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

Abstract

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® 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.

A Biopredictive In Vitro Comparison of Oral Locally Acting Mesalazine Formulations by a Novel Dissolution Model for Assessing Intraluminal Drug Release in Individual Subjects

“…Experiments in which the physiologically relevant buffer system, that is, the bicarbonate buffer system was used to simulate SI passage 22,23 were performed with an online Paddle dissolution system (DT 728; Erweka GmbH). Media volume, temperature, and agitation speed corresponded to that of the experiments with conventional biorelevant buffers.…”

“…20 However, although these media properly fit with the physicochemical parameters, they do not take into account the detailed ionic composition of the physiological fluids. Therefore, Blank CarbSIF (CarbSIF without bile compounds) 23 was used as the baseline medium for creating the small-intestinal pH-gradient. The physiological media set was complemented by Blank Carbonate-based Simulated Colonic Fluid, a bicarbonate buffer containing acetate ions.…”

“…Therefore, most recently, we introduced a carbonate-based simulated intestinal fluid (SIF) pH 6.8 (Carbonate-SIF [CarbSIF]) containing 120-mM sodium chloride, 5-mM potassium chloride, 15-mM sodium bicarbonate, and physiological concentrations of bile compounds 22 as a medium addressing average pH and ionic composition of fasted small intestinal fluid for designing discriminatory test methods with biopredictive power. 22,23 Moreover, with the pHysio-grad device, a dynamic system for the simulation of fasting intraluminal pH-gradients, 24 we were able to vary intestinal pH conditions according to a given pH profile during a release experiment. State of the art is thus a dissolution model that enables to mimic individual GI pH profiles and transit times by using physiologically relevant dissolution media.…”

Potential prediction of formulation performance in paediatric patients using biopharmaceutical tools and simulation of clinically relevant administration scenarios of nifedipine and lorazepam

“…These media were based on the available literature on the composition of paediatric luminal fluids and the established adult media . Experimental dissolution parameters that mimic paediatric conditions have been proposed . The search for alternatives to clinical trials is essential, especially in paediatrics, given the ethical and methodological difficulties involved in performing trials in paediatric patients .…”

Pediatric Drug Development and Dosage Form Design

“…Taking into account that drug administration in children can be challenging for caregivers and often food is used to facilitate the process, it is worthwhile to investigate different dosing scenarios (11), but also suitable gastrointestinal digestion models (12). Mixing drugs into foodstuff is one approach to additionally mask the taste of pharmaceuticals and facilitate the swallowing procedure.…”