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181
8 Suprachoroidal and Intrascleral Drug Delivery
0.0
Intravitreal Injection
Suprachoroidal Injection
Free Bev / Tissue (ug/mg)Free Bev / Tissue (ug/mg)
0510 15
Days
Days
20 25
6mm Choroid
6mm Retina
Foveal sclera
Remainder Vitreous
Posterior Vitreous
Anterior Vitreous
Peripheral Choroid
Peripheral Retina
6mm Choroid
6mm Retina
Foveal sclera
Remainder Vitreous
Posterior Vitreous
Anterior Vitreous
Peripheral Choroid
Peripheral Retina
30
0510 15 20 25 30
0.5
1.0
1.5
2.0
0.0
0.5
1.0
1.5
2.5
2.0
3.0
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Fig. 8.7 Graph comparing the days postinjection (x-axis) with local tissue drug levels (y-axis).
The studies clearly demonstrate more rapid decrease in drug levels injected using the suprachoroidal route (bottom) than with the intravitreal route (top graph)
distribution of the latex to nearly 50% of the entire suprachoroidal space (see Fig. 8.4).
Furthermore, the injected latex distributed to the suprachoroidal space adjacent to the
area centralis (i.e., macula) in 56% of eyes injected (Gilger and Salmon 2010).
In another study using porcine cadaver eyes (Fig. 8.9), an optimal volume for injection into the suprachoroidal space was determined to be 250 ml and this volume of
ultrasound contrast agent injected into the anterior suprachoroidal space distributed to
the space adjacent to the area centralis in over 80% of eyes, as determined by ocular
ultrasound (Gilger, unpublished data). These studies suggest that access to the anterior
suprachoroidal, either by cannula or microneedles, may allow the distribution of drugs
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Fig. 8.8 (Hemotoxalin and eosin stain at 100×) The arrow on this histopathology section points to
a granulomatous reaction in the porcine eye to a humanized antibody (bevacizumab). This reaction
was only seen in intravitreal injections and not in suprachoroidal injections using the same agent
Fig. 8.9 Contrast ultrasound image of a cadaver porcine eye after injection of 500 ml of microbubble
contrast agent (Targestar-P, Targeson Inc) into the anterior suprachoroidal space. Note that the top of
this image represents the anterior globe while the inferior portion represents the posterior pole. The
contrast agent initially is visualized at the injection site (1), followed by the opposite anterior suprachoroidal space (2), followed by the suprachoroidal space at the posterior pole of the eye (3)
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to a large area of the ocular posterior segment and to the macular area of the eye.
Further studies are needed to determine the effect of the choroidal blood flow on the
distribution of specific medications to the retina and macula.
8.6 Summary
The suprachoroidal and deep lamellar scleral delivery are viable routes for delivery
of drugs to posterior segment tissues of the eye. Key advantages of these routes
include a bypass of the optical pathways (an issue with intravitreal injections), direct
drug diffusion to the choroidal stroma and RPE, a bypass of the diffusional barriers
that occur in transscleral delivery, and potentially an advantageous immune response
toward biologic agents. Finally, future development of sustained release particles,
advantageous formulations, or delivery devices could optimize diffusional kinetics
from the deep sclera and suprachoroidal space. Deep scleral and suprachoroidal
routes of drug delivery offer a unique avenue for routine injections that are safe and
effective in targeting retinal and macular diseases. We anticipate significant future
advances in this field of research.
