Background:
Dapagliflozin, developed as an SGLT-2 inhibitor, has a low melting point
and high hygroscopicity, which needs extreme care during pharmaceutical production to keep the
active pharmacological property. Various attempts have been made to overcome these problematic
properties.
Objectives:
To develop dapagliflozin prodrugs that have similar pharmacological effects with improved
hygroscopicity and thermal stability.
Methods:
The novel dapagliflozin ester prodrugs containing pharmaceutically acceptable moieties
were synthesized and their pharmacokinetics (PK) and physical properties were compared with
dapagliflozin propanediol hydrate (DPD, Farxiga®). The PK in dog and rat, in vitro stability, hygroscopicity,
and physical property studies in accelerated conditions (40°C, 75% RH) were performed
with prodrugs.
Results and Discussion:
Among the eight synthesized prodrugs, Cmax and AUC0-48h values of prodrug
8b (1.35 μg/ml and 14.78 μg·h/ml, respectively) were similar to those of DPD (1.67 μg/ml and
14.27 μg·h/ml, respectively). However, the rest of the prodrugs 8a, 8c, 8d, 8e, 8f, 8g and 8h showed
significantly lower Cmax and AUC0-48h values than DPD. Prodrug 8b completely converted into parent
drug in the body.
Conclusion:
The novel prodrug 8b exhibited comparative PK profile to that of DPD, but with low
hygroscopic property and better thermal stability than DPD.