Chemistry Reference
In-Depth Information
Figure 10.10.
In vivo
blood plasma concentration versus time data for various forms of
itraconazole orally dosed to beagle dogs. HME-processed Soluplus dispersion exhibits 2.3-fold
higher area under the curve (AUC) than the marketed product Sempera and 23-fold higher AUC
than the crystalline itraconazole. Reproduced with permission from BASF SE.
effect is not only large but is also sustained. Various substituted HPMC polymers were
dispersed with a model drug using HME that again shows how the duration of
supersaturation can vary between related dispersions [26]. All dispersions exhibited
gelling properties around the dissolving particle, but dissolution was not consistent,
showing that speci
c molecular interactions with drug in the supersaturated environment
are also signi
cant.
Guth et al. [27] showed improved bioavailability using Soluplus in a solid dispersion
with itraconazole. The formulation formed by hot melt extrusion showed a 2.3-fold
increase in bioavailability compared with a commercialized formulation using HPMC-
based drug-layered pellets. Beagle dog pharmacokinetic data for the solid dispersion are
shown in Figure 10.10 compared with the reference pellet product (Sempera
)and
crystalline API all dosed at 100 mg itraconazole.
More detailed characterization of dissolution processes have been reported for the
commercialized Meltrex
HME technology [28]. Photon correlation spectroscopy
measurements identi
60 nm mean particle size for the disperse phase that was
formed from a ritonavir/copovidone/Span 20/silica solid dispersion. Analysis of placebo
controls indicated that the dispersed particles were neither pure drug nor pure silica. The
colloidal phase likely contains drug/polymer/surfactant, forming a relatively stable
structure that maintains this mean size over 24 h. Changes in turbidity and the existence
of larger particles indicate the system is heterogeneous and not thermodynamically
stable, but the temporary formation of this dispersion is important for understanding
dissolution behavior from the multicomponent solid dispersion. This colloidal system
did not yield large concentrations of dissolved drug in a traditional dissolution test
condition, but the addition of bile salt to the dissolution media produced a large change in
dissolution behavior, with signi
ed 50
-
cant supersaturation observed.
It is evident that the main focus of formulation optimization for amorphous
dispersions of poorly soluble drugs relates to dissolution performance. The topic of
designing
in vitro
dissolution test conditions is a critical aspect of the development effort
for these systems, but is beyond the scope of this chapter.
