Contact Lens Drug Delivery

Review
Contact lenses as a platform for

ocular drug delivery
Lokendrakumar C Bengani, Kuan-Hui Hsu, Samuel Gause &
Anuj Chauhan
1.
Introduction
2.
Ocular transport of drug

released by a contact lens
3.
Key requirements for

drug-eluting contact lenses
4.
Drug delivery by soak and
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

For personal use only.
release from unmodified

commercial contact lenses
5.
Novel approaches for

controlled and extended drug
release from contact lenses
6.
Conclusions
7.
Expert opinion
University of Florida, Department of Chemical Engineering, Gainesville, FL, USA
Introduction: Most ophthalmic drugs are delivered through eye drops even
though only about 1 -- 5% of the drug reaches the target tissue and the
patient compliance is not good. Drug-eluting contact lenses could significantly increase bioavailability, reduce side effects and improve patient
compliance.
Areas covered: Recent research on drug-eluting contact lenses has focused on
increasing the release duration through molecular imprinting, dispersion of
barriers or nanoparticles, increasing drug binding to the polymer, sandwiching a PLGA (poly[lactic-co-glycolic acid]) layer in a lens and developing novel
materials. This review covers all these studies with a specific focus on the
transport mechanisms and advantages and disadvantages of each approach.
Expert opinion: The main reason for prior failures was the short duration of
release from the lenses. The new technologies can provide extended drug
release for hours to days. The in vivo animal and clinical studies have proven
the safety and efficacy of drug-eluting contact lenses, while showing considerable improvements compared to eye drops. The future appears to be promising but several challenges remain such as processing and storage issues,
regulatory hurdles, high costs of clinical studies, potential lack of acceptance
by the elderly, etc.
Keywords: bioavailability, contact lenses, drug delivery, imprinting, nanoparticles, vitamin E
Expert Opin. Drug Deliv. (2013) 10(11):1483-1496
1.
Introduction
Ocular drug delivery (ODD) to the anterior region of the eye is most commonly
achieved through eye drops in form of solutions and suspensions [1], even though
it is well understood that only a very small fraction of drug delivered through eye
drops reaches the target tissue [2]. There are several factors that contribute to the
inefficiencies of eye drops. A human tear film contains about 7 l of fluid [3] and
even though it can hold a larger amount after an eye drop instillation, a fraction
of the instilled 30 l eye drop is quickly squeezed out of the eye [2]. The remaining
drug mixes within the entire tear volume and then exits through canalicular drainage into the nose or transports across the corneal and the conjunctival epithelia. The
area of the conjunctiva is about 16 -- 18 times the area of the cornea, and the conjunctiva permeability is also higher than the corneal permeability, and thus the net
drug flux into cornea is much lower than that into the conjunctiva [4,5]. A very large
fraction of the drug absorbed into the conjunctiva and that drained into the
nose enter systemic circulation, leading to the very low corneal bioavailability
of < 5% [2]. The fraction of the delivered drug that enters the systemic circulation
escapes the first-pass metabolism and enters all major organs, with a potential for
side effects [6,7]. The problem of low bioavailability is exacerbated by the short
tear film residence time of only about 2 -- 3 min, leading to a necessity of a frequent
dosing regimen [2]. In certain cases, hourly instillations of eye drops are required for
delivery of dexamethasone phosphate disodium (DXP) for anti-inflammatory
10.1517/17425247.2013.821462 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593
All rights reserved: reproduction in whole or in part not permitted
1483
L. C. Bengani et al.
Article highlights.
.
.
.
.
Corneal bioavailability for ophthalmic drugs delivered

through contact lenses could be 50%.
Vitamin E incorporation in commercial contact lenses
increases release duration without compromising any
other property.
Nanoparticle incorporation in contact lenses can improve
drug release profiles, but degradation and drug release
during storage is an issue.
Imprinting can improve drug delivery profiles but
increase in modulus is an issue.
Animal studies have proven safety and efficacy of
drug-eluting extended wear contact lenses.

This box summarizes key points contained in the article.
therapy [8] and delivery of cysteamine for the treatment of

corneal crystal formation in nephropathic cystinosis [9]. The
high instillation frequency leads to reduced patient compliance,
which is also impacted by the difficulties in precisely delivering
the eye drop, particularly in elderly patients. The compliance to
the eye drop regimen is further reduced when multiple medications are recommended, which is common in about 50% of
glaucoma patients [10,11]. Finally, the stability of eye drop formulations is sometimes limited. For example, the recently
released cysteamine eye drop formulation (Cystaran) is
required to be kept frozen at temperatures < -15 C and after
thawing it has a maximum shelf life of 1 week, even under
refrigerated conditions [12].
The deficiencies of the eye drops has led to considerable
research focusing on developing improved ODD formulations
such as high-viscosity formulations, polymeric gels, mucoadhesive and in situ forming gels, bioadhesive polymers, biodegradable or nondegradable inserts, punctal plugs, etc [2,13-16]. Also
new approaches focusing on driving the drug into the cornea
have been explored such as iontophoresis and microneedles [17,18]. In spite of all the deficiencies described above, eye
drops have been the main stay of ocular therapies because
most other approaches for ODD also suffered from at least
some of the deficiencies of eye drops. It is, however, clear that
eye drops are far from optimal for delivering ophthalmic drugs
and a better approach is required for increasing bioavailability,
improving patient compliance and reducing the potential for
side effects.
The optimal ODD system needs to overcome the deficiencies of eye drops, while maintaining all the key requirements
regarding physical properties, pharmacokinetics and pharmacodynamics. An ODD system must be highly biocompatible,
easy to administer, comfortable and should not have any
adverse effect on vision or normal eye functions such as blinking. Also, the device should preferably provide extended drug
release at therapeutic rates, with increased corneal bioavailability. It is also critical that the drug pharmacokinetics is
maintained at least comparable to the eye drop regimen.
There are additional factors to consider including costs and
1484
the regulatory approval process. For an ODD device to significantly improve the corneal bioavailability, it must be
preferentially located closer to the cornea, compared to the
conjunctiva, making a contact lens the obvious choice. It
was, thus, natural to explore contact lenses for delivering ocular drugs and several studies focusing on this goal were
attempted as early as several decades ago. While several studies
proved the feasibility of the concept, drug-eluting contact
lenses never reached the market mainly because the earliest
attempts were conducted with lenses that were not ideally
suited for drug delivery. The increasing research and latest
advances in biomaterials and nanotechnology has now led to
the design of drug-eluting contact lenses which have overcome
most of the technological challenges and so commercialization
is likely in near future. In this review, we focus on summarizing prior research, while specifically emphasizing on mechanisms and noting the advantages and disadvantages of
various approaches and finally present our opinion on the
challenges and future of this field.
Ocular transport of drug released by a

