Achieving Antral Grinding Forces in Biorelevant In Vitro Models: Comparing the USP Dissolution Apparatus II and the Dynamic Gastric Model with Human In Vivo Data

Abstract

Assessment of the disintegration, dissolution and drug release profiles of oral drug formulations are routinely performed by subjecting them to standard pharmacopeial test methods. However, the unpredictable failure of dosage forms in vivo has drawn attention to the need for more biorelevant test methods. There are several factors which affect the disintegration and dissolution of a formulation within the gastrointestinal (GI) tract, including the physiology of the GI tract in terms of composition of the secretions and motility (shear forces and turbulent flow), and other factors such as the presence of food or alcohol (1,2). The dilution and digestion of the ingested bolus in the stomach occurs not only as a consequence of the addition of gastric acid and enzyme secretions, but also is largely influenced by the grinding forces applied by contraction waves as they move down from the body of the stomach into the antrum. The mechanical processing of the gastric bolus reduces the size of solid particles. Sieving solid materials as a function of their particle size occurs prior to emptying via the pylorus into the duodenum. This means that initially liquid and small particulates tend to be emptied preferentially into the duodenum (3). This effect is very important in the case of tablets, and several studies have shown that the passage through the pylorus of an ingested tablet (and capsules) is related not only to their dimensions and density (4–8), but also to the position of the administered tablet within the stomach (9). Thus, the mechanical forces exerted by the stomach and the shear forces generated within its content can influence the mixing, disintegration and erosion of administered tablets, resulting in inhomogeneous mixing and in some cases an undesirable and unpredictable release of the active ingredient from the formulation. This functional failure is particularly well documented for diclofenac extended release tablets for which the presence of two peaks on the plasma profile has been found to be formulation dependent and due to dose dumping induced by the peristaltic forces applied by the stomach (10). Several studies (11,12) have investigated the flow pattern of systems such as the Dissolution Apparatus USP-I (basket) and USP-II (paddle) at various speeds by using Computational Fluid Dynamics. However, the hydrodynamics of these systems are far from that calculated for the human stomach (13). In fact, the drug dissolution from a solid formulation is greatly influenced by fluid flow and mechanical forces, and this must be taken into account when designing an in vitro method which aims to predict the in vivo behaviour of a formulation. Thus, a more comprehensive simulation of the gastric digestion should not only mimic the biochemistry of the process but also its mechanical forces, since only a combined approach of the two will result in a close simulation of the in vivo scenario. More physiologically relevant media have been designed in order to simulate the composition of the stomach contents in both fasted and fed states (14,15), along with apparatuses which attempt to replicate the complexity of the stresses applied to an ingested formulation to recreate gastric pressure, shear and flows (10,16), the physical mechanical stress encountered by the tablet once in the GI tract (17) or the hydrodynamics of the stomach (18). However, these models are not able to quantitatively recreate the grinding forces produced in vivo by the human stomach. In this study, the grinding forces of a recently developed computer-controlled, real-time physical simulator of gastric processing, the Dynamic Gastric Model (DGM) (19,20) and a Dissolution Apparatus USP-II, operated at two rotational speeds (50 and 100 rpm), were measured using the breakdown of agar gel beads of various fracture strengths in high- and low-viscosity meals. The DGM was designed to replicate the real-time changes in pH, enzyme addition, shearing, mixing, and retention time of an adult human stomach. The model can be fed ‘meals’ ranging from a glass of water to high fat meals (i.e. the FDA high fat American breakfast) and deliver samples from its ‘antrum’ in the same processed form and at the same rate as seen in vivo. The data used to program the DGM were derived from echo-planar imaging studies (21,22) and from published references detailing physiological ranges for the rate of production of gastric secretions (23). The results obtained from the DGM and the USP II were compared to those previously observed in human volunteers (24).