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9 Advances in Biodegradable Ocular Drug Delivery Systems
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Fig. 9.7 Ozurdex sustained-release drug delivery system. The dexamethasone drug pellet at a
dose of 350 or 700
Fig. 9.8 Photographic
images showing
biodegradation of PLGA
dexamethasone 700-mg
implant (Ozurdex) in a
monkey eye over a 6-month
period (Allergan, data on file)
mg is inserted using a 22-gauge microinjector
edema due to various causes (diabetic macular edema, retinal vein occlusion, uveitis,
or Irvine–Gass syndrome). The results showed that the treatment resulted in significant improvement in visual acuity, angiographic fluorescein leakage, and central retinal thickness at day 90, with the visual acuity improvements lasting out to 180 days
(Kuppermann et al. 2007). The study was not sufficiently powered to show significant
differences in effects among disease subtypes, and similar efficacy results were seen
in patients with macular edema due to different causes; however, the effect of treatment appeared to be slightly greater in patients with macular edema due to uveitis or
Irvine–Gass syndrome than in patients with macular edema due to other causes.
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Most ocular adverse events in patients treated with Ozurdex were mild, reported
within 1 week after surgery, and similar in frequency between the treatment and
observation groups beyond day 8. A mild increase in the incidence of hyperemia,
pruritus, vitreous hemorrhage, and anterior chamber cells was observed in the treatment groups relative to the control groups on day 8, which was expected as a result
of the surgical procedure. After day 8, only two adverse events occurred significantly more frequently in the treatment group: anterior chamber flare (5% for
Ozurdex vs. 0% for observation only) and increased intraocular pressure (6 and 0%,
respectively). Only 2 patients (2%) in each of the Ozurdex treatment groups and
1 patient (1%) in the observation group had an intraocular pressure increase of
mmHg or more from baseline at day 90. No cases of sterile endophthalmitis were
10
reported, which may have been related to the favorable drug-release characteristics
of Ozurdex (i.e., the injectable pellet does not result in the particle dispersion and
visual obscuration effects commonly associated with intravitreal triamcinolone
acetonide injections).
A multicenter phase 2 pilot study recently examined the safety and performance
of Ozurdex 0.7 mg administered using a nonincisional applicator system as compared
with pars plana incisional placement of the same drug delivery system in patients
with clinically observable macular edema resulting from diabetic retinopathy, retinal vein occlusion (branch and central vein), uveitis, or Irvine–Gass syndrome
(Haller et al. 2009). With both procedures, a substantial percentage of patients
showed significant improvements in visual acuity (up to a 3-line increase) as
compared with a control group, with therapeutic effects persisting up to 180 days in
some eyes. The procedures were well tolerated, and neither resulted in endophthalmitis or retinal detachment. Furthermore, none of the patients in the applicator
group required sutures to close the insertion wound. Notably, the incidence of ocular adverse events, vitreous hemorrhage, and intraocular pressure elevation was
lower with the applicator system than with pars plana incisional placement.
Ozurdex was recently evaluated in a prospective, multicenter, randomized,
single-masked controlled study using data from a subset of patients (n
= 41) with
persistent macular edema resulting from uveitis or Irvine–Gass syndrome. A significantly greater percentage of patients who received Ozurdex 0.35 or 0.7 mg had at
least a 10-letter improvement in best-corrected visual acuity [41.7% (5/12) and
53.8% (7/13), respectively] as compared with an observation-only control group
[14.3% (2/14)] and the improvement in visual acuity persisted to day 180. There
were also significantly greater reductions in fluorescein leakage in treated patients
than in observed patients. Ozurdex was well tolerated throughout the study.
Intraocular pressure increases of >10 mmHg were seen in 5 of 13 patients in the
0.7-mg group, 1 of 12 patients in the 0.35-mg group, and no patients in the observation group. No cases of endophthalmitis were reported (Williams et al. 2009).
