INTRODUCTION
Once the active treatment agent is determined, the next biggest issue in drug development to treat diseases of the retina and vitreous are the obstacles inherent to back of the eye drug delivery. Generally, when it comes to patient safety, comfort, affordability, and ease of use, eye drops are superior to other forms of ocular drug delivery. But of all the routes (topical, systemic, intraocular, and periocular), topical is the least effective at delivering therapeutic concentrations to the retina.1 Although a few new topical medications for retinal diseases are in clinical development, the majority of the development effort in retina therapeutics is focused on novel non-topical delivery.

Commercially available methods for intraocular drug delivery, which currently consist of only intravitreal injections and implantation, have several drawbacks. Intravitreal injections for chronic conditions, such as age-related macular degeneration (AMD), require frequent (monthly or bi-monthly) out-patient visits and can carry the risk of serious complications, including vitreous hemorrhage, retinal detachment, and endophthalmitis.2 Intraocular implants require an inpatient, surgical environment and may require explantation in the case of an adverse event or if they are nonbiodegradable.

In the past few years, however, researchers have made strides toward the development of intraocular devices with fewer complications and relatively safe, sustained, and effective localized administration. Particulate polymeric drug delivery systems, known as microparticles and nanoparticles, as well as phospholipid bilayer encapsulated drug delivery systems called liposomes, are being investigated as possible ways to lengthen drug bioavailability compared with standard solution injections. Iontophoresis, in which an electronic current is used to drive ionized drugs into tissues, is another promising new delivery technique for reaching the posterior segment and retina. In this article, we summarize some of the recent progress in ophthalmic drug delivery to the posterior segment.

INTRAVITREAL INJECTION
Since their first use in patients in 1945,3 intravitreal injections have proven to provide superior drug bioavailability in the posterior segment compared to topical and systemically delivered agents. In the past 5 years, their use has increased dramatically due to the effectiveness of anti-VEGF therapeutics, like ranibizumab (Lucentis, Genentech, Inc.) and bevacizumab (Avastin, Genentech, Inc.) for the treatment of wet AMD.4,5

Unfortunately, present formulations of ranibizumab or bevacizumab typically need to be re-injected every 4 to 6 weeks. One of the ways to increase the interval between the injections could be the use of hydrogels. From the results of a recently published study in rabbits, it appears possible that thermoresponsive polymers could eventually be used to achieve sustained release of anti-VEGF proteins, such as ranibizumab and bevacizumab, lasting 3 to 6 months.6 At room temperature these hydrogels are in a liquid gel-like phase, but once exposed to body temperature they solidify into a porous mass capable of steadily releasing protein for prolonged periods of time.6

In order to decrease the occurrence of complications associated with intravitreal injections, researchers are investigating new applicator systems that can provide safe, effective, and sutureless drug delivery. In initial clinical trials, a new intravitreal drug applicator known as the Dexamethasone Posterior Segment Drug Delivery System (dexamethasone DDS; Allergan, Inc.), developed for the treatment of macular edema, was well tolerated and improved visual acuity, and decreased macular thickness and fluorescein leakage in patients with persistent ME.7

MICROPARTICLES, NANOPARTICLES, AND LIPOSOMES
One problem that limits the effectiveness of intravitreal injections is the lack of homogeneity of the human vitreous caused by gradients. Many injected drugs do not spread uniformly throughout the vitreous and significant variability in drug concentration can exist at the target site. These issues have spurred researchers to develop new formulations which can spread more uniformly throughout the vitreous, increase the duration of action, and decrease peak concentration, through the use of micro- or nanoparticles.

Injectable nanoparticles (1 nm to 1000 nm in diameter) and microparticles (1 µm to 1000 µm in diameter) made of polymer encapsulated drug are relatively new delivery systems which aim to increase the duration of action to several weeks for small molecules and the penetration of an agent. Particulate systems can be in the form of a uniform polymer-drug combination, known as nanospheres and microspheres, in which the drug is dispersed homogeneously throughout a polymer matrix, or they can be in the form of nanocapules and microcapsules, in which the drug is surrounded by spherical polymer capsule and released through its pores. The speed of release of a drug from both types of particulate systems is determined primarily by the speed of biodegradation of the polymer.8

Almost any drug can be encapsulated, avoiding the solubility issues inherent to liquid intravitreal injections. These delivery systems can aid in stabilizing the active form of a drug, increase half-life, increase drug absorption due to a slower elimination rate, and decrease peak concentrations reducing the risk of toxicity.9 One drawback is that nanoparticles and microparticles are heavier than the vitreous, so when injected they tend to sink to the bottom of the vitreous cavity, leading to an uneven drug distribution. Particle size can also have profound effects on the drug bioavailability after injection, with larger particulate systems tending to maintain superior sustained drug release. In rabbits, polylactic acid microspheres can remain in the vitreous for 1.5 months.10 Nanoparticles diffuse more rapidly into ocular tissues possibly providing more evenly distributed bioavailability.

