2-乙醯基-4,8-二氫苯并[1,2-b:5,4-b’]二噻吩-4,8-二酮之預配方研究; Preformulation Study of 2-Acetyl-4,8- dihydrobenzo[1,2-b:5,4-b’]dithiophene-4,8-dione

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Title:	2-乙醯基-4,8-二氫苯并[1,2-b:5,4-b’]二噻吩-4,8-二酮之預配方研究;Preformulation Study of 2-Acetyl-4,8- dihydrobenzo[1,2-b:5,4-b’]dithiophene-4,8-dione
Authors:	廖昌亮;Chang-Liang , Liao
Contributors:	中國醫藥大學藥物化學研究所
Keywords:	預配方;preformulation;dithiophene
Date:	1993
Issue Date:	2009-12-24 11:01:12 (UTC+8)
Abstract:	2-acetyl-4,8-dihydrobenzo[1,2-b:5,4-b’]dithiophene-4,8- dione (ADDD)對多種細胞株的GI50 均小於0.04 μM，其具有很強的抗癌活性。本論文的目標為ADDD之預配方研究，內容如下: 建立ADDD之高效液相層析法，以C-8管柱，移動相為甲醇:水 = 55 : 45 (含0.1%三乙胺，以冰醋酸調整pH至5.5)，於UV檢測波長273 nm下，確效ADDD之分析方法。將ADDD分別於0.1N NaOH、0.1N HCl及pH=7.0，0.1M之磷酸緩衝液下，皆以60℃的條件，進行化學安定性試驗，結果顯示: ADDD於鹼性下安定性差；於酸性下亦不安定；唯在pH=7.0，0.1M之磷酸緩衝液下較為安定，最安定的pH範圍在6.0-7.0之間。 ADDD之pH值-溶解度的輪廓圖顯示pH =5.0-7.0下，溶解度較好。以正八醇(Octanol)為油相之油水分配係數為20。選用不同助溶劑與含量對ADDD所進行安定性研究，其皆遵守擬似一級動力學。比較不同助溶劑對ADDD溶解度，選取最佳之助溶劑Tween 20，發展靜脈注射劑配方。於家兔體內進行藥動學研究；於二室模式下，得到良好的配適。其血中濃度之變化，可用下列方程式表示: Cp = 0.047e-0.144 t + 0.066e-0.006 t; ADDD, 2-acetyl-4,8-dihydrobenzo[1,2-b:5,4-b’]dithiophene-4,8- dione, has GI50 less than 0.04 μM on several cell lines. It shows strong anticancer activity. In this study, the preformulation on ADDD was performed. An high-performance liquid chromatographic assay method was established. A C-8 column with a mobile phase: methanol: water = 55:45 was used. The detective wavelength was set at 273 nm. The HPLC method was validated both as a stability indicating method and a pharmacokinetical assay method. When ADDD were under 0.1 N NaOH, 0.1 N HCl, and 0.1M, pH=7.0 phosphate buffer solution at 60℃, it was stable under 0.1M, pH=7.0 phosphate buffer solution and degraded fast under 0.1 N NaOH and 0.1 N HCl solution. The pH-solubility profile of ADDD showed better solubility under pH = 5.0-7.0. The partition coefficient of ADDD was 20. The stabilities of ADDD in solutions of different solubilizers and different concentrations were investigated. The solubilizers used in this study were Tween 20, 40, 60, and 80, individually. And the concentrations used in this study were 5, 10, 15, and 20% (v/v), respectively. The kinetic profiles of ADDD in Tween solutions followed first order kinetics. The result showed 20% of Tween 20 solution was the better medium for ADDD intravenous formulation. The ADDD intravenous injection was injected into rabbits for pharmacokinetic study. The result showed ADDD in rabbit followed two-compartment model. The pharmaco- kinetic profile of ADDD in the blood followed the equation as: Cp = 0.047e-0.144 t + 0.066e-0.006 t
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