Biomedical Engineering Reference
In-Depth Information
The main findings can be grouped according to the delivery strategy:
iii.
Modified biodistribution
. The first works in the 1980s, found that primaquine
loaded in neutral or anionic MLV (PC: PS: chol, 4:1:5 M ratio) was increasedly
accumulated in liver and spleen, while its concentration was decreased in other
organs (lungs, kidney, heart and brain), upon i.v. administration. However, the
decreased toxicity of primaquine was not followed by an increase of anti-malaria
activity. This was due to the preferential capture of high sized MLV by Kupffer
cells in the liver and spleen macrophages instead and not by infected hepato-
cytes (Smith et al.
1983
; Pirson et al.
1982
).
iii.
Increased half life upon i.v. administration.
The first work at the end of the
1990s showed that i.v. administered arteether loaded in MLV (DPPC: dibehe-
noylphosphatidylcholine: chol, 1:1:2 M ratio) increased its half life in circula-
tion and also upon oral administration the bioavailability was increased in
rabbits (Bayomi et al.
1998
). Further work employed nanocapsules, for instance
made of copolymer (PLA-PEG) polymeric wall nanocapsules and medium
chain triglycerides core, to load halofrantine. These nanocapsules showed sim-
milar or higher antimalarial activity than that of free drug, after a single dose to
mice severely infected with
P. berghei
(Mosqueira et al.
2004
). Halofantrine in
nanocapsules had also six folds higher plasma AUC than free drug (up to 70 h).
It also allowed a faster control of parasitemia in the absence of toxic effects up
to a maximal dose of 100 mg/kg, while toxicity of free halofrantine dissolved in
PEG-dimethylacetamide was shown at lower concentration. Halofantrine loaded
in poly-e-caprolactone showed better results than PLA-PEG nanocapsules at a
dose of 1 mg/kg in
P. berghei
infected mice and a significant reduction in halo-
fantrine cardiotoxicity, with a reduction of the QT interval prolongation of ECG
in rats (Leite et al.
2007
). On the other hand, quinine loaded in poly-e-caprolac-
tone and polysorbate 80 nanocapsules showed increased efficacy against
P. ber-
ghei
infected rats compared to the free drug. However, pharmacokinetic
parameters of quinine in nanocapsules were similar to those of free quinine.
It was observed that nanoencapsulation doubled the drug penetration into red
blood cells of
P. berghei-
infected rats, justifying the improvement in quinine
efficacy when nanoencapsulated (Haas et al.
2009
). Recently, artemether loaded
in solid lipid nanoparticles (consisting of a solid matrix made of a blend of solid
lipid trimyrstin (triglyceride of C14) with the liquid soybean oil) at 5 mg/kg
body weight, significantly prolonged the survival period of
P. berghei
infected
mice in comparison to the untreated group, and to those treated with artemether
solution and marketed formulation. The three treated groups resulted in an ini-
tial decrease of parasitemia; parasitemia however only reappeared in the groups
treated with marketed formulation and artemether solution. This result was
attributed to the bioavailability of the drug when formulated as lipid nanoparti-
cles, provided by a burst release followed by a sustained release. In this way, the
fast metabolism of artemether could be minimized reducing thereafter the pro-
duction of high toxicity levels of dihydroartemisinin (Aditya et al.
2010a
).
iii.
Sustained drug release
. Chloroquine loaded in anionic MLV (DPPC/DPPG) led
to a dozen-fold increase of maximum permissible dose, as compared to free
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