Humbert H, Cabiac M D, Bosshardt H
Pharmaceutical Research Centre, Sandoz Laboratories, Ruell-Malmaison, France.
J Pharm Sci. 1994 Feb;83(2):131-6. doi: 10.1002/jps.2600830205.
The dissolution rate profile of a new modified-release (MR) oral tablet of ketotifen (Zaditen SRO tablet, Sandoz Ltd.) was determined under different conditions (pH, rpm, paddle or basket) with the U.S.P. apparatus. Three different variants of MR tablets were tested. In addition, the in vivo bioavailabilities of these MR tablets were evaluated after a single-dose administration under different conditions (fasting state, with food in morning and/or evening). Several possibilities were evaluated to obtain a correlation between in vitro and in vivo data of the three MR tablets. An excellent linear correlation (r = 0.997) was obtained between the cumulative dissolved percent in vitro and the cumulative absorbed percent in vivo at each time under certain conditions. This was obtained in vitro with the dissolution rate performed in distilled water (37 degrees C) with the U.S.P. apparatus 2 (rotating paddle) and in vivo after a single-dose administration in the morning, fasting state. On the basis of this correlation, of the in vitro dissolution rate for a given variant, and of a simple method of calculation, a reliable prediction of the plasma concentrations obtained following a single dose or at steady state was found. The reliability of this prediction was validated from variants of MR tablet presenting different in vitro dissolution rate profiles and with an upscaled batch which was tested in vivo. This result allows the specifications (upper and lower limits) of the dissolution rate for the MR tablet to be defined and ensures good in vivo characteristics for the different batches of Zaditen SRO tablets during manufacture.
使用美国药典装置，在不同条件（pH值、转速、桨法或篮法）下测定了酮替芬新型缓释口服片剂（Zaditen SRO片剂，山德士有限公司）的溶出速率曲线。测试了三种不同变体的缓释片剂。此外，在不同条件（禁食状态、早晚进食）下单次给药后，评估了这些缓释片剂的体内生物利用度。评估了几种可能性，以获得三种缓释片剂体外和体内数据之间的相关性。在特定条件下，每次体外累积溶解百分比与体内累积吸收百分比之间获得了极好的线性相关性（r = 0.997）。这是在体外使用美国药典装置2（旋转桨法）在蒸馏水（37℃）中进行溶出速率测定，并在早上禁食状态下单次给药后在体内获得的。基于这种相关性、给定变体的体外溶出速率以及一种简单的计算方法，发现了单次给药或稳态后血浆浓度的可靠预测。这种预测的可靠性通过呈现不同体外溶出速率曲线的缓释片剂变体以及在体内测试的放大批次进行了验证。该结果允许定义缓释片剂溶出速率的规格（上限和下限），并确保在生产过程中不同批次的Zaditen SRO片剂具有良好的体内特性。
