From paediatric formulations development to access: Advances made and remaining challenges.

Developing suitable paediatric formulations and ensuring access to them by the greatest number of the 2.2 billion children worldwide are equally important to provide optimal pharmacotherapy. This review focuses on the progress made over the last two decades with paediatric oral formulations with respect to evidence for acceptability and dosing flexibility of liquid and solid oral dosage forms. It also discusses the clinical needs for, and the access to, paediatric formulations for existing authorised medicines. A significant body of new knowledge now supports the acceptability of solid oral dosage forms in children, resulting in an increasing number of medicines commercialised as multiparticulates, including minitablets that are starting to be brought to market. However, there are gaps with these formulations that deserve more research. Even though efforts have been made to identify medicines in need of age-appropriate formulations, there is no common priority list shared internationally. Such prioritisation would help to develop paediatric formulations with the greatest potential for providing a health benefit to children worldwide. In addition, available data highlight that paediatric formulation access is fragmented and unequal, with commercialisation of suitable paediatric formulations too often limited to some countries/regions. We propose actions to better align decisions during the development of paediatric formulations and promote a more globalised approach to facilitate registration pathways between different jurisdictions. Furthermore, discussions about alignment between approval, pricing and reimbursement processes should also happen, leaving working in siloes behind us. It is time for adults to start thinking outside the box for children.

Path towards efficient paediatric formulation development based on partnering with clinical pharmacologists and clinicians, a conect4children expert group white paper.

Improved global access to novel age-appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age-appropriate paediatric medicines. This position paper recommends the use of a paediatric Quality Target Product Profile as an efficient tool to facilitate early planning and decision making across all teams involved in paediatric formulation development during the children-centric formulation design for new chemical entities, or to repurpose/reformulate off-patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age-appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure postmarketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however, the proposed paediatric Quality Target Product Profile could be a valuable collaborative tool for planning and decision making to expedite paediatric product development, particularly for those with limited experience in developing a paediatric product.

Electrospinning Optimization of Eudragit E PO with and without Chlorpheniramine Maleate Using a Design of Experiment Approach.

Electrospinning is increasingly becoming a viable means of producing drug delivery vehicles for oral delivery, particularly as issues of manufacturing scalability are being addressed. In this study, electrospinning is explored as a taste-masking manufacturing technology for bitter drugs. The taste-masking polymer Eudragit E PO (E-EPO) was electrospun, guided by a quality by design approach. Using a design of experiment, factors influencing the production of smooth fibers were investigated. Polymer concentration, solvent composition, applied voltage, flow rate, and gap distance were the parameters examined. Of these, polymer concentration was shown to be the only statistically significant factor within the ranges studied ( p-value = 0.0042). As the concentration increased, smoother fibers were formed, coupled with an increase in fiber diameter. E-EPO (35% w/v) was identified as the optimum concentration for smooth fiber production. The optimized processing conditions identified were a gap distance of 175 mm, an applied voltage of between 15 and 20 kV, and a flow rate of 1 mL/h. Using this knowledge, the production optimization of electrospun E-EPO with chlorpheniramine maleate (CPM), a bitter antihistamine drug, was explored. The addition of CPM in drug loads of 1:6 up to 1:10 CPM/E-EPO yielded smooth fibers that were electrospun under conditions similar to placebo fibers. Solid-state characterization showed CPM to be molecularly dispersed in E-EPO. An electronic tasting system, or E-tongue, indicated good taste-masking performance as compared to the equivalent physical mixtures. This study therefore describes a means of producing, optimizing, and assessing the performance of electrospun taste-masked fibers as a novel approach to the formulation of CPM and potentially other bitter drug substances.

In Vitro Dissolution Model Can Predict the in Vivo Taste Masking Performance of Coated Multiparticulates.

