Section 4 Translational Basic Science

Chapter Drug Delivery

38  Erin B. Lavik, Baruch D. Kuppermann, Mark S. Humayun

INTRODUCTION the systemic delivery of a molecule that is released in the ocular

tissues.8 However, in and of themselves, targeted systems do not
Drug delivery has the potential to have a tremendous impact on provide sustained delivery of drugs. They can be engineered to
treatment of retinal diseases. There are a large number of drugs do so, but if one looks at the half-life of doxorubicin, it is still on
that are reasonably effective to treat retinal conditions, but those the order of hours as opposed to days or weeks. This does
drugs are limited by delivery issues such as the need to have the not mean that targeting cannot be combined with sustained
molecule cross the blood–eye barrier, be present for long times, delivery, but they are two components to consider.
or the need to mitigate side-effects. The challenges of having Sustained delivery is better termed controlled delivery. The
drugs at a physiologically relevant concentration for extended fundamental difference is that controlled delivery is dictated by
periods or in a localized delivery system are challenges that can the device and not the environment around the device.9 This is
be solved with drug delivery technology, whether it is using fundamental to the drug delivery. One does not want to admin-
cellular delivery systems, microelectromechanical (MEMs)- ister a device to a patient and have different patients get the drug
based devices, polymer matrices, or gene delivery systems. over different time courses, particularly in an unexpected way.
One of the first controlled delivery systems was actually in the
A BRIEF HISTORY OF THE FIELD OF eye, the Ocusert system to deliver pilocarpine for glaucoma. The
DRUG DELIVERY Ocusert system is a reservoir system that relies on the transport
of the drug through a membrane. Membranes are effective for
The most common form of administration of a medication is the
small molecules (less than 600 Da),10 but are not suitable for
pill. There is evidence of the use of pills at least as early as
delivering larger molecules such as antibodies, growth factors,
ancient Egypt in the Ebers Papyrus (1500 BC). They consist, gen-
and proteins more broadly.
erally, of a medication mixed with a number of excipients or
The watershed in the drug delivery world occurred in 1976.
additives such as sugars and starches to protect and stabilize the
Robert Langer and Judah Folkman showed that large molecules
formulation.1 The basic concept is that one swallows the pill, it
could be delivered over days and weeks from polymer matrices,
dissolves in the stomach, and the medication is absorbed in the
and they showed that the release profile could be tailored based
intestines to the circulation. This approach works well for many
on the matrix.11 The concept was not warmly received and there
drugs, but not for those which can break down in the stomach.
were huge questions about the mechanism and plausibility of
Insulin is usually presented as a case in point which must be
the approach,12 but the drug delivery field has grown from being
injected because it cannot survive the environment of the
nonexistent in the USA in the 1980s to 11.5 billion dollars in
stomach. Insulin is injected into the fatty tissue2 and is then
1996,13 to an estimated 85 billion dollars in 2010.14 The economic
absorbed into the systemic circulation.
impact is a reflection of a number of factors, including the ability
Systemic administration of medications by either route can be
to provide new patent protection for off-patent medications, but
problematic for certain tissues, particularly those with strong
it also reflects the impact on human health.
barrier characteristics or those which are poorly vascularized.
Several of the applications of drug delivery technology have
Early versions of local delivery systems to the eye involve oint-
been in the eye, as discussed in this chapter, but we have barely
ments which were described in ancient Mesopotamia.3 Pilocar-
begun to realize the potential. Drug delivery provides the means
pine drops have been used for at least 100 years to lower
to improve patient compliance, increase efficacy, and reduce
intraocular pressure (IOP) and treat glaucoma.4
side-effects of ocular medications.
Drug delivery systems are a broad area that includes targeted
systems as well as systems that provide controlled release of the
drug. One of the earliest targeted systems was the liposome, DRUG DELIVERY
which has been shown to build up in tumors due to the enhanced
permeation effect.5 Liposomes were discovered in the 1960s and Formulating sustained-delivery systems
the first US Food and Drug Administration (FDA) approval There are five broad approaches for the sustained delivery of
came with Doxil, the liposomal-encapsulated formulation of drugs (Fig. 38.1). The first approach involves attaching mole-
doxorubicin, an anticancer agent in the 1990s.6 More recent vari- cules to the drug to increase its residence time. Poly(ethylene
ants on targeted systems have focused on adding molecules on gycol) or PEG is the workhorse of this approach. PEGylating
the outside of liposomes or other nanoparticles that can allow or attaching PEG molecules can increase the circulation time
them to target the tissue of interest.7 Targeted systems may allow of a drug in the bloodstream by creating a highly hydrated
 Fig. 38.1 Approaches for delivering drugs.
PEGyating molecules to increase residence time in circulation PEG, poly(ethylene gycol).
735
H2
HO C H
+ =

Chapter 38
C O
H2
n
Poly(ethylene glycol)
Molecule of interest

Drug Delivery
Reservoir

Membrane
Drug
Membrane

Matrix-based systems

Drug
Polymer
Excipient

Osmotic-based systems

Drug
Osmotic material

Pump-based system (with osmotic driving force)

