Abstract
Three 1,5-diarylpyrazoles were synthesized and pre-formulated with polyvinylpyrrolidone to enhance the antidiabetic activity, evaluated on in vivo non-insulin dependent diabetes mellitus model. Additionally, an in vivo subacute test was conducted to quantify antidiabetic, lipidic profile and antidyslipidemic activity. Spectroscopic techniques together with microscopy confirmed drug-carrier interaction. Notably, the antidiabetic activity of a dehalogenated pyrazole was twofold enhanced with the pre-formulation. This treatment also displayed antihyperglycemic activity without producing hypoglycemia, while a sub-acute study demonstrated that the solid dispersion has benefits in improving dyslipidemia, specifically reducing triacylglycerols, an effect scarcely observed with the reference drug metformin. Therefore, solid dispersion pre-formulation offers a simple but effective approach for enhancing the peripheral action of cannabinoid receptor 1 antagonist, thus minimizing undesired effects while enhancing antidiabetic and related metabolic properties.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Boyd BJ, Bergström CAS, Vinarov Z et al (2019) Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems. Eur J Pharm Sci 137:104967. https://doi.org/10.1016/j.ejps.2019.104967
Christopoulou FD, Kiortsis DN (2011) An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther 36:10–18. https://doi.org/10.1111/j.1365-2710.2010.01164.x
Cid AG, Simonazzi A, Palma S, Bermúdez JM (2019) Solid dispersion technology as a strategy to improve the bioavailability of poorly soluble drugs. Ther Deliv 10:363–382. https://doi.org/10.4155/tde-2019-0007
Cinar R, Iyer MR, Kunos G (2020) The therapeutic potential of second and third generation CB1R antagonists. Pharmacol Therapeut 208:107477. https://doi.org/10.1016/j.pharmthera.2020.107477
Cooper ME, Regnell SE (2014) The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake. Br J Clin Pharmacol 77:21–30. https://doi.org/10.1111/bcp.12102
Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. https://doi.org/10.1038/srep42717
Després JP, Ross R, Boka G, Almerás N, Lemieux I (2009) Effect of rimonabant on the high-triglyceride/ low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-Lipids trial. Arterioscler Thromb Vasc Biol 29(3):416–423. https://doi.org/10.1161/ATVBAHA.108.176362
Fink C, Sun D, Wagner K et al (2019) Evaluating the role of solubility in oral absorption of poorly water-soluble drugs using physiologically-based pharmacokinetic modeling. Clin Pharmacol Therapeut 107:650–661. https://doi.org/10.1002/cpt.1672
Hasegawa S, Hamaura T, Furuyama N, Kusai A, Terada K (2005) Effects of water content in physical mixture and heating temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by closed melting method. Int J Pharm 302:103–112. https://doi.org/10.1016/j.ijpharm.2005.06.021
Hernández-Vázquez E, Méndez-Lucio O, Hernández-Luis F (2013a) Activity landscape analysis, CoMFA and CoMSIA studies of pyrazole CB1 antagonists. Med Chem Res 22:4133–4145. https://doi.org/10.1007/s00044-012-0418-y
Hernández-Vázquez E, Aguayo-Ortiz R, Ramírez-Espinosa JJ, Estrada-Soto S, Hernández-Luis F (2013b) Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model. Eur J Med Chem 69:10–21. https://doi.org/10.1016/j.ejmech.2013.07.054
Hernández-Vázquez E, Ocampo-Montalban H, Cerón-Romero L, Gomez Zamudio J, Hiriart-Valencia G, Estrada-Soto S (2017) Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: a potent pyrazole derivative against diabetes and related diseases. Eur J Pharmacol 803:159–166. https://doi.org/10.1016/j.ejphar.2017.03.036
Hernández-Vázquez E, Young-Peralta S, Cerón-Romero L, Estrada-Soto S (2018) Acute and subacute antidiabetic studies of ENP-9, a new 1,5-diarylpyrazole derivative. J Pharm Pharmacol 70:1031–1039. https://doi.org/10.1111/jphp.12933
