Novel drug delivery
E Lavik1, MH Kuehn2and YH Kwon2
Reduction of intraocular pressure (IOP) by
pharmaceutical or surgical means has long
been the standard treatment for glaucoma.
A number of excellent drugs are available that
are effective in reducing IOP. These drugs are
typically applied as eye drops. However,
patient adherence can be poor, thus reducing
the clinical efficacy of the drugs. Several novel
delivery systems designed to address the issue
of adherence and to ensure consistent reduction
of IOP are currently under development. These
delivery systems include contact lenses-
releasing glaucoma medications, injectables
such as biodegradable micro- and nanoparticles,
and surgically implanted systems. These new
technologies are aimed at increasing clinical
efficacy by offering multiple delivery options
and are capable of managing IOP for several
months. There is also a desire to have
complementary neuroprotective approaches for
those who continue to show progression,
despite IOP reduction. Many potential
neuroprotective agents are not suitable for
traditional oral or drop formulations. Their
potential is dependent on developing suitable
delivery systems that can provide the drugs in a
sustained, local manner to the retina and optic
nerve. Drug delivery systems have the potential
to improve patient adherence, reduce side
effects, increase efficacy, and ultimately,
preserve sight for glaucoma patients. In this
review, we discuss benefits and limitations of
the current systems of delivery and application,
as well as those on the horizon.
Eye (2011) 25, 578–586; doi:10.1038/eye.2011.82;
published online 8 April 2011
Keywords: nanoparticle; PLGA; drug delivery;
clinical trials; glaucoma
Glaucoma: drugs and targets
It is estimated that 2.2 million people in the
United States and 67 million people worldwide
have glaucoma,1and glaucoma is the second
leading cause of irreversible blindness.2,3
Glaucoma is a disease in which the axons of
retinal ganglion cells (RGCs), which make up
the optic nerve, degenerate. The loss of RGCs
leads to loss of vision, and if untreated, to
The incidence of glaucoma increases with
age.4–6With the aging of the US population, it is
estimated that within 15 years, this disease will
afflict 50% more people.7Current glaucoma
therapy relies on drugs that lower intraocular
pressure (IOP), and several glaucoma
medications are effective at lowering IOP when
administered properly. However, poor
adherence is a fundamental problem that
increases with the age of the patient,8and
approximately 20% of patients eventually
require surgery to lower IOP.9
An alternative treatment approach may lie in
the use of neuroprotective agents, designed to
promote RGC survival independent of IOP.10,11
Although IOP reduction can maintain and
control glaucoma in most patients, there are
those who show progressive loss of visual field
even with adequate reduction in IOP.12For these
patients, alternative or complementary
approaches to IOP reduction are highly
desirable. Neuroprotective agents that can
reduce the loss of RGCs and degeneration of
optic nerve fibers are attractive targets for
therapy, although, no neuroprotective drugs
have been approved by the FDA at this time.
In addition, many potential neuroprotective
agents, when delivered systemically, have
significant side effects.13Therefore, the
development of novel, local drug delivery
systems is necessary before neuroprotective
drugs are likely to be viable for clinical
treatment of glaucoma.
Novel delivery systems have great potential
to mitigate the challenges of patient adherence
and provide local, sustained delivery of the
drug while reducing side effects. Because
proper topical administration of drugs can be
Received: 11 March 2011
Accepted: 11 March 2011
Published online: 8 April
1Department of Biomedical
Engineering, Case Western
Cleveland, OH, USA
Ophthalmology & Visual
Sciences, University of Iowa,
Iowa, IA, USA
Correspondence: E Lavik,
Department of Biomedical
Engineering, Case Western
10900 Euclid Ave,
Wickenden 309, Cleveland,
OH 44106, USA.
Tel: þ216 368 0400.
Eye (2011) 25, 578–586
& 2011 Macmillan Publishers Limited All rights reserved 0950-222X/11
challenging for many elderly patients, more effective
delivery systems that bypass the patient adherence factor
and reduce side effects have the potential to
fundamentally improve patient care and clinical
outcomes in glaucoma.
It is fortuitous that many effective drugs already exist
for glaucoma, and the major challenge is their delivery.
With clinically appropriate delivery platforms, there is
real potential to fundamentally improve patient care and
Elevated IOP is a significant risk factor for primary open-
angle glaucoma, even though some cases of glaucoma
develop in the absence of elevated IOP (sometimes
referred to as normal tension glaucoma). However, there
is good evidence that lowering the IOP reduces the
progression of glaucoma in approximately 90% of cases,12
including in cases of normal tension glaucoma.14–17The
most common way to reduce IOP is topical
administration of eye drops one or more times daily.
Topical glaucoma medications are effective but only
when administered appropriately. Proper administration
of topical medications requires the correct placement of
the eye drop onto the surface of the globe, the correct
number of administrations per day, and the correct time
interval between multiple dosings or multiple
medications. It requires diligence and manual dexterity,
which many patients, particularly older patients, find
challenging. In practice, glaucoma medical adherence
with topical medication is poor,18,19and studies suggest
that fewer than half of the patients are able to maintain
consistently lowered IOP with topical timolol.20
Furthermore, o1% of topical administered drug reaches
the aqueous humor.21Eye drops lead to significant
systemic absorption (up to 80%),22which can result in
adverse side effects, based on the types of medication
used.23Together, these factors make topical application
challenging, especially in the aging population, which
exhibits lower adherence and greater vulnerability to
From the standpoint of drug delivery systems, it is
crucial to understand the chemical structure and
mechanism of the specific drug to be delivered as well as
the potential side effects associated with it. There are
several classes of effective topical glaucoma medications
that lower the IOP. They include prostaglandin analogs
(eg, latanoprost), beta-blockers (eg, timolol), alpha-
adrenergics (eg, brimonidine), carbonic anhydrase
inhibitors (eg, dorzolamide), and cholinergics
(eg, pilocarpine). Each of these classes of drugs has its
own specific characteristics that impact their delivery.