The efficacy of Ozurdex in the treatment of vision loss due to macular edema
associated with retinal vein occlusion was recently examined in two identical,
multicenter, masked, randomized, 6-month, sham-controlled clinical trials consisting
of 1,267 patients in total. Ozurdex led to significant and more rapid improvements
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in best-corrected visual acuity at days 30–90 as compared with sham treatment
(Haller et al. 2010).
Ozurdex received US FDA approval in June 2009 for the treatment of macular edema
associated with retinal vein occlusion; as of October 2009, more than 2,500 patients
have been enrolled in Ozurdex clinical trials. Phase 3 trials are currently in progress to
evaluate Ozurdex for the treatment of patients with diabetic macular edema (clinicaltrials.gov study IDs NCT00168389 and NCT00168337) and uveitis (NCT00333814).
9.5.2 Surodex
Surodex™ (Allergan, Inc., Irvine, CA) is a rod-shaped biodegradable matrix implant
(1.0 × 0.5 mm) consisting of dexamethasone and PLGA with hydroxypropyl methylcellulose (HPMC). It is designed to provide sustained drug release at a constant
rate of 60
is well tolerated (Lee and Chee 2005; Lee et al. 2008). The implant is inserted in the
anterior chamber to control postoperative inflammation following cataract surgery;
it has been shown to significantly reduce anterior chamber cells and flare and to
have anti-inflammatory efficacy at least as good as that of topical steroids (Chang
et al. 1999; Tan et al. 1999, 2001; Seah et al. 2005).
mg over 7–10 days (Lee et al. 2008), does not require suture fixation, and
9.5.3 Verisome
Verisome™ (Ramscor, Inc., Menlo Park, CA) is a nonpolymer-based and proprietary intraocular drug delivery technology. It was developed to provide zero-order
sustained release of drugs in the form of long-acting biodegradable solids, gels, or
liquids that can be administered intravitreally via a standard 30-gauge injection.
The technology has a customizable duration of action and can be adapted for a
variety of pharmacotherapies using methods involving small molecules, peptides,
proteins, and monoclonal antibodies (http://www.iconbioscience.com/Technology-
Overview.html). IBI 20089, an investigational triamcinolone acetonide formula-
tion employing the Verisome system, was shown in rabbits to provide sustained
delivery of triamcinolone at a mean daily dose of 1.1 mg/mL for up to 1 year per
injection (Hu et al. 2008). The safety and efficacy of IBI 20089 was recently
investigated in a phase 1 trial in 10 patients with cystoid macular edema associated with retinal vein occlusion (Lim et al. 2009). An IBI 20089 formulation
delivering 13.8 mg triamcinolone was found to significantly reduce macular thickness after 120 days of treatment and was more effective than a 6.9-mg formulation. The size of the delivery system was visibly reduced as the drug was released
and it was well tolerated, with the exception of one case of intraocular pressure
elevation that required surgery.
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9.5.4 Lacrisert
Lacrisert® (Aton Pharma, Inc., Lawrenceville, NJ), introduced in 1981, is a sterile,
translucent, rod-shaped, water-soluble, biodegradable ophthalmic insert made of
hydroxypropyl cellulose (HPC) (5 mg), a physiologically inert substance that
stabilizes and thickens the precorneal tear film and prolongs tear breakup time. The
implant is designed for daily administration into the inferior cul-de-sac of the eye and
is approved to relieve the signs and symptoms of moderate to severe dry eye syndrome,
including keratitis sicca (Lacrisert prescribing information 2007).
Lacrisert can be particularly beneficial for patients who respond poorly to therapy with artificial tears. Once-daily treatment with Lacrisert was shown to provide
greater relief of dry eye symptoms than four-times-daily treatments with topical
artificial tears. Survey results also indicate that patients prefer Lacrisert over artificial tears (Lacrisert Prescribing Information 2007). The implant can be self-administered up to twice a day, using a specially designed applicator, and is generally well
tolerated. Side effects, typically mild and transient, include blurred vision, ocular
discomfort/irritation, eyelash matting/stickiness, photophobia, hypersensitivity,
eyelid edema, and hyperemia.