contact lens
2.
The mechanisms relevant to ophthalmic drug delivery by contact lenses are illustrated in Figure 1. A normal human tear
film is about 7 -- 10 m in thickness, while a typical contact
lens has a central thickness of about 80 -- 150 m [19]. On
insertion of a contact lens, the tear film partitions into a
pre-lens tear film (PLTF) and post-LTF (POLTF), which
are a few microns in thickness [19]. A drug-loaded contact
lens releases drug both into the PLTF and POLTF. The
drug that is released into the POLTF can either diffuse into
the cornea or diffuse radially out into the outer tear lake.
Owing to the very large disparity in the thickness (~ 5 m)
and the radius (5 mm) of the POLTF, almost the entire
drug amount released into the POLTF by the contact lens
diffuses into the cornea, even after accounting for the
enhancement of radial transport due to lens motion. The
drug released by the contact lens into the PLTF will likely
absorb into the conjunctiva or drain through the canaliculi
and eventually enter the systemic circulation. It is difficult
to predict the ratio of the masses of drug released into the
PLTF and POLTF but the ratio can be expected to be about
unity if both of the tear volumes are considered to be sinks.
A ratio of one between the releases into the PLTF and POLTF
will likely yield about 50% corneal bioavailability, compared
to about 1 -- 5% with eye drops. Detailed mathematical
modeling based on the basic mechanisms described above
shows that the bioavailability from drug-eluting contact lenses
could be 50% or possibly higher [20]. The model also suggests
that the POLTF is likely a perfect sink in spite of the very
small tear volume because the drug released from the lenses
diffuses into the cornea ensuring that the POLTF drug concentration remains low. The sink assumption for the POLTF
becomes more accurate for contact lenses with extended drug
Expert Opin. Drug Deliv. (2013) 10(11)
Contact lenses as a platform for ODD
Post-lens tear
film (POLTF)
Drug eluting
contact lens
Pre-lens
tear film (PLTF)

Eyelid
Cornea
Figure 1. Mechanism of ophthalmic drug delivery by contact

lenses.
delivery as the timescale for drug release from the lens

becomes much longer than the timescale for drug transport
from the POLTF into the cornea. The latter timescale can
be estimated to be the ratio of the POLTF thickness and the
permeability of the cornea to the drug of interest. The
POLTF thickness is about 5 m and while there is considerable variability in corneal permeability, for most drugs it
ranges from about 10-5 to 10-7 cm/s [5], and thus the timescale
for transport from the POLTF to the cornea is about 1 s to
1 min. As discussed later, most contact lenses release drugs
for at least a few hours, which is sufficiently long to ensure
very small drug concentrations in the POLTF, justifying the
sink assumption. The transport of drug from the PLTF to
the conjunctiva could yield sink conditions in the PLTF as
well. The PLTF, however, rapidly breaks during the interblink and could reduce the drug flux from the lens toward
the PLTF. Thus, while the exact corneal bioavailability from
contact lenses is unknown, it is likely that at least 50% of
the drug loaded into the lenses reaches the cornea. This prediction has considerable support from several animal and
human studies described later which shows that contact lenses
can achieve the same therapeutic effect as eye drops but with
considerably lower drug loadings.
Key requirements for drug-eluting

contact lenses
3.
As discussed above, a contact lens is ideally suited for increasing corneal bioavailability. Contact lenses also meet several of
the other requirements such as biocompatibility, ease of insertion, transparency, with minimal effect of ocular functions; at
least for the population that wear contact lenses for vision
correction. The remaining key requirements are related to

the pharmacokinetics and the pharmacodynamics, which are
in turn closely related to the drug transport in the contact
lens. It is obvious that the contact lens needs to have a sufficient drug payload to achieve the therapeutic response. The
optimal choice of the total drug release duration from the
contact lens is, however, far from clear and would at least partially depend on the most common contact lens modality in
terms of the wear schedule. Clearly, a very short duration of
the order of 1 h is undesirable as that could necessitate
multiple contact lenses each day, which would increase cost
and reduce patient compliance. Currently based on the wear
schedule, contact lenses can be categorized into disposable
or frequent replacement. Among the disposable lenses, the
daily disposable type are worn just for 1 day, while the other
type are extended wear lenses which can be worn continually
for long periods of 1, 2 or 4 weeks depending on the specific
lens type, without even taking the lenses off at night. The frequent replacement lenses can last for several weeks but these
are worn during the day, taken off and cleaned during the
night and replaced in the eyes in the morning. Since there
are several different wearing options, it would be prudent to
develop different types of drug-eluting contact lenses suited
for the various wearing patterns. Thus, there appears to be a
need to develop contact lenses with controllable release
durations ranging from 1 day to possibly 1 -- 4 weeks. Since
the release duration is a key characteristic for the drugeluting contact lenses, researchers have measured the in vitro
release profiles from contact lenses for a wide variety of drugs.
Also, several approaches have been developed for extending
the drug releases. In addition to the in vitro studies, there
are several reports in literature focusing on in vivo animal
studies or human clinical studies. Below we discuss these
studies, first for typical commercial contact lenses that are
designed for vision correction followed by those with contact
lenses which are designed to increase the drug release
duration.
Drug delivery by soak and release from

unmodified commercial contact lenses
4.
The earliest reports on the use of contact lenses for drug