Therefore, it is important to understand the defining
features of the medications to understand the delivery
benefits and potential challenges.
Pilocarpine HCl is a parasympathomimetic first
isolated in 1877 and one of the oldest drugs used to treat
glaucoma.24It reduces IOP by increasing the outflow of
the aqueous. As a drop, it requires four doses a day to
maintain a reduced IOP. It has a number of side effects
including brow ache, blurred vision, a risk for retinal
detachment, as well as systemic effects including nausea,
vomiting, and diarrhea. With the advent of other
medications in the late 1970’s and 1980’s, pilocarpine use
has declined steadily and is currently utilized after others
have been tried.24However, it was one of the first drugs
used in a sustained release implant in the 1970’s to
circumvent the need for repeated daily dosing and
reduce the side effects as the Ocusert implant, described
In 1979, Timolol maleate was approved for ophthalmic
use. Timolol maleate, a b-adrenergic receptor antagonist,
provides an average IOP reduction of 20–35%.25,26Since
its approval, timolol maleate has become the US Food
and Drug Administration’s (FDA) ‘gold standard’ drug
for IOP reduction.22Timolol, however, has significant
cardiac side effects and usually requires dosing twice per
day to maintain a well-controlled IOP. The molecule is
extremely stable and highly water soluble, which makes
it attractive for several methods of delivery, including
novel drop formulations, implants, and injectables.
In recent years, the prostaglandin analogs have found
favor and prescriptions of latanoprost, travoprost, and
bimatoprost have outpaced timolol. Although timolol
decreases the production of aqueous humor, the
prostaglandins increase the outflow of the aqueous
humor to lower IOP. The prostaglandin analogs are very
hydrophobic prodrugs that are enzymatically cleaved to
their active form. Because the enzymes that cleave these
molecules are present in the eye but are present in low
concentrations systemically, the prostaglandin family
tends to have minimal systemic side effects when
administered topically.27In addition, they require only
once a day dosing, making them very attractive to
patients.27Because of the great success with the
prostaglandin analogs, there is strong interest to develop
drug delivery systems for these molecules to further
reduce the need for daily dosing. These drugs are very
hydrophobic and thus, lend themselves to delivery via
many of the common hydrophobic polymers used for
drug delivery in the eye, such as poly(ethylene-co-vinyl
acetate) and poly(lactic acid). It is important to realize
that they are prodrugs and therefore, alterations of the
drug conformation as a result of the delivery process
could inhibit cleavage. The prostaglandins are also
associated with local ocular side effects, including
discoloration of the iris and surrounding skin, as well as
Novel drug delivery systems
E Lavik et al
conjunctival hyperemia. There is a concern that sustained
local delivery could exacerbate these side effects.
However, ocular side effects can be reduced by using
sustained delivery implants compared with bolus
administration of the drug.28
Although reduction of IOP is effective in the majority of
cases, there is great interest to develop neuroprotective
strategies, either as a supplemental or as an alternative
treatment regimen. Currently, there is no FDA-approved
neuroprotective drug for glaucoma. Nevertheless, for
neuroprotective drugs to be clinically viable, drug
delivery paradigms need to be carefully considered, and
each tailored to the particular compound under
A number of drugs have been studied in clinical trials
for neuroprotection of the central nervous system. These
include small molecules such as statins,29progesterone,29
memantine,30and cyclosporine A,29as well as
neurotrophic proteins including glial cell-derived
neurotrophic factor (GDNF),31ciliary neurotrophic factor
(CNTF),32and erythropoietin.33Results of
neuroprotective drugs in clinical trials have revealed the
challenges of using these drugs. Many of these
neuroprotective agents exhibit significant side effects
when administered systemically. For example, systemic
delivery of CNTF in an amyotrophic lateral sclerosis
clinical trial was associated with significant side effects
including weight loss and cough. These side effects were
severe enough to limit the dose, and ultimately, the
efficacy of the drug.13Successful treatment strategies
may involve local, sustained delivery of these drugs in a
way that maximizes the efficacy while limiting side effect
to an acceptable level.
The delivery of proteins is particularly challenging
because of their large size, conformation necessary for
bioactivity, susceptibility to enzymatic degradation, and
relatively low affinity to typical materials used for drug
delivery systems.34The significant production cost of
many of the growth factors is also an important and
potentially limiting factor in their application.
