Aqueous solubility of kinase inhibitors: I the effect of hydrophilic polymers on their γ-cyclodextrin solubilization

Abstract

Most small-molecule protein kinase inhibitors (KIs) are neutral or weakly basic lipophilic compounds with very poor solubility in aqueous media that decreases their ability to permeate biological membranes from an aqueous exterior and consequently bestow them with low bioavailability after oral and topical administration. Cyclodextrin (CD) complexation can increase water-solubility of poorly soluble drugs without affecting their ability to permeate biological membranes. The aim of the present study was to enhance aqueous solubility of six KIs that is axitinib, cediranib, dovitinib, motesanib, pazopanib and regorafenib, through formation of drug/γ-cyclodextrin (γCD)/polymer ternary complexes. The complexes were prepared in an aqueous environment by heating technique. The phase-solubility profiles showed formation of binary KI/γCD complexes of Bs-type. γCD alone had significant solubilizing effect on dovitinib (stability constant (K1:1) = 684 M−1 and complexation efficacy (CE) = 0.011). The aqueous solubility of the binary KI/γCD complexes was pH-dependent. Hexadimethrine bromide (HDMBr) was the most effective polymer of the ones tested. The ternary complexes formed nano-sized aggregates with diameter between 200 and 400 nm. Osmolarity and pH were also monitored. TEM study showed formation of complex aggregates in aqueous media.