delivery date back to the 1960s [21,22]. Most of the early studies focused on soaking the commercial contact lenses in a drug
solution followed by lens insertion in the eye. This method
has received the maximum attention from researchers, likely
due to the simplicity of the approach. In addition to the large
number of in vitro studies, several animal and human studies
have been conducted with the soak and release approach to
explore delivery of various molecules to eyes including fluorescein in rabbits [23], pilocarpine in humans [24], dexamethasone phosphate in humans (89 subjects) [25], chloromycetin,
gentamicin or carbenicillin in humans (466 subjects) [26], gentamicin, kanamycin, tobramycin, ciprofloxacin and ofloxacin
in humans (265 patients) [27] and lomefloxacin in rabbits [28].
1485
transparency, modulus, wettability, lubricity, ion and oxygen

permeabilities, etc. The successful approaches for increasing
the drug release durations are described below.
Vitamin E barriers
Drug transport in any device can be attenuated by creating a
barrier in the path of the drug. Creation of barriers in contact
lens is, however, complicated due to the requirement of transparency and minimal impact on modulus and ion and oxygen
permeability. Chauhan et al. have demonstrated that vitamin
E barriers can be created in extended wear contact lenses
with minimal impact on other key lens properties [38-40].
The vitamin E barriers can be created in situ in polymerized
contact lenses by soaking the lenses in a solution of vitamin
E in ethanol, followed by extraction of ethanol by soaking
in water. Since the solubility of vitamin E in ethanol is very
high, the contact lenses are loaded with vitamin E during
soaking in ethanol. When the lenses are withdrawn from ethanol and soaked in water, ethanol diffuses out but vitamin E
remains trapped in the lens due to its minimal aqueous
solubility. Owing to the unique biphasic microstructure of
silicone hydrogel contact lenses, the vitamin E loaded in the
lenses phase separates into high aspect ratio disc-shaped nanobarriers, likely located at the interface between the silicone
and the hydrophilic phases in the lenses. The vitamin E aggregates are smaller than the wavelength of the visible light and
thus the lenses remain transparent (Figure 2) for vitamin E
loadings as high as 70% w/w. The high aspect ratio vitamin
E aggregates act as barriers for hydrophilic ophthalmic drugs.
The drug molecules are forced to diffuse in a tortuous path
around the barriers resulting in an increase in the release durations. The microstructure of the vitamin E barriers in the
lenses and the mechanism of drug transport are illustrated
in Figure 3.
Vitamin E incorporation is effective in increasing the
release duration of several ophthalmic drugs. This approach
is particularly effective for hydrophilic drugs such as timolol,
fluconazole and DXP which are ionized in physiological conditions, which leads to negligible solubility of the drugs in
vitamin E and consequently excellent barrier-effect [38]. Since
the attenuation of drug transport by vitamin E is purely due
to the increased tortuosity, the ratio of drug release durations
with and without vitamin E should be same for any drug. It
has been shown that the relative increase in release durations
is in fact similar for timolol, fluconazole and DXP. Also, the
release durations increase quadratically with vitamin E loadings because the release times scale as the square of path length
for diffusion control processes [38]. The release durations of
timolol, fluconazole and DXP increase by a factor of about
5 and 40 for 10 and 40% vitamin E loadings, respectively.
The vitamin E also acts as a barrier for certain hydrophobic
drugs such as dexamethasone and cyclosporine likely due to
its high viscosity [39,40]. The release time of dexamethasone
increases about 16-fold with 30% vitamin E loading [39].
Amphiphilic drugs are able to adsorb on the surface of the
5.1

Figure 2. Image of pure NIGHT & DAY lens (right) and NIGHT
& DAY with 30% vitamin E loading (left).
The in vivo studies clearly proved the feasibility of the concept

of using drug-eluting contact lenses, while also showing
improved efficacy compared to eye drops. The superior performance of a contact lens compared to eye drops suggests
an increase in bioavailability due to an increase in the residence time of the drug in the tears. The increase in bioavailability increases the drug concentration in cornea and
aqueous humor, which can act as drug reservoirs and thus
also extend the duration of effect compared to eye drops [29-31].
In spite of the proven benefits of contact lenses, the early studies have not resulted in a commercial product even after five
decades. This most likely can be attributed to the short duration of release from the unmodified commercial contact
lenses. While the exact release duration depends on both the
drug and the lens properties, the release durations are usually
only a few minutes to a few hours for all ophthalmic drugs in
the size range of 300 to 500 Da where majority of the drug is
released in an initial burst [32-37]. A contact lens with release
duration of 1 -- 2 h is superior to the eye drops due to
increased residence time and bioavailability, but the benefits
are perhaps not considered sufficient by pharmaceutical companies to invest the large resources necessary to commercialize
a new drug delivery device. The past few decades have seen
rapid advances in development of new types of contact lenses
that are safer and can be worn continuously for extended periods of time. The advances in the contact lens field have led to
renewed interest in developing therapeutic contact lenses.
Since the short release duration is the major limitation of
the soak and release approach from commercial contact
lenses, most recent studies have focused on developing lenses
with extended drug release duration.
Novel approaches for controlled and

extended drug release from contact lenses
5.
Several approaches have been developed to increase the drug

release duration from contact lenses. It is important to
note that the increase in release duration must be achieved
without compromising any of the key properties, including
1486

Polymer matrix
VE diffusion barrier
Drug molecule
Figure 3. Concept of vitamin E diffusion barrier effect to

drug transport retardation.
vitamin E aggregates and then diffuse along the surface,

leading to minimal barrier effect [41].
The safety and efficacy of vitamin E-loaded extended wear
contact lenses were successfully demonstrated in a glaucoma
model in Beagle dogs [42,43]. These studies focused on delivering timolol to the dogs by eye drops, unmodified contact
lenses and the vitamin E-loaded contact lenses. These studies
demonstrated that both unmodified and vitamin E-loaded
contact lenses can significantly reduce the intraocular pressure
even when the amount of timolol loaded in the lenses is significantly smaller than that in drops. The unmodified contact
lenses had to be replaced daily, while the vitamin E-loaded
lenses were worn continuously for 4 days.
The vitamin E-modified contact lenses have been extensively characterized to show that all the key lens properties
are suitable for extended wear. Vitamin E incorporate also
improves some of the properties such as UV blocking [38].
Although vitamin E incorporation reduces oxygen and ion
permeabilities, the reduced values are still adequate for
extended wear for vitamin E loadings of < 20%. The major
advantages of using vitamin E barriers for extending the
release durations are the ease of implementation and the possibility of attenuating transport of several drugs possibly
even simultaneously.
Molecular imprinting
Molecular imprinting is commonly used for increasing the
partitioning of a solute in biomaterials. The approach relies
on creation of cavities that exhibit a very high affinity for
5.2
the desired solute, which is also called the template. These