9.6 Experimental Biodegradable Ocular Drug Implants Under
Preclinical Development
Numerous polymer-based ocular drug delivery systems designed for the delivery of
a wide range of drugs (steroids, hormones, anticancer drugs, antifungals, etc.) and
incorporating a variety of different types of polymers (e.g., PLA, PLGA, PLGC,
PLTMC, PCL, POE, and PAH) have been evaluated in preclinical in vitro and
in
vivo studies (Table 9.6).
9.6.1 Poly(Lactic Acid)-Based Implants
A biodegradable intrascleral implant consisting of betamethasone phosphate and
PDLLA has been evaluated in a preliminary pharmacokinetic/safety study (Okabe
et al. 2003). Drug release from the implants in vitro occurred in a biphasic pattern,
with an initial burst followed by a second phase of diffusional release, and persisted
for at least 8 weeks. Following implantation of the betamethasone-PDLLA discs
into the scleral pocket in rabbits, drug concentrations in the vitreous and retinachoroid remained within the therapeutic range for suppression of inflammation for
more than 8 weeks. Drug concentrations were higher in the retina-choroid than in
the vitreous and undetectable in the aqueous humor. The implant showed good ocular
biocompatibility based on electrophysiological and histological assessments, and
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Table 9.6 Examples of biodegradable polymeric ocular drug delivery systems at the preclinical
stage of development
Polymer/drug Application/model
Polyanhydrides (PAH)
Taxol/etoposide Glaucoma filtration surgery in nonhuman
Polyorthoesters (POE)
5-Chlorouracil Glaucoma filtration surgery model in rabbits
5-Fluorouracil Glaucoma filtration surgery model in rabbits
Polylactic acid (PLA)
Betamethasone Betamethasone scleral implant (Okabe et
Ganciclovir Cytomegalovirus retinitis (Yasukawa et
Retinal progenitor cells PLLA/PLGA based composite grafts for delivery
Triamcinolone acetonide Intrascleral implant for experimental uveitis
Polylactic-co-glycolic acid (PLGA)
All-trans retinoic acid Experimental proliferative vitreoretinopathy in
N-4-(benzoylaminophenylsulfonyl glycine) Diabetic cataracts in rats (Aukunuru et al. 2002)
cis-Hydroxyproline Scleral implant for experimental proliferative
Cyclosporine Pharmacokinetics and toxicity in rabbits (Theng
Dexamethasone Safety and pharmacokinetics in rabbits (Fialho
Fluconazole Scleral implant for fungal endophthalmitis in
Fluorouracil Experimental proliferative vitreoretinopathy in
Ganciclovir Cytomegalovirus retinitis in rabbits (Sakurai
GDNF Microspheres for glaucoma in rats (Jiang et al.
Tacrolimus (FK-506) Scleral plug for experimental uveitis (Sakurai
Triamcinolone acetonide Adjunct with artificial intraocular lens for
Retinal progenitor cells PLGA/PLLA-based cell scaffolding and
primates (Jampel et al. 1993, 1990)
(Polak et al. 2008)
(Einmahl et
2003)
Sakurai et
of retinal progenitor cells (Tomita et
(Shin et al. 2009)
rabbits (Dong et al. 2006b)
vitreoretinopathy in rabbits (Yasukawa et al.
2002)
et al. 2003); high-risk corneal transplantation
in rats (Kagaya et al. 2002)
et al. 2006); Surodex in high-risk corneal
transplantation model in rats (Kagaya et al.
