3D Printing of Pediatric Medication: The End of Bad Tasting Oral Liquids?—A Scoping Review

Pediatric drug formulations require an accurate and flexible dosing strategy, child-friendly dosage forms and specific suitability of the excipients for children. Therefore, the development of pediatric drug formulations is challenging and complex. Furthermore, it is inhibited by a lack of economic incentive [1].

In Europe, before the introduction of European Union (EU) legislation on medicines for children in 2006, pediatric-centered treatment was very limited [2]. Children were often prescribed medicines that were authorized for adults, but that had not been tested or adapted for the pediatric population. These medicines were, therefore, used off-label and could be unsuitable for children in terms of dose, dosage form, and used excipients [3]. In the years before the pediatric regulation [4], between 2004 and 2006, only 30 new medicines and indications were authorized specifically for pediatric use. Between 2014 and 2016, 10 years later, this was increased to 74 new medicines and indications [2]. While the number of new medicines and indications for pediatric use has increased, it is still not enough to meet the need for pediatric-centered drug formulations.

In practice, it is often still necessary to either adjust a marketed drug before it can be administered to a child, or to prepare an extemporaneous formulation (e.g., oral liquid) by the pharmacist. Manipulation of marketed drugs, e.g., crushing or splitting tablets or diluting a solution, often holds two specific reasons, namely, to acquire the needed dosage strength, or to adapt an unsuitable dosage form, i.e., poor swallowability or palatability of the dosage form. A combination of these reasons also occurs [5,6,7,8].

Studies conducted in a children’s hospital in the Netherlands and pediatric wards in a German hospital show that manipulation was necessary for 37% of oral medicine prior to administration [7,8]. Similar studies conducted in Norway and Sweden found a lower manipulation prevalence of 17% and 15.5%, respectively, for orally administered pediatric medicines [5,6]. The lower manipulation rate could be explained by a difference in the definition of drug manipulation. Moreover, in the Netherlands, 30% of the pediatric outpatient drug administrations had to be manipulated before use [7]. Dosing accuracy and bioavailability can potentially be negatively influenced by such manipulation of the drug product [5,9].

Another portion of drug administrations in the pediatric population is through extemporaneous, or magistral, preparations. Often, these consist of oral liquids with certain disadvantages, such as stability issues, bad taste, harmful excipients and risk of dosing errors. There is a lack of insight into the extent to which pharmacy preparations are used to treat children. Most prescriptions entail marketed drugs and the percentage of overall prescriptions that need to be compounded varies from <1% to 10% with a high variability, probably due to demographic characteristics [10,11,12,13]. A survey conducted in hospitals in Japan found that 9.6% of all pediatric oral prescriptions needed to be compounded [14]. Interestingly, pharmacy preparations seem to make a comeback as drug policy shifts towards personalized medicine [15,16]. Personalized medicine asks for tailored medication which can be provided by compounding. Besides an individualized dose, other specific patient needs, such as sensory processing disorders, food allergies or dietary needs, can be taken into account when compounding personalized medicines [17]. However, compounding brings along the risk of contamination, supra- and subtherapeutic errors [18]; moreover, it demands highly trained personnel and premises which are no longer available in all pharmacies.

It is obvious that there is still an unmet medical need in the pediatric population for suitable dosages, dosage forms and formulations. The use of three-dimensional (3D) printing of personalized medicine holds the promise to aid the development of pediatric drugs [1,19,20]. Its principle is based on building an object layer-by-layer onto a printing plate from a computer model. Using computer-aided design (CAD), the model can be adjusted to meet the user’s requirements. Various 3D printing techniques can be employed to produce flexible dosage forms in terms of dosage, geometry, drug release kinetics and composition [21,22]. Extrusion-based 3D printing techniques are most often employed. Examples of extrusion-based 3D printing techniques are fused deposition modelling (FDM) [23], semi-solid extrusion (SSE) [24] and direct powder extrusion (DPE) [25]. Extrusion-based 3D printers extrude a molten or semi-solid formulation through a nozzle onto the printing plate. They can be either heated or non-heated, depending on the specific technique and formulation. Powder-solidification 3D printing techniques bind powder particles together with a binder fluid or through sintering. They include drop-on-powder (DoP) and selective laser sintering (SLS) [26]. Inkjet printing is a drop-on-demand method. Small droplets are deposited in a specific place, usually onto a substrate [21]. Finally, liquid-solidification techniques, also known as vat photopolymerization, entail amongst others stereolithography (SLA) and digital light processing (DLP) [27]. A liquid formulation is solidified in specific places to create the desired model.

It is because of the high flexibility that 3D-printed medicines are a promising asset in the treatment of the pediatric population, as was also previously mentioned in the mini-review by Preis and Öblom [19]. Indeed, these innovative developments are studied intensively both by pharmaceutical companies and universities.

There is a need for a comprehensive and timely overview of literature on 3D-printed medicine in the pediatric population. This scoping review aims to provide an overview of the developments, possibilities and limitations of the 3D printing technique for the production of pediatric drug formulations. As a secondary objective, it aims to provide a roadmap towards the integration of 3D-printed medicine in the daily treatment of pediatric patients.