Towards the development of a standard toolbox for compatibility testing of pediatric drug products with common dosing vehicles − Fruit juice, apple sauce, yogurt, and pudding

Abstract

Co-administration of oral drug products with dosing vehicles is common practice in pediatric drug administration. The present work focused on the development of a set of standard vehicles that reflects the key characteristics of four different vehicle types commonly used in the administration of pediatric drug formulations. The aim was to rationalize and standardize the compatibility assessment of pediatric dosage forms with individual vehicle types and thereby contribute to a better risk assessment regarding this route of administration. In order to develop the standard vehicles, a comprehensive number of fruit juices, apple sauces, yogurts, and puddings were characterized with regard to their physicochemical properties. The characterization results served as target values for a set of standard vehicles which was successfully developed and followed a design of experiments approach. These standard vehicles represent the first and central components of a standardized vehicle toolbox designed for global use. Their use will enable pharmaceutical developers and regulatory authorities to gain insight into the compatibility of pediatric medicines with these dosing vehicles. Pending validation through comparative studies with the original vehicles, for which data are forthcoming, the toolbox is expected to serve as a valuable resource for assessing the safety and feasibility of combining pediatric formulations with liquid or semi-solid vehicles, thereby supporting more informed decision-making in drug development.

Introduction

Oral administration of medicines is the most common and often the preferred route of drug administration, particularly as it is non-invasive and can be carried out by the patient or caregiver. Nevertheless, this route of administration also entails a number of challenges, among which the acceptance of the drug product is one of the fundamental aspects for the success of the therapy. The European Medicines Agency (EMA) defines patient acceptability as the ability and willingness of the patient to use and its caregiver to administer the medicine as intended [1]. In the context of oral drug products administration to children, both aspects can play an important role. Children represent a very heterogeneous group of patients, and characteristics such as age and the associated physiological stage of development typically influence their willingness and ability to take their medications. While an average healthy adult usually has little or no difficulty in taking solid oral dosage forms, in children the swallowability of a dosage form due to its size and/or palatability often poses a major problem [2]. Palatability issues are often linked to an unpleasant (bitter) taste, after-taste, or texture, and are particularly reported for younger children, who have been shown to be more sensitive to bitterness than older children [3]. Once children have associated a medication with a bad experience, their willingness to repeatedly take the medication can be compromised [3].

In pediatric drug development, it is important to consider appropriate methods of administration that will encourage all children to take the medicine. If the lack of acceptability of an oral drug product is primarily due to its poor swallowability or palatability, it may be appropriate to mix the dosage form with food or drinks prior to administration [1]. This measure is already frequently used by caregivers, as it is often the only way to ensure that the child takes the medication. Typically, the dosage form is administered with small portions of liquids and soft foods, which are also referred to as “dosing vehicles” or “vehicles” in this context [4,5].

If a drug product is co-administered with a vehicle, it must be ensured that this type of administration does not compromise the product’s quality, specifically its stability and intended in vivo performance. However, the variety of theoretically applicable soft foods and liquids, their availability across different geographical regions as well as age-specific, regional, and cultural preferences can pose considerable challenges. Ideally, the quality of a drug product should remain unaffected by the co-administration with any of the potential vehicles. However, this requirement is virtually impossible to achieve for each drug product under consideration. To ensure a safe and effective drug therapy, it is therefore important to identify suitable vehicles for a given drug product and to include clear labeling instructions whenever drug product quality may be compromised by co-administration [4].

Given the large number of potential food and liquid types that could serve as vehicles, an appropriate strategy for identifying suitable options is essential in the context of pediatric drug product development. Regulatory authorities have already emphasized the need for standardized methods to assess drug-vehicle compatibility [1,4,6,7]. For certain aspects, such as the volume of the vehicle to be used and how to prepare a pre-mix of dosage form and vehicle prior to administration, standardization of compatibility assessment appears to be quite straightforward and some suggestions in this regard have already been made in the U.S. Food and Drug Administration (FDA) Draft Guidance “Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments” [4]. However, no detailed information is provided on how many different vehicle types and how many individual vehicles within a certain vehicle type are required to properly capture the variability in composition and physicochemical properties of commercial products/brands.

A logical starting point for identifying suitable vehicles for co-administration is to examine those currently recommended in product labels and regulatory guidances for pediatric medicines. The FDA Draft Guidance lists 27 “commonly used dosing vehicles” in Appendix A [4], which could theoretically serve as an initial reference. However, it should be noted that this guidance was not specifically developed for the pediatric population, but rather for all patient groups who may benefit from the use of dosing vehicles. Therefore, some vehicles listed in Appendix A are not suitable particularly for very young children (e.g., honey) or may even pose safety concerns in the context of drug administration (e.g., grapefruit juice). Freerks et al. [8] conducted an analysis of the composition, caloric content, and physicochemical properties of one randomly selected (commercial) product for each of the vehicle types listed in Appendix A. The study highlighted substantial variability in critical attributes and identified vehicle characteristics that need to be considered when developing in vitro methods for product quality assessment. As anticipated, the vehicle types exhibited considerable differences in both composition and physicochemical properties. Interestingly, no clear correlation could be established between the nutritional content and the physicochemical properties of a vehicle [8]. In addition, Freerks et al. compared their findings with previously published data from studies that investigated the same vehicle types but different (commercial) products [[9], [10], [11], [12]]. A thorough review of the available data reveals the considerable variability in vehicle characteristics even within the same vehicle type [[8], [9], [10], [11], [12]]. The impact of this variability on drug release was impressively demonstrated in a set of in vitro release experiments by Martir et al. [13,14]. In these studies, a two-stage in vitro model designed to simulate the pH conditions of the stomach and small intestine revealed statistically significant differences in the release profiles of montelukast and mesalazine formulations when administered with two different commercial products of the same vehicle type. To highlight the most prominent example, the amount of mesalazine released from two different extended-release (ER) granule formulations, one of which was also enteric-coated, was approximately twice as high within the 4-hour test period when one brand of apple sauce was substituted for another. Comparable results were observed in analogous experiments with two immediate-release (IR) montelukast formulations, specifically a granule formulation and a chewable tablet. Similarly pronounced effects were observed when one type of yogurt was replaced with another. Moreover, the use of alternative vehicles such as milk or fruit squash also resulted in considerable, and in some cases statistically significant, differences in drug release [13].