2002)
rabbits (Miyamoto et al. 1997)
rabbits (Rubsamen et
et al. 2001)
2007)
et
al. 2003)
cataract surgery (Eperon et al. 2008)
composite grafts (Ng et al. 2007; Tomita
et al. 2005)
al. 2001)
al. 2001)
al. 1994)
al.
al. 2000;
al. 2005)
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Table 9.6 (continued)
Polymer/drug Application/model
Polycaprolactone (PCL) and poly glycolide-co-lactide-co-caprolactone (PGLC) copolymer
Dexamethasone PCL-based intravitreal implant in rabbits
Cyclosporine PGLC-based delivery system for experimental
Tacrolimus (FK506) PGLC-based delivery system for prolongation of
Triamcinolone acetonide In vitro ocular tolerability of PCL-based delivery
Polymethylidene malonate (PMM)
Triamcinolone acetonide Pharmacokinetics and tolerability in rabbits
Polypropylene fumarate (PPF)/poly-N-vinyl pyrrolidone (PVP)
Acetazolamide In vitro release kinetics and in vivo ocular
Dichlorphenamide
Timolol maleate
Fluocinolone acetonide
Poly(
l-lactide-co-1,3-trimethylene carbonate) (PLTMC)
Polyvinvyl alcohol (PVA)
Cyclosporine Matrix reservoir implant for the treatment of
(Silva-Cunha et al. 2009; Fialho et al. 2008)
uveitis in rabbits (Dong et al. 2006a)
corneal allograft survival in rabbits (Shi et
2005)
system (Beeley et al. 2005)
(Felt-Baeyens et
tolerability in rabbits (Hacker et al. 2009)
In vitro release kinetics of PLTMC/PDLGA
composite-based drug delivery system
(Huhtala et
compatibility (Rönkkö et al. 2009)
recurrent uveitis in horses (Gilger et
al. 2006)
al. 2008) and in vivo ocular
al.
al. 2006)
no significant retinal toxicity was observed. These preliminary data suggest the
potential of intrascleral betamethasone-PDLLA implants for treating inflammation
in the posterior segment of the eye. A PDLLA-based (mixed molecular weights)
scleral implant has been investigated for the delivery of ganciclovir to treat cytomegalovirus retinitis. In rabbits, the implants showed a triphasic release pattern with
long-term diffusional drug release and only a minor burst effect in the late phase,
and no significant retinal toxicity was observed (Yasukawa et al. 2000). A discshaped intrascleral PDLLA-based implant for the delivery of triamcinolone acetonide has recently been investigated in a rabbit model of uveitis and was found to
be effective in suppressing inflammation for at least 4 weeks (Shin et
9.6.2 PLGA-Based Implants
One of the earliest reports on the use of PLGA copolymers in biodegradable ocular
drug implants was published in 1994 by Rubsamen and colleagues, who evaluated
the therapeutic efficacy of a biodegradable, intravitreal fluorouracil-PLGA implant
al. 2009).
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for the treatment of tractional retinal detachment due to experimental proliferative
vitreoretinopathy in rabbits (Rubsamen et al. 1994). The implant, which contained
1 mg of fluorouracil, produced sustained intravitreal concentrations of fluorouracil
between 1 and 13 mg/mL for at least 14 days, and the concentrations remained
above 0.3 mg/mL for nearly 21 days. Successful retina attachment occurred in 8 of
9 rabbits that received the fluorouracil-PLGA implant, but in only 1 of 9 rabbits that
received drug-free PLGA implants, and the drug implant was also uniquely effective in preventing epiretinal membrane proliferation. Electroretinographic and
histopathologic assessments revealed no evidence of toxicity associated with either
the drug implant or PLGA alone.
In 1997, Miyamoto and associates examined the feasibility of using a biodegradable PLGA-based scleral implant to deliver fluconazole (a bis-triazole antifungal
agent) for the treatment of fungal endophthalmitis (Miyamoto et al. 1997).
