Challenges in the Oral Administration of Gastro-Resistant Formulations: The Role of Vehicles and Bottled Waters

Abstract

Background/Objectives: Gastro-resistant multiparticulate systems are designed to protect drugs in acidic environments and to ensure intestinal release. In practice, the method of administration may need to be modified: pellet-containing capsules opened or tablets halved for patients with swallowing difficulties, yet the type of liquid used for administration is often not specified. This study examined the stability of gastro-resistant coated pellets after exposure to various aqueous media prior to ingestion.

Methods: To evaluate administration instructions, 103 Summaries of Product Characteristics of gastro-resistant products were reviewed. Pellets were produced using a bottom-spray fluidized bed process and coated with Eudragit L 30 D-55. Dissolution testing in pH 1.2 medium was performed after pre-soaking the pellets for 5, 15, and 30 min in beverages with various pH and conductivity. Drug release was measured by UV-VIS method, and morphological changes were assessed by image analysis. Marketed gastro-resistant products were also examined visually.

Results: SmPC review revealed that the beverage for intake was frequently unspecified. Among the tested beverages differences in pH and conductivity were observed. Alkaline medicinal mineral waters induced increased and time-dependent premature drug release compared to tap and filtered water. Image analysis indicated a reduction in surface area after exposure to alkaline media.

Conclusions: Contact with non-specified aqueous media before swallowing may weaken the protective function of gastro-resistant films. More explicit recommendations on suitable administration manipulation and media may improve therapeutic consistency.

Introduction

Oral administration remains the most common route for drug delivery due to its convenience and high patient compliance. In recent decades, pellet-based multiparticulate systems have become an essential focus of pharmaceutical research [1]. Their distinct technological and biopharmaceutical advantages over single-unit dosage forms make them highly valuable in both formulation design and drug development [2,3]. The pellets containing active pharmaceutical ingredient(s) (API) can be used for multiparticulate systems, or, in other words, multiple-unit pellet systems (MUPS) [4]. The presence of the pellets within a single dosage form, for example, filled in a capsule [5] or compressed in a tablet, provides several technological, physiological, and even therapeutic advantages [6,7].

Pellets and other multiparticulate systems are designed to divide the dose of API into discrete subunits, facilitating more predictable transit through the gastrointestinal tract and reducing the risk of dose dumping or local irritation [8]. Their regular spherical shape and favorable size distribution enable efficient processing, coating, and blending of different drug substances, thereby providing greater flexibility in formulation design [9,10]. Multiparticulate systems can be produced using various manufacturing techniques, each with specific process conditions that result in products with distinct physicochemical characteristics. From the point of view of the API amount distribution, the conventional pellet can be matrix (homogeneous) or layered (heterogeneous) [11,12].

One way to modify the drug-release profile is by coating. Coating of multiparticulate systems may be performed to achieve specific functional properties, improve chemical stability, optimize physical characteristics, or enhance patient acceptability [13,14]. Functional coatings, such as films that dissolve in the intestine or stomach, are widely used in oral drug delivery to protect APIs from degradation in the stomach, to control the location and rate of drug release. Enteric coatings remain intact in the acidic gastric environment (pH 1–3) and dissolve at higher pH values in the small intestine (pH 5.5–7.5), facilitating targeted delivery and reducing drug degradation in the stomach [15,16]. This protective mechanism is achieved by ionizing carboxylic acid groups, thereby allowing the polymer to dissolve. Anionic methacrylate copolymers, such as Eudragit L 30 D-55, are among the most commonly used pH-dependent gastro-resistant materials due to their predictable dissolution behavior at specified pH and suitability for aqueous coating processes [17,18]. Gastro-resistant polymers have been widely used in multiparticulate dosage forms to improve stability in the stomach and modulate the in vitro drug release profile, even when the administration method is altered [19].

Solid oral dosage forms, such as capsules and tablets, are still widely used, despite a significant percentage of the population having difficulty swallowing [20,21,22]. These patients with dysphagia who do not follow recommendations in the prescriptions may not receive the maximum benefit of the medications [23,24]. In case of some drugs, manipulating the administration form is permitted; however, inappropriate medication use can alter the drug’s pharmacokinetics and pharmacodynamics and compromise treatment efficacy and patient safety [25]. To overcome swallowing difficulties in patients with dysphagia, innovative film-coating materials can be used [26], or medications can be split and administered with soft foods or other vehicles, or delivered via feeding tubes [27,28], especially for the elderly [29,30].

