How sweet it isn't: a new formulation of sodium phenylbutyrate and the challenge of palatability for medicines for children
- Departments of Paediatrics, Physiology and Pharmacology, Medicine, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
- Correspondence to Dr Michael Rieder, Department of Paediatrics, Children's Hospital, 800 Commissioner's Road East, London, Ontario, Canada, N6C 2V5;
- Accepted 30 September 2012
The development of medications for children presents unique challenges that test the ingenuity of investigators and industry in their search for drugs that are safe, effective – and can be taken by children. One of the most telling challenges relates to palatability. Children – especially under the age of 5 – usually require medication to be in a liquid form, and as medications are typically bitter, children may find this to be, as one might say, a difficult thing to swallow. While this area has been historically understudied, recent work has clearly established that this is an important concern with clear implications for adherence and, ultimately, therapeutic efficacy.1–3
Guffon et al4 describe a series of studies exploring a new dosage form of sodium phenylbutyrate, a compound used in the management of urea cycle disorders. Urea cycle disorders are rare but serious inherited disorders which untreated produce serious neurological symptoms, including coma and death. Treatment includes dietary measures as well as sodium phenylbutyrate, which is metabolised to phenylacetic acid, the acetylation of which to phenylacetylglutamine removes 2 moles of nitrogen per mole of drug. Sodium phenylbutyrate is a drug that illustrates many of the palatability problems of paediatric drug treatment; with a notorious bitter taste, taste aversion makes compliance with chronic treatment problematic.
The approach taken by Guffon et al provides fascinating insights into new approaches to the problem of palatability.4 In the development of a new formulation of sodium phenylbutyrate, the research team decided to use a taste-masking strategy by applying the drug to microgranular sugar cores that were then coated with a taste-masking solution. They then determined that this did not alter the dissolution characteristics of the drug, a key consideration in that the taste-masking strategy must not alter the drug's kinetics or efficacy. This was followed by a formal pharmacokinetic study in healthy adult volunteers to compare the kinetics of the new formulation with the current standard formulation. In addition to pharmacokinetic testing, the team evaluated taste using two approaches – an in vitro assessment using an “electronic tongue” and formal taste testing among the adult volunteers. Using this approach, the research team have described the development of a new formulation that is kinetically equivalent – but which tastes better.
Some important limitations should be noted. The work involving adminstration of the drug to people was done exclusively in adult volunteers. This is appropriate for the pharmacokinetic study – there being no a priori reason to suspect that the kinetics would be any different in children than adults, notably as most of the subjects were young adults. However, there are well-described differences in taste preference between adults and children and it will be illustrative for this new formulation to be evaluated in the children who are likely to receive it.2 ,5
There are also important lessons to be learnt from these studies. The first is the team itself – a collaboration between academia and industry and across two countries to deal with an important issue in the care of children with a chronic and life-threatening disease. The second is the comprehensiveness of the approach – which included careful in vitro studies leading to formal pharmacokinetic analysis to ensure that the taste-masking approach did not alter drug efficacy. The third lesson is the use of two validated techniques for taste assessment – one in vitro and a formal taste assessment in volunteers receiving the drug. Paediatricians and child health researchers pursuing practical issues in paediatric therapeutics would be well advised to read this study carefully.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.