Fluconazole-PLGA implants were shown to gradually release fluconazole over a
period of 4 weeks in vitro, with faster release rates (1 week) observed for implants
containing high fluconazole concentrations (50 vs. 10–30%). In rabbits that received
the implant, vitreal fluconazole concentrations remained within the 99% inhibitory
concentration for Candida albicans for 3 weeks after implantation.
An intravitreal all-trans retinoic acid-PLGA implant was investigated for its ability to inhibit proliferative vitreoretinopathy induced in rabbits by core vitrectomy
and fibroblast injection (Dong et al. 2006b). The safety and efficacy of the implants,
formulated with PLGA (MW = 109,000 kDa) and either 420, 650, or 1,070 mg alltrans retinoic acid, were compared with those of nonmedicated implants and a nointervention control group. The severity of proliferative vitreoretinopathy was
significantly reduced in rabbits that received the 650- and 1,070-mg implants but not
in rabbits that received the 420-mg implant or the control treatments. In rabbits
implanted with the all-trans retinoic acid drug delivery system, drug release was
found to peak at 6–7 weeks and no retinal toxicity was observed.
A biodegradable drug delivery system consisting of triamcinolone and PLGA
has been investigated for the treatment of postsurgical complications in rabbits
following cataract removal and intraocular lens implantation (Eperon et
al.
2008). The drug delivery system was formulated using PLGA with a molecular
weight of 48,000 and had a loading capacity of roughly 1,050 mg triamcinolone.
High-molecular weight PLGA (i.e., 80,000) was found to have slower drug
release kinetics as compared with lower molecular weight PLGA (i.e., 34,000 or
48,000). Following cataract surgery, intraocular lenses were inserted along
with a nonmedicated drug delivery system or 1–2 triamcinolone-PLGA implants.
At days 63–84, postoperative ocular inflammation, measured by inflammatory
cell infiltration and protein leakage in the aqueous humor, was significantly
reduced in rabbits that received a single triamcinolone-PLGA implant and was
reduced to an even greater degree in rabbits that received two implants.
These results suggested that the triamcinolone-PLGA drug delivery system
could replace oral drug treatment and reduce the need for intraocular drug injections
in human cataract patients.
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The pharmacokinetics and safety profile of a biodegradable dexamethasone
acetate-PLGA drug delivery system has been investigated in rabbits (Fialho et al.
2006). The implant, consisting of 1,000 mg dexamethasone in a 50:50 PLGA matrix,
produced vitreous drug concentrations that were within the anti-inflammatory
therapeutic range (0.15–4.00 mg/mL) over an 8-week period. A release burst was
noted after 4 weeks and the levels of dexamethasone acetate started to decline after
7 weeks. The implant was not associated with significant electroretinographic or
histological abnormalities or elevation of intraocular pressure. The study’s authors
suggested that the implant could be used as an alternative to repeated intravitreal
triamcinolone injections for the treatment of subacute retinal disorders, such as
diabetic macular edema, retinal vein occlusion, and Irvine–Gass syndrome.
A biodegradable polymeric scleral plug consisting of ganciclovir in an 80:20
PLGA (MW = 70,000 and 5,000, respectively) matrix was investigated by Sakurai
and associates in a rabbit model of human cytomegalovirus retinitis (Sakurai et al.
2001). Following induction of experimentally induced cytomegalovirus retinitis,
rabbits treated with a single intravitreal injection of ganciclovir solution showed
a significant reduction, as compared with untreated animals, in vitreoretinal lesions
after 1 week; however, this difference waned by week 2. In contrast, rabbits
implanted with the ganciclovir-PLGA scleral plug showed significant reduction in
vitreoretinal lesions out to 3 weeks. Implantation of the plug was not associated
with surgical complications such as hypotony or endophthalmitis. The results of the
study suggested the potential use of the biodegradable ganciclovir scleral plug as an
®
alternative to the nonbiodegradable ganciclovir implant Vitrasert
.
