Preparation and pharmaceutical evaluation of liposomes entrapping salicylic acid/γ-cyclodextrin conjugate

Abstract

To evaluate the potential use of a drug/cyclodextrin (CyD) conjugate for efficient entrapment in liposomes and prolonged residence of a drug in tissues, we synthesized a salicylic acid (SA) conjugate bound covalently with γ-cyclodextrin (SA/γ-CyD conjugate), a model drug/CyD conjugate, and then liposomes entrapping the conjugate (conjugate-in-liposome) were prepared by a freezing-thawing method. The chemical and physicochemical properties of the SA/γ-CyD conjugate in solution and solid state were investigated and then the physicochemical properties of conjugate-in-liposome, in vitro cellular uptake/release and in vivo disposition of SA/γ-CyD conjugate after intravenous administration of aqueous suspension containing conjugate-in- liposome in rats, were evaluated, comparing with those of the liposome-entrapped SA alone (SA-in-liposome) or the liposome-entrapped noncovalent SA/γ-CyD complex (complex-in-liposome). As a result, it was found that the conjugate was amorphous powder and the release of SA from the conjugate in phosphate-buffered saline (PBS) was tolerated to chemical and enzymatic degradation. Meanwhile, the particle sizes and stability of these liposomes were almost identical, and the entrapment ratio of SA/γ-CyD conjugate in liposomes was higher than those of SA alone and SA/γ-CyD complex. The cellular uptake of these liposomes was almost equivalent, but the release of SA/γ-CyD conjugate from RAW264.7 cells was markedly slower, compared with that of SA from cells following cellular uptake of the SA-in-liposome and complex-in-liposome. The disposition of SA or SA/γ-CyD conjugate following intravenous administration of aqueous suspensions containing each liposome system in rats was comparable, but the residence time of the conjugate in tissues significantly prolonged, compared with that of the SA-in-liposome and complex-in-liposome systems. These results suggest the potential use of SA/γ-CyD conjugate for efficient entrapment in liposomes as well as of liposomes containing SA/γ-CyD conjugates for prolonged residence of drugs in tissues. © 2006 Pharmaceutical Society of Japan.