Chemistry Reference
In-Depth Information
the pH increased through the action of a PPI, exposure decreased as did the gastric and
intestinal drug levels. It is apparent, therefore, that the assessment of the intraluminal
behavior of solid dispersions using the GI sampling technique may be critical to unravel
the precise mechanisms of absorption enhancement and to guide optimization of
in vitro
evaluation tools.
While data are limited to this point, there is a general feeling that current
in vitro
systems overestimate precipitation and excipient effects compared with
in vivo
obser-
vations. While there may be a variety of reasons for this, poor biorelevance may be a
contributing factor. The nature of drug nucleation and crystal growth
in vitro
may poorly
resemble that
in vivo
based on factors like secondary nucleation, hydrodynamics,
absorption, and related features. Attempts to generate appropriate biorelevant models
for solid dispersions are therefore an important goal [75].
8.5 CONCLUSIONS
Useful preclinical and clinical models for assessing solid dispersion
fitness will contribute
to the drug development process in many important ways, from both the drug enablement
viewpoint and the increasing ef
ciency and probability of success by reducing cycle time
and rework. While the ultimate goal may be to generate predictive
in silico
paradigms, a
number of factors need to be elucidated prior to a true model-based drug development
approach is at hand [114]. Speci
cally,
in vitro
methods with improved biorelevance
need to be considered. In addition, those API, formulation, and biopharmaceutical
features that impact the choice of an animal or human model need to be better articulated
and systematized. All of these efforts will rely on a better understanding of human and
animal gastrointestinal physiology and systems biology so that important critical success
factors can be deconstructed and included into the relevant models. These processes
include, but are not limited to, gastric motility, hydrodynamic and mechanical forces,
volume effects and changes as a function of GI transit, the interaction of not only the API
with the GI environment but also the possible excipient interactions [32,76,115
-
117]. As
data accrue, improved formulation design and assessment will result.
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