Mathias Dam Mønster Sørensen

In the treatment of e.g. infectious diseases, administration of multiple drugs over extended periods is common. Long-acting injectables are used to improve patient compliance. However, formulating a single suspension containing multiple drug compounds may further improve patient compliance. This study therefore investigates the physical stability of two compounds in co-suspension focusing on stabiliser selection, stabiliser concentration, and their influence on milling efficiency and stability in both single-drug suspensions and co-suspensions prepared by wet bead milling investigating three model compounds as the dispersed phase. In total, nine stabilisers were screened in combination with itraconazole and carbamazepine in individual systems and in co-suspension of which three were selected for further evaluation with cinnarizine and itraconazole in combination, and for stabiliser concentration screening of itraconazole and carbamazepine. Physical stability was assessed by laser diffraction over 28 days of storage at 40 °C. Poloxamer 338 effectively reduced particle size while maintaining good stability in itraconazole and in co-suspensions, whereas PVP K30 was most effective for carbamazepine despite challenges with foaming. The milling behaviour of co-suspensions containing itraconazole and carbamazepine more closely resembled that of itraconazole single-drug formulations, whereas no clear stabilisation trend was observed for cinnarizine in combination with itraconazole. The stability of co-suspensions did not directly reflect that of either individual system. The optimal concentration for particle size reduction did not consistently correspond to the optimal concentration for stability, where slightly higher concentrations provided optimal stability. Increased stabiliser concentrations negatively impacted milling efficiency in carbamazepine suspensions, whereas the opposite tendency was observed for itraconazole in some systems and similarly in co-suspensions. Interestingly, co-suspensions stabilised with 0.50% (w/v) polysorbate 80 and several concentrations of poloxamer 338 produced smaller particles than the corresponding single-drug suspensions suggesting a synergistic effect when in combination.