Investigation of liposomes for oral delivery of peptidomimetic drugs
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Date
2004-02
Authors
Sheue Nee, Ling (Sharon)
Journal Title
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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.
Description
Keywords
Delivery of peptidomimetic drugs