Liposomal glucocorticoids: pharmaceutical, preclinical and clinical aspects

Abstract

Liposomes have proven to be well tolerated drug delivery vehicles that offer the possibility of drug delivery for a wide range of therapeutic agents, for instance for the treatment of rheumatoid arthritis. Optimal liposomal physicochemical properties depend on the administration route: large-sized liposomes show good retention upon local injection, while small-sized liposomes are better suited to achieve passive targeting upon intravenous infusion. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time (so-called ‘long-circulating liposomes’), resulting in increased localization at the inflamed sites. The phenomenon of ‘passive targeting’ to pathological sites can be attributed to locally enhanced permeability of the vascular endothelium, allowing long-circulating small-sized PEG-liposomes to extravasate and accumulate in the extravascular tissue, known as the ‘enhanced permeability and retention’ (EPR) effect. Additionally, targeting ligands can be attached to the liposomal surfaces to achieve selective delivery of the encapsulated drug to specific target cells, referred to as ‘active targeting’.

Glucocorticoids have proven to be powerful drugs in the treatment of rheumatic diseases.However, the use of glucocorticoids is hampered by unfavorable pharmacokinetic behavior, which necessitates high and frequent dosing to maintain therapeutic levels at sites of inflammation, thereby increasing the risk for severe adverse effects. To improve their therapeutic index, glucocorticoids can be encapsulated in long-circulating liposomes. The work presented in this thesis aims to show that these liposomal glucocorticoids can effectively and safely be used as intravenous targeted drug delivery vehicles for the treatment of rheumatoid arthritis. Selective delivery of a drug to the inflamed joints improved the efficacy, while the systemic exposure of the drug was reduced. As a result of the long-circulating and targeting properties of PEGylated liposomes, the dose level and dosing frequency can likely be reduced dramatically.

Optimization of the liposomal glucocorticoid formulation was performed at the level of the encapsulated drug to start with, by selecting glucocorticoids with a high clearance rate to minimize the occurrence of side effects. Second, an attempt was made to reduce the occurrence of hypersensitivity reactions upon infusion of PEGylated liposomes, by changing the PEG profile at the liposomal surface. All formulations tested caused mild activation of the complement system in vitro. One particular formulation, however, wherein the PEG is anchored to cholesterol, turned out to be an extremely strong activator of the complement cascade. Further study of this phenomenon might be useful to elucidate the mechanism behind complement activation by liposomal formulations in general. Lastly, the stability of the liposomal formulation was improved by spray-drying or freeze-drying the formulation, using hydroxypropyl-β-cyclodextrin to stabilize the liposomal membranes during the drying process.

The in vivo performance of a liposomal formulation is critically dependent on its physicochemical characteristics. Typically, small changes in one of these characteristics can have a huge impact on the in vivo behavior of the administered liposomes. Therefore, the characterization of the liposomal formulation is of major importance. The work presented in this thesis shows that the characterization procedures and regulation of liposomal drug products leave some room for improvement.