Skip to main content
SpringerLink
Log in

Enhanced Solubility and Bioavailability of Naringenin via Liposomal Nanoformulation: Preparation and In Vitro and In Vivo Evaluations

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

This study was aimed at preparing orally administered naringenin-loaded liposome for pharmacokinetic and tissue distribution studies in animal models. The liposomal system, consisting of phospholipid, cholesterol, sodium cholate, and isopropyl myristate, was prepared using the thin-film hydration method. Physicochemical characterization of naringenin-loaded liposome such as particle size, zeta potential, and encapsulation efficiency produced 70.53 ± 1.71 nm, −37.4 ± 7.3 mV, and 72.2 ± 0.8%, respectively. The in vitro release profile of naringenin from the formulation in three different media (HCl solution, pH 1.2; acetate buffer solution, pH 4.5; phosphate buffer solution, pH 6.8) was significantly higher than the free drug. The in vivo studies also revealed an increase in AUC of the naringenin-loaded liposome from 16648.48 to 223754.0 ng·mL−1 h as compared with the free naringenin. Thus, approximately 13.44-fold increase in relative bioavailability was observed in mice after oral administration. The tissue distribution further showed that the formulation was very predominant in the liver. These findings therefore indicated that the liposomal formulation significantly improved the solubility and oral bioavailability of naringenin, thus leading to wider clinical applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Shulman M, Cohen M, Soto-Gutierrez A, Yagi H, Wang H, Goldwasser J, et al. Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin. Plos ONE. 2011;6, e18033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wilcox LJ, Borradaile NM, Huff MW. Antiatherogenic properties of naringenin, a citrus flavonoid. Cardiovasc Drug Rev. 1999;17(2):160–78.

    Article  CAS  Google Scholar 

  3. Lee YS, Reidenberg MM. A method for measuring naringenin in biological fluids and its disposition from grapefruit juice by man. Pharmacology. 1998;56(6):314–7.

    Article  CAS  PubMed  Google Scholar 

  4. Cayci C, Wahlquist TC, Seckin SI, Ozcan V, Tekinay AB, Martens TP, et al. Naringenin inhibits neointimal hyperplasia following arterial reconstruction with interpositional vein graft. Ann Plast Surg. 2010;64(1):105–13.

    Article  CAS  PubMed  Google Scholar 

  5. Fernandez X, Merck F, Kerdudo A. Conservateurs pour cosmétiques–Antioxydants et Anti-UV. Techniques de l’Ingénieur. 2012.

  6. Di PT, Auteri A. Action of S 5682 on the complement system. In vitro and in vivo study. Int Angiol J Int Union Angiol. 1988;7(3):475.

    Google Scholar 

  7. Cushnie TP, Lamb AJ. Recent advances in understanding the antibacterial properties of flavonoids. Int J Antimicrob Agents. 2011;38(2):99–107.

    Article  CAS  PubMed  Google Scholar 

  8. Lee C, Jeong T, Choi Y, Hyun B, Oh G, Kim E, et al. Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun. 2001;284(3):681–8(8).

    Article  CAS  PubMed  Google Scholar 

  9. Lee MH, Yoon S, Moon JO. The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol Pharm Bull. 2004;27(1):72–6.

    Article  CAS  PubMed  Google Scholar 

  10. Park JH, Jin CY, Lee BK, Kim GY, Choi YH, Jeong YK. Naringenin induces apoptosis through downregulation of Akt and caspase-3 activation in human leukemia THP-1 cells. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2008;46(12):3684–90.

    Article  CAS  Google Scholar 

  11. Peter F, Kim D-H. In vitro inhibition of dihydropyridine oxidation and aflatoxin B1 activation in human liver microsomes by naringenin and other flavonoids. Carcinogenesis. 1990;11(12):2275–9.

    Article  Google Scholar 

  12. Kanaze FI, Bounartzi MI, Georgarakis M, et al. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr. 2007;61(4):472–7.

    CAS  PubMed  Google Scholar 

  13. Erlund I, Silaste ML, Alfthan G, et al. Plasma concentrations of the flavonoids hesperetin, naringenin and quercetin in human subjects following their habitual diets, and diets high or low in fruit and vegetables. Eur J Clin Nutr. 2002;56(9):891–8.

    Article  CAS  PubMed  Google Scholar 

  14. Jonathan G, Cohen PY, Wenyu L, 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(5):963–71.

    Article  Google Scholar 

  15. Richard A J, Zhaleh A V, Ribnicky D M, et al. Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes. Evidence-based complementary and alternative medicine: eCAM. 2013;2013(4):549750–549750.