Presently, micro- or nanoparticles are at the stage of preclinical testing. They are being studied as ways to facilitate gene therapy for diseases of the retina. Gene-based drugs can express their protein products for prolonged periods and oligonucleotides, such as formivirsen (Vitravene, Novartis), which is currently available as an intravitreal injection for the treatment of CMV retinitis, may provide even longer lasting treatment if encapsulated. Additionally, a particular type of nanoparticles/polycion complex (PIC) micelles that can be laser-activated are in development and have successfully inserted DNA into rat retinas through a process called photochemical internalization, in which light induces the transfer of DNA directly into cells.11 In a rat model of choroidal neovascularization, DNA inserted into a complex with cationic peptides and enveloped inside a photosensitizing compound was laser irradiated after subconjunctival injection to produce transgene expression of antiangiogenic factors.11

In addition to polymer particulate systems, drugs can be encapsulated into liposomes, microscopic vesicles comprised of phospholipid bilayer. Liposomes can bind to a cell membrane and facilitate drug transfer across the membrane, but are less stable than particles made of polymer. Both hydrophobic and hydrophilic drugs can be encapsulated into liposomes, and research has shown that they can effectively carry genes to the rat retina following injection.12

INTRAOCULAR IMPLANTS
Ocular implants are designed to provide drug release into the posterior chamber for a longer period of time (months or even years) compared to particles or solutions.13 The implant is usually placed intravitreally at the level of pars plana during a surgical procedure. Compared to injections, drugs released from implants deliver more consistent levels, avoid the side effects associated with frequent injections, minimize peak concentrations, and result in a smaller quantity of drug needed during treatment.1,9 Like solution and particle injections, implants can also result in unequal drug distribution due to vitreous heterogeneity and placement of the implant peripheral to the retina to avoid disruption of the visual field. Implants do, however, come closer than solution injections to following zero-order kinetics, in which the level of administered drug remains constant throughout the delivery period.

Ocular implants can be either biodegradable or nonbiodegradable. Biodegradable implants do not require surgical removal, but often show variability in release kinetics due to differing rates of vitreous turnover and have a final burst in their drug release profile. Non-biodegradable implants provide more controlled drug delivery but require a second surgical procedure for their removal.

Two ocular implants, Vitrasert (ganciclovir 4.5 mg, Bausch & Lomb, Rochester, NY) and the recently approved Retisert (fluocinolone acetonide 0.59 mg, Bausch & Lomb), are commercially available for the treatment of AIDS-related cytomegalovirus (CMV) retinitis, and posterior uveitis, respectively. The nonbiodegradable Vitrasert implant releases ganciclovir for approximately 5 to 8 months, while Retisert (also nonbiodegradable) can release fluocinolone for up to 30 months, and is currently the only approved treatment for noninfectious uveitis of the posterior segment.14

Recently, a novel doughnut shaped biodegradable implant has been investigated in vitro for delivery of ganciclovir and foscarnet. The central hole within the implant allows for easier suturing, and the implant does not ever need to be removed from the vitreous.15 Other intraocular implants in development include the biodegradable Posurdex (Allergan, Irvine, CA), a small pellet which delivers dexamethasone for the treatment of macular edema associated with retinal vein occlusion, and Iluvien (Alimera, Alpharetta, GA), a nonbiodegradable insert which releases the corticosteroid fluocinolone acetonide for the treatment of diabetic macular edema and is designed to sustain therapy for 24 to 36 months.16 Both implants are currently in phase 3 trials.

IONTOPHORESIS AND SUPRACHOROIDAL DRUG ADMINSTRATION
Iontophoresis (see "Iontopherisis Drug Delivery System" on page 49 for more information) is a method of drug delivery in which an electrical current drives charged drug molecules through either the cornea or sclera and into the vitreous and retina.17 It could offer a noninvasive alternative to intravitreal injections, particles, or implants. In a rabbit model, a drug loaded hydrogel iontophoresis system was able to produce high concentrations of dexamethasone in the retina following transcleral administration.18 The current leader in clinical ocular iontophoresis is EyeGate Pharma (Waltham, MA), which is currently investigating this technology for drug delivery.19

For patients with retinal tumors, iontophoresis is being researched as a potential noninvasive alternative to the use of systemic chemotherapy. In a mouse model, investigators found that iontophoresis could successfully transport carboplatin, a cytotoxic compound for treatment of retinoblastoma, to the retina.20

Another delivery mechanism that is currently under study is suprachoroidal drug delivery. IScience Interventional Corporation (Menlo Park, CA) has developed a microcatheter system that shows the ability to access the suprachorial space (See "Suprachoroidal Drug Delivery" on page 47 for more information). Supra-choroidal drug delivery has been evaluated in animals in a safety and pharmacokinetic study with trimacinolone acetonide.21 A study is underway in Europe to evaluate the delivery of combined bevacizumab (Avastin, Genentech, Inc.) and triamcinolone acetonide for AMD and another study is planned for the United States later this year.

