Purpose: Chronic drooling or sialorrhoea is evident in the pediatric population and is particularly prominent in those who suffer with neurological disorders such as cerebral palsy. Prior to the development of this formulation, the only options available to clinicians for the treatment of pediatric patients with glycopyrronium bromide were either unlicensed, compounded formulations or formulations containing inappropriate excipients for children. The aim of this development program was to develop an aqueous, multi-dose oral liquid formulation of glycopyrronium bromide 2mg/5ml that would be appropriate for the symptomatic treatment of severe sialorrhoea in pediatric patients aged 3 years and older with chronic neurological disorders. A liquid formulation enables the flexible dosing by varying the dose volume according to age and body weight. Glycopyrronium bromide is a bitter tasting, odorless, white crystalline powder with solubility in water of 1 in 4.2. It is completely ionized at physiological pH levels, is stable under normal heat and light conditions and is most stable in solutions at low pH. Above pH 6 it undergoes ester hydrolysis. A Quality Target Product Profile (QTPP) for the paediatric liquid is detailed in Table 1.
Methods: The design of the formulation and selection of excipients took into consideration the guidance provided by the European Medicines Agency (EMA) for pediatric formulations. Additionally, the levels of excipients used were also guided by the EC Notice to Applicants Guideline 3B. Formulations with alternative combinations of appropriate preservatives, flavors, sweeteners and pH modifiers were assessed and the lead system was identified by taste assessment and short-term stability testing. The lead candidate formulation was subjected to electronic tongue evaluation and also taste assessment in healthy adult volunteers to confirm palatability. An in vitro nasogastric and enteral tube recovery study with a wide range of feeding tubes was also performed to determine the flushing volumes required if the drug product was to be administered to children through feeding tubes.
Results: The output of the development program resulted in an age-appropriate, oral solution formulation in line with the QTPP and containing only five excipients. The electronic tongue testing and human volunteer taste testing confirmed the palatability and acceptability of the formulation. The liquid is non-viscous and complete clearance of glycopyrronium bromide through the range of feeding tubes was demonstrated following a single 10ml water rinse. Stability testing of scaled-up batches in the chosen pack has confirmed a shelf-life of 24 months for the product and an EU-wide PUMA was granted in September 2016 and the product has been launched with the proprietary name Sialanar® (Figure 1)
Conclusion: There was a specific need for the development of a paediatric formulation of glycopyronnium bromide as previous treatment options were not ideal for the target age group. Based on the knowledge of the physicochemical properties of the drug substance, consideration of regulatory guidance and the selection of appropriate excipients, including flavors and sweeteners, it was possible to design a stable, palatable and scalable formulation that would provide flexibility of dosing to children aged 3 years and older.
Nazim Kanji– Quotient Sciences
Nazim Kanji– Quotient Sciences
Huw Jones– Quotient Sciences
Peter Scholes– Chief Scientific Officer, Quotient Sciences, Nottingham
Simon Bryson– Director and Founder, Proveca Ltd.
Clare Gleeson– Operations Manager, Proveca Ltd.
Peter Scholes– Chief Scientific Officer, Quotient Clinical, Nottingham