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Current Drug Delivery

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ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

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Research Article

Formulation and Characterization of Phytosomes as Drug Delivery System of Formononetin: An Effective Anti-Osteoporotic Agent

Author(s): Arun Agarwal, Muhammad Wahajuddin*, Swati Chaturvedi, Sandeep K. Singh, Mamunur Rashid, Richa Garg, DIvya Chauhan, Nazneen Sultana and Jiaur R. Gayen

Volume 21, Issue 2, 2024

Published on: 08 February, 2023

Page: [261 - 270] Pages: 10

DOI: 10.2174/1567201820666230124114906

Price: $65

Abstract

Background: Formononetin (FNT), a methoxy isoflavone, is a potential phytoconstituent utilized for refurbishing fractures in bone tissue. Conceding to its involvement in first-pass metabolism followed by glucuronidation, its absorption efficacy is limited. Hence, it belongs to the BCS class II classification.

Objective: We designed the present work to enhance FNT oral bioavailability by using Phospholipids (PL) as a promising carrier. Formononetin Phospholipid Complex (FNT-PC) was prepared by the solvent evaporation method and characterized.

Methods: FNT-PC was prepared by solvent evaporation method and characterization (FNT-PC) was performed using aqueous/n-octanol solubility and partition coefficient, FTIR, NMR, SEM, and in vivo pharmacokinetic study in female SD rats at 50 mg/kg.

Results: Physicochemical properties like aqueous/n-octanol solubility and partition coefficient were enhanced in FNT-PC. The FTIR spectrum confirmed there was no involvement of functional groups in the preparation of FNT-PC. Whereas, the NMR study resulted in the attachment of carbon (C-8) position of FNT by replacing the quaternary amine of PL to form FNT-PC. When scrutinized for its surface morphology, the FNT-PC exhibited the amorphous geometry that remarkably enhanced the dissolution of FNT (p<0.05) from its pure form. This dissolution effect was also affirmed by the per-oral administration of FNT-PC in female Sprague Dawley (SD) rats at 50 mg/kg dose. The pharmacokinetic profile showed the free FNT levels were markedly increased, correspondingly decreasing the conjugated FNT levels in rat plasma.

Conclusion: To summarize, FNT-PC could substantially reduce the first-pass metabolism with enhanced free concentration, improving oral bioavailability for therapeutic use.

