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The influence of particle size and surface mannose modification on the uptake of liposomes by alveolar macrophages (AMs) was investigated in-vitro and in-vivo. Non-modified liposomes of five different particle sizes (100, 200, 400, 1000 and 2000 nm) and mannosylated liposomes with 4-aminophenyl-alpha-D-mannopyranoside (particle size 1000 nm) were prepared, and the uptake characteristics by rat AMs in-vitro and in-vivo were examined. The uptake of non-modified liposomes by rat AMs in-vitro increased with an increase in particle size over the range of 100-1000 nm, and became constant at over 1000 nm. The uptake of non-modified liposomes by AMs after pulmonary administration to rats in-vivo increased with an increase in particle size in the range 100-2000 nm. The uptake of mannosylated liposomes (particle size 1000 nm) by rat AMs both in-vitro and in-vivo was significantly greater than that of non-modified liposomes (particle size 1000 nm). The results indicate that the uptake of liposomes by rat AMs is dependent on particle size and is increased by surface mannose modification.

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We prepared two kinds of surface-coated liposomes and investigated their potencies as oral dosage forms for peptide drugs by focusing on their effects on the gastrointestinal (GI) transit of drugs. The surface of the liposomes was coated with poly(ethylene glycol) 2000 (PEG-Lip) or the sugar chain of mucin (Mucin-Lip). As a model peptide drug, insulin was encapsulated in these liposomes. Coating the surface with poly(ethylene glycol) was found to reduce the transit rate of liposomes in the small intestine after oral administration to rats in vivo. Mucin-Lip was retained in the stomach longer than PEG-Lip or uncoated liposomes. The effect of surface coating on the intestinal transit of liposomes was determined by means of in situ single pass perfusion in the rat small intestine. Statistical moment analysis was applied to the outflow pattern of both liposomes and encapsulated insulin. The mean transit time (MTT) and deviation of transit time (DTT) in the intestinal tract were calculated. The MTT of PEG-Lip was much longer than those of uncoated liposomes and Mucin-Lip and was significantly shortened after removal of the intestinal mucous layer. These results indicated that PEG-Lip interacts strongly with the intestinal mucous layer, leading to its slow transit in the intestine. In contrast, coating the liposome's surface with mucin did not affect either the MTT or DTT of liposomes in the intestine. This result is in accordance with the in vivo observation that Mucin-Lip was highly retained in the stomach, but not in any region of the small intestine in vivo. Both the MTT and DTT values of insulin encapsulated in PEG-Lip and Mucin-Lip were almost the same as those of liposomes themselves, suggesting that surface-coated liposomes retained insulin in the intestinal tract. However, MTT and DTT of insulin were significantly shorter than those of uncoated liposomes because these liposomes degraded and released significant amounts of insulin during single pass perfusion. The ability of surface-coated liposomes, especially of PEG-Lip, to interact with the mucus layer and slow the transit rate in the GI tract is considered desirable for oral delivery of peptide drugs. Modification of the liposomal surface with appropriate materials, therefore, should be an effective method by which to achieve the oral delivery of peptide drugs.