Simulating Different Dosing Scenarios for a Child-Appropriate Valproate ER Formulation in a New Pediatric Two-Stage Dissolution Model

Predictive in vitro test methods addressing the parameters relevant to drug release in the pediatric gastrointestinal tract could be an appropriate means for reducing the number of in vivo studies in children. However, dissolution models addressing the particular features of pediatric gastrointestinal physiology and typical pediatric dosing scenarios have not yet been described. The objective of the present study was to combine the knowledge on common vehicle types and properties and current information on pediatric gastrointestinal physiology to design a dissolution model that enables a biorelevant simulation of the gastrointestinal conditions in young children. The novel dissolution setup consists of a miniaturized dissolution system allowing the use of small fluid volumes, physiological bicarbonate-based test media, and a proper pH control during the experiment using a pHysio-stat (R) device. Following design and assembly of the novel in vitro setup, a set of experiments screening in vitro drug release from a valproate-extended release formulation under typical dosing conditions in infants was performed. In vitro drug release profiles indicated a controlled drug release of the test product over 12 h and were in good agreement with information given in the Summary of Product Characteristics and the Patient Information Leaflet, as well as with results from an in vivo food effect study performed with the same product and reported in the literature. The new dissolution setup thus represents a promising in vitro screening tool in the development of pediatric dosage forms and may help to reduce the number of pharmacokinetic studies in children.