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Contact Lens & Anterior Eye 31 (2008) 57–64

Review

Polymeric hydrogels for novel contact lens-based ophthalmic drug

delivery systems: A review

Li Xinming a,*, Cui Yingde a,1, Andrew W. Lloyd b,2, Sergey V. Mikhalovsky b,3,Susan R. Sandeman b,4, Carol A. Howel b,4, Liao Liewen c,5

a Department of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Technology, No. 24 Dongsha Street,

Fangzhi Road, Haizhu District, Guangzhou 510225, Guangdong, PR Chinab School of Pharmacy and Biomolecular Science, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK

c School of Materials Science and Engineering, Northwestern Polytechnical University, No. 127 Youyixi Road, Xi’an 710072, Shanxi, PR China

Abstract

Only about 5% of drugs administrated by eye drops are bioavailable, and currently eye drops account for more than 90% of all ophthalmic

formulations. The bioavailability of ophthalmic drugs can be improved by a soft contact lens-based ophthalmic drug delivery system. Several

polymeric hydrogels have been investigated for soft contact lens-based ophthalmic drug delivery systems: (i) polymeric hydrogels for

conventional contact lens to absorb and release ophthalmic drugs; (ii) polymeric hydrogels for piggyback contact lens combining with a drug

plate or drug solution; (iii) surface-modified polymeric hydrogels to immobilize drugs on the surface of contact lenses; (iv) polymeric

hydrogels for inclusion of drugs in a colloidal structure dispersed in the lens; (v) ion ligand-containing polymeric hydrogels; (vi) molecularly

imprinted polymeric hydrogels which provide the contact lens with a high affinity and selectivity for a given drug. Polymeric hydrogels for

these contact lens-based ophthalmic drug delivery systems, their advantages and drawbacks are critically analyzed in this review.

# 2007 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Hydrogels; Contact lens; Ophthalmic drug delivery system

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

2. Polymeric hydrogels for conventional contact lens to absorb and release ophthalmic drugs. . . . . . . . . . . . . . . . . . . . . . . . . 58

3. Polymeric hydrogels for piggyback contact lens combining with a drug plate or drug solution . . . . . . . . . . . . . . . . . . . . . . 59

4. Surface-modified polymeric hydrogels to immobilize drugs on the surface of contact lenses. . . . . . . . . . . . . . . . . . . . . . . . 59

5. Polymeric hydrogels for inclusion of drugs in a colloidal structure dispersed in the lens . . . . . . . . . . . . . . . . . . . . . . . . . . 60

6. Ion ligand-containing polymeric hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

7. Molecularly imprinted polymeric hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

8. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

* Corresponding author. Tel.: +86 20 8901 3955; fax: +86 20 3428 0984.

E-mail addresses: lixinming@sina.com (L. Xinming), cuigdut@yahoo.com.cn (C. Yingde), A.W.lloyd@brighton.ac.uk (A.W. Lloyd),

S.Mikhalovsky@brighton.ac.uk (S.V. Mikhalovsky), s.sandeman@brighton.ac.uk (S.R. Sandeman), c.a.howell@brighton.ac.uk (C.A. Howel),

liaolw@163.com (L. Liewen).1 Tel.: +86 20 8900 3002; fax: +86 20 3428 0984.2 Tel.: +44 1273 642049; fax: +44 1273 642031.3 Tel.: +44 1273 642034; fax: +44 1273 679333.4 Tel.: +44 1273 642015.5 Tel.: +86 130 2201 5152.

1367-0484/$ – see front matter # 2007 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.clae.2007.09.002

L. Xinming et al. / Contact Lens & Anterior Eye 31 (2008) 57–6458

1. Introduction

The success of the therapy of eye ailments with

ophthalmic drugs strongly depends on achieving sufficient

drug concentration on the cornea for a sufficient period of

time, but the typical delivery of drugs by eye drops which

currently account for more than 90% of all ophthalmic

formulations is very inefficient and in some instances leads

to serious side effects [1–3]. Upon instillation in the eye, the

drug mixes with the fluid present in the tear film and has a

short residence time of approximately 2 min in the film.

