Enhancement of Dissolution Rate of Quercetin Using Solid Dispersion Approach: In Vitro and In Vivo Evaluation

Author(s): Raghvendra Chaubey, Nimisha Srivastava*, Apoorva Singh

Journal Name: Nanoscience & Nanotechnology-Asia

Volume 10 , Issue 3 , 2020

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Graphical Abstract:


Abstract:

Objective: The objective of present study was to enhance the potential activities of Quercetin by improving its solubility and dissolution profiles through solid dispersion approach.

Method: A three level full factorial design (32) was adopted to study the possible combinations of polyethylene glycol (PEG) 6000 & pluronic F 127 (PF 127). The solid dispersions were prepared by solvent evaporation method and evaluated for percentage yield, drug content, aqueous solubility and drug release. For in vivo evaluations SD4 was incorporated into Carbopol base gel and subjected to anti-inflammatory activity using carrageenan-induced rat paw edema method.

Results: SD4 batch with drug to carrier ratio 1:1 showed release of 82.96 ± 1.76 % in 240 min following Higuchi’s model. It was 5.54 fold increment in solubility as compared to quercetin. SD4 batch was further evaluated by FTIR, DSC, PXRD and SEM. The crystallinity was significantly reduced and drug was homogeneously dispersed in the carrier as shown by the results of DSC, PXRD and SEM. The DPPH scavenging assay showed significance in the IC50 value of SD4 as compared to pure quercetin and ascorbic acid when subjected to one way ANOVA at 0.05 level of significance (P<0.0001). In vivo anti-inflammatory study showed 78.17 ± 0.156 % inhibition of edema by SD4 and 58.64 ± 0.640 % by pure quercetin which is significantly lower (P<0.05).

Conclusion: These findings demonstrate that the solid dispersion of quercetin shows increased solubility, dissolution profile, drug release and significant potential in enhancing the antiinflammatory activity of drug.

Keywords: Quercetin, solid dispersion, solubility, dissolution, anti-inflammatory, edema.