The majority of active pharmaceutical ingredients (APIs) are bitter. Therefore, compliance can be a problem where adequate taste masking has not been achieved; this is most problematic in pediatrics. Taste masking is thus a key stage during pharmaceutical development with an array of strategies available to the formulation scientist. Solid oral dosage forms can be taste-masked quite simply by polymer coating, which prevents drug release in the mouth, without unwantedly impairing drug release further down the gastrointestinal tract. At the early stages of pharmaceutical development, an in vitro method for the assessment of taste masking is necessary given the lack of toxicological data preventing the use of human taste panels. Currently, there is no such tool allowing prediction of taste masking efficiency. In this study, drug dissolution in the context of aversive taste thresholds was proposed as a means to bridge this knowledge gap. Thus, a biorelevant buccal dissolution test was developed in which previously determined taste thresholds in vivo were used to evaluate taste masking efficiency: if drug release exceeded said thresholds, the formulation was deemed to be poorly taste-masked, and vice versa. This novel dissolution test was compared to the USP I (basket) dissolution test, and the biopharmaceutical implications of taste masking were also assessed by performing USP I (basket) dissolution testing in simulated gastric fluid (SGF). Chlorphenamine maleate, a model bitter BCS class 1 API, was layered onto sugar spheres and taste-masked using polymer coatings. An array of coating technologies were employed and assessed single blinded: two pH-independent water-insoluble coatings (Surelease:Opadry at 8, 12, and 16% weight gain and Opadry EC at 4, 6, and 8% weight gain) and a pH-dependent water-insoluble reverse-enteric coating (developmental fully formulated system based on Kollicoat Smartseal 100P at 10% weight gain). Both the biorelevant buccal and the USP I dissolution tests were capable of discriminating between both type and level of coating used. However, only the buccal dissolution test was able to provide absolute quantification of the level of taste masking achieved in the context of previously determined taste thresholds, while the USP I test merely provided a relative comparison between the different technologies assessed. When the release data from the buccal test were assessed in parallel to that in SGF, it was possible to predict in vitro optimized taste masking without compromising bioavailability. The fully formulated system based on Smartseal 100P was identified as the most effective coating and Surelease:Opadry the least effective. The developed methodology provides true insight for the formulator, enabling more informed patient-centric formulation decisions, better taste masking, and ultimately more effective medicines.

Making Medicines Baby Size: The Challenges in Bridging the Formulation Gap in Neonatal Medicine.

The development of age-appropriate formulations should focus on dosage forms that can deliver variable yet accurate doses that are safe and acceptable to the child, are matched to his/her development and ability, and avoid medication errors. However, in the past decade, the medication needs of neonates have largely been neglected. The aim of this review is to expand on what differentiates the needs of preterm and term neonates from those of the older paediatric subsets, in terms of environment of care, ability to measure and administer the dose (from the perspective of the patient and carer, the routes of administration, the device and the product), neonatal biopharmaceutics and regulatory challenges. This review offers insight into those challenges posed by the formulation of medicinal products for neonatal patients in order to support the development of clinically relevant products.

Co-Processed Excipients for Dispersible Tablets-Part 1: Manufacturability.

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr's index ˂ 20), excellent tabletability (tensile strength > 3.0 MPa at 0.85 solid fraction), very low friability (< 1% after 15 min), rapid disintegration times (27-49 s) and produced dispersions of ideal fineness (< 250 µm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.

Co-Processed Excipients for Dispersible Tablets-Part 2: Patient Acceptability.