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[1]
Nie, T.; Zhao, S.; Mao, L.; Yang, Y.; Sun, W.; Lin, X.; Liu, S.; Li, K.; Sun, Y.; Li, P.; Zhou, Z.; Lin, S.; Hui, X.; Xu, A.; Ma, C.W.; Xu, Y.; Wang, C.; Dunbar, P.R.; Wu, D. The natural compound, formononetin, extracted from Astragalus membranaceus increases adipocyte thermogenesis by modulating PPARγ activity. Br. J. Pharmacol., 2018, 175(9), 1439-1450.
[http://dx.doi.org/10.1111/bph.14139] [PMID: 29315511]
[2]
Clifton-Bligh, P.B.; Nery, M-L.; Clifton-Bligh, R.J.; Visvalingam, S.; Fulcher, G.R.; Byth, K.; Baber, R. Red clover isoflavones enriched with formononetin lower serum LDL cholesterol-a randomized, double-blind, placebo-controlled study. Eur. J. Clin. Nutr., 2015, 69(1), 134-142.
[http://dx.doi.org/10.1038/ejcn.2014.207] [PMID: 25369831]
[3]
Zhou, R.; Xu, L.; Ye, M.; Liao, M.; Du, H.; Chen, H. Formononetin inhibits migration and invasion of MDA-MB-231 and 4T1 breast cancer cells by suppressing MMP-2 and MMP-9 through PI3K/AKT signaling pathways. Horm. Metab. Res., 2014, 46(11), 753-760.
[http://dx.doi.org/10.1055/s-0034-1376977] [PMID: 24977660]
[4]
Wu, Y.; Zhang, X.; Li, Z.; Yan, H.; Qin, J.; Li, T. Formononetin inhibits human bladder cancer cell proliferation and invasiveness via regulation of miR-21 and PTEN. Food Funct., 2017, 8(3), 1061-1066.
[http://dx.doi.org/10.1039/C6FO01535B] [PMID: 28139790]
[5]
Yang, Y.; Zhao, Y.; Ai, X.; Cheng, B.; Lu, S. Formononetin suppresses the proliferation of human non-small cell lung cancer through induction of cell cycle arrest and apoptosis. Int. J. Clin. Exp. Pathol., 2014, 7(12), 8453-8461.
[PMID: 25674209]
[6]
Auyeung, K.K.W.; Law, P.C.; Ko, J.K.S. Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. Oncol. Rep., 2012, 28(6), 2188-2194.
[http://dx.doi.org/10.3892/or.2012.2056] [PMID: 23023137]
[7]
Singh, S.P. Wahajuddin; Tewari, D.; Pradhan, T.; Jain, G.K. PAMPA permeability, plasma protein binding, blood partition, pharmacokinetics and metabolism of formononetin, a methoxylated isoflavone. Food Chem. Toxicol., 2011, 49(5), 1056-1062.
[http://dx.doi.org/10.1016/j.fct.2011.01.012] [PMID: 21266188]
[8]
Wang, D.S.; Yan, L.Y.; Yang, D.Z.; Lyu, Y.; Fang, L.H.; Wang, S.B.; Du, G.H. Formononetin ameliorates myocardial ischemia/reperfusion injury in rats by suppressing the ROS-TXNIP-NLRP3 pathway. Biochem. Biophys. Res. Commun., 2020, 525(3), 759-766.
[http://dx.doi.org/10.1016/j.bbrc.2020.02.147] [PMID: 32145915]
[9]
Wang, G.; Liu, H.; Liu, Y.; Li, H.; Li, Z.; Shao, G.; Lv, X. Formononetin alleviates Streptococcus suis infection by targeting suilysin. Microb. Pathog., 2020, 147, 104388.
[http://dx.doi.org/10.1016/j.micpath.2020.104388] [PMID: 32687939]
[10]
Yi, L.; Lu, Y.; Yu, S.; Cheng, Q.; Yi, L. Formononetin inhibits inflammation and promotes gastric mucosal angiogenesis in gastric ulcer rats through regulating NF-κB signaling pathway. J. Recept. Signal Transduc., 2020, 42(1), 16-22.
[http://dx.doi.org/10.1080/10799893.2020.1837873] [PMID: 33100111]
[11]
Yuan, W.Y.; Li, L.Q.; Chen, Y.Y.; Zhou, Y.J.; Bao, K.F.; Zheng, J.; Hua, Y.Q.; Jiang, G.R.; Hong, M. Frontline Science: Two flavonoid compounds attenuate allergic asthma by regulating epithelial barrier via G protein‐coupled estrogen receptor: Probing a possible target for allergic inflammation. J. Leukoc. Biol., 2020, 108(1), 59-71.
