Formulation and evaluation of a folic acid receptor-targeted oral vancomycin liposomal dosage form

Purpose. To demonstrate utility of folic acid-coated liposomes far enhancing the delivery of a poorly absorbed glycopeptide, vancomycin, via the oral route. Methods. Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitro in the Caco-2 cell model and in vivo in male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces. Results. Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution. Conclusions. The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the sat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.