Regulations on excipients used in 3D printing of pediatric oral forms

Abstract

A promising solution to customize oral drug formulations for the pediatric population has been found in the use of 3D printing, in particular Fused Deposition Modeling (FDM) and Semi-Solid Extrusion (SSE). Although formulation development is currently limited to research studies, the rapid advances in 3D printing warn of the need for regulation. Indeed, even if the developed formulations include pharmaceutical excipients used to produce traditional oral forms such as tablets, the quantities of excipients used must be adapted to the process. Therefore, the aim of this literature review is to provide a synthesis of the available safety data on excipients mainly used in extrusion-based 3D printing for the pediatric population. A total of 39 relevant articles were identified through two scientific databases (PubMed and Science Direct). Then, groups of the main excipients were listed including their general information (name, chemical structure and pharmaceutical use) and a synthesis of the available safety data extracted from several databases. Finally, the role of the excipients in 3D printing, the amount used in formulations and the oral dose administered per form are presented.

Introduction

Most part of the medicines (capsules, tablets) are designed to meet the needs of adult patients and are not suitable for children. In fact, treatments developed for adults cannot always be administered to the youngest patients, as the development of medicines suitable for children has its own guidelines (O’Brien et al., 2019). Despite this, off-label use remains common in pediatrics, affecting around 40 % of medicines used in pediatric intensive care and up to 80 % of those prescribed in neonatology (Kaguelidou et al., 2022). However, the immaturity of newborn’s organs and physiological system can alter the absorption and distribution of Active Pharmaceutical Ingredient (API) and excipients. For example, the pH of a newborn’s gastric fluid is higher (1.8–6.1) than that of an adult (1.4–2.1), resulting in increased absorption of basic APIs and decreased absorption of acidic ones (Neal-Kluever et al., 2019, O’Brien et al., 2019).

Similarly, intestinal transit is slower in newborns than in adults, inducing a higher absorption. The influence of the physiological variations illustrates why formulations (choice of excipient and quantity) need to be adapted to the pediatric population in order to reduce variations in pharmacokinetic parameters (O’Brien et al., 2019). For example, propylene glycol, commonly used in solid dosage forms as a humectant and preservative, can cause damage to the central nervous system if exposed to high doses, particularly in patients under 4 years of age (Kaguelidou et al., 2022, Rouaz et al., 2021). Thus, the choice of excipients depends not only on the population (adult or pediatric) but also on the age of the patient. Indeed, the pediatric population cannot be reduced to a single group, but is divided into several subcategories: neonates, infants (28 days-23 months), children (2–11 years) and adolescents (12–16 years).Then, the medicine, through it API and excipient concentration must be adapted to each patient category (Belayneh et al., 2020). As a result, the development of targeted population medicines remains challenging and, from an industry perspective, adopting a patient-centered approach for such a small target group is costly (Hanning et al., 2016).

To improve the safety of medicines for children, European Medicine Agency (EMA) has published guidelines for each age group with the following information:

Have dosages adapted to the weight of the child,
Have a concentration or dose adapted to the volumes to be administered,
Allow for a limited number of daily doses,
Not contain potentially dangerous excipients, especially in neonates or for chronic use,
Be acceptable in terms of palatability,
Be easy for the caregiver or family to administer. (European Medicine Agency (EMA), 2018)

With all these specifications to be considered, developing pediatric medicines is a challenge. The APIs and excipients (nature and concentration) must comply with the safety regulations of EMA, while the medicine has to be easily administrated to children. The choice of excipient therefore also depends on the final form of the medicine, which adds further requirements. An ideal pediatric formulation should meet all of these requirements (long term storage, swallowability) and offer flexibility in dosing (Bracken et al., 2022, O’Brien et al., 2019). For young patients, oral liquid formulations may be preferred as they are easy to swallow and allow dose flexibility. However, the use of concentrated liquids forms can lead to errors in volume measurement (i.e. 1 ml instead of 0.1 ml) (Smith, Leggett, et Borg 2022). Liquid dosage forms also present stability issues that require the addition of excipients such as preservatives at concentrations that may not be appropriate for children.

Contrary to liquid forms, solid medicines are often preferred by the pharmaceutical industry due to their lower manufacturing costs and their long-term stability. However, the acceptability of solid oral forms, such as tablets, depends on several criteria such as swallowability, amount of water needed for the intake and palatability. Thus, conventional oral solid forms are limited for the pediatric population, as most children are not able to take tablets regularly before the age of 8–10 years old. In order to facilitate the administration and the dose adjustment, there are tablet designed to be broken or crushed, however, dose flexibility is still limited (Mfoafo et al., 2021, Smith et al., 2022). All these constraints make the development of customized solid formulations a challenge.

To overcome these drawn-backs, new products are being developed using conventional methods, such as orodispersible tablets, films or chewable formulations. Orodispersible forms are designed to disintegrate and be absorbed in the oral cavity, but do not allow flexible dosing. Chewable formulations avoid swallowing, making them more acceptable to children over the age of two. Yet, depending on children’s ability to chew, drug release and therapeutic effect may change, resulting in pharmacokinetics variability (Mfoafo et al., 2021). The still remaining limitations on the development of more adapted patient medicines can be overcome by the use of 3D printing. 3D printing is an additive manufacturing process that builds 3D objects by depositing material layer by layer. The advantages of 3D printing technology include low production costs, time savings, high flexibility with local control of material composition and microstructure, and negligible variability among printed objects. Since its conception, 3D printing has been democratized in many industries such as automotive, aerospace, food or health (printing prosthetics). In recent years, research has also focused on using this technology to print personalized medicines leading to an increasing number of scientific articles on pediatric 3D printing (Fig. 1).

3D printing includes several techniques such as extrusion-based printing, inkjet, binder jet or selective laser sintering (SLS). Among them, two extrusion-based printing are mainly used in pharmaceutical applications, Fused Deposition Modelling (FDM) and Semi-Solid Extrusion (SSE). In FDM, a filament material is heated and extruded through a nozzle and the layers of molten material are deposited into the desired product and solidify. While SSE, also known as pressure assisted micro syringe (PAM), is based on the deposition of a gel or paste at room temperature or low temperature (40 °C). A more detailed presentation of these two techniques and the parameters to be considered for their use in the preparation of pharmaceutical forms is explained in the section below.