high-affinity cavities provide binding sites to the drugs, thus
increasing the overall partition coefficient. When a molecularly imprinted material loaded with the drug is soaked in a
release medium, the unbound drug diffuses, thereby creating
a driving force for the drug bound to the imprinted cavity
to desorb and then diffuse. The net effect of the drug binding
to the high-affinity cavities is a decrease in the effective diffusivity of the drug, which results in an increase in the release
duration [44-50]. It is noted that it may be feasible to design a
cavity with very strong affinity such that the desorption timescales are rate-limiting and thus the overall transport is limited
by the rate of drug desorption from the cavity. However, in
most cases, the transport process is diffusion-controlled with
attenuated effective diffusivity.
The formation of high-affinity cavities requires inclusion
of one or more suitable functional monomers to the polymerization mixture, along with the drug molecules, which serve
as the templates. The functional monomers assemble around
the drug template due to the favorable interactions to create
the cavity, which is then locked in place during the polymerization (Figure 4). The drug molecules are extracted after the
polymerization leaving behind drug-recognizing cavities that
have a high affinity for the template drug molecules. The
drug molecules can then be reloaded into the polymer by
soaking in an aqueous solution to produce the polymer with
a higher drug partition coefficient, along with reduced drug
diffusivity.
The key requirement of the imprinting approach is identification of the suitable functional monomers that have a strong
favorable interaction with the drug. Commonly used functional
monomers for contact lenses include acrylic acid (AA), acrylamide (AM), methacrylic acid (MAA), methyl methacrylate
(MMA) and N-vinyl 2-pyrrolidone (NVP) [51-57]. These functional monomers are compatible with the typical contact lens
materials and can interact with the drug through hydrogen
binding, hydrophobic or ionic interactions. The relative
increase in partitioning due to imprinting depends on the fraction of the functional monomers in the lenses, and additionally
on several other factors including temperature, pressure, drugfunctional monomer ratio, initiator concentration and degree
of crosslinking. The ophthalmic drugs of interest typically
bind to specific receptors in the eyes and thus the best imprinting would mimic the structure of the receptor. Ali et al. and
Venkatesh et al. developed a biomimetic extended release lens
for delivery of antihistamine ketotifen fumarate by focusing
on a formulation with AA, AM, NVP, hydroxyethyl methacrylate (HEMA) and polyethylene glycol (200) dimethyacrylate
(PEG200DMA) to mimic the interactions between H1receptor and the drug [53,58]. Ali and Byrne developed a hyaluronic acid-releasing lens by using AM, NVP, 2-(diethylamino)
ethyl methacrylate (DEAEM) as the functional monomers to
mimic the binding of CD44 proteins to hyaluronic acid [54].
The imprinting approach can significantly benefit by use of
Monte Carlo or molecular dynamics simulations to identify
1487
Functional monomers
Drug template
Crosslinker
Self-assembling due to favorable interactions

Extraction
Polymer
Formation of high-affinity cavity
Polymerization
Figure 4. Schematic illustration of the formation of high-affinity cavities for molecular imprinting.
the most suitable functional monomers for the drug of interest.

Such simulations can be effectively used to predict the influence
of interactions between components on the imprinting [59,60].
Table 1 summarizes the studies on imprinted drug-eluting
contact lenses, and some specific studies are described below.
Timolol is the most common drug used in the imprinting
studies [51,55,61,62]. Hiratani and Alvarez-Lorenzo showed
that imprinted gels based on MAA as the functional monomer
showed two to three times higher timolol-loading capacity
than the non-imprinted gels [51]. Alvarez-Lorenzo et al. used
AA as functional monomer to develop imprinted hydrogels
with high norfloxacin loading (up to 300 times that of polyHEMA (p-HEMA) hydrogels) and a release duration of about
24 h [52]. Venkatesh et al. combined four functional monomers and demonstrated a sixfold increase in loading of ketotifen fumarate compared to the control and threefold increase
compared to gels with two or three functional monomers [63].
While most of the research with imprinted contact lenses
has focused on small molecules, researchers have begun
exploring imprinting of larger molecules in contact lenses
due to the potential benefit of increased comfort. Ali and
Byrne designed a daily disposable molecularly imprinted
contact lenses that released hyaluronic acid (1,200,000 Da)
at a rate of roughly 6 g/h [54]. White et al. designed a
silicone hydrogel-based molecularly imprinted contact lens
to release hydroxypropylmethylcellulose (HPMC) (120k
Dalton) for > 50 days [56].
1488
Yanez et al. proposed that the imprinting cavities can be

created in a fully polymerized gel by impregnation with a
solution of the drug in supercritical CO2. They exposed
Hilafilcon B contact lenses to three cycles of supercritical
solvent impregnation and extraction to imprint the lenses
with flurbiprofen and showed that the loading capacity
increased 450% after the three cycles of treatment. The
increased imprinting also led to an increase in release duration
after each cycle, with an overall increase of about threefold
after the three cycles [64]. Costa et al. also focused on increasing drug-loading capacity of a lens by impregnation with a
solution of the drug in supercritical CO2 [65,66].
The safety and efficacy of the imprinted contact lenses has
been demonstrated in several animal studies. Hiratani et al.
tested N, N-diethylacrylamide (DEAA), MAA and ethylene
glycol methacrylate (EGDMA) copolymerized imprinted
lenses loaded with timolol in rabbits and showed that the
imprinted lenses could sustain measurable timolol concentration in the tear sample threefold longer than eye drops [62]. In
addition, the area under the timolol concentration--time curve
(AUC) for the imprinted lenses was 8.7-fold compared to eye
drops. In a similar in vivo study conducted by Tieppo et al.,
ketotifen fumarate-imprinted lenses consisted of HEMA,
AA, AM, NVP crosslinked with PEG200DMA were tested
in rabbits [67]. The results showed that the residence time
and AUC increased 50 and 94 times, respectively, with
imprinted contact lenses compared to eye drops.
EGDMA
EGDMA
MAA
MAA (4:1, 8:1, 16:1,

