黄体酮阴道缓释凝胶的药学研究

发布时间：2018-03-04 10:27

  本文选题：黄体酮　切入点：缓释凝胶　出处：《大连理工大学》2016年硕士论文　论文类型：学位论文

【摘要】：正常的黄体功能对于维持妊娠和胚胎着床是必不可少的。辅助生殖技术中的控制性促排卵及卵泡抽吸会降低黄体期的激素水平,导致黄体功能不全、妊娠率下降、流产率增加,影响治疗效果。所以黄体支持成为辅助生殖技术的常规治疗。为了有效地提供黄体支持,降低全身副作用,提高患者的顺应性,本研究拟对一种黄体酮阴道缓释凝胶的处方、制备工艺和质量标准等进行研究。根据国外相关产品雪诺同@的文献资料与辅料的性质特点,初步确定黄体酮阴道缓释凝胶的处方。以凝胶的微相结构、体外释放度和粘度为指标,优化黄体酮缓释凝胶的处方组成及制备工艺。制得的黄体酮阴道缓释凝胶是一种含有8%(w/w)微粉化黄体酮的水包油型乳液分散在聚卡波菲基质中的凝胶制剂,通过一个特殊的给药装置阴道给药。其中聚卡波菲确保凝胶黏附到阴道上皮细胞,而该乳液形式提供油相储库,使黄体酮连续从油相释放到水相进而进入阴道组织。采用混合剪切工艺可制备出均匀细腻的白色黄体酮缓释凝胶。在释放度对比测试中,自制样品与国外样品的释放曲线的相似因子f2为74.82,大于50,表明两者释放行为无差异。参考《中国药典(2015年版)》以及《新药质量研究技术指导原则》,我们对凝胶进行了质量研究,建立了含量测定、有关物质检查和微生物限度检查方法,确定了体外释放度测定条件及检测方法。建立了微生物检查方法,采用平皿法对细菌、真菌和霉菌进行计数检查。该方法回收在0.5-2.0范围内,适用于黄体酮凝胶的微生物检查。为建立黄体酮阴道缓释凝胶质量标准提供依据。最后,对黄体酮凝胶的稳定性进行了初步研究。影响因素试验表明黄体酮缓释凝胶在高温(60℃)、高湿(RH 90%±5%)和强光照射(4500 1x+500 1x)条件下,药物稳定,无新杂质产生。但在高温条件下,性状轻微变化,凝胶略有变干,可能是部分水分挥发造成的。加速实验结果表明,在30℃,RH65%的条件下放置2个月后,凝胶的性状、含量及有关物质均无显著变化,各时间点的累计释放率无明显差异,后续稳定性试验仍在进行中。参照上述试验结果和雪诺同@的保存条件,黄体酮缓释凝胶适合于密封低于25℃环境保存。
[Abstract]:Normal luteal function is essential for maintaining pregnancy and embryo implantation. Controlled ovulation and follicular aspiration in assisted reproductive technology can reduce hormone levels in the luteal phase, leading to inadequate luteal function, decreased pregnancy and increased abortion. In order to effectively provide luteal support, reduce systemic side effects and improve patients' compliance, this study is intended to prescribe a progesterone vaginal sustained-release gel. The preparation process and quality standard were studied. According to the characteristics of the literature and excipients of Snow @, the formulation of progesterone vaginal sustained-release gel was preliminarily determined. The microphase structure of the gel was used. In vitro release and viscosity were used as indicators, The formulation and preparation of progesterone sustained-release gel were optimized. The prepared gel was a kind of water-in-oil emulsion containing 8w / w micro-powdered progesterone dispersed in the polyCarbofi matrix. Through a special drug delivery device, vaginal administration, in which Poly Carbofi ensures that the gel adheres to the vaginal epithelial cells, while the emulsion provides an oil reservoir, Progesterone was continuously released from oil phase to water phase and then into vaginal tissue. A uniform and fine white sustained release gel of progesterone could be prepared by mixed shear process. The similarity factor f _ 2 of the release curve between domestic and foreign samples is 74.82, which indicates that there is no difference in release behavior between the two. Referring to "Chinese Pharmacopoeia (2015)" and "Technical guiding principles for New Drug quality Research", we have studied the quality of gel. The methods of content determination, related substances examination and microbial limit test were established, and the conditions and methods of in vitro release were determined. The method of microbiological examination was established, and the bacteria were tested by plate method. The method is suitable for microbiological examination of progesterone gel. It provides the basis for establishing the quality standard of progesterone vaginal sustained-release gel. The stability of progesterone gel was preliminarily studied. The experimental results showed that under the conditions of high temperature (60 鈩，

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