Hernandez-Vazquez E, Castaneda-Arriaga R, Medina-Campos ON, Ramirez-Espinosa JJ, Hernández-Luis F, Pedraza-Chaverri J, Estrada-Soto S (2015) 1,5-Diarylpyrazole and vanillin hybrids: synthesis, biological activity and DFT studies. Eur J Med Chem 100:106–118. https://doi.org/10.1016/j.ejmech.2015.06.010
Hernandez-Vazquez E, Castaneda-Arriaga R, Ramirez-Espinosa JJ et al (2015) 1,5-Diarylpyrazole and vanillin hybrids: synthesis, biological activity and DFT studies. Eur J Med Chem 100:106–118. https://doi.org/10.1016/j.ejmech.2015.06.010
Hernandez-Vazquez E, Salgado-Barrera S, Ramírez-Espinosa JJ, Hernández-Luis F (2016) Synthesis and molecular docking of N0-arylidene-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazides as novel hypoglycemic and antioxidant dual agents. Bioorg Med Chem 24:2298–2306. https://doi.org/10.1016/j.bmc.2016.04.007
Homayouni A, Sadeghi F, Nokhodchi A, Varshosaz J, Garekani HA (2014) Preparation and characterization of celecoxib solid dispersions; comparison of poloxamer-188 and PVP-K30 as carriers. Iran J Basic Med Sci 17:322–331
International Diabetes Federation (2019) IDF Diabetes, ISBN: 978–2–930229–87–4, 9 ed. Brussels, Belgium. Online version of IDF Diabetes Atlas: http://www.diabetesatlas.org
Ito I, Ito A, Unezaki S (2016) Preparation of an oral acetaminophen film that is expected to improve medication administration: effect of polyvinylpyrrolidone on physical properties of the film. Drug Discov Ther 10:156–162. https://doi.org/10.5582/ddt.2016.01034
Kavitha R, Abdul A, Hasan A (2012) Enhancement of solubility of repaglinide by solid dispersion technique. Int J Chem Sci 10:377–390
Khadkaa P, Roa J, Kim H et al (2014) Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm Sci 9:304–316. https://doi.org/10.1016/j.ajps.2014.05.005
Lee AS, Twigg SM, Flack JR (2021) Metabolic syndrome in type 1 diabetes and its association with diabetes complications. Diabet Med 38:e14376. https://doi.org/10.1111/dme.14376
Liu G, Gong L, Zhang J, Wu Z, Deng H, Deng S (2020) Development of nimesulide amorphous solid dispersions via supercritical anti-solvent process for dissolution enhancement. Eur J Pharm Sci 152:105457. https://doi.org/10.1016/j.ejps.2020.105457
Micale V, Drago F, Noerregaard PK, Elling CE, Wotjak C (2019) The cannabinoid CB1 antagonist TM38837 with limited penetrance to the brain shows reduced fear-promoting effects in mice. Front Pharmacol 10:207. https://doi.org/10.3389/fphar.2019.00207
Morales P, Lago-Fernandez A, Hurst DP, Sotudeh N, Brailoiu E, Reggio PH, Abood ME, Jagerovic N (2020) Therapeutic exploitation of GPR18: beyond the cannabinoids? J Med Chem 63:14216–14227
Prentis RA, Lis Y, Walker SR (1988) Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964–1985). Br J Clin Pharmacol 25:387–396. https://doi.org/10.1111/j.1365-2125.1988.tb03318.x
Qarta C, Cota D (2020) Anti-obesity therapy with peripheral CB1 blockers: from promise to safe(?) practice. Int J Obes 44:2179–2193. https://doi.org/10.1038/s41366-020-0577-8
Rao Q, Qiu Z, Huang D, Luo D, Pan P, Zhang L, Liu Y, Guan S, Li Q (2019) Enhancement of the apparent solubility and bioavailability of Tadalafil nanoparticles via anti solvent precipitation. Eur J Pharm Sci 128:222–231. https://doi.org/10.1016/j.ejps.2018.12.005
Regulska K, Regulski M, Wzgarda A, Kotowska A, Ignasiak A, Cwiertnia B, Stanisz B (2019) Does Polyvinylpyrrolidone improve the chemical stability of cilazapril in solid state? Iran J Pharm Res 18:579–595. https://doi.org/10.22037/ijpr.2019.1100640
Rogera C, Bucha C, Mullera T, Leemput J, Demizieux L, Pasilly-Degrace P, Kunos G, Verges B, Degrace P, Jourdan T (2020) Simultaneous inhibition of peripheral CB1R and iNOS mitigates obesity-related dyslipidemia through distinct mechanisms. Diabetes 69:2120–2132. https://doi.org/10.2337/db20-0078