[1]
Scalbert, A.; Williamson, G. Dietary intake and bioavailability of polyphenols. J. Nutr., 2000, 130(8S), 2073S-2085S.
[http://dx.doi.org/10.1093/jn/130.8.2073S] [PMID: 10917926]
[2]
Zsila, F.; Bikádi, Z.; Simonyi, M. Probing the binding of the flavonoid, quercetin to human serum albumin by circular dichroism, electronic absorption spectroscopy and molecular modelling methods. Biochem. Pharmacol., 2003, 65(3), 447-456.
[http://dx.doi.org/10.1016/S0006-2952(02)01521-6] [PMID: 12527338]
[3]
Ross, J.A.; Kasum, C.M. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr., 2002, 22(1), 19-34.
[http://dx.doi.org/10.1146/annurev.nutr.22.111401.144957] [PMID: 12055336]
[4]
Leopoldini, M.; Russo, N.; Chiodo, S.; Toscano, M. Iron chelation by the powerful antioxidant flavonoid quercetin. J. Agric. Food Chem., 2006, 54(17), 6343-6351.
[http://dx.doi.org/10.1021/jf060986h] [PMID: 16910729]
[5]
Kelly, G.S. Quercetin. Monograph. Altern. Med. Rev., 2011, 16(2), 172-194.
[PMID: 21649459]
[6]
Cao, J.; Zhang, Y.; Chen, W.; Zhao, X. The relationship between fasting plasma concentrations of selected flavonoids and their ordinary dietary intake. Br. J. Nutr., 2010, 103(2), 249-255.
[http://dx.doi.org/10.1017/S000711450999170X] [PMID: 19747418]
[7]
Lakhanpal, P.; Rai, D.K. Quercetin: A versatile flavonoid. Internet J. Med. Update, 2007, 2(2), 22-37.
[8]
Kamei, H.; Kojima, T.; Koide, T.; Hasegawa, M.; Umeda, T.; Teraba, K.; Hashimoto, Y. Influence of OH group and sugar bonded to flavonoids on flavonoid-mediated suppression of tumor growth in vitro. Cancer Biother. Radiopharm., 1996, 11(4), 247-249.
[http://dx.doi.org/10.1089/cbr.1996.11.247] [PMID: 10851544]
[9]
Kim, H.P.; Mani, I.; Iversen, L.; Ziboh, V.A. Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins Leukot. Essent. Fatty Acids, 1998, 58(1), 17-24.
[http://dx.doi.org/10.1016/S0952-3278(98)90125-9] [PMID: 9482162]
[10]
Lee, K.M.; Hwang, M.K.; Lee, D.E.; Lee, K.W.; Lee, H.J. Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells. J. Agric. Food Chem., 2010, 58(9), 5815-5820.
[http://dx.doi.org/10.1021/jf903698s] [PMID: 20377179]
[11]
Chuang, C-C.; Martinez, K.; Xie, G.; Kennedy, A.; Bumrungpert, A.; Overman, A.; Jia, W.; McIntosh, M.K. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-α-mediated inflammation and insulin resistance in primary human adipocytes. Am. J. Clin. Nutr., 2010, 92(6), 1511-1521.
[http://dx.doi.org/10.3945/ajcn.2010.29807] [PMID: 20943792]
[12]
Ortega, M.G.; Saragusti, A.C.; Cabrera, J.L.; Chiabrando, G.A. Quercetin tetraacetyl derivative inhibits LPS-induced nitric oxide synthase (iNOS) expression in J774A.1 cells. Arch. Biochem. Biophys., 2010, 498(2), 105-110.
[http://dx.doi.org/10.1016/j.abb.2010.04.014] [PMID: 20417174]
[13]
Rivera, L.; Morón, R.; Sánchez, M.; Zarzuelo, A.; Galisteo, M. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity (Silver Spring), 2008, 16(9), 2081-2087.
[http://dx.doi.org/10.1038/oby.2008.315] [PMID: 18551111]
[14]
Mamani-Matsuda, M.; Kauss, T.; Al-Kharrat, A.; Rambert, J.; Fawaz, F.; Thiolat, D.; Moynet, D.; Coves, S.; Malvy, D.; Mossalayi, M.D. Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators. Biochem. Pharmacol., 2006, 72(10), 1304-1310.
[http://dx.doi.org/10.1016/j.bcp.2006.08.001] [PMID: 16959220]
[15]
Moon, Y.J.; Wang, L.; DiCenzo, R.; Morris, M.E. Quercetin pharmacokinetics in humans. Biopharm. Drug Dispos., 2008, 29(4), 205-217.
[http://dx.doi.org/10.1002/bdd.605] [PMID: 18241083]
[16]
Chebil, L.; Humeau, C.; Anthoni, J.; Dehez, F.; Engasser, J-M.; Ghoul, M. Solubility of flavonoids in organic solvents. J. Chem. Eng. Data, 2007, 52(5), 1552-1556.
[http://dx.doi.org/10.1021/je7001094]
[17]
Srinivas, K.; King, J.W.; Howard, L.R.; Monrad, J.K. Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water. J. Food Eng., 2010, 100(2), 208-218.
[http://dx.doi.org/10.1016/j.jfoodeng.2010.04.001]
[18]
Sun, M.; Wang, S.; Nie, S.; Zhang, J. Enhanced oral bioavailability of quercetin by nanostructured lipid carriers (1044.24). FASEB J., 2014, 18(1 Suppl.), 1044-1124.
[19]
Cai, X.; Fang, Z.; Dou, J.; Yu, A.; Zhai, G. Bioavailability of quercetin: problems and promises. Curr. Med. Chem., 2013, 20(20), 2572-2582.
[http://dx.doi.org/10.2174/09298673113209990120] [PMID: 23514412]
[20]
Vo, C.L-N.; Park, C.; Lee, B-J. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur. J. Pharm. Biopharm., 2013, 85(3 Pt B), 799-813.
[http://dx.doi.org/10.1016/j.ejpb.2013.09.007] [PMID: 24056053]
[21]
Xie, Y.; Li, G.; Yuan, X.; Cai, Z.; Rong, R. Preparation and in vitro evaluation of solid dispersions of total flavones of Hippophae rhamnoides L. AAPS PharmSciTech, 2009, 10(2), 631-640.
[http://dx.doi.org/10.1208/s12249-009-9246-x] [PMID: 19452282]
[22]
Li, B.; Konecke, S.; Harich, K.; Wegiel, L.; Taylor, L.S.; Edgar, K.J. Solid dispersion of quercetin in cellulose derivative matrices influences both solubility and stability. Carbohydr. Polym., 2013, 92(2), 2033-2040.
