Improved In Vivo Effect of Chrysin As an Absorption Enhancer Via the Preparation of Ternary Solid Dispersion with Brij®L4 and Aminoclay

Overview

Journal Curr Drug Deliv

Publisher Bentham Science Publishers

Specialty Pharmacology

Date 2018 Sep 25

PMID 30246640

Citations 12

Authors

Sang Hoon Lee

Yeo-Song Lee

Jae Geun Song

Hyo-Kyung Han

Affiliations

Soon will be listed here.

Abstract

Background: Chrysin is a strong inhibitor of breast cancer resistance protein (BCRP) but it is practically insoluble in water. Effective solubilization of chrysin is critical for its pharmaceutical application as an absorption enhancer via inhibition of BCRP-mediated drug efflux.

Objective: This study aimed to develop an effective oral formulation of chrysin to improve its in vivo effect as an absorption enhancer.

Method: Solid dispersions (SDs) of chrysin were prepared with hydrophilic carriers having surface acting properties and a pH modulator. In vitro and in vivo characterizations were performed to select the optimal SDs of chrysin.

Results: SDs with Brij®L4 and aminoclay was most effective in increasing the solubility of chrysin by 13-53 fold at varying drug-carrier ratios. Furthermore, SDs significantly improved the dissolution rate and extent of drug release. SDs (chrysin: Brij®L4: aminoclay=1:3:5) achieved approximately 60% and 83% drug release within 1 h and 8 h, respectively, in aqueous medium, while the dissolution of the untreated chrysin was less than 13%. XRD patterns indicated the amorphous state of chrysin in SDs. The SD formulation was effective in improving the bioavailability of topotecan, a BCRP substrate in rats. Following oral administration of topotecan with the SDs of chrysin, the Cmax and AUC of topotecan was enhanced by approximately 2.6- and 2-fold, respectively, while the untreated chrysin had no effect.

Conclusion: The SD formulation of chrysin with Brij®L4 and aminoclay appeared to be promising in improving the dissolution of chrysin and enhancing its in vivo effect as an absorption enhancer.

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References

Jonker J, Smit J, Brinkhuis R, Maliepaard M, Beijnen J, Schellens J . Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000; 92(20):1651-6. DOI: 10.1093/jnci/92.20.1651. View

Walle T, Otake Y, Brubaker J, Walle U, Halushka P . Disposition and metabolism of the flavonoid chrysin in normal volunteers. Br J Clin Pharmacol. 2001; 51(2):143-6. PMC: 2014445. DOI: 10.1111/j.1365-2125.2001.01317.x. View

Taipalensuu J, Tornblom H, Lindberg G, Einarsson C, Sjoqvist F, Melhus H . Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther. 2001; 299(1):164-70. View

Kruijtzer C, Beijnen J, Rosing H, Ten Bokkel Huinink W, Schot M, Jewell R . Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 2002; 20(13):2943-50. DOI: 10.1200/JCO.2002.12.116. View

Havsteen B . The biochemistry and medical significance of the flavonoids. Pharmacol Ther. 2002; 96(2-3):67-202. DOI: 10.1016/s0163-7258(02)00298-x. View

Zhang S, Yang X, Morris M . Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol. 2004; 65(5):1208-16. DOI: 10.1124/mol.65.5.1208. View

Zhang S, Wang X, Sagawa K, Morris M . Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (-/-) mice. Drug Metab Dispos. 2004; 33(3):341-8. DOI: 10.1124/dmd.104.002501. View

Karatas A, Yuksel N, Baykara T . Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol. Farmaco. 2005; 60(9):777-82. DOI: 10.1016/j.farmac.2005.04.014. View

Mao Q, Unadkat J . Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 2005; 7(1):E118-33. PMC: 2751502. DOI: 10.1208/aapsj070112. View

10.

Castro G, Ferretti F, Blanco S . Determination of the overlapping pK(a) values of chrysin using UV-vis spectroscopy and ab initio methods. Spectrochim Acta A Mol Biomol Spectrosc. 2005; 62(1-3):657-65. DOI: 10.1016/j.saa.2005.02.013. View

11.

Yamagata T, Kusuhara H, Morishita M, Takayama K, Benameur H, Sugiyama Y . Effect of excipients on breast cancer resistance protein substrate uptake activity. J Control Release. 2007; 124(1-2):1-5. DOI: 10.1016/j.jconrel.2007.08.021. View

12.

Khoo B, Chua S, Balaram P . Apoptotic effects of chrysin in human cancer cell lines. Int J Mol Sci. 2010; 11(5):2188-99. PMC: 2885101. DOI: 10.3390/ijms11052188. View

13.

Gresa-Arribas N, Serratosa J, Saura J, Sola C . Inhibition of CCAAT/enhancer binding protein δ expression by chrysin in microglial cells results in anti-inflammatory and neuroprotective effects. J Neurochem. 2010; 115(2):526-36. DOI: 10.1111/j.1471-4159.2010.06952.x. View

14.

Seo S, Han H, Chun M, Choi H . Preparation and pharmacokinetic evaluation of curcumin solid dispersion using Solutol® HS15 as a carrier. Int J Pharm. 2012; 424(1-2):18-25. DOI: 10.1016/j.ijpharm.2011.12.051. View

15.

Chen Y, Yang Z, Wen C, Chang Y, Wang B, Hsiao C . Evaluation of the structure-activity relationship of flavonoids as antioxidants and toxicants of zebrafish larvae. Food Chem. 2012; 134(2):717-24. DOI: 10.1016/j.foodchem.2012.02.166. View

16.

Vo C, Park C, Lee B . Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013; 85(3 Pt B):799-813. DOI: 10.1016/j.ejpb.2013.09.007. View

17.

Yang L, Shao Y, Han H . Improved pH-dependent drug release and oral exposure of telmisartan, a poorly soluble drug through the formation of drug-aminoclay complex. Int J Pharm. 2014; 471(1-2):258-63. DOI: 10.1016/j.ijpharm.2014.05.009. View

18.

Prasad D, Chauhan H, Atef E . Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects. J Pharm Sci. 2014; 103(11):3511-3523. DOI: 10.1002/jps.24137. View

19.

Samarghandian S, Azimi-Nezhad M, Samini F, Farkhondeh T . Chrysin treatment improves diabetes and its complications in liver, brain, and pancreas in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol. 2016; 94(4):388-93. DOI: 10.1139/cjpp-2014-0412. View

20.

Sassa-Deepaeng T, Pikulkaew S, Okonogi S . Development of chrysin loaded poloxamer micelles and toxicity evaluation in fish embryos. Drug Discov Ther. 2016; 10(3):150-5. DOI: 10.5582/ddt.2016.01039. View