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Synthesis and Evaluation of Dapagliflozin Ester Prodrugs with Improved Hygroscopicity and Thermal Stability

[ Vol. 17 , Issue. 11 ]

Author(s):

Si Young Sung, Yu Na Chae, Dae Young Lee, Kyeong Min Kim, Eun Jung Kim, Ji Hye Han, Wook Kim and Sung-Hwa Yoon*   Pages 1409 - 1421 ( 13 )

Abstract:


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.

Objective: To develop dapagliflozin prodrugs that have similar pharmacological effects with improved hygroscopicity and thermal stability.

Method: 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 Discussions: 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.

Keywords:

Prodrug, dapagliflozin, Farxiga®, SGLT-2 inhibitor, thermal stability, diabetes.

Affiliation:

Department of Molecular Science and Technology, Ajou University, Suwon 16499, Research Institute, Dong -A ST Co., Ltd., Yongin 17073, Research Institute, Dong -A ST Co., Ltd., Yongin 17073, Research Institute, Dong -A ST Co., Ltd., Yongin 17073, Research Institute, Dong -A ST Co., Ltd., Yongin 17073, Department of Molecular Science and Technology, Ajou University, Suwon 16499, Department of Molecular Science and Technology, Ajou University, Suwon 16499, Department of Molecular Science and Technology, Ajou University, Suwon 16499



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