[http://dx.doi.org/10.1016/j.carbpol.2012.11.073] [PMID: 23399255]
[23]
Trapani, G.; Franco, M.; Latrofa, A.; Pantaleo, M.R.; Provenzano, M.R.; Sanna, E.; Maciocco, E.; Liso, G. Physicochemical characterization and in vivo properties of Zolpidem in solid dispersions with polyethylene glycol 4000 and 6000. Int. J. Pharm., 1999, 184(1), 121-130.
[24]
Ghanem, A.S.M.; Ali, H.S.M.; El-Shanawany, S.M.; Ibrahim, E-S.A. Solubility and dissolution enhancement of quercetin via preparation of spray dried microstructured solid dispersions. Thaiphesatchasan, 2013, 37, 12-24.
[25]
Fraile, M.; Buratto, R.; Gómez, B.; Martín, Á.; Cocero, M.J. Enhanced delivery of quercetin by encapsulation in poloxamers by supercritical antisolvent process. Ind. Eng. Chem. Res., 2014, 53(11), 4318-4327.
[http://dx.doi.org/10.1021/ie5001136]
[26]
Shah, T.J.; Amin, A.F.; Parikh, J.R.; Parikh, R.H. Process optimization and characterization of poloxamer solid dispersions of a poorly water-soluble drug. AAPS PharmSciTech, 2007, 8(2), 29.
[http://dx.doi.org/10.1208/pt0802029] [PMID: 17622107]
[27]
Won, D-H.; Kim, M-S.; Lee, S.; Park, J-S.; Hwang, S-J. Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process. Int. J. Pharm., 2005, 301(1-2), 199-208.
[http://dx.doi.org/10.1016/j.ijpharm.2005.05.017] [PMID: 16024189]
[28]
Modi, A.; Tayade, P. Enhancement of dissolution profile by solid dispersion (kneading) technique. AAPS PharmSciTech, 2006, 7(3), 68.
[http://dx.doi.org/10.1208/pt070368] [PMID: 17025249]
[29]
Park, S.H.; Song, I-S.; Choi, M-K. Preparation and characterization of quercetin-loaded solid dispersion by solvent evaporation and freeze-drying method. Mass Spectro. Lett., 2016, 7(3), 79-83.
[http://dx.doi.org/10.5478/MSL.2016.7.3.79]
[30]
Singh, D.; Rawat, M.S.; Semalty, A.; Semalty, M. Quercetin-phospholipid complex: An amorphous pharmaceutical system in herbal drug delivery. Curr. Drug Discov. Technol., 2012, 9(1), 17-24.
[http://dx.doi.org/10.2174/157016312799304507] [PMID: 21644920]
[31]
Lesjak, M.; Beara, I.; Simin, N.; Pintać, D.; Majkić, T.; Bekvalac, K.; Orčić, D.; Mimica-Dukić, N. Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J. Funct. Foods, 2018, 40, 68-75.
[http://dx.doi.org/10.1016/j.jff.2017.10.047]
[32]
Rogerio, A.P.; Dora, C.L.; Andrade, E.L.; Chaves, J.S.; Silva, L.F.; Lemos-Senna, E.; Calixto, J.B. Anti-inflammatory effect of quercetin-loaded microemulsion in the airways allergic inflammatory model in mice. Pharmacol. Res., 2010, 61(4), 288-297.
[http://dx.doi.org/10.1016/j.phrs.2009.10.005] [PMID: 19892018]
[33]
Misal, G.; Dixit, G.; Gulkari, V. Formulation and evaluation of herbal gel. Indian J. Nat. Prod. Resour., 2012, 3(4), 501-505.
[34]
Zeng, Y.; Nikitkova, A.; Abdelsalam, H.; Li, J.; Xiao, J. Activity of quercetin and kaemferol against Streptococcus mutans biofilm. Arch. Oral Biol., 2019, 98, 9-16.
[http://dx.doi.org/10.1016/j.archoralbio.2018.11.005] [PMID: 30419487]
[35]
Cheng, S-C.; Wu, Y-H.; Huang, W-C.; Pang, J.S.; Huang, T-H.; Cheng, C-Y. Anti-inflammatory property of quercetin through downregulation of ICAM-1 and MMP-9 in TNF-α-activated retinal pigment epithelial cells. Cytokine, 2019, 116, 48-60.
[http://dx.doi.org/10.1016/j.cyto.2019.01.001] [PMID: 30685603]
[36]
de Mello Costa, A.R.; Marquiafável, F.S.; de Oliveira Lima Leite Vaz, M.M.; Rocha, B.A.; Pires Bueno, P.C.; Amaral, P.L.M.; da Silva Barud, H.; Berreta-Silva, A.A. Quercetin-PVP K25 solid dispersions: preparation, thermal characterization and antioxidant activity. J. Therm. Anal. Calorim., 2010, 104(1), 273-278.
[http://dx.doi.org/10.1007/s10973-010-1083-3]
[37]
Li, Y-L.; Yang, Y.; Bai, T-C.; Zhu, J-J. Heat capacity for the binary system of quercetin and poly (vinylpyrrolidone) K30. J. Chem. Eng. Data, 2010, 55(12), 5856-5861.
[http://dx.doi.org/10.1021/je1008203]
[38]
Zhao, Y.; Xin, T.; Ye, T.; Yang, X.; Pan, W. Solid dispersion in the development of a nimodipine delayed-release tablet formulation. Asian J. Pharmaceut. Sci., 2014, 9(1), 35-41.
[http://dx.doi.org/10.1016/j.ajps.2013.11.006]
[39]
Homayouni, A.; Sadeghi, F.; Nokhodchi, A.; Varshosaz, J.; Garekani, H.A. Preparation and characterization of celecoxib solid dispersions; comparison of poloxamer-188 and PVP-K30 as carriers. Iran. J. Basic Med. Sci., 2014, 17(5), 322-331.
[PMID: 24967060]
[40]
Aboutaleb, A.E.; Abdel-Rahman, S.I.; Ahmed, M.O.; Younis, M.A. Improvement of domperidone solubility and dissolution rate by dispersion in various hydrophilic carriers. J. Appl. Pharm. Sci., 2016, 6(7), 133-139.
[http://dx.doi.org/10.7324/JAPS.2016.60720]


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VOLUME: 10
ISSUE: 3
Year: 2020
Page: [330 - 349]
Pages: 20
DOI: 10.2174/2210681209666190919095128
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