Only about 5% of the drug is absorbed into the cornea and

the remaining either gets absorbed in the conjunctiva or

flows through the upper and the lower canaliculi into the

lacrimal sac [4,5]. The drug containing tear fluid is carried

from the lacrimal sac into the nasolacrimal duct. The

nasolacrimal duct empties into the nasal cavity, where the

drug is then absorbed into the bloodstream. This absorption

leads to drug wastage, and more importantly, the presence of

certain drugs in the bloodstream leads to undesirable side

effects. Furthermore, the application of ophthalmic drugs by

eye drops results in a rapid variation in the drug delivery

rates to the cornea and this limits the efficacy of the

therapeutic system [6,7]. In addition, dosage through eye

drops is inconsistent and difficult to regulate, as most of the

drug is released in an initial burst of concentration [8,9]. To

increase the residence time of the drug in the eye, thereby

reducing wastage and minimizing side effects, a number of

researchers have proposed using contact lenses for

ophthalmic drug delivery. It has been shown that in the

presence of a lens, ophthalmic drugs have a much longer

residence time in the post-lens tear film, compared with

2 min in the case of topical application as eye drops [10–13].

The longer residence time will result in higher drug flux

through the cornea and reduce the drug inflow into the

nasolacrimal sac, thus reducing drug absorption into the

bloodstream. Several methods have been proposed to make

ophthalmic drugs deliverable by soft contact lens. In this

review, the advantages and drawbacks of polymeric

hydrogels for novel contact lens-based ophthalmic drug

delivery systems are critically analyzed.

2. Polymeric hydrogels for conventional contact lens

to absorb and release ophthalmic drugs

Conventional soft contact lenses have the ability to absorb

a number of drugs when the lenses are pre-soaked in the drug

solution, subsequently releasing them into the post-lens

lacrimal fluid. As an alternative, one can also insert

conventional soft contact lenses into eyes then apply eye

drops. By this means, drugs can be absorbed and released by

the soft contact lens, minimizing clearance and sorption

through the conjunctiva [13–16]. Several polymeric hydro-

gels have been investigated as a conventional soft contact

lens-based ophthalmic drug delivery system. Poly-hydro-

xyethylmethacrylate (pHEMA) hydrogels which are widely

used for preparing soft contact lenses, have been investigated

for delivery of several ophthalmic drugs [17,18]. To enhance

the potential of pHEMA hydrogels as an effective biomaterial

for contact lens-based ophthalmic drug delivery system, 4-

vinylpyridine (VP) and N-(3-aminopropyl)methacrylamide

(APMA) were incorporated into the network [19]. The

incorporated monomers did not change the viscoelastic

properties of the contact lens or the state of water within the

contact lens, but remarkably increased the amount of

ibuprofen (up to 10-fold) and diclofenac (up to 20-fold)

loaded. Dried loaded pHEMA–APMA and pHEMA–VP

hydrogels quickly swelled in water; but ionic/hydrophobic

interactions limited the drugs released to be below 10%. By

contrast, once the water-swollen hydrogels were transferred to

pH 5.8 or 8.0 phosphate buffers or NaCl solutions, the release

was prompted by competition with ions in the media. The

remaining hydrophobic interactions and the high polymeric

density of the pHEMA hydrogels contributed to sustaining the

release process for at least 24 h for ibuprofen and almost 1

week for diclofenac. This release rate was also independent of

the salt content and pH in the physiological range of values,

which enables the design of hydrogel-based delivery systems

with predictable release rates.

