Third, drug diffusion from the suprachoroidal space avoids the barriers seen with transscleral delivery; namely, restrictive kinetic barriers of the sclera that have been demonstrated to increase with larger molecules (Olsen et al. 1995). Fourth, drug diffusion from this space may actually target the RPE in a more direct manner. Fifth, sustained release agents, formulations, or devices could optimize diffusional kinetics from this space (Gilger et al. 2006; Olsen et al. 2006). And finally, there may be advantageous immune responses to this space with larger biologic or immunogenic agents (Olsen et al. 2010). Perhaps this route of delivery will offer a unique avenue for future routine injections that are safe and effective in targeting retinal and macular diseases, such as diabetic retinopathy, retinal degeneration, and age-related macular degeneration (AMD). Efficacious local delivery methodology combined with low systemic levels represents a key concept in technology design.

8.2  Background

Posterior segment eye diseases are a common cause of blindness in ophthalmology, both in humans as well as in veterinary medicine. The total amount or volume of tissue in the posterior segment is quite small relative to other organ systems. For this reason, local drug delivery has become a very active area of research in vision sciences (Geroski and Edelhauser 2000).

Two important issues are driving new discoveries and treatment options for posterior segment disease. First, newer and more potent, targeted therapies are evolving specifically toward diseases of the posterior segment of the eye. One such remarkable therapy is the use of antivascular endothelial growth factor (anti-VEGF) agents for the treatment of neovascular AMD (Brown et al. 2006; Rosenfeld et al. 2006; Gragoudas et al. 2004). Importantly, these drugs are not given systemically. Instead, they are delivered locally. Clearly, numerous potential therapies are transforming management of posterior segment disease to a pharmacologic and pharmacotherapeutic era in ophthalmology. Larger biologic agents, with targeted therapeutic and highly selective effects, are creating new challenges in delivery. Second, local delivery minimizes systemic side effects by taking advantage of the fact that we only need to treat a small volume of tissue relative to the rest of the body. The eye is approximately 1:1,000 of the total body volume, and the macula itself is proportionally small relative to the eye at 1:1,000 of the volume of the eye. Thus, local drug delivery for macular disease targets a small amount of tissue and minimizes the potential for collateral damage from systemic side effects. More potent and more highly efficacious agents reduce the dosing requirements, and allow for smaller quantitative amounts of drug.

Ophthalmology has long depended upon topical drug delivery for many diseases of the anterior segment, where diffusional barriers are minimal and access to critical tissues are simple and immediate. Topical drops have been used to treat anterior segment disease by optimizing formulation of each specific medication. Many of the key barrier issues in achieving therapeutic drug levels have been addressed, such

as a drug’s ability to cross the corneal epithelial and endothelial barriers. Anterior segment tissues that are readily accessible with topical therapy include the conjunctiva, cornea, iris, and even the ciliary body. For small molecules with optimized formulations, achieving a therapeutic drug level in these key tissues has been achieved using many different agents, compounds, and formulations.

8.3  Posterior Segment Delivery

Despite remarkable successes in treatment of anterior segment ophthalmic disease, treatment of posterior segment disease is clearly more challenging. Limitations for topical application of medications reaching significant therapeutic levels in the posterior pole, largely involves the aqueous humor fluid dynamics. Essentially, there is a bulk flow of fluid that removes drugs applied topically from the eye before reaching posterior segment tissues. The crystalline lens is also a barrier to posterior diffusion of drug into the vitreous. The vitreous itself modifies diffusion in unexpected ways that we do not yet fully understand and is likely to be highly dependent upon the levels of vitreous syneresis. Additionally, there are barriers for entry of drugs into the neurosensory retina; namely, the blood retinal barrier, the internal limiting membrane, and the tight junctions formed between the RPE cells and retinal vascular endothelium.

There are other ocular flow systems that are gaining interest as important barriers to achieving local drug delivery. Specifically, the choroid and the choroidal blood flow as well as lymphatic circulation (Robinson et al. 2006). The effects of the choroidal vasculature on drugs that diffuse through the sclera or on drugs that are inserted or injected into the suprachoroidal space are now recognized as important determinants in the pharmacokinetics of the posterior segment. The rapid blood flow of the choroidal circulation remains a poorly understood variable in the pharmacokinetics in this region (Fig. 8.1). For this reason, fluid dynamics within the subretinal space and suprachoroidal space are currently under intensive study. Other unknown variables that influence uveoscleral outflow include, but are not limited to, the role of the vortex ampullae, the influence of the RPE, Bruch’s membrane, and several other factors.

