Applications

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The Dynamic Gastric Model can be used to assess the effect of food on the bio-performance of API and pharmaceutical dosage forms. 

Case study: 

Chessa S et al. (2014). Application of the Dynamic Gastric Model to evaluate the effect of food on the drug release characteristics of a hydrophilic matrix formulation. Int J Pharm; 466(1-2): 359-367. https://doi.org/10.1016/j.ijpharm.2014.03.031

Background: 

The impact of food on the performance of modified release dosage forms can be difficult to characterise. Chessa and colleagues at the Quadram Institute Bioscience (Formerly the Institute of Food Research) assessed the suitability of the Dynamic Gastric Model (DGM) for studying food effect on a hydrophilic matrix formulation in comparison with the conventional United States Pharmacopeia (USP) dissolution methodology. 

Methods: 

The extended-release matrix was prepared with Hydrochlorothiazide (HCTZ). Standard USP dissolution testing to measure drug release was carried out with bio-relevant media and compared to the DGM. A simulated fasted state was prepared by adding the HCTZ tablet to the primed DGM, followed by the addition of gastric acid and an enzymatic mix during digestion. The model was run for 30 minutes, with 6 samples taken at 5-minute intervals. When the tablet was ejected, it was transferred to a duodenal compartment with a pool of the gastric samples. In the duodenal compartment, the pH was neutralised and hepatic and pancreatic enzyme mix was added for a shaking incubation of 3-hours. Samples were taken every 15-miutes for analysis. Additionally, a high fat breakfast was masticated and added to the primed DGM. After 30-minutes the HCTZ tablet was added. Samples were then taken every 20-minutes for 4-hours. As with the fasted state, once the tablet was ejected, the sample was transferred to a duodenal compartment. The HCTZ was quantified in the samples using HPLC. 

Results:

Under fasted conditions, the drug release rate maintained similar in the DGM and intestinal model. Additionally, the fasted state dissolution profiles measured from the DGM and the USP methods were comparable. However, this was not the case under fed conditions. Dissolution data measured with the compendial methods indicated the HCTZ tablet was not sensitive to food-effect, whereas the DGM detected changes in physical properties and drug release performance. Indicating this model can provide good detail on the dosage form properties. 

The Dynamic Gastric Model can be used to study the metabolic stability of pro-drugs and gastric delivery API’s. 

Metabolic stability assays evaluate the length of time drug remains stable before being metabolised by enzymes in the body. 

The Dynamic Gastric Model can be used to assess the extent of alcohol-based interactions with modified release dosage forms. The model can be used to simulate alcohol intake regimes that are not readily evaluable in human studies. 

The Dynamic Gastric Model can be used to assess biorelevant disintegration and dissolution of dosage forms. In addition, dissolution characterisation for low solubility APIs such as BCS class II and IV can be modelled. 

In vitro dissolution testing is a method used to predict the in vivo performance of an oral drug and understand the release rate of a drug from its dosage form under gastrointestinal conditions. Dissolution testing is an important method for product development, quality control and bioequivalence studies.

References of previous work: Mercuri A et al. (2009), Chessa S et al. (2014), Vardakou M et al. (2011).

Case study:

Vardakou M et al. (2011). Predicting the human in vivo performance of different oral capsule shell types using a novel in vitro dynamic gastric model. Int J Pharm; 419(1-2): 192-199. https://doi.org/10.1016/j.ijpharm.2011.07.046

Background: 

Disintegration of the capsule shell of oral pharmaceutical products can vary based on the composition of the capsule and if consumption was during a fed or fasted state. Research conducted by Vardakou and colleagues at the Quadram Institute Bioscience (Formerly the Institute of Food Research) investigated the use of the Dynamic Gastric Model (DGM) for understanding the performance of pharmaceutical products, comparing the results to classical dissolution tests and scintigraphy studies. Paracetamol was used as a model drug. 

Methods: 

Three types of capsules were assessed: hydroxypropyl methylcellulose (HPMC) with carrageenan as gelling agent, HPMC with gellan gum as gelling agent and hard gelatin. Fasted state analysis was carried out by loading the capsule into the DGM with 200 mL water. Fed state analysis used a high fat breakfast meal, which was masticated and added to the DGM with the capsule placed on top of the meal. HPLC analysis was carried out for the detection of paracetamol in the digesta, while capsule rupture times were determined by the release of indigo carmine dye. 

Results: 

Rupture times of all capsules and gastric emptying profiles measured by the DGM in fasted state aligned with in vivo gamma scintigraphy and plasma profiling. The DGM also showed rupture time in the fed state was longer compared to the fasted state as expected and explained by a low shear in the fundus and embedding in a higher viscosity food matrix. The rupture times of the fed state from the DGM were longer than scintigraphy results, although these differences can be explained by the differences in the sampling methods. The study concludes the DGM could be a useful tool for assessing different capsule formulations.  

The Dynamic Gastric Model can assess bioequivalence and behaviour of oral formulations such as the use of enteric coating. 

Bioequivalence testing is used to assess similarity of pharmaceutical products with the same active ingredients. This can be used to compare generic and reference drugs, and for the development of new formulations. 

The Dynamic Gastric Model can be used for modified release dosage form development and gastro-retentive dosage forms through understanding mechanical integrity and drug release. 

Dosage form is the specific form in which a drug is administered, such as tablet, capsule and liquid. 

