Formulations containing nanosized drug particles such
as nanocrystals
and nanosized amorphous drug aggregates recently came into light as
promising strategies to improve the bioavailability of poorly soluble
drugs. However, the increased solubility due to the reduction in particle
size cannot adequately explain the enhanced bioavailability. In this
study, the mechanisms and extent of enhanced passive permeation by
drug particles were investigated using atazanavir, lopinavir, and
clotrimazole as model drugs. Franz diffusion cells with lipid-infused
membranes were utilized to evaluate transmembrane flux. The impact
of stirring rate, receiver buffer condition, and particle size was
investigated, and mass transport analyses were conducted to calculate
transmembrane flux. Flux enhancement by particles was found to be
dependent on particle size as well as the partitioning behavior of
the drug between the receiver solution and the membrane, which is
determined by both the drug and buffer used. A flux plateau was observed
at high particle concentrations above amorphous solubility, confirming
that mass transfer of amorphous drug particles from the aqueous solution
to the membrane occurs only through the molecularly dissolved drug.
Mass transport models were used to calculate flux enhancement by particles
for various drugs at different conditions. Good agreements were obtained
between experimental and predicted values. These results should contribute
to improved bioavailability prediction of nanosized drug particles
and better design of formulations containing colloidal drug particles.
Toxic metals and phthalates are introduced in the manufacturing of plastic toys and modeling clays. In Lebanon, inexpensive plastic toys and modeling clays (sold in dollar stores) are affordable and popular, and there is no legislation to monitor or regulate such toys. This study aimed to assess the quality of inexpensive plastic toys and modeling clays imported in Lebanon. Metal concentrations in toys, namely, zinc [not detectable (ND) to 3,708 μg/g], copper (ND to 140), chromium (ND to 75 μg/g), tin (ND to 39 μg/g), and cadmium (Cd) (ND to 20 μg/g), were lower than the European Union (EU) Directive limits, whereas lead (ND to 258 μg/g) in 10% of samples and antimony (Sb) (ND to 195 μg/g) in 5% of samples were greater than the EU limits. In modeling clays, most of the metals were lower than the EU Directive limits except for Cd and arsenic (As). Cd was detected in 83% of samples, with a mean level of 9.1 μg/g, which is far greater than the EU Directive limit (1.9 μg/g). The As mean level of 4.5 μg/g was greater than the EU limit (4.0 μg/g) and was detected in 9% of samples. Phthalic acid esters (PAEs) were found in 60% of children's toys and 77% of modeling clays. Phthalic acid butyl ester had the highest-level PAE encountered and was ≤59.1 % in one type of clay. However, among children's toys, di(4-octyl) ester terephthalic acid was the highest encountered phthalate at a concentration of 25.7%. The community survey indicated that 82% of households purchase their toys from inexpensive shops and that only 17% of parents were aware of the health hazard of such toys. Consequently, an intervention plan was proposed for the provision of safe toys to children.
The spontaneous formation of amorphous drug nanoparticles
following
the release of a drug from a supersaturating formulation is gaining
increasing attention due to their potential contribution to increased
oral bioavailability. The formation of nanosized drug particles also
has considerable implications for the interpretation of in
vitro and in vivo data. However, the membrane
transport properties of these drug particles remain less well understood.
Herein, the membrane permeation of nanosized amorphous drug particles
of a model drug atazanavir was evaluated using different artificial
membrane-based, cell-based, and animal tissue-based models. Results
showed that flux enhancement by particles was different for the various
systems used. Generally, good agreement was obtained among experiments
performed using the same apparatus with different model membranes,
with the exception of the Madin-Darby canine kidney cell monolayer
and the Long-Evans rat intestine tissue, which showed lower flux enhancements.
Franz cell-based models showed slightly higher flux enhancements by
particles compared to Transwell and intestinal tissue sac models.
Mass transport analysis suggested that the extent of flux enhancement
by particles is dependent on the geometry of the apparatus as well
as the properties of the membrane and buffer used, whereas the flux
plateau concentration is dependent on the unstirred water later (UWL)
asymmetry. These results highlight the complexity in characterizing
the permeability advantage of these nonmembrane permeable drug particles
and suggest that caution should be used in selecting the appropriate in vitro model to evaluate the overall permeability of colloidal
drug particles.
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