Chemistry Reference
In-Depth Information
long-term complications [40]. Approximately 55
85% of infections become chronic, and
chronic hepatitis C (CHC) can lead to serious liver disease [41]. Cirrhosis develops within
20 years in 4
-
-
20% of patients with CHC [42]. Patients diagnosed with cirrhosis have an
18
-
29% risk of developing decompensated liver disease within 5
-
10 years, and a 10
-
30%
risk of developing hepatocellular carcinoma after 20 years [43].
Telaprevir acts by binding competitively to the viral NS3:4a protease, which is
essential for HCV replication [44]. As an active-site inhibitor, the molecule needs to be
both sterically and electrostatically predisposed to attach to the site where NS3:4a
normally binds and cleaves other viral proteins. From a pharmaceutical perspective, this
poses a certain set of challenges. As our colleagues describe in Chapter 7, the NS3:4a
active site, like the active sites of many proteases, is predominantly apolar; thus,
telaprevir needs to be largely apolar as well in order to bind effectively. Telaprevir
does in fact bind effectively, with nanomolar af
nity, but because it is apolar, the
compound is only sparingly soluble in water
less so, in fact, than marble [38]. Low
aqueous solubility is a less than optimal trait for a drug candidate meant to be dosed
orally; without an adequate concentration of dissolved drug in the aqueous environment
of the stomach and (particularly) the intestine, the compound is unlikely to be absorbed
and reach the systemic circulation.
After initial investigations on several options, the decision was made to advance
telaprevir through development as an amorphous dispersion as discussed in Chapter 7.
To render the compound amorphous, management decided to rely on spray drying. The
advantages of spray drying are described in Section 11.1.2 and include the need for
organic solvents (congenial to a lipophilic API like telaprevir), the low wastage of (at the
time) scarce compound during spray drying method development, and the relative ease
of scaling up the process. As our colleagues described in Chapter 7, excipients, namely,
stabilizing polymers [45], would be a necessary addition to the spray drying mixture. The
mixture would have to be spray dried [46], secondary dried to remove excess residual
solvent, and then tableted
—
—
a procedure that involved blending the dried SDD with
tablet-speci
c excipients, compressing the blend into tablets, and covering the tablets
with a
film coating. The overall process for the compound
'
is formulation development is
shown in Figure 11.5.
Figure 11.5.
High-level manufacturing process
flow diagram for telaprevir spray-dried
dispersion and tablet.