[http://dx.doi.org/10.1002/JLB.3HI0220-342RR] [PMID: 32303124]
[12]
Yi, L.; Cui, J.; Wang, W.; Tang, W.; Teng, F.; Zhu, X.; Qin, J.; Wuniqiemu, T.; Sun, J.; Wei, Y.; Dong, J. Formononetin attenuates airway inflammation and oxidative stress in murine allergic asthma. Front. Pharmacol., 2020, 11, 533841.
[http://dx.doi.org/10.3389/fphar.2020.533841] [PMID: 33013383]
[13]
Zhang, Y.; Chen, C.; Zhang, J. Effects and significance of formononetin on expression levels of HIF 1α and VEGF in mouse cervical cancer tissue. Oncol. Lett., 2019, 18(3), 2248-2253.
[http://dx.doi.org/10.3892/ol.2019.10567] [PMID: 31452725]
[14]
Chaturvedi, S.; Azmi, L.; Shukla, I.; Naseem, Z.; Rao, C.V. Agarwal, NKJPM Gastroprotective effect of formononetin against ethanol-induced gastric ulceration in rats via augmentation of cytoprotective markers and curtailing apoptotic gene expression. Pharmacogn., 2018, 14(59), 605-612.
[15]
Jia, X.; Chen, J.; Lin, H.; Hu, M. Disposition of flavonoids viaenteric recycling: Enzyme-transporter coupling affects metabolism of biochanin A and formononetin and excretion of their phase II conjugates. J. Pharmacol. Exp. Ther., 2004, 310(3), 1103-1113.
[http://dx.doi.org/10.1124/jpet.104.068403] [PMID: 15128864]
[16]
Wu, B.; Kulkarni, K.; Basu, S.; Zhang, S.; Hu, M. First-pass metabolism viaUDP-glucuronosyltransferase: A barrier to oral bioavailability of phenolics. J. Pharm. Sci., 2011, 100(9), 3655-3681.
[http://dx.doi.org/10.1002/jps.22568] [PMID: 21484808]
[17]
Luo, L.Y.; Fan, M.X.; Zhao, H.Y.; Li, M.X.; Wu, X.; Gao, W.Y. Pharmacokinetics and bioavailability of the isoflavones formononetin and ononin and their in vitro absorption in ussing chamber and Caco-2 cell models. J. Agric. Food Chem., 2018, 66(11), 2917-2924.
[http://dx.doi.org/10.1021/acs.jafc.8b00035] [PMID: 29504397]
[18]
Chen, L.; Choi, J.; Leonard, S.W.; Banuvar, S.; Barengolts, E.; Viana, M.; Chen, S.N.; Pauli, G.F.; Bolton, J.L.; van Breemen, R.B. No clinically relevant pharmacokinetic interactions of a red clover dietary supplement with cytochrome p450 enzymes in women. J. Agric. Food Chem., 2020, 68(47), 13929-13939.
[http://dx.doi.org/10.1021/acs.jafc.0c05856] [PMID: 33197178]
[19]
Guo, B.; Xu, D.; Liu, X.; Liao, C.; Li, S.; Huang, Z.; Li, X.; Yi, J. Characterization and cytotoxicity of PLGA nanoparticles loaded with formononetin cyclodextrin complex. J. Drug Deliv. Sci. Technol., 2017, 41, 375-383.
[http://dx.doi.org/10.1016/j.jddst.2017.08.010]
[20]
Liu, X.; Xu, D.; Liao, C.; Fang, Y.; Guo, B. Development of a promising drug delivery for formononetin: Cyclodextrin-modified single-walled carbon nanotubes. J. Drug Deliv. Sci. Technol., 2018, 43, 461-468.
[http://dx.doi.org/10.1016/j.jddst.2017.11.018]
[21]
Urandur, S.; Banala, V.T.; Shukla, R.P.; Mittapelly, N.; Pandey, G.; Kalleti, N.; Mitra, K.; Rath, S.K.; Trivedi, R.; Ramarao, P.; Mishra, P.R. Anisamide-anchored lyotropic nano-liquid crystalline particles with AIE effect: A smart optical beacon for tumor imaging and therapy. ACS Appl. Mater. Interfaces, 2018, 10(15), 12960-12974.
