Posterior segment diseases, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), retinal vein occlusion (RVO), uveitis, and endophthalmitis, are responsible for causing visual impairment and blindness worldwide. The use of topical, systemic, transscleral, and intravitreal administration of pharmaceutical agents for treating these conditions has been the subject of myriad laboratory and clinical trial investigations.
Until recently, and with a few notable exceptions,1-4 there was limited evidence from large clinical trials that pharmacotherapy demonstrated a useful biological effect or comparable clinical outcome compared with laser, vitreoretinal surgery or other approaches for the primary treatment of posterior segment disease. Within the past decade this paradigm has shifted, and drug delivery to the posterior segment has become important for treating several major visionthreatening ocular conditions, with strong evidence demonstrating superior efficacy compared with previous gold standards for treating neovascular AMD and central RVO with intravitreal vascular endothelial growth factor (VEGF) inhibiting agents5-8 and corticosteroids9 respectively.
The use of intravitreal implants has also seen a recent increase, with several new corticosteroid-containing devices in or about to enter clinical practice for the treatment of a variety of posterior segment conditions. These may offer a longer duration of effective drug concentration, thereby potentially reducing the frequency of treatments.
Additionally, advances in nanotechnology have led to the experimental use of topical permeation-enhancing liposomes and emulsions and biodegradable microspheres that can contain ocular pharmacologic agents and thereby provide improved intravitreal delivery of a variety of medications. These technologies may allow sustained-release drug therapy and improve the sideeffect profiles of currently available clinical treatments.
ANATOMIC CHALLENGES OF
POSTERIOR SEGMENT DRUG DELIVERY
High intravitreal drug concentrations are required in
the treatment of posterior segment diseases; however,
the anatomy, physiology, and biochemistry of the eye
make the eye resistant to significant concentrations of
foreign substances. An understanding of the characteristics
of the blood-eye barrier is important in efforts to
achieve drug delivery for ophthalmic diseases. This barrier,
which compartmentalizes the eye, is maintained by
tight junctions at the retinal vascular endothelium, the
iris vascular epithelium, and the nonpigmented ciliary
epithelium.10 It comprises two components: an outer
component formed by junctional complexes of the retinal
pigmented epithelium (RPE) and the pigment epithelial
cells of the pars plana, and an inner component
formed by tight junctions between endothelial cells in
the retinal capillaries. The barrier blocks pathogens from
reaching ocular tissues but also hinders systemic pharmacologic
agents from reaching potential targets inside the
eye.11,12 It also reduces convection of molecules because
it has no cellular components and is selectively permeable
to more lipophilic molecules.13 Because of this, many
strategies developed to deliver treatment for posterior segment
disease have failed to show clinical efficacy. Figure 1
demonstrates an overview of potential mechanisms for
posterior segment drug delivery.
TOPICAL DRUG ADMINISTRATION
Topical drug application, the most common method
of ocular drug delivery, is useful in the treatment of many
anterior segment disorders.14 This noninvasive mode of
drug delivery selectively targets the anterior chamber
structures; however, the cornea represents a significant
barrier for efficient drug delivery. The corneal epithelium
is a lipophilic tissue and contributes to a major reduction
in penetration by hydrophilic drugs; less than 5% of the
total administered topical dose reaches the aqueous
humor,15 and far less penetrates into the posterior segment.
16,17 A major fraction of drug following topical
administration is lost through lacrimation, tear dilution,
nasolacrimal drainage, and tear turnover.18 Such precorneal
losses result in very low ocular bioavailability.
There are, however, several approaches to altering the method and route of topically applied agents that may increase their posterior segment penetration. These include use of cyclodextrins, prodrug formulations, permeability enhancers, transcorneal diffusion, and transconjunctival or transscleral penetration directly through the pars plana.
Cyclodextrins—cylindrical oligonucleotides with a hydrophilic outer surface and a lipophilic inner surface that are capable of forming inclusion complexes with lipophilic drugs—have been combined with corticosteroids, chloramphenicol, diclofenac, cyclosporine, and sulfonamide carbonic anhydrase inhibitors to form complexes that demonstrate significant corneal penetration. 19,20 One study determined that dexamethasonecyclodextrin complexes delivered topically to rabbit eyes reached significant levels in the retina and vitreous.21 This approach may be useful in the treatment of vitreoretinal diseases requiring chronic drug delivery.
Prodrug strategies have been attempted for improving the therapeutic efficacy of many drug molecules. Prodrug formulations use pharmacologically inactive derivatives of drug molecules that are better able to penetrate the cornea than the standard formulation of the drug.22,23 Within the cornea or after corneal penetration the prodrug is metabolized to the active parent compound. Most prodrugs, including the antiviral prodrugs ganciclovir and acyclovir, are delivered conventionally by topical application.
Although straightforward application of topical antiviral agents is insufficient for effective posterior segment drug concentration, enhancement of drug absorption has been shown when these drugs are combined with liposome permeability enhancers.
