Chemistry Reference
In-Depth Information
transfer protein (MTP) inhibitor R103757 [94]. Dispersions were generated using three
processing techniques, including melt extrusion and bead coating, both of which used
HPMC as the glassy carrier, as well as through the use of a glass thermoplastic system
(GTS) method. The GTS is a multicomponent dispersion containing HPMC, HP-
-CD,
and citric acid, which are dissolved with the drug in a common solvent, the solvent is
removed, and the residue formed is placed into dosage forms through encapsula-
tion [95,96]. A dog model was applied after which clinical testing was completed in
both the fed and fasted states. While no absorption was observed in the dog for the
crystalline drug incorporated in a standard tablet, solubilizing the API using a 10% w/v
aq. HP-
β
-CD solution resulted in good exposure. The coated bead concept was also
assessed in this dog study that suggested an exposure lower than that of the cyclodextrin
solution, but signi
β
cantly higher than that of the crystalline drug formulated in a tablet. In
the human oral bioavailability studies, three solid dispersion concepts, administered
either in gelatin capsules (GTS and beads) or as pressed tablets (melt extrudate), were
assessed and compared with a reference cyclodextrin (25% w/v aq. HP-
-CD) solution
(Table 8.2). Results found that while all dosage forms contained amorphous API,
β
TABLE 8.2. Pharmacokinetic Parameters (
SD) for R103757 after Human Dosing of
Various Prototype Formulations in Fed and Fasted Conditions
±
AUC
(ng h/ml)
∞
Formulation
Fasted State
Fed State
Film-coated beads
148
±
72
252
±
13
ME tablet
225
±
80
253
±
46
GTS
381
±
103
∗
590
±
98
∗
HP-
β
-CD solution
402
99
∗
±
C
max
(ng/ml)
Fasted State
Fed State
Film-coated beads
17.2
±
12.6
45.3
±
24.0
ME tablet
37.9
±
14.9
38.9
±
15.1
101
±
17
∗
GTS
62.1
±
21.9
71.8
±
21.1
∗
HP-
β
-CD solution
t
max
(h)
Fasted State
Fed State
Film-coated beads
1.9
±
0.3
2.3
±
0.6
3.0
±
0.6
∗
3.3
±
1.7
∗
ME tablet
GTS
2.5
±
1.0
1.8
±
0.7
HP-
β
-CD solution 1.6
±
0.6
Asterisks denote significantly different means (
p
<
0.05) calculated using ANOVA and a
post hoc
multiple
range test.