Sakurai and coworkers also evaluated a biodegradable polymeric scleral plug
consisting of the immunosuppressive agent tacrolimus (FK506) in a 50:50 PLGA
matrix (MW = 63,000) for the treatment of experimental uveitis in a rabbit model
(Sakurai et al. 2003). The tacrolimus-PLGA plug implanted in the vitreous cavity
was effective in achieving vitreal drug concentrations of 480–350 ng/g for 4 weeks
and produced significant inhibition of uveitic inflammation for at least 6 weeks, as
assessed by anterior chamber cell counts, flare, vitreous opacity, and protein leakage. Histopathologic and electroretinographic assessments showed that the plug
was not associated with significant retinal toxicity. The authors suggested the potential use of the tacrolimus-PLGA plug for the treatment of patients with severe
chronic uveitis who are intolerant to currently available therapies.
The Oculex drug delivery system (Oculex Pharmaceuticals, Inc., Sunnyvale,
CA) is a biodegradable intraocular implant consisting of cyclosporine in a biodegradable PLGA matrix. Preliminary studies by Theng and colleagues on the pharmacokinetics of the Oculex drug delivery system (containing 0.5
mg cyclosporine)
implanted in the anterior segment of rabbit eyes indicate that high drug concentrations can be sustained in the corneal epithelium, stroma, and endothelium for at
least 3 months, while low concentrations are achieved in the aqueous, and systemic
absorption is negligible (Theng et al. 2003). The Oculex drug delivery system
was not associated with any adverse reactions. The authors concluded that further
studies were warranted to determine the potential of the device for the prophylaxis
and treatment of corneal transplant rejection in humans.
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Yasukawa and associates investigated the efficacy of biodegradable PLGAbased scleral implants containing cis-hydroxyproline, an inhibitor of collagen
secretion, on experimental proliferative vitreoretinopathy in rabbits (Yasukawa
et al. 2002). PLGA formulations with copolymer ratios of 65:35 (MW = 103,000)
and 50:50 (MW = 93,000) were compared following induction of proliferative
vitreoretinopathy with autologous fibroblasts. Drug release occurred in a triphasic manner and was sustained over 4 and 7 weeks, respectively, with PLGA 65:35
and PLGA 50:50 implants. PLGA 65/35 implants decreased the incidence of
retinal detachment from 89% in controls to 57% on day 28 whereas PLGA 50:50
implants had no significant effect. A synergetic therapeutic effect was observed
in rabbits that received dual PLGA 65:35 and PLGA 50:50 implants. The
implants, which did not demonstrate any significant signs of toxicity, were suggested for further development as a potential treatment for proliferative
vitreoretinopathy.
Aukunuru and colleagues developed a sustained-release biodegradable subcutaneous implant consisting of a matrix of N-4-(benzoylaminophenylsulfonyl glycine)
(BAPSG), a novel aldose reductase inhibitor, and PLGA (85:15). They evaluated
the therapeutic efficacy of the device in a diabetic rat model (Aukunuru et
al. 2002).
The implant, which released approximately 44% of its loaded drug after 18 days,
was found to reduce cataract scores, vascular endothelial growth factor expression,
galactitol accumulation, and glutathione depletion in ocular tissues. Thus, the
BAPSG-PLGA implant may someday prove to be valuable for the treatment of
human diabetic retinopathy and other secondary ocular complications associated
with diabetes.
In addition to being investigated as a component of biodegradable implantable
drug matrix pellets, PLGA has been evaluated as a constituent in injectable, biodegradable microsome drug delivery systems for the treatment of intraocular
pathologies. For example, Jiang and colleagues recently evaluated the ability of
intravitreally injected biodegradable microspheres loaded with glial cell linederived neurotrophic factor (GDNF) to protect retinal ganglion cells and their
axons in a rat model of glaucoma (Jiang et
al. 2007). GDNF microsphere treatment significantly increased retinal ganglion cell survival and axon survival,
attenuated the reduction of retinal inner plexiform layer thickness, decreased glial
cell activation in the retina and optic nerve, and led to a moderate reduction in
optic nerve head cupping. These results suggest that GDNF-PLGA microspheres
may be useful as a neuroprotective therapy in human glaucoma.
