Impact of Food and Drink Administration Vehicles on Paediatric Formulation Performance Part 2: Dissolution of Montelukast Sodium and Mesalazine Formulations

Abstract

Paediatric medicines are not always age-appropriate, causing problems with dosing, acceptability and adherence. The use of food and drinks as vehicles for medicine co-administration is common practice, yet the impact on drug bioavailability, safety and efficacy remains unaddressed. The aim of this study was to use in vitro dissolution testing, under infant simulating conditions, to evaluate the effect of co-administration with vehicles on the dissolution performance of two poorly soluble paediatric drugs. Dissolution studies of mesalazine and montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: simulated gastric fluid followed by addition of simulated intestinal fluid. The testing scenarios were designed to reflect daily administration practices: direct administration of formulation; formulation co-administered with food and drinks, both immediately after mixing and 4 h after mixing. Drug dissolution was significantly affected by medicine co-administration with vehicles, compared to the direct administration of formulation. Furthermore, differences were observed on drug dissolution when the formulations were mixed with different vehicles of the same subtype. The time between preparation and testing of the drug-vehicle mixture also impacted dissolution behaviour. Drug dissolution was shown to be significantly affected by the physicochemical properties and composition of the vehicles, drug solubility in each vehicle and drug/formulation characteristics. Ultimately, in this study, we show the potential of age-appropriate in vitro dissolution testing as a useful biopharmaceutical tool for estimating drug dissolution in conditions relevant to the paediatric population. The setup developed has potential to evaluate the impact of medicine co-administration with vehicles on paediatric formulation performance.

Keywords: dissolution; drinks; drug manipulation; food; mini-paddle; multivariate analysis; paediatrics.

Fig. 1

Chemical structure of a montelukast sodium and b mesalazine (ChemDraw Professional 18.1)

Fig. 2

Mean percentage of montelukast dissolved (± S.D.) from Singulair^® granules (top panel) and Actavis^® chewable tablets (bottom panel) after direct administration of formulation, after mixing with selected vehicles (full lines) and with vehicles of the same subtype (dashed lines). Dotted vertical lines represent the time of medium change

Fig. 3

Mean percentage of mesalazine dissolved (± S.D.) from Pentasa^® (top panel) and Salofalk^® granules (bottom panel) after direct administration of formulation, after mixing with selected vehicles (full lines) and with vehicles of the same subtype (dashed lines). Dotted vertical lines represent the time of medium change

Fig. 4

Effect of co-administration of formulation with vehicles on percentage of drug dissolved at 4 h from the tested formulations. Asterisk symbol denotes a statistical difference on drug dissolution between direct administration (dashed line) and co-administration with vehicles (bars; red: drinks, blue: soft foods). a denotes statistical difference when vehicles of the same subtype were tested (p < 0.05)

Fig. 5

Mean percentage of montelukast dissolved (± S.D.) from Singulair^® granules (top panel) and Actavis^® chewable tablets (bottom panel), under two administration scenarios: testing immediately after mixing (dashed lines) and 4 h after mixing (full lines). Dotted vertical lines represent the time of medium change

Fig. 6

Mean percentage of mesalazine dissolved (± S.D.) from Pentasa^® granules (top panel) and Salofalk^® granules (bottom panel) under two administration scenarios: testing immediately after mixing (dashed lines) and 4 h after mixing (full lines). Dotted vertical lines represent the time of medium change

Fig. 7

Effect of a 4-h delay between mixing and testing of formulation with vehicles on drug dissolution from the tested formulations. Asterisk symbol denotes a statistical difference on drug dissolution between testing immediately after mixing (dashed bars) and testing 4 h after mixing (full bars)

Fig. 8

Mean percentage of drug dissolved (± S.D.) of montelukast from Singulair^® granules (top panel) and mesalazine from Pentasa^® granules (bottom panel), after testing under two agitation rate conditions: 50 rpm (dashed bars) and 100 rpm (full bars). Dotted vertical lines represent the time of medium change

Fig. 9

Effect of dissolution hydrodynamics on AUC_{0–4 h} of Singulair^® (montelukast) and Pentasa^® (mesalazine) granules. Asterisk symbol denotes a statistical difference in AUC_{0–4 h} between drug dissolution when agitation rate was set at 50 (dashed bars) and 100 rpm (full bars)

Fig. 10

Standardised coefficients corresponding to the variables studied for dissolution of montelukast, mesalazine and both drugs. Colour denotes coefficients with a moderate (lighter colour) and significant (darker colour) impact on the response (VIP > 0.7 and 1, respectively). (B.C., buffer capacity; ST, surface tension)