References
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S (2006)
Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J
Med 355:1432–1444
Choy YB, Park JH, McCarey BE, Edelhauser HF, Prausnitz MR (2008) Mucoadhesive microdiscs
engineered for ophthalmic drug delivery: effect of particle geometry and formulation on pre-
ocular residence time. Invest Ophthalmol Vis Sci 49:4808–4815
Einmahl S, Savoldelli M, D’Hermies F, Tabatabay C, Gurny R, Behar-Cohen F (2002) Evaluation
of a novel biomaterial in the suprachoroidal space of the rabbit eye. Invest Ophthalmol Vis Sci
43:1533–1539
Geroski DH, Edelhauser HF (2000) Drug delivery for posterior segment eye disease. Invest
Ophthalmol Vis Sci 41:961–964
Gilger BC, Salmon JH (2010) Ocular posterior segment drug distribution from a single injection
into the anterior suprachoroidal space. ARVO. Ft. Lauderdale, FL, Invest ophthalmol Vis Sci
Gilger BC, Reeves KA, Salmon JH (2005) Ocular parameters related to drug delivery in the canine
and equine eye: aqueous and vitreous humor volume and scleral surface area and thickness. Vet
Ophthalmol 8:265–269
Gilger BC, Salmon JH, Wilkie DA, Cruysberg LP, Kim J, Hayat M, Kim H, Kim S, Yuan P, Lee
SS, Harrington SM, Murray PR, Edelhauser HF, Csaky KG, Robinson MR (2006) A novel
bioerodible deep scleral lamellar cyclosporine implant for uveitis. Invest Ophthalmol Vis Sci
47:2596–2605
Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR (2004) Pegaptanib for
neovascular age-related macular degeneration. N Engl J Med 351:2805–2816
Jiang J, Geroski DH, Edelhauser HF, Prausnitz MR (2006) Measurement and prediction of lateral
diffusion within human sclera. Invest Ophthalmol Vis Sci 47:3011–3016
Jiang J, Gill HS, Ghate D, McCarey BE, Patel SR, Edelhauser HF, Prausnitz MR (2007) Coated
microneedles for drug delivery to the eye. Invest Ophthalmol Vis Sci 48:4038–4043
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Jiang J, Moore JS, Edelhauser HF, Prausnitz MR (2009) Intrascleral drug delivery to the eye using
hollow microneedles. Pharm Res 26:395–403
Lewis RA, von Wolff K, Tetz M, Koerber N, Kearney JR, Shingleton BJ, Samuelson TW (2009)
Canaloplasty: circumferential viscodilation and tensioning of Schlemm canal using a flexible
microcatheter for the treatment of open-angle glaucoma in adults: two-year interim clinical
study results. J Cataract Refract Surg 35:814–824
Maurice DM, Polgar J (1977) Diffusion across the sclera. Exp Eye Res 25:577–582
Olsen TW, Edelhauser HF, Lim JI, Geroski DH (1995) Human scleral permeability. Effects of age,
cryotherapy, transscleral diode laser, and surgical thinning. Invest Ophthalmol Vis Sci
36:1893–1903
Olsen TW, Aaberg SY, Geroski DH, Edelhauser HF (1998) Human sclera: thickness and surface
area. Am J Ophthalmol 125:237–241
Olsen TW, Sanderson S, Feng X, Hubbard WC (2002) Porcine sclera: thickness and surface area.
Invest Ophthalmol Vis Sci 43:2529–2532
Olsen TW, Feng X, Wabner K, Conston SR, Sierra DH, Folden DV, Smith ME, Cameron JD
(2006) Cannulation of the suprachoroidal space: a novel drug delivery methodology to the
posterior segment. Am J Ophthalmol 142:777–787
Olsen TW, Feng X, Wabner K, Csaky KG, Cameron JD, Pambuccian S, Nguyen T (2010)
Microcannula suprachoroidal versus intravitreal injections of bevacizumab in the pig model.
ARVO, Fort Lauderdale, FL
Robinson MR, Lee SS, Kim H, Kim S, Lutz RJ, Galban C, Bungay PM, Yuan P, Wang NS, Kim J,
Csaky KG (2006) A rabbit model for assessing the ocular barriers to the transscleral delivery
of triamcinolone acetonide. Exp Eye Res 82:479–487
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab
for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431
Chapter 9
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Advances in Biodegradable Ocular Drug
Delivery Systems
Susan S. Lee, Patrick Hughes, Aron D. Ross, and Michael R. Robinson
Abstract The limitations of existing medical therapies for ocular disorders include
low drug bioavailability, nonspecificity, side effects, and poor treatment adherence to
therapy. These limitations may be overcome through the use of sustained-release
intraocular drug delivery systems. Critical to the development of such systems has
been the introduction of biocompatible polymers (biodegradable and nonbiodegradable) that allow for drug release kinetics to be tailored for specific drugs and ocular
diseases. Drug delivery systems composed of biodegradable polymers, such as polylactic-co-glycolic acid, appear to be particularly well suited for such applications.
