Terry B. Ernest

Developing paediatric medicines: identifying the needs and recognizing the challenges

There is a significant need for research and development into paediatric medicines. Only a small fraction of the drugs marketed and utilized as therapeutic agents in children have been clinically evaluated. The majority of marketed drugs are either not labelled, or inadequately labelled, for use in paediatric patients. The absence of suitable medicines or critical safety and efficacy information poses significant risks to a particularly vulnerable patient population. However, there are many challenges associated with developing medicines for the paediatric population and this review paper is intended to highlight these. The paediatric population is made up of a wide range of individuals of substantially varied physical size, weight and stage of physiological development. Experimentation on children is considered by many to be unethical, resulting in difficulties in obtaining critical safety data. Clinical trials are subject to detailed scrutiny by the various regulatory bodies who have recently recognized the need for pharmaceutical companies to invest in paediatric medicines. The costs associated with paediatric product development could result in poor or negative return on investment and so incentives have been proposed by the EU and US regulatory bodies. Additionally, some commonly used excipients may be unsuitable for use in children; and some dosage forms may be undesirable to the paediatric population.

Patient-Centred Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations

Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populations.

Specific aspects of gastro-intestinal transit in children for drug delivery design.

This mini-review discusses relevant aspects of gastro-intestinal transit in different ages of paediatric patients with an attempt to highlight factors which should be considered in oral dosage form design, in particular multi-particulate dosage forms. This emphasis is due to multi-particulates possessing many of the benefits of liquid oral formulations (such as ease of swallowing and dose adaptability) without many of their drawbacks (such as stability issues and lack of enteric or modified release functionalities). It is commonly stated that children are not merely small adults with regards to medicines. However, there has been very little research regarding how different dosage forms transit through the gastro-intestinal tract in children compared to adults, due to both ethical and practical hurdles. Due to this lack of studies on dosage form transit in children, information which was available on the transit of food, milk and liquids (often dependent upon the age of the patient) has been used to look at how various aspects of transit vary with age and, where possible, when they reach adult values and how these may affect the fate of dosage forms in vivo: swallowability, oesophageal transit, gastric emptying and pH, intestinal and colonic transit are discussed.

Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms

Introduction: Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. Areas covered: The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems. Expert opinion: Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery.

Application of in vitro biopharmaceutical methods in development of immediate release oral dosage forms intended for paediatric patients.

Biopharmaceutics is routinely used in the design and development of medicines to generate science based evidence to predict in vivo performance; the application of this knowledge specifically to paediatric medicines development is yet to be explored. The aim of this review is to present the current status of available biopharmaceutical tools and tests including solubility, permeability and dissolution that may be appropriate for use in the development of immediate release oral paediatric medicines. The existing tools used in adults are discussed together with any limitations for their use within paediatric populations. The results of this review highlight several knowledge gaps in current methodologies in paediatric biopharmaceutics. The authors provide recommendations based on existing knowledge to adapt tests to better represent paediatric patient populations and also provide suggestions for future research that may lead to better tools to evaluate paediatric medicines.

Non-human tools for the evaluation of bitter taste in the design and development of medicines: a systematic review.

Taste evaluation is a crucial factor for determining acceptance of medicines by patients. The human taste panel test is the main method used to establish the overall palatability and acceptability of a drug product to a patient towards the end of development. Non-human in vitro and in vivo taste-evaluation tools are very useful for pre-formulation, quality control and screening of formulations. These non-human taste assessment tools can be used to evaluate all aspects of taste quality. The focus of this review is bitterness because it is a key aspect of taste in association with the development of medicines. In this review, recent in vitro (analytical) and in vivo (non-human) tools are described for the assessment of the bitter taste of medicines. Their correlations with human taste data are critically discussed. The potential for their use in early screening of the taste of active pharmaceutical ingredients (APIs) to expedite paediatric formulation development is also considered.

Towards the development of a paediatric biopharmaceutics classification system: Results of a survey of experts.

The aim of this research survey was to understand current global thinking around the need for and development of a paediatric biopharmaceutics classification system (pBCS) to be used for the development of paediatric medicines and regulatory purposes (e.g. Biowaivers). A literature review highlighted the paucity of data in this area and therefore a survey was developed to better understand this topic to identify areas of common thinking and highlight future research needs. Global experts in paediatric biopharmaceutics were identified from existing networks and public forums. An online survey was developed and circulated broadly to maximise participation. Sixty individuals (including academics, health care professionals, pharmaceutical industry scientists and regulators) completed the survey, bringing together their views on the need for a pBCS. The results highlighted that the area of greatest concern was the definition of BCS II and IV drugs within this population and additional research is required to generate evidence to underpin this issue. In questions relating to permeability and dissolution consensus was generally reached within the expert population suggesting that little additional research is required to define suitable criteria. More than 90% of those experts who participated agreed that a pBCS would be useful for paediatric populations with a greater need identified for the younger populations (newborn and infants compared to adolescents). The results presented will facilitate further discussion and research into the evidence to underpin a relevant pBCS. These results highlight the need for additional evidence and guidance in this area.

Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations

The selection and design of age-appropriate formulations intended for use in paediatric and geriatric patients are dependent on multiple factors affecting patient acceptability, safety and access. The development of an economic and effective product relies on a balanced consideration of the risks and benefits of these factors. This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost. Patient acceptability has been examined utilising an evidence-based approach to evaluate regulatory guidance and literature. Safety considerations including excipients and potential risk of administration errors of the different dosage forms are also discussed, together with possible manufacturing and supply challenges. Age appropriate drug product design should consider and compare i) acceptability ii) safety and iii) access, although it is important to recognise that these factors must be balanced against each other, and in some situations a compromise may need to be reached when selecting an age-appropriate formulation.

Patient centric formulations for paediatrics and geriatrics: Similarities and differences

Paediatrics and geriatrics both represent highly heterogenous populations and require special consideration when developing appropriate dosage forms. This paper discusses similarities, differences and considerations with respect to the development of appropriate medicine formulations for paediatrics and geriatrics. Arguably the most significant compliance challenge in older people is polypharmacy, whereas for children the largest barrier is taste. Pharmaceutical technology has progressed rapidly and technologies including FDCs, multi-particulates and orodispersible dosage forms provide unprecedented opportunities to develop novel and appropriate formulations for both old and new drugs. However, it is important for the formulation scientists to work closely with patients, carers and clinicians to develop such formulations for both the paediatric and geriatric population.

Acceptability of placebo multiparticulate formulations in children and adults

Patient acceptability is an important consideration in the design of medicines for children. The aim of this study was to investigate acceptability of multiparticulates in healthy children and adults. A randomised, single-blind acceptability testing was performed involving 71 children (4–12 years) and 61 adults (18–37 years). Each participant received three 500 mg samples of microcrystalline cellulose pellets administered on a medicine spoon with water at 5–10 minutes intervals. Acceptability was measured based on voluntary intake of the samples, facial expressions, ratings on hedonic scales and reported willingness to take multiparticulates everyday as a medicine. Multiparticulates were voluntarily swallowed by 92% of children and 100% of adults. However, palatability issues were identified, with emphasis on textural aspects. Grittiness perception received negative ratings on hedonic scales by 60% of children and 51% of adults. Researcher observations revealed that 72% of children and 42% of adults displayed negative facial expressions towards the samples. Children reported their willingness to take multiparticulates as a medicine in 30% of the cases, compared to 74% in adults. This study demonstrates that multiparticulates may be a suitable formulation platform for children and adults, although palatability concerns have been highlighted. Additional work is required to define acceptability criteria and to standardise methodologies.