Researchers have also been investigating the copolymer

hydrogels of N,N-dimethylacrylamide (DMAAM) and 2-(N-

ethylperfluorooctanesulfonamido)ethyl acrylate (FOSA) for

potential application of contact lens-based drug delivery

systems [20]. Since hydrogels of poly(DMAAM) exhibit

rather low mechanical strength, FOSA, a hydrophobic

monomer, can be incorporated into the networks to modify

the glass transition temperature and water sorption and

desorption kinetics of the hydrogels by changing the

structure, location, or concentration of the hydrophobic

group. When pheniramine maleate (PM) was used as a

model drug, it was found that copolymerizing FOSA with

DMAAM-based hydrogels decreased (i) the media penetra-

tion velocity through the hydrogels, (ii) the change in

hydrogels volume during swelling, (iii) the equilibrium

media content in the hydrogels, and (iv) the drug diffusion

rate through the hydrogels. The pH of the aqueous media

into which the drug substance diffused had a much less

dramatic effect on the hydrogels, but it was found that

increasing the media pH slightly slowed the diffusion of the

drug substance by decreasing the swelling ability of the

hydrogels. Copolymer hydrogels of HEMA and acrylic acid

(AA) were also investigated as a contact lens-based

ophthalmic drug delivery system [21]. Soft contact lenses

based on commercially available silicon-containing hydro-

gels and poly-vinyl alcohol (PVA) hydrogels were also

examined for delivery of ophthalmic drugs [22–26]. Results

showed that the ability of conventional soft contact lenses to

be a drug reservoir strongly depends on the water content

and thickness of the lens, the molecular weight of the drug,

the concentration of the drug loading solution, the solubility

of the drugs in the gel matrix, and the time the lens remains

L. Xinming et al. / Contact Lens & Anterior Eye 31 (2008) 57–64 59

Fig. 1. Chemical structures of model drugs and monomers for conventional soft contact lens materials to absorb and release ophthalmic drugs.

in it. The maximum drug loading by pre-soaking the lenses

in the drug solutions was finite, and they were only able to

deliver most drugs for a period of a few hours. Thus, they

cannot be used for long-term drug delivery. Chemical

structures of model drugs and monomers for conventional

soft contact lens materials to absorb and release ophthalmic

drugs are shown in Fig. 1.

Fig. 2. Chemical structures of monomers for piggyback soft contact lens

materials combining a drug plate or drug solution for release of ophthalmic

drugs.

3. Polymeric hydrogels for piggyback contact lens

combining with a drug plate or drug solution

Another method to make ophthalmic drugs deliverable by

soft contact lens, involves incorporating the drug solution or

drug plate in a hollow cavity made by bonding two separate

pieces of lens material [27,28]. Bourlais et al. [29] created

‘‘Drug plates’’ (8.0 mm diameter, 0.2 mm thickness, and

7.5 mm base curve) by freeze drying a mixture of

levofloxacin (fluoroquinolon antibiotic) (20, 30, and

40 wt.%) and PVA, coated with a block styrene-(ethyl/

butene)-styrene (SEBS) polymer solution (5.0, 7.5, and

10.0 wt.%). The drug plate was placed between a 55% water

content hydrophilic lens (poly-N-vinylpyrrolidone) and a

nonhydrophilic lens (copolymer of butyl acrylate/butyl

methacrylate). In vivo assessment in albino rabbit eyes

showed that the delivery of the drug to the aqueous humor

with the piggyback drug delivery system (DDS) was about

15 times more effective than frequently instilling eye drops.

The presence of a nonhydrophilic lens over the DDS reduced

evaporation from the drug plate. However, the oxygen and

carbon dioxide permeability of the combined system was

lower than that recommended for the safe daily wear of

contact lenses, the contact lens was too thick to accept, and it

proved ineffective at delivering medication for extended

periods of time. Chemical structures of monomers for

piggyback soft contact lens materials combining a drug plate

or drug solution for release of ophthalmic drugs are shown in

Fig. 2.

4. Surface-modified polymeric hydrogels to

immobilize drugs on the surface of contact lenses

Surface-modified polymer hydrogels have been investi-

gated with the aim of immobilizing ophthalmic drugs onto

the surface of commercial disposable soft contact lenses and

making them deliverable to treat eye disease [30], the

immobilization process of ophthalmic drugs on the surface-

modified soft contact lens is shown in Fig. 3. In the first step,

polyethylenimine was covalently bounded onto the hydroxyl

groups available on the surface of a commercial contact lens

L. Xinming et al. / Contact Lens & Anterior Eye 31 (2008) 57–6460

Fig. 3. Immobilization of ophthalmic drugs on the surface-modified soft

contact lens.

