Generic placeholder image

Mini-Reviews in Organic Chemistry

Editor-in-Chief

ISSN (Print): 1570-193X
ISSN (Online): 1875-6298

Mini-Review Article

Metformin, Chlorpropamide, and Glibenclamide: Interactions with Metal Ions and Cyclodextrins

Author(s): Jeovani González-Barbosa, Adrián Ricardo Hipólito-Nájera, Rodolfo Gómez-Balderas, Norma Rodríguez-Laguna* and Rosario Moya-Hernández*

Volume 21, Issue 3, 2024

Published on: 07 April, 2023

Page: [272 - 294] Pages: 23

DOI: 10.2174/1570193X20666230117105443

Price: $65

Abstract

In the field of Chemistry, it is essential to study molecules with biological activity on chronic degenerative diseases to design drugs that help to improve the health of people with diseases such as diabetes, arterial hypertension, rheumatoid arthritis, cancer, among others; and that in turn may have fewer side effects. Diabetes mellitus is a serious metabolic disorder that affects millions of people worldwide; due to the illness severe affectations, there is a great interest in improving pharmacological treatments (hypoglycemic drugs) used in this disease. Nowadays, it has been reported that metallodrugs and drug-cyclodextrin inclusion compounds have higher therapeutic activity than free drugs, with fewer side effects. In the present work, we compile, analyze, synthesize and discuss published information on the hypoglycemic drugs Metformin (C4H11N5), Chlorpropamide (C10H13ClN2O3S) and Glibenclamide (C23H28ClN3O5S) complexed with metal ions or included in cyclodextrins in aqueous solution. Nowadays, this type of complex should be widely studied for the treatment of type 2 diabetes mellitus. Physicochemical and thermodynamic properties, synthesis, mechanism of action, as well as analytical studies on the interaction of hypoglycemic agents with different complexing agents, are discussed.

