Chemistry Reference
In-Depth Information
exposures signi
cantly varied in the following order (in fasted individuals): GTS
melt
>
extrusion
coated bead. The GTS was 2.6-fold more bioavailable than the
film-coated
>
beads (
p
0.05) and 1.7-fold more bioavailable than the melt-extruded tablets. There
was a positive food effect with all three formulations with the GTS exposure increasing
2.3-fold. In the fasted state, the relative oral bioavailabilities for the three formations
relative to the cyclodextrin solution were 27% (coated beads), 75% (melt-extruded
tablets), and 97% (GTS).
Clinical assessments to investigate itraconazole supersaturation (indirectly) have
also been completed. Itraconazole is a widely studied compound in this context with
numerous
in vitro
,
in vivo
, and clinical evaluations completed [85]. The compound is an
triazolon broad-spectrum antifungal agent and was the first orally bioavailable pharma-
ceutical with ef
<
cacy against both
Candida
and
Aspergillus
, the most commonly
occurring human fungal pathogens. The development of dosage forms for itraconazole
is complicated by its challenging physicochemical properties: log
P
5, p
K
a
∼
4, and
>
aqueous solubility
∼
1 ng/ml at neutral pH and
∼
3
μ
g/ml in 0.1 N HCl [97]. One
bene
cial property of the compound is its ability to form a stable chiral nematic
mesophase [98]. When developing potential solid dispersions, several formulation
trajectories were assessed, including a
film-coated bead (using HPMC as the carrier)
filled into a gelatin capsule (and marketed as Sporanox
oral capsule) [99], a melt-
extruded dispersion (also using HPMC) wherein the extrudate is milled to various
particle sizes and compressed into tablets with other excipients [100], and a spray-dried
dispersion in which lactose is used as a carrier and the powder is then compressed into a
tablet with other excipients [101]. The assessment of the various possible dispersion-
based formulations proceeded in several phases, including assessing dissolution in an
appropriate model, testing dispersions in human pharmacokinetic studies, and evaluation
of the
in vitro
and
in vivo
relationships of these dosage forms.
Dissolution methods that may be useful in constructing IVIVCs were considered.
The solubility of itraconazole was determined in media at various pH values and in the
presence of other solubilizing additives. The effect of paddle speed and surfactant or
cyclodextrin concentration on dissolution rate of the innovator formulation (Sporanox
100 mg oral capsules) was assessed and correlated with a number of pharmacokinetic
parameters derived from human clinical studies. These
in vitro
in vivo
relationships were
optimized as a function of Tween20 concentrations and stirring speed. The optimized
systems used a USP type II apparatus operating at 100 rpm and using 900ml of 0.01 N
HCl (SGF
w/oPepsin
) containing 1% Tween20 maintained at 37
-
C. Under these conditions,
the following correlation could be generated: %dissolution (1 h)
°
20.0
63.3
AUC
=
+
ratio (
r
0.96) (Figure 8.3).
The solid dispersion formulations as well as crystalline itraconazole were compared. The
formulations assessed included the coated bead (
0.96) and %dissolution (1 h)
21.9
61.7
C
max
ratio (
r
=
=
+
=
(filled into a capsule, Sporanox 100mg
oral capsule), a spray-dried powder and a melt extrudate milled to two different particle
sizes and included in a tablet. Crystalline itraconazole undergoes incomplete and slow
dissolution (
5%). All other systems generated supersaturated levels of itraconazole that
were sustained for at least 1 h. All of the dispersed systems were amorphous as assessed
by DSC, modulated DSC, and powder X-ray diffraction (XRD) and released 100% of the
formulated drug within 1 h. Having said that, the rate of dissolution was different with the
∼