This review examines the characteristics of these polymers for medical applications,
as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of sight-threatening ocular diseases.
Abbreviations
EVA
Ethylene vinyl acetate
HEMA Hydroxyethylmethacrylate
HPC Hydroxypropyl cellulose
HPMC Hydroxypropyl methylcellulose
PAH Polyanhydride
PBMA Polybutyl methacrylate
PCL Poly(-e-caprolactone)
PCL-PEG Poly(e-caprolactone)-poly(ethylene glycol)
PDLLA d,l-poly(lactic acid)
PDO Polydioxane
S.S. Lee (*)
Allergan, Inc., Irvine, CA, USA
e-mail: lee_susan@allergan.com
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_9,
© American Association of Pharmaceutical Scientists, 2011
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PDS Poly-p-dioxane
PETP Polyethylene terephthalate
PGA Poly(glycolic acid)
PGLC Poly(glycolide-co-lactide-co-caprolactone)
PHEMA Poly(2-hydroxyethylmethacrylate)
PLA Poly(lactic acid)
PLGA Poly(lactic-co-glycolic acid)
PLLA Poly(l-lactic acid)
PLTMC
PMM Polymethylidene malonate
POE Poly(ortho ester)
PPF Polypropylene fumarate
PVA Polyvinyl alcohol
PVP Poly(N-vinyl pyrrolidone)
TMC Trimethylene carbonate
Poly(l-lactide-co-1,3-trimethylene carbonate)
9.1 Introduction
Chronic retinal diseases are the leading contributor to visual impairment and blindness worldwide. The most common forms of retinal disease leading to loss of vision
include glaucoma, age-related macular degeneration, diabetic retinopathy, retinal
vein occlusion, uveitis, infectious retinitis, retinal detachment, and inherited degenerative conditions such as retinitis pigmentosa. The number of people with visual
impairment worldwide in 2002 was in excess of 161 million, of whom about 37
million were blind (Resnikoff 2004). The annual worldwide cost of blindness due to
lost productivity was estimated in 1993 to be $108 billion USD. It has been estimated that the number of blind individuals worldwide will likely increase to 76
million in 2020, with associated costs expected to reach $1,546
and Foster 2003).
Topical drug therapy is the mainstay of treatment for ocular disorders of the
anterior segment such as ocular surface diseases (e.g., conjunctivitis, dry eye), for
glaucoma or ocular hypertension, and for anterior uveitis (Conway 2008; Ghate and
Edelhauser 2006; Kearns and Williams 2009). However, topical therapies are limited for treating disorders of the posterior segment due to the greater diffusional
distance (Yasukawa et al. 2006) as well as anatomical and physiological barriers in
the eye. These barriers, such as the corneal epithelium and conjunctival clearance
mechanisms, not only protect against the entry of xenobiotics but also greatly
impede drug uptake, thus making it difficult to achieve therapeutic drug concentrations (Conway 2008; Ghate and Edelhauser 2006; Kearns and Williams 2009; Myles
et al. 2005). Although successful in rodent models (Tanito et al. 2007; Ni and Hui
2009), the efficacy of topical therapies for retinal diseases has yet to be demon-
strated in human clinical trials.
billion USD (Frick
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Systemically administered drugs also have been used for treating a variety of
ocular diseases. However, drug penetration in ocular tissues is greatly limited by the
blood-aqueous and blood-retinal barriers. As a result systemically administered
drugs must be given at high doses, which increase drug exposure in nonocular
tissues and consequently, the risk of adverse systemic side effects (Ghate and
Edelhauser 2006, 2008).
Intravitreal drug injections have also been explored for delivering drugs to
target tissues in the eye at therapeutic concentrations. However, many intravitreally administered agents, such as low molecular weight drugs like corticosteroids, have short half-lives, ranging from 2 to 6 h (Kwak and D’Amico 1992); as
a result, efficacy can be transient and frequent injections may be needed to maintain therapeutic drug concentrations (Kiernan and Mieler 2009). Higher molecular weight compounds, such as vascular endothelial growth factor antibodies and
antigen-binding fragments, have longer half-lives, but monthly injections are
still required to maximize their efficacy in preserving visual acuity in patients
(Spaide et al. 2009; Pieramici et al. 2008; Dafer et al. 2007; Rosenfeld et al.