Graphical Abstract

[1]
Sosa-Durán, E.E. Epidemiological overview of cancer in Mexico. Rev Mex Anestesiol., 2013, 36(1), 130-132.
[2]
Yendapally, R.; Sikazwe, D.; Kim, S.S.; Ramsinghani, S.; Fraser-Spears, R.; Witte, A.P.; La-Viola, B. A review of phenformin, metformin, and imeglimin. Drug Dev. Res., 2020, 81(4), 390-401.
[http://dx.doi.org/10.1002/ddr.21636] [PMID: 31916629]
[3]
DRAFT Official Mexican Standard PROY-NOM-015-SSA2-2018, For the prevention, detection, diagnosis, treatment and control of Diabetes Mellitus. SEGOB, 2018. Available from: https://www.dof.gob.mx/nota_detalle.php?codigo=5521405&fecha=03/05/2018#gsc.tab=0
[4]
American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2020. Diabetes Care, 2020, 43(Suppl. 1), S98-S110.
[http://dx.doi.org/10.2337/dc20-S009] [PMID: 31862752]
[5]
Scully, T. Diabetes in numbers. Nature, 2012, 485(7398), S2-S3.
[http://dx.doi.org/10.1038/485S2a] [PMID: 22616094]
[6]
World Health Organization. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/diabetes (Accessed on: 15 December 2022).
[7]
Sarwar, N.; Gao, P.; Seshasai, S.R.; Gobin, R.; Kaptoge, S.; Di Angelantonio, E.; Ingelsson, E.; Lawlor, D.A.; Selvin, E.; Stampfer, M.; Stehouwer, C.D.; Lewington, S.; Pennells, L.; Thompson, A.; Sattar, N.; White, I.R.; Ray, K.K.; Danesh, J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet, 2010, 375(9733), 2215-2222.
[http://dx.doi.org/10.1016/S0140-6736(10)60484-9] [PMID: 20609967]
[8]
Rodríguez-Rivera, N.; Cuautle-Rodríguez, P.; Molina-Guarneros, J. Oral hypoglycemic agents for the treatment of type 2 diabetes mellitus: Use and regulation in Mexico. Rev. Hosp. Jua Mex., 2017, 84(4), 203-211.
[9]
Rojas, R.; Basto, A.; Aguilar, C.; Zárate, E.; Villalpando, S.; Barrientos, T. Prevalence of diabetes by previous medical diagnosis in Mexico. Salud Publica Mex., 2018, 60(3), 224-232.
[http://dx.doi.org/10.21149/8566]
[10]
Bommer, C.; Sagalova, V.; Heesemann, E.; Manne-Goehler, J.; Atun, R.; Bärnighausen, T.; Davies, J.; Vollmer, S. Global economic burden of diabetes in adults: Projections From 2015 to 2030. Diabetes Care, 2018, 41(5), 963-970.
[http://dx.doi.org/10.2337/dc17-1962] [PMID: 29475843]
[11]
Diagnosis and classification of diabetes mellitus. Diabetes Care, 2010, 33(Suppl. 1), S62-S69.
[http://dx.doi.org/10.2337/dc10-S062] [PMID: 20042775]
[12]
Mesa, E.; Gómez-Huelgas, R.; Ampudia-Blasco, F.J. Pioglitazone on glycemic control, lipid profile, and cardiovascular risk: Updated review on its benefits and emerging data on its safety. Av. Diabetol., 2013, 29(Suppl. 1), 1-12.
[http://dx.doi.org/10.1016/S1134-3230(13)70025-5]
[13]
Polonsky, K.S. The past 200 years in diabetes. N. Engl. J. Med., 2012, 367(14), 1332-1340.
[http://dx.doi.org/10.1056/NEJMra1110560] [PMID: 23034021]
[14]
International Diabetes Federation. 2021. Available from: https://www.idf.org/aboutdiabetes/type-1-diabetes.html (Accessed on: 15 December 2022).
[15]
Hernández-Ávila, M. Official Mexican norm NOM-015-SSA2- 2010, for prevention, treatment and control of mellitus diabetes. D. Oficial Fed., 2010, 2010.
[16]
Denova-Gutiérrez, E.; Lopez-Gatell, H.; Alomia-Zegarra, J.L.; López-Ridaura, R.; Zaragoza-Jimenez, C.A.; Dyer-Leal, D.D.; Cortés-Alcala, R.; Villa-Reyes, T.; Gutiérrez-Vargas, R.; Rodríguez-González, K.; Escondrillas-Maya, C.; Barrientos-Gutiérrez, T.; Rivera, J.A.; Barquera, S. The association of obesity, type 2 diabetes, and hypertension with severe coronavirus disease 2019 on admission among mexican patients. Obesity (Silver Spring), 2020, 28(10), 1826-1832.
[http://dx.doi.org/10.1002/oby.22946] [PMID: 32610364]
[17]
Vardanyan, R.; Hruby, V. Hyperglycemic and hypoglycemic drugs, in synthesis of best-seller drugs; Elsevier: Amsterdam, 2016, pp. 419-458.
[http://dx.doi.org/10.1016/B978-0-12-411492-0.00026-2]
[18]
Balamuralokrishna, K. International Journal of Pharmaceutical and Chemical Sciences. Available from: https://ijpcsonline.com/ (Accessed on: 15 December 2022).
[19]
Chaudhury, A.; Duvoor, C.; Reddy Dendi, V.S.; Kraleti, S.; Chada, A.; Ravilla, R.; Marco, A.; Shekhawat, N.S.; Montales, M.T.; Kuriakose, K.; Sasapu, A.; Beebe, A.; Patil, N.; Musham, C.K.; Lohani, G.P.; Mirza, W. Clinical review of antidiabetic drugs: Implications for type 2 diabetes mellitus management. Front. Endocrinol. (Lausanne), 2017, 8, 6.http://journal.frontiersin.org/article/10.3389/fendo.2017.00006/full
[http://dx.doi.org/10.3389/fendo.2017.00006] [PMID: 28167928]
[20]
Skillman, T.G.; Feldman, J.M. The pharmacology of sulfonylureas. Am. J. Med., 1981, 70(2), 361-372.
[http://dx.doi.org/10.1016/0002-9343(81)90773-7] [PMID: 6781341]
[21]
Cordiner, R.L.M.; Pearson, E.R. Reflections on the sulphonylurea story: A drug class at risk of extinction or a drug class worth reviving? Diabetes Obes. Metab., 2019, 21(4), 761-771.
[http://dx.doi.org/10.1111/dom.13596] [PMID: 30471177]
[22]
Benavide-Moraz, M.J.; Bruscas-Alijarde, M.J.; Mozota Duarte, M.; Medrano-Sanz, S. The new oral antidiabetics for the treatment of type 2 diabetes mellitus. Med. Int., 2000, 36(9), 355.
[23]