(Hioxifilcon B), followed by NHS–PEG–biotin molecules

being bonded onto the surface amine groups by carbodii-

mide chemistry. Neutravidin was then bonded onto the

PEG–biotin layer, and liposomes containing PEG-biotiny-

lated lipids were docked onto the surface-immobilized

Neutravidin. Consecutive addition of further Neutravidin

and liposome layers enabled fabrication of multilayers.

Multilayers of liposomes were also produced by exposing

contact lenses coated with Neutravidin to liposome

aggregates produced by the addition of free biotin in

solution. The release kinetics of a fluorescent dye

demonstrated that intact liposomes had been immobilized

onto the contact lens surface, with the stability showing

temperature dependence. The surface-bonded liposomes can

be stored up to 1 month at 48 8C with little release of their

content. The multilayer scheme utilized provides strong

interfacial bonding, consisting of either covalent bonding or

biotin/avidin affinity between the individual layers, thus

minimizing the risk of liposome detaching from contact lens

surfaces. The drawbacks of this method include the risk of

the liposomes detaching from contact lens surface, and the

multilayer scheme of the liposomes decreases the oxygen

permeability, although the risk of the liposomes detaching

from the surface can be decreased. The release rate of

ophthalmic drugs from liposomes was found to display a

behavior indicative of diffusion control, thus the release

profile is difficult to regulate.

5. Polymeric hydrogels for inclusion of drugs in acolloidal structure dispersed in the lens

Researchers have been dispersing micro-emulsion drops

of ophthalmic drugs into soft contact lenses to treat eye

ailments [31–34]. First, ophthalmic drug formulations have

been encapsulated in dimyristoyl phosphatidylcholine

(DMPC) liposomes, and the drug-laden liposomes were

dispersed in the lens material. If the nanoparticle size and

loading are sufficiently low (the exact value depends on the

refractive index mismatch between the gel and the particles),

the particle-loaded lens remains transparent. Upon insertion

into the eye, the drug will diffuse from the particles, travel

through the lens matrix, and enter the pre-lens (the film

between the air and the lens) and the post-lens (the film

between the cornea and the lens) tear films. The p-HEMA

hydrogels matrix has been synthesized by bulk or solution-

free radical polymerization of HEMA monomers in the

presence of a cross-linker such as ethylene glycol-di-

methacrylate (EGDMA). Addition of drug-laden micro-

emulsion drops in the polymerizing medium results in

particle dispersion in the hydrogels matrix. In the presence

of a lens, drug molecules have a much longer residence time

in the post-lens tear film than the residence time of 2 min

that is the case with topical application of drugs as eye drops.

This longer residence time would presumably result in

higher drug flux through the cornea and reduce the drug

absorption into the blood stream through the conjunctiva or

the nasolacrimal duct. In addition, as a result of the slow

diffusion of the drug molecules through the particles and the

lens matrix, drug-laden contact lenses could provide

continuous drug release for extended periods. However, it

was found that the transparency of micro-emulsion-loaded

contact lenses decreased with increasing micro-emulsion

loading, and the system was unstable during preservation

and transportation because the loaded drugs diffused into the

gel matrix. Another drawback of this type of ophthalmic

drug delivery by nanoparticle-laden gels is the decaying

release rate.

