisartan tablets, and the dissolution conditions are different, mainly caused by different prescriptions or production processes. In this paper, the dissolution conditions of different insoluble drugs were studied, and the dissolution curves of different processes and prescriptions were compared and analyzed according to the optimal conditions, which provided strategies and guidance for the study and establishment of reasonable dissolution methods. It also provides a useful reference for further study on in vitro and in vivo correlation of dissolution.
【学位授予单位】：浙江工业大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R917

【参考文献】