Subcutaneous, intravenous, oral, and topical
administration usually result in very low doses in the
target tissue of the eye (ie, vitreous, retina, or optic
nerve), due to failure to cross the barriers including the
cornea and blood–retina barrier,35as well as rapid
degradation of the protein or peptide. As these methods
are ineffective at delivering large molecules, several
alternative approaches have been developed to deliver
neurotrophic factors to the ocular target tissue for
sustained periods. Among them are transfection of
retinal cells with viral36or non-viral particles37,38carrying
the gene of interest, and transplantation of stem cells to
the retina, which are engineered to produce the
neurotrophic factor of interest.39
Novel delivery systems for neuroprotective molecules
are discussed below. These technologies may hold
promise as complementary or alternatives to the
conventional IOP-lowering treatment of glaucoma.
Clinically available delivery systems
Oral carbonic anhydrase inhibitors (eg, acetazolamide)
have been available for decades and are still very
effective in lowering the IOP. However, their use is
associated with significant systemic side effects
(eg, fatigue, diuresis, electrolyte imbalance). They are
typically used as a short-term therapy when the IOP is
still very high on maximal topical medications.40,41
Although patients can take oral timolol to lower IOP, it is
less effective than eye drops.20
Topical eye drops and gels
As a result of the challenges associated with crossing the
blood–retinal barrier, oral medications have very low
bioavailability in the eye. Topical delivery of
IOP-lowering medications is the current standard for
glaucoma treatment. As noted above, o1% of the drug
reaches the aqueous after topical administration,21and
multiple daily dosing may be needed to be clinically
effective.20Delivery of topically applied drugs to the
vitreous and retina is possible,42,43but transport of most
medications to the vitreous and retina is very low with
limited bioavailability. The barriers to transport with
drops include the increase in tear drainage with
administration of an eye drop, low corneal transport,
and low conjunctival and scleral transport.44Transport
through the ocular tissues is dependent on the
particular chemistry of the drug. Hydrophobic
molecules have a tendency to accumulate more
in the vitreous, whereas hydrophilic molecules
tend to show greater concentrations in the aqueous
To reduce the number of doses per day, several gel
formulations have been developed for topical
medications. Timolol can be delivered using once daily
gel-forming solutions (0.5% Timoptic-XE (Merck & Co.,
Whitehouse, NJ, USA) and Nyogel (Novartis AG, Basel,
Switzerland)).46,47These gels are essentially timolol plus
water soluble polymers that increase the viscosity of the
solution. These formulations have been shown to reduce
dosing (from twice a day to once a day) and may reduce
the side effects associated with timolol. However, they
can lead to blurred vision.48
Novel drug delivery systems
E Lavik et al
Ocular inserts have been developed that can deliver
drugs over multiple days. One of the best known and
most widely studied is the Ocusert system, which
consists of two membranes of poly(ethylene-co-vinyl
acetate) and a ring of the same material filled with
pilocarpine.49The insert is designed to be placed in the
inferior fornix and deliver the medication for 7 days.
Although it is effective, some patients complained that
the device would fall out or cause discomfort.50There
have been subsequent design changes to the original
insert that fit better and is less likely to fall out.51Similar
inserts have also been developed to deliver other
glaucoma medications such as timolol.52However, these
improvements do not address fundamental limitations in
the design. Inserts require patient education to use the
device successfully as well as manual dexterity to
manipulate and place the insert appropriately.
Consequently, younger glaucoma patients were more
likely to utilize and achieve efficacy with the device than
Surgical implants have the potential to deliver drugs for
very long period in the eye. Implants for long-term
steroid delivery are already clinically available. They
include Ozurdex (Allergan, Irvine, CA, USA), a
dexamethasone implant that delivers the steroid
intravitreally for 6 months,54and Retisert (Bausch and
Lomb, Rochester, NY, USA), an intravitreal implant that
delivers fluocinolone acetonide for up to 30 months for
chronic uveitis.28In addition, the Surmodics (Eden
Prairie, MN, USA) I-vation implant, a helical screw
coated with triamcinolone acetonide that delivers the
drug intravitreally for 36 months has undergone Phase I
clinical trial.28Although surgical implants can be
effective for a long period, disadvantages include cost
and invasiveness of initial surgery, as well as any
subsequent surgery to remove the implant should an
adverse reaction occur. For the majority of glaucoma
patients who maintain their vision, associated surgical
risks may deter widespread use.
For neuroprotective drugs, however, surgical implants
may provide an attractive delivery option. They can
facilitate the delivery of the neuroprotective drug to the
retina for a prolonged period of time. For example, CNTF
can be delivered from a rice-sized implant via
encapsulated cell technology for up to a year.55The
implant has been studied in a Phase I trial for retinitis
pigmentosa; the patients tolerated it well and some
showed improvements in visual acuity.56
An ideal drug delivery system for glaucoma would
offer sustained release of the drug for 3–4 months from a
single application that can be performed in an office
setting (rather than surgical theater). The 3–4 months
drug release period would work well with recommended
intervals for glaucoma follow-up evaluations. Using one
or more of the existing IOP-lowering medications, such
slow-release ocular delivery systems that circumvent
patient adherence factors may offer an attractive
alternative to traditional topical eye drops for many
Novel delivery systems
Liposomes and nanospheres: improving topical
Although pilocarpine is no longer used commonly, it has
been used in the development of novel drop
formulations. It has been encapsulated in liposomes and
delivered in solution as an eye drop.57Monem et al57
studied the effect of the charge on the surface of the
liposomes on IOP reduction in rabbits. Neutrally charged
liposomes resulted in similar IOP reduction but lasted
twice as long as the conventional eye drop, suggesting
that the liposomes increased the residence time of the
drug.57This would reduce dosing of pilocarpine from
four times daily to twice daily. However, prostaglandin
analogs are still easier to use because of its once a day
DeCampos et al58have studied the role of charge on
colloidal solutions of nanocapsules administered as
drops in the eye. They reported that neutral particles
showed greater delivery of the drug (rhodamine used as
a model drug) than negatively charged particles.
