Contact Lens Drug Delivery

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

release from unmodified

commercial contact lenses

5. Novel approaches for

controlled and extended drug

release from contact lenses

6. Conclusions

7. Expert opinion

Review

Contact lenses as a platform forocular drug deliveryLokendrakumar C Bengani, Kuan-Hui Hsu, Samuel Gause &Anuj Chauhan

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 signifi-

cantly 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, sandwich-

ing 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 consid-

erable improvements compared to eye drops. The future appears to be prom-

ising 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 commonlyachieved through eye drops in form of solutions and suspensions [1], even thoughit is well understood that only a very small fraction of drug delivered through eyedrops reaches the target tissue [2]. There are several factors that contribute to theinefficiencies of eye drops. A human tear film contains about 7 l of fluid [3] andeven though it can hold a larger amount after an eye drop instillation, a fractionof the instilled 30 l eye drop is quickly squeezed out of the eye [2]. The remainingdrug mixes within the entire tear volume and then exits through canalicular drain-age into the nose or transports across the corneal and the conjunctival epithelia. Thearea of the conjunctiva is about 16 -- 18 times the area of the cornea, and the con-junctiva permeability is also higher than the corneal permeability, and thus the netdrug flux into cornea is much lower than that into the conjunctiva [4,5]. A very largefraction of the drug absorbed into the conjunctiva and that drained into thenose enter systemic circulation, leading to the very low corneal bioavailabilityof < 5% [2]. The fraction of the delivered drug that enters the systemic circulationescapes the first-pass metabolism and enters all major organs, with a potential forside effects [6,7]. The problem of low bioavailability is exacerbated by the shorttear film residence time of only about 2 -- 3 min, leading to a necessity of a frequentdosing regimen [2]. In certain cases, hourly instillations of eye drops are required fordelivery of dexamethasone phosphate disodium (DXP) for anti-inflammatory

10.1517/17425247.2013.821462 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1483All rights reserved: reproduction in whole or in part not permitted

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therapy [8] and delivery of cysteamine for the treatment ofcorneal crystal formation in nephropathic cystinosis [9]. Thehigh instillation frequency leads to reduced patient compliance,which is also impacted by the difficulties in precisely deliveringthe eye drop, particularly in elderly patients. The compliance tothe eye drop regimen is further reduced when multiple medica-tions are recommended, which is common in about 50% ofglaucoma patients [10,11]. Finally, the stability of eye drop for-mulations is sometimes limited. For example, the recentlyreleased cysteamine eye drop formulation (Cystaran) isrequired to be kept frozen at temperatures < -15C and afterthawing it has a maximum shelf life of 1 week, even underrefrigerated conditions [12].

The deficiencies of the eye drops has led to considerableresearch focusing on developing improved ODD formulationssuch as high-viscosity formulations, polymeric gels, mucoadhe-sive and in situ forming gels, bioadhesive polymers, biodegrad-able or nondegradable inserts, punctal plugs, etc [2,13-16]. Alsonew approaches focusing on driving the drug into the corneahave been explored such as iontophoresis and micronee-dles [17,18]. In spite of all the deficiencies described above, eyedrops have been the main stay of ocular therapies becausemost other approaches for ODD also suffered from at leastsome of the deficiencies of eye drops. It is, however, clear thateye drops are far from optimal for delivering ophthalmic drugsand a better approach is required for increasing bioavailability,improving patient compliance and reducing the potential forside effects.

The optimal ODD system needs to overcome the deficien-cies of eye drops, while maintaining all the key requirementsregarding physical properties, pharmacokinetics and pharma-codynamics. An ODD system must be highly biocompatible,easy to administer, comfortable and should not have anyadverse effect on vision or normal eye functions such as blink-ing. Also, the device should preferably provide extended drugrelease at therapeutic rates, with increased corneal bioavai-lability. It is also critical that the drug pharmacokinetics ismaintained at least comparable to the eye drop regimen.There are additional factors to consider including costs and

the regulatory approval process. For an ODD device to signi-ficantly improve the corneal bioavailability, it must bepreferentially located closer to the cornea, compared to theconjunctiva, making a contact lens the obvious choice. Itwas, thus, natural to explore contact lenses for delivering ocu-lar drugs and several studies focusing on this goal wereattempted as early as several decades ago. While several studiesproved the feasibility of the concept, drug-eluting contactlenses never reached the market mainly because the earliestattempts were conducted with lenses that were not ideallysuited for drug delivery. The increasing research and latestadvances in biomaterials and nanotechnology has now led tothe design of drug-eluting contact lenses which have overcomemost of the technological challenges and so commercializationis likely in near future. In this review, we focus on summariz-ing prior research, while specifically emphasizing on mecha-nisms and noting the advantages and disadvantages ofvarious approaches and finally present our opinion on thechallenges and future of this field.

2. Ocular transport of drug released by acontact lens

The mechanisms relevant to ophthalmic drug delivery by con-tact lenses are illustrated in Figure 1. A normal human tearfilm is about 7 -- 10 m in thickness, while a typical contactlens has a central thickness of about 80 -- 150 m [19]. Oninsertion of a contact lens, the tear film partitions into apre-lens tear film (PLTF) and post-LTF (POLTF), whichare a few microns in thickness [19]. A drug-loaded contactlens releases drug both into the PLTF and POLTF. Thedrug that is released into the POLTF can either diffuse intothe 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 entiredrug amount released into the POLTF by the contact lensdiffuses into the cornea, even after accounting for theenhancement of radial transport due to lens motion. Thedrug released by the contact lens into the PLTF will likelyabsorb into the conjunctiva or drain through the canaliculiand eventually enter the systemic circulation. It is difficultto predict the ratio of the masses of drug released into thePLTF and POLTF but the ratio can be expected to be aboutunity if both of the tear volumes are considered to be sinks.A ratio of one between the releases into the PLTF and POLTFwill likely yield about 50% corneal bioavailability, comparedto about 1 -- 5% with eye drops. Detailed mathematicalmodeling based on the basic mechanisms described aboveshows that the bioavailability from drug-eluting contact lensescould be 50% or possibly higher [20]. The model also suggeststhat the POLTF is likely a perfect sink in spite of the verysmall tear volume because the drug released from the lensesdiffuses into the cornea ensuring that the POLTF drug con-centration remains low. The sink assumption for the POLTFbecomes more accurate for contact lenses with extended drug

Article highlights.