Porous membrane

Osmotic material Drug

volume around the drug.15 The second broad approach is to The third approach involves mixing the drug with polymers
encapsulate the drug of interest in a reservoir system that which entrap the drug in a matrix. The drug typically phase
includes a membrane that allows the drug to diffuse through separates on the micro- or nanoscale from the polymer, leading
the device and into the surrounding tissue. This approach lies to veins of the drug in the polymer matrix. The tortuosity of the
at the basis of drug delivery systems, including the Ocusert veins plays a tremendous role in the release of the drug. With
implant delivering pilocarpine.16 Diffusion-based systems work nondegradable polymers, the drug delivery profile is dictated
for limited, typically small, molecules with molecular weights by diffusion.17 With degradable polymers, the drug delivery
less than 600  Da.10 There are great benefits to the membrane- profile is dictated by a combination of diffusion and degradation
based systems, such as the ability to deliver many drugs over events that occur over time.17 The challenges in the matrix-based
very long timescales, but there are risks, including the rupture approaches involve achieving good mixing of the drug in the
of the membrane, leading to spontaneous delivery of the entire matrix to form tortuous pathways as well as promoting interac-
reservoir.9 tions between the drug and matrix. The closer the two associate
 with each other, the more likely one will achieve very long but they rely on relatively high polymer-to-drug ratios, which
(weeks to months to years) release. Thinking about this interac- makes them more suitable for applications where one can either
736 tion becomes part of the process of formulating drug delivery deliver a large volume of material (which is unlikely in the eye)
systems. or where one has a relatively potent medication. As we will see
The fourth approach involves osmotic systems. In these in the examples below, many of the commonly used drugs are
systems the diffusion of water into the matrix leads to swelling effective at low concentrations, but it is an important consider-
Section 4

and drives the release of the drug via diffusion. Typically, ation. Membrane and pump systems can both deliver larger
osmotic systems lead to relatively fast release of drugs with a amounts of drugs over time, but the volume they deliver deter-
significant burst effect. Investigators are developing asymmetric mines the necessary reservoir size and overall device dimen-
membranes to control the delivery in a more uniform manner sions. The time course is the second critical component.
over time,18 but osmotic systems have not been used extensively Membrane and pump approaches can both lead to very constant
other than as components to drive pump technologies which do delivery depending on the geometry of the devices.10 Careful
Translational Basic Science
Basic Science and Translation to Therapy

have robust, long-term delivery. formulation can lead to very constant delivery over time from
Pump systems, the fifth approach, permit tight control of drug matrix-based formulations, but they are prone to burst release
delivery over time for a wide range of medications. Pumps can due to drug adsorbed on or near the surface of the materials.10
either be continuous and passive or actively directed to deliver There are clear benefits and challenges to all of these
medications, and in some cases, pumps are refillable. The major approaches, and multiple approaches may achieve the same
limitation of pumps has been their size. Historically, they have desired effect. The key is to know one’s drug and desired deliv-
been bulky and require more extensive implantation and place- ery profile and then to determine which approaches are likely to
ment than some of the other materials which are more amenable be the most effective. One must then consider the route of
to delivery via small needles. administration to narrow down the approach finally to the one
In thinking about which approach makes the most sense in that is the most likely to be effective. If one wants to inject a
formulating a drug delivery system, one needs to consider the material through a 33-gauge needle into the intravitreal space,
following: the size, nature, and stability of the drug, the length one will have a very different set of potential approaches than if
of time one wants to deliver the drug, and the amount of the one is looking for an implant to sit in or near the tear duct. The
drug one wants to deliver over time. Regarding size, small mol- examples outlined in this chapter will help to provide specific,
ecules (<600 Da) can diffuse through polymers such as silicone.10 real-world examples of how the formulation challenges can
Larger molecules, macromolecules such as proteins, are not able be approached successfully to develop therapeutically viable
to diffuse through polymers on a useful timescale for most appli- treatments.
cations.11 If one is hoping to deliver larger molecules, one will
need to consider the methods outside of the membrane approach. Delivering drugs in a targeted manner
The nature of the drug refers to its charge and solubility. Most One simple way to achieve targeted drug delivery is to place the
of the popular biodegradable polymers are extremely hydropho- device in the area where one wants to deliver the drug. For a
bic. If the drug of interest is very hydrophilic, it can be challeng- number of ocular conditions, this probably makes the most
ing to encapsulate the hydrophilic drug in the hydrophobic sense. If one wants long-term, local delivery of a drug that one
polymer matrix. One of the classic methods to overcome this is already injecting intravitreally every 4–6 weeks like the anti-
challenge is to use excipients that interact with both the drug vascular endothelial growth factor (VEGF) medications, being
and the polymer. Fu et al. showed how excipients could greatly able to deliver the same drug with the same injection method
improve loading and delivery of glial cell line-derived neuro- but for several months or years would be very attractive. Inject-
trophic factor (GDNF) through the use of excipients.19 Likewise, ing a device or matrix into the intravitreal space is a reasonable
charged molecules can interact poorly in uncharged or similarly way to provide local delivery.
charged polymer systems. Poly(lactic-co-glycolic acid) (PLGA) For some compounds, though, one may want either to deliver
can be synthesized with a carboxyl group on the end that carries them systemically or to deliver them to a particular cell type
a negative charge depending on the pH. This can improve the in the eye and not to all cell types. A good example of this
encapsulation of positively charged molecules. would be the delivery of a specific agent for a specific cell type,
The stability of the drug is crucial. Delivery of a drug that has such as the retinal pigment epithelium (RPE).20 The most
lost its bioactivity is fruitless. Large molecules, in particular, are common forms of targeting have involved creating particles,
susceptible to losing bioactivity via cleavage or conformational typically nanoparticles, from either liposomes or other polymers
changes during encapsulation or storage. The techniques used that are covered in PEG arms to reduce their aggregation and
to encapsulate molecules play a tremendous role in preserving promote transport, and attaching molecules to the particles that
their bioactivity. When water-soluble molecules are exposed to bind to receptors or molecules on the cells of interest. Antibod-
fewer organic solvents and less energy during processing, it is ies,21 peptides,22 and aptamers23,24 have all been used to facilitate
more likely that the bioactivity will be preserved; however, it is targeting.
always critical to check bioactivity upon release. One of the excit- The key issues to consider in designing a targeting molecule
ing findings in the matrix-based approaches has been that, for are the specificity and affinity of the targeting moiety to the
many drugs, if the drug is active upon encapsulation, the activity molecule of interest on the cell. Poor affinity or specificity will
can be maintained for long times with drugs which are released lead to poor targeting. Once one has identified targeting mole-
years after encapsulation. cules with appropriate affinity and specificity, one needs to
Beyond the drug, one needs to consider the amount of the insure the stability of targeting molecule in vivo. Larger mole-
drug one needs to deliver and the time course. Matrix-based cules, such as antibodies, have the potential to be denatured or
formulations have been shown to deliver medications for years, enzymatically cleaved in vivo, which has motivated the
identification of smaller molecules with similar specificity and cell cycle.32 There are significant safety concerns with both ret-
affinity such as aptamers.23,24 roviral and lentiviral vectors because they have the potential to
Targeting is primarily used to concentrate systemically admin- insert into the genome. Of the three major classes, adenoviruses 737
istered particles in the tissue of interest. In the retina, much of have drawn tremendous interest for gene therapy because they
the work has focused on targeting the choroidal vessels.25,26 do not incorporate into the genome, which is thought to reduce

