阿戈美拉汀舌下片的处方工艺及其在比格犬体内的药代动力学研究

发布时间：2017-12-27 14:29

本文关键词：阿戈美拉汀舌下片的处方工艺及其在比格犬体内的药代动力学研究　出处：《安徽中医药大学》2016年硕士论文　论文类型：学位论文

【摘要】：阿戈美拉汀片是法国施维雅公司(Les Laboratoires Servier)研制出的一种具有显著疗效的抗抑郁症药。它是一种薄膜包衣的普通片,规格为25mg,几乎能够治疗各种抑郁症,作用效果更好,副作用小,在医生和患者中得到广泛的使用。阿戈美拉汀片虽口服吸收良好,但由于首过效应大,其生物利用度低,且个体差异较大,治疗效果没有得到充分的发挥。本文针对该药物的这一缺陷,决定改变给药方式,解决这一难题,考虑将其制成舌下片,采用舌下给药这一新型给药方式,以期减少其用量,降低个体间的差异,提高生物利用度,让这个疗效显著的抗抑郁药物更大的发挥其作用。目的:研究阿戈美拉汀舌下片的处方及制备工艺,制备出抗抑郁药阿戈美拉汀的新剂型舌下片,再分别测定舌下片及普通片在比格犬体内的血药浓度,通过比较两种制剂的药代动力学参数,考察该舌下片是否能够达到预期目的,提高生物利用度,减小个体差异。方法:本课题在充分研究该原料药的各种理化性质后,结合舌下片的质量标准,进行一系列的处方筛选,确定最终的处方及制备工艺。研制出阿戈美拉汀舌下片后,选用6只比格犬,采用两种给药途径,分别口服给药和舌下给药,在不同时间点用采血针进行采血,血浆处理后采用液质联用法进行血药浓度检测,将二者的药代动力学参数进行数据的处理和分析比较。结果:在处方筛选之前,充分考察了阿戈美拉汀原料药及各辅料性质,以乳糖、微晶纤维素、交联羧甲基纤维素钠、聚乙二醇4000、阿斯巴甜、泊洛沙姆为辅料,先进行单因素考察,在此基础上通过正交试验优化处方。试验结果显示,优化之后的处方设计比较合适,制备工艺较稳定,该舌下片三批间重现性良好。成功建立了阿戈美拉汀的溶出度及含量的检测方法,结果证明各方法准确可靠,专属性强、精密度好,能有效控制舌下片的质量,以外观性状、口感、崩解时限、溶出度、含量及有关物质等因素作为考察指标,结果显示均符合要求。对该舌下片进行初步稳定性实验,但由于时间匆促,没有对长期实验和加速实验的后期进行深入研究。由影响因素试验结果表明,本片的稳定性良好。由此,该舌下片已可用于进行药代动力学试验,试验结果为舌下片和普通片的Tmax分别为(0.22±0.14)h和(0.54±0.36)h,Cmax分别为(59.72±29.11)和(90.05±46.02),AUC(0~6h)分别为(28.91±10.59)和(79.56±41.48)。结论:由本课题研究结果可知,抗抑郁药阿戈美拉汀舌下片制备工艺成熟,在此基础上进行采用比格犬进行了药代动力学血药浓度检测,药物动力学参数表明,舌下片的达峰时间比普通片提前,即药物快速吸收,但Cmax及AUC在规格只有普通片的4%的情况下比普通片偏低,没有达到预期的效果,但研究意义巨大,可进行后续的研究。
[Abstract]:Agomelatine Tablets is a French Servier company (Les Laboratoires Servier) a significant efficacy of antidepressant drugs developed. It is a thin film coated ordinary tablet, the specification is 25mg, almost can treat various kinds of depression, the effect is better, the side effect is small, it is widely used in doctors and patients. Agomelatine Tablets has good oral absorption, but due to the first pass effect, its bioavailability is low, and the individual differences, the treatment effect has not been fully exploited. Aiming at the defects of the drug, decided to change the mode of administration, to solve this problem, consider from the sublingual tablet by the sublingual administration of this new mode of administration, in order to reduce their consumption, reduce the differences between individuals, improve the bioavailability, play its role make the curative effect the antidepressant drugs more. Objective: To study the agomelatine sublingual tablets formulation and preparation, preparation of antidepressant agomelatine new formulations of sublingual tablets, then determination of sublingual tablets and conventional tablets in blood concentration in beagle dogs, the pharmacokinetic parameters of two kinds of preparation, the sublingual tablets can to achieve the desired objectives, improve the bioavailability, reduce the individual differences. Methods: after fully studying the physical and chemical properties of the API, combined with the quality standard of sublingual tablets, we screened a series of prescriptions to determine the final formulation and preparation process. Developed agomelatine sublingual tablets, selection of 6 beagle dogs using two kinds of route of administration, and were orally administered under the tongue, blood for blood sampling needle at different time points after treatment, plasma by liquid chromatography-mass spectrometry for the detection of blood concentration, two the pharmacokinetic parameters comparison of data processing and analysis of. Results: in the prescription screening before fully investigated agomelatine and supplementary material properties, lactose, microcrystalline cellulose, croscarmellose sodium, polyethylene glycol 4000, aspartame, Bo Losham as the supplementary material, the single factor investigation, on the basis of the formulation was optimized by orthogonal test. The test results showed that the optimized formulation was more suitable, the preparation process was more stable, and the three batches of the sublingual tablets had a good reproducibility. Successfully established a method for determination of dissolution of agomelatine and content, it is proved that the method is accurate and reliable, strong specificity, good precision, can effectively control the quality of tablets under the tongue, the appearance, taste, disintegration, dissolution, content and related substances of such factors as the index, the results showed that to meet the requirements. Preliminary stability experiments on the sublingual tablets, but due to time constraints, there is no in-depth study on long-term experiment and accelerated the end of the experiment. The results of the influence factor test show that the stability of the film is good. Therefore, the sublingual tablets can be used for pharmacokinetic tests. The results of Tmax test for sublingual and normal tablets were (0.22 + 0.14) H and (0.54 + 0.36) h, Cmax were (59.72 + 29.11) and (90.05 + 46.02) respectively, and AUC (0~6h) were (28.91 + 10.59) and (79.56 + 10.59) respectively. Conclusion: from the research results, the antidepressant agomelatine sublingual tablets mature preparation process, on the basis of the Beagle dogs were pharmacokinetics blood drug concentration detection, showed pharmacokinetic parameters, sublingual tablets peak time than normal tablets in advance, that the drug is absorbed quickly, but Cmax and AUC in the specification only ordinary sheet of 4% cases lower than normal tablets, did not achieve the desired effect, but of great significance, for the follow-up study.
【学位授予单位】：安徽中医药大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943;R96

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