In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Inf
- PDF / 1,122,083 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 1 Downloads / 195 Views
Research Article In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants J. Martir,1 T. Flanagan,2,3 J. Mann,2 and N. Fotaki1,4
Received 6 May 2020; accepted 22 September 2020 Abstract. In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by coadministration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population. KEY WORDS: paediatrics; drug manipulation; food; in vitro dissolution; mini-paddle; in vitro-in vivo relationship; paediatric biorelevant media.
INTRODUCTION Understanding the dissolution profile of a pharmaceutical dosage form and linking it to its in vivo pharmacokinetic (PK) profile is a vital requirement for ensuring product quality and safety of use (1–3). Dissolution profiles can be analysed through different approaches: using modeldependent methods where experimental data are fitted using mathematical equations, model-independent methods (single values such as mean dissolution time and area under the dissolution curve (AUC) are used for data evaluation) and/or
1
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK. 2 Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK. 3 UCB Pharma, Chemin du Foriest, B - 1420, Braine-l’Alleud, Belgium. 4 To whom correspondence should be addressed. (
Data Loading...
