The swallowing process is an essential prerequisite for the oral supply of calories and nutrients, and thus also for a healthy growth and maturation of children. However, dysphagia is particularly common in children, especially in neonates and preterm infants, and it is estimated that more than half of all children with developmental disabilities and almost all children with cerebral palsy are at risk of dysphagia (Schwemmle & Arens, 2018). Since swallowing problems always carry the risk of aspiration and, in the long run, the development of chronic malnutrition (Darrow & Harley, 1998), it is important to address them through alternative routes of nutrient administration. When children are unable to swallow food, there are basically two options to ensure a sufficient nutrient supply: parenteral- and enteral nutrition (EN). While parenteral nutrition is primarily reserved for children whose gastrointestinal tract is not (yet) working properly, EN therapy, i.e., the administration of EN formulas comprising critical macro- and micronutrients, is the preferred method of nutritional intervention for a variety of indications (Yi, 2018). EN formulas are typically administered via feeding tubes that provide access to the stomach or small intestine. Based on the expected duration of EN, mainly two different kinds of enteral feeding tubes (EFTs) are used. For short-term EN treatment, covering only a few weeks, nasogastric (NG) tubes are placed, which are inserted through a nostril and slid into the stomach. Long-term EN treatment, by contrast, requires a surgical procedure to place a percutaneous endoscopic gastrostomy (PEG) tube that allows direct access to the stomach while bypassing the oral cavity and the esophagus.

Apart from being fed via feeding tubes, the respective children often also require medication which then is frequently also given via the enteral access. In this context, it should be noted that many oral drug products were not developed for enteral administration and thus may present with unintended effects when given via an EFT. When composing a therapeutic regimen, liquid drug formulations are the formulations of choice, not only because they are readily available in liquid form, but because they offer a high degree of dose flexibility, especially for very young patients who require a highly individualised dosing regimen. Although the use of liquid medicinal products offers the advantage of high dose flexibility, they also present some disadvantages regarding their use for enteral administration.

In contrast to solid dosage forms, which, if intended, are designed to allow drug delivery over longer periods of time, most liquid dosage forms are rapid-release formulations. Accordingly, they may require a higher dosing frequency, which in turn may increase the number of administrations required (Williams, 2008). In addition, the use of liquid formulations with a high osmolality or high concentrations of characteristic excipients such as mannitol, lactose, sucrose, or sorbitol can lead to bloating, vomiting or diarrhoea, which makes them unsuitable for enteral administration (Beckwith et al., 2004). Another important aspect to consider is whether a solution or a dispersion should be administered. To ensure the required dosing accuracy, many suspensions have a relatively high viscosity to prevent sedimentation of the disperse phase. In combination with a high solids content, the viscosity of the preparation may pose a higher risk of tube clogging. To minimise this risk, an initial dilution step is often recommended before administering such formulations (Bradnam, 2015). Common techniques for administering liquid formulations include proper flushing of the EFT with water for injection (WFI) before and after medication dosing. In addition, as indicated earlier, dilution of the liquid formulation with WFI may be required to either reduce viscosity and/or osmolality. While dilution with an equal volume of WFI may be sufficient to reduce viscosity (Bradnam, 2015) hypertonic formulations may require 10 to 20 times dilution according to Equation (1) to prevent unwanted side effects (Klang et al., 2013).AV=OsmolalityMedicationOsmolalitydesired∙DVEquation (1): Calculation of the administration volume (AV) based on the osmolality of the medication and the dose volume (DV) (adapted from Klang et al., 2013).

Although enteral administration of medicinal products is practiced daily in clinical settings, there is still little known about this route of administration. While some in vitro studies focusing on the enteral administration of multiparticulates have been performed in the past (Dunn et al., 1999, Devlin et al., 2006, Stewart et al., 2009, Karkossa et al., 2022), little to no attention has been paid to ready-to-use or extemporaneous suspensions and their dosing accuracy when administered enterally. Although data exist from in vitro studies investigating the administration of aqueous suspensions, these were typically suspensions obtained by manipulating solid dosage forms, i.e., by dispersing (crushed) tablets or capsule contents in water, to allow for the administration of these dosage forms via an EFT (Crean et al., 2013, Morita et al., 2016, Santangelo et al., 2022, Tanaka et al., 2021). Beyond this, however, there is still a lack of systematic studies investigating the impact of the combination of the EN equipment with the properties of the liquid formulation and the administration parameters on dosing accuracy.