32:1)
DEAA, HEMA,
SiMA/DMAA
(50:50 v/v)
MMA/DMAA
(50:50 v/v)z
DMAA/TRIS
(50:50 v/v)z
Hyaluronic acid
(1,200000, Da)
Timolol
AA, VP (0-2.5 mol%)*
AA, AM, NVP
AM, NVP, DEAEMz
AA (6:1 -- 32:1)
HEMA
HEMA
Nelfilcon A formulation
with modified PVAz
macromer
HEMA
Ketotifen fumarate
Norfloxacin
ITC technique was used to identify the optimal molar ratio

between functional monomer and drug template. M/T = 6
provided the longest release duration, but loading capacity
was lower than gels with higher M/T ratio.
Different M/T ratios were tested to evaluate their influence on

imprinted results. Changing M/T ratio had no influence on gels
swelling property. M/T = 16 revealed the best loading capacity
and release duration time
In vivo study was carried out by using rabbits. Results showed
that molecularly imprinted lens provided could sustain
measurable timolol concentration in collected tear sample for
threefold longer than eye drops and also, a 8.7-fold increment
in calculated AUC
Two functional monomers were investigated in delivering
nonsteroidal anti-inflammatory drugs. Higher loading capacity
was achieved. Release duration was sustained for at least 24h
for ibuprofen and 1 week for diclofenac
ITC studies were used to determine the optimum M/T ratio.
Results revealed that AA: drug = 1:3 or 1:4 led to a timolol
release duration of at least 24h
A combination of multiple functional monomer is more effective
in creating imprinting effects. A eightfold reduction in diffusivity
was achieved
Compared to nelfilcon A, the diffusivity of hyaluronic acid was
reduced 1.6 times within AM-co-NVP-co-DEAEM imprinted gels
Low crosslinking density imprinted hydrogel was synthesized.

Imprinted hydrogel had a roughly 10 times increase in overall
drug affinity than non-imprinted ones. Release was sustained
for more than 24 h
Four different backbone monomers were compared and HEMA
showed the best loading capacity and release duration time
Comments on molecular imprinting performance
[55]
[54]
[53,58]
[52]
[98]
[62]
[97]
[61]
[51]
Refs.
*The mole percentage of crosslinker or functional monomer are added into the mixtures of backbone monomer, functional monomer, crosslinker and template molecules.
z
1-(tristrimethyl-siloxysilylpropyl)-metharylate (SiMA), N, N-dimethylacrylamide (DMAA), tris(trimethylsiloxy)silylpropyl methacrylate (TRIS), 4-vinyl-pyridine (VP), N-(3-aminopropyl) methacrylamide (APMA), polyvinyl alcohol
(PVA), 2-(diethylamino) ethyl methacrylate (DEAEM), 1-vinylimidazole(1VI), 4-vinylimidazole (4VI), N-hydroxyethyl acrylamide (HEAA).
The M/T ratios are explored in this study.

{
Lotrafilcon B formulation is patented by CIBA Vision, Inc.
ITC: Isothermal titration calorimetry; M/T: Monomer/Template.
EGDMA
PEG200DMA
EGDMA
Ibuprofen,
diclofenac
VP, APMAz
HEMA
EGDMA
MAA
Timolol
Timolol
Timolol
Timolol
Drugs (template
molecules)
DEAA
EGDMA
EGDMA
(0.32-8.34 mol%)*
MAA (1.28-5.12 mol%) *
DEAA
Crosslinker
Functional monomers
Backbone monomers
Table 1. Summary of recent studies with imprinted contact lenses.

1489
1490
MAA (4:1, 6:1, 8:1)
AA, AM, NVP
DEAEM (1:1, 3.5:1,

10.5:1)
Acetic acid, AA (4:1,

8:1, 16:1)
HEMA
HEMA
HEMA
3.6g of HEMA/ 0.4g

of TRIS
EGDMA
PEG200DMA
PEG200DMA
EGDMA
PEG200DMA,
EGDMA
EGDMA
Crosslinker
Ciprofloxacin
Diclofenac sodium
Prednisolone
acetate
Ketotifen fumarate
HPMC(120 kDA)z
Acetazolamide,
Ethoxzolamide
Drugs (template
molecules)
The pHEMA-zinc methacrylate imprinted hydrogel had a very

low transparency and was not suitable for contact lens wearing.
The NVP-co-DMA imprinted with 4VI, HEAA and zinc ion as
functional monomers remained transparent and increased drug
affinity by twofold. The release was sustained for roughly 9h for
acetazolamide and 1 week for ethoxzolamide
Silicone hydrogels were imprinted for extended release of HPMC.
By adjusting M/T ratio, the release profile could be tailored to
release 1000g of HPMC for a period of more than 50 days.
HPMC loading amount, M/T ratio and crosslinking density should
be finely controlled to obtain transparent lenses
Different M/T ratio were tested and M/T = 4 exhibited the best
loading capacity and release duration time up to 48h
In vivo studies using rabbit model. The results showed a 50-fold
increase in MRT, and 94-fold in AUC
The loading capacity increased fivefold with the presence of
DEAEM. M/T = 10.5 exhibited the longest release duration
of more than 24h
Imprinting could extend the release duration to 3 -- 14 days
Comments on molecular imprinting performance
[102]
[101]
[67]
[57]
[56]
[99,100]
Refs.
*The mole percentage of crosslinker or functional monomer are added into the mixtures of backbone monomer, functional monomer, crosslinker and template molecules.
z
1-(tristrimethyl-siloxysilylpropyl)-metharylate (SiMA), N, N-dimethylacrylamide (DMAA), tris(trimethylsiloxy)silylpropyl methacrylate (TRIS), 4-vinyl-pyridine (VP), N-(3-aminopropyl) methacrylamide (APMA), polyvinyl alcohol
(PVA), 2-(diethylamino) ethyl methacrylate (DEAEM), 1-vinylimidazole(1VI), 4-vinylimidazole (4VI), N-hydroxyethyl acrylamide (HEAA).
The M/T ratios are explored in this study.

