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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.

The preparation of biodegradable hydrogel microspheres in the absence of surfactants was carried out by a two-step procedure which involved the formation of non-crosslinked microspheres from gelatin based on its inherent gelation nature at low temperatures and the subsequent glutaraldehyde (GA) crosslinking. The size of the microspheres was controlled in the range of 3 to 100 μm by changing the concentration of gelatin or GA, the emulsification method, and the crosslinking time. Neutral aqueous solutions of proteins with different isoelectric points (IEPs) and molecular weights (Mws) were infused into freeze-dried hydrogel microspheres to produce protein-incorporated gelatin microspheres. In vitro protein release from the microspheres depended on the protein's IEP but not on the Mw. The incorporated basic proteins with IEPs > 7.0 were released initially from the acidic gelatin microspheres, followed by no substantial release, whereas a larger initial release of the incorporated acidic proteins with IEPs < 7.0 was observed. The basic gelatin microspheres exhibited an opposite relationship between proteins IEP and protein release. Noncharged dextran rapidly diffused out of acidic gelatin microspheres, irrespective of the Mw. These findings indicate that an ionic interaction with gelatin constituted hydrogel microspheres prevented oppositely charged protein from being released from gelatin under in vitro non-degradation conditions.