6. Ion ligand-containing polymeric hydrogels

Ion ligand-containing polymer hydrogels have been

synthesized for a contact lens-based ophthalmic drug

delivery system. Ionized ophthalmic drugs were bound in

the soft contact lenses through ion ligands, and released into

tear fluid by ion exchange. Hydrogels containing cationic

functional groups in their side chain were investigated by

copolymerization of methacrylamide propyltrimethylam-

monium chloride (MAPTAC) and HEMA (chemical

structures of the model drug and monomers for cationic

ion ligand-containing soft contact lens materials are shown

in Fig. 4), and their capability to store the anionic drug based

on ion-exchange reaction was examined. It is expected that

the incorporated anionic drug would be released under

physiological conditions [35]. A size change in the

hydrogels was found before and after drug release (size

change during drug release of ion ligand-containing

polymeric hydrogels for soft contact lens-based ophthalmic

drug delivery systems is schematically illustrated in Fig. 5);

however, the addition of an anionic monomer such as

methacrylic acid (MAA) or 2-methacryloxyethyl acid

phosphate (MOEP) to the above-mentioned composition

was effective in preventing the size change.

L. Xinming et al. / Contact Lens & Anterior Eye 31 (2008) 57–64 61

Fig. 4. Chemical structures of the model drug and monomers for cationic ion ligand-containing soft contact lens materials.

Fig. 5. Size change during drug release of ion ligand-containing polymeric hydrogels for soft contact lens-based ophthalmic drug delivery systems.

Hydrogels that contain phosphate groups in side chains

were also studied for their usefulness in drug delivery soft

contact lenses (SCL) [36]. Naphazoline, a model drug

containing a cationic group, was incorporated into SCL via

its phosphate groups and was released over a period of about

14 h (chemical structures of the model drug and the

hydrogels are shown in Fig. 6). For the SCL, the naphazoline

Fig. 6. Chemical structures of the model drug and poly(HEMA-co-MOEP-co-M

drawbacks include the size change of the contact lens that may occur before and aft

drug concentration cannot exceed the ion concentration in the tear fluid, because

content was equivalent to the phosphate group content. It has

been suggested that drug delivery SCL can be designed to

contain the required amount of a drug through the choice of

the ionic group acting as the ligand, and amide groups and

phosphate groups must be introduced into the polymer in

equimolar amounts to give the necessary polymer–drug

interaction.

Am) hydrogels. For ion ligand-containing polymeric hydrogels, the main

er drug release as a result of drug concentration change, and the incorporated

the release of drugs relies on ion exchange.

L. Xinming et al. / Contact Lens & Anterior Eye 31 (2008) 57–6462

7. Molecularly imprinted polymeric hydrogels

Molecularly imprinted polymer hydrogels were recently

investigated biomaterials for contact lens-based ophthalmic

drug delivery systems. In general, the preparation of

molecularly imprinted polymers involves the self-assembly

of functional monomers and target molecules, followed by

polymerization with cross-linker in the presence of an inert

solvent as a porogen. Upon removal of the target molecules,

cavities that can recognize the spatial features and bonding

preferences of the target molecules are created, providing the

contact lens with a high affinity and selectivity for a given

drug. Although the polymerization is usually performed in an

organic solvent to give a macro-porous structure that allows

the target molecules access to the imprinted sites, one can

avoid the use of any solvent, taking advantage of the liquid

state of the monomers in preparation of molecular imprinted

polymer hydrogels. Molecularly imprinted polymer hydro-

gels have been prepared by dissolution of ethylene glycol

dimethacrylate (EGDMA, cross-linker) in HEMA with

methacrylic acid (MAA, functional monomer) or methyl

methacrylate (MMA, functional monomer) and with timolol

maleate (template, medicine for increasing the pressure in the

eye). Initiation of polymerization by addition of 2,2-azo-

bis(isobutyronitrile) (AIBN, initiator), resulting in a contact

lens and timolol release device [37]. Timolol release kinetics

in 0.9% NaCl, phosphate buffer (pH 7.4) and artificial

lacrimal fluid, and the timolol loading capacity at various pH

demonstrated that both water uptake and timolol release

exhibit Fickian kinetics. The incorporation of MAA as co-

monomer increases the timolol loading capacity to ther-

apeutically useful levels while retaining appropriate release

characteristics.