. Corneal bioavailability for ophthalmic drugs deliveredthrough contact lenses could be 50%.

. Vitamin E incorporation in commercial contact lensesincreases release duration without compromising anyother property.

. Nanoparticle incorporation in contact lenses can improvedrug release profiles, but degradation and drug releaseduring storage is an issue.

. Imprinting can improve drug delivery profiles butincrease in modulus is an issue.

. Animal studies have proven safety and efficacy ofdrug-eluting extended wear contact lenses.

This box summarizes key points contained in the article.

L. C. Bengani et al.

1484 Expert Opin. Drug Deliv. (2013) 10(11)

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delivery as the timescale for drug release from the lensbecomes much longer than the timescale for drug transportfrom the POLTF into the cornea. The latter timescale canbe estimated to be the ratio of the POLTF thickness and thepermeability of the cornea to the drug of interest. ThePOLTF thickness is about 5 m and while there is consider-able variability in corneal permeability, for most drugs itranges from about 10-5 to 10-7 cm/s [5], and thus the timescalefor transport from the POLTF to the cornea is about 1 s to1 min. As discussed later, most contact lenses release drugsfor at least a few hours, which is sufficiently long to ensurevery small drug concentrations in the POLTF, justifying thesink assumption. The transport of drug from the PLTF tothe conjunctiva could yield sink conditions in the PLTF aswell. The PLTF, however, rapidly breaks during the inter-blink and could reduce the drug flux from the lens towardthe PLTF. Thus, while the exact corneal bioavailability fromcontact lenses is unknown, it is likely that at least 50% ofthe drug loaded into the lenses reaches the cornea. This pre-diction has considerable support from several animal andhuman studies described later which shows that contact lensescan achieve the same therapeutic effect as eye drops but withconsiderably lower drug loadings.

3. Key requirements for drug-elutingcontact lenses

As discussed above, a contact lens is ideally suited for increas-ing corneal bioavailability. Contact lenses also meet several ofthe other requirements such as biocompatibility, ease of inser-tion, transparency, with minimal effect of ocular functions; atleast for the population that wear contact lenses for vision

correction. The remaining key requirements are related tothe pharmacokinetics and the pharmacodynamics, which arein turn closely related to the drug transport in the contactlens. It is obvious that the contact lens needs to have a suffi-cient drug payload to achieve the therapeutic response. Theoptimal choice of the total drug release duration from thecontact lens is, however, far from clear and would at least par-tially depend on the most common contact lens modality interms of the wear schedule. Clearly, a very short duration ofthe order of 1 h is undesirable as that could necessitatemultiple contact lenses each day, which would increase costand reduce patient compliance. Currently based on the wearschedule, contact lenses can be categorized into disposableor frequent replacement. Among the disposable lenses, thedaily disposable type are worn just for 1 day, while the othertype are extended wear lenses which can be worn continuallyfor long periods of 1, 2 or 4 weeks depending on the specificlens type, without even taking the lenses off at night. The fre-quent replacement lenses can last for several weeks but theseare worn during the day, taken off and cleaned during thenight and replaced in the eyes in the morning. Since thereare several different wearing options, it would be prudent todevelop different types of drug-eluting contact lenses suitedfor the various wearing patterns. Thus, there appears to be aneed to develop contact lenses with controllable releasedurations ranging from 1 day to possibly 1 -- 4 weeks. Sincethe release duration is a key characteristic for the drug-eluting contact lenses, researchers have measured the in vitrorelease profiles from contact lenses for a wide variety of drugs.Also, several approaches have been developed for extendingthe drug releases. In addition to the in vitro studies, thereare several reports in literature focusing on in vivo animalstudies or human clinical studies. Below we discuss thesestudies, first for typical commercial contact lenses that aredesigned for vision correction followed by those with contactlenses which are designed to increase the drug releaseduration.

4. Drug delivery by soak and release fromunmodified commercial contact lenses

The earliest reports on the use of contact lenses for drugdelivery date back to the 1960s [21,22]. Most of the early stud-ies focused on soaking the commercial contact lenses in a drugsolution followed by lens insertion in the eye. This methodhas received the maximum attention from researchers, likelydue to the simplicity of the approach. In addition to the largenumber of in vitro studies, several animal and human studieshave been conducted with the soak and release approach toexplore delivery of various molecules to eyes including fluo-rescein in rabbits [23], pilocarpine in humans [24], dexametha-sone phosphate in humans (89 subjects) [25], chloromycetin,gentamicin or carbenicillin in humans (466 subjects) [26], gen-tamicin, kanamycin, tobramycin, ciprofloxacin and ofloxacinin humans (265 patients) [27] and lomefloxacin in rabbits [28].

Post-lens tearfilm (POLTF)

Cornea

Drug elutingcontact lens

Pre-lenstear film (PLTF)

Eyelid

Figure 1. Mechanism of ophthalmic drug delivery by contact

lenses.

