Paediatric Drug Development and Formulation Design—a European Perspective

Abstract

Abstract.The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize Bbetter^medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the BGuideline on the Pharmaceutical Development of Medicines for Paediatric Use.^Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.

Quality Assessment in the Extemporaneous Pediatric Preparation of Powder Papers Containing Crushed Tablets of Spironolactone or Amiodarone

“…[42] For example, crushed tablets may be poorly accepted for their flavor and, the excipients used in adult tablets are not necessarily safe in pediatrics. [13] Modified release tablets (prolonged, pulsatile or delayed, with enteric or gastro-resistant layers) should not be placed in papers due the risk of changes in bioavailability of drugs. [53] As an extemporaneous formulations, the powder papers must be consumed in a few days, therefore, long-term studies of physical, chemical and microbiological stability are not warranted, But stability should be assured during the period of storage and use, especially if the drugs are unstable to light or moisture.…”

“…[8] In addition, an excipient added to the formulations, to fulfill some specific function, can cause harmful results in the patients, [10,11] for example the respiratory distress syndrome observed in babies exposed to the benzyl alcohol used as preservative in solutions for injection. [12,13] Also, the hyperactivity due to azo dyes; activation of symptomatic in patients with gluten, lactose, fructose or galactose intolerance and potential allergies due to the presence of peanut, sesame or soya oils. To mitigate this situation, it is necessary to establish daily levels of excipients in children, particularly the most vulnerable, to ensure their safety from a clinical point of view.…”

“…[13,29] In this regard, some alternatives have been proposed to replace traditional tablets, such as multiparticulates (granules, pellets), dispersible formulations, orodispersible films, mini-tablets (disintegrable, uncoated, and coated) and chewable tablets. [30][31][32][33] These products are not found in all countries and there are significant problems due to the lack of pediatric formulations available in the market.…”

Pediatric Drug Development and Dosage Form Design

“…gives an overview on the European perspective regarding the development and design of pediatric drugs (2), and the key aspects of the recent European BGuideline on the Pharmaceutical Development of Medicines for Paediatric Use^are discussed. Subsequent articles in this theme issue address the pharmaceutical formulation challenges associated with a Pediatric Investigation Plan (Europe) or Pediatric Study Plan (United States).…”

Improving the Pipeline for Developing and Testing Pharmacological Treatments in Pregnancy

“…In parallel, there is a need for ongoing postmarketing surveillance (with good linkage to paediatric developmental outcome data) of drugs licensed for other medical conditions that are used commonly but without adequate knowledge on dosing (e.g., antibiotics, or low-molecular-weight heparin for thromboprophylaxis) or used rarely but where there are compelling reasons to continue treatment (e.g., biologics). New European Union regulations introduced in 2007 mandated the requirement for a Paediatric Investigational Plan for all applications for marketing authorisation for new medicines (unless the medicine is exempt because of a deferral or waiver) [11]. Such an obligation could be proposed for pregnancy at a legislative level to increase the formal testing of medicines on women who are pregnant.…”