Design and process parameter evaluation of bilayer capsule systems for targeted ileal drug delivery

Abstract

The dynamic and transitory nature of the distal small intestine makes targeted drug delivery to this region particularly challenging. This study aimed to develop a bilayer capsule system for site-specific drug release in the terminal ileum. The capsules consisted of an inner water-soluble layer based on hydroxypropyl methylcellulose (HPMC) and pullulan, combined with an outer ethylcellulose layer incorporating sodium alginate as a pore-forming agent.

The influence of alginate concentration and curing conditions (temperature and relative humidity) on capsule structure and performance was systematically investigated. Thermal analysis by differential scanning calorimetry guided plasticizer selection and curing parameters. Capsule morphology and surface properties were characterized by scanning electron microscopy and roughness analysis, while functional performance was evaluated through disintegration, water ingress, and dissolution studies under sequential pH conditions simulating the gastrointestinal tract.

Alginate concentration significantly influenced surface morphology and permeability of the outer layer, whereas curing conditions modulated film cohesion and porosity. Lead formulations (4–6% alginate, cured at 70 °C and 40% RH) exhibited low water ingress under acidic conditions, maintained capsule integrity, and enabled delayed release at pH 7.4. Compared with reference enteric capsules (Capsugel® Enprotect® capsules), these systems showed a delayed release profile, with potential for targeting of the distal ileum.

Overall, this study highlights the critical role of formulation and process parameters in controlling capsule microstructure and provides a robust platform for site-specific oral drug delivery to the distal small intestine.

Introduction

Oral drug delivery remains the most widely preferred route of administration due to its convenience, patient acceptability and cost-effectiveness (Begum et al., 2018). Over the past decades, significant advances have been made in the development of modified-release systems designed to control drug release kinetics and enable site-specific delivery within the gastrointestinal (GI) tract. In particular, considerable research effort has focused on regional targeting strategies, especially for colonic drug delivery, where physiological triggers such as pH variation, transit time, and microbial activity can be effectively exploited (Kotla et al., 2019; Ferraro et al., 2024).

In contrast, reliable targeting of the distal small intestine, and specifically the terminal ileum, remains more challenging. This region presents a dynamic and transient physiological environment characterized by relatively short and variable residence times, progressively increasing pH, and a gradual rise in microbial density compared to the proximal small intestine. While several delivery platforms have demonstrated partial success in reaching the ileal region, achieving consistent and reproducible drug release specifically at this site remains difficult (Huntsman et al., 2021). As a result, the terminal ileum remains comparatively less well addressed than the colon in the context of oral modified-release systems.

Nevertheless, the terminal ileum constitutes a highly relevant therapeutic target. It is a primary site of inflammation in Crohn’s disease and represents a key absorption region for certain drugs and emerging therapeutic modalities, including biologics and nucleic acid-based therapies. Targeted delivery to this region offers the potential to enhance local efficacy while minimizing systemic exposure and off-target effects. These considerations highlight the need for dosage forms capable of withstanding gastric and proximal intestinal conditions while enabling controlled and predictable drug release in the distal small intestine.

Conventional hard capsules, typically fabricated from gelatin or cellulose-derived polymers, are primarily designed as immediate-release systems that rapidly hydrate and disintegrate in the gastric environment. While suitable for conventional oral dosing, this inherent behavior often leads to premature drug release and insufficient protection of acid-labile or sensitive APIs before reaching their intended site of action. As a result, unmodified capsule shells are not well adapted for applications requiring site-specific or regional delivery along the gastrointestinal (GI) tract (Hoffmann et al., 2025). To overcome these limitations, modern capsule design increasingly relies on the use of functional polymers and tailored architectures capable of delaying disintegration and enabling controlled or targeted drug release (Millet et al., 2025).

Among capsule-forming polymers, hydroxypropyl methylcellulose (HPMC) is widely used due to its favorable film-forming properties, mechanical robustness, and compatibility with a broad range of active pharmaceutical ingredients (Millet et al., 2025). Pullulan, a neutral polysaccharide, also exhibits excellent film-forming properties and has been explored as a capsule material due to its mechanical strength and biocompatibility. Importantly, both HPMC and pullulan can contribute to hydration-driven disintegration, while pullulan may additionally be susceptible to enzymatic degradation under intestinal conditions (Aghajannataj Ahangarkola et al., 2024).

For delayed-release applications, ethyl cellulose (EC), a water-insoluble polymer, is commonly used to form diffusion-controlling barriers that limit premature drug release (Giakoumis et al., 2026). In such systems, permeability is typically tuned through the incorporation of water-soluble or swellable excipients acting as pore formers. Sodium alginate, a hydrophilic and biodegradable polysaccharide is particularly relevant in this context, as it can modulate film permeability through hydration, swelling, and potential enzymatic degradation within the intestinal environment (Tønnesen and Karlsen, 2002).

Alginate is a natural polysaccharide susceptible to degradation by microbiota-derived enzymes, primarily alginate lyases belonging to different polysaccharide lyase (PL) families (e.g., PL6 and PL17), which cleave mannuronate and guluronate residues through a β-elimination mechanism (Rønne et al., 2023, 2024). These enzymes are produced by specific members of the gut microbiota, particularly Bacteroides species, which harbor dedicated polysaccharide utilization loci enabling the depolymerization and fermentation of alginate (Fu et al., 2023; Mathieu et al., 2018). Although alginate degradation is generally considered to occur predominantly in the colon due to the higher microbial density and enzymatic activity, recent studies have demonstrated that the ileal microbiota also exhibits a fibrolytic potential, including the presence of carbohydrate-active enzymes involved in the degradation of complex polysaccharides (Patrascu et al., 2017). Therefore, the onset of alginate degradation may already occur in the distal ileum, although to a lesser extent and depending on the local microbial composition and activity.

