(T1230-07-40) Evaluating the Gastric Integrity of Capsugel® Enprotect® Capsules in Fasted and Fed State Using the Dynamic Gastric Model (DGM)

Purpose: Despite the potential benefits of enteric hard capsules, such as protection against degradation, minimizing local side effects and improving bioavailability, there is limited data supporting their effectiveness in vivo. Most evidence is based on simple compendial in vitro setups that do not replicate the dynamics and complexity of the human gastrointestinal (GI) tract – in particular in the fed state. The purpose of this study was to evaluate the gastric integrity of the Capsugel® Enprotect® capsules using the Dynamic Gastric Model (DGM) that simulates the hydrodynamics, fluid compositions, digestion, emptying and pH profile of the human GI tract (1). The effectiveness of the capsules to resist rupture in the stomach as well as disintegration time upon intestinal entry was studied in conditions simulating fasted state and fed state after intake of either a light European style breakfast (Yoghurt meal, ⁓500 kcal) or the high-fat breakfast (FDA meal, ⁓900 kcal). The capsules were filled with 25 mg caffeine as a marker for capsule rupture due to high solubility/dissolution rate.

Methods: Fasted state DGM experiments: One Capsugel® Enprotect® capsule was administered along with 240 mL of tap water to the DGM, which contained 35 mL of gastric acid solution. During the experiment, gastric acid solution and gastric enzyme solution were added at a dynamic rate depending on pH and stomach content, respectively, to reach pH ~ 2. The composition of the gastric solutions can be found in Table 1. Samples of approx. 45 mL were ejected every 4 min. Immediately after ejection, the weight and pH of the samples were measured and a sample of 1 mL was withdrawn. This sample was centrifuged at 10,000 rpm for 10 min, and the supernatant diluted with an organic solvent and analyzed for caffeine concentration using HPLC-UV. The remaining sample was transferred to the intestinal module. Fed state DGM experiments: The meal (Yoghurt or FDA) was prepared, chewed and put into the DGM, which contained 35 mL of gastric acid solution. After 30 min of digestion (in line with the regulatory protocol), one Capsugel® Enprotect® capsule was administered to the DGM along with 240 mL of tap water (2). During the experiment, gastric acid solution and gastric enzyme solution were added at a dynamic rate depending on pH and stomach (caloric) content, respectively, to reach pH ~ 2. Samples of approx. 75 mL was ejected every 16 min. Immediately after ejection, the weight and pH of the samples were measured and a sample of 1 mL was withdrawn. This sample was centrifuged at 10,000 rpm for 10 min, and the supernatant diluted with an organic solvent and analyzed for caffeine concentration using HPLC-UV. The remaining sample was transferred to the intestinal module. Intestinal module: After ejection from the DGM, the samples were pooled in a 600 mL or 2000 mL thermostated jacketed glass vessel equilibrated to 37 °C under stirring, along with 5 mL or 10 mL of concentrated x10 fasted state simulated intestinal fluid (FaSSIF) or x8 fed state simulated intestinal fluid (FeSSIF) for fasted and fed state experiments, respectively. Throughout the experiment, the pH was continuously adjusted to 6.5 (fasted) or 5.8 (fed) through addition of 1M NaOH. Prior to addition of the following DGM sample and concentrated FaSSIF/FeSSIF, a sample of 1 ml was withdrawn from the vessel. This sample was centrifuged at 10,000 rpm for 10 min, and the supernatant diluted with an organic solvent and analyzed for caffeine concentration using HPLC-UV. After addition of the last DGM sample, the intestinal digestion process was continued for 120 min with sampling every 15 min.

Results: The release of caffeine in the intestinal module after dosing is shown in Figure 1. As can be seen, the median intestinal entry time for the Capsugel® Enprotect® capsule was 29 min, 177 min and 241 min for fasted state, Yoghurt meal and FDA meal, respectively. The higher gastric residence time for the FDA meal compared to the Yoghurt meal is due to higher caloric content leading to slower gastric emptying. The relatively high gastric residence times observed is likely due to the fact that the capsule was floating on top of the chyme in both fasted and fed state experiments. The capsule remained intact throughout gastric transit (as evident visually and from HPLC analyses) and ruptured 30-45 min after intestinal entry in the fasted state experiments and 45-60 min after intestinal entry in both fed state experiments. The longer rupture times in the fed state may be attributed to the higher viscosity of the chyme.

Conclusion: In this study, the performance of Capsugel® Enprotect® capsules was evaluated using the DGM-intestinal model after intake in fasted and fed state. The findings suggest robust gastro-resistant and intestinal disintegration properties of the investigated capsules. Furthermore, postprandial intake of the capsules (using two different meal types) did not compromise their gastric integrity.

References: 1. Wickham, M.J.S., Faulks, R.M., Mann, J., & Mandalari, G. The design, operation, and application of a dynamic gastric model. Dissolution Technology, 19(3), 15-22 (2010).
2. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Assessing the Effects of Food on Drugs in INDs and NDAs — Clinical Pharmacology Considerations. Guidance for Industry, 1-18 (2022)

Figure 1: Intestinal caffeine dissolution profiles in fasted state conditions (red) and in fed state conditions after intake of a Yoghurt meal (blue) or an FDA meal (green) using the DGM-intestinal model. The dashed lines indicate median gastric emptying/intestinal entry of the intact Capsugel® Enprotect® capsule.

Table 1: Composition of the DGM gastric solutions.