One of the solubilization of poorly water-soluble drugs is the use of cyclodextrin (CD)-based inclusion complexes. On the other hand, few studies have investigated how CD functions on the solubility of drugs in the presence of multiple drugs that interact with each other. In this study, we used indomethacin (IND) and diclofenac (DIC) as acidic drugs, famotidine (FAM) and cimetidine (CIM) as basic drugs, and imidazole (IMZ), histidine (HIS), and arginine (ARG) as compounds structurally similar to basic drugs. We attempted to clarify the effect of β-CD on the solubility change of each drug in the presence of multiple drugs. IND and DIC formed a eutectic mixture in the presence of CIM, IMZ, and ARG, which greatly increased the intrinsic solubility of the drugs as well as their affinity for β-CD. Furthermore, the addition of high concentrations of β-CD to the DIC-FAM combination, which causes a decrease in solubility due to the interaction, improved the solubility of FAM, which was decreased in the presence of DIC. These results indicate that β-CD synergistically improves the solubility of drugs in drug-drug combinations, where the solubility is improved, whereas it effectively improves the dissolution rate of drugs in situations where the solubility is reduced by drug-drug interactions, such as FAM-DIC. This indicates that β-CD can be used to improve the physicochemical properties of drugs, even when they are administered in combination with drugs that interact with each other.
Keywords: NSAIDs; complexation efficiency; cyclodextrin; phase solubility diagram; polypharmacy.