{
Lotrafilcon B formulation is patented by CIBA Vision, Inc.
ITC: Isothermal titration calorimetry; M/T: Monomer/Template.
AA
Zinc methacrylate, zinc

nitrate hexahydrate,1VI,
4VI, HEAAz
HEMA, NVP/DMA
(20/80 molar ratio)
Betacon
macromere/TRIS/DMA
Functional monomers
Backbone monomers
Table 1. Summary of recent studies with imprinted contact lenses (continued).


Figure 5. Image of control (left) and 10% cationic surfactantloaded 1-Day Acuvue contact lens (right) containing a drop
of water (0.1 ml).
The above-described studies clearly prove that molecular

imprinting techniques can effectively increase the loading
capacity and the release duration from contact lenses. The
imprinted contact lenses are transparent and are shown to
be safe in animal studies. Effect of the imprinting on ion
and oxygen permeabilities has not been explored but both of
these properties will not likely be significantly impacted.
While most imprinting studies have been conducted with
hydrogels, there are some recent studies on imprinting in silicone hydrogels, which are the materials in extended wear
contact lenses. A potential downside for the imprinting
approach is the requirement of relatively high degree of crosslinking which increases the modulus and reduces water
content, which can impact oxygen transport and comfort.
Micro and nanoparticles

The imprinting approach is based on creation of highaffinity sites in the contact lenses. An alternate approach for
designing lenses with high-affinity regions is through dispersion or surface immobilization of nanoparticles that are specifically designed to possess high affinity for the drug of
interest. The nanoparticles can increase partitioning and
thus reduce the effective diffusivity as the drug partitioned
in the particles does not directly diffuse. Due to the excellent
biocompatibility, liposomes are good candidates for dispersion or surface immobilization on contact lenses. Dimyristoylphosphatidylcholine liposomes were dispersed in p-HEMA
hydrogels to provide extended release of lidocaine for about
6 days. The release profiles displayed an initial burst release
followed by a sustained release over the next few days [68].
Danion et al. immobilized liposomes on the surface of
commercial contact lenses and showed extended release of
carboxyfluorescein [69].
Several studies have focused on dispersing microemulsions
(MEs) in contact lenses. The p-HEMA hydrogels were loaded
with lidocaine-base-containing MEs with hexadecane oil and
Brij 97 surfactant and an additional silica shell for further
stabilization. The hydrogels released lidocaine for about
7 -- 8 days, but about 50% of the drug was released within
5.3
the first few hours. Also, the gels were 1 mm thick, which is
about 10 times thicker than most contact lenses [70]. MEs of
canola oil stabilized by Tween 80 with an additional silica
shell were also explored for extended release of lidocaine
from p-HEMA hydrogels. The hydrogels were reported to
be opaque due to the aggregation and segregation during
polymerization. The transparency loss was minimized by dispersing MEs stabilized by Brij 97 with an additional silica
shell, but the drug release profiles still contained a burst followed by a slow release for a few days [71]. To minimize the
initial burst, Ferreira et al. loaded silicone-coated particles
containing flurbiprofen, Brij 35 and decane into HEMA-coMAA hydrogels. The release profiles still contained an initial
burst, followed by sustained release over 8 days [72]. Jung
and Chauhan prepared highly crosslinked spherical nanoparticles of propoxylated glyceryl triacrylate with covalently
attached timolol, and then loaded the particles in both
p-HEMA and silicone hydrogels by direct addition to the
polymerization mixture. The gels exhibited a sustained release
for about 30 days at room temperature due to the slow hydrolysis of the ester bond that connected timolol to the lens
matrix. The release duration was, however, considerably
shorter at physiological temperatures due to the higher reaction rates. The timolol-linked nanoparticles were also loaded
into commercial contact lenses by soaking the lenses in a solution of the nanoparticles in ethanol followed by evaporation
of ethanol. The efficacy of the timolol-releasing lenses was
demonstrated in a glaucoma animal model by measuring the
intraocular pressure after insertion of the lenses. The particleloaded lenses achieved intraocular pressure reduction comparable to eye drops but with about one-tenth of the drug loading,
which is in agreement with the predicted increase in bioavailability from about 5% for eye drops to about 50% for contact
lenses. The intraocular pressure (IOP) decreased for about
4 days, which correlated well with the in vitro release profiles
at physiological temperatures, suggesting that the in vitro
release under sink conditions is a reasonable model for the
in vivo release in the eyes [73]. In another study with nanoparticles, p-HEMA hydrogels loaded with pullulan and polycaprolactone copolymer core-shell nanospheres exhibited
antibacterial activity for about 3 days due to extended release
of ciprofloxacin [74]. Recently, a 30-day release of dexamethasone acetate was reported from lenses loaded with rod-like
silica shell crosslinked methoxy micelles [75].
In most of the studies described above, nanoparticles were
first fabricated, and then incorporated into the lenses either
by soaking or through its addition to the polymerization mixture. To avoid the two-step process, non-ionic Brij surfactant
aggregates were self-assembled into p-HEMA hydrogels by
addition of the surfactant to the polymerization mixture.
The 50 -- 100 nm size surfactant aggregates exhibited high
partitioning for hydrophobic drug cyclosporine and significantly reduced the diffusion rates [76,77].
The approach of incorporating nanoparticles into contact
lenses for extended drug release is certainly effective and can
1491
be adapted to most drugs due to the versatility in choosing

