DESIGN, SYNTHESIS AND CHEMICAL HYDROLYSIS STUDY OF CODRUGS OF METOPROLOL WITH METFORMIN
Abstract
In the present study we have synthesized ester prodrugs (Pa-i) of Metoprolol (I) by using pthalic anhydride and derivatives of succinic and maleic anhydride. Different codrugs (COa-i) were synthesized from prodrugs of metoprolol. All the codrugs were characterized by melting point, FTIR, NMR and Mass Spectroscopy. The chemical hydrolysis of COa-i were investigated at the pH 1.2, 6.8 and 7.4. Presence of maleate, methyl maleate, dimethyl maleate and succinate group as linker were found to possess good hydrolysis when compared to that of other substitutes. Among the synthesized codrugs, COf is found to be the best one among the series.
Keywords:
Chemical hydrolysis, codrugs, metformin, metoprolol, prodrugsDOI
https://doi.org/10.25004/IJPSDR.2018.100207References
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2. Ganga S, Ramarao P, Singh J. Effect of Azone on the iontophoretic transdermal delivery of metoprolol tartrate through human epidermis in vitro. Journal of Controlled Release. 1996; 42(1): 57-64.
3. Strack T. Metformin: A Review. Drugs Today. 2008; 44: 303–14.
4. Jackson RA, Hawa MI, Jaspan JB, Sim BM, Disilvio L, Featherbe D, Kurtz AB. Mechanism of Metformin Action in Non-Insulin-Dependent Diabetes. Diabetes. 1987; 36: 632–40.
5. Klip A, Leiter LA. Cellular Mechanism of Action of Metformin. Diabetes Care. 1990; 13: 696–704.
6. Wu MS, Johnston P, Sheu WHH, Hollenbeck CB, Jeng CY, Goldfine ID, Chen YDI, Reaven GM. Effect of Metformin on Carbohydrate and Lipoprotein Metabolism in NIDDM Patients. Diabetes Care. 1990; 13: 1–8.
7. Bhalla RC, Toth KF, Tan E, Bhatty RA, Mathias E, Sharma RV. Vascular Effects of Metformin. Possible Mechanisms for Its Antihypertensive Action in the Spontaneously Hypertensive Rat. Am J Hypertens. 1996; 9: 570–76.
8. Katakam PV, Ujhelyi MR, Hoenig M, Miller AW. Metformin ImprovesVascular Function in Insulin-Resistant Rats. Hypertension. 2000;35: 108–12.
9. Montanari G, Bondioli A, Rizzato G, Puttini M, Tremoli E, Mussoni L, Mannucci L, Pazzucconi F, Sirtori CR. Treatment with Low Dose Metformin in Patients with Peripheral Vascular Disease. Pharmacol Res. 1992; 25: 63–73.
10. Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin Kinetics in Healthy Subjects and in Patients with Diabetes Mellitus. Br J Clin Pharmacol. 1981; 12: 235–46.
11. Dandona P, Fonseca V, Mier A, Beckett AG. Diarrhea and Metformin in a Diabetic Clinic. Diabetes Care. 1983; 6: 472–4.
12. Krentz AJ, Ferner RE, Bailey CJ. Comparative Tolerability Profiles of Oral Antidiabetic Agents. Drug Saf. 1994;11: 223–41.
13. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of Metformin in Type II Diabetes: Results of a Double-Blind, Placebo-Controlled, Dose-Response Trial. Am J Med. 1997; 103: 491–7.
14. Belcher G, Lambert C, Edwards G, Urquhart R, Matthews DR. Safety and Tolerability of Pioglitazone, Metformin, and Gliclazide in the Treatmentof Type2 Diabetes. Diabetes Res Clin Pract. 2005; 70: 53–62.
15. Oster JR, Materson BJ, Epstein M. Diabetes mellitus and hypertension. Cardiovasc Risk Factors. 1990; l: 25-46.
16. Reaven GM, Hoffman BB (eds): Symposium on diabetes and hypertension. Am J Med 1989; 87(suppl 6A):1S-42S.
17. Sowers JR, Levy J, Zemel MB. Hypertension and diabetes. Med ClinNAm. 1988; 72: 1399-414.
18. Sowers JR, Zemel MB. Clinical implications of hypertension in the diabetic patient: A Review. Am J Hypertens. 1990; 3: 415-24.
19. Brown GR, Clarke DS, Faull AW, Foubister AJ, Smithers MJ. Design of dual acting thromboxane antagonist-synthase inhibitors by a mutual prodrug approach. Bioorg Med Chem Lett. 1996; 6(3): 273-8.
20. Vigroux A, Bergon M. Synthesis of prodrug and a mutual prodrug of chlorzoxazone and acetaminophen based on a masked benzoxazolone. Bioorg Med Chem Lett. 1995; 5(5): 427-30.
21. Andhale GS, Giles D, Das AK, Bose A, Metikurki. Design, Synthesis and Chemical Hydrolysis study of codrugs of propranolol with metformin. Eur J Pharma Med Res. 2018; 5(3): 395-404.
22. Baidya M, Das AK. Synthesis and Hydrolytic Kinetic study of some Antihypertensive Co-drugs. Indian J Hetero Chem. 2011; 20(2): 343-6.
23. Nielsenw NW, Bundgaard H. Glycolamide esters as biolabile prodrugs of carboxylic acid agents: synthesis, stability, bioconversion, and physicochemical properties. J Pharm Sci. 1988; 77: 285–98.
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01-03-2018
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“DESIGN, SYNTHESIS AND CHEMICAL HYDROLYSIS STUDY OF CODRUGS OF METOPROLOL WITH METFORMIN”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 10, no. 2, Mar. 2018, pp. 95-102, https://doi.org/10.25004/IJPSDR.2018.100207.
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“DESIGN, SYNTHESIS AND CHEMICAL HYDROLYSIS STUDY OF CODRUGS OF METOPROLOL WITH METFORMIN”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 10, no. 2, Mar. 2018, pp. 95-102, https://doi.org/10.25004/IJPSDR.2018.100207.
