There’s much more to developing a paediatric medicine than simply scaling down the adult dose to suit the weight of the child, and paediatric dose development poses several challenges to manufacturers when creating a product that is safe, effective and palatable for children
When it comes to administering medicines, children should not be regarded merely as smaller versions of adults.
Not only is there a wide variation in size among the paediatric patient population — even within children of the same age — but physiologically, there are marked and rapid changes as children mature that can affect the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug and that need to be considered. This makes the development and formulation of paediatric medicines highly complex, time-consuming and costly.
For example, during the first few weeks of life and through the weaning phase, a baby’s gastric pH changes dramatically, as does its intestinal fluid volume and composition, bile and pancreatic fluid secretion, and intestinal transit time.
The rate of permeation through the epithelial layer of the gastrointestinal tract is usually lower for children, but the effect may vary from one active pharmaceutical ingredient (API) to another, so must be investigated on a case-by-case basis.
Plasma protein binding, metabolic enzymes and total body water also vary as a human grows and matures, and there will be differences in the first pass effect, glomerular filtration and in both renal secretion and absorption.
Furthermore, excipients that are acceptable for adult use are not necessarily appropriate for use in children because they may have different effects on developing organ systems, depending on the age and developmental stage of the child.1
This creates a very challenging scenario for the drug developer. Not only is there a need to create a range of different doses and formulations in a variety of dosage forms, but the size of the patient population may also be relatively small, particularly in the case of rare or orphan diseases, affecting the potential profitability of a final product or the viability of a research programme.
A further complication is that there are currently no standardised techniques to assess product quality, making the identification of effective formulations complex and slow. This leads to potentially excessive iteration in formulation development studies, with the associated costs and risks of producing a suboptimal product.
These commercial realities are well understood by the regulatory authorities; the pharmaceutical industry therefore uses authoritarian frameworks to make business decisions regarding paediatric clinical trials. The regulatory authorities have revised their recommendations and guidelines many times, both to clarify guidance and to give incentives to companies to do specific research and develop drugs for children.
The regulatory requirements are designed to ensure that products are available for infants and children in different age groups that have an acceptable risk–benefit profile.
For drug developers, creating a paediatric oral solid formulation is particularly challenging. Such a dosage form must be easy-to-administer but have sufficient flexibility to meet the various needs of children at different growth stages.
Additionally, dosing frequency must be minimised; and, of course, the medication must be safe and palatable. A large tablet or capsule could lead to a child choking, whereas a very small tablet may be aspirated … both of which are potentially very dangerous. Oral liquid formulations make it easier to tailor the individual dose, but these in turn carry a greater risk of microbial contamination, whereas physical and chemical stability may be more difficult to achieve.
The European Medicines Agency recommends that patient acceptability should be evaluated as part of all development projects for paediatric products.2 If a medicine tastes bitter, a child may refuse to take it again, so having an effective taste masking strategy is important to ensure compliance.
Several taste masking techniques have been explored, from the simple use of sweeteners and flavours to more advanced techniques such as complexation with ion exchange resins and cyclodextrins, polymer film-coating, hot-melt coating, spray congealing, melt extrusion or melt granulation.
Oral solid dosage forms are becoming more popular for those children who are old enough to swallow them; but, for babies and others who cannot successfully be dosed in this way, multiparticulates or granules that include taste-masking technologies to increase their palatability may help to improve adherence.
Meanwhile, the development of mini-tablets that are suitable for toddlers has provided a new option. Clinical trials have shown that children as young as 2 years old can swallow a spoonful of fruit-flavoured jelly in which multiple mini-tablets are suspended, whereas another trial found that mini-tablets can be more successful in new-born babies than syrups.
Additionally, there are also data to suggest that chewable products and those that disperse in the mouth are preferred by all ages to multiparticulate formulations such as sprinkles.
Even when a suitable dosage form has been established, there will need to be a range of flexible options to ensure the correct dose of medication is administered. Although it is relatively straightforward to change the dose of liquid formulations or soluble powders by altering the volume that is dispensed, the situation is less so for an oral solid dosage form.
One approach is to create conventional formulations in different dosage strengths, although changes in formulation may be necessary. Another alternative would be to use a counting device filled with mini-tablets to dispense the appropriate number needed to meet the prescribed dose.
Meanwhile, innovators are collaborating to gain insights and to address the specific challenges of paediatric formulation and drug delivery. In 2017, the Catalent Applied Drug Delivery Institute entered into a collaboration with the Department of Pharmacy Practice at Rutgers University to undertake further research into the development and administration of medicines for children.
Catalent also acquired the UK-based dose form development and clinical manufacturing specialist, Juniper Pharmaceuticals, in 2018, making its Nottingham (UK) facility a European early development centre of excellence within Catalent’s global network.
This addition, alongside Catalent’s existing centres of excellence for early drug development in the United States and Europe, has strengthened the company’s developmental offerings and complements its integrated global clinical and commercial supply network.
Juniper Pharmaceuticals is one of the companies that participated in the Smart Paediatric Drug Development (SPaeDD) initiative, an open innovation R&D project aimed at accelerating paediatric formulation development. Cofunded by Innovate UK, the UK’s innovation agency, the collaboration also involved several major pharmaceutical companies — AstraZeneca, Bristol-Myers Squibb, GSK and Pfizer — and academics from Aston University, University of Bath, University of Birmingham and UCL School of Pharmacy.
The goal of the consortium was to establish an industry standard framework and suite of tools to develop safe and efficacious paediatric dosage forms.
Among the areas investigated were the requirements of paediatric formulations from an industry and hospital practitioner’s perspective, how to perform in vitro taste testing of paediatric medicines, the use of PK/PD modelling applied to paediatrics, novel paediatric formulations, ways in which the acceptability of formulations can be tested in paediatrics and how the knowledge gained can then be applied.
The project began in July 2014 and ended in 2018, and its output will provide novel predictive analytical and in silico tools that will contribute to a smarter and more efficient route to developing age-appropriate and acceptable children’s medicines.
These tools will provide potential benefits regarding the speed, cost and quality of paediatric formulation development by selecting the most appropriate formulations to support development and commercialisation, while also contributing to a greater probability of regulatory and technical success in an increasingly challenging environment.
The more rapid, cost-effective development of medications that are safe, efficacious and palatable to paediatric populations remains an important goal for the pharmaceutical industry.
To achieve this will require careful consideration regarding how medicines behave at different stages of a child’s physical development, as well as determining the most suitable dosage form for the target age range and its acceptability to both the child and the caregiver. Only then can the needs of paediatric patients be met in a safe and effective way.