Chapter 38
There is evidence that, when particles are small enough, they can their oncogenic potential, and they are extremely effective at
cross through to the retina when administered systemically,27 transducing cells.32 However, adenoviruses have been found to
which opens up the possibility of delivering targeted nanopar- be very immunogenic, and one of the early clinical trials using
ticles to the retina via systemic administration. an adenovirus had to be halted when an 18-year-old died due to
a systemic inflammatory response syndrome.31
The role of devices in drug delivery Adenovirus-based vectors have continued to be pursued in
The term “devices” can include everything from membrane- the eye because of the local delivery and immune-privileged

Drug Delivery
based depots to microparticles, implants, hydrogels, and MEMs- nature. GenVec has used an adenovirus to deliver the gene for
based systems.28 In the novel delivery systems, a number of pigment epithelium-derived factor (PEDF) for the treatment of
devices will be discussed along with their advantages and neovascular AMD in a phase I trial.33 The adenovirus-based
limitations. delivery system was well tolerated by patients with only tran-
Devices that are based on pumps and other microfluidic deliv- sient, mild inflammation in some patients which was managed
ery systems have the potential to facilitate extremely well- with topical medications. There was no control group in this
controlled delivery of drugs over long times and, in some cases, phase I trial, but the size of the choroidal neovascular lesions
may be refilled. The initial implantation of a device may be more was smaller in the high-dose group. Much of the follow-on
involved than a simple injection of a drug, but that one time research has focused on repeated administrations, longer-term
invasiveness may be countered if a drug can be delivered for expression of PEDF, and using inducible promoters to direct
exceptionally long times in a controlled manner or if the device expression of the protein of interest.34–36
can be refilled and permit far fewer invasive injections. A variant on the adenovirus, first found as a contaminant of
The remaining classes of device rarely exhibit the ability to be adenoviruses, the adeno-associated virus (AAV), has proven to
refilled, with the one potential exception of affinity-based be an effective alternative. Like adenoviruses, AAV vectors do
systems which are in the very early stage of preclinical testing. not integrate into the genome. Furthermore, they do not elicit a
However, if one designs the geometry properly, many of the strong immune response.32 One of the first major successes for
implant systems can be administered in a minimally invasive gene therapy with AAV vectors has been the treatment of Leber
manner, and with careful formulation many implants achieve congenital amaurosis, a severe form of retinal degeneration that
very well-controlled delivery of the drugs of interest. leads to vision loss in early childhood.37 A replication-deficient
AAV vector was used to deliver a gene for isomerohydrolase
activity (AAV-hRPE65v2). The vector was injected subretinally,
GENE DELIVERY and vision gains were found in younger patients.
Gene therapy has the potential to replace or restore function in
the retina as well as produce growth factors which protect the Nonviral systems
eye. It is very challenging, though, to get the genetic material Viruses are extraordinarily effective at delivering genetic mate-
both to the cells and into the genome without breakdown of the rial to cells, but there are safety concerns, and the size of the
material. There have been many studies looking at the transfec- vector limits the amount of genetic material that can be deliv-
tion efficiency of deoxyribonucleic acid (DNA) through routes ered. Nonviral vectors have been pursued to address these
of administration, including drops, subconjunctival, intravitreal, issues.
and subretinal injections, and in all cases the transfection effi- There are five basic steps that have to be achieved to transfect
ciency has been low to the retina and the subsequent protein a cell (Fig. 38.2). The genetic material must get to the cell, into
expression is typically small and over a short duration.29 the cell, out of the endosome, to the nucleus, and into the nucleus.
To facilitate more effective delivery of DNA and subsequent Viruses have evolved a complex set of tools to achieve this. For
protein expression, a number of vectors have been pursued. The example, the adenovirus has a targeting moiety for the cell of
two basic approaches involve viral and nonviral delivery of con- interest and leverages the pH drop in the endosome by having
structs to the retina. Viruses have adapted over millions of years the capsid undergo a conformational change which opens the
to deliver genes to cells efficiently, and viral delivery is generally endosome. It is thought to bind to dynein, a molecular motor
efficient. Viral delivery does raise safety concerns and there were that moves along the microtubules to travel to the nucleus.38
substantial complications and deaths in early viral-based gene Nonviral systems have been designed to address one or more
therapy trials.30,31 Nonviral gene delivery has sought to provide of these issues, and the more recent systems have been designed
safer alternatives, but the challenge lies in getting efficient deliv- to address several or all of these critical steps for transfection.
ery and incorporation of the genetic material. Liposomes were among the earliest transfection agents. Lipo-
somes are capable of shielding DNA from enzymatic breakdown
Viral systems until the material gets to the cell, but their fusion with the cell
There are three major classes of virus that have been used for membranes is not efficient.39 However, in 1987, the use of cat-
transduction: retroviruses, lentiviruses, and adenoviruses. Ret- ionic liposomes was first identified as a means to facilitate high
roviral vectors only infect dividing cells, making them relatively rates of transfection.40 The cationic component of the system
unattractive for ocular applications.32 Lentiviral vectors are facilitates interactions with the negatively charged cell mem-
designed to infect nondividing cells in the G0 or G1 phase of the branes and the subsequent cell fusion which delivers the DNA
 attractive for ex vivo engineering of cells where one can sort for
Step 1: Into the cell
the cells which produce the factor of interest. Viral vectors may
738 also be more attractive because the safety of the cells can be well
assessed before introduction in vivo.
Step 3: To the nucleus The attraction of using cells for the delivery of therapeutic
agents is that cells can deliver a molecule for very long periods
Section 4

