Drug Delivery

ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20

A review on therapeutic contact lenses for ocular

drug delivery

Furqan A. Maulvi, Tejal G. Soni & Dinesh O. Shah

To cite this article: Furqan A. Maulvi, Tejal G. Soni & Dinesh O. Shah (2016) A review on
therapeutic contact lenses for ocular drug delivery, Drug Delivery, 23:8, 3017-3026, DOI:
10.3109/10717544.2016.1138342

To link to this article: http://dx.doi.org/10.3109/10717544.2016.1138342

Published online: 29 Jan 2016.

Submit your article to this journal

Article views: 855

View related articles

View Crossmark data

Citing articles: 1 View citing articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=idrd20

Download by: [112.215.65.39] Date: 14 May 2017, At: 10:58

 http://informahealthcare.com/drd
ISSN: 1071-7544 (print), 1521-0464 (electronic)

Drug Deliv, 2016; 23(8): 30173026

! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.3109/10717544.2016.1138342

CRITICAL REVIEW

A review on therapeutic contact lenses for ocular drug delivery

Furqan A. Maulvi1, Tejal G. Soni2, and Dinesh O. Shah3,4,5
1
Maliba Pharmacy College, Uka Tarsadia University, Gujarat, India, 2Faculty of Pharmacy, Dharmsinh Desai University, Gujarat, India,
3
Shah-Schulman Center for Surface Science and Nanotechnology, Dharmsinh Desai University, Gujarat, India, 4Department of Chemical
Engineering and Department of Anaesthesiology, University of Florida, FL, USA, and 5School of Earth and Environmental Sciences, Columbia
University, New York, USA

Abstract Keywords
Contact lenses for ophthalmic drug delivery have become very popular, due to their unique Challenges, critical lens property, ophthalmic
advantages like extended wear and more than 50% bioavailability. To achieve controlled and drug delivery, sustained drug delivery,
sustained drug delivery from contact lenses, researchers are working on various systems like therapeutic contact lenses
polymeric nanoparticles, microemulsion, micelle, liposomes, use of vitamin E, etc. Numerous
scientists are working on different areas of therapeutic contact lenses to treat ocular diseases History
by implementing techniques like soaking method, molecular imprinting, entrapment of drug-
laden colloidal nanoparticles, drug plate/film, ion ligand polymeric systems, supercritical fluid Received 17 November 2015
technology, etc. Though sustained drug delivery was achieved using contact lens, the critical Revised 31 December 2015
properties such as water content, tensile strength (mechanical properties), ion permeability, Accepted 02 January 2016
transparency and oxygen permeability were altered, which limit the commercialization of
therapeutic contact lenses. Also issues like drug stability during processing/fabrication (drug
integrity test), zero order release kinetics (prevent burst release), drug release during monomer
extraction step after fabrication (to remove un-reacted monomers), protein adherence, drug
release during storage in packaging solution, shelf life study, cost-benefit analysis, etc. are still
to be addressed. This review provides an expert opinion on different methodology to develop
therapeutic contact lenses with special remark of their advantages and limitations.

