Design and manufacturing of fixed-dose combination coated minitablets for pediatric GERD therapy

Abstract

This study aimed to develop an innovative pediatric-friendly fixed-dose combination (FDC) of omeprazole (OMZ) and domperidone (DOM) for the treatment of gastro-esophageal reflux disease (GERD) in children. The formulation strategy focused on enteric-coated minitablets (MTs), a dosage form that poses significant technological challenges when co-formulating two APIs within the same small-sized unit, particularly with respect to powder processability, content uniformity, and manufacturability, but offers advantages in terms of dose accuracy, dosing flexibility, ease of swallowing, and acceptability. Preformulation studies (thermoanalysis, infrared spectroscopy, and hot-stage microscopy) confirmed the absence of physicochemical incompatibilities between OMZ and DOM. Due to the high drug load and the small MTs size (≈2 mm), melt granulation using Macrogol 6000 was selected to improve flowability and compactability. The manufacturing process was progressively optimized using placebo formulations and OMZ-only granules before application to the FDC system. The resulting granules were compressed into MTs containing 2 mg OMZ and 1 mg DOM per unit, consistent with pediatric dosing requirements, using a laboratory-scale eccentric press (final weight: 8.39 ± 0.26 mg). The optimized MTs were subsequently seal-coated (5% weight gain) and enteric-coated using a methacrylic acid copolymer (20% weight gain) using a laboratory-scale fluid-bed system to protect OMZ from gastric degradation and ensure intestinal drug release. Coated FDC-MTs were characterized for morphology, mass and content uniformity, mechanical strength, disintegration behavior, and dissolution performance and met the European Pharmacopoeia requirements. Overall, this proof-of-concept study demonstrates the feasibility of producing co-formulated FDC MTs as accurate, flexible, and child-appropriate dosage form addressing an unmet need in pediatric GERD.

Introduction

Gastro-esophageal reflux disease (GERD) is a common disorder in both adults and children, with a high and increasing global prevalence [1,2]Common symptoms in children include abdominal pain, vomiting, excessive belching, and dysphagia, which, if persistent, may lead to complications such as erosive esophagitis or Barrett’s esophagus. Additional associated manifestations include poor weight gain, sleep disturbances, and respiratory disorders. The management of pediatric GERD typically involves both pharmacological and nutritional interventions.

Pharmacological treatment in children primarily relies on use of histamine H2-receptor antagonists (e.g., cimetidine) and proton pump inhibitors (PPIs), such as omeprazole (OMZ), its enantiomeric form esomeprazole and lansoprazole [3]. PPIs are more potent inhibitors of gastric acid secretion than H2-antagonists and have demonstrated superior efficacy in promoting the healing of erosive esophagitis in both adults and children [4,5]. Owing to its favorable balance of efficacy, safety, and cost, OMZ remains the only PPI included in the WHO Model List of Essential Medicines for Children [6]. In pediatric GERD, esophageal dysmotility and delayed gastric emptying may reduce the effectiveness of PPIs by prolonging their gastric residence time. Consequently, the co-administration of a prokinetic agent may be beneficial by enhancing esophageal peristalsis, gastric emptying, and intestinal motility [7,8]. Clinical evidence obtained in adult patients supports this therapeutic strategy. In a randomized controlled trial, a capsule containing a combination of enteric-coated OMZ (20 mg) and sustained-release DOM (30 mg) demonstrated superior efficacy compared with OMZ alone (20 mg) in relieving reflux symptoms and promoting esophagitis healing, without an increased incidence of adverse effects or clinically relevant drug–drug interactions [9]. In addition, the efficacy and tolerability of this combination have been confirmed in a meta-analysis [10] and in cohort studies in patients with functional dyspepsia [11].

Furthermore, fixed-dose combinations (FDCs) of OMZ (or esomeprazole) and DOM are commercially available in several Asian countries for the treatment of GERD in adults. These products are typically formulated as sustained-release capsules containing enteric-coated PPI pellets (e.g., esomeprazole or OMZ 20 mg) combined with immediate-release prokinetic units of domperidone maleate equivalent to 30 mg DOM, incorporated as an uncoated or bilayer sustained-release tablet. Such formulations are intended for patients who do not achieve adequate symptom control with PPI monotherapy, further supporting the clinical rationale for combining acid suppression with prokinetic therapy. OMZ and DOM have not previously been formulated together for this indication in pediatric patients, while the therapeutic benefit of combining PPIs with DOM has also been reported in children with difficult-to-treat asthma, where esomeprazole plus DOM was more effective than esomeprazole alone in improving asthma severity [12].

