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Owing to considerable differences observed in anatomy and physiology between paediatric subsets, it has been well established that children respond to drugs differently compared to adults. Furthermore, from a formulation perspective, there is a distinct challenge to develop a dosage form that is capable of safely, accurately, and reliably delivering the dose across the whole paediatric population. Orally disintegrating mini-tablets (ODMT) have widely been considered as an age-appropriate formulation option that possess the ability for adequate dose flexibility, avoids swallowing difficulties, and exhibits superior stability due to its solid state. Within this study, two strengths (0.5 mg and 2 mg) of carvedilol ODMT formulations were developed using an excipient composition and load that is appropriate for paediatric use. The formulations demonstrated adequate mechanical strength (>20 N) and fast disintegration times (<30 s). Dissolution profiles observed were robust and comparable to the marketed conventional tablet formulation across various parts of the gastrointestinal (GI) tract in both the fed and fasted state, signifying appropriate efficacy, quality, and performance. As such, the formulations developed in this study show potential to address the need of an ‘age-appropriate’ formulation of carvedilol, as highlighted by the European Medicines Agency (EMA) Inventory of the Needs for Paediatric Medicine.

There are certain aspects of the directive which sow the seed of change within the pharmaceutical industry. For the ®rst time, a quali®ed person will be required to perform the release of the investigational medicinal product (IMP) for use in a clinical trial. Good manufacturing practice in the manufacture of IMPs will be a legal requirement universally across the EU. This was previously dependent on member states instituting controls voluntarily. There are also changes in the pre-approval process for some biopharmaceutical products prior to trial commencement. In this paper we will explore the contents of the Directive and consider how this will impact the biopharmaceutical industry.

The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time.