Development of propranolol hydrochloride extended-release lipid matrix tablets for pediatric use

Abstract

Although solid oral dosage forms are widely used in adult drug therapy, age-appropriate formulations for pediatric patients remain limited. The development of suitable dosage forms is challenged by specific requirements regarding excipient safety, tablet size, and dose flexibility, as well as the need to improve therapy adherence in the context of frequent dosing. This study aimed to develop a pediatric-appropriate extended-release matrix tablet based on lipid matrix formers, with particular attention to the use of safe excipients and the selection of excipients based on sustainability considerations. Lipid-based excipients, selected due to their natural origin and similarity to dietary fats, were investigated and compared with conventional matrix formers. A formulation screening approach was applied to identify promising candidates based on drug release after one hour, followed by further evaluation of manufacturability, tablet hardness, and extended-release performance. In addition, the influence of a physiological pH-gradient, bile salts, and long-term storage on drug release was assessed. The selected formulations showed good manufacturability, uniformity, and sustained drug release. Overall, several lipid-based matrix formulations suitable for pediatric use were identified, providing a promising basis for the development of solid oral extended-release dosage forms for children.

1. Introduction

Solid oral dosage forms, such as tablets, are the most commonly used dosage forms in adult pharmacotherapy. However, conventional tablet sizes are often too large for pediatric patients to swallow, particularly in young children, who may have difficulty or are unable to swallow tablets designed for adults (Lopez et al., 2015, Ranmal et al., 2016, Walsh et al., 2018, Zuccari et al., 2022). For this reason, liquid formulations are frequently used in pediatric drug therapy due to their ease of administration (Walsh et al., 2018). However, liquid dosage forms present several disadvantages compared to solid oral dosage forms, including poor palatability and reduced physical, microbial and chemical stability. As a result, they often require special storage conditions and/or the addition of multiple excipients, despite limited safety data on excipient use in pediatric populations (Meyers, 2020, Münch et al., 2023a, Rouaz et al., 2021, Walsh et al., 2018). Therefore, there is a clear need for solid oral dosage forms tailored to pediatric patients, particularly in the form of smaller tablets, to improve safe and effective treatment and adherence.

In the development of solid oral dosage forms for pediatric use, minitablets (MTs) have gained increasing attention in recent years (Aleksovski et al., 2015, Lura et al., 2025, Meruva et al., 2024, Meyers, 2024, Zuccari et al., 2022). Although no formal definition currently exists, MTs are commonly defined as tablets with a diameter of ≤ 4 mm (Lennartz and Mielck, 1998, Lura et al., 2025, Meruva et al., 2024, van Riet-Nales et al., 2016). Owing to their small size and flexible dosing, MTs are considered easier for children to swallow (Aleksovski et al., 2015, Meruva et al., 2024, Zuccari et al., 2022). Several studies have investigated the acceptability of small tablets in pediatric populations, with some reporting a preference for MTs over liquid formulations. In particular, it has been shown that MTs can be given to very young children. Münch et al. reported that children as young as 6 months are able to swallow 2 mm tablets, whereas 3 mm tablets can be administered from the age of 3 years (Münch et al., 2023a, Münch et al., 2023b). Furthermore other studies have reported that children of pre-school age (3–5 years) are able to swallow tablets with a diameter up to 5 mm, while tablets with a diameter up to 10 mm are also accepted from the age of 6 years (Bracken et al., 2020, Spomer et al., 2012). These findings suggest that a reduction in tablet size may be beneficial, as it increases the potential to cover a wider range of pediatric age groups, even with only a slight increase beyond the typical MT size range.

In addition to appropriate tablet size, dosing frequency is another important factor for the safe and effective treatment of pediatric patients, as repeated administration of medication throughout the day can impose a considerable burden on children and their caregivers (Alessandrini et al., 2021, Lopalco and Denora, 2020, Meyers, 2024). Many commonly used pediatric medicines require multiple daily doses, often necessitating administration outside the child’s familiar home environment. This can be a significant source of stress for both children and caregivers (Meyers, 2024). Accordingly, there is a clear need for extended-release (ER) oral dosage forms for pediatric use. Only a limited number of such formulations are currently available on the market (Lura et al., 2025).
Various strategies can be employed to achieve sustained drug release of oral dosage forms. One common approach is the application of ER coatings. However, pediatric patients may chew solid dosage forms, potentially compromising the integrity of functional coatings (Aleksovski et al., 2015, Kluk et al., 2015). Defects in the coating can result in dose dumping, particularly in formulations containing high drug loads, which may increase the risk of adverse drug reactions. An alternative approach is the use of matrix tablets, in which the drug release is controlled by the tablet core itself. In contrast to coating-based systems, matrix systems are generally less susceptible to surface defects. While conventional hydrophilic matrix systems, based on swelling and erosion mechanisms, have shown limited robustness under gastrointestinal hydrodynamic and mechanical stress conditions, non-swelling and non-erodible lipid-based matrix systems represent an interesting alternative for pediatric applications (Garbacz and Klein, 2012, Shameem et al., 1995).