Palatability and patient acceptability are critical attributes of dispersible tablet formulation. Co-processed excipients could provide improved organoleptic profile due to rational choice of excipients and manufacturing techniques. The aim of this study was to identify the most suitable co-processed excipient to use within directly compressible dispersible tablet formulations. Nine excipients, selected based on successful manufacturability, were investigated in a randomised, preference and acceptability testing in 24 healthy adult volunteers. Excipients were classified in order of preference as follows (from most preferred): SmartEx QD100 > F-Melt Type C > F-Melt Type M > MicroceLac > Ludiflash > CombiLac > Pharmaburst 500 > Avicel HFE-102 > Avicel PH-102. Broad differences were identified in terms of acceptability, with SmartEx QD100 being 'very acceptable', F-Melt Type C, F-Melt Type M and MicroceLac being 'acceptable', Ludiflash, CombiLac and Pharmaburst 500 being 'neutral' and Avicel products being 'very unacceptable' based on ratings using five-point hedonic scales. Organoleptic differences were ascribed to different composition and physical properties of excipients, resulting in dissimilar taste and mouth-feel. Excipients with particle size in water larger than 200-250 µm were considered poorly acceptable, which supports the use of this value as a threshold for maximum particle size of dispersible formulation. The most promising co-processed excipients for directly compressible dispersible tablets were successfully identified.

Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

PURPOSE: Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. CONCLUSION: These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

European Paediatric Formulation Initiative (EuPFI)-Formulating Ideas for Better Medicines for Children.

The European Paediatric Formulation Initiative (EuPFI), founded in 2007, aims to promote and facilitate the preparation of better and safe medicines for children through linking research and information dissemination. It brings together the capabilities of the industry, academics, hospitals, and regulators within a common platform in order to scope the solid understanding of the major issues, which will underpin the progress towards the future of paediatric medicines we want.The EuPFI was formed in parallel to the adoption of regulations within the EU and USA and has served as a community that drives research and dissemination through publications and the organisation of annual conferences. The membership and reach of this group have grown since its inception in 2007 and continue to develop and evolve to meet the continuing needs and ambitions of research into and development of age appropriate medicines. Five diverse workstreams (age-appropriate medicines, Biopharmaceutics, Administration Devices, Excipients and Taste Assessment & Taste Masking (TATM)) direct specific workpackages on behalf of the EuPFI. Furthermore, EuPFI interacts with multiple diverse professional groups across the globe to ensure efficient working in the area of paediatric medicines. Strong commitment and active involvement of all EuPFI stakeholders have proved to be vital to effectively address knowledge gaps related to paediatric medicines, discuss potential areas for further research and identify issues that need more attention and analysis in the future.

Educational paper: formulation-related issues in pediatric clinical pharmacology.

Developmental physiological changes occur throughout childhood, with important changes observed within the first few weeks and months from birth, potentially affecting drug pharmacokinetics. The impact of confounding factors in relation to the availability of clinically relevant and adequate drug formulations and administration devices is underestimated. Hence, it is important to highlight presently the relevance of formulation issues. Since 2007, the EU Paediatric Regulation enforces paediatric investigation plans in which the applicant has to justify the clinical relevance of each dosage form proposed in relation to age subsets involved and the suitability of administration modalities. Therefore, pediatric drug development has become more relevant, and the importance of using age-appropriate drug formulations has been acknowledged by investigators and other stakeholders. Palatability and acceptability assessment is considered to be important by the regulatory bodies as well as excipient safety and tolerability, as it can be an issue particularly in very young children. However, there remains a lack of research into pediatric biopharmaceutics (methodological input regarding in vitro tools and bridging studies). Clinical pharmacologists with expertise ranging from pharmacodynamics, pharmacokinetics, adverse drug effects, and toxicology should actively contribute in advancing drug formulation issues in children.

A new reconstitutable oral paediatric hydrocortisone solution containing hydroxypropyl-ß-cyclodextrin.