Interestingly, relatively uniform intracellular rhodamine
content was observed when the nanocapsules were
imaged at different time points after topical
administration. They suggested that the nanocapsules
are taking an intracellular route through the corneal
epithelium. Alternatively, the nanocapsules, consisting of
a diblock copolymer with a hydrophilic component
(poly(ethylene glycol)) and a hydrophobic block
(polycaprolactone) are releasing their payload very
quickly or fusing with the cell membranes.59
The strategy of providing the drug with a carrier that
allows it to stay longer on the surface of the cornea is an
effective approach to reduce dosing frequency. However,
this technology does not eliminate the fundamental
problems of patient adherence and proper
administration of topical eye drops.
Contact lenses as delivery vehicles
At least 38 million people in the United States wear
contact lenses.60There has been a great deal of interest in
Novel drug delivery systems
E Lavik et al
using contact lenses as the delivery device because of its
familiarity with clinical practices and patient
experiences.61Soft contact lenses are hydrogels, water-
soluble polymers that are crosslinked to form networks.
Hydrogels have a tremendous number of biomedical
applications including drug delivery.62One of the
greatest challenges with using hydrogels for drug
delivery is that water-soluble drugs, such as those likely
to be used in glaucoma, tend to elute very quickly from
the highly hydrated polymer networks.63However,
soft contact lenses, consisting of polymers of
N,N-diethylacrylamide and methacrylic acid, have
been shown to deliver timolol for longer periods
(approximately 24h).64A pilot study of contact lenses
delivering timolol (on three patients) demonstrated that
contact lenses delivering timolol can effectively lower
IOP.65This suggests that lenses may be an attractive
alternative to eye drops for delivering drugs for glaucoma.
One obvious limitation of contact lens delivery system is
that it requires patients to wear the contact lens at all times.
Another potential limitation is that lenses are generally
stored in a hydrated state, which has the potential for the
drug to leach out of the lens over time.
Sophisticated surgical implants
As noted above, surgical implants have the potential to
deliver drugs for a very long period in the eye. Beyond
those currently available, more sophisticated implants
for ocular delivery are on the horizon.
Ideally, one would like a system in which one could
administer the medication to lower IOP in the
ophthalmologist’s office in a minimally invasive manner
in a way that allowed the medication to last for 3–4
months until the patient returned for a regular visit. One
novel approach is to implant a reservoir system in the
subconjunctival space. The microelectromechanical
system (MEMS) uses electrolysis to create bubbles that
push the drug out of the reservoir of the device, which
has a port that allows multiple loading of the drug.66
Surgical steps required would be similar to currently
available glaucoma drainage devices. It can be reloaded
several times and has been well tolerated in initial rabbit
studies.67Such a system has the potential for delivering
both small and large neuroprotective molecules such as
Another advantage of a MEMS-based system is that
one can regulate the rate of drug release from the device
by controlling the electrolysis. An active delivery system
can allow the clinician to change the rate of delivery,
based on the clinical assessment. It also has the potential
for intravitreal administration or the administration of
multiple drugs with minor modification. Long-term
studies are needed to evaluate the stability and sustained
function of the device. A main disadvantage is that it
must be surgically implanted in the eye with associated
short-term and long-term risks.
It is possible to develop a long-term release (eg, 3–4
months) formulation of a glaucoma medication that can
be injected in an office setting. Subconjunctival
administration of glaucoma medications in extended-
release formulations can avoid the patient adherence
issue. Unlike MEMS devices, they are passive delivery
systems, capable of sustained, long-term delivery of
Injection of existing drugs into the subconjunctival
space can lead to prolonged delivery compared with
simple topical application, in the order of hours or
days.69To achieve more prolonged delivery over weeks
or months in the subconjunctival space, a delivery
vehicle, based on a polymer, is an attractive alternative.
Both degradable and nondegradable polymers have been
studied for injectable systems for ocular delivery.70
Non-degradable polymers such as poly(ethylene-co-
vinyl acetate) exhibit long term, constant rates of delivery
for a number of drugs;71however, their disadvantage is
the continued presence of a foreign body with a resulting
immune response. Degradable polymers such as
poly(lactic acid) or poly(lactic-co-glycolic acid) are an
appealing alternative. They can exhibit nonlinear release
kinetics with a large initial burst of drug.72The burst is
particularly more pronounced for hydrophilic drugs
because the drug interacts poorly with degradable
polymers that tend be hydrophobic.73Fortunately,
creative formulation using suitable excipients or
additives can greatly reduce the burst effect and lead to
greater polymer–drug interaction, resulting in drug
delivery at a rate that correlates with the polymer
degradation.73These polymers degrade by hydrolysis.