Whenever marketed products are manipulated (capsules opened, tablets halved, etc.), concerns about achieving the required API dose arise, and the method of manipulation is also essential [31]. Patients can use non-standard vehicles to take their medicines, although standardized pharmacopeial media are typically used for dissolution testing [32,33,34]. In most cases, patients are advised to take their oral drugs with liquid; however, it is not certain which vehicles the patient will choose. Although some Summary of Product Characteristics (SmPCs) allow the method of intake to be manipulated, the type of liquid used for dispersion is often not explicitly specified. The vehicles can be different kinds of water, cola, beer, or milk, and the choice can alter the medication [35]. Research suggests that people choose between tap water and bottled water mostly based on taste, sensory perception, and perceived water quality. Certain groups (such as children) are more likely to prefer bottled water, especially if they have had previous negative experiences with the quality or taste of tap water [36,37].

Maintaining the integrity of the enteric coating is critical, particularly for acid-labile drugs [38] whose therapeutic efficacy depends entirely on protection from gastric degradation. Premature coating failure may result in drug degradation in the stomach, subtherapeutic plasma concentrations, treatment failure, or, in some cases, increased gastric side effects, with potentially serious consequences for patient safety and treatment outcomes.

These considerations highlight that, in the context of oral administration, the vehicle used during ingestion may influence not only the active pharmaceutical ingredient (e.g., ciplofloxacin in milk) but also the used excipients, and that impairment of excipient function may in turn compromise the overall performance of the dosage form. Accordingly, this study reviewed patient information leaflets (PILs) and Summary of Product Characteristics (SmPCs) of 103 gastro-resistant medicines to assess the prevalence of non-specific guidance, characterized commonly consumed beverages to identify conditions relevant to gastro-resistant coatings, and evaluated the effects of selected media on marketed products. Finally, a model pellet containing a suitable drug (caffeine) with a gastro-resistant coating was formulated to quantitatively investigate the impact of pre-soaking duration and fluid type on drug release.

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Materials

For pellet production, inert microcrystalline cellulose cores were used: Cellets 780 in the size range of 710 μm–850 μm (IPC Process-Center GmbH & Co. KG, Dresden, Germany). The active ingredient of the pellets was caffeine (Molar Chemicals Kft., Halásztelek, Hungary), as a model drug. Sunset Yellow FCF (303CC Sensient Food Colors UK Ltd., Norfolk, UK) was used as the coloring agent for the drug-containing layer. Hydroxypropyl methylcellulose (HPMC; Pharmacoat 606, Shin-Etsu Chemical Ltd., Tokyo, Japan) was used as the binder excipient during the drug layering process. Eudragit L 30 D-55 (Evonik Industries AG, Essen, Germany), a methacryl-ethyl-acrylate copolymer, was used to formulate the release-modifying coating. Micronized talc powder (Harke Pharma GmbH, Mülheim, Germany) was incorporated into the film-coating dispersion to improve adhesion. Triethyl citrate (TEC; Sigma-Aldrich Chemie GmbH, Darmstadt, Germany) served as the plasticiser for the film coating.

For the dissolution studies, different kinds of liquids were used: Peridot (Peridot Aqua Kft., Budapest, Hungary), Salvus (Salvus Kft., Pilisszentiván, Hungary), Parádi (Medaqua Kft., Gyöngyös, Hungary), and Hunyadi (Medaqua Kft., Gyöngyös, Hungary) bottled waters, apple juice (Sonny Kft., Budapest, Hungary), filtered water (Culligan Hungary Kft., Budapest, Hungary), and pH 1.2 ± 0.05 hydrochloric acid medium

Demeter, A.K.; Farkas, D.; Király, M.; Barna, Á.T.; Ludányi, K.; Antal, I.; Kállai-Szabó, N. Challenges in the Oral Administration of Gastro-Resistant Formulations: The Role of Vehicles and Bottled Waters. Pharmaceutics 2026, 18, 453. https://doi.org/10.3390/pharmaceutics18040453