to a large area of the ocular posterior segment and to the macular area of the eye. Further studies are needed to determine the effect of the choroidal blood flow on the distribution of specific medications to the retina and macula.

8.6  Summary

The suprachoroidal and deep lamellar scleral delivery are viable routes for delivery of drugs to posterior segment tissues of the eye. Key advantages of these routes include a bypass of the optical pathways (an issue with intravitreal injections), direct drug diffusion to the choroidal stroma and RPE, a bypass of the diffusional barriers that occur in transscleral delivery, and potentially an advantageous immune response toward biologic agents. Finally, future development of sustained release particles, advantageous formulations, or delivery devices could optimize diffusional kinetics from the deep sclera and suprachoroidal space. Deep scleral and suprachoroidal routes of drug delivery offer a unique avenue for routine injections that are safe and effective in targeting retinal and macular diseases. We anticipate significant future advances in this field of research.

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Chapter 9

Advances in Biodegradable Ocular Drug

Delivery Systems

Susan S. Lee, Patrick Hughes, Aron D. Ross, and Michael R. Robinson

Abstract  The limitations of existing medical therapies for ocular disorders include low drug bioavailability, nonspecificity, side effects, and poor treatment adherence to therapy. These limitations may be overcome through the use of sustained-release intraocular drug delivery systems. Critical to the development of such systems has been the introduction of biocompatible polymers (biodegradable and nonbiodegradable) that allow for drug release kinetics to be tailored for specific drugs and ocular diseases. Drug delivery systems composed of biodegradable polymers, such as poly- lactic-co-glycolic acid, appear to be particularly well suited for such applications. This review examines the characteristics of these polymers for medical applications, as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of sight-threatening ocular diseases.

Abbreviations

S.S. Lee (*)

Allergan, Inc., Irvine, CA, USA e-mail: lee_susan@allergan.com

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 185 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_9,

© American Association of Pharmaceutical Scientists, 2011

9.1  Introduction

Chronic retinal diseases are the leading contributor to visual impairment and blindness worldwide. The most common forms of retinal disease leading to loss of vision include glaucoma, age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, uveitis, infectious retinitis, retinal detachment, and inherited degenerative conditions such as retinitis pigmentosa. The number of people with visual impairment worldwide in 2002 was in excess of 161 million, of whom about 37 million were blind (Resnikoff 2004). The annual worldwide cost of blindness due to lost productivity was estimated in 1993 to be $108 billion USD. It has been estimated that the number of blind individuals worldwide will likely increase to 76 million in 2020, with associated costs expected to reach $1,546 ­billion USD (Frick and Foster 2003).

Topical drug therapy is the mainstay of treatment for ocular disorders of the anterior segment such as ocular surface diseases (e.g., conjunctivitis, dry eye), for glaucoma or ocular hypertension, and for anterior uveitis (Conway 2008; Ghate and Edelhauser 2006; Kearns and Williams 2009). However, topical therapies are limited for treating disorders of the posterior segment due to the greater diffusional distance (Yasukawa et al. 2006) as well as anatomical and physiological barriers in the eye. These barriers, such as the corneal epithelium and conjunctival clearance mechanisms, not only protect against the entry of xenobiotics but also greatly impede drug uptake, thus making it difficult to achieve therapeutic drug concentrations (Conway 2008; Ghate and Edelhauser 2006; Kearns and Williams 2009; Myles et al. 2005). Although successful in rodent models (Tanito et al. 2007; Ni and Hui 2009), the efficacy of topical therapies for retinal diseases has yet to be demonstrated in human clinical trials.

Systemically administered drugs also have been used for treating a variety of ocular diseases. However, drug penetration in ocular tissues is greatly limited by the blood-aqueous and blood-retinal barriers. As a result systemically administered drugs must be given at high doses, which increase drug exposure in nonocular tissues and consequently, the risk of adverse systemic side effects (Ghate and Edelhauser 2006, 2008).

Intravitreal drug injections have also been explored for delivering drugs to target tissues in the eye at therapeutic concentrations. However, many intravitreally administered agents, such as low molecular weight drugs like corticosteroids, have short half-lives, ranging from 2 to 6 h (Kwak and D’Amico 1992); as a result, efficacy can be transient and frequent injections may be needed to maintain therapeutic drug concentrations (Kiernan and Mieler 2009). Higher molecular weight compounds, such as vascular endothelial growth factor antibodies and antigen-binding fragments, have longer half-lives, but monthly injections are still required to maximize their efficacy in preserving visual acuity in patients (Spaide et al. 2009; Pieramici et al. 2008; Dafer et al. 2007; Rosenfeld et al. 2006). With increasing frequency of intravitreal injections, however, there also is an increased risk of serious adverse events including retinal detachment, endophthalmitis, and vitreous hemorrhage, as well as adverse manifestations in the anterior segment such as cataract formation and intraocular pressure elevation (Jager et al. 2004; Berinstein 2003). Although the incidence rates of these serious side effects may be relatively low, they can be sight threatening. Due to the anatomic and physiologic barriers to both topical and systemic drug therapy, the relatively short half-life of compounds administered by intravitreal injection, and other general limitations of these routes of administration (Table 9.1), sustained-release drug delivery systems have been developed over the past decade and now play an important role in treating a variety of ocular diseases.

Table 9.1  Limitations of ocular drug delivery methods