http://tpx.sagepub.com Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations Brian G. Short Toxicol Pathol 2008; 36; 49 DOI: 10.1177/0192623307310955 The online version of this article can be found at: http://tpx.sagepub.com/cgi/content/abstract/36/1/49
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Toxicologic Pathology, 36:49-62, 2008 Copyright © 2008 by Society of Toxicologic Pathology ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1177/0192623307310955
Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations BRIAN G. SHORT From Allergan, Inc., Irvine, California, USA. ABSTRACT Development of new drug candidates and novel delivery techniques for treatment of ocular diseases has recently accelerated. Treatment of anteriorsegment diseases has witnessed advances in prodrug formulations and permeability enhancers. Intravitreal, subconjunctival, and periocular routes of administration and sustained-release formulations of nanoparticles and microparticles, as well as nonbiodegradable and biodegradable implants to deliver drugs to the posterior segment of the eye, are becoming popular therapeutic approaches. Without adequate regulatory guidance for ocular drugs, such routes of administration and novel formulations can pose unique challenges to those involved in designing nonclinical programs, including considering clinical and nonclinical factors and choosing species, strains, and ocular toxicity parameters. Toxicologic pathologists also contribute practical experience to evaluating morphological effects of these novel formulations. Lastly, understanding species’ anatomical differences is useful for interpreting toxicological and pathological responses to the eye and is important for human risk assessment of these important new therapies for ocular diseases. Keywords: Ocular drug delivery; intravitreal; subconjunctival; periocular; ocular implant.
INTRODUCTION Millions of people suffer from a wide variety of ocular diseases, many of which lead to visual impairment and ocular blindness and cost the federal government approximately $4 billion annually (Clark and Yorio, 2003). Certain ocular diseases are quite rare, whereas others, such as cataracts, age-related macular degeneration (AMD), and glaucoma, are very common, especially in the aging population (Table 1). A rapid expansion of new technologies in ocular drug delivery and new drug candidates, including biologics, to treat these challenging diseases in the anterior and posterior segments of the eye have recently emerged. These approaches are necessary because the eye has many unique barriers to drug delivery (Figure 1). Current routes of administration include but are not limited to topical administration, systemic administration, intravitreal injections, and intraocular implants, each of which has its own set of complications and disadvantages (Figure 2). Ocular bioavailability after topical ocular eyedrop administration, the most common form of ocular medication, is less than 5% and often less than 1%, and therefore, only the diseases of the anterior segment of the eye can be treated with eyedrops. Blood-ocular barriers, Address correspondence to: Brian G. Short, Allergan, Inc., 2525 Dupont Dr. RD-2A, Irvine, CA 92612. Abbreviations: AMD, age-related macular degeneration; CNTF, ciliary neurotrophic factor; DDS, drug delivery system; ECT, encapsulated cell technology; ERG, electroretinogram; EVA, ethylene vinyl acetate; FIHS,...