  16. Goldwasser J, Cohen PY, Yang E, et al. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARα, PPARγ and LXRα. Plos ONE. 2010;5(8), e12399.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sessa G, Weissmann G. Phospholipid spherules (liposomes) as a model for biological membranes. Journal of Lipid Research. 1968;9(3).

  18. Liu D, Hu H, Lin Z, Chen D, Zhu Y, Hou S, et al. Quercetin deformable liposome: preparation and efficacy against ultraviolet B induced skin damages in vitro and in vivo. J Photochem Photobiol B Biol. 2013;127c(1627):8–17.

    Article  Google Scholar 

  19. Tester CC, Brock RE, Wu CH, Krejci MR, Weigand S, Joester D. In vitro synthesis and stabilization of amorphous calcium carbonate (ACC) nanoparticles within liposomes. Crystengcomm. 2011;12(12):3975–8.

    Article  Google Scholar 

  20. Slingerland M, Guchelaar HJ, Gelderblom H. Liposomal drug formulations in cancer therapy: 15 years along the road. Drug Discov Today. 2012;17(3):160–6.

    Article  CAS  PubMed  Google Scholar 

  21. Huang Z, Li X, Zhang T, Song Y, She Z, Li J, et al. Progress involving new techniques for liposome preparation. Asian J Pharm Sci. 2014;9:176–82.

    Article  Google Scholar 

  22. Fan Y, Ma L, Zhang W, Cui X, Zhen Y, Suolangzhaxi, et al. Liposome can improve the adjuvanticity of astragalus polysaccharide on the immune response against ovalbumin. Int J Biol Macromol. 2013;60(6):206–12.

    Article  CAS  PubMed  Google Scholar 

  23. Fan Y, Liu J, Wang D, Song X, Yuanliang HU, Zhang C, et al. The preparation optimization and immune effect of epimedium polysaccharide-propolis flavone liposome. Carbohydr Polym. 2013;94(1):24–30.

    Article  CAS  PubMed  Google Scholar 

  24. Senior JH. Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst. 1987;3(2):123–93.

    CAS  PubMed  Google Scholar 

  25. Zhu Y, Wang M, Zhang J, Peng W, Firempong CK, Deng W, et al. Improved oral bioavailability of capsaicin via liposomal nanoformulation: preparation, in vitro drug release and pharmacokinetics in rats. Arch Pharm Res. 2014;38:512–21.

    Article  PubMed  Google Scholar 

  26. Yuan Z, Yu J, Tong S, Li W, Min P, Xia C, et al. Preparation and in vitro evaluation of povidone-sodium cholate-phospholipid mixed micelles for the solubilization of poorly soluble drugs. Arch Pharm Res. 2010;33(6):911–7.

    Article  Google Scholar 

  27. Chang C, Shan-Shan T, Ying X, Li W, Min F, Yan-Ru G, et al. Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo. Acta Pharmacol Sin. 2011;32(7):973–80.

    Article  Google Scholar 

  28. Yi C, Fu M, Cao X, Tong S, Zheng Q, Firempong CK, et al. Enhanced oral bioavailability and tissue distribution of a new potential anticancer agent, Flammulina velutipes sterols, through liposomal encapsulation. J Agric Food Chem. 2013;61(25):5961–71.

    Article  CAS  PubMed  Google Scholar 

  29. Arouri A, Hansen AH, Rasmussen TE, Mouritsen OG. Lipases, liposomes and lipid-prodrugs. Curr Opin Colloid Interface Sci. 2013;18(5):419–31.

    Article  CAS  Google Scholar 

  30. Choudhury H, Gorain B, Karmakar S, Biswas E, Dey G, Barik R, et al. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm. 2014;460(1–2):131–43.

    Article  CAS  PubMed  Google Scholar 

  31. Fang JY, Hwang TL, Huang YL, Fang CL. Enhancement of the transdermal delivery of catechins by liposomes incorporating anionic surfactants and ethanol. Int J Pharm. 2006;310(1–2):131–8.

    Article  CAS  PubMed  Google Scholar 

  32. Bshara H, Osman R, Mansour S, El-Shamy EHA. Chitosan and cyclodextrin in intranasal microemulsion for improved brain buspirone hydrochloride pharmacokinetics in rats. Carbohydr Polym. 2014;99(1):297–305.