Kennedy, M.N. Diabetes education online, diabetes teaching center at the university of California, San Francisco. Available from: https://dtc.ucsf.edu/es/tipos-de-diabetes/diabetes-tipo-2/tratamien-to-de-la-diabetes-tipo-2/medicamentos-y-terapias-2/terapias-no-in-sulinicas-para-la-diabetes-tipo-2/tabla-de-medicamentos/ Accessed on: 15 December 2022).
[24]
Ghasemi, F.; Ghasemi, K.; Rezvani, A.R.; Shokrollahi, A.; Refahi, M.; García-Granda, S.; Mendoza-Meroño, R. A novel salt of antidiabetic drug metformin resulting from a proton transfer reaction: Synthesis, characterization, crystal structure and solution studies. J. Mol. Struct., 2017, 1131, 30-35.
[http://dx.doi.org/10.1016/j.molstruc.2016.11.011]
[25]
Ghasemi, F.; Rezvani, A.R.; Ghasemi, K.; Graiff, C. Glycine and metformin as new counter ions for mono and dinuclear vanadium(V)-dipicolinic acid complexes based on the insulin-enhancing anions: Synthesis, spectroscopic characterization and crystal structure. J. Mol. Struct., 2018, 1154, 319-326.
[http://dx.doi.org/10.1016/j.molstruc.2017.10.055]
[26]
Rojas, L.B.A.; Gomes, M.B. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol. Metab. Syndr., 2013, 5(1), 6.
[http://dx.doi.org/10.1186/1758-5996-5-6] [PMID: 23415113]
[27]
Sanchez-Rangel, E.; Inzucchi, S.E. Metformin: clinical use in type 2 diabetes. Diabetologia, 2017, 60(9), 1586-1593.
[http://dx.doi.org/10.1007/s00125-017-4336-x] [PMID: 28770321]
[28]
Gomes, M.B.; Rathmann, W.; Charbonnel, B.; Khunti, K.; Kosiborod, M.; Nicolucci, A.; Pocock, S.J.; Shestakova, M.V.; Shimomura, I.; Tang, F.; Watada, H.; Chen, H.; Cid-Ruzafa, J.; Fenici, P.; Hammar, N.; Surmont, F.; Ji, L. Treatment of type 2 diabetes mellitus worldwide: Baseline patient characteristics in the global DISCOVER study. Diabetes Res. Clin. Pract., 2019, 151, 20-32.
[http://dx.doi.org/10.1016/j.diabres.2019.03.024] [PMID: 30904743]
[29]
Dillon, C.T.; Hambley, T.W.; Kennedy, B.J.; Lay, P.A.; Weder, J.E.; Zhou, Q. Copper and zinc complexes as antiinflammatory drugs in metal ions in biological systems. Met. Ions Biol. Syst., 2004, 41, 253-277.
[30]
Mura, P. Analytical techniques for characterization of cyclodextrin complexes in aqueous solution: A review. J. Pharm. Biomed. Anal., 2014, 101, 238-250.
[http://dx.doi.org/10.1016/j.jpba.2014.02.022] [PMID: 24680374]
[31]
Popielarski, S.R.; Mishra, S.; Davis, M.E. Structural effects of carbohydrate-containing polycations on gene delivery. 3. Cyclodextrin type and functionalization. Bioconjug. Chem., 2003, 14(3), 672-678.
[http://dx.doi.org/10.1021/bc034010b] [PMID: 12757394]
[32]
Morin-Crini, N.; Fourmentin, S.; Fenyvesi, É.; Lichtfouse, E.; Torri, G.; Fourmentin, M.; Crini, G. 130 years of cyclodextrin discovery for health, food, agriculture, and the industry: A review. Environ. Chem. Lett., 2021, 19(3), 2581-2617.
[http://dx.doi.org/10.1007/s10311-020-01156-w]
[33]
Templeton, D.M.; Ariese, F.; Cornelis, R.; Danielsson, L-G.; Muntau, H.; van Leeuwen, H.P.; Lobinski, R. Guidelines for terms related to chemical speciation and fractionation of elements. Definitions, structural aspects, and methodological approaches (IUPAC Recommendations 2000). Pure Appl. Chem., 2000, 72(8), 1453-1470.
[http://dx.doi.org/10.1351/pac200072081453]
[34]
Yuen, K.H.; Peh, K.K. Simple high-performance liquid chromatographic method for the determination of metformin in human plasma. J. Chromatogr., Biomed. Appl., 1998, 710(1-2), 243-246.
[http://dx.doi.org/10.1016/S0378-4347(98)00117-0] [PMID: 9686895]
[35]
Al-Rimawi, F. Development and validation of an analytical method for metformin hydrochloride and its related compound (1-cyanoguanidine) in tablet formulations by HPLC-UV. Talanta, 2009, 79(5), 1368-1371.
[http://dx.doi.org/10.1016/j.talanta.2009.06.004] [PMID: 19635372]
[36]
Uria-Canseco, E.; Perez-Casas, S.; Navarrete-Vázquez, G. Thermodynamic characterization of the inclusion complexes formation between antidiabetic new drugs and cyclodextrins. J. Chem. Thermodyn., 2019, 129, 55-60.
[http://dx.doi.org/10.1016/j.jct.2018.09.013]
[37]
Puranik, R.; Bao, S.; Bonin, A.M.; Kaur, R.; Weder, J.E.; Casbolt, L.; Hambley, T.W.; Lay, P.A.; Barter, P.J.; Rye, K.A. A novel class of copper(II)- and zinc(II)-bound non-steroidal anti-inflammatory drugs that inhibits acute inflammation in vivo. Cell Biosci., 2016, 6(1), 9.
[http://dx.doi.org/10.1186/s13578-016-0076-8] [PMID: 26855766]
[38]
Agotegaray, M.; Gumilar, F.; Boeris, M.; Toso, R.; Minetti, A. Enhanced analgesic properties and reduced ulcerogenic effect of a mononuclear copper(II) complex with fenoprofen in comparison to the parent drug: promising insights in the treatment of chronic inflammatory diseases. BioMed Res. Int., 2014, 2014, 1-9.
[http://dx.doi.org/10.1155/2014/505987] [PMID: 25050353]
[39]
Kathuria, D.; Bankar, A.A.; Bharatam, P.V. “What’s in a structure?” The story of biguanides. J. Mol. Struct., 2018, 1152, 61-78.
[http://dx.doi.org/10.1016/j.molstruc.2017.08.100]
[40]
Bailey, C.J.; Day, C. Traditional plant medicines as treatments for diabetes. Diabetes Care, 1989, 12(8), 553-564.
[http://dx.doi.org/10.2337/diacare.12.8.553] [PMID: 2673695]
[41]
Werner, E.A.; Bell, J. CCXIV. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. J. Chem. Soc. Trans., 1922, 121(0), 1790-1794.
