Novel Soft Dosage Forms for Paediatric Applications: Can We 3D-Print Them or Not?

Over the past years, numerous novel dosage forms, including gels, have been investigated for paediatric treatment due to the need to provide flexible dose adjustment possibilities, as well as a patient-friendly approach to drug delivery. Simultaneously, 3D printing technology is continuously advancing and gaining interest as a tool for personalised formulation development. Multiple additive manufacturing methods, including the semi-solid extrusion, especially used in gel printing, provide flexibility regarding the dose of active ingredients and the adjustment of the design of soft dosage forms. 3D printing techniques can be considered as a possible answer to the demand for medicines tailored to small patients’ needs. This review intends to present an overview of the current possibilities, comparing gel-like and non-gel-formulated dosage forms and crucial aspects of developing those cutting-edge dosage forms by 3D printing. This paper discusses soft formulations such as chewing gums, which still require extensive evaluation, and explores the question of the three-dimensional printing process. Furthermore, it highlights soft dosage forms, such as gel-based gummies and hydrogels, for which 3D fabrication has been intensively studied in previous years. However, the research still needs to advance.

Developing drugs suitable for the paediatric population maintains its status as a vital challenge for regulatory stakeholders, the pharmaceutical industry, science, politics and patients. It is significant internationally since every day, millions of children are seen by healthcare professionals due to potentially fatal illnesses [1]. The need to ensure adherence by providing acceptable medicines and accessible age-appropriate drug delivery products, is growing [2].

Nowadays, healthcare professionals or caregivers face daily challenges, due to numerous non-child-friendly medicines. This often results in the adaptation of medicines intended for adults, by pharmaceutical compounding and manipulation [3]. The off-label use of drugs (outside the terms of the marketing authorisation) may lead to an increased risk of side effects [4]. Additionally, various studies have emphasized the challenge of obtaining an accurate dose from tablet manipulation [5]. Consequently, these practices cannot be regarded as an equivalent for commercially available drugs, produced according to Good Manufacturing Practice [6]. Nonetheless, involving the dose adaptation by pharmacists, nurses or parents remains the most commonly used solution to the lack of therapeutics for children [7]. These practices pose significant risks and may cause harm, including a lack of therapeutic effectiveness and toxicity [8].

Currently, the children population, that is people under 18 years old, is 2,415,319,658 [9], with around 654,028,000 under 5 years old [10]. In this paediatric population, we can distinguish several groups based on their age [11] (in completed days, months or years). Although there is some variation in how these age groups are categorized, the International Congress on Harmonization (ICH) offers a commonly used classification. According to the ICH E11 guidance, the paediatric populations can be divided into: preterm newborn infants, term newborn infants (0 to 27 days), infants and toddlers (28 days to 23 months), children (2 to 11 years) and adolescents (dependent on region: 12 to 16–18 years). Age classification is based on overlap in developmental issues, however, it is to some degree arbitrary. Therefore, a flexible approach is essential in studies.

The issue of billions of paediatric patients still lacking access to appropriate therapy prompted stakeholders to introduce new regulatory frameworks as an incentive for the development of child-friendly medicines. Nowadays, the pharmaceutical industry must include children in the drug development process with a Paediatric Investigation Plan (EU) or Paediatric Study Plan (USA). Moreover, multiple regulations have been implemented by the United States of America, including Title V of the Food and Drug Administration Safety and Innovation Act (FDASIA) [12], which reauthorizes and amends provisions of the Best Pharmaceuticals for Children Act (BPCA) and the Paediatric Research Equity Act (PREA). Similarly, the European Union introduced the EU Paediatric Regulation: (EC) No. 1901/2006 and (EC) No. 1902/2006 [13] and the World Health Organisation launched the Make Medicines Child Size initiative [14]. Simultaneously, several initiatives, including the European Paediatric Formulation Initiative (EuPFI; 2007) [8] and the Global Accelerator for Paediatric Formulations (GAP-f) [15] focused on age-appropriate drug formulation development. Moreover, numerous organisations conducted workshops, such as the workshop on Paediatric Formulation Development: Challenges of Today and Strategies for Tomorrow [2] and the 6th APV Winter Conference Patient-Centric Drug Product Development [16], to tackle the issues of formulations tailored for paediatric patients. Across the previously mentioned workshops and initiatives, there is a recurring issue of lack of acceptability and willingness of paediatric patients to use the drugs.

Acceptability is a critical attribute to ensure paediatric patients’ adherence to drugs, according to 90% of paediatricians [2]. Commonly used formulations, such as tablets or oral liquids may be problematic due to unpleasant taste or tablet size, reducing children’s acceptability [15]. Conventional tablet use in children is also limited by the risk of choking or aspiration and the restriction of available doses [3]. In contrast, novel soft dosage forms may be an interesting solution, providing paediatric patients with an acceptable drug product. Illustratively, orodispersible dosage forms and chewable tablets are considered the dosage forms of choice for school-age children (6–11 years) and adolescents. Among these novel drug delivery approaches, the use of gels is observed [17]. Gels can be described as semisolid or elastic solid systems composed of three-dimensional lattices interpenetrated by liquid domains formed by solutions or suspensions of small inorganic particles. As gelling agents, various types of polymers can be applied, including cellulose derivatives, alginates, gums, carrageenans [18] and gelatine. Gel-based formulations have numerous advantages, such as size, shape and dose flexibility, as well as the fact that they can be easily swallowed. In addition, pharmaceutical forms, such as chewing gums, may be suitable for paediatric dosage forms, since they are easy to administer, do not require water and most children are familiar with them.

Soft novel drug delivery systems (DDSs) may be divided into gel-formulated and non-gel-formulated based on the composition of the medicine and its physicochemical properties. However, this division is to some extent arbitrary since there is no strict categorization. For the purpose of this article, various factors, including the specific composition, concentration, interaction of excipients, method of development and the original research authors’ incentive to name the DDS as a gel were considered.

There is no perfect commercially available formulation that is capable of meeting the needs of all age groups of paediatric patients [3]. However, three-dimensional printing (3DP) can be a useful tool for developing customized drug delivery for paediatrics [19]. Also referred to as additive manufacturing (AM), the 3DP technology provides vital attributes that distinguish it from other conventional manufacturing processes, including personalization, on-demand manufacturing and product complexity [20]. Three-dimensional printing offers geometrical flexibility of drugs, such as size, appearance, shape and design to address the paediatric patient desires and potentially increase compliance. Furthermore, this technique enables optimization of the dose according to the gender, age, weight, genetic profile and disease severity of the treated patient [21]. This paper discusses the development of 3D printing in paediatrics, focusing on the novel soft dosage formulation. This review intends to present an overview of current possibilities in additive manufacturing, comparing gel-like and non-gel-formulated dosage forms.