Liposomes as a Potential Oral Drug Delivery System.

Attempts to use liposomes as an oral dosage form have been a major focus in drug delivery research since it has been suggested that liposomes may either protect their entrapped drugs from digestive degradation or increase the absorption of poorly absorbed drugs from the gastrointestinal tract. Despite twenty years of research in this area, their general utility as drug delivery systems is still open to question. Not only is the effect on absorption of liposomally entrapped drug not clear, there is no consensus as to either the stability of liposomes in the gastrointestinal tract or the mechanism by which liposomal incorporation may increase drug absorption after oral administration. The studies presented in this thesis were conducted to determine the feasibility of using liposomes as an oral drug delivery system and to evaluate the effects of liposomal entrapment on the gastrointestinal uptake of drugs. Specifically, we have studied the stability of liposomes in the environment of the gastrointestinal tract and the intestinal uptake of liposomes and their entrapped markers. The results of these studies can be summarized as follows: (1) In vitro stability studies show that even for liposomes that are considered to be stable to the environment of the gastrointestinal tract, significant leakage of marker is apparent when the liposomes are challenged with conditions they are likely to encounter in the gastrointestinal tract. The cumulative effects of low pH, and the presence of physiological concentrations of bile salts and phospholipid lipase resulted in 50% leakage of glucose in two hours. (2) Neither liposomes, their lipid constituents nor their entrapped markers are transported across intestinal membranes as determined by both in vitro diffusion cell and everted sac experiments. Liposomal entrapment not only fails to facilitate the uptake of non-absorbable drugs but also prevents the transport of normally absorbable ones. (3) Previously reported "apparent" uptake of multilamellar liposomes and their entrapped markers from intestinal segments using the modified Doluisio system is due to flocculation and /or aggregation of the liposomes. Neither the liposomes nor their entrapped markers are actually absorbed and both can be recovered when the gastrointestinal tract is exhaustively washed. (4) Liposomal entrapment does not facilitate the in vivo absorption of non-absorbable drug (PEG-4000) and does not affect the excretion patterns of absorbable drugs (hydrocortisone and salicylic acid). These results are in agreement with the in vitro uptake studies and indicate that liposomes do not protect the drugs from the environment of the gastrointestinal tract. Based on these results, we conclude that liposomes do not influence the intestinal absorption of entrapped drugs, and , moreover, they do not even protect entrapped drugs from the environment of the gastrointestinal tract. Therefore, we conclude that liposomes are not a viable drug delivery system for oral administration. The increased oral bioavailability of liposomally incorporated drugs occasionally reported in the literature may be due to factors other than liposomal uptake.Ph.D.Pharmaceutical sciencesUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161076/1/8621261.pd