Development of metoprolol tartrate extended-release matrix tablet formulations for regulatory policy consideration

作     者：Nellore, RV Rekhi, GS Hussain, AS Tillman, LG Augsburger, LL 

作者机构：Univ Maryland Sch Pharm Dept Pharmaceut Sci Baltimore MD 21201 USA Roche Biosci Palo Alto CA 94304 USA US FDA Ctr Drug Evaluat & Res Div Prod Qual Res Rockville MD 20857 USA ISIS Pharmaceut Carlsbad CA 92008 USA 

出 版 物：《JOURNAL OF CONTROLLED RELEASE》 (控制释放杂志)

年 卷 期：1998年第50卷第1-3期

页      面：247-256页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 

主　　题：hydrophilic matrix tablet HPMC extended-release formulation dissolution manufacturing Scale-Up and Post-Approval Changes (SUPAC) regulation guidance 

摘      要：This research study was designed to develop model extended-release (ER) matrix tablet formulations for metoprolol tartrate (100 mg) sufficiently sensitive to manufacturing variables and to serve as the scientific basis for regulatory policy development on scale-up and post approval changes for modified-release dosage forms (SUPAC-MR), Several grades and levels of hydroxypropyl methylcellulose (Methocel K4M, K15M, K100M and K100LV), fillers and binders were studied. Three granulation processes were evaluated;direct compression, fluid-bed or high-shear granulation. Lubrication was performed in a V-blender and tablets were compressed on an instrumented rotary tablet press. Direct compression formulations exhibited poor flow, picking and sticking problems during tableting. High-shear granulation resulted in the formation of hard granules that were difficult to mill but yielded good tablets. Fluid-bed granulations were made using various binders and appeared to be satisfactory in terms of flow and tableting performance, In vitro drug release testing was performed in pH 6.8 phosphate buffer using USP apparatus 2 (paddle) at 50 rpm. At a fixed polymer level, drug release from the higher viscosity grades (K100M) was slower as compared to the lower viscosity grades (K100LV). In addition, release from K100LV was found to be more sensitive to polymer level changes. Increase in polymer level from 10 to 40% and/or filler change from lactose to dicalcium phosphate resulted in about 25-30% decrease in the amount of metoprolol release after 12 h. The results of this study led to the choice of Methocel K100LV as the hydrophilic matrix polymer and fluid-bed granulation as the process of choice for further evaluation of critical and non-critical formulation and processing variables. (C) 1998 Elsevier Science B.V.