Abstract
Naringenin exerts anti-inflammatory, hypolipidemic, and hepatoprotective effects; however, it shows low oral bioavailability because of poor water solubility. In this work, cocrystals of naringenin were formed to address these issues. Using the solution crystallization method, various naringenin cocrystals were prepared with different cocrystal coformers, including naringenin-nicotinamide, naringenin-isonicotinamide, naringenin-caffeine, naringenin-betaine, and naringenin-L-proline. The formation of these cocrystals was assayed by using DSC, XRD, and FT-IR spectroscopy. The stoichiometric ratio of naringenin and the CCFs in the corresponding cocrystals was investigated by NMR. The solubility of naringenin, as well as its dissolution rate, was markedly improved by forming cocrystals. The oral bioavailability of naringenin administered as naringenin-L-proline and naringenin-betaine cocrystals was achieved significantly greater than that of pure naringenin (p < 0.05). In particular, the Cmax of naringenin-L-proline and naringenin-betaine cocrystals were 2.00-fold and 3.35-fold higher, and the AUC of naringenin-L-proline and naringenin-betaine cocrystals were 2.39-fold and 4.91-fold, respectively, higher than pure naringenin in rats. With the naringenin-betaine cocrystals for oral delivery, the drug distribution in the liver was significantly increased compared to pure naringenin. Accordingly, the naringenin-betaine cocrystals showed improved anti-hyperlipidemia effects on the C57 BL/6J PNPLA3 I148M transgenic mouse hyperlipidemia model. Collectively, cocrystal formation is a promising way to increase the bioavailability of naringenin for treating hyperlipidemia.
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References
Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420:1–10.
Cascone S. Modeling and comparison of release profiles: effect of the dissolution method. Eur J Pharm Sci. 2017;106:352–61.
Hu J, Johnston KP, Williams RO. Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs. Drug Dev Ind Pharm. 2004;30:233–45.
Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev. 2007;59:617–30.
Chun NH, Lee MJ, Song GH, Chang KY, Kim CS, Choi GJ. Combined anti-solvent and cooling method of manufacturing indomethacin-saccharin (IMC-SAC) co-crystal powders. J Cryst Growth. 2014;408:112–8.
Karashima M, Sano N, Yamamoto S, Arai Y, Yamamoto K, Amano N, et al. Enhanced pulmonary absorption of poorly soluble itraconazole by micronized cocrystal dry powder formulations. Eur J Pharm Biopharm. 2017;115:65–72.
Otaki T, Tanabe Y, Kojima T, Miura M, Ikeda Y, Koide T, et al. In situ monitoring of cocrystals in formulation development using low-frequency Raman spectroscopy. Int J Pharm. 2018;542:56–65.
Renugadevi J, Prabu SM. Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol. 2010;62:171–81.
Yoon H, Kim TW, Shin SY, Park MJ, Yong Y, Kim DW, et al. Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells. Bioorg Med Chem Lett. 2013;23:232–8.
Subramanian P, Arul D. Attenuation of NDEA-induced hepatocarcinogenesis by naringenin in rats. Cell Biochem Funct. 2013;31:511–7.
Ekambaram G, Rajendran P, Magesh V, Sakthisekaran D. Naringenin reduces tumor size and weight lost in N-methyl-N-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Nutr Res. 2008;28:106–12.
Francis AR, Shetty TK, Bhattacharya RK. Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N-nitro-N-nitrosoguanidine. Carcinogenesis. 1989;10:1953–5.
Leonardi T, Vanamala J, Taddeo SS, Davidson LA, Murphy ME, Patil BS, et al. Turner, apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats. Exp Biol Med(Maywood). 2010;235:710–7.
Arul D, Subramanian P. Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Biochem Biophys Res Commun. 2013;434:203–9.
Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, Ortega N, Perez-Mateos M, Muñiz P. Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric. 2010;90:1238–44.
Goldwasser J, Cohen PY, Lin W, Kitsberg D, Balaguer P, Polyak SJ, et al. Naringenin inhibits the assembly and long-term production of infectious hepatitis C virus particles through a PPAR-mediated mechanism. J Hepatol. 2011;55:963–71.
Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, et al. Apolipoprotein B dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008;47:1437–45.
Ortiz-Andrade RR, Sánchez-Salgado JC, Navarrete-Vázquez G, Webster SP, Binnie M, García-Jiménez S, et al. Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation. Diabetes Obes Metab. 2018;10:1097–104.
Seeram NP, Zhang Y, Henning SM, Lee R, Niu Y, Lin G, et al. Pistachio skin phenolics are destroyed by bleaching resulting in reduced antioxidative capacities. J Agric Food Chem. 2006;54:7036–40.
Zygmunt K, Faubert B, MacNeil J, Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. J Mol Struct. 2010;398:178–83.
Wang MJ, Chao PDL, Hou YC, Hsiu SL. Pharmacokinetics and conjugation metabolism of naringin and naringenin in rats after single dose and multiple dose administrations. J Food Drug Anal. 2006;14:247–53.
Kanaze F, Bounartzi M, Georgarakis M, Niopas I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr. 2007;61:472–7.
Xu XR, Yu HT, Hang L, Shao Y, Ding SH, Yang XW. Preparation of naringenin/ β-cyclodextrin complex and its more potent alleviative effect on choroidal neovascularization in rats. Biomed Res Int. 2014;2014:623509.