Contact lenses as a platform for ODD

Expert Opin. Drug Deliv. (2013) 10(11) 1485

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The in vivo studies clearly proved the feasibility of the conceptof using drug-eluting contact lenses, while also showingimproved efficacy compared to eye drops. The superior per-formance of a contact lens compared to eye drops suggestsan increase in bioavailability due to an increase in the resi-dence time of the drug in the tears. The increase in bioavai-lability increases the drug concentration in cornea andaqueous humor, which can act as drug reservoirs and thusalso extend the duration of effect compared to eye drops [29-31].In spite of the proven benefits of contact lenses, the early stud-ies have not resulted in a commercial product even after fivedecades. This most likely can be attributed to the short dura-tion of release from the unmodified commercial contactlenses. While the exact release duration depends on both thedrug and the lens properties, the release durations are usuallyonly a few minutes to a few hours for all ophthalmic drugs inthe size range of 300 to 500 Da where majority of the drug isreleased in an initial burst [32-37]. A contact lens with releaseduration of 1 -- 2 h is superior to the eye drops due toincreased residence time and bioavailability, but the benefitsare perhaps not considered sufficient by pharmaceutical com-panies to invest the large resources necessary to commercializea new drug delivery device. The past few decades have seenrapid advances in development of new types of contact lensesthat are safer and can be worn continuously for extended peri-ods of time. The advances in the contact lens field have led torenewed interest in developing therapeutic contact lenses.Since the short release duration is the major limitation ofthe soak and release approach from commercial contactlenses, most recent studies have focused on developing lenseswith extended drug release duration.

5. Novel approaches for controlled andextended drug release from contact lenses

Several approaches have been developed to increase the drugrelease duration from contact lenses. It is important tonote that the increase in release duration must be achievedwithout compromising any of the key properties, including

transparency, modulus, wettability, lubricity, ion and oxygenpermeabilities, etc. The successful approaches for increasingthe drug release durations are described below.

5.1 Vitamin E barriersDrug transport in any device can be attenuated by creating abarrier in the path of the drug. Creation of barriers in contactlens is, however, complicated due to the requirement of trans-parency and minimal impact on modulus and ion and oxygenpermeability. Chauhan et al. have demonstrated that vitaminE barriers can be created in extended wear contact lenseswith minimal impact on other key lens properties [38-40].The vitamin E barriers can be created in situ in polymerizedcontact lenses by soaking the lenses in a solution of vitaminE in ethanol, followed by extraction of ethanol by soakingin water. Since the solubility of vitamin E in ethanol is veryhigh, the contact lenses are loaded with vitamin E duringsoaking in ethanol. When the lenses are withdrawn from eth-anol and soaked in water, ethanol diffuses out but vitamin Eremains trapped in the lens due to its minimal aqueoussolubility. Owing to the unique biphasic microstructure ofsilicone hydrogel contact lenses, the vitamin E loaded in thelenses phase separates into high aspect ratio disc-shaped nano-barriers, likely located at the interface between the siliconeand the hydrophilic phases in the lenses. The vitamin E aggre-gates are smaller than the wavelength of the visible light andthus the lenses remain transparent (Figure 2) for vitamin Eloadings as high as 70% w/w. The high aspect ratio vitaminE aggregates act as barriers for hydrophilic ophthalmic drugs.The drug molecules are forced to diffuse in a tortuous patharound the barriers resulting in an increase in the release dura-tions. The microstructure of the vitamin E barriers in thelenses and the mechanism of drug transport are illustratedin Figure 3.

Vitamin E incorporation is effective in increasing therelease duration of several ophthalmic drugs. This approachis particularly effective for hydrophilic drugs such as timolol,fluconazole and DXP which are ionized in physiological con-ditions, which leads to negligible solubility of the drugs invitamin E and consequently excellent barrier-effect [38]. Sincethe attenuation of drug transport by vitamin E is purely dueto the increased tortuosity, the ratio of drug release durationswith and without vitamin E should be same for any drug. Ithas been shown that the relative increase in release durationsis in fact similar for timolol, fluconazole and DXP. Also, therelease durations increase quadratically with vitamin E load-ings because the release times scale as the square of path lengthfor diffusion control processes [38]. The release durations oftimolol, fluconazole and DXP increase by a factor of about5 and 40 for 10 and 40% vitamin E loadings, respectively.The vitamin E also acts as a barrier for certain hydrophobicdrugs such as dexamethasone and cyclosporine likely due toits high viscosity [39,40]. The release time of dexamethasoneincreases about 16-fold with 30% vitamin E loading [39].Amphiphilic drugs are able to adsorb on the surface of the

Figure 2. Image of pure NIGHT & DAY lens (right) and NIGHT

& DAY with 30% vitamin E loading (left).



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vitamin E aggregates and then diffuse along the surface,leading to minimal barrier effect [41].

The safety and efficacy of vitamin E-loaded extended wearcontact lenses were successfully demonstrated in a glaucomamodel in Beagle dogs [42,43]. These studies focused on deliver-ing timolol to the dogs by eye drops, unmodified contactlenses and the vitamin E-loaded contact lenses. These studiesdemonstrated that both unmodified and vitamin E-loadedcontact lenses can significantly reduce the intraocular pressureeven when the amount of timolol loaded in the lenses is sig-nificantly smaller than that in drops. The unmodified contactlenses had to be replaced daily, while the vitamin E-loadedlenses were worn continuously for 4 days.

The vitamin E-modified contact lenses have been exten-sively characterized to show that all the key lens propertiesare suitable for extended wear. Vitamin E incorporate alsoimproves some of the properties such as UV blocking [38].Although vitamin E incorporation reduces oxygen and ionpermeabilities, the reduced values are still adequate forextended wear for vitamin E loadings of < 20%. The majoradvantages of using vitamin E barriers for extending therelease durations are the ease of implementation and the pos-sibility of attenuating transport of several drugs possiblyeven simultaneously.