[http://dx.doi.org/10.1021/acsami.7b19109] [PMID: 29577719]
[22]
Dias, P.H.; Scopel, M.; Martiny, S.; Bianchi, S.E.; Bassani, V.L.; Zuanazzi, J.A.S. Hydroxypropyl-β-cyclodextrin-containing hydrogel enhances skin formononetin permeation/retention. J. Pharm. Pharmacol., 2018, 70(7), 865-873.
[http://dx.doi.org/10.1111/jphp.12915] [PMID: 29635682]
[23]
Rao, T.; Gong, Y.F.; Peng, J.B.; Wang, Y.C.; He, K.; Zhou, H.H.; Tan, Z.R.; Lv, L.Z. Comparative pharmacokinetic study on three formulations of Astragali radix by an LC–MS/MS method for determination of formononetin in human plasma. Biomed. Chromatogr., 2019, 33(9), e4563.
[http://dx.doi.org/10.1002/bmc.4563] [PMID: 31025385]
[24]
Peter, V.H. Review–an update on the use of oral phospholipid excipients. Eur. J. Pharm. Sci., 2017, 108, 1-12.
[http://dx.doi.org/10.1016/j.ejps.2017.07.008] [PMID: 28711714]
[25]
Kuche, K.; Bhargavi, N.; Dora, C.P.; Jain, S. Drug-phospholipid complex—A go through strategy for enhanced oral bioavailability. AAPS PharmSciTech, 2019, 20(2), 43.
[http://dx.doi.org/10.1208/s12249-018-1252-4] [PMID: 30610392]
[26]
Alhakamy, N.A.A.; Fahmy, U.; Badr-Eldin, S.M.; Ahmed, O.A.; Asfour, H.Z.; Aldawsari, H.M. Optimized icariin phytosomes exhibit enhanced cytotoxicity and apoptosis-inducing activities in ovarian cancer cells. Pharmaceutics, 2020, 12(4), 346.
[http://dx.doi.org/10.3390/pharmaceutics12040346] [PMID: 32290412]
[27]
Maiti, K.; Mukherjee, K.; Gantait, A.; Ahamed, H.N.; Mukherjee, P. Enhanced therapeutic benefit of quercetin–phospholipid complex in carbon tetrachloride–induced acute liver injury in rats: A comparative study. IJPT, 2005, 4, 84-90. http://dx.doi.org/1735-2657/05/42-84-90
[28]
Zhang, Y.; Huo, M.; Zhou, J. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput. Methods Programs Biomed., 2010, 99(3), 306-314.
[http://dx.doi.org/10.1016/j.cmpb.2010.01.007] [PMID: 20176408]
[29]
Mazumder, A.; Dwivedi, A.; du Preez, J.L.; du Plessis, J. In vitro wound healing and cytotoxic effects of sinigrin–phytosome complex. Int. J. Pharm., 2016, 498(1-2), 283-293.
[http://dx.doi.org/10.1016/j.ijpharm.2015.12.027] [PMID: 26706438]
[30]
Wang, H.; Cui, Y.; Fu, Q.; Deng, B.; Li, G.; Yang, J. A phospholipid complex to improve the oral bioavailability of flavonoids. Drug Dev. Ind. Pharm., 2015, 41(10), 1693-1703.
[http://dx.doi.org/10.3109/03639045.2014.991402] [PMID: 25496311]
[31]
Jermain, S.V.; Brough, C.; Williams, R.O. III Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update. Int. J. Pharm., 2018, 535(1-2), 379-392.
[http://dx.doi.org/10.1016/j.ijpharm.2017.10.051] [PMID: 29128423]
[32]
Tan, Q.; Liu, S.; Chen, X.; Wu, M.; Wang, H.; Yin, H.; He, D.; Xiong, H.; Zhang, J. Design and evaluation of a novel evodiamine-phospholipid complex for improved oral bioavailability. AAPS PharmSciTech, 2012, 13(2), 534-547.
[http://dx.doi.org/10.1208/s12249-012-9772-9] [PMID: 22454136]
[33]
Singh, C.; Bhatt, T.D.; Gill, M.S.; Suresh, S. Novel rifampicin–phospholipid complex for tubercular therapy: Synthesis, physicochemical characterization and in vivo evaluation. Int. J. Pharm., 2014, 460(1-2), 220-227.
[http://dx.doi.org/10.1016/j.ijpharm.2013.10.043] [PMID: 24188983]

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