of time, potentially years. Furthermore, cells have the potential

to integrate into the retina and deliver molecules in layers that
may not be easily reached by standard drug delivery of gene
therapy approaches. For example, it can be challenging to deliver
genes to the retina and to get robust expression of the molecule
of interest via intravitreal injections.47 However, there are studies
Translational Basic Science
Basic Science and Translation to Therapy

showing that certain cells may be able to migrate and integrate

Step 4: Into the nucleus with the retina following intravitreal administration and produce
molecules such as GDNF and brain-derived neurotrophic factor
Step 2: Out of the endosome
(BDNF) to preserve retinal cells in a number of models of retinal
degeneration.48,49 Mesenchymal stem cells,49 embryonic stem
cells,48 Schwann cells,50 and fibroblasts51 have all been engineered
as a means to promote neuroprotection and have all successfully
been used for several months in animal models.
Fig. 38.2 The challenges involved in getting genes from outside cells
to the nucleus. Engineering materials for
immunological protection
into the cell. While this is a tremendous improvement over pre- While the eye is immune-privileged,52,53 the presence of disease
vious nonviral approaches, the efficiency is still far lower than can alter this privilege, and long-term survival of transplanted
viral systems. cells is not guaranteed. Since the primary purpose of the engi-
Positively charged polymers like polylysine and polyethyleni- neered cells is to deliver their molecular payload, encapsulating
mine (PEI) were very early in the nonviral vector development them to protect them from the host while allowing their mole-
timeline. PEI, one of the major cationic polymers, was first cules to reach the retina makes a great deal of sense. It also
shown to be an effective polymer for gene delivery in 1995.41 It facilitates their removal should complications arise.
does two critical things. First, it is a positively charged polymer As noted in the section on sustained delivery systems, solid
that complexes with negatively charged DNA to create posi- polymer membranes do not allow large molecules (> 600 Da) to
tively charged nanoparticles which stick to the anionic mem- diffuse through.10 Most of the growth factors noted above are
branes of cells. Second, it is a proton sponge, meaning that as significantly greater than 600 Da. The solution, then, is to engi-
the pH is lowered in the endosome, the amines on the polymer neer the materials with higher-molecular-weight cutoffs that
take up the hydrogen ions and the polymer protonates. It does allow the growth factors through but still block the transport of
this to the point that it swells and bursts the endosome. The antibodies and other larger molecules.
polymer, however, has no specific method for getting the DNA Alginate gels and variants on alginate gels have been one of
to or into the nucleus. PEI tends to be most effective in dividing the most used materials to encapsulate cells for this purpose
cells where the organization of the mitotic spindles facilitates since the early 1980s. Alginate is an attractive material in that it
movement of the particles to the nucleus.41,42 PEI has been used does not adsorb proteins, facilitating their transport, but the
in animal models for transfection of retinal cells.43 The particles molecular weight of the transported molecules can be controlled
were taken up primarily by what appear to be Müller glial cells by the crosslinking density.54–56 Because alginate gels are cross-
but no quantification is discussed so it is not possible to assess linked water-swollen gels, the encapsulated cells are able to
what sort of efficiency was achieved. remain hydrated and transport of nutrients and waste is main-
In light of the complexities of getting DNA to the nucleus, tained. Other materials, primarily synthetic hydrogels, have
more recent research has focused on developing multicompo- become popular because the permeability can be tightly con-
nent systems that incorporate protection of DNA with endo- trolled through crosslinking agents and density, membrane
somal escape mechanisms and nuclear targeting moieties.44–46 thickness, and the use of multiple layers.57,58 Kristi Anseth’s
The challenges of specific transfection of retinal cells in the eye group has shown that functionalizing hydrogels with moieties
with nonviral vectors are significant, and it is likely that careful that interact with cells can still maintain the long-term delivery
engineering of the vector will be needed for successful, long- of the protein of interest while leading to higher and longer-term
term transfection, but the field is moving forward rapidly. It is cell viability, the ultimate goal of these encapsulation systems.59
likely to be a very different landscape in the next decade.
ROUTES OF DELIVERY TO THE RETINA
CELLULAR DELIVERY FOR SUSTAINED
DRUG DELIVERY Traditional routes of administration
Oral delivery
Engineering cells for delivery Oral delivery is the most preferred route of delivery of medica-
While using nonviral vectors for engineering cells in vivo in the tions by patients. Drugs such as timolol maleate can be given
retina may not be efficient, nonviral vectors can be very orally and do have an ocular effect, namely the lowering of
IOP.60 However, the presence of the blood–retinal barrier makes sense in that many patients are familiar with them and their
transport to the eye difficult and the challenges of stabilizing use.78 Soft contact lenses, those primarily used at this point, are
drugs through the gut to systemic absorption and further on to hydrogels, water-soluble polymers that are crosslinked to form 739
the eye are possible but very difficult. Therefore, most ocular networks, and hydrogels are a potential material for controlled
medications have been delivered topically. drug delivery.79 It should be noted, however, that when drug