5.2 Molecular imprintingMolecular imprinting is commonly used for increasing thepartitioning of a solute in biomaterials. The approach relieson creation of cavities that exhibit a very high affinity for

the desired solute, which is also called the template. Thesehigh-affinity cavities provide binding sites to the drugs, thusincreasing the overall partition coefficient. When a molecu-larly imprinted material loaded with the drug is soaked in arelease medium, the unbound drug diffuses, thereby creatinga driving force for the drug bound to the imprinted cavityto desorb and then diffuse. The net effect of the drug bindingto the high-affinity cavities is a decrease in the effective diffu-sivity of the drug, which results in an increase in the releaseduration [44-50]. It is noted that it may be feasible to design acavity with very strong affinity such that the desorption time-scales are rate-limiting and thus the overall transport is limitedby the rate of drug desorption from the cavity. However, inmost cases, the transport process is diffusion-controlled withattenuated effective diffusivity.

The formation of high-affinity cavities requires inclusionof one or more suitable functional monomers to the polymer-ization mixture, along with the drug molecules, which serveas the templates. The functional monomers assemble aroundthe drug template due to the favorable interactions to createthe cavity, which is then locked in place during the polymer-ization (Figure 4). The drug molecules are extracted after thepolymerization leaving behind drug-recognizing cavities thathave a high affinity for the template drug molecules. Thedrug molecules can then be reloaded into the polymer bysoaking in an aqueous solution to produce the polymer witha higher drug partition coefficient, along with reduced drugdiffusivity.

The key requirement of the imprinting approach is identifi-cation of the suitable functional monomers that have a strongfavorable interaction with the drug. Commonly used functionalmonomers for contact lenses include acrylic acid (AA), acryl-amide (AM), methacrylic acid (MAA), methyl methacrylate(MMA) and N-vinyl 2-pyrrolidone (NVP) [51-57]. These func-tional monomers are compatible with the typical contact lensmaterials and can interact with the drug through hydrogenbinding, hydrophobic or ionic interactions. The relativeincrease in partitioning due to imprinting depends on the frac-tion of the functional monomers in the lenses, and additionallyon several other factors including temperature, pressure, drug-functional monomer ratio, initiator concentration and degreeof crosslinking. The ophthalmic drugs of interest typicallybind to specific receptors in the eyes and thus the best imprint-ing would mimic the structure of the receptor. Ali et al. andVenkatesh et al. developed a biomimetic extended release lensfor delivery of antihistamine ketotifen fumarate by focusingon a formulation with AA, AM, NVP, hydroxyethyl methacry-late (HEMA) and polyethylene glycol (200) dimethyacrylate(PEG200DMA) to mimic the interactions between H1-receptor and the drug [53,58]. Ali and Byrne developed a hyalur-onic acid-releasing lens by using AM, NVP, 2-(diethylamino)ethyl methacrylate (DEAEM) as the functional monomers tomimic the binding of CD44 proteins to hyaluronic acid [54].The imprinting approach can significantly benefit by use ofMonte Carlo or molecular dynamics simulations to identify

Polymer matrix

VE diffusion barrier Drug molecule

Figure 3. Concept of vitamin E diffusion barrier effect to

drug transport retardation.



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the most suitable functional monomers for the drug of interest.Such simulations can be effectively used to predict the influenceof interactions between components on the imprinting [59,60].

Table 1 summarizes the studies on imprinted drug-elutingcontact lenses, and some specific studies are described below.Timolol is the most common drug used in the imprintingstudies [51,55,61,62]. Hiratani and Alvarez-Lorenzo showedthat imprinted gels based on MAA as the functional monomershowed two to three times higher timolol-loading capacitythan the non-imprinted gels [51]. Alvarez-Lorenzo et al. usedAA as functional monomer to develop imprinted hydrogelswith high norfloxacin loading (up to 300 times that of poly-HEMA (p-HEMA) hydrogels) and a release duration of about24 h [52]. Venkatesh et al. combined four functional mono-mers and demonstrated a sixfold increase in loading of ketoti-fen fumarate compared to the control and threefold increasecompared to gels with two or three functional monomers [63].While most of the research with imprinted contact lenseshas focused on small molecules, researchers have begunexploring imprinting of larger molecules in contact lensesdue to the potential benefit of increased comfort. Ali andByrne designed a daily disposable molecularly imprintedcontact lenses that released hyaluronic acid (1,200,000 Da)at a rate of roughly 6 g/h [54]. White et al. designed asilicone hydrogel-based molecularly imprinted contact lensto release hydroxypropylmethylcellulose (HPMC) (120kDalton) for > 50 days [56].

Yanez et al. proposed that the imprinting cavities can becreated in a fully polymerized gel by impregnation with asolution of the drug in supercritical CO2. They exposedHilafilcon B contact lenses to three cycles of supercriticalsolvent impregnation and extraction to imprint the lenseswith flurbiprofen and showed that the loading capacityincreased 450% after the three cycles of treatment. Theincreased imprinting also led to an increase in release durationafter each cycle, with an overall increase of about threefoldafter the three cycles [64]. Costa et al. also focused on increas-ing drug-loading capacity of a lens by impregnation with asolution of the drug in supercritical CO2 [65,66].

The safety and efficacy of the imprinted contact lenses hasbeen demonstrated in several animal studies. Hiratani et al.tested N, N-diethylacrylamide (DEAA), MAA and ethyleneglycol methacrylate (EGDMA) copolymerized imprintedlenses loaded with timolol in rabbits and showed that theimprinted lenses could sustain measurable timolol concentra-tion in the tear sample threefold longer than eye drops [62]. Inaddition, the area under the timolol concentration--time curve(AUC) for the imprinted lenses was 8.7-fold compared to eyedrops. 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 testedin rabbits [67]. The results showed that the residence timeand AUC increased 50 and 94 times, respectively, withimprinted contact lenses compared to eye drops.

