dc.description.abstract |
Poor oral bioavailability is a major challenge affecting the new drugs reaching the
market due to its low aqueous solubility. Nanocrystals have the potential and rapidly
providing a platform solution to substantially increase dissolution rate, solubility with
subsequent enhanced bioavailability and effectiveness via the oral route of
administration of a range of poor water soluble drugs. The current study is comprised on
two parts utilized antimalarial drugs: the first part was comprised on fabrication of
artemether (ARTM) and lumefantrine (LMF) nanoparticles using a novel top down wet
milling approach (DENA DM-100) and in the second part: cost effective simplest
approach of re-precipitation combined with ultrasonication was utilized for fabrication of
artemisinin (ART) nanoparticles with the aims to enhance their dissolution and hence the
bioavailability of these antimalarial drugs.
Smart nanocrystals of artemether (ARTM) and lumefantrine (LMF) were
fabricated in the form of nanosuspensions in shortest milling time (less than 1 hr) in both
aqueous and acidic medium using a novel wet milling technology (DENA DM-100).
Both high feedstock concentration (10% w/w) and low feedstock concentration (2.5%
w/w) of ARTM and LMF yielded nanocrystals with maximum recovery of the active
contents.
Similarly, we revisited the simplest approach of re-precipitation combined with
ultrasonication for fabrication of artemisinin nanoparticles in the form nanosuspensions.
Different critical parameters, including the effect of different concentrations of
stabilizers, temperature as well as optimum parameters/conditions were identified,
which was found to be very critical not only for fabrication as well as for scale up of the
batch size, which is critical issue associated with this approach.
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Additionally, the physical stability studies of artemether, lumefantrine and
artemisinin were conducted for 90 days at different storage temperatures demonstrated
that nanocrystals stored at 2-8°C and 25°C were most stable compared to the samples
stored at 40°C. There was not observed any chemical degradation in the APIs during the
chemical stability studies which was monitored for 07 days. Similarly artemether,
lumefantrine and artemisinin nanocrystals were produced in the size ranges of 161±1.5
nm and 214.1±1.2 nm, 98.77±1.5 nm respectively, where they showed significantly
enhanced solubility, dissolution rate and enhanced antimalarial efficacy (in vitro and in
vivo) compared to its unprocessed, micronized, microsuspension and their marketed
counterparts in relatively low dose.
In summary the study demonstrates that both novel top down DENA (DM-100)
technology and standard crystallization combined with ultrasonication are effective in
producing stable nanocrystals with smallest particle sizes, increased saturation solubility
and enhanced dissolution rate with enhanced in vitro and in vivo antimalarial activities
while controlling the key experimental and process conditions. |
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