2006). With increasing frequency of intravitreal injections, however, there also is
an increased risk of serious adverse events including retinal detachment,
endophthalmitis, and vitreous hemorrhage, as well as adverse manifestations in
the anterior segment such as cataract formation and intraocular pressure elevation (Jager et al. 2004; Berinstein 2003). Although the incidence rates of these
serious side effects may be relatively low, they can be sight threatening. Due to
the anatomic and physiologic barriers to both topical and systemic drug therapy,
the relatively short half-life of compounds administered by intravitreal injection,
and other general limitations of these routes of administration (Table 9.1),
sustained-release drug delivery systems have been developed over the past decade
and now play an important role in treating a variety of ocular diseases.
Table 9.1 Limitations of ocular drug delivery methods
Method Limitations
Topical administration Limited uptake
Intravitreal injection Targeted delivery
Systemic administration Limited ocular penetration
Nonbiodegradable implants Invasive surgery
Tear dilution/washout
Short acting
Poor adherence to therapy
Invasive/inconvenient/short lasting
Adverse events related to injection
Systemic toxicity
Require removal
Adverse events related to implantation
or removal surgery
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Sustained-release intrascleral and intravitreal drug implants and inserts have
been developed for the treatment of ocular diseases. These polymer-based drug
delivery systems are designed to achieve prolonged therapeutic drug concentrations in ocular target tissues that are not readily accessible by conventional means,
while limiting the side effects from systemic drug exposure, frequent intraocular
injections, and high peak drug concentrations associated with pulsed dosing, as
well as improving patient compliance. Such drug delivery systems also offer
potential cost savings over other shorter acting therapies, such as intravitreal
injections, which require more frequent retreatment and a greater number of physician’s office visits. Various types of polymeric delivery systems have been
explored for sustained drug delivery to the eye. Such systems can be distinguished
on the basis of whether they are constructed using biodegradable or nonbiodegradable polymers (Yasukawa et al. 2006; Kiernan and Mieler 2009; Gaudana
et al. 2009).
9.2 Nonbiodegradable Ocular Drug Delivery Systems
The two most common types of nonbiodegradable implants are reservoir-type
devices (in which a drug core is slowly released across a nonbiodegradable semipermeable polymer or is released from a nonbiodegradable polymer with an opening of
fixed area) and implant-type devices (in which a nonbiodegradable free-floating pellet is injected intravitreally or a nonbiodegradable plug is anchored to the sclera).
Most of the clinically available ocular implants to date have been of the nonbiodegradable reservoir type, typically consisting of a combination of polyvinyl alcohol (PVA) and ethylene vinyl acetate (EVA) (Davis et al. 2004). PVA, a permeable
nonbiodegradable polymer, is used as the main structural element, and EVA, a nonbiodegradable polymer that is hydrophobic and relatively impermeable to hydrophilic drugs, is used for the device’s drug-restricting membrane (Conway
Kearns and Williams 2009; Yasukawa et al. 2006; Davis et al. 2004). Drug release
from reservoir-type devices occurs following diffusion of water through the outer
EVA coating, which partially dissolves the enclosed drug and forms a saturated drug
solution that diffuses into the surrounding tissue (Conway 2008; Kearns and
Williams 2009). Reservoir-type systems display near zero-order drug-release kinetics after establishing a steady-state concentration gradient across the nonbiodegradable semipermeable membrane and have relatively constant release rates as long as
solid drug remains within the core. The duration of drug release is limited mainly
by the rate of drug dissolution within the reservoir. The rate of drug release can be
delayed by increasing the surface area or thickness of the drug-restricting polymer,
and hastened by increasing the surface area available for drug diffusion or by using
a more permeable membrane. Nonbiodegradable reservoir-type devices are typically designed to release drug over a span of months or years for the treatment of
chronic conditions that require long-term drug therapy.
2008;
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Although nonbiodegradable implants can be useful in some clinical situations, they have several distinct drawbacks (Table 9.1). For example, large incisions and sutures or some other form of anchoring may be necessary. Furthermore,
additional implants may be required in order to maintain efficacy once the drug
supply in the initial implant is exhausted. Lastly, removal procedures may be
needed to prevent fibrous encapsulation of drug-depleted implants. The implantation and removal of nonbiodegradable implants can be associated with serious
side effects such as retinal detachment, vitreous hemorrhage, and cataract
formation (Conway 2008; Kearns and Williams 2009; Yasukawa et al. 2006;
Kiernan and Mieler 2009; Chu 2008; Kimura and Ogura 2001; Mohammad
et al. 2007).