the appropriate nanoparticles. There are also significant
downsides to this approach due to the potential for particle
destabilization or aggregation and segregation during polymerization, sterilization or storage, which could alter the
drug release profiles and possibly reduce transparency.
Ionic interactions
The transport of drug in a contact lens is typically diffusioncontrolled but the effective diffusivity is impacted by the
binding of the drug to the polymer matrix. Several researchers
have attempted to take advantage of increased drug-binding
to the lens matrix to increase the release durations of the
drugs. Since a large number of ophthalmic drugs are charged
at physiological conditions, ionic interactions are the natural
choice to increase drug-binding to the matrix. Sato et al.
fabricated p-HEMA gels with cationic side chains by incorporation of methacrylamide propyltrimenthylammonium chloride (MAPTAC) for extended delivery of anionic drug
azulene. The hydrogels exhibited extended release for about
8 h in saline but the lens volume changed during the release,
which is undesirable. The volume change was minimized by
incorporation of anionic molecules such as MAA or 2-methacryloxyethyl phosphate (MOEP) into the lenses in addition to
the cationic MAPTAC [78]. In a similar study, an anionic lens
was prepared by inclusion of MAA and MOEP anions in the
p-HEMA gel. The uptake of cationic drug naphazoline was
shown to be directly proportional to the fraction of anionic
ligands in of the hydrogel [79]. Anionic silicone hydrogel lenses
containing MAA and 2-methacryloyloxyethyl hydrogen
succinic acid and 3-methacryloxypropyl tris(trimethylsiloxy)
silane were also explored for delivery of ofloxacin. It was
shown that in addition to the ionic interaction, the silyl group
also increases the drug release duration likely due to the reduction in transport of water, which is required for the solvation
of the drug [80]. In a recent study, ionic lenses loaded with
MAA and antibiotics (gatifloxacin and moxifloxacin) were
tested in a Staphylococcus aureus infection model in rabbits.
The ionic lenses exhibited increased uptake of both antibiotics
in proportion to the fraction of MAA incorporation and
extended release duration of about 2 -- 3 days. The in vivo
study with contact lenses showed an undetectable bacterial
concentration in tears and much higher drug concentrations
in the cornea, aqueous humor and crystalline lens compared
to eye drops [81]. The concentration profile in the ocular tissue
exhibited trends similar to the in vitro release profiles suggesting a good correlation between in vitro and in vivo release.
The uptake of puerarin in p-HEMA hydrogels was improved
by incorporation of NVP into the lenses, possibly due to the
interaction between the OH-rich puerarin and the carbonyl
group of polyvinylpyrrolidone (PVP). Animal studies in rabbits showed about sixfold increase in residence time of the
drug in the tears compared to 1% eye drops [82]. Addition
of ionic molecules prior to polymerization could impact the
structure and properties of the lenses, so Bengani and

5.4
1492
Chauhan recently proposed to adsorb ionic surfactants to a preformed lens to impart the charge. Cationic surfactants were
adsorbed on the p-HEMA and a commercial contact lens to
design a lens for extended release of an anionic drug dexamethasone phosphate. The surfactant incorporation increased the
release duration by about 100-fold in the p-HEMA lens and
about 10-fold in the commercial lenses. Commercial 1-Day
Acuvue lenses loaded with cationic surfactant remained
transparent, and the presence of surfactant had the additional
benefit of increased surface wettability (Figure 5) [83].
Other approaches
Kim et al. designed silicone-hydrogel contact lenses comprising of a hydrophilic monomer N,N-dimethylacrylamide
(DMA) and a silicone monomer methacryloxypropyltris
(trimethylsiloxy)silane (TRIS), with a new macromer bisalpha, omega-(methacryloxypropyl) polydimethylsiloxane
(MW 7152) to produce lenses that exhibited extended release
of both hydrophobic and hydrophilic drugs. The lenses
released timolol and dexamethasone for extended periods
ranging from 2 weeks to 3 months depending on the composition. Also, several key properties including transparency,
ion permeability and modulus were shown to be suitable for
contact lens applications [84]. Xu et al. incorporated
b-cyclodextrins (BCD) in HEMA hydrogels to increase
release durations of puerarin, which complexes with the
BCD. The addition of BCD into the polymer resulted in
increased equilibrium swelling ratio and tensile strength.
The BCD incorporation led to a 40% increase in drug uptake
and an increase in the release times [85]. BCD incorporation in
HEMA hydrogels also increased loading by about 1300% and
led to continuous release rate for 12 days [86]. A copolymer of
DMA and 2-(N-ethylperfluorooctanesulfonamido) ethyl acrylate (FOSA) was prepared by free-radical polymerization, and
it was shown that the inclusion of FOSA led to a decrease in
the diffusion coefficient of pheniramine maleate [87].
Ciolino et al. sandwiched drug-loaded poly(lactic-co-glycolic
acid) (PLGA) films in a p-HEMA contact lens for extended
delivery of fluorescein and ciprofloxacin. The lenses exhibited
extended release for about 1 month at zero-order rates. The
same approach was shown to be effective for extended release
of econazole at adequate rates to provide antifungal activity
against Candida albicans fungi [88,89].
5.5
6.
Conclusions
Drug-eluting contact lenses appear to be highly suitable for

drug delivery to the anterior chamber, due to the significant
increase in bioavailability to about 50% compared to
1 -- 5% for eye drops. However, the early attempts to deliver
ophthalmic drugs via contact lenses did not lead to a successful clinical product because the lenses were not designed
appropriately. The simple soak and release approach, which
was the method of choice in the early studies, is not the optimal method for drug incorporation because of the short

