Investigation of liposomes for oral delivery of peptidomimetic drugs

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Date
2004-02
Authors
Sheue Nee, Ling (Sharon)
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Abstract
The potential of liposome formulations as a novel drug delivery system for oral administration of peptidomimetic drugs was investigated using cefotaxime as the model hydrophilic drug. A high performance liquid chromatographic method with ultraviolet detection was successfully developed for the determination of plasma concentration of cefotaxime. The method was simple, sensitive, reproducible and requires only a small sample volume, lending it suitable for use in subsequent bioavailability studies. In vitro studies showed that liposomes prepared from various pro-liposomes were in " nanometer size range with narrow size distribution. Liposomes prepared from Pro-lipo duo® were smallest in size and were most stable compared to other pro-liposomes. Moreover, satisfactory entrapment of cefotaxime was achieved with Pro-lipo duo® and hence, were selected for further in vivo evaluation. Dielectric spectroscopy afso showed that the entrapped drug reached equilibrium faster and therefore suitable to be prepared extemporaneously. In vivo comparative bioavailability study was conducted in rats to evaluate the oral bioavailability of cefotaxime administered as an aqueous solution, cefotaxime-loaded liposomes and physical mixture of cefotaxime solution with blank liposomes. The extent of bioavailability of liposomally-entrapped cefotaxime was increased appioximately-2.Taricf2J times-cornpa.rea- to -tnat--ortne-a.queous~soiutfon- a.ncrlne physical mixture, respectively. However, no significant difference was observed between the bioavailability of the aqueous drug solution and the physical mixture. Hence, the oral bioavailability of cefotaxime was attributed to the drug being entrapped in the liposomes. The possible contribution of liposomes in enhancing lymphatic transport of cefotaxime was evaluated using an anaesthetised rat model. The concentration of cefotaxime in lymph and plasma were determined following intragastric infusion of either cefotaxime aqueous solution or cefotaxime-loaded liposomes. The ratios of lymph/plasma cefotaxime concentrations for cefO'tttxime-loaded liposomes were consistently higher than those obtained with cefotaxime aqueous solution, suggesting that the liposomes could promote the lymphatic transport of the hydrophilic drug after absorption from the gastrointestinal lumen. The role of receptor-mediated endocytosis in further enhancing the oral bioavailability of cefotaxime-loaded liposomes was investigated by physically incorporating folic acid as the ligand. In vivo evaluation using rats showed that both the AUCo-oo and Cmax of cefotaxime obtained with folic acid-coupled liposomes was approximately 2 times higher as compared to the folic acid-free liposomes. Therefore, the drug-loaded liposomes appeared to be amenable to receptor-mediated endocytosis for further enhancement of their uptake and hence further enhancing the oral bioavailability of entrapped cefotaxime. Folic acid which was physically coupled to the liposomes without any chemical conjugation or bonding was found to be a suitable ligand for inducing the uptake of the liposomes via receptor-mediated endocytosis.
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Delivery of peptidomimetic drugs
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