Drug delivery for posterior segment eye disease.

In recent years, significant advances have been made in optimizing the delivery of drugs to target tissues within the eye and in maintaining effective drug doses within those tissues. Most pharmacologic management of ocular disease, however, continues to use the topical application of solutions to the surface of the eye as drops. Factors that can limit the usefulness of topical drug application include the significant barrier to solute flux provided by the corneal epithelium and the rapid and extensive precorneal loss that occurs as the result of drainage and tear fluid turnover. After the instillation of an eyedrop (maximum of 30 ml) into the inferior fornix of the conjunctiva, the drug mixes with the lacrimal fluid, and drug contact time becomes a function of lacrimation, tear drainage and turnover, and to some extent the composition of the precorneal tear film itself. It has been estimated that typically less than 5% of a topically applied drug permeates the cornea and reaches intraocular tissues. The major portion of the instilled dose is absorbed systemically by way of the conjunctiva, through the highly vascular conjunctival stroma and through the lid margin vessels. Significant systemic absorption also occurs when the solution enters the nasolacrimal duct and is absorbed by the nasal and nasopharyngeal mucosa. Despite the relatively small proportion of a topically applied drug dose that ultimately reaches anterior segment ocular tissues, topical formulations remain effective, largely because of the very high concentrations of drugs that are administered. Recent advances in topical drug delivery have been made that improve ocular drug contact time and drug delivery, including the development of ointments, gels, liposome formulations, and various sustained and controlled-release substrates, such as the Ocusert, collagen shields, and hydrogel lenses. The development of newer topical delivery systems using polymeric gels, colloidal systems, and cyclodextrins will provide exciting new topical drug therapeutics. The delivery of therapeutic doses of drugs to the tissues in the posterior segment of the eye, however, remains a significant challenge. Approximately 1.7 million Americans over the age of 65 suffer from age-related macular degeneration (AMD) and as the nation ages, this number will grow by an estimated 200,000 new cases per year. Severe vision loss from AMD and other diseases affecting the posterior segment, including diabetic retinopathy, glaucoma, and retinitis pigmentosa accounts for most cases of irreversible blindness world wide. Currently, the treatment of posterior segment disease is to a significant extent limited by the difficulty in delivering effective doses of drugs to target tissues in the posterior eye (Fig.1). Four approaches may be used to deliver drugs to the posterior segment–topical, systemic, intraocular, and periocular (including subconjunctival, sub-Tenon’s, and retrobulbar). Topically applied drugs may enter the eye by crossing the conjunctiva and then diffusing through the sclera, but for reasons previously cited, this approach typically does not yield therapeutic drug levels in the posterior vitreous, retina, or choroid, and although systemic administration can deliver drugs to the posterior eye, the large systemic doses necessary are often associated with significant side effects. An intravitreal injection provides the most direct approach to delivering drugs to the tissues of the posterior segment, and therapeutic tissue drug levels can be achieved. Intravitreal injections, however, have the inherent potential side effects of retinal detachment, hemorrhage, endophthalmitis, and cataract. Repeat injections are frequently required, and they are not always well tolerated by the patient. Further, drugs injected directly into the vitreous are rapidly eliminated. Intravitreal sustained-release devices have been used to avoid repeated injections. The best known of these devices is the Vitrasert ganciclovir implant, used in the treatment of cytomegalovirus retinitis. These and other intravitreal sustained release systems, including other implant devices, microspheres, and liposomes, are exciting new modalities of drug delivery that offer effective treatment of visually devastating diseases. The devices, however, do require intraocular surgery, must be replaced periodically, and have potential side effects similar to those associated with intravitreal injection. Periocular drug delivery using subconjunctival or retrobulbal injections or placement of sustained-release devices provides another route for delivering drugs to the posterior tissues of the eye. This approach to drug delivery is safer and less invasive than intravitreal injection and also offers the exciting potential for localized, sustained-release drug delivery. Drug delivery by this vector ideally would be transscleral and thus could take advantage of the large surface area of the sclera. The average 17-cm surface area of the human sclera accounts for 95% of the total surface area of the globe and provides a significantly larger avenue for drug diffusion to the inside of the eye than the 1-cm surface area of the cornea. Also, regional differences in scleral thickness could be used to further optimize transscleral drug diffusion if sustained-release delivery devices or systems could be placed in regions where scleral permeability was greatest. The sclera, for example, is 1.0 mm thick near the optic nerve and an average of 0.53 mm thick at the corneoscleral limbus and thins to an average of 0.39 mm at the equator, where it can be as thin as 0.1 mm in a significant number of eyes. Further, an increasing body of evidence suggests that the sclera is quite permeable to a wide From the Department of Ophthalmology, Emory University Eye Center, Atlanta, Georgia. Submitted for publication December 21, 1999; accepted January 6, 2000. Commercial relationships policy: N. Corresponding author: Henry F. Edelhauser, Department of Ophthalmology, Emory University Eye Center, Suite B2600, 1365B Clifton Road NE, Atlanta, GA 30322. ophthfe@emory.edu