發(fā)布時(shí)間：2017-12-27 14:29

  本文關(guān)鍵詞：阿戈美拉汀舌下片的處方工藝及其在比格犬體內(nèi)的藥代動(dòng)力學(xué)研究　出處：《安徽中醫(yī)藥大學(xué)》2016年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 阿戈美拉汀 舌下片 生物利用度 個(gè)體差異 藥代動(dòng)力學(xué)參數(shù)

【摘要】：阿戈美拉汀片是法國施維雅公司(Les Laboratoires Servier)研制出的一種具有顯著療效的抗抑郁癥藥。它是一種薄膜包衣的普通片,規(guī)格為25mg,幾乎能夠治療各種抑郁癥,作用效果更好,副作用小,在醫(yī)生和患者中得到廣泛的使用。阿戈美拉汀片雖口服吸收良好,但由于首過效應(yīng)大,其生物利用度低,且個(gè)體差異較大,治療效果沒有得到充分的發(fā)揮。本文針對(duì)該藥物的這一缺陷,決定改變給藥方式,解決這一難題,考慮將其制成舌下片,采用舌下給藥這一新型給藥方式,以期減少其用量,降低個(gè)體間的差異,提高生物利用度,讓這個(gè)療效顯著的抗抑郁藥物更大的發(fā)揮其作用。目的:研究阿戈美拉汀舌下片的處方及制備工藝,制備出抗抑郁藥阿戈美拉汀的新劑型舌下片,再分別測定舌下片及普通片在比格犬體內(nèi)的血藥濃度,通過比較兩種制劑的藥代動(dòng)力學(xué)參數(shù),考察該舌下片是否能夠達(dá)到預(yù)期目的,提高生物利用度,減小個(gè)體差異。方法:本課題在充分研究該原料藥的各種理化性質(zhì)后,結(jié)合舌下片的質(zhì)量標(biāo)準(zhǔn),進(jìn)行一系列的處方篩選,確定最終的處方及制備工藝。研制出阿戈美拉汀舌下片后,選用6只比格犬,采用兩種給藥途徑,分別口服給藥和舌下給藥,在不同時(shí)間點(diǎn)用采血針進(jìn)行采血,血漿處理后采用液質(zhì)聯(lián)用法進(jìn)行血藥濃度檢測,將二者的藥代動(dòng)力學(xué)參數(shù)進(jìn)行數(shù)據(jù)的處理和分析比較。結(jié)果:在處方篩選之前,充分考察了阿戈美拉汀原料藥及各輔料性質(zhì),以乳糖、微晶纖維素、交聯(lián)羧甲基纖維素鈉、聚乙二醇4000、阿斯巴甜、泊洛沙姆為輔料,先進(jìn)行單因素考察,在此基礎(chǔ)上通過正交試驗(yàn)優(yōu)化處方。試驗(yàn)結(jié)果顯示,優(yōu)化之后的處方設(shè)計(jì)比較合適,制備工藝較穩(wěn)定,該舌下片三批間重現(xiàn)性良好。成功建立了阿戈美拉汀的溶出度及含量的檢測方法,結(jié)果證明各方法準(zhǔn)確可靠,專屬性強(qiáng)、精密度好,能有效控制舌下片的質(zhì)量,以外觀性狀、口感、崩解時(shí)限、溶出度、含量及有關(guān)物質(zhì)等因素作為考察指標(biāo),結(jié)果顯示均符合要求。對(duì)該舌下片進(jìn)行初步穩(wěn)定性實(shí)驗(yàn),但由于時(shí)間匆促,沒有對(duì)長期實(shí)驗(yàn)和加速實(shí)驗(yàn)的后期進(jìn)行深入研究。由影響因素試驗(yàn)結(jié)果表明,本片的穩(wěn)定性良好。由此,該舌下片已可用于進(jìn)行藥代動(dòng)力學(xué)試驗(yàn),試驗(yàn)結(jié)果為舌下片和普通片的Tmax分別為(0.22±0.14)h和(0.54±0.36)h,Cmax分別為(59.72±29.11)和(90.05±46.02),AUC(0~6h)分別為(28.91±10.59)和(79.56±41.48)。結(jié)論:由本課題研究結(jié)果可知,抗抑郁藥阿戈美拉汀舌下片制備工藝成熟,在此基礎(chǔ)上進(jìn)行采用比格犬進(jìn)行了藥代動(dòng)力學(xué)血藥濃度檢測,藥物動(dòng)力學(xué)參數(shù)表明,舌下片的達(dá)峰時(shí)間比普通片提前,即藥物快速吸收,但Cmax及AUC在規(guī)格只有普通片的4%的情況下比普通片偏低,沒有達(dá)到預(yù)期的效果,但研究意義巨大,可進(jìn)行后續(xù)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.
【學(xué)位授予單位】：安徽中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R943;R96

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