Chemically conjugated novel liposomal formulation for intravenous delivery of cyclosporin A

The aim of the present study was to develop a novel liposomal formulation of cyclosporin A (CsA) based on chemical conjugation, of which the method allows avoiding the commonly used emulsifying agents that invariably cause local and systemic side effects. The CsA was modified and conjugated with dioleoylphos-phatidylethanolamine (DOPE) by using water-soluble 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) as the coupling agent. The CsA liposomes were synthesized with only the mixture of CsA-DOPE conjugate, additional DOPE and cholesterol (CHOL). At molar ratio of 10: 43.4: 46.6 (CsA-DOPE, DOPE and CHOL), the CsA liposomes showed good physical stability during storage at 4 degrees C for 3 weeks, maintaining a mean particle size around 230 nm, and also remained stable for up to 24 h at 37 degrees C in the presence of serum. When the influence of pH, types of salts and ionic strength of the buffer on the physicochemical properties of the CsA liposomes were evaluated, specifically, pH and salt type dependent variability were clearly observed for the sizes of CsA liposomes. In vitro analyses of the CsA-DOPE conjugates on model T cells confirmed retention of immunosuppressive activity equivalent to the unmodified CsA. Furthermore, from the in vivo pharmacokinetic studies with rats, compared with the clinically available Sandimmune Injection, CsA liposomes exhibited larger volume of distribution (12.72 +/- 3.23 Lkg(-1)) and increased plasma half-life (9.39 h). Overall, in this research, we demonstrated that the proposed CsA liposomes could be an appropriate alternative for the currently available CsA intravenous formulations. (C) 2016 Elsevier B.V. All rights reserved.