Hydrocortisone (HC) despite a low aqueous solubility and a very poor palatability is frequently used unlicensed in paediatric practice. Hence a reconstitutable taste masked hydrocortisone solution with the potential to be easily produced extemporaneously was developed. Excipients for the reconstitutable dry powder mix were selected based on their aqueous solubility, compatibility, safety profile in children and stability at the optimum pH for HC. Formulations were visually inspected and pH was checked. The chemical and microbiological stability was assessed by a validated HPLC method and the European Pharmacopeia tests. A taste assessment study was performed on 20 young healthy adults to determine the optimum sweetener. HC was flavored (orange tangerine), preserved (methyl paraben sodium salt/potassium sorbate), adjusted to pH 4.2 (citric acid buffer) and included in a 1:6 hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) complex which allowed complete solubilization of the drug following reconstitution within 1 min of handshake. Neotame 0.075% was found to be the sweetener of choice to mask the unpalatable taste and aftertaste of HC. All formulations tested at different storage conditions were found to be chemically stable after reconstitution with a HC recovery of >95% for 1 month. Microbiological assessment showed that the selected preservative combination was efficient and the presence of preservative ensured the recommended acceptance criteria for microbiological quality after reconstitution with repetitive sampling. The successfully developed 5 mg/mL reconstituted oral palatable paediatric HC solution was stable for 1 month after reconstitution and has the potential to facilitate dosing, acceptability, availability and affordability.

Responsive Sensory Evaluation to Develop Flexible Taste-Masked Paediatric Primaquine Tablets against Malaria for Low-Resource Settings.

Primaquine is an important antimalarial drug for malaria transmission blocking and radical cure, but it is not currently available in child-friendly formulations in appropriate doses. Adult-strength tablets are often crushed and dissolved in water to obtain the required dose, which exposes the drug's bitter taste. As part of the developing paediatric primaquine (DPP) project, this study adopted a responsive sensory pharmaceutics approach by integrating real-time formulation development and pre-clinical taste assessment to develop palatable, flavour-infused primaquine tablets. A design of experiment (DoE) approach was used to screen different taste-masking agents and excipient blends with trained, expert sensory assessors, with quinine hydrochloride as a model bitter tastant. The taste-masking efficacy of selected prototype formulation blends was validated with naïve assessors using the highest 15 mg primaquine dose. The mean bitterness intensity rating, measured on a discrete 11-point scale, was halved from 7.04 for the unflavoured control to 2.74-3.70 for the formulation blends. Sucralose had the biggest impact on bitterness suppression and improving palatability. Two different flavouring systems have been developed, and their acceptability in paediatric patients will be assessed as part of upcoming validation field clinical trials in Africa.

Colour of Medicines and Children's Acceptability? A Systematic Literature Review of Children's Perceptions about Colours of Oral Dosage Forms.

The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient's expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children's opinions on colours of medicines and to what extent medicines' colour affects their acceptability. To address this gap, a systematic search in PubMed, Scopus, MEDLINE, and Web of Science was conducted. Two authors independently screened the titles, abstracts, and references of all articles and selected studies conducted on children (0-18 years old), assessing children's preferences or opinions about colour of oral dosage forms as either a primary or secondary objective or as an anecdotal record. A total of 989 publications were identified and, after screening, 18 publications were included in the review. Red and pink were the most liked colours and there appeared to be a relationship between the colour of a medicine and expected taste/flavour. The review also highlighted a scarcity of information, usually collected as an anecdotal record. Several gaps in the current knowledge were underlined, emphasizing the need of patient-centred studies to understand if the use of certain colours can improve or worsen the acceptability of a paediatric medicine. This will help inform pharmaceutical manufacturers and regulators on the role and need of colours in children's medicines beyond quality purposes.

Taste assessment for paediatric drug Development: A comparison of bitterness taste aversion in children versus Naïve and expert young adult assessors.

Medicines for children often taste bitter, presenting a significant challenge to treatment compliance. However, most studies on paediatric drug development rely on adult volunteers for sensory research, and the level of expertise required from these assessors is unclear. This study aimed to address this gap by investigating perceived bitterness aversion to taste strips impregnated with different concentrations of quinine hydrochloride in 439 school-aged children. Expert (n = 26) and naïve (n = 65) young adult assessors evaluated quinine solutions as well as taste strips, for methodological bridging purposes. All assessors differentiated the aversiveness of the taste strips in a dose dependent manner. Younger children aged 4-8 years had difficulty discriminating higher bitter concentrations, whereas pre-adolescents 9-11 years and naive adults showed better discrimination at the top of the scale. Naive assessors showed similar bitter perception as children. However, the results were slightly different between strips and solution in adults. These findings highlight the key role that adult panels can play in paediatric formulation development. Taste strips show promise as a safe and pragmatic tool for sensory pharmaceutical evaluations, though further studies are warranted to establish the relationship between age and hedonic taste perception using compounds with diverse physicochemical and sensory qualities.

