Best practices for selection of excipients for paediatrics - Workshop reflection.

The development of age appropriate formulations for the paediatric population has become one of the key areas of focus for the pharmaceutical industry - with a subsequent influence on excipient use. Selection of excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. Various factors influence selection of excipients, including target age group, route of administration and dosage form. Evaluation of these factors and a clear rationale and justification is expected by the regulators when it comes to selecting excipients for paediatric formulation. Scientists are encouraged to apply the principle of benefit to risk balance to assess the suitability of excipients to the specific paediatric population for whom the formulation is intended. In order to understand how scientists approach the task of establishing the risk to benefit analysis, a workshop was organised by the European Paediatric Formulation Initiative (EuPFI) to reflect on the current scenario and the different practices employed by formulation scientists in the selection of excipients for paediatric formulations. Aspects assessed by regulators were also canvassed. Finally, the participants were asked to comment on how selecting excipients for use in paediatric formulations may differ from the considerations applied in selecting excipients for formulations for other age groups. Based on the workshop discussion, some recommendations and questions to consider emerged regarding the selection of excipients in paediatric drug development. These best practice recommendations provided a good starting point for a more systematic strategy for selecting excipients for paediatric formulation development.

Access to age-appropriate essential medicines: a retrospective survey of compounding of medicines for children in hospitals in Nigeria and implications for policy development.

Policies to improve access to medicines for children in Nigeria do not include compounding as a source of medicines. Compounding is often applied as a last resort in health institutions to provide age-appropriate formulations usually for oral use in young children; but it bears some risk. Some countries have adopted policies aimed at reducing the risk based on available data. There is not much data for Nigeria. This retrospective study examined compounding records from January to December 2011 in a sample of seven hospitals to describe what medicines for oral use were commonly compounded in Nigeria. It then determined if these medicines were commercially available in forms suitable for use in children in selected countries­the United Kingdom, United States and India. The study found that out of 2845 items compounded, over 65% were medicines for cardiovascular conditions, diarrhoea or tuberculosis. The main reason (96%, n = 2399) for compounding was the unavailability of age-appropriate formulations. Medicines were almost all compounded using simple syrup, vitamin C or vitamin B syrups as suspending vehicles. Final products were all oral liquids. Comprehensive stability testing was not reported for the products. Almost all of the commonly compounded medicines were found to be commercially available in dosage forms suitable for use in children in the selected countries. These medicines were all listed in the World Health Organization Essential Medicines List for children as well as in the current edition of the Essential Medicines List of Nigeria. The fact that they were compounded highlights the need for improved access to age-appropriate dosage forms for children in Nigeria. The study recommends policy expansion through a three-pronged approach to improving access: increased supply through facilitated importation/accelerated product registration, or in-country manufacturing; rational drug use including therapeutic substitution, and establishment of a national formulary for compounding.

Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature.

The use of unlicensed and off-label medicines in children is common because trials in children have not usually been performed during the drug development process. Consequently, the information available to paediatricians may not always be as detailed or as robust as that available when prescribing a medicine that is licensed for an approved indication. This has led to concerns that children may be receiving drugs at dosages that either lack efficacy or present safety problems. The latter in particular has received a great deal of attention. In this narrative review, we have evaluated the use of off-label and unlicensed medicines in children and whether and how frequently this predisposes to adverse drug reactions.

Inappropriate oral formulations and information in paediatric trials.

Previously, quality of formulations information provided for oral medications used in paediatric clinical trials published in 10 highly cited journals between 2002 and 2004 raised concerns. This short report explores if there was any subsequent improvement on how the formulations used in trials involving children <12 years reported in the same journals. Studies published between 2004 and 2008 were hand-searched and classified as containing adequate, some or no formulation information. Those involving solid dosage forms were further analysed. Only 31% (44/140) of publications provided adequate information, 5% less compared to 2002-2004 (28/76). There was a significant 12% rise (p<0.05) of no formulation information at all (37/140) and in tablets/capsules use (53/140), of which 3/4 gave no administration details, even for those under 6 years old, but a 12% decline in suitable paediatric formulations use (52/140 compared to 37/76). Contrary to expectations, overall quality of formulation information reported markedly deteriorated, jeopardising validity of clinical outcomes. The situation may reflect continued lack of awareness among investigators and other stakeholders of the importance of using suitable age-appropriate formulations.

The National Institute for Health Research Medicines for Children Research Network.

The UK has established the National Institute for Health Research Medicines for Children Research Network to provide infrastructure to facilitate the conduct of randomized trials and other well designed studies sponsored by the pharmaceutical industry and public funding bodies. Clinical Studies Groups of experts establish priorities and assist in the development of protocols whilst Local Research Networks and an Extended Neonatal Network facilitate their implementation and conduct. Two Clinical Trials Units and a co-ordinating center assist in the development and conduct of studies and performance manage the network. Work streams on formulation and experimental medicine have been established. As of August 2008, 16 commercially sponsored studies had been adopted (from 12 different companies) and 65 publicly sponsored studies.

Physicochemical stability of parenteral nutrition supplied as all-in-one for neonates.

BACKGROUND: Common clinical practice for the provision of parenteral nutrition of neonates is to administer the nutrients in separate solutions. The aim of this study was to introduce and examine an alternative way of parenteral feeding for neonates, providing all-in-one parenteral regimes. METHODS: Stability studies were carried out on 2 all-in-one admixtures. Stability assays consisted of the assessment of the admixture's (1) macroscopic aspect, (2) drop size measurement, (3) pH measurement, (4) peroxide value, and (5) alpha-tocopherol concentration. For the measurements, the admixtures were stored at 2 different temperatures, 4 degrees C (storage) and 25 degrees C (compounding), and then analyzed at a starting time, 24 hours, 48 hours, and 7 days after compounding. RESULTS: The 2 all-in-one parenteral admixtures for neonates were shown to be physically stable under analysis conditions, and there were no particles larger than 1 mum. The maximum loss of alpha-tocopherol was approximately 24%. In all-in-one admixtures, lipid peroxide occurred within 24 hours after the addition of the lipid emulsion. CONCLUSIONS: The addition of fat emulsion and fat-soluble vitamins did not alter the physical stability of parenteral admixtures for neonates. Moreover, the admixtures examined were relatively chemically stable for 24 hours, as far as vitamin E is concerned. Lipid peroxidation was the limiting factor for application stability of an all-in-one neonatal parenteral regimen.

Formulation of medicines for children.

The development of age-adapted dosage forms and taste-masking of bitter-tasting drugs administered orally for children, are formidable challenges for formulation scientists. Childhood is a period of maturation requiring knowledge of developmental pharmacology to establish dose but the ability of the child to manage different dosage forms and devices also changes. Paediatric formulations must allow accurate administration of the dose to children of widely varying age and weight. Whilst the oral route will be preferred for long term use and the intravenous route for the acutely ill, many of the dosage forms designed for adults, such as oro-dispersible tablets, buccal gels and transdermal patches, would also benefit children if they contained an appropriate paediatric dose. The age at which children can swallow conventional tablets is of great importance for their safety. Liquid medicines are usually recommended for infants and younger children so the ability to mask unpleasant taste with sweeteners and flavours is crucial. More sophisticated formulations such as granules and oro-dispersible tablets may be required but there will be limitations on choice and concentration of excipients. There are many gaps in our knowledge about paediatric formulations and many challenges for the industry if suitable preparations are to be available for all ranges. A CHMP points to consider document is soon to be released. More research and clinical feedback are important because a formulation with poor acceptability may affect compliance, prescribing practice and ultimately commercial viability.