Chapter 7

Transscleral Drug Delivery

Dayle H. Geroski and Henry F. Edelhauser

Abstract  The treatment of diseases of the posterior segment of the eye remains limited by the ability to deliver effective doses of drugs to target tissues in the posterior eye. Topical delivery as drops and systemic delivery require large doses and remain limited in delivering effective doses to the back of the eye. Intravitreal injection and implantation of intravitreal sustained-release delivery devices are effective but invasive, and both modes of delivery share potential risks of retinal detachment, endophtalmitis, hemorrhage, and cataract. Numerous studies have demonstrated that drugs and solutes can diffuse across the sclera in vitro and in situ when delivered by a periocular approach. Transscleral delivery could provide an effective alternative approach for delivering therapeutic agents to the posterior tissues of the eye.

7.1  Introduction

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 worldwide.

As exciting new treatment modalities are being explored and developed for retinal degenerations and posterior segment disease, effective modes of drug delivery to the back of the eye are limited. Successful treatment of these visually devastating diseases will most likely require delivering effective doses of pharmacologic agents to the posterior segment, possibly in conjunction with surgical (including cell transplant) or genetic intervention.

H.F. Edelhauser (*)

Emory University Eye Center, Emory University, 1365 Clifton Road NE, Atlanta, GA 30332, USA

e-mail: ophthfe@emory.edu

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 159 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_7,

© American Association of Pharmaceutical Scientists, 2011

The treatment of posterior segment eye disease remains limited by the difficulty in achieving effective doses of drugs in target tissues in the posterior eye. 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 utilize the topical application of solutions to the surface of the eye as drops or ointments. 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. Following 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. (Lang 1995) 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.

The sclera offers another potential route to obtain therapeutic vitreous and retinal drug concentrations, using periocular injection, or by the placement of a sustainedrelease device. Delivering drugs across the permeable sclera would be safer and less invasive than intravitreal injections or devices, yet potentially could provide a more effective retinal dose than systemic or topical delivery.

7.2  Drug Delivery to Posterior Segment Ocular Tissues

Four general approaches may be employed to deliver drugs to the posterior segment – topical, systemic, intraocular, and periocular (including subconjunctival, subtenons, and retrobulbar), Fig. 7.1. Topically applied drugs may enter the eye by crossing the conjunctiva and then diffusing through the sclera (Ahmed and Patton 1985; Ahmed et al. 1987). Because of the barrier provided by the corneal epithelium and extensive precorneal loss, this approach does not typically 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

Fig. 7.1  Routes for delivering drugs to tissues of the posterior ocular segment. Drugs delivered topically (a) must diffuse across the cornea, ciliary body, and vitreous before reaching target tissues in the posterior eye. Systemic delivery (b – not shown) has a poor dose–response profile for the posterior segment. Also, the high systemic doses required to achieve therapeutic levels in posterior segment tissues can be associated with systemic toxicities. Intravitreal injection or implant (c) or periocular delivery with transscleral diffusion (d) may be employed for improved delivery of drugs to tissues in the posterior of the eye

well tolerated by the patient. Further, drugs injected directly into the vitreous are rapidly eliminated. Intravitreal sustained-release devices have been employed to avoid repeated injections. The best known of these devices is perhaps the Vitrasert ganciclovir implant, used in the treatment of CMV retinitis.(Sanborn et al. 1992) 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, they must be periodically replaced, and they have potential side effects similar to those associated with intravitreal injection.

Periocular drug delivery using subconjunctival or retrobulbar 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 it also offers the potential for localized, sustainedrelease drug delivery. Drug delivery by this vector would ideally be transscleral, and it could thus take advantage of the large surface area of the sclera. The average 17 cm2 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 cm2 surface area of the cornea. Also, regional differences in scleral thickness could be utilized to further optimize transscleral drug diffusion

if sustained-release delivery devices or systems could be placed in regions where scleral permeability was greatest. Further, an increasing body of evidence suggests that the sclera is quite permeable to a wide range of solutes and holds significant potential for posterior segment drug delivery.

In recent years, experiments in our laboratory have been targeted at investigating the potential for delivering drugs across the sclera by periocular injection or by the placement of a sustained-release device. The relatively high scleral permeability, as compared to the cornea, could, perhaps, be used to good advantage in developing methods for transscleral drug delivery, especially for compounds that need to be administered to the posterior part of the eye. Additionally, the sclera provides a very large surface area. It comprises 95% of the surface area of the human eye. (Olsen et al. 1998) This large area not only provides a potentially large region for transscleral drug absorption, but also offers the exciting possibility for delivering neuroprotective agents, antioxidants, or angiostatic agents to specific regions of the retina.

7.3  Scleral Structure and Drug Delivery

The structure and composition of the sclera are comparable to those of the corneal stroma. The principal components of the scleral stroma are collagen fibers, a sparse population of fibroblasts, proteoglycans, and a few elastic fibers. Collagen is the major component of the sclera, comprising some 75% of the scleral dry weight, with type I being the major collagen type. As one moves from central cornea into the sclera, collagen fibril size and fiber organization change progressively from the lamellar, orderly array of uniform fibers seen in the central cornea to the branched and interwoven array of fibrils varying in diameter seen in the sclera. (Borcherding et al. 1975) Because of the similarities in structure, it is perhaps not surprising that the solute permeability of the sclera is, in general, quite comparable to that of corneal stroma.

The large surface area of the sclera is also advantageous to intraocular drug delivery. In a series of experiments reported by Olsen et al. (1998) the regional thickness and surface area of human sclera was investigated in donor eyes. The mean (± SD) scleral thickness at the limbus was determined as 0.53 ± 0.14 mm. Near the equator of the globe, 13 mm from the limbus, the sclera was found to have a mean thickness of 0.39 ± 0.17 mm. Scleral thickness in the equatorial region was found to be significantly less than that at the limbus. Interestingly, five of the 55 eyes studied had a scleral thickness of 0.1 mm or less at the equator. Using measurements from regions 12–17 mm posterior to the limbus, which is approximately at the equator, 38% of the eyes studied had scleral thickness measurements of 0.25 mm or less. Thickness was found to increase gradually as one moved toward the posterior. A maximal thickness of 0.9–1.0 mm was observed near the optic nerve.

In this same series of experiments, scleral surface area was measured by dissecting the scleral tissue from donor globes and making flat preparations. For the adult