3D-Printed Chewable Gummies: A Customizable Approach to Formulate Propranolol in the Paediatric Population

Abstract

Paediatric patients, representing over 30% of the global population, continue to face a critical shortage of age-appropriate pharmaceutical formulations. This gap is largely attributed to the high cost and complexity of paediatric drug development, resulting in the widespread off-label use of adult medications in children—an approach that compromises safety, therapeutic efficacy and adherence. Conventional manufacturing methods often fail to meet essential paediatric requirements such as dose flexibility, palatability, and ease of administration, all of which are pivotal for ensuring treatment adherence. Providing that the European Paediatric Formulation Initiative (EuPFI) and EMA reflection papers suggest that chewable dosage forms are generally acceptable starting at around age 3, chewables are usually considered acceptable for children from about 3–5 years onward.

This study proposes a semisolid extrusion-based 3D printing methodology for the fabrication of chewable paediatric dosage forms—referred to as gummies—incorporating propranolol hydrochloride as a model hydrophilic drug commonly prescribed for cardiovascular and cardiac conditions in children. A hydrogel matrix consisting of 7% w/w iota-carrageenan and 3% w/w sodium alginate was optimized to ensure appropriate rheological properties, printability, and structural integrity. Fourier-transform infrared (FTIR) spectroscopy confirmed the uniform distribution of the active pharmaceutical ingredient within the matrix. Texture profile analysis revealed desirable mechanical properties when compared to those of commercially available gummy formulations (Haribo® teddy bears, Bonn, Germany). Furthermore, the printed dosage units conformed to the European Pharmacopoeia quality specifications for mass uniformity and content uniformity. Notably, the simplicity and scalability of the presented approach suggest its suitability for implementation in both hospital and community pharmacy environments, facilitating decentralized manufacturing of personalized paediatric medications.

Introduction

The development of age-appropriate pediatric medications remains a significant concern in the pharmaceutical field. Despite children’s specific physiological requirements, many commercially available medications are developed with a one-size-fits-all approach causing dosing, acceptance, and adherence to be very challenging [1], [2], [3]. Propranolol (PR) is a beta-blocking active pharmaceutical ingredient (API) commonly used in children to treat conditions such as infantile hemangiomas, arrhythmias, and certain cases of hypertension and migraine [4], [5], [6]. It works by reducing heart rate and blood pressure and controlling abnormal blood vessel growth. In pediatric patients, the dosage is typically tailored from physicians based on weight and the specific condition being treated. Usually, the prescribed amounts arise around 0.5-4, up to 8 mg/kg/day divided into two or three doses and gradually adjusted as needed [7]. Currently, Hemangiol® is the only propranolol hydrochloride liquid formulation specifically developed and approved for pediatric use. It is an oral solution (3.75 mg/mL) indicated for infants aged 5 weeks to 12 months with proliferating infantile hemangiomas, administered twice daily with dose adjustments based on weight. However, being 40 mg tablets the only other therapeutic alternative, there is a significant lack of PR-based formulations specifically designed for pediatric use, which raises difficulties in ensuring accurate dosing and administration for younger children (age > 3 years) that may require PR for other diseases such as arrhythmias or hypertension [8]. This problem is often faced by the manipulation of already existing formulations such as tablets or capsules, actions that can compromise efficacy and safety of the treatment [3]. This significant gap is only one of the several examples underscoring the need for age-appropriate medications to improve treatment adherence and safety in young patients.

In this context, 3D printing (3DP) has emerged as a revolutionizing manufacturing technology with the potential to address these challenges. By allowing for an easy and precise fabrication of dosage forms with desired shapes, sizes, and amount of loaded drug, 3DP offers unique opportunities to produce tailored batches of medications that deal with the specific needs of single patients [9]. This provides age-appropriate dosing and improvements in compliance. Moreover, the adaptability and simplicity of 3DP, as well as its decentralized nature, make it suitable for integration into hospital and community pharmacy settings where it enables the on-demand production of personalized medications with accurate dosing tailored to individual patient needs [10].