Chapter 38
delivery researchers start looking at contact lenses or modified
Topical delivery
lenses as the solution to patient- and clinician-friendly inserts,
A large range of medications are delivered topically either as
they often forget that most patients remove their contact lenses
solutions or as gels. Because a large portion of the drop or gel is
at night. If one wants to use contact lenses as a depot for drug
cleared from the tear film quickly, topical delivery leads to sig-
delivery, one either needs to account for the actual time patients
nificant (typically 80%) systemic absorption of the drug.61 There
wear the lenses or design a wearable long-term lens.
is also relatively limited adsorption of the drug to the ocular
While hydrogels can be used as a drug delivery vehicle, water-

Drug Delivery
tissues.62 There are a number of models of pharmacokinetics of
soluble drugs, such as those likely to cross the conjunctiva most
topically delivered medications, and the drug chemistry, par-
effectively, tend to elute very quickly from the highly hydrated
ticularly the hydrophobic versus hydrophilic nature of the drug,
polymer networks on the order of minutes or hours.80 Timolol
plays a role, but overall, there is very little drug delivered to the
maleate, a water-soluble drug for lowering IOP, has been shown
vitreous and the retina.63 This makes topical administration chal-
to be able to be delivered from contact lenses consisting of
lenging for retinal diseases.
polymers of N,N-diethylacrylamide and methacrylic acid for
There have been clinical trials in Europe looking at delivery of
approximately 24 hours.81 A study of 3 patients using contact
nerve growth factor (NGF) for neuroprotection of the retina, and
lenses delivering timolol showed the lenses controlled IOP as
in particular, there are trials looking at topical administration of
well as drops.82 While this is promising, timolol, like pilocarpine,
NGF for glaucoma.64 Three glaucoma patients who were losing
does not have to reach the retina. It only needs to be in a
vision received drops containing murine NGF four times daily
reasonable concentration near the ciliary body to affect aqueous
for 3 months. There are no data from the human or animal
production.
studies regarding the concentration of NGF that reaches the back
Getting molecules into lenses or inserts that then are delivered
of the eye, but some patients undergoing this treatment exhib-
to the retina requires crossing many physical barriers in the eye.
ited some signs of improvements in their electroretinograms.
Liposomes, surfactants, and penetrating agents may facilitate
Injections transport through these barriers,83 but a formulation that achieves
When oral medications and drops are not effective, injections are this safely has yet to be demonstrated.
typically considered. Subconjunctival injections are one of the
MEMs devices
least invasive injections but there are several barriers between
Using a MEMs-based approach is exciting in that one can actively
the subconjunctival space and the retina, although a number of
control the drug release by dictating the rate of electrolysis. An
molecules can diffuse in low concentrations to the retina with
active delivery system allows the clinician to change the rate of
this approach, depending on their size and chemistry.65–67 Intra-
delivery based on assessments. None of the other systems pre-
vitreal injections, though more invasive, provide a means to put
sented up to this point permits active control of the delivery of
molecules near the retina. The vitreous is also capable of acting
the drug. MEMS-based systems also have the potential for the
as a sink for many molecules, absorbing them and slowly releas-
delivery of multiple drugs with minor modifications, which
ing them, which can increase the residence time of these mole-
increases the potential impact of these devices on treating retinal
cules in the intravitreal space.68–70 Subtenon injections have
disease.
drawn more interest with the thought that the drug will be
delivered over a prolonged period through this route.71–73 Replenish external scleral fixated refillable device
Implanting a reservoir system in the subconjunctival space
opens the door to well-controlled long-term delivery of both
Novel approaches for administration small and large molecules without the need for repeated intra-
Devices vitreal injections. The MEMs device uses electrolysis to create
Inserts bubbles that push the drug out of the reservoir of the implant-
The Ocusert system is one of the best-known and most widely able device, and there is a port that facilitates loading of the drug
studied membrane-based drug delivery systems. The device into the system.84 Implantation of the device is similar to a glau-
consists of two membranes of poly(ethylene-co-vinyl acetate) coma drainage device in complexity and it can be reloaded
and a ring of the same material filled with pilocarpine to lower several times and has been well tolerated in initial rabbit studies.85
IOP.74 The insert was designed to deliver the drug for 7 days Ionophoresis system
when placed in the cul de sac of the eye. The system worked to EyeGate Pharma has developed a delivery system composed of
manage IOP, but patients found that the device could be uncom- an annular scleral ionthoresis reservoir which is filled with drug
fortable especially if it twisted, and it could fall out.75 While (Fig. 38.3). A potential is applied between an electrode on the
follow-on designs sought to make the insert remain in the eye,76 forehead of the patient and the device to drive the charged drug
a fundamental problem was that patients had to be taught how into the anterior and posterior segments of the eye over 2–4
to use the insert systems and older patients did not like the minutes. This device is currently in clinical trials, including a
device.9 study to assess the safety and efficacy of a dexamethasone phos-
The landscape for inserts may be changing. Approximately 40 phate iontophoresis formulated solution (EGP-437) at two dif-
million people in the USA wear contact lenses and the contact ferent dose levels for dry eye (NCT01129856), and a trial of four
lens market is expanding.77 Modifying contact lenses makes iontophoretic doses of EGP-437 in patients with noninfectious
 Current source
740
Anode Cathode
Section 4

