BACKGROUND: Liposomes are promising systems for the delivery of macromolecules and poorly absorbed drugs, owing to their ability to compartmentalize drugs, their biodegradability and biocompatibility. OBJECTIVE: The aim of the present study was to formulate and evaluate conventional and modified glucosamine sulphate (GluS) and chondroitin sulphate (CS) liposomal formulations, to enhance their oral permeation for the treatment of osteoarthritis (OA). METHOD: Liposomal formulations were prepared by the thin-film hydration method using two types of phospholipids; Epikuron 200© and Epikuron 200© SH, and three permeation enhancers; poloxamer 407, cetylpyridinium chloride, and sodium deoxycholate. In-vitro characterization of liposomal formulations was conducted in terms of entrapment efficiency, particle size, zeta potential, viscosity, physical stability and mucoadhesive strength. Surface morphology and vesicle shape, ex-vivo intestinal permeation, and histopathological studies were further carried out on the selected formulation. RESULTS: Results showed that the liposomal formulation containing sodium deoxycholate was the most optimum formula, showing high entrapment efficiency (60.11% for GluS and 64.10% for CS) with a particle size of 4.40 µm, zeta potential of -17.2 mV and viscosity of 2.50 cP. CONCLUSION: The aforementioned formula displayed the highest cumulative % permeated of GluS and CS through rabbit intestinal mucosa compared to the solution of drugs and other liposomal formulations (64.20% for GluS and 78.21% for CS) after 2 hours. There were no histopathological alterations in the intestinal tissue, suggesting the safety of the utilized liposomal formulation. In light of the above, liposomes can be considered promising oral permeation-enhancer system for GluS and CS, which is worthy of future bioavailability experimentation.