Functional monomers

Drug template Crosslinker

Self-assembling due to favorable interactions

Polymer

PolymerizationFormation of high-affinity cavity

Extraction

Figure 4. Schematic illustration of the formation of high-affinity cavities for molecular imprinting.



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Table

1.Summary

ofrecentstudieswithim

printedcontact

lenses.

Backbonemonomers

Functionalmonomers

Crosslinker

Drugs(template

molecules)

Comments

onmolecularim

printingperform

ance

Refs.

DEAA

MAA

(1.28-5.12mol%

)*

EGDMA

(0.32-8.34mol%

)*Tim

olol

Low

crosslinkingdensity

imprintedhyd

rogelwassynthesized.

Imprintedhyd

rogelhadaroughly

10timesincrease

inoverall

drugaffinitythannon-imprintedones.

Release

wassustained

formore

than24h

[51]

DEAA,HEMA,

SiM

A/DMAA

(50:50v/v)

MMA/DMAA

(50:50v/v)z

MAA

EGDMA

Tim

olol

Fourdifferentbackbonemonomers

were

comparedandHEMA

showedthebest

loadingcapacity

andrelease

durationtime

[61]

DMAA/TRIS

(50:50v/v)z

MAA

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

32:1)

EGDMA

Tim

olol

DifferentM/T

ratioswere

testedto

evaluate

theirinfluence

on

imprintedresults.

ChangingM/T

ratiohadnoinfluence

ongels

swellingproperty.

M/T

=16revealedthebest

loadingcapacity

andrelease

durationtime

[97]

DEAA

MAA

EGDMA

Tim

olol

Invivo

studywascarriedoutbyusingrabbits.

Resultsshowed

thatmolecu

larlyim

printedlensprovidedco

uld

sustain

measurable

timololco

ncentrationin

collectedtearsample

for

threefold

longerthaneye

dropsandalso,a8.7-fold

increment

incalculatedAUC

[62]

HEMA

VP,APMAz

EGDMA

Ibuprofen,

diclofenac

Twofunctionalmonomers

were

investigatedin

delivering

nonsteroidalanti-inflammatory

drugs.

Higherloadingcapacity

wasach

ieved.Release

durationwassustainedforatleast

24h

foribuprofenand1weekfordiclofenac

[98]

HEMA

AA,VP(0-2.5

mol%

)*EGDMA

Norfloxacin

ITC

studieswere

usedto

determ

inetheoptimum

M/T

ratio.

ResultsrevealedthatAA:drug=1:3

or1:4

ledto

atimolol

release

durationofatleast

24h

[52]

HEMA

AA,AM,NVP

PEG200DMA

Ketotifenfumarate

Aco

mbinationofmultiple

functionalmonomerismore

effective

increatingim

printingeffects.

Aeightfold

reductionin

diffusivity

wasach

ieved

[53,58]

NelfilconA

form

ulation

withmodifiedPVAz

macromer

AM,NVP,DEAEMz

Hyaluronic

acid

(1,200000,Da)

Comparedto

nelfilconA,thediffusivity

ofhyaluronic

acidwas

reduced1.6

timeswithin

AM-co-N

VP-co-D

EAEM

imprintedgels

[54]

HEMA

AA

(6:1

--32:1)

EGDMA

Tim

olol

ITC

tech

niquewasusedto

identify

theoptimalmolarratio

betw

eenfunctionalmonomeranddrugtemplate.M/T

=6

providedthelongest

release

duration,butloadingcapacity

waslowerthangelswithhigherM/T

ratio.

[55]

*Themole

percentageofcrosslinkerorfunctionalmonomerare

addedinto

themixturesofbackbonemonomer,functionalmonomer,crosslinkerandtemplate

molecu

les.

z 1-(tristrim

ethyl-siloxysilylpropyl)-metharylate

(SiM

A),N,N-dim

ethylacrylamide(DMAA),tris(trimethylsiloxy)silylpropyl

methacrylate

(TRIS),4-vinyl-pyridine(VP),N-(3-aminopropyl)methacrylamide(APMA),polyvinyl

alcohol

(PVA),2-(diethylamino)ethyl

methacrylate

(DEAEM),1-vinylim

idazo

le(1VI),4-vinylim

idazo

le(4VI),N-hyd

roxyethyl

acrylamide(HEAA).

TheM/T

ratiosare

exp

loredin

thisstudy.

{ LotrafilconBform

ulationispatentedbyCIBA

Vision,Inc.

ITC:Isotherm

altitrationcalorimetry;

M/T:Monomer/Template.



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Table

1.Summary

ofrecentstudieswithim

printedcontact

lenses(continued).

Backbonemonomers

Functionalmonomers

Crosslinker

Drugs(template

molecules)

Comments

onmolecularim

printingperform

ance

Refs.

HEMA,NVP/DMA

(20/80molarratio)

Zincmethacrylate,zinc

nitrate

hexahyd

rate,1VI,

4VI,HEAAz

EGDMA

Acetazo

lamide,

Ethoxzolamide

ThepHEMA-zincmethacrylate

imprintedhyd

rogelhadavery

low

transparency

andwasnotsuitable

forco

ntact

lenswearing.

TheNVP-co-D

MA

imprintedwith4VI,HEAA

andzincionas

functionalmonomers

remainedtransparentandincreaseddrug

affinitybytw

ofold.Therelease

wassustainedforroughly

9hfor

acetazo

lamideand1weekforethoxzolamide

[99,100]

Betaco

nmacromere/TRIS/DMA

AA

PEG200DMA,

EGDMA

HPMC(120kDA)z

Silico

nehyd

rogelswere

imprintedforextendedrelease

ofHPMC.