TOPICAL ADMINISTRATION OF LIPOSOMES
Liposomes are composed of a membrane-like lipid bilayer
formed from phospholipids and cholesterol surrounding
an aqueous compartment, which allows encapsulation of a variety of drug molecules including proteins,
nucleotides, and plasmids.24 The liposome membranes are
stable and can be deformed without disruption, potentially
allowing injection through small-gauge needles. As a
permeability enhancer, the liposome may facilitate slow
drug release without alteration of the intrinsic characteristics
of the encapsulated pharmaceutical agent. The binding
affinity of liposomes to the cornea suggests that that
uptake by the cornea is greatest for positively charged liposomes.
In rabbit corneas, positively charged liposomes
demonstrated enhanced transcorneal flux of penicillin G
more than fourfold compared with controls.25
Similarly, immunoliposomes of antiviral drugs, such as ganciclovir and iododeoxyuridine, using monoclonal antibodies to glycoprotein D of herpes simplex virus, have also been formulated and reported.26 The permeability of ganciclovir solution was compared with a liposomal formulation containing ganciclovir. Transcorneal permeability and area under the curve were 3.9- and 1.7-fold higher than the solution, respectively. Ocular tissue distribution was also higher in the sclera, cornea and vitreous humor with the liposomal formulation.26 Another study reported that site-specific and sustained release immunoliposomes may act as improved vehicles for drug delivery in treatment of ocular herpes simplex virus infection. Antisense oligonucleotides that can be efficaciously used to treat ocular diseases such as cytomegalovirus retinitis can be encapsulated in liposomes and efficiently targeted to the retina.28
In a rabbit model, a single injection of liposome-encapsulated 100 μg cidofovir prevented herpes simplex virus retinitis for more than 8 months.29 Studies by Bochot et al showed that 37% of administered antiviral oligonucleotides were retained in the vitreous humor after 15 days.30 Another group demonstrated that administration of liposome- encapsulated antiviral phosphodiester oligonucleotides resulted in sustained release into the vitreous and choroid, compared with release from a solution alone, and in a reduced distribution within the sclera and lens.31 Similar to microparticles and nanoparticles, liposomes can also impair vitreous clarity.30 Furthermore, the long-term effects of liposomal injections in the eye are unknown.
Despite some advantages that make liposomes a potentially useful system for ocular drug delivery, the utility of liposomes may be limited by a short shelf life, limited drugcarrying capacity and difficulty associated with thorough sterilization. Additionally, using topical delivery, liposomes may not be able to release the entire payload of active drug relative to a free solution form.31 Liposomal formulations, however, can release active drug, especially oligonucleotides, in a sustained manner following intravitreal injection.28 PEGylated liposomes containing oligonucleotides resulted in a higher percentage of active drug (30% of the total dose) after 2 weeks compared with release from solution. Some researchers have formulated liposomes coated with an envelope of inactivated hemagglutinating virus of Japan to treat choroidal neovascularization (CNV) in rats. They successfully delivered phosphorothioate oligonucleotides to inhibit VEGF.30 Direct intravitreal administration of liposomes is a more definitive method of posterior segment drug delivery than topical administration, but it is more invasive and associated with greater risks of bleeding and infection. Furthermore, frequent injections may be required depending on the half-life of the pharmacologic agent.
IONTOPHORESIS
Iontophoresis is a noninvasive technique in which a small
electric current is applied to enhance ionized drug penetration
into tissue.33,34 The drug is applied with a weak electric
current that drives charged molecules across the sclera and
into the choroid, retina, and vitreous body.33 A ground
electrode of the opposite charge is placed elsewhere on the body to complete the circuit. The drug serves as the conductor
of the current through the tissue. Transcorneal and
transscleral iontophoresis have been studied with a variety
of ophthalmic drugs in animals and to a limited extent in
humans. Iontophoresis is noninvasive and therefore avoids
the risks of surgical implantation or intravitreal injections,
and it does not affect drug half-life.35
Animal studies have shown that transscleral iontophoresis can be used to deliver therapeutic levels of bioactive proteins to the retina and the choroid, which may offer a viable and less invasive alternative for delivering anti-VEGF agents.36,37 Human studies involving healthy volunteers showed no clinically significant ophthalmologic changes following transscleral iontophoresis.38 A burning sensation was noted by a few subjects at the applicator site at higher current levels. Iontophoresis has the advantage of being noninvasive and therefore avoids the risks of surgical implantation or intravitreal injection.
TRANSSCLERAL DRUG DELIVERY
Transscleral drug delivery is another transport mechanism
for posterior drug delivery with topical drops.
