Liposomal drug delivery : thermodynamic and chemical kinetic considerations

Abstract The thermodynamics of encapsulation and the kinetics of efflux were studied for a series of small molecular-weight drugs in multilamellar and unilamellar liposomes. Liposome concentration and drug partition coefficient are proposed to be the dominant factors in drug encapsulation. The theoretical basis for this conclusion is presented together with supportive experimental data for progesterone, vinblastine, pilocarpine, serotonin, leu-enkephalin and a model tripeptide. The kinetics and mechanism of drug efflux were evaluated according to Eyring's absolute rate theory. For all systems studied, the data supported a mechanism of two parallel, first-order processes for the efflux of the encapsulated and the unencapsulated drug, respectively. An inverse dependence, which is proposed to be an expression of deviations from ideality, was found between the rate constant for the efflux of the encapsulated drug and liposome concentration. At liposome concentrations of 100 to 150 (mM lipid), the rate constants for efflux of encapsulated progesterone, vinblastine, serotonin and pilocarpine from MLV are 6 × 10 −4 , 3 × 10 −3 , 1.3 × 10 −2 and 7 × 10 −2 (h −1 ), respectively. Under similar experimental conditions, the corresponding data for unilamellar liposomes are 7 × 10 −4 , 0.3 and 0.4 (h −1 ) for progesterone, serotonin and pilocarpine, respectively. The application of kinetic studies of this type for the optimization of shelf-life conditions of liposome/drug systems with respect to drug retention is presented and discussed.