title: In vitro evaluation of liposomes containing bio-enhancers for the oral delivery of macromolecules.
abstract: The aim of this work was to develop a new type of liposomes containing bio-enhancers for oral delivery of hydrophilic macromolecules. The study focused on EPC/cholesterol-based formulations combined with TPGS 1000 and 400, cholylsarcosine (CS), cetylpyridinium chloride (CpCl) and stearylamine (SA) covering a broad range of different types of enhancers. Most of the tested liposomal formulations and enhancers showed neither influence on cell viability in the Alamar Blue® assay nor an increase in lactate dehydrogenase LDH release. But, at a concentration of 1 mM, CpCl exhibited a strong toxicity after 2 h, TPGS 1000 reduced the cell viability at the same concentration after 8h significantly. Only one liposomal formulation with 25% CpCl led to a decrease in viability to 60.0% after 8h at a total lipid concentration of 5 mM. In the Caco-2 Transwell® model, one formulation with 5% TPGS 400 improved the permeation of FITC-dextran 70 kDa 3.34 ± 0.62-fold, one with 10% CpCl 3.69 ± 0.67 and one with 10% CS and 2.5% SA 3.41 ± 0.51-fold without influencing the TER. Liposomes with 10% SA or 25% CpCl increased the permeation of FITC-dextran 29.02 ± 5.84, respectively 39.28 ± 2.10-fold, but led also to a strong reduction in the TER. Especially, the three formulations which enhanced the permeation of FITC-dextran around 3.5-fold without showing any cell toxicity or decrease in TER should be safe and effective candidates for the development of an oral delivery system for hydrophilic macromolecules.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Heidelberg, Heidelberg, Germany. parmentier@uni-hd.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Parmentier
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Hartmann
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000032:analysis / Q000378:metabolism*; D018938:Caco-2 Cells; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D002793:Cholic Acids / Q000032:analysis / Q000378:metabolism*; D003911:Dextrans / Q000032:analysis / Q000378:metabolism*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D046911:Macromolecular Substances / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000032:analysis / Q000138:chemical synthesis / Q000378:metabolism; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000378:metabolism
chemical_list: D000588:Amines; D002793:Cholic Acids; D003911:Dextrans; D004337:Drug Carriers; D008081:Liposomes; D046911:Macromolecular Substances; D010713:Phosphatidylcholines; C015219:fluorescein isothiocyanate dextran; D014810:Vitamin E; D011092:Polyethylene Glycols; D002784:Cholesterol; C009317:stearylamine; D016650:Fluorescein-5-isothiocyanate; C061997:cholylsarcosine; C014225:tocophersolan; D012521:Sarcosine