A Guide to Best Practice in Sensory Analysis of Pharmaceutical Formulations.

It is well established that treatment regime compliance is linked to the acceptability of a pharmaceutical formulation, and hence also to therapeutic outcomes. To that end, acceptability must be assessed during the development of all pharmaceutical products and especially for those intended for paediatric patients. Although acceptability is a multifaceted concept, poor sensory characteristics often contribute to poor patient acceptability. In particular, poor taste is often cited as a major reason for many patients, especially children, to refuse to take their medicine. It is thus important to understand and, as far as possible, optimise the sensory characteristics and, in particular, the taste/flavour/mouthfeel of the formulation throughout the development of the product. Sensory analysis has been widely practiced, providing objective data concerning the sensory aspects of food and cosmetic products. In this paper, we present proposals concerning how the well-established principles of sensory analysis can best be applied to pharmaceutical product development, allowing objective, scientifically valid, sensory data to be obtained safely. We briefly discuss methodologies that may be helpful in reducing the number of samples that may need to be assessed by human volunteers. However, it is only possible to be sure whether or not the sensory characteristics of a pharmaceutical product are non-aversive to potential users by undertaking sensory assessments in human volunteers. Testing is also required during formulation assessment and to ensure that the sensory characteristics remain acceptable throughout the product shelf life. We provide a risk assessment procedure to aid developers to define where studies are low risk, the results of a survey of European regulators on their views concerning such studies, and detailed guidance concerning the types of sensory studies that can be undertaken at each phase of product development, along with guidance about the practicalities of performing such sensory studies. We hope that this guidance will also lead to the development of internationally agreed standards between industry and regulators concerning how these aspects should be measured and assessed throughout the development process and when writing and evaluating regulatory submissions. Finally, we hope that the guidance herein will help formulators as they seek to develop better medicines for all patients and, in particular, paediatric patients.

Evaluating the Taste Masking Ability of Two Novel Dispersible Tablet Platforms Containing Zinc Sulfate and Paracetamol Reconstituted in a Breast Milk Substitute.

Milk is often used as a dispersion medium for medicines administration in young children but its taste-masking ability is unknown. A human taste panel was conducted to assess the potential of infant formula milk (Aptamil® 1) to mask the taste of two model WHO priority medicines, zinc sulfate and paracetamol, manufactured as dispersible tablets. Simultaneously, the palatability of powder blends of the tablet platforms was assessed. Twenty healthy adult volunteers performed a swirl-and-spit assessment of placebos and API-containing blends in either a lactose-based or a mannitol-based dispersible tablet platform, reconstituted in 10 mL of either water or Aptamil® 1. Eighteen samples were rated for aversion using a 100-mm Visual Analogue Scale, grittiness using a 5-point Likert scale, and "acceptability-as-a-medicine" evaluated as: "Would you find this sample acceptable to swallow as a medicine?" with binary answers of Yes/No. The API-containing formulations were more aversive than the placebos; the paracetamol-containing samples being more aversive than zinc sulfate samples. The platforms themselves were not aversive. Non-gritty samples had four-fold greater odds of being acceptable as a medicine. Aptamil® 1 masked the taste of zinc sulfate in the mannitol-based formulation but did not mask the taste of paracetamol in either platform, suggesting a limited taste-masking ability, which may be API and formulation dependent.

Opportunities for enteral drug delivery for neonates, infants, and toddlers: a critical exploration.