[http://dx.doi.org/10.1039/CT9222101790]
[42]
Bailey, C.J. Metformin: historical overview. Diabetologia, 2017, 60(9), 1566-1576.
[http://dx.doi.org/10.1007/s00125-017-4318-z] [PMID: 28776081]
[43]
Castro-Martínez, M.G.; Castillo-Anaya, V.; Ochoa-Aguilar, A.; Godínez-Gutiérrez, S.A. Metformin and its current applications in the clinic. Med. Interna Mex., 2014, 30(5), 562-574.
[44]
Cheng, C.L.; Yu, L.X.; Lee, H.L.; Yang, C.Y.; Lue, C.S.; Chou, C.H. Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. Eur. J. Pharm. Sci., 2004, 22(4), 297-304.
[http://dx.doi.org/10.1016/j.ejps.2004.03.016] [PMID: 15196586]
[45]
9. Pharmacologic approaches to glycemic treatment: Standards of medical care in Diabetes—2019. Diabetes Care, 2019, 42(Suppl. 1), S90-S102.
[http://dx.doi.org/10.2337/dc19-S009] [PMID: 30559235]
[46]
Abdallah, O.M.; Elbashir, A.A. Inclusion complex of metformin and β-cyclodextrin spectroscopic study and analytical application. Pharm. Lett., 2020, 12(6), 19-30.
[47]
Corti, G.; Cirri, M.; Maestrelli, F.; Mennini, N.; Mura, P. Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-β-cyclodextrin. Eur. J. Pharm. Biopharm., 2008, 68(2), 303-309.
[http://dx.doi.org/10.1016/j.ejpb.2007.06.004] [PMID: 17616379]
[48]
Wang, Y.; Tang, Y.; Gu, J.; Fawcett, J.P.; Bai, X. Rapid and sensitive liquid chromatography?tandem mass spectrometric method for the quantitation of metformin in human plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2004, 808(2), 215-219.
[http://dx.doi.org/10.1016/j.jchromb.2004.05.006] [PMID: 15261814]
[49]
Defang, O.; Shufang, N.; Wei, L.; Hong, G.; Hui, L.; Weisan, P. In vitro and in vivo evaluation of two extended release preparations of combination metformin and glipizide. Drug Dev. Ind. Pharm., 2005, 31(7), 677-685.
[http://dx.doi.org/10.1080/03639040500216410] [PMID: 16207615]
[50]
Nayak, A.K.; Pal, D.; Pradhan, J.; Hasnain, M.S. Fenugreek seed mucilage-alginate mucoadhesive beads of metformin HCl: Design, optimization and evaluation. Int. J. Biol. Macromol., 2013, 54, 144-154.
[http://dx.doi.org/10.1016/j.ijbiomac.2012.12.008] [PMID: 23246901]
[51]
Block, L.C. Effect of binders on 500 mg metformin hydrochloride tablets produced by wet granulation. Rev. Cienc. Farm. Basica Apl., 2009, 30(2), 145-152.
[52]
Sweetman, S.C. Martindale: the complete drug reference, 33rd ed; Pharmaceutical Press: London, 2002.
[53]
Mandal, U.; Gowda, V.; Ghosh, A.; Selvan, S.; Solomon, S.; Pal, T.K. Formulation and optimization of sustained release matrix tablet of metformin HCl 500 mg using response surface methodology. Yakugaku Zasshi, 2007, 127(8), 1281-1290.
[http://dx.doi.org/10.1248/yakushi.127.1281] [PMID: 17666882]
[54]
Malleswararao, C.S.N.; Suryanarayana, M.V.; Mukkanti, K. Simultaneous determination of sitagliptin phosphate monohydrate and metformin hydrochloride in tablets by a validated UPLC Method. Sci. Pharm., 2012, 80(1), 139-152.
[http://dx.doi.org/10.3797/scipharm.1110-13] [PMID: 22396910]
[55]
Lindeman, R.D. Severe hypoglycemia caused by chlorpropamide. Diabetes, 1960, 9(2), 110-113.
[http://dx.doi.org/10.2337/diab.9.2.110] [PMID: 14417084]
[56]
Nunes, F.; Alves-Filho, J.C.; Alves Bastos, C.M.; Tessele, P.M.; Caberlon, E.; Moreira, K.B.; Ferreira, T.M.; de Oliveira, J.R. Effect of the chlorpropamide and Fructose-1,6-bisphosphate on soluble TNF receptor II levels. Pharmacol. Res., 2004, 49(5), 449-453.
[http://dx.doi.org/10.1016/j.phrs.2003.10.015] [PMID: 14998554]
[57]
Pallardo, Sánchez LF Sulfonylureas in the treatment of patients with type 2 diabetes mellitus. Endocrinol. Nutr., 2008, 55(Supplement_ 2), 17-25.
[http://dx.doi.org/10.1016/S1575-0922(08)76259-4]
[58]
Henquin, J.C. The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work? Diabetologia, 1992, 35(10), 907-912.
[http://dx.doi.org/10.1007/BF00401417]
[59]
Feldman, J.M. Glyburide: A second-generation sulfonylurea hypoglycemic agent: history, chemistry, metabolism, pharmacokinetics, clinical use and adverse effects. Pharmacotherapy, 1985, 5(2), 43-62.
[http://dx.doi.org/10.1002/j.1875-9114.1985.tb03404.x]
[60]
Pernia, S.; DeMaagd, G. The new pregnancy and lactation labeling rule. P&T, 2016, 41(11), 713-715.
[PMID: 27904304]
[61]
Burt, H.J.; Neuhoff, S.; Almond, L.; Gaohua, L.; Harwood, M.D.; Jamei, M.; Rostami-Hodjegan, A.; Tucker, G.T.; Rowland-Yeo, K. Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions. Eur. J. Pharm. Sci., 2016, 88, 70-82.
[http://dx.doi.org/10.1016/j.ejps.2016.03.020] [PMID: 27019345]
[62]
Lizy Roselet, S.; Prema Kumari, J. An investigation on host-guest complexation of Metformin hydrochloride with hydroxypropyl-α-cyclodextrin for enhanced oral bioavailability. Mater. Today Proc., 2020, 21, 514-518.
[http://dx.doi.org/10.1016/j.matpr.2019.06.650]
[63]
Sheela, N.R.; Muthu, S.; Sampath-Krishnan, S. FTIR, FT raman and UV-visible spectroscopic analysis on metformin hydrochloride. Asian J. Chem., 2010, 22(7), 5049-5056.
[64]
Barot, B.; Parejiya, P.; Patel, T.; Parikh, R.; Gohel, M. Development of directly compressible metformin hydrochloride by the spray-drying technique. Acta Pharm., 2010, 60(2), 165-175.
