Fixed-dose combination of poorly water-soluble drugs, indomethacin and carbamazepine, formulated as a multi-composed amorphous solid dispersion: a potential therapy for HC-tic (part 1).

Hemicrania continua-trigeminal neuralgia is a rare, but severe pain syndrome treated with a combination of indomethacin and carbamazepine. Combination therapy is often associated with high pill burden, which reduces patient compliance and compromises therapeutic outcomes. Fixed-dose combinations, which combine multiple drugs into a single formulation, address the issue of high pill burden by reducing the number of pills patients need to take, thereby improving patient compliance. However, both drugs exhibit poor aqueous solubility, which limits their oral bioavailability. To overcome this limitation, various formulation strategies have been developed, including amorphous solid dispersions (ASDs). This study aimed to address both challenges by developing multi-composed ASDs (MC-ASDs) containing indomethacin and carbamazepine dispersed within a single polymer matrix (PVPVA, PVP, or HPMC).The MC-ASDs as well as the corresponding binary ASDs were prepared by spray drying and characterized using modulated differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro dissolution behaviour was evaluated using a USP II apparatus with a pH-shift method simulating gastrointestinal conditions, while physical stability was assessed for one month under stress conditions. MC-ASDs containing PVPVA and HPMC outperformed the crystalline counterparts and, for carbamazepine, even the binary ASDs. Furthermore, the MC-ASDs exhibited good physical stability. Overall, multi-composed ASDs represent a promising approach for the development of fixed-dose combinations of poorly water-soluble drugs.