Examples of nonbiodegradable polymeric drug delivery systems that have been
used clinically for the treatment of ocular disorders include Retisert® (fluocinolone
acetonide), Ocusert® (pilocarpine hydrochloride), Vitrasert® (ganciclovir), I-vation™
(triamcinolone acetonide), Iluvien™ (fluocinolone acetonide), and Lumitect®
(cyclosporine) (Table 9.2).
9.2.1 Retisert
Retisert® (Bausch and Lomb, Inc., Rochester, NY/pSivida Ltd.) is a disc-shaped,
nonbiodegradable intravitreal implant (3 × 2 × 5 mm) consisting of a matrix of fluocinolone coated with silicone and PVA attached to a 5.5-mm silicone suture tab
(Kiernan and Mieler 2009; Conway 2008). It is surgically inserted in the vitreous at
the pars plana near the ciliary processes through a 3- to 4-mm incision and is affixed
using sutures. The device has an initial drug delivery rate of 0.6 mg/day and reaches
a steady-state delivery rate of 0.3–0.4 mg/day over roughly 30 months. In April
2005, Retisert® received fast-track approval status and orphan drug designation
from the U.S. Food and Drug Administration for the treatment of chronic noninfectious uveitis of the posterior segment (Mohammad et
trial in patients with diabetic macular edema, the implant showed efficacy but was
associated with a high incidence of cataract (95%) and intraocular pressure elevation (35%) after 3 years, indicating that it may not be suitable for long-term treatment (Kane et al. 2008).
al. 2007). In a phase 3 clinical
9.2.2 Ocusert
Ocusert® is a nonbiodegradable conjunctival insert that provides sustained delivery
(zero-order kinetics) of pilocarpine hydrochloride for the treatment of glaucoma
(Macoul and Pavan-Langston 1975; Quigley et al. 1975). Launched in the mid-1970s
by Alza Corp., Ocusert® was the first commercially marketed controlled-release
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treatment of
glaucoma (no longer
marketed)
phase 2b trial
suspended in 2008
(Clinicaltrials.gov
ID# NCT00692614)
Investigational: DME
intravitreal
implant
treatment of AIDS-
related CMV
FDA approved for the
reservoir system
a
treatment of uveitis
retinitis
FDA approved for the
disc-shaped
RVO
Investigational: DME,
intravitreal
implant
(3 × 2 × 5 mm)
Duration of
drug release Characteristics Eye diseases
Table 9.2 Nonbiodegradable drug delivery implants for the treatment of chronic ocular diseases: approved systems and devices under clinical development
Brand name Manufacturer Materials Active agent
Up to 7 days Nonbiodegradable FDA approved for the
(Ocusert
Pilo-20,
20 mg/h;
Alza Corp. EVA, alginic acid Pilocarpine
2006;
Pilo (Conway
®
2008; Ghate and
Edelhauser
Kearns and Williams
Nonbiodegradable implants
Ocusert
Ocusert
Pilo-40,
40 mg/h)
2009; Macoul and
Pavan-Langston
1975; Quigley et al.
1975; Chien 1992)
2 Years Nonbiodegradable
acetonide
(1–3 mg/day)
Triamcinolone
nonferrous alloy
helix (PBMA/PVA;
Bravo drug delivery
SurModics Drug-polymer-coated
Kiernan and Mieler
2008; Kearns and
Williams 2009;
I-vation™ (Conway
5–8 months Implantable
(4.5 mg)
polymer matrix)
Bausch & Lomb EVA/PVA Ganciclovir
(Kedhar and
®
2009)
Jabs 2007)
Vitrasert
Up to 3 years Nonbiodegradable
acetonide
Silicone/PVA Fluocinolone
pSivida Ltd.
Bausch & Lomb/
(Conway 2008;
®
Kiernan and Mieler
et al. 2008)
2009; Mohammad
et al. 2007; Kane
Retisert
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