Excipients in Neonatal Medicinal Products: Never Prescribed, Commonly Administered

Abstract

To attain effective and safe pharmacotherapy, formulations in (pre)term neonates should enable extensive dose flexibility. During product development and subsequent authorization and clinical use of such formulations, there is also a need for informed decisions on excipient exposure: in addition to the need to improve the knowledge on active compounds, there is a similar need to improve the knowledge on excipients in neonates. Excipients are added to formulations as co-solvent, surfactant, preservative, colorant and/or sweetener as vehicle(s) to result in a suitable (e.g. taste, shelf life, stability) product. Progress has been made in the awareness, knowledge and access to this knowledge on the clinical pharmacology of excipients in neonates. This is thanks to different initiatives focussing on epidemiological data, excipient pharmacokinetics, or building datasets to create this knowledge. We highlight the Safe Excipient Exposure in Neonates and Small Children (SEEN) and propylene glycol project to illustrate the feasibility to build knowledge, and discuss the methods applied and problems observed during these studies. The information generated in these and other studies (European Study on Neonatal Exposure to Excipients, ESNEE) should be integrated in repositories like the Safety and Toxicity of Excipients for Paediatrics (STEP) to facilitate access to all stakeholders. This merged knowledge should have impact and assist in improving the quality of risk assessment and decision making during drug development, applying a risk-benefit framework (explicit justification of excipients, plan product development early and engage all stakeholders, data sharing and modeling, challenges related to new excipients, context sensitive risk-benefit analysis).

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

“…A risk of exposure to excipients through the oral administration route exists, since excipients are used in oral dosage forms to improve, for instance, patient acceptability, the solubility of the drug substance or the shelf-life of the drug product [10]. Excipients such as preservatives, colorants, sweeteners, ethanol and propylene glycol can be harmful to children, especially for infants and neonates [10][11][12]. Garcia-Palop et al discovered in a Spanish University Hospital that at least one harmful excipient was present in 62% of orally administered drugs used for neonates [13].…”

Benefits and Prerequisites Associated with the Adoption of Oral 3D-Printed Medicines for Pediatric Patients: A Focus Group Study among Healthcare Professionals

“…The participants in this study believed that, in case the printing method used does not enable printing of a QR code, other measures should be taken to ensure identification of the drug product and, thus, to prevent medication errors. In drug development of pediatric medicines, one must consider that the colorant as well as other excipients are safe for use in children, since investigations have shown that neonates and infants are extensively exposed to harmful excipients during oral administration of medicines [38][39][40]. Furthermore, this study shows that healthcare professionals prefer dosage forms containing excipients that enable the administration of the dosage form through enteral feeding tubes as well as after dissolving or dispersing the dosage form in liquid, e.g., water.…”

<p>Safety and Biopharmaceutical Challenges of Excipients in Off-Label Pediatric Formulations</p>

“…This rapid growth of cell receptors leads pediatric patients to give toxic and fast responses to different excipients. 17,18 Pharmaceutical excipients are necessary to maintain the quality and improve patient acceptability of medicines. Excipients ideally have limited pharmacological activity; however, some are associated with toxicity in neonates.…”

“…43 As the WHO and FDA recommended, the maximum amount of ethanol in pediatric medications should not be more than 0.5% v/v for children under 6 years, 5% for children 6-12 years, 10% for children over 12 years. 17 The American Academy of Pediatrics (AAP) also established that the quantity of ethanol in pediatric formulations should not produce a blood concentration higher than 25 mg/100 mL after the administration of a single suggested therapeutic dose. 44 Propylene Glycol and Polyethylene Glycol Propylene glycol (PEG) is a dihydroxy alcohol used as a pharmaceutical solvent, preservative, and humectant.…”

“…Due to this, the bioavailability of both drugs is decreased by 20%. 17 The study done on healthy male volunteers in the UK showed that the absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to…”