ByadjustingM/T

ratio,therelease

profile

could

betailoredto

release

1000g

ofHPMC

foraperiodofmore

than50days.

HPMC

loadingamount,M/T

ratioandcrosslinkingdensity

should

befinely

controlledto

obtain

transparentlenses

[56]

HEMA

MAA

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

EGDMA

Prednisolone

acetate

DifferentM/T

ratiowere

testedandM/T

=4exh

ibitedthebest

loadingcapacity

andrelease

durationtimeupto

48h

[57]

HEMA

AA,AM,NVP

PEG200DMA

Ketotifenfumarate

Invivo

studiesusingrabbitmodel.Theresultsshoweda50-fold

increase

inMRT,and94-fold

inAUC

[67]

HEMA

DEAEM

(1:1,3.5:1,

10.5:1)

PEG200DMA

Diclofenacsodium

Theloadingcapacity

increasedfivefold

withthepresence

of

DEAEM.M/T

=10.5

exh

ibitedthelongest

release

duration

ofmore

than24h

[101]

3.6gofHEMA/0.4g

ofTRIS

Aceticacid,AA

(4:1,

8:1,16:1)

EGDMA

Ciprofloxacin

Imprintingco

uld

extendtherelease

durationto

3--14days

[102]

*Themole

percentageofcrosslinkerorfunctionalmonomerare

addedinto

themixturesofbackbonemonomer,functionalmonomer,crosslinkerandtemplate

molecu

les.

z 1-(tristrim

ethyl-siloxysilylpropyl)-metharylate

(SiM

A),N,N-dim

ethylacrylamide(DMAA),tris(trimethylsiloxy)silylpropyl

methacrylate

(TRIS),4-vinyl-pyridine(VP),N-(3-aminopropyl)methacrylamide(APMA),polyvinyl

alcohol

(PVA),2-(diethylamino)ethyl

methacrylate

(DEAEM),1-vinylim

idazo

le(1VI),4-vinylim

idazo

le(4VI),N-hyd

roxyethyl

acrylamide(HEAA).

TheM/T

ratiosare

exp

loredin

thisstudy.

{ LotrafilconBform

ulationispatentedbyCIBA

Vision,Inc.

ITC:Isotherm

altitrationcalorimetry;

M/T:Monomer/Template.



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The above-described studies clearly prove that molecularimprinting techniques can effectively increase the loadingcapacity and the release duration from contact lenses. Theimprinted contact lenses are transparent and are shown tobe safe in animal studies. Effect of the imprinting on ionand oxygen permeabilities has not been explored but both ofthese properties will not likely be significantly impacted.While most imprinting studies have been conducted withhydrogels, there are some recent studies on imprinting in sil-icone hydrogels, which are the materials in extended wearcontact lenses. A potential downside for the imprintingapproach is the requirement of relatively high degree of cross-linking which increases the modulus and reduces watercontent, which can impact oxygen transport and comfort.

5.3 Micro and nanoparticlesThe imprinting approach is based on creation of high-affinity sites in the contact lenses. An alternate approach fordesigning lenses with high-affinity regions is through disper-sion or surface immobilization of nanoparticles that are spe-cifically designed to possess high affinity for the drug ofinterest. The nanoparticles can increase partitioning andthus reduce the effective diffusivity as the drug partitionedin the particles does not directly diffuse. Due to the excellentbiocompatibility, liposomes are good candidates for disper-sion or surface immobilization on contact lenses. Dimyristoyl-phosphatidylcholine liposomes were dispersed in p-HEMAhydrogels to provide extended release of lidocaine for about6 days. The release profiles displayed an initial burst releasefollowed by a sustained release over the next few days [68].Danion et al. immobilized liposomes on the surface ofcommercial contact lenses and showed extended release ofcarboxyfluorescein [69].

Several studies have focused on dispersing microemulsions(MEs) in contact lenses. The p-HEMA hydrogels were loadedwith lidocaine-base-containing MEs with hexadecane oil andBrij 97 surfactant and an additional silica shell for furtherstabilization. The hydrogels released lidocaine for about7 -- 8 days, but about 50% of the drug was released within

the first few hours. Also, the gels were 1 mm thick, which isabout 10 times thicker than most contact lenses [70]. MEs ofcanola oil stabilized by Tween 80 with an additional silicashell were also explored for extended release of lidocainefrom p-HEMA hydrogels. The hydrogels were reported tobe opaque due to the aggregation and segregation duringpolymerization. The transparency loss was minimized by dis-persing MEs stabilized by Brij 97 with an additional silicashell, but the drug release profiles still contained a burst fol-lowed by a slow release for a few days [71]. To minimize theinitial burst, Ferreira et al. loaded silicone-coated particlescontaining flurbiprofen, Brij 35 and decane into HEMA-co-MAA hydrogels. The release profiles still contained an initialburst, followed by sustained release over 8 days [72]. Jungand Chauhan prepared highly crosslinked spherical nanopar-ticles of propoxylated glyceryl triacrylate with covalentlyattached timolol, and then loaded the particles in bothp-HEMA and silicone hydrogels by direct addition to thepolymerization mixture. The gels exhibited a sustained releasefor about 30 days at room temperature due to the slow hydro-lysis of the ester bond that connected timolol to the lensmatrix. The release duration was, however, considerablyshorter at physiological temperatures due to the higher reac-tion rates. The timolol-linked nanoparticles were also loadedinto commercial contact lenses by soaking the lenses in a solu-tion of the nanoparticles in ethanol followed by evaporationof ethanol. The efficacy of the timolol-releasing lenses wasdemonstrated in a glaucoma animal model by measuring theintraocular pressure after insertion of the lenses. The particle-loaded lenses achieved intraocular pressure reduction compara-ble to eye drops but with about one-tenth of the drug loading,which is in agreement with the predicted increase in bioavail-ability from about 5% for eye drops to about 50% for contactlenses. The intraocular pressure (IOP) decreased for about4 days, which correlated well with the in vitro release profilesat physiological temperatures, suggesting that the in vitrorelease under sink conditions is a reasonable model for thein vivo release in the eyes [73]. In another study with nanopar-ticles, p-HEMA hydrogels loaded with pullulan and poly-caprolactone copolymer core-shell nanospheres exhibitedantibacterial activity for about 3 days due to extended releaseof ciprofloxacin [74]. Recently, a 30-day release of dexametha-sone acetate was reported from lenses loaded with rod-likesilica shell crosslinked methoxy micelles [75].

