Formulation of targeted liposomes for the oral delivery of poorly-absorbed drugs.

摘要

The application of liposomes in the oral delivery of poorly-absorbed, watersoluble drugs has had limited success to date. Issues of stability and specific uptake by the gastro-intestinal tract require attention. Hence, a multi-faceted study was initiated to address in vitro requirements of formulation design and in vivo performance in a rat model.; A strategy of liposome surface coating by a polymer-modified nutritional factor was pursued. Some physicochemical aspects of phospholipid monolayer behavior were examined at the chlorobenzene/water interface and quantitative changes in monolayer characteristics led to the development of a polymer impact ratio, from which the degree of change in monolayer integrity could be predicted.; The targeting strategy employed hydrophobically-derivatized folic acid (folic acid-poly(ethylene oxide) (PEO)-cholesterol) adsorbed at liposome surfaces, designed to improve the intestinal uptake of liposomes through folic acid-receptor-mediated endocytosis. The derivatized folic acid retained specificity for binding receptors, improved the transport of PEO 3350 MW across Caco-2 cells 8-fold compared to underivitized PEO-bis(amine), and, when employed as a liposome surface-modifier, improved the transport of liposome-entrapped Texas Red dextran 3000 MW across Caco-2 cells 5-fold.; DSPC:CH:DCP:FA-PEO-CH (3:1:0.25:0.05 mole ratio (m.r.)) was identified as an optimized liposome system for the oral delivery of a model glycopeptide vancomycin. Liposomes were prepared as dehydration-rehydration vesicles at an average size of 200 nm resulting in an encapsulation efficiency for vancomycin of 25 percent, of which 65 percent remained entrapped after exposure to simulated intestinal fluids containing 10 mM bile salts solution for 2 h at 37°C. In contrast to Texas Red dextran, vancomycin was not transported across Caco-2 cells to any appreciable extent when loaded in targeted liposomes, although 14 percent of the dose was indirectly determined to be delivered intracellularly.; In vivo, a 3.9- and 12.5-fold increase in bioavailability of vancomycin was found using non-targeted liposomes (6.7 percent bioavailable) and targeted liposomes (21.8 percent bioavailable), respectively when compared to a vancomycin solution (1.74 percent bioavailable). The potential for development of an oral peptide delivery system based on folic acid-targeted liposomes was realized.