+Ion and +drug –Ion and –drug

Negative-charged
semipermeable membrane
Translational Basic Science
Basic Science and Translation to Therapy

–Ion and –analyte +Ion and +analyte

Fig. 38.4 Comparison of size of Iluvien, Retisert, and Vitrasert implants

Fig. 38.3 A schematic of the design of the EyeGate Pharma® (left to right).
ionthoresis system for drug delivery through the sclera. (Courtesy of
Juan Carlos Gutierrez MD, Research Fellow at the Doheny Retina
Institute.)

anterior-segment uveitis (NCT00694135). While the system has

not yet been tested for diseases of the retina, it may be an alterna-
tive to different retinal pathologies due to the good penetration
in human sclera of drugs like bevacizumab.86
Implants
Vitrasert ganciclovir implant
There are several implants either in or through clinical trials
which deliver drugs to the retina for long periods of time, up to
several years. The Vitrasert implant was approved by the FDA
in 1996 for the treatment of cytomegalovirus (CMV) retinitis.87
The implant delivers ganciclovir, an antiviral drug, from an
implant of poly(vinyl alcohol) and poly(ethylene vinyl acetate),
one of the early workhorses of the controlled-release field.9 The
implant delivers the medication for approximately 32 weeks and Fig. 38.5 Iluvien implant and injector.
has been shown to halt the progression of CMV.88,89 One of the
challenges with a nondegradable implant is removal, and to deal
with this, the implant is sutured to the eye wall once inserted.90
Figure 38.4 shows a comparison of the sizes of the Iluvien,
Retisert, and Vitrasert implants.
Retisert fluocinolone implant
Retisert is an implant the size of a grain of rice that delivers
fluocinolone acetonide intravitreally for 30 months for uveitis
and was approved in 1995.91 It has also been studied in trials for Fig. 38.6 Ozurdex implant and applicator.
diabetic retinopathy.91 The implant consists of a blend of the
drug with poly(vinyl alcohol) and methylcellulose in a tablet
geometry that is secured with a suture once inserted into the
vitreal space through a scleral incision, similarly to the Vitrasert with the higher-dose (0.5 µg/day) system required IOP-lowering
implant. The implant is very effective at treating uveitis, but drops and one patient required a glaucoma drainage device.93 A
there are side-effects, including an increase in IOP associated total of 34% of the low-dose patients and 71% of the high-dose
with the steroid delivery and formation of cataracts.92 patients showed progression of cataracts, and 14% and 29% in
Iluvien fluocinolone implant each group had surgery.93 Some improvements in visual func-
The Iluvien implant is composed of the same materials and drug tion were seen, and all patients showed reduction in foveal
as the Retisert implant but is designed with a very different thickness.
geometry (a narrow cylinder 3.5 × 0.37 mm) that can be injected Ozurdex dexamethasone implant
into the intravitreal space through a 25-gauge needle.93 The Ozurdex (Allergan) is a dexamethasone implant that delivers the
implant and injector are shown in Fig. 38.5. The system delivers steroid intravitreally for 6 months.94,95 The implant consists of
a lower level of fluocinolone than the Retisert implant and in poly(lactic-co-glycolic acid), a degradable polyester and dexa-
clinical trials for diabetic macular edema, there have been fewer methasone. It is inserted into the intravitreal space with a single-
complications. In the lowest dose format (0.2 µg/day), no eleva- use applicator through a 22-gauge needle. The implant and
tion in IOP has been seen in a phase II trial.93 Five of 17 subjects applicator are shown in Fig. 38.6. The implant is not tethered in
 Fig. 38.7 I-vation implant.