[http://dx.doi.org/10.2478/v10007-010-0016-9] [PMID: 21134853]
[66]
Desai, D.; Wong, B.; Huang, Y.; Ye, Q.; Tang, D.; Guo, H.; Huang, M.; Timmins, P. Surfactant-mediated dissolution of metformin hydrochloride tablets: Wetting effects versus ion pairs diffusivity. J. Pharm. Sci., 2014, 103(3), 920-926.
[http://dx.doi.org/10.1002/jps.23852] [PMID: 24549733]
[67]
Chhetri, H.P.; Thapa, P.; Van Schepdael A Simple HPLC-UV method for the quantification of metformin in human plasma with one step protein precipitation. Saudi Pharm. J., 2014, 22(5), 483-487.
[http://dx.doi.org/10.1016/j.jsps.2013.12.011]
[68]
Graham, G.G.; Punt, J.; Arora, M.; Day, R.O.; Doogue, M.P.; Duong, J.K.; Furlong, T.J.; Greenfield, J.R.; Greenup, L.C.; Kirkpatrick, C.M.; Ray, J.E.; Timmins, P.; Williams, K.M. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet., 2011, 50(2), 81-98.
[http://dx.doi.org/10.2165/11534750-000000000-00000] [PMID: 21241070]
[69]
Pentikäinen, P.J. Bioavailability of metformin. Comparison of solution, rapidly dissolving tablet, and three sustained release products. Int. J. Clin. Pharmacol. Ther. Toxicol., 1986, 24(4), 213-220.
[PMID: 3710634]
[70]
Bhoyar, P.K.; Amgaonkar, Y.M. Taste masking and molecular properties of metformin hydrochloride-indion 234 complexes. J. Young Pharm., 2011, 3(2), 112-118.
[http://dx.doi.org/10.4103/0975-1483.80294] [PMID: 21731355]
[71]
Chatkon, A.; Chatterjee, P.B.; Sedgwick, M.A.; Haller, K.J.; Crans, D.C. Counterion affects interaction with interfaces: The antidiabetic drugs metformin and decavanadate. Eur. J. Inorg. Chem., 2013, 2013(10-11), 1859-1868.
[http://dx.doi.org/10.1002/ejic.201201345]
[72]
Hernández, B.; Pflüger, F.; Kruglik, S.G.; Cohen, R.; Ghomi, M. Protonation–deprotonation and structural dynamics of antidiabetic drug metformin. J. Pharm. Biomed. Anal., 2015, 114, 42-48.
[http://dx.doi.org/10.1016/j.jpba.2015.04.041] [PMID: 26004226]
[73]
Moffat, A.C.; Osselton, M.D.; Widdop, B.; Watts, J. Clarke’s analysis of drugs and poisons: in pharmaceutical, body fluids and postmortem material, 4th ed; Pharmaceutical Press: London, 2011.
[74]
Schönherr, D.; Wollatz, U.; Haznar-Garbacz, D.; Hanke, U.; Box, K.J.; Taylor, R.; Ruiz, R.; Beato, S.; Becker, D.; Weitschies, W. Characterisation of selected active agents regarding pKa values, solubility concentrations and pH profiles by SiriusT3. Eur. J. Pharm. Biopharm., 2015, 92, 155-170.
[http://dx.doi.org/10.1016/j.ejpb.2015.02.028] [PMID: 25758123]
[75]
Furman, B.L. Chlorpropamide. In: Reference Module in Biomedical Sciences; Elsevier: Amsterdam, 2016; p. B97801280-12383980000.
[http://dx.doi.org/10.1016/B978-0-12-801238-3.97989-3]
[76]
Barzegar-Jalali, M.; Dastmalchi, S. Kinetic analysis of chlorpropamide dissolution from solid dispersions. Drug Dev. Ind. Pharm., 2007, 33(1), 63-70.
[http://dx.doi.org/10.1080/03639040600762636] [PMID: 17192252]
[77]
Boldyreva, E.V.; Dmitriev, V.; Hancock, B.C. Effect of pressure up to 5.5 GPa on dry powder samples of chlorpropamide form-A. Int. J. Pharm., 2006, 327(1-2), 51-57.
[http://dx.doi.org/10.1016/j.ijpharm.2006.07.019] [PMID: 16920295]
[78]
Remko, M. Theoretical study of molecular structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some hypoglycemic agents. J. Mol. Struct. THEOCHEM, 2009, 897(1-3), 73-82.
[http://dx.doi.org/10.1016/j.theochem.2008.11.021]
[79]
Mallet, L.; Cooper, J.W. Chlorpropamide toxicity. Am. J. Med., 1988, 85(5), 756-757.
[http://dx.doi.org/10.1016/S0002-9343(88)80276-6] [PMID: 3189391]
[80]
Fioritto, A.F.; Bhattachar, S.N.; Wesley, J.A. Solubility measurement of polymorphic compounds via the pH-metric titration technique. Int. J. Pharm., 2007, 330(1-2), 105-113.
[http://dx.doi.org/10.1016/j.ijpharm.2006.09.003] [PMID: 17049191]
[81]
Sarwade, S.S.; Jadhav, W.N.; Khade, B.C. Metal complexes of first generation sulfonylurea antidiabetic drug chlorpropamide: Synthesis, structural and biological evaluation. J. Chem. Bio. Phy. Sci. Sec. A., 2014, 4(2), 978-982.
[82]
Bakare, M.T.; Mustapha, A.; Abdu-Aguye, I. An improved high-performance liquid chromatographic determination of chlorpropamide in human plasma. Chromatographia, 1994, 39(1-2), 107-109.
[http://dx.doi.org/10.1007/BF02320468]
[83]
Hill, R.E.; Crechiolo, J. Determination of serum tolbutamide and chlorpropamide by high-performance liquid chromatography. J. Chromatogr., 1978, 145(1), 165-168.
[http://dx.doi.org/10.1016/S0378-4347(00)81682-5]
[84]
Chiesi, P.; Ventura, P.; Canale, M.D. High solubility multicomponent inclusion complexes consisting of an acidic drug, a cyclodextrin and a base. WO1995028965A1, 1995.
[85]
Albert, A.; Serjeant, E.P. The determination of ionization constants. A laboratory manual; 3th ed, 1984.
[86]
Hajdu, P.; Kohler, K.F.; Schmidt, F.H.; Spingler, H. Quantitative determination of clobazam in serum and urine by gas chromatography, thin layer chromatography and fluorometry. Arzneimittelforschung, 1969, 19, 1381.
[87]
Byrn, S.R.; McKenzie, A.T.; Hassan, M.M.A.; Al-Badr, A.A. Conformation of glyburide in the solid state and in solution. J. Pharm. Sci., 1986, 75(6), 596-600.
[http://dx.doi.org/10.1002/jps.2600750615]
[88]