The rate of degradation is controlled by the ratio of lactic
acid to glycolic acid subunits, the molecular weight of the
polymers, and, in the case of poly(L-lactic acid), the
crystallinity of the polymer. The FDA has approved a
number of devices using these materials and much
research has been carried out by evaluating these
polymers for ocular use.74
The use of degradable polymer systems is well suited
for subconjunctival injection, which is an office-based
procedure. Sustained delivery of drugs from degradable
polyesters has been studied for subconjunctival
administration, including antibiotics after cataract
surgery,75carboplatin for murine retinoblastoma,76and
celecoxib to reduce oxidative stress in the rat.77
Unfortunately, sustained delivery from degradable
polymers have been more difficult to achieve for the
Novel drug delivery systems
E Lavik et al
traditional IOP-lowering glaucoma medications. One
reason for this is the poor drug–polymer interaction.
Another reason is that the injectable formulations
typically contain particles with very high surface to
volume ratios, and the large surface area results in rapid
diffusion of the drug from the polymer.78However, by
carefully tailoring the polymer formulation one can
control the encapsulation and delivery of the drug.
One formulation of polyester microspheres
encapsulating timolol has been shown to deliver the
drug for greater than 90 days in vitro. These microspheres
can be injected subconjunctivally through a small
For large molecules that may offer neuroprotection
(eg, growth factors), additional challenges remain
beyond the polymer–drug interaction and high surface
area of injectable formulations. The challenges include
retaining the bioactivity of the drug once delivered and
poor transport to target tissues, specifically the retina and
optic nerve.80However, intravitreal administration
through a small gauge needle can overcome some of
these issues. In addition to the CNTF-secreting
implant that is currently in clinical trials, there have been
efforts to develop cell-free injectable formulations of
brain-derived neurotrophic factor (BDNF) and GDNF.
The PLGA microspheres delivering BDNF have been
shown to improve the survival of transplanted
retinal progenitor cells81and improve functional
recovery, following an ischemic retinal injury when
administered intravitreally82in animals. Similarly,
PLGA microspheres of BDNF can protect the retina
in the DBA/2J mouse model of pigmentary
glaucoma83and in large animal retinal ischemic injury
In summary, any injectable slow-release (over several
months) delivery system needs to consider the following
issues. First, one must consider the effective dose of the
drug. There are limits to the amount of drug that
can be formulated with a polymer and limits on the
amount that can be delivered to the eye. Several studies
indicate that both the IOP-lowering medications and
potential neuroprotective agents have a low enough
effective concentration to be suitable for sustained
delivery.24Second, one must consider the drug’s stability
and its interaction with, what is most likely, a
hydrophobic polymer environment. Stronger association
between a drug and polymer increases the likelihood for
long-term, sustained delivery. Third, one must
determine whether the drug, especially a complex
large molecule such as a growth factor, is bioactive after
being released from the polymer carrier. Formulations
that overcome these three challenges have great
clinical potential as a viable alternative to conventional
There are many effective topical medications currently
available for treating glaucoma. However, their clinical
efficacy is limited by inefficient delivery systems,
resulting in poor target bioavailability, increased
systemic absorption/side effects, and poor patient
adherence. Novel, more efficient delivery systems are on
the horizon with potential to improve patient care by
eliminating patient adherence factor and reducing side
effects. Ultimately, these novel delivery systems for both
IOP-lowering and potential neuroprotective drugs can
lead to greater treatment options and preservation of
vision in glaucoma.
Two search engines, PubMed and ISI Science Citation
Index were used in this review.
Search terms included: polymer and drug and eye,
glaucoma and polymer, glaucoma and drug, eye and
drug delivery, glaucoma neuroprotection, and IOP and
Conflict of interest
Dr Lavik, Dr Kuehn, and Dr Kwon have filed a patent on
the delivery of timolol from microspheres in the eye.
All three authors were supported by the Wallace H
Coulter Foundation. In addition, EL was supported by a
NIH grant DP2OD007338. MK was supported by a NIH
grant EY017142. YHK was supported by the Clifford M &
Ruth M Altermatt Professorship, Marlene S & Leonard A
Hadley Glaucoma Research Fund, and Research to
1 Quigley HA. Number of people with glaucoma worldwide.
Br J Ophthalmol 1996; 80(5): 389–393.
Blomdahl S, Calissendorff BM, Tengroth B, Wallin O.
Blindness in glaucoma patients. Acta Ophthalmol Scand 1997;
Munier A, Gunning T, Kenny D, O’Keefe M. Causes of
blindness in the adult population of the Republic of Ireland.
Br J Ophthalmol 1998; 82(6): 630–633.
Leske MC, Nemesure B, He Q, Wu SY, Hejtmancik JF,
Hennis A. Patterns of open-angle glaucoma in the Barbados
Family Study. Ophthalmology 2001; 108(6): 1015–1022.
Mukesh BN, McCarty CA, Rait JL, Taylor HR. Five-year
incidence of open-angle glaucoma: the visual impairment
project. Ophthalmology 2002; 109(6): 1047–1051.
Novel drug delivery systems
E Lavik et al
6Schoff EO, Hattenhauer MG, Ing HH, Hodge DO,
Kennedy RH, Herman DC et al. Estimated incidence of
open-angle glaucoma in Olmsted County, Minnesota.
Ophthalmology 2001; 108(5): 882–886.