Sakurai A, Sakai T, Sako K, Maitani Y (2012) Polymer combination increased both physical stability and oral absorption of solid dispersions containing a low glass transition temperature drug: physicochemical characterization and in-vivo study. Chem Pharm Bull (Tokyo) 60:459–464. https://doi.org/10.1248/cpb.60.459
Shah TJ, Amin A, Parikh JR, Parikh RH (2007) Process optimization and characterizations of poloxamer solid dispersions of a poorly water-soluble drug. AAPS Pharm Sci Tech 8:E18–E24. https://doi.org/10.1208/pt0802029
For recent works concerning the synthesis of CB1R restricted peripheral blockers, see: a) Amato G, Manke A, Wiethe R, Vasukuttan V, Snyder R, Decker A, Runyon S, Maitra R. Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1 Receptor. J Med Chem 2019; 62: 6330–6345. https://doi.org/10.1021/acs.jmedchem.9b00727.; b) Matthews JM, McNally JJ, Connolly PJ, Xia M, Zhu B, Black S, Chen C, Tang Y, Macielag MJ. Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists. Bioorg Med Chem Lett 2016; 26: 5346–5349. https://doi.org/10.1016/j.bmcl.2016.09.025; c) Sharma MK, Machhi J, Murumkar P, Yadav MR. New role of phenothiazine derivatives as peripherally acting CB1 receptor antagonizing anti-obesity agents Sci Rep 2018; 8: 1650. https://doi.org/10.1038/s41598-018-20078-w
Shin H, Han JH, Yoon J, Sim HJ, Yang S, Lee EK, Kulkarni RN, Egan JM, Kim W (2018) Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. J Cell Mol Med 22:2337–2345. https://doi.org/10.1111/jcmm.13523
Shrestha N, Cuffe J, Hutchinson DS, Headrick JP, Perkins AV, McAinch AJ, Hryciw DH (2018) Peripheral modulation of the endocannabinoid system in metabolic disease. Drug Discov Today 23:592–604. https://doi.org/10.1016/j.drudis.2018.01.029
Tam J, Szanda G, Drori A et al (2017) Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling. Mol Metab 6:1113–1125. https://doi.org/10.1016/j.molmet.2017.06.010
Tudurí E, Imbernon M, Hernández-Bautista RJ, Tojo M, Ferno J, Diéguez C, Nogueiras R (2017) GPR55: a new promising target for metabolism? J Mol Endocrinol 58:R191–R202. https://doi.org/10.1530/JME-16-0253
Tyurenkov IN, Kurkin DV, Bakulin DA, Volotova EV, Morkovin EI, Chafeev MZ, Karapetian RN (2018) Chemistry and hypoglycemic activity of GPR119 agonist ZB-16. Front Endocrinol 19:543. https://doi.org/10.3389/fendo.2018.00543
Wagh VT, Jagtap VA, Shaikh TJ, Nandedkar SY (2012) Formulation and evaluation of glimepiride solid dispersion tablets for their solubility enhancement. J Adv Sci Res 3:36–41
Yanjane SA, Ghurghure SM (2020) Formulation and in vitro characterization of oseltamivir fast dissolving tablets using super disintegrants. Asian J Res Chem Pharm Sci 8:40–52. https://doi.org/10.36673/AJRCPS.2020.v08.i01.A07
Acknowledgements
The authors appreciative to Rosa Isela del Villar, Georgina Duarte Lisci, Margarita Guzmán Villanueva, Marisela Gutiérrez Franco, Margarita Portilla Bazua, Elvia Reynoso Herrera, and Iván Puente Lee for the analytical support. Also are indebted with L.O. Flores-Sánchez, T.E. Villamar-Duque, and F. Barrón-Moreno from FES-Iztacala, UNAM for animal facilities.
Funding
This study was supported by Instituto de Ciencia y Tecnología del Distrito Federal (ICYTDF235/2010) and CONACyT (Proyecto de Ciencia Básica A1-S-13540). Eduardo Hernández-Vázquez is granted to the CONACyT for his doctoral fellowship (number 216082).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
All authors declare no conflict of interest in the current research work.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hernández-Vázquez, E., Estrada-Soto, S., Lumbreras-Zavala, N. et al. Enhancing the antidiabetic and antidyslipidemic activity of a 1,5-diarylpyrazole by solid dispersion pre-formulation. Chem. Pap. 76, 5551–5560 (2022). https://doi.org/10.1007/s11696-022-02260-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-022-02260-7