In recent years, this knowledge gap and the increasing importance of this topic have also been recognised by the authorities. However, at present, there is also limited regulatory guidance on how to conduct in vitro administration tests that could shed light on this issue. General information on the aspects that should be considered when designing in vitro administration tests is given in the EMA “Guideline on pharmaceutical development of medicines for paediatric use” which is supplemented by a Q&A document on the EMA website (European Medicines Agency, 2014, European Medicines Agency, 2018a). These documents identify dose recovery after application and tube flushing as the key parameters, but also underline that in evaluating the suitability of this route of administration, it is important to consider a variety of formulation aspects, such as particle size and viscosity, the type and nature of the tube, and details of the administration process, in particular the dosing and flushing volume. However, the guidance does not provide any details on the EFT equipment that should be included in an in vitro study and how the study should be performed. In contrast, some relevant details can be found in the Q&A document. Regarding tube size, this document states that the EFTs used in in vitro studies should be tailored to the relevant patient population, e.g., CH 4–6 tubes for neonates and CH 8–12 tubes for other children and adults. It is also noted that, in consideration of the physicochemical (in)compatibility of the drug formulation and the EFT, it is advisable to evaluate tubes made of different materials. Finally, it is recommended to use a design of experiments (DoE) with a bracketing or worst-case approach for the experiments to be conducted to minimise the number of combinations of tube types, dosages, and flush volumes to be tested (European Medicines Agency, 2018a). With the aim of ensuring the safety and efficacy of oral medicinal products following their administration via an EFT, the FDA Draft Guidance “Oral Drug Products Administered Via Enteral Feeding Tube: In Vitro Testing and Labeling Recommendations” published in June 2021 provides more detailed recommendations on the performance of in vitro administration tests (Food and Drug Administration, 2021). In addition to the aspects outlined in the cited EMA guideline, this FDA draft guidance highlights the importance of determining an appropriate EFT equipment. Since feeding tubes may differ in size (inner and outer diameter), material, and design (closed or open end) testing of at least three different tube configurations is recommended to address the variety of EN tube equipment that is available on the market. In addition, the draft guidance highlights that as part of each in vitro study, a detailed description of the preparation and administration procedure of the oral medicinal product should be documented and that factors that influence the administration process, e.g., the dispersion medium, the flushing volume and the holding position of the tube and syringe, should be addressed. For an oral suspension as an immediate release formulation, dose recovery is considered a key parameter for assessing successful delivery via the feeding tube. However, the draft guidance also points out that for this type of formulation, other formulation-related aspects such as sedimentation/redispersion behaviour and particle size distribution can provide valuable information for the assessment of its successful administration (Food and Drug Administration, 2021).

The FDA draft guidance refers generally to the administration of drugs via EFTs, but not specifically to children. However, the use of this route of drug administration for children, especially very young children, poses a further challenge. Another point to consider when administering medicines to children via EFTs is the total fluid volume that can be administered at one time. The administration procedure as such usually comprises a pre-flushing step, the administration of the medicine and a post-flushing step. The total fluid volume is thus equal to the sum of these three partial volumes. Since even very young patients may have to be administered several drugs per day, this quickly results in a total volume that may be far too large. This fact may necessitate reducing the volume used to flush the tube before, between, and after drug dosing. As reported in a recent review article on the gastrointestinal physiology of children by Wollmer et al. (Wollmer et al., 2022), there is little to no data on the capacity of the stomach or typical maximum fluid volumes that can be given to children of different ages. For the most critical group of very young children, results of a few individual studies indicate that the mean ingested milk volume for newborns is between 11 and 70 mL and increases to 21 to 120 mL for young infants (Wollmer et al., 2022). Although these are not solid data from systematic studies, they can give a first indication of gastric capacity. However, it should also be considered that milk is not given as a bolus when breastfeeding or bottle feeding, but over a period so that it can be diluted in the stomach, but also continuously emptied from the stomach. When administering drugs via EFTs, the dilution and flushing steps are performed with WFI rather than milk or artificial nutrition for reasons of compatibility and stability. Nonetheless, the primary assumption should be that one should not exceed the gastric capacity. Therefore, determining a minimum flushing volume that ensures proper delivery of the entire drug dose(s) without overloading the paediatric gastrointestinal tract with fluid would be extremely helpful.

If a minimum fluid volume for a given administration scenario is to be determined, it would be sensible to use an example that is relevant to daily practice. Considering the types of medications administered in paediatric care, adequate pain management plays a key role for a number of conditions from respiratory, nervous, or cardiovascular diseases to injuries or intoxications, to endocrine, nutritional or immunological disorders (Heneghan et al., 2020). Among the non-opioid analgesics used to treat mild pain and fever, ibuprofen is the most frequently prescribed drug in Germany (Rashed et al., 2015). Liquid ibuprofen formulations are mostly prepared as suspensions due to the poor aqueous solubility of ibuprofen in an acidic environment (Moriarty & Carroll, 2016). Paediatric ibuprofen suspensions are available in dose strengths of 20 mg/mL or 40 mg/mL. Ibuprofen is dosed based on patient age and bodyweight (Table 1) and common paediatric dose volumes range from 1.25 to 7.5 mL.

Although there are various general recommendations on how to administer liquid formulations via EFTs (Williams, 2008, Beckwith et al., 2004, Bradnam, 2015, Estoup, 1994, Belknap et al., 1997, Gilbar and Pract, 1999, Bankhead et al., 2009, Bandy et al., 2019), it is still not known to what extent formulation properties may influence the amount of drug that reaches the site of absorption. Considering regulatory and patient safety aspects, a systematic in vitro study investigating the administration of liquid dosage forms via paediatric EFTs would provide a significant contribution regarding therapy safety in enteral-fed children and might reveal common problems leading to incorrect dosing or tube clogging and in approaches to avoid them.

The aim of the present study was to develop an appropriate administration test design to simulate the administration of paediatric suspensions via paediatric EFTs as realistically as possible. This was then to be used to identify formulation- and device-related factors that might influence dose accuracy. Due to its relevance in oral paediatric drug therapy, ibuprofen was selected as a model drug and extemporaneously prepared as well as marketed paediatric ibuprofen suspensions were administered via a variety of EFTs differing in type, size, and tube material in a systematic study.