Pharmaceutical Research

, Volume 24, Issue 5, pp 899–908 | Cite as

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

  • K. Sonaje
  • J. L. Italia
  • G. Sharma
  • V. Bhardwaj
  • K. Tikoo
  • M. N. V. Ravi Kumar
Research Paper

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.

Key words

bioavailability biodegradable cyclosporine A ellagic acid free radicals nanoparticles nephrotoxicity oral delivery 

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

Notes

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.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • K. Sonaje
    • 1
  • J. L. Italia
    • 1
    • 2
  • G. Sharma
    • 1
    • 2
  • V. Bhardwaj
    • 1
  • K. Tikoo
    • 3
  • M. N. V. Ravi Kumar
    • 1
    • 2
  1. 1.Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)MohaliIndia
  2. 2.Centre for Pharmaceutical NanotechnologyNational Institute of Pharmaceutical Education and Research (NIPER)MohaliIndia
  3. 3.Department of Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research (NIPER)MohaliIndia

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