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 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. 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.
Subject(s)
Antioxidants/therapeutic use , Cyclosporine/toxicity , Ellagic Acid/therapeutic use , Kidney Diseases/drug therapy , Nanoparticles/chemistry , Administration, Oral , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacokinetics , Biocompatible Materials/chemistry , Biological Availability , Cyclosporine/administration & dosage , Diffusion , Drug Compounding/methods , Ellagic Acid/chemistry , Ellagic Acid/pharmacokinetics , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/toxicity , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Lactic Acid/chemistry , Male , Microscopy, Polarization/methods , Permeability , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/chemistry , Polyvinyl Alcohol/chemistry , Rats , Rats, Sprague-Dawley , Treatment OutcomeABSTRACT
Ellagic acid (EA) is a potent antioxidant marketed as a nutritional supplement. Its pharmacological activity has been reported in wide variety of disease models; however its use has been limited owing to its poor biopharmaceutical properties, thereby poor bioavailability. The objective of the current study was to develop chitosan-glycerol phosphate (C-GP) in situ gelling system for sustained delivery of ellagic acid (EA) via subcutaneous route. EA was incorporated in the system employing propylene glycol (PG) and triethanolamine (TEA) as co-solvents; on the other hand EA loaded PLGA nanoparticles (np) were dispersed in the gelling system using water. These in situ gelling systems were thoroughly characterized for mechanical, rheological and swelling properties. These systems are liquid at room temperature and gels at 37 degrees C. The EA C-GP system showed an initial burst release in vitro with about 85% drug released in 12 h followed by a steady release till 160 h, on the other hand EA nanoparticles entrapped in the C-GP system displayed sustained release till 360 h. The histopathological analysis indicates the absence of inflammation on administration, suggesting that these formulations are safe during the studied period. Furthermore, the antioxidant potential of EA C-GP and EA np C-GP gels has been evaluated against cyclosporine induced nephrotoxicity in rats. The data indicates that formulations were effective against cyclosporine induced nephrotoxicity, where the EA C-GP gels showed activity at 10 times lower dose and the EA np C-GP gels at 150 times lower dose when compared to orally given EA. Formulating nanoparticles of EA and incorporating them in C-GP system results in 15 times lowering of dose in comparison EA C-GP gels which is quite significant. Together, these results indicate that the bioavailability of ellagic acid can be improved by subcutaneous formulations administered as simple EA or EA nps.
