Influence of environmental tonicity changes on lipophilic drug release from liposomes

Abstract

Introduction: Liposomes as drug delivery systems has been widely studied as a way to solubilize poorly soluble drugs, reduce side effects of chemotherapeutics and increase circulation time in vivo. Since the first descriptions of liposomes over 60 years ago, they have shown tendencies to shrink and swell when the external environment of the liposomes is altered. This phenomenon has been studied in recent years and it is now known that liposomes’ shape is affected by osmotic pressure. Aim: The aim of this thesis was to clarify if changing the tonicity (i.e. concentration of solutes) outside of large unilamellar vesicles (LUVs) would affect the release of lipophilic drugs from them. Methods: LUVs were made by evaporating the solvent from a solution consisting of lipid, drug and solvents in phosphate buffered saline (PBS), and subsequently extruded to the desired sizes. The LUVs were characterized in terms of average diameter, size distribution, surface charge and percentage of drug entrapped inside the LUVs. To understand how tonicity affects the size of vesicles, the external environment of the LUVs was changed, and the size distributions of the LUVs were measured over time. The permeation properties of hydrocortisone and methylprednisolone were studied using Franz cells setup at different osmotic pressures using cellulose hydrate membranes or Permeapad® biomimetic barrier for both drug suspensions and drug-liposomal dispersions. Results and conclusion: We demonstrated that the LUVs shrank and swelled when the tonicity of the external environment was altered. We also demonstrated that the permeability of drugs (incorporated into LUVs) through cellulose hydrate membranes were highly affected by changes in tonicity. A significantly lower permeability for both hydrocortisone and methylprednisolone from the liposomal formulation in hypertonic external environment was measured, whereas no significant changes were found for the hypotonic external environment. The permeability studies on hydrocortisone incorporated LUVs employing the, Permeapad® showed a significantly higher permeability when changing the tonicity to hypotonic environment.