Effect of Medicine Co-administration with Food and Drinks on Drug Dissolution
Dissolution of montelukast from the two formulations revealed a significant effect of medicine co-administration with food and drink vehicles, compared with the direct administration scenario (Figs. 2 and 4).
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
For Singulair® granules, the AUC0–4h was significantly lower for the direct administration scenario compared with when the granules were mixed with vehicles, except for orange juice, blackcurrant squash and applesauce UK. For the co-administration with drinks scenario, drug dissolution was higher at 4 h when the formulation was mixed with milk (61.9%), followed by when it was mixed with formula, orange squash, blackcurrant squash and orange juice (percentage of drug dissolved = 41.1, 16.7, 10.8 and 7.7, respectively). For an ionisable compound like montelukast (amphoteric; pKa basic 2.7 and pKa acidic 5.8 (34)), an increase in pH can affect the ionisation percentage of the drug. Therefore, drug solubilisation and dissolution are higher when the formulation is mixed with a dairy drink (pH between 6.5 and 6.8 (11)) in comparison with other vehicles due to an increase in the drug ionisation percentage. For co-administration with soft foods, the highest drug dissolution was observed when the granules were mixed with plain yoghurt (39.3%) and the lowest when the formulation was mixed with applesauce UK (6.4%). Drug dissolution differed when vehicles of the same subtype were tested (AUC0–4h differed between milk/formula, and between squashes, yoghurts and applesauces; p < 0.05). The pH of the dissolution media at 4 h was 6.8 ± 0.15 for all tested scenarios. The lower drug dissolution observed when the granules were mixed with applesauce UK, in comparison with when mixed with the other soft foods, is probably due to the presence of starch in its composition, which forms a net gel around the formulation that is strengthened by fruit pieces and negatively impacts drug dissolution (13). Results show that vehicles of the same type (e.g. soft foods) have a distinct impact on drug dissolution (e.g. extremely low to no drug dissolution in the case of mixing with applesauce UK but not when formulation was mixed with plain yoghurt) and it can be hypothesised that this vehicle-impact may, ultimately, affect drug behaviour in vitro. This is of particular importance considering that the recommendations for administration of Singulair® granules are to mix with ‘a spoonful of cold soft foods’ (26). Therefore, the differences observed in drug dissolution indicate the potential risk of not following vehicle recommendations in clinical practice. Moreover, when evaluating vehicle suitability during drug development, the physicochemical properties of the vehicles should be considered.
Dissolution of the crushed Actavis® chewable tablets mixed with vehicles resulted in a higher percentage of drug dissolved at 4 h and significantly higher AUC0–4h in comparison with direct administration of the crushed formulation. Amongst vehicles, drug dissolution was the highest when the crushed tablets were mixed with milk and formula (72.5 and 67.8%, respectively) and the lowest when the formulation was mixed with blackcurrant squash (11.1%). Significant differences in AUC0–4h were revealed between mixing the formulation with milky and fruity drinks, and between mixing with the different squashes tested. Twofold differences were observed between AUC0–4h when mixing with vehicles of the same subtype (plain in comparison with Greek yoghurt and between the applesauce UK and applesauce USA; p < 0.05). These differences could be attributed to the physicochemical properties (e.g. different pH and protein content of dairy vs fruity drinks, and different viscosity of the applesauces) and macronutrient composition of the vehicles (e.g. different sugar content between the squashes), which affect drug solubilisation and may impact drug dissolution behaviour (11).
Dissolution of mesalazine from Pentasa® and Salofalk® granules also revealed a significant effect of co-administration with food and drink vehicles (Figs. 3 and 4).
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)
For Pentasa® granules, co-administration with the different vehicles resulted in a lower percentage of drug dissolved at 4 h compared with the direct administration scenario. The calculated AUC0–4h were significantly lower when the formulation was mixed with vehicles, except blackcurrant squash (p < 0.05). For co-administration with drinks, the percentage of drug dissolved (4 h) was higher for mixing with blackcurrant squash and formula (38.1 and 37.9%, respectively) followed by orange squash (35.5%), orange juice (24.1%) and milk (23.4%). Significant differences in AUC0–4h were revealed between mixing the Pentasa® granules with milk and formula (p < 0.05), but not between mixing with the different squashes tested. For co-administration with soft foods, AUC0–4h significantly differed when mixing with the different applesauces demonstrating that vehicles of the same subtype can distinctly affect dissolution of different drugs.
The percentage of mesalazine dissolved from Salofalk® granules (4 h) was also affected by the different vehicles. The percentage of drug dissolution was the highest when the granules were mixed with orange squash (17.3%), followed by blackcurrant squash (16.7%), formula (16.1%), milk (12.4%), orange juice (11.7%), direct introduction (11.4%) and soft foods. AUC0–4h was significantly different for the direct administration scenario compared with co-administration with vehicles, except milk, orange juice and applesauce DE (p > 0.05). For co-administration with soft foods, the percentage of drug dissolved at 4 h was the lowest when the formulation was mixed with Greek yoghurt (0.6%) and the highest when mixed with applesauce DE (9.9%), indicating that vehicles of the same type (e.g. soft foods) have a distinct impact on drug dissolution. The lower drug dissolution observed when the granules were mixed with soft foods was likely due to a physical barrier that these vehicles create around the formulation, which prevents mixing with GI fluids and hinders drug release, ultimately, reducing drug exposure at the site of absorption (13). Dissolution of mesalazine from Salofalk® granules also differed when mixed with vehicles of the same subtype, namely, applesauce UK vs USA, milk vs formula and plain vs Greek yoghurt (p < 0.05).
Interestingly, the two mesalazine formulations were oppositely affected when mixed with drinks compared with direct introduction of the granules: for Pentasa®, drug dissolution was lower, whereas for Salofalk® granules was higher. The mode of drug release of the two formulations is different; Pentasa® granules have a pH-independent extended release, whereas Salofalk® granules have a pH-dependent delayed release (Table I). Therefore, the vehicle-impact on drug dissolution from different formulations will depend not only on vehicle properties but also on formulation properties (e.g. differences in the mode of drug release, type of dosage form).
Overall, it was possible to observe a significant effect of medicine co-administration with soft foods and drinks on the dissolution of both drugs from all the formulations tested. Results show a vehicle-induced impact on drug dissolution due to changes in drug ionisation percentage and, consequently, drug solubility (e.g. higher percentage of montelukast dissolved when formulation is mixed with milk), changes in formulation environment (e.g. higher viscosity of applesauce hindering drug release/dissolution) and alteration of formulation factors (e.g. different coating of the tested mesalazine granules).