Periocular routes for retinal drug delivery

Abstract

Despite numerous scientific efforts, delivery of therapeutic amounts of a drug to the retina remains a challenge. This challenge is compounded if chronic therapy is desired. The inability or inefficiency of topical and systemic routes for retinal delivery of existing drugs is now widely accepted. Although the intravitreal route offers high local concentrations in the vitreous and, hence, retina, these advantages are offset by side effects, such as cataracts, endophthalmitis and retinal detachment, following repeated intravitreal injections, or intravitreal placement of sustained-release implants. As discussed in this review, periocular routes, including subconjunctival, sub-tenon, retrobulbar, peribulbar and posterior juxtascleral routes, potentially offer a more promising alternative for enhanced drug delivery to the retina compared with topical and systemic routes. Periocular routes exploit the permeability of sclera for retinal drug delivery, and they are particularly useful for administering sustained-release systems of potent drugs. This review discusses the various periocular routes with respect to their anatomical location, pharmacokinetics, safety and mechanisms of drug delivery. In the coming years, several innovations in absorption enhancement, drug delivery systems and drug administration devices are anticipated for improving retinal drug delivery via periocular routes.

Figure 1.. Schematic representation of periocular routes of administration.

Figure 2.. Local delivery is responsible for higher ocular tissue availability of celecoxib following subconjunctival administration.

Celecoxib suspension was administered SC to one eye at a dose of 3 mg/rat, and drug levels were estimated in the tissues from the dosed (ipsilateral) eye as well as the undosed (contralateral) eye. In addition, drug suspension was administered intraperitoneally at a dose of 3 mg and the drug levels were estimated in various ocular tissues. The area under the tissue concentration versus time plot (AUC_0−∞) is expressed as mean ± s.d. for n = 4 for subconjunctival injection and n = 6 for intraperitoneal injection [44]. AUC: Area under the curve; SC: Subconjunctivally.

Figure 3.. Subconjunctival route for retinal delivery of drugs in rats and rabbits.

(A) Celecoxib levels in the vitreous and plasma of Sprague–Dawley rats following subconjunctival injection of a 50 μl suspension containing 3 mg drug. The data are expressed as mean ± s.d. for n = 4 [44]. (B) Prednisolone levels in various tissues after subconjunctival injection of a 50 μl solution containing prednisolone at 1 mg/kg dose in New Zealand white rabbits. The data are expressed as mean ± s.e.m. for n = 3 [45].

Figure 4.

Permeabilities of various solutes across human sclera [–57].

Figure 5.. Pathways for intraocular and systemic delivery of drugs following periocular administration.

ILM: Inner limiting membrane; OLM: Outer limiting membrane; RPE: Retinal pigment epithelium.

Figure 6.. Budesonide nano- and microparticles sustained ocular tissue levels of budesonide after subconjunctival administration in rats.

Budesonide was administered in the eyes of rats, either in the form of a solution (50 or 75 μg to one eye; white and light grey circles, respectively), nanoparticles (50 μg to one eye; dark grey circles), or microparticles (75 μg to one eye; black circles), and drug levels were estimated in (A) retina, (B) vitreous, (C) cornea and (D) lens. Data are expressed as the mean ± s.d. of results in four experiments. Data are shown for the ipsilateral eye. Drug levels were below detection limits in the contralateral eye. Budesonide levels were below detection limits on day 14 in the solution and nanoparticle groups. Reproduced with permission from KOMPELLA UB, BANDI N, AYALASOMAYAJULA SP: Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest. Ophthalmol. Vis. Sci. (2003) 44(3):1192–1201, Copyright © Association for Research in Vision and Ophthalmology [62].