Takla, P.G. Glibenclamide. Anal Profiles Drug Substances; Elsevier: Amsterdam, 1981, pp. 337-355.
[http://dx.doi.org/10.1016/S0099-5428(08)60644-9]
[89]
Sakurai, H.; Yoshikawa, Y.; Yasui, H. Current state for the development of metallopharmaceutics and anti-diabetic metal complexes. Chem. Soc. Rev., 2008, 37(11), 2383-2392.
[http://dx.doi.org/10.1039/b710347f]
[90]
Meyer, J.A.; Spence, D.M. A perspective on the role of metals in diabetes: past findings and possible future directions. Metallomics, 2009, 1(1), 32-41.
[http://dx.doi.org/10.1039/B817203J]
[91]
Kiss, T.; Enyedy, É.A.; Jakusch, T. Development of the application of speciation in chemistry. Coord. Chem. Rev., 2017, 352, 401-423.
[http://dx.doi.org/10.1016/j.ccr.2016.12.016]
[92]
Vasantha, P.; Sathish Kumar, B.; Shekhar, B.; Anantha Lakshmi, P.V. Cobalt(II)–metformin complexes containing α ‐diimine/α‐diamine as auxiliary ligand: DNA binding properties. Appl. Organomet. Chem., 2018, 32(2), e4074.https://onlinelibrary.wiley.com/doi/10.1002/aoc.4074
[http://dx.doi.org/10.1002/aoc.4074]
[93]
Shahabadi, N.; Heidari, L. Synthesis, characterization and multi-spectroscopic DNA interaction studies of a new platinum complex containing the drug metformin. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2014, 128, 377-385.
[http://dx.doi.org/10.1016/j.saa.2014.02.167] [PMID: 24682051]
[94]
Shahabadi, N.; Heidari, L. Binding studies of the antidiabetic drug, metformin to calf thymus DNA using multispectroscopic methods. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2012, 97, 406-410.
[http://dx.doi.org/10.1016/j.saa.2012.06.044] [PMID: 22820043]
[95]
Bolotin, D.S.; Demakova, M.Y.; Novikov, A.S.; Avdontceva, M.S.; Kuznetsov, M.L.; Bokach, N.A.; Kukushkin, V.Y. Bifunctional reactivity of amidoximes observed upon nucleophilic addition to metal-activated nitriles. Inorg. Chem., 2015, 54(8), 4039-4046.
[http://dx.doi.org/10.1021/acs.inorgchem.5b00253] [PMID: 25822628]
[96]
Alvino de la-Sota, N.; Pacheco-Calderón, J.; Rigo-Roghi, C.G. Design of vanadium antidiabetic agents: Recent developments and advances. Rev Química., 2007, 21(1), 37-48.
[97]
Ghasemi, K.; Ghasemi, F.; Rezvani, A.R.; Graiff, C.; Notash, B. Potential antidiabetic drugs of metformin with insulin-enhancing anions [VO2(dipic)]− and [VO2(dipic-OH)]− Synthesis, characterization and X-ray crystal structure. Polyhedron, 2015, 102, 239-245.
[http://dx.doi.org/10.1016/j.poly.2015.09.053]
[98]
Farzanfar, J.; Ghasemi, K.; Rezvani, A.R.; Delarami, H.S.; Ebrahimi, A.; Hosseinpoor, H.; Eskandari, A.; Rudbari, H.A.; Bruno, G. Synthesis, characterization, X-ray crystal structure, DFT calculation and antibacterial activities of new vanadium(IV, V) complexes containing chelidamic acid and novel thiourea derivatives. J. Inorg. Biochem., 2015, 147, 54-64.
[http://dx.doi.org/10.1016/j.jinorgbio.2015.02.007] [PMID: 25770009]
[99]
Pardasani, R.T. Magnetic properties of vanadyl complex with metformin and dimethylformin in magnetic properties of paramagnetic compounds. A Gupta; Springer Materials, 2017.
[http://dx.doi.org/10.1007/978-3-662-53974-3]
[100]
Pardasani, R.T.; Pardasani, P. Magnetic properties of paramagnetic compounds; Springer: Berlin, Heidelberg, 2017.
[101]
Chinthala, C.P.; Angappan, S. Effect of solvent coordination on the structure of β-diketone-based vanadyl complexes and assessment of in vitro antidiabetic activity and cytotoxicity. Appl. Organomet. Chem., 2017, 31(9), e3700.
[http://dx.doi.org/10.1002/aoc.3700]
[102]
Olar, R.; Badea, M.; Cristurean, E.; Lazar, V.; Cernat, R.; Balotescu, C. Thermal behavior, spectroscopic and biological characterization of Co(II), Zn(II), Pd(II) and Pt(II) complexes with N,N-dimethylbiguanide. J. Therm. Anal. Calorim., 2005, 80(2), 451-455.
[http://dx.doi.org/10.1007/s10973-005-0676-8]
[103]
Treviño, S.; Velázquez-Vázquez, D.; Sánchez-Lara, E.; Diaz-Fonseca, A.; Flores-Hernandez, J.Á.; Pérez-Benítez, A.; Brambila-Colombres, E.; González-Vergara, E. Metforminium decavanadate as a potential metallopharmaceutical drug for the treatment of diabetes mellitus. Oxid. Med. Cell. Longev., 2016, 2016, 1-14.
[http://dx.doi.org/10.1155/2016/6058705] [PMID: 27119007]
[104]
Orvig, C.; Thompson, K.H.; Battell, M.; McNeill, J.H. Vanadium compounds as insulin mimics. Met. Ions Biol. Syst., 1995, 31(5), 575-594.
[PMID: 8564818]
[105]
Thompson, K.H.; McNeill, J.H.; Orvig, C. Vanadium compounds as insulin mimics. Chem. Rev., 1999, 99(9), 2561-2572.
[http://dx.doi.org/10.1021/cr980427c] [PMID: 11749492]
[106]
Lu, L.; Gao, X.; Zhu, M.; Wang, S.; Wu, Q.; Xing, S.; Fu, X.; Liu, Z.; Guo, M. Exploration of biguanido–oxovanadium complexes as potent and selective inhibitors of protein tyrosine phosphatases. Biometals, 2012, 25(3), 599-610.
[http://dx.doi.org/10.1007/s10534-012-9548-4] [PMID: 22547055]
[107]
Adam, A.M.A.; Sharshar, T.; Mohamed, M.A.; Ibrahim, O.B.; Refat, M.S. Study of chemical bonding, physical and biological effect of metformin drug as an organized medicine for diabetes patients with chromium(III) and vanadium(IV) ions. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2015, 149, 323-332.
[http://dx.doi.org/10.1016/j.saa.2015.04.115] [PMID: 25965516]
