Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model.
We have previously reported that repeated oral doses of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduced diabetes-induced retinal vascular endothelial growth factor (VEGF) expression [Ayalasomayajula, S.P., Kompella, U.B., 2003. Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model. Eur J Pharmacol 458, 283-289] and that retinal celecoxib delivery can be improved by several-fold following subconjunctival administration [Ayalasomayajula, S.P., Kompella, U.B., 2004. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration. Pharm Res 21, 1797-1804]. The objective of the current study was to determine whether polymeric microparticles of celecoxib sustain retinal drug levels following subconjunctival administration and alleviate diabetes-induced oxidative stress in a streptozotocin-induced diabetic rat model. Biodegradable poly (lactide-co-glycolide) (PLGA; 85:15) microparticles of celecoxib were prepared using solvent evaporation method and characterized for their size, morphology, encapsulation efficiencies, and in vitro release. The celecoxib-PLGA microparticles or solution containing 75 microg of celecoxib was administered subconjunctivally to one eye (ipsilateral) of Sprague Dawley rats and drug levels in the retina, vitreous, lens, and cornea of ipsilateral and contralateral eyes were determined on 1, 7, and 14 days using high-performance liquid chromatography (HPLC). The effect of subconjunctivally administered celecoxib-PLGA microparticles on oxidative stress in day 14 diabetic rat retinas was determined by measuring the retinal glutathione (reduced (GSH) and oxidized (GSSG)), thiobarbituric acid reactive substances, and 4-hydroxynonenal levels using spectrofluorometric and colorimetric methods. Solvent evaporation method produced spherical celecoxib-PLGA microparticles with mean diameters of 3.9+/-0.6 microm and 68.5% loading efficiency. These microparticles sustained celecoxib release during the 49-day in vitro release study. Subconjunctivally administered celecoxib-PLGA microparticles sustained retinal and other ocular tissue drug levels during the 14-day study in rats. No detectable celecoxib levels were observed in the contralateral eye. The celecoxib-PLGA microparticles significantly inhibited the diabetes-induced increases in thiobarbituric acid reactive substance (P=0.012) and 4-hydroxynonenal levels (P=0.029). The particles also inhibited the GSH depletion and the increase in GSSH/GSH ratio associated with diabetes but the effects were not statistically significant (P=0.12). Thus, following subconjunctival administration, celecoxib-PLGA microparticles sustained retinal celecoxib delivery and inhibited diabetes-induced retinal oxidative damage, indicating their potential usefulness in treating diabetes-induced retinal abnormalities.
Ayalasomayajula
Surya P
SP
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
Kompella
Uday B
UB
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000068579:Celecoxib; D003228:Conjunctiva; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D003692:Delayed-Action Preparations; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D000447:Aldehydes; D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D011108:Polymers; D011720:Pyrazoles; D013449:Sulfonamides; D017392:Thiobarbituric Acid Reactive Substances; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005978:Glutathione; D000068579:Celecoxib; C027576:4-hydroxy-2-nonenal; D019803:Glutathione Disulfide