The combination of EC and alginate therefore provides a means to engineer a functional layer with controlled permeability that evolves in response to both physicochemical conditions and microbiota-derived enzymatic activity along the gastrointestinal tract.
In this context, bilayer capsule shell systems represent a promising approach to decouple the structural and functional roles of the capsule shell (Millet et al., 2025). The inner layer can be designed to ensure mechanical integrity and controlled disintegration, while the outer layer provides a protective barrier against gastric and proximal intestinal conditions. However, most commercially available or reported capsule systems rely predominantly on pH-dependent polymer dissolution, typically triggering release in the jejunum or early ileum (e.g., at pH ∼6.5–6.8). Such systems may not provide sufficient delay to consistently reach the terminal ileum.

The present work proposes a bilayer capsule design specifically engineered to achieve delayed release in the distal ileum through a combination of diffusion-controlled and environmentally responsive mechanisms. The outer layer, composed of ethylcellulose and sodium alginate, acts as a semi-permeable barrier, where EC provides hydrophobicity and structural resistance, while alginate progressively increases permeability through hydration and pore formation at elevated pH. In addition, the susceptibility of alginate to microbiota-derived enzymatic degradation provides a further level of responsiveness that may contribute to region-specific permeability in the distal small intestine. In contrast to purely pH-triggered systems, this approach introduces a time-dependent diffusion barrier that delays drug release beyond the proximal small intestine.

The inner layer, based on HPMC or HPMC/pullulan blends, provides structural support and governs disintegration once the outer barrier is sufficiently weakened. The inclusion of pullulan introduces the potential for enhanced hydration and enzymatic susceptibility, which may further contribute to capsule opening in the distal small intestine, where microbial activity increases relative to the proximal intestine. Together, the combination of a diffusion-limiting outer layer and a responsive inner structural layer provides a mechanistic basis for targeting drug release to the terminal ileum rather than the colon.

The objective of this study was therefore to design and characterize bilayer capsule shells fabricated exclusively by a double dip molding process, a comparatively simple, robust, and industrially scalable manufacturing approach enabling precise modulation of capsule shell architecture while maintaining process reproducibility (Millet et al., 2025). Capsules were manufactured in size #1, a format recently shown to empty efficiently from the porcine stomach and therefore particularly relevant for future translational studies in a porcine model (Hoffmann et al., 2025). The systems were designed to enable site-specific drug release in the distal small intestine through the combined effects of formulation composition and processing conditions. In particular, the influence of sodium alginate concentration and curing parameters (temperature and relative humidity) on capsule microstructure, surface properties, permeability, and in vitro performance was systematically investigated. This study was conceived as a proof-of-concept approach aimed at screening key formulation and processing parameters in order to establish structure–function relationships and identify lead capsule prototypes. These systems are intended for subsequent evaluation under biorelevant conditions and, ultimately, for further translational assessment in physiologically relevant models. This work therefore provides a rational framework for the iterative development of capsule-based systems for ileum-targeted oral drug delivery.

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Materials

The inner layer of the capsule was made with pullulan sourced from Hayashibara (Okayama, Japan), and hydroxypropyl methylcellulose (HPMC, Tylopur® 65SH-5) provided by Shin-Etsu (Wiesbaden, Germany).

The outer layer of the double layer capsule was made with an ethylcellulose aqueous dispersion supplied by Ashland (Aquarius® Control ECD, Waalwijk, Netherlands) and sodium alginate purchased from IFF (Vormedal, Norway). For the plasticizers screening dibutyl sebacate (DBS) obtained from Merck KGaA (Darmstadt, Germany), triethyl citrate (TEC) and triethyl 2-acetyl citrate (ATEC) supplied by Sigma Aldrich (Saint Louis, MO, USA) were selected. Polysorbate 80 (PS80) was supplied by BTC (Paris, France).

Then for the disintegration and water ingress, acidic media and phosphate buffer were prepared with fuming hydrochloric acid (37%), disodium hydrogen phosphate dodecahydrate (Na₂HPO₄·12H₂O) and potassium dihydrogen phosphate (KH₂PO₄) obtained from Merck KGaA. Citric acid monohydrate was purchased from Thermo Fisher Scientific (Waltham, MA, USA). Sodium chloride (NaCl) was purchased from Sigma-Aldrich (Burlington, MA, USA). Capsules were filled with thymol blue (Merck KGaA) as a colorant and either lactose (Pharmatose® 200M, DFE Pharma, Germany) for disintegration studies or mannitol (Pearlitol® 200 SD, Roquette, France) for water ingress experiments. And for dissolution analytical-grade trisodium phosphate dodecahydrate, hydrochloric acid (2 N and 37%) and anhydrous caffeine (ReagentPlus®, 100.0%) obtained from Merck KGaA were used and UPLC/MS-CC/SFC-grade methanol was purchased from Biosolve Chimie SARL (Dieuze, France). Glacial acetic acid (analytical reagent grade, ≥ 99.7%) was sourced from Fisher Chemical (Loughborough, United Kingdom) and sodium hydroxide (5 N) was obtained from Honeywell (Seelze, Germany).

Elisa Millet, Sofie S.T. Vandenbroucke, Joseph P O’Shea, Brendan T Griffin, Vincent Jannin, Design and process parameter evaluation of bilayer capsule systems for targeted ileal drug delivery, European Journal of Pharmaceutical Sciences, Volume 224, 2026, 107601, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2026.107601.