Development of Biodegradable Nanoparticles for Oral Delivery of Ellagic Acid and Evaluation of Their Antioxidant Efficacy Against Cyclosporine A-Induced Nephrotoxicity in Rats
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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.
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.
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 wordsbioavailability biodegradable cyclosporine A ellagic acid free radicals nanoparticles nephrotoxicity oral delivery
Biopharmaceutical classification system
Bowman’s capsule diameter
blood urea nitrogen
capillary tuft diameter
Didodecyldimethyl ammonium bromide
reversed phase high performance liquid chromatography
thiobarbituric acid reacting substances
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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