INTRODUCTION: The field of neonatal, infant and toddler pharmaceutical development is constantly improving, however a lag still remains in comparison to older children and adults. Their rapid anatomical, physiological and behavioral developmental rates pose extra challenges in diagnosing, treating, or preventing their disease. In turn, this brings complexity in formulating truly age-appropriate medicinal products that suit this heterogeneous pediatric subset. Progress in the availability of such products has ensued following the introduction of the 2007 European Union Pediatric Regulation, and in recent years, oral multiparticulate and dispersible solid formulations have gained interest alongside liquid formulations. However, the need is still great for dosage forms that do not compromise on pharmaceutical efficacy, safety and global accessibility in those aged under 2. AREAS COVERED: This article highlights some of the formulation challenges correlated with this age group and critically explores recent solid age-appropriate formulations and their administration devices for enteral drug delivery. EXPERT OPINION: There are many formulation requirements to consider when formulating drug products for children aged under 2. Efforts are required into understanding acceptability in this age group and of their carers, and whether innovation or optimization is required, to help guide formulators toward optimal approaches without impacting access.

Modernising Orodispersible Film Characterisation to Improve Palatability and Acceptability Using a Toolbox of Techniques.

Orodispersible films (ODFs) have been widely used in paediatric, geriatric and dysphagic patients due to ease of administration and precise and flexible dose adjustments. ODF fabrication has seen significant advancements with the move towards more technologically advanced production methods. The acceptability of ODFs is dependent upon film composition and process of formation, which affects disintegration, taste, texture and mouthfeel. There is currently a lack of testing to accurately assess ODFs for these important acceptability sensory perceptions. This study produced four ODFs formed of polyvinyl alcohol and sodium carboxymethylcellulose using 3D printing. These were assessed using three in vitro methods: Petri dish and oral cavity model (OCM) methods for disintegration and bio-tribology for disintegration and oral perception. Increasing polymer molecular weight (MW) exponentially increased disintegration time in the Petri dish and OCM methods. Higher MW films adhered to the OCM upper palate. Bio-tribology analysis showed that films of higher MW disintegrated quickest and had lower coefficient of friction, perhaps demonstrating good oral perception but also stickiness, with higher viscosity. These techniques, part of a toolbox, may enable formulators to design, test and reformulate ODFs that both disintegrate rapidly and may be better perceived when consumed, improving overall treatment acceptability.

WHO essential medicines for children 2011-2019: age-appropriateness of enteral formulations.

INTRODUCTION: The WHO Essential Medicine List for children (EMLc) is used for promoting access to medicines. The age-appropriateness of enteral (oral and rectal) formulations for children depend on their adaptability/flexibility to allow age-related or weight-related doses to be administered/prescribed and the child's ability to swallow, as appropriate. There is scant information on the age-appropriateness of essential enteral medicines for children. OBJECTIVE: To evaluate the age-appropriateness of enteral essential medicines. MATERIALS AND METHODS: Age-appropriateness of all enteral formulations indicated and recommended in the EMLc 3rd to 7th (2011-2019) editions were determined by assessing swallowability and/or dose adaptability for children under 12 years, stratified into five age groups. RESULTS: Enteral formulations in the EMLc were more age-appropriate for older children aged 6-11 years than for younger children. In the 3rd edition, for older children, 77%, n=342, of formulations were age-appropriate. For younger children, age-appropriateness decreased with age group: 34% in those aged 3-5 years, 30% in those aged 1-2 years, 22% among those aged 28 days to 11 months and 15% in those aged 0-27 days. Overall, similar proportions were found for the 7th edition. In contrast, the majority of medicines in the 7th list were age-appropriate in targeted diseases like HIV and tuberculosis. CONCLUSION: Most recommended enteral essential medicines in EMLc 2011 and 2019 were not age-appropriate for children <6 years. Medicines which are not age-appropriate must be manipulated before administration, leading to potential issues of safety and efficacy. Evaluation of the age-appropriateness of formulations for medicines to be included in EMLc could improve access to better medicines for children in the future.