Another type of molecularly imprinted hydrogels were

prepared considering the preformation of complexes

between methacrylic acid (functional monomers), timolol

(target molecules), polymerization with N,N-diethylacryla-

mide (DEAAM), and ethylenglycol dimethacrylate

(EGDMA, cross-linker) by UV irradiation at room

temperature [38]. After polymerization, timolol molecules

were removed by washing. When the gels were immersed in

timolol solutions, the imprinted gels adsorbed greater

amount of timolol than the corresponding non-imprinted

ones. The imprinted contact lenses significantly improved

the affinity of the hydrogels for timolol. These results

indicate that adsorption sites capable of capturing the target

Fig. 7. Chemical structures of monomers for molecularly imprinted polymer

molecules were encoded effectively into the polymer

network by the molecularly imprinting technique and, in

consequence, improved the drug loading capacity of the

gels. Loaded imprinted contact lenses were able to prolong

timolol release in 0.9% NaCl aqueous solution for more than

24 h.

Other molecularly imprinted polymeric hydrogels inves-

tigated for contact lens-based ophthalmic drug delivery

systems include norfloxacin imprinted poly-HEMA [39];

timolol imprinted lenses prepared by UV irradiation of N,N-

diethylacrylamide (DEAAM), 2-hydroxyethylmethacrylate

(HEMA), 1-(tristrimethyl-siloxysilylpropyl)-methacrylate

(SiMA) and N,N-dimethylacrylamide (DMAAM) (50:50,

v/v), or methylmethacrylate (MMA) and DMAAM (50:50,

v/v) solutions, with functional monomer methacrylic acid

(MAA) and cross-linker ethyleneglycol dimethacrylate

(EGDMA) [40]; timolol imprinted lenses prepared by

copolymerization of N,N-diethylacrylamide (DEAAM,

main component of the matrix), methacrylic acid (MAA,

functional monomer) and ethylene glycol dimethacrylate

(EGDMA, cross-linker) [41]; timolol imprinted lenses

prepared from N,N-dimethylacrylamide (DMAAM) and

tris(trimethylsiloxy) sililpropyl methacrylate, methacrylic

acid (MAA, functional monomer), ethylene glycol dimetha-

crylate (EGDMA, cross-linker) [42]; natural receptor-based

poly(AA-co-AM-co-HEMA-co-PEG200DMA), poly(AM-

co-HEMA-co-PEG200DMA), poly(AA-co-AM-co-NVP-

co-HEMA-co-PEG200DMA), and poly(AA-co-HEMA-

co-PEG200DMA) [43]. Although all the results indicate

drug-loading capacity of contact lenses was improved by the

molecularly imprinting method, and the imprinted hydrogels

showed a higher affinity for template molecules are some

drawbacks. The maximum drug loading was limited by the

template molecules and functional monomers, and the

contact lenses deform on the release of drug. In addition, it is

difficult to regulate the release profile of drugs. Chemical

structures of some monomers for molecularly imprinted

polymeric hydrogels for contact lens-based ophthalmic drug

delivery systems are shown in Fig. 7.

8. Perspectives

Currently worldwide, approximately 100 million people

are estimated to be wearing contact lenses, and the number is

increasing exponentially [44]. Although the main use of

ic hydrogels for contact lens-based ophthalmic drug delivery systems.

L. Xinming et al. / Contact Lens & Anterior Eye 31 (2008) 57–64 63

contact lenses is for correcting ametropia problems, they

also hold interest as therapeutic devices for delivery of

ophthalmic drugs. An ideal soft contact lens-based

ophthalmic drug delivery system would exhibit (i) improved

maximum drug loading property for extended delivery

period; (ii) controllable zero-order release profiles; (iii)

shape retaining and transparency stability during release of

drug; (iv) stability during preservation and transportation;

(v) no burst release drug profiles; (vi) drug concentration in

the tear fluid between maximum safe concentration (MSC)

and minimum effective concentration (MEC); (vii) accep-

table oxygen and carbon dioxide permeability and contact

lens thickness. We believe that the ability of soft contact

lenses to provide an alternative ophthalmic drugs delivery

system warrants further investigation.

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