Skip to main content
SpringerLink
Log in

Development of Biodegradable Nanoparticles for Oral Delivery of Ellagic Acid and Evaluation of Their Antioxidant Efficacy Against Cyclosporine A-Induced Nephrotoxicity in Rats

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Ellagic acid (EA), a dietary antioxidant associated with poor biopharmaceutical properties, was encapsulated into poly(lactide-co-glycolide) (PLGA) and polycaprolactone (PCL) nanoparticles to improve oral bioavailability.

Materials and Methods

EA-loaded nanoparticles were prepared following emulsion–diffusion–evaporation method employing didodecyldimethyl ammonium bromide (DMAB) and polyvinyl alcohol (PVA) as stabilizers. In vitro release was investigated in phosphate buffer (pH 7.4). The in situ permeation studies were performed in rats. The antioxidant potential of the DMAB-stabilized nanoparticulate formulations was evaluated against cyclosporine A (CyA)-induced nephrotoxicity in rats.

Results

EA-loaded PLGA and PCL nanoparticles have been succesfully prepared employing PEG 400 as co-solvent to solubilize EA. The stabilizers influenced the particle size and encapsulation efficiency. DMAB when used as stabilizer to particles of ~120 nm and ~50% encapsulation, whereas PVA led to ~290 nm and ~60% encapsulation at 5% initial loading (w/w of polymer). The in vitro release of EA from the nanoparticles followed Higuchi's square root pattern and was faster with PVA-stabilized particles in comparison to those stabilized with DMAB. From the in situ permeation studies in rats, it was evident that intestinal uptake of EA as DMAB-stabilized nanoparticles was significantly higher as compared to the sodium carboxymethyl cellulose suspension and the PVA-stabilized particles. EA and EA nanoparticles were able to prevent the CyA-induced nephrotoxicity in rats as evident by biochemical parameters as well as kidney histopathology.

Conclusion

The present study demonstrates the potential of EA nanoparticulate formulations in the prevention of CyA-induced nephrotoxicity at three times lower dose suggesting improved oral bioavailability of EA.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Abbreviations

BCS:

Biopharmaceutical classification system

BD:

Bowman’s capsule diameter

BUN:

blood urea nitrogen

CD:

capillary tuft diameter

CMC:

carboxy-methyl cellulose

CyA:

cyclosporine A

DMAB:

Didodecyldimethyl ammonium bromide

EA:

ellagic acid

EDE:

emulsion-diffusion-evaporation

GIT:

gastro-intestinal tract

mEDE:

modified emulsion-diffusion-evaporation

PC:

plasma creatinine

PCL:

Polycaprolactone

PEG:

polyethylene glycol

PLGA:

poly(lactide-co-glycolide)

PVA:

polyvinyl alcohol

RP-HPLC:

reversed phase high performance liquid chromatography

SD:

Sprague Dawley

TBARS:

thiobarbituric acid reacting substances

References

  1. H. Sies. Oxidative stress: oxidants and antioxidants. Exp. Physiol. 82:291–295 (1997).

    PubMed  CAS  Google Scholar 

  2. B. Halliwell and J. M. Gutteridge. Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet 13:96–1397 (1984).

    Google Scholar 

  3. M. Hashida. Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes. J. Control. Release 109:101–107 (2005).

    Article  PubMed  CAS  Google Scholar 

  4. Y. Gilgun-sherki, E. Melamed, and D. Offen. Oxidative stress induced neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40:959–975 (2001).

    Article  PubMed  CAS  Google Scholar 

  5. S. Beatty, H. Koh, M. Phil, D. Henson, and M. Boulton. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv. Ophthalmol. 45:115–134 (2000).

    Article  PubMed  CAS  Google Scholar 

  6. R. A. Floyd. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc. Soc. Exp. Biol. Med. 222:236 (1999).

    Article  PubMed  CAS  Google Scholar 

  7. R. Rezzani. Exploring cyclosporine A-side effects and the protective role-played by antioxidants: the morphological and immunohistochemical studies. Histol. Histopathol. 21:301–316 (2006).

    PubMed  CAS  Google Scholar 

  8. A. Atessahin, S. Yilmaz, I. Karahan, A. Ceribasi, and A. Karaoglu. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 212:116–123 (2005).

    Article  PubMed  CAS  Google Scholar 

  9. M. Khan, J. C. Shobha, I. K. Mohan, M. U. R. Naidu, C. Sundaram, S. Singh, P. Kuppusamy, and V. K. Kutala. Protective effect of Spirulina against doxorubicin-induced cardiotoxicity. Phytother. Res. 19:1030–1037 (2005).

