Use of the Dynamic Gastric Model as a tool for investigating fed and fasted sensitivities of low polymer content hydrophilic matrix formulations.

The Dynamic Gastric Model (DGM) is an in-vitro system which aims to closely replicate the complex mixing, dynamic biochemical release and emptying patterns of the human stomach. In this study, the DGM was used to understand how the polymer content of hydrophilic matrices influences drug release in fasted and fed dissolution environments. Matrices containing a soluble model drug (caffeine) and between 10 and 30% HPMC 2208 (METHOCEL(®) K4M CR) were studied in the DGM under simulated fasted and fed conditions. The results were compared with compendial USP I and USP II dissolution tests. The USP I and II tests clearly discriminated between formulations containing different polymer levels, whereas the fasted DGM test bracketed drug release profiles into three groups and was not able to distinguish between some different formulations. DGM tests in the fed state showed that drug release was substantially influenced by the presence of a high fat meal. Under these conditions, there was a delay before initial drug release, and differences between matrices with different polymer contents were no longer clear. Matrices containing the typical amount of HPMC polymer (30% w/w) exhibited similar release rates under fed and fasted DGM conditions, but matrices with lower polymer contents exhibited more rapid drug release in the fasted state. In both the fasted and fed states erosion mechanisms appeared to dominate drug release in the DGM: most likely a consequence of the changing, cylindrical forces exerted during simulated antral cycling. This is in contrast to the USP tests in which diffusion played a significant role in the drug release process. This study is one of the first publications where a series of extended release (ER) formulations have been studied in the DGM. The technique appears to offer a useful tool to explore the potential sensitivity of ER formulations with respect to the gastric environment, especially the presence of food.

The influence of polymer content on early gel-layer formation in HPMC matrices: The use of CLSM visualisation to identify the percolation threshold.

Percolation theory has been used for several years in the design of HPMC hydrophilic matrices. This theory predicts that a minimum threshold content of polymer is required to provide extended release of drug, and that matrices with a lower polymer content will exhibit more rapid drug release as a result of percolation pathways facilitating the faster penetration of the aqueous medium. At present, percolation thresholds in HPMC matrices have been estimated solely through the mathematical modelling of dissolution data. This paper examines whether they can be also identified in a novel way: through the use of confocal laser scanning fluorescence microscopy (CLSM) to observe the morphology of the emerging gel layer during the initial period of polymer hydration and early gel formation at the matrix surface. In this study, matrices have been prepared with a polymer content of 5-30% w/w HPMC 2208 (Methocel K4M), with a mix of other excipients (a soluble drug (caffeine), lactose, microcrystalline cellulose and magnesium stearate) to provide a typical industrially realistic formulation. Dissolution studies, undertaken in water using USP apparatus 2 (paddle) at 50rpm, provided data for the calculation of the percolation threshold through relating dissolution kinetic parameters to the excipient volumetric fraction of the dry matrix. The HPMC percolation threshold estimated this way was found to be 12.8% v/v, which was equivalent to a matrix polymer content of 11.5% w/w. The pattern of polymer hydration and gel layer growth during early gel layer formation was examined by confocal laser scanning fluorescence microscopy (CLSM). Clear differences in gel layer formation were observed. At polymer contents above the estimated threshold a continuous gel layer was formed within 15min, whereas matrices with polymer contents below the threshold were characterised by irregular gel layer formation with little evidence of HPMC particle coalescence. According to percolation theory, this implies that a continuous cluster of HPMC particles was not formed. The images provide the first direct evidence of how the percolation threshold may be related to the success or failure of early gel layer development in HPMC matrices. It also shows how extended release characteristics are founded on the successful coalescence of hydrated polymer particles to form a continuous coherent diffusion barrier, which can then inhibit further percolation of the hydration medium. The correlation between percolation thresholds estimated from dissolution and imaging techniques suggests that confocal imaging may provide a more rapid method for estimating the percolation thresholds, facilitating the rational design of HPMC extended release matrices at lower polymer contents with minimal risk of dose dumping.