A number of approaches for the preparation of lipid-based tablets using Compritol® 888 ATO as a matrix former have been reported in the literature. In addition to its role as a matrix-forming agent, Compritol® 888 ATO has been widely used as a lubricant, for hot-melt coating, and for taste masking applications (Aburahma and Badr-Eldin, 2014, Roberts et al., 2015). Its suitability for direct compression has also been investigated in multiple studies using different concentrations in the respective formulations. For example, Dzajkowska et al. developed 3 mm MTs containing carbamazepine with 40% Compritol® 888 ATO (Dzajkowska et al., 2017), whereas Roberts et al. prepared 2–4 mm MTs containing theophylline with 15–45% of the same lipid (Roberts et al., 2012). Comparable drug release behavior has also been reported for Precirol® ATO 5-based formulations highlighting its potential as an alternative to Compritol® 888 (Gu et al., 2004). Furthermore, glycerol monostearate (GMS) has also been investigated as a lipid matrix former for directy compressed matrix systems. For example, Nyavanandi et al. developed 10 mm matrix tablets containing either 10% GMS in combination with 5% hydroxypropyl methylcellulose (HPMC) or 20% GMS with 5% polyvinylpyrrolidone (PVP) (Nyavanandi et al., 2021). While these studies demonstrate the feasibility of direct compression, lipid-based matrix formers are still predominantly used in ER formulations produced via melt-based techniques, such as melt extrusion or melt granulation (Aburahma and Badr-Eldin, 2014, Reitz et al., 2008, Roberts et al., 2015, Roberts et al., 2012).

In addition to the selection of a suitable matrix polymer, the safety of the excipients is a key aspect in the development of pediatric dosage forms. Children require special attention with regard to excipients safety, as physiological characteristics can vary considerably between different age groups, potentially increasing the risk of excipient-related adverse effects. Therefore, a clear definition of the target age group(s) is essential. According to the ICH-Guideline ‘Clinical Investigation of Medicinal Products in the Pediatric Population’, pediatric patients are classified into preterm- and term newborn infants (0 to 27 days), infants and toddlers (28 days to 23 months), children (2 to 11 years) and adolescents (12 to 16–18 years (dependent on region)) (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2017). Additional subdivisions within these categories are sometimes applied. Particular caution is required when developing medicinal products for infants and young children, as in these age groups rapid developmental changes and immature physiological functions, especially in metabolism, elimination, and blood–brain barrier integrity, may affect the safety profile of excipients (Rouaz et al., 2021). Consequently, excipients considered safe in adults or older pediatric populations may pose risks in younger age groups. To support excipient risk assessment in pediatric formulations, several tools are available, including the ‘The Safety and Toxicity of Excipients for Paediatrics’ (STEP) database, and the more recently developed ‘Paediatric Excipient Risk Assessment’ (PERA) tool (Agrawal et al., 2024, Rouaz et al., 2021, Salunke et al., 2013).

Beyond the safety of the excipients, sustainability has become an increasingly important consideration in pharmaceutical development. In addition to resource-efficient manufacturing processes, the use of environmentally friendly excipients and active pharmaceutical ingredients (APIs) is gaining attention (Bading et al., 2024a, Bading et al., 2024b, Kümmerer, 2019, Milanesi et al., 2020). Biodegradability and biocompatibility are particularly relevant for polymer-based dosage forms, as many polymers used in the pharmaceutical industry are not biodegradable (Bading et al., 2024b). Non-biodegradable polymers may contribute to microplastic pollution in the environment, thereby posing a potential long-term threat to ecosystems (Ardila-Fierro and Hernández, 2021). Methacrylate-based polymers, for example, are non-biodegradable and are also applied in the development of pediatric matrix tablets (Lura et al., 2025).

The aim of this study was to develop pediatric ER lipid matrix tablet formulations using propranolol hydrochloride (HCl) as a model drug. Propranolol HCl was selected because of its established use in pediatric patients, its relatively short elimination half-life, and its high aqueous solubility, representing a challenging model compound for evaluating the feasibility of small ER matrix tablets. The study addresses the need for age-appropriate solid oral dosage forms that combine improved swallowability through miniaturized tablet size with sustained drug release with the long-term goal of reducing dosing frequency and improving treatment adherence in pediatric patients, while also considering sustainability aspects in excipient selection. Accordingly, this proof-of-concept study focused on evaluating the feasibility of developing small-diameter lipid matrix tablets capable of providing sustained drug release over clinically relevant time periods. Rather than optimizing the formulation towards a predefined quantitative dissolution profile, the objective was to investigate whether formulation-dependent release profiles suitable for either twice-daily or, ideally, once-daily administration could be achieved.

2. Materials and methods

2.1. Materials

Propranolol HCl (Selectchemie China, Ningbo, China) was used as a model drug. The lipid matrix formers Compritol® 888 ATO and Precirol® ATO 5 were kindly provided by Gattefossé (Saint-Priest Cedex, France). Glyceryl monostearate (GMS) was purchased from Caesar & Loretz (Hilden, Germany) and Dynasan® 114 was kindly provided by IOI Oleo (Hamburg, Germany). Ethylcellulose (EC) 10 cp (Sigma-Aldrich Chemie, Taufkirchen) was used as an alternative hydrophobic matrix polymer. Hydrophilic matrix polymers included hydroxypropyl cellulose (HPC H FP-grade, kindly donated by NISSO CHEMICAL EUROPE, Düsseldorf, Germany) and hydroxypropyl methylcellulose (HPMC, Methocel K100M, kindly provided by DuPont de Nemours, Wilmington, USA). Emcompress® Premium (calcium hydrogen phosphate dihydrate, kindly provided by JRS Pharma, Rosenberg, Germany) and microcrystalline cellulose (MCC, Ceolus™ UF-711, KG-802 and KG-1000, kindly provided by Asahi-Kasei, Tokyo, Japan) were used as fillers. Colloidal silicon dioxide (Fagron, Glinde, Germany) and magnesium stearate (Sigma-Aldrich Chemie, Taufkirchen, Germany) were purchased from the respective suppliers and used as glidant and lubricant, respectively. All other chemicals were of analytical grade and obtained from commercial suppliers.

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Stefanie Broocks, Melanie Gebhardt, Sandra Klein, Development of propranolol hydrochloride extended-release lipid matrix tablets for pediatric use, International Journal of Pharmaceutics, Volume 702, 2026, 127234, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2026.127234.