Gliclazide 體外體內相關性之建構
中文摘要
本研究目的為建立gliclazide 間質型口服控釋錠的體外體內相關性( In vitro/in vivo correlation, IVIVC )。以羥丙烷基甲基纖維素( hydroxypropyl methylcellulose, HPMC )、微晶纖維素 ( microcrystalline cellulose, Avicel® PH 101)與乳糖
( lactose )製備三種不同釋放速率的處方。採用直接壓製法製備錠片，每顆錠片總 重240 mg，內含 80 mg gliclazide。首先研究 gliclazide 在不同酸鹼值媒液中不同 添加量的硫酸月桂鈉 ( sodium lauryl sulfate, SLS )對溶解度之影響，了解 pH-溶 解度之關係，以篩選出適宜的體外溶離環境。建構三種不同釋放速率處方在不同 溶離環境下之溶離曲線，作為IVIVC 之體外參數值，分別為 pH 1.2、pH 4.5 + 1% SLS 和 pH 6.8 ( 50 rpm )，並進行 pH change ( 100 rpm 與 150 rpm )，以模擬
人體胃腸道不同段之溶離環境。將這三種不同釋放速率處方在18 名健康受試者
進行三相交叉人體試驗，得到體內血中濃度數據，並計算藥物動力學參數 ( Tmax、Cmax、AUC0-24 和 AUC0-inf )與使用數學上 deconvolution 方式演算體內 吸收百分比( % absorbed in vivo )，以作為建構等級 A( level A )與等級 C( level C )體外體內相關性之體內參數。並計算%PECmax、%PEAUC 以評估建立的體外 體內相關性的好壞。
結果顯示，使用pH 1.2、pH 6.8 和 pH change( 150 rpm )的溶離環境皆可成功建立 具備高度線性相關的等級C IVIVC，相關係數(r2)皆大於 0.9，且具有良好的內 部檢測力。而pH change( 150 rpm )的溶離環境則是建構等級 A 相關性的體外溶
離條件之較佳選擇。由此所建構的gliclazide 體外體內相關性，若通過內部檢測，
未來在處方修飾或製程改變，將可能可以體外溶離代替體內人體試驗，以減少 資源浪費。
英文摘要
The aim of this study was to develop an in vitro-in vivo correlation (IVIVC) of gliclazide as a surrogate for bioequivalence when formulation changes or process modifications. Hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (Avicel® PH 101) and lactose were used to formulate tablets with three different release rates. The direct compression method was employed to prepare 240mg tablets containing 80mg gliclazide. Firstly, the influence of the various adding amount of sodium lauryl sulfate (SLS) on pH-solubility of gliclazide was examined. In vitro dissolution data were collected for each formulation using the ChP Apparatus II in three media of pH 1.2, pH 4.5 + 1% SLS, and pH 6.8 buffers stirred at 50rpm and in a pH change medium stirred at 100rpm and 150rpm. In vivo plasma concentration data were obtained from 18 healthy volunteers after administration of three different release rate dosage forms in a three-way crossover study. The pharmacokinetic parameters (Tmax, Cmax, AUC0-24 and AUC0-inf) were calculated as in vivo
parameters to construct in vitro-in vivo correlation of level C. Direct mathematical deconvolution approach was utilized to calculate the fraction of drug absorbed to construct level A IVIVC. Percent prediction error (%PE) was estimated for Cmax and area under the curve (AUC) to determine the validity of the correlation.
Linear level C IVIVC models with high correlation coefficient (r2>0.9) in pH 1.2, pH 6.8 buffers and a pH change medium(150rpm) were successfully developed and had acceptable %PE. The best choice for constructing level A IVIVC was to conduct dissolution measurement in a pH change medium stirred at 150rpm. These constructed IVIVC correlations was expectable to be useful as a surrogate for bioequivalence when formulation changes or process modifications.
