Delivery of celecoxib for treating diseases of the eye: influence of pigment and diabetes

Abstract

Importance of the field: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two major causes of blindness. In these disorders, growth factors such as vascular endothelial growth factor (VEGF) are upregulated, leading to either enhanced vascular permeability or proliferation of endothelium. While corticosteroid therapies available at present suffer from side effects including cataracts and elevated intraocular pressure, anti-VEGF antibody therapies require frequent intravitreal injections, a procedure that can potentially lead to retinal detachment or endophthalmitis. Thus, there is a need to develop safe, sustained release therapeutic approaches for treating AMD and DR.

Areas covered in this review: This review discusses the pharmacological basis for using celecoxib, an anti-inflammatory drug capable of selectively inhibiting cycloxygenase 2, in treating AMD and DR. In addition, this article discusses the safety, delivery advantage and efficacy of celecoxib by transscleral retinal delivery, a periocular delivery approach that is less invasive to the globe compared with intravitreal injections.

What the reader will gain: The reader will gain insights into the development of a pharmacological agent and a sustained release delivery system for treating DR and AMD. Further, the reader will gain insights into the influence of eye physiology including pigmentation and disease states such as DR on retinal drug delivery.

Take home message: Transscleral sustained delivery of anti-inflammatory agents is a viable option for treating retinal disorders.

Figure 1

Secretion of Prostaglandin E₂ in control, diabetic control, celecoxib and SC-560 incubated rat retinas. Data are presented as mean ± s.d for n = 4. Based on data from Ayalasomayajula et al., 2004; Eur J Pharmacol 498(1-3):275-278.

Figure 2

Inhibition of VEGF secretion in ARPE-19 cells with increased concentration of celecoxib. Data are presented as mean ± s.d for n = 4. Based Amrite et al, 2006; Invest Ophthalmol Vis Sci 47(3): 1149-1160.

Figure 3

Extent of celecoxib delivery (AUC_0-∞, μg.hr/g tissue) to the ocular tissues following intraperitoneal and periocular injection (3 mg to one eye) in normal Sprague Dawley rats. Data are presented as mean ± s.d for n = 4. Based on the data from Ayalasomayajula and Kompella, 2003; Pharm Res 21(10): 1797-1804.

Figure 4

Relative delivery of celecoxib in diabetic rats compared to control rats following periocular injection of celecoxib Data are presented as the ratio of the mean AUCs or concentrations for n = 4. With kind permission from Springer Science+Business Media: Cheruvu NP, Amrite AC, Kompella UB. Effect of diabetes on transscleral delivery of celecoxib. Pharm Res 2009 Feb;26(2):404-14.

Figure 5

Ratio of ocular tissue AUCs (for celecoxib suspension) or tissue concentrations (for celecoxib-PLA particles) between pigmented BN rats and albino SD rats. Data are presented as the ratio of the mean AUCs or concentrations for n = 4. In the celecoxib-PLA microparticle group, drug levels could not be detected in the contralateral sclera, lens, and cornea in albino SD rats and in contralateral lens and cornea of BN rats. reproduced with permission from Cheruvu NP, Amrite AC, Kompella UB. Effect of eye pigmentation on transscleral drug delivery. Invest OphthalmolVisSci 2008;49(1):333-41. Copyright (2008) ARVO.

Figure 6

Apparent permeability (Papp) of Celecoxib across bovine sclera, sclera-choroid and choroid. Data are presented as mean ± s.d. for n = 12. Based on data from Cheruvu and Kompella, 2006; Invest Ophthalmol Vis Sci 47(10): 4513-4522.

Figure 7

Inhibitory effects of celecoxib-PLGA microparticles on diabetes induced elevations in (A) retinal PGE2 (n = 4); (B) retinal VEGF (n =8–9); (C) vitreous-plasma protein ratio (n= 4); and (D) blood–retinal barrier leakage (n= 4). The parameters were estimated 60 days after periocular administration of the placebo or celecoxib-PLGA microparticles to rats. Data are expressed as the mean ± SD. Significantly different from the *diabetic group, the †diabetic + placebo group, or the ‡contralateral eye. Based on data from Amrite et al., 2006; Invest Ophthalmol Vis Sci 47(3): 1149-1160.

Figure 8

Probable mechanisms for celecoxib effectiveness in AMD and DR. Panel A: mechanism of choroidal neovascularization in AMD. Panel B: Celecoxib inhibits choroidal neovascularization in AMD by inhibiting VEGF secretion as well inhibiting endothelial cell proliferation. Panel C: Changes in retina as a result of diabetes. Panel D: Celecoxib inhibits Cox-2 leading to decreased oxidative stress, prostaglandins and decreased retinal VEGF leading to a decrease in vascular leakage in the retina.

Figure 9

Selection of drugs for enhanced transscleral retinal drug delivery. Drugs that bind to pigment exhibit low permeability across the choroid layer and potentially retinal pigment epithelium, with the drug delivery differences being more dramatic for slow release systems. By selecting more permeable drugs, transscleral retinal delivery and hence effects can be potentially enhanced. Arrows indicate solute release or overall permeability. Tissue layers are not drawn to scale. Key: D1 – drug 1; D2 – drug 2.