    Article  PubMed  CAS  Google Scholar 

  10. R. K. Y. Zee-Cheng and C. C. Cheng. Ellagic acid. Drugs Future 11:1029–1033 (1986).

    Google Scholar 

  11. D. Venkat Ratnam, D. D. Ankola, V. Bhardwaj, D. K. Sahana, and M. N. V. R. Kumar. Role of antioxidants in prophylaxis and therapy: a pharmaceutical perspective. J. Control. Release 113:189–207 (2006).

    Article  PubMed  CAS  Google Scholar 

  12. G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413–420 (1995).

    Article  PubMed  CAS  Google Scholar 

  13. I. Bala, V. Bhardwaj, S. Hariharan, and M. N. V. R. Kumar. Analytical methods for assay of ellagic acid and its solubility studies. J. Pharm. Biomed. Anal. 40:206–210 (2006).

    Article  PubMed  CAS  Google Scholar 

  14. I. Bala, V. Bhardwaj, S. Hariharan, S. V. Kharade, N. Roy, and M. N. V. R. Kumar. Sustained release nanoparticulate formulation containing antioxidant ellagic acid as potential prophylaxis system for oral administration. J. Drug Target. 14:27–34 (2006).

    Article  PubMed  CAS  Google Scholar 

  15. B. Doyle and L. A. Griffiths. The metabolism of ellagic acid in the rat. Xenobiotica 10:247–256 (1980).

    Article  PubMed  CAS  Google Scholar 

  16. R. W. Teel. Distribution and metabolism of ellagic acid in the mouse following intraperitoneal administration. Cancer Lett. 34:165–171 (1987).

    Article  PubMed  CAS  Google Scholar 

  17. V. Bhardwaj, S. Hariharan, I. Bala, A. Lamprecht, N. Kumar, R. Panchagnula, and M. N. V. R. Kumar. Pharmaceutical aspects of polymeric nanoparticles for oral delivery. J. Biomed. Nanotech. 1:235–258 (2005).

    Article  CAS  Google Scholar 

  18. S. Hariharan, V. Bharadwaj, I. Bala, J. Sitterberg, U. Bakowsky, and M. N. V. R. Kumar. Design of estradiol loaded PLGA nanoparticulate formulations: a potential oral delivery system for hormone therapy. Pharm. Res. 23:184–195 (2005).

    Article  CAS  Google Scholar 

  19. L. Araujo, M. Sheppard, R. Lobenberg, and J. Kreuter. Uptake of PMMA nanoparticles from the gastrointestinal tract after oral administration to rats: modification of the body distribution after suspension in surfactant solutions and in oil vehicles. Int. J. Pharm. 176:209–224 (1999).

    Article  CAS  Google Scholar 

  20. P. Arbos, M. A. Campanero, M. A. Arangoa, and J. M. Irache. Nanoparticles with specific bioadhesive properties to circumvent the pre-systemic degradation of fluorinated pyrimidines. J. Control. Release 96:55–65 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. I. Bala, S. Hariharan, and M. N. V. R. Kumar. PLGA Nanoparticles in drug delivery: the state of the art. Crit. Rev. Ther. Drug Carr. Syst. 21:387–422 (2004).

    Article  CAS  Google Scholar 

  22. I. Bala, V. Bhardwaj, S. Hariharan, J. Sitterberg, U. Bakowsky, and M. N. V. R. Kumar. Design of biodegradable nanoparticles: a novel approach to encapsulating poorly soluble phytochemical ellagic acid. Nanotechnology 16:2819–2822 (2005).

    Article  CAS  Google Scholar 

  23. H. Ohkawa, N. Ohishi, and K. Yagi. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351–358 (1979).

    Article  PubMed  CAS  Google Scholar 

  24. C. Hsu, Z. Cui, R. J. Mumper, and M. Jay. Preparation and characterization of novel coenzyme Q10 nanoparticles engineered from microemulsion precursors. AAPS PharmSciTech 4:1–12 (2003).

    Article  Google Scholar 

  25. M. H. El-Shabouri. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int. J. Pharm. 249:101–108 (2002).

    Article  PubMed  CAS  Google Scholar 

  26. S. K. Sahoo, J. Panyam, S. Prabha, and V. Labhasetwar. Residual polyvinyl alcohol associatedwith poly (d,l-lactide-co-glycolide). nanoparticles affects their physical properties and cellular uptake. J. Control. Release 82:105–114 (2002).