duration of release. The past few years have seen a significant

growth in research focused on improving the drug release profiles from contact lenses by several approaches including
molecular imprinting, dispersion of barriers or nanoparticles,
increasing drug-binding to the polymer, sandwiching a PLGA
layer in a lens and developing novel materials. The new technologies significantly improve the drug release profiles with
minimal impact on critical lens properties such as transparency, modulus, ion and oxygen permeabilities, protein binding, etc. Each technology has advantages and disadvantages
and simultaneous optimization of various approaches will be
critical to commercialize drug-eluting contact lenses because
the optimal drug release profiles may vary across diseases
and will also depend on patient choice.
7.
Expert opinion
The past few years have seen renewed scientific as well as commercial interest in developing contact lenses for ODD. In
addition to several research studies, a number of patents based
on MEs [90], nanoparticles [91], organic--inorganic chitosansilica nanocarrier [92], multilayer structure [93], imprinting
and vitamin E incorporation [94,95] are recently published or
issued. Moreover, a Phase III study has been recently concluded on release of ketotifen fumarate from contact lenses
using the soak and release technology to develop antiallergy contact lenses [96]. Most recent focus has been on
increasing the drug release durations, which are just a few
hours for most drugs in commercial contact lenses. Several
technologies have been successfully utilized to extend the
release durations for several drugs including glaucoma drug
timolol, dry eye drug cyclosporine, anti-inflammatory
dexamethasone, anesthetic lidocaine, antibiotics, antivirals,
antifungals, etc. Most of the technologies are based on
p-HEMA contact lenses and are thus unsuitable for continuous wear. Some of those technologies can create continuous
wear silicone hydrogel contact lenses with release duration
consistent with the wear schedule, thus affording the possibility of continuous drug delivery without lens replacement for
2 -- 4 weeks. Several of the lens designs have also been tested
in various animal models which demonstrate the superiority
of these modified contact lenses, though there are very few
human studies. In addition, detailed characterization to determine if the extended release contact lenses can meet all the
requirements for the extended wear contact lenses, including
transparency, ion and oxygen permeability, modulus, protein

binding etc., is lacking for many technologies. It also remains
to be demonstrated whether the technologies and also the
drugs of interest are compatible with current lens manufacturing processes including sterilization and storage. While several
approaches can provide extended drug release, most fail to
provide a zero-order release, which is considered to be the
optimal release profile. However a lack of zero-order profile
does not appear to be a significant problem as long as the
maximum release is below the toxic limit and the release during the entire wear time is within the therapeutic window.
Another critical issue that has not received much attention is
the potential for desensitization of the ocular receptors due
to continuous drug delivery from contact lenses. If desensitization occurs for any specific drug--target pair due to constant
exposure to the drug, contact lenses will not be suitable for
treatment of that disease unless the release profiles can be
modified to provide pulsatile release.
While the future appears to be promising for drugeluting contact lenses, several challenges remain. Several ophthalmic diseases are more common in the elderly patients but
they may not be suitable for drug therapy by contact lenses
because of reduced tear volume and dryness, which can
make contact lens use uncomfortable. Contact lens wear is
still uncomfortable for a large number of people and prolonged contact lens wear is associated with risk of infection
such as microbial keratitis. Additionally, processing and storage issues, regulatory hurdles and high costs of clinical studies
are major barriers to commercialization and clinical implementation. All these barriers have to be overcome to move
forward and to accomplish that it is critical to focus efforts
on the diseases that benefit the most by contact lensbased drug delivery. It may not be sufficient to just prove
improved efficacy compared to eye drops, and improved
patient compliance may be critical. While extending the
drug release duration to 2 -- 4 weeks could be scientifically
interesting and would also be the ideal design to maximize
compliance, the optimal release duration will depend on the
disease, patient acceptance and regulatory issues.
Declaration of interest
The authors thank the National Science Foundation (CBET
CMMI Grant 1129932) for providing partial support for
this work.
1493
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Affiliation
Lokendrakumar C Bengani, Kuan-Hui Hsu,
Samuel Gause & Anuj Chauhan
Author for correspondence

University of Florida,
Department of Chemical Engineering,
1006 Center Drive, Gainesville,
FL 32611, USA
Tel: +1 352 392 2592;
Fax: +1 352 392 9513;
E-mail: chauhan@che.ufl.edu

Contact Lens Drug Delivery

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Contact Lens Drug Delivery

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Review

Contact lenses as a platform for

Ocular transport of drug

Key requirements for

Drug delivery by soak and

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

release from unmodified

Novel approaches for

University of Florida, Department of Chemical Engineering, Gainesville, FL, USA

Corneal bioavailability for ophthalmic drugs delivered

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

This box summarizes key points contained in the article.

therapy [8] and delivery of cysteamine for the treatment of

Ocular transport of drug released by a

Expert Opin. Drug Deliv. (2013) 10(11)

Contact lenses as a platform for ODD

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

Figure 1. Mechanism of ophthalmic drug delivery by contact

delivery as the timescale for drug release from the lens

Key requirements for drug-eluting

correction. The remaining key requirements are related to

Drug delivery by soak and release from

The earliest reports on the use of contact lenses for drug

Expert Opin. Drug Deliv. (2013) 10(11)

transparency, modulus, wettability, lubricity, ion and oxygen

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

The in vivo studies clearly proved the feasibility of the concept

Novel approaches for controlled and

Several approaches have been developed to increase the drug

Expert Opin. Drug Deliv. (2013) 10(11)

Contact lenses as a platform for ODD

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

Figure 3. Concept of vitamin E diffusion barrier effect to

vitamin E aggregates and then diffuse along the surface,

the desired solute, which is also called the template. These

Expert Opin. Drug Deliv. (2013) 10(11)

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

Formation of high-affinity cavity

the most suitable functional monomers for the drug of interest.

Yanez et al. proposed that the imprinting cavities can be

Expert Opin. Drug Deliv. (2013) 10(11)

MAA (4:1, 8:1, 16:1,

AA, VP (0-2.5 mol%)*

AA, AM, NVP

AM, NVP, DEAEMz

Expert Opin. Drug Deliv. (2013) 10(11)

ITC technique was used to identify the optimal molar ratio

Different M/T ratios were tested to evaluate their influence on

Low crosslinking density imprinted hydrogel was synthesized.

Comments on molecular imprinting performance

The M/T ratios are explored in this study.

MAA (1.28-5.12 mol%) *

Table 1. Summary of recent studies with imprinted contact lenses.

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by HINARI on 02/10/14

Contact lenses as a platform for ODD

Expert Opin. Drug Deliv. (2013) 10(11)

MAA (4:1, 6:1, 8:1)

AA, AM, NVP

DEAEM (1:1, 3.5:1,

Acetic acid, AA (4:1,

3.6g of HEMA/ 0.4g

The pHEMA-zinc methacrylate imprinted hydrogel had a very

Comments on molecular imprinting performance

The M/T ratios are explored in this study.