Intravitreal 741
implant

Chapter 38
A

Drug Delivery
C B

the vitreous, like many of the other devices. Because it degrades,

Membrane Seal
it does not have to be removed. It has been approved for the
treatment of uveitis and macular edema caused by retinal vein
occlusion, and it is associated with relatively few side-effects,
with 15% of patients exhibiting increased IOP in trials and no
differences in cataract surgeries between the treatment and sham
groups.95 Suture clip Cells Scaffold
There is always a concern with implants and any delivery Fig. 38.8 Neurotech encapsulated cell technology implant.
technology that if there is a problem, how will the implant or
drug delivery system be removed? By using well-characterized
drugs and well-defined delivery systems, that risk may be more
immortalized RPE cells engineered to deliver CNTF in an encap-
limited, but careful assessment of side-effects in the clinical trials
sulated format, and it is inserted into the vitreous cavity and
is critical. There are instances where drug delivery technologies
sutured to the eye wall. A schematic is shown in Fig. 38.8. The
have led to new side-effects not seen with the drug on its own
implant was studied in a phase I trial for retinitis pigmentosa, it
due to the changes in pharmacokinetics associated with the new
was well tolerated by patients, and some patients showed
formulation. The classic example of this is Doxil, a PEGylated
improvements in visual acuity.101 The implant (designated
liposomal formulation of doxorubicin. The formulation is much
NT-501) was then studied in phase II trials for early- and late-
more effective than free doxorubicin at treating cancer, but the
stage retinitis pigmentosa. The retinal thickness was higher for
longer circulation time due to the liposomal formulation and
those receiving the implant over a year, and Neurotech, the
ability to circulate through the capillary beds of the hands and
company developing the implant, has been given a fast-track
feet can lead to hand–foot syndrome.96,97
designation by the FDA for the treatment of visual loss from
I-vation triamcinolone implant retinitis pigmentosa.
Surmodics has developed the I-vation implant, a helical screw
ECT technology anti-VEGF implant
coated with triamcinolone acetonide that delivers the drug intra-
Neurotech is also developing an anti-VEGF ECT implant for the
vitreally for 36 months.98,99 The implant is designed to be inserted
treatment of age-related macular degeneration (NT-503). Like
through the sclera once a hole has been made with a 25-gauge
the CNTF implant, the anti-VEGF implant uses human cells
needle. The implant and a schematic are shown in Fig. 38.7.
encapsulated to protect them from the immune system but
The helical design increases the surface area from which the
allowing the release of the secreted molecule. At this time, Neu-
drug is released. One of the striking features of the implant is
rotech is in preclinical models with this implant and hopes to
that the drug is entirely within the coating on the helical struc-
start phase I trials in the near future.
ture and not within the bulk of the device. Like the Retisert
device, long-term usage is associated with an increase in IOP and Injectables
cataracts.98 Micro- and nanoparticles
Encapsulated cell technology (ECT) ciliary neurotropic The majority of micro- and nanoparticles used in the eye are
factor (CNTF) implant based on the degradable polyesters poly(lactic acid) (PLA) and
CNTF can be delivered from a rice-sized implant via ECT for an PLGA. These polymers degrade by hydrolysis and the rate of
estimated time of 2 years or more.100 The implant contains degradation is controlled by the ratio of lactic acid to glycolic
 acid subunits, the molecular weight of the polymers, and, in the intravitreal space. The system is currently in a phase I trial deliv-
case of poly(L-lactic acid) (PLLA), the crystallinity of the polymer. ering corticosteroid prodrug for the treatment of diabetic macular
742 The FDA has approved a number of devices using these materi- edema (clinical trial identifier NCT00665106). The system
als and there is a wealth of literature looking at these materials involves combining the prodrug such as lipophilic ester of dexa-
for use in the eye.102 methasone with an oil such as mineral or vegetable oil, a surfac-
Micro- and nanoparticles based on PLA and PLGA have been tant, and glycerol. The combination of these components leads
Section 4

used for many years to deliver a range of drugs from small to the formation of an emulsion that can be injected intravitreally
molecules to large proteins. One of the biggest challenges associ- and deliver the prodrug for 1–6 months.113
ated with these polymers in spherical form is that they tend to Ocular uptake of systemically
release the drug in multiple phases (typically triphasic) begin- delivered nanoparticles
ning with a burst phase.103 However, by adding the appropriate
Size plays a critical role in whether nanoparticles can be deliv-
excipients that interact with both the polymer and the drug, such
Translational Basic Science
Basic Science and Translation to Therapy

