April 2014, Issue 68

Evolving Drug Delivery Techniques for Treating AMD

Stephen G. Schwartz, MD, MBA Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL

Harry W. Flynn, Jr., MD Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL

Michael W. Stewart, MD Department of Ophthalmology Mayo Clinic School of Medicine Jacksonville, FL

Standard treatment of neovascular age-related macular degeneration (AMD) consists of repeated intravitreal injections of drugs that inhibit vascular endothelial growth factor (VEGF).¹ Although this strategy is effective for many patients, the cumulative risks of endophthalmitis² and other vision-threatening complications, and the financial burdens on patients, family members, and the health care system increase with repeated injections. Alternate treatment strategies such as treat-and-extend³ and as-needed⁴ regimens reduce but do not eliminate re-injections.

Sustained-release intravitreal delivery systems might be preferable to repeated injections if the duration of drug release exceeds inter-injection intervals and if the safety profile is favorable.⁵ Three extended release intravitreal therapy strategies are being evaluated: noninvasive techniques, intravitreal implants, and colloidal carriers.⁶

Noninvasive techniques do not require intravitreal injections. Studied approaches include iontophoresis (the use of low-intensity electrical current to facilitate diffusion)⁷ and hydrogel contact lenses.⁸ Other “noninvasive” techniques that require scleral perforation without violating the vitreous include submacular suprachoroidal effusion⁹ and microneedle injections into the suprachoroidal space.¹⁰

Intravitreal implants may be either bioerodable or nonbioerodable. In general, nonbioerodable implants offer more precise drug release over a longer duration, but the implant is permanently retained in the eye.¹¹ A bioerodable dexamethasone delivery system (DDS, Ozurdex, Allergan, Irvine, CA)¹² and a nonbioerodable fluocinolone implant (Retisert, Bausch & Lomb, Rochester, NY)¹³ have received FDA approval for retinal vein occlusions and posterior uveitis. A smaller nonbioerodable fluocinolone insert (Iluvien, Alimera, Alpharetta, GA) has been approved in Europe for the treatment of diabetic macular edema.¹⁴ Other implants, including encapsulated cell synthesis of ciliary neurotrophic factor,¹⁵ a nonbioerodable intracapsular ring implant containing bevacizumab, and a refillable trans-scleral reservoir containing ranibizumab, have been investigated.¹⁶ Variations on this strategy include a nonbioerodable implant with mechanical puncture or laser induced drug release¹⁷ and a programmable, refillable mini drug pump.¹⁸

Colloidal carriers are liquid suspensions of liposomes (0.01-10 µm), microparticles
(> 1 µm) or nanoparticles (< 1 µm) that reduce drug degradation and toxicity, and extend duration of action. Liposomes are synthetic bioerodable spheres of lipid bilayers surrounding a drug-containing aqueous compartment¹⁹ that are utilized in many FDA-approved (e.g. verteporfin) and investigational (e.g. bevacizumab²⁰ and SU5416 [an anti-angiogenic agent]²¹) medications. Microparticles and nanoparticles are made of either natural or synthetic materials including bioerodable substances such as polylactic-co-glycolic acid (PLGA), used in the casing of the DDS, and polyethylene-glycol (PEG), used to extend the duration of action and prevent the catabolism of pegaptanib.²² Particles containing various anti-angiogenic compounds have been reported, including bevacizumab,²³ TG-0054,²⁴ gold,²⁵ and a serpin-derived peptide.²⁶ Dendrimers, globular structures containing branch-like structures surrounding a drug-containing core, have delivered an anti-VEGF oligonucleotide²⁷ and fluocinolone.²⁸ Thermoresponsive hydrogels also have been studied for drug delivery²⁹ and have been reported to release bevacizumab.³⁰

In theory, a sustained-release anti-VEGF intravitreal delivery system would benefit patients, and embedding these drugs inside FDA-approved carriers such as liposomes, PEG, or PLGA is easy to envision. In practice, however, an extended-release system would not become widely adopted unless it offered improvement in efficacy, safety, convenience, or cost. Because the as-needed and treat-and-extend injection regimens are successful for many patients, an extended-release system would have to provide several months of drug delivery to represent a worthwhile advance. As the duration of drug delivery increases, patients and ophthalmologists would likely be more willing to accept higher costs or decreased convenience, such as surgical implantation as opposed to in-office injections. However, treatments that offer extended durations of action may require longer clinical trials to achieve FDA approval. As we continue to collect investigational data, the future role of extended-release therapy for neovascular AMD will become clearer.

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