Gera S, Talluri S, Rangaraj N, Sampathi S. Formulation and evaluation of naringenin nanosuspensions for bioavailability enhancement. AAPS PharmSciTech. 2017;18:1–12.
Wang Y, Wang S, Firempong CK, Zhang H, Wang M, Zhang Y, et al. Enhanced solubility and bioavailability of naringenin via liposomal nanoformulation: preparation and in vitro and in vivo evaluations. AAPS PharmSciTech. 2017;18:586–94.
Khan AW, Kotta S, Ansari SH, Sharma RK, Ali J. Enhanced dissolution and bioavailability of grapefruit flavonoid naringenin by solid dispersion utilizing fourth generation carrier. Drug Dev Ind Pharm. 2015;41:772–9.
Zhang L, Li S, Zhang P, Liu T, Li Z, Yang G, et al. Solubilities of naringin and naringenin in different solvents and dissociation constants of naringenin. J Chem Eng Data. 2015;60:932–40.
Variankaval N, Wenslow R, Murry J, Hartman R, Helmy R, Kwong E, et al. Preparation and solid-state characterization of nonstoichiometric cocrystals off a phosphodiesterase-IV inhibitor annul L-tartaric acid. Cryst Growth Des. 2006;6:690–700.
Fang T, Wang Y, Ma Y, Su W, Bai Y, Zhao P. A rapid LC/MS/MS quantitation assay for naringin and its two metabolites in rats plasma. J Pharm Biomed Anal. 2006;40:454–9.
Pi J, Wang S, Li W, Kebebe D, Zhang Y, Zhang B, et al. A nano-cocrystal strategy to improve the dissolution rate and oral bioavailability of baicalein. Asian J Pharm Sci. 2018;3:57.
Pinto SS, Diogo HP. Thermochemical study of two anhydrous polymorphs of caffeine. J Chem Thermodyn. 2006;38:1515–22.
Kang Y, Gu J, Hu X. Syntheses, structure characterization and dissolution of two novel cocrystals of febuxostat. J Mol Struct. 2017;1130:480–6.
Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodríguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm. 2013;453:101–25.
Vasisht K, Chadha K, Karan M, Bhalla Y, Chadha R, Khullar S, et al. Co-crystals of hesperitin: structural, pharmacokinetic and pharmacodynamic evaluation. Cryst Growth Des. 2017;17:2386–405.
Semalty A, Semalty M, Singh D, Rawat MSM. Preparation and characterization of phospholipid complexes of naringenin for effective drug delivery. J Incl Phenom Macrocycl Chem. 2010;67:253–60.
Gao Y, Zu H, Zhang J. Enhanced dissolution and stability of adefovir dipivoxil by cocrystal formulation. J Pharm Pharmacol. 2011;63:483–90.
Hong C, Xie Y, Yao Y, Li G, Yuan X, Shen H. A novel strategy for pharmaceutical cocrystal generation without knowledge of stoichiometric ratio: myricetin cocrystals and a ternary phase diagram. Pharm Res. 2015;32:47–60.
Huang Y, Zhang B, Gao Y, Zhang J, Shi L. Baicalein-nicotinamide cocrystal with enhanced solubility, dissolution, and oral bioavailability. J Pharm Sci. 2014;103:2330–7.
Luo YH, Sun BW. Pharmaceutical co-crystals of pyrazinecarboxamide (PZA) with various carboxylic acids: crystal-lography, hirshfeld surfaces, and dissolution study. Cryst Growth Des. 2013;13:2098–106.
Maddileti D, Jayabun SK, Nangia A. Soluble cocrystals of the xanthine oxidase inhibitor febuxostat. Cryst Growth Des. 2013;13:3188–96.
Zhang X, Sun F, Zhang T, Jia J, Su H, Wang C, et al. Three pharmaceuticals cocrystals of adefovir: syntheses, structures and dissolution study. J Mol Struct. 2015;1100:395–400.
Li J, Wang L, Ye YQ, Fu X, Ren Q, Zhang H, et al. Improving the solubility of dexlansoprazole by cocrystallization with isonicotinamide. Eur J Pharm Sci. 2016;85:47–52.
Smith AJ, Kavuru P, Wojtas L, Zaworotko MJ, Shytle RD. Cocrystals of quercetin with improved solubility and oral bioavailability. Mol Pharm. 2011;8:1867–76.
Childs SL, Kandi P, Lingireddy SR. Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability. Mol Pharm. 2013;10:3112–27.
Liu MY, Hong C, Yao YS, Shen HY, Ji G, Li GW, et al. Development of a pharmaceutical cocrystal with solution crystallization technology: preparation, characterization, and evaluation of myricetin-proline cocrystals. Eur J Pharm Biopharm. 2016;107:151–9.
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This study was funded and supported by the National Natural Science Foundation of China (81673612).
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Cui, W., He, Z., Zhang, Y. et al. Naringenin Cocrystals Prepared by Solution Crystallization Method for Improving Bioavailability and Anti-hyperlipidemia Effects. AAPS PharmSciTech 20, 115 (2019). https://doi.org/10.1208/s12249-019-1324-0
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DOI: https://doi.org/10.1208/s12249-019-1324-0