8.4  Transscleral and Intrascleral Drug Delivery

Transscleral diffusion for drug delivery to the retina and RPE drug delivery offers a relatively safe and direct pathway to posterior segment tissues. The transscleral route avoids entry through the outer tunic of the globe. From clinical experience, an agent such as triamcinolone can be delivered to the ocular posterior segment using a periocular injection into the subtenon’s location. Presumably, the effect on uveal tissues and inflammation is mediated through simple diffusion of the corticosteroid

Fig. 8.1  An indocyanine green angiogram in the early transit phase of a rhesus macaque (Olsen), demonstrating the normal retinal vasculature overlying a more complex choroidal blood supply. This image demonstrates the extensive nature of the choroidal blood flow relative to the retinal vasculature

compound through the sclera and into the uveal tissues. Conceivably, the mechanism of drug transport into the eye could also occur via the systemic circulation or through more complex diffusional kinetics such as trans-conjunctival mediated topical delivery (i.e., serving as a depot for sustained topical release).

Earlier work (Maurice and Polgar 1977) demonstrated that molecules traverse the sclera. Later in vitro studies of human cadaveric sclera mounted in Ussing chambers demonstrated that the molecular size of a compound and the scleral thickness were key determinants of diffusion across the sclera chambers (Olsen et al. 1995). Mean scleral thickness as well as total scleral surface areas from a series of eyebank eyes helped determine the parameters of transscleral diffusion (Olsen et al. 1998). For small molecules, diffusion is rapid through the sclera. However, for larger biologic agents, such as ranibizumab or bevacizumab, there are significant limitations to the transscleral route and effective intraocular levels may be suboptimal.

Various animal studies have investigated transscleral barriers and parameters that influence diffusional kinetics in various species (Gilger et al. 2005; Olsen et al. 2002). Looking specifically at delivery of cyclosporine to treat equine recurrent uveitis (ERU), placement of a biodegradable, matrix-reservoir cyclosporine A (CsA) implant has demonstrated the advantage of deep scleral implantation compared with transscleral diffusion (Gilger et al. 2006).

8.5  Suprachoroidal Drug Delivery

Evidence that direct access to the suprachoroidal space is possible was first described by Einmahl et al. in 2002 using a rabbit model (2002). The authors used poly-ortho ester as a sustained drug delivery system with a solid, olive-tipped cannulae into the suprachoroidal space. They demonstrated that material was present in the suprachoroidal space for 3 weeks, yet there were pigment irregularities at the site of injection. In 2006, the use of a flexible, fiberoptic microcannula to access the suprachoroidal space in the pig model was reported (Olsen et al. 2006). This cannula (Fig. 8.2a, b) was originally used to access Schlemm’s canal for circumferential viscodilation during canaloplasty surgery (Lewis et al. 2009).

By accessing the suprachoroidal space in 94 porcine eyes, the authors demonstrated safety, and sustained local delivery for 120 days with very low systemic drug levels and few complications (Olsen et al. 2006). Pre and postinjection histology demonstrated that the potential space of the suprachoroidal region returns to a normal configuration after a brief period of time (Fig. 8.3a, b). Also, using dye-casting methods, the suprachoroidal space is rather extensive and has the capacity to expand and accommodate a relatively large volume of material (Fig. 8.4). The pharmacologic data demonstrated sustained local tissue levels from the sustained release formulation of triamcinolone in the suprachoroidal space along with either very low or undetectable systemic levels.

More recent studies have sought to determine the kinetics of larger biologic agents; such as bevacizumab injections into the suprachoroidal space accessed using the same flexible microcannula system. Clearly, intravitreal injections of both ranibizumab and bevacizumab are effective. However, there are several theoretic advantages to the suprachoroidal route. Specifically, the diffusion through the choroidal stroma and through a damaged Bruch’s membrane may offer more direct delivery to the disease-affected tissue than diffusion across the neurosensory retina. Early studies suggest a very different profile of drug kinetics comparing the intravitreal route (Fig. 8.5) with the suprachoroidal route (Fig. 8.6), especially when looking at a large molecular weight biologic, such as bevacizumab. Preliminary data (Fig. 8.7) indicate that large biologic proteins, such as bevacizumab, are rapidly removed from the suprachoroidal space, especially when these agents are not optimally formulated for sustained release (Olsen et al. 2010). Early studies also demonstrate a significant difference in the immune response to these two routes of administration. Intravitreal administration in the pig model of a human antibody (bevacizumab) has shown a granulomatous reaction (both vasculitis and vitritis; Fig. 8.8) in a small percentage of eyes injected intravitreally, as compared to a similar dose injected into the suprachoroidal space with no resultant inflammation.

Technologies are also evolving to optimize the ease of accessing this space. The use of either coated or hollow microneedles to access the deeper scleral tissues and even gain local access to the suprachoroidal region have been evaluated (Choy et al. 2008; Jiang et al. 2006, 2007, 2009). In studies using cadaver canine and porcine eyes, a single injection of liquid latex into the anterior suprachoroidal space accessed by a small sclerotomy created 5–7 mm posterior to the superior limbus resulted in the

Fig. 8.2  (a) Top image of the microcannulation system (iScience Interventional Inc. Menlo Park, CA). The box houses a fiberoptic so that the tip of the device can be identified in the suprachoroidal space. The syringe is for injecting viscous material through the cannula. (b) Bottom image demonstrates the relative size of the tip (bottom) along with the depth markers so that one can determine how far the cannula is extended into the suprachoroidal space