Generic placeholder image

Letters in Drug Design & Discovery

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*

DOI: 10.2174/1570180817999200618162949

DownloadDownload PDF Flyer Cite As
Synthesis and Evaluation of Dapagliflozin Ester Prodrugs with Improved Hygroscopicity and Thermal Stability

Page: [1409 - 1421] Pages: 13

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

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.

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 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.

Graphical Abstract

[1]
International Diabetes Federation. Diabetes Atlas. 4th ed; International Diabetes Federation: Montreal, Canada 2009.
[2]
Song KS, Lee SH, Kim MJ, et al. Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors. ACS Med Chem Lett 2010; 2(2): 182-7.
[http://dx.doi.org/10.1021/ml100256c ] [PMID: 24900297]
[3]
Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15(7): 539-53.
[http://dx.doi.org/10.1002/(SICI)1096-9136(199807)15:7<539:AID-DIA668>3.0.CO;2-S ] [PMID: 9686693]
[4]
Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106(2): 171-6.
[http://dx.doi.org/10.1172/JCI10583 ] [PMID: 10903330]
[5]
Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest 2011; 121(6): 2094-101.
[http://dx.doi.org/10.1172/JCI45887 ] [PMID: 21633177]
[6]
Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet 2017; 389(10085): 2239-51.
[http://dx.doi.org/10.1016/S0140-6736(17)30058-2 ] [PMID: 28190580]
[7]
Isaji M. SGLT2 inhibitors: molecular design and potential differences in effect. Kidney Int Suppl 2011; 79(120): S14-9.
[http://dx.doi.org/10.1038/ki.2010.511 ] [PMID: 21358697]
[8]
Madaan T, Akhtar M, Najmi AK. Sodium glucose CoTransporter 2 (SGLT2) inhibitors: Current status and future perspective. Eur J Pharm Sci 2016; 93: 244-52.
[http://dx.doi.org/10.1016/j.ejps.2016.08.025 ] [PMID: 27531551]
[9]
Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract 2014; 104(3): 297-322.
[http://dx.doi.org/10.1016/j.diabres.2014.02.014 ] [PMID: 24735709]
[10]
Qiu F. Scrivens G Accelerated Predictive Stability (APS). 1st ed. Academic Press 2018.
[11]
Deng JH, Lu TB, Sun CC, Chen JM. Dapagliflozin-citric acid cocrystal showing better solid state properties than dapagliflozin. Eur J Pharm Sci 2017; 104: 255-61.
[http://dx.doi.org/10.1016/j.ejps.2017.04.008 ] [PMID: 28412482]
[12]
Gougoutas JZ, Lobinger H, Ramakrishnan S. Crystalline solvates and complexes of (IS)-1,5-anhydro-L-C-(3-((phenyl)methyl) phenyl)-D-glucitol derivatives with amino acids as SGLT2 inhibitors for the treatment of diabets WO Patent Application 20080028242006.
[13]
Srinivasan TR, Sajja E. Process for the preparation of (1S)-1,5- anhydro-1-C-[4-chloro-3-[(4-ehtoxyphenyl)methyl]phenyl]-Dglucitol and its solvate thereof WO Patent Application 2015- 132803 2014.
[14]
Marom E. Co-crystals of dapagliflozin WO Patent Application 2014-178040, 2013.
[15]
Kim KL, Park CH, Lee JH, Chang YK. Crystallline composite comprising dapagliflozin and method for preparing same WO Patent Application 2016-018024 2014.
[16]
Kim KL, Park CH, Lee JH, Chang YK. Novel hydrate complex of dapagliflozin and method for preparing same KR Patent Application 10-2016-0016025, 2014.
[17]
Bauer JF. A critical consideration in pharmaceutical development, manufacturing, and stability Journal of validation technology 2008; 15-23.
