Challenge For Oral Delivery Of Middle-molecular Drugs: Use Of Osmolarity-sensitive Liposome As A Drug Carrier In The GI Tract

Abstract This study aims to develop a novel oral delivery system for middle-molecular drugs, such as bioactive peptides, using osmolarity-sensitive liposomes. Osmolarity-sensitive liposomes were prepared to include hypertonic sucrose solution (1.0 M) inside the liposomes (hypertonic liposomes) and were expected to release the encapsulated drug quickly depending on the osmotic difference between inside/outside the liposomes. As a first step, fluorescein isothiocyanate-dextran 4000 (FD-4), a non-degradable middle molecular compound, was used as a model drug. In vitro experiments were performed using dialysis film and Caco-2 cell monolayers to measure permeation rates of FD-4 from liposomes under various conditions. Liposomes composed of distearoylphosphatidylcholine (DSPC-Lip) showed a high stability in the intestinal fluid and released the encapsulated FD-4 depending on the osmotic difference. In contrast, liposomes composed of dipalmitoylphosphatidylcholine (DPPC-Lip) was unstable in the intestinal fluid to release FD-4 quickly regardless of the osmotic difference. Addition of cholesterol in DPPC improved the stability of liposomes whereas the encapsulated efficiency of FD-4 decreased. In vivo intestinal absorption of FD-4 from those liposomes well reflected in vitro observations. Hypertonic DSPC-Lip showed the highest absorption of FD-4 (about 20% dose/4 h s) which was more than 10-times higher than that from FD-4 solution. Observation of fluorescence intensity in the intestinal loop after incubation with FD-4 solution or DSPC-Lip demonstrated that liposomes can be retained in the intestinal tract for longer period. In conclusion, osmolarity-sensitive liposomes composed of DSPC lipid were proven to have a high potency to enhance the absorption of middle-molecular drugs having low membrane permeability.