Relevancy of Drug Loading to Liposomal Formulation Therapeutic Efficacy

Liposomes were first described nearly 40 years ago and have been useful models for studying the physical chemistry of lipid bilayers and the biology of the cell membrane (rev. in 1–3). More than 30 years ago it was also realized that liposomes might be used as vehicles for the delivery of drugs and other active agents as well as in the field of gene transfer (rev. in 2–4). The achievements of liposomology after major efforts in both academia and in industry, resulting in the development of ten approved parenteral products, are described in Table 1, while Table 2 lists current major deficiencies in the way of new advances. This short paper focuses on two of these deficiencies: the ability (i) to achieve a high level of loading of an active agent in the liposome and to make this loading stable during handling and storage, irrespective of the nature of the agent and (ii) to fit the release rate of the loaded active agent to specific therapeutic aims of the liposome formulation. Different rules apply for drugs which are expected to act mainly near the site of injection (i.e. local anesthetics) and those that should affect sites which cannot be approached by local administration (i.e. systemic or metastatic diseases). For the latter, intravenous (i.v.) administration is most commonly used, and therefore the loading is even more of a challenge since in order to extravasate into the disease site the liposomes should be smaller than 120 nm. However, the very small intraliposome aqueous volume of such small liposomes requires very efficient