Surodex® is an implantable rod-shaped biodegradable polymer matrix consisting
of 60 mg dexamethasone and PLGA. The efficacy of the Surodex implant has been
investigated in a rat model of high-risk corneal transplantation (Kagaya et al. 2002).
After 8 weeks, all corneal grafts were rejected in untreated rats and 83% of grafts
were rejected in rats treated with 0.1% betamethasone eye drops TID; however, no
grafts were rejected in rats that received the Surodex drug delivery system implanted
into the anterior chamber. These findings suggest the potential of Surodex implants
as an immunosuppressive and anti-inflammatory agent for the suppression of graft
rejection following corneal transplantation.
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9.6.3 Poly(d,l-Lactic-Co-Glycolic Acid)/Poly(l-Lactide-Co-1,
3-Trimethylene Carbonate)-Based Composite Implants
Preliminary data have recently been reported comparing the ocular biocompatibility
of 50:50 PDLGA, 85:15 PDLGA, and Inion GTR™ [a 70:30 blend of 85:15 PLGA
and 70:30 poly(l-lactide-co-1,3-trimethylene carbonate) (PLTMC)] copolymers in
cell line cultures from various ocular tissues (i.e., human corneal epithelial cells,
rabbit stromal fibroblasts, bovine corneal endothelial cells, human conjunctival
epithelial cells, and human retinal pigment epithelial cells) (Huhtala et al. 2008). All
three polymers showed acceptable in vitro biocompatibility. Following exposure to
degradation products extracted from the polymers, cell viabilities ranged from 80 to
95% for PDLGA 50:50, 47–87% for PDLGA 85:15, and 66–92% for Inion GTR.
The Inion GTR membrane has been estimated to have the longest half-life of the
three polymers tested, with a degradation time of 1–2 years vs. 2–4 months for
PDLGA 50:50 and 6–12 months for PDLGA 85:15; the faster degradation time of
PDLGA 50:50 relative to PDLGA 85:15 is due to a higher content of hydrophilic
glycolic units. The authors suggested that all three biopolymers can be used as scaffolds for tissue engineering or surgical implants in the therapy of ocular diseases.
An ocular tolerability study in rabbits examined the effects of implantation of these
three polymers in comparison with those of a collagen implant (AquaFlow™) as a
benchmark (Rönkkö et al. 2009). The implants caused a similar degree of very mild
eye irritation and all implants showed initial fine fibrous tissue encapsulation, which
resolved after the implants had completely degraded. Infrared microscopy showed
that spectral characteristics of the tissue capsule surrounding the PLTMC and 50:50
PDLGA implants differed significantly from the tissue capsule that formed around
85:15 PDLGA. Despite these differences in tissue response, all of the implants were
deemed to be acceptable biomaterials for drainage devices in glaucoma surgery.
9.6.4 Poly(e-Caprolactone)- and Poly(Glycolide-Co-Lactide-
Co-Caprolactone)-Based Implants
Ocular drug delivery systems using PCL, a slowly degrading polymer, and
PGLC (a PCL/PLGA copolymer) have been investigated in several animal studies.
The results of a preliminary study in rabbits on the long-term safety and pharmacokinetics of a dexamethasone-PCL intravitreous implant have recently been
reported by Silva-Cunha et al. (2009). The implant provided controlled and sustained
delivery of dexamethasone at concentrations within the therapeutic range for at
least 55 weeks, at which time approximately 79% of the drug remained in the
implant, indicating a very slow rate of degradation. Clinical and histologic observations showed that the implants were well tolerated. The study suggested the feasibility of using PCL implants to provide sustained drug delivery for months to
years. Fialho and colleagues reported the development of a biodegradable intravitreal
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