[108]
Ortega-Pacheco, D.; Jiménez-Pérez, M.M.; Serafín-López, J.; Juárez-Rojas, J.G.; Ruiz-García, A.; Pacheco-García, U. Vanadyl sulfate effects on systemic profiles of metabolic syndrome in old rats with fructose-induced obesity. Int. J. Endocrinol., 2018, 2018, 1-12.
[http://dx.doi.org/10.1155/2018/5257216] [PMID: 30675160]
[109]
Ghasemi, K.; Rezvani, A.R.; Rosli, M.M.; Abdul Razak, I.; Moghimi, A.; Ghasemi, F. Potential antidiabetic drug involving a zinc anionic complex of dipic and metformin as counter ions: Synthesis, characterization, crystal structure and electrochemical studies. J. Mol. Struct., 2014, 1074, 79-84.
[http://dx.doi.org/10.1016/j.molstruc.2014.05.048]
[110]
Valtierra-Alvarado, M.A.; Gonzalez-Ponce, M.R.; Segoviano-Garfias, J.J.N. Association studies of copper(II)-metformin complexes and their interaction with halides for their potential application in diabetes II. Jóvenes Investigadores., 2014, 1(1), 117-125.
[111]
Shoair, A.G.F.; Ibrahim, M.M.; Soliman, M.; Abu-Melha, K.A. Spectroscopic, electrochemical, DNA binding and antioxidant biomimetic catalytic activities of metformin-based copper(II) complexes. J. Mol. Liq., 2015, 212, 865-871.
[http://dx.doi.org/10.1016/j.molliq.2015.10.041]
[112]
P, V.; B, S.K.; B, S.; P v, A.L. Copper-metformin ternary complexes: Thermal, photochemosensitivity and molecular docking studies. Mater. Sci. Eng. C, 2018, 90, 621-633.
[http://dx.doi.org/10.1016/j.msec.2018.04.052] [PMID: 29853132]
[113]
Ansari, F.B.; Mazahar, F.; Quadri, S.H. Complexation of some metal ions with metformin hydrochloride in acidic aqueous solutions. Orient. J. Chem., 2010, 26(2), 667-670.
[114]
Kulish, K.I.; Novikov, A.S.; Tolstoy, P.M.; Bolotin, D.S.; Bokach, N.A.; Zolotarev, A.A.; Kukushkin, V.Y. Solid state and dynamic solution structures of O-carbamidine amidoximes gives further insight into the mechanism of zinc(II)-mediated generation of 1,2,4-oxadiazoles. J. Mol. Struct., 2016, 1111, 142-150.
[http://dx.doi.org/10.1016/j.molstruc.2016.01.038]
[115]
Hatzidimitriou, A.G.; Kessissoglou, D.P.; Manoussakis, G.E. Synthesis, characterization, and molecular modeling of Cu(II) and Au(III) complexes with hypoglycemic drugs as ligands. J. Inorg. Biochem., 1993, 49(3), 157-169.
[http://dx.doi.org/10.1016/0162-0134(93)80001-P]
[116]
Hatzidimitriou, A.G.; Kessissoglou, D.P.; Manoussakis, G.E.; Kourounakis, P.N.; Economidis, G. Solid and solution behavior of sulphonylurea complexes with ions of IIa group metals. Molecular modeling of K[Zn(ClCH4SO2NCONHC3H7)3] and Action of zinc-sulphonylurea complexes as hypoglycemic agents. J. Inorg. Biochem., 1990, 39(3), 263-276.
[http://dx.doi.org/10.1016/0162-0134(90)84009-E] [PMID: 2394999]
[117]
Kessissoglou, D.P.; Manoussakis, G.E.; Hatzidimitriou, A.G.; Kanatzidis, M.G. Synthesis and characterization of sulfonylurea complexes with Cd2+, Hg2+, and Ag+. Crystal and molecular structures of K[Cd(chlorpropamide)3] and Hg(tolbutamide)2. Inorg. Chem., 1987, 26(9), 1395-1402.
[http://dx.doi.org/10.1021/ic00256a013]
[118]
Brasseur, R.; Deleers, M. Theoretical study on conformation-related activity of hypoglycemic sulfonylureas. Pharmacol. Res. Commun., 1983, 15(10), 901-907.
[http://dx.doi.org/10.1016/S0031-6989(83)80020-4] [PMID: 6336538]
[119]
Tewari, P.C.; Tandon, S.K. Influence of glibenclamide on the efficacy of calcium trisodium pentetat as an antidote for cadmium toxicity. Toxicol. Ind. Health, 1988, 4(1), 39-47.
[http://dx.doi.org/10.1177/074823378800400104] [PMID: 2838934]
[120]
Mohamed, G.G.; Abdallah, S.M.; Zayed, M.A.; Nassar, M.M.I. Biological potential study of metal complexes of sulphonylurea glibenclamide on the house fly, Musca domestica (Diptera—Muscidae): Preparation, spectroscopic and thermal characterization. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2009, 74(3), 635-641.
[http://dx.doi.org/10.1016/j.saa.2009.07.011] [PMID: 19674929]
[121]
Fox, C. Zinc and/or cerium containing sulfonylurea hypoglucemyc agents, preparation and use thereof. WO1979000435, 1979.
[122]
Zaman, M.K.; Arayne, M.S.; Sultana, N.; Farooq, A. Synthesis and characterization of glibenclamide complexes of magnesium, chromium, cobalt, nickel, zinc and cadmium salts. Pak. J. Pharm. Sci., 2006, 19(2), 114-118.
[PMID: 16751121]
[123]
Rasheed, K.; Tariq, M.I.; Munir, C.; Hussain, I.; Siddiqui, H.L. Synthesis, characterization and hypoglycemic activity of Zn(II), Cd(II) and Hg(II) complexes with glibenclamide. Chem. Pharm. Bull. (Tokyo), 2008, 56(2), 168-172.
[http://dx.doi.org/10.1248/cpb.56.168] [PMID: 18239301]
[124]
Attia, H.; Al-Rasheed, N.; Al-Rasheed, N.; Faddah, L. The combination of zinc and glibenclamide limits cardiovascular complications in diabetic rats via multiple mechanisms. Pak. J. Pharm. Sci., 2015, 28(2), 499-508.
[PMID: 25730804]
[125]
Sonaimuthu, M.; Balakrishnan, S.B.; Kuppu, S.V.; Veerakanellore, G.B.; Thambusamy, S. Spectral and proton transfer behavior of 1,4-dihydroxylanthraquinone in aqueous and confined media; molecular modelling strategy. J. Mol. Liq., 2018, 259, 186-198.
[http://dx.doi.org/10.1016/j.molliq.2018.03.042]
[126]