Because the sclera is made up of fibrous tissue, it offers
less resistance to permeability of drugs than the cornea,
allowing improved absorption and increased retinal and
intravitreal concentrations.39 Molecules up to approximately
70 kDa can readily penetrate the sclera, whereas
the size limit to pass through the cornea is less than
1 kDa. In addition, the sclera provides a large surface area
of 17 cm2, comprising 95% of the surface area of the
human eye. This area provides a large region for transscleral
drug absorption and allows delivery of neuroprotective
agents, antioxidants, or angiostatic agents to specific
regions of the retina.40 Even large molecules such as tissue
plasminogen activator have been shown to reach significant
intraocular drug levels in the posterior segment.41-43
OT-551 (Othera Pharmaceuticals) is a topical antioxidant that was investigated as a treatment for dry AMD. The drug is a small lipophilic molecule that readily penetrates the cornea and is converted by ocular esterases to TEMPOL-H (TP-H), an active metabolite that is a potent free-radical scavenger. In animal studies, topical therapy has resulted in excellent ocular bioavailability, with significant levels of TP-H achieved in the retina.44
The drug OT-551 was shown to possess antiinflammatory, antiangiogenic, and antioxidant properties. OT-551 has also been shown to protect against oxidative damage in vitro, protect against light damage in vivo, suppress photoreceptor cell death in animal models, and block angiogenesis stimulated by growth factors.45 Based on these preclinical data, OT-551 was investigated as a therapy for geographic atrophy for AMD. A 2-year, phase 2 trial, known as the OT-551 Multicenter Evaluation of Geographic Atrophy (OMEGA) study, was halted after 18 months due to an apparent lack of efficacy in preventing the enlargement rate of GA in AMD.
Mecamylamine (ATG003), a nicotinic antagonist that was approved by the US Food and Drug Administration as an antihypertensive and as a smoking-cessation medication, was developed by CoMentis, Inc. A phase 1 trial in patients with neovascular AMD has been completed, and a phase 2 trial is currently enrolling patients. Inhibition of the nAChR pathway blockade may inhibit angiogenesis, and thus the use of mecamylamine may be an effective adjunct to anti-VEGF treatment, including ranibizumab.45
For neovascular AMD, the anti-VEGF agent pazopanib, developed by GlaxoSmithKline, has completed both phase 1 safety and efficacy trials and is currently being evaluated in several phase 2 trials. Pazopanib blocks tyrosine kinase receptors including VEGF receptors 1, 2, and 3, PDGFR, c-Kit, and fibroblast growth factor receptor 1, and has been shown to inhibit CNV in a mouse model.46 By blocking multiple receptors, this agent may inhibit new blood vessel development and induce regression of established CNV.
THE EMERGING ROLE OF TOPICAL DRUG
DELIVERY TO THE POSTERIOR SEGMENT
Effective treatment of ocular diseases is a formidable
challenge for physicians because of the nature of the diseases
and the presence of ocular barriers precluding
delivery to the posterior segment. An ideal therapy
should maintain effective levels of drug for long durations
following a single application.
Drug delivery to the posterior segment by the topical route is limited in the amount of effective drug delivered, although permeability enhancers may make this route of delivery more effective in the future. There has been considerable effort in the development of transscleral drug delivery systems; however, these modes have yet to demonstrate a clinical benefit over intravitreal delivery for treating retinal diseases.
Drug delivery by periocular route can potentially overcome many of these limitations and provide sustained drug levels in a number of ocular pathologies. Novel delivery approaches using sustained-release intravitreal implants will likely provide much-needed benefit for patients with conditions resistant to more conservative therapy, although long-term data on ocular tissue response to continuous corticosteroid exposure is lacking.
Periocular depot injections of microparticulate-encapsulated drugs or transscleral iontophoresis may also allow transscleral drug transfer into the eye and provide a technique less invasive than intravitreal injection or sustained- release implants.
For neovascular AMD, however, frequent injections of anti-VEGF compounds are the current standard of care. Unmet needs in this population include therapies that reduce the treatment burden and improve visual acuity in a greater percentage of patients. Transporter targeted delivery, microspheres, liquid drug delivery systems (Verisome, Icon Bioscience Inc.)47 and thermoresponsive hydrogels48 are also strategies that show promise for incorporation with many pharmacologic drug molecules. Colloidal carriers can substantially improve current therapy and may emerge as an alternative for periocular administration.
In the future, the efforts of pharmaceutical researchers will likely be placed on achieving noninvasive, sustained drug release for eye disorders of the posterior segment.
Jennifer I. Lim, MD, is a Professor of Ophthalmology, Director of the Retina Service, and the Charles I. Young Chair of Ocular Research at the Illinois Eye and Ear Infirmary, University of Illinois, Chicago. Dr. Lim states that she is on the speakers' bureau of Genentech, Inc. She can be reached at +1 312 413 0704; or via e-mail at jennylim@uic.edu.
Daniel F. Kiernan, MD, is a Vitreoretinal Surgical Fellow at the llinois Eye and Ear Infirmary, University of Illinois, Chicago. Dr. Kiernan states that he has no financial arrangements relevant to the products and companies discussed in this article. He may be reached at danielkiernan714@ yahoo.com.
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