Oral dosage forms are the most exploited route of administration, thanks to their convenient and easy handling [11]. However, swallowing remains a concern, particularly in the paediatric population. For this reason, chewable oral dosage forms are gaining a lot of interest, also being more appealing to young patients and thus raising therapeutical adherence [3]. Nonetheless, one of the most persistent challenges in developing chewable formulations is palatability, which significantly influences acceptability. Regulatory bodies such as the European Medicines Agency (EMA) have emphasized the importance of palatability testing in early stages of pediatric drug development. According to the EMA guideline on pharmaceutical development of medicines for pediatric use [12], palatability—defined as the overall appreciation of a medicine’s organoleptic properties such as taste, texture and mouthfeel—is a key determinant of acceptability. More recently, a validated composite endpoint framework that integrates swallowability and palatability to assess oral formulations across pediatric age groups offering a standardized approach to evaluate sensory attributes was proposed [13]. Despite these advances, chewable formulations still face hurdles due to the lack of universally accepted sensory testing protocols and the variability in children’s taste preferences. Moreover, standardized and validated tools for assessing palatability in pediatric populations are still evolving, underlining the need for robust, evidence-based evaluation approaches during formulation development [14].

According to guidance from the European Paediatric Formulation Initiative (EuPFI) and the EMA reflection paper [15], chewable dosage forms are considered suitable for pediatric use from around 3 years of age, with consistent acceptability generally observed in children aged 3 to 5 years. Thus, Semisolid extrusion-based (SSE) 3DP technique has been recently explored to produce gummy-like oral dosage forms in an easy and versatile way. The “ink” is pre-formulated usually in the form of a gel or paste and subsequently loaded into the 3D printer. This allows to customize the formulation according to the needs, giving the possibility to easily and quickly adjust the overall amount of API in the final dosage form [16]. For instance, 3D-printed chewable formulations of lamotrigine, ranitidine, ondansetron, metformin, and amoxicillin, demonstrated feasibility in dose accuracy, shape personalization, and mechanical strength [17], [18], [19], [20]. Furthermore, SSE 3DP widens the range of excipients that can be employed, in respect to their rheological properties, which are fundamental when considering this 3DP technique. Natural polymers such as carrageenan and sodium alginate present additional advantages being biocompatible, low-toxic and versatile materials [21], [22]. They enhance the functionality of the dosage forms but also align with the growing demand for safer and more sustainable pharmaceutical ingredients.

The present study aims to develop and optimize a hybrid hydrogel based on safe and generally recognised as safe (GRAS) algae-derived polymers that presents enhanced and optimized rheological properties for SSE 3DP. The gel matrix was employed as an alternative manufacturing way to produce customizable chewable oral dosage forms containing PRHCl that target the paediatric population (age > 3 years old). For this reason, heart shaped gummy-like dosage forms that can be easily chewed and swallowed were printed. The 3D printing ‘‘ink’’ was formulated to contain 4% w/w of PRHCl, selected as a representative dose based on concentrations commonly found in commercially available formulations. However, given the ability of 3DP to precisely adjust the amount of active pharmaceutical ingredient (API) in each dosage unit by simply modifying the amount of extruded material during the printing process, different design dimensions were produced to demonstrate the versatility of the manufacturing process. This enables accurate, patient-specific dose customization without the need for dosage manipulation such as tablet splitting, crushing, or dissolving—procedures that are often associated with dosing inaccuracies, drug loss, and safety concerns [10]. The resulting 3D-printed gummies were tested in terms of quality standards required by the European Pharmacopoeia. Moreover, the uniformity of drug distribution within and across individual dosage forms was assessed, alongside evaluations of the solid-state properties, mechanical strength, and drug release behaviour of the formulations.

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Materials

Sodium Alginate (SA, Protanal PC 6850, 400-600 cps) was obtained from Biochim (Italy), while iota-Carrageenan (ι-K, 60072/24) from Java Biocolloid Europe s.r.l. (Italy). Propranolol hydrochloride (PRHCl) and saccharin sodium (E954) were acquired from Farmalabor (Italy). Calcium Chloride (CaCl2) was purchased from Carlo Erba reagents (Italy).

Costanza Fratini, Annalisa Aluigi, Mattia Tiboni, Luca Casettari, 3D-Printed Chewable Gummies: A Customizable Approach to Formulate Propranolol in the Paediatric Population, Journal of Drug Delivery Science and Technology, 2025, 107581, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107581.