In most of the studies described above, nanoparticles werefirst fabricated, and then incorporated into the lenses eitherby soaking or through its addition to the polymerization mix-ture. To avoid the two-step process, non-ionic Brij surfactantaggregates were self-assembled into p-HEMA hydrogels byaddition of the surfactant to the polymerization mixture.The 50 -- 100 nm size surfactant aggregates exhibited highpartitioning for hydrophobic drug cyclosporine and signifi-cantly reduced the diffusion rates [76,77].

The approach of incorporating nanoparticles into contactlenses for extended drug release is certainly effective and can

Figure 5. Image of control (left) and 10% cationic surfactant-

loaded 1-Day Acuvue contact lens (right) containing a drop

of water (0.1 ml).



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be adapted to most drugs due to the versatility in choosingthe appropriate nanoparticles. There are also significantdownsides to this approach due to the potential for particledestabilization or aggregation and segregation during poly-merization, sterilization or storage, which could alter thedrug release profiles and possibly reduce transparency.

5.4 Ionic interactionsThe transport of drug in a contact lens is typically diffusion-controlled but the effective diffusivity is impacted by thebinding of the drug to the polymer matrix. Several researchershave attempted to take advantage of increased drug-bindingto the lens matrix to increase the release durations of thedrugs. Since a large number of ophthalmic drugs are chargedat physiological conditions, ionic interactions are the naturalchoice to increase drug-binding to the matrix. Sato et al.fabricated p-HEMA gels with cationic side chains by incorpo-ration of methacrylamide propyltrimenthylammonium chlo-ride (MAPTAC) for extended delivery of anionic drugazulene. The hydrogels exhibited extended release for about8 h in saline but the lens volume changed during the release,which is undesirable. The volume change was minimized byincorporation of anionic molecules such as MAA or 2-metha-cryloxyethyl phosphate (MOEP) into the lenses in addition tothe cationic MAPTAC [78]. In a similar study, an anionic lenswas prepared by inclusion of MAA and MOEP anions in thep-HEMA gel. The uptake of cationic drug naphazoline wasshown to be directly proportional to the fraction of anionicligands in of the hydrogel [79]. Anionic silicone hydrogel lensescontaining MAA and 2-methacryloyloxyethyl hydrogensuccinic acid and 3-methacryloxypropyl tris(trimethylsiloxy)silane were also explored for delivery of ofloxacin. It wasshown that in addition to the ionic interaction, the silyl groupalso increases the drug release duration likely due to the reduc-tion in transport of water, which is required for the solvationof the drug [80]. In a recent study, ionic lenses loaded withMAA and antibiotics (gatifloxacin and moxifloxacin) weretested in a Staphylococcus aureus infection model in rabbits.The ionic lenses exhibited increased uptake of both antibioticsin proportion to the fraction of MAA incorporation andextended release duration of about 2 -- 3 days. The in vivostudy with contact lenses showed an undetectable bacterialconcentration in tears and much higher drug concentrationsin the cornea, aqueous humor and crystalline lens comparedto eye drops [81]. The concentration profile in the ocular tissueexhibited trends similar to the in vitro release profiles suggest-ing a good correlation between in vitro and in vivo release.The uptake of puerarin in p-HEMA hydrogels was improvedby incorporation of NVP into the lenses, possibly due to theinteraction between the OH-rich puerarin and the carbonylgroup of polyvinylpyrrolidone (PVP). Animal studies in rab-bits showed about sixfold increase in residence time of thedrug in the tears compared to 1% eye drops [82]. Additionof ionic molecules prior to polymerization could impact thestructure and properties of the lenses, so Bengani and

Chauhan recently proposed to adsorb ionic surfactants to a pre-formed lens to impart the charge. Cationic surfactants wereadsorbed on the p-HEMA and a commercial contact lens todesign a lens for extended release of an anionic drug dexameth-asone phosphate. The surfactant incorporation increased therelease duration by about 100-fold in the p-HEMA lens andabout 10-fold in the commercial lenses. Commercial 1-DayAcuvue lenses loaded with cationic surfactant remainedtransparent, and the presence of surfactant had the additionalbenefit of increased surface wettability (Figure 5) [83].

5.5 Other approachesKim et al. designed silicone-hydrogel contact lenses com-prising of a hydrophilic monomer N,N-dimethylacrylamide(DMA) and a silicone monomer methacryloxypropyltris(trimethylsiloxy)silane (TRIS), with a new macromer bis-alpha, omega-(methacryloxypropyl) polydimethylsiloxane(MW 7152) to produce lenses that exhibited extended releaseof both hydrophobic and hydrophilic drugs. The lensesreleased timolol and dexamethasone for extended periodsranging from 2 weeks to 3 months depending on the com-position. Also, several key properties including transparency,ion permeability and modulus were shown to be suitable forcontact lens applications [84]. Xu et al. incorporatedb-cyclodextrins (BCD) in HEMA hydrogels to increaserelease durations of puerarin, which complexes with theBCD. The addition of BCD into the polymer resulted inincreased equilibrium swelling ratio and tensile strength.The BCD incorporation led to a 40% increase in drug uptakeand an increase in the release times [85]. BCD incorporation inHEMA hydrogels also increased loading by about 1300% andled to continuous release rate for 12 days [86]. A copolymer ofDMA and 2-(N-ethylperfluorooctanesulfonamido) ethyl acry-late (FOSA) was prepared by free-radical polymerization, andit was shown that the inclusion of FOSA led to a decrease inthe diffusion coefficient of pheniramine maleate [87].Ciolino et al. sandwiched drug-loaded poly(lactic-co-glycolicacid) (PLGA) films in a p-HEMA contact lens for extendeddelivery of fluorescein and ciprofloxacin. The lenses exhibitedextended release for about 1 month at zero-order rates. Thesame approach was shown to be effective for extended releaseof econazole at adequate rates to provide antifungal activityagainst Candida albicans fungi [88,89].

