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The efficacy of many drugs is improved by liposomal formulations. The greatest improvements in therapeutic benefits are achieved if the drug is retained in the liposomes for several hours after administration. Many basic drugs can be concentrated efficiently into liposomes in response to a transmembrane pH gradient. However, the rate of release from liposomal formulations is drug-dependent; for example, doxorubicin is released slowly from liposomes whereas vincristine leaks out rapidly. The aim of this study was to identify the causes of the rapid release of drugs from liposomes and then to apply this knowledge to the development of more stable formulations. Our initial focus was to explore the influence of liposomal size on the rate of release of drugs. The retention of doxorubicin within liposomes was independent of the particle size as far as this experimental condition was concerned. However, the rate of release of vincristine varied in relation to the particle size of the liposomes; vincristine was retained more effectively in larger liposomes. Experimental data generated using (31)P-NMR analysis and trap volume measurements, indicated that the number of lipid bilayers in liposomes increased as the particle size was increased. Additional lipid bilayers are likely to present a more effective barrier thereby slowing the release of drugs.

A liposomal formulation of UCN-01 was studied to prevent binding of drug to human alpha1-acid glycoprotein (hAGP). The release of drug from liposomes added to various media was investigated by monitoring the concentration of UCN-01 in different fractions. Protein bound UCN-01 was separated from liposomal UCN-01 and free UCN-01 by gel chromatography and the drug content in the fractions was measured by high-performance liquid chromatography. Also, the blood levels of hAGP bound drug and drug retained in liposomes were assessed after intravenous administration to rats of UCN-01 liposomes together with hAGP. In media containing hAGP, but not rat AGP, UCN-01 was released from liposomes. When UCN-01 liposomes were mixed with rat plasma plus hAGP, the UCN-01 in the liposomes was only gradually released so that some drug remained in the liposomes, and therefore not bound to hAGP, for up to 24 h. After the mixture of liposomal UCN-01 and hAGP was injected into rats, some UCN-01 was retained in liposomes for several hours. Encapsulation of UCN-01 into liposomes is an effective method of preventing binding of UCN-01 to hAGP.