In recent years, the pharmaceutical industry has shown growing interest in FDC medicinal products, as they can improve clinical outcomes by enhancing patient adherence, therapeutic efficacy, and safety compared with monotherapy, provided that the pharmacokinetic profiles of the combined drugs are compatible [13]. This aspect is particularly relevant in pediatric therapy, where optimizing dosing regimens and minimizing treatment burden are essential to ensure long-term adherence. The WHO actively promotes the development and use of FDCs in pediatric medicine and strongly encourages the design of age-appropriate formulations. Several FDCs are routinely prescribed in children and are included in the WHO Model List of Essential Medicines for Children, such as amoxicillin/clavulanic acid, sulfamethoxazole/trimethoprim, and, more recently, combinations for the treatment of tuberculosis (isoniazid + rifampicin ± pyrazinamide), HIV (lamivudine + nevirapine + zidovudine), and malaria caused by Plasmodium falciparum (artemether + lumefantrine). These FDCs, in which the APIs are co-formulated within the same matrix, have demonstrated clear clinical advantages over monotherapy, including improved treatment adherence, reduced pill burden, and a lower risk of resistance development.

In light of this context, the aim of the present work was to develop an innovative pediatric platform based on a fixed-dose combination (FDC) of OMZ and DOM for the treatment of GERD in children. This approach required addressing key formulation challenges, primarily the design of an age-appropriate dosage form to ensure accurate dose adjustment and improve treatment adherence, as well as the development of a suitable drug delivery system. To meet the first objective, a multiparticulate strategy based on minitablets (MTs) was selected. MTs are particularly suitable for pediatric use due to their dose accuracy, dosing flexibility, ease of swallowing, and high acceptability [[14], [15], [16], [17]] mainly as a result of their small size (typically <4 mm) [18].

Secondly, the formulation design must ensure appropriate release of both APIs. Although this drug combination is well established in adults, currently available products and clinical studies do not provide it as a true fixed-dose system, as the two APIs are typically formulated as physically separate units within the same dosage form. In particular, OMZ is generally administered as an enteric-coated (delayed-release) drug due to its instability in acidic environments, whereas DOM is formulated as an immediate- or sustained-release compound, reflecting their different biopharmaceutical requirements.

In this work, the technological approach was based on the development of enteric-coated MTs, primarily aimed at ensuring OMZ gastroprotection while enabling the co-administration of both APIs within a single, child-appropriate dosage form and promoting their release in the intestinal environment.

Based on pediatric dosing recommendations (10–20 mg/day for OMZ depending on body weight [6] and 0.5 mg/kg/day for DOM [19]), the FDC minitablets (Ø = 2 mm) were designed to contain a theoretical dose of 2 mg OMZ and 1 mg DOM each, enabling flexible dosing. Accordingly, a daily dose of approximately ten minitablets would be suitable for a child weighing around 20 kg.

The development of this novel FDC platform posed several technological and formulation challenges. First, a comprehensive physicochemical compatibility assessment was required, as both APIs were co-formulated within the same small dosage unit. Second, producing 2 mm MT containing a high drug load (approximately 37.5% w/w) represents a significant manufacturing challenge, as the powder blend must exhibit excellent flowability and compressibility to ensure compliance with content uniformity requirements. To overcome these limitations, the evaluation of an intermediate granulation step was necessary to improve powder processability and compactability, with careful selection of the most suitable granulation technique given the sensitivity of OMZ. Furthermore, owing to the differing physicochemical properties of the APIs, the MTs were designed to protect OMZ from the acidic gastric environment while ensuring the release of both drugs in the intestine. Therefore, the feasibility of producing a delayed-release multiparticulate FDC by coating MTs was investigated. Overall, these considerations highlight the complexity of the manufacturing process and underscore the importance of an integrated formulation and process-development approach. Finally, uncoated and coated MTs were characterized in terms of weight variation, mechanical strength, friability, content uniformity, disintegration behavior and in vitro drug release.

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Materials

OMZ (batch n°0121214) and DOM (batch n° 13J29-B08-321194) were purchased from A.C.E.F. S.p.A (PC. Italy). Pre-gelatinized maize starch (Starch 1500), Avicel Ph 101 (microcrystalline cellulose, 50 μm) and Ph102, Macrogol 6000, Colloidal anhydrous silica (Aerosil® 200) and magnesium stearate were purchased from Fagron (BO, Italy). Precipitated amorphous silica (Tixosil® 38A) was supplied by Solvay (MI, Italy). Sucrose powder (Ph. Eur. grade, 80% < 100 μm) was kindley donated by Giusto Faravelli S.p.A (MI, Italy). Finally, Starch 1500, Opadry®YS-1-7027 white (based on hydroxypropyl methylcellulose (HPMC)), Opadry®QX white (based on a polyvinyl alcohol–polyethylene glycol (PVA-PEG) copolymer and Acryl-EZE® clear (based on EUDRAGIT®L100-55 as methacrylic acid copolymer) were kindly donated by Colorcon Ltd. (Dartford, Kent, UK).

Beatrice Albertini, Serena Bertoni, Eleonora De Renzis, Alberto Genovesi, Nadia Passerini, Design and manufacturing of fixed-dose combination coated minitablets for pediatric GERD therapy, Journal of Drug Delivery Science and Technology, Volume 123, 2026, 108480, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108480.

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