[18]
Nie H, Byrn SR, Zhou QT. Stability of pharmaceutical salts in solid oral dosage forms. Drug Dev Ind Pharm 2017; 43(8): 1215-28.
[http://dx.doi.org/10.1080/03639045.2017.1304960 ] [PMID: 28276282]
[19]
Grothe E, Meekes H, Vlieg E, Horst JH, Gelder R. Solvates, salts, and cocrystals: A proposal for a feasible classification system. Cryst Growth Des 2016; 16: 3237-43.
[http://dx.doi.org/10.1021/acs.cgd.6b00200]
[20]
Healy AM, Worku ZA, Kumar D, Madi AM. Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals. Adv Drug Deliv Rev 2017; 117: 25-46.
[http://dx.doi.org/10.1016/j.addr.2017.03.002 ] [PMID: 28342786]
[21]
Rautio J, Meanwell NA, Di L, Hageman MJ. The expanding role of prodrugs in contemporary drug design and development Nature reviews | drug discovery, 2018; 17: 559-87.
[http://dx.doi.org/10.1038/nrd.2018.46]
[22]
Shirke S, Shewale S, Satpute M. Prodrug design: an overview. Int J Pharm Chem Biol Sci 2015; 5(1): 232-41.
[23]
Jornada DH, dos Santos Fernandes GF, Chiba DE, de Melo TR, dos Santos JL, Chung MC. The prodrug approach: A successful tool for improving drug solubility. Molecules 2015; 21(1): 42-72.
[http://dx.doi.org/10.3390/molecules21010042 ] [PMID: 26729077]
[24]
Beaumont K, Webster R, Gardner I, Dack K. Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist. Curr Drug Metab 2003; 4(6): 461-85.
[http://dx.doi.org/10.2174/1389200033489253 ] [PMID: 14683475]
[25]
Karpagavalli L, Vigneshwar M, Monisha M, Prabavathi M, Prasanth P, Zairudeen K. A review on prodrugs. Int J Novel Trends Pharm Sci 2016; 6(1): 1-5.
[26]
Kwak WY, Sung SY, Kim JH, et al. 2017.
[27]
Murikipudi V, Gupta P, Sihorkar V. Efficient throughput method for hygroscopicity classification of active and inactive pharmaceutical ingredients by water vapor sorption analysis. Pharm Dev Technol 2013; 18(2): 348-58.
[http://dx.doi.org/10.3109/10837450.2011.618947 ] [PMID: 21981708]
[28]
Wu S, Wang L, Huang X, et al. Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380. Bioorg Med Chem 2014; 22(19): 5234-40.
[http://dx.doi.org/10.1016/j.bmc.2014.08.006 ] [PMID: 25182964]
[29]
Li F, Maag H, Alfredson T. Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J Pharm Sci 2008; 97(3): 1109-34.
[http://dx.doi.org/10.1002/jps.21047 ] [PMID: 17696166]
[30]
Stella VJ, Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW. Prodrugs: Challenges and Rewards Part 1 Springer: New York. : 2007.
[http://dx.doi.org/10.1007/978-0-387-49785-3]
[31]
Hu L. The prodrug approach to better targeting Curr Drug Discov 2004; 28-32.
[32]
Testa B, Mayer JM. Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology. Wiley-VCH 2003.
[http://dx.doi.org/10.1002/9783906390444]
[33]
Du F, Hinke SA, Cavanaugh C, et al. Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents. J Pharmacol Exp Ther 2018; 365(3): 676-87.
[http://dx.doi.org/10.1124/jpet.118.248575 ] [PMID: 29674332]
[34]
Tatarkiewicz K, Polizzi C, Villescaz C, et al. Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice. Diabetes Obes Metab 2014; 16(4): 376-80.
[http://dx.doi.org/10.1111/dom.12237 ] [PMID: 24251534]
[35]
Byrn SR, Pfeiffer RR, Stowel JG. Solid-state chemistry of drugs. 2nd ed SSCI Inc.: West Lafayette .. 1999.
[36]
Qiu Y, Chen Y. Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice. Academic Press 2008.