ered systemically and be found in the retina. While there is a

as GDNF, one can achieve reduced burst and relatively constant
blood–retina barrier, in one study, a small concentration of
delivery over very long times up to several months from mic-
20 nm gold nanoparticles was found in the retina in mice follow-
roparticles.104 GDNF microspheres based on this approach have
ing intravenous administration114; 100 nm gold nanoparticles
been used in vivo in the DBA/2 J mouse model of retinal gan-
were not found. In another study, PLA-based nanoparticles
glion cell (RGC) degeneration. The spheres delivering GDNF
encapsulating rhodamine (100–200 nm) were not found in
were injected intravitreally and led to significantly higher
normal rat retinas, but a few were seen in a rat model of experi-
numbers of fluorogold-labeled RGCs as compared to the blank
mental autoimmune uveoretinitis where the blood–retinal
spheres or untreated animals.105 The same formulation was
barrier is compromised.25 Generally, few nanoparticles of any
shown to preserve RGC and function in the pig following a
size make it to the retina. The vast majority are likely picked up
model of acute ocular ischemia and found that GDNF micro-
by the reticuloendothelial system and cleared.115,116
spheres led to the preservation of a greater number of RGCs as
well as improved function over time as measured by multifocal Nanocomposites for topical delivery
electroretinogram.106 Eye drops are far preferred by patients and clinicians to more
A number of drugs have been formulated into microspheres invasive injections, and a great deal of research has focused on
for intravitreal and subconjunctival administration. PLGA mic- methods to make drops a viable system for delivery of drugs
roparticles delivering celecoxib have been administered subcon- to the posterior segment of the eye. Nanocomposites typically
junctivally to reduce the concentration of VEGF in the retina and involve liposomes or other nanoscaled particles to deliver the
vascular leakage in a diabetic rat model.107 Likewise, micropar- drug. One of the primary objectives of nanocomposite research
ticles delivering the corticosteroid, budesonide, have been has been to increase the residence time of the solution on the
injected subconjunctivally in rats to alter VEGF expression.108 eye to facilitate transport of the drug. The charge or lack
Nanoparticles delivering carboplatin for a mouse model of reti- thereof on the nanoparticles plays a critical role in their behav-
noblastoma showed a reduction in tumors.109 Nanoparticles ior. Neutrally charged liposomes delivering pilocarpine were
delivering dexamethasone showed a reduction in choroidal shown to lead a drop in IOP for twice as long as free drug
neovascularization in a laser-induced rat model.110 Intravitreal alone, suggesting that the liposomes increased the residence of
administration of microspheres delivering BDNF showed neu- the drug following administration.117 Providing more direct
roprotective effects in a rat model of retinal ischemia.111 evidence, rhodamine-loaded colloidal solutions of nanocap-
The difference between nanoparticles and microparticles in sules were administered as drops in the eye.118 Neutral parti-
this format is really just one of size. The size does have effects, cles showed greater delivery of rhodamine than negatively
including obvious things like increasing the surface area of the charged particles.
delivery vehicle as the particle size shrinks, which tends to lead The question, though, is whether these nanocomposite systems
to faster release of the drug. Size also has an effect on the con- can lead to drug delivery in the back of the eye. Hironaka et al.
centration of particles which can be administered through a investigated the delivery of coumarin-6 to the retina via nano-
small-gauge needle. Since one of the greatest attractions of the composites of liposomes containing coumarin-6 as eye drops in
micro- and nanoparticle formulations is that they can be sus- mice.119 Coumarin-6 was found in the inner plexiform layer over
pended in saline and injected using standard techniques, it is the first 60 minutes postadministration. The group found that
critical to be able to inject them at reasonable concentrations there was better delivery with smaller liposomes, and coating
through fine-bore needles. When one is performing an intravit- with mucoadhesive molecules increased the delivery of
real injection, in particular, there is very little volume that can coumarin-6. The mechanism for delivery was not clear in this
be added safely, so one would like to be able to inject as much work, but the group hypothesized that conjunctival adsorption
of the drug delivery system and as little saline as possible. played a role. What is also not clear from this work is how much
With careful formulation, and a few predictive models,112 one of the dose was absorbed and how much went into the systemic
can develop injectable formulations that facilitate long-term circulation. The group extended this work to rabbits and
delivery (typically over several months) of the drug of interest monkeys with similar results.120
at drug-loading efficiencies and with release kinetics that are It is impressive that any measurable amount of a molecule can
suitable for long-term therapy for retinal diseases. reach the retina via topical administration. Whether enough
drug could be delivered to be effective without substantial sys-
Nanoscale systems temic or ocular side-effects remains to be seen, but the possibility
Novagali Pharma is developing an emulsion-based delivery does exist that nanocomposites could be formulated to permit
system called Eyeject for the sustained delivery of drugs to the delivery to the back of the eye.
PHARMACOKINETICS IN THE EYE the eye are being published, leading to more data regarding
the diffusivities of the drugs through the major barriers in the
The delivery of a drug is dictated not only by the delivery device eye. Often, simple compartment models based on traditional 743
but also by the transport parameters in the tissue of interest. diffusion can be used to predict surprisingly well the potential
When in vitro release studies are conducted, they are almost pharmacokinetics of a drug delivery system placed in the sub-
always conducted under unlimited or infinite sink conditions,

Chapter 38
conjunctival versus intravitreal space.133–136 The availability of
meaning the sink into which the drug is delivered is not limited this data increases the probability of efficiently designing
and does not put a boundary condition on the rate of delivery. delivery systems for treating the retina.
In the eye there are several barriers to delivery as well as tissues
and fluids that can act as drug sinks and delivery systems. Both
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