These results emphasize that not only the type of vehicle but also the specific product used within a given vehicle category can significantly influence drug release behavior in vitro. While the co-administration with different vehicle types can variably affect the in vivo performance of an orally administered dosage forms, ranging from no effect [11,12] to substantial impact [10,13,14], the variability within a single vehicle type and its implications for formulation compatibility have not yet been systematically investigated. This highlights the need for a more detailed approach to in vitro compatibility assessments, considering not just the general vehicle category but also product-specific characteristics, and thus different vehicle types should be considered for any in vitro compatibility assessment. The experimental effort for such comprehensive compatibility testing would be huge, given the immense number of globally available vehicles of the same type. Accordingly, a global, standardized approach for in vitro compatibility studies, which captures the variability of the relevant characteristics of individual vehicle types, would be highly desirable.

The aim of the present work was to establish a set of standardized (simulated) vehicles that reflect the natural variability in composition and physicochemical characteristics of vehicles commonly used in the administration of pediatric medicines, which would allow an appropriate compatibility risk assessment. For this purpose, the vehicles that are most frequently used to increase acceptability of oral pediatric drug products were first identified. Then, a variety of individual vehicles of one type was characterized regarding their composition and physicochemical properties. This information was then used to develop a set of standardized vehicles for each of the selected vehicle types as a foundation for a standard vehicle toolbox for global use, to more easily assess the potential impacts of vehicles on drug products.

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Materials

Care was taken to ensure that the selected original vehicles represented a diverse range of products, considering both their geographical origin and composition. The original vehicles were purchased in local supermarkets or international online stores. Some of the vehicles (freshly squeezed orange juice, apple sauce, and chocolate pudding) were freshly prepared prior to testing. All soft foods and liquids analyzed in the study are listed by product type in Supplementary Tables 1–4. For the preparation of the homemade chocolate pudding, milk chocolate (Alpen-Vollmilch, ja!, Stollwerck, Norderstedt, Germany), 3.5 % milk (haltbare Milch, Molkerei Weihenstephan, Freising, Germany), cocoa powder (Kakao zum Backen, Dr. August Oetker, Bielefeld, Germany), sugar (Raffinade Zucker, Pfeifer & Langen, Köln, Germany), and corn starch (Unsere Speisestärke, RUF Lebensmittelwerk, Quakenbrück, Germany) were used. The following dairy products were used for the preparation of pudding from ready-mixed pudding powders: milk with 0.3 % fat (entrahmte H-Milch, Gut & Günstig, Edeka, Hamburg, Germany), 1.5 % fat (frische fettarme Milch, ja!, AF Deutschland, Düsseldorf, Germany), and 3.5 % fat (haltbare Milch, Molkerei Weihenstephan, Freising, Germany), respectively.

The following ingredients were used for the preparation of the standard vehicles: Maltodextrin 19 (Nutricia, Erlangen, Germany), Fresubin® protein powder (Fresenius Kabi, Bad Homburg, Germany), Lipofundin® MCT/LCT 20 % emulsion (B. Braun, Melsungen, Germany), fructose (Caesar & Loretz, Hilden, Germany), sodium chloride (Caesar & Loretz, Hilden, Germany), sodium citrate dihydrate (Fagron, Barsbüttel, Germany), anhydrous citric acid (Caesar & Loretz, Hilden, Germany), hydrochloric acid (AppliChem, Darmstadt, Germany), maleic acid (Sigma-Aldrich, Steinheim, Germany), sodium hydroxide (Caesar & Loretz, Hilden, Germany), lecithin (Lecithin-Granulat, dm-drogerie markt, Karlsruhe, Germany), medium chain triglycerides (Miglyol® 812, Caesar & Loretz, Hilden, Germany), and peanut oil (Raffiniertes Erdnussöl, Caesar & Loretz, Hilden, Germany). All chemicals and solvents used for the physicochemical characterization of the original and standard vehicles were of analytical quality.

Carolin Eckert, Cordula Stillhart, Leonie Wagner, Emmanuel Scheubel, Isabelle Prevot, Marc Lindenberg, Sandra Klein, Towards the development of a standard toolbox for compatibility testing of pediatric drug products with common dosing vehicles − Fruit juice, apple sauce, yogurt, and pudding, European Journal of Pharmaceutics and Biopharmaceutics, Volume 217, 2025, 114868, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114868.

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