    Article  CAS  PubMed  Google Scholar 

  33. Yan YX, Yun MSPC, Qi NP. Preparation of silymarin proliposome: a new way to increase oral bioavailability of silymarin in beagle dogs. Int J Pharm. 2006;319(1–2):162–8.

    Article  Google Scholar 

  34. Zhu Y, Peng W, Zhang J, Wang M, Firempong CK, Feng C, et al. Enhanced oral bioavailability of capsaicin in mixed polymeric micelles: preparation, in vitro and in vivo evaluation. J Funct Foods. 2014;8(1):358–66.

    Article  CAS  Google Scholar 

  35. Zhu Y, Peng W, Zhang J, et al. Enhanced oral bioavailability of capsaicin in mixed polymeric micelles: preparation, in vitro and in vivo evaluation. J Funct Foods. 2014;8:358–66.

    Article  CAS  Google Scholar 

  36. Zhu Y, Zhang J, Zheng Q, et al. In vitro and in vivo evaluation of capsaicin‐loaded microemulsion for enhanced oral bioavailability. J Sci Food Agric. 2015;95(13):2678–85.

    Article  CAS  PubMed  Google Scholar 

  37. Yang Y, Xie X, Yang Y, et al. Photo–responsive and NGR–mediated multifunctional nanostructured lipid carrier for tumor–specific therapy. J Pharm Sci. 2015;104(4):1328–39.

    Article  CAS  PubMed  Google Scholar 

  38. Dressman JB, Reppas C. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2000;11 suppl 2:S73–80.

    CAS  Google Scholar 

  39. Guo L, Chen J, Qiu Y, Zhang S, Xu B, Gao Y. Enhanced transcutaneous immunization via dissolving microneedle array loaded with liposome encapsulated antigen and adjuvant. Int J Pharm. 2013;447(1–2):22–30.

    Article  CAS  PubMed  Google Scholar 

  40. Rane S, Prabhakar B, Bombay M. Influence of liposome composition on paclitaxel entrapment and pH sensitivity of liposomes. Int J Pharmtech Res. 2009;1(3):914–7.

    CAS  Google Scholar 

  41. Moog R, Brandl M, Schubert R, et al. Effect of nucleoside analogues and oligonucleotides on hydrolysis of liposomal phospholipids. Int J Pharm. 2000;206(1–2):43–53.

    Article  CAS  PubMed  Google Scholar 

  42. Schroeder A, Kost J, Barenholz Y. Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes. Chem Phys Lipids. 2009;162(1–2):1–16.

    Article  CAS  PubMed  Google Scholar 

  43. Liu X, Wei S, Bo Z, et al. Clarithromycin-loaded liposomes offering high drug loading and less irritation. Int J Pharm. 2013;443(1–2):318–27.

    Article  CAS  PubMed  Google Scholar 

  44. Sharma SK, Vij AS, Sharma M. Mechanisms and clinical uses of capsaicin. Eur J Pharmacol. 2013;720(1):55–62.

    Article  CAS  PubMed  Google Scholar 

  45. Ma Y, Li P, Chen D, Fang T, Li H, Su W. LC/MS/MS quantitation assay for pharmacokinetics of naringenin and double peaks phenomenon in rats plasma. Int J Pharm. 2006;307(2):292–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant 30973677, 81373371), the Doctoral Fund of Ministry of Education of China (Grant 20113227110012), Special Funds for 333 and 331 projects (BRA2013198) and Industry-University-Research Institution Cooperation (JHB2012-37, GY2013055) in Jiangsu province and Zhenjiang, and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors are grateful to Emmanuel Omari-Siaw at Jiangsu University for English correcting. The authors also thank the University Ethics Committee for the kind guidance in the animal experiments.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, 212013, People’s Republic of China

    Yuanwen Wang, Shicheng Wang, Caleb Kesse Firempong, Huiyun Zhang, Miaomiao Wang, Ya Zhang, Yuan Zhu, Jiangnan Yu & Ximing Xu

Authors
  1. Yuanwen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shicheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caleb Kesse Firempong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huiyun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miaomiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ya Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiangnan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ximing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jiangnan Yu or Ximing Xu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Wang, S., Firempong, C.K. et al. Enhanced Solubility and Bioavailability of Naringenin via Liposomal Nanoformulation: Preparation and In Vitro and In Vivo Evaluations. AAPS PharmSciTech 18, 586–594 (2017). https://doi.org/10.1208/s12249-016-0537-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-016-0537-8

KEY WORDS

Search

Navigation