本文選題：甲磺酸哌啶醇黃芩素 + 穩(wěn)定性�。� 參考：《大連理工大學(xué)》2014年碩士論文

【摘要】：黃芩為傳統(tǒng)中藥材,主要有效成分為黃芩苷,其水解產(chǎn)物黃芩素(BA)活性更強(qiáng)。BA是一種天然黃酮類選擇性CDK1抑制劑。但存在溶解度差、生物利用度低、血藥濃度較低等問題,直接使用遠(yuǎn)達(dá)不到臨床治療癌癥和艾滋病的要求。因此,BA的結(jié)構(gòu)修飾引起人們的廣泛關(guān)注。最有成效為黃芩素Mannich堿衍生物。本課題組以BA為先導(dǎo)化合物經(jīng)Mannich反應(yīng)得到了一種新型結(jié)構(gòu)的CDK1抑制劑甲磺酸哌啶醇黃芩素(BA-j),相比于先導(dǎo)化合物BA,其具有更好的選擇性誘導(dǎo)腫瘤細(xì)胞和被激活的淋巴細(xì)胞凋亡的作用。 本文對BA-j穩(wěn)定性進(jìn)行了實(shí)驗(yàn)研究。采用液相色譜與多級質(zhì)譜聯(lián)用(LC-MS/MS)方法,在BA-j水溶液中分離鑒定出8種BA-j氧化降解物,7個(gè)為新化合物。BA-j水溶液在光照下首先被氧化成水溶性8-羥甲基氧化黃芩素(M298),M298不穩(wěn)定,進(jìn)一步聚合成水不溶性8,8’-亞甲基雙黃芩素(M552)。分離得到M552進(jìn)行了波譜結(jié)構(gòu)表征。氧化降解物中主要成分為M298、其次為M552,以及少量BA和雙黃芩素等。BA-j水溶液在室溫下可被Fe3+完全氧化降解為M298,提示在藥物制劑生產(chǎn)過程中注意水分和不銹鋼設(shè)備的影響。 采用HPLC-UV法建立了氧化降解物M298和M552的測定方法,并對其進(jìn)行了實(shí)驗(yàn)驗(yàn)證。在1.25-20μg/ml范圍內(nèi),BA-j, M298,M552回歸方程分別為y=233619x+19454(R2=0.9997, n=6), y=133164x+2026.2(R2=0.9998, n=5), y=241023x-23460(R2=0.9998, n=5),線性關(guān)系良好；相對BA-j校正因子M298和M552分別為1.75和0.97；精密度RSD%分別為2.32%(n=6),4.32%(n=6),符合規(guī)定(5.0%)；定量限分別為0.24μg/ml和0.34μg/ml。在避光操作下,該方法選擇性良好,準(zhǔn)確度、重復(fù)性、耐用性均符合測定要求,可用于BA-j氧化降解物限量檢查。 對BA-j進(jìn)行了穩(wěn)定性影響因素、加速試驗(yàn)及長期穩(wěn)定性試驗(yàn)。試驗(yàn)結(jié)果表明BA-j原料穩(wěn)定性良好。采用HPLC-UV法對BA-j進(jìn)行了臨床條件下的藥品穩(wěn)定性試驗(yàn)。BA-j水溶液光照后可產(chǎn)生降解物M552黃色沉淀,提示本品不適宜制備成注射液。BA-j原料藥穩(wěn)定,溶解性能良好,可制備成注射用粉針劑。用氯化鈉葡萄糖注射液溶解BA-j稀釋后4h內(nèi)穩(wěn)定性良好。用復(fù)方氯化鈉注射液溶解稀釋4h后出現(xiàn)降解物M552黃色沉淀。提示BA-j注射用粉針劑不能用復(fù)方氯化鈉注射液稀釋后靜脈點(diǎn)滴給藥。BA-j在模擬人工胃液和腸液中4h內(nèi)穩(wěn)定。提示BA-j可制成口服給藥劑型。上述研究結(jié)果為進(jìn)一步藥劑學(xué)研究提供了依據(jù)。
[Abstract]:Scutellaria baicalensis is a traditional Chinese medicine and its main active component is baicalin. The hydrolysate baicalin has stronger activity. BA is a natural flavonoid selective CDK1 inhibitor.However, there are some problems such as poor solubility, low bioavailability and low blood drug concentration, which can not meet the requirements of clinical treatment of cancer and AIDS.Therefore, the structural modification of BA has attracted wide attention.The most effective is baicalin Mannich base derivative.A new type of CDK1 inhibitor, baicalein mesylate, was synthesized by Mannich reaction with BA as the lead compound. Compared with the lead compound BA, it has better selectivity in inducing tumor cells and activated lymphoid.The role of apoptosis in human paracellular apoptosis.In this paper, the stability of BA-j is studied experimentally.By means of liquid chromatography and multistage mass spectrometry, eight kinds of BA-j oxidative degradation compounds were isolated and identified from BA-j aqueous solution. Seven new compounds. BA-j aqueous solution was first oxidized to water-soluble 8-hydroxymethyl baicalin oxide M298M298 under light irradiation.Further polymerization was carried out to form water insoluble 8o 8U-methylene bis-baicalein M 552.The spectral structure of M 552 was characterized.The main component of oxidation degradation is M298, followed by M552, and a small amount of BA and dibaicalein can be completely oxidized to M298 by Fe3 at room temperature, indicating that attention should be paid to the effects of water and stainless steel equipment in the production of pharmaceutical preparations.An HPLC-UV method was established for the determination of M298 and M552, and the results were verified by experiments.鍦，

本文編號：1771142