Assessment of the Impact of Different Administration Practices on Drug Dissolution Behaviour
Delaying testing by 4 h after mixture preparation revealed significant differences on drug dissolution in comparison with testing immediately after mixing (montelukast: Figs. 5 and 7; mesalazine: Figs. 6 and 7).
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)
For Singulair® granules, delaying testing by 4 h after mixing led to a higher percentage of drug dissolved and a significantly higher AUC0–4h for co-administration with milk, orange juice and applesauce UK (p < 0.05). This is probably due to the solubility of montelukast in these vehicles, which resulted in an increased drug solubilisation and dissolution during the 4-h delay (11). From the three cases, the differences in drug dissolution between the two testing scenarios were most accentuated when the granules were mixed with milk. As observed in the ‘Effect of Medicine Co-administration with Food and Drinks on Drug Dissolution’ section, this is probably due to the pH of milk which leads to an increase in drug solubilisation and dissolution, in comparison with when the granules are mixed with other vehicles. Results from this test show that this increase is even more evident if there is a delay between preparation and administration of the mixture. In contrast, delaying testing after mixing the Singulair® granules with blackcurrant squash had no effect on drug dissolution, whereas delaying the time between mixing with plain yoghurt and testing resulted in a significantly lower AUC0–4h. Delaying testing by 4 h after mixing the granules with applesauce UK and plain yoghurt led to a drop in drug concentration after the media change from SGFsp pH 1.2 to SIFsp pH 6.8. This might be related to the sudden change in pH and increase in media volume (10).
For the crushed Actavis® chewable tablets, a 4-h delay between mixing the formulation with the vehicles and testing, resulted in a higher percentage of drug dissolved for co-administration with milk and orange juice, but not when the formulation was mixed with blackcurrant squash, applesauce and plain yoghurt. AUC0–4h was significantly different when the crushed chewable tablets were mixed with milk, orange juice (both higher) and plain yoghurt (lower), in comparison with immediate administration of the vehicle-formulation mixtures (p < 0.05).
For Pentasa® granules, increasing the time between preparation and testing of the granules-vehicle mixtures resulted in a higher percentage of drug dissolved (4 h), and significantly higher AUC0–4h, when the formulation was mixed with milk, applesauce UK and plain yoghurt.
For Salofalk® granules, increasing the time between mixing the formulation with milk and testing resulted in a significantly higher AUC0–4h and 3-fold increase on percentage of drug dissolved (4 h), observed from the beginning of dissolution (pH 1.2). The Salofalk® granules have a pH-dependent modified release coating (due to the presence of the coating polymers Eudragit L and NE 40 D which only disintegrate at pH ≥ 6), and therefore no release is intended during the gastric passage. A 4-h delay between mixing the granules with milk (pH 6.8) and testing resulted in a pH-induced loss of integrity of the coating and, consequently, earlier drug release and dissolution. In contrast, the 4-h delay between mixing the Salofalk® granules with the other vehicles (pH between 2 and 4.5 (11)) and testing did not alter drug dissolution in the first hour of the test (pH 1.2) due to the polymer coating. AUC0–4h was significantly higher when delaying testing after mixing the formulation with plain yoghurt (pH 4.5) (p < 0.05). This testing scenario was also associated with large variation in dissolution between replicate tests, probably due to the loss of integrity of the formulation during the mixing which resulted in an unimpaired release.
Overall, results indicate that when medicines are co-administered with vehicles, the mixtures should be administered as soon as possible after preparation (unless specific data is available). Immediate administration reduces to the potential risk of dosing errors, exposure to light, hydrolysis, oxygen and microbiological contamination, but also minimises other vehicle-effects on drug dissolution (e.g. increased drug solubilisation, potential stability issues). Depending on the formulation, and particularly for enteric-coated dosage forms (case study, Salofalk®), delaying administration of the prepared formulation-vehicle mixture could result in changes in drug dissolution behaviour which might alter drug absorption and, consequently, drug safety and efficacy. Other potential consequences of delaying the administration of the drug-vehicle mixture are an increase of the risk of adverse side effects, depending on the drug category (e.g. for nonsteroidal anti-inflammatory drugs, it might lead to irritation of the GI mucosa and, ultimately, ulcers) (13).