Development and physico-chemical characterization of a liposomal formulation of istaroxime

Istaroxime, an investigational new drug that targets defective Ca(2+) cycling without compromising cardiac efficiency, may represent a promising and safe treatment of both acute and chronic heart failure. Even though the compound demonstrated good tolerability in a phase I/II safety study, symptoms related to the gastro-intestinal tract and pain at the injection site were reported as the most frequent side effects. The aim of this study was to encapsulate istaroxime in a drug delivery system (DDS) that could minimize the pain perceived upon administration. The DDS was designed to be quickly destabilized in plasma, in order to minimize alteration of the pharmacokinetic profile of istaroxime. To meet those requirements, a balance between the encapsulation efficiency and the release rate was sought. Transmembrane pH-gradient liposomes formulated with different phosphatidylcholines were investigated as vehicles for an efficient active drug loading. Poly(ethylene glycol)-660-hydroxystearate (PEG-HS) was chosen as excipient to modulate the bilayer fluidity and the release properties of the liposomes. A fast and efficient encapsulation was obtained by modulating the drug-to-lipid ratio, the amount of PEG-HS, and the incubation temperature. High encapsulation efficiency was achieved by incubating the drug with liposomal dispersions at room temperature for 10 min. Almost complete release was obtained in physiological conditions in less than 10 min, suggesting a model formulation potentially useful for drugs presenting similar features and side effects.