Development of biodegradable nanoparticles for oral delivery of ellagic acid and evaluation of their antioxidant efficacy against cyclosporine A-induced nephrotoxicity in rats.
OBJECTIVE
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.


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 successfully 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 approximately 120 nm and approximately 50% encapsulation, whereas PVA led to approximately 290 nm and approximately 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.


CONCLUSIONS
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.
Sonaje
K
K
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India.
Italia
J L
JL
Sharma
G
G
Bhardwaj
V
V
Tikoo
K
K
Kumar
M N V Ravi
MN
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001672:Biocompatible Materials / Q000737:chemistry; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000633:toxicity*; D004058:Diffusion; D004339:Drug Compounding / Q000379:methods; D004610:Ellagic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008859:Microscopy, Polarization / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D010539:Permeability; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D011142:Polyvinyl Alcohol / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D000975:Antioxidants; D001672:Biocompatible Materials; D007166:Immunosuppressive Agents; D011091:Polyesters; D011108:Polymers; D004610:Ellagic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; C016240:polycaprolactone; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D016572:Cyclosporine; D011142:Polyvinyl Alcohol