Utilizing the dynamic gastrointestinal model (DGM) to evaluate the gastric integrity of Capsugel® Enprotect® capsules in fasted and fed states

This study aimed to evaluate if the Dynamic Gastrointestinal Model (DGM) is able to simulate the gastro-resistant behavior of Capsugel® Enprotect® capsules under physiologically relevant fasted and fed states. Enprotect® capsules were filled with a caffeine powder blend and tested under three conditions: fasted state, a light meal (∼500 kcal), and a high-fat meal (∼900 kcal). Results showed that the capsules remained intact in the stomach across all conditions and released their contents only after intestinal entry. Dissolution and pharmacokinetic predictions closely aligned with published clinical data for the fasted state and light meal.

The extended gastric residence and elevated pH of the high-fat meal did not compromise capsule integrity possibly due to a combination of capsule floating and acid pocket formation on the top of the digesting meal. These findings confirm the robustness of Enprotect® capsules and demonstrate the utility of the DGM in predicting oral dosage form behavior and performance under physiologically relevant gastrointestinal conditions.

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Introduction

Despite the potential benefits of enteric capsules, such as protection against gastric degradation, minimizing local gastrointestinal side effects, and enhancing the bioavailability of acid-labile or irritant compounds, evidence supporting their gastric integrity and clinical effectiveness remains limited. Most available literature supporting enteric capsule performance is derived from conventional, compendial in vitro dissolution tests [1]. These tests, while standardized and reproducible, typically rely on static conditions and do not adequately replicate the complex and dynamic environment of the human gastrointestinal (GI) tract. This is particularly true in the fed state, where variations in meal composition, gastric motility, pH fluctuations, enzymatic activity, and gastric emptying can significantly influence dosage form behavior [2,3].

To address these limitations, advanced in vitro models that more closely mimic the physiology of the human GI tract are required. One such model is the dynamic gastrointestinal model (DGM). The DGM simulates the physical, hydrodynamic and biochemical conditions of the human stomach such as peristalsis and gastric shear, gastric secretions, enzymatic digestion, pH gradients, and gastric emptying kinetics [4]. In a recent study, Knopp et al. [5] demonstrated the ability of the DGM to predict plasma profiles and food effect for a range of commercially available oral drug products (cinnarizine, diclofenac and paracetamol) covering a range of relevant physicochemical properties that display both positive and negative food effect. Besides being a powerful tool for predicting the performance for immediate release, the ability of the DGM to simulate both hydrodynamic and compositional changes in the GI environment [4] also makes it suitable for studying enteric dosage forms, where precise timing of release is critical for therapeutic effectiveness. Among the available enteric capsule technologies, Capsugel® Enprotect® capsules have shown to provide acid resistance for up to 2 h. Enprotect® capsules are bi-layered, comprising an inner shell of hydroxypropyl methylcellulose (HPMC) bonded to an outer layer of HPMC-acetate succinate (HPMC-AS) [6].

Previous clinical studies have demonstrated robust gastro-resistant and enteric disintegration properties of caffeine-filled Enprotect® capsules in both fasted and fed state through a combination of saliva caffeine assay and magnetic resonance imaging (MRI) [6,7]. However, the fed state study utilized an acidic meal matrix (light meal, ∼500 kcal) that possibly could favor the gastric integrity of pH-triggered enteric capsules by maintaining a low gastric pH [7]. While these studies support capsule robustness under certain postprandial scenarios, they do not represent the full range of physiological variation in gastric content following meal ingestion, particularly with meals that elevate gastric pH and extend gastric emptying, such as the high-fat and high-calorie meal composition recommended by the U.S.Food and Drug Administration (FDA) to study food effects [8].

Thus, the purpose of this study was to evaluate if the DGM can simulate the behavior of the caffeine-filled Enprotect® capsules in fasted and fed (light meal) state observed in the published clinic studies [6,7] and predict the performance after ingestion of the high-fat and high-calorie FDA meal (∼900 kcal), known to elevate gastric pH and extend gastric emptying [3]. Testing under these conditions provides a more rigorous assessment of gastric resistance of the Enprotect® capsules and allows evaluation of capsule performance in less favorable, more challenging gastric environments.

Materials

Enprotect® size 0 capsules were provided by Capsugel France SAS (Colmar, France). Caffeine (anhydrous), sodium chloride, potassium chloride, acetic acid glacial, calcium chloride, trifluoroacetic acid, sodium dihydrogen phosphate, hydrochloric acid, sodium hydroxide, pepsin from porcine pancreas, pancreatin from porcine pancreas and lipase R Oryzae were sourced by Sigma-Aldrich (St. Louis, MO, USA). Instant SIF (simulated intestinal fluid) powder was purchased from Biorelevant (London, United Kingdom).

Matthias Manne Knopp, Vincent Jannin, Vanessa Gonzalez, Anette Müllertz,
Utilizing the dynamic gastrointestinal model (DGM) to evaluate the gastric integrity of Capsugel® Enprotect® capsules in fasted and fed states,
European Journal of Pharmaceutics and Biopharmaceutics,
Volume 219, 2026, 114962, ISSN 0939-6411,
https://doi.org/10.1016/j.ejpb.2025.114962.