RESUMEN
The objective of this study, was to examine the influence of critical formulation and processing variables as described in the AAPS/FDA Workshop II report on scale-up of oral extended-release dosage forms, using a hydrophilic polymer hydroxypropyl methylcellulose (Methocel K100LV). A face-centered central composite design (26 runs+3 center points) was selected and the variables studied were: filler ratio (lactose:dicalcium phosphate (50:50)), polymer level (15/32.5/50%), magnesium stearate level (1/1.5/2%), lubricant blend time (2/6/10 min) and compression force (400/600/800 kg). Granulations (1.5 kg, 3000 units) were manufactured using a fluid-bed process, lubricated and tablets (100 mg metoprolol tartrate) were compressed on an instrumented Manesty D3B rotary tablet press. Dissolution tests were performed using USP apparatus 2, at 50 rpm in 900 ml phosphate buffer (pH 6.8). Responses studied included percent drug released at Q1 (1 h), Q4, Q6, Q12. Analysis of variance indicated that change in polymer level was the most significant factor affecting drug release. Increase in dicalcium phosphate level and compression force were found to affect the percent released at the later dissolution time points. Some interaction effects between the variables studied were also found to be statistically significant. The drug release mechanism was predominantly found to be Fickian diffusion controlled (n=0.46-0.59). Response surface plots and regression models were developed which adequately described the experimental space. Three formulations having slow-, medium- and fast-releasing dissolution profiles were identified for a future bioavailability/bioequivalency study. The results of this study provided the framework for further work involving both in vivo studies and scale-up.
Asunto(s)
Preparaciones de Acción Retardada/farmacocinética , Metilcelulosa/química , Metoprolol/administración & dosificación , Administración Oral , Química Farmacéutica , Lactosa/análogos & derivados , Metilcelulosa/análogos & derivados , Oxazinas , Análisis de Regresión , Solubilidad , ComprimidosRESUMEN
This research study was designed to develop model extended-release (ER) matrix tablet formulations for metoprolol tartrate (100 mg) sufficiently sensitive to manufacturing variable 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 and 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. Increased 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.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Control de Medicamentos y Narcóticos , Metoprolol/administración & dosificación , Preparaciones de Acción Retardada , Comprimidos , ViscosidadRESUMEN
The center of gravity (CG) of a drug level curve [c(t)] has the time coordinate AUMC/AUC and the concentration coordinate AUCC/2AUC, where AUC, AUMC, and AUCC are the integrals from time t = zero to t = infinity of c(t), tc(t), and c(t).c(t), respectively. An algorithm and computer program for determining CG when c(t) is given by a sum of exponentials is presented and its use is demonstrated with oral cimetidine data. Simulations indicate that the CG appears more suitable for comparison of absorption rates than mean absorption time (MAT) parameters. The limitation of the MAT parameter is due to the fact that this parameter is scale independent in that it only considers the shape and not the magnitude of the drug level or absorption rate curve. The MAT is therefore independent of the extent (F) of absorption. This limitation is not shared by the CG. When dealing with first-order absorption, the absorption rate of drug from product A will consistently (all t greater than 0) be larger than the absorption rate from product B (tested in the same subject) if MATA greater than MATB and AUCA/AUCB greater than MATA/MATB (assuming a time-invariant linear disposition). The above inequality relationships strongly contrast the common thinking about the "nonproblematic" use of MAT in absorption rate comparisons. Since both CG and MAT suffer some fundamental limitations, it is recommended that whenever problems arise, one should compare absorption rates by nonparametric system analysis methods (e.g., deconvolution) if possible.
Asunto(s)
Disponibilidad Biológica , Farmacocinética , Absorción , Cimetidina/farmacocinética , Humanos , Inyecciones Intravenosas , Modelos BiológicosRESUMEN
The activity of serum angiotensin converting enzyme (ACE) for healthy horses was 64 +/- 13 mUnits/ml. In vitro, equine serum ACE was sensitive to the following inhibitors (IC50): enalapril (570 nM or 215 ng/ml), captopril (190 nM or 41.3 ng/ml), and enalaprilat (6 nM or 2.1 ng/ml). The intravenous (i.v.) administration of angiotensin I to six healthy horses produced a dose proportional pressor response. The maximal increase in mean arterial pressure over baseline values was 65.6 mmHg at angiotensin I doses of 500 ng/kg bodyweight (bwt). The attenuation of this response to angiotensin I was further demonstrated in a single horse by the prior administration of enalaprilat at an i.v. dose of 8.71 micrograms/kg bwt.