本文選題：高效液相色譜法　切入點(diǎn)：他克莫司膠囊　出處：《浙江大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：他克莫司(Tacrolimus,FK506)是繼環(huán)孢素A以后的又一細(xì)胞因子合成抑制劑,體內(nèi)外實(shí)驗(yàn)均已證實(shí)FK506免疫抑制作用是環(huán)孢素的10-100倍,臨床可有效預(yù)防腎移植后急性排斥反應(yīng)的發(fā)生,并能逆轉(zhuǎn)難治性排斥,市場應(yīng)用前景廣闊。為確保臨床用藥安全有效,我們對他克莫司膠囊進(jìn)行了較全面的質(zhì)量研究。目的：建立他克莫司膠囊的質(zhì)量控制方法,確定他克莫司膠囊的質(zhì)量標(biāo)準(zhǔn)、包裝方式及材質(zhì)、儲存條件及產(chǎn)品貨架期。方法：按照中國藥典附錄、ICHQ 1 A-F、ICHQ6A-B、ICHQ3A-D的相關(guān)指導(dǎo)原則,主要采用液相色譜及傳統(tǒng)分析技術(shù)對他克莫司膠囊的檢測方法及穩(wěn)定性進(jìn)行了研究。由于本品分子結(jié)構(gòu)的特點(diǎn)與發(fā)酵工藝對其質(zhì)量影響的復(fù)雜性,有關(guān)物質(zhì)的研究成為本文質(zhì)量研究的重點(diǎn),其次對他克莫司異構(gòu)體Ⅰ及異構(gòu)體Ⅱ的互變異構(gòu)現(xiàn)象、降解破壞試驗(yàn)、有關(guān)物質(zhì)的結(jié)構(gòu)確認(rèn)、溶出度條件的篩選、原方法與現(xiàn)有方法的比較等進(jìn)行了詳細(xì)的研究。并對方法進(jìn)行了方法學(xué)驗(yàn)證。他克莫司膠囊的穩(wěn)定性考察,主要涉及加速試驗(yàn)(40℃±2℃/75%RH±5%RH)、長期試驗(yàn)(25℃±2℃/60%RH±5％RH),包裝材料的選擇、包裝方式的選擇,產(chǎn)品貨架期的確定。結(jié)果：使用乙腈作為溶劑,他克莫司異構(gòu)體Ⅰ及異構(gòu)體Ⅱ的互變異構(gòu)迅速達(dá)到平衡,溶液不需要靜止,更能準(zhǔn)確測定異構(gòu)體Ⅰ及異構(gòu)體Ⅱ。通過紅外、核磁共振、質(zhì)譜等儀器進(jìn)行結(jié)構(gòu)分析,確定了雜質(zhì)A、雜質(zhì)C、雜質(zhì)D及雜質(zhì)P的結(jié)構(gòu),定義了合理的限度。方法驗(yàn)證參數(shù)包括專屬性、線性、精密度、回收率、檢測限及定量限、降解試驗(yàn)、過濾試驗(yàn)、提取試驗(yàn)、溶液穩(wěn)定性、有關(guān)物質(zhì)結(jié)構(gòu)解析等。試驗(yàn)表明,用本文建立的方法能較好分離酸、堿、氧化、光照、高溫高濕破壞的降解物及相關(guān)的雜質(zhì)。溶出度采用槳法,介質(zhì)為0.1%SDS和0.1N鹽酸溶液,轉(zhuǎn)速50rpm,進(jìn)行溶出曲線對比,結(jié)果仿制藥與原研藥溶出性能一致,溶出性能良好。選用PVC/PVDC鋁泡加干燥劑及鋁袋的包裝形式上市銷售,采用此包裝形式的他克莫司膠囊在加速試驗(yàn)6個月及長期試驗(yàn)36個月下均較穩(wěn)定。結(jié)論：上述方法簡便實(shí)用、準(zhǔn)確、專屬性強(qiáng)、重現(xiàn)性好,能較好的控制產(chǎn)品的質(zhì)量。試驗(yàn)結(jié)果表明PVC/PVDC鋁泡加干燥劑及鋁袋包裝的他克莫司膠囊在高溫高濕的條件下較穩(wěn)定,為他克莫司膠囊的上市包裝及貨架期提供了依據(jù)。
[Abstract]:Tacrolimus (FK506) is another cytokine synthesis inhibitor after cyclosporine A. the immunosuppressive effect of FK506 in vivo and in vitro has been proved to be 10-100 times of that of cyclosporine, which can effectively prevent the occurrence of acute rejection after renal transplantation. In order to ensure the safety and effectiveness of clinical drug use, we conducted a comprehensive quality study on tacrolimus capsules. Objective: to establish a quality control method for tacrolimus capsules. To determine the quality standard, packing method and material, storage conditions and shelf life of tacrolimus capsules. Methods: according to the relevant guiding principles of ICHQ 1 A-FN ICHQ6A-BUICHQ3A-D in Chinese Pharmacopoeia, the quality standard, packing method, storage conditions and shelf life of tacrolimus capsules were determined. The detection method and stability of tacrolimus capsules were studied by liquid chromatography and traditional analytical techniques. The study of related substances has become the focus of the quality research in this paper. Secondly, the tautomoisomerism phenomenon of tacrolimus isomer 鈪，

本文編號：1607383