EFFECTS OF A NEW LIPID-BASED DRUG-DELIVERY SYSTEM ON THE ABSORPTION OF LOW-MOLECULAR-WEIGHT HEPARIN (FRAGMIN) THROUGH MONOLAYERS OF HUMAN INTESTINAL EPITHELIAL CACO-2 CELLS AND AFTER RECTAL ADMINISTRATION TO RABBITS

The effects of a novel drug delivery system, consisting of a lipid matrix and a drug, on the permeability, morphology and drug transport across monolayers of human intestinal epithelial cells were investigated. A 1:3 mixture (w/w) of chromatographically purified soybean phosphatidylcholine and medium chain monoacylglycerol was chosen as lipid matrix (PC:MG) and mannitol (mel. wt. 182) and Fragmin (low molecular weight heparin; mean mel. wt. 5000) were chosen as hydrophilic model drugs. PC:MG had an immediate and dose-dependent effect on the permeability of the cell monolayers, and on epithelial morphology (as seen under transmission electron microscopy). PC:MG (4-10 mM) dose-dependently enhanced the transport rate of mannitol and Fragmin, causing an approximately 10-fold increase in the transport rate of Fragmin at concentrations of 6-8 mM. The increase was independent of the dose of Fragmin and was reversible in concentrations up to 6 mM. At higher doses, clear effects on the apical cell membranes were observed although the tight junctions remained intact. PC:MG also enhanced Fragmin absorption in vivo after rectal administration to New Zealand White rabbits. Co-administration of Fragmin with PC:MG (7 mM) resulted in an increase in the relative bioavailability (compared with s.c. administration) from < 1% (without PC:MG) to 21 +/- 12%. A maximal increase in relative bioavailability to 90 +/- 19% was obtained at a PC:MG concentration of 35 mM. Thus, PC:MG functions as an absorption enhancer both in the cell monolayer model and in vivo, in the same concentration range. The results indicate that as well as providing mechanistic information, studies of absorption enhancers in Caco-2 monolayers also provide information on suitable dosage regimens for in vivo studies.