Friedman DS, Wolfs RC, O’Colmain BJ, Klein BE, Taylor HR,
West S et al. Prevalence of open-angle glaucoma among
adults in the United States. Arch Ophthalmol 2004; 122(4):
Gurwitz JH, Glynn RJ, Monane M, Everitt DE, Gilden D,
Smith N et al. Treatment for glaucoma: adherence by the
elderly. Am J Pub Health 1993; 83(5): 711–716.
Schmier JK, Covert DW, Lau EC, Robin AL. Trends in
annual medicare expenditures for glaucoma surgical
procedures from 1997 to 2006. Arch Ophthalmol 2009; 127(7):
Danesh-Meyer HV. Neuroprotection in glaucoma: recent and
future directions. Curr Opin Ophthalmol 2011; 22(2): 78–86.
Baltmr A, Duggan J, Nizari S, Salt TE, Cordeiro MF.
Neuroprotection in glaucoma: is there a future role? Exp Eye
Res 2010; 91(5): 554–566.
AGIS Investigators T. The Advanced Glaucoma
Intervention Study (AGIS): 7. The relationship between
control of intraocular pressure and visual field
deterioration.. Am J Ophthalmol 2000; 130(4): 429–440.
Lotz B, Brooks B, Sanjak M, Weasler C, Roelke K, Parnell J
et al. A double-blind placebo-controlled clinical trial of
subcutaneous recombinant human ciliary neurotrophic
factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology
1996; 46(5): 1244–1249.
Collaborative Normal-Tension Glaucoma Study Group. The
effectiveness of intraocular pressure reduction in the
treatment of normal-tension glaucoma. Am J Ophthalmol
1998; 126(4): 498–505.
Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L,
Komaroff E. Factors for glaucoma progression and the effect
of treatment: the early manifest glaucoma trial. Arch
Ophthalmol 2003; 121(1): 48–56.
Leskea MC, Heijl A, Hyman L, Bengtsson B, Komaroff E.
Factors for progression and glaucoma treatment: the Early
Manifest Glaucoma Trial. Curr Opin Ophthalmol 2004; 15(2):
Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z.
Predictors of long-term progression in the early manifest
glaucoma trial. Ophthalmology 2007; 114(11): 1965–1972.
Sleath B, Robin AL, Covert D, Byrd JE, Tudor G, Svarstad B.
Patient-reported behavior and problems in using glaucoma
medications. Ophthalmology 2006; 113(3): 431–436.
Schwartz GF, Quigley HA. Adherence and persistence
with glaucoma therapy. Surv Ophthalmol 2008; 53(Suppl 1):
Rotchford AP, Murphy KM. Compliance with timolol
treatment in glaucoma. Eye 1998; 12: 234–236.
Patrick M, Mitra AK. Overview of ocular drug delivery and
iatrogenic ocluar cytopathologies. In: Mitra AK (ed).
Ophthalmic Drug Delivery Systems. Marcel Dekker:
New York, 1993, pp 1–27.
Marquis RE, Whitson JT. Management of glaucoma:
focus on pharmacological therapy. Drugs Aging 2005; 22(1):
Schuman JS. Antiglaucoma medications: a review of safety
and tolerability issues related to their use. Clin Ther 2000;
Hoyng PF, van Beek LM. Pharmacological therapy for
glaucoma: a review. Drugs 2000; 59(3): 411–434.
25 Wilson RP, Kanal N, Spaeth GL. TimololFits effectiveness in
different types of glaucoma. Ophthalmology 1979; 86(1): 43–50.
Zimmerman TJ, Kaufman HE. Beta-adrenergic blocking-
agent for treatment of glaucoma. Arch Ophthalmol 1977;
Linden C. Therapeutic potential of prostaglandin analogues
in glaucoma. Expert Opin Investig Drugs 2001; 10(4): 679–694.
Schwartz SG, Flynn Jr HW. Fluocinolone acetonide
implantable device for diabetic retinopathy. Curr Pharm
Biotechnol 2011; 12(3): 347–351.
Loane DJ, Faden AI. Neuroprotection for traumatic brain
injury: translational challenges and emerging therapeutic
strategies. Trends Pharmacol Sci 2010; 31(12): 596–604.
Danesh-Meyer HV, Levin LA. Neuroprotection:
extrapolating from neurologic diseases to the eye. Am J
Ophthalmol 2009; 148(2): 186–191e2.
Koeberle P, Ball A. Effects of GDNF on retinal ganglion cell
survival following axotomy. Vision Res 1998; 38: 1505–1515.
Sendtner M, Schmalbruch H, Stockli KA, Carroll P,
Kreutzberg GW, Thoenen H. Ciliary neurotrophic factor
prevents degeneration of motor neurons in mouse mutant
progressive motor neuronopathy. Nature 1992; 358(6386):
Maurer MH, Schabitz WR, Schneider A. Old friends in new
constellationsFthe hematopoetic growth factors G-CSF,
GM-CSF, and EPO for the treatment of neurological
diseases. Curr Med Chem 2008; 15(14): 1407–1411.
Langer R. New methods of drug delivery. Science 1990;
Urtti A. Challenges and obstacles of ocular
pharmacokinetics and drug delivery. Adv Drug Deliv Rev
2006; 58(11): 1131–1135.
Di Polo A, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ.
Prolonged delivery of brain-derived neurotrophic factor by
adenovirus-infected Muller cells temporarily rescues
injured retinal ganglion cells. Proc Natl Acad Sci USA 1998;
Farjo R, Skaggs J, Quiambao AB, Cooper MJ, Naash MI.