Case study: 

Mercuri A et al. (2011). The effect of composition and gastric conditions on the self-emulsification process of ibuprofen-loaded self-emulsifying drug delivery systems: a microscopic and dynamic gastric model study. Pharm Res; 28(7): 1540-1551. https://doi.org/10.1007/s11095-011-0387-8

Background: 

Self-emulsifying drug delivery systems (SEDDS) are lipid-based formulations that can improve the bioavailability of certain drugs. However, the link between composition, emulsification and bio-availability is not well understood. Additionally, it is believed the behaviour of SEDDS is species dependent, due to the effect of the amount of liquid in the gastrointestinal tract. Therefore, Mercuri and colleagues at the University of East Anglia investigated the link between formulation and the emulsification process in the human stomach using the Dynamic Gastric Model (DGM). 

Methods: 

SEDDSs were prepared with soybean oil 65%, Tween 80 17.5% and Span 80 17.5%, for placebo and with ibuprofen 6% as the model drug for droplet size analysis with a volumetric flask method, USP dissolution apparatus and the DGM. For the volumetric flask method, SEDDS were dispersed in aqueous medium and gently inverted 20 times. For the next method, the USP Dissolution apparatus II was filled with 250 mL aqueous medium and capsules containing the SEDDS and glass beads. The paddle was set to 60rpm, and samples were collected after 25 minutes. Finally, the DGM was run in a fasted state with 250 mL of water, and the SEDDS capsule. Acid and enzymatic secretions were added with the computer-controlled system. A total of 8 samples were collected over 25 minutes at regular intervals. Additionally, the DGM was validated by comparing particle size of the chyme from a test to an in vivo human study. 

Results: 

When validating the DGM, the mean droplet size was within the same order of magnitude as those obtained in vivo, though they were numerically lower. Despite this, there was no significant differences in particle size for 5 of the 6 sampling points. These results indicate the DGM could be used to monitor processing of SEDDS in the stomach. 

The droplet size of the SEDDS were dependent on the method of preparation. Samples from the DGM showed particle size remained broadly similar for both the drug and placebo, suggesting the mechanical agitation superseded changes in emulsification. Additionally, the results from the USP show much smaller droplet size compared to the DGM and volumetric flask model. Finally, the emulsion was stable in the model stomach, with only little changes until the final measurement. 

The Dynamic Gastric Model can be use to assess microbial survival under gastrointestinal conditions, useful for assessing probiotics and live vaccines. 

References of previous work: Lo Curto A et al. (2011), Pitino L et al. (2011), Pitino I et al. (2010), Rodes L et al. (2014). 

Case study:

Pitino I et al. (2010). Survival of Lactobacillus rhamnosus strains in the upper gastrointestinal tract. Food Microbiol; 27(8): 1121-1127. https://doi.org/10.1016/j.fm.2010.07.019

Background: 

Lactobacillus rhamnosus species are commonly used as probiotics for food formulations. Research conducted by Pitino and colleagues at the University of Catania investigated the survival of L. rhamnosus using the Dynamic Gastric Model (DGM) for in vitro simulation of human gastric processing. 

Methods: 

Cell suspensions of six L. rhamnosus strains isolated from Pecorino cheese were prepared and added to water for digestion with the DGM. Using simulated gastric secretions, bile and pancreatic juice the DGM carried out digestion under adult fasted conditions, producing 6 samples over a total period of 78 minutes. Aliquots of each sample were then processed with duodenal digestion by incubating them at 37°C for 2 hours with hepatic mix and pancreatic enzyme solutions. Samples were taken throughout for viable cell counts using plating. 

Results:

The study found all six L. rhamnosus strains could survive gastric digestion and gastric with duodenal digestion, despite a decreasing bacterial number in correlation with the pH. Additionally, three strains displayed strong recovery of up to 276%. Lactic acid production was also measured at each time point, indicating metabolic activity of the bacteria during digestion. The study highlights the use of the DGM for evaluating the viability of probiotic formulas. 

The Dynamic Gastric Model can be used to assess health implications of food such as survival of allergenic proteins and determination of Glycaemic Index.

Reference of previous work: Ballance S et al. (2013). 

The Dynamic Gastric Model can be used to understand the nutritional effects of food after gastric digestion such as bioavailability of nutrients and the behaviour of prebiotics. 

Reference from previous work: Edwards C H et al. (2021), Grassby T et al. (2017), Mandalari G et al. (2018), Mandalari G et al. (2013), Salt LJ et al. (2023).  Thuenemann EC et al. (2015). 

Case study: 

Salt LJ et al. (2023). Mechanisms of interesterified fat digestibility in a muffin matrix using a dynamic gastric model. Food & Function, 14(22), 10232–10239. https://doi.org/10.1039/d3fo02963h

Background:

Trans-Fats have been linked to cardiovascular disease and as a result, interesterified (IE) fats are being used as alternatives in food production. IE fat is modified to create products wit reduced saturated fat content. Salt and colleagues at the Quadram Institute Bioscience investigated the health impacts of consuming IE fats, looking into the effect on digestibility, metabolism and uptake. 

Methods:

Muffins were prepared with either IE or non-IE fats, both with an 80:20 mixture of palm stearin and palm kernel oil. Muffins prepared with rapeseed oil were used as a control. Muffins were digested with a simulated oral phase, followed by simulated gastric digestion in the Dynamic Gastric Model. The muffins were digested with simulated gastric acid and gastric enzyme solution, with samples taken every 14-minutes. Gastric samples measured at 14, 70 and 126 minutes were transferred to a duodenal phase by adding duodenal digestion solution, adjusting the pH to 7.0, adding porcine pancreatin and incubating for 2 hours. Samples of digested and undigested muffin were tested for lipolysis rates and visualised by microscopy. 

Results: 

The IE and non-IE fats showed differences in digestion to the control RO fat, but not to each other. Both the IE and non-IE fat were largely solid in the gastric phase and showed no significant difference in lipolysis rates. Suggesting interesterification of palm-based fats does not impact digestibility and absorption.