Rekharsky, M.V.; Inoue, Y. Complexation thermodynamics of cyclodextrins. Chem. Rev., 1998, 98(5), 1875-1918.
[http://dx.doi.org/10.1021/cr970015o] [PMID: 11848952]
[127]
Khaled, E.; Kamel, M.S. Cyclodextrin-based potentiometric sensors for metformin. Sens. Electroanal., 2011, 6, 323-336.
[128]
Kaur, K.; Jindal, R.; Jindal, D. Synthesis, characterization and studies on host-guest interactions of inclusion complexes of metformin hydrochloride with β–cyclodextrin. J. Mol. Liq., 2019, 282, 162-168.
[http://dx.doi.org/10.1016/j.molliq.2019.02.127]
[129]
Haruhisa-Ueda, T.N. Nuclear magnetic resonance (NMR) spectroscopy of inclusion compounds of tolbutamide and chlorpropamide with β-cyclodextrin in aqueous solution. Chem. Pharm. Bull. (Tokyo), 1980.
[130]
Hye-Jeong, K.; Soo-Kim, K.; Soon-Ku, Y. Inclusion complexation of chlorpropamide with cyclodextrins. Yakhak Hoeji, 1986, 30(2), 87-96.
[131]
Sonoda, Y.; Hirayama, F.; Arima, H.; Uekama, K. Effects of 2-hydroxypropyl-β-cyclodextrin on polymorphic transition of chlorpropamide in various conditions: Temperature, humidity and moulding pressure. J. Incl. Phenomena, 2004, 50(1-2), 73-77.
[http://dx.doi.org/10.1007/s10847-003-8842-8]
[132]
Ishiguro, T.; Hirayama, F.; Iohara, D.; Arima, H.; Uekama, K. Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-β-cyclodextrin solution. Eur. J. Pharm. Sci., 2010, 39(4), 248-255.
[http://dx.doi.org/10.1016/j.ejps.2009.12.008] [PMID: 20036739]
[133]
Uekama, K.; Hirayama, F.; Nasu, S.; Matsuo, N.; Irie, T. Determination of the stability constants for inclusion complexes of cyclodextrins with various drug molecules by high performance liquid chromatography. Chem. Pharm. Bull. (Tokyo), 1978, 26(11), 3477-3484.
[http://dx.doi.org/10.1248/cpb.26.3477]
[134]
Cirri, M.; Righi, M.F.; Maestrelli, F.; Mura, P.; Valleri, M. Development of glyburide fast-dissolving tablets based on the combined use of cyclodextrins and polymers. Drug Dev. Ind. Pharm., 2009, 35(1), 73-82.
[http://dx.doi.org/10.1080/03639040802192798] [PMID: 18821153]
[135]
Lucio, D.; Irache, J.M.; Font, M.; Martínez-Ohárriz, M.C. Nanoaggregation of inclusion complexes of glibenclamide with cyclodextrins. Int. J. Pharm., 2017, 519(1-2), 263-271.
[http://dx.doi.org/10.1016/j.ijpharm.2017.01.028] [PMID: 28111282]
[136]
Radi, A.E.; Eissa, S. Voltammetric and spectrophotometric study on the complexation of glibenclamide with β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem., 2010, 68(3-4), 417-421.
[http://dx.doi.org/10.1007/s10847-010-9801-9]
[137]
Zerrouk, N.; Corti, G.; Ancillotti, S.; Maestrelli, F.; Cirri, M.; Mura, P. Influence of cyclodextrins and chitosan, separately or in combination, on glyburide solubility and permeability. Eur. J. Pharm. Biopharm., 2006, 62(3), 241-246.
[http://dx.doi.org/10.1016/j.ejpb.2005.08.010] [PMID: 16226882]
[138]
Savolainen, J.; Järvinen, K.; Taipale, H.; Jarho, P.; Loftsson, T.; Järvinen, T. Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms. Pharm. Res., 1998, 15(11), 1696-1701.
[http://dx.doi.org/10.1023/A:1011900527021] [PMID: 9833990]
[139]
Esclusa-Díaz, M.T.; Torres-Labandeira, J.J.; Kata, M.; Vila-Jato, J.L. Inclusion complexation of glibenclamide with 2-hydroxy-propyl-β-cyclodextrin in solution and in solid state. Eur. J. Pharm. Sci., 1994, 1(6), 291-296.
[http://dx.doi.org/10.1016/0928-0987(94)90037-X]
[140]
Singh, S.K.; Srinivasan, K.K.; Singare, D.S.; Gowthamarajan, K.; Prakash, D. Formulation of ternary complexes of glyburide with hydroxypropyl-β-cyclodextrin and other solubilizing agents and their effect on release behavior of glyburide in aqueous and buffered media at different agitation speeds. Drug Dev. Ind. Pharm., 2012, 38(11), 1328-1336.
[http://dx.doi.org/10.3109/03639045.2011.650645] [PMID: 22283512]
[141]
Buchanan, C.M.; Alderson, S.R.; Cleven, C.D.; Dixon, D.W.; Ivanyi, R.; Lambert, J.L.; Lowman, D.W.; Offerman, R.J.; Szejtli, J.; Szente, L. Synthesis and characterization of water-soluble hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins). Carbohydr. Res., 2002, 337(6), 493-507.
[http://dx.doi.org/10.1016/S0008-6215(01)00328-7] [PMID: 11890887]
[142]
Kurkov, S.V.; Loftsson, T. Cyclodextrins. Int. J. Pharm., 2013, 453(1), 167-180.
[http://dx.doi.org/10.1016/j.ijpharm.2012.06.055] [PMID: 22771733]
[143]
Hamdan, I.I.; El-Sabawi, D.; Abdel Jalil, M. Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation. Drug Dev. Ind. Pharm., 2016, 42(3), 418-428.
[http://dx.doi.org/10.3109/03639045.2015.1071834]
[144]
Hipólito-Nájera, A.R.; Rodríguez-Laguna, N.; Reyes-García, L.I.; Gómez-Vidales, V.; Rojas-Hernández, A.; Gómez-Balderas, R.; Moya-Hernández, R. Thermodynamics of inclusion within cyclodextrins and structural evidence of Cu(indomethacin) 2 and Zn(indomethacin) 2 complexes in aqueous solutions. New J. Chem., 2020, 44(46), 20222-20234.
[http://dx.doi.org/10.1039/D0NJ03335A]
[145]
Rodríguez-Laguna, N.; Reyes-García, L.I.; Moya-Hernández, R.; Rojas-Hernández, A.; Gómez-Balderas, R. Chemical speciation of the system Cu(II)-indomethacin in ethanol and water by UV-Vis spectrophotometry. J. Chem., 2016, 2016, 1-12.
[http://dx.doi.org/10.1155/2016/9804162]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy