38.1 Introduction

Posterior segment pathology can be treated with medications delivered by a variety of routes; however, the anatomy of the eye creates multiple barriers to prevent delivery of therapeutic doses of medications to the posterior segment. The blood–ocular barrier is maintained by the tight junctions of the retinal vascular endothelium, the retinal pigment epithelium (RPE), and the nonpigmented ciliary epithelium. ¹ Drugs can be delivered to the posterior segment by topical drops, long-acting, slow-release conjunctival inserts, periocular injections, intravitreal injections, surgically implanted intravitreal sustained release implants, or injected intravitreal sustained release implants. In addition, various experimental techniques, based on advances in biomaterials and nanotechnology, have been developed to deliver drugs to the posterior segment. Systemic delivery is usually via oral, intramuscular, or intravenous routes. This chapter discusses the various local methods for posterior segment drug delivery excluding the intravitreal injection procedure, which is discussed in Chapter 37.

38.2 Periocular Injections

Drugs are absorbed following periocular injections by one of two ways: slow drainage from the injection site into the tear film and through the cornea or permeation across the sclera and choroid into the RPE, retina, and vitreous. ² The amount of drug entering the eye after periocular injection is related to the ability of the drug molecule to penetrate the sclera, choroid, and RPE. Lipid-soluble molecules, such as prednisolone acetate, can be expected to penetrate the eye better than water-soluble compounds, such as tobramycin. The sclera permits the diffusion of molecules up to 70 kDa in size, while the cornea does not allow diffusion of molecules >1kDa in size. ² Periocular injections are a relatively inefficient delivery route; only 2 to 4% of the administered dose actually penetrates the eye. ³ However, they are an effective means of drug delivery to the posterior segment compared with systemic administration, with which a negligible percentage of drug reaches the eye. ² In particular, lipophilic drugs, which may cause systemic toxicity, are delivered efficiently by the periocular route while limiting systemic toxicity.

Periocular corticosteroid injections are given relatively commonly. Most often, they are used to treat noninfectious inflammation of the posterior segment and cystoid macular edema. The injections can be given as frequently as weekly for short periods of time, but are generally spaced much further apart. To maximize delivery to the posterior segment, injections are typically placed as posteriorly as possible in the sub-Tenon’s space. Many techniques for periocular injections have been described. Either an inferotemporal or superotemporal approach can be used; however, it is felt that the superotemporal approach allows for more posterior placement of drug. ⁴ The superotemporal approach is associated with blepharoptosis and orbital fluocinolone acetonide prolapse. Both approaches may cause skin hypopigmentation, especially in darkly pigmented individuals, although this problem occurs more commonly with the inferotemporal approach. ^{5 ,​ 6 ,​ 7}

Posterior sub-Tenon’s injection (PSTI) of triamcinolone has been used with excellent results to treat noninfectious anterior, intermediate, posterior, and panuveitis. ^{8 ,​ 9 ,​ 10 ,​ 11 ,​ 12} Multiple studies have shown that while PSTI of triamcinolone controls inflammation, the percentage of patients remaining inflammation-free decreases by 3 months; however, repeat injections can be given to achieve long-term control. Steroid-related side effects including elevated intraocular pressure (IOP) and cataract progression may limit the use of repeated injections.

A few initial studies that investigated PSTI of triamcinolone to treat diabetic macular edema (DME) showed promising results with improvement in visual acuity ^{13 ,​ 14 ,​ 15 ,​ 16} and reduced side effects compared to intravitreal triamcinolone acetonide injection (IVTA). ^{17 ,​ 18} The Diabetic Retinopathy Clinical Research Network (DRCR.net) performed a phase II, randomized, prospective, pilot study (Protocol E) to determine the safety and efficacy of PSTI of triamcinolone either alone or in combination with focal laser to treat mild DME. In this study, PSTI of triamcinolone was not beneficial, and was associated with adverse effects from the injections including elevated IOP and blepharoptosis. ¹⁹ This study included only patients with good visual acuity, so PSTI of triamcinolone may still be a useful adjunct for patients with diffuse DME and poor visual acuity when performed prior to grid focal laser, as has been suggested by other studies. ^{20 ,​ 21}

The duration of effect has been found to be longer following IVTA compared to PSTI. ^{22 ,​ 23} PSTI of triamcinolone is associated with increased IOP but the degree of IOP increase is lower than with IVTA. ^{24 ,​ 25} Other side effects reported after PSTI of triamcinolone include reactivation of infectious retinitis, ²⁶ cutaneous hypopigmentation, ⁵ retinal and choroidal vascular occlusion, ²⁷ infectious crystalline keratopathy, ²⁸ herpetic keratitis, ²⁹ orbital abscess, ^{30 ,​ 31 ,​ 32} encapsulated cyst, ³³ and infectious scleritis. ³⁴

38.3 Nonbiodegradable Implants

Nonbiodegradable sustained release implants are based on one of two designs: matrix or reservoir systems. Reservoir systems consist of a central drug core surrounded by layers of nonbiodegradable materials that are either semipermeable or impermeable. ^{35 ,​ 36} By finely tweaking the design of the semipermeable and impermeable layers, the implant drug release rate can be controlled. ^{35 ,​ 36} The release rate of reservoir implants is based on the surface area over which the drug is released, the thickness of the semipermeable coatings, the shape of the implant, and the ease with which the drug diffuses through the semipermeable coating. The release profile follows zero-order kinetics and is characterized by a minimal initial burst of drug release followed by constant drug release over time. In contrast, in matrix systems the drug is dispersed homogeneously within the matrix material. Drug release relies on the slow diffusion of the drug through the polymatrix material. Nonbiodegradable implants contain small amounts of drug but can produce therapeutic drug concentrations in the eye.

Drug delivery from nonbiodegradable implants generally depends on simple diffusion of the drug from the implant to the aqueous or vitreous. The vitreous is in contact with the retina, and indirectly with the choroid and sclera, the posterior chamber, and the posterior lens capsule. Drug molecules released from the implant diffuse throughout the vitreous and then move into the surrounding tissues. The vitreous concentration of any drug is dependent on the implant release rate, the volume of the posterior segment, intravitreal metabolism, and the drug elimination rate through the surrounding tissues. The ocular distribution volume is determined by the size of the eye, the amount of protein in the eye, and the lipophilicity of the surrounding tissues. Furthermore, despite its high water content, drug molecules are not distributed uniformly through the vitreous because the local concentration gradient is influenced by different elimination rates through each boundary tissue. ³⁷

Depending on drug solubility, the implant configuration, and polymeric coatings, nonbiodegradable drug delivery implants can be designed to release drug over extended time periods. Because of this long release duration, nonbiodegradable sustained release implants are particularly suitable for treating chronic conditions such as glaucoma, cytomegalovirus retinitis, age-related macular degeneration (AMD), diabetes, and uveitis. ^{35 ,​ 38 ,​ 39 ,​ 40 ,​ 41}

Two different sustained release fluocinolone acetonide implants have been approved for the treatment of ocular diseases: a nonbioerodable, extended release, implantable fluocinolone acetonide device (Retisert, Bausch and Lomb) which must be surgically implanted in the operating room (Fig. 38-1) and a much smaller, nonbioerodable, injectable fluocinolone acetonide insert (Iluvien, Alimera) which can be injected in the outpatient clinic. The fluocinolone acetonide implant is currently approved in the United States for the treatment of noninfectious posterior uveitis. ⁴² The fluocinolone acetonide insert is approved for the treatment of DME in the United States and in certain countries in Europe. ⁴³

The surgically placed fluocinolone acetonide implant releases 0.59 µg/day of fluocinolone acetonide over 3 years. ⁴² This system provides constant drug release and thereby avoids the peak and trough effect of steroid solutions injected into the vitreous or by bioerodable implants. The fluocinolone acetonide implant has been used to treat severe uveitis refractory to conventional systemic immunosuppression and periocular steroid injections. A multicenter, randomized, dose-masked clinical trial was conducted to determine the safety and efficacy of a sustained release fluocinolone acetonide intravitreal implant in patients with posterior segment uveitis. ⁴⁴ The fluocinolone acetonide implant reduced the aggregate recurrence rate for the implanted eyes from 51.4% in the 34 weeks preceding implantation to 6.1% postimplantation (p < 0.0001) in the study eyes, while there was a significant increase in the nonimplanted eye recurrence rate. Adjunctive therapy use was also significantly decreased postimplantation. The multicenter uveitis steroid treatment (MUST) trial randomized patients with intermediate, posterior, or panuveitis to the fluocinolone acetonide implant or corticosteroids plus systemic immunosuppression to evaluate the change in best-corrected visual acuity as the main outcome measure. While there was not a statistically significant difference in the improvement of visual acuity between the two groups, there was a trend towards better visual acuity in the fluocinolone acetonide implant group. ⁴⁵ The implant group was found to have greater improvement in vision-related quality of life, lower rates of residual active uveitis, and lower rates of prescription requiring systemic infections. The most common serious adverse events observed by 2 years after placement of the fluocinolone acetonide implant were cataract progression requiring cataract extraction (80%), elevation of IOP by more than 10 mm Hg from baseline (65%), and filtering procedures (26%). ^{45 ,​ 46} In this difficult-to-treat patient population, the fluocinolone acetonide implant controlled inflammation and was associated with visual acuity improvement in a significant proportion of the eyes studied; however, because of the fluocinolone implant’s effect on IOP and lens clarity, these patients must be closely monitored in the postoperative period.

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