Efficient non-viral ocular gene transfer with compacted
DNA nanoparticles. PLoS One 2006; 1: e38.
Thumann G, Stocker M, Maltusch C, Salz AK, Barth S,
Walter P et al. High efficiency non-viral transfection of
retinal and iris pigment epithelial cells with pigment
epithelium-derived factor. Gene Therapy 2010; 17(2): 181–189.
Harper MM, Adamson L, Blits B, Bunge MB, Grozdanic SD,
Sakaguchi DS. Brain-derived neurotrophic factor released
from engineered mesenchymal stem cells attenuates
glutamate- and hydrogen peroxide-mediated death of
staurosporine-differentiated RGC-5 cells. Exp Eye Res 2009;
Realini T. A history of glaucoma pharmacology. Optom Vis
Sci 2011; 88(1): 36–38.
Toris CB. Pharmacotherapies for glaucoma. Curr Mol Med
2010; 10(9): 824–840.
Genead MA, Fishman GA. Efficacy of sustained topical
dorzolamide therapy for cystic macular lesions in patients
with retinitis pigmentosa and usher syndrome. Arch
Ophthalmol 2010; 128(9): 1146–1150.
Sivaprasad S, Bunce C, Wormald R. Non-steroidal anti-
inflammatory agents for cystoid macular oedema following
cataract surgery: a systematic review. Br J Ophthalmol 2005;
Ghate D, Edelhauser HF. Barriers to glaucoma drug
delivery. J Glaucoma 2008; 17(2): 147–156.
Novel drug delivery systems
E Lavik et al
45Worakul N, Robinson JR. Ocular pharmacokinetics/
pharmacodynamics. Eur J Pharm Biopharm 1997; 44(1): 71–83.
Shedden A, Laurence J, Tipping R. Efficacy and tolerability
of timolol maleate ophthalmic gel-forming solution vs
timolol ophthalmic solution in adults with open-angle
glaucoma or ocular hypertension: a six-month, double-
masked, multicenter study. Clin Ther 2001; 23(3): 440–450.
Uusitalo H, Nino J, Tahvanainen K, Turjanmaa V, Ropo A,
Tuominen J et al. Efficacy and systemic side-effects of topical
0.5% timolol aqueous solution and 0.1% timolol hydrogel.
Acta Ophthalmol Scand 2005; 83(6): 723–728.
Uusitalo H, Kahonen M, Ropo A, Maenpaa J, Bjarnhall G,
Hedenstrom H et al. Improved systemic safety and
risk-benefit ratio of topical 0.1% timolol hydrogel compared
with 0.5% timolol aqueous solution in the treatment of
glaucoma. Graefes Arch Clin Exp Ophthalmol 2006; 244(11):
Macoul KL, Pavan-Langston D. Pilocarpine ocusert system
for sustained control of ocular hypertension. Arch
Ophthalmol 1975; 93(8): 587–590.
Pollack IP, Quigley HA, Harbin TS. Ocusert pilocarpine
system-advantages and disadvantages. South Med J 1976;
Saettone MF, Salminen L. Ocular inserts for topical delivery.
Adv Drug Deliv Rev 1995; 16(1): 95–106.
Urtti A, Rouhiainen H, Kaila T, Saano V. Controlled ocular
timolol delivery: systemic absorption and intraocular
pressure effects in humans. Pharm Res 1994; 11(9): 1278–1282.
Stewart RH, Novak S. Introduction of the ocusert ocular
system to an ophthalmic practice. Ann Ophthalmol 1978;
Haller JA, Bandello F, Belfort Jr R, Blumenkranz MS, Gillies
M, Heier J et al. Randomized, sham-controlled trial of
dexamethasone intravitreal implant in patients with
macular edema due to retinal vein occlusion. Ophthalmology
2010; 117(6): 1134–1146.e3.
Thanos CG, Bell WJ, O’Rourke P, Kauper K, Sherman S,
Stabila P et al. Sustained secretion of ciliary neurotrophic factor
to the vitreous, using the encapsulated cell therapy-based NT-
501 intraocular device. Tissue Eng 2004; 10(11–12): 1617–1622.
Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ,
Fullmer KR et al. Ciliary neurotrophic factor (CNTF) for
human retinal degeneration: phase I trial of CNTF delivered
by encapsulated cell intraocular implants. Proc Natl Acad Sci
USA 2006; 103(10): 3896–3901.
Monem AS, Ali FM, Ismail MW. Prolonged effect of
liposomes encapsulating pilocarpine HCl in normal and
glaucomatous rabbits. Int J Pharm 2000; 198(1): 29–38.
De Campos AM, Sanchez A, Gref R, Calvo P, Alonso MJ.
The effect of a PEG versus a chitosan coating on the
interaction of drug colloidal carriers with the ocular
mucosa. Eur J Pharm Sci 2003; 20(1): 73–81.
Uchida T. Introduction of macromolecules into mammalian
cells by cell fusion. Exp Cell Res 1988; 178(1): 1–17.
American Academy of Ophthalmology. Eye Health Statistics
at a Glance, 2009. Available at http://www.aao.org/
White CJ, Byrne ME. Molecularly imprinted therapeutic
contact lenses. Expert Opin Drug Deliv 2010; 7(6): 765–780.