6. Conclusions

Drug-eluting contact lenses appear to be highly suitable fordrug delivery to the anterior chamber, due to the significantincrease in bioavailability to about 50% compared to1 -- 5% for eye drops. However, the early attempts to deliverophthalmic drugs via contact lenses did not lead to a success-ful clinical product because the lenses were not designedappropriately. The simple soak and release approach, whichwas the method of choice in the early studies, is not the opti-mal method for drug incorporation because of the short



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duration of release. The past few years have seen a significantgrowth in research focused on improving the drug release pro-files from contact lenses by several approaches includingmolecular imprinting, dispersion of barriers or nanoparticles,increasing drug-binding to the polymer, sandwiching a PLGAlayer in a lens and developing novel materials. The new tech-nologies significantly improve the drug release profiles withminimal impact on critical lens properties such as transpar-ency, modulus, ion and oxygen permeabilities, protein bind-ing, etc. Each technology has advantages and disadvantagesand simultaneous optimization of various approaches will becritical to commercialize drug-eluting contact lenses becausethe optimal drug release profiles may vary across diseasesand will also depend on patient choice.

7. Expert opinion

The past few years have seen renewed scientific as well as com-mercial interest in developing contact lenses for ODD. Inaddition to several research studies, a number of patents basedon MEs [90], nanoparticles [91], organic--inorganic chitosan-silica nanocarrier [92], multilayer structure [93], imprintingand vitamin E incorporation [94,95] are recently published orissued. Moreover, a Phase III study has been recently con-cluded on release of ketotifen fumarate from contact lensesusing the soak and release technology to develop anti-allergy contact lenses [96]. Most recent focus has been onincreasing the drug release durations, which are just a fewhours for most drugs in commercial contact lenses. Severaltechnologies have been successfully utilized to extend therelease durations for several drugs including glaucoma drugtimolol, dry eye drug cyclosporine, anti-inflammatorydexamethasone, anesthetic lidocaine, antibiotics, antivirals,antifungals, etc. Most of the technologies are based onp-HEMA contact lenses and are thus unsuitable for continu-ous wear. Some of those technologies can create continuouswear silicone hydrogel contact lenses with release durationconsistent with the wear schedule, thus affording the possibil-ity of continuous drug delivery without lens replacement for2 -- 4 weeks. Several of the lens designs have also been testedin various animal models which demonstrate the superiorityof these modified contact lenses, though there are very fewhuman studies. In addition, detailed characterization to deter-mine if the extended release contact lenses can meet all therequirements for the extended wear contact lenses, including

transparency, ion and oxygen permeability, modulus, proteinbinding etc., is lacking for many technologies. It also remainsto be demonstrated whether the technologies and also thedrugs of interest are compatible with current lens manufactur-ing processes including sterilization and storage. While severalapproaches can provide extended drug release, most fail toprovide a zero-order release, which is considered to be theoptimal release profile. However a lack of zero-order profiledoes not appear to be a significant problem as long as themaximum release is below the toxic limit and the release dur-ing the entire wear time is within the therapeutic window.Another critical issue that has not received much attention isthe potential for desensitization of the ocular receptors dueto continuous drug delivery from contact lenses. If desensiti-zation occurs for any specific drug--target pair due to constantexposure to the drug, contact lenses will not be suitable fortreatment of that disease unless the release profiles can bemodified to provide pulsatile release.

While the future appears to be promising for drug-eluting contact lenses, several challenges remain. Several oph-thalmic diseases are more common in the elderly patients butthey may not be suitable for drug therapy by contact lensesbecause of reduced tear volume and dryness, which canmake contact lens use uncomfortable. Contact lens wear isstill uncomfortable for a large number of people and pro-longed contact lens wear is associated with risk of infectionsuch as microbial keratitis. Additionally, processing and stor-age issues, regulatory hurdles and high costs of clinical studiesare major barriers to commercialization and clinical imple-mentation. All these barriers have to be overcome to moveforward and to accomplish that it is critical to focus effortson the diseases that benefit the most by contact lens-based drug delivery. It may not be sufficient to just proveimproved efficacy compared to eye drops, and improvedpatient compliance may be critical. While extending thedrug release duration to 2 -- 4 weeks could be scientificallyinteresting and would also be the ideal design to maximizecompliance, the optimal release duration will depend on thedisease, patient acceptance and regulatory issues.

Declaration of interest

The authors thank the National Science Foundation (CBETCMMI Grant 1129932) for providing partial support forthis work.



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AffiliationLokendrakumar 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: [email protected]



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AbstractIntroductionOcular transport of drug released by a contact lensKey requirements for drug-eluting contact lensesDrug delivery by soak and release' from unmodified commercial contact lensesNovel approaches for controlled and extended drug release from contact lensesVitamin E barriersMolecular imprintingMicro and nanoparticlesIonic interactionsOther approaches

ConclusionsExpert opinionDeclaration of interestBibliography

Documents

Contact Lens Drug Delivery