Chemistry Reference
In-Depth Information
increase in thermodynamic activity [21,84]. This is in contrast to other approaches that
may increase apparent solubility but not the free drug concentration as in cases of micelle
formation (i.e., the effect of surfactants), complexation (i.e., cyclodextrin interactions),
or the use of cosolvents.
8.3
IN VIVO
EVALUATION AND MODELS
A number of
in vivo
assessments of the potential utility of amorphous solid dispersions
have been completed using various animal models. Most of these approaches assessed
supersaturating solid dispersions indirectly in that they compared exposure and phar-
macokinetics associated with an amorphous solid dispersion to a nonenabled formula-
tion. Newman et al. have outlined the general use of animal models in this context along
with accompanying
in vitro
characterization, including dissolution testing, and surveyed
40 published studies [85]. Bevernage et al. described indirect and direct approaches for
assessing the
in vivo
performance of dispersions [54]. Traditional pharmacokinetic and
bioavailability studies can be considered indirect assessments as the behavior of the solid
dispersion, that is, the nature and extent of supersaturation at the absorption site, is
unknown and not assessed. These studies are, however, critical to proof-of-concept
testing to encourage development of potential formulations and further narrow the
excipient space of concepts based on safety and related concerns. Newman et al. found
that in published studies, dispersions increased oral bioavailability in more than 80% of
cases with exposure increases of 2
80-fold relative to reference dosage forms or
API [85]. In the review, dogs and rats were most commonly used in the bioavailability
comparisons, although other species were also referenced including the rabbit and
monkey. These data are useful in positioning the biopharmaceutical usefulness of
dispersions and the effect of rendering the drug amorphous. In selecting a useful model,
testing ef
-
ciency and translation to man based on factors such as intestinal pH, transit
time, and enzymatic characteristics should be considered. The dog is arguably the easiest
to test with regard to dosage form dimensions. The rat requires some modi
cation in
terms of amorphous dispersion testing, including administration of an amorphous
dispersion powder by gavage or formulation of an amorphous solid dispersion in
appropriate capsules (e.g., size No. 9). Other important criteria include the effect of
food in the selected animal model as this impacts a large number of physiological factors
such as GI pH, motility, regional water content, hydrodynamics, mechanical force, and
various other parameters [54]. Taken in aggregate, it is clear that API, pharmaceutical,
and biopharmaceutical considerations will all play a role in guiding the selection of the
most useful animal model for testing a speci
c dispersion [32]. Blood or plasma levels of
the drug administered as an amorphous solid dispersion can be analyzed using
physiologically based pharmacokinetic (PBPK) model to estimate
in vivo
precipitation
time, transit time, and related factors [86
88]. Alternatively, with appropriate input,
PBPK modeling can attempt to predict blood levels from a solid dispersion with
appropriately measured
in vitro
properties such as kinetic solubility, precipitation
time, and dissolution rate. In this way, the weak base nel
-
navir and the farnesyltransfer-
ase inhibitor FTI2600 have been assessed [89]. While traditional modeling relies on