CONCLUSION
Several novel ophthalmic drug delivery systems are available or in development for the posterior segment eye diseases. The intensive efforts in this field offer hope for more effective, precise and safe treatment to patients with diseases of the retina and vitreous, the primary cause of blindness in the developed world.

Radouil T. Tzekov, MD, PhD, is the Director of the Retina Department at Ora, Andover, MA. Dr. Tzekov can be reached via e-mail at rtzekov@oraclinical.com.

Mark B. Abelson MD, CM, FRCSC, is Chairman and Chief Scientific Officer of Ora.

Daniel Dewey-Mattia is a Medical Writer with Ora. He can be reached via e-mail at ddewey-mattia@oraclinical.com.

None of the authors report a financial interest.

  1. Hughes PM, Olejnik O, Chang-Lin JE, Wilson CG. Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev. 2005;57(14):2010–2032.
  2. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol. 2008;246(1):81–87.
  3. Von Sallmann L. Penicillin therapy of infections of the vitreous. Arch Ophthalmol. 1945;33:455.
  4. Shams N, Ianchulev T. Role of vascular endothelial growth factor in ocular angiogenesis. Ophthalmol Clin North Am 2006;19(3):335–344.
  5. Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases. Ann Pharmacother. 2007;41(4):614–625.
  6. Kang Derwent JJ, Mieler WF. Thermoresponsive hydrogels as a new ocular drug delivery platform to the posterior segment of the eye. Trans Am Ophthalmol Soc. 2008;106:206–213; discussion 13–14.
  7. Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125(3):309–317.
  8. Csernus VJ, Szende B, Schally AV. Release of peptides from sustained delivery systems (microcapsules and microparticles) in vivo. A histological and immunohistochemical study. Int J Pept Protein Res. 1990;35(6):557–565.
  9. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2008;13(3-4):135–143.
  10. Bakri SJ, Couch SM, McCannel CA, Edwards AO. Same-day triple therapy with photodynamic therapy, intravitreal dexamethasone, and bevacizumab in wet age-related macular degeneration. Retina. 2009;29(5):573–578.
  11. Tamaki Y. [Novel approach for management of age-related macular degeneration—antiangiogenic therapy and retinal regenerative therapy]. Nippon Ganka Gakkai Zasshi. 2007;111(3):232-68; discussion 69.
  12. Masuda I, Matsuo T, Yasuda T, Matsuo N. Gene transfer with liposomes to the intraocular tissues by different routes of administration. Invest Ophthalmol Vis Sci. 1996;37(9):1914–1920.
  13. Bourges JL, Bloquel C, Thomas A, et al. Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev. 2006;58(11):1182–1202.
  14. Hsu J. Drug delivery methods for posterior segment disease. Curr Opin Ophthalmol. 2007;18(3):235–239.
  15. Choonara YE, Pillay V, Carmichael T, Danckwerts MP. Studies on a novel doughnut-shaped minitablet for intraocular drug delivery. AAPS PharmSciTech. 2007;8(4):E118.
  16. Alimera. Iluvien: Addressing the Ophthalmic Crisis of Diabetes. 2008; v. 2009.
  17. Myles ME, Neumann DM, Hill JM. Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis. Adv Drug Deliv Rev. 2005;57(14):2063–2079.
  18. Eljarrat-Binstock E, Raiskup F, Frucht-Pery J, Domb AJ. Transcorneal and transscleral iontophoresis of dexamethasone phosphate using drug loaded hydrogel. J Control Release. 2005;106(3):386–390.
  19. EyeGate. Pipeline [Internet]. Waltham, MA, 2009.
  20. Hayden B, Jockovich ME, Murray TG, et al. Iontophoretic delivery of carboplatin in a murine model of retinoblastoma. Invest Ophthalmol Vis Sci. 2006;47(9):3717–3721.
  21. Olsen TW, Feng X, Wabner K, et al. Cannulation of the suprachoroidal space: a novel drug delivery methodology to the posterior segment. Am J Ophthalmol. 2006;142(5):777–787.