    Article  PubMed  CAS  Google Scholar 

  27. I. Durak, H. I. Karabacak, S. Buyukkocak, M. Y. Cimen, M. Kacmaz, E. Omeroglu, and H. S. Ozturk. Impaired antioxidant defense system in the kidney tissues from rabbits treated with cyclosporine. Protective effects of vitamins E and C. Nephron 78:207–211 (1998).

    Article  PubMed  CAS  Google Scholar 

  28. K. C. Mun. Effect of epigallocatechin gallate on renal function in cyclosporine-induced nephrotoxicity. Transplant. Proc. 36:2133–2134 (2004).

    Article  PubMed  CAS  Google Scholar 

  29. V. Chander, N. Tirkey, and K. Chopra. Resveratrol, a polyphenolic phytoalexin protects against cyclosporine-induced nephrotoxicity through nitric oxide dependent mechanism. Toxicology 210:55–64 (2005).

    Article  PubMed  CAS  Google Scholar 

  30. M. Tariq, C. Morais, S. Sobki, M. Al Sulaiman, and A. Al Khader. N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats. Nephrol. Dial. Transplant. 14:923–929 (1999).

    Article  PubMed  CAS  Google Scholar 

  31. K. V. Kumar, M. U. Naidu, A. A. Shifow, A. Prayag, and K. S. Ratnakar. Melatonin: an antioxidant protects against cyclosporine-induced nephrotoxicity. Transplantation 67:1065–1068 (1999).

    Article  PubMed  CAS  Google Scholar 

  32. G. Inselmann, J. Hannemann, and K. Baumann. Cyclosporine A induced lipid peroxidation and influence on glucose-6-phosphatase in rat hepatic and renal microsomes. Res. Commun. Chem. Pathol. Pharmacol. 68:189–203 (1990).

    PubMed  CAS  Google Scholar 

  33. J. L. Italia, V. Bhardwaj, and M. N. V. R. Kumar. Disease, destination, dose and delivery aspects of ciclosporin: the state of the art. Drug Discov. Today 11:846–854 (2006).

    Article  PubMed  CAS  Google Scholar 

  34. T. F. Andoh, M. P. Gardner, and W. M. Bennett. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 64:1236–1240 (1997).

    Article  PubMed  CAS  Google Scholar 

  35. W. M. Bennett, A. DeMattes, and M. M. Meyer. Chronic cyclosporine nephropathy: the Achilles’ heel of immunosuppressive therapy. Kidney Int. 50:1089–1100 (1996).

    PubMed  CAS  Google Scholar 

  36. N. Origlia, M. Migliori, V. Panichi, C. Filippi, A. Bertelli, A. Carpi, and L. Giovannini. Protective effect of L-propionylcarnitine in chronic cyclosporine-a induced nephrotoxicity. Biomed. Pharmacother. 60:77–81 (2006).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported in partial by research grants from Department of Biotechnology (DT/PR5097/BRB/10391/2004) and Department of Science and Technology (no. SR/FTP/CS-32/2004), Government of India. Start-up funds to MNVRK, MS fellowship to KS, JLI, GS and PhD fellowship to VB from NIPER are gratefully acknowledged. Thanks are due to Rahul Mahajan and Dinesh Singh for providing the technical assistance.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India

    K. Sonaje, J. L. Italia, G. Sharma, V. Bhardwaj & M. N. V. Ravi Kumar

  2. Centre for Pharmaceutical Nanotechnology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India

    J. L. Italia, G. Sharma & M. N. V. Ravi Kumar

  3. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India

    K. Tikoo

Authors
  1. K. Sonaje
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. L. Italia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Bhardwaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Tikoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. N. V. Ravi Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. N. V. Ravi Kumar.

Additional information

This paper is dedicated to Ramesh C. Gupta, Professor and Agnes Brown Duggan Chair in Oncological Research, University of Louisville, US, who inspired me with his scientific approach, honesty and human warmth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sonaje, K., Italia, J.L., Sharma, G. et al. Development of Biodegradable Nanoparticles for Oral Delivery of Ellagic Acid and Evaluation of Their Antioxidant Efficacy Against Cyclosporine A-Induced Nephrotoxicity in Rats. Pharm Res 24, 899–908 (2007). https://doi.org/10.1007/s11095-006-9207-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-9207-y

Key words

Search

Navigation