Introduction 1974; Burns & Mulley, 1992; Stone et al., 2009). High-dosing
frequency exaggerates the side effects and reduces patient
Drug delivery to the anterior chamber of eye is a very
compliance, especially in treatment of chronic diseases like
challenging task for scientists, due to the complex anatomy of
glaucoma and dry eye syndrome (Patel & Spaeth, 1995;
eye and resistance to foreign substances, including drugs
Frishman et al., 2000; Fechtner & Realini, 2004; Sklubalova
(Shell, 1982; Lang, 1995; Ding, 1998; Gaudana et al., 2010).
& Zatloukal, 2005).
At present, majority of the ocular medications are instilled
To overcome the limitations associated with conventional
topically either through eye drop solutions or suspensions.
eye drop therapy, novel delivery systems and devices have
However, the conventional eye drop therapy commonly shows
being explored by many researchers (Nicolson & Vogt, 2001;
low bioavailability to target ocular tissue, due to various pre-
Shah et al., 2003; Alvarez-Lorenzo et al., 2006a). The ideal
corneal loss factors, such as tearing and blinking (tear
drug delivery system delivers a required amount of drug to the
dynamics), non-productive absorption through conjunctiva,
ocular tissue with comfort, easy to administer, and does not
nasolacrimal drainage and also due to low permeability of the
interfere with vision or normal eye functioning. In this
corneal membrane (Prausnitz & Noonan, 1998; Yokoi &
context, therapeutic contact lenses have being proposed for
Komuro, 2004; Zhu & Chauhan, 2005; Urtti, 2006; Del Amo
controlled and sustained ocular drug delivery, due to their
& Urtti, 2008). Thus, due to physiological and anatomical
unique properties like extended wear and more than 50%
restrictions, the eye drop solution shows a reduced-drug
bioavailability in comparison to eye drop formulation (Li &
residence time of 13 minutes in the tear film and conse-
Chauhan, 2006; Peng et al., 2010, 2012; Gonzalez-Chomon
quently a very-low bioavailability of 13%. To compensate for
et al., 2013,). Drug releases from therapeutic contact lenses in
the low bioavailability, clinicians are forced to prescribe eye
pre- and post-lens tear film, leading to a residence time of
drops with frequent doses at high-drug loading, to attain
more than 30 minutes, in comparison to just 13 minutes for
desired therapeutic drug level at the target tissue (Chrai et al.,
eye drop solutions (Mcnamara et al., 1999; Creech et al.,
2001). The high drug residence time increases the bioavail-
*Address for correspondence: Furqan A. Maulvi, Maliba Pharmacy
ability up to 50%, which eventually reduces the dose, dosing
College, Uka Tarsadia University, Bardoli Mahuva Road, Tarsadi, Dist.
Surat 394350, Gujarat, India. Tel: +91 8238651055. Fax: +91 02625 frequency, systemic drug absorption and its associated side
255882. Email: furqan.maulvi@utu.ac.in effects (Jain, 1988; Li & Chauhan, 2006; Li & Chauhan,
3018 F. A. Maulvi et al.
2007; Xinming et al., 2008). There are many innovations on
therapeutic contact lenses to treat anterior ocular diseases
which uses soaking method, molecular imprinting, entrap-
ment of drug-laden colloidal nanoparticles, drug plate, ion
ligand polymeric systems, supercritical fluid technology, etc.
(Xinming et al., 2008; Guzman-Aranguez et al., 2013; Hsu
et al., 2014; Carvalho et al., 2015). Scientists do achieve
controlled and sustained drug delivery using contact lenses,
but the critical properties such as swelling, storage modulus,
ion permeability, transparency and oxygen permeability was
affected, thus limiting the use of therapeutic contact lenses.
This review provides a detailed discussion on different
methodology to develop therapeutic contact lenses highlight-
ing their advantages and disadvantages.
Methodology to design therapeutic contact lenses
Soaking method
The most simple, cost effective and conventional way to load
drug into the contact lenses is by soaking method, which
involves soaking the preformed contact lenses in the drug
solution, followed by drug uptake and release in pre- and
post-lens tear film (Hehl et al., 1999; Sedlacek, 1999;
Peterson et al., 2006; Bengani et al., 2013). Contact lenses
have internal channels/cavity for receiving/accommodating
the drug molecules. Their drug reservoir ability strongly
depends on the water content, thickness of lenses, the
molecular weight of the drug, soaking time period and
concentration of drug in soaking solution (Xinming et al.,
2008). As an alternative, one can also insert contact lenses
into the eyes and then apply eye drops. By this means, drugs
can be absorbed and released by the contact lens (Schrader
et al., 2006).
Use of therapeutic contact lenses prepared by soaking
method, to deliver ophthalmic drugs like timolol (Li &
Chauhan, 2007), pilocarpine (Ruben & Watkins, 1975),
dexamethasone (Kim & Chauhan, 2008), hyaluronic acid
(Maulvi et al., 2015), brimonidine tartrate (Schultz et al.,
2009), etc. have been explored by many researchers. Anthony
Soluri and co-workers investigated soaking technology using
ketotifen fumarate, and found that lenses with charged
surfaces [Balafilcon A, Etafilcon A, and Etafilcon A (daily
disposable)] showed improvement in drug uptake and release
duration. The contact lenses were able to exceed the total
amount of drug instilled in eye drop therapy (twice-daily,
0.025%w/v ketotifen fumarate solution). The lenses showed
burst release and reached a plateau concentration of drug
quickly within few hours (Soluri et al., 2012). Jinku-Xu
evaluated soaking method, by loading ketotifen fumarate in
silicon hydrogel contact lenses. The drug uptake and in-vitro
release kinetics were dependent on the hydrogel composition
(hydrophilic/hydrophobic monomers) of the contact lenses.
The lenses showed higher drug uptake with increase in
hydrophilic phase, while sustained release was observed with
increase in hydrophobic phase in the contact lens matrix. In
animal study, a more stable drug concentration (424 hours)
was observed in tear fluid, in comparison to eye drop therapy
(Xu et al., 2011). Schultz investigated uptake and release of
timolol maleate and brimonidine tartrate from soaking
solution using contact lenses. In-vitro release showed burst
Drug Deliv, 2016; 23(8): 30173026
release of drug attaining plateau within 1 h, while clinical data
in glaucoma patients (30 minutes wear per day for two weeks)
showed reduction in IOP, which was equivalent to eye drop
treatment with 10-times lower dose (Schultz et al., 2009). To
extend the release duration, Jinah Kim developed extended
wear silicone contact lenses to deliver drugs (timolol,
dexamethasone, and dexamethasone 21-acetate) for a period
of weeks to months by varying ratios of monomers. Lenses
showed diffusion-limited transport and extended release
which varied from 20 days to 3 months depending on the
composition of hydrophobic and hydrophilic monomers of
silicone hydrogels (Kim et al., 2008). Eva Garcia and co-
workers improved the drug-loading capacity of triamcinolone
acetonide and modulated release profile from soft contact
lenses by optimizing hydrogel monomer composition and
microstructural modifications using water during the fabrica-
tion process (Garca-Millan et al., 2015).
Though soaking method is simple and cost effective, it has
several limitations. High molecular weight drugs or polymers
like hyaluronic acid, do not penetrate the aqueous channels of
contact lenses and remain on the surface only, which shows
failure in sustained drug delivery for the treatment of dry eye
syndrome (Maulvi et al., 2015). Contact lenses have low
affinity for most of the ophthalmic drugs like timolol maleate,
olopatadine HCl, brimonidine tartrate, etc. (Schultz et al.,
2009; Maulvi et al., 2014). Due to low affinity, the drug is
poorly retained by the contact lenses and released quickly
(burst release) followed by a steep decline, indicating that the
therapeutic levels were not attained, and drug (extended
release) was not released within therapeutic window
(Gonzalez-Chomon et al., 2013). For example, drugs like
prednisolone, pilocarpine, ciprofloxacin, ketotifen fumarate,
timolol, hyaluronic acid were released from hydrogel lenses
within few hours (Hull et al., 1974; Ruben & Watkins, 1975;
Lesher & Gunderson, 1993; Karlgard et al., 2003). Also, only
few scientists have focused on the effects of sterilization and
packaging processes on the stability of therapeutic contact
lenses, which may cause premature release of the drug.
Molecular imprinting
Molecular imprinting (MI) is one of the advanced methodol-
ogies explored by Alvarez-Lorenzo and co-workers using
hydrogel contact lenses for high drug loading and controlled
drug delivery (Andrade Vivero et al., 2007). In this technique,
the target drug is mixed with functional monomers, which
rearrange and interact with drug molecules. After polymer-
ization, the drug from contact lens is removed, which results
in formation of tailored active sites or imprinted pockets
called macromolecular memory sites, i.e. the 3D structure of
drug is left behind within a flexible macromolecular network.