Hoffman A. Hydrogels for biomedical applications. Adv
Drug Deliv Rev 2002; 54(1): 3–12.
63 Peppas N, Bures P, Leobandung W, Ichikawa H. Hydrogels
in pharmaceutical formulations. Eur J Pharm Biopharm 2000;
Hiratani H, Alvarez-Lorenzo C. Timolol uptake and release
by imprinted soft contact lenses made of N,N-
diethylacrylamide and methacrylic acid. J Control Release
2002; 83(2): 223–230.
Schultz CL, Poling TR, Mint JO. A medical device/drug
delivery system for treatment of glaucoma. Clin Exp Optom
2009; 92(4): 343–348.
Saati S, Lo R, Li PY, Meng E, Varma R, Humayun MS. Mini
drug pump for ophthalmic use. Trans Am Ophthalmol Soc
2009; 107: 60–70.
Saati S, Lo R, Li PY, Meng E, Varma R, Humayun MS. Mini
drug pump for ophthalmic use. Curr Eye Res 2010; 35(3):
Staples M, Daniel K, Cima MJ, Langer R. Application of
micro- and nano-electromechanical devices to drug
delivery. Pharm Res 2006; 23(5): 847–863.
Kim TW, Lindsey JD, Aihara M, Anthony TL, Weinreb RN.
Intraocular distribution of 70-kDa dextran after
subconjunctival injection in mice. Invest Ophthalmol Vis Sci
2002; 43(6): 1809–1816.
Mansoor S, Kuppermann BD, Kenney MC. Intraocular
sustained-release delivery systems for triamcinolone
acetonide. Pharm Res 2009; 26(4): 770–784.
Okabe K, Kimura H, Okabe J, Kato A, Kunou N, Ogura Y.
Intraocular tissue distribution of betamethasone after
intrascleral administration using a non-biodegradable
sustained drug delivery device. Invest Ophthalmol Vis Sci
2003; 44(6): 2702–2707.
Bao W, Zhou J, Luo J, Wu D. PLGA microspheres with high
drug loading and high encapsulation efficiency prepared by
a novel solvent evaporation technique. J Microencapsul 2006;
Fu K, Harrell R, Zinski K, Um C, Jaklenec A, Frazier J et al. A
potential approach for decreasing the burst effect of
protein from PLGA microspheres. J Pharm Sci 2003; 92(8):
Shive M, Anderson J. Biodegradation and biocompatibility
of PLA and PLGA microspheres. Adv Drug Deliv Rev 1997;
Cardillo JA, Paganelli F, Melo Jr LA, Silva Jr AA, Pizzolitto
AC, Oliveira AG. Subconjunctival delivery of antibiotics in a
controlled-release system: a novel anti-infective prophylaxis
approach for cataract surgery. Arch Ophthalmol 2010; 128(1):
Kang SJ, Durairaj C, Kompella UB, O’Brien JM,
Grossniklaus HE. Subconjunctival nanoparticle carboplatin
in the treatment of murine retinoblastoma. Arch Ophthalmol
2009; 127(8): 1043–1047.
Ayalasomayajula SP, Kompella UB. Subconjunctivally
administered celecoxib-PLGA microparticles sustain
retinal drug levels and alleviate diabetes-induced oxidative
stress in a rat model. Eur J Pharmacol 2005; 511(2-3):
Namur JA, Cabral-Albuquerque EC, Quintilio W,
Santana MH, Politi MJ, de Araujo PS et al. Poly-lactide-co-
glycolide microparticle sizes: a rational factorial design and
surface response analysis. J Nanosci Nanotechnol 2006; 6(8):
Bertram J, Saluja SS, McKain JA, Lavik EB. Sustained
delivery of timolol maleate from poly(lactic-co-glycolic
Novel drug delivery systems
E Lavik et al
acid)/poly(lactic acid) microspheres for over 3 months. Download full-text
J Microencapsul 2009; 26(1): 18–26.
Lee TWY, Robinson JR. Drug delivery to the posterior
segment of the eye II: development and validation of a
simple pharmacokinetic model for subconjunctival
injection. J Ocul Pharmacol Ther 2004; 20(1): 43–53.
Seiler MJ, Thomas BB, Chen Z, Arai S, Chadalavada S,
Mahoney MJ et al. BDNF-treated retinal progenitor sheets
transplanted to degenerate rats: improved restoration of
visual function. Exp Eye Res 2008; 86(1): 92–104.
Grozdanic SD, Lazic T, Kuehn MH, Harper MM, Kardon
RH, Kwon YH et al. Exogenous modulation of intrinsic optic
nerve neuroprotective activity. Graefes Arch Clin Exp
Ophthalmol 2010; 248(8): 1105–1116.
Ward MS, Khoobehi A, Lavik EB, Langer R, Young MJ.
Neuroprotection of retinal ganglion cells in DBA/2J mice
with GDNF-loaded biodegradable microspheres. J Pharm Sci
2007; 96(3): 558–568.
Kyhn M, Klassen H, Johansson U, Warfvinge K,
Lavik E, Kiilgaard J et al. Delayed administration of
glial cell line-derived neurotrophic factor (GDNF)
protects retinal ganglion cells in a pig model of
acute retinal ischemia. Exp Eye Res 2009; 89(6):
Novel drug delivery systems
E Lavik et al