title: Formulation and evaluation of a folic acid receptor-targeted oral vancomycin liposomal dosage form.
abstract: OBJECTIVE
  To demonstrate utility of folic acid-coated liposomes for 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 rat 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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: K E
authors.initials: KE
authors.lastname: Anderson
authors.forename: L A
authors.initials: LA
authors.lastname: Eliot
authors.forename: B R
authors.initials: BR
authors.lastname: Stevenson
authors.forename: J A
authors.initials: JA
authors.lastname: Rogers
mesh_terms: D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002352:Carrier Proteins / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D008081:Liposomes; D008297:Male; D011092:Polyethylene Glycols; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D013056:Spectrophotometry, Ultraviolet; D014640:Vancomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D005079:Excipients; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D011956:Receptors, Cell Surface; D011092:Polyethylene Glycols; D014640:Vancomycin; D005492:Folic Acid