The monomers in the hydrogel matrix are organized in such a
way that high drug affinity molecular sites are created. These
molecular imprinted sites mimic the drugs receptors or its
structurally similar analogy, which increase drug loading
capacity (Alvarez Lorenzo et al., 2002; Hiratani et al., 2005b;
White & Byrne, 2010). Drug affinity and its release profile
are therefore governed by the type of functional monomers
used as well as their ratio in the polymeric matrix. Thus one
can tailor the release pattern based on monomer composition.
DOI: 10.3109/10717544.2016.1138342
Stable imprinted cavities can be achieved, by increasing the
degree of cross-linking in hydrogel matrix (Alvarez-Lorenzo
et al., 2006b; Ali et al., 2007; Venkatesh et al., 2007;
Venkatesh et al., 2008; Tieppo et al., 2012).
Carmen Alvarez-Lorenzo evaluated the influence of
monomers like HEMA, methacrylic acid (MAA) and methyl
methacrylate (MMA; 100400 mM) on drug-loading capacity
and release of drug from molecular imprinted contact lenses.
They found that, incorporation of MAA as co-monomer
(100 mM MAA) in hydrogels increased the timolol-loading
capacity (Alvarez Lorenzo et al., 2002). Later Haruyuki
Hiratani uncovered the influence of MAA/drug ratio on the
conformation of the imprinted cavities. Two-fold increase in
release duration was observed with increase in the ratio of
MAA/drug (1:161:32) (Hiratani et al., 2005b). Likewise,
Fernando studied the effect of norfloxacin to acrylic acid ratio
(1:2 to 1:16) on drug uptake and release from imprinted
hydrogels. Imprinted hydrogels synthesized using 1:4 molar
ratio showed maximum sustained release up to 24 h (Alvarez-
Lorenzo et al., 2006b). The effect of different monomer to
template ratios and ionic non-covalent interactions was also
explored by Arianna Tieppo, to develop molecular imprinted
diclofenac-poly(HEMA-co-DEAEM-co-PEG200DMA) soft
contact lenses. Zero-order release kinetic was achieved
when ratio was increased up to 10.5 (release rate decreases
from 11.72 mg/h to 6.75 mg/h during the first 48 hours)
(Tieppo et al., 2012). Instead of single monomer use in MI
technology, Siddarth demonstrated the use of multiple
functional monomers which showed eight times higher drug
loading and sustained drug delivery, (Venkatesh et al., 2008).
The in-vivo performance of MI contact lenses was evaluated
by Hiratani et al. (2005a), they found that lenses developed by
the MI technology with 34 mg dose delivered timolol
concentrations in the tear fluid for a duration 2- and 3-fold
longer than the non-MI lenses with 21 mg dose and eye drops
with 125 mg dose respectively. Molecular imprinting strategy
was also used by Charles J. White to treat dry eye syndrome,
using 120 kDa Hydroxypropyl methylcellulose (HPMC).
Extended release up to 60 days was achieved with the rate
of 16 mg/day, which significantly varied with functional
monomer to template ratio (M/T) (White et al., 2011b).
Maryam Ali demonstrated biomimetic MI technology, to
deliver hyaluronic acid for 24 h with 6 mg/h release rate (Ali &
Byrne, 2009). In summary, the results clearly suggest the
influence of functional monomers like MMA, MAA and AA
on drug uptake and release kinetics in molecular imprint
technology.
The limitation of molecular imprinting methodology is the
highly cross-linked structure of hydrogel which affects the
optical and physical performance of contact lens (White et al.,
2011a). The drug-loading capacity is limited by the template
molecules and functional monomers, and the deformation
(change in dimension) of contact lenses after release of drug
was also noted (Schrader et al., 2006). The fall in water
content (decrease in swelling) leads to an insufficient ion and
oxygen permeability which limit the use of contact lenses for
extended wear (Byrne & Salian, 2008). Lei Tang and co-
workers developed crowding-assisted molecularly imprinted
polymer using polystyrene to achieve zero order release
kinetics of drug from contact lenses. The effective diffusivity
Review on ocular drug delivery 3019
was two-fold smaller in magnitude than conventional molecu-
lar imprinting (Tang et al., 2015). Tailoring molar ratios of
HEMA-drug-functional monomer-cross-linker, Malakooti co-
workers et al., (2015) developed imprinted contact lenses, to
achieve sustain the release of polymyxin B and vancomycin.
Colloidal nanoparticles laden therapeutic contact lens
The technique is based on the ability of colloidal nanopar-
ticles (polymeric nanoparticles, liposomes, niosomes, micro-
emulsion, micelles, etc.) to entrap or encapsulate drug and
control its release rate from contact lenses (Gupta & Chauhan,
2010; Jung et al., 2013; Hsu et al., 2014). Such formulated
nanoparticular system (10 to 100 nm) is dispersed in HEMA
monomers and polymerized using ethylene glycol-dimetha-
crylate (EGDMA) and photo initiator (Darocur ) to fabricate
therapeutic contact lenses (Gulsen & Chauhan, 2004; Bazzaz
et al., 2014). Drug laden nanoparticles prevent the interaction
of drug with polymerization mixture and also offer additional
resistance to drug release. Thus the nanoparticles loaded
contact lenses can deliver drugs at controlled rate for
extended period of time. Drug loaded nanoparticles or
globules (microemulsion) also bypass, to some extent, drug
metabolism from the enzymes like lysosomes, present in the
tear/corneal epithelial surface (Gulsen & Chauhan, 2005;
Gulsen et al., 2005; Jung et al., 2013). The researchers have
being successful in developing therapeutic contact lenses for
extended drug delivery, while at the same time the transpar-
ency (optical), oxygen permeability, ion permeability, mech-
anical properties, and swelling behavior of contact lenses was
altered for comfort wear.
Polymeric nanoparticles
Many researchers have focused on polymeric nanoparticles
using biodegradable and non-biodegradable polymers, to
develop therapeutic contact lenses to treat ocular diseases.
To treat glaucoma, Hyun Jung and co-workers developed
therapeutic contact lenses, by dispersing timolol loaded
propoxylated glyceryl triacylate (PGT) nanoparticles in
contact lenses. In-vitro release profile shows the presence of
drug for one month, and animal studies in Beagle dogs
confirmed the reduction in IOP. Although the system showed
sustained release, the incorporation of nanoparticle in the
silicone hydrogel contact lenses caused reduction in both ion
and oxygen permeability, and an increase in storage modulus,
suggesting the limitation of the technique (Jung et al., 2013).
In another work by Anuj Chauhan and co-workers, timolol
encapsulated highly cross-linked nanoparticles (3.5 nm in
size) was dispersed in contact lenses which showed increase
in drug release duration up to four weeks. The cross-linked
nanoparticles were prepared from monomers with multivinyl
functionalities such as EGDMA (ethylene glycol dimethacry-
late) and PGT (propoxylated glyceryl triacylate). They
proposed the mechanism of drug transport, as hydrolysis of
ester bonds that link timolol to the particle matrix. The results
were very encouraging, though the increase in storage
modules (mechanical property) and decrease in water content
was observed with increase in particle loading (Jung &
Chauhan, 2012). Bibi Sedigheh and co-workers assessed the
antimicrobial effects of silver nanoparticles (NP) impregnated
3020 F. A. Maulvi et al.
in hydrogels. They evaluated the antimicrobial effect against
Pseudomonas aeruginosa and Staphylococcus aureus, and
concluded that, the antimicrobial effect was sufficient to
decrease the risk of microbial-related adverse events for
extended contact lens wear (Bazzaz et al., 2014). Hardik
Chandasana designed corneal targeted nanoparticles laden
contact lenses, in order to reduce dose and dosing frequency
of natamycin. In-vitro release studies showed extended
release up to 8 hours and in-vivo results, showed significant
improvement in AUC and MRT in comparison with the
marketed preparation (Chandasana et al., 2014). Wenji and
co-workers dispersed bovine serum albumin-coated melox-
icam nanocrystals (nanoaggregates) in contact lens material to
treat post-cataract endophthalmitis. The developed contact
lenses showed reduction in ocular irritancy and sustained drug
delivery for five days (Zhang et al., 2014).
Cyclodextrins
In another approach, polymers like cyclodextrins (CDs) and
their derivatives were used to achieve sustained drug delivery
of hydrophobic drugs. CDs can accommodate many different
hydrophobic molecules in their hydrophobic interior (ring-
shaped structure), to achieve controlled drug delivery
(Loftsson et al., 2004). Jinku Xu developed pHEMA/b-CD
hydrogels by copolymerization of HEMA with puerarin-b-CD
complex. The incorporation of b-CD in the hydrogels resulted
in increased swelling and tensile strength. The animal study
data revealed increase in drug residence time, with higher
concentration of the drug in the tear fluid and vitreous humor
in comparison with conventional hydrogel lenses or eye drops
therapy (Xu et al., 2010). Garca-Fernandez and co-workers
developed therapeutic contact lenses with drug-poly-CD
laden hydrogels, crossed linked using citric acid, to achieve
sustained delivery of acetazolamide to treat glaucoma. In-
vitro studies, reported an increase in the drug solubility in
poly-CD, an increase of its concentration in the cornea and an
extended release over several weeks (Garca-Fernandez et al.,
2013). Santos and co-workers copolymerized hydroxyethyl
methacrylate with a methacrylated-beta-CD to tailor mech-
anical, drug (hydrocortisone and acetazolamide) loading and
release rate from hydrogel contact lenses. They also observed
changes in swelling and storage moduli, with increase in beta-
CD in contact lenses (Dos Santos et al., 2008). Contact lenses
functionalized with cyclodextrins for controlled drug delivery
have been generated by Jose-Fernando and co-workers.
Hydrogels were copolymerized with glycidyl methacrylate
(GMA) and grafted with b-cyclodextrin (b-CD). The b-CDs
do not participate or interfere in the hydrogel fabrication
process, and thus do not significantly change the optical and
physical properties of hydrogel matrix. Improvement in drug
(diclofenac) loading by 1300% and sustained drug delivery up
to two weeks was detected in lacrimal fluids (Dos Santos
et al., 2009). Antimicrobial (5,6-dimethoxy-1- indanone N-4-
allyl thiosemicarbazone) therapeutic contact lenses were
developed by Romina J. Glisoni and co-workers, by engin-
eering pHEMA-co-b-CD, to deliver antimicrobial agent for 2
weeks. Uptake and release profiles were influenced by
proportion of b-CD units, mesh size, and degree of swelling
of hydrogels (Glisoni et al., 2013). Arslan and co-workers
Drug Deliv, 2016; 23(8): 30173026
achieved controlled release of puerarin from hydrogels
fabricated using thiol-modified b-cyclodextrin and allyl-
terminated PEGs via the radical thiolene click chemistry.
The swelling, morphology and rheological behavior of
hydrogels were modified by tailoring the PEG chain length
or by varying the amount of b-CD cross-linker (Arslan et al.,
2015). Xiaohong improved the performance of hydrogels for
ocular drug delivery by using b-cyclodextrin functionalized
hydrogels. Along with sustained drug delivery, b-CD
functionalization hydrogels also showed increase in hydro-
philicity and reduction in protein adherence (Hu et al., 2016).
Liposomes
Liposomes are biocompatible and biodegradable, due to their
biological membrane-like structure and used in numerous
drug delivery applications including ophthalmic drug delivery
through contact lenses. Derya Gulsen encapsulated lidocaine-
loaded dimyristoyl phosphatidylcholine liposomes in the
contact lens material. The results show that the hydrogel
laden liposomes are transparent and releases lidocaine for a
period of about eight days (Gulsen et al., 2005). Drug-eluting
contact lenses prepared by Roonal (Jain & Shastri, 2011)
using ciprofloxacin-loaded unilamellar liposomes (RELs) and
multilamellar liposomes (MLs), were prepared using reverse-
phase evaporation and lipid film hydration method respect-
ively. ML liposomes showed greater sustained release in
comparison to REL liposomes, because of the presence of
several lipid bilayers. Also, the amount of drug entrapped and
released was found to be affected by cholesterol content.
Danion immobilized levofloxacin-liposomes on contact lens.
In step 1 polyethylenimine was covalently bound onto the
hydroxyl groups present on surface contact lens, followed by
attachment of NHS-PEG-biotin molecules onto the surface
amine groups by carbodiimide chemistry. In step 2,
NeutrAvidin was bonded onto the polyethylene glycol
(PEG)-biotin layer, and liposomes containing PEG-biotiny-
lated lipids were docked onto the surface-immobilized
NeutrAvidin. Subsequent addition of further NeutrAvidin
and liposome layers enabled formation of multilayers (Danion
et al., 2007b; Guzman-Aranguez et al., 2013). Liposome-
laden contact lenses were found to be biocompatible in
cytotoxicity study (Danion et al., 2007c). Hydrogel contact
lenses with two layers of liposomes showed drug release up to
30 hours, while with 10 layers the drug was released up to 120
hours (Danion et al., 2007a). Though liposomes laden contact
lenses showed promising results in extended drug delivery,
the presence of multilayer liposomes decreased oxygen and
carbon dioxide permeability.
Microemulsion and micelles
Drug-loaded microemulsion and micelles laden therapeutic
contact lenses showed promising results, due to their
thermodynamic stability, easy preparation, high drug-loading
capacity, increased wettability (low protein adherence) and
easy tailoring of drug release pattern. Due to nano size
(5100 nm) the optical property of hydrogels remained
unaltered.
Many researchers focused on the use of microemulsions.
Chi-Chung developed timolol-contact lenses with o/w type
DOI: 10.3109/10717544.2016.1138342
microemulsions using ethyl butyrate and Pluronic F127. The
microemulsion showed controlled release of timolol, due to
the presence of a tightly packed surfactant at the oilwater
interface (Li et al., 2007). Lokendrakumar and co-workers
developed ACUVUE contact lenses with ionic surfactants to
increase the affinity of ionic dexamethasone 21-disodium
phosphate on the charged surface of contact lens. The
presence of surfactant did not alter the optical property of
the contact lenses, and also had the advantage of increase in
wettability, i.e. reduction in protein absorption on contact lens
surface. With 10% surfactant loading, the drug release
duration was increased from 2 h to 50 h, demonstrating the
viability of using surfactant to increase drug-release durations
(Bengani & Chauhan, 2013). Derya Gulsen encapsulated
timolol in microemulsion which was further stabilized with a
silica shell using octadecyltrimethoxysilane (OTMS), fol-
lowed by dispersion in hydrogels. The fabricated hydrogels
showed extended drug release over eight days without
affecting the transparency of hydrogels (Gulsen & Chauhan,
2005). Yash Kapoor and co-workers developed nanostruc-
tured microemulsions or micelles of Brij 97 laden hydrogels
for extended delivery of cyclosporine. The in-vitro release
profiles for both micelles and microemulsion-laden hydrogels
were relatively similar, with parallel surfactant loading. The
article also claims that the developed hydrogels retained their
effectiveness even after exposure to all the processing
conditions like removal of un-reacted monomers (extraction
step), sterilization and packaging (Kapoor & Chauhan,
2008b).
Hydrogel contact lenses loaded with silica shell cross-
linked methoxy(polyethylene glycol)-block-polycaprolactone
(MePEG-b-PCL) micelles (rod-like morphology) were devel-
oped by Changhai Lu, for sustained release of dexamethasone
acetate. Drug was loaded into the silica shell micelles before
fabricating the hydrogels. In-vitro release study showed
extended release over a month without altering transparency
of hydrogel material for contact lens wear (Lu et al., 2013).
Using Brij 98 as the surfactant, Kapoor and co-workers
developed and validated a model by varying hydrogel
thickness and surfactant loading, to tune the drug release
rates from drug-surfactant-hydrogels. The model proposed
that, increase in surfactant loading by four fold, can cause
reduction in percentage release by two folds (Kapoor &
Chauhan, 2008a). To increase the bioavailability of cyclo-
sporine, Chauhan and co-workers developed Brij-laden
hydrogels that can release drug at a controlled rate. The
hydrogels were found to be effective for cyclosporine, but not
as effective for dexamethasone and dexamethasone 21 acetate
because of lower partitioning inside the surfactant aggregates-
laden contact lenses (Kapoor et al., 2009). Yu Jin Cho and co-
workers successfully reduced protein adsorption on hydrogel
material by synthesizing a novel tri-branched PEG-substituted
hydrazide on hydrogel materials (Cho & Jee, 2015).
Use of vitamin E
To improve the drug-release duration, Chauhan and his co-
workers proposed an approach of in-situ creation of Vitamin
E as transport barriers for drug molecules. The release of
timolol was significantly extended by increasing Vitamin E
Review on ocular drug delivery 3021
loading from 10 to 40% in contact lenses, while at the same
time complicating oxygen and ion permeability (Peng et al.,
2010). Jinah and co-workers developed dexamethasone con-
tact lenses with 30% Vitamin E loading. The drug-release
duration was extended for 9 days, which was 16 folds higher
compared to the drug-release duration by contact lens without
Vitamin E (Kim et al., 2010). Cheng-Chun Peng also
developed cyclosporine-laden contact lenses, using Vitamin
E as barrier. The in-vitro flux results showed sustained drug
release for about a month, using silicon hydrogel contact
lenses, due to high partition coefficient of drug in gel, in
comparison to hydrogel ACUVUE lens, which showed
release for only 24 hrs (due to hydrophilic nature). Such
silicon contact lenses demonstrate the promising potential of
delivering cyclosporine for the treatment of chromic dry eyes
(Peng & Chauhan, 2011). Kuan-Hui Hsu and co-workers
incorporated vitamin E as diffusion barriers into the contact
lenses to increase the release duration of cysteamine. They
observed that loading vitamin E increases the release duration
from 10 min to 3 h, thus allowing the possibility of extended
drug delivery. In addition to control of drug-release rate,
vitamin E also prevented oxidation of cysteamine (Hsu et al.,
2013). Cheng-Chun Peng used nano sized hydrophobic
vitamin E aggregates as diffusion barrier in silicone contact
lenses to extend the release duration for 7 days, for charged (at
physiologic pH) esthetic drugs (lidocaine, bupivacaine, and
tetracaine). The developed therapeutic contact lenses can be
useful for post-operative pain, after photorefractive keratec-
tomy surgery (Peng et al., 2011). Cheng also incorporated
vitamin E as a diffusion barrier in ACUVUE TruEye
contact lenses. They found significant reduction in IOP in
beagle dogs, with only 20% of drug dose when compared with
eye drops therapy (Peng et al., 2012). Kuan-Hui Hsu and co-
workers developed drug-eluting contact lenses for treatment
of glaucoma by releasing two drugs (timolol and dorzola-
mide) from single contact lens. The sustained drug release
was achieved by using vitamin E as physical barrier (Hsu
et al., 2015).
Vitamin E, due to its powerful anti-oxidant property
protects cornea from UV radiations, and also prevents
oxidation of many susceptible drugs. (Nagata et al., 1999;
Bilgihan et al., 2001; Ylmaz et al., 2007) Although vitamin E
was found to be a promising biocompatible diffusion barrier,
which retards the release of many hydrophilic drugs, the
researchers should keep in mind the limitations of vitamin E,
such as reduction in ion permeability, oxygen permeability,
increase in storage module, i.e. change in mechanical
properties, protein adsorption due to hydrophobic nature of
vitamin E, etc. which may limit the use of vitamin E for
development of therapeutic contact lenses.
Supercritical fluid technology
Supercritical fluid technology (SCF) is one of the most-
effective technologies to load/impregnate both hydrophilic
and hydrophobic drug in contact lenses using supercritical
solvent like CO2. Impregnation process involve dissolution of
drug in supercritical solvent like CO2 (at subcritical or
supercritical conditions), followed by interaction with hydro-
gel contact lenses. The drug loading amount and its release
3022 F. A. Maulvi et al.
kinetics are controlled by tailoring operational parameters like
pressure, temperature, processing time and depressurization
rate.
Viviana P. Costa impregnated acetazolamide and timolol
maleate in Balafilcon A contact lenses using a discontinuous
supercritical solvent (CO2 + EtOH and CO2 +H2O) impreg-
nation (SSI) methodology. By modifying the co-solvent type
and/or its composition, different level of drug impregnation is
possible, which can tailor the amount of drug loading and
release pattern from the contact lenses without altering the
optical and physical properties (Costa et al., 2010a). To
overcome the limited application of soaking (can be used for
water soluble drugs only) and molecular imprinting tech-
niques, Fernando Yanez developed novel supercritical fluid
(SCF)-assisted molecular imprinting technique to endow
contact lenses (Hilafilcon B) with the ability to load specific
drugs and to control/tailor their release profile. Flurbiprofen-
loading capacity was increased by sequential SCF flurbipro-
fen impregnation. The process showed a recognition ability
and higher affinity for flurbiprofen in aqueous solution than
for the structurally-related ibuprofen and dexamethasone,
which propose the formation of molecularly imprinted
cavities driven by both physical and chemical interactions.
Application of SCF technique, did not alter the critical
functional properties of contact lens and showed improved
drug loading and extended release, in comparison to conven-
tional molecular imprinting methodology (Yanez et al., 2011).
Viviana also studied the effects and interactions of different
polymers (hydrogels), operational pressure, impregnation
duration and addition of a co-solvent (ethanol) on overall
drug loading (amount/yield) in supercritical solvent impreg-
nation technology (SSI). The author demonstrated that, drug
impregnation can be easily controlled by tailoring operational
conditions, without altering critical lens properties. Such
therapeutic contact lenses can be used for extended delivery
of both hydrophilic and hydrophobic drugs (Costa et al.,
2010b). Ana Rita fabricated molecularly imprinted contact
lenses of two template drugs (salicylic acid and acetylsalicylic
acid) using supercritical fluid technology. Poly(diethylene
glycol dimethacrylate) was synthesized using supercritical
CO2 and carboxylic acid end-capped perfluoropolyether oil as
stabilizer. The release profile data suggested a correlation
between the amount of drug present during the fabrication
step, the percentage of impregnated drug and hence the drug
release rate (Duarte et al., 2006). Ana Rita also impregnated
flurbiprofen in poly(methyl methacrylate-co ethyl hexyl
acrylate co- ethylene glycol dimethacrylate), P(MMA-EHA-
EGDMA) contact lens matrix, and achieved controlled release
for 3 months (Duarte et al., 2007). Yuta and co-workers
investigated the influence of temperature and pressure on
impregnation of salicylic acid using supercritical CO2. They
observed that, increase in temperature and low pressure
during impregnation process lead to sustained drug delivery
from the contact lenses (Yokozaki et al., 2015).
Other techniques
To circumvent the alterations in optical property of contact
lenses, Ciolino and co-workers impregnated ciprofloxacin-
PLGA (poly[lactic-co-glycolic acid]) films in contact lenses.
Drug Deliv, 2016; 23(8): 30173026
Prototype contact lenses showed nominal initial burst release
and demonstrated controlled release for 4 weeks under
infinite sink conditions. The release rate from lenses was
tailored by changing the drug: PLGA ratios (Ciolino et al.,
2009). Later on, they designed latanoprost-eluting contact
lens for the treatment of glaucoma, by encapsulating film in
methafilcon lenses. In-vivo results showed sustained release
for one month. Though the issues associated with alterations
in mechanical properties, ion and oxygen permeability,
protein adherence, etc. are yet to be addressed (Ciolino
et al., 2014).
To overcome the limitation of drug release during storage
and the loss in mechanical properties, Ho-Joong Kim
embedded timolol-loaded Nano-Diamond in contact lenses,
which releases timolol only in presence of lysozyme
(enzyme-triggered chitosan degradation) (Kim et al., 2014).
Koji Kakisu and co-workers investigated the uptake and
release of gatifloxacin and moxifloxacin from novel synthe-
sized hydrogel contact lenses (anionic group monomers)
using an ion ligand mechanism. Antibiotic uptake and release
duration was increased with increase in anionic group
monomers in hydrogels. Burst release was observed with all
the batches at initial hour, followed by sustained release up to
72 h. In-vivo results showed improvement in penetration of
drug into the eye, as well as prevention of bacterial
proliferation, in comparison to eye drop therapy (Kakisu
et al., 2013). Isabelle and co-workers grafted nisin (an
antimicrobial peptide) on hyaluronic acid to achieve an
antimicrobial biopolymer in various applications such as
wound dressings, contacts lenses, cosmetics formulations, etc.
The grafted biomaterial showed antimicrobial activity against
Staphylococcus epidermidis, S. aureus and P. aeruginosa
(Lequeux et al., 2014). P. Ferreira and co-workers developed a
new vancomycin chlorhydrate-eluting contact lens to prevent
inflammation after corneal substitution (keratoprosthesis)
(Carreira et al., 2014). Table 1 summarizes the methodologies
used to develop therapeutic contact lenses for ocular drug
delivery with limitations.
Conclusion
The therapeutic contact lenses are an excellent alternative to
treat chronic ocular diseases, due to their ability to release the
drug for extended period of time. In the last 25 years, many
novel drug delivery systems have been developed to increase
the drug-loading capacity and control the drug-release rate.
However the commercialization of such products is still
limited. Researchers need to address the issues like impact on
critical lens properties such as transparency, mechanical
property, water content, ion and oxygen permeability for
comfort day and night wear contact lenses. Also issues like
lack of drug stability during processing/fabrication (drug
integrity test), zero-order release kinetics (prevention of burst
release), drug release during monomer extraction step, protein
adherence, drug release during storage in packaging solution,
shelf-life study, cost-benefit analysis, etc. need to be
addressed. Further advancement and improvement in contact
lens technology is expected to develop to optimize therapeutic
contact lenses, which can be used for extended period of time,
without altering optical and physical properties. Once these
Table 1. Summary of methodology used in drug delivery by contact lenses.

Methodology Model drug Findings/Results Comments/Notes Reference

Soaking method Triamcinolone acetonide Simple and cost effective method. Improved drug High burst release. (Garca-Millan et al., 2015)
loading capacity, by optimizing hydrogel com- Drug release up to 24 hours.
position and micro structure modification using
water during polymerization step. Incorporation
of 40% v/v of water in hydrogel showed highest
DOI: 10.3109/10717544.2016.1138342

drug loading.

Soaking method Hyaluronic acid (HA) Surface adsorption of high molecular weight poly- Low affinity of HA for contact (Maulvi et al., 2015)
mer (HA). No significant alterations in critical lens.
lens property. First order release kinetics.

Molecular imprinting
Polymeric nanoparticles
Polymeric nanoparticles
Aminoglutethimide High drug loading. Crowding-assisted molecularly
imprinted contact lenses using polystyrene. Zero
order release kinetics. Sustained drug delivery up to
18 hours.
Meloxicam Developed bovine serum albumin-coated meloxicam
nanocrystals laden contact lenses to treat postcatar-
act endophthalmitis. Exhibited reduction in ocular
irritancy and sustained drug delivery for five days
Timolol Dispersed timolol loaded propoxylated glyceryl
triacylate nanoparticles in contact lenses. One
month release (in vitro). Reduction in IOP
(Beagle dogs study).
Testing mechanical property of (Tang et al., 2015)
lenses is required. Changes in
dimension after drug leaching.
Presence of nanoparticles showed (Zhang et al., 2014)
reduction in storage modulus and
swelling behavior.
Reduction in both ion and oxygen (Jung et al., 2013)
permeability.
Increase in storage modulus.

Cyclodextrins Puerarin Fabricated poly(ethylene glycol) (PEG) based chem- Need sufficient in vivo data, to (Arslan et al., 2015)
ically cross-linked hydrogels containing discrete prove the efficacy and safety of
b-cyclodextrin. Controlled release up to 8 hours. hydrogels.
Cyclodextrins Orfloxacin Improved the performance of hydrogels for ocular Testing mechanical property of (Hu et al., 2016)
drug delivery by using b-cyclodextrin functionalized contact lenses is required.
hydrogels. Increased hydrophilicity and reduce pro-
tein adherence.
Liposomes Ciprofloxacin Biocompatible and biodegradable. Better control of Presence of multilayer liposomes (Jain & Shastri, 2011)
release rate. Multilamellar liposomes showed greater decreased oxygen and carbon diox-
sustained release in comparison to unilamellar ide permeability.
liposomes. Drug release was affected by cholesterol
content.
Microemulsion Timolol Ethyl butyrate/water microemulsions stabilized by Rapid release of drug in saline and (Li et al., 2007)
Pluronic F127. Controlled release up to weeks in buffer media.
distilled water. High drug loading was achieved.
Microemulsion Timolol High drug loading using microemulsion, which was Need to establish animal safety (Gulsen & Chauhan, 2005)
further stabilized with silica shell coating. data.

(continued )
Review on ocular drug delivery
3023
3024 F. A. Maulvi et al. Drug Deliv, 2016; 23(8): 30173026

issues are resolved, the therapeutic contact lenses will change

the way ocular diseases are treated.

(Yokozaki et al., 2015)

(Ciolino et al., 2014)

Reference
Declaration of interest

(Kim et al., 2014)

(Hsu et al., 2015)
The authors report no conflicts of interest and have no
proprietary or commercial interests in any concept or product
or material discussed in this paper.

References
Ali M, Byrne ME. (2009). Controlled release of high molecular weight

permeability, mechanical property,

rate profile could be observed, as

Studies like mechanical properties,

needed, to confirm the effective-

Need supporting data of oxygen

from person to person and diseases

status. Lack of in vivo data to
ion and oxygen permeability are

Intra subject variability in release

the level of lysozyme may vary

hyaluronic acid from molecularly imprinted hydrogel contact lenses.

effect of packaging solution, etc.

Pharm Res 26:71426.
Ali M, Horikawa S, Venkatesh S, et al. (2007). Zero-order therapeutic
Comments/Notes

release from imprinted hydrogel contact lenses within in vitro

Drug release up to 8 h.

physiological ocular tear flow. J Control Release 124:15462.

Alvarez-Lorenzo C, Hiratani H, Concheiro A. (2006a). Contact lenses
for drug delivery. Am J Drug Deliv 4:13151.

support concept.
ness of system.

Alvarez Lorenzo C, Hiratani H, Gomez Amoza JL, et al. (2002). Soft

contact lenses capable of sustained delivery of timolol. J Pharm Sci
91:218292.
Alvarez-Lorenzo C, Yanez F, Barreiro-Iglesias R, Concheiro A. (2006b).
Imprinted soft contact lenses as norfloxacin delivery systems.
J Control Release 113:23644.
Andrade Vivero P, Fernandez Gabriel E, Alvarez Lorenzo C, Concheiro
A. (2007). Improving the loading and release of NSAIDs from
pHEMA hydrogels by copolymerization with functionalized mono-
trolled drug delivery. Reduction in IOP for 4 days

Designed latanoprost-eluting contact lens. In-vivo

by cross-linking polyethyleneimine coated nano-

diamonds and partially N-acetylated chitosan. Delay
resulted in sustained release from contact lens.

results showed sustained release for one month. The

contact lens appeared safe in both cell culture and

Synthesized timolol loaded nano-diamond nanogels

Extended drug release over 8 days without affecting

Simultaneous loading of timolol and dorzolamide.

Inclusion of Vitamin E aggregates showed con-

Improved drug loading capacity. Higher temperature

and low pressure in the impregnation process

release up to 48 h was noted in presence of lacrimal

mers. J Pharm Sci 96:80213.

Arslan M, Gevrek TN, Sanyal R, Sanyal A. (2015). Fabrication of poly
(ethylene glycol)-based cyclodextrin containing hydrogels via thiol-
ene click reaction. Eur Polym J 62:42634.
Table 1. Continued

Bazzaz BSF, Khameneh B, Jalili-Behabadi MM, et al. (2014).

Preparation, characterization and antimicrobial study of a hydrogel
Findings/Results

the optical property of hydrogels.

(soft contact lens) material impregnated with silver nanoparticles.

Cont Lens Anterior Eye 37:14952.
was observed in Beagle dog.

Bengani LC, Chauhan A. (2013). Extended delivery of an anionic drug

Fickian controlled release.

by contact lens loaded with a cationic surfactant. Biomaterials 34:

281421.
Bengani LC, Hsu KH, Gause S, Chauhan A. (2013). Contact lenses as a
platform for ocular drug delivery. Expert Opin Drug Deliv 10:
fluid lysozyme.
animal studies.

148396.
Bilgihan K, Adiguzel U, Sezer C, et al. (2001). Effects of topical vitamin
E on keratocyte apoptosis after traditional photorefractive keratec-
tomy. Ophthalmologica 215:1926.
Burns E, Mulley G. (1992). Practical problems with eye-drops among
elderly ophthalmology outpatients. Age Ageing 21:16870.
Byrne ME, Salian V. (2008). Molecular imprinting within hydrogels II:
Progress and analysis of the field. Int J Pharm 364:188212.
Timolol and Dorzolamide

Carreira A, Ferreira P, Ribeiro M, et al. (2014). New drug-eluting lenses

to be applied as bandages after keratoprosthesis implantation. Int J
Pharm 477:21826.
Model drug

Carvalho I, Marques C, Oliveira R, et al. (2015). Sustained drug release

by contact lenses for glaucoma treatment a review. J Control Release
Salicylic acid

202:7682.
Latanoprost

Chandasana H, Prasad YD, Chhonker YS, et al. (2014). Corneal targeted

Timolol

nanoparticles for sustained natamycin delivery and their PK/PD

indices: An approach to reduce dose and dosing frequency. Int J
Pharm 477:31725.
Cho, YJ, Jee, JP. (2015). Hydrogel lenses functionalized with surface-
immobilized PEG layers for reduction of protein adsorption. Asian J
Pharm Sci.
Impregnation of film in contact
Supercritical fluid technology

Chrai SS, Makoid MC, Eriksen SP, Robinson JR. (1974). Drop size and
initial dosing frequency problems of topically applied ophthalmic
drugs. J Pharm Sci 63:3338.
Ciolino JB, Hoare TR, Iwata NG, et al. (2009). A drug-eluting contact
lens. Invest Ophthalmol Vis Sci 50:334652.
Enzyme triggered

Ciolino JB, Stefanescu CF, Ross AE, et al. (2014). In vivo performance
Methodology

of a drug-eluting contact lens to treat glaucoma for a month.

Vitamin E

Biomaterials 35:4329.
Costa VP, Braga ME, Duarte CM, et al. (2010a). Anti-glaucoma drug-
loaded contact lenses prepared using supercritical solvent impregna-
lens

tion. J Supercrit Fluids 53:16573.

DOI: 10.3109/10717544.2016.1138342
Costa VP, Braga ME, Guerra JP, et al. (2010b). Development of
therapeutic contact lenses using a supercritical solvent impregnation
method. J Supercrit Fluids 52:30616.
Creech J, Chauhan A, Radke C. (2001). Dispersive mixing in the
posterior tear film under a soft contact lens. Ind Eng Chem Res 40:
301526.
Danion A, Arsenault I, Vermette P. (2007a). Antibacterial activity of
contact lenses bearing surface-immobilized layers of intact liposomes
loaded with levofloxacin. J Pharm Sci 96:235063.
Danion A, Brochu H, Martin Y, Vermette P. (2007b). Fabrication and
characterization of contact lenses bearing surface-immobilized layers
of intact liposomes. J Biomed Mater Res A 82:4151.
Danion A, Doillon CJ, Giasson CJ, et al. (2007c).
Biocompatibility and light transmission of liposomal lenses. Optom
Vis Sci 84:95461.
Del Amo EM, Urtti A. (2008). Current and future ophthalmic drug
delivery systems. A shift to the posterior segment. Drug Discov Today
13:13543.
Ding S. (1998). Recent developments in ophthalmic drug delivery.
Pharm Sci Tech Today 1:32835.
Dos Santos JFR, Alvarez-Lorenzo C, Silva M, et al. (2009). Soft contact
lenses functionalized with pendant cyclodextrins for controlled drug
delivery. Biomaterials 30:134855.
Dos Santos JFR, Couceiro R, Concheiro A, et al. (2008). Poly
(hydroxyethyl methacrylate-co-methacrylated-b-cyclodextrin) hydro-
gels: Synthesis, cytocompatibility, mechanical properties and drug
loading/release properties. Acta Biomaterialia 4:74555.
Duarte ARC, Casimiro T, Aguiar-Ricardo A, et al. (2006). Supercritical
fluid polymerisation and impregnation of molecularly imprinted
polymers for drug delivery. J Supercrit Fluids 39:1026.
Duarte ARC, Simplicio AL, Vega-Gonzalez A, et al. (2007).
Supercritical fluid impregnation of a biocompatible polymer for
ophthalmic drug delivery. J Supercrit Fluids 42:3737.
Fechtner RD, Realini T. (2004). Fixed combinations of topical glaucoma
medications. Curr Opin Ophthalmol 15:1325.
Frishman W, Kowalski M, Nagnur S, et al. (2000). Cardiovascular
considerations in using topical, oral, and intravenous drugs for the
treatment of glaucoma and ocular hypertension: focus on beta-
adrenergic blockade. Heart Dis 3:38697.
Garca-Fernandez M, Tabary N, Martel B, et al. (2013). Poly-(cyclo)
dextrins as ethoxzolamide carriers in ophthalmic solutions and in
contact lenses. Carbohydr Polym 98:134352.
Garca-Millan E, Koprivnik S, Otero-Espinar FJ. (2015). Drug loading
optimization and extended drug delivery of corticoids from pHEMA
based soft contact lenses hydrogels via chemical and microstructural
modifications. Int J Pharm 487:2609.
Gaudana R, Ananthula HK, Parenky A, Mitra AK. (2010). Ocular drug
delivery. AAPS J 12:34860.
Glisoni RJ, Garca-Fernandez MJ, Pino M, et al. (2013). b-Cyclodextrin
hydrogels for the ocular release of antibacterial thiosemicarbazones.
Carbohydr Polym 93:44957.
Gonzalez-Chomon C, Concheiro A, Alvarez-Lorenzo C. (2013). Soft
contact lenses for controlled ocular delivery: 50 years in the making.
Ther Deliv 4:114161.
Gulsen D, Chauhan A. (2004). Ophthalmic drug delivery through contact
lenses. Invest. Ophthalmol Vis Sci 45:23427.
Gulsen D, Chauhan A. (2005). Dispersion of microemulsion drops in
HEMA hydrogel: a potential ophthalmic drug delivery vehicle. Int J
Pharm 292:95117.
Gulsen D, Li CC, Chauhan A. (2005). Dispersion of DMPC liposomes
in contact lenses for ophthalmic drug delivery. Curr Eye Res 30:
107180.
Gupta C, Chauhan A. (2010). Drug transport in HEMA conjunctival
inserts containing precipitated drug particles. J Colloid Interface Sci
347:3142.
Guzman-Aranguez A, Colligris B, Pintor J. (2013). Contact lenses:
promising devices for ocular drug delivery. J Ocul Pharmacol Ther 29:
18999.
Hehl EM, Beck R, Luthard K, et al. (1999). Improved penetration of
aminoglycosides and fluoroquinolones into the aqueous humour of
patients by means of Acuvue contact lenses. Eur J Clin Pharmacol 55:
31723.
Hiratani H, Fujiwara A, Tamiya Y, et al. (2005a). Ocular release of
timolol from molecularly imprinted soft contact lenses. Biomaterials
26:12938.
Review on ocular drug delivery 3025
Hiratani H, Mizutani Y, Alvarez -Lorenzo C. (2005b). Controlling drug
release from imprinted hydrogels by modifying the characteristics of
the imprinted cavities. Macromol Biosci 5:72833.
Hsu KH, Carbia BE, Plummer C, Chauhan A. (2015). Dual drug delivery
from vitamin E loaded contact lenses for glaucoma therapy. Eur J
Pharm Biopharm 94:31221.
Hsu KH, Fentzke RC, Chauhan A. (2013). Feasibility of corneal drug
delivery of cysteamine using vitamin E modified silicone hydrogel
contact lenses. Eur J Pharm Biopharm 85:53140.
Hsu KH, Gause S, Chauhan A. (2014). Review of ophthalmic drug
delivery by contact lenses. J Drug Deliv Sci Technol 24:12335.
Hu X, Tan H, Wang X, Chen P. (2016). Surface functionalization of
hydrogel by thiol-yne click chemistry for drug delivery. Colloids Surf
A Physicochem Eng Asp 489:297304.
Hull DS, Edelhauser HF, Hyndiuk RA. (1974). Ocular penetration of
prednisolone and the hydrophilic contact lens. Arch Ophthalmol 92:
4136.
Jain M. (1988). Drug delivery through soft contact lenses. Br J
Ophthalmol 72:1504.
Jain RL, Shastri J. (2011). Study of ocular drug delivery system using
drug-loaded liposomes. Int J Pharm Investig 1:3541.
Jung HJ, Abou-Jaoude M, Carbia BE, et al. (2013). Glaucoma therapy by
extended release of timolol from nanoparticle loaded silicone-
hydrogel contact lenses. J Control Release 165:829.
Jung HJ, Chauhan A. (2012). Temperature sensitive contact lenses for
triggered ophthalmic drug delivery. Biomaterials 33:2289300.
Kakisu K, Matsunaga T, Kobayakawa S, et al. (2013). Development and
efficacy of a drug-releasing soft contact lens. Invest Ophthalmol Vis
Sci 54:255161.
Kapoor Y, Chauhan A. (2008a). Drug and surfactant transport in
Cyclosporine A and Brij 98 laden p-HEMA hydrogels. J Colloid
Interface Sci 322:62433.
Kapoor Y, Chauhan A. (2008b). Ophthalmic delivery of Cyclosporine A
from Brij-97 microemulsion and surfactant-laden p-HEMA hydrogels.
Int J Pharm 361:2229.
Kapoor Y, Thomas JC, Tan G, et al. (2009). Surfactant-laden soft contact
lenses for extended delivery of ophthalmic drugs. Biomaterials 30:
86778.
Karlgard C, Wong N, Jones L, Moresoli C. (2003). In vitro uptake and
release studies of ocular pharmaceutical agents by silicon-containing
and p-HEMA hydrogel contact lens materials. Int J Pharm 257:
14151.
Kim HJ, Zhang K, Moore L, Ho D. (2014). Diamond nanogel-embedded
contact lenses mediate lysozyme-dependent therapeutic release. ACS
Nano 8:29983005.
Kim J, Chauhan A. (2008). Dexamethasone transport and ocular delivery
from poly (hydroxyethyl methacrylate) gels. Int J Pharm 353:20522.
Kim J, Conway A, Chauhan A. (2008). Extended delivery of ophthalmic
drugs by silicone hydrogel contact lenses. Biomaterials 29:225969.
Kim J, Peng CC, Chauhan A. (2010). Extended release of dexametha-
sone from silicone-hydrogel contact lenses containing vitamin E.
J Control Release 148:1106.
Lang JC. (1995). Ocular drug delivery conventional ocular formulations.
Adv Drug Deliv Rev16:3943.
Lequeux I, Ducasse E, Jouenne T, Thebault P. (2014). Addition of
antimicrobial properties to hyaluronic acid by grafting of antimicro-
bial peptide. Eur Polym J 51:18290.
Lesher GA, Gunderson GG. (1993). Continuous drug delivery through
the use of disposable contact lenses. Optom Vis Sci 70:10128.
Li CC, Abrahamson M, Kapoor Y, Chauhan A. (2007). Timolol transport
from microemulsions trapped in HEMA gels. J Colloid Interface Sci
315:297306.
Li CC, Chauhan A. (2006). Modeling ophthalmic drug delivery by
soaked contact lenses. Ind Eng Chem Res 45:371834.
Li C, Chauhan A. (2007). Ocular transport model for ophthalmic
delivery of timolol through p-HEMA contact lenses. J Drug Deliv Sci
Technol 17:6979.
Loftsson T, Masson M, Brewster ME. (2004). Self-association of
cyclodextrins and cyclodextrin complexes. J Pharm Sci 93:10919.
Lu C, Yoganathan RB, Kociolek M, Allen C. (2013). Hydrogel
containing silica shell cross-linked micelles for ocular drug delivery.
J Pharm Sci 102:62737.
Malakooti N, Alexander C, Lorenzo-Alvarez C. (2015). Imprinted
Contact Lenses for Sustained Release of Polymyxin B and Related
Antimicrobial Peptides. J Pharm Sci 104:338694.
3026 F. A. Maulvi et al.
Maulvi FA, Soni TG, Shah DO. (2014). Effect of timolol maleate
concentration on uptake and release from hydrogel contact lenses
using soaking method. J Pharm Appl Sci 1:1723.
Maulvi FA, Soni TG, Shah DO. (2015). Extended release of hyaluronic
acid from hydrogel contact lenses for dry eye syndrome. J Biomater
Sci Polym Ed 26:103550.
Mcnamara NA, Polse KA, Brand RJ, et al. (1999). Tear mixing under a
soft contact lens: effects of lens diameter. Am J Ophthalmol 127:
65965.
Nagata M, Kojima M, Sasaki K. (1999). Effect of vitamin E eye drops on
naphthalene-induced cataract in rats. J Ocul Pharmacol Ther 15:
34550.
Nicolson PC, Vogt J. (2001). Soft contact lens polymers: an evolution.
Biomaterials 22:327383.
Patel, SC, Spaeth, GL. (1995). Compliance in patients prescribed
eyedrops for glaucoma. Ophthalmic Surg Lasers Imaging 26:2336.
Peng CC, Burke MT, Carbia BE, et al. (2012). Extended drug
delivery by contact lenses for glaucoma therapy. J Control Release
162:1528.
Peng CC, Burke MT, Chauhan A. (2011). Transport of topical
anesthetics in vitamin E loaded silicone hydrogel contact lenses.
Langmuir 28:147887.
Peng CC, Chauhan A. (2011). Extended cyclosporine delivery by
silicone-hydrogel contact lenses. J Control Release 154:26774.
Peng CC, Kim J, Chauhan A. (2010). Extended delivery of hydrophilic
drugs from silicone-hydrogel contact lenses containing vitamin E
diffusion barriers. Biomaterials 31:403247.
Peterson RC, Wolffsohn JS, Nick J, et al. (2006). Clinical performance of
daily disposable soft contact lenses using sustained release technol-
ogy. Cont Lens Anterior Eye 29:12734.
Prausnitz MR, Noonan JS. (1998). Permeability of cornea, sclera, and
conjunctiva: a literature analysis for drug delivery to the eye. J Pharm
Sci 87:147988.
Ruben M, Watkins R. (1975). Pilocarpine dispensation for the soft
hydrophilic contact lens. Br J Ophthalmol 59:4558.
Schrader S, Wedel T, Moll R, Geerling G. (2006). Combination of serum
eye drops with hydrogel bandage contact lenses in the treatment of
persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol 244:
13459.
Schultz CL, Poling TR, Mint JO. (2009). A medical device/drug delivery
system for treatment of glaucoma. Clin Exp Optom 92:3438.
Sedlacek J. (1999). Possibilities of application of eye drugs with the aid
of gel contact lenses. Cesk Oftalmol 21:50912.
Shah C, Raj C, Foulks GN. (2003). The evolution in therapeutic contact
lenses. Ophthalmol Clin North Am 16:95101.
Shell JW. (1982). Pharmacokinetics of topically applied ophthalmic
drugs. Surv Ophthalmol 26:20718.
Sklubalova Z, Zatloukal Z. (2005). Systematic study of factors
affecting eye drop size and dosing variability. Die Pharmazie 60:
91721.
Soluri A, Hui A, Jones L. (2012). Delivery of ketotifen fumarate by
commercial contact lens materials. Optom Vis Sci 89:11409.
Drug Deliv, 2016; 23(8): 30173026
Stone JL, Robin AL, Novack GD, et al. (2009). An objective evaluation
of eyedrop instillation in patients with glaucoma. Arch. Ophthalmol
127:7326.
Tang L, Zhao CY, Wang XH, et al. (2015). Macromolecular crowding of
molecular imprinting: a facile pathway to produce drug delivery
devices for zero-order sustained release. Int J Pharm 496:82233.
Tieppo A, Pate KM, Byrne ME. (2012). In vitro controlled release of an
anti-inflammatory from daily disposable therapeutic contact lenses
under physiological ocular tear flow. Eur J Pharm Biopharm 81:
1707.
Urtti A. (2006). Challenges and obstacles of ocular pharmacokinetics
and drug delivery. Adv Drug Deliv Rev 58:11315.
Venkatesh S, Saha J, Pass S, Byrne ME. (2008). Transport and structural
analysis of molecular imprinted hydrogels for controlled drug
delivery. Eur J Pharm Biopharm 69:85260.
Venkatesh S, Sizemore SP, Byrne ME. (2007). Biomimetic hydrogels for
enhanced loading and extended release of ocular therapeutics.
Biomaterials 28:71724.
White C, Tieppo A, Byrne M. (2011a). Controlled drug release from
contact lenses: a comprehensive review from 1965-present. J Drug
Deliv Sci Technol 21:36984.
White CJ, Byrne ME. (2010). Molecularly imprinted therapeutic contact
lenses. Expert Opin Drug Deliv 7:76580.
White CJ, Mcbride MK, Pate KM, et al. (2011b). Extended release of
high molecular weight hydroxypropyl methylcellulose from molecu-
larly imprinted, extended wear silicone hydrogel contact lenses.
Biomaterials 32:5698705.
Xinming L, Yingde C, Lloyd AW, et al. (2008). Polymeric hydrogels for
novel contact lens-based ophthalmic drug delivery systems: a review.
Cont Lens Anterior Eye 31:5764.
Xu J, Li X, Sun F. (2010). Cyclodextrin-containing hydrogels for contact
lenses as a platform for drug incorporation and release. Acta
Biomaterialia 6:48693.
Xu J, Li X, Sun F. (2011). In vitro and in vivo evaluation of ketotifen
fumarate-loaded silicone hydrogel contact lenses for ocular drug
delivery. Drug Deliv 18:1508.
Yanez F, Martikainen L, Braga ME, et al. (2011). Supercritical fluid-
assisted preparation of imprinted contact lenses for drug delivery.
Acta Biomaterialia 7:101930.
Ylmaz T, Aydemir O, O _ U
zercan I, stundag B. (2007). Effects of vitamin
E, pentoxifylline and aprotinin on light-induced retinal injury.
Ophthalmologica 221:15966.
Yokoi N, Komuro A. (2004). Non-invasive methods of assessing the tear
film. Exp Eye Res 78:399407.
Yokozaki Y, Sakabe J, Ng B, Shimoyama Y. (2015). Effect of
temperature, pressure and depressurization rate on release profile of
salicylic acid from contact lenses prepared by supercritical carbon
dioxide impregnation. Chem Eng Res Des100:8994.
Zhang W, Zu D, Chen J, et al. (2014). Bovine serum albuminmeloxicam
nanoaggregates laden contact lenses for ophthalmic drug delivery in
treatment of postcataract endophthalmitis. Int J Pharm 475:2534.
Zhu H, Chauhan A. (2005). A mathematical model for ocular tear and
solute balance. Curr Eye Res 30:84154.