Herein, Mo is the initial mass of aerosol in a hollow sphere of radius (R), M(t) is the mass deposited in time, t (time), and D is the molecular diffusivity.

For deposition by settling, stirred settling seems applicable with an exponential decay in the aerosol concentration. Deposition can be represented as:

M (t) = M0 [1− exp(−βt)]

Herein, the deposition rate coefficient, β, is expressed as the terminal velocity of sedimentation divided by the length scale of the enclosure. For the spherical geometry, the following expression for β applies:

β = 43Rv

In this equation, v denotes the settling velocity. The corresponding deposition represents a much faster rate than that observed in animal systems. The stirred settling model lacks an adequate representation of the movement of the gas phase. As particles move downward, they pull the surrounding gas down and a compensatory upward drift of gas fills the void, inhibiting particle deposition. At higher particle concentration, this effect is more significant.

The aerosol delivery of drug nanoparticles represents a novel method to deliver therapeutic agents to the posterior segment during an injection in the clinic or during vitrectomy surgery in the operating room. Drug deposition occurs primarily by diffusion. Careful design of the aerosol generation and delivery parameters (aerosol particle size, delivery mode, and exposure time) and the formulation composition could lead to controlled and sustained release of the therapeutic agents with modification of the wound-healing response. Aerosolized delivery of drugs to the posterior segment is a novel methodology for phar­ macologic management of posterior-segment disorders and takes advantage of the gas phase of vitrectomy to treat conditions such as PVR following retinal detachment in high-risk eyes. Additional uses could include antibiotics for endophthalmitis, antiviral for infectious retinitis, antiangiogenic compounds for proliferative disorders, or immunomodulation.

FUTURE DIRECTIONS AND

TECHNOLOGIES

Systems will continue to evolve to deliver drugs to the posterior segment. The marketplace will likely drive innovative methods of local drug delivery that will optimize the local tissue effects, minimize systemic risks, and optimize safety. As new agents are developed for targeted disease, such as gene therapy for Leber’s congenital amaurosis, more sophisticated delivery systems will be incorporated into our practices.

SUMMARY AND KEY POINTS

Investigation of the pharmacokinetics of drug delivery to the posterior segment of the eye remains a very active area of ophthalmic research. Our clinical interventions as we enter the pharmacologic era of treating posterior-segment disease will continue to change. Significant improvements in visual outcomes and lifestyles for our patients will continue to drive this active area of research. The important points to consider in choosing or developing drug delivery systems include the following: match the delivery modality with the disease process (acute disease, chronic disease, subacute disease); optimize safety; avoid inter-

ference with the visual system; allow for replacement or recharging the system; ensure safe and simple removal, and keep the system inexpensive.

ACKNOWLEDGMENT

This study was supported by an unrestricted grant from Research to Prevent Blindness (RPB).

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John J. Huang, MD

INTRODUCTION

Vitreoretinal disorders have been gaining attention due to the aging population of the industrialized nations at risk of or suffering from permanent visual loss due to retinal disorders such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion. These disorders are increasing in prevalence together with the increased life expectancy and the incidence of obesity in our population. This is fortunately paralleled by the rapid progress in the biomedical sciences of vitreoretinal disease such as antisense RNAmolecules, designer corticosteroids, aptamers, and monoclonal antibodies for the treatment of neovascular AMD and diabetic retinopathy. The current treatments all require repeated intravitreal injections for the delivery of these drugs. The future for the treatment of these chronic posterior-segment conditions will ideally involve drug devices that can safely deliver localized medications at a steady level for a long duration, at 100% bioactivity or efficacy. The device can be replaced or completely biodegraded, and easily applied with other drugs for combination therapies. Currently, several different methods of sustained-release drug devices are available or under testing, including: (1) nonbiodegradable intraocular implants; (2) biodegradable intraocular implants; (3) injectable microand nanoparticles; (4) injectable liposomes; and (5) encapsulated cell technology (ECT).1–5 Each of these methods has advantages and disadvantages based on the need for surgical implantation, duration of drug release, type, and size of the drug molecules (Table 12.1).

HISTORY

The first ophthalmic sustained-release drug was developed in the 1960s in the former Soviet Union. Pilocarpine and mydriatics were embedded in an acrylate co-polymer-based matrix for insertion into the conjunctival fornix. The drug insert provided a delayed release of several hours as the polymer matrix dissolved.1 Ocusert (Alza), a sustained-release pilocarpine, was introduced in the western world in the 1970s. This insert released the drug for a week at a constant rate of 40 µg/hour through ethylene vinyl acetate membranes.1 This was followed by Lacrisert (Merck), a sustained-release hydroxypropyl cellulose fornix-based insert for the treatment of dry-eye syndrome. These inserts did not become popular in part due to difficulties with placement of the drug polymer by the elderly population, and extrusion of the inserts. Additional innovations in the drug delivery system included drug-immersed contact lenses and ocular liposomes in the 1970s and 1980s. The early devices in sustained-release technology provided the initial concept for sustainedrelease ocular drug delivery. Unfortunately, vitreoretinal diseases are not amenable to treatment using the topical delivery system.

KEY CONCEPTS AND FUNDAMENTAL POINTS IN SUSTAINED-RELEASE DRUG DELIVERY

The treatment of retinal disorders has changed significantly during the past decade. Thermal laser photocoagulation therapy for the treatment

of diabetic macular edema (DME) and choroidal neovascular complex has been replaced by intravitreal injections of triamcinolone acetonide, dexamethasone, pegaptanib (Macugen), bevacizumab (Avastin), and ranibizumab (Lucentis). The efficacy of these medications has brought new excitement to the field of ophthalmology and hope to patients suffering from retinal disorders. These therapies all have the major disadvantages related to complications of repeated intravitreal injections, such as: endophthalmitis, cataract formation, vitreous hemorrhage, and retinal detachment. Sustained-release technology may offer future patients less frequent dosing for chronic retinal conditions such as AMD, diabetic retinopathy, retinal vein occlusion, and even non­ retinal disorders such as glaucoma.

Ocular tissues can be reached by local or systemic drug administration. The surface tissue of the eye limits the penetration of drugs to the targeted tissue. The cornea and conjunctiva epithelium is a barrier to topical medication. The blood–retina barrier limits the delivery of drug from the systemic circulation to the retina. The retinal pigment epithelium (RPE) and the retinal vessel walls form this tight blood–retina barrier. The difference in drug levels between the anterior chamber and the vitreous cavity is several orders of magnitude after topical administration of eye drops. Intravitreal injection can provide a rapid therapeutic dose of medication to the posterior segment. The procedure must be repeated often and is associated with a variety of ocular complications.

The eye is an ideal organ for sustained-release drug delivery devices. Intraocular structures can be easily accessed through an intravitreal drug delivery system or surgical implantation. The blood–retina barrier further helps to localize the intraocular concentration of the drug while minimizing the systemic absorption and side-effects. The eye is also an immunologically privileged site, which limits the amount of inflammation related to the sustained-release device.1–3

EXISTING SUSTAINED-RELEASE DRUG DEVICES

Existing intraocular implants are designed to provide consistent release of drug from the polymeric implant for long duration. The intraocular implant must be placed surgically in the pars plana region. The major benefits of intraocular implant are: reduction of systemic side-effects of the medication, decreased risk of repeated intravitreal injections, decreasd total amount of drugs used for treatment, and localized therapeutic drug levels bypassing the blood–retina barrier.1–5

The ganciclovir implant (Vitrasert) by Bausch & Lomb was the first intraocular sustained-release drug device approved for the treatment of cytomegalovirus (CMV) retinitis. Before the era of highly active antiretroviral therapy (HAART), CMV retinitis was a common cause of morbidity in acquired immunodeficiency syndrome (AIDS) patients and a harbinger of increased mortality as well. Intravenous and oral administration of ganciclovir and foscarnet is highly effective in the treatment of disease and the prevention of recurrence. Their use was limited by serious side-effects such as myelosuppression and renal toxicity, commonly encountered in AIDS patients. Intraocular administration of ganciclovir